60 
Other Solid Tumors
  INTRODUCTION
Head and neck cancer, melanoma, sarcoma, and carcinoma of
unknown primary site are distinct malignancies each with its own
epidemiology, histopathology, treatment, and prognosis. Head
and neck cancer and melanoma are relatively common, but sar-
comas and unknown primary carcinoma are rare. Recent advances
in understanding of the molecular biology of cancer and the
interaction between the immune system and malignancy have
improved therapeutic options for patients with these diseases.
  HEAD AND NECK CANCER
Definition and Epidemiology
Head and neck cancers are squamous cell carcinomas that arise
from the mucosal lining of the oral cavity, oropharynx, nasophar-
ynx, hypopharynx, and larynx (Fig. 60-1). Other malignancies
arising from structures within the head and neck, such as salivary
gland tumors or thyroid cancers, differ in regard to biology, pre-
sentation, natural history, pathology, and response to therapy.
Head and neck cancer accounts for 3.2% of new cancer diag-
noses in the United States. In 2013, there were expected to be
53,640 patients diagnosed with this disease and 11,520 deaths.
Chronic exposure to tobacco smoke and alcohol have been con-
sidered the strongest risk factors for developing this disease, but
in recent decades human papilloma virus (HPV) has been
responsible for a dramatic increase in the incidence of oropha-
ryngeal squamous cell carcinoma. Patients with HPV-associated
oropharyngeal cancer are typically younger than patients with
HPV-negative disease and often have minimal history of tobacco
or alcohol use. Rather, these patients share a history of high-risk
sexual behaviors, including earlier age at first intercourse and a
large number of partners. Nasopharyngeal squamous cell carci-
noma is relatively uncommon in the United States and is distinct
from other head and neck cancers, given its association with
Epstein-Barr virus (EBV) infection.
Pathology
Approximately 95% of all cancers arising from the squamous
epithelium of the upper aerodigestive tract are squamous cell
carcinomas. Mucosal melanomas, adenocarcinomas, and neuro-
endocrine tumors are also encountered. Squamous cell carcino-
mas are subdivided into well differentiated, moderately well
differentiated, and poorly differentiated types based on their
degree of resemblance to normal squamous epithelium. Poorly
differentiated disease is more aggressive and has a worse progno-
sis. Nasopharyngeal carcinomas are also classified as either
Michael J. McNamara
keratinizing or nonkeratinizing, the latter strongly associated
with EBV infection.
The increasingly common HPV-associated oropharyngeal
cancer differs in molecular profile from alcohol- and smoking-
related squamous cell carcinoma. For example, head and neck
cancer related to alcohol and tobacco smoke is frequently asso-
ciated with mutations in the tumor suppressor gene TP53 and
decreased expression of the cell cycle regulatory protein p16-
INK4a. Conversely, HPV-associated oropharyngeal cancer dis-
plays wild-type TP53 with increased expression of p16-INK4a.
Immunohistochemistry results demonstrating p16-INK4a estab-
lishes a diagnosis of HPV-related disease.
Clinical Presentation
The presentation of patients with head and neck cancer depends
on the location of the primary tumor and the extent of local
disease. Disease dissemination to distant sites is uncommon at
the time of diagnosis, so patients rarely have signs or symptoms
of metastatic disease at presentation. Tumors of the nasopharynx
often block the Eustachian tube or cause epistaxis. Oral cavity
tumors may manifest with a painful, ulcerated lesion. HPV-
associated oropharynx cancer usually manifests with cervical
lymphadenopathy; the primary tumors are often small and
asymptomatic. Cancer of the hypopharynx manifests with dys-
phagia and that of the larynx with hoarseness.
Metastases develop late in the course of this disease, com-
monly in lung or bone. Patients may also develop hypercalcemia
as a paraneoplastic syndrome related to ectopic production of
parathyroid hormone–related protein.
Diagnosis and Differential Diagnosis
The diagnosis of squamous cell carcinoma requires biopsy.
Staging is accomplished by a combination of imaging and careful
inspection of the upper aerodigestive tract. Second primary
cancers are common in patients with a history of heavy alcohol
and tobacco abuse. CT, MRI, and positron emission tomography
(PET) can detect nodal involvement not appreciated on physical
examination as well as distant metastases. Patients with squa-
mous cell carcinoma who have cervical lymphadenopathy and
no apparent primary site at presentation require random biopsies
of the base of the tongue and surrounding tissues, in combina-
tion with an ipsilateral tonsillectomy, to identify the occult
primary site.
Treatment and Prognosis
The prognosis of head and neck cancer depends on tumor stage.
The American Joint Committee on Cancer (AJCC) TNM staging
613
614 Section IX  Oncologic Disease
Paranasal sinuses
Nasal cavity
Oral cavity
Nasopharynx
Oropharynx
Hypopharynx
Salivary glands
Larynx
Trachea
system is used. Patients with early-stage disease have an excellent
prognosis, with 5-year survival rates approaching 90%. However,
only a minority of patients are diagnosed with early-stage disease;
cancer is usually locally advanced at the time of diagnosis, with
large, invasive primary tumors or regional lymph node metasta-
ses. Cure is possible with multimodality therapies, but the aggre-
gate outcome is less favorable.
The prognosis for patients with HPV-associated oropharyn-
geal cancer is better than for those whose cancer is related to
tobacco smoke and alcohol abuse. Both the biology of the disease
and medical comorbidities contribute to the poorer prognosis.
Furthermore, these patients are at high risk for development of
second primary cancers of the upper aerodigestive tract, includ-
ing lung cancer and esophageal cancer—so-called field canceriza-
tion: the entire upper aerodigestive epithelium is at increased risk
for malignant transformation.
Both surgery and radiotherapy are potentially curative in
patients with head and neck cancer. Chemotherapy alone is not
a curative treatment, but chemotherapy given simultaneously
with radiotherapy, termed chemoradiotherapy, may enhance the
cytotoxic effects of radiation. Chemoradiotherapy is more effica-
cious but more toxic than radiotherapy alone. The choice of treat-
ment is based on the location of the primary tumor and the
extent of disease. Surgery or radiotherapy alone can cure early-
stage disease. Patients with locally advanced cancers require
more aggressive management, either chemoradiotherapy or a
combination of chemoradiotherapy and surgery.
Radiation-based treatment may be used instead of surgery for
disease for which tumor resection could cause cosmetic defor-
mity or loss of organ function. For example, chemoradiotherapy
may be used to treat locally advanced laryngeal cancer without the
Pharynx
Esophagus
FIGURE 60-1  Anatomic regions of the head
and neck.
need to sacrifice the larynx. Although chemoradiotherapy may
permit organ preservation, it has both acute and chronic toxicity.
Metastatic disease is incurable, and therapy is palliative. Che-
motherapy may mitigate cancer-related symptoms and produce
a modest improvement in the median survival time compared
with supportive care alone.
  MELANOMA
Definition and Epidemiology
Melanoma, a malignant disorder of melanocytes, differs from
other common skin cancers by its aggressive behavior and pro-
clivity for regional and distant metastasis. The incidence of mela-
noma is increasing; it is now the fifth most common cancer in the
United States. There were expected to be 76,690 new diagnoses
and 9,480 deaths from melanoma in 2013. Melanoma is more
common in fair-skinned individuals who tend not to darken with
sun exposure. Although there are multiple risk factors for mela-
noma, sun exposure is the most important. Intense and intermit-
tent sun exposure, especially during childhood and early
adulthood, is the strongest risk factor for development of this
disease. Chronic or occupational sun exposure does not confer
the same degree of risk but may contribute to the development
of melanoma on sun-exposed areas such as the head and neck.
Other risk factors for melanoma include a family or personal
history of this disease, multiple typical nevi, and the presence of
atypical nevi.
Pathology
Melanocytes are derived from neural crest cells that have migrated
to the epidermis. They occupy the basal layer of the epidermis

and function in part to produce and transfer melanin to keratino-
cytes, thereby determining the color of skin and hair. There are
also benign proliferative disorders of melanocytes, including the
common acquired nevus (mole).
Melanoma has four major clinicopathologic subtypes. The
most common subtype is superficial spreading melanoma, which
can occur anywhere on the body but has a predilection for the
torso and legs. Lentigo maligna melanoma manifests typically as
a tan macule on chronically sun-exposed areas in older individu-
als. Nodular melanoma is associated with vertical growth into the
dermis and manifests as a dark, nodular lesion. Acral lentiginous
melanoma is an uncommon variant found on the palmar and
plantar surfaces as well as subungual areas. This subtype is the
most common form of melanoma in dark-skinned individuals.
Other variants have also been described. Although this classifica-
tion, which dates from the 1960s, captures the clinical heteroge-
neity of melanoma, it does not provide prognostic information
or help determine clinical management.
Pathologic features that have prognostic relevance include the
depth of invasion, the presence of ulceration, and the presence
and number of mitotic figures. All of these features are incorpo-
rated into the AJCC TNM staging system of malignant mela-
noma. Increasing depth of invasion predicts a poor prognosis.
The risk of lymph node metastasis, distant metastasis, and death,
exists on a continuum with increasing tumor thickness. There-
fore, patients with thin melanomas (≤1 mm thickness) generally
have favorable outcomes, whereas patients with thick melanomas
(>4 mm thickness), even in the absence of nodal disease, have a
5 year survival rate often less than 50% (Table 60-1).
Clinical Presentation
Most patients with cutaneous melanoma have early-stage disease
at presentation. Approximately 15% of patients have clinically
apparent regional adenopathy or radiographic evidence for meta-
static disease at the time of diagnosis. A number of benign lesions
share morphologic features with melanoma, making identifica-
tion by physical examination challenging. Because survival for
patients with limited disease is excellent, early detection is
important.
TABLE 60-1  ESTIMATED OVERALL SURVIVAL FOR
PATIENTS WITH MELANOMA BASED ON
THE DEPTH OF INVASION AND NUMBER
OF INVOLVED REGIONAL LYMPH NODES.
DEPTH OF PRIMARY 5-YR OVERALL
TUMOR INVASION (mm) AJCC T STAGE SURVIVAL (%)
≤1 T1
1.01-2.0 T2
2.01-4.0 T3
>4.0 T4
NUMBER OF
INVOLVED REGIONAL 5-YR OVERALL
LYMPH NODES AJCC N STAGE SURVIVAL (%)
1 N1
2-3 N2
≥4 N3
Data from Edge S, Byrd DR, Compton CC, et al: AJCC Cancer Staging Manual, ed 7,
New York, 2010, Springer.
AJCC, American Joint Committee on Cancer.
Chapter 60  Other Solid Tumors 615
Features favoring malignancy are suggested by the ABCDE
rule: asymmetry, irregular borders, variable color, diameter
greater than 6 mm, and evolving lesion. A lesion that is changing
in shape, size, or color should be considered suspicious.
Melanoma typically disseminates to regional lymph nodes.
Regional lymph nodes should be examined. Metastatic disease
also occurs in the liver, lung, skin, bone, and brain. Symptoms of
advanced disease are highly variable.
In contrast to cutaneous melanoma, mucosal melanoma is
often advanced at the time of diagnosis. This disease is rare, and
the sites include the head and neck, anorectum, and vulvovaginal
areas. Presenting symptoms are similar to those of the more
common malignant diseases of these regions.
Diagnosis and Differential Diagnosis
The diagnosis of melanoma requires histologic evaluation of a
biopsy specimen. In general, pigmented lesions suspicious for
melanoma should undergo an excisional biopsy. This allows ade-
quate assessment of tumor thickness, which informs decisions
regarding the need for a sentinel lymph node biopsy and the
width of subsequent local excision. If an excisional biopsy cannot
be performed, a full-thickness punch biopsy is recommended.
So-called shave biopsies of suspicious lesions make subsequent
determination of tumor thickness difficult and may provide insuf-
ficient material for diagnosis. The histologic diagnosis is based on
characteristic morphology and on immunohistochemical stain-
ing for markers such as S100, HMB45, and MART1.
In general, imaging investigations for staging purposes are not
required for patients with thin or intermediate-thickness mela-
noma. The likelihood of demonstrating metastatic disease is low.
Patients with thick melanomas or lymph node metastasis detected
on clinical examination or by sentinel lymph node biopsy are at
high risk for disease dissemination and need radiographic staging
by CT of the chest, abdomen, and pelvis. Further imaging
depends on the clinical context. For example, patients with clini-
cally advanced melanoma and new, diffuse bone pain should
undergo a bone scan; those with neurologic symptoms should
undergo brain imaging.
Treatment and Prognosis
The prognosis of melanoma can be accurately estimated using the
AJCC TNM staging system. Overall survival depends on the
thickness of the primary tumor and the presence and number of
regional lymph node metastases. Tumor ulceration and high
mitotic rate are associated with a poor prognosis. Metastatic
disease is incurable, and the clinical course depends on the
pattern and extent of dissemination. An elevated serum lactate
95 dehydrogenase (LDH) level is an independent poor prognostic
85
70
factor for patients with metastases.
55 Surgery with wide margins is the cornerstone of curative
therapy for nonmetastatic disease. The optimal margin depends
on the depth of invasion and the location of the primary lesion
but is typically between 1 and 2 cm. Patients with tumors larger
65 than 1 mm in thickness and a negative physical examination
55 should also undergo regional lymph node biopsy to evaluate for
35
metastasis. Patients with melanoma in the initial node or nodes
merit lymph node dissection for more accurate staging and to
remove any residual disease.
616 Section IX  Oncologic Disease
Adjuvant therapy with high-dose interferon may be consid-
ered for patients with a high risk of recurrence after complete
resection—that is, those with a primary tumor larger than 4 mm
or lymph node metastasis. Adjuvant interferon is administered
over the course of 1 year; it has substantial morbidity. The
improvement in outcome is modest, and the effect on overall
survival remains unclear.
For patients with metastatic disease, new agents have been
developed based on the molecular biology of the disease and the
immune response to malignancy. Ipilimumab, for example, is a
monoclonal antibody which targets cytotoxic T-lymphocyte
antigen 4 (CTLA-4), an immune regulatory molecule that inhib-
its T cell activation. The immunomodulatory effects of ipilim-
umab result in an immune response against tumor antigens,
improving the survival of patients with metastatic disease (level
A evidence).
Approximately 45% of cutaneous melanomas have activating
mutations of the proto-oncogene BRAF, a component of the
mitogen-activated protein kinase (MAPK) signaling pathway.
Vemurafenib and dabrafenib are oral BRAF inhibitors that
improve the survival of patients with metastatic disease who
harbor specific BRAF mutations (level A evidence). Trametinib
is an orally active agent that targets MEK, another component of
the MAPK pathway downstream of BRAF. This agent has also
demonstrated activity in patients with BRAF-mutant metastatic
melanoma.
  SARCOMA
Definition and Epidemiology
Sarcomas are heterogeneous solid tumors of mesenchymal
origin. These tumors are broadly categorized as sarcomas of bone
or sarcomas of soft tissue, with several distinct clinicopathologic
subtypes. There were expected to be 11,410 new diagnoses of soft
tissue sarcoma and 3,010 new diagnoses of bone sarcoma in the
United States in 2013. Overall, sarcomas account for fewer than
1% of all new cancer diagnoses.
Most sarcomas are sporadic, but risk factors include prior
radiation exposure, chemical carcinogens, and genetic predispo-
sition (familial adenomatous polyposis [FAP], Li-Fraumeni syn-
drome). Moreover, human herpesvirus 8 (HHV-8) infection is
associated with the development of Kaposi’s sarcoma.
Soft tissue sarcomas can be further classified by their anatomic
site of origin: head and neck, visceral, retroperitoneal, intra-
abdominal, and extremity. This categorization is useful for
staging, assessing prognosis, and establishing a therapeutic
approach. The most common soft tissue sarcomas are gastroin-
testinal stromal tumors (GISTs), pleomorphic sarcoma, liposar-
coma, leiomyosarcoma, and synovial sarcoma. The most
commonly encountered sarcomas of bone are the Ewing’s family
of sarcomas, chondrosarcomas, and osteosarcomas.
Clinical Presentation
Given the heterogeneity of this group of diseases, including
differences in tumor biology and in anatomic site of origin,
the clinical presentation is variable. Soft tissue sarcomas of the
extremities and of the head and neck usually manifest as a
progressively enlarging, often painless, mass. Visceral and
intra-abdominal sarcomas including GISTs are often found
incidentally and are not symptomatic until they are locally
advanced. Symptoms are often nonspecific but may include
early satiety, abdominal fullness, bloating, or discomfort.
Bone sarcomas, such as Ewing’s sarcoma and osteosarcoma,
typically manifest with pain. The most frequently involved loca-
tions are the femur, tibia, and humerus. The physical examination
may reveal a palpable mass, which is often tender to palpation.
Symptoms may be present for several months before diagnosis.
Most patients have locally confined disease at diagnosis; the
lungs and bone are the most common sites of metastatic spread.
Diagnosis and Differential Diagnosis
The diagnosis of sarcoma can be established only by obtaining
histologic confirmation, for which a biopsy is required. This
disease must be distinguished from more common malignancies
such as lymphoma, melanoma, and poorly differentiated carci-
noma. The diagnosis of sarcoma is based on characteristic mor-
phology but may be aided by the use of immunohistochemical
and molecular studies. For example, Ewing’s sarcoma is often
associated with a characteristic reciprocal translocation between
chromosomes 11 and 22, t(11 : 22). Several other molecular
derangements have been identified and are helpful in establishing
the specific diagnosis.
For bone sarcomas, plain films often demonstrate a mixture of
lytic and blastic components with associated soft tissue edema.
For osteosarcoma, the periosteal reaction produces a “sunburst”
appearance as new bone forms at right angles to the tumor, as
opposed to the “onion peel” appearance caused by layering of
reactive bone, which is more commonly associated with Ewing’s
sarcoma.
Treatment and Prognosis
Surgery is the primary therapy for locally confined disease.
Radiotherapy before or after surgery may decrease the likelihood
of local recurrence. Chemotherapy patients with certain histo-
logic subtypes of sarcoma (Ewing’s sarcoma, osteosarcoma) may
improve local control, decrease the risk of distant recurrences,
and improve overall survival.
Patients with metastatic sarcoma may occasionally benefit
from surgical extirpation of their disease. However, once meta-
static dissemination has been detected, the intent of therapy is
palliative. Chemotherapy can reduce the overall tumor burden
and minimize cancer-related symptoms; doxorubicin, ifosfamide,
and gemcitabine are used.
Targeted therapies have revolutionized the management of
GISTs. The small-molecule tyrosine kinase inhibitor, imatinib, is
highly active in patients with GISTs. It rapidly reduces tumor
burden with sustained benefit. Imatinib is currently administered
to patients with GISTs in the perioperative and advanced/
metastatic settings (level A evidence).
  CANCER OF UNKNOWN PRIMARY SITE
Definition and Epidemiology
Malignancies for which there is no apparent site of origin after
a thorough history, physical examination, imaging investigations,
and appropriate diagnostic procedures are referred to as cancers

of unknown primary site (CUP). CUP accounts for approximately
2% of all new cancer diagnoses in the United States, with 31,860
new cases anticipated in 2013. CUPs are heterogeneous with a
highly variable clinical presentation and prognosis. Although the
primary site rarely becomes evident during the course of the
disease, molecular profiling suggests that CUP is frequently a
result of occult lung, kidney, bladder, or pancreaticobiliary
cancer.
Clinical Presentation
Most patients with CUP have nonspecific complaints. Constitu-
tional symptoms such as anorexia, weight loss, and fatigue are
typical of advanced disease and are commonly present at the time
of diagnosis. Pain at the time of presentation is more variable but
is frequently experienced by patients with bone metastasis. Less
common presenting signs and symptoms include epidural spinal
cord compression, hypercalcemia, isolated brain metastasis,
ascites, and venous thromboembolic disease.
However, many patients have very few symptoms initially,
such as progressive lymphadenopathy only. Occasionally, the
diagnosis is arrived at incidentally, during evaluation for an unre-
lated condition.
Pathology
CUPs are categorized based on histologic evaluation. Most
CUPs demonstrate adenocarcinoma histology. However, squa-
mous cell carcinoma, neuroendocrine carcinoma, and poorly
differentiated carcinoma are also commonly encountered. Poorly
differentiated carcinoma must be distinguished from melanoma,
lymphoma, and sarcoma, because the treatments differ by
disease.
Immunohistochemistry may disclose the site of origin. For
example, in the case of poorly differentiated tumors, the
presence of S100 and HMB45 supports a diagnosis of mela-
noma, whereas CD45 supports a diagnosis of lymphoma.
Chromogranin and synaptophysin suggest neuroendocrine dif-
ferentiation. Cytokeratin 5 (CK5) and CK6 are strongly
expressed by squamous cell carcinomas, whereas the expression
pattern of CK7 and CK20 can limit the differential diagnosis
of adenocarcinomas.
Molecular tumor profiling studies suggest that gene expression
profiles can identify the primary site in 60% to 80% of patients.
However, it remains unclear whether gene expression profiling
improves patient outcomes.
Treatment and Prognosis
CUP confers a median survival time of 8 to 11 months. Therapy
is almost always offered with palliative intent. Chemotherapy can
Chapter 60  Other Solid Tumors 617
mitigate cancer-related symptoms and improve overall survival.
However, there are several clinical presentations for which the
prognosis is more favorable and therapy can be curative. For
example, a woman presenting with adenocarcinoma isolated to
unilateral axillary lymph nodes should be evaluated and treated
as for a locally advanced breast cancer, regardless of whether
imaging investigations demonstrate a primary breast malignancy.
Likewise, a patient with squamous cell carcinoma isolated to cer-
vical lymph nodes at presentation should receive therapy for
locally advanced head and neck cancer, again regardless of
whether a primary lesion can be identified. In both these circum-
stances, therapy may prove curative. Another clinical scenario for
which specific therapy is beneficial is that of a young man with a
poorly differentiated midline tumor: A favorable response to a
chemotherapy regimen for germ cell cancers may be beneficial.
Assays that provide a molecular tumor profile, which may
more accurately identify the primary site than standard clinico-
pathologic variables, are currently available.
For a deeper discussion on this topic, please see Chapters
190, “Head and Neck Cancer,” 202, “Sarcomas of Soft
Tissue and Bone, and Other Neoplasms of Connective
Tissues,” 203, “Melanoma and Nonmelanoma Skin
Cancers,” and 204, “Cancer of Unknown Primary Origin,”
in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib
in melanoma with BRAF V600E mutation, N Engl J Med 364:2507–2516,
2011.
Fletcher CDM, Unni KK, Mertens F: World Health Organization classification
of tumors: pathology and genetics of tumors of soft tissue and bone, Lyon,
2002, IARC Press.
Hainsworth JD, Rubin MS, Spigel DR, et al: Molecular gene expression profiling
to predict the tissue of origin and direct site-specific therapy in patients with
carcinoma of unknown primary site: a prospective trial of the Sarah Cannon
Research Institute, J Clin Oncol 31:217–223, 2012.
Rajendra R, Pollack SM, Jones RL: Management of gastrointestinal stromal
tumors, Future Oncol 9:193–206, 2013.
Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus decarbazine for
previously untreated metastatic melanoma, N Engl J Med 364:2517–2526,
2011.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013, CA Cancer J Clin
63:11–30, 2013.
Wisco OJ, Sober AJ: Prognostic factors for melanoma, Dermatol Clin 30:469–
485, 2012.
Zandberg DP, Bhargava R, Badin S, et al: The role of human papillomavirus in
nongenital cancers, CA Cancer J Clin 63:57–81, 2013.
 61 
Complications of Cancer and
Cancer Treatment
Bassam Estfan and Alok A. Khorana

  INTRODUCTION Pathology
Patients with cancer can experience various complications as a The hypercoagulable state in patients with cancer is a result of
direct result of their disease or its treatment. Cancer complica- activation of the coagulation system by neoplastic cells. Certain
tions can be localized or systemic (Table 61-1). Cancer treat- cancers such as pancreas, stomach, lung, lymphoma, and brain
ments, especially chemotherapy and radiation therapy, have are particularly associated with venous thromboembolism.
potentially significant side effects and complications; most are Cancer treatments including chemotherapy, anti-angiogenic
temporary, but some, such as peripheral neuropathy, can become agents, and hormonal therapy further increase the risk. Other
permanent (Table 61-2). The significance of complications of risk factors include central venous catheters, obesity, and prior
cancer and its treatment goes beyond quality of life; cancer out- history of thrombosis and use of erythropoiesis-stimulating
comes can be affected by resulting treatment delay or cessation, agents. Biomarkers, including elevated platelet and leukocyte
dose reduction, and hospitalization. Frequently, the management counts, have also been shown to be predictive. However, risk
of cancer complications requires a multidisciplinary approach. cannot be determined on the basis of single risk factors alone,
This chapter highlights some important complications of cancer because the etiology is multifactorial. The Khorana Score is a
and its treatment. validated risk that incorporates five simple clinical and laboratory
variables has been endorsed by various guidelines for risk
assessment.
  CANCER-ASSOCIATED THROMBOSIS
Epidemiology Clinical Presentation
Patients with cancer are at increased risk for both venous and Clinical suspicion should be high in cancer patients whose pre-
arterial thromboembolism; thromboembolic events are the senting symptoms include dyspnea, cough, wheezing, chest pain,
second leading cause of death among patients with cancer. tachycardia, upper abdominal pain, or extremity swelling. Throm-
bosis remains a consideration even in ambulatory patients and
those already receiving adequate anticoagulation. Incidental pul-
TABLE 61-1  COMPLICATIONS OF CANCER monary embolisms may be identified on imaging studies con-
LOCALIZED SYSTEMIC ducted for staging of cancer; they are also associated with adverse
Brain metastases Anorexia/cachexia outcomes and should be treated appropriately.
Cancer-related pain Cancer-associated thrombosis
Cord compression/cauda equina syndrome Cancer-related anemia
Malignant effusions Cancer-related fatigue Treatment
Pathologic fractures Hypercalcemia Venous thromboembolism can be prevented with the use of pro-
Superior vena cava syndrome Paraneoplastic syndromes
Visceral obstruction Tumor lysis syndrome phylaxis in hospitalized cancer patients. Unfractionated heparin,
low-molecular-weight heparins (LMWHs), and fondaparinux are
safe and effective. Prophylaxis is being investigated in the ambula-
tory setting and appears to be beneficial in highly selected
TABLE 61-2  COMPLICATIONS OF CANCER
TREATMENT patients.
Alopecia
Established thrombosis should be treated with anticoagula-
Central line thrombosis/infections tion. Oral anticoagulation with warfarin is frequently compli-
Cytopenias cated by interactions with chemotherapeutic agents, variable
Febrile neutropenia
Hot flashes
nutritional status, and relative resistance. In a randomized clini-
Hypertension cal trial, the LMWH dalteparin, given for up to 6 months,
Nausea and vomiting was more effective than warfarin in preventing recurrent throm-
Peripheral neuropathy
Secondary malignancies
bosis, and this class of anticoagulants is preferred for first-line
Skin toxicity therapy.
Stomatitis Vena caval interruption using filters should be considered only
Tumor lysis syndrome
if anticoagulation is clearly contraindicated (e.g., in the presence

618
 Chapter 61  Complications of Cancer and Cancer Treatment 619
of active bleeding) or after failure of LMWHs. Novel oral antico-
agulants have not yet been studied in the cancer setting.
  SPINAL CORD COMPRESSION
Epidemiology
Spinal cord compression is the second most common neurologic
complication of cancer after brain metastasis; it is estimated that
2.5% of cancer patients will suffer from cord compression. Breast,
lung, and prostate cancers and multiple myeloma are the most
common etiologies.
Pathology
Most cases (60% to 70%) occur at the level of the thoracic spine,
followed by the lumbar and cervical spine. The conus medullaris
terminates at the level of the L1 or L2 vertebral body; epidural
disease below that level is associated instead with a cauda equina
syndrome. Most spinal metastases affect the vertebral body; com-
pression results from posterior extension of the tumor to the
thecal sac. This leads to obstruction of the epidural venous circu-
lation and vasogenic edema of the white and gray matter.
Clinical Presentation
Cord compression usually manifests with gradually worsening
back pain around the level of involvement. Sudden positional
back pain should raise the suspicion for vertebral compression
fracture instead. Pain can become radicular and is usually wors-
ened by the Valsalva maneuver. Sensorimotor neurologic deficit
is a sign of advanced cord compression. Motor weakness is more
common at presentation (up to 85% of patients); it is usually
symmetric, but radicular motor weakness may be noticed with
lateral vertebral metastases. Sensory deficit is less common and
can manifest as paresthesia or lack of sensation. Bowel and
bladder incontinence and urinary retention are usually late
findings.
Diagnosis
Cord compression should be suspected clinically with any new
back pain in the setting of cancer and rapidly investigated with
spinal imaging. Plain radiographs of the vertebrae can reveal
abnormalities such as lytic lesions or vertebral fractures, but mag-
netic resonance imaging (MRI) is the preferred diagnostic
imaging modality. MRI of the full spine should be obtained even
with localized symptoms, because multiple vertebral levels may
be affected.
Treatment
The magnitude of the neurologic deficit before treatment is a
good predictor of response and outcome. On diagnosis, pain
management is important to allow better ambulation. Gluco-
corticoids have been used, while definitive therapy is awaited,
at doses between 16 and 96  mg/day with both symptomatic
and functional relief. There is no proven advantage to higher
doses, which can be associated with more side effects. Surgical
decompression and radiation are the two main treatment
modalities.
In a phase III trial, 101 cancer patients with spinal cord com-
pression were randomly assigned to receive radiation alone
(30 Gy in ten fractions) or surgical decompression followed by
the same radiation regimen. More people in the surgical arm were
ambulatory at interim analysis (84% versus 57%), and more
people in that group regained the ability to walk (10/16 versus
3/16). Radiation therapy alone is useful for palliation of symp-
toms and local control; it is usually reserved for patients with
spinal cord compromise without neurologic deficit or for those
with an expected shorter survival time. Initial chemotherapy can
be used in highly chemosensitive malignancies such as certain
lymphomas or small cell lung carcinoma. Patient age, overall
prognosis, and other comorbidities should be considered in
treatment decision making.
  SUPERIOR VENA CAVA SYNDROME
Definition
Superior vena cava syndrome in malignancy is the result of flow
obstruction by either external compression or intravascular
thrombosis. The superior vena cava is thin walled and therefore
easily compressed. The most common malignant causes are lung
cancer and lymphoma.
Clinical Presentation
Presentation depends on the rate of obstruction. Slow compres-
sion allows for the development of collaterals from the azygos,
internal mammary, paraspinous, lateral thoracic, and esophageal
venous systems. The azygos vein is the most important of these,
and obstruction below its level is not well tolerated. Symptoms
can be sudden or insidious. Most patients experience dyspnea
(60% to 70%) and facial or neck swelling (50%). Cough, pain,
arm swelling, and dysphagia are less common. Symptoms are
frequently exacerbated by leaning forward or lying down. Physi-
cal findings may include venous distention of neck and chest wall,
facial edema, plethora, cyanosis, and upper extremity edema.
Diagnosis
Plain chest radiographs are usually abnormal; mediastinal widen-
ing (64%) and pleural effusion (26%) are the most common
findings. The diagnosis is best established with contrast-enhanced
computed tomographic scanning of the chest. It demonstrates
the location and size of masses, the presence of intravascular
thrombosis, and collateral venous drainage. When superior vena
cava syndrome is the initial manifestation of malignancy, patho-
logic diagnosis is the first step in establishing the proper initial
treatment modality.
Treatment
The goals of treatment are to alleviate symptoms urgently and to
treat the underlying malignancy. General supportive measures
include head elevation and administration of glucocorticoids and
diuretics. It is essential not to start radiation or glucocorticoids
before obtaining a biopsy, because they could mask the diagnosis.
Specific management depends on the underlying pathology.
Chemotherapy is the preferred first line of therapy for chemosen-
sitive malignancies such as lymphoma, small cell lung cancer,
or germ cell tumors. For non–small cell lung cancers and other
less chemosensitive tumors, initial radiation therapy may be
preferred.
620 Section IX  Oncologic Disease
Symptomatic relief can occur within 2 weeks but is often tem-
porary; therefore, systemic management should be initiated
when indicated. Some tumors require surgical treatment. Persis-
tent symptoms not relieved by chemotherapy or irradiation and
those severe enough to warrant intervention before diagnosis can
be successfully managed with endovascular stent placement with
or without balloon angioplasty. For catheter-related thrombosis,
anticoagulation is indicated; the decision regarding catheter
removal should be individualized.
  HYPERCALCEMIA
Epidemiology
Hypercalcemia complicates cancer in up to 10% of cases, occur-
ring in both hematologic and solid malignancies. The most
common etiologies are multiple myeloma, breast cancer, and
squamous cell carcinoma.
Pathology
Mechanisms leading to hypercalcemia include osteolysis due to
bony involvement and tumor production of parathyroid
hormone–related protein (PTHrP), calcitriol, or cytokines. Even
in the presence of cancer, primary hyperparathyroidism should
be ruled out. Many cancer patients have low albumin and calcium
levels that should be corrected.
Clinical Presentation
Early symptoms of hypercalcemia include constipation, polydip-
sia, polyuria, nausea, vomiting, and bradycardia. Most patients
have signs of dehydration. Altered mental status is often a pre-
senting symptom. The severity of symptoms depends on the time
course over which hypercalcemia has developed rather than the
absolute calcium level.
Treatment
Calcium supplements, vitamin D, and diuretics should be
stopped. Aggressive fluid resuscitation with normal saline at 200
to 300 mL/hour should be started to maintain a high urine
output. This should be done carefully in patients with compro-
mised cardiac or renal function. These measures may be adequate
for mild hypercalcemia, but moderate and severe hypercalcemias
require further interventions.
Bisphosphonates are the preferred agents for management.
They inhibit osteoclasts and bone resorption. Intravenous pami-
dronate and zoledronic acid are the two most commonly used
bisphosphonates. In a pooled analysis, zoledronic acid was asso-
ciated with a higher rate of calcium normalization and longer
control. Calcium response to bisphosphonates can take a few
days; therefore, if a rapid reduction is required for acute hyper-
calcemia, subcutaneous calcitonin (4 units/kg) can be given 2 to
4 times daily. Calcitonin works by increasing calcium renal excre-
tion and reducing bone resorption. Other agents less commonly
used in the management of hypercalcemia include gallium nitrate
and glucocorticoids. Management should eventually include
control of the underlying disease. Frequently, new or recurring
hypercalcemia indicates disease progression or treatment resis-
tance, which should be addressed with systemic therapy.
  FEBRILE NEUTROPENIA
Definition
Febrile neutropenia is a common complication of chemotherapy.
It is defined as a temperature of 100.4° F (38° C) in the setting of
a neutrophil count lower than 500/µL (or lower than 1000/µL
with a predicted decrease to less than 500/µL in the next 48
hours). The risk of febrile neutropenia increases with the inten-
sity of the chemotherapy regimen and the severity and duration
of neutropenia. It can lead to treatment delays or interruptions,
prolonged hospitalizations, decreased quality of life, and
increased morbidity and mortality.
Treatment
Although most cases are managed in the hospital, low-risk
patients may occasionally be successfully managed as outpa-
tients. The American Society of Clinical Oncology (ASCO)
has published guidelines for outpatient management that are
based on a risk-stratified scoring system. All patients should
have a history and physical examination to identify possible
focal sources of infection. Attention should be given to the
presence of mucositis and to swelling or induration and ery-
thema around indwelling catheters as possible sources of infec-
tion. The initial workup should include a full chemistry profile,
complete blood count with differential, blood cultures with at
least one from each existing catheter tip, urinalysis, and chest
radiography.
Once the diagnosis is established and cultures have been
obtained, empiric treatment with broad-spectrum antibiotics
must be initiated. Frequently, organisms are not identified on
cultures. Therapy is usually directed to coverage of gram-
negative bacteria with cefipime or piperacillin-tazobactam. If
line infection or mucosal or skin infection is suspected, van-
comycin is indicated. Prolonged neutropenia increases the risk
of fungal infections, and antifungal agents should be consid-
ered. The duration of antimicrobial treatment is determined
on an individual basis, but it should continue at least until
there is evidence of bone marrow recovery (usually a neu-
trophil count >500). Prophylaxis with myeloid growth factors
such as filgrastim or pegfilgrastim can reduce the risk of febrile
neutropenia from chemotherapy and is used in high-risk
settings.
  CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING
Definition
Nausea and vomiting are perhaps the most feared adverse effects
of chemotherapy. Chemotherapy agents are stratified according
to risk of emetogenicity (Table 61-3). Nausea and emesis are
typically categorized as acute, delayed, or anticipatory. Acute
nausea and vomiting occurs during the first 24 hours of treat-
ment, whereas delayed nausea occurs 2 to 5 days after treatment
initiation. Patients with high levels of anxiety or prior poor
control of nausea may also suffer symptoms in anticipation of
starting treatment. The risk of chemotherapy-induced nausea
and vomiting is greater in younger patients and in women. A
history of increased alcohol consumption is associated with
lower risk.
 Chapter 61  Complications of Cancer and Cancer Treatment 621
TABLE 61-3  NAUSEA AND VOMITING RISK WITH CANCER THERAPY
PERCENTAGE OF
EMETIC RISK PATIENTS AFFECTED REPRESENTATIVE AGENTS
High >90 Cisplatin, high-dose cyclophosphamide
Moderate 30-90 Oxaliplatin, doxorubicin, irinotecan
Low 10-30 Paclitaxel, etoposide, gemcitabine
Minimal <10 Vincristine, bleomycin
5HT3, Serotonin receptor; NK1, neurokinin 1.
Pathology
The mechanism is not completely understood but involves an
effect of chemotherapy on the gastrointestinal mucosa and
central nervous system, such as the chemoreceptor trigger zone
(area postrema). The neurotransmitters that are involved include
dopamine, serotonin, and substance P.
Treatment
The best approach for treatment is prevention. The prophylactic
antiemetic protocol depends on the chemotherapy regimen and
emetic risk (see Table 61-3). Randomized clinical trials have
established that the combination of a neurokinin 1 (NK1) recep-
tor antagonist (aprepitant or fosaprepitant), a 5HT3 serotonin
receptor antagonist, and dexamethasone is the regimen of choice
for highly emetogenic chemotherapy. For moderately emeto-
genic chemotherapy, a 5HT3 antagonist with dexamethasone is
usually adequate. All patients should be given a dopamine or
5HT3 receptor antagonist as rescue therapy for intermittent
nausea.
Dexamethasone is the preferred treatment for delayed nausea
and vomiting in highly and moderately emetogenic chemother-
apy. Other agents with proven efficacy include olanzapine for the
prevention of both acute and delayed nausea and vomiting.
Anticipatory nausea or vomiting is best treated with proper
control of symptoms in the initial cycles. When it occurs, it is best
treated with a benzodiazepine before chemotherapy.
  DERMATOLOGIC TOXICITY
Many chemotherapeutic and targeted agents are associated with
dermatologic toxicity, which can lead to patient morbidity, alter
quality of life, and affect therapeutic dosing.
Clinical Presentation
Acneiform eruptions are observed with agents targeted against
epidermal growth factor receptor (EGFR) in 70% to 80% of
patients. The rash is usually erythematous with pustulopapular
eruptions over the face, scalp, and upper trunk.
Palmar-plantar erythema, or so-called hand-foot syndrome, is
seen with chemotherapeutic agents such as 5-fluorouracil and
capecitabine or with tyrosine kinase inhibitors such as sorafenib,
sunitinib, and regorafenib. Manifestations can differ slightly
between classes of drugs, but they usually involve symmetrical
redness of the palms or soles. Tingling and pain may accompany
erythema. With progression, painful blistering or skin peeling
may occur. Symptoms are frequently observed at pressure areas,
such as on the soles of the feet after prolonged standing or
running.
RECOMMENDED PREVENTIVE ANTIEMETIC
NK1 antagonist + dexamethasone + 5HT3 antagonist
5HT3 antagonist + dexamethasone
Dexamethasone or 5HT3 antagonist or dopamine
antagonist
Not needed
Treatment
Treatment of skin rash associated with anti-EGFR therapies is
tailored to the severity of the rash and may include topical ste-
roids, oral antibiotics (minocycline or doxycycline), and dose
modification or cessation. Sunscreens, reduced sun exposure,
and lotions for dry skin should be used for prevention. For hand-
foot syndrome, preventive measures such as sunscreens and
routine application of lotion to hands and feet are helpful. The
most effective treatment is a brief treatment break (typically for
several days, until complete resolution occurs), followed by
resumption but with a reduced dose of the inciting agent.
  TUMOR LYSIS SYNDROME
Definition
Tumor lysis syndrome occurs in malignancies with a high prolif-
erative rate (such as aggressive lymphoma or leukemia), usually
after the initiation of cytotoxic chemotherapy. It is an oncologic
emergency. Rarely, it can occur spontaneously.
Pathology
Massive tumor cell lysis causes the release of large amounts of
potassium, phosphate, and nucleic acids into blood. This leads to
rapidly increased production of uric acid, which can precipitate
in the renal tubules, causing acute renal insufficiency.
Diagnosis
Tumor lysis syndrome should be suspected in the presence of
hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocal-
cemia. Elevated creatinine can occur with renal damage from uric
acid precipitation.
Treatment
In the appropriate clinical setting, tumor lysis syndrome should
be anticipated and prevented. An international panel has devel-
oped a risk stratification scheme. Aggressive hydration is key to
preventing this syndrome and should continue until the tumor
burden is largely resolved. Allopurinol at a dose of 150 mg—or,
in high-risk cases, rasburicase at a dose of 0.2 mg/kg—can be
used for prophylaxis. Rasburicase may also be used to treat severe
hyperuricemia and to prevent renal insufficiency.
For a deeper discussion on this topic, please see Chapters
176, “Hypercoagulable States,” Chapter 179, “Tumor Lysis,”
Chapter 245, “Hypercalcemia,” and Chapter 400, “Spinal
Cord Compression” in Goldman-Cecil Medicine, 25th
Edition.
622 Section IX  Oncologic Disease
SUGGESTED READINGS
Bayo J, Fonseca PJ, Hernando S, et al: Chemotherapy-induced nausea and
vomiting: pathophysiology and therapeutic principles, Clin Trans Oncol
14:413–422, 2012.
Connors JM: Prophylaxis against venous thromboembolism in ambulatory
patients with cancer, N Engl J Med 370:2515–2519, 2014.
Cooper KL, Madan J, Whyte S, et al: Granulocyte colony-stimulating factors for
febrile neutropenia prophylaxis following chemotherapy: systematic review
and meta-analysis, BMC Cancer 11:404, 2011.
Flowers CR, Seidenfeld J, Bow EJ, et al: Antimicrobial prophylaxis and outpatient
management of fever and neutropenia in adults treated for malignancy:
American Society of Clinical Oncology clinical practice guideline, J Clin
Oncol 31:794–810, 2013.
Howard SC, Jones DP, Pui CH: The tumor lysis syndrome, N Engl J Med
364:2011, 1844-1854.
Huang V, Anadkat M: Dermatologic manifestations of cytotoxic therapy,
Dermatol Ther 24:401, 2011.
LeGrand SB: Modern management of malignant hypercalcemia, Am J Hosp
Palliat Care 28:515–517, 2011.
Lepper PM, Ott SR, Hoppe H, et al: Superior vena cava syndrome in thoracic
malignancies, Respir Care 56:653–666, 2011.
Loblaw DA, Mitera G, Ford M, et al: A 2011 updated systematic review and
clinical practice guideline for the treatment of malignant extradural spinal cord
compression, Int J Radiat Oncol Biol Phys 84:312–317, 2012.
Lyman GH, Khorana AA, Kuderer NK, et al: Venous thromboembolism
prophylaxis and treatment in patients with cancer: American Society of
Clinical Oncology practice guideline update, J Clin Oncol 31:2189–2204,
2013.
Patchell RA, TIbbs PA, Regine WF, et al: Direct decompressive surgical resection
in the treatment of spinal cord compression caused by metastatic cancer:
a randomized trial, Lancet 366:643–648, 2005.
Roila F, Herrstedt J, Aapro M, et al: Guideline update for MASCC and ESMO in
the prevention of chemotherapy- and radiotherapy-induced nausea and
vomiting: results of the Perugia consensus conference, Ann Oncol 21(Suppl
5):v232–v243, 2010.
Wu PA, Balagula Y, Lacouture ME, et al: Prophylaxis and treatment of
dermatologic adverse events from epidermal growth factor receptor inhibitors,
Curr Opin Oncol 23:343–351, 2011.
X
ESSENTIALS

Endocrine Disease and

Metabolic Disease
62  Hypothalamic-Pituitary Axis
Kawaljeet Kaur and Diana Maas

63  Thyroid Gland

Theodore C. Friedman

64  Adrenal Gland

Theodore C. Friedman

65  Male Reproductive Endocrinology

Glenn D. Braunstein

66  Diabetes Mellitus, Hypoglycemia

Robert J. Smith

67  Obesity
Osama Hamdy

68  Malnutrition, Nutritional Assessment, and Nutritional Support in Hospitalized Adults

Thomas R. Ziegler

69  Disorders of Lipid Metabolism

Geetha Gopalakrishnan and Robert J. Smith

623
 62 
Hypothalamic-Pituitary Axis
Kawaljeet Kaur and Diana Maas

  ANATOMY AND PHYSIOLOGY

The pituitary gland sits in the skull base in a bony structure called
the sella turcica. It weighs approximately 600 mg and is com-
posed of three lobes, the adenohypophysis (anterior lobe), the
neurohypophysis (posterior lobe), and the intermediate lobe.
The infundibular stalk, which contains the portal plexus circula-
tion, connects the hypothalamus to the pituitary gland. The pitu-
itary gland is surrounded by important structures that can be
compromised by its enlargement, including the optic chiasm,
located superior to the gland, and the cavernous sinuses, located
on both sides of the gland. The cavernous sinuses each contain
the internal carotid artery and cranial nerves III, IV, V1, V2, and
VI. (Fig. 62-1).
The anterior pituitary gland produces six hormones that are
produced by specific cell types within the gland: adrenocortico-
tropic hormone (ACTH), follicle-stimulating hormone (FSH),
luteinizing hormone (LH), growth hormone (GH), prolactin,
and thyroid-stimulating hormone (TSH or thyrotropin). These
hormones are regulated by stimulatory and inhibitory peptides
produced within the ventral hypothalamus and are transported
to the anterior pituitary gland by the infundibular portal system.
The posterior pituitary gland makes up about 20% of the total
pituitary mass and stores and secretes two major peptide hor-
mones: vasopressin (AVP or antidiuretic hormone) and oxyto-
cin. These neurohypophyseal hormones are synthesized by the
supraoptic and paraventricular nuclei of the hypothalamus and
transported to the posterior lobe in neurosecretory granules
along the supraopticohypophyseal tract. (Table 62-1) The inter-
mediate lobe regresses in humans at about 15 weeks gestation
and is absent in the adult normal pituitary gland.
On imaging studies, the normal adult pituitary gland has a flat FIGURE 62-1  Coronal section and corresponding magnetic reso-
nance imaging scan of the pituitary gland and surrounding structures,
superior border and a vertical height of approximately 8 to
including cranial nerves III (oculomotor), IV (trochlear), V1 (trigeminal,
10 mm. The anterior pituitary is homogeneous in signal on mag- ophthalmic branch), V2 (trigeminal, maxillary branch), and VI (abdu-
netic resonance imaging (MRI), the preferred imaging method, cens). CC, Carotid artery (intracavernous); CS, cavernous sinus (left); IC,
and enhances homogeneously after intravenous administration internal carotid artery; OC, optic chiasm; Pit, pituitary gland; SS, sphe-
of a contrast agent (see Fig. 62-1). During periods of increased noid sinus. (From Jesurasa A, Kailaya-Vasan A, Sinha S: Surgery for pitu-
itary tumors, Surgery 29:428–433, 2011, Figure 1.)
hormonal activity, most notably during pregnancy, the pituitary
gland can increase in size and change shape. The posterior pitu-
itary lobe is distinguished from the anterior lobe on T1-weighted the sella, accounting for more than 90% of masses that develop
MRI as a bright spot in the posterior aspect of the gland, best in that area, and they are usually benign. Their true incidence
seen on a sagittal view. The bright appearance is thought to result is difficult to determine because they are often asymptomatic,
from the presence of AVP and/or phospholipid vesicles within but the prevalence is about 10% to 20% in radiologic studies.
the normal neurohypophysis. Most pituitary tumors are slow growing, but some have higher
growth rates and can be invasive. Pituitary carcinomas are very
  PITUITARY TUMORS rare and are defined by the presence of a metastasis that is
Pituitary tumors account for approximately 10% to 15% of noncontiguous with the original tumor or cerebrospinal fluid
intracranial tumors. They are the most commmon tumors in dissemination.

624
 Chapter 62  Hypothalamic-Pituitary Axis 625

TABLE 62-1  PITUITARY–TARGET ORGAN HORMONE AXIS

PERIPHERAL PERIPHERAL
HYPOTHALAMIC PITUITARY PITUITARY TARGET HORMONE
HORMONE TARGET CELL HORMONE AFFECTED GLAND AFFECTED
STIMULATORY
Anterior Lobe of Pituitary Gland
Thyrotropin-releasing Thyrotroph Thyroid-stimulating Thyroid gland Thyroxine (T4)
hormone (TRH) hormone (TSH) Triiodothyronine (T3)
Growth hormone- Somatotroph Growth hormone (GH) Liver Insulin-like growth
releasing hormone factor-I (IGF-I)
(GHRH)
Gonadotropin-releasing Gonadotroph Luteinizing hormone (LH) Ovary Progesterone
hormone (GnRH) Testis Testosterone
Follicle-stimulating Ovary Estradiol
hormone (FSH) Testis Inhibin
Corticotropin-releasing Corticotroph Adrenocorticotrophic Adrenal gland Cortisol
hormone hormone (ACTH)
Posterior Lobe of Pituitary Gland
Vasopressin (AVP) Kidney
Oxytocin Uterus
Breast
INHIBITORY
Somatostatin Somatotroph GH Thyroid
Thyrotroph TSH Liver
Dopamine Lactotroph Prolactin Breast

Pituitary tumors are classified by size and functionality or

secretory capacity. Tumors that are smaller than 10 mm in diam- TABLE 62-2  PREVALENCE OF PITUITARY TUMORS
eter are called microadenomas, whereas lesions 10 mm or larger TUMOR PREVALENCE (%)
are called macroadenomas. Hormone-producing tumors are Prolactinomas 40-45
called secretory adenomas, and those that do not secrete a hormone Somatotroph adenomas 20
are known as nonsecretory adenomas. Pituitary tumors may be Corticotroph adenomas 10-12
Gonadotroph adenomas 15
composed of any of the anterior pituitary cell types, with multiple Null cell adenomas 5-10
cell types forming plurihormonal tumors or nonsecretory Thyrotroph adenomas 1-2
tumors. Prolactin-secreting pituitary tumors are the most
common type. Table 62-2 reviews the prevalence of the various
pituitary tumors, and Table 62-3 describes the screening tests extension into the cavernous sinuses results in ophthalmoplegia,
used to determine the secretory status of a new pituitary tumor. diplopia, or ptosis due to compression of cranial nerves III, IV, or
The clinical manifestations of pituitary tumors are usually VI or facial pain due to compression of V1 or V2. Compromise
signs and symptoms caused by hormone overproduction or of normal pituitary tissue by a tumor can cause hormone loss or
underproduction or mass effect. Common clinical features of hypopituitarism. Screening tests for pituitary hormone defi-
pituitary mass effect include headaches, visual field defects, and ciency are shown in Table 62-3; typically, a destructive pituitary
cranial nerve palsies. Superior extension of a tumor compresses lesion causes loss of pituitary hormones in the following progres-
the optic chiasm, causing bitemporal hemianopsia; lateral sion: first GH, then FSH and LH, then TSH, and finally ACTH.

Disorders of Anterior Pituitary Hormones

  PROLACTIN
Definition and Epidemiology
The mature prolactin polypeptide contains 199 amino acids
and is formed after a 28-amino acid signal peptide is pro-
teolytically cleaved from the prolactin prohormone (pre-
prolactin). Prolactin synthesis and secretion by pituitary
lactotrophs is under tonic inhibitory control by hypothalamic-
derived dopamine, which keeps prolactin at its basal levels.
Factors stimulating prolactin synthesis and secretion, in addi-
tion to reduced dopamine availability to the lactotrophs, include
thyrotropin-releasing hormone (TRH), estrogen, vasoactive
intestinal polypeptide (VIP), AVP, oxytocin, and epidermal
growth factor.
Prolactin levels physiologically increase during pregnancy.
After delivery, prolactin induces and maintains lactation of the
primed breast. Once lactation has been initiated by these eleva-
tions in prolactin, prolactin falls to basal levels and lactation is
maintained by the infant’s suckling reflex. Hyperprolactinemia,
regardless of the etiology, can cause hypogonadism through its
inhibitory effect on gonadotropin release, infertility, galactor-
rhea, and/or bone loss from the hypogonadism.
626 Section X  Endocrine Disease and Metabolic Disease
TABLE 62-3  SCREENING TESTS FOR PITUITARY DISORDERS
DISORDER TESTS
PITUITARY TUMOR
Acromegaly IGF-I
OGTT: measure blood sugar and GH (0, 60, 120 min)
Prolactinoma Basal serum prolactin
ACTH-secreting 24-hr urine-free cortisol and creatinine level
tumor 1-mg overnight dexamethasone suppression test
11 pm salivary cortisol
Serum ACTH
Dexamethasone-CRH test
Bilateral inferior petrosal sinus sampling
TSH-secreting tumor Serum TSH, FT4, FT3
Gonadotropin- FSH, LH, alpha subunit
secreting tumor
ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone;
IGF-I, insulin-like growth factor-I; ITT, insulin tolerance test; LH, luteinizing hormone; OGTT, oral glucose tolerance test; T4, thyroxine; TSH, thyroid-stimulating hormone; TFT, thyroid
function test.
Prolactinomas and hyperprolactinemia are more common in
women, with a peak prevalence between 25 and 35 years of age.
The mean prevalence of patients medically treated for hyperpro-
lactinemia is approximately 20 per 100,000 in men and approxi-
mately 90 per 100,000 in women. Prolactinomas are rare in
childhood or adolescence.
Clinical Presentation
The clinical presentation of a prolactinoma varies with the age
and gender of the patient. Typically, the patient is a young woman
with menstrual irregularities, galactorrhea, and infertility. Galac-
torrhea occurs in 50% to 80% of affected women. Men may
report a decrease in libido and erectile dysfunction as result of
hypogonadism caused by reduced secretion of LH and FSH.
Typically, however, their tumors are diagnosed after symptoms
of tumor compression appear, including headache, neurologic
deficits, and vision changes. Galactorrhea and gynecomastia are
rare in men. Because of the early presentation of menstrual irreg-
ularities in women, microprolactinomas are more common in
women; macroprolactinomas are more frequent in men and in
postmenopausal women.
Diagnosis and Differential Diagnosis
Hyperprolactinemia is diagnosed by a single measurement of
serum prolactin; a level above the upper limit of normal confirms
the diagnosis. For prolactinomas, serum prolactin levels typically
parallel tumor size. A prolactin level greater than 250 ng/mL
usually indicates the presence of a prolactinoma. Dynamic testing
is not needed to diagnose hyperprolactinemia.
Two types of artifacts can occur during the standard measure-
ment of prolactin: the presence of macroprolactin and the hook
effect. When a patient with mild hyperprolactinemia does
not have the expected clinical features of hyperprolactinemia
(e.g., galactorrhea, menstrual disturbance, infertility), one should
consider the presence of macroprolactin. Although 85% of circu-
lating prolactin is monomeric, serum also contains the macrop-
rolactin, a polymeric form of prolactin that is biologically
inactive. Most commercially available prolactin assays do not
detect macroprolactin, but it can be detected inexpensively in the
serum by polyethylene glycol precipitation. The estimated inci-
dence of macroprolactin accounting for a significant proportion
of hyperprolactinemia is 10% to 20%. The hook effect should be
DISORDER TESTS
HYPOPITUITARISM
GH deficiency IGF-I
GH provocative test: ITT
Arginine-GHRH
Glucagon stimulation test
Gonadotropin Women: basal estradiol, LH, FSH
deficiency Men: 8 am fasting testosterone (total; free), LH, FSH
TSH deficiency Serum TSH, free T4
ACTH deficiency ACTH
Provocative test: ITT
Metyrapone test
Cosyntropin-stimulation test (1 µg and 250 µg)
considered whenever a patient has a very large pituitary mass
but only a mild elevation in prolactin. The hook effect is an
assay artifact that occurs when very high serum prolactin concen-
trations saturate antibodies in the standard two-site immunora-
diometric assay, resulting in falsely lower levels. This artifact can
be overcome by repeating the prolactin measurement on a 1 : 100
serum sample dilution.
Physiologic increases in prolactin occur with pregnancy, physi-
cal or emotional stress, exercise, and chest wall stimulation.
Other causes for hyperprolactinemia include some drugs, such as
metoclopramide and risperidone, that can increase prolactin to
greater than 200 ng/mL. Mild to moderate hyperprolactinemia
(25 to 200 ng/mL) in the presence of a larger pituitary mass is
more likely to be caused by a non–prolactin-secreting tumor with
infundibular stalk compression and inhibition of dopamine
transport to the lactotroph. Other causes include hypothalamic-
pituitary disorders, systemic disorders, and neurogenic and idio-
pathic etiologies.
Treatment and Prognosis
Medical management with a dopamine agonist—bromocriptine
or cabergoline—is the recommended treatment. The dopamine
agonists normalize prolactin, decrease tumor size, and restore
gonadal function in more than 80% of patients with prolactino-
mas. Because of the rapidity and efficacy of the dopamine ago-
nists in treating these tumors, they are also the initial treatment
for macroprolactinomas that have caused compromise in vision,
neurologic deficits, or pituitary dysfunction.
Cabergoline, the newer agent, is preferred to other dopamine
agonists because it has higher efficacy in normalizing prolactin
levels and shrinking tumor size and has fewer side effects. The
most common side effects seen with dopamine agonists are
nausea, vomiting, orthostatic lightheadedness, dizziness, and
nasal congestion. Because of the concern for cabergoline-related
cardiac valvulopathy that was reported in patients who had Par-
kinson’s disease treated with high doses of cabergoline and the
possible long-term need for treatment, bromocriptine could be
used in young patients if it is tolerated. Transsphenoidal resection
of the tumor is indicated for patients who cannot tolerate the
dopamine agonists or who do not respond to medical treatment.
No treatment is required for patients who have microprolactino-
mas that are asymptomatic.
 Chapter 62  Hypothalamic-Pituitary Axis 627
Recent studies have shown that dopamine agonists may be
safely withdrawn in patients who have maintained normal pro-
lactin levels for 2 years and who have no visible tumor remnant
on tapering doses of dopamine agonist. Once the dopamine
agonist is discontinued, prolactin levels should be checked every
3 months for 1 year and then annually. An MRI should be
obtained only if the prolactin level becomes elevated again.
Recurrence risk after drug withdrawal ranges from 26% to 69%
and is predicted by the initial prolactin level and tumor size.
  GROWTH HORMONE
Definition
GH is a single-chain polypeptide hormone consisting of 191
amino acids that is synthesized, stored, and secreted by the ante-
rior pituitary somatotrophs. GH secretion is regulated by two
factors derived from the hypothalamus: growth hormone–
releasing hormone (GHRH) and somatostatin. GHRH stimu-
lates somatotroph GH release, and somatostatin inhibits it. GH
stimulates secretion of insulin-like growth factor-I (IGF-I) by the
liver. IGF-I circulates in the blood attached to binding proteins;
although there are six binding proteins in serum, more than 80%
of IGF-I is bound to a protein called IGFBP3. Postnatally and
through puberty, GH and IGF-I are critical in determining lon-
gitudinal skeletal growth, skeletal maturation, and acquisition of
bone mass. In adulthood, they are instrumental in the mainte-
nance of skeletal architecture and bone mass. GH also has effects
on the metabolism of carbohydrates, lipids, and proteins by
antagonizing insulin action, increasing lipolysis and free fatty acid
production, and increasing protein synthesis.
Growth Hormone Deficiency
Epidemiology
Childhood-onset GH deficiency is most commonly idiopathic,
but it may be genetic or associated with congenital anatomic
malformations in the brain or sellar region. The most common
cause of GH deficiency in adults is a pituitary macroadenoma
and its treatment; deficiency of one or more pituitary hormones
occurs in 30% to 60% of such cases. The incidence of hypopitu-
itarism 10 years after irradiation of the sellar region is approxi-
mately 50%.
Clinical Presentation
Children with GH deficiency exhibit growth retardation, short
stature, and fasting hypoglycemia. Manifestations of adult GH
deficiency include reduced bone mineralization, decreased
muscle strength and exercise performance, decreased lean body
mass with increase in fat mass and abdominal adiposity, glucose
intolerance and insulin resistance, abnormal lipid profile includ-
ing elevated low-density lipoprotein and triglyceride levels
with decreased high-density lipoprotein, depressed mood, and
impaired psychosocial well-being.
Diagnosis and Differential Diagnosis
Because of the pulsatile nature of pituitary GH secretion, a single
random measurement of serum GH is not helpful to diagnose
GH deficiency. In adults with GH deficiency due to a pituitary
tumor and concomitant hypopituitarism involving any three
other pituitary hormones, a low IGF-I level is sufficient to diag-
nose GH deficiency, and provocative testing is not warranted.
Falsely low IGF-I levels are also seen in malnutrition, acute
illness, celiac disease, poorly controlled diabetes mellitus, liver
disease, and estrogen ingestion. In children, there tends to be
greater variation in IGF-I levels that do not correspond to the
true GH status, so provocative testing is required.
The historical “gold standard” stimulatory test is insulin-
induced hypoglycemia (insulin tolerance test or ITT). Symptom-
atic hypoglycemia with a serum glucose level lower than 45 mg/
dL is a potent stimulus for GH secretion; the normal GH
response is greater than 10 ng/mL in children and greater than
5 ng/mL in adults. Because of the unavailability in the United
States of GHRH, which is as sensitive and specific as the ITT in
stimulating GH secretion, glucagon stimulation is being used,
especially in adults with ischemic heart disease or seizures. A
normal response with the glucagon stimulation test is defined as
a GH peak greater than 3 ng/mL.
Treatment and Prognosis
Recombinant human growth hormone (hGH) is administered to
promote linear growth in short children. The U.S. Food and Drug
Administration (FDA) has approved GH treatment for condi-
tions involving complete absence of GH associated with severe
growth retardation or partial GH deficiency resulting in short
stature. Short stature is defined as height more than 2.5 standard
deviations below the mean for age-matched normal children,
growth velocity less than the 25th percentile, delayed bone age,
and predicted adult height less than the mean parental height.
The conditions approved by the FDA to use GH include GH
deficiency, idiopathic short stature, Turner’s syndrome, Prader-
Willi syndrome, chronic kidney disease, AIDS-associated muscle
wasting, SHOX gene deficiency, Noonan’s syndrome, and chil-
dren born small for gestational age. Combined clinical evalua-
tions, along with an inadequate pituitary GH response to
provocative testing, are used in the assessment of childhood GH
deficiency. Higher doses of GH are recommended for children
without GH deficiency disorders or with partial GH deficiency.
In adults, GH is administered as a daily subcutaneous injection
starting at 0.1 to 0.3 mg, with dose increases at 6-week intervals
based on clinical response, side effects, and IGF-I levels. Absolute
contraindications to GH therapy in adults include active neo-
plasm, intracranial hypertension, and proliferative diabetic reti-
nopathy; uncontrolled diabetes and untreated thyroid disease are
relative contraindications. Side effects of GH therapy are usually
transient and include arthralgias, fluid retention, carpal tunnel
syndrome, and glucose intolerance. Additional side effects in
children include slipped capital femoral epiphysis and
hydrocephalus.
Acromegaly or Growth Hormone
Hypersecretion
Definition and Epidemiology
Acromegaly is literally translated as abnormal enlargement of the
extremities of the skeleton. It is caused by hypersecretion of GH
in adulthood. In children, excessive GH secretion before closure
of the epiphyseal growth plate leads to gigantism. In both cases,
the cause is almost always a GH-secreting pituitary tumor.
628 Section X  Endocrine Disease and Metabolic Disease

Approximately, 30% of GH-secreting pituitary adenomas are approximately 70% of cases of acromegaly are caused by pituitary
plurihormonal and also secrete prolactin. The incidence of acro- macroadenomas. Rarely, GH hypersecretion is caused by ectopic
megaly is about 2 to 4 per million population, and the mean age GHRH-secreting tumors, including hypothalamic hamartomas
at diagnosis is 40 to 50 years. and gangliocytomas, pancreatic islet cell tumors, small cell carci-
noma of the lung, carcinoid, adrenal adenomas, and pheochro-
Pathology mocytomas. Ectopic GH secretion has also been reported in
GH-secreting tumors are caused by a clonal expansion of pure pancreatic, lung, and breast cancers.
somatotrophs or mixed somatomammotrophs. A variety of
genetic abnormalities can be found in GH-secreting pituitary Treatment and Prognosis
adenomas. GH hypersecretion due to somatotroph hyperplasia Treatment of acromegaly requires both treatment of the tumor
and adenomas is also seen in patients with McCune-Albright and normalization of GH and IGF-I levels, along with manage-
syndrome, which is caused by a G protein–activating mutation. ment of the comorbidities and metabolic abnormalities caused
There are also familial syndromes associated with GH-secreting by the excess GH. Treatment often requires the use of multiple
pituitary adenomas, including multiple endocrine neoplasia type modalities to achieve adequate control of the disease. Primary
1, Carney complex (myxomas, skin pigmentation, and therapy is almost always transsphenoidal surgery, with the cure
testicular, adrenal, and pituitary tumors) and mutations in AIP rate being directly proportional to tumor size. Patients with intra-
(aryl hydrocarbon receptor interacting protein). sellar microadenomas have a 75% to 95% cure rate with surgery.
Even in patients with noninvasive macroadenomas, surgical
Clinical Presentation removal results in normalization of IGF-I in 40% to 68% of
Acromegaly is a rare disease, and the rate of change of symptoms patients.
and signs is slow and insidious. The usual period from earliest Approximately 40% to 60% of tumors are not controlled with
onset of symptoms and signs to diagnosis is 8 to 10 years, during surgery alone because of cavernous sinus invasion or intracapsu-
which time many patients undergo medical and surical treatments lar intra-arachnoid invasion. Additional treatment options
for many of the metabolic abnormalities and morbidities caused include primary medical therapy or primary surgical debulking
by GH excess. Characteristic clinical findings of this disease of the tumor followed by medical therapy for hormonal control
include physical changes of the bone and soft tissue and with and/or radiation therapy for treatment of residual tumor. Con-
multiple endocrine and metabolic abnormalities (Table 62-4). ventional radiotherapy can normalize GH and IGF-I levels in
more than 60% of patients, but the maximum response takes 10
Diagnosis and Differential Diagnosis to 15 years to achieve. Focused single-dose gamma knife radio-
Measurement of serum IGF-I can be used to diagnose excess GH therapy has a 5-year remission rate of 29% to 60%. Hypopituita-
in most patients with acromegaly. An alternative is an oral glucose rism is seen in more than 50% of patients within 5 to 10 years
tolerance test using a 100-g glucose load. Normally, glucose sup- after radiotherapy.
presses GH levels to less than 1 ng/mL after 2 hours; in patients Currently, three drug classes are used to treat acromegaly:
with acromegaly, GH levels may paradoxically increase, remain dopamine agonists, somatostatin receptor ligands (SRLs) such
unchanged, or decrease but not below 1 ng/mL. Most acrome- as octreotide and lanreotide, and GH receptor antagonists. SRLs
galic patients have GH-secreting pituitary tumors, and work mainly through the somatostatin receptor subtypes 2 and
5, causing a decrease in tumor GH secretion. In acromegaly,
SRLs are indicated for first-line treatment when there is low
TABLE 62-4  CLINICAL FEATURES OF ACROMEGALY probability of surgical cure, after a failed surgical cure of GH
CHANGE MANIFESTATIONS hypersecretion, preoperatively to improve severe comorbidities
SOMATIC CHANGES that prevent or could complicate immediate surgery, and to
Acral changes Enlarged hands and feet provide GH and IGF-I control or partial control while waiting
Musculoskeletal changes Arthralgias for radiotherapy to achieve its maximum effect. SRLs reduce
Prognathism
Malocclusion GH and IGF-I levels to normal in 40% to 65% of patients and
Carpal tunnel syndrome shrink tumor size in approximately 50% of cases. Side effects of
Proximal myopathy SRLs include diarrhea, abdominal cramping, flatulence, and
Skin changes Sweating
Colon changes Polyps cholelithiasis (15%).
Carcinoma Pegvisomant is the only GH receptor antagonist available. It
Cardiovascular symptoms Cardiomegaly works by blocking the peripheral action of GH through blockade
Hypertension
Visceromegaly Tongue of the GH receptors located on the liver. Pegvisomant is indi-
Thyroid cated for patients who have persistent elevation in IGF-I even
Liver with maximum doses of SRLs. This drug is highly effective in the
ENDOCRINE-METABOLIC CHANGES treatment of acromegaly and normalizes IGF-I levels in 97% of
Reproduction Menstrual abnormalities patients; transient elevation in liver function enzymes is seen in
Galactorrhea
Decreased libido
25% of those treated, and tumor growth in fewer than 2%.
Carbohydrate metabolism Impaired glucose tolerance Cabergoline is the most efficacious of the dopamine agonists
Diabetes mellitus for treatment of acromegaly, but it is effective in fewer than 10%
Lipids Hypertriglyceridemia
of patients.
 Chapter 62  Hypothalamic-Pituitary Axis 629
Thyroid-Stimulating Hormone
TSH is a glycoprotein secreted from the thyrotroph cells of the
anterior pituitary. It is composed of alpha and beta subunits. Its
release is regulated by TRH (stimulatory) and somatostatin
(inhibitory). In addition, it is subject to the negative feedback of
thyroid hormones released from the thyroid gland.
Evaluation
Assessment of the pituitary-thyroid axis requires checking levels
of TSH as well as thyroid hormones released by the thyroid gland
(i.e., thyroxine [T4] and triiodothyronine [T3]). Dynamic testing
using TRH is no longer available.
Deficiency of TSH
Definition and Epidemiology
Deficiency of TSH leads to secondary hypothyroidism: The
diminished secretion of TSH from the pituitary provides inade-
quate stimulation to the thyroid gland for thyroid hormone
release. The estimated prevalence of TSH deficiency is about 1 in
80,000 to 120,000 individuals.
Pathology
Hypopituitarism due to encroachment of a tumor on the normal
pituitary can cause deficiency of one or more pituitary hormones.
Radiation treatment of the pituitary gland can also cause hypo-
pituitarism over time.
Clinical Presentation
The usual signs and symptoms of hypothyroidism are weight
gain, fatigue, cold intolerance, and constipation. If the condi-
tion is caused by an underlying sellar tumor, symptoms of
mass effect may also be present, depending on the size of the
tumor.
Diagnosis and Differential Diagnosis
Secondary hypothyroidism is characterized by low levels of free
T4 along with low or inappropriately normal TSH. The differen-
tial diagnosis includes euthyroid sick syndrome, which is often
seen in the setting of an acute illness. This syndrome does not
require any intervention, and the laboratory results normalize on
repeat testing after resolution of the acute illness.
Treatment and Prognosis
Management focuses on replacement of the thyroid hormones,
as in primary hypothyroidism. However, measurement of free T4,
rather than TSH, is used as a guide to adjust therapy. Underlying
adrenal insufficiency should always be excluded and treated
before treatment of secondary hypothyroidism to avoid precipi-
tating an adrenal crisis.
TSH-Secreting Pituitary Tumors
Definition and Epidemiology
TSH-secreting pituitary tumors are rare and are characterized by
inappropriate release of TSH that is refractory to the negative
feedback mechanism of the thyroid hormones released by the
thyroid gland. The prevalence of TSH-secreting pituitary adeno-
mas is 1 to 2 cases per million in the general population.
Pathology
The pathogenesis of TSH-secreting pituitary tumors is unknown.
Clinical Presentation
The most common age of presentation is in the early fifth decade,
and there is no gender bias. Presenting symptoms can be the
result of a mass effect of the tumor or, most commonly, there
are symptoms and signs of hyperthyroidism, including weight
loss, tremors, heat intolerance, and diarrhea. Diffuse goiter is
observed in up to 80% of patients. Many times, these tumors
are initially misdiagnosed as primary hyperthyroidism and
patients are mistakenly treated with radioactive iodine. Some-
times, the TSH produced by these tumors is biologically inactive
and the tumors are diagnosed as an incidental finding on imaging
studies.
Diagnosis and Differential Diagnosis
The diagnosis is made in the setting of elevated or inappropri-
ately normal TSH along with elevated levels of thyroid hormones
(free and total T4 and T3). The differential diagnosis includes
genetic resistance to thyroid hormone and euthyroid hyperthy-
roxinemia, which is characterized by normal TSH, high total
T4, normal free T4, and elevated thyroxine-binding globulin
levels. Imaging studies (MRI) should be done only after
biochemical confirmation because of the high incidence of
incidental pituitary tumors.
Treatment and Prognosis
Surgery (transsphenoidal resection) is the first-line treatment
and should be performed by an experienced neurosurgeon.
Radiotherapy can be used if surgery is declined or contraindi-
cated. Medical therapy with somatostatin analogues (e.g., octreo-
tide, lantreotide) may also be used for persistent hyperthyroidism
after surgery. Most patients do well and achieve control of symp-
toms of thyrotoxicosis as well as reduction in tumor burden.
  ADRENOCORTICOTROPIC HORMONE
ACTH is a 39-amino-acid peptide hormone that is formed from
a precursor molecule, pro-opiomelanocortin (POMC) and is
synthesized and secreted by corticotrophs in the anterior pitu-
itary. It is stimulated by hypothalamic corticotropin-releasing
hormone (CRH). ACTH, in turn, stimulates release of glucocor-
ticoids and androgens from the adrenal cortex.
ACTH Deficiency
Definition and Pathology
ACTH deficiency causes secondary adrenal insufficiency leading
to decreased cortisol and adrenal androgens. Aldosterone secre-
tion from the adrenal glands is not impaired because it is main-
tained via the renin-angiotensin axis. ACTH deficiency can result
from a large pituitary tumor impinging on the normal pituitary.
Secondary or tertiary adrenal insufficiency is most commonly
iatrogenic, caused by the use of steroids for other disease
processes.
630 Section X  Endocrine Disease and Metabolic Disease

day) should be initiated. Patient education regarding stress

Clinical Presentation
Both primary and secondary adrenal insufficiency are character-
ized by weight loss, fatigue, muscle weakness, orthostatic
symptoms, nausea, vomiting, diarrhea, and abdominal pain. Bio-
chemical abnormalities include hyponatremia, azotemia, eosino-
philia, and anemia. Importantly, hyperpigmentation of the skin
and hyperkalemia are seen only with primary adrenal insuffi-
ciency, not with ACTH deficiency.
Diagnosis and Differential Diagnosis
The gold standard for diagnosis of secondary adrenal insuffi-
ciency has been an insulin tolerance test. The test is contrain-
dicated in elderly patients and in those with a history of seizures,
cardiovascular disease, or cerebrovascular disease. A safer test
is an 8 am fasting rapid ACTH stimulation test. This test mea-
sures the cortisol response to synthetic ACTH or cosyntropin.
ACTH and cortisol levels are measured at baseline, followed
by cortisol levels at 30 and 60 minutes. An 8 am cortisol level
of less than 5  µg/dL suggests adrenal insufficiency. A peak
plasma cortisol level higher than 18 to 20  µg/dL is considered
a normal response.
Treatment
Glucocorticoid replacement therapy in the form of hydrocorti-
sone (10 mg in am and 5 mg in pm) or prednisone (5 to 7.5 mg/
dosing of steroids is important. Mineralocorticoids are usually
not needed in patients with central adrenal insufficiency.
ACTH-Secreting Pituitary Tumors  
(Cushing’s Disease)
Definition and Epidemiology
ACTH-secreting pituitary tumors (by definition, Cushing’s
disease) account for about 80% of the cases of Cushing’s syn-
drome; they are usually microadenomas. There is a female pre-
ponderance (female-to-male ratio, about 3 : 1).
Pathology
The chronic stimulation by excessive ACTH causes simple
diffuse hyperplasia of the bilateral adrenal glands or sometimes
multinodular hyperplasia, both leading to excessive cortisol
production.
Clinical Presentation
Signs and symptoms of Cushing’s disease are related to the hyper-
cortisolism and include central obesity, hirsutism, facial plethora,
violaceous striae, supraclavicular and dorsocervical fat pads, and
muscle weakness (Fig. 62-2). Additional manifestations of Cush-
ing’s disease are type 2 diabetes mellitus, hypertension, dyslipid-
emia, osteoporosis, and hypogonadism.

A B C D

E F G H
FIGURE 62-2  Clinical features of Cushing’s syndrome. A, Centripetal and some generalized obesity and dorsal kyphosis in a 30-year-old woman
with Cushing’s disease. B, Moon facies, plethora, hirsutism, and enlarged supraclavicular fat pads in the same woman as in A. C, Facial rounding,
hirsutism, and acne in a 14-year-old girl with Cushing’s disease. D, Central and generalized obesity and moon facies in a 14-year-old boy with Cush-
ing’s disease. Typical centripetal obesity with livid abdominal striae in a 41-year-old woman (E) and a 40-year-old man (F) with Cushing’s disease.
G, Striae in a 24-year-old patient with congenital adrenal hyperplasia treated with excessive doses of dexamethasone as replacement therapy.
H, Typical bruising and thin skin of a patient with Cushing’s disease. In this case, the bruising has occurred without obvious injury. (From Larsen PR,
Kronenberg H, Melmed S, et al: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2003, Saunders.)
 Chapter 62  Hypothalamic-Pituitary Axis 631
Diagnosis and Differential Diagnosis
Three different tests are performed in combination to assess for
endogenous hypercortisolism. A 24-hour urine collection may
show an elevated cortisol level, but this test is not reliable in
patients with renal dysfunction. A second test, the 1-mg dexa-
methasone suppression test, measures an 8 am fasting cortisol
level after a dose of 1  mg dexamethasone given at 11 pm the
night before. Cortisol suppression to less than 1.8  µg/dL is
considered a normal response. Another diagnostic test is the
late-night salivary cortisol measurement, using saliva collected
at 11 pm on two consecutive nights. The test relies on a normal
sleep cycle. Individuals who are using inhaled or topical steroids
are not good candidates because of a high rate of false-positive
results. A single positive finding is not sufficient to make this
diagnosis and must be repeated and confirmed by doing addi-
tional tests. Because of the potential of cyclic ACTH overpro-
duction by these tumors, repeat testing is recommended for
individuals with high clinical suspicion but negative initial
testing.
Pathologic hypercortisolism should be differentiated from
physiologic activation of the hypothalamic-pituitary-adrenal axis,
which can be observed in conditions such as critical illness,
eating disorders, alcoholism, pregnancy, severe neuropsychiatric
illness, and poorly controlled diabetes. Further, pathologic
hypercortisolism can be ACTH dependent or independent.
Once the diagnosis of ACTH-dependent hypercortisolism is
established, a pituitary MRI should be performed, because
most of these patients have a corticotroph adenoma; however,
40% to 45% of ACTH-secreting pituitary tumors are not seen
even with MRI scanning. In those cases, patients with ACTH-
dependent Cushing’s syndrome should have inferior petrosal
sinus sampling (IPSS) for ACTH with CRH stimulation;
this differentiates between pituitary and ectopic ACTH over-
production by demonstrating a pituitary-to-peripheral ACTH
gradient.
Treatment and Prognosis
The treatment involves removal of the pituitary tumor by an
experienced neurosurgeon. Options after a failed resection
include reoperation, bilateral adrenalectomy, radiotherapy, or
pharmacotherapy. Pharmacotherapeutic agents include ketocon-
azole, metyrapone, mitotane, cabergoline, pasireotide, and mife-
pristone. In severe cases, intravenous etomidate may be used to
stabilize patients for surgery. Long-term remission after resection
of a pituitary microadenoma ranges from 69% to 98%, with a
recurrence rate of 3% to 19%.
  GONADOTROPINS
The two gonadotropins, LH and FSH, are glycoprotein hor-
mones that are synthesized and secreted by gonadotrophs in
anterior pituitary. They are both composed of an alpha and a beta
subunit, the latter of which gives each its specific biologic func-
tion. These hormones bind to the receptors in the gonads (ovaries
and testes) and modulate gonadal function. Secretion is regulated
both by gonadotropin-releasing hormone (GnRH) from the
hypothalamus and by feedback from circulating sex steroids
(estrogen and testosterone).
Gonadotropin Deficiency (Hypogonadotropic
Hypogonadism)
Definition
Hypogonadotropic hypogonadism is characterized by decreased
or absent secretion of LH and FSH, which causes reduced secre-
tion of the sex steroids (estrogen and testosterone).
Clinical Presentation
Signs and symptoms depend on the time of onset and the extent
of gonadotropin deficiency. If deficiency occurs during fetal life,
it can cause ambiguous genitalia. If deficiency occurs after birth
but before puberty, it can cause delayed or absent sexual develop-
ment. Onset after puberty often causes insidious changes and
may remain undiagnosed for years, especially in men. The usual
presentation after puberty includes symptoms of hypogonadism
as well as infertility.
Diagnosis and Differential Diagnosis
The diagnosis is made by the presence of low or inappropriately
normal FSH and LH levels along with low sex steroids (estrogen
or testosterone). Causes of gonadotropin deficiency can be con-
genital (Kallman’s syndrome, Prader-Willi syndrome, septo-optic
dysplasia) or acquired, as in hemochromatosis, hyperprolac-
tinemia, sellar tumors, cranial irradiation, and inflammatory and
infiltrative disorders.
Treatment
For women, replacement therapy in the form of oral or transder-
mal estrogen should be continued until the age of natural meno-
pause. Progesterone addition to induce withdrawal bleeding is
essential in women with an intact uterus to prevent endometrial
hyperplasia. For men, testosterone replacement is available in
multiple forms, including an intramuscular injection product,
several gels, and a patch. Fertility treatment requires additional
therapy with recombinant FSH and LH in women or human
chorionic gonadotropin (hCG) and FSH in men.
Gonadotropin-Secreting Pituitary Tumors
Definition and Epidemiology
Gonadotropin-secreting pituitary tumors are usually large and
typically manifest with signs and symptoms of mass effect.
Patients can also have symptoms of hypogonadism and other
pituitary hormone deficiencies. These tumors can secrete FSH,
LH, and/or alpha subunit.
Diagnosis and Differential Diagnosis
Hormonal evaluation reveals elevated FSH, LH, and/or alpha
subunit in the absence of low estrogen or testosterone. Immuno-
peroxidase staining on surgical specimens is also needed to estab-
lish the diagnosis, especially in the case of postmenopausal
women.
Treatment
Primary treatment is transsphenoidal surgical removal. Radiation
therapy may be used as an adjunct treatment because of the size
and more aggressive nature of these tumors, compared with true
nonsecretory pituitary tumors.
632 Section X  Endocrine Disease and Metabolic Disease

Disorders of Posterior Pituitary Hormones

AVP and oxytocin are the two hormones that are produced in
the hypothalamus and stored in and released from the poste-
rior pituitary.
  DIABETES INSIPIDUS
Definition
Diabetes insipidus (DI) is characterized by AVP deficiency
and excretion of large volumes of dilute urine.
Pathology
Central DI can be familial due to an autosomal dominant
mutation in the vasopressin gene that affects the functioning
of the AVP-producing neurons. It can also be acquired sec-
ondary to intrasellar and suprasellar tumors, infiltration of the
hypothalamus and posterior pituitary, infection, trauma or
surgery, or as part of an autoimmune condition. Table 62-5
gives a more extensive list of causes of diabetes insipidus.
Clinical Presentation
Polyuria (defined as excretion of more than 3 L of urine per
day) and polydipsia are the clinical hallmarks of DI.
Diagnosis and Differential Diagnosis
DI can be central, caused by AVP deficiency, or nephrogenic,
caused by resistance to AVP. As long as access to free water
is maintained and the thirst mechanism is intact, patients with
DI are usually able to maintain normal serum sodium levels
and osmolality. The water deprivation test is the primary test
used to make the diagnosis and to differentiate the cause of DI.
In patients with DI, the serum sodium level and osmolality
increase in response to water deprivation. The response to a
synthetic analogue of vasopressin is analyzed if the normal rise
in urine osmolality and decrease in urine volume are not seen.
Patients with central DI respond to the synthetic analogue by
increasing urine osmolality and decreasing urine volume. In con-
trast, patients with nephrogenic DI do not respond to the syn-
thetic vasopressin. Patients with partial central DI may have a
limited response.
Primary polydipsia is characterized by increased water intake
without a deficiency or resistance to AVP. Patients with primary
polydipsia concentrate their urine without the need for synthetic
vasopressin.
Treatment
Replacement therapy with desmopressin (DDAVP), an analogue
of AVP, is available in oral, parenteral, and intranasal forms.
Aqueous vasopressin is a shorter-acting analogue of AVP that can
be given subcutaneously in the immediate postoperative period.
Additional AVP analogues include DDAVP, which is available in
subcutaneous, intranasal, and intravenous forms, and desmopres-
sin, the only tablet form. Because of the transient nature of DI
and a possible shift to a transient syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) phase in the patient
who has undergone pituitary surgery, AVP is given cautiously and
not as a scheduled medication to avoid hyponatremia.

  SYNDROME OF INAPPROPRIATE SECRETION

TABLE 62-5  CAUSES OF DIABETES INSIPIDUS OF ANTIDIURETIC HORMONE
CENTRAL DIABETES INSIPIDUS SIADH is covered in the discussion of hyponatremia in
Idiopathic Chapter 27.
Familial
Hypophysectomy
Infiltration of hypothalamus and posterior pituitary
Langerhans cell histiocytosis SUGGESTED READINGS
Granulomas Biller BM, Grossman AB, Stewart PM, et al: Treatment of adrenocorticotropin-
Infection
dependent Cushing’s syndrome: a consensus statement, J Clin Endocrinol
Tumors (intrasellar and suprasellar)
Autoimmune Metab 93:2454–2462, 2008.
Fleseriu M, Petersenn S: Medical management of Cushing’s disease: what is the
NEPHROGENIC DIABETES INSIPIDUS future? Pituitary 15:330–341, 2012.
Idiopathic Freda P, Beckers A, Katznelson L, et al: Pituitary incidentaloma: an Endocrine
Familial Society clinical practice guideline, J Clin Endocrinol Metab 96:894–904, 2011.
V2 receptor gene mutation Melmed S: Medical progress: acromegaly, N Engl J Med 355:2558–2573, 2006.
Aquaporin-2 gene mutation Melmed S, Casanueva F, Hoffman A, et al: Diagnosis and treatment of
Chronic renal disease (e.g., chronic pyelonephritis, polycystic kidney disease,
hyperprolactinemia: an Endocrine Society clinical practice guideline, J Clin
or medullary cystic disease)
Hypokalemia Endocrinol Metab 96:273–288, 2011.
Hypercalcemia Melmed S, Colao A, Barkan A, et al: Guidelines for acromegaly management: an
Sickle cell anemia update, J Clin Endocrinol Metab 94:1509–1517, 2009.
Drugs Nieman L, Biller B, Findling J, et al: The diagnosis of Cushing’s syndrome: an
Lithium Endocrine Society clinical practice guideline, J Clin Endocrinol Metab
Fluoride 93:1526–1540, 2008.
Demeclocycline Swearingen B, Biller B: Diagnosis and management of pituitary disorders, New
Colchicine York, 2008, Humana Press.

  INTRODUCTION
The thyroid gland secretes thyroxine (T4) and triiodothyronine
(T3), both of which modulate energy utilization and heat produc-
tion and facilitate growth. The gland consists of two lateral lobes
joined by an isthmus (E-Fig. 63-1). The weight of the adult gland
is 10 to 20 g. Microscopically, the thyroid is composed of several
follicles that contain colloid surrounded by a single layer of
thyroid epithelium. The follicular cells synthesize thyroglobulin,
which is stored as colloid. Biosynthesis of T4 and T3 occurs by
iodination of tyrosine molecules in thyroglobulin.
  THYROID HORMONE PHYSIOLOGY
Thyroid Hormone Synthesis
Dietary iodine is essential for synthesis of thyroid hormones.
Iodine, after conversion to iodide in the stomach, is rapidly
absorbed from the gastrointestinal tract. After active transport
from the bloodstream across the follicular cell basement mem-
brane, iodide is enzymatically oxidized by thyroid peroxidase,
which also mediates the iodination of the tyrosine residues in
thyroglobulin, to form monoiodotyrosine and diiodotyrosine.
The iodotyrosine molecules couple to form T4 (3,5,3′,5′-
tetraiodothyronine) or T3 (3,5,3′-triiodothyronine). Once iodin-
ated, thyroglobulin containing newly formed T4 and T3 is stored
in the follicles. Secretion of free T4 and T3 into the circulation
occurs after proteolytic digestion of thyroglobulin, which is stim-
ulated by thyroid-stimulating hormone (TSH). Deiodination of
monoiodotyrosine and diiodotyrosine by iodotyrosine deiodin-
ase releases iodine, which then re-enters the thyroid iodine pool
(E-Fig. 63-2).
Thyroid Hormone Transport
T4 and T3 are tightly bound to the serum carrier proteins
thyroxine-binding globulin (TBG), thyroxine-binding prealbu-
min, and albumin. The unbound or free fractions are the biologi-
cally active fractions; they represent only 0.04% of the total T4
and 0.4% of the total T3.
Peripheral Metabolism of Thyroid Hormones
The normal thyroid gland secretes T4, T3, and reverse T3, a
biologically inactive form of T3. Most of the circulating T3 is
derived from deiodination of circulating T4 in the peripheral
tissues. Deiodination of T4 can occur at the outer ring
(5′-deiodination), producing T3 (3,5,3′-triiodothyronine), or at
the inner ring (5-deiodination), producing reverse T3 (3,3,5′-
triiodothyronine).
63 
Thyroid Gland
Theodore C. Friedman
Control of Thyroid Function
Hypothalamic thyrotropin-releasing hormone (TRH) is trans-
ported through the hypothalamic-hypophyseal portal system
to the thyrotrophs of the anterior pituitary gland, stimulating
synthesis and release of TSH (Fig. 63-1). TSH, in turn,
increases thyroidal iodide uptake and iodination of thyro-
globulin, releases T3 and T4 from the thyroid gland by increas-
ing hydrolysis of thyroglobulin, and stimulates thyroid cell
growth. Hypersecretion of TSH results in thyroid enlargement
(goiter). Circulating T3 exerts negative feedback inhibition of
TRH and TSH release.
Physiologic Effects of Thyroid Hormones
Thyroid hormones increase the basal metabolic rate by increasing
oxygen consumption and heat production in several body tissues.
Thyroid hormones also have specific effects on several organ
systems (Table 63-1). These effects are exaggerated in hyperthy-
roidism and lacking in hypothyroidism, accounting for the well-
recognized signs and symptoms of these two disorders.
  THYROID EVALUATION
A careful thyroid examination is essential in evaluating a patient
with thyroid disease (Video 63-1). Thyroid gland function and
structure can be evaluated by (1) determining serum thyroid
hormone levels, (2) imaging thyroid gland size and architecture,
(3) measuring thyroid autoantibodies, and (4) performing a
thyroid gland biopsy by fine-needle aspiration (FNA).
HYPOTHALAMUS
–
TRH
+
PITUITARY BLOODSTREAM
–
TSH
+
T3
THYROID
T3
T4
TISSUES
T4
FIGURE 63-1  Hypothalamic-pituitary-thyroid axis. T4 is converted
to T3 in peripheral tissues. T3, Triiodothyronine; T4, thyroxine; TRH,
thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
633
 Chapter 63  Thyroid Gland 633.e1

Thyroid cartilage

Cricothyroid ligament

Common carotid artery

Medial margin of
sternocleidomastoid muscle

Cricothyroid muscle

Cricoid cartilage

Thyroid gland

Cupula (dome) of pleura

Trachea

E-FIGURE 63-1  Frontal view of the neck with chin raised shows typical location of the thyroid gland in relation to the larynx and trachea. (From
www.netterimages.com.)

Na+
K+

NIS Cl–
Pendrin I
I– I–
Na+ H2O2
Peroxidase
E-FIGURE 63-2  Thyroid cellular mechanisms for
Deiodination

Tg
e

+ Iodination
Tyrosin

iodine transport, thyroxine and triiodothyronine for-

mation, and thyroxine and triiodothyronine release Tg and
Peroxidase coupling
into the blood. Thyroglobulin is a precursor for the
thyroid hormones. DIT, Diiodotyrosine; ER, endoplas- ER Golgi
mic reticulum; MIT, monoiodotyrosine; NIS, sodium/
iodide symporter; RT3, reverse triiodothyronine; T3, MIT, DIT MIT
triiodothyronine; T4, thyroxine; Tg, thyroglobulin. DIT
Tg T3
(From Hall JE: Thyroid metabolic hormones. In Hall JE, RT3 Secretion T3
editor: Guyton and Hall textbook of medical physiol- T3 T4 RT3
Pinocytosis T4
T4 Proteases Colloid
ogy, ed 12, Philadelphia, 2011, Saunders, Figure
76-2.) droplet
634 Section X  Endocrine Disease and Metabolic Disease
TABLE 63-1  PHYSIOLOGIC EFFECTS OF THYROID
HORMONE
SYSTEM EFFECTS
Cardiovascular Increased heart rate and cardiac output
Gastrointestinal Increased gut motility
Skeletal Increased bone turnover and resorption
Pulmonary Maintenance of normal hypoxic and hypercapnic
drive in the respiratory center
Neuromuscular Increased muscle protein turnover and increased
speed of muscle contraction and relaxation
Metabolism of lipids Increased hepatic gluconeogenesis and
and carbohydrates glycogenolysis, as well as intestinal glucose
absorption
Increased cholesterol synthesis and degradation
Increased lipolysis
Sympathetic nervous Increased numbers of β-adrenergic receptors in
system the heart, skeletal muscle, lymphocytes, and
adipose cells
Decreased cardiac α-adrenergic receptors
Increased catecholamine sensitivity
Hematopoietic Increased red blood cell 2,3-diphosphoglycerate,
facilitating oxygen dissociation from hemoglobin
with increased oxygen available to tissues
Tests of Serum Thyroid Hormone Levels
Measurements of total serum T4 and total T3 indicate the total
amount of hormone bound to thyroid-binding proteins by radio-
immunoassay. Total T4 and T3 levels are elevated in hyperthy-
roidism and low in hypothyroidism. Increased production of
TBG (as with pregnancy or estrogen therapy) increases the total
T4 and T3 levels without actual hyperthyroidism. Similarly, total
T4 and T3 are low despite euthyroidism in conditions associated
with low levels of thyroid-binding proteins (e.g., congenital
decrease, protein-losing enteropathy, cirrhosis, nephrotic syn-
drome). Therefore, further tests to assess the free hormone levels,
which reflect biologic activity, must be performed. Free T4 and
free T3 levels can be measured directly or by dialysis or
ultrafiltration.
Serum TSH is measured by a third-generation immunometric
assay that accurately discriminates between normal TSH levels
and levels below the normal range. Thus, the TSH assay can diag-
nose clinical hyperthyroidism (elevated free T4 and free T3 and
suppressed TSH) and subclinical hyperthyroidism (normal free
T4 and free T3 and suppressed TSH). In hyperthyroidism, the
free T3 may be elevated in the presence of a normal free T4. In
primary (thyroidal) hypothyroidism, serum TSH is supranormal
because of diminished feedback inhibition. The TSH is usually
low but may be normal in secondary (pituitary) or tertiary
(hypothalamic) hypothyroidism.
Serum thyroglobulin measurements are useful in the
follow-up of patients with papillary or follicular carcinoma. After
thyroidectomy and iodine-131 (131I) ablation therapy, thyro-
globulin levels should be less than 0.5  µg/L while the patient
is on suppressive levothyroxine treatment. Levels in excess of
this value indicate the possibility of persistent or metastatic
disease.
Calcitonin is produced by the C cells of the thyroid and
has a minor role in calcium homeostasis. Calcitonin measure-
ments are invaluable in the diagnosis of medullary carcinoma
of the thyroid and for monitoring the effects of therapy for
this entity.
TABLE 63-2  HIGH-RISK FACTORS FOR MALIGNANCY
IN A THYROID NODULE
HISTORY
Head and neck irradiation
Exposure to nuclear radiation
Rapid growth
Recent onset
Young age
Male sex
Familial incidence (medullary and about 5% of papillary carcinomas)
PHYSICAL EXAMINATION
Hard consistency of nodule
Fixation of nodule
Lymphadenopathy
Vocal cord paralysis
Distant metastasis
LABORATORY AND IMAGING STUDIES
Elevated serum calcitonin
Cold nodule on technetium scan
Ultrasonography:
Presence of microcalcifications
Presence of nodule hypoechogenicity compared with the normal thyroid
parenchyma
Presence of increased nodular vascularity
Presence of irregular infiltrative margins
Nodule taller than wide on transverse view
Absent halo
Suspicious cervical lymphadenopathy
Partially cystic nodule
Spongiform appearance, defined as an aggregation of multiple microcystic
components in >50% of the nodule volume
Thyroid Imaging
Technetium-99m (99mTc) pertechnetate is concentrated in the
thyroid gland and can be scanned with a gamma camera, yielding
information about the size and shape of the gland and the loca-
tion of the functional activity in the gland (thyroid scan). The
thyroid scan is often performed in conjunction with a quantita-
tive assessment of radioactive iodine (123I) uptake by the thyroid.
Functioning thyroid nodules are called warm or hot nodules; cold
nodules are nonfunctioning. Malignancy is usually associated
with a cold nodule; 16% of surgically removed cold nodules are
malignant.
Thyroid ultrasound evaluation is useful in the differentia-
tion of solid nodules from cystic nodules. It also may be
used to guide the clinician during FNA of a nodule (E-Fig.
63-3), and ultrasound characteristics of thyroid nodules may
be helpful to distinguish those that are more likely to be
malignant (Table 63-2).
Thyroid Antibodies
Autoantibodies to several different antigenic components in the
thyroid gland, including thyroglobulin (TgAb), thyroid peroxi-
dase (TPO Ab, formerly called antimicrosomal antibodies), and
the TSH receptor, can be measured in the serum. A strongly posi-
tive test for TPO Ab indicates autoimmune thyroid disease.
Elevated TSH receptor antibody occurs in Graves’ disease (see
later discussion).
Thyroid Biopsy
FNA of a nodule to obtain thyroid cells for cytologic evaluation
is the best way to differentiate benign from malignant disease.
 Chapter 63  Thyroid Gland 634.e1

A B
E-FIGURE 63-3  Ultrasound images of thyroid nodules. A, Transverse image of left thyroid lobe shows a complete thin rim of calcification encircling
a thyroid nodule (eggshell calcification). B, Longitudinal image of a benign thyroid nodule in a different patient shows an incomplete, delicate thin
rim of calcification at the inferior pole of a nodule proven to represent a benign hemorrhagic cyst. (From Desser TS, Kamaya A: Ultrasound of thyroid
nodules, Neuroimaging Clin N A 18:463–478, 2008.)
 Chapter 63  Thyroid Gland 635

FNA requires adequate tissue samples and interpretation by an thyroid hormone secretion. Ophthalmopathy results from
experienced cytologist. inflammatory infiltration of the extraocular eye muscles by lym-
phocytes with mucopolysaccharide deposition. The inflamma-
  HYPERTHYROIDISM tory reaction that contributes to the eye signs in Graves’ disease
Thyrotoxicosis is the clinical syndrome that results from elevated may be caused by sensitization of lymphocytes to antigens that
levels of circulating thyroid hormones. Clinical manifestations of are common to the orbital muscles and the thyroid.
thyrotoxicosis result from the direct physiologic effects of the
thyroid hormones as well as the increased sensitivity to catechol- Clinical Presentation
amines. Tachycardia, tremor, stare, sweating, and lid lag are all The common manifestations of thyrotoxicosis (see Table 63-3)
caused by catecholamine hypersensitivity. are characteristic features of younger patients with Graves’
disease. In addition, patients may exhibit a diffuse goiter or the
Signs and Symptoms eye signs characteristic of Graves’ disease. Older patients often
Table 63-3 lists the signs and symptoms of hyperthyroidism. Thy- do not have the florid clinical features of thyrotoxicosis, and
rotoxic crisis, or thyroid storm, is a life-threatening complication the condition termed apathetic hyperthyroidism is exhibited as
of hyperthyroidism that can be precipitated by surgery, radioac- flat affect, emotional lability, weight loss, muscle weakness,
tive iodine therapy, or severe stress (e.g., uncontrolled diabetes
mellitus, myocardial infarction, acute infection). Patients develop
fever, flushing, sweating, significant tachycardia, atrial fibrillation, Clinical suspicion of hyperthyroidism
and cardiac failure. Significant agitation, restlessness, delirium,
and coma frequently occur. Gastrointestinal manifestations may Ultrasensitive TSH
include nausea, vomiting, and diarrhea. Hyperpyrexia out of pro-
portion to other clinical findings is the hallmark of thyroid storm. Normal
Low
Differential Diagnosis Free T4
Thyrotoxicosis usually reflects excess secretion of thyroid hor- Free T4
T3 RIA Normal Elevated
mones resulting from Graves’ disease, toxic adenoma, multinod-
ular goiter, or thyroiditis (Table 63-4 and Fig. 63-2). However, it
Hyper- Pituitary
may be the result of excessive ingestion of thyroid hormone or, thyroidism MRI
rarely, thyroid hormone production from an ectopic site (as in Elevated ruled out for TSH-
struma ovarii). secreting
Low or tumor
Hyperthyroidism normal
Graves’ Disease
Graves’ disease, the most common cause of thyrotoxicosis, is an Possible
Radioactive normal vs.
autoimmune disease that is more common in women, with a peak iodine uptake subclinical
incidence between 20 and 40 years of age. One or more of the and scan hyperthyroidism
following features are present: (1) goiter; (2) thyrotoxicosis; (3)
eye disease ranging from tearing to proptosis, extraocular muscle ↑Uptake
Observe
paralysis, and loss of sight as a result of optic nerve involvement; ↓Uptake
Graves’ disease
and (4) thyroid dermopathy, usually observed as significant skin Toxic adenoma
thickening without pitting in a pretibial distribution (pretibial MNG Thyroiditis
myxedema). Other cases of
thyrotoxicosis

Pathogenesis FIGURE 63-2  Algorithm for differential diagnosis of hyperthyroid-

Thyrotoxicosis in Graves’ disease is caused by overproduction of ism. MNG, Multinodular goiter; MRI, magnetic resonance imaging; RIA,
an antibody that binds to the TSH receptor. These thyroid- radioimmunoassay; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-
stimulating hormone.
stimulating immunoglobulins increase thyroid cell growth and

TABLE 63-4  CAUSES OF THYROTOXICOSIS

TABLE 63-3  SIGNS AND SYMPTOMS OF COMMON CAUSES Thyrotoxicosis factitia
HYPERTHYROIDISM Postpartum thyroiditis (probably
Graves’ disease
SYMPTOMS SIGNS Toxic adenoma (solitary) variant of silent thyroiditis)
Palpitations Tachycardia Toxic multinodular goiter RARE CAUSES
Nervousness Atrial fibrillation LESS COMMON CAUSES Struma ovarii
Shortness of breath Wide pulse pressure Metastatic thyroid carcinoma
Heat intolerance Brisk reflexes Subacute thyroiditis (de Quervain’s
or granulomatous thyroiditis) Hydatidiform mole
Fatigue and weakness Fine tremor
Hashimoto’s thyroiditis with TSH-secreting pituitary tumor
Increased appetite Proximal limb-girdle myopathy
Weight loss Chemosis (swelling of conjunctiva) transient hyperthyroid phase
Oligomenorrhea Thyroid bruit (Graves’ disease) TSH, Thyroid-stimulating hormone.
636 Section X  Endocrine Disease and Metabolic Disease
congestive heart failure, and atrial fibrillation resistant to stan-
dard therapy.
Eye signs associated with Graves disease may also occur as a
nonspecific manifestation of hyperthyroidism from any cause
(e.g., thyroid stare). In Graves’ disease, a specific inflammatory
infiltrate of the orbital tissues leads to periorbital edema, con-
junctival congestion and swelling, proptosis, extraocular muscle
weakness, or optic nerve damage with visual impairment
(E-Fig. 63-4).
Pretibial myxedema (thyroid dermopathy) (E-Fig. 63-5)
occurs in 2% to 3% of patients with Graves’ disease and results in
a thickening of the skin over the lower tibia without pitting. Ony-
cholysis, characterized by separation of the fingernails from their
beds, often occurs in patients with Graves’ disease. Thyroid acro-
pachy, or clubbing, may also occur.
Diagnosis
Elevated total or free T4 or T3 (or both) and a suppressed
TSH confirm the clinical diagnosis of thyrotoxicosis. Thyroid-
stimulating immunoglobulin is usually elevated, and its mea-
surement may be useful in patients with eye signs who do
not have other characteristic clinical features. Increased uptake
of 123I differentiates Graves’ disease from early subacute or
Hashimoto’s thyroiditis, in which uptake is low in the pres-
ence of hyperthyroidism. Magnetic resonance imaging or
ultrasonography of the orbit usually shows orbital muscle
enlargement, whether or not clinical signs of ophthalmopathy
are observed.
Treatment
Three treatment modalities are used to control the hyperthyroid-
ism of Graves’ disease: antithyroid drugs, radioactive iodine
therapy, and surgery.
Antithyroid Drugs
The thiocarbamide drugs propylthiouracil, methimazole, and
carbimazole block thyroid hormone synthesis by inhibiting
thyroid peroxidase. Propylthiouracil also partially inhibits
peripheral conversion of T4 to T3. Medical therapy is usually
administered for a prolonged period (1 to 3 years), with the dose
gradually reduced until spontaneous remission occurs. One
approach is to gradually decrease the dose while maintaining T4
and T3 in the normal range. After cessation of medication, 40%
to 60% of patients remain in remission. Those who experience
relapse can either resume therapy with thiocarbamide drugs or
undergo definitive surgery or radioactive iodine treatment. Side
effects of the thiocarbamide regimen include pruritus and rash
(in about 5% of patients), elevated liver function enzymes, cho-
lestatic jaundice, acute arthralgias, and, rarely, agranulocytosis
(<0.5% of patients).
Methimazole is less toxic to the liver than propylthiouracil and
has now become the preferred medical treatment for hyperthy-
roidism. Patients must be instructed to discontinue the medica-
tion and consult a physician if they develop fever or sore throat,
because those symptoms may indicate agranulocytosis. At the
onset of treatment during the acute phase of thyrotoxicosis,
β-adrenergic receptor blockers are used to help alleviate tachy-
cardia, hypertension, and atrial fibrillation. As the thyroid
hormone levels return to normal, the treatment with β-blockers
is tapered.
Radioactive Iodine
In terms of cost, efficacy, ease, and short-term side effects, radio-
active iodine has a better benefit profile than either surgery or
antithyroid drugs; however, 80% to 90% of patients become
hypothyroid after radiotherapy and require lifelong thyroid
hormone replacement. 131I is often the treatment of choice in
adults with Graves’ disease. It is contraindicated in women who
are pregnant, but it does not increase the risk of birth defects in
offspring conceived after 131I therapy. Patients with severe thyro-
toxicosis, very large glands, or underlying heart disease should be
rendered euthyroid with antithyroid medication before receiving
radioactive iodine, because 131I treatment can cause a release of
preformed thyroid hormone from the thyroid gland that could
precipitate cardiac arrhythmias and exacerbate symptoms of
thyrotoxicosis.
After administration of radioactive iodine, the thyroid gland
shrinks; patients become euthyroid and later hypothyroid over a
period of 6 weeks to 3 months. Serum free T4 and TSH levels
should be monitored, and replacement with levothyroxine should
be instituted when hypothyroidism occurs. Hypothyroidism
always occurs after surgical total thyroidectomy, frequently after
subtotal thyroidectomy or administration of radioactive iodine,
and in a smaller percentage of patients after antithyroid medica-
tion; therefore, lifelong monitoring of all patients with Graves’
disease is mandated.
Surgery
Either subtotal or total thyroidectomy is the treatment of choice
for patients with very large glands and obstructive symptoms,
those with multinodular glands, and sometimes in those who
desire pregnancy within the next year. It is essential that the
surgeon be experienced in thyroid surgery. Preoperatively,
patients receive 6 weeks of treatment with antithyroid drugs to
ensure that they are euthyroid at the time of surgery. Two weeks
before surgery, oral saturated solution of potassium iodide is
administered daily to decrease the vascularity of the gland. Per-
manent hypoparathyroidism and recurrent laryngeal nerve palsy
occur postoperatively in fewer than 2% of patients.
Graves’ orbitopathy can be treated with glucocorticoids,
orbital radiotherapy, or surgery. It was recently found that sele-
nium is effective for Graves’ orbitopathy.
Toxic Adenoma
Solitary toxic nodules, which are usually benign, occur more
frequently in older patients. The clinical manifestations are
those of thyrotoxicosis. Physical examination shows a distinct
solitary nodule. Laboratory investigation shows suppressed TSH
and significantly elevated T3 levels, often with only moderately
elevated T4. Thyroid scan shows a hot nodule in the affected
lobe with partial or complete suppression of the unaffected
lobe. Solitary toxic nodules are usually treated with radioactive
iodine. Euthyroidism results if the unaffected lobe has sup-
pressed uptake on a thyroid scan, and often hypothyroidism
occurs if the unaffected lobe does not have suppressed uptake.
For large nodules, unilateral lobectomy after the administration
 Chapter 63  Thyroid Gland 636.e1

B
E-FIGURE 63-4  Graves’ ophthalmopathy. A, A 59-year-old woman
with excess proptosis, moderate eyelid edema, and erythema with
moderate eyelid retraction affecting all four eyelids. Conjunctival che-
mosis (edema) and erythema with bilateral edema of the caruncles and
prolapse of the right caruncle are evident. B, A 40-year-old woman with
excess proptosis, minimal bilateral injection, and chemosis with slight
erythema of the eyelids. She also had evidence, on slit lamp examina-
tion, of moderate superior limbic keratoconjunctivitis. (From Bahn RS:
Graves’ ophthalmopathy, N Engl J Med 362:726–738, 2010.)
636.e2 Section X  Endocrine Disease and Metabolic Disease

A B

D E
E-FIGURE 63-5  Thyroid dermopathy (localized myxedema) in five patients. A, Nonpitting edema form in pretibial area. B, Plaque form in pretibial
area. C, Nodular form in ankle and foot. D, Elephantiasic form. E, Occurrence of thyroid dermopathy in scar tissue. (From Schwartz KM, Fatourechi V,
Ahmed DD, Pond GR: Dermopathy of Graves’ disease (pretibial myxedema): long-term outcome, J Clin Endocrinol Metab 87:438–446, 2002.)

of antithyroid drugs to render the patient euthyroid may be
required.
Toxic Multinodular Goiter
Toxic multinodular goiter occurs in older patients with long-
standing multinodular goiter, especially in patients from iodine-
deficient regions when they are exposed to increased dietary
iodine or receive iodine-containing radiocontrast dyes. The pre-
senting clinical features are frequently tachycardia, heart failure,
and arrhythmias. Physical examination shows a multinodular
goiter. The diagnosis is confirmed by laboratory features of sup-
pressed TSH, elevated T3 and T4, and a thyroid scan showing
multiple functioning nodules. The treatment of choice is often
131
I ablation. It is especially effective in patients with small glands
and a high degree of radioactive uptake. Larger glands may
require surgery.
Subclinical Hyperthyroidism
In subclinical hyperthyroidism, total or free T4 and T3 levels are
normal and TSH is suppressed. The causes of this condition
include early presentation of any form of hyperthyroidism (e.g.,
Graves’ disease, toxic adenoma, toxic multinodular goiter).
Because these patients, especially those who are older, are at an
increased risk for cardiac dysrhythmias, many patients with a
persistently suppressed TSH should be treated with thiocarba-
mide drugs or radioactive iodine. A decreased bone mineral
density is another indication for treatment.
Thyroiditis
Thyroiditis may be classified as acute, subacute, or chronic.
Although thyroiditis may eventually result in clinical hypothy-
roidism, the initial presentation is often that of hyperthyroidism
as a result of acute release of T4 and T3. Hyperthyroidism caused
by thyroiditis can be readily differentiated from other causes of
hyperthyroidism by suppressed uptake of radioactive iodine in
the thyroid gland, reflecting decreased hormone production by
damaged cells.
A rare disorder, acute suppurative thyroiditis, is caused by
infection, usually bacterial. Patients exhibits high fever, redness
of the overlying skin, and thyroid gland tenderness; the condi-
tion may be confused with subacute thyroiditis. If blood cultures
are negative, FNA should identify the organism. Intensive anti-
biotic treatment and, occasionally, incision and drainage are
required.
Subacute Thyroiditis
Subacute thyroiditis (also known as de Quervain’s thyroiditis
or granulomatous thyroiditis) is an acute inflammatory disorder
of the thyroid gland that probably is caused by a viral infec-
tion and resolves completely in 90% of cases. Patients with
subacute thyroiditis complain of fever and anterior neck pain.
The patient may have symptoms and signs of hyperthyroidism.
The classic feature on physical examination is an exquisitely
tender thyroid gland. Laboratory findings vary with the course
of the disease. Initially, the patient may be symptomatically
thyrotoxic with elevated serum T4, depressed serum TSH, and
low radioactive iodine uptake on the thyroid scan. Subsequently,
the thyroid status fluctuates through euthyroid and hypothyroid
Chapter 63  Thyroid Gland 637
phases and may return to euthyroidism. An increase in radioac-
tive iodine uptake on the scan reflects recovery of the gland.
Treatment usually includes high-dose aspirin or other nonste-
roidal anti-inflammatory drugs, but a short course of prednisone
may be required if pain and fever are severe. During the hypo-
thyroid phase, replacement therapy with levothyroxine may be
indicated.
Postpartum thyroiditis resembles subacute thyroiditis in its
clinical course. It usually occurs within the first 6 months after
delivery and goes through the triphasic course of hyperthyroid-
ism, hypothyroidism, and then euthyroidism, or it may develop
with only hypothyroidism. Some patients have underlying
chronic thyroiditis.
Chronic Thyroiditis
Chronic thyroiditis (Hashimoto’s or lymphocytic thyroiditis),
caused by destruction of the normal thyroidal architecture by
lymphocytic infiltration, results in hypothyroidism and goiter.
Riedel’s struma is probably a variant of Hashimoto’s thyroiditis;
it is characterized by extensive thyroid fibrosis resulting in a
rock-hard thyroid mass. Hashimoto’s thyroiditis is more common
in women and is the most common cause of goiter and
hypothyroidism in the United States. Occasionally, patients
with Hashimoto’s thyroiditis have transient hyperthyroidism
with low radioactive iodine uptake owing to the release of
T4 and T3 into the circulation. Chronic thyroiditis can be
differentiated from subacute thyroiditis in that, in the former,
the gland is nontender to palpation and antithyroid antibodies
are present in high titer. TPO Ab is usually present early and
typically remains present for years. Presence of TgAb does
not reflect Hashimoto’s thyroiditis and does not provide addi-
tional information beyond the TPO Ab finding. Serum T3
and T4 levels are either normal or low; when they are low,
the TSH is elevated. FNA of the thyroid shows lymphocytes
and Hürthle cells (enlarged basophilic follicular cells). Hypo-
thyroidism and significant glandular enlargement (goiter) are
indications for levothyroxine therapy. Adequate doses of levo-
thyroxine are administered to normalize TSH levels and shrink
the goiter.
Thyrotoxicosis Factitia
Patients with thyrotoxicosis factitia ingest excessive amounts of
thyroxine, often in an attempt to lose weight, and exhibit typical
features of thyrotoxicosis. Serum T3 and T4 levels are elevated
and TSH is suppressed, as is the serum thyroglobulin concentra-
tion. Radioactive iodine uptake is absent. Patients may require
psychotherapy.
Rare Causes of Thyrotoxicosis
Struma ovarii occurs when an ovarian teratoma contains thyroid
tissue that secretes thyroid hormone. A body scan confirms the
diagnosis by demonstrating uptake of radioactive iodine in the
pelvis.
Hydatidiform mole is caused by proliferation and swelling of
the trophoblast during pregnancy, with excess production of cho-
rionic gonadotropin, which has intrinsic TSH-like activity. The
hyperthyroidism remits with surgical and medical treatment of
the molar pregnancy.
638 Section X  Endocrine Disease and Metabolic Disease

water, causes the edema; this condition, termed myxedema, is

  HYPOTHYROIDISM responsible for the thickened features and puffy appearance of
Hypothyroidism is a clinical syndrome caused by deficiency of patients with severe hypothyroidism.
thyroid hormones. In infants and children, hypothyroidism Severe untreated hypothyroidism can result in myxedema
causes retardation of growth and development and may result in coma, which is characterized by hypothermia, extreme weakness,
permanent motor and mental retardation. Congenital causes of stupor, hypoventilation, hypoglycemia, and hyponatremia and is
hypothyroidism include agenesis (complete absence of thyroid often precipitated by cold exposure, infection, or psychoactive
tissue), dysgenesis (ectopic or lingual thyroid gland), hypoplastic drugs.
thyroid, thyroid dyshormogenesis, and congenital pituitary dis-
eases. Adult-onset hypothyroidism results in a slowing of meta- Diagnosis
bolic processes and is reversible with treatment. Hypothyroidism Laboratory abnormalities in patients with primary hypothyroid-
is usually primary (thyroid failure), but it may be secondary ism include elevated serum TSH and low total and free T4. A low
(hypothalamic or pituitary deficiency) or rarely the result of or low-normal morning serum TSH level in the setting of hypo-
resistance at the thyroid hormone receptor (Table 63-5). thalamic or pituitary dysfunction characterizes secondary hypo-
In adults, autoimmune thyroiditis (Hashimoto’s thyroiditis) is thyroidism. Often, the serum total and free T4 levels are at the
the most common cause of hypothyroidism. This condition may lower limits of normal.
be isolated, or it may be part of polyglandular failure syndrome Hypothyroidism is often associated with hypercholesterol-
type II (Schmidt’s syndrome), which also includes insulin- emia and elevated creatine phosphokinase skeletal muscle (MM)
dependent diabetes mellitus, adrenal insufficiency, pernicious fraction (the fraction representative of skeletal muscle). Anemia
anemia, vitiligo, gonadal failure, hypophysitis, celiac disease, is usually normocytic and normochromic but may be macrocytic
myasthenia gravis, and primary biliary cirrhosis. Iatrogenic (with vitamin B12 deficiency resulting from associated pernicious
causes of hypothyroidism include 131I therapy, thyroidectomy, anemia) or microcytic (caused by nutritional deficiencies or
and treatment with lithium or amiodarone. Iodine deficiency or menstrual blood loss in women). Because TPO Ab is usually
excess can also cause hypothyroidism. positive in Hashimoto’s thyroiditis, the major cause of hypothy-
roidism in adults, its measurement is helpful in deciding whether
Clinical Presentation levothyroxine treatment is appropriate in patients with subclini-
The clinical presentation of hypothyroidism (Table 63-6) cal hypothyroidism (discussed later).
depends on the age at onset and the severity of the thyroid defi-
ciency. Infants with congenital hypothyroidism (also called cre- Differential Diagnosis
tinism) may exhibit feeding problems, hypotonia, inactivity, an Because the initial manifestations of hypothyroidism are subtle,
open posterior fontanelle, and edematous face and hands. Mental early diagnosis demands a high index of suspicion in patients
retardation, short stature, and delayed puberty occur if treatment with one or more of the signs and symptoms (see Table
is delayed. 63-6). Early symptoms that are often overlooked include
Hypothyroidism in adults usually develops insidiously. menstrual irregularities (usually menorrhagia), arthralgias, and
Patients often complain of fatigue, lethargy, and gradual weight myalgias.
gain for years before the diagnosis is established. A delayed relax- Laboratory diagnosis may be complicated by the finding of a
ation phase of deep tendon reflexes (hung-up reflexes) is a valu- low total T4 level in euthyroid states associated with low TBG,
able clinical sign that is characteristic of severe hypothyroidism. such as nephrotic syndrome, cirrhosis, or TBG deficiency. TSH
Subcutaneous infiltration by mucopolysaccharides, which bind and free T4 levels are normal in these instances. A low total T4
level may also be found with nonthyroidal illness (euthyroid sick
syndrome), a condition occurring in acutely ill patients. In such
TABLE 63-5  CAUSES OF HYPOTHYROIDISM patients, total and occasionally free T4 levels are low’ the serum
PRIMARY HYPOTHYROIDISM Hypoplastic thyroid TSH level is usually normal but may be mildly elevated. This
Autoimmune Biosynthetic defects condition can be differentiated from primary hypothyroidism by
Hashimoto’s thyroiditis SECONDARY HYPOTHYROIDISM absence of a goiter, negative antithyroid antibodies, and elevated
Part of polyglandular failure Hypothalamic Dysfunction serum reverse T3 levels as well as by the clinical presentation.
syndrome, type II
Neoplasms
Iatrogenic Tuberculosis
131
I therapy Sarcoidosis TABLE 63-6  CLINICAL FEATURES OF
Langerhans cell histiocytosis
Thyroidectomy
Hemochromatosis HYPOTHYROIDISM
Drug-Induced Radiation treatment CHILDREN Weight gain
Learning disabilities Constipation
Iodine deficiency Pituitary Dysfunction
Mental retardation Menstrual irregularities
Iodine excess
Neoplasms Short stature Dry, coarse, cold skin
Lithium
Pituitary surgery Delayed bone age Periorbital and peripheral edema
Amiodarone
Postpartum pituitary necrosis Delayed reflexes
Antithyroid drugs Delayed puberty
Idiopathic hypopituitarism Bradycardia
Congenital Glucocorticoid excess (Cushing’s ADULTS Arthralgias, myalgias
Thyroid agenesis syndrome) Fatigue
Thyroid dysgenesis Radiation treatment to the pituitary Cold intolerance

The thyroid hormone levels return to normal with resolution of
the acute illness, and patients do not require levothyroxine
therapy.
Treatment
Hypothyroidism should be treated initially with synthetic levo-
thyroxine. Administration of levothyroxine results in physiologic
levels of bioavailable T3 and T4. Levothyroxine has a half-life of
8 days; consequently, it needs to be given only once a day. The
average replacement dose of levothyroxine for adults is 75 to
150 µg/day. In healthy adults, 1.6 µg/kg/day is an appropriate
starting dose. In some older patients and patients with cardiac
disease, levothyroxine should be increased gradually, starting at
25 µg/day and increasing the dose by 25 µg every 2 weeks;
however, most patients can safely be started on a full replacement
dose. The therapeutic response to levothyroxine therapy should
be monitored clinically and with measurement of serum TSH
levels 6 weeks after a dose adjustment. TSH levels between 0.5
and 2 mU/L are optimal. Because TSH measurements are not a
useful guide in patients with secondary hypothyroidism (pitu-
itary or hypothalamic dysfunction), these patients should be
given levothyroxine until their free T4 is in the mid-normal range.
Recent studies have suggested that a percentage of patients
treated with levothyroxine for hypothyroidism continue to have
hypothyroid symptoms despite normalization of TSH. Further-
more, a large study found that more than 20% of athyreotic
patients treated with levothyroxine replacement did not maintain
free T3 or free T4 values in the normal range despite normal TSH
levels. This reflects the inadequacy of peripheral deiodination to
compensate for the absent T3 secretion. Because of these studies,
there is renewed interest (accompanied by a large amount of
controversy) in treating hypothyroid patients who have not had
an adequate clinical response to levothyroxine replacement with
a combination of levothyroxine and liothyronine, or with desic-
cated thyroid preparations that contain levothyroxine and
liothyronine.
In patients with myxedema coma, 500 to 800 μg of levothy-
roxine is administered intravenously as a loading dose, followed
by 100 μg/day of levothyroxine, hydrocortisone (100 mg IV
intravenously three times daily), and intravenous fluids. Steroids
should be given before thyroxine in autoimmune conditions. The
underlying precipitating event should be corrected. Respiratory
assistance and treatment of hypothermia with warming blankets
may be required. Although myxedema coma carries a high mor-
tality rate despite appropriate treatment, many patients improve
in 1 to 3 days.
Subclinical Hypothyroidism
In subclinical hypothyroidism, T4 and T3 levels are normal or
low-normal, and TSH is mildly elevated. Some of these patients
develop overt hypothyroidism. The decision as to when to treat
patients who have a mildly elevated TSH level is controversial. It
is frequently recommended that patients should be treated with
levothyroxine if they have a TSH level greater than 5 mU/L on
two occasions and either positive anti–TPO Ab test results or a
goiter. If the patient does not have an appreciable goiter and has
negative anti–TPO Ab test results, many experts suggest that
levothyroxine should be given only if the TSH level is greater
Chapter 63  Thyroid Gland 639
than 10 mU/L on two occasions. Other experts suggest treat-
ment at lower TSH levels depending on the presence of TPO
antibody.
  GOITER
Enlargement of the thyroid gland is called a goiter. Patients with
goiters may be euthyroid (simple goiter), hyperthyroid (toxic
nodular goiter or Graves’ disease), or hypothyroid (nontoxic
goiter or Hashimoto’s thyroiditis). Thyroid enlargement (often
focal) may also be the result of a thyroid adenoma or carcinoma.
In nontoxic goiter, inadequate thyroid hormone synthesis leads
to TSH stimulation with resultant enlargement of the thyroid
gland. Iodine deficiency (endemic goiter) was once the most
common cause of nontoxic goiter. Since the widespread avail-
ability of iodized salt, endemic goiter is less common in North
America.
Goitrogens are agents that can cause a goiter, and iodine and
lithium are the two chemicals or drugs that frequently cause a
goiter. Natural goitrogens include thioglucosides found in vege-
tables such as cabbage, broccoli, brussel sprouts, turnips, cauli-
flower, kale, and other greens. Other foods that are goitrogens
include soybeans and soybean products, peanuts, spinach, sweet
potatoes, and fruits (e.g., strawberries, pears, and peaches).
Thyroid hormone biosynthetic defects can cause goiter associ-
ated with hypothyroidism (or, with adequate compensation,
euthyroidism).
A careful thyroid examination coupled with thyroid hormone
tests can reveal the cause of the goiter. A smooth, symmetrical
gland, often with a bruit, and hyperthyroidism are suggestive of
Graves’ disease. A nodular thyroid gland with hypothyroidism
and positive antithyroid antibodies is consistent with Hashimo-
to’s thyroiditis. A diffuse, smooth goiter with hypothyroidism and
negative antithyroid antibodies may be indicative of iodine defi-
ciency or a biosynthetic defect. Goiters can become very large,
extending substernally and causing dysphagia, respiratory dis-
tress, or hoarseness. An ultrasound evaluation or radioactive
iodine scan delineates the thyroid gland, and measurement of the
TSH level determines the functional activity of the goiter.
Hypothyroid goiters are treated with thyroid hormone at a
dose that normalizes TSH. Previously, euthyroid goiters were
treated with levothyroxine therapy; however, regression with
levothyroxine therapy is unlikely and is no longer recommended.
Surgery is indicated for nontoxic goiter only if obstructive symp-
toms develop or substantial substernal extension is present.
  SOLITARY THYROID NODULES
Thyroid nodules are common. They can be detected clinically in
about 4% of the population and are found in about 50% of
the population at autopsy. Benign thyroid nodules are usually
follicular adenomas, colloid nodules, benign cysts, or nodular
thyroiditis. Patients may have one prominent nodule on clinical
examination, but thyroid ultrasound evaluation may reveal mul-
tiple nodules. Although most nodules are benign, a small percent-
age are malignant. Fortunately, most thyroid cancers are low-grade
malignancies. History, physical examination, and laboratory tests
can be helpful in differentiating benign from malignant lesions
(see Table 63-2). For example, lymph node involvement or
hoarseness is strongly suggestive of a malignant tumor.
640 Section X  Endocrine Disease and Metabolic Disease
The major etiologic factor for thyroid cancer is childhood
or adolescent exposure to head and neck radiation. Previ-
ously, radiation was used to treat an enlarged thymus, tonsillar
disease, hemangioma, or acne. More recently, exposure to
radiation from nuclear plants (e.g., Chernobyl, Ukraine) con-
tributed to an increased incidence of thyroid cancer. Patients
with a history of irradiation should have a baseline thyroid
ultrasound study, and careful palpation of their thyroid every
1 to 2 years.
A dominant nodule (>1 to 1.5 cm) or nodules with ultrasound
features compatible with neoplasia should undergo FNA, which
is a safe procedure that has reduced the need for surgical excision.
An expert cytologist can identify most benign lesions (75% of all
biopsies). In addition, malignant lesions (5% of biopsies), such
as papillary, anaplastic, and medullary carcinomas, can be specifi-
cally identified. Follicular neoplasms, however, cannot be diag-
nosed as benign or malignant by FNA; a cytology report of
follicular neoplasia, along with “suspicious” cytology, requires
surgical excision. Molecular testing can now be performed on
FNA specimens to help determine whether follicular lesions have
molecular characteristics of malignancy and should be removed.
If the patient has a follicular lesion and a suppressed TSH level,
a thyroid scan should be performed, because hot nodules are
rarely malignant.
Although in the past benign thyroid nodules were treated with
levothyroxine suppression, this is no longer recommended
because it is uncommon for thyroid nodules to shrink substan-
tially with levothyroxine.
  THYROID CARCINOMA
The types and characteristics of thyroid carcinomas are presented
in Table 63-7. Papillary carcinoma is associated with local inva-
sion and lymph node spread. Indicators of poor prognosis include
thyroid capsule invasion, size greater than 2.5 cm, age at onset
older than 45 years, tall cell or Hürthle cell variant, and lymph
node involvement. Follicular carcinoma is slightly more aggres-
sive than papillary carcinoma and can spread by local invasion of
lymph nodes or hematogenously to bone, brain, or lung. Many
tumors show both papillary and follicular cell types. Patients may
exhibit metastases before diagnosis of the primary thyroid lesion.
Anaplastic carcinoma tends to occur in older individuals, is very
aggressive, and rapidly causes pain, dysphagia, and hoarseness.
Medullary thyroid carcinoma is derived from calcitonin-
producing parafollicular cells and is more malignant than papil-
lary or follicular carcinoma. It is multifocal and spreads both
locally and distally. It may be either sporadic or familial. When
TABLE 63-7  CHARACTERISTICS OF THYROID CANCERS
TYPE OF PERCENTAGE OF AGE AT
CANCER THYROID CANCERS ONSET (YR)
Papillary 80 40-80
Follicular 15 45-80
Medullary 3 20-50
Anaplastic 1 50-80
Lymphoma 1 25-70
familial, it is inherited in an autosomal dominant pattern and is
part of multiple endocrine neoplasia type IIA (medullary carci-
noma of the thyroid, pheochromocytoma, and hyperparathy-
roidism) or multiple endocrine neoplasia type IIB (medullary
carcinoma of the thyroid, mucosal neuromas, intestinal ganglio-
neuromas, marfanoid habitus, and pheochromocytoma). Ele-
vated basal serum calcitonin levels confirm the diagnosis.
Evaluation for RET proto-oncogene mutations should be per-
formed in patients with medullary carcinoma; if mutations are
present, all first-degree relatives should be examined.
Treatment
Lobectomy may be performed for isolated papillary microcarci-
noma. However, larger papillary tumors and most follicular
tumors require thyroidectomy with a central compartment
lymph node dissection, as well as a modified neck dissection if
evidence of lateral lymph node metastases is found. After surgery,
patients with low-risk, small carcinomas may be administered
doses of levothyroxine sufficient to keep the TSH level in the
low-normal or slightly suppressed range and monitored with
serum thyroglobulin determinations and neck ultrasound exami-
nations. Patients with large lesions and those at high risk for
persistence or metastatic disease should be treated with radioac-
tive iodine. Sufficient levothyroxine is then administered to sup-
press serum TSH to subnormal levels. Frequent clinical and
ultrasound neck examinations for masses should be accompanied
by measurement of serum thyroglobulin levels.
Thyroid cancer patients are considered to have no residual
disease if neck ultrasound imaging studies are negative and serum
thyroglobulin is suppressed after recombinant TSH stimulation.
Recurrence and metastases are also evaluated by 131I whole body
scans carried out under conditions of TSH stimulation, which
increase 131I uptake by the thyroid tissue. Elevated TSH levels can
be achieved by withdrawal of thyroxine supplementation for 6
weeks or by treatment with recombinant human TSH adminis-
tered while the patient maintains therapy with thyroid hormone
replacement. The latter avoids symptomatic hypothyroidism. A
rise in serum thyroglobulin levels suggests recurrence of thyroid
cancer. Local or metastatic lesions that take up 131I on whole body
scanning can be treated with radioactive iodine after the patient
has stopped thyroid hormone replacement, whereas those that
do not take up 131I can be treated with surgical excision or local
x-ray therapy. Conventional chemotherapy has limited efficacy in
the treatment of differentiated thyroid cancer, but newer biologic
agents targeting the molecular pathogenesis of these tumors
appear promising.
TREATMENT PROGNOSIS
Thyroidectomy, followed by radioactive Good
iodine ablation
Thyroidectomy, followed by radioactive Fair to good
iodine ablation
Thyroidectomy and central Fair
compartment lymph node dissection
Isthmusectomy followed by palliative Poor
x-ray treatment
X-ray therapy or chemotherapy or both Fair

Medullary carcinoma of the thyroid requires total thyroidec-
tomy with removal of the central lymph nodes in the neck. Com-
pleteness of the procedure and monitoring for recurrence are
determined by measurements of serum calcitonin.
Anaplastic carcinoma is treated with isthmusectomy to
confirm the diagnosis and to prevent tracheal compression, fol-
lowed by palliative x-ray treatment. Thyroid lymphomas are also
treated with x-ray therapy or chemotherapy or both.
The prognosis for well-differentiated thyroid carcinomas is
good. The patient’s age at the time of diagnosis and sex are the
most important prognostic factors. Men older than 40 years of
age and women older than 50 years of age have higher recurrence
and death rates than do younger patients. The 5-year survival rate
for invasive medullary carcinoma is 50%, whereas the mean sur-
vival time for anaplastic carcinoma is 6 months.
For a deeper discussion on this topic, please see Chapter
226, “Thyroid,” in Goldman-Cecil Medicine, 25th Edition.
Chapter 63  Thyroid Gland 641
SUGGESTED READINGS
Abraham P, Avenell A, McGeoch SC, et al: Antithyroid drug regimen for treating
Graves’ hyperthyroidism, Cochrane Database Syst Rev CD003420, 2010.
Alexander EK, Kennedy GC, Baloch ZW, et al: Preoperative diagnosis of benign
thyroid nodules with indeterminate cytology, N Engl J Med 367:705–715,
2012.
Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid
Association management guidelines for patients with thyroid nodules and
differentiated thyroid cancer, Thyroid 19:1167–1214, 2009.
Franklyn JA: The thyroid—too much and too little across the ages: the
consequences of subclinical thyroid dysfunction, Clin Endocrinol (Oxf) 78:
1–8, 2013.
Gharib H, Papini E, Paschke R, et al: American Association of Clinical
Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid
Association Medical guidelines for clinical practice for the diagnosis and
management of thyroid nodules: executive summary of recommendations,
Endocr Pract 16:468–475, 2010.
Gullo D, Latina A, Frasca F, et al: Levothyroxine monotherapy cannot guarantee
euthyroidism in all athyreotic patients, PLoS ONE 6:e22552, 2011.
Wiersinga WM: Do we need still more trials on T4 and T3 combination therapy
in hypothyroidism?, Eur J Endocrinol 161:955–959, 2009.
 64 
Adrenal Gland
Theodore C. Friedman

The synthesis of all steroid hormones begins with cholesterol

  PHYSIOLOGY
The adrenal glands (Fig. 64-1) lie at the superior pole of each
kidney and are composed of two distinct regions: the cortex and
the medulla. The adrenal cortex comprises three anatomic zones:
the outer zona glomerulosa, which secretes the mineralocorticoid
aldosterone; the intermediate zona fasciculata, which secretes
cortisol; and the inner zona reticularis, which secretes adrenal
androgens. The adrenal medulla, lying in the center of the adrenal
gland, is functionally related to the sympathetic nervous system
and secretes the catecholamines epinephrine and norepinephrine
in response to stress.
Adrenal Adrenal
medulla cortex
(center) (outer)
A B
Zona Glomerulosa–mineralocorticoids
Zona Fasciculata–glucocorticoids
Zona Reticularis–androgens
Cortex
C tors. The intracellular enzyme 11β-hydroxysteroid dehydroge-
D sium (K+) and hydrogen (H+) secretion by the renal tubules. The
FIGURE 64-1  A, Anatomic location of the adrenal glands. B, Distri-
bution of adrenal cortex and medulla. C, Zones of the adrenal cortex.
D, Magnetic resonance images of the abdomen showing the position
and relative size of the normal adrenal glands (arrows). (D, From
Nieman LK: Adrenal cortext. In Goldman L, Schafer AI, editors: Cecil-
Goldman medicine, ed 24, Philadelphia, 2012, Saunders, Figure
234-1.)
and is catalyzed by a series of regulated, enzyme-mediated reac-
tions (Fig. 64-2). Glucocorticoids affect metabolism, cardiovas-
cular function, behavior, and the inflammatory and immune
responses (Table 64-1). Cortisol, the natural human glucocorti-
coid, is secreted by the adrenal glands in response to adrenocor-
ticotropic hormone (ACTH), a 39-amino-acid neuropeptide
that is regulated by corticotropin-releasing hormone (CRH) and
vasopressin (AVP) produced in the hypothalamus (see Chapter
62). Glucocorticoids exert negative feedback on CRH and
ACTH secretion. The brain hypothalamic-pituitary-adrenal
(HPA) axis (Fig. 64-3) interacts with and influences the func-
tions of the reproductive, growth, and thyroid axes at many levels,
with major participation of glucocorticoids at all levels.
The renin-angiotensin-aldosterone system (Fig. 64-4) is the
major regulator of aldosterone secretion. Renal juxtaglomerular
cells secrete renin in response to a decrease in circulating volume
or a reduction in renal perfusion pressure or both. Renin is the
rate-limiting enzyme that cleaves the 60-kD angiotensinogen
molecule, synthesized by the liver, to produce the bioinactive
decapeptide angiotensin I. Angiotensin I is rapidly converted to
the octapeptide angiotensin II by angiotensin-converting enzyme
in the lungs and other tissues. Angiotensin II is a potent vasopres-
sor; it stimulates aldosterone production but does not stimulate
cortisol production. Angiotensin II is the predominant regulator
of aldosterone secretion, but plasma potassium concentration,
plasma volume, and ACTH level also influence aldosterone
secretion. ACTH also mediates the circadian rhythm of aldoste-
rone, and as a result, the plasma concentration of aldosterone is
highest in the morning. Aldosterone binds to the type I miner-
alocorticoid receptor. In contrast, cortisol binds to both the type
I mineralocorticoid receptor and type II glucocorticoid recep-
nase (11β-HSD) type II, which catabolizes cortisol to inactive
cortisone, limits the functional binding to the former receptor.
The availability of cortisol to bind to the glucocorticoid receptor
is modulated by 11β-HSD type I, which interconverts cortisol
and cortisone. Binding of aldosterone to the cytosol mineralo-
corticoid receptor leads to sodium (Na+) absorption and potas-
resultant increase in plasma Na+ and decrease in plasma K+
provide a feedback mechanism for suppressing renin and, subse-
quently, aldosterone secretion.
Adrenal androgen precursors include dehydroepiandros-
terone (DHEA) and its sulfate and androstenedione. These are
synthesized in the zona reticularis under the influence of ACTH
and other adrenal androgen-stimulating factors. Although they

642
 Chapter 64  Adrenal Gland 643

Cholesterol
1
2 3 4 5 6
Pregnenolone Progesterone 11-Deoxy- Corticosterone Aldosterone Mineralocorticoids
corticosterone
(DOC)
7 7
3 4 5
17-Hydroxy- 17-Hydroxy- 11-Deoxy- Cortisol Glucocorticoids
pregnenolone progesterone cortisol

7 7
3 9
Dehydroepian- ∆4-Androstene- Estrone Sex Steroids
drosterone (DHEA) dione

8 8
9
Testosterone Estradiol Sex Steroids

Enzyme Number Enzyme (Current and Trivial Name)

1 StAR; Steroidogenic acute regulatory protein
2 CYP11A1; Cholesterol side-chain cleavage enzyme/desmolase
3 3β-HSD II; 3β-Hydroxylase dehydrogenase
4 CYP21A2; 21α-Hydroxylase
5 CYP11B1; 11β-Hydroxylase
6 CYP11B2; Corticosterone methyloxidase
7 CYP17; 17α-Hydroxylase/17, 20 lyase
8 17β-HSD; 17β-Hydroxysteroid dehydrogenase
9 CYP19; Aromatase

FIGURE 64-2  Pathways of steroid biosynthesis.

have minimal intrinsic androgenic activity, they contribute to
androgenicity by their peripheral conversion to testosterone and
dihydrotestosterone. In men, excessive levels of adrenal andro-
gens have no clinical consequences, but in women they result in
acne, hirsutism, and virilization. Because of gonadal production
of androgens and estrogens and the secretion of norepinephrine
by sympathetic ganglia, deficiencies of adrenal androgens and
catecholamines are not clinically recognized.
  SYNDROMES OF ADRENOCORTICAL HYPOFUNCTION
Adrenal Insufficiency
Glucocorticoid insufficiency can be primary, resulting from
destruction or dysfunction of the adrenal cortex, or secondary,
resulting from ACTH hyposecretion (Table 64-2). Autoimmune
destruction of the adrenal glands (Addison’s disease) is the most
common cause of primary adrenal insufficiency in the industrial-
ized world, accounting for about 65% of cases. Usually, both glu-
cocorticoid and mineralocorticoid secretions are diminished in
this condition which, if left untreated, can be fatal. Isolated glu-
cocorticoid or mineralocorticoid deficiency may also occur, and
it is becoming apparent that mild adrenal insufficiency (similar
to subclinical hypothyroidism, discussed in Chapter 63) should
also be diagnosed and, in some cases, treated. Adrenal medulla
function is usually spared. About 70% of patients with Addison’s
disease have antiadrenal antibodies.
Tuberculosis used to be the most common cause of adrenal
insufficiency. However, its incidence in the industrialized world
has decreased since the 1960s, and it now accounts for only 15%
to 20% of patients with adrenal insufficiency; calcified adrenal
glands can be observed in 50% of these patients. Rare causes of
adrenal insufficiency are listed in Table 64-2. Many patients with
human immunodeficiency virus (HIV) infection have decreased
adrenal reserve without overt adrenal insufficiency.
Addison’s disease may be part of two distinct autoimmune
polyglandular syndromes. The triad of hypoparathyroidism,
adrenal insufficiency, and mucocutaneous candidiasis character-
izes type I polyglandular autoimmune syndrome, which usually
manifests in childhood. Other, less common manifestations
include hypothyroidism, gonadal failure, gastrointestinal malab-
sorption, insulin-dependent diabetes mellitus, alopecia areata
and totalis, pernicious anemia, vitiligo, chronic active hepatitis,
keratopathy, hypoplasia of dental enamel and nails, hypophysitis,
asplenism, and cholelithiasis. Type II polyglandular autoimmune
syndrome, also called Schmidt’s syndrome, is characterized by
Addison’s disease, autoimmune thyroid disease (Graves’ disease
or Hashimoto’s thyroiditis), and insulin-dependent diabetes mel-
litus. Other associated diseases include pernicious anemia, viti-
ligo, gonadal failure, hypophysitis, celiac disease, myasthenia
gravis, primary biliary cirrhosis, Sjögren’s syndrome, lupus ery-
thematosus, and Parkinson’s disease. This syndrome usually
develops in adults.
Common manifestations of adrenal insufficiency are anorexia,
weight loss, increasing fatigue, occasional vomiting, diarrhea, and
salt craving. Muscle and joint pain, abdominal pain, and postural
dizziness may also occur. Signs of increased pigmentation
644 Section X  Endocrine Disease and Metabolic Disease

Site Site
Catecholamines,
Liver Angiotensinogen (452 A.A.)
Brain cytokines, growth –
factors
Kidney Prorenin Renin

Angiotensin I (10 A.A.)

– CRH – Lung,
Hypothalamus AVP Angiotensin-converting
plasma
enzyme
Angiotensin II (8 A.A.)
Pituitary – ACTH
Adrenal, Angiotensin II receptor
vascular

Adrenal Cortisol Adrenal Aldosterone

FIGURE 64-3  Brain hypothalamic-pituitary-adrenal axis. Minus signs
indicate negative feedback. ACTH, Adrenocorticotropic hormone; AVP,
arginine vasopressin; CRH, corticotropin-releasing hormone.
TABLE 64-1  ACTIONS OF GLUCOCORTICOIDS
METABOLIC HOMEOSTASIS
Regulate blood glucose level (permissive effects on gluconeogenesis)
Increase glycogen synthesis
Raise insulin levels (permissive effects on lipolytic hormones)
Increase catabolism, decrease anabolism (except fat), inhibit growth
hormone axis
Inhibit reproductive axis
Stimulate mineralocorticoid receptor by cortisol
CONNECTIVE TISSUES
Cause loss of collagen and connective tissue
CALCIUM HOMEOSTASIS
Stimulate osteoclasts, inhibit osteoblasts
Reduce intestinal calcium absorption, stimulate parathyroid hormone
release, increase urinary calcium excretion, decrease reabsorption of
phosphate
CARDIOVASCULAR FUNCTION
Increase cardiac output
Increase vascular tone (permissive effects on pressor hormones)
Increase sodium retention
BEHAVIOR AND COGNITIVE FUNCTION
Daytime fatigue
Nocturnal hyperarousal
Decreased short-term memory
Decreased cognition
EUPHORIA OR DEPRESSION
IMMUNE SYSTEM
Increase intravascular leukocyte concentration
Decrease migration of inflammatory cells to sites of injury
Suppress immune system (thymolysis; suppression of cytokines, prostanoids,
kinins, serotonin, histamine, collagenase, and plasminogen activator)
(initially most significant on the extensor surfaces, palmar creases,
and buccal mucosa) often occur secondary to the increased pro-
duction of ACTH and other related peptides by the pituitary
gland (E-Fig. 64-1). Laboratory abnormalities may include hypo-
natremia, hyperkalemia, mild metabolic acidosis, azotemia,
hypercalcemia, anemia, lymphocytosis, and eosinophilia. Hypo-
glycemia may also occur, especially in children.
Acute adrenal insufficiency is a medical emergency, and treat-
ment should not be delayed pending laboratory results. In a criti-
cally ill patient with hypovolemia, a plasma sample for cortisol,
FIGURE 64-4  Renin-angiotensin-aldosterone axis. A.A., Amino acids.
ACTH, aldosterone, and renin should be obtained, and then
treatment with hydrocortisone (100 mg IV bolus) and parenteral
saline administration should be initiated. Sepsis-induced adrenal
insufficiency is recognized by a basal cortisol level lower than
10 µg/dL or a change in cortisol of less than 9 µg/dL after
administration of 0.25 mg ACTH (1-24) (cosyntropin). In
severe illness, albumin and cortisol-binding globulin (CBG) are
low, resulting in a low level of total cortisol but not free cortisol;
therefore, a low total cortisol level may not be diagnostic of
adrenal insufficiency in this setting.
In a patient with chronic symptoms suggestive of adrenal
insufficiency, a basal morning plasma cortisol measurement or a
1-hour cosyntropin test, or both, should be performed. In the
latter test, 0.25 mg of cosyntropin is given intravenously or intra-
muscularly, and plasma cortisol is measured after 0, 30, and 60
minutes. A normal response is a plasma cortisol concentration
higher than 20 µg/dL at any time during the test. A patient with
a basal morning plasma cortisol concentration lower than 5 µg/
dL and a stimulated cortisol concentration lower than 18 µg/dL
probably has adrenal insufficiency and should receive treatment.
A basal plasma morning cortisol concentration between 10 and
18 µg/dL in association with a stimulated cortisol concentration
lower than 18 µg/dL probably indicates impaired adrenal reserve
and a requirement for receiving cortisol replacement under stress
conditions (see later discussion).
Once the diagnosis of adrenal insufficiency is made, the dis-
tinction between primary and secondary adrenal insufficiency
needs to be established. Secondary adrenal insufficiency results
from inadequate stimulation of the adrenal cortex by ACTH (see
Chapter 62). Hyperpigmentation does not occur. In addition,
because mineralocorticoid levels are normal in secondary adrenal
insufficiency, symptoms of salt craving, as well as the laboratory
abnormalities of hyperkalemia and metabolic acidosis, are not
present, although hyponatremia may be observed. Hypothyroid-
ism, hypogonadism, and growth hormone deficiency may also be
present. To distinguish primary from secondary adrenal insuffi-
ciency, a basal morning plasma ACTH value should be obtained,
along with a standing (upright for at least 2 hours) serum aldo-
sterone level and a measurement of plasma renin activity (PRA).
A plasma ACTH value greater than 20 pg/mL (normal, 5 to
30 pg/mL) is consistent with primary adrenal insufficiency,
whereas a value lower than 20 pg/mL probably represents
 Chapter 64  Adrenal Gland 644.e1

B C

D E
E-FIGURE 64-1  Pigmentation in Addison’s disease. A, Hands of an 18-year-old woman with autoimmune polyendocrine syndrome and Addison’s
disease. Pigmentation in a patient with Addison’s disease before (B) and after (C) treatment with hydrocortisone and fluorocortisone. Notice the
additional presence of vitiligo. D, Similar changes are also seen in a 60-year-old man with tuberculous Addison’s disease before and after corticosteroid
therapy. E, Buccal pigmentation in the same patient as in D. (B and C, Courtesy Professor C.R.W. Edwards. From Larsen PR, Kronenberg HM, Melmed
S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2002, Saunders.)
 Chapter 64  Adrenal Gland 645

treatment, if feasible, results in less suppression of the HPA axis

TABLE 64-2  SYNDROMES OF ADRENOCORTICAL than does daily glucocorticoid therapy. Complete recovery of the
HYPOFUNCTION HPA axis can take 1 year or more, and the rate-limiting step
PRIMARY ADRENAL DISORDERS appears to be recovery of the CRH-producing neurons.
Combined Glucocorticoid and Mineralocorticoid Deficiency Under stress, cortisol secretion is increased. Therefore, the
Autoimmune concept of adrenal fatigue, proposed by some alternative provid-
  Isolated autoimmune disease (Addison’s disease) ers, has no biologic validity.
  Polyglandular autoimmune syndrome, type I
  Polyglandular autoimmune syndrome, type II After stabilization of acute adrenal insufficiency, patients with
Infectious Addison’s disease require lifelong replacement therapy with both
  Tuberculosis glucocorticoids and mineralocorticoids. Many patients are over-
  Fungal
  Cytomegalovirus treated with glucocorticoids and undertreated with mineralo-
  Human immunodeficiency virus corticoids. Because overtreatment with glucocorticoids results
Vascular in insidious weight gain and osteoporosis, the minimal cortisol
  Bilateral adrenal hemorrhage
  Sepsis dose that can be tolerated without symptoms of glucocorticoid
  Coagulopathy insufficiency (usually joint pain, abdominal pain, or diarrhea)
  Thrombosis, embolism is recommended. An initial regimen of 15 to 20  mg hydrocor-
  Adrenal infarction
Infiltration tisone first thing in the morning plus 5  mg hydrocortisone at
  Metastatic carcinoma and lymphoma about 3:00 pm mimics the physiologic dose and is recom-
  Sarcoidosis mended; a third dose is occasionally needed. Whereas gluco-
  Amyloidosis
  Hemochromatosis corticoid replacement is fairly uniform in most patients, the
Congenital requirement for mineralocorticoid replacement varies greatly.
  Congenital adrenal hyperplasia The initial dose of the synthetic mineralocorticoid fludrocorti-
  21-Hydroxylase deficiency
  3β-ol Dehydrogenase deficiency sone should be 100  µg/day (often in divided doses), and the
  20,22-Desmolase deficiency dosage should be adjusted to keep the standing PRA value
  Adrenal unresponsiveness to ACTH between 1 and 3  ng/mL/hour.
  Congenital adrenal hypoplasia
  Adrenoleukodystrophy Under the stress of a minor illness (e.g., nausea, vomiting, fever
  Adrenomyeloneuropathy >100.5° F), the hydrocortisone dose should be doubled for as
Iatrogenic short a period as possible. An inability to ingest hydrocortisone
  Bilateral adrenalectomy
  Drugs: metyrapone, aminoglutethimide, trilostane, ketoconazole, pills may necessitate parenteral hydrocortisone administration.
o,p′-DDD, mifepristone, pasireotide Patients undergoing a major stressful event (e.g., surgery neces-
Mineralocorticoid Deficiency without Glucocorticoid Deficiency sitating general anesthesia, major trauma) should receive 150 to
  Corticosterone methyl oxidase deficiency 300 mg parenteral hydrocortisone daily (in three divided doses)
  Isolated zona glomerulosa defect with a rapid taper to normal replacement during recovery. All
  Heparin therapy patients should wear a medical information bracelet and should
  Critical illness
  Angiogensin-converting enzyme inhibitors be instructed in the use of intramuscular emergency hydrocorti-
SECONDARY ADRENAL DISORDERS sone injections.
Secondary Adrenal Insufficiency
Hyporeninemic Hypoaldosteronism
Hypothalamic-pituitary dysfunction
Exogenous glucocorticoids Mineralocorticoid deficiency can result from decreased renin
After removal of an ACTH-secreting tumor secretion by the kidneys. Resultant hypoangiotensinemia leads
Hyporeninemic Hypoaldosteronism to hypoaldosteronism with hyperkalemia and hyperchloremic
Diabetic nephropathy metabolic acidosis. The plasma sodium concentration is usually
Tubulointerstitial diseases normal, but total plasma volume is often deficient. PRA and aldo-
Obstructive uropathy
Autonomic neuropathy
sterone levels are low and unresponsive to stimuli, including
Nonsteroidal anti-inflammatory drugs hypokalemia. Diabetes mellitus and chronic tubulointerstitial
β-Adrenergic drugs diseases of the kidney are the most common underlying condi-
ACTH, Adrenocorticotropic hormone; o,p′-DDD, o,p′-dichlorodiphenyldichloroethane tions leading to impairment of the juxtaglomerular apparatus. A
(mitotane). subset of hyporeninemic hypoaldosteronism is caused by auto-
nomic insufficiency and is a frequent cause of orthostatic hypo-
tension. Stimuli such as upright posture or volume depletion,
secondary adrenal insufficiency. An upright PRA value greater mediated by baroreceptors, do not cause a normal renin response.
than 3 ng/mL/hour in the setting of a suppressed aldosterone Administration of pharmacologic agents such as nonsteroidal
level is consistent with primary adrenal insufficiency, whereas a anti-inflammatory agents, angiotensin-converting enzyme inhib-
value lower than 3 ng/mL/hour probably represents secondary itors, and β-adrenergic antagonists can also produce conditions
adrenal insufficiency. The 1-hour cosyntropin test is suppressed of hypoaldosteronism. Salt administration often with fludrocor-
in both primary and secondary adrenal insufficiency. tisone and the α1-receptor agonist midodrine are effective in cor-
Secondary adrenal insufficiency occurs commonly after the recting the orthostatic hypotension and electrolyte abnormalities
discontinuation of glucocorticoids. Alternate-day glucocorticoid caused by hypoaldosteronism.
646 Section X  Endocrine Disease and Metabolic Disease
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH) refers to autosomal
recessive disorders of adrenal steroid biosynthesis that result
in glucocorticoid and mineralocorticoid deficiencies and com-
pensatory increase in ACTH secretion (see Fig. 64-2). Five
major types of CAH exist, and the clinical manifestations of
each type depend on which steroids are in excess and which
are deficient. 21α-Hydroxylase (CYP21) deficiency is the most
common of these disorders and accounts for about 95% of
patients with CAH. In this condition, there is a failure of
21-hydroxylation of 17-hydroxyprogesterone and progesterone
to 11-deoxycortisol and 11-deoxycorticosterone, respectively,
with deficient cortisol and aldosterone production. Cortisol
deficiency leads to increased ACTH release, resulting in adrenal
hyperplasia and overproduction of 17-hydroxyprogesterone
and progesterone. Increased ACTH production also leads to
increased biosynthesis of androstenedione and DHEA, which
can be converted to testosterone. Patients with 21-hydroxylase
deficiencies can be divided into two clinical phenotypes:
classic 21-hydroxylase deficiency, which usually is diagnosed
at birth or during childhood, and late-onset 21-hydroxylase
deficiency, which develops during or after puberty. Two thirds
of patients with classic 21-hydroxylase deficiency have various
degrees of mineralocorticoid deficiency (salt-losing form); the
remaining one third have the non–salt-losing type (simple
virilizing form). Both decreased aldosterone production and
increased concentrations of precursors that are mineralocor-
ticoid antagonists (progesterone and 17-hydroxyprogesterone)
contribute to salt loss.
Late-onset 21-hydroxylase deficiency represents an allelic
variant of classic 21-hydroxylase deficiency and is characterized
by a mild enzymatic defect. This deficiency is the most common
autosomal recessive disorder in humans and is present at high
frequency in Ashkenazi Jews. The syndrome usually develops at
the time of puberty with signs of virilization (hirsutism and acne)
and amenorrhea or oligomenorrhea. This diagnosis should be
considered in women who have unexplained hirsutism and men-
strual abnormalities or infertility.
The most useful initial measurement for the diagnosis of
classic 21-hydroxylase deficiency is that of plasma 17-
hydroxyprogesterone. A value greater than 200 ng/dL is consis-
tent with the diagnosis. The diagnosis of late-onset 21-hydroxylase
deficiency is based on the finding of an elevated level of plasma
17-hydroxyprogesterone (>1500 ng/dL) 30 minutes after
administration of 0.25 mg of synthetic ACTH (1-24).
The aim of treatment for classic 21-hydroxylase deficiency is
to replace glucocorticoids and mineralocorticoids, suppress
ACTH and androgen overproduction, and allow for normal
growth and sexual maturation in children. A proposed approach
to treating classic 21-hydroxylase deficiency recommends physi-
ologic replacement with hydrocortisone and fludrocortisone in
all affected patients. Virilizing effects can be prevented by the use
of an antiandrogen (flutamide) and an aromatase inhibitor (tes-
tolactone). Although the traditional treatment for late-onset
21-hydroxylase deficiency is dexamethasone (0.5 mg/day), the
use of an antiandrogen such as spironolactone (100 to 200 mg/
day) or flutamide (125 mg/day) is probably equally effective and
has fewer side effects. Mineralocorticoid replacement is not
needed in late-onset 21-hydroxylase deficiency.
11β-Hydroxylase (CYP11B1) deficiency accounts for about
5% of patients with CAH. In this syndrome, the conversions of
11-deoxycortisol to cortisol and 11-deoxycorticosterone to cor-
ticosterone (the precursor to aldosterone) are blocked. Affected
patients usually have hypertension and hypokalemia because of
increased amounts of precursors with mineralocorticoid activity.
Virilization occurs, as with 21-hydroxylase deficiency, and a late-
onset form manifesting as androgen excess also occurs. The diag-
nosis is made from the finding of elevated plasma 11-deoxycortisol
levels, either basally or after ACTH stimulation.
Rare forms of CAH are 3β-HSD type II deficiency,
17α-hydroxylase (CYP17) deficiency, and steroidogenic acute
regulatory protein (StAR) deficiency.
  SYNDROMES OF ADRENOCORTICAL HYPERFUNCTION
Hypersecretion of the glucocorticoid hormone cortisol results in
Cushing’s syndrome, a metabolic disorder that affects carbohy-
drate, protein, and lipid metabolism. Hypersecretion of miner-
alocorticoids such as aldosterone results in a syndrome of
hypertension and electrolyte disturbances.
Cushing’s Syndrome
Pathophysiology
Increased production of cortisol is seen in both physiologic and
pathologic states (Table 64-3). Physiologic hypercortisolism
occurs with stress, during the last trimester of pregnancy, and in
persons who regularly perform strenuous exercise. Pathologic
conditions of elevated cortisol levels include exogenous or
endogenous Cushing’s syndrome and several psychiatric states,
such as depression, alcoholism, anorexia nervosa, panic disorder,
and alcohol or narcotic withdrawal.
Cushing’s syndrome may be caused by exogenous administra-
tion of ACTH or glucocorticoid or by endogenous overproduc-
tion of these hormones. Endogenous Cushing’s syndrome is
either ACTH dependent or ACTH independent. ACTH depen-
dency accounts for 85% of patients and includes pituitary sources
of ACTH (Cushing’s disease) and ectopic sources of ACTH.
Pituitary Cushing’s disease accounts for 90% of patients with
ACTH-dependent Cushing’s syndrome. Ectopic secretion of
ACTH occurs most commonly in patients with small cell lung
carcinoma. These patients are older, usually have a history of
smoking, and primarily exhibit signs and symptoms of lung
cancer rather than those of Cushing’s syndrome. Patients with
the clinically apparent ectopic ACTH syndrome, in contrast,
have mostly intrathoracic (lung and thymic) carcinoids. ACTH-
independent causes account for 15% of patients with Cushing’s
syndrome and include adrenal adenomas, adrenal carcinomas,
micronodular adrenal disease, and autonomous macronodular
adrenal disease. The female-to-male ratio for noncancerous forms
of Cushing’s syndrome is 4 : 1.
Clinical Presentation
The clinical signs, symptoms, and common laboratory findings
of hypercortisolism observed in patients with Cushing’s syn-
drome are listed in Table 64-4 (see also Fig. 64-2). Patients with
 Chapter 64  Adrenal Gland 647

TABLE 64-3  SYNDROMES OF ADRENOCORTICAL TABLE 64-4  SIGNS, SYMPTOMS, AND

HYPERFUNCTION LABORATORY ABNORMALITIES  
STATES OF GLUCOCORTICOID STATES OF OF HYPERCORTISOLISM
EXCESS MINERALOCORTICOID EXCESS PERCENTAGE
Physiologic States Primary Aldosteronism FEATURE OF PATIENTS
Stress Aldosterone-secreting adenoma Fat redistribution (dorsocervical and supraclavicular 95
Strenuous exercise Bilateral adrenal hyperplasia fat pads, temporal wasting, centripetal obesity,
Last trimester of pregnancy Aldosterone-secreting carcinoma weight gain)
Glucocorticoid-suppressible Menstrual irregularities 80 (of affected
Pathologic States women)
hyperaldosteronism
Psychiatric conditions (pseudo- Thin skin and plethora 80
Cushing’s disorders) Adrenal Enzyme Deficiencies Moon facies 75
Depression 11β-Hydroxylase deficiency Increased appetite 75
Alcoholism 17α-Hydroxylase deficiency Sleep disturbances 75
Anorexia nervosa 11β-Hydroxysteroid dehydrogenase Nocturnal hyperarousal 75
Panic disorders type II deficiency Hypertension 75
Alcohol and drug withdrawal Hypercholesterolemia and hypertriglyceridemia 70
ACTH-dependent states Exogenous Mineralocorticoids Altered mentation (poor concentration, decreased 70
  Pituitary adenoma (Cushing’s Licorice memory, euphoria)
disease) Carbenoxolone Diabetes mellitus and glucose intolerance 65
  Ectopic ACTH syndrome Fludrocortisone Striae 65
  Bronchial carcinoid Hirsutism 65 (of affected
Secondary Hyperaldosteronism
  Thymic carcinoid women)
  Islet cell tumor Associated with hypertension Proximal muscle weakness 60
  Small cell lung carcinoma   Accelerated hypertension Psychological disturbances (emotional lability, 50
  Ectopic CRH secretion   Renovascular hypertension depression, mania, psychosis)
ACTH-independent states   Estrogen administration Decreased libido and erectile dysfunction 50 (of affected
  Adrenal adenoma   Renin-secreting tumors men)
  Adrenal carcinoma Without hypertension Acne 45
  Micronodular adrenal disease   Bartter’s syndrome Osteoporosis and pathologic fractures 40
  Sodium-wasting nephropathy Easy bruisability 40
Exogenous Sources
  Renal tubular acidosis Poor wound healing 40
Glucocorticoid intake   Diuretic and laxative abuse Virilization 20 (of affected
ACTH intake   Edematous states (cirrhosis, women)
nephrosis, congestive heart Edema 20
failure) Increased infections 10
Cataracts 5
ACTH, Adrenocorticotropin hormone; CRH, corticotropin-releasing hormone.

thrombocytosis, hypercholesterolemia, hypertriglyceridemia,

Cushing’s syndrome often have some, but not all, of the signs and
symptoms discussed here. Typically, the obesity is centripetal,
with a wasting of the arms and legs, which is distinct from the
generalized weight gain observed in idiopathic obesity. Rounding
of the face (called moon facies) and a dorsocervical fat pad (buffalo
hump) may occur in obesity not related to Cushing’s syndrome,
whereas facial plethora and supraclavicular filling are more spe-
cific for Cushing’s syndrome. Patients with Cushing’s syndrome
may have proximal muscle weakness; consequently, the inability
to stand up from a squat or to comb one’s hair can be revealing.
Sleep disturbances and insomnia, hyperarousal in the evening
and night, mood swings, and other psychological abnormalities
are frequently seen. Cognitive dysfunction and severe fatigue are
often present. Menstrual irregularities often precede other
cushingoid symptoms in affected women. Patients of both sexes
complain of a loss of libido, and affected men frequently com-
plain of erectile dysfunction. Adult-onset acne or hirsutism in
women could also suggest Cushing’s syndrome. The skin striae
observed in patients with Cushing’s syndrome are violaceous
(i.e., purple or dark red) with a width of at least 1 cm. Thinning
of the skin on the top of the hands is a specific sign in younger
adults with Cushing’s syndrome. Old pictures of patients are
extremely helpful for evaluating the progression of the physical
stigmata of Cushing’s syndrome.
Associated laboratory findings in Cushing’s syndrome include
elevated plasma alkaline phosphatase levels, granulocytosis,
and glucose intolerance and/or diabetes mellitus. Hypokalemia
or alkalosis usually occurs in patients with severe hypercorti-
solism as a result of the ectopic ACTH syndrome.
Diagnosis
If the history and physical examination findings are suggestive of
hypercortisolism, then the diagnosis of Cushing’s syndrome can
usually be established by collecting urine for 24 hours and mea-
suring the urinary free cortisol (UFC). This test is extremely
sensitive for diagnosis of Cushing’s syndrome because in 90% of
affected patients, the initial UFC level is greater than 50 µg/24
hours (Fig. 64-5).
The overnight dexamethasone suppression test has been
widely used as a screening tool to evaluate patients who may have
hypercortisolism. Dexamethasone, 1 mg, is given orally at 11:00
pm or midnight, and plasma cortisol is measured the following
morning at 8:00 am. A morning plasma cortisol level greater than
1.8 µg/dL suggests hypercortisolism. This test produces a signifi-
cant number of both false-positive and false-negative results, but
it is still recommended in the 2008 Endocrine Society consensus
guidelines.
Cortisol is normally secreted in a diurnal manner: The plasma
concentration is highest in the early morning (between 6:00 and
8:00 am) and lowest around midnight. Most patients with Cush-
ing’s syndrome have blunted diurnal variation. Nighttime plasma
cortisol values greater than 50% of the morning values are
648 Section X  Endocrine Disease and Metabolic Disease

Diagnosis History and physical examination

consistent with hypercortisolism

Urinary free cortisol (UFC)

Nighttime plasma or salivary cortisol
Dexamethasone suppression tests

UFC normal UFC elevated

Normal nighttime plasma Elevated nighttime
or salivary cortisol plasma or salivary cortisol
Failure to suppress
with dexamethasone

Confirm with additional UFC

Cushing’s syndrome
and/or salivary cortisol or
unlikely
nighttime plasma cortisol

Cushing’s syndrome likely;

proceed to differential
diagnosis

Measure plasma ACTH

Differential
diagnosis

ACTH suppressed ACTH normal or elevated

Mass seen on adrenal
CT or MRI

Cushing’s disease (pituitary

Adrenal tumor likely adenoma) or ectopic ACTH
syndrome

Unilateral
Adrenalectomy

"Dynamic" pituitary MRI

oCRH-stimulation test and/or
high-dose dexamethasone test and/or
bilateral inferior petrosal sinus
sampling (IPSS) with oCRH

Negative results Increase in cortisol/ACTH after oCRH

Suppression during the high-dose
dexamethasone test
Ectopic ACTH syndrome
Central-to-peripheral ACTH gradient after
oCRH administration in IPSS

If Tumor is Localized,
Surgical Removal of Tumor
Cushing’s disease

Transsphenoidal Surgery

FIGURE 64-5  Flowchart for evaluation of a patient with possible Cushing’s syndrome. ACTH, Adrenocorticotropic hormone; CT, computed tomog-
raphy; MRI, magnetic resonance imaging; oCRH, ovine corticotropin-releasing hormone.

considered to be consistent with Cushing’s syndrome. Because of
the difficulty of obtaining nighttime plasma cortisol levels, mea-
surement of late-night salivary cortisol has been developed to
assess hypercortisolism. This test appears to have a high degree
of sensitivity and specificity for diagnosis of Cushing’s syndrome.
Multiple measurements of UFC or salivary cortisol may be needed
either diagnose or exclude Cushing’s syndrome, especially in sub-
jects with suggestive signs and symptoms of hypercortisolism.
Differential Diagnosis
Once the diagnosis of Cushing’s syndrome is established, the
cause of the hypercortisolism needs to be ascertained by bio-
chemical studies that evaluate the feedback regulation of the
HPA axis; this can be accomplished by venous sampling and
imaging procedures. The initial approach is to measure basal
ACTH levels, which are normal or elevated in Cushing’s disease
and the ectopic ACTH syndrome but are suppressed in primary
adrenal Cushing’s syndrome. Patients with a suppressed ACTH
level can proceed to adrenal imaging studies. To distinguish
between Cushing’s disease and the ectopic ACTH syndrome, the
high-dose or 8-mg overnight dexamethasone suppression test,
the ovine CRH (oCRH) test, and bilateral simultaneous inferior
petrosal sinus sampling (IPSS) are used.
In the dexamethasone suppression test (Liddle test), 0.5 mg
of dexamethasone is given orally every 6 hours for 2 days (low
dose), followed by 2 mg of dexamethasone every 6 hours for
another 2 days (high dose). On the second day of high-dose
dexamethasone, the UFC level will be suppressed to less than
10% of the baseline collection value in patients with pituitary
adenomas but not in patients with the ectopic ACTH syndrome
or adrenal cortisol-secreting tumors. The Liddle test has some
methodologic drawbacks, and results should be interpreted cau-
tiously; other confirmatory tests should be performed before
surgery is recommended.
An overnight high-dose dexamethasone suppression test is
helpful in establishing the cause of Cushing’s syndrome. In this
test, a baseline cortisol level is measured at 8:00 am, and then
8 mg of dexamethasone is given orally at 11:00 pm. At 8:00 am
the following morning, a plasma cortisol measurement is
obtained. Suppression, which occurs in patients with pituitary
Cushing’s disease, is defined as a decrease in plasma cortisol to
less than 50% of the baseline level.
The oCRH test can also be used to establish the cause of Cush-
ing’s syndrome, but this test was not available in the United States
in 2014.
Bilateral IPSS is an accurate and safe procedure for distin-
guishing pituitary Cushing’s disease from the ectopic ACTH
syndrome. Venous blood from the anterior lobe of the pituitary
gland empties into the cavernous sinuses and then into the supe-
rior and inferior petrosal sinuses. Venous plasma samples for
ACTH determination are obtained from both inferior petrosal
sinuses, along with a simultaneous peripheral sample, both before
and after intravenous bolus administration of oCRH. Significant
gradients at baseline and after oCRH stimulation between petro-
sal sinus and peripheral samples suggest pituitary Cushing’s
disease. In baseline measurements, an ACTH concentration gra-
dient of 1.6 or more between a sample from either of the petrosal
sinuses and the peripheral sample is strongly suggestive of
Chapter 64  Adrenal Gland 649
pituitary Cushing’s disease, whereas patients with the ectopic
ACTH syndrome or adrenal adenomas have no ACTH gradient
between their petrosal and peripheral samples. After oCRH
administration, a central-to-peripheral gradient of more than 3.2
is consistent with pituitary Cushing’s disease. The use of oCRH
has enabled complete distinction of pituitary from nonpituitary
Cushing’s syndrome. An ACTH gradient ipsilateral to the side of
the tumor is found in 70% to 80% of pituitary Cushing’s disease
patients sampled. Although this procedure requires an radiolo-
gist who is experienced in IPSS, it is available at many tertiary
care facilities.
Magnetic resonance imaging (MRI) with gadolinium is the
preferred procedure for localizing a pituitary adenoma. In many
centers, a dynamic MRI is performed; the pituitary is visualized
as the gadolinium enters and leaves the gland. Because about 10%
of normal individuals are found to have a nonfunctioning pitu-
itary adenoma on pituitary MRI, pituitary imaging should not be
the sole criterion for the diagnosis of pituitary Cushing’s disease.
Treatment
The preferred treatment for all forms of Cushing’s syndrome is
appropriate surgery or, in some cases, radiation therapy (see
Chapter 62). A more appealing option for patients with Cush-
ing’s disease who remain hypercortisolemic after pituitary surgery
is bilateral adrenalectomy followed by lifelong glucocorticoid and
mineralocorticoid replacement therapy.
In patients with the ectopic ACTH syndrome, the goal is to
localize the tumor by appropriate scans so it can be removed
surgically. A unilateral adrenalectomy is the treatment of choice
in patients with a cortisol-secreting adrenal adenoma. Cortisol-
secreting adrenal carcinomas initially should also be managed
surgically; however, the prognosis is poor, with only 20% of
patients surviving more than 1 year after diagnosis.
Medical treatment for hypercortisolism may be needed to
prepare patients who are undergoing or have undergone pituitary
irradiation and are awaiting its effects before surgery as well as
those who are not surgical candidates or elect not to have surgery.
Ketoconazole, o,p′-DDD (mitotane), metyrapone, aminogluteth-
imide, mifepristone, and trilostane are the most commonly used
agents for adrenal blockade and can be used alone or in combina-
tion. The somatostatin analogue, pasireotide, which decreases
ACTH and may decrease tumor size, is a recently FDA-approved
drug for treating Cushing’s disease.
Primary Mineralocorticoid Excess
Pathophysiology
The causes of primary aldosteronism (see Table 64-3) are
aldosterone-producing adenoma (75%), bilateral adrenal hyper-
plasia (25%), adrenal carcinoma (1%), and glucocorticoid-
remediable hyperaldosteronism (<1%). Adrenal enzyme defects
(11β-HSD type II, 11β-hydroxylase, and 17α-hydroxylase defi-
ciencies) and apparent mineralocorticoid excess (from ingestion
of licorice or carbenoxolone, which inhibit 11β-HSD type II, or
from a congenital defect in this enzyme) are also states of func-
tional mineralocorticoid overactivity. Secondary aldosteronism
(see Table 64-3) results from an overactive renin-angiotensin
system.
650 Section X  Endocrine Disease and Metabolic Disease
Primary aldosteronism is usually recognized during evaluation
of hypertension or hypokalemia and represents a potentially
curable form of hypertension. Up to 5% of patients with hyper-
tension have primary aldosteronism. These patients are usually
between the ages of 30 and 50 years, and the female-to-male ratio
is 2 : 1.
Clinical Presentation
Hypertension, hypokalemia, and metabolic alkalosis are the
main clinical manifestations of hyperaldosteronism; most of the
presenting symptoms are related to hypokalemia. Symptoms in
patients with mild hypokalemia are fatigue, muscle weakness,
nocturia, lassitude, and headaches. If more severe hypokalemia
exists, polydipsia, polyuria, paresthesias, and even intermittent
paralysis and tetany can occur. Blood pressure can range from
minimally elevated to very high. A positive Trousseau or Chvostek
sign may occur as a result of metabolic alkalosis.
Diagnosis and Treatment
Initially, hypokalemia in the presence of hypertension must be
documented (Fig. 64-6). The patient must have adequate salt
intake and discontinue diuretics before potassium measurement.
A morning plasma aldosterone level (measured in ng/dL) and a
Hypertension
Measure plasma K+
Low
Suspect hyperaldosteronism
Plasma aldosterone/PRA
Aldosterone/plasma renin activity >
20 ng/dL
ng/mL/hr
and serum aldosterone > 15 ng/dL
Confirm with either oral sodium loading,
saline infusion, fludrocortisone suppression,
or captopril challenge
Adrenal imaging (CT or MRI)
Bilateral adenoma or Adrenal
bilateral hyperplasia adenoma
Confirm with adrenal venous sampling
Medical Treatment Unilateral
(Spironolactone or Adrenalectomy
Epleronone)
FIGURE 64-6  Flowchart for evaluation of a patient with probable
primary hyperaldosteronism. Plasma aldosterone is measured in ng/dL,
and plasma renin activity (PRA) is measured in ng/mL/hour. CT, Com-
puted tomography; MRI, magnetic resonance imaging.
PRA value (in ng/mL/hour) should be obtained. A ratio of
serum aldosterone to PRA greater than 20 with a serum aldoste-
rone level greater than 15 ng/dL suggests the diagnosis of
hyperaldosteronism. Confirmatory tests for hyperaldosteronism
should be performed, such as oral sodium loading, saline infu-
sion, fludrocortisone suppression, or captopril challenge.
Once the diagnosis of primary aldosteronism has been dem-
onstrated, it is important to distinguish between an aldosterone-
producing adenoma and bilateral hyperplasia, because the former
is treated with surgery and the latter is treated medically. A com-
puted tomography (CT) scan of the adrenal glands should be
performed to localize the tumor. The patient should undergo
unilateral adrenalectomy if a discrete adenoma is observed in one
adrenal gland and the contralateral gland is normal. Patients in
whom biochemical and localization study findings are consistent
with bilateral hyperplasia should be treated medically with a
potassium-sparing diuretic, usually eplerenone or spironolac-
tone. Hyperaldosteronism and hypertension secondary to activa-
tion of the renin-angiotensin system can occur in patients with
accelerated hypertension, in those with renovascular hyperten-
sion, in those receiving estrogen therapies, and, rarely, in patients
with renin-secreting tumors. Hyperaldosteronism without
hypertension occurs in patients with Bartter’s syndrome, sodium-
wasting nephropathy, or renal tubular acidosis, as well as those
who abuse diuretics or laxatives.
  ADRENAL MEDULLARY HYPERFUNCTION
The adrenal medulla synthesizes the catecholamines norepineph-
rine, epinephrine, and dopamine from the amino acid tyrosine.
Norepinephrine, the major catecholamine produced by the
adrenal medulla, has predominantly α-agonist actions, causing
vasoconstriction. Epinephrine acts primarily on the β-receptors,
having positive inotropic and chronotropic effects on the heart
and causing peripheral vasodilation and increasing plasma
glucose concentrations in response to hypoglycemia. The action
of circulating dopamine is unclear. Whereas norepinephrine is
synthesized in the central nervous system and sympathetic post-
ganglionic neurons, epinephrine is synthesized almost entirely in
the adrenal medulla. The adrenal medullary contribution to total
body norepinephrine secretion is relatively small. Hypofunction
of the adrenal medulla has little physiologic effect, whereas
hypersecretion of catecholamines produces the clinical syn-
drome of pheochromocytoma.
Pheochromocytoma
Pathophysiology
Although pheochromocytomas can occur in any sympathetic
ganglion in the body, more than 90% arise from the adrenal
medulla. Most extra-adrenal tumors occur in the mediastinum
or abdomen. Bilateral adrenal pheochromocytomas are present
in about 5% of the cases and may occur as part of familial
syndromes. Pheochromocytoma occurs as part of multiple endo-
crine neoplasia type IIA or IIB. The former (Sipple’s syndrome)
is marked by medullary carcinoma of the thyroid, hyperpara-
thyroidism, and pheochromocytoma; the latter is characterized
by medullary carcinoma of the thyroid, mucosal neuromas,
intestinal ganglioneuromas, marfanoid habitus, and pheochro-
mocytoma. Pheochromocytomas are also associated with

neurofibromatosis, cerebelloretinal hemangioblastosis (von
Hippel–Lindau disease), and tuberous sclerosis.
Clinical Presentation
Because most pheochromocytomas secrete norepinephrine as
the principal catecholamine, hypertension (often paroxysmal) is
the most common finding. Other symptoms include the triad of
headache, palpitations, and sweating as well as skin blanching,
diarrhea, anxiety, nausea, fatigue, weight loss, and abdominal and
chest pain. Emotional stress, exercise, anesthesia, abdominal
pressure, or intake of tyramine-containing foods may precipitate
these symptoms. Orthostatic hypotension can also occur. Wide
fluctuations in blood pressure are characteristic, and the hyper-
tension associated with pheochromocytoma usually does not
respond to standard antihypertensive medicines. Cardiac abnor-
malities, as well as idiosyncratic reactions to medications, may
also occur.
Diagnosis and Treatment
Although measurements of fractionated catecholamine and
metanephrine levels in the urine are often used as screening tests,
plasma free metanephrine and normetanephrine levels are the
best tests for confirming or excluding pheochromocytoma. A
plasma free metanephrine level greater than 0.61 nmol/L and a
plasma free normetanephrine level greater than 0.31 nmol/L are
consistent with the diagnosis of a pheochromocytoma. If these
levels are only mildly elevated, a clonidine suppression test can
be performed. In patients with pheochromocytoma, levels are
unchanged or increased. Once the diagnosis of pheochromocy-
toma is made, a CT scan of the adrenal glands should be per-
formed. Most intra-adrenal pheochromocytomas are readily
visible on this scan and enhance with contrast. If the CT scan is
negative, then extra-adrenal pheochromocytomas can often be
localized by iodine 131–labeled metaiodobenzylguanidine (131I-
MIBG), positron emission tomography, octreotide scan, or
abdominal MRI. Pheochromocytomas show high signal intensity
on T2-weighted images.
The treatment of pheochromocytoma is surgical if the lesion
can be localized. Patients should undergo preoperative
α-blockade with phenoxybenzamine 1 to 2 weeks before surgery.
β-Adrenergic antagonists should be used before or during
surgery. About 5% to 10% of pheochromocytomas are malignant.
131
I-MIBG or chemotherapy may be useful, but the prognosis
is poor. α-Methyl-p-tyrosine, an inhibitor of tyrosine hydroxy-
lase, the rate-limiting enzyme in catecholamine biosynthesis,
may be used to decrease catecholamine secretion from the tumor.
Incidental Adrenal Mass
Clinically inapparent adrenal masses may be discovered inadver-
tently in the course of diagnostic testing or treatment for other
clinical conditions not related to the signs and symptoms of
adrenal disease; they are commonly known as incidentalomas
(E-Fig. 64-2). Some of these tumors secrete a small amount of
Chapter 64  Adrenal Gland 651
excess cortisol, leading to a condition called subclinical Cushing’s
syndrome. A morning plasma ACTH level and an overnight 1-mg
dexamethasone test are recommended for patients with an
adrenal incidentaloma. Patients with hypertension should also
undergo measurement of serum potassium, plasma aldosterone
concentration, PRA, and urine or plasma free metanephrines.
Surgery should be considered for all patients with functional
adrenal cortical tumors that are hormonally active or larger than
4 cm. Tumors not associated with hormonal secretion that are
smaller than 4 cm can be monitored with repeated imaging and
hormonal assessment.
Primary Adrenal Cancer
Primary adrenal carcinomas are rare, with an incidence of 1
to 5 per 1 million persons. The female-to-male ratio is 2.5 : 1,
and the mean age at onset is 40 to 50 years. About 25% of
patients have symptoms, including abdominal pain, weight loss,
anorexia, and fever. Eighty percent of primary adrenal carci-
nomas are functional, with secretion of glucocorticoid alone
(45%) or glucocorticoid plus androgens (45%) being most
common.
At presentation, metastatic spread is evident in 75% of
cases. An incidentally discovered adrenal mass that is large is
more likely to be malignant. Resection is recommended for
tumors larger than 6  cm and often for those larger than 4  cm.
In patients who do not have a known cancer, most adrenal
masses that turn out to be malignant are primary adrenocorti-
cal carcinomas, whereas in patients with a known malignancy,
an adrenal mass is likely to be a metastasis in about 75% of
cases.
The treatment of adrenocortical carcinomas is surgery.
These cancers are usually resistant to radiation and chemo-
therapy, but the adrenolytic compound mitotane has been
shown to improve survival. Adrenocortical carcinomas carry
a poor prognosis, with overall 5-year survival rates of less
than 20%.
For a deeper discussion on this topic, please see Chapter
227, “Adrenal Cortex,” in Goldman-Cecil Medicine, 25th
Edition.
SUGGESTED READINGS
Annane D: Adrenal insufficiency in sepsis, Curr Pharm Des 14:1882–1886,
2008.
Neary N, Nieman L: Adrenal insufficiency: etiology, diagnosis and treatment,
Curr Opin Endocrinol Diabetes Obes 17:217–223, 2010.
Nieman LK, Biller BM, Findling JW, et al: The diagnosis of Cushing’s syndrome:
an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab
93:1526–1540, 2008.
Vassiliadi DA, Tsagarakis S: Endocrine incidentalomas: challenges imposed by
incidentally discovered lesions, Nat Rev Endocrinol 7:668–680, 2011.
Young WF Jr: Adrenal causes of hypertension: pheochromocytoma and primary
aldosteronism, Rev Endocr Metab Disord 8:309–320, 2007.
 Chapter 64  Adrenal Gland 651.e1

A B
E-FIGURE 64-2  A, Adrenal incidentaloma discovered in a woman undergoing investigation for abdominal pain. B, Incidentally discovered right
adrenal myelipoma. (From Larsen PR, Kronenberg HM, Melmed S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2002,
Saunders.)
 65 
Male Reproductive
Endocrinology
Glenn D. Braunstein

Biochemical evaluation of the hypothalamic-pituitary-Leydig

  INTRODUCTION axis is carried out by measurement of serum LH and testosterone
The testes are composed of Leydig (interstitial) cells, which concentrations, whereas a semen analysis and serum FSH deter-
secrete testosterone and estradiol, and the seminiferous tubules, mination provide an assessment of the hypothalamic-pituitary-
which produce sperm. They are regulated by the luteinizing seminiferous tubular axis. The ability of the pituitary to release
hormone (LH) and follicle-stimulating hormone (FSH), which gonadotropins can be tested dynamically through GnRH stimu-
are secreted by the anterior pituitary under the influence of the lation, and the ability of the testes to secrete testosterone can be
hypothalamic decapeptide gonadotropin-releasing hormone evaluated through injections of human chorionic gonadotropin
(GnRH) (Fig. 65-1). LH stimulates the Leydig cells to secrete (HCG), a glycoprotein hormone that has biologic activity similar
testosterone, which feeds back in a negative fashion at the level to that of LH.
of the pituitary and hypothalamus to inhibit further LH produc-
tion. FSH stimulates sperm production through interaction with   HYPOGONADISM
the Sertoli cells in the seminiferous tubules. Feedback inhibition Either testosterone deficiency or defective spermatogenesis con-
of FSH is through gonadal steroids, as well as through inhibin, a stitutes hypogonadism. Often both disorders coexist. The clinical
glycoprotein produced by Sertoli cells. manifestations of androgen deficiency depend on the time of
onset and the degree of deficiency. Testosterone is required for
development of the wolffian duct into the epididymis, vas defer-
– Hypothalamus ens, seminal vesicles, and ejaculatory ducts, as well as for viriliza-
tion of the external genitalia through the major intracellular
testosterone metabolite, dihydrotestosterone (DHT). Conse-
GnRH
quently, early prenatal androgen deficiency leads to the forma-
+
tion of ambiguous genitalia and to male pseudohermaphroditism.
– Pituitary gonadotrophs – Androgen deficiency occurring later during gestation may result
in micropenis or cryptorchidism, the unilateral or bilateral absence
of testes in the scrotum resulting from the failure of normal tes-
ticular descent.
During puberty, androgens are responsible for male sexual dif-
LH FSH Inhibin
Testosterone ferentiation, which includes growth of the scrotum, epididymis,
Testosterone
Estradiol vas deferens, seminal vesicles, prostate, penis, skeletal muscle,
Estradiol
and larynx. Additionally, androgens stimulate the growth of axil-
lary, pubic, facial, and body hair and increase sebaceous gland
activity. They are also responsible through conversion to estro-
gens for the growth and fusion of the epiphyseal cartilaginous
plates, clinically seen as the pubertal growth spurt. Prepubertal
androgen deficiency leads to poor muscle development,
+ Testicle + decreased strength and endurance, a high-pitched voice, sparse
Testosterone axillary and pubic hair, and the absence of facial and body hair.
+ The long bones of the lower extremities and arms may continue
Leydig cell Seminiferous to grow under the influence of growth hormone; this condition
tubule Sperm leads to eunuchoid proportions (i.e., arm span exceeding total
height by ≥5 cm) and greater growth of the lower extremities
FIGURE 65-1  Regulation of the hypothalamic-pituitary-testicular relative to total height. Postpubertal androgen deficiency may
axis. The plus (+) and minus (−) symbols indicate positive and negative result in a decrease in libido, impotence, low energy, fine wrin-
feedback, respectively. FSH, Follicle-stimulating hormone; GnRH, kling around the corners of the eyes and mouth, and diminished
gonadotropin-releasing hormone; LH, luteinizing hormone.
facial and body hair.

652
 Chapter 65  Male Reproductive Endocrinology 653
Male hypogonadism may be classified into three categories
according to the level of the defect (Table 65-1). Diseases directly
affecting the testes result in primary or hypergonadotropic hypogo-
nadism, which is characterized by oligospermia or azoospermia
and low testosterone levels but exhibits elevations of LH and
FSH because of a decrease in the negative feedback regulation on
the pituitary and hypothalamus by androgens, estrogens, and
inhibin. In contrast, hypogonadism from lesions in the hypo-
thalamus or pituitary gives rise to secondary or hypogonadotropic
hypogonadism; the low testosterone level or ineffective spermato-
genesis results from inadequate concentrations of the gonadotro-
pins. The third category of hypogonadism is the result of defects
in androgen action.
Hypothalamic-Pituitary Disorders
Panhypopituitarism occurs congenitally from structural defects or
from inadequate production or release of the hypothalamic-
releasing factors. The condition may also be acquired through
replacement by tumors, infarction from vascular insufficiency,
infiltrative disorders, autoimmune diseases, trauma, and
infections.
Kallmann syndrome is a form of hypogonadotropic hypogo-
nadism that is associated with problems in the ability to discrimi-
nate odors, either incompletely (hyposmia) or completely
(anosmia). This syndrome results from a defect in the migration
of the GnRH neurons from the olfactory placode into the hypo-
thalamus. Therefore, it represents a GnRH deficiency. Patients
remain prepubertal, with small, rubbery testes, and they develop
eunuchoidism (E-Fig. 65-1).
Hyperprolactinemia may result in hypogonadotropic hypogo-
nadism because prolactin elevation inhibits normal release of
GnRH, decreases the effectiveness of LH at the Leydig cell level,
and also inhibits some of the actions of testosterone at the level
of the target organ. Normalization of prolactin levels through
withdrawal of an offending drug, by surgical removal of the pitu-
itary adenoma, or with the use of dopamine agonists reverses this
form of hypogonadism.
TABLE 65-1  CLASSIFICATION OF MALE
HYPOGONADISM
HYPOTHALAMIC-PITUITARY DISORDERS (SECONDARY
HYPOGONADISM)
Panhypopituitarism
Isolated gonadotropin deficiency
Complex congenital syndromes
Hyperprolactinemia
Hypothalamic dysfunction
GONADAL DISORDERS (PRIMARY HYPOGONADISM)
Klinefelter’s syndrome and associated chromosomal defects
Myotonic dystrophy
Cryptorchidism
Bilateral anorchia
Seminiferous tubular failure
Adult Leydig cell failure
Androgen biosynthesis enzyme deficiency
DEFECTS IN ANDROGEN ACTION
Testicular feminization (complete androgen insensitivity)
Incomplete androgen insensitivity
5α-Reductase deficiency
Weight loss or systemic illness in male patients can cause
another form of secondary hypogonadism, hypothalamic dysfunc-
tion. Weight loss or illness induces a defect in the hypothalamic
release of GnRH and results in low levels of gonadotropin and
testosterone. This condition is commonly observed in patients
with cancer, AIDS, or chronic inflammatory processes.
Primary Gonadal Abnormalities
The most common congenital cause of primary testicular failure
is Klinefelter’s syndrome, which occurs in about 1 of every 600 live
male births and is usually caused by a maternal meiotic chromo-
somal nondisjunction that results in an XXY genotype. At
puberty, clinical findings include the following: a variable degree
of hypogonadism; gynecomastia; small, firm testes measuring
less than 2 cm in the longest axis (normal testes, 3.5 cm or
greater); azoospermia; eunuchoid skeletal proportions; and ele-
vations of FSH and LH (E-Fig. 65-2). Primary gonadal failure is
also found in patients with another congenital condition, myo-
tonic dystrophy, which is characterized by progressive weakness;
atrophy of the facial, neck, hand, and lower extremity muscles;
frontal baldness; and myotonia.
About 3% of full-term male infants have cryptorchidism, which
spontaneously corrects during the first year of life in most cases;
consequently, by 1 year of age, the incidence of this condition is
about 0.75%. When the testes are maintained in the intra-
abdominal position, the increased temperature leads to defective
spermatogenesis and oligospermia. Leydig cell function usually
remains normal, resulting in normal levels of adult testosterone.
Bilateral anorchia, also known as the vanishing testicle syn-
drome, is a rare condition in which the external genitalia are fully
formed, indicating that ample quantities of testosterone and DHT
were produced during early embryogenesis. However, the testicu-
lar tissue disappears before or shortly after birth, and the result
is an empty scrotum. This condition is differentiated from crypt-
orchidism by an HCG stimulation test. Patients with cryptorchi-
dism have an increase in serum testosterone level after an injection
of HCG, whereas patients with bilateral anorchia do not.
Acquired gonadal failure has numerous causes. The adult semi-
niferous tubules are susceptible to a variety of injuries, and semi-
niferous tubular failure is found after infections such as mumps,
gonococcal or lepromatous orchitis, irradiation, vascular injury,
trauma, alcohol ingestion, and use of chemotherapeutic drugs,
especially alkylating agents. The serum FSH concentration may
be normal or elevated, depending on the degree of damage to the
seminiferous tubules. The Leydig cell compartment may also be
damaged by these same conditions. In addition, some men expe-
rience a gradual decline in testicular function as they age, possibly
because of microvascular insufficiency. Patients with decreased
testosterone production may clinically exhibit lowered libido and
potency, emotional lability, fatigue, and vasomotor symptoms
such as hot flushes. The serum LH concentration is usually ele-
vated in this situation.
Defects in Androgen Action
When either testosterone or its metabolite, DHT, binds to the
androgen receptor in target cells, the receptor is activated and
binds DNA; the resulting stimulation of transcription, protein
synthesis, and cell growth collectively constitutes androgen
 Chapter 65  Male Reproductive Endocrinology 653.e1

E-FIGURE 65-1  A boy aged 15 years, 10 months, with isolated

gonadotropin deficiency and anosmia (Kallmann syndrome). He had
undescended testes, but after administration of 10,000 U of human
chorionic gonadotropin (HCG), the testes descended and were palpa-
ble in the scrotum. Height was 163.9 cm (−1.5 standard deviation); the
upper-to-lower body ratio was 0.86, which is eunuchoid. The phallus
measured 6.3 × 1.8 cm, and the testes were 1.2 × 0.8 cm. The concentra-
tion of plasma luteinizing hormone (FSH) was 1.2 ng/mL, and that  
of testosterone was 16 ng/mL. After administration of 100 µg of
LH-releasing hormone (LHRH), the plasma LH (LER-960) was 0.7 ng/mL,
and the FSH (LER-869) was 2.4 ng/mL. (From Styne DM, Grumbach MM:
Puberty in the male and female: its physiology and disorders. In Yen
SCC, Jaffee RB, editors: Reproductive endocrinology, ed 2, Philadelphia,
1986, Saunders, p. 313–384.)
653.e2 Section X  Endocrine Disease and Metabolic Disease

A C D
E-FIGURE 65-2  A, A 19-year-old phenotypic male with chromatin-positive seminiferous tubule dysgenesis (Klinefelter’s syndrome). The karyotype
was 47,XXY, gonadotropin levels were elevated, and testosterone levels were low-normal. Notice normal virilization with long legs and gynecomastia
(B). C, The testes were small and firm and measured 1.8 × 0.9 cm. Testicular biopsy revealed a severe degree of hyalinization of the seminiferous
tubules and clumping of Leydig cells. D, A 48-year-old male with 47,XXY Klinefelter’s syndrome with severe leg varicosities. (From Larsen PR, Kronen-
berg HM, Melred S, et al, editors: Williams textbook of endocrinology, ed 10, Philadelphia, 2002, Saunders.)
654 Section X  Endocrine Disease and Metabolic Disease

action. An absence of androgen receptors causes the syndrome
of testicular feminization, a form of male pseudohermaphroditism.
These genetic males have cryptorchid testes but appear to be
phenotypic females. Because androgens are inactive during
embryogenesis, the labial-scrotal folds fail to fuse, and a short
vagina results. The fallopian tubes, uterus, and upper portion of
the vagina are absent because the testes secrete müllerian duct
inhibitory factor during early fetal development. At puberty,
these patients have breast enlargement because the testes secrete
a small amount of estradiol and the peripheral tissues convert
testosterone and adrenal androgens to estrogens. Axillary and
pubic hair does not grow because androgen action is required for
their development. The serum testosterone concentrations are
elevated as a result of continuous stimulation by elevated concen-
trations of LH. LH is high because of the inability of the testos-
terone to act in a negative feedback fashion at the hypothalamus.
Patients may have incomplete forms of androgen insensitivity
caused by point mutations affecting the androgen receptor gene,
and clinically these patients show varying degrees of male
pseudohermaphroditism.
Patients who lack the 5α-reductase enzyme that is required
to convert testosterone to DHT are born with a bifid scrotum,
which reflects abnormal fusion of the labial-scrotal folds, and
hypospadias, in which the urethral opening is in the perineal area
or in the shaft of the penis. At puberty, androgen production is
sufficient to partially overcome the defect; the scrotum, phallus,
and muscle mass enlarge, and these patients appear to develop
into physiologically normal men.
Diagnosis
Figure 65-2 illustrates an algorithm for the laboratory evaluation
of hypogonadism in a phenotypic man. Serum concentrations of
LH, FSH, and testosterone should be obtained, and a semen
analysis should be performed. A low testosterone level with low
concentrations of gonadotropins indicates a hypothalamic-
pituitary abnormality, which needs to be evaluated with serum
prolactin determination and radiographic examination. Elevated
concentrations of gonadotropins with a normal or low testoster-
one level reflect a primary testicular abnormality. If no testes are
palpable in the scrotum and careful milking of the patient’s lower
abdomen does not bring retractile testes into the scrotum, an
HCG stimulation test should be performed. A rise in serum tes-
tosterone concentrations indicates the presence of functional
testicular tissue, and a diagnosis of cryptorchidism can be made.
Absence of a rise in testosterone suggests bilateral anorchia.
Small, firm testes in the scrotum are highly suggestive of

LH, FSH, testosterone (T), semen analysis

↓Sperm count ↓Sperm count ↓Sperm count

↓LH ↓FSH, ↓T ↑LH or FSH, ↓or NL T NL T & LH; NL or ↑FSH

Primary testicular Are sperm present?

Hypothalamic-pituitary
abnormality abnormality

Are testes present Yes No

Measure PRL; in scrotum?
MRI of hypothalamic-
pituitary region Seminal fluid
fructose

No Yes

Present Absent
HCG stimulation Size and consistency

Testicular Congenital
biopsy absence of
seminal
↑T No ↑T Small and Postpubertal vesicles and
firm size, NL or soft vas deferens
Abnormal
Cryptorchidism Anorchia
Probable Acquired
Klinefelter’s primary Spermatogenic
failure NL
syndrome hypogonadism

Perform Ductal
karyotype obstruction

FIGURE 65-2  Laboratory evaluation of hypogonadism. ↑, Elevated; ↓, decreased or low; FSH, follicle-stimulating hormone; HCG, human chorionic
gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging; NL, normal; PRL, prolactin.
 Chapter 65  Male Reproductive Endocrinology 655
Klinefelter’s syndrome; this diagnosis needs to be confirmed
with a chromosomal karyotype. Testes that are more than 3.5 cm
in longest diameter and that are either of normal consistency or
are soft indicate postpubertal acquired primary hypogonadism.
If the major abnormality is a deficient sperm count with or
without an elevation of FSH, differentiation between a ductal
problem and acquired primary hypogonadism must be made. If
spermatozoa are present, at least the ducts emanating from one
testicle are patent; this condition indicates an acquired testicular
defect. If the patient has no sperm in the ejaculate, a primary
testicular or ductal problem may be responsible. The seminal
vesicles secrete fructose into the seminal fluid. Therefore, the
presence of fructose in the ejaculate should be followed by a
testicular biopsy to determine whether the defect results from
spermatogenic failure or from an obstruction of the ducts leading
from the testes to the seminal vesicles. Absence of seminal fluid
fructose indicates a congenital absence of the seminal vesicles
and vas deferens.
Male Infertility
Infertility affects about 15% of couples, and male factors appear
to be responsible in about 40% of cases. Female factors account
for another 40%, and a couple factor is present in about 20% of
cases. In addition to the defects in spermatogenesis that occur in
patients with hypothalamic, pituitary, testicular, or androgen
action disorders, hyperthyroidism, hypothyroidism, adrenal
abnormalities, and systemic illnesses can result in defective sper-
matogenesis, as can microdeletions of genetic material on the Y
chromosome. Disorders of the vas deferens, seminal vesicles, and
prostate may also lead to infertility, as may diseases affecting the
bladder sphincter that result in retrograde ejaculation, in which the
sperm passes into the bladder rather than through the penis. Ana-
tomic defects of the penis (as observed in patients with hypospa-
dias), poor coital technique, and the presence of antisperm
antibodies in the male or female genital tract also are associated
with infertility.
Therapy for Hypogonadism and Infertility
Treatment of androgen deficiency in patients who have
hypothalamic-pituitary or primary testicular abnormalities is best
accomplished with exogenous testosterone administration—
either intramuscular injection of intermediate-acting testosterone
esters or transdermal testosterone patches or gel. Testosterone
therapy increases libido, potency, muscle mass, strength, athletic
endurance, and hair growth on the face and body. Side effects
include acne, fluid retention, erythrocytosis, benign prostate
hyperplasia, and, rarely, sleep apnea. This therapy is contraindi-
cated in patients with cancer of the prostate.
If fertility is desired, patients with hypothalamic abnormalities
may develop virilization and spermatogenesis with the use of
GnRH delivered in a pulsatile fashion subcutaneously by an
external pump. Direct stimulation of the testes in patients with
hypothalamic or pituitary abnormalities may be accomplished
with the use of exogenous gonadotropins, which increase testos-
terone and sperm production. If primary testicular failure is
present and the patient has oligospermia, an attempt can be made
to concentrate the sperm for intrauterine insemination or in vitro
fertilization. If the azoospermia is caused by ductal obstruction,
repair of the obstruction may be undertaken or aspiration of
sperm from the epididymis may be accomplished for in vitro
fertilization.
  GYNECOMASTIA
Gynecomastia refers to a benign enlargement of the male breast
that results from proliferation of the glandular component. This
common condition is found in as many as 70% of pubertal boys
and in about one third of adults 50 to 80 years old. Estrogens
stimulate and androgens inhibit breast glandular development;
gynecomastia results from an imbalance between estrogen and
androgen actions at the breast tissue level. This condition may
result from an absolute increase in free estrogens, a decrease in
endogenous free androgens, androgen insensitivity of the tissues,
or enhanced sensitivity of the breast tissue to estrogens. Table
65-2 lists the common conditions associated with gynecomastia.
Gynecomastia must be differentiated from fatty enlargement
of the breasts without glandular proliferation and from other dis-
orders of the breasts, especially breast carcinoma. Male breast
cancer usually manifests as a unilateral, eccentric, hard or firm
mass that is fixed to the underlying tissues. It may be associated
with skin dimpling or retraction or with crusting of the nipple or
nipple discharge. In contrast, gynecomastia occurs concentrically
around the nipple and is not fixed to the underlying structures.
Although physical examination is usually sufficient to differenti-
ate gynecomastia from breast carcinoma, mammography may be
required.
Painful and tender gynecomastia in a pubertal adolescent
should be monitored with periodic examinations because, in
most patients, pubertal gynecomastia disappears within 1 year.
Incidentally discovered, asymptomatic gynecomastia in an adult
requires a careful assessment for alcohol, drug, or medication
TABLE 65-2  CONDITIONS ASSOCIATED WITH
GYNECOMASTIA
PHYSIOLOGIC CONDITIONS
Neonatal
Pubertal
Involutional
PATHOLOGIC CONDITIONS
Neoplasms
  Testicular
  Adrenal
  Ectopic production of human chorionic gonadotropin
Primary gonadal failure
Secondary hypogonadism
Enzyme defects in testosterone production
Androgen insensitivity syndromes
Liver disease
Malnutrition with refeeding
Dialysis
Hyperthyroidism
Excessive extraglandular aromatase activity
Drugs
  Estrogens and estrogen agonists
  Gonadotropins
  Antiandrogens or inhibitors of androgen synthesis
  Cytotoxic agents
  Efavirenz
Alcohol
Human immunodeficiency virus infection
Idiopathic
656 Section X  Endocrine Disease and Metabolic Disease

Measure serum HCG, LH, T, E2

↑HCG ↑LH, ↓T ↓or normal LH, ↓T ↑LH, ↑T ↑E2, ↓or normal LH Normal

Testicular Primary Measure serum Measure T4, Testicular Idiopathic

ultrasonography hypogonadism prolactin TSH ultrasonography gynecomastia

Mass Normal Mass Normal

↑T4, ↓TSH Normal

Leydig or Adrenal CT
Testicular Extragonadal Elevated Normal Sertoli or MRI
germ cell germ cell tumor cell tumor
tumor or HCG-secreting
nontrophoblastic
neoplasm Hyperthyroidism Androgen
resistance
Mass Normal

Chest film
Abdominal CT Probable Secondary
prolactin- hypogonadism Adrenal Increased
secreting neoplasm extraglandular
pituitary aromatase
tumor activity

FIGURE 65-3  Diagnostic evaluation for causes of gynecomastia based on measurements of serum human chorionic gonadotropin (HCG), lutein-
izing hormone (LH), testosterone (T), and estradiol (E2). ↑, Increased; ↓, decreased; CT, computed tomography; MRI, magnetic resonance imaging; T4,
thyroxine; TSH, thyroid-stimulating hormone. (From Braunstein GD: Gynecomastia, N Engl J Med 328:490–495, 1993.)

use; liver, lung, or kidney dysfunction; and signs and symptoms
of hypogonadism or hyperthyroidism. If these conditions are not
present, only follow-up is required. In contrast, in an adult with
recent onset of progressive painful gynecomastia, thyroid, liver,
and renal function should be determined. If test results are
normal, serum concentrations of HCG, LH, testosterone, and
estradiol should be measured. Further evaluation should be
carried out according to the schema outlined in Figure 65-3.
Removal of the offending drug or correction of the underlying
condition causing the gynecomastia may result in regression of
the breast glandular tissue. If the gynecomastia persists, a trial of
antiestrogens (e.g., tamoxifen) may be given for 3 months to see
whether regression occurs. Gynecomastia that has been present
for longer than 1 year usually contains a fibrotic component that
does not respond to medications. In these cases, correction
usually requires surgical removal of the tissue.
For a deeper discussion on this topic, please see Chapter
236, “Reproductive Endocrinology and Infertility,” in
Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Bhasin S, Basaria S: Diagnosis and treatment of hypogonadism in men, Best Pract
Res Clin Endocrinol Metab 25:251–270, 2011.
Dickson G: Gynecomastia, Am Fam Physician 88:716–722, 2012.
Mathers MJ, Sperling H, Rubben H, et al: The undescended testis: diagnosis,
treatment and long-term consequences, Dtsch Arztebl Int 106:527–532, 2009.
Palermo GD, Neri QV, Monahan D, et al: Development and current applications
of assisted fertilization, Fertil Steril 97:248–260, 2012.
Shamlaul R, Ghanem H: Erectile dysfunction, Lancet 381:153–165, 2013.
Stahl PJ, Stember DS, Goldstein M: Contemporary management of male
infertility, Annu Rev Med 63:525–540, 2012.
Wikstrom AM, Dunkel L: Klinefelter syndrome, Best Pract Res Clin Endocrinol
Metab 25:239–250, 2011.

Diabetes Mellitus, Hypoglycemia
  DIABETES MELLITUS
Definition and Diagnostic Criteria
Diabetes mellitus is not a single disease but a group of disorders
that develop as a consequence of absolute or relative deficiency
of the hormone insulin. Inadequate actions of insulin in stimulat-
ing the uptake of glucose by body tissues and regulating the
metabolism of carbohydrate, fat, and protein result in hyperglyce-
mia. Other metabolic disturbances in addition to hyperglycemia
typically occur in uncontrolled diabetes, including altered lipo-
protein dynamics and elevated free fatty acid levels. These abnor-
malities contribute to the acute and chronic clinical consequences
of diabetes.
The criteria used to diagnose diabetes mellitus in nonpregnant
individuals are summarized in Table 66-1. The diagnosis can be
made on the basis of a fasting blood glucose level of 126 mg/dL
or higher, a random blood glucose concentration (i.e., deter-
mined at any time in association with meals or fasting) of
200 mg/dL or higher, or a 2-hour glucose level of 200 mg/dL or
higher as part of a 75-g oral glucose tolerance test. Alternatively,
diabetes can be diagnosed if the hemoglobin A1c (HbA1c) level is
6.5% or higher. HbA1c, a measure of the percentage of hemoglo-
bin in circulating erythrocytes that is glycosylated, correlates
with mean circulating glucose levels. HbA1c provides an index of
the average blood glucose level over the preceding 2 to 3 months.
Because HbA1c accumulates progressively throughout the life­
span of an erythrocyte, spurious values may occur in states of
altered erythrocyte turnover (e.g., with various anemias) or with
certain hemoglobinopathies that increase or decrease the suscep-
tibility of hemoglobin to glycosylation. In patients with marked
elevations in blood glucose or HbA1c and coincident symptoms
typical for hyperglycemia (e.g., polyuria and polydipsia), the
TABLE 66-1  CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS
MEASUREMENT NORMAL
Plasma glucose (mg/dL)
  Fasting* <100
  2-hr Postload‡ <140
  Random‖
Hemoglobin A1c (%) ≤5.6
Data from the American Diabetes Association clinical practice recommendations 2013, Diabetes Care 36(Suppl 1):S11–S66, 2013.
*Fasting: no caloric intake for ≥8 hr.
†
Impaired fasting glucose.
‡
Postload: Following a standardized 75-g oral glucose load or after a meal.
§
Impaired glucose tolerance.
‖
Random: any time of day, unrelated to meals.
66 
Robert J. Smith
diagnosis can be made based on a single test result. With less
marked glucose elevations in the absence of symptoms, the diag-
nosis should be confirmed by repeat testing on a separate day.
Patients who have mild elevations in plasma glucose levels that
do not reach the threshold for diagnosis of diabetes (e.g., HbA1c
levels between 5.7% and 6.4%) are at increased risk for progres-
sion to diabetes and therefore are considered to have prediabetes.
Prediabetes patients with fasting blood glucose levels between
100 and 125 mg/dL are more specifically labeled as having
impaired fasting glucose, and those with 2-hour postprandial
plasma glucose levels between 140 and 199 mg/dL (most reli-
ably measured after a standardized 75-g oral glucose load) have
impaired glucose tolerance (see Table 66-1). Although not all indi-
viduals with prediabetes will become diabetic, the mean progres-
sion rate to overt diabetes is approximately 6% per year. There
also is evidence from observational studies that the prediabetic
state is associated with an increased risk of cardiovascular disease.
Gestational diabetes mellitus (GDM) is a term applied to diabe-
tes first recognized during pregnancy. The most widely accepted
thresholds for diagnosis of GDM are a fasting plasma glucose
level of 92 mg/dL or higher at any gestational stage and values
on a 75-g oral glucose tolerance test at 24 to 28 weeks’ gestation
of 92 mg/dL or higher fasting, 180 mg/dL or higher at 1 hour,
or 153 mg/dL or higher at 2 hours after glucose loading (Table
66-2). Untreated diabetes in pregnancy is associated with
increased fetal malformations, problems in delivery, and possibly
more frequent diabetes complications in the mother.
Etiologic Classification
Once the diagnosis is made based on elevated blood glucose or
HbA1c values, it is important to establish the specific subtype of
diabetes based on a combination of clinical and molecular patho-
physiologic features Table 66-3.
PREDIABETES DIABETES MELLITUS
100-125† ≥126
140-199§ ≥200
≥200
5.7-6.4 ≥6.5
657
658 Section X  Endocrine Disease and Metabolic Disease

decarboxylase (GAD or GAD65) antibodies, and also by a clini-

TABLE 66-2  CRITERIA FOR THE DIAGNOSIS OF cal course demonstrating an ongoing need for insulin to control
GESTATIONAL DIABETES MELLITUS hyperglycemia. A fasting C-peptide level can be measured later
MEASUREMENT DIAGNOSTIC THRESHOLD (mg/dL) in the disease to confirm marked deficiency in insulin secretion.
Plasma glucose C-peptide is a fragment of the insulin precursor proinsulin, which
  Fasting* ≥92 is cleaved during the synthesis of insulin. It is secreted and circu-
After 75-g oral glucose load
  1 hr ≥180 lates in proportion to endogenous insulin production but is
  2 hr <153 absent from injected exogenous insulin preparations.
Data from the American Diabetes Association clinical practice recommendations 2013, Type 2 diabetes (T2DM) is a heterogeneous, clinically defined
Diabetes Care 36(Suppl 1):S11–S66, 2013. subtype that accounts for more than 90% of all diabetes in the
*Fasting: no caloric intake for ≥8 hr.
United States. It typically has a gradual onset with progression
over multiple years or even decades. There is often prolonged
preservation of at least partial insulin secretory capacity together
TABLE 66-3  ETIOLOGIC CLASSIFICATION OF with evidence of insulin resistance. Most patients have associated
DIABETES MELLITUS obesity (80% to 90%), although a subset of patients with a clini-
TYPE 1 DIABETES MELLITUS cal picture otherwise typical for T2DM are nonobese. T2DM
Immune-mediated (type 1a)
usually can be presumptively distinguished from T1DM by its
Idiopathic (type 1b) indolent course in the presence of risk factors such as obesity and
TYPE 2 DIABETES MELLITUS by the milder hyperglycemia and absence of ketoacidosis due to
OTHER SPECIFIC TYPES residual insulin secretion. If there is clinical suspicion of T1DM
Genetic defects of beta-cell function
based on earlier age at onset, degree of hyperglycemia, absence
  Maturity-onset diabetes of the young (MODY) and other disorders of obesity, or presence of ketoacidosis, an autoantibody panel
Genetic defects in insulin action (which should be negative) and a C-peptide level (which should
  Insulin receptor mutations and other disorders
Diseases of the exocrine pancreas
be positive) can be measured.
Endocrinopathies An expanding number of diabetes etiologies distinct from
  Cushing’s syndrome, acromegaly, and other disorders T1DM and T2DM are classified under a broad category des-
Drug- or chemical-induced
  Glucocorticoids most common
ignated other specific types. Although these forms of diabetes
Infections are uncommon (1% to 2% of all diabetes), it is important to
Uncommon forms of immune-mediated diabetes recognize them in clinical practice. They include a group of
  Insulin receptor–blocking antibodies and other disorders
Other genetic syndromes sometimes associated with diabetes
inherited, autosomal dominant disorders historically designated
maturity-onset diabetes of the young (MODY); many of these
GESTATIONAL DIABETES MELLITUS
patients have clinical features similar to those of T2DM but
Data from the American Diabetes Association clinical practice recommendations 2013,
Diabetes Care 36(Suppl 1):S67–S74, 2013.
onset typically before 25 years of age. Patients with MODY3
(hepatocyte nuclear factor-1alpha mutations) are particularly
sensitive to sulfonylureas, whereas those with MODY2 (gluco-
Type 1 diabetes (T1DM) is characterized by extensive destruc- kinase mutations) have mild, nonprogressive blood glucose
tion of the insulin-producing beta cells within the islets of Lang- elevations and often require no treatment except during preg-
erhans in the pancreas and dependence on insulin therapy for nancy. For this reason, patients with early-onset diabetes, lack
survival. In previous medical literature, the terms juvenile-onset of autoimmune markers, and family histories suggestive of
diabetes or insulin-dependent diabetes were used for T1DM. This autosomal dominant inheritance should be considered for
terminology is no longer used, because T1DM not uncommonly MODY gene sequencing.
has its onset in adulthood, and multiple other forms of diabetes Much less common genetic defects include mutations in
often require treatment with insulin. T1DM accounts for 5% to insulin receptors or various other genes involved in insulin
10% of all diabetes in the United States. In most patients, it action. Exocrine pancreatic disease from causes such as chronic
involves autoimmune mechanisms leading to beta cell destruc- pancreatitis or surgery results in loss of the glucagon-producing
tion (the type 1A form). Rare individuals have no markers for islet alpha-cells as well as the insulin-producing beta cells. These
autoimmunity and are classified as having type 1B (idiopathic) patients often exhibit greater sensitivity to insulin and more of
diabetes. Most patients with T1DM progress to marked insulin a propensity for hypoglycemia than T1DM patients because of
deficiency over a period of several weeks to months after initial the absent insulin counter-regulatory effects of glucagon. Endo-
presentation. A smaller number of individuals with evidence of crine disorders with excess production of hormones that coun-
beta cell autoimmunity but much slower disease progression teract insulin, such as growth hormone in acromegaly or
have a variant form of T1DM that is designated latent autoim- glucocorticoids in Cushing’s syndrome, are important to recog-
mune diabetes of adulthood (LADA). nize as causes of diabetes because removal of the source of
In patients with marked elevations in glucose and accompany- excess hormone can lead to resolution of the diabetic state.
ing ketoacidosis, particularly if they are young and nonobese, the Many drugs have been associated with diabetes, most notably
diagnosis of T1DM is highly probable. This can be confirmed by glucocorticoids.
measuring autoantibodies, often as a panel including insulin, anti- The category GDM includes any woman in whom diabetes is
IA2 (anti–tyrosine phosphatase), anti-insulin, and glutamic acid first recognized during pregnancy and usually represents T2DM.
 Chapter 66  Diabetes Mellitus, Hypoglycemia 659

phosphatases) are generated for the most part in response to

Type 1 Diabetes
Epidemiology and Pathology
The principal features of T1DM, contrasted with T2DM, are
summarized in Table 66-4. The peak incidence occurs between
the ages of 6 and 14 years, but onset in approximately half of
patients with T1DM occurs after the age of 20. The role of genetic
factors in T1DM risk is supported by an observed increased inci-
dence of T1DM among family members of affected patients:
approximately 5% in siblings, 6% in offspring of a diabetic father,
and 2% in offspring of a diabetic mother. On a background of
genetic risk factors, it is hypothesized that the immune destruc-
tion of beta cells is precipitated by environmental factors that still
are not well understood but may include microbial, chemical, or
dietary triggers (Fig. 66-1). The operation of a combination of
genetic and environmental factors is thought to explain the high
but not absolute concordance observed in monozygotic twins
(30% to 50%).
The prevalence of T1DM varies substantially in different pop-
ulations; for example, it is relatively high in northwestern Europe
and much lower in parts of Asia. The overall prevalence in the
United States is approximately 2.4 cases per 1000 population.
The frequent onset before age 20 makes T1DM one of the most
common chronic, serious childhood diseases. It is the most
common subtype of diabetes in childhood, accounting for
approximately 70% of all cases, with T2DM accounting for most
of the remainder. LADA, a variant form of autoimmune T1DM,
is characterized by onset in adulthood and a more prolonged
waxing and waning course than is typical for T1DM.
The onset of overt T1DM follows a preclinical phase of vari-
able duration (typically extending from months to years) during
which there is specific destruction of beta cells resulting pre-
dominantly from cell-mediated immune mechanisms (mononu-
clear cells; mainly CD8+ T lymphocytes). It is believed that the
autoantibodies (to islet cells, insulin, GAD, and tyrosine
exposure of beta cells and islets and are not themselves mediators
of the destructive process. Demonstration of one or more auto-
antibodies also represents the most sensitive and useful way to
establish preclinical disease in patients at risk (e.g., first-degree
relatives of patients with T1DM).
The complement of islets in a healthy individual normally
provides enough excess beta cell secretory capacity to maintain
blood glucose levels until 80% to 90% of beta cells have been
lost. In some patients, the subclinical loss of beta cells may
be unmasked, resulting in hyperglycemia during the course of
an intercurrent illness such as an incidental upper respiratory
tract infection. Hyperglycemia and even ketogenesis can result
from a lack of adequate insulin, decreased glucose excretion
due to hypovolemia, accelerated gluconeogenesis, increased
insulin resistance, and hepatic ketogenesis. After diagnosis and
institution of insulin and other therapy, stress-induced insulin
resistance resolves, and there may be some degree of recovery
of beta cell function. Some patients revert to a state in which
no insulin is required. This phenomenon, designated the hon-
eymoon period, lasts for several weeks to as long as 1 year.
Patients generally should continue insulin administration at
doses low enough to be tolerated during this interval, because
progressive beta cell function can be expected eventually to
result in recurrent hyperglycemia and, potentially, diabetic
ketoacidosis (DKA).
Screening for T1DM is not a part of standard medical care.
Screening for autoantibody determinations in individuals at risk
is not clinically useful.
Clinical Presentation
T1DM most often manifests clinically with symptoms resulting
from hyperglycemia and consequent osmotic diuresis. Patients
typically have a history extending over days to weeks of worsen-
ing polyuria, plus polydipsia (as a compensatory response to

TABLE 66-4  GENERAL COMPARISON OF THE TWO MOST COMMON TYPES OF DIABETES MELLITUS
Previous terminology
Age at onset
Genetic predisposition
Human leukocyte antigen
associations
Other associations
Precipitating and risk factors
Findings at diagnosis
Endogenous insulin levels
Insulin resistance
Prolonged fast
Stress, withdrawal of insulin
GAD, Glutamic acid decarboxylase; IA-2, IA-2β, insuloma-associated protein 2 and 2β (tyrosine phosphatases); IAA, insulin autoantibodies; ICA, islet cell antibody; ICA512, islet cell
autoantigen 512 (fragment of IA-2).
TYPE 1
Insulin-dependent diabetes mellitus, type I; juvenile-onset
diabetes
Usually <30 yr, particularly childhood and adolescence, but
any age
Moderate; environmental factors required for expression;
35-50% concordance in monozygotic twins; multiple
candidate genes proposed
Linkage to DQA and DQB, influenced by DRB3 and DRB4
(DR2 protective)
Autoimmune; Graves’ disease, Hashimoto’s thyroiditis,
vitiligo, Addison’s disease, pernicious anemia
Largely unknown; microbial, chemical, dietary, other
85-90% of patients have one and usually more
autoantibodies to ICA512, IA-2, IA-2β, GAD65, IAA
Low or absent
Only with hyperglycemia
Hyperglycemia, ketoacidosis
Ketoacidosis
TYPE 2
Non–insulin-dependent diabetes mellitus, type II;
adult-onset diabetes
Usually >40 yr, but increasingly at younger ages
Strong; 60-90% concordance in monozygotic twins; many
candidate genes proposed
None known
Heterogeneous group, ongoing subclassification based on
identification of specific pathogenic processes and genetic
defects
Age, obesity (central), sedentary lifestyle, previous gestational
diabetes
Possibly complications (microvascular and macrovascular)
caused by significant hyperglycemia in the preceding
asymptomatic period
Usually present (relative deficiency), early hyperinsulinemia
Mostly present
Euglycemia
Nonketotic hyperglycemia, occasionally ketoacidosis
660 Section X  Endocrine Disease and Metabolic Disease

Precipitating environmental insult

• Microbial, chemical, dietary
Genetic susceptibility
HLA-DQβ, -DR3/DR4 • Beta-cell antigen presentation
• T-cell activation (Th1/Th2), CD8+

Beta-cell mass/function/insulin reserve (%)

100% • Activated NK cells and macrophages
• Cytokines IL-1, TNF-α
• Insulitis/beta-cell destruction/Th1

Positive autoantibodies to
GAD65, ICA512, IA-2/IA-2β,
insulin (IAA)

Destruction and
regeneration of beta cells

Plasma glucose
5%-10%

0% Serum insulin

Time (yr) “Honeymoon” phase

Clinical diabetes
FIGURE 66-1  Natural history of type 1 diabetes mellitus. The honeymoon period with temporary improvement in beta-cell function occurs with
the initiation of insulin therapy at the time of clinical diagnosis. GAD, Glutamic acid decarboxylase; HLA, human leukocyte antigen; IA-2, IA-2β, tyrosine
phosphatases; ICA, islet cell antibody; ICA512, islet cell autoantigen 512 (fragment of IA-2); IL-1, interleukin-1; NK, natural killer; Th1, subset of CD4+
helper T cells responsible for cell-mediated immunity; Th2, subset of CD4+ helper T cells responsible for humoral immunity; TNF-α , tumor necrosis
factor-α.

hypovolemia and increased serum osmolality). The polyuria may
be evident as bed wetting or daytime incontinence in children
and as nocturia in adults. There typically also is weight loss, and
patients often describe low energy and lethargy. Approximately
25% of patients with T1DM have progressed to DKA by the time
of clinical presentation.
Treatment
The management of T1DM involves immediate treatment at the
outset to correct hyperglycemia, fluid deficits, and DKA, if
present, plus attention to possible precipitating or complicating
factors such as infection. The initial treatment of T1DM should
be coupled with education of patients and their family members
(appropriate to the patient’s age) concerning the needed skills to
manage insulin administration, blood glucose testing, nutrition,
and exercise. This often is best accomplished by a team involving
the physician, educators (typically specially trained nurses or
pharmacists), and a dietician. Medical advice, patient education,
and psychological support should be provided on an ongoing,
long-term, individualized basis. The primary goal of glucose man-
agement is to minimize the degree of hyperglycemia, and its
attendant risks of long-term complications of diabetes, while
avoiding the acute and chronic risks of hypoglycemia. Medical
care also should include attention to control of lipid levels, blood
pressure, and other factors that affect the risks of long-term dia-
betes complications. Routine assessments of foot care, peripheral
nerve function, retinal status, and renal function should be used
to detect incipient diabetes complications and enable early treat-
ment interventions. Other sources should be consulted for
information on specific issues related to T1DM management in
children and adolescents.
Blood Glucose Control
Patients with T1DM have an absolute requirement for exogenous
insulin. The Diabetes Control and Complications Trial (DCCT)
and other studies have established that improved glycemic
control in patients with T1DM decreases long-term microvascu-
lar complications (retinopathy, nephropathy, and neuropathy). A
follow-up study of the same patients (the Epidemiology of Dia-
betes Interventions and Complications [EDIC] study) further
demonstrated lower cardiovascular morbidity and mortality with
intensive insulin management. Based on these and other studies,
the most generally accepted target goal for HbA1c in T1DM is
7.0%. For patients who have difficulty sensing hypoglycemia or
who have other factors complicating blood glucose management
(e.g., renal failure), it is appropriate to set an individualized HbA1c
goal of 8.0% or even higher.
Many preparations of insulin are available. They differ in rapid-
ity of onset, degree of peaking of blood levels, and duration of
action after subcutaneous injection (Table 66-5). The different
kinetics of recombinant human insulin preparations derive from
their specific complexing with proteins and zinc. Additionally,
multiple analogues of human insulin are available that have rapid
or slow kinetics as a consequence of altered solubility at subcu-
taneous injection sites. Most insulin preparations are provided at
a concentration of 100 U/mL (U-100). Self-monitoring of blood
glucose (SMBG) by patients using glucose meters is critical to
the implementation of an effective insulin regimen. Ideally,
 Chapter 66  Diabetes Mellitus, Hypoglycemia 661

TABLE 66-5  TYPES OF INSULIN*

PREPRANDIAL
INSULIN TYPE GENERIC NAME INJECTION TIMING (HR) ONSET (HR) PEAK (HR) DURATION (HR) BG NADIR (HR)
Rapid-acting Lispro† 0-0.2 0.1-0.5 0.5-2 <5 2-4
Aspart‡ 0-0.2 0.1-0.3 0.6-3 3-5 1-3
Glulisine§ 0-0.25 (15 min before a 0.15-0.3 0.5-1.5 1-5.3 2-4
meal or within 20 min
after starting a meal)
Short-acting Regular 0.5-1 0.3-1 2-6 4-8 3-7
Intermediate-acting NPH 0.5-1 1-3 6-15 16-26 6-13
Long-acting Glargine‖** Once daily¶ or twice daily 1.1-4 Little or no 10.8->24 Before next dose
(approx 12 hourly) peak
Detemir** Once daily¶ or twice daily 1.1-4 Little or no 12-24 Before next dose
(approx 12 hourly) peak
HUMAN PREMIXED
NPH/regular 70/30 0.5-1 0.5-1 2-12 14-24 3-12
NPH/regular 50/50 0.5-1 0.5-1 2-5 14-24 3-12
INSULIN ANALOGUE PREMIXED
NPL/lispro 75/25 0.25 0.15-0.25 1 14-24 —
NPA/aspart 70/30 0.25 0.15-0.3 2-4 24 —
NPL/lispro 50/50 0.25 0.15-0.25 1 14-24 —
BG, Blood glucose; NPA, neutral protamine aspart; NPH, neutral protamine Hagedorn; NPL, neutral protamine lispro.
*Time profiles depend on several factors, including dose, anatomic site of injection, method (profiles in this table are for subcutaneous injections), duration of diabetes, type of diabetes,
degree of insulin resistance, level of physical activity, presence of obesity, and body temperature. Some time ranges are wide to include data from several separate studies. Preprandial
injection timing depends on premeal BG values and insulin type. If BG is low, it may be necessary to inject insulin and eat immediately (carbohydrate portion of meal first). If BG is high, it
may be necessary to delay the meal after insulin injection and the eat the carbohydrate portion last.
†
Insulin analogue with reversal of lysine and proline at positions 28 and 29 on the B chain of the insulin molecule.
‡
lnsulin analogue with substitution of aspartic acid for proline at position 28 on the B chain of the insulin molecule.
§
lnsulin analogue with substitution of lysine for asparagine at position 3 on the B chain and glutamic acid for lysine at position 29 on the B chain of the insulin molecule.
‖
Insulin analogue with substitution of glycine for asparagine at position 21 on the A chain and addition of two arginines to the carboxyl terminus of the B chain of the insulin molecule.
¶
Administer at same time each day, unrelated to meals. Morning administration may result in greater glucose lowering and less nocturnal hypoglycemia.
**Do not mix glargine or detemir with other insulins.

SMBG should be performed as frequently as practicable: fasting,
preprandial, 2 hours postprandial, at bedtime, and occasionally
at 2:00 to 3:00 am. Values and times are saved in most meters for
subsequent review. It is helpful for patients to manually record
these data on a flow chart, and it is also possible to download
meter data to a computer. SMBG records are most useful when
annotated with relevant details on food intake, exercise, or the
occurrence of symptoms. HbA1c determinations should be
obtained every 3 months.
Most cases of T1DM should be managed with an intensive
insulin therapy regimen involving multiple (three or more) daily
subcutaneous injections or continuous subcutaneous insulin
infusion (CSII) using an insulin pump. Multiple-injection regi-
mens, also termed basal-bolus therapy, typically involve injections
of a long-acting insulin analogue (such as glargine or detemir)
once or twice daily to establish a stable basal insulin level.
Regular insulin or a rapid-acting insulin analogue is additionally
injected three or more times daily (before each meal and some-
times before snacks) to provide appropriate post-meal peaks
in insulin levels. Usually, once glucose levels are stabilized on
a regimen, the doses of long-acting insulin are kept constant
from day to day. The rapid-acting insulin doses can be kept
constant with efforts to ingest a fixed amount of carbohydrate
and total calories at each meal. Alternatively, better control and
greater flexibility can be achieved if rapid-acting insulin doses
are adjusted according to the blood glucose level (measured
before each meal) and the carbohydrate calories ingested with
the meal. The long-acting insulin glargine and detemir analogues
cannot be mixed in a single syringe with other insulins; for
this reason, basal-bolus regimens often require four or more
daily injections.
For patients newly diagnosed with T1DM, a typical starting
dose of insulin is a total of 0.2 to 0.4 U/kg/day, with the expecta-
tion that this will be increased to 0.6 to 0.7 U/kg/day over time.
Approximately half of the total dose should be given as basal
insulin. Depending on individual patient blood glucose responses,
the basal glargine or detemir insulin may be administered as a
single daily dose (in the morning or at bedtime), or two equally
divided doses may be required. For a neutral protamine Hage-
dorn (NPH) basal regimen, two thirds of the dose should be
given in the morning and one third at bedtime. This decreases the
risk of nocturnal hypoglycemia and times the maximum NPH
peak to approximately match the midday meal. The rapid-acting
component of the daily insulin dose is distributed before meals
according to meal size and content.
An insulin pump (CSII) represents the preferred method of
insulin administration for many T1DM patients. These small,
wearable devices contain a reservoir of rapid-acting insulin that
is infused via an easily placed subcutaneous catheter. A
microprocessor-controlled pump provides the basal insulin infu-
sion and can be programmed to adjust basal rates at multiple
points during the day according to predetermined patient needs.
The patient further instructs the pump to make bolus insulin
injections to cover meals, snacks, or needed corrections in hyper-
glycemia. Controlled studies have shown that modestly better
blood glucose control can be achieved with CSII, compared to
basal-bolus regimens with multiple daily injections. When used
appropriately, CSII represents the most flexible means of
662 Section X  Endocrine Disease and Metabolic Disease
managing insulin doses, with options for dose adjustments and
supplementation that do not require separate injections. Limita-
tions include need for greater patient involvement, lack of a long-
acting pool, and pump failure. Newly diagnosed T1DM should
be managed for a period of time (at least 6 to 12 months) with
intermittently injected insulin before transition to a pump is con-
sidered. During the transition from intermittent insulin injec-
tions to CSII in a patient with well-controlled blood glucose
levels (HbA1c ≤7.0%), the total daily insulin dose typically is
decreased by 10% to 20% initially.
Many CSII patients require a slightly higher basal infusion rate
in the early morning hours to accommodate the dawn phenome-
non, a period of decreased insulin sensitivity secondary to circa-
dian changes in secretion of insulin counter-regulatory hormones
such as growth hormone. Adjustments in the basal rate may also
be needed at other times of day because of changes in insulin
sensitivity that may occur (e.g., after exercise). Premeal insulin
boluses are calculated to include a correction dose if needed,
based on the premeal blood glucose level, plus a meal coverage
dose calculated from the patient’s predetermined individual
carbohydrate/insulin ratio. It often is most effective for a patient
to be seen in a specialty setting during transition to CSII, so that
an experienced educator (often a specially trained RN) can assist
with needed patient education. Devices are available that provide
continuous glucose monitoring (CGM), either as a separate
device or integrated with an insulin pump. Because of concern
about their consistent accuracy, insulin infusion rates are not
adjusted automatically in response to the measured glucose levels
by current devices; rather, patient intervention is required to
make changes.
Intensive insulin therapy is not appropriate for all T1DM
patients. Some patients are unwilling or unable to manage the
required frequent glucose monitoring, diet adherence, and mul-
tiple insulin boluses. In other patients, the tight blood glucose
control and low HbA1c targets that are the goals of intensive
insulin therapy may not be feasible. For example, there may be an
increased risk of hypoglycemia because of autonomic neuropathy
and inability to sense hypoglycemia, or gastrointestinal neuropa-
thy may cause gastroparesis resulting in unpredictable variations
in nutrient digestion and absorption. Under such circumstances,
simpler approaches to insulin therapy and blood glucose manage-
ment, previously termed conventional insulin therapy, may be
appropriate. Such a regimen may be based, for example, on two
injections per day of intermediate-acting insulin with or without
short- or rapid-acting insulin. As one example, a split-mixed
regimen uses NPH/regular or NPH/lispro (or aspart or glulisine)
formulations twice daily. Initially, two thirds of the estimated
total daily dose is given before breakfast and one third before
dinner; at each of these times, two thirds of the insulin is given
as NPH and one third as regular or a rapid-acting insulin. The
amount of each insulin type at each of the injection times is then
adjusted according to measured blood glucose levels, with the
expectation that the peak of the morning NPH will cover lunch,
the rapid-acting insulins will cover the other meals, and the NPH
will otherwise ensure adequate basal blood glucose control. Two
daily injections are made possible by mixing the intermediate-
and rapid-acting insulins in a single syringe. Premixed insulin
preparations, such as 70% NPH plus 30% rapid-acting insulin or
50% NPH plus 50% regular insulin, also are available for injection
with syringes or with preloaded insulin pens. Premixed insulins
provide greater ease of use but are less likely to achieve good
glycemic control.
Hypoglycemia Management
Irrespective of the specific treatment regimen, patients with
T1DM need to learn how to manage hypoglycemia. Patients
usually experience adrenergic symptoms (e.g., sweating, anxiety,
tremulousness) as blood glucose levels decrease below the
normal range (<50 to 70 mg/dL). If glucose levels decrease
markedly enough, patients may experience central nervous
system (CNS) symptoms ranging from difficulty thinking clearly
to confusion, obtundation, and loss of consciousness. If low
blood glucose is confirmed (e.g., <70 mg/dL), 10 to 15 g of
rapidly absorbed carbohydrate should be ingested. For a glucose
level lower than 50 mg/dL, 20 to 30 g of carbohydrate is advis-
able. This can be provided as orange juice or crackers, or patients
can carry glucose tablets or squeeze tubes of glucose solution
(obtainable over-the-counter from pharmacies) for use in treat-
ing hypoglycemia. The blood glucose level should be retested
after 15 minutes, and the treatment should be repeated as needed
until hypoglycemia is resolved. An alternative is to inject gluca-
gon. For patients who have a history of hypoglycemia severe
enough (including loss of consciousness) to require assistance
from others, it often is helpful for a family member to be trained
in glucagon injection. With severe hypoglycemia, there is a risk
of injury, such as from a fall or automobile accident, as well as
neurologic damage if hypoglycemia is sustained.
Nutritional Management
Appropriate nutritional management is an essential component
of an effective T1DM treatment program. This ideally should be
individualized to the patient’s lifestyle, exercise regimen, eating
habits, culture, and financial resources. Many expert panel rec-
ommendations allow individualized decisions regarding the rela-
tive amounts of carbohydrate, fat, and protein consumed within
a general set of guidelines. For example, the American Diabetes
Association (ADA) recommends the following:
• Fat intake, less than 7% of total calories with minimal amounts
of trans-fats
• Total cholesterol intake, less than 200 mg/day
• Dietary protein intake, 15% to 20% of total calories in the
absence of renal failure
• Fiber intake, at least 14 g per 1000 total calories
• Reduced sodium intake (1500 mg/day), especially in the
context of even mild hypertension.
Patients should work with a medical professional who is trained
in diabetes care to establish nutritional goals.
Most diets focus on measuring and controlling the amounts
rather than the sources of carbohydrates. Patients can be taught
to estimate the grams of carbohydrate in a meal (carbohydrate
counting) as a means of ensuring that a consistent amount of
carbohydrate is ingested. Alternatively, they can use carbohydrate
 Chapter 66  Diabetes Mellitus, Hypoglycemia 663
counting with each meal as part of a strategy that enables day-to-
day variations in consumption with adjustments of mealtime
insulin doses according to a predetermined, patient-specific
insulin/carbohydrate ratio. It is advisable to avoid foods that
contain supplemental fructose as a sweetener because of the
potential adverse effects of fructose on lipid metabolism. Alcohol
consumption in moderation is acceptable (one drink or less for
women and two drinks or less for men per day).
Because of the contribution of excess body weight to increased
cardiovascular risk, a fundamental goal of nutritional manage-
ment should be to maintain normal body weight or to achieve
weight reduction in overweight or obese patients. Eating disor-
ders including binge eating, anorexia nervosa, and bulimia are
relatively common in T1DM, especially among younger female
patients.
Exercise
Regular physical exercise should be encouraged for its beneficial
effects on weight control, risks of long-term complications, and
overall quality of life. The general recommendation of several
expert panels is 30 minutes or more of moderate-intensity physi-
cal exercise on at least 5 days per week. Physical exercise burns
calories in proportion to its duration and intensity and also may
result in increased insulin sensitivity after exercise (sometimes
lasting for many hours). It often is most effective for patients to
schedule regular exercise periods with a consistent temporal rela-
tionship to meals and insulin injections. Blood glucose should be
tested before and after exercise, and exercise should not be under-
taken if the initial blood glucose level is low (because of increased
risk of hypoglycemia) or if it is higher than 250 mg/dL (because
of risk of inducing further blood glucose elevation and develop-
ment of ketosis). Patients with T1DM should be encouraged to
pursue age- and overall health-appropriate athletic interests,
including competitive sports, but this should be done only with
careful attention to blood glucose monitoring and appropriate
adjustments in insulin regimen and diet.
Type 2 Diabetes
Epidemiology and Pathology
T2DM is an extraordinarily common disorder, affecting 8% to
10% of the population in the United States and with a similar
prevalence in most other developed or developing countries.
Many patients with T2DM are undiagnosed, and many additional
individuals (approximately 6% of the U.S. population) have a
prediabetic state. T2DM is characterized by varying degrees of
insulin resistance and insulin deficiency, which are believed to
result from the impact of environmental factors on a background
of genetic risk. The principal features of T2DM, contrasted with
T1DM, are summarized in Table 66-4. The prevalence of T2DM
has increased more than 10-fold over the past 50 years, driven
primarily by increased calorie intake, decreased exercise, and
resulting obesity. More than 80% of patients with T2DM are
obese. The peak incidence of T2DM occurs in the fifth and sixth
decades; however, T2DM now accounts for up to 30% of child-
hood diabetes in some populations. The lifetime risk of develop-
ing T2DM is approximately 40% among the offspring of a single
affected parent, and approximately 70% if both parents are
affected. The incidence of T2DM in the United States is higher
in Hispanic/Latino populations, among African Americans, and
in some east Asian populations, compared to populations of
northern and western European ancestry. This is thought to result
in part from effects of socioeconomic and cultural factors (e.g.,
differences in consumption of low-cost, calorie-dense foods) but
also from genetic differences among these populations. The
genetic predisposition in all populations that have been studied
is thought to reflect the combined influence of more than 40
genes. No single gene or small group of genes with dominant
influence on diabetes risk in any population has been identified.
T2DM is typically preceded by a prolonged preclinical or pre-
diabetic phase during which there is a gradual deterioration in
glucose tolerance (Fig. 66-2). This process occurs over a decade
or more on average, with marked individual variation in the rate
of progression. Most patients are insulin resistant during the pre-
clinical phase but are able to compensate by producing more
insulin (hyperinsulinemia) to maintain euglycemia. With time,
there is progressive deterioration in the capacity to compensate
for the insulin resistance. This is associated with a decrease in beta
cell mass during the preclinical phase of T2DM, but substantial
residual beta cells (typically 40% to 50% of the normal comple-
ment) are still present at the time that overt hyperglycemia devel-
ops. Therefore, there is compromised function as well as a
reduced number of beta cells in T2DM. As blood glucose levels
rise, the hyperglycemia itself may contribute to progression of the
diabetic state by further decreasing insulin secretion and insulin
resistance through mechanisms that are not well understood
(referred to as glucotoxicity).
Screening of certain high-risk populations for T2DM and pre-
diabetes by determination of a fasting or random plasma glucose
measurement is considered cost-effective. More than 30% of
people with T2DM and an even higher percentage of those with
prediabetes are undiagnosed. Expert panel recommendations
from the ADA for screening based on age, lifestyle factors, family
history, and ethnicity are summarized in Table 66-6. Because of
the insidious nature of T2DM, patients have a high risk for devel-
opment of complications by the time of clinical diagnosis (see
later discussion).
Clinical Presentation
Many patients are asymptomatic and are diagnosed on routine
blood glucose testing. Blood glucose levels that rise high enough
to exceed the renal threshold for glucose reabsorption (>170 mg/
dL) induce an osmotic diuresis, resulting in the typical present-
ing symptoms of polyuria and polydipsia, as well as blurred vision
secondary to osmotic shifts in the lens. Patients may also have
weight loss or bacterial urinary tract or cutaneous fungal infec-
tions at presentation. Osmotic diuresis secondary to hyperglyce-
mia may lead to electrolyte abnormalities and even occasionally
to a severe hyperosmolar state associated with clinical symptoms
and signs including fatigue, weakness, and ultimately compro-
mised mental status that can range from confusion to coma (see
later discussion). This most frequently occurs in elderly patients
who may have compromised baseline renal function. In contrast
to patients with T1DM, those with T2DM usually have enough
664 Section X  Endocrine Disease and Metabolic Disease

Risk Factors Glucotoxicity

• Genes Metabolic IR
Insulin resistance Beta-cell defect Beta-cell decompensation Beta-cell failure
Diabetes
Obesity Insulin
• Intrauterine growth resistance
retardation
• Environment
Lifestyle–sedentary
Diet–high fat, high
calorie
• Insulin resistance Plasma
• Obesity (abdominal/ glucose
central)
• Age
• Ethnicity

Serum
insulin
Postprandial
hyperglycemia Fasting
hyperglycemia

20 40 60 80
Compensated Impaired glucose Early-onset Insulin-requiring
insulin resistance tolerance type 2 diabetes type 2 diabetes
• Euglycemia • Postprandial • Fasting
• Hyperinsulinemia hyperglycemia hyperglycemia
• Asymptomatic • Hyperinsulinemia • HGP
• Asymptomatic • Symptomatic
Time/age (years)

FIGURE 66-2  Natural history of type 2 diabetes mellitus. The numbers for time/age markers in years for the different phases of beta-cell decom-
pensation toward overt diabetes and an insulin-requiring state are approximate guides. Certain groups are more insulin sensitive and require a greater
loss of beta-cell function to precipitate diabetes, compared with obese insulin-resistant people, who develop diabetes after small declines in beta-cell
function. Use of insulin in patients with type 2 diabetes varies considerably and is not age dependent. HGP, Hepatic glucose production; IR, insulin
resistance.

residual insulin activity to partially suppress lipolysis, and this
protects them from developing DKA. In a subset of T2DM
patients, DKA can develop, possibly reflecting individual varia-
tions in the degree of suppression of insulin secretion by
glucotoxicity.
As a consequence of prolonged exposure to hyperglycemia
and associated metabolic disturbances, patients with T2DM may
already have developed long-term microvascular or macrovascu-
lar complications of diabetes by the time of diagnosis. Therefore,
patients may experience a cardiovascular event, such as acute
myocardial infarction, and then incidentally be found to have
T2DM.
The Metabolic Syndrome
Susceptibility to cardiovascular disease is further increased by the
frequent association of insulin resistance, prediabetes, and T2DM
with other cardiac risk factors, including abdominal or visceral
obesity, dyslipidemia, and hypertension. The term metabolic syn-
drome has been applied to patients who have a combination of
these cardiovascular risk factors. Different but overlapping diag-
nostic criteria for the metabolic syndrome have been proposed
by various expert panels. The National Cholesterol Education
Program Adult Treatment Panel III (ATP III) defines this syn-
drome as the presence of any three of the following five
characteristics:
1. Fasting blood glucose level ≥100 mg/dL or drug treatment
for elevated blood glucose
2. High-density lipoprotein (HDL)-cholesterol <40 mg/dL in
men or <50 mg/dL in women or drug treatment for low
HDL-cholesterol
3. Plasma triglycerides ≥150 mg/dL or drug treatment for ele-
vated triglycerides
4. Abdominal obesity (waist ≥102 cm in men or ≥88 cm in
women
5. Blood pressure ≥130/85 mm Hg or drug treatment for
hypertension.
There is debate about whether the metabolic syndrome repre-
sents a discrete pathologic entity, but its recognition does draw
attention to the frequent clustering of cardiovascular risk factors.
Treatment
Patients with T2DM should receive nutrition counseling starting
at the time of diagnosis. This should include efforts at weight loss
in overweight or obese patients. Adjustments in diet, especially
reductions in calorie intake, can rapidly improve blood glucose
levels in many patients independent of other interventions.
Weight reduction by as little as 10% to 20% of body weight can
have marked beneficial effects on insulin resistance and glycemia
in some patients.
 Chapter 66  Diabetes Mellitus, Hypoglycemia 665
TABLE 66-6  SCREENING CRITERIA FOR DIABETES IN
ASYMPTOMATIC ADULTS
1. Testing for diabetes should be considered in all persons ≥45 yr of age; if
normal, the test should be repeated at 3-yr intervals.
2. Testing should be considered at a younger age (<30 yr) or performed
more frequently in individuals who
a. Are overweight (BMI ≥25) or who have central obesity with normal
BMI (18.5-24.9)
b. Have an habitually sedentary lifestyle
c. Have a first-degree relative with diabetes (i.e., parent or sibling)
d. Are members of a high-risk ethnic population (e.g., African
American, Latino/Hispanic American, Native American, Asian
American, Pacific Islander)
e. Have delivered a baby weighing >9 lb (4 kg), have experienced
unexplained perinatal death of a child, or have been diagnosed with
gestational diabetes
f. Are hypertensive (≥140/90 mm Hg)
g. Have an HDL cholesterol level <35 mg/dL (0.9 mmol/L) and/or a
triglyceride level >250 mg/dL (2.82 mmol/L)
h. Had, on previous testing, impaired glucose tolerance (plasma
glucose ≥140 mg/dL [7.8 mmol/L] but <200 mg/dL
[11.1 mmol/L] 2 hr after 75-g oral glucose tolerance test), impaired
fasting glucose (plasma glucose 100-125 mg/dL [5.6-6.9 mmol/L]),
or HbA1C ≥5.7%
i. Have other clinical conditions associated with insulin resistance (e.g.,
PCOS, acanthosis nigricans)
j. Have a history of cardiovascular disease
Modified from the American Diabetes Association Clinical Practice Recommendations
2013, Diabetes Care 36(Suppl 1):S11–S66, 2013.
BMI, Body mass index (weight [kg]/height [m2]); HbA1C, glycosylated hemoglobin;
HDL, high-density lipoprotein; PCOS, polycystic ovary syndrome; T1DM, type 1 diabetes
mellitus; T2DM, type 2 diabetes mellitus.
Depending on initial blood glucose levels, the presence or
absence of symptoms related to hyperglycemia, and the presence
of other complicating medical conditions, a decision can be made
on whether to treat the patient initially with diet alone or to
also start medication. Patients with marked hyperglycemia, fluid
deficits, altered mental status related to hyperosmolar state, and
DKA should be hospitalized for acute treatment (see later
discussion).
For most patients, treatment of T2DM can be conducted on
an outpatient basis. Useful and frequently updated guidelines are
available on line from the ADA and the European Association for
the Study of Diabetes. Most expert panels recommend starting
with one or two oral glucose-lowering medications (depending
on the degree of hyperglycemia) with progression to a third oral
agent or insulin if this proves ineffective. In patients with marked
hyperglycemia (>300 mg/dL or HbA1c >9.0% to 9.5%), consid-
eration should be given to starting insulin from the outset. There
typically is gradually progressive loss of beta cell function in
T2DM, extending sometimes over many years, and this results in
a need over time for increased doses or additional glucose-
lowering agents and often, ultimately, the use of insulin. As for
T1DM, the overall management of T2DM should include not
only the treatment of hyperglycemia but also interventions that
assess, decrease the risks for, and treat long-term microvascular
and macrovascular complications.
Blood Glucose Control
The United Kingdom Prevention of Diabetes Study (UKPDS)
and other randomized, controlled trials have established that
improved blood glucose control lowers the risk of microvascular
long-term complications (retinopathy, nephropathy, and neu-
ropathy) in T2DM. The risk appears to increase progressively,
starting with any increment above normoglycemia. Randomized
clinical trial data have not convincingly demonstrated improved
macrovascular (i.e., cardiovascular disease) outcomes in T2DM.
HbA1c goals therefore should be developed on an individualized
basis, such that the benefits of improving microvascular compli-
cations are balanced against the risks of hypoglycemia. T2DM
patients, particularly those who are older or have complicating
comorbid conditions, may have limited capacity to manage a
tight blood glucose control regimen and also increased suscepti-
bility to adverse effects of hypoglycemia. Whereas an HbA1c of
7.0% or less is an appropriate target for younger T2DM patients,
8.0% or less may be an acceptable and safer target for older
patients with complicating medical conditions and limited life
expectancy. Patients or their caregivers should perform regular
glucose monitoring (SMBG) to assess ongoing blood glucose
control, identify potential hypoglycemia, and detect marked
increases in blood glucose that may occur during an intercurrent
illness. HbA1c determinations provide important supplemental
information about blood glucose control and should be per-
formed at intervals of 3 to 6 months.
Non-Insulin Pharmacologic (Antidiabetic)
Agents in T2DM
Non-insulin pharmacological agents from many different drug
classes are available for treatment of T2DM, some taken orally
and others by injection (Table 66-7). When non-insulin phar-
macologic agents are appropriate, metformin is first-line therapy
because of its glucose-lowering efficacy, absence of weight gain
and hypoglycemia, favorable safety and tolerability profile based
on many years of clinical experience, and low cost. For patients
who are unable to tolerate metformin, a sulfonylurea is a
reasonable choice, again based on efficacy, tolerability, and low
cost. Sulfonylureas have the disadvantages of inducing modest
weight gain in many patients, and they carry a risk of causing
hypoglycemia. Agents in other drug classes can be considered
for first-line therapy, but there is less knowledge or more
concern about their long-term safety profiles, and they have
higher cost.
If a single drug is tolerated but does not adequately control
blood glucose levels, the usual practice is to continue that drug
and add a second. Drug combinations often are selected from
classes with complementary mechanisms of actions. For example,
the combination of an insulin sensitizer such as metformin and
an insulin secretagogue such as a sulfonylurea has theoretical
appeal in providing greater potential for additive or synergistic
actions. Patients with marked hyperglycemia that is not judged
severe enough to merit insulin treatment may be started on two
agents from the outset. This has the potential advantage of more
rapidly achieving blood glucose control but the disadvantage of
exposing patients to the potential side effects of taking two drugs
simultaneously. Many combination preparations are available for
administration of more than one drug; these are more convenient
for patients and sometimes less expensive than taking the mul-
tiple drugs separately.
Available non-insulin antidiabetic agents are summarized here
and in Table 66-7. Current manufacturer information should be
666 Section X  Endocrine Disease and Metabolic Disease
TABLE 66-7  NON-INSULIN ANTIDIABETIC AGENTS BY DRUG CLASS*
DRUG CLASS AVAILABLE AGENTS (GENERIC NAME)
Biguanides Metformin
Sulfonylureas Glipizide, glyburide, glimeperide, gliclazide,
chlorpropamide, tolazamide
Meglitinides Repaglinide, nateglinide
Thiazolidinediones Pioglitazone, rosiglitazone
GLP-1 analogues Exenatide, liraglutide, albiglutide
DPP-4 inhibitors Sitagliptin, saxagliptin, linagliptin, alogliptin
α-Glucosidase inhibitors Acarbose, miglitol
Amylin mimetics Pramlintide
SGLT2 inhibitors Canagliflozin, dapagliflozin, empagliflozin
DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium glucose transport protein subtype 2.
*Consult current manufacturer information for details on available combinations, prescribing, and safety.
consulted before prescribing these drugs to ensure updated and
adequately detailed information on available single and combina-
tion agents and their effective and safe use.
Metformin
Metformin is an oral agent in the biguanide class that produces
its most prominent effects by decreasing gluconeogenesis and
thus reducing hepatic glucose production. This insulin-sensitizing
effect is associated with a low risk of hypoglycemia. It has been
in use for more than 30 years and is available in inexpensive
generic form. The usual starting dose is 500 mg once or twice
daily with incremental advancement at several-week intervals to
a usual maximum of 2000 mg daily in two or three divided doses.
Metformin typically decreases HbA1c by about 1.5%. Further
benefits include modest weight loss (approximately 3 kg on
average) and a small improvement in plasma lipid profile
(decrease in low-density lipoprotein [LDL]-cholesterol and tri-
glycerides and increase in HDL). Adverse reactions include gas-
trointestinal effects and, rarely, lactic acidosis. The drug should
be avoided in patients with renal insufficiency.
Sulfonylureas
Sulfonylureas stimulate endogenous insulin secretion by binding
and activating potassium channels in beta cells. In patients with
adequate residual beta cell function, they can lower HbA1c levels
by 1% to 2%. Drugs in this class have been in clinical use for more
than 40 years, and many inexpensive, generic sulfonylureas are
available that differ in duration of action, metabolism, and mode
of clearance. Because they can increase insulin secretion even in
the absence of hyperglycemia, they have significant potential to
cause hypoglycemia. Patients need to be instructed how to rec-
ognize and treat hypoglycemia before starting a sulfonylurea.
Factors that increase the risk for hypoglycemia with sulfonylureas
include advanced age, poor nutrition, alcohol ingestion, and
hepatic and renal insufficiency. Other disadvantages of this drug
class are a tendency to cause weight gain and a loss of effective-
ness over time.
Meglitinides
Repaglinide and nateglinide activate beta cell potassium channels
and thus stimulate endogenous insulin secretion through a mech-
anism similar to that of sulfonylureas, although they generally
result in less reduction in blood glucose than sulfonylureas. They
have rapid action and have less tendency to cause hypoglycemia
ROUTE OF ADMINISTRATION MODE OF ACTION
Oral Insulin sensitizer
Oral Insulin secretagogue
Oral Insulin secretagogue
Oral Insulin sensitizer
Subcutaneous injection Incretin mimetic
Oral Incretin amplifier
Oral Delay carbohydrate digestion/absorption
Subcutaneous injection Delay gastric emptying, suppress glucagon
Oral Increase urinary glucose excretion
than sulfonylureas. Their use has been limited by high cost and
lack of advantage over the sulfonylureas.
Thiazolidinediones
The thiazolidinediones (TZDs) activate the nuclear peroxisome
proliferator-activated receptor-γ (PPAR-γ), which leads to
changes in transcription rates of multiple genes. The net effect
is reduced insulin resistance, and the resulting augmented actions
of insulin lead to increased glucose uptake in peripheral tissues
and reduced hepatic glucose production. Pioglitazone typically
lowers HbA1c by 0.5% to 1.4% and carries a low risk of hypo-
glycemia. Potential side effects include weight gain and
hepatotoxicity.
Glucagon-Like Peptide-1 Analogues
Glucagon-like peptide-1 (GLP-1) is one of several hormones
produced in the small intestine (designated incretins) that modify
gastrointestinal motility and insulin secretion. The GLP-1 ana-
logues, exenatide, liraglutide, and albiglutide, bind to GLP-1
receptors and improve blood glucose control by enhancing
insulin-dependent insulin secretion, slowing gastric emptying,
suppressing postprandial glucagon production, and decreasing
food intake through enhanced satiety. This results in decreases in
HbA1c by 0.5% to 1.5% and modest weight loss (in the range of
3 kg). They are administered via injection with prefilled pens—
exenatide twice daily or once weekly in long-acting form, liraglu-
tide once daily, and albiglutide once weekly. The most common
side effects are nausea and sometimes diarrhea, likely related to
the drugs’ effects on gastrointestinal motility. GLP-1 analogue
use is tempered by the inconvenience of injection, relatively high
cost, and a lack of long-term data on durability of weight loss or
other outcome benefits. They most often are used as second-line
agents in conjunction with other glucose-lowering drugs or
insulin.
Dipeptidyl Peptidase-4 Inhibitors
The dipeptidyl peptidase-4 (DPP-4) inhibitors—sitagliptin,
saxagliptin, linagliptin, and alogliptin—block the deactivation of
GLP-1 (described in the previous section) and glucose-dependent
insulinotropic peptide (GIP), peptide hormones that are impor-
tant in the regulation of glucose homeostasis. Some of the effects
of DPP-4 inhibitors may overlap with those of administered
GLP-1 analogues, but they likely have additional actions by
increasing levels of hormones other than GLP-1. DPP-4
 Chapter 66  Diabetes Mellitus, Hypoglycemia 667
inhibitors are taken orally and result in decreased HbA1c in the
range of 0.5% to 1.0%. They can be used as monotherapy or in
combination with one or more other agents and have favorable
side effect profiles.
α-Glucosidase Inhibitors
The α-glucosidase inhibitors, acarbose and miglitol, are oral
agents that improve glycemia by inhibiting the enzymatic break-
down of complex carbohydrates within the lumen of the small
intestine. They have modest glucose-lowering effects, decreasing
HbA1c in the range of 0.5% to 0.8%. Their use is limited by the
frequent occurrence of flatulence and diarrhea as a consequence
of undigested carbohydrates reaching lower intestinal regions.
Pramlintide
Pramlintide is a stable analogue of the beta cell peptide, amylin,
which has actions that include slowing of gastric emptying,
satiety effects that decrease food intake, and decrease in postmeal
glucagon. It is not widely used because of required multiple injec-
tions and limited efficacy in lowering HbA1c.
SGLT2 Inhibitors
Canagliflozin, dapagliflozin, and empagliflozin are recently
approved oral agents that function by inhibiting the subtype 2
sodium glucose transport protein (SGLT2). SGLT2 mediates
more than 90% of glucose reabsorption in the renal tubules, and
the drug lowers blood glucose levels by promoting excretion of
glucose in the urine. This results in a decrease in HbA1c in the
range of 0.5% to 1.0% and modest weight loss. Concerns about
potential side effects of increased cardiovascular events, increased
LDL-cholesterol, urinary and genital infections, hypotension,
and hypoglycemia are under investigation.
Insulin Treatment in T2DM
For patients who have inadequate glycemic control with oral
agents, insulin may be started as a basal supplement to the oral
regimen. Frequently used choices include glargine (once daily),
detemir (once or twice daily), or NPH (once daily at bedtime)
(see later discussion and Table 66-5 for more details on different
types of insulin). Starting doses are typically in the range of 10 U
(or can be more specifically calculated as 0.2 U/kg), with
increases of 2 to 4 U at intervals of 3 days or longer. Oral agent
regimens commonly are simplified at the time of starting insulin
(e.g., shifting from multiple agents to a single oral agent). For
patients who do not achieve adequate control with basal insulin,
mealtime coverage is provided by a rapid-acting insulin. Often,
under this circumstance, all oral agents are discontinued, and
blood glucose control is achieved with the use of exogenous
insulin alone. Compared to patients with T1DM, those with
T2DM may not require as tight a match of carbohydrate to
insulin doses at meals, perhaps because of some residual insulin
secretion. For this reason, insulin pumps are only rarely used in
T2DM.
Nutritional and Weight Management
Patients should receive counseling from a dietician and be
assisted in developing a nutritional plan that is individualized to
their lifestyle, exercise, culture, and financial resources.
Guidelines from many current expert panels allow flexibility in
the relative amounts of carbohydrate, fat, and protein. Nutritional
management in T2DM often has a major focus on achieving
reductions in calorie intake and weight loss. Achieving weight
loss may be made more difficult by a tendency of some oral anti-
diabetic agents and also insulin to induce a degree of weight gain.
An important goal of nutritional management should be to
balance the timing and quantities of ingested macronutrients
with medications and exercise to help achieve targets for blood
glucose control without periods of hypoglycemia.
For overweight or obese patients, it often is practical to set an
initial goal of losing 5% to 10% of body weight. This may signifi-
cantly improve diabetes control and increase the patient’s motiva-
tion to then set goals for further weight loss (see Chapter 67).
Bariatric surgical procedures represent a method for achieving
weight loss and potentially dramatic improvements in glycemia
and risk factors for long-term complications in T2DM. Patients
typically have improvements in glycemic control and lower
requirements for antidiabetic medications within days after
undergoing the Roux-en-Y gastric bypass procedure. This is
thought to reflect changes in gut hormones and metabolic factors
independent of weight loss. Beneficial effects on glucose control
develop more gradually after the placement of an adjustable
gastric band or sleeve gastrectomy. Randomized trials comparing
bariatric surgery with medical nutrition therapy alone for weight
loss have shown greater efficacy in achieving HbA1c goals with
surgery, and some studies have shown dramatic rates of remis-
sion, with 75% of patients or more becoming normoglycemic off
all antidiabetic agents (see Chapter 67).
Exercise
Physical exercise should be encouraged in T2DM as an impor-
tant component of weight loss regimens and also for its beneficial
effects in decreasing the risks of long-term complications. The
general recommendation of several expert panels is 30 minutes
or more of moderate-intensity physical exercise on at least 5 days
per week, but the regimen needs to be highly individualized
according to a patient’s capabilities and limitations imposed by
other medical conditions such as cardiovascular disease. Patients
who are unwilling or unable to undertake significant aerobic exer-
cise should be encouraged to do daily walking or other physical
activities within their limitations.
Standards of Care in T1DM and T2DM in
Addition to Blood Glucose Control
A number of assessments and interventions should be performed
at intervals in patients with T1DM or T2DM. These include
blood pressure measurement and examination of the feet at each
physician visit. Patients who smoke should receive counseling at
each visit about the importance of and strategies for discontinu-
ing. A dilated eye examination should be performed annually, or
more often in patients with diabetic eye disease. A dental exami-
nation also should be performed at least annually. Starting 5 years
after disease onset in T1DM and at the time of diagnosis in
T2DM, patients should have annual measurement of their
urinary albumin/creatinine ratio with confirmation if elevated
(>30 mg albumin per gram of creatinine). A fasting lipid profile
should be obtained annually. Aspirin (75 to 162 mg daily) is
668 Section X  Endocrine Disease and Metabolic Disease
usually recommended for secondary prevention of cardiovascu-
lar disease (supported by clinical trial evidence) or for primary
prevention in patients with a 10-year cardiovascular risk greater
than 10% (based on expert opinion). Influenza vaccination
should be provided yearly; pneumococcal immunization should
be given once and then repeated after age 65.
Management of Diabetes during   diabetes. Up to 40% of women with GDM go on to develop
Intercurrent Illness
Diabetes often requires changes in the blood glucose manage-
ment regimen during an intercurrent illness to accommodate
potential decreases in nutrient intake and increases in insulin
resistance secondary to disease-related release of stress hor-
mones. Patients with T1DM require exogenous insulin adminis-
tration at all times to prevent marked hyperglycemia and DKA,
even if they are unable to consume nutrients during an illness
(e.g., with gastroenteritis). Depending on the degree and dura-
tion of interruption of food intake, they may require a transient,
partial reduction in insulin dosage as well as more frequent
glucose monitoring. Alternatively, if they are consuming a normal
diet, they may require a modest increase in insulin dose because
of insulin resistance related to the stress of illness. T2DM patients
taking oral agents who are undergoing surgical procedures or are
hospitalized for serious illness often require discontinuation of
the oral agents and use of insulin to control blood glucose until
normal eating patterns are resumed.
For hospitalized patients, blood glucose target goals are
adjusted to prevent marked hyperglycemia and at the same time
protect against hypoglycemia. For noncritical illness, typical
blood glucose targets include lowest levels of 90 to 100 mg/dL,
premeal levels lower than 140 mg/dL, and random levels lower
than 180 mg/dL. For critically ill patients, intravenous insulin
infusion may be needed to allow for rapid adjustments in dosage,
and the blood glucose range recommended by most expert
panels is 140 to 180 mg/dL.
Gestational Diabetes
The hormonal environment of pregnancy results in insulin resis-
tance and therefore predisposes to the development or unmask-
ing of diabetes during pregnancy. GDM occurs in 2% to 5% of all
pregnancies and is associated with consequences for both mother
and fetus if untreated. For this reason, screening for GDM is
routinely performed between 24 and 28 weeks of gestation in
women older than 25 years of age and in younger women who
fulfill one or more of the risk criteria in Table 66-6 (2a through
2d and 2g). Women who are at high risk (i.e., those who are
obese, have a personal history of GDM, glycosuria, or have a
first-degree relative with diabetes) should be screened earlier, at
their initial obstetric or prenatal visit. A broadly accepted
approach to screening is a 2-hour 75-g oral glucose tolerance test
with cutoff values as specified in Table 66-2.
A detailed discussion of the approach to managing GDM and
also preexisting diabetes during pregnancy is beyond the scope
of this chapter. The fundamental principles include diet, exercise,
and glucose-lowering oral agents or insulin as needed. Blood
glucose goals are set lower than in nonpregnant individuals
because of the importance of minimizing exposure of the fetus to
hyperglycemia: fasting, 95 mg/dL (5.3 mmol/L) or lower;
1-hour postprandial, 140 mg/dL (7.8 mmol/L) or lower; and
2-hours postprandial, 120 mg/dL (6.7 mmol/L) or lower. HbA1c
levels may be useful in establishing the presence of hyperglyce-
mia before its discovery during pregnancy, but they have limited
value in managing GDM. Women with GDM should be reevalu-
ated with a 75-g glucose tolerance test 6 to 12 weeks after deliv-
ery, at which point approximately 10% will still have overt
diabetes in the subsequent 20 years, with this risk varying sub-
stantially depending on ethnic background and obesity. Preg-
nancy serves as a provocative test and not as a risk factor for the
future development of diabetes.
Management of Severe Metabolic
Decompensation in Diabetes
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) develops most commonly in
patients with T1DM (approximately 2.5 cases per 100 T1DM
patients per year). It also can occur in those with T2DM, espe-
cially during acute illness (severe infection, medical illness, or
trauma), and in a subset of ketosis-prone T2DM patients. DKA
is present in approximately 25% of T1DM patients at diagnosis
and otherwise most often develops when patients with known
T1DM stop taking prescribed insulin. It is a potentially life-
threatening condition that has an overall mortality rate of
approximately 2.5%, with most deaths resulting from complicat-
ing or precipitating medical conditions rather than the metabolic
disturbances of DKA itself.
The pathophysiology of DKA results from the combined
effects of insulin deficiency and increased levels of insulin counter-
regulatory (stress) hormones. With insulin deficiency, glucose
levels rise as a consequence of decreased uptake and metabolism
by body tissues, the breakdown of hepatic glycogen stores (gly-
cogenolysis), and net glucose production by the liver and kidney
(gluconeogenesis). Catabolism of muscle proteins as a result of
low insulin levels leads to the release of amino acids, which
provide substrate that further drives gluconeogenesis. Because
glucose is being synthesized endogenously, blood glucose levels
rise markedly, even in the fasted state. Blood glucose levels
greater than 170  mg/dL result in glycosuria. Excretion of glucose
in the urine necessitates the co-excretion of large amounts of
water and electrolytes (Na+ and K+). Patients experience polyuria
but cannot compensate adequately and become progressively
more fluid and electrolyte depleted. The osmotic diuresis is
characterized by greater losses of water than electrolytes, and
this leads to progressively increasing hyperosmolality. Because
of insulin deficiency, there is decreased lipogenesis and acceler-
ated lipolysis leading to increased levels of circulating free fatty
acids, which serve as a substrate for the hepatic synthesis of
ketone bodies (β-hydroxybutyrate, acetoacetate, and acetone).
β-Hydroxybutyrate and acetoacetate are acids, and their rising
plasma levels contribute to the development of a metabolic
acidosis.
These processes can result from simple insulin deficiency, but
often they are exacerbated by an underlying or precipitating
illness, such as an infection. Infection results in insulin resistance
secondary to increased levels of stress hormones (cortisol,
 Chapter 66  Diabetes Mellitus, Hypoglycemia 669
catecholamines, glucagon, and growth hormone). A series of
positive feedback loops are thus generated and lead to ever-
accelerating hyperglycemia, fluid and electrolyte depletion,
ketosis, and metabolic acidosis. More than simple restoration of
insulin dosing is required, and patients usually need hospital
admission and multicomponent interventions.
Common presenting symptoms in DKA include polyuria,
thirst and polydipsia, recent weight loss (especially in new-onset
diabetes), blurred vision, weakness, anorexia, nausea and vomit-
ing, abdominal pain (which can mimic acute abdomen), and
mental status changes varying from somnolence to coma. DKA
and these associated symptoms usually evolve over 2 to 4 days
but can have an onset of less than 12 hours in patients using
insulin pumps. On physical examination, patients typically have
evidence of dehydration including decreased skin turgor, hypo-
tension, and tachycardia. The skin may be warm and dry from the
vasodilating effects of acidosis, and marked hypotension should
generate concern for impending vascular collapse. Patients often
have deep, rapid respirations (Kussmaul breathing) as respiratory
compensation for the metabolic acidosis, together with a charac-
teristic fruity odor on their breath from exhaled acetone. The
diagnosis is made in patients who have (1) a high blood glucose
concentration (>250 mg/dL), (2) moderate to severe ketonemia
(β-hydroxybutyrate >5 mmol/L or positive ketone levels by
Ketostix at a serum dilution of 1 : 2 or higher), and (3) acidosis
(pH <7.3 or plasma bicarbonate ≤15 mEq/L). Measurements of
urine ketones may be misleading, because urinary ketones can be
positive during fasting in the absence of DKA.
Additional evaluation besides the diagnostic tests already
mentioned should include electrolytes, blood urea nitrogen, cre-
atinine, phosphate, liver function tests, and amylase; arterial or
mixed venous blood gases (including pH); complete blood
count; urinalysis; electrocardiogram; and chest radiographs. The
serum anion gap, which is usually greater than 12 mEq/L in
DKA, should be calculated (anion gap = [Na+] − [Cl− + HCO3−]).
Serum osmolality should be measured directly or calculated: esti-
mated osmolality = (2 × [Na+]) + ([glucose in mg/dL]/18).
Precipitating causes of DKA include infection (most common),
myocardial infarction (including silent infarction), inflammatory
processes (appendicitis, pancreatitis), and medications (espe-
cially glucocorticoids).
Treatment of DKA should start promptly with institution of
measures to correct life-threatening abnormalities, including
insulin deficiency, fluid and electrolyte depletion, potassium
(K+) depletion, and metabolic acidosis. In a typical regimen,
insulin is administered as a regular insulin bolus (0.1 U/kg) fol-
lowed by a continuous intravenous infusion at 0.1 U/kg/hour.
Plasma glucose is monitored hourly until it is less than 250 mg/
dL, and the rate of insulin infusion is adjusted as needed to target
a rate of blood glucose decline of 75 to 100 mg/dL/hour to avoid
potential complications of rapid shifts in osmolality.
At the time of starting insulin, it is essential to begin fluid and
electrolyte replacement. The initial fluid deficit should be esti-
mated based on the magnitude of weight loss (if known), mucous
membrane dryness, skin turgor, and whether or not there is pos-
tural hypotension, with the knowledge that losses in DKA usually
range from 3 to 8 L. A typical program for intravenous fluid
replacement starts with 1 L of normal saline in the first hour.
Normal saline may then be continued at 15 mL/minute for a
second hour depending on the estimated severity of initial fluid
depletion. This then may be changed to 0.45% (half-normal)
saline at 7.5 mL/minute for the next 2 hours and gradually
tapered thereafter to achieve full replacement of the estimated
fluid deficit in approximately 8 hours. During that time, there
should be frequent monitoring for jugular venous distention and
chest auscultation to ensure early detection of fluid overload.
Central venous pressure should be monitored in patients who are
at risk for congestive heart failure.
Potassium repletion is needed in all patients, and there should
be careful monitoring and replacement to ensure that patients do
not develop potentially harmful hypokalemia or hyperkalemia.
Urine output should be verified with the use of a Foley catheter
if necessary before K+ replacement is started. Unless patients are
anuric, K+ replacement should be initiated within 1 to 2 hours
after starting insulin. A key goal is to maintain serum K+ at all
times higher than 3.5 mEq/L, and it is especially important to
administer K+ early in the course of treatment if there is initial
hypokalemia or if bicarbonate is administered to correct acidosis,
because the latter action promotes a shift of extracellular K+ into
cells. Potassium typically is withheld if the serum K+ is 5 mEq/L
or higher; otherwise, it is administered as part of the intravenous
fluid regimen at 10 to 40 mEq/hour depending on the measured
serum level. Serum K+ should be monitored every 2 hours if it is
less than 4 or greater than 5 mEq/L.
Bicarbonate infusion in general should be avoided but needs
to be considered for patients who have a pH lower than 7, a serum
bicarbonate level lower than 5.0 mEq/L, a K+ concentration
greater than 6.5 mEq/L, hypotension unresponsive to fluid
replacement, severe left ventricular failure, or respiratory depres-
sion. Under these circumstances, 50 to 100 mEq (1 to 2 ampules)
of bicarbonate may be infused intravenously over 2 hours.
As DKA resolves, it is important to continue providing ade-
quate insulin to effectively resolve the ketosis, which may correct
more slowly than the other abnormalities. This can be accom-
plished by adding glucose to the intravenous regimen (e.g., 5%
glucose in half-normal saline) when blood glucose levels decrease
to less than 200 to 250 mg/dL and continuing insulin infusion at
1 to 2 U/hour.
In patients with resolved DKA, transition to subcutaneous
insulin can be made when the patient is clinically stable with
normal vital signs, the acidosis is fully corrected, the patient is
able take fluids orally without nausea or vomiting, and any pre-
cipitating conditions (e.g., infection) are controlled.
Hyperglycemic Hyperosmolar State
A hyperglycemic hyperosmolar state (HHS) occurs almost exclu-
sively in patients with T2DM, one third of whom have not been
previously diagnosed. Patients often are elderly and frequently
have compromised renal function. Insulin deficiency, often exac-
erbated by insulin resistance resulting from the stress, leads to
hyperglycemia, glucosuria, and an osmotic diuresis. However, the
presence of some endogenous insulin secretion suppresses lipol-
ysis and ketogenesis enough to prevent ketoacidosis. Patients
with HHS typically develop more marked hyperglycemia, fluid
and electrolyte deficits, and hyperosmolality compared to those
with DKA. HHS usually develops insidiously over days to weeks,
670 Section X  Endocrine Disease and Metabolic Disease
and patients may be vulnerable to development of more severe
hyperglycemia and volume deficits over this extended period.
HHS is associated with infections (40%), diuretic use (35% to
40%), and residency in nursing homes (25% to 30%). Other
precipitating and complicating factors may include intestinal
obstruction, mesenteric thrombosis, pulmonary embolism, peri-
toneal dialysis, subdural hematoma, and an extensive list of medi-
cations. The overall mortality rate exceeds that of DKA (10% to
40%), with higher mortality rates associated with age older than
70 years, nursing home residency, and higher osmolality or serum
Na+ concentration. Clinically, patients have evidence of the
marked fluid and electrolyte deficits and tend to have more prom-
inent neurologic abnormalities than those with DKA, including
confusion, obtundation, and coma.
Therapy for HHS follows the same general principles as that
for DKA, with a greater volume replacement required (typically
8 to 12  L in fully developed HHS). Restoration of the fluid
and electrolyte deficits should proceed more slowly than in
DKA, ideally over 36 to 72 hours. Insulin therapy should be
started only after rehydration is in progress. There is a need
for K+ replacement, but less than in DKA. Patients with HHS
may be more sensitive to insulin than those with DKA and
may require lower insulin doses. In view of the severe dehydra-
tion and predisposition to vascular thrombosis, heparin pro-
phylaxis usually should be provided. Despite the very marked
hyperglycemia of HHS, patients may be able to return to oral
treatment eventually.
Chronic Complications of Diabetes
Chronic complications of T1DM and T2DM are similar and
include microvascular complications (nephropathy, retinopathy,
and neuropathy) and macrovascular or cardiovascular complica-
tions (coronary artery disease, peripheral vascular disease, and
cerebrovascular disease). The long-term complications of diabe-
tes result in substantial morbidity and shorten the average life­
span by 10 years. Candidate mechanisms for microvascular and
macrovascular complications include activation of the polyol
pathway (with accumulation of sorbitol), formation of glycated
proteins and advanced glycation end products (cross-linked gly-
cated proteins), abnormalities in lipid metabolism, increased
oxidative damage, hyperinsulinemia, hyperperfusion of certain
tissues, hyperviscosity, platelet dysfunction (increased aggrega-
tion), endothelial dysfunction, and activation of various growth
factors.
Microvascular Complications
Retinopathy
Diabetic retinopathy affects almost all patients with T1DM and
60% to 80% of those with T2DM by 20 years after the diagnosis
of diabetes. It is the most common cause of blindness in persons
between the ages of 20 and 74 years in the developed world. The
incidence and progression of diabetic retinopathy increase with
duration of diabetes, poor glycemic control, the type of diabetes
(T1DM more than T2DM), and the presence of hypertension,
smoking, dyslipidemia, nephropathy, and pregnancy.
Early interventions often are beneficial in slowing or some-
times reversing diabetic retinopathy, but most patients have no
symptoms until the lesions are advanced. Therefore, annual
ophthalomologic screening is recommended starting at 5 years
after diagnosis in T1DM and at the time of diagnosis in T2DM.
In nonproliferative retinopathy, the progression to visual loss
in patients with clinically significant macular edema is improved
by focal laser photocoagulation. Panretinal photocoagulation
improves outcomes in patients with proliferative retinopathy and
also in the subset of T2DM patients with severe nonproliferative
diabetic retinopathy. Patients who have had vitreous hemorrhage
and resulting visual loss may have significant restoration of vision
with vitrectomy. In addition to diabetic retinopathy, patients with
diabetes are at increased risk for development of cataracts.
Nephropathy
Diabetic nephropathy is the most common cause of end-stage
renal disease (ESRD) in developed countries (about 30% of
cases). However, the risk of progression to ESRD has been mark-
edly decreasing over the last several decades. ESRD now appears
to affect fewer than 10% of patients. The risk of developing
advanced renal disease in diabetes is increased by poor glycemic
control, hypertension, smoking, and possibly use of oral contra-
ceptives, obesity, and more advanced age.
Diabetic nephropathy is primarily a glomerulopathy, with
pathologic features that include mesangial expansion, glomerular
basement membrane thickening, and glomerular sclerosis. Many
but not all patients develop albuminuria early in the course, and
the level of albumin correlates with the rate of progression and
the degree of renal injury. For this reason, patients should be
monitored annually for albuminuria starting 5 years after diagno-
sis in T1DM and at the time of diagnosis in T2DM. Measure-
ment of the ratio of microalbumin to creatinine in a random urine
sample is adequate, because this ratio correlates well with results
from 24-hour collections. Albumin excretion of 30 to 300 mg per
gram of creatinine is designated moderately increased albuminuria
(previously called “microalbuminuria”) and indicates probable
diabetic nephropathy. Albumin excretion of greater than 300 mg
per gram of creatinine is designated severely increased albuminuria
(formerly “macroalbuminuria”); these patients are at high risk for
progression to nephrotic-range proteinuria and ESRD.
Efforts to achieve blood glucose targets and rigorously control
blood pressure (appropriate to age and overall risk profile) should
be part of the strategy for primary prevention of nephropathy in
all patients with diabetes. Blood pressure should be maintained
lower than 130/80 mm Hg unless otherwise contraindicated.
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin
receptor blockers (ARBs) are preferable first-line agents. The
calcium channel blockers diltiazem and verapamil can be used as
alternatives in patients who are unable to tolerate ACE inhibitors
or ARBs, or as additive therapy in patients who need multiple
drugs to control blood pressure. Diuretics and moderate Na+
restriction also frequently are needed to reach blood pressure
goals.
Neuropathy
The likelihood of development of diabetic neuropathy increases
with duration of disease and is influenced by the degree of glyce-
mic control (occurring overall in up to 70% of people with dia-
betes). Any part of the peripheral or autonomic nervous system
may be affected. Peripheral polyneuropathy occurs most
 Chapter 66  Diabetes Mellitus, Hypoglycemia 671
commonly, usually manifesting as a bilaterally symmetrical,
distal, primarily sensory polyneuropathy (with or without motor
involvement) in a glove-and-stocking distribution. Pain, numb-
ness, hyperesthesias, and paresthesias progress to sensory loss.
This condition, together with loss of proprioception, can lead to
an abnormal gait with repeated trauma and potential for fractures
of the tarsal bones, sometimes resulting in the development of
Charcot joints. These changes lead to abnormal pressures in the
feet that, together with the soft tissue atrophy related to periph-
eral arterial insufficiency, result in foot ulcers that may progress
to osteomyelitis and gangrene. Detailed, regular neurologic
examination of all patients is essential to elicit the early loss of
light touch (using a size 5.07/10-g monofilament), reflexes, and
vibratory sensation.
A second common form of diabetic neuropathy is autonomic
neuropathy, which may develop in concert with or separate from
distal polyneuropathy. Resulting symptoms can be debilitating,
including postural hypotension leading to falls or syncope, gas-
troparesis, enteropathy with constipation or diarrhea, and bladder
outflow obstruction with urinary retention. Diabetic autonomic
neuropathy together with vascular disease is a contributor to
erectile dysfunction in males. Gastrointestinal dysfunction with
autonomic neuropathy can complicate efforts to achieve blood
glucose control by causing variable absorption of food. A sus-
pected diagnosis of autonomic neuropathy can be strengthened
by demonstrating loss of normal variability in heart rate with
deep respirations or the Valsalva maneuver.
Other, less common manifestations of diabetic neuropathy
include thoracic and lumbar nerve root polyradiculopathies, indi-
vidual peripheral and cranial nerve mononeuropathies, and
asymmetrical neuropathies of multiple peripheral nerves (mono-
neuropathy multiplex). Diabetic amyotrophy causing muscle
atrophy and weakness most often involving the anterior thigh
muscles and pelvic girdle is an uncommon form of diabetic neu-
ropathy that often resolves after several months.
The primary approach to all diabetic neuropathies consists
of efforts to improve blood glucose control. Clinical trials have
shown decreased development of distal polyneuropathy with
improved glycemia in T1DM. It also is particularly important
for patients with neuropathies to receive regular foot care, includ-
ing daily self-inspection of the feet, regular physician examina-
tions, and early interventions for developing callouses, infections,
or other foot lesions. Painful polyneuropathies cause substantial
morbidity and are difficult to treat. First-line drugs include
amitriptyline, venlafaxine, duloxetine, and pregabalin. For
patients who do not respond adequately to one drug, combina-
tion therapy with two drugs of different classes can be tested.
Alternative treatments that may be effective in some patients
include topical capsaicin cream, lidocaine patch, α-lipoic
acid, isosorbide dinitrate topical spray, and transcutaneous elec-
trical nerve stimulation (TENS). Gastroparesis secondary to
autonomic neuropathy may improve symptomatically with
metoclopramide or domperidone (dopamine D2 antagonists),
erythromycin (motilin agonist) for bacterial overgrowth, cis-
apride (cholinergic agonist), or mosapride (selective serotonin
5-HT4 receptor agonist). Diarrhea may respond to loperamide
or diphenoxylate and atropine. Orthostatic hypotension can be
treated by attention to mechanical factors such as elevation of
the head of the bed, gradual rising from a lying to standing
position, use of support stockings, and sometimes use of the
mineralocorticoid fludrocortisone.
Macrovascular Complications
The risk of macrovascular disease including cardiovascular
disease, transient ischemic attacks and strokes, and peripheral
vascular disease is increased twofold to fourfold and accounts for
70% to 80% of deaths in patients with diabetes. This increased
risk is believed to result from the altered metabolism in diabetes
and also from the frequent occurrence of associated risk factors
in diabetic patients, including hypertension and dyslipidemia.
Screening for macrovascular disease and predisposing factors
were discussed earlier. Approaches to decreasing the risk of mac-
rovascular disease should include optimization of blood glucose
control, weight loss for overweight and obese patients, smoking
cessation, control of blood pressure, and treatment of dyslipid-
emia. (See Chapter 69 for details on the management of
dyslipidemia.)
  HYPOGLYCEMIA
Definition
Hypoglycemia most often occurs in patients with T1DM or
T2DM under circumstances in which insulin or other antidia-
betic therapies result in blood glucose levels’ decreasing below
the lower limit of normal (<50 to 60 mg/dL for most laborato-
ries). This may be caused by overtreatment with glucose-lowering
agents, failure to take in anticipated calories, or the combination
of increased glucose utilization and increased insulin sensitivity
induced by exercise.
Hypoglycemia much less commonly occurs as a primary dis-
order in patients who do not have drug-treated diabetes. Under
these circumstances, clinically significant hypoglycemia can be
difficult to identify based on blood glucose measurements alone,
because the normal lower limit of blood glucose varies in indi-
viduals and is influenced by duration of fasting and gender.
Plasma glucose levels during a fast in men decrease to approxi-
mately 55 mg/dL at 24 hours and 50 mg/dL at 48 and 72 hours,
whereas in premenopausal women they may be as low as 35 mg/
dL at 24 hours without symptoms of hypoglycemia. In evaluating
glucose determinations, it is important to recognize that plasma
levels are approximately 15% higher than glucose levels in whole
blood. Clinically significant hypoglycemia can be most readily
established if patients manifest Whipple’s triad, which refers to the
combination of: (1) symptoms suggestive of hypoglycemia, (2)
documented low plasma glucose levels (<50 to 60 mg/dL), and
(3) prompt resolution of symptoms when the low blood glucose
is corrected.
Signs and Symptoms
Typical signs and symptoms of hypoglycemia are listed in Table
66-8. Autonomic symptoms result from sympathetic neural
outflow that occurs as part of the counter-regulatory response to
hypoglycemia. Although most patients appear to fully recover
CNS function after a neuroglycopenic episode, there is a risk of
irreversible brain damage or death with sustained or repeated
episodes of severe neuroglycopenia.
672 Section X  Endocrine Disease and Metabolic Disease

TABLE 66-8  SIGNS AND SYMPTOMS OF TABLE 66-9  ETIOLOGIC CLASSIFICATION OF

HYPOGLYCEMIA HYPOGLYCEMIC DISORDERS
AUTONOMIC MANIFESTING IN ADULTS
Sweating Palpitations Hunger DRUG-INDUCED
Pallor Tachycardia Nausea Antidiabetic agents (insulin, sulfonylureas, meglitinides)
Anxiety Hypertension Vomiting Alcohol
Tremor Irritability Paresthesias Other pharmacologic agents (β-blockers, ACE inhibitors, pentamidine,
NEUROGLYCOPENIC quinine, quinolones and many others)
Difficulty thinking Dizziness Seizures ALTERED GASTROINTESTINAL FUNCTION
Fatigue, weakness Visual blurring Loss of consciousness Alimentary hypoglycemia
Somnolence Confusion Coma
Headache Abnormal behavior Death BETA-CELL INSULIN OVERSECRETION
Insulinoma
Non-insulinoma pancreatogenous hypoglycemia (without or with bariatric
Pathology surgery)
Hypoglycemic disorders can result when there is overproduction NON–ISLET CELL NEOPLASMS
of hormones that lower glucose concentrations, underproduc- Tumor insulin-like growth factor-II secretion
tion of hormones that serve to elevate glucose levels, deficiency Tumor glucose consumption
of substrates for endogenous glucose synthesis, or changes in AUTOIMMUNE
cells and tissues that result in their increased consumption of Circulating insulin antibodies
glucose. Insulin receptor activating antibodies
ENDOCRINE DEFICIENCIES
Etiologic Classification Glucocorticoids (adrenal insufficiency), growth hormone, catecholamines,
Causes of hypoglycemia by etiologic categories are listed in glucagon
Table 66-9. SEVERE ILLNESS
Sepsis
Drug-Induced Hepatic failure
Renal failure
The most common causes of hypoglycemia are excess insulin or
MALNUTRITION
insulin secretagogues (especially sulfonylureas) administered in
Anorexia nervosa
the treatment of diabetes. Ethanol is another commonly used
drug that can cause hypoglycemia. This most often occurs in the ACE, Angiotensin-converting enzyme.

context of chronic alcoholism in an individual who is nutrition-

ally depleted, often after binge drinking for several days or longer.
Under these circumstances, hepatic glycogen stores become
depleted, and the process of alcohol metabolism blocks gluco-
neogenesis by depriving the liver of nicotinamide adenine
dinucleotide (NAD+). Commonly used pharmacologic agents
that have been associated with hypoglycemia include β-
blockers (especially nonselective β2-adrenergic antagonists),
ACE inhibitors, pentamidine (through toxic effects on beta
cells), quinine, and quinolones.
Excess Endogenous Insulin or
Insulin-like Hormones
Alimentary hypoglycemia is a disorder in which low blood glucose
levels occur typically 90 to 180 minutes after meals in patients
who have undergone gastric outlet surgery with resulting acceler-
ated gastric emptying. This is distinct from the more common
dumping syndrome, which results from rapid entry of an osmotic
load into the small intestine and associated fluid shifts and auto-
nomic responses and is not associated with hypoglycemia. “Reac-
tive hypoglycemia” is a now outmoded term that previously was
applied to adrenergic symptoms occurring 2 to 4 hours after a
meal in patients who are not hypoglycemic; these individuals
may experience decreased symptoms with frequent feedings and
avoidance of high-carbohydrate meals.
Tumors of islet beta cells (insulinomas) can cause hypoglyce-
mia by producing excess insulin in an unregulated manner. They
are uncommon (1 in 250,000 patient-years), but it is important
to recognize them when they do occur. Insulinomas usually are
small (1 to 2 cm), benign (>90%), solitary (>90%), and confined
to the endocrine pancreas (99%). Some patients have an indolent
course extending over many years before diagnosis, but insulino-
mas can produce profound hypoglycemia. There is a tendency for
adrenergic symptoms to become suppressed as a consequence of
repeated exposures to hypoglycemia, and neuroglycopenic symp-
toms may predominate, including sometimes bizarre behavioral
abnormalities. Patients may eat frequently in response to the
hypoglycemia and exhibit moderate weight gain.
Non-insulinoma pancreatogenous hypoglycemia is a disorder that
may manifest with symptoms similar to those of insulinomas, but
the pathology involves beta-cell hypertrophy and hyperplasia
rather than the presence of a discrete tumor. More recently, the
development of hypoglycemia with similar beta-cell hyperplasia
has been described in a small number of patients, more often in
females, months to years after Roux-en-Y gastric bypass surgery.
Non–islet cell neoplasms are a rare cause of hypoglycemia; they
produce an insulin-like growth factor (IGF), usually a partially
processed form of IGF-II designated big IGF-II, that can have
insulin-like effects. The tumors typically are large and malignant
and are most often located in the retroperitoneal space, abdomen,
or thoracic cavity. Tumor types include hemangiopericytomas,
hepatocellular carcinomas, lymphomas, adrenocortical carcino-
mas, gastrointestinal carcinoids, and mesenchymal tumors. Some
large tumors cause hypoglycemia in the absence of detectable
insulin-like factors.
 Chapter 66  Diabetes Mellitus, Hypoglycemia 673
Hormone Deficiencies
Deficiencies of insulin counter-regulatory hormones, which nor-
mally function to raise glucose levels, can result in or contribute
to hypoglycemia. An example is low levels of corticosteroids
caused by primary or secondary adrenocorticoid insufficiency.
Deficiencies of other hormones, including catecholamines, glu-
cagon, and growth hormone, also can cause hypoglycemia.
Severe Illness
Hypoglycemia can occur during severe illness through a number
of different mechanisms in association with sepsis, hepatic insuf-
ficiency, and renal failure. Patients with severe illness appear to
be particularly vulnerable to hypoglycemia when they are poorly
nourished, although malnutrition alone is rarely associated with
hypoglycemia.
Approach to the Diagnosis
For patients who have well-documented hypoglycemia, the diag-
nosis often is evident or strongly suggested by the clinical setting,
history, and physical examination findings. Hypoglycemia
induced by insulin or other glucose-lowering agents in diabetic
patients often is immediately apparent from the medical history.
Alcohol-induced hypoglycemia may be suspected in a patient
with a known or suspected history of alcohol abuse and binge
drinking. Identification of other candidate drugs as a cause of
hypoglycemia requires a thorough medical history, and the con-
dition can be expected to resolve if the suspect medication is
stopped. The patient may have a known diagnosis of adrenal
insufficiency, or this may be suggested by other clinical findings
(e.g., orthostatic hypotension, increased skin pigmentation) or
the development of markedly increased insulin sensitivity in a
patient with T1DM. The patient may have a known tumor sug-
gesting the possibility of a non–islet cell neoplasm as a cause of
hypoglycemia. There may be a history of Roux-en-Y bypass
surgery, raising the possibility of beta-cell hyperplasia. The
co-occurrence of sepsis, hepatic failure, renal failure, profound
malnutrition, or a known diagnosis of anorexia nervosa may
suggest one of these potential underlying causes.
A number of algorithms have been developed to guide the
evaluation of documented or potential hypoglycemia, including
a recommended approach from an expert panel published by
the Endocrine Society. If there is an opportunity to observe
the patient during a symptomatic episode of presumed hypo-
glycemia, plasma should be obtained, if possible before treat-
ment, for measurement of glucose, insulin, proinsulin, C-peptide,
β-hydroxybutyrate, and screening for sulfonylureas and megli-
tinides. Hypoglycemia can be rapidly, provisionally confirmed
with a test meter. After blood samples have been obtained for
the tests described, glucose should be administered orally (15
to 30  g) or intravenously (25  g, or 1 ampule of 50% dextrose),
and recovery of glucose levels and symptoms should be
observed.
For patients with suspected or confirmed hypoglycemia devel-
oping specifically in the fasted state, it may be possible to replicate
the condition by observing during several hours of daytime
fasting, with or without a preceding overnight fast. The same
laboratory testing panel as described earlier then can be obtained
if symptoms suggestive of hypoglycemia occur. For patients who
describe postprandial hypoglycemic symptoms (within 5 hours
after a meal), a mixed meal (not a pure glucose load) should be
provided, with blood sampling at baseline and every 30 minutes
thereafter for 5 hours
For patients who do not manifest hypoglycemia with the
testing procedures described despite a strong suspicion of hypo-
glycemia, the most frequently utilized approach is a 72-hour fast
according to a protocol developed at the Mayo Clinic. Blood is
obtained every 6 hours and at test termination. The test is ended
at 72 hours or at an earlier time point if the plasma glucose level
decreases (by glucose meter testing) with associated symptoms
to 45 mg/dL (2.5 mmol/L) or lower or to less than 55 mg/dL
(3 mmol/L) in a patient with prior documentation of Whipple’s
triad. At the end of the 72-hour test period, the patient is given
1 mg of glucagon intravenously, and blood is obtained at 10, 20,
and 30 minutes, after which the patient is given a meal. The final
blood sample obtained at the end of the fast (before glucagon
administration) is analyzed additionally for β-hydroxybutyrate
and a sulfonylurea/meglitinide panel.
For any of these test protocols, elevations of insulin, proin-
sulin, and C-peptide associated with hypoglycemia at the same
time point are consistent with an insulinoma, beta-cell hyper-
plasia, the effects of an insulin secretagogue (sulfonylurea or
meglitinide), or the presence of insulin antibodies. An elevation
in these three hormones during a meal test in a patient who has
had gastric surgery is suggestive of alimentary hypoglycemia.
Plasma insulin, proinsulin, and C-peptide are not elevated in
patients with hypoglycemia secondary to extrapancreatic neo-
plasms. This diagnosis usually can be further confirmed by evi-
dence of a large tumor with various imaging techniques. High
insulin levels, together with low proinsulin and C-peptide con-
centrations in the presence of hypoglycemia, is indicative of
exogenous insulin administration. Factitious hypoglycemia sec-
ondary to insulin or insulin secretagogue administration is
uncommon and has been observed in individuals with or without
diabetes.
Treatment
The most important therapeutic step in hypoglycemia is to iden-
tify and treat the underlying causes, including drugs, alcohol,
serious infection, tumors, and hypoadrenalism. The occurrence
of hypoglycemia usually can be substantially improved in patients
with alimentary hypoglycemia by a modified feeding regimen
with frequent, small meals and avoidance of concentrated sources
of rapidly digested and absorbed carbohydrate.
Non–islet cell tumor hypoglycemia is treated by tumor resec-
tion if possible. For nonresectable tumors, a debulking procedure
may be effective in reducing hypoglycemia. Hypoglycemia in
patients with insulinomas can be cured by resection. Persistent
hypoglycemia secondary to nonresectable insulinoma can some-
times be treated effectively with diazoxide, long-acting soma-
tostatin analogues (octreotide or lanreotide), verapamil, or
phenytoin. For patients with beta-cell hyperplasia after bariatric
surgery, first-line treatment includes diet modifications with
more frequent, small meals and avoidance of concentrated
sources of carbohydrate to decrease meal-induced insulin
secretion.
674 Section X  Endocrine Disease and Metabolic Disease
For a deeper discussion of this topic, please see Chapter
229, “Diabetes Mellitus,” and Chapter 230, “Hypoglycemia/
Pancreatic Islet Cell Disorders,” in Goldman-Cecil Medi-
cine, 25th Edition.
SUGGESTED READINGS
American Diabetes Association clinical practice recommendations 2013,
Diabetes Care 36(Suppl 1):S1–S108, 2013.
Bril V, England J, Franklin GM, et al: Evidence-based guideline: treatment of
painful diabetic neuropathy. Report of the American Academy of Neurology,
the American Association of Neuromuscular and Electrodiagnostic Medicine,
and the American Academy of Physical Medicine and Rehabilitation,
Neurology 76:1758–1765, 2011.
Coustan DR: Gestational diabetes mellitus, Clin Chem 59:1310–1321, 2013.
Cryer PE, Axelrod L, Grossman AB, et al: Evaluation and management of adult
hypoglycemic disorders: an Endocrine Society clinical practice guideline,
J Clin Endocrinol Metab 94:709–728, 2009.
Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome, Lancet 365:1415–
1428, 2005.
Eringsmark Regnéll S, Lernmark A: The environment and the origins of islet
autoimmunity and type 1 diabetes, Diabet Med 30:155–160, 2013.
Forbes JM, Cooper ME: Mechanisms of diabetic complications, Physiol Rev
93:137–188, 2013.
Gross JL, de Azevedo MJ, Silveiro SP, et al: Diabetic nephropathy: diagnosis,
prevention, and treatment, Diabetes Care 28:164–176, 2005.
Insulin pump therapy, Drug Ther Bull 50:105–108, 2012.
Inzucchi SE, Bergenstal RM, Buse JB, et al: Management of hyperglycemia in
type 2 diabetes: a patient-centered approach. Position statement of the
American Diabetes Association (ADA) and the European Association for the
Study of Diabetes (EASD), Diabetes Care 35:1364–1379, 2012.
Kavvoura FK, Owen KR: Maturity onset diabetes of the young: clinical
characteristics, diagnosis and management, Pediatr Endocrinol Rev 10:234–
242, 2012.
Mauras N, Fox L, Englert K, et al: Continuous glucose monitoring in type 1
diabetes, Endocrine 43:41–50, 2013.
Nathan DM, Cleary PA, Backlund JY, et al: Intensive diabetes treatment and
cardiovascular disease in patients with type 1 diabetes. Diabetes Control
and Complications Trial/Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research Group, N Engl J Med
353:2643–2653, 2005.
Pickup JC: Insulin-pump therapy for type 1 diabetes mellitus, N Engl J Med
366:1616–1624, 2012.
Seaquist ER, Anderson J, Childs B, et al: Hypoglycemia and diabetes: a report of
a workgroup of the American Diabetes Association and the Endocrine Society,
J Clin Endocrinol Metab 98:1845–1859, 2013.
Torres JM, Cox NJ, Philipson LH: Genome wide association studies for diabetes:
perspective on results and challenges, Pediatr Diabetes 14:90–96, 2013.

  DEFINITION AND EPIDEMIOLOGY
Obesity is a disease that is usually defined as a body mass index
(BMI) greater than or equal to 30 kg/m2 (weight [kg]/(height
[m])2). A BMI of 30 to 34.9 is considered class 1 obesity, 35 to
39.9 is class 2 obesity, and 40 or higher is class 3 or severe obesity.
The term “morbid obesity” previously was applied to individuals
weighing at least 45 kg (100 lb) more than, or typically about
60% more than, desirable body weight; the term also has been
applied to any individual with a BMI greater than or equal to
40 kg/m2.
There is increasing recognition of limitations to defining
obesity based on BMI resulting from the variable correlation
between BMI and amount of body fat in different ethnic (genetic)
populations or in individuals with different degrees of muscular-
ity. Many investigators and clinicians are moving toward a defini-
tion that defines obesity as an excess of body fat sufficient to
confer risk. Linking obesity to cardiometabolic risk, body fat dis-
tribution, and waist circumference is more important than mea-
suring percentage body fat or BMI alone. People who accumulate
visceral fat and clinically have higher waist circumference (meta-
bolic obesity) are at much higher risk for cardiovascular disease
and diabetes than those with the same BMI or the same percent-
age of body fat but a lower waist circumference. The National
Cholesterol Education Program Adult Treatment Panel III (ATP
III) considered a waist circumference greater than 40 inches
(102 cm) in American men or 35 inches (88 cm) in American
women to be among the five criteria that define the cardiometa-
bolic syndrome. In spite of its limitations, BMI remains a simple
measurement with utility in estimating a person’s health risks and
comparing outcomes between trials.
During the last 30 years, there has been a dramatic increase
in the percentage of both adults and children in the United
States who are overweight (defined as BMI of 25 to 30) or
obese. According to the 2009-2010 National Health and Nutri-
tion Examination Survey (NHANES) conducted by the Centers
for Disease Control and Prevention (CDC), more than one
third of U.S. adults (35.7%) were obese. This was more than
double the prevalence in the 1976-1980 NHANES data (15.0%).
Non-Hispanic blacks had the highest age-adjusted rates of
obesity (49.5%), followed by Mexican Americans (40.4%), all
Hispanics (39.1%), and non-Hispanic whites (34.3%). More
recently, there appears to have been a slowing of the rate of
increase or even a leveling off. Obesity prevalence varies sig-
nificantly across states, from a low of 20.5% in Colorado to a
high of 34.7% in Louisiana in 2012. In general, higher prevalence
of adult obesity was found in the midwest (29.5%) and the
67 
Obesity
Osama Hamdy
south (29.4%) and lower prevalence in the northeast (25.3%)
and the west (25.1%).
The percentage of children and adolescents who are over-
weight or obese has almost tripled since 1980. Currently, 17% of
children and adolescents aged 2 to 19 years (12.5 million indi-
viduals) are obese. NHANES data from 1976-1980 and from
2009-2010 show the prevalence of obesity increasing from 5.0%
to 12.1%, respectively, for children aged 2 to 5 years and from
5.0% to 18.4% for those aged 12 to 19 years. Among low-income
preschool children, the prevalence of obesity increased between
1998 and 2003 from 13.0% to 15.2%, and severe obesity from
1.8% to 2.2%. These rates decreased slightly between 2003 and
2010: obesity from 15.2% to 14.9%, and severe obesity from 2.2%
to 2.1%.
Overweight and obesity and their associated health problems
have a significant economic impact on the U.S. health care system
through direct medical expenses and indirect costs (e.g., loss of
work time and productivity). Medical costs of obesity account
for an estimated 10% of total U.S. medical expenditures. The
estimated total annual medical costs of obesity in the United
States was $147 billion in 2008, with medical costs on average
$1429 higher per year for obese compared with normal-weight
individuals. Approximately half of these costs were paid by Med-
icaid and Medicare.
  PATHOLOGY OF OBESITY
Obesity develops as a consequence of genetic-environmental
interactions, such that genetically prone individuals who lead a
sedentary lifestyle and consume larger amounts of dietary calo-
ries are at higher risk. Children of obese parents are 80% more
likely to become obese, and it is believed that this results from a
combination of genetic and environmental influences.
The genetic contributions to obesity are most commonly con-
sidered to reflect the combined effects of variations in multiple
genes and only rarely appear to result from a defect in a single
powerful gene. Single-gene defects identified in experimental
animals have been useful to demonstrate appetite and satiety
mechanisms, and mutations in some of these same genes have
subsequently been identified in rare human forms of genetic
obesity. For example, loss-of-function mutations in the leptin
gene and in the cellular receptor for leptin were first identified as
a cause of obesity in laboratory mice (ob/ob and db/db mice,
respectively). Leptin is a hormone that is produced in fat cells,
mostly in subcutaneous fat. It is a potent satiety factor that acts
in the arcuate nucleus of the hypothalamus to reduce the produc-
tion of neuropeptide Y, a stimulator of food intake. After its dis-
covery in mice, leptin gene mutations were identified as a cause
675
676 Section X  Endocrine Disease and Metabolic Disease
of a rare form of heritable human obesity. Affected individuals
develop marked obesity in childhood as a consequence of
increased food intake. Leptin secretion normally follows a circa-
dian pattern, with higher levels during evening and night hours.
Loss of leptin secretion has particularly marked effects during
these hours, resulting in a phenomenon known as night-eating
syndrome, in which patients tend to consume large amounts of
food during the night.
Other single-gene defects identified as rare causes of human
obesity include loss-of-function mutations in genes encoding
carboxypeptidase E, melanocortin-4 or melanocortin-3 recep-
tors, and serotonin-2C or serotonin-1B receptors. Obesity is also
a feature of many other genetic disorders in which the specific
mechanisms of the obesity are less well understood. These differ-
ent syndromes may have autosomal dominant, autosomal reces-
sive, or X-linked inheritance patterns, consistent with multiple
different genetic causes. Among the best known of these disor-
ders, the Bardet-Biedl syndrome, is an autosomal recessive disor-
der characterized by obesity and other abnormalities, including
hypogonadism in men, mental retardation, retinal dystrophy,
polydactyly, and renal malformations. In Prader-Willi syndrome,
loss of portions of the long arm of chromosome 15 (q11-13) is
associated with obesity, poor muscle tone in infancy, defects in
cognition, behavioral abnormalities (irritability), short stature,
and hypogonadotropic hypogonadism.
Although known single-gene mutations account for only a
small percentage of human obesity, there is evidence for wide-
spread heritable influences in more common forms of human
obesity. For example, in twin and adoptee studies, both members
of identical twin pairs tend to become obese in concordance with
the same weight pattern as their biologic parents, even when
raised apart. Metabolic rate, spontaneous physical activity, and
thermic response to food seem to be heritable to a variable extent,
but the specific genes that contribute to prevalent forms of
human obesity have not yet been defined. Genomic analyses in
large populations have identified multiple genes or genetic
regions in which polymorphisms are associated with obesity risk.
These include polymorphisms in or near genes for the
melanocortin-4 receptor (a protein involved in appetite suppres-
sion pathways in the hypothalamus), brain-derived neurotrophic
factor (role in energy balance); the β3-adrenergic receptor (role
in visceral fat accumulation), and peroxisome proliferator-
activated receptor-γ2 (PPAR-γ2, a transcription factor involved
in adipocyte differentiation. Multiple other sites of genetic varia-
tion associated with increased obesity risk have been identified
for which potential mechanistic links to obesity are not yet appar-
ent. It is hypothesized that the heritable component of common
forms of human obesity derives from the effects of variations in
these and many yet unidentified genes acting both additively and
synergistically.
Important environmental factors driving the recent increased
prevalence of obesity include increased caloric intake (reflecting
greater availability of high-calorie, low-cost foods) and decreased
energy expenditure (as a consequence of decreased physical
activity). Lower socioeconomic status, lower education level,
cessation of smoking, and consumption of carbohydrates with a
high glycemic index have been identified as specific confounders
of obesity. Additional factors that may influence obesity risk
include intrauterine growth and nutritional history, levels of
reproductive and other hormones, and factors that may alter the
feedback between energy intake and expenditure. Ultimately, an
increase in total body fat results from energy intake that exceeds
energy expenditure. This occurs through the operation of genetic
and environmental influences, together with individual behav-
ioral characteristics.
  PATHOLOGY OF OBESITY-ASSOCIATED HEALTH RISKS
Adipose tissue is not just a passive depot for lipids. Adipocytes
also function as a complex and active endocrine organ with meta-
bolic and secretory products (hormones, prohormones, cyto-
kines, and enzymes) that play a major role in whole-body
metabolism. Relationships between obesity and both insulin
resistance and endothelial dysfunction (the early stage of athero-
sclerosis) are mediated through the release of several hormones
from adipose tissue. These hormones, designated adipocytokines
or adipokines, comprise a group of pharmacologically active low-
and medium-molecular-weight proteins that possess autocrine
and paracrine effects and are known products of the inflamma-
tory and immune systems. They play an important role in adipose
tissue physiology and in initiating metabolic and cardiovascular
abnormalities, not only in overweight and obese individuals but
also in lean persons with higher visceral fat mass. Adipokines
include adiponectin, leptin, tumor necrosis factor-α (TNF-α),
interleukin-6 (IL-6), resistin, plasminogen activator inhibitor-1
(PAI-1), angiotensinogen, and monocyte chemoattractant
protein-1 (MCP-1). An increased amount of adipose tissue or its
disproportionate distribution between central and peripheral
body regions is related to altered serum levels of these factors.
With the exceptions of leptin and adiponectin, the adipokines are
produced both from fat cells and from adipose tissue–resident
macrophages in the stromal tissues surrounding fat cells. For
unknown reasons, an increase in the amount of body fat is associ-
ated with increases in the number of adipose tissue macrophages
and their production of cytokines.
Human adiponectin is a relatively abundant, 244-amino-acid
polypeptide in plasma, accounting for 0.01% of total plasma pro-
teins. Adiponectin gene expression in adipose tissue is associated
with obesity, insulin resistance, and type 2 diabetes (T2DM).
Hypoadiponectinemia is more strongly related to the degree of
insulin resistance than to the degree of adiposity or glucose intol-
erance. Genetic polymorphisms may influence the regulation of
adiponectin and lead to variations in its levels among different
individuals. Several human studies have shown that high adipo-
nectin levels protect against development of T2DM and point to
the possible future use of adiponectin as an indicator of diabetes
risk. Low plasma concentrations of adiponectin are observed in
patients with coronary artery disease (CAD), and lower adipo-
nectin levels have been found in diabetic patients with CAD than
in those without CAD. In obesity, a 10% reduction in body
weight leads to a significant increase in adiponectin (40% to
60%) in both diabetic and nondiabetic patients. Adiponectin is
also involved in the modulation of inflammatory responses
through attenuation of TNF-α–mediated inflammatory effects,
regulation of endothelial function, and inhibition of growth
factor–induced proliferation of vascular smooth muscle cells.
Leptin is a 167-amino-acid adipocyte-derived hormone that
circulates in the plasma in free and bound forms. It affects energy
balance by activating specific centers in the hypothalamus to

decrease food intake, increase energy expenditure, modulate
glucose and fat metabolism, and alter neuroendocrine function.
Leptin plasma levels increase exponentially with increased fat
mass (fourfold higher in obese compared with lean individuals in
one study), and this is thought to reflect resistance to leptin in
obesity. Leptin therapy in lipodystrophic patients has been
shown to lower blood glucose, improve insulin-stimulated
hepatic and peripheral glucose metabolism, and reduce hepatic
and muscle triglyceride content, suggesting that leptin acts as a
signal that contributes to regulation of total body sensitivity to
insulin. It has also been found that leptin is independently associ-
ated with cardiovascular mortality. Although both adiponectin
and leptin are integrally related to insulin resistance, adiponectin
is more strongly related to visceral abdominal fat stores, whereas
leptin is more closely related to subcutaneous fat.
Adipose tissue serves as a major source of TNF-α and substan-
tial amounts of IL-6. Levels of these two proinflammatory cyto-
kines correlate with obesity and are strongly related to insulin
resistance. Several studies have demonstrated a strong link
between TNF-α and cardiovascular disease. Plasma levels of
TNF-α are increased in individuals with premature cardiovascu-
lar disease independent of insulin sensitivity. Conversely, circu-
lating levels of TNF-α decrease after weight reduction in parallel
with improvements in endothelial function.
Resistin is an adipocyte-derived, cysteine-rich signaling
protein that is expressed predominantly in white adipose tissue
and is also detectable in serum. Resistin is thought to act at sites
remote from adipose tissue, similar to other adipokines, and to
contribute to insulin resistance in obesity. PAI-1 is another bioac-
tive peptide produced by subcutaneous and visceral fat. Its circu-
lating levels correlate better with visceral than with subcutaneous
adiposity and are a strong predictor of CAD. High PAI-1 levels
are associated with increased blood coagulability. Improvement
in insulin sensitivity by either weight reduction or medication
lowers circulating levels of PAI-1. This decrease in PAI-1 corre-
lates with the amount of weight loss and the decline in serum
triglycerides.
Visceral and subcutaneous fat differ in their production of spe-
cific adipokines, pointing to differences in endocrine function
between these two adipose depots. Removal of a significant
amount of only subcutaneous fat by liposuction in obese indi-
viduals with and without diabetes resulted in reduction in serum
leptin but did not change the serum levels of other cytokines or
any other metabolic parameters. It also did not improve insulin
sensitivity or decrease the high serum insulin level observed ini-
tially in those individuals. In animal models, removal of subcuta-
neous fat resulted in an increase in mesenteric fat volume and
increased production of TNF-α by visceral fat. Although surgical
removal of visceral fat has not been attempted in humans, two
studies of aging in rodent models showed that removal of visceral
fat reduces the production of inflammatory adipokines and
improves glucose tolerance and insulin sensitivity.
Risks Associated with Obesity
Overweight and obese individuals are at increased risk for the
following health conditions:
• Cardiometabolic syndrome
• Type 2 diabetes (T2DM)
Chapter 67  Obesity 677
• Hypertension
• Dyslipidemia
• Coronary heart disease
• Congestive heart failure
• Atrial fibrillation
• Osteoarthritis
• Stroke
• Gall bladder disease
• Fatty liver and nonalcoholic steatohepatitis
• Sleep apnea
• Asthma
• Gastroesophageal reflux (GERD)
• Some cancers (endometrial, breast, and colon)
• Gynecologic disorders (abnormal menses, infertility, polycys-
tic ovarian syndrome)
Weight loss of 7%-10% is associated with reduced risk for
many if not all of these disorders. Recent studies have shown that
significant weight reduction (15% to 25% of initial body weight)
after gastric bypass surgery in class 2 and class 3 obese patients
with T2DM results in transient remission of diabetes for 2 to 10
years. The relative importance of the weight loss itself and the
hormonal changes associated with gastric bypass surgery to
terms of diabetes remission is not yet understood.
  DIAGNOSIS AND ASSESSMENT OF OBESITY
The form of obesity that characteristically occurs in men—
android or abdominal obesity (apple-shaped body configura-
tion)—is closely associated with metabolic complications such
as insulin resistance, hypertension, dyslipidemia, and hyperurice-
mia. By contrast, the typical female or gynecoid obesity (pear-
shaped body configuration), in which fat accumulates in the hips
and gluteal and femoral regions, has milder metabolic complica-
tions. The waist-to-hip circumference ratio (WHR) has been
used to distinguish these forms of obesity. A ratio greater than 1.0
in men or greater than 0.8 in women, indicative of visceral fat
deposition and abdominal obesity, correlates with increased
health risks.
Previously, the “gold standard” technique for measuring total
body fat was hydrodensitometry (underwater weighing). This is
based on the principle that fatty tissue is less dense than muscle.
Currently, dual-energy x-ray absorptiometry (DEXA) scanning
is used to accurately measure body composition, particularly fat
mass and fat-free mass. It has an additional advantage of measur-
ing regional fat distribution. DEXA is more accurate than anthro-
pometric measures and is more cost-effective than computerized
tomography (CT) or magnetic resonance imaging (MRI) scans.
However, DEXA cannot distinguish between subcutaneous and
visceral abdominal fat depots, nor between subcutaneous and
intramuscular peripheral fat depots. Bioelectric impedance is a
simpler and less expensive method for measuring total body fat,
but it is greatly affected by the hydration state of the body and is
less accurate overall than DEXA.
BMI is widely used as measure of obesity. It is calculated by
dividing a person’s body weight in kilograms by the square of
the person’s height in meters; alternatively, weight in pounds ×
703 is divided by the square of the height in inches). A BMI
between 19 and 27 has little association with cardiometabolic
risk in whites. Adverse health consequences occur with a BMI
678 Section X  Endocrine Disease and Metabolic Disease
of 27 or more and increase with increasing levels of BMI. Risks
associated with increased BMI are more pronounced in older
patients.
Waist circumference or WHR or both are often used to indi-
rectly estimate intra-abdominal fat volume in epidemiologic
studies. Although these measures show good correlation with
intra-abdominal fat volume as measured by CT, they are less
accurate than CT. At present, waist circumference is the easiest
anthropometric measurement for routine use by health care pro-
fessionals to estimate visceral adiposity and monitor changes in
visceral fat volume.
The current gold standard techniques for measuring visceral
fat volume are abdominal CT (at the L4-L5 vertebral level) and
MRI. These methods are not widely used because of high cost
and radiation exposure. In contrast to CT, MRI requires addi-
tional definition of adipose tissue by adjusting settings on the
MRI scanner. Several commercial software packages are available
for calculation of visceral fat volume, and it is possible to further
subdivide body fat into at least three separate and measurable
compartments: subcutaneous, intramuscular, and visceral fat.
Visceral fat volume determination by abdominal ultrasonogra-
phy has been investigated for use in research and clinical settings.
Several studies found good correlation between intra-abdominal
fat volume measured by abdominal ultrasound and that mea-
sured by abdominal CT scanning. Measurements should be per-
formed with the patient in the supine position at the end of a
quiet inspiration with compression of the transducer against the
abdomen. Intra-abdominal fat is quantified based on the distance
between the peritoneum and the lumbar spine. Studies have
shown that intra-abdominal fat measured by ultrasound has a
stronger association with metabolic risk factors for CAD than
does waist circumference or WHR. Recently, visceral fat has been
measured using bioelectric impedance, but this technique is less
accurate than CT.
  TREATMENT OF OBESITY
Current guidelines for treatment of obesity are summarized in
Table 67-1. The preferred intervention varies with the obesity
level based on five BMI categories. The major four therapeutic
options are lifestyle modification (diet and exercise), behavior
modification, pharmacologic intervention, and bariatric surgery.
In general, better results are obtained with a combination of dif-
ferent interventions rather than a single modality.
Lifestyle Modification
Key components of effective lifestyle modification most often
include structured dietary interventions and individualized
TABLE 67-1  GUIDE TO SELECTING TREATMENT BASED ON BMI CATEGORY*
TREATMENT 25-26.9 27-29.9
Diet, physical activity, Yes with comorbidities Yes with comorbidities
behavior therapy
Pharmacotherapy Yes with comorbidities
Weight-loss surgery
From National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI), North American Association for the Study of Obesity (NAASO): The practical guide to the
identification, evaluation, and treatment of overweight and obesity in adults. NIH Publication No. 00-4084, Bethesda, Md., October 2000, NIH. http://www.nhlbi.nih.gov/files/docs/
guidelines/prctgd_c.pdf. Accessed November 2014.
*“Yes” indicates that the treatment is indicated regardless of comorbidities.
physical activity programs. Behavior modification strategies and
patient education are also critical for achievement and mainte-
nance of target weight loss. Evidence-based dietary guidelines
should be used to design individualized patient plans in consulta-
tion with a registered dietitian or qualified health care provider.
First, daily caloric intake should be reduced by a modest 250 to
500 calories. Reasonable and paced reductions can help patients
continue on the recommended dietary plan for a longer time.
Daily calories from carbohydrate should be reduced to approxi-
mately 40% to 45% of intake, with a total daily carbohydrate
intake of no less than 130 g/day. Except in patients with renal
impairment (creatinine clearance <60 mL/min) or significant
microalbuminuria, protein intake should not be less than 1.2 g/
kg of adjusted body weight (adjusted body weight = ideal body
weight + 0.25 [current weight − ideal body weight]). This typi-
cally accounts for 20% to 30% of total calorie intake and is
intended to minimize loss of lean body mass during weight reduc-
tion. The remaining 30% to 35% of calorie intake should come
from fat. Trans-fats should be eliminated, and saturated fat should
be reduced to less than 7% of total calorie intake. Meal plans
should also include substantial soluble fiber (e.g., from fresh
fruits and vegetables) and consumption of healthy carbohydrates,
especially foods that are high in fiber and have a low glycemic
index. Approximately 14 g of fiber per 1000 calories (20 to 35 g
of fiber) per day is recommended.
Caloric intake should be adjusted downward over time until
weight loss is achieved. Underlying all of these steps should be
the goal of designing an individualized plan that can be main-
tained over the long term. Many patients find it helpful to receive
a structured dietary intervention that includes specific sugges-
tions for daily meals. Such structured diets may increase adher-
ence and can be easier to follow than a list of general guidelines.
Nutritionally complete meal replacement (e.g., in the form of
shakes or bars) can be useful for some patients, especially at the
start of a weight reduction program. If meal replacement is used,
100- to 200-calorie snacks (e.g., fruits and nuts) may be added at
breakfast, lunch, or between meals.
Each patient should meet with an exercise physiologist to
construct an individualized plan that is responsive to his or
her lifestyles, capabilities, and potential cardiovascular risks.
Because obese individuals frequently have difficulty exercising,
this process requires careful attention. A balanced exercise plan
incorporates a mix of cardiovascular, stretching, and strength
exercises and should be graded to increase gradually in both
duration and intensity. Patients can start with 10 to 20 minutes
of daily stretching and aerobic exercise (e.g., moderate-intensity
walking) with subsequent progressive increases. Any exercise
BMI CATEGORY
30-34.9 35-39.9 ≧40
Yes Yes Yes
Yes Yes Yes
Yes with comorbidities Yes with comorbidities Yes with comorbidities

should be preceded by a warm-up period to minimize
injuries.
Long-term lifestyle modification trials, such as the Diabetes
Prevention Program, have targeted 150 minutes of exercise per
week. Newer guidelines recommend 60 to 90 minutes of daily
exercise, with a minimum of 150 to 175 minutes per week needed
to obtain weight loss benefit. Emphasis should be placed on
moderate-intensity exercise, such as walking 20-minute miles,
rather than strenuous exercise. Because patients who are not used
to exercising may find it difficult to incorporate physical activity
into daily practice, it is also important to use a variety of exercises
to maintain interest. Increasing exercise duration to 300 minutes/
week was found to help in long-term maintenance of weight
reduction. Frequent short bouts of exercise as brief as 10 minutes
each can increase adherence to a regimen.
Behavior Modification and Patient Education
Cognitive-behavioral intervention and patient education are
important components of successful weight loss programs.
Whenever possible, cognitive-behavioral intervention should be
conducted by an experienced psychologist. The fundamental
principles of intervention typically include behavioral goal
setting, stimulus control techniques, cognitive restructuring,
assertive communication skills, stress management, and relapse
prevention. Cognitive-behavioral support conducted in a group
setting with weekly meetings is frequently successful. Patients
should learn how to set SMART goals (specific, measurable,
action-oriented, realistic, time-limited). It can be helpful to
emphasize real-life examples (e.g., success stories, logbook learn-
ing, recommitting to progress). The behavioral modification
strategy should assist patients in identifying precipitants for devi-
ations from a diet (e.g., timing, types of food or exercise, situa-
tions, feelings), overcoming challenges (planning ahead, delay
and distraction, problem solving), managing automatic negative
thinking (“detour thoughts”), coping with cravings through
mindful strategic eating, preventing relapses using logbook learn-
ing, navigating social eating, and setting personal weight mainte-
nance plans.
Pharmacologic Options
The four anti-obesity drugs currently licensed for use in the
United States are orlistat, phentermine, lorcaserin, and the com-
bination of phentermine and long-acting topiramate. Except for
phentermine by itself, the three other medications are approved
for long-term management of obesity.
Orlistat
Orlistat limits caloric intake through inhibition of the lipase-
mediated breakdown of fat in the gastrointestinal tract. This
mechanism results in an approximately 30% reduction of fat
absorption and an increase in fecal fat content. In addition to
weight loss, orlistat use has been associated with decreased inci-
dence of diabetes, improved concentrations of total cholesterol
and low-density lipoprotein (LDL)-cholesterol, and improved
blood pressure and glycemic control in patients with diabetes.
However, high-density lipoprotein (HDL)-cholesterol has been
found to be slightly lowered. Most people develop side effects
with variable degrees of diarrhea, flatulence, oily stools, fecal
Chapter 67  Obesity 679
urgency, and, rarely, fecal incontinence. There also is an increased
risk of cholelithiasis. Gastrointestinal side events are usually pro-
portional to the amount of fat intake. Supplemental fat-soluble
vitamins A, D, E, and K must be taken to prevent possible defi-
ciencies. The usual dose of orlistat is 120 mg before each meal. A
60 mg dose formulation is currently available over the counter;
it is less effective but is also associated with fewer side effects.
Phentermine
Phentermine is approved for short-term treatment of obesity (up
to 6 months). Because phentermine has actions similar to
amphetamines, it can elevate blood pressure, increase heart rate,
and stimulate the central nervous system (frequently causing
insomnia), in addition to suppressing the appetite. The recom-
mended phentermine dose is 30 mg once daily. Combining
phentermine with tricyclic antidepressants or monoamine
oxidase inhibitors may result in substantial increases in blood
pressure and other serious reactions because of elevated sero-
tonin levels in the blood.
Lorcaserin
Lorcaserin is a selective serotonin (5-hydroxytryptamine) recep-
tor agonist with specificity for the 5-HT2C receptor subtype. The
activation of these receptors in the hypothalamus is thought to
activate production of proopiomelanocortin (POMC) and, con-
sequently, to promote weight loss through satiety signals. Lorca-
serin has 100-fold higher selectivity for 5-HT2C versus the
closely related 5-HT2B receptor. Activation of the 5-HT2B
receptor by the less selective agents fenfluramine and dexfenflu-
ramine previously was linked to serious cardiac valvulopathy, but
there is no evidence for this adverse effect with lorcaserin. Clini-
cal trials showed that 47.5% of patients treated with lorcaserin
lost at least 5% of their initial body weight, and 22.6% lost at least
10%, in 1 year. Lorcaserin treatment also resulted in significantly
lower glycosylated hemoglobin (HbA1c) values in patients with
T2DM and improved lipid profile and decreased blood pressure
in clinical studies.
Lorcaserin is approved for use as an adjunct to a reduced-
calorie diet and exercise for chronic weight management in
patients with initial BMI values of 30 kg/m2 or higher and in
those with BMI values of 27 kg/m2 or higher with at least one
weight-related comorbid condition (e.g., hypertension, dyslipid-
emia, T2DM). It is given in a dose of 10 mg twice daily. Side
effects usually are mild to moderate, with the most common
being headache, upper respiratory tract infection, nasopharyngi-
tis, sinusitis, dizziness, nausea, and fatigue. The U.S. Drug
Enforcement Administration has classified lorcaserin as a sched-
ule IV drug because it has hallucinogenic properties that could
lead to psychiatric complications.
Phentermine and Long-Acting Topiramate
Phentermine is an appetite suppressant and stimulant of the
amphetamine and phenethylamine class (see earlier discussion
for details on the use of phentermine alone for weight reduction).
Topiramate is an anticonvulsant that was found to have weight
loss side effects. The combination of phentermine plus low doses
of topiramate has been shown to have synergistic effects on
weight loss. As with lorcaserin, this combination tablet is
680 Section X  Endocrine Disease and Metabolic Disease
indicated as an adjunct to a reduced-calorie diet and exercise for
chronic weight management. Clinical trials showed that average
weight loss after 1 year of 10.9% for patients receiving the
maximum dose (phentermine/topiramate, 15 mg/92 mg) and
5.1% for those taking the recommended starting dose
(3.75 mg/23 mg). The drug is taken once daily in the morning
to avoid insomnia caused by the phentermine component. The
initial dose of 3.75 mg/23 mg is given for 2 weeks before titration
to 7.5 mg/46 mg for another 12 weeks. If a patient has not lost
at least 3% of baseline body weight on the higher dosage, the drug
may be discontinued or the dose may be escalated to
11.25 mg/69 mg for an additional 2 weeks before a further
increase to the maximum dose of 15 mg/92 mg. If a patient has
not lost at least 5% of baseline body weight after 12 weeks, the
drug is discontinued gradually. Side effects include paresthesias,
dry mouth, constipation, metabolic acidosis, nasopharyngitis,
upper respiratory infection, and headache.
Data indicate that fetuses exposed during the first trimester to
topiramate (when used alone as an anticonvulsant) have an
increased risk (9.6%) of cleft lip with or without cleft palate.
Therefore, the drug should not be given to women of child-
bearing age unless an effective method of contraception is used
and a pregnancy test is conducted monthly during use.
Phentermine/topiramate may increase resting heart rate up to 20
beats/minute, so the drug should be used cautiously in patients
with a history of cardiac or cerebrovascular disease. Topiramate
also increases the risk of suicidal thoughts or behaviors and mood
disorders including depression, anxiety, and insomnia. It can also
cause cognitive dysfunction, including impairment of concentra-
tion or attention, difficulty with memory, and speech or language
problems, particularly word-finding difficulties. It is contraindi-
cated in patients with closed-angle glaucoma because it increases
intraocular pressure and the risk of permanent loss of vision.
Contrave is a combination of Bupropion and Naltrexone just
approved by the FDA for weight loss (Medical Letter November
10, 2014).
Bariatric Surgery
At present, there are three broad categories of bariatric surgical
procedures: (1) pure gastric restriction; (2) gastric restriction
with some malabsorption, as represented by the Roux-en-Y
gastric bypass (RYGB) procedure; and (3) gastric restriction
with significant intestinal malabsorption (discussed later). The
VBG LAGB RYGB
FIGURE 67-1  Common bariatric procedures. BPD, Biliopancreatic diversion; VBG, Vertical banded gastroplasty; LAGB, laparoscopic adjustable
gastric band; RYGB, Roux-en-Y gastric bypass; SLG, sleeve gastrectomy; BPD, biliopancreatic diversion; BPD/DS, BPD with duodenal switch.
number of bariatric procedures performed in the United States
increased from an estimated 13,365 in 1998 to almost 220,000
in 2008. Bariatric surgery is considered to be indicated for
adults with class 3 obesity (BMI ≥40  kg/m2). In patients with
less severe obesity (BMI 35 to 40  kg/m2), bariatric surgery can
be considered if there are one or more high-risk comorbid
conditions present, such as life-threatening cardiopulmonary
disease (e.g., severe sleep apnea, obesity-related cardiomyopathy)
or uncontrolled T2DM. Bariatric surgery is sometimes per-
formed for patients with diabetes or metabolic syndrome and
a BMI of 30 to 35  kg/m2, although current evidence on benefit
is limited. For teenagers younger than 17 years old who have
attained skeletal maturity (usually by 13 years for girls and 15
years for boys), bariatric surgery has been recommended with
different guidelines: BMI 35 to 40  kg/m2 with at least one
serious comorbid condition (e.g., T2DM, obstructive sleep
apnea, pseudotumor cerebri) or BMI 50  kg/m2 or higher with
less serious comorbidities. Contraindications for bariatric
surgery include high operative risk (e.g., congestive heart failure,
unstable angina), active substance abuse, and significant
psychopathology.
Different types of commonly used bariatric procedures are
shown in Figure 67-1. Gastric restriction procedures induce
weight loss by producing early satiety and limiting food intake.
Gastric restriction by vertical banded gastroplasty (VBG) typi-
cally limits the volume of the upper gastric pouch into which the
esophagus empties to 15 to 45 mL and restricts the pouch outlet
to the remaining stomach to 10 to 11 ml. Currently, the laparo-
scopic adjustable gastric band (LAGB) has almost completely
replaced the VBG procedure, because it is less invasive, adjust-
able, and reversible and has better outcomes.
LAGB is associated with substantially better maintenance of
weight loss than lifestyle intervention alone, and it carries a
very low operative mortality rate (0.1%). However, it is associ-
ated with significantly lower loss of excess weight at 5 years
and 10 years and with smaller reductions in fat-free mass com-
pared with RYGB. LAGB has been demonstrated to be safe in
patients older than 55 years of age. Complications associated
with the LAGB procedure include band slippage, band erosion,
balloon failure, injection port malposition, band and port infec-
tions, and esophageal dilatation. Some of these problems have
been decreased by use of a different method of band insertion
and revision of the port connection. Overall, complication and
SLG BPD BPD/DS

mortality rates are much lower for LAGB than for RYGB.
Nevertheless, RYGB is currently the most commonly performed
bariatric procedure in the United States because it achieves
greater weight loss.
In RYGB, the upper stomach is transected, thereby creating a
very small proximal gastric pouch measuring 10 to 30 mL. The
gastric pouch is anastomosed to a Roux-en-Y proximal jejunal
segment, bypassing the remaining stomach, duodenum, and a
small portion of jejunum. The standard Roux (alimentary) limb
length is about 50 to 100 cm, and the biliopancreatic limb is 15
to 50 cm. As a result, the RYGB serves to limit food intake and
induces some nutrient malabsorption.
Sleeve gastrectomy (SLG) is another restrictive surgery in
which the stomach is reduced to about 25% of its original size by
surgical removal of a large portion of the stomach fundus, result-
ing in a tube-like structure. Although the procedure permanently
reduces stomach size, some dilatation of the stomach may occur
later. The procedure is frequently performed by a laparoscopic
technique. Because it has low operative risk, the use of sleeve
gastrectomy currently is increasing more rapidly than other types
of bariatric surgery. Other procedures, including biliopancreatic
diversion (BPD), biliopancreatic diversion with duodenal switch
(BPD/DS), and staged bariatric surgical procedures, are less
commonly performed.
There is a need for more data to guide the choice of bariatric
procedures for individual patients. Most procedures currently are
being performed laparoscopically. This approach has the advan-
tages of fewer wound complications, less postoperative pain, a
shorter hospital stay, and more rapid postoperative recovery with
comparable efficacy. However, these advantages may be offset by
more frequent complications associated with techniques used for
laparoscopic gastrojejunostomy creation, anastomotic strictures,
and higher rates of postoperative bowel obstructions.
The Agency for Healthcare Research and Quality (AHRQ)
identified a 0.19% in-hospital mortality rate for all bariatric dis-
charges in the United States. A recent meta-analysis showed that
mortality rate from bariatric surgery within 30 days was 0.08%
and the mortality rate after 30 days was 0.31%. Bariatric surgery
is not uniformly a “low-risk” procedure, and judicious patient
selection and diligent perioperative care are mandatory. Preop-
erative patient selection and education as well as careful postsur-
gical follow-up are important for successful outcomes.
The benefits of bariatric surgery extend beyond calorie restric-
tion and weight loss. Foregut bypass leads to improvement in the
physiologic responses of gut hormones involved in glucose regu-
lation and appetite control, including ghrelin, glucagon-like
peptide-1 (GLP-1) and peptide YY3-36 (PYY). Mechanical
improvements include less weight-bearing burden on joints,
improved lung compliance, and reduced fatty tissue around the
neck, which can relieve obstruction to breathing and sleep apnea.
In an extensive meta-analysis of 22,000 bariatric surgeries,
patients lost on average 61% of excess body weight and exhibited
improvements in T2DM, hypertension, sleep apnea, and dyslip-
idemia. The beneficial effect of obesity surgery on T2DM is one
of the most important outcomes observed, with gastric bypass
and malabsorptive procedures having the greatest impact. A
shorter duration of diabetes and greater weight loss are indepen-
dent predictors of diabetes remission after bariatric surgery.
Chapter 67  Obesity 681
Improvements in fasting blood glucose levels occur before signifi-
cant weight loss is achieved. Insulin-treated patients experience
significant decreases in insulin requirements, and most T2DM
patients are able to discontinue insulin therapy by 6 weeks after
surgery. Euglycemia is maintained in some patients for up to 14
years after RYGB. Two recent randomized controlled studies
compared RYGB to intensive lifestyle intervention in moderately
obese patients with T2DM and found RYGB to be superior in
inducing diabetes remission and reducing use of antihyperglyce-
mic medications.
Weight loss after malabsorptive bariatric surgery usually
reaches a nadir after 12 to 18 months. Over the following decade,
there is weight regain of approximately 10% of body weight.
Weight loss is more gradual for the restrictive LAGB procedure
and may continue for several years. In purely restrictive proce-
dures, failure to experience optimal weight loss has been associ-
ated with consumption of calorically dense liquids that can pass
through the stoma without producing satiety.
  PROGNOSIS
Although recent clinical data show that patients on average can
maintain a 4% to 5% weight loss for 10 years with ongoing medi-
cally supervised intensive lifestyle intervention, many patients
are subjected to less intensive intervention and regain their initial
weight loss over months or years. Weight regain even after bariat-
ric surgery is not uncommon and most often occurs after 2 years
of peak weight loss. Loss of 10% to 20% of the initial body weight
is associated with a decrease in total and resting energy expendi-
ture, a change that retards further weight loss. Similarly, weight
gain is associated with an increase in energy expenditure, which
retards further weight gain. These observations suggest that the
human body adopts a biologic set point or mechanism that tends
to maintain body weight, and they lend support to the theory that
behavior is not the sole determinant of obesity. Although long-
term intensive lifestyle intervention in obese patients with T2DM
resulting in approximately 5% body weight loss can significantly
decrease the risks of chronic kidney disease and depression and
further improve glucose control, blood pressure, physical fitness,
and some lipid parameters, it has not been shown to reduce car-
diovascular events or mortality. Further understanding of genetic
and hormonal regulation of obesity may help researchers create
more effective and long-lasting interventional tools.
For a deeper discussion on this topic, please see Chapter
220, “Obesity,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Aldahi W, Hamdy O: Adipokines, inflammation, and the endothelium in diabetes,
Curr Diabetes Rep 3:293–298, 2003.
Angrisani L, Lorenzo M, Borrelli V: Laparoscopic adjustable gastric banding
versus Roux-en-Y gastric bypass: 5-year results of a prospective randomized
trial, Surg Obes Relat Dis 3:127–134, 2007.
Chang SH, Stoll CR, Song J, et al: The effectiveness and risks of bariatric surgery:
an updated systematic review and meta-analysis, 2003–2012, JAMA Surg
149:275–287, 2014.
Després J-P, Moorjani S, Lupien PJ, et al: Regional distribution of body fat,
plasma lipoproteins, and cardiovascular disease, Arteriosclerosis 10:497–511,
1990.
Hamdy O: The role of adipose tissue as an endocrine gland, Curr Diabetes Rep.
5:317–319, 2005.
682 Section X  Endocrine Disease and Metabolic Disease
Hamdy O, Carver C: The Why WAIT program: improving clinical outcomes
through weight management in type 2 diabetes, Curr Diabetes Rep. 8:413–
420, 2008.
Ikramuddin S, Korner J, Lee WJ, et al: Roux-en-Y gastric bypass vs intensive
medical management for the control of type 2 diabetes, hypertension, and
hyperlipidemia: the Diabetes Surgery Study randomized clinical trial, JAMA
309:2240–2249, 2013.
Look AHEAD Research Group, Wing RR, Bolin P, et al: Cardiovascular effects
of intensive lifestyle intervention in type 2 diabetes, N Engl J Med 369:145–
154, 2013.
Maggard MA, Shugarman LR, Suttorp M, et al: Meta-analysis: surgical treatment
of obesity, Ann Intern Med 142:547–559, 2005.
Schauer PR, Kashyap SR, Wolski K, et al: Bariatric surgery versus intensive
medical therapy in obese patients with diabetes, N Engl J Med 366:1567–1576,
2012.
Sjostrom L, Lindroos AK, Peltonen M, et al: Swedish Obese Subjects Study
Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years
after bariatric surgery, N Engl J Med 351:2683–2693, 2004.
Strauss RS, Bradley LJ, Brolin RE: Gastric bypass surgery in adolescents with
morbid obesity, J Pediatr 138:499–504, 2001.

Malnutrition, Nutritional
Assessment, and Nutritional
Support in Hospitalized Adults
  MALNUTRITION IN HOSPITALIZED PATIENTS
Numerous surveys conducted in developed countries in the
21st century continue to demonstrate the frequent rate of
protein-energy malnutrition as well as depletion of specific
micronutrients in patients with chronic illnesses and those
requiring elective or emergent hospital admission. Hospitalized
patients commonly receive inadequate amounts of calories,
protein, vitamins, and minerals during their stay, and ad libitum
intake of prescribed diets is typically inadequate. Studies have
shown that worsening of malnutrition during hospitalization
is common. This is problematic, because adequate intake of
essential macronutrients (energy, carbohydrate, protein/amino
acids, and fats) and micronutrients (vitamins, minerals, and
electrolytes) is critical for optimal cellular and organ structure
and function, muscle mass, tissue repair, immune function,
ambulatory capacity, and patient recovery. Significant erosion
of lean body mass (predominately derived from skeletal muscle)
and deficiencies of specific vitamins and minerals are variously
associated with weakness and fatigue, increased rates of infec-
tion, impaired wound healing, and delayed convalescence. This
relationship is especially apparent in patients with chronic
protein-energy malnutrition and body weight loss associated
with illness.
Patients with acute or chronic illnesses typically have experi-
enced several days to several months of continuous or intermit-
tent decreased food intake due to anorexia, gastrointestinal
symptoms, depression and anxiety, and other medical factors.
They may also have had food intake restricted by surgical opera-
tions or diagnostic or therapeutic procedures and recovery from
these. Some patients have abnormal nutrient losses due to diar-
rhea (e.g., with chronic malabsorptive and maldigestive disorders
or infectious diarrhea), vomiting, polyuria (as in uncontrolled
diabetes mellitus), wound drainage, dialysis, or other causes.
Certain drugs, including corticosteroids, chemotherapeutic
agents, antirejection drugs, and diuretics, are associated with
skeletal muscle breakdown, gastrointestinal injury, or loss of elec-
trolytes or water-soluble vitamins. Bedrest or markedly decreased
ambulation are common in outpatient and inpatient settings and
are associated with skeletal muscle wasting and impaired protein
synthesis.
68 
Thomas R. Ziegler
Catabolic and critical illnesses are associated with concomi-
tantly increased blood concentrations of “counterregulatory”
hormones derived from the adrenal glands and pancreas (e.g.,
cortisol, catecholamines, glucagon); release of pro-inflammatory
cytokines from stimulated immune, endothelial, and epithelial
cells, such as interleukins (e.g., IL-1, IL-6, IL-8) and tumor
necrosis factor-α (TNF-α); and peripheral tissue resistance to
anabolic hormones such as insulin and insulin-like growth
factor-I (IGF-I). These hormonal and cytokine alterations
increase the availability of endogenous metabolic substrates that
are critical for cellular and organ function, wound healing, and
host survival (e.g., glucose via glycogenolysis and gluconeogen-
esis, amino acids via skeletal muscle breakdown, and free fatty
acids via lipolysis). This combination of decreased nutrient intake
and increased tissue nutrient losses (from the actions of these
hormones and cytokines), coupled with increased energy
(calorie), protein, and micronutrient needs due to inflammation,
infection, and cytokinemia, is responsible for the wasting and
micronutrient depletion commonly observed in medical patients
with acute and chronic illnesses. Common causes of protein-
energy malnutrition and micronutrient depletion in medical
patients are shown in Table 68-1. Obesity has become a wide-
spread medical problem and is also a form of malnutrition; it is
considered in detail in Chapter 67.
  NUTRITIONAL ASSESSMENT
Serial assessment of nutritional status is a critically important
component of routine medical care. The major objectives are
to detect preexisting depletion of body protein, energy reserves,
and micronutrients; to identify risk factors for malnutrition
(see Table 68-1); and to take steps to prevent nutrient defi-
ciencies, depletion of lean body mass, and loss of skeletal
muscle. There are still no practical “gold standard” tests that
can provide an index of general nutritional status. Blood con-
centrations of specific micronutrients (e.g., copper, zinc, thia-
mine, 25-hydroxyvitamin D, vitamin B6, folate, vitamin B12)
and electrolytes (e.g., magnesium, potassium, phosphorus) are
important to guide needs and repletion responses. Nutritional
assessment involves an integration of multiple factors, including
the patient’s medical and surgical history, type and severity of
the acute or chronic underlying illness and its anticipated
683
684 Section X  Endocrine Disease and Metabolic Disease
TABLE 68-1  COMMON CAUSES OF PROTEIN-ENERGY
MALNUTRITION AND MICRONUTRIENT
DEPLETION IN MEDICAL PATIENTS WITH
ACUTE OR CHRONIC ILLNESSES
Decreased spontaneous food intake due to anorexia from chronic or acute
illness, gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain),
or depression and anxiety
Restricted food intake required for surgical operations or diagnostic or
therapeutic procedures and gastrointestinal dysfunction after these
procedures
Abnormal macronutrient and micronutrient losses from the body due to
malabsorption (e.g., celiac sprue, short gut syndrome, inflammatory bowel
disease, cystic fibrosis, diarrhea), maldigestion (e.g., pancreatitis), emesis,
polyuria (e.g., in diabetes), wound drainage, or renal replacement therapy
Periods of increased energy expenditure (caloric needs), protein
requirements, and micronutrient needs (e.g., critical illness, increased
inflammation)
Catabolic effects of counterregulatory hormones (e.g., cortisol,
catecholamines, glucagon), release of pro-inflammatory cytokines from
stimulated immune cells and endothelial and epithelial cells such as
interleukins (e.g., IL-1, IL-6, IL-8) and tumor necrosis factor-α (TNF-α),
and peripheral tissue resistance to the anabolic hormones insulin and
insulin-like growth factor-I (IGF-I).
Bedrest, decreased ambulation, and chemical paralysis during mechanical
ventilation (skeletal muscle wasting due to impaired protein synthesis)
Administration of drugs that induce skeletal muscle breakdown,
gastrointestinal injury, or loss of electrolytes and water-soluble vitamins
(e.g., corticosteroids, chemotherapeutic agents, diuretics, antirejection
regimens)
Socioeconomic deprivation, inadequate caregivers, ambulation difficulties in
the home setting
Inadequate provision of calories, protein, and essential micronutrients
(vitamins, minerals, trace elements) during hospitalization
medical and surgical course, fluid drainage sites and amounts,
physical examination findings, history of body weight change
(degree and temporal aspects), dietary intake pattern, use of
nutritional supplements including prior administration of spe-
cialized enteral nutrition (EN) or parenteral nutrition (PN),
evaluation of current organ function and fluid status, and deter-
mination of selected vitamin, mineral, and electrolyte concen-
trations in blood (E-Table 68-1). In the intensive care unit
(ICU) setting, measured body weight typically reflects recent
intravenous fluid administration and is typically much higher
than recent “dry” or preoperative body weight, which is the
best parameter to use.
Integration of the factors outlined in E-Table 68-1 provides
important information on whether patients are likely to be ade-
quately nourished; to have mild, moderate, or severe protein-
energy malnutrition; or to have depletion or deficiency of specific
vitamins, minerals, or electrolytes. Patients who have experi-
enced an involuntary body weight loss of 5% to 10% or more of
their usual body weight in the previous few weeks or months,
those who weigh less than 90% of their ideal body weight
(IBW), and those who have a body mass index (BMI) lower than
18.5 kg/m2 should be carefully evaluated, because these indi-
viduals are likely to be malnourished.
Among hospitalized patients, especially those in the ICU, cir-
culating concentrations of proteins (e.g., albumin, prealbumin)
are often quite low and not useful as protein nutritional status
biomarkers given their lack of specificity. Plasma concentrations
of albumin and prealbumin typically fall during active inflamma-
tion or infection, in critical illness, and after traumatic injury (due
to deceased synthesis by the liver and catabolism of blood pro-
teins).They are markedly affected by non-nutritional factors,
including fluid status, capillary leak, decreased hepatic synthesis,
and increased clearance from blood. Because of the long circulat-
ing half-life of albumin (18 to 21 days), concentrations in blood
remain low despite adequate feeding and are slow to respond to
nutritional repletion, irrespective of other confounding factors.
Prealbumin has a much shorter circulating half-life (several days),
and serial blood levels can be used as a general indicator of
protein status in clinically stable outpatients. E-Table 68-2 illu-
strates physical examination findings that may be observed in
associated with depletion of specific nutrients.
Energy requirements can be estimated with the use of stan-
dard equations, such as the Harris-Benedict equation, which
incorporate the patient’s age, gender, weight, and height to
determine basal energy expenditure (BEE) (see E-Table 68-1).
Physical activity and the thermic effect of macronutrient admin-
istration can be added to the BEE to arrive at the energy pre-
scription to maintain current body weight; for most hospitalized
patients and outpatients, this is estimated as 1.2 to 1.3 times
the BEE, unless energy needs are decreased because the patient
is sedated or on bedrest (common in the ICU). The estimated
maintenance energy requirement is approximately 1.3 times BEE
in ambulatory subjects. Typically, lower amounts of calories are
now given in ICU patients (as discussed later). Use of data
obtained from a bedside metabolic cart machine (indirect calo-
rimeter), which measures expired breath to determine oxygen
consumption and carbon dioxide production, provides accurate
actual energy expenditure in most settings and can be very
useful (see E-Table 68-1).
A simple and relatively accurate method to estimate energy
needs is simply to use 20 to 25 kcal/day per kilogram of actual
weight, dry weight, or IBW in most patients. Values for IBW are
obtained from standard tables or equations. This estimation
assumes that the body weight used does not reflect intravenous
fluid administration or capillary leak syndromes (discussed
earlier). In ICU patients, even lower caloric doses (equivalent to
15-20 kcal/kg dry weight/day) have been advocated by some,
based on known complications of overfeeding (see later discus-
sion) and limited data on clinical outcome as a function of energy
dose. In clinically stable, malnourished, non-ICU patients who
require nutritional repletion, higher doses of calories (up to
35 kcal/kg/day) appear to be generally well tolerated if refeeding
syndrome is avoided (see later discussion). In obese subjects
(defined for these calculations as patients with body weight
>20% to 25% greater than ideal), an adjusted body weight value
should be used for calculation of energy and protein needs, as
determined by the following equation:
Adjusted body weight = (current weight − IBW ) × 0.25 + IBW
Guidelines for protein or amino acid administration are given
in E-Table 68-3. Studies in nonburned ICU patients indicate that
protein loads of more than 2.0 g/kg/day are not efficiently uti-
lized for protein synthesis, and the excess may be oxidized, con-
tributing to azotemia. In most catabolic patients requiring
specialized feeding, a recommended protein dose is 1.5 g/kg/day
for individuals with normal renal function. This is about twice the
recommended dietary allowance (RDA) for healthy adults of
0.8 g/kg/day. The administered protein dose should be adjusted
downward as a function of the degree and tempo of azotemia (in
the absence of dialysis therapy) and of hyperbilirubinemia (see
 Chapter 68  Nutritional Support in Hospitalized Adults 684.e1

E-TABLE 68-1  COMPREHENSIVE NUTRITIONAL ASSESSMENT OF MEDICAL AND SURGICAL PATIENTS

1. Review past medical and surgical history and current illness
a. Degree of catabolic stress (e.g., fever, infections, sepsis, surgeries, lung failure)
b. Organ function (e.g., liver, kidneys, lung, heart/vascular, GI)
c. Use of medications that may decrease nutrient absorption (e.g., phenytoin, sulfasalazine, elixir-based medications), alter metabolism or utilization (e.g.,
warfarin, isoniazid, methotrexate), or increase excretion (e.g., gentamicin, loop diuretics)
d. Recent intravenous fluid and electrolyte therapy
e. Medical and surgical procedures that are likely in the near term
f. Hemodynamic status and requirements for pressor agents to maintain blood pressure
2. Obtain body weight history
a. Current body weight (dry weight if available preoperatively or from a recent clinic visit) + usual body weight when healthy or clinically stable; calculate %
body weight loss from usual body weight over the last several weeks or months
b. Calculate current weight as % of ideal body weight*
c. Determine BMI (weight in kg divided by square of height in m); BMI <18.5 is considered underweight
3. Determine dietary intake pattern in relation to nutrient needs
a. General food and beverage intake pattern, % of usual dietary intake consumed in recent weeks and months, unusual or excessive consumption of specific
foods or beverages (including alcoholic beverages)
b. Previous use and type of enteral tube feedings or parenteral nutritional support
c. Previous use of liquid or solid nutritional supplements, multivitamin-multimineral preparations, specific vitamins or minerals
d. Consult registered dietitian for more detailed nutrient intake assessment
4. Perform detailed physical examination
a. Skeletal muscle wasting (cannot be assessed accurately in overweight or obese patients)
b. Loss of body fat stores
c. Presence and qualities of wounds
d. Skin, hair, tongue, and conjunctival lesions suggestive of micronutrient deficiency (see E-Table 68-2)
e. Evidence of organ dysfunction (GI, liver, renal, cardiopulmonary)
f. Fluid status (e.g., normal, dehydrated, fluid overload, capillary leak); daily fluid requirements are typically 30-40 mL/kg body weight
5. Evaluate GI tract function
a. Swallowing or chewing difficulties, nausea, emesis, abdominal pain
b. Intestinal ileus, motility disorders, partial or complete obstruction
c. Diarrhea history (frequency, amount, other characteristics)
d. Acute or chronic GI bleeding
e. Presence of fistulas; history of recent abdominal surgery
f. Drainage tube losses (e.g., gastric, biliary, intestinal, peritoneal)
6. Determine functional status
a. Ability to perform daily activities, ambulatory capacity, bedrest, chemical paralysis
b. History or physical examination evidence of muscle weakness and fatigue
c. Mental capacity, history of psychiatric disorders that may preclude oral food intake
7. Serial evaluation of selected biochemical tests
a. Standard blood measures of organ function
b. Electrolyte concentrations (e.g., calcium, magnesium, phosphorus, potassium)
c. Blood pH (in ICU patients on mechanical ventilation)
d. Blood triglyceride concentrations (in patients receiving intravenous lipid emulsion)
e. Blood concentrations of selected vitamins and minerals if suggested by medical or dietary history, physical examination, or underlying illness (e.g., zinc,
selenium, copper, thiamine, vitamin B6, vitamin B12, folate, 25-hydroxyvitamin D, iron, ferritin)
f. Serum prealbumin (in stable outpatients)†
8. Estimate caloric (kcal), protein and micronutrient needs
a. Caloric needs are based on the Harris-Benedict equation‡, guidelines on kcal/kg body weight§, or indirect calorimetry results (use serially in ICU patients
and in the initial assessment of very underweight or obese hospital patients requiring prolonged nutritional support)
b. Protein needs vary as a function of recognized clinical situations (see E-Table 68-3)
c. Vitamin and mineral needs are based on conventional requirements, serial blood levels, and clinical judgment regarding intake and estimated losses from
comprehensive nutritional assessment
d. Nitrogen balance studies are not useful in nonresearch settings because of their variability and inaccuracy
e. Serial body composition measurements for lean body mass and body fat estimates may be useful in the outpatient setting (by BIA or DEXA) but are not
practical or reliable in inpatient nonresearch settings because of fluid shifts and other factors
9. Evaluate enteral and parenteral access for nutrient delivery
a. Ability to take oral diet and/or liquid supplements
b. Central venous or PICC line access; peripheral line access
c. Nasogastric, nasoenteric, or percutaneous feeding tube availability or feasibility
10. Consultation with multidisciplinary nutrition support team
BIA, Bioelectrical impedance analysis; BMI, body mass index; DEXA, dual energy x-ray absorptiometry; GI, gastrointestinal; ICU, intensive care unit; PICC, peripherally inserted central
venous catheter.
*Ideal body weight can be estimated in men as 48 kg (106 lb) per 5 ft of height + 2.7 kg (6 lb) for each inch of height above 5 ft and in women as 45 kg (100 lb) per 5 ft of height +
2.3 kg (5 lb) for each inch of height above 5 ft.
†
Blood concentrations of albumin and prealbumin in hospitalized patients, especially in the ICU setting, are markedly affected by non-nutritional factors (e.g., inflammation, infection,
fluid status, capillary leak, decreased hepatic synthesis, increased clearance from blood).
‡
Harris-Benedict equation to estimate basal energy expenditure (BEE) in kcal/24 hr: for males, BEE = 66.5 + (13.8 × kg body weight) + (5.0 × height in cm) − (6.8 × age in years); for
females, BEE = 655 + (9.6 × kg body weight) + (1.8 × height in cm) − (4.7 × age in years).
§
Caloric needs can also be estimated as follows (using dry weight or ideal body weight in ICU patients with fluid overload): in ICU settings, 20-25 kcal/kg/day (some studies suggest
that 15-20 kcal/kg/day or lower may be appropriate); in non-ICU settings, 25-35 kcal/kg/day.
684.e2 Section X  Endocrine Disease and Metabolic Disease

E-TABLE 68-2  CLINICAL MANIFESTATIONS OF E-TABLE 68-3  ESTIMATION OF PROTEIN OR AMINO

SPECIFIC NUTRIENT DEFICIENCIES ACID REQUIREMENTS IN ADULT
SIGN OR SYMPTOM OF SPECIFIC NUTRIENTS PATIENTS
NUTRIENT DEPLETION* DEPLETED PROTEIN OR AMINO
Muscle and fat wasting, weakness Calories, protein, combined calories CLINICAL CONDITION ACID DOSE (g/kg/day)*
+ protein Well-nourished with acute illness 1.2-1.5
Anorexia Calories, protein Malnourished and/or severe catabolic stress 1.5-1.8
Glossitis (discolored, smooth, Folate, vitamin B12, niacin, riboflavin, Postoperative 1.2-1.5
painful tongue) thiamine, iron Hepatic failure 0.6-1.2
Cheliosis, angular stomatitis Riboflavin, niacin, folate, vitamin B12 Encephalopathy 0-0.6
Symmetrical motor/sensory Thiamine (beriberi) Acute renal failure, not on renal replacement 0.6-0.8
dysfunction, ataxia, nystagmus, therapy
heart failure, mental status changes Renal failure, on renal replacement therapy 1.2-2.5
or confusion
Peripheral edema Thiamine (heart failure), protein *Oral/enteral nutrient supplements and tube feedings contain either intact or partially
(low oncotic pressure) hydrolyzed high-quality protein (typically casein, soy, and/or whey). Parenteral nutrition
solutions for peripheral or central vein administration provide known essential l-amino
Loss of vibratory or position sense, Vitamin B12
acids combined with several nonessential amino acids. These may be limiting in certain
fatigue conditionally essential amino acids (e.g., cysteine, taurine) in some clinical conditions.
Dermatitis (sun-exposed skin), Niacin (pellagra)
diarrhea, dementia
Bleeding gums, petechiae, Vitamins C and K
ecchymosis
Poor wound healing Calories, protein, calories + protein,
vitamin C, vitamin A, zinc, others
Bone pain Vitamin D (osteomalacia)
Follicular hyperkeratosis, night Vitamin A
blindness, Bitot’s spots
Flaky, whitish dermatitis Essential fatty acid (linoleic,
α-linolenic)
Hair sparse or easily pluckable Zinc, protein
Pale skin, nail spooning Iron
(koilonychia)
Loss of taste; reddish dermatitis Zinc
around nose, mouth, groin; hair
loss
Peripheral neuropathies, gait Copper
abnormalities, weakness, fatigue
Muscle pain, heart failure, Selenium
Paresthesias, carpal pedal spasm Calcium, magnesium, phosphorus,
or potassium
*Typically, severe deficiency of specific nutrients (with depletion initially in tissue and later
in blood) has occurred before physical manifestations of deficiency are evident.
 Chapter 68  Nutritional Support in Hospitalized Adults 685
E-Table 68-3). These strategies take into account the relative
inability of catabolic patients to efficiently utilize exogenous
nutrients and knowledge that most protein and lean tissue reple-
tion occurs over a period of several weeks to months during post-
hospital convalescence. Adequate nonprotein energy is essential
to allow amino acids to be effectively used for protein synthesis
and not oxidized for production of energy (adenosine triphos-
phate, or ATP). The ratio of nonprotein calories to nitrogen used
in most centers typically ranges from 75 : 1 to 125 : 1. Because
nitrogen = protein/6.25, this equates to 75 to 125 nonprotein
kilocalories for each 6.25 g of protein or amino acid administered.
  NUTRITIONAL SUPPORT
Table 68-2 lists common clinical scenarios in which specialized
oral/EN or PN support may be indicated. In these settings, con-
sultation with a multidisciplinary nutrition support team, if avail-
able, has been shown to reduce complications and costs and to
increase the appropriate use of EN and PN in both academic and
community medical centers.
Oral Nutrition Support
Oral nutrition supplementation includes provision of balanced
oral diets of usual foods supplemented with complete liquid (or
solid) nutrient products, protein supplements (e.g., hydrolyzed
whey or casein powder that can be mixed with dietary bever-
ages), high-potency multivitamin-multimineral supplements,
and/or specific micronutrients required to treat a diagnosed defi-
ciency (e.g., zinc, copper, vitamin B6, vitamin B12, vitamin D).
Special supplements designed for patients with chronic renal
failure (featuring concentrated calories and low amounts of
protein and electrolytes) are available, as are a variety of formula-
tions designed for other specific disease categories (see later dis-
cussion). Several studies have shown that convalescence after
stresses such as total hip replacement or gastrointestinal surgery
TABLE 68-2  SOME CLINICAL INDICATIONS FOR
SPECIALIZED ORAL/ENTERAL OR
PARENTERAL NUTRITION SUPPORT
Patient currently exhibits moderate to severe protein or protein-energy
malnutrition or has evidence of specific deficiency of one or more essential
micronutrients
Patient with involuntary body weight loss of 5-10% or more of their usual
body weight in the previous few weeks or months, weighs less than 90% of
ideal body weight, or has a BMI lower than 18.5 kg/m2.
Dietary food intake in a hospital or outpatient setting likely to be <50% of
needs for more than 5-10 days due to underlying illness
Patient with severe catabolic stress (e.g., ICU care, serious infection) and
adequate nutrient intake unlikely for >3-5 days.
After major gastrointestinal surgery or other major operation (e.g., hip
replacement, partial organ resection)
Medical illness associated with prolonged (>5-10 days) GI dysfunction
(diarrhea, nausea and vomiting, GI bleeding, severe ileus, partial
obstruction) and/or short bowel syndrome, chronic or severe diarrhea, or
other malabsorptive disorders
Clinical settings in which adequate oral food intake may be contraindicated
or otherwise significantly decreased, such as respiratory or other acute or
severe organ failure, dementia, dysphagia, chemotherapy or irradiation,
inflammatory bowel disease, pancreatitis, high-output enterocutaneous
fistula, alcoholism, drug addiction
Chronic obstructive lung disease, chronic infection, or other chronic
inflammatory or catabolic disorders with documented poor nutrient intake
and/or recent weight loss
BMI, Body mass index; GI, gastrointestinal; ICU, intensive care unit; PN, parenteral
nutrition.
is enhanced with the addition of one or two containers per day
of complete liquid nutrient supplements. These provide calories,
carbohydrate, high-quality protein, fat, and micronutrients; are
lactose and gluten free; and may contain small peptides and
medium-chain triglycerides to facilitate absorption of amino acid
and fat, respectively. Some formulations also contain soluble fiber
or prebiotics (e.g., fructo-oligosaccharides) designed to decrease
diarrhea. It is probably prudent to place outpatients who exhibit
or are at risk for undernutrition (see E-Tables 68-1 and 68-2) and
can tolerate oral medications on a potent oral multivitamin-
multimineral preparation, at least for several months.
Administration of Enteral Tube Feeding
Patients with conditions outlined in Table 68-2 may have a func-
tional gastrointestinal tract and yet be unable to consume ade-
quate diet orally due to medical or surgical conditions (e.g.,
mechanically ventilation, pancreatitis, dementia, dysphagia,
trauma or burns). Although PN is commonly administered in
these settings, this practice is not evidence based; academic
guidelines strongly suggest that oral nutritional supplements or
enteral tube feedings should be used if specialized nutrition
support is indicated in patients with a functional gastrointestinal
tract (”if the gut works, use it”). E-Table 68-4 shows major char-
acteristics of common complete liquid tube feeding formulations
and the types of patients for which these are typically prescribed.
These products can be used for oral nutrient supplementation as
tolerated. When delivered in appropriate amounts, the liquid
diets provide complete nutrition for most patients, although
some ICU patients and patients with malabsorption or other
conditions may have special needs (see later discussion).
The feedings can be delivered by conventional nasogastric
tubes into the stomach or by small-bore nasogastric or nasojen-
unal tubes, percutaneous gastrostomy or jejunostomy tubes, or
percutaneous gastrojejunostomy tubes (in which the gastric port
may be used for suction and the jejunal port for feeding). Gastric
feedings can be administered by either continuous or bolus feeds,
whereas small bowel feeds must employ a continuous slow infu-
sion using an infusion pump to avoid diarrhea. Tube feedings
should be initiated at a slow rate (e.g., 10 to 20 mL/hour) for 8
to 24 hours and slowly advanced to the goal rate in 8- to 24-hour
increments to deliver the calculated caloric and protein needs
over the next 24 to 48 hours, depending on clinical tolerance and
clinical conditions. Recent guidelines emphasize placing tube-
fed patients in the semirecumbent position (e.g., increase head of
bed), advancing feedings cautiously (with serial evaluations for
diarrhea, nausea, emesis, abdominal distention, and significant
gastric residuals), and using prokinetic agents and/or postpyloric
feedings if gastric feedings are not well tolerated. Recent data
suggest that higher volumes of gastric residuals (e.g., >250 mL)
are usually well tolerated in patients being tube fed.
Primarily based on results of animal studies, EN is associated
with improved gut barrier function, decreased infectious compli-
cations, less hypermetabolism, and decreased morbidity and
mortality in catabolic models, compared with PN. Salutary clini-
cal outcomes have been shown in randomized clinical trials in
patients with pancreatitis receiving EN into the jejunum, com-
pared with PN. Based on available data, recent guidelines for ICU
patients by international expert panels and academic societies
suggest that enteral tube feeds should be started within 1 to 3
 Chapter 68  Nutritional Support in Hospitalized Adults 685.e1

E-TABLE 68-4  COMPLETE ENTERAL NUTRIENT

FORMULAS AND CLINICAL
INDICATIONS
FORMULA TYPE AND
CHARACTERISTICS* CLINICAL INDICATION
Intact protein, complex† Normal intestinal function
Hydrolyzed protein/peptides, Gut mucosal disease, injury
semi-elemental‡
High calories, lower protein, lower Renal failure
electrolytes§
High calories, complex§ Fluid restriction (e.g., cardiac failure)
“Immune-modulating” enriched in Postoperative, immunosuppressed,
arginine, glutamine, nucleotides, severe stress, injury, gut mucosal
omega-3 fatty acids, and/or disease
antioxidants||,¶
EPA, γ-linolenic acid, and ARDS
antioxidants#
ARDS, Acute respiratory distress syndrome; EPA, eicosapentanoic acid; MCT,
medium-chain triglycerides.
*All formulations are lactose and gluten free, are relatively low in sodium, and provide
adequate vitamins and minerals with daily volumes of 1-1.5 L.
†
Least expensive; protein sources are intact casein, whey, and/or soy; fat sources are
corn, safflower, or soy oils and MCT; carbohydrate sources are maltodextrin, corn syrup,
hydrolyzed corn starch, sucrose; caloric density varies from 1 to 2.0 kcal/mL (primarily by
increasing fat content); may feature high-protein composition and soluble fiber or
prebiotics; osmolality 350-550 mOsm/kg.
‡
Protein sources are hydrolyzed casein, soy, and/or whey; may feature more MCT,
hydrolyzed corn starch, and sucrose for enhanced digestion and absorption; caloric density
is 1 to 1.5 kcal/mL.
§
Calorically dense (2.0 kcal/mL); low to moderate protein; low potassium,
magnesium, phosphorus, and vitamin A content; higher calcium content.
||
Use in septic or hemodynamically compromised patients is currently controversial.
¶
Glutamine is supplied as l-glutamine or glutamine peptides; several randomized,
controlled clinical trials show conflicting results regarding decrease in infections with
enteral glutamine supplementation; some formulas combine glutamine and other
supplements (e.g., enriched in antioxidants, omega-3 fatty acids).
#
Several, but not all, randomized, controlled clinical trials show clinical efficacy with
this formulation in patients who require mechanical ventilation due to ARDS; formula is
not enriched in arginine, glutamine, or nucleotides.
686 Section X  Endocrine Disease and Metabolic Disease
days after ICU admission if adequate caloric needs (e.g., >60%)
cannot be achieved with oral diet and supplements alone, espe-
cially for patients with existing malnutrition. Many studies have
shown that ICU patients actually receive only 60% to 75% of the
amount of tube feeding ordered by physicians. This can occur
because of tube feeding intolerance (e.g., high gastric residuals,
emesis, diarrhea, tube dislodgement) or discontinuation of
feeding for diagnostic tests or therapeutic interventions. Although
supplemental PN (see later discussion) is commonly ordered in
patients who are not able to achieve tube feeding rates adequate
for their needs, this practice remains controversial because of the
limited number of good clinical trials. Rigorous studies are now
in progress to address the efficacy of this approach, motivated by
data suggesting that an increase in net caloric deficit (i.e., the
difference between daily calorie requirements and daily actual
calories delivered, summed over time) is associated with worse
clinical outcomes in medical and surgical ICU patients.
Most outpatients and hospitalized ICU and non-ICU patients
tolerate standard, inexpensive enteral formulas delivered via
gastric or intestinal routes that provide between 1.0 and 1.5 kcal/
mL. A large variety of enteral tube feeding products is available
for clinical use. The specific product chosen should be based both
on clinical conditions and underlying organ function, as outlined
in E-Table 68-4. Because EN products can be marketed without
efficacy data from randomized, controlled clinical trials, there
remains a clear need for such trials to determine optimal EN
formulations for different clinical conditions.
Complications of enteral feeding include diarrhea. Diarrhea is
common in hospital patients receiving tube feedings but is typi-
cally caused by factors independent of the feeding, including
administration of antibiotics, sorbitol-containing or hypertonic
medications (e.g., acetaminophen elixir), and infections. Diar-
rhea caused by tube feeding itself does occur with rapid formula
administration, in patients with underlying gut mucosal disease,
and in those with severe hypoalbuminemia, which causes bowel
wall edema. A fiber-containing enteral formula is sometimes
useful to decrease diarrhea. Other complications of tube feeding
include aspiration of tube feedings into the lung; mechanical
problems with nasally placed feeding tubes, including discom-
fort, sinusitis, pharyngeal or esophageal mucosal erosion due to
local tube trauma; and, with percutaneous feeding tubes, entrance
site leakage, skin breakdown, cellulitis, and pain. Metabolic com-
plications of tube feeding include fluid imbalances, hyperglyce-
mia, electrolyte abnormalities, azotemia, and, occasionally,
refeeding syndrome (discussed later). In general, if tube feedings
are deemed to be required for more than 4 to 6 weeks, a percu-
taneous feeding tube should be placed.
In tube-fed patients who are receiving either subcutaneous or
intravenous insulin to control hyperglycemia, significant hypo-
glycemia due to the continued actions of insulin may occur if
tube feedings are discontinued inadvertently or for diagnostic or
therapeutic tests. Hospitalized patients receiving tube feedings
should have their blood glucose concentration monitored on a
daily basis (or several times per day as indicated) and their blood
electrolytes (including magnesium, potassium, and phosphorus)
and renal function monitored several times each week (or daily
in the ICU setting). Other blood chemistries should be deter-
mined at least weekly. This should be accompanied by close
monitoring of intake and output records (including urine, stool,
and drainage outputs) and gastrointestinal tolerance. When
patients are able to consume oral food, tube feeding should be
decreased and then discontinued (e.g., with daily calorie counts
by a registered dietitian). For patients requiring home tube
feeding, it is important to consult social service professionals to
ensure appropriate care and follow-up.
Administration of Parenteral Nutrition
The basic principle in considering PN therapy is that the patient
must be unable to achieve adequate nutrient intake via the enteral
route. PN support includes administration of standard complete
nutrient mixtures that contain dextrose, l-amino acids, lipid
emulsion, electrolytes, vitamins, and minerals (in addition to
certain medications as indicated, such as insulin or octreotide),
given via a peripheral or central vein. Administration of complete
PN therapy to patients with gastrointestinal tract dysfunction has
become a standard of care in most hospitals and ICUs through-
out the world, although use in individual institutions varies
widely. PN is life-saving in patients with intestinal failure (e.g.,
short bowel syndrome). Existing data indicate that PN benefits
patients with preexisting moderate to severe malnutrition or
critical illness by decreasing overall morbidity, and possibly mor-
tality, compared with patients receiving inadequate EN or hydra-
tion (intravenous dextrose) therapy alone. A consensus is
emerging, based on recent rigorous studies in critical illness, that
PN should probably not be initiated until days 3 to 4 after ICU
admission in patients who are unable to tolerate adequate EN.
Compared with PN, EN is less expensive, probably maintains
intestinal mucosal structure and function to a greater extent, is
safer in terms of mechanical and metabolic complications (see
later discussion), and is associated with reduced rates of nosoco-
mial infection. Therefore, the enteral route of feeding should be
used and advanced whenever possible, and the amount of admin-
istered PN should be correspondingly reduced.
Generally recognized indications for PN include the following
situations:
1. Patients with short bowel syndrome or other conditions
causing intestinal failure (e.g., motility disorders, obstruction,
severe ileus, severe inflammatory bowel disease), especially
those with preexisting malnutrition.
2. Clinically stable patients in whom adequate enteral feeding
(e.g., >50% of needs) is unlikely for 7 to 10 days because of an
underlying illness.
3. Patients with severe catabolic stress requiring ICU care in
whom adequate enteral nutrient intake is unlikely for more
than 3 to 5 days.
There is no reason to withhold PN in hospitalized patients for
any period of time if they exhibit preexisting moderate to severe
malnutrition and are deemed to be unlikely to meet their needs
by the oral or enteral route.
Generally accepted contraindications for PN include the fol-
lowing conditions:
1. If the GI tract is functional and access for enteral feeding is
available.
 Chapter 68  Nutritional Support in Hospitalized Adults 687
2. If PN is thought to be required for 5 days or less.
3. If the patient cannot tolerate the extra intravenous fluid
required for PN or has severe hyperglycemia or electrolyte
abnormalities on the planned day of PN initiation
4. If the patient has an uncontrolled bloodstream infection or
severe hemodynamic instability.
5. If new placement of an intravenous line solely for PN poses
undue risks based on clinical judgment
6. On an individualized basis, if aggressive nutritional support is
not desired by the competent patient or legally authorized
representative, such as in premorbid patients or those with
terminal illness.
PN can be delivered either as peripheral vein solutions or as
central vein solutions through a percutaneous subclavian vein or
internal jugular vein catheter for infusion into the superior vena
cava (nontunneled in the hospital setting), through a subcutane-
ously tunneled central venous catheter (e.g., Hickman catheter)
or central venous port (for chronic home PN therapy), or through
a peripherally inserted central venous catheter (PICC). Although
data are limited, it is clearly preferable to manage long-term
central venous PN to be managed at home with the use of a tun-
neled central venous catheter rather than a PICC line because of
the higher rate of local complications (e.g., phlebitis, catheter
breakage) and possibly catheter-associated infections with PICC
lines.
A comparison of typical fluid, macronutrient, and micronutri-
ent content of peripheral and central vein PN solutions is shown
in Table 68-3. Intravenous lipid emulsions (typically added to PN
as a 20% soybean oil–based solution in the United States) provide
both essential linoleic and α-linolenic fatty acids and energy
(10 kcal/g); these are typically infused over a 24-hour period in
the complete PN administration bag. The maximal recom-
mended rate of fat emulsion infusion is approximately 1.0 g/kg/
day. Most patients are well able to clear triglyceride from plasma
after intravenous administration of fat emulsion. Recently, an
intravenous lipid emulsion of 80% olive oil/20% soybean oil was
approved for use in adult PN in the United States. It is important
to monitor blood triglyceride levels at baseline and then approxi-
mately weekly and as indicated to assess clearance of intravenous
fat; triglyceride levels should be maintained lower than 400 mg/
dL to decrease the risk of pancreatitis or diminished pulmonary
diffusion capacity in patients with severe chronic obstructive
lung disease.
Central venous administration of PN allows higher concentra-
tions of dextrose (3.4 kcal/g) and amino acids (4 kcal/g) to be
delivered as hypertonic solutions; thus, lower amounts of fat
emulsion are needed to reach caloric goals (see Table 68-3).
Requirements for potassium, magnesium, and phosphorus are
typically higher with central vein PN compared to peripheral vein
PN. The higher concentrations of dextrose and amino acids allow
most patients to achieve caloric and amino acid goals with only
1 to 1.5 L of PN per day. In central vein PN, initial orders typically
provide 60% to 70% of non–amino acid calories as dextrose and
30% to 40% of non–amino acid calories as fat emulsion. These
percentages are adjusted as indicated based on levels of blood
glucose and triglyceride, respectively. Based on comprehensive
data associating hyperglycemia with hospital morbidity and
TABLE 68-3  COMPOSITION OF TYPICAL PARENTERAL
NUTRITION SOLUTIONS
COMPONENT* PERIPHERAL PN CENTRAL PN
Volume (L/day) 2-3 1-1.5
Dextrose (%) 5 10-25
Amino acids (%)† 2.5-3.5 3-8
Lipid (%)‡ 3.5-5.0 2.5-5.0
Sodium (mEq/L) 50-150 50-150
Potassium (mEq/L) 20-35 30-50
Phosphorus (mmol/L) 5-10 10-30
Magnesium (mEq/L) 8-10 10-20
Calcium (mEq/L) 2.5-5 2.5-5
Trace elements§
Vitamins||
*Electrolytes in parenteral nutrition (PN) are adjusted as indicated to maintain serially
measured serum levels within the normal range. The percentage of sodium and potassium
salts as chloride is increased to correct metabolic alkalosis, and the percentage of salts as
acetate is increased to correct metabolic acidosis. Regular insulin is added to PN as needed
to achieve blood glucose goals (separate intravenous insulin infusions are commonly
required with hyperglycemia in intensive care unit settings).
†
Provides all essential amino acids and several nonessential amino acids. The dose of
amino acids is adjusted downward or upward to goal as a function of the degree of
azotemia or hyperbilirubinemia in patients with renal or hepatic failure, respectively.
‡
Lipid is given as soybean oil– or olive oil/soybean oil–based fat emulsion in the
United States. In Europe and other non-U.S. countries, intravenous fish oil, olive oil,
medium-chain triglycerides, and combinations of these are available for use in PN. Lipid is
typically mixed with dextrose and amino acids in the same PN infusion bag (“all-in-one”
solution).
§
Trace elements added on a daily basis to peripheral vein and central vein PN are
mixtures of chromium, copper, manganese, selenium, and zinc. (These elements can also
be supplemented individually.)
||
Vitamins added on a daily basis to peripheral vein and central vein PN are mixtures
of vitamins A, B1 (thiamine), B2 (riboflavin), B3 (niacinamide), B6 (pyridoxine), B12, C, D,
and E, biotin, folate, and pantothenic acid. Vitamin K is added on an individual basis (e.g.,
for patients with cirrhosis). Specific vitamins can also be supplemented individually.
mortality, expert panels now recommend tight blood glucose
control in ICU settings (between 80 and 130 to 150 mg/dL) and
close blood glucose monitoring. Separate intravenous insulin
infusions should usually be administered in the ICU when
patients receiving central vein PN develop hyperglycemia.
Specific requirements for intravenous trace elements and vita-
mins have not been rigorously defined for patient subgroups, and
in most stable patients, therapy is directed at meeting published
recommended doses using standardized intravenous prepara-
tions to maintain blood levels in the normal range (see Table
68-3). Several studies have shown that a significant proportion of
ICU patients have low levels of zinc, selenium, vitamin C, vitamin
E, and vitamin D despite receiving specialized PN (or EN).
Depletion of these essential nutrients may impair antioxidant
capacity, immunity, wound healing, and other important body
functions, and supplementation is recommended if serum con-
centrations are low. For example, zinc (and other micronutrients
such as copper) should probably be increased in the PN of
patients with burns, large wounds, significant gastrointestinal
fluid losses, and other conditions if serum concentrations indi-
cate low levels. Recent data suggest that thiamine depletion is not
uncommon in patients receiving chronic diuretic therapy or in
those with severe malabsorption.
The most common complication of peripheral vein PN is local
phlebitis resulting from use of the catheter. In such cases, a small
dose of hydrocortisone and heparin is typically added to the
solution. Alterations in blood electrolytes can be treated with
adjustment of concentrations in the peripheral PN prescription.
Hypertriglyceridemia typically responds well to lowering of the
total PN lipid dose. Central vein PN is associated with a much
688 Section X  Endocrine Disease and Metabolic Disease
higher rate of mechanical, metabolic, and infectious complica-
tions than peripheral vein PN. Mechanical complications include
those related to insertion of the central venous catheter (e.g.,
pneumothorax, hemothorax, malposition of the catheter, throm-
bosis). Infectious complications include catheter-related blood-
stream infections and non–catheter-related infections. The risk
for these infections appears to be increased with use of non–
subclavian vein central venous access (e.g., jugular vein, femoral
vein) and multiple-use catheters with non-dedicated PN infusion
ports used for additional purposes such as blood drawing or
medication administration. Poorly controlled blood glucose
levels (>140 to 180 mg/dL) are not uncommon in patients
requiring central vein PN and are associated with an increased
risk of nosocomial infection. Risk factors for hyperglycemia
include poorly controlled blood glucose at PN initiation; use of
high dextrose concentrations (>10%) in the initial few days of
PN administration or too rapid an increase in total dextrose load;
insufficient exogenous insulin administration; inadequate moni-
toring of blood glucose responses to central vein PN administra-
tion; and administration of corticosteroids and vasopressor
agents such as noreprinephrine (which stimulate gluconeogen-
esis and cause insulin resistance).
Recent data also suggest that inadequate or no provision of the
amino acid glutamine may increase infection risk in patients
requiring PN. This amino acid appears to be conditionally essen-
tial in catabolic states and serves as an important fuel for immune
cells and cells of the gut mucosa. Several expert panels now rec-
ommend that glutamine be routinely added to the PN in ICU
patients, but this practice remains controversial because some
studies show no benefit (or even harm) in certain patient sub-
groups and an improvement in hospital mortality has not been
documented.
Studies on nutrient utilization efficiency and metabolic com-
plications in severely catabolic patients suggest that lower
amounts of total energy and protein/amino acids should be
administered than were routinely given in the past, particularly
in unstable and ICU patients. High calorie, carbohydrate, amino
acid, and fat loads (“hyperalimentation”) are easily administered
via central vein PN but can induce severe metabolic complica-
tions, including carbon dioxide overproduction, azotemia,
hyperglycemia, electrolyte alterations, and hepatic steatosis and
injury (E-Table 68-5). Dextrose and lipid doses in PN should be
advanced over several days after initiation, with close monitoring
of the blood glucose concentration, electrolytes, triglycerides,
organ function tests, intake and output measurements, and the
clinical course.
Refeeding syndrome with central vein PN administration is
relatively common in patients at risk, including those with pre-
existing malnutrition, electrolyte depletion, alcoholism, or pro-
longed periods of intravenous hydration therapy (e.g., 5%
dextrose) without nutritional support, all of which are common
in hospital patients. Refeeding syndrome is mediated by admin-
istration of excessive intravenous dextrose (>150 to 250 g, for
example in 1 L of PN containing 15% to 25% dextrose). This,
in turn, markedly stimulates insulin release, which rapidly lowers
blood concentrations of potassium, magnesium, and especially
phosphorus as a result of intracellular shifts and utilization in
carbohydrate metabolic pathways. Administration of high doses
of carbohydrate also consumes thiamine, which is required as a
cofactor for carbohydrate metabolism and can precipitate symp-
toms of thiamine deficiency (see E-Table 68-2), especially in
patients with poor thiamine nutriture at baseline. Hyperinsu-
linemia also tends to cause sodium and fluid retention at the
level of the kidney. Together, fluid and sodium retention, the
drop in electrolytes (which can cause arrhythmias), and hyper-
metabolism due to excessive calorie provision can result in heart
failure, especially in patients with preexisting heart disease and
cardiac muscle atrophy due to prolonged protein-energy malnu-
trition. Prevention of refeeding syndrome requires vigilance to
identify patients at risk; use of initially low PN dextrose con-
centrations; empiric provision of higher doses of potassium,
magnesium, and phosphorus based on current blood levels and
renal function; and supplemental thiamine (100 mg/day for 3
to 5 days).
If home PN is indicated, the primary physician should consult
with social service professionals to identify appropriate home
care companies and nutrition support professionals to assess
intravenous line access, metabolic status, and the home PN order
and to arrange for follow-up care and monitoring of PN. It is
important not to arrange for rapid discharge of hospitalized
patients newly started on PN. Obtaining appropriate venous
access and monitoring of fluid and electrolyte status over a 2- to
3-day period is an important aspect of care for most patients
started on PN, and it is imperative for those with severe malnutri-
tion and those at risk for refeeding syndrome.
For a deeper discussion on this topic, please see Chapters
214, “Nutritional Assessment,” and 215, “Protein-Energy
Malnutrition” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Casaer MP, Mesotten D, Hermans G, et al: Early versus late parenteral nutrition
in critically ill adults, N Engl J Med 365:506–517, 2011.
Doig GS, Simpson F, Sweetman EA, et al, and Early PN Investigators of the
ANZICS Clinical Trials Group: Early parenteral nutrition in critically ill
patients with short-term relative contraindications to early enteral nutrition: a
randomized controlled trial, JAMA 309:2130–2138, 2013.
Gershengorn HB, Kahn JM, Wunsch H: Temporal trends in the use of parenteral
nutrition in critically ill patients, Chest 145:508–517, 2014.
Heidegger CP, Berger MM, Graf S, et al: Optimisation of energy provision with
supplemental parenteral nutrition in critically ill patients: a randomised
controlled clinical trial, Lancet 381:385–393, 2013.
Heighes PT, Doig GS, Sweetman EA, et al: An overview of evidence from
systematic reviews evaluating early enteral nutrition in critically ill patients:
more convincing evidence is needed, Anaesth Intensive Care 38:167–174,
2010.
McClave SA, Kozar R, Martindale RG, et al: Summary points and consensus
recommendations from the North American Surgical Nutrition Summit,
JPEN J Parenter Enteral Nutr 37(5 Suppl):99S–105S, 2013.
McClave SA, Martindale RG, Vanek VW, et al: Guidelines for the provision and
assessment of nutrition support therapy in the adult critically ill patient:
Society of Critical Care Medicine (SCCM) and American Society for
Parenteral and Enteral Nutrition (A.S.P.E.N.), JPEN J Parenter Enteral Nutr
33:277–316, 2009.
Ziegler TR: Parenteral nutrition in the critically ill patient, N Engl J Med
361:1088–1097, 2009.
Ziegler TR: Nutrition support in critical illness: bridging the evidence gap, N
Engl J Med 365:562–564, 2011.

E-TABLE 68-5  SOME COMMON METABOLIC
COMPLICATIONS OF PARENTERAL
NUTRITION
PN ORDER PROBLEM
Excess kcal, CHO, fat
Excess kcal, CHO, fat
Excess CHO
Excess fluid, kcal, CHO, fat
Excess amino acids
Excess sodium and fluid
Excess CHO, inadequate insulin
Inadequate or excessive electrolytes
Excess fluid, kcal, sodium, CHO,
inadequate electrolytes
Excess CHO, inadequate electrolytes,
thiamine
CHO, Carbohydrate; kcal, calories; PN, parenteral nutrition.
Chapter 68  Nutritional Support in Hospitalized Adults 688.e1
METABOLIC OR
CLINICAL CONSEQUENCE
Abnormal liver function tests
Hepatic steatosis
Hypercapnia
Respiratory insufficiency
Azotemia
Sodium and fluid retention
Hyperglycemia-mediated immune
cell dysfunction, infection
Abnormal blood electrolyte levels
Cardiac failure, arrhythmias
Refeeding syndrome

Disorders of Lipid Metabolism
Geetha Gopalakrishnan and Robert J. Smith
  DEFINITION AND EPIDEMIOLOGY
Lipids such as free fatty acids (FFA), cholesterol, and triglycer-
ides are hydrophobic molecules that bind proteins for transport.
Nonesterified FFA travel as anions complexed to albumin. Esteri-
fied complex lipids are transported in lipoprotein particles. Lipo-
proteins have a hydrophobic core (cholesteryl esters and
triglycerides) and an amphiphilic surface monolayer (phospho-
lipids, unesterified cholesterol, and apolipoproteins). Ultracen-
trifugation separates lipoproteins into five classes based on their
density (Table 69-1).
Proteins on the surface of lipoproteins (i.e., apolipoproteins)
activate enzymes and receptors that guide lipid metabolism.
Defects in the synthesis and catabolism of lipoproteins result in
dyslipidemia. Prevalence of dyslipidemia in the United States is
approximately 20% and varies with the population studied. An
estimated 70% of individuals with premature coronary heart
disease (CHD) have dyslipidemia. In clinical trials, treatment of
dyslipidemia improved both CHD and all-cause mortality rates.
Two classes of lipids, triglyceride and cholesterol, play a signifi-
cant, yet modifiable, role in the pathogenesis of atherosclerosis
and therefore are the focus of this chapter.
  PATHOLOGY
In the intestinal lumen, dietary triglycerides and cholesterol
esters are hydrolyzed by pancreatic lipase to produce glycerol,
FFA, and free cholesterol. Formation of micelles enables the
absorption of glycerol and FFA into the intestinal cell. The trans-
port of free cholesterol is mediated by a cholesterol gradient
that exists between the lumen and the intestinal cell. Within the
cell, glycerol combines with three fatty acid chains to form tri-
glycerides, and cholesterol is esterified to form cholesterol esters.
Chylomicrons are formed from triglycerides (85% of chylomi-
cron mass) and cholesterol esters assembled with surface lipo-
proteins. Chylomicrons enter into the circulation and acquire
more surface apolipoproteins such as apo C-II and apo E from
high-density lipoprotein (HDL) particles (Fig. 69-1). Apo C-II
TABLE 69-1  PROPERTIES OF LIPOPROTEINS
LIPOPROTEIN CLASS DENSITY (g/mL)
Chylomicrons <0.95
VLDL <1.006
IDL 1.006-1.019
LDL 1.019-1.063
HDL 1.063-1.25
HDL, High-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride; VLDL, very-low-density lipoprotein.
69 
activates lipoprotein lipase (LPL), which is located on the capil-
lary endothelium. LPL hydrolyzes the core chylomicron triglyc-
erides to release FFA, which function as an energy source. Excess
fatty acids are stored in adipose tissue or utilized in hepatic
lipoprotein synthesis. The triglyceride-poor chylomicron
remnant is then cleared from the circulation by hepatic LDL
receptors. These receptors are  activated by apo E, which is
located on the surface of chylomicrons.
Very-low-density lipoproteins (VLDL) are synthesized by the
liver (see Fig. 69-1). FFA and cholesterol obtained from the
circulation or synthesized by the liver are incorporated into
VLDL particles. Any condition that increases the flux of FFA
to the liver, such as poorly controlled diabetes, will increase
VLDL production. The liver assembles triglycerides (55% of
VLDL mass), cholesterol (20%), and surface apolipoproteins
to form VLDL particles. Apo C-II, the cofactor for LPL, hydro-
lyzes the triglyceride core of VLDL particles to generate VLDL
remnant or intermediate-density lipoprotein (IDL). The IDL,
depleted of triglycerides (25%), can be cleared from the circula-
tion by apo E–mediated LDL receptors, or it can be hydrolyzed
further to form low-density lipoproteins (LDL). LDL particles
are triglyceride poor (5% of LDL mass) and consist mostly of
cholesterol esters (60%) and apolipoproteins. Apo B100 on the
surface of LDL binds LDL receptors and facilitates LDL clear-
ance from the circulation. Internalized LDL-cholesterol is used
to synthesize hormones, produce cell membranes, and store
energy.
In the liver, LDL-cholesterol is used to synthesize bile acids
(see Fig. 69-1), which are secreted into the intestinal lumen along
with free cholesterol. Bile acids help transport fat. Approximately
50% of the cholesterol and 97% of the bile acid entering the
lumen is reabsorbed back into the circulation. The reabsorbed
cholesterol regulates cholesterol and LDL receptor synthesis.
Many cells in the body, including liver parenchymal cells, syn-
thesize cholesterol (Fig. 69-2). Acetate is converted to 3-hydroxy-
3-methylglutaryl–coenzyme A (HMG-CoA). HMG-CoA
reductase converts HMG-CoA to mevalonic acid, which is then
ORIGIN APOLIPOPROTEINS LIPID
Intestine C-II, E TG (85%), cholesterol (10%)
Liver B100, C-II, E TG (55%), cholesterol (20%)
VLDL catabolism B100, E TG (25%), cholesterol (35%)
IDL catabolism B100 TG (5%), cholesterol (60%)
Liver, intestine A-I, E TG (5%), cholesterol (20%)
689
690 Section X  Endocrine Disease and Metabolic Disease

Dietary fat
cholesterol

Bile acids

Intestine
LPL
Chylomicron Chylomicron
remnant
apo E apo C-II
apo E
FFA

Peripheral sites FC B,E

Adipose
B
HDL
FFA FFA
Liver
LDL IDL VLDL
LPL LPL
apo B100 apo C-II apo E apo C-II

B,E
FIGURE 69-1  Normal metabolism of plasma lipoproteins (see text for details). apo, Apolipoprotein; B,E, membrane receptor for lipoproteins con-
taining apo B and apo E (synonymous with the LDL receptor); FC, free (unesterified) cholesterol; FFA, free (unesterified) fatty acids; HDL, high-density
lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very-low-density lipoprotein.

LDL Cholesterol Uptake from Circulation

LDL

B100
LDL Circulation

B100
B100
Endogenous Cell surface
cholesterol synthesis LDL-C

Acetate LDL (B,E)

receptor
expression
HMG-CoA

HMG-CoA
mRNA Cell
inhibitors

Mevalonic acid

Cholesterol
pool

Cholesterol LDL receptor gene

FIGURE 69-2  Regulation of low-density lipoprotein (LDL) receptor expression (see text for details). B100, Apolipoprotein B100; B,E, membrane
receptor for lipoproteins containing apo B and apo E (synonymous with the LDL receptor); HMG-CoA, 3-hydroxy-3-methylglutaryl–coenzyme A;
LDL-C, LDL-cholesterol; mRNA, messenger RNA.

converted to cholesterol through a series of steps. HMG-CoA
reductase is the rate-limiting step in the cholesterol synthesis
pathway. Drugs that inhibit this enzyme decrease cholesterol bio-
synthesis and cellular cholesterol pools. Internalization of LDL
particles into cells is regulated by negative feedback (see Fig.
69-2). A negative cholesterol balance increases the expression of
LDL receptors and subsequent uptake of cholesterol from the
circulation. A positive cell cholesterol balance suppresses LDL
receptor expression and decreases uptake of LDL-cholesterol
into cells. Circulating LDL then enter macrophages and other
tissues via scavenger receptors. Because the scavenger receptors
are not regulated, these cells accumulate excess intracellular
 Chapter 69  Disorders of Lipid Metabolism 691

cholesterol, resulting in the formation of foam cells and athero-
matous plaques.
The anti-atherogenic effect of HDL is attributed to the removal
of excess cholesterol from tissue sites and other lipoproteins.
HDL is synthesized in the liver and intestine (see Fig. 69-1).
Excess phospholipids, cholesterol, and apolipoproteins on
remnant chylomicrons, VLDL, IDL, and LDL, are transferred to
HDL particles and thus increase HDL mass. Apo A-I, a surface
lipoprotein on HDL particles, mobilizes cholesterol from intra-
cellular pools and accepts cholesterol released during lipolysis of
triglyceride-rich lipoproteins. It also activates lecithin-cholesterol
acyltransferase (LCAT), an enzyme that esterifies cholesterol.
These cholesterol esters move the hydrophilic HDL surface to
the hydrophobic HDL core. Cholesterol ester transfer protein
(CETP) transfers core HDL cholesterol esters to other lipopro-
teins such as VLDL. These lipoproteins deliver cholesterol to
peripheral sites for hormone and cell membrane synthesis.
Defects in the production or removal of lipoproteins results in
dyslipidemia. Both genetic and acquired conditions have been
implicated in the pathogenesis of lipid disorders (Tables 69-2 and
61-3). These are discussed later in the chapter.
  CLINICAL PRESENTATION
Dyslipidemia plays a significant role in the development of ath-
erosclerosis. Increased incidence of CHD with high LDL- and
low HDL-cholesterol is well documented. Excess LDL results in
the formation of cholesterol plaques that deposit in arteries (ath-
eroma), skin and tendon (xanthomas), eyelids (xanthelasma),
and iris (corneal arcus). The impact of triglycerides on vascular
disease is less clear. Metabolic disorders such as diabetes and
obesity are often associated with vascular disease and hypertri-
glyceridemia, and the atherogenic impact of other elements in
these disorders is difficult to separate from the effect of hypertri-
glyceridemia. However, in several population-based studies,
abnormal triglyceride levels correlated with increased risk for
CHD. Marked hypertriglyceridemia (>1000 mg/dL) is associ-
ated with the chylomicronemia syndrome, characterized by pan-
creatitis and xanthomas.
  DIAGNOSIS
Dyslipidemia is defined by a total cholesterol, triglyceride, or
LDL level greater than the 90th percentile or an HDL level lower
than the 10th percentile for the general population. Because chy-
lomicrons are present in plasma for up to 10 hours after a meal,
fasting total cholesterol, triglyceride, and lipoprotein assessments
are required for diagnosis. It is advisable to confirm dyslipidemia
with two separate determinations.
Total cholesterol, triglyceride, and HDL levels can be mea-
sured directly; VLDL and LDL levels usually are calculated. If the
triglyceride concentration is lower than 400 mg/dL, then VLDL
is calculated by dividing the triglyceride level by 5. LDL-
cholesterol is estimated by subtracting VLDL and HDL from the
total cholesterol. VLDL and LDL cannot be determined if tri-
glyceride levels are greater than 400 mg/dL. In that case, the
lipoprotein abnormality can be identified by inspecting
the serum. When the triglyceride level exceeds 350 mg/dL, the

TABLE 69-2  GENETIC DISORDERS OF LIPID METABOLISM

DISORDER GENETIC DEFECT DYSLIPIDEMIA
Familial hypercholesterolemia Mutation in the gene that encodes LDL receptor Elevated TC and LDL
Familial defective apolipoprotein B100 Impaired binding of LDL to LDL receptor due to a defect in apo Elevated TC and LDL
B100 protein
Elevated plasma Lp(a) Increased binding of LDL to apolipoprotein(a) Elevated Lp(a)
Polygenic hypercholesterolemia Increased binding of apo E4–containing lipoprotein to LDL Elevated TC and LDL
receptor resulting in downregulation of the LDL receptor
Familial combined hyperlipoproteinemia Polygenic disorder associated with increased hepatic VLDL Elevated TC, LDL, and TG
production, resulting in increased LDL and decreased HDL Low HDL
production; some individuals have a mutation in the LPL gene
that affects expression and function of LPL
Familial dysbetalipoproteinemia Lower affinity of apo E2 for LDL receptor Elevated TG, TC, and LDL
Lipoprotein lipase deficiency Mutation in the LPL gene Elevated TG
Apolipoprotein C-II deficiency Decrease in activation of LPL due to a deficiency of apo CII Elevated TG
Familial hypertriglyceridemia Overproduction of hepatic VLDL and increased catabolism of HDL Elevated TG
Low HDL
HDL, High-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglyceride; VLDL, very low-density lipoprotein.

TABLE 69-3  MECHANISMS OF SECONDARY HYPERLIPIDEMIA

CLINICAL ELEVATED LIPOPROTEIN MECHANISM
Diabetes Chylomicron, VLDL, LDL Increase in VLDL production and decrease in VLDL/LDL clearance
Obesity Chylomicron, VLDL, LDL Increase in VLDL production and decrease in VLDL/LDL clearance
Lipodystrophy VLDL Increase in VLDL production
Hypothyroidism LDL, VLDL Decrease in LDL/LDL clearance
Estrogen VLDL Increase in VLDL production
Glucocorticoids VLDL, LDL Increase in VLDL production and conversion to LDL
Alcohol VLDL Increase in VLDL production
Nephrotic syndrome VLDL, LDL Increase in VLDL production and conversion to LDL
LDL, Low-density lipoprotein; VLDL, very-low-density lipoprotein.
692 Section X  Endocrine Disease and Metabolic Disease

serum is cloudy. After refrigeration, a white surface layer depicts evidence supports statin use in primary and secondary preven-
excess chylomicrons, whereas a dispersed, opaque infranatant tion of CHD (level A). Treatment effects of statin can be assessed
reflects a VLDL dysfunction. after 1 to 2 months. Additional agents can be considered if
Current guidelines recommend selective screening of children target goals are not achieved with maximal drug dosing.
who have a family history of lipoprotein abnormality or prema- A fasting lipid panel is required to diagnose hypertriglyceride-
ture vascular disease and adults who have an increased risk for mia. Triglyceride levels higher than 200 mg/dL are classified as
CHD. The U.S. Preventive Services task force recommended abnormal. Borderline triglyceride levels range from 150 to
universal screening starting at 35 years of age for men and at 200 mg/dL, and normal values are lower than 150 mg/dL. A diet
45 years of age for women; there is a paucity of data supporting and exercise program is recommended for all individuals with
long-term benefits from screening of younger individuals. Either abnormal triglyceride levels (level C). However, pharmacologic
a fasting or a nonfasting total cholesterol and HDL measurement treatments to reduce triglyceride levels may be considered if
can be the initial screen. If the total cholesterol value is greater fasting levels are higher than 200 mg/dL, especially if the indi-
than 200  mg/dL or the HDL value is less than 40  mg/dL, then vidual is at risk for CHD or pancreatitis (see Table 69-7). Fibrates,
a repeat fasting lipid panel is required. If the total cholesterol fish oil, and nicotinic acid should be considered if the triglyceride
value is less than 200  mg/dL and the HDL value is greater than level is higher than 500 mg/dL (level C). However, for levels
40  mg/dL, then retesting is recommended every 5 years. Indi- lower than 500 mg/dL, statins are first-line therapy (level B).
viduals with CHD, risk factors for CHD, or CHD equivalents Low HDL concentrations (<40  mg/dL) can also increase the
(i.e., symptomatic carotid artery disease, peripheral arterial risk for CHD. In the Framingham Heart Study, every decrease
disease, abdominal aortic aneurysm, or diabetes) should be in HDL of 5  mg/dL increased the risk for myocardial infarction.
screened more frequently based on risk assessment, as shown Both lifestyle modifications (e.g., diet low in saturated fat, exer-
in Table 69-4. CHD risk factors include age (men >45 years, cise) and pharmacologic therapy (e.g., nicotinic acid, fibrate)
women >55 years), family history of premature CHD (affected can improve HDL levels. However, target goals and treatment
male first-degree relative <55 years or female first-degree relative recommendations have not been established due to a lack of
<65 years of age), smoking, hypertension, and low HDL evidence.
(<40  mg/dL). HDL concentrations higher than 60  mg/dL are
cardioprotective. Overall, the level of evidence to support screen-
ing is fair (level B) but increases with age, male gender, and
CHD (level A). TABLE 69-5  THERAPEUTIC APPROACH TO
REDUCE LEVELS OF LOW-DENSITY
  TREATMENT
LIPOPROTEIN–CHOLESTEROL*
Treatment is initiated after two abnormal lipid findings. Treat- TREATMENT LIFESTYLE DRUG
ment of elevated total cholesterol and LDL-cholesterol can slow RISK GOAL: CHANGES: THERAPY:
the development and progression of CHD. Meta-analysis of CATEGORY LDL (mg/dL) LDL (mg/dL) LDL (mg/dL)
primary and secondary prevention trials indicates that CHD ≤One risk factor <160 ≥160 ≥160-190
≥Two risk <130 ≥130 ≥130-160
mortality decreases by approximately 15% for every 10% reduc- factors
tion in serum cholesterol. LDL-cholesterol treatment strategies CHD or CHD <100 (optional <70) ≥100 ≥100-130
are based on risk indicators (Table 69-5). There is strong evi- risk equivalent
dence that dietary modifications can reduce LDL-cholesterol CHD, Coronary heart disease; HDL, high-density lipoprotein–cholesterol;
and triglyceride levels (Table 69-6). However, evidence that LDL, low-density lipoprotein–cholesterol.
*Recommendations of the Adult Treatment Panel III, National Cholesterol Education
lifestyle-induced lipid modifications improve cardiovascular Program (NCEP), as modified in 2004. CHD risk factors include age (men >45 yr, women
outcomes is limited (level C). If target goals are not achieved, >55 yr), family history of premature CHD (male first-degree relative <55 yr, female
first-degree relative <65 yr), smoking, hypertension, diabetes mellitus, and HDL <40 mg/
then pharmacologic therapy is considered (Table 69-7). Ample dL. Subtract a risk factor if HDL >60 mg/dL. CHD risk equivalents include symptomatic
carotid artery disease, peripheral arterial disease, abdominal aortic aneurysm, and diabetes
mellitus.

TABLE 69-4  RECOMMENDATIONS FOR SCREENING

FOR DYSLIPIDEMIA*
1. A fasting lipid profile is recommended at age 20 yr TABLE 69-6  RECOMMENDATIONS FOR
2. Rescreen every 5 yr if NUTRITIONAL INTAKE*
• LDL <160 mg/dL in patients with 0-1 risk factor
• LDL <130 mg/dL in patients with ≥2 risk factors NUTRIENT RECOMMENDED INTAKE
3. Rescreen every year if Total Fat 25-35% of total calories
• LDL 130-159 mg/dL in patients with ≥2 risk factors   Saturated   <7%
• LDL <100 mg/dL in patients with CHD or CHD risk equivalent   Polyunsaturated   <10%
CHD, Coronary heart disease; HDL, high-density lipoprotein–cholesterol;   Monounsaturated   <20%
LDL, low-density lipoprotein–cholesterol. Carbohydrates 50-60% of total calories
*Recommendations of the Adult Treatment Panel III, National Cholesterol Education Protein 15% of total calories
Program (NCEP), as modified in 2004. CHD risk factors include age (men >45 yr, women Cholesterol <200 mg/day
>55 yr), family history of premature CHD (male first-degree relative <55 yr, female Fiber 20-30 g/day
first-degree relative <65 yr), smoking, hypertension, and HDL <40 mg/dL. Subtract a risk
factor if HDL >60 mg/dL. CHD risk equivalents include symptomatic carotid artery *Recommendations of the Adult Treatment Panel III, National Cholesterol Education
disease, peripheral arterial disease, abdominal aortic aneurysm, and diabetes mellitus. Program (NCEP), as modified in 2004.
 Chapter 69  Disorders of Lipid Metabolism 693
TABLE 69-7  DRUGS COMMONLY USED FOR THE TREATMENT OF HYPERLIPIDEMIA
DRUG CLASS LDL (% CHANGE) HDL (% CHANGE)
HMG-CoA inhibitors ↓ 20-60 ↑ 5-10
Cholesterol absorption ↓ 17 No effect
inhibitors
Bile acid sequestrants ↓ 15-30 Slight increase
Fibric acid ↓ 5-20 ↑ 5-20
Nicotinic acid ↓ 10-25 ↑ 15-35
Omega-3 fatty acids ↑ 4-49 ↑ 5-9
HMG-CoA, Hydroxymethylglutaryl–coenzyme A reductase.
Lifestyle Modification
Lifestyle modification should be the initial step in the manage-
ment of hyperlipidemia (see Table 69-6). Restricting the dietary
intake of fat lowers total cholesterol by approximately 15% and
LDL cholesterol by 25%. Low-fat diets that limit saturated fat
content promote LDL receptor expression and increase the
uptake of LDL-cholesterol from the circulation. By contrast,
saturated fat downregulates hepatic LDL receptors and increases
circulating LDL. Because unsaturated fats (polyunsaturated and
monounsaturated) generally do not have this effect, they are the
preferred form of fat intake. However, polyunsaturated fats con-
taining fatty acids with a trans rather than cis double bond con-
figuration (trans-fatty acids) increase plasma cholesterol levels
similarly to saturated fat.
Limiting the intake of saturated and trans-unsaturated fatty
acids requires appropriate calorie substitutions. Increasing carbo-
hydrate content to achieve this goal can increase the hepatic syn-
thesis of triglyceride. Dietary substitution with soluble fibers
(e.g., oat bran) has been recommended, because these fibers have
a limited effect on triglyceride levels. They also bind bile acids in
the gut and thereby decrease cholesterol levels. Other polyun-
saturated fats, such as omega-3 fatty acids, are cardioprotective.
They are abundant in fatty fish, flaxseed oil, canola oil, and nuts.
They reduce VLDL production, inhibit platelet aggregation, and
decrease CHD. Even two servings per week of fatty fish such as
salmon can be beneficial.
Dietary restriction of fat (<10%) is essential for the treatment
of marked hypertriglyceridemia. Other factors such as carbohy-
drate and alcohol intake can also increase the synthesis of triglyc-
eride. Restriction of alcohol intake to 1 or 2 servings per week
and adherence to a low-fat, high-fiber diet will improve
hypertriglyceridemia.
Exercise has been shown to increase LPL activity. Even a single
exercise session can reduce triglycerides and increase HDL. The
impact of exercise on LDL is less clear. With low- to moderate-
intensity exercise regimens, clearance of VLDL particles increases
LDL production. However, this effect is not seen with high-
intensity exercise programs. A decrease in LDL-cholesterol
occurs with high-intensity exercise, and this effect is independent
of weight loss.
Pharmacotherapy
If diet and exercise modifications do not sustain a normal lipid
profile, then drug therapy is appropriate (see Table 69-7). Likely
TRIGLYCERIDES
(% CHANGE) SIDE EFFECTS
↓ 10-30 Liver toxicity, myositis, rhabdomyolysis; enhanced warfarin effect
↓ 7-8 Abnormal liver enzymes in combination with an HMG-CoA
inhibitor, myalgia, hepatitis, rhabdomyolysis, pancreatitis, potential
increase in cancer risk and cancer death
No effect Nausea, bloating, cramping, abnormal liver function; interferes with
absorption of other drugs such as warfarin and thyroxine
↓ 35-50 Nausea, cramping, myalgias, liver toxicity, enhanced warfarin effect
↓ 25-30 Hepatotoxicity, hyperuricemia, hyperglycemia, flushing, pruritus,
nausea, vomiting, diarrhea
↓ 23-45 Eructation, taste perversion, dyspepsia
benefit needs to be balanced against potential adverse effects
when determining drug therapy. Many patients require two or
three agents to achieve adequate control.
HMG-CoA reductase is the rate-limiting enzyme involved in
cholesterol biosynthesis. Inhibition of this enzyme decreases
intracellular cholesterol pools and subsequently increases uptake
of LDL cholesterol from the circulation. HMG-CoA reductase
inhibitors (e.g., lovastatin, pravastatin, simvastatin, fluvastatin,
atorvastatin, and rosuvastatin) increase cholesterol utilization,
decrease VLDL synthesis, and increase HDL synthesis. As a
result, lower LDL and triglyceride levels and higher HDL levels
are observed with treatment. Meta-analysis of primary and sec-
ondary CHD prevention trials found reductions in all-cause and
cardiovascular mortality rates with statin therapy. These agents
limit progression and may even cause regression of coronary ath-
erosclerosis. Therefore, they represent first-line therapy in the
management of abnormal LDL-cholesterol levels. Elevated liver
enzymes and muscle toxicity are potential dose-related complica-
tions. Myositis can occur with statins alone, but the risk is higher
when statins are used in combination with nicotinic acid or fibric
acid derivatives. Some of these agents can also potentiate the
effect of warfarin.
Cholesterol absorption inhibitors (e.g., ezetimibe) function by
interfering with the transport of cholesterol at the intestinal
brush border. They increase cholesterol utilization and decrease
LDL-cholesterol levels. Despite reductions in LDL-cholesterol,
improvements in cardiovascular events and mortality have not
been reported with treatment. Ezetimibe may be used as a single
agent or in combination with an HMG-CoA reductase inhibitor
to lower LDL-cholesterol levels. In combination, this agent can
increase serum transaminase levels and potentially increase the
risk of cancer and cancer death.
Drugs that interfere with the absorption of cholesterol from
the intestinal lumen increase cholesterol utilization and decrease
circulating levels of cholesterol. Bile acid sequestrants (e.g., cho-
lestyramine, colestipol, and colesevelam) bind bile acids in the
intestinal lumen and increase fecal excretion. Subsequently, more
LDL-cholesterol is used by the liver to synthesis bile acids. The
decrease in cellular cholesterol pools upregulates LDL receptors
and decreases the amount of LDL-cholesterol in the circulation.
Mild increases in HDL-cholesterol are also seen with this agent
as a result of increased intestinal HDL formation. Treatment is
associated with a reduction in the incidence of CHD. Bile acid
sequestrants may be used alone for mild lipid dysfunction or in
694 Section X  Endocrine Disease and Metabolic Disease
combination with another lipid-lowering agent such as an
HMG-CoA reductase inhibitor. Abnormal liver function and gas-
trointestinal symptoms (e.g., nausea, bloating, cramping) are
common side effects that limit the use of bile acid sequestrants.
They can also interfere with the absorption of other drugs such
as warfarin and thyroxine.
Fibric acid derivatives such as gemfibrozil and fenofibrate
increase FFA oxidation in muscle and liver. The reduced lipogen-
esis in the liver decreases VLDL and subsequent LDL produc-
tion. Fibric acid derivatives also enhance LPL activity and HDL
synthesis. As a result, treatment is usually associated with not
only lower triglyceride and LDL levels, but also higher HDL
levels. Reduced cardiovascular events have been demonstrated in
a subset of individuals with high triglyceride (>200 mg/dL) and
low HDL (<40 mg/dL) levels, but improvements in cardiovas-
cular or all-cause mortality otherwise have not been confirmed
with these agents. Liver toxicity and myositis are potential side
effects of fibric acid derivatives, and they also interfere with
the metabolism of warfarin, leading to a need for its dose
adjustment.
Nicotinic acid has an antilipolytic effect and therefore
decreases the influx of FFA to the liver. As a result, hepatic VLDL
synthesis and LDL production are reduced. Nicotinic acid also
decreases HDL catabolism. Lower triglyceride and LDL levels
and higher HDL levels are observed with treatment. In addition,
nicotinic acid stimulates tissue plasminogen activator and pre-
vents thrombosis. It is the preferred agent for the reduction of
lipoprotein(a) or Lp(a) (discussed later). The cardioprotective
effect of nicotinic acid may be linked to its effect on Lp(a) and
HDL. Side effects include hepatotoxicity, hyperuricemia, hyper-
glycemia, and flushing.
Omega-3 fatty acids reduce VLDL production and subse-
quently lower triglyceride levels (by 35%). They also modestly
increase HDL (3%) and LDL (5%). The impact on lipids can
occur over months to years and requires treatment doses as high
as 3 to 4 g of fish oil per day. However, reductions in death due
to sudden cardiac events and CHD are observed within weeks of
treatment initiation. This benefit can be seen with lower treat-
ment doses (fish oil <2 g/day) and is most likely related to the
impact of omega-3 fatty acid on cardiac electrophysiology.
Omega-3 fatty acids constitute 30% to 50% of fish oil supple-
ments and 85% of prescribed pharmacologic preparations (i.e.,
Lovaza and Vascepa). In clinical trials, both Lovaza and Vascepa
4 g/day lowered triglyceride levels by 45%. Fish oil supplements
seem to be a reasonable, cost-effective means to reduce triglycer-
ide levels; side effects include eructation, taste perversion, and
dyspepsia.
Other agents to consider are neomycin, lomitapide, and
mipomersen. These agents can be considered in the management
of patients with refractory LDL elevations. Neomycin complexes
with bile acid and lowers LDL levels. It also inhibits production
of apolipoprotein(a) in the liver and lowers Lp(a). It is recom-
mended as adjuvant therapy for patients with familial hypercho-
lesterolemia and Lp(a) excess. Important side effects include
nephrotoxicity and ototoxicity. Lomitapide inhibits microsomal
triglyceride transfer protein in the liver and decreases apo B. Sig-
nificant reductions in LDL (up to 50%) are seen with treatment.
Liver toxicity is a serious adverse event associated with this agent.
Mipomersen is another agent approved for use in homozygous
familial hypercholesterolemia. It binds apo B messenger RNA
and inhibits apo B production. Apo B is a structural component
of VLDL, IDL, and LDL. Treatment reduces LDL by up to 50%.
Side effects include flu-like symptoms, injection site reactions,
elevations in liver enzymes, and liver toxicity. The side effect
profile and expense associated with both lomitapide and
mipomersen limit the use of these agents to individuals with
homozygous familial hypercholesterolemia.
  LIPID DISORDERS
A number of specific disorders of overproduction or impaired
removal of lipoproteins result in dyslipidemia (see Tables 69-2
and 69-3). These disorders are often familial, but secondary
causes also need to be considered. Comorbid conditions (diabe-
tes, hypothyroidism), medications (estrogen, glucocorticoids,
β-blockers), and lifestyle factors (diet, alcohol) can increase the
production and clearance of lipoproteins. Addressing these
factors can often normalize lipid levels. If abnormalities persist,
evaluation of genetic factors and treatment with pharmacologic
therapy may need to be considered.
Familial Hypercholesterolemia
Mutations in the gene that encodes the LDL (apo B/E) recep-
tor result in familial hypercholesterolemia. Impairment in LDL
receptor synthesis or function decreases the clearance of LDL
and increases circulating LDL levels, resulting in cholesterol
plaque formation. These plaques deposit in the arteries (ath-
eroma), skin or tendons (xanthoma), eyelids (xanthelasma),
and iris (corneal arcus). The homozygous form of this autosomal
dominant disorder is rare. Affected individuals present early in
life with elevated levels of total cholesterol (600 to 1000  mg/
dL) and LDL-cholesterol (550 to 950  mg/dL). Triglyceride
and HDL-cholesterol levels are normal. These patients develop
CHD, aortic stenosis due to atherosclerosis of the aortic root,
and tendon xanthomas (often in the Achilles tendon). If the
condition remains untreated, patients with homozygous familial
hypercholesterolemia typically die of myocardial infarction
before 20 years of age. The heterozygous form of familial
hypercholesterolemia affects 1 in every 500 individuals, with
the partial receptor defect resulting in cells that display half the
normal number of fully functional LDL receptors. These indi-
viduals have less strongly elevated concentrations of total cho-
lesterol (>300 to 600  mg/dL) and LDL-cholesterol (250 to
500  mg/dL) than do those with the homozygous form. Pre-
mature CHD (before 45 years of age in men and 55 years in
women) and tendon xanthomas are characteristic clinical
findings.
Although familial hypercholesterolemia can be established by
identifying one of the many gene mutations in the LDL receptor
or by demonstrating diminished LDL receptor function, the
diagnosis of familial hypercholesterolemia usually is made on the
basis of clinical features. Elevated total cholesterol (>300 mg/
dL) and LDL-cholesterol (>250 mg/dL) in an individual with a
personal or family history of premature CHD and tendon xan-
thomas identifies patients at risk for familial hypercholesterol-
emia. Treatment requires a low-fat (<20% of total calories), low
cholesterol (<100 mg/day) diet in combination with drug
 Chapter 69  Disorders of Lipid Metabolism 695
therapy. Usually, patients with familial hypercholesterolemia
require multiple agents to lower cholesterol levels to the target
range. In patients who do not tolerate the medications or who
have limited receptor function, liver transplantation to provide
functional receptors, ileal bypass surgery to decrease gastrointes-
tinal absorption of bile acids, or LDL apheresis to remove excess
LDL may be considered. Both lomitapide and mipomersen may
also be considered as adjuvant therapy.
Familial Defective Apolipoprotein B100
In this autosomal dominant disorder, a defect in the apo B100
protein results in impaired binding of LDL particles to the LDL
receptor. The disorder affects as many as 1 in 750 Caucasians with
hypercholesterolemia. The clinical presentation is similar to
familial hypercholesterolemia, with elevated total cholesterol and
LDL-cholesterol levels associated with premature CHD and
tendon xanthomas. However, the homozygous and heterozygous
clinical forms of familial defective apo B100 are milder
than familial hypercholesterolemia, because apo E–mediated
clearance of remnant particles is still functional. Total cholesterol
concentration ranges from 350 to 550 mg/dL in the homozygous
and 200 to 350 mg/dL in the heterozygous disorder. DNA analy-
sis can identify the apo B100 gene mutation and confirm the
diagnosis, but genetic diagnosis is not necessary to initiate
therapy. A low-cholesterol, low-fat diet in combination with a
statin, bile acid resin, and/or niacin is recommended to lower
cholesterol levels to target ranges.
Elevated Plasma Lipoprotein(a)
Lp(a) is a specialized form of LDL that is assembled extracellu-
larly from apolipoprotein(a) and LDL. Lp(a), when present at
elevated levels, interferes with fibrinolysis by competing with
plasminogen. This leads to decreased thrombolysis and increased
clot formation. Lp(a) also binds macrophages, promoting foam
cell formation and atherosclerotic plaques. Screening should be
considered in individuals who have a family or personal history
of premature CHD without dyslipidemia and in those for whom
cholesterol-lowering therapy has failed. The diagnosis can be
made by documenting Lp(a) levels higher than 30 mg/dL in a
patient with premature CHD. The primary goal of therapy is to
lower LDL levels with agents such as statins. If LDL goals cannot
be achieved, then Lp(a)-lowering therapy with niacin and neo-
mycin may be considered.
Polygenic Hypercholesterolemia
Hypercholesterolemia in a population is mostly due to small
influences of many different genes. The exact nature of these
genetic defects is poorly defined, but apo E may play a role in
the pathogenesis. Apo E4 on chylomicrons and VLDL remnants
has a high affinity for the LDL receptor. Elevated binding of
apo E4–containing lipoproteins to LDL receptors may down-
regulate LDL receptor synthesis and increase circulating LDL
levels. Environmental factors such as diet can influence produc-
tion of chylomicrons and VLDL, resulting in downregulation
of the LDL receptor in conditions with high apo E4. This leads
to an increased propensity for CHD, and treatment with LDL-
lowering agents is recommended based on risk factors (see
Table 69-7).
Familial Combined Hyperlipoproteinemia
Familial combined hyperlipoproteinemia (FCHL) is an autoso-
mal dominant polygenic disorder that affects 1% to 2% of the
population. Factors such as diet, glucose intolerance, and medica-
tions can influence the phenotypic presentation. In FCHL, the
liver synthesizes excess VLDL. VLDL is hydrolyzed by LPL to
produce LDL. Mutations in the LPL gene affecting its expression
or function can decrease the efficiency of VLDL catabolism. Dys-
function of LPL is observed in one third of patients with FCHL.
Diminished LPL activity increases circulating VLDL-triglyceride;
furthermore, fewer VLDL remnant particles are available for
HDL synthesis. Therefore, FCHL needs to be considered in all
patients whose total cholesterol level is greater than 250 mg/dL,
triglycerides greater than 175 mg/dL, or HDL-cholesterol less
than 35 mg/dL.
There are no definitive diagnostic tests, but family screening
can help confirm the diagnosis. The phenotype of FCHL is vari-
able, with individuals displaying high LDL-cholesterol, high
VLDL-triglyceride, or both based on the genetic defect and envi-
ronmental factors. Patients also typically have high apo B
(>120 mg/dL) and a low ratio of LDL-cholesterol to apo B100
(<1.2). They accumulate small dense LDL particles, which are
thought to be atherogenic and contribute to premature CHD.
Xanthomas or xanthelasmas are not a feature of this disorder.
Affected individuals require a low-fat, low-cholesterol diet plus
multiple lipid-lowering drugs to achieve target goals. Fibric acid
derivatives, which hydrolyze the triglyceride core of VLDL par-
ticles and increase LDL production, are recommended for treat-
ment of the hypertriglyceridemia. Patients with FCHL often
additionally require a statin or niacin to lower their LDL-
cholesterol level.
Familial Dysbetalipoproteinemia
Apo E on the surface of lipoprotein particles binds LDL recep-
tors and facilitates clearance of remnant particles from the
circulation. The apo E2 allele has a lower affinity for LDL recep-
tors than apo E3 or apo E4. In individuals who are homozygous
for apo E2, LPL hydrolyzes the triglyceride core and the result-
ing cholesterol-rich chylomicrons. VLDL and IDL remnant
particles accumulate in the circulation. Expression of this phe-
notype usually requires a precipitating condition that increases
lipoprotein production (e.g., diabetes, alcohol consumption) or
decreases clearance (e.g., hypothyroidism). In addition to the
more common autosomal recessive mutation of apo E described
earlier, several apo E mutations have been described that result
in an autosomal dominant phenotype manifesting in childhood.
Premature CHD, peripheral vascular disease, and xanthomas
involving the palmer crease are characteristic clinical features.
Individuals with familial dysbetalipoproteinemia have elevated
levels of total cholesterol (300 to 400  mg/dL) and triglycerides
(300 to 400  mg/dL). Definitive diagnosis requires genetic
testing to identify apo E2 homozygosity or mutation. Treatment
of coexisting conditions such as diabetes and hypothyroidism
can normalize lipid levels in apo E2 homozygotes. If target levels
are not achieved, dietary therapy and lipid-lowering drugs such
as fibric acid derivatives and HMG-CoA reductase inhibitors
should also be considered.
696 Section X  Endocrine Disease and Metabolic Disease
Lipoprotein Lipase Deficiency
Mutations in the LPL gene resulting in deficiency of LPL synthe-
sis or function lead to increased circulating chylomicron and
VLDL particles and severe hypertriglyceridemia. Homozygous
LPL deficiency is rare. It manifests in childhood with triglyceride
levels higher than 1000 mg/dL. Heterozygous LPL deficiency
occurs in 2% to 4% of the population and usually requires a pre-
cipitating factor, such as uncontrolled diabetes or estrogen
therapy, to manifest the phenotype. These individuals have mod-
erate hypertriglyceridemia (250 to 750 mg/dL) that can increase
to levels greater than 1000 mg/dL with secondary factors. This
can result in the chylomicronemia syndrome, which is character-
ized by marked hypertriglyceridemia (>1000 to 2000 mg/dL),
pancreatitis, eruptive xanthomas, lipemia retinalis, and hepato-
splenomegaly. Visual inspection demonstrates lipemic plasma.
After refrigeration for 12 hours, a creamy top layer (increased
chylomicrons) or turbid plasma infranatant (increased VLDL),
or both, can be demonstrated. Documentation of diminished
LPL activity confirms the diagnosis. A diet low in fat (<10% of
total calories or 20 to 25 g/day) is the primary treatment. Sec-
ondary factors such as uncontrolled diabetes and alcohol use
should be addressed, and VLDL-lowering agents (e.g., fibric
acid derivatives, niacin) may be needed to prevent severe
hypertriglyceridemia.
Apolipoprotein C-II Deficiency
Apo C-II is an activating cofactor for LPL. Deficiency of apo C-II
is a rare autosomal recessive disorder that leads to increased chy-
lomicrons and VLDL particles in the circulation, resulting in
severe hypertriglyceridemia. Clinical manifestations are similar
to those of LPL deficiency, including hypertriglyceridemia
(>1000 mg/dL) and symptoms of pancreatitis, eruptive xantho-
mas, lipemia retinalis, and hepatosplenomegaly. Treatment rec-
ommendations include appropriate management of secondary
factors such as diabetes and hypothyroidism, dietary fat restric-
tion (<10% of calories), and drug therapy (e.g., fibric acid deriva-
tives). For severe hypertriglyceridemia, plasma transfusion (with
apo C-II) can be considered.
Familial Hypertriglyceridemia
Familial hypertriglyceridemia is an autosomal dominant disorder
that is characterized by overproduction of hepatic VLDL. The
exact defect or mutation is unknown. Secondary factors that
increase VLDL, such as diabetes, alcohol ingestion, and estrogen
therapy, appear to exacerbate this condition. Low HDL
associated with familial hypertriglyceridemia is related to
increased catabolism. Individuals with this condition have hyper-
triglyceridemia (200 to 500 mg/dL) and low HDL-cholesterol
(<35 mg/dL) at presentation. This diagnosis is considered in
individuals who have a family and personal history of hypertri-
glyceridemia, CHD, and normal LDL levels. Cloudy infranatant
after overnight refrigeration of plasma identifies a disorder of
VLDL metabolism. Treatment starts with management of sec-
ondary factors that may exacerbate the condition. Dietary fat
restriction (<10% of calories) and drug therapy with fish oil,
niacin, and fibric acid derivates should be initiated if target goals
are not achieved.
For a deeper discussion on this topic, please see Chapter
206, “Disorders of Lipid Metabolism,” in Goldman-Cecil
Medicine, 25th Edition.
SUGGESTED READINGS
Carroll MD, Lacher DA, Sorlie PD, et al: Trends in serum lipids and lipoproteins
of adults, 1960-2002, JAMA 294:1773–1781, 2005.
Expert Panel on Integrated Guidelines for Cardiovascular Health and
Risk Reduction in Children and Adolescents, National Heart, Lung, and
Blood Institute: Summary report, Pediatrics 128(Suppl 5):S213–S256,
2011.
Genest JJ, Martin-Munley SS, McNamara JR, et al: Familial lipoprotein disorders
in patients with premature coronary artery disease, Circulation 85:2025–2033,
1992.
Gordon T, Castelli WP, Hjartland MC, et al: High density lipoprotein as a
protective factor against coronary artery disease. The Farmingham Study, Am
J Med 62:707–715, 1997.
Grundy SM, Cleeman JI, Merz CN, et al: Implications of recent clinical trials for
the National Cholesterol Education Program (NCEP) Adult Treatment Panel
III guidelines, Circulation 110:227–239, 2004.
Hokanson JE, Austin MA: Plasma triglyceride level is a risk factor for
cardiovascular disease independent of high-density lipoprotein cholesterol: a
meta-analysis of population-based prospective studies, J Cardiovasc Risk
3:213–224, 1996.
Jenkins DJ, Kendall CW, Marchie A, et al: Effects of a dietary portfolio of
cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive
protein, JAMA 290:502–510, 2003.
Kumana CR, Cheung BM, Lauder IJ: Gauging the impact of statins using number
needed to treat, JAMA 282:1899–1901, 1999.
National Cholesterol Education Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III): Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III) final report,
Circulation 106:3143–3421, 2002.
U.S. Preventive Services Task Force: Screening for lipid disorders in adults: U.S.
Preventive Services Task Force recommendation statement, 2008. Available at:
http://www.uspreventiveservicestaskforce.org/uspstf/uspschol.htm. Accessed
August 1, 2014.
XI
ESSENTIALS

B
s s
s s
A

e
C - p ep t i d

Women’s Health
70  Women’s Health Topics
Kelly McGarry, Kimberly Babb, Laura Edmonds, Christine Duffy, Michelle Anvar, and Jennifer Jeremiah

697
 70 
Women’s Health Topics
Kelly McGarry, Kimberly Babb, Laura Edmonds,
B
s s
s s
A
e
C -p e p ti d
Christine Duffy, Michelle Anvar, and Jennifer Jeremiah
  THE SPECIALTY OF WOMEN’S HEALTH
The specialty of women’s health grew out of the recognition that
differences in the biology of men and women are responsible for
differences in the prevalence, presentation, and management of
some diseases. The focus of women’s health is on conditions
unique to women (e.g., pregnancy), conditions that are more
common in women (e.g., breast cancer, osteoporosis, some rheu-
matologic diseases), and conditions that have different presenta-
tions, natural history, risk factors, and prevention or treatment
strategies in women and men (e.g., heart disease, sexually trans-
mitted infections, urinary tract infections). Specialists in this area
come from all disciplines and include obstetrician-gynecologists,
general internists, subspecialty internists, family medicine, radi-
ologists, and surgeons. In this chapter, we focus on medical issues
unique to women and highlight what is known about gender dif-
ferences in common diseases. For more detailed discussions of
specific topics, please refer to the appropriate chapters in this
edition of Cecil Essentials of Medicine and the 25th edition of
Goldman-Cecil Medicine.
  WHAT MAKES WOMEN DIFFERENT FROM MEN?
There are substantial biologic, physiologic, and psychosocial dif-
ferences between men and women. Although we have an in-depth
understanding of some of the differences, others are just begin-
ning to be elucidated, and still others remain undiscovered.
Women tend to be physically smaller than men. Women have
less renal mass, and defining normal renal function takes this into
account. Women typically have a 15% lower creatinine clearance
rate than men with the same level of creatinine. The volume of
muscle and fat varies by gender and age, which affects the metab-
olism of medications and estimates of kidney function. Women
have smaller blood vessels than men. Until smaller intravascular
catheters were created, this biologic difference made cardiac cath-
eterizations in women technically more challenging.
Gender also influences treatment. A study of more than 700
physicians presented with several hypothetical patient scenarios
found that the race and sex of a patient independently influenced
how physicians managed chest pain. Women, particularly black
women, were significantly less likely to be referred for catheter-
ization than white men.
Differences in physiology affect biologic responses. For
example, to increase cardiac output, women increase heart rate,
whereas men increase stroke volume, in part by increasing vascu-
lar resistance. These physiologic differences may have different
pathophysiologic consequences for men and women. Sympa-
thetic tone varies by gender. Women have reduced sympathetic
698
activity and enhanced parasympathetic activity compared with
men. This may be one reason that premenopausal women tend
to have lower blood pressure than age-matched men and why
women may be more susceptible to orthostatic hypotension and
fainting than men.
Hepatic drug clearance varies by gender, ethnicity, and race.
Gender-related differences in pharmacokinetics in part deter-
mine the clinical effectiveness and potential adverse effects of
drug therapy. Physiologic differences include the usually lower
body weight and organ size, higher percentage of body fat, lower
glomerular filtration rate, and different gastric motility in women
compared with men. Molecular differences involve drug trans-
porters and drug-metabolizing enzymes. Clinically important
gender differences in pharmacodynamic processes include risk of
QT prolongation, which can lead to a potentially fatal ventricular
arrhythmia, torsades de pointes. A much higher percentage of
women than men develop torsades after taking a variety of drugs,
including certain antibiotics, antiarrhythmics, and antipsychot-
ics. In addition to differences in drug transport and metabolism
that result in different plasma and intracellular drug levels, the
baseline electrocardiographic rate of corrected QT interval
(QTc) is naturally longer in women than in men. Because there
are gender differences in the rate of cardiac repolarization, drugs
that are known to prolong the QTc interval should be carefully
prescribed and monitored.
The approach to menstrual disorders is guided by an under-
standing of the physiology of reproduction. Estrogen levels vary
substantially throughout life. With the onset of puberty, the
hypothalamus begins releasing gonadotropin-releasing hormone
(GnRH), leading to ovarian stimulation. The normal menstrual
cycle requires precise regulation and feedback of hormones
involving the hypothalamus, pituitary gland, and ovaries, with
the uterus acting as an end organ for ovarian steroid effects. The
menstrual cycle consists of the follicular or proliferative phase,
ovulation, and the luteal or secretory phase. The physiologic
changes that define the menstrual cycle, including variations in
hormones, the uterine lining, and basal body temperature (taken
on awakening), are graphically represented in Figure 70-1.
During the follicular phase, the hypothalamus secretes GnRH,
which stimulates the pituitary to release gonadotropins, lutein-
izing hormone (LH), and follicle-stimulating hormone (FSH).
LH and FSH then stimulate ovarian follicular development and
estrogen secretion. Estrogen secretion results in proliferation of
the endometrium. Eventually, one follicle with its oocyte becomes
dominant, and maturation results in ovulation, which occurs
soon after an LH surge. With ovulation, the oocyte leaves the
dominant follicle and migrates toward the fallopian tube. The
 Chapter 70  Women’s Health Topics 699

Ovarian
cycle
B
s s
s s
A

e
C-peptid

Growing follicle Ovulation Corpus luteum Corpus albicans

37° C

temp.
Body
36° C

hormones Luteinizing hormone (LH)

pituitary
Anterior

Follicle-stimulating
hormone (FSH)

Progesterone
Estradiol
hormones
Ovarian
Uterine
cycle

Menses Menses
Follicular phase Luteal phase
0 days 14 days 28 days
Ovulation
FIGURE 70-1  The physiologic changes that define the menstrual cycle.

remaining cells in the follicle become the corpus luteum, which
produces progesterone during the luteal phase. If fertilization
does not occur, progesterone is secreted for about 14 days, and
the follicle then involutes. This is associated with decreasing
levels of estrogen and progesterone. The endometrium is shed in
response to the falling estrogen and progesterone levels, and
menstruation occurs.
Normal menstrual cycles usually occur monthly from adoles-
cence until the time of menopause, which begins between the
ages of 45 and 55 years. Cycle duration tends to become consis-
tent within several years of menarche due to maturation of the
hypothalamic-pituitary-ovarian hormonal axis. The median men-
strual cycle length is 28 days, with a normal range between 25
and 35 days. The duration of menses typically is between 2 and
7 days. Delays in the expected onset and abnormalities of men-
strual cycles often require evaluation for possible disease, includ-
ing hormonal and structural disorders.
Estrogen receptors have been identified throughout the body,
including reproductive organs and nonreproductive organs such
as the brain, arteries, bone, smooth muscle, and urethra. Declin-
ing levels of estrogen at menopause explain some of the systemic
changes that occur in postmenopausal women. The diagnostic
approach to abnormal genital bleeding and menopause is dis-
cussed later in this chapter.
Gender Differences in Societal Factors
Complex societal factors, including processes of socialization,
expectations about work and home, lifestyle behaviors, and other
psychosocial factors, can explain differences in the health of men
and women. Research shows that women still occupy different
positions in society than men. Women are less likely to be
employed and more likely to have lower incomes, live in poverty,
and be single parents than men. Men are more likely than women
to smoke, consume alcohol, eat an unbalanced diet, and be over-
weight. Women are more likely than men to be physically inac-
tive. However, both men and women of lower socioeconomic
status (SES) have a higher prevalence of risky lifestyle behaviors.
Women are more likely to report health problems, in part due to
higher social demands and perceived obligations. Gender differ-
ences exist in perceived control and self-esteem, with women
reporting lower levels of both than men, although women do
report higher levels of social support.
Research has documented a relationship between health
inequalities and socioeconomic inequalities in income,
 700 Section XI  Women’s Health
education, occupational status, and employment status. Women
B
may have overall lower rates of mortality, but they paradoxically
report higher levels of depression, psychiatric disorders, distress,
s s
s s
A
e
C-peptid
and a variety of chronic illnesses than men. It is important to
recognize the impact of these social determinants on the health
of all patients and to understand that the pathways through which
social position, behavior, and psychosocial forces influence
health are different for men and women. Patients must be encour-
aged to engage in a healthy lifestyle because healthy behaviors
help to prevent weight gain, high blood pressure, cardiovascular
disease, diabetes, arthritis, and early mortality.
  WOMEN’S HEALTH ISSUES OVER THE LIFESPAN
Issues for Adolescents
Adolescence is a period of rapid physical and emotional change,
and patients may have both pediatric and adult issues. Adoles-
cents often do not have a good understanding of health issues and
are embarrassed or nervous about asking questions. Health care
providers must help adolescents navigate this period of change
and educate them about healthy behaviors in an open and non-
judgmental manner to create a therapeutic relationship.
Gender, Sexual Identity, and Sexual History
Adolescents often struggle with issues of gender, sexuality, and
sexual behavior. They often avoid discussing these topics because
of embarrassment, fear of being judged, or concerns about con-
fidentiality. Discussing these issues in a safe, nonjudgmental
manner can improve adolescents’ understanding and promote
healthy and responsible choices.
Individuals who identify themselves as lesbian, gay, bisexual,
or transgender are at higher risk for substance abuse, intimate
partner violence, and mental health issues. Asking about gender
identity and sexual orientation is an important part of taking a
sexual history. Many adolescents experiment, and their sexual
behavior is not always a reflection of their gender identity or
sexual orientation. A sexual history should include the number
and gender of partners; use of contraception and barrier protec-
tion; types of sexual activities, including oral, vaginal, and anal
sex; history of sexual abuse and intimate partner violence; history
of coerced or forced sexual interactions; and use of alcohol or
illicit substances during sex. Adolescents should be encouraged
to make healthy choices regarding sexual activity, including
abstaining from sex, using contraception and barrier protection,
and seeking respectful partners.
Confidentiality
Adolescents often come to medical visits accompanied by a
parent, and parental consent should be obtained for treatment of
many medical issues. It is also important to interview all adoles-
cents alone for part or all of the visit to discuss social and health
history, because they do not feel comfortable discussing many
issues in front of parents. Their history should remain confiden-
tial unless they divulge something that puts them or another
individual at risk or have certain illnesses that are reportable to
the department of public health. Regulations on confidentiality
vary from state to state.
Adolescents often underestimate their parents’ ability to
understand their issues. Physicians should encourage adolescents
to be open with their parents about health issues and bridge the
communication divide.
Eating Disorders
Eating disorders often begin during the adolescent period. They
include anorexia, bulimia, binge eating, and other disordered
eating behaviors. These illnesses are characterized by distorted
body image and dysfunctional behaviors that can lead to long-
term physical and psychological issues. Rates of eating disorders
are increasing, and white females tend to be disproportionately
affected. Eating disorders often start with dieting and progres-
sively develop into dysfunctional behaviors. Physicians who take
care of adolescents should monitor weight and body mass index
(BMI) and screen for alterations in body image and behaviors
that suggest disordered eating. Management of eating disorders
often requires a multidisciplinary approach with a primary care
physician, psychologist, and nutritionist.
Sexually Transmitted Infections
Sexually transmitted infections (STIs) are common among ado-
lescents. Human papillomavirus (HPV), Chlamydia trachomatis,
and Trichomonas infections account for most cases, although
gonorrhea, syphilis, herpesvirus, and human immunodeficiency
virus (HIV) infections also occur.
All patients between the ages of 13 and 21 years should be
screened for chlamydial and gonorrheal infections annually.
Annual opt-out HIV testing is also recommended by the Centers
for Disease Control and Prevention (CDC) for all patients
between the ages of 13 and 64 years.
The HPV vaccine has been added to the standard pediatric
immunization schedule and is recommended for girls and boys 9
to 11 years of age. If the HPV vaccine was not part of the normal
schedule, it is approved for patients up to 26 years old. The vac-
cines have proved to be highly safe and effective, providing
another means to prevent cervical cancer.
Primary Amenorrhea
Amenorrhea is defined as the lack of menses in a sexually mature
female. It is categorized as primary or secondary amenorrhea.
Primary amenorrhea is the lack of menarche by age 16 despite
normal sexual development or the lack of menarche by age 14 in
the absence of sexual development.
Primary amenorrhea is often caused by genetic or anatomic
abnormalities. Breast development, presence of a uterus, and the
levels of FSH and LH are important factors in determining the
cause of primary amenorrhea. , Lack of a uterus despite breast
development may suggest androgen insensitivity or müllerian
agenesis. If the uterus exists, an outflow tract obstruction such as
an imperforate hymen or a transverse vaginal septum may be
identified. However, if secondary sexual characteristics are
missing, measuring FSH and LH levels can help to determine the
difference between hypogonadotropic hypogonadism (i.e., con-
stitutional delay or pituitary or hypothalamic failure) and hyper-
gonadotropic hypogonadism (i.e., premature ovarian failure or
Turner syndrome).
 Chapter 70  Women’s Health Topics 701
Issues for Adult Women
Promoting Wellness and Preventive Health
Comprehensive health care for women includes gender-specific
and general services and counseling to promote healthful behav-
iors and practices to prevent disease. Table 70-1 highlights
evidence-based recommendations for preventive care specifically
for women at average risk.
Screening for Cervical Cancer
Cervical cancer, the tenth leading cause of cancer death in
the Unites States, occurs most often in women who have
never been screened or not screened in the past 5 years.
Infections with high-risk strains of HPV (16 and 18) are
responsible for approximately70% of cervical cancer cases.
The incidence increases with early onset of intercourse; greater
number of lifetime sexual partners; co-infection with other
STIs, including HIV; high parity; long-term use of oral con-
traceptives; and cigarette smoking. Peak incidence of HPV
infection occurs among women younger than 25 years of
age, but most of these infections are transient. Approximately
10% of women remain HPV positive 5 years after infection.
Cervical abnormalities that do transform into cancer are
thought to progress over time from less severe to more severe
lesions.
The U. S. Preventive Services Task Force (USPSTF) and the
American Cancer Society (ACS), American Society of Colpos-
copy and Cervical Pathology (ASCCP), and American Society
for Clinical Pathology (ASCP) published consensus guidelines
for screening average-risk women. These recommendations do
not apply to women who have had cervical intraepithelial neo-
plasia with moderately abnormal cells (i.e., CIN 2) or higher-
grade cervical lesions, cervical cancer, or in utero diethylstilbestrol
(DES) exposure or to women who are immunocompromised or
HIV positive (Table 70-2).
Contraception
Approximately 62% of reproductive-age women in the United
States are using some form of contraception, but almost one
half of pregnancies are unintended. When helping patients
choose a contraceptive method, several important variables
should be considered. The first is efficacy and a patient’s ability
to adhere to the method. The efficacy of contraceptive methods
depends on appropriate use (Table 70-3). Patients’ past experi-
ences with different forms of contraception and personal prefer-
ences may help to predict how well they will comply with current
regimens.
Obtaining a thorough personal and family medical history
can help to determine what methods are appropriate. Certain
medical issues can make a choice too risky for one patient but
provide a health benefit for another. For example, oral contracep-
tives that increase the risk of thrombosis are contraindicated for
a patient with a strong family history of venous thrombosis, but
they could correct anemia in a patient with menorrhagia. The
patient’s sexual history and assessment of the risk for STIs play
a role in contraceptive choice and education about the use of
barrier methods.
Methods of Contraception
Barrier methods include the male and female condom, dia-
phragm, and cervical cap. The diaphragm and cervical cap need
B
A
s
s
s
s
C-peptid
e
to be fitted by a medical professional, require a prescription, and
need to be left in 6 to 8 hours after intercourse to be effective. The
male condom, which can be purchased over the counter, has the
added benefit of helping to prevent the transmission of STIs.
Combination hormonal contraceptives are the most common
form of hormonal birth control. They typically contain a low dose
of estrogen (≤35 µg) and one of several progesterones. Delivery
methods include pills, patches, and intravaginal rings. Contrain-
dications to combination hormonal contraception are related to
the estrogen component and include a personal history of a
thromboembolic event or known thrombogenic mutation, cere-
brovascular accident (CVA), coronary artery disease (CAD),
uncontrolled hypertension, migraine with aura, smoking after
age 35, breast cancer, estrogen-dependent neoplasms, undiag-
nosed abnormal vaginal bleeding, liver tumors, and pregnancy.
Potential noncontraceptive benefits of combination oral con-
traceptives include regulation of menstrual flow and improve-
ment in ovarian cyst recurrence, endometriosis, acne, polycystic
ovarian syndrome, and mittelschmerz (i.e., midcycle pain). Long-
term use of combination oral contraceptives has been associated
with a reduced lifetime risk of endometrial and ovarian cancers.
The World Health Organization (WHO) medical eligibility
criteria for contraceptive use provide excellent guidance for
the choice of contraceptive methods based on patients’ risk
factors (available at http://www.who.int/reproductivehealth/
publications/family_planning/9789241563888/en/index.html
[accessed August 1, 2014]). Patients should be able to take pills
at approximately the same time each day.
The contraceptive patch is a form of combination hormonal
contraception that is delivered transdermally. The patch is applied
on a weekly basis for 3 weeks and then discontinued for 1 week.
The patch delivers a higher average dose of estrogen but has lower
peak doses. Another form of combination hormone delivery is
the intravaginal ring. A flexible ring is inserted intravaginally for
3 weeks and then removed for 1 week when menses occur. The
patch and the ring are reasonable options for patients concerned
with medication compliance.
Progesterone-only contraceptives are an option for women
intolerant of estrogen or at increased risk for thromboembolic
events. Contraindications include active CAD, breast cancer,
liver tumor, and phlebitis. They are slightly less efficacious than
the combination pills, and women may experience breakthrough
bleeding.
Depot medroxyprogesterone acetate (DMPA) is a
progesterone-only injection administered every 12 weeks. It is a
very reliable form of contraception. Major side effects include
irregular bleeding (which resolves over time) and amenorrhea
(50% at 1 year). Weight gain, hair changes, and acne are possible
side effects. The U.S. Food and Drug Administration (FDA)
issued a black box warning that DMPA may decrease bone
density, especially in adolescents.
The intrauterine device (IUD) can be a great option for
women who do not desire pregnancy in the next 5 to 10 years.
Worldwide, it is the most widely used method of reversible
 702 Section XI  Women’s Health

B
TABLE 70-1  PREVENTIVE HEALTH RECOMMENDATIONS FOR WOMEN
s s
s

SCREENING RECOMMENDATION AGE AND INTERVAL

s
A

e
C-peptid

Alcohol All women should be screened for alcohol misuse. Hazardous Beginning at age 18 and at contact with health care provider
drinking defined as >7 drinks/week or >3/occasion. Drinking
results in physical, social, and psychological harms, and women
engaged in hazardous drinking should be provided with
behavioral counseling interventions.
Cardiovascular disease All women should be assessed for their CV disease risk At contact with health care provider
(hypertension, tobacco use, diabetes, family history, physical
inactivity, unhealthy dietary lipids, overweight and obesity) and
counseled on risk reduction strategies. The 10-yr CV risk can be
calculated with risk assessment tool calculator.
Lipid disorders screening includes total cholesterol, HDL, LDL, Women age ≥45 and women 20-44 yr if other risk factors present;
and triglycerides after a 12-hr fast interval not clear, but every 5 yr if low risk
Cancer
  Breast cancer Mammography ACS suggests annually at age 40 for as long as in good health; yearly
for women of any age with greater than 20% lifetime risk
USPSTF suggests biennial screening for women age 50-74. Biennial
screening before age 50 should be addressed on an individual
basis. Women in poor health are unlikely to benefit from
screening. Current evidence insufficient to assess the additional
benefits and harms of screening in women >75 yr.
MRI Based on breast cancer risk calculated using NCI’s breast cancer risk
assessment tool
  Cervical cancer See Table 70-2
  Ovarian cancer Routine screening is not recommended by any organization.
Women at high risk (strong family history, BRCA1 and BRCA2
genes) may consider screening.
  Uterine cancer Routine screening is not recommended by any organization. Women at high risk for HNPCC can be offered screening with
endometrial biopsy at age 35.
Depression All women should be screened; multiple screening tools available. At contact with health care provider
Brief intervention: (1) “Over the past 2 weeks, have you felt
down, depressed, or hopeless?” (2) “Over the past 2 weeks, have
you had little interest or pleasure in doing things?”
Infectious diseases
  STIs Counseling recommended High-intensity behavioral counseling to prevent STIs for all sexually
active adolescents and adults at increased for STIs
  Chlamydia Testing recommended All sexually active women ages 24 and younger and older women
who are at increased risk
  Gonorrhea Testing recommended All sexually active women if they are at increased risk for infection
  Hepatitis C Testing recommended Screen women at high risk for infection and offer one-time
screening if born between 1945 and 1965
  HIV Testing recommended Adolescents and adults ages 15-65 yr; younger adolescents and
older adults who are at increased risk and all pregnant women
  HPV See Table 70-2
Obesity All women should be screened. Women with a BMI >30 kg/m2 At contact with health care provider
should be referred for behavioral interventions.
Osteoporosis Insufficient evidence to recommend combined calcium and
vitamin D supplementation for primary prevention. Women
should be counseled about daily calcium and vitamin D
requirements and adequate weight-bearing and resistance
exercises for prevention.
DEXA bone density test; fracture risk can be assessed by FRAX All women ≥65 yr and women <65 yr whose fracture risk is equal to
or greater than that of a 65-yr-old woman with no additional risk
factors. Women 50-64 yrs with a 9.3% 10-yr fracture risk
determined by FRAX
Stroke Daily aspirin for prevention of stroke when potential benefit of Women 55-79 yr
ischemic stroke reduction outweighs potential harm of increased
gastrointestinal hemorrhage
Thyroid disorders USPSTF finds insufficient evidence to recommend for or against
routine screening for asymptomatic women; testing
recommended for symptoms.
Tobacco use All women should be screened and provided with smoking At contact with health care provider
cessation interventions.
Violence Screening and counseling for interpersonal and domestic violence At contact with health care provider
ACS, American Cancer Society; BMI, body mass index; CV, cardiovascular; DEXA, dual-energy x-ray absorptiometry; FRAX, fracture risk assessment tool; HDL, high-density lipoprotein
cholesterol; HIV, human immunodeficiency virus; HNPCC, hereditary nonpolyposis colon cancer; HPV, human papillomavirus; LDL, low-density lipoprotein cholesterol; MRI, magnetic
resonance imaging; NCI, National Cancer Institute; STIs, sexually transmitted infections; USPSTF, U.S. Preventive Services Task Force.
 Chapter 70  Women’s Health Topics 703

TABLE 70-2  SCREENING RECOMMENDATIONS FOR CERVICAL CANCER B

s s
s

AGE USPSTF ACS/ASCCP/ASCP COMMENTS AND RATIONALE

s
A

e
C-peptid

<21 No screening before the age of 21
despite time of sexual activity
21-29 Screening with liquid-based or
conventional cytology alone every
3 yr; HPV testing should not be
performed.
30-65 Cytology alone every 3 yr or
cytology with co-testing every
5 yr
>65 No further testing if adequately
screened in the past and not
otherwise at increased risk for
cervical cancer
After hysterectomy No further screening if no CIN2 or
higher grade neoplasia
HPV vaccinated Continue recommended screening
ACS, American Cancer Society; ASCCP, American Society of Colposcopy and Cervical Pathology; ASCP, American Society for Clinical Pathology; CIN 2, cervical intraepithelial neoplasia
with moderately abnormal cells; HPV, human papillomavirus; Pap, Papanicolaou smear; USPSTF, U.S. Preventive Services Task Force.
No screening before the age of 21 despite
time of sexual activity
Screening with liquid-based or conventional
cytology alone every 3 yr; HPV testing
should not be performed.
Co-testing with cytology and HPV every
5 yr (preferred method) or cytology alone
every 3 yr if HPV testing in not available
No further testing if adequately screened in
the past
No further screening if no CIN2 or higher
grade neoplasia
Continue recommended screening
HPV positivity and cytologic abnormalities are likely
to regress in young women.
HPV co-testing should not be used for women <30  yr
of age because incidence of HPV is high and
cytologic abnormalities are often transient, leading
to unnecessary and sometimes harmful
interventions
Adequate screening defined as two negative results in
the past 10 yr with one in the past 5 yr and no
history of CIN2 or greater grade neoplasia. Because
cancer risk decreases with age and prior normal Pap
tests, overtesting may to lead to false-positive test
results.
Clinicians should confirm that total hysterectomy was
performed.

contraception. Two types of IUDs are available in the US, and
both are almost as effective as sterilization. The copper IUD can
be left in 10 years, and the progesterone IUD can be left in for 5
years. The copper IUD can be associated with heavier menstrual
bleeding and cramps. The progesterone IUD may initially have
breakthrough bleeding, but almost one half of users become
amenorrheic. Implanon is a progesterone rod that is implanted
under the skin and is highly effective for 3 years. It can be placed
in outpatient offices and is helpful in limiting dysmenorrhea, but
it is associated with irregular menses.
Postcoital emergency contraception can be achieved with one
or several hormonal options or with placement of a copper IUD.
Hormonal options are available over the counter in the United
States, and recommended use is up to 72 hours after intercourse.
After contraception is discontinued, the time of return to fertility
depends on the type of contraceptive used. The average time for
return to fertility with combination hormonal contraceptives is
3 months. With DMPA, fertility can be delayed by 12 to 22
months.
Pregnancy
Preconception Counseling and Pregnancy Planning
Preconception counseling begins by obtaining a through medical
history to assess potential risks to the mother and fetus. Women
with a personal or family history of genetic disorders may benefit
from formal genetic counseling. For the woman with no signifi-
cant medical problems and no serious family medical history,
education about maintaining a healthy lifestyle, nutritional sup-
plementation, and avoidance of toxicities to the fetus are
important.
In 2009, the Institute of Medicine published guidelines for
weight gain during pregnancy and recommended that women
planning pregnancy achieve their normal BMI before concep-
tion. Advising and assisting the overweight or obese patient in
weight loss efforts before pregnancy can prevent gestational dia-
betes, adverse fetal outcomes, and pathologic musculoskeletal
conditions. Avoidance of tobacco, alcohol, and illicit drugs is
critical because they are harmful to both mother and fetus. All
women planning pregnancy or capable of becoming pregnant
should be advised to take a daily multivitamin with folic acid
(400 to 800 µg) to reduce the risks of neural tube defects and
other congenital anomalies, including cardiovascular defects,
urinary defects, and cleft lip.
Routine laboratory evaluation includes rubella titer, varicella
titer (in women with a negative history of varicella), hepatitis B
surface antigen, and a complete blood count (CBC), assessing for
hemoglobinopathy. Women should receive HIV testing and
counseling.
An important goal is to ensure that women are immune to
measles, mumps, rubella, tetanus, diphtheria, poliomyelitis, and
varicella. Women should receive influenza vaccine in pregnancy
due to the increased risk of complications from influenza infec-
tion. Ideally, women should receive all indicated vaccinations at
least 1 month before conception. Live vaccines (e.g., rubella)
should not be given during pregnancy.
The patient’s medications, including prescribed, over-the-
counter, and herbal medications, should be reviewed to identify
potential teratogens. Medications not considered absolutely nec-
essary for the well-being of the mother or fetus should be stopped.
This is not always possible or indicated for women being treated
for chronic medical conditions.
Medical conditions known to increase the risk of adverse preg-
nancy outcomes for women and their offspring include diabetes,
thyroid disease, seizure disorders, hypertension, rheumatoid
arthritis, chronic renal disease, thrombophilias, asthma, and car-
diovascular disease. Preconception care of these conditions can
improve pregnancy outcomes. Patients usually are referred to
high-risk pregnancy care for evaluation. Approximately 1% of
pregnancies in the United States are complicated by pregesta-
tional diabetes. Gestational diabetes (GDM) occurs in approxi-
mately 7% of pregnancies. GDM has a high recurrence rate (30%
to 80%) in subsequent pregnancies and a significantly increased
 704 Section XI  Women’s Health

B
TABLE 70-3  COMPARISON OF LONG-ACTING, REVERSIBLE CONTRACEPTION METHODS
s s
s s

PERCENTAGE OF WOMEN WITH AN UNINTENDED

A

e
C-peptid

PREGNANCY DURING FIRST YEAR OF USE

PERCENTAGE OF WOMEN
METHOD Typical Use* Perfect Use† CONTINUING USE AT 1 YEAR‡
No method§ 85 85
Spermicides|| 29 18 42
Withdrawal 27 4 43
Fertility awareness–based methods 25 51
Standard days method¶ 5
Two-day method¶ 4
Ovulation method¶ 3
Sponge
  Parous women 32 20 46
  Nulliparous women 16 9 57
Diaphragm# 16 6 57
Condom**
  Female (Reality) 21 5 49
  Male 15 2 53
Combined pill and progestin-only pill 8 0.3 68
Evra patch 8 0.3 68
NuvaRing 8 0.3 68
Depo-Provera 3 0.3 56
Intrauterine device (IUD)
  ParaGard (copper T) 0.8 0.6 78
  Mirena (levonorgestrel intrauterine system) 0.2 0.2 80
  Implanor 0.05 0.05 84
Female sterilization 0.5 0.5 100
Male sterilization 0.15 0.10 100
Emergency contraceptive pills Use within 72 hr after unprotected
intercourse reduces risk of
pregnancy ≥75%.††
Lactational amenorrhea method Highly effective, temporary
method of contraception‡‡
Modified from Trussell J, Wynn LL: Reducing unintended pregnancy in the United States, Contraception 77:1–5, 2008.
*Among typical couples who initiate use of a method (not necessarily for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop
use for any other reason. Estimates of the probability of pregnancy during the first year of typical use for spermicides, withdrawal, fertility awareness–based methods, the diaphragm, the
male condom, the pill, and Depo-Provera are taken from the 1995 National Survey of Family Growth (NSFG), corrected for underreporting of abortion; see the reference above for the
derivation of estimates for other methods.
†
Among couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly), the percentage who experience an accidental
pregnancy during the first year if they do not stop use for any other reason. Trussell and Wynn (2008) provide the derivation of the estimate for each method.
‡
Among couples attempting to avoid pregnancy, the percentage who continue to use a method for 1year.
§
The percentages for becoming pregnant in columns 2 and 3 are based on data from populations in which contraception is not used and from women who cease using contraception to
become pregnant. Among these populations, about 89% become pregnant within 1 year. This estimate was lowered slightly (to 85%) to represent the percentage who would become
pregnant within 1 year among women now relying on reversible methods of contraception if they abandoned contraception altogether.
||
Foams, creams, gels, vaginal suppositories, and vaginal film.
¶
The ovulation and 2-day methods are based on evaluation of cervical mucus. The standard days method avoids intercourse on cycle days 8 to 19.
#
With spermicidal cream or jelly.
**Without spermicides.
††
The treatment schedule is one dose within 120 hr after unprotected intercourse and a second dose 12 hr after the first dose. Both doses of plan B can be taken at the same time. Plan B
(one dose is one white pill) is the only dedicated product specifically marketed for emergency contraception. The U.S. Food and Drug Administration also has declared the following 22
brands of oral contraceptives to be safe and effective for emergency contraception: Ogestrel or Ovral (one dose is two white pills); Levlen or Nordetto (one dose is four light orange pills),
Cryselle, Levore, Low Ogestrel, Lo/Ovral, or Quasense (one dose is four white pills), Tri Levlen or Triphasil (one dose is four yellow pills), Jolessa, Portia, Seasonale, or Trivora (one dose is
four pink pills), Seasonique (one dose is four light blue-green pills), Empresse (one dose is four orange pills), Alesse, Lessira, or Levlite (one dose is five pink pills), Aviane (one dose is five
orange pills), and Lutera (one dose is five white pills).
‡‡
To maintain effective protection against pregnancy, another method of contraception must be used as soon as menstruation resumes, the frequency or duration of breast-feedings is
reduced, bottle feedings are introduced, or the baby reaches 6 months of age. The best estimates of failure rate of all types of tubal sterilization is 1.31 after 5 years and 1.85 per 100 women
after 10 years; it is highest for tubal fulguration and lowest for segmental resection in the 10 years after the procedure.

risk for future development of type 2 diabetes. In women with
pregestational diabetes and GDM, adequate control of diabetes
reduces the risk of congenital malformations.
Thyroid disease is the second most common endocrine disease
that affects reproductive-age women. Hyperthyroidism and overt
hypothyroidism occur in approximately 0.2% and 2.5% of all
pregnancies, respectively. Adequate treatment of thyroid illness
improves pregnancy outcomes. Approximately 70% to 80% of
women with rheumatoid arthritis experience remission of disease
during pregnancy, although the remaining women have active or
worsening disease in pregnancy. Women with systemic lupus ery-
thematosus (SLE) often experience exacerbations in pregnancy.
SLE increases the risk of adverse fetal outcomes, including spon-
taneous abortion, fetal growth restriction, and preterm birth.
A few conditions confer significant mortality risks to the
mother and fetus. Pulmonary hypertension (especially Eisen-
menger’s syndrome), congenital heart disease with hypoxia, poor
functional class, and arrhythmias are associated with adverse
maternal outcomes.
Medications in Pregnancy
Pregnant women should avoid the use of most medications
(Table 70-4). However, the benefits of medications may out-
weigh the risks, particularly for women with chronic medical
 Chapter 70  Women’s Health Topics 705
TABLE 70-4  FOOD AND DRUG ADMINISTRATION
CATEGORIES OF DRUG SAFETY  
DURING PREGNANCY
CATEGORY INTERPRETATION
A Adequate, well-controlled studies in pregnant women have
not shown an increased risk to the fetus in any trimester
of pregnancy.
B Animal studies have revealed no evidence of harm to the
fetus; however, there are no adequate and well-controlled
studies in pregnant women.
Or
Animal studies have shown an adverse effect, but adequate
and well-controlled studies in pregnant women have
failed to demonstrate a risk to the fetus in any trimester.
C Animal studies have shown an adverse effect, and there are
no adequate and well-controlled studies in pregnant
women.
Or
No animal studies have been conducted, and there are no
adequate and well-controlled studies in pregnant women.
D Adequate, well-controlled, or observational studies in
pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the
potential risk.
X Adequate, well-controlled or observational studies in
animals or pregnant women have demonstrated positive
evidence of fetal abnormalities or risks, and the use of
the product is contraindicated in women who are or may
become pregnant.
conditions. Few medications are absolutely contraindicated in
pregnancy. Decisions about continuing or stopping medications
require a discussion about the risks and benefits and an informed
decision on the part of the woman.
Pregnancy Complications and families.
Risk of Future Diseases
Women with a history of gestational diabetes are at increased risk
for diabetes later in life. Women whose pregnancies were compli-
cated by a gestational hypertensive disorder, such as preeclamp-
sia or gestational hypertension, are at increased risk for subsequent
essential hypertension. Women who have a history of a child with
a neural tube defect should take 4 g of folic acid daily. Women
with a prior problem pregnancy may benefit from close follow-up
with an obstetric provider such as a high-risk pregnancy specialist
to reduce subsequent problems.
Two important conditions to recognize are postpartum
depression and postpartum thyroiditis. Postpartum depression
may complicate 10% to 15% of pregnancies. The symptoms are
the same as those of clinical depression in a nonpregnant woman.
Risk factors for postpartum depression include a history of
depression before pregnancy and depression during the current
pregnancy. Postpartum thyroiditis may be seen in 7% to 8% of
women. Only about one third of women have the classic hyper-
thyroid phase followed by hypothyroidism and recovery. Another
30% exhibit only hyperthyroidism, and the remaining 40% to
50% have only hypothyroidism. Unexpected symptoms after
delivery should prompt an evaluation of thyroid function.
Lesbian Health
Being lesbian is not a homogeneous experience. The racial,
ethnic, and socioeconomic diversity of the United States is mir-
rored in the lesbian community. The Institute of Medicine
TABLE 70-5  CAUSES OF SECONDARY AMENORRHEA
B
s s
s
CAUSE EXAMPLES
s
A
e
C-peptid
Physiologic changes Pregnancy, lactation, menopause
Ovarian changes Radiation- or chemotherapy-induced ovarian failure,
chromosomal abnormalities, autoimmune or
idiopathic
Anovulation Hyperandrogenism (polycystic ovary syndrome,
congenital adrenal hyperplasia), hyperprolactinemia
(prolactinoma, phenothiazines, narcotics, and other
medications), hyperthyroidism, hypothyroidism,
hypopituitarism, pituitary adenoma, Cushing’s
syndrome, hypothalamic hypogonadism (eating
disorder, athletic triad, stress)
Medications Hormonal, cytotoxic, others
Uterine outflow Surgery, Asherman’s syndrome
abnormalities
released a report acknowledging that lesbian, gay, bisexual, and
transgender (LGBT) individuals experience unique health care
disparities and encouraged health care providers to increase cul-
tural competence to care for these populations. Lesbians are sig-
nificantly more likely than heterosexual women to experience
discrimination during health care visits. Many providers do not
take a sexual history or inquire about sexual orientation. Health
care providers may inadvertently assume heterosexuality and
communicate heterosexist attitudes, making it more difficult for
patients to disclose their sexual orientation. Physicians can create
a safe and welcome environment for their lesbian patients by
consistently adopting gender-neutral language. For example, “Do
you have a significant other?” rather than “Are you married?” It is
also important that confidentiality is ensured and that staff are
aware of and comfortable with lesbian patients and their
Between 50% and 80% of lesbians report heterosexual sexual
activity (which confers the highest risk for HPV acquisition) at
some point in their lives, and screening for cervical cancer should
follow the same guidelines as for heterosexual women. Although
many STIs occur less frequently in lesbians, screening should be
considered when appropriate. Counseling about lifestyle issues
and screening when appropriate are the same for lesbians as for
heterosexual women.
Gynecologic Issues
Menstrual disorders are common and usually categorized as
amenorrhea and abnormal uterine bleeding. Abnormalities may
indicate problems related to the reproductive system or may be
an early sign of an important underlying systemic illness.
Amenorrhea
Amenorrhea occurs in 5% of women each year. It is the absence
of menses for at least 3 to 6 months outside of the setting of
pregnancy or lactation. Women with a previously established
menstrual pattern have secondary amenorrhea (Table 70-5). Oli-
gomenorrhea occurs when menses are irregular or infrequent,
with a cycle length usually greater than 35 to 40 days, and it is
often associated with chronic anovulation or oligo-ovulation. The
most common cause of secondary amenorrhea is pregnancy. Lac-
tation causes amenorrhea for up to 6 months in a woman who is
exclusively breast-feeding her infant. Prolonged amenorrhea can
follow cessation of some hormonal contraceptives, especially
 706 Section XI  Women’s Health
DMPA. Menopause should be suspected in a woman older than
B
45 years.
Amenorrhea and oligomenorrhea may be caused by patho-
s s
s s
A
e
C-peptid
logic changes at any point in the endometrial-ovarian-pituitary-
hypothalamic axis. The differential diagnosis for secondary
amenorrhea is broad and is categorized by the primary organ
failure or dysfunction: ovarian, hypothalamic, pituitary, and
uterine (in descending order of frequency).
Evaluation should begin with a history, physical examination
to assess comorbidities and anatomy, and urine test for human
chorionic gonadotropin (HCG). If not pregnant, further evalua-
tion should include serum levels of TSH, prolactin, and FSH. For
women who have evidence of hyperandrogenism, the serum
levels of total testosterone, 17-hydroxyprogesterone, and dehy-
droepiandrosterone sulfate (DHEAS) should be measured.
Additional testing and evaluation should be pursued based on
these findings.
For women with elevated prolactin levels, normal or low FSH
levels with no clear reason (e.g., weight loss, exercise, recent
illness, stress) or with visual symptoms or headaches, magnetic
resonance imaging (MRI) of the brain should be performed to
look for pituitary abnormalities. A high serum FSH level indi-
cates premature ovarian failure, and women should be counseled
regarding management, fertility concerns, and estrogen replace-
ment. If a woman has a normal FSH level and a history of uterine
manipulation, she should have a progestin challenge to rule out
outflow tract abnormalities. Women with low or normal FSH
levels and a history consistent with functional hypothalamic
amenorrhea due to weight loss or exercise should be counseled
about healthy weight and physical activity.
Abnormal Bleeding
Abnormal bleeding can be caused by many abnormalities, includ-
ing anovulation, endometrial pathology, and coagulopathies.
Women with polymenorrhea have a cycle less than 21 days long;
women with oligomenorrhea have an interval greater than 40 days.
Women with excessive bleeding in duration or quantity have
menorrhagia. Menometrorrhagia is excessive bleeding at irregular
intervals.
Women should be asked about their bleeding, including the
onset, duration, pattern, and quantity of bleeding. A classification
system (Fig. 70-2) for abnormal uterine bleeding (AUB) is orga-
nized by cause (i.e., structural or nonstructural). It has eliminated
the terms menorrhagia and menometrorrhagia and replaced them
with heavy menstrual bleeding and intermenstrual bleeding,
Abnormal Uterine Bleeding (AUB)
• Heavy menstrual bleeding (AUB/HMB)
• Intermenstrual bleeding (AUB/IMB)
PALM: Structural Causes COEIN: Nonstructural Causes
Polyp (AUB-P) Coagulopathy (AUB-C)
Adenomyosis (AUB-A) Ovulatory dysfunction (AUB-O)
Leiomyoma (AUB-L) Endometrial (AUB-E)
Submucosal myoma (AUB-LSM) Iatrogenic (AUB-I)
Other myoma (AUB-LO) Not yet classified (AUB-N)
Malignancy and hyperplasia (AUB-M)
respectively. In the PALM-COEIN classification, the four main
structural causes for AUB are polyp, adenomyosis, leiomyoma,
and malignancy or hyperplasia, and the five nonstructural causes
are coagulopathy, ovulatory dysfunction, endometrial, iatrogenic,
and not yet classified.
Evaluation of AUB assesses for evidence of ovulatory cycles by
inquiring about symptoms such as breast tenderness, cramping,
and fluid retention before the onset of bleeding. Absence of these
symptoms suggests anovulatory bleeding and focuses the differ-
ential diagnosis on hormonal causes. Anovulatory bleeding is the
result of failed ovulation and the absence of a luteal phase. The
ovary secretes estrogen unopposed by progesterone and leads to
continued proliferation of the endometrium. This endometrium
is unstable, which results in periodic, irregular, and often heavy
bleeding. Bleeding due to coagulopathy follows a typically ovula-
tory pattern and produces heavy, regular bleeding. A personal or
family history of bleeding disorders should be sought, because a
significant fraction (5% to 32%) of women with heavy menstrual
bleeding have an underlying bleeding disorder.
A general physical examination seeks evidence of anemia and
a systemic cause of AUB such as thyroid disease or polycystic
ovary syndrome. Genitourinary examination should verify the
source of bleeding and may identify a cervical polyp, which typi-
cally is associated with postcoital bleeding, or an enlarged uterus,
suggesting uterine fibroids. Pregnancy must always be excluded
with a urine pregnancy test; a Pap smear and cervical cultures
should be obtained to assess for cervical disease or infection.
Laboratory testing should include a CBC, thyroid studies, and
coagulation studies. Endometrial sampling should be performed
for women age 45 or older and for women younger than 45 years
of age who are at risk for endometrial hyperplasia or endometrial
cancer (i.e., women with obesity or a history of chronic anovula-
tion, failed medical therapy or persistent symptoms).For women
with suspected structural abnormalities, a transvaginal ultra-
sound study should be pursued initially.
Management of abnormal bleeding depends on the underlying
pathology identified and the degree of anemia caused by the
bleeding. Hemodynamically unstable women may require uterine
curettage or intravenous estrogen. For hemodynamically stable
women, control of bleeding is usually achieved through the use
of a combination of estrogen and progestin preparations such as
oral contraceptive pills. Levonorgestrel-releasing IUDs can be
used for women who have contraindications to estrogen therapy
or for women who require long-term therapy. Nonsteroidal anti-
inflammatory drugs (NSAIDs) can be used by women who do
FIGURE 70-2  The PALM-COEIN classification of abnormal
uterine bleeding. (From Munro MG, Critchley HO, Broder MS,
Fraser IS; FIGO Working Group on Menstrual Disorders: FIGO
classification system (PALM-COEIN) for causes of abnormal
uterine bleeding in nongravid women of reproductive age,
Int J Gynaecol Obstet 113:3–13, 2011.)
 Chapter 70  Women’s Health Topics 707
not require contraception and who have dysmenorrhea. Surgical
options, including endometrial ablation and hysterectomy, are
usually reserved for women who have failed other treatments and
do not desire future pregnancy.
Infertility
According to the CDC, 11% of U.S. women have trouble conceiv-
ing or carrying a pregnancy to term. Infertility is a failure to
conceive after 1 year of regular intercourse without contracep-
tion. Infertility is more common with increasing age and is
becoming more prevalent as women are deferring pregnancy and
attempting to conceive at older ages.
Infertility may be caused by female factors or male factors. The
most common female cause is an ovulatory factor (20% to 35%),
which is often related to metabolic abnormalities, followed by
tubal disease (20% to 25%) and uterine factors (5% to 15%).
Approximately 20% to 30% of couples experience unexplained
infertility. Evaluation should include a complete reproductive,
medical, and gynecologic history and a physical examination to
help identify metabolic or structural gynecologic abnormalities.
Testing may include TSH, FSH, and prolactin levels in women
with irregular menses or oligmenorrhea luteal phase serum pro-
gesterone levels or basal body temperature charting to confirm
ovulation, and day 3 FSH testing in women 35 years of age or
older to evaluate ovarian reserve. Further evaluation and treat-
ment are usually performed by reproductive specialists.
Menopause
Menopause occurs when a woman has not had a menstrual cycle
for 12 consecutive months or when her ovaries have been
removed. The average age at menopause in western countries is
51.4 years, with a range of 40 to 58 years. Women who smoke
experience an earlier menopause in a dose-dependent fashion,
with an average of 1.5 years sooner than nonsmokers. Because
the life expectancy of women is almost 80 years, many women
spend at least one third of their lifetime in the postmenopausal
period.
Although symptoms such as hot flashes and vaginal dryness
may develop during menopause, the process itself is a normal
part of the life cycle. This transition offers clinicians the oppor-
tunity to help women focus on important preventive health mea-
sures and define their risk for major chronic diseases, such as
osteoporosis and CAD, as early as possible.
Transition from Perimenopause to Menopause
Much of our information about the menopausal transition is
from the Study of Women’s Health Across the Nation (SWAN).
This multisite, multiethnic cohort study of women was designed
to better understand the health of women during their middle
years.
The transition to menopause can be erratic and prolonged over
a 5- to 10-year period. It is characterized by ovarian and endo-
crine changes that ultimately result in the depletion of primordial
oocyte stores and the cessation of ovarian estrogen production.
An accelerated loss of follicles begins at about 37 years of age and
is correlated with a small increase in FSH and decrease in inhibin
levels. As the FSH concentration increases, the follicular phase of
the cycle decreases, and one of the earliest clinical signs of the
menopausal transition is shortening of the menstrual cycle from
a mean length of 30 days in the early reproductive years to 25 B
days in the early menopausal transition.
s s
s s
A
e
C-peptid
Later in the menopausal transition, the few remaining follicles
respond poorly to FSH, and anovulation may occur. Menstrual
cycles may become erratic with prolonged periods of oligo-
menorrhea. Ovulation may still occur, and women in this time
period are advised to continue effective contraception until 12
months of amenorrhea have occurred. Ultimately, when ovarian
follicles are depleted, the ovary no longer secretes estradiol but
continues to secrete androgens due to continued stimulation
by LH.
Perimenopausal Symptoms
Menstrual irregularities (experienced by almost 75% of women)
are usually the first change noticed by women entering the meno-
pausal transition. Although changes in the menstrual flow are
expected and most women can be reassured, clinicians need to
be aware of bleeding patterns that may represent underlying
pathology and require evaluation (Table 70-6).
Sleep disturbances in perimenopausal women are a well-
documented phenomenon. Hot flashes or sweats can disturb
sleep patterns and interfere with sleep quality, resulting in fatigue,
irritability, and difficulty concentrating. Vaginal dryness and dys-
pareunia are common symptoms that can interfere with sexual
function.
Changes in mood and cognition are common complaints
during the menopausal transition, but a causative link between
hormonal fluctuations and mood disturbances and cognitive
changes has not been established. Women who do experience
significant depression at this time are more likely to have experi-
enced depression earlier in their lives, particularly at times of
hormonal change (e.g., postpartum depression, premenstrual
dysphoric disorder [PMDD]). Mood issues during the peri-
menopausal transition should be approached in the same manner
as at other ages. In addition to mood, many women in perimeno-
pause complain of difficulties with concentration and memory.
In the SWAN cohort, women had a small, transient decline in
cognitive abilities during perimenopause, but anxiety and depres-
sion also had independent negative effects on cognition. Most
epidemiologic studies do not demonstrate an increased risk of
depression or a decline in cognitive skills during the menopausal
transition.
The hot flash is the hallmark symptom of menopause. In the
United States, up to 75% of women who experience a natural
menopause and 90% of women who experience a surgical meno-
pause have these vasomotor symptoms. Hot flashes may occur a
few times per year or several times each day; 10% to 15% of
TABLE 70-6  ABNORMAL UTERINE BLEEDING
PATTERNS IN POSTMENOPAUSAL
WOMEN
Heavy menstrual bleeding (>80 mL), especially with clots
Menstrual bleeding lasting >7 days or ≥2 days longer than usual
Intervals of <21 days from the onset of one menstrual period to the onset of
the next period
Spotting or bleeding between periods
Uterine bleeding after sexual intercourse
 708 Section XI  Women’s Health
women have hot flashes that are very frequent or severe. For most
B
women, vasomotor symptoms are self-limited, lasting on average
1 to 2 years; however, up to 25% of women may have symptoms
s s
s s
A
e
C-peptid
for longer than 5 years.
The exact cause of a hot flash is not understood, although it is
related to a disturbance of hypothalamic thermoregulation.
Women experience a sudden onset of warmth, ranging from
noticeable to markedly uncomfortable, especially over the face
and upper body. This may be accompanied by significant perspi-
ration. There are racial and ethnic differences in reported hot
flashes, with African American women experiencing increased
rates compared with white women and Hispanic and Asian
women experiencing lower rates.
In the 1950s, it was discovered that estrogen could relieve hot
flashes, and its use became widespread. In 1975, a study pub-
lished in the New England Journal of Medicine showed that women
who used estrogen for more than 7 years had a 14-fold increase
in uterine cancer. Subsequent research determined that endome-
trial hyperplasia and cancer is reduced to essentially zero when
low-dose progestin is continued for 12 to 13 days per month.
Women on estrogen with an intact uterus must use progestin
therapy to prevent endometrial hyperplasia and cancer.
Hormone treatment (i.e., estrogen or combined estrogen and
progestin for women with an intact uterus) remains the most
effective treatment of menopausal vasomotor symptoms (level A
evidence). It is also FDA approved for the treatment of urogenital
atrophy and the prevention of osteoporosis. In the 1990s, the
results of the Heart and Estrogen/Progestin Replacement Study
(HERS) found that women with preexisting heart disease had
increased numbers of cardiac events when placed on estrogen.
The Women’s Health Initiative (WHI) was designed to look
at various hormone regimens and their effects on disease pre-
vention, particularly cardiovascular disease, in postmenopausal
women. More than 16,000 women participated in the trials,
which ran for 5.6 years in the combined estrogen-progestin
arm and 6.8 years in the estrogen-only arm. In the combined-
therapy group, there was an increased risk for coronary heart
disease (CHD) (hazard ratio [HR] = 1.29), an increased risk
for stroke (HR = 1.41), an increased risk for pulmonary embo-
lism (HR = 2.13), and increased risk for breast cancer (HR =
1.26). The combined-therapy trial was discontinued because of
this excess risk.
The conclusion from the combined-therapy trial was that com-
bination estrogen-progestin therapy should not be initiated or
continued for the prevention of CHD. The estrogen-only trial did
not find a significant increase in CHD or breast cancer but did
show an increased risk of stroke (HR = 1.39). The conclusion was
that estrogen alone should not be recommended for the preven-
tion of chronic disease in postmenopausal women and hormone
therapy should not be prescribed for disease prevention.
Postmenopausal Therapy
Hormone Therapy
Several medical societies have published guidelines for the use of
postmenopausal hormone therapy, including the American
College of Obstetricians and Gynecologists (ACOG) and the
North American Menopause Society (NAMS). Most guidelines
agree that estrogen and estrogen-progestin therapy are
appropriate for the treatment of moderate to severe vasomotor
symptoms and for urogenital atrophy in women who have been
appropriately counseled on the risks and benefits (level B evi-
dence). If hormone therapy is initiated, the lowest dose needed
to treat the symptoms should be used and usually for a short term
(i.e., 2 to 3 years and not more than 5 years). For women who
have only vaginal dryness, vaginal estrogen can be used instead
of oral estrogen. It may be acceptable under some circumstances,
provided the woman is aware of the potential benefits and risks,
to extend low-dose therapy if the benefits of treatment outweigh
the risks, and a woman has failed attempts to stop (level C
evidence).
Alternative Therapies
Interest in nonhormonal and “natural” alternatives in the treat-
ment of menopausal symptoms is extremely high. As many as
75% of menopausal women have used some form of alternative
or complementary treatment to relieve menopausal symptoms.
Behavioral options such as dressing in layers, regular exercise,
stress reduction techniques, and avoidance of known triggers are
safe and may be helpful for a number of women. Some of the
more common herbal remedies for menopausal symptoms
include isoflavones (e.g., soy, red clover) and black cohosh. None
of these therapies has consistently been shown to decrease hot
flashes beyond placebo in rigorous randomized, controlled trials.
There are effective nonhormonal medication options for treat-
ment of hot flashes, although hormone therapy is superior to
these alternatives. Although paroxetine is the only other FDA-
approved medical treatment for hot flashes, paroxetine and ven-
lafaxine have been shown to decrease hot flash frequency, but
they may cause sexual side effects. Gabapentin and clonidine
have been shown to reduce hot flash frequency beyond placebo.
Sexual Dysfunction
According to the largest study of prevalence of female sexual
dysfunction in the United States (PRESIDE study), more than
40% of women report some form of sexual problems. Women
between 45 and 65 years of age are disproportionately affected,
just before and after the menopausal transition. Female sexual
dysfunction diagnoses in the Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) include disorders of
desire, arousal, and orgasm; dyspareunia; and vaginismus. Disor-
ders of desire and arousal are the most common. Risk factors for
dysfunction include depression and anxiety, relationship conflict,
stress and fatigue, and a history of abuse. Medical and physical
issues, such as pelvic floor disorders, endometriosis, and psychi-
atric and neurologic disease, can negatively affect sexuality.
Symptomatic vaginal atrophy occurs in up to 40% of post-
menopausal women. As women age and enter menopause, the
decline in estrogen levels causes thinning of the vaginal epithe-
lium, decreased vaginal elasticity, and decreased vaginal lubrica-
tion, resulting in painful intercourse. Evaluation should include a
thorough medical and sexual history and a pelvic examination,
including vaginal cultures for STIs if there is pain or vaginal
discharge.
Management of sexual dysfunction should be based on the
underlying cause, such as evaluation of selective serotonin
reuptake inhibitors (SSRIs), antihistamines, β-blockers, and
 Chapter 70  Women’s Health Topics 709
antipsychotics that may affect sexual function. Nonpharmaco-
logic therapies include counseling, lifestyle changes to decrease
stress and anxiety, physical therapy for vaginismus and pelvic
floor dysfunction, and lubricants and vaginal moisturizers for
dyspareunia caused by vaginal dryness. For some women, vaginal
lubricants and moisturizers may be sufficient and are the first-line
therapy.
Pharmacologic therapy for sexual dysfunction has primarily
focused on hormonal therapy. In the WHI, hormone therapy did
not have a beneficial effect on sexual dysfunction, but a Cochrane
review examined hormone therapy for sexual function and found
a small to moderate benefit in perimenopausal or early post-
menopausal women. Topical vaginal estrogen results in little sys-
temic absorption and is very effective in relieving the symptoms
of vaginal atrophy.
Genitourinary Symptoms
Urinary incontinence rates increase with age. Urinary inconti-
nence is common after menopause, with about 25% of women
affected. The cause is often multifactorial. The endothelium of the
urethra and bladder becomes more fragile and less elastic with
menopause. Urethral tone also decreases with age. Uterine pro-
lapse, cystoceles, and rectoceles increase the risk of incontinence.
Risk also increases as body weight increases due to increased
pressure on the bladder. Urinary incontinence and its behavioral
and pharmacologic treatment options are discussed in Chapter
26, “Incontinence,” in Goldman-Cecil Medicine, 25th Edition.
  MEDICAL PROBLEMS WITH UNIQUE
CONSIDERATIONS FOR WOMEN
Obesity, Metabolic Syndrome, Polycystic
Ovary Syndrome, and Diabetes
Rates of obesity have increased steadily in recent decades, and
more than one third of U.S. adults are obese (BMI >30). Overall,
obesity appears to affect men and women equally, although
women of lower SES are disproportionately affected. Obesity
increases the risk for many diseases, including CAD, which is
the leading cause of death for men and women. In women,
central obesity (waist-hip ratio >0.9) predicts the risk of CAD.
The risk of many cancers (e.g., endometrial cancer) is increased
for obese individuals. Obesity has specific implications for
women during pregnancy. It increases the risk of numerous
pregnancy-related complications, including gestational diabetes
mellitus, fetal macrosomia, hypertension, shoulder dystocia, and
cesarean delivery, and contributes postpartum complications
such as thrombosis and infection. Obesity is also associated
with irregular menses and higher rates of anovulation.
Metabolic effects related to obesity have been elucidated. The
risk of cardiovascular disease related to the metabolic syndrome
appears to have a stronger correlation in women. The National
Cholesterol Education Program/Adult Treatment Panel III
defines metabolic syndrome as the presence of three or more of
five risk factors that increase the chance of developing heart
disease or stroke: central obesity, elevated triglyceride levels,
low levels of high-density lipoprotein (HDL) cholesterol, hyper-
tension, and impaired fasting glucose values. Metabolic syn-
drome significantly increases the risk of type 2 diabetes and
cardiovascular disease, and these patients should be targeted for
aggressive lifestyle modification to reduce contributory risk B
factors.
s s
s s
A
e
C-peptid
Polycystic ovary syndrome (PCOS) is an endocrine disorder
primarily of androgen excess that affects approximately 5% to
10% of women worldwide. Reproductive and metabolic effects
include anovulation, infertility, acne, hirsutism, obesity, and
metabolic syndrome. Increased insulin resistance is a significant
consequence of the syndrome, increasing the risk of type 2 dia-
betes, particularly in obese women. Women with PCOS are at
increased risk for endometrial and ovarian cancers.
The risk of type 2 diabetes mellitus increases with obesity, and
like obesity, the incidence of diabetes has been on the rise in the
United States. More than 10% of adult Americans carry the diag-
nosis of diabetes, and many remain undiagnosed. Rates of diabe-
tes are highest in black, Hispanic, and Native American groups.
The increased cardiovascular disease risk conferred by diabetes is
greater for women than for men, and women with diabetes have
lower survival rates and quality of life after a cardiovascular event
than their male counterparts. Women also have higher rates of
blindness associated with diabetes. Identifying women with
impaired fasting glucose values (i.e., prediabetes) can help to
identify women likely to develop diabetes in the future. In addi-
tion to reviewing traditional risk factors for diabetes, a history of
gestational diabetes and infant birth weight greater than 9 pounds
should be considered when evaluating female patients for the risk
of diabetes.
Breast Pain, Discharge, and Masses
Breast symptoms are common in practice and cause significant
anxiety to patients. Although most breast complaints are about
benign conditions, it is important to evaluate breast symptoms
thoroughly to ensure that breast cancers are not being missed.
Initial evaluation starts with obtaining a history and asking when
symptoms began and how they evolved. For instance, a mass that
is prominent premenstrually and then decreases in size in the
follicular phase of menses is likely a benign cyst.
Breast pain is a common, nonspecific symptom that is usually
benign. Localized breast pain is the only symptom in 10% to 15%
of women with newly diagnosed breast cancer. Breast pain has
cyclical and noncyclical patterns. Approximately two thirds of
breast pain is cyclical in nature and related to the normal hor-
monal variations in the menstrual cycle. Noncyclical breast pain
does not follow the usual menstrual pattern and is usually unilat-
eral. Causes of noncyclical breast pain include large breasts, diet
and lifestyle factors (e.g., caffeine, nicotine), inflammatory breast
cancer, and various medications, including oral contraceptives,
antidepressants, and antibiotics. In women older than 35 years of
age, diagnostic mammography should be completed. If mam-
mography and the physical examination are normal, reassurance
can be provided. In women younger than 35 years of age, normal
examination results can obviate the need for further testing.
Breast discharge is an uncommon sign of malignancy. About
5% of women with breast cancer have discharge as a symptom.
Concern for malignancy is increased if the discharge occurs
without provocation, is persistent, and is unilateral; if the dis-
charge is serous, serosanguineous, or bloody; if it occurs in an
older patient; or if it is associated with a mass or lump. The most
 710 Section XI  Women’s Health
common malignancy causing discharge is ductal carcinoma in
B
situ. However, a benign intraductal papilloma is the most
common cause of bloody nipple discharge.
s s
s s
A
e
C-peptid
Most bilateral discharge that occurs only with manipulation is
a normal physiologic response. Galactorrhea, bilateral milk pro-
duction occurring in a nonlactating woman, can be seen in many
conditions, including prolactinomas, thyroid dysfunction, and
chronic renal failure. It can be a response to many drugs, includ-
ing antipsychotics, oral contraceptives, and marijuana.
Initial evaluation for breast discharge includes a pregnancy
test, prolactin level determination, and thyroid tests. If there is
concern about malignancy, a breast specialist performs cytology,
immunology, and occult blood testing on the discharge and
obtains mammography and ultrasound studies.
There are four categories of breast masses: abscesses, benign
masses, benign tumors, and cancer. Benign masses include cysts,
galactoceles, papillomas, and fibroadenomas. Cancerous masses
are typically painless, dominant masses that persist. Although
breast cancers have characteristically been described as hard and
immobile with irregular borders, no examination finding reliably
distinguishes between a benign and cancerous mass.
Persistent masses require evaluation, which may include ultra-
sound, mammography, and biopsy, depending on the findings
from the history, physical examination, and patient’s age. Women
younger than 30 years of age are at lower risk for malignancy.
Ultrasound is the first imaging modality indicated for young
women. If the mass is a cyst, it can be aspirated if symptomatic.
If the mass is solid and is not characteristic of a fibroadenoma
(which can be observed or biopsied), a biopsy is indicated to rule
out malignancy. In women older than 30 years of age, mammog-
raphy is the first diagnostic test that should be ordered, even if
the woman had a recent negative screening mammogram. Ultra-
sound is often done simultaneously to further evaluate the mass
or an area of abnormality detected on the mammogram. Negative
imaging results should not preclude further work-up of a clini-
cally suspicious mass. Mammography misses 10% to 20% of clini-
cally palpable breast cancers.
Pelvic Pain
Pelvic pain is characterized as acute or chronic, and both types
are commonly encountered in primary care practice. Acute pelvic
pain usually manifests over hours to days and may be gyneco-
logic, gastrointestinal, or urologic in origin. Life-threatening con-
ditions, including ruptured ectopic pregnancy and appendicitis,
need to be ruled out. Gynecologic causes include complications
of pregnancy, acute pelvic infection, and ovarian pathology,
including cyst and torsion.
Chronic pelvic pain (CPP) is lower abdominal pain of at least
6 months’ duration, and it is severe enough to cause functional
impairment or require treatment. Approximately 10% of ambula-
tory gynecologic referrals are for CPP. The history obtained for
evaluation of CPP should include characteristics of the pain; a
thorough review of systems; prior medical, surgical, gynecologic,
and obstetric history; and a thorough psychiatric and social
history, including episodes of domestic violence as a child or an
adult and periods of substance abuse.
The most common conditions associated with CPP include
endometriosis, chronic pelvic inflammatory disease, interstitial
cystitis, irritable bowel syndrome, pelvic floor myalgia,
myofascial pain, and neuralgia. Interstitial cystitis or painful
bladder syndrome is a clinical diagnosis consisting of pain, pres-
sure, or discomfort related to the bladder and associated with
lower urinary tract symptoms lasting more than 6 weeks and
occurring in the absence of infection or other identifiable causes.
Mental health issues, including substance abuse, somatization,
depression, and physical or sexual abuse, can also cause CPP and
are important to identify so that women need not undergo
unnecessary testing and interventions.
Physical examination should assess for focal areas of pain,
scars, hernias, or masses in the abdomen, and a pelvic examina-
tion should be performed. After the most likely diagnosis has
been identified, an empirical, targeted treatment may be instituted
and followed for efficacy. Further work-up should be considered
if the patient does not respond or symptoms change. If empirical
therapy and a thorough investigation do not yield a diagnosis,
laparoscopy may be considered to identify pelvic pathology.
Depending on the underlying cause, management strategies
may include heat therapy (for musculoskeletal pain), counseling
and psychiatric referral, gastrointestinal referral, medications
(e.g., gabapentin for neuropathic pain, NSAIDs, hormonal con-
traceptives), hysterectomy, and nerve transection procedures.
Multidisciplinary approaches, including medications and inter-
ventions that address dietary and psychosocial factors, may be
superior to medical treatment alone.
Intimate Partner Violence
Intimate partner violence (IPV) is a serious, preventable public
health problem. In 2013, the USPSTF revised their guidelines to
recommend that clinicians screen women of childbearing age (14
to 46 years old) for IPV and provide or refer women to interven-
tion services when appropriate. Several screening instruments
detect IPV effectively, and most experts think the benefits of
detection outweigh the potential harm. Providers can choose
among many tools for screening, including Hurt-Insult-Threaten-
Scream (HITS), Ongoing Abuse Screen/Ongoing Violence
Assessment Tool (OAS/OVAT), and Abuse Assessment Screen
(AAS).
A short but effective survey may be more practical. The STaT
(i.e., slapped, threatened, and thrown things) screening tool is
relatively easy to implement by asking three questions: Have you
ever been in a relationship in which your partner has pushed or
slapped you? Have you ever been in a relationship in which your
partner threatened you with violence? Have you ever been in a
relationship in which your partner has thrown, broken, or
punched things?
A self-administered questionnaire may be even more effective
than face-to-face questioning. When screening for and discussing
IPV, the provider must be nonjudgmental and compassionate
and must ensure confidentiality.
Even when historical or physical examination clues are evident,
IPV often remains undiagnosed by providers. Patients often
conceal abusive relationships. They may blame themselves for the
abuse, or they may not be emotionally ready to acknowledge the
abuse. Although there are risk factors for IPV, victims are found
among people of all ages, races, ethnicities, and gender and sexual
identities.
Identified risk factors for IPV include younger age, female sex,
lower SES, and a family history or personal history of violence.
 Chapter 70  Women’s Health Topics 711
Clues in the history include frequent emergency room visits,
delay in seeking treatment, an inconsistent explanation of inju-
ries, missed appointments, repeated abortions, late initiation of
prenatal care, medication noncompliance, inappropriate affect,
overly attentive or verbally abusive partner, apparent social isola-
tion, and reluctance to undress or difficulty with examination of
genitals or rectum. Common presenting complaints include
somatic symptoms (e.g., chronic pain, headaches, irritable bowel
symptoms), psychological symptoms (e.g., depression, anxiety,
panic disorder, posttraumatic stress disorder, substance use), and
gynecologic symptoms (e.g., STIs, chronic pelvic pain, unin-
tended pregnancy). After identification, a woman may be referred
to a mental health provider or social worker.
Psychiatric Issues
Fewer than one half of people who meet the diagnostic criteria
for psychological disorders are identified. Patients are also reluc-
tant to seek professional help. Only two of every five people with
a mood, anxiety, or substance use disorder seek assistance within
a year of onset of the disorder. Overall rates of psychiatric disor-
ders are almost identical for men and women. However, substan-
tial gender differences exist in the rates of common mental
disorders, including depression, anxiety, and somatic complaints.
In the United States, the estimated lifetime prevalence is 21% for
women and 13% for men. Depression is the most common
women’s mental health problem, and it may have a worse prog-
nosis for women because it is often more persistent than in men.
Advances have been made in understanding mood distur-
bances during specific phases of women’s reproductive lives, spe-
cifically during the postpartum period, the premenstrual phase
(i.e., premenstrual syndrome and PMDD), and the menopausal
transition. Depression occurring at these times may represent a
specific biologic response to the effects of hormonal fluctuations
in the brain and may require different treatments from depression
unrelated to these periods. For treating PMDD, SSRIs, oral con-
traceptives, alprazolam (a benzodiazepine), and GnRH agonists
are effective in some women.
The disability associated with mental illness is worse for indi-
viduals with three or more comorbid disorders. Women are more
likely than men to have comorbid conditions, including anxiety
disorders, eating disorders, and somatization. Gender-specific
risk factors for common mental disorders that disproportionately
affect women include gender-based violence, low income and
income inequality, low or subordinate social status, and the
responsibility as caretaker of others. The high prevalence of
sexual violence against women correlates with the higher preva-
lence of post-traumatic stress disorder (PTSD) among women
than men. Somatization disorders are diagnosed almost exclu-
sively in women. Lifetime prevalence is 0.2% to 2% if strict crite-
ria are used. Somatoform disorders are associated with significant
disability and a significantly greater number of clinic and emer-
gency room visits than for other psychiatric diagnoses. There
seem to be genetic and environmental contributions to risk.
Generalized anxiety disorder and panic disorder are about
twice as prevalent among women than men, with lifetime preva-
lences of 5% and 3.5%, respectively. Although there is a higher
prevalence of social anxiety disorder among women than men,
more men may seek treatment for the disorder. Social expecta-
tions and gender roles may play a role in this difference.
More than 90% of eating disorders, anorexia nervosa, and
bulimia occur in women. Approximately 0.5% to 1% of women B
between the ages of 15 and 30 years have anorexia, and about 1%
s s
s s
A
e
C-peptid
to 3% of women have bulimia. There is a strong association
between eating disorders and mood disorders, particularly
depression. There are no marked gender differences in the rates
of severe mental disorders such as schizophrenia and bipolar dis-
order, which affect less than 2% of the population.
Accessing mental health care is different for men and women.
Women are more likely to seek help from and disclose mental
health problems to their primary health care physician, whereas
men are more likely to seek specialist mental health care and are
the principal users of inpatient care. Evidence exists for possible
gender bias in the treatment of psychological disorders. Physi-
cians are more likely to diagnose depression in women than men,
even when they have similar scores on standardized measures of
depression or have identical symptoms at presentation. Women
are more likely to be prescribed mood-altering psychotropic
drugs.
Coronary Artery Disease
There are significant gender differences in the epidemiology and
clinical manifestations of CAD. CAD remains the leading cause
of death for men and women, but since the mid-1980s, more
women than men die each year of this disease. Women with CAD
tend to be diagnosed at a later age (approximately 10 years later)
than men. Most CAD in women occurs postmenopausally, when
estrogen levels decline. Estrogen increases levels of protective
HDL cholesterol, which may affect atherosclerotic plaque pro-
gression and regression. Estrogen may also be beneficial due to
its vasodilatory, antiinflammatory, and antioxidative properties.
Women with CAD are more likely than men to experience
atypical symptoms, such as fatigue, abdominal pain, indigestion,
nausea and vomiting, and shortness of breath. These nonclassic
symptoms may partially explain why women tend to seek health
care later than men. Even when women seek health care, they
have a longer time to diagnosis and a longer time to medical
intervention than men. Women are also more likely than men to
have sudden cardiac death at presentation. They are less likely to
receive proven effective therapies, such as β-blockers, aspirin,
thrombolytics, and statins, and they are less often referred for
invasive testing and coronary artery bypass grafting (CABG).
Women are also more likely to die after a myocardial infarction
and CABG compared with men.
Black and Hispanic women have a higher prevalence of car-
diovascular disease risk factors than white women, including
hypertension, cigarette smoking, sedentary lifestyle, hypercho-
lesterolemia, diabetes, and obesity. Although some of these dif-
ferences may be genetically based, others are likely influenced
by behavioral, cultural, and psychological factors. Women of
lower SES, regardless of race, have a higher prevalence of cardio-
vascular risk factors than women of higher SES.
Racial differences exist in the management of myocardial
infarction. Black women are offered reperfusion therapy and
coronary angiography at lower rates, and in-hospital mortality
rates are higher compared with those of white women.
Patient factors and physician factors may contribute to the
observed clinical differences in CAD between men and women.
Women may delay their own care because they are caretakers.
 712 Section XI  Women’s Health
Many women are unaware of the prevalence of CAD. In a 2006
B
survey, only 55% of women identified cardiovascular disease as
the leading cause of death among women. Studies have shown
s s
s s
A
e
C-peptid
that physicians also underestimate the magnitude of cardiovascu-
lar disease in women and that they tend to place women in lower
risk categories compared with men despite equivalent risk pro-
files. Much of the evidence used to guide the treatment of coro-
nary disease in women is based on trials predominantly enrolling
men. Treatments and interventions found to benefit men might
not provide the same benefit to women.
Osteoporosis
More than 10 million Americans have osteoporosis; 8 million are
women. It is a disease that disproportionately affects women,
particularly as they age. The lifetime risk of fracture of a patient
with osteoporosis is as high as 40%. Most osteoporosis trials have
involved mostly white women, limiting generalizability to all
races and ethnicities. Racial minorities are diagnosed and treated
less often.
Human Immunodeficiency Virus Infection
Since the beginning of the HIV epidemic in the 1980s, the per-
centage of women affected has grown considerably, with women
now accounting for 25% of those living with HIV in the United
States, compared with 7% when the epidemic began. African
American women and Latinas are disproportionately affected. In
2010, the rate of new infections among black women was 20
times that of white women and almost 5 times that of Hispanic
women (38.1 versus 1.9 and 8.0 per 100,000, respectively). Mor-
tality rates are higher among racial minorities than among white
women.
Many factors affect racial disparities. Communities in which
there is a higher HIV prevalence (many African American and
Latino communities) pose a greater risk of acquisition of HIV
with every sexual encounter. Other factors include economic bar-
riers, lack of insurance, stigma, and higher levels of STIs, which
increase the likelihood of acquiring and transmitting HIV.
There are unique barriers to prevention of HIV in women.
Women may be unaware of the partner’s risk factors for HIV, such
as injection drug use, multiple partners, or unprotected sex with
men. Unprotected vaginal sex is a much higher risk for women
than for men, and unprotected anal sex is riskier than unpro-
tected vaginal sex. Women who have experienced sexual abuse
are more likely to engage in high-risk sexual behaviors, such as
exchanging sex for drugs, having multiple partners, or having sex
with a partner who is physically abusive.
Although many of the clinical manifestations of HIV infection
and acquired immunodeficiency syndrome (HIV/AIDS) in
women are similar to those in men, significant gender-based dif-
ferences exist. Women may not prioritize their own care. Women
are also disproportionately affected by poverty, IPV, unstable
housing, substance abuse, lack of transportation, lack of insur-
ance, and the necessity of finding child care, all of which pose
barriers to care.
Biologic differences also exist. Although women typically have
lower viral loads than men despite the same level of CD4 counts,
the rates of disease progression are similar. Rates of opportunistic
infections are similar for men and women. Women may have
gynecologic complaints as their initial manifestation of HIV/
AIDS, including Candida vaginitis, pelvic inflammatory disease,
abnormal Papanicolaou smear results, and STIs such as herpes
simplex virus, chancroid, and syphilis.
Risk for cervical abnormalities and cervical cancer is related to
the degree of immunosuppression, age, and co-infection with
high-risk HPV genotypes (16, 18, 52, and 58). Women with
preserved CD4 counts and negative HPV test results are at rela-
tively low risk for cervical cytologic abnormalities. Women with
HIV infection are more likely to progress more rapidly to cervical
cancer. The CDC recommends two cervical cytology screens at
6-month intervals in the first year after an HIV diagnosis. Those
with normal results and deemed low risk (i.e., no prior abnormal
Pap smear, HPV infection, or AIDS) may have the Pap smear
performed annually, with more frequent examinations performed
for those deemed high risk. Vulvar and perianal intraepithelial
neoplasias are more common in women with HIV than HIV-
seronegative women, and the lesions should be evaluated.
Antiretroviral therapy and follow-up monitoring are similar
for men and women with HIV/AIDS. Women should be coun-
seled to also use a barrier contraceptive (i.e., male or female
condom), because this has proven efficacy in reducing the trans-
mission of HIV and other STIs, although it is less effective for
pregnancy prevention.
For a deeper discussion on this topic, please see Section
XIX, “Women’s Health,” in Goldman-Cecil Medicine, 25th
Edition.
SUGGESTED READINGS
Breslau J, Kendler KS, Aguilar-Gaxiola S, et al: Lifetime prevalence and
persistence of psychiatric disorders across ethnic groups in the United States,
Psychol Med 1:35–45, 2005.
Committee on Practice Bulletins–Gynecology: Practice bulletin no. 128.
Diagnosis of abnormal uterine bleeding in reproductive-aged women, Obstet
Gynecol 120:197–206, 2012.
Department of Reproductive Health, World Health Organzation (WHO):
Medical eligibility criteria for contraceptive use, ed 4, 2010. Available at
http://www.who.int/reproductivehealth/publications/family_planning/
9789241563888/en/. Accessed July 30, 2014.
Dunlop AL, Jack BW, Bottalico JN, et al: The clinical content of preconception
care: women with chronic medical conditions, Am J Obstet Gynecol 199(Suppl
B):S310–S327, 2008.
Moyer VA, U.S. Preventive Services Task Force: Screening for intimate partner
violence and abuse of elderly and vulnerable adults: U.S. preventive services
task force recommendation statement, Ann Intern Med 158:478–486, 2013.
Nelson H: Menopause, Lancet 371:760–770, 2008.
North American Menopause Society: The 2012 hormone therapy position
statement of North American Menopause Society, Menopause 19:257–271,
2012.
Trussell J: Contraceptive technology, rev ed 19, New York, 2007, Ardent Media.
U.S. Preventive Services Task Force: Screening for family and intimate
partner violence: recommendation statement. Available at http://www
.uspreventiveservicestaskforce.org/3rduspstf/famviolence/famviolrs.htm.
Accessed July 30, 2014
Vesco KK, Whitlock EP, Eder M, et al: Risk factors and other epidemiologic
considerations for cervical cancer screening: a narrative review for the U.S.
Preventive Services Task Force, Ann Intern Med 155:698–705, 2011.
XII
ESSENTIALS

Men’s Health
71  Men’s Health Topics
David James Osborn, Douglas F. Milam, and Joseph A. Smith, Jr.

713
 71 
Men’s Health Topics
O
David James Osborn, Douglas F. Milam, and Joseph A. Smith, Jr.
  INTRODUCTION
This chapter addresses disorders that are unique to men because
they involve the male genitalia and reproductive system. It
A. Androgen Deficiency in Adult Men
  DEFINITION AND EPIDEMIOLOGY
Several clinical guidelines address the syndrome of symptomatic
low testosterone levels in men. The two most referenced are from
the Endocrine Society and from a collaboration of five societies,
including the International Society for the Study of the Aging
Male (ISSAM), International Society of Andrology (ISA), Euro-
pean Association of Urology (EAU), European Academy of
Andrology (EAA), and American Society of Andrology (ASA).
One guideline uses the term “androgen deficiency in adult men”
and the other uses the term “late-onset hypogonadism” to refer
to a disease process characterized by low serum testosterone
levels and clinical symptoms.
The syndrome of androgen deficiency in adult men (late-onset
hypogonadism) can be defined as a low level of serum testoster-
one (total or free) combined with three symptoms of low testos-
terone such as erectile dysfunction (ED), decreased libido, and
lethargy or sleep disturbance. Using this general definition, the
incidence of androgen deficiency ranges from 2.1% to 6% in the
literature. On the other hand, the incidence of low serum testos-
terone (so-called low T) in men older than 40 years of age is
much higher, between 17% and 38.7% in multiple studies. The
clinical guidelines require only one symptom for the diagnosis of
androgen deficiency, so the true incidence of androgen defi-
ciency is probably closer to that of low T.
Over the last 10 years, there has been increased coverage of
low T in the mainstream press and media. In addition, clinics
specializing in testosterone replacement have proliferated. As a
result, androgen use among men has increased threefold, from
0.8% in 2001 to 2.91% in 2011. This increase in the prescribing
of testosterone is probably the result of both a heightened aware-
ness about the problem and overutilization in men who have
been improperly diagnosed. The diagnosis and treatment of
androgen deficiency is challenging and full of potential pitfalls.
Therefore, it is imperative for physicians to have a thorough
understanding of this disease process, particularly in these times
when information in the media and on the Internet creates an
eager and motivated patient population.
714
incorporates commonly encountered and clinically important
aspects of voiding, oncology, reproductive function, and
endocrinology.
  PATHOPHYSIOLOGY
Normal aging sometimes results in malfunctions of the
hypothalamic-pituitary-gonadal axis that lead to decreased
serum testosterone levels. One of these errors is termed primary
hypogonadism (testicular failure). In this disease process, the
testicles produce an inadequate amount of testosterone (and
sperm) even though there is adequate stimulation from the
anterior pituitary gland in the form of elevated or normal
release of luteinizing hormone (LH). Low serum testosterone
also can result from failure of the pituitary gland to secrete
an adequate amount of LH. When this occurs, the Leydig
cells of the testicle that produce testosterone are not adequately
stimulated and hence do not make a normal amount of tes-
tosterone. This form of testosterone deficiency is termed sec-
ondary hypogonadism. It can result from disease processes such
as pituitary tumors, hemochromatosis, and obstructive sleep
apnea.
Measurements of total testosterone (TT) include the con-
centrations of both unbound (free) and bound testosterone in
the serum. Only 2% of testosterone is unbound; the other
98% is bound to proteins such as albumin or sex hormone
binding globulin (SHBG). Because it is not bound to another
substance, free testosterone (FT) is the more biochemically
active form of testosterone. If a man has a low normal TT
level but a low FT level and has clinical manifestations of this
hormone deficiency, he is considered to have androgen defi-
ciency syndrome.
Increased levels of SHBG in the serum can decrease the level
of FT. The level of SHBG increases with smoking, coffee con-
sumption, age, and disease processes such as hepatitis and hyper-
thyroidism. Therefore, increased levels of SHBG can contribute
to androgen deficiency. Obesity decreases levels of SHBG, but it
can cause androgen deficiency through the peripheral conversion
of testosterone into estrogen in adipose cells. Conditions such as
extreme exercise, recreational drug use, nutritional deficiency,
stress, use of certain medications, and acute illness can transiently
lower serum testosterone.
 Chapter 71  Men’s Health Topics 715

was a 25% reduction in TT levels in healthy men 60 minutes after

  CLINICAL PRESENTATION an oral glucose tolerance test. Strength training also transiently
Low testosterone levels can affect a patient’s general, sexual, decreases serum testosterone levels in healthy men (but typically O

physical, and psychological health. In Table 71-1, these symp-
toms are grouped according to their specific relation to androgen
deficiency. Various studies have categorized and used the symp-
toms of androgen deficiency in different ways. For example, one
clinical trial looking at the incidence of androgen deficiency
defined the syndrome as the presence of 3 of 12 clinical symp-
toms combined with a low serum FT or TT level, whereas, in a
similar trial, patients were considered to be androgen deficient if
they had a low testosterone and exhibited three specific sexual
symptoms. The guidelines simply state that clinicians should use
the different symptoms as means to decide whether to check a
patient’s serum testosterone level. According to the guidelines, a
patient with treatable androgen deficiency must have at least one
symptom. The symptom most closely associated with androgen
deficiency is decreased libido.
  DIAGNOSIS
For several reasons, the diagnosis of androgen deficiency is not
straightforward. By the very simplest of definitions, it requires a
low serum testosterone level in conjunction with at least one
clinical symptom. Most clinical guidelines suggest measuring a
TT in any adult man who has symptoms associated with andro-
gen deficiency. In general, recognizing that laboratory standards
may differ, if the TT level is greater than 350 ng/dL (12.1 nmol/L),
the patient does not have androgen deficiency; if the TT is lower
than 200 ng/dL (6.9 nmol/L), then a symptomatic patient is
considered to have androgen deficiency. If the TT level falls
between those two values, FT should be assessed, and low values
(typically 5 to 9 ng/dL) indicate androgen deficiency. FT tests
are not recommended initially because of their greater cost. In
addition, screening of asymptomatic men for low testosterone is
not medically necessary.
In men with borderline testosterone levels, repeat measure-
ment of a morning testosterone level is warranted because there
is significant day-to-day variability and testosterone levels vary on
a circadian rhythm. Ideally, levels should be checked within 4
hours of waking (usually between 7 and 11 a.m.), when testos-
terone levels are highest. It is not necessary to fast before a tes-
tosterone laboratory test; however, in a study from 2013, there
not outside the normal range).
Testosterone levels should not be checked during acute or
subacute illness. However, physicians should have a lower thresh-
old to check the testosterone level in patients with chronic ill-
nesses that are known to cause a symptomatically lower
testosterone concentration, such as diabetes mellitus, chronic
obstructive lung disease, inflammatory arthritic disease, renal
disease, human immunodeficiency virus (HIV)-related disease,
obesity, metabolic syndrome, and hemochromatosis. In fact, one
guideline states that all patients who have a pituitary mass, HIV-
associated weight loss, or a low-trauma fracture should have their
testosterone level checked regardless of symptoms.
In addition, one guideline recommends checking LH levels to
rule out secondary hypogonadism in all patients, whereas another
recommends that LH and prolactin should be measured only in
patients with TT lower than 150 ng/dL (5.2 nmol/L). In patients
with disease processes (e.g., obesity, hepatitis and hyperthyroid-
ism) that are known to alter the level of SHBG, it may be prudent
to initially check FT rather than TT.
Men being considered for testosterone replacement should
have their prostate-specific antigen (PSA) level measured and a
digital rectal examination (DRE) performed to assess the pros-
tate. If either is abnormal, referral to an urologist should be con-
sidered. Table 71-2 provides helpful guidelines for evaluating
possible androgen deficiency.
  TREATMENT
Testosterone therapy is recommended for men with androgen
deficiency, and the goal of therapy should be to maintain second-
ary sex characteristics and improve sexual function, sense of well-
being, and bone mineral density. In addition, metabolic and
cardiovascular benefits are suggested by available data. Before
starting treatment, clinicians should obtain baseline hematocrit
and PSA levels.
There are at least nine different types of testosterone replace-
ment formulations. In the United States, the most commonly
used forms are testosterone enanthate or cypionate by intramus-
cular (IM) injection, transdermal testosterone patches, testoster-
one gels, and implantable timed-release pellets. Because of the

TABLE 71-1  SIGNS AND SYMPTOMS OF ANDROGEN
DEFICIENCY
SPECIFIC SIGNS AND
SYMPTOMS
Reduced sexual desire (libido) and
activity
Decreased spontaneous erections
Breast discomfort, gynecomastia
Less axillary and pubic hair and less
shaving
Very small or shrinking testes
Infertility and low sperm count
Height loss and low bone mineral
density
Hot flashes and sweats
LESS SPECIFIC SIGNS AND
SYMPTOMS
Decreased energy and self-
confidence
Feeling sad, depressed mood
Poor concentration and memory
Sleep disturbance and sleepiness
Mild anemia (normochromic,
normocytic)
Reduced muscle bulk and strength
Increased body fat and body mass
index
Diminished physical or work
performance
LH, Luteinizing hormone; PSA, prostate-specific antigen.
TABLE 71-2  ANDROGEN DEFICIENCY DIAGNOSIS
DO’S AND DON’TS
Do check total testosterone (TT) in every symptomatic adult male >40 yr
Do confirm borderline tests with a repeat measurement
Do check in the morning
Do have a lower threshold to check testosterone in patients with certain
chronic illnesses
Do consider measuring prolactin and LH level in patients with very low
testosterone
Do consider checking hematocrit and PSA levels with the testosterone level
to decrease blood draws
Don’t check the testosterone level during acute or subacute illness
Don’t start with measurement of free testosterone in most cases ($$$)
Don’t monitor testosterone treatment with measurements of free
testosterone ($$$)
Don’t consider testosterone replacement in a patient trying to father a child
 716 Section XII  Men’s Health
frequency of significant skin irritation with the testosterone
patch, many practitioners prefer one of the other modes, usually
O
based on patient preference. For dosage and administration of gel
testosterone formulations, the clinician should refer to the
package insert. For IM testosterone, a good starting dosage is
100 mg every 2 weeks. Pellet implantation is an office procedure,
but adequate testosterone levels are typically maintained for 3 to
4 months.
Side Effects of Testosterone Therapy
Testosterone therapy causes decreased sperm production and
usually decreased testicular volume, and it may cause acne, oily
skin, and breast tenderness. In addition, testosterone can increase
hematocrit and cause life-threatening erythrocytosis. If the
hematocrit becomes elevated, then testosterone replacement
should be suspended. Occasionally, a patient requires phlebot-
omy to avoid or treat dangerous erythrocytosis. Testosterone
replacement is not a treatment for infertility and has in fact been
investigated as method of male contraception. Patients who are
interested in fathering children should not take testosterone. If
necessary, human chorionic gonadotropin (HCG) may be
administered for men wishing to preserve fertility.
Only oral testosterone has negative affects on the liver, so it
is not necessary to monitor liver function during treatment.
Testosterone therapy may worsen obstructive sleep apnea and
congestive heart failure; therefore, patients in whom these condi-
tions are untreated should not be started on testosterone therapy.
Present data suggest that testosterone therapy does not worsen
levels of high-density lipoproteins. Patients should be aware that
testosterone therapy suppresses endogenous testosterone and
sperm production. Depending on the duration of treatment, it
B. Erectile Dysfunction
ED is defined as the inability to maintain an erection for sat-
isfactory sexual function in the absence of premature ejaculation.
Premature ejaculation is not technically a form of ED. Impo-
tence is the most common cause of ED in the United States
and is defined by an inability to attain or maintain adequate
penile rigidity sufficient for intercourse. Other important,
although less common, causes of ED are Peyronie’s disease
and trauma.
ED affects millions of American men. According to the Mas-
sachusetts Male Aging Study, 52% of men older than 40 years of
age are afflicted with some form of impotence. The prevalence of
impotence triples between age 40 and 70 years. By age 70 years,
15% of men experience complete ED. Age and physical health are
the most important predictors of the onset of ED. Smoking is the
most important lifestyle variable.
Recently, many clinics that specifically treat ED and premature
ejaculation have opened across America to meet a growing need
for treatment of these conditions. However, these clinics often
charge money for treatments and medications that primary care
physicians can provide and are covered by insurance. Therefore,
it is more important than ever for primary care physicians to have
a thorough understanding of this disease process.
may take 1 to 2 months or longer after treatment discontinua-
tion for testosterone and sperm production to return to baseline
levels.
Testosterone Therapy and the Prostate
In general, testosterone therapy should be avoided in patients
with a history of prostate or breast cancer. However, this is a
controversial issue. Some urologists may decide that replacement
is acceptable under specific circumstances because there are data
to suggest that testosterone replacement may not pose an undue
risk of prostate cancer recurrence or progression. In addition,
there is no conclusive evidence that testosterone replacement has
any effect on benign prostatic hypertrophy (BPH).
Monitoring Testosterone Treatment
TT should be measured 5 to 12 weeks after initiation of testoster-
one treatment. If IM testosterone is being administered every 2
weeks, morning TT levels should be checked 1 week after an
injection. If a testosterone gel is used, morning TT should be
checked at least 1 month after initiation of treatment. Hematocrit
values should be assessed at 3 months and 6 months and then
annually. If the hematocrit level is greater then 54%, the treat-
ment should be stopped. If testosterone therapy was started to
help with osteoporosis or osteopenia, a bone mineral density test
should be done after 1 to 2 years. If there is an abnormality in the
PSA level or it increases by 0.75 ng/mL in 1 year, referral to a
urologist should be considered. If the TT level is low, the clinician
should increase the dosage and reassess after 5 to 12 weeks. The
goal of therapy should be a level between 400 and 600 ng/dL.
Finally, therapy should be discontinued if the patient does not
have clinical improvement.
  MECHANISM OF ERECTION
Psychogenic or tactile sexual stimulation is usually the initial step
in the pathway leading to penile erection. Nerve signals are
carried through the pelvic plexus into the cavernous nerves of the
penis. The pelvic plexus receives input from both the sympathetic
and the parasympathetic nervous system. Sympathetic fibers
originate in the thoracolumbar spinal cord, and parasympathetic
fibers originate in the second through fourth sacral spinal cord
segments (S2 through S4). Afferent somatic sensory signals are
carried from the penis through the pudendal nerve to S2 through
S4. This information is routed both to the brain and to spinal cord
autonomic centers. Adrenergic innervation appears to play a role
in the process of detumescence. High concentrations of norepi-
nephrine have been demonstrated in the tissue of the corpora
cavernosa and tributary arterioles. Afferent signals capable of ini-
tiating erection can originate within the brain, as with psycho-
genic stimulation, or they can result from tactile stimulation.
There is no discreet center for psychogenic erections; however,
the temporal lobe appears to be important.
Sexual stimulation causes the release of nitric oxide (NO)
by the cavernous nerves into the neuromuscular junction
 Chapter 71  Men’s Health Topics 717

(Fig. 71-1). NO activates guanylyl cyclase, which converts gua- the corpora cavernosa. Cardiovascular disease may decrease erec-
nosine triphosphate (GTP) into cyclic guanosine monophos- tile ability by decreasing blood flow to the penile arteries, by
phate (cGMP). Protein kinase G is activated by cGMP and in mechanical obstruction of the vascular lumen, or, more com- O

turn activates several proteins that decrease the intracellular con- monly, by endothelial dysfunction. Endothelial dysfunction is
centration of calcium ions (Ca2+). Decreased Ca2+ concentration the most common cause of ED. It results from interruption of the
in the smooth muscle causes muscular relaxation, cavernosal neural control mechanism of vascular smooth muscle function
artery dilation, increased blood flow, and subsequent penile erec- and leads to decreased blood flow and pressure in the corpora
tion. The control of blood flow on the venous outflow side is less cavernosa.
well understood. The principal blood vessels supplying the corpora cavernosa
are the cavernosal arteries, which are terminal branches of the
  CAUSES OF ERECTILE DYSFUNCTION internal pudendal artery. Diseases of large and small arteries may
Psychogenic ED was once thought to be the most common type decrease corporal blood pressure and lead to decreased penile
of ED. However, advances in understanding of the mechanics and lengthening and rigidity. Veno-occlusive disease in the penis is
neurophysiology of erectile function have identified other more also a significant cause of ED. These patients often experience
common causes. Psychogenic ED is now thought to account for normal initial rigidity, but quickly lose their erection before ejac-
fewer than 15% of patients seen by ED specialists. The anatomic ulation occurs.
site now believed to be the most common cause of ED is the
neuromuscular junction. This is the place where the cavernosal Neurogenic Erectile Dysfunction
nerves meet the smooth muscle and endothelium of the deep Because the nervous system plays an integral part in the physiol-
cavernous penile arteries. The decreased release of NO by caver- ogy of an erection, any disease process that affects the brain, the
nosal nerves and the impaired response by smooth muscle cells spinal cord, or the peripheral nerves can cause ED. For example,
that occurs at the neuromuscular junction is termed endothelial dementia, Parkinson’s disease, and stroke are diseases of the brain
dysfunction. Other common causes of ED include certain endo- associated with ED. Patients with spinal cord injury commonly
crine disorders, vascular diseases, central and peripheral nerve have ED. Because of an intact reflex pathway, most patients with
disorders, and medications. spinal cord injury respond to tactile sensation, but they usually
require medical therapy to maintain the erection through inter-
Cardiovascular Disease course. Iatrogenic injury to nerves during surgery (e.g., prostatec-
In the United States, atherosclerotic vascular disease, hyperlipid- tomy, rectal surgery) is also a common cause of neurogenic ED.
emia, smoking, and hypertension are frequent causes of ED. Neurogenic ED due to decreases in penile tactile sensation can
These relationships are expected because erection is achieved by occur with increasing age.
a combination of relaxation of arteriolar smooth muscle and
increased venous resistance of channels penetrating the wall of Endocrine Disorders
Testosterone plays a permissive role in erectile function, and
many endocrine disorders can directly or indirectly decrease
PDE5 Protein kinase G plasma free or bound testosterone. However, androgen defi-
ciency is an uncommon primary cause of ED because erectile
ATP ability is only partially androgen dependent. Patients with andro-
5'-GMP GTP cGMP gen deficiency typically have decreased or absent libido in addi-
Proteins Protein P
tion to loss of erectile rigidity. Androgen replacement may induce
return of erectile function in patients with very low or undetect-
Guanylyl cyclase able serum testosterone concentrations. More commonly,
Decreased
smooth however, the impotent patient has normal or mildly decreased
muscle Ca++ levels of circulating androgens. Testosterone replacement rarely
NO restores erectile function in men with mildly decreased serum
testosterone. Testosterone supplementation is never indicated
for patients with normal circulating androgen levels.
Cavernosal The most common endocrine disorder affecting erectile ability
artery smooth
muscle is diabetes mellitus. In addition to causing atherosclerotic and
Cavernosal relaxation microvascular disease, diabetes affects both the autonomic and
nerve the somatic nervous system, including loss of function of long
autonomic nerves. The loss of long cholinergic neurons results
Sexual Penile in interruption of the efferent side of the erectile reflex arc.
stimulation erection
Diabetes also appears to produce dysfunction of the neuro-
FIGURE 71-1  Sexual stimulation causes the release of nitric oxide muscular junction at the level of arterial smooth muscle
(NO) by the cavernous nerve into the neuromuscular junction. ATP, in the penile corpora cavernosa. Studies have indicated mark-
Adenosine triphosphate; cGMP, cyclic guanosine monophosphate; edly decreased acetylcholine and NO concentrations in the
GMP, guanosine monophosphate; GTP, guanosine triphosphate; PDE5, trabeculae of the corpora cavernosa in diabetic patients. These
phosphodiesterase type 5.
findings probably represent a combination of neural loss and
 718 Section XII  Men’s Health
neuromuscular junction dysfunction. Other endocrine disorders,
such as hypothyroidism, hyperthyroidism, and adrenal dysfunc-
O
tion, can also cause ED. Because of the uncommon occurrence
of thyroid and adrenal disorders in patients presenting for
treatment of ED, testing of those axes is not a part of the
routine work-up of ED.
Medication-Induced Erectile Dysfunction
Many commonly prescribed medications can cause or contribute
to decreased erectile function. Table 71-3 lists the major classes
of medications implicated in ED and suggests how commonly
these medications interfere with erectile function. Changing
medications may restore erectile function in some patients.
However, proceeding directly to treatment of ED is usually the
preferred option in all but the most straightforward cases.
Medical and Surgical Therapies
Since the introduction of sildenafil in 1998, the Process of Care
Model for the evaluation and treatment of ED has been adopted.
It targets the primary care provider as the initial source of care
for patients with ED. Currently available therapies for ED include
oral phosphodiesterase type 5 (PDE5) inhibitors, intraurethral
alprostadil, intracavernous vasoactive injection therapy, vacuum
constriction devices, and penile prosthesis implantation. A
stepwise treatment approach starting with oral agents and pro-
gressing to more invasive therapeutic interventions should be
used (Fig. 71-2). Informed patient decision making is critical to
successful progression through the Process of Care pathway.
Patient referral is primarily based on the need or desire for spe-
cialized diagnostic testing and management.
Oral Phosphodiesterase Type 5 Inhibitors
Current medical therapy is based on inhibition of PDE5, which
degrades cGMP to inactive 5′-GMP, as shown in Figure 71-1.
Sildenafil, vardenafil, avanafil, and tadalafil competitively inhibit
PDE5 breakdown of cGMP. Use of a PDE5 inhibitor results in
improved erectile rigidity even in patients with decreased NO or
cGMP synthesis. However, not all patients respond to PDE5
inhibition. Adequate sexual stimulation and intact neural and
TABLE 71-3  FREQUENCY OF DECREASED ERECTILE
RIGIDITY AND EJACULATORY
DYSFUNCTION BY MEDICATION CLASS
DECREASED
MEDICATION CLASS ERECTILE RIGIDITY
β-Adrenergic Common
antagonists
Sympatholytics Expected
α1-Agonists Uncommon
α2-Agonists Common
α1-Antagonists Uncommon
Angiotensin-converting Uncommon
enzyme inhibitors
Diuretics Less common
Antidepressants Common†
Antipsychotics Common
Anticholinergics Less common
*Patients are able to ejaculate, but retrograde ejaculation is seen in 5% to 30%.
†
Uncommon with serotonin reuptake inhibitors.
‡
Delayed or inhibited ejaculation with serotonin reuptake inhibitors.
vascular pathways are necessary to produce an adequate amount
of NO and cGMP to increase deep penile artery blood flow.
PDE5 inhibitors are effective in men with organic, psychogenic,
neurogenic, and mixed cases of ED. The overall response rate to
PDE5 inhibitors is 70%.
Unless contraindicated, PDE5 inhibition should be consid-
ered first-line therapy for most men. The combination of PDE5
inhibitors and α-adrenergic receptor blockers can result in tran-
sient hypotension. This interaction is complex and depends on
the specific medication in each category. In general, it is safe to
use selective α-blockers such as tamsulosin and alfluzosin with
any PDE5 inhibitor. However, PDE5 inhibitors should not be
used concurrently with nitrate medications because a large
(>25 mm Hg) synergistic drop in blood pressure occurs in many
patients. Periodic follow-up is necessary to determine therapeu-
tic efficacy, side effects related to PDE5 inhibition, and changes
in health status. Overall, 30% of men do not respond to this class
of medication.
Alprostadil Intraurethral Drug Therapy
In PDE5 inhibition is not successful, an acceptable second-line
medical treatment is intraurethral administration of prostaglan-
din E1 (alprostadil [Muse]), which can be inserted into the
urethra with the use of a pellet applicator. This method of deliv-
ery assumes substantial venous communications between the
corpus spongiosum surrounding the urethra and the corpus cav-
ernosum, and it is effective in many patients who fail oral PDE5
inhibitor medications. It is not as effective as intracavernous
injection (described later). Some patients experience difficulty
initiating this type of treatment, so it may be beneficial to admin-
ister the first dose in an office setting. To lubricate the urethra,
patients should void before insertion of the pellet.
Up to one third of patients have normal, transient burning
penile pain, and this should be discussed with the patient before
treatment. Dizziness and presyncope are uncommon complica-
tions. This medication has rapid onset and minimal risk of pria-
pism. It can be used with increased efficacy in combination with
PDE5 inhibitors. Transient burning pain in the sexual partner can
occur and is caused by leakage of the medication from the urethra
into the vagina. This can be managed by wearing a condom.
Impotence
EJACULATORY
DYSFUNCTION
Phosphodiesterase inhibition
Less common
Common
Uncommon
Less common Injection therapy Vacuum device
Less common*
Uncommon
Uncommon
Uncommon‡ Venous surgery Penile implant
Common
Uncommon
FIGURE 71-2  A logical treatment algorithm for impotence.

Intracavernosal Injection Therapy
Pharmacologic injection therapy involves the injection of vasodi-
lator agents into the corpora cavernosa to produce erection by
dilating the corporal artery smooth muscle. More than 90% of
patients with ED respond to this type of therapy. Commonly
used agents include alprostadil, papaverine, and phentolamine
(Regitine). These medications can be used alone or in combina-
tion. As monotherapy, alprostadil is most commonly used. Of the
three, only alprostadil has been evaluated in rigorous clinical
trials and has specific marketing approval from the U.S. Food and
Drug Administration for the treatment of ED. Phentolamine is
used to potentiate the action of papaverine and can be used in
combination with both alprostadil and papaverine. These vasoac-
tive drugs can be formulated with different combinations of
medications and concentrations to achieve increased efficacy and
decreased side effects. Bimix and trimix are terms used to refer
to a combination of two or three of these medications,
respectively.
The common side effects of this type of treatment are bruising
and penile pain (50%). Penile pain is more common in young
patients and is usually worse with alprostadil. Therefore, a com-
bination using lower-dose alprostadil or just papaverine and
phentolamine might be beneficial in younger patients. Other,
more serious risks of injection therapy include priapism and cor-
poral scarring (Peyronie’s disease). Priapism has been reported
to occur in 1% to 4% of patients. Prolonged erections occur more
commonly in patients with neurogenic ED, especially young men
with spinal cord injury. Significant acquired penile curvature
(Peyronie’s disease) is seen uncommonly and usually follows
several years of injection therapy. Penile curvature appears to be
less common with use of alprostadil than with papaverine. The
most common problem with pharmacologic injection therapy is
not complications from therapy but rather the fact that 50% to
60% of patients stop using the technique within 1 year.
As with intraurethral alprostadil, initial treatment should be
performed under the supervision of a physician. The medication
can be injected using a self-contained medication-syringe kit or
a 29-gauge (5/8-inch) insulin syringe with medication drawn
from a refrigerated vial. It is advisable to start with a small test
dose and slowly titrate the dosage for desired affect over several
weeks. The patient should not use the medication more than
C. Benign Prostatic Hyperplasia
BPH, a nonmalignant enlargement of the prostate gland, is a
common condition in the aging male patient. It is estimated that
more than 90% of all men will develop histologic evidence of
BPH during the course of their lifetime; of those, at least 50%
will develop lower urinary tract symptoms (LUTS) that prompt
them to seek medical care. Broadly speaking, LUTS can be
divided into two groups: obstructive voiding symptoms and
overactive bladder symptoms (Table 71-4).
Although most patients who seek medical care for BPH do so
because of the associated LUTS, these same symptoms
can also result from other illnesses such as diabetes mellitus,
spine disease, Parkinson’s disease, multiple sclerosis, and
Chapter 71  Men’s Health Topics 719
once in 24 hours and should be instructed to seek medical care
promptly for prolonged painful erections lasting longer than 4
hours. Typically, administration of the test dose should be carried O
out in the morning, and the patient should be expected to stay in
close proximity to the medical office to monitor for priapism. If
a patient experiences priapism after a test dose, he should seek
prompt medical attention within 4 hours of injection. Priapism
usually resolve without sequelae after intracavernosal injection of
0.5 to 1 mL of a 250 µg/mL solution (0.5 mg diluted in 2 mL of
normal saline) of phenylephrine in a setting where blood pres-
sure and heart rate are monitored. Formal guidelines for the treat-
ment of priapism are available on the website of the American
Urologic Association (AUA).
Vacuum Constriction Devices
Vacuum constriction devices enclose the penis in a plastic tube
with an airtight seal at the penile base. Air is pumped out of the
cylinder, creating a vacuum. Blood flows into the corporal bodies,
leading to penile erection. A constriction band slid from the cyl-
inder to the base of the penis maintains the erection. Simultane-
ous use of a vacuum device and a PDE5 inhibitor is safe and may
improve outcomes. Some of the common side effects that affect
patient satisfaction with these devices are coldness, numbness,
and bruising of the penis.
Penile Prosthesis
A penile prosthesis, either semirigid or inflatable, is implanted in
the operating room. Most patients prefer the inflatable devices
because they provide a more natural erection when inflated and
a flaccid penis when deflated. Although implantation of a penile
prosthesis is more invasive than the other techniques, this device
is the most effective long-term option for impotence treatment.
Ninety percent of patients and partners are satisfied with the
result.
Important interval improvements have been made in the
design of implantable penile prostheses to make them more
durable and resistant to infection. Improvements in the connec-
tion between tubing and corporal cylinders have cut the mechan-
ical failure rate to less than 5% in 5 years. Components also have
special coatings that either contain antibiotics or absorb antibiot-
ics applied topically at the time of implantation. These improve-
ments have cut the rate of postoperative infection in half.
cerebrovascular disease (Fig. 71-3). It is important to evaluate all
patients for these non–BPH-related conditions to ensure optimal
management. It is also important to pay close attention to medi-
cation use because a number of medications used in the elderly
population can result in various urologic symptoms, including
both obstructive and overactive bladder voiding symptoms.
  PATHOPHYSIOLOGY
Prostate growth and the subsequent development of BPH occur
under the influence of testosterone and the more metabolically
active dihydrotestosterone (DHT). Testosterone produced by
the testes is converted to DHT by the action of the enzyme
 720 Section XII  Men’s Health

5α-reductase. DHT is the major intracellular androgen and is characterized, is the response of the bladder muscle to the
believed to be responsible for the development and maintenance increase in outlet resistance provided by those two mechanisms.
O

of the hyperplastic cell growth characteristics of BPH. As bladder outlet resistance increases, the bladder responds by
BPH develops predominantly in the periurethral prostatic increasing the force of contraction. This added work results in
tissue, referred to as the transition zone (Fig. 71-4). Tissue growth physical and mechanical changes in bladder function.
in this area leads to the phenomenon of bladder outlet obstruc- Early in the course of BOO, the bladder is able to compensate;
tion (BOO), which leads to LUTS. BOO occurs as a result of two however, with persistent obstruction, the patient typically devel-
mechanisms: mechanical obstruction from increased tissue ops LUTS, particularly overactive bladder symptoms such as
volume in the periurethral zone of the prostate and dynamic nocturia, frequency, and urgency. These symptoms frequently
obstruction, which is caused by decreased bladder neck relax- drive patients to seek medical care. Later during the course of the
ation during voiding and increased smooth muscle tone in the obstructive process, the bladder wall becomes thickened and
bladder neck and prostate gland. Also important, but less well loses compliance. The subsequent loss of compliance results in a
decreased functional capacity of the bladder, which exacerbates
the patient’s overactive bladder symptoms.
TABLE 71-4  SYMPTOMS OF LOWER URINARY TRACT
SYNDROME   DIAGNOSIS
OVERACTIVE BLADDER OBSTRUCTIVE VOIDING The initial evaluation of a patient with LUTS suggestive of BPH
Frequency Hesitancy should include a detailed medical history that focuses on the
Nocturia Slow stream patient’s urinary symptoms as well as the past medical history,
Urgency Stop-and-start voiding including comorbid conditions and any previous surgical proce-
Urge incontinence Sensation of incomplete emptying
dures, general health conditions, and history of alcohol and
tobacco use. The assessment of symptoms can be facilitated with
Neurologic the use of the AUA Symptom Index (also known as the Interna-
disease tional Prostate Symptom Score, or IPSS). This is a self-administered,
(e.g., multiple sclerosis)
validated questionnaire consisting of seven questions related to
the symptoms of BPH and BOO. The AUA Symptom Index clas-
BPH Excessive sifies symptoms as mild (0 to 7), moderate (8 to 19), or severe
fluid intake
(20 to 35). Validated instruments such as the AUA Symptom
Index are useful during the initial evaluation as an overall assess-
Lower
Urinary ment of symptom severity and during follow-up visits to assess
Medications
Tract the effectiveness of any medical or surgical interventions.
Symptoms A general physical examination should be performed that
Systemic includes a DRE and a focused neurologic examination. Urinaly-
Bladder disease
cancer (e.g., diabetes sis, either by dipstick or by microscopic examination of urine
mellitus) sediment, is also mandatory to rule out hematuria and evidence
of urinary tract infection. Glycosuria can be a significant finding,
Prostate cancer
particularly if not previously identified. The initial clinical prac-
FIGURE 71-3  Causes of lower urinary tract symptoms (LUTS). BPH, tice guidelines for the diagnosis of BPH recommended a serum
Benign prostatic hyperplasia. creatinine measurement to assess renal function in all patients

Transition zone
Urethra
Anterior fibromuscular area

Urethral muscle

Urethra
Ejaculatory ducts

Central zone

Peripheral zone

FIGURE 71-4  Zonal anatomy of the prostate gland.


with signs or symptoms suggestive of BPH. However, this recom-
mendation came under scrutiny because of its low yield for the
detection of renal insufficiency secondary to obstructive uropa-
thy. Serum creatinine measurement is no longer a routine part of
the BPH work-up. According to the same clinical practice guide-
lines, PSA measurement is optional during the initial evaluation.
PSA can function as a surrogate for prostate volume measure-
ment in addition to being a screening test for prostate cancer. The
Medical Therapy of Prostatic Symptoms (MTOPS) study, spon-
sored by the National Institutes of Health, demonstrated that
PSA increases linearly with prostate volume and that a PSA level
greater than 4 ng/mL conveys a 9% risk of requiring surgical
therapy for benign disease over a 4.5-year period.
The following additional diagnostic tests are also considered
optional; however, they may be useful, particularly in patients
with moderate to severe AUA symptom scores, in determining
whether the patient’s symptoms are compatible with obstruction
from BPH. Uroflowmetry is a noninvasive method of measuring
urinary flow rate. The maximal urinary flow rate, Qmax, is consid-
ered the most useful measurement for identifying patients with
BOO. However, patients with diminished flow rates may also
have impaired bladder contraction. Typical values range from
25 mL/second in a young man without BOO to 10 mL/second
or slower in a man with significant BOO. Of note, patients with
a flow rate of less than 15 mL/second have better outcomes after
transurethral resection of the prostate (TURP, discussed later).
Measurement of postvoid residual (PVR) urine may be accom-
plished by urethral catheterization or, preferably, by ultrasonog-
raphy. Elevated PVR volumes indicate an increased risk for acute
urinary retention and eventual need for surgical intervention.
The MTOPS study demonstrated that 7% of men with PVR
greater than 39 mL required surgical intervention over a 4.5-year
period. Elevation of PVR to greater than 200 mL raises the ques-
tion of functional impairment of the bladder and warrants further
evaluation with urodynamic testing.
Routine evaluation of the upper urinary tracts (kidneys and
ureters) with excretory urography or ultrasonography is not rec-
ommended for the average BPH patient unless there is concomi-
tant urinary pathology (i.e., hematuria, urinary tract infection,
renal insufficiency, a history of prior urologic surgery, or a his­
tory of nephrolithiasis). Likewise, transrectal ultrasonography
(TRUS) is not routinely recommended unless it is used for pre-
operative assessment of prostate gland size while planning surgi-
cal intervention.
  DIFFERENTIAL DIAGNOSIS
Many conditions can cause LUTS in the aging male. A DRE and
PSA testing are helpful in distinguishing between BPH and pros-
tate cancer. Early-stage prostate cancer is typically asymptomatic,
and patients can have both conditions concurrently. Although
PSA testing is not sufficiently sensitive or specific to reliably dif-
ferentiate BPH from prostate cancer, it is a useful tool to stratify
a patient’s risk for the presence of prostate cancer.
In response to ongoing controversy about PSA screening, the
AUA released a new guideline in 2013 pertaining to the early
detection (screening) of prostate cancer. According to this guide-
line, the purpose of early detection is to decrease prostate cancer
mortality. Overall, the guideline recommends against routine
Chapter 71  Men’s Health Topics 721
prostate cancer screening (PSA and DRE) in men younger than
55 years of age. However, prostate cancer screening should be
considered between the ages of 40 and 55 years in men who have O
higher risk of prostate cancer (i.e., family history or African
American race). For men ages 55 to 69 years, the guideline rec-
ommends an individualized approach with discussion about the
benefits of prostate cancer screening versus the known risks of
screening and treatment. The guideline did not recommend
screening in any man older than 70 years of age or in any man
with less than 10 to 15 years of life expectancy.
Both the DRE and serum PSA determination have a role in the
early diagnosis of prostate cancer. Prostate cancer typically arises
from the peripheral portion of the prostate, which can be pal-
pated on DRE. Induration or nodularity of the prostate on DRE
should be considered suspicious for prostate cancer. PSA is a
protein produced by both benign and malignant prostate cells.
Serum PSA levels may be elevated in the face of prostate enlarge-
ment, inflammation, or cancer. Although an elevated PSA level is
not diagnostic of prostate cancer, it can lead to a prostate biopsy
to exclude cancer. Probably because of progressive enlargement
in prostate size, serum PSA values increase as men age. The his-
torical view that a PSA value lower than 4 ng/mL is “normal” has
been abandoned since the recognition that PSA represents a con-
tinuum of risk based on age with no lower threshold. The com-
parative rate of change for PSA over time, sometimes termed PSA
velocity, can be informative. In general, a change in PSA of more
than 0.75 ng/mL is considered worrisome and may prompt a
prostate biopsy.
Prostatitis is another condition that can cause LUTS. It may
result from bacterial infection or from a nonbacterial inflamma-
tory process, and the symptoms may substantially overlap those
of BPH, particularly in older men. Diabetes mellitus, neurologic
diseases such as Parkinson’s disease or cerebrovascular disease,
and other conditions of the urinary tract, such as urethral stric-
tures, may result in LUTS in patients with BPH. Finally, many
medications, particularly those with significant anticholinergic
side effects, can cause symptoms mimicking those associated
with BPH.
  MEDICAL MANAGEMENT
Medical management is the preferred first-line treatment option
for patients diagnosed with LUTS due to BPH. Most cases can
be managed effectively with a minimum of side effects. The
MTOPS study demonstrated that combination therapy with a
long-acting α-blocker and a 5α-reductase inhibitor was more
effective than single-agent therapy alone. In general, medical
management is initiated for patients with moderate to severe
AUA symptom scores. However, in the absence of indications for
surgery (refractory urinary retention, hydronephrosis with or
without renal impairment, recurrent urinary tract infections,
recurrent gross hematuria, or bladder calculi), the decision to
embark on any course of therapy, medical or otherwise, is prin-
cipally driven by the bothersomeness of the patient’s symptoms.
Every patient has a different perception of his symptoms: Noctu-
ria twice nightly may be a minor nuisance for some but may
represent a significant problem for others. There is no absolute
AUA symptom score or other objective measure that dictates the
need for initiation of therapy for symptomatic BPH. Each patient
 722 Section XII  Men’s Health
must be evaluated individually, and the treatment course must be
tailored to the patient’s individual situation.
O
α-Adrenergic Antagonists
α-Blockers are the most commonly prescribed medications for
the treatment of LUTS associated with BPH. The bladder neck
and prostate are richly innervated with α-adrenergic receptors,
specifically α1a-receptors, which constitute about 70% to 80% of
the total number of α-receptors in these areas. α1b-Receptors
modulate vascular smooth muscle contraction and are located in
the bladder neck and prostate to a lesser degree.
Doxazosin, terazosin, tamsulosin, and extended-release alfuzo-
sin are long-acting α-receptor antagonists. They are typically
administered once daily, usually at bedtime to minimize the
potential for orthostatic hypotension. These medications act
through α1-receptors and can cause vasodilation resulting in tran-
sient hypotension and lightheadedness. Blood pressure reduc-
tion is greater in patients with hypertension (average reduction,
10 to 15 mm Hg) relative to normotensive patients (average
reduction, 1 to 4 mm Hg). Overall, 10% to 20% of patients expe-
rience some (often transient) side effects from these medications,
including dizziness, asthenia, headaches, peripheral edema, and
nasal congestion. Dose titration is recommended for doxazosin
and terazosin to minimize occurrence of these adverse effects and
optimize the therapeutic response. Doxazosin and terazosin
require at least 4 or 5 mg, respectively, to achieve a therapeutic
effect. Maximal response is usually seen within 1 to 2 weeks with
doxazosin and within 3 to 6 weeks with terazosin. Overall, these
drugs reduce symptom scores by 40% to 50% and improve
urinary flow rates by 40% to 50% in about 60% to 65% of patients
treated.
Tamsulosin is a selective α1a-receptor antagonist with a long
half-life. It has a significantly lower degree of nonspecific
α-receptor binding compared with other α-receptor antagonists.
Therefore, side effects such as postural hypotension and dizziness
are less common. This drug does not appreciably affect blood
pressure in hypertensive or normotensive patients. Maximal
response is usually seen within 1 to 2 weeks after the initiation of
therapy.
5α-Reductase Inhibitors
(Finasteride and Dutasteride)
Finasteride and dutasteride block the intracellular conversion
of testosterone to DHT by inhibiting the action of the enzyme
5α-reductase. This results in an approximate 18% to 25% reduc-
tion in prostate gland size over 6 to 12 months. It is most effec-
tive in reducing symptoms and preventing disease progression
in patients with large prostate glands (>40  mL [Prostate mea-
surement for clinical purposes is usually described in mL, but
1  mL= 1  g = 1  cc]), although recent evidence suggests that
symptomatic improvement and stabilization of disease progres-
sion may occur in treated men with prostates as small as 30  mL.
5α-Reductase inhibition has also been shown to decrease the
risk for urinary retention and subsequent surgical intervention,
again predominantly in those patients with larger glands. Initial
response is seen within 6 months, and maximal effect occurs
12 to 18 months after the initiation of therapy.
Finasteride and dutasteride reduce serum PSA by about 50%.
This must be taken into consideration when interpreting PSA
values in men taking these agents. After 6 months of therapy, the
effective PSA level in a patient taking finasteride or dutasteride
may be calculated by doubling the measured PSA value. Free PSA
(the percentage of non–protein-bound PSA) is also reduced by
about 50%. Use of finasteride or dutasteride may result in sexual
dysfunction, including decreased erectile rigidity, decreased
libido, and decreased ejaculate volume. ED caused by 5α-reductase
inhibitor therapy is reversible and returns to baseline within 2 to
6 months after discontinuation of therapy.
Phosphodiesterase Type 5 Inhibitors
Although they are more often thought of as medications for the
treatment of ED, sildenafil, vardenafil, and tadalafil have been
shown to be efficacious in the treatment of the symptoms of
BPH. As previously discussed, these medications work by pre-
venting the degradation of cGMP by PDE5. This results in lower
intracellular calcium levels and, consequently, smooth muscle
relaxation. This process works in the vasculature of the penis as
well as the smooth muscle cells of the prostate, urethra, and
bladder neck. A number of randomized, double-blind, placebo-
controlled trials have shown improvements in LUTS in men
treated with a once-daily regimen of one of these medications.
Although it has not been conclusively shown that PDE5 inhibi-
tors are more efficacious than α-blockers, it does appear that the
combination of the two medications works better than either one
of them alone. The common side effects of these medications are
headache, nasal stuffiness, and facial flushing.
Anticholinergic Medications
For most men, symptoms of overactive bladder make up a
large component of LUTS associated with BPH. Most men
with bladder outlet obstruction have symptoms of urgency,
frequency, and nocturia. As in female patients, one of the best
ways to treat these symptoms of overactive bladder is with
daily use of anticholinergic medications such as oxybutynin,
tolterodine, or solifenacin. When these medications are used
in combination with an α-blocker, there can be significant
improvement in LUTS in men with symptoms of overactive
bladder. Except in patients with small prostates (<29  mL), it
does not appear that anticholinergic monotherapy is better than
combination therapy or α-blocker monotherapy. The typical
side effects of this class of medications include dry mouth,
constipation, nausea, and impaired cognition. The risk of urinary
retention related to the use of these medications in men appears
to be minimal.
  SURGICAL MANAGEMENT
Minimally Invasive Therapy
Although TURP remains the standard for surgical treatment
of BPH, substantial effort has been devoted to the development
of less invasive and less morbid methods of treating patients
with symptomatic BPH. This has led to a number of minimally
invasive therapies, primarily using different methods of generat-
ing heat within the prostate gland to cause tissue destruction.
These office-based heat techniques transiently increase bladder
outlet obstruction for 1 to 2 weeks due to postprocedure swell-
ing. Maximal tissue reduction and treatment effect occur within
12 weeks.

Transurethral microwave thermotherapy (TUMT) is one
of the most widely studied minimally invasive methods of treat-
ing symptomatic BPH. Catheter-mounted transducers use
microwave energy (30 to 300 Hz) to heat prostatic tissue, result-
ing in coagulative necrosis and shrinkage of the prostate gland.
The subsequent reduction in prostate transition zone volume
results in an improvement in flow rates and symptom scores.
Transurethral needle ablation (TUNA) uses low-level radio fre-
quency energy to effect similar changes within the prostate gland.
Other therapies currently available or in development include
interstitial lasers and high-intensity focused ultrasound. All of
these therapies are designed to deliver sufficient energy to the
prostate to cause tissue destruction, resulting in a smaller prostate
gland consequent improvement in the patient’s symptoms.
The most common side effects of these treatments are tempo-
rary increases in overactive bladder symptoms, transient urinary
retention, hematuria, and ejaculatory dysfunction (primarily ret-
rograde ejaculation). Late complications such as urethral stric-
tures and ED have been reported but are significantly less
common than with traditional surgical approaches. The major
benefits of these less invasive therapies are the reduction in tra-
ditional surgical morbidities (e.g., bleeding) and risks associated
with general or spinal anesthesia and decreased rates of long-term
complications such as incontinence, ED, bladder neck contrac-
tures, and urethral strictures. Additionally, most of these proce-
dures can be accomplished safely on an outpatient basis, either
in the office or in an ambulatory surgical setting.
Success rates for the heat-based minimally invasive therapies
are intermediate between those achieved with medical manage-
ment and those of traditional surgical therapy, with 65% to
75% of patients experiencing symptomatic improvement and
improved flow rates. The long-term durability of these therapies
appears to be good but is presently being evaluated.
Traditional Surgical Management
TURP remains the “gold standard” for the surgical management
of symptomatic BPH. A TURP procedure involves removal of
the transition zone of the prostate through the penis using a
cutting electrocautery loop. The goals of the surgery are to reduce
the transition zone prostate tissue to the level of the prostatic
capsule and to create a smooth, open appearance of the prostatic
urethra and bladder neck. Improvements in the conventional
technique have included bipolar electrosurgical cutting, which
allows saline irrigation and eliminates the chance of transient
urinary retention syndrome.
Newer operating room–based therapies have evolved that
produce end results similar to those of TURP. Holmium
laser enucleation (HOLEP) is a surgical technique performed
by specially trained urologists, generally indicated for large
size prostates. Other procedures include various forms of
TABLE 71-5  SUCCESS IN MEDICAL VERSUS SURGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA
DEGREE OF IMPROVEMENT α1- BLOCKERS
Symptoms (%) 48
Flow rate (%) 40-50
Mean probability (%) of achieving 74
the stated improvements
TUIP, Transurethral incision of the prostate; TURP, transurethral resection of the prostate.
Chapter 71  Men’s Health Topics 723
vaporization of the transition zone tissue of the prostate. In
contrast to the TURP, no pieces of prostate are removed with
these procedures. The various vaporization procedures include O
potassium titanyl phosphate (KTP or GreenLight) laser therapy,
also called photovaporization of the prostate, and bipolar plasma
vaporization of the prostate (button TURP). With the exception
of HOLEP, all of these procedures are useful for all but the
largest prostate glands (>100  mL), which are typically best
managed with open surgical enucleation. Rates of urinary incon-
tinence, retrograde ejaculation, and urethral stricture are all
higher after operating room procedures than after office-based
therapies. Perioperative morbidity, including the need for blood
transfusion, although substantially decreased by technical
improvements, is likewise higher after TURP and similar pro-
cedures. However, standard electrosurgical resection of the pros-
tate (TURP) is the most effective surgical treatment for
symptomatic BPH short of enucleation. Success rates, as mea-
sured by improved symptom scores and increased urinary flow
rates, are 80% to 90% after TURP.
Transurethral incision of the prostate (TUIP) is a more limited
surgical procedure consisting of incision of the bladder neck and
proximal prostatic urethra. Although it is more invasive than the
heat-based therapies, success rates approach those of TURP in
properly selected patients (i.e., those with prostate glands
<30 mL). Morbidity after TUIP is significantly less than after
TURP, but long-term durability of symptom relief is less than
that seen with TURP.
Open surgical enucleation (open or simple prostatectomy) is
reserved for patients with very large glands. This is an invasive
surgery that typically involves a 5- to 10-cm incision in the
midline of the lower abdomen and an incision in the bladder
neck or the capsule of the prostate. After the incision has been
made, the transition zone of the prostate (prostatic adenoma) is
bluntly removed. Success rates are high, but the rate of complica-
tions is higher than with any of the other traditional surgical
approaches (Table 71-5). This surgery is uncommonly per-
formed in the United States, having been replaced by HOLEP in
many centers.
  CONCLUSION
The management of LUTS resulting from BPH has undergone a
dramatic shift from principally a surgical approach to a medical
approach. This evolution of care, coupled with the aging of the
U.S. population, has resulted in a shift of care for these patients
from the urologist to the primary care physician. In the absence
of severe LUTS or indications for early surgical intervention, the
primary care physician can now successfully manage most cases
of mild to moderate BPH. If there is no response to medical
therapy, the patient can be offered office-based minimally
invasive surgical therapy.
FINASTERIDE TURP TUIP OPEN SURGERY
31 82 73 79
17 120 100 185
67 88 80 98
 724 Section XII  Men’s Health
O
D. Testis Cancer
Testicular tumors are the most common solid malignancies in
men aged 15 to 34 years, and the incidence of testis cancer
appears to have increased over the last 25 years. The advent of
platinum-based chemotherapy in the 1970s and a more recent
systematic multidisciplinary approach have greatly improved the
survival of patients with testicular cancer over the last 40 years.
Survival now approaches 99% for low-risk disease and 80% for
high-risk disease.
Cryptorchidism (undescended testicle) is a well-accepted risk
factor for subsequent development of testicular cancer. Abnor-
malities in spermatogenesis are well documented and are thought
to be a primary effect of testicular tumors; up to 15% of patients
are diagnosed with testicular cancer during a work-up for male
factor infertility. Also, it appears that patients with an atrophic
testicle have an increased risk of testicular cancer. Testicular
microlithiasis does not appear to connote an increased risk of
testicular cancer, although this conclusion is somewhat contro-
versial; patients with this incidental finding on testicular ultraso-
nography do not require additional surveillance beyond monthly
testicular examinations. Between 2% and 3% of patients have
bilateral tumors at presentation, and 5% to 10% of those with
involvement of only one testicle will go on to develop cancer in
the normal contralateral testicle. Despite impairments in sper-
matogenesis, most men with testicular cancer are capable of
fathering children; discussion of fertility issues is extremely
important, especially in patients who may require adjuvant thera-
pies such as external-beam radiation and systemic chemotherapy.
The most common presenting sign or symptom of testis cancer
is a firm, painless mass arising from the testis. However, patients
may also have an acute scrotum at presentation as a result of
tumor hemorrhage, and up to 33% of patients are treated for pre-
sumed epididymitis. Scrotal ultrasonography is diagnostic; testis
cancer is usually distinguishable from benign scrotal disease
because of the clear involvement of the testicular parenchyma
rather than the paratesticular tissues. Signs and symptoms of
advanced disease include cough, gastrointestinal symptoms
(mass), back pain (retroperitoneal metastasis), neurologic symp-
toms (brain metastasis), lower-extremity swelling (iliac or infe-
rior vena cava thrombus), and supraclavicular lymphadenopathy.
  DIAGNOSIS AND STAGING
Initial management of the primary tumor is inguinal orchiect­
omy with high ligation of the spermatic cord. Histopathology
distinguishes germ cell tumors (GCTs) from stromal tumors.
Seminoma is the most common GCT occurring in pure form.
Teratoma, yolk sac tumor, embryonal carcinoma, and chorio-
carcinoma are classified as nonseminomatous GCT and fre-
quently occur as mixed GCT (more than one histologic pattern
within the primary tumor). Testicular cancer is unique in that
serum tumor markers (STMs) play an important role in tumor
staging. STMs include HCG, α-fetoprotein (AFP), and serum
lactate dehydrogenase. Elevations of serum HCG may be seen
in choriocarcinomas, in embryonal carcinomas, and in 15% of
seminomas. Elevated AFP can be seen in yolk sac tumors and
embryonal carcinomas, and this finding excludes a diagnosis of
seminoma. These STMs may be secreted either by the primary
tumor or by metastatic foci (Table 71-6).
The retroperitoneal lymph nodes are the most common initial
site of metastasis. Therefore, staging of the retroperitoneum with
an abdominal CT scan is important in evaluating the extent of
disease. However, accurate staging of the retroperitoneum
remains problematic, with the literature quoting false-negative
and false-positive rates of 20% to 30% with CT scanning.
Common landing zones for lymph node metastasis include the
precaval, interaortocaval, and preaortic lymph nodes below the
renal hilum and above the aortic bifurcation. Chest radiography
or thoracic CT scanning completes the clinical staging because
the lungs and posterior mediastinum are the most common sites
of distant metastatic disease.
  TREATMENT
Histopathology, pathologic stage, and STM status are used to
determine subsequent treatment after inguinal orchiectomy. All
patients with elevated STMs after orchiectomy receive cisplatin-
based chemotherapy, regardless of histology. Radiation therapy
and retroperitoneal lymph node dissection (RPLND) have a
high likelihood of failure in the face of elevated STMs.
Seminoma manifests as clinical stage I in 70% of cases, stage
II in 20%, and stage III in 10%. In the past, most experts recom-
mended radiation therapy to the retroperitoneum for patients
with stage I or II disease because of the radiosensitivity of semi-
nomas. However, patients with stage I seminoma are now more
likely to undergo surveilance because of the recognition that new
retroperintoneal metastases found during surveilance are sensi-
tive to either chemotherapy or radiation. Patients with bulky
stage II disease (lymph node >5 cm) and those with stage III
disease should receive combination chemotherapy.
Nonseminomatous GCTs manifest more frequently at an
advanced stage (stage I, in 30%, stage II in 40%, and stage III
in 30%). RPLND is frequently recommended in patients with
clinical stage I or low-volume stage II disease. Reasons for
recommending RPLND include accurate pathologic staging of
the retroperitoneum, low relapse rate (<2%) after properly
performed RPLND, curative potential in the face of viable
GCT, and the potential for retroperitoneal teratoma, which is
resistant to chemotherapy. Side effects associated with RPLND
include lymphocele, chylous ascites (0.4%), and small bowel
obstruction (1% to 2%). Nerve-sparing RPLND is able to
preserve antegrade ejaculation in more than 80% of patients.
TABLE 71-6  TESTIS CANCER STAGING STUDIES
Tumor markers
  AFP—elevated only with nonseminomatous tumors
  HCG—may be increased with either seminoma or nonseminomatous
tumors
Abdominal CT scan—retroperitoneal nodes are most common site of
regional nodal metastasis
Chest radiograph or CT scan—lung is most frequent site of distant
metastasis
AFP, α-Fetoprotein; HCG, β-human chorionic gonadotropin; CT, computed tomography.

Primary chemotherapy is sometimes recommended to patients
with stage I or II nonseminomatous testis cancers. Also, some
men may choose surveillance alone for a stage I tumor, which
implies normal serum marker status and a normal abdominal
CT scan. Up to 25% may be expected to develop recurrence,
usually within 2 years, and chemotherapy is used after evidence
of recurrence.
E. Male Infertility
Approximately 90% of all couples are able to conceive a child in
the first year. For this reason, a male patient should not be evalu-
ated for infertility unless he has tried to have a child for at least 1
year. Although it is difficult to localize the cause of infertility to
one gender, the prevalence of male factor infertility in infertile
couples is probably 25% to 50%. From a very basic perspective,
male infertility is caused by problems delivering sperm, from
either a decreased amount of sperm or a deficiency in the quality
of the sperm. These problems can result from ED, retrograde
ejaculation, ejaculatory duct obstruction, obstruction of the
vas deferens, endocrine dysfunction, varicoceles, or genetic
abnormalities.
  HISTORY AND PHYSICAL EXAMINATION
The evaluation of a patient with infertility should begin with a
thorough history and physical examination. During the history,
the clinician should include questions about how long and how
frequently the couple has been trying to conceive, prior pregnan-
cies with current or previous partners, erectile function, and use
of lubricants. A detailed past medical, surgical, social, and family
history is also very important.
The physical examination should commence with an overall
assessment of the patient’s general health. Next, the clinician
should focus on examination of the genitalia. The surface of the
testicle should be closely examined because studies have shown
an increased incidence of testicular cancer in patients with infer-
tility. Testicular size and consistency should also be assessed. The
normal testicle has a volume of approximately 20 mL and does
not feel soft or spongy. In addition, the spermatic cord should be
carefully examined to confirm the presence of a vas deferens on
each side. The scrotum should be examined for the presence of a
varicocele, with and without performance of the Valsalva maneu-
ver. Finally, a rectal examination should be performed to palpate
for abnormalities of the prostate and seminal vesicles.
  SEMEN ANALYSIS
Semen analysis is probably the most important part of the evalu-
ation of an infertile male patient. The patient should abstain from
ejaculation for 2 to 7 days before the test, and clinical decision
making should be based on at least two tests performed 7 days
apart. Sperm concentration increases with days of abstinence. In
a study from 2004 looking at the effect of frequency of ejaculation
on sperm concentration, the concentration continued to increase
after 10 days of abstinence. After the specimen has been collected
by the patient, it should be delivered to the laboratory at body
temperature as soon as possible. Motility significantly decreases
after 2 hours.
Chapter 71  Men’s Health Topics 725
Platinum-based chemotherapy is the standard for patients
with advanced disease. Cure rates of 70% to 80% are achieved
even in patients who have relatively bulky metastatic disease at O
presentation. Side effects of chemotherapy include renal dysfunc-
tion, neuropathy, Raynaud’s phenomenon, hematologic toxicity,
pulmonary toxicity, cardiovascular toxicity, and a 0.5% risk for
secondary leukemia.
The most important parts of the microscopic examination of
the semen sample are sperm concentration, morphology, and
motility. The normal sperm concentration is greater than 20
million sperm per milliliter, and a value lower than 20 million per
milliliter is termed oligospermia. The absence of sperm is termed
azoospermia. Depending on the laboratory, sperm morphology is
usually reported as a percentage. Typically, normal morphology
in more than 50% of sperm examined is considered acceptable.
Morphologic studies primarily assess the size and shape of the
head and tail. Motility is also expressed as a percentage and refers
to the percentage of sperm that are moving in a coordinated and
progressive manner. Mortality values higher than 50% are con-
sidered to be normal. Abnormal sperm motility is termed asthe-
nospermia, and abnormal morphology is teratospermia.
Other factors checked during a semen analysis include semen
volume, pH, and fructose positivity. A semen volume between 2
and 4 mL is considered normal. A volume of less than 2 mL may
be a sign of ejaculatory duct obstruction (absent fluid from vas
deferens and seminal vesicle) or retrograde ejaculation. Because
the testicles contribute only a small portion of the fluid released
during ejaculation, a vasectomy should not affect ejaculate
volume. The normal range of semen pH is 7.2 to 8.0. An acidic
pH may be a sign of congenital absence of the vas deferens or
seminal vesicle hypoplasia. Depending on the laboratory, the
fructose test result should be positive or in the normal range.
Fructose is made by the seminal vesicles and provides nutrition
for the sperm. Low or absent fructose may also be a sign of ejacu-
latory duct obstruction or seminal vesicle hypoplasia.
  OTHER DIAGNOSTIC TESTS
If a patient has an abnormal semen analysis, an endocrine evalu-
ation should be performed. The complete initial endocrine evalu-
ation includes measurements of LH, follicle-stimulating hormone
(FSH), prolactin, and testosterone. These hormone levels should
be checked in the morning (before 11 a.m.). In general, an ele-
vated FSH is a bad prognostic sign indicating that the patient will
not be found to have a correctable form of infertility. From a
simplistic point of view, this is because the hypothalamic-pituitary
access is trying to stimulate sperm production but the testicle is
not responding. Genetic testing in the form of a chromosome
analysis (karyotype and Y-linked microdeletion assessment)
should be considered in patients with severe oligospermia or azo-
ospermia to rule out disorders such as Klinefelter’s syndrome and
abnormalities of the Y chromosome.
As long as a normal physical examination can be performed,
there is no need to do a scrotal ultrasound study on patients with
infertility. If the patient has a body habitus that makes physical
 726 Section XII  Men’s Health
examination difficult, a scrotal ultrasonography may aid in the
diagnosis of a clinical varicocele. In general, patients in need of
O
further diagnostic evaluation of infertility should be referred to a
specialist.
  TREATMENT OF MALE INFERTILITY
IN PRIMARY CARE
There are several options for the treatment of male infertility, and
the choice of treatment depends on the results of the history,
physical examination, and diagnostic evaluation. First, fertility is
a reflection of a patient’s overall general health. Decreasing the
patient’s stress level, improving sleep habits, and fostering a
healthy diet may all have beneficial effects on fertility. There is
conflicting evidence as to whether antioxidants in the form of
vitamins or diet modification improve the viability of sperm.
Patients can purchase antioxidant multivitamins at most super-
markets and health food stores. Because the evidence for benefit
is mixed, it is important to tell the patient not to overspend on
this treatment.
Other lifestyle modifications may also improve fertility. For
example, avoiding hot baths and whirlpools may provide more
optimal conditions for sperm production. In addition, tobacco,
alcohol, and marijuana use have all been shown to negatively
affect fertility in males. Certain medications also can have a nega-
tive impact on infertility. α-Blockers used to treat BPH can cause
retrograde ejaculation. Exogenous testosterone replacement
decreases sperm production, and at least 2 months are required
for sperm production to recover once testosterone therapy is
stopped.
The timing and frequency of intercourse can affect the ability
to conceive. Ovulation predictor kits are readily available to
patients without a prescription and may improve fertility.
Because sperm can survive at least 2 days in the female genital
tract, having intercourse every 2 days may maximize male sperm
concentration and delivery. In addition, patients should make
sure that they are not using a lubricant that has spermicidal
activity.
F. Benign Scrotal Diseases
  VARICOCELE
A varicocele is classically described as an abnormal dilation
of the veins of the pampiniform plexus that can be palpated
as a “bag of worms” with or without having the patient
performing the Valsalva maneuver while standing. When exam-
ining a patient for any scrotal pathology, it is important to
have the patient stand. A clinical varicocele is one that can
be palpated on physical examination. Because the occurrence
of varicoceles increases with age, the prevalence in the litera-
ture is highly variable. The prevalence of a unilateral palpable
left-sided varicocele is between 6.5% and 22%, and that of
bilateral palpable varicoceles ranges from 10% to 20%. The
prevalence of an isolated right-sided palpable varicocele is less
than 1%; because of their very rare association with retro-
peritoneal malignancy, many clinicians perform axial imaging
on patients with a unilateral right-sided varicocele. In general,
Patients who have a palpable varicocele and oligospermia with
or without defects in sperm morphology or motility may benefit
from a varicocelectomy and should be referred to a urologist for
further evaluation (see later discussion). The most common
methods of surgical correction are varicocelectomy and gonadal
vein embolization.
Patients with oligospermia and a normal or low FSH level may
benefit from treatment with clomiphene citrate (Clomid). The
typical dosage is 25 mg daily or 50 mg every other day for at least
2 months (it takes 64 days for new sperm to be made). Most
studies of this drug have shown a significant increase in sperm
production but little impact on fertility. However, it may be ben-
eficial for selected patients with the above-mentioned laboratory
values.
If a varicocele is present in an infertility patient or severe oli-
gospermia or azoospermia does not respond to the treatments
already mentioned, referral to a urologist for additional testing
is warranted. Oligospermia or azoospermia with a low semen
volume and a negative fructose result may suggest ejaculatory
duct obstruction. If azoospermia is present with no sonographic
evidence of ejaculatory duct obstruction, a testicular biopsy
might be the prudent next step. If retrograde ejaculation is sus-
pected (oligospermia, normal fructose, and low semen volume),
the urologist may elect to examine a postejaculation, centrifuged
urine specimen for the presence of sperm.
Once the evaluation by the urologist has been completed, he
or she may recommend that the patient proceed with assisted
reproductive technology (ART). The simplest form of ART is
intrauterine insemination, for which patients with oligospermia
and normal motility are excellent candidates. In vitro fertilization
(IVF) and intracytoplasmic sperm injection (ICSI) are more
costly but often successful. Even patients with azoospermia due
to Klinefelter’s syndrome have had frequent success (46% rate of
pregnancy) with ICSI.
a left-sided varicocele does not have clinical significance unless
it can be palpated on physical examination. A left-sided vari-
cocele that is incidentally found during ultrasonography of
the scrotum and is not palpable on examination is considered
a subclinical varicocele and is typically not the source of any
pathology.
Palpable and nonpalpable varicoceles are most commonly
found incidentally and in most cases have no clinical significance.
However, palpable varicoceles can cause ipsilateral testicular
atrophy. Therefore, it is important for the clinician to compare
the size of the testicles in patients who desire future fertility. If
the physical examination is unclear, scrotal ultrasonography can
be used to accurately measure the size of both testicles. Any
patient who desires future children and has a size discrepancy
greater than 20% should be monitored closely and possibly
referred to a urologist. Although varicoceles are most commonly
found incidentally, they may also be found during a work-up for

male factor infertility, scrotal pain, or asymptomatic testicular
atrophy.
The pathophysiology of varicoceles is poorly understood but
involves dilation of the internal spermatic vein and transmission
of increased hydrostatic pressure across dysfunctional venous
valves. Stasis of blood in the venous system disturbs the counter-
current heat exchange that is responsible for maintaining testicu-
lar temperature and may result in testicular parenchymal damage
and impaired spermatogenesis.
Varicoceles are the most common cause of both primary infer-
tility (patient has fathered no children) and secondary infertility
(patient has fathered at least one child), accounting for 33% of
cases. However, most men with palpable varicoceles are able to
father children without difficulty. In a man with infertility and a
palpable varicocele, semen analysis commonly reveals a low
sperm count and abnormal sperm morphology and motility.
After surgical correction of a varicocele in a patient with infertil-
ity, semen parameters improve in 60% to 80% and subsequent
pregnancy rates range from 20% to 60%.
It is prudent to perform scrotal ultrasonography on any patient
with chronic testicular pain. Varicoceles are commonly found
during this evaluation, but usually only palpable (clinical) varico-
celes are considered as a source of pain. If a nonpalpable varico-
cele is found on an ultrasound examination, the patient should
not be told that it is the cause of his pain. More than 80% of men
with chronic pain from a palpable varicocele have improvement
in their pain after surgical correction.
Common operative techniques for treatment of a varicocele
include high retroperitoneal ligation of the internal spermatic
vein, microsurgical inguinal and subinguinal varicocelectomy,
laparoscopic varicocelectomy, and gonadal vein embolization.
The inguinal approach using microscopic magnification has
the highest success and lowest complication and recurrence
rates. The most common complication is hydrocele formation,
whereas a rare complication is inadvertent ligation of the
testicular artery resulting in testicular atrophy and loss. Surgi-
cal intervention for subclinical (nonpalpable) varicoceles is
not indicated.
  SPERMATOCELE (EPIDIDYMAL CYST)
Spermatoceles and epididymal cysts are dilations of the tubes
that connect the testicle to the epididymis (ductuli efferentes).
Although they are technically the same thing, many clinicians
refer to small lesions as epididymal cysts and larger ones as sper-
matoceles. These cystic lesions are very common and are found
in 29% of asymptomatic men on ultrasonography. After a vasec-
tomy, 35% of men develop a new small spermatocele; therefore,
distal obstruction likely contributes to their development.
On physical examination, spermatoceles are somewhat
mobile, firm masses that are separate and distinguishable from
the smooth border of the testicle. It may be possible to transil-
luminate larger lesions. They are filled with a clear fluid that
usually contains abundant amounts of sperm. If the lesion
cannot be transilluminated, it is advisable to perform an ultra-
sound study of the scrotum to distinguish a spermatocele from
a solid mass. Of note, the vast majority of solid masses of the
epididymis are benign. Small spermatoceles and epididymal
cysts normally have no clinical significance and are typically
Chapter 71  Men’s Health Topics 727
not the source of a patient’s chronic testicular pain. They can
be surgically removed if they are large or are causing discomfort
for the patient. O
  ACUTE EPIDIDYMITIS
Acute epididymitis is a clinical syndrome that may manifest with
fever, acute scrotal pain, and impressive swelling and induration
of the epididymis. Pathophysiologically, epididymitis is most
often caused by retrograde bacterial spread from the bladder or
urethra. In men younger than 35 years of age, the most common
causative agents are those organisms associated with urethritis—
namely, Neisseria gonococcus and Chlamydia trachomatis. In older
men, acute epididymitis is usually caused by a coliform bacteria
such as Escherichia coli and often occurs in association with
another lower urinary tract infection or bladder outlet
obstruction.
The most important consideration in diagnosing acute epi-
didymitis is differentiating this disease from acute testicular
torsion. Physical examination can be nonspecific, although focal
epididymal swelling and tenderness are suggestive, and the pres-
ence of white cells and bacteria in the urine is indicative of an
infectious etiology. Scrotal sonography with Doppler flow can be
extremely helpful in differentiating acute epididymitis from
torsion in difficult cases.
Patients with acute epididymitis have significant inflammation
that can also involve the testicle (epididymo-orchitis). Patients
with severe epididymitis involving the testicle are often systemi-
cally ill. In most instances, initial treatment should consist of
antibiotics, nonsteroidal anti-inflammatory medications, and
possibly oral narcotics. In some cases, broad-spectrum antibiot-
ics or even hospital admission may be necessary. In general,
patients younger than 35 years of age should be treated with
ceftriaxone and doxycycline or a single dose of azithromycin.
Older patients are usually empirically treated with a fluoroquino-
lone or trimethoprim sulfamethoxazole for 2 to 4 weeks. Com-
plications associated with acute epididymitis include abscess
formation, testicular infarction, infertility, and chronic epididy-
mitis or orchalgia.
  HYDROCELE
A hydrocele is a serous fluid collection located between the pari-
etal and visceral layers of the tunica vaginalis of the scrotum.
Noncommunicating hydroceles usually surround the testicle and
spermatic cord. Communicating hydroceles are actually indirect
inguinal hernias; they contain only fluid and not bowel or fat
because the opening into the peritoneal cavity is small. Com-
municating hydroceles can be distinguished from noncommuni-
cating hydroceles on physical examination by gently pushing the
fluid out of the scrotum and into the peritoneum. Communicat-
ing hydroceles are more commonly identified in the pediatric age
group.
Patients with a noncommunicating hydrocele usually have
complaints of heaviness in the scrotum, scrotal pain, or an enlarg-
ing scrotal mass. Usually the diagnosis is easily made based on
the physical examination and transillumination of the scrotum. If
the testis is not palpable, an ultrasound study should be per-
formed to rule out a testicular tumor associated with a secondary
or reactive hydrocele. Noncommunicating hydroceles are caused
 728 Section XII  Men’s Health
by increased secretion or decreased reabsorption of serous fluid
by the tunica vaginalis. Infection, trauma, surgery, neoplastic
O
disease, and lymphatic disease are causative in many adults,
whereas the remainder of cases are idiopathic.
Treatment of symptomatic noncommunicating hydroceles is
surgical. Although the recurrence rate is significantly higher with
aspiration and sclerotherapy, this approach can be a good option
in patients who are considered poor surgical candidates. Hydro-
celectomy procedures involve either excision of the redundant
tunica vaginalis or a plication of the sac without excision. After
surgery, the rates of hydrocele recurrence and chronic pain are
9% and 1%, respectively.
  TESTICULAR TORSION
Testicular torsion is considered a true urologic emergency. The
testicle receives its blood supply from the testicular artery (aorta),
the vasal artery (inferior vesicle artery), and the cremasteric
artery (inferior epigastric artery). All three vessels are transmit-
ted to the testicle through the spermatic cord. Torsion of the
spermatic cord impairs arterial inflow as well as venous outflow.
If detorsion is not performed within 6 to 8 hours, testicular
infarction and hemorrhagic necrosis are likely to occur. Typically,
patients are younger than 21 years of age, although testicular
torsion can occur later. Delay in presentation and diagnosis is
more common in the adult patient population and is related to
patient and physician factors.
The characteristic signs and symptoms of acute testicular
torsion are the acute onset of scrotal pain, swelling, nausea, vom-
iting, loss of normal rugae of the scrotal skin, absent cremasteric
reflex, and a high-riding, rotated, tender testicle. The diagnosis of
testicular torsion remains a clinical one, however; if ultrasound
equipment is readily available, all patients should have a scrotal
ultrasound study before surgery. In rare cases, surgical explora-
tion is undertaken when the index of suspicion is high but
imaging is not available. Doppler ultrasonography is extremely
useful in differentiating testicular torsion from other causes of
acute scrotum, such as acute epididymitis, torsion of the appen-
dix testis, and trauma.
It is possible to untwist testicular torsion by manipulating the
testicle through the scrotum in the emergency room or in a physi-
cian’s office. After giving the patient parenteral narcotics, the tes-
ticle can be untwisted by gently pulling down on it and, usually,
rotating it laterally (like opening a book). If this is successful, the
testicle will uncoil like a spring and fall into its normal position,
with immediate relief of the patient’s pain. Even if the procedure
is successful, patients should still be taken to the operating room
for bilateral orchiopexy. Of note, testicular torsion is the result of
medial twisting of the testicle only 68% of the time.
Important surgical principles include surgical detorsion and
assessment of testicular viability in the operating room. If the
testis is determined to be viable, bilateral orchiopexy is per-
formed using the technique of three-point fixation (sutures
placed medially, laterally, and inferiorly). In the presence of
infarction, orchiectomy is recommended. Orchiopexy of the con-
tralateral testicle is always performed simultaneously. When diag-
nosis and surgery occur in a timely fashion, testicular salvage rates
approach 70%. Delayed surgical therapy results in dropoff of the
salvage rate to 40%.
SUGGESTED READINGS
Androgen Deficiency in Adult Men
Baillargeon J, Urban RJ, Ottenbacher KJ, et al: Trends in androgen prescribing in
the United States, 2001 to 2011, JAMA Intern Med 173:1465–1466, 2013.
Bhasin S, Cunningham GR, Hayes FJ, et al: Testosterone therapy in men with
androgen deficiency syndromes: an Endocrine Society clinical practice
guideline, J Clin Endocrinol Metab 95:2536–2559, 2010.
Caronia LM, Dwyer AA, Hayden D, et al: Abrupt decrease in serum testosterone
levels after an oral glucose load in men: implications for screening for
hypogonadism, Clin Endocrinol (Oxf) 78:291–296, 2013.
Kvorning T, Andersen M, Brixen K, et al: Suppression of endogenous testosterone
production attenuates the response to strength training: a randomized,
placebo-controlled, and blinded intervention study, Am J Physiol Endocrinol
Metab 291:E1325–E1332, 2006.
Meriggiola MC, Bremner WJ, Costantino A, et al: Low dose of cyproterone
acetate and testosterone enanthate for contraception in men, Hum Reprod
13:1225–1229, 1998.
Morgentaler A: Testosterone therapy in men with prostate cancer: scientific and
ethical considerations, J Urol 189(1 Suppl):S26–S33, 2013.
Nieschlag E, Swerdloff R, Behre HM, et al: Investigation, treatment, and
monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU
recommendations, J Androl 27:135–137, 2006.
Rhoden EL, Morgentaler A: Risks of testosterone-replacement therapy and
recommendations for monitoring, N Engl J Med 350:482–492, 2004.
Svartberg J, Midtby M, Bønaa KH, et al: The associations of age, lifestyle factors
and chronic disease with testosterone in men: the Tromsø Study, Eur J
Endocrinol 149:145–152, 2003.
Wu FCW, Tajar A, Beynon JM, et al: Identification of late-onset hypogonadism
in middle-aged and elderly men, N Engl J Med 363:123–135, 2010.
Erectile Dysfunction
American Urological Association: AUA guideline on the management of erectile
dysfunction: diagnosis and treatment recommendations, 2005 (website).
http://www.auanet.org/education/guidelines/erectile-dysfunction.cfm.
Accessed November 2014.
American Urological Association: Guideline on the management of priapism,
2003 (website). http://www.auanet.org/education/guidelines/priapism.cfm.
Accessed November 2014.
Cappelleri JC, Rosen RC: The Sexual Health Inventory for Men (SHIM): a 5-year
review of research and clinical experience, Int J Impotence Res 17:307–319,
2005.
Carson CC, Lue TF: Phosphodiesterase type 5 inhibitors for erectile dysfunction,
Br J Urol Int 96:257–280, 2005.
Costa P, Potempa A-J: Intraurethral alprostadil for erectile dysfunction: a review
of the literature, Drugs 72:2243–2254, 2012.
Feldman HA, Goldstein I, Hatzichristou DG, et al: Impotence and its medical
and psychosocial correlates: results of the Massachusetts Male Aging Study,
J Urol 151:54–61, 1994.
Kostis JB, Jackson G, Rosen R, et al: Sexual dysfunction and cardiac risk (the
Second Princeton Consensus Conference), Am J Cardiol 96:313–321, 2005.
Montague DK, Jarow JP, Broderick GA, et al: for the Erectile Dysfunction
Guideline Update Panel: The management of erectile dysfunction: an AUA
update, J Urol 174:230–239, 2005.
Benign Prostatic Hyperplasia
Carter B, Albertsen P, Barry M, et al: Early detection of prostate cancer: AUA
Guideline,, Linthicum, Md., 2013, American Urological Association.
D’Amico AV, Chen MH, Roehl KA, et al: Preoperative PSA velocity and the risk
of death from prostate cancer after radical prostatectomy, N Engl J Med
351:125–135, 2004.
Eggener SE, Roehl KA, Catalona WJ: Predictors of subsequent prostate cancer in
men with a prostate specific antigen of 2.6 to 4.0 ng/ml and an initially negative
biopsy, J Urol 174:500–504, 2005.
Kaplan SA, Roehrborn CG, Rovner ES, et al: Tolterodine and tamsulosin for
treatment of men with lower urinary tract symptoms and overactive bladder:
a randomized controlled trial, JAMA 296:2319–2328, 2006.
Lowe FC, McConnell JD, Hudson PB, et al: for the Finasteride Study Group:
Long-term 6-year experience with finasteride in patients with benign prostatic
hyperplasia, Urology 61:791–796, 2003.
XIII
ESSENTIALS

Diseases of Bone and Bone Mineral

Metabolism
72  Normal Physiology of Bone and Mineral Homeostasis
Andrew F. Stewart

73  Disorders of Serum Minerals

Steven P. Hodak and Andrew F. Stewart

74  Metabolic Bone Diseases

Mara J. Horwitz and Andrew F. Stewart

75  Osteoporosis
Susan L. Greenspan

731
 72 
Normal Physiology of Bone and
Mineral Homeostasis
Andrew F. Stewart
  CALCIUM HOMEOSTASIS
The maintenance of normal calcium homeostasis is critical to
survival for at least three reasons. First, the serum calcium con-
centration regulates the degree of membrane excitability in
muscle and nervous tissue. Increases in serum calcium levels
produce refractoriness to stimulation of neurons and muscle
cells, which translates clinically into coma and muscular weak-
ness. Conversely, reductions in serum calcium levels lead to
increases in neuromuscular excitability that translate clinically
into convulsions and spontaneous muscle cramps and contrac-
tions referred to as carpopedal spasm or tetany. Second, terrestrial
life requires the existence of a skeleton, and calcium is the major
structural cation in the skeleton. The mineral phase of the skel-
eton is composed of a calcium salt called hydroxyapatite, and
reductions in bone mineral content lead to spontaneous frac-
tures. Third, intracellular calcium has a major intracellular signal-
ing role, and control of intracellular calcium is essential to the
survival of all cells. This mechanism is used to advantage pharma-
cologically through the widespread clinical use of drugs that
regulate intracellular calcium concentrations and calcium-
channel activity for the treatment of a wide variety of human
diseases. Physicians, regardless of their specialty, encounter dis-
orders of calcium homeostasis on a regular basis.
The serum total calcium concentration is normally maintained
at about 9.5 mg/dL. Of this total amount, about 4.5 mg/dL is
bound to serum proteins, principally albumin, and about 0.5 mg/
dL circulates as insoluble complexes such as calcium sulfate,
phosphate, and citrate. The remaining 4.5 mg/dL circulates as
free or unbound or ionized calcium. This free, ionized serum
calcium is important clinically and physiologically. This calcium
is available to be filtered at the glomerulus, to interact with cell
membranes to regulate their electrical potential or excitability,
and to enter and exit the skeletal hydroxyapatite crystal lattice.
It is important to maintain normal levels of ionized serum
calcium, although total serum calcium is customarily measured
in most clinical laboratories. In some instances, total serum
calcium can change without a change in the ionized calcium level.
For example, if the serum albumin level declines as a result of
hepatic cirrhosis or the nephrotic syndrome, the total serum
calcium also declines, but the ionized serum calcium concentra-
tion remains normal. Measuring the ionized serum calcium level
directly is sometimes important.
A complex group of regulatory processes have evolved to
protect the integrity of this system. When a physician encounters
732
patients in whom hypercalcemia, hypocalcemia, or disorders of
skeletal mineralization have occurred, multiple safety control
points have been breached (discussed later).
To maintain homeostatic control, the calcium ion interfaces
with three important compartments, as shown in the calcium
physiologic black box in Figure 72-1. Although intracellular
calcium is important in intracellular signaling, it is quantitatively
unimportant in overall systemic calcium homeostasis. The three
critical regulatory fluxes that maintain normal serum calcium
concentration are those of the intestine, kidney, and skeleton.
Calcium Fluxes into and out  
of Extracellular Fluid
Intestinal Calcium Absorption
The normal dietary calcium intake for an adult is about 1000 mg
per day. About 300 mg of the total is absorbed (i.e., unidirectional
absorption is about 30%), and this absorption occurs in the duo-
denum and proximal jejunum. About 150 mg of calcium per day
is secreted by the liver (in bile), the pancreas (in pancreatic secre-
tions), and the intestinal glands such that net absorption (called
fractional absorption) of calcium is about 15% of intake.
The efficiency of calcium absorption is regulated at the level of
the small intestinal epithelial cell, the enterocyte, by the active
form of vitamin D, 1,25-dihydroxyvitamin D (1,25[OH]2D),
ECF Ca2+
1000 mg 500 mg
1000 mg
150 mg Serum Ca 0 mg
9.5 mg/dL
500 mg
10,000 mg
Skeleton
GI tract
850 mg 150 mg Kidney
FIGURE 72-1  The calcium physiologic black box. The central box
represents extracellular fluid (ECF), which contains a total of about
1000 mg of calcium. It has three regulatory interfaces with the gastro-
intestinal (GI) tract, skeleton, and kidney. The fluxes into and out of the
ECF are measured in milligrams per day.
 Chapter 72  Normal Physiology of Bone and Mineral Homeostasis 733
also called calcitriol. Increases in 1,25(OH)2D enhance calcium
absorption, and decreases in 1,25(OH)2D reduce absorption of
dietary calcium. Dietary calcium absorption can be increased
over the short term by increasing calcium intake or increasing
plasma 1,25(OH)2D concentrations, or both. Pathologic
increases in serum calcium (i.e., hypercalcemia) can be caused by
increases in circulating 1,25(OH)2D (e.g., in sarcoidosis) or by
excessive calcium intake (i.e., milk-alkali syndrome). Conversely,
hypocalcemia can result from a decline in 1,25(OH)2D (e.g.,
chronic renal failure, hypoparathyroidism). If a normal individual
consumes 1000 mg of calcium per day and the net absorption
from the gastrointestinal (GI) tract is 150 mg per day, 850 mg of
calcium will be excreted in the feces each day.
Renal Calcium Handling
The filtered load of calcium by the kidneys is about 10,000 mg
per day. In terms of overall regulation of calcium homeostasis,
this number is very large, making the point that the kidney is the
most important moment-to-moment regulator of the serum
calcium concentration. The amount also emphasizes that disor-
ders of renal calcium handling (e.g., thiazide diuretic use,
hypoparathyroidism) can be expected to produce significant
abnormalities in serum calcium homeostasis.
Of the 10,000 mg filtered at the glomerulus each day, about
9000 mg (90%) is reabsorbed proximally by the proximal convo-
luted tubule, the pars recta, and the thick ascending limb of Henle
loop. This 90% is absorbed in conjunction with sodium and chlo-
ride reabsorption and is not subject to regulation by parathyroid
hormone (PTH). The remaining 10% (1000 mg) that arrives at
the distal tubule on a daily basis is subject to regulation by PTH,
which stimulates renal calcium reabsorption. The anticalciuric
effect of PTH can be extremely efficient, and elevated PTH con-
centrations can essentially eliminate calcium excretion into the
urine. This action is a potent mechanism for retaining calcium
under conditions of calcium deprivation (e.g., a low-calcium diet,
vitamin D deficiency, intestinal malabsorption) and can contrib-
ute to hypercalcemia under pathologic conditions, as in primary
hyperparathyroidism.
About 150 mg of calcium is excreted by the kidney in the final
urine on a daily basis in a healthy individual. If the kidney filters
10,000 mg of calcium each day, and if 150 mg is excreted in the
final urine, 9850 mg (98.5%) is reabsorbed at proximal and distal
sites. A healthy person is in zero calcium balance with respect to
the outside world: intake (1000 mg/day) − output [(850 mg/
day in feces) + (150 mg/day in urine)] = 0.
Skeletal Biology and Calcium Homeostasis
The skeletal compartment contains about 1.2 kg of calcium in a
male adult and 1.0 kg in a female adult. Most of this calcium is in
the form of crystal hydroxyapatite, a calcium phosphate salt.
Although calcium contributes in an important way to the struc-
tural integrity of the skeleton, the skeleton also serves as a quan-
titatively large reservoir (i.e., a sink) for adding and removing
calcium to and from the extracellular fluid (ECF) compartment
at appropriate times.
The adult skeleton is composed of two types of bone: cortical
(or lamellar) bone and trabecular (or cancellous) bone (Fig.
72-2). Cortical bone predominates in the skull and the shafts of
FIGURE 72-2  The structure of human bone. A human proximal
femur examined using a gross pathologic specimen (left panel) and a
radiograph of the same section (right panel). Notice that two types of
bone are represented. One type is cortical bone (i.e., lamellar bone),
and the other is cancellous bone (i.e., trabecular bone). The proportion
of trabecular and cortical bone differs by location. For example, the
shaft of the femur contains mostly cortical bone, whereas the proximal
end of the femoral neck and the greater trochanter contain little corti-
cal bone and almost exclusively contain trabecular bone. This distinc-
tion is important, because most osteoporotic fractures occur at sites in
which trabecular bone predominates, including the greater trochanter,
the femoral neck, the vertebrae, and the distal radius. (Courtesy
Webster S. S. Jee, MD, University of Utah, Salt Lake City, Utah.)
long bones, and trabecular bone predominates at other sites, such
as the distal radius, the vertebral bodies, and the trochanters of
the hip.
Bone is not an inert tissue, as might be imagined from visiting
the dinosaur room at a natural history museum; instead, bone is
a vital tissue that is continually turning over. The adult skeleton
is completely remodeled every 3 to 10 years. Remodeling is
perhaps best appreciated by recalling that orthopedic surgeons
routinely and intentionally set fractures imperfectly, knowing
that the normal processes of bone remodeling will restore the
bone’s original shape with the passage of time.
The cells that regulate bone turnover can be divided into those
that remove old bone, those that provide new bone (Fig. 72-3)
(see Chapter 74), and those that regulate these two processes.
Cells that remove, or resorb, old bone are osteoclasts. These cells
are large, metabolically active, multinucleated cells derived from
the fusion of circulating macrophages. They deposit themselves
on the surface of bone and form a sealing zone over the bone
surface into which they secrete protons (i.e., acid), proteases
(e.g., collagenase), and proteoglycan-digesting enzymes (e.g.,
hyaluronidase). The acid solubilizes hydroxyapatite crystals,
releasing calcium, and the enzymes digest bone proteins and pro-
teoglycans (e.g., collagen, osteocalcin, osteopontin), which con-
stitute the nonmineral, or osteoid, component of bone. Osteoclasts
move along the surface of trabecular bone plates and drill tunnels
in cortical bone, periodically releasing the digested contents
within their sealed zones into the bone marrow space and thereby
creating resorption lacunae, called Howship’s lacunae, on the tra-
becular bone surface. The released calcium contributes to the
ECF calcium pool, and the released proteolytic products, such as
734 Section XIII  Diseases of Bone and Bone Mineral Metabolism

Bone marrow
CFU-GM CFU-F

Osteoclasts Osteoblasts

Osteoclasts on the bone Osteoblasts appearing

surface resorbing old bone at the resorption site

Quiescent bone surface

covered by lining cells

Osteoid becoming mineralized Osteoblasts filling the

resorption cavity with osteoid

FIGURE 72-3  Cellular components of bone remodeling. Bone remodeling is a continuous process that involves the activation of osteoclast precur-
sors in the macrophage lineage (i.e., colony-forming units of granulocyte-macrophage progenitors [CFU-GM]) that become actively resorbing osteo-
clasts, which tunnel into the bone surface to dig resorption lacunae. Osteoblast precursors in the fibroblast–bone marrow stromal cell lineage (CFU-F)
then appear and become active at the sites of prior resorption, and they secrete new osteoid, which later mineralizes to fill the lacunae created by
osteoclastic bone resorption. (From Manolagas SC, Jilka RL: Bone marrow, cytokines, and bone remodeling: emerging insights into the pathophysiol-
ogy of osteoporosis, N Engl J Med 332:305–311, 1995.)

deoxypyridinoline cross-links (i.e., collagen fragments and
hydroxyproline), can be used clinically as indices of bone
resorption.
New bone formation is accomplished by osteoblasts, which are
derived from marrow stromal cells or bone surface lining cells.
Osteoblasts synthesize and secrete the components of the non-
mineral phase of bone, called osteoid. The components are mostly
proteins and include collagen, osteopontin, osteonectin, osteo-
calcin, proteoglycans, and a plethora of growth factors, including
transforming growth factor-β and insulin-like growth factor-I.
This complex provides the scaffolding on which the mineral
crystal hydroxyapatite forms lattices.
In the past decade, attention has focused on a third, previously
underappreciated bone cell type, the osteocyte. These cells are
descendants of osteoblasts and are embedded into the mineral-
ized phase of bone. Osteocytes physically connect with one
another and to cells at the mineral surface through long dendritic
processes. The dendritic processes extensively permeate the min-
eralized phase of bone through an elaborate canalicular network.
Osteocytes serve a critical role in sensing biomechanical strain
within bone, and through their cellular extensions to the cell
surface, they communicate signals that attract, activate, or repress
osteoclasts and osteoblasts. In this way, they determine which
areas of the skeleton require new bone formation and which need
to be targets of osteoclastic bone remodeling.
Through the process of bone turnover, or bone remodeling,
osteoclasts continually remove old bone, and osteoblasts
continually produce new osteoid that mineralizes, eventually
replacing the old bone removed by osteoclasts with new bone.
This process replaces old bone—and by implication, defective or
damaged bone with microfractures and reduced mechanical
strength—with new, mechanically strong bone, although the evi-
dence for this action is limited. The principal therapy for osteo-
porosis is with the use of antiresorptives such as estrogens,
estrogen-like drugs, and bisphosphonates, which dramatically
reduce bone turnover while improving bone mass and bone
mechanical properties.
Bone remodeling is important for systemic calcium homeosta-
sis. Osteoclasts can be used to access calcium from the skeleton
in times of need to maintain a normal serum calcium concentra-
tion. Conversely, unmineralized osteoid produced by osteoblasts
can be used at appropriate times as a sink into which excess serum
calcium can be deposited. Under normal circumstances, osteo-
clasts resorb bone at a rate such that about 500 mg of calcium is
removed per day from the skeleton and delivered to the ECF
compartment. At the same time, osteoblasts produce osteoid that
mineralizes at a rate such that about 500 mg of calcium leaves the
ECF and enters the skeleton at new sites. From the perspective
of the black box shown in Figure 72-1, the skeleton is in zero
calcium balance with the ECF, and the whole organism is in zero
calcium balance with the external environment.
Considering the complexity of this calcium homeostatic
system and the importance of maintaining tight control of serum
calcium levels, an obvious need exists for systemic regulation and
 Chapter 72  Normal Physiology of Bone and Mineral Homeostasis 735
integration of the calcium fluxes across the GI, skeletal, and renal
compartments. The two key metabolic regulatory hormones that
coordinate these activities are PTH and the active form of vitamin
D, 1,25(OH)2D.
Regulatory Hormones
Parathyroid Hormone
PTH is a peptide hormone produced by the four parathyroid
glands (Fig. 72-4). These glands are located behind the normal
thyroid lobes, with two on the right and two on the left. Through
the calcium sensor—a G protein–coupled receptor for calcium
that is located on the surface of the parathyroid cell—the serum
ionized calcium concentration is continuously monitored. In this
exquisitely sensitive system, minor (e.g., 0.1 mg/dL) reductions
in serum ionized calcium lead to PTH secretion, and minor
increments in serum calcium lead to suppression of PTH
secretion.
PTH is secreted as an 84-amino-acid peptide hormone that is
rapidly (half-life of about 3 to 5 minutes) cleaved by the Kupffer
cells in the liver into an active amino-terminal form; the carboxyl-
terminal form is inactive. Continuous monitoring of the serum
calcium concentration by the parathyroid glands, the immediate
secretion of PTH in response to hypocalcemia, and the rapid
clearance of PTH after secretion enable the parathyroid gland
and PTH to regulate serum calcium with remarkable precision.
PTH targets three organs, two directly and one indirectly. The
first directly targeted organ is the kidney, in which renal calcium
excretion is inhibited by PTH. PTH also inhibits phosphate and
bicarbonate reabsorption, which produces phosphaturia and
hypophosphatemia and proximal renal tubular acidosis, respec-
tively. The renal actions of PTH occur immediately. PTH also
stimulates the production of the active form of vitamin D,
1,25(OH)2D.
PTH also directly targets the skeleton. PTH can mobilize
calcium immediately from the skeleton through activation of
PTH(1-84)
N C
PTH(1-34) PTH C-term fragments
Actions of PTH
Kidney: Stimulate 1,25(OH)2D production
Stimulate cAMP production
Stimulate calcium reabsorption
Block phosphate reabsorption
Bone: Activate osteoclastic resorption (acute)
Activate osteoblastic bone formation
(subacute, chronic)
Intestine: Activate calcium transport (indirect by 1,25(OH)2D)
FIGURE 72-4  Structure and actions of parathyroid hormone (PTH).
PTH is secreted as an 84-amino-acid protein, which is cleaved in the
liver to derivative amino-terminal and carboxyl-terminal (C-term)
forms. Actions of the amino-terminally intact forms of PTH are   liver and kidney to yield the biologically active form of vitamin D:
listed. cAMP, Cyclic adenosine monophosphate; 1,25(OH)2D, 1,25-dihy-
droxycholecalciferol.
osteoclastic bone resorption. Over days to weeks, PTH stimu-
lates the activity of osteoblasts to produce new bone and thereby
remove calcium from the circulation. The ability to stimulate
osteoclasts acutely without activating bone formation is impor-
tant for the rapid delivery of calcium to the ECF.
PTH has the indirect effect of increasing intestinal calcium
absorption by increasing renal synthesis of 1,25(OH)2D. Seen in
concert, PTH is secreted in response to hypocalcemia, and the
actions of PTH combine to restore a low serum calcium concen-
tration to normal by preventing renal calcium losses, by adding
calcium to the ECF from the skeleton, and by indirectly stimulat-
ing (through 1,25(OH)2D) increases in intestinal calcium
absorption.
Vitamin D Metabolism
Vitamin D is two compounds: ergocalciferol (vitamin D2) and
cholecalciferol (vitamin D3) (Fig. 72-5). Both substances are
inactive precursors. One (D3) is derived principally from skin
exposed to sunlight, and the other (D2) is derived from plant
sterols. Both D2 and D3 are found in multivitamins and commer-
cial dietary supplements.
Both precursors are converted constitutively by the enzyme
vitamin D 25-hydroxylase (CYP2R1) in the liver to their respec-
tive 25-hydroxyvitamin D (25[OH]D) derivatives. The deriva-
tives also are inactive precursors, but they have two types of
clinical significance. First, severe liver disease such as cirrhosis
prevents this essential step and leads to vitamin D–deficient syn-
dromes collectively called hepatic osteodystrophy. Second, 25(OH)
D is the standard clinical laboratory measure of the vitamin D
status (i.e., repletion or deficiency) of patients with hypocalce-
mia, osteomalacia or rickets, osteoporosis and intestinal malab-
sorption, and other similar conditions.
25(OH)D is converted, or activated, in the renal proximal
tubule by the enzyme 25-hydroxyvitamin D3 1α-hydroxylase
(CYP27B1) to the active form of the vitamin, 1,25(OH)2D. This
substance, which is also called calcitriol, is regulated by PTH.
Increases in PTH stimulate 1,25(OH)2D production, and
decreases in PTH diminish 1,25(OH)2D synthesis. The primary
D2 D3 Inactive
(Ergocalciferol) (Cholecalciferol)
Liver
25-OH D (Calcidiol) Inactive
+
PTH Kidney
Active
1,25(OH)2D (Calcitriol)
FIGURE 72-5  The vitamin D metabolic pathway. Biologically inactive
vitamin D exists in two forms, D2 and D3, which are hydroxylated in the
1,25-dihydroxycholecalciferol (1,25[OH]2D), also called calcitriol.
PTH, Parathyroid hormone.
736 Section XIII  Diseases of Bone and Bone Mineral Metabolism
action of 1,25(OH)2D is to regulate intestinal calcium absorp-
tion. PTH, through 1,25(OH)2D, indirectly regulates calcium
absorption from the diet by the intestine. The hypocalcemia of
hypoparathyroidism is a result, in part, of inadequate intestinal
calcium absorption. Conversely, hyperparathyroidism is associ-
ated with hypercalciuria and nephrolithiasis, both of which
directly result from increases in circulating 1,25(OH)2D levels.
Measurement of 1,25(OH)2D can be used as an index of parathy-
roid function and intestinal calcium absorption.
Calcitonin
Calcitonin is produced by the parafollicular or C cells of the
thyroid gland in response to hypercalcemia. It was once viewed
as an essential calcium-regulating hormone. Pharmacologic
doses of calcitonin may reduce serum calcium levels, but little
evidence exists that calcitonin has homeostatic relevance in
humans.
Integration of Calcium Homeostasis
Ingestion of a greater than normal dietary calcium load (Fig.
72-6A) leads to a mild rise in the serum calcium level, followed
by immediate suppression of PTH. This action immediately
permits marked increases in renal calcium excretion by the distal
tubule. It also immediately deceases osteoclastic activity, which
prevents continued bone resorption but allows continued
calcium entry from the ECF into an unmineralized osteoid sink.
These two effects produce a rapid, short-term reduction in serum
calcium to normal levels. However, if the high-calcium diet is
maintained over the long term, these adaptations are insufficient.
Continued renal calcium wasting leads to hypercalciuria (with
nephrolithiasis and nephrocalcinosis), and unopposed osteoblas-
tic bone formation leads to excessive skeletal mineralization (i.e.,
osteopetrosis).
Two additional responses (see Fig. 72-6B) are required to
prevent the long-term adverse effects of a high-calcium diet. First,
subacute or chronic suppression of PTH reduces circulating
1,25(OH)2D. This reduces the efficiency of calcium absorption
from the intestine, calcium entry into the ECF, and urinary
Acute response to a high calcium intake
PTH ↓
0 mg
2000 mg
300 mg Serum Ca 500 mg
9.8 → 9.5 mg/dL
500 mg
10,000 mg
Skeleton
GI tract
1700 mg 300 mg Kidney
A B
FIGURE 72-6  Responses to increases in calcium intake. A, The acute response. B, The chronic response. Details are provided in the text.
GI, Gastrointestinal.
calcium excretion. Second, a chronic decrement in PTH leads to
a chronic decline in osteoblastic activity. No osteoid is formed,
and the ability to deposit calcium into the skeletal sink is lost.
Conversely, during brief periods of dietary calcium deficiency
(Fig. 72-7A), as occurs between meals, the serum calcium level
declines almost imperceptibly and the PTH rises, which imme-
diately prevents renal calcium losses from continuing. At the
same time, an acute activation of osteoclasts occurs, delivering
calcium into the ECF. The acute response to low calcium intake
is the appropriate elimination of renal calcium losses and devel-
opment of a new source of calcium entry into the ECF.
Over the longer term, the initial response is inadequate and
leads to skeletal demineralization. A longer-term solution is
required, and the adaptation is twofold (see Fig. 72-7B). First, a
chronic low calcium intake, as may occur in a person with lactose
intolerance, leads to a chronic elevation in PTH, and over a
matter of days to weeks, this leads to an increase in the
1,25(OH)2D level, which increases the efficiency of calcium
absorption from the intestine (i.e., increase in the fractional
absorption of calcium) to compensate for the reduction in dietary
intake. Second, chronically elevated PTH leads to an increase in
osteoblast activity and osteoid synthesis, with resultant increases
in skeletal calcium deposition. In this steady-state adaptation to
a low-calcium diet, PTH levels are elevated, and coupled increases
in osteoclastic and osteoblastic activities take place (i.e., increased
bone turnover), but net skeletal calcium losses are negligible or
normal.
From an evolutionary standpoint, as life moved from a
calcium-rich marine environment to a terrestrial setting in which
calcium availability was unpredictable, a complex, elegant regula-
tory mechanism evolved that permitted survival without requir-
ing intentional behavioral adaptations to the vagaries of calcium
supply. As discussed in Chapter 73, disorders that cause hyper-
calcemia or hypocalcemia are always caused by abnormalities at
the interfaces of the ECF with the intestine, kidney, and skeleton.
The physician need only recall these homeostatic premises to
dissect the pathophysiologic process with precision and treat the
underlying disorder effectively.
Chronic response to a high calcium intake
PTH ↓
0 mg
2000 mg
160 mg Serum Ca 0 mg
9.5 mg/dL
0 mg
10,000 mg
Skeleton
GI tract
1840 mg 160 mg Kidney
 Chapter 72  Normal Physiology of Bone and Mineral Homeostasis 737

Acute response to a low calcium intake Chronic response to a low calcium intake

PTH ↑ PTH ↑
500 mg 1000 mg
400 mg 400 mg
60 mg Serum Ca 500 mg 140 mg Serum Ca 0 mg
9.5 → 9.2 mg/dL 9.5 mg/dL
1000 mg 1000 mg
10,000 mg 10,000 mg
Skeleton Skeleton

GI tract GI tract

340 mg 0 mg Kidney 260 mg 140 mg Kidney

A B

FIGURE 72-7  Responses to decreases in calcium intake. A, The acute response. B, The chronic response. Details are provided in the text. GI, Gas-
trointestinal; PTH, parathyroid hormone.

TABLE 72-1  THERAPEUTIC PHOSPHORUS PREPARATIONS

COMPOSITION* mOsm/ PHOSPHATE PHOSPHORUS SODIUM POTASSIUM
PREPARATION (per mL) pH kg H2O (mmol/mL) (mg/mL) (mEq/mL) (mEq/mL)
ORAL
Cow’s milk (whole) — — 288 0.029 0.9 0.025 0.035
Neutra-Phos† Na2HPO4, NaH2PO4, K2HPO4, KH2PO4 7.3 — 0.107 3.33 0.095 0.095
Phospho-Soda† 180 mg Na2HPO4 • 7H2O + 480 mg 4.8 8240 4.150 128.65 4.822 0
NaH2PO4 • H2O
Acid sodium phosphate 136 mg Na2HPO4 • 7H2O + 58.8 mg H3PO4 4.9 1740 1.018 35.54 1.015 0
(NF 85%)
Neutral sodium phosphate 145 mg Na2HPO4 • 7H2O + 18.2 mg 7.0 1390 0.673 20.86 1.214 0
NaH2PO4 • H2O
PARENTERAL
Neutral sodium phosphate 10.07 mg Na2HPO4 + 2.66 mg 7.35 202 0.090 2.80 0.161 0
NaH2PO4 • H2O
Neutral sodium, 11.5 mg Na2HPO4 + 2.58 mg KH2PO4 7.4 223 0.100 3.10 0.162 0.019
potassium phosphate
Sodium phosphate† 142 mg Na2HPO4 + 276 mg NaH2PO4 • H2O 5.7 5580 3.000 93.00 4.000 0
Potassium phosphate† 236 mg K2HPO4 + 224 mg KH2PO4 6.6 5840 3.003 93.11 0 4.360
From Lentz RD, Brown DM, Kjellstrand CM: Treatment of severe hypophosphatemia, Ann Intern Med 89:941-944, 1978.
H2O, Water; K2HPO4, dipotassium hydrogen phosphate; KH2PO4, potassium dihydrogen phosphate; Na2HPO4, disodium hydrogen phosphate; NaH2PO4, sodium dihydrogen
phosphate.
*Hydration states are important. For example, 268 mg Na2HPO4 • 7H2O (molecular weight 268) equals 1.00 mmol, whereas 268 mg Na2HPO4 (molecular weight 142) equals
1.89 mmol.
†
Commercial preparations: Neutra-Phos, Willen Drug Company, Baltimore, Md. (Neutra-Phos K has twice as much potassium and no sodium); Phospho-Soda, C.B. Fleet Company,
Lynchburg, Va. (enema is one-third the strength of Phospho-Soda and can be used orally); sodium phosphate, Abbott Laboratories, North Chicago, Ill.; potassium phosphate, Invenex
Pharmaceuticals, Grand Island, N.Y., or Abbott Laboratories. Because Neutra-Phos was not readily dissolved and its specific composition is unknown, data shown are those provided by the
manufacturer.

  PHOSPHATE HOMEOSTASIS
Phosphorus is an inorganic element, abbreviated as P in physical
chemistry literature and as Pi in physiologic use. The biologically
relevant molecule is the negatively charged, trivalent phosphate
ion (PO4). Phosphorus is the form that most clinical laboratories
measure rather than the more biologically relevant phosphate
ion.
Phosphate is an important physiologic buffer, and at neutral pH
in blood, phosphate is apportioned between HPO4 (divalent) and
H2PO4 (monovalent). Physicians need to be aware that phospho-
rus measurements in blood are reported in milligrams per deciliter
(mg/dL), whereas pharmaceutical preparations list phosphorus
in millimoles (mmol). A chart converting milligrams to milli-
moles for some common phosphate-containing preparations is
provided in Table 72-1. These values and total doses should be
reviewed for the specific phosphorus preparation being pre-
scribed in consultation with the pharmacist and hospital formu-
lary if necessary.
Phosphate regulates or participates in the regulation of an
enormous number of biologic processes fundamental to life.
They include being an integral component of the DNA double
helix, shuttling oxygen from hemoglobin to cells and vice versa
using 2,3-diphosphoglycerate (2,3-DPG), intracellular signaling
through kinases that attach phosphate groups to other molecules,
facilitating critical intracellular messenger systems such as cyclic
monophosphate (cAMP) and inositol phosphates, maintaining
basic intracellular redox status through the nicotinamide adenine
dinucleotide phosphate (NADP-NADPH) system, and serving
738 Section XIII  Diseases of Bone and Bone Mineral Metabolism
as the gateway to the glucose metabolic pathway through glucose
6-phosphate.
Phosphorus is primarily an intracellular ion. In addition to its
critical intracellular roles, phosphate has a key extracellular role.
The anion pairs with calcium in the hydroxyapatite crystal lattice
that provides structural integrity to the skeleton (discussed
earlier). As with calcium, phosphate is critical to skeletal strength,
and disorders of phosphorus homeostasis, such as hypophospha-
temic rickets, lead to pathologic skeletal fractures. The skeleton
also serves as a major storage site for phosphate that is accessed
in times of severe phosphate deficiency.
The broad intracellular roles for phosphate have two corollar-
ies. First, clinically significant intracellular phosphate deficiency
may exist without marked hypophosphatemia. Second, life-
threatening phosphate deficiency is often unrecognized because
its manifestations (i.e., reduced levels of consciousness, hypoten-
sion, respirator dependence, and muscular weakness) are non-
specific but common in intensive care unit settings. Astute
clinicians learn to recognize general debility as a potential sign of
phosphorus deficiency. Phosphate repletion in this setting may
produce dramatic results.
In contrast to regulation of the serum calcium concentration,
which is very tight, the regulation of serum phosphate concentra-
tions is relatively lax. The serum phosphorus level is maintained
in a broad range between about 3.0 and 4.5 mg/dL. In contrast
to extracellular calcium concentrations, extracellular phosphate
concentrations are not critically important. Because phosphate is
abundant in most diets, a tight systemic regulatory mechanism
for serum phosphate is unnecessary.
A physiologic black box can be developed for phosphate
metabolism (Fig. 72-8). The box represents the ECF, and as with
calcium, it has interfaces with the GI tract, kidney, and skeleton.
Because most phosphate is contained within cells, the phosphate
black box has a quantitatively significant interface with the intra-
cellular compartment.
Intestinal Phosphate Absorption
A normal diet contains about 1200 to 1600 mg of phosphorus,
and about two thirds of this amount, or 800 to 1200 mg, is
ICF
~750 mg
1200 mg
800 mg Serum PO4 0 mg
3.3 mg/dL
~750 mg
8000 mg
Skeleton
GI tract
400 mg 800 mg Kidney
FIGURE 72-8  The phosphate physiologic black box. See Figure 72-1
for nomenclature and the text for details. GI, Gastrointestinal; ICF, intra-
cellular fluid.
absorbed each day. This fixed fractional absorption of about 67%
occurs in the duodenum and jejunum. In the normal world of
phosphate abundance, this intake is more than ample. Under
conditions of dietary phosphorus deficiency, as occurs in chronic
alcoholism, intensive care units, intestinal malabsorption, or
phosphate-binding antacid use, failure of adequate phosphorus
absorption presents a physiologic challenge for which no physi-
ologic remedy exists.
Skeletal Phosphate Fluxes
As with calcium, osteoclastic bone resorption and osteoblastic
new bone formation (see Figs. 72-1 and 72-3) lead to skeletal
phosphate exit or entry, respectively. Although the skeleton can
be used as a source of phosphorus, phosphorus can be viewed as
a passive passenger with calcium in the calcium regulatory
process. Under pathophysiologic conditions, skeletal calcium
fluxes may become important. For example, skeletal destruction
in multiple myeloma or severe immobilization syndromes leads
to hypercalcemia and hyperphosphatemia, which with the con-
comitant hypercalcemia leads to nephrocalcinosis and renal
failure. Conversely, osteoblastic metastases in prostate and breast
cancers and the hungry bone syndrome after parathyroidectomy
lead to clinically significant hypophosphatemia.
Intracellular-Extracellular Phosphate Fluxes
Phosphate shuttles from extracellular to intracellular compart-
ments. This issue becomes important in certain clinical settings.
For example, in the setting of metabolic acidosis, phosphate
leaves the intracellular compartment and may lead to hyperphos-
phatemia, whereas under conditions of alkalosis, serum phos-
phate concentrations decline, and hypophosphatemia develops
as phosphate enters the intracellular compartment.
The intracellular phosphate level has important clinical impli-
cations, in part, in the settings of crush injury (i.e., rhabdomy-
olysis) and tumor lysis syndrome. In both conditions, large
intracellular loads of phosphate are delivered into the ECF and
result in hypocalcemia, seizures, nephrocalcinosis, and renal
failure. Conversely, glucose shifts phosphate into cells as glucose
6-phosphate, and overzealous intravenous or oral caloric restitu-
tion in the undernourished patient can result in severe hypo-
phosphatemia and sudden death.
Renal Phosphate Handling
The most important mechanism for maintaining a normal serum
phosphorus concentration is renal phosphorus regulation. As
with calcium, phosphate is filtered by the glomerulus, and 90%
is reabsorbed (i.e., tubular reabsorption of filtered phosphate
[TRP]). The remaining 10% is excreted (i.e., fractional excretion
of phosphorus [FEPi]). The FEPi can be calculated in a spot urine
sample as follows:
FE Pi = (urine Pi[mg/dL]/urine creatinine [mg/dL])
(serum creatinine [mg/dL]/serum phosphorus [mg/dL])
The TRP is simple to calculate:
TRP = 1 − FE Pi
The renal handling of phosphorus is best considered as a
tubular maximum (Tm)–regulated process. The TmP is normally
 Chapter 72  Normal Physiology of Bone and Mineral Homeostasis 739

identical to a normal serum phosphorus concentration in blood,
about 3.3  mg/dL. If the serum phosphate concentration rises
above this level, phosphaturia occurs, and the serum phos-
phorus declines to 3.3  mg/dL. If the serum phosphate con-
centration declines below 3.3  mg/dL, filtered phosphate is
entirely reabsorbed, and urinary phosphate excretion declines
to zero.
The TmP can be considered as a dam in the phosphate reser-
voir, over which excess phosphate spills and whose level controls
the concentration of serum phosphorus. The TmP is not fixed but
can be moved upward or downward, depending on metabolic
needs and prevailing metabolic conditions (described later).
The TRP or FEPi can be readily calculated, and the TmP can
be derived from the nomogram of Bijvoet, which is shown in
Figure 72-9. This process proves enormously useful in clinical
practice because it is the central starting point for determining
whether hypophosphatemia is principally renal or nonrenal in
origin.
Parathyroid Hormone and Phosphatonins
PTH has long been appreciated to be phosphaturic; it lowers
the TmP or, more accurately, inhibits proximal renal tubular
phosphate reabsorption. This characteristic explains the hypo-
phosphatemia associated with primary and secondary hyper­
parathyroidism and the hyperphosphatemia associated with
hypoparathyroid states. Excessive PTH lowers the TmP, whereas
low PTH values allow the TmP to rise to supranormal levels.
0
.0
0.0 10.0
00
0.
The TmP level is regulated by other factors.. For example,
experimental dietary phosphorus deprivation in laboratory
animals and humans leads to a PTH-independent increase in the
TmP, and high-phosphate feeding results in a PTH-independent
decline in the TmP. For decades, investigators in this area have
postulated the existence of a phosphaturic hormones called phos-
phatonins, one of which is fibroblast growth factor-23 (FGF-23).
This field has progressed rapidly over the past decade, but much
remains to be worked out. The main physiologic points are that
a hormonal system independent of PTH also regulates renal
phosphorus handling and that the kidney is the prime regulatory
organ for phosphate homeostasis.
  REGULATION OF SERUM MAGNESIUM
Magnesium is a divalent cation. Magnesium homeostasis paral-
lels phosphorus homeostasis. Magnesium and phosphate are
principally intracellular, with concentrations inside the cell that
far exceed those outside the cell. Both substances govern key
intracellular regulatory processes. In the case of magnesium,
these processes include fundamental events such as DNA replica-
tion and transcription, translation of RNA, the use of adenosine
triphosphate as an energy source, and regulated peptide hormone
secretion.
Both substances are abundant inside all kinds of cells. Because
they are well supplied in vegetarian and carnivorous diets, little
evolutionary pressure exists to develop a complex regulatory
network, and as with phosphate, serum magnesium concentra-
tions are not tightly regulated. Because magnesium is principally
intracellular, measurement of serum levels may provide false esti-
2.0 5.0 mates of actual total body and intracellular magnesium status.
Because magnesium is essential for fundamental processes such
1.8 as gene transcription and cellular energy use, life-threatening
Renal threshold phosphate conc. (TmPO4/GFR)

0.2
magnesium deficiency is often unrecognized because its symp-
Actual plasma phosphate conc. (PO4)

1.0 0.4 1.6 4.0

toms are frustratingly nonspecific: weakness, respirator depen-
1.4 dence, diffuses neurologic syndromes (including seizures), and
0.6
cardiovascular collapse.
99
0. 1.2 3.0 Magnesium has a molecular weight of 24 (1 mole = 24 g), and
2.0 0.8 95
TR

1 0.
.0 90 because it is divalent, one equivalent is 12 g. Blood magnesium
P

0
05 0. 1.0
1.0 0. 80 measurements are often provided in milligrams per deciliter
10 0. .70
0.
CP

0 60 (mg/dL) or milliequivalents per liter (mEq/L); oral magnesium

20 0. 50 0.8 2.0
O4

3.0 1.2 0. .30

/C

0 40 0. 0 supplements are expressed in milligrams per tablet or milliequiv-

cr

0. 50 4
0.
ea

1.4 0 0.6 alents per vial; and urinary magnesium excretion values are given
t

0. 0 .3
6 0 in milliequivalents or milligrams per 24 hours. Constructing a
0. 20
4.0 1.6 70 0. 0.4 1.0
0. black box for magnesium is helpful (Fig. 72-10), and the magne-
80 10 sium values are provided in milligram and milliequivalent units.
1.8 0. 0.
90 0 As with phosphorus, magnesium has quantitatively important
0. .0
00.0
5.0 2.0 0.0 interfaces with the intestine, skeleton, intracellular supplies, and
00
1. kidney. At the level of the intestine, magnesium is widely avail-
able in normal diets, and regulation is limited; the body absorbs
FIGURE 72-9  Nomogram shows the tubular maximum for the phos-
phorus glomerular filtration rate (TmP-GFR). It allows conversion of the about one third of what is ingested. In normal circumstances,
fractional excretion of phosphorus (or its inverse, the tubular reabsorp- dietary magnesium is abundant, absorption is ample, and mag-
tion of filtered phosphate [TRP]) into the TmP-GFR. The TRP is calcu- nesium deficiency does not occur. However, deficiency may
lated, and a line is drawn extending from the serum phosphorus level occur with alcoholism, in intensive care unit settings in which
(left vertical line), through the TRP (middle diagonal line), to the right
adequate nutrition often is not provided, or with intestinal
vertical line, which represents the TmP/GFR. TmP values are provided in
millimolar and milligram per deciliter units. TmP values below 1.0 mmol malabsorption.
or 2.5 mg/dL are abnormal and indicate phosphaturia. Ccreat, Creatinine At the level of the skeleton, magnesium is incorporated into
concentration; CPO4, phosphate concentration. (From Walton RJ, Bijvoet the hydroxyapatite crystal as mineralization of osteoid occurs,
OL: Nomogram for derivation of renal threshold phosphate concentra- and it is released by osteoclastic bone resorption (see Figs. 72-1
tion, Lancet 2:309–310, 1975.)
and 72-3). In quantitative terms, these fluxes are small.
740 Section XIII  Diseases of Bone and Bone Mineral Metabolism

With regard to homeostatic regulation, magnesium homeosta-

sis can best be viewed as a renal Tm-regulated process (see Renal
ICF
Phosphate Handling), with the renal Tm for magnesium set at a
fixed level of about 2.2 mg/dL. In this scenario, abundant dietary
magnesium exists, and excessive magnesium intake is managed
~? mg by spillage of excess magnesium over the Tm set at 2.2 mg/dL
300 mg
(25 mEq) Serum Mg and into the urine. Conversely, in settings of dietary magnesium
2.0 mg/dL 0 mg deficiency, which equate evolutionarily with caloric deficiency,
100 mg (1.7 mEq/L)
short-term deficiency is prevented when serum levels fall below
(8 mEq) 2500 mg ~? mg
(200 mEq)
the renal Tm of 2.0 mg/dL. No known independent hormonal
Skeleton regulatory system for magnesium exists.

  PROSPECTUS FOR THE FUTURE

GI tract
200 mg 100 mg Kidney
(16 mEq) (8 mEq)
FIGURE 72-10  The magnesium physiologic black box. See Figure
72-1 for nomenclature and the text for details. Magnesium values are
provided in milligrams (mg) and milliequivalents (mEq). GI, Gastroin-
testinal; ICF, intracellular fluid.
Many instances of magnesium deficiency are caused by exces-
sive renal losses. Examples include the magnesuria that accom-
panies saline infusions, diuretic use, alcohol use, and secondary
hyperaldosteronism states such as cirrhosis and ascites. As with
calcium and phosphorus, the fractional excretion of magnesium
(FEMg) can be calculated, and it should be used as an index of
whether the kidney is appropriately conserving magnesium in
states of hypomagnesaemia or whether renal magnesium wasting
is the cause of the hypomagnesaemia. The normal FEMg is 2% to
4%. Hypomagnesemic individuals have FEMg values below 1%
to 2%.
Although it may seem that calcium, PTH, vitamin D, magnesium,
and phosphorus homeostasis and skeletal biology are well under-
stood, it should be clear that many of the physiologic details
described in this chapter have been elucidated only during the
past 10 to 15 years, and new regulatory proteins (e.g., fibroblast
growth factor 23) and diseases continue to be identified. This
area of research is dynamic, with many unanswered questions
remaining.
SUGGESTED READINGS
Christov M, Juppner H: Insights form genetic disorders of phosphate homeostasis,
Semin Nephrol 33:143–157, 2013.
Lentz RD, Brown DM, Kjellstrand CM: Treatment of severe hypophosphatemia,
Ann Intern Med 89:941–944, 1978.
Melmed S, Polonsky KS, Larsen PR, et al, editors: Williams textbook of
endocrinology, ed 12, Philadelphia, 2012, Saunders.
Rosen CJ, editor: The American Society for Bone and Mineral Research primer
on metabolic bone diseases and disorders of mineral metabolism, ed 8,
Washington, D.C., 2013, American Society for Bone and Mineral Research.

Disorders of Serum Minerals
Steven P. Hodak and Andrew F. Stewart
  INTRODUCTION
In this chapter, we consider disorders that lead to increases or
decreases in the circulating concentrations of calcium, phospho-
rus, and magnesium. Chapter 72 describes normal calcium, phos-
phorus, and magnesium metabolism.
The optimal approach to diagnosing and treating these disor-
ders is to understand their underlying physiology and patho-
physiology. Coherent diagnostic and successful therapeutic plans
can then be developed. Years of experience suggest a persistent
propensity to jump to the common items on the differential diag-
nosis list without fully considering the other options. In so doing,
the correct and often easily treatable diagnosis is overlooked. For
example, hypercalcemia in the setting of a pulmonary nodule
may indicate the humoral hypercalcemia of malignancy, and
many physicians jump to this diagnosis with its grim prognosis.
However, this complex may represent hypercalcemia in a patient
with treatable tuberculosis or primary hyperparathyroidism
(HPT) in a person with a long-standing and inactive pulmonary
scar. Complete differential diagnoses are provided in the tables
that follow.
  HYPERCALCEMIA
Symptoms and Signs
Hypercalcemia causes hyperpolarization of neuromuscular cell
membranes and therefore refractoriness to stimulation (see
Chapter 72). This condition manifests clinically as skeletal mus-
cular weakness, smooth muscle hypoactivity with constipation
and ileus, and the full spectrum of neurologic dysfunction, pro-
gressing from lassitude to mild confusion to deep coma. Hyper-
calcemia also leads to renal failure. It reduces the glomerular
filtration rate (GFR) through afferent arteriolar vasoconstriction
and activation of the calcium receptor in the distal nephron. It
causes a form of nephrogenic diabetes insipidus that is associated
with polydipsia and polyuria. These events lower the extracellular
fluid (ECF) volume and lower the GFR.
Hypercalcemia may lead to interstitial calcium phosphate
crystal deposition in the kidney (i.e., nephrocalcinosis or
interstitial nephritis) and nephrolithiasis with obstructive uropa-
thy. Hypercalcemia may also lead to shortening of the QTc
interval on the electrocardiogram. Frequently, however, asymp-
tomatic hypercalcemia is discovered on routine laboratory
testing.
Whether a person develops symptoms depends on several
factors. One is the degree of hypercalcemia. People with serum
calcium values above 13 mg/dL usually are symptomatic. The
73 
duration of hypercalcemia is also important. A gradual increase
in serum calcium, even into the severe 15- to 17-mg/dL range,
may cause few symptoms if it occurs slowly enough. The overall
health status and age of the person with hypercalcemia influence
the severity of symptoms. For example, a child with severe
immobilization-induced hypercalcemia in the 15-mg/dL range
may be completely alert, whereas an elderly person with underly-
ing Alzheimer’s disease and narcotic use may become comatose
with a serum calcium level of 11.5 mg/dL.
Pathophysiology
The physiologic black box described in Chapter 72 should be
considered when attempting to diagnose or treat hypercalcemia.
These disorders can be grouped into factitious disorders (e.g.,
abnormalities in serum proteins), renal disorders (e.g., thiazide
diuretics, lithium use), gastrointestinal disorders (e.g., sarcoid,
milk-alkali syndrome), skeletal disorders (e.g., hypercalcemia of
malignancy, immobilization hypercalcemia), and combined dis-
orders. Primary HPT is a good example of the latter, with impor-
tant gastrointestinal (GI) and renal components. The diagnoses
in Table 73-1 should be considered with regard to the underlying
pathophysiologic mechanism and the clinical setting.
Differential Diagnosis
Malignancy-Associated Hypercalcemia
The most common cause of hypercalcemia among hospitalized
patients is cancer. Hypercalcemia occurs late in the course of
cancer and usually progresses rapidly, followed by death. About
50% of patients with cancer survive 30 days after the develop-
ment of hypercalcemia.
Hypercalcemia usually is encountered only in patients with
large tumor burdens. Conversely, small, occult cancers rarely
cause hypercalcemia. The exceptions to this rule are small neuro-
endocrine tumors, such as islet cell tumors and bronchial carci-
noids. Certain tumors are common causes of hypercalcemia,
including breast, renal, squamous, and ovarian carcinomas and
multiple myeloma and lymphoma. Other common cancers, such
as colon, prostate, and gastric carcinomas, are not commonly
associated with hypercalcemia.
Cancer may lead to hypercalcemia through several mecha-
nisms, the most common of which is humoral hypercalcemia of
malignancy (HHM). HHM accounts for about 80% of patients
with malignancy-associated hypercalcemia (MAHC) and is the
result of excessive secretion by tumors of parathyroid hormone–
related protein (PTHrP). PTHrP mimics the actions of parathy-
roid hormone (PTH) on the kidney to prevent calcium excretion
741
742 Section XIII  Diseases of Bone and Bone Mineral Metabolism

often a breast cancer or a hematologic neoplasm such as multiple

TABLE 73-1  DISORDERS ASSOCIATED WITH myeloma, leukemia, or lymphoma. Local factors are secreted by
HYPERCALCEMIA tumors in the bone marrow that induce osteoclastic bone resorp-
Malignancy-associated   Vitamin D and derivatives tion. They include PTHrP, macrophage inflammatory protein 1α
hypercalcemia (calcitriol, dihydrotachysterol)
  Humoral hypercalcemia of   Vitamin A (including retinoic acid (MIP-1α), receptor-activating nuclear factor-κB ligand
malignancy derivatives) (RANKL), interleukin-6, and interleukin-1. These patients have
  Hypercalcemia caused by   Foscarnet reductions in PTH, PTHrP, and 1,25(OH)2D levels, and have
1,25-dihydroxyvitamin D3 Milk-alkali syndrome
(1,25[OH]2D3)–secreting Immobilization plus high bone normal to elevated serum phosphorus values.
lymphomas turnover A third form of MAHC is secretion of 1,25(OH)2D by lym-
  Hypercalcemia caused by direct   Juvenile skeleton phomas and dysgerminomas. This form is unusual, and the mech-
skeletal invasion   Paget’s disease
  True ectopic hyperparathyroidism   Myeloma and breast cancer with anism is interesting. Although direct bone involvement may
Primary and tertiary bone metastases occur and may contribute to hypercalcemia, the increase in
hyperparathyroidism   Prehumoral hypercalcemia of 1,25(OH)2D leads to intestinal calcium hyperabsorption and to
Familial hypocalciuric hypercalcemia malignancy
or familial benign hypercalcemia   Mild primary systemically driven bone resorption. This condition is essentially
Granulomatous disorders hyperparathyroidism a malignant version of the hypercalcemia that occurs in sarcoid-
  Sarcoid   Secondary hyperparathyroidism osis (see Granulomatous Disorders).
  Berylliosis (e.g., from continuous
  Foreign body ambulatory peritoneal dialysis)
  Tuberculosis Chronic and acute renal failure Primary and Tertiary Hyperparathyroidism
  Coccidioidomycosis   Recovery phase of Although MAHC is the most common cause of hypercalcemia
  Blastomycosis rhabdomyolysis-induced acute
  Histoplasmosis renal failure among inpatients, primary HPT is by far the most common cause
  Granulomatous leprosy   Chronic hemodialysis among healthy outpatients. Together, MAHC and HPT account
  Eosinophilic granuloma   Calcitriol for about 90% of cases of hypercalcemia. Most often, the hyper-
  Histiocytosis   Immobilization
  Inflammatory bowel disease   Decreased calcium clearance calcemia of HPT is mild, with serum calcium values in the range
Endocrine disorders other than   Calcium carbonate of 10.6 to 11.5 mg/dL. However, HPT occasionally produces
hyperparathyroidism Total parenteral nutrition (TPN) spectacular hypercalcemia in the 20-mg/dL range. In about 85%
  Hyperthyroidism   Calcium-containing TPN in
  Pheochromocytoma patients with decreased of patients, hypercalcemia results from a single parathyroid
  Addisonian crisis glomerular filtration rate adenoma that overproduces PTH, and in about 15% of patients,
  Vasoactive intestinal peptide–   Chronic TPN in patients with it results from multiple-gland hyperplasia. In less than 1% of
producing tumor (VIPoma); short bowel syndrome
watery diarrhea, hypokalemia, Hyperproteinemia patients, HPT may result from parathyroid carcinoma. For all
and achlorhydria (WDHA)   Volume contraction with these etiologies, the diagnosis is made by the discovery of an
syndrome hyperalbuminemia elevated serum PTH level in a patient with hypercalcemia. Hypo-
Medications   Myeloma with calcium-binding
  Thiazides immunoglobulin phosphatemia, a reduction in the TmP, increased plasma
  Aminophylline End-stage liver disease 1,25(OH)2D and serum chloride levels, and a reduction in the
  Lithium Manganese intoxication serum bicarbonate concentration are typical features.
  Estrogen/antiestrogen in breast
cancer with bone metastases Primary HPT often is asymptomatic. However, some patients
(estrogen flare) develop hypercalciuria and calcium nephrolithiasis, most often as
a result of calcium oxalate and, less commonly, calcium phos-
phate stones. Some patients with HPT, especially those with a
more severe form, have a reduction in bone mineral density char-
and on the skeleton to activate osteoclasts and induce bone acterized histologically as hyperparathyroid bone disease, also
resorption. PTHrP is the product of many normal cell types and, called osteitis fibrosa cystica (see Chapter 74). Other patients may
in health, is typically produced at low levels. develop mild to severe renal failure as a result of the mechanisms
Tumors classically associated with the HHM mechanism are described earlier. Each of the previously described conditions—
squamous carcinomas of any site (i.e., larynx, lung, cervix, and significant osteopenia, kidney stones, reduced renal function, and
esophagus), renal carcinomas, ovarian carcinomas, and breast a serum calcium concentration greater than 1 mg/dL above
cancer. Hypercalcemia in HHM occurs in the absence of skeletal normal—is an indication for parathyroidectomy. Other patients
metastases or in the setting of a few skeletal metastases. If tumor may be monitored conservatively. In patients who refuse or are
resection or ablation is possible, hypercalcemia reverses. In addi- unable to undergo surgery, medical management of hypercalce-
tion to hypercalcemia, these patients have elevations in PTHrP mia may be attempted using bisphosphonates or the calcium
concentrations and reductions in the levels of PTH, receptor mimetic cinacalcet.
1,25-dihydroxyvitamin D3 (1,25[OH]2D), and serum phospho- HPT can occur as part of one of the multiple endocrine neo-
rus and the tubular maximum for phosphorus (TmP) (see plasia (MEN) syndromes. It is associated with pituitary and islet
Chapter 72). tumors (MEN 1) and with pheochromocytomas and medullary
A second form of MAHC is caused by local tumor invasion of carcinoma of the thyroid (MEN 2).
the skeleton, a process called local osteolytic hypercalcemia (LOH). Secondary HPT is an appropriate increase in circulating PTH
LOH accounts for about 20% of patients with MAHC. In these associated with eucalcemia or hypocalcemia. It occurs in an
patients, unlike those with HHM, the skeletal metastatic or attempt to correct hypocalcemia resulting, for example, from
primary tumor burden is large, and the offending tumor is most vitamin D deficiency or chronic renal failure
 Chapter 73  Disorders of Serum Minerals 743
Tertiary HPT refers to HPT associated with hypercalcemia
that occurs in the setting of prolonged stimulation of the parathy-
roid glands, such as chronic renal failure with hypocalcemia or
chronic vitamin D deficiency resulting from malabsorption.
Chronic parathyroid stimulation leads to parathyroid hyperplasia
and sometimes adenomas, and these conditions may fail to sup-
press normally and cause hypercalcemia. The classic example is
development of PTH-dependent hypercalcemia after successful
renal transplantation.
Familial Hypocalciuric Hypercalcemia
Familial hypocalciuric hypercalcemia, also called familial benign
hypercalcemia, is an autosomal dominant inherited disorder that
results from heterozygous inactivating mutations in the calcium
receptor. Parathyroid glands that bear such a defective receptor
on their surface inappropriately perceive circulating calcium con-
centrations to be low. They therefore behave as though the patient
is hypocalcemic and appropriately secrete additional PTH. This
action causes the serum calcium concentration to rise, and the
PTH equilibrates at a high-normal to elevated level. The hyper-
calcemia is usually mild, in the 11- to 12-mg/dL range, but it may
be higher. Because the partially inactivated calcium receptors are
expressed in the kidney, the kidney inappropriately conserves
calcium, leading to hypocalciuria and contributing to hypercal-
cemia. Because these same calcium receptors are also expressed
in the central nervous system, the hypercalcemia is not perceived,
and affected individuals are therefore asymptomatic. The two
names of this syndrome describe it accurately.
With the exception of the hypocalciuria and the autosomal
dominant pattern of inheritance, these individuals are similar bio-
chemically to patients with primary HPT. Because affected indi-
viduals are asymptomatic and do not develop adverse sequelae
from the syndrome, its primary importance is that affected indi-
viduals be properly identified and protected from unnecessary
and ineffective parathyroidectomy. Homozygous individuals,
usually infants, develop severe hypercalcemia requiring urgent
total parathyroidectomy.
Granulomatous Disorders
Most granulomatous disorders can lead to hypercalcemia (see
Table 73-1). The prototypes are sarcoidosis, tuberculosis, and the
fungal diseases listed. As with the kidney, granulomas have the
ability to convert inactive 25-hydroxyvitamin D to the active
metabolite, 1,25(OH)2D. When exposed to sunlight, ultraviolet
radiation, or relatively trivial quantities of dietary vitamin D, indi-
viduals with these disorders may develop mild to severe
hypercalcemia.
Hypercalcemia results from intestinal calcium hyperabsorp-
tion and 1,25(OH)2D-induced bone resorption; the former is
the important component in most cases. Because of the hyper-
calcemia, PTH is suppressed, and the serum phosphorus level is
elevated. The combination of hypercalcemia and hyperphospha-
temia may lead to nephrocalcinosis and renal failure. Treatment
focuses on correcting the underlying disorder. Measures include
a low dietary calcium intake, a low vitamin D intake, limiting sun
exposure, and hydration. Loop diuretics are administered to
accelerate calcium clearance, and if the hypercalcemia is severe,
glucocorticoids are used.
Endocrine Disorders Other Than
Hyperparathyroidism
In addition to HPT, four other endocrine disorders have been
associated with the development of hypercalcemia. As many as
50% of people with hyperthyroidism have at least mild hypercal-
cemia. The hypercalcemia is rarely greater than 11 mg/dL. The
mechanism is thought to be an increase in osteoclast activation
by thyroid hormone.
A second disorder is pheochromocytoma. Some of these indi-
viduals are hypercalcemic as a result of primary HPT occurring
in the MEN 2 syndrome, but others become hypercalcemic as a
result of PTHrP secretion by a pheochromocytoma. Hypercalce-
mia has also been reported in patients with hypoadrenalism and
those with islet cell tumors called VIPomas.
Medications
Drugs that may cause hypercalcemia include thiazide diuretics,
lithium, aminophylline, theophylline, vitamins D and A, foscar-
net, and estrogens and tamoxifen in the setting of breast cancer
with extensive skeletal metastases.
Milk-Alkali Syndrome
The normal intake of calcium is in the range of 600 to 1200 mg/
day for most people. As reviewed in Chapter 72, absorption of
calcium from the diet is tightly controlled. However, ingestion of
very large quantities of calcium may overwhelm this system and
lead to hypercalcemia. This condition was originally described in
the 1940s in patients ingesting enormous quantities of milk,
cream, and antacids. It is still encountered with some regularity
in patients ingesting large quantities of calcium carbonate or
other calcium-containing antacids for peptic ulcer disease. For
hypercalcemia to occur, calcium intake must exceed 4 g/day, and
it is often in the 10- to 20-g/day range. Severe hypercalcemia is
common and may lead to renal failure.
Immobilization
Hypercalcemia due to immobilization requires two conditions:
complete immobilization (e.g., quadriplegia) for a period of weeks,
occurring on a background of high bone turnover, as occurs in
young adults or children, HPT, Paget’s disease, and malignant
skeletal disease such as breast cancer with bone metastases or
multiple myeloma. Immobilization activates osteoclastic bone
resorption and inhibits osteoblastic activity, producing a severe
uncoupling of bone resorption from formation, with rapid and
enormous net losses of calcium from the skeleton into the ECF.
Left untreated, the condition results in severe demineralization.
The syndrome is associated with hypercalciuria, which with
chronic urinary catheterization leads to urinary tract infection
and severe calcium nephrolithiasis.
The most effective treatment for hypercalcemia is active weight
bearing. Hydration and antiresorptive drugs such as the bisphos-
phonates may be used.
Chronic and Acute Renal Failure
Chronic and acute renal failure has been associated with hyper-
calcemia. The more common initial abnormality is hypocalcemia
induced by a reduction in kidney-derived 1,25(OH)2D and an
744 Section XIII  Diseases of Bone and Bone Mineral Metabolism
increase in serum phosphate as a result of diminished glomerular
filtration. However, hypercalcemia may occur in patients with
chronic renal failure as a result of calcium antacid use or as a result
of 1,25(OH)2D or paracalcitol treatment to prevent renal
osteodystrophy.
Parenteral Nutrition
Enteric and parenteral forms of nutrition have been associated
with hypercalcemia. Large doses of oral calcium provided in
hypercaloric enteric feeding regimens, particularly in the setting
of reduced renal function, may lead to a form of the milk-alkali
syndrome. More mysterious is the well-described hypercalcemic
syndrome occurring in patients treated with total parenteral
nutrition (TPN). These patients typically have short-bowel syn-
drome and are on long-term TPN. In some patients, the hyper-
calcemia can be traced to large amounts of calcium, vitamin D,
or aluminum in the TPN solution.
Hyperproteinemia
About 50% of circulating calcium is bound to serum albumin
and other proteins. Increases in serum proteins naturally lead
to an artifactual increase in total, but not ionized, serum
calcium concentrations. This increase is commonly observed
in settings of volume depletion and dehydration. Patients with
this syndrome do not display features typical of authentic
hypercalcemia: reduced mental status, prolonged QTc interval
on the electrocardiogram, and hypercalciuria. Treatment of the
“hypercalcemia” should be avoided, because it may lead to
hypocalcemic symptoms and signs such as paresthesia, tetany,
and seizures.
Treatment of Hypercalcemia
A point worth emphasizing is that not everyone requires treat-
ment for hypercalcemia. Patients with mild HPT with borderline
serum calcium values and without other complications may be
observed. Patients with end-stage refractory cancer with severe
hypercalcemia arguably may be best served by withholding
therapy. Familial hypocalciuric hypercalcemia is best left
untreated.
Therapy for hypercalcemia is optimally directed at reversing
the underlying pathophysiologic abnormality. Disorders associ-
ated with increased intestinal calcium absorption (e.g., sarcoid,
milk-alkali syndrome, 1,25[OH]2D3-secreting lymphomas) are
best treated by consuming a low-calcium diet and avoiding
vitamin D. Hypercalcemia in the setting of volume depletion and
diminished renal function is managed by expanding the ECF
volume and GFR with saline and encouraging diuresis with loop
diuretics.
Medications that induce hypercalcemia should be discon-
tinued. Disorders associated with increased osteoclastic bone
resorption, such as MAHC and immobilization hypercalcemia,
are best treated using inhibitors of bone resorption such as
the bisphosphonates pamidronate or zoledronate. Disorders
with multiple abnormalities require combinations of these
measures. Resection of parathyroid tissue in patients with
parathyroid disease is effective, and cinacalcet or bisphos-
phonates may be used if parathyroid surgery cannot be
performed.
  HYPOCALCEMIA
Symptoms and Signs
Hypocalcemia leads to a reduction in the potential difference
across cell membranes, producing hyperexcitability, particularly
of cells of the neuromuscular class (see Chapter 72). Neuromus-
cular cells spontaneously fire and produce spontaneous seizures,
paresthesias, and skeletal muscle contractions (i.e., carpal spasm,
pedal spasm, or tetany).
Two physical signs are observed on examination: Trousseau
sign, which is spontaneous contraction of the forearm muscles in
response to application of a blood pressure cuff around the upper
arm and inflation to above systolic pressure, and Chvostek sign,
which is twitching of the facial muscles with gentle tapping of the
facial nerve as it exits the parotid gland. An electrocardiographic
sign is a prolonged QTc interval. Prolonged hypoparathyroidism
may be associated with basal ganglia calcification, which is
asymptomatic but impressive on computed tomography scans
and plain x-ray films of the skull.
Pathophysiology
Hypocalcemia may result from five mechanisms: a reduction in
serum binding proteins (e.g., albumin), an increase in serum
phosphate with a resultant increase in the calcium-phosphate
solubility product, an increase in renal calcium excretion, a
reduction in intestinal calcium absorption, or a loss of calcium
from the ECF into the skeleton. In practice, several of these
factors are operative in several disorders. For example, in hypo-
parathyroidism, a reduction in intestinal calcium absorption
combines with an inability to reabsorb calcium from the distal
tubule to cause hypocalcemia, or in breast cancer with extensive
osteoblastic metastases, increases in osteoblast activity remove
calcium from the ECF, and anorexia leads to a reduction in intes-
tinal calcium intake. This knowledge is important because effec-
tive therapy requires the underlying disorder to be appropriately
managed. Giving oral vitamin D supplements to a patient with
sprue may not be effective unless the underlying malabsorption
is treated; parenteral vitamin D may be more effective.
Differential Diagnosis
Disorders that may lead to hypocalcemia are summarized in the
following sections and Table 73-2.
Hypoparathyroidism
Hypoparathyroidism causes hypocalcemia as a result of a decrease
in intestinal calcium absorption combined with reduced renal
calcium reabsorption in the distal tubule. Hypoparathyroidism
may be idiopathic or autoimmune, occurring in isolation or as
part of the polyglandular failure syndrome in association with
Graves’ hyperthyroidism, Hashimoto’s thyroiditis, Addison’s
disease, type 1 diabetes, vitiligo, mucocutaneous candidiasis, and
other autoimmune disorders. Hypoparathyroidism may com-
monly be encountered as surgical hypoparathyroidism in patients
who have undergone thyroid, parathyroid, or laryngeal surgery.
Surgical and autoimmune hypoparathyroidism together account
for most patients with hypoparathyroidism. Less common causes
include congenital hypoparathyroidism caused by DiGeorge syn-
drome, isolated parathyroid failure, or genetic mutations. Rarely,
 Chapter 73  Disorders of Serum Minerals 745

TABLE 73-2  DIFFERENTIAL DIAGNOSIS OF Pseudohypoparathyroidism

HYPOCALCEMIA Pseudohypoparathyroidism refers to a group of disorders that
Hypoparathyroidism   Vitamin D–dependent rickets, have in common resistance to the actions of PTH. In most cases,
  Surgical renal 1α-hydroxylase deficiency,
  Idiopathic and autoimmune 1,25-dihydroxyvitamin resistance results from different inactivating mutations in the
  Infiltrative diseases D–receptor defects signal-transducing protein Gsα. The most common form of the
  Wilson’s disease (copper)   Chronic renal failure syndrome, type Ia, is associated with multiple hormone resis-
  Hemochromatosis   Hepatic failure
  Sarcoidosis Hypoalbuminemia tance and a phenotype referred to as Albright’s hereditary osteo-
  Metastatic (breast) cancer Sepsis dystrophy, which includes short stature, shortened fourth and
  Congenital Hypermagnesemia and fifth metacarpals and metatarsals, obesity, mental retardation,
  Isolated, sporadic hypomagnesemia
  DiGeorge syndrome Rapid bone formation subcutaneous calcifications, and cafe au lait spots.
  Infant of mother with   Hungry bone syndrome after Patients resemble those with hypoparathyroidism; they are
hyperparathyroidism parathyroidectomy or hypocalcemic and have hyperphosphatemia. The diagnosis is
Hereditary thyroidectomy
  X-linked   Osteoblastic metastases made by the finding of an elevated circulating PTH level in a
  Parathyroid gland calcium   Vitamin D therapy of patient with hypocalcemia and hyperphosphatemia for whom
receptor (Gα11 subunit)– osteomalacia, rickets other causes of hypocalcemia and secondary hypoparathyroid-
activating mutations Hyperphosphatemia
  Parathyroid hormone (PTH)   Crush injury, rhabdomyolysis ism have been excluded. The treatment is similar to that of
signal peptide mutation   Renal failure hypoparathyroidism.
  GCM2 (formerly GCMB)   Tumor lysis
mutation   Excessive phosphate (PO4) Vitamin D Disorders
Pseudohypoparathyroidism administration (PO, IV, PR)
  Type Ia: multiple hormone Medications Active vitamin D, 1,25(OH)2D, is required to absorb calcium
resistance, Albright’s hereditary   Mithramycin, plicamycin from the intestine. Activation of vitamin D requires adequate
osteodystrophy   Bisphosphonates
  Type Ib: PTH resistance without   Calcitonin amounts of vitamin D from the diet or sunlight exposure, an
other abnormalities   Fluoride intact intestine through which to absorb calcium and vitamin D,
  Type Ic: specific PTH resistance,   Ethylenediaminetetraacetic acid an intact liver with which to convert vitamin D to
resulting from defect in catalytic (EDTA)
subunit of PTH-receptor   Citrate 25-hydroxyvitamin D, and an intact kidney to convert
complex   Intravenous contrast 25-hydroxyvitamin D to 1,25(OH)2D (see Chapter 72).
  Type II: specific PTH resistance,   Foscarnet Developing hypocalcemia and osteomalacia or rickets (see
postreceptor defect of adenylyl Pancreatitis
cyclase, undefined   Hypoalbuminemia Chapter 74) in settings in which one or more of the conversion
Vitamin D disorders   Hypomagnesemia steps is disrupted is common. Malabsorption syndromes, such
  Absent ultraviolet exposure   Calcium soap formation as short-bowel syndrome and celiac sprue, lead to hypocalcemia
  Vitamin D deficiency
  Fat malabsorption as a result of calcium and vitamin D malabsorption. Chronic
liver diseases, particularly primary biliary cirrhosis, lead to
hypocalcemia and osteomalacia. Chronic renal insufficiency
leads to failure to produce 1,25(OH)2D, with reductions in
tissue infiltrative diseases such as breast cancer, hemochromato- serum calcium levels and inefficient absorption of intestinal
sis (i.e., iron deposition), or sarcoidosis may destroy or replace calcium.
normal parathyroid tissue. Although Western diets are supplemented with vitamin D in
The diagnosis is made by finding a low serum ionized calcium milk and multivitamins, diets composed of no milk, human milk,
level in a patient with an inappropriately reduced serum PTH or unsupplemented bovine milk are vitamin D deficient. Rela-
concentration. The phosphorus concentration usually is high tively trivial exposure to sunlight can provide ample vitamin D
normal or frankly elevated, and plasma 1,25(OH)2D concentra- and replace dietary needs for vitamin D. However, vitamin D
tions are reduced (see Chapter 72). deficiency can occur in settings in which both sun exposure and
Treatment is normally directed at increasing intestinal calcium dietary intake of vitamin D are poor (i.e., cloudy climates, exces-
absorption through the use of large doses of calcium (up to 6-8 sive clothing or body covering, prolonged nursing by infants, and
g of elemental calcium per day) and, when necessary, the addi- the standard tea and toast diet of older adults), vitamin D defi-
tion of the active form of vitamin D (1,25[OH]2D), in replace- ciency is the rule rather than the exception.
ment amounts of 0.25 to 1.0 µg/day. The goal is to induce Certain genetic syndromes affecting vitamin D conversion can
sufficient intestinal calcium hyperabsorption to overwhelm the result in severe hypocalcemia. Long-term, high-dose treatment
ability of the kidney to excrete it. It carries the risk of inducing with anticonvulsants such as phenytoin or phenobarbital or their
significant hypercalciuria and therefore nephrocalcinosis and derivatives may lead to hypocalcemia and osteomalacia.
nephrolithiasis. Accordingly, 24-hour urinary calcium levels must
be measured regularly to identify dangerously high hypercalci- Hypoalbuminemia
uria. The serum calcium concentration is maintained in the low- Reductions in serum albumin, as occur in burn patients, the
normal range, about 8.5 to 9.0 mg/dL. In some instances, nephrotic syndrome, malnutrition, and cirrhosis, lead to reduc-
addition of a thiazide diuretic such as hydrochlorothiazide, which tions in serum total calcium without a reduction in the ionized
stimulates renal calcium reabsorption, may be effective in pre- total serum calcium level. Several formulas exist for correcting
venting hypercalciuria while raising the serum calcium level. total serum calcium for albumin, but none is entirely accurate.
746 Section XIII  Diseases of Bone and Bone Mineral Metabolism
Measuring ionized calcium directly is important if the authentic
ionized serum calcium concentration is needed.
Sepsis
Gram-positive and gram-negative sepsis have been associated
with hypocalcemia that usually is mild. The mechanisms are
poorly understood. Hypocalcemia occurring in the setting of
sepsis appears to confer a particularly adverse prognosis.
Hypermagnesemia
Magnesium is a divalent cation, as is calcium, and in very high
concentrations, it may mimic the actions of calcium to suppress
PTH. In so doing, it leads to a functional type of hypoparathy-
roidism and hypocalcemia. In practice, this condition is
uncommon.
Hypomagnesemia
Hypomagnesemia is one of the most common causes of hypo-
calcemia. It is encountered often in patients with alcoholism,
malnutrition, cisplatin therapy for cancer, and intestinal malab-
sorption syndromes. Hypomagnesemia inhibits PTH secretion
(i.e. magnesium adenosine triphosphatase is required for PTH
secretion) and prevents the calcemic actions of PTH on the
kidney and skeleton. Magnesium deficiency causes a functional
form of hypoparathyroidism and resistance to PTH. The treat-
ment is straightforward: magnesium replacement, which corrects
the syndrome in minutes to hours. Intravenous calcium or
vitamin D is ineffective.
Rapid Bone Formation
Increased rates of bone mineralization that are out of proportion
to the rate of bone resorption lead to net calcium entry into the
skeleton and, if these rates are large, to hypocalcemia. This state
occurs in several clinical settings. One condition is the hungry
bone syndrome that may follow parathyroidectomy, usually per-
formed for HPT. Preoperatively, the rates of bone turnover (i.e.,
resorption and formation) are very high but are approximately
coupled. Postoperatively, the rate of osteoclastic bone resorption
abruptly declines with the decline in PTH, but the elevated rate
of mineralization continues for days. Because of this acute post-
operative imbalance, the skeleton becomes a sink for calcium,
and hypocalcemia ensues.
Rapid bone formation also may occur in patients with vitamin
D deficiency who have severe osteomalacia or rickets and large
amounts of unmineralized osteoid. When these patients are
treated with vitamin D, rapid mineralization of unmineralized
osteoid occurs, the skeleton becomes a sink for calcium, and
hypocalcemia ensues. Another example of this phenomenon
occurs in the setting of extensive osteoblastic bone metastases,
such as in prostate or breast cancer and occasionally in other
malignancies.
Hyperphosphatemia
Disorders that lead to hyperphosphatemia may cause hypocalce-
mia as a result of exceeding the calcium-phosphate solubility
product in serum. Examples of disorders that may cause the kind
of severe hyperphosphatemia required include rhabdomyolysis
(e.g., crush injuries), renal failure, and the tumor lysis syndrome.
Severe hyperphosphatemia may be seen after ingestion of large
amounts of phosphate-containing purgatives in preparation for
colonoscopy, inadvertent perforation of the rectum during the
administration of phosphate enemas, and overzealous adminis-
tration of intravenous phosphate. In these examples, the onset of
hyperphosphatemia is relatively abrupt, and the hypocalcemia is
immediate and severe. Commonly, the first sign of this sequence
of events is a seizure.
Treatment involves reducing the serum phosphorus level by
whatever means necessary. Giving intravenous calcium should be
avoided because it is precipitated into soft tissues.
Medications
Certain medications may cause hypocalcemia, including those
used to treat hypercalcemia. Fluoride compounds (e.g., anes-
thetic gas), chelating agents such as ethylenediaminetetraacetic
acid (EDTA) and citrate (i.e., in stored blood), radiographic
intravenous contrast agents, and the antiviral drug foscarnet may
cause hypocalcemia.
Pancreatitis
When pancreatitis causes hypocalcemia, it is a poor prognostic
sign. The classic mechanism involves the formation of calcium-
free fatty acid soaps by lipases that are released from the inflamed
pancreas. The free lipases then autodigest omental and retroperi-
toneal fat into negatively charged ions that tightly bind calcium
in the ECF, causing hypocalcemia. The hypocalcemia is revers-
ible by calcium infusion, and it self-terminates when the pancre-
atitis improves.
  HYPERPHOSPHATEMIA
Symptoms and Signs
Hyperphosphatemia produces no specific signs. It is usually iden-
tified incidentally on routine chemical screens or as a result of the
induction of hypocalcemia.
Pathophysiology
Hyperphosphatemia develops as a result of two mechanisms.
One is a large load of phosphate delivered into the ECF through
the GI tract, intravenous medications, or endogenous sources
such as muscle or tumor. The second mechanism is the inability
to excrete phosphate, as occurs in acute or chronic renal failure.
Essentially all natural foods contain phosphate, and therefore
almost any diet contains substantial quantities of phosphate (see
Chapter 72). Normally, phosphate is easily cleared by the healthy
kidney, but this ability is lost as the GFR declines below 20 to
30 mg/dL.
Differential Diagnosis
The differential diagnoses of hyperphosphatemia are listed in the
following sections and in Table 73-3.
Artifactual Occurrence
Hyperphosphatemia may occur artifactually as a result of
hemolysis in blood collection tubes. One clue is that the same
phenomenon occurs with potassium. The occurrence of unex-
plained hyperkalemia and hyperphosphatemia should trigger the
 Chapter 73  Disorders of Serum Minerals 747

TABLE 73-3  CAUSES OF HYPERPHOSPHATEMIA TABLE 73-4  CAUSES OF HYPOPHOSPHATEMIA

Artifactual Endogenous phosphate loads Inadequate phosphate (PO4) intake   Oncogenic osteomalacia
  Hemolysis   Tumor lysis syndrome   Starvation   Fanconi’s syndrome
Increased gastrointestinal intake   Rhabdomyolysis (crush injury)   Malabsorption   Alcoholism
  Rectal enemas   Hemolysis   PO4-binding antacid use Excessive skeletal mineralization
  Oral Phospho-Soda purgatives Reduced renal clearance   Alcoholism   Hungry bone syndrome after
  Gastrointestinal bleeding   Chronic or acute renal failure Renal PO4 losses parathyroidectomy
Intravenous phosphate loads   Hypoparathyroidism   Primary, secondary, or tertiary   Osteoblastic metastases
  K-Phos   Acromegaly hyperparathyroidism   Healing osteomalacia, rickets
  Blood transfusions   Tumoral calcinosis   Humoral hypercalcemia of PO4 shift into extracellular fluid
malignancy (parathyroid   Recovery from metabolic acidosis
hormone–related protein)   Respiratory alkalosis
  Diuretics, calcitonin   Starvation refeeding, intravenous
collection of a fresh sample and immediate repeat determination   X-linked hypophosphatemic glucose
rickets
of the serum phosphate level.   Autosomal dominant
hypophosphatemic rickets
Increased Gastrointestinal Intake
Hyperphosphatemia may occur in patients receiving large oral phosphate is specifically defective, leads to chronic hyperphos-
phosphate loads. In a literature review, most cases of phosphate- phatemia and accumulation of calcium-phosphate salts around
induced hypocalcemia were caused by the administration of large joints of the appendicular skeleton. Children, particularly
phosphate-containing purgatives as preparation for colonoscopy. adolescents, have higher serum phosphate concentrations than
Another underappreciated cause of this phenomenon is inadver- adults.
tent perforation of the rectum during the administration of a
rectal Phospho-Soda enema, with delivery of large amounts of
  HYPOPHOSPHATEMIA
phosphate directly into the peritoneal cavity, from which it is
rapidly absorbed. Upper GI tract bleeding from ulcers of gastritis Symptoms and Signs
provides a large GI phosphate load and may be associated with Phosphate participates in a vast array of key cellular processes,
hyperphosphatemia. including DNA synthesis and replication, energy generation and
use, oxygen uptake and delivery by erythrocytes, and mainte-
Intravenous Phosphate Loads nance of the redox state of every cell in the body (see Chapter
Large amounts of phosphate may be administered during treat- 72). The signs of phosphate depletion are nonspecific, diffuse,
ment to replete potassium using potassium phosphate prepara- and often life-threatening. These signs may include respirator
tions. What appear to be trivial quantities of potassium dependence, congestive heart failure, coma, hypotension, and
preparation (e.g., 20 to 40 mEq of K-Phos) actually contain large generalized weakness and malaise. Because the signs and symp-
amounts of phosphate and may lead to severe hyperphosphate- toms are nonspecific, they are frequently attributed to other
mia and hypocalcemia (see Chapter 72). A second vehicle for causes and are left untreated. They typically occur in intensive
delivering phosphate intravenously is transfusions of red blood care units (ICUs). In these settings, oral nutrition is nonexistent,
cells, which ultimately hemolyze and release their copious phos- intravenous phosphate repletion is inadequate, and diuretics and
phate stores. saline infusions accelerate renal phosphate losses. Appropriate
therapy can produce startling results, with patients suddenly
Endogenous Phosphate Loads returning from being moribund to being ambulatory, extubated,
Hyperphosphatemia may result from the destruction of large and conversant.
amounts of tissue in three situations. One is the tumor lysis Chronic hypophosphatemia leads to defects in skeletal min-
syndrome, typified by a large Burkitt lymphoma responding eralization, a phenomenon called rickets in children or osteoma-
promptly to chemotherapy with massive cell death. A second lacia in adults. These syndromes produce weakness, bone pain,
phenomenon is acute rhabdomyolysis releasing phosphate from bowing of the long bones, and fractures or pseudofractures (see
skeletal muscle, and a third is severe hemolysis. In each case, a Chapter 74).
large phosphate load is delivered into the ECF. Combined with
renal impairment common in these situations, this results in Differential Diagnosis
renal failure, severe hypocalcemia, seizures, and sometimes Disorders can be divided into hypophosphatemia resulting from
death. inadequate intake, from excessive renal losses, from excessive
skeletal uptake, or from shifts of phosphate from the ECF into
Reduced Renal Clearance cells (Table 73-4). From a diagnostic standpoint, measuring the
Renal clearance of phosphate is the main mechanism for main- TmP (see Chapter 72) is important because it provides rapid
taining phosphate homeostasis. Acute and chronic disorders determination of which type of hypophosphatemia the patient is
of the kidney lead to hyperphosphatemia. Because PTH pre- confronting.
vents phosphate reabsorption in the proximal nephron, hypo-
parathyroidism is typically associated with high-normal to Inadequate Phosphate Intake
frankly elevated serum phosphorus values. A condition called Disorders that involve inadequate phosphate intake are associ-
tumoral calcinosis, in which the ability of the kidney to clear ated with a high TmP. Because essentially all foods are rich in
748 Section XIII  Diseases of Bone and Bone Mineral Metabolism

phosphate, becoming phosphate depleted based on inadequate
dietary intake is difficult. However, in settings of severe caloric
deprivation, inadequacies can occur. Examples include anorexia
nervosa, prisoner-of-war camps, prolonged ICU care, malabsorp-
tion syndromes, and chronic alcoholism. In the first three disor-
ders, caloric intake is scant, and little phosphate is consumed. In
alcoholism, caloric intake may be high, but alcohol is devoid of
phosphate. The use of phosphate-binding antacids such as alumi-
num hydroxide gels may lead to severe phosphate deficiency,
hypophosphatemia, and osteomalacia.
Excessive Renal Phosphate Losses
Disorders involving excessive losses are associated with a low
TmP. PTH is phosphaturic, and all types of HPT are associated
with hypophosphatemia as long as renal function is normal. This
situation is widely appreciated for primary HPT but is less well
appreciated for secondary HPT, particularly in the setting of
vitamin D and calcium malabsorption. A low serum phosphate
level may be the first and only noticeable clue to severe vitamin
D deficiency. This fact has led to the diagnosis of celiac sprue in
unsuspected cases on many occasions.
PTHrP (see Malignancy-Associated Hypercalcemia) is phos-
phaturic, as is PTH, and patients with humoral hypercalcemia of
malignancy are commonly hypophosphatemic for this reason as
long as their renal function is intact. Thiazide and loop diuretics
are potent phosphaturic agents, and their use without phosphate
replacement therapy leads to hypophosphatemia. Ethanol is also
in this category.
Certain genetic disorders may lead to severe renal phosphate
wasting (see Chapter 74). These disorders include X-linked
hypophosphatemia (XLH), also called vitamin D–resistant rickets,
and autosomal dominant hypophosphatemic rickets (ADHR).
Another renal phosphate-wasting syndrome is oncogenic osteo-
malacia, also called tumor-induced osteomalacia (see Chapter 74).
Acquired or inherited diffuse renal proximal tubular disorders,
such as Fanconi’s syndrome, may lead to hypophosphatemia as a
result of renal phosphate wasting.
Excessive Skeletal Mineralization
Increased bone mineralization with respect to bone resorption
results in large amounts of phosphate entering the skeleton,
leading to hypophosphatemia. One example is the hungry bone
syndrome that occurs after parathyroidectomy (see Hypocal-
cemia). Other examples are osteoblastic metastases and the
treatment of vitamin D–deficient rickets or osteomalacia with
vitamin D.
hypophosphatemia and sudden death due to respiratory or circu-
latory failure. Refeeding of starvation victims should be accom-
plished slowly and with attention to phosphate repletion.
Treatment
Phosphorus replacement is best accomplished through the oral
route and usually is given in two to four divided doses that deliver
2000 to 4000 g/day. Doses greater than 1000 to 2000 mg/day
often cause diarrhea initially (phosphate is used as a purgative),
but with gradual increments, larger doses may be well tolerated.
Intravenous phosphate should be given only with a clear under-
standing of the quantities involved (see Chapter 72) and to
patients for whom oral administration is not an option. Frequent
monitoring of serum phosphorus, calcium, and creatinine levels
is required. Intravenous dosages up to 500 to 800 mg/day may
be required.
  HYPERMAGNESEMIA
Symptoms and Signs
Clinically significant hypermagnesemia is uncommon. The
symptom is drowsiness, and the signs are hyporeflexia and even-
tual neuromuscular, respiratory, and cardiovascular collapse. It
may also lead to hypocalcemia (see Hypocalcemia). Hypermag-
nesemia is seen in two settings: severe renal failure accompanied
by the administration of magnesium-containing antacids and
after the intravenous administration of large doses of magnesium
sulfate for eclampsia or preeclampsia.
Differential Diagnosis
The differential diagnosis of hypermagnesemia is brief and is
limited to the two disorders previously described (Table 73-5).
Mild hypermagnesemia is common in patients on dialysis, but
severe hypermagnesemia occurs only in the settings of renal
failure accompanied by parenteral or oral magnesium salt admin-
istration, such as the use of magnesium-containing antacids or
phosphate binders. Hypermagnesemia occurs commonly but in
a controlled fashion in the treatment of eclampsia.
  HYPOMAGNESEMIA
Symptoms and Signs
Hypomagnesemia is common, particularly in the ICU setting,
but as with hypophosphatemia, it is often overlooked or ignored.
Magnesium is essential for a broad range of biologic processes,

Phosphate Shift into Extracellular Fluid TABLE 73-5  CAUSES OF HYPERMAGNESEMIA AND
Phosphate can be shifted from serum into the intracellular HYPOMAGNESEMIA
compartment by a rise in ECF pH. Recovery from a metabolic Hypermagnesemia  
acidosis (e.g., diabetic ketoacidosis) and development of a respi-   Renal failure accompanied by  
magnesium antacid use  
ratory alkalosis lead to hypophosphatemia. One of the most stun-   Parenteral magnesium sulfate  
ning examples of this phenomenon is the shift of phosphate into administration for eclampsia  
cells after administration of oral carbohydrate or parenteral Hypomagnesemia  
  Inadequate intake  
glucose to victims of starvation or anorexia nervosa. Insulin   Starvation
increases the rate of glucose uptake into cells and its subsequent   Malabsorption  
phosphorylation to glucose-6-phosphate. In the setting of   Alcoholism  
  Vomiting, nasogastric suction  
significantly depleted phosphate reserve, rapid consumption of   Excessive renal losses  
oral carbohydrate or parenteral glucose may lead to profound
Diuretics
Saline infusion
Secondary aldosteronism
Cirrhosis
Congestive heart failure
Osmotic diuresis, hyperglycemia
Cisplatin, aminoglycoside
antibiotics, amphotericin
Hypokalemia
Hypercalcemia, hypercalciuria
Proximal tubular diseases
Genetic defects
 Chapter 73  Disorders of Serum Minerals 749
and hypomagnesemia may cause hypocalcemia, seizures, and
paresthesias independent of hypocalcemia and cause a broad
array of neuromuscular, cardiovascular, and respiratory
symptoms.
Differential Diagnosis
Differential diagnoses are listed in the following sections and in
Table 73-5.
Inadequate Intake
Inadequate intake of magnesium is common among alcoholics
and the generally undernourished. It may occur as part of an
intestinal malabsorption syndrome and may result from continu-
ous vomiting or nasogastric suctioning. These situations are
common in ICU settings and are often overlooked.
Excessive Renal Losses
Excessive renal losses of magnesium are common in clinical prac-
tice. Thiazide and loop diuretics cause renal magnesium losses,
and saline infusion has a similar effect. Magnesium is lost by the
kidney in response to aldosterone in primary hyperaldosteron-
ism but more commonly in the secondary hyperaldosteronism
associated with cirrhosis, volume depletion, congestive heart
failure, and other common disorders. Osmotic diuresis, as occurs
with poorly controlled diabetes mellitus, causes renal magnesium
loss. Certain nephrotoxic drugs such as cisplatin, aminoglycoside
antibiotics, and amphotericin induce proximal tubular injury and
a severe form of renal magnesium wasting. Hypokalemia, hyper-
calcemia, and hypercalciuria also lead to renal magnesium excre-
tion. Many diseases that lead to proximal tubular injury, such as
Fanconi’s syndrome and interstitial nephritis, may lead to mag-
nesium wasting.
Treatment
Magnesium can be replaced intramuscularly or intravenously.
Usually, 24 to 48 mEq per 24 hours as magnesium sulfate is pro-
vided (see Chapter 72). Oral magnesium salts such as magne-
sium oxide are also available, but administering large doses of
magnesium orally is difficult because of the cathartic effects of
magnesium.
SUGGESTED READINGS
Bilezikian JP, Khan AA, Potts JT: Guidelines for the management of asymptomatic
primary hyperparathyroidism: summary statement from the third international
workshop, J Clin Endocrinol Metab 94:335–339, 2009.
Christov M, Juppner H: Insights from genetic disorders of phosphate homeostasis,
Semin Nephrol 33:143–157, 2013.
Nakajima K, Tamai M, Okaniwa S, et al: Humoral hypercalcemia of malignancy
associated with a gastric carcinoma secreting parathyroid hormone, Endocr J
60:557–562, 2013.
Nazeri AS, Reilly RF Jr: Hereditary etiologies of hypomagnesemia, Nat Clin Pract
Nephrol 4:80–89, 2008.
Nesbitt MA, Hanan FM, Howles SA, et al: Mutations affecting G-protein subunit
alpha-11 in hypercalcemia and hypocalcemia, N Engl J Med 368:2476–2486,
2013.
Rosen CJ, editor: The American Society for Bone and Mineral Research primer
on metabolic bone diseases and disorders of mineral metabolism, ed 8,
Washington, D.C., 2013, American Society for Bone and Mineral Research.
Stewart AF: Hypercalcemia associated with cancer, N Engl J Med 352:373–379,
2005.
Stewart AF: Translational implications of the parathyroid calcium receptor,
N Engl J Med 351:324–326, 2004.
 74 
Metabolic Bone Diseases
Mara J. Horwitz and Andrew F. Stewart

allows assessment of the rates and efficacy of skeletal mineraliza-

  INTRODUCTION tion (see Fig. 74-1B and F).
Metabolic bone disease is a general term used to describe a host of
diffuse skeletal disorders. Many are associated with low bone
  DIFFERENTIAL DIAGNOSIS
mass, and some are not metabolic but have genetic, infectious, or
other causes. However, metabolic bone disease remains a useful Paget’s Disease of Bone
umbrella term. In its broadest sense, it includes common diseases Paget’s disease, also called otitis deformans, is the second most
such as osteoporosis (see Chapter 75), rare osteosclerotic disor- common bone disease after osteoporosis. It affects approximately
ders such as fluoride intoxication, genetic disorders, and focal 2% of the population older than 45 years of age in the United
skeletal diseases such as polyostotic fibrous dysplasia. States, but the incidence varies geographically. It is most common
In this chapter, the focus is on the more common members in those of European descent and rare in those of African or Asian
of this family (Table 74-1) that may be encountered by an inter- descent.
nist. Many additional rare metabolic bone diseases exist and, In contrast to most metabolic bone diseases, which are diffuse
depending on the context, should be sought. Normal skeletal and involve the entire skeleton, Paget’s disease is a focal bone
homeostasis and histopathology are reviewed in Chapter 72 and disorder. It can be monostotic (involving a single bone) or polyos-
Figure 74-1. totic (involving multiple bones). Paget’s disease may affect any
Osteoclast and osteoblast activity and osteoid mineralization skeletal site, but it most commonly involves the pelvis, vertebrae,
can be assessed by undecalcified bone biopsy of the anterior iliac skull, tibia, and femur. Although Paget’s disease is a chronic con-
crest, which is the standard for assessing bone histology. Unde- dition and original lesions may expand, new lesions rarely
calcified sections are essential because the acid-mediated decal- develop.
cification performed on routine pathology specimens removes The primary cellular abnormality of Paget’s disease is
calcium and therefore cannot distinguish between mineralized increased osteoclastic bone resorption, which is followed by
mature bone and unmineralized osteoid that may be normal or exuberant formation of new bone that is of poor quality (see
pathologic. The examples shown in Figure 74-1 employ histo- Fig. 74-1C). This marked increase in osteoblast activity accounts
logic sections of undecalcified bone and highlight osteoclasts, for the typical sclerotic lesions seen on radiographic examination
osteoblasts, and osteoid. Because tetracycline is fluorescent and (Fig. 74-2A-C), for the increased uptake of radionuclide seen
incorporated into the hydroxyapatite crystals as osteoid mineral- on a bone scan (see Fig. 74-2D), and for increases in serum
izes, administering tetracycline to patients before a bone biopsy levels of alkaline phosphatase, which is the biochemical hallmark
of Paget’s disease.
Most patients with Paget’s disease are asymptomatic, and the
disorder is most often detected unexpectedly by an increased
TABLE 74-1  CONDITIONS, DISEASES, AND serum alkaline phosphatase level on routine testing or on a
MEDICATIONS THAT CAUSE OR routine radiograph obtained for other reasons. At clinical presen-
CONTRIBUTE TO METABOLIC BONE tation, patients may have bone pain, skeletal deformities, frac-
DISEASE tures, related complications such as osteoarthritis, and nerve
Osteoporosis (see Chapter 75)   Osteoporosis-pseudoglioma compression syndromes (e.g., deafness, spinal stenosis). Rare
Paget disease of bone syndrome complications include hypercalcemia in immobilized patients
Hyperparathyroid bone disease (i.e.,   X-linked osteoporosis
osteitis fibrosa cystica)   Miscellaneous factors and high-output cardiac failure. Because pagetic lesions tend to
Osteomalacia and rickets Infiltrative diseases be highly vascular, the skin over affected bones may be warmer
  Hypophosphatemic syndromes   Multiple myeloma than in other areas. The most dreaded complication of Paget’s
  Vitamin D syndromes   Lymphoma, leukemia
  Anticonvulsants   Sarcoid disease is the rare (<1%) development of osteosarcoma in a
  Aluminum   Malignant histiocytosis pagetic lesion.
  Metabolic acidosis   Mastocytosis The cause of Paget’s disease is unknown but may include
Renal osteodystrophy   Gaucher’ disease
Genetic diseases   Hemolytic diseases (e.g., a viral origin and a genetic predisposition. Paget’s disease is
  Osteogenesis imperfecta thalassemia, sickle cell anemia) most often diagnosed using a combination of biochemical
  Hypophosphatasia Transplantation osteodystrophy markers for bone turnover and radiologic studies. For most

750
 Chapter 74  Metabolic Bone Diseases 751

Bone marrow
Bone marrow
Osteoblasts
Trabecular bone

Osteoclast
Osteoid
Trabecular bone The two mineralization fronts
A B

*
*
C D

E F

G H
FIGURE 74-1  A, Normal bone histology, showing a normal bone-remodeling unit as seen in an undecalcified human anterior iliac crest biopsy.
On the left, a multinucleated osteoclast has moved across the mineralized trabecular bone surface over the previous week or two, resorbing (remov-
ing) old bone. On the extreme right, the bone surface is covered by osteoid secreted by the overlying osteoblasts. In between the osteoclast- and
osteoblast-covered surfaces of the trabecular bone are a large number of flat, fibroblastoid cells referred to as lining cells. No osteocytes are visible
in this section. B, Tetracycline labeling of a bone biopsy from a patient with hyperparathyroid bone disease. Notice the bright yellow parallel lines
on the trabecular bone surface. These lines represent the two sets of tetracycline labeling, which occurred 14 days apart. From these sets, the min-
eralization rate can be described in micrometers (microns) per day, the so-called mineral apposition rate, and it is increased dramatically in this
example, as is typical of hyperparathyroid bone disease. Contrast with example F, which has no tetracycline labeling. C, Paget’s disease. Enormous
and abundant highly multinucleated osteoclasts (open arrowheads) are resorbing trabecular bone, and a comparably enormous number of osteo-
blasts (closed arrowheads) are making new but disorganized bone. The marrow space is replaced by fibrous cells. D, Primary hyperparathyroidism
has the classic features of osteitis fibrosa cystica. Far more osteoid and osteoblasts (closed arrowheads) and osteoclasts (open arrowhead) exist than
in the normal example (A). Three large microcysts (asterisks) have been created by aggressive osteoclastic bone resorption. These microcysts account
for the cystica component of osteitis fibrosa cystica. The marrow space, particularly within the microcysts, is filled with fibroblasts, which make up
the fibrosa component of osteitis fibrosa cystica. E, Osteomalacia or rickets. Notice the abundant quantities of partially and chaotically mineralized
osteoid (orange). These seams are the thick osteoid seams and represent osteoid that has been produced by osteoblasts but that cannot mineralize,
which is the signature defect in osteomalacia and rickets. F, Tetracycline labeling reveals a complete absence of mineralization, diagnostic of osteo-
malacia or rickets. Compare with example B. G, Renal osteodystrophy. This photomicrograph of a biopsy from a patient on dialysis demonstrates
many of the classic features of renal osteodystrophy, including evidence of aggressive osteoclastic bone resorption (i.e., numerous osteoclastic
lacunae on the bone surface compared with the smooth surfaces in example A) and abundant, partially and chaotically mineralized areas of osteoid
(orange). H, Infiltrative bone disease as exemplified by multiple myeloma. The bone marrow is replaced by plasma cells, and two large osteoclasts in
lacunae are actively resorbing the trabecular bone surface.
752 Section XIII  Diseases of Bone and Bone Mineral Metabolism

Normal

A Paget’s

C D
FIGURE 74-2  Typical radiologic abnormalities Paget’s disease. A, Compare the normal skull (top) with the skull (bottom) with the classic cotton-
wool appearance, an enormously expanded calvarium, and osteosclerosis of the petrous bones. B, Classic asymmetrical involvement of the pelvis
with a mixture of lytic and blastic lesions. C, Bowing deformity of the femur with a markedly thickened cortex. D, A whole body radionuclide scan
demonstrates polyostotic Paget’s disease.

patients, elevated concentrations of total serum alkaline phos-
phatase is an adequate and sensitive indicator of disease activity.
However, the serum level of bone-specific alkaline phosphatase
may be a more sensitive marker than serum total alkaline
phosphatase for assessing disease in patients with low levels
of disease activity. A bone scan at the time of diagnosis can
define the location and extent of lesions (see Fig. 74-2D).
Radiographs of the affected areas confirm Paget’s disease, and
they are useful for evaluating complications and local disease
progression (Fig. 74-2A-C).
The two major goals of therapy are to relieve symptoms and
prevent complications. Indications for treatment include alleviat-
ing symptoms (e.g., bone pain, headache, neurologic complica-
tions), decreasing blood flow preoperatively to minimize
bleeding during elective surgery on a pagetic site, managing
hypercalcemia in an immobilized patient with severe Paget’s
disease, and preventing future complications of progressive local
disease, such as bowing deformities of the long bones, hearing
loss as a result of temporal bone involvement, and neurologic
complications resulting from foramen magnum or vertebral
involvement. Treatment of Paget’s disease usually involves a
combination of nonpharmacologic therapy (i.e., physical
therapy) and pharmacologic therapy, including antiresorptive
agents and analgesics for pain management.
The mainstay of therapy is bisphosphonates, including potent
aminobisphosphonates such as zoledronate, which decrease
bone resorption at pagetic sites by inhibiting osteoclasts. Calcium
and vitamin D supplementation is recommended for patients
taking the more potent bisphosphonates to prevent hypocalce-
mia or secondary hyperparathyroidism.
Orthopedic surgery may be indicated when a complete frac-
ture occurs through pagetic bone. Surgery also is indicated for
realignment of a severely arthritic knee and for total joint arthro-
plasty in a severely affected hip or knee.
 Chapter 74  Metabolic Bone Diseases 753

bone histology. Patients may complain of bone pain or diffuse

Hyperparathyroid Bone Disease
Hyperparathyroid bone disease, also called osteitis fibrosa cystica
(OFC), results from chronically elevated concentrations of para-
thyroid hormone (PTH). Elevated PTH concentrations may
result from primary hyperparathyroidism, in which elevated
PTH levels most often result from a parathyroid adenoma or
rarely from hyperplasia or carcinoma.
Secondary hyperparathyroidism is an appropriate increase in
PTH levels caused by malabsorption, vitamin D deficiency, or
chronic renal failure. Calcium levels are normal or subnormal.
Tertiary hyperparathyroidism refers to elevated PTH resulting
from long-standing stimulation of the parathyroid glands
along with hypercalcemia, as in the setting of renal failure (see
Chapter 73). Chronic stimulation results in hyperplasia or
adenomas.
Primary and tertiary forms of hyperparathyroidism are
characterized by hypercalcemia. Patients with secondary hyper-
parathyroidism are eucalcemic or hypocalcemic and have ele-
vated PTH levels.
The skeletal disease in hyperparathyroidism is typified by
high turnover, which is characterized by coupled increases in
osteoclastic bone resorption and osteoblastic synthesis of
osteoid, accelerated rates of bone mineralization accompanied
by microcysts in the cortex and trabeculae (the cystica of OFC),
and increased numbers of fibroblasts and marrow stroma (the
fibrosa of OFC) (see Fig. 74-1B and D). Levels of both serum
markers of bone formation (i.e., alkaline phosphatase and osteo-
calcin) and markers of bone resorption (i.e., N-terminal and
C-terminal telopeptides) are usually increased, reflecting the
aches and pains.
Bone density, assessed by dual-energy x-ray absorptiometry
(DEXA), may be normal or low. The pathognomonic radiologic
signs of severe hyperparathyroid bone disease are a salt-and-
pepper appearance of the calvarium, resorption of the tufts of the
terminal phalanges and distal clavicles, subperiosteal resorption
of the radial aspect of the cortex of the second phalanges (Fig
74-3), and Brown tumors (i.e., collections of osteoclasts that
produce gross lytic lesions) of the pelvis and long bones. These
radiologic signs disappear with parathyroidectomy, and bone
mass, as assessed by DEXA, typically increases rapidly and mark-
edly after parathyroidectomy.
The treatment of hyperparathyroid bone disease involves
remediation of the chronically elevated PTH concentrations
by parathyroidectomy in primary or tertiary hyperparathyroid-
ism or correction of the underlying cause of secondary
hyperparathyroidism (see Chapter 73). If the hypercalcemia
is mild and the bone mass is normal, no treatment may be
required.
Serum calcium levels can be reduced by using a parathy-
roid calcium receptor mimetic. Cinacalcet is indicated for
patients with chronic renal failure with secondary hyperpara-
thyroidism, patients with parathyroid carcinoma who have
failed surgical resection, and patients with severe primary
hyperparathyroidism.
Moderate to severe hypocalcemia may be seen after parathy-
roidectomy. This condition is referred to as the hungry bone
syndrome (see Chapter 73). Hyperparathyroid bone disease
may be pure, occurring in patients with severe primary

A B C
FIGURE 74-3  Skeletal radiographic changes of hyperparathyroidism. A, A hand film from a patient with primary hyperparathyroidism. The arrow
indicates a typical giant cell tumor (brown tumor), which is a collection of osteoclasts that lead to macrocystic changes in bone. The arrowhead
indicates the irregular radial surface of a phalanx resulting from subperiosteal bone resorption, which is typical of hyperparathyroidism. The brown
tumor and the subperiosteal resorption refill and disappear when the offending parathyroid tumor or hyperplasia is resected. B, Radiograph of a
normal hand for comparison. No brown tumors are seen, and the phalangeal periosteal surfaces are smooth. C, The classic salt-and-pepper appear-
ance of the skull in hyperparathyroidism. The periosteal surfaces of the inner and outer cortices or tables of the calvarium are indistinct as a result
of subperiosteal bone resorption. The lateral view of the calvarium is hazy and indistinct, showing micropunctations. (Courtesy J. Towers, MD, and D.
Armfield, MD, University of Pittsburgh, Pittsburgh, Penn.)
754 Section XIII  Diseases of Bone and Bone Mineral Metabolism

hyperparathyroidism caused by a parathyroid adenoma, or it may
be mixed, occurring in patients with vitamin D–deficient osteo-
malacia, immunosuppressant-induced transplant bone disease,
or renal osteodystrophy.
Osteomalacia and Rickets
Although common in the United States and throughout the
world, osteomalacia and rickets are often overlooked. Osteoma-
lacia and rickets are essentially the same disorders, but by defini-
tion, rickets occurs in children with open growth plates (i.e.,
epiphyses), and osteomalacia occurs in adults with closed
epiphyses.
The fundamental abnormality in these disorders is an inability
to mineralize (i.e., form hydroxylapatite crystals) osteoid seams
(see Fig. 74-1). These patients have osteoblasts and can synthe-
size osteoid, but it is mineralized inefficiently or not at all. This
fundamental inability to mineralize osteoid results in accumula-
tion of the characteristic thick osteoid seams seen on bone biopsy
(see Fig. 74-1E and F) and a reduction in the mineral content of
bone so that it is mechanically deficient. These events lead to
bone pain, pseudofractures, fractures, bowing of the long bones,
and other skeletal deformities (Fig. 74-4). In children with
rickets, the inability to mineralize the growth plate leads to
bulbous, knobby deformities of the knees, ankles, and costochon-
dral junctions (i.e., rachitic rosary) and to dental abnormalities.
The characteristic radiologic signs of osteomalacia are Looser’s
zones or Milkman’s pseudofractures.
Mineralization disorders result from an inability to form
hydroxyapatite (calcium phosphate) crystals in osteoid, the non-
mineralized phase of bone. This inability may result from hypo-
phosphatemia (common), calcium deficiency (rare), or vitamin
D deficiency (common). Toxins that interfere with mineraliza-
tion include aluminum, incompletely defined inhibitors of min-
eralization in uremic plasma, and long-term, high-dose
anticonvulsants. Because calcium salts are acid soluble, chronic
metabolic acidoses can result in osteomalacia or rickets. Disor-
dered mineralization can be caused by vitamin D deficiency (e.g.,
malabsorption, liver disease), hypophosphatemic disorders (e.g.,
X-linked hypophosphatemic rickets, autosomal dominant hypo-
phosphatemia, oncogenic osteomalacia), metabolic acidoses,
drug-related disorders, and genetic conditions (e.g., vitamin D–
dependent rickets types I and II, hypophosphatasia) (see
Chapter 73).
The diagnosis is suggested in the setting of low bone mass,
the characteristic radiologic signs described previously, hypo-
calcemia, elevated PTH and alkaline phosphatase levels, and
unexplained bone pain or weakness. However, these are late
signs, and the disorder is optimally identified and treated
early. The diagnosis is supported by demonstrating reductions
of plasma 25-hydroxyvitamin D or its active form, 1,25-
dihydroxyvitamin D3 (1,25[OH]2D3); hypophosphatemia; or
increased alkaline phosphatase levels in an appropriate clinical
setting. Hypocalciuria is typical of vitamin D deficiency.
Inappropriate phosphaturia with a low tubular maximum for

A B C
FIGURE 74-4  A, A typical example of rickets, with bowing of the femurs and tibias. B, A skeletal radiograph of a child with rickets. The weight-
bearing bones of the lower extremities are bowed, and the epiphyses are open, mottled, and overgrown. C, Looser’s zones or pseudofractures (arrows)
are characteristic of osteomalacia or rickets. The closed epiphyses indicate the patient is an adult. This radiograph is diagnostic of osteomalacia.
 Chapter 74  Metabolic Bone Diseases 755
phosphorus or glomerular filtration rate (see Chapter 72) typi-
fies renal phosphate wasting disorders. The diagnosis can often
be made clinically but can also be confirmed using undecalci-
fied bone biopsy after applying oral double tetracycline labeling
techniques, which are used to quantitate the degree of failure
of mineralization (Fig 74-1E and F).
Treatment depends on the underlying cause and may include
vitamin D formulations, calcium and phosphate supplementa-
tion, and removal of the inhibitor of mineralization when possi-
ble. These diseases are gratifying to treat because the responses
are often dramatic, and patients change rapidly from being chron-
ically ill to feeling robust and healthy.
Renal Osteodystrophy
Renal osteodystrophy is a collection of moderate to severe disor-
ders that produce bone pain, pathologic fractures, and deminer-
alization in the setting of end-stage renal disease or dialysis.
Subclinical renal osteodystrophy is common and occurs early
as a result of increased levels of phosphorous and fibroblast
growth factor 23 (FGF23), which cause defects in skeletal
mineralization.
Secondary hyperparathyroidism also may occur as a result of
defective renal production of 1,25(OH)2d combined with an
increased serum phosphate concentration and calcium-phosphate
precipitation into soft tissues (see Chapters 72 and 73). This
circumstance evokes a marked increase in PTH secretion that
causes significant increases in bone turnover, demineralization,
and fracture. These patients may respond dramatically to oral or
parenteral replacement of 1,25(OH)2d or the calcium receptor
mimetic cinacalcet, or both.
Other patients with renal osteodystrophy have adequately
controlled serum levels of calcium and phosphate as a result of
adequate oral calcium supplementation and phosphate binders
and therefore have standard PTH levels, but they have severe
osteomalacia characterized by bone pain, reduced bone mineral
density on DEXA or bone biopsy, and thickened osteoid seams
with a mineralization defect seen on bone biopsy (see Fig.
74-1G). These patients may respond dramatically to 1,25(OH)2d
replacement.
Some patients with renal osteodystrophy have combinations
of secondary hyperparathyroidism and osteomalacia (see Fig.
74-1G). Others have low bone turnover or aplastic bone disease.
The latter terms describe patients on dialysis who have little or
no osteoblastic activity, osteoid, or osteoclastic activity—the
opposite of secondary hyperparathyroidism and osteomalacia.
The condition may result from previous use of inhibitors of bone
turnover (e.g., aluminum intoxication); from excessive treatment
with 1,25(OH)2d with suppression of PTH, causing low bone
turnover; or from unidentified causes.
For all bone diseases, determining the cause is essential for
effective treatment. Early recognition enables treatment before
bone pain and fractures occur.
Genetic Diseases
Monogenic disorders that lead to reductions in bone mass are
uncommon but are seen with some frequency in practices
devoted to skeletal disease. The most common of these disorders
is osteogenesis imperfecta, which may be very mild or very severe
and may manifest in neonates or older people, depending on the
mutation involved. Patients with osteogenesis imperfecta have
bone fragility and deformities, and they may have involvement of
collagen-containing tissues, including the tendons, skin, and
eyes.
Osteogenesis imperfecta most often results from mutations in
the genes for type I collagen. In contrast, hypophosphatasia
results from mutations in the tissue-nonspecific alkaline phos-
phatase gene (ALPL). These patients have demineralization, frac-
ture, and bone pain, and they have little or no measurable serum
alkaline phosphatase.
New monogenic causes of bone disease continue to appear.
For example, the rare osteoporosis-pseudoglioma syndrome (i.e.,
severe autosomal dominant osteoporosis with blindness) results
from inactivating mutations in the low-density lipoprotein
receptor–related protein 5 gene (LRP5). Activating mutations in
this gene lead to an autosomal dominant form of very high
bone mass.
Infiltrative Diseases
Patients with multiple myeloma or Waldenström’s macroglobu-
linemia classically develop skeletal demineralization, which is
also true for some patients with leukemia and marrow lympho-
mas (see Fig 74-1H). Other disorders associated with diffuse
marrow infiltration by benign or less malignant processes can
lead to diffuse osteopenia, bone pain, and fracture, and they
should be considered in the evaluation of unexplained osteopo-
rosis. Examples include hemolytic anemias such as thalassemia
or sickle cell disease, sarcoidosis with diffuse marrow involve-
ment, Gaucher’s disease with lipid-laden marrow giant cells,
malignant mastocytosis, and diffuse histiocytosis.
Transplantation Osteodystrophy
Patients who have undergone or are undergoing organ transplan-
tation commonly have severe osteoporosis. In some patients, this
condition is caused by treatment with immunosuppressive drugs
such as glucocorticoids, tacrolimus, or cyclosporine, which are
potent inhibitors of bone formation and regularly lead to reduc-
tions in bone mass.
In many patients, decreased bone mineral density exists before
transplantation as a result of organ failure or its treatment. For
example, those with primary biliary cirrhosis also may have
osteoblast failure and calcium or vitamin D deficiency. In those
with end-stage lung or cardiac disease, physical inactivity and
generalized malnutrition may contribute to bone demineraliza-
tion. Patients with end-stage renal disease have all of the compo-
nents of renal osteodystrophy. This disorder can be expected to
become increasingly common as the number of organ transplan-
tations increases.
  TREATMENT
Treatment depends on the underlying disorder. If clinically indi-
cated, primary and tertiary hyperparathyroidism are treated with
surgical resection of the affected parathyroid tissue. Osteomala-
cia and rickets improve when the appropriate replacement drug
is administered (i.e., vitamin D, calcium, or phosphate alone or
in combination) or the offending agent (e.g., anticonvulsants) is
removed.
756 Section XIII  Diseases of Bone and Bone Mineral Metabolism
Secondary hyperparathyroidism in a patient on dialysis can be
treated with a combination of the active form of vitamin D
(1,25[OH]2D3 [calcitriol] or analogues), calcium supplementa-
tion, phosphate binders, and cinacalcet, depending on the clini-
cal situation. Secondary hyperparathyroidism due to vitamin D
deficiency should be treated with the oral parent compound,
vitamin D. Other items in Table 74-1 require attention during
treatment of the underlying disorder.
These disorders are commonly amenable to treatment, and
patients can have dramatic and satisfying responses to therapy.
The main stumbling block is that these diagnoses may not be
considered; instead, the DEXA report of osteoporosis is passively
accepted without further investigation. When a patient is diag-
nosed with osteoporosis on the basis of a bone density study or
radiograph, the physician should review the checklist in Table
74-1 and eliminate or investigate alternative disorders.
  For a deeper discussion on this topic, please see Chapter
242, “Approach to the Patient with Metabolic Bone
Disease,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Christov M, Pereira R, Wesselig-Perry K: Bone biopsy in renal osteodystrophy:
continued insights into a complex disease, Curr Opin Nephrol Hypertens
22:210–215, 2013.
Khosla S, Westendorf JJ, Oursler MJ: Building bone to reverse osteoporosis and
repair fractures, J Clin Invest 118:421–428, 2008.
Lindsay R, Cosman F, Zhao H, et al: A novel tetracycline labeling strategy for
longitudinal evaluation of the short term effects of anabolic therapy with a
single iliac crest bone biopsy, J Bone Miner Res 21:366–373, 2006.
Moe S, Drueke T, Cunningham J, et al: Definition, evaluation and classification
of renal osteodystrophy: a position statement from Kidney Disease: Improving
Global Outcomes (KIDIGO), Kidney Int 69:1945–1953, 2006.
Ralston SH: Paget’s disease of bone, N Engl J Med 368:644–650, 2013.
Rosen CJ, editor: Primer on the metabolic bone diseases and disorders of mineral
metabolism, ed 8, Ames Iowa, 2013, J Wiley & Sons and American Society for
Bone and Mineral Research.
Stewart AF: Translational implications of the parathyroid calcium receptor,
N Engl J Med 351:324–326, 2004.
 75 
Osteoporosis
Susan L. Greenspan

  INTRODUCTION
Osteoporosis, the most common disorder of bone and mineral
metabolism, affects about 50% of women and 25% of men older
than 50 years. The National Institutes of Health Consensus
Development Panel on Osteoporosis Prevention defines osteo-
porosis as a skeletal disorder characterized by compromised bone
strength, predisposing a person to an increased risk of fracture.
Bone strength has two main components: bone density and bone
quality. Bone density reflects the peak adult bone mass and the
amount of bone lost in adulthood. Bone quality is determined by
bone architecture, bone geometry, bone turnover, mineraliza-
tion, and damage accumulation (i.e., microfractures) (Fig. 75-1).
  DEFINITION AND EPIDEMIOLOGY
In the United States, 2 million osteoporotic fractures occur each
year. There are almost 300,000 hip fractures each year, which are
associated with a mortality rate of more than 20% during the first
year. More than 50% of patients with hip fracture are unable to
return to their previous ambulatory state, and about 20% of them
are placed in long-term care facilities. When defined by bone
mineral densitometry, 48 million Americans have low bone mass,
and 9 million have osteoporosis. Although morbidity is less with
vertebral fractures, the 5-year mortality rate is similar to that for
hip fractures. Only one third of radiologically diagnosed vertebral
fractures receive medical attention.
  PATHOLOGY AND RISK FACTORS
Peak bone mass is determined primarily by genetic factors. Men
have a higher bone mass than women, and African Americans
and Hispanics have a higher bone mass than whites. Other factors
that contribute to the development of peak bone mass are the use
of gonadal steroids, timing of puberty, calcium intake, exercise,
and growth hormone.
The causes of bone loss in adults are multifactorial. The pattern
of bone loss is different in women than than in men, and bone

Lumbar Spine
Young normal Osteoporotic

FIGURE 75-1  Three-dimensional reconstruction by microcomputed tomography of a lumbar spine sample from a young adult normal woman and
from a woman with postmenopausal osteoporosis. In the osteoporotic woman, bone mass is reduced and microarchitectural bone structure is
deteriorated. Whereas the platelike structure in the normal case is very isotropic, the structure in the osteoporotic case shows preferential loss of
horizontal struts; the plates have become rods that are thin and farther apart, and there is a concomitant loss of trabecular connectivity. These
changes lead to a reduction in bone strength that is more than would be predicted by the decrease in bone mineral density. (From Riggs BL, Khosla
S, Melton LJ 3rd: Sex steroids and the construction and conservation of the adult skeleton, Endocr Rev 23:279–302, 2002; Courtesy Ralph Mueller,
PhD, Swiss Federal Institute of Technology [ETH] and University of Zurich, Switzerland.)

757
758 Section XIII  Diseases of Bone and Bone Mineral Metabolism
loss is greater in sites rich in trabecular bone (e.g., spine) than
cortical bone (e.g., femoral neck) (Fig. 75-2). Women lose sig-
nificantly more trabecular bone than men. Estrogen deficiency
during menopause contributes significantly to bone loss in
women, and they may lose 1% to 5% of bone mass per year in the
first few years after menopause. Women continue to lose bone
mass throughout the remainder of their lives, with another accel-
eration of bone loss occurring after age 75 years. The mechanism
of this accelerated loss in old age is not clear.
Multiple causes of secondary bone loss contribute to osteopo-
rosis and fractures. Medications that commonly cause bone loss
include glucocorticoids, antiseizure medications, excess thyroid
hormone, heparin, androgen deprivation therapy, aromatase
inhibitors, and depo-medroxyprogesterone. Endocrine diseases
resulting in female or male hypogonadism also lead to bone loss.
Hyperparathyroidism, hyperthyroidism, and hypercortisolism
commonly cause bone loss, as can vitamin D deficiency. Gastro-
intestinal problems can contribute to decreased absorption of
calcium and vitamin D (Table 75-1). Risk factors for falls (e.g.,
age, poor vision, previous falls, immobility, orthostatic hypoten-
sion, cognitive impairment, vitamin D insufficiency, poor balance,
gait problems, weak muscles) also contribute to fractures.
  CLINICAL PRESENTATION
Unlike many other chronic diseases with multiple signs and
symptoms, osteoporosis is considered a silent disease until frac-
tures occur. Whereas 90% of hip fractures occur after a fall, two
thirds of vertebral fractures are silent and occur with minimal
stress, such as lifting, sneezing, and bending. An acute vertebral
fracture may result in significant back pain that decreases gradu-
ally over several weeks with analgesics and physical therapy.
Patients with significant vertebral osteoporosis may have height
loss, kyphosis, and severe cervical lordosis, also known as a dowa-
ger’s hump. Prolonged bisphosphonate use (>5 years) may result
in an atypical femoral fracture, which may manifest as unilateral
or bilateral thigh pain and result in a femoral shaft fracture with
no or minimal trauma.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis of osteoporosis is made after an acute clinical ver-
tebral or hip fracture or on assessment of bone mineral density.
Menopause
WOMEN
100
90
% of initial BMD
80
70
60
50
50 60 70 80 90 50 60 70
Age (yr) Age (yr)
Radiography
Radiographs can reveal a vertebral compression fracture (Fig.
75-3). However, low bone mass may not be evident on radio-
graphs until 30% of the mass has been lost. When assessing bone
mass, radiographs may be read inappropriately as a result of over-
penetration or underpenetration of the film. Radiographs there-
fore are a poor indicator of osteoporosis (with the exception of
vertebral fractures), and the diagnosis is instead often based on
bone mineral densitometric results.
Bone Mineral Density and Other  
Bone Mass Assessments
In 1994, the World Health Organization (WHO) developed a
classification system for osteoporosis and low bone mass based
on data from white, postmenopausal women (Table 75-2).
Osteoporosis is defined as a bone mineral density less than or
equal to 2.5 standard deviations (SDs) below young adult peak
bone mass (T-score ≤ −2.5 SD). Low bone mass (i.e., osteopenia)
is defined as a bone mass measurement between 1.0 and 2.5 SDs
below adult peak bone mass (T-score between −1.0 and −2.5
SD). Normal bone mineral density is defined as assessments
above 1.0 SD below adult peak bone mass (T-score ≥ −1.0 SD).
The standard for assessing bone mineral density is dual-energy
x-ray absorptiometry (DEXA), which has excellent precision and
accuracy. Measurements are made at the hip and spine, and in
about 30% of cases, discordance is found between these measure-
ments (Fig. 75-4). Classification should be made only if two or
more vertebrae are available for analysis because of the high error
rate when a single vertebra is assessed. Classification is based on
the lowest value (i.e., total spine, total hip, or femoral neck).
In patients with hyperparathyroidism, in which cortical bone
loss is often seen, forearm DEXA using the one-third distal radius
site should also be assessed. Forearm assessments may be helpful
in older patients who often have falsely elevated bone mineral
density measurements at the spine as a result of atypical calcifica-
tions from degenerative joint disease, sclerosis, or aortic calcifica-
tions or in obese patients whose weight exceeds the table limit.
Bone mineral density can be measured by hip or spine quan-
titative computed tomography (QCT). However, less normative
data are available for hip QCT, vertebral precision is inferior to
MEN
100
90
% of initial BMD
80
70
FIGURE 75-2  Patterns of age-related bone loss
60
in women and in men. Dashed lines represent tra-
50 becular bone, and solid lines represent cortical
bone. The figure is based on multiple cross-
sectional and longitudinal studies using dual-
energy x-ray absorptiometry. BMD, Bone mineral
80 90 density. (From Khosla S, Riggs BL: Pathophysiology
of age-related bone loss and osteoporosis, Endo-
crinol Metab Clin North Am 34:1015–1030, 2005.)
 Chapter 75  Osteoporosis 759

TABLE 75-1  CONDITIONS, DISEASES, AND MEDICATIONS THAT CAUSE OR CONTRIBUTE TO

OSTEOPOROSIS AND FRACTURES
LIFESTYLE FACTORS Panhypopituitarism RHEUMATOLOGIC AND Post-transplantation bone disease
Premature and primary ovarian AUTOIMMUNE DISEASES Sarcoidosis
Alcohol abuse
Excessive thinness failure Ankylosing spondylitis Weight loss
Secondary gonadal failure
Excess vitamin A Lupus MEDICATIONS
Falling Turner’s syndrome, Klinefelter’s Rheumatoid arthritis
syndrome Aluminum (in antacids)
High salt intake Other rheumatic and autoimmune
Anticoagulants (heparin)
Immobilization ENDOCRINE DISORDERS diseases
Anticonvulsants
Inadequate physical activity CENTRAL NERVOUS SYSTEM
Adrenal insufficiency Aromatase inhibitors
Low calcium intake DISORDERS
Cushing’s syndrome Barbiturates
Smoking (active or passive)
Diabetes mellitus (types 1 and 2) Epilepsy Cancer chemotherapeutic drugs
Vitamin D insufficiency
Hyperparathyroidism Multiple sclerosis Cyclosporine and tacrolimus
GENETIC FACTORS Thyrotoxicosis Parkinson’s disease Depo-medroxyprogesterone
(premenopausal contraception)
Cystic fibrosis GASTROINTESTINAL DISORDERS Spinal cord injury
Ehlers-Danlos syndrome Stroke Glucocorticoids (≥5 mg/day of
Gaucher’s disease
Celiac disease prednisone or equivalent for ≥3mo)
Gastric bypass MISCELLANEOUS CONDITIONS Gonadotropin-releasing hormone
Glycogen storage diseases AND DISEASES
Gastrointestinal surgery (GnRH) antagonists and agonists
Hemochromatosis
Inflammatory bowel disease Human immunodeficiency virus Lithium
Homocystinuria
Malabsorption (HIV) infection/acquired Methotrexate
Hypophosphatasia
Pancreatic disease immunodeficiency syndrome Parenteral nutrition
Idiopathic hypercalciuria
Primary biliary cirrhosis (AIDS) Proton pump inhibitors
Marfan syndrome
Osteogenesis imperfecta HEMATOLOGIC DISORDERS Alcoholism Selective serotonin reuptake inhibitors
Parental history of hip fracture or Amyloidosis Tamoxifen (premenopausal use)
Hemophilia Thiazolidinediones (e.g., Actos,
osteoporosis Chronic metabolic acidosis
Leukemia and lymphomas Avandia)
Porphyria Chronic obstructive lung disease
Monoclonal gammopathies Thyroid hormones (in excess)
Congestive heart failure
HYPOGONADAL STATES Multiple myeloma
Depression
Sickle cell disease
Anorexia nervosa and bulimia End-stage renal disease
Systemic mastocytosis
Athletic amenorrhea Hypercalciuria
Thalassemia
Hyperprolactinemia Idiopathic scoliosis
Male hypogonadism Muscular dystrophy
Modified from National Osteoporosis Foundation: 2013 clinician’s guide to Prevention and treatment of osteoporosis. Available at http://nof.org/files/nof/public/content/file/917/
upload/481.pdf. Accessed August 23, 2014.

TABLE 75-2  WORLD HEALTH ORGANIZATION

CLASSIFICATION FOR OSTEOPOROSIS
CLASSIFICATION CRITERIA FOR BONE MINERAL DENSITY
Normal Above −1.0 SD of young adult peak mean value
Low bone mass Between −1.0 and −2.5 SD of young adult peak
(osteopenia) mean value
Osteoporosis Below −2.5 SD of young adult peak mean value
SD, Standard deviation.

The National Osteoporosis Foundation (NOF) recommends

FIGURE 75-3  Lateral spine radiograph demonstrates a thoracic ante-
rior wedge compression fracture.
that of DEXA, and radiation doses are significantly higher than
those of DEXA. Single-photon absorptiometry of the forearm
and peripheral measures, such as heel ultrasound, have also been
used to assess bone mass. However, the WHO classification
should be used only with the central DEXA measurements.
obtaining a bone mineral density assessment in all women 65
years old or older and postmenopausal women younger than 65
years with a risk factor (Table 75-3). The U.S. Preventive Services
Task Force (USPSTF) recommends bone density tests in all
women age 65 or older and women between 60 and 64 years of
age with a risk factor. The NOF recommends obtaining a bone
mineral density value for men 70 years old or older; the USPSTF
has not recommended screening in men. Databases are available
for white, African American, Asian, and Hispanic men and
women. These guidelines from the NOF and USPSTF for screen-
ing patients for osteoporosis are relatively similar for postmeno-
pausal women but differ for older men. At the time of their
review, the USPSTF did not feel there was ample evidence to
determine screening guidelines for men.
The WHO developed a fracture risk assessment tool (FRAX)
to predict the 10-year risk for hip or any major osteoporotic frac-
ture for women and men between 40 and 90 years of age. The
FRAX for the individual patient incorporates femoral neck
760 Section XIII  Diseases of Bone and Bone Mineral Metabolism

k = 1.145, d0 = 53.2
93  97
k = 1.135, d0 = 48.6
116  137

Total Total

1.6 1.6

1.4 1.4

1.2 1.2
BMD

BMD

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4

0.2 0.2
20 25 30 35 40 45 50 55 60 65 70 75 80 85 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Age Age

Region Area BMC BMD T- PR Z- AM Region Area BMC BMD T- PR Z- AM

(cm2) (g) (g/cm2) Score (%) Score (%) (cm2) (g) (g/cm2) Score (%) Score (%)
L1 12.52 8.04 0.642 –2.6 69 –2.0 74 Neck 4.68 1.89 0.404 –4.0 48 –1.6 69
L2 13.41 9.74 0.726 –2.7 71 –2.1 76 Troch 10.63 4.13 0.388 –3.1 55 –1.3 75
L3 16.21 11.96 0.738 –3.1 68 –2.5 73 Inter 16.59 9.90 0.597 –3.2 54 –1.3 74
L4 17.42 13.94 0.800 –2.9 72 –2.2 77 Total 31.89 15.91 0.499 –3.6 53 –1.5 74
Total 59.56 43.68 0.733 –2.9 70 –2.2 75 Ward's 1.19 0.32 0.268 –4.0 37 –0.9 72
Total BMD CV 1.0%, ACF = 1.028, BCF = 1.006, TH = 5.848 Total BMD CV 1.0%, ACF = 1.028, BCF = 1.006, TH = 5.163
WHO Classification: Osteoporosis WHO Classification: Osteoporosis
Fracture Risk: High Fracture Risk: High

FIGURE 75-4  Left, This patient has a lumbar spine (L1 through L4) bone mineral density (BMD) of 0.733 g/cm2 (white circle with cross on the graph)
as measured by dual-energy x-ray absorptiometry (DEXA) and a T-score of −2.9. The reference database graph displays age- and sex-matched mean
BMD levels ±2 standard deviations (SDs) (shaded areas) derived from a normative database from the manufacturer (Hologic, Inc., Bedford, Mass.). The
T-score indicates the difference in SD between the patient’s BMD and that of the predicted sex-matched mean peak of a young adult; the z-value is
the difference in SD between the patient’s BMD and the sex-, age-, and ethnicity-matched mean BMD; and the percentage of mean is the patient’s
BMD as a percentage of the mean peak young adult BMD or age-matched BMD level. Right, This patient has a total hip BMD of 0.499 g/cm2 (white
circle with cross on the graph) as measured by DEXA, a femoral neck T-score of −4.0, and a total hip T-score of −3.6. The reference database graph
displays age- and sex-matched mean BMD levels ±2 SDs (shaded areas) derived from the third National Health and Nutrition Examination Survey.
The T-score indicates the difference in SD between the patient’s BMD and the predicted sex-matched mean peak young adult BMD; the z-score is
the difference in SD between the patient’s BMD and the sex-, age-, and ethnicity-matched mean BMD; and the percentage of mean is the patient’s
BMD as a percentage of the mean peak young adult BMD or age-matched BMD level. (Bone densitometry report for the QDR-4500A bone densitom-
eter, Bedford, Mass., Hologic, Inc.)

T-score, age, gender, height, weight, and specific risk factors,
including history of adult fracture, parental hip fracture, current
smoking, glucocorticoid use, rheumatoid arthritis, alcohol (≥3
drinks per day), and secondary osteoporosis. The fracture risk
prediction is specific for race and country and should be used for
patients not on therapy.
Bone mineral density determined by DEXA usually can be
monitored after 2 years of therapy, depending on the site to be
assessed and the type of therapy prescribed. For example, tra-
becular bone, which has greater surface area and is more meta-
bolically active than cortical bone, is more likely to show
improvements with stronger-acting antiresorptive agents.
Changes in bone mass with potent antiresorptive therapy are
more prominent in the spine compared with other areas. Seeing
no changes in forearm bone mineral density over time is common
despite good precision. Although the heel has a high percentage

TABLE 75-3  NATIONAL OSTEOPOROSIS
FOUNDATION RECOMMENDATIONS   FOUNDATION GUIDELINES
FOR BONE MINERAL DENSITY TESTING
• Women age ≥65 yr and men ≥70 yr, regardless of clinical risk factors
• Younger postmenopausal women, women in the menopausal transition,
and men age 50-69 yr with clinical risk factors for fracture
• Adults who have a fracture after age 50 yr
• Adults who have a condition (e.g., rheumatoid arthritis) or are taking a
medication (e.g., glucocorticoids in a daily dose of ≥5 mg prednisone
or equivalent for ≥3 mo) associated with low bone mass or bone loss
of trabecular bone, precision is poor, and monitoring should not
be done at this site.
All patients with osteoporosis or low bone mass should have
a work-up for secondary causes of bone loss. It should include a
serum calcium level (corrected for albumin) to rule out hyper-
parathyroidism or malnutrition; a 25-hydroxyvitamin D level to
assess for vitamin D deficiency or insufficiency; an alkaline phos-
phatase level to assess for Paget’s disease, malignancy, cirrhosis,
or vitamin D deficiency; liver and renal function tests to assess
for abnormalities; a 24-hour urine calcium and creatinine assay
to evaluate for hypercalciuria or malabsorption; a test for sprue
in patients with anemia, malabsorption, or hypocalciuria; a thy-
rotropin level to rule out hyperthyroidism; and serum protein
electrophoresis to rule out myeloma in older adults with anemia.
Measurement of the parathyroid hormone (PTH) level often is
needed to interpret the calcium and vitamin D levels. Total tes-
tosterone levels are recommended for men.
A more extensive work-up can be done in severe or unusual
cases. A bone biopsy is rarely needed. Markers of bone turnover
vary considerably in clinical practice, and these tests usually are
reserved for research. However, they may be useful for assessing
the rate of bone turnover after prolonged bisphosphonate use or
a bisphosphonate holiday.
  PREVENTION
General preventive measures for all patients include adequate
calcium and vitamin D intake, exercise, and fall prevention tech-
niques. The recommended daily allowance of calcium for adults,
as reviewed by the Institute of Medicine, is 1200 mg. Calcium
intake can be accomplished by dietary consumption, supplemen-
tation, or the combination of diet plus supplement. The supple-
ments should be pure calcium carbonate or pure calcium citrate,
taken in divided doses of about 500 to 600 mg twice daily.
Calcium carbonate should be taken with meals for best absorp-
tion, whereas calcium citrate may be taken with or without food.
Calcium supplements are available as tablets and in chewable and
liquid forms. Foods such as orange juice, cereals, breads, and
nutrition bars are calcium fortified. There is no benefit to taking
more than 1200 mg per day, and excess intake may increase the
risk of kidney stones and cardiovascular disease (although data
are controversial).
Vitamin D is important for calcium absorption and bone min-
eralization. Vitamin D has nonskeletal benefits and has been asso-
ciated with improvement in muscle strength and prevention of
falls. Vitamin D comes from two sources: diet and photosynthe-
sis. Because dietary sources of vitamin D are limited (e.g., forti-
fied milk, yogurt) and patients are often advised to avoid sun
Chapter 75  Osteoporosis 761
TABLE 75-4  NATIONAL OSTEOPOROSIS
 
FOR TREATMENT
• An adult hip or vertebral fragility fracture
• Osteoporosis by DEXA T-score ≤ −2.5 SD for lumbar spine, total hip, or
femoral neck after appropriate evaluation
• Low bone mass by DEXA T-scores between −1.0 and −2.5 SD at the
lumbar spine or femoral neck and a WHO FRAX 10-year probability of a
hip fracture ≥3% or a 10-year probability of major osteoporosis-related
fractures ≥20% based on a WHO algorithm
DEXA, Dual-energy x-ray absorptiometry; FRAX, fracture risk assessment tool; SD,
standard deviation; WHO, World Health Organization.
exposure for prevention of skin cancer and wrinkles, many studies
have documented vitamin D deficiency and insufficiency in older
adults. Older patients have a reduced ability to synthesize vitamin
D in the skin. Low vitamin D levels can lead to secondary
hyperparathyroidism.
Vitamin D can be taken in a multivitamin, in a calcium supple-
ment, or in pure form and is available as cholecalciferol (D3) or
ergocalciferol (D2). Based on data from noninstitutionalized
patients without osteoporosis, the daily dose recommended by
the Institute of Medicine is 600 IU per day for adults up to age
70 and 800 units for those older than 70 years to achieve a level
of at least 20 ng/dL (50 nmol/L). However, the NOF suggests
800 to 1000 IU per day. Elderly patients, those with malabsorp-
tion, and obese patients may need greater amounts of vitamin D.
Older patients with severe vitamin D deficiency may be given
50,000 IU of vitamin D once per week for 3 months to bring
serum vitamin D into the normal range. Activated vitamin D is
rarely needed and should not be given on a regular basis for
postmenopausal osteoporosis.
Weight-bearing exercise is important for maintaining skeletal
integrity. Study results are controversial concerning different
types and durations of exercise by postmenopausal women and
men. However, weight-bearing or resistance training exercises
usually are suggested and have been shown to improve bone mass
or maintain skeletal integrity. In patients with new vertebral frac-
tures, physical therapy is important for improving posture and
increasing the strength of back muscles.
Because 90% of hip fractures and a significant number of ver-
tebral fractures occur during a fall, preventive measures are sug-
gested for frail older patients at risk for falling. Fall-proofing the
household includes installing grab bars in the bathroom and hand
rails on stairways, avoiding loose throw rugs and cords, ensuring
good lighting by the bedside, and moving objects within easy
reach in the kitchen. Other fall prevention measures include
eliminating medications that cause dizziness or postural hypo-
tension (if possible), assessing the need for assistive devices (e.g.,
canes, walkers), and ensuring appropriate footwear and good
vision. The benefits of hip protectors for hip fracture reduction
are disappointing and controversial, and compliance with these
products is often poor.
  TREATMENT AND PROGNOSIS
The NOF developed treatment guidelines that incorporate a
10-year fracture risk prediction. The NOF suggests treatment for
postmenopausal women and men 50 years old or older, as shown
in Table 75-4.
762 Section XIII  Diseases of Bone and Bone Mineral Metabolism

Patients taking glucocorticoids can fracture despite having
normal bone density. The American College of Rheumatology
suggests that patients starting glucocorticoids who will be treated
for 3 months or longer have a bone density test and start antire-
sorptive therapy if indicated according to their guidelines.
Bisphosphonates
Bisphosphonates are the mainstay of osteoporosis prevention
and treatment. They inhibit the cholesterol synthesis pathway in
osteoclasts, causing early apoptosis and inhibiting osteoclast
migration and attachment. Unlike other agents, bisphosphonates
are incorporated into bone, the half-life is long, and the agent may
be recycled.
In the United States, the bisphosphonates alendronate, rise-
dronate, ibandronate, and zoledronic acid have been approved for
the prevention and treatment of osteoporosis. Alendronate can
increase bone mass by about 8% at the spine and 4% at the hip
over 3 years. This increase has been associated with an approxi-
mately 50% reduction in spine, hip, and forearm fractures (Table
75-5). Alendronate is prescribed at 35 mg once weekly for osteo-
porosis prevention and 70 mg once weekly for the treatment of
osteoporosis. Alendronate has been approved for use in men and
patients with glucocorticoid-induced osteoporosis.
Risedronate is approved for the prevention and treatment of
osteoporosis at a dose of 35 mg per week or 150 mg per month
or as a delayed dose after breakfast of 35 mg per week. Large-
scale, multicenter studies have shown improvements in bone
mass of about 6% to 7% at the spine and 3% at the hip over 3
years. These studies revealed a 50% reduction in vertebral frac-
tures, 40% reduction in nonvertebral fractures, and 40% reduc-
tion in hip fractures (see Table 75-5). Risedronate is approved for
the treatment of osteoporosis in men and for the prevention and
treatment of patients with glucocorticoid-induced osteoporosis.
Oral ibandronate is approved for the prevention and treatment
of postmenopausal osteoporosis. After 3 years of treatment, iban-
dronate increased bone density by 6.5% at the spine and 3.4% at
the hip, and it reduced new vertebral fractures by 62%. No reduc-
tions in nonvertebral or hip fractures occurred. Ibandronate is
approved at an oral dose of 150 mg monthly and for treatment at
an intravenous dose of 3 mg every 3 months.
Zoledronic acid is approved for the treatment of postmeno-
pausal osteoporosis, osteoporosis in men, and steroid-induced
bone loss. The 3-year pivotal trial demonstrated increases of 6.9%
of bone density at the spine and 6.0% at the hip, and the drug
reduced spinal fractures by 70%, nonvertebral fractures by 25%,
and hip fractures by 41%. Zoledronic acid is given at a dose of
5 mg intravenously once per year for treatment and 5 mg intra-
venously every 24 months for prevention.
Because oral bisphosphonates are poorly absorbed, they must
be taken first thing in the morning on an empty stomach with a
full glass of water. Patients must wait 30 minutes (when taking
alendronate and risedronate) to 60 minutes (when taking iban-
dronate) before eating and must not lie down. A delayed-release
form of risedronate can be taken after breakfast.
Potential side effects of bisphosphonates include epigastric
distress, heartburn, and esophagitis. Intravenous bisphospho-
nates have been associated with an influenza-like syndrome after
infusion. Bisphosphonates can also cause arthralgias and myal-
gias. They are contraindicated in patients with renal insufficiency
(i.e., estimated glomerular filtration rate of 30 to 35 mL/minute).
Osteonecrosis of the jaw is a rare adverse event of abnormal bone
growth in the jaw, which is more often associated with high-dose
intravenous bisphosphonates in patients with cancer and poor
oral hygiene. Atypical femoral shaft fractures have been reported
rarely after long-term use (>5 years) of bisphosphonates. These
fractures may manifest with a prodrome of unilateral or bilateral
thigh pain, and fractures may occur with minimal activity. These
fractures are rare after osteoporosis treatment but common in
cancer patients receiving frequent high doses intravenously.
Calcitonin
Calcitonin is a 32-amino-acid peptide produced by the parafol-
licular cells of the thyroid gland. The pivotal clinical treatment
trial did not show significant changes in bone mineral density
after 3 years. However, the 200-IU dose of nasal calcitonin was
associated with a 50% reduction in vertebral fractures (see

TABLE 75-5  U.S. FOOD AND DRUG ADMINISTRATION–APPROVED THERAPIES FOR PREVENTION AND TREATMENT
OF OSTEOPOROSIS
VERTEBRAL
PREVENTION/ FRACTURE HIP FRACTURE WOMEN/ STEROID-
AGENT TREATMENT DOSAGE REDUCTION REDUCTION MEN INDUCED OP
Alendronate* Yes/yes Prev: 35 mg/wk PO Yes Yes Yes/yes Yes
Treat: 70 mg/wk PO
Ibandronate* Yes†/yes 150 mg/mo PO, 3 mg q3mo IV Yes No Yes/no No
Risedronate* Yes/yes Prev/treat: 35 mg/wk PO, 35 mg/wk Yes Yes Yes/yes Yes
PO delayed release, 150 mg/mo PO
Zoledronic acid* Yes/yes Prev: 5 mg q2yr IV Yes Yes Yes/yes Yes
Treat: 5 mg/yr IV
Calcitonin No/yes 200 IU/day intranasal Yes No Yes/no No
Denosumab No/yes 60 mg q6mo SC Yes Yes Yes/yes Yes
Hormone/estrogen Yes‡/no Various preparations available Yes Yes Yes§/no No
therapy
Raloxifene Yes/yes 60 mg/day PO Yes No Yes/no No
Teriparatide (PTH [1-34]) No/yes 20 µg/day SC Yes No Yes/yes Yes
OP, Osteoporosis; PO, oral administration; prev, prevention; PTH, parathyroid hormone; SC, subcutaneous administration; Treat, treatment.
*Alendronate, risedronate, ibandronate, and zoledronic acid are bisphosphonates.
†
Oral only.
‡
Short-term prevention or management.
§
For management.

Table 75-5). No reduction in nonvertebral or hip fractures was
found. The U.S. Food and Drug Administration (FDA) advisory
panel is reviewing an association with cancer.
Denosumab
The receptor activator of nuclear factor-κB (RANK) and its
ligand (RANKL) are mediators of osteoclast activity. Compared
with placebo, denosumab, an antibody to RANKL, produced a
relative increase in bone mineral density at the spine of 9.2% and
hip of 6.0% over 3 years, and it reduced fractures by 68% at the
spine, 40% at the hip, and 20% at nonvertebral sites. Denosumab
is approved for postmenopausal women and men with osteopo-
rosis, for men with prostate cancer on androgen deprivation
therapy, and for postmenopausal women with breast cancer on
aromatase inhibitors. It is given as a subcutaneous 60-mg injec-
tion every 6 months.
Estrogen Agonists-Antagonists
Estrogen agonists-antagonists were previously called selective
estrogen receptor modulators (SERMs) because they have some
estrogen-like and anti–estrogen-like benefits. Raloxifene is
approved for the prevention and treatment of osteoporosis. The
Multiple Outcomes of Raloxifene Evaluation (MORE) trial
found that bone mass was increased by 4% at the spine and 2.5%
at the femoral neck over 3 years. This increase was associated with
a 50% reduction in vertebral fractures. No reduction in nonver-
tebral or hip fractures was seen (see Table 75-5). Treatment was
associated with improved lipid status, as shown by decreased
total and low-density lipoprotein cholesterol.
Raloxifene is not associated with endometrial hyperplasia, and
patients should not have bleeding or spotting. They do not have
breast tenderness or swelling. Raloxifene reduces the risk for
invasive breast cancer in postmenopausal women with osteopo-
rosis and in women at high risk for invasive breast cancer. Patients
have the same small risk of deep vein thrombosis or pulmonary
embolus that is found with hormone therapy. Raloxifene does
not relieve postmenopausal symptoms and may exacerbate hot
flashes. Studies have not found a significant impact on cardiovas-
cular disease. Raloxifene can be given with or without food in a
daily oral dose of 60 mg per day.
Hormone Therapy
Investigators of the Women’s Health Initiative, a large, random-
ized, placebo-controlled, multicenter trial evaluating hormone
therapy, reported a 36% reduction in hip and vertebral fractures
after 5.2 years. In addition to improvements in bone mass, ben-
efits include an improved lipid profile, decreased colon cancer
incidence, and decreased menopausal symptoms. However,
because of the potential risks of hormone therapy (i.e., cardiovas-
cular events, breast cancer, deep vein thrombosis, pulmonary
embolus, and gallbladder problems), it should be used only for
prevention or management of menopausal symptoms, and other
agents should be used for the treatment of osteoporosis.
Parathyroid Hormone
Recombinant human PTH (1-34), or teriparatide, is an osteo-
anabolic agent that increases spinal bone mineral density by 9.7%
Chapter 75  Osteoporosis 763
and hip bone mineral density by 2.6% in 18 months. It is associ-
ated with a 65% reduction in vertebral fractures and a 53% reduc-
tion in nonvertebral fractures. Teriparatide is taken for up to 2
years as a subcutaneous, 20-µg daily dose for postmenopausal
women and men at high risk for fracture. After therapy, patients
benefit from antiresorptive therapy to prevent bone loss. Recom-
binant human PTH (1-84) is approved for use in Europe.
Alternative Therapies
Medical Therapies
Strontium ranelate is an approved agent for the treatment of
osteoporosis in Europe, but it is not FDA approved in the United
States. The mechanism of action is not fully understood, but
strontium is thought to stimulate osteoblast proliferation and
inhibit osteoclast formation. Inhibition of the protease cathepsin
K appears to prevent bone resorption with no major impact on
bone formation. Another promising osteoanabolic therapeutic
target is the inhibition of sclerostin, a potent inhibitor of bone
formation, with an antibody.
Combination therapy has been examined with two antiresorp-
tive agents or an antiresorptive and osteoanabolic agent together.
Overall, studies with combination therapy have suggested minor
improvements in bone mass over therapy with single agents.
Because studies have not shown greater fracture reduction, this
type of combination therapy with two antiresorptive agents or an
antiresorptive plus an osteoanabolic usually is not recommended.
However, it is recommended to follow osteoanabolic therapy
using teriparatide with an antiresorptive therapy such as a
bisphosphonate to maintain the gain.
Vertebroplasty and Kyphoplasty
Vertebroplasty involves injection of cement (i.e., polymethyl-
methacrylate) into a compressed vertebra to prevent the verte-
bral body from further collapse. Kyphoplasty introduces a
balloon into the vertebral body to expand it, followed by cement
placement inside the vertebral body. This approach expands the
vertebral body and may increase height. Some studies suggest a
significant reduction in pain early on, but the long-term pain
reduction may be similar to that of placebo. Ongoing studies are
needed to determine whether differences in outcomes can be
found between vertebroplasty and kyphoplasty. These proce-
dures are recommended only for patients with significant pain
from vertebral fractures and are not routinely performed in
asymptomatic patients with vertebral osteoporosis.
SUGGESTED READINGS
Institute of Medicine: Dietary reference intakes for calcium and vitamin D,
Washington, D.C., 2011, The National Academies Press.
Kanis JA: Diagnosis of osteoporosis and assessment of fracture risk, Lancet
359:1929–1936, 2002.
National Osteoporosis Foundation: Clinician’s guide to prevention and treatment
of osteoporosis, Washington, D.C., 2013, The Foundation.
Nelson HD, Helfand M: Screening for postmenopausal osteoporosis. Systematic
evidence review no. 17. (Prepared by the Oregon Evidence-based Practice
Center for the Agency for Healthcare Research and Quality.) Rockville, Md.,
2002, Agency for Healthcare Research and Quality. Accessed at http://www
.ahrq.gov/downloads/pub/prevent/pdfser/osteoser.pdf on 3 June 2010.
XIV
ESSENTIALS

Musculoskeletal and Connective

Tissue Disease
76  Approach to the Patient with Rheumatic Disease
Niveditha Mohan

77  Rheumatoid Arthritis

Rayford R. June and Larry W. Moreland

78  Spondyloarthritis
Douglas W. Lienesch

79  Systemic Lupus Erythematosus

Amy H. Kao and Susan Manzi

80  Systemic Sclerosis

Robyn T. Domsic

81  Systemic Vasculitis

Kimberly P. Liang

82  Crystal Arthropathies

Ghaith Noaiseh

83  Osteoarthritis
C. Kent Kwoh

84  Nonarticular Soft Tissue Disorders

Niveditha Mohan

85  Rheumatic Manifestations of Systemic Disorders; Sjögren Syndrome

Yong Gil Hwang

765
 76 
Approach to the Patient with
Rheumatic Disease
Niveditha Mohan
Demographic data provide useful information. The age of the
  INTRODUCTION patient can point to a specific rheumatic disorder. The spondylo-
Rheumatic diseases encompass a range of musculoskeletal and arthropathies are more commonly diagnosed in young men, SLE
systemic disorders that involve the joints and periarticular tissues. in young women, gout in middle-aged men and postmenopausal
Tissue degeneration results from autoimmune responses, chronic women, and osteoarthritis in the older population. Asymmetrical
inflammation, local trauma, and infection, producing gout, osteo- pain and swelling in the knees have different connotations in a
arthritis, and connective tissue diseases such as rheumatoid 70-year-old patient than they do in a 20-year-old patient.
arthritis and systemic lupus erythematosus (SLE). Immune status may affect the diagnosis of rheumatic disease.
Differentiating localized from systemic processes, executing Immunocompromised patients should be evaluated for infec-
logical diagnostic procedures, and embarking on appropriate tious arthritis. Patients with human immunodeficiency virus
therapeutic courses demand careful clinical evaluation. The (HIV) infection may have a severe form of Reiter’s syndrome or
medical history and physical examination are paramount in this a sudden flare of psoriasis or psoriatic arthritis.
process. Laboratory tests are more confirmatory than diagnostic. The patient’s history provides the basis for differentiating
The connective tissue screen is performed at the bedside, not in inflammatory from noninflammatory arthropathies. Inflamma-
the laboratory. Confirmation or exclusion of systemic connective tory arthritis is characterized by pain at rest, morning stiffness
tissue disease on the basis of laboratory results is unreliable and (i.e., gelling), joint swelling, and joint tenderness. In osteoarthri-
therefore unwise. tis and nonarthritic musculoskeletal problems, pain usually does
not occur at rest and is precipitated by activity. Some osteoar-
  MUSCULOSKELETAL HISTORY AND EXAMINATION thritic joints are stiff initially but are improved with activity. The
A logical approach to musculoskeletal complaints is indispens- onset of disease is abrupt in crystal-induced arthritis, less so in
able in arriving at the correct diagnosis. Features in the medical septic arthritis, and slow and insidious in most other disorders.
history that are useful for distinguishing different types of arthri- Patterns of joint involvement are typical of certain disorders:
tis are listed in Tables 76-1 and 76-2. When a patient has a monoarthritis (one joint), as in septic or crystal-induced arthri-
musculoskeletal complaint, a thorough history and physical tis; pauciarthritis or oligoarthritis (two to four joints), as in Reit-
examination usually provide the diagnosis, although further er’s syndrome or psoriatic arthritis; and polyarthritis (five or
investigations may be necessary for confirmation. more joints), as in rheumatoid arthritis or SLE. Symmetry, migra-
The first step is to confirm that the complaint originates from tory features, large versus small joint involvement, and axial
the musculoskeletal system and is not referred pain caused by versus appendicular locations are characteristic features of spe-
other organ system pathology (e.g., left shoulder pain due to cific diseases and should be sought in the patient’s history. Enthe-
cardiac disease). The next step is to define whether the problem sopathy (i.e., disease at the attachment of tendons or ligaments
is articular or extra-articular based on the history and clinical to bone) can indicate a spondyloarthropathy.
presentation. Constitutional features such as fatigue, weight loss, and fever
are seen in systemic autoimmune disease and infection but not
in localized conditions. A thorough review of systems can
provide clues to the primary diagnosis by defining associated
TABLE 76-1  CLINICAL FEATURES THAT ARE HELPFUL systemic syndromes. Although there are many exceptions to
IN THE EVALUATION OF ARTHRITIS these demographic and clinical generalizations, they provide
Age, sex, ethnicity, family history Constitutional symptoms and signs helpful starting points when a patient is being evaluated for the
Pattern of joint involvement (e.g., fever, fatigue, weight loss) first time.
Monoarticular, oligoarticular, Synovitis, bursitis, tendinitis On physical examination, active and passive range of motion
polyarticular Involvement of other organ systems
Large versus small joints (e.g., rash, mucous membrane in all joints should be carefully assessed, and tenderness, swelling,
Symmetry lesions, nail lesions) warmth, erythema, deformity, and joint effusions should be eval-
Insidious versus rapid onset Arthritis-associated diseases (e.g., uated (Fig. 76-1). Patients are frequently unaware of detectable
Inflammatory versus psoriasis, inflammatory bowel
noninflammatory pain (e.g., disease) joint abnormalities, including deformity and effusion, which are
morning stiffness, gelling, Anemia, proteinuria, azotemia signs of joint disease. Reported pain may be referred from another
night pain) Erosive joint disease site, which can be determined by examination. Pain in the knee

766
 Chapter 76  Approach to the Patient with Rheumatic Disease 767

TABLE 76-2  DIFFERENTIATING FEATURES OF COMMON ARTHRITIDES

DISEASE DEMOGRAPHICS JOINTS INVOLVED SPECIAL FEATURES LABORATORY FINDINGS
Gout Men, postmenopausal women Monoarticular or Podagra, rapid onset of attack, SF: Crystals, high WBC
oligoarticular polyarticular gout, tophi count, >80% PMNs
Septic arthritis Any age Usually large joints Fever, chills SF: High WBC count, >90%
PMNs, culture
Osteoarthritis Increases with age Weight-bearing, hands Noninflammatory SF
Rheumatoid arthritis Any age, predominantly Symmetrical, small joints Rheumatoid nodules, SF: High WBC count, >70%
women ages 20-50 yr disease extra-articular PMNs
Reactive arthritis (Reiter’s Young males Oligoarticular, asymmetrical Urethritis, conjunctivitis, skin SF: Moderate WBC count,
syndrome) and mucous membranes >50% PMNs
Spondyloarthropathy Young to middle-aged men Axial skeleton, pelvis Uveitis, aortic insufficiency,
(sacroiliac joints) enthesopathy
Systemic lupus erythematosus Women in childbearing years Hands, knees Nonerosive joint disease, SF: Low to moderate WBC
autoantibodies, mostly count, almost 100% have
mononuclear; multiorgan antinuclear antibodies
disease
PMNs, Neutrophils; SF, synovial fluid; WBC, white blood cell.

Muscle Synovial membrane:

inflammation Joint space: Synovitis (Rheumatoid
Muscle Bursa Joint space Synovial Tendon (myositis) Bursa joint infection arthritis)
membrane
Tendon

Enthesis:
Periosteum Enthesis Periosteum Enthesopathy
(ankylosing
Bony end plate spondylitis)
Bony end Joint Cartilage Joint space (avascular necrosis) Joint Cartilage:
plate capsule capsule cartilage Joint space:
degeneration microcrystalline
(osteoarthritis) arthritis (gout)
FIGURE 76-1  Anatomic structures of the musculoskeletal system (left). Locations of musculoskeletal disease processes (right). (From Gordon DA:
Approach to the patient with musculoskeletal disease. In Bennett JC, Plum F, editors: Cecil textbook of medicine, ed 20, Philadelphia, 1996, WB
Saunders, p 1440.)

is often a sign of hip disease and may be reproduced on examina-
tion of the hip. Palpable synovitis (i.e., thickening of the synovial
membrane) is helpful in diagnosing inflammatory arthritides
such as rheumatoid arthritis.
Different diseases have distinctive patterns of joint in­
volvement, which provide critical diagnostic information. For
example, prominent disease of distal interphalangeal joints is
seen in psoriasis and inflammatory osteoarthritis. Wrist and
metacarpophalangeal involvement are almost universal in rheu-
matoid arthritis but rare in osteoarthritis. Examination of the
axial skeleton may reveal diminished lumbar flexion, decreased
rotational motion of the spine, and decreased chest expansion,
features of ankylosing spondylitis and other spondyloarthropa-
thies. Patients may report symptoms in only a single joint, but
finding additional affected joints on physical examination can
change the entire evaluation.
Because rheumatic diseases may involve any organ system, a
full physical examination should be performed for all patients.
Alopecia and funduscopic changes (in SLE), uveitis (in spondy-
loarthropathy and juvenile arthritis), conjunctivitis (in reactive
arthritis), sicca symptoms (in Sjögren syndrome), oral and other
mucous membrane ulcers (in reactive arthritis, SLE, and Behçet
syndrome), lymphadenopathy (in SLE and Sjögren syndrome),
and cutaneous lesions (in psoriasis, dermatomyositis, sclero-
derma, SLE, and vasculitides) should be considered. Recurrent
otorhinolaryngologic complaints, such as sinusitis, should raise
suspicion for granulomatosis with polyangiitis (i.e., Wegener’s
granulomatosis). Lesions of psoriasis in the scalp, umbilicus, and
anal crease; thickening of the skin on the fingers in scleroderma;
and mucous membrane ulcers are often overlooked.
The lung examination may find evidence of interstitial fibrosis
(in scleroderma, SLE, rheumatoid arthritis, and myositis), and
a cardiac evaluation may reveal aortic insufficiency (in SLE
and spondyloarthropathy), pulmonary hypertension (in sys-
temic sclerosis), or evidence of cardiomyopathy (in systemic
sclerosis, myositis, and amyloidosis). Pleural and pericardial
rubs may be detected in SLE, rheumatoid arthritis, and sclero-
derma. Hepatosplenomegaly (in SLE and rheumatoid arthritis)
and abdominal distention (in scleroderma) are also valuable
clinical clues.
768 Section XIV  Musculoskeletal and Connective Tissue Disease
Muscle examination may reveal weakness from myositis, neu-
ropathy (in vasculitis and SLE), myopathy (in steroid myopathy),
or synovitis (in rheumatoid arthritis, SLE, and spondyloarthrop-
athy). A complete neurologic examination may reveal carpal
tunnel syndrome, peripheral neuropathy such as mononeuritis
multiplex (i.e., asymmetrical sensory or motor neuropathy seen
in many vasculitides), and central nervous system disease (in SLE
and vasculitis). Recurrent miscarriages, livedo reticularis, Ray­
naud’s phenomenon, and recurrent thrombotic events indicate
antiphospholipid antibody syndrome (in primary or secondary
SLE).
The initial evaluation must determine whether diagnosis and
treatment of the patient’s problem requires urgent attention.
Infectious processes need immediate treatment. Acute joint
inflammation, fever, and systemic signs such as chills, night
sweats, and leukocytosis provide supporting evidence for infec-
tion. Gouty arthritis may share some or all of these clinical fea-
tures, but its onset tends to be more abrupt. Inflammation
extending beyond the margins of the joint is characteristic of
septic arthritis and is otherwise seen only in crystal disease and
rheumatoid arthritis. Nonarticular processes such as cellulitis,
septic bursitis, tenosynovitis, and phlebitis may mimic infectious
arthritis. Analysis of synovial fluid is the key to diagnosis.
Acute nerve entrapment or spinal cord compression, tendon
rupture, and fractures may occur in the absence of obvious
trauma. Spinal cord compression may be the result of a herni-
ated disk or vertebral subluxation. Tendon rupture may occur
in inflammatory arthritides, particularly in the wrist of patients
with rheumatoid arthritis. Pelvic and other insufficiency fractures
may be seen in patients with osteoporosis or osteomalacia.
Careful musculoskeletal and neurologic examinations help in
the detection of these disorders, all of which require urgent
treatment.
The onset of systemic rheumatic diseases is usually insidious,
and the clinical course is prolonged. Treatment is usually not
urgent and can be safely deferred, particularly if the diagnosis is
uncertain. However, potential threats to life or the possibility of
serious and irreversible organ damage may require urgent therapy.
Patients with SLE or systemic vasculitis may have central or
peripheral nervous system disease, including brain and periph-
eral nerve infarcts; glomerulonephritis; inflammatory or hemor-
rhagic lung disease; coronary artery involvement; intestinal
infarcts; and digital infarcts. Threatened digit loss may also be
seen in cases of scleroderma and Raynaud’s disease. Renal crisis
TABLE 76-3  CLASSIFICATION OF SYNOVIAL EFFUSIONS BY SYNOVIAL WHITE BLOOD CELL COUNT
GROUP SAMPLE DIAGNOSES
Normal
I. Noninflammatory Osteoarthritis; trauma
II. Mildly inflammatory Systemic lupus erythematosus
III. Severely inflammatory Gout
(noninfectious) Pseudogout
Rheumatoid arthritis
IV. Severely inflammatory Bacterial infections
(infectious)
Tuberculosis
PMNs, Neutrophils; WBC, white blood cell.
*Range, with mean values in parentheses.
may occur in scleroderma, with vasculopathy leading to renal
infarcts, azotemia, microangiopathy, and severe hypertension.
Acute blindness is a potential complication of giant cell arteritis,
and the diagnosis requires urgent therapy even before confirma-
tory biopsy.
Acute inflammatory myositis should be promptly treated
because it may progress rapidly and involve the respiratory mus-
culature. In some cases, major organ involvement may be occult.
When systemic disease is suggested, the patient’s lungs and
kidneys should be carefully evaluated.
  LABORATORY TESTING
Synovial fluid analysis is an important part of the evaluation of
arthritis (Table 76-3). It helps to distinguish between inflamma-
tory and noninflammatory arthritis, and results can be diagnostic
of infectious arthritis or crystal disease.
Synovial fluid consists of an ultrafiltrate of plasma plus hyal-
uronic acid that is secreted by synovial lining cells. Evaluation of
synovial fluid should include a cell count and differential, exami-
nation for sodium urate and calcium phosphate dehydrate crys-
tals, Gram stain, and culture. Synovial fluid glucose and protein
levels are not useful tests. Synovial fluid examination should be
performed for all acute arthritides and all situations in which
joint infection is likely. It should be performed at least once to
evaluate chronic inflammatory arthritis. Aspiration and analysis
of fluid before therapy are essential for appropriate decision
making.
Although autoantibodies are often considered the hallmark of
rheumatic diseases, their utility in diagnosing individual patients
is much less than commonly assumed. Although almost 95% of
patients with SLE have antinuclear antibodies (ANAs), as do
most patients with scleroderma and autoimmune myositis, the
proportion of patients with other rheumatic diseases who have
positive test results is much lower. Conversely, 15% to 25% of
healthy persons have ANAs, sometimes in high titers, when com-
mercial test kits are used. Older persons and patients with
nonrheumatic systemic diseases such as malignancies and non-
rheumatic autoimmune diseases such as thyroiditis or hypothy-
roidism have even higher frequencies of ANAs.
The very low specificity of a positive ANA result in the absence
of clinical findings for an autoimmune disorder precludes its use
as a screening test for disease in the general population. Other
autoantibodies may be more useful and are discussed in subse-
quent chapters.
SYNOVIAL FLUID
APPEARANCE WBC COUNT (MM3)* PMN CELLS (%)
Clear, pale yellow 0-200 <10
Clear to slightly turbid 50-2000 (600) <30
Clear to slightly turbid 100-9000 (3000) <20
Turbid 2000-160,000 (21,000) ≈70
Turbid 500-75,000 (14,000) ≈70
Turbid 2000-80,000 (19,000) ≈70
Very turbid 5000-250,000 (80,000) ≈90
Turbid 2500-100,000 (20,000) ≈60
 Chapter 76  Approach to the Patient with Rheumatic Disease 769
Rheumatoid factor is found in approximately 80% of patients
with rheumatoid arthritis but also found in other rheumatic dis-
eases, chronic infection, neoplasia, and almost any disease state
that can cause chronic hyperglobulinemia. Neither positive nor
negative test results are diagnostic, and the results should be
interpreted only in the clinical context. Although the specificity
of the rheumatoid factor is low, it does predict more aggressive
joint disease and extra-articular joint manifestations.
Antibodies to cyclic citrullinated peptides are helpful in diag-
nosing rheumatoid arthritis because they have a high specificity
(>90%). Their sensitivity varies from about 50% to 75%. Anti-
body tests should be ordered and repeated only if they can help
in making the diagnosis, assessing the prognosis, or altering the
treatment plan.
Tests for acute phase proteins, C-reactive protein, and the
erythrocyte sedimentation rate are nonspecific, but positive
results suggest an inflammatory disease. In some cases, such as in
patients with giant cell arteritis and polymyalgia rheumatica,
these tests may be useful for the diagnosis and monitoring the
course of disease and therapy. Anemia may suggest chronic
disease or hemolytic anemia. Leukopenia, especially lymphope-
nia, suggests SLE, and thrombocytosis indicates active inflamma-
tion. Leukocytosis may reflect inflammation or infection, and
glucocorticoid therapy also elevates the neutrophil cell count by
demarginalization. Urinalysis should always be performed for
patients with systemic disease. Proteinuria, red blood cells, and
casts should be considered evidence of occult renal disease. Lab-
oratory tests should always be considered in the context of the
clinical presentation.
  RADIOGRAPHIC STUDIES
Radiographic studies often show changes characteristic of par-
ticular diseases. In patients with established rheumatoid arthritis,
radiographs may demonstrate classically erosive disease of the
small joints of the wrists, the ulnar styloid, the metacarpophalan-
geal and proximal interphalangeal joints, and the small joints in
the foot. The erosions are bland and nonreactive. In contrast,
erosive psoriatic arthritis causes a sclerotic reaction, and the
patient may have characteristic telescoping of joints, also called
pencil-in-cup lesions. Large erosions with overhanging sclerotic
margins and even juxta-articular tophi may be seen in gout.
In ankylosing spondylitis, sacroiliitis is observed on pelvic
x-ray films and has high diagnostic specificity. Syndesmophytes
(i.e., calcification of the outer rim of the annulus fibrosis), bridg-
ing osteophytes, calcification of spinal ligaments, and a typical
bamboo spine in the late stages are seen on lumbar and chest
radiographs. Joint space narrowing, bony spurs, and sclerosis are
seen in osteoarthritis. Chondrocalcinosis is a common finding. It
may be asymptomatic or may lead to crystal arthritis (i.e., pseu-
dogout). In acute arthritis, radiographs are much less helpful
because bony changes take time to develop; only in septic joint
disease is destruction observed in the early stages.
Imaging modalities such as magnetic resonance imaging
(MRI), radionuclide scans, ultrasound, and computed tomogra-
phy are often useful in assessing diseases of bones, joints, muscle,
and soft tissues. Ultrasound may be used to detect synovial cysts,
especially Baker’s cysts of the knee, and it is being used more
frequently in the outpatient setting to guide procedures.
MRI is the procedure of choice for evaluating early avascular
necrosis of bone, especially the hips, and for meniscal or rotator
cuff disease. MRI is preferred for evaluating intervertebral disk
disease with radiculopathy and spinal stenosis, and it is useful for
assessing solid lesions of bone and joints, including neoplastic
lesions. The sensitivity of MRI for detecting edema (i.e., water)
enables evaluation of infectious and noninfectious inflammatory
muscle diseases. MRI is a sensitive but not a specific modality for
evaluating osteomyelitis, properties shared with radionuclide
imaging. MRI should not supplant clinical evaluation or plain
radiography.
In many instances, diagnosis can be made with certainty only
by pathologic examination of tissue. Muscle biopsy may be neces-
sary to establish a diagnosis of inflammatory muscle disease, and
nerve biopsy may be needed to detect vasculitis. Skin biopsy is
useful in differentiating the many causes of rheumatologic skin
disease. Renal biopsy is often needed for determination of the
diagnosis, treatment, and prognosis.
  SUMMARY
The evaluation of arthritis begins with a detailed history consist-
ing of the location and pattern of joint involvement, differentia-
tion of inflammatory from mechanical and other causes, and a
thorough review of systems to determine the nonarticular sys-
temic features. The patient’s age and sex, family history, medica-
tion history, and coexisting medical conditions have a bearing on
the diagnosis and treatment plan. Radiographic and laboratory
studies, particularly synovial fluid analysis, provide confirmatory
and sometimes diagnostic information.
For a deeper discussion of these topics, please see Chapter
256, “Approach to the Patient with Rheumatic Disease,” in
Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Felson DT: Epidemiology of the rheumatic diseases. In Koopman WJ, editor:
Arthritis and allied conditions, ed 13, Baltimore, 1997, Williams & Wilkins,
p 3.
Gordon DA: Approach to the patient with musculoskeletal disease. In Goldman
L, Bennett JC, editors: Cecil textbook of medicine, ed 21, Philadelphia, 2000,
WB Saunders, pp 1472–1475.
Sergent JS: Approach to the patient with pain in more than one joint. In Kelley
WN, Harris ED Jr, Ruddy S, et al, editors: Textbook of rheumatology, ed 5,
Philadelphia, 1997, WB Saunders, p 381.
 77 
Rheumatoid Arthritis
Rayford R. June and Larry W. Moreland
  DEFINITION AND EPIDEMIOLOGY
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory
disorder of unknown cause that is characterized by symmetrical,
polyarticular pain and swelling, morning stiffness, and fatigue.
RA has a variable course, often with periods of exacerbations and,
less frequently, true remissions. Outcomes range from rarely seen
remitting disease to severe disease that produces disability and,
for some patients, premature death.
Without treatment, most patients have progressive joint
damage and significant disability within a few years. Since the
introduction of tumor necrosis factor-α (TNF-α) inhibitors in
the 1990s, there has been a change in the treatment paradigm,
and many conventional and biologic therapies are now available
to treat this previously debilitating chronic disease.
RA is a worldwide problem, with a prevalence of 0.5% to 1%
of the adult population and an annual incidence of 0.03%. RA is
three times more common among woman than men, and the
disease affects individuals at any age, including infants and the
elderly. However, it occurs most commonly in women between
the ages of 40 and 50 years. RA is uncommon among men
younger than 45 years of age, but the incidence rises steeply with
increasing age. Among women, the incidence rises until age 45,
plateaus until age 75, and then declines. Numerous studies have
demonstrated increased mortality rates for patients with RA
compared with the general population. The increased mortality
rate is attributed to infectious and cardiovascular complications.
The underlying cause of RA (i.e., triggers in the susceptible
host) is unknown. RA may consist of multiple diseases now
defined by common clinical manifestations, and there may not
be a single predominant mechanism of initiation or perpetuation.
As for most autoimmune diseases, RA is thought to result from
a complex interaction of genetic and environmental factors.
Smoking, obesity, silica exposure, mineral oil, and organic sol-
vents have been associated with the development of RA. Smoking
has the most impact, particularly on anti–cyclic citrullinated
peptide (CCP) antibody–positive disease.
An individual’s genetic profile also plays a critical role in the
susceptibility to and severity of RA. Supporting a genetic com-
ponent, studies have revealed a 15% concordance in monozy-
gotic twins that is approximately four times greater than the rate
in dizygotic twins. The genes with the greatest impact lie in the
class II major histocompatibility (MHC) locus, which accounts
for one third of the genetic risk for RA. A specific sequence on
the HLA-DR haplotype involved in antigen recognition is called
the shared epitope because it is strongly associated with
more severe RA and extra-articular manifestations. Although
770
important, the shared epitope does not fully explain RA because
it occurs in only 25% to 35% of the white population. The chance
of developing RA in carriers is only 1 in 25.
The interplay between environmental and genetic factors is
most clearly seen with the increased risk of RA associated with
smoking and the MHC class II loci. The exact association
between the two is unclear, but research has shown that the bac-
teria in periodontal disease, which are increased with smoking,
can promote citrullination. Anti-CCP antibodies are associated
with a more aggressive disease.
For a deeper discussion of these topics, please see Chapter
264, “Rheumatoid Arthritis,” in Goldman-Cecil Medicine,
25th Edition.
  PATHOLOGY AND PATHOGENESIS
RA is a heterogeneous disease with a complex pathogenesis. RA
is a clinical diagnosis and a single phenotype, but the underlying
genotype may not be unique. Instead, several signaling pathways
may lead to the same clinical presentation.
Synovial inflammation characterizes RA, along with loss of
tolerance, autoantibody production, bone destruction, and sys-
temic inflammation. Many advances have been made in under-
standing the cell-cell interactions and cytokine signaling, but
little is known about the loss of tolerance. Many of the insights
into the pathogenesis of RA have resulted from analyzing the
responses to cytokine inhibition (i.e., interleukin-1 [IL-1], TNF-
α, and interleukin6 [IL-6]) and to specific T- and B-cell–directed
therapies.
The process of synovial inflammation and proliferation may be
initiated by an interaction between antigen-presenting cells
(APCs) and CD4+ T cells. APCs display complexes of class II
MHC molecules and peptide antigens that bind to specific recep-
tors on the T cells. Clonal expansion of T-cell subsets occurs with
an appropriate second signal or costimulation delivered by the
APC to the T cell. Activated TH1 and TH17 cell subsets appear
to predominate in synovial tissues. These cell types stimulate
synovial macrophages to secrete proinflammatory cytokines such
as IL-1, TNF-α, and IL-6 to activate many inflammatory
pathways.
The humoral immune system is also involved in the pathogen-
esis of RA. The autoantibodies found most frequently in patients
with RA are immunoglobulin M (IgM) rheumatoid factor (RF)
and anti-CCP. RF and anti-CCP are associated with aggressive,
erosive RA (see Diagnosis and Differential Diagnosis) and are
found in serum before the development of clinical RA. Although
a causal link has not been confirmed, CCP antibodies, combined

with genetic and environmental factors (e.g., smoking, periodon-
tal disease), are involved in the development of RA.
RA pathogenesis occurs in stages. In the induction phase, the
joint’s environment enables recruitment of inflammatory cells.
Cigarette smoke, bacterial products, viral components, and other
environmental stimuli may amplify this process. A genetic pro-
pensity for autoreactivity may initiate an irreversible pathway
to RA.
The destructive phase, which can be antigen dependent or
independent, involves mesenchymal elements such as fibroblasts
and synoviocytes. Bone erosions result from local differentiation
and activation of osteoclasts, whereas cartilage damage appears
to be caused by proteolytic enzymes produced by synoviocytes,
macrophages, and synovial fluid neutrophils. Counter-regulatory
mechanisms (e.g., soluble TNF-α receptors, suppressive cyto-
kines, protease inhibitors, natural cytokine antagonists) are not
produced in high enough levels, leading to a loss of tolerance.
Cytokines, which are hormone-like proteins that regulate
many immune cell functions, have been implicated in synovial
inflammation. The inflammatory milieu of the joint is dominated
by proinflammatory factors produced by macrophages and fibro-
blasts, especially in the synovial intimal lining. IL-1, IL-6, TNF-
α, and many other cytokines and chemokines have been identified
at the protein and mRNA levels in the synovium.
Joint damage in RA results from proliferation of the synovial
intimal layer that forms a pannus that overgrows, invades, and
destroys adjacent cartilage and bone (Fig. 77-1). Fibroblast-like
Fluid phase
Immune
B cell complexes
Prostaglandins
MMPs
Pannus
SC
TNF, IL-1
MNC
T cell
Tissue phase
FIGURE 77-1  Pathogenetic events in rheumatoid arthritis. The proliferative synovial pannus invades at the bone-cartilage interface. Interleukin-1
(IL-1) and tumor necrosis factor-α (TNF) activate synovial cells (SC) to produce prostaglandins and matrix metalloproteinases (MMPs). In the synovial
fluid, polymorphonuclear leukocytes (PMN), activated by immune complexes and complement, produce mediators of inflammation and destruction.
CD, Chondrocytes; MNC, mononuclear cell; OC, osteoclast.
Chapter 77  Rheumatoid Arthritis 771
synoviocytes and macrophages are the predominant cellular
components of the invading pannus of the synovium. Extracel-
lular matrix damage resulting from synovial expansion is caused
by several families of enzymes, including serine proteases, cathep-
sins, and matrix metalloproteinases.
For a deeper discussion of these topics, please see Chapter
264, “Rheumatoid Arthritis,” in Goldman-Cecil Medicine,
25th Edition.
  CLINICAL PRESENTATION
Articular Manifestations
RA manifests with a symmetrical polyarthritis that typically
starts with the small joints of the hands, wrists, and feet and
progresses to the synovium of the shoulders, elbows, hips, knees,
and ankles. Patients have an insidious onset of inflammatory pain,
which is pain and stiffness that is worse with inactivity and is
improved with movement. Prolonged morning stiffness, usually
lasting more than 1 hour, is a classic feature of RA (Table 77-1).
Any diarthrodial (synovial) joint may be involved, including the
apophyseal (spinal), temporomandibular, and cricoarytenoid
joints. Involved joints are swollen, warm, and tender, and they
may have effusions. The synovium, which is normally a few cell
layers thick, becomes palpable on examination (i.e., synovitis).
Without treatment, RA progresses in some patients to joint
destruction and deformity. Erosive lesions of bone and cartilage
Prostaglandins
Leukotrienes
Reactive oxygen
PMN species
Lysosomal
enzymes
CD
Cartilage
OC
Subchondral
bone
772 Section XIV  Musculoskeletal and Connective Tissue Disease
TABLE 77-1  CLINICAL CHARACTERISTICS OF
RHEUMATOID ARTHRITIS
ARTICULAR FEATURES EXTRA-ARTICULAR FEATURES
Morning stiffness or gelling Rheumatoid nodules: subcutaneous,
Symmetrical joint swelling pulmonary, sclera
Predilection for wrists and proximal Lung disease
interphalangeal, Vasculitis, especially skin and
metacarpophalangeal, and peripheral nerves
metatarsophalangeal joints Pleuropericarditis
Erosions of bone and cartilage Scleritis and episcleritis
Joint subluxation and ulnar deviation Leg ulcers
Inflammatory joint fluid
Felty’s syndrome
Carpal tunnel syndrome
Baker’s cyst
often are visible radiographically at the margins of bone and car-
tilage, the sites of synovial attachment. However, not all patients
with RA have erosive disease. Tenosynovitis (i.e., inflammation
of tendon sheaths) leads to tendon malalignment and stretching
or shortening.
Common deformities are ulnar deviation at the metacarpo-
phalangeal joints and volar subluxation at those joints and at the
wrists. Flexion and extension contractures in the proximal and
distal interphalangeal (PIP and DIP) joints of the fingers lead to
the characteristic swan-neck deformity (i.e., flexion contracture
at the DIP joint and hyperextension at the PIP joint) or bouton-
nière deformity (i.e., flexion contracture at the PIP and hyperex-
tension at the DIP joint).
Synovitis at the wrists can lead to median nerve compression
and carpal tunnel syndrome. Rarely, long-standing cervical spine
disease may lead to C1-C2 subluxation and spinal cord compres-
sion. Rupture of synovial fluid from the knee into the calf (i.e.,
Baker’s cyst) may mimic deep vein thrombosis or occasionally
imitate cellulitis.
Extra-articular Manifestations
RA is a systemic disease with multiple extra-articular manifesta-
tions (see Table 77-1). Constitutional symptoms include fatigue,
low-grade fever, weight loss, and myalgia. Extra-articular
manifestations are more common in RF-positive patients with
uncontrolled articular disease. On the skin, grossly palpable sub-
cutaneous rheumatoid nodules are common along other exten-
sor tendon surfaces, especially at the elbows, and are associated
with RF positivity. Less commonly, rheumatoid nodules may
occur in the lungs, pleura, pericardium, sclerae, and other sites,
including the heart in rare cases. In the eyes, RA commonly is
associated with keratoconjunctivitis sicca with coexistent Sjögren
syndrome and less often with scleritis and episcleritis.
Lung involvement in RA usually includes interstitial lung
disease and may include pleuropericarditis, producing pleural
and pericardial effusions. The cardiovascular effects of RA can
range from long-term inflammation leading to progressive coro-
nary artery disease to pericarditis to a small and medium-sized
vasculitis. The vasculitis of RA can produce cutaneous lesions
(e.g., ulcers, skin necrosis) and mononeuritis multiplex.
RA commonly has hematologic complications and is associ-
ated with anemia of chronic disease and thrombocytosis. Patients
with RA also have an increased incidence of lymphoma. Felty’s
syndrome (i.e., splenomegaly, leukopenia, and recurrent
TABLE 77-2  2010 ACR/EULAR CLASSIFICATION
CRITERIA FOR RHEUMATOID ARTHRITIS
For patients who have at least 1 joint with definite synovitis and for whom
the synovitis is not better explained by another disease, a score of at least 6
of 10 points is needed for the classification of definite rheumatoid arthritis.
A. Joint involvement (0-5 points)
1 large joint (0)
2-10 large joints (1)
1-3 small joints (with or without involvement of large joints) (2)
4-10 small joints (or without involvement of large joints) (3)
>10 joints (with involvement of at least 1 small joint) (5)
B. Serology (0-3 points)
Negative RF and negative anti-CCP (0)
Low-positive RF or low-positive anti-CCP (2)
High positive RF or high positive anti-CCP (3)
C. Acute phase reactants (0-1 points)
Normal CRP and normal ESR (0)
Abnormal CRP or abnormal ESR (1)
D. Duration of symptoms (0-1 points)
<6 weeks (0)
≥6 weeks (1)
Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid arthritis classification criteria: an
American College of Rheumatology/European League Against Rheumatism collaborative
initiative, Arthritis Rheum 62:2569–2581, 2010.
ACR, American College of Rheumatology; CCP, cyclic citrullinated peptide; CRP,
C-reactive protein; ESR, erythrocyte sedimentation rate; EULAR, European League
Against Rheumatism; RF, rheumatoid factor.
pulmonary infections) is a rare complication and is often accom-
panied by leg ulcers and vasculitis.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
RA is a clinical diagnosis based on a thorough history and physi-
cal examination. Classic symptoms include morning stiffness
associated with symmetrical synovitis of small joints. No single
diagnostic test enables a diagnosis of RA to be made with cer-
tainty. Instead, the diagnosis depends on the accumulation of
characteristic symptoms, signs, laboratory data, and radiologic
findings.
Classification criteria are useful in guiding the clinical diagno-
sis of RA. The classification criteria have been updated to include
early RA (Table 77-2) because prompt diagnosis and treatment
are important to prevent disease progression, joint deformities,
and disability.
The differential diagnosis for RA includes viral arthritis (e.g.,
parvovirus, rubella, hepatitis B and C), thyroid disorders, sar-
coidosis, reactive arthritis, psoriatic arthritis, Sjögren syndrome,
systemic lupus erythematosus (SLE), bacterial endocarditis,
rheumatic fever, calcium pyrophosphate disease (CPPD),
chronic tophaceous gout, polymyalgia rheumatic, erosive osteo-
arthritis, and fibromyalgia. A history and physical examination,
including a thorough review of systems, help to determine the
diagnosis.
RF is an antibody (typically IgM but also IgG or others) that
binds to the Fc fragment of IgG. RF and IgG join to form immune
complexes that are detectable in the serum of 70% to 80% of
patients with RA. However, RF is not specific for RA and fre-
quently occurs in patients with SLE, Sjögren syndrome, endocar-
ditis, sarcoidosis, and lung and liver diseases (including hepatitis
B and C infection) and in healthy individuals. In an individual
patient, the titer does not correlate with disease activity, but high
titers are associated with severe erosive arthritis and extra-
articular disease. The finding of RF in serum alone does not
 Chapter 77  Rheumatoid Arthritis 773
establish a diagnosis of RA, but it can help to confirm the clinical
impression.
Anti-CCP antibodies are a more specific marker for RA. Anti-
CCP antibodies have a higher specificity (>95%) than RF, with
similar sensitivity (68% to 80%). These antibodies can be
detected several years before the development of clinical RA (and
before RF), and they are associated with severe RA outcomes,
including radiographic joint damage and a poor prognosis.
Because of their higher specificity for RA, anti-CCP antibodies
are useful in differentiating RA from other conditions positive for
RF, including Sjögren syndrome, infection, and hepatitis.
Acute phase reactants, such as the erythrocyte sedimentation
rate and C-reactive protein, are usually elevated in active inflam-
mation but are not sensitive or specific for the diagnosis of RA.
They are useful for differentiating RA from noninflammatory
conditions such as osteoarthritis or fibromyalgia. Even when
there is clinical evidence of joint inflammation, the values for
acute phase reactants may be normal. Inflammation in RA often
leads to anemia of chronic disease and thrombocytosis.
Synovial fluid analysis is usually not necessary when the diag-
nosis is already established, but arthrocentesis should be per-
formed to rule out infection or crystalline arthropathy if only one
joint is involved. Synovial fluid analysis is nonspecific but indi-
cates inflammation. Radiographs, although not part of the 2010
RA classification criteria, may show characteristic periarticular
osteopenia, marginal erosions, and uniform joint space narrow-
ing in a symmetrical distribution.
For a deeper discussion of these topics, please see Chapter
257, “Laboratory Testing in Rheumatoid Arthritis,” Chapter
258, “Imaging Studies in the Rheumatic Diseases,” Chapter
263, “Bursitis, Tendinitis, and Other Periarticular Disorders
and Sports Medicine,” and Chapter 264, “Rheumatoid
Arthritis,” in Goldman-Cecil Medicine, 25th Edition.
  TREATMENT
The ultimate goals of RA management are to reduce pain and
discomfort, prevent deformities and loss of normal joint func-
tion, and maintain normal physical and social function. Although
there is no cure for RA, remission can be maintained in a subset
of patients. Treatment begins with effective communication
between the physician and patient regarding the nature of the
disease and the goals of treatment.
Nonpharmacologic therapeutic options include reduction of
joint stress and physical and occupational therapy. Local rest of
an inflamed joint can reduce joint stress, as can weight reduction,
splinting, and the use of walking aids. Vigorous activity should
be avoided during disease flares. Full range of motion of joints,
however, should be maintained by a graded exercise program to
prevent contractures and muscle atrophy. Physical therapy
improves muscle strength and conditioning and maintains joint
mobility. Occupational therapy can provide various appliances to
protect joints and make daily activities easier.
Pharmacologic Approach
Studies have revealed that disease-modifying antirheumatic
drug (DMARD) therapy early in the course of RA slows
disease progression more effectively than delayed therapy.
Effective treatment can improve signs, symptoms, and radio-
graphic progression, even in long-standing disease. The inflam-
mation of RA should be controlled as completely as possible, as
soon as possible, and for as long as possible. Conventional
DMARDs and biologic DMARDs prevent disease progression
and disability.
Symptomatic Control and Bridging Therapy
DMARDs require 1 to 6 months to work. Consequently, nonste-
roidal anti-inflammatory drugs (NSAIDs), which are not disease
modifying, are frequently used early in the disease process for
symptomatic control. NSAIDs have significant side effects,
including renal failure and increased risk of gastrointestinal
bleeding, and should be used with caution in patients with mul-
tiple medical comorbidities.
Glucocorticoids remain important in the treatment of RA,
especially for acute exacerbations of disease. These agents are
used sparingly in low to medium doses. Although glucocorticoids
are useful for brief exacerbations and decrease bone erosions, the
long-term side effects of glucocorticoids can be substantial. They
should be used primarily as bridging therapy for further DMARD
effects. Side effects include osteoporosis, avascular necrosis of
bone, obesity, hypertension, and glucose intolerance. Screening,
prevention, and treatment for osteoporosis should be considered
for all patients who receive long-term glucocorticoid therapy
for prevention of glucocorticoid-induced osteoporosis. Intra-
articular glucocorticoids are extremely effective treatment for
exacerbations involving only a few joints.
For a deeper discussion of these topics, please see Chapter
243, “Osteoporosis,” in Goldman-Cecil Medicine, 25th
Edition.
Conventional and Biologic Disease-
Modifying Antirheumatic Drugs
Many DMARDs are available for treating RA. All conventional
DMARDs have a slow onset, taking 1 to 6 months to become
fully effective, and they need close monitoring for toxicity.
Methotrexate is universally used as the initial DMARD in
patients with moderate to severe RA because of its established
efficacy and known toxicity profile (level A evidence, multiple
randomized controlled trials). It can be administered once weekly
by the oral or parenteral route. Known side effects include oral
ulcers, nausea, hepatotoxicity, and pneumonitis.
After methotrexate failure, the subsequent choice of conven-
tional and biologic DMARDs is not standardized and is instead
based on the preferences of patients and physicians. For patients
with mild RA, hydroxychloroquine or sulfasalazine, or both, may
be used as first-line drugs (level B evidence). Triple therapy, the
combination of methotrexate, hydroxychloroquine, and sul-
fasalazine, was shown in two randomized, controlled trials to be
noninferior to biologic TNF-α inhibitors (level A). Tofacitinib
is an oral Janus kinase inhibitor and the first kinase inhibitor of
its class that reduces cytokine levels.
Biologic DMARDs are targeted, immune-based therapies that
were introduced in the 1990s with the initiation of cytokine-
directed TNF-α inhibitors. TNF-α inhibitors were the first of
nine biologic DMARDs approved by the U.S. Food and Drug
774 Section XIV  Musculoskeletal and Connective Tissue Disease

subsequent morbidity. In every RA patient, bone health should

TABLE 77-3  DISEASE-MODIFYING ANTIRHEUMATIC be addressed to prevent development of osteoporosis. RA is also
DRUGS a risk factor for cardiovascular disease due to chronic inflamma-
CONVENTIONAL AGENTS TOXICITIES tion and should be aggressively monitored.
Hydroxychloroquine Retinal toxicity, requires Caution should be taken preoperatively when the RA patient
ophthalmologic monitoring is being anesthetized to avoid C1-C2 subluxation and spinal cord
Sulfasalazine Nausea, bone marrow suppression
Methotrexate Oral ulcers, nausea, bone marrow compression. Joint replacement surgery plays an important role
suppression, pneumonitis; for patients who have had severe, destructive joint disease, par-
contraindicated in pregnancy and ticularly in the knees and hips.
coexistent lung disease
Leflunomide Bone marrow and hepatic toxicity;
cholestyramine washout if toxic;   PROGNOSIS
contraindicated in pregnancy Although the underlying cause of RA is unknown, advances in
Tofacitinib (oral DMARD) Infection rate similar to biologic
DMARDs; bone marrow and cell biology, immunology, and molecular biology have led to dra-
hepatic toxicity, hyperlipidemia matic therapeutic advancements for this disease. Conventional
BIOLOGIC AGENTS MECHANISMS and biologic DMARDs improve short- and long-term outcomes.
Adalimumab, certolizumab, Cytokine directed, anti-TNF-α Bone erosions occur within 1 to 2 years of disease onset, and early
etanercept, golimumab, infliximab initiation of DMARDs is essential to prevent further morbidity.
Tocilizumab Cytokine directed, anti-IL-6 RF positivity, CCP positivity, and extra-articular features are
Anakinra Cytokine directed, anti-IL-1
Abatacept T-cell directed, inhibits characteristic of severe disease. The incidence of lymphoma and
costimulation other malignancies is increased among patients with RA, and the
Rituximab B-cell directed, anti-CD20 overall mortality rate is increased by coexisting cardiovascular
DMARDs, Disease-modifying antirheumatic drugs; IL, interleukin; TNF, tumor necrosis disease and infection.
factor.
Although up to 15% of patients can go into drug-free remis-
sion, long-term disability is significant. Fifty percent of patients
Administration (FDA) for the treatment of RA (Table 77-3). with RA are not working after 10 years, approximately 10 times
Five TNF-α–directed therapies are available. The TNF-α inhibi- the rate in the normal population. Most patients fall between
tors are the most widely used biologic agents because of the rapid these extremes with various levels of disability. Some have a
improvement they produce in patients resistant to methotrexate waxing and waning course over a period of years, with acute
therapy. They are recommended in addition to methotrexate after episodes of single- or multiple-joint exacerbations.
methotrexate failure (level A evidence). Future developments will include guidelines about when to
Most biologic DMARDs are given by intravenous or subcuta- institute biologic DMARDS, novel targeted biologic agents, and
neous injection and are quite expensive. Some have an increased personalized approaches based on an understanding of individ-
risk of infection, including risk of reactivation of tuberculosis. ual disease pathogenesis.
Other cytokine-directed therapies include the IL-6 receptor
antagonist tocilizumab and the IL-1 receptor antagonist anakinra. SUGGESTED READINGS
Biologic DMARDs also include an inhibitor of T-cell costimula- Aletaha D, Neogi T, Silman AJ, et al: 2010 Rheumatoid arthritis classification
tion, abatacept; and a B-cell–depleting agent, rituximab criteria: an American College of Rheumatology/European League Against
Rheumatism collaborative initiative, Arthritis Rheum 62:2569–2581, 2010.
For a deeper discussion of these topics, please see Chapter Karlson EW, Ding B, Keenan BT, et al: Association of environmental and genetic
36, “Biologic Agents,” in Goldman-Cecil Medicine, 25th factors and gene-environment interactions with risk of developing rheumatoid
Edition. arthritis, Arthritis Care Res (Hoboken) 65:1147–1156, 2013.
McInnes IB, O’Dell JR: State-of-the-art: rheumatoid arthritis, Ann Rheum Dis
69:1898–1906, 2010.
Medical Care Specialized   McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis, N Engl J Med
for Rheumatoid Arthritis 365:2205–2219, 2011.
Moreland LW, O’Dell JR, Paulus HE, et al: A randomized comparative
RA is a chronic disease that requires focused care for comorbidi- effectiveness study of oral triple therapy versus etanercept plus methotrexate
ties. DMARDs themselves require frequent laboratory moni­ in early aggressive rheumatoid arthritis: the treatment of Early Aggressive
toring for toxicities, including bone marrow suppression, Rheumatoid Arthritis Trial, Arthritis Rheum 64:2824–2835, 2012.
hepatotoxicity, and renal dysfunction. Opportunistic infections O’Dell JR, Mikuls TR, Taylor TH, et al: Therapies for active rheumatoid arthritis
after methotrexate failure, N Engl J Med 369:307–318, 2013.
can occur in patients receiving biologic therapies and DMARDs.
Saag KG, Teng GG, Patkar NM, et al: American College of Rheumatology 2008
In the setting of acute infection, DMARDs and biologic therapies recommendations for the use of nonbiologic and biologic disease-modifying
should be withheld. Prophylactically, all RA patients should be antirheumatic drugs in rheumatoid arthritis, Arthritis Rheum 59:762–784,
vaccinated for pneumococcal, influenza, and hepatitis B infec- 2008.
tion. Herpes zoster vaccine to prevent shingles should be given Singh JA, Furst DE, Bharat A, et al: 2012 update of the 2008 American College
of Rheumatology recommendations for the use of disease-modifying
prior to biological agents because the vaccine is live.
antirheumatic drugs and biologic agents in the treatment of rheumatoid
RA itself is a risk factor for osteoporosis, and combined with arthritis, Arthritis Care Res (Hoboken) 64:625–639, 2012.
glucocorticoid use, it can lead to severe osteoporosis and

Spondyloarthritis
  DEFINITION
Spondyloarthritis, formerly called seronegative arthritis or sponydy-
loarthopathy, is the name of a group of related inflammatory dis-
orders that share certain clinical features unique among rheumatic
diseases. The six types of spondyloarthritis in adults are ankylos-
ing spondylitis, reactive arthritis, arthritis of inflammatory bowel
disease (i.e., Crohn’s disease and ulcerative colitis), psoriatic
arthritis, and undifferentiated spondyloarthropathy. The juvenile
form of spondyloarthropathy is similar to ankylosing spondylitis
and usually persists into adulthood.
The cardinal clinical feature of spondyloarthritis is inflamma-
tion of the sacroiliac joints (i.e., sacroiliitis) and the spine (i.e.,
spondylitis). Inflammation of tendon insertion sites (i.e., enthesi-
tis), inflammation of entire digits (i.e., dactylitis), and inflamma-
tion of one to four lower extremity joints (i.e., oligoarthritis) are
typical extraspinal skeletal findings. A positive family history, eye
inflammation (i.e., anterior uveitis or conjunctivitis), and the
absence of rheumatoid factor and subcutaneous nodules are
common.
Further classification of these disorders is based on the finding
of psoriatic skin or nail changes, inflammatory bowel disease, or
a history of preceding gastrointestinal or genitourinary infection.
Alternatively, patients with spondyloarthritis can be classified
based on the distribution pattern of joint involvement. Cases
with dominant spinal disease are classified as axial spondyloar-
thritis (i.e., prototypically ankylosing spondylitis), and those
without spinal disease are classified as predominately peripheral
spondyloarthritis.
Spondyloarthritis is strongly associated with human leukocyte
antigen B27 (HLA-27), a specific allele of the B locus of the
HLA-encoding class I major histocompatibility complex genes.
The frequency of HLA-B27 among whites is approximately 8%.
However, up to 90% of white patients with ankylosing spondylitis
and 80% of white patients with reactive arthritis or juvenile spon-
dyloarthritis are HLA-B27 positive, and these percentages are
even higher among patients with uveitis. The rate of HLA-B27
positivity among patients with inflammatory bowel disease or
psoriasis with peripheral arthritis is not markedly increased
unless they have spondylitis, in which case the frequency of
HLA-B27 is 50%. The frequency of HLA-B27 varies widely
among other ethnic groups and accounts for the broad variation
of the prevalence of ankylosing spondylitis in different
populations.
Ankylosing spondylitis is much more common among ado­
lescent boys and young men, but this finding may reflect
78 
Douglas W. Lienesch
underdiagnosis in women, in whom disease manifestations may
be milder than they are in men. Reactive arthritis is more common
among men when it follows genitourinary Chlamydia trachomatis
infection, but the sex distribution is even among patients after
dysentery. Inflammatory arthritis including spondylitis affects
approximately 5% to 8% of patients with psoriasis and 10% to
25% of patients with ulcerative colitis or Crohn’s disease. Men
and women are affected equally. The prevalence of spondyloar-
thritis, particularly psoriatic and reactive arthritis, is increased in
populations with high human immunodeficiency virus (HIV)
infection rates.
  PATHOLOGY
Although the strong association of HLA-B27 with spondyloar-
thritis is well established, a specific role in the pathogenesis of
these disorders has not been elucidated. Animal models in which
rodents transgenic for HLA-B27 develop inflammatory abnor-
malities strikingly similar to those seen in HLA-B27–associated
human diseases provide compelling indirect evidence for a
pathogenic role. When raised in a germ-free environment, these
animals remain disease free, suggesting a key additional environ-
mental factor.
In addition to the strong genetic links for the risk of spondy-
loarthritis, important associations exist between specific bacterial
agents and disease pathogenesis. Genitourinary infection with C.
trachomatis or diarrheal illness with Shigella, Salmonella, Campy-
lobacter, and Yersinia species can induce reactive arthritis. Several
additional infectious agents are less commonly implicated. They
appear to trigger an inflammatory response, possibly as a result
of persistence of bacterial antigens, or cause an aberrant immu-
nologic response to infection that results in misfolding of
HLA-B27 molecules in antigen-presenting cells, generating a
persistent inflammatory reaction.
No one theory of pathogenesis of spondyloarthritis explains
the clinical spectrum of these disorders, and more research is
clearly needed to solidify an understanding of their origin. The
complex role of the immune system in the spondyloarthritis is
highlighted by the observation that patients infected with HIV
appear more likely to have severe disease, especially psoriatic
arthritis. When HIV infection is treated with antiviral agents, the
incidence of spondyloarthritis declines.
Although many of the cellular and molecular mechanisms of
inflammatory joint disease have been elucidated, the pathophysi-
ology of spondyloarthritis remains incompletely understood.
Inflammation of the sacroiliac joints, spine, and entheses is a
unique feature of these disorders. Pathophysiologic studies show
775
776 Section XIV  Musculoskeletal and Connective Tissue Disease

that the inflammation originates at the interface of bone and
cartilage in the sacroiliac joint and bone and fibrocartilage in the
enthesis. Macrophages and CD4+ and CD8+ T cells are present,
and the proinflammatory cytokines tumor necrosis factor-α
(TNF-α) and interleukin-23 (IL-23) are abundant.
Synovial tissue becomes inflamed, and osteoclasts are acti-
vated, leading to bone resorption, reminiscent of rheumatoid
arthritis joint inflammation. Unlike in rheumatoid arthritis, early
bone resorption is followed by a secondary phase during which
osteoblast activity predominates, leading to new bone formation
in periarticular bone (i.e., hyperostosis) and around joints (i.e.,
osteophytosis) or vertebral bodies (i.e., syndesmophytes). Ulti-
mately, bony fusion of joints (ankylosis) occurs. The relationship
between these paradoxical phases of bone resorption and prolif-
eration is an area of active investigation.
  CLINICAL PRESENTATION
Common Clinical Features   When peripheral arthritis of spondyloarthritis occurs, it fre-
of Spondyloarthritis
All forms of spondyloarthritis have considerable clinical overlap
with one another and are most easily considered as a group of
related disorders. Table 78-1 outlines the clinical features of these
disorders. The cardinal clinical features common to all of them
are inflammatory spine pain and an asymmetrical, predominantly
lower extremity inflammatory joint or tendon disease. Inflamma-
tory spine pain should be suspected in young patients (<40
years) who have an insidious onset of chronic low back pain or
buttock pain associated with prolonged morning stiffness and
relieved by exercise.
The characteristic peripheral joint disease involves one to four
joints, usually in the lower extremities, and may be associated
with tendon insertion inflammation (i.e., enthesitis) or sausage
digits (i.e., dactylitis). Symmetrical polyarthropathy involving
the upper extremities and clinically similar to rheumatoid arthri-
tis is seen in some forms of psoriatic or inflammatory bowel
disease–related spondyloarthritis. Anterior uveitis, enthesitis,
dactylitis, psoriatic skin or nail changes, inflammatory bowel
disease, a family history of spondyloarthritis, or a history of pre-
ceding gastrointestinal or genitourinary infection suggests spon-
dyloarthritis. Subcutaneous nodules, rheumatoid factor, and
antinuclear antibodies are usually absent.
In a given patient, the clinical features of these disorders may
accumulate over a prolonged period. Some patients do not ini-
tially demonstrate the typical findings of a specific disorder. They
are considered to have undifferentiated spondyloarthritis. Early
disease can be subcategorized as predominately axial spondylo-
arthritis or predominately peripheral spondyloarthritis, depend-
ing on the site of the dominant symptoms. Many patients later
have clinical findings consistent with a specific subtype of
spondyloarthritis.
Inflammatory spine pain is the cardinal feature of axial disease
and results from inflammation in the sacroiliac joints and spinal
elements. Uncontrolled disease may lead to ankylosis (i.e., bony
fusion) at sacroiliac joints and throughout the vertebral column,
culminating in loss of spinal and costovertebral motion, defor-
mity, and restrictive extrapulmonary physiology.
Enthesitis can occur in many different anatomic locations.
They include spinous processes, costosternal junctions, ischial
tuberosities, plantar aponeuroses, and Achilles tendons.
quently begins as an episodic, asymmetrical, oligoarticular
process that often involves the lower extremities. The arthritis
can progress and may become chronic and disabling. A unique
feature of spondyloarthritis is the appearance of fusiform swell-
ing of an entire finger or toe, referred to as dactylitis or sausage
digits.
Anterior uveitis, or inflammation of the anterior chamber of
the eye, is a common extra-articular manifestation of spondylo-
arthritis, especially among HLA-B27–positive patients. Acute
bouts of uveitis are usually monocular, painful, and accompanied
by eye redness and blurred vision. Recurrent attacks are common
and can lead to blindness. Scleritis, episcleritis, and conjunctivitis
are less commonly associated phenomena.
Spondyloarthritis may occasionally involve other organ
systems and may cause significant morbidity and mortality. Aor-
titis, especially occurring in the ascending segment, can result in
aortic insufficiency from aortic root dilation, aortic dissection,
and cardiac conduction system abnormalities. Pulmonary fibro-
sis of the apical regions can occur, often in an insidious fashion.
Spinal cord compression can result from atlantoaxial joint sub-
luxation, cauda equina syndrome, or vertebral fractures. In rare
cases, long-standing spondyloarthritis is associated with second-
ary amyloidosis.

TABLE 78-1  COMPARISON OF THE SPONDYLOARTHRITIS

ANKYLOSING POSTURETHRAL POSTDYSENTERIC ENTEROPATHIC PSORIATIC
FEATURES SPONDYLITIS REACTIVE ARTHRITIS REACTIVE ARTHRITIS ARTHRITIS ARTHRITIS
Sacroiliitis +++++ +++ ++ + ++
Spondylitis ++++ +++ ++ ++ ++
Peripheral arthritis + ++++ ++++ +++ ++++
Articular course Chronic Acute or chronic Acute or chronic Acute or chronic Chronic
HLA-B27 95% 60% 30% 20% 20%
Enthesopathy ++ ++++ +++ ++ ++
Extra-articular Eye, heart Eye, GU, oral and/or GI, GU, eye GI, eye Skin, eye
manifestations heart
Other names Bekhterev’s arthritis, Reiter’s syndrome, SARA, Reiter’s syndrome Crohn’s disease,
Marie-Strümpell disease NGU, chlamydial arthritis ulcerative colitis
Data from Cush JJ, Lipsky PE: The spondyloarthropathies. In Goldman L, Bennett JC, editors: Cecil textbook of medicine, ed 21, Philadelphia, 2000, Saunders, pp 1499–1507.
GI, Gastrointestinal tract; GU, genitourinary tract; HLA, human leukocyte antigen; NGU, nongonococcal urethritis; SARA, sexually acquired reactive arthritis; +, relative prevalence of
a specific feature.

Specific Clinical Features of
Spondyloarthritis
Ankylosing Spondylitis
The cardinal clinical feature of ankylosing spondylitis is inflam-
matory spine pain. Over time, spine involvement ascends from
the sacroiliac joints to involve all levels of the spine. Progressive
loss of motion results from ankylosis of the vertebral column and
apophyseal joints. Costovertebral involvement leads to decreased
chest expansion and restrictive lung physiology.
Loss of mobility and secondary osteoporosis of the vertebral
bodies increase the risk of traumatic spine fracture. Axial involve-
ment of the shoulders and hips is common and associated with a
worse prognosis. Peripheral oligoarthritis, enthesitis, and dacty-
litis are more common in females. Diagnosis requires demonstra-
tion of radiographic sacroiliitis (i.e., sacroiliac joint erosions,
sclerosis, and ankylosis). Anterior uveitis is common. Aortitis,
upper lobe pulmonary fibrosis, cauda equina syndrome, and
amyloidosis are less common and seen in late disease.
Reactive Arthritis
Among the unique clinical features of reactive arthritis are ure-
thritis, conjunctivitis, and certain dermatologic problems (Fig.
78-1). The urethritis may result from the chlamydial infection
that triggers the disease, or it may be a sterile inflammatory dis-
charge seen in diarrhea-associated disease. Conjunctivitis may be
mild in reactive arthritis and is distinct from uveitis.
Keratoderma blennorrhagicum is a distinct papulosquamous
rash usually found on the palms or soles. Circinate balanitis is a
rash that may appear on the penile glans or shaft of men with
reactive arthritis. Nonpitting nail thickening and oral ulcers may
also occur in patients with reactive arthritis. These lesions can be
confused with similar findings in patients with psoriasis and
inflammatory bowel disease, respectively.
Most cases are self-limited. Chronic or relapsing arthritis and
chronic spondylitis are associated with HLA-B27 and Chlamydia
infection.
Psoriatic Arthritis
Five identifiable clinical patterns of psoriatic arthritis are recog-
nized: distal interphalangeal joint involvement with nail pitting;
A B
FIGURE 78-1  Reactive arthritis. A, Keratoderma blennorrhagicum. Red to brown papules, vesicles, and pustules with central erosion show char-
acteristic crusting and peripheral scaling on the dorsolateral and plantar foot. B, Balanitis circinata. Moist, well-demarcated erosions with a slightly
raised micropustular circinate border on the glans penis. C, Bilateral conjunctivitis associated with anterior uveitis. (From Fitzpatrick TB, Johnson RA,
Wolff K, et al: Color atlas and synopsis of clinical dermatology, ed 3, New York, 1983, McGraw-Hill, pp 393, 395.)
Chapter 78  Spondyloarthritis 777
asymmetrical oligoarthropathy of large and small joints; arthritis
mutilans, a severe, destructive arthritis; symmetrical polyarthri-
tis, which is identical to rheumatoid arthritis; and predominately
axial disease. These patterns are not exclusive, and clinical overlap
is significant.
Spondylitis or sacroiliitis may occur along with any of the
other patterns. The prevalence of HLA-B27 is increased among
the patients with spondylitis or sacroiliitis but not among patients
with the other patterns. Psoriatic skin or nail disease predates
arthritis in most cases, but both may occur concomitantly, or
joint disease may precede skin involvement. Rarely, joint disease
indistinguishable from psoriatic arthritis, which can occur in
patients with a family history but no personal history of psoriatic
skin disease.
Enteropathic Arthritis:
Inflammatory Bowel Disease
Crohn’s disease and ulcerative colitis (see Chapter 38) are fre-
quently associated with inflammatory spine disease and periph-
eral arthritis. The peripheral arthritis is typically nonerosive,
oligoarticular, and episodic, and the degree of joint involvement
fluctuates with gut activity. A more chronic, symmetrical polyar-
thritis may occur in patients with Crohn’s disease.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis of spondylarthritis remains a clinical diagnosis
made by identifying typical history and physical examination
phenomena, analyzing selected laboratory tests, and using mus-
culoskeletal imaging. The diagnosis is suggested by inflammatory
spine pain or chronic lower extremity asymmetric inflammatory
oligoarthritis in two to four joints. In this setting, features that
increase the probability of spondyloarthritis include uveitis, pso-
riasis, enthesitis, dactylitis, inflammatory bowel disease, family
history of spondylarthropathy, elevated C-reactive protein (CRP)
level, HLA-B27, preceding gastrointestinal or genitourinary
infection, and sacroiliitis on radiography, computed tomography
(CT), or magnetic resonance imaging MRI).
Differentiating spondyloarthritis from other inflammatory or
degenerative joint or spine diseases can be challenging. Crystal-
line arthropathies can manifest with peripheral oligoarthritis,
often in the lower extremities. However, the spine is rarely
C
778 Section XIV  Musculoskeletal and Connective Tissue Disease

involved, and intracellular crystals can be demonstrated in the

synovial fluid. Rheumatoid arthritis and other systemic autoim-
mune diseases usually manifest with symmetrical polyarthritis of
the upper and lower extremities associated with abnormal serolo-
gies such as rheumatoid factors, anti–cyclic citrullinated peptide
(CCP) antibodies, or antinuclear antibodies. Predominately axial
spondyloarthritis must be differentiated from indolent infections
of the sacroiliac joints, vertebrae, or intravertebral disks; degen-
erative disease of the spine and disks (i.e., spondylosis); and
diffuse idiopathic skeletal hyperostosis (DISH).
The radiographic features of the spondyloarthritis are highly
specific and, in the correct clinical setting, greatly increase the
certainty of the diagnosis. Sacroiliitis is usually the earliest radio-
graphic sign of spine disease and results in sclerosis and erosions
of the sacroiliac joints with eventual bony fusion (Fig. 78-2A).
Many radiographic changes result from chronic spondylitis,
including ossification of the annulus fibrosus, calcification of
spinal ligaments, bony sclerosis and squaring of vertebral bodies,
and ankylosis of apophyseal joints. These changes can lead to
vertebral fusion and a bamboo spine appearance (see Fig. 78-2B).
Radiographic findings progress over many years of illness and
may not be apparent in early disease. However, during this pre-
radiographic period, MRI demonstrates bone inflammation (i.e.,
osteitis) and erosion at the sacroiliac joints and vertebral bodies,
and CT shows bony sclerosis and joint erosions.
Bone erosions, sclerosis, and new bone formation may occur
at sites of enthesitis. Erosions at bone-cartilage interface (i.e.,
subchondral erosions), sclerosis, and bone proliferation are hall-
marks of spondyloarthritis involving peripheral joints. In severe
cases such as the arthritis mutilans form of psoriatic arthritis,
total or subtotal bone resorption (i.e., osteolysis) of a phalange
may occur.
  TREATMENT
No cure has been found for any form of spondyloarthritis, but
effective treatment for many of the manifestations is available.
Patient education regarding the disease is essential and allows
identification of affected family members and early detection of
urgent clinical features such as uveitis. Physical therapy, including
a daily stretching program, postural adjustments, and strengthen-
ing, helps to maintain proper bony alignment, reduce deformi-
ties, and maximize function, particularly for those with axial
disease. Selective use of orthopedic surgery may be highly effec-
tive in correcting significant spinal deformities or instability.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can provide
significant relief of spinal pain and stiffness, and many patients
take these drugs continually for years (Centre for Evidence Based
Medicine; level 1 evidence). No clear evidence indicates that
systemic glucocorticoids benefit patients with spondyloarthritis,
and these agents are usually avoided. Intra-articular glucocorti-
coid injection into the sacroiliac or other involved joints may
provide temporary relief. Similarly, the role and efficacy of older
immunosuppressive agents in the treatment of axial spondyloar-
thritis have not been established. In contrast, clinical trials have
shown that the peripheral manifestations of spondylarthritis
improve with sulfasalazine and methotrexate (level 2).
TNF-α blockers (i.e., infliximab, etanercept, adalimumab, and
golimumab) represent a substantial breakthrough in the treat-
ment of spondyloarthritis. The efficacy of these agents is well
established, and they have rapidly become the treatment of
choice for patients with axial inflammation who do not satisfac-
torily or fully respond to NSAIDs and physical therapy (level 1
evidence). TNF-α blockers can significantly reduce pain, improve
function, and improve quality of life. They may also prevent or

FIGURE 78-2  A, Bilaterally symmetrical sacroiliitis in ankylosing spondylitis. B, Lumbar spondylitis in ankylosing spondylitis with symmetrical,
marginal bridging syndesmophytes and calcification of the spinal ligament. (From Cush JJ, Lipsky PE: The spondyloarthropathies. In Goldman L,
Bennett JC, editors: Cecil textbook of medicine, ed 21, Philadelphia, 2000, Saunders, pp 1499–1507.)

slow disease progression and structural damage. The drugs are
effective in psoriatic arthritis, suppress the skin and nail disease
of psoriasis, and retard radiographic progression in the peripheral
joints. Infliximab and adalimumab reduce gut inflammation in
ulcerative colitis and Crohn’s disease, with concomitant reduc-
tion in symptoms of joint and spine inflammation. Ustekinumab,
an inhibitor of IL-23, has demonstrated efficacy in psoriasis and
psoriatic arthritis (level 1).
Flares of uveitis require care by an ophthalmologist experi-
enced in treating inflammatory eye diseases. Topical or intraocu-
lar glucocorticoids may suffice, but systemic therapy with
glucocorticoids or immunosuppressive medications may be nec-
essary to control the inflammation and prevent permanent visual
loss. Methotrexate and TNF-α inhibitors are frequently employed
(level 2 evidence).
Reactive arthritis is usually self-limited, and joint symptoms
are managed with NSAIDs or intra-articular corticosteroid injec-
tions. When chronic arthritis or spondylitis develops, interven-
tions are similar to those employed for other forms of
spondyloarthritis. Evaluation and treatment of C. trachomatis and
associated sexually transmitted diseases in patients with reactive
arthritis and their sex partners are essential. Early treatment
reduces the frequency of reactive arthritis. Long-term antibiotics
are ineffective for gastroenteritis-associated reactive arthritis.
Clinical trials of long-term antibiotics for reactive arthritis after
C. trachomatis infection have had mixed results, and this practice
requires further study before it can be adopted.
Chapter 78  Spondyloarthritis 779
  SUMMARY
Disability due to spondyloarthritis varies according to the
subtype and severity of the specific syndrome. Historically,
patients with spondyloarthritis usually experienced a lesser
degree of disability compared with those with rheumatoid arthri-
tis. Some patients with reactive arthritis experience self-limited
disease with no long-term sequelae. Alternatively, those with
more severe disease can have deformation and destruction of the
axial and peripheral joints, leading to severe disability. Serious
and potentially fatal extraskeletal manifestations can manifest.
With the advent of effective immunosuppressant medications
such as methotrexate in psoriatic disease and biologic agents (i.e.,
TNF-α and IL-23 inhibitors), patients with more severe mani-
festations have markedly improved symptom control and quality
of life.
SUGGESTED READINGS
Hreggvidsdottir H, Noordenbos T, Baeten D: Inflammatory pathways in
spondyloarthritis, Mol Immunol 57:28–37, 2014.
Sieper J, Rudwaleit M, Baraliakos X, et al: The Assessment of Spondyloarthritis
international Society (ASAS) handbook: a guide to assess spondyloarthritis,
Ann Rheum Dis 68(Suppl lII):ii1–ii44, 2009.
Smolen JS, Braun J, Dougados M, et al: Treating spondyloarthritis, including
ankylosing spondylitis and psoriatic arthritis, to target: recommendations of
an international task force, Ann Rheum Dis 73:6–16, 2014.
 79 
Systemic Lupus Erythematosus
Amy H. Kao and Susan Manzi
  DEFINITION AND EPIDEMIOLOGY
Systemic lupus erythematosus (SLE) is the classic systemic auto-
immune disease. The cause is unknown. SLE predominantly
affects young women of childbearing age but can also afflict
young men and older individuals of either sex.
The clinical manifestations are protean, ranging from mild
symptoms of fatigue and oral ulcerations to life-threatening renal
and neurologic disease. Typically, the disease fluctuates with
periods of flares and clinical quiescence. However, recurrent
disease flares and their treatment may ultimately lead to irrevers-
ible organ damage.
SLE is diagnosed by a thorough history, physical examination,
and laboratory testing. A single diagnostic laboratory test for SLE
is not available, and the diagnosis is often difficult, requiring
many patient visits to numerous doctors.
Although there is no cure for SLE, patients are treated for the
many chronic medical conditions associated with the disease
with a variety of medications, primarily immunosuppressants.
Unique consideration must be given to SLE patients regarding
pregnancy, bone health, cardiovascular disease (CVD), and
malignancy.
The reported incidence and prevalence of SLE vary greatly,
reflecting the heterogeneity of the disease. The incidence of SLE
worldwide is estimated at 1.8 to 7.6 cases per 100,000 persons
per year and appears to have increased over time. Prevalence rates
range from 14.6 to 149.5 cases per 100,000 persons.
During the childbearing years, the female-to-male ratio of
SLE prevalence is 10 : 1 to 15 : 1. This gender discrepancy also
exists but is less distinct (2 : 1) in young children and older
patients. SLE also has a predilection for nonwhite ethnic popula-
tions, with greater prevalence rates for African Americans (three
times), Afro-Caribbeans (five times), Asians (two times), and
Hispanics than for whites. These patients also tend to have more
severe SLE disease and worse overall prognoses than those who
are white.
  PATHOLOGY
Although SLE pathogenesis remains poorly understood, indi-
viduals who develop SLE likely have a genetic predisposition
in the setting of immune system dysregulation, environmental
triggers, and altered hormonal milieu. The genetic contribution
to SLE is emphasized by the high concordance rate for mono-
zygotic twins (>20%) and a lower concordance rate among other
siblings (<5%). The search for genes involved in SLE pathogen-
esis is an active area of research. Genes coding for certain human
leukocyte antigens, complement system components, immuno-
780
globulin receptors, and various other proteins are being consid-
ered as candidate genes for SLE.
The many immune abnormalities in SLE implicate dysregula-
tion of the humoral and cellular immune systems in the patho-
genesis of the disease. Dysregulation leads to loss of self-tolerance
and autoimmune destruction of healthy tissues, hallmarked by
the production of autoantibodies and immune complexes.
Various environmental triggers, including microorganisms
and ultraviolet light exposure, may influence the development of
SLE and lupus activity. The striking differences in SLE prevalence
between genders and the effect of pregnancy on disease activity
suggest a role for hormones in SLE pathogenesis.
  CLINICAL PRESENTATION
Virtually any organ system may be involved in SLE. Table 79-1
outlines some of the many clinical manifestations of SLE.
Constitutional Manifestations
Fatigue, fever, lymphadenopathy, and generalized arthralgias and
myalgias are common in SLE patients. The most common
symptom, fatigue (>90%), can also be the most debilitating.
Other reasons for fatigue, including anemia, hypothyroidism,
and fibromyalgia, should be excluded when attempting to diag-
nose SLE.
Mucocutaneous Manifestations
Oral ulcerations may be painful or painless and are classically
located on the tongue or palate. Skin manifestations of SLE are
common and include the classic malar (butterfly) rash, discoid
lesions (i.e., permanent scarring and disfigurement), alopecia,
and photosensitivity. Subacute cutaneous SLE can manifest with
a psoriasiform rash or annular lesions mimicking tinea corporis.
Frequently, acne rosacea is mistaken for a malar rash. A key dis-
tinguishing feature is that erythema in lupus malar rash does not
cross the nasolabial folds.
Musculoskeletal Manifestations
Arthralgias and inflammatory arthritis are common manifesta-
tions in SLE (>75%). Lupus arthritis is usually nonerosive
(unlike rheumatoid arthritis), but 10% of patients have Jaccoud’s
arthropathy with reversible hand deformities due to inflamma-
tion and joint tendon laxity.
Cardiopulmonary Manifestations
More than 60% of SLE patients have pericarditis and pleuritis
during their disease course. Subsequent pericardial or pleural
effusions are typically exudative. Valvular thickening and
 Chapter 79  Systemic Lupus Erythematosus 781

noninfective Libman-Sacks endocarditis are frequently observed

TABLE 79-1  CLINICAL MANIFESTATIONS OF on echocardiography and autopsy studies. Myocarditis should be
SYSTEMIC LUPUS ERYTHEMATOSUS suspected in patients with cardiopulmonary symptoms and fever.
CONSTITUTIONAL NEUROPSYCHIATRIC
Fatigue Seizures* Renal Manifestations
Fever Cerebritis/aseptic meningitis Nephritis, which manifests with hematuria and proteinuria, is a
Lymphadenopathy Cerebrovascular disease
Weight loss Transverse myelitis major cause of morbidity and mortality for SLE patients. The
Anorexia Chorea International Society of Nephrology/Renal Pathology Society
MUCOCUTANEOUS Headache (ISN/RPS) revisited the 1982 World Health Organization clas-
Cognitive impairment
Oral, genital, nasal ulcers* Autonomic dysfunction sification of lupus nephritis (classes I through VI). ISN/RPS class
Angioedema Cranial neuropathy IV (i.e., diffuse, proliferative) lupus nephritis is the most common
Alopecia Peripheral neuropathy
Photosensitivity*
form and has the worst prognosis, but it is also the most ame-
Psychosis*
Malar (butterfly) rash* Anxiety nable to aggressive immunosuppressive therapy.
Discoid lesions* Depression
Subacute cutaneous lupus Mood disorder Neuropsychiatric Manifestations
Tumid lupus
HEMATOLOGIC Neuropsychiatric symptoms are broad, including sensorimotor
Panniculitis
Vasculitis Leukopenia* neuropathy, headache, cognitive dysfunction, mood disorders,
Chilblain Lymphopenia*
Urticaria Hemolytic anemia*
psychosis, life-threatening ischemic stroke, cerebritis, and trans-
Periungual erythema Nonhemolytic anemia (anemia of verse myelitis. In 2010, the European League Against Rheuma-
MUSCULOSKELETAL chronic disease, iron-deficiency) tism task force recognized that “mild or moderate cognitive
Thrombocytopenia*
Arthritis* Antiphospholipid antibody
dysfunction is common in SLE” and recommended the “manage-
Arthralgias syndrome ment of SLE and non–SLE-associated factors, as well as psycho-
Jaccoud’s arthropathy educational support to prevent further deterioration of cognitive
VASCULAR
Avascular necrosis
Myositis Raynaud’s phenomenon function.”
CARDIAC Livedo reticularis
Arterial or venous thrombosis Hematologic Manifestations
Pericarditis* Vasculitis (almost any location)
Pericardial effusion Leukopenia, primarily lymphopenia, anemia, and thrombocyto-
OCULAR
Myocarditis penia are common in SLE. Anemia is typically results from
Valvular thickening Keratoconjunctivitis sicca hemolysis or chronic disease. Antiphospholipid antibodies
Libman-Sacks endocarditis Episcleritis
Atherosclerotic heart disease Scleritis (APAs) are detected in approximately 33% of SLE patients and
PULMONARY Retinal vasculitis are associated with recurrent thromboses, thrombocytopenia,
Arterial and venous occlusions and recurrent spontaneous miscarriages.
Pleuritis* Optic neuritis
Pleural effusion
Pneumonitis
GASTROINTESTINAL Vascular Manifestations
Alveolar hemorrhage Hypomotility
Interstitial lung disease Mesenteric vasculitis
More than 40% of SLE patients have Raynaud’s phenomenon.
Bronchiolitis obliterans Malabsorption Venous clots (e.g., pulmonary emboli, deep vein thromboses)
Pulmonary hypertension Protein-losing gastroenteropathy and arterial clots typically result from APAs. Leg ulcers, gangrene,
Pulmonary emboli pancreatitis
Vasculitis Lupus enteropathy
thrombophlebitis, nail fold infarcts, cutaneous necrosis, and nec-
Acute reversible hypoxemic Thrombosis of mesenteric and rotizing purpura may also be seen. Small vessel vasculopathy or
syndrome hepatic vasculature vasculitis can occur in any organ system and can be a life-
Shrinking lung syndrome Hepatitis
Hepatomegaly
threatening manifestation.
RENAL
Splenomegaly
Cellular casts or glomerulonephritis* Pancreatitis Ocular Manifestations
Proteinuria or membranous Acalculous cholecystitis
nephropathy or nephrotic Peritonitis
Keratoconjunctivitis sicca from secondary Sjögren’s syndrome
syndrome* (see Chapter 85) is the most common ocular manifestation of
SEROLOGIC
SLE. Episcleritis, scleritis, and retinal vasculitis can occur but are
Autoantibodies*
Hypocomplementemia less common.
Elevated acute phase reactants
For a deeper discussion of these topics, please see Chapter
REPRODUCTIVE
266, “Systemic Lupus Erythematosus” in Goldman-Cecil
Recurrent spontaneous abortions Medicine, 25th Edition.
Premature fetal delivery
Neonatal lupus
*An item in the 1997 American College of Rheumatology classification criteria for SLE.   DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
SLE is a clinical diagnosis; no single test or feature is definitively
diagnostic of the disease. The clinical disease of most patients
evolves over time, and, in most situations, only after several years
(and several different physicians’ visits) are patients recognized
as having SLE.
782 Section XIV  Musculoskeletal and Connective Tissue Disease

manifestations. More than 95% of patients with SLE test positive

Classification
Classification criteria for SLE were established for conducting
more uniform SLE research. The commonly used American
College of Rheumatology classification criteria for SLE (Table
79-2) was updated in 1997. Using this system, meeting 4 of 11
criteria classifies a patient as having definite SLE.
In 2012, the Systemic Lupus International Collaborating
Clinics (SLICC) further revised the classification criteria (Table
79-3) to improve clinical relevance and incorporate new knowl-
edge into the definition of SLE immunopathogenesis. Based on
the SLICC system, a patient is classified as having SLE if she has
at least four of the criteria (including at least one clinical criterion
and one immunologic criterion) listed in Table 79-3 or has
biopsy-proven lupus nephritis (i.e., stand-alone criterion) in the
setting of antinuclear antibodies (ANAs) or anti–double-
stranded DNA (anti-dsDNA) antibodies. Although these classi-
fication criteria are not used for diagnostic purposes, practicing
clinicians can use them along with a comprehensive examination
to support the diagnosis.
Various autoantibodies are found in patients with SLE, and the
prevalence of autoantibodies varies across different SLE patient
cohorts and ethnic groups (Table 79-4). These autoantibodies
often can be detected before the onset of SLE clinical
for ANAs with titers of 1 : 160 or higher.
ANAs are evaluated by the indirect immunofluorescence
antibody test, and results are reported in titers and patterns. The
most common pattern in SLE is homogenous (i.e., diffuse).
Antibodies to dsDNA and Smith antigen are highly specific for
SLE, whereas antibodies to SSA/Ro and SSB/La antigens are
also commonly found in patients with Sjögren’s syndrome and
rheumatoid arthritis. Certain antibodies are associated with
specific clinical manifestations, particularly anti-dsDNA antibod-
ies with lupus nephritis and anti–U1-RNP antibodies with
overlapping features of systemic sclerosis or myositis. Autoan-
tibodies alone are not diagnostic for any autoimmune disease
and must be interpreted in the context of the patient’s clinical
presentation.
Overlap Syndrome
Some patients with clinical and laboratory features of two or
more autoimmune diseases have an overlap syndrome. Mixed
connective tissue disease is characterized by overlaps among
SLE, scleroderma, and myositis with a high titer of anti–U1-RNP
antibody levels. For patients who have multiple autoimmune
manifestations but do not meet the criteria of a specific autoim-
mune disease, the term undifferentiated connective tissue disease is

TABLE 79-2  1997 AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA FOR CLASSIFICATION OF SYSTEMIC
LUPUS ERYTHEMATOSUS*
CRITERIA DEFINITIONS
1. Malar rash Fixed, flat or raised erythema is observed over the malar eminences, tending to spare the nasolabial folds.
2. Discoid rash Erythematous, raised patches develop with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in
older lesions.
3. Photosensitivity Rash occurs as a result of unusual reaction to sunlight, determined by patient history or physician observation.
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, is observed by the physician.
5. Arthritis Nonerosive arthritis involves two or more peripheral joints, characterized by tenderness, swelling, or effusion.
6. Serositis a. Pleuritis: convincing history of pleuritic pain exists or rub is heard by a physician or pleural effusion is in evidence.
or
b. Pericarditis: documented by electrocardiogram or rub or evidence of pericardial effusion.
7. Renal disorder a. Persistent proteinuria is >0.5 g/day or scored >3+ if quantitation is not performed.
or
b. Cellular casts: may be red cell, hemoglobin, granular, tubular, or mixed.
8. Neurologic disorder a. Seizures: occurs in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or
electrolyte imbalance).
or
b. Psychosis: occurs in the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis,
electrolyte imbalance)
9. Hematologic disorder a. Hemolytic anemia: develops with reticulocytosis.
or
b. Leukopenia: <4000/mm3 is documented on two or more occasions.
or
c. Lymphopenia: <1500/mm3 is documented on two or more occasions.
or
d. Thrombocytopenia: <100,000/mm3 develops in the absence of offending drugs.
10. Immunologic disorder a. Anti–double-stranded DNA: antibody to native DNA in abnormal titer.
or
b. Anti-Smith: presence of antibody to Smith nuclear antigen.
or
c. Positive finding of antiphospholipid antibodies is based on (1) an abnormal serum level of IgG or IgM anticardiolipin
antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test
for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent
treponemal antibody absorption test.
11. ANA An abnormal titer of antinuclear antibody is documented by immunofluorescence or an equivalent assay at any point in time
and in the absence of drugs known to be associated with drug-induced lupus syndrome.
Data from Tan EM, Cohen AS, Fries, et al: The 1982 revised criteria of the classification of systemic lupus erythematosus, Arthritis Rheum 25:1271, 1982; Hochberg MC: Updating the
American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 40:1725, 1997.
*This classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a patient is classified as having definite SLE if any 4 or more of the 11 criteria are
present (cumulative) during any interval of observation.
 Chapter 79  Systemic Lupus Erythematosus 783

TABLE 79-3  SYSTEMIC LUPUS INTERNATIONAL COLLABORATING CLINICS (SLICC) CLASSIFICATION CRITERIA OF
SYSTEMIC LUPUS ERYTHEMATOSUS
CLINICAL CRITERIA* EXAMPLES
1. Acute cutaneous lupus Bullous lupus
Lupus malar rash (not malar discoid)
Maculopapular lupus rash
Photosensitive lupus rash (in the absence of dermatomyositis)
Subacute cutaneous lupus
Toxic epidermal necrolysis variant of SLE
2. Chronic cutaneous lupus Classic discoid rash
Localized (above the neck)
Generalized (above and below the neck)
Chilblains lupus
Discoid lupus/lichen planus overlap
Hypertrophic (verrucous) lupus
Lupus erythematosus tumidus
Lupus panniculitis (profundus)
Mucosal lupus
3. Oral ulcers Palate, buccal, tongue, or nasal ulcers (in the absence of other causes: vasculitis, Behçet’s disease, infection, inflammatory
bowel disease, reactive arthritis, and acidic foods)
4. Nonscarring alopecia Diffuse thinning or hair fragility with visible broken hairs (in the absence of other causes: alopecia areata, drugs, iron
deficiency, and androgenic alopecia)
5. Synovitis (≥2 joints) Characterized by swelling or effusion or tenderness with ≥30 minutes of morning stiffness
6. Serositis Typical pleurisy for >1 day or pleural effusions or pleural rub
Typical pericardial pain for >1 day or pericardial effusion or pericardial rub or pericarditis by ECG (in the absence of other
causes: infection, uremia, and Dressler’s pericarditis)
7. Renal Urine protein/creatinine (or 24-hr protein) ≥500 mg of protein/24 hr or red blood cell casts
8. Neurologic Acute confusional state (in the absence of other causes: toxic-metabolic, uremia, and drugs)
Mononeuritis multiplex (in the absence of other known causes: primary vasculitis)
Myelitis
Peripheral or cranial neuropathy (in the absence of other known causes: primary vasculitis, infection, and diabetes mellitus)
Psychosis
Seizure
9. Hemolytic anemia
10. Leukopenia <4000 cells/mm3 detected at least once (in the absence of other known causes: Felty’s syndrome, drugs, and portal
hypertension)
  or Lymphopenia <1000 cells/mm3 detected at least once (in the absence of other known causes: corticosteroids, drugs, and infection)
11. Thrombocytopenia <100,000 cells/mm3 detected at least once (in the absence of other known causes: drugs, portal hypertension, and thrombotic
thrombocytopenic purpura)
IMMUNOLOGIC CRITERIA
1. ANAs Above laboratory reference range
2. Anti-double stranded DNA Above laboratory reference range, except ELISA: two times greater than laboratory reference range
3. Anti-Smith
4. Antiphospholipid Any of the following: lupus anticoagulant, false-positive RPR, medium- or high-titer anticardiolipin (IgA, IgG, or IgM), or
anti-β2 glycoprotein I (IgA, IgG, or IgM)
5. Low complement Low C3
Low C4
Low CH50
6. Direct Coombs test In the absence of hemolytic anemia
Modified from Petri M, Orbai AM, Alarcón GS, et al: Derivation and validation of Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus,
Arthritis Rheum 64:2677–2686, 2012.
ANAs, Antinuclear antibodies; ECG, electrocardiogram; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; RPR, rapid plasma reagin; SLE, systemic lupus
erythematosus.
*Criteria are cumulative. A patient is classified as having SLE using lupus nephritis as a stand-alone criterion (in the setting of ANAs or anti-dsDNA antibodies) or four criteria (with at
least one of the clinical criteria and one of the immunologic criteria).

used. These patients typically are early in their disease course and
TABLE 79-4  PREVALENCE OF AUTOANTIBODIES IN eventually develop a specific autoimmune disease.
SYSTEMIC LUPUS ERYTHEMATOSUS
TARGET AUTOANTIGEN POSITIVE (%)   TREATMENT
Nuclear antigens >95 No cure for SLE has been identified, and treatment is aimed at
Double-stranded DNA 30-60 educating patients, reducing inflammation, suppressing the
Smith 10-44
Ribonucleoprotein (U1-RNP) 25-40
immune system, and closely monitoring patients to identify
SSA/Ro 30-40 disease manifestations as early as possible. Treatment with gluco-
SSB/La 38 corticoids and immunosuppressive agents has reduced the mor-
Phospholipids 16-60
Ribosomal P 5-10
bidity and mortality of patients with SLE, although the treatments
Histone 21-90 themselves are associated with extensive toxicity. Physicians
Data from Wallace D, Hahn BH: Other clinical laboratory tests in SLE. In Dubois’ lupus
caring for SLE patients must carefully weigh the benefits of
erythematosus and related syndromes, ed 8, Philadelphia, 2013, Saunders, pp 526–531. therapy against the known risks of treatment.
784 Section XIV  Musculoskeletal and Connective Tissue Disease
Patient education and prophylactic measures to prevent
disease flares are crucial in the care of patients with SLE. Sun-
screens (SPF ≥50) and ultraviolet radiation–protective clothing
are effective in preventing photosensitivity skin rashes and sys-
temic flares. Low-dose aspirin is frequently prescribed for patients
with positive APA assays to prevent thrombotic events. Other
treatments for antiphospholipid antibody syndrome (APS) are
discussed later. Routine immunizations (e.g., influenza, pneumo-
coccus) with nonlive vaccines are recommended for all patients.
Psychological support is essential for patients with SLE because
the disease may lead to depression and feelings of being
overwhelmed.
Nonsteroidal anti-inflammatory medications may be used for
mild arthralgias, but glucocorticoids remain the primary anti-
inflammatory agent and one of the most effective medications for
SLE. Glucocorticoids are used for almost all manifestations of
SLE in regimens ranging from low, alternate-day doses to large,
intravenous doses. Given the chronic nature of the disease, glu-
cocorticoids are often used over many years, and the cumulative
exposure may lead to extensive toxicity, including obesity, diabe-
tes mellitus, accelerated atherosclerosis, osteoporosis, avascular
necrosis, cataracts, and increased risk of infections. To avoid
these toxicities, steroid-sparing immunomodulating or immuno-
suppressant agents are used.
Antimalarial medications (primarily hydroxychloroquine) are
effective in SLE and are considered standard care. Antimalarials
are especially beneficial for the fatigue, mild arthritis, and muco-
cutaneous manifestations of SLE. These medications are often
used chronically and are safe to use in pregnancy. The most
serious side effect is retinal toxicity, although it is uncommon.
Patients taking antimalarials should have a baseline and annual
ophthalmologic examination with visual field testing.
Azathioprine and methotrexate are immunosuppressive
agents prescribed for SLE when glucocorticoids alone are not
fully effective or to allow for a reduction in glucocorticoid dose.
Toxicities of azathioprine include cytopenias, increased infection
risk, and potential malignant hematologic disease. Azathioprine
may be used during pregnancy for severe internal organ lupus,
especially nephritis. Methotrexate is particularly effective in
treating inflammatory arthritis associated with SLE. In addition
to cytopenias and infections, liver function abnormalities, alope-
cia, nausea, and pneumonitis are potential side effects of metho-
trexate. Because it is teratogenic, methotrexate should be stopped
3 to 6 months before pregnancy. Azathioprine and methotrexate
require regular laboratory monitoring.
Mycophenolate mofetil (MMF) is increasingly used to treat
patients with internal organ involvement, particularly nephritis.
Mycophenolic acid, the active metabolite of MMF, can be used
in place of MMF because it may have fewer gastrointestinal side
effects for some patients. Clinical trials have shown that MMF is
as efficacious as intravenous cyclophosphamide for inducing
remission of active lupus nephritis. MMF also has a category D
rating in pregnancy, and toxicities include gastrointestinal distur-
bance and leukopenia.
Patients with neurologic lupus, rapidly progressive nephritis,
or vasculitis of internal organs are often treated with cyclophos-
phamide, the most potent immunosuppressive agent used to treat
SLE. Because of potential toxicities, this drug is usually reserved
for the most severe manifestations of SLE. Acute toxicities of
cyclophosphamide include pancytopenia, alopecia, mucositis,
and hemorrhagic cystitis. Long-term use of cyclophosphamide
may lead to transitional cell carcinoma, malignant hematologic
disease, sterility, premature menopause, and opportunistic
infections.
Great potential and optimism exist for biologic immunomod-
ulating agents that focus on various aspects of the immune
system, including B cells, interactions between B and T cells, and
cytokines. The most promising agents are those that target B
cells, which produce autoantibodies. Belimumab, a monoclonal
antibody that inhibits B-lymphocyte stimulator, is the first thera-
peutic agent approved for the treatment of SLE in more than 50
years.
For a deeper discussion of these topics, please see Chapter
35, “Immunosuppressing Drugs including Corticosteroids”
in Goldman-Cecil Medicine, 25th Edition.
  SPECIAL ISSUES IN THE CARE OF PATIENTS WITH SLE
Pregnancy
Pregnant women with SLE have higher rates of pregnancy
loss (i.e., miscarriage and stillbirths) and preterm delivery (i.e.,
premature rupture of membranes, preeclampsia, and intrauterine
growth restriction) than their healthy counterparts. Lupus
activity preceding conception, especially nephritis, hyperten-
sion, and APS, are risk factors for pregnancy complications
in SLE. Pregnancy itself may place women with SLE at a
greater risk of a flare, particularly if the disease was active
before conception.
Neonatal lupus is a rare disorder in which maternal anti-SSA/
Ro or SSB/La antibodies, or both, cross the placenta and affect
the fetus. Mothers with these autoantibodies have a 2% risk of
having a child with congenital heart block. These mothers are
screened with fetal heart tones and fetal echocardiography begin-
ning at 16 weeks’ gestation. Treatment with a fluorinated corti-
costeroid (i.e., dexamethasone or betamethasone) may be
beneficial, but many children with congenital heart block do not
survive (30%) or have morbidities, with more than 60% requir-
ing pacemakers.
More common manifestations of neonatal SLE are rashes,
cytopenias, and hepatosplenomegaly, all of which typically
resolve in 6 to 8 months after maternal antibodies are removed
from the child’s circulation. Mothers of children with neonatal
SLE do not necessarily have SLE themselves.
With careful prenatal screening and planning, women with
SLE can successfully have a healthy child. Prenatal monitoring of
anti-SSA/Ro and anti-SSB/La antibodies and APAs and pre-
pregnancy consultation with obstetricians caring for high-risk
pregnancies are critical. Ideally, women with SLE should have
clinical quiescence for 6 months before considering a planned
pregnancy.
Hormone Therapy
Hormones were thought to play a role in the development of SLE
because of its female predominance. Rheumatologists have his-
torically been hesitant to prescribe estrogen therapy for fear of
 Chapter 79  Systemic Lupus Erythematosus 785
inducing a flare. Randomized, placebo-controlled clinical trials
have helped to guide hormonal therapy in women with SLE.
A multicenter, randomized trial revealed that oral contracep-
tive therapy does not increase the risk of SLE flares in women
with mild or stable SLE disease activity. However, this is not
generalizable to all SLE women, particularly those whose disease
is active or severe and those with prior thrombotic events or
APAs. An effective form of birth control is necessary for young,
sexually active women with SLE, especially those on teratogenic
medications. Physicians must carefully discuss the risks and ben-
efits of birth control with SLE patients.
Hormonal therapy is a controversial topic regardless of SLE
status. However, it is of particular interest in SLE because some
women reach menopause prematurely. In a clinical trial of hor-
monal therapy in SLE patients with mild or stable disease with
no prior thrombotic events, APAs, or gynecologic or breast
cancers, no SLE patients had severe clinical flares, but 20% did
have mild to moderate flares. These findings suggest that brief
(1-year) hormonal therapy may be considered for alleviating
menopausal symptoms in a subset of SLE women.
Bone Health
SLE patients have higher rates of low bone mineral density, osteo-
porosis, and fractures than do healthy age-matched subjects. The
increased risk is accounted for by traditional risk factors, such as
female sex, white or Asian race, older age, and low body weight,
and by SLE-associated factors. Fatigue and articular symptoms
due to SLE may limit physical activity, leading to loss of bone
strength.
Therapies commonly used for SLE contribute to overall loss
of bone health. Corticosteroids reduce bone mass and are an
independent risk factor for fractures in women with SLE. Cyclo-
phosphamide use can lead to premature ovarian failure, another
risk factor for osteoporosis. Lupus disease damage, regardless of
steroid use, leads to low bone mineral density. SLE patients
are advised to avoid sun exposure, which can lead to low
25-hydroxyvitamin D levels and insufficient absorption of
calcium.
Because of SLE-specific risk factors for low bone mineral
density, prevention of osteoporosis is extremely important (see
Chapter 75). Although osteoporosis screening guidelines for
SLE patients are the same as for the general population, bone
density scans should be considered for patients with premature
menopause and those who are or will be on chronic (>3 months)
corticosteroids.
Cardiovascular Disease
As survival and therapies for SLE have improved and patients are
living longer, CVD has emerged as a leading cause of morbidity
and mortality. SLE patients are 5 to 10 times more likely than
healthy individuals to have a coronary event. More striking, pre-
menopausal women between 35 and 44 years of age are more
than 50 times as likely as healthy women to have a myocardial
infarction.
Autopsy series reveal atherosclerotic heart disease as the
underlying mechanism of CVD in SLE. The cause of premature
atherosclerosis in SLE is multifactorial and includes inflamma-
tory mediators, SLE-related factors (e.g., premature menopause,
corticosteroid therapy, disease activity), and traditional cardio-
vascular risk factors.
Although no firm cardiovascular management guidelines exist
for SLE patients, the 2011 updated guidelines from the American
Heart Association for prevention of CVD in women included
(for the first time) autoimmune diseases (i.e., SLE and rheuma-
toid arthritis) in the increased-risk category. Physicians should
consider premature atherosclerotic CVD and aggressively evalu-
ate SLE patients with typical and atypical cardiac symptoms,
regardless of age and sex.
Secondary Antiphospholipid Syndrome
APS is a disorder characterized by recurrent vascular thrombosis
or recurrent pregnancy loss, or both, in the setting of APAs
(Table 79-5). Lupus anticoagulant is part of the antiphospholipid
laboratory panel and is paradoxically associated with thrombosis
and recurrent pregnancy loss. The term lupus anticoagulant is a
misnomer because the in vitro anticoagulant effect reflects the
prolonged activated partial thromboplastin time (aPTT), but the
term does not indicate a diagnosis of SLE or an increased risk of
bleeding.
Diverse proteins binding to APAs have been recognized. APS
is considered primary if it occurs in isolation and secondary if it
occurs in conjunction with other autoimmune diseases. There are
no major differences in severity or clinical consequences between
primary and secondary APS. The reported prevalence of various
APAs in SLE ranges from 16% to 55%. SLE patients with APAs
have an increased risk of thromboembolism and pregnancy com-
plications and have a higher prevalence of pulmonary hyperten-
sion, Libman-Sacks endocarditis, and neurologic complications.
The term catastrophic APS has been coined to describe patients
who exhibit multiple microthromboses, are positive for APAs,
and often have a life-threatening illness resulting in multiorgan
failure that can be clinically indistinguishable from sepsis or
thrombotic thrombocytopenic purpura.
Treatment for APS is tailored to the patient and the clinical
manifestations. For patients with vascular thrombosis, indefinite
anticoagulation is usually prescribed as prophylaxis against recur-
rence. Warfarin is the usual drug of choice for long-term therapy,
with a target of an international normalized ratio (INR) between
2 and 3. Higher INR levels (3 to 4) are not more effective and
are associated with bleeding complications. Unfractionated and
low-molecular-weight heparin is also an effective anticoagulant
for APS and is used for patients who suffer recurrent events while
on warfarin therapy or patients who are or plan to become
pregnant.
Malignancy
A multicenter international cohort (SLICC) of more than 16,000
SLE patients reported an increased risk of malignancy among
them compared with the general population. Most striking was a
fourfold increased risk of non-Hodgkin’s lymphoma. Other
hematologic, vulvar, lung, and thyroid cancers were described
with increased frequency, whereas breast and endometrial
cancers were observed less than expected in SLE patients com-
pared with the general population. Malignancy risk appears to be
highest early in the disease course, but risk remains elevated
throughout a patient’s lifespan. Although lymph node
786 Section XIV  Musculoskeletal and Connective Tissue Disease

TABLE 79-5  REVISED CLASSIFICATION CRITERIA OF ANTIPHOSPHOLIPID SYNDROME

CLASSIFICATION CRITERIA* DEFINITION
CLINICAL CRITERIA
1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ.
Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies
or histopathology). For histopathologic confirmation, thrombosis should be present without significant evidence of
inflammation in the vessel wall.
2. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks’ gestation, with normal
fetal morphology documented by ultrasound or by direct examination of the fetus
or
b. One or more premature births of a morphologically normal neonate before 34 weeks’ gestation because of (i)
eclampsia or severe pre-eclampsia or (ii) recognized features of placental insufficiency
or
c. Three or more unexplained consecutive spontaneous abortions before 10 weeks’ gestation, with maternal anatomic
or hormonal abnormalities and paternal and maternal chromosomal causes excluded
LABORATORY CRITERIA
1. Lupus anticoagulant LAC detected in plasma on two or more occasions at least 12 wk apart
2. Anticardiolipin antibody The ACA antibody of IgG and/or IgM isotype in serum or plasma in medium or high titer (i.e., >40 GPL units, or
>the 99th percentile) on two or more occasions at least 12 weeks apart, measured by a standardized ELISA
3. Anti-β2 glycoprotein I antibody B2GPI antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), detected on two or
more occasions at least 12 weeks apart, measured by a standardized ELISA
Modified from Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS), J
Thromb Haemost 4:295–306, 2006.
ACA, Anticardiolipin antibody; ELISA, enzyme-linked immunosorbent assay; B2GPI, anti-β2 glycoprotein I antibody; Ig, immunoglobulin; LAC, lupus anticoagulant.
*Antiphospholipid antibody syndrome is diagnosed if at least one clinical criterion and one laboratory criterion are met.

enlargement is a common manifestation of SLE, physicians must
consider malignancy if the lymphadenopathy does not resolve
with SLE treatment, is nontender or nonmobile, or if it occurs
without other lupus symptoms.
  PROGNOSIS
In 1955, patients with SLE had a 5-year survival rate of only 50%.
Advances in early diagnosis and treatment of lupus patients have
led to the current 5- and 10-year survival rates of more than 90%
and approximately 90%, respectively, in developed countries.
A bimodal pattern of mortality is seen in SLE. Early deaths (<5
years from diagnosis) are attributed to active SLE disease and
infections, whereas later deaths (>5 years from diagnosis) result
from chronic SLE complications and medications, atheroscle-
rotic CVD, and infections. Data suggest that malignancy-
associated morbidity and mortality are lifelong risks, but rates are
the greatest early in the disease. With recent and ongoing
improvements in the treatment of SLE and increasing survival
rates of patients with SLE, we need to pay additional attention to
comorbid conditions associated with SLE and its treatment, spe-
cifically premature atherosclerotic heart disease, malignancy,
bone health, and psychosocial well-being.
SUGGESTED READINGS
Arbuckle MR, McClain MT, Rubertone MV, et al: Development of autoantibodies
before the clinical onset of systemic lupus erythematosus, N Engl J Med
349:1526–1533, 2003.
Austin HA 3rd, Klippel JH, Balow JE, et al: Therapy of lupus nephritis. Controlled
trial of prednisone and cytotoxics, N Engl J Med 314:614–619, 1986.
Bernatsky S, Ramsey-Goldman R, Labrecque J, et al: Cancer risk in systemic
lupus: an updated international multi-center cohort study, J Autoimmun
42:130–135, 2013.
Bertsias GK, Ioannidis JPA, Aringer M, et al: EULAR recommendations for the
management of systemic lupus erythematosus with neuropsychiatric
manifestations: report of a task force of the EULAR standing committee for
clinical affairs, Ann Rheum Dis 69:2074–2082, 2010.
Danchenko D, Satia JA, Anthony MS: Epidemiology of systemic lupus
erythematosus: a comparison of worldwide disease burden, Lupus 15:308–
318, 2006.
Furie R, Petri M, Zamani O, et al: A phase III, randomized, placebo-controlled
study of belimumab, a monoclonal antibody that inhibits B lymphocyte
stimulator, in patients with systemic lupus erythematosus, Arthritis Rheum
63:3918–3930, 2011.
Ginzler EM, Dooley MA, Aranow C, et al: Mycophenolate mofetil or intravenous
cyclophosphamide for lupus nephritis, N Engl J Med 353:2219–2228, 2005.
Lee C, Ramsey-Goldman R: Bone health and systemic lupus erythematosus,
Curr Rheumatol Rep 7:482–489, 2005.
Manzi S, Meilahn EN, Rairie JE, et al: Age-specific incidence rates of myocardial
infarction and angina in women with systemic lupus erythematosus:
comparison with the Framingham Study, Am J Epidemiol 145:408–415, 1997.
Mosca L, Benjamin EJ, Berra K, et al: Effectiveness-based guidelines for the
prevention of cardiovascular disease in women—2011 update: a guideline
from the American Heart Association, J Am Coll Cardiol 57:1404–1423, 2011.
Miyakis S, Lockshin MD, Atsumi T, et al: International consensus statement on
an update of the classification criteria for definite antiphospholipid syndrome
(APS), J Thromb Haemost 4:295–306, 2006.
Petri M, Kim MY, Kalunian KC, et al: Combined contraceptives in women with
systemic lupus erythematosus, N Engl J Med 353:2550–2558, 2005.
Petri M, Orbai AM, Alarcón GS, et al: Derivation and validation of the Systemic
Lupus International Collaborating Clinics classification criteria for systemic
lupus erythematosus, Arthritis Rheum 64:2677–2686, 2012.
Wallace D, Hahn BH, editors: Other clinical laboratory tests in SLE. In Dubois’
lupus erythematosus and related syndromes, ed 8, Philadelphia, 2013,
Saunders, pp 526–531.
 80 
Systemic Sclerosis
Robyn T. Domsic

A familial pattern of inheritance is not as evident in SSc as in

  INTRODUCTION
Systemic sclerosis (SSc) is a connective tissue disease that is char-
acterized by cutaneous and visceral fibrosis. The more common
term for the disease, scleroderma, reflects its derivation from the
Greek scleros, which means thick, and derma, which means skin.
The disorder can range from a relatively benign condition to a
rapidly progressive disease leading to significant morbidity or
death. Although cutaneous manifestations are the most obvious
features, visceral involvement can be severe and disabling. Moni-
toring for potential organ complications is essential in caring for
SSc patients, because early detection and treatment may mini-
mize morbidity and mortality.
other connective tissue diseases. Twin studies have demonstrated
only a 5% rate of concordance in monozygotic and dizygotic
twins, implying that there are significant environmental contri-
butions to its occurrence. Many patients with SSc, however, have
family histories of other autoimmune diseases (e.g., thyroid
disease, rheumatoid arthritis, systemic lupus erythematosus
[SLE]). Genome-wide association studies have revealed a
handful of genes associated with SSc that are shared with other
diseases such as rheumatoid arthritis and SLE (e.g., major histo-
compatibility complex class I and II genes STAT4 and IRF5).
These findings suggest a shared genetic predisposition to autoim-
mune conditions.

  EPIDEMIOLOGY
The annual U.S. incidence of SSc is approximately 20 cases per
million persons. Because patients with SSc often live for many
years, the prevalence is 240 cases per million persons. Incidence
and prevalence vary somewhat throughout the world, and they
typically are lower in Europe and Asia. SSc more commonly
affects women, with a 3 : 1 female-to-male ratio. It occurs in indi-
viduals of all ages, from childhood to the elderly, but it most
frequently affects those between the ages of 40 and 60 years.
  PATHOLOGY
The pathogenesis of SSc has not been fully elucidated. There are
three clearly identified components: endothelial and vascular
injury with associated vasculopathy, immune system activation,
and fibrosis with overproduction of collagen and other connec-
tive tissue matrix proteins (Fig. 80-1). Involvement of these
systems initially became evident from autopsy studies. Vascular
changes include endothelial cell injury and subintimal thickening
leading to luminal narrowing with occasional vascular occlusion

Immune cell homing Vascular injury and proliferation

IL-4 Endothelin
PDGF
TGF-β IL-1

Accumulation of interstitial matrix

FIGURE 80-1  Pathogenetic processes in systemic sclerosis. Vascular injury leads to intimal proliferation of endothelial cells (red) and smooth muscle
cells (blue). Fibroblasts are activated to deposit increased amounts of interstitial matrix. IL, Interleukin; PDGF, platelet-derived growth factor; TGF-β,
transforming growth factor-β.

787
788 Section XIV  Musculoskeletal and Connective Tissue Disease

and periadventitial fibrosis. Vascular changes are seen in the skin the upper arms, thighs, or trunk at some time during the disease
and may occur in the pulmonary, cardiac, and renal blood vessels, course. Few patients (<1%) have no skin thickening but have one
affecting arteries, arterioles, and capillaries. True vasculitis is con- or more typical SSc visceral manifestation.
spicuously absent. The term scleroderma sine scleroderma has been used to describe
Cutaneous inflammatory infiltrates consist of activated mono- dcSSc patients whose clinical course resembles that of individu-
nuclear cells, T lymphocytes, and monocytes in the dermis, often als with lcSSc. The distinct cutaneous patterns are important,
occurring in a perivascular distribution. Dermal thickening is because patients with dcSSc are more likely to develop internal
accompanied by excessive deposition of collagen fibrils and organ complications (e.g., renal crisis, cardiac involvement) early
fibrous replacement of subcutaneous fat and secondary skin in their illness, whereas those with lcSSc can develop internal
appendages such as hair follicles and sebaceous glands. organ involvement throughout their disease, even decades after
The interplay between the vascular, immunologic, and connec- the initial symptoms (Table 80-1). Some patients with lcSSc or
tive tissue changes is complex. Most hypotheses focus on interac- dcSSC may have typical features of another connective tissue
tions between early vascular and immunologic events leading to disease (most commonly polymyositis, SLE, or rheumatoid
activation of fibroblasts, which are thought to be the effector cells arthritis-like features), and they are considered to have SSc in
in this disease. Fibroblasts are found in increased numbers in the overlap.
skin and other tissues, and they develop an SSc phenotype when
grown in vitro, producing an overabundance of collagen and Serologic Classification
living longer in tissue culture. Fibroblast persistence in culture Serologic classification refers to SSc-associated serum autoanti-
suggests a perpetuated abnormality not requiring continued bodies. Patients with the same autoantibody tend to have a
immune stimulation. similar cutaneous pattern, natural history of disease, and risk of
Other factors that may contribute to fibrosis include hypoxia internal organ involvement.
and local cytokine changes. Early vascular involvement consists
of an imbalance between vasodilatory and vasoconstrictive
factors, endothelial cell activation with resultant leukocyte migra-
tion, smooth muscle cell proliferation, and defective vasculogen- TABLE 80-1  MANIFESTATIONS OF SYSTEMIC
esis. Vascular activation can induce fibrosis by interleukin-mediated SCLEROSIS BY CLINICAL
mechanisms. CLASSIFICATION
Immune system activation is evident in several respects. First, DIFFUSE LIMITED
serum levels of inflammatory markers (based on the sedimenta- MANIFESTATIONS (N = 1434) (N = 1718)
tion rate) and circulating cytokines are increased. Second, serum CUTANEOUS
autoantibodies are detected in more than 95% of patients with Puffy fingers 82% 78%
SSc. One of nine autoantibodies is relatively specific for the Skin induration, thickening Widespread: trunk, Face, below the
face, extremities elbow and knee
disease. All of the antibodies are directed against distinct nuclear Telangiectasias 58% 70%
antigens. They are helpful in classifying patients, but their patho- Calcinosis 14% 22%
genic role has not been elucidated. Third, there is evidence of PERIPHERAL VASCULAR
T-cell activation, with a TH2-predominant cytokine profile. Ele- Raynaud’s phenomenon 95% 97%
vated levels of interleukins (i.e., IL-1, IL-2, IL-2R, IL-4, IL-8, Digital ulcerations 42% 39%
IL-13, and IL-17) and interferon have been reported. The role of PULMONARY
TH17 cells is not understood, but studies suggest that dysregula- Interstitial lung disease 37% 34%
tion of these proinflammatory T cells contributes to disease Pulmonary arterial 5% 16%
hypertension
pathogenesis. Fourth, there is increasing evidence of innate
immune dysregulation in the setting of activated macrophages CARDIAC
and altered expression and function of toll-like receptors. Arrhythmias 16% 14%
Diastolic dysfunction 4% 5%
Myocarditis 6% 2%
  CLINICAL PRESENTATION Pericarditis 4% 3%
Patients with SSc can have several clinical presentations, although RENAL
Raynaud’s phenomenon is the most common symptom. Distinc- Renal crisis 18% 2%
tive phenotypes may manifest differently. SSc can have many GASTROINTESTINAL
internal organ manifestations, producing various clinical presen- Esophageal hypomotility, 79% 77%
tations and requiring tailored work-up protocols. reflux
Small intestine dysmotility 18% 13%
Classification by Cutaneous Features Malabsorption 11% 9%
Incontinence 2% 2%
Historically, SSc has been separated into two major clinical
JOINT AND MUSCULOSKELETAL
subsets defined by the degree and extent of skin involvement:
Tendon friction rubs 53% 5%
limited cutaneous (lc) and diffuse cutaneous (dc) disease. Joint contractures 88% 38%
Patients with lcSSc experience skin thickening limited to the Myositis 10% 6%
distal extremities (i.e., below the elbows and knees). The dcSSc Bland myopathy 2% 1%
patients have similar distal changes in addition to involvement of Data from the University of Pittsburgh Scleroderma Databank, 1980-2012.

Serologic classification can augment the clinical classification
described previously. For example, 95% of patients with anticen-
tromere antibody have lcSSc and are at increased risk for pulmo-
nary hypertension during the follow-up period. Individuals with
anti–topoisomerase I (i.e., anti-SCL70) or anti–RNA polymerase
III antibody are more likely to have dcSSc. Those with anti–RNA
polymerase III antibody have an increased risk of renal crisis, and
those with anti-SCL70 have a higher frequency of interstitial lung
disease.
The primary internal organ risks and cutaneous associations
are depicted in Figure 80-2, which illustrates the combined
clinical-serologic classification of SSc. It is uncommon for
patients to have more than one SSc autoantibody.
Raynaud’s Phenomenon and Peripheral
Vascular Involvement
Most patients with SSc experience Raynaud’s phenomenon
during their disease course. Raynaud’s phenomenon is a triphasic
vasospastic response to cold consisting of pallor (i.e., blanching)
with or without cyanosis (i.e., bluish discoloration followed by
reactive hyperemia (i.e., erythema) with a characteristic distinct
line of demarcation on the digits separating the affected from
unaffected areas.
The onset of Raynaud’s phenomenon can precede the devel-
opment of skin changes by years in some patients. Severe involve-
ment may result in ischemia with loss of digital tip tissue,
including digital pitting scars, ulcers, and gangrene (rare). Digital
tip ulcers are more frequent in patients who are anticentromere
or anti–topoisomerase I autoantibody positive. Lower extremity
ulcerations in SSc patients have been increasingly reported in
recent years.
Interstitial Lung Disease
Interstitial lung disease (ILD) can be one of the most serious
complications of SSc and should be monitored for routinely (see
Chapter 17). The initial presentation is often a nonproductive
Diffuse
Scl-70
ILD (60%), DU
Myopathy (non-inflammatory)
RNA polymerase III
Severe skin
SRC
U3-RNP
Myositis, PH
Cardiomyopathy,
Severe GI
FIGURE 80-2  Clinical-serologic classification of systemic sclerosis and antibody-associated internal organ manifestations. Bold text indicates an
antibody; clinical manifestations listed below are associated with that antibody. DU, Digital ulcers; ILD, interstitial lung disease; Ku, 70/80-kD protein
(XRCC6/XRCC5); PH, pulmonary hypertension; PM, polymyositis; RNP, ribonucleoprotein; Scl, sclerosis; SRC, scleroderma renal crisis.
Chapter 80  Systemic Sclerosis 789
cough and a gradual onset of dyspnea on exertion over several
months to years. However, the onset can be abrupt.
High-resolution chest computed tomography (CT) typically
shows bibasilar fibrotic changes, which can be progressive. Pul-
monary function tests reveal reduced forced vital capacity (FVC).
On pathologic examination, the most frequently seen pattern is
nonspecific interstitial pneumonitis. Patients with anti-SCL70
autoantibody are at the highest risk for ILD.
Pulmonary Hypertension
SSc patients can develop pulmonary hypertension of three World
Health Organization (WHO) classifications (see Chapter 18).
Pulmonary arterial hypertension (PAH, group 1) is the most
common, with an estimated 10% to 15% of patients in cohort
studies developing PAH. It occurs most commonly in those with
lcSSc. The clinical presentation includes rapidly progressive
dyspnea occurring over several months. Pulmonary function
tests reveal a reduced diffusion capacity for carbon monoxide
(Dlco) out of proportion to any concomitant reduction in
the FVC.
Less frequently, SSc patients develop pulmonary hypertension
associated with ILD (group 3) or pulmonary hypertension asso-
ciated with left ventricular diastolic dysfunction from myocardial
fibrosis or non–SSc-associated left ventricular disorders (group
2). Screening for all types of pulmonary hypertension is per-
formed by echocardiogram, and results should be confirmed by
right heart cardiac catheterization.
Scleroderma Renal Crisis
Scleroderma renal crisis (SRC) manifests as the abrupt onset of
accelerated arterial hypertension accompanied by a rise in serum
creatinine levels and by microscopic hematuria and proteinuria
on urinalysis. Microangiopathic hemolytic anemia and thrombo-
cytopenia are common. Although once the major cause of mor-
tality in SSc, SRC is now managed by aggressive blood pressure
control with an angiotensin-converting enzyme (ACE) inhibitor.
Overlap Limited
U1-RNP Centromere
Myositis (25%) PH
ILD, Joints Calcinosis, DU
PM/Scl ILD (30–40%)
Myositis (>50%) Th/To
Calcinosis PH (all types)
Ku ILD
Myositis (65%) U11/U12 RNP
ILD (severe)
790 Section XIV  Musculoskeletal and Connective Tissue Disease
The typical setting for SRC is early dcSSc with a recent increase
in skin thickening, palpable tendon friction rubs, and anti–RNA
polymerase III antibody. During active, early dcSSc, patients
should check their blood pressure once weekly and report a rise
in systolic blood pressure of more than 20 mm Hg from baseline.
Prednisone given at a dose of 15 mg daily or higher has been
associated with the development of SRC and should be avoided
in at-risk patients.
Cardiac Manifestations
Patients with SSc have three primary types of cardiac involve-
ment: pericarditis, myocarditis, and myocardial fibrosis. The
latter can lead to congestive heart failure and arrhythmias due to
fibrosis of the conduction system. These complications can be
asymptomatic and underrecognized in SSc patients, but patho-
logic changes have been found in most patients in older autopsy
series. Later studies using cardiac magnetic resonance imaging
(MRI) have confirmed the autopsy findings.
Diastolic dysfunction is becoming increasingly recognized as
a complication of fibrosis and can be evaluated by echocardio-
gram during pulmonary hypertension screening. Many SSc
deaths occur suddenly, possibly due to ventricular arrhythmias.
It is prudent to obtain a resting electrocardiogram early in the
disease course. Palpitations noticed by the patient should be
addressed with a formal cardiac arrhythmia evaluation.
Gastrointestinal Tract Manifestations
At least one gastrointestinal manifestation will affect 80% or
more of SSc patients, and all areas of the gastrointestinal tract
may be affected. Gastrointestinal involvement is a significant
cause of morbidity.
When the esophagus is affected, patients experience heartburn
due to relaxation of the esophageal sphincter and distal dys-
phagia for solid foods due to esophageal dysmotility. Neuro-
pathic changes and fibrosis of the muscularis of the small
intestine can lead to motor dysfunction and symptoms of
postprandial abdominal distention. Small intestinal hypomotility
may lead to bacterial overgrowth, causing bloating and
diarrhea.
When severe atony of the small intestine develops, patients
occasionally develop a functional ileus or intestinal pseudo-
obstruction. Parenteral nutrition may be necessary for severe
malabsorption with accompanying weight loss and steatorrhea.
Similar to the small bowel, the colon may develop impaired
motor function leading to constipation and occasionally overflow
diarrhea. Wide-mouthed diverticula on the antimesenteric
border of the colon can be seen. The internal anal sphincter may
become fibrotic, resulting in fecal incontinence.
Musculoskeletal Manifestations
Musculoskeletal manifestations are common. Tendons can
become inflamed and fibrotic, particularly in early, diffuse disease.
Palpable tendon or bursal friction rubs are virtually pathogno-
monic of SSc and often are a harbinger of progression to dcSSc
before widespread skin thickening has occurred. Finger joint
flexion contractures develop frequently within the first 2 years of
diffuse SSc. True arthritis with palpable synovitis should raise the
question of overlap with rheumatoid arthritis.
Some patients develop a bland myopathy with nonprogressive,
mild proximal muscle weakness and wasting. A few, particularly
with features that overlap with other connective tissue diseases,
can develop true myositis, which can result in morbidity and
disability.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Raynaud’s disease (i.e., primary Raynaud’s phenomenon) is
prominent in the differential diagnosis for SSc. Features that
identify Raynaud’s patients who have or may later develop SSc or
another connective tissue disease are abnormal nail fold capillar-
ies (i.e., capillary dilation, megacapillaries, and avascular areas),
tissue loss at the tips of the fingers, and a positive antinuclear
antibody (ANA) test result. None of these features is found in
Raynaud’s disease.
Mixed connective tissue disease (MCTD) is also on the dif-
ferential for SSc. MCTD patients have features of two or more
autoimmune diseases. This most frequently includes SSc, poly-
myositis, and SLE. Patients are positive for anti–U1-RNP anti-
body, a serologic marker for MCTD. Patients with MCTD can
develop any or all of the following SSc manifestations: Raynaud’s
phenomenon, puffy fingers, limited or diffuse skin thickening,
myositis, ILD, PAH, and esophageal dysmotility.
Scleroderma mimics are sometimes difficult to distinguish
from SSc (Table 80-2). They include eosinophilic fasciitis, the
localized forms of scleroderma such as linear scleroderma (more
frequently seen in children), and plaque or generalized morphea.
Nephrogenic systemic fibrosis is a complication of gadolinium
administration for radiographic studies that occurs in the setting
of renal failure. Nephrogenic systemic fibrosis manifests as sym-
metrical, bilateral, fibrotic, indurated papules, plaques, or subcu-
taneous nodules, which can be erythematosus and occur on the
lower legs or hands. The lesions are often preceded by edema and
may initially be misdiagnosed as cellulitis. This diagnosis should
be considered in patients being evaluated for a fibrotic disorder
who have renal failure, regardless of the cause of renal disease.
Scleromyxedema and scleredema are cutaneous fibrotic disor-
ders in which excessive mucin accumulation is found on skin
biopsy. Scleromyxedema can mimic dcSSc on the physical exami-
nation or can manifest with multiple, firm, nodular skin lesions
(i.e., papular mucinosis). A frequent association is a monoclonal
gammopathy (i.e., immunoglobulin [IgG] paraprotein). Scler-
edema typically involves the nape of the neck and shoulders,
sparing the distal extremities. All SSc mimics lack Raynaud’s phe-
nomenon, characteristic SSc internal organ involvement, and
SSc-associated serum antibodies.
  TREATMENT
Because no single therapy exists for SSc, patients must be appro-
priately monitored for visceral involvement to allow early identi-
fication and therapy targeted at specific organ complications.
Consultation with a rheumatologist is helpful in this respect, and
referral of severely affected patients to a dedicated scleroderma
center should be the rule.
All patients should undergo screening evaluation for ILD and
pulmonary hypertension throughout the course of their disease.
Current expert recommendations suggest that patients with
early, diffuse disease should be monitored at least yearly for these

TABLE 80-2  SCLERODERMA MIMICS
DISORDER DISTINGUISHING FEATURES
OTHER DISEASES
Morphea One or more discrete lesions; patchy or linear in
distribution
Eosinophilic fasciitis Finger flexures without sclerodactyly; characteristic
groove sign when the arms are raised; puckering
or dimpling of the upper arm and thigh skin;
peripheral blood eosinophilia; fascia and deep
subcutaneous fibrosis
Scleredema (Buschke’s Prominent involvement of neck, shoulders, and
disease) upper arms; hands spared; associated with
diabetes
Scleromyxedema Association with gammopathy; skin lichenoid and
thickened but not tethered; may have Raynaud’s
phenomenon
Graft-versus-host Skin changes similar to scleroderma; vasculopathy
disease
Nephrogenic fibrosing Indurated plaques or nodules on the legs or arms,
dermopathy sparing the face; administration of gadolinium in
the setting of renal dysfunction; often preceded
by edema
REACTIONS TO ENVIRONMENTAL AGENTS AND DRUGS
Bleomycin Skin and lung fibrosis similar to scleroderma
L-Tryptophan (1980s) Eosinophilia-myalgia syndrome from L-tryptophan
contaminant or metabolite (first described in the
1980s); fever, eosinophilia, neurologic
manifestations
Organic solvents (e.g., Clinically indistinguishable from idiopathic
trichloroethylene) systemic sclerosis
Pendazocine Localized lesions at injection sites
Toxic oil syndrome Contaminated rapeseed oil (Spanish epidemic in
1981); similar to eosinophilia myalgia syndrome
Vinyl chloride Vascular lesions, acro-osteolysis, sclerodactyly, no
visceral disease
Gadolinium Nephrogenic fibrosing dermopathy
complications. Patients with active dcSSc should undergo weekly
monitoring of blood pressure because the abrupt appearance of
hypertension suggests SRC. Early dcSSc patients should also
have skin thickness scores assessed for progression or regression
of cutaneous disease. For dcSSc and lcSSc, initial esophageal
motility studies should be performed, and further objective
studies should be ordered on the basis of symptoms.
Education of patients and family members regarding the
disease and the patient’s classification (i.e., early or late, diffuse or
limited disease) can help to alleviate patients’ anxiety. An excel-
lent publication, The Scleroderma Book: A Guide for Patients and
Families, is available.
Raynaud’s Phenomenon
Calcium-channel blockers have been widely used for decades,
and they are generally well tolerated by patients. Long-acting
nifedipine is effective in more than one half of patients, and newer
agents such as amlodipine are frequently prescribed (level 1B
evidence). The angiotensin-receptor blocker losartan reduced
the severity and frequency of Raynaud’s phenomenon attacks in
a placebo-controlled trial. ACE inhibitors have not proved effec-
tive in several controlled trials. Phosphodiesterase-5 (PDE-5)
inhibitors have been shown to improve Raynaud phenomenon
(level 1A evidence).
In patients with digital ulcerations, more aggressive therapy
may be warranted. PDE-5 inhibitors have been helpful (level 1B
Chapter 80  Systemic Sclerosis 791
evidence) has been helpful. Topical nitroglycerin as a paste, gel,
or patch placed at the base of the fingers may be a useful adjunct.
In randomized, placebo-controlled trials, bosentan prevented the
formation of new digital ulcerations in patients with SSc and
Raynaud’s phenomenon, although it has not been approved by
th U.S. Food and Drug Administration (FDA) for this indication
(level 1B evidence). Iloprost, an intravenous prostacyclin, has
also been shown to reduce digital ulcerations and is frequently
used in Europe, but also it is not FDA approved in the United
States (level A evidence).
For patients with digital ulcers involving adjacent fingers,
assessment of the ulnar and radial artery should be performed
with arterial Doppler or angiography because larger arteries can
become severely narrowed. Surgical interventions include sym-
pathectomy of the digital, radial, or ulnar artery and venous
bypass for ulnar or radial artery occlusion. In SSc patients with
recurrent digital ulcers or other thrombotic events, evaluation for
a hypercoagulable state, particularly for lupus anticoagulant,
should be performed. In this circumstance, aspirin or other anti-
coagulants are indicated.
Cutaneous Disease
No therapeutic agent has been found to improve skin thickening
in a randomized, placebo-controlled trial for patients with dcSSc.
Several methodologic issues have contributed to the negative
findings, including the drugs chosen, patient populations, and
trial designs. In the past, considerable attention was given to
methotrexate and d-penicillamine, but no convincing data
support the use of either drug.
Case series with historical controls and comparisons with
clinical trials have suggested a benefit for mycophenolate mofetil,
although it has not been studied in a randomized setting (level B
evidence).
Several reports on the benefit of autologous stem cell trans-
plantation have been published. In an ILD study, cyclophospha-
mide use showed significant improvement in skin thickening in
treated patients compared with placebo. Unless there is a serious
internal organ complication, this potent therapy cannot be rec-
ommended because of the concern about life-threatening adverse
effects, including malignancy.
Scleroderma Renal Crisis
Early diagnosis and prompt initiation of ACE inhibitors are the
keys to improved survival and outcomes of SRC. ACE inhibitors
should be titrated to maintain a normal blood pressure (level 3
evidence), preferably less than 125/75 mm Hg. β-Blockers are
relatively contraindicated.
Even if patients with SRC become dialysis dependent initially,
some may experience a slow reversal of renal vascular damage if
ACE inhibitor therapy is maintained. Because up to 50% of SRC
patients can spontaneously come off dialysis, transplantation
evaluation should be delayed until at least 2 years after SRC
onset.
Interstitial Lung Disease
Early recognition of inflammatory ILD is important if treatment
is to prevent progression to distortion of lung architecture
and irreversible fibrosis. A recent large, randomized,
792 Section XIV  Musculoskeletal and Connective Tissue Disease
placebo-controlled trial demonstrated statistically significant
but modest FVC improvement with oral cyclophosphamide
at 1 year. However, after an additional year off therapy,
cyclophosphamide-treated patients lost their benefit, suggesting
that other treatment options are needed.
Case series with and without historical controls support the
potential benefit of mycophenolate mofetil, and this drug is the
subject of an ongoing randomized controlled trial. Lung trans-
plantation can be considered for end-stage ILD.
Pulmonary Hypertension
Several agents have been approved for the treatment of PAH
(see Chapter 18). Subset analyses of several placebo-controlled
drug trials have shown improvement in established SSc or
connective tissue disease–related PAH. They have included
phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), endo-
thelial receptor antagonists (e.g., bosentan, ambrisentan), and
prostacyclin analogues (e.g., treprostinil, epoprostenol) (level
A evidence).
Theoretically, treatment of patients with early, less severe
disease should improve outcomes, but studies are only beginning
to be reported. Because patients with SSc-related PAH have a
worse prognosis than those with idiopathic PAH, SSc patients
with PAH should be recommended to a tertiary care facility with
a dedicated pulmonary hypertension clinic.
Cardiac Manifestations
Combined corticosteroids and immunosuppression can be used
for myocarditis. Conventional treatment is recommended for
symptomatic pericarditis (see Chapter 10), arrhythmias (see
Chapter 9), and congestive heart failure (see Chapter 5).
Gastrointestinal Manifestations
Gastroesophageal reflux, which occurs in most SSc patients, can
be treated with proton pump inhibitors and conservative mea-
sures, including elevation of the head of the bed and avoidance
of alcohol and caffeine. If untreated, reflux esophagitis can prog-
ress to distal esophageal stricture formation.
Patients with severe esophageal, gastric, or small bowel dys-
motility may improve with the use of prokinetic drugs such as
metoclopramide, erythromycin, or octreotide. Rotating antibiot-
ics may be of assistance for bacterial overgrowth. For advanced
small bowel involvement with malabsorption, supplementation
of iron, calcium, and fat-soluble vitamins may be required. Occa-
sionally, total parental nutrition is necessary. Unexplained iron-
deficiency anemia in SSc patients suggests the possibility of
gastric antral vascular ectasias (i.e., watermelon stomach), which
are treated with laser photocoagulation.
Skeletal Muscle, Joint, and  
Tendon Manifestations
Bland myopathy usually is nonprogressive and is treated with
physical therapy. If there is evidence of myositis with elevated
serum levels of muscle enzymes or abnormal electromyography
or muscle biopsy, corticosteroids and immunosuppressive
therapy (e.g., methotrexate, azathioprine) may be helpful.
Patients with lcSSc or dcSSc can develop contractures of the
hands due to tendon involvement. Physical therapy with daily
stretching exercises directed at the finger joints should be insti-
tuted as soon as possible to prevent further loss of finger motion.
For a deeper discussion of these topics, please see Chapter
267, “Systemic Sclerosis (Scleroderma),” in Goldman-Cecil
Medicine, 25th Edition.
SUGGESTED READINGS
Kowal-Bielecka O, Landewé R, Avouac J, et al: EULAR recommendations for the
treatment of systemic sclerosis: a report from the EULAR scleroderma trials
and research group (EUSTAR), Ann Rheum Dis 68:620–628, 2009.
Maurer B, Distler O: Emerging targeted therapies in scleroderma lung and skin
fibrosis, Best Pract Res Clin Rheumatol 25:843–858, 2011.
Mayes MD: The scleroderma book: a guide for patients and families, New York,
1999, Oxford University Press.
Medsger TA: Natural history of systemic sclerosis and the assessment of disease
activity, severity, functional status, and psychologic well-being, Rheum Dis
Clin North Am 29:255–275, 2003.
 81 
Systemic Vasculitis
Kimberly P. Liang

classification criteria and definitions for epidemiologic purposes,

  DEFINITION AND EPIDEMIOLOGY
The primary systemic vasculitides are inflammatory disorders of
blood vessels that are characterized by immune-mediated injury
leading to vessel necrosis, thrombosis, stenosis, or some combi-
nation of these. Vessels in any organ may be affected, but each
vasculitis is characterized by different preferential vessel size or
territory and tissue targeting. Although these disorders are rare,
they may be organ- or life-threatening, so prompt diagnosis and
treatment are necessary. The vasculitides are defined according to
the 1990 American College of Rheumatology (ACR) classifica-
tion criteria and the 1994 Chapel Hill Consensus Conference
(CHCC) based on generally affected vessel size (small, medium,
or large). Antineutrophil cytoplasmic antibody (ANCA)–associ-
ated vasculitides (AAVs) have known associations with charac-
teristic autoantibodies. Figure 81-1 shows the major types of
vasculitides. Although the ACR and CHCC definitions were not
designed as diagnostic criteria, classification criteria such as these
are important in clinical research study design, treatment, and
prognosis. The ACR and the European League Against Rheuma-
tism (EULAR) are currently in the process of refining diagnostic
and classification criteria for primary vasculitides.
Determining the incidence and prevalence of each of the vas-
culitides is challenging given the rarity of the disorders, imperfect
and some clinicopathologic overlaps that occur between certain
types (e.g., AAVs).
Small Vessel Vasculitis
ANCA-Associated Vasculitides
Granulomatosis with polyangiitis (GPA; previously known as
Wegener’s granulomatosis), microscopic polyangiitis (MPA),
eosinophilic granulomatosis with polyangiitis (EGPA; previ-
ously known as Churg-Strauss syndrome), and renal-limited vas-
culitis (RLV) affect small and medium-sized blood vessels and
may be associated with ANCA. Various studies have shown AAVs
to have an incidence of approximately 10 to 20 per million. The
peak age at onset is 65 to 74 years, with a female-to-male ratio of
1.5 : 1. EGPA is the least common of the AAVs, with an incidence
of approximately 1.0 to 3.0 per million, and it also has a weaker
association with ANCA than GPA and MPA do.
Henoch-Schönlein Purpura
Henoch-Schönlein purpura (HSP) is a small vessel vasculitis that
occurs most frequently in young children, with a peak age at
onset of 4 to 6 years, but can also occur in adults. HSP accounts
for almost half of all cases of childhood vasculitis. In children

Capillary
Arteriole Venule
Small artery Vein
Large to medium-
sized artery

Cutaneous leukocytoclastic angiitis

Aorta
¨
Henoch-Schonlein purpura and
essential cryoglobulinemic vasculitis

Microscopic polyangiitis (microscopic polyarteritis)

Wegener’s granulomatosis and Churg-Strauss syndrome

Polyarteritis nodosa and Kawasaki disease

Giant cell (temporal) arteritis

and Takayasu’s arteritis
FIGURE 81-1  The vascular spectrum of the vasculitides. (From Jennette JC, Falk RJ, Andrassy K, et al.: Nomenclature of systemic vasculitides:
proposal of an international consensus conference, Arthritis Rheum 37:187–192, 1994.)

793
794 Section XIV  Musculoskeletal and Connective Tissue Disease
younger than 17 years of age, the annual incidence of HSP is
approximately 20 per 100,000. Males are more commonly
affected than females (approximately 2 : 1), and HSP occurs
more frequently during the winter and spring months.
Medium Vessel Vasculitis
Polyarteritis nodosa (PAN) is a medium vessel vasculitis that is
characterized by arterial aneurysmal and stenotic lesions of mus-
cular arteries, often located at segmental and branch points. In
contrast to small vessel vasculitis, renal involvement in PAN is
not characterized by glomerulonephritis but rather by aneurysms
and stenoses of renal arteries that may result in hypertension or
renal dysfunction or both. PAN may occur either as a primary
vasculitis or secondary to viral infections, mainly hepatitis B or
C, or human immunodeficiency virus (HIV). Determining the
incidence of this vasculitis is difficult, because PAN and MPA
were not differentiated until 1994.
Kawasaki disease is a medium vessel vasculitis most often seen
in boys younger than 5 years of age. It is the second most common
vasculitis in childhood after HSP, accounting for about 23% of all
childhood vasculitis cases. In the United States, the annual inci-
dence in children younger than 5 years old is 20 per 100,000.
Large Vessel Vasculitis
Giant cell arteritis (GCA), also known as temporal arteritis, is the
most common form of vasculitis in adults. It is a large vessel
vasculitis that typically affects patients of Eastern European
descent, with a mean age at onset of 70 to 75 years. It affects
women more commonly than men (3 : 1). About 40% of patients
with GCA have the related condition, polymyalgia rheumatica
(PMR), which is characterized by subacute onset of aching and
stiffness in the muscles of the neck, shoulder girdle, and hip
girdle. However, only 10% to 25% of patients with PMR have or
will develop GCA.
Takayasu’s arteritis (TAK), or “pulseless disease,” is a rare large
vessel vasculitis that was initially identified in young women from
East Asia in the 1800s but is now described worldwide. In adults,
the female-to-male ratio is about 8 : 1, with an average age at
diagnosis in the mid-20s.
  PATHOLOGY
For most of the systemic vasculitides, the etiology and pathogen-
esis of disease are largely unknown. It has been proposed that a
number of diverse mechanisms contribute to the development of
vascular inflammation and subsequent injury on the background
of genetic susceptibility (Fig. 81-2). Proposed triggers of disease
include infection and environmental exposures (e.g., chemicals,
pollutants). For most vasculitides, these associations remain
speculative.
Humoral and cellular immune responses, cytokine release,
chemokine activation, and immune complex deposition are
important in disease pathogenesis. Normal protective and repair
processes in the vessel can also contribute to injury and ischemia.
For example, after injury, cellular migration and proliferation
occurring as part of vessel repair can result in intimal hyperplasia,
and the procoagulant milieu that is protective against hemor-
rhage may lead to thrombosis and vessel occlusion. Impairment
of blood flow in injured vessels results in tissue ischemia and
Genetic factors
• Gender
• Ethnicity...
• Variation or effectiveness
Route of pathogen
of immune response
• Effective down regulation
acquisition
Pathogen/products
• Cleared Mosaic of
• Retained illness
• Cleared, tissue altered
Pathogen or
Different activation
thresholds pathogen-products
dose effects
Tissue diversity–target
vulnerability
Native + acquired changes
FIGURE 81-2  Factors affecting disease vulnerability and expression.
damage. The degree of blood flow impairment varies along a
broad spectrum of severity and may depend on the type of vas-
culitis as well as the size and location of the vessels involved.
Among the AAVs, the pathology of GPA is typically character-
ized by necrotizing granulomatous inflammation of small blood
vessels supplying the upper and lower respiratory tract. In both
GPA and MPA, renal pathology shows a pauci-immune necrotiz-
ing crescentic glomerulonephritis. In EGPA, there is a strong
association with allergic and atopic disorders, including allergic
rhinitis, nasal polyposis, and asthma. Approximately 70% of
patients with EGPA have elevated levels of immunoglobulin E
(IgE) and eosinophilia of peripheral blood and tissue. Small
vessel histopathology typically reveals transmural eosinophilic
infiltrates with scattered plasma cells and lymphocytes and extra-
vascular granulomas.
The pathology of HSP is characterized by a leukocytoclastic
vasculitis of small vessels with IgA deposition seen on immuno-
fluorescence. Various infectious agents, including bacteria and
viruses, have been reported as triggers for HSP.
The pathology of GCA and TAK are very similar histologically.
In both, large vessels demonstrate a lymphoplasmacytic inflam-
matory infiltrate. Giant cells and granulomas may be seen in the
media, and lumen-occlusive arteritis may occur from exuberant
intimal hyperplasia. Additional pathologic features include pro-
liferation of vascular smooth muscle cells and fragmentation of
the internal elastic lamina.
  CLINICAL PRESENTATION AND DIAGNOSIS
Clinical manifestations of the systemic vasculitides are diverse
and differ not only among disorders but also among patients.
Typical clinical manifestations associated with the size of the
affected vessel are detailed in Table 81-1.
Small Vessel Vasculitis
ANCA-Associated Vasculitides
GPA most commonly affects the sinuses and upper airway, the
lungs, and the kidneys, although almost any organ system may be
affected. Chronic refractory sinusitis, nasal crusting and ulcers,

TABLE 81-1  TYPICAL CLINICAL FEATURES* BASED
ON VESSEL SIZE
LARGE MEDIUM SMALL
Limb claudication Cutaneous nodules Purpura
Asymmetrical blood Ulcers Vesiculobullous lesions
pressures
Absence of pulses Livedo reticularis Alveolar hemorrhage
Bruits Digital gangrene Glomerulonephritis
Aortic dilatation Mononeuritis multiplex Mononeuritis multiplex
Aortic primary branch Microaneurysms of Cutaneous
stenoses and/or mesenteric and/or extravascular
aneurysms renal branch arteries necrotizing
granulomas
Splinter hemorrhages
Scleritis, episcleritis,
uveitis
*Constitutional symptoms in all types are fever, weight loss, malaise, anorexia, arthralgias,
and myalgias.
epistaxis, septal perforations, and otitis media are common pre-
senting manifestations. Chronic nasal cartilaginous inflammation
and destruction may lead to the characteristic “saddle nose”
deformity. Lung involvement in GPA or MPA can include pul-
monary nodules (often cavitary in GPA), infiltrates, or diffuse
alveolar hemorrhage due to capillaritis. Importantly, life-
threatening pulmonary hemorrhage may manifest simply as pro-
gressive acute dyspnea with hypoxia or respiratory failure, and
not necessarily hemoptysis. Laryngotracheal disease may mani-
fest as hoarseness or subglottic stenosis; orbital pseudotumors
can also occur from GPA, and they may cause optic nerve com-
pression, proptosis, and/or extraocular muscle palsies.
The renal manifestations in GPA, MPA, or RLV are those of
acute renal failure. Renal biopsy reveals pauci-immune necrotiz-
ing crescentic glomerulonephritis. Additional organ manifesta-
tions that may occur in either GPA or MPA include neurologic,
cutaneous, musculoskeletal, cardiovascular, and constitutional
signs and symptoms. Patients may have subacute symptoms
(weeks to months of sinusitis, arthralgias, and fatigue) or may
exhibit acute “pulmonary-renal syndrome” with rapidly progres-
sive glomerulonephritis and life-threatening alveolar hemorrhage
with respiratory failure.
In EGPA, the clinical features comprise severe asthma, eosino-
philia (>1500 cells/mL), and vasculitis involving two or more
organs. Additional organ involvement in EGPA may include the
nervous system, kidneys, skin, heart, and gastrointestinal tract.
Sinus involvement in EGPA is typically not destructive as in
GPA, and pulmonary infiltrates may be fleeting.
The diagnosis of any of the AAVs is most frequently estab-
lished by tissue biopsy (e.g., kidney, lung, skin, sinus, nerve).
ANCA testing plays an important diagnostic role in suspected
small vessel vasculitis and is helpful in differentiating between
GPA and MPA. Almost 90% of patients with renal disease have
positive ANCA on testing. Most GPA patients have the cytoplas-
mic (cANCA) antiproteinase 3 (anti-PR3) type, whereas most
MPA patients have the perinuclear (pANCA) antimyeloperoxi-
dase (anti-MPO) type. The differential diagnosis for positive
ANCA testing includes drug-induced effects, infections, and
other autoimmune conditions. EGPA can be distinguished from
other AAVs on the basis of a prior history of adult-onset asthma
or allergic rhinitis and blood or tissue eosinophilia.
Chapter 81  Systemic Vasculitis 795
FIGURE 81-3  Palpable purpura on the lower extremities of a patient
with small vessel vasculitis affecting the skin. These lesions are “pal-
pable” because they are slightly raised (i.e., palpable even with the eyes
closed), and they are typically nonblanching when palpated. (Modified
from Molyneux ID, Moon T, Webb AK, Morice AH: Treatment of cystic
fibrosis associated cutaneous vasculitis with chloroquine, J Cystic Fibro-
sis 9:439–441, 2010. Copyright 2010 European Cystic Fibrosis Society.)
The differential diagnosis for any small vessel vasculitis
includes infection, disorders of coagulation, drug toxicity, athero-
sclerotic and embolic disease, malignancy, and secondary vascu-
litides associated with other autoimmune diseases.
Henoch-Schönlein Purpura
Patients with HSP have lower extremity purpura, arthritis (typi-
cally of the large joints), abdominal pain, and renal disease at
presentation (Fig. 81-3). In children, arthritis and abdominal
pain affect about 75% of patients; the gastrointestinal manifesta-
tions may precede the purpura by up to 2 weeks and include
hematochezia. The most common renal manifestation is micro-
scopic hematuria with or without proteinuria.
The diagnosis of HSP is most often based on clinical and labo-
ratory evidence, although skin or renal biopsy revealing IgA
deposition may be helpful in solidifying the diagnosis. By clas-
sification criteria from the EULAR, patients with HSP must have
purpura or petechiae with lower limb predominance and at least
one of the following: arthritis or arthralgias; abdominal pain;
histopathology demonstrating IgA deposition; and renal involve-
ment. The differential for HSP includes other causes of abdomi-
nal pain, other causes of purpura in childhood, and hypersensitivity
vasculitis. Hypersensitivity vasculitis is also a small vessel vascu-
litis that may occur in both children and adults and may be idio-
pathic or triggered by infections or drug exposures. It typically
manifests as an isolated cutaneous leukocytoclastic vasculitis that
is self-limited with treatment of the underlying cause (e.g., treat-
ment of infection, discontinuation of drug culprit).
Medium Vessel Vasculitis
Polyarteritis Nodosa
The most common organ systems affected in PAN are the gas-
trointestinal, renal, and nervous systems. Mesenteric aneurysms
or stenoses resulting in gut ischemia lead to symptoms of
abdominal pain or “intestinal angina” (pain after eating). Renal
796 Section XIV  Musculoskeletal and Connective Tissue Disease
artery aneurysms or stenoses result in hypertension or renal
dysfunction, rather than glomerulonephritis as in MPA. Neu-
rologic involvement may manifest as mononeuritis multiplex.
Orchitis may be seen, manifesting as acute testicular pain.
Anemia, elevated erythrocyte sedimentation rate or C-reactive
protein or both, and hypertension (if renal artery involvement
is present) are common. As in all vasculitides, constitutional
symptoms may also be present.
The diagnosis of PAN is made based on angiographic or
biopsy findings in the appropriate clinical setting. ANCA typi-
cally are absent in PAN. A work-up for infection, including
tests for hepatitis B and C and HIV, is warranted, given their
known associations with PAN. The differential diagnosis includes
MPA and mixed cryoglobulinemic vasculitis. The latter vasculitis
shares many clinical features with PAN, including peripheral
neuropathy, arthralgias, myalgias, purpura, and association with
hepatitis C.
Kawasaki Disease
The clinical presentation of Kawasaki disease includes fever
lasting longer than 5 days, conjunctival injection, oropharyngeal
changes (strawberry tongue, mucous membrane desquamation),
peripheral extremity changes (cutaneous desquamation), poly-
morphous rash, and cervical lymphadenopathy. Arthralgias,
abdominal pain, hepatitis, aseptic meningitis, and uveitis have
also been reported. Coronary artery aneurysms, one of the most
serious complications of this vasculitis, appear within the first 4
weeks after onset of disease and are often detectable with echo-
cardiography. Although areas of ectasia and small aneurysms may
regress, larger aneurysms often persist and can result in coronary
ischemia at any time after development, even into adulthood.
Kawasaki disease is a triphasic disease, consisting of an acute
febrile period lasting up to 14 days, a subacute phase of 2 to 4
weeks, and a convalescent phase that can last months to years. In
the acute phase, the fever is persistent and high (>38.5° C) and
is minimally responsive to antipyretics.
The differential diagnosis is wide and includes viral infections,
toxin-mediated illnesses (e.g., toxic shock syndrome, scarlet
fever), systemic juvenile idiopathic arthritis, hypersensitivity
reactions, and drug reactions (e.g., Stevens-Johnson syndrome).
Large Vessel Vasculitis
Giant Cell Arteritis or Temporal Arteritis
At presentation, patients with GCA most commonly have new
continuous headache, jaw claudication, visual disturbances (e.g.,
amaurosis fugax, diplopia), fatigue, and arthralgias. They are
usually older than 50 years of age, have tender or thickened tem-
poral arteries, and have an elevated erythrocyte sedimentation
rate (>50 mm/hour by the Westergren method). Disease onset
may be insidious or acute. Blindness due to anterior ischemic
optic neuropathy occurs in 10% to 15% of patients with GCA and
can occur at disease onset. Given the association between GCA
and PMR, patients with PMR should be educated regarding signs
and symptoms of GCA, and patients with GCA should be moni-
tored for symptoms of PMR.
The diagnosis of GCA is often made by a biopsy of the
superficial temporal artery. It is important to obtain a sufficient
length of tissue (2 to 3  cm) because the vasculitis can have
“skip lesions.”
Takayasu’s Arteritis
The typical clinical manifestations of TAK include a systolic
blood pressure difference of greater than 10 mm Hg between the
arms, decreased brachial or radial artery pulses, bruits auscultated
over the subclavian arteries or aorta, claudication of extremities,
neck or jaw pain, headache, dizziness, hypertension, constitu-
tional symptoms, arthralgias, and myalgias.
The diagnosis of TAK is often based on vascular imaging
studies that demonstrate long, tapering stenotic lesions or
aneurysmal lesions in the aorta and primary branches. The
differential diagnosis includes syphilis, spondyloarthropathies,
rheumatoid arthritis, inflammatory bowel disease, and connec-
tive tissue disorders. Vascular imaging studies including com-
puted tomographic angiography and magnetic resonance
angiography are typically performed for both diagnosis and
disease surveillance.
  TREATMENT AND PROGNOSIS
Small Vessel Vasculitis
ANCA-Associated Vasculitides
Glucocorticoids, often with other agents, are uniformly used to
induce and maintain remission in AAV. They are typically initi-
ated at a prednisone equivalent dose of 1 mg/kg/day with or
without pulse methylprednisolone (1 g IV daily × 3 days), fol-
lowed by a gradual taper over approximately 6 to 12 months. In
addition, the standard. In addition, the standard of care in both
GPA and MPA has traditionally been cyclophosphamide, either
oral or intravenous, for 3 to 6 months. This has been reported to
yield remission rates varying from 30% to 93% in GPA and from
75% to 89% in MPA.
Rituximab, an anti-CD20 chimeric monoclonal antibody that
depletes B cells, was shown to be noninferior to cyclophospha-
mide in remission induction for AAV in several randomized con-
trolled trials (RITUXVAS and RAVE trials).
Plasmapheresis, or plasma exchange therapy, is often used in
combination with remission induction therapy in patients with
life-threatening disease such as alveolar hemorrhage, or rapidly
progressive glomerulonephritis (pulmonary-renal syndrome).
The MEPEX study was a randomized controlled trial comparing
plasmapheresis with high-dose methylprednisolone for severe
renal vasculitis. Plasmapheresis was shown to be superior to
methylprednisolone in reducing the number of patients remain-
ing dependent on dialysis.
For limited (early) GPA, such as disease confined to the upper
respiratory tract, methotrexate may be used for remission
induction, rather than cyclophosphamide; this conclusion was
supported by level I evidence in the NORAM trial. Trimethoprim-
sulfamethoxazole was shown in two randomized controlled trials
to be helpful in preventing relapses after remission induction
in GPA.
Remission maintenance therapies in AAV (level I evidence)
include methotrexate, azathioprine, or mycophenolate mofetil.
Because there are known risks of bladder cancer, hemorrhagic
cystitis, and bone marrow suppression with cumulative use of

cyclophosphamide, it no longer has a role in remission mainte-
nance in AAV.
Although AAVs were once considered diseases with consider-
able mortality (80% at 2 years if left untreated), the prognosis has
improved significantly over the last 30 years because of improved
treatments. Patient survival is now reported to be as high as 45%
to 91% at 5 years. Among AAV patients with renal involvement
at presentation, 20% develop end-stage renal disease within 5
years.
Henoch-Schönlein Purpura
In mild cases, the therapy for HSP is simply supportive care (i.e.,
hydration and analgesics). However, glucocorticoids are com-
monly used to hasten the resolution of symptoms; early use of
glucocorticoids has been associated with improved outcomes,
especially when there is severe gastrointestinal involvement. In
life-threatening cases and in severe acute renal failure, additional
immunosuppressive agents or plasmapheresis may be consid-
ered. The prognosis of HSP is generally good, with fewer than 1%
of patients developing end-stage renal disease.
Medium Vessel Vasculitis
Polyarteritis Nodosa
Treatment of PAN includes glucocorticoids or nonsteroidal anti-
inflammatory drugs (NSAIDs) or both. If disease is severe and
persistent or relapsing, additional immunosuppressive agents are
used, such as cyclophosphamide (especially for gastrointestinal
or cardiac involvement), methotrexate, colchicine, or intravenous
immunoglobulin (IVIG). In cases of PAN associated with hepa-
titis B or C, antiviral therapy is required not only for attaining
control of the viral infection but also for treatment of the associ-
ated vasculitis itself. Corticosteroids and cyclophosphamide have
improved patient outcomes, and the 1-year survival rate is now
85%. Prognosis is typically worse with more systemic complica-
tions such as renal or neurologic involvement.
Kawasaki Disease
Treatment of Kawasaki disease includes high-dose aspirin (80 to
100 mg/kg/day) for the first 48 hours, then 3 to 5 mg/kg/day.
IVIG is standard therapy and has significantly decreased the inci-
dence of coronary artery aneurysm complications in this disease.
The initial IVIG dose is 2 g/kg within the first 10 days after pre-
sentation, with at least one repeat dose typically given if the first
IVIG dose fails to improve the child’s condition. The prognosis
of Kawasaki disease, if promptly treated, is good; however,
approximately 15% to 25% of patients develop coronary artery
aneurysms that increase morbidity and mortality.
Large Vessel Vasculitis
Giant Cell Arteritis or Temporal Arteritis
Glucocorticoids are the cornerstone of therapy in GCA. To
prevent vision loss, treatment should be instituted immediately
(within 24 hours) if clinical suspicion for GCA is high or if
visual disturbances are present. The initial dose of glucocorti-
coids is typically 1  mg/kg/day with a gradual taper. Most
patients require a glucocorticoid treatment duration of 1 to 2
Chapter 81  Systemic Vasculitis 797
years, but it may be longer, especially in those with symptoms
of PMR . In PMR without GCA, lower doses of glucocorticoids
(10 to 20  mg/day of prednisone equivalent) are effective and
provide prompt clinical response.
If patients experience relapse with glucocorticoid tapering,
other immunosuppressive agents may be used. Methotrexate was
shown in a meta-analysis of three randomized controlled trials to
be a beneficial adjunctive agent in reducing risks of first and
second relapses in GCA, with a significant decrease in the cumu-
lative dose of glucocorticoids. Low-dose aspirin is an important
adjunctive therapy in protecting against cranial ischemic events
(level II evidence from two large retrospective studies). Biologic
agents in GCA are still under investigation.
Takayasu’s Arteritis
Glucocorticoids are also the cornerstone of therapy for TAK;
they are typically initiated at a dose of 0.5 to 1 mg/kg/day.
Although most patients respond to the initial dose, relapses occur
in more than 50% of patients during glucocorticoid tapering.
Hence, steroid-sparing agents are often used to aid in maintaining
disease remission. The most commonly used steroid-sparing
agents are methotrexate and azathioprine. In TAK, unlike in
GCA and PMR, the tumor necrosis factor (TNF) inhibitors have
shown promise in treating refractory disease. As in GCA, low-
dose aspirin is believed to play a beneficial adjunctive role in
preventing ischemic complications.
Revascularization interventions are often indicated in patients
with TAK whose presenting symptoms include cerebrovascular
disease, coronary artery disease, moderate to severe aortic regur-
gitation, renovascular hypertension, progressive limb claudica-
tion, or progressive aneurysm enlargement. Elective intervention
should be performed when the disease is quiescent.
In both GCA and TAK, aortitis—a common manifestation of
large vessel involvement—can lead to an increased risk of aortic
aneurysm and subsequent dissection and rupture. In both GCA
and TAK, disease flares occur in most patients, rendering them
chronic, progressive and relapsing conditions.
  ADDITIONAL CONSIDERATIONS IN TREATMENT
Immunosuppressive therapy is associated with an increased risk
of infection. Patients receiving combination therapy with moder-
ate- to high-dose glucocorticoid (>20 mg/day of prednisone
equivalents) and another immunosuppressive agent should also
receive prophylaxis for Pneumocystis jiroveci pneumonia (previ-
ously known as PCP). Furthermore, infections can often mimic
or result in flares of systemic vasculitis. Glucocorticoid therapy
should never be discontinued abruptly, even in the setting of
infection, because of the risk of adrenal crisis or disease relapse
or both. In most cases, other immunosuppressive agents should
be discontinued if infection is suspected or diagnosed.
Glucocorticoid therapy is a common cause of bone loss
(osteopenia, osteoporosis). Because significant bone loss can
occur even within the first 6 months of therapy, calcium and
vitamin D supplementation should be initiated, and a baseline
bone density study should be obtained. Consideration should be
given to additional bone protection therapies (e.g., bisphospho-
nates). Methotrexate and cyclophosphamide are teratogenic, and
cyclophosphamide may result in premature ovarian failure. These
798 Section XIV  Musculoskeletal and Connective Tissue Disease
factors must be considered when choosing therapies for women
of child-bearing age. Immunosuppressive agents also can be asso-
ciated with bone marrow suppression and with additional long-
term risks such as malignancy.
Acknowledgments
The author wishes to acknowledge the assistance of Kathleen
Maksimowicz-McKinnon, MD and Kelly Liang, MD.
For a deeper discussion on this topic, please see
Chapter 270, “The Systemic Vasculitides,” in Goldman-
Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Bloch DA, Michel BA, Hunder GG, et al: The American College of Rheumatology
1990 criteria for the classification of vasculitis: patients and methods, Arthritis
Rheum 33:1068–1073, 1990.
Hoffman GS, Cid MC, Rendt-Zagar KE, et al: Infliximab for maintenance of
glucocorticosteroid-induced remission of giant cell arteritis: a randomized
trial, Ann Intern Med 146:621–630, 2007.
Hunder GG, Bloch DA, Michel BA, et al: The American College of Rheumatology
1990 criteria for the classification of giant cell arteritis, Arthritis Rheum
33:1122–1128, 1990.
Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides:
proposal of an international consensus conference, Arthritis Rheum 37:187–
192, 1994.
Jones RB, Tervaert JW, Hauser T, et al: Rituximab versus cyclophosphamide in
ANCA-associated renal vasculitis, N Engl J Med 363:211–220, 2010.
Specks U, Merkel PA, Seo P, et al: Efficacy of remission-induction regimens for
ANCA-associated vasculitis, N Engl J Med 369:417–427, 2013.
Stone JH, Merkel PA, Spiera R, et al: Rituximab versus cyclophosphamide for
ANCA-associated vasculitis, N Engl J Med 363:221–232, 2010.
Weiss PF: Pediatric vasculitis, Pediatr Clin North Am 59:407–423, 2012.
 82 
Crystal Arthropathies
Ghaith Noaiseh

Gout
Only about 20% of hyperuricemic patients develop gout
  INTRODUCTION during their lifetime. Additional factors, which are still poorly
The term gout refers to a heterogeneous group of diseases that defined, are required for crystal formation.
result from deposition of monosodium urate (MSU) crystals in The total body uric acid pool is closely related to the net purine
joints and soft tissue. Gout typically begins as an intermittent accumulation, which comes from three sources: dietary purine
monoarthritis in the lower extremities; it may progress over time intake, nucleic acid release from ongoing cell degradation, and de
into a chronic, deforming and debilitating arthritis affecting novo synthesis (endogenous purine biosynthesis). About two
almost any peripheral joint. thirds of the daily excretion of uric acid occurs in the kidneys; the
Gout is associated with hyperuricemia, which is defined as a rest is eliminated by the gut. The balance between these mecha-
serum urate level greater than 6.8 mg/dL. Above that concentra- nisms determines total uric acid body stores.
tion, urate can form uric acid crystals in normal physiologic Hyperuricemia is caused by an imbalance between synthesis
conditions. and elimination. Renal underexcretion is the cause for approxi-
mately 90% of hyperuricemia cases (Table 82-1). In the remain-
  EPIDEMIOLOGY ing 10%, hyperuricemia is caused by uric acid overproduction
More than 6 million adults in the United States have had gout (>1000 mg of uric acid in a 24-hour urine collection while on a
attacks. The incidence and prevalence are markedly increasing. standard Western diet) or by a combination of overproduction
This is thought to be related to the aging of the population, with renal underexcretion.
increased use of certain medications such as diuretics, and Figure 82-1 summarizes the de novo biosynthesis and salvage
increasing prevalence of comorbidities such as obesity, hyperten- pathways of purine metabolism. Abnormalities in the activities of
sion, renal disease, cardiovascular disease, and metabolic key enzymes can lead to increased serum uric acid levels and
syndrome. development of gout. Overall, enzymatic deficiencies account for
The incidence and prevalence are proportional to age and the a small fraction of uric acid overproduction; most cases of uric
degree and duration of serum urate elevation. Men are three to
six times more likely to have gout than women, but the sex dispar-
ity decreases with aging, in part due to the declining levels of TABLE 82-1  CAUSES OF HYPERURICEMIA
estrogen in postmenopausal women. Estrogen has a uricosuric URATE OVERPRODUCTION URATE UNDEREXCRETION
effect, and this also explains why gout is uncommon in premeno- METABOLIC DISORDERS Renal insufficiency
pausal women. HGPRT deficiency (homozygous or
Volume depletion
Metabolic acidosis (lactic acidosis
heterozygous)
and ketoacidosis)
PRPP synthetase hyperactivity
Obesity
  PATHOGENESIS G6PD deficiency
Ethanol
Glycogen storage diseases
Pathophysiology of Hyperuricemia Medications: low dose salicylate,
OTHERS diuretics (thiazides, loop
Uric acid is the end product of purine metabolism in humans. Myeloproliferative and diuretics), cyclosporine,
Unlike many other species, humans lack the enzyme uricase, lymphoproliferative disorders tacrolimus, l-dopa, ethambutol
Familial juvenile hyperuricemic
which catalyzes the conversion of uric acid into allantoin, a very Erythropoietic disorders (hemolytic
nephropathy
anemia, megaloblastic anemia,
soluble metabolite. Most individuals maintain uric acid levels sickle cell disease, thalassemia, Medullary cystic kidney disease
between 4 and 6.8 mg/dL and a total body uric acid pool of other hemoglobinopathies) Lead nephropathy
approximately 1000 mg. However, accumulation of uric acid can Solid tumors
Diffuse psoriasis
occur and may lead to supersaturation of urate in blood. Serum Ethanol (particularly beer)
uric acid levels greater than 6.8 mg/dL under normal pH and Medications: cyctotoxic agents,
temperature may result in the precipitation of MSU crystals in nicotinic acid
Shellfish, organ meat, red meat
joints, soft tissues, and other organs. Urate crystallization is a Fructose
critical step in the progression from asymptomatic hyperurice- Obesity
mia to clinical gout. Unlike soluble urate molecules, MSU crys- HGPRT, Hypoxanthine-guanine phosphoribosyltrasferase; PRPP, 5′-phosphoribosyl
tals are a potent promoter of acute inflammation. 1-pyrophosphate; G6PD, glucose-6-phosphate dehydrogenase.

799
800 Section XIV  Musculoskeletal and Connective Tissue Disease
Ribose-5-PO4 + ATP
DNA, RNA PRPP + glutamine DNA, RNA
Adenylic acid Inosinic acid Guanylic acid
Adenosine Inosine Guanosine
Adenine Hypoxanthine Guanine
PRPP Xanthine PRPP
PRPP synthetase
APRT, HGPRT Uric acid
Xanthine oxidase
Feedback inhibition
De novo synthesis pathways
Salvage pathways
FIGURE 82-1  Biochemical pathways of purine synthesis, intercon-
version, and degradation. APRT, Adenine phosphoribosyl transferase;
ATP, adenosine triphosphate; HGPRT, hypoxanthine-guanine phospho-
ribosyltransferase; PRPP, 5′-phosphoribosyl 1-pyrophosphate.
acid overproduction result from increased reutilization of purine
bases through salvage pathways (see Fig. 82-1). The de novo syn-
thesis of purine is driven by the enzyme 5′-phosphoribosyl
1-pyrophosphate (PRPP) synthetase. In PRPP synthetase over-
activity, overproduction of PRPP increases purine production.
In salvage pathways, tissue-derived intermediate purine products
(hypoxanthine, guanine, and adenine) are reutilized rather than
undergoing further degradation to xanthine and uric acid. Defi-
ciencies of hypoxanthine-guanine phosphoribosyltrasferase
(HGPRT) activity result in impaired purine salvage and increased
substrate for uric acid generation (Lysch-Nyhan syndrome and
Kelley-Seegmiller syndrome).
Diseases associated with increased cell turnover (e.g., hemoly-
sis, ineffective hematopoiesis, psoriasis) or with other causes of
enhanced purine nucleotide breakdown (ethanol or fructose
ingestion) can lead to hyperuricemia. Purine-rich foods comprise
a significant portion of the daily purine load and can worsen
hyperuricemia. On the other hand, consumption of low-fat dairy
products is associated with reduced serum urate levels and may
decrease the risk of gout.
A very small proportion of serum urate is bound to plasma
proteins; therefore, urate is almost completely filtered in the
glomeruli. Subsequent reabsorption and secretion occur through
various organic acid transporters located on the luminal side of
the proximal convoluted tubule epithelium. Only about 10% of
the total filtered uric acid is excreted in the urine.
In addition to the bidirectional transport of uric acid, organic
acid transporters are also responsible for eliminating other
organic acids and certain medications. The function of these
transporters is affected by certain medications, including thia-
zides, low-dose aspirin, and cyclosporine, leading to decreased
uric acid excretion and hyperuricemia. Conversely, medications
such as probenecid and losartan, when excreted in the tubular
lumen, exert their uricosuric effect by displacing uric acid from
the transporter and increasing uric acid excretion. Certain genetic
mutations affecting these transporters may lead to uric acid
underexcretion. Renal insufficiency can cause hyperuricemia
though decreased uric acid filtration.
Pathophysiology of Acute Gouty Attack
In some patients with prolonged hyperuricemia, tissue deposits
of MSU crystals, called microtophi, form in the synovium and on
the surface of cartilage. During an acute attack, microtophi break
apart, shedding a large number of MSU crystals into the joint
space and activating synovial macrophages and fibroblasts that
phagocytize the crystals. This, in turn, leads to the activation of a
cytosolic multiprotein complex, the NALP3 (NACHT, LRR,
and PYD domains–containing protein 3) inflammasome, which
generates interleukin-1β. Interleukin-1β production activates
bloodstream neutrophils and endothelial cells, allowing neutro-
phils to cross the capillary endothelium into the joint space.
Inflammation is propagated by further activation of the newly
recruited neutrophils, which leads to the clinical signs of inflam-
mation characteristic of the acute gouty attack.
MSU crystals undergo clearance by inflammatory cells that
then undergo apoptosis. This, along with other mechanisms,
eventually leads to resolution of the acute inflammatory process,
typically after 10 to 14 days. Even after complete resolution of
symptoms, a low-grade level of inflammation (intercritical
inflammation) can persist in the otherwise asymptomatic joint.
This inflammation may become clinically apparent in long-
standing gout, and it contributes to chronic synovitis, cartilage
loss, and bony erosions.
  CLINICAL FEATURES
Gout has three stages: asymptomatic hyperuricemia, acute inter-
mittent gout, and chronic gout.
Acute Gouty Attacks
The classic picture of acute gout is rapid development of an
inflammatory arthritis involving one (or occasionally two) joints.
Severe pain, erythema, swelling and exquisite tenderness typi-
cally occur. The most commonly involved joints are the first
metatarsophalangeal joint (podagra), followed by the joints of
the ankle, midfoot, and knee. The pain intensifies over 8 to
24 hours. Acute attacks usually resolve, even without therapy,
within 5 to 14 days. The clinical resolution is complete, and
the patient is asymptomatic between attacks. This clinical picture
can be easily confused with that of septic arthritis or cellulitis,
because many patients can mount an intense systemic inflam-
matory response with fever, chills, and elevated inflammatory
markers.
Attack-provoking factors include use of diuretics, alcohol,
surgery, trauma, and consumption of foods containing high
purine levels. Each of these can cause fluctuation in serum urate
levels. Initiation of urate-lowering therapy can trigger attacks in
the early phase by the same mechanism.
Subsequently, involvement of the upper extremities can occur,
affecting the small joints of the hands, wrists, and elbows.
Chronic Gout
Transition to the chronic phase can occur if hyperuricemia is
inadequately treated. This phase, called chronic gout (also referred
 Chapter 82  Crystal Arthropathies 801

to as chronic tophaceous gout or chronic advanced gout), typically

develops 10 or more years after the onset of acute attacks. This
phase is characterized by less severe attacks compared with the
early flares and incomplete resolution of symptoms between
flares as the patient continues to experience some baseline joint
pain.
The characteristic lesion of chronic gout is the tophus, a pal-
pable collection of MSU crystals in soft tissue or joints. It is
detected in about 75% of patients who have had gout for more
than 20 years. The severity and duration of hyperuricemia deter-
mine the likelihood of tophus development. Although the ears,
fingers, wrist, and olecranon bursa are the typical locations, tophi
can occur anywhere in the body.
  DIAGNOSIS
The typical presentation of acute gouty arthritis in a characteris-
tic joint distribution is strongly suggestive of the diagnosis, par-
ticularly if there is a history of similar attacks that completely
resolved. Nevertheless, the diagnosis should be confirmed by
aspiration of the involved joint. This is a critical step to rule out
septic arthritis and other crystalline arthropathies such as CPPD
deposition disease, which is caused by deposits of calcium pyro-
phosphate dihydrate (CPPD) crystals in the cartilage (see later
discussion). During acute attacks, intracellular, strongly negative
birefringent, needle-shaped MSU crystals are typically identified
by polarized compensated microscopy. MSU crystals can also be
demonstrated in tophus aspiration (Fig. 82-2A).
Bacterial infection can coexist with urate crystals in the syno-
vial fluid; Gram stain and culture should be performed. Aspirated
fluid appears cloudy, and synovial fluid analysis shows inflamma-
tory fluid (>2000 white blood cells per microliter) with as many
as 50,000 to 100,000 cells/µL or even more). Serum uric acid is
not a diagnostically reliable test during acute flares because the
serum urate level may be normal or even low. Laboratory testing
may reveal leukocytosis and elevated inflammatory markers, both
of which are nonspecific. Between attacks, MSU crystals can
often be demonstrated in previously inflamed joints. This can
provide support for a diagnosis of gout when the patient is
asymptomatic.
Radiologic Features
During an acute attack, a plain radiograph may only show soft
tissue swelling. After many years of the disease and during the
chronic phase, well defined, “punched out” juxtaarticular ero-
sions with overhanging bony edges and sclerotic margins may be
seen. The joint space is preserved until late in the course of the
disease. Soft tissue masses may be detected in patients with tophi.
Periarticular osteopenia is absent. Ultrasound can be a promising
tool in the diagnosis and management of gout.
Gout in Transplantation Patients
Hyperuricemia occurs much more frequently in transplantation
patients using cyclosporine than in the normal population. Com-
pared to patients with classic gout, these patients exhibit a signifi-
cantly shorter period of asymptomatic hyperuricemia (0.5 to 4
years versus 20 to 30 years), a shorter stage of acute intermittent
gout (1 to 4 years versus 10 to 15 years), and rapid development
of tophi as early as 1 year after transplantation. Gouty attacks can
be atypical and less severe, in part because of the concomitant
use of prednisone.
  DIFFERENTIAL DIAGNOSIS
Acute gouty arthropathy should be distinguished from septic
arthritis and other crystal-induced arthropathies such as CPPD
deposition disease. The onset of acute CPPD arthropathy is
usually less abrupt, and attacks tend to last longer, up to 1
month or more. Attacks occur more often in large joints such
as the knee and wrist. Forms of spondyloarthritis including
reactive arthritis, psoriatic arthritis, ankylosing spondylitis, and
inflammatory bowel related arthritis can also manifest with
monoarticular arthritis. In these disorders, synovial fluid is
inflammatory, with a leukocyte count usually in the range of
10,000 to 50,000/µL, but crystals are absent and fluid culture
is negative.
In its chronic phase, gout can be confused with rheumatoid
arthritis and tophi can be confused with rheumatoid nodules.
Aspiration of chronically inflamed joints or a tophus can help in
distinguishing the two entities.

A B
MSU CPPD
FIGURE 82-2  Polarized microscopy image of (A) strongly negative birefringent monosodium urate crystals and (B) weakly positive calcium pyro-
phosphate dihydrate crystals. Arrows indicate axis of polarization. (A, Modified from the ACR Slide Collection on the Rheumatic Diseases. Available
at http://images.rheumatology.org/. Accessed January 2015; B, Modified from Saadeh C, Diamond HS: Calcium pyrophosphate deposition disease.
Available at: http://emedicine.medscape.com/article/330936-overview#showall. Found under “Multimedia Library.” Accessed January 2015.)
802 Section XIV  Musculoskeletal and Connective Tissue Disease
  TREATMENT
Management of Acute Gouty Attack
The goal of management is to quickly control the inflammation
and pain. Affected joints should be rested. Application of ice to
the joint is usually helpful in reducing symptoms, but it is rarely
sufficient to adequately control symptoms.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibu-
profen, naproxen, indomethacin, and diclofenac are typically
used, and all seem to be equally effective. Full doses of NSAIDs
should be initiated immediately, and a treatment duration of 7 to
10 days may be necessary for complete resolution of symptoms.
NSAIDs are inappropriate in patients with peptic ulcer disease,
inflammatory bowel disease, or renal insufficiency, and they must
be used with caution in patients who are at risk for cardiovascular
events.
Oral colchicine can be effective if it is used early in an acute
attack (i.e., within the first 24 to 48 hours). A commonly pre-
scribed dose is 1.2 mg, followed by 0.6 mg 4 hours later for the
first day, followed by dose tapering until the attack is resolved.
The drug should be stopped if nausea or loose stool occurs. Use
of intravenous colchicine is discouraged because of the unaccept-
able risk of bone marrow suppression. Intraarticular corticoste-
roid injection is a very effective therapy for patients with
monoarticular or oligoarticular disease in whom other systemic
therapies need to be avoided. Enteral or parenteral glucocortico-
steroids are effective in patients with renal insufficiency, intoler-
ance to NSAIDs or colchicine, or treatment resistance. This
approach is usually reserved for polyarticular flares when intraar-
ticular injection is not practical (i.e., too many involved joints).
A common starting corticosteroid dose is prednisone, 30 to
50 mg daily.
Urate-lowering therapy (ULT) should not be interrupted
during acute attacks. Patients with established disease should be
encouraged to maintain a supply of their medication for acute
attacks and to start it promptly at the onset of typical symptoms;
this may shorten the duration of attacks.
Management of Intercritical  
and Chronic Gout
Urate-Lowering Therapy
The aim of chronic treatment is to prevent recurrent attacks and
to minimize joint damage by depleting tophaceous deposits in
joints and soft tissue. This is achieved by lowering the uric acid
level to less than 6 mg/dL. A target serum uric acid concentration
of less than 5 mg/dL should be considered in patients with
chronic tophaceous gout because it can result in a faster, more
effective reduction in tophus size and flare frequency. Indications
for ULT in patients with gout include two or more attacks in a
single year, recurrent nephrolithiasis, and presence of tophi or
chronic gouty arthritis.
ULT agents are divided into three categories: those that
decrease uric acid production (uricostatic), those that increase
renal excretion (uricosuric), and those that metabolize uric acid
(uricolytic). The optimal duration of ULT is not known, and
lifelong therapy is usually recommended. ULT is typically started
after resolution of an acute attack.
Uricostatic Therapy
Allopurinol and febuxostat are xanthine oxidase inhibitors that
prevent urate formation. They are effective in both overproducers
and undersecretors of uric acid.
Allopurinol remains the first-line and most commonly used
ULT agent, particularly in patients with chronic renal insuffi-
ciency, uric acid stones, or uric acid overproduction. If renal
function is normal, a starting dose of 100  mg daily is recom-
mended because higher doses may increase the risk of allopurinol
hypersensitivity, a potentially lethal complication. The risk of
early flares may also be increased with higher doses. It is rec-
ommended that the allopurinol dose be titrated up by 100  mg
increments every 2 to 5 weeks until the uric acid goal is reached.
The maximal dose is 800  mg/day. Adverse events include rash
(2%), hepatitis, vasculitis, eosinophilia, and bone-marrow
suppression.
Allopurinol hypersensitivity reaction can be fatal, and the risk
may be higher with concomitant use of thiazides and in patients
with penicillin allergy. Fever, severe exfoliative dermatitis, eosin-
ophilia, and hepatic and renal failure can occur. If the uric acid
goal is not achieved with allopurinol titration, or if side effects
occur, then febuxostat may be used.
If the target uric acid level is not achieved with monotherapy,
combination therapy with a uricosuric agent and a xanthine
oxidase inhibitor may be considered.
Uricosuric Therapy
In the United States, probenecid is the only available uricosuric
agent. It may be used as a first-line ULT in uric acid undersecre-
tors (<600 mg in a 24-hour urine collection), but it is ineffective
in patients with renal insufficiency (glomerular filtration rate
<50 mL/minute) and is contraindicated in patients with nephro-
lithiasis. Patients should maintain high urine volume by drinking
at least 1.5 L of fluid daily.
Uricolytic Therapy
Pegloticase (pegylated recombinant uricase), administered intra-
venously every 2 weeks, is considered for patients whose gout is
refractory to conventional ULT.
Rasburicase, another recombinant uricase, is used to prevent
tumor lysis syndrome but has no role in the management
of gout.
Non–Urate-Lowering Prophylactic Therapy
Anti-inflammatory prophylaxis using low-dose colchicine or
NSAIDs is usually recommended in conjunction with ULT to
decrease the risk of flares that often accompany initiation of ULT.
Prophylactic treatment is usually continued for 6 months after
the serum uric acid goal is achieved.
Lifestyle Modifications and Education
A patient newly diagnosed with gout should be evaluated for
potentially modifiable risk factors and associated illnesses such
as obesity, hypertension, and hyperlipidemia. Decreased con-
sumption of high-purine foods (e.g., shellfish, liver, sweetbreads)
and fructose-containing beverages, as well as reduced alcohol
intake, should be recommended. Diuretics should be avoided if
possible.
 Chapter 82  Crystal Arthropathies 803
Treatment of Hyperuricemia in
Patients Without Gout
Allopurinol and rasburicase have been used for prevention and
treatment of tumor lysis syndrome associated with hyperurice-
mia occurring after chemotherapy. Apart from this indication,
there is no evidence to support their use for the routine treatment
of asymptomatic hyperuricemia.
  CALCIUM PYROPHOSPHATE DIHYDRATE
DEPOSITION DISEASE
Calcium pyrophosphate dihydrate (CPPD) deposition disease
is a clinically heterogeneous disorder that is characterized by
the presence of intraarticular CPPD crystals. These crystals are
deposited primarily in the cartilage, in the normally unmineral-
ized pericellular matrix of hyaline and fibrocartilage. Calcification
of the cartilage is promoted by alterations in the metabolism
of inorganic pyrophosphate (PPi) and extracellular matrix
leading to extracellular accumulation of PPi, which is necessary
to the formation of CPPD crystals. Crystals are phagocytized
by resident synovial macrophages, activating the intracellular
NALP3 inflammasome complex and leading to recruitment and
influx of neutrophils into the joint space.
CPPD deposition disease typically affects the elderly popula-
tion. Up to 50% of individuals older than 85 years of age have
radiographic evidence of CPPD crystal accumulation in cartilage
(chondrocalcinosis), but most are asymptomatic. The most com-
monly involved joints are the knee menisci and the triangular
fibrocartilage of the wrist.
The clinical course of CPPD deposition disease may be asymp-
tomatic, acute, subacute, or chronic. The most common clinical
manifestation, occurring in more than 50% of patients, is a pecu-
liar type of osteoarthritis called pseudo-osteoarthritis; it is a non-
inflammatory arthritis involving joints not typically affected by
osteoarthritis, such as the wrist, shoulder, ankle, and metacarpo-
phalangeal joints. Asymptomatic disease may be an incidental
finding on radiographs showing chondrocalcinosis. Pseudogout
is an acute monoarthritis similar in presentation to the acute
gouty attack. A chronic symmetric polyarticular arthritis pattern
resembling rheumatoid arthritis and a severe destructive arthrop-
athy that mimics neuropathic arthritis on radiographs may be
seen.
It is uncommon for CPPD deposition disease to affect
patients younger than 50 years of age, unless the disease is
familial or related to a metabolic abnormality (e.g., hyperpara-
thyroidism). Acute pseudogout attacks may be precipitated by
trauma, surgery (particularly parathyroidectomy for hyperpara-
thyroidism), or severe medical illness. Administration of intraar-
ticular viscosupplementation may also trigger a CPPD flare.
Attacks are usually monoarticular or oligoarticular; if left
untreated, they may last from a few days to a few months.
Involved joints are swollen, with variable erythema and warmth.
Fever, elevated erythrocyte sedimentation rate, and leukocytosis
can occur.
The diagnosis is confirmed by demonstration in synovial fluid
of intracellular rod- or rhomboid-shaped crystals with weak posi-
tive birefringence when examined by compensated polarized
light microscopy (see Fig. 82-2B). These crystals can be difficult
to detect in some patients and are frequently missed in clinical
specimens.
The presence of chondrocalcinosis (radiodense deposits on
radiographs) is highly suggestive of the diagnosis in the appro-
priate clinical context. Joint aspiration should always be per-
formed to rule out the possibility of infection. Importantly, joint
infection can cause crystal shedding, leading to a concomitant
crystal-related inflammation. Synovial fluid is inflammatory
(>2000 white blood cells per microliter), with an average of
24,000  cells/µL.
Therapy for CPPD deposition disease is indicated for symp-
tomatic patients. There is no effective treatment to remove CPPD
deposits from synovium or cartilage. Treatment options include
intraarticular glucocorticoid injection of the affected joint or
joints. NSAIDs are effective, but their potential toxicity in elderly
patients may limit their utility. Severe polyarticular attacks may
require short courses of systemic corticosteroids. In patients with
frequent pseudogout attacks, prophylactic daily low-dose colchi-
cine may decrease the frequency.
  APATITE-ASSOCIATED ARTHROPATHY
Abnormal accumulation of apatite (basic calcium phosphate, or
BCP) may occur in hypercalcemic states and other illnesses.
Unlike MSU or CPPD crystals, individual BCP crystals are not
identifiable by polarized microscopy and can be seen only by
electron microscopy. The most common apatite-associated con-
dition is calcific periarthritis, which typically occurs in the
shoulder.
Milwaukee shoulder is an extremely destructive BCP-associated
arthropathy that occurs more commonly in elderly women. It is
characterized by a large noninflammatory effusion (i.e. <2000
white blood cells per microliter) and results in destruction of the
rotator cuff with subsequent marked instability and destruction
of glenohumeral cartilage.
Other manifestations include acute reversible inflammatory
arthropathies that resemble gout, referred to as  pseudo-
pseudogout, and ossifications along the anterolateral aspect of
spinal vertebrae, termed diffuse idiopathic skeletal hyperostosis
(DISH). Acute attacks of arthritis or bursitis may be self-limited.
Intraarticular or periarticular injection of corticosteroids or the
use of NSAIDs may shorten the duration and intensity of
symptoms.
  CALCIUM OXALATE DEPOSITION DISEASE
In calcium oxalate deposition disease, or oxalosis, calcium oxalate
crystals are deposited in tissue. In primary oxalosis, a hereditary
metabolic disorder, this deposition leads to nephrocalcinosis,
renal failure, and early mortality. Secondary oxalosis complicates
long-term hemodialysis or peritoneal dialysis; crystals are depos-
ited in bone, cartilage, synovium, and periarticular tissue. Crystal
shedding into the joint space may result in inflammatory arthritis
of peripheral joints. Chondrocalcinosis or soft tissue calcifica-
tions can be seen on plain radiographs. The presence of strongly
birefringent bipyramidal crystals is characteristic. Treatment
with NSAIDS, intraarticular corticosteroids, or colchicine usually
results in moderate improvement.
804 Section XIV  Musculoskeletal and Connective Tissue Disease
Acknowledgment
The author would like to thank Dr. Douglas Lienesch, MD, for
his valuable suggestions.
SUGGESTED READINGS
Choi HK: Epidemiology, pathology, and pathogenesis, chap 12. In Stone JH,
Crofford LJ, White PH, editors: Primer on the rheumatic diseases, ed 13, New
York, 2008, Springer.
Edwards L: Crystal deposition diseases, chap 28. In Goldman L, Schafer AI,
editors: Goldman’s Cecil Medicine, ed 24, Philadelphia, 2012, Saunders.
Ghosh P, Cho M, Rawat G, et al: Treatment of acute gouty arthritis in complex
hospitalized patients with anakinra, Arthritis Care Res 65:1381–1384, 2013.
Harrold L: New developments in gout, Curr Opin Rheumatol 25:304–309, 2013.
Jordan KM: Up-to-date management of gout, Curr Opin Rheumatol 24:145–
151, 2012.
Khanna D, Fitzgerald JD, Khanna PP, et al: 2012 American College of
Rheumatology guidelines for management of gout. Part 1: systematic nonphar-
macologic and pharmacologic therapeutic approaches to hyperuricemia,
Arthritis Care Res 64:1431–1446, 2012.
Khanna D, Khanna PP, Fitzgerald JD, et al: 2012 American College of
Rheumatology guidelines for management of gout. Part 2: therapy and anti-
inflammatory prophylaxis of acute gouty arthritis, Arthritis Care Res 64:1447–
1461, 2012.
Neogi T: Gout, N Engl J Med 364:443–452, 2011.

  DEFINITION AND EPIDEMIOLOGY
Osteoarthritis, also known as degenerative joint disease, is the
most common type of arthritis and musculoskeletal disease. It is
a disease of synovial joints that encompasses the pathophysio-
logic changes that result from alterations in joint structure due to
failed repair of joint damage and the individual’s experience of
illness, which is most often characterized by pain.
More than 26.9 million Americans older than 25 years have
some form of osteoarthritis, and the prevalence increases with
age. The radiographic prevalence varies by the joint involved.
Twenty-seven percent of adults and more than 80% of those
older than 65 years have evidence of hand osteoarthritis, and 37%
of those older than 60 years have radiographic evidence of knee
disease. The prevalence of symptomatic osteoarthritis is lower,
with 7% of adults having symptomatic hand disease and 17%
of those older than 45 years having symptomatic knee
involvement.
Hand and knee osteoarthritis is more common among women,
especially after 50 years of age, and it is more common among
African Americans. Nodal osteoarthritis, involving the distal and
proximal interphalangeal joints, is significantly more common in
women and among female first-degree relatives.
Osteoarthritis is associated with major morbidity and is the
leading cause of long-term disability in the United States. Lower
extremity osteoarthritis is the most common cause of difficulty
with walking or climbing stairs, preventing an estimated 100,000
elderly Americans from independently walking from their bed to
the bathroom.
Osteoarthritis has a large economic impact because of direct
medical costs (e.g., physician visits, laboratory tests, medications,
surgery) and indirect costs (e.g., lost wages, home care). With the
aging of the U.S. population, the burden of osteoarthritis is
expected to increase in the coming years.
For a deeper discussion of these topics, please see Chapter
262, “Osteoarthritis,” in Goldman-Cecil Medicine, 25th
Edition.
  PATHOLOGIC FACTORS
The causes of osteoarthritis are complex and heterogeneous, and
its pathophysiology is not well understood. The cardinal feature
is progressive loss of articular cartilage with associated remodel-
ing of subchondral bone. In normal cartilage, there is continuous
extracellular matrix turnover with a balance between synthesis
and degradation. In osteoarthritis, there is an imbalance of these
two processes, with an excess of matrix degradation that exceeds
83 
Osteoarthritis
C. Kent Kwoh
ongoing matrix synthesis. Excess degradation results from over-
production of catabolic factors such as proinflammatory cyto-
kines and reactive oxygen species.
Osteoarthritis is best defined as joint failure, a disease process
that involves the total joint, including the subchondral bone, liga-
ments, joint capsule, synovial membrane, periarticular muscles,
and articular cartilage. After bone trauma or repetitive injury,
joint failure may result from joint instability caused by muscle
weakness and ligamentous laxity; nerve injury and neuronal sen-
sitization or hyperexcitability, or both. Also contributing are low-
grade systemic inflammation caused by subacute metabolic
syndrome and local inflammation resulting from synovitis. Iden-
tifiable risk factors for osteoarthritis include biomechanical,
metabolic, and inflammatory processes; congenital or develop-
mental deformities of the joint that alter its shape; and genetic
factors. Age, sex, and race are prominent risk factors for
osteoarthritis.
Biomechanical contributors include repetitive or isolated joint
trauma related to certain occupations or physical activities that
involve repeated joint stress and predispose to early osteoar-
thritis. Altered joint shape may contribute to osteoarthritis
through biomechanical factors. Obesity may contribute biome-
chanically or systemically through subacute or overt metabolic
syndromes, both of which are associated with low-grade systemic
inflammation.
Metabolic disorders such as hemochromatosis, ochronosis,
Wilson’s disease, and Gaucher’s disease are associated with
osteoarthritis. High bone mineral density is associated with hip
and knee involvement. Estrogen deficiency may be a risk factor
for hip or knee disease. Candidate gene studies and genome-
wide scans have identified several potential genetic markers.
Patients often have a family history of osteoarthritis or joint
replacement.
Inflammatory joint diseases such as rheumatoid arthritis may
result in cartilage degradation and biomechanical effects that lead
to secondary osteoarthritis. The destruction of the joint, includ-
ing articular cartilage damage, osteophyte formation, and sub-
chondral bone remodeling, is best viewed as joint failure and the
final product of a variety of etiologic factors.
The earliest finding is fibrillation of the most superficial layer
of the articular cartilage. Over time, disruption of the articular
surface becomes deeper, with fibrillations extending to subchon-
dral bone, fragmentation of cartilage with release into the joint,
matrix degradation, and eventually, complete loss of cartilage,
leaving only exposed bone.
Early in the process, the cartilage matrix demonstrates
increased water and decreased proteoglycan content, unlike the
805
806 Section XIV  Musculoskeletal and Connective Tissue Disease
dehydration of cartilage that occurs with aging. The tidemark
zone, separating the calcified cartilage from the radial zone, is
invaded by capillaries. Chondrocytes initially are metabolically
active and release a variety of cytokines and metalloproteinases,
contributing to matrix degradation. In the later stages, this results
in the penetration of fissures to the subchondral bone and the
release of fibrillated cartilage into the joint space.
An imbalance between tissue inhibitors of metalloproteinases
and the production of metalloproteinases may be operative in
osteoarthritis. Subchondral bone remodels and increases in
density. Cystlike bone cavities containing myxoid, fibrous, or car-
tilaginous tissue may form. Osteophytes or bony proliferations at
the margin of joints at the site of the bone-cartilage interface may
form at capsule insertions. Osteophytes contribute to joint
motion restriction and are thought to be the result of new bone
formation in response to the degeneration of articular cartilage,
but the precise mechanism for their production remains
unknown.
Several crystals have been identified in synovial fluid and other
tissues from osteoarthritic joints, most notably calcium pyro-
phosphate dehydrate and hydroxyapatite. Although these crystals
have potent inflammatory potential, their role in the pathogene-
sis of osteoarthritis remains unclear. Frequently, the crystals are
asymptomatic and do not correlate with extent or severity of
disease.
The diversity of risk factors predisposing to osteoarthritis sug-
gests that many insults to the joints, including biomechanical
trauma, chronic articular inflammation, and genetic and meta-
bolic errors, can contribute to or trigger the cascade of events that
results in the characteristic pathologic features described earlier.
At some point, the cartilage degradative process becomes irre-
versible. With progressive changes in articular cartilage, joint
mechanics become altered, perpetuating the degradative process.
  CLINICAL PRESENTATION
Pain is the characteristic feature of osteoarthritis and the most
common presenting symptom. Pain is usually worse with activ-
ity or weight bearing and better with rest. In later stages, pain
may also occur at rest. Early in the disease course, pain tends
to be transient, intermittent, and unpredictable. The pain may
be characterized as severe, and its unpredictable nature is an
extremely bothersome feature that limits activity and affects
quality of life. With disease progression, pain tends to become
constant but is reported to be less severe and have an aching
quality. Other prominent symptoms, such as stiffness, gelling,
fatigue, and sleep disturbance, often lead to functional limitation
and disability.
Pain tends to localized to the specific joint involved, but it
may be referred to a more distant site. The cause of pain is unclear
but is likely to be heterogeneous. Pain may result from interac-
tions among structural pathology; the motor, sensory, and auto-
nomic innervation of the joint; and pain signal processing at the
spinal and cortical levels. Specific individual and environmental
factors also may be important. A subset of patients may have
neuropathic pain.
Patient-specific factors may modify pain reception and pain
reporting. Patients’ affective status, such as depression, anxiety,
and anger, may influence the level of pain reported.
Their cognitive status, including pain beliefs, expectations, and
memories of past pain, and their communication skills may deter-
mine how pain is perceived and reported. Studies have shown
that demographic factors such as age, sex, socioeconomic status,
race or ethnicity, and cultural background may affect pain
reporting.
Patients may have stiffness, particularly after prolonged inac-
tivity, but it is not a major feature of osteoarthritis and usually
lasts for less than 30 minutes. Patients do not report systemic
features such as fever.
Examination of an involved joint may reveal tenderness and
bony enlargement. Joint effusion and soft tissue swelling may
occur with knee involvement, but they tend to be intermittent.
Persistent inflammation with joint warmth, erythema, effusion,
and soft tissue swelling is usually not seen. Crepitus with move-
ment, limitation of joint motion, and joint deformity, malalign-
ment, and joint laxity or instability may be detected on evaluation.
Joint deformity as manifested by lateral subluxation is fixed and
not reducible. Muscle weakness and gait abnormalities may be
seen.
Several subtypes of osteoarthritis have been identified. The
nodal form involves the distal interphalangeal joints (DIPs), also
known as Heberden’s nodes, and the proximal interphalangeal
joints (PIPs), also known as Bouchard’s nodes. It is most common
in middle-aged women, typically those with a strong family
history among first-degree relatives. Erosive, inflammatory osteo-
arthritis is associated with prominent destructive changes, espe-
cially in the finger joints, and it is often quite symptomatic.
Generalized osteoarthritis is characterized by involvement of the
DIP, PIP, and first carpal-metacarpal joints, as well as the knees,
feet, and hips.
For a deeper discussion of these topics, please see Chapter
256, “Approach to the Patient with Rheumatic Disease,”
and Chapter 262, “Osteoarthritis,” in Goldman-Cecil
Medicine, 25th Edition.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The diagnosis of osteoarthritis is based on the signs and symp-
toms previously outlined. Although there are characteristic radio-
graphic features, they are not necessary to make the clinical
diagnosis. Imaging may be used to confirm the diagnosis and
exclude other diseases, but radiographs are insensitive and may
not show findings early in the disease course. Despite radio-
graphic findings of osteoarthritis, pain may have other sources,
such as bursitis, tendonitis, or referred pain. For example, hip
disease may manifest as knee pain.
Osteoarthritis must be distinguished from inflammatory joint
diseases such as rheumatoid arthritis and the spondyloarthropa-
thies. This is accomplished by identifying the characteristic
pattern of joint involvement and the nature of the individual joint
deformity. Joints commonly involved in osteoarthritis include
the DIPs, PIPs, first carpal-metacarpal, cervical and lumbar spine
facet joints, hips, knees, and first metatarsophalangeal joints.
Involvement of the metacarpal phalangeal joints (MCPs), wrist,
elbows, shoulders, and ankles is uncommon, except in the case
of trauma, congenital disease, or coexisting endocrine or meta-
bolic disease.

The characteristic radiographic features of osteoarthritis
include joint space narrowing as a surrogate for cartilage loss;
osteophytes and subchondral sclerosis as an indicator of new
bone formation, which is characteristic of osteoarthritis; and sub-
chondral cysts as a manifestation of myxoid or fibrous degenera-
tion of subchondral bone. Bone attrition and subchondral bone
remodeling may result in changes in bone shape. Magnetic reso-
nance imaging (MRI) can demonstrate additional morphologic
abnormalities, such as bone marrow lesions in subchondral bone,
meniscal degeneration, and synovitis.
The pain and swelling of erosive hand osteoarthritis may
suggest rheumatoid arthritis, although systemic inflammatory
signs and other typical features of rheumatoid arthritis are absent.
The prevalence of false-positive findings of rheumatoid factor and
antinuclear antibody, sometimes in significant titers, is higher
with increasing age. Osteoarthritis more commonly affects the
distal small joints in the hands (DIPs > PIPs > MCPs and wrists),
whereas rheumatoid arthritis more commonly affects proximal
small joints in the hands (MCPs and wrists > PIPs > DIPs.
For a deeper discussion of these topics, please see Chapter
258, “Imaging Studies in the Rheumatic Diseases,” Chapter
264, “Rheumatoid Arthritis,” and Chapter 265, “The Spon-
dyloarthropathies,” in Goldman-Cecil Medicine, 25th
Edition.
  TREATMENT
The natural history of osteoarthritis includes periods of relative
stability interspersed with rapid deterioration. Management
should be individually tailored and may include a combination
of nonpharmacologic, pharmacologic, and surgical approaches.
The primary goal of treatment is to improve pain and function
and reduce disability.
Patients should be educated regarding the objectives of treat-
ment and the importance of lifestyle changes, exercise, pacing of
activities, and other measures to unload the damaged joints. The
initial focus should be on self-help and patient-driven treatments
rather than on passive therapies. Patients should be encouraged
to adhere to nonpharmacologic and pharmacologic therapies.
Physical therapists may be helpful in providing instruction in
appropriate exercises to reduce pain and preserve functional
capacity. For knee and hip osteoarthritis, assistive devices such as
walking aids may be useful. Graded regular aerobic, muscle-
strengthening, and range-of-motion exercises are beneficial. Tai
chi may also be useful.
Overweight patients should be encouraged to lose weight. A
knee brace can reduce pain, improve stability, and diminish the
risk of falling for patients with knee osteoarthritis and mild or
moderate varus or valgus instability. Advice concerning appropri-
ate footwear is also important. Spinal orthoses may provide
benefit to patients with significant cervical or lumbar involve-
ment. Local applications of heat, ultrasound, or transcutaneous
electrical nerve stimulation (TENS) may provide short-term
benefit. Acupuncture may also offer symptomatic benefit for
these patients.
Pharmacologic therapy provides symptomatic relief but does
not alter the course of the disease. Pharmacologic therapy should
therefore be selected based on its relative efficacy and safety. The
Chapter 83  Osteoarthritis 807
use of concomitant medications in the setting of comorbidities
should be taken into account.
Acetaminophen (up to 3 g/day with caution) may be an effec-
tive initial oral analgesic for mild to moderate pain. In patients
with symptomatic osteoarthritis, nonsteroidal anti-inflammatory
drugs (NSAIDs) should be used at the lowest effective dose,
although their long-term use should be avoided if possible. If
patients are at risk for increased gastrointestinal toxicity, a
cyclooxygenase-2 (COX2)–selective agent or a nonselective
NSAID with co-prescription of a proton pump inhibitor or miso-
prostol for gastroprotection should be considered. All NSAIDs,
including nonselective and COX2-selective agents, should be
used with caution in patients with cardiovascular risk factors.
Topical NSAIDs and capsaicin may be effective alternatives to
oral analgesic or anti-inflammatory agents in knee and hand
osteoarthritis and may be used as adjunctive agents, particularly
in elderly patients.
Meta-analyses have shown that oral glucosamine and chon-
droitin sulfate have limited benefit in patients with knee osteoar-
thritis. If other interventions have been ineffective or are
contraindicated, weak opioids and narcotic analgesics may be
considered for the treatment of refractory pain. Stronger opioids
should be used for the management of severe pain only in excep-
tional circumstances. Occasional injection of intra-articular cor-
ticosteroids (no more than once every 4 months) may provide
modest short-term symptomatic benefit with minimal toxicity,
especially in the knee. Patients with moderate to severe pain and
effusion or other local signs of inflammation may be more
responsive. Intra-articular hyaluronate appears to have little or no
benefit based on current evidence.
Surgical management includes total joint replacement, which
is extremely effective in relieving pain, decreasing disability, and
improving function. With improvements in surgical technique
and technology, the indications for total joint replacement have
expanded to include younger and older age groups. Other surgi-
cal options include osteotomy and unicompartmental knee
replacement. Arthroscopy is not recommended for the manage-
ment of knee osteoarthritis.
  PROGNOSIS
Given the obesity epidemic and the marked contact loads that
increased weight places on the knee, obesity is likely the most
important modifiable risk factor for the development and pro-
gression of knee osteoarthritis. One kilogram of weight loss
decreases the load on the knee by 4 kg. Varus and valgus malalign-
ments have also been identified as important risk factors for the
progression of knee osteoarthritis.
For a deeper discussion of these topics, please see Chapter
262, “Osteoarthritis,” in Goldman-Cecil Medicine, 25th
Edition.
SUGGESTED READINGS
Blagojevic M, Jinks C, Jeffery A, et al: Risk factors for onset of osteoarthritis of
the knee in older adults: a systematic review and meta-analysis, Osteoarthritis
Cartilage 18:24–33, 2013.
Helmick CG, Felson DT, Kwoh CK, et al: Estimates of the prevalence of arthritis
and other rheumatic conditions in the United States. Part I, Arthritis Rheum
58:15–25, 2008.
808 Section XIV  Musculoskeletal and Connective Tissue Disease

Hochberg MC, Altman RD, April KT, et al: American College of Rheumatology
2012 recommendations for the use of nonpharmacologic and pharmacologic
therapies in osteoarthritis of the hand, hip, and knee, Arthritis Care Res
64:465–474, 2012.
Litwic A, Edwards MH, Dennison EM, et al: Epidemiology and burden of
osteoarthritis, Br Med Bull 105:185–199, 2013.
Zhang W, Moskowitz RW, Kwoh CK, et al: OARSI recommendations for the
management of hip and knee osteoarthritis, part I: critical appraisal of existing
treatment guidelines and systematic review of current research evidence,
Osteoarthritis Cartilage 15:981–1000, 2007.
Zhang W, Moskovitz RW, Nuki G, et al: OARSI recommendations for the
management of hip and knee osteoarthritis, part II: OARSI evidence-based,
expert consensus guidelines, Osteoarthritis Cartilage 16:137–162, 2008.

Nonarticular Soft Tissue
Disorders
  INTRODUCTION
The nonarticular soft tissue disorders account for most musculo-
skeletal complaints in the general population. These disorders
include a large number of anatomically localized conditions (e.g.,
bursitis, tendinitis) and fibromyalgia syndrome, a generalized
pain disorder. For most nonarticular soft tissue conditions, the
etiologic factors and pathogenesis are poorly understood.
The nonarticular soft tissue syndromes can be classified
according to the anatomic region involved, such as shoulder pain.
After the region is defined, an attempt is made to identify the
structure at fault, such as the supraspinatus tendon, bicipital
tendon, or subacromial bursa. In the case of back pain, precise
anatomic delineation of the structure involved (e.g., interverte-
bral disk, facet joint, ligament, paraspinal muscle) is frequently
impossible.
  EPIDEMIOLOGY
Precise data for prevalence or incidence of most nonarticular soft
tissue syndromes are not available, but these conditions account
for up to 30% of all outpatient visits. Fibromyalgia is considered
to be the most common cause of generalized musculoskeletal
pain in women between the ages of 20 and 55 years. The global
mean prevalence is 2.7%.
  ETIOLOGIC FACTORS AND PATHOGENESIS
The precise pathophysiology of most nonarticular soft tissue
disorders remains unknown, although predisposing factors, such
as overuse or repetitive activities (e.g., tennis elbow, lateral epi-
condylitis) or biomechanical factors (e.g., leg-length discrepancy
in trochanteric bursitis), can be identified in many cases.
The term tendinitis implies tendon sheath inflammation, but
small tendon tears, periostitis, and nerve entrapment have been
proposed as potential mechanisms. Similarly, although the term
bursitis implies bursal inflammation, demonstrable inflammation
is difficult to find. In some cases (e.g., acute bursitis of the olec-
ranon or prepatellar bursa), the mechanism is an acute inflamma-
tory response to sodium urate crystals deposited in the soft
tissue, an extra-articular manifestation of gout. The favorable
response of tendinitis and bursitis to anti-inflammatory agents,
including corticosteroids, supports the view that at least one
component of these syndromes is the result of an inflammatory
process.
In myofascial pain syndrome, the causes are even more ob-
scure. Frequently, overuse and trauma are cited as etiologic fac-
tors, but many cases lack antedating mechanical considerations.
84 
Niveditha Mohan
Investigators have examined diverse mechanisms for fibromy-
algia syndrome, including studies of muscle, sleep physiologic
processes, neurohormonal function, and psychological status.
Although the pathophysiologic mechanisms remain unknown,
an increasing body of literature points to central (central nervous
system) rather than peripheral (muscle) mechanisms. Muscle
tissue has been a focus of investigation for many years. Initial
studies, including histologic and histochemical studies, suggested
a possible metabolic myopathy; however, carefully controlled
studies indicated that these abnormalities were the result of
deconditioning.
Sleep studies suggested that disruption of deep sleep (stage
IV) by so-called alpha-wave intrusion (i.e., normal awake electro-
encephalographic pattern) may play a causal role, but this finding
was later observed in other disorders and more likely indicates an
effect than a cause.
In some cases, musculoskeletal injury has been implicated as
a trigger for fibromyalgia, but social and legal issues cloud its
causative role. Several studies have suggested that subtle
hypothalamic-pituitary-adrenal axis hypofunction may occur in
fibromyalgia syndrome, although it remains uncertain whether
these changes are constitutive or are the result of fibromyalgia. A
prevailing theory of pathogenesis is dysregulation of pain path-
ways leading to central sensitization and marked by neurotrans-
mitter, neurohormone, and sleep physiology irregularities.
Fibromyalgia has long been linked to psychological distur-
bance. Most studies have confirmed high lifetime rates of
major depression, which range from 34% to 71%, associated
with fibromyalgia syndrome. High lifetime rates of migraine,
irritable bowel syndrome, and panic disorder have also been
associated with fibromyalgia syndrome, suggesting that fibro-
myalgia may be part of an affective spectrum group of
disorders.
  CLINICAL PRESENTATION
Many of the soft tissue rheumatic syndromes involve bursae,
tendons, ligaments, and muscles. Bursae are closed sacs lined
with mesenchymal cells that are similar to synovial cells; the sacs
are strategically located to facilitate tissue gliding. Subcutaneous
bursae (e.g., olecranon, prepatellar) form after birth in response
to normal external friction. Deep bursae (e.g., subacromial bursa)
usually form before birth in response to movement between
muscles and bones and may or may not communicate with adja-
cent joint cavities. Adventitious bursae (e.g., over the first meta-
tarsal head) form in response to abnormal shearing stresses and
are not uniformly found. Although most forms of bursitis involve
809
810 Section XIV  Musculoskeletal and Connective Tissue Disease

isolated, local conditions, some may be the result of systemic
conditions such as gout.
Tendinitis, bursitis, and myofascial disorders should be distin-
guished from articular disorders. In most cases, this can be
accomplished by a careful examination of the involved structure
(Table 84-1). General principles of the musculoskeletal examina-
tion are as follows:
tribution that is frequently nonanatomic and associated with
hyperalgesia in the involved area.
Fibromyalgia syndrome is characterized by widespread pain
and a host of other symptoms, including insomnia, cognitive dys-
function, depression, anxiety, recurrent headaches, dizziness,
fatigue, morning stiffness, extremity dysesthesia, irritable bowel
syndrome, and irritable bladder syndrome.

1. Observation: If deformity or soft tissue swelling is detected,

  DIAGNOSIS AND TREATMENT
is it fusiform (i.e., surrounding the entire joint in a symmetri-
cal fashion) or is it localized? Local rather than fusiform defor- Septic Bursitis
mity distinguishes nonarticular disorders from articular Superficial forms of bursitis, particularly olecranon bursitis and
disorders. prepatellar and occasionally infrapatellar bursitis, are more fre-
2. Palpation: Is tenderness localized or in a fusiform distribu- quently infected or involved with crystal deposition than are
tion? Is there an effusion? Local (not fusiform or joint line) deep forms of bursitis, presumably due to direct extension of
tenderness distinguishes nonarticular disorders from articular organisms through subcutaneous tissues. Most commonly,
disorders. An effusion typically indicates an articular Staphylococcus aureus is isolated from infected superficial bursae.
disorder. Septic bursitis should be suspected when there is cellulitis, ery-
3. Assessing range of motion: The musculoskeletal examination thema, fever, and peripheral leukocytosis.
includes the assessment of active range of motion (i.e., patient Definitive diagnosis and exclusion of infection of subcutane-
attempts to move the symptomatic structure) and passive ous bursae usually require aspiration of the distended bursa. The
range of motion (i.e., examiner moves the symptomatic struc- bursal fluid should be assessed for cell count, Gram stain, and
ture). Articular disorders usually are characterized by equal culture and examined for crystals.
impairment in active and passive movements as a result of the
mechanical limitation of joint motion resulting from prolifera- Nonseptic Bursitis
tion of the synovial membrane, an effusion, or derangement Nonseptic bursitis frequently appears as an overuse condition
of intra-articular structures. Impairment of active movement associated with sudden or unaccustomed repetitive activity of the
characterizes nonarticular disorders to a much greater degree associated extremity. The two most common types of bursitis are
than passive movement. subacromial and trochanteric bursitis (Table 84-2).
Subacromial bursitis is the most common overall cause of
Clinical symptoms include pain, warmth, and swelling over shoulder pain over the lateral upper arm or deltoid muscle that is
the site of the bursa that are worse with activity and better with exacerbated with abduction of the arm. Subacromial bursitis is
rest. Bursitis can be distinguished from tendinitis by the pain the result of compression of the inflamed rotator cuff tendon
during active and passive range of movement; in tendinitis, pain between the acromion and humeral head. Because the rotator
is elicited only during active range of movement. However, for cuff forms the floor of the subacromial bursa, bursitis in this loca-
many patients these patterns often occur simultaneously. tion often results from tendinitis of the rotator cuff. Occasionally,
Muscle sprains or strains are typically diagnosed based on a
history of preceding activity causing the symptom along with
pain and limitation of movement when the muscle is contracted
against resistance. The clinical signs and symptoms of chronic TABLE 84-2  BURSITIS SYNDROMES
myofascial pain are more nonspecific and characterized by a dis- LOCATION SYMPTOM FINDING
Subacromial Shoulder pain Tender subacromial
space
Olecranon Elbow pain Tender olecranon
swelling
Iliopectineal Groin pain Tender inguinal region
TABLE 84-1  DIFFERENTIATING NONARTICULAR SOFT Trochanteric Lateral hip pain Tender at greater
TISSUE DISORDERS FROM ARTICULAR trochanter
DISEASE Prepatellar Anterior knee pain Tender swelling over
NONARTICULAR SOFT ARTICULAR patella
MANIFESTATION TISSUE DISORDERS DISEASE Infrapatellar Anterior knee pain Tender swelling lateral
or medial to patellar
Limitation of motion Active > passive Active = tendon
passive Anserine Medial knee pain Tender medioproximal
Crepitus of articular surfaces 0 +/0 tibia (below joint line
(structural damage) of knee)
Tenderness Ischiogluteal Buttock pain Tender ischial spine (at
  Synovial (fusiform pattern) 0 + gluteal fold)
  Local + 0 Retrocalcaneal Heel pain Tender swelling
Swelling between Achilles
  Synovial (fusiform pattern) 0 + tendon insertion and
  Local +/0 0 calcaneus
Calcaneal Heel pain Tender central heel pad
+, Present; 0, absent.
 Chapter 84  Nonarticular Soft Tissue Disorders 811

subacromial bursitis or rotator cuff tendinitis results from osteo-

phyte compression of the rotator cuff tendon originating from TABLE 84-3  TENDINITIS SYNDROMES
the acromioclavicular joint. The differential diagnosis includes LOCATION SYMPTOM FINDING
tears of the rotator cuff, intra-articular pathologic mechanisms of Extensor pollicis brevis Wrist pain Pain on ulnar deviation
the glenohumeral joint, bicipital tendinitis, cervical radiculopa- and abductor pollicis of the wrist, with the
longus (de Quervain thumb grasped by the
thy, and referred pain from the chest. tenosynovitis) remaining four
Trochanteric bursitis is the result of inflammation at the inser- fingers (i.e.,
tion of the gluteal muscles at the greater trochanter. It produces Finkelstein test)
Flexor tendons of Triggering or locking of Tender nodule on
lateral thigh pain, which is often worse when the patient lies on fingers fingers in flexion flexor tendon on
the affected side. Women seem to be more prone to develop this palm over metacarpal
condition, perhaps because of increased traction of the gluteal joint
Medial epicondyle Elbow pain Tenderness of medial
muscles as a result of the relatively broader female pelvis. Other epicondyle
potential risk factors include weight gain, local trauma, overuse Lateral epicondyle Elbow pain Tenderness of lateral
activities such as jogging, and leg-length discrepancies (primarily epicondyle
Bicipital tendon Shoulder pain Tenderness along
on the side with the longer leg). These factors are thought to lead bicipital groove
to increased tension of the gluteus maximus on the iliotibial Patella Knee pain Tenderness at insertion
band, producing bursal inflammation. The differential diagnosis of patellar tendon
Achilles Heel pain Tender Achilles tendon
of trochanteric bursitis includes lumbar radiculopathy (particu- Tibialis posterior Medial ankle pain Tenderness under
larly of the L1 and L2 nerve roots), meralgia paresthetica (i.e., medial malleolus
entrapment of the lateral cutaneous nerve of the thigh as it passes with resisted
inversion of ankle
under the inguinal ligament), true hip joint disease, and intra- Peroneal Lateral midfoot or Tenderness under
abdominal pathologic processes. Other bursitis syndromes are ankle pain lateral malleolus with
less common and listed in Table 84-2. passive inversion
Septic bursitis is treated with a combination of serial aspira-
tions of the infected bursa and antibiotics, initially directed peroneal and posterior tibial tendinitis may occur in the setting
against S. aureus and then adjusted depending on the results of of an underlying seronegative arthropathy such as Reiter’s disease
bursal fluid cultures. Recurrent septic bursitis may need surgical or psoriatic arthritis. A history and clinical evaluation for these
excision of the bursa. The approach to nonseptic bursitis should disorders should be pursued for the appropriate patient.
include rest, local heat, and unless contraindicated by peptic ulcer Therapy for tendinitis—NSAIDs, local heat, and corticoste-
disease, renal disease, or advanced age, nonsteroidal anti- roid injection—is similar to that for bursitis. Rest, physical
inflammatory drugs (NSAIDs). therapy, occupational therapy, and occasionally ergonomic
The most effective approach usually is local injection of a cor- modification are useful adjuncts. The goal of corticosteroid
ticosteroid. Superficial bursae with obvious swelling should be injection in tendinitis is to infiltrate the tendon sheath rather
aspirated before the corticosteroid is injected. For deep bursae, than the tendon itself because direct injection into a tendon
such as the subacromial or trochanteric bursae, aspiration yields may result in rupture of the tendon. Corticosteroid injection
little or no fluid, and direct injection of a corticosteroid without of the Achilles tendon should be avoided because of the pro-
attempted aspiration is reasonable. Caution is advised in pensity of this tendon to rupture. Surgical management of
attempted aspiration or injection of the iliopsoas bursa, the tendinitis is indicated only after failure of conservative treat-
ischiogluteal bursa, and the gastrocnemius-semimembranosus ment. For example, chronic impingement of the supraspinatus
bursa (i.e., Baker’s cyst). These bursae lie close to important tendon that is refractory to conservative treatment may require
neural and vascular structures, and aspiration under ultrasound subacromial decompression.
guidance is recommended.
Fibromyalgia Syndrome
Tendinitis Descriptions of fibromyalgia syndrome exist far back in the
Most tendinitis syndromes are the result of inflammation in the medical literature, but it remains a diagnosis of exclusion due to
tendon sheath. Overuse with microscopic tearing of the tendon the lack of objective diagnostic or pathologic findings. Fibromy-
is the most common risk factor for tendinitis. Tendon compres- algia syndrome as defined by the American College of Rheuma-
sion by an osteophyte may occur, such as in the rotator cuff tology (ACR) 1990 definition for use in clinical trials is a chronic,
tendon compressed by an osteophyte originating from the acro- widespread pain condition with characteristic tender points on
mioclavicular joint. physical examination, often associated with a constellation of
A common form of tendinitis is lateral epicondylitis, also symptoms such as fatigue, sleep disturbance, headache, irritable
known as tennis elbow (Table 84-3). This is a common overuse bowel syndrome, and mood disorders. In 2010, the ACR devel-
syndrome among tennis players, but it can be seen in many other oped preliminary diagnostic criteria based only on symptoms
settings requiring repetitive extension of the forearm (e.g., paint- because of well-documented issues with the tender point exami-
ing overhead). The diagnosis is confirmed by exclusion of elbow nation (Table 84-4). These criteria do not require a tender point
joint pathology and the finding of local tenderness at the lateral examination, but they provide a scale for measuring the severity
epicondyle, which is typically exacerbated by forearm extension of symptoms that are characteristic of fibromyalgia and show
against resistance. Enthesopathies such as Achilles tendinitis and good correlation with the 1990 ACR criteria.
812 Section XIV  Musculoskeletal and Connective Tissue Disease
TABLE 84-4  2010 AMERICAN COLLEGE OF
RHEUMATOLOGY FIBROMYALGIA
DIAGNOSTIC CRITERIA
CRITERIA
1. Widespread pain index (WPI) ≥7, symptom severity (SS) scale score ≥5,
or WPI of 3-6 and SS scale score ≥9
2. Symptoms manifest at a similar level for at least 3 months
3. Exclusion of other explanation for the pain
ASCERTAINMENT
1. WPI score
The number of areas where the patient has had pain over the past week is
assessed from 19 possible sites: left shoulder girdle, right shoulder
girdle, left upper arm, right upper arm, left lower arm, right lower arm,
left hip, right hip, left upper leg, right upper leg, left lower leg, right
lower leg, left jaw, right jaw, chest, abdomen, upper back, lower back,
and neck.
2. SS scale score
For fatigue, waking unrefreshed, cognitive symptoms, and somatic
symptoms,* the level of severity during the past week is assessed as
follows: 0 = no symptoms; 1 = few symptoms; 2 = moderate number
of symptoms; 3 = many symptoms.
The SS scale score is the sum of the severity of the first three symptoms
plus the severity of somatic symptoms in general. The final score is
between 0 and 12.
*Somatic symptoms may include muscle pain or weakness, irritable bowel syndrome,
fatigue or tiredness, cognitive or memory problems, headache, numbness or tingling,
dizziness, insomnia, depression, nervousness, seizures, abdominal pain or cramps
(especially upper abdomen), constipation, diarrhea, nausea, vomiting, fever, dry mouth,
itching, chest pain, wheezing, Raynaud’s phenomenon, hives or welts, tinnitus, hearing
difficulties, heartburn, oral ulcers, loss of or change in taste, dry eyes, blurred vision,
shortness of breath, loss of appetite, rash, sun sensitivity, easy bruising, hair loss, frequent
or painful urination, and bladder spasms.
The clinical presentation of fibromyalgia syndrome is an insid-
ious onset of chronic, diffuse, poorly localized musculoskeletal
pain, typically accompanied by fatigue and sleep disturbance. The
physical examination reveals a normal musculoskeletal system,
with no deformity or synovitis. However, widespread tenderness
occurs, especially at tendon insertion sites, indicating a general
reduction in the pain threshold.
Approximately one third of the patients identify antecedent
trauma as a precipitant for their symptoms, one third of patients
describe a viral prodrome, and one third have no clear precipi-
tant. A variety of less typical presentations has been described,
including a predominantly neuropathic presentation with pares-
thesias (i.e., numbness and tingling) in a nondermatomal distri-
bution, an arthralgic rather than myalgic presentation, and an
axial skeletal manifestation resembling degenerative disk disease.
Many patients may have undergone invasive diagnostic tests and,
in some cases, inappropriate procedures such as carpal tunnel
release or cervical or lumbar laminectomies.
Conditions that should be considered in the differential diag-
nosis of fibromyalgia syndrome include polymyalgia rheumatica
(in older patients), hypothyroidism, polymyositis, and early sys-
temic lupus erythematosus or rheumatoid arthritis. However,
symptoms are exhibited for many months or years without evi-
dence of other signs or symptoms of an underlying connective
tissue disease, making other possible diagnoses unlikely.
Results of laboratory and radiographic studies are usually
normal for patients with fibromyalgia syndrome. Exclusion of
other conditions, such as osteoarthritis, rheumatoid arthritis, and
systemic lupus erythematosus, by radiography, erythrocyte sedi-
mentation rate, assays for rheumatoid factor or antinuclear anti-
body, and other tests is no longer considered necessary for the
diagnosis of fibromyalgia syndrome. Fibromyalgia should be
diagnosed on the basis of positive criteria.
The treatment of fibromyalgia includes reassurance that the
condition is not a progressive, crippling, or life-threatening entity.
A combination of treatment options, including medication and
physical measures, is helpful for most patients. Medications
found to be helpful in short-term, double-blind, placebo-
controlled trials include amitriptyline and cyclobenzaprine. Low
doses of these medications (e.g., 10 to 30 mg of amitriptyline, 10
to 30 mg of cyclobenzaprine) are moderately effective and gener-
ally well tolerated. Studies have shown that newer antidepres-
sants of the serotonin-norepinephrine reuptake inhibitor group
(e.g., duloxetine, venlafaxine, bupropion) and α2δ ligands (e.g.,
gabapentin, pregabalin) are also effective, particularly in combi-
nation with low doses of tricyclic antidepressants.
Patients should be encouraged to take an active role in the
management of their condition. If possible, they should begin a
progressive, low-level aerobic exercise program to improve mus-
cular fitness and provide a sense of well-being. A combination
approach is effective for most patients in alleviating symptoms,
although a small minority of patients requires more intensive
treatment strategies, such as psychiatric treatment or referral to a
pain center.
SUGGESTED READINGS
Goldenberg DL, Burkhardt C, Crofford L: Management of fibromyalgia
syndrome, JAMA 292:2388–2395, 2004.
Littlejohn GO: Balanced treatments for fibromyalgia, Arthritis Rheum 50:2725–
2729, 2004.
 85 
Rheumatic Manifestations
of Systemic Disorders;
Sjögren’s Syndrome
Yong Gil Hwang

ment by the tumor, as in dermatomyositis in patients with ovarian

  INTRODUCTION cancer.
Rheumatologic manifestations may herald a variety of systemic The incidence of malignancy with rheumatic manifestations is
conditions, including malignancy, endocrinopathy, and sarcoid- unclear, but musculoskeletal symptoms occur more frequently
osis (Tables 85-1 and 85-2). Musculoskeletal symptoms can with hematologic malignancies than with solid tumors. No single
precede or follow the diagnosis of these diseases. Patients may laboratory test can confirm the diagnosis of a rheumatic illness
complain of joint pain, muscle weakness and pain, or reduced in a patient with cancer. All patients with rheumatologic syn-
range of motion. Other chapters in this textbook provide detailed dromes should be evaluated with a thorough history, physical
reviews of these systemic diseases, including rheumatologic examination, and age-appropriate malignancy screening.
manifestations.
Hypertrophic Osteoarthropathy
  RHEUMATIC SYNDROMES HOA is characterized by digital clubbing, periostitis of the long
ASSOCIATED WITH MALIGNANCY bones, and arthritis. Arthritis is most prominent in large joints,
Paraneoplastic rheumatologic manifestations include hypertro- and periostitis develops mostly at the distal ends of the femur,
phic osteoarthropathy (HOA), arthritis (i.e., inflammatory
arthritis and carcinomatous polyarthritis), myositis, vasculitis,
systemic lupus erythematosus (SLE)–like symptoms, and sclero- TABLE 85-2  MUSCULOSKELETAL MANIFESTATIONS
derma. The pathophysiologic mechanisms of musculoskeletal OF ENDOCRINE DISEASE
symptoms in a patient with cancer are often unknown and remain ENDOCRINE DISEASE MUSCULOSKELETAL MANIFESTATIONS
speculative. The association is presumed if there is a close tem- Diabetes mellitus Carpal tunnel syndrome
Charcot’s arthropathy
poral relationship between the diagnosis of a malignancy and the Adhesive capsulitis
onset of musculoskeletal symptoms or the rheumatic syndrome Syndrome of limited joint mobility
resolves after successful treatment of the malignancy. In many (cheiroarthropathy)
Diabetic amyotrophy
cases, however, the association may be coincidental. Diabetic muscle infarction
Cancer may directly invade articular or periarticular structures Hypothyroidism Proximal myopathy
and mimic rheumatic syndromes, as in chondrosarcoma, giant Arthralgia
Joint effusions
cell tumor, and osteogenic sarcoma. Musculoskeletal symptoms Carpal tunnel syndrome
can occur as paraneoplastic phenomena without direct involve- Chondrocalcinosis
Hyperthyroidism Myopathy
Osteoporosis
Thyroid acropachy
TABLE 85-1  SYSTEMIC CONDITIONS ASSOCIATED Hyperparathyroidism Myopathy
WITH RHEUMATIC MANIFESTATIONS Arthralgia
Erosive arthritis
MALIGNANT DISORDERS ENDOCRINOPATHIES Chondrocalcinosis
Hypertrophic osteoarthropathy Diabetes Hypoparathyroidism Muscle cramps
Lymphoma Hypothyroidism Soft tissue calcifications
Leukemia Hyperthyroidism Spondyloarthropathy
Carcinoma polyarthritis Hyperparathyroidism Acromegaly Carpal tunnel syndrome
Acromegaly Myopathy
HEMATOLOGIC DISORDERS
Raynaud’s phenomenon
GASTROINTESTINAL DISORDERS
Hemophilia Back pain
Sickle cell disease Spondyloarthropathies Premature osteoarthritis
Thalassemia Whipple disease Cushing’s syndrome Myopathy
Multiple myeloma Hemochromatosis Osteoporosis
Amyloidosis Primary biliary cirrhosis Avascular necrosis

813
814 Section XIV  Musculoskeletal and Connective Tissue Disease
tibia, and radius. The primary form of HOA (i.e., primary pachy-
dermoperiostosis) is usually a self-limited disease of childhood.
The secondary form may be generalized or localized and is mainly
associated with lung cancer and suppurative lung disease.
HOA is also associated with cardiovascular disease (e.g., cya-
notic congenital heart disease, infective endocarditis), hepatobili-
ary disorders (e.g., liver cirrhosis, primary biliary cirrhosis), and
gastrointestinal disease (e.g., inflammatory bowel disease, celiac
disease). Periostitis without digital clubbing can be seen in
thyroid acropachy, hypervitaminosis A, fluorosis, venous stasis,
hyperphosphatemia, and sarcoidosis. Isolated chronic digital
clubbing, which is mainly associated with pleuropulmonary
disease, does not seem to cause HOA.
The pathogenesis of HOA remains unknown, although several
possible mechanisms have been proposed. HOA is usually
accompanied by bone and joint pain associated with periarticular
periostitis. The pain is usually exacerbated by dependency and
relieved with limb elevation. Typical signs of periostitis include
periosteal new bone along the distal ends of long bones, which
can be seen on plain radiographs. When periostitis is not obvious
on plain radiography, a bone scan is useful to demonstrate early
evidence of disease. When HOA is clinically suspected, radio-
logic evaluation of the thorax is important because of the associa-
tion between HOA and lung neoplasms.
In many cases, symptomatic management with nonsteroidal
anti-inflammatory drugs or other analgesics while treating the
underlying disorder provides significant relief of symptoms. In
refractory cases, bisphosphonates such as pamidronate and zole-
dronic acid have been reported to be effective.
Rheumatoid Arthritis–Like Syndrome
Inflammatory rheumatoid arthritis–like syndrome has been asso-
ciated with solid neoplasms and hematologic malignancies. Clini-
cal characteristics associated with this paraneoplastic syndrome
include acute onset or late onset, asymmetrical disease frequently
involving the lower extremities, nonspecific synovitis in large
joints that spares the wrists and hands without bony erosion,
negative results for rheumatoid factor and cyclic citrullinated
peptide antibody. However, these features are not specific and
may be confused with elder-onset rheumatoid arthritis, seronega-
tive rheumatoid arthritis, spondyloarthropathy, remitting serone-
gative symmetrical synovitis with pitting edema (RS3PE), or
polymyalgia rheumatica (PMR).
RS3PE manifests with sudden onset of polyarthritis, pitting
edema, and prominent constitutional symptoms. More than one
half of RS3PE cases are associated with malignancy. Lympho­
proliferative disorders such as leukemia and lymphoma may
simulate various rheumatic syndromes from direct invasion of
the synovium, articular tissues, or juxta-articular bone, produc-
ing synovitis or bone pain.
Lupus-Like Syndrome
Antinuclear antibodies (ANAs) can be seen in patients with solid
neoplasms (e.g., gastric, cervical, and breast carcinomas, testicu-
lar seminoma), lymphomas, or myelodysplastic disorders, but
the significance of these autoantibodies is not well understood.
The association between SLE and occult malignancy is uncertain.
It is not necessary to search for underlying malignancy in a
patient with typical manifestations of SLE. However, lupus-like
autoantibodies and unexplained Coombs- positive hemolytic
anemia or thrombocytopenia without clinical signs of rheumatic
disease warrant further investigation for an occult neoplasm.
Raynaud’s Phenomenon and  
Scleroderma-Like Syndrome
The sudden onset of Raynaud’s phenomenon and scleroderma-
like syndrome can herald an underlying tumor such as hemato-
logic malignancies and carcinomas of the liver, ovary, testis,
bladder, breast, or stomach. Scleroderma-like skin changes may
also occur in patients with osteosclerotic myeloma with polyneu-
ropathy, organomegaly, endocrinopathy, monoclonal gammopa-
thy, and skin abnormalities (i.e., POEMS syndrome) and in those
with carcinoid tumors.
Characteristics that suggest secondary Raynaud’s phenome-
non include age at onset older than 50 years, symptom asym-
metry, symptoms that persist year round, and rapid digital
ulceration and necrosis. Secondary Raynaud’s is also suggested
by scleroderma-like syndromes in patients older than 50 years,
rapid progression of skin sclerosis, or a poor response to therapy.
The lack of Raynaud’s phenomenon can be another distinguish-
ing characteristic of paraneoplastic scleroderma-like syndrome
because Raynaud’s phenomenon occurs in approximately 95% of
cases of systemic sclerosis.
Polymyalgia Rheumatica
Clinical symptoms and signs of PMR include shoulder and pelvic
girdle pain and morning stiffness, a high erythrocyte sedimenta-
tion rate (ESR), and anemia of chronic disease. Although the
association between PMR and cancer is controversial, several
features are atypical for PMR and may suggest an occult malig-
nancy: disease onset before the age of 50 years, asymmetrical or
localized involvement of typical sites, an ESR less than 40 or
higher than 100 mm/hr, and a poor response to low doses of
glucocorticoids.
Myelodysplastic syndromes and myeloproliferative syn-
dromes are frequently associated with PMR. Myelodysplastic
syndromes also are associated with a variety of musculoskeletal
symptoms and signs, including cutaneous vasculitis, monoarticu-
lar or polyarticular arthritis, lupus-like conditions, Raynaud’s
phenomenon, polychondritis, and pyoderma gangrenosum.
Vasculitides
Vasculitis is rarely associated with malignancy and is most com-
monly seen in patients with lymphoproliferative disorders and
myelodysplastic syndrome. Cutaneous leukocytoclastic vasculi-
tis is the most common manifestation of vasculitic paraneoplas-
tic. Although clinical presentations of paraneoplastic vasculitides
are indistinguishable from those of the idiopathic condition, a
chronic, relapsing disease with cytopenias and poor response to
conventional treatment suggest a hidden malignancy.
Inflammatory Myopathies
The association between inflammatory myopathies and malig-
nancies has been well established.
 Chapter 85  Rheumatic Manifestations of Systemic Disorders; Sjögren’s Syndrome 815
For a deeper discussion of these topics, please see Chapter
269, “Inflammatory Myopathies,” in Goldman-Cecil Med-
icine, 25th Edition.
Miscellaneous Conditions
Other rheumatologic syndromes that may be harbingers of neo-
plasia include eosinophilic fasciitis, palmar fasciitis, reflex sympa-
thetic dystrophy, erythromelalgia, Sweet’s syndrome, and
osteomalacia. Up to 15% cases of Sweet’s syndrome (i.e., acute
neutrophilic dermatosis) are associated with malignancy, and it
can manifest as an acute, self-limited polyarthritis or vasculitis.
Knee pain or shoulder pain with normal physical examination
findings can be a referred pain from various neoplasms.
  HEMATOLOGIC DISORDERS WITH
RHEUMATIC MANIFESTATIONS
Hemophilia
Acute, painful hemophilic arthropathy of the knees, elbows, and
ankles is the most common manifestation of hemophilia.
Repeated episodes of hemarthrosis result in synovial prolifera-
tion and chronic inflammation, causing chronic hemophilic
arthropathy.
Chronic hemophilic arthropathy is characterized by joint
deformity, fibrous ankylosis, and osteophyte overgrowth. Radi-
ography typically shows degenerative arthritis. Besides prompt
administration of factor concentrate replacement, acute hem-
arthrosis must be treated conservatively with cold applications
and joint immobilization followed by a structured physical
therapy program. Aspiration (after factor replacement) is needed
only if concomitant sepsis is suspected or the joint is very
tense.
Sickle Cell Disease
Musculoskeletal complications of sickle cell disease include
painful crises, arthropathy, dactylitis, osteonecrosis, and osteo-
myelitis. Sickle cell crisis is the most common musculoskeletal
feature, and it can produce painful arthritis of the large joints and
noninflammatory joint effusions adjacent to areas of bony crisis.
Osteonecrosis of the femoral head, shoulder, and tibial plateau
may result from repeated local bone ischemia or infarct.
Dactylitis manifesting as bilateral, painful, swollen hands or
feet (i.e., hand-foot syndrome) may be the first manifestation of
the disease in infants and young children. It usually resolves spon-
taneously in a few weeks. Increased risk of septic arthritis and
osteomyelitis, most often due to Salmonella species, has been
associated with hemoglobinopathies.
Multiple Myeloma
Rheumatologic manifestations of multiple myeloma include
bone pain resulting from lytic bone lesions, pathologic fractures,
and osteoporosis. Thoracolumbar pain in the setting of hypercal-
cemia, renal insufficiency, and anemia suggests the possibility of
multiple myeloma. Multiple myeloma can manifest atypically
and mimic specific autoimmune disorders such as Sjögren’s syn-
drome (SS) and SLE.
Amyloidosis
Amyloidosis is a disorder of protein folding in which insoluble
fibrillar proteins are deposited in the extracellular space in one or
more organs, disrupting tissue structure and function. The
clinical manifestations and prevalence depend on the type of
amyloidosis.
Myeloma-associated amyloidosis (i.e., amyloid light-chain
[AL] amyloidosis) is one of the most common forms of systemic
amyloidosis. Amyloid proteins derived from monoclonal light
chains can involve the synovium and the articular cartilage, pro-
ducing rheumatoid arthritis–like polyarthritis. Joint stiffness is
more pronounced in amyloid arthropathy, and deposition of
amyloid protein at the glenohumeral joint produces enlargement
of the anterior shoulder, called the shoulder pad sign. Other rheu-
matic manifestations of AL amyloidosis include muscle weak-
ness, pseudohypertrophy of muscles, and pathologic fracture
from osteolytic lesions, jaw claudication that mimics giant cell
arteritis, and sicca syndrome due to exocrine gland infiltration.
The amyloid protein can be identified as apple green birefrin-
gence on Congo red staining of an abdominal fat pad aspiration
or rectal mucosal biopsy specimen. The other principal systemic
forms of amyloidosis are secondary amyloidosis (i.e., deposition
of amyloid A [AA] protein), hereditary amyloidosis, and β2-
microglobulin–associated amyloidosis.
Endocrine Disorders
Endocrine diseases usually manifest with diffuse, poorly defined
musculoskeletal symptoms and joint pain that is more often
periarticular than articular. Clinical suspicion of endocrinopathy
is by far the most important diagnostic step. Routine clinical
laboratory tests such as ESR, ANA, rheumatoid factor, uric acid
level, and an antistreptolysin O (ASO) titer are usually not
helpful, and radiographs often first suggest the possibility of
endocrinopathy.
Diabetes
One of the most common musculoskeletal complications of dia-
betes is diabetic cheiroarthropathy (i.e., diabetic hand syndrome).
It is characterized by insidious development of waxy thickening
of the skin of the fingers and hands and by flexion contractures
of the metacarpophalangeal joints and interphalangeal joints.
Patients cannot press the palms together completely without a
gap with the wrists fully flexed (i.e., prayer sign). Although this
syndrome is associated with the duration of diabetes and the
control of blood sugar, it may develop before the onset of overt
diabetes and mimic sclerodactyly.
Dupuytren contracture and stenosing flexor tenosynovitis
(i.e., trigger finger) may be identified. People with diabetes are
more prone to develop a carpal tunnel syndrome. Diabetic peri-
arthritis of the shoulders (i.e., adhesive capsulitis or frozen shoul-
der) is more common in patients with diabetes, especially in
women with a long history of diabetes. Capsulitis is characterized
by staged progression of pain and restriction of shoulder motion,
and bilateral involvement occurs in about one half of patients.
Patients with long-standing, poorly controlled diabetes may
develop a painless, swollen, deformed joint known as a Charcot
816 Section XIV  Musculoskeletal and Connective Tissue Disease
joint or neuropathic arthropathy. Tarsal, metatarsophalangeal,
and tarsometatarsal joints are most commonly involved, and it
can be confused with osteomyelitis on radiographs.
Diffuse idiopathic skeletal hyperostosis (DISH) is seen in up
to 20% of diabetic patients, who are typically obese and older
than 50 years. It is associated with neck and back stiffness rather
than pain. Lateral radiographic views of the spine show four or
more contiguously fused vertebrae as a result of flowing ossifica-
tion of the anterior longitudinal ligament without involvement of
apophyseal (facet) joints.
Diabetic amyotrophy (i.e., diabetic lumbosacral radiculo-
plexus neuropathy) is remarkable for acute or subacute onset of
severe hip, buttock, or thigh pain followed by progressive weak-
ness of the affected extremity. It occurs typically in older male
patients who have relatively well-controlled diabetes, and there
are often preceding anorexia, weight loss, and unsteady gait.
Hypothyroidism
Almost one third of patients with hypothyroidism have muscu-
loskeletal symptoms. Arthritis of hypothyroidism can resemble
early rheumatoid arthritis, affecting small joints of the hands and
wrists, but it is not erosive or deforming. In contrast, myxedema-
tous arthropathy classically involves large joints such as knees.
Many hypothyroid patients experience carpal tunnel syn-
drome, trigger finger, Raynaud phenomenon, and pseu­dogout.
Acute pseudogout can be a presenting feature of hypothyroidism.
Hypothyroidism can also cause a broad spectrum of muscular
diseases. Hypothyroid patients may have asymptomatic elevation
of muscle enzymes, but a few patients develop proximal muscle
weakness or polymyositis-like syndrome. Patients may complain
of fatigue, malaise, and fibromyalgia-like generalized muscle pain.
Rarely, hypothyroid myopathy manifests with muscle enlarge-
ment, stiffness, and muscle cramps (i.e., Hoffmann’s syndrome).
Hyperthyroidism
Common rheumatic symptoms of hyperthyroidism include
proximal myopathy, periarthritis of the shoulder, thyroid acro-
pachy (i.e., thickened skin with periosteal new bone formation),
and osteoporosis. Proximal muscle weakness is more frequently
observed in elderly patients with apathetic or masked hyperthy-
roidism. Asking a patient to stand from a squat position can
reveal the proximal muscle weakness.
Hyperparathyroidism
Musculoskeletal symptoms, often widespread and nonspecific,
are common in hyperparathyroidism and can be the clinical pre-
sentation for many patients. The musculoskeletal manifestations
of hyperparathyroidism include osteitis fibrosa cystica (i.e., bone
pain, osteopenia, and bony cysts), subperiosteal resorption, pseu-
dogout, rheumatoid arthritis–like disorder, diffuse osteopenia,
spinal compression fracture, and proximal myopathy. Secondary
hyperparathyroidism is the leading cause of renal osteodystrophy
in chronic kidney disease.
Acromegaly
Acromegalic arthropathy commonly develops in the large joints
and is seen in approximately 70% of the patients with acromegaly.
Overgrowth of cartilage initially produces joint space widening,
but it may eventually lead to severe osteoarthritis with pain,
limited range of motion, and deformity.
  GASTROINTESTINAL DISEASES WITH
RHEUMATIC MANIFESTATIONS
Whipple’s Disease
Whipple’s disease is a rare, multisystemic disease that most
often affects the gastrointestinal tract. It is caused by infection
with Tropheryma whippelii. Musculoskeletal symptoms of Whip-
ple’s disease are the most common prodrome, and they may
exist for years before the diagnosis. Intermittent migratory
oligoarthritis of large joints is typical, but some patients may
have a florid polyarthritis. Synovial fluid is usually inflamma-
tory with predominant mononuclear cells. Radiographs are
often normal.
Hemachromatosis
Hemochromatosis is one of the most common genetic diseases
among people with northern European ancestry, and it is
frequently associated with osteoarthritis-like arthropathy, chon-
drocalcinosis, and osteoporosis. The second and third metacar-
pophalangeal joints of both hands are typically involved, and
hooklike osteophytes on the radial side of the metacarpal are
characteristic in radiographs. Chondrocalcinosis of the wrist and
knee is very common in patients with hemochromatosis. Acute
attacks of pseudogout can be a predominant clinical manifesta-
tion. Treatment with regular phlebotomies and iron chelation has
little effect on the arthropathy.
Primary Biliary Cirrhosis
Primary biliary cirrhosis is frequently associated with other auto-
immune diseases, such as limited scleroderma, rheumatoid
arthritis, SS, and autoimmune thyroid disease. Vitamin D defi-
ciency is highly prevalent among patients with primary biliary
cirrhosis, and the risk of developing osteoporosis is markedly
increased in women with this disease.
  OTHER SYSTEMIC ILLNESSES WITH
RHEUMATIC MANIFESTATIONS
Human Immunodeficiency Virus Infection
Patients with human immunodeficiency virus (HIV) disease may
have osteomyelitis, osteonecrosis, reactive arthritis, or psoriatic
arthritis.
Sarcoidosis
Clinical features of sarcoidosis can mimic those of many acute
and chronic rheumatic diseases. Acute sarcoidosis or Löfgren’s
syndrome manifests with fever, erythema nodosum, hilar lymph-
adenopathy, and acute polyarthritis, almost invariably involving
the ankles and knees. The arthritis is usually self-limited and
tends to be nondeforming and nonerosive.
Chronic sarcoid arthritis is less common and usually associ-
ated with active multisystemic disease. Osseous involvement can
be a focal or generalized and occurs in about 5% of patients
with sarcoidosis. Bone cysts are usually asymptomatic, but they
can manifest in the phalanges with sausage-like fingers or
 Chapter 85  Rheumatic Manifestations of Systemic Disorders; Sjögren’s Syndrome 817

pseudoclubbing. Focal osteolytic changes can lead to pathologic

fractures. Sarcoid muscle involvement is often asymptom- TABLE 85-3  EXTRAGLANDULAR CLINICAL FEATURES
atic, but it may manifest with proximal pain, progressive weak- OF SJÖGREN’S SYNDROME
ness, or atrophy. SKIN AND MUCOUS
MEMBRANES CENTRAL NERVOUS SYSTEM
Lower extremity purpura associated Focal defects including multiple
  SJÖGREN’S SYNDROME with hyperglobulinemia and/or sclerosis, stroke
leukocytoclastic vasculitis on Diffuse deficits including dementia,
Definition and Epidemiology biopsy cognitive dysfunction
SS is a chronic autoimmune disorder characterized by infiltration Photosensitive lesions Spinal cord involvement including
indistinguishable from those of transverse myelitis
of exocrine glands by predominantly CD4+ T lymphocytes, subacute cutaneous lupus
resulting in dry eyes (i.e., keratoconjunctivitis sicca) and dry erythematosus
mouth (i.e., xerostomia). SS can occur as a primary disorder or PULMONARY SYSTEM PERIPHERAL NERVOUS SYSTEM
can be associated with other autoimmune diseases (i.e., second- Chronic bronchitis due to dryness Peripheral sensorimotor neuropathy
ary SS) such as rheumatoid arthritis and SLE. of the tracheobronchial tree Trigeminal sensory neuropathy, optic
Lymphocytic interstitial nerve
SS is the second most common rheumatic disease, with a com- pneumonitis, interstitial
munity prevalence of primary SS ranging from 0.1% to 0.6% in pulmonary fibrosis, chronic
different studies. However, many patients remain undiagnosed, obstructive lung disease,
cryptogenic organizing
and little is known about the prevalence of SS in the general pneumonia, pseudolymphoma
population. The disease is diagnosed nine times more often in with intrapulmonary nodules
women than in men and tends to manifest in patients older than MUSCULOSKELETAL SYSTEM RETICULOENDOTHELIAL SYSTEM
40 years, although it may be seen among people of all ages. Polymyositis Splenomegaly
Polyarthralgia, polyarthritis Lymphadenopathy and development
Pathogenesis and Pathology of pseudolymphoma
The pathogenesis of SS is not fully understood, although accu- RENAL SYSTEM HEPATOBILIARY SYSTEM
mulating evidence shows that chronic immune system stimula- Tubulointerstitial nephritis Hepatomegaly
tion in genetically predisposed individuals (HLA-DR3) is Type 1 renal tubular acidosis Primary biliary cirrhosis
important. Upregulation of type 1 interferon-regulated genes VASCULAR SYSTEM ENDOCRINE SYSTEM
(i.e., interferon signature) and abnormal expression of B-cell acti- Raynaud’s phenomenon Hypothyroidism caused by
Small vessel vasculitis, with a Hashimoto’s thyroiditis
vating factor (BAFF) and its receptors appear to play an impor- mononuclear perivascular Other autoimmune endocrinopathies
tant role in the development of SS. infiltrate or leukocytoclastic
Exocrine gland involvement is characterized by a focal lym- changes on biopsy
phocytic sialadenitis and hyperplasia of salivary ductal epithe-
lium seen on minor salivary gland biopsy. Parenchymal atrophy
fibrosis or fatty infiltration, or both, are common in the elderly
and should not be confused with SS. Skin
The major cutaneous manifestations of SS include dry, scaly
Clinical Presentation skin, itchy annular erythema, cutaneous vasculitis, and Raynaud’s
The clinical features of SS can be divided into exocrine gland phenomenon. Cutaneous vasculitis occurs in approximately 10%
dysfunction and extraglandular manifestations. Subjective symp- of patients with SS. It typically involves small and medium-
toms of dry eyes and mouth are the most common problems for sized vessels, leading to palpable purpura, urticaria, or skin
most affected patients. Many years can elapse before the diagno- ulceration. Raynaud’s phenomenon can precede other features
sis is established because of nonspecific initial manifestations. by many years, and it does not cause digital ulceration or
Patients with keratoconjunctivitis sicca complain of chronic infarcts.
gritty or sandy eye irritation rather than describing dryness. They
may also report itching, photophobia, and the accumulation of Pulmonary Disease
thick mucous filaments at the inner canthus. Severe dry eyes can Lung manifestations of SS include asymptomatic interstitial lung
result in vision impairment and punctate keratopathy, which can disease, pulmonary function abnormalities, and cryptogenic
be detected by fluorescein, lissamine green, or rose bengal organizing pneumonia by lymphocytic infiltration around bron-
staining. chioles. Lymph node enlargement of the lung and pulmo-
Decreased saliva production can lead to dental caries, gingival nary lymphoproliferative disease typically is seen only in patients
recession, oral candidiasis, chronic esophagitis, weight loss due with primary SS.
to difficulty chewing and swallowing, and nocturia. Other exo-
crine gland dysfunction includes recurrent nonallergic rhinitis Joints
and sinusitis, vaginal dryness with associated dyspareunia in About one half of primary SS patients are affected by joint pain,
women with SS and dry cough due to laryngeal, tracheal, and with or without evident synovitis. It usually involves the hands
bronchial involvement. SS is a systemic disease and one third of and knees symmetrically. Arthropathy is typically nonerosive and
patients with primary SS have various extraglandular features nondeforming. Identification of rheumatoid factor is associated
(Table 85-3). with a higher prevalence of articular symptoms.
818 Section XIV  Musculoskeletal and Connective Tissue Disease
Renal Disease
Urine acidification abnormalities of the distal renal tubule
leading to complete or incomplete distal renal tubular acidosis
are the most common manifestation of renal involvement, but
overt renal disease is less common. Glomerular diseases such as
membranoproliferative glomerulonephritis and membranous
nephropathy can occur in patients with SS and SLE overlap or
those with cryoglobulinemia and hypocomplementemia.
Cardiovascular System
Although pericardial effusion can be seen on the echocardio-
gram, primary SS patients rarely have acute pericarditis. Placental
transmission of maternal anti-Ro/SSA and anti-La/SSB antibod-
ies can cause neonatal lupus and fatal fetal congenital heart block.
In women with these antibodies, there is 5% risk of their first
child being born with heart block. This risk rises to 15% with
subsequent pregnancies. Fetal heart rate monitoring in the ante-
natal period is essential.
Neuromuscular Disease
Peripheral neuropathy occurs in about 10% of patients with SS
and can precede sicca symptoms. Diagnosis of small fiber neu-
ropathy may require quantitative sudomotor autonomic reflex
testing or measurement of epidermal nerve density by biopsy.
Cranial nerves, particularly the trigeminal and optic nerves, can
be involved as a consequence of vasculitis. Although the fre-
quency of central nervous system involvement remains contro-
versial, focal or diffuse brain lesions and multiple sclerosis–like
syndromes have been reported. Myalgia is very common, but
symptomatic inflammatory myopathy is rare.
Lymphoproliferative Disease
Patients with SS are predisposed to develop lymphoma (primar-
ily B cell in origin). Risk factors include cutaneous vasculitis,
peripheral neuropathy, rheumatoid factor, cryoglobulinemia, and
hypocomplementemia. Development of new masses with consti-
tutional symptoms or persistent lymph node enlargement should
raise concern for malignancy.
Gastrointestinal and Hepatobiliary Disease
Dysphagia commonly results from dryness of the pharynx and
esophagus. Lymphocytic infiltration, predominantly by CD4+ T
cells, may cause chronic atrophic gastritis, achlorhydria, and per-
nicious anemia. Although liver involvement in primary SS
patients is rare, histologic features show a clear association
between SS and hepatic abnormalities. However, other causes of
abnormal liver function test results in SS, particularly hepatitis C
infection and drug toxicity, should be considered.
Diagnosis and Differential Diagnosis
Although there are no established diagnostic criteria for SS, clas-
sification criteria were developed for use in research. The
American-European Consensus Group (AECG) classification is
most widely accepted, and it requires demonstration of the
following:
1. Signs and symptoms of inadequate tear production and
decreased salivary gland function
2. Detection of autoantibodies (anti-Ro/SSA or anti-La/SSB, or
both)
3. Exclusion of underlying diseases that may mimic SS, including
head and neck irradiation, hepatitis C, acquired immune defi-
ciency syndrome, preexisting lymphoma, sarcoidosis, graft-
versus-host disease, and anticholinergic drug use.
A provisional classification was proposed by American College
of Rheumatology and the Sjögren International Collaborative
Clinical Alliance investigators (ACR-SICCA), but it has not been
validated completely. The MAIN differences between the AECG
and ACR-SICCA criteria are that ocular or oral dryness symp-
toms are not required in the latter and the ACR criteria do not
distinguish between primary and secondary forms of SS.
The diagnosis of SS is made on the basis of compatible
clinical and laboratory features and after the exclusion of other
causes of sicca symptoms. Various tests are used to evaluate
the objective glandular component of the disease. To confirm
keratoconjunctivitis sicca, the Schirmer test, the rose bengal
test, and tear breakup time can be used. Salivary gland scin-
tigraphy with uptake of technetium-99m, parotid sialography,
and measurement of unstimulated production of saliva (i.e.,
Saxon test) may provide objective evidence of xerostomia. A
labial salivary gland biopsy is often essential in evaluating patients
with suspected SS, particularly when the patients lack anti-Ro/
SSA or anti-La/SSB antibodies. Rheumatoid factor and ANAs
are commonly detected, and patients may be erroneously diag-
nosed with rheumatoid arthritis. Common laboratory findings
include anemia, thrombocytopenia, leukopenia, raised ESR,
monoclonal gammopathy, and hypergammaglobulinemia.
Other conditions can produce keratoconjunctivitis sicca
symptoms, xerostomia, or lacrimal and salivary gland enlarge-
ment. The differential diagnosis of SS must consider infectious
diseases such as diffuse infiltrative lymphadenopathy syndrome
associated with HIV, hepatitis B and C, human T-cell lympho-
tropic virus infection, syphilis, and infection with mycobacteria,
and it must take into account infiltrative diseases such as sarcoid-
osis and amyloidosis. Anticholinergic side effects from many
drugs, including over-the-counter products, should be consid-
ered during assessment of dry eyes and dry mouth. Sicca symp-
toms may result from overlap syndromes, which may have
features of SS and SLE or of SS and scleroderma.
Treatment
No cure for SS is available. Because of the diverse symptoms of
SS, several medications are used to ameliorate the symptoms
outlined in Table 85-4. Patients with moderate to severe involve-
ment may require systemic medical therapy, including the use of
immunosuppressive and biologic agents. There is no evidence
that azathioprine, low-dose steroids, cyclosporine, infliximab, or
methotrexate are useful. Hydroxychloroquine normalizes the
ESR and immunoglobulin levels, but it does not increase the sali-
vary flow rate significantly. Many clinicians use it to treat rash,
fatigue, myalgia, and arthralgia. B-cell and anticytokine or
antichemokine-directed therapies are active areas of research.
Prognosis
Primary and secondary forms of SS are characterized by chronic
courses and different rates of progression. Systemic involvement
 Chapter 85  Rheumatic Manifestations of Systemic Disorders; Sjögren’s Syndrome 819

For a deeper discussion of these topics, please see Chapter

TABLE 85-4  TREATMENT OPTIONS FOR SJÖGREN’S 268, “Sjögren’s Syndrome,” in Goldman-Cecil Medicine,
SYNDROME 25th Edition.
LOCAL TREATMENT OF EXOCRINE DYSFUNCTION
Keratoconjunctivitis Sicca SUGGESTED READINGS
Artificial tears, preservative free Cordner S, De Ceulaer K: Musculoskeletal manifestations of hemoglobinopa-
Eyeglasses and/or goggles thies, Curr Opin Rheumatol 15:44–47, 2003.
Punctal occlusion (plugs or electrocautery)
Garcia-Carrasco M, Ramos-Casals M, Rosas J, et al: Primary Sjögren syndrome:
Topical cyclosporine drops
clinical and immunologic disease patterns in a cohort of 400 patients, Medicine
Xerostomia (Baltimore) 81:270–280, 2002.
Artificial saliva Hansen A, Lipsky PE, Dorner T: Immunopathogenesis of primary Sjögren’s
Salivary stimulators, mechanical or electrical syndrome: implications for disease management and therapy, Curr Opin
Fluoride treatments and/or fastidious dental care Rheumatol 17:558–565, 2005.
Sugar-free lozenges, lemon drops King JK, Costenbader KH: Characteristics of patients with systemic lupus
Dyspareunia erythematosus (SLE) and non-Hodgkin’s lymphoma (NHL), Clin Rheumatol
Vaginal lubricants or propionic acid gels 26:1491–1494, 2007.
Rigorous treatment of infection Markenson JA: Rheumatic manifestations of endocrine diseases, Curr Opin
Rheumatol 22:64–71, 2010.
SYSTEMIC TREATMENT OF EXOCRINE DYSFUNCTION
Ravindran V, Anoop P: Rheumatologic manifestations of benign and malignant
Pilocarpine or cevimeline haematological disorders, Clin Rheumatol 30:1143–1149, 2011.
When possible, avoid or discontinue medications with anticholinergic effects Shiboski SC, Shiboski CH, Criswell L, et al: American College of Rheumatology
TREATMENT OF SYSTEMIC MANIFESTATIONS classification criteria for Sjögren’s syndrome: a data-driven, expert consensus
Salivary gland infection: tetracycline and nonsteroidal anti-inflammatory approach in the Sjögren’s International Collaborative Clinical Alliance cohort,
drugs Arthritis Care Res 64:475–487, 2012.
Arthralgia: hydroxychloroquine or chloroquine St Clair EW, Levesque MC, Prak ET, et al: Rituximab therapy for primary
Systemic vasculitis and glomerulonephritis: glucocorticoids and/or Sjögren’s syndrome: an open-label clinical trial and mechanistic analysis,
cyclophosphamide Arthritis Rheum 65:1097–1106, 2013.
Leukocytoclastic vasculitis: no specific therapy
Interstitial lung disease: glucocorticoid, cyclophosphamide

of lungs, kidneys, nervous system, and skin may develop, and the
risk of developing lymphoma is increased among patients with
primary SS, particularly those with the previously described risk
factors. The overall mortality rate for SS is not higher than that
of the general population.
XV
Infectious Disease
86  Host Defenses against Infection
Bharat Ramratnam and Edward J. Wing
87  Laboratory Diagnosis of Infectious
Diseases
Kimberle Chapin
88  Fever and Febrile Syndromes
Ekta Gupta and Maria D. Mileno
89  Bacteremia and Sepsis Syndrome
Russell J. McCulloh and Steven M. Opal
90  Infections of the Nervous System
Allan R. Tunkel, Marjorie A. Janvier, and
Avindra Nath
91  Infections of the Head and Neck
Edward J. Wing
92  Infections of the Lower Respiratory Tract
John R. Lonks
93  Infections of the Heart and Blood Vessels
Cheston B. Cunha and Eleftherios Mylonakis
94  Skin and Soft Tissue Infections
Sajeev Handa
95  Intraabdominal Abscess and Peritonitis
Edward J. Wing
ESSENTIALS
96  Infectious Diarrhea
Awewura Kwara
97  Infections Involving Bones and Joints
Jerome Larkin
98  Infections of the Urinary Tract
Joao Travares and Steven M. Opal
99  Health Care−Associated Infections
Steven “Shaefer” Spires and Thomas R. Talbot
100  Sexually Transmitted Infections
Philip A. Chan and Susan Cu-uvin
101  Human Immunodeficiency Virus Infection and
Acquired Immunodeficiency Syndrome
Brian T. Montague, Aadia I. Rana, Edward J. Wing, and
Timothy P. Flanigan
102  Infections in the Immunocompromised Host
Staci A. Fischer
103  Infectious Diseases of Travelers: Protozoal and
Helminthic Infections
Rebecca Reece, Aadia I. Rana, and Erna Milunka Kojic
821
 86 
Host Defenses Against Infection
Bharat Ramratnam and Edward J. Wing
  HOST VERSUS PATHOGEN: VICTORY,
DEATH, OR COEXISTENCE
Many factors determine whether we live successfully in sym-
biosis with our normal microbial flora, whether we can resist
exposure to outside pathogens, and whether we live or die
in an environment filled with an incredibly wide spectrum of
microbes. Factors include age, nutrition, underlying medical
conditions (e.g., diabetes mellitus, chronic lung disease), and
the nature of the exposure (e.g., microbial virulence, inoculum).
The outcome is determined by our host defenses, including
barriers (e.g., skin), innate immunity (e.g., phagocytes), and
specific responses that include antibodies and T cell–mediated
events.
The human host has developed a multilayered host defense
system to counter infectious organisms, and the resulting duel
between pathogen and human can lead to one of four outcomes:
death of the human host, elimination of the pathogen, peaceful
coexistence of both in a symbiotic relationship, or an association
whose latent nature changes with time and under additional bio-
logic pressures. For example, pneumococcal pneumonia may kill
the individual, or the host’s defenses may eliminate the organism.
Escherichia coli and Bacteroides fragilis in the gut survive and help
to protect the host in a symbiotic relationship. Most individuals
exposed to Mycobacterium tuberculosis are asymptomatic and
latently infected with an inactive nonreplicating organism.
Almost one third of the world’s population is latently infected,
but only about 10% progress to active disease. Immunologic
impairment (e.g., human immunodeficiency virus [HIV] infec-
tion) and factors such as age increase the risk of progressing from
latent to active disease.
The asymptomatic nature of an infection should not automati-
cally be equated with latency or dormancy of the pathogen. For
example, chronic HIV-1 infection was incorrectly characterized
as having a prolonged latent or silent stage before the host devel-
oped immunodeficiency and opportunistic infections. However,
most untreated HIV-1–infected individuals harbor actively repli-
cating virus that kill CD4+ T lymphocytes on a daily basis,
although the aggregate effects are not appreciated until CD4+ T
lymphocyte levels are reduced to below 200 cells/mL after 8 to
10 years of infection. Infected individuals are infectious despite
their relatively asymptomatic state, and in resource-rich coun-
tries, treatment is recommended regardless of CD4+ T lympho-
cyte levels. Treatment halts viral immune destruction, reduces
viral burden in genital secretions, and decreases an infected indi-
vidual’s risk of transmitting HIV-1.
822
  CATEGORIES OF HOST DEFENSES
AND RISKS OF INFECTION
The relative importance of the innate and adaptive defenses is
best illustrated by hosts who are deficient in a particular compo-
nent. For example, chemotherapy leading to the depletion of
immune cells such as neutrophils renders the host more suscep-
tible to bacterial and fungal infections. Congenital deficiency of
immunoglobulins increases the risk of infections that are usually
thwarted by antibody responses such as those associated with
Streptococcus pneumoniae and Haemophilus influenzae. Pharmaco-
logic inhibition of tumor necrosis factor-α (TNF-α) increases
the risk of developing active tuberculosis among those with latent
infection. Astute clinicians, recognizing the increased incidence
of atypical infections such as those caused by Pneumocystis jirove-
cii among young men, sounded the alarm that a novel immuno-
deficiency syndrome had appeared that was later ascribed to
HIV-1.
Host defenses to infection can be classified as nonimmuno-
logic host defenses, innate immunity, and specific or adaptive
immunity. Immune host defenses against microbial pathogens
are composed of cells and molecules located in peripheral sites,
such as the skin and submucosal regions, and in secondary lym-
phoid tissues, such as the lymph nodes, tonsils, spleen, and
Peyer’s patches.
For a deeper discussion of these topics, please see Chap-
ters 45 through 50 in Section VII, “Principles of Immunol-
ogy and Inflammation,” in Goldman-Cecil Medicine, 25th
Edition.
Nonimmunologic Host Defenses
Nonimmunologic host defenses include epidermal and mucosal
barriers that physically prevent the entry of pathogens into the
body. The respiratory tract defenses depend on mucus that
entraps pathogens and on ciliary action and cough that continu-
ously clear the mucus and organisms from the lungs and upper
airways. Respiratory viruses, including influenza, may inhibit
ciliary action or denude the mucous membrane completely,
allowing bacteria to colonize and cause infection. Stroke, medi-
cations, or other causes of reduced cough reflex may lead to
poor clearance of secretions, mucus, and pathogens and cause
lung infection. Smoking and industrial exposure to toxins such
as silica may similarly reduce lung host defenses, such as reduc-
ing ciliary action that leads to infection. In addition to mucus
and ciliary action, alveolar macrophages located in the lung
 Chapter 86  Host Defenses Against Infection 823
parenchyma play an essential role in initial clearance and killing
of pathogens.
Gastrointestinal defenses include gastric acidity, which kills
many organisms, and vomiting and diarrhea, which help to clear
pathogens from the gut. Bacteria vary greatly in their susceptibil-
ity to gastrointestinal host defenses. For example, as few as 10
Shigella organisms can cause infection, whereas 105 to 108 Vibrio
cholera organisms are required for infection.
The urinary tract is protected physically by regular urine flow,
the acidity of the urine, and antibacterial proteins. Conditions
that interfere with these factors (e.g., prostatic hypertrophy, renal
stones) may lead to stasis and infection. Mechanical injection of
bacteria through the urethra into the bladder, as occurs in women
during sexual intercourse, can lead to colonization of the bladder
and infection. Injuries or devices that damage or bypass anatomic
barriers frequently lead to infection. Examples include burns,
intravenous catheters, intubation, urinary tract catheters, surgery,
and trauma.
The normal microbiologic flora on the skin and in the respira-
tory and gastrointestinal tracks is an important component of
host defenses. Normal florae compete with pathogens for nutri-
ents and have antimicrobial activity of their own. Disruption of
the normal flora by antibiotics allows superinfecting organisms
such as Candida species and Clostridium difficile in the gut to colo-
nize and then cause infection.
Organs that clear organisms from the bloodstream and lymph,
including the liver, spleen, and lymph nodes, play an essential role
after a pathogen has breached the primary anatomic barriers.
Lack of a spleen increases a person’s susceptibility to overwhelm-
ing sepsis caused by encapsulated bacteria including S. pneu-
moniae, Neisseria meningitidis, and H. influenzae. Cirrhosis of the
liver allows portal vein blood to bypass the liver, increasing sus-
ceptibility to infection by gut flora.
Innate Immunity
Innate immunity refers to cells, molecules, and cellular receptors
that recognize pathogens and promote inflammation nonspecifi-
cally at the site of infection. Table 86-1 compares innate and
adaptive immunity. The response of innate immunity is relatively
nonspecific, invariant, rapid, and without memory. Adaptive
immunity is highly specific, slow during primary infection, and
TABLE 86-1  FEATURES OF THE INNATE AND
ADAPTIVE IMMUNE RESPONSES
INNATE RESPONSE ADAPTIVE RESPONSE
No memory: quality and intensity of Memory: response adapts with each
response invariant exposure
Recognizes limited number of Recognizes vast array of specific
nonvarying, generic molecular antigens* on or made by pathogens
patterns on or made by pathogens
Pattern recognition mediated by a Antigen recognition mediated by a
limited array of receptors vast array of antigen-specific
receptors
Response immediate on first Response on first encounter takes
encounter 1-2 weeks; on second encounter,
3-7 days
From Kumar P, Clark M, editors: Kumar and Clark’s clinical medicine, ed 8, London, 2012,
Elsevier.
*Antigen is a molecular structure (e.g., protein, peptide, lipid, carbohydrate) that
generates an immune response.
can be recalled after primary infection with a more rapid, robust
response.
The molecules involved in innate and acquired immunity
include cytokines, chemokines, and integrins. Cytokines are
soluble proteins that have numerous functions, including pro-
moting cellular growth and activation as well as regulating the
adaptive immune response (Table 86-2). Their functions range
from stimulating the production of and activating inflammatory
cells, including neutrophils, macrophages, and eosinophils, to the
direct antiviral action of interferons. Some activate endothelial
cells and cause fever, whereas others are regulatory and down-
regulate the inflammatory response.
Concentration gradients of chemokines in tissue attract leuko-
cytes to areas of inflammation. Integrins on the surface of leuko-
cytes allow adhesion to receptors on other types of cells such as
vascular endothelium. This is the first step in attracting and local-
izing leukocytes to areas of inflammation.
Relatively nonspecific pathogen recognition receptors on
phagocytes include toll-like receptors (TLRs), which were origi-
nally described in the fruit fly, Drosophila; oligomerization
domain–like receptors (often abbreviated as Nod-like receptors);
C-type lectin-like receptors; and intracellular receptors that
detect double-stranded RNA. TLRs have been studied exten-
sively (Table 86-3). TLRs are located on several cell types,
including macrophages and dendritic cells. When a pathogen is
detected by its adherence to a TLR on the surface of a cell, activa-
tion of nuclear transcription factors, including nuclear factor-κB,
occurs. This stimulates the production of numerous cytokines
important in the inflammatory response, including interleukin-1
(IL-1), IL-6, IL-10, IL-15, TNF-α, and growth factors (see Table
86-2). These cytokines amplify the inflammatory response by
activating effector cells and by stimulating the production of
many other inflammatory factors, including IL-2, interferons,
C-reactive protein, complement components, and growth factors.
Complement factors are soluble proteins and enzymes that are
produced in the liver. Complement activation occurs through
several pathways that are involved in the innate and acquired host
defense system as shown in Figure 86-1. Complement activation
can occur as a result of antigen-antibody immune complex
binding of C1, the mannose-binding lectin pathway, or the alter-
native pathway, which can be activated by bacterial cell wall
components.
The complement cascade results in C3 convertase, a protein
that cleaves C3. Cleavage of C3 leads to the production of mul-
tiple proteins (C3a, C4a, and C5a) that stimulate histamine
release from mast cells leading to vasodilatation, increased endo-
thelial permeability, and attraction of activated neutrophils. A
second cleavage product of C3, C3b, in conjunction with immu-
noglobulin G (IgG) stimulates phagocytosis of pathogens. Acti-
vation of C5-9 results in bacterial lysis. Patients deficient in the
complement components C5-9 appear to be particularly suscep-
tible to organisms such as N. meningitides and Neisseria gonor-
rhoeae. Complement activation is regulated by several regulatory
proteins, such as C1 esterase inhibitor that inhibits the inappro-
priate activation of the classic complement activation pathway.
The inflammatory response results in the clinical signs of
inflammation, including erythema, tenderness, warmth, and
swelling. It can be initiated by microorganisms in tissue, tissue
824 Section XV  Infectious Disease

TABLE 86-2  CYTOKINES

CYTOKINE CELLULAR SOURCE TARGETS FUNCTION RECEPTOR
IL-1α Epi, fibroblasts, damaged Wide variety “Dual function” cytokine involved in CD121a or CD121b
or dying cells initiating inflammatory response and
modifying gene expression
IL-1β M, B T, B, M, End, other Leukocyte activation, increases CD121a or CD121b
endothelium adhesion
IL-2 T TB, NK, M, oligo T cell proliferation, regulation CD122/CD25
IL-3 T,* Mas, Eos, NK, End Ery, G Proliferation and differentiation of CD123/CDw131
hematopoietic precursors
IL-4 Mas, T, M B, T, End Differentiation of TH2 and B cells CD124/CD132
IL-5 Mas, T, Eos Eos, B Growth differentiation of B cells and CD125/CDw131
eosinophils
IL-6 T, B, M, astrocytes, End T, B, others Hematopoiesis, differentiation, CD126/CD130
inflammation
IL-7 Bone marrow and pB, pT Pre/pro-B proliferation, T, upregulation CD127/CD132
thymic stroma of proinflammatory cytokines
IL-8 M, L, others PMN, Bas, L Chemoattractant CD128
IL-9 TH2* T, B Potentiates production of IgM, IgG, IgE
IL-10 CD8+ T,* TH2, (B),† M T, B, Mas, M Inhibits IFN-γ,TNF-β, IL-2 by TH1 cells, CD210
DTH, stimulates TH2
IL-11 Bone marrow stroma Osteoclast formation
IL-12 DC, B, T T, NK Potentiates IFN-γ and TNF-α production CD212
by T and NK, downregulates IL-10
IL-13 TH2,* Mas, NK TH2, B, M TH2 modulator, downregulated IL-1,
IL-6, IL-8, IL-10, IL-12
IL-14 T B* Stimulates proliferation, inhibits Ig
secretion
IL-15 M, Epi T, B* Proliferation
IL-16 Eos, CD8+ T* CD4+ T* CD4* chemoattractant
IL-17 (T) Epi, End, others Osteoclastogenesis, angiogenesis
IL-18 M TH1, NK Induces IFN-γ production, enhances NK
activity
IL-32 Tn, NK, Epi Wide variety Proinflammatory
TGF-β Eos, others Many cell types Anti-inflammatory, promotes wound
healing
TNF-α M,* PMN, T, B, NK M, PMN, T, End, others Mediator of inflammatory reactions CD120a and CD120b
TNF-β L Wide variety Mediator of inflammatory reactions CD120a and CD120b
IFN-α L, Epi, fibroblasts Wide variety Upregulates MHC class I, inhibits viral
proliferation
IFN-β Epi, fibroblasts Wide variety Upregulates MHC class I, inhibits viral
proliferation
+ +
IFN-γ CD8 ,* (CD4 *), NK T, B, M, NK, End Antiviral, antiparasitic, inhibits CD119
proliferation, enhances MHC class I
and II expression
M-CSF L, M, G, End, Epi, others M Growth and differentiation of Ms CD115
G-CSF T,* M, End G Growth and differentiation of Gs
GM-CSF T, M, End, Mas pG, pMye Stimulates growth and differentiation of CD116
Gs and Mye lineage cells
MIF M M Antiapoptotic activity for macrophages,
promotes M survival
From Doan T, Melvold R, Viselli S, Waltenbaugh C: Immunology, ed 2, Philadelphia, 2012, Lippincott, Williams & Wilkins.
B, B cells; Bas, basophils; CSF, colony-stimulating factor; DC, dendritic cells; DTH, delayed-type hypersensitivity; End, endothelium; Eos eosinophil; Epi, epithelium; Ery,
erythrocytes; G, granulocytes; IFN, interferon; IL, interleukin; L, lymphocytes; M, macrophage; Mas, mast cells; MHC, major histocompatibility complex; MIF, macrophage migration
inhibitory factor; Mye, myeloid; NK, natural killer cells; p, precursor; PMN, neutrophils; oligo, oligodendrocytes; T, T cell; TGF, transforming growth factor; TH, helper T cell subset; TNF,
tumor necrosis factor.
*Activated cells.
†
Parentheses indicate that only a subset of the designated cell types produce the cytokine.

injury, or dysfunctional adaptive immunity (e.g., autoantibod-

TABLE 86-3  TOLL-LIKE RECEPTORS ies). The response includes inflammatory molecules as previously
PRR PAMP PATHOGEN PRR EXPRESSION described and tissue and migrating leukocytes. Neutrophils are
TLR2 Peptidoglycan Gram-positive mDC central to the clinical manifestations of inflammation in tissue,
bacteria and patients with neutropenia often lack the signs of inflamma-
TLR3 Double-stranded RNA Viruses mDC tion at the site of serious infection.
TLR4 Lipopolysaccharide Gram-negative mDC
bacteria Neutrophils are bone marrow–derived phagocytes whose pro-
TLR7 Single-stranded RNA Viruses pDC duction is greatly stimulated by infection through the action of
TLR9 Double-stranded DNA Viruses pDC macrophage-produced growth factors, including granulocyte
From Kumar P, Clark M, editors: Kumar and Clark’s clinical medicine, ed 8, London, 2012, colony-stimulating factor (G-CSF) and granulocyte-macrophage
Elsevier.
mDC, Mature dendritic cell; PAMP, pathogen-associated molecular pattern; pDC,
colony-stimulating factor (GM-CSF). Neutrophils circulate
precursor dendritic cell; PRR, pattern recognition receptor; TLR, toll-like receptor. in blood, are attracted to sites of inflammation, and are activated
 Chapter 86  Host Defenses Against Infection 825

Classic Mannose-binding Alternative Basophils in blood and mast cells in tissue contain granules
pathway lectin pathway with histamine. They can be activated by complement factors and
Antigen-antibody pathway antigen-IgE binding on the surface of mast cells. Histamine is a
immune complexes short-acting, low-molecular-weight amine that acts through four
bind C1 Bacterial
cell wall different histamine receptors. Its actions include bronchocon-
C1 striction and bronchial smooth muscle contraction, itching, pain,
vasodilation, and increased vascular permeability. Histamine also
C1s protein subunit plays a role in gastric acid secretion, motion sickness, and sleep
cleaves C4 and C2 suppression. Commonly used antihistamines counter these
C4 C3 effects.
C2
Blood monocytes are produced in the bone marrow and cir-
culate for several days in the blood. They then migrate into
Cleavage of C3 tissues, where they phagocytize pathogens and debris and kill
microorganisms when activated by bacterial products such as
Inflammation Cleavage of C5 Opsonization lipopolysaccharide (LPS), interferon-γ, and other cytokines.
(C3a/C4a/C5a) of pathogens The properties and function of macrophages depend on the
C6 (C3b) tissue. Alveolar macrophages in the lung are continuously
C7 exposed to airborne particles and pathogens, whereas microglia
C8 in the brain have a very different environment and function. Mac-
C9
rophages clear cellular debris after acute inflammation, and thus
Final common pathway are the janitors of peripheral tissue. Macrophages produce a
variety of cytokines important in the inflammatory process,
Lysis of cells including IL-1, TNF-α, IL-6, IL-15, and leukocyte growth
(membrane attack complex)
(C5b–C9) factors.
Fever during inflammation and infection results from cyto-
FIGURE 86-1  The complement pathway and other effector func- kines such as IL-1 and TNF-α that are released by macrophages
tions. (From Kumar P, Clark M, editors: Kumar and Clark’s clinical medi-
cine, ed 8, London, 2012, Elsevier.)
into the circulation. These molecules increase the level of prosta-
glandins in the hypothalamus, which elevates the normal tem-
perature set point. This stimulates thermoregulatory mechanisms
by chemotactic factors, including formyl peptides derived from to elevate the core body temperature.
bacteria, complement C3a and C5a, IL-8, interferon, and leuko­ Macrophages play a central role in granuloma formation. For
trienes, particularly leukotriene B4. Neutrophils migrate from the example, macrophages are critical in controlling difficult-to-kill
endovascular space into inflammatory tissue through a compli- acid-fast mycobacteria such as M. tuberculosis or fungi by walling
cated integrin-regulated process that includes receptors on neu- off viable organisms in granulomas. Macrophages also present
trophils and endothelial cells. Activated neutrophils then migrate antigen derived from microbial pathogens to T cells, helping to
down a chemoattractive (i.e., chemokine) gradient toward the initiate the adoptive immune response. Cells of the myeloid
site of inflammation. lineage can control the immune response and are known as
Neutrophils are killing machines containing granules that have myeloid-derived suppressor cells.
up to 100 different antimicrobial molecules. The contents of Dendritic cells are derived from myeloid or lymphocytic pre-
granules are released intracellularly into phagosomes after phago- cursors. Dendritic cells are found primarily in tissues where
cytosis of a pathogen or released extracellularly in the vicinity of pathogens are likely to enter the body, such as the skin, gastroin-
pathogens. Phagocytosis is greatly enhanced by opsonization testinal tract, spleen, and respiratory tract. These cells have
(i.e., antibody and complement binding) of pathogens. The branchlike cytoplasmic extensions (for which they are named),
major microbicidal mechanism of neutrophils is the superoxide and they phagocytize pathogens in a manner similar to macro-
burst (i.e., production of superoxide anion catalyzed by NADPH phages. They are the major antigen-presenting cells (APCs) in
oxidase) and then the dismutation to hydrogen peroxide. Many the body.
other granule molecules, such as cathepsins, elastases, defensins, Natural killer (NK) cells are T lymphocytes that kill abnormal
and collagenase contribute to the killing process. Similar mecha- cells, including virus-infected cells and certain tumor cells. They
nisms exist in other phagocytes such as macrophages. do not require antigen sensitization for the production of perfo-
Eosinophils, which are found more in tissue than the circula- rin, a pore-forming protein with lethal effects. They are part of
tion, are primarily important in host defenses against multicel- the first line of defense against viral infections while adaptive
lular parasites such as parasitic worms. Growth and differentiation immunity is developing.
of eosinophils is promoted by IL-5. Eosinophils are activated and
recruited by a variety of mediators, including complement factors Adaptive Immunity
and leukotrienes. Eosinophil granules contain specific cationic The adaptive immune response produces exquisitely speci-
proteins that are toxic to parasites. Eosinophils also play key roles fic, protective mechanisms against microbial pathogens (see
in the pathogenesis of allergic reactions and diseases such as Table 86-1). The specific response can be recalled rapidly by
asthma. memory B and T cells years after infection if the particular
826 Section XV  Infectious Disease
pathogen is encountered again. The capacity of the adaptive
immune system to protect against different pathogens is truly
astounding. It has been estimated that B cells can produce 1014
different immunoglobulin molecules, and that T cells can have
up to 1018 different T-cell receptors (TCRs) for specific
antigens.
B Lymphocytes
Antibodies are glycoproteins produced by B cells that recognize
specific structural motifs (i.e., epitopes) on microbial pathogens.
In antimicrobial defense, binding of an antibody to a pathogen
may inhibit the ability of the pathogen to infect a cell or the
ability of a toxin to be effective (i.e., neutralization); prompt
phagocytosis by phagocytic cells such as neutrophils and macro-
phages (i.e., opsonization); activate the complement cascade; or
kill an infected cell through the process of antibody-dependent
cellular cytotoxicity (ADCC).
Antibody-mediated host defense occurs mainly in the extra-
cellular space. T cell–mediated host defenses act primarily on
intracellular organisms (i.e., those that enter cells and survive
intracellularly). The five major classes (i.e., isotypes) of antibod-
ies are summarized in Table 86-4. Complement fixation is accom-
plished by IgM and IgG molecules, whereas opsonization is
effected by IgG and IgA molecules. IgG antibodies cross the pla-
centa, providing protective immunity to newborns for months.
IgA molecules are secretory antibodies that act at mucosal sur-
faces and are the predominant antibody in external secretions
such as mucus. IgE is responsible for allergic responses and host
defenses against parasites. IgD acts as an immunomodulatory
molecule with the capacity to trigger innate immune responses.
Structurally, antibodies are composed of two large heavy
chains and two small light chains (Fig. 86-2). Each heavy and
light chain has a constant and a variable region. Each of the five
isotypes of heavy chains designates a specific antibody class (i.e.,
IgM, IgG, IgA, IgE, and IgD) and two types of light chains (i.e.,
κ and λ). The antigen-binding site of each molecule is composed
of the variable region of a heavy chain and the variable region of
a light chain. There are two such binding sites for each molecule.
The B-cell receptor is composed of the specific immunoglobulin
associated with that B cell. Unstimulated B cells express single
IgM molecules on their cell surfaces. When stimulated, B cells
may initially produce IgM antibodies. Later, a B cell may switch
the type of immunoglobulin produced (e.g., from IgM to IgG)
TABLE 86-4  PROPERTIES OF HUMAN IMMUNOGLOBULINS
PROPERTY IgG IgA
H chain class γ α
Molecular weight 150,000 170,000
(approx.)
Complement fixation ++ 0 ++++
(classic)
Opsonic activity (for ++++ ++
binding)
Reaginic activity 0 0
Serum concentration 1500 mg/dL 150-350 mg/dL
(approx.)
Serum half-life 23 days 6 days
Major functions Recall response; opsonization; Secretory immunity
transplacental immunity
Ig, Immunoglobulin; +, minimal; ++++, maximal.
and become a plasma cell producing large amounts of antibody
or become a long-term memory cell. B cells do not change their
antigen specificity.
The constant region of the two heavy chains comprises the Fc
portion, which after immunoglobulin has bound to antigen, can
then bind to Fc receptors on the cell surface of neutrophils, mac-
rophages, and dendritic cells. This interaction binds antigen-
antibody complexes to phagocytic cells and allows opsonization
and phagocytosis or activation of the classic complement
pathway, depending on the isotype.
Humans can generate billions of different antibodies, and
this diversity results from organization of the genes that encode
the variable regions of antibodies. The two major genetic strate-
gies that allow humans to produce antibody specific to virtually
any microorganism are somatic hypermutation and recombina-
tion of the variable (V), diversity (D), and joining ( J) gene
segments of the immunoglobulin light and heavy chains. The
variable region of the heavy chain is encoded by V, D, and J
genes. The variable region of the light chain is encoded by V
and J genes.
There are more than 1000 different V, D, and J genes. During
B-cell differentiation, somatic translocations randomly select
the V, D, and J heavy chain genes and the V and J light chain
genes. In this manner, an enormously diverse set of variable
chains is assembled. Further genetic variation arises from somatic
mutations in B cells as they encounter antigen in lymphoid
tissues. B cells have specific Ig antibodies on their surface,
with specificity produced by V(D)J recombinations that rec-
ognize three-dimensional structures. These molecular structures
are on the surface of pathogens or are toxins produced by
pathogens.
The adaptive immune cell response begins with recognition of
antigen by specific B cells in lymph node follicles. IgM antibodies
are produced by B cells whose Ig surface receptors have affinity
for the antigen. Interaction with complementary T cells in lymph
nodes may result in class switching (e.g., from IgM to IgG classes
or others). The switch is called an isotype switch and is driven by
specific cytokines, such as IL-4, IL-10, IL-5, and others produced
by T cells. The isotype switch allows the host to take advantage
of the different functions of different isotypes specific for the
same antigen (e.g., complement fixation for IgM, opsonic activity
for IgG). T-cell interaction through surface coreceptors and stim-
ulatory soluble molecules results in B-cell division and increased
IgM IgD IgE
µ δ ε
900,000 180,000 190,000
0 0
0 0 0
0 0 ++++
100-150 mg/dL 2 mg/dL 2 mg/dL
5 days 3 days 2.5 days
Primary response; Immune modulation Allergy; anthelmintic
complement fixation of inflammation immunity
 Chapter 86  Host Defenses Against Infection 827

Fab end
Fc end Antigen-binding site

Heavy chain

Fc receptor Antigen-binding site

C1q Light chain

A B
FIGURE 86-2  Structure of antibodies. Antibody molecules are composed of two heavy chains (red lines) and two light chains (blue lines) held
together by disulfide bonds. The two heavy chains join to form a tail (Fc end), which can interact with receptors (FcR) on a variety of cells. The heavy
and light chains contribute to the Fab end. At the 5′ or amino-terminal end, these chains form two identical antigen-binding sites, much like two
lobster claws. Near the hinge region of the antibody, there is a binding site for C1q, the first component of the complement cascade. (From Birdsall
H: Adaptive immunity: antibodies and immunodeficiencies. In Bennett JE, Dolin R, Blaser M, editors: Mandell, Douglas, and Bennett’s principles and
practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.)

antibody production. B cells may also differentiate into plasma
cells that do not contain surface antibody but secrete large
amounts of a single specific isotype immunoglobulin.
B cells may also undergo somatic hypermutation. In this
process, cells producing antibody develop point source muta-
tions in the immunoglobulin DNA that may increase the affinity
to antigen. This may stimulate increased production of the
higher-affinity antibody, thus fine tuning the B-cell response.
Driven by T-cell interaction, a portion of the B cells are formed
for life, and these memory cells have the capacity to secrete anti-
bodies rapidly on antigen reexposure that have extremely high
avidity for a particular antigen.
B cells can be activated by two routes. Some antigens can
stimulate B cells to proliferate and produce antibody directly
without the presence of helper CD4+ T cells. They include
microbial-derived molecules such as LPS, which have broad
stimulatory properties. Others, such as microbial-derived repeti-
tive motifs on polysaccharides, stimulate mature B cells more
specifically. More commonly, B cells are stimulated through syn-
ergistic action with CD4+ T cells. Specific antigen is bound to the
surface immunoglobulin of the B cell, which triggers endocyto-
sis, degradation of the antigen, and presentation of peptide frag-
ments in association with MHC class II molecules on the cell
surface. CD4+ T cells with TCR specificity for the antigen inter-
acts with the B cell through adhesion molecules and costimula-
tory activation molecules such as CD28 and CD80/86. CD4+ T
cells then produce cytokines such as IL-4 that drive antibody
production by the B cells.
T Lymphocytes
T cells are produced in the bone marrow and then are processed
and selected in the thymus. T lymphocytes have CD4 or CD8
molecules on their surface along with a TCR that has exquisite
antigen specificity. During development, the TCR is produced in
a process involving gene rearrangement and selection of V, D, and
J clusters similar to B-cell antibody differentiation. The potential
number of epitopes that T cells can respond to is greater than
those that induce B cells.
As maturation takes place in the thymus, T cells whose TCRs
have too high an affinity for self-molecules are eliminated. Naïve
T cells, usually in regional lymph nodes or similar tissues such as
Peyer’s patches in the gut, are sensitized by interaction with an
APC such as the dendritic cell. The APC processes a microbial
peptide antigen and then presents the antigen to the associated
T cell. Presentation of antigen occurs in association with human
leukocyte antigen (HLA) class II molecules for CD4+ cells or
HLA class I molecules for CD8+ cells. CD4+ cells are called
helper T cells and develop into TH1, TH2, and TH17 subsets.
CD8+ cells are cytotoxic T cells (Fig. 86-3).
CD4+ T cells are key enhancing cells that are permissive and
amplify the response of B lymphocytes, other CD4+ T cells, and
CD8+ T cells. They also can activate cells such as phagocytes.
CD4+ T cells orchestrate host defenses against pathogens that are
initially recognized by phagocytic cells during phagocytosis or
pinocytosis. Dendritic cells, for example, incorporate external
pathogens or antigens by phagocytosis or pinocytosis and then
degrade them within phagosomes.
Short-chain peptide antigens, which are produced by proteo-
lytic degradation, attach to a grove in the MHC class II mole-
cules. The complex is then transported to the surface for
presentation to naïve T lymphocytes expressing CD4 molecules
on their surface. CD4+ T lymphocytes with specificity for the
antigen then adhere to the MHC class II/antigen complex on the
surface of the APC. Accessory molecules, such as the adhesion
molecule lymphocyte function–associated antigen 1(LFA-1) on
T cells, which interacts with intercellular adhesion molecule 1
(ICAM-1) on the APC, are necessary to stabilize the interaction.
Activating adhesion complexes such as CD28 (on T cells) and
CD80/86 (on APCs) are necessary for sensitization, prolifera-
tion, and activation of T cells. Activation and proliferation is also
driven by IL-2.
Activated CD4+ T cells (initially called TH0 cells) can be
driven by IL-12 and other cytokines to become TH1 cells or by
IL-4 and IL-10 to become TH2 cells. TH17 cell differentiation is
driven by transforming growth factor-β (TGF-β), IL-6, and
IL-23. TH1 cells mediate host defenses against intracellular
pathogens such as M. tuberculosis or Toxoplasma gondii. They do
so by producing γ-interferon that activates APCs such as macro-
phages that then destroy the invading intracellular pathogen. TH1
cells also produce Il-12, Il-2, and TNF-α, which can enhance the
immune response. They also activate cytotoxic T lymphocytes to
lyse infected cells.
828 Section XV  Infectious Disease

Antigen
Antigen Coactivating
Coactivating signals
signals

Class II
Class I
APC MHC CD4 TH cell CD8
MHC
(dendritic cell) (CD4+) APC TCTL cell
(dendritic cell) (CD8)

Acute phase Acute phase

cytokines + No IL-12 cytokines and IL-12
TGF-β

Killing
TH17 TH2 TH1
Effector Apoptosis
TC cell (CTL)
Inflammatory IgG, IgE, Cell- and IgG-
responses in an IgA mediated
immunotolerant responses
environment
FIGURE 86-3  Overview of T-cell activation. The dendritic cell (DC) initiates the interaction with a CD4+ or CD8+ T cell through a major histocompat-
ibility complex (MHC)–peptide interaction with the T cell receptor. The DC provides an 11-amino-acid peptide on the class II MHC, B7 coreceptor,
and cytokines to activate CD4+ T cells. The CD8+ T cell is activated through the class I MHC and 8- to 9-amino-acid peptide plus the B7 coreceptor
and cytokines. Presentation of antigen to CD4 T cells and cross-presentation to CD8+ T cells is shown. The cytokines produced by the DCs determine
the type of helper T (TH) cell. Activated CD8+ T cells can interact with and lyse target cells through T-cell receptor recognition of peptide in class I MHC
molecules on target cells. APC, Antigen-presenting cell; CTL, cytotoxic T lymphocyte; Ig, immunoglobulin; TGF-β, transforming growth factor-β. (From
Rosenthal KS, Tan MJ, editors: Rapid review microbiology and immunology, ed 3, Philadelphia, 2011, Mosby.)

Alternatively, CD4+ T cells can become TH2 cells that drive
processes such as antiparasitic activity. TH2 cells stimulate B cells
to produce antibodies against extracellular pathogens through
the production of IL-4, and they stimulate proliferation of eosin-
ophils for activity against parasites (e.g., worms) through the
production of IL-5.
TH17 cells are stimulated by IL-23 and produce IL-17, which
plays an important role in amplifying the inflammatory response
by attracting neutrophils to sites of infection caused by extracel-
lular bacteria and possibly fungi. The complexity of these CD4+
T-cell subsets is still being explored.
CD8+ T cells respond to pathogens that initially enter phago-
cytic cells directly, such as viruses. Upon intracellular replication,
viral proteins are marked for destruction by covalent binding to
the protein ubiquitin. The tagged molecules are then degraded by
a proteasome, which is a cytoplasmic enzyme complex. Resulting
peptide chains of 6 to 24 amino acids then associate with MHC
class 1 molecules in a complex intracellular process in the APC
and are presented on the surface of the APC. Naïve CD8+ cells
that are specific for the presented antigen adhere to the presented
MHC class I/antigen complex and express IL-2 receptors. CD4+
TH1 antigen-specific cells also interact with the APC, which
stimulates the production of IL-2 by the CD4+ cell and increases
CD80/86 expression by the APC. CD28 on the CD8+ T cell
interacts with the CD80/86 on the APC to stimulate the CD8+
T cell to proliferate and differentiate into cytotoxic T lympho-
cytes. The cytotoxic T cells can lyse target cells expressing the
appropriate MHC class I/antigen complex. Several signals,
including MHC class I/antigen recognition, IL-2 stimulation,
and CD28 and CD80/86 adherence, combine to optimally initi-
ate CD8+ cytotoxic T cells to attack virus-infected cells.
CD4+ and CD8+ T cells help to regulate the immune response.
CD4+ regulatory T cells (Tregs) express CD4 and CD25 and
help to regulate immune responses, particularly those related to
autoimmune diseases but also some infectious diseases. CD8+
suppressor T cells inhibit some autoimmune inflammatory
processes.
  HOST DEFENSE RESPONSE TO PATHOGENS
Humans are constantly threatened by microbial pathogens.
Organisms such as S. pneumoniae, group A streptococci, and
respiratory viruses colonize the respiratory tract. S. aureus, fungi,
and many other organisms live on the skin. Every type of patho-
gen lives in the gastrointestinal tract; some are benign, and some
are dangerous.
Host defenses need to react continuously and appropriately to
breaches in nonimmunologic host defenses as described earlier.
For example, if a person suffers a cut on the hand, the skin barrier
is breached, and pathogens may be inoculated into the subcuta-
neous tissues. This stimulates an immediate nonimmunologic
host defense response that includes phagocytosis by cells such as
macrophages, which produce cytokines such as IL-1 and TNF-α.
Cytokines stimulate the expression of adhesion molecules on
vascular endothelium. Neutrophils then bind to the endothe-
lium, move into tissues, and are attracted by a chemokine gradi-
ent to the site of invasion.
 Chapter 86  Host Defenses Against Infection 829
A second process that breaches nonimmune host defenses
results from infection by respiratory viruses. Influenza virus may
damage upper and lower respiratory host defenses by destroying
the respiratory epithelium, inhibiting ciliary action and mucus
production. Bacterial pathogens, most commonly S. pneumoniae,
that colonize the respiratory tract in normal hosts may then
colonize and invade the lower respiratory tract, leading to pneu-
monia. Organisms such as M. tuberculosis, an intracellular patho-
gen, may evade upper respiratory and lower respiratory defenses
and lodge in alveolar macrophages in the lung, where they can
survive and multiply. Interference with alveolar macrophage
function (e.g., silica exposure) may increase susceptibility to
tuberculosis.
The innate immune system is critical during the early phases
of infection. The response is rapid, although nonspecific, and
eliminates the pathogen or holds the infection in check until the
more powerful, highly specific adaptive immune system has time
to respond. Phagocytes such as tissue macrophages patrol the
periphery and detect pathogens through receptors such as TLRs.
This activates the phagocyte, induces phagocytosis and killing,
and stimulates the phagocyte to produce cytokines and chemo-
kines that initiate the inflammatory response.
Complement may be activated through the alternative pathway
and produce products to attract neutrophils, opsonize pathogens,
and lyse pathogens. Vasodilation results from histamine release,
and circulating neutrophils are localized to the vascular endothe-
lium nearest the site of invasion by integrins, pass through the
vascular wall, and move down a chemokine gradient to the site
of infection. Opsonization helps neutrophils and other immune
cells ingest and kill the pathogen. These immediate inflammatory
and innate immune responses are initiated immediately and
increase over hours to days. Although they are effective, these
responses are temporizing measures while more specific and
more effective host responses of the adaptive immune system are
developing.
Immature dendritic cells in peripheral tissues are watchman
for foreign molecules. Through pinocytosis and phagocytosis ini-
tiated by TLRs and other receptors, they detect pathogens; when
identified, dendritic cells migrate to regional lymph nodes. There
the dendritic cells mature, stop phagocytosis, and process antigen
for presentation to T cells, initiating the specific adoptive immune
response. The type of response depends on the type of pathogen.
Intracellular pathogens such as M. tuberculosis stimulate a T cell–
mediated response, whereas S. pneumoniae stimulates primarily a
B-cell, antibody-mediated (humoral) response. Most infections
produce components of cellular and humoral host responses in
various degrees that often act in concert. For example, influenza
virus induces a B-cell and T-cell response.
Humoral Response
Early in infection, complement and preexisting circulating or
tissue antibodies react to pathogens directly and can initiate
direct lysis, opsonization, and neutralization of pathogens. B cells
may be activated by T cell–independent antigens or through
interaction with CD4+ T cells and T cell–dependent antigens.
B-cell populations proliferate and produce IgM antibodies ini-
tially and then with isotype switching produce other types of
antibodies, including IgG and IgA. Antibodies acting in the extra-
cellular space bind to pathogens or their products, potentially
leading to neutralization, opsonization, complement fixation,
and ADCC.
Cell-Mediated Response
Naïve T cells with specificity for the invading pathogen are acti-
vated, proliferate, and produce cytokines. CD4+ T cells produce
cytokines that stimulate other T cells, enhance the overall inflam-
matory response, activate phagocytes for killing, and stimulate
antibody production. Previously sensitized T cells may react
rapidly with activation and proliferation on exposure to a previ-
ously recognized intracellular pathogen.
SUGGESTED READINGS
Bennett JE, Dolin R, Blaser M, editors: Mandell, Douglas, and Bennett’s principles
and practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.
Medzhitov R, Shevach EM, Trinchieri G, et al: Highlights of 10 years of
immunology in Nature Reviews Immunology, Nat Rev Immunol 11:693–702,
2011.
 87 
Laboratory Diagnosis of
Infectious Diseases
Kimberle Chapin
  INTRODUCTION
The ability to diagnose a greater number of infectious diseases
rapidly and accurately represents a significant recent advance in
medicine. Diagnosis has become readily available with point-of-
care (POC) testing that is automated, molecularly based, and
technologically advanced. At the same time, specimen acquisi-
tion, test selection, test performance parameters, and result inter-
pretation have become more complex.
Up to 70% of individual patient medical diagnoses are made
with the aid of a laboratory test result. Implementation of the
right diagnostic technology can affect patient safety, morbidity,
mortality, and health care costs. Examples of how test results can
optimize patient care have been published for Clostridium difficile
toxin molecular testing and infection control practices; algo-
rithms for identification and treatment of sepsis to reduce
morbidity and mortality; screening for colonization with
methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus,
allowing decontamination and targeted antibiotic therapy in
high-risk surgical procedures; and use of rapid molecular testing
to aid in successful anti-infective intervention and stewardship
programs.
This chapter highlights significant components of testing for
infectious diseases and the trends in the laboratory and diagnos-
tic technology that affect patient care. More information is avail-
able in the 2013 American Society for Microbiology (ASM) and
Infectious Disease Society of America (IDSA) guideline on use
of the microbiology laboratory for the diagnosis of infectious
diseases. This excellent resource summarizes laboratory diagno-
sis of infectious diseases by basic disease categories (e.g., respira-
tory, genital) and contains numerous tables for rapid access of
information. The document is well referenced and is updated on
a regular basis; it is now available as part of the Sanford
Guide–Lab Diagnosis of Infectious Diseases (http://www
.sanfordguide.com/).
  SPECIMEN COLLECTION AND PROCESSING
Collection of the specimen and its preservation during transpor-
tation are components of infectious disease diagnosis that are
often overlooked. As part of their accreditation and inspection
process, laboratories have collection procedures and criteria for
rejection of specimens that are deemed inappropriate to process.
These evidenced-based protocols ensure that results can reliably
be used to treat patients. Examples include rejection of a sputum
specimen after initial smear evaluation shows the specimen is
contaminated with squamous epithelial cells and indicates
830
normal mouth flora rather than a deep respiratory specimen.
Another example is rejection of a hard stool for C. difficile toxin
testing because it is inconsistent for a person with C. difficile infec-
tion, which produces watery diarrhea.
All personnel (e.g., physicians, nurses, phlebotomists) collect-
ing specimens should be familiar with the appropriate collection
devices, recommended collection techniques, and requirements
for transportation to the laboratory to ensure optimal identifica-
tion of the pathogen. If the practitioner requests a microbiology
test not typically performed, such as for anaerobic organisms
from a cerebral spinal fluid (CSF) specimen, a call should be
made to the laboratory to clarify the order.
  RAPID DIAGNOSTIC METHODS
Rapid or STAT is no longer a term foreign to direct testing for
infectious diseases and the microbiology laboratory. All major
areas of diagnostic testing, including direct visualization of speci-
mens; detection of organism-specific antigens, proteins, and
nucleic acids; and cell counts and biomarkers can be performed
in 1 to 4 hours. Test results are often available during the time a
practitioner is involved with the patient.
Table 87-1 lists the most common U.S. Food and Drug Admin-
istration (FDA)–cleared direct testing methods used in laborato-
ries for primary specimens. Examples include Gram stain for
bacteria and yeast, fluorescent calcofluor staining for fungi, Legio-
nella urinary antigen for legionnaires disease, and polymerase
chain reaction (PCR) for enterovirus in CSF.
Direct and rapid do not necessarily equate to high predictive
values for a true positive or negative test result. As a result, tests
commonly used in the past (e.g., bacterial antigen and India ink
in CSF) are no longer routinely recommended because false-
positive results are common.
  DIRECT SMEAR INTERPRETATION
A direct smear interpretation can be exceedingly helpful in con-
firming a suspected cause (e.g., Gram stain of sputum for pneu-
mococcal pneumonia) and can be performed usually in a few
minutes to hours from receipt in the laboratory. High sensitivity
and specificity, however, depend on specimens being collected
appropriately (e.g., obtained before antibiotic administration)
and sometimes on knowing the immune status of the patient.
Fluorescent staining with calcofluor (Fig. 87-1) and auramine
have increased sensitivity for direct detection of fungal elements
and acid-fast bacilli (AFB), respectively. Direct fluorescent anti-
body staining for parasites, viruses, or Pneumocystis jirovecii is
specific and rapid compared with staining of histologic tissue
 Chapter 87  Laboratory Diagnosis of Infectious Diseases 831

TABLE 87-1  FDA-CLEARED METHODS OF DIRECT

TESTING FROM SPECIMENS
TEST DIAGNOSTIC
METHODS* METHOD ANALYTE DETECTED
Smear stain Gram stain Bacteria, yeast
preparations Fluorescence DFA: Pneumocystis jirovecii,
viruses†
Auramine: mycobacteria
Calcofluor: fungi
Special: acid-fast Smear use determined by
(Kinyoun), partial laboratory and based on
acid-fast (PAF), India primary stained specimen§
Ink‡
Wright stain Leukocyte differentiation
and count
Antigen-antibody Latex agglutination Legionella or Streptococcus
pneumoniae urinary antigen FIGURE 87-1  Calcofluor fluorescent stain depicts fungal hyphae
Cryptococcal antigen in from a wound specimen.
serum and CSF
Lateral flow antibody/ GAS, RSV, influenza A or B
antigen of these tests depend on the specimen type collected (e.g., naso-
Serology for IgG, IgM, Multiple analytes; detection
Western blot and/or confirmation of pharyngeal swab is better than a throat swab for influenza A or B
immune status and acute testing), the test analyte (e.g., group A streptococci performance
disease is more reliable than influenza A or B), and the prevalence of
Biomarker Procalcitonin,‖ C-reactive
protein disease at the time of testing.
Molecular¶ Hybridization and HPV, bacterial vaginosis or False-positive results for rapid antigen tests are unusual, and
signal amplification vaginitis, GAS the patient can be treated based on a positive result. In contrast,
Amplification of RNA Small bundle with ≤5
or DNA or both targets: sexually a negative test result can be quite misleading. For example, data
transmitted pathogens from the novel H1N1 influenza outbreak demonstrated very
(GC, CT, TV) poor sensitivity for rapid antigen tests (about 50%) compared
Multiplex amplification with
≥10 targets: blood sepsis, with molecular tests. When a multiplex viral panel was used,
respiratory, gastrointestinal other viral pathogens were identified as the cause of influenza-
pathogens like illness in more than 50% of patients admitted to hospitals
Chip array: multiple targets,
HCV genotyping (Fig. 87-2). Molecular detection of influenza is recommended for
Amplification with HIV, HCV, HBV hospitalized patients with influenza-like illness if a rapid antigen
quantification of test result is negative. Many manufacturers have submitted ampli-
nucleic acids
fied testing assays for influenza, seeking Clinical Laboratory
CSF, Cerebrospinal fluid; CT, Chlamydia trachomatis; DFA, direct fluorescent antibody;
DNA, deoxyribonucleic acid; FDA, U.S. Food and Drug Administration; GAS, group A
Improvement Amendment (CLIA)–waived status for rapid influ-
streptococci; GC, Neisseria gonorrhoeae; HBV, hepatitis B virus; HCV, hepatitis C virus; enza detection tests that can be performed in the laboratories of
HIV, human immunodeficiency virus; HPV, human papillomavirus; Ig, immunoglobulin;
RNA, ribonucleic acid; RSV, respiratory syncytial virus; TV, Trichomonas vaginalis
physicians’ offices or urgent care centers.
*One-hour, same-day testing.
†
Because the direct fluorescent antibody (DFA) is organism specific (e.g., P. jirovecii, Molecular Assays
varicella zoster, herpes simplex 1 or 2, cytomegalovirus), these smears are better than
histologic stains (e.g., silver stain) and Tzanck preparations (e.g., nucleated giant cells), Molecular identification of infectious diseases has intensified in
which can yield similar appearances for many infectious causes.
‡
Cryptococcal antigen from cerebrospinal fluid (CSF) or serum is the recommended
the past 10 years. The basic categories are shown in Table 87-1.
test. India ink often yields false-positive results and is used by the laboratory for FDA-cleared direct molecular tests include hybridization and
confirmation of suspected yeast in a Gram stain of CSF.
§
For example; partial acid fast testing is performed if the Gram stain shows branching
amplification methods. The main difference between these
of gram-positive rods and Nocardia is suspected; acid fast testing is performed if the methods is that with hybridization methods, the nucleic acid is
auramine-stained sample is positive.
‖
Procalcitonin is a better marker for identification of bacterial sepsis than C-reactive
not multiplied beyond what is already in the sample. For assays
protein. that target DNA, the sensitivity is limited because DNA exists as
¶
Common examples of pathogens are listed for each group, but many more analytes
are available.
a single copy. For assays that target proteins or RNA, detection
sensitivity is somewhat increased because these components are
preparations, which may take days. However, because adequate naturally amplified in the microbe. Familiar hybridization assays
specimens are often difficult to obtain, sensitivity may be lacking include fluorescent in situ hybridization (FISH) for targets in
with smear and culture, and alternative methods such as molecu- tissue and the protein nucleic acid (PNA) smear (Fig. 87-3).
lar and empirical therapy are still warranted in specific cases. Hybridization assay systems can increase their sensitivity by
pairing with signal amplification, such as for human papillomavi-
  POINT-OF-CARE OR NEAR-PATIENT TESTING rus (i.e., Qiagen/Digene HPV test).
POC or near-patient testing offers rapid results, typically while In contrast, amplification assays increase the original nucleic
the patient is still in the clinical care setting, and it allows directed acid copy number through a variety of processes, including
treatment. However, most tests done in practitioners’ offices or PCR, transcription-mediated amplification (TMA), and isother-
on-site laboratories are rapid antigen tests. The predictive values mal loop amplification (LAMP). Real-time PCR refers to
832 Section XV  Infectious Disease

450
400
350
300

N patients
250
200
150
100
50
0
0

12

12
0

12

12
1
11

11
11

11

1
01

01
01

01
20

20
20

20
20

20

20

20
r2

r2
r2

r2
ay

ay
ly

ly
y

ch

ch
be

be
be

be
ar

ar
Ju

Ju
M

M
ar

ar
nu

nu
em

em
m

m
M

M
te

te
Ja

Ja
ov

ov
p

p
Se

Se
N

N
Influenza A Rhinovirus Adenovirus Metapneumovirus
Influenza B RSV Corona Parainfluenza
FIGURE 87-2  The graph represents the respiratory viruses detected from hospitalized patients who had influenza-like illness over a period of two
respiratory seasons. Viral epidemiology was determined using a multiplex respiratory viral assay for 14 viral pathogens. The viral epidemiology pro-
vides helpful information for decreasing antibiotic use and discussing the likely cause of illness with patients.

quantification of the viral load for purposes of long-term treat-

ment and assessment of clearance (i.e., human immunodefi-
ciency virus, hepatitis B virus, and hepatitis C viral loads).

FIGURE 87-3  A protein nucleic acid (PNA) hybridization probe can
be used to identify yeast from a positive blood culture. The Yeast Traffic
Light PNA FISH assay identified Candida albicans and/or Candida parap-
silosis (green), Candida tropicalis (yellow), and Candida glabrata and/or
Candida krusei (red).
amplification and detection occurring simultaneously, enabling
the analyte to be detected more quickly. Amplification assays
can detect a single analyte (e.g., enterovirus from CSF) or a
group of pathogens for a disease entity from a single specimen,
such as sexually transmitted infections (e.g., Chlamydia tracho-
matis, Neisseria gonorrhoeae, and Trichomonas vaginalis).
These assays can detect numerous pathogens from a single
specimen in a multiplex amplification testing format (i.e., FDA-
cleared multiplex assays for 14 to 24 targets exist for respiratory
or acute gastroenteritis pathogens). They also allow
Culture
Despite advances in rapid direct and molecular diagnostics,
culture is still a mainstay for infectious disease diagnosis of
most specimen types, but techniques for rapid identification of
cultures have been enhanced with updated technology. Blood
and AFB specimens are incubated in continuously monitoring
incubator cabinets that signal when a specimen is positive based
on algorithmic growth curves. A positive specimen can be iden-
tified at any time of day, pulled and stained immediately after
signaling positive, and tested for definitive identification and
susceptibility.
Table 87-2 lists the most common identification methods used
from positive broth cultures (e.g., blood) and from colony growth
on a culture plate. They include several molecular hybridization
methods that have become standard practice for many laborato-
ries (see Fig. 87-3).
Although most laboratories still rely on biochemical and enzy-
matic phenotypic methods for identification, 16s and 18s
sequencing of microbial genomes has demonstrated that the bio-
chemical methods lack specificity. In addition, they require
growth for reactions to take place, resulting in further delay of
organism identification. The increased use of matrix-assisted laser
desorption ionization–time of flight mass spectrometry (MALDI-
TOF MS) represents a significant methodologic change. This
technique relies on the protein spectral analysis of the organism
for identification and takes only minutes rather than days. The
technique is described in Figure 87-4.
Susceptibility testing typically requires growth of an organism
in the presence of the antibiotics that are appropriate for
treatment of the organism. Molecular technology has improved
 Chapter 87  Laboratory Diagnosis of Infectious Diseases 833

TABLE 87-2  RAPID IDENTIFICATION METHODS FOR A POSITIVE CULTURE BROTH OR COLONY
METHOD* ORGANISMS DETECTED TIME COST TECHNICAL EXPERTISE
PNA fluorescent smear Bacteria, fungi (yeast) 1-2 hr $$ +
MALDI-TOF Bacteria, fungi, mycobacteria Minutes $ +
Hybridization probes Bacteria, dimorphic fungi, mycobacteria 1-4 hr $$ ++
Amplification† Bacteria, viruses, mycobacteria 1-4 hr $$$ ++
16s/18s sequencing Bacteria, fungi 1-12 hr $$$ +++
HPLC Mycobacteria 24 hr $$$ +++
MALDI-TOF, Matrix-assisted laser desorption ionization–time of flight mass spectrometry; PLC, high-pressure liquid chromatography; PNA, peptide nucleic acid; $, relative cost; +, relative
level of required expertise.
*Rapid methods require 2 to 24 hours. Methods presented are U.S. Food and Drug Administration cleared or have had test performance validated in the clinical laboratory. Due to
required technical expertise and cost, some of these assays may not be available in the routine laboratory, and providers should inquire about availability
†
Includes many different technologies, such as polymerase chain reaction (PCR), transcription-mediated amplification (TMA), and isothermal loop amplification (LAMP).

1.00

MS detector
(mass-to-charge (m/z) ratio)

0.50

Neutral field
(drift) TOF 0.00
513 1013 1123
MS profile
(match to database)
––– Laser –––

Electrostatic field
(acceleration) 1
A B C D E F G H I J K L

2
3
+++ 4 +++
5
6
7 Protein and matrix
8
9
10

FIGURE 87-4  Matrix-assisted laser desorption–time of flight mass spectrometry (MALDI-TOF MS). Bacterial or fungal growth is selected from a
culture plate and applied directly onto a MALDI slide. Samples are overlaid with a matrix and dried. Samples are then bombarded by a laser, which
results in sublimation and ionization of the sample and the matrix. The ions are separated based on their mass-to-charge ratio in a tube that measures
the time it takes the ions to travel. A spectral representation of these ions is generated and analyzed by software that generates a profile that is
subsequently compared with a database of reference MS spectra and matched, generating identification. The process takes only minutes. Although
the instrumentation is expensive, the technology is U.S. Food and Drug Administration cleared, and it yields rapid, robust, and reliable
identification.

traditional screening tests for the detection of MRSA, vancomycin-
resistant enterococci (VRE), carbapenem-resistant organisms,
and rifampin-resistant Mycobacterium tuberculosis. However, the
medical implications of detecting a resistance gene sequence and
its expression are not fully understood.
  TRENDS IN THE DIAGNOSIS OF
INFECTIOUS DISEASES
Evidence-based guidelines exist for specimen work-ups in an
effort to standardize reporting and interpretation of microbio-
logic results. They are especially useful for specimens submitted
from sites potentially contaminated with normal commensal
flora (e.g., urine, surface wounds, respiratory sources).
There are limitations on which microbes and how many differ-
ent microbes should have full identification and susceptibility
testing according to the specimen type submitted. For instance,
a clean catch urine specimen is called mixed if three or more
organisms are present in equal amounts (even if they are potential
pathogens) because the significance of any one organism cannot
be determined. The specimen must be recollected. Likewise for
other specimen types, listing every organism present is not con-
sidered helpful.
Other trends include limiting test ordering and the use of
algorithms that may be disease or health care system based; con-
tinued efforts between microbiologists, pharmacists, and practi-
tioners to optimize the stewardship of anti-infectives; use of
multiplex testing to streamline the diagnosis of complex entities
such as acute gastroenteritis; developing data on the relevance of
a positive molecular result; and the increasing use of metagenom-
ics and sequencing data to perform direct testing (e.g., blood,
orthopedic specimens) and to identify infectious disease
outbreaks.
SUGGESTED READINGS
BalcI C, Sungurtekin H, Gürses E, et al: Usefulness of procalcitonin for diagnosis
of sepsis in the intensive care unit, Crit Care 7:85–90, 2003.
834 Section XV  Infectious Disease
Barenfanger J, Graham DR, Kolluri L, et al: Decreased mortality associated with
prompt Gram staining of blood cultures, Am J Clin Pathol 130:870–8706,
2008.
Baron EJ, Miller JM, Weinstein MP, et al: A guide to utilization of the microbiology
laboratory for diagnosis of infectious diseases: 2013 recommendations by the
Infectious Diseases Society of America (IDSA) and the American Society for
Microbiology (ASM), Clin Infect Dis 57:e22–e121, 2013.
Buss SN, Alter R, Iwen PC, et al: Implications of culture-independent panel-
based detection of Cyclospora cayetanensis [letter], J Clin Microbiol 51:3909,
2013.
Clark AE, Kaleta EJ, Arora A, et al: Matrix-assisted laser desorption ionization-
time of flight mass spectrometry: a fundamental shift in the routine practice of
clinical microbiology, Clin Microbiol Rev 26:547–603, 2013.
Forrest GN, Mehta S, Weekes E, et al: Impact of rapid in situ hybridization testing
on coagulase-negative staphylococci positive blood cultures, J Antimicrob
Chemother 58:154–158, 2006.
McCulloh R, Andrea S, Reinert S, et al: Potential utility of multiplex amplification
respiratory viral panel (RVP) testing in the management of acute respiratory
infection in children: a retrospective analysis, J Pediatr Infect Dis Soc 3:146–
153, 2014.
McCulloh RJ, Koster M, Chapin KC: Respiratory viral testing: new frontiers in
diagnostics and implications for antimicrobial stewardship, Virulence 4:1–2,
2013.
Mermel LA, Jefferson J, Blanchard K, et al: Reducing Clostridium difficile
incidence, colectomies, and mortality in the hospital setting: a successful
multi-disciplinary approach, Jt Comm J Qual Patient Saf 39:298–305, 2013.
Musher DM: The usefulness of sputum Gram stain and culture [letter], Arch
Intern Med 165:470–471, 2005.

Fever and Febrile Syndromes
  INTRODUCTION
Fever is one of the most common problems requiring medical
evaluation. Fever is an elevation in core body temperature greater
than normal daily variation, which is 36.8° C ± 0.4° C (98.2° F ±
0.7° F). Documentation of true fever can be important evidence
of infectious processes that warrant investigation. Although fever
is characteristic of most infections, it also occurs in noninfectious
conditions such as autoimmune and inflammatory diseases,
malignancy, and trauma.
This chapter reviews the pathogenesis of the febrile response,
the approach to the acutely ill patient with fever, and fever of
unknown origin. Fever can be associated with infections, such as
those from animal exposures, or with common clinical scenarios
in which it may occur as the sole complaint, manifest with rash,
or develop with lymphadenopathy. A word of caution about the
difference between true and factitious fever is offered at the end
of the chapter.
  PATHOGENESIS
Thermoregulation of core body temperature is one of the most
important mechanisms in mammalian and human physiology.
The hypothalamic heat-regulating set point shifts in response to
infection or inflammation mediated primarily by the host’s
monocytes and macrophages, which are activated as they encoun-
ter exogenous bacterial substances, toxins, or the cellular prod-
ucts of trauma.
Monocytes and macrophages produce small proteins called
cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis
factor (TNF). They are collectively known as endogenous pyrogens
because they actively increase body temperature by increasing
the hypothalamic set point, which is the normal temperature for
the body that is controlled by the hypothalamus. IL-1 and other
endogenous pyrogens are released by macrophages at the site of
infection and travel through the bloodstream to the hypothala-
mus, where they elevate levels of prostaglandin E2 (PGE2). Ele-
vated PGE2 levels increase the set point, and thermoregulatory
mechanisms raise the body’s core temperature. IL-1 also induces
production of PGE2 in peripheral tissues, which causes the non-
specific myalgias and arthralgias that often accompany fever.
Prostaglandin inhibitors such as aspirin or acetaminophen block
prostaglandin synthesis and reduce elevated temperatures.
Thermoregulatory control is initiated through sensory neurons
in the skin, abdomen, and spinal cord. Central nervous system
(CNS) thermoreceptors sense and integrate temperature infor-
mation. After the hypothalamic set point is raised, the firing rates
of neurons in the vasomotor center are altered, causing peripheral
88 
Ekta Gupta and Maria D. Mileno
vasoconstriction and producing a noticeable cold sensation in
the hands and feet. Blood is shunted away from the periphery to
the internal organs, and this process is sufficient to raise core
body temperature by 1° to 2° C.
Other signaling mechanisms have roles in thermoregulation.
The adipocyte-derived hormone leptin actively controls energy
homeostasis, and thermogenesis in fat tissue contributes to
increasing core temperature. Thermogenesis is important in
fighting infection and in responding to cold-induced heat pro-
duction. Fever has direct antimicrobial effects in some infections
such as neurosyphilis and salmonellosis, and elevated tempera-
ture augments humoral and cellular immune responses. IL-1 acts
independently on two physiologic systems: thermoregulation
and iron metabolism. IL-1 can stimulate a wide range of host
defenses to conduct a synergistic response to infection.
Fever also can have deleterious effects. It may lead to disorien-
tation and confusion in persons with underlying brain disease
and in healthy older individuals. Tachycardia can increase cardio-
pulmonary work, precipitating congestive heart failure or myo-
cardial infarction in persons with significant cardiopulmonary
disease. Fever should be controlled with antipyretics for comfort
and to avoid compromising individuals with multiple medical
problems. Acetaminophen is preferred for control of fever in chil-
dren because of the risk of Reye’s syndrome with salicylate use.
The terms fever, hyperthermia, and hyperpyrexia are not syn-
onymous. Although most patients with elevated temperature
have fever (>38.3° C or 100.9° F), some conditions can increase
the body temperature by overriding or bypassing the normal
homeostatic mechanism and may even produce body tempera-
tures in excess of 41° C or 105.8° F (i.e., hyperthermia), which
can be rapidly fatal and does not respond to antipyretics. Rapid
cooling is critical to the patient’s survival in hyperthermic condi-
tions such as heat stroke. Even in otherwise healthy individuals,
heat stroke can occur after vigorous exercise and prolonged expo-
sure to high environmental temperatures and humidity. Heat
stroke is marked by temperatures greater than 40.6° C (105.1° F),
altered sensorium or coma, and cessation of sweating. Treatment
includes covering the patient with wet compresses followed by
intravenous infusion of fluids appropriate to correct fluid and
electrolyte losses.
Severe hyperthermia may be a heritable reaction to anesthetics
(i.e., malignant hyperthermia) or a response to phenothiazines
(i.e., neuroleptic malignant syndrome). Serotonin syndrome,
which often includes fever, is classically associated with the simul-
taneous administration of two serotonergic agents. It can also
occur after initiation of a single serotonergic drug that increases
the serotonin level of individuals who are particularly sensitive to
835
836 Section XV  Infectious Disease
serotonin. Occasionally, persons with CNS disorders such as
paraplegia and persons with severe dermatologic conditions are
unable to dissipate heat and can experience hyperthermia.
Hyperpyrexia is the term for extraordinarily high fever
(>41.5°  C or 106.7°  F), which can occur in patients with
severe infections but is most commonly observed in persons
with CNS hemorrhages.
  DIAGNOSTIC APPROACH TO THE
ACUTELY ILL PATIENT WITH FEVER
Patterns of fever should be considered when assessing acutely ill,
febrile persons. Evaluation includes determining the normal
diurnal variation in body temperature, which often persists when
patients have fever. Normally, body temperature peaks in the late
afternoon or early evening.
Rigors (i.e., bed-shaking chills) often mark the onset of bacte-
rial infection, typically bacteremia, although they may occur in
other clinical situations, such as drug-induced fever or transfu-
sion reactions. Wide swings in temperature may indicate an
abscess. Malaria should be considered for anyone with fever who
has visited or lived in malarious regions or who has relapsing
fever accompanied by episodes of shaking chills and high fever
separated by 1 to 3 days of normal body temperature and relative
well-being. The timing of administration of anti-inflammatory
drugs should be assessed because they may alter or blunt the
febrile response. Most infectious diseases manifest with fever as
an early finding and with subclinical and eventual clinical involve-
ment of specific organ systems.
TABLE 88-1  COMMON INFECTIONS IN TRAVELERS BY INCUBATION PERIOD
DISEASE
INCUBATION <14 DAYS
Malaria, Plasmodium falciparum
Dengue
Chikungunya
Spotted fever, rickettsiae
Leptospirosis
Enteric fever
Malaria, Plasmodium vivax
Influenza
Acute human immunodeficiency virus (HIV)
infection
Legionellosis
Encephalitis, arboviral (e.g., Japanese
encephalitis, tick-borne encephalitis, West
Nile virus)
INCUBATION 14 DAYS TO 6 WEEKS
Malaria, enteric fever, leptospirosis
Hepatitis A
Hepatitis E
Acute schistosomiasis (Katayama syndrome)
Amebic liver abscess
INCUBATION >6 WEEKS
Malaria, amebic liver abscess, hepatitis E,
hepatitis B
Tuberculosis
Leishmaniasis, visceral
Modified from Centers for Disease Control and Prevention: CDC health information for international travel, 2012, New York, 2012, Oxford University Press.
If fever occurs as the sole complaint or is associated with local-
ized symptoms and signs, the diagnostic approach includes
taking a thorough history, including an extensive review of
systems, medical and surgical histories, and immunizations,
including those from childhood. Antipyretics may be withheld to
allow assessment of the fever trajectory. Elderly individuals,
persons taking corticosteroids, and patients with chronic liver or
renal disease may be less likely to mount a fever. All likely sources
of disease, including travel, exposure to Mycobacterium tuberculo-
sis, and occupational, hobby, animal, insect, and sexual contacts,
should be assessed. Previous itineraries and activities, geographic
risks of diseases, and the seasonality and incubation periods of
possible disease exposures should be considered in returning
travelers (Table 88-1).
Viral Infection
Acute febrile illnesses in young healthy adults usually are caused
by viral infections, which do not require precise diagnosis because
they are self-limited and seldom have therapeutic options. Upper
respiratory tract symptoms of rhinorrhea, sore throat, cough, and
hoarseness most often result from rhinovirus, coronavirus, para-
influenza virus, and adenoviruses. Adenovirus outbreaks occur
among persons living in close quarters such as military barracks
or college dormitories. Respiratory syncytial virus, human meta-
pneumovirus, and human bocavirus infections occur in similar
conditions and sometimes manifest with pneumonia.
A coronavirus causes the potentially fatal upper respiratory
viral infection called Middle East respiratory syndrome (MERS).
USUAL INCUBATION PERIOD (RANGE) DISTRIBUTION
6-30 days Tropics, subtropics
4-8 days (3-14 days) Topics, subtropics
2-4 days (1-14 days) Tropics, subtropics (Eastern Hemisphere)
Few days to 2-3 weeks Causative species vary by region
7-12 days (2-26 days) Widespread; most common in tropical areas
7-18 days (3-60 days) Especially in Indian subcontinent
8-30 days (often >1 month to 1 year) Widespread in tropics/subtropics
1-3 days Worldwide; can also be acquired en route
10-28 days (10 days to 6 weeks) Worldwide
5-6 days (2-10 days) Widespread
3-14 days (1-20 days) Specific agents vary by region
See earlier incubation periods for relevant See earlier distribution for relevant diseases
diseases
28-30 days (15-50 days) Most common in developing countries
26-42 days (2-9 weeks) Widespread
4-8 weeks Most common after travel to sub-Saharan
Africa
Weeks to months Most common in developing countries
See earlier incubation periods for relevant See earlier distribution for relevant diseases
diseases
Primary, weeks; reactivation, years Global distribution; rates and levels of
resistance vary widely
2-10 months (10 days to years) Asia, Africa, South America
 Chapter 88  Fever and Febrile Syndromes 837
It has caused pneumonia with acute respiratory distress syn-
drome (ARDS) and death in one half of infected individuals, and
it is highly contagious.
Meningitis symptoms occur predominantly from enterovirus
infections during summer months, although the symptom
complex warrants urgent treatment of bacterial causes while the
diagnostic process occurs. Febrile syndromes without meningitis
are more common manifestations of enteroviral infections.
Arthropod-borne viruses such as California encephalitis virus;
eastern, western, and Venezuelan equine encephalitis viruses; St.
Louis encephalitis virus; and West Nile virus can produce self-
limited febrile illnesses and encephalitis. Colorado tick fever is a
biphasic illness seen after northwestern and southwestern tick
exposures. It is characterized by high fevers and leukopenia. In
New York State, a deer tick virus has been associated with numer-
ous cases of fever and confusion.
Influenza causes sore throat, cough, myalgias, arthralgias, and
headache in addition to fever, and it most often manifests in an
epidemic pattern during winter months. It is unusual for fever to
persist beyond 5 days in uncomplicated influenza. Prolonged
fever in persons with diagnosed influenza warrants investigation
and treatment of bacterial superinfection.
Early recognition of fever and dry cough led to the discovery
and containment of the outbreak of severe acute respiratory syn-
drome (SARS). The epidemics of avian influenza and H1N1
pandemic strains in recent years are sobering reminders that
influenza viruses have a remarkable ability to mutate, producing
new immune-resistant strains on a regular basis. Preventive yearly
influenza vaccination is important.
Mononucleosis syndromes of fever with detectable lymph
node enlargement typify infections with Epstein-Barr virus
(EBV), cytomegalovirus (CMV), primary human immunodefi-
ciency virus (HIV), and Toxoplasma gondii (i.e., toxoplasmosis).
Other manifestations of these infections include abnormal liver
function test results, respiratory tract symptoms, and neurologic
symptoms. Diagnosis of acute HIV infection, which can produce
a mononucleosis-like syndrome, is an urgent issue.
Bacterial Infections
Pathogenic bacteria can infect all body parts and can cause a
spectrum of localized illness warranting antibiotic therapy. For
example, Staphylococcus aureus may cause skin abscesses or cel-
lulitis. Highly pathogenic organisms may colonize individuals
who have had contact with the health care system. Most concern-
ing is the event of bacteria entering the bloodstream. Obtaining
timely blood cultures before administering the antibiotics indi-
cated for presumed bacterial infections in persons with common
clinical syndromes can help to identify bloodstream pathogens
and define the required course of treatment.
Fever may be the predominant clinical manifestation of S.
aureus illness. This organism and the methicillin-resistant form
(i.e., MRSA) frequently cause sepsis without an obvious primary
site of infection. It should be considered in patients undergoing
intravenous therapy or hemodialysis and in those who use intra-
venous drugs or who have severe chronic dermatitis. Bacteremia
with staphylococci may cause hematogenous seeding of bones
leading to osteomyelitis and heart valves leading to endocarditis
in individuals; the bacteremia may also reflect these underlying
processes. Other common causes of bacteremia and their sources
include Streptococcus pneumoniae (i.e., pneumonia), Escherichia
coli (i.e., urinary tract and gastrointestinal sources), streptococci
(i.e., skin), and anaerobes (i.e., gastrointestinal tract).
Listeria monocytogenes bacteremia is seen predominantly in
persons with depressed cell-mediated immunity. It is the most
common manifestation of listeriosis in these hosts. Many with
listeriosis may have meningitis and warrant lumbar puncture for
cerebrospinal fluid culture.
Typhoid and paratyphoid fever (i.e., enteric fever) are common
in many low-income countries. Patients may have fever alone as
the primary clinical manifestation. Travelers to six countries
account for 80% of U.S. cases: India, Mexico, Philippines, Paki-
stan, El Salvador, and Haiti. Fever with headache and an insidious
onset with an unremarkable physical examination is common,
although a faint and transient rash (i.e., rose spots) may appear
by the second week of illness. Symptoms may include diarrhea,
constipation, vague abdominal discomfort, and sometimes dry
cough. Diagnosis depends on the culture of blood or stool.
Fever with Localized Symptoms and Signs
Localized bacterial infection can be apparent, as in cases of
abscess, cellulitis, or otitis media, or clinically occult. It can
develop as an undifferentiated febrile syndrome. Careful inspec-
tion of mucous membranes and conjunctiva may reveal pete-
chiae, which are clues to meningococcemia or infective
endocarditis. Finding heart murmurs in the setting of fever may
suggest endocarditis and warrant additional blood cultures. Pul-
monary signs in pneumonia include rales and evidence of con-
solidation, but persons with cryptococcosis, coccidioidomycosis,
histoplasmosis, psittacosis, legionellosis, or pneumocystis pneu-
monia may show few signs.
These infections should be suspected based on exposure
history and the host’s immune status. It is important to assess the
size of the liver, spleen, and lymph nodes, particularly in cases of
viral infection. A swollen joint may indicate septic arthritis. A
complete neurologic examination, including cranial nerves and
testing for meningeal signs, may indicate CNS infection.
Malaria, bacterial sepsis, and bacterial infections of the lung,
urinary tract, CNS, and intestines with resultant bacteremia
warrant urgent initiation of empirical treatment while awaiting
final identification and sensitivities. For febrile patients with fea-
tures suggesting a bacterial infection, evaluation should include
complete blood counts with differential and platelet counts,
blood smears for those at risk for malaria or babesiosis, urinalysis,
throat and blood cultures, and a chest radiograph.
Fevers with rash as a prominent feature warrant exclusion of
life-threatening infectious diseases, including meningococcemia,
toxic shock syndrome (TSS), and Rocky Mountain spotted fever
(RMSF). Characterization of the rash can help. Clues to some of
the common infections exhibiting fever as the sole feature and
those causing fever with rash are provided in Tables 88-2, 88-3,
and 88-4. Tables 88-5 and 88-6 list common syndromes associ-
ated with imported fevers when assessing travelers.
  FEVER OF UNKNOWN ORIGIN
Most febrile conditions resolve or are readily diagnosed and
treated, but some fevers can persist and remain unexplained.
838 Section XV  Infectious Disease

TABLE 88-2  INFECTIONS EXHIBITING FEVER AS THE SOLE OR DOMINANT FEATURE

DISTINCTIVE CLINICAL AND
INFECTIOUS AGENT OR SOURCE EPIDEMIOLOGIC EXPOSURE AND HISTORY LABORATORY FINDINGS
VIRUSES
Rhinovirus, adenovirus, parainfluenza None (adenovirus in epidemics) Often URI symptoms; throat and rectal cultures; rapid viral
antigen testing
Middle East respiratory syndrome (MERS) Travel to Arabian Peninsula or contact from Pneumonia with ARDS; viral antigen testing of sputum; PCR
Middle East of normally sterile sites (CDC)
Enteroviruses (nonpolioviruses: Summer, epidemic Occasionally aseptic meningitis, rash, pleurodynia,
coxsackieviruses, echovirus) herpangina; serologic or nucleic acid testing (PCR)
Influenza Winter, epidemic Headache, myalgias, arthralgias; nasopharyngeal culture,
rapid viral antigen testing
EBV, CMV Close personal contact; blood or tissue exposure; Monospot test, EBV specific antibodies; EBV PCR in
occupational or perinatal exposure immunocompromised; CMV IgM shell vial assay; CMV
antigenemia assay; CMV DNA of CSF; culture and
histopathology of tissues
Colorado tick fever Southwest and northwest regions, tick exposure Biphasic illness, leukopenia; blood, CSF cultures, serologic or
PCR
Deer tick virus (Powassan virus) New York State tick exposure Altered mentation or encephalitis; serum and CSF IgM
(CDC)
BACTERIA
Staphylococcus aureus IV drug users, IV catheters, hemodialysis, Must exclude endocarditis; blood cultures
dermatitis
Listeria monocytogenes Depressed cell-meditated immunity Meningitis may also be present; blood, CSF cultures
Salmonella typhi, Salmonella paratyphi Food or water contaminated by carrier or patient Headache, myalgias, diarrhea, or constipation, transient rose
spots; blood, marrow, or stool cultures
Streptococci Valvular heart disease Low-grade fever, fatigue; blood cultures
ANIMAL EXPOSURE
Coxiella burnetii (Q fever) Exposure to infected livestock, parturient animals Headache, occasionally pneumonitis, hepatitis, culture-
negative endocarditis; serologic testing
Leptospira interrogans Water contaminated by urine Headache, myalgias, conjunctival suffusion, biphasic illness,
From dogs, cats, rodents, small mammals aseptic meningitis; serologic testing
ARDS, Acute respiratory disease syndrome; CDC, Centers for Disease Control and Prevention case definition; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus;
IgM, immunoglobulin M; IV, intravenous; PCR, polymerase chain reaction; URI, upper respiratory infection.

TABLE 88-3  DIFFERENTIAL DIAGNOSIS OF INFECTIOUS AGENTS PRODUCING FEVER AND RASH
MACULOPAPULAR, ERYTHEMATOUS LESIONS DIFFUSE ERYTHRODERMA
Enterovirus Group A streptococci (scarlet fever, toxic shock syndrome)
EBV, CMV, Toxoplasma gondii Staphylococcus aureus (toxic shock syndrome)
Acute HIV infection DISTINCTIVE RASH
Colorado tick fever virus
Salmonella typhi Ecthyma gangrenosum: Pseudomonas aeruginosa
Leptospira interrogans Erythema migrans: Lyme disease
Measles virus MUCOUS MEMBRANE LESIONS
Rubella virus
Hepatitis B virus Vesicular pharyngitis: coxsackievirus A
Treponema pallidum Palatal petechiae: rubella, EBV, scarlet fever (group A streptococci)
Parvovirus B19 Erythema: toxic shock syndrome (Staphylococcus aureus and group A
Human herpesvirus 6 streptococci)
Oral ulceronodular lesion: Histoplasma capsulatum
VESICULAR LESIONS Koplik’s spots: measles virus
Varicella-zoster virus
Herpes simplex virus
Coxsackievirus A
Vibrio vulnificus
CUTANEOUS PETECHIAE
Neisseria gonorrhoeae
Neisseria meningitidis
Rickettsia rickettsii (Rocky Mountain spotted fever)
Rickettsia typhi (murine typhus)
Ehrlichia chaffeensis
Echoviruses
Streptococcus viridans (endocarditis)
CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.
 Chapter 88  Fever and Febrile Syndromes 839

TABLE 88-4  FEVER AND RASH IN VIRAL INFECTION

VIRUS DISEASE FEATURES INCUBATION AND EARLY SYMPTOMS
Coxsackie, ECHO virus Maculopapular rubelliform, 1-3 mm, faint pink, begins on face, Summertime
spreading to chest and extremities No itching or lymphadenopathy
Herpetiform vesicular stomatitis with peripheral exanthema (papules Multiple cases in household or community-wide
and clear vesicles on an erythematous base), including palms and epidemic
soles (hand, foot, and mouth disease) Mostly diseases of children
Measles Erythematous, maculopapular rash begins on upper face and spreads Incubation period 10-14 days First, severe upper
down to involve extremities, including palms and soles. Koplik’s spots respiratory symptoms, coryza, cough, and
are blue-gray specks on a red base found on buccal mucosa near conjunctivitis; then Koplik’s spots, then rash
second molars. Atypical measles occurs in individuals who received
killed vaccine and then are exposed to measles. The rash begins
peripherally and is urticarial, vascular, or hemorrhagic.
Rubella Maculopapular rash beginning on face and moving down; petechiae on Incubation 12-23 days
soft palate Adenopathy; posterior auricular, posterior cervical,
and suboccipital
Varicella Generalized vesicular eruption; pruritic lesions in different stages from Incubation 14-15 days; late winter, early spring
erythematous macules to vesicles to crusted; spread from trunk Herpes zoster is a reactivation, occurs any season
centrifugally; zoster lesions are painful and often dermatomal
Herpes simplex virus Oral primary: small vesicles on pharynx, oral mucosa that ulcerates; Incubation 2-12 days
painful and tender
Recurrent: vermilion border, one or few lesions, genital; may be
asymptomatic or appear similar to oral lesions on genital mucosa
Hepatitis B and C virus Prodrome in one fifth; erythematous, maculopapular rash, urticaria Arthralgias, arthritis; abnormal liver function test
Leukocytoclastic vasculitis occurs in hepatitis C results; hepatitis B antigenemia
Epstein-Barr virus Erythematous, maculopapular rash on trunk and proximal extremities Transiently occurs in 5-10% of patients during first
Occasionally urticarial or hemorrhagic week of illness
Human immunodeficiency virus Maculopapular truncal rash may occur as early manifestation of Associated fever, sore throat, and lymph node
infection enlargement may persist for 2 or more weeks

TABLE 88-5  COMMON SYNDROMES AND DISEASES ASSOCIATED WITH FEVER IN RETURNED TRAVELERS
SORE THROAT COUGH ABDOMINAL PAIN ARTHRALGIA OR MYALGIA DIARRHEA
Bacterial pharyngitis Amebiasis (hepatic) Amebiasis (intestinal) Arboviruses Amebiasis (intestinal)
Diphtheria Anthrax Anthrax Dengue Anthrax
Infectious mononucleosis Bacterial pneumonia Campylobacter enteritis Yellow fever Campylobacter enteritis
HIV seroconversion Filarial fever Legionnaires disease Babesiosis HIV seroconversion
Lyme disease TPE Malaria Bartonellosis Legionnaires disease
Poliomyelitis Histoplasmosis Measles Brucellosis Malaria melioidosis
Psittacosis Legionnaires’ disease Melioidosis Erythema nodosum leprosum Plague
Tularemia Leishmaniasis (visceral) Plague Hepatitis (viral) Relapsing fever
Viral hemorrhagic fever (Lassa) Loeffler syndrome Relapsing fevers Histoplasmosis Salmonellosis
Nonspecific viral URTI Malaria Salmonellosis HIV seroconversion Schistosomiasis (acute)
Measles Schistosomiasis (acute) Legionnaires disease Shigellosis
Melioidosis Shigellosis Leptospirosis Typhoid in children
Plague Typhoid fever Lyme disease Viral hemorrhagic fevers
Q fever Viral hemorrhagic fevers Malaria Yersiniosis
Relapsing fever Yersiniosis Plague
Schistosomiasis (acute) Poliomyelitis
Toxocariasis Q fever
Trichinosis Relapsing fevers
Tuberculosis Secondary syphilis
Tularemia Toxoplasmosis
Typhoid and paratyphoid Trichinosis
Typhus Trypanosomiasis (African)
Viral hemorrhagic fevers Tularemia
Nonspecific viral URTIs Typhoid and paratyphoid
Typhus
Viral hemorrhagic fevers
From Beeching N, Fletcher T, Wijaya L: Returned travelers. In Zuckerman JN, editor: Principles and practice of travel medicine, ed 2, Boston, 2013, Wiley-Blackwell, p 271.
HIV, Human immunodeficiency virus; TPE, tropical pulmonary eosinophilia; URTI, upper respiratory tract infection.

Table 88-7 shows the most common causes of unexplained
fevers.
The term fever of unknown origin (FUO) identifies a pattern of
fever with temperatures greater than 38.3° C (101° F) on several
occasions over more than 3 weeks after an initial diagnostic
work-up for which the diagnosis remains uncertain. Verifying the
presence or absence of fever is important; up to 35% of 347
patients admitted to the National Institutes of Health (NIH) for
evaluation of prolonged fever were determined not to have sig-
nificant fever or had fever of factitious origin. Cases of FUO are
840 Section XV  Infectious Disease

TABLE 88-6  COMMON CLINICAL FINDINGS AND TABLE 88-7  COMMON CAUSES OF FEVER OF
ASSOCIATED INFECTIONS UNKNOWN ORIGIN
INFECTIONS TO CONSIDER AFTER INFECTIONS
CLINICAL FINDINGS TROPICAL TRAVEL Abscesses
Fever and rash Dengue, chikungunya, rickettsial Brucellosis
infections, enteric fever (skin lesions Catheter infections
may be sparse or absent), acute HIV Cytomegalovirus
infection, measles, acute Coccidioidomycosis
schistosomiasis Histoplasmosis
Fever and abdominal pain Enteric fever, amebic liver abscess Human immunodeficiency virus (HIV) infection
Undifferentiated fever and Dengue, malaria, rickettsial infection, Infective endocarditis
normal or low white blood enteric fever, chikungunya Intra-abdominal, subdiaphragmatic, and pelvic disease
cell count Liver and biliary tract disease
Fever and hemorrhage Viral hemorrhagic fevers (dengue and Lyme disease
others), meningococcemia, Mycobacterium tuberculosis
leptospirosis, rickettsial infections Osteomyelitis
Fever and eosinophilia Acute schistosomiasis; drug Sinusitis
hypersensitivity reaction; fascioliasis Toxoplasmosis
and other parasitic infections (rare) Urinary tract infection
Fever and pulmonary infiltrates Common bacterial and viral pathogens; AUTOIMMUNE CONDITIONS
legionellosis, acute schistosomiasis, Q
fever, melioidosis Adult Still’s disease
Fever and altered mental status Cerebral malaria, viral or bacterial Familial Mediterranean sarcoidosis
meningoencephalitis, African Rheumatoid arthritis
trypanosomiasis Systemic lupus erythematosus
Mononucleosis syndrome Epstein-Barr virus, cytomegalovirus, Temporal arteritis
toxoplasmosis, acute HIV infection MALIGNANCY
Fever persisting >2 weeks Malaria, enteric fever, Epstein-Barr virus,
cytomegalovirus, toxoplasmosis, acute Hepatocellular carcinoma
HIV, acute schistosomiasis, brucellosis, Leukemia
tuberculosis, Q fever, visceral Metastatic cancers
leishmaniasis (rare) Pancreatic cancer
Fever with onset >6 wk after Vivax malaria, acute hepatitis (B, C, Renal cell carcinoma
travel or E), tuberculosis, amebic liver abscess MISCELLANEOUS CAUSES
Modified from Centers for Disease Control and Prevention: CDC health information for Deep vein thrombosis, pulmonary embolism
international travel 2012, New York, 2012, Oxford University Press. Hyperthyroidism
HIV, Human immunodeficiency virus. Kikuchi’s disease
Periodic fever (tumor necrosis factor receptor associated)

categorized as classic FUO, health care–associated FUO, neutro-

penic (immune-deficient) FUO, and HIV-related FUO. Each of
these FUO subtypes can have unique causes.
Classic Fever of Unknown Origin
The most common causes of classic FUO are infections, malig-
nancies, and noninfectious inflammatory disorders; miscella-
neous causes and undiagnosed cases account for the remaining
categories. Historically, infections have made up the largest cat-
egory, representing 25% to 50% of cases. Abscesses, endocarditis,
tuberculosis, complicated urinary tract infections, and biliary
tract diseases have consistently been among the most important.
Abscesses account for almost one third of infectious causes, and
most are intra-abdominal or pelvic in origin. Perforation of a
colonic diverticulum or appendicitis can sometimes lead to large,
walled-off abdominal abscesses with few localizing signs.
During the past 50 years, the improvement of imaging studies
and their greater accessibility have made abdominal or pelvic
abscesses and malignancies more easily detected and less likely
to be the cause of prolonged, undiagnosed fever. Malignant neo-
plasms can induce fever directly through the production and
release of pyrogenic cytokines and indirectly by undergoing
spontaneous or induced necrosis or creating conditions condu-
cive to secondary infections. Endovascular infections are usually
detectable by blood cultures, although slow-growing or fastidious
organisms may make detection difficult.
Infections, including tuberculosis, typhoid fever, malaria, and
amebic liver abscesses, remain the most frequent causes of FUO
in developing countries. The incidence of some FUOs vary in
incidence according to geographic location. Classic FUO may
occur as familial Mediterranean fever among Ashkenazi Jews; in
Kikuchi’s disease, which is an unusual form of necrotizing lymph-
adenitis seen primarily in Japan; and as TNF receptor–associated
periodic fever (TRAPS), formerly called familial Hibernian fever,
which is an inherited periodic fever syndrome described origi-
nally in Ireland.
The proportion of FUOs due to noninfectious inflammatory
diseases and undiagnosed conditions has risen. Of the connective
tissue diseases, juvenile rheumatoid arthritis (i.e., Still’s disease),
other variants of rheumatoid arthritis, and systemic lupus erythe-
matosus predominate among younger patients. Temporal arteri-
tis and polymyalgia rheumatica syndromes are more common
among elderly patients.
Fever may be blunted or absent in up to one third of elderly
individuals with serious conditions. Older people may more
often have atypical clinical presentations of common infectious
and noninfectious diseases. For example, elderly persons may
have tuberculosis without cough or fever, infective endocarditis
with fatigue and weight loss but without fever, abdominal
abscesses with little abdominal tenderness found on physical
examination. Leukocytosis and increased band forms are more
 Chapter 88  Fever and Febrile Syndromes 841
likely to be associated with a serious infection. HIV should be
considered as a possible cause of FUO in older patients, although
it is not usually suspected early in the course of FUO.
Fever in returned travelers is most often caused by common
infections, such as malaria and respiratory or urinary tract infec-
tions. However, fever cased by dengue, typhoid fever, or amebic
liver abscess is increasingly identified, especially among interna-
tional travelers returning from the tropics. Katayama fever is a
febrile syndrome occurring after exposure to fresh water schisto-
somes in endemic areas. It may resolve spontaneously or may
require treatment with antiparasitic agents to prevent sequelae
that carry severe morbidity. A travel history should be obtained,
and it may redirect the entire work-up.
Health Care–Associated Fever   comprehensive history, repeated physical examinations, appro-
of Unknown Origin
Some FUOs are associated with health care practices, including
surgical procedures, urinary and respiratory tract instrumenta-
tion, intravascular devices, drug therapy, and immobilization.
Quality control measures are set up to minimize and avoid blood-
stream infections and decubitus ulcers. Drug-related fever, septic
thrombophlebitis, recurrent pulmonary emboli, and Clostridium
difficile colitis must be considered in the work-up of hospitalized
patients who develop fever greater than 38° C (100.4° F) for
more than 3 days if it was not present on admission.
Immune Deficiency–Associated   investigations that may obfuscate the true diagnosis.
Fever of Unknown Origin
Immunosuppressed individuals have the highest incidence of
FUO of any group of patients. Due to impaired immune
responses, signs of inflammation other than fever are notoriously
absent or diminished, producing atypical clinical manifestations
and an absence of radiologic abnormalities for what otherwise
would be readily diagnosed infections. In patients with impaired
cell-mediated immunity, FUO often results from conditions
other than pyogenic bacterial infections (e.g., fungi, CMV).
Neutropenia is a dangerous condition that can be considered
a subclass of immunodeficiency. Persons with profound neutro-
penia are at high risk for bacterial and fungal infections. Episodes
of fever are common in patients with neutropenia. Many epi-
sodes are short lived because they respond quickly to treatment
or are manifestations of rapidly fatal infections.
Bacteremia and sepsis can cause rapid deterioration in neutro-
penic patients, and empirical, broad-spectrum antibiotics should
be administered promptly without waiting for the results of cul-
tures. However, only about 35% of prolonged episodes of febrile
neutropenia respond to broad-spectrum antibiotic therapy. If
fevers persist after 3 days of treatment with broad-spectrum anti-
biotics, diagnostic tests to explore fungal causes should be con-
sidered along with empirical antifungal treatment.
Human Immunodeficiency Virus–Related
Fever of Unknown Origin
The primary phase of HIV infection is characterized by a
mononucleosis-like illness in which fever is a prominent feature
(see Chapter 101). After symptoms of the primary phase of HIV
infection resolve, patients enter a long period of subclinical infec-
tion during which they are usually afebrile. In the later phases of
untreated HIV infection, episodes of fever become common,
often signifying a superimposed illness. Many of these are poten-
tially devastating opportunistic infections, which tend to mani-
fest in atypical fashion because of the severe immunodeficiency.
Patients with acquired immunodeficiency syndrome (AIDS)
often have multiple infections simultaneously. After highly active
antiretroviral therapy (HAART) has been started and the HIV
viral load is effectively suppressed, the frequency of FUO in HIV-
infected patients falls markedly.
Approach to the Patient with  
Fever of Unknown Origin
Evaluation of a patient with FUO typically includes verification
that the patient has fever, consideration of the fever pattern, a
priate laboratory investigations, key imaging studies, and invasive
diagnostic procedures. The physical examination should scruti-
nize the patient more closely than usual because key physical
abnormalities in patients with FUO are subtle and require
repeated examinations to be appreciated.
Work-up of a patient with an FUO should focus on the history,
physical examination, and initial laboratory data. In place of ratio-
nal diagnostic thinking, there is a temptation to order multiple
comprehensive laboratory and imaging studies. Rather than
leading to a diagnosis, this shotgun approach may result in enor-
mous expense, false-positive results, and unnecessary additional
A fundamental principle in the management of classic FUO is
that therapy should be withheld, whenever possible, until the
cause of the fever has been determined, so that treatment can be
tailored to a specific diagnosis. The exception is in the setting of
the immunocompromised host because rapid empirical treat-
ment is most often needed.
  SPECIFIC CONDITIONS AND
EXPOSURES CAUSING FEVER
Fever after Animal Exposures
Q Fever
Q fever is a widespread zoonotic infection caused by the patho-
gen Coxiella burnetii that has acute and chronic manifestations.
The primary source of infection is infected cattle, sheep, and
goats. The organism can exist for months in soil and can become
airborne. The onset of disease is typically abrupt, and high-grade
fever (40° C or 104° F), fatigue, headache, and myalgias are the
most common symptoms. Acute Q fever is usually a mild disease
that resolves spontaneously within 2 weeks. Q fever endocarditis
usually occurs in patients with previous valvular damage or
immunocompromise, and it is often the predominant manifesta-
tion of chronic infection.
An immunofluorescence assay is the reference method for the
serodiagnosis of Q fever. Consideration of doxycycline therapy is
warranted only for patients who are symptomatic.
Leptospirosis
Leptospirosis is a zoonotic infection with protean manifestations
caused by the spirochete Leptospira interrogans. It is distributed
worldwide, but most clinical cases occur in the tropics. The
842 Section XV  Infectious Disease
organism infects rodents, cattle, swine, dogs, horses, sheep, and
goats, and it is shed in the urine. Humans most often become
infected after exposure to environmental sources, such as con-
taminated water.
Leptospirosis may manifest as a subclinical illness followed by
seroconversion, a self-limited systemic infection, or a severe,
potentially fatal illness accompanied by multiorgan failure. Acute
illness manifests with the abrupt onset of fever, rigors, myalgias,
and headache in 75% to 100% of patients. Conjunctival suffusion
in a patient with a nonspecific febrile illness accompanied by
lymphadenopathy, hepatomegaly, and splenomegaly points to a
diagnosis of leptospirosis.
During the second phase of illness, fever is less pronounced,
but headache and myalgias can be severe, and aseptic meningitis
is an important manifestation. In some patients with leptospiro-
sis, the clinical course may be complicated by jaundice (although
liver failure is rare), renal failure, uveitis, hemorrhage, ARDS,
myocarditis, and rhabdomyolysis (i.e., Weil’s syndrome).
Because the clinical features and routine laboratory findings of
leptospirosis are not specific, a high index of suspicion must be
maintained. The diagnosis is usually made by serologic testing for
L. interrogans. Symptomatic individuals warrant treatment with
doxycycline.
Brucellosis
Brucellosis is a zoonotic infection caused by Brucella melitensis. It
is transmitted to humans by contact with fluids from infected
animals (i.e., sheep, cattle, goats, pigs, or other animals) or derived
food products such as unpasteurized milk and cheese.
Clinical manifestations of brucellosis include fever, night
sweats, malaise, anorexia, arthralgias, fatigue, weight loss, and
depression. Patients may have fever and a multitude of com-
plaints but no other objective findings. The onset of symptoms
may be abrupt or insidious, developing over several days to
weeks. The musculoskeletal and genitourinary systems are the
most common sites of involvement. Neurobrucellosis, endocar-
ditis, and hepatic abscesses occur in 1% to 2% of cases.
The diagnosis of brucellosis should be considered for an indi-
vidual with otherwise unexplained fever and nonspecific com-
plaints who has had a possible exposure. Ideally, the diagnosis is
made by culture of the organism from blood or other sites, such
as bone marrow. Serologic tests include tube agglutination and
enzyme-linked immunosorbent assay (ELISA). For adults with
nonfocal disease, treatment with doxycycline and rifampin is
suggested.
Fever and Rash
The most concerning diseases associated with fever and rash are
meningococcemia, staphylococcal TSS, and RMSF.
Bacterial Meningitis
Neisseria meningitidis is the leading cause of bacterial meningitis
in children and young adults in the United States. Recent experi-
ence in New York City identified HIV patients as being at
increased risk for meningococcal disease.
Manifestations of meningococcal disease can range from tran-
sient fever and bacteremia to fulminant disease, with death
ensuing within hours of the onset of clinical symptoms. Acute
systemic meningococcal disease may manifest as one of three
syndromes: meningitis alone, meningitis with accompanying
meningococcemia, and meningococcemia without clinical evi-
dence of meningitis.
The typical initial symptoms of meningitis due to N. meningiti-
dis consists of the sudden onset of fever, nausea, vomiting, head-
ache, decreased ability to concentrate, and myalgias in an
otherwise healthy patient. A petechial rash appears as discrete
lesions 1 to 2 mm in diameter, most frequently occurring on the
trunk and lower portions of the body. More than 50% of patients
have petechiae at clinical presentation. Petechiae can coalesce
into larger purpuric and ecchymotic lesions.
Staphylococcal Toxic Shock Syndrome
S. aureus strains produce exotoxins that cause three syndromes:
food poisoning, caused by ingestion of S. aureus enterotoxin;
scalded skin syndrome, caused by exfoliative toxin; and TSS,
caused by toxic shock syndrome toxin 1 (TSST-1) and other
enterotoxins. About one half of reported TSS cases are men-
strual, associated with bacterial growth on highly absorbent
tampons. Nonmenstrual TSS has been associated with surgical
and postpartum wound infections, mastitis, septorhinoplasty,
sinusitis, osteomyelitis, arthritis, burns, cutaneous and subcuta-
neous lesions (especially of the extremities, perianal area, and
axillae), and respiratory infections after influenza. Some MRSA
strains can produce TSST-1, and patients infected with these
strains may develop TSS.
The Centers for Disease Control and Prevention (CDC) case
definition for a confirmed case includes several criteria. Patients
must have fever greater than 38.9° C, hypotension, diffuse eryth-
roderma, desquamation (unless the patient dies before desqua-
mation can occur), and involvement of at least three organ
systems. Although 80% to 90% of TSS patients have S. aureus
isolated from mucosal or wound sites, the isolation of S. aureus is
not required for the diagnosis of staphylococcal TSS.
Rickettsial Infections
RMSF is a potentially lethal but usually curable tick-borne
disease. Most cases of RMSF occur in the spring and early
summer in endemic areas, particularly in the south central and
southeastern states, when outdoor activity is most common. The
etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate
intracellular bacterium that is usually transmitted through a tick
bite. Up to one third of patients with proven RMSF do not recall
a recent tick bite or recent tick contact.
In the early phases of illness, most patients have nonspecific
signs and symptoms such as fever, headache, malaise, myalgias,
arthralgias, and nausea with or without vomiting. Most patients
with RMSF develop a rash between the third and fifth days of
illness. The rash typically begins with pink, blanching macules
that evolve to a deep red color and then become hemorrhagic.
The lesions begin at the wrists, forearms, and ankles and then
spread to the arms, thighs, trunk, and face.
The diagnosis of RMSF is based on a constellation of symp-
toms and signs in an appropriate epidemiologic setting (e.g.,
endemic area in the spring or early summer). In later illness,
the diagnosis can be made by skin biopsy and confirmed
serologically.
 Chapter 88  Fever and Febrile Syndromes 843
Murine typhus is a worldwide illness caused by Rickettsia typhi
organisms that are transmitted by fleas. It produces a moderately
severe illness characterized by fever, rash, and headache. Disease
in the United States has been reported in Texas and Southern
California.
Rickettsia africae, the cause of African tick-bite fever, occurs in
travelers returning from East Africa. It produces a large eschar
with a febrile syndrome similar to RMSF. Rickettsial infections
respond to treatment with doxycycline and warrant rapid initia-
tion of treatment.
Lyme Disease
Lyme disease is a tick-borne illness caused by pathogenic species
of the spirochete Borrelia burgdorferi in the United States. Other
species in Europe and Asia can cause more aggressive presenta-
tions. Localized disease includes erythema migrans in 80% of
patients and nonspecific findings that resemble a viral syndrome.
Erythema migrans is an expanding macule that forms an annular
lesion with a clearing middle.
Early disseminated Lyme disease with acute neurologic or
cardiac involvement usually occurs weeks to several months after
the tick bite and may be the first manifestation of the disease.
Nonspecific symptoms (e.g., headache, fatigue, arthralgias) may
persist for months after treatment of Lyme disease. There is no
evidence that these persistent subjective complaints represent
ongoing active infection. Co-infection with Babesia and Ehrlichia
is common, and these infections should be considered in persons
diagnosed with Lyme disease.
Human Ehrlichiosis
The principal vector of Ehrlichia chaffeensis, the agent that causes
human monocytic ehrlichiosis (HME), is the Lone Star tick
(Amblyomma americanum). Patients typically have an acute
illness that has an incubation period of 1 to 2 weeks. Most patients
are febrile and have nonspecific symptoms such as malaise,
myalgia, headache, and chills.
One feature that may distinguish HME from human granulo-
cytic anaplasmosis (HGA), another tick-borne illness caused by
Anaplasma phagocytophilum, is a rash (macular, maculopapular,
or petechial). This rash occurs in about 30% of patients with
HME but is rare in patients with HGA.
The preferred and most widely available diagnostic method for
ehrlichiosis is the indirect fluorescent antibody test. The diagno-
sis should be considered in all patients with Lyme disease or
babesiosis. Treatment with doxycycline should be initiated for all
patients suspected of having ehrlichiosis or anaplasmosis.
Viral Infections Associated with Rash
The typical manifestations of viral infections associated with rash
may unequivocally establish the cause of a febrile syndrome. For
example, varicella-zoster virus infection manifests with distinc-
tive lesions of chickenpox or herpes zoster (i.e., shingles). The
resurgence of measles mandates the ability to recognize its rash.
Acute onset of high fever characterizes viral hemorrhagic
fevers, along with bleeding complications and high mortality
rates in some cases. Arthropods often transmit viral infections,
including dengue, which is one of the most common causes of
fever in returned travelers. The deer tick virus identified in New
York State causes a syndrome of fever and confusion with or
without rash.
Fever with Lymphadenopathy
Generalized and localized lymphadenopathy can be major
manifestations of some infectious diseases, such as in mononu-
cleosis syndromes, tuberculosis, HIV infection, and pyogenic
infections.
Infectious mononucleosis is characterized by a triad of fever,
tonsillar pharyngitis, and lymphadenopathy. EBV is a widely dis-
seminated herpesvirus that is spread by intimate contact between
susceptible persons and EBV shedders. Lymph node involve-
ment in infectious mononucleosis is typically symmetrical and
more commonly involves the posterior cervical than the anterior
chains. The posterior cervical nodes are deep beneath the sterno-
cleidomastoid muscles and must be carefully palpated. The nodes
may be large and moderately tender. Lymphadenopathy may also
become more generalized including enlargement of the spleen,
which distinguishes infectious mononucleosis from other causes
of pharyngitis.
Lymphadenopathy peaks in the first week and then gradually
subsides over 2 to 3 weeks. Splenomegaly is seen in 50% of
patients with infectious mononucleosis and usually begins to
recede by the third week of the illness.
Patients with a clinical picture of infectious mononucleosis
should have a white blood cell count with differential and a
heterophile (Monospot) test. If the heterophile test result is
positive, no further testing is necessary when the clinical sce-
nario is compatible with typical infectious mononucleosis. If
the heterophile test result is negative but there is still a strong
clinical suspicion of EBV infection, the Monospot test can
be repeated because results can be negative early in clinical
illness.
If the clinical syndrome is prolonged or the patient does not
have a classic EBV syndrome, immunoglobulin M (IgM) and
immunoglobulin G (IgG) viral capsule antigen (VCA) and
Epstein-Barr nuclear antigen (EBNA) antibodies should be
measured. IgG EBNA detected within 4 weeks of symptom onset
excludes acute primary EBV infection as an explanation
and should prompt consideration of EBV-negative causes of
mononucleosis.
Cytomegalovirus
The spectrum of human illness caused by CMV is diverse and
mostly depends on the host. CMV infection in the immunocom-
petent host usually is asymptomatic or may manifest as a
mononucleosis-like syndrome. Transmission occurs through
multiple routes.
The mononucleosis syndrome associated with CMV infection
has been described as typhoidal because systemic symptoms and
fever predominate, and signs of enlarged cervical nodes and sple-
nomegaly are not as commonly seen as they are in EBV infection.
Diarrhea, fever, fatigue, and abdominal pain are common symp-
toms. Immunocompromised patients, such as those who have
received transplants, may have serious, life-threatening infections
such as pneumonitis, hepatitis, colitis, and retinitis. Serology pro-
vides indirect evidence of recent CMV infection based on
changes in antibody titers at different time points during the
844 Section XV  Infectious Disease
clinical illness. Serologies are also helpful in determining past
exposure to CMV. This information is particularly relevant for
monitoring immunosuppressed hosts at risk for CMV reactiva-
tion syndromes.
Primary Human Immunodeficiency Virus Infection
Because a variety of symptoms and signs may be associated
with acute, symptomatic HIV infection, all patients with
mononucleosis syndromes should undergo HIV testing. Pub-
lished series consistently report that the most common find-
ings are fever, generalized lymphadenopathy, sore throat, rash,
myalgia or arthralgia, and headache. The HIV plasma viral
load should be assessed to detect acute infection because
the ELISA result may not indicate positivity for HIV until
months later.
Toxoplasmosis
Toxoplasmosis, an infection with a worldwide distribution, is
caused by the intracellular protozoan parasite T. gondii. Humans
can acquire Toxoplasma organisms through ingestion of contami-
nated meat, vertical transmission, blood transfusion, exposure to
oocysts from cat feces, or organ transplantation.
Immunocompetent persons with primary infection are usually
asymptomatic, but latent infection can persist for the life of the
host. When symptomatic infection does occur, the most common
manifestation is bilateral, symmetrical, nontender cervical ade-
nopathy. Patients may have headache, fever, and fatigue. Symp-
toms usually resolve within several weeks. In AIDS patients or
other immunocompromised hosts who have been previously
infected, T. gondii infection may reactivate in the brain, causing
abscesses and encephalitis.
Infections Causing Regional
Lymphadenopathy
Scrofula (i.e., tuberculous cervical adenitis) develops in a sub-
acute to chronic pattern. Low-grade fever is usually associated
with a large mass of matted cervical lymph nodes. In children, M.
tuberculosis is the etiologic agent, but in adults, Mycobacterium
avium complex and Mycobacterium scrofulaceum are more com-
monly found. Surgical excision is the treatment of choice.
Cat-Scratch Disease
Cat-scratch disease, a condition caused by Bartonella henselae, is
characterized by self-limited regional lymphadenopathy after a
cat scratch or transmission from another vector. Other manifesta-
tions can include visceral organ, neurologic, and ocular involve-
ment. In 85% to 90% of children, cat-scratch disease manifests as
a localized cutaneous and lymph node disorder near the site of
organism inoculation. In some individuals, the organisms dis-
seminate and infect the liver, spleen, eye, bone, or CNS. Patients
with localized disease usually have a self-limited illness, whereas
those with disseminated disease can have life-threatening com-
plications. B. henselae infection should be considered in the initial
evaluation of FUO in children.
The diagnosis of cat-scratch disease is based on typical clinical
findings (i.e., lymphadenopathy) associated with probable expo-
sure to cats or fleas. Laboratory testing that supports the diagno-
sis includes a positive B. henselae antibody titer or biopsy of a
lymph node with a positive Warthin-Starry stain or polymerase
chain reaction (PCR) analysis of tissue.
Pyogenic Infection
S. aureus and group A streptococcal (GAS) infections can
produce acute, suppurative lymphadenitis. Enlarged and tender
lymph nodes usually are found in the submandibular, cervical,
axillary, or inguinal areas. Patients have fever and leukocytosis.
Pyoderma, pharyngitis, and periodontal infections are usually
the primary sites of infection. Management includes drainage
and antibiotics.
Plague
Bubonic plague is a bacterial syndrome caused by Yersinia pestis
that usually consists of fever, headache, and a large mat of ingui-
nal, axillary, or cervical lymph nodes. Lymph nodes suppurate
and drain spontaneously. The diagnosis should be considered for
acutely ill patients in the southwestern United States with pos-
sible exposure to fleas and rodents. Gram-negative coccobacilli
can be seen in lymph node aspirates. The characteristic safety-pin
appearance of Y. pestis with dark blue staining of polar bodies is
seen with Wayson stain.
Sexually Transmitted Diseases
Inguinal lymphadenopathy associated with sexually transmitted
diseases can be unilateral or bilateral. In primary syphilis, enlarged
nodes are discrete, firm and nontender. Tender lymphadenopa-
thies with matting are seen in lymphogranuloma venereum. The
lymphadenopathy of chancroid is most often unilateral and mani-
fests with pain and fused lymph nodes. Primary genital herpes
infection also causes tender inguinal lymphadenopathy.
  FACTITIOUS FEVER AND SELF-INDUCED ILLNESS
In most case series, factitious fever or self-induced illness is a rela-
tively uncommon cause of FUO, but it may occur more often
than generally appreciated. Patients with these conditions are
often young women, and 50% have had training in some aspect
of health care. They are often well educated, cooperative, articu-
late, and manipulative of family and caregivers. Patients can no
longer manipulate thermometers because electronic or infrared
thermometry is used, and causing factitious fever is difficult.
Clues to the factitious fever diagnosis include absence of a toxic
appearance despite high temperature readings, lack of tachycar-
dia, and absent diurnal variation. Patients may appear well
between episodes of fever.
Genuine fever can be induced if an individual injects or ingests
pyrogenic substances such as bacterial suspensions, urine, or
feces. Although intermittent polymicrobial bacteremia may
suggest a diagnosis of intra-abdominal abscess, it represents self-
induced infection. The discovery of needles and substances for
injection in the patient’s belongings may help in the diagnosis.
In most cases, a psychogenic basis for the behavior is assumed.
However, one study with detailed psychological patient analyses
found no evidence of major psychiatric diagnoses among indi-
viduals with self-induced or simulated illnesses. Munchausen’s
syndrome and Munchausen by proxy are the most extreme forms
of factious fever. Patients often agree stoically to numerous highly
invasive procedures to diagnose and treat themselves or their
 Chapter 88  Fever and Febrile Syndromes 845
children (i.e., proxy). All of these individuals require objective
but complete, tactful, and compassionate assessments and con-
siderable psychiatric care.
SUGGESTED READINGS
Aduan RP, Fauci AS, Dale DC, et al: Prolonged fever of unknown origin (FUO):
a prospective study of 347 patients, Clin Res 26:558A, 1978.
Aduan RP, Fauci AS, Dale DC, et al: Factitious fever and self-induced infection:
a report of 32 cases and review of the literature, Ann Intern Med 90:230–242,
1979.
Cannon J: Perspective on fever: the basic science and conventional medicine,
Complement Ther Med 21(Suppl 1):S54–S60, 2013.
Hayakawa K, Balaji R, Pranatharthi C: Fever of unknown origin: an evidence-
based review, Am J Med Sci 344:307–316, 2012.
Rezai-Zadeh K, Munzberg H: Integration of sensory information via central
thermoregulatory leptin targets, Physiol Behav 121:49–55, 2013.
Weber D, Cohen M, Morrell D: The acutely iii patient with fever and rash. In
Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s
principles and practice of infectious diseases, ed 7, Philadelphia, 2010,
Churchill Livingstone, pp 791–807.
 89 
Bacteremia and Sepsis
Russell J. McCulloh and Steven M. Opal
  DEFINITION
Sepsis is a leading cause of morbidity and death among hospital-
ized patients. The disease process results from a complex inter-
play of host immune responses and infectious microorganisms.
As defined by the Surviving Sepsis Campaign, sepsis consists of
proven or suspected infection combined with systemic manifes-
tations of infection. Manifestations can include fever, altered
mental status, and abnormalities in inflammation and coagula-
tion. Severe cases can progress to multiple organ system dysfunc-
tion followed by organ failure and death.
Diagnostic criteria for sepsis are provided in Table 89-1. Severe
sepsis results from sepsis-induced tissue hypoperfusion and con-
sequent organ dysfunction. Septic shock is a combination of
severe sepsis and persistent hypotension despite adequate fluid
resuscitation or the need to use vasopressors to maintain a mean
arterial pressure (MAP) higher than 65 mm Hg. The continuum
of disease manifestations from localized infection to multiorgan
failure and refractory septic shock is depicted in Figure 89-1.
Recently, a revised set of definitions was proposed. The term
sepsis as currently used lacks specificity. Sepsis should imply a
deleterious situation in which the infection-induced systemic
inflammatory and coagulopathic responses have become injuri-
ous to the host. Sepsis is an infectious process characterized by
tissue injury from hypoperfusion and immune dysregulation.
Because sepsis always has severe ramifications for the patient, the
term sepsis should be used instead of the current “severe sepsis.”
Severe infection should be used to describe an infection that is
accompanied by systemic inflammation but without evidence of
organ dysfunction remote from the site of infection (i.e., the
former definition of sepsis). Whether these revised definitions
can resolve the current confusion in terminology remains to be
seen.
Understanding the pathophysiology of sepsis syndrome has
proved helpful in differentiating and treating severe inflammatory
processes that manifest with symptoms similar to sepsis, includ-
ing pancreatitis, severe trauma, thermal burns, and certain toxin
or environmental exposures. These processes can produce a sys-
temic inflammatory response syndrome (SIRS), but they lack the
component of infection needed to establish a diagnosis of sepsis.
The remarkable clinical similarity between these severe, “sterile”
inflammations and septic shock reflects their molecular profiles.
Identical signaling pathways for the immune response are acti-
vated by highly conserved pathogen-associated molecular pat-
terns (PAMPs), which are molecular motifs recognized by cells
of the host’s innate immune system. Damage-associated molecu-
lar patterns (DAMPs) are molecules released by injured host cells
846
that act as endogenous danger signals to promote the inflamma-
tory response (see Pathophysiology of Septic Shock).
  EPIDEMIOLOGY
The worldwide incidence of sepsis is difficult to assess due to
limited data from developing countries. In industrialized coun-
tries, reported rates of sepsis range from 22 to 300 cases per
100,000 people. Sepsis may account for up to 6% of adult deaths.
In the United States, more than 750,000 cases of sepsis and
200,000 sepsis-related deaths occur annually. The risk of mortal-
ity depends on the severity of illness and multiple host factors
(discussed later). Overall, estimates of death from sepsis range
TABLE 89-1  DIAGNOSTIC CRITERIA FOR SEPSIS*
GENERAL VARIABLES
Fever (>38.3° C)
Hypothermia (core temperature <36° C)
Heart rate>90 beats/min or more than 2 SD above the normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over 24 hr)
Hyperglycemia (plasma glucose >140 mg/dL or 7.7 mmol/L) in the absence
of diabetes
INFLAMMATORY VARIABLES
Leukocytosis (WBC count >12,000 mm3)
Leukopenia (WBC count <4000 mm3)
Normal WBC count with more than 10% immature forms
Plasma C-reactive protein >2 SD above the normal value
Plasma procalcitonin >2 SD above the normal value
HEMODYNAMIC VARIABLES
Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or an SBP
decrease [40 mm Hg in adults or <2 SD below normal for age])
ORGAN DYSFUNCTION VARIABLES
Arterial hypoxemia (Pao2/FIO2 <300)
Acute oliguria (urine output <0.5 mL/kg/hr for at least 2 hr despite
adequate fluid resuscitation)
Creatinine increase (0.5 mg/dL or 44.2 µmol/L)
Coagulation abnormalities (INR >1.5 or aPTT >60 sec)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count <100,000/mm3)
Hyperbilirubinemia (plasma total bilirubin, 4 mg/dL or 70 µmol/L)
TISSUE PERFUSION VARIABLES
Hyperlactatemia (1 mmol/L)
Decreased capillary refill or mottling
From Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock, 2012, Intensive Care Med
39:165–228, 2013.
aPTT, Activated partial thromboplastin time; Fio2, fraction of inspired oxygen; INR,
international normalized ratio; MAP, mean arterial pressure; Pao2, partial pressure of
oxygen; SBP, systolic blood pressure; SD standard deviations; WBC, white blood cell.
*The criteria include documented or suspected infection and some of the variables
listed.
 Chapter 89  Bacteremia and Sepsis 847

Pathophysiology

Renal
dysfunction

Hepatic
dysfunction
Cardiovascular
insufficiency Endothelial
dysfunction
Systemic
inflammatory Metabolic
Local Systemic response dysfunction
Pathogenic inflammatory inflammatory plus evidence Death
microorganism response response Gastrointestinal
of inadequate
organ dysfunction
perfusion Immune system
dysfunction

Respiratory Central nervous

insufficiency system dysfunction
Hematologic
dysfunction

Clinical entity Local Sepsis Severe Septic Acute

infection sepsis shock respiratory
distress Multiorgan
syndrome dysfunction
FIGURE 89-1  The spectrum of illness and nomenclature for sepsis pathophysiology.

TABLE 89-2  MICROORGANISMS COMMONLY IDENTIFIED IN SEPTIC PATIENTS BASED ON HOST FACTORS
HOST FACTOR ORGANISMS TO CONSIDER
Asplenia Encapsulated organisms, particularly Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga
canimorsus
Cirrhosis Vibrio, Salmonella, and Yersinia species; encapsulated organisms, other gram-negative rods
Alcohol abuse Klebsiella species, S. pneumoniae
Diabetes Mucormycosis, Pseudomonas species, Escherichia coli, group B streptococci
Neutropenia Enteric gram-negative rods, Pseudomonas, Aspergillus, Candida, Mucor species, Staphylococcus aureus, streptococcal species
T-cell dysfunction Listeria, Salmonella, and Mycobacterium species, herpesviruses (including herpes simplex, cytomegalovirus, varicella-zoster
virus)
Acquired immunodeficiency Salmonella species, S. aureus, Mycobacterium avium complex, S. pneumoniae, group B streptococci
syndrome

from 20% of mild to moderate cases to more than 60% of patients
with septic shock.
The financial impact of sepsis cases is immense. Each episode
of sepsis costs approximately $50,000 in health care expendi-
tures, for a total of more than $17 billion dollars annually in the
United States alone.
Bacterial infections are the most common cause of sepsis.
Bloodstream infections due to bacteria account for the largest
proportion of hospitalizations. The rates are highest for prema-
ture infants, the advanced elderly (especially those older than 85
years of age), and patients with intravenous catheters, implanted
devices, or severe medical morbidities such as severe burns or
hematologic malignancies.
Pathogens most commonly identified in bloodstream infec-
tions include staphylococci (e.g., Staphylococcus aureus), group
A streptococci, Escherichia coli, Klebsiella species, Enterobacter
species, and Pseudomonas aeruginosa. Immunocompromised
patients and patients with long-term intravascular catheters are
at increased risk for fungal bloodstream infections from Candida
species, and some species may be resistant to commonly used
antifungal medications. Given the broad variety of potential
pathogens, clinicians face the dual challenges of an accurate and
timely diagnosis and choice of appropriate empirical therapy.
Several epidemiologic factors can guide the clinician in cases
of sepsis when a source has not been identified. Table 89-2 lists
microorganisms that are associated with certain host factors
that predispose a patient to infection and sepsis. Host factors
associated with worse outcomes include extremes of age, use of
immunomodulating or immunosuppressing medications, and
concomitant chronic medical conditions.
Several diagnostic and treatment factors are associated with
severity of illness and clinical outcome. Delay in effective antimi-
crobial therapy correlates with worse outcomes. Infection with
multidrug-resistant organisms may cause a delay in effective
therapy, and for some organisms, particularly gram-negative
enteric rods, the delay may be independently related to worse
outcomes. Certain organisms (e.g., P. aeruginosa) are more viru-
lent. The primary infection site also is important; respiratory sites
848 Section XV  Infectious Disease

are the most common, and the central nervous system often is
the most lethal site of infection. The number of organ systems
involved plays a role, with mortality increasing as the number of
dysfunctional organ systems increase.
  PATHOLOGY AND IMMUNOPATHOGENESIS
The pathologic findings of fatal septic shock are often rather
bland on gross examination and even histologic examination of
tissue samples. The most common finding is increased tissue
edema in the interstitial spaces and excess lung fluid and pleural
fluid. Signs of hyaline membrane formation and fibrin deposition
in the alveoli are common and indicate the fibroproliferative
stage of acute respiratory distress syndrome (ARDS). Occasion-
ally, punctate or macroscopic evidence can be detected in the
adrenal tissues, as can diffuse petechiae in tissues and mucosal
surfaces that indicate disseminated intravascular coagulation
(DIC).
The kidneys usually appear normal, and necrosis of kidney
tissues is distinctly uncommon. The term acute tubular necrosis is
a misnomer, and the term acute kidney injury (AKI) is more
appropriate for describing the functional and usually reversible
loss of kidney function found in septic shock without accompa-
nying evidence of glomerular or tubular necrosis.
An important finding at autopsy is identification of the infec-
tious focus that caused septic shock. The focal infection that pre-
cipitated sepsis is readily identifiable in most deceased patients
despite days to weeks of seemingly appropriate antimicrobial
therapy directed against the pathogens. If careful histochemical
studies are performed shortly after a patient succumbs to sepsis,
excessive apoptosis (but not necrosis) of immune effector cells
is identifiable in lung, spleen, lymph nodes, and hepatic tissues.
Electron microscopy of tissues after death from sepsis often
reveals loss of tight junctions along epithelial and endothelial
surfaces. Electron microscopy also demonstrates diffuse mito-
chondrial swelling and degradation and clearance of intracellular
organelles (i.e., autophagy).
  PATHOPHYSIOLOGY OF SEPTIC SHOCK
The molecular mechanisms that underlie the basic pathophysiol-
ogy of septic shock have been determined. Sepsis is triggered
when a pathogen or cluster of pathogens breaches the epithelial
barriers at a tissue site, evades clearance by humoral and cellular
innate immune defenses, and causes an invasive infection. On
entry into the host tissues, microbial pathogens are first sensed
by myeloid cells of the innate immune system by pattern recogni-
tion receptors (e.g., toll-like receptors [TLRs]) on the cell surface
and in endosomal compartments. TLRs detect highly conserved
molecular motifs of microbes. Examples include lipopolysaccha-
ride (LPS), the endotoxin produced by gram-negative bacteria;
bacterial lipopeptides from gram-positive bacteria; β-glucans of
the cell wall of fungi; viral RNA genomes and proteins; bacterial
flagella; and DAMPs released from injured host cells, including
intracellular structures such as histone proteins, mitochondrial
DNA, and high-mobility group box 1 (Fig. 89-2).
TLRs and related intracellular pattern recognition receptors,
including the inflammasome elements, retinoic acid–inducible
gene 1 (RIG1)–like helicases, and cytoplasmic microbial TLR4,
alert the host to infection. TLR4 is the long sought-after LPS

Binding of lipopolysaccharide Endothelium

of gram-negative bacilli Binding of lipopeptides and
MD2 lipoteichoic acid of
CDI4 TLR2 gram-positive bacteria
TLR4
Transcription of Prostaglandins
immunomodulatory cytokines, Leukotrienes
complement and procoagulants Proteases
Oxidants
TLR1

NF-kB Sepsis
Activation and
binding of
Increased myeloid cells
Release of NF-κB activity of iNOS
and transfer to nucleus

Increased NO

NO

Vasodilation

FIGURE 89-2  Immunopathogenesis of sepsis. Early recognition of bloodstream infection begins with sensing by pattern recognition receptors:
toll-like receptor 4 (TLR4); cluster determinant 14 (CD14); myeloid differentiation factor 2 (MD2) for gram-negative bacterial lipopolysaccharide and
TLR2 for lipoteichoic acid and other elements from gram-positive bacteria. Engagement of the TLRs by their ligands signals transcription of the acute
phase response genes by the nuclear factor-κ light-chain enhancer of activated B cells (NF-κΒ, which is a monocyte). Septic shock is initiated by
systemic release of an array of vasoactive mediators, including nitric oxide (NO) produced by cytokine-inducible NO synthase (iNOS).
 Chapter 89  Bacteremia and Sepsis 849
receptor of the human innate immune system. LPS is released
from the cell membrane of gram-negative bacteria on their
destruction. LPS is first bound to a carrier protein, LPS-binding
protein, and the LPS monomer is then delivered to a membrane-
associated, multiligand, pattern recognition receptor, CD14. LPS
monomers are then passed to a soluble protein (i.e., myeloid dif-
ferentiation factor 2 [MD2]) and bind to the ectodomain of
TLR4. After this LPS/MD2/TLR4 complex is completed and
dimerized, intracellular signaling alerts the host to the invasive
infectious challenge. The pathway induces a series of phosphory-
lation events of adaptor proteins and signaling molecules that
terminate in the activation and translocation of transcriptional
activating factors such as nuclear factor-κB (NF-κB) into the
nucleus. The transcription factors bind to promoter sites of the
acute phase protein network, resulting in an acute outpouring of
inflammatory, host defense, and coagulation components.
Other TLRs, such as TLR5 (i.e., bacterial flagella) and the
TLR2/TLR1 and TLR2/TLR6 heterodimers (i.e., bacterial
lipopeptides, lipoteichoic acid, and other elements of bacteria
and fungi), are expressed on the cell surface of immune effector
cells that recognize different molecular patterns. Nucleic acid
recognition–specific TLRs reside in endosomal vacuoles, where
they detect microbial DNA (TLR9), single-stranded RNA
(TLR7 and TLR8), and double-stranded RNA (TLR3).
An array of complement elements, cytokines, chemokines,
prostanoids (e.g., prostaglandins), vasoactive peptides, platelet-
activating factor, and proteases are generated, resulting in activa-
tion of neutrophils, monocytes, macrophages, dendritic cells,
lymphocytes, and endothelial cells in a combined effort to wall
off the infectious process, clear the pathogens, and begin the
process of tissue repair. This defense system efficiently clears
pathogens from the host after local injury and the inevitable
minor breaches of the epithelial barriers by microorganisms that
occur over a lifetime.
If the inflammatory process is unchecked and accompanied by
large numbers of pathogens or even a few highly virulent organ-
isms (e.g., plague, tularemia, anthrax, hemorrhagic fever viruses)
to which the host has no preexisting immunity, a generalized,
inflammatory, and injurious process known as sepsis evolves over
a short time, and it can be deleterious or lethal to the host. The
same inflammatory response that can be lifesaving in localized
infection can become life-threatening if it becomes sustained and
generalized.
Endothelial membranes throughout the body are activated
and become proadherent and procoagulant surfaces that promote
neutrophil and platelet adherence. Neutrophils release proteases,
cytokines, reactive oxygen radicals, and vasoactive prostanoids
that damage endothelial cells and their function. Cytokine-
inducible nitric oxide synthase is upregulated, resulting in
massive generation of nitric oxide (NO). NO is a potent vasodila-
tor, and in combination with other vasoactive peptides and phos-
pholipid mediators, it promotes diffuse opening of capillary beds
and increased permeability, with loss of intravascular fluids into
the interstitial spaces. Reactive oxygen species combine with NO
to generate highly injurious reactive nitrogen intermediates (e.g.,
peroxynitrite) that damage mitochondrial function and induce
apoptosis. Systemic hypotension rapidly develops, and septic
shock ensues. Immediate action by the clinician is mandatory to
correct the hemodynamic status and resolve the underlying
infection.
  CLINICAL PRESENTATION
Despite the vast improvements in understanding the pathophysi-
ologic basis of sepsis, clinical diagnosis remains limited to the
medical history, symptomatic assessment, and nonspecific labo-
ratory and hemodynamic criteria. Compounding the problem is
the need for prompt institution of appropriate antimicrobial
therapy, making early recognition of sepsis critically important.
Patients with general findings as outlined in Table 89-1 should
undergo thorough and prompt evaluation for a possible infec-
tious cause, including bacterial cultures of blood and (when indi-
cated) other body fluids. Localizing signs and symptoms should
prompt a thorough physical examination and directed imaging to
identify a nidus of infection. Defects of natural defensive barriers,
such as transcutaneous devices or intravascular catheters, should
be assessed for infection and removed if suspected to be the
origin of the septic process.
Many patients have fever or chills, but older patients and those
on immunomodulating medications may not mount a fever.
Hypothermia portends a worse prognosis or more severe illness.
Tachypnea may be an indicator of respiratory compensation for
underlying metabolic acidosis or the early signs and symptoms
of ARDS.
Mental status changes can result from metabolic derange-
ments caused by sepsis, hypoglycemia, the underlying infectious
process, or concomitant hypotension. This symptom can be dif-
ficult to identify in the elderly patient with dementia, and caution
should be exercised in the evaluation and treatment of the other-
wise stable elderly patient with possible mental status changes.
Skin findings (e.g., cellulitis, abscess) can provide clues to the
cause of sepsis and may indicate the state of peripheral systemic
perfusion. Several microorganisms can cause specific skin mani-
festations in systemic infection. S. aureus and streptococci can
cause diffuse erythroderma, bullous lesions, or generalized des-
quamation. Bacteremia caused by several gram-negative organ-
isms, including P. aeruginosa and enteric organisms, can result in
ecthyma gangrenosum, particularly in immunocompromised
patients. These lesions are round and 1 to 15 cm in diameter, and
they have a central area of necrosis and peripheral erythema.
Infection with Neisseria meningitidis can result initially in lower
extremity petechiae progressing to diffuse purpura, which likely
portends septic shock and a high risk of death. A similar clinical
presentation can be observed in other unusual infectious dis-
eases, such as overwhelming pneumococcal sepsis in the asplenic
host or disseminated neisserial infections in patients with late
complement deficiencies.
Hemodynamic instability, particularly hypotension with or
without accompanying oliguria, is commonly associated with
sepsis. Instability can result from poor cardiac output, intravas-
cular fluid depletion, or low systemic vascular resistance. Hypo-
tension can initially respond to intravenous fluid resuscitation,
but in cases of severe sepsis and septic shock, it may require
additional support with vasopressors. Intensive cardiac monitor-
ing may be necessary to gauge the relative need for intravenous
fluids or vasopressors after initial fluid resuscitation measures are
attempted.
850 Section XV  Infectious Disease
Patients in septic shock can be tachycardic and hypotensive.
They may have relatively warm extremities (i.e., warm shock or
distributive shock), or they may be peripherally vasoconstricted,
with mottled and cool extremities (i.e., cold shock). Warm shock
is the predominant finding in most adult patients at the onset of
septic shock, with evidence of diffuse vasodilation, bounding
pulses, and a compensatory high cardiac output despite evidence
of diminished myocardial performance. Increased cardiac output
is accomplished primarily by increased heart rate in an attempt
to maintain blood pressure and perfuse vital organs. If shock is
not promptly corrected, myocardial dysfunction ensues and cold
shock evolves over the next several hours. Older patients with
limited cardiac reserves tolerate shock poorly and are more likely
to develop cold shock. Evidence of septic shock at presentation
that is refractory to early resuscitation portends a poor prognosis,
with mortality rates exceeding 70%.
Besides hypotension, oliguria can represent developing AKI.
It can arise from a combination of the disease process, infecting
organism, and medications. Inflammatory cytokines, microbial
toxins, systemic hypotension, and iatrogenic renal injury from
medications can result in AKI. Other causes of renal injury
include interstitial injury from infection or medications and
immune complex–mediated injury, as seen in cases of
endocarditis.
Besides tachypnea, pulmonary symptoms seen in septic
patients include marked hypoxia due to interstitial edema,
inflammation, or hemodynamic instability. ARDS is defined as
an arterial partial pressure of oxygen less than 50  mm  Hg despite
fractional inspired oxygen of greater than 50%, together with
diffuse alveolar infiltrates and a pulmonary capillary wedge pres-
sure of less than 18  mm  Hg. ARDS occurs in up to 40% of
septic patients. The diffuse pulmonary inflammation in ARDS
results in increased pulmonary vascular permeability, which
complicates fluid resuscitation efforts because excessive fluid can
exacerbate pulmonary edema and hypoxia. Altered mental status
and sepsis-related myopathy also result in airway compromise
and weak respiratory effort, necessitating invasive ventilatory
support.
Patients with sepsis can have marked hematologic changes.
They may have neutrophilic leukocytosis, which is often accom-
panied by increased immature cell counts, or they can be mark-
edly leukopenic (particularly lymphopenic), often in cases of
severe septic shock. Transient neutropenia is often seen in the
early phase of septic shock and results from activation and adher-
ence of neutrophils along endothelial surfaces in the microcircu-
lation. This is rapidly followed by prolonged neutrophilia as
sepsis-induced inflammatory cytokines stimulate bone marrow
synthesis of new white blood cells.
Thrombocytopenia and coagulopathy can occur, and patients
have petechiae or purpura at presentation. Severe derangements
in coagulation can produce DIC, which can lead to thrombin
deposition throughout the microcirculation. Excessive activation
and degradation of clotting factors can deplete coagulation
factors, resulting in diffuse hemorrhage. Excessive mucosal bleed-
ing around airway tubes and prolonged bleeding from venipunc-
ture sites presage internal bleeding events. Massive gastrointestinal
hemorrhage can occur, which can cause or exacerbate hypoten-
sion and shock.
Derangements in glucose homeostasis can be seen at presenta-
tion. This can take the form of hyperglycemia in diabetics receiv-
ing glucose-containing fluids or acute metabolic derangement
due to infection. Hypoglycemia is more common in patients with
underlying liver disease. Increased anaerobic metabolism due to
poor tissue oxygenation and coupled with mitochondrial dys-
function and impaired hepatic clearance of lactic acid may result
in increased serum lactate levels and metabolic acidosis.
  DIAGNOSIS
Accurate diagnosis of sepsis relies on the history, physical exami-
nation, and general laboratory investigation. Diagnostic criteria
for sepsis in adults based on the Surviving Sepsis Campaign
guidelines are listed in Table 89-1.
Accurate and timely identification of the underlying infectious
cause is essential. For patients able to provide a history, an assess-
ment of medical comorbidities, potential exposures, prior infec-
tions, and immune system abnormalities may help to guide
empirical antimicrobial therapy and the laboratory investigation,
particularly microbial cultures. Two sets of blood cultures drawn
from a fresh venipuncture and from existing indwelling intravas-
cular lines (before initiation of empirical antimicrobial therapy if
possible) help to identify the causative organism in many cases.
Symptomatic assessment and physical examination should
suggest a location of focal infection that can help to guide radio-
logic studies and interventions to drain pus.
Beyond microbial cultures, several other laboratory studies
can help to define the severity of illness and provide baseline data
for monitoring the response to therapy. Basic laboratory testing,
including a complete blood count with differential, chemistries,
and creatinine and aminotransferase levels, can help to identify
significant organ dysfunction. Oxygen saturation by pulse oxim-
etry should be measured promptly to identify gas exchange
capacity and the need for ventilatory support. Coagulation
studies should be obtained, particularly for patients with evi-
dence of DIC and those who are thrombocytopenic. For patients
with altered mental status or marked respiratory difficulty, arte-
rial blood gas sampling can help define the underlying derange-
ment and physiologic compensation and can indirectly gauge the
severity of illness.
Levels of inflammatory markers, including C-reactive protein
and procalcitonin, usually are elevated. An elevated procalcitonin
level can help to establish the diagnosis of severe sepsis and
provide some prognostic data and a measure of response to
therapy. In cases of sepsis due to pneumonia, serial measurement
of procalcitonin can help to guide the duration of antibiotic
therapy.
Other testing should be directed toward identifying the poten-
tial cause. Patients with severe diarrhea should undergo testing
for antibiotic-associated Clostridium difficile infection. Imaging
studies should focus on identifying infectious sources and facili-
tate drainage of fluid collections or abscesses. Computed tomog-
raphy may be of use in such circumstances, although for the
critically ill patient who is not stable for transport, bedside radio-
graphic studies, especially ultrasound, should be considered.
Multiple tests of physiologic function and advanced microbio-
logic diagnostic tests are increasingly used in clinical practice.
They include polymerase chain reaction (PCR)–based assays for
 Chapter 89  Bacteremia and Sepsis 851

identifying bacteria and viruses and various assays of inflamma-

tory cytokines and other biomarkers alone and in combination
as potential diagnostic and prognostic aids.
  TREATMENT
Septic shock is a medical emergency. Immediate attempts to rees-
tablish physiologic hemodynamics, vital organ support, and
oxygen delivery to tissues should accompany early diagnosis and
treatment of infection. Patients should be transferred to the
intensive care unit as soon as possible to receive optimal monitor-
ing, hemodynamic support, and expert supportive care.
Early recognition, prompt resuscitation, and early institution
of appropriate antimicrobial agents are the most important deter-
minants of a successful outcome. If appropriate, draining infec-
tious foci (i.e., source control) should be done as soon as possible.
Key elements of the 2012 Surviving Sepsis Champaign guide-
lines are summarized in Table 89-3.
An essential element in the treatment of sepsis is early admin-
istration of antibiotics active against the causative pathogen.
Treatment is best given within 1 hour of the onset of septic shock,
and an empirical, broad-spectrum antimicrobial regimen is
usually employed until the results of cultures of blood and the
site of infection become available. A suggested initial treatment
regimen is provided in Table 89-4. Failing to treat the causative
pathogen until its identity and susceptibility profile become
available days later is associated with adverse outcomes. After the
pathogen is identified, de-escalation to the simplest monother-
apy to which it is susceptible is important.
  PROGNOSIS
Despite advances in clinical practice and treatment, sepsis mor-
tality rates remain high, ranging from 20% to 30% among rela-
tively healthy adults to more than 80% among the elderly,
immunocompromised, and those with significant chronic
medical comorbidities. Patients may experience significant weak-
ness, wasting, and debilitation due to severe catabolism, poor
TABLE 89-3  RECOMMENDED INITIAL MANAGEMENT
OF SEPSIS IN ADULTS
• Start resuscitation immediately in patients with hypotension or serum
lactate level >4 mmol/L.
• Obtain appropriate cultures before starting antibiotics if doing so does
not significantly delay therapy.
• Evaluate for a focus of infection amenable to source control (e.g., abscess
drainage).
• Remove intravascular catheters if potentially infected.
• Begin broad-spectrum antibiotics within the first hour of severe sepsis
and septic shock. Initial antibiotic regimen is based on likely source of
sepsis, likely pathogens, and local antibiotic susceptibility patterns of
common pathogens.
• Begin fluid resuscitation using crystalloids as the first choice. If colloids
are used, avoid starches and consider albumin in selected patients who
have hypoalbuminemia or require large-volume fluid resuscitation.
• Give fluid challenge of up to 30 mL/kg of crystalloids over 15-30 min in
septic patients with suspected volume depletion; larger volumes of fluids
may be needed in some patients. The goals for resuscitation should be a
central venous pressure of 8-12 mm Hg, a mean arterial pressure (MAP)
≥65 mm Hg, and a superior vena cava oxygen saturation ≥70% or mixed
venous oxygen saturation ≥65%.
• Maintain targeted MAP of ≥65 mm Hg; if fluids are not effective in
reestablishing adequate blood pressure, begin vasopressors. After
hemodynamic parameters are stabilized, limit fluid therapy to prevent
pulmonary fluid accumulation and exacerbation of hypoxemia.
• Use norepinephrine, centrally administered, as the vasopressor of choice.
Epinephrine is the second choice, followed by vasopressin as salvage
therapy. Dobutamine may be useful if an inotrope is needed. Avoid
dopamine except for special situations (i.e., low risk of tachyarrhythmia
and persistent bradycardia).
• Give red blood cells when the hemoglobin concentration decreases to
<7 g/dL; target hemoglobin level is 7-9 g/dL.
• Target a tidal volume of 6 mL/kg in patients with acute respiratory
distress syndrome.
• Give low-molecular-weight heparin or unfractionated heparin for deep
vein thrombosis prophylaxis; use graduated pressure stockings or
intermittent compression devices if heparin therapy is contraindicated.
• Provide stress ulcer prophylaxis using histamine H2-blockers or a proton
pump inhibitor.
• Provide expert supportive care; provide low-dose nutrition for the first
week; consider stress-dose steroids if refractory septic shock occurs;
maintain blood glucose in the 110-180 mg/dL range.
Data from Dellinger RP, Levy MM, et al: Surviving Sepsis Campaign: international
guidelines for the management of severe sepsis and septic shock, 2012, Crit Care Med
41:580–637, 2013.

TABLE 89-4  INITIAL ANTIBIOTIC RECOMMENDATIONS FOR ADULT PATIENTS WITH SEPSIS
INDICATION RECOMMENDED DOSAGES*
Empirical coverage (source unknown) Vancomycin 15 mg/kg q12h plus piperacillin-tazobactam† 3.375 g IV q6h or imipenem 0.5 g IV q6h or meropenem
1.0 g IV q8h with or without an aminoglycoside (e.g., tobramycin 5 mg/kg IV q24).‡
Community-acquired pneumonia (CAP) Ceftriaxone 1 g IV q24h plus azithromycin 500 mg IV q24h or a fluoroquinolone (e.g., moxifloxacin
400 mg IV q24h or levofloxacin 750 mg IV q24h).§
Community-acquired urosepsis Piperacillin-tazobactam 3.375 g IV q6h or ciprofloxacin 400 mg. IV q12h
Meningitis Vancomycin 15 mg/kg IV q6h plus ceftriaxone 2 g IV q12h plus dexamethasone 0.15 mg/kg IV q6h × 2-4 days,
preferably before antibiotics; add ampicillin 2 g IV q4h if Listeria is suspected.
Nosocomial pneumonia Vancomycin 15 mg/kg q12h plus piperacillin-tazobactam 4.5 g IV q6h or imipenem 0.5 g IV q6h or meropenem
1 g IV q8h or cefepime 2 g IV q8h plus an aminoglycoside (e.g., amikacin 15 mg/kg IV q24h or tobramycin
5-7 mg/kg IV q24h) or levofloxacin 750 mg IV q24h. Some authorities substitute linezolid 600 mg IV q12h for
vancomycin if MRSA is a significant concern or known to be the cause.
Neutropenia Cefepime 2 g IV q8h; add vancomycin 15 mg/kg IV q12h if a central line is present and infection is a concern. Add
antifungal coverage with caspofungin 70 mg IV × 1, then 50 mg IV q24h if fever persists ≥5 days. For suspected or
proven invasive aspergillosis, voriconazole 6 mg/kg IV q12h × 2, then 4 mg/kg IV q12h should be used.
Cellulitis and skin infections Vancomycin 15 mg/kg IV q12h. Add piperacillin-tazobactam 3.375 g IV q6h in diabetics and immunocompromised
patients. If necrotizing fasciitis is suspected, add clindamycin 900 mg. IV; surgical débridement is crucial.
IV, Intravenous; MRSA, methicillin-resistant Staphylococcus aureus.
*Assumes normal renal function; dose adjustments are required with impaired creatinine clearance.
†
Substitute aztreonam 2 g IV q8h if patient is allergic to penicillin.
‡
Monitor drug levels of aminoglycosides (i.e., peak and trough).
§
Substitute Cefepime or a carbapenem and azithromycin ± an aminoglycoside if the patient has severe CAP or health care–associated pneumonia.
852 Section XV  Infectious Disease
nutrition, and prolonged hospitalization. Prolonged rehabilita-
tion in a skilled facility after the initial hospitalization and addi-
tional home-based therapy may be required. Patients may have
permanent disabilities, including impaired renal function or per-
sistent debilitation from procedures required to treat the underly-
ing infection.
SUGGESTED READINGS
Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in
the United States: analysis of incidence, outcome, and associated costs of care,
Crit Care Med 29:1303–1310, 2001.
Angus D, van der Poll T: Severe sepsis and septic shock, N Engl J Med 369:840–
851, 2013.
Black G: Gyroscope: a survival of sepsis, West Conshohocken, Pa., 2011, Infinity
Publishing.
Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign:
international guidelines for management of severe sepsis and septic shock,
2012, Intensive Care Med 39:165–228, 2013.
Hotchkiss RS, Coopersmith CM, McDunn JE, et al: The sepsis seesaw: tilting
toward immunosuppression, Nat Med 15:496–497, 2009.
Melamed A, Sorvillo FJ: The burden of sepsis-associated mortality in the United
States from 1999 to 2005: an analysis of multiple-cause-of-death data, Crit
Care 13:R28, 2009.
Vincent JL, Opal SM, Marshall JC, et al: Sepsis definitions: time for a change,
Lancet 381:774–775, 2013.

Infections of the Central
Nervous System
Allan R. Tunkel, Marjorie A. Janvier, and Avindra Nath
  INTRODUCTION
Infections of the central nervous system (CNS) are associated
with significant morbidity and mortality. This chapter focuses on
meningitis, encephalitis, and brain abscesses in the parenchyma
and parameningeal areas.
  MENINGITIS AND ENCEPHALITIS
Contact with offending infectious agents such as viruses, bacte-
ria, fungi, protozoa, and helminths can cause inflammation of the
meninges covering the brain and spinal cord (i.e., meningitis) or
lead to inflammation of the brain parenchyma (i.e., encephalitis).
These infectious agents can penetrate the CNS by direct seeding
or hematogenous spread and cause a constellation of symptoms.
The clinician must rapidly initiate a diagnostic evaluation and
begin appropriate management.
Meningitis
Definition
Meningitis is defined as inflammation of the leptomeninges that
cover the brain and spinal cord. It is identified by an abnormal
increase in the number of white blood cells in cerebrospinal fluid
(CSF). Inflammation can be caused by many infectious agents
(i.e., bacteria, viruses, fungi, and parasites) and also can occur as
a result of noninfectious conditions, including tumors or cysts,
medications (e.g., nonsteroidal anti-inflammatory drugs, antimi-
crobial agents), systemic illnesses (e.g., systemic lupus erythema-
tosus, Behçet’s disease, sarcoidosis), or neurologic procedures
(e.g., neurosurgery, spinal anesthesia, intrathecal injections).
The clinical presentation can be acute, subacute, or chronic
based on the virulence of the organism. Acute meningitis is a
syndrome characterized by the onset of symptoms within hours
to several days, whereas chronic meningitis characterized by
clinical and CSF findings that remain abnormal for at least 4
weeks. Acute meningitis is most often caused by bacteria and
viruses, whereas chronic meningitis is most often caused by spi-
rochetes, mycobacteria, and fungi.
Epidemiology and Etiology
Bacterial Meningitis
In the United States, the epidemiology of bacterial meningitis
has changed significantly over the past several decades with the
introduction of conjugate vaccines against Haemophilus influen-
zae and Streptococcus pneumoniae. A surveillance study found
that about 4000 cases of bacterial meningitis and 500 deaths
90 
occurred annually between 2003 and 2007. The leading causes
of bacterial meningitis were S. pneumoniae (58% of cases), Strep-
tococcus agalactiae (18% of cases), Neisseria meningitidis (14%
of cases), H. influenzae (7% of cases), and Listeria monocytogenes
(3% of cases).
Specific etiologic agents may be more likely based on the
patient’s age and various risk factors (Table 90-1). In one study
of 352 episodes of community-acquired pneumococcal meningi-
tis, 70% of cases were associated with an underlying disorder.
Conditions associated with pneumococcal meningitis include
splenectomy or asplenic states, multiple myeloma, hypogamma-
globulinemia, alcoholism, malnutrition, chronic liver or kidney
disease, and diabetes mellitus. Patients often have contiguous or
distant foci of infection such as pneumonia, otitis media, mas-
toiditis, sinusitis, endocarditis, and head trauma with a CSF leak.
The group B streptococcus (i.e., S. agalactiae) is a common
etiologic agent of meningitis in neonates, with 52% of cases
occurring during the first year of life. Risk factors for S. agalactiae
meningitis in adults include age older than 60 years, pregnancy
or the postpartum state, diabetes mellitus, and other chronic dis-
eases and immunosuppressed states.
N. meningitidis usually causes meningitis in children and adults.
Most cases in the United States are caused by serogroups B, C,
and Y; serogroups A and W135 usually cause disease outside of
the United States. Because of N. meningitidis in the upper
TABLE 90-1  COMMON BACTERIAL PATHOGENS AND
FACTORS PREDISPOSING TO MENINGITIS
PREDISPOSING
FACTOR BACTERIAL PATHOGENS
Age
  <1 mo Streptococcus agalactiae, Escherichia coli, Listeria
monocytogenes
  1-23 mo S. agalactiae, E. coli, Haemophilus influenzae,
Streptococcus pneumoniae, Neisseria meningitidis
  2-50 yr S. pneumoniae, N. meningitidis
  >50 yr S. pneumoniae, N. meningitidis, L. monocytogenes,
aerobic gram-negative bacilli
Immunocompromised S. pneumoniae, N. meningitidis, L. monocytogenes,
state aerobic gram-negative bacilli (including
Pseudomonas aeruginosa)
Basilar skull fracture S. pneumoniae, H. influenzae, group A β-hemolytic
streptococci
Head trauma; post Staphylococcus aureus, coagulase-negative
neurosurgery staphylococci (especially Staphylococcus
epidermidis), aerobic gram-negative bacilli
(including P. aeruginosa)
From Tunkel AR, van de Beek D, Scheld WM: Acute meningitis. In Bennett JE, Dolin R,
Blaser M, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious
diseases, ed 8, Philadelphia, 2015, Saunders.
853
854 Section XV  Infectious Disease
respiratory tract, outbreaks of meningitis due to N. meningitidis
may occur in persons living in close quarters, such as among
household members, in daycare, in college dormitories, and
among the incarcerated. One outbreak of serogroup C disease
was reported in New York City among men who have sex with
men, and outbreaks caused by serogroup B were reported on the
campuses of Princeton University and University of California,
Santa Barbara. Patients with deficiencies in the terminal comple-
ment components (C5-C8 and perhaps C9) and properdin are
at increased risk for meningococcal infections.
The incidence of meningitis due to H. influenzae has declined
more than 90% with the widespread use of routine vaccination
with the H. influenzae type b conjugate vaccine. Isolation of this
microorganism in older children and adults suggests certain
underlying conditions, such as sinusitis, otitis media, epiglottitis,
pneumonia, diabetes mellitus, alcoholism, splenectomy or
asplenic states, head trauma with CSF leak, and immune
deficiency.
Meningitis caused by L. monocytogenes is most common in
neonates, adults older than 50 years, alcoholics, immunosup-
pressed adults, and in patients with chronic conditions such
as diabetes mellitus and renal disease. Given the likely gastro-
intestinal portal of entry for this microorganism, outbreaks of
listerial infection have been associated with ingestion of con-
taminated coleslaw, raw vegetables, milk, and cheese. Sporadic
cases have been linked to contaminated turkey franks, alfalfa
tablets, cantaloupe, diced celery, hog’s head cheese, and
processed meats.
Gram-negative meningitis is rare; it usually affects debilitated
persons and those with a breach in the meninges as a result of
trauma or neurosurgical procedures. Staphylococcus aureus men-
ingitis is usually found in the early period after neurosurgery or
trauma, in those with CSF shunts, or in patients with underlying
conditions such as diabetes mellitus, alcoholism, chronic kidney
disease requiring hemodialysis, injection-drug use, and malig-
nancies. Staphylococcus epidermidis is the most common cause of
meningitis in patients with CSF shunts.
Viral Meningitis
Enteroviruses are the leading identifiable cause of the aseptic men-
ingitis syndrome, a term used to define any meningitis (particu-
larly with lymphocytic pleocytosis) for which a cause is not
apparent after initial evaluation, routine CSF stains, and cultures.
The Centers for Disease Control and Prevention (CDC) estimate
that 10 to 15 million symptomatic enteroviral infections occur
annually in the United States; of these, 30,000 to 75,000 are men-
ingitis cases.
Many other viruses can cause the aseptic meningitis syn-
drome, including mumps virus (in unimmunized populations),
human immunodeficiency virus (HIV), several arboviruses (e.g.,
St. Louis encephalitis virus, the California encephalitis group of
viruses, Colorado tick fever virus, West Nile virus), and herpes-
viruses. The syndrome of herpes simplex virus (HSV) meningitis
is most commonly associated with primary genital infection. The
DNA of HSV has been detected in the CSF of patients with the
syndrome of recurrent benign lymphocytic meningitis (previ-
ously known as Mollaret’s meningitis), with almost all cases
caused by herpes simplex virus type 2 (HSV-2).
Spirochetal Meningitis
The most common spirochetes associated with meningitis are
Treponema pallidum (the etiologic agent of syphilis) and Borrelia
burgdorferi (the etiologic agent of Lyme disease). The incidence
of syphilitic meningitis is greatest in the first 2 years after initial
infection, occurring in 0.3% to 2.4% of untreated cases. The
overall incidence of neurosyphilis has increased, with many cases
reported in patients with HIV infection. The nervous system is
involved in at least 10% to 20% of patients with Lyme disease
while erythema migrans is apparent or 1 to 6 months later.
Tuberculous Meningitis
Tuberculous meningitis accounts for approximately 15% of cases
of extrapulmonary tuberculosis in the United States. CNS disease
is much more common in less developed areas of the world.
Factors associated with reactivation of latent foci and progression
to the syndrome of late generalized tuberculosis include advanced
age, immunosuppressive drug therapy, gastrectomy, pregnancy,
and chronic medical conditions. The epidemiology of tuberculo-
sis has been influenced by the advent of HIV infection, in which
extrapulmonary disease (including CNS disease) occurs in more
than 70% of cases.
Fungal Meningitis
The incidence of fungal meningitis has increased dramatically in
recent years because of the increased numbers of immunosup-
pressed patients. Cryptococcus neoformans is the most common
fungal cause of clinically recognized meningitis, occurring most
commonly in persons who are immunosuppressed or have
chronic medical conditions. HIV-infected patients are in the
highest-risk group. Cases have also been documented in appar-
ently healthy individuals.
Coccidioides immitis is a thermal dimorphic fungus that is
endemic in the semiarid regions of the Americas and desert areas
of the southwestern United States (e.g., California, Arizona, New
Mexico, Texas), where about one third of the population is
infected. Less than 1% of patients develop disseminated infec-
tion, and one third to one half of those have meningeal
involvement.
Other fungi less commonly cause CNS infection. Histoplasma
capsulatum is endemic to fertile river valleys, principally the
Mississippi and Ohio River basins. Candida meningitis is
uncommon.
Clinical Presentation
Acute Meningitis
Adult patients with acute meningitis typically seek medical atten-
tion within hours to days of illness. Patients with bacterial men-
ingitis classically exhibit fever, headache, meningismus, and signs
of cerebral dysfunction (i.e., confusion, delirium, or a declining
level of consciousness ranging from lethargy to coma). All signs
may not be seen in a given patient. The meningismus may be
subtle, marked, or accompanied by Kernig’s sign or Brudzinski’s
sign, although the sensitivity of these signs is only 5% in adults.
Cranial nerve palsies (especially involving cranial nerves III, IV,
VI, and VII) and focal cerebral signs are seen in 10% to 20% of
cases. Seizures occur in about 30% of patients. Older adult
patients with bacterial meningitis, especially those with
 Chapter 90  Infections of the Central Nervous System 855
underlying conditions (e.g., diabetes mellitus, cardiopulmonary
disease), may have disease that manifests insidiously with leth-
argy or obtundation, no fever, and various signs of meningeal
inflammation. Older adult patients may have an antecedent or
concurrent bronchitis, pneumonia, or paranasal sinusitis.
Viral meningitis is typically a self-limited illness. The clinical
manifestations of enteroviral meningitis depend on the host’s age
and immune status. In adolescents and adults, more than one half
of the patients have nuchal rigidity. Adults usually have headache,
which often is severe and frontal. Photophobia is also common
in older patients. Nonspecific symptoms and signs include vomit-
ing, anorexia, rash, diarrhea, cough, upper respiratory findings
(especially pharyngitis), and myalgias. Other clues to the diagno-
sis of enteroviral disease are the time of year (more prevalent in
summer and autumn months) and known epidemic disease in
the community. The duration of illness of enteroviral meningitis
is usually less than 1 week, and many patients report improve-
ment after lumbar puncture, presumably from the reduction in
intracranial pressure.
Meningitis associated with HSV-2 infections is usually charac-
terized by stiff neck, headache, and fever. Patients with recurrent
benign lymphocytic meningitis characteristically develop a few
to 10 episodes of meningitis lasting 2 to 5 days, followed by
spontaneous recovery. These patients have acute onset of head-
ache, fever, photophobia, and meningism; about 50% of patients
have transient neurologic manifestations, including seizures,
hallucinations, diplopia, cranial nerve palsies, or altered
consciousness.
Subacute or Chronic Meningitis
Subacute or chronic meningitis caused by spirochetes, myco-
bacteria, or fungi in the adult patient can linger for weeks to
years before clinical presentation. The patient may initially have
no overt symptoms, suffer from low-grade headaches and fever,
or experience gradual mental status and other neurologic
changes.
Syphilitic meningitis usually manifests in a manner similar to
that of other forms of aseptic meningitis. Patients complain of
headache, nausea, and vomiting. Other findings include stiff neck
(60%), fever, seizures, cranial nerve palsies, and less commonly,
other focal neurologic abnormalities.
Meningitis is the most important neurologic abnormality of
acute disseminated Lyme disease, usually following erythema
migrans by 2 to 10 weeks. Patients with Lyme meningitis have
headache as the single most common symptom. Other findings
include photophobia, nausea, vomiting, and stiff neck. About one
half of patients with Lyme meningitis have mild cerebral symp-
toms consisting most commonly of somnolence, emotional labil-
ity, depression, impaired memory and concentration, and
behavioral symptoms. Approximately 50% of patients also have
cranial neuropathies, with facial nerve palsy occurring in 80% to
90% of cases.
In the usual patient with tuberculous meningitis, an insidious
prodrome characterized by malaise, lassitude, low-grade fever,
intermittent headache, and changing personality ensues. Within
2 to 3 weeks, the meningitic phase manifests as protracted head-
ache, meningismus, vomiting, and confusion. In some adults, the
initial prodromal stage may take the form of a slowly progressive
dementia, whereas others may have a rapidly progressive menin-
gitis syndrome indistinguishable from pyogenic bacterial menin-
gitis. Fever is an inconstant finding on physical examination
(50% to 98% of cases). Meningismus and signs of meningeal
irritation are not uniform findings (absent in 25% to 80% of chil-
dren and adults). Focal neurologic signs frequently consist of
unilateral or, less commonly, bilateral cranial nerve palsies;
cranial nerve VI is most commonly affected.
The time course of fungal meningitis depends on the clinical
setting. Cases may manifest acutely, subacutely, or chronically;
some of the fungal meningitides may cause symptoms that persist
for years in the absence of antifungal treatment. In contrast, the
same organisms can produce severe symptoms and signs within
a few days and without clinical signs of meningeal irritation in the
immunocompromised patient. In patients without acquired
immunodeficiency syndrome (AIDS), cryptococcal meningitis
typically manifests as a subacute process after days to weeks of
symptoms. Headache is the most frequent complaint. Fever,
meningismus, and personality changes also may occur; confu-
sion, irritability, and other personality changes reflecting menin-
goencephalitis occur in about one half of patients. Ocular
abnormalities occur in about 40% of patients and include papill-
edema and cranial nerve palsies.
In AIDS patients, manifestation of cryptococcal meningitis
can be subtle, with minimal or no symptoms. AIDS patients may
have only headache and lethargy. Although fever is common,
meningeal signs occur in a minority of these patients.
Patients with meningeal coccidioidomycosis usually complain
of headache, low-grade fever, weight loss, and mental status
changes. About one half of patients develop disorientation, leth-
argy, confusion, or memory loss. Meningeal signs are uncom-
mon. The presenting symptoms of Histoplasma meningitis are
nonspecific. Symptoms usually include headache and fever. Only
about one half of patients have focal neurologic mental status
symptoms. Candidal meningitis also manifests with nonspecific
findings.
Diagnosis
Clinically suspected meningitis is diagnosed by analysis of CSF
obtained by lumbar puncture (Table 90-2). Table 90-3 illustrates
general findings for patients with meningitis based on cause, and
the following sections detail specific methods for establishing an
etiologic diagnosis.
Bacterial Meningitis
Gram stain examination of CSF permits rapid, accurate identifi-
cation of the causative microorganism in 60% to 90% of patients
with bacterial meningitis, and it has a specificity of nearly 100%.
CSF culture is the gold standard in diagnosis and is positive in
80% to 90% of patients with community-acquired bacterial men-
ingitis if CSF is obtained before the start of antimicrobial therapy.
The probability of identifying the organism decreases for patients
who have received prior antimicrobial therapy. It has been sug-
gested that CSF sterilization may occur more rapidly after initia-
tion of parenteral antimicrobial therapy than previously suggested,
with complete sterilization of CSF containing meningococcus
within 2 hours and the beginning of sterilization of pneumococ-
cus by 4 hours into therapy.
856 Section XV  Infectious Disease

Several rapid diagnostic tests have been developed to aid in the Nucleic acid amplification tests, such as polymerase chain
etiologic diagnosis of bacterial meningitis. Latex agglutination reaction (PCR), have been used to amplify DNA from patients
techniques detect the antigens of H. influenzae type b, S. pneu- with meningitis caused by several meningeal pathogens. The test
moniae, N. meningitidis, E. coli K1, and the group B streptococci. characteristics for broad-based bacterial PCR demonstrated a
However, because bacterial antigen testing does not appear to sensitivity of 100%, a specificity of 98.2%, a positive predictive
modify the decision to administer antimicrobial therapy and value of 98.2%, and a negative predictive value of 100%.
false-positive results have been reported, routine use of this
modality for rapid determination of the bacterial cause of men- Differentiation of Bacterial from Viral Meningitis
ingitis is not recommended. It can be considered for patients who In patients without a positive CSF Gram stain or culture, the
have been pretreated with antimicrobial therapy and when CSF diagnosis of acute bacterial meningitis is often difficult to estab-
Gram stain and culture results are negative. lish or reject. A combination of clinical features, with or without
test results, has been assessed to develop models in an attempt to
accurately predict the likelihood of bacterial meningitis com-
TABLE 90-2  CEREBROSPINAL FLUID TESTS FOR pared with other potential causes (most often viruses). In a pub-
PATIENTS WITH SUSPECTED CENTRAL lished meta-analysis of bacterial meningitis score validation
NERVOUS SYSTEM INFECTION studies in which 5312 patients were identified from eight studies,
ROUTINE TESTS 4896 (92%) had sufficient clinical data to calculate the bacterial
WBC count with differential
meningitis score, which identified children with CSF pleocytosis
RBC count* who were at very low risk for bacterial meningitis. Low-risk fea-
Glucose concentration† tures were a negative CSF Gram stain, a CSF absolute neutrophil
Protein concentration
Gram stain
count less than 1000 cells/mm3, a CSF protein level less than
Bacterial culture 80 mg/dL, and a peripheral absolute neutrophil count less than
SELECTED TESTS BASED ON CLINICAL SUSPICION 10,000 cells/mm3. Despite the positive results of this meta-
Viral culture‡ analysis and other studies, clinical judgment should continue to
Smears and culture for acid-fast bacilli be used in decisions about the need for administration of empiri-
Venereal Disease Research Laboratory (VDRL) test cal therapy in patients with suspected bacterial meningitis.
India ink preparation
Cryptococcal polysaccharide antigen Several proteins have been examined for their usefulness in the
Fungal culture diagnosis of acute bacterial meningitis. C-reactive protein (CRP)
Antibody tests (IgM or IgG, or both)§ detected in serum or CSF and serum procalcitonin concentra-
Nucleic acid amplification tests (e.g., PCR)‖
Cytology¶ tions have been elevated in patients with acute bacterial menin-
Flow cytometry gitis and may be useful in discriminating between bacterial and
From Tunkel AR: Approach to the patient with central nervous system infection. In viral meningitis. In patients with meningitis in whom the CSF
Bennett JE, Dolin R, Blaser M, editors: Mandell, Douglas, and Bennett’s principles and Gram stain result is negative and analysis of other parameters is
practice of infectious diseases, ed 8, Philadelphia, 2015, Saunders.
CSF, Cerebrospinal fluid; IgG, immunoglobulin G; IgM, immunoglobulin M; PCR, inconclusive, serum concentrations of CRP or procalcitonin that
polymerase chain reaction; RBCs, red blood cells; WBCs, white blood cells. are normal or below the limit of detection have a high negative
*Check in the first and last tubes; in patients with a traumatic tap, there should be a
decrease in the number of RBCs with continued flow of CSF. The following formula can be predictive value in the diagnosis of bacterial meningitis.
used for determining whether the numbers of CSF red blood cells and white blood cells PCR is the most promising alternative to viral culture for the
are consistent with a traumatic tap (all units are number of cells/cubic mm):
diagnosis of enteroviral meningitis. Enteroviral reverse transcrip-
Adjusted WBCs in CSF
tion PCR (RT-PCR) has been tested in clinical settings by
WBCs in blood × RBCs in CSF
= Actual WBCs in CSF − numerous investigators and found to be more sensitive than
RBCs in blood
†
Compare with serum glucose concentration measured just before lumbar puncture.
culture for the detection of the enterovirus; the sensitivity has
‡
Yield of viral culture may be low. ranged from 86% to 100% and specificity from 92% to 100% for
§
May be useful for specific causes of meningitis and encephalitis.
‖
Most useful for specific viral causes of encephalitis and causes of chronic meningitis.
the diagnosis of enteroviral meningitis. For patients with HSV-2
¶
In patients with suspected malignancy. meningitis, PCR appears promising for the diagnosis. In patients

TABLE 90-3  CEREBROSPINAL FLUID FINDINGS FOR PATIENTS WITH INFECTIOUS CAUSES OF MENINGITIS
WHITE BLOOD CELL
CAUSE OF MENINGITIS COUNT (cells/mm3) PRIMARY CELL TYPE GLUCOSE (mg/dL) PROTEIN (mg/dL)
Viral 50-1000 Mononuclear* >45 <200
Bacterial 1000-5000† Neutrophilic‡ <40§ 100-500
Tuberculous 50-300 Mononuclear‖ <45 50-300
Cryptococcal 20-500¶ Mononuclear <40 >45
From Tunkel AR: Approach to the patient with central nervous system infection. In Bennett JE, Dolin R, Blaser M, editors: Mandell, Douglas, and Bennett’s principles and practice of
infectious diseases, ed 8, Philadelphia, 2015, Saunders.
*May be neutrophilic early in presentation.
†
May range from <100 to >10,000 neutrophils/mm3.
‡
About 10% of patients have a cerebrospinal fluid (CSF) lymphocyte predominance.
§
Should always be compared with a simultaneous serum glucose level; ratio of CSF to serum glucose is ≤0.4 in most cases.
‖
A therapeutic paradox may exist in which a mononuclear predominance becomes neutrophilic during antituberculosis therapy.
¶
More than 75% of patients with acquired immunodeficiency syndrome have <20 cells/mm3.
 Chapter 90  Infections of the Central Nervous System 857
with recurrent benign lymphocytic meningitis, detection of
HSV-2 has been strongly associated with typical cases in patients
without symptoms or signs of genital infection.
Spirochetal Meningitis
For the diagnosis of CNS involvement in patients with syphilis,
no single routine laboratory test is definitive. The specificity
of the CSF Venereal Disease Research Laboratory (VDRL) test
for the diagnosis of neurosyphilis is high, but the sensitivity
is low (reactive tests in only 30% to 70% of patients). A reac-
tive CSF VDRL test result in the absence of blood contamina-
tion is sufficient to diagnose neurosyphilis; a nonreactive result
does not exclude the diagnosis. The diagnosis of neurosyphilis
is based on elevated CSF concentrations of white blood cells
or protein, or both, in the appropriate clinical and serologic
setting.
The best currently available laboratory test for the diagnosis of
Lyme disease is demonstration of specific serum antibody to B.
burgdorferi, and this positive test result for a patient with a com-
patible neurologic abnormality is strong evidence for the diagno-
sis. However, these tests are not standardized, and marked
variations are seen between laboratories.
Tuberculous Meningitis
The identification of tuberculous organisms in CSF by specific
stains is difficult because of the small population of organisms. In
many series, less than 25% of specimens were smear positive and
less than 50% were culture positive. The technique of PCR for
detecting fragments of mycobacterial DNA in CSF specimens
appears to be a promising tool. The Gen-Probe technique is based
on amplification of ribosomal RNA derived from Mycobacterium
tuberculosis using a labeled DNA probe. A 5-year retrospective
study of the performance of this test found a sensitivity and speci-
ficity of 94% and 99%, respectively, for patients with positive CSF
cultures.
Fungal Meningitis
Conclusive proof that a fungal organism is causing the meningitis
rests on identification of the fungus in CSF, although CSF cul-
tures are not always positive in cases of fungal meningitis. The
yield of CSF culture in cryptococcal meningitis is excellent for
non-AIDS and AIDS patients. For patients with cryptococcal
meningitis, CSF India ink examination remains a rapid, effective
test that is positive in 50% to 75% of cases; the yield increases
up to 88% among patients with AIDS. In contrast, only 25% to
50% of patients with other fungal meningitis have positive CSF
cultures.
Because cultures may be negative or require long periods
before yielding positive results for patients with fungal meningi-
tis, adjunctive studies (particularly serologic tests) may be helpful
for the diagnosis. The latex agglutination test for cryptococcal
polysaccharide antigen is sensitive and specific for the diagnosis
of cryptococcal meningitis. Cryptococcal polysaccharide antigen
also can be found in the serum and CSF, usually in severely
immunosuppressed patients such as those with AIDS. Serologic
antibody tests (i.e., coccidioidal and histoplasmal antigens) and
antigen urine tests (i.e., histoplasmal antigen) may be useful in
other cases of fungal meningitis.
Treatment
Initial Treatment of the Patient with Acute
Meningitis
Acute bacterial meningitis is a life-threatening illness, and early
detection, work-up, and antimicrobial therapy are imperative to
reduce morbidity and mortality. The initial management of a
patient with presumed bacterial meningitis includes performance
of a lumbar puncture to determine whether the CSF formula is
consistent with that diagnosis (Fig. 90-1). If meningitis is puru-
lent, institution of antimicrobial therapy should be based on the
results of Gram staining (Table 90-4). However, if no etiologic
agent can be identified by this means or performance of the
lumbar puncture is delayed, institution of empirical antimicrobial
therapy after obtaining blood cultures should be based on the
patient’s age and underlying disease status (Table 90-5).
It is reasonable to proceed with the lumbar puncture without
computed tomography (CT) of the head if the patient does not
meet any of the following criteria: new-onset seizures, an immu-
nocompromised state, signs that are suspicious for space-
occupying lesions (i.e., papilledema or focal neurologic signs, not
including cranial nerve palsy), or moderate to severe impairment
of consciousness. Patients at risk should undergo CT of the head
before lumbar puncture to rule out brain shift (i.e., result of an
intracranial mass lesion or generalized brain edema) because of
Suspicion for bacterial meningitis
Yes
Immunocompromise, history of CNS disease, new-onset seizure,
papilledema, altered consciousness, or focal neurologic deficit*; or delay
in performance of diagnostic lumbar puncture
No Yes
Blood cultures and lumbar
Blood cultures STAT
puncture STAT
Dexamethasone† + empiric Dexamethasone† + empiric
antimicrobial therapy‡,§ antimicrobial therapy‡
CSF findings c/w bacterial meningitis Negative CT scan of the head
Positive CSF Gram stain Perform lumbar puncture
Yes
No
Dexamethasone† + empirical Dexamethasone† + targeted
antimicrobial therapy‡ antimicrobial therapy
FIGURE 90-1  Management algorithm for adults with suspected bac-
terial meningitis. *Palsy of cranial nerve VI or VII is not an indication to
delay lumbar puncture. †See text for recommendations for use of
adjunctive dexamethasone in patients with bacterial meningitis. ‡See
Table 90-5. §Dexamethasone and antimicrobial therapy should be
administered immediately after CSF is obtained. ‖See Table 90-4. CNS,
Central nervous system; CT, computed tomography; c/w, consistent
with; STAT, intervention should be done emergently. (From Tunkel AR,
Hartman BJ, Kaplan, SL, et al: Practice guidelines for the management
of bacterial meningitis, Clin Infect Dis 39:1267–1284, 2004.)
858 Section XV  Infectious Disease

TABLE 90-4  Recommended Antimicrobial Therapy TABLE 90-6  ANTIMICROBIAL THERAPY FOR
for Acute Bacterial Meningitis PATIENTS WITH MENINGITIS
Microorganism* Antimicrobial Therapy MICROORGANISM THERAPY OF CHOICE
Haemophilus influenzae type b Third-generation cephalosporin† BACTERIA
Neisseria meningitidis Third-generation cephalosporin† Haemophilus influenzae
Streptococcus pneumoniae Vancomycin plus a third-generation   β-Lactamase negative Ampicillin
cephalosporin†,‡   β-Lactamase positive Ceftriaxone or cefotaxime
Listeria monocytogenes Ampicillin or penicillin G§ Neisseria meningitidis
Streptococcus agalactiae Ampicillin or penicillin G§   Penicillin MIC <0.1 µg/mL Penicillin G or ampicillin
Modified from Tunkel AR, Hartman BJ, Kaplan, SL, et al: Practice guidelines for the   Penicillin MIC 0.1-1.0 µg/mL Ceftriaxone or cefotaxime
management of bacterial meningitis, Clin Infect Dis 39:1267–1284, 2004. Streptococcus pneumoniae
*Pathogen presumptively identified by positive Gram stain.   Penicillin MIC ≤0.06 µg/mL Penicillin G or ampicillin
†
‡
Cefotaxime or ceftriaxone.   Penicillin MIC ≥0.12 µg/mL
Some experts would add rifampin if dexamethasone is also given.    Ceftriaxone or cefotaxime MIC Ceftriaxone or cefotaxime
§
Addition of an aminoglycoside should be considered.
<1.0 µg/mL
   Ceftriaxone or cefotaxime MIC Vancomycin* plus ceftriaxone or
≥1.0 µg/mL cefotaxime
Enterobacteriaceae† Ceftriaxone or cefotaxime
TABLE 90-5  EMPIRICAL THERAPY FOR PURULENT Pseudomonas aeruginosa Ceftazidime‡ or cefepime‡
MENINGITIS Acinetobacter baumannii† Meropenem
PREDISPOSING FACTOR ANTIMICROBIAL THERAPY Listeria monocytogenes Ampicillin or penicillin G‡
Streptococcus agalactiae Ampicillin or penicillin G‡
Age Staphylococcus aureus
  <1 mo Ampicillin plus cefotaxime or ampicillin   Methicillin-sensitive Nafcillin or oxacillin
plus an aminoglycoside   Methicillin-resistant Vancomycin*
  1-23 mo Vancomycin plus a third-generation Staphylococcus epidermidis Vancomycin*
cephalosporin*†
  2-50 yr Vancomycin plus a third-generation SPIROCHETES
cephalosporin*†‡ Treponema pallidum Penicillin G
  >50 yr Vancomycin plus ampicillin plus a Borrelia burgdorferi Ceftriaxone or cefotaxime
third-generation cephalosporin*
Immunocompromised state Vancomycin plus ampicillin plus MYCOBACTERIA
cefepime or meropenem Mycobacterium tuberculosis Isoniazid + rifampin +
Basilar skull fracture Vancomycin plus a third-generation pyrazinamide + ethambutol
cephalosporin*
FUNGI
Head trauma; after neurosurgery Vancomycin plus ceftazidime, cefepime,
or meropenem Cryptococcus neoformans Amphotericin B preparation§ +
flucytosine
Modified from Tunkel AR, Hartman BJ, Kaplan, SL, et al: Practice guidelines for the Coccidioides immitis Fluconazole
management of bacterial meningitis, Clin Infect Dis 39:1267–1284, 2004.
Histoplasma capsulatum Liposomal amphotericin B
*Cefotaxime or ceftriaxone.
†
Some experts add rifampin if dexamethasone is also given. Candida species Amphotericin B preparation§ ±
‡
Add ampicillin if meningitis caused by Listeria monocytogenes is suspected. flucytosine
MIC, Minimum inhibitory concentration.
*Addition of rifampin may be considered; see text for indications.
the potential risk of herniation if a lumbar puncture is performed. †
The choice of a specific antimicrobial agent must be guided by in vitro susceptibility
In this setting, emergency empirical antimicrobial therapy, and testing.
‡
Addition of an aminoglycoside should be considered.
adjunctive dexamethasone therapy (if indicated), after obtaining §
Amphotericin B deoxycholate, liposomal amphotericin B, or amphotericin B lipid
blood cultures should be initiated before sending the patient to complex.

the CT scanner.

Specific Antimicrobial Therapy for Meningitis
After the infecting meningeal pathogen is isolated and suscepti-
bility testing results are known, antimicrobial therapy can be
modified for optimal treatment of patients with bacterial menin-
gitis (Table 90-6). Recommended dosages of antimicrobial
agents for adults with infections of the CNS are shown in
Table 90-7.
One pathogen requires special discussion. Specific therapy for
pneumococcal meningitis depends on the in vitro susceptibility
of the organism to penicillin and the third-generation cephalo-
sporins. Results of surveillance studies in the United States show
that the prevalence of penicillin-resistant S. pneumoniae ranges
from 25% to more than 50%; rates are as high as 60% in some
parts of Latin America and as high as 80% in some countries in
Asia. Penicillin can never be recommended as empirical therapy
in patients with suspected pneumococcal meningitis. As an
empirical regimen, the combination of vancomycin plus a third-
generation cephalosporin (i.e., cefotaxime or ceftriaxone) is
recommended. After susceptibility studies of the isolated pneu-
mococcus are performed, antimicrobial therapy can be modified
for optimal treatment (see Table 90-7).
Viral meningitis is usually a benign self-limited illness. Recov-
ery of patients with HSV-2 meningitis is usually complete without
neurologic sequelae, and it is not clear whether antiviral treat-
ment alters the course of mild meningitis.
The preferred antimicrobial regimen for the treatment of CNS
syphilis is intravenous aqueous crystalline penicillin G at a dosage
of 18 to 24 million units daily in divided doses every 4 hours
or by continuous infusion for 10 to 14 days. Alternatively, pro-
caine penicillin (2.4 million units intramuscularly daily) plus
probenecid (500 mg orally four times daily), both for 10 to 14
days, can be used.
Parenteral antimicrobial therapy is usually needed to treat the
neurologic manifestations of Lyme disease, including meningitis.
The current recommendation is to treat most patients with Lyme
meningitis with intravenous ceftriaxone at a dosage of 2 g daily
 Chapter 90  Infections of the Central Nervous System 859

itraconazole for at least 1 year. Amphotericin B, alone or in com-

TABLE 90-7  RECOMMENDED DOSAGES OF bination with flucytosine, also is the treatment of choice for
ANTIMICROBIAL AGENTS FOR Candida meningitis.
MENINGITIS IN ADULTS WITH NORMAL
RENAL AND HEPATIC FUNCTION Adjunctive Therapy
ANTIMICROBIAL DOSING For adult patients with bacterial meningitis, adjunctive dexa-
AGENT TOTAL DAILY DOSE* INTERVAL (hr)
†
methasone should be administered to those with suspected or
Amikacin 15 mg/kg 8
Amphotericin B 0.7-1.0 mg/kg 24 proven pneumococcal meningitis. This recommendation is based
deoxycholate on a prospective, randomized, double-blind trial enrolling 301
Ampicillin 12 g 4 adults with bacterial meningitis. Adjunctive dexamethasone was
Cefepime 6 g 8
Cefotaxime 8-12 g 4-6 associated with a reduction in the proportion of patients who had
Ceftazidime 6 g 8 unfavorable outcomes (15% vs. 25%, P = .03) and in the propor-
Ceftriaxone 4 g 12-24 tion of patients who died (7% vs. 15%, P = .04). The benefits were
Ethambutol§ 15 mg/kg 24
Fluconazole 400-800 mg‡ 24 most striking for the subgroup of patients with pneumococcal
Flucytosine§,‖ 100 mg/kg 6 meningitis and those with moderate to severe disease as assessed
Gentamicin† 5 mg/kg 8 by the admission Glasgow Coma Scale.
Isoniazid§,¶ 300 mg 24
Liposomal 3-4 mg/kg 24 Dexamethasone is administered at a dosage of 10  mg intra-
amphotericin B venously every 6 hours (with the first dose given concomitant
Meropenem 6 g 8 with or just before the first dose of an antimicrobial agent for
Nafcillin 9-12 g 4
Oxacillin 9-12 g 4 maximal attenuation of the subarachnoid space inflammatory
Penicillin G 24 million units 4 response) for 4 days. Adjunctive dexamethasone should not
Pyrazinamide§ 15-30 mg/kg 24 be used in patients who have already received antimicrobial
Rifampin§ 600 mg 24
Tobramycin† 5 mg/kg 8 therapy or the meningitis is found not to be caused by
Sulfamethoxazole- 10-20 mg/kg** 6-12 S. pneumoniae. Despite the positive benefits of adjunctive dexa-
trimethoprim methasone for adults with bacterial meningitis described previ-
Vancomycin†† 30-60 mg/kg 8-12
ously, the routine use of adjunctive dexamethasone for patients
*Unless indicated, therapy is administered intravenously. with bacterial meningitis in the developing world has been
†
Need to monitor peak and trough serum concentrations.
‡
Dose of 800-1200 mg is recommended for patients with coccidioidal meningitis. controversial.
§
Oral administration. Tuberculous meningitis is associated with persistent mor­
‖
Maintain serum concentrations of 50-100 µg/mL.
¶
Initiate therapy at a dose of 10 mg/kg. bidity and mortality despite the availability of effective antituber-
**
Dosage based on trimethoprim component. culous chemotherapy. Use of adjunctive corticosteroids has
††
Maintain serum trough concentrations of 15-20 µg/mL.
abrogated the signs and symptoms of disease, and early treatment
for 14 days (range, 10 to 28 days); no evidence supports treat- with adjunctive dexamethasone should be used in all patients
ment durations longer than 4 weeks. with tuberculous meningitis.
In patients with tuberculous meningitis, the most important Patients with cryptococcal meningitis may have increased
principle of therapy is early initiation on the basis of strong clini- intracranial pressure or hydrocephalus, or both. Therapeutic
cal suspicion; it should not be delayed until proof of infection has modalities for these complications include shunting of CSF and
been obtained. The American Thoracic Society, in conjunction frequent, high-volume lumbar punctures.
with the CDC and the Infectious Diseases Society of America,
recommends 2 months of isoniazid, rifampin, ethambutol,
Encephalitis
and pyrazinamide, followed by 7 to 10 months of isoniazid
and rifampin for patients with drug-sensitive tuberculous menin- Definition
gitis. Therapy for tuberculous meningitis may need to be indi- Encephalitis is inflammation of the brain parenchyma that is asso-
vidualized, with longer durations of therapy used for patients ciated with neurologic dysfunction. In the absence of pathologic
with more severe illness or HIV. evidence of brain inflammation, an inflammatory response in the
Therapy for cryptococcal meningitis in patients with AIDS is CSF or parenchymal abnormalities on neuroimaging are often
usually an amphotericin B preparation (i.e., amphotericin B used as surrogate markers of brain inflammation; however,
deoxycholate, liposomal amphotericin B, or amphotericin B lipid encephalitis can occur without significant CSF pleocytosis or
complex) plus flucytosine for 2 weeks, followed by consolidation demonstrable neuroimaging abnormalities. Encephalitis and
therapy with fluconazole for 8 weeks. For non-AIDS patients meningitis share many features. Both syndromes can manifest
with cryptococcal meningitis, the optimal use of fluconazole is with fever, headache, and altered mental status, although the
less clear. In a retrospective review of HIV-1–negative patients encephalitis patient suffers from more severe alterations in mental
with CNS cryptococcosis, the patients were more likely to receive status.
an induction regimen containing amphotericin B and subsequent There is also clinical overlap between encephalitis and enceph-
therapy with fluconazole. Most experts recommend high-dose alopathy. Patients with encephalopathy, however, exhibit confu-
fluconazole (800 to 1200 mg daily) as first-line therapy for coc- sion early in the course of their illness that can quickly progress
cidioidal meningitis. to obtundation. Causes of encephalopathy include metabolic dis-
The current recommendation is to treat Histoplasma meningi- turbances, hypoxia, ischemia, intoxications, organ dysfunction,
tis with liposomal amphotericin B over 4 to 6 weeks, followed by paraneoplastic syndromes, and systemic infections.
860 Section XV  Infectious Disease
Epidemiology and Etiology
Encephalitis causes significant morbidity and mortality, and it is
a significant burden on the health care system. The hospital
admission rate in one study was 7.3 per 100,000 people. The
case-fatality rate among patients with encephalitis varies from
3.8% to 7.4% and is significantly higher among patients also
infected with HIV. There is significant morbidity among survi-
vors of encephalitis, with resultant loss of productivity and the
need for prolonged rehabilitation or skilled nursing care.
Infectious causes of encephalitis are diverse and include
viruses (most common), bacteria, fungi, and parasites. Clues in
the patient’s history that aid identification include seasonal varia-
tion, geographic location, prevalence of disease in the local com-
munity, travel history, recreational activities, occupational
exposures, insect contact, animal contact, vaccination history,
and immune status of the patient.
The most commonly identified viral causes in the United
States are herpes simplex virus type 1 (HSV-1), West Nile virus,
and the enteroviruses, followed by other herpesviruses (e.g.,
varicella-zoster virus). Other agents may be highly endemic
regionally (e.g., La Crosse virus in the Midwest) or internation-
ally (e.g., rabies virus, Japanese encephalitis virus). Bacterial
agents, including Ehrlichia species and Rickettsia rickettsii, are
potentially treatable causes of encephalitis, and prompt adminis-
tration of appropriate antimicrobial therapy may be lifesaving.
Perhaps the most challenging aspect of encephalitis is that no
pathogen is identified in 50% to 70% of cases. Up to 10% of
patients have a noninfectious cause.
Clinical Presentation
Because encephalitis is infrequently confirmed by pathologic
means, the signs and symptoms of neurologic dysfunction are
used as surrogate markers, and they are often nonspecific. The
clinical signs and symptoms of encephalitis are determined by
the specific area of the brain involved and by the severity of the
infection. Some organisms show neurotropism for particular ana-
tomic sites. HSV-1 infection almost universally involves the tem-
poral lobe, and the clinical presentation typically includes
temporal lobe seizures. With this comes an associated change in
personality, decreasing consciousness, focal neurologic findings
(including dysphagia), paresthesias and weakness, and focal sei-
zures. Sudden onset of fever and headache can also accompany
these mental status changes.
Diffuse brain involvement is frequently seen with arboviral
infections, and it is associated with global impairment in neuro-
logic function and coma. Fever and headache frequently precede
the onset of altered mental status, which can range from mild
confusion to obtundation. Other neurologic manifestations may
include behavioral changes (e.g., psychosis), focal paresis or
paralysis, cranial nerve palsies, and movement disorders (e.g.,
chorea). About 80% of patients infected with West Nile virus are
asymptomatic, and about 20% have only fever. Symptomatic
patients may have fever, headache, myalgia, and flaccid paralysis.
A maculopapular rash is seen in 50% of patients.
Evidence of inflammation or infection at sites distant from the
CNS may be useful in making a microbiologic diagnosis for
patients with encephalitis and myelitis. For instance, rickettsial
diseases, varicella-zoster virus, and West Nile virus often have
associated skin manifestations. Stomatitis and ulcerative lesions
in the mouth or an exanthem in a peripheral distribution can
suggest enterovirus infection. Patients with tuberculous and
fungal meningoencephalitis may have suggestive pulmonary
findings.
A syndrome frequently misclassified as encephalomyelitis
based on the similar clinical presentation is postinflammatory
encephalomyelitis. The most widely cited example is acute dis-
seminated encephalomyelitis (ADEM), which is seen primarily
in children and adolescents. ADEM is characterized by poorly
defined white matter lesions on magnetic resonance imaging
(MRI) that enhance after gadolinium administration. Postin-
flammatory encephalomyelitis is likely mediated by an immuno-
logic response to an antecedent antigenic stimulus such as
infection or immunization. Viral infections associated with
ADEM include measles, mumps, rubella, varicella-zoster,
Epstein-Barr, cytomegalovirus, herpes simplex, hepatitis A, and
coxsackievirus. Immunizations temporally associated with
ADEM include vaccines for Japanese encephalitis, yellow fever,
measles, influenza, smallpox, anthrax, and rabies, but a direct
causal association with these vaccines is difficult to establish.
ADEM usually begins between 2 days and 4 weeks after the anti-
genic stimulus, and patients develop rapid onset of encephalopa-
thy, with or without meningeal signs. The neurologic features
depend on the location of the lesions.
Another important disorder to consider is anti–N-methyl-d-
aspartate receptor (NMDAR) encephalitis, which is the most
common cause of autoimmune encephalitis after ADEM. The
disorder is seen in patients of all ages but occurs mostly in young
adults and children with or without teratomas. Patients usually
have an acute behavioral change, psychosis, and catatonia that
evolves to include seizures, memory deficit, dyskinesias, speech
problems, and autonomic and breathing dysregulation. Symp-
toms are more often neurologic in children and psychiatric in
adults, but in most cases, symptoms progress to a similar
syndrome.
Diagnosis
The initial laboratory testing of an individual should include a
complete blood count, tests of renal and hepatic function, and
coagulation studies. A low white blood cell count, low platelet
count, and elevated liver transaminase levels may suggest Ehrlichia
or Anaplasma infection. A baseline chest radiograph should be
obtained because a focal infiltrate can suggest particular patho-
gens (e.g., fungal or mycobacterial infections).
Neuroimaging studies are important to perform for all patients
with encephalitis; MRI is more sensitive at detecting abnor-
malities than CT, and it is the preferred study. Diffusion-
weighted MRI is superior to conventional MRI for the detection
of early signal abnormalities in viral encephalitis caused by
HSV, enterovirus 71, and West Nile virus. In patients with
HSV encephalitis, there may be significant edema and hemor-
rhage in the temporal lobes. Patients with flavivirus (e.g., West
Nile virus, Japanese encephalitis virus) encephalitis may display
characteristic patterns of mixed-intensity or hypodense lesions
on T1-weighted images of the thalamus, basal ganglia, and
midbrain. In patients with ADEM, MRI usually reveals multiple
 Chapter 90  Infections of the Central Nervous System 861
focal or confluent areas of signal abnormality in the subcortical
white matter and, sometimes, in subcortical gray matter on
T2-weighted and fluid attenuation inversion recovery (FLAIR)
sequences; the lesions are usually enhancing and display similar
stages of evolution.
Electroencephalography is rarely specific for a given pathogen
in patients with encephalitis, but results can be helpful in identi-
fying the degree of cerebral dysfunction by detecting subclinical
seizure activity, and it may provide information about the specific
area of the brain involved. Many patients with HSV encephalitis
demonstrate a temporal lobe focus with periodic lateralizing epi-
leptiform discharges (PLEDs).
Lumbar puncture with CSF analysis (i.e., cell count and dif-
ferential, glucose and protein levels) and a measurement of the
opening pressure should be performed unless there is a specific
contraindication. Most patients with viral encephalitis have a
mononuclear cell pleocytosis with cell counts ranging from 10 to
1000/mm3. Early in the disease process, CSF pleocytosis may be
absent, or there may be an elevation in neutrophils. The CSF
protein concentration is typically elevated, but usually less than
100 to 200 mg/dL, whereas the CSF glucose concentration
is typically normal. CSF viral cultures are usually not
recommended.
Brain biopsy has largely been replaced by CSF molecular tests.
For certain types of infections, however, brain biopsy may be
diagnostic. In rabies infections, for example, Negri bodies are a
distinctive histopathologic feature. Intranuclear eosinophilic
amorphous bodies surrounded by a halo may be seen in diseases
such as HSV encephalitis.
Testing for specific agents includes laboratory methods such
as antigen detection, culture, serology, and molecular diagnos-
tics. HSV encephalitis is a treatable and relatively common cause
of encephalitis, and an HSV PCR should be performed on the
CSF of all patients with a clinical diagnosis of encephalitis. False-
negative PCR test results can occur within the first 72 hours after
onset, and if HSV encephalitis is strongly suspected (e.g., in a
patient with temporal lobe involvement), a repeat HSV PCR on
a second sample of CSF within 3 to 7 days is recommended.
Enterovirus and varicella PCR should be done on CSF because
they are also common causes of encephalitis; however, detection
of antibodies to varicella-zoster virus in the CSF appears to have
greater sensitivity than detection of viral DNA.
Testing for other agents should be individualized with consid-
eration of the patient’s exposures, travel, season of the year, and
clinical and laboratory characteristics. Many infections require
acute and convalescent (i.e., paired) serum samples to determine
a diagnosis. A serum specimen collected during the acute phase
of the illness should be stored and tested in parallel when the
convalescent serum sample is drawn. Immunoglobulin M (IgM)
and immunoglobulin G (IgG) capture enzyme-linked immuno-
sorbent assays (ELISAs) have become useful and widely available
for the diagnosis of arboviral encephalitis. Detection of intrathe-
cal IgM antibody is a specific and sensitive method for the diag-
nosis of West Nile virus infection. There is substantial
cross-reactivity among the flaviviruses (e.g., West Nile virus, St.
Louis encephalitis virus, Japanese encephalitis virus); plaque-
reduction neutralization assays may be helpful in distinguishing
which flavivirus is involved in the event of elevated titers.
Serologic testing for Rickettsia, Ehrlichia, and Anaplasma
species should be performed for all encephalitis patients during
the appropriate season and with travel to or residence in endemic
areas, especially because these are treatable causes. Empirical
therapy should not be withheld from patients with a compatible
clinical presentation because antibodies are not always detectable
early in the course of illness.
Identification of NMDAR antibodies confirms the diagnosis
of anti-NMDAR encephalitis and should lead to the search for a
tumor. The tumor is almost always an ovarian teratoma.
Treatment
One of the most important first steps in managing encephalitis is
to consider treatable causes. Specific antiviral therapy is usually
limited to infections caused by herpesviruses (especially HSV-1
and varicella-zoster virus) and HIV. Acyclovir (10 mg/kg intra-
venously every 8 hours in adults with normal renal function)
should be administered to patients with encephalitis. Empirical
therapy for acute bacterial meningitis should be initiated when
clinical and laboratory testing is compatible with bacterial infec-
tion. If rickettsial or ehrlichial infections are suspected, empirical
doxycycline should be administered. The management of West
Nile virus infection is supportive care.
In patients with suspected postinfectious encephalomyelitis
(i.e., ADEM), high-dose intravenous corticosteroids (1 g of
methylprednisolone intravenously daily for at least 3 to 5 days)
are usually recommended, followed by an oral taper for 3 to 6
weeks. For patients diagnosed with anti-NMDAR encephalitis,
treatments have included corticosteroids, intravenous immuno-
globulins, and plasmapheresis. If a tumor is detected, removal is
important because it accelerates improvement and decreases
relapses.
  BRAIN ABSCESS
CNS infections can manifest as abscesses in the parenchyma or
as parameningeal infections. Prion infections produce clinical
signs confined to the brain and spinal cord.
Definition
A brain abscess is a focal collection of infected material in the
brain parenchyma that results in a necrotic center surrounded by
inflammatory cells.
Pathology and Pathophysiology
Brain abscesses produce symptoms and findings similar to those
of other space-occupying lesions (e.g., brain tumors), but they
often progress more rapidly and affect meningeal structures more
frequently than tumors. They originate or extend from extracere-
bral locations. Examples include blood-borne metastases from
unknown sources, lungs, or heart (i.e., endocarditis); direct
extensions from parameningeal sites of infection (i.e., otitis,
cranial osteomyelitis, facial infections, and sinusitis); and infec-
tions from sites of recent or remote head trauma or neurosurgical
procedures.
The infection is often polymicrobial. Commonly isolated
pathogens are aerobic and microaerobic streptococci and gram-
negative anaerobes such as Bacteroides and Prevotella. Less
common are gram-negative aerobes and Staphylococcus.
862 Section XV  Infectious Disease
Actinomyces, Nocardia, and Candida are found even less often. In
immunosuppressed individuals, Cryptococcus (i.e., microab-
scesses) and Toxoplasma are common causes of abscesses. Surgi-
cal specimens are culture positive for 70% of antibiotic-treated
patients and 95% of patients undergoing surgery before antibi-
otic administration.
Clinical Presentation
The classic clinical picture is composed of elements reflecting
the infectious nature of the lesion (e.g., fever), those related to
focal brain involvement, and those due to an increasing intra-
cranial mass effect. Elements of one or two categories are often
absent in a given case, particularly early in the disease course.
For example, almost one half of patients may not have a fever
or leukocytosis. Recent onset of a headache is the most common
symptom, which may increase in severity associated with focal
signs related to the location of the abscess (e.g., hemiparesis,
aphasia), followed by obtundation and coma. Seizures precede
the diagnosis in 30% of cases. Toxoplasma abscesses are often
associated with movement disorders due to their propensity
for the basal ganglia. The period of evolution may be as brief
as hours or as long as days to weeks with more indolent
organisms.
Diagnosis
CSF examination should be avoided; it is seldom diagnostic, and
results can be normal. Lumbar puncture in the setting of a mass
lesion carries the risk of transtentorial herniation. Because the
brain abscess is seeded from a peripheral site of infection, a search
for other sites of infection can help to identify the causative
organisms and determine adequate treatment.
MRI with intravenous gadolinium provides better soft tissue
contrast than CT and is particularly useful for detecting multiple
A B
FIGURE 90-2  Magnetic resonance imaging features of a brain abscess. A, Contrast-enhanced scan shows a ring-enhancing lesion in the left frontal
lobe. B, The diffusion-weighted image shows restricted diffusion in the cavity due to viscous pus and cellular material. C, Corresponding apparent
diffusion coefficient map shows dark, viscous material in the cavity and surrounding edema.
abscesses and posterior fossa abscesses or for demonstrating
cerebritis, the extent of a mass effect, associated venous throm-
bosis, and the response to therapy. In the early cerebritis stage,
CT results may be normal, but the MRI FLAIR sequence is very
sensitive for visualization of brain edema. On T1-weighted
images, the area of cerebritis is seen initially as a low-signal-inten-
sity, ill-defined area. T1-weighted images in the later stages of
infection show the formation of a rim of slightly higher signal
intensity and central necrosis. Contrast administration typically
shows ring enhancement with central necrosis. This area of
central necrosis appears bright on diffusion-weighted images and
dark on apparent diffusion coefficient (ADC) images (Fig. 90-2).
MRI of tumors shows the opposite features. Differentiating a
brain abscess from tumor is important for the stereotactic
approach to ring-enhancing lesions before biopsy or surgical
excision. An abscess should be drained centrally, whereas a tumor
should be biopsied along its rim.
Nocardia brain abscesses are often mutilobulated. Listeria
brain abscesses are often located in the brain stem.
Treatment
A suspected brain abscess requires urgent intervention. Unless
the surgical procedure poses a substantial risk, aspiration of the
lesion is needed for microbial diagnosis. If treatment of cerebral
edema is necessary, high-dose intravenous dexamethasone (16 to
24 mg/day in four divided doses) may be used for short periods
until surgical intervention is possible. Corticosteroids may retard
formation of a capsule around the brain abscess and the immune
response to infection.
Seizures should be controlled because the tonic phase of a
generalized seizure may increase intracranial pressure. In a patient
with a large abscess, seizures may trigger a brain herniation.
Seizure prophylaxis should be initiated in all patients with
C
 Chapter 90  Infections of the Central Nervous System 863
cortical or temporal lobe abscesses. Anticonvulsants that can be
administered intravenously are the drugs of choice.
Successful antibiotic management of brain abscess is based on
knowledge of proven or suspected pathogens and antibiotic
properties, such as CNS drug penetration capabilities and the
spectrum of activity. Empirical antibiotic therapy without surgi-
cal intervention may be used if the primary source of infection
outside of the CNS is identified, in patients with cerebritis
without capsule formation, or in those with multiple, small
abscesses or abscesses in basal ganglia or brain stem. If the organ-
ism is unknown, empirical therapy may include vancomycin,
metronidazole, and a third-generation cephalosporin. In brain
stem abscesses, the possibility of Listeria infection should be con-
sidered, and treatment should include intravenous ampicillin. In
HIV-infected patients with multiple ring-enhancing lesions,
empirical therapy for toxoplasmosis should be initiated even if
the patient is seronegative for Toxoplasma.
Patients undergoing empirical therapy should be followed
with repeated CT or MRI. Those who fail to respond should
undergo surgical intervention. An important aspect of the man-
agement strategy is eradication of the predisposing condition or
cause of the brain abscess, such as an oral, ear, cardiac, or pulmo-
nary infection.
  PARAMENINGEAL INFECTIONS
Definition
Parameningeal infections include those infections that produce
suppuration in potential spaces covering the brain and spinal
cord (i.e., epidural abscess and subdural empyema) and those
that produce occlusion of the contiguous venous sinuses and
cerebral veins (i.e., cerebral venous sinus thrombosis).
Subdural Empyema
Definition
Subdural empyema refers to infection in the space separating the
dura and arachnoid.
Pathology and Pathophysiology
Two thirds of subdural empyemas result from frontal or ethmoid
sinus infections, 20% from inner ear infections, and the remain-
der from trauma or neurosurgical procedures. The empyema is
caused by direct or indirect extension from infected paranasal
sinuses through a retrograde thrombophlebitis. Unilateral
empyema is most common because the falx prevents passage
across the midline, but bilateral or multiple empyemas can occur.
Cortical venous thrombosis or brain abscess develops in about
one fourth of patients. In some patients, the subdural empyema
may be associated with an epidural abscess or meningitis. These
infections occur more often in children than in adults.
Clinical Presentation
Initial symptoms are caused by chronic otitis or sinusitis with
superimposed lateralized headache, fever, and obtundation.
Vomiting, meningeal signs, and focal neurologic abnormalities
(i.e., hemiparesis or seizures) follow. If untreated, obtundation
progresses, and the septic mass and swollen underlying brain
produce venous thrombosis or death from herniation.
The major differential diagnosis is meningitis. Nuchal rigidity
and obtundation occur in meningitis and subdural empyema, but
papilledema and lateralizing deficits are more common in
empyema.
Diagnosis
Lumbar puncture should be avoided in patients with subdural
empyema to prevent cerebral herniation. Contrast-enhanced CT
or MRI can be diagnostic of empyema, showing an extra-axial,
crescent-shaped mass with an enhancing rim lying just below the
inner table of the skull over the cerebral convexities or in the
interhemispheric fissures. On MRI, subdural empyemas have
decreased signal intensity on T1-weighted imaging and increased
signal intensity on T2-weighted scans. Similar to brain abscess,
subdural empyema has high signal intensity on diffusion-
weighted images and low signal intensity on ADC maps.
Treatment
Treatment requires prompt surgical drainage of the empyema
cavity and high-dose intravenous antibiotics directed at organ-
isms found at the time of craniotomy.
  MALIGNANT EXTERNAL OTITIS
Chapter 91 discusses infections of the head and neck.
  SPINAL EPIDURAL ABSCESS
Definition and Epidemiology
A spinal epidural abscess is an infection in the epidural space
between the dura and the bones of the spine around the spinal
cord. It can cause paralysis and death. The incidence is 0.5 to 1.0
cases per 10,000 hospital admissions in the United States, and the
frequency is increased among injection drug users.
Pathology and Pathophysiology
Infections of the epidural space originate from contiguous spread
or through hematogenous routes from a distant source. Cutane-
ous infection, particularly in the back, is the most common
remote source, especially among injection drug users. Abdomi-
nal, respiratory tract, and urinary sources are also common. As
the use of epidural catheters has increased for pain management,
epidural abscess and hematoma have been increasingly reported.
The anatomy of the epidural space dictates the location of the
abscess. Because the size of the intravertebral canal remains rela-
tively constant but the circumference of the spinal cord changes,
abscess formation is maximal in the thoracic and lumbar regions
and minimal at the cervical spine enlargement. Due to the loose
connections between the dura and the bones of the spine, the
abscess can extend to multiple levels, causing severe and exten-
sive neurologic manifestations.
Causative organisms can be identified by culture or Gram stain
from pus obtained at exploration (90% of patients), blood cul-
tures (60% to 90%), or CSF (20%). S. aureus is most common,
followed by streptococci and gram-negative organisms. Tubercu-
lous abscesses may occur in as many as 25% of patients in high-
risk populations. In a recent epidemic, iatrogenic infection
864 Section XV  Infectious Disease

occurred with rare fungi after epidural injections of corticoste-
roids that were contaminated with a plant pathogen, Exserohilum
rostratum, that rarely infects humans.
Clinical Presentation
The classic triad of fever, spinal pain, and neurologic deficits may
not be identified in all patients, leading to a delay in diagnosis.
Patients are usually febrile and have acute or subacute neck or
back pain. An important physical finding is focal tenderness over
the affected spinous processes. Stiff neck and headache are
common. The pain can be mistaken for sciatica, a visceral abdom-
inal process, chest wall pain, or cervical disk disease. If it goes
unrecognized at this stage, the symptoms can evolve over a few
hours to a few days to weakness, loss of lower extremity reflexes,
and paralysis distal to the spinal level of the infection. In this
clinical setting, spinal epidural abscess should be assumed, sys-
temic antibiotics begun, and urgent neuroradiologic imaging
pursued.
Diagnosis
The diagnosis is made by CT or MRI (Fig. 90-3). The differ-
ential diagnosis includes transverse myelitis, intervertebral disk
herniation, epidural hemorrhage, and metastatic tumor. These
conditions can usually be detected by MRI. Epidural abscess
is often accompanied by diskitis or osteomyelitis of the vertebral
bodies.
Treatment
Unless culture and sensitivities dictate otherwise, a penicillinase-
resistant penicillin should be started empirically as antistaphylo-
coccal treatment for presumed bacterial infection. If methicillin
resistance is suspected, vancomycin should be used. Considering
the severity of the disease, additional gram-negative coverage
with a third-generation cephalosporin or a quinolone may be
needed.
Surgical decompression was previously considered manda-
tory, but early diagnosis by MRI may allow for effective medical
therapy if started before the occurrence of neurologic complica-
tions. These patients should be monitored closely, and if signs of
neurologic deterioration emerge, surgical intervention may be
necessary.
  SINUS THROMBOSIS
Septic Cavernous Sinus Thrombosis
Septic cavernous sinus thrombosis usually results from spread of
infection from facial structures through facial veins or from the
sphenoid or ethmoid sinuses. Symptoms include headache or
lateralized facial pain, followed in a few days to weeks by fever
and involvement of the orbit (i.e., proptosis and chemosis due to
obstruction of the ophthalmic vein). Paralysis of oculomotor
nerves follows rapidly. In some instances, sensory dysfunction
occurs in the first and second divisions of the trigeminal nerve
along with a decrease in the corneal reflex. Further involvement
of the contiguous orbital contents follows, with mild papilledema
and decreased visual acuity that sometimes progresses to
blindness.
Extension to the opposite cavernous sinus or to other intracra-
nial sinuses with cerebral infarction or increased intracranial pres-
sure due to impaired venous drainage can result in stupor, coma,
and death. The CSF is abnormal if there is accompanying men-
ingitis or parameningeal infection. The most common causative
organism is S. aureus, followed by streptococci and pneumococci;
anaerobic infection may occur.

A B
FIGURE 90-3  Magnetic resonance imaging shows an epidural abscess due to Staphylococcus in the cervical spine of a patient with human immu-
nodeficiency virus infection. A, Noncontrast T1-weighted image shows an extensive lesion in the epidural space that extends from C2 to C7. Notice
straightening of the cervical spine. B, After a laminectomy from C2 to T1 and fusion, the short tau inversion recovery (STIR) image shows fluid col-
lection in the epidural space as a high-signal-intensity lesion. Normal curvature of the spine is seen.
 Chapter 90  Infections of the Central Nervous System 865
Diagnosis of cavernous sinus thrombosis is usually made by
MRI with a venogram. Radiologic evaluation includes imaging of
the sphenoidal and ethmoidal sinuses, which may require drain-
age if infected. Empirical antimicrobial therapy should include an
antistaphylococcal agent. An empirical combination therapy
with parenteral metronidazole, vancomycin, and ceftriaxone can
achieve reasonable CSF and brain penetration and is likely to be
active against S. aureus and the usual sinus pathogens. Parenteral
nafcillin can be added for identified or suspected methicillin-
sensitive S. aureus.
Lateral Sinus Thrombosis
Septic thrombosis of the lateral sinus results from acute or
chronic infections of the middle ear. The infection spreads
through emissary veins that connect the mastoid with the lateral
venous sinus. It may spread to involve the sigmoid sinus. The
symptoms include ear pain followed over several weeks by fever,
headache, nausea, vomiting, and vertigo. Mastoid swelling may
be seen. Sixth cranial nerve palsies and papilledema can occur,
but other focal neurologic signs are rare.
The diagnosis can be established by magnetic resonance angi-
ography. Treatment includes an empirical regimen of broad-
spectrum intravenous antibiotics to cover staphylococci and
anaerobes (i.e., nafcillin or oxacillin with penicillin or metronida-
zole), but surgical drainage (i.e., mastoidectomy) may be required.
Septic Sagittal Sinus Thrombosis
Septic sagittal sinus thrombosis is uncommon and occurs as a
consequence of purulent meningitis, infections of the ethmoidal
or maxillary sinuses spreading through venous channels, infected
compound skull fractures, or neurosurgical wound infections
(rare). Symptoms include manifestations of elevated intracranial
pressure (i.e., headache, nausea, and vomiting) that evolve rapidly
to stupor and coma. Diagnosis and treatment is similar to the
lateral venous sinus thrombosis described earlier.
  NEUROLOGIC COMPLICATIONS
OF INFECTIVE ENDOCARDITIS
Epidemiology
Neurologic complications occur in one third of patients with
bacterial endocarditis, and they triple the mortality rate of the
disease. Most complications are related to valvular vegetations.
Cerebral (but not systemic) emboli from mitral valve endocardi-
tis are increasingly common. Most emboli, regardless of the bac-
terial cause of the infection, occur before or early in the course of
treatment. By 2 weeks of therapy, the risk of embolization
decreases dramatically. Mycotic aneurysms in the brain compli-
cate endocarditis in 2% to 10% of patients and are more common
in acute than subacute disease.
Pathophysiology and Clinical Manifestations
Cerebral emboli are distributed in the brain in proportion to
cerebral blood flow. Most emboli lodge in the branches of the
middle cerebral artery peripherally, with resultant hemiparesis.
Focal seizures may result. Multiple microabscesses, however, can
result in a diffuse encephalopathy similar to that seen in sepsis.
Mycotic aneurysms occur most commonly in the middle cere-
bral artery, with the aneurysms located distally in the vessel. This
differentiates them from congenital berry aneurysms.
Clinical Manifestations
Patients often develop strokes, impaired consciousness, meningi-
tis, focal seizures, and new-onset severe headaches. Strokes may
manifest as ischemic lesions or hemorrhagic lesions in the brain
parenchyma or subarachnoid space. Patients may have other
signs of systemic microembolisms or retinal lesions, splinter
hemorrhages in the nail bed, or microscopic hematuria.
Diagnosis
The diagnosis of neurologic involvement from endocarditis is
best made with CT or MRI. MRI findings in endocarditis include
ischemic lesions, hemorrhagic lesions, subarachnoid hemor-
rhage, brain abscess, mycotic aneurysm, and cerebral micro-
bleeds. The CSF is abnormal in 70% of patients and simulates
purulent meningitis (i.e., polymorphonuclear predominance,
elevated protein level, and low glucose level) or a parameningeal
infection (i.e., lymphocytic predominance, modest protein eleva-
tion, and normal glucose level). Multiple blood cultures may be
needed to identify the organisms.
Multidetector CT angiography may be necessary to diagnose
aneurysms. Small brain abscesses may complicate the course of
endocarditis, but macroscopic abscesses are rare, with most
occurring in the setting of acute rather than subacute endocardi-
tis. Multiple microabscesses may escape detection on CT and are
not amenable to surgical drainage.
Treatment
Antibiotic treatment of the primary disease is indicated. Stroke
is usually treated conservatively. There are no controlled trials for
the management of unruptured mycotic aneurysms. The aneu-
rysms may decrease in size with antibiotic therapy, but the risk
of rupture is high, and most clinicians advocate surgical manage-
ment with clipping of the aneurysm or endovascular coiling.
However, endovascular coiling may not prevent hemorrhage
associated with rupture of a new aneurysm. Patients with infec-
tive endocarditis who do not respond to conservative medical
therapy can have prompt valve replacement despite intracerebral
hemorrhage.
  PRION DISEASES
Etiology
Several human diseases have been attributed to a unique infec-
tious protein, the prion. The infectious form of the prion protein
is rich in β-sheets, detergent insoluble, multimeric, and resistant
to proteinase K treatment.
Prion illnesses (i.e., transmissible spongiform encephalopa-
thies) can be classified as sporadic, hereditary, or acquired. The
most common form is sporadic Creutzfeldt-Jakob disease
(sCJD). Familial forms include Gerstmann-Sträussler-Scheinker
syndrome and familial fatal insomnia.
Acquired forms are caused by the transmission of an abnormal
prion protein (PrP) from human to human or from cattle to
humans. Accidental transmission of CJD between humans
866 Section XV  Infectious Disease
appears to have occurred with cadaveric dura mater grafting,
corneal transplantation, receipt of human growth hormone or
pituitary gonadotropin, contaminated electroencephalogram
electrodes, and contaminated surgical instruments. This form of
CJD has been called iatrogenic CJD (iCJD).
The appearance of variant CJD (vCJD) in Great Britain, which
was associated with the outbreak of bovine spongiform encepha-
lopathy and the contamination of beef, greatly increased interest
in this group of illnesses. Kuru is another transmissible spongi-
form encephalopathy that was spread in New Guinea by canni-
balism, a practice that ceased in the 1950s. The disease is now
almost extinct.
Sporadic Creutzfeldt-Jakob Disease
Epidemiology
Illness from sCJD is seen worldwide, with an incidence of 0.5 to
1.0 cases per 1 million people in the general population per year.
Clinical Manifestations
CJD is frequently diagnosed incorrectly initially. Prodromal
symptoms include altered sleep patterns and appetite, weight
loss, changes in sexual drive, and impaired memory and con-
centration. Disorientation, hallucinations, depression, and emo-
tional lability are early signs, followed by a rapidly progressive
dementia associated with myoclonus (about 90% of patients).
Myoclonus is usually provoked by tactile, auditory, or visual
startle stimuli. CJD has an abrupt onset in 10% to 15% of
patients.
Other distinctive features include seizures, autonomic dys-
function, and lower motor neuron disease, suggesting amyo-
trophic lateral sclerosis. Cerebellar ataxia occurs in one third of
patients.
Pathology
The pathologic hallmarks of CJD are spongiform or vacuolar
changes in the brain without cellular inflammatory infiltrates. The
pathogenic isoform of the prion protein can be demonstrated in
brain tissue by immunocytochemical staining and by Western
blot analysis. The fundamental process involved in human prion
propagation is intercellular induction of protein misfolding and
seeded aggregation of misfolded prion protein.
Diagnosis
The clinical tetrad supporting the diagnosis of CJD consists of a
subacute progressive dementia, myoclonus, typical periodic
complexes on electroencephalography, and normal CSF. FLAIR
MRI sequences shows extensive curvilinear hyperintensity along
the neocortex, called cortical ribboning, which affects frontal, pari-
etal, and temporal lobes (in decreasing order of frequency).
Routine CSF study is usually normal. A CSF test for the protein
14-3-3, which is released into spinal fluid when brain cells die, in
the appropriate clinical context is highly specific and sensitive
for CJD.
Treatment
No effective therapy exits. The disease is inexorably progressive.
The median time to death from onset is 5 months, and 90% of
patients with sporadic CJD die within 1 year.
Although the illness is not communicable in the conventional
sense, a risk exists in handling material contaminated with the
prion protein. Gloves should be worn when handling blood, CSF,
and other body fluids. Instruments must be disinfected and steril-
ized appropriately.
For a deeper discussion of these topics, please see Chapter
412, “Meningitis: Bacterial, Viral, and Other”; Chapter 413,
“Brain Abscess and Parameningeal Infections”; Chapter
414, “Acute Viral Encephalitis”; and Chapter 415, “Prion
Diseases,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Brouwer MC, Thwaites GE, Tunkel AR, et al: Dilemmas in the diagnosis of acute
community-acquired bacterial meningitis, Lancet 380:1684–1692, 2012.
Carfrae MJ, Kesser BW: Malignant otitis externa, Otolaryngol Clin North Am
41:537–549, 2008.
Colby DW, Prusiner SB: Prions, Cold Spring Harb Perspect Biol 3:a006833,
2011.
Connor DE Jr, Chittiboina P, Caldito G, et al: Comparison of operative and
nonoperative management of spinal epidural abscess: a retrospective review of
clinical and laboratory predictors of neurological outcome, J Neurosurg Spine
19:119–127, 2013.
Glaser CS, Honarmand S, Anderson LJ, et al: Beyond viruses: clinical profiles and
etiologies associated with encephalitis, Clin Infect Dis 43:1565–1577, 2006.
Solomon T, Michael BD, Smith PE, et al: Management of suspected viral
encephalitis in adults—Association of British Neurologists and British
Infection Association National Guidelines, J Infect 64:347–373, 2012.
Thigpen MC, Whitney CG, Messonnier NE, et al: Bacterial meningitis in the
United States, 1998-2007, N Engl J Med 364:2016–2025, 2011.
Titulaer MJ, McCracken L, Gabilondo I, et al: Treatment and prognostic factors
for long-term outcome in patients with anti-NMDA receptor encephalitis: an
observational cohort study, Lancet Neurol 12:157–165, 2013.
Tunkel AR, Glaser CA, Block KC, et al: The management of encephalitis: clinical
practice guidelines by the Infectious Diseases Society of America, Clin Infect
Dis 47:303–327, 2008.
Tunkel AR, Hartman BJ, Kaplan SL, et al: Practice guidelines for the management
of bacterial meningitis, Clin Infect Dis 39:1267–1284, 2004.
van de Beek D, Brouwer MC, Thwaites GE, et al: Advances in treatment of
bacterial meningitis, Lancet 380:1693–1702, 2012.
van de Beek D, Drake JM, Tunkel AR: Nosocomial bacterial meningitis, N Engl
J Med 362:146–154, 2010.
Venkatesan A, Tunkel AR, Bloch KC, et al: Case definitions, diagnostic
algorithms, and priorities in encephalitis; consensus statement of the
International Encephalitis Consortium, Clin Infect Dis 57:1114–1128, 2013.
Weisfelt M, van de Beek D, Spanjaard L, et al: Clinical features, complications,
and outcome in adults with pneumococcal meningitis: a prospective case
series, Lancet Neurol 5:123–129, 2006.

Infections of the Head and Neck
  COMMON COLD
Definition and Epidemiology
The common cold is a syndrome of sore throat, rhinorrhea, and
nasal congestion caused by viruses. Adults average two or three
colds per year, and children have five to seven colds each year.
The common cold accounts for 110 million visits to health care
providers, an estimated 20 million lost work days, and at least $3
billion in expenses for medications. Viruses are transmitted most
efficiently by direct contact, but aerosol transmission also occurs.
Pathogenesis and Microbiology
The pathogenesis varies with the pathogen. For example, rhino-
virus has no histological effect on the mucosal epithelium,
whereas influenza virus destroys it. The syndrome is caused by
many viruses including rhinovirus (30% to 40%), influenza virus,
parainfluenza virus, adenovirus, coronavirus, respiratory syncy-
tial virus, enteroviruses and metapneumovirus. No organism can
be identified in 25% to 30% of cases.
Clinical Presentation
Symptoms include an initial sore throat that develops into rhinor-
rhea, nasal congestion, sneezing, and cough after several days.
Patients may also complain of fever, malaise, and hoarseness. The
presence of myalgias may indicate influenza virus, whereas con-
junctivitis may indicate adenovirus or enteroviruses. Symptoms
peak from 3 to 6 days and last from 7 to 10 days, but viral shed-
ding can occur 2 to 3 weeks after infection.
Laryngitis frequently accompanies the common cold. Patients
complain of hoarseness, voice breaks or aphonia. Laryngitis typi-
cally lasts 3 days and is self limited. Unusual causes of laryngitis
include group A streptococci, Hemophilus influenzae, Corynebac-
terium diphtheriae, Mycobacterium tuberculosis, and fungi.
Croup is a subglottic viral infection manifesting in children
typically under 3 years of age. Patients present with a character-
istic rough and stridulous cough and stridor on breathing. Diag-
nosis is clinical and treatment symptomatic.
Treatment
Treatment of the common cold is symptomatic; treatments
include decongestants for nasal congestion, nonsteroidal anti-
inflammatory drugs (NSAIDs) for fever and myalgia, lozenges
for sore throat, and dextromethorphan for cough. Zinc and Echi-
nacea have not been shown to be effective. There is also no con-
vincing evidence supporting preventative measures. Viral
laryngitis and croup are treated symptomatically; there is no evi-
dence that antibiotics help.
91 
Edward J. Wing
For a deeper discussion of these topics, please see Chapter
361, “The Common Cold,” in Goldman-Cecil Medicine,
25th Edition.
  ACUTE BACTERIAL SINUSITIS
This section focuses on acute community-acquired bacterial
sinusitis.
Definition and Epidemiology
Bacterial sinusitis is inflammation and bacterial infection of the
paranasal sinuses. Bacterial sinusitis follows the common cold in
0.5% to 2.0% of cases in adults and in 6% to 13% of cases in
children. Sinusitis accounts for 23 million health care visits each
year and 20 million antibiotic prescriptions per year.
Pathogenesis
Sinusitis occurs when the sinus ostias narrow from inflammation,
mucosal cilia become dysfunctional and disrupted, and mucus
becomes viscous. The sinuses, which are normally sterile, become
colonized with nasal bacteria and infection results. The major
organisms identified by sinus puncture are Streptococcus pneu-
moniae and H. influenzae (Table 91-1); 30% to 40% of cultures
are negative. Fungi cause a rare syndrome of rhinocerebral
mucormycosis in diabetics.
Clinical Presentation
The symptoms and signs of acute bacterial sinusitis have a large
overlap with the common cold. Table 91-2 shows the sensitivity
and specificity of symptoms and signs in sinusitis. Nasal
discharge/obstruction, facial pain, and maxillary toothache are
suggestive. Physical findings of nasal discharge, facial pain, and
pain on palpation of the sinuses are nonspecific and variable.
Most important is that symptoms of the common cold peak
between days 3 and 6 and resolve by day 10. Sinus infection
occurs characteristically after 10 days of infection. There are three
patterns of acute bacterial sinusitis: symptoms persisting for
more than 10 days; severe symptoms, including fever and puru-
lent nasal discharge over 3 to 4 days; and common cold symp-
toms that improve and then suddenly worsen.
Diagnosis
The diagnosis of acute bacterial sinusitis is most often made on
clinical grounds as noted previously. Imaging can be helpful in
situations in which the diagnosis is unclear or there are complica-
tions. Unfortunately, the common cold can also result in positive
findings. Computed tomography (CT) is the procedure of choice
if indicated.
867
868 Section XV  Infectious Disease

TABLE 91-1  BACTERIAL CAUSE OF ACUTE SINUSITIS

ADULTS (n = 339) CHILDREN (n = 30)
ORGANISM Number of Isolates % of Isolates Number of Isolates % of Isolates
Streptococcus pneumoniae 92 41 17 41
Haemophilus influenza 79 35 11 27
Anaerobes 16 7
Streptococcal species 16 7 3 7
Moraxella catarrhalis 8 4 9 22
Staphylococcus aureus 7 3
Other 8 4 1 2
Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 7, Philadelphia, 2009, Churchill Livingstone.

TABLE 91-2  DAGNOSTIC SIGNS AND SYMPTOMS OF SINUSITIS

SYMPTOM OR SIGN SENSITIVITY (%) SPECIFICITY (%) LIKELIHOOD RATIO
Maxillary toothache 18 93 2.5
No improvement with decongestants 41 80 2.1
Cough 70 44 1.3
Sore throat 52 56 1.2
Headache 68 30 1.0
Purulent secretion 51 76 2.1
Abnormal transillumination 73 54 1.6
Sinus tenderness 48 65 1.4
Fever 16 83 0.9
From Williams JW Jr, Simel DL, Roberts L, Samsa GP: Clinical evaluation for sinusitis: making the diagnosis by history and physical examination, Ann Intern Med 117:705–710, 1992.

Stomatitis, laryngitis, and epiglottitis are similar processes in the

Treatment
Acute bacterial sinusitis resolves spontaneously within 2 weeks
without antibiotic therapy. Antibiotic therapy hastens the resolu-
tion of symptoms and is recommended by guidelines from the
major national organizations of internists, pediatricians, aller-
gists, and otolaryngologists. Careful review of randomized con-
trolled trials as reported in the Cochrane Database Systemic
Reviews, however, concludes that the risks of antibiotics out-
weigh the benefits in routine cases in adults. The antibiotics of
choice are amoxicillin or amoxicillin and clavulinic acid given for
10 days. Macrolides, sulfamethoxazole-trimethoprim, and doxy-
cycline may be less effective because common bacteria are devel-
oping resistance. Patients should respond within 48 to 72 hours.
Intranasal saline irrigation has been shown to give symptomatic
relief. Intranasal steroids may help individuals with underlying
allergic rhinitis. There are no convincing data supporting use of
antihistamines or α-adrenergic agonists. Surgery may be indi-
cated for people with unresponsive sinusitis or those with intra-
cranial or orbital complications.
Complications that are unusual include intracranial pathology
such as subdural empyema, epidural abscess, brain abscess, men-
ingitis and venous sinus thrombosis. Extracranial complications
include orbital cellulitis, orbital abscess and subperiosteal abscess
(Fig. 91-1). Immediate surgical intervention is indicated for
orbital or intracranial abscesses. Refer to the Infectious Diseases
Society of America guidelines for upper/respiratory tract infec-
tions for treat details.
  PHARYNGITIS, STOMATITIS,
LARYNGITIS, AND EPIGLOTITIS
Pharyngitis
Definition and Epidemiology
Pharyngitis or sore throat is mucous membrane inflammation
localized to the posterior pharynx and contiguous membranes.
indicated locations. These infections are extremely common. In
the acute care setting in the United States, for example, pharyn-
gitis accounts for 7 million pediatric and 6 million adult visits
each year. Peak incidence is typically in the winter months.
Etiology
Viruses cause 70% to 90% of cases of pharyngitis with rhinovirus
being the most common. Adenovirus, which typically occurs in
the late winter, is common in children less than 5 years of age
and in young adults. Enteroviruses cause syndromes of herpan-
gina (e.g., coxsackie group A); hand, foot, and mouth disease
(e.g., coxsackie A16 and enterovirus 71); and nonspecific illnesses
(e.g., group B coxsackie and echovirus). Herpes simplex virus
causes pharyngitis and stomatitis in children and college students.
Many other viruses cause pharyngitis, including Epstein-Barr
virus, influenza virus, parainfluenza virus, and cytomegalovirus.
Group A streptococci (GAS) accounts for 10% to 30% of cases
in children and 5% to 0% of cases in adults. In winter months up
to 50% of cases may be due to GAS. Other bacterial causes,
including group C and G streptococci and Fusobacterium nec-
rophorum, are much less common. Noninfectious causes of phar-
yngitis include Beçhet’s syndrome, Kawasaki disease, and
aphthous stomatitis.
Clinical Presentation
The main job of clinicians is to distinguish GAS from viral phar-
yngitis. Typically, GAS presents with sudden onset of pain on
swallowing, tender cervical lymph nodes and fever without
cough and coryza. Viral etiologies may be accompanied by cough,
coryza, and conjunctivitis (typically adenovirus). Scarlet fever
consisting of a fine maculopapular rash like “sand paper” that
desquamates and a strawberry tongue (prominent lingual papil-
lae) indicates GAS. However, even experienced clinicians can
distinguish viral from bacterial causes of pharyngitis only 50% of
the time.
 Chapter 91  Infections of the Head and Neck 869

FIGURE 91-1  A, A child has an orbital abscess as a complication of

ethmoid sinusitis. Notice the marked edema and proptosis. B, Computed
tomography scan of the orbit shows a subperiosteal abscess (arrow).
(A, Courtesy Gary Williams, MD; B, From DeMuri GP, Wald ER: Sinusitis. In
Bennett JE, Dolin R, Blaser M, editors: Mandell, Douglas, and Bennett’s
principles and practice of infectious diseases, ed 8, Philadelphia, 2015,
A Saunders.)

Complications include peritonsillar abscess or Quinsy that

occur in adolescents and young adults. Patients appear ill and
may have a muffled or “hot potato” voice and foul-smelling
breath. The uvula may be displaced and there may be trismus and
drooling. Less common complications include contiguous neck
space infections. F. necrophorum can cause a rare syndrome called
postangina septicemia or Lemierre’s syndrome, which manifests
with severe sore throat and fever. The lateral pharyngeal space
becomes infected with resulting septic thrombophlebitis of the
internal jugular vein. The mortality rate can be as high as 50%.
Treatment is intravenous penicillin and drainage of any abscess.
Table 91-3 lists the danger signs in patients with sore throat.
TABLE 91-3  SEVEN DANGER SIGNS IN PATIENTS
WITH SORE THROAT
1. Persistence of symptoms longer than 1 week without improvement
2. Respiratory difficulty, particularly stridor
3. Difficulty in handling secretions
4. Difficulty in swallowing
5. Severe pain in the absence of erythema
6. A palpable mass
7. Blood, even small amounts, in the pharynx or ear
(non–life-threatening allergy), clindamycin or clarithromycin for
10 days, or azithromycin for 5 days are reasonable alternatives.

Diagnosis
Identifying GAS infection is important because treatment can
prevent poststreptococcal complications including acute rheu-
matic fever, scarlet fever and peritonsillar abscess (i.e., quinsy).
Rapid antigen detection tests for GAS are specific but only 66%
to 90% sensitive. The diagnostic standard is a culture of a careful
swab of the tonsils and pharynx. If clinical and epidemiological
data suggest GAS, a rapid antigen detection test should be per-
formed. If positive, the patient should be treated. If negative in
children and adolescents, a culture should be done and if the
culture is positive treatment is indicated. In adults, culture is not
always necessary because the rate of complications is low and the
incidence of a rheumatic fever is exceptionally low. Otherwise,
symptomatic therapy is indicated.
Treatment
Treatment of viral pharyngitis is symptomatic; treatment of GAS
pharyngitis is oral penicillin or amoxicillin for 10 days. For
patients with a penicillin allergy, first generation cephalosporins
Oral Cavity Infections
Stomatitis
Many viruses can cause stomatitis (see Pharyngitis). In particu-
lar, herpes simplex virus causes stomatitis and is characterized by
vesicles and moderate pain. Treatment of primary infection is
with oral acyclovir or valcyclovir. Other viruses such as enterovi-
ruses can also cause stomatitis.
Periodontal Infections
Periodontal infections include gingivitis, periodontitis (i.e., the
major cause of tooth loss in adults), and periodontal abscess.
Acute necrotizing ulcerative gingivitis or Vincent’s angina is char-
acterized by acute pain of the gingiva, a pseudomembrane, and
halitosis. Débridement and antibiotics are indicated.
Neck Space Infections
Neck space infections usually result from dental caries. Dental
infections can lead to neck space infections involving the lateral
870 Section XV  Infectious Disease

pharyngeal space, the retropharyngeal space, and the subman-
dibular and sublingual space (e.g., Ludwig’s angina). These infec-
tions are medical emergencies and need to be dealt with surgically
as well as with antibiotic treatment. Ludwig’s angina is character-
ized by swelling in the submandibular space, an elevated tongue,
and difficulty eating (Fig. 91-2). Treatment consists of surgical
decompression and drainage and intravenous antibiotics. Table
91-4 lists neck space infections requiring drainage and
decompression.
Aphthous Ulcers
Aphthous ulcers are shallow ulcerations typically lasting for
several days to weeks located on the anterior structures of the
mouth. The cause is unknown. Treatment is symptomatic except
for individuals with extensive persistent disease in whom steroids
or thalidomide may be indicated
Thrush
Thrush refers to superficial Candida albicans infection of the
tongue, hard and soft palate, and pharynx, which results in a sore
mouth and oropharyngeal pain on swallowing. On inspection
there are creamy white plaques on the tongue, hard and soft
palates, and the pharynx. Patients who are immunocompromised
secondary to corticosteroid treatment or underlying conditions
such as HIV are susceptible. Treatment is typically topical anti-
fungal agents or oral fluconazole for 5 to 7 days.
Bacterial Epiglottitis
Acute bacterial epiglottitis caused by H. influenzae was previously
an uncommon but life-threatening illness of children under the
age of 5. With widespread use of the H. influenzae vaccine in
children, the incidence has decreased by 99% in children. More
often, the disease occurs in adults in whom a variety of bacteria
are responsible, including S. pneumoniae, Staphylococcus aureus,
β-hemolytic streptococci, and Klebsiella pneumoniae. Patients
typically present with fever and toxicity, drooling, dysphagia, and
holding the head extended. Speaking is painful and the laryngeal
tracheal area is very tender. Examination may reveal a cherry red
visible epiglottitis. Coordinated care, if necessary in the OR, is
critical to maintain the airway. Broad-spectrum antibiotics are
indicated. Steroids are commonly used but data are lacking to
support their use.

  ACUTE BACTERIAL OTITIS EXTERNA AND MEDIA

Acute Bacterial Otitis Externa
Acute localized otitis externa is a superficial infection of the
outer portion of the ear canal usually related to furunculosis
caused by S. aureus. It can be treated with oral anti-staphylococcal
antibiotics. Acute diffuse otitis externa (i.e., swimmer’s ear)
begins with itching and progresses to moderate/severe pain on
manipulation of the pinna or tragus. The canal is erythematous
and swollen. The usual organism is Pseudomonas aeruginosa.
Treatment consists of acetic acid and alcohol lavage with or
without topical antibiotics such as ciprofloxacin or neomycin
plus polymyxin.
Malignant otitis externa is a rare infection usually found in
elderly diabetic patients that progresses over weeks to months. It
is characterized by deep seated pain, otorrhea and granulation
tissue on the posterior inferior wall of the external canal. CT scan
is the initial imaging modality of choice. The infection can
progress to skull-based osteomyelitis and meningitis and has a
FIGURE 91-2  Early appearance of a patient with Ludwig’s angina, significant mortality. Treatment is surgical débridement and
who has a brawny, boardlike swelling in the submandibular spaces. antipseudomonal systemic therapy.
(From Megran DW, Scheifele DW, Chow AW: Odontogenic infections,
Pediatr Infect Dis 3:262, 1984.)
Acute Bacterial Otitis Media
Definition and Epidemiology
Acute bacterial otitis media is an acute bacterial infection of the
TABLE 91-4  PARAPHARYNGEAL SOFT TISSUE SPACE middle ear. Almost all children have at least one episode of otitis
INFECTIONS AND INDICATIONS FOR media in the first 10 years of life, making it the most common
SURGICAL DRAINAGE bacterial infection seen in children. It accounts for one fourth
INFECTION INDICATIONS FOR SURGERY of all office visits and is the second most common reason for
Peritonsillar abscess (quinsy) Abscess or respiratory compromise surgical procedures in children (the most common is circumci-
Lateral pharyngeal space abscess Abscess
Jugular vein septic thrombophlebitis Febrile after 5-6 days of medical
sion). It appears that about one third of children are prone to
therapy infection and have multiple episodes, another third have interme-
Retropharyngeal abscess Abscess or respiratory compromise diate susceptibility, whereas another third will be relatively
Ludwig’s angina Abscess or respiratory compromise
resistant.
 Chapter 91  Infections of the Head and Neck 871
External ear Middle ear
Auricle
External acoustic meatus
Cartilage
Tympanic membrane
FIGURE 91-3  Eustachian tube. (From Drake RL: Gray’s basic anatomy, Philadelphia, 2012, Elsevier, pp 413–592.)
Pathogenesis
While the disease in adults mimics that in children, children are
more susceptible because their Eustachian tubes are shorter and
more horizontal (Fig. 91-3). Disease typically results from Eusta-
chian tube blockage and dysfunction that occurs during viral
infection. Bacteria colonize the middle ear and cannot be elimi-
nated. The most common causative bacteria are S. pneumoniae,
nontypable H. influenzae, and Moraxella catarrhalis.
Clinical Presentation
Acute bacterial otitis media presents with ear pain in over two
thirds of patients. The diagnosis can be difficult in young children
because the history may be absent or inaccurate. Physical diag-
nosis typically shows middle ear effusion and an abnormal tym-
panic membrane that is red and bulging or retracted. Movement
of the membrane is limited on application of positive or negative
pressure. Perforation, drainage, fever and decreased hearing may
occur. Patients may also have vertigo, tinnitus, and nystagmus.
The course of otitis media is usually self-limited with most cases
resolves within one week.
Treatment
Treatment has been controversial because for most patients otitis
media is a self-limited disease. Studies suffer from the difficultly
in making an accurate diagnosis and lack of placebo controls.
Overuse of antibiotics has resulted in the development of resis-
tant organisms in the United States, complicating treatment of
respiratory infections. Antibiotics shorten the course of the
disease and may prevent complications such as mastoiditis, facial
palsy, brain abscess, epidural abscess and cholesteatoma, although
convincing data are lacking because the incidence of these com-
plications has decreased in all patient populations.
Internal ear
Internal acoustic meatus
Pharyngotympanic tube
Pharynx
Guidelines recommend the use of antibiotics in otitis media,
particularly for patients at high risk, for patients in whom there
is complicated disease, or when pain relief is important. The
failure rate with antibiotics is less. The concerns about antibiotic
resistance, however, have made withholding antibiotics and
closely observing the patient a reasonable option. A Cochrane
review of antibiotics for sore throat, acute otitis media, bronchi-
tis, and the common cold concluded that antibiotics could be
delayed if clinicians felt it safe. If symptoms worsen or persist over
48 to 72 hours, then antibiotics should be initiated.
S. pneumoniae, H. influenzae, and M. catarrhalis have each
shown significant resistance to penicillin in resistant years.
Despite these increased rates, amoxicillin or amoxicillin/
clavulinic acid continue to be the drugs of choice. Alternative
choices include cephalosporins or macrolide antibiotics. If there
is no improvement after three days, switching antibiotics should
be considered.
Serous otitis media refers to fluid in the ear in the absence of
signs or symptoms of infection. This is usually self-limited and
resolves in 2 to 4 weeks. Persistent fluid for greater than 3 months
associated with hearing loss, however, is an indication for tube
placement.
SUGGESTED READINGS
Carfrae MJ, Kesser BM: Malignant otitis externa, Otolaryngol Clin North Am
41:537–549, 2008.
Lemiengre MB, van Driel ML, Merenstein D, et al: Antibiotics for clinically
diagnosed acute rhinosinusitis in adults, Cochrane Database Syst Rev
10:CD006089, 2012.
Shulman ST, Bisno AL, Clegg HW, et al: Clinical practice guideline for the
diagnosis and management of group A streptococcal pharyngitis: 2012 update
by the Infectious Diseases Society of America, Clin Infect Dis 55:1279–1282,
2012.
Spurling GK, Del Mar CB, Dooley L, et al: Delayed antibiotics for respiratory
infections, Cochrane Database Syst Rev (4):CD004417, 2013.
 92 
Infections of the Lower
Respiratory Tract
John R. Lonks
  DEFINITION AND EPIDEMIOLOGY
Pneumonia, which is inflammation of the lung parenchyma, is
usually caused by an acute infection. When the disease onset
occurs outside of the hospital, it is referred to as community-
acquired pneumonia. It ranges in severity from a mild, self-limited
disease to one that is fatal. Community-acquired pneumonia is
common, and most patients with pneumonia are treated in the
outpatient setting.
Pneumonia is one of the most common reasons for hospital-
ization among all age groups and accounts for approximately 1
million hospitalizations per year. Each year, approximately 50,000
people in the United States die of influenza and pneumonia.
Influenza or pneumonia is the leading cause of death due to infec-
tion and the ninth most common cause of death overall.
Numerous microorganisms cause pneumonia, including bac-
teria, viruses, mycobacteria, and fungi. These agents range from
microorganisms that are part of the normal flora to exogenous
microorganisms that are inhaled. Noninfectious diseases can
mimic pneumonia. The incidence of pneumonia is lowest during
early adulthood and increases with each decade of life
(Fig. 92-1).
6000
Pneumonia hospitalizations per 100,000
1997–1999 (Pre-PCV7)
2001–2006 (Early PCV7)
5000
2007–2009 (Late PCV7)
4000
3000
2000
1000
0 increases susceptibility to pneumonia. Those infected with
2 2–4 5–17 18–39 40–64 65–74 75–84 
Age group (yr)
FIGURE 92-1  Rate of hospitalization for pneumonia by age group.
PCV7, 7-valent pneumococcal conjugate vaccine. (From Griffin MR, Zhu
Y, Moore MR, et al: U.S. hospitalizations for pneumonia after a decade
of pneumococcal vaccination, N Engl J Med 369:155–163, 2013.)
872
  PATHOLOGY
Bacterial pneumonia usually causes lobar pneumonia, which is
consolidation of an entire lobe or a large portion of a lobe, or
bronchopneumonia, which is patchy consolidation of the lung.
Pneumococcal lobar pneumonia has four stages of the inflamma-
tory response: consolidation, red hepatization, gray hepatization,
and resolution. The initial congestion is characterized by fluid,
with some neutrophils and bacteria, filling the alveoli. Red hepa-
tization is characterized by red blood cells along with numerous
neutrophils and fibrin filling the alveoli. With gray hepatization,
there is breakdown of red blood cells and persistence of fibrin
and neutrophils. The consolidated exudate within the alveolar
spaces then undergoes resolution.
Pathophysiology
The lower respiratory tract is virtually sterile. Normal host
defenses that protect against pneumonia include mucus produc-
tion and cilia; in combination, they form the mucociliary
escalator.
Impairment of host defenses leads to increased risk of pneu-
monia. Loss or suppression of the cough reflex due to stroke and
other neurologic diseases, drugs, and alcohol increases the risk of
developing pneumonia, as do aging and associated medical
illnesses.
Environmental factors such as smoking and respiratory irri-
tants impair ciliary function and increase the risk of developing
pneumonia. Mechanical obstruction of an airway by a tumor or
foreign body leads to decreased clearance of microorganisms and
may produce postobstructive pneumonia. In addition to mechan-
ical clearance, innate host defenses such as phagocytes and anti-
bodies are essential after microorganisms reach the alveoli.
Alveolar macrophages and other components of innate immunity
are the first line of defense. Subsequently, opsonizing antibodies
and neutrophils play an essential role. Impairment of these host
defenses (e.g., alveolar macrophages by silica exposure, neutro-
phils by chemotherapy, antibodies by hypogammaglobulinemia)
85 human immunodeficiency virus (HIV) are at increased risk for
pneumococcal pneumonia.
The two main mechanisms of entry of microorganism into the
lung are microaspiration of organisms that colonize the upper
respiratory tract and inhalation of airborne particles that contain
a pathogenic microorganism. When a sufficient inoculum enters
 Chapter 92  Infections of the Lower Respiratory Tract 873
the lung and normal host defenses are not able to clear the inocu-
lum; bacterial replication leads to a lower respiratory tract
infection.
Transmission of Respiratory Pathogens
Some pathogens are transmitted from person to person by
droplet transmission. Droplets are created when a person coughs,
sneezes, or talks. Transmission can occur during medical proce-
dures such as suctioning, endotracheal intubation, cardiopulmo-
nary resuscitation, or cough-producing procedures. The greatest
distance of transmission is unresolved. Historically, a distance of
3 feet or less was assumed for person-to-person droplet transmis-
sion. Some data suggest that transmission may occur from as far
away as 6 feet. Respiratory droplets have also been defined by
their size, usually greater than 5 µm in diameter.
Crowding, as occurs in prisons, barracks, and shelters, is asso-
ciated with increased spread. Pathogens that are transmitted by
the droplet route include Streptococcus pneumoniae, Mycoplasma
pneumoniae, and influenza virus.
Infectious agents such as Mycobacterium tuberculosis, fungi,
and anthrax spores are airborne. Microorganisms transmitted in
this fashion can be spread over long distances (>6 feet) by air
currents and normal airflow. The size of the droplet nuclei par-
ticles that are transmitted by the airborne route are usually 5 µm
or less in diameter.
Etiologic Agents
Many bacteria and viruses cause pneumonia. S. pneumoniae (i.e.,
pneumococcus) is the most common, and the classic description
of pneumonia is based on disease caused by pneumococci. Most
cases of pneumococcal pneumonia occur between December
and April. Pneumococci transiently colonize the upper respira-
tory tract. Microaspiration leads to entry into the lower respira-
tory tract. If aspirated in sufficient quantity so that normal host
defenses do not clear the bacteria, the patient develops pneumo-
nia. Pneumococci have a polysaccharide capsule that prevents
phagocytosis. Antibodies against the polysaccharide capsule,
which are acquired from prior exposure or vaccination, opsonize
pneumococci, enabling phagocytosis.
Other bacteria that can colonize the oropharynx and cause
pneumonia when aspirated include Haemophilus influenzae, less
commonly Staphylococcus aureus, and rarely Streptococcus pyo-
genes (i.e., group A β-hemolytic streptococcal infection). Simi-
larly, Moraxella catarrhalis in patients with chronic obstructive
pulmonary disease and in the elderly and Klebsiella pneumoniae in
alcoholics colonize the oropharynx and cause pneumonia. Most
cases of community-acquired pneumonia are monomicrobial.
Patients with pneumococcal pneumonia can develop infec-
tions at other sites, including empyema, pericarditis, meningitis,
endocarditis, and septic arthritis. Approximately one of five
patients with pneumococcal pneumonia has bacteremia.
M. pneumoniae usually causes milder disease. Its peak inci-
dence is during the first 2 decades of life. Patients usually do not
require hospitalization, but some develop severe disease.
Chlamydophila pneumoniae (formerly called Chlamydia pneu-
moniae) is a common cause of community-acquired pneumonia.
It usually causes a milder disease and is seen more commonly
among patients treated in the outpatient setting.
Legionella, an environmental organism, can cause pneumonia.
Legionella pneumophila is the most common species of pneumo-
nia, but Legionella micdadei and Legionella bozemanii can also
cause pneumonia. Most cases are sporadic. Outbreaks have
occurred from contaminated point sources such as cooling towers
and air conditioning units. Transmission usually occurs through
inhalation of aerosol particles; microaspiration of water contain-
ing Legionella has also occurred.
Infrequently, S. aureus causes bacterial pneumonia, sometimes
as a complication of influenza infection. Community-acquired
methicillin-resistant strains (MRSA) have caused secondary bac-
terial pneumonias.
Viruses, particularly influenza viruses, cause a minority of
pneumonias in adults. Patients with influenza are at risk for sec-
ondary bacterial pneumonia, most commonly due to S. pneu-
moniae, H. influenzae, or S. aureus. Respiratory syncytial virus
(RSV), a pathogen that usually infects children, has been found
more frequently as a cause of pneumonia among the elderly.
Adenovirus rarely causes pneumonia in young adults. During
2003, the severe acute respiratory syndrome (SARS) virus
emerged in Guangdong Province in southern China, and after
initial international spread, it was contained. In 2012, the Middle
East respiratory syndrome coronavirus (MERS-CoV) emerged
as a cause of severe pneumonia. Most cases occurred in the
Middle East.
Viruses such as the influenza viruses predispose patients to
secondary bacterial pneumonia. Influenza infection may damage
the respiratory epithelium, and resulting dysfunctional innate
immune responses enhance susceptibility to secondary bacterial
infection.
Fungi that cause pneumonia are not part of the normal flora.
Certain dimorphic fungi (e.g., Histoplasma capsulatum, Blastomy-
ces dermatitidis, and Coccidioides immitis) that reside in the soil
cause pneumonia when they are inhaled. Dimorphic fungi form
hyphae at ambient temperatures and yeasts at body temperature.
The hyphal form is the transmissible form of the fungus. The
yeast form is not transmissible from person to person.
These fungi are limited to certain geographic areas: H. capsu-
latum in the Mississippi, Missouri, and Ohio River valleys; B.
dermatitidis in Southern states bordering the Mississippi and
Ohio River basins and Midwestern states bordering the great
lakes; and C. immitis in the Southwestern United States. H. cap-
sulatum, B. dermatitidis, and C. immitis cause disease in the normal
host. Aspergillus, a mold, is ubiquitous in the environment; it
rarely causes disease in the immunocompetent host. Patients
who are immunocompromised or have abnormal airways are at
risk for infection with Aspergillus but rarely with other molds
such as Zygomycetes species (Mucorales order), which do have a
predisposition for infecting patients with diabetes mellitus.
M. tuberculosis is not part of the normal flora. It is transmitted
by small aerosol particles (<5 µm) that are inhaled directly into
the alveolus. M. tuberculosis is a slow-growing organism that
usually causes chronic symptoms; however, it rarely can manifest
acutely. Patients with HIV infection, those treated with biologic
agents such as tumor necrosis factor (TNF) inhibitors, and the
very young and old are particularly susceptible.
The normal flora of an acutely ill hospitalized patient is differ-
ent from that of a healthy outpatient. Hospitalized patients are
874 Section XV  Infectious Disease

more frequently colonized with S. aureus, including methicillin-
resistant strains, and gram-negative bacilli, including Pseudomo-
nas aeruginosa. When a hospitalized patient aspirates his or her
oropharyngeal flora, it may contain one of these organisms.
Microorganisms that almost never cause pneumonia include
Candida species and enterococci.
For a deeper discussion of these topics, please see Chapter
9, “Overview of Pneumonia,” in Goldman-Cecil Medicine,
25th Edition.
  CLINICAL PRESENTATION
Patients with pneumonia usually have an acute onset of fever,
chills, cough, sputum production, dyspnea, and sometimes pleu-
ritic chest pain. Patients may produce blood-tinged sputum that
appears rust colored, a classic sign of pneumonia due to S. pneu-
moniae. Extrapulmonary signs and symptoms may include
nausea, vomiting, diarrhea, abdominal pain, headache, confu-
sion, arthralgia, myalgias, and change in mental status. Signs and
symptoms can be blunted or absent in the elderly. Rales or
rhonchi may be heard on auscultation of the chest. A leukocyto-
sis with a left shift (i.e., increased band forms), pulmonary signs
and symptoms, and a new infiltrate seen on the chest radiograph
are used to diagnose pneumonia.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
When pneumonia is suspected, the next step is to determine the
etiologic diagnosis. Unfortunately, there is no single diagnostic
test with a high sensitivity and high specificity. The sputum Gram
stain provides useful diagnostic information. Although epithelial
cells from the upper respiratory tract and oropharyngeal flora
may contaminate an expectorated sputum sample, careful exami-
nation of the sputum Gram stain can reveal an area of the speci-
men that originated from the lower respiratory tract and contains
neutrophils, and examination for bacteria in that area can be
helpful. However, some patients do not produce sputum, and
prior antibiotic use can alter sputum results.
S. pneumoniae is a gram-positive coccus that forms pairs
and chains; the cocci are sometimes pointed at one end (i.e.,
lancet shaped). H. influenzae is a pleomorphic gram-negative
rod. S. aureus is a gram-positive coccus that forms “grape-like”
clusters. M. catarrhalis is gram-negative diplococcus. These
distinct morphologic features allow a presumptive diagnosis
of a specific etiologic agent when seen on a Gram stain of
sputum (Fig. 92-2).
Mycoplasma, Legionella, Mycobacterium, and Chlamydophila
species are not seen on the sputum Gram stain. Mycobacteria are
seen with special acid-fast staining.
Culture of sputum can reveal the etiologic diagnosis, and
results should be correlated with findings from the sputum Gram
stain. However, pneumococci are fastidious. A study of patients
with bacteremic pneumococcal pneumonia found that only 55%
of sputum cultures grew pneumococci. Mycoplasma species,
Legionella species, Mycobacterium species, and C. pneumoniae do
not grow on routine agar. Special culture media are required
for certain bacteria, such as Löwenstein-Jensen medium for

A B

C D
FIGURE 92-2  Sputum Gram stain. A, Streptococcus pneumoniae. B, Haemophilus influenzae. C, Moraxella catarrhalis. D, Staphylococcus aureus. PCV7,
7-Valent pneumococcal conjugate vaccine. (A, From Murray PR: Medical microbiology, ed 7, Philadelphia, 2013, Elsevier; B, From de la Maza LM,
Pezzlo MT, Shigei JT, Peterson EM: Color atlas of medical bacteriology, Washington, D.C. 2004, ASM Press; C, From Ferri F: Ferri’s color atlas and text
of clinical medicine, Philadelphia, 2009, Elsevier; D, From Donowitz GR: Acute pneumonia. In Mandell GL, Bennett JE, Dolin R, editors: Mandell,
Douglas, and Bennett’s principles and practice of infectious diseases, ed 8, Philadelphia, 2015, Churchill Livingstone.)
 Chapter 92  Infections of the Lower Respiratory Tract 875

Mycobacteria and buffered charcoal yeast extract (BCYE) for
Legionella.
Blood cultures can be helpful. However, the ratio of bactere-
mic to nonbacteremic pneumococcal pneumonia is approxi-
mately 1 : 4. A positive blood culture is very helpful because the
etiologic agent is definitely identified and susceptibility data are
available to determine appropriate therapy.
Other diagnostic studies used to identify the causative organ-
ism include Legionella urinary antigen, Histoplasma urinary
antigen, polymerase chain reaction (PCR) for respiratory viruses,
and serologic testing for Mycoplasma and C. immitis.
Chest radiography of patients with pneumococcal pneumonia
can show a consolidative lobar infiltrate or a bronchopneumonic
(patchy) pattern; less commonly, it causes an interstitial pattern.
A definitive etiologic diagnosis cannot be made based on the
chest radiographic appearance.
Not all patients with a new pulmonary infiltrate have pneumo-
nia. Congestive heart failure is commonly confused with pneu-
monia. Noninfectious causes of pulmonary infiltrates and fever
include pulmonary infarction, granulomatosis with polyangiitis
(i.e., Wegener’s granulomatosis), drug reactions, tumor, crypto-
genic organizing pneumonia, hypersensitivity pneumonitis, col-
lagen vascular disease, and acute respiratory distress syndrome
(ARDS).
  TREATMENT
The definitive treatment for pneumonia is to eradicate the infect-
ing microorganism. Antibiotics are used to kill bacteria and
decrease or stop the spread of infection in the lungs. Normal host
responses are needed to repair the inflammatory damage in the
lungs.
Penicillin therapy has reduced the mortality rate of bacteremic
pneumococcal pneumonia from 84% to 17%. However, antibiot-
ics have little to no effect on the mortality rate during the first 5
days of illness.
After the etiologic agent has been identified, the appropriate
antibiotic can be given (Table 92-1). If a specific etiologic diag-
nosis is not made, empirical treatment with one of many antimi-
crobial agents is recommended. Guidelines are available at
http://www.idsociety.org/IDSA_Practice_Guidelines (accessed
November 1, 2014).
The decision to admit a patient with pneumonia is based on
clinical prediction rules. The pneumonia severity index (PSI)
stratifies patients into one of five risk groups. Those in a low-risk
group are treated as outpatients, whereas those in a higher-risk
group are admitted to the hospital for treatment. The CURB-65
score (confusion, urea, respiratory rate, blood pressure, and age
≥65 years) developed by Lim and colleagues is easier to calculate
but has not been as rigorously validated as the PSI. Psychosocial
and other factors that affect the decision to admit a patient are
not included in the PSI or CURB-65.
For a deeper discussion of these topics, please see Chapter
9, “Overview of Pneumonia,” in Goldman-Cecil Medicine,
25th Edition.
  PROGNOSIS AND PREVENTION
Patients with bacteremic pneumococcal pneumonia have a
higher mortality rate (21%) compared with those who have non-
bacteremic pneumococcal pneumonia (13%). Among patients
with bacteremic pneumococcal pneumonia, the mortality rate
increases with advancing age (Fig. 92-3), number of lobes
involved (i.e., one lobe, 12%; two lobes, 24%; and three lobes,
63%), and white blood cell (WBC) count (i.e., leukopenia, 35%;
normal peripheral WBC count, 24%; and leukocytosis, 14%).
Mortality rates are different for each capsular type of pneumo-
coccus. For example the mortality rate for patients infected with
capsular type I is 3%, compared with 22% for patients infected
with capsular type III. Patients who survive usually recover
without sequelae.
The influenza vaccine protects against not only influenza but
also bacterial pneumonia, because patients who do not have
influenza are not at risk for secondary bacterial pneumonia. The
13-valent pneumococcal conjugate vaccine followed 6 to 12
months later by the 23-valent pneumococcal polysaccharide
vaccine is recommended for those 65 years of age and older
who have not been previously vaccinated. Adults less than
65 years with certain immunocompromising conditions or

TABLE 92-1  TREATMENT OF PNEUMONIA BY 90

SPECIFIC ETIOLOGIC AGENT
80
PREFERRED ALTERNATIVE
70
ETIOLOGIC AGENT ANTIMICROBIAL ANTIMICROBIAL
60
Mortality (%)

Streptococcus Penicillin Cephalosporin,

pneumoniae moxifloxacin, 50
levofloxacin 40
Haemophilus influenzae Cefuroxime, ceftriaxone 30
Mycoplasma Macrolide Moxifloxacin,
pneumoniae levofloxacin 20
Legionella species Macrolide or quinolone 10
Methicillin-susceptible Nafcillin Cephalosporin
0
Staphylococcus aureus
19

29

39

49

59

69

79

89

Methicillin-resistant Vancomycin (intravenous) Sulfamethoxazole-

90
–

–
12

20

30

40

50

60

70

80

Staphylococcus aureus trimethoprim

(oral) or Age (years)
doxycycline
Moraxella catarrhalis Amoxicillin/clavulanate, FIGURE 92-3  Mortality rates for bacteremic pneumococcal pneu-
cefuroxime, ceftriaxone, monia by age group. (Data from Austrian R, Gold J: Pneumococcal
sulfamethoxazole- bacteremia with especial reference to bacteremic pneumococcal pneu-
trimethoprim monia, Ann Intern Med 60:759–776, 1964.)
 876 Section XV  Infectious Disease

Vaccine introduced (Fig. 92-4). Use of the pediatric conjugate vaccine has reduced
18
2–4 yr old the number of adult hospital admissions for pneumonia (see Fig.
16 92-1). It also has decreased antibiotic resistance because the cap-
Incidence (cases per 100,000)

5–19 yr old
14 20–39 yr old sular types of pneumococci that are more likely to be antibiotic
40–64 yr old
12 65 yr old resistant are included in the vaccine.
10
8 SUGGESTED READINGS
6 Austrian R, Gold J: Pneumococcal bacteremia with especial reference to
4 bacteremic pneumococcal pneumonia, Ann Intern Med 60:759–776, 1964.
Fine M, Auble T, Yealy D: A prediction rule to identify low-risk patients with
2
community acquired pneumonia, N Engl J Med 336:243–250, 1997.
0 Griffin M, Zhu Y, Moore M: U.S. hospitalizations for pneumonia after a decade
1996 1997 1998 1999 2000 2001 2002 2003 2004 of pneumococcal vaccination, N Engl J Med 369:155–163, 2013.
FIGURE 92-4  Incidence of penicillin-resistant pneumococcal infec- Kyaw M, Lynfield R, Schaffner W, et  al: Effect of introduction of the
tion from before and after the introduction of the pneumococcal con- pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumonia,
jugate vaccine for different age groups. (From Kyaw MH, Lynfield R, N Engl J Med 354:1455–63, 2006.
Schaffner W, Schaffner W, et al: Effect of introduction of the pneumo- Lim WS, Van der Eerden MM, Laing R: Defining community acquired pneumonia
coccal conjugate vaccine on drug-resistant Streptococcus pneumoniae, severity on presentation to hospital: an international derivation and validation
N Engl J Med 354:1455–1463, 2006.) study, Thorax 58:377–382, 2003.
Mandell L, Wunderink R, Anzueto A: Infectious Diseases Society of America/
American Thoracic Society consensus guidelines on the management of
specific underling medical conditions that put them at a higher community-acquired pneumonia in adults, Clin Infect Dis 44:S27–S72, 2007.
Tomczyk S, Bennett NM, Stoecker C, et al: Use of 13-valent pneumococcal
risk of pneumococcal infections should also be vaccinated. The
conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among
conjugate pneumococcal vaccine has reduced invasive pneumo- adults aged ≥65 years: recommendations of the Advisory Committee on
coccal disease in children, and decreased carriage in children Immunization Practices (ACIP), MMWR Morb Mortal Wkly Rep 63(37):
has reduced transmission and subsequent disease in adults 822–825, 2014.

Infections of the Heart and
Blood Vessels
Cheston B. Cunha and Eleftherios Mylonakis
  INFECTIVE ENDOCARDITIS
Definition
Infective endocarditis (IE) is an infection of the endocardium of
one or more cardiac valves or, less commonly, the mural endo-
cardium. The pathologic lesion of IE is the vegetation (infected
platelet and fibrin thrombus). The pathologic findings of IE were
first described in 1646 by Lazare Rivière, a French physician at
the University of Montpellier. At autopsy, Rivière described
“small round outgrowths resembling the lungs in texture, the
largest of which was about the size of a hazelnut, which blocked
the aortic valve.” The term endocarditis was first used in 1835 by
the French physician Jean-Baptiste Bouillaud, but it was not
until the 1880s that Sir William Osler was able to synthesize
many of the prior clinical, pathologic, and microbiologic findings
into a unified description of the disease.
Over the past 6 decades, the epidemiology, risk factors, and
treatment of endocarditis have changed significantly. In the pre-
antibiotic era, IE was uniformly fatal. Since the advent of antibi-
otics and valve replacement surgery, IE can be effectively treated
and mortality can be significantly reduced, provided the diagno-
sis is made early. Despite progress, new challenges continue to
arise in diagnosis and treatment. As more patients undergo intra-
vascular manipulation, have intracardiac or intravascular devices
placed, and harbor more resistant organisms, effective therapy for
IE remains a challenge.
Traditionally, IE has been classified, based on the acuteness
of onset, as subacute bacterial endocarditis (SBE) or acute bac-
terial endocarditis (ABE). This classification reflects the viru-
lence of the causative agent: Staphylococcus aureus is a common
cause of ABE, whereas low-virulence organisms such as viridans
streptococci are more likely to be the cause of SBE. IE may
also be subdivided according to the nature of the involved valve,
as native valve endocarditis (NVE) or prosthetic valve endo-
carditis (PVE), or by the number of valves involved (multival-
vular IE). Some hosts, particularly intravenous drug abusers,
are predisposed to IE. IE from invasive procedures is classified
as health care–associated IE or nosocomial IE. Endocarditis may
be further divided according to the causative organism. These
categories are often combined (e.g., S. aureus tricuspid valve
nosocomial ABE).
Epidemiology
SBE is most common in older adults, and over the last 50 years,
the average age of patients diagnosed with IE has gradually
93 
increased. More than one half of all cases of IE occur in patients
older than 50 years of age. Rheumatic heart disease has decreased
in the modern era and is now a less common predisposing factor.
Recent estimates are that the overall annual incidence of IE in
the United States is 12.7 cases per 100,000 persons, a significant
increase from prior years. The age-adjusted hospital admission
rate has increased by 2.4% annually, mirroring this increase in
incidence. SBE usually involves the mitral valve or, less com-
monly, the aortic valve. IE of the pulmonic valve is relatively rare,
and right-sided ABE occurs primarily in intravenous drug
abusers. Individuals with congenital heart disease may be predis-
posed to IE, depending on the lesion.
Pathogenesis
Normal cardiac endothelium is relatively resistant to bacterial
invasion. If the cardiac endothelium is damaged, an uninfected
platelet and fibrin thrombus may form. This nonbacterial throm-
botic endocarditis may become infected due to bacteremia,
forming a vegetation. Endothelial damage may result from degen-
erative valvular disease, rheumatic heart disease, congenital heart
disease, or intracardiac instrumentation or devices.
Predisposing Cardiac Factors
Approximately 15% of patients diagnosed with NVE have under-
lying congenital heart disease. Of these diseases, tetralogy of
Fallot has the highest IE potential. Other lesions that predispose
to IE include ventricular septal defect, bicuspid valves, and coarc-
tation of the aorta. Significant mitral valve regurgitation is the
most important predisposing factor for IE, with mitral valve pro-
lapse accounting for 20% of NVE cases. Degenerative valvular
disease predisposes to SBE in the elderly, and the mitral valve is
most frequently involved. Aortic valve IE is rare in hypertrophic
cardiomyopathy or asymmetric septal hypertrophy.
Noncardiac Predisposing Factors
Central venous catheters and intracardiac devices can cause
endocardial injury, predisposing to IE. The most frequent noso-
comial IE pathogens are S. aureus, coagulase-negative staphylo-
cocci, group D enterococci, and aerobic gram-negative bacilli.
Infections with these organisms usually occur less than 1 month
after the procedure. Nosocomial IE may affect normal or abnor-
mal valves. Because ABE pathogens are more virulent, nosoco-
mial IE is associated with a high mortality rate.
Low-virulence and noninvasive organisms (e.g., viridans
streptococci) are the most common SBE pathogens. The SBE
877
878 Section XV  Infectious Disease

potential of viridans streptococci is directly related to the thick-

ness of the capsule, which permits adherence to damaged cardiac TABLE 93-1  CLINICAL FINDINGS FOR SUBACUTE
valves. Viridans streptococci are normal inhabitants of the mouth BACTERIAL ENDOCARDITIS (SBE) AND
and gastrointestinal tract. Invasive dental procedures frequently ACUTE BACTERIAL ENDOCARDITIS (ABE)
cause transient bacteremias that may result in SBE on damaged SYMPTOMS AND
FINDINGS* ABE SBE
but not normal cardiac valves. Transient bacteremias of viridans
Anorexia − +
streptococci may form a vegetation in the sterile platelet and Weight loss − ±
fibrin thrombus covering an area of damaged endothelium. The Myalgias or arthralgias + ±
gastrointestinal or genitourinary tract is the usual source of Fatigue − +
Dyspnea + −
bacteremia in cases of native valve SBE due to group D Pleuritic chest pain† + −
enterococci. Low back pain + +
Headache + ±
Mental status changes + ±
Diagnosis Acute confusion + −
Cerebrovascular − +
Clinical Features accident
Sudden unilateral − +
The cardinal clinical features of IE are fever (90% of cases) blindness
and heart murmur (85%). In the antibiotic era, fever may Left upper quadrant Splenic abscess Splenic infarct
not be present if the patient has been taking antibiotics for pain
Fever >102° F‡ <102° F
another reason. SBE often manifests with sweats, malaise, and New or changing heart ± −
anorexia. The course of SBE tends to be more indolent and murmur
may be accompanied by back pain, joint pains (>50% of Splenomegaly − +
Petechiae + +
patients), or embolic stroke. As SBE progresses, circulating Osler’s nodes − +
immune complexes may deposit in the kidney, causing inter- Janeway’s lesions + −
stitial nephritis, glomerulonephritis, and even renal failure. Splinter hemorrhages ± +
Roth’s spots − +
Osler’s nodes (painful, subcutaneous nodules on the distal
Congestive heart failure + −
pads of the fingers or toes), Janeway’s lesions (hemorrhagic, (LVF)
nonpainful macules on the palms and soles) and Roth’s spots Modified from Cunha BA, Gill MV, Lazar JM: Acute infective endocarditis: diagnostic and
(retinal hemorrhages with small central clearing) are classic therapeutic approach, Infect Dis Clin North Am 10:811–834, 1996.
LVF, Left ventricular fibrillation; +, present; −, absent; ±, present or absent.
findings related to microemboli and SBE immune-mediated *Otherwise unexplained.
vasculitis. †
With septic pulmonary emboli from tricuspid valve ABE.
‡
Fever may be <102° F in intravenous drug abusers with ABE.
Patients with ABE tend to have a more fulminant course
because of the greater virulence of the pathogen. The fever of
ABE is usually high (>102° F) and is often accompanied by Early PVE pathogens such as S. aureus and Pseudomonas aeru-
rigors. If there is mechanical dysfunction of the valve, symptoms ginosa are typically highly virulent and invasive. Late PVE more
of congestive heart failure will predominate. Often, a presenting closely resembles SBE, is caused by less virulent pathogens, and
feature of right-sided ABE is septic pulmonary emboli with pleu- has a more indolent course. The most common etiologic agents
ritic chest pain. The clinical findings of SBE and ABE are pre- are coagulase-negative staphylococci, but viridans streptococci
sented in Table 93-1. also cause late PVE. Nosocomial IE results from invasive intra-
Clinically, PVE may be considered as early (<2 months after vascular or intracardiac procedures that damage the endothelium
implantation of the valve) or late (>2 months). Early PVE is or the valves; it can also be caused by direct extension of infec-
caused by virulent pathogens (e.g., S. aureus) that infect the pros- tion, such as from ABE associated with a pacemaker wire. The
thetic valve before endothelialization is complete. Endothelial- organisms causing nosocomial IE originate from the skin (e.g.,
ization of a mechanical valve is partially protective against S. aureus, coagulase-negative staphylococci), from gastrointesti-
transient bacteremias in late PVE. Over time, bioprosthetic valves nal or genitourinary procedures (e.g., group D enterococci), or
have the same IE potential as mechanical ones. from central venous catheters, ports, or hemodialysis catheters
An otherwise unexplained high-grade or continuous bactere- (e.g., Candida spp, aerobic gram-negative bacilli). IE related to
mia and murmur should suggest IE. An acute versus subacute total parenteral nutrition (TPN) is most often caused by Candida
presentation correlates with the virulence of the IE pathogen. If spp; other TPN-associated fungemias cause IE less frequently. In
blood cultures are negative, a diagnosis of infectious culture- intravenous drug abusers, tricuspid valve ABE is usually caused
negative endocarditis (CNE) should be considered if a murmur, by S. aureus or P. aeruginosa (depending on the geography and
vegetation, and peripheral manifestations of IE are present. The drug-related materials).
clinical diagnosis of IE relies on a combination of clinical, labora- Infectious CNE is caused by organisms that are difficult to
tory, and echocardiographic findings. Epidemiologic clues to the culture, such as Legionella spp, Brucella spp, Tropheryma whipplei,
potential IE pathogens are outlined in Table 93-2. The most and Coxiella burnetii (which produces Q fever). Legionnaires’
important finding in IE is the demonstration of continuous bac- disease may cause NVE or PVE. CNE due to Brucella spp can be
teremia, usually by multiple positive blood cultures. Table 93-3 a difficult diagnosis, but an antecedent history of contact with
contains the modified Duke criteria that are frequently used to livestock or consumption of unpasteurized dairy products should
predict the likelihood that a patient has IE. suggest the diagnosis, and echocardiography often reveals large
 Chapter 93  Infections of the Heart and Blood Vessels 879

TABLE 93-2  CLUES TO THE LIKELY PATHOGEN IN TABLE 93-3  MODIFIED DUKE CRITERIA FOR
INFECTIVE ENDOCARDITIS DIAGNOSIS OF INFECTIVE
EPIDEMIOLOGIC ENDOCARDITIS
FEATURES PATHOGENS DIAGNOSTIC CRITERIA
Intravenous drug abuse Staphylococcus aureus Definite IE (any of the following):
Pseudomonas aeruginosa Positive findings for IE in the pathology or microbiology of the vegetation
β-Hemolytic streptococci Two major criteria
Aerobic GNB One major and three minor criteria
Polymicrobial Five minor criteria
Fungi Possible IE (any of the following):
Indwelling S. aureus One major and one minor criteria
cardiovascular device CoNS Three minor criteria
Aerobic GNB Not IE (any of the following):
Corynebacterium spp Definite alternative diagnosis or resolution with <4 days of antibiotic
Genitourinary Enterococcus spp therapy
disorders, infection, Group B streptococci (Streptococcus agalacti, Does not meet the criteria of possible IE
manipulation Listeria monocytogenes)
Aerobic GNB MAJOR CRITERIA
Chronic skin disorders S. aureus Positive blood cultures for IE (any of the following):
β-Hemolytic streptococci Typical microorganism for IE from two separate blood cultures:
Poor dentition, dental Viridans streptococci • Viridans streptococci, Streptococcus gallolyticus (formerly Streptococcus
procedures Nutritionally variant streptococci (Abiotrophia bovis biotype I), or the nutritional variant strains (Granulicatella spp
spp, Granulicatella spp) and Abiotrophia defectiva)
Gemella spp • HACEK group: Haemophilus spp, Aggregatibacter
HACEK organisms† actinomycetemcomitans), Cardiobacterium hominis, Eikenella corrodens,
Alcoholic cirrhosis Streptococcus pneumoniae and Kingella kingae
Bartonella spp • Staphylococcus aureus
L. monocytogenes Community-acquired enterococci, in the absence of a primary focus
β-Hemolytic streptococci Persistently positive blood culture, defined as recovery of a microorganism
Burns S. aureus consistent with IE from any of the following:
Aerobic GNB Blood cultures drawn more than 12 hr apart
P. aeruginosa All of three or a majority of four or more separate blood cultures, with first
Fungi and last drawn at least 1 hr apart
Diabetes mellitus S. aureus *Single positive blood culture for Coxiella burnetii or antiphase I IgG
β-Hemolytic streptococci antibody titer >1 : 800
S. pneumoniae Evidence of endocardial involvement
Early PVE S. aureus Positive echocardiogram for IE:
Aerobic GNB *TEE is recommended in patients with prosthetic valves rated at least
Fungi “possible IE” by clinical criteria, or with complicated IE (paravalvular
Corynebacterium spp abscess); TTE as first test in other patients
Late PVE CoNS Definition of positive echocardiogram (any of the following):
S. aureus • Oscillating intracardiac mass, on valve or supporting structures, or in
Viridans streptococci the path of regurgitant jets, or on implanted material, in the absence
Enterococcus spp of an alternative anatomic explanation
Corynebacterium spp • Abscess
Legionella spp • New partial dehiscence of prosthetic valve
Dog or cat exposure Bartonella spp New valvular regurgitation (increase in or change in preexisting murmur is
Pasteurella spp not sufficient)
Capnocytophaga spp
MINOR CRITERIA (*Echocardiographic minor
Contact with Brucella spp
criteria have been eliminated)
contaminated milk or Coxiella burnetii (Q fever)
infected farm animals Erysipelothrix rhusiopathiae Predisposition: predisposing heart condition or intravenous drug use
Homelessness Bartonella spp. Fever: 38.0° C (100.4° F)
Human S. pneumoniae Vascular phenomena: major arterial emboli, septic pulmonary infarcts,
immunodeficiency Salmonella spp mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages,
virus infection S. aureus Janeway’s lesions
Pneumonia and S. pneumoniae Immunologic phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots,
meningitis* rheumatoid factor
Solid organ transplants S. aureus Microbiologic evidence: positive blood culture but not meeting major
Aspergillus fumigatus criterion (excluding single positive cultures for coagulase-negative
Enterococcus spp staphylococci and organisms that do not cause endocarditis) or serologic
Candida spp evidence of active infection with organism consistent with IE
Gastrointestinal lesions Streptococcus bovis
Modified from Li JS, Sexton DJ, Mick N, et al: Proposed modifications to the Duke criteria
Enterococcus spp for the diagnosis of infective endocarditis, Clin Infect Dis 30:633–638, 2000.
Modified from Baddour LM, Wilson WR, Bayer AS, et al: Infective endocarditis: diagnosis, IE, Infective endocarditis; IgG, immunoglobulin G; TEE, transesophageal
antimicrobial therapy, and management of complications: a statement for healthcare echocardiography; TTE, transthoracic echocardiography.
professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki *Represents a change from the previously published Duke criteria.
Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical
Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart
Association; endorsed by the Infectious Diseases Society of America, Circulation
111:e394–e433, 2005.
CoNS, Coagulase-negative staphylococci; GNB, gram-negative bacilli; PVE, prosthetic
valve endocarditis.
*With alcoholic cirrhosis.
†
HACEK organisms: Haemophilus spp, Aggregatibacter actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
880 Section XV  Infectious Disease
TABLE 93-4  NONPECIFIC LABORATORY TESTS FOR
INFECTIVE ENDOCARDITIS
LABORATORY FINDINGS PERCENTAGE
Anemia 70-90
Leukocytosis 20-30
Elevated ESR 90-100
C-reactive protein (CRP) 100
Histiocytes in blood smear 25
Positive rheumatoid factor (RF) 50
Circulating immune complexes 65-100
Microscopic hematuria 30-50
Data from Brusch JL: Clinical manifestations of endocarditis. In Brusch JL, editor:
Infective endocarditis, New York, 2007, Informa Healthcare, pp 143–166.
ESR, Erythrocyte sedimentation rate.
vegetations. A difficult infectious CNE diagnosis is Q fever. Q
fever SBE may be suggested by a history of animal contact. Clini-
cal findings of Q fever are often present, but the diagnosis can be
missed because Q fever vegetations are not easily visualized.
Laboratory Findings
With IE, many nonspecific laboratory abnormalities may occur
(Table 93-4); when placed in the appropriate context, these can
be a significant aid to diagnosis.
Echocardiography is an important element in diagnosis and
management; it should be performed for all patients with sus-
pected IE. In those with a low likelihood of having IE or small
body habitus, a transthoracic echocardiogram (TTE) may be suf-
ficient. Although TTE is often sufficient to screen for NVE, the
“gold standard” remains transesophageal echocardiogram (TEE),
which is more sensitive at detecting smaller vegetations, paraval-
vular abscess, and PVE. If the TTE or TEE demonstrates a vegeta-
tion but blood cultures remain negative, the diagnosis of
infectious CNE should be considered. A tiered diagnostic
approach to such cases is presented in Table 93-5.
Diagnosis of Legionella-related IE is based on an antecedent
pneumonia and elevated titers of urinary antigen. Brucella-related
IE is confirmed by titers or by polymerase chain reaction or both.
A clue to Q fever CNE is enhanced valve uptake on positron-
emission tomography (PET) or computed tomography (CT),
and such a result should prompt testing for Q fever. With the
advent of sophisticated microbiologic testing, HACEK organ-
isms (Haemophilus spp, Aggregatibacter actinomycetemcomitans
[formerly called Actinobacillus actinomycetcomitans], Cardiobacte-
rium hominis, Eikenella corrodens, and Kingella kingae) grow rela-
tively rapidly and no longer manifest as CNE.
Radiologic testing in IE is primarily focused on identifying
complications of IE. Although echocardiography is still the pre-
ferred method for detecting vegetations, improvements in mul-
tislice CT scans have allowed chest CT to detect vegetations and
valvular abnormalities in addition to the septic emboli seen in
right-sided IE. Magnetic resonance imaging (MRI) of the spine
is useful in patients with IE who report back pain; it is the pre-
ferred method to detect the presence of vertebral osteomyelitis
caused by IE. Mental status changes should prompt CT or MRI
imaging of the head to assess for septic emboli to the brain.
Although it is less invasive than TEE, cardiac MRI often lacks the
special resolution to detect smaller vegetations; however, it may
TABLE 93-5  DIAGNOSTIC APPROACH TO CULTURE-
NEGATIVE ENDOCARDITIS
VALVULAR BIOPSY UNAVAILABLE
1. Q fever and Bartonella serology: If negative, then use lysis-centrifugation
system for blood cultures and inform microbiology laboratory of
concern for fastidious organisms to allow use of special media and
culture techniques: thioglycolate-, pyridoxal hydrochloride–, or
l-cystine–enriched media for Abiotrophia; buffered charcoal yeast extract
(BCYE) agar for Legionella; prolonged incubation for HACEK
organisms*
2. Rheumatoid factor (RF), antinuclear antibodies (ANA)
3. PCR for Bartonella spp and Tropheryma whipplei
4. Nested PCR for fungi, tissue for Cryptococcus neoformans capsular
antigen and urine for Histoplasma capsulatum antigen: If negative, then
obtain serum serology studies for Mycoplasma pneumoniae, Legionella
pneumophila, Brucella melitensis, and Bartonella spp by Western blot
VALVULAR BIOPSY AVAILABLE
1. Broad-range PCR for bacteria (16S rRNA) and fungi (18S rRNA)
2. Histologic examination with direct staining for Chlamydia spp, Coxiella
burnetii, Legionella spp, fungi, and T. whipplei
3. Primer extension enrichment reaction (PEER) or
autoimmunohistochemistry (AIHC)
Modified from Fournier PE, Thuny F, Richet H, et al: Comprehensive diagnostic strategy
for blood culture-negative endocarditis: a prospective study of 819 new cases, Clin Infect
Dis 51:131–140, 2010; and Mylonakis E, Calderwood SB: Infective endocarditis in adults,
N Engl J Med 345:1320, 2001.
PCR, Polymerase chain reaction; rRNA, ribosomal RNA.
*HACEK organisms: Haemophilus spp, Aggregatibacter actinomycetemcomitans,
Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
be helpful in identifying aortic root pseudoaneurysms, sinus of
Valsalva aneurysms, and embolic vascular lesions.
Differential Diagnosis and Mimics
The diagnosis of SBE is based an otherwise unexplained high-
grade or continuous bacteremia caused by a known endocarditis
pathogen plus a cardiac vegetation. Depending on the duration
before presentation (usually 1 to 3 months), IE may be accom-
panied by peripheral manifestations such as Osler’s nodes, Jane-
way’s lesions, splinter hemorrhages, or conjunctival hemorrhages.
Splenomegaly or embolic phenomena may also accompany SBE.
However, peripheral manifestations that are seen in SBE may also
be present in other disorders. Before ascribing peripheral mani-
festations to SBE, physicians need to rule out other systemic
disorders and confirm the diagnosis of SBE.
Clinically, the disorders most likely to mimic SBE are Libman-
Sacks endocarditis (associated with systemic lupus erythemato-
sus [SLE]), marantic endocarditis (caused by a malignancy,
usually lymphoma, lung cancer, or pancreatic cancer), and atrial
myxoma. Myocarditis of any etiology may mimic SBE with fever,
murmur, and peripheral embolic phenomena. Cardiomegaly,
which is usually present with myocarditis, is typically absent with
SBE. Leukopenia and thrombocytopenia may be clues to viral
myocarditis, and either finding argues against a diagnosis of SBE.
Cardiac echocardiography shows myocarditis but no vegetations,
and bacteremia is not present.
SLE, particularly between flares, may mimic SBE with low-
grade fevers, murmur, peripheral manifestations, and splenomeg-
aly. Laboratory findings in SLE include the anemia of chronic
disease and a mildly to moderately elevated erythrocyte sedi-
mentation rate (ESR). Even if Libman-Sacks vegetations are
present, SBE is rare in SLE. A lupus flare may resemble ABE with
high fevers (>102° F), tender fingertips (mimicking Osler’s
 Chapter 93  Infections of the Heart and Blood Vessels 881
nodes), and funduscopic findings of cotton-wool spots or Roth’s
spots. Conjunctival and splinter hemorrhages are rare in SLE but
common in SBE. Microscopic hematuria is the usual renal mani-
festation of SBE (i.e., focal glomerulonephritis), but full-blown
nephritis with proteinuria and hematuria are typical of SLE renal
involvement. Although clinical findings of SLE and SBE may
overlap, SBE is ruled out by the absence of high-grade or continu-
ous bacteremia.
Atrial myxomas may mimic SBE with fever, murmurs, and
embolic phenomena (e.g., splinter hemorrhages). Highly elevated
ESR levels are common with atrial myxomas, but biologically
false-positive results on Venereal Disease Research Laboratory
(VDRL) testing, elevated rheumatoid factors, and renal involve-
ment are not seen. On TTE or TEE, atrial myxomas appear as
masses or vegetations on the atrial surface rather than on a
valve as in IE. SBE is ruled out by the absence of bacteremia.
Besides clinical mimics of SBE, there are also echocardio-
graphic mimics, including papillary fibromas, thrombi, calcified
valves, myxomatous degeneration, and marantic endocarditis.
These disorders are usually unaccompanied by fever or bactere-
mia. The term marantic endocarditis refers to uninfected vegeta-
tions with a murmur and negative blood cultures that occur
secondary to malignancy. Patients with marantic endocarditis are
afebrile unless fever is caused by the underlying malignancy (e.g.,
lymphoma). The patient with marantic endocarditis due to lym-
phoma may have fever, splenomegaly, and other manifestations
of SBE. Negative blood cultures effectively rule out IE. Infectious
CNE (e.g., Q fever) may show little or no visible vegetations.
Infectious CNE should be considered if fever, murmur, and veg-
etation are present along with peripheral manifestations of IE.
Treatment
Effective treatment of IE depends on the antibiotic susceptibility
of the pathogen, the penetration of the antibiotic into the vegeta-
tion, and the appropriate duration of antibiotic therapy. Antibiot-
ics selected for IE preferably should be bactericidal. In IE, the
organisms are deeply embedded in the vegetation, and prolonged
therapy is necessary for penetration and sterilization of the veg-
etation. Early in IE therapy, blood cultures rapidly become nega-
tive, but treatment is continued because infection in the
vegetation has not been eradicated. Multiplication of bacteria,
which is required for bactericidal activity of antibiotics, is reduced
within vegetations and is one reason for the requirement for pro-
longed antibiotics. It is important to note that in cases of Staphy-
lococcus aureus endocarditis, blood cultures may not clear rapidly
and may remain positive for days despite appropriate antibiotic
therapy. Penetration into the vegetation is critical; for example,
viridans streptococci are highly susceptible to β-lactam antibiot-
ics but require a prolonged course of antimicrobial therapy to
eradicate the pathogens in the vegetation.
Whereas some cases of uncomplicated IE may be treated with
2 weeks of antimicrobial therapy, the usual duration of mono-
therapy or combination therapy is 4 to 6 weeks, depending on
the pathogen. Effective antimicrobial therapy does not eliminate
supportive or embolic complications of endocarditis. Therapeu-
tic failure is usually related to valvular destruction, a complication
that may require valve replacement. Suppurative intracardiac or
extracardiac complications usually require drainage for cure of
TABLE 93-6  PRINCIPLES OF THERAPY FOR INFECTIVE
ENDOCARDITIS
1. Antibiotic selection initially is made empirically on the basis of physical
examination and clinical history.
2. Bactericidal antibiotics are prescribed.
3. The MIC and MBC are measured to insure adequate dosing of the agent.
4. Intermittent dosing provides superior penetration into the thrombus
compared with continuous infusion; penetration is directly related to
peak serum level.
5. The patient should be treated in a health care facility for the first 1-2 wk.
6. The usual duration of therapy is 4-6 wk.
7. A 4-wk course is appropriate for an uncomplicated case of NVE (a
shorter course of 2 wk may be appropriate in some cases); a 6-wk course
is required for the treatment of PVE and those infections with large
vegetations (i.e., infection by HACEK organisms*).
Modified from Brusch JL: Diagnosis of infective endocarditis. In Brusch JL, editor:
Infective endocarditis, New York, 2007, Informa Healthcare, pp 241–254.
MBC, Minimal bactericidal concentration; MIC, minimal inhibitory concentration.
*HACEK organisms: Haemophilus spp, Actinobacillus actinomycetcomitans,
Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.
IE. The overarching principles of IE therapy are presented in
Table 93-6, and Table 93-7 provides an outline of specific antibi-
otic regimens that may be used to treat IE.
Complications of endocarditis may be intracardiac or extracar-
diac, and they may also be classified by damage mechanism (i.e.,
immunologic versus infectious). The infectious intracardiac com-
plications of IE include purulent pericarditis and paravalvular
abscess; they manifest clinically with persistent fever or persis-
tent bacteremia despite appropriate antibiotic therapy. Compli-
cations may be septic or immunologic; for example, splenic
involvement may be immunologic (splenic infarct) or septic
(splenic abscess). Embolic events are related to vegetation size.
Bland central nervous system emboli (e.g., aseptic meningitis)
may complicate SBE, whereas septic emboli (e.g., acute bacterial
meningitis) may complicate ABE. Particularly with ABE, there
may be valvular perforation or destruction resulting in acute con-
gestive heart failure. It is often these complications that dictate
whether and when surgery will occur. The indications for surgical
intervention are shown in Table 93-8. As a general principle,
paravalvular abscess or intractable congestive heart failure
requires urgent surgical intervention. Persistent vegetations or
embolic disease that occurs after 1 week of appropriate antibiotic
therapy should also prompt surgical consideration.
Prognosis
The prognosis of all forms of IE depends directly on any com-
plications related to the infection. Consequently, early diagnosis
and initiation of appropriate antibiotic therapy is the key to
limiting mortality. Recent studies have supported the role of
early surgical intervention, when appropriate, as a significant aid
to decreasing morbidity and mortality, specifically in relation to
having fewer embolic events. If treated in a timely fashion and
with appropriate antibiotics, the cure rate for viridans strepto-
cocci and S. bovis is estimated to be 98% in NVE and up to
88% in PVE. Right-sided endocarditis in intravenous drug
abusers is usually caused by S. aureus and typically has a cure
rate of 90% in NVE and 75% to 80% in PVE. However, among
non–intravenous drug abusers, cure rates in IE involving S. aureus
are far lower: 60% to 70% in NVE and 50% in PVE. When
gram-negative bacilli or fungal organisms are the causative agent,
882 Section XV  Infectious Disease

TABLE 93-7  ANTIMICROBIAL TREATMENT OF INFECTIVE ENDOCARDITIS

NATIVE VALVE PROSTHETIC VALVE
CAUSATIVE
ORGANISM ANTIBIOTIC THERAPY COMMENTS ANTIBIOTIC THERAPY COMMENTS
Penicillin-susceptible Penicillin G or ceftriaxone A 2-wk regimen of penicillin G or Penicillin G for 6 wk and Shorter duration of treatment
viridans streptococci, for 4 wk* ceftriaxone combined with gentamicin gentamicin for 2 wk* with an aminoglycoside (2 wk)
Streptococcus bovis, and may be considered in patients with is usually appropriate for PVE
other streptococci right-sided NVE without evidence of due to penicillin-susceptible
with MIC of penicillin embolic disease (excluding pulmonary viridans streptococci, S. bovis,
≤0.1 µg/mL emboli) or other complications. or other streptococci with
MIC of penicillin ≤0.1 µg/mL.
Relatively penicillin- Penicillin G for 4 wk and Penicillin G for 6 wk and
resistant streptococci gentamicin for 2 wk* gentamicin for 4 wk*
(MIC of penicillin
>0.1 to 0.5 µg/mL)
Streptococcus species Penicillin G or ampicillin 6 wk of therapy is recommended for Penicillin G or ampicillin A recent study by Fernando-
with MIC of penicillin and gentamicin for patients with symptoms lasting >3 mo, and gentamicin for Hidalgo et al. showed that the
>0.5 µg/mL, 4-6 wk* myocardial abscess, or selected other 6 wk* combination of ampicillin and
Enterococcus species, complications. ceftriaxone is as effective as the
or Abiotrophia species combination of ampicillin and
gentamicin for treating
Enterococcus faecalis IE.
Methicillin-susceptible Nafcillin or oxacillin for In the few patients infected with a Nafcillin or oxacillin with It may be prudent to delay
staphylococci 4-6 wk, with or without penicillin-susceptible staphylococcus, rifampin for 6 wk and initiation of rifampin for 1 or 2
addition of gentamicin penicillin G may be substituted for gentamicin for 2 wk† days, until therapy with two
for the first 3-5 days of nafcillin or oxacillin. other effective
therapy† antistaphylococcal drugs has
been initiated.
Methicillin-resistant Vancomycin, with or Vancomycin with rifampin If the staphylococcus is resistant
staphylococci without addition of for 6 wk and gentamicin to gentamicin, an alternative
gentamicin, for the first for 2 wk third agent should be chosen
3-5 days of therapy on the basis of in vitro
susceptibility testing.
Right-sided Nafcillin or oxacillin with This 2-wk regimen has been studied for
staphylococcal NVE gentamicin for 2 wk infections caused by an oxacillin- and
in selected patients aminoglycoside-susceptible isolate.
Exclusions to short-course therapy
include any cardiac or extracardiac
complications associated with IE,
persistence of fever for ≥7 days, and
infection with HIV. Patients with
vegetations >1-2 cm should probably
be excluded from short-course therapy.
HACEK organisms‡ Ceftriaxone for 4 wk Ampicillin and gentamicin for 4 wk is an Ceftriaxone for 6 wk Ampicillin and gentamicin for
alternative regimen, but some isolates 6 wk is an alternative regimen,
may produce β-lactamase, thereby but some isolates may produce
reducing the efficacy of this regimen. β-lactamase, thereby reducing
the efficacy of this regimen.
Modified from Mylonakis E, Calderwood SB: Infective endocarditis in adults, N Engl J Med 345:1318–1330, 2001.
HIV, Human immunodeficiency virus; IE, infective endocarditis; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis.
*Vancomycin therapy is indicated for patients with confirmed immediate hypersensitivity reactions to β-lactam antibiotics.
†
For patients who have IE due to methicillin-susceptible staphylococci and are allergic to penicillin, a first-generation cephalosporin or vancomycin may be substituted for nafcillin or
oxacillin. Cephalosporins should be avoided in patients with confirmed immediate-type hypersensitivity reactions to β-lactam antibiotics.
‡
HACEK organisms: Haemophilus spp, Actinobacillus actinomycetcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae.

cure rates are significantly lower (40% to 60%). Increased age,
diabetes, aortic valve involvement, and developing complications
of IE including congestive heart failure and emboli to the central
nervous system are all highly predictive of increased mortality
and morbidity.
Infective Endocarditis Prophylaxis
The most recent American Heart Association guidelines state
that not all patients require antibiotic prophylaxis and that pro-
phylaxis should be considered only for a specific subset of
patients. Antibiotic prophylaxis is indicated for patients with
prosthetic heart valves, cardiac transplant recipients with valvular
disease, patients with a history of IE, and patients with certain
forms of congenital heart disease. Among patients with
congenital heart disease, only those with unrepaired or partially
repaired lesions and those with prosthetic material should receive
prophylactic antibiotics (grade IIa recommendation).
Typically, antibiotic regimens used for prophylaxis against
IE prior to invasive procedures above the waist are directed
against viridans streptococci. For invasive dental procedures,
the recommended prophylactic agent is amoxicillin, 2  g PO
as a single dose 30 to 60 minutes before the procedure. In
patients with penicillin allergy, clindamycin or a macrolide may
be substituted.
  ENDARTERITIS AND SUPPURATIVE PHLEBITIS
The term infectious endarteritis refers to an intravascular infec-
tion of the arteries that affects coarctation of the aorta, aortic
 Chapter 93  Infections of the Heart and Blood Vessels 883
TABLE 93-8  ECHOCARDIOGRAPHIC INDICATIONS
FOR SURGICAL INTERVENTION IN
INFECTIVE ENDOCARDITIS
VEGETATION
Persistent vegetation after systemic embolization
Anterior mitral valve leaflet vegetation (particularly if ≥1 embolic events
occur during the first 2 wk of antimicrobial therapy)*
Increase in vegetation size despite appropriate antimicrobial therapy*†
VALVULAR DYSFUNCTION
Acute aortic or mitral insufficiency with signs of ventricular failure†
Heart failure unresponsive to medical therapy†
Valve perforation or rupture†
Large abscess or extension of abscess despite appropriate antimicrobial
therapy†
PARAVALVULAR EXTENSION
Valvular dehiscence, rupture, or fistula†
New heart block†
Large abscess or extension of abscess despite appropriate antimicrobial
therapy†
Modified from Baddour LM, Wilson WR, Bayer AS, et al: Infective Endocarditis:
diagnosis, antimicrobial therapy, and management of complications: a statement for
healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and
Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on
Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart
Association; endorsed by the Infectious Diseases Society of America, Circulation
111:e394–e433, 2005.
*Surgery may be required because of risk of embolization.
†
Surgery may be required because of failure of medical therapy or heart failure.
valve shunts, or a patent ductus arteriosus, analogous to IE at
other sites. As with IE, continuous or high-grade bacteremia
in the absence of an intracardiac vegetation should suggest the
diagnosis. Imaging studies (e.g., PET scans) delineate the extent
of arterial involvement. Treatment is the same as for IE.
The term suppurative thrombophlebitis refers to an intravenous
infection that is characterized by an intravenular abscess; it is a
complication of the use of central venous catheters. Patients have
phlebitis with high fevers (>102° F, compared with <102° F in
uncomplicated phlebitis with fevers) and bacteremia due to a
skin organism (e.g., S. aureus). Treatment consists of a combina-
tion of antibiotic therapy and resection of the involved venous
segment.
  CENTRAL VENOUS CATHETER–RELATED
BLOODSTREAM INFECTIONS
Central venous catheter–related bloodstream infections are rela-
tively common, with an annual incidence of approximately
200,000 in the United States. Central venous catheter infection
should be suspected if the patient develops fevers, chills, or hypo-
tension without another obvious source of infection. The likeli-
hood of infection increases with the length of time the catheter
is in place. In addition to the clinical signs, blood cultures, drawn
from the periphery as well as the line, should demonstrate growth
of the causative organism. If the culture drawn from the catheter
shows growth of bacteria at least 2 hours earlier than the periph-
eral blood cultures do, infection associated with the central line,
rather than bacteremia in the setting of a catheter, should be
strongly suspected.
Treatment of catheter-related infections varies depending on
what action will be taken with the catheter (i.e., removal,
exchange, or salvage). In any case, empirical antibiotic therapy
should be initiated against the most likely pathogens. Empirical
therapy should cover S. aureus and nosocomial gram-negative
bacilli. Therapy may then be modified based on the results of
blood cultures or catheter tip culture. If a catheter-related blood-
stream infection is suspected, immediate removal of the catheter
should occur if the infection has led to septic shock or IE. The
line also should be removed if blood cultures remain positive for
the causative organism for 72 hours longer, or if evidence of
septic thrombophlebitis develops.
Salvage therapy may be considered in hemodynamically stable
patients except when the infection is caused by S. aureus, P. aeru-
ginosa, Bacillus spp, Micrococcus spp, Propionibacterium acnes or
other propionibacteria, fungi, or mycobacteria. Salvage therapy
relies on concurrent use of systemic antimicrobial agents and
antibiotic or ethanol locks.
Guidewire exchange should be reserved for cases in which
there is a high risk for complications if the original catheter were
to be removed. Guidewire exchange has a lower chance of elimi-
nating the infection than does removal of the catheter.
For a deeper discussion of these topics, please see Chapter
76, “Infective Endocarditis,” in Goldman-Cecil Medicine,
25th Edition.
SUGGESTED READINGS
Baddour LM, Cha YM, Wilson WR: Clinical practice: infections of cardiovascular
implantable electronic devices, N Engl J Med 367:842–849, 2012.
Bor DH, Woolhandler S, Nardin R, et al: Infective endocarditis in the U.S., 1998–
2009: a nationwide study, PLoS ONE 8(e60033):2013.
Brouqt P, Raoult D: Endocarditis due to rare and fastidious bacteria, Clin
Microbiol Rev 14:177–207, 2001.
Fournier PE, Thuny F, Richet H, et al: Comprehensive diagnostic strategy for
blood culture-negative endocarditis: a prospective study of 819 new cases, Clin
Infect Dis 51:131–140, 2010.
Fernández-Hidalgo N, Almirante B, Gavaldà J, et al: Ampicillin plus ceftriaxone
is as effective as ampicillin plus gentamicin for treating Enterococcus faecalis
infective endocarditis, Clin Infect Dis 56:1261–1268, 2013.
Garcia-Cabera E, Fernandez-Hidalgo N, Almirante B, et al: Neurological
complications of infective endocarditis: risk factors, outcome, and impact of
cardiac surgery: a multicenter observational study, Circulation 127:2272–
2284, 2013.
Kang DH, Kim YJ, Kim SH, et al: Early surgery versus conventional treatment for
infective endocarditis, N Engl J Med 366:2466–2473, 2012.
Kiefer T, Park L, Tribouilloy C, et al: Association between valvular surgery and
mortality among patients with infective endocarditis complicated by heart
failure, JAMA 306:2239–2247, 2011.
Li JS, Sexton DJ, Mick N, et al: Proposed modifications to the Duke criteria for
the diagnosis of infective endocarditis, Clin Infect Dis 30:633–638, 2000.
Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the diagnosis
and management of intravascular catheter-related infection: 2009 Update by
the Infectious Disease Society of America, Clin Infect Dis 49:1–45, 2009.
Mylonakis E, Calderwood SB: Infective endocarditis in adults, N Engl J Med
345:1318–1330, 2001.
Wilson W, Taubert KA, Gewitz M, et al: Prevention of infective endocarditis:
guidelines from the American Heart Association: a guideline from the
American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki
Disease Committee, Council on Cardiovascular Disease in the Young, and the
Council on Clinical Cardiology, Council on Cardiovascular Surgery and
Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary
Working Group, Circulation 116:1736–1754, 2007.
 94 
Skin and Soft Tissue Infections
Sajeev Handa
  DEFINITION
Skin and soft tissue infections (SSTIs) comprise infections of
skin, subcutaneous tissue, fascia, and the muscle by a multitude
of organisms.
  EPIDEMIOLOGY
SSTIs are among the most common infections found in all age
groups, although the exact incidence is unknown. Several factors
predispose to development of SSTIs:
• Epidermal breaks caused by trauma, surgical wounds, human
or animal bites, or dry and irritated skin with concomitant
tinea infection
• Immunosuppressed states caused by malnutrition, diabetes
mellitus, or acquired immunodeficiency syndrome (AIDS)
• Chronic venous or lymphatic insufficiency
  PATHOLOGY
Infectious Mechanisms
Microbes penetrate the integument after entering through a cut,
bite, or hair follicle. Components of the host’s defense system,
including oxygen radicals, complement, immunoglobulins, mac-
rophages, lymphocytes, and granulocytes, are recruited to the site
of invasion through a vast plexus of dermal capillaries.
Bacteria contain proteins whose N-terminal amino acid
sequence begins with an N-formyl-methionine group that is che-
moattractive to phagocytes, including macrophages and granulo-
cytes. Other microbial cell wall components, such as the zymosan
of yeast, endotoxins of gram-negative bacteria, and the peptido-
glycans of gram-positive bacteria, activate the alternative comple-
ment pathways, producing serum-derived chemotactic factors.
Efflux of phagocytes occurs from the capillary through endothe-
lial cell interstices and follows the gradient of chemotactic factors
derived from bacteria and serum to the site of active infection.
Activated endothelial cells also produce chemotactic cyto-
kines such as interleukin-8 (IL-8). Activated granulocytes syn-
thesize leukotriene B4 from arachidonic acid, a potent
chemoattractant for leukocytes. Production of proinflammatory
cytokines such as IL-1, IL-6, and tumor necrosis factor augments
immune function, inducing fever, priming neutrophils, and
increasing antibody production and synthesis of acute phase
reactants such as C-reactive protein.
Cytokine-driven stimulation of endothelial cells generates
nitric oxide and prostaglandins, both of which cause
884
vasodilatation. The net physiologic effect is greater blood flow to
the tissue, causing acute inflammation. As described by Celsus
(30 bc-38 ad), acute inflammation is characterized by rubor (i.e.,
redness), calor (i.e., increased heat), tumor (i.e., swelling), dolor
(i.e., pain), and, as added by Virchow in the 19th century, func-
tion laesa (i.e., loss of function). Chapter 86 discusses host
defenses against infection in more depth.
Pathologic Manifestations
Impetigo is characterized by thick, crusted lesions with rounded
or irregular margins that typically occur on the face. Most cases
are caused by Staphylococcus aureus, including methicillin-
resistant S. aureus (MRSA), or by group A streptococci (e.g.,
Streptococcus pyogenes). Certain strains of streptococci causing
impetigo have been implicated in the development of poststrep-
tococcal glomerulonephritis.
Folliculitis is a superficial bacterial infection of the hair folli-
cles. Purulent material is found in the epidermis. It manifests as
clusters of multiple, small, raised, pruritic, erythematous lesions
that are typically less than 5 mm in diameter.
Furuncles (i.e., boils) are infections of the hair follicle. Puru-
lent material extends through the dermis into the subcutaneous
tissue, where small abscesses may form. A carbuncle is coales-
cence of several inflamed follicles into a single inflammatory
mass. Purulent drainage exudes from multiple follicles.
Cellulitis is superficial inflammation of the skin and underly-
ing tissues. It is characterized by erythema, warmth, and tender-
ness of the involved area (Fig. 94-1). Erysipelas is a variant of
cellulitis that is predominantly caused by toxin-producing S. pyo-
genes. It manifests as a superficial, spreading, warm, erythematous
(fiery red) lesion distinguished by its indurated and elevated
margin. Lymphatic involvement and vesicle formation are
common. Groups B, C, and D streptococci may also be impli-
cated (Fig. 94-2).
Necrotizing fasciitis is a progressive and rapidly spreading
inflammatory reaction deep in the fascia that is associated with
secondary necrosis of the subcutaneous tissues. Thrombosis of
the dermal vessels is responsible for tissue necrosis. Necrotizing
fasciitis may be polymicrobial (type I), involving aerobic
microbes (e.g., streptococci, staphylococci, gram-negative bacilli)
and anaerobes (e.g., Peptostreptococcus, Bacteroides, Clostridium
species), or it may be monomicrobial (type II) and caused by S.
pyogenes (Fig. 94-3). When involving the scrotum and perineal
area, it is known as Fournier’s gangrene.
Pyomyositis is a less serious infection involving the muscula-
ture that results from direct inoculation of bacteria. For example,
 Chapter 94  Skin and Soft Tissue Infections 885
FIGURE 94-1  Ill-defined erythema and edema with bullae formation
is characteristic of lower extremity cellulitis. (From Pride HB: Cellulitis
and erysipelas. In Zaoutis LB, Chiang VW, editors: Comprehensive pedi-
atric hospital medicine, Philadelphia, 2007, Mosby, Fig. 156-1.)
FIGURE 94-2  Sharply defined erythema and edema is characteristic
of erysipelas. (From Pride HB: Cellulitis and erysipelas. In Zaoutis LB,
Chiang VW, editors: Comprehensive pediatric hospital medicine, Phila-
delphia, 2007, Mosby, Fig. 156-2.)
FIGURE 94-3  Spontaneous necrotizing fasciitis due to Clostridium
septicum. The patient developed sudden onset of severe pain in the
forearm. Swelling rapidly ensued, and he sought medical treatment.
Crepitus was found on physical examination, and gas in the soft tissue
was verified with routine radiographs. Immediate surgical débride-
ment revealed necrotizing fasciitis but sparing of the muscle. Notice
the purple-violaceous appearance of the skin. (From Stevens DL,
Aldape MJ, Bryant AE. Necrotizing fasciitis, gas gangrene, myositis and
myonecrosis. In Cohen J, Powderly WG, Opal SM, editors: Infectious
diseases, ed 3, London, 2010, Mosby, Fig. 10-11.)
infection can result from injection drug use or from secondary
seeding by S. aureus or group A β-hemolytic streptococci from
an incidental bacteremia or a hematoma caused by nonpenetrat-
ing trauma.
Ecthyma is an ulcerative pyoderma of the skin that extends
into the dermis (unlike impetigo). It is caused by group A strep-
tococci and Pseudomonas species.
  ETIOLOGY AND CLINICAL PRESENTATION
Causative Organisms
A multitude of organisms can cause SSTIs. However, three
are most common: S. pyogenes, S. aureus, and Streptococcus
agalactiae.
S. pyogenes (i.e., group A β-hemolytic streptococci) is a gram-
positive coccus that may cause erysipelas, streptococcal cellulitis,
necrotizing fasciitis, myositis, myonecrosis, and streptococcal
toxic shock syndrome. Streptococcal cellulitis arises from infec-
tion of wounds, burns, or surgical incisions and may progress to
involve large areas. Injection drug users and individuals with
impaired lymphatic drainage are at high risk. Systemic manifesta-
tions include fever, chills, malaise with or without associated
lymphangitis, and bacteremia. In contrast to erysipelas, the
affected area is not raised, and the demarcation between involved
skin and uninvolved skin is indistinct. The lesions tend to be
more pink than fiery red.
Streptococcal toxic shock syndrome manifests with hypoten-
sion and is associated with acute kidney injury, elevated amino-
transferases, rash or soft tissue necrosis, and coagulopathy. It may
be complicated by the acute respiratory distress syndrome. Isola-
tion of the organism from a sterile site provides a definite
diagnosis.
S. aureus is a gram-positive coccus that is found in the anterior
nares of up to 30% of healthy people. It is responsible for a variety
of invasive and suppurative infections. Localized SSTIs include
furuncles, carbuncles, bullous and nonbullous impetigo, mastitis,
ecthyma, cellulitis, and wound and foreign body infections. Bac-
teremia may be complicated by septicemia, endocarditis, pericar-
ditis, pneumonia, empyema, osteomyelitis, and abscesses of the
soft tissue, muscle, and viscera.
Staphylococcal toxic shock syndrome is typically associated
with tampon use but may occur after childbirth or surgery
and can be associated with cutaneous lesions. It manifests
with the acute onset of fever, erythroderma, hypotension,
and multisystem involvement (e.g., acute kidney injury, elevated
levels of aminotransferases, coagulopathy, nausea, vomiting,
diarrhea).
Community-associated MRSA is the most common identifi-
able cause of SSTIs in the emergency department. Isolates
contain genes encoding for multiple toxins, including cytotoxins
that result in leukocyte destruction and tissue necrosis.
S. agalactiae (a group B streptococcus) is a gram-positive dip-
lococcus. It may account for up to one third of SSTIs among
adults. Cellulitis, foot ulcers, and infection of decubitus ulcers are
common manifestations. Cellulitis has been associated with
foreign bodies such as breast or penile implants. Less commonly,
polymyositis, blistering dactylitis, and necrotizing fasciitis may
occur.
886 Section XV  Infectious Disease
Other Organisms
Aeromonas hydrophila, Aeromonas veronii, and Aeromonas schuber-
tii are gram-negative rods found in salt and fresh water. They may
cause mild to severe wound infections after injury, producing
cellulitis, myonecrosis, and rhabdomyolysis. Necrotizing fasciitis
has been reported with A. veronii and A. schubertii infections.
Aeromonas wound infections have also been reported as a result
of the medicinal use of leeches.
Arcanobacterium haemolyticum is a gram-positive, weakly acid-
fast bacillus. It has been isolated from soft tissue infections,
including chronic ulcers, cellulitis, and paronychia.
Bacillus anthracis is a gram-positive bacillus that forms spores.
Transdermal inoculation of the spores from even incidental
trauma can result in cutaneous anthrax. It manifests initially as a
small, pruritic papule that becomes surrounded by painless, non-
purulent vesicles that easily rupture, leaving a black eschar at the
base of the ulceration. Uncomplicated disease heals without scar
formation in 1 to 3 weeks. Serious cutaneous disease is marked
by extensive edema, worsening inflammation, and toxemia
(Fig. 94-4).
Bartonella henselae is a gram-negative bacillus that causes cat-
scratch disease. Between 3 and 10 days after a bite or scratch from
a cat or other vector, a tender, erythematous papule appears.
Lymphadenopathy ipsilateral to the site of inoculation occurs 1
to 3 weeks later, and the patient typically experiences constitu-
tional symptoms. The lymphadenopathy may take months to
resolve.
Capnocytophaga canimorsus is a thin, gram-negative bacillus
with tapered ends. It is strongly associated with dog (primarily)
and cat bites and scratches. Asplenic patients are at particular risk
for sepsis due to this organism.
Clostridium perfringens is an anaerobic, large, gram-positive
rod. It can cause cellulitis or life-threatening necrotizing infec-
tions of skin, muscle, and other soft tissues. The latter is
characterized by rapidly progressive tissue destruction, gas in
tissues, shock, and death. Conditions such as trauma or illicit
drug injection produce anaerobic tissue conditions that favor
FIGURE 94-4  Cutaneous anthrax lesion on the skin of the forearm
caused by the bacterium Bacillus anthracis. (From Centers for Disease
Control and Prevention: Public health image library. Available at http://
phil.cdc.gov/Phil/home.asp. Accessed October 31, 2014.)
the organism. The condition can also develop in patients with
bowel carcinoma or neutropenia. Gram stain of tissue or
exudate reveals large, gram-positive rods and no inflammatory
cells.
Edwardsiella tarda is a gram-negative rod found in fresh water
environments. It is associated with wound infections, abscesses,
and bacteremia. The mortality rate is high among patients with
liver disease and iron overload.
Eikenella corrodens is a gram-negative bacillus that is part of the
normal human oral flora. It is an important pathogen in human
bite wounds, closed-fist injuries, and infections seen in chronic
finger or nail biters. Severe soft tissue infection may occur, leading
to septic arthritis and osteomyelitis.
Erysipelothrix rhusiopathiae is a gram-positive rod, but it may
appear as gram-negative because of rapid decolorization. Its
major reservoir is in domestic swine, and infection occurs by
direct cutaneous contact through a cut or abrasion. Disease is
characterized as erysipeloid (i.e., subacute cellulitis with vesicula-
tion), as a diffuse cutaneous eruption with systemic symptoms,
or as bacteremia that is often associated with endocarditis.
Francisella tularensis is a gram-negative coccobacillus found in
rabbits, hares, hamsters, and rodents. Ulceroglandular tularemia
occurs 3 to 5 days after humans are inoculated cutaneously during
contact with any of these species. A papule is formed initially,
followed by ulceration with enlargement of the regional lymph
nodes. Vesicles may be seen. If left untreated, the ulcer remains
for weeks before healing, leaving a residual scar. Suppuration of
the affected lymph nodes is the most common complication,
occurring despite appropriate treatment (Fig. 94-5). B. anthracis
and F. tularensis have been used as agents in bioterrorism.
Cryptococcus neoformans, Candida albicans, Histoplasma capsu-
latum, Blastomyces dermatitidis, Coccidioides immitis, and oppor-
tunistic fungi can have skin manifestations. Opportunistic fungi,
including Aspergillus species, fungi in the order Mucorales, and
Fusarium species, can infect the skin of immunocompromised
patients. Skin manifestations of fungal infections include papules,
nodules, circumscribed erythematous lesions, ulcers, verrucous
lesions, and eschars.
FIGURE 94-5  Tularemic ulcer with eschar formation after percutane-
ous inoculation of Francisella tularensis. (From Beard CB, Dennis DT:
Tularemia. In Cohen J, Powderly WG, Opal SM, editors: Infectious dis-
eases, ed 3, London, 2010, Mosby.)
 Chapter 94  Skin and Soft Tissue Infections 887
Exposure to herpes simplex virus types 1 and 2 (HSV-1 and
HSV-2) at abraded skin sites allows entry into the epidermis and
dermis. Infection typically occurs from sexual contact, but it
occasionally occurs at extraoral or extragenital sites, such as the
hands of health care workers, producing a painful erythema pri-
marily at the junction of the nail bed and skin (i.e., whitlow). This
progresses to a vesicopustular lesion that can mimic a bacterial
infection (i.e., paronychia). Sexually transmitted diseases are dis-
cussed in Chapter 100.
Mycobacterium marinum is an atypical, acid-fast bacillus; it is
the most common atypical mycobacterium that causes infection
in humans. After inoculation of a skin abrasion or puncture
wound in salt or fresh water (nonchlorinated), lesions appear as
papules on an extremity. Lesions progress to shallow ulcers and
form scars. Typically, lesions are solitary, but they may take on
the appearance of ascending, sporotrichoid-like, nodular lym-
phangitis that may involve the local joint or tendons.
Mycobacterium leprae is a slow-growing, acid-fast bacillus that
cannot be grown in vitro. It is the cause of leprosy (Hansen’s
disease). It is primarily transmitted by the airborne route and
causes chronic disfiguring skin lesions and nerve damage.
For a deeper discussion of this topic, please see Chapter
326, “Leprosy (Hansen’s Disease)” in Goldman-Cecil Med-
icine, 25th Edition.
Pasteurella multocida is a gram-negative coccobacillus that may
occur at the site of a scratch or bite from a dog or cat. Cellulitis
results within 24 hours of the injury, producing swelling, ery-
thema, tenderness, serous or purulent discharge with or without
regional lymphadenopathy, chills, and fever.
Pseudomonas aeruginosa is a gram-negative rod and primarily
a nosocomial pathogen. In the community, serogroup 0 : 11 may
cause folliculitis related to the use of hot tubs, whirlpools, and
swimming pools. Typically, the eruption occurs 48 hours after
exposure and consists of tender, pruritic papules, papulopustules,
or nodules. It is an important pathogen in burn wound infections,
which may progress to sepsis.
Sporothrix schenckii is a dimorphic fungus ubiquitous primarily
in the tropical parts of North and South America. Cutaneous
inoculation from thorny plants (e.g., rose bushes) is followed by
development of a painless papule that enlarges slowly to become
a nodular lesion with a violaceous hue or ulceration. Secondary
lesions may form along the lymphatic drainage distribution.
Primary varicella-zoster virus (VZV) infection occurs by the
respiratory route but may occur through contact with infected
lesions. Viremia results in crops of papules that primarily occur
on the trunk and progress to vesicles and then to pustules, fol-
lowed by crusting. Zoster or shingles represents reactivation of
the latent virus in the sensory neurons of the dorsal root ganglion,
resulting in pain that proceeds to a rash in the distribution of the
affected dermatome in a few days. The appearance of papules and
vesicles in a unilateral dermatomal distribution confirms the
diagnosis. Ramsay Hunt syndrome occurs when the VZV infec-
tion involves the geniculate ganglia and causes a painful eruption
in the ear canal and tympanic membrane that is associated with
ipsilateral seventh cranial nerve palsy. Vesicles that appear on the
tip of the nose (i.e., Hutchinson’s sign) may be preceded by devel-
opment of ophthalmic zoster and involvement of the cornea.
Immunosuppressed individuals are at higher risk for dissemi-
nated disease.
Vibrio vulnificus is a gram-negative bacillus that is spread by
contamination of a superficial wound with warm seawater. It
can cause rapidly developing and intense cellulitis, necrotizing
vasculitis, and ulcer formation. Aggressive soft tissue infection
may occur with necrosis, fever, sepsis, and bullae formation.
Ingestion of raw oysters, particularly by immunocompromised
(e.g., liver cirrhosis, iron overload) patients may be followed
1 to 3 days later by septicemia associated with necrotizing
cutaneous lesions.
Table 94-1 provides a classification for the spectrum of skin
involvement by bacteria and fungi.
  DIAGNOSIS
A thorough medical history is critical; it should assess the specific
risk factors, such as travel history, animal contacts, marine expo-
sures, occupational and avocational hazards (e.g., farming, gar-
dening), and immune status. If an animal bite has occurred, the
timing of the bite, circumstances of injury, and health
status of the animal should be determined. Human bites are clas-
sified as self-inflicted, occlusal (i.e., intentional), or closed-fist
injuries.
In addition to wound assessment, evaluation for other trans-
missible pathogens, including human immunodeficiency virus
(HIV), HSV, Treponema pallidum (the etiologic agent of syphi-
lis), and hepatitis B and C viruses, should be pursued. A thorough
clinical examination should follow. Initial antimicrobial manage-
ment, if indicated, is directed by the history and physical exami-
nation findings.
Evaluation of hospitalized patients should include a complete
blood count and a basic metabolic panel. The C-reactive protein
level may be useful as a marker for inflammation and guidance
for treatment. The creatine phosphokinase concentration may be
helpful, but it is not specific for cases of compartment syndrome
and necrotizing fasciitis involving the musculature. Cultures are
not indicated for uncomplicated common forms of SSTIs
managed in the outpatient setting. The benefit of blood cultures
for cellulitis in hospitalized patients is uncertain because the yield
is low. Cultures are indicated for patients who require incision
and drainage because of the risk of deep structure and underlying
tissue involvement.
The most sensitive and specific test for the diagnosis of HSV
and VZV cutaneous lesions is nucleic acid amplification. A
sample is scraped from the base of an active dermal lesion with a
swab. Direct fluorescent antibody testing is less sensitive. Incision
and drainage of these lesions is contraindicated.
Special Diagnostic Considerations
Animal Bites
Blood cultures, tissue biopsy, and aspirates for culture of aerobic
or anaerobic organisms are preferred methods in cases of animal
bites.
Human Bites
Wounds swabs may produce misleading information in cases
of human bites. A Gram stain should be performed to assess
888 Section XV  Infectious Disease

TABLE 94-1  CLASSIFICATION OF BACTERIAL AND MYCOTIC INFECTIONS OF THE SKIN

DISEASE OR DISORDER MICROORGANISMS
PRIMARY PYODERMAS
Impetigo Staphylococcus aureus, group A streptococci
Folliculitis S. aureus, Candida spp, Pseudomonas aeruginosa (diffuse folliculitis)
Furuncles and carbuncles S. aureus
Paronychia S. aureus, group A streptococci, Candida, P. aeruginosa
Ecthyma Group A streptococci, Pseudomonas spp.
Erysipelas Group A streptococci
Chancriform lesions Treponema pallidum, Haemophilus ducreyi, Sporothrix, Bacillus anthracis, Francisella tularensis,
Mycobacterium ulcerans, Mycobacterium marinum
Membranous ulcers Corynebacterium diphtheriae
Cellulitis Group A or other streptococci, S. aureus; rarely, various other organisms
INFECTIOUS GANGRENE AND GANGRENOUS CELLULITIS
Streptococcal gangrene and necrotizing fasciitis Group A streptococci, mixed infections with Enterobacteriaceae and anaerobes
Progressive bacterial synergistic gangrene Anaerobic streptococci plus a second organism (S. aureus, Proteus spp.)
Gangrenous balanitis and perineal phlegmon Group A streptococci, mixed infections with enteric bacteria (Escherichia coli, Klebsiella spp.), anaerobes
Gas gangrene, crepitant cellulitis Clostridium perfringens and other clostridial species; Bacteroides spp., peptostreptococci, Klebsiella spp.,
E. coli
Gangrenous cellulitis in immunosuppressed patients Pseudomonas, Aspergillus spp., agents of mucormycosis
PREEXISTING SKIN LESIONS WITH SECONDARY BACTERIAL INFECTIONS
Burns P. aeruginosa, Enterobacter spp., various other gram-negative bacilli, various streptococci, S. aureus,
Candida spp., Aspergillus spp.
Eczematous dermatitis and exfoliative erythrodermas S. aureus, group A streptococci
Chronic ulcers (varicose, decubitus) S. aureus, streptococci, coliform bacteria, P. aeruginosa, peptostreptococci, enterococci, Bacteroides spp.,
C. perfringens
Dermatophytosis S. aureus, group A streptococci
Traumatic lesions (abrasions, animal bites, insect Pasturella multocida, C. diphtheriae, S. aureus, group A streptococci
bites)
Vesicular or bullous eruptions (varicella, pemphigus) S. aureus, group A streptococci
Acne conglobata Propionibacterium acnes
Hidradenitis suppurativa S. aureus, Proteus spp. and other coliforms, streptococci, peptostreptococci, P. aeruginosa, Bacteroides spp.
Intertrigo S. aureus, coliforms, Candida spp.
Pilonidal and sebaceous cysts Peptostreptococci, Bacteroides sp., coliforms, S. aureus
Pyoderma gangrenosa S. aureus, peptostreptococci, Proteus spp. and other coliforms, P. aeruginosa
CUTANEOUS INVOLVEMENT IN SYSTEMIC INFECTIONS
Bacteremias S. aureus, group A streptococci (and other groups such as D), Neisseria meningitidis, Neisseria gonorrhoeae,
P. aeruginosa, Salmonella typhi, Haemophilus influenzae
Infective endocarditis Viridans streptococci, S. aureus, group D streptococci, and others
Fungemias Candida spp., Cryptococcus spp., Blastomyces dermatitidis, Fusarium
Listeriosis Listeria monocytogenes
Leptospirosis (Weil’s disease and pretibial fever) Leptospira interrogans serotypes
Rat-bite fever Streptobacillus moniliformis, Spirillum minus
Melioidosis Burkholderia pseudomallei
Glanders Burkholderia mallei
Carrión’s disease (verruga peruana) Bartonella bacilliformis
SCARLET FEVER SYNDROMES
Scarlet fever Group A streptococci, rarely S. aureus
Scalded skin syndrome S. aureus (phage group II)
Toxic shock syndrome Group A streptococci, S. aureus (pyrogenic toxin–producing strains)
PARAINFECTIOUS AND POSTINFECTIOUS NONSUPPURATIVE COMPLICATIONS
Purpura fulminans (manifestation of disseminated Group A streptococci, N. meningitidis, S. aureus, pneumococcus
intravascular coagulation)
Erythema nodosum Group A streptococci, Mycobacterium tuberculosis, Mycobacterium leprae, Coccidioides immitis, Leptospira
autumnalis, Yersinia enterocolitica, Legionella pneumophila
Erythema multiforme–like lesions (rarely), guttate Group A streptococci
psoriasis
OTHER LESIONS
Erythrasma Corynebacterium minutissimum
Nodular lesions Candida, Sporothrix, S. aureus (botryomycosis), M. marinum, Leishmania brasiliensis; leprosy due to M.
leprae can cause popular lesions, nodular, and ulcerative lesions
Hyperplastic (pseudoepitheliomatous) and Nocardia spp., Pseudallescheria boydii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Phialophora,
proliferative lesions (e.g., mycetomas) Cladosporium
Vascular papules/nodules (bacillary angiomatosis, Bartonella henselae, Bartonella quintana
epithelioid angiomatosis)
Annular erythema (erythema chronicum migrans) Borrelia burgdorferi
Modified from Mandell GL, Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of infectious diseases, ed 7, Philadelphia, 2009, Churchill Livingstone.
 Chapter 94  Skin and Soft Tissue Infections 889
organisms, neutrophils (i.e., inflammation), and squamous epi-
thelial cells (i.e., superficial contamination). If feasible, tissue
biopsy or aspiration of the infected site can provide specimens
for aerobic and anaerobic culture.
Traumatic Wounds
The optimal time to acquire specimens for cultures is immedi-
ately after débridement of the wound site. Analysis of initial cul-
tures should focus on common pathogens, and additional testing
should be reserved for uncommon or rare infections associated
with unusual circumstances, such as Vibrio species after salt water
exposure. Tissue biopsy and special stains may be required in
certain situations, such as suspected infection with M. marinum.
Burn Wounds
Before sampling, the burn area must be clean and devoid of
topical antimicrobial agents. Surface swabs or tissue biopsies are
recommended for obtaining culture samples, and histopatho-
logic examination can monitor for the presence and extent of
infection. Quantitative evaluation of swab or culture specimens
is recommended twice weekly to monitor colonization. Evidence
of systemic infection related to the wound should prompt blood
cultures.
Diabetic Foot Infections
Superficial swab cultures of ulcerations can be misleading and
should be avoided. If surgical débridement is performed, deep
tissue specimens should be sent to the microbiology laboratory
for evaluation.
Radiographs should be obtained if bone involvement is sus-
pected, and they may also be useful in demonstrating soft tissue
gas before crepitus is detected (Fig. 94-6). Magnetic resonance
imaging is the most sensitive modality. Chapter 87 discusses the
laboratory diagnosis of infectious diseases in more detail.
Differential Diagnosis
Many noninfectious conditions can mimic SSTIs:
• Brown recluse spider bite
• Contact dermatitis
• Gout
• Psoriatic arthritis with distal dactylitis
• Reiter’s syndrome
FIGURE 94-6  Radiograph of patient with clostridial myonecrosis
shows gas in the tissues. (Courtesy J.W. Tomford, MD.)
• Relapsing polychondritis
• Ruptured Baker’s cyst
• Mixed cryoglobulinemia due to immune complex disease from
chronic hepatitis C or B infection (may have an erythematous
rash)
• Pyoderma gangrenosum
• Sweet’s syndrome (acute febrile neutrophilic dermatosis)
• Venous stasis
  TREATMENT
Pharmacologic and Supportive Care
Mild cases of cellulitis may be managed on an outpatient basis
with dicloxacillin, amoxicillin, or cephalexin. Clindamycin or
levofloxacin may be used in patients allergic to penicillin. Severe
cellulitis should be managed with parenteral cefazolin, nafcillin,
or oxacillin. Clindamycin or vancomycin may be used in patients
with allergies to penicillin. Concomitant tinea infection should
be treated with a topical antifungal agent such as clotrimazole or
terbinafine.
Mild cases of community-acquired MRSA may be managed
with clindamycin, trimethoprim-sulfamethoxazole, or tetracy-
cline if antibiotics are indicated. The latter two agents do not,
however, provide adequate streptococcal coverage. Severe cases
requiring parenteral antibiotics require vancomycin, daptomycin,
telavancin, ceftaroline, clindamycin, or linezolid. A β-lactam anti-
biotic may be considered for hospitalized patients with nonpuru-
lent cellulitis, with modification to MRSA-active treatment if is
there is no clinical response. Cellulitis associated with an abscess
requires surgical drainage.
In addition to supportive care, urgent surgical consultation
should be obtained in the event that crepitus, bullae, rapidly
evolving cellulitis, or pain disproportional to physical examina-
tion findings suggests necrotizing fasciitis. Initial parenteral
therapy with vancomycin, daptomycin, linezolid with piperacillin-
tazobactam, cefepime plus metronidazole, or a carbapenem is
appropriate. Type II necrotizing fasciitis due to S. pyogenes or
clostridial myonecrosis should prompt combined therapy with
parenteral penicillin and clindamycin. The use of intravenous
immune globulin in cases of necrotizing fasciitis remains
controversial.
Compartment syndrome requires emergent surgical decom-
pression to prevent muscle necrosis and irreversible neuronal
damage. Cellulitis or wound infections attributed to A. hemolyti-
cum may be treated with clindamycin, erythromycin, vancomy-
cin, or tetracycline. HSV and VZV infections are susceptible to
acyclovir, famciclovir, or valacyclovir if treatment is indicated.
Special Treatment Considerations
Animal Bites
Mild cases of animal bites may be treated with amoxicillin-
clavulanate. For patients with a penicillin allergy, a fluoroquino-
lone plus clindamycin or sulfamethoxazole-trimethoprim plus
metronidazole are alternatives that may be used in oral or paren-
teral forms. Inpatient parenteral agents including ampicillin-
sulbactam or piperacillin-tazobactam may be used for patients
who are not allergic to penicillin.
890 Section XV  Infectious Disease
Tularemia is treated with gentamicin, tobramycin, streptomy-
cin, doxycycline, or ciprofloxacin. Azithromycin is the drug of
choice for cat-scratch disease. For individuals at risk for E.
rhusiopathiae infection, the treatment of choice is penicillin or
ampicillin or use of a third-generation cephalosporin or fluoro-
quinolone in penicillin-allergic patients.
Animal handlers with cutaneous anthrax infection require
treatment with ciprofloxacin or levofloxacin. Cases of suspected
bioterrorism must be reported immediately.
Marine Lacerations and Punctures
The treatment regimen for marine lacerations and punctures
should include doxycycline and ceftazidime or a fluoroquino-
lone. Treatment of fresh water injuries should include a third- or
fourth-generation cephalosporin (i.e., ceftazidime or cefepime)
or a fluoroquinolone. If M. marinum is suspected, treatment with
clarithromycin, minocycline, doxycycline, sulfamethoxazole-
trimethoprim, or rifampin plus ethambutol is appropriate.
Human Bites
Patients who have human bite wounds without evidence of infec-
tion should receive prophylactic treatment with amoxicillin-
clavulanate for 3 to 5 days. Closed-fist injuries require radiographic
evaluation and consultation with a hand surgeon for possible
wound exploration. Parenteral treatment with ampicillin-
sulbactam or moxifloxacin is recommended.
Burn Wounds
Systemic therapy with antibiotics and antifungals are reserved for
burn patients demonstrating signs of sepsis or septic shock. Infec-
tion due to mucormycoses requires liposomal amphotericin B.
Diabetic Foot Infections
Simple infections such as cellulitis are most often caused by
group A streptococci or S. aureus and should be managed accord-
ingly. If ulcers do not have purulence or inflammation, antimicro-
bials are not indicated. Severe limb-threatening infections require
surgical evaluation and broad-spectrum antibiotic coverage
because infection tends to include aerobic and anaerobic
organisms. Empirical therapy directed at P. aeruginosa is not
usually necessary unless the patient has other risk factors. MRSA-
active treatment is recommended for patients with a history of
MRSA, when the local prevalence of MRSA is high in the com-
munity, or if the infection is severe. All wounds require adequate
wound irrigation and débridement.
  PROGNOSIS
Full recovery is expected for patients with simple SSTIs provided
they receive appropriate treatment. For those who develop com-
plications such as necrotizing fasciitis, the estimated mortality
rate is between 30% and 70%. The prognosis is guarded for
patients with multiple comorbidities and those who are
immunosuppressed.
SUGGESTED READINGS
Baddour L: Skin abscesses, furuncles and carbuncles, UpToDate. Available at
http://www.uptodate.com/contents/skin-abscesses. Accessed October 31,
2014.
Baron EJ, Miller JM, Weinstein MP, et al: A guide to utilization of the
microbiology laboratory for diagnosis of infectious diseases: 2013
recommendations by the Infectious Diseases Society of America (IDSA) and
the American Society of Microbiology (ASM). Available at http://
www.idsociety.org/uploadedFiles/IDSA/Guidelines-Patient_Care/PDF
_Library/Laboratory%20Diagnosis%20of%20Infectious%20Diseases%20
Guideline.pdf
Cohen J, Powderly WG, Opal SM, editors: Infectious diseases, ed 3, London,
2010, Mosby.
Golstein EJ: Bite wounds and infectious, Clin Infect Dis 14:633–640, 1992.
Herchline T: Cellulitis treatment and management. Available at http://
emedicine.medscape.com/article/214222-overview. Accessed October 31,
2014.
Lipsky BA, Berendt AR, Cornia PB, et al: 2012 Infectious Diseases Society of
America clinical practice guideline for the diagnosis and treatment of diabetic
foot infections, Clin Infect Dis 54:132–173, 2012.
Liu C, Bayer A, Cosgrove SE, et al: Clinical practice guidelines by the Infectious
Diseases Society of America for the treatment if methicillin-resistant
Staphylococcus aureus infectious in adults and children, Clin Infect Dis 52:e18–
e55, 2011.
Stevens DL, Bisno AL, Chambers HF, et al: Practice guidelines for the diagnosis
and management of skin and soft-tissue infections, Clin Infect Dis 41:1373–
1406, 2005.
 95 
Intraabdominal Infections
Edward J. Wing

less common causes are tumors, mesenteric lymphadenitis, para-

  INTRODUCTION sites, and seeds. Obstruction leads to swelling, compromise of
Intraabdominal infections are serious conditions that usually the blood supply, and inflammation with a resulting neutrophilic
result from perforation or obstruction of abdominal organs. infiltrate of the appendicular wall. Gangrene of the wall and
These infections often require surgical intervention to drain rupture eventually occurs.
abscesses, repair perforations, and relieve obstructions. The cause
is typically polymicrobial infection, including aerobic and anaer-
obic bacteria that require broad antibiotic coverage. Guidelines TABLE 95-2  REGIMENS USED FOR INITIAL EMPIRICAL
TREATMENT OF BILIARY INFECTION IN
for diagnosis and therapy have been developed by the Surgical
ADULTS
Infection Society and the Infectious Diseases Society of America
INFECTION REGIMEN
(Tables 95-1, 95-2, and 95-3). This chapter focuses on the most
Community-acquired acute Cefazolin, cefuroxime, or ceftriaxone
common intraabdominal infections found in adults. cholecystitis of mild to
moderate severity
Community-acquired acute Imipenem-cilastatin, meropenem,
  APPENDICITIS cholecystitis of severe doripenem, piperacillin-tazobactam,
physiologic disturbance, ciprofloxacin, levofloxacin, or cefepime,
Definition and Epidemiology advanced age, or each in combination with
Appendicitis is an acute inflammation of the appendix that is immunocompromised status metronidazole*
Acute cholangitis after Imipenem-cilastatin, meropenem,
usually caused by an obstruction of the lumen by an appendico- bilioenteric anastomosis of any doripenem, piperacillin-tazobactam,
lith. Appendicitis is the most common cause of emergency severity ciprofloxacin, levofloxacin, or cefepime,
surgery worldwide. In the United States in 2007, appendicitis each in combination with
metronidazole*
accounted for 295,000 hospital discharges and $7.4 billion in Health care–associated biliary Imipenem-cilastatin, meropenem,
hospital costs. The lifetime risk is 7% to 12%, with a slight pre- infection of any severity doripenem, piperacillin-tazobactam,
ponderance among men. ciprofloxacin, levofloxacin, or cefepime,
each in combination with
metronidazole, vancomycin added to
Pathology each regimen*
The normal appendix is 5 to 10 cm long and typically lies anterior From Solomkin JS, Mazuski JE, Gradley JS, et al: Diagnosis and management of complicated
to the cecum. Locations that affect the clinical manifestations intraabdominal infection in adults and children: guidelines by the Surgical Infection Society
and the Infectious Diseases Society of America, Surg Infect 11:79–109, 2010.
include retrocecal, pelvic, and retroileal variants. Obstruction of *Because of increasing resistance of Escherichia coli to fluoroquinolones, local
the proximal appendix is typically caused by an appendicolith; population susceptibility profiles and, if available, isolate susceptibility should be reviewed.

TABLE 95-1  AGENTS AND REGIMENS FOR THE INITIAL EMPIRICAL TREATMENT OF EXTRABILIARY COMPLICATED
INTRAABDOMINAL INFECTION
COMMUNITY-ACQUIRED INFECTION IN ADULTS
COMMUNITY-ACQUIRED
REGIMEN INFECTION IN CHILDREN Mild to Moderate Severity * High Risk or Severity †
Single agent Ertapenem, meropenem, imipenem- Cefoxitin, ertapenem moxifloxacin, tigecycline, Imipenem-cilastatin, meropenem,
cilastatin, ticarcillin-clavulanate, and and ticarcillin-clavulanic acid doripenem, and piperacillin-tazobactam
piperacillin-tazobactam
Combination Ceftriaxone, cefotaxime, cefepime, or Cefazolin, cefuroxime, ceftriaxone, cefotaxime, Cefepime, ceftazidime, ciprofloxacin, or
ceftazidime, each in combination with ciprofloxacin, or levofloxacin, each in levofloxacin, each in combination with
metronidazole; gentamicin or combination with metronidazole‡ metronidazole*
tobramycin, each in combination with
metronidazole or clindamycin and with
or without ampicillin
From Solomkin JS, Mazuski JE, Gradley JS, et al: Diagnosis and management of complicated intraabdominal infection in adults and children: guidelines by the Surgical Infection Society and
the Infectious Diseases Society of America, Surg Infect 11:79–109, 2010, Table 2.
*Includes perforated or abscessed appendicitis and other infections of mild to moderate severity.
†
Includes severe physiologic disturbance, advanced age, and immunocompromised states.
‡
Because of increasing resistance of Escherichia coli to fluoroquinolones, local population susceptibility profiles and, if available, isolate susceptibility should be reviewed.

891
892 Section XV  Infectious Disease

TABLE 95-3  INTRAVENOUS ANTIBIOTICS FOR Ileum

EMPIRICAL TREATMENT OF Umbilical
Ascending
COMPLICATED INTRAABDOMINAL colon
ring
INFECTION McBurney’s
ANTIBIOTIC ADULT DOSAGE* point
β-LACTAM/β-LACTAMASE INHIBITOR COMBINATION Anterior
superior Anterior
Piperacillin-tazobactam 3.375 g q6h†
iliac superior
Ticarcillin-clavulanic acid 3.1 g q6h; FDA labeling indicates iliac
200 mg/kg/day in divided doses spine
spine
q6h for moderate infection and Veriform
300 mg/kg/day in divided doses appendix
q4h for severe infection
CARBAPENEMS Cecum
Doripenem 500 mg q8h
Ertapenem 1 g q24h
Imipenem-cilastatin 500 mg q6h or 1 g q8h
Meropenem 1 g q8h
CEPHALOSPORINS
Cefazolin 1-2 g q8h FIGURE 95-1  Various anatomic positions of the vermiform
Cefepime 2 g q8-12h appendix.
Cefotaxime 1-2 g q6-8h
Cefoxitin 2 g q6h
Ceftazidime 2 g q8h
Ceftriaxone 1-2 g q12-24h umbilicus (Fig. 95-1). Seventy-five percent of patients vomit
Cefuroxime 1.5 g q8h once or twice.
Tigecycline 100-mg initial dose, then 50 mg q12h
Evidence of peritoneal irritation includes rebound and guard-
FLUOROQUINOLONES
ing. Patients are typically supine and do not want to move. Pain
Ciprofloxacin 400 mg q12h may also be elicited by flexion and internal rotation of the right
Levofloxacin 750 mg q24h
Moxifloxacin 400 mg q24h hip (i.e., obturator sign) or passive extension of the right hip (i.e.,
Metronidazole 500 mg q8-12h or 1500 mg q24h psoas sign). Palpation of the left lower quadrant pain may produce
AMINOGLYCOSIDES right lower quadrant pain (i.e., Rovsing’s sign).
Gentamicin or tobramycin 5-7 mg/kg‡ q24h§ Patients usually have little fever or tachycardia. Determining
Amikacin 15-20 mg /kg‡ q24h§ whether a patient has a ruptured appendix, which occurs in 25%
Aztreonam 1-2 g q6-8h
of cases, can be difficult. If the clinical presentation is delayed 4
Vancomycin 15-20 mg/kg‖ q8-12h§
to 5 days and rupture has occurred, there may be fever, tachycar-
From Solomkin JS, Mazuski JE, Gradley JS, et al: Diagnosis and management of
complicated intraabdominal infection in adults and children: guidelines by the Surgical dia, and a palpable mass.
Infection Society and the Infectious Diseases Society of America, Surg Infect 11:79–109, Variations in the presentation include initial right lower quad-
2010.
FDA, U.S. Food and Drug Administration. rant pain, back and flank pain (i.e., retrocecal appendix), supra-
*Dosages are based on normal renal and hepatic function.
†
pubic pain (i.e., pelvic appendix), and left lower quadrant pain
For Pseudomonas aeruginosa infection, dosage may be increased to 3.375 g q4h or
4.5 g q6h. (i.e., long appendix). The elderly may have no periumbilical or
‡
Initial dosage regimens for aminoglycosides should be based on adjusted body right lower quadrant pain. Children may not be able to give
weight.
§
Monitoring of serum drug concentration should be considered for dosage an accurate history, and in pregnant women, the appendix may
individualization.
‖
be pushed upward by the expanding uterus. At 8 months’ gesta-
Initial dosage regimens for vancomycin should be based on total body weight.
tion, the pregnant woman’s pain may be in the right upper
quadrant.

The bacteriology of acute appendicitis, including rupture, is Diagnosis

polymicrobial, with gut aerobes (Escherichia coli is most com-
mon) and anaerobes (Bacteroides fragilis is most common).
Typically, 10 to 14 different organisms can be isolated. This
picture is similar to other intraabdominal infections such as
diverticulitis.
Clinical Presentation
Classically, acute appendicitis begins with anorexia followed by
periumbilical pain. The pain is steady, moderately severe, and
sometimes cramping. After 4 to 6 hours, the pain migrates to the
right lower quadrant, where the site of maximal tenderness is
located at McBurney’s point. This point is 0.5 to 2 inches inside
the right anterior spinous process of the ilium on a line to the
The diagnosis of acute appendicitis is important but can be dif-
ficult. A careful meta-analysis reported that the history, physical
examination, and inflammatory markers are singly unreliable pre-
dictors of the diagnosis, but when combined, they are accurate.
A careful history and physical examination should be obtained.
Pain migrating from the umbilical area to the right lower quad-
rant should be sought in the history. Signs of peritoneal irritation,
including rebound, percussion tenderness, guarding, and rigidity,
should be determined. The total white blood cell count, number
of neutrophils, percentage of bands, and level of C-reactive
protein should be measured.
The Alvarado system was developed to aid in the diagnosis of
appendicitis (Table 95-4). Using the mnemonic MANTRELS, it
 Chapter 95  Intraabdominal Infections 893

scores the impact of eight factors: migration, anorexia, nausea thickening of the cecal wall, and pericecal fat stranding. An
and vomiting, tenderness in the right lower quadrant, rebound of appendicolith is a helpful sign. If perforation has occurred, exten-
pain, elevation of temperature, leukocytosis, and shift to the left. sive inflammatory changes are seen, which may include an abscess
A patient with a score of 5 or 6 is usually observed, but an indi- cavity. Although there has been controversy about whether CT
vidual with a score of 7 or greater should undergo surgery. scans are necessary or more accurate than clinical assessment in
Two prospective trials demonstrated the accuracy of helical every case, the current standard of care in emergency depart-
computed tomography (CT) with contrast for the diagnosis of ments includes a CT scan. Use of CT has reduced the rate of
acute appendicitis. The initial CT findings of appendicitis are finding normal appendices at surgery from between 11% and
enlargement of the appendix, usually to an appendiceal diameter 15% to between 3% and 5%.
of more than 6 mm (Fig. 95-2). The wall is thickened and Diagnostic ultrasound is accurate if carefully performed and
enhances with contrast. Later findings include inflammation, can be particularly useful in small children and pregnant women.
Because of its accuracy and lack of ionizing radiation, magnetic
resonance imaging (MRI) has become the scanning modality of
TABLE 95-4  ALVARADO OR MANTRELS* SYSTEM choice in many centers for children, pregnant women, and other
FOR DIAGNOSING ACUTE APPENDICITIS patients. Nonetheless, CT scanning is rapid and more likely avail-
FEATURES able, and it is therefore the procedure of choice for most patients.
SCORED VARIABLE VALUE The differential diagnosis for acute appendicitis is long. It
Symptoms Migration 1 includes urinary tract infection and stones; gynecologic prob-
Anorexia 1 lems such as a ruptured ovarian cyst, ectopic pregnancy, and
Nausea-vomiting 2
Signs Tenderness in right lower quadrant 2 pelvic inflammatory disease; and bowel pathology, including
Rebound of pain 1 diverticulitis and Crohn’s disease.
Elevation of temperature (≥37.3° C) 1
Laboratory values Leukocytosis (white blood cell count 2 Treatment
>10.000/µL)
Shift to the left (>75% neutrophils) 1 Laparoscopic (75% of procedures) or open appendectomy is the
Total score 10 treatment of choice for emergent cases. If rupture is identified,
From Wray CJ, Kao LS, Millas SG, et al: Acute appendicitis: controversies in diagnosis and antibiotics and drainage are indicated. Pretreatment antibiotics
management, Curr Probl Surg 50:54–86, 2013.
*MANTRELS mnemonic: Migration, anorexia, nausea and vomiting, tenderness in
in all cases prevent wound infection and intraabdominal infec-
right lower quadrant, rebound of pain, elevation of temperature, leukocytosis, shift to the left. tions as indicated by a Cochran review. Antibiotics to cover E. coli

A B

C D
FIGURE 95-2  Computed tomography (CT) of acute appendicitis. A, CT scan of uncomplicated appendicitis shows an appendicolith (arrow). B, CT
scan shows a dilated appendix (arrow) and surrounding inflammation in the pericolic fat. C and D, Two views at different levels of perforated appen-
dicitis with abscess formation. C, Cecum. (From Novelline RA, editor: Squire’s fundamentals of radiology, ed 6, Cambridge, Mass., 1964, Harvard
University Press, Figures 13.43 and 13.44.)
894 Section XV  Infectious Disease
and B. fragilis are recommended by the guidelines from the Surgi-
cal Infection Society and Infectious Diseases Society of America
(see Tables 95-1 and 95-3). The recommendations also apply to
other intraabdominal infections, such as diverticulitis. Antibiot-
ics should be stopped after surgery in simple cases. If rupture has
occurred, it is usually safe to stop antibiotics after 5 to 7 days.
Some studies over the past decade have advocated antibiotics
alone for the treatment of acute appendicitis. Although provoca-
tive and potentially a future direction for care, the lack of a suf-
ficient number of controlled trials, the difficulty of confirming
the diagnosis in trials, and the high recurrence and complication
rates make this approach unsuitable for general application.
Prognosis
The mortality rate in the United States is extremely low for
uncomplicated cases. Rupture, however, results in an overall 1%
mortality rate and a 5% rate in elderly patients. Wound infection
occurs in 1% to 20%. The rate of fetal loss in pregnant women
with appendicitis is 1.5%, but the rate is 20% to 35% in cases of
rupture.
  DIVERTICULITIS
Definition and Epidemiology
Diverticulitis is inflammation and infection resulting from perfo-
ration of diverticula of the bowel wall, usually in the sigmoid
colon. Diverticulitis is diagnosed in more than 2 million patients
each year and accounted for 219,000 hospital discharges in 2009
in the United States. It is also the most common cause of sigmoid
colon resection.
Diverticula occur in less than 10% of people younger than 40
years and in 50% to 80% of those older than 80 years. Between
10% and 25% of individuals with diverticulosis develop diver-
ticulitis. Rates of diverticulosis in rural Africa and Asia are less
than 1%. Diet is thought to be a critical risk factor. Supporting
this hypothesis was a study measuring diverticulosis in Japanese
populations in Japan (1% prevalence) and individuals of Japanese
heritage living in the United States (52% prevalence).
Pathology
Diverticula are herniations of the mucosa and muscularis through
the colonic wall between the taeniae coli where the main blood
vessels penetrate the wall. Diverticulitis results from macroscopic
or microscopic perforations, resulting in inflammation, local
infection, and in severe cases, free air and diffuse peritonitis
(Fig. 95-3).
Clinical Presentation and Diagnosis
Noninflamed diverticula cause no symptoms. Patients with
uncomplicated diverticulitis have left lower quadrant pain often
accompanied by nausea and fever. CT, which is the diagnostic test
of choice, may show pericolic soft tissue stranding, colonic wall
thickening, and a phlegmon. Between 10% and 20% of patients
have severe pain, tenderness, fever, and leukocytosis, and they
require hospital admission for intravenous antibiotics. The dif-
ferential diagnosis for diverticulitis includes urinary tract infec-
tion, gastroenteritis, inflammatory bowel disease, perforated
colonic cancer, appendicitis, and bowel obstruction.
Complicated diverticulitis occurs when the perforation is
not contained. Patients may have severe abdominal pain, free
air, guarding, rigidity, and multisystem failure. Complications
include abscess seen in pericolic, retroperitoneal, or pelvic areas
on CT; purulent or feculent peritonitis; and colovesical, colovagi-
nal, or coloenteric fistulas (5% occurrence). Percutaneous drain-
age of abscesses or surgery, including sigmoid resection, is usually
indicated in these situations.
Treatment and Prognosis
Uncomplicated diverticulitis can be treated on an outpatient
basis with oral antibiotics, and more severe cases are treated with
intravenous antibiotics for 7 to 10 days on an inpatient basis (see
Tables 95-1 and 95-3). Although data from a Cochrane review
and a controlled trial conducted in Sweden suggest that not all
patients need to be treated with antibiotics, the standard of care
in the United States is to treat with antibiotics. The most impor-
tant organisms to cover in this polymicrobial infection are E. coli
and B. fragilis. Complicated diverticulitis requires point source
control (i.e., drainage or bowel resection), intravenous antibiotics
to cover bowel flora, and systemic resuscitation. Fistulas require
surgical resection and repair.
Colonoscopy should be done 6 to 8 weeks after an episode of
diverticulitis to rule out colonic cancer. The recurrence rate of
diverticulitis is approximately 20%. A high-fiber diet, weight loss,
and exercise are recommended to prevent recurrence. Sigmoid
resection may be considered after the second recurrence, depend-
ing on age, medical condition, and the frequency and severity of
episodes. If the sigmoid colon is removed, more than 95% of
patients have no further episodes.
  CHOLECYSTITIS AND CHOLANGITIS
Definition and Epidemiology
Gallstones occur in 11% to 36% of the population. Approxi-
mately 20% of patients with gallstones develop temporary
obstruction of the cystic duct at some time. This results in biliary
colic (i.e., episodes of right upper quadrant pain) lasting 1 to 5
hours. Cholecystitis occurs when the cystic duct is obstructed for
longer periods. Intraluminal pressure increases, compromising
blood and lymphatic flow, and it may result in acute inflammation
and infection.
Among patients with gallstones, 6% to 12% have stones in the
common duct or choledocholithiasis. Cholangitis results from
obstruction of the common duct, usually by common duct
stones, leading to inflammation and often to severe infection.
Clinical Presentation
Patients with biliary pain have various sites of maximal pain and
radiation of pain (Fig. 95-4). Classic signs of acute cholecystitis
include unremitting right upper quadrant pain that is more severe
than biliary colic, fever, anorexia, nausea, and vomiting. Murphy’s
sign (i.e., inspiratory arrest with deep palpation of the right upper
quadrant) is positive. Accuracy is increased by assessing the gall-
bladder with ultrasound and eliciting pain with the probe (i.e.,
sonographic Murphy’s sign).
Elderly patients and patients with diabetes may have more
subtle clinical presentations. A mild leukocytosis may be
 Chapter 95  Intraabdominal Infections 895

Peritoneum
Circular muscle
Taenia coli
Epiploic
Diverticulum
appendix

Mucosa

Concentration
in diverticulum

Blood vessel
piercing
musculature
Relationship of diverticula
to blood vessels and taeniae (schematic)

FIGURE 95-3  Diverticulosis. (From the Netter Collection of Medical Illustrations. Available at www.netterimages.com. Accessed October 31, 2014.)

identified. Bacterial contamination of the gallbladder occurs in
15% to 30%. If obstruction continues, gangrenous cholecystitis,
necrosis of the gallbladder wall and abscess or empyema may
occur. Perforation, which rarely occurs, is usually limited to the
subhepatic space. Infection by gas-forming organisms may result
in emphysematous cholecystitis.
Acute cholangitis with common duct obstruction can cause
mild and self-limited disease to fulminant, life threatening
infection. Two thirds of patients have Charcot’s triad (i.e., right
upper quadrant pain, fever, and jaundice). Fever is often accom-
panied by rigors. The addition of hypotension and mental status
changes results in Reynolds pentad (i.e., jaundice, fever, abdomi-
nal pain, shock, and altered mental status), a sign of severe
disease. Leukocytosis and elevated alkaline phosphatase and bili-
rubin levels are typical. Bile cultures usually show bowel organ-
isms, and blood cultures are positive in 30% to 40% of cases.
896 Section XV  Infectious Disease

Treatment
Biliary colic is usually self-limited. Acute cholecystitis usually
requires intervention to relieve obstruction of the cystic duct, but
it may remit spontaneously. Laparoscopic cholecystectomy is
2 indicated emergently if there is gangrene or perforation; other-
2 wise, surgery should be done within 1 to 3 days. Antibiotics are
2 9 6
routinely given to cover bowel flora. Ceftriaxone can be given for
14
15
7 mild to moderate disease, whereas broader coverage such as
64 imipenem-cilastatin or piperacillin-tazobactam should be given
for more severe disease (see Tables 95-1, 95-2, and 95-3).
50 24 1 4
13 5 4 Acute cholangitis should be treated initially with fluid resusci-
tation and antibiotics. ERCP is indicated for diagnosis and relief
4 1
of obstruction. Emergency decompression of the biliary tract by
ERCP or surgery may be indicated for severely ill patients.
A

  INFECTIONS OF SOLID ORGANS

3 cases per million people per year, and the incidence of amebic
9 6
11 35 33
2
3
2
15
2 11 2 3
19
3
5 20% to 40% of cases, no cause is found. The bacteriology of
2 hepatic abscess reflects the source, with polymicrobial bowel
B flora being the most common. Hematogenous sources are usually
FIGURE 95-4  A, Sites of the most severe pain during an episode of
biliary pain in 107 patients with gallstones (% values add up to >100%
because of multiple responses). The subxiphoid and right subcostal
areas were the most common sites; note that the left subcostal region
was not an unusual site of pain. B, Sites of pain radiation (%) during an
episode of biliary pain in the same group of patients. (Modified from
Burnicardi FC, Andersen DK, Billiar TR, et al: Schwartz’s principles of
surgery, ed 9, New York, 2009, McGraw-Hill.)
For a deeper discussion of these topics, please see Chapter
155, “Diseases of the Gallbladder and Bile Ducts,” in
Goldman-Cecil Medicine, 25th Edition.
Diagnosis
Ultrasonography is 95% sensitive and specific for the diagnosis.
In cholecystitis, ultrasound shows a thickened gallbladder wall
and pericholecystic fluid. In cholangitis, ultrasound shows a
dilated common duct, but obstructing gallstones are difficult to
identify. Endoscopic retrograde cholangiopancreatography
(ERCP) is required for a definitive diagnosis of cholangitis. The
differential diagnosis includes peptic ulcer disease with or
without perforation, pancreatitis, appendicitis, hepatitis, myocar-
dial infarction, and pneumonia.
Hepatic Abscess
Liver abscess is usually caused by bacteria or Entamoeba histo-
lytica. Both are rare. The incidence of bacterial abscess is 10 to 20
abscess is 1 case per million per year in the United States. World-
wide, however, 10% of people are infected with gastrointestinal
E. histolytica, and liver abscess is the most common extraintestinal
manifestation.
The biliary tract is the most common source of infection for
bacterial hepatic abscess. Other sources include direct extension
(e.g., perforated appendicitis), portal vein (e.g., abdominal infec-
tion), hepatic artery (e.g., bacterial line infection), and trauma. In
staphylococcal or streptococcal species. Less common organisms
include Klebsiella pneumoniae, which is identified particularly in
case series from Asia, and Candida species found in immunocom-
promised patients.
Liver abscess usually manifests with fever for days to weeks.
Right upper quadrant abdominal pain and tenderness are found
in one half of patients and jaundice in one fourth. Peripheral
blood leukocyte counts are elevated in three fourths, and two
thirds have an obstructive liver profile with an elevated alkaline
phosphatase level. Table 95-5 illustrates the differences between
amebic and bacterial liver abscesses.
Patients with amebic liver abscess tend to be younger men
with more right upper quadrant pain and a more acute course
than those with bacterial hepatic abscess. There often is a history
of travel or residence in a highly endemic geographic area.
Ultrasound is the preferred initial diagnostic test because it is
rapid and can help to identify biliary sources. CT is more specific
and can identify other causes of liver abscess, such as extension
from an intraabdominal abscess. The right lobe is most com-
monly infected, and 50% of cases are multifocal.
Drainage of liver abscesses is essential. Percutaneous aspira-
tion of the abscess is therapeutic and diagnostic. Repeated aspira-
tions or catheter placement may be necessary. Antibiotics are
directed by the likely source and by results of Gram stain and
culture. Blood cultures are positive in 50% of cases and may be
 Chapter 95  Intraabdominal Infections 897

TABLE 95-5  AMEBIC AND PYOGENIC LIVER Splenic Abscess

ABSCESSES Splenic abscess usually results from a hematogenous source, par-
AMEBIC LIVER PYOGENIC ticularly endocarditis; consequently, the infecting bacteria are
FEATURE ABSCESS LIVER ABSCESS
usually streptococcal and staphylococcal species. Patients have
EPIDEMIOLOGY left upper quadrant pain, fever, an enlarged spleen, and an ele-
Male-to-female ratio 5-18 1.0-2.4 vated white blood cell count. Ultrasound is diagnostic, and sple-
Age (yr) 30-40 50-60
Duration (days) <14 (≈75% of cases) 5-26 nectomy is curative. Percutaneous aspiration plus antibiotics can
Mortality (%) 10-25 0-5 also be effective.
SYMPTOMS AND SIGNS*
Extravisceral Abscesses
Fever 80 80
Weight loss 40 30 Extravisceral abscesses typically occur from perforation of the
Abdominal pain 80 55 bowel, resulting from inflammation or iatrogenic sources such
Diarrhea 15-35 10-20
Cough 10 5-10 as endoscopy and surgery. Other causes include peritonitis, rup-
Jaundice 10-15 10-25 tured solid organ abscess, and penetrating trauma. The clinical
Right upper quadrant 75 25-55 presentation varies widely with the location and cause. CT is
tenderness
the most useful imaging modality. Point source control, usually
LABORATORY TESTS*
with percutaneous aspiration or surgical drainage, is essential
Leukocytosis 80 75 for treatment. Antibiotic coverage is secondary and should be
Elevated alkaline phosphatase 80 65
Solitary lesion 70 70 directed at the cause as identified by location, Gram stain, and
From Sifri CD, Madoff LC: Infections of the liver and biliary system. In Mandell GL,
culture.
Bennett JE, Dolin R, editors: Mandell, Douglas, and Bennett’s principles and practice of
infectious diseases, ed 7, Philadelphia, 2009, Churchill Livingstone.
*Approximate percentage of cases.   PERITONITIS
the only positive culture. Therapy is usually given for 4 to 6 Primary Peritonitis
weeks. Rupture or sepsis syndrome occurs rarely. Surgery may be Primary or spontaneous bacterial peritonitis usually occurs in
necessary if there is a lack of response, rupture, or complex mul- patients with cirrhosis and ascites or in children with nephrotic
tilocular abscesses. syndrome. The source is not apparent. The bacteriologic analysis
The serologic analysis for E. histolytica is 95% sensitive but reflects aerobic bowel flora, including E. coli, K. pneumoniae, and
cannot distinguish gastrointestinal disease from hepatic abscess. gram-positive organisms. Anaerobes are uncommon.
Treatment for amebic infection is oral metronidazole for 7 to 10 Clinical presentation includes fever, abdominal pain, ascites,
days. and deteriorating liver function test results. Diagnosis is likely if
aspirated ascitic fluid has greater than 250 neutrophils/µL. A
Pancreatic Infection diagnosis of primary peritonitis is made if a secondary source is
Although most episodes of pancreatitis are self-limited, infected ruled out. Culture and Gram stain may be negative. Patients
necrotizing pancreatitis has a mortality rate approaching 30%. usually respond after 48 to 72 hours of antibiotics. Patients with
Acute pancreatitis is characterized by upper abdominal pain that cirrhosis and ascites who have had one episode of spontaneous
often radiates to the back and is accompanied by nausea and peritonitis are at risk for further episodes and are candidates for
vomiting. The serum amylase concentration is greater than three antibiotic prophylaxis. A meta-analysis of 13 trials concluded
times the normal value, and CT shows typical inflammation in that prophylaxis resulted in decreased morbidity and mortality.
the pancreas. Eighty percent of acute pancreatitis cases are mild,
whereas 20% of cases are moderate to severe. Secondary Peritonitis
Patients with infected necrotizing pancreatitis typically Secondary peritonitis usually results from perforation of bowel
develop fever, leukocytosis, and increased abdominal pain several and contamination by mixed enteric organisms. Other sources
weeks after the onset of pancreatitis. The standard of care includes include rupture of the urinary tract or gynecologic organs. Bac-
antibiotics to cover cultured microorganisms (typically enteric teriology usually identifies polymicrobial infection with aerobes
bacteria or Staphylococcus aureus), and surgical débridement is and anaerobes, reflecting the mucosal surface of the source. The
delayed for 4 to 6 weeks if possible. Because early surgical inter- peripheral blood leukocyte count is usually elevated.
vention may increase the mortality rate, delayed débridement is Patients are usually febrile and have signs of peritoneal irrita-
recommended. tion: abdominal wall tenderness, rebound, and rigidity. Tender-
Pancreatic abscess usually occurs 2 to 6 weeks after an episode ness may be maximal over the origin of the peritonitis (e.g.,
of acute pancreatitis. Treatment is percutaneous drainage plus ruptured viscus). Because movement causes pain, patients keep
antibiotics. Distinguishing pancreatic necrosis from necrosis plus their knees bent and have quiet respirations.
infection and pseudocyst from abscess can be difficult. Ultrasound and CT may reveal the origin of peritonitis. Aspi-
ration of ascitic fluid usually reveals the causative organisms.
For a deeper discussion of these topics, please see Chapter Antibiotic therapy to cover the suspected or identified organisms
144, “Pancreatitis,” in Goldman-Cecil Medicine, 25th should be begun immediately. It usually includes coverage of bac-
Edition. teria causing intraabdominal infection as discussed previously.
898 Section XV  Infectious Disease
Surgical approach is aimed at controlling the source (e.g., perfo-
rated appendix), débridement, and drainage of abscesses.
Peritonitis during Peritoneal Dialysis
Rates of peritonitis during long-term peritoneal dialysis average
less than 1 case in 24 months, but a few patients have higher rates.
Bacteria usually represent skin flora, with Staphylococcus epider-
midis, S. aureus, and streptococcal species predominating. Most
patients have abdominal pain and tenderness but no fever. Neu-
trophil counts greater than 100 cells/µL and bacteria in a cloudy
dialysate confirm the diagnosis.
Treatment can usually be accomplished intraperitoneally on
an outpatient basis. Several antibiotic regimens have proved
effective. Removal of the peritoneal catheter may be necessary
(10% to 20% of cases) if there is a catheter tunnel infection, an
unusual organism such as a fungus, or persistent infection.
Tuberculous Peritonitis
Primary tuberculous peritonitis often has a gradual onset. Symp-
toms include fever, abdominal pain, and weight loss. Pulmonary
tuberculosis often exists. Signs may include tender, “doughy”
masses or ascites. Symptoms and signs may be subtle.
Peritoneal fluid is exudative and contains 500 to 2000 cells/µL,
mostly lymphocytes. Culture of peritoneal fluid is positive in
only 25% of cases. The diagnosis is made by biopsy of nodules
seen on the peritoneum during laparoscopy. Treatment consists
of standard antituberculous therapy.
SUGGESTED READINGS
Alvarado A: A practical score for the early diagnosis of acute appendicitis, Ann
Emerg Med 15:557–564, 1986.
Attasaranya S, Fogel EL, Lehman GA: Choledocholithiasis, ascending cholangitis
and gallstone pancreatitis, Med Clin North Am 92:925–960, 2008.
Chabok A, Pahlman L, Hjern F, et al: Randomized clinical trial of antibiotics in
acute uncomplicated diverticulitis, Br J Surg 99:532–539, 2012.
Fagenholz PJ, Demoya MA: Acute inflammatory surgical disease, Surg Clin
North Am 94:1–30, 2014.
Shabanzadeh DM, Wille-Jorgensen P: Antibiotics for uncomplicated diverticulitis,
Cochrane Database Syst Rev (11):CD009092, 2012.
Soares-Weber K, Brezis M, Tur-Kaspa R, et al: Antibiotic prophylaxis of bacterial
infections in cirrhotic inpatients: a meta-analysis of randomized controlled
trials, J Gastroenterol 38:193–200, 2003.
Solomkin JS, Mazuski JE, Gradley JS, et al: Diagnosis and management of
complicated intra-abdominal infection in adults and children: guidelines by
the Surgical Infection Society and the Infectious Diseases Society of America,
Surg Infect 11:79–109, 2010.
Wilkins T, Embry K, George R: Diagnosis and management of acute diverticulitis,
Am Fam Physician 87:612–620, 2013.
Wray CJ, Kao LS, Millas SG, et al: Acute appendicitis: controversies in diagnosis
and management, Curr Probl Surg 50:54–86, 2013.

Infectious Diarrhea
  DEFINITION AND EPIDEMIOLOGY
Acute diarrhea is defined as an increase in frequency of bowel
movements, to three or more times daily with at least 200 g of
stool per day, lasting less than 14 days. In clinical practice, three
or more loose stools per day is considered to represent diarrhea.
Infectious diarrhea is diarrhea that has an infectious etiology and
is often associated with symptoms and signs of enteric involve-
ment, such as nausea, vomiting, abdominal cramps, passage of
bloody stool (dysentery), or systemic symptoms. When diarrhea
lasts longer than 14 days, it is considered to be persistent diarrhea.
The term chronic diarrhea refers to illness that last longer than 1
month. Organisms responsible for infectious diarrhea include
bacteria, viruses, and parasites.
Globally, there are an estimated 1.7 billion cases of diarrhea
annually, with acute infectious diarrhea causing more than 2
million deaths per year. Infectious diarrhea is the second leading
cause of death in children younger than 5 years of age, killing an
estimated 760,000 such children every year. In the United States,
an estimated 211 to 375 million episodes of acute diarrhea occur
annually, with more than 900,000 hospitalizations and about
6000 deaths. Foodborne illnesses alone account for about 76
million cases and 5000 deaths in the US each year.
  PATHOLOGY
Diarrhea is an alteration of movement of ions and water that leads
to an increase in water content, volume, or frequency of stools.
Under normal conditions, up to 9 L of fluid is passed through the
adult gastrointestinal tract daily. Almost 98% of this fluid is
absorbed, and only 100 to 200 mL is excreted in stools. Enteric
pathogens or microbial toxins that are ingested can overcome
host defenses and alter this balance toward a net secretion,
leading to diarrhea. A large number of microorganisms are nor-
mally ingested with every meal. Host defense mechanisms against
enteric pathogens include low gastric pH, rapid transit of bacteria
through the proximal small intestine, cellular immune responses,
and antibody production. In addition, large numbers of normal
bacterial flora inhabit the intestines and prevent colonization by
enteric pathogens.
Alteration of the normal defense mechanisms can put indi-
viduals at risk for infectious diarrhea. Individuals with gastric
resection or achlorhydric states have increased frequency of
infection due to Salmonella, Giardia lamblia, and helminths,
whereas some organisms, such as Shigella or rotavirus, survive the
extreme acidity of the gastric environment. Some viral, bacterial,
and parasitic infections are more common in patients with
impaired cellular or humoral immunity. More than 99% of the
96 
Awewura Kwara
normal colonic flora is made up of anaerobic bacteria; they
produce fatty acids and cause acidic pH, which is important for
resistance to colonization. Alteration of the bacterial flora due to
broad-spectrum antibiotic therapy predisposes some individuals
to the development of Clostridium difficile infection.
The virulence factors employed by enteric pathogens include
inoculum size, adherence factors, toxin production, and invasion.
Organisms such as Shigella, enterohemorrhagic Escherichia coli
(EHEC), G. lamblia, and Entamoeba histolytica need as few as 10
to 100 organisms to produce infection, whereas Vibrio cholerae
needs 105 to 108 organisms to cause disease. Many pathogens,
including V. cholerae and enterotoxigenic E. coli (ETEC), must
adhere to the gastrointestinal tract to establish infection. They
produce virulence factors that allow the organisms to attach to
the brush border of the intestinal epithelium. Several enteric
pathogens produce disease through the production of toxins.
These include enterotoxins that cause secretory diarrhea, cyto-
toxins that cause cell destruction and inflammatory diarrhea, and
neurotoxins that act on the nervous system. Other bacteria cause
disease by invasion and destruction of mucosal epithelial cells.
Enterotoxin-Induced Secretory Diarrhea
Ingested enterotoxin-producing bacteria colonize the small
bowel and multiply to large numbers. The bacteria then produce
enterotoxin, which binds to the mucosa and causes watery diar-
rhea through hypersecretion of isotonic fluid that overwhelms
the absorptive capacity of the colon. V. cholerae produces the
cholera toxin, a heterodimeric protein composed of one A and
five B subunits. The enterotoxin binds to the intestinal mucosa
and activates adenylate cyclase to produce cyclic adenosine
monophosphate (cAMP), which causes increased chloride secre-
tion and decreased sodium absorption, leading to hypersecretion
of fluid. ETEC, which causes traveler’s diarrhea, produces both a
heat-labile enterotoxin that acts by the same mechanism as the
cholera toxin and a heat-stable enterotoxin that causes secretory
diarrhea through activation of guanylate cyclase to produce cyclic
guanosine monophosphate (cGMP).
Cytotoxin-Induced Diarrhea
In contrast to enterotoxins, cytotoxins elaborated by enteric
pathogens destroy mucosal epithelial cells, causing bloody diar-
rhea with inflammatory cells (dysentery). Shigella dysenteriae
produces the shiga toxin, which causes dysenteric diarrhea in
patients with shigellosis. Other toxin-producing bacteria include
Vibrio parahaemolyticus, C. difficile, and shiga toxin–producing
strains of E. coli (STEC) that cause hemorrhagic colitis and
hemolytic-uremic syndrome (HUS).
899
900 Section XV  Infectious Disease

in vivo toxin production often results in disease with a longer

Invasive Diarrhea
Some bacteria cause dysentery through direct invasion and
destruction of intestinal mucosa rather than through production
of a cytotoxin. Shigella and enteroinvasive E. coli invade and mul-
tiply in epithelial cells and spread to adjacent cells. Diarrhea is
often accompanied by fever, abdominal cramps, and small
amounts of bloody mucoid stools. Other bacteria, such as Salmo-
nella typhi and Yersinia enterocolitica, penetrate the mucosa before
disseminating into the bloodstream to cause a systemic illness.
Bacterial Food Poisoning
Bacterial food poisoning is caused by ingestion of preformed
toxins in food; this results in a toxic illness rather than an enteric
infection. The toxins may include cytotoxins, enterotoxins, and
neurotoxins. Pathogens that produce bacterial food poisoning
include Staphylococcus aureus, Clostridium perfringens, and Bacil-
lus cereus. These organisms grow in food and produce toxins that
are ingested directly in the food. Symptoms occur soon after food
ingestion, with incubation periods of 1 to 16 hours and high
attack rates. The illness is rarely associated with fever, and symp-
toms usually resolve within 12 to 24 hours after onset.
The staphylococcal and B. cereus toxins act on the nervous
system to cause vomiting. S. aureus causes vomiting and diarrhea
within 2 to 7 hours after ingestion of improperly cooked or stored
food containing its heat-stable enterotoxin. C. perfringens pro-
duces secretory and cytotoxin-induced watery diarrhea within 8
to 14 hours after ingestion of contaminated vegetables, meat, or
poultry. B. cereus often contaminates fried rice, vegetables, or
sprouts; it produces one of two toxins which cause disease resem-
bling that of S. aureus or C. perfringens infection within 1 to 6
hours after ingestion. Ingestion of the bacteria with subsequent
incubation period (8 to 16 hours).
  SPECIFIC PATHOGENS
The epidemiologic and clinical features of common enteric
pathogens and the recommended methods for diagnosis and
treatment are summarized in Tables 96-1 and 96-2.
Shigella
Diarrhea due to Shigella occurs after ingestion of fecally contami-
nated food or water. The main species include S. dysenteriae, Shi-
gella flexneri, Shigella boydii, and Shigella sonnei. Ingestion of as
few as 10 to 100 microorganisms can lead to infection because
the bacteria are relatively resistant to gastric acid. Person-to-
person transmission is common, and the attack rate is highest
among infants and young children in child care centers. The incu-
bation period is 6 to 72 hours. Illness may initially manifest as
noninflammatory, watery diarrhea caused by enterotoxin produc-
tion or multiplication of bacteria in the small intestines. Invasion
of the colonic epithelium and mucosa often manifests as dysen-
tery. Complications of shigellosis include HUS, which is associ-
ated with S. dysenteriae type 1, and Reiter’s chronic arthritis
syndrome, which is associated with S. flexneri infection.
Salmonella
Salmonella typhi causes typhoid fever, but not diarrhea. Nonty-
phoidal salmonellosis results from ingestion of contaminated
meat, dairy, or poultry products or from direct contact with
animals such as birds, pet turtles, snakes, and other reptiles. An
oral inoculum of 105 to 108 organisms is needed but smaller
inocula can cause disease in patients with impaired gastric acidity
or compromised immunity. The organisms invade the distal

TABLE 96-1  EPIDEMIOLOGIC AND CLINICAL CHARACTERISTICS OF COMMON ENTERIC PATHOGENS

ORGANISM
Campylobacter jejuni
Vibrio cholerae
Clostridium difficile
Enterotoxigenic Escherichia coli
Nontyphoidal Salmonella
Shigella
Shiga toxin–producing E. coli
Noncholeraic Vibrio
Yersinia enterocolitica
Norovirus
Cyclospora
Cryptosporidium
Entamoeba histolytica
Giardia lamblia
EPIDEMIOLOGIC FEATURES
Consumption of undercooked poultry, travel to tropical and
semitropical regions
Inadequately cooked seafood, travel to endemic regions
Antibiotic use, recent hospitalization, elderly patients with
coexisting conditions
Travel to tropical and semitropical regions
Foodborne outbreaks, exposure to animals
Person-to-person transmission, daycare center contact
Foodborne outbreaks, undercooked hamburgers, raw seed sprouts,
water and wading pool exposure
Ingestion of shellfish and undercooked seafood
Contaminated food or water, inadequately cooked meats,
unpasteurized milk
Winter outbreaks in congregate settings, outbreaks on cruise ships
Foodborne outbreaks, travel to tropical and subtropical regions
(especially Nepal)
Waterborne outbreaks, travel to tropical and subtropical regions
Travel to tropical regions, recent immigration from endemic
regions
Waterborne outbreaks, travel to mountainous areas of North
America, Russia
COMMON CLINICAL FEATURES
Acute watery diarrhea, fever, abdominal pain, fecal
evidence of inflammation (positive fecal leukocytes,
lactoferrin, or occult blood)
Acute dehydrating watery diarrhea; fever is usually
absent
Diarrhea with fever, fecal evidence of inflammation,
marked leukocytosis
Watery diarrhea, abdominal cramps, nausea and
vomiting; leukocytes absent in stools
Acute watery diarrhea, fever, abdominal pain, evidence
of inflammation
Severe diarrhea with fever, abdominal pain, bloody
diarrhea, fecal evidence of inflammation
Abdominal pain, bloody stools, absence of fever, fecal
evidence of inflammation
Watery diarrhea, abdominal cramps, nausea; fever and
vomiting are less frequent
Acute watery diarrhea, fever, abdominal pain, bloody
diarrhea
Watery diarrhea, nausea, vomiting, abdominal pain
Persistent noninflammatory diarrhea
Persistent noninflammatory diarrhea
Bloody diarrhea, extraintestinal involvement (liver
abscess)
Abdominal pain, persistent watery diarrhea, flatulence,
steatorrhea, nausea and vomiting
 Chapter 96  Infectious Diarrhea 901

TABLE 96-2  DIAGNOSIS AND RECOMMENDED ANTIMICROBIAL TREATMENT FOR DIARRHEA WITH SPECIFIC
PATHOGENS IN ADULTS
ORGANISM
Campylobacter jejuni
Vibrio cholerae O1
Clostridium difficile
Enterotoxigenic Escherichia coli
Nontyphoidal Salmonella
Shigella
Shiga toxin–producing E. coli
Noncholeraic Vibrio
Yersinia enterocolitica
Cyclospora
Cryptosporidium
Isospora
Entamoeba histolytica
Giardia
bid, Twice a day; EIA, enzyme immunoassay; PCR, polymerase chain reaction; qid, four times a day; tid, three times a day; TCBS, thiosulfate-citrate-bile salts-sucrose agar; TMP-SMZ,
trimethoprim-sulfamethoxazole.
DIAGNOSIS
Routine stool culture
Stool culture in special salt-containing media
(TCBS), test isolate for O1 serotype
Stool test for C. difficile toxin A or B by EIA, or
PCR for the B toxin gene
Stool culture for E. coli, with assay for enterotoxin
Routine stool culture
Routine stool culture
Stool culture with sorbitol-MacConkey agar,
followed by serotyping for O157, then H7,
with EIA for shiga toxins
Stool culture in special salt-containing media
(TCBS)
Stool culture on MacConkey media incubated at
25° to 28° C
Stool trichrome or acid-fast stain for parasites
Stool trichrome or acid-fast stain for parasites,
EIA for Cryptosporidium species
Stool trichrome or acid-fast stain for parasites
Stool examination for ova and parasites, EIA for
E. histolytica
Stool examination for ova and parasites, EIA for
Giardia species
RECOMMENDATIONS
Erythromycin 250 mg qid or azithromycin 500 mg daily for 7 days
Doxycycline 300 mg single dose, or single dose of fluoroquinolone, or
tetracycline 500 mg qid for 3 days, or TMP-SMZ 160/800 mg bid for
3 days
Stop implicated antibiotic. For mild to moderate illness, metronidazole
500 mg tid for 10 days; for severe illness, vancomycin 125 mg qid for
10-14 days
Fluoroquinolone orally for 3 days (e.g., ciprofloxacin 500 mg bid,
levofloxacin 500 mg daily, norfloxacin 400 mg bid). If susceptible,
TMP-SMZ 160/800 mg bid for 3 days
Antimicrobials not recommended. If extraintestinal involvement or
immunocompromise is present, TMP-SMZ (if susceptible) or quinolone
as above, or ceftriaxone 100 mg/kg/day in one or two divided doses for
7 to 14 days, or longer if endovascular infection or relapsing
Fluoroquinolone for 3 days (e.g., ciprofloxacin 500 mg bid, levofloxacin
500 mg daily, norfloxacin 400 mg bid). If susceptible, TMP-SMZ
160/800 mg bid for 3 days
Antibiotics and antimotility drugs should be avoided
Fluoroquinolone orally for 3-5 days (ciprofloxacin 500 mg bid,
levofloxacin 500 mg daily, norfloxacin 400 mg bid)
Antibiotics usually not required. For severe infection or bacteremia, treat
with TMP-SMZ or fluoroquinolone or doxycycline plus aminoglycoside
TMP-SMZ 160/800 mg bid for 7-10 days
Self-limited in immunocompetent persons. If severe or if patient is
immunocompromised, consider paromomycin 500 mg tid for 7 days
TMP-SMZ 160/800 mg bid for 7-10 days
Metronidazole 750 mg tid for 5-10 days, plus iodoquinol 650 mg tid for 20
days or paromomycin 500 mg tid for 7 days
Metronidazole 500 to 750 mg tid for 7-10 days

ileum and cause diarrhea with fever, nausea, or vomiting. Diar-
rhea usually resolves in 2 to 3 days. Complications include bac-
teremia and metastatic seeding of atherosclerotic plaques and
prostheses. Antimicrobial treatment does not shorten the dura-
tion of diarrhea and may prolong intestinal carriage in stools;
therefore, antibiotics are indicated only for cases of severe disease
or extraintestinal involvement.
Campylobacter jejuni
Disease caused by Campylobacter jejuni usually results from
ingestion of undercooked poultry or direct contact with animals.
The infective dose is 104 to 106 organisms, with an incubation
period of 1 to 5 days. Acute watery diarrhea is the most common
presentation; less frequently, systemic symptoms including fever
may occur. Prodromal symptoms such as fever, myalgia, head-
ache, and malaise may precede diarrhea. Complications include
reactive arthritis, especially associated with the human leukocyte
antigen B27 (HLA-B27), and Guillain-Barré syndrome, which
can occur 2 to 3 weeks after diarrhea has resolved. Antibiotic
therapy shortens the carriage state.
Vibrio
V. cholerae can be divided by the O-antigen of lipopolysaccharide
into more than 150 strains. The toxigenic strains V. cholerae O1
and O139 produce cholera toxin and are associated with clinical
illness. The infectious oral inoculum is about 105 to 108 organ-
isms, with an incubation period of 6 hours to 5 days. Classic
cholera starts with vomiting, abdominal pain, and diarrhea. Diar-
rhea progresses to voluminous watery stools which have been
described as “rice water” because they are clear with flecks of
mucus. Massive diarrhea can lead to dehydration and shock
within a few hours. The illness may be fulminant, with death
occurring 3 to 4 hours after onset. Fever and bacteremia are rare.
In endemic areas, the diagnosis is usually made on clinical
grounds.
The characteristics of noncholeraic Vibrio species are covered
in Tables 96-1 and 96-2.
Diarrhea-Causing Escherichia coli
There are several types of diarrheagenic E. coli, each with a differ-
ent pathogenesis leading to diarrhea. In addition to ETEC and
STEC, these include enteropathogenic, enteroinvasive, enteroag-
gregative, and diffusely adherent E. coli. ETEC is the most
common cause of traveler’s diarrhea. It results in an enterotoxin-
mediated watery diarrhea with abdominal cramps and vomiting.
Enteropathogenic E. coli has been associated with epidemic diar-
rhea in neonates.
EHEC or STEC is acquired by eating contaminated food or
water. The oral inoculum is 10 to 100 organisms, with an incuba-
tion period of 3 to 4 days. Most disease in the United States is
caused by E. coli O157:H7, an enterohemorrhagic strain. It is
classically associated with bloody diarrhea, abdominal pain,
and fecal leukocytes. Systemic complications include HUS in
children and thrombotic thrombocypenia purpura in adults.
902 Section XV  Infectious Disease
Antibiotic therapy has not been shown to reduce morbidity and
may increase the risk of HUS in children.
Clostridium difficile
C. difficile is the main cause of nosocomial diarrhea among adults
in the United States. Virtually all antibiotics have been implicated
in the development of C. difficile infection, but the most common
agents are clindamycin, cephalosporins, fluoroquinolones, and
penicillins. Spores occur in the environment and are resistant to
alcohol-based handwashing solutions. The spores of toxigenic C.
difficile are ingested, survive gastric acidity, geminate, and colo-
nize the lower intestinal tract, where they elaborate two exotox-
ins, toxin A (an enterotoxin) and toxin B (a cytotoxin). The toxins
disrupt cell and tight junctions, leading to fluid leakage. The cel-
lular toxicity results in formation of a pseudomembrane.
The epidemic strain referred to as the North American pulsed-
field gel electrophoresis type 1 (NAP1) strain is associated with
a severe course, higher mortality, and increased risk of relapse.
Three bacterial factors have been implicated in outbreaks of C.
difficile infection caused by the NAP1 strain, including increased
production of toxins A and B, fluoroquinolone resistance, and
production of a binary toxin. Patients often have abdominal pain
and watery diarrhea but may also have bloody stools. Markers of
severe infection include pseudomembranous colitis, acute renal
failure, marked leukocytosis, hypotension, and toxic megacolon.
The indigenous intestinal microbiota is important for coloniza-
tion resistance and for recovery from antibiotic-associated C. dif-
ficile colitis.
Yersinia enterocolitica
Y. enterocolitica is a zoonosis caused by ingestion of contaminated
food or water or undercooked meats. Oral inoculation requires
109 organisms for infection, with an incubation period of 3 to 7
days. The illness may mimic acute appendicitis and may be com-
plicated by ileal perforation, mesenteric adenitis, or terminal
ileitis. Postinfectious reactive polyarthritis and Reiter’s syndrome
may occur.
Viral Causes of Diarrhea
Viruses tend to cause diarrhea by adhering to the intestinal
mucosa and disrupting the absorptive and secretory processes
without causing inflammation. They may invade intestinal villous
epithelial cells and cause sloughing of villi. Rotavirus was the
most common cause of severe diarrhea in children in the past,
but the incidence has fallen dramatically with widespread use of
the rotovirus vaccine. Norovirus is highly contagious and is a very
common cause of foodborne gastroenteritis in adults and chil-
dren in the United States. It has been the cause of epidemic diar-
rhea on cruise ships. There is neither a vaccine nor specific
treatment. Other viruses that cause diarrhea are adenoviruses,
sapoviruses, and astroviruses. The incubation period is usually
longer than 14 hours, and vomiting may be a prominent feature
of diarrheal disease caused by viral agents.
Protozoan Causes of Diarrhea
Important parasitic causes of diarrhea include G. lamblia, Cryp-
tosporidium parvum, and E. histolytica. Contaminated water
sources tend to be the cause of outbreaks. G. lamblia multiplies
in the small intestine and attaches to or invades, but does not
destroy, mucosa cells. Ingestion of a few organisms can lead to
disease. C. parvum, Isospora belli, and Cyclospora cayetanesis occa-
sionally cause self-limited diarrhea in immunocompetent indi-
viduals but may cause severe disease in patients with advanced
acquired immunodeficiency syndrome (AIDS). E. histolytica
causes a syndrome ranging from mild diarrhea to fulminant
amebic colitis and extraintestinal amebic abscesses.
Traveler’s Diarrhea
Traveler’s diarrhea affects 10% to 40% of travelers from industri-
alized countries who visit tropical and semitropical developing
countries. The causative agent is identified in about one half of
cases, and 80% of those identified are bacterial pathogens, most
often ETEC or enteroaggregative E. coli. Other bacterial causes
include Shigella, Salmonella, Campylobacter, Aeromonas, nonchol-
eraic Vibrio, and Plesiomonas. The viral etiologies include rotavi-
rus and norovirus; parasitic causes are rare. Patients with traveler’s
diarrhea should be treated empirically with antibiotics without
stool examination.
  CLINICAL PRESENTATION
The epidemiologic and clinical characteristics are important to
identify the potential etiologic agent and to guide management
(see Table 96-1). The initial evaluation should consider the sever-
ity of illness, signs of dehydration, and intestinal inflammation
indicated by the fever, abdominal pain, blood in stools (dysen-
tery), or tenesmus. Important epidemiologic clues in the history
include age, travel history, ingestion of undercooked or raw food
and meat, antibiotic use, sexual activity, daycare attendance, and
outbreaks involving others with similar exposure (see Table
96-1). Fever (temperature 38.5° C or 101.3° F or higher) is asso-
ciated with invasive pathogens that cause intestinal inflammation.
The examination should determine the severity of dehydration
and need for rehydration as well as the likely cause. Signs of
dehydration or hypovolemia include lax skin turgor and tenting,
dry mucus membranes, decreased urination, tachycardia, and
hypotension.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
The approach to diagnosis and management of infectious diar-
rhea is shown in Figure 96-1. Examination of stools for erythro-
cytes and white blood cells (leukocytes) using methylene blue
staining or the lactoferrin test can help differentiate diarrhea
caused by invasive pathogens from that caused by noninvasive
pathogens. Most cases of diarrheal illnesses are self-limited, and
almost half resolve within 1 day. Therefore, microbiologic inves-
tigation is usually not necessary for patients who are seen within
24 hours of the onset of illness unless certain conditions are
present.
The indications for stool culture include severe diarrhea (six
or more stools per day), diarrhea lasting longer than 1 week, fever,
dysentery, hospitalization, inflammatory diarrhea, and multiple
cases in a suspected outbreak. Routine stool culture will identify
Shigella, Salmonella, Campylobacter, and Aeromonas. If the patient
has bloody diarrhea or HUS, stool culture for E. coli O157 and
tests for shiga-like toxin should be performed. Enzyme immuno-
assay for C. difficile toxins A and B or polymerase chain reaction
 Chapter 96  Infectious Diarrhea 903

ASK ABOUT:

Fever Seafood eaten‡

Outbreak#
Tenesmus Antibiotic use§
Sexual exposure**
Abd. pain* Weight loss
Other disease††
Blood† Travel¶

If seriously ill,
hospitalize and Yes No

Cup stool examination Rehydrate

Culture for Shigella, for WBC or blood with ORS
Salmonella, Yersinia, Yes No
(and parasite (or IV)
and Campylobacter trophozoites) and observe

Consider antimicrobal therapy

for Shigella and Campylobacter
Treat protozoa (Entamoeba, Giardia,
Isospora) with appropriate
Plus
antimicrobials
Treat Salmonella with antimicrobials
only in infants or others at risk for
extraintestinal infection

FIGURE 96-1  Approach to the diagnosis and management of acute infectious diarrhea. Abd., Abdominal; IV, intravenous; ORS, oral rehydration
solution; WBC, white blood cell. *If unexplained abdominal pain and fever suggest an appendicitis-like syndrome, culture for Yersinia enterocolitica.
†
Bloody diarrhea, in the absence of fecal leukocytes, suggests enterohemorrhagic Escherichia coli or amebiasis (where leukocytes are destroyed
by the parasite). ‡Ingestion of inadequately cooked seafood prompts consideration of Vibrio infections or noroviruses. §Associated antibiotics
should be stopped and Clostridium difficile considered. ‖Persistence of diarrhea (>10 days) with weight loss prompts consideration of giardiasis,
cryptosporidiosis, or inflammatory bowel disease. ¶Travel to tropical areas increases the chance of enterotoxigenic E. coli (ETEC) as well as viral,
protozoal (Giardia, Entamoeba, Cryptosporidium), and, if fecal leukocytes are present, invasive bacterial pathogens. #Outbreaks should prompt
consideration of Staphylococcus aureus, Bacillus cereus, Clostridium perfringens, ETEC, Vibrio, Salmonella, Campylobacter, or Shigella infection. **Sig-
moidoscopy in symptomatic homosexual men should distinguish proctitis in the distal 15  cm (caused by herpesvirus, gonococcal, chlamydial, or
syphilitic infection) from colitis (Campylobacter, Shigella, or C. difficile infection). ††In immunocompromised hosts, a wide range of viral (e.g., cyto-
megalovirus, herpes simplex virus, rotavirus), bacterial (e.g., Salmonella, Mycobacterium avium complex, C. difficile), protozoal (e.g., Cryptosporidium,
Isospora, Microsporidium, Entamoeba, Giardia) and parasitic (Strongyloides hyperinfection syndrome) agents should be considered. (Modified from
Guerrant RL, Shields DS, Thorson SM, et  al: Evaluation and diagnosis of acute infectious diarrhea, Am J Med 78:91–98, 1985.)

for toxin B should be obtained if there is a history of recent anti-
biotic use, hospitalization, or age greater than 65 years with coex-
isting conditions, immunosuppression, or neutropenia. Consider
protozoa, and check stools for ova and parasites (e.g., trophozo-
ites) and/or for Giardia antigen test if diarrhea duration is greater
than 7 days. If a patient has AIDS, stools should be checked for
Cryptosporidium, Microsporidium, and Mycobacterium avium
complex.
of salt (NaCl), and one fourth of a teaspoon of baking soda
(NaHCO3) to 1 L of boiled drinking water. In the United States,
fluids containing sodium in the range of 45 to 75 mEq/L (such
as Pedialyte or Rehydrolyte solutions) are recommended. Fluid
should be administered in large quantities until there is clinical
evidence that fluid balance is restored, and then as maintenance
therapy. Oral rehydration therapy can be life-saving for patients
in developing countries with severe diarrhea.

  TREATMENT Intravenous Fluid Therapy

Initial therapy should include fluid and electrolyte repletion with
or without antimicrobial therapy. Oral rehydration is often ade-
quate unless the patient is comatose or severely dehydrated.
Nutritional support with continued feeding improves outcomes
in children. In children, the BRAT diet (bananas, rice, apple-
sauce, and toast) with avoidance of milk products is often recom-
mended, but supporting evidence is limited.
Massive fluid loss due to diarrhea should be rapidly replaced
by the administration of intravenous fluids. Lactated Ringer’s
solution is the fluid of choice because the composition is similar
to electrolyte loss during diarrhea. The rate of fluid administra-
tion and maintenance should be guided by clinical signs includ-
ing vital signs, appearance of the mucosa, neck veins, and skin
turgor.

Oral Fluid Therapy Antimicrobial Therapy

In most patients with diarrhea, fluid repletion can be achieved Most cases of infectious diarrhea do not require antimicrobial
with oral rehydration therapy using isotonic fluids containing therapy. However, antibiotics may decrease the volume of diar-
glucose and electrolytes. An effective solution can be prepared by rhea (e.g., in cholera) or the duration and severity of the illness.
the addition of 2 tablespoons of sugar, one fourth of a teaspoon Antibiotics are effective in the treatment of shigellosis, traveler’s
904 Section XV  Infectious Disease
diarrhea, Campylobacter infection, and C. difficile infection. In
uncomplicated salmonellosis, antibiotics may prolong the shed-
ding of salmonella. The choice and dose of antimicrobials for
specific pathogens are described in Table 96-2. For traveler’s
diarrhea in adults, empiric therapy with ciprofloxacin 500 mg
twice a day, or trimethoprim-sulfamethoxazole (TMP-SMZ)
160/800 mg twice a day, for 3 to 5 days is adequate. For antibiotic-
associated C. difficile colitis, broad-spectrum antibiotics should
be discontinued, if possible. The first-line therapy is metronida-
zole 500 mg three times a day orally for 10 to 14 days. For severely
ill patients, oral vancomycin 125 mg four times a day for 10 to 14
days should be initiated. Persistently recurrent C. difficile disease
has been treated successfully with replacement of bowel flora.
Symptomatic Therapy
Antidiarrheal agents such as loperamide and bismuth subsalicy-
late can be used in some instances for symptomatic relief. Loper-
amide inhibits intestinal peristalsis and has some antisecretory
properties. When used with or without antibiotics in cases of
traveler’s diarrhea, it may reduce the duration of diarrhea by
about 1 day. Antimotility agents should be avoided in patients
with bloody or suspected inflammatory diarrhea. The use of these
agents has been implicated in prolonging the duration of fever in
shigellosis, development of toxic megacolon in C. difficile colitis,
and development of HUS in children with STEC infection.
Bismuth subsalicylate can alleviate stool output in children as
well as the symptoms of abdominal pain, diarrhea, and nausea in
patients with traveler’s diarrhea.
  PROGNOSIS
The prognosis is generally good but is variable depending on the
etiology and the severity of illness. Most patients recover com-
pletely within 3 to 5 days. However, serious complications includ-
ing death, can occur. Serious disease and death is usually seen in
individuals who become severely dehydrated, infants, elderly
patients, and those with underlying medical conditions or immu-
nosuppression (e.g., AIDS). Untreated severe dehydration may
lead to shock, renal failure, and death. Postinfectious reactive
polyarthritis and Reiter’s syndrome can complicate cases due to
Yersinia, Campylobacter, Shigella, and Guillain-Barré syndrome
may occur after diarrhea caused by Campylobacter.
SUGGESTED READINGS
Dupont HL: The Practice Parameters Committee of the America College of
Gastroenterology: Guidelines on acute infectious diarrhea in adults, Am J
Gastroenterol 92:1962–1975, 1997.
Dupont HL: Bacterial diarrhea, N Engl J Med 361:1560–1569, 2009.
Guerrant RL, Van Gilder T, Steiner TS, et al: Practice guidelines for the
management of infectious diarrhea, Clin Infect Dis 32:331–351, 2001.
Kelly CP, Lamont JT: Clostridium difficile—more difficult than ever, N Engl J Med
359:1932–1936, 2008.
Thielman NM, Guerrant RL: Acute infectious diarrhea, N Engl J Med 350:38–47,
2004.

Infections Involving
Bones and Joints
  DEFINITION
The term osteomyelitis refers to infection of any component of the
bony skeleton, whereas septic arthritis refers to infection of native
or prosthetic joints. Associated structures such as tendons, liga-
ments, and bursae can also become infected, especially if they
involve prosthetic or biografted material. Osteomyelitis and
septic arthritis can each occur as a result of seeding during an
episode of bacteremia, as a consequence of vascular insufficiency,
as a complication of trauma, or by extension from a contiguous
focus of infection in an adjacent tissue or structure.
In the case of hematogenous infection, the bacteremia itself
may be relatively transient and of little clinical consequence.
Hematogenous osteomyelitis is common in children but accounts
for only about 20% of osteomyelitis in adults. The vertebrae and
pelvis are the most commonly involved sites.
Peripheral vascular disease leading to tissue hypoxia, often
related to diabetes, hypertension, hyperlipidemia, or smoking, is
the biggest risk factor for the development of osteomyelitis in
adults older than 50 years of age. There is often antecedent soft
tissue infection or destruction as a result of vascular insufficiency
and neuropathy. It is most common in the lower extremities,
particularly in the feet, and often occurs in diabetics.
Trauma, especially when it involves open fracture, with its
attendant disruption of the bony architecture and vascular supply,
is a major risk factor for development of osteomyelitis and septic
arthritis. This is particularly true when an open fracture (such as
from a fall or a motor vehicle accident), is heavily contaminated
with soil or other environmental materials. Such fractures often
require internal fixation (i.e., placement of rods, screws, or other
metal devices) to stabilize the bone. The presence of such internal
fixation devices provides a nidus for bacteria and other microor-
ganisms, including fungi, to elude the immune system and incu-
bate. Chronic osteomyelitis is a possible complication of such
injuries and is often a result of multiple or unusual organisms. It
may occur despite aggressive débridement and prophylactic anti-
biotic treatment at the time of injury and can arise months or
even years afterward. Individuals who experience prolonged
periods of immobility (e.g., paraplegia) are also at risk for osteo-
myelitis. Infection typically involves the pelvis, sacrum, and
lower spine, corresponding to areas of unrelieved pressure and
resulting pressure sores.
Osteomyelitis may be thought of as being acute or chronic.
The former is typically hematogenous and associated with signs
of inflammation in the overlying soft tissue, with onset occurring
over the course of days to 1 week. Radiographs are usually normal
97 
Jerome Larkin
at presentation. Chronic osteomyelitis is typically more indolent,
with onset over the course of months. It is more likely to show
bony destruction on plain radiographs at the time of presentation
and is often associated with a draining sinus tract. Sequestra
(areas of dead bone) and involucra (new bone formed around
sequestra) may also be seen on radiographs. Whereas with acute
osteomyelitis, a 6-week course of antibiotics may effect a cure,
chronic osteomyelitis more typically requires surgical interven-
tion and a prolonged (≥3 months) course of antibiotic therapy.
  PATHOPHYSIOLOGY
Characteristics of the vascular supply of the bone and properties
of the most common pathogen, Staphylococcus aureus, may
combine to lead to infection. Although bone is generally resistant
to infection, the vasculature of the metaphysis contains capillary
loops composed of a single layer of discontinuous endothelial
cells, which may allow bacteria to enter the extracellular matrix.
Additionally, these capillary beds appear to lack functionally
active phagocytes. S. aureus is able to elaborate proteins expressed
on its surface that promote adherence to tissues of the extracel-
lular matrix. When engulfed by osteoblasts, S. aureus can survive
for prolonged periods in an almost sporelike state, leading to
potential recurrences of infection. Finally, many bacteria can
elaborate biofilms that allow them to elude clearance by the
immune system. Prosthetic material, such as that used in joint
replacements and other grafts, can serve as a platform for the
formation of such biofilms.
In the case of septic arthritis, there is usually some underlying
joint abnormality (e.g., rheumatoid arthritis), although this
abnormality may be as mundane as osteoarthritis. It is hypothe-
sized that relatively trivial injuries, which may even go unnoticed
or unremembered by the patient, can cause minor bleeding into
the joint, providing a hospitable environment for bacteria to
incubate.
  CLINICAL PRESENTATION AND DIAGNOSIS
Patients with osteomyelitis often have pain at the site of infection.
The overlying soft tissue may have signs of inflammation or tissue
destruction; the latter is often seen in diabetics with soft tissue
ulceration. Historically, the diagnosis of osteomyelitis relied on
the presence of lucency on plain radiographs of the affected area.
The diagnosis could be confirmed histologically by bone biopsy
with culture to identify the pathogenic organism. Currently, the
diagnosis is typically based on magnetic resonance imaging
(MRI) with gadolinium, which demonstrates marrow edema
with or without bony destruction. Alternatively, the diagnosis
905
906 Section XV  Infectious Disease
may be made by three-phase bone scanning or computed tomog-
raphy. These modalities may be especially helpful for patients
with renal insufficiency who cannot undergo gadolinium-
enhanced studies due to the risk of nephrogenic systemic fibrosis.
An elevated C-reactive protein (CRP) level or erythrocyte sedi-
mentation rate (ESR) supports the diagnosis.
Microbiologic diagnosis of osteomyelitis is made by positive
blood cultures or by bone biopsy and culture. Culture of cutane-
ous ulcers is typically not helpful because the results usually dem-
onstrate multiple colonizing organisms and do not correlate with
organisms isolated on bone culture. An exception is the isolation
of S. aureus or Salmonella from a draining fistula or, on occasion,
Pseudomonas from an ulcer. In the former case, the bacterium can
be presumed to be the pathogen; in the latter, a decision would
have to be made to include coverage of Pseudomonas spp in an
empirical antibiotic regimen. If cultures of bone obtained by
bone aspirate under radiographic guidance are negative, either
the procedure should be repeated or an open biopsy with culture
should be performed.
Septic arthritis almost always manifests with the cardinal fea-
tures of inflammation (i.e., erythema, swelling, warmth, and
pain) when it involves the extremities. Fever is frequently present,
and there is often an associated bacteremia. Septic arthritis of
the spine, pelvis, or hip may require imaging, usually MRI,
because these sites are difficult to assess by examination alone.
Persistent back, pelvic, or hip pain that is otherwise unexplained
should prompt radiographic evaluation even in the absence of
fever.
The diagnosis of septic arthritis ultimately relies on joint aspi-
ration. Such procedures should occur before the administration
of antibiotics. Fluid should be sent for cell count with differential,
crystal analysis, Gram stain, aerobic and anaerobic culture, and
fungal and acid-fast stains and cultures. Positive stains or cultures
are taken as evidence of infection in most cases in which an
appropriate clinical syndrome is also present. White blood cell
(WBC) counts higher than 50,000 cells/µL are suggestive of
infection. In cases that are difficult to diagnosis and in instances
in which antibiotics were given before aspiration, it may be
appropriate to have cultures held for up to 14 days. Specialized
culture techniques for fastidious organisms such as anaerobes
and nutritionally deficient streptococci may be required. Ulti-
mately, tagged WBC scans may help to clarify the presence or
absence of septic arthritis in difficult cases. Evolving molecular
technologies such as polymerase chain reaction (PCR) and 16S
ribosomal sequencing may offer alternative and more rapid and
precise diagnosis in the future.
Most cases of osteomyelitis and septic arthritis are caused by
Staphylococcus spp, Streptococcus spp, and aerobic gram-negative
bacilli, although almost any pathogenic microorganism can cause
such an infection in the appropriate circumstance. Infecting
Staphylococcus spp include both S. aureus and coagulase-negative
staphylococci. The latter are often implicated in prosthetic joint
infections and infections associated with orthopedic hardware.
Streptococcus spp that cause bone and joint infections include
groups A, B, C, G, and F, as well as Abiotrophia and Gemella
(formerly termed “nutritionally deficient streptococci”).
Gram-negative organisms account for as many as 30% of
hematogenous infections. They are seen more commonly in the
elderly as a result of urinary tract infection with associated bac-
teremia. Isolated species include Escherichia coli, Haemophilus
influenzae, and Haemophilus parainfluenzae. Infections with Ser-
ratia marcescens and Pseudomonas spp are associated with expo-
sure to water and are usually nosocomial or related to intravenous
drug use.
Fungi such as Candida, Aspergillus, and Zygomycetes may cause
bone and joint infections particularly in immune-compromised
patients, diabetics, and those who have suffered trauma. Nocardia
and other acid-fast organisms may be seen after trauma or in
association with prosthetic joints, and several attempts at débride-
ment may be needed before the organism can be isolated. Propi-
onibacterium acnes is often isolated from shoulder infections,
especially those involving prosthetic joints. The variety of poten-
tial pathogens underscores the need to obtain appropriate speci-
mens for culture before administration of antibiotics.
Infection with Borrelia burgdorferi, the causative agent of Lyme
disease, can lead to a multifocal or monoarticular septic arthritis.
Fluid analysis is consistent with bacterial septic arthritis but is
negative for typical organisms on culture. Associated findings of
erythema migrans, diffuse myalgias and arthralgias, cranial nerve
palsies, fever, and aseptic meningitis may also be present. PCR
analysis of joint fluid has a reported sensitivity between 30% and
75%. Diagnosis relies on serology and associated findings in
patients who reside in endemic areas. Later-stage disease may
manifest with a less inflammatory-appearing effusion, often
without any other symptoms. Treatment is with doxycycline or
ceftriaxone, depending on the stage of disease.
Neisseria gonorrhoeae can cause a solitary or multifocal septic
arthritis often associated with tenosynovitis and skin lesions. It is
usually seen in sexually active younger adults. Culture of the joint
fluid may be negative, but testing of specimens from the pharynx,
urethra, or rectum is usually positive by nucleic acid amplifica-
tion. The treatment of choice is ceftriaxone.
  DIFFERENTIAL DIAGNOSIS
The differential diagnosis of both osteomyelitis and septic arthri-
tis includes noninfectious inflammatory disorders such as gout,
pseudogout, rheumatoid arthritis, inflammatory bowel disease,
and other inflammatory and autoimmune disorders. Occasion-
ally, neoplasms such as sarcomas or metastatic lesions may mani-
fest similarly to osteomyelitis. Infection with several viruses such
as rubella, parvovirus B19, and hepatitis B virus can manifest
with arthritis.
Chronic recurrent multifocal osteomyelitis is a noninfectious
inflammatory lesion of bone that is thought to be autoimmune
in nature and is characterized by findings on MRI similar to those
of osteomyelitis. It is culture-negative and unresponsive to anti-
biotics. The diagnosis is one of exclusion and often is made only
after several attempts at diagnosing and treating presumed bacte-
rial osteomyelitis. Although it is typically seen in children, it can
also occur in adults.
  TREATMENT
Treatment of osteomyelitis involves débridement of appropriate
infected or necrotic tissue and the administration of antibiotics.
It is critically important to remove all necrotic or devitalized
tissue. If not removed, such tissue may serve as a nidus of chronic
 Chapter 97  Infections Involving Bones and Joints 907
or recurrent infection. In this regard, it is often necessary to
remove any fixating hardware, plastic device, bone graft, or other
donor tissue if the infection has been present for longer than 1
month or is recurrent. Cadaveric donor tissue infections often are
caused by atypical organisms such as Clostridium spp. Histori-
cally, sequestra developed in sites of chronically infected bone.
These are produced by the action of the immune system and
histologically are characterized by granulomatous tissue that
serves to isolate the infection. Although this reaction is effective
in containing the infection, it represents a risk for recurrence as
well as an area of bone weakening. Any sequestra that are discov-
ered should be surgically excised.
Infection that occurs in the immediate postoperative period
(i.e., within 1 month after placement of hardware and grafts) and
appears to involve only the soft tissue may be treated with
débridement and antibiotics alone with a reasonable chance of
success. Occasionally, infected hardware must be left in place to
stabilize the bone while a fracture is healing. In such cases, it may
be necessary to continue antibiotic treatment until the hardware
can be removed. Infected spine hardware, which must remain in
place, may necessitate prolonged antibiotic treatment, at times
even indefinitely. The addition of rifampin for susceptible staphy-
lococcal infections with retained hardware improves the overall
cure rates.
Septic arthritis requires either repeated aspiration or serial
débridement of the joint until active purulence has resolved. This
is indicated by decreasing cell counts and sterilization of joint
fluid cultures. Prosthetic joint infection typically requires removal
of the infected prosthesis and placement of an antibiotic spacer
for 4 to 6 weeks while antibiotics are administered. This is
followed by placement of a new prosthesis after all signs and
symptoms of infection have resolved. Selected infections with
coagulase-negative Staphylococcus and Streptococcus spp may be
treated with débridement, joint retention, and a course of antibi-
otics lasting 6 weeks or longer. Consideration should then be
given to chronic suppressive antibiotic therapy, assuming that an
appropriate agent is available.
Antibiotic treatment should be with agents that are active
against the infecting organism, depending on culture and suscep-
tibility data. β-lactams are the preferred agents in most cases.
Therapy with quinolones for Enterobacteriaceae and, in combi-
nation with rifampin, for Staphylococcus spp may be considered.
These drugs have the advantage of high oral bioavailability that
results in tissue levels that approach or are equal to those achieved
when they are given intravenously. Care should be taken regard-
ing drug interactions with rifampin as well as the risks of Clos-
tridium difficile colitis and Achilles tendon rupture with
quinolones. In the face of negative cultures, empirical therapy
with an agent that is active against typical pathogens, including
methicillin-resistant S. aureus (MRSA), is reasonable. Caution
should be exercised in the use of daptomycin because there have
been failures in the treatment of bone infections with this drug.
Vancomycin remains the standard agent for empirical therapy to
cover resistant staphylococci (e.g., MRSA). Prior administration
of antibiotics may lead to negative cultures even in cases of
unequivocal infection. In this situation, empirical therapy should
be based on the activity of the agents previously administered as
well as the potential pathogens based on exposure history.
In all cases, the clinical response to treatment of the infection
should inform subsequent decision making regarding the need
for additional débridement or changes in antibiotic therapy.
Monitoring of inflammatory markers such as CRP or ESR is
helpful in determining the adequacy of response to treatment.
In particular, if these markers are elevated at the start of treat-
ment, they should fall to normal or near-normal levels by the
time the treatment is finished. Signs and symptoms of inflam-
mation at the site of infection should have also resolved by the
cessation of treatment. There have been few randomized con-
trolled trials comparing different durations of antimicrobial
therapy. In general, acute osteomyelitis should be treated for 4
to 6 weeks. It is reasonable to continue treatment if the patient
has improved but has failed to resolve elevated inflammatory
markers or local signs of inflammation. Such patients should be
closely monitored and evaluated for the need for additional
débridement or other measures aimed at diagnosis and source
control. Chronic osteomyelitis may require 12 or more weeks
of therapy, and treatment is usually individualized based on the
clinical situation.
Patients undergoing therapy should also be monitored weekly
for toxicity to antibiotics. Assessment of renal and hepatic func-
tion, complete blood counts, and drug levels are typically moni-
tored, depending on the specific agent used. In the case of
aminoglycosides, renal function and peak and trough levels of
antibiotics should be measured twice weekly. Adjunctive thera-
pies such as bone grafting, revascularization procedures, and the
placement of muscle flaps to cover and protect exposed bone may
be used in the appropriate clinical situation.
Native joint septic arthritis may be treated with a 4-week
course of antibiotics; prosthetic joint infections are typically
treated for 6 weeks or longer. Monitoring for toxicity and response
to treatment is similar to that for osteomyelitis.
  PROGNOSIS
The prognosis for most cases of osteomyelitis or septic arthritis
is excellent, assuming adequate diagnosis, débridement, and anti-
microbial therapy. The most common complication is residual
pain and/or decreased function of the affected bone or joint.
However, these effects are relatively rare and relatively minor. An
exception is prosthetic joint infections: 25% to 50% of patients
experience some loss of function as a result of the infection.
Recurrence rates for chronic osteomyelitis, especially in diabet-
ics, may be as high as 30%. In more complex cases, such as open
contaminated fractures or infected hardware that require reten-
tion, complications including non-union, prosthesis failure, and
chronic osteomyelitis may occur. Ultimately, infections that
cannot be controlled may lead to the need for amputation and its
attendant loss of function and mobility. Occasionally, bone or
joint infections can disseminate to other joints or to the blood-
stream, resulting in life-threatening sepsis. Such cases usually
involve infection with S. aureus and fortunately remain the
exception.
For a deeper discussion on this topic, please see Chapter
272, “Infections of Bursae, Joints, and Bones,” in Goldman-
Cecil Medicine, 25th Edition.
908 Section XV  Infectious Disease
SUGGESTED READINGS
Lew DP, Waldvogel FA: Osteomyelitis, Lancet 364:369–379, 2004.
Osmon DR, Berbari EF, Berendt AR, et al: Diagnosis and management of
prosthetic joint infection: clinical practice guidelines by the Infectious Diseases
Society of America. Executive summary, Clin Infect Dis 56:1–25, 2013.
Ross JJ: Septic arthritis, Infect Dis Clin North Am 19:799–817, 2005.
Shuford JA, Steckelberg JM: Role of oral antimicrobial therapy in the management
of osteomyelitis, Curr Opin Infect Dis 16:515–519, 2003.
Spielberg B, Lipsky BA: Systemic antibiotic therapy for chronic osteomyelitis in
adults, Clin Infect Dis 54:393–497, 2012.
Stengel D, Bauwens K, Sehouli J, et al: Systematic review and meta-analysis of
antibiotic therapy for bone and joint infections, Lancet Infect Dis 1:175–188,
2001.
Tice AD, Hoaglund PA, Shoultz DA: Outcomes of osteomyelitis among patients
treated with outpatient parenteral antimicrobial therapy, Am J Med 114:723–
728, 2003.
Waldvogel FA, Medoff G, Swartz MN: Osteomyelitis: a review of clinical features,
therapeutic consideration and unusual aspects, N Engl J Med 282:316–322,
1970.

Urinary Tract Infections
  DEFINITION AND DIAGNOSIS
The term urinary tract infection (UTI) refers to significant bacte-
riuria in a patient with symptoms or signs attributable to the
urinary tract and no alternative diagnosis. UTI includes asymp-
tomatic bacteriuria, urethritis, cystitis, pyelonephritis, catheter-
associated UTI, prostatitis, and urosepsis. This chapter focuses
primarily on the two major forms of UTI, cystitis and
pyelonephritis.
A practical classification divides these infections into uncom-
plicated and complicated UTI. Uncomplicated UTIs are epi-
sodes of cystitis and mild pyelonephritis occurring in healthy,
premenopausal, sexually active, nonpregnant women with no
history suggestive of abnormalities in the urinary tract. All other
episodes of UTI are deemed to be potentially complicated and
deserving of further evaluation.
The presence of dysuria, increased frequency of urination,
suprapubic tenderness, and hematuria associated with bacteri-
uria or pyuria on urinalysis is unequivocally consistent with the
diagnosis of cystitis. Back or flank pain, nausea, vomiting, and the
presence of fever or rigors suggest infection of the upper urinary
tract, although it is not easy to distinguish cystitis from pyelone-
phritis on clinical grounds alone. The diagnosis of UTI gets more
difficult when patients cannot ascribe symptoms to the urinary
tract (e.g., patients with paraplegia or neurogenic bladder, con-
fused elderly or sedated patients) or when they have atypical
symptoms, such as changes in mental status, agitation, or hypo-
tension. Sometimes patients have urinary symptoms without
bacteriuria (the pyuria-dysuria or “urethral syndrome” com-
monly caused by Chlamydia trachomatis or other difficult-to-
culture genitourinary pathogens).
Bacteriuria is the hallmark of UTI. In women, asymptomatic
bacteriuria is defined as two consecutive voided midstream urine
specimens with isolation of the same bacterial strain at levels of
at least 105 colony-forming units (CFU) per milliliter from
patients without genitourinary symptoms. In men, a single clean-
catch, midstream voided urine specimen with one bacterial
species at a concentration greater than 105 CFU/mL defines
asymptomatic bacteriuria. The diagnosis of asymptomatic bacte-
riuria is also established in both women and men from a single
catheterized urine specimen (not an indwelling catheter) with
one bacterial species isolated at concentrations greater than
102 CFU/mL.
To increase the sensitivity of the tests, significant bacteriuria is
defined as greater than 102 CFU/mL of urine in a woman with
symptoms of uncomplicated cystitis and pyuria (≥5 white blood
98 
Joao Tavares and Steven M. Opal
cells per milliliter of urine per high-power field). Among women
with symptoms of uncomplicated pyelonephritis and men with
UTI, significant bacteriuria is defined as greater than104 CFU/
mL plus pyuria. In patients with complicated UTI, a concentra-
tion of 105 CFU/mL or higher is required for the definition of
significant bacteriuria independently of pyuria.
In order for these definitions to be valid, the urine must remain
in the bladder for at least 2 hours, and after urine collection the
sample should be incubated immediately. If urine is not incu-
bated immediately, it can be refrigerated for up to 8 hours before
proper incubation.
The presence of asymptomatic bacteriuria is not equivalent
to UTI except for pregnant women, neutropenic patients, and
individuals with anatomic or functional defects in the urinary
tract. The presence of white blood cell casts indicates pyelone-
phritis, and this finding suggests a complicated UTI with
obstructive lesions of the kidney or collecting system (e.g.,
papillary necrosis). It is difficult to define asymptomatic bac-
teriuria in the patient who has undergone renal transplantation,
and bacteriuria in such patients often indicates the need to treat
for UTI.
  LABORATORY FINDINGS
Young, sexually active women with typical symptoms of UTI
have a high pretest probability for UTI. Therefore, no laboratory
test is indicated. In this population, pretreatment urine analysis
and culture are indicated only if the diagnosis is not straightfor-
ward or if an antibiotic-resistant organism is suspected. Urine
analysis and culture are indicated in all cases of suspected com-
plicated UTI. Blood cultures are mandatory for patients with
suspected pyelonephritis. Imaging studies are indicated if kidney
stones, malignancy, obstructive uropathy, and urologic malfor-
mations are suspected.
  EPIDEMIOLOGY
At the extremes of age, men are more prone to UTI than women.
In young boys, urethral malformation is commonly the cause,
and in older men, UTI is usually caused by bladder neck obstruc-
tion secondary to prostatic hypertrophy. Homosexual men are at
increased risk for acquiring UTIs. Teenage girls and sexually
active women have more UTIs than their male counterparts. A
higher than expected incidence of UTI among young girls might
suggest sexual abuse. Sexually active women have the highest rate
of UTI. Postmenopausal women have increased prevalence of
UTI due to estrogen deficiency and age-related pelvic relaxation
with poor bladder emptying.
909
910 Section XV  Infectious Disease

The most common etiologic agent in patients with uncompli-
cated UTI is Escherichia coli (90% of cases), followed by Staphy-
lococcus saprophyticus. Other agents include Klebsiella spp,
Enterococcus faecalis, Enterococcus faecium, Proteus spp, Providencia
stuartii, and Morganella morganii. In patients with complicated
UTI, E. coli is still the most frequent uropathogen, but at a lower
rate than in uncomplicated UTI. Other causative organisms are
Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter
spp, Serratia marcescens, Stenotrophomonas maltophilia, Enterococ-
cus spp, and Candida spp.
Anaerobic agents are infrequent causes of UTI; when present,
they represent fistulae between the digestive tract and the urinary
tract. Staphylococcus aureus UTI most often represents bactere-
mia with bacteriuria resulting from clearance of bloodstream
bacteria by the kidney. Whereas 1% of individuals with a UTI get
pyelonephritis, 20% to 40% of pregnant women with a UTI
develop pyelonephritis, and 30% of patients with pyelonephritis
have bacteremia. In diabetic and transplanted patients with UTI,
the incidence of bacteremia is higher.
  PATHOGENESIS
There are at least three routes by which bacteria can enter the
bladder or kidney: ascending, hematogenous, and lymphatic.
Lymphatic spread is the least common route. The hematogenous
route is important for gram-positive organisms such as S. aureus
or Candida spp but unimportant for gram-negative bacilli. The
ascending route is the most important for enteric bacteria, and
this mechanism is supported by higher frequency of UTI in
women, given the shorter length of the female urethra, and in
individuals with an indwelling Foley catheter.
Before reaching the urinary bladder or kidney, the microor-
ganism must colonize the external part of the urinary tract.
Probably the most important aspect in the establishment of UTI
is the interaction between host factors (e.g., secretor phenotype,
P1 blood group, uroplakin I and II) and bacterial virulence
factors (the adhesins, P fimbriae, and type I fimbriae [pili]). The
urinary bladder is normally covered by a glycosaminoglycan
surface that prevents binding of bacteria that transiently enter the
bladder. P-fimbriated uropathogenic E. coli bind to alpha 1-4
linked, galactose-galactose disaccharide moieties found on uro-
epithelial cells, and these gal-gal glycolipids are also expressed on
the P1 blood group. People with P1 blood group are overrepre-
sented among individuals with either recurrent UTI and pyelo-
nephritis. Also, people who lack P1 blood group are less prone to
complicated UTI.
Studies have shown that P-fimbriated E. coli is present in 60%
to 100% of isolates from patients with UTI. Ascending UTI
infection can be inhibited experimentally by epithelial cell surface
receptor analogues. Type I fimbriae bind to glycoprotein uropla-
kin I and II. E. coli expressing type I fimbriae are responsible for
most cases of cystitis.
Once E. coli is attached to uroepithelial cells, both mechanical
and biochemical factors facilitate the development of full-blown
UTI. The local trauma and mechanical massage of the urethra
during sexual intercourse help deliver bacteria into the bladder
and, if vesicoureteral reflux or another ureteral anatomic defect is
present, into the kidney. Foley catheter placement also helps to
propel bacteria into the bladder, and all patients with a long-term
indwelling catheter in place will eventually develop UTI. All uro-
pathogenic organisms have the ability to multiply in the urine.
From the standpoint of the host, other factors associated with
the development of UTI are a new sex partner (within 1 year),
use of diaphragms and spermicides, family history of UTI in a
first-degree relative, and lower expression of CXCR1, an

TABLE 98-1  THERAPY FOR UNCOMPLICATED URINARY TRACT INFECTIONS

CYSTITIS PYELONEPHRITIS
ANTIMICROBIAL USEFUL DOSE AND USEFUL DOSE AND
AGENT THERAPEUTICALLY DURATION COMMENTS THERAPEUTICALLY DURATION COMMENTS
Nitrofurantoin *Yes, first line 100 mg bid for 5 Cheap, well tolerated No NA Reduced renal tissue
monohydrate days SE: N, H penetration
macrocrystals Low impact on
microbiome
Trimethoprim- *Yes, first line 160/800 mg bid If resistance is known Yes 160/800 mg bid *If organism
sulfamethoxazole for 3 days to be <20% for 14 days susceptibility is
SE: rash, urticaria, known
‡
N, V If not, give an initial
LA IV agent
Fosfomycin *Yes, first line 3 g single-dose May be less efficient No NA Active against
trometamol sachet SE: N, D, H MRSA ESBL,
VRE
†
Fluoroquinolones Yes, second line 3-day regimen High collateral damage *Yes, first line Dose varies; 7-14 If resistance is
(ciprofloxacin 250 mg bid SE: N, V, D, H, days known to be <10%
levofloxacin) 250 mg qd tendinitis
‡ ‡ ‡
β-Lactams Yes, second line Dose varies by Less effective, Yes Dose varies; Give an initial LA
agent; 5-7 days increased side effects Use cautiously Less 10-14 day IV agent
SE: N, V, D, rash, efficient regimen
urticaria
Data from Gupta K, Hooton TM, Naber KG, et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by
the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases—executive summary, Clin Infect Dis 52:561–564, 2011.
D, Diarrhea; ESBL, extended-spectrum β-lactamase; H, headache; IV, intravenous; LA, long acting; N, nausea; NA, not applicable; MSRA, methicillin-resistant Staphylococcus aureus;
SE, side effects; V, vomiting; VRE, vancomycin-resistant enterococci.
*AI level of evidence from current guidelines.
†
AIII level of evidence from current guidelines.
‡
BI level of evidence from current guidelines.
 Chapter 98  Urinary Tract Infections 911
interleukin 8 receptor. Pathogenic factors associated with the
development of UTI are flagellae, diverse adhesins, siderophores,
toxins, polysaccharide coating, and the ability to cause a deleteri-
ous inflammatory response.
Patient behaviors that are not associated with UTI include
precoital or postcoital voiding patterns, daily beverage consump-
tion, frequency of urination, delayed voiding habits, wiping pat-
terns, tampon use, douching, use of hot tubs, and type of
underwear.
  TREATMENT
The goal of treatment in uncomplicated UTI is to decrease symp-
toms and prevent complications. Treatment should be guided by
two important principles: the prevalence of resistant genitouri-
nary pathogens in the community and collateral damage to eco-
logic microbiota (i.e., the risk of propagation of resistant
organisms). First-line agents for uncomplicated UTI are nitrofu-
rantoin, trimethoprim-sulfamethoxazole (TMP-SMX), and fos-
fomycin trometamol; alternative agents are the fluoroquinolones
(except moxifloxacin) and the β-lactams (Table 98-1).
Treatment of complicated UTI should be based on culture
results and the other comorbidities that are present. Recurrent
UTI in sexually active women can be prevented with postcoital
TMP-SMX 40/200  mg single dose (if the patient has more
than two UTIs per year related to coitus) or with daily, every
other day, or weekly antibiotic. If the patient has a UTI
unrelated to coitus or there are fewer than two UTIs per year
related to coitus, the prevention of the UTI recurrence can be
achieved with patient-initiated therapy. Daily topical application
of intravaginal estriol can be helpful in postmenopausal women.
After completion of the treatment, urine culture is indicated
for pregnant women and on an individualized basis for other
patients with complicated UTI.
For a deeper discussion on this topic, please see Chapter
284, “Approach to the Patient with Urinary Tract Infection,”
in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Gupta K, Hooton TM, Naber KG, et al: International clinical practice guidelines
for the treatment of acute uncomplicated cystitis and pyelonephritis in women:
a 2010 update by the Infectious Diseases Society of America and the European
Society for Microbiology and Infectious Diseases—executive summary, Clin
Infect Dis 52:561–564, 2011.
Gupta K, Trautner B: In the clinic: urinary tract infection [review], Ann Intern
Med 156:ITC3-1–ITC3-15, quiz ITC-13–ITC-16, 2012.
Hooton TM: Clinical practice: uncomplicated urinary tract infection [review], N
Engl J Med 366:1028–1037, 2012.
Hooton TM, Bradley SF, Cardenas DD, et al: Diagnosis, prevention, and
treatment of catheter-associated urinary tract infection in adults: 2009
International Clinical Practice Guidelines from the Infectious Diseases Society
of America, Clin Infect Dis 50:625–663, 2010.
Nicolle LE, Bradley S, Colgan R, et al: Infectious Diseases Society of America
guidelines for the diagnosis and treatment of asymptomatic bacteriuria in
adults, Clin Infect Dis 40:643–654, 2005.
 99 
Health Care–Associated
Infections
Steven “Shaefer” Spires and Thomas R. Talbot
  INTRODUCTION
A health care–associated infection (HAI) is an infection that did
not exist or was not incubating at the time of admission to the
health care facility. Infections with an onset of more than 48
hours after admission and within 7 to 30 days after facility dis-
charge are defined as HAIs. These infections can occur in all types
of health care settings, including acute care units, long-term care
facilities, rehabilitation facilities, outpatient dialysis clinics, and
outpatient surgical centers.
HAIs cause a substantial degree of morbidity and mortality. A
2011 survey conducted by the Centers for Disease Control and
Prevention (CDC) Emerging Infection Program reported an
acute care hospital HAI prevalence of 6.8%. Extrapolating from
acute care admission data (about 35 million admissions per
year), approximately 2 million acute care HAIs occur annually in
the United States. Beyond the extensive morbidity and mortality
they cause, HAIs are costly, calculated as $13,973 per infection
in one review. These costs are likely to be underestimated because
of incomplete estimation of the outpatient costs of parenteral
antibiotics, skilled nursing care, physical rehabilitation, and lost
work days.
As of January 2011, the Centers for Medicare and Medicaid
Services (CMS) required public reporting of certain facility-
specific HAI outcomes as part of value-based purchasing. As
of January 2013, the following acute care–related HAIs are
required for reporting by CDC’s National Healthcare Safety
Network (NHSN): catheter-associated urinary tract infections
(CAUTIs) and central line–associated bloodstream infections
(CLABSIs) in intensive care units (ICUs), colon and abdominal
hysterectomy surgical site infections (SSIs), hospital-onset
Clostridium difficile infections (CDIs), and hospital-onset
methicillin-resistant Staphylococcus aureus (MRSA) bacteremias.
The importance of preventing HAIs has never been more
apparent.
The major types of HAIs include the infections reported to
CMS, hospital-acquired pneumonia (HAP) or ventilator-
associated pneumonia (VAP), and multidrug-resistant organisms
(MDROs). MDROs are pathogens with resistance to various
important antibiotics (e.g., MRSA, vancomycin-resistant Entero-
coccus (VRE), antibiotic-resistant gram-negative bacilli). This
chapter reviews the major classes of HAIs, with a focus on pre-
vention, diagnosis, and treatment.
912
  HEALTH CARE EPIDEMIOLOGY AND
INFECTION PREVENTION
In the age of increasing MDROs, shortage of new antibiotics, and
public reporting of HAIs, the importance of efforts to prevent
HAIs is growing. The fields of health care epidemiology and
infection prevention focus on the practices of tracking HAIs in a
systematic fashion (i.e., surveillance) to implement evidence-
based HAI prevention practices.
Although HAIs were once thought to be the cost of being
critically ill and receiving care in a hospital, several key events
occurred during the past decade that shifted that perception.
In 2006, Pronovost and colleagues implemented a “simple
and inexpensive intervention” in 103 ICUs in the state of
Michigan while participating in the Michigan Health and Hos-
pital Association Keystone ICU project. This landmark study
showed a reduction in the median rate of CLABSIs from 2.7
per 1000 catheter days to zero. These results shifted the dis-
cussion from merely controlling HAIs to preventing them.
Other major events have included recognition and effective-
ness of using bundles of evidence-based practices to reduce
HAIs; recognition of the HAI burden in nonacute, non-ICU
settings; and importance of quality improvement science in
reducing HAIs.
The prevention of HAIs has become increasingly possible, and
various types of prevention interventions can reduce the HAI
burden dramatically. In 2010, Wenzel and Edmund described
these interventions as horizontal and vertical strategies (Table
99-1). Horizontal infection prevention strategies are broad prac-
tices (e.g., hand hygiene, isolation precautions) aimed at prevent-
ing many or all types of HAIs, regardless of the specific pathogen,
procedure, or device. Vertical HAI prevention strategies are
directed at specific types of HAIs or target a specific organism.
Vertical strategies include using procedural checklists or stan-
dardized bundles and MRSA decolonization.
  CATHETER-ASSOCIATED URINARY TRACT INFECTIONS
In a survey performed by the CDC in 2011, CAUTIs were the
second most common device-associated infection. The incidence
of CAUTIs in 2011 ranged from 0 to 4.2 per 1000 catheter days,
compared with the 2006-2007 period, when rates were between
3.4 and 7.7 per 1000 catheter days. The estimated additional cost
of a CAUTI was $589 to $758 per infection in 1998 dollars, and
 Chapter 99  Health Care–Associated Infections 913
TABLE 99-1  STRATEGIES FOR PREVENTING HEALTH CARE–ASSOCIATED INFECTIONS
HORIZONTAL STRATEGIES (TO PREVENT CLABSI
ALL OR MANY TYPES OF HAI)
1. Standard precautions
• Hand hygiene
• Use of appropriate PPE
• Respiratory hygiene and cough etiquette
• Appropriate environmental cleaning and waste disposal
2. Chlorhexidine bathing in ICUs*
3. Isolation precautions appropriate for pathogen
4. Steps to prevent needlestick injuries
5. MDRO decolonization
6. Education of health care workers on IC/IP protocols
VERTICAL STRATEGIES (SPECIFIC TO HAI TYPE)
CAUTI
Urinary catheter placed only for appropriate indications:
Urinary retention or obstruction
Need for accurate UOP measurement in critical illness
Incontinence and perineal or sacral wounds
Comfort care use for terminal illness
Consider alternatives:
Condom catheters
Intermittent catheterization
Proper insertion and maintenance:
Maintain aseptic technique
Properly secure catheter to patient
Maintain closed drainage system
Maintain unobstructed flow
Urinary catheter premeditated stop order or RN-initiated discontinuation
policy
Anti-infective catheters if infection rates remain high
VAP
Use noninvasive ventilation when able
On intubation:
Semirecumbent position (30-45 degrees) unless contraindicated
Hypopharyngeal suctioning
Avoid gastric overdistention
Use cuffed ET tube
Oral care (with chlorhexidine oral rinse), tooth brushing
Keep ventilatory circuit closed unless changing for soiling or malfunctioning
Daily targeted sedation management
Spontaneous breathing trial if screening finds applicable
Use weaning protocols to minimize duration of ventilation
CAUTI, Catheter-associated urinary tract infection; CDI, Clostridium difficile infection; CLABSI, central line–associated bloodstream infection; ET, endotracheal; HAI, health care–
associated infection; IC/IP, infection control or prevention; ICU, intensive care unit; MDRO, multidrug-resistant organism; OR, operating room; PPE, personal protective equipment;
RN, registered nurse; SSI, surgical site infection; UOP, urine output; VAP, ventilator-associated pneumonia.
*Current data are not strong for prevention of CAUTI, VAP, and CDI by this method.
the total annual cost associated with CAUTIs in U.S. hospitals in
2007 was estimated between $390 and $450 million.
CAUTI complications include cystitis, pyelonephritis, and in
up to 4%, bacteremia. Although urinary catheter–associated bac-
teremias are rare, they are an underappreciated cause of health
care–associated bacteremias and have been estimated to cost an
additional $3744 per episode. Most of the epidemiologic data on
CAUTIs are from ICU patients. However, some studies describe
rates of CAUTI among the non-ICU population that are similar
to rates among ICU patients when calculated in catheter days,
and in some instances, the absolute number of infections is
higher outside of the ICU.
Most health care–associated urinary tract infections are cath-
eter associated. A catheterized patient’s daily risk of developing
bacteruria is about 3% to 10%. Indwelling urinary catheters
disrupt several mechanisms of the natural defense against
infection, including urine flow, length of the urethra, and micturi-
tion to prevent attachment of potential pathogens to the
Use checklist for device insertion:
Bundle supplies
All present use at least face mask, then proceduralist uses sterile gown and
gloves, mask, and head cap
Avoid femoral line placement if possible
Skin antisepsis with alcohol and >0.5% chlorhexidine
Use of chlorhexidine-impregnated dressing or sponge at insertion site
Empower personnel to stop nonemergent insertion if improper technique is
followed
Maintenance:
Access as infrequently as feasible
Scrub the access hub or port with antiseptic
Daily audits for assessment of device need and potential discontinuation
SSI
Preoperative strategies:
Nonirritative hair removal with clippers (not razors)
Eradicate remote infection
Decolonization of Staphylococcus aureus if carrier
Smoking cessation
Glucose control, hemoglobin A1c <7% if possible
Avoid immunosuppressive medication in perioperative period
Identify and address malnutrition
Intraoperative strategies:
In OR: proper ventilation, minimize traffic, proper attire, and surgical scrub
Proper skin preparation (chlorhexidine plus alcohol or povidone plus alcohol)
and draping
Antimicrobial prophylaxis; proper timing, dosing, and intraoperative redosing
Maintain normothermia
Glucose control
Tissue oxygenation, preoperative and postoperative supplementation
CDI
Prevention of acquisition:
Antimicrobial stewardship
Prevention of transmission:
Contact precautions (e.g., empirical placement for those suspected of CDI
before confirmation of diagnosis)
Hand hygiene with soap and water before leaving the patient’s room
Continue contact precautions until discharge
Appropriate environmental cleaning with bleach-containing agents
uroepithelium. Tamm-Horsfall proteins, the most abundant
soluble proteins in the urine, play a significant role by binding
uropathogenic bacteria, facilitating wash out, and lowering the
threshold for activating local innate immunity. These soluble pro-
teins are prevented from entering the lower urinary tract by the
catheters.
An indwelling catheter allows colonization, attachment, and
biofilm formation by certain microorganisms. Most of the organ-
isms causing CAUTIs arrive by ascending the urethra from
the meatus and perineum. The most common uropathogens
identified in CAUTIs are Escherichia coli, Candida species, Kleb-
siella species, Pseudomonas aeruginosa, and Enterococcus species
(Fig. 99-1).
Common symptoms of a urinary tract infection (e.g., dysuria,
urinary frequency) may not be useful in diagnosing a patient with
an indwelling catheter. However, the most common clinical
manifestations of a CAUTI are fever (≥38° C) and bacteruria.
Other signs and symptoms of a CAUTI can include rigors,
914 Section XV  Infectious Disease
100% Candida species
90% Acinetobacter baumannii
Pseudomonas aeruginosa
80% Enterobacter species
70% Escherichia coli
60% Klebsiella species
Coagulase-negative
50% staphylococci
40% Enterococcus species
30% Staphylococcus aureus
20%
10%
0%
CLABSI CAUTI VAP SSI
FIGURE 99-1  Causative pathogens by specific type of health care–
associated infection as reported to the Centers for Disease Control and
Prevention National Healthcare Safety Network. CAUTI, Catheter-
associated urinary tract infections; CLABSI, central line–associated
bloodstream infections; SSI, surgical site infections; VAP, ventilator-
associated pneumonia. (Modified from Sievert DM, Ricks P, Edwards JR,
et al: Antimicrobial-resistant pathogens associated with healthcare-
associated infection: summary of data reported to the National Health-
care Safety Network at the Centers for Disease Control and Prevention,
2009-2010, Infect Control Hosp Epidemiol 34:1–14, 2013.)
altered mental status, pelvic or suprapubic pain, costovertebral
angle tenderness, and acute onset of hematuria without another
underlying cause. One of these signs or symptoms plus a positive
urine culture with a known uropathogen (>105 colony-forming
units) strongly suggests a CAUTI. Pyuria (>5 leukocytes/mL of
urine) is not always a reliable indicator for infection in patients
with indwelling catheters; pyuria and asymptomatic bacteruria
are not necessarily indications for treatment. Risk factors for
CAUTI acquisition include duration of catheterization, underly-
ing fatal illness, age older than 50 years, having a nonsurgical
underlying illness, and nonadherence to proper catheter care
(E-Table 99-1).
The most effective method of preventing CAUTIs is to avoid
placing urinary catheters unless absolutely necessary and to
restrict catheter use to institutionally accepted indications.
Proper insertion and care of urinary catheters are paramount (see
Table 99-1). Maintenance of unobstructed flow with the collec-
tion bag below the bladder, use of a closed catheter system (even
when sampling urine), and discontinuation of the catheter as
soon as appropriate are key elements for preventing a CAUTI.
Nurse-directed discontinuation protocols in which frontline per-
sonnel have defined parameters for removing catheters without
requiring a provider’s order are increasingly used to eliminate
unnecessary catheters. The routine use of antimicrobial-coated
catheters is not recommended except when infection rates remain
elevated despite proper adherence to all other prevention
strategies.
Treatment of asymptomatic bacteriuria usually is not recom-
mended. Treatment of CAUTI is based on current Infectious
Disease Society of America (IDSA) guidelines, and the choice of
antimicrobial regimen should be based on the local antibiogram
and identified syndrome (e.g., pyelonephritis). Before treatment,
urine culture and sensitivity results are used to evaluate a resistant
organism and tailor an empirical antimicrobial regimen.
Most clinicians prefer to replace or discontinue the catheter
after a urinary tract infection is diagnosed. Guidelines recom-
mend replacement if it has been in place for more than 2 weeks.
TABLE 99-2  DEFINITIONS OF TYPES OF
NOSOCOMIAL PNEUMONIA
PNEUMONIA TYPE DEFINITION
Health care–associated Pneumonia in any patient who was hospitalized
pneumonia (HCAP) in an acute care hospital for 2+ days within 90
days of infection; resided in an NH or LTCF;
received recent IV antibiotic therapy,
chemotherapy, or wound care within the past
30 days of the current infection; or attended a
hospital or hemodialysis clinic
Hospital-acquired Pneumonia that occurs at least 48 hours after
pneumonia (HAP) admission and that was not incubating at the
time of admission
Ventilator-associated Pneumonia that arises 48-72 hours after
pneumonia (VAP) endotracheal intubation
Data from American Thoracic Society, Infectious Diseases Society of America: Guidelines
for the management of adults with hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia, Am J Respir Crit Care Med 171:388–416, 2005.
IV, Intravenous; LTCF, long-term care facility; NH, nursing home.
There is good evidence based on review by expert committees
(grade A-III evidence) that duration of treatment can be 7 days
if symptoms quickly resolve or 10 to 14 days if resolution is
delayed. There is moderate evidence based on expert commit-
tees’ opinions (grade B-III) that a 5-day course of levofloxacin
can be considered if patients are not severely ill and the organism
is sensitive to the drug. In nonpregnant women younger than 65
years of age, a 3-day course of antibiotic therapy can be consid-
ered after the urinary catheter has been removed (grade B-II).
  HOSPITAL-ACQUIRED PNEUMONIA
HAP has become the most common HAI. Most HAPs occur in
the ICU, and more than 90% are VAPs. Health care–associated
pneumonia (HCAP) is considered along with HAP because
of the etiologic similarities. Other definitions are given in
Table 99-2.
The incidence of HAP or VAP is difficult to determine due to
the various definitions that have been used for surveillance and
the subjective nature of these diagnoses. Some studies have esti-
mated that the incidence of VAP ranges from 2 to 16 cases per
1000 ventilator days. VAP is associated with increased length of
hospital stay (10 days in one study), costs (approximately
$40,000), and mortality (attributable mortality rate of 13%,
highest among surgical patients).
Risk factors for VAP include conditions that lead to increased
aspiration or impairment of host defenses and bacterial coloniza-
tion of the respiratory and upper gastrointestinal tracts (see
E-Table 99-1). In a ventilated patient, the body’s natural mechan-
ical defense mechanisms (e.g., ciliated epithelium, mucus, cough)
are interrupted, leading to colonization of the lower airways by
potentially pathogenic organisms. The most significant source of
these organisms tends to be the patient’s own oropharynx and
upper gastric contents.
The most commonly implicated respiratory pathogens are S.
aureus and P. aeruginosa, followed by several Enterobacteriaceae
species and Acinetobacter baumannii (see Fig. 99-1). Colonization
with MDROs correlates with increasing duration of hospitaliza-
tion. Guidelines argue that late (>4 days after admission) com-
pared with early HAP may be the most useful factor when
determining empirical antimicrobial therapy. Although bacteria
play the largest role in HAP, fungi and viruses also must be con-
sidered in immunosuppressed patients.
 Chapter 99  Health Care–Associated Infections 914.e1

E-TABLE 99-1  RISK FACTORS FOR DEVELOPING A

HOSPITAL-ACQUIRED INFECTION
CATHETER-ASSOCIATED URINARY TRACT INFECTION
Duration
Female gender
Age >50 yr
Not maintaining an unobstructed, closed drainage system
VENTILATOR-ASSOCIATED PNEUMONIA
Endotracheal tube
Underlying chronic lung disease
Age >70 yr
Depressed levels of consciousness
Gastric alkalinization
Nasogastric or enteral feeding tube
Previous antibiotic exposure
CENTRAL LINE–ASSOCIATED BLOODSTREAM INFECTION
Prolonged hospitalization before insertion
Duration of catheterization
Site of catheterization (femoral > subclavian)
Heavy colonization at the site of insertion and on the hub
Neutropenia
Total parenteral nutrition
Substandard maintenance of the catheter
SURGICAL SITE INFECTION
Increased age
Perioperative hyperglycemia
Obesity
Smoking
Immunosuppressive medications
Infections present at time of surgery
Malnutrition
Operative characteristics: inadequate surgical scrub and skin preparation
have been implicated, along with poor timing and dosing of antimicrobial
prophylaxis, lower-skilled surgeon, longer operative time, inappropriate
tissue oxygenation, and not maintaining normothermia
CLOSTRIDIUM DIFFICILE INFECTION
Age >65 yr
Antimicrobial exposure
Health care exposure
Gastric acid suppression (controversial whether this is an independent risk
factor)
 Chapter 99  Health Care–Associated Infections 915
TABLE 99-3  MODIFIED CLINICAL PULMONARY
INFECTION SCORE (CPIS)
CLINICAL CRITERIA INFORMATION
Temperature (° C) ≥36.5 and ≤38.4
≥38.5 and ≤38.9
≤36 or ≥39
Leukocyte count (per µL) ≥4,000 and ≤11,000
<4,000 or >11,000
<4,000 or >11,000 + ≥500 bands
Tracheal secretions Absent/rare
Abundant/nonpurulent
Abundant + purulent
PaO2/FIO2 (mm Hg) >240 or ARDS
≤240 and no evidence of ARDS
Chest radiographic findings No infiltrate
Diffuse or patchy infiltrate
Localized infiltrate
Microbiology† Negative
Positive
Data from Fartoukh M, Maitre B, Honore S, et al: Diagnosing pneumonia during
mechanical ventilation: the clinical pulmonary infection score revisited, Am J Respir Crit
Care Med 168:173–179, 2003.
ARDS, Acute respiratory distress syndrome.
*With the use of these clinical criteria, a clinical pulmonary infection score of 6 or
greater has an 85% sensitivity for detecting pulmonary infection.
†
Gram stain results of directed or blind, protected endotracheal aspirate.
One definition of HAP or VAP includes clinical, radiographic,
and microbiologic criteria. The Clinical Pulmonary Infection
Score (CPIS) system is useful in determining when antimicrobial
therapy is necessary (Table 99-3). A score of 6 or greater has 85%
sensitivity in diagnosing a pulmonary infection. Signs and symp-
toms indicating an infection include fever (≥38° C), peripheral
leukocytosis, purulent sputum, and worsening respiratory status.
A tracheal aspirate for Gram stain and culture provides the last
piece of diagnostic information. When several of these signs and
symptoms exist in the absence of a pulmonary infiltrate, alterna-
tive diagnoses should be considered, including ventilator-
associated tracheobronchitis.
Duration of hospitalization is a significant factor to consider
when initiating empirical therapy because of the increasing likeli-
hood of MDRO colonization with prolonged length of stay. In
early HAP (≤4 days), more community-acquired organisms may
be targeted, except when the patient has certain qualifiers for
HCAP (see Table 99-2) or is known to be colonized with resis-
tant organisms. However, in late HAP (including VAP and
HCAP), the IDSA guidelines recommend adding empirical cov-
erage for resistant gram-positive organisms (including MRSA)
and for multidrug-resistant Enterobacteriaceae (level II evidence
according to the American Thoracic Society [ATS]/IDSA guide-
lines for HAP). Dual coverage for multidrug-resistant P. aerugi-
nosa should also be considered. An example of an empirical
regimen for late-onset HAP is vancomycin or linezolid plus an
antipseudomonal β-lactam/β-lactamase inhibitor, carbapenem,
or cephalosporin.
  INFECTIONS ASSOCIATED
WITH VASCULAR CATHETERS
The NHSN collects data on CLABSIs, and public reporting
is required for CLABSIs in ICUs. In 2011, the incidence of
CLABSIs ranged from 0 to 3.7 cases per 1000 catheter days,
compared with 1 to 5.6 cases per 1000 catheter days in 2006
through 2007. Although CLABSIs have the lowest prevalence
among HAIs, the cost per episode and morbidity rate remain
high. The estimated additional cost of an infection related to an
POINTS* intravenous catheter is $4000 to $56,000 per episode. The attrib-
0 utable increase in length of stay has been between 6.5 and 22
1 days, and the attributable mortality rate is about 10% among
2
0 hospitalized patients.
1 The most common pathogens that cause primary CLABSIs are
2 flora arising at the percutaneous insertion site or from contami-
0
1 nation of the catheter hub. Hematogenous seeding from a gastro-
2 intestinal or other endovascular source occurs but is less likely.
0 The most common pathogens that cause CLABSIs are coagulase-
2
0 negative staphylococci, Candida species, S. aureus, and Enterococ-
1 cus species (see Fig. 99-1). The risk factors for CLABSI are
2 provided in E-Table 99-1. The rising proportion of infections
0
caused by Enterococcus species and Candida species since the
2
2006-2007 period suggests that skin colonization is being ade-
quately addressed by the adoption of evidence-based prevention
strategies and that an increasing fraction of CLABSIs are caused
by secondary hematogenous seeding. Patients who are more
severely ill, are neutropenic, have burns, or are on total parenteral
nutrition are also at increased risk for candidemia. Other types
of catheter-related infections include phlebitis, exit site infection,
and pocket and tunnel infection.
Many CLABSIs are preventable through the use of evidence-
based prevention practices for line insertion and maintenance.
Strategies include appropriate decolonization of the skin before
insertion with chlorhexidine plus alcohol, use of maximal sterile
barriers (i.e., proceduralist wears sterile gloves and gown, cap,
and mask, and a large barrier drape is placed over the patient),
hand hygiene, and sterile technique (see Table 99-1). Appropri-
ate maintenance of the central line mandates scrubbing the hub
with antiseptic and discontinuing the catheter as soon as it is not
needed.
For a patient with a fever or systemic symptoms who has a
central venous catheter, a bloodstream infection should be sus-
pected. The diagnostic evaluation should begin with paired
peripheral and catheter blood samples for culture before initia-
tion of antimicrobial therapy. In a suspected case of bloodstream
infection, the exudate at the exit site should be cultured.
The type of device (e.g., peripheral vs. central, short term vs.
long term), associated infectious complications, and the impli-
cated organism all play a role in treatment. For CLABSIs associ-
ated with short-term, nontunneled catheters and no complicating
factors (e.g., suppurative thrombophlebitis, endocarditis, intra-
vascular hardware), it may be appropriate to treat for 7 to 14
days after removal of the catheter. However, for long-term cath-
eters, salvage may be attempted with systemic plus antibiotic
lock therapy (level B-II evidence, indicating a moderate amount
of evidence from well-designed clinical trials or cohort or case
series). Salvage of catheters associated with S. aureus bacteremia
and fungemia have largely been unsuccessful, and it is not rec-
ommended. In the setting of an endovascular complication,
removal of the catheter is strongly recommended, and systemic
antibiotic therapy should be prolonged (i.e., 4 to 6 weeks) (level
B-II). In many cases, septic thrombophlebitis may require surgi-
cal attention. Tunnel and pocket infections may also require
débridement, but after the catheter is removed, 7 to 14 days of
antimicrobial therapy should be sufficient.
916 Section XV  Infectious Disease
  SURGICAL SITE INFECTIONS
Standard definitions of SSIs classify them as superficial inci-
sional, deep incisional (involving fascia or muscle), and organ
space depending on the depth of tissue involvement. Most SSIs
occur within 30 days of the operation, but some may develop
later, especially in the setting of implanted foreign bodies (e.g.,
arthroplasty). During 2006 to 2008, the overall risk of SSI was
1.9 cases per 100 procedures. Approximately 500,000 SSIs occur
annually, costing an estimated $45 billion per year. Patients who
develop an SSI have an increased risk of death.
Endogenous seeding from the patient’s skin flora is the most
common avenue of infection. S. aureus and coagulase-negative
Staphylococcus cause more than 40% of SSIs. In clean-
contaminated operations, including open abdominal surgeries,
gram-negative bacilli are predominant. An SSI should be sus-
pected when postoperative patients have wound-associated
purulent drainage, pain, tenderness, swelling, or redness. Posi-
tive culture growth from an aseptically obtained specimen is
most convincing.
Many practices are used to prevent SSIs (see Table 99-1). One
of the earliest and most effective strategies has been active sur-
veillance and subsequent reporting of infection rates to the sur-
geons and staff. Much of the reduction in rates was attributed the
Hawthorne effect (i.e., active monitoring changes the behaviors
of those being monitored). Other important interventions
designed to reduce SSIs include antimicrobial prophylaxis (i.e.,
the right drug at the right dose and right time), appropriate skin
antisepsis, and maintenance of glucose control (see Table 99-1).
Management of SSIs often involves opening of the incision,
evacuation of infected tissue, and allowing the wound to heal by
second intention. The decision for initiating antibiotics is made
on an individual basis and depends on the appearance of the
wound, systemic signs of infection, depth of the infection, host’s
immune system, and type of surgery. Culture and Gram stain
results help to dictate antibiotic coverage. For SSIs from a clean
operation, empirical therapy covering S. aureus and Streptococcus
species is recommended. For procedures involving the perineum,
intestinal tract, or urogenital tract, broader coverage is needed to
address gram-negative and anaerobic pathogens. When the SSI
occurs within 48 hours of the index operation, Streptococcus pyo-
genes and Clostridium species are often implicated.
  IMPORTANCE OF ANTIMICROBIAL STEWARDSHIP:
CLOSTRIDIUM DIFFICILE INFECTION
CDI is defined as diarrhea or toxic megacolon with detection of
the C. difficile organism or toxin A or B, or both, in the stool or
evidence of pseudomembranous colitis detected endoscopically,
surgically, or histopathologically. This colonic infection is often
accompanied by fever and leukocytosis.
The incidence and severity of CDIs have been increasing, and
most reports implicate the emerging BI/NAP1/027 strain and
the aging population of hospitalized patients, who are dispropor-
tionately affected by CDI. The BI/NAP1/027 strain hypersporu-
lates (i.e., produces more of toxins A and B than previous strains)
and produces a third binary toxin. Although resistance to the
primary antimicrobials used to treat CDI—metronidazole and
oral vancomycin—is rare, the BI/NAP1/027 epidemic strains
show an increased resistance to fluoroquinolones. There is a
concern that the increasing widespread use of fluoroquinolones
may be providing a selective advantage for this epidemic strain.
However, virtually every antibiotic has been associated with
increasing the risk of CDI.
The continued rise of CDI, increasing resistance to antimicro-
bials by many different pathogens, and lack of antimicrobials with
novel mechanisms of action underscore the importance of anti-
microbial stewardship. Antimicrobial stewardship is a strategy
that emphasizes optimal selection, dose, and duration of antimi-
crobial therapy, producing the best clinical outcome while
decreasing the risk of subsequent complications.
The consequences of poor stewardship include the emergence
of resistance, CDI, and excessive drug expenditures. Antimicro-
bials have different probabilities of invoking resistance or CDI.
Strategies implemented by antimicrobial stewardship programs
include provider education and guidelines, de-escalation or tai-
loring of empirical therapy when possible, use of more appropri-
ate empirical treatments, and front-end restriction of certain
antibiotics.
For a deeper discussion of these topics, please see Chapter
283, “Approach to the Patient with Suspected Enteric
Infection,” and Chapter 296, “Clostridial Infections,” in
Goldman-Cecil Medicine, 25th Edition.
  MULTIDRUG-RESISTANT PATHOGENS
MDROs are organisms that are resistant to more than one class
of antimicrobial agents, although the names of some (e.g., MRSA,
VRE) imply resistance to only one drug. According to NHSN
data reported from the 2009-2010 period, more than one half of
reported HAIs were caused by MDROs (Table 99-4).
Infections caused by MDROs lead to increased length of hos-
pitalization, health care costs, and mortality rates for patients
compared with those who are infected by antimicrobial-
susceptible organisms. Kollef and colleagues found that patients
who received inadequate antimicrobial therapy for their HAIs
had an infection-related mortality rate 2.37 times that of those in
the ICU who received adequate coverage. The principal reason
for inadequate coverage was multidrug resistance.
The predominant gram-positive MDRO pathogens are MRSA
and VRE. Methicillin resistance in S. aureus is caused by the
production of an alternate penicillin-binding protein (PBP2A)
that has a low affinity for β-lactam antibiotics and forms stable
peptidoglycan products in the presence of adequate levels of the
β-lactam. MRSA infections tend to have worse outcomes com-
pared with methicillin-susceptible S. aureus (MSSA), but the
typical health care–acquired strains are not necessarily more
virulent. However, community-acquired MRSA, the most preva-
lent of which is the USA-300 strain, tends to be more virulent,
and 87% of these isolates produce the Panton-Valentine leukoci-
din toxin, which is associated with greater leucocyte destruction
and tissue necrosis. The largest reservoirs of MRSA are patients
with the greatest contact with the health care system, and most
carriers are asymptomatic.
Vancomycin resistance in S. aureus is another concern. Vanco-
mycin intermediate-resistant strains, vancomycin heteroresistant
strains, and vancomycin-resistant strains are being detected.
 Chapter 99  Health Care–Associated Infections 917

TABLE 99-4  PATHOGENIC ISOLATES RESISTANT TO SELECTED ANTIMICROBIAL AGENTS ACCORDING TO THE NHSN,
2009-2010
ORGANISM ANTIMICROBIAL CLABSI CAUTI VAP SSI
Staphylococcus aureus Oxacillin 54.6% 58.7% 48.4% 43.7%
Enterococcus faecium Vancomycin 82.6% 82.5% 82.6% 62.3%
Klebsiella pneumoniae Ceftriaxone or ceftazidime 28.8% 26.9% 23.8% 13.2%
Carbapenems 12.8% 12.5% 11.2% 11.2%
Escherichia coli Ceftriaxone or ceftazidime 19.0% 12.3% 16.3% 10.9%
Fluoroquinolones 41.8% 31.2% 35.2% 25.3%
Enterobacter spp. Ceftriaxone or ceftazidime 37.5% 38.5% 30.1% 27.7%
Carbapenems 4.0% 4.6% 3.6% 2.4%
Pseudomonas aeruginosa Fluoroquinolones 30.5% 33.5% 32.7% 16.9%
Piperacillin-tazobactam 17.4% 16.6% 19.1% 6.8%
Cefepime 26.1% 25.2% 28.4% 10.2%
Carbapenems 26.1% 21.3% 30.2% 11.0%
Acinetobacter baumannii Carbapenems 62.6% 74.1% 61.2% 37.3%
Modified from Sievert DM, Ricks P, Edwards JR, et al: Antimicrobial-resistant pathogens associated with healthcare-associated infection: summary of data reported to the National
Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010, Infect Control Hosp Epidemiol 34:1–14, 2013.
CAUTI, Catheter-associated urinary tract infection; CLABSI, central line–associated bloodstream infection; NHSN, National Healthcare Safety Network; SSI, surgical site infection;
VAP, ventilator-associated pneumonia.

The intermediate resistance or decreased susceptibility to vanco-
mycin is thought to result from cell wall and biomatrix thicken-
ing, making the drug target more difficult to reach. Complete
vancomycin resistance occurs by acquisition of the vanA gene
from VRE. VRE, unlike many MRSA strains, is almost entirely a
health care–associated phenomenon. Clusters of vanA or vanB
genes are carried on mobile genetic elements that are readily
transmitted between strains. These genes encode peptidoglycan
precursors that have a low affinity for vancomycin.
Gram-negative MDROs have a greater tendency to form resis-
tance to multiple antimicrobials, and new antimicrobials to target
these pathogens are not available. The Enterobacteriaceae are
gram-negative bacteria that usually reside in the gastrointestinal
tract, are glucose fermenters, and account for about 29% of HAIs.
These organisms tend to be the most common pathogens in SSIs
associated with abdominal operations. The non–glucose fer-
menting organisms, including P. aeruginosa, Acinetobacter bau-
mannii, and Stenotrophomonas maltophilia, account for about 9%
of HAIs.
Multidrug-resistant gram-negative bacteria are making their
way into the limelight largely due to the emergence of isolates
that are resistant to most or all available antimicrobials
(e.g., MDROs that exhibit β-lactamases, extended-spectrum
β-lactamases, carbapenem and fluoroquinolone resistance). The
predominant carbapenem-resistance mechanisms are the loss of
OprD, an outer membrane protein, Klebsiella pneumoniae car-
bapenemases (KPCs), and the metalo-β-lactamases (MBLs),
which hydrolyze the carbapenem. The New Delhi metalo-β-
lactamase 1 (NDM1) is one of the first MBLs to cause outbreaks
in the United States. The carbapenemases and MBLs are easily
transmissible and tend to be associated with other genes encod-
ing mechanisms of resistance to other antimicrobial classes.
Fluoroquinolone resistance can occur by efflux pumps or muta-
tions in genes encoding the drug targets DNA gyrase and topoi-
somerase IV.
Limiting the spread of MDROs in the health care setting
should be a comprehensive and system-wide program at any
institution. Infection prevention programs should include opti-
mized surveillance practices to identify emerging MDROs and
appropriate intervention strategies. The mainstay of these pro-
grams includes use of evidence-based prevention practices and
antimicrobial stewardship programs.
SUGGESTED READINGS
American Thoracic Society, Infectious Diseases Society of America: Guidelines
for the management of adults with hospital-acquired, ventilator-associated,
and healthcare-associated pneumonia, Am J Respir Crit Care Med 171:388–
416, 2005.
Cosgrove SE: The relationship between antimicrobial resistance and patient
outcomes: mortality, length of hospital stay, and health care costs, Clin Infect
Dis 42(Suppl 2):S82–S89, 2006.
Hooton TM, Bradley SF, Cardenas DD, et al: Diagnosis, prevention, and
treatment of catheter-associated urinary tract infection in adults: 2009
international clinical practice guidelines from the Infectious Diseases Society
of America, Clin Infect Dis 50:625–663, 2010.
Kollef MH, Hamilton CW, Ernst FR: Economic impact of ventilator-associated
pneumonia in a large matched cohort, Infect Control Hosp Epidemiol 33:250–
256, 2012.
Mermel LA, Allon M, Bouza E, et al: Clinical practice guidelines for the diagnosis
and management of intravascular catheter-related infection: 2009 update by
the Infectious Diseases Society of America, Clin Infect Dis 49:1–45, 2009.
Pronovost P, Needham D, Berenholtz S, et al: An intervention to decrease
catheter-related bloodstream infections in the ICU, N Engl J Med 355:2725–
2732, 2006.
Scott RD II: The direct medical costs of healthcare-associated infections in U.S.
hospitals and the benefits of prevention. Available at: http://www.cdc.gov/
hai/pdfs/hai/scott_costpaper.pdf. Accessed November 1, 2014.
Stevens DL, Bisno AL, Chambers HF, et al: Practice guidelines for the diagnosis
and management of skin and soft-tissue infections, Clin Infect Dis 41:1373–
1406, 2005.
Wenzel RP, Edmond MB: Infection control: the case for horizontal rather than
vertical interventional programs, Int J Infect Dis 14(Suppl 4):S3–S5, 2010.
 100 
Sexually Transmitted Infections
Philip A. Chan and Susan Cu-uvin
  INTRODUCTION
Sexually transmitted infections (STIs) encompass a wide variety
of organisms that have been causing human disease for thousands
of years. Recognition of STIs can be challenging due to the het-
erogeneous nature and multiple symptoms of a single disease.
Diagnosis and management of STIs is further complicated by
underlying social bias and hesitancy by medical providers and
patients to discuss issues related to sexuality and disease
transmission.
The diagnosis of STIs should be based on a detailed history
with special attention to sexual orientation and behaviors, a phys-
ical examination, and laboratory confirmation when appropriate.
Professional and respectful attitudes by medical providers are
essential to obtaining an accurate clinical history pertinent to
STIs. Patients often deny risky behavior because of embarrass-
ment or social stigma. Patients may also underestimate risky
behaviors, and the diagnosis of STIs should therefore be based
on a combination of history, clinical examination, and diagnostic
testing.
A detailed sexual history should be obtained from all individu-
als with a suspected STI. They should be informed that the infor-
mation is necessary to appropriately diagnose and manage STIs.
The history should include the sexual preferences of male and
female partners; the number of main, casual, and one-time part-
ners; and the use of condoms, drugs, and alcohol. The history of
partners should be elicited, including current symptoms and
diagnosed STIs. If possible, counseling and education should be
incorporated during the encounter. Prevention topics include
abstinence, routine testing, disclosure of STIs to partners, behav-
ior modification (i.e., avoiding risky sexual activities), condom
use, and prophylactic treatment for exposures.
Because of the diverse nature of STIs, it is useful to categorize
the infections in a few major groups. There is overlap between
different categories, and clinical judgment must be used to accu-
rately diagnose STIs. For example, STIs that typically manifest
with an ulcer may occasionally manifest with urethritis. Many
STIs are asymptomatic. When an individual has one STI, others
should be considered. The main categories of STIs are urethritis
and cervicitis, genital ulcer disease, and genital warts. Symptom-
atic individuals with an STI usually fit into one of these
categories.
  URETHRITIS AND CERVICITIS
Urethritis and cervicitis are characterized by dysuria, burning,
and urethral discharge. The discharge may range from barely
918
noticeable to watery to frank pus. Urethritis has been categorized
as gonococcal (i.e., caused by Neisseria gonorrhoeae and visible on
Gram stain) or nongonococcal (i.e., commonly caused by Chla-
mydia trachomatis). Nongonococcal urethritis can be caused by
other organisms, many of which are rarely tested for. Urethritis
has historically been classified as gonococcal or nongonococcal
because N. gonorrhoeae can easily be visualized on Gram stain.
Most patients with symptomatic urethritis should be treated
empirically with antibiotics directed against gonorrheal and chla-
mydial organisms without waiting for test results.
Chlamydia
Definition and Epidemiology
Chlamydia is the most prevalent bacterial STI in the United
States and the world. The infection is caused by the bacterium C.
trachomatis, which causes 30% to 40% of nongonococcal urethri-
tis and cervicitis cases. In the United States, approximately 1.4
million cases were reported to the Centers for Disease Control
and Prevention (CDC) in 2011, with an estimated number of
infections that is more than twice the number of reported cases.
Age is a factor. Chlamydia has a 5% to 10% prevalence among
adolescents and young adults. Other risk factors include having
multiple sex partners, having unprotected sex, or living in a lower
socioeconomic area. In men, chlamydia is rarely associated with
complications. In women, untreated chlamydia is associated with
potentially severe complications, including pelvic inflammatory
disease (PID), ectopic pregnancy, and infertility.
The CDC recommends all sexually active women age 25 years
or younger and other at-risk women be screened for chlamydia.
Screening should also be considered for individuals who have a
history of chlamydia or other STIs, have new or multiple sex
partners, or exchange sex for drugs or money. All pregnant
women should be screened. Men who have sex with men (MSM)
should be screened at least annually and more frequently if there
are ongoing risk factors such as multiple partners. The rationale
for screening men is to prevent symptomatic epididymitis, proc-
titis, and urethritis.
Pathology
C. trachomatis is an obligate intracellular, gram-negative bacte-
rium that is evolutionary distinct from other bacteria. Several
serovars of C. trachomatis are associated with human disease.
They include serovars A-C (i.e., trachoma or ocular disease), D-K
(i.e., anogenital disease), and L1-L3 (i.e., lymphogranuloma
venereum [LGV]). C. trachomatis exists as an extracellular
 Chapter 100  Sexually Transmitted Infections 919
elementary body before attachment to susceptible epithelial cells
and subsequent endocytosis. On entering the cell, the elemen-
tary form of C. trachomatis reorganizes into a reticulate body
within vacuoles that is functionally active, leading to growth and
replication of the organism.
Clinical Presentation
Chlamydia may manifest with signs and symptoms ranging from
none to life-threatening PID in women. When individuals have
symptoms, the most common is urethritis in men and cervicitis
in women. The incubation period varies but is usually 7 to 14 days
after exposure.
Among men, 40% to more than 90% of chlamydia cases may
be asymptomatic. Urethritis usually manifests as dysuria or dis-
charge. C. trachomatis and N. gonorrhoeae infections are common
causes of epididymitis in younger men. The infection typically
manifests with unilateral testicular pain, swelling, and tenderness.
C. trachomatis infection may also cause prostatitis and proctitis;
the latter is typically found in MSM. The rates of transmission
from infected men to women are as high as 65%.
In women and men, more than 85% of infections are asymp-
tomatic. When symptomatic, C. trachomatis infection in women
can be difficult to diagnose due to the nonspecific nature of
symptoms. The classic manifestation is cervicitis, which can
cause discharge, bleeding, pelvic pain, cervical friability, and
ulcers. Complications of chlamydia include chronic pelvic pain,
infertility, ectopic pregnancy, and PID. The incidence of PID due
to C. trachomatis infection depends on the population studied,
but it ranges from 0% (in lower-risk populations) to 30%. PID
usually manifests as abdominal or pelvic pain, cervical motion
tenderness, and uterine or adnexal tenderness. Infection may also
cause perihepatitis (i.e. Fitz-Hugh–Curtis syndrome), which is
inflammation of the liver capsule. It occurs in 5% to 15% of PID
cases. Chlamydia is the leading cause of preventable infertility
worldwide.
Chlamydia may cause conjunctivitis and ocular trachomatis,
the most common cause of preventable blindness worldwide.
The disease also may manifest with pharyngitis and LGV. Clas-
sically a disease endemic in Africa, Southeast Asia, and the
Caribbean, LGV has been identified in the United States and
Europe, particularly among MSM with symptoms of proctitis.
Typically, LGV manifests with genital ulceration and inguinal
lymphadenopathy.
Diagnosis and Differential Diagnosis
C. trachomatis cannot be routinely cultured on growth media,
which has made diagnosis difficult. The introduction of nucleic
acid amplification testing (NAAT) was a major advance and is
now the standard diagnostic test. NAAT encompasses several
laboratory methods including polymerase chain reaction (PCR),
transcription-mediated amplification, and strand displacement
amplification. The reported sensitivity of NAAT is 80% to 90%,
with a specificity of 99%. The test may be performed on urine and
vaginal or urethral (men) endocervical swab specimens. NAAT
may also be performed on rectal and pharyngeal swab specimens,
but it must be validated before use.
Individuals who test positive and are treated for chlamydia
should not be retested for at least 3 weeks after treatment. NAAT
may remain positive during this time due to remnant material
that does not signify persistent infection. Repeat testing to dem-
onstrate cure should be performed for pregnant women or those
with a concern about persistent infection. Individuals are usually
retested every 3 months and at least once each year. Having had
an STI places individuals at risk for becoming infected again. For
individuals with multiple partners, including MSM, general STI
testing that includes chlamydia is recommended every 3 to 6
months.
Treatment
Standard treatment regimens for urethritis or cervicitis due to
chlamydia are azithromycin (1 g taken once orally) or doxycy-
cline (100 mg twice daily for 7 days). These two medications are
equally effective and cure more than 95% of infections. Azithro-
mycin is the preferred agent due to simplicity of dosing, which
facilitates adherence. Azithromycin can also be used in preg-
nancy. Other drugs that are effective in treating chlamydia include
quinolones and penicillin. Sulfonamides (e.g., Bactrim) and
cephalosporins should not be used. Doxycycline, ofloxacin, and
levofloxacin are contraindicated in pregnant women.
Epididymitis due to chlamydia should be treated with doxy-
cycline (100  mg taken orally twice per day for 10 days). Treat-
ment for LGV proctitis depends on the severity of symptoms
and should include doxycycline (100  mg orally twice each day
for up to 3 weeks). In women, PID should be treated with
ceftriaxone (250  mg given once intramuscularly) to cover gon-
orrhea and doxycycline (100  mg taken orally twice each day
for 14 days) for chlamydia. Women who are pregnant or who
have concerning symptoms should be hospitalized and started
on intravenous antibiotics, including cefoxitin (2  g given intra-
venously every 6 hours) or cefotetan (2  g given intravenously
every 12 hours) and doxycycline (100  mg taken orally every
12 hours). The duration depends on clinical improvement but
is usually 2 weeks. Alternative treatment regimens include clinda-
mycin (900  mg given intravenously every 8 hours) and genta-
micin (2-mg/kg loading dose followed by 1.5  mg/kg every
8 hours).
Prognosis
The natural history of untreated C. trachomatis infection varies.
Individuals may remain asymptomatic for long periods, and the
infection may resolve spontaneously or progress to symptoms
and complications. Approximately 20% of individuals diagnosed
with chlamydia but without symptoms may clear the infection
before returning for treatment. Infection does not translate to
protective immunity, and reinfection is common (10% to 20%).
In some regions, expedited partner therapy is allowed, and
medical providers may prescribe treatment for sex partners
without seeing them.
Gonorrhea
Definition and Epidemiology
Gonorrhea is caused by the bacterium N. gonorrhoeae and is the
second most common reportable STI in the United States behind
chlamydia. Similar to chlamydia, gonorrhea is a significant cause
of urethritis in men and cervicitis in women and has the same
920 Section XV  Infectious Disease
complications. In the United States, the rate of gonorrhea
declined in 2009 to a nadir of 98.1 cases per 100,000 people.
Much of this was attributed to screening and treatment programs.
Since 2009, however, cases of gonorrhea have increased each year
to 104.2 cases per 100,000, with more than 300,000 cases
reported in 2011.
Most individuals diagnosed with gonorrhea are adolescents or
young adults. MSM have also emerged as an important at-risk
group. Risk factors for infection include younger age, multiple
sexual partners, race or ethnicity, low socioeconomic status, and
previous STIs. African Americans and Latinos have significantly
higher rates of gonorrhea than whites in the United States.
Pathology
N. gonorrhoeae is a gram-negative bacterium with an outer mem-
brane, peptidoglycan cell wall, and cytoplasmic membrane.
Several components contribute to the virulence of the organism.
Attachment to columnar epithelial cells is facilitated by pili,
which extend from the cell surface and allow entry into the host
cell by endocytosis. Organisms without pili are thought to be
noninfectious. Gonococci are able to replicate within host epi-
thelial cells and phagocytes. After mucosal infection, immune
activation of neutrophils produces significant inflammation and
exudate as pus.
Clinical Presentation
Gonorrhea is transmitted during sex with an infected partner.
The risk of infection ranges from 20% to 50% per single act of
sexual intercourse and increases with multiple acts. The incuba-
tion period is 2 to 7 days. When symptomatic, individuals with
gonorrhea tend to have more purulent discharge than individuals
with nongonococcal urethritis. In men, urethritis is the most
common symptom at clinical presentation. Ten percent of men
may be asymptomatic. Other manifestations of gonorrhea
include epididymitis, proctitis, and pharyngitis. Rare but severe
complications include abscesses and urethral strictures.
Between 50% and 80% of women with gonorrhea are asymp-
tomatic. Typical symptoms include those of cervicitis, such as
pelvic or adnexal pain, discharge, dysuria, and abnormal bleed-
ing. As in men, gonorrhea can cause proctitis and pharyngitis in
women. Most of these infections are asymptomatic. The most
common complication of gonorrhea is PID, which occurs in 10%
to 40% of women. It may result in severe infection, chronic pelvic
pain, and infertility. Infection during pregnancy may lead to com-
plications such as premature labor, rupture of membranes, and
spontaneous abortions.
Gonorrhea infection may also be associated with perihepatitis
(Fitz-Hugh–Curtis syndrome). In less than 3% of individuals,
disseminated gonococcal infection can lead to a classic triad
of tenosynovitis (i.e., affecting multiple tendons), dermatitis
(i.e., painless, few transient pustular lesions), and polyarthralgias
(i.e., nonpurulent forms). Alternatively, individuals with dis-
seminated infection may have purulent arthritis alone. Clinical
presentation usually includes fever and other nonspecific sys-
temic symptoms.
Diagnosis and Differential Diagnosis
N. gonorrhoeae is a gram-negative diplococcic that can be visual-
ized easily on Gram stain of purulent material. However, the most
common method of diagnosis is NAAT, which has more than
98% sensitivity. The major disadvantage of NAAT is the inability
to evaluate antibiotic susceptibilities. N. gonorrhoeae can also be
cultured from swab specimens from the rectum, urethra, pharynx,
or cervix. Samples often contain many different microorganisms.
Selective media such as modified Thayer-Martin media (with
vancomycin, colistin, nystatin, and trimethoprim) is used to
inhibit growth of indigenous flora. The sensitivity of cultures
varies from 65% to 95%. When drug resistance is a concern,
cultures should be sent for sensitivity testing.
Treatment
Antibiotic resistance of N. gonorrhoeae continues to be a world-
wide problem. In the last decade, treatment of gonorrhea has
been complicated by a slow and progressive increase in higher
minimum inhibitory concentrations (MICs) for commonly used
antibiotics, including first-line cephalosporins. The resistance
patterns of gonorrhea vary by region.
To address the concern of antibiotic resistance, uncomplicated
urogenital gonorrhea should be treated with dual therapy; one
agent should be ceftriaxone (250 mg given once intramuscularly)
and the other azithromycin (1 g taken once orally). Azithromy-
cin can also treat concurrent chlamydia. Alternatively, doxycy-
cline (100 mg taken orally twice each day for 7 days) may be
given instead of azithromycin. High resistance rates (10% to
20%) limit the use of tetracyclines. This regimen is 99% effective
in curing gonorrhea. Cefixime (400 mg taken once orally) should
be reserved only if there is ceftriaxone resistance. In patients aller-
gic to ceftriaxone, azithromycin monotherapy (2 g taken orally
once) may be used cautiously. Gastrointestinal side effects are
common with the higher dose of azithromycin.
Other antibiotics with activity against gonorrhea include spec-
tinomycin. Antibiotics that should not be used to treat gonorrhea
due to resistance include penicillins and fluoroquinolones. Dis-
seminated or complicated gonococcal infections should be
treated with intravenous ceftriaxone and doxycycline or azithro-
mycin. The duration of these regimens depend on the clinical
course and response to therapy.
Prognosis
Gonorrhea is curable with proper antibiotic therapy. Untreated
disease often resolves over several weeks, but prompt treatment
halts transmission and prevents complications.
Vaginitis
Definition and Epidemiology
The term vaginitis refers to disorders of the vagina characterized
by inflammation or irritation of the vulva and an abnormal
vaginal discharge. Although a separate entity from urethritis,
there is significant overlap of symptoms and the organisms that
cause vaginitis and urethritis. The three main types of infectious
vaginitis are Candida vulvovaginitis, bacterial vaginosis, and
trichomoniasis. The latter two are strongly associated with sexual
transmission.
Trichomoniasis is the most common nonviral STI worldwide.
In the United States, 3.1% of women between the ages of 14 and
49 years are infected with Trichomonas vaginalis. Screening is rec-
ommended for trichomoniasis in women who are at high risk for
 Chapter 100  Sexually Transmitted Infections 921
other STIs as determined by commonly accepted measures (i.e.,
having new or multiple partners). Screening for bacterial vagino-
sis in pregnant women is a controversial topic.
Pathology
Candida albicans and Candida glabrata are the most common
organisms responsible for Candida vulvovaginitis. These species
may colonize asymptomatic women but their presence does not
necessarily mean infection. Symptomatic cases are caused by an
overgrowth of the species and penetration of the superficial
vaginal epithelial cells. Overgrowth can result from increased
estrogen levels or suppression of other vaginal flora by
antibiotics.
Trichomoniasis is caused by the protozoan T. vaginalis, which
infects the squamous epithelium in the urogenital tract. T. vagi-
nalis is not normally present in the vagina and has an incubation
period of a few days.
Bacterial vaginosis is caused by a variety of organisms flourish-
ing in the vaginal ecosystem in conjunction with a reduction of
normally occurring lactobacilli. The bacterium Gardnerella vagi-
nalis is especially prominent in cases of bacterial vaginosis and is
thought to infect the vaginal epithelium, creating a biofilm to
which other bacteria may adhere. G. vaginalis is also the organism
thought to play the most likely role in sexual transmission of
bacterial vaginosis.
Clinical Presentation
Symptoms of vaginitis may include pruritus (i.e., primary feature
of Candida vulvovaginitis); a change in the volume, color, or odor
of discharge; burning; irritation; erythema; dyspareunia; spot-
ting; and dysuria. In the case of trichomoniasis and bacterial
vaginosis, infection is often asymptomatic but can be transmitted
sexually. Symptomatic trichomoniasis in women most com-
monly includes a purulent vaginal discharge and erythema and
irritation of the vulva. An abnormal odor is also often associated
with infection.
Bacterial vaginosis manifests with milder symptoms of irrita-
tion and erythema and is rarely associated with dysuria or dyspa-
reunia. Patients with bacterial vaginosis most commonly have a
notably fishy odor in the vaginal discharge, which may also be
abnormally colored or textured.
Diagnosis and Differential Diagnosis
Laboratory testing and microscopy are needed for a diagnosis of
vaginitis. Examination of vaginal pH can be a helpful differentiat-
ing tool. Candida vulvovaginitis typically does not cause a change
in vaginal pH, whereas bacterial vaginosis and trichomoniasis do
increase the pH up to 6. The identification of Candida organisms
on a wet mount or culture of discharge from women with char-
acteristic clinical symptoms indicates Candida vulvovaginitis.
The diagnosis of trichomoniasis may be based on laboratory
testing (NAAT), motile trichomonads on a wet mount, or posi-
tive culture results. Amsel’s criteria or Nugent’s criteria may be
used to diagnose bacterial vaginosis when Gram stain or micros-
copy is available.
Treatment
Vaginitis is curable with proper antibiotic therapy. Trichomonia-
sis is treated with metronidazole (2 g taken orally once or 500 mg
orally twice each day for 7 days) or tinidazole. Pregnant women
can be treated with 2 g of metronidazole in a single dose at any
stage of pregnancy. The safety of tinidazole has not been fully
established.
Treatment of all recent sexual partners is recommended
because trichomoniasis is almost exclusively transmitted by
sexual contact. The same twice-daily regimen of 500 mg of oral
metronidazole is the primary treatment for bacterial vaginosis;
however, the single 2-g oral dose is not recommended for treat-
ment of bacterial vaginosis. Treatment of Candida vulvovaginitis
with a single 150-mg dose of fluconazole is highly effective. Use
of a topical agent depends on whether the case is considered
complicated or uncomplicated. Only topical azole therapies,
applied for 7 days, are recommended for use by pregnant women.
Prognosis
Bacterial vaginosis is treatable with various antibiotics, but the
primary concern is failure of normal Lactobacillus flora to rees-
tablish colonization in the vagina. This leads to repeated infec-
tions and necessitates prolonged treatment. Oral and vaginal
administration of Lactobacillus bacteria is sometimes recom-
mended. Bacterial vaginosis increases risk of infection with
human immunodeficiency virus (HIV), herpes simplex virus
type 2 (HSV-2), and N. gonorrhoeae, making treatment critical for
the management of other STIs.
Other Causes of Nongonococcal Urethritis
There are several other known causes of urethritis and cervicitis
and likely more that are unknown. Significant causes may include
Mycoplasma genitalium, HSV, Treponema pallidum, adenovirus,
and Ureaplasma urealyticum. U. urealyticum can be part of the
normal flora, and its role in urethritis has not been validated.
The most common of these organisms is M. genitalium. It is a
bacterium that lacks a cell wall, cannot be Gram stained, and is
very difficult to grow in culture. The organism accounts for 15%
to 25% of men with nongonococcal urethritis in the United States
and is thought to be a cause of cervicitis and PID in women.
Empirical treatment of symptomatic individuals includes azithro-
mycin (1 g taken orally once) and doxycycline (100 mg orally
twice daily for 7 days).
  GENITAL ULCER DISEASE
Genital ulcers are a major manifestation of several STIs. Genital
ulcers are best classified as painful (e.g., HSV, chancroid) or non-
painful (e.g., syphilis). LGV due to Chlamydia also manifests with
ulcerations. Ulcers may be classified as single (e.g., syphilis, chan-
croid) or multiple or grouped (e.g., HSV). All of these STIs mani-
fest with diverse signs and symptoms, and clinical examination
alone may be inadequate for accurate diagnosis (Table 100-1).
Syphilis
Definition and Epidemiology
Syphilis is caused by the spirochete T. pallidum, which can result
in a wide spectrum of clinical disease. At the beginning of the
20th century, it was thought that an astounding 10% of the
general population in the United States had syphilis. The CDC
began reporting rates of syphilis in 1941. The rates peaked in the
early 1940s at almost 600,000 cases and subsequently reached a
922 Section XV  Infectious Disease

TABLE 100-1  DIFFERENTIAL DIAGNOSIS OF GENITAL ULCER DISEASE

SYSTEMIC DIAGNOSIS AND
DISEASE PRIMARY LESION ADENOPATHY FEATURES TREATMENT
Genital herpes
(HSV-1/2)
  Primary Incubation 2-7 days; multiple, painful Tender, soft, and usually bilateral Fever, malaise Viral cultures, DFA, antibody
vesicles on erythematous base; lasts testing, Tzanck smear
7-14 days Tx: acyclovir, famciclovir, or
  Recurrent Grouped, painful vesicles on None None valacyclovir for 7-10 days
erythematous base; lasts 3-10 days (shorter for recurrent cases)
Primary syphilis Incubation 10-90 days (average, 21) 1 wk after chancre appears; During later stages Nontreponemal tests (RPR,
(Treponema Chancre: painless papule that bilateral or unilateral; firm, VDRL), treponemal tests
pallidum) ulcerates with firm, raised border discrete, no overlying skin (FTA-ABS), darkfield
and smooth base; usually single; changes, painless, microscopy; cannot be
may be genital or almost anywhere; nonsuppurative cultured
heals in 3-6 wk without treatment Tx: see Table 100-3
Chancroid Incubation 3-5 days; vesicle or papule 1 wk after primary in 50%; None Gram stain and culture.
(Haemophilus to pustule to ulcer; soft, not painful, unilateral in two thirds; Tx: azithromycin, ceftriaxone,
ducreyi) indurated; very painful suppurative ciprofloxacin
Lymphogranuloma Incubation 5-21 days; self-limited, 5-21 days after primary; one third Fever, arthritis, NAAT for Chlamydia
venereum painless papule, vesicle, or ulcer; bilateral, tender, matted iliac or pericarditis, proctitis, Tx: incision and drainage,
(Chlamydia lasts 2-3 days; found in only 10-40% femoral groove sign; multiple meningoencephalitis, doxycycline
trachomatis serovars abscesses; coalescent, caseating, keratoconjunctivitis,
L1, L2, L3) suppurative; thick yellow pus; preauricular
sinus tracts; fistulas; strictures; adenopathy,
genital ulcerations erythema nodosum
Granuloma inguinale Incubation 9-50 days; at least one No true adenopathy; in one fifth Metastatic infection of Wright or Giemsa staining with
(donovanosis) painless papule that gradually of patients, subcutaneous spread bones, joints, liver short, plump, bipolar staining
ulcerates; ulcers are large (1-4 cm), through lymphatics leads to pattern, Donovan bodies in
irregular, nontender, with indurated swelling or abscesses macrophage vacuoles
thickened; rolled margins and beefy of groin (pseudobuboes) Tx: doxycycline
red tissue at base; older portions of
ulcer show depigmented scarring,
white areas; advancing edge
contains new papules
Condyloma Characteristic large, soft, fleshy, None None Clinical diagnosis, biopsy if
acuminatum (genital cauliflower-like excrescences around necessary
warts) vulva, glans, urethral orifice, anus, Tx: topical podophyllin, surgery,
perineum others
DFA, Direct fluorescent antibody test; FTA-ABS, fluorescent treponemal antibody absorption test; HSV, herpes simplex virus; NAAT, nucleic acid amplification test; RPR, rapid plasma
reagin; Tx, treatment; VDRL, venereal disease research laboratory.

nadir in 2000 with a rate of 2.1 cases per 100,000 people in the
general population. However, since that time, the number of
reported syphilis cases has been increasing. The major at-risk
group is MSM, but the disease is observed in people across all
ages, genders, sexual orientations, socioeconomic status, and
racial and ethnic classes.
The resurgence of a generalized syphilis epidemic among
MSM with HIV infection or acquired immunodeficiency syn-
drome (HIV/AIDS) has had important consequences. Clini-
cians at STI clinics and those treating individuals with HIV/
AIDS need to be aware of guidelines for the diagnosis and treat-
ment of syphilis in this population. Given the increasing number
of MSM living with HIV/AIDS, it is not uncommon to see
co-infection in this population. All MSM, regardless of HIV
status, should be considered for syphilis screening on an annual
basis and more frequently if they have other risk factors.
Pathology
T. pallidum organisms are thinly coiled bacteria that move in a
corkscrew motion. T. pallidum cannot be cultured, hindering
diagnosis and study of the organism. T. pallidum infects and pen-
etrates mucosal membranes, resulting in the classic chancre
lesion. The organism then infects local lymph nodes and dissemi-
nates systemically. The median incubation period is
approximately 3 weeks. In more than 60% of infected individuals,
syphilis does not progress to tertiary stages. Immune host factors
are thought to contribute to the development of tertiary
syphilis.
Clinical Presentation
Ninety-five percent of primary syphilis cases involve the genitals.
The estimated risk of transmission from an individual with
primary syphilis to an uninfected individual is 30% per sexual act.
Syphilis may also be transmitted through oral-genital exposure
and with any contact of a primary lesion. Inoculation of the
organism by surgeons through needlesticks has been well docu-
mented and typically does not result in a chancre at the site of
infection (i.e., syphilis d’emblee).
The four classic stages of syphilis are primary, secondary,
latent, and tertiary. Staging is best thought of as a continuum
rather than discrete stages of infection. The states can manifest
individually, but individuals often have symptoms consistent
with primary and secondary symptoms. The primary and sec-
ondary stages of syphilis are extremely infectious, and cases of
transmission during the tertiary stage have been reported.
It can be very difficult to diagnose primary syphilis based
solely on the physical examination. The primary chancre is a pain-
less, clean-based, indurated ulcer. The borders are firm and raised.
 Chapter 100  Sexually Transmitted Infections 923

It is teeming with spirochetes and should be considered extremely symptoms of the central nervous system at the time of initial
infectious. It is rare for a primary chancre to be absent, but it may infection. Early neurosyphilis may be characterized by signs
go unnoticed. The chancre spontaneously heals without treat- and symptoms of meningitis and milder symptoms, including
ment over several weeks. headache. Other manifestations of neurosyphilis include oto-
Secondary syphilis usually manifests as a diffuse, maculopapu- syphilis (i.e., hearing loss) and ocular syphilis, which is clas-
lar rash that classically involves the palms and soles. However, a sically characterized as posterior uveitis. Late neurosyphilis may
wide range of early skin manifestations exists, including macular, manifest with general paresis (i.e., progressive dementia, for-
papular, pustular, vesicular, or any combination of these. Vesicu- getfulness, psychiatric disease, and personality change), Argyll-
lar lesions may easily be confused with other STIs, including Robertson pupils (i.e., no response to light but normal
herpes simplex. Syphilis may also have late skin manifestations, accommodation), and tabes dorsalis (i.e., ataxia and lancinating
including nodular, squamous, or gummous appearances. pains). The most common finding in late neurosyphilis is
The rash typically develops a few weeks after the chancre and irregular pupils.
results from dissemination of the organism. Up to 80% of patients Gummas, a result of immune system activation, may develop
have some cutaneous manifestations of disease. The rash is in any tissue or organ in the body. Classic cardiovascular symp-
usually symmetrical and pink, with no pain or burning, and it toms of syphilis include aortitis, which often affects the ascend-
usually spares the face. It resolves on its own over weeks to ing thoracic aorta causing a tree-bark appearance with dilation
months and may be confused with pityriasis rosea, erythema and aortic valve regurgitation.
multiforme, drug rashes, tinea, measles, and seborrheic dermati-
tis. The maculopapular rash of secondary syphilis is considered Diagnosis and Differential Diagnosis
noninfectious, although lesions in axillary or inguinal folds or The diagnosis of syphilis is limited by the inability of T. pal-
other regions exposed to chaffing may erode and become lidum to grow on standard laboratory media. Diagnostic testing
infectious. for syphilis relies on the direct and indirect measurement of
Syphilis then enters a latent stage, during which an infected antibodies against treponema. Nontreponemal tests such as the
individual has no symptoms but does have positive serologic test rapid plasma regain (RPR) and venereal disease research labora-
results (Table 100-2). Tertiary syphilis may then develop at any tory (VDRL) test rely on anticardiolipin antibodies, which
point from years to decades after the initial infection. usually resemble antibodies against treponema. These tests are
Approximately 30% to 40% of individuals with untreated usually sensitive but nonspecific, and false-positive results are
syphilis infection develop tertiary disease, which can include relatively common, especially in individuals with other autoim-
neurosyphilis, cardiovascular syphilis, and gummatous disease. mune diseases or who are pregnant. Nontreponemal tests report
Neurosyphilis has classically been thought of as a complication antibodies in terms of dilutions; a titer of 1 : 2 is extremely low
of tertiary syphilis. However, T. pallidum may invade and cause compared with a titer of 1 : 1024. This measurement can be
used as a general representation of spirochete load in the patient.
With treatment, nontreponemal test results often revert to
nonreactive.
TABLE 100-2  SEROLOGIC TESTING FOR SYPHILIS Treponemal tests such as the fluorescent treponemal antibody
FEATURES NONTREPONEMAL TREPONEMAL
absorption (FTA-ABS) test rely on antibodies that directly target
the organism and are therefore more specific. Tests results may
Technique Antibody to cardiolipin- Antibody to Treponema
lecithin (RPR, VDRL) pallidum (FTA-ABS, be positive or negative, and a positive result usually remains so
EIA) for life. The normal testing algorithm employs the sensitive, non-
Indications Screening and assessing Confirmatory test; treponemal tests, followed by a more specific, treponemal test to
response to therapy; usually remains
should be quantified by positive for life; may confirm the diagnosis. The inherent limitation of antibody testing
diluting serum and be used as a screening results in many cases of unclear diagnoses.
reporting in titers test in some settings Several mistakes may be made by clinicians in the diagnosis of
Positive for syphilis
  Primary 77% 86% syphilis. In primary syphilis, the initial nontreponemal test result
  Secondary 98% 100% may be negative. A patient with a lesion suspicious for syphilis
  Early latent 95% 99% should undergo repeat testing or empirical treatment regardless
  Late latent 73% 96%
False positives 1-2% of the population Borderline positive is of the serologic results. In the event of a recent exposure, a patient
may have a false-positive common in should be counseled that a syphilis test and HIV antibody test
RPR/VDRL; common pregnancy, and test may be negative. A patient who is treated early in the course of
in pregnancy, recent should be repeated
immunization, disease may never develop an antibody response and may there-
autoimmune diseases, fore never have a positive test result.
acute infectious illness, After successful treatment, patients with an initial episode of
HIV, chronic liver
disease, prozone syphilis should see a fourfold decrease in nontreponemal titers at
reaction (negative result 6 months. Titers may never return to normal and should be fol-
due to high antibody lowed periodically. For MSM, CDC guidelines suggest yearly STI
titers)
testing and more frequent testing (3 to 6 months) for patients
EIA, Enzyme immunoassay; FTA-ABS, fluorescent treponemal antibody absorption test;
HIV, human immunodeficiency virus infection; RPR, rapid plasma reagin; VDRL, venereal
with multiple partners, anonymous partners, or other risk factors
disease research laboratory test. for infection.
924 Section XV  Infectious Disease

Individuals with neurosyphilis should be treated with intrave-

Treatment nous penicillin G for 10 to 14 days. In tertiary disease with mani-
Despite the classic staging of syphilis as primary, secondary, festations of neurologic disease, treatment with intravenous
latent, or tertiary, the disease is best thought of in terms of early penicillin halts disease progression but does not reverse existing
infection (<1 year) or late infection (≥1 year) when considering structural damage. Ocular disease or other similar neurologic
treatment. T. pallidum remains sensitive to penicillin. Individuals manifestations should be treated as neurosyphilis. Nontrepone-
with early syphilis can be treated with a single intramuscular mal titers should be followed to ensure an appropriate response.
injection of benzathine penicillin G (Bicillin), which achieves Repeat treatment may be necessary in a small number of cases.
high and prolonged serum concentrations. Individuals with late
syphilis or disease of unknown duration should be treated with Prognosis
three weekly injections of intramuscular benzathine penicillin G Although penicillin is the treatment of choice for syphilis, it has
(Table 100-3). This cures most patients. not been validated in clinical trials but is based on a long history
Although penicillin remains the drug of choice, doxycycline of clinical use. However, a significant number of individuals with
may also be used in individuals who have severe allergies to peni- syphilis do not respond with the recommended decline in non-
cillin. However, every effort should be made to use penicillin treponemal titer. Individuals who do not respond should be
because of the sensitivity of the organism. For pregnant women retreated.
who are allergic to penicillin, penicillin desensitization should
For a deeper discussion of these topics, please see Chapter
occur in collaboration with a pharmacist and an allergist special-
319, “Syphilis,” in Goldman-Cecil Medicine, 25th Edition.
ist. As a result of treatment, individuals may experience a febrile
reaction (i.e., Jarisch-Herxheimer reaction). Symptoms are
caused by killing of the spirochetes and should not be confused
Herpes Simplex Virus
with an allergic reaction.
The co-epidemic of syphilis and HIV has led to an increase in Definition and Epidemiology
individuals with manifestations of neurosyphilis. In cases of Herpes simplex virus types 1 and 2 (HSV-1/2) cause a wide
syphilis with neurologic symptoms, a lumbar puncture is war- variety of clinical disease. HSV-1 is usually the cause of herpes
ranted to rule out neurologic involvement. Any pleocytosis or labialis (i.e., cold sores), and HSV-2 is the cause of genital herpes,
increase in protein concentration warrants treatment for neuro- although there may be overlap. After infection occurs, HSV-1/2
syphilis. A cerebrospinal fluid (CSF) sample should be sent for enters a latent state and may later reactivate to cause disease in a
VDRL testing, but the test lacks sensitivity (50%), and a negative subset of individuals.
test result does not rule out neurosyphilis. Usually, HIV-negative The overall prevalence of HSV-1 and HSV-2 in the population
individuals with syphilis without neurologic symptoms should is approximately 60% and 20%, respectively. However, the inci-
not undergo a lumbar puncture. Many HIV-infected individuals dence of HSV-1 infection approaches 90% to 100% among
with syphilis, however, have asymptomatic neurosyphilis. The middle-aged adults. Seroprevalence of HSV-2 is associated with
clinical implications of this are unclear, but these individuals may a patient’s sexual activity, including number of partners and
fail intramuscular therapy at a high rate. Some experts recom- history of other STIs, and with age, gender (women ae at higher
mend CSF examination in all HIV-infected individuals with a risk than men), and race or ethnicity. More than 50 million
CD4+ count lower than 350 cells/µL or a nontreponemal titer people in the United States are infected with genital HSV-1/2,
greater than 1 : 32. These criteria capture almost everyone with and most are asymptomatic. CDC guidelines do not recommend
asymptomatic neurosyphilis. routine screening for HSV-1/2 in people without symptoms.
There is no evidence that screening for HSV-1/2 reduces its
spread or has an impact on the disease. HSV-1/2 is not a report-
able disease in the United States.
TABLE 100-3  SYPHILIS TREATMENT
CLINICAL REGIMEN OF Pathology
CATEGORY CHOICE ALTERNATIVE*
HSV-1 and HSV-2 are two of eight double-stranded DNA human
Early syphilis Benzathine penicillin, Penicillin desensitization
(<1 year) 2.4 million units IM, Doxycycline, 100 mg PO bid herpesviruses. Others are varicella-zoster virus (VZV), cytomeg-
given once for 14 days alovirus (CMV), Epstein-Barr virus (EBV), and human herpes-
Tetracycline, 500 mg PO qid viruses 6, 7, and 8. Infection with one type of HSV does not
for 14 days
Azithromycin 2 g PO qd prevent or increase the chances of infection with other types.
Late syphilis Benzathine penicillin, Penicillin desensitization After initial infection, HSV-1/2 enters a latent state within neu-
(≥1 year) or 2.4 million units IM, Doxycycline, 100 mg PO bid ronal cells of sensory or autonomic peripheral ganglia. Reactiva-
unknown given once each week for 28 days
duration for 3 wk Tetracycline, 500 mg PO qid tion can occur at any time and is mediated in part by immune
for 28 days factors. HSV-1 most commonly infects the trigeminal ganglia and
Neurosyphilis Penicillin G, 4 million Penicillin desensitization HSV-2 the sacral nerve root ganglia (S2-S5).
units IV q4h or 24 Ceftriaxone 2 g qd IM or IV
million units by for 10-14 days
continuous infusion Clinical Presentation
qd for 10-14 days Transmission of HSV-1/2 is through skin-to-skin contact, includ-
*If patient has a penicillin allergy. ing sexual contact at mucosal surfaces, including the oropharynx,
 Chapter 100  Sexually Transmitted Infections 925
vagina, rectum, cervix, and conjunctivae. Importantly, transmis-
sion may occur in the absence of symptoms.
The stages of HSV-1/2 infection include primary, latent, and
recurrent. Primary infection of genital HSV-1/2 may include
fever, headache, other systemic symptoms, and the classic local
symptoms of painful genital vesicles or ulcers (multiple) and
lymphadenopathy. Oral infections of HSV-1 may include gingi-
vostomatitis and pharyngitis. Symptoms may vary from none to
serious and require hospitalization. HSV-1/2 then enters a latent
state. Reactivation occurs in a subset of individuals with symp-
toms less severe than those of primary infection. Some individu-
als have no reactivation, and others have more than three
reactivations per year.
Complications of HSV-1/2 infection include meningitis and
proctitis. Recurrent episodes of meningitis (i.e., Mollaret’s men-
ingitis) may be caused by HSV-1/2. Other manifestations of
HSV-1/2 include herpetic whitlow (e.g., infection of a finger of a
health care worker), herpes gladiatorum (e.g., HSV-1/2 skin
infections in athletes such as wrestlers), and ocular disease
(e.g., keratitis, acute retinal necrosis). HSV-1/2 infection may
rarely be associated with erythema multiforme, hepatitis, and
encephalitis.
Diagnosis and Differential Diagnosis
The diagnosis of HSV-1/2 is typically made clinically. If possible,
lesions should be tested for HSV-1/2 using viral culture (50%
sensitivity), PCR, or direct fluorescent antibody (DFA) testing.
Alternatively, serology testing for immunoglobulin M (IgM) and
immunoglobulin G (IgG) antibodies is available. This test should
be reserved for individuals with suspected primary infection or
to document chronic infection, and it should usually not be used
for screening purposes.
Treatment
Recommended regimens for primary HSV-1/2 infection include
acyclovir (400 mg orally three times per day for 7 to 10 days or
200 mg orally five times per day for 7 to 10 days), famciclovir
(250 mg orally three times each day for 7 to 10 days), or valacy-
clovir (1 g orally twice each day for 7 to 10 days). Treatment can
also be used for reactivation disease: acyclovir (400 mg orally
three times each day for 5 days, 800 mg orally twice each day for
5 days, or 800 mg orally three times each day for 2 days), famci-
clovir (125 mg orally twice each day for 5 days or 1000 mg orally
twice each day for 1 day or 500 mg once followed by 250 mg
twice each day for 2 days), or valacyclovir (500 mg twice each
day for 3 days or 1 g orally once each day for 5 days).
Individuals with frequent recurrences may be candidates for
suppressive therapy. Severe disease should be treated with intra-
venous acyclovir (5 to 10 mg/kg intravenously every 8 hours).
Duration and transition to oral medication should be based on
clinical improvement but is usually 7 to 10 days. The safety of
systemic acyclovir, valacyclovir, and famciclovir therapy in preg-
nant women is not established.
Prognosis
Although HSV-1/2 infection cannot be cured, most people are
asymptomatic, and suppressive therapy is available. Individuals
with HSV-1/2 infection should be educated regarding the
disease, including transmission and available treatments. They
should be encouraged to discuss their status with sexual partners,
including the possibility that transmission may occur in the
absence of symptoms. Individuals should abstain from sex during
an outbreak.
Chancroid
Chancroid is a rare cause of genital ulceration in the United
States. The infection is caused by the gram-negative rod Hae-
mophilus ducreyi and is endemic in parts of Africa and the Carib-
bean. Classic symptoms include a single or multiple, painful,
nonindurated genital ulcers and inguinal lymphadenopathy.
Growth of the organism in cultures requires hemin-containing
media, and it may appear as a school of fish on Gram stain. PCR
may be available in certain areas.
Testing for HSV-1/2 and syphilis should always be performed.
Recommended treatment regimens include azithromycin (1 g
orally once), ceftriaxone (250 mg intramuscularly once), or cip-
rofloxacin (500 mg orally twice each day for 3 days). Ciprofloxa-
cin is contraindicated in pregnant and lactating women.
Granuloma Inguinale
Granuloma inguinale is also known as donovanosis. It is caused
by the gram-negative bacterium Klebsiella granulomatis. The
disease is rare in the United States (24 cases in 2010) but endemic
in regions of Africa, India, Oceania, and the Caribbean. Clinical
manifestations include painless, ulcerative genital lesions with
erythema. Classic Donovan bodies may be observed on
histopathology.
The recommended treatment regimen is doxycycline (100 mg
orally twice each day for at least 3 weeks). Alternative regimens
include azithromycin, ciprofloxacin, and sulfamethoxazole-
trimethoprim. Azithromycin may be useful for treating granu-
loma inguinale during pregnancy. Doxycycline and ciprofloxacin
are contraindicated in pregnant women.
Other Causes of Genital Ulcers
Other causes of genital ulcers should be considered when the
results of routine testing are negative. Noninfectious causes
include trauma, Behçet’s disease, malignancy, and drug-mediated
disease
  OTHER SEXUALLY TRANSMITTED INFECTIONS
Genital Warts
Human papillomavirus (HPV) is responsible for a spectrum of
cutaneous and mucosal disease, ranging from genital warts to
invasive cancer. HPV has been linked to cervical, anal, and oro-
pharyngeal cancer. There are more than 100 types of HPV. Sexu-
ally transmitted HPV infection is responsible for genital warts
and anogenital carcinoma. More than 80% of sexually active
adults acquire HPV infection in their lifetime. Genital warts tend
to be benign and asymptomatic, and 90% are caused by HPV
types 6 and 11. The HPV types most often linked to anogenital
carcinoma are 16 and 18; HPV-16 is the most common.
Warts are usually described as flat and papular in the genital
regions. Diagnosis of genital warts is usually made by clinical
examination. If unclear, a biopsy may be performed. Treatment
926 Section XV  Infectious Disease
of genital warts may include podofilox (0.5% solution or gel),
imiquimod (5% cream), sinecatechins (15% ointment), cryo-
therapy, podophyllin resin (10% t0 25% concentration), trichlo-
roacetic acid (TCA), and surgical excision.
HPV vaccination is available with Gardasil (quadrivalent
vaccine) and Cervarix (bivalent vaccine). The main objective of
vaccination is to prevent cervical and other cancers. The vaccines
are also effective in preventing genital warts. The vaccines are
most effective before sexual debut. Guidelines suggest vaccina-
tion of males and females between the ages of 11 to 26 years.
Vaccines may be administered to individuals as young as 9 years
old. The guidelines state there is insufficient evidence to vacci-
nate individuals older than 26 years.
Pubic Lice
Pubic lice (i.e., Pediculosis pubis) may spread from the genitalia to
other areas of the body. The most common symptom is pruritus.
Small macules and localized lymphadenopathy may occur. Diag-
nosis of this STI is made by light microscopy of the organism.
Treatment includes permethrin (1% cream applied to affected
areas, rinsed off in 10 minutes) or pyrethrins (similar applica-
tion). Alternative medications include malathion (0.5% lotion)
or ivermectin. Clothing, bed sheets, and other linens should be
thoroughly washed.
Scabies
Scabies is caused by the skin mite Sarcoptes scabiei. Transmission
occurs by skin contact, and among adults, it is usually sexual.
Clinical presentation usually includes pruritus and small ery-
thematous papules that are classically present on the wrists, fore-
arms, fingers, and genital areas.
Diagnosis is usually based on clinical presentation and exami-
nation of skin scrapings. Recommended treatment regimens
include permethrin (5% cream applied from the neck down and
washed off after 8 to 14 hours) or ivermectin.
SUGGESTED READINGS
Centers for Disease Control and Prevention: Sexually transmitted diseases
surveillance 2012, Atlanta, 2013, U.S. Department of Health and Human
Services.
Cook RL, Hutchison SL, Østergaard L, et al: Systematic review: noninvasive
testing for Chlamydia trachomatis and Neisseria gonorrhoeae, Ann Intern Med
142:914–925, 2005.
Geisler WM, Lensing SY, Press CG, et al: Spontaneous resolution of genital
Chlamydia trachomatis infection in women and protection from reinfection,
J Infect Dis 207:1850–1856, 2013.
Jensen JS: Mycoplasma genitalium: the aetiological agent of urethritis and other
sexually transmitted diseases, J Eur Acad Dermatol Venereol 18:1–11, 2004.
Platt R, Rice PA, McCormack WM: Risk of acquiring gonorrhea and prevalence
of abnormal adnexal findings among women recently exposed to gonorrhea,
JAMA 250:3205–3209, 1983.
Rockwell DH, Yobs AR, Moore MB Jr: The Tuskegee study of untreated syphilis:
the 30th year of observation, Arch Intern Med 114:792–798, 1964.
Schroeter AL, Lucas JB, Price EV, et al: Treatment for early syphilis and reactivity
of serologic tests, JAMA 221:471–476, 1972.
Vall-Mayans M, Caballero E, Sanz B: The emergence of lymphogranuloma
venereum in Europe, Lancet 374:356, 2009.
Workowski KA, Berman S, et al, for the Centers for Disease Control and
Prevention (CDC): Sexually transmitted diseases treatment guidelines, 2010,
MMWR Recomm Rep 59:1–110, 2010.

Human Immunodeficiency
Virus Infection and Acquired
Immunodeficiency Syndrome
Brian T. Montague, Aadia I. Rana, Edward J. Wing, and Timothy P. Flanigan
  DEFINITION AND EPIDEMIOLOGY
The human immunodeficiency virus (HIV) is a retrovirus from
the lentivirus family. The first descriptions of the disease came in
1982, when HIV-associated wasting occurring in large numbers
of young adults in a Ugandan fishing community was described
as “slim disease.” In the United States in the same year, the desig-
nation acquired immunodeficiency syndrome, or AIDS, was
applied to a syndrome identified in previously healthy men who
had sex with men (MSM). It was characterized by serious infec-
tions with unusual opportunistic pathogens, such as pneumonia
from Pneumocystis carinii (now called Pneumocystis jirovecii) or
development of the formerly rare tumor, Kaposi’s sarcoma. Such
infections had previously been found only among patients with
severe cellular immunodeficiency, and studies confirmed pro-
found immunodeficiency in these individuals. When similar
opportunistic infections (OIs) were subsequently observed in
injection drug users and in men with hemophilia along with their
female sexual partners, it became clear that this syndrome was
caused by an agent transmitted either through sexual contact or
through infusion of blood or blood products.
The HIV virus was identified in 1983, and its role as the caus-
ative agent of AIDS was confirmed in 1984. By 1993, AIDS had
become the leading cause of death among American adults aged
25 to 44 years, a trend that was dramatically reversed by the
introduction of effective combination antiretroviral therapy
(ART) at the end of 1995. By the end of 2006, approximately 1.1
million persons in the United States were living with HIV and
AIDS, and an estimated 56,300 persons are estimated to have
become infected that year. More than 20% of people living with
HIV remain unaware of their status; they are at risk for serious
health complications and for transmitting the virus to others.
  TRANSMISSION
Although it was initially observed most frequently among homo-
sexual men and intravenous drug users in the United States, het-
erosexual intercourse has been the dominant mode of HIV
transmission throughout most of the world. The virus is present
in semen and cervicovaginal secretions of infected individuals
and can be transmitted by either partner during vaginal or anal
101 
intercourse. The concurrent presence of other sexually transmit-
ted diseases, especially those associated with genital ulcerations,
strongly facilitates sexual transmission of HIV.
Vertical transmission of HIV from an infected mother to her
child may occur in utero, during labor, or through breastfeeding.
In the absence of antiretroviral treatment (ART), HIV infects
25% to 30% of infants born to HIV-infected mothers. The rate of
vertical transmission can be reduced to less than 2% by prenatal
and perinatal treatment of the mother and postnatal treatment of
the infant with effective antiretroviral drugs.
Before the nationwide implementation of a blood screening
test in late 1985, infection by means of transfused blood or blood
products accounted for almost 3% of AIDS cases in the United
States. Since 1985, all blood products in North America have
been screened for HIV antigens and antibodies to HIV. The risk
of transfusion-acquired HIV infection in North America and
western Europe is now exceedingly small, but not absent.
HIV infection may occur after accidental parenteral exposures
among health care workers. After injury by an HIV-contaminated
hollow needle, the risk of infection is approximately 0.3%. Obser-
vational data suggest that this risk can be reduced at least 10-fold
by prompt postexposure prophylaxis.
For a deeper discussion of these topics, please see Chapter
387, “Prevention of Human Immunodeficiency Virus Infec-
tion,” in Goldman-Cecil Medicine, 25th Edition.
  EPIDEMIOLOGY
HIV is a reportable condition in the United States. Individual
states and the Centers for Disease Control and Prevention
(CDC) together monitor incident cases of HIV, the number of
persons known to be living with HIV, and the incidence of AIDS
diagnosis. The CDC has established clear surveillance criteria for
the diagnosis of AIDS, which include having a CD4+ T-helper
lymphocyte count (CD4 count) lower than 200 cells/mm3,
having been diagnosed with any of a large number of OIs indica-
tive of defects in cellular or humoral immunity, and having certain
neoplasms or other conditions associated with severe immuno-
deficiency. With ART, the clinical significance of an AIDS diag-
nosis is more limited, although tracking the number of AIDS
927
928 Section XV  Infectious Disease

cases remains important epidemiologically as a marker of late
diagnosis and limitations in access to care.
Since the early 1980s, HIV infection has become a worldwide
pandemic. HIV continues to spread throughout all continents.
Since the late 1990s, exceptionally rapid transmission has
occurred throughout India, Southeast Asia, Southern Africa, the
former Soviet Union, and some parts of Eastern Europe. Because
of latency between HIV infection and the development of AIDS-
associated illnesses, the clinically recognized epidemic of AIDS
has lagged 6 to 8 years behind the spread of the virus into new
populations. Worldwide, 1.7 million deaths were attributed to
HIV in 2011, and an estimated 34 million people were living with
HIV, including 3.3 million children. In 2011, an estimated 2.5
million people were newly infected with HIV—a 24% decrease
from the 3.1 million estimated in 2001. In 2009, there were an
estimated 370,000 new infections in children and between
42,000 and 60,000 maternal deaths. Persons from sub-Saharan
Africa accounted for 70% of all new HIV infections globally. Mor-
bidity and mortality from HIV and associated infections in many
resource-poor communities has been high. As access to ART in
low- and middle-income countries improves, morbidity and
mortality from HIV should fall, leading to an increase in the
prevalence of those living with HIV.
In the United States, HIV infection has increased rapidly
among women in the last decade; in several rural areas of the
Southeast, women accounted for more than one half of new cases
in 2005. Over the last several years, there has also been a resur-
gence of HIV infection among young MSM. A disproportionate
number of North American men and women infected by HIV are
African American or Hispanic. Transmission by injection drug
use has been a major factor in this imbalance, given that it has
occurred most commonly in impoverished inner-city areas,
where intravenous drug abuse is most prevalent. Since 2003,
transmission by injection drug use has significantly declined in
the United States, whereas heterosexual transmission has contin-
ued to increase. Recent studies in the United States have shown
clearly that even when treatment is readily available, the fraction
of persons who are retained in care and achieve virologic suppres-
sion remains as low as 25% (Fig. 101-1). There are increasing calls
for coordinated interventions directed toward identifying persons
with HIV, linking them to care, promoting retention, and sup-
porting sustained adherence to antiviral therapy. This is termed
the Seek, Test, Treat, and Retain (STTR) strategy for HIV control.
For a deeper discussion of these topics, please see Chapter
384, “Epidemiology of Human Immunodeficiency Virus
Infection and Acquired Immunodeficiency Syndrome,” in
Goldman-Cecil Medicine, 25th Edition.
  PATHOLOGY
The core of HIV contains two single-stranded copies of the viral
RNA genome, together with the virus-encoded enzymes reverse
transcriptase, protease, and integrase (Fig. 101-2). Surrounding
the structural (p24 and p18) proteins is a lipid bilayer derived
from the host cell, through which protrude the transmembrane
(gp41) and surface (gp120) envelope glycoproteins. The HIV
envelope glycoproteins have a high affinity for the CD4 molecule
on the surface of T-helper lymphocytes and other cells of
monocyte-macrophage lineage. After HIV binds to CD4, the
envelope undergoes a conformational change that facilitates

HIV Treatment Cascade

90%

80%
CDC
Gardner
70%

60%

50%

40%

30%
25%
20%

10%

0%
Diagnosed Linked to care Retained to Prescribed ART HIV
care suppressed
FIGURE 101-1  The HIV treatment cascade. Estimates show the progressive loss to follow-up as one moves from diagnosis to linkage to care, reten-
tion, and achievement of virologic suppression with antiretroviral therapy. (Data from HIV in the United States: the Stages of Care. CDC Fact Sheet,
2012. Available at http://www.cdc.gov/hiv/pdf/research_mmp_StagesofCare.pdf. Accessed November 3, 2014; and from Gardner EM, McLees MP,
Steiner JF, et al: The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection, Clin Infect Dis
52:793-800, 2011.)
 Chapter 101  Human Immunodeficiency Virus Infection 929

Retroviral Mature
particle retroviral
particle

Budding

CD4
Attachment

Cell membrame

Structural Assembly

Chemokine proteins
receptor

Cytoplasm

Penetration
Translation
Regulatory
proteins
Two-LTR
Uncoating circular
viral DNA

Linear unintegrated Unspliced

Reverse viral DNA mRNA
transcription
Multiple
One-LTR spliced
circular viral mRNAs
DNA
Preintegration Transcription
complex Nucleus
Integrated
proviral DNA

FIGURE 101-2  HIV viral replication. Key steps in the pathway targeted by antiretroviral therapy include membrane binding and fusion, reverse
transcription, integration of proviral DNA, and protein synthesis. LTR, Long terminal repeat; mRNA, messenger RNA. (Modified from Furtado MR, Cal-
laway DS, Phair JP, et al: Persistence of HIV-1 transcription in patients receiving potent antiretroviral therapy, N Engl J Med 340:1614–1622, 1999.)

binding to another cellular coreceptor (the most important of
these are the chemokine receptors CCR5 and CXCR4). This
second binding event promotes a major conformational change
that causes approximation of the viral and cellular membranes;
fusion of these membranes is mediated by insertion of the newly
exposed fusion domain of the envelope gp41 into the host cell
membrane.
As a result of these processes, the HIV nucleoprotein complex
enters the cytoplasm, where the RNA viral genome undergoes
reverse transcription by the virally encoded reverse transcriptase.
The resulting double-stranded viral DNA enters the nucleus,
where proper localization of the viral preintegration complex is
mediated by host proteins, and integration of the DNA provirus
into the host chromosome is catalyzed by the retroviral integrase.
Latently infected resting memory CD4 lymphocytes serve as res-
ervoirs of persistent infection for the life of the infected patient
even with effective ART (see later discussion). However, the bulk
of viral replication takes place in activated T cells, which are both
more susceptible to HIV infection and more capable of support-
ing productive HIV replication.
When a CD4 lymphocyte is activated, expression of HIV mes-
senger RNA (mRNA) is enhanced. Core proteins, viral enzymes,
and envelope proteins are encoded by the gag, pol, and env genes
of HIV, respectively. Recent data indicate that more than 100 host
930 Section XV  Infectious Disease
proteins, in addition to the viral proteins, may be important for
viral replication. Viral particles are assembled at the cell mem-
brane, each containing two copies of unspliced mRNA within the
core as the viral genome, and virions then are released from the
cell by budding. Productive viral replication is lytic to infected T
cells. A number of other host cells, including macrophages and
certain dendritic cells, are also infected by HIV, but viral replica-
tion does not appear to be lytic to these cells.
Following acute infection, high-level viral multiplication
occurs in mucosal lymphoid tissues of the gut and in other lym-
phatic sites, and plasma HIV RNA levels (i.e., the plasma viral
load [PVL]) often exceed 1 million copies per milliliter during
the second to fourth weeks after infection. Almost all instances
of acute HIV infection are caused by R5 tropic viruses, viruses
that use the chemokine receptor CCR5 for cellular entry. During
subsequent weeks, the PVL decreases, often rapidly. This decrease
in viremia results largely from a partially effective immune
response. After 6 to 12 months, the PVL typically stabilizes at a
level denoted the viral set point, and it may remain at approxi-
mately that level for several years (Fig. 101-3). The set point,
assessed as the PVL at 6 to 12 months after infection, is a signifi-
cant predictor of the subsequent rate of progression of HIV
disease but accounts for only half of the population variability in
disease progression rates.
After recovery from the acute retroviral syndrome, the patient
may feel entirely well for several years, but even in the asymptom-
atic infected individual, more than 100 billion new virions may
be produced daily. Rapid production and turnover of circulating
CD4 cells also occurs throughout the course of HIV infection,
Symptoms Symptoms
Circulating CD4 lymphocytes
Plasma HIV RNA
Viremia
0 1 2 3 2 4 6 8 10 12
Months from infection Years from infection
FIGURE 101-3  Natural history of HIV without antiretroviral therapy.
Following acute infection, an initial burst of viral replication causes an
immediate drop in the CD4 count. Partially effective cell-mediated
immunity suppresses viral replication to a nadir level and allows for a
rise in the CD4 count to a plateau that is less than a normal CD4 count.
Left without treatment, the CD4 count declines somewhat proportion-
ally to the nadir viral level until the patient begins to experience sig-
nificant immune deficiency. At that time, the viral count may rise and
the patient typically becomes symptomatic. Though this usually occurs
within 8 to 10 years, considerable variability exists, with some patients
progressing to AIDS within a few years and others without a significant
decline in CD4 count after 20 years.
and a progressive decline in circulating CD4 cells occurs in most
individuals. As disease progresses, a more dramatic CD4 cell
decline is observed, following a sharp rise in the PVL (see Fig.
101-3). Cell lysis associated with HIV replication accounts only
partially for this progressive loss of CD4 cells. During the years
of clinical latency, virions are present in large numbers in the fol-
licular dendritic processes of the germinal centers of the lymph
nodes, which undergo both hyperplasia and progressive fibrosis.
As HIV disease progresses over several years, the lymphatic tissue
atrophies and plasma viremia intensifies. In later-stage HIV
disease, there is often persistent high-level viremia.
The decline in the number of CD4 cells is accompanied by
profound functional impairment of the remaining lymphocyte
populations. Anergy may develop early in HIV infection and
eventually occurs in almost all persons with AIDS. T-helper lym-
phocyte proliferation in response to antigenic stimuli is dramati-
cally impaired, T-cell cytotoxic responses are diminished, and
natural killer cell activity against virus-infected cells is greatly
impaired. Decrease in function as well as number of CD4 cells is
central to the immune dysfunction, and this impairment partly
underlies the failure of B-lymphocyte function, as measured
by impaired capacity to synthesize antibody in response to new
antigens.
For a deeper discussion of these topics, please see Chapter
385, “Immunopathogenesis of Human Immunodeficiency
Virus Infection,” in Goldman-Cecil Medicine, 25th Edition.
  CLINICAL PRESENTATION
Acute HIV Infection and the  
Acute Retroviral Syndrome
Up to 50% of HIV-infected persons report a mononucleosis-like
syndrome (acute retroviral syndrome) occurring 2 to 6 weeks after
initial infection. The symptoms may include fever, sore throat,
lymph node enlargement, rash, arthralgias, and headache, and
they usually persist for several days to 3 weeks (Table 101-1). The
rash is typically maculopapular and short-lived and usually affects
the trunk or face. Ten percent of infected individuals experience
an acute, self-limited aseptic meningitis, which on lumbar punc-
ture is characterized by cerebrospinal fluid (CSF) pleocytosis
with detectable HIV in the CSF. The acute retroviral syndrome
is often sufficiently severe that the patient seeks medical atten-
tion. It is critical to maintain a high index of suspicion for acute
HIV retroviral syndrome because a very high plasma HIV RNA
level during this period indicates a high likelihood of HIV trans-
mission to sexual or needle-sharing partners, or from mother to
infant.
TABLE 101-1  SIGNS AND SYMPTOMS ASSOCIATED
WITH HIV ACUTE RETROVIRAL
SYNDROME
SIGN OR SYMPTOM FREQUENCY (%)
Fever 98
Lymph node enlargement 75
Sore throat 70
Myalgia or arthralgia 60
Rash 50
Headache 35
 Chapter 101  Human Immunodeficiency Virus Infection 931
Spectrum of Disease Associated with HIV
Untreated HIV infection usually results in a slow, nonlinear pro-
gression to severe immunodeficiency. However, the progression
of disease varies greatly among individuals. Within 10 years after
infection, approximately 50% of untreated individuals will
develop AIDS, 30% will have milder symptoms, and fewer than
20% will be entirely asymptomatic (see Fig. 101-3). Children and
adolescents progress to AIDS at a slower rate than older persons;
fewer than 30%, in the absence of ART, will develop AIDS within
10 years after HIV infection. The rate of progression of immuno-
deficiency is not influenced by the route of HIV transmission
and, in the long term, does not appear to differ by gender,
although typically women with HIV infection tend to experience
more rapid disease progression with lower levels of HIV in
plasma.
First Impacts of HIV
Clinically recognized lymph node enlargement occurs in 35% to
40% of asymptomatic HIV-infected persons but is not signifi-
cantly associated with either rate of progression of immunodefi-
ciency or subsequent development of lymphoma. During early
HIV infection, thrombocytopenia, probably caused by autoim-
mune platelet destruction, is common. Most HIV-infected indi-
viduals remain asymptomatic until their CD4 count falls to less
than 200 cells/mm3, a fact that contributes to the late diagnosis
of disease. In parts of the world where tuberculosis is hyperen-
demic, persons with HIV with CD4 counts greater than 200
cells/mm3 are at high risk for development of tuberculosis.
Early Immunodeficiency
Patients with moderate immunodeficiency (CD4 counts between
200 and 500 cells/mm3) exhibit diminished antibody response
to protein and polysaccharide antigens, as well as decreased cell-
mediated immune function. These functional impairments are
manifested clinically by a threefold to fourfold increase in the
incidence of bacteremic pneumonias caused by common pulmo-
nary pathogens (especially Streptococcus pneumoniae and Hae-
mophilus influenzae) and by a marked increase in incidence of
active pulmonary tuberculosis in endemic areas (Table 101-2).
Mucocutaneous lesions may be the first manifestations of
immune dysfunction. These include reactivation of varicella-
zoster (shingles), recurrent genital herpes simplex virus (HSV)
infections, oral or vaginal candidiasis, and oral hairy leukoplakia
(see later discussion). The earliest clinical manifestation of HIV
infection in women may be frequent recurrence of Candida vagi-
nitis in the absence of predisposing factors. Recurrent large,
painful genital, perianal, or perineal ulcers caused by HSV type
2, are more frequent in women than in men. HIV-infected women
show an increased prevalence of high-grade squamous intraepi-
thelial lesions on Papanicolaou (Pap) smear. Both men and
women may show similarly increased rates of dysplasia or neo-
plasia on rectal Pap smear.
Opportunistic Infections
With advanced immunodeficiency, indicated by CD4 counts
lower than 200 cells/mm, patients are at high risk for develop-
ment of OIs (see Table 101-2). Before the availability of effective
TABLE 101-2  PROGRESSIVE COMPLICATIONS OF HIV
INFECTION BY CD4 COUNT
CD4 COUNT
(CELLS/MM3) OPPORTUNISTIC INFECTION OR NEOPLASM
>500 Herpes zoster
Tuberculosis
200-500 Oral hairy leukoplakia
Candida pharyngitis (thrush)
Kaposi’s sarcoma, mucocutaneous
Bacterial pneumonia, recurrent
Cervical or anal neoplasia
100-200 Pneumocystis jirovecii pneumonia
Histoplasmosis capsulatum infection, disseminated
Kaposi’s sarcoma, visceral
Progressive multifocal leukoencephalopathy
Lymphoma, non-Hodgkin’s
<100 Candida esophagitis
Cytomegalovirus retinitis
Mycobacterium avium-intercellulare
Toxoplasma gondii encephalitis
Cryptosporidium parvum enteritis
Cryptococcus neoformans meningitis
Herpes simplex virus, chronic, ulcerative
Cytomegalovirus esophagitis or colitis
Primary central nervous system lymphoma
antiretroviral drugs and use of prophylactic antibiotics, 60% of
HIV-infected North American men developed Pneumocystis
pneumonia (PCP). Incidence of Toxoplasma encephalitis before
the availability of ART in the United States was estimated to be
as high as 3.9 per 100 patient-years. CD4 counts lower than 50
cells/mm3 indicate profound immunosuppression and, in the
absence of effective ART, are associated with a high mortality rate
within the subsequent 12 to 24 months.
Cytomegalovirus (CMV) retinitis, which can lead rapidly to
blindness, and disseminated Mycobacterium avium-intracellulare
(MAI) infection occur frequently in the absence of therapy. They
respond adequately to specific therapy only if it is accompanied
by effective control of viral replication.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Identification of persons with HIV and support of linkage to
effective care are critical public health priorities. Recent studies
have demonstrated reduced transmission of HIV associated with
ART. Despite the acknowledged priority of early diagnosis, the
median CD4 count at diagnosis has remained fairly constant in
the range of 175 cells/mm3, indicating persistent delays in testing
and treatment.
The CDC and the U.S. Preventive Services Task Force recom-
mend that all persons between the ages of 13 and 64 years be
tested for HIV once, with repeat testing and testing outside of
this age group based on assessed risk for infection and reinfec-
tion. All pregnant women should routinely be offered HIV
testing. The CDC, to meet this goal, further recommends that
HIV testing be considered a part of routine medical care, without
any requirement for written consent or formal pretest and post-
test counseling. Pretest discussion is important to ensure that
patients appreciate that they are being tested and that treatment
is available if they are found to be HIV positive.
Standard testing for HIV infection begins with detection of
antibodies to HIV in serum or in oral fluid. Positive antibody
tests are confirmed by assessing for the presence of at least two
932 Section XV  Infectious Disease
viral proteins through Western blot assays. These techniques are
highly sensitive in detecting HIV antibody, but individuals who
have been infected recently may be antibody negative. During a
window period, typically 1 to 2 weeks, infected persons have
detectable HIV RNA and core p24 antigen in their plasma. If the
initial enzyme-linked immunosorbent assay (ELISA) result is
negative in a person recently exposed to HIV, repeat ELISA at 6
weeks and 3 months are indicated. In a person who is at high risk
for HIV exposure, an indeterminate Western blot reaction pattern
often represents early seroconversion; in such cases, a positive
plasma HIV RNA concentration (i.e., >10,000 copies/mL) indi-
cates acute HIV infection.
Rapid point-of-care testing methods play an important role in
HIV testing in many clinical and community settings. These rapid
test kits can provide results within 30 minutes, but they require
confirmation by antibody-based tests. Fourth-generation assays
for HIV have recently been developed; they combine tests for
antibodies and viral proteins in a single assay.
  TREATMENT
Initial Counseling and Ambulatory Evaluation
Once HIV infection is recognized, the physician should discuss,
in an unhurried manner, the clinical course and treatment of HIV
infection and the use of immunologic and virologic studies (e.g.,
CD4 counts, PVL assays) to guide therapy. The physician should
then emphasize that, with effective currently available ART, HIV
disease progression can be prevented indefinitely. Stigma related
to HIV remains an important concern and a key barrier to engage-
ment in care. Addressing this as part of post-test counseling and
intake to care is key to retention in care for persons newly
diagnosed.
Prevention of further transmission through unprotected sex or
sharing of needles must be discussed at the first visit and periodi-
cally thereafter. It is important to emphasize that these high-risk
activities place not only the other person but also the patient at
risk because they may lead to transmission of new and potentially
drug-resistant HIV strains to the patient.
The initial evaluation should include both an HIV-oriented
review of systems and a complete physical examination. In par-
ticular, the skin must be examined for HIV-associated rashes and
Kaposi’s sarcoma. Examination of the oral cavity may reveal
thrush, gingivitis, hairy leukoplakia, superficial ulcers caused
by HSV, aphthous ulcers, or lesions characteristic of Kaposi’s
sarcoma. In persons with very advanced disease, the optic fundi
may have hemorrhagic lesions characteristic of CMV retinitis.
Lymph node enlargement, hepatomegaly, splenomegaly, and any
genital lesions should all be carefully noted. Neurologic examina-
tion for both peripheral neuropathy and decreased global cogni-
tion deserves close attention.
Laboratory Monitoring
The CD4 count and the PVL should be measured at the first visit,
and the patient should be shown the results. Graphic illustrations
of the interaction between PVL and CD4 can be useful to increase
patient understanding. HIV genotyping to assess for drug resis-
tance should also be performed (see later discussion).
The PVL is a key measure of treatment adherence and is
repeated at intervals, initially every 3 to 4 months. For patients
with suppressed virus who are stable on ART, current guide-
lines allow for PVL monitoring at 6-month intervals. For
those who are not taking or have only recently started ART
and have a CD4 count lower than 200 cells/mm3, CD4 moni-
toring is typically repeated every 3 to 4 months along with
the PVL monitoring. Once a patient is stable on treatment,
with suppressed virus (<200 copies) and CD4 counts higher
than 200  cells/mL, the value of CD4 monitoring is less clear,
and guidelines allow for extending the monitoring interval to
yearly.
Screening for Associated Infections
Tuberculosis
Purified protein derivative (PPD) testing should be performed
early in the course of HIV infection. Induration of 5 mm or more
should be considered positive. Any patient with a positive PPD
test result should be evaluated for the presence of active tubercu-
losis; if no active disease is present, the patient should receive 9
months of prophylaxis with isoniazid or combination drug
therapy for a shorter period (see Chapter 92). If active tubercu-
losis is identified, multidrug therapy should be initiated after
careful consideration of possible interactions with antiretroviral
medications.
Sexually Transmitted Diseases
Serologic testing for syphilis should be followed by prompt treat-
ment if the patient is confirmed to be positive. Syphilis infections
are common within many populations highly impacted by HIV,
and co-infection with syphilis increases the risk of transmission
of HIV to others. Regular screening is recommended.
Hepatitis
Liver disease is an important cause of morbidity and mortality
for persons with HIV. Screening for hepatitis A, B, and C at
baseline is recommended, and those not immune to hepatitis
A or B should receive immunization. Hepatitis C is highly
prevalent among persons who acquired HIV from injection
drug use, and increasing numbers of cases of sexual transmis-
sion of hepatitis C among MSM with HIV are being described.
Given the lack of an effective vaccine for hepatitis C, regular
screening is recommended for persons with ongoing risk of
exposure.
Other Infections
Screening for antibodies to Toxoplasma gondii should be consid-
ered for persons with low CD4 counts who are potentially in
need of prophylaxis. Persons from endemic areas may be screened
for histoplasmosis and coccidiomycosis and considered for pro-
phylaxis if positive.
Immunization
Antibody responses to polysaccharides are better among patients
with higher CD4 counts. The optimal timing of immunization
is uncertain. For persons with low CD4 counts, most physicians
provide initial immunization and reimmunization for certain
vaccines after immune reconstitution occurs. Live vaccines
should be avoided in persons with CD4 counts lower than 200
cells/mm3.
 Chapter 101  Human Immunodeficiency Virus Infection 933

still in effect, reflecting in part the allocation of limited resources

Pneumococcus to those who are likely to experience the most immediate
All persons with HIV should receive a dose of PCV14 benefits.
(Prevnar13), followed by a dose of PPV23 (Pneumovax) at least
8 weeks later. If previously vaccinated with PPV23, the patients Antiretroviral Drug Regimens
should receive PCV13 at least 1 year after PPV23. Patients should Evidence-based guidelines for ART have been developed by the
have a CD4 cell count greater than or equal to 200/microliter. A U.S. Department of Health and Human Services. The most com-
second PPV23 dose is recommended 5 years after the first monly used antiretroviral agents are presented in Table 101-3.
PPV23. The current preferred and alternative regimens for first-line treat-
ment are summarized in Table 101-4. With rare exceptions, all
Influenza Virus recommended regimens consist of at least three fully active
Persons with HIV have excess morbidity and mortality associ- drugs. Increasingly, coformulation of medications has allowed
ated with influenza and its complications. They should receive the combination of multiple drugs to be taken in single tablets.
seasonal influenza vaccination yearly. Three single-tablet daily regimens are currently approved for the
treatment of HIV, and more are in development. The reduced pill
Herpes Zoster burden can significantly improve adherence to treatment and
Reactivation of herpes zoster viral infection, resulting in shingles, minimize the risk of treatment failure. The World Health Orga-
is a significant cause of morbidity among persons with HIV nization publishes guidelines for HIV treatment programs in
disease. Because the singles vaccine is a live attenuated vaccine, resource-limited settings. They delineate first- and second-line
additional studies were conducted to assess the safety of this therapies selected based on efficacy, cost, and availability.
vaccine in persons with HIV. Although there were no reports of Clinical trials assessing the benefits of early treatment have
excess risk in these trials, final review is still pending, and the demonstrated the many health impacts of HIV that occur even
vaccine does not carry an indication from the U.S. Food and before the onset of demonstrable immune deficiency. Persons
Drug Administration (FDA) for use in persons with HIV. who undergo structured treatment interruptions and delay treat-
ment until their CD4 count drops to less than 500 cells/mm3
Human Papillomavirus experience higher rates of cardiovascular disease, kidney disease,
The CDC recommends use of the human papillomavirus (HPV) liver disease, and neurocognitive disorders. Although the risk
vaccine in boys or girls at age 11 or 12 regardless of HIV status, increases with declining CD4 count and worsening immune
in MSM, and in persons with immune compromise, including function, early effects can in some cases be demonstrated before
those with HIV, up to the age of 26 if not previously vaccinated. the onset of marked immunodeficiency. The demonstrated
benefit of initiating ART before the CD4 count drops to less than
Hepatitis A and B Viruses 500 cells/mm3 was primarily attributable to these noninfectious
Persons with HIV should be assessed by serology for prior expo- complications of HIV disease.
sure to hepatitis A and B. Those found to be susceptible to infec-
tion should receive immunization.
TABLE 101-3  MOST FREQUENTLY USED
ANTIRETROVIRAL MEDICATIONS BY
Other Health Screening
CLASS
Cervical Cancer DRUG CLASS MEDICATION
HIV-infected women should have two Pap smears 6 months Nucleoside/nucleotide reverse transcriptase Tenofovir
apart; if the they are both normal, Pap smears should be repeated inhibitors (NRTIs) Abacavir
Lamivudine
once a year. Persons with cellular atypia on a Pap smear should Emtricitabine
be referred for colposcopy. Zidovudine
Didanosine*
Rectal Cancer Stavudine*
Non-nucleoside reverse transcriptase inhibitors Efavirenz
HPV is associated with risk of cervical cancer in women and (NNRTIs) Nevirapine
rectal cancer in both men and women. Although some advocate Etravirine
Rilpivirine
for regular screening, clear guidelines have not yet been devel- Protease inhibitors† Atazanavir
oped for rectal cancer. Darunavir
Fosamprenavir
  ANTIRETROVIRAL THERAPY Lopinavir
Saquinavir
The goal of ART is to ensure that HIV-infected persons can Integrase inhibitors Raltegravir
lead symptom-free, productive lives. Currently available therapy Elvitegravir
Dolutegravir
makes achieving this goal possible in almost all individuals with CCR5 inhibitor Maraviroc
early, asymptomatic HIV infection who have not acquired major Fusion inhibitor Fuseon
resistance mutations as a result of earlier, suboptimal ART. The *Infrequently used due to toxicity.
current recommendations in the United States are that therapy †
Most protease inhibitors require a second medication to boost the levels of the drug
by inhibiting drug metabolism. Ritonavir at a dose of 100 mg daily is most commonly
should be offered to all persons infected with HIV. In much of used. Cobicistat was recently approved for use as part of a fixed-dose combination, and its
the world, thresholds for treatment based on CD4 count are potential for expansion is currently being studied.
934 Section XV  Infectious Disease

TABLE 101-4  PREFERRED AND ALTERNATIVE REGIMENS FOR FIRST-LINE ANTIRETROVIRAL THERAPY ACCORDING
TO DHHS GUIDELINES
PILL BURDEN COMBINATION* LIMITATIONS†
PREFERRED REGIMENS
Single pill Atripla (tenofovir, emtricitabine, efavirenz) CrCl >50, teratogenicity
2 pills once daily Truvada (tenofovir, emtricitabine) + dolutegravir CrCl >50
3 pills once daily Truvada (tenofovir, emtricitabine) + atazanavir + CrCl >50, cirrhosis Child Pugh class A
ritonavir
3 pills once daily Truvada (tenofovir, emtricitabine) + darunavir + ritonavir CrCl >50, cirrhosis Child Pugh class A
BID regimen: 1 pill daily, 1 pill twice daily Truvada (tenofovir, emtricitabine) + raltegravir CrCl >50
ALTERNATIVE REGIMENS
Single pill Complera (tenofovir, emtricitabine, rilpivirine) CrCl >50,† PPI contraindicated
Single pill Stribild (tenofovir, emtricitabine, elvitegravir, cobicistat) CrCl >70,† cirrhosis Child Pugh class A
Single pill Triumeq (abacavir lamivudine dolutegravir) HLAB5701 negative, CrCl >50
3 pills once daily Epzicom (abacavir, lamivudine) + atazanavir + ritonavir HLA-B5701 negative,‡ CrCl >50,† cirrhosis Child
Pugh score <5
3 pills once daily Epzicom (abacavir, lamivudine) + rilpivirine HLA-B5701 negative, CrCl >50,† PPI
contraindicated, cirrhosis Child Pugh score <5
BID regimen: 1 pill daily, 1 pill twice daily Truvada (tenofovir, emtricitabine) OR Epzicom CrCl >50,† HLA-B5701 negative (abacavir),
(abacavir, lamivudine) + etravirine cirrhosis Child Pugh score <5 (abacavir)
4 pills once daily Truvada (tenofovir, emtricitabine) OR Epzicom CrCl >50,† HLA-B5701 negative (abacavir),
(abacavir, lamivudine) + fosamprenavir + ritonavir cirrhosis Child Pugh score <5 (abacavir)
5 pills once daily Truvada (tenofovir, emtricitabine) OR Epzicom CrCl >50,† HLA-B5701 negative (abacavir),
(abacavir, lamivudine) + lopinavir/ritonavir cirrhosis Child Pugh score <5 (abacavir)
CrCl, Creatinine clearance (measured in mL/min/17.3 m2); DHHS, U.S. Department of Health and Human Services; HLA, human leukocyte antigen; PPI, proton pump inhibitors.
*New antiretroviral medications as well as new formulations of medications are approved frequently. For the most up-to-date listing of preferred and alternative regimens, refer to the
DHHS Guidelines for the Use of Antiretroviral Medications (see Recommended Readings).
†
Tenofovir, lamivudine, and emtricitabine all require dose adjustment when the CrCl drops to <50, preventing the use of fixed-dose combinations.
‡
HLA-B5701 is a genetic marker indicating risk for a hypersensitivity reaction to abacavir. Screening is indicated before the medication is started, and abacavir should not be used if the
marker is present.

As persons with HIV live longer on ART, more typical diseases
associated with aging become the focus of care. It can be chal-
lenging to distinguish what additive effects HIV may have to the
risks associated with these conditions, particularly if comorbid
substance use, smoking, and other risk factors are highly preva-
lent. As HIV is controlled with treatment, recognizing these risks
and focusing on providing the best quality primary care will be
critical to helping ensure that patients with HIV live full and
healthy lives.
Baseline Resistance Testing and
Development of Drug Resistance
Inconsistent intake of ART can lead to the development of HIV
strains resistant to antiviral medications. At least 16% of new
infections (one in six) contain mutations affecting susceptibility
to one or more antiretroviral medications. For this reason, mea-
surement of baseline resistance is recommended before ART is
initiated. Close monitoring of persons with inconsistent adher-
ence is critical. Some resistance mutations, particularly M184V,
which confers resistance to lamivudine and emtricitabine, have
been observed to develop with as little as a few weeks of incon-
sistent treatment.
When to Change Therapy
When an effective antiretroviral regimen is initiated in an asymp-
tomatic patient with no previous ART, the PVL should decrease
sharply, usually by 10-fold in 4 weeks and to an undetectable level
(<50 copies/mL) within 16 to 24 weeks. If reduction of this
magnitude is not achieved, the physician should assess with the
patient whether adherence has been adequate. If adherence has
been nearly complete (>95%), the physician and patient should
consider retesting for resistance mutations and changing to
another effective regimen. Minority viral subpopulations
carrying resistance mutations can rapidly overtake the sensitive
virus once the selective pressure exerted by the medications.
These subpopulations may become detectable only while on
treatment.
If a given regimen achieves a reduction of PVL below detect-
able limits and continuing adherence is achieved, the patient can
anticipate effective viral suppression for many years and perhaps
indefinitely. Small elevations in PVL on a single determination
are usually not significant. One may consult the International
AIDS Society—USA resistance guidelines, which are regularly
updated (www.iasusa.org/guidelines/index.html). If an antiret-
roviral drug must be stopped for any reason, it is important to
stop temporarily all antiretroviral drugs. Alternatively, a com-
pletely new effective regimen may be initiated to sustain com-
plete virologic suppression.
Prophylaxis against Opportunistic Infections
During the first 15 years of the HIV pandemic, the most effective
medical interventions for HIV infection were prophylactic mea-
sures against OIs. The greatest success was in preventing PCP in
individuals with CD4 counts lower than 200 cells/mm3; routine
use of prophylaxis resulted in a greater than fourfold decrease
(from 60% to <15%) in the frequency of PCP as the initial OI in
North American men with HIV infection.
Specific antimicrobial prophylaxis (Table 101-5) is also effec-
tive for prevention of T. gondii encephalitis in patients with anti-
Toxoplasma antibodies and CD4 counts lower than 100 cells/
mm3 and for prevention of active tuberculosis in patients with
positive tuberculin skin test results at any CD4 level. Prophylaxis
against disseminated MAI infection is recommended at lower
CD4 counts (<50 cells/mm3). Prophylaxis against CMV retinitis
 Chapter 101  Human Immunodeficiency Virus Infection 935

TABLE 101-5  RECOMMENDATIONS FOR PRIMARY AND SECONDARY PROPHYLAXIS FOR PERSONS WITH HIV
INFECTION
CD4 THRESHOLD
PATHOGEN (CELLS/MM3) ADDITIONAL INDICATION PREFERRED ALTERNATE
PRIMARY PROPHYLAXIS
Pneumocystis jirovecii <200 TMP-SMX SS or Dapsone, atovaquone
DS tablet daily
Toxoplasmosis <100 Anti-Toxoplasma IgG detectable TMP-SMX SS or Pyrimethamine-dapsone and
DS tablet daily pyrimethamine-sulfadoxine
Mycobacterium <50 Azithromycin Clarithryomicin 500 mg bid
avium-intercellulare 1200 mg weekly
SECONDARY PROPHYLAXIS
Mycobacterium tuberculosis Any History of exposure to TB Isoniazid depending Rifampin, isoniazid+rifapentene
confirmed by PPD test or IGRA on sensitivities
Cryptococcosis <200 History of cryptococcal meningitis Fluconazole NA
or cryptococcal antigen positive
Coccidomycosis <150 Antihistoplasma IgG detectable or Fluconazole or NA
history of coccidiomycosis itraconazole
Histoplasmosis <150 Anticoccidomyces IgG detectable Itraconazole NA
Cytomegalovirus (CMV) <50 Ocular or extraocular findings Ganciclovir 3 g/day NA
consistent with CMV infection
DS, Double-strength; IgG, immunoglobulin G; IGRA, interferon-γ release assay; NA, not applicable; PPD, purified protein derivative; SS, single-strength; TB, tuberculosis; TMP-SMX,
trimethoprim-sulfamethoxazole.

is moderately effective in patients with CD4 counts lower than
50 cells/mm3, but prompt initiation of effective ART with early
treatment of active disease is the currently preferred strategy.
Prophylaxis is very effective against recurrent HSV type 2 infec-
tion (with acyclovir, famciclovir, or valacyclovir) and against
recurrent Candida esophagitis (with fluconazole) but should
generally be reserved for those patients with recurrent symptom-
atic disease. Persons from areas where histoplasmosis or coccid-
iomycosis is endemic should be considered for primary
prophylaxis (with fluconazole) if they have detectable antibodies
and their CD4 count is lower than 150 cells/mm3. No guidelines
exist for cryptococcal antigen screening.
After the CD4 count rises on ART, withdrawal of prophylaxis
against specific OIs is reasonable. After initiation of effective ART
and two consecutive CD4 counts at least 3 months apart that
exceed 100 cells/mm3, prophylaxis against CMV and MAI may
be withdrawn safely; likewise, if the two consecutive counts
exceed 200 cells/mm3, prophylaxis against PCP and T. gondii
may be withdrawn.
For a deeper discussion of these topics, please see Chapter
389, “Prophylaxis and Management of Complications of
HIV/AIDS: Infectious, Neoplastic, and Metabolic,” in
Goldman-Cecil Medicine, 25th Edition.
  MANAGEMENT OF SPECIFIC CLINICAL
MANIFESTATIONS OF HIV INFECTION
Clinical manifestations of HIV include not only OIs associated
with immunodeficiency but also HIV-associated malignancies
and other noninfectious complications of HIV. The manifesta-
tions of HIV vary significantly in time of onset (see Table 101-2).
Before the onset of infectious complications, some HIV-
associated cancers such as non-Hodgkin’s lymphoma and HPV-
associated carcinomas can develop. Infectious complications
such tuberculosis can manifest at any CD4 count and occur with
increased frequency in association with HIV. Infectious compli-
cations that occur with higher CD4 counts respond to routine
therapy for the specific infection (e.g., appropriate β-lactam anti-
biotic for pneumococcal pneumonia, standard multidrug therapy
for pulmonary tuberculosis), whereas OIs occurring with CD4
counts lower than 200 cells/mm3 require chronic suppressive
therapy after treatment of the acute infection (e.g., PCP pneumo-
nia, CMV retinitis, Cryptococcus neoformans meningitis).
For a deeper discussion of these topics, please see Chapter
389, “Prophylaxis and Management of Complications of
HIV/AIDS: Infectious, Neoplastic, and Metabolic,” in
Goldman-Cecil Medicine, 25th Edition.
Initial Assessment of HIV- 
Associated Illnesses
Assessment of a patient’s immunologic status is key in the evalu-
ation of persons with HIV when there is a new presenting illness
or complaint. If the patient is on ART and has had a recent CD4
assessment, that count is the best indicator of their status. Persons
without recent CD4 testing should be presumed to be immuno-
compromised unless there is clear information to suggest the
contrary. If there has been a treatment interruption, the CD4
count should return to its prior nadir after about 12 months of
interruption. During an acute illness, the absolute CD4 count
may decline; therefore, a measured CD4 count during an acute
illness can underestimate an individual’s true immune function.
Constitutional Symptoms
Nonspecific symptoms may be the initial clinical manifestations
of severe immunodeficiency. Patients may develop unexplained
fever, night sweats, anorexia, weight loss, or diarrhea. These
symptoms may last for weeks or months before the development
of identifiable OIs in patients who do not receive effective ART.
Most persistent fevers occurring late in the course of HIV infec-
tion reflect a definable OI. The most common cause of unex-
plained fever and anemia in patients with CD4 counts lower
than 50 cells/mm3 is disseminated MAI infection. This may be
diagnosed by bone marrow biopsy, but blood cultures in
936 Section XV  Infectious Disease
Mycobacterium-selective media are usually positive. Treatment
usually results in resolution of fever and weight gain. Aggressive
non-Hodgkin’s lymphoma may cause unexplained fever and
weight loss, a rapidly enlarging spleen, or asymmetrical lymph
node enlargement.
Wasting and Changes in Body Morphology
Cachexia may be prominent in advanced HIV disease. In some
instances, the wasting is caused by an intercurrent infectious
process. Heightened production of tumor necrosis factor may
contribute to fever, cachexia, and hypertriglyceridemia in
advanced HIV disease. If orthostatic hypotension occurs, espe-
cially if it is associated with hyperkalemia, the possibility of
adrenal insufficiency, which rarely can result from CMV adrenal-
itis, should be investigated. Most patients with AIDS-associated
cachexia gain weight and achieve a sense of well-being after initia-
tion of effective ART. If the cachexia is refractory, weight gain
may be enhanced by administration of recombinant growth
hormone, nonmethylated androgens, or megestrol, but definitive
indications for these therapies have not been established.
Older antiviral agents, particularly nucleoside/nucleotide
reverse transcriptase inhibitors (e.g., didanosine, stavudine) and
the early protease inhibitors, were associated with alterations
in fat distribution known as lipodystrophy and lipoatrophy.
Patients with long-term exposure to these medications may
develop a loss of fat in the face and on the extremities. At
the same time, they develop prominent central obesity includ-
ing a buffalo hump and marked abdominal obesity. These
changes typically persist even after the medication is discon-
tinued and are associated with increased risk of cardiovascular
disease.
Cutaneous Disease
Cutaneous infections ultimately occur in most patients with
untreated HIV infection. Persons with HIV experience both
higher rates of more typical skin infections (e.g., folliculitis, cel-
lulitis) and OIs such as disseminated herpes zoster or HSV, bacil-
lary angiomatosis, and fungal infections. Most of these diseases
respond to specific therapy. Noninfectious skin manifestations
include exacerbation of underlying psoriasis, seborrhea dermati-
tis, and eosinophilic folliculitis. Skin lesions can equally be asso-
ciated with some disseminated infectious complications or
malignancies. If a patient has unexplained constitutional symp-
toms, a thorough skin examination may provide important find-
ings to support a diagnosis.
For a deeper discussion of these topics, please see Chapter
392, “Skin Manifestations in Patients with Human Immu-
nodeficiency Virus Infection,” in Goldman-Cecil Medicine,
25th Edition.
Oral Disease
Oral Candida stomatitis (thrush) is often the earliest recognized
OI. Early thrush may be entirely asymptomatic; as the infection
becomes more extensive, it causes pain on eating. The character-
istic cheesy white exudate on the mucous membranes can easily
be scraped off, and the underlying mucosa may be normal or
inflamed.
Xerostomia is common among patients with HIV and is often
underappreciated. It can be a significant contributor to poor den-
tition and gingivitis, which can contribute to other adverse health
consequences for the patient.
Severe gingivitis can be a significant problem in patients with
AIDS, leading to local and systemic infection as well as loss of
teeth.
Oral ulcers may be caused by HSV, but often they represent
aphthous lesions of uncertain cause. Small oral aphthous ulcers
may respond to topical corticosteroids, whereas large oral or
esophageal ulcers require oral administration of thalidomide or
corticosteroids. It is important to obtain cultures for HSV and
CMV to exclude a viral origin before initiating corticosteroid or
thalidomide therapy. Thalidomide should not be used in women
of childbearing age because of its teratogenic effect.
Oral hairy leukoplakia is a white, lichenified, plaque-like lesion
most commonly seen on the lateral surfaces of the tongue that is
probably caused by Epstein-Barr virus (EBV). It is painless, may
remit and relapse spontaneously, and almost always responds to
effective ART.
Kaposi’s sarcoma has a predilection for the oral cavity and skin.
Oral lesions may be purple, red, or blue and may be raised or flat.
Usually painless, these lesions cause symptoms when they
enlarge, bleed, or ulcerate (see later discussion).
Esophageal Disease
Symptomatic esophageal disease seldom occurs with CD4 counts
greater than 100 cells/mm3. Pain on swallowing and substernal
burning are common and most often indicate Candida esophagi-
tis, particularly when oral thrush is present. Diagnostic esopha-
goscopy with biopsy, cytology, and culture should be performed
if symptoms do not rapidly respond (within 3 to 5 days) to anti-
fungal therapy.
If esophagoscopy shows ulcerative lesions, they are usually
caused by CMV (50%), aphthae (45%), or HSV (5%). Because
each of these lesions is responsive to appropriate therapy, defini-
tive etiologic diagnosis is essential. CMV esophageal ulcers
respond well to intravenous ganciclovir or foscarnet therapy for
2 to 3 weeks or until resolution is confirmed endoscopically.
Esophageal ulcerations caused by HSV usually respond well to
intravenous acyclovir.
For a deeper discussion of these topics, please see Chapter
390, “Gastrointestinal Manifestations of HIV and AIDS,” in
Goldman-Cecil Medicine, 25th Edition.
Pulmonary Diseases
Pulmonary infections are common in persons living with HIV
and range from nonspecific interstitial pneumonitis to life-
threatening pneumonias (Table 101-6). HIV-infected persons
have a threefold to fourfold increased risk of bacterial pneumo-
nia, usually caused by encapsulated bacteria, including S. pneu-
moniae and H. influenzae. The increased risk begins with modest
degrees of immunodeficiency (CD4 counts of 200 to 500 cells/
mm3). The onset is often abrupt, and the response to prompt
initiation of therapy is usually good; however, delay in appropri-
ate antimicrobial therapy may result in a fulminant downhill
course. For those with CD4 counts greater than 200 cells/mm3,
 Chapter 101  Human Immunodeficiency Virus Infection 937
TABLE 101-6  PULMONARY COMPLICATIONS OF HIV INFECTION: DIFFERENTIAL DIAGNOSIS AND TREATMENT
CONDITION CHARACTERISTICS
Pneumocystis jirovecii Subacute onset, dry cough,
pneumonia dyspnea
Bacterial (Pneumococcus, Acute onset, productive cough,
Haemophilus most fever, chest pain
common)
Tuberculosis Chronic cough, weight loss, fever
Kaposi’s sarcoma Asymptomatic or mild cough
BAL, Bronchoalveolar lavage; TMP-SMX, trimethoprim-sulfamethoxole.
therapy should follow existing guidelines for empirical treatment
of pneumonia (see Chapter 92). Pursuit of diagnostic studies that
can support a definitive diagnosis is important, particularly if the
patient’s CD4 count is near 200 cells/mm3 or the features or
clinical course of pneumonia are atypical.
As with acute bacterial pneumonia, active pulmonary tubercu-
losis may develop at a time when the CD4 count remains well
above 200 cells/mm3 (see Table 101-6). Chest radiographs in
HIV-infected patients may show features of primary tuberculosis,
including hilar adenopathy, lower or middle lobe infiltrates,
miliary pattern, or pleural effusions, as well as classic patterns of
reactivation. Extrapulmonary Mycobacterium tuberculosis infec-
tion also occurs with increased frequency in patients with
advanced immunodeficiency. Both pulmonary and extrapulmo-
nary tuberculosis respond promptly to the use of four antituber-
culosis drugs.
Pneumonia caused by PCP remains a common life-threatening
infection in persons with AIDS. Patients frequently report a
gradual onset of nonproductive cough, fever, and shortness of
breath with exertion; a productive cough suggests another
process. A substernal “catch” with inspiration is common and is
suggestive of PCP. In contrast to the acute onset of PCP in other
immunocompromised patients, AIDS patients with PCP may
have pulmonary symptoms for weeks before consulting a physi-
cian. Arterial hypoxemia is typical and rapidly worsens with
slight exertion. Oxygen desaturation with exercise, as measured
by pulse oximetry, can suggest the diagnosis. The chest radio-
graph often shows a subtle interstitial pattern but may be entirely
normal. The presence of pleural effusions suggests a cause other
than PCP.
If PCP is suspected clinically, therapy should be started imme-
diately; treatment for several days does not interfere with the
ability to make a specific diagnosis. Confirmation of PCP is
essential; delay in establishing a correct diagnosis of another
treatable condition may be lethal. An induced sputum sample
can sometimes confirm the diagnosis, but most patients require
bronchoalveolar lavage, which is adequate to diagnose PCP in
more than 95% of patients. Treatment with high-dose
trimethoprim-sulfamethoxazole (TMP-SMX) for 3 weeks is
effective therapy (see Table 101-6). Patients with PCP and arte-
rial hypoxemia (oxygen tension 75 mm H2O on breathing of
room air) benefit from the administration of corticosteroids
(40 mg of prednisone twice daily), with tapering of the drug
over a 3-week period.
CHEST RADIOGRAPH DIAGNOSIS TREATMENT
Interstitial infiltrate most BAL or induced sputum for TMP-SMX, pentamidine or
common organism by stain atovaquone or primaquine
+ clindamycin
Lobar or localized infiltrate Sputum Gram stain and Cefuroxime or alternative
culture, blood culture antibiotics
Localized infiltrate, Sputum acid-fast stain and Isoniazid, rifampin,
lymphadenopathy mycobacterial culture pyrazinamide, ethambutol
Pulmonary nodules, pleural Open lung biopsy Chemotherapy
effusion
For a deeper discussion of these topics, please see Chapter
391, “Pulmonary Manifestations of Human Immunodefi-
ciency Virus and Acquired Immunodeficiency Syndrome,”
in Goldman-Cecil Medicine, 25th Edition.
Disseminated histoplasmosis and coccidioidomycosis occur
with much greater frequency in persons with HIV infection.
Either fungal infection can cause nodular infiltrates or a miliary
pattern on chest radiography. Histoplasmosis usually involves
bone marrow as well as skin, and examination of the bone marrow
often shows the organism. Standard treatment of disseminated
mycoses in AIDS patients is high-dose liposomal amphotericin.
Because relapse is common, oral azole therapy (fluconazole for
coccidioidomycosis, itraconazole for histoplasmosis) must be
continued even after resolution of signs and symptoms. For
patients treated for histoplasmosis, secondary prophylaxis may
be discontinued after 1 year of therapy, provided that the CD4
count is at least 150 cells/mm3, blood cultures are negative, and
the HIV serum Histoplasma antigen titers are low. Patients treated
for systemic, meningeal, or diffuse pulmonary coccidioidomyco-
sis have a greater risk of relapse and probably should continue
suppressive therapy indefinitely.
For a deeper discussion of these topics, please see Chapter
332, “Histoplasmosis,” and Chapter 333, “Coccidioidomy-
cosis,” in Goldman-Cecil Medicine, 25th Edition.
Cardiovascular Disease
As the population with HIV ages, cardiovascular disease is
becoming an increasingly important cause of morbidity and mor-
tality. Persons with HIV experience higher rates of cardiovascular
disease. Even with suppressive ART, some increased risk remains,
likely attributable in part to risk factors such as persistent residual
immunologic activation, high rates of tobacco use, hyperlipid-
emia, metabolic syndrome, diabetes, or chronic kidney disease.
Pericarditis and Pericardial Effusions
Pericardial effusions are a well recognized complication of HIV
disease and may be result from infections or malignancy (see
Chapter 10). In many cases, no specific cause is identified and
effusions resolve without specific treatment. In places where
tuberculosis is endemic, constrictive pericarditis secondary to
tuberculosis is an important consideration. In addition, pericar-
ditis and effusions secondary to acute infections and both non-
Hodgkin’s lymphoma and Kaposi’s sarcoma may occur.
938 Section XV  Infectious Disease
Congestive Heart Failure
In addition to ischemic cardiomyopathy, persons with HIV may
develop congestive heart failure due to an HIV-associated dilated
cardiomyopathy and infectious myocarditis.
Gastrointestinal Diseases
HIV affects the gastrointestinal tract early in infection, with pro-
found depletion of memory CD4 T cells in gut-associated lym-
phoid tissue within the first few weeks of infection. However,
symptomatic disease of the gut is unusual in the early stage of
infection.
With advanced immunodeficiency (CD4 count <50 cells/
mm3), gastrointestinal disease manifesting as dysphagia, diar-
rhea, or colitis is common. Each process may contribute to inad-
equate nutrition, compounding the weight loss associated with
advanced HIV disease. Nausea and vomiting are often related to
medications. If symptoms of nausea and vomiting do not respond
to empirical therapy with histamine-2 (H2) antagonists or anti-
emetics, more extensive gastrointestinal evaluation is indicated.
For a deeper discussion of these topics, please see Chapter
390, “Gastrointestinal Manifestations of HIV and AIDS,” in
Goldman-Cecil Medicine, 25th Edition.
Diarrhea
Diarrhea occurs, at least intermittently, in many persons with
advanced immunodeficiency and may be caused by a variety of
microorganisms (Table 101-7) as well as by certain antiretroviral
and other medications. In many instances, no clear cause is
found. Stool specimens should be cultured for the common bac-
terial pathogens. Salmonella, Campylobacter, and Yersinia species
are frequent causes; the diarrhea usually responds to standard
antimicrobial therapy. Patients may also have recurrent episodes
of diarrhea associated with Clostridium difficile toxin; this proba-
bly reflects the frequent use of broad-spectrum antibiotics.
In cases of persistent diarrhea, a fresh stool specimen should
be examined for parasites, using a modified acid-fast stain for
Cryptosporidium parvum, microsporidia, and Isospora belli, the
most common enteric protozoal infections in AIDS patients.
Microsporidial infection may require biopsy with electron
microscopy for diagnosis. Although cryptosporidiosis can be
self-limited, massive diarrhea (up to 10 L/day) may occur.
TABLE 101-7  AIDS-ASSOCIATED DIARRHEA: DIFFERENTIAL DIAGNOSIS AND TREATMENT
CAUSE CHARACTERISTICS
Cryptosporidium parvum Variable from high-frequency to
large-volume diarrhea
Clostridium difficile Abdominal pain, fever common
Cytomegalovirus Small bowel movements with blood or
mucus (colitis)
Mycobacterium avium-intracellulare Abdominal pain, fever, retroperitoneal
lymphadenopathy
Salmonella or Campylobacter Sometimes with blood or mucus in
bowel movements (colitis)
Microsporidia Watery diarrhea
Isospora belli Watery diarrhea
ART, Antiretroviral therapy; TMP-SMX, trimethoprim-sulfamethoxazole.
Isosporiasis responds to oral TMP-SMX, and several microspo-
ridial species respond to albendazole. Symptoms of both crypto-
sporidiosis and isosporiasis resolve with effective ART.
If stool diagnostic studies are negative and diarrhea persists,
patients should undergo endoscopy (see Chapter 34). Biopsy of
the duodenum or small bowel may show histologic evidence of
cryptosporidial, microsporidial, MAI, or CMV infection. Biopsy
of the colon may be indicate HSV proctitis, CMV colitis, or MAI
infection. For patients with refractory diarrhea, symptomatic
treatment may improve the quality of life.
Hepatitis
Abnormalities on liver function testing are common in HIV
disease and often are nonspecific. Elevations of serum alanine
aminotransferase and aspartate aminotransferase often represent
chronic active hepatitis B or C but may reflect hepatic inflamma-
tion caused by medications, including TMP-SMX and antiretro-
viral agents. Alcohol use is highly prevalent among persons with
HIV and may contribute, as can use of other drugs such as
MDMA (“ecstasy”).
Marked elevations in serum alkaline phosphatase levels may
reflect infiltrative disease of the liver (e.g., MAI, CMV, tubercu-
losis, tumor) but also may occur in patients with acalculous cho-
lecystitis, cryptosporidiosis, or AIDS-associated sclerosing
cholangitis. Syphilitic hepatitis has been well described and may
be characterized by a more pronounced elevation in alkaline
phosphatase.
Viral hepatitis, particularly hepatitis C, is an important cause
of morbidity and mortality among persons with HIV. More than
80% of persons with HIV who have a history of injection drug
use are co-infected with hepatitis C, and the risk of progression
to end-stage liver disease is greater for those with HIV hepatitis
C co-infection. Occult hepatitis infections (antibody negative
but with detectable RNA or DNA) have been described for both
hepatitis B and hepatitis C, particularly in the context of advanced
immunodeficiency. The response to hepatitis C therapy has his-
torically been significantly worse for those co-infected with HIV,
but this may be less true with the new generation of direct-acting
agents for treatment of hepatitis C.
Genital Diseases
Primary and secondary syphilis remains a concern among
persons with HIV, particularly MSM. Early neurologic
DIAGNOSIS TREATMENT
Acid-fast stain of stool Nitazoxanide ART
C. difficile toxin in stool or endoscopy Metronidazole or vancomycin
Colonoscopy and biopsy Ganciclovir
Blood culture or endoscopy with Multidrug regimen including
biopsy clarithromycin, ethambutol
Stool culture Fluoroquinolone (check sensitivities)
Calcofluor white or trichrome staining Albendazole, ART
of stool; electron microscopy of
biopsy material
Acid-fast stain of stool TMP-SMX
 Chapter 101  Human Immunodeficiency Virus Infection 939

involvement has been well described, and a thorough history and develop focal neurologic complications characterized by spastic
examination to exclude neurologic complications is important in weakness of the lower extremities and incontinence secondary to
the evaluation of incident cases. Treatment regimens for persons vacuolar myelopathy.
with HIV, based on stage of presentation, are the same as for
those without HIV. However, persons with HIV take longer to Focal Lesions of the Central Nervous System
achieve a full reduction in rapid plasma reagin (RPR) titer and A large variety of neurologic problems can complicate the later
may continue to have low-level demonstrable RPR titers even stages of HIV infection. A neuroanatomic classification of these
after successful treatment. manifestations is presented in Table 101-8. Some of the more
Recurrent genital ulcers are most often caused by HSV. Viral frequent or treatable problems are discussed here and in the next
culture or specific immunofluorescence of ulcer scrapings con- section.
firms the diagnosis. Several opportunistic complications of HIV infection produce
Candida species, most often Candida albicans, can cause an focal CNS lesions. Patients with focal neurologic signs, seizures
irritating vulvovaginitis in women with HIV infection as well as of new onset, or recent onset of rapidly progressive cognitive
in healthy HIV-seronegative women. A potassium hydroxide impairment should undergo magnetic resonance imaging
preparation of the cheesy white exudate reveals budding yeast or (MRI) or CT of the brain. Toxoplasmosis, CNS lymphoma,
pseudohyphae. and progressive multifocal leukoencephalopathy (PML) are
Bacterial vaginosis and trichomoniasis are common, and the most common causes of CNS focal lesions in this setting
although both typically respond to specific treatment (e.g., met- (Table 101-9).
ronidazole), bacterial vaginosis often recurs. In the absence of ART, T. gondii encephalitis occurs in up to
For more information on sexually transmitted diseases, see one third of HIV-infected patients who have serologic evidence
Chapter 100. of T. gondii infection, but is rare in individuals who have no such
antibodies. Patients often have progressive headache and focal
Nervous System Diseases neurologic abnormalities, usually associated with fever. CT with
Nervous system complications ultimately occur in most persons contrast usually shows multiple ring-enhancing lesions. MRI is a
with untreated HIV infection. They range from mild cognitive more sensitive technique and often shows multiple small lesions
disturbances or peripheral neuropathy to severe dementia and
life-threatening central nervous system (CNS) infections. As
with other lentiviruses, HIV enters microglial cells of the CNS TABLE 101-8  NEUROANATOMIC CLASSIFICATION OF
early in the course of infection. Both direct neuronal destruction NEUROLOGIC COMPLICATIONS OF HIV
and effects of viral proteins on neuronal cell function may con- INFECTION
tribute to nervous system disease in AIDS. CATEGORY CONDITION
Meningitis and headache Aseptic meningitis
Cognitive Dysfunction Cryptococcal meningitis
Tuberculous meningitis
Intellectual impairment rarely occurs early in HIV infection, but Neurosyphilis
subtle changes (e.g., decreased learning accuracy and learning Diffuse brain diseases
speed) may be present in patients with only moderate immuno-   With preservation of AIDS dementia complex
consciousness Neurosyphilis
deficiency. AIDS dementia complex (ADC) often begins insidi-   With decreased arousal Toxoplasma encephalitis
ously and usually progresses over months to years. ADC is Cytomegalovirus encephalitis
characterized by poor concentration, diminished memory, Focal brain diseases Tuberculous brain abscess
Primary central nervous system lymphoma
slowing of thought processes, motor dysfunction, and occasion- Progressive multifocal leukoencephalopathy
ally behavioral abnormalities characterized by social withdrawal Cerebral toxoplasmosis
and apathy. Symptoms of clinical depression overlap with many Neurosyphilis
Myelopathies Subacute or chronic progressive vacuolar
of the characteristics of early ADC and must be considered care- myelopathy
fully in differential diagnosis and therapy. Cytomegalovirus myelopathy
Computed tomography (CT) of the head in ADC reveals only Peripheral neuropathies Predominantly sensory polyneuropathy
Toxic neuropathies
atrophy, with enlarged sulci and ventricles, but these findings do Autonomic neuropathy
not reliably predict cognitive deficits. The CSF is most often Cytomegalovirus polyradiculopathy
normal on examination. Motor abnormalities may include a pro- Myopathies Noninflammatory myopathy
gressive gait ataxia. As the disease progresses, patients may Zidovudine myopathy

TABLE 101-9  NEUROLOGIC COMPLICATIONS OF HIV INFECTION

CLINICAL ONSET NEURORADIOLOGIC FEATURES
CONDITION Time Alertness Fever Number of Lesions Characteristics of Lesions Location of Lesions
Cerebral toxoplasmosis Days Reduced Common Usually multiple Spherical, ring enhancing Basal ganglia, cortex
Primary CNS lymphoma Days to weeks Variable Absent One or few Irregular, weakly ring enhancing Periventricular
PML Weeks to months Variable Absent Often multiple Multiple lesions visible on MRI White matter
MRI, Magnetic resonance imaging; PML, progressive multifocal lymphoma.
940 Section XV  Infectious Disease
not apparent on CT. Management includes initiation of empirical
therapy with pyrimethamine, sulfadiazine, and folinic acid. Brain
biopsy should be reserved for patients with neurologic deteriora-
tion, those with no serum antibodies to T. gondii who have neu-
roimaging findings atypical for toxoplasmosis, those with
discordant results between PCR of the CSF for EBV and thallium-
enhanced single-photon emission computed tomography
(SPECT) scans, and those whose lesions do not respond after 10
to 14 days of antiprotozoal treatment. After the initial response,
patients must remain on chronic suppressive therapy until a sus-
tained rise in CD4 count (>200 cells/mm3) is achieved with
effective ART.
Primary CNS lymphoma complicates advanced HIV infection
in 3% to 6% of cases and is almost invariably associated with
detectable EBV DNA in the CSF. Lesions may be single or mul-
tiple and are often weakly ring enhancing. Irradiation often pro-
vides remission, which may be sustained as immune function is
restored by effective ART.
PML is a demyelinating disease caused by a papovavirus ( JC
virus). Presenting signs and symptoms may include progressive
dementia, visual impairment, seizures, and hemiparesis. MRI
usually shows multiple lesions predominantly involving the
white matter. These lesions are usually less visible on CT than on
MRI and are not ring enhancing, helping to distinguish PML
from other mass lesions of the CNS. There is no effective specific
treatment for PML; the disease often, but not always, regresses
in response to effective ART.
For a deeper discussion of these topics, please see Chapter
394, “Neurologic Complications of Human Immunodefi-
ciency Virus Infection,” in Goldman-Cecil Medicine, 25th
Edition.
Central Nervous System Diseases without
Prominent Focal Signs
Evaluation of the HIV-infected patient with fever and headache
is difficult because of the often subtle manifestations of serious
CNS lesions in immunocompromised patients. Management of
bacterial meningitis is the same as for non-immunocompromised
patients. Meningeal diseases in HIV-infected patients often fall
into the broad categories of aseptic meningitis, chronic meningi-
tis, and meningoencephalitis.
For a deeper discussion of these topics, please see Chapter
394, “Neurologic Complications of Human Immunodefi-
ciency Virus Infection,” in Goldman-Cecil Medicine, 25th
Edition.
Aseptic Meningitis
Patients with aseptic meningitis, which can be a manifestation of
the acute retroviral syndrome, complain most often of headache.
Their sensorium is generally intact, and findings on neurologic
examination are normal. In the individual with established HIV
infection, aseptic meningitis may result from several potentially
treatable causes.
Chronic Meningitis
Patients with chronic meningitis characteristically have head-
ache, fever, difficulty in concentrating, or changes in sensorium.
CSF examination shows low glucose concentration, elevated
protein level, and mild to modest lymphocytic pleocytosis.
Cryptococcal meningitis is the most common type. The pres-
ence of cryptococcal antigen in serum or CSF or a positive CSF
India ink preparation establishes the diagnosis. Treatment with
amphotericin B for at least 2 weeks, followed by high-dose fluco-
nazole, is usually effective. Serial lumbar punctures, with removal
of CSF to decrease intracranial pressure, may be necessary in the
early management of cryptococcal meningitis.
M. tuberculosis can cause subacute or chronic meningitis in the
HIV-infected patient. Antituberculosis therapy should be consid-
ered in the setting of chronic meningitis if the cryptococcal
antigen test is negative.
Coccidioides immitis or Histoplasma capsulatum may cause sub-
acute or chronic meningitis in patients who reside in, or have a
history of travel to, endemic regions (i.e., the U.S. southwestern
deserts and the Ohio and Mississippi River drainage areas,
respectively).
Neurosyphilis in patients with HIV is more common and may
manifest earlier after infection. Patients may experience head-
aches and dizziness in the early phases, which can be followed
by personality change, ischemic strokes, ataxia, seizures, and
paralysis.
Meningoencephalitis
Patients with meningoencephalitis manifest alterations in senso-
rium varying from mild lethargy to coma. Patients are usually
febrile, and neurologic examination often shows evidence of
diffuse CNS involvement. CT or MRI may show only nonspecific
abnormalities, whereas electroencephalography often is consis-
tent with diffuse disease of the brain.
CMV encephalitis is rare and difficult to diagnose; it occurs
only in the setting of CD4 counts lower than 50 cells/mm3.
Patients may demonstrate confusion, cranial nerve abnormali-
ties, or long tract signs. CSF findings may resemble those of bac-
terial meningitis, with a modest polymorphonuclear leukocyte
pleocytosis and depressed CSF glucose levels. CT scanning or
MRI may reveal periventricular abnormalities. Many patients
have associated CMV retinitis. PCR detection of CMV DNA in
CSF appears to be a sensitive and specific method for diagnosis
of CMV encephalitis and polyradiculopathy (persistent back
pain and weakness of the lower extremities).
Meningoencephalitis caused by HSV is unusual in HIV
infection.
HIV-Associated Malignancies
The incidence of AIDS-associated malignancies has declined sig-
nificantly since the advent of effective ART. Among HIV-infected
MSM, the frequency of Kaposi’s sarcoma fell from 40% at the
outset of the epidemic to less than 15% in 1999. Human herpes-
virus 8 is the causative agent. In many instances, lesions resolve
after institution of effective ART. Systemic chemotherapy can
cause remission in many patients with symptomatic visceral
disease. Kaposi’s sarcoma remains common in many parts of the
developing world.
Non-Hodgkin’s lymphomas (largely B cell, with small non-
cleaved or immunoblastic histology) occur 150 to 250 times
more often in HIV-infected persons than in the general
 Chapter 101  Human Immunodeficiency Virus Infection 941
population. Up to 40% of AIDS-related systemic lymphomas,
and almost all of those in a primary CNS location, are related to
EBV. Extranodal presentation of these tumors is the rule, and
there is a high frequency of gastrointestinal or intracranial pre-
sentation. Chemotherapy for systemic disease or radiation
therapy for CNS disease usually provides a clinical response,
which may be maintained if it is accompanied by effective ART.
Other malignancies, including Hodgkin’s disease, have an
increased incidence in patients with untreated HIV infection.
Now that more treated persons are surviving , an increasing inci-
dence of a variety of non-AIDS–defining malignancies is being
observed. Among these, increased rates of anal cancer, non–small
cell lung cancer, Hodgkin’s disease, and liver cancer (related to
hepatitis viruses) have been associated with HIV.
For a deeper discussion of these topics, please see Chapter
394, “Neurologic Complications of Human Immunodefi-
ciency Virus Infection,” in Goldman-Cecil Medicine, 25th
Edition.
Renal Disorders
Renal insufficiency in patients with HIV may be a consequence
of nephrotoxic drug administration, long-term use of certain anti-
viral agents (particularly tenofovir), substance use (e.g., heroin),
or HIV-associated nephropathy (HIVAN). HIVAN typically
improves with ART. In some cases, renal biopsy is indicated to
establish a diagnosis, particularly if rapid decline in glomerular
function is observed. In the United States, HIVAN is seen almost
exclusively in African Americans and usually manifests as heavy
proteinuria and progressive renal insufficiency. Without treat-
ment, most patients develop end-stage renal disease within
several months. Treatment is primarily with combination antiret-
roviral drugs.
Musculoskeletal and   sexually active men in the United States and western Europe,
Rheumatologic Disorders
Musculoskeletal complaints are common among patients with
HIV, and distinguishing acute complications of HIV from more
indolent degenerative joint disease or recurrent muscle strain is
important. Septic arthritis is a particular concern in persons who
use injection drugs or have hemophilia.
Reiter’s syndrome has been associated with HIV, and patients
with HIV may experience a more severe or more prolonged
course. Flares related to immune reconstitution have been
described; they frequently respond quickly to doxycycline.
Declining CD4 counts in persons with psoriasis is associated
with flares of both cutaneous disease and psoriatic arthritis. Stan-
dard therapy for both can now be supplemented if necessary with
disease-modifying antirheumatic drugs.
Both lupus and rheumatoid arthritis, when present, may be
relatively quiescent in persons with low CD4 counts. When treat-
ment for HIV is initiated and the CD4 count rises, these persons
may experience flares of their underlying connective tissue
disease.
Avascular necrosis of the hip has been well described in
persons with HIV, including those on ART. MRI may be neces-
sary to confirm the diagnosis, and surgery is the mainstay of
treatment.
Muscle weakness, if localized, may be indicative of myelopathy-
neuropathy. If weakness is proximal or is associated with myalgia
and tenderness, myopathy should be suspected. ART is the
primary treatment for HIV-associated myopathy. Myopathy may
rarely be caused by zidovudine toxicity.
Immune Reconstitution  
Inflammatory Syndrome
Persons with low CD4 counts at the start of treatment who expe-
rience a rapid rise in CD4 count on treatment may be at risk for
development of what is termed the immune reconsitution inflam-
matory syndrome (IRIS). The syndrome results from the devel-
opment of a pronounced immune response to a previously
tolerated antigen, usually an infection. The specific symptoms
depend on the pathogen or antigen and the involved area of the
body. Entities commonly associated with IRIS include M. tuber-
culosis and other mycobacteria, Pneumocystis pneumonia, crypto-
coccal infections, herpesviruses, and hepatitis B or C virus.
Treatment is supportive, although in severe cases, for example
IRIS associated with meningitis or inflammation of the lungs
leading to respiratory compromise, corticosteroids may be used
to reduce inflammation and alleviate the symptoms.
For a deeper discussion of these topics, please see Chapter
395, “Immune Reconstitution Inflammatory Syndrome in
HIV/AIDS,” in Goldman-Cecil Medicine, 25th Edition.
  PREVENTION OF HUMAN
IMMUNODEFICIENCY VIRUS INFECTION
Three approaches—behavioral modification, treatment of sexu-
ally transmitted diseases, and ART—have had a major impact
on HIV transmission. All of these activities are supported by
expanded testing and improved linkage to care.
In several communities at increased risk for HIV (e.g., homo-
young adults in Uganda and Thailand), adoption of safer sexual
practices, specifically the use of condoms during sexual activity,
has been associated with a decrease in incidence of HIV infec-
tion. Sustaining these behavioral changes over long periods is
challenging and requires behavioral reinforcement. Several
recent controlled trials have demonstrated that male circumci-
sion can decrease the risk of acquiring HIV infection by more
than half.
Increasingly, ART is becoming a key goal of prevention pro-
grams. Antiretroviral treatment of HIV-infected pregnant women
and their infants in the peripartum period has decreased maternal-
child transmission from 25% to less than 5% in North America.
If a pregnant woman maintains viral suppression during preg-
nancy and during breast-feeding, the risk of transmission to her
infant is less than 1%.
Prophylactic use of ART has been shown to be effective for
postexposure prophylaxis after occupational exposures to HIV
and after unprotected sexual exposures. Recently, studies have
shown the benefit of preexposure prophylaxis in preventing
transmission of HIV among high-risk MSM, and the fixed-dose
combination of tenofovir and emtricitabine has received an FDA
indication for this use. The most compelling reinforcement of the
importance of ART for prevention was a large multisite clinical
942 Section XV  Infectious Disease
trial of discordant couples that demonstrated a reduction of
almost 100% in transmission to partners.
The development of an effective vaccine is the target of active
research. Early clinical trials of vaccine candidates are ongoing
but to date have demonstrated, at most, limited protection.
Induction of brisk T-cell responses to HIV antigens has neither
protected against HIV acquisition nor decreased the magnitude
of HIV replication among vaccinated subjects. A legitimate goal
for vaccines, the induction of antibody responses that can broadly
inhibit or neutralize the infectivity of diverse HIV strains, has so
far eluded vaccine developers.
For a deeper discussion of these topics, please see Chapter
387, “Prevention of Human Immunodeficiency Virus Infec-
tion,” in Goldman-Cecil Medicine, 25th Edition.
  PROGNOSIS
With ART, survival in many cohorts approaching that of age-
matched controls. Because of the high rates of co-infection with
viral hepatitis in many populations, liver disease remains a signifi-
cant cause of morbidity and mortality, accounting for a signifi-
cant portion of the early mortality still associated with HIV. In
endemic areas, tuberculosis is a similar cause of early mortality
among persons with HIV infection. Even with effective ART,
persons with HIV still experience some excess risk of cardiovas-
cular disease as well some non–AIDS-defining malignancies such
as non-Hodgkin’s lymphoma. The key message for persons living
with HIV is that if they stay in care and maintain adherence to
ART, they can expect to live a relatively normal life.
SUGGESTED READINGS
Aberg JA, et al: Primary care guidelines for the management of persons infected
with HIV: 2013 update by the HIV Medicine Assocation of the Infectious
Diseases Society of America, Clin Infect Dis 58:1–10, 2014.
Castel AD, Magnus M, Greenberg AE: Pre-exposure prophylaxis for human
immunodeficiency virus, Infect Dis Clin North Am 28(4):563–583, 2014.
Center for Disease Control and Prevention, Project Workgroup: Rec­
ommendations for HIV prevention with adults and adolescents with HIV
in the United States, 2014. Available at: http://stacks.cdc.gov/view/
cdc/26062. Accessed December 2014.
Cohen MS, Chen YQ, McCauley M, et al: Prevention of HIV-1 infection with
early antiretroviral therapy, N Engl J Med 365(6):493–505, 2011.
Gardner EM, McLees MP, Steiner JF, et al: The spectrum of engagement in HIV
care and its relevance to test-and-treat strategies for prevention of HIV
infection, Clin Infect Dis 52:793–800, 2011.
International Antiviral Society–USA: Practice Guidelines, Topics in Antivi­
ral Medicine, Available at: https://www.iasusa.org/guidelines. Accessed
December 2014.
Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the
use of antiretroviral agents in HIV-1-infected adults and adolescents, Department
of Health and Human Services, Available at: http://aidsinfo.nih.gov/
contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed December
2014.
Rajasuriar R, Wright E, Lewin SR: Impact of antiretroviral therapy (ART) timing
on chronic immune activation/inflammation and end-organ damage, Curr
Opin HIV AIDS 10:35–42, 2015.
Smith CJ, Ryom L, Weber R, et al: Trends in underlying causes of death in people
with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration, Lancet
384:241–248, 2014.
World Health Organization: Global health observatory (GHO), HIV/AIDS,
Available at: http://www.who.int/gho/hiv/en/. Accessed December 2014.

Infections in the
Immunocompromised Host
  INTRODUCTION
With the development of increasingly complex and potent treat-
ments for autoimmune, malignant, and chronic end-organ dis-
eases, the spectrum of opportunistic infections continues to
grow. Infections are the primary complication of many condi-
tions causing immune deficiency, from congenital syndromes
manifesting early in life to malignancy occurring in the elderly
(Table 102-1). Success in challenging fields such as transplanta-
tion depends on preventing, quickly diagnosing, and effectively
treating infections.
  DEFINITION AND EPIDEMIOLOGY
The approach to the immunocompromised patient with possible
infection should begin with an assessment of the arms of the
immune system affected by the patient’s underlying diseases and
treatments.
Neutropenia
Neutropenia is a combined absolute neutrophil and band count
of less than 500 cells/mm3. It is common after chemotherapy and
may be prolonged in patients with hematologic malignancies and
after hematopoietic stem cell transplantation (HSCT) (see Table
102-1). In these settings, patients may develop infections from
their own microbial flora or from ubiquitous environmental
organisms (Table 102-2). Because some chemotherapy agents
cause mucositis and other breaches of protective barriers, bacte-
rial infections predominate in this setting, most commonly as
oral mucosal, skin, soft tissue, and sinopulmonary infections.
Intravenous catheter-related infections and translocation of bac-
teria from the gastrointestinal tract may also occur. Because Pseu-
domonas species are associated with the highest mortality rate in
this setting, empirical therapy for fever in the neutropenic patient
should always include antibacterial therapy to cover this
organism.
Neutropenic patients are at risk for invasive fungal infection,
particularly in the setting of prolonged neutropenia. Candida
species infections are common. Sinopulmonary infections caused
by Aspergillus and the molds of the Mucorales order are associ-
ated with considerable morbidity and mortality.
Nonchemotherapy drugs may also cause neutropenia, with
a less predictable risk of infection. Responsible agents include
β-lactam antibiotics, carbapenems, amphotericin B, antipsychot-
ics, antiepileptics (e.g., carbamazepine, valproic acid, phenytoin),
hydralazine, sulfonamides, and nonsteroidal anti-inflammatory
agents.
102 
Staci A. Fischer
The risk of infection in patients with neutropenia is inversely
related to their absolute neutrophil count (i.e., neutrophils plus
bands); the lower the neutrophil count and the more prolonged
the period of neutropenia, the higher the risk of infection.
Because chemotherapeutic agents attack native cells with rapid
turnover rates, mucosae in the oropharyngeal and gastrointesti-
nal tracts are frequently interrupted, allowing commensal and
colonizing bacteria (e.g., viridans streptococci, Escherichia coli,
Klebsiella, Enterococcus, Pseudomonas), viruses (most commonly
herpes simplex virus), and fungi (especially Candida) to escape
and replicate. In patients on prophylactic antimicrobials while
neutropenic, resistant organisms can break through, resulting in
bloodstream infections and sepsis with multidrug-resistant
organisms.
Cell-Mediated Immunity Defects
Cell-mediated immunity defects may result from infection with
certain viruses (notably human immunodeficiency virus [HIV],
hepatitis C virus, and cytomegalovirus [CMV]) or from immu-
nosuppressive agents routinely used in solid organ transplanta-
tion and in the prophylaxis and treatment of graft-versus-host
disease (GVHD) in allogeneic HSCT recipients (see Table 102-
1). Cell-mediated immunity defects complicate T-cell lymphoma
and primary immunosuppressive conditions such as common
variable immune deficiency disease (CVID). CVID, the most
common primary immunodeficiency, manifests with recurrent
bacterial infections (notably pneumonia and bronchitis), usually
between the ages of 20 and 50 years. Patients with T-cell dysfunc-
tion or deficiency are at risk for opportunistic infections such as
Listeria monocytogenes, CMV, Pneumocystis jirovecii, and invasive
fungal infections (see Table 102-2).
L. monocytogenes is the most common cause of bacterial men-
ingitis in transplant recipients. CMV causes latent infection in T
cells, and the seropositive patient with late-stage HIV infection
or a transplant may reactivate CMV, causing viremia or focal
infection of the gastrointestinal tract, liver, lungs, or retina. Sero-
negative recipients of seropositive organs are at high risk for
developing donor-transmitted CMV infection, which can result
in long-term allograft dysfunction in addition to symptomatic
infection.
P. jirovecii, a fungal pathogen, causes hypoxemia and interstitial
pulmonary infiltrates in those with advanced HIV infection or
T-cell dysfunction from transplantation or GVHD. Reactivation,
acquisition, or donor-derived transmission of endemic fungal
infections, including Blastomyces, Coccidioides, and Histoplasma,
can occur. Environmental fungi, including Aspergillus, Mucorales
943
944 Section XV  Infectious Disease

TABLE 102-1  CONDITIONS CAUSING IMMUNE TABLE 102-2  ORGANISMS ASSOCIATED WITH
DEFICIENCY IMMUNE DYSFUNCTION
NEUTROPHILS AND PHAGOCYTES NEUTROPHILS AND Cryptococcus neoformans
PHAGOCYTES Aspergillus species
Neutropenia
Candida species
• Congenital syndromes Staphylococcus auerus
Pneumocystis jirovecii
• Drug-related neutropenia (e.g., chemotherapy, antimicrobial agents, Pseudomonas aeruginosa
Strongyloides stercoralis
antipsychotics, anticonvulsants) Enterobacteriaceae
Cryptosporidium species
• Autoimmune neutropenia Streptococcus mitis, viridans
Toxoplasma gondii
• Cyclic neutropenia streptococci
Leishmania species
• Myelodysplastic syndrome Aspergillus species
• Fanconi’s anemia Candida species HUMORAL IMMUNITY
• Aplastic anemia Mucorales order fungi (cause Mycoplasma species
• Myeloproliferative disorders (e.g., acute myeloid leukemia) mucormycosis) Streptococcus pneumoniae
Neutrophil dysfunction Fusarium species Haemophilus influenzae
• Chédiak-Higashi syndrome Herpes simplex virus (HSV) Campylobacter jejuni
• Hyperimmunoglobulin E syndrome ( Job’s syndrome) CELL-MEDIATED IMMUNITY Ureaplasma urealyticum
• Chronic granulomatous disease Chlamydia pneumoniae
• Leukocyte adhesion deficiency Herpesviuruses (HSV, varicella-
Salmonella species
• Immunosuppressive medications (e.g., mycophenolate, azathioprine) zoster virus, Epstein-Barr virus,
Giardia lamblia
• Warts, hypogammaglobulinemia, infections, and myelokathexis human herpesviruses 6 and 8)
Echovirus
(WHIM) JC virus
Varicella-zoster virus
• Viral infections (e.g., human immunodeficiency virus, human BK virus (especially in kidney
herpesvirus 6) transplants) COMPLEMENT DEFICIENCY
Human papilloma virus (HPV) Recurrent sinopulmonary infections
CELL-MEDIATED IMMUNITY Respiratory viruses (e.g., influenza, Streptococcus pneumoniae
Immunosuppressive agents for transplantation metapneumovirus, parainfluenza, Haemophilus influenzae
• Cyclosporine, tacrolimus, sirolimus respiratory syncytial virus) Neisseria gonorrhoeae
• Daclizumab, basiliximab Listeria monocytogenes
Neisseria meningitidis
• Mycophenolate, azathioprine Nocardia species
• Antilymphocyte therapies (e.g., Thymoglobulin, alemtuzumab) Salmonella species
Corticosteroids Mycobacterium species (M. avium
Cytotoxic drugs (e.g., cyclophosphamide) complex in human
Fludarabine immunodeficiency virus infection)
Anti–tumor necrosis factor-α agents (e.g., adalimumab, etanercept,
infliximab, certolizumab, golimumab)
Graft-versus-host disease (GVHD)
DiGeorge syndrome (i.e., thymic hypoplasia)
Severe combined immunodeficiency (SCID)
order fungi (which cause mucormycosis) and other molds, may
Ataxia-telangiectasia be inhaled, causing sinopulmonary infections in neutropenic
Wiskott-Aldrich syndrome hosts. Infection may be complicated by dissemination to sites
End-stage renal disease
Malnutrition
such as the skin and brain.
Human immunodeficiency virus (HIV) infection Bacterial infection with organisms such as Nocardia and Legio-
T-cell lymphoma nella and parasitic or protozoal infections such as Strongyloides
Idiopathic CD4+ lymphopenia
stercoralis and Babesia are common in patients with cell-mediated
HUMORAL IMMUNITY immune defects.
Common variable immune deficiency (CVID)
Splenectomy, splenic aplasia (e.g., sickle cell disease) Humoral Immunity
Nephrotic syndrome
Protein-losing enteropathy Humoral immunity is critical to control infection by encap­
Multiple myeloma sulated bacteria such as Neisseria meningitidis, Streptococcus
B-cell lymphoma
Chronic lymphocytic leukemia pneumoniae, and Haemophilus influenzae. Patients with hypogam-
Waldenstrom’s macroglobulinemia maglobulinemia, protein-losing conditions such as enteropathy
Severe combined immune deficiency or nephrotic syndrome, splenectomy, or chronic lymphocytic
Ataxia-telangiectasia
Wiskott-Aldrich syndrome leukemia have significant defects in humoral immunity, predis-
Hyperimmunoglobulin M syndrome posing them to infection with these organisms (see Table 102-1).
Selective IgA deficiency Transplant recipients on immunosuppressive therapy for many
X-linked agammaglobulinemia
Immunosuppressive therapies (e.g., cyclophosphamide, azathioprine, years may develop hypogammaglobulinemia, predisposing them
mycophenolate) to similar infections. The use of agents such as rituximab, a mono-
Medications (e.g., rituximab, azathioprine, sulfasalazine, gold, cyclosporine, clonal antibody against CD20, in malignancy and transplantation
carbamazepine, valproic acid, phenytoin, alemtuzumab, chloroquine)
Hypogammaglobulinemia complicating solid organ and hematopoietic stem may result in significant B-cell defects and infection with encap-
cell transplantation sulated bacteria.
COMPLEMENT DEFICIENCY
Complement Deficiency
C2 deficiency
Mannose-binding lectin deficiency Patients deficient in complement factors have a higher risk of
C3 deficiency autoimmune disease and can develop recurrent infections. Sino-
Factor H deficiency
Factor I deficiency pulmonary infections, particularly from S. pneumoniae and H.
Terminal pathway (C5-C9) deficiency influenzae, are common. Patients with deficiencies of terminal
 Chapter 102  Infections in the Immunocompromised Host 945
pathway components (C5 to C9) develop recurrent infections
with N. meningitidis and Neisseria gonorrhoeae.
Although this chapter focuses on systemic immune deficien-
cies, it is important to consider local processes that increase the
risk of focal infections in certain hosts. For example, the cystic
fibrosis or chronic obstructive pulmonary disease patient with
multiple bouts of pneumonia may develop localized bronchiec-
tasis, in which normal mucociliary clearance mechanisms are
inadequate to control and prevent infection. These areas are
prone to recurrent bacterial infections, particularly with Pseudo-
monas. Similarly, the patient with lymphedema of a limb lacks the
benefit of lymphatic drainage of early infections and is predis-
posed to recurrent cellulitis of the affected extremity.
  PATHOLOGY
Infections in the immunocompromised host are often caused by
organisms of low virulence that are able to cause infection due to
impaired or absent normal defense mechanisms. Diagnosis of
infection may be hampered by the small number of organisms
required to cause disease and by the lack of inflammation associ-
ated with immunosuppressive conditions and therapies.
  CLINICAL PRESENTATION
The clinical presentation of immunocompromised hosts with
infection may be different from that seen in the immunocompe-
tent patient. In the transplant population, typical signs and symp-
toms of infection such as fever, erythema, and leukocytosis may
be absent as a result of the effect of immunosuppressive medica-
tions. Infections that are normally limited in scope may become
disseminated in the immunocompromised host. For example,
pyelonephritis involving the renal allograft may be complicated
by bacteremia and acute kidney injury, both of which are uncom-
mon in normal hosts.
Assessing the immunocompromised host with possible infec-
tion involves performing a detailed physical examination, includ-
ing close inspection of the oral and periodontal tissues, perianal
area, and skin. Even minor changes (e.g., faint erythematous rash,
gum line erythema) may point to the source of a fever. Symptoms
and signs of infection such as fever may not exist. On review of
systems, subtle findings such as chills and sweats may be the only
sign of an opportunistic infection. A classic finding is perianal or
rectal pain without swelling or erythema, indicating a perirectal
abscess in neutropenic patients. Laboratory clues to infection
such as leukocytosis in the patient with systemic bacterial infec-
tion or eosinophilia in the patient with disseminated Strongyloi-
des infection may be absent as a result of immunosuppressive
therapy.
In many cases, the initial presentation of congenital or acquired
immune deficiency states is the development of unusual or recur-
rent infections, and recognition of the immune defects associated
with the infections can guide the diagnostic work-up. For
example, the nonimmunosuppressed patient with P. jirovecii
infection should undergo investigation for T-cell immune defects,
most importantly HIV infection. The patient with recurrent N.
meningitidis infections should be tested for possible late compo-
nent complement deficiencies. Details on the manifestations of
infection with the pathogens listed in Table 102-2 are found else-
where in this textbook.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
Diagnosis of infection in the immunocompromised host can be
more difficult than in the normal host, and the differential diag-
nosis of infections can be quite broad. Because defects in humoral
and cell-mediated immunity may limit the ability to develop anti-
body responses to infection, serologic tests have poor sensitivity
for these patients. Cultures—including standard bacterial cul-
tures and those facilitating growth of acid-fast bacilli and fungi—
are often critical to making a diagnosis of infection. Because some
of the pathogens causing infection in these settings are commen-
sals or colonizers, interpretation of a positive culture result may
be difficult. For example, the growth of Candida species in bron-
choscopy specimens most likely reflects upper airway and pha-
ryngeal colonization.
Sensitive assays to detect the DNA or RNA of opportunistic
viruses—most commonly through quantitative polymerase
chain reaction (PCR)—have become crucial diagnostic tests for
infections such as CMV, human herpesvirus 6 (HHV-6), and BK
virus, and they may help to guide the duration of antiviral therapy.
Biologic markers of fungal infection such as serum galactoman-
nan and β-d-glucan assays may suggest a diagnosis of invasive
infection with molds such as Aspergillus.
In many cases, the diagnosis of infection may be elusive,
requiring biopsy and histopathologic examination of involved
tissues to determine the underlying pathogen. This process com-
bined with tissue cultures may be needed to make a definitive
diagnosis of infection in the immunocompromised host, and it
can help differentiate colonization from infection with a particu-
lar organism. Biopsy of skin lesions, bone marrow, or liver may
provide a diagnosis when cultures and other standard tests are
unrevealing.
In neutropenic patients with fever, the procalcitonin level may
be elevated in the setting of bacteremia, but it is normal in patients
with fungal infections. 18-Fluorodeoxyglucose positron-emission
tomography/computed tomography can help localize infection
in the immunocompromised patient, in whom the sensitivity of
nuclear medicine studies with indium-111, technetium-99m, or
gallium may be limited.
  TREATMENT AND PREVENTION OF INFECTIONS
Treatment of infections in the immunocompromised host
requires rapid diagnosis and, when possible, improvement of the
underlying immune disorder to help reconstitute natural immune
function. In many cases, treatment must be broad spectrum and
empirical while awaiting results of diagnostic testing. Delay of
therapy for these patients is associated with a higher risk of dis-
semination and death. Details on the specific treatment recom-
mendations for individual pathogens are found elsewhere in this
textbook.
Neutropenia
For patients with neutropenic fever, empirical therapy should
always include coverage for Pseudomonas aeruginosa because it is
associated with a high mortality rate. Empirical therapy should
also be guided by the individual patient’s antimicrobial adminis-
tration history, prior infections, colonization status (e.g.,
methicillin-resistant S. aureus [MRSA], vancomycin-resistant
946 Section XV  Infectious Disease

Enterococcus [VRE]), and local susceptibility data. Broad- patients on a mucositis-inducing chemotherapy regimen. Anti-
spectrum agents such as piperacillin-tazobactam and cefepime fungal prophylaxis with voriconazole or posaconazole decreases
may be used. Carbapenems may be indicated in the patient with the incidence of invasive fungal infections in patients undergo-
recent hospitalization, recent broad-spectrum antibacterial ing HSCT and those with hematologic malignancies undergoing
administration, or with a history of infection with extended- induction chemotherapy. Certain cancer patients, including
spectrum β-lactamase–producing Enterobacteriaceae. After a those with acute lymphoblastic leukemia or those on high-dose
pathogen is identified in cultures and susceptibility data are avail- corticosteroids, methotrexate, fludarabine, bleomycin,
able, antimicrobial therapy should be narrowed. l-asparaginase, or cytarabine, have sufficient T-cell dysfunction
If a neutropenic patient remains febrile for 3 to 5 days without to warrant prophylaxis against P. jirovecii (discussed later).
an identified locus or pathogen of infection, empirical glycopep- Herpes simplex virus (HSV) prophylaxis with acyclovir is indi-
tide therapy (e.g., vancomycin to cover S. aureus, particularly in cated for those with a history of symptomatic HSV infection
the setting of an indwelling central catheter) and antifungal or seropositivity.
therapy are recommended to cover staphylococci and Aspergillus
and other fungi common in this setting. Although amphotericin Humoral Immunity Defects
B products have been a mainstay of therapy for many years, vori- Patients with hypogammaglobulinemia and CVID are at risk for
conazole is the preferred agent to treat suspected aspergillosis infection with encapsulated organisms such as S. pneumoniae.
because of its better efficacy in the neutropenic host. Replacement of immunoglobulin G (IgG) with intravenous
Reconstitution of immune function in the patient with neu- immune globulin (IVIG) at a dose of 400 to 600 mg/kg monthly
trophil deficiency or dysfunction can help prevent or treat infec- can help prevent infections in these patients. Immunization may
tion. Administration of granulocyte colony-stimulating factor not be protective against S, pneumoniae, H. influenzae, or N. men-
(G-CSF) (i.e., filgrastim or pegfilgrastim) with chemotherapy for ingitidis due to poor seroconversion rates.
solid tumors can prevent and treat absolute neutropenia and
therefore reduce the risk of infection. For patients with drug- Hematopoietic Stem Cell Transplantation
induced neutropenia, similar benefit can be attained. G-CSF Infection risk after HSCT depends on the source of stem cells,
usually is contraindicated in patients with myeloid malignancies the type of conditioning chemotherapy regimen administered,
and myelodysplasia due to the potential for stimulation of growth and the risk and degree of GVHD (Fig. 102-1). Myeloablative
of dysplastic or malignant cells. regimens (including chemotherapy and total body irradiation)
Several measures can help decrease the risk of infection in often result in severe mucositis, putting patients at risk for the
patients with neutropenia, including prevention of exposure to infections detailed previously. Although the risk of infection in
potential pathogens and antimicrobial prophylaxis. Periodontal autologous transplants is relatively low due to earlier engraft-
care with oral rinses with sterile water or saline four to six times ment, recipients of matched unrelated donor allogeneic
per day and gentle teeth brushing may help prevent periodontal
infection and streptococcal bacteremia. Daily chlorhexidine
bathing may decrease colonization with multidrug-resistant Pre-engraftment Period (day 0 – day 30)
organisms that can be acquired while hospitalized. Ingestion of a Gram-negative bacilli (including
low-microbial diet (e.g., no raw fruits or vegetables) and avoid- Pseudomonas)
Neutropenia Gram-positive cocci
ance of dried or fresh flowers and potted plants may decrease (Staphylococcus,
exposure to fungi, including Aspergillus. Breaks in cutaneous Streptococcus, Enterococcus)
Housing in high-efficiency particulate air (HEPA)–filtered and mucosal barriers Candida species
(e.g., IV catheters, Aspergillus and other invasive
rooms with positive air pressure and adequate ventilation is the mucositis and cystitis molds
standard of care in HSCT units to decrease the risk of exposure caused by chemotherapy) HSV
to airborne pathogens. For patients at home, avoiding construc- BK virus (hemorrhagic cystitis)
Respiratory viruses
tion areas (including home renovation projects) while neutro-
penic may decrease the risk of invasive fungal infection. Patients Early Post-engraftment Period (day 30 – day 100)
visiting medical offices or hospitals should wear a mask, includ- S. pneumoniae, H. influenzae,
ing when ambulating in the hallways or being transported for N. meningitidis
testing. Strict handwashing and hand hygiene are paramount to Listeria monocytogenes
Cell-mediated immune Nocardia
preventing infection. Avoidance of rectal thermometers, sup- suppression (acute GVHD Pneumocystis jirovecii
positories, enemas, and tampons while neutropenic has been prophylaxis and treatment) Aspergillus species
recommended to prevent infection. Patients with well water Other molds
Hypogammaglobulinemia CMV
should use filters to decrease the risk of Cryptosporidium infec- HHV-6
tion. Minimization of mucositis with newer chemotherapeutic Adenovirus
agents can help decrease the risk of infection in patients with Respiratory viruses
malignancy. Chronic GVHD: prolonged risk of post-engrafment infections
Solid data support the use of quinolones (e.g., ciprofloxacin, FIGURE 102-1  Timing of infection after hematopoietic stem cell
levofloxacin) as prophylaxis for serious infection in patients transplantation. CMV, Cytomegalovirus; GVHD, graft-versus-host
with anticipated neutropenia for 7 or more days. Penicillin is disease; HHV, human herpesvirus; HSV, herpes simplex virus; IV,
intravenous.
often added to prevent infection with viridans streptococci in
 Chapter 102  Infections in the Immunocompromised Host 947

transplants are at significant and prolonged risk for opportunistic
infections due to the high rate of GVHD associated with these
allografts, resulting in prolonged T-cell–mediated immunosup-
pression and delayed immune reconstitution. Umbilical cord
blood transplants are associated with prolonged neutropenia as a
result of the small volume of cells available for transplantation,
placing patients at risk for infection. The risk of GVHD, however,
is lower with the use of umbilical cord cells.
Immediately after HSCT, stem cell recipients are neutropenic.
During this pre-engraftment period, pathogens characteristic of
prolonged neutropenia can cause infection. Prophylaxis with
voriconazole or posaconazole, levofloxacin or ciprofloxacin, acy-
clovir, and penicillin is common to prevent infections during this
vulnerable period.
After engraftment, the risk of GVHD is high for many alloge-
neic transplant recipients, resulting in administration of cortico-
steroids, methotrexate, cyclosporine, tacrolimus, sirolimus, or
mycophenolate for prophylaxis. After GVHD develops, high-
dose corticosteroids usually are given. In refractory cases,
additional T-cell–active immunosuppressive agents, including
antithymocyte globulin, tacrolimus, sirolimus, cyclophospha-
mide, and alemtuzumab, may be required. Patients on these
agents are at risk for infections from CMV, Nocardia, HHV-6, P.
jirovecii, adenovirus, invasive molds, and other opportunists. In
some cases, patients require chronic immunosuppressive therapy
to control GVHD, putting them at risk for infection indefinitely
and requiring long-term antibiotic prophylaxis. If GVHD is suc-
cessfully prevented, immunosuppressive therapy is discontinued
after 6 to 12 months.
In uncomplicated HSCT cases without GVHD, functional
humoral immunity takes 1 to 2 years to return to normal, and
patients are at risk for encapsulated organisms despite being suc-
cessfully engrafted. Standard immunizations are re-administered
1 to 2 years after transplantation because pretransplantation anti-
bodies are often lost.
Human Immunodeficiency Virus Infection
Chapter 101 provides a detailed discussion of treatment and pro-
phylaxis of infections occurring in HIV-infected patients.
Solid Organ Transplantation
Organ transplant recipients are at lifelong risk of infection,
although the pathogens involved change over time (Fig. 102-2).
In the first month after transplantation, patients develop infec-
tions related to the surgical procedures and hospitalization.
Urinary tract infection in the renal transplant recipient, pneumo-
nia in the lung transplant recipient, and sternal wound infection
in the heart transplant recipient tend to manifest in the first 4
weeks postoperatively. Common nosocomial infections such
as catheter-related bloodstream infection and Clostridium difficile
may also occur. Anastomotic leaks in pancreas and liver
transplant recipients may cause polymicrobial intra-abdominal
abscesses.
Patients with incubating infection at the time of transplanta-
tion and induction immunosuppression can develop dissemi-
nated infection with viral or bacterial pathogens, which is
associated with a high mortality rate. Careful evaluation of the
recipient at the time of hospital admission for transplantation is

Postoperative Opportunistic infections: Late infections:

infections (e.g., CMV VZV
pneumonia, UTI, EBV Toxoplasmosis
wound infection, HHV-6 Encapsulated
catheter-related VZV bacteria*
BSI, anastomotic Pneumocystis jirovecii Cryptococcus
leaks causing peri- Toxoplasma gondii Respiratory
allograft abscess) Nocardia species viruses
Listeria monocytogenes Adenovirus
Incubating Legionella pneumophila Coccidioides
infection in the Mycobacterium species
recipient at the Strongyloides stercoralis
time of Trypanosoma cruzi
transplantation BK virus (kidney transplants)

Donor-derived
infections (e.g.,
LCMV, West Nile
virus, rabies)
Patients with acute and chronic rejection are at
prolonged risk for opportunistic infections (e.g., CMV)

Early period Middle period Late period

0 1 3 6 9 12
Months after transplantation

*Especially in patients with hypogammaglobulinemia complicating immune suppression

FIGURE 102-2  Timing of infections after solid organ transplantation. BSI, Bloodstream infection; CMV, cytomegalovirus; COPD, chronic obstructive
pulmonary disease; EBV Epstein-Barr virus; HCV, hepatitis C virus; HHV-6, human herpesvirus 6; HIV, human immunodeficiency virus; LCMV, lympho-
cytic choriomeningitis virus; UTI, urinary tract infection; VZV, varicella-zoster virus.
948 Section XV  Infectious Disease
essential for positive early outcomes. Rarely, donor-transmitted
infections can occur, including viral pathogens such as rabies
virus, West Nile virus, lymphocytic choriomeningitis virus
(LCMV), HIV, and hepatitis B and C viruses. Organ banks and
transplantation centers continue to work to improve the sensitiv-
ity and specificity of donor testing paradigms to prevent trans-
mission of infection.
The most common time for opportunistic infections such as
CMV, Listeria, Legionella, and invasive fungal infections such as
Aspergillus is 1 to 6 months after transplantation. Later infection
may be seen in those receiving lymphocyte-depleting induction
agents (e.g., thymoglobulin, alemtuzumab) to prevent acute
rejection at the time of transplantation or in those with episodes
of acute rejection.
Because CMV causes symptomatic infection and is associated
with chronic allograft dysfunction, prophylaxis or preemptive
treatment of infection with valganciclovir is used. Seronegative
recipients of a CMV-seropositive organ are at highest risk for
infection. Lung transplant recipients, who are at significant risk
for Aspergillus infection in the first 6 months after transplantation,
receive prophylactic voriconazole to prevent invasive fungal
infection. Lung recipients are at lifelong risk for respiratory viral
infections. Lung transplant recipients may also receive azithro-
mycin to improve the prognosis for bronchiolitis obliterans syn-
drome, the most common manifestation of chronic allograft
dysfunction.
Heart transplant recipients are at particular risk for reactiva-
tion of donor-transmitted infection with Toxoplasma gondii,
which can cause early myocarditis or late cerebral disease.
Serologic (IgG) screening of the donor and recipient, with
sulfamethoxazole-trimethoprim prophylaxis used in seropositive
recipients or seronegative recipients of a seropositive heart, is the
standard of care in cardiac transplantation centers.
P. jirovecii can cause infection in solid organ transplant recipi-
ents, which usually occurs 6 to 12 months after transplantation.
Pneumonitis similar to that seen in patients with HIV is the most
common manifestation, although extrapulmonary infection
(particularly in the liver and spleen) can be seen in transplant
recipients. Prophylaxis with sulfamethoxazole-trimethoprim (or
atovaquone in sulfa-allergic patients) is indicated for 12 months
after transplantation. If high-dose corticosteroids or antilympho-
cyte therapy is required for treatment of acute rejection, prophy-
laxis should be restarted.
Almost all liver transplant recipients with underlying active
hepatitis B or C have reactivation of the infection. Treatment of
hepatitis B with lamivudine or other antiviral agents is often suc-
cessful in suppressing infection when started at the time of
transplantation. Although more difficult, post-transplantation
treatment of symptomatic hepatitis C with interferon, ribavirin,
and protease inhibitors may prolong hepatic function. Newer
direct acting agents are being studied in the post-transplant
setting.
In patients with no episodes of acute rejection, the risk of
opportunistic infections often declines with time. Late infections
(≥12 months after transplantation) may still occur, with varicella-
zoster virus (VZV), HSV (particularly encephalitis) Cryptococcus
neoformans, JC virus (i.e., progressive multifocal leukoencepha-
lopathy), and community-acquired infections such as influenza
and S. pneumoniae most commonly reported. Patients with
hypogammaglobulinemia complicating long-term immunosup-
pressive therapy may benefit from IVIG to help prevent
infections.
Although not always possible, especially with lifesaving heart,
lung, or liver transplants, reduction of immunosuppression in the
organ transplant recipient with invasive fungal infection, viral
infection, or bacterial sepsis may assist in recovery. Reinstitution
of immunosuppressive therapy may be indicated as infection
resolves.
A significant challenge in treating infections in the patient with
a solid organ transplant or GVHD complicating HSCT is the
cytochrome P-450 metabolism of antimicrobial agents such as
the azoles, macrolides, rifampin, echinocandins, nucleoside
reverse transcriptase inhibitors (NRTIs), protease inhibitors, and
non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Careful monitoring of levels of calcineurin inhibitors (e.g., cyclo-
sporine, tacrolimus) is indicated for patients on these and other
agents that can induce or inhibit P-450 metabolism.
Although the immunocompromised patient may not serocon-
vert from vaccinations such as the annual influenza vaccine,
immunization of household contacts and health care workers can
prevent exposure and therefore infection of the most vulnerable
hosts. Immunocompromised patients should avoid live virus vac-
cines (e.g., measles/mumps/rubella, varicella, yellow fever) that
can be associated with disseminated infection. Specialized proto-
cols exist for immunization of immunocompromised children.
  PROGNOSIS
The prognosis of infections in immunocompromised hosts
relies on accurate and rapid diagnosis and early institution
of appropriate antimicrobial therapy. Use of cidal therapies
(versus static agents) is recommended. Manipulation of the
immune response to infection through G-CSF administration
(in neutropenic patients), administration of IVIG (in hypo-
gammaglobulinemic patients), or decreasing immunosuppres-
sive therapy (in kidney or pancreas transplant recipients) may
improve survival.
The prognosis for infections in these settings is worse for
older patients, those requiring intensive care unit (ICU) admis-
sion, and those in whom rapid immune reconstitution is not
possible. Tumor lysis syndrome, acute respiratory failure, and
sepsis increase mortality. Patients with underlying acute leuke-
mia and those with other comorbidities, including cardiovascular
disease, renal failure, liver disease, or lung disease have a signifi-
cantly worse prognosis, particularly in the setting of invasive
fungal infection. The attributable mortality rate for invasive
aspergillosis is 20% to 50% when patients require ICU admission
(Fig. 102-3).
  CONCLUSIONS
Care of the immunocompromised host with infection requires
meticulous monitoring of symptoms, detection of often subtle
physical findings, and an understanding of the arms of the
immune system involved in a particular patient’s illness. With
successes in treatment of malignancies and end-organ disease,
the breadth of infections causing infection in these hosts contin-
ues to widen.
 Chapter 102  Infections in the Immunocompromised Host 949

B C
FIGURE 102-3  Invasive pulmonary aspergillosis in a kidney transplant recipient with myelodysplasia. At presentation, the patient was afebrile and
had dyspnea on exertion without cough. A, Anteroposterior and lateral chest radiographs (top) and computed tomography scans (bottom) of the
chest. B, Transbronchial lung biopsy demonstrates hyphae in tissue (hematoxylin and eosin stain, ×100). C, Silver stain of biopsy tissue demonstrates
acute-angle branching hyphae. Cultures grew Aspergillus fumigatus.

SUGGESTED READINGS
Bennett CL, Djulbegovic B, Norris LB, et al: Colony-stimulating factors for
febrile neutropenia during cancer therapy, N Engl J Med 368:1131–1139,
2013.
Blumberg EA, Danziger-Isakov L, Kumar D, et al: Infectious disease guidelines,
ed 3, Am J Transplant 13:1–371, 2013.
Bow EJ, Bacteriol D: Infection in neutropenic patients with cancer, Crit Care Clin
29:411–441, 2013.
Boysen AK, Jensen BR, Poulsen LO, et al: Procalcitonin as a marker of infection
in febrile neutropenia: a systematic review, Mod Chemother 2:8–14, 2013.
Buckley RH: Primary cellular immunodeficiencies, J Allergy Clin Immunol
109:747–757, 2002.
Choi SW, Levine JE, Ferrara JL: Pathogenesis and management of graft-versus-
host-disease, Immunol Allergy Clin North Am 30:75–191, 2009.
Copelan EA: Hematopoietic stem-cell transplantation, N Engl J Med 354:1813–
1826, 2006.
Fischer SA: Emerging viruses in transplantation: there is more to infection after
transplant than CMV and EBV, Transplantation 86:1327–1339, 2008.
Flowers CR, Seidenfeld J, Bow EJ, et al: Antimicrobial prophylaxis and outpatient
management of fever and neutropenia in adults treated for malignancy:
American Society of Clinical Oncology clinical practice guideline, J Clin Oncol
31:794–810, 2013.
Freifeld AG, Bow EJ, Sepkowitz KA, et al: Executive summary: clinical practice
guideline for the use of antimicrobial agents in neutropenic patients with
950 Section XV  Infectious Disease
cancer: 2010 update by the Infectious Diseases Society of America, Clin Infect
Dis 52:427–431, 2011.
Furst DR: Serum immunoglobulins and risk of infection: how low can you go?
Semin Arthritis Rheum 39:18–29, 2008.
Green M, Michaels MG: Epstein-Barr virus infection and posttransplant
lymphoproliferative disorder, Am J Transplant 13:41–54, 2013.
Kotton CN: CMV: prevention, diagnosis and therapy, Am J Transplant 13:24–40,
2013.
Paul M, Yahav D, Bivas A, et al: Anti-pseudomonal beta-lactams for the initial,
empirical, treatment of febrile neutropenia: comparison of beta-lactams
[review], Cochrane Database Syst Rev 11:1–117, 2010.
Steinberg JP, Robichaux C, Tejedor SC, et al: Distribution of pathogens in central
line-associated bloodstream infections among patients with and without
neutropenia following chemotherapy: evidence for a proposed modification to
the current surveillance definition, Infect Control Hosp Epidemiol 34:171–
175, 2013.
Tam JS, Routes JM: Common variable immunodeficiency, Am J Rhinol Allergy
27:260–265, 2013.
Thom KA, Kleinberg M, Roghmann MC: Infection prevention in the cancer
center, Clin Infect Dis 57:579–585, 2013.
Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious
complications among hematopoietic cell transplantation recipients: a global
perspective, Biol Blood Marrow Transplant 15:1143–1238, 2009.

Infectious Diseases of
Travelers: Protozoal and
Helminthic Infections
Rebecca Reece, Aadia I. Rana, and Erna Milunka Kojic
  INTRODUCTION
Medical advice for overseas travelers, recommended protective
measures, and the diagnosis and treatment of common parasitic
diseases endemic in the United States and abroad are reviewed in
this chapter.
  PREPARATION OF TRAVELERS
More than 27 million Americans travel internationally every
year, and more than 60% of them travel to developing regions
of the world. Increases in international travel are associated with
exposures to infectious diseases worldwide and bring the issues
of prevention and management of health problems in travelers
into the office of every physician. The risk of becoming ill while
traveling internationally depends on the destination and dura-
tion of the trip, the underlying health and age of the traveler,
and activities undertaken while abroad. Major issues to be
addressed before traveling include required and recommended
immunizations, malaria prophylaxis, and traveler’s diarrhea, as
well as measures to prevent tick and mosquito bites. Informa-
tion about health risks in specific geographic areas, updated
weekly, can be obtained from the Centers for Disease Control
and Prevention (CDC) through its publications or website
(www.cdc.gov/travel/destinations/list).
Immunizations
All international travelers should ensure they are up-to-date on
routine vaccinations. Only yellow fever vaccination may be
required by law for international travel, but other immunizations
are often strongly recommended, depending on the destination,
type, and duration of travel. Before immunization, a thorough
history should be obtained to determine the safety of immuniza-
tions and any allergies to eggs or chick embryo cells. Pregnant
women and individuals who are immunocompromised by human
immunodeficiency virus (HIV), malignancy, or chemotherapy
pose specific and important concerns requiring review before
receiving vaccinations.
Hepatitis A
In the United States, the most frequently identified risk for
hepatitis A infection is travel. The risk varies with living
103 
conditions, length of stay, and incidence of hepatitis A in the
area visited. In some areas, the disease affects an estimated 1
of every 500 to 1000 travelers on a 2- to 3-week trip. Therefore,
hepatitis A vaccination is recommended for all susceptible
persons traveling to or working in countries with intermediate
or high endemicity of infection. Hepatitis A vaccine should be
given at least 2 weeks before departure but remains effective if
given up until the time of travel. A single dose provides protec-
tion for 1 to 2 years; a booster 6 to 18 months later is required
for long-lasting immunity (at least 20 years and possibly
lifelong).
Influenza
Although influenza is not necessarily considered a travel-related
illness, the influenza vaccine should be considered in the panel
of vaccines offered to the traveler. Influenza seasons can occur at
different times of the year in different parts of the world. If a
patient cannot be immunized, a course of the antiviral medica-
tion oseltamivir can be provided to take at the first sign of a flu-
like illness.
Japanese Encephalitis
Japanese encephalitis ( JE) virus is closely related to the West
Nile and Saint Louis encephalitis viruses and is transmitted to
humans through the bite of an infected mosquito. JE virus is
the most common vaccine-preventable cause of encephalitis in
Asia. It occurs throughout most of Asia and parts of the western
Pacific. The overall incidence of JE among people from non-
endemic countries traveling to Asia is estimated to be less than
1 case per 1 million travelers. However, expatriates and travelers
who stay for prolonged periods in rural areas with active JE
virus transmission are likely to be at similar risk as the suscep-
tible resident population (i.e., 5 to 50 cases per 100,000 children
per year). Even during brief trips, travelers might be at increased
risk if they have extensive outdoor or nighttime exposure in
rural areas during periods of active transmission. Short-term
(<1  month) travelers whose visits are restricted to major urban
areas are at minimal risk for JE. A new inactivated JE vaccine,
a two-dose series given 28 days apart, was approved in 2009
for use in people 17 years of age and older; pediatric clinical
trials are being conducted to enable its licensure for use in
children.
951
952 Section XV  Infectious Disease
Measles
In the United States, most measles cases result from international
travel, and measles remains a common disease in many parts of
the world. Currently, measles vaccination is recommended at 15
months of age, with a second vaccination after age 5. Individuals
born after 1956 who have no physician-documented record of
immunization or who have not received a booster after early
childhood should have a one-time booster before travel.
Meningococcal Meningitis
Vaccination for meningococcal disease is recommended to
persons who travel to or reside in countries in which the bacte-
rium Neisseria meningitidis is hyperendemic or epidemic, particu-
larly if they will be in close contact with the local population.
Vaccination is recommended for travelers to Saudi Arabia during
the Hajj, along the meningitis belt of sub-Saharan Africa, and in
other locations for which travel advisories have been issued
(information available on the CDC website). The meningococcal
conjugate vaccine (MCV4) is preferred for people age 9 months
through 55 years, and the meningococcal polysaccharide vaccine
(MPSV4) is the recommended vaccine for persons older than 55.
Polio
Polio remains endemic in some regions of Asia and Africa. Before
traveling to areas where poliomyelitis cases are still occurring,
travelers should ensure that they have completed the recom-
mended age-appropriate polio vaccine series and have received a
booster dose with the inactivated polio vaccine as an adult.
Typhoid
International travelers are at greatest risk for contracting typhoid
in the Indian subcontinent, Central America, western South
America, and sub-Saharan Africa. Vaccination is recommended
for travel to endemic areas where exposure to contaminated food
and water is likely. Both a live oral vaccine (four enteric-coated
capsules given over 7 days) and an injectable vaccine (single-
dose) are available; they are essentially equivalent in effective-
ness, which ranges from 50% to 70%.
Yellow Fever
The yellow fever vaccine is a live, attenuated virus vaccine that is
recommended for persons traveling to areas in South America
and Africa where yellow fever is endemic. Vaccination is protec-
tive for at least 10 years and must be given at designated vaccina-
tion centers. Severe adverse events are rare and include yellow
fever vaccine–associated viscerotropic and neurologic disease,
both of which are more common in elderly persons and in those
with thymus disease. Because the adverse events occur more
commonly in people older than 60 years of age, a careful assess-
ment of risks and benefits for these travelers should be made
before vaccination.
Other Vaccines
Some individuals live for prolonged periods in developing coun-
tries or are at special risk for contracting certain highly conta-
gious diseases. Consideration should be given to immunization
against hepatitis B, plague, and rabies. Tetanus vaccinations
should be up to date: for travel, a tetanus booster within the
previous 5 years is recommended. The cholera vaccine is not
available in the United States. Worldwide, two oral cholera vac-
cines are available, but vaccination offers limited protection.
Therefore, the vaccine is not recommended for travelers,
but standard cholera prevention and control measures are
emphasized.
Malaria Prophylaxis
Malaria infection is associated with significant morbidity and
mortality, particularly if the causative agent is Plasmodium falci-
parum. The need for, as well as the type of, malaria prophylaxis
depends on known resistance patterns and the exact itinerary
within a given country because the risk of transmission is
regional. In general, travelers to areas where chloroquine-
sensitive P. falciparum strains are exclusively found (i.e., parts of
Central America, the Caribbean, North Africa, and the Middle
East) should take chloroquine phosphate (300-mg base or
500-mg salt) weekly, starting 1 week before travel to malarious
areas and continuing during the trip and for 4 weeks after leaving
the area.
Travelers to Southeast Asia, sub-Saharan Africa, South
America, and South Asia, where chloroquine-resistant P. falci-
parum is common may take mefloquine (Lariam), atovaquone-
proguanil (Malarone), or doxycycline. Mefloquine may be
associated with neurologic side effects (dizziness, tinnitus, and
vivid dreams) and, rarely, with significant neuropsychiatric side
effects. A U.S. Food and Drug Administration (FDA) black box
warning issued in 2013 indicated that the neurologic side effects
can occur at any time and persist indefinitely; this has lent some
caution to the prescription of mefloquine. Mefloquine is also
not completely effective in Myanmar, rural Thailand, or some
parts of East Africa, where resistance is a growing problem.
Atovaquone-proguanil and doxycycline are effective in Southeast
Asia and may be used in other areas of chloroquine resistance.
Atovaquone-proguanil is well tolerated but must be taken every
day. Daily doxycycline can be associated with photosensitivity,
esophagitis, and, occasionally, vaginal candidiasis.
Where it is approved, primaquine can be used for primary
prophylaxis in areas with higher rates of Plasmodium vivax or
Plasmodium ovale infection. It has the advantage of both prevent-
ing acute infection from all malaria parasites and preventing the
later recurrent infections of P. vivax and P. ovale. It cannot be used
in individuals with glucose-6-phosphate dehydrogenase (G6PD)
deficiency. Emphasis must also be given to the use of mosquito
bite prevention measures, including netting, screens, permethrin
for clothing, and insect repellents.
Traveler’s Diarrhea
Each year between 20% and 50% of international travelers
develop diarrhea. Bacterial infections such as enterotoxigenic
Escherichia coli are most common, but other causes include para-
sites and viruses. The average duration of an episode of traveler’s
diarrhea is 3 to 6 days, but about 10% of episodes last longer than
1 week. The diarrhea may be accompanied by abdominal cramp-
ing, nausea, headache, low-grade fever, vomiting, or bloating.
Travelers with fever greater than 101° F (38° C), bloody stools, or
both should see a physician at once (see Chapter 96).
 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 953
Diarrheal illness can be avoided by taking precautions with
regard to food and beverages. All water and ice should be pre-
sumed to be unsafe. Salads are often contaminated by protozoal
cysts; along with street vendor foods, they are the most dan-
gerous foods encountered by most travelers. Food should be
well cooked, and unpasteurized dairy products should be
avoided.
Prophylactic antibiotics are not generally recommended.
Diphenoxylate (Lomotil) and loperamide (Imodium) may
provide symptomatic relief of mild diarrhea. First-line treatment
includes fluoroquinolones, taken orally for 3 days. In some coun-
tries, such as Thailand and Nepal, fluoroquinolone resistance,
especially among Campylobacter species, has been on the rise;
azithromycin is an alternative in these situations.
Special Problems
Pregnant Women
Although travel is rarely contraindicated during a normal preg-
nancy, complicated pregnancies require special consideration
and may warrant a recommendation that travel be delayed. The
risk of obstetric complications is highest during the first and third
trimesters.
Most live-virus vaccines are contraindicated during pregnancy.
Yellow fever vaccine, for which pregnancy is considered a precau-
tion by the Advisory Committee on Immunization Practices
(ACIP), should be avoided if possible. If travel is unavoidable and
the risks for yellow fever virus exposure are believed to outweigh
the risks of vaccination, a pregnant woman should be vaccinated.
Pregnant women should avoid or delay travel to malaria-endemic
areas because no prophylactic measures provide complete pro-
tection. If travel is unavoidable, pregnant women should take
utmost precautions to avoid mosquito bites; for chemoprophy-
laxis, chloroquine and mefloquine are the drugs of choice
for destinations with chloroquine-sensitive and chloroquine-
resistant malaria, respectively.
Acquired Immunodeficiency Syndrome
Many countries bar entry to persons with acquired immunodefi-
ciency syndrome (AIDS). Several countries require serologic
testing for the human immunodeficiency virus (HIV) from all
travelers applying for visa lasting longer than 3 months; official
documentation is required well in advance of travel. Patients with
HIV infection need special preparation before travel to develop-
ing countries because of their increased susceptibility to certain
illnesses (e.g., pneumococcal infection, tuberculosis). Issues of
HIV infection and other sexually transmitted diseases should be
discussed, especially with young, sexually active adults.
The Returning Traveler
The most common medical problems encountered by travelers
after their return home are diarrhea, fever, respiratory illnesses,
and skin lesions. A detailed history should focus on the traveler’s
exact itinerary, including dates of travel, exposure history (e.g.,
food indiscretions, drinking-water sources, freshwater contact,
sexual activity, animal contact, insect bites), style of travel (urban
versus rural), immunization history, and use of antimalarial
chemoprophylaxis.
Diarrhea
Traveler’s diarrhea is an acute condition that usually resolves
within 2 weeks. If the traveler’s diarrhea is not responsive to
empiric antibiotic treatment, a work-up should be performed to
evaluate for Giardia lamblia (see later discussion). Three stool
specimens for ova and parasites and a stool culture are indicated
(E-Fig. 103-1). If Giardia tests are negative, an empirical trial of
metronidazole for treatment of a possible infection with Giardia
or other protozoan (e.g., amebiasis) should be considered. Non-
infectious causes such as temporary lactose intolerance, irritable
bowel syndrome, and, less commonly, inflammatory bowel
disease should also be in the differential diagnosis.
Fever
Malaria should be the first diagnosis considered in a febrile trav-
eler who has returned from a malarious area. P. falciparum malaria
can be fatal if it is not diagnosed and treated promptly. Detection
of the Plasmodium species on Giemsa-stained blood smears by
light microscopy is the standard tool for diagnosis of malaria.
Rapid diagnostic tests for detection of malaria parasite antigens
are becoming increasingly important tools in resource-limited
endemic settings because of their accuracy and ease of use.
Travelers with chloroquine-sensitive P. falciparum malaria
should be treated with chloroquine. Reasonable agents for
uncomplicated malaria caused by chloroquine-resistant P. falci-
parum include atovaquone-proguanil, artemisinin derivative
combinations (if available), and mefloquine- or quinine-based
regimens. Quinine- and mefloquine-based regimens are more
frequently associated with adverse effects, and mefloquine should
not be used to treat P. falciparum malaria acquired in the Thai-
Myanmar-Cambodia area because of high resistance rates.
Severe malaria is defined as acute malaria with major signs of
organ dysfunction or a high level of parasitemia (>5%) or both.
It should be treated with intravenous quinidine for 7 days with
close monitoring of the QTc interval. In many parts of the world,
intravenous artesunate is used, but it may be associated with high
rates of relapse.
Other important causes of fever after travel include viral hepa-
titis (hepatitis A and E), typhoid fever, bacterial enteritis, arbo-
viral infections (e.g., dengue, chicungunya), rickettsial infections,
and, in rare instances, leptospirosis, acute HIV infection, and
amebic liver abscess.
Skin Diseases
Sunburn, insect bites, skin ulcers, and cutaneous larva migrans
are the most common skin conditions affecting travelers after
their return home. Persistent skin ulcers should prompt a work-up
for cutaneous leishmaniasis, mycobacterial infection, or fungal
infection. Careful, complete inspection of the skin is important
in detecting the rickettsial eschar in a febrile patient or the central
breathing hole in a “boil” caused by myiasis.
  PROTOZOAL INFECTIONS
Protozoal infections, though endemic to certain regions, can be
encountered all around the world, partly because of the increase
in travel and migration (Table 103-1). They cause a tremendous
burden of disease in the tropics and subtropics as well as more
 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 953.e1

E-FIGURE 103-1  Giardia wet preparation.

954 Section XV  Infectious Disease

TABLE 103-1  PROTOZOAL INFECTIONS

PROTOZOAN SETTING VECTORS DIAGNOSIS SPECIAL CONSIDERATIONS TREATMENT
ENDEMIC IN THE UNITED STATES
Babesia microti New England Ixodid ticks, Thick or thin blood smear Severe disease in asplenic Quinine and
transfusions persons clindamycin
Giardia lamblia Mountain states Humans, small Microscopic examination of Common in homosexual men, Quinacrine,
mammals stool or duodenal fluid travelers, children in daycare nitazoxanide, or
centers metronidazole
Toxoplasma gondii Ubiquitous Domestic cats, raw Clinical; serologic Pregnant women, Pyrimethamine and
meat confirmation immunosuppressed host sulfadiazine
(AIDS)
Entamoeba histolytica Southeast Human Microscopic examination of Common in homosexual men, Metronidazole
stool or touch preparation travelers, institutionalized
from ulcer persons
Cryptosporidium species Ubiquitous Human Acid-fast stain of stool Severe in immunosuppressed Nitazoxanide
hosts (AIDS)
Trichomonas vaginalis Ubiquitous Human Wet preparation of genital Common cause of vaginitis Metronidazole
secretions
PRIMARILY SEEN IN TRAVELERS AND IMMIGRANTS
Plasmodium species Africa, Asia, South Anopheles mosquito Thick and thin blood Consider in returning travelers Dependent on
America smears with fever regional resistance
pattern (see text)
Leishmania donovani Middle East Sandfly Tissue biopsy Consider in immigrants with Sodium
fever and splenomegaly stilbogluconate
Trypanosoma species Africa, South Reduviid bugs, Direct examination of Very rare in travelers, Dependent on species
America transfusion blood or CSF transfusion associated and stage of disease
AIDS, Acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.

temperate climates. Immunosuppression associated with various
conditions, particularly HIV infection, leads to more severe man-
ifestations. Of all protozoal diseases, malaria causes the most
deaths globally, approximately 1 million people each year.
Protozoal Infections in the United States
Giardiasis
Giardiasis is a common cause of nonbloody diarrhea in returning
travelers. G. lamblia and Giardia intestinalis are found worldwide,
including in the United States. However, giardiasis is most com-
monly diagnosed in travelers returning from Latin America,
Southeast Asia, or the Middle East. Transmission is by the fecal-
oral route in the setting of contaminated food or water or public
swimming areas, or by person-to-person contact in certain risk
populations such as men who have sex with men. It is usually a
self-limited diarrheal illness that lasts 2 to 4 weeks but may persist
longer. Rarely, individuals have associated fevers, nausea, or vom-
iting. The diagnosis is made by microscopic examination of stool
for cysts or trophozoites or by an antigen detection test. Treat-
ment options include metronidazole, tinidazole, or nitazoxanide.
Amebiasis
Amebiasis is another diarrheal illness that occurs in travelers.
Like Giardia, Entamoeba histolytica is found worldwide, and
transmission is by the fecal-oral route. However, most infected
individuals (80%) are asymptomatic. The presentation in those
acutely infected includes bloody or watery diarrhea with abdomi-
nal cramping lasting up to 4 weeks. In immunocompromised
individuals, a severe invasive infection can occur with risk of
necrotizing colitis or bowel perforation. Extraintestinal amebiasis
can occur as well, particularly liver abscesses. The diagnosis can
be made by microscopic examination of stool for ova and
parasites or by antigen detection tests of stool or serum. Treat-
ment is with metronidazole or tinidazole in symptomatic indi-
viduals, followed by paromomycin or iodoquinol.
Protozoal Infections Common  
in Travelers and Immigrants
Leishmaniasis
Leishmaniasis is transmitted by the sandfly and can manifest with
cutaneous, mucocutaneous, or visceral involvement. The skin
finding is a persistent ulcer with raised edges in a traveler return-
ing from the Middle East (Old World: Leishmania major, Leish-
mania tropica) or Latin America (New World: Leishmania
braziliensis, Leishmania peruviana, others). Diagnosis is by tissue
biopsy. Visceral leishmaniasis can have hepatic, splenic, or bone
marrow involvement and is more commonly identified in immi-
grants from Asia (Leishmania donovani) or South America (Leish-
mania chagasi). Diagnosis is by tissue biopsy or culture of the
involved organ.
Treatment varies based on severity of presentation and resis-
tance characteristics. Most cutaneous lesions are self-limited, but
treatment options include sodium stibogluconate (Pentostam)
or paromomycin. For visceral involvement, treatment includes
sodium stibogluconate, amphotericin B, or a combination of
these two agents.
African Trypanosomiasis
African trypanosomiasis, or African sleeping sickness, is a proto-
zoal infection caused by Trypanosoma rhodesiense (East Africa) or
Trypanosoma gambiense (Central and West Africa), which is
transmitted by the tsetse fly. Presenting symptoms include fever,
headache, and central nervous system involvement. The disease
is rarely reported in travelers returning from sub-Saharan Africa
 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 955

TABLE 103-2  HELMINTHIC INFECTIONS

HELMINTH SETTING VECTORS DIAGNOSIS TREATMENT
ENDEMIC IN THE UNITED STATES
Pinworm (enterobiasis) Ubiquitous Human Direct examination for ova Mebendazole, albendazole
Ascaris lumbricoides Southeast Human Stool examination for ova Mebendazole, albendazole
Trichuris trichiura Southeast Human Stool examination for ova Mebendazole, albendazole
Hookworm Southeast Human Stool examination for ova Mebendazole, albendazole
COMMON IN TRAVELERS AND IMMIGRANTS
Strongyloides stercoralis Developing world Human Stool examination for larvae Thiabendazole, ivermectin
Schistosoma species Developing world Snails Stool or urine examination for ova Praziquantel
Wuchereria and Brugia species Asia, some parts of Africa Mosquitoes Nocturnal blood examination Ivermectin
Onchocerca volvulus Africa, South and Central Black flies Biopsy Ivermectin
America
Loa loa Africa Tabanid flies Blood examination, clinical setting Diethylcarbamazine or
ivermectin
Clonorchis sinensis Asia Undercooked fish Stool examination for ova, radiology Praziquantel
and snails
Echinococcus species Worldwide Canines and Radiology, serology, biopsy Surgery, supportive therapy
livestock
Taenia solium (cysticercosis) Developing world Humans, pigs Radiology, serology Surgery, albendazole
T. solium, Taenia saginata, Worldwide Pigs, bovine, fish Stool examination for ova or proglottids Praziquantel
Diphyllobothrium latum
(tapeworms)

but should be considered in immigrants from these areas. Fre-
quently, the patient remembers a chancre at the site of the insect
bite (E-Fig. 103-2). The diagnosis is made by microscopic exami-
nation of blood, lymph, or cerebrospinal fluid for the parasite
(E-Figs. 103-3 and 103-4). Treatment varies by species and is
highly toxic. Consultation with an expert in infectious disease or
tropical medicine is recommended.
American Trypanosomiasis
American trypanosomiasis, or Chagas’ disease, is caused by Try-
panosoma cruzi and is endemic in Central and South America.
Transmitted by contact with feces of reduviid bugs (kissing bugs)
(E-Fig. 103-5), it can also be acquired through blood transfusion
or organ transplantation from an infected individual. The risk to
travelers is extremely low but increases with prolonged stays in
poor-quality housing. The presentation has an acute phase of 3
months followed by a chronic infection for life. The classic acute
presentation involves swelling and erythema of the eyelid and
ocular tissue at the entry site of infection, known as the Romana
sign. However, most individuals are asymptomatic throughout
the infection and are identified only at the time of blood dona-
tion. Between 20% and 30% of individuals develop manifesta-
tions of chronic infection decades later that can include
cardiomegaly and heart failure, megaesophagus, or megacolon.
Diagnosis in the acute phase is by microscopic examination of
peripheral blood (E-Fig. 103-6). In the chronic phase, various
serologic analyses are available to aid in diagnosis. Treatment is
recommended early because it may prevent chronic manifesta-
tions. In the United States, antitrypansomal drugs are available
through the CDC in consultation with an expert in the field. For
most chronic manifestations, however, treatment is supportive.
  HELMINTHIC INFECTIONS
Infestation by nematodes, or roundworms, is the most common
parasitic infection in the world. The intestinal nematodes Ascaris
and Trichuris are the two most prevalent types. Other important
helminths include Strongyloides, Enterobius, schistosomes, and
tapeworms (see later discussion). Although most helminths are
found worldwide, they disproportionately affect the developing
world and pose potential risk to travelers to those areas
(Table 103-2).
Helminthic Infections Common  
in the United States
Pinworm
Enterobiasis is common in the United States and worldwide.
Children are predominantly infected, and transmission is by the
fecal-oral route. The clinical presentation is perianal pruritus.
Diagnosis is made by the tape test, in which transparent tape is
applied to the perianal skin overnight and then examined micro-
scopically for ova on the tape. Treatment is with mebendazole.
Roundworm
Ascaris lumbricoides is found worldwide, including in the United
States, but mostly affects people in the developing world.
Although affected individuals are usually asymptomatic, some
develop pulmonary infiltrates during the migration phase of the
worm or obstruction of the biliary, pancreatic, or intestinal tract.
These manifestations usually occur in the setting of high worm
burden. Diagnosis is by stool examination for ova and parasites
(E-Fig. 103-7). Treatment is with mebendazole.
Whipworm
Trichuris trichiura are called whipworms because of their charac-
teristic shape in the adult form. Like Ascaris, this is an intestinal
nematode that infects mostly children. It is usually asymptomatic
except in the setting of heavy worm burden, which can lead to
rectal prolapse and bloody diarrhea among children in the devel-
oping world. Diagnosis is made by stool examination for ova and
parasites or by endoscopy revealing colitis and the presence of
adult worms. The treatment of choice is mebendazole.
 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 955.e1

E-FIGURE 103-4  African trypanosomiasis morula in cerebrospinal

fluid.

E-FIGURE 103-2  African trypanosomiasis chancre.

E-FIGURE 103-3  African trypanosomiasis blood smear. E-FIGURE 103-5  Reduviid bug (“kissing bug”) on the skin.
955.e2 Section XV  Infectious Disease

E-FIGURE 103-6  Chagas disease blood smear.

E-FIGURE 103-7  Ascaris egg from wet preparation.

956 Section XV  Infectious Disease
Hookworm
Ancylostoma duodenale and Necator americanus (hookworms) are
similar to roundworms in their worldwide distribution and are
common among immigrants from Asia and sub-Saharan Africa.
Infection occurs through direct penetration of the skin by the
larvae, which travel through the lymphatics and the bloodstream
to the lungs and are then swallowed. Infected individuals may be
asymptomatic, or they may develop pruritic dermatitis at the site
of entry. As with the roundworm, pulmonary infiltrates can occur
during the migration phase; this is known as Loeffler’s syndrome.
Chronic iron deficiency anemia associated with heavy hook-
worm infection can be severe and debilitating. Eosinophilia is
common. The diagnosis is made by stool examination for ova and
parasites (E-Fig. 103-8). The treatment is mebendazole.
Helminth Infections Common   Loa loa (Eyeworm)
in Travelers and Immigrants
Strongyloidosis
Strongyloides stercoralis is a helminthic parasite that is found
worldwide, although more commonly in the tropics. Infection
occurs from contact with contaminated soil; the larva penetrates
the skin, migrates to the lungs, and is then swallowed by the
individual. The infection is usually asymptomatic, but infection
can persist into the chronic phase decades later. Those with
symptoms usually have gastrointestinal complaints of bloating,
diarrhea, and abdominal pain. Eosinophilia is a common finding
in these individuals. In immunocompromised individuals, a
hyperinfection syndrome with dissemination of the organism
can occur. Hyperinfection syndrome has a higher mortality rate
and occurs usually in immigrants who become immunosup-
pressed as a result of chemotherapy, use of steroids, or illness.
Diagnosis is made by stool examination (approximately 30% to
50% sensitivity) (E-Fig. 103-9) or by serology but does not dis-
tinguish between chronic and acute disease. Treatment is with
ivermectin for 2 days; in the setting of hyperinfection, a longer
course is required.
Schistosomiasis
Schistosomiasis is found throughout the tropics and the develop-
ing world. Also known as blood flukes, schistosomes use fresh-
water mollusks as their intermediate host and penetrate the skin
of individuals, leading to infection. The three major species are:
Schistosoma mansoni (Africa, Middle East, South America), Schis-
tosoma haematobium (Africa, Middle East), and Schistosoma
japonicum (China, Philippines, and Southeast Asia). Acute infec-
tion can manifest with dermatitis, although most cases are
asymptomatic. Chronic infection develops from the immune
response to egg deposition. S. haematobium can lead to urinary
obstruction or hematuria, whereas S. mansoni and S. japonicum
can lead to hepatosplenomegaly, hepatic fibrosis, obstruction of
portal blood flow, and varices. S. japonicum can infect the central
nervous system causing ring enhancing lesions and seizures.
Diagnosis is by examination of stool or urine for schistosome
eggs in individuals from endemic areas, who have a high egg
burden; among travelers, in whom the egg burden is usually low,
serology is used for diagnosis The treatment of choice is
praziquantel.
Lymphatic Filariasis (Elephantiasis)
Wuchereria bancrofti and Brugia malayi are found throughout the
tropics; they are lymph-dwelling filariae that cause elephantiasis.
The presentation can vary from acute lymphadenitis, to asymp-
tomatic microfilaremia, filarial fevers, or tropical pulmonary
eosinophilia. Lymphadentitis can involve both upper and lower
extremities with both of these filarial species, but scrotal involve-
ment only occurs with W. bancrofti. The diagnosis is made
by examination of a peripheral blood smear for microfilariae
obtained between 10 pm and 4 am because these organisms are
nocturnally periodic.
Diethylcarbamazine is used for lymphatic filariasis to eradicate
the microfilariae and the adult worms. However, the manage-
ment of chronic lymphatic obstruction remains a challenge
because it is not fully reversible and requires supportive therapy.
Loiasis is caused by the eyeworm (Loa loa) and is found in West
and Central Africa. Presentation can vary and may include pru-
ritus, subcutaneous swellings, joint manifestations, or neurologic
symptoms. In the rarest presentation, the adult worm can be seen
in the anterior chamber of the individual’s eye. Diagnosis is con-
firmed by the presence of microfilariae in blood samples or isola-
tion of the adult worm. Treatment is as for lymphatic filariasis,
with diethylcarbamazine.
River Blindness
Onchocerca volvulus infection mostly occurs in regions of West
and Central Africa but also in South and Central America. Pru-
ritic dermatitis is the most common presentation; but involve-
ment of the eye is the most serious presentation. Ocular
involvement occurs in endemic areas in individuals with heavy
worm burden. The complications can begin with conjunctivitis
and photophobia. Corneal involvement with the microfilariae
causes an inflammatory reaction leading to sclerosing keratitis
and blindness. River blindness is the most common cause of
blindness in Africa. The diagnosis is made by examination of skin
snips for microfilariae. Ivermectin is the drug of choice; an initial
single dose is followed by a repeat dose at 3 or 6 months to sup-
press any further microfilariae.
Clonorchiasis
Clonorchis sinensis is the Chinese liver fluke. This is an important
infection to consider in Asian immigrants who have symptoms
consistent with biliary tract disease, including right upper quad-
rant pain, anorexia, and weight loss. Though the disease is uncom-
mon, untreated infections can lead to cholangiocarcinoma.
Treatment is curative with praziquantel in 85% of cases.
Cysticercosis
Cysticercosis is caused by the pork tapeworm, Taenia solium.
Individuals report new-onset seizures or headaches. Head com-
puted tomographic (CT) scans show ring-enhancing lesions.
The diagnosis is usually based on the history and imaging find-
ings, and confirmation can be made by immunoblot assay. Treat-
ment depends on the site of infection and symptoms. It may
include antiparasitic treatment, antiseizure medications, and
surgical removal. The antiparasitic drug of choice is praziquantel
 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 956.e1

E-FIGURE 103-8  Hookworm egg.

E-FIGURE 103-9  Strongyloides stool wet preparation.

 Chapter 103  Infectious Diseases of Travelers: Protozoal and Helminthic Infections 957
or albendazole. Expert consultation before treatment is recom-
mended because of the risk of increasing focal cerebral edema
and seizure activity.
Intestinal Tapeworms
Tapeworms that commonly infect humans include Taenia solium
(from raw pork), Taenia saginata (raw beef), and Diphylloboth-
rium latum (raw fish). Most infections are asymptomatic except
in the case of invasive disease with T. solium, as discussed earlier
(see Cysticercosis). Praziquantel is the treatment of choice for all
three tapeworms.
Echinococcus
The tapeworm Echinococcus granulosus causes hydatid disease
with production of a cystic liver mass. This occurs in immigrants
from sheep-raising parts of the world such as South America,
Central Asia, and the Middle East. The characteristic appearance
of the cyst includes a calcified wall with a dependent hydatid on
CT scans. This appearance and the supporting history help to
make the diagnosis; the serologic testing available can be falsely
negative. Treatment is surgical removal of the cyst without
rupture or spillage of the contents. Albendazole is usually given
before surgical removal.
Less common is Echinococcus multilocularis, which causes alve-
olar cyst disease. This more aggressive infection leads to liver
lesions as well as brain and lung involvement. Treatment includes
resection of liver lesions in combination with antiparasitic
therapy with mebendazole or albendazole. However, these agents
are not parasitocidal, so the mortality rate remains high. Other
potential therapies, such as amphotericin B and nitrazoxanide,
are being explored.
SUGGESTED READINGS
Arguin P: Approach to the patient before and after travel. In Goldman L, Schafer
A, editors: Cecil Textbook of Medicine, ed 24, Philadelphia, 2012, Saunders,
pp 1800–1803.
Centers for Disease Control and Prevention: CDC Health Information for
International Travel 2014, New York, 2014, Oxford University Press.
Jeronimo S, de Queiroz Sousa A, Pearson R: Leishmaniasis. In Guerrant RL,
Walker DH, Weller PF, editors: Tropical Infectious Diseases: Principles,
Pathogens, and Practices, ed 3, Philadelphia, 2011, Saunders, pp 696–706.
Kirchoff L: Trypanosoma species (American trypanosomiasis, Chagas’ disease):
biology of trypanosomes. In Mandell GL, Bennett JE, Dolin R, editors:
Principles and Practice of Infectious Diseases, ed 7, Philadelphia, 2010,
Churchill Livingstone, pp 3481–3488.
Leder K, Torresi J, Libman M, et al: GeoSentinel surveillance of illness in
returned travelers, 2007-2011, Ann Intern Med 158:456–468, 2013.
U.S. Department of Commerce, Office of Travel and Tourism Industries: Profile
of U.S. resident travelers visiting overseas destinations: 2011 Outbound.
Available at: http://travel.trade.gov/outreachpages/download_data_table/
2011_Outbound_Profile.pdf. Accessed November 3, 2014.
XVI
Neurologic Disease
104  Neurologic Evaluation of the Patient
Frederick J. Marshall
105  Disorders of Consciousness
Mohamad Chmayssani and Paul M. Vespa
106  Disorders of Sleep
Selim R. Benbadis
107  Cortical Syndromes
Sinéad M. Murphy and Timothy J. Counihan
108  Dementia and Memory Disturbances
Frederick J. Marshall
109  Major Disorders of Mood, Thoughts,
and Behavior
Jeffrey M. Lyness
110  Autonomic Nervous System Disorders
William P. Cheshire, Jr.
111  Headache, Neck and Back Pain, and
Cranial Neuralgias
Timothy J. Counihan
112  Disorders of Vision and Hearing
Eavan McGovern and Timothy J. Counihan
113  Dizziness and Vertigo
Kevin A. Kerber
ESSENTIALS
ss
114  Disorders of the Motor System
Kevin M. Biglan
115  Congenital, Developmental, and
Neurocutaneous Disorders
Maxwell H. Sims and Jennifer M. Kwon
116  Cerebrovascular Disease
Mitchell S.V. Elkind
117  Traumatic Brain Injury and Spinal Cord Injury
Geoffrey S.F. Ling
118  Epilepsy
Michel J. Berg
119  Central Nervous System Tumors
Bryan J. Bonder and Lisa R. Rogers
120  Demyelinating and Inflammatory Disorders
Anne Haney Cross
121  Neuromuscular Diseases: Disorders of the Motor
Neuron and Plexus and Peripheral Nerve Disease
Carlayne E. Jackson
122  Muscle Diseases
Jeffrey M. Statland and Robert C. Griggs
123  Neuromuscular Junction Disease
Emma Ciafaloni
959
 104 
Neurologic Evaluation
of the Patient
ss
Frederick J. Marshall
  INTRODUCTION
To arrive at an accurate neurologic diagnosis, the clinician gen-
erates and tests hypotheses about the location and the mecha-
nism of injury to the nervous system. Hypotheses are refined
as the clinician progresses from the interview to the physical
examination to the laboratory assessment of the patient. The
focus is first placed on entities that are common, serious, and
treatable. Typical clinical presentations of patients with common
diseases account for 80% of cases, unusual presentations of
patients with common diseases account for 15%, typical pre-
sentations of patients with rare diseases account for 5%, and
unusual presentations of patients with rare diseases account for
less than 1%.
  TAKING A NEUROLOGIC HISTORY
The clinician must determine the location, quality, and timing of
symptoms. He or she must ask the patient to report the progres-
sion of symptoms rather than a litany of diagnostic procedures
and specialty evaluations. Establishing when the patient last felt
normal is important. Ambiguous descriptors such as dizzy should
be rejected in favor of evocative descriptors such as light-
headed (which may implicate cardiovascular insufficiency) or off
balance (which may implicate cerebellar or posterior column
dysfunction).
Family members and other witnesses should corroborate his-
torical information when appropriate. Historical information
should include the medical and surgical histories; current medi-
cations; allergies; family history; review of systems; and social
history, including the patient’s level of education, work history,
possible toxin exposures, substance use, sexual history, current
life circumstance, and overall function.
Clues to localization are sought during the interview. For
example, pain is usually caused by a lesion of the peripheral
nervous system, whereas aphasia (i.e., disordered language pro-
cessing) indicates an abnormality of the central nervous system.
Because sensory and motor functions are anatomically relatively
distant in the cerebral cortex but progressively closer together as
fibers converge in the brain stem, spinal cord, roots, and periph-
eral nerves, the coexistence of sensory loss and motor dysfunc-
tion in a limb implies a large lesion at the level of the cortex or a
smaller lesion lower down in the neuraxis. Small lesions in areas
of high traffic such as the spinal cord or brain stem can result in
widespread neurologic dysfunction, whereas small lesions else-
where may be asymptomatic.
960
Table 104-1 lists the potential localizing values of common
neurologic symptoms to help address the issue of lesion localiza-
tion. Tables 104-2 and 104-3 list symptoms that are commonly
associated with lesions at specific locations in the nervous system.
Some symptoms can result from a lesion at any of several levels
of the nervous system. For example, double vision can result from
a focal lesion in the brain stem, peripheral nerves (cranial nerve
III, IV, or VI), neuromuscular junction, or extraocular muscles;
or it can be nonfocal and result from an increase in intracranial
pressure. Associated symptoms (or their lack) may lead the inter-
viewer to reject certain hypotheses that at first seemed most
likely. Table 104-4 lists the most important types of neuropatho-
logic conditions and provides examples of diseases in each
category.
Some neuroanatomic locations point to a specific diagnosis or
a limited number of diagnoses. For example, disease of the neu-
romuscular junction is usually caused by an autoimmune process
such as myasthenia gravis (common) or Eaton-Lambert myas-
thenic syndrome (uncommon). The exceptions—botulism and
congenital myasthenic disorders—are rare. Alternatively, some
areas of the nervous system (e.g., the cerebral hemispheres) are
vulnerable to practically any of the categories of disease outlined
in Table 104-4.
The pace and temporal order of symptoms are important.
Degenerative diseases usually progress gradually, whereas vascu-
lar diseases (e.g., stroke, aneurysmal subarachnoid hemorrhage)
progress rapidly. Certain symptoms such as double vision almost
invariably develop abruptly, even if the underlying disorder has
been developing gradually over days to weeks.
TABLE 104-1  POTENTIAL LOCALIZING VALUE OF
COMMON NEUROLOGIC SYMPTOMS
POTENTIAL LOCALIZING VALUE SIGN OR SYMPTOM
High Focal weakness, sensory loss, or pain
Focal visual loss
Language disturbance
Neglect or anosognosia
Medium Vertigo
Dysarthria
Clumsiness
Low Fatigue
Headache
Insomnia
Dizziness
Anxiety, confusion, or psychosis
 Chapter 104  Neurologic Evaluation of the Patient 961

TABLE 104-2  SYMPTOM LOCALIZATION IN THE TABLE 104-3  SYMPTOM LOCALIZATION IN THE ss

CENTRAL NERVOUS SYSTEM MOTOR UNIT*

SIGN OR SYMPTOM
CEREBRAL HEMISPHERES
Unilateral weakness or sensory
complaints
Language dysfunction
Spatial disorientation
Anosognosia (lack of insight into
deficit)
Hemivisual loss
Flattening of affect or social
disinhibition
Alteration of consciousness
Alteration of memory
CEREBELLUM
Limb clumsiness
Unsteadiness of gait or posture
BASAL GANGLIA
Slowness of voluntary movement
Involuntary movement
BRAIN STEM
Contralateral weakness or sensory
complaints in the body with
ipsilateral weakness or sensory
complaints in the face
Double vision
Vertigo
Alteration of consciousness
SPINAL CORD
Weakness and spasticity (ipsilateral)
and anesthesia (contralateral)
below a specified level
Unsteadiness of gait
Bilateral (can be asymmetrical)
weakness and sensory complaints
in multiple contiguous radicular
distributions
LOCATION
Contralateral cerebral hemisphere
Left hemisphere (frontal and
temporal)
Right hemisphere (parietal and
occipital)
Right hemisphere (parietal)
Contralateral hemisphere (occipital,
temporal, and parietal)
Bihemispheric (frontal and limbic)
Bihemispheric (diffuse)
Bihemispheric (hippocampus,
fornix, amygdala, and mammillary
bodies)
Ipsilateral cerebellar hemisphere
Midline cerebellar structures
Substantia nigra and striatum
Striatum, thalamus, and subthalamus
Midbrain, pons, and medulla
Midbrain and pons
Pons and medulla
Midbrain, pons, medulla (reticular
formation)
Corticospinal and spinothalamic
tracts
Posterior columns
*Anterior horn cell and the peripheral nervous system.
Central cord
SIGN OR SYMPTOM LOCATION
ANTERIOR HORN CELL
Weakness and wasting with muscle Anterior horn of spinal cord
twitching (fasciculation) but no (diffuse or segmental)
sensory complaints
SPINAL ROOT
Weakness and sensory loss confined to a Cervical, thoracic, lumbar, and
known radicular distribution (pain, a sacral
common feature, may spread)
PLEXUS
Pain, weakness, and sensory loss in a Brachial and lumbosacral (may
limb; not limited to a single radicular also be caused by
or peripheral nerve distribution polyradiculopathy)
NERVE
Pain, distal weakness, and/or sensory Peripheral nerves
changes confined to a single (mononeuropathy)
peripheral nerve distribution
Pain, distal weakness, and/or sensory Peripheral nerves
changes affecting both sides (polyneuropathy)
symmetrically (usually starting in feet)
Pain, distal weakness, and/or sensory Peripheral nerves
changes affecting scattered single (mononeuropathy multiplex)
peripheral nerve distributions
Unilateral special sensory loss Cranial nerves I, II, V, VII, VIII,
and IX
Unilateral facial weakness involving Cranial nerve VII (ipsilateral)
entire one half of face
NEUROMUSCULAR JUNCTION
Progressive weakness with repeated use Ocular, pharyngeal, and skeletal
of a muscle; no sensory complaints
MUSCLE
Proximal weakness; no sensory Diffuse and various patterns
complaints

TABLE 104-4  CATEGORIES OF NEUROLOGIC DISEASE

DISEASE CATEGORY EXAMPLE DISEASE CATEGORY EXAMPLE
GENETIC DEGENERATIVE
Autosomal dominant Huntington’s disease Central Parkinson’s disease
Autosomal recessive Friedreich’s ataxia Central and peripheral Amyotrophic lateral sclerosis
X-linked recessive Duchenne muscular dystrophy
AUTOIMMUNE
Mitochondrial Progressive external ophthalmoplegia
Sporadic Down syndrome Central demyelinating Multiple sclerosis
Peripheral demyelinating Guillain-Barré syndrome
NEOPLASTIC
Neuromuscular junction Myasthenia gravis
Intrinsic Glioblastoma
TOXIC AND METABOLIC
Extrinsic Metastatic melanoma
Paraneoplastic Cerebellar degeneration Endogenous Uremic encephalopathy
Exogenous Alcoholic neuropathy
VASCULAR
OTHER STRUCTURAL
Stroke Thrombotic, embolic, lacunar,
hemorrhagic Trauma Spinal cord injury
Structural Arteriovenous malformation Hydrodynamic Normal pressure hydrocephalus
Inflammatory Cranial arteritis Psychogenic Hysterical paraparesis
INFECTIOUS
Bacterial Meningococcal meningitis
Viral Herpes encephalitis
Protozoal Toxoplasmosis
Fungal Cryptococcal meningitis
Helminthic Cysticercosis
Prion Creutzfeldt-Jakob disease
 962 Section XVI  Neurologic Disease
ss
  NEUROLOGIC EXAMINATION
Performance of the main elements of a general screening neuro-
logic examination is imperative (Table 104-5), but the examina-
tion should be tailored to confirm or disprove the clinical
hypotheses generated from the patient’s history. Unexpected
signs must be explained, often with a return to the history for
further clarification.
The examination is approached as if only one of two possible
injuries has occurred—the final common pathway to a structure
is disrupted, or the input to that pathway is disrupted
(Fig. 104-1). In the case of the motor system, the final common
pathway is the motor unit and includes the anterior horn cells
giving rise to axons in a nerve, the nerve itself, the neuromuscular
junction, and the muscle. Injury to any of these structures results
in dysfunction of the muscle. Conversely, if these structures are
intact, observing the muscle function may be possible under the
TABLE 104-5  ELEMENTS OF A GENERAL SCREENING NEUROLOGIC EXAMINATION
SYSTEMIC PHYSICAL EXAMINATION
Head (trauma, dysmorphism, and bruits)
Neck (tone, bruits, and thyromegaly)
Cardiovascular (heart rate, rhythm, and murmurs; peripheral pulses and jugular
venous distention)
Pulmonary (breathing pattern, cough and cyanosis)
Abdomen (hepatosplenomegaly)
Back and extremities (skeletal abnormalities, peripheral edema, and straight-leg
raising)
Skin (neurocutaneous stigmata and hepatic stigmata)
MENTAL STATUS
Level of consciousness (awake, drowsy, and comatose)
Attention (coherent stream of thought, serial 7s)
Orientation (temporal and spatial)
Memory (short and long term)
Language (naming, repetition, comprehension, fluency, reading, and writing)
Visuospatial skills (clock drawing and figure copying)
Judgment, insight, thought content (psychotic)
Mood (depressed, manic, and anxious)
CRANIAL NERVES
Olfactory (smell in each nostril)
Optic (afferent pupillary function, funduscopic examination, visual acuity,
visual fields, and structural eye findings)
Oculomotor, trochlear, and abducens (smooth pursuit and saccadic eye
movements, nystagmus, efferent pupillary function, and eyelid opening)
Trigeminal (jaw jerk, facial sensation, afferent corneal reflex, and muscles of
mastication)
Facial (efferent corneal reflex, facial expression, eyelid closure, nasolabial folds,
and power and bulk)
Vestibulocochlear (nystagmus, speech discrimination, Weber test, and Rinne
test)
Glossopharyngeal and vagus (afferent and efferent gag reflex and uvula
position)
Spinal accessory (power and bulk of sternocleidomastoid and trapezii muscles)
Hypoglossal (position, bulk, and fasciculations of tongue)
MOTOR EXAMINATION
Pronator drift (subtle corticospinal lesion)
Tone and bulk of muscles (basal ganglia lesion yields rigidity, cerebellar lesion
yields hypotonia, corticospinal lesion yields spasticity, nonspecific
bihemispheric disease yields paratonia, hypertrophy indicates dystonia,
pseudohypertrophy indicates muscle disease, and atrophy indicates lower
motor neuron disease)
Adventitious movements (tremor, tic, dystonia, and chorea indicate disease
of the basal ganglia; asterixis and myoclonus may indicate toxic metabolic
process)
Power of major muscle groups (scale 0-5)
right circumstances. If all modes of engaging the final common
pathway fail to elicit a response, the clinician can conclude that
the lesion is located somewhere within the final common
pathway.
For example, a man with paralysis of facial movement on one
side that is caused by a lesion of cranial nerve VII cannot smile
voluntarily, close his eye, or wrinkle his forehead on the affected
side. Spontaneous laughter or smiling as an automatic response
to a joke also fails to move the paretic side. If the problem is
central, however, facial movement with involuntary (spontane-
ous) smiling may be preserved or increased. This observation is
common in patients with facial weakness caused by a stroke.
Central input to a final common pathway in the nervous
system is usually tonically inhibitory. Damage to this input typi-
cally results in overactivity of the involved muscle group. Signs of
damage to central inhibitory systems include spasticity and
hyperreflexia (i.e., motor cortex, subcortical white matter,
Upper extremities: deltoids, biceps, triceps, wrist extension and flexion, finger
extension and flexion, and interossei
Lower extremities: hip flexion, extension, abduction, and adduction; knee
extension and flexion; ankle dorsiflexion, plantar flexion, inversion, and
eversion; toe extension and flexion
SENSORY EXAMINATION
Light touch (posterior columns)
Pinprick (spinothalamic tract)
Temperature (spinothalamic tract)
Joint position sense (posterior columns)
Vibration (posterior columns)
Graphesthesia (cortical sensory)
Double simultaneous stimulation (cortical sensory)
Two-point discrimination (posterior columns and cortical sensory)
REFLEX EXAMINATION
Standard reflexes (grades 0-4)
Biceps
Triceps
Brachioradialis
Knee jerk
Ankle jerk
Pathologic reflexes
Babinski’s sign (if present)
Myerson’s sign (if present)
Snout (if present)
Jaw jerk (if brisk)
Palmomental (if present)
Hoffmann sign (if brisk)
COORDINATION AND GAIT
Finger-nose-finger (action tremor suggesting cerebellar disease)
Rapid alternating movements (dysdiadochokinesia suggesting cerebellar
disease)
Fine motor movements (slowness and small amplitude suggesting basal ganglia
or corticospinal tract abnormalities)
Heel-to-shin (ataxia suggesting cerebellar disease)
Arising from chair with arms folded across chest (inability in advanced basal
ganglia, cerebellar, corticospinal, or muscle disease)
Walking naturally (look for decreased arm swing, spasticity, broad base,
festination, waddle, footdrop, start hesitation, and dystonia)
Tandem gait (look for ataxia)
Walking with feet everted or inverted (look for latent dystonia)
Hopping on each foot separately (look for latent dystonia)
Stand with feet together and eyes open, eyes closed (sensory ataxia and
cerebellar disease)
Response to retropulsive stress (loss of postural righting mechanisms)
 Chapter 104  Neurologic Evaluation of the Patient 963
Upper motor
neuron
Lower motor
neuron
Effector
(muscle)
Central
connections
Peripheral
nerve
FIGURE 104-1  The nervous system can be conceptually reduced to
a series of higher-order inputs that converge on final common path-
ways. For example, upper motor neurons converge on lower motor
neurons, whose axons form the final common pathway to an effector
muscle.
or corticospinal pathways in the brain stem and spinal cord);
dystonia, rigidity, tremor, and tic (i.e., basal ganglia or extrapyra-
midal systems); and ataxia and dysmetria (i.e., cerebellum). An
exception is hypotonia, which is caused by cerebellar disease.
  TECHNOLOGIC ASSESSMENT
Laboratory investigations and special testing should be used to
confirm a clinical suggestion and to finalize the diagnosis. Testing
should be selectively performed because of expense, risk, and
discomfort to the patient. Frequently helpful tests are discussed
in subsequent sections. Diagnostic tests should never be ordered
without a specific differential diagnosis firmly in mind. Many
neurodiagnostic tests disclose incidental abnormalities unrelated
to a patient’s symptomatic disease process.
Lumbar Puncture
Investigation of the cerebrospinal fluid (CSF) is indicated in a
small number of specific circumstances, usually meningitis and
encephalitis (Table 104-6). When taken, a CSF specimen should
be routinely sent for laboratory testing to determine cell and dif-
ferential counts, protein and glucose levels, and bacterial cultures.
The CSF should also be examined for its color and clarity. Cloudy
or discolored CSF should be centrifuged and examined for xan-
thochromia in comparison with water. Additional, special studies
may be obtained as appropriate, including Gram stain; fungal,
viral, and tuberculous cultures; cryptococcal and other antigens;
tests for syphilis; Lyme titers; malignant cytologic patterns; para-
neoplastic and other specific protein antibodies; and oligoclonal
bands. Polymerase chain reaction for specific viruses may also be
appropriate. Assessment of specific CSF proteins such as tau,
phosphorylated tau, and amyloid-β in patients at risk for demen-
tia is considered more useful in research than clinical settings.
The 14-3-3 protein may be found in patients with rapid-onset
dementia.
Recording the opening and closing pressures is important.
Tissue infection in the region of the puncture site is an absolute
contraindication to lumbar puncture. Relative contraindications
TABLE 104-6  INDICATIONS FOR LUMBAR PUNCTURE ss
URGENT (DO NOT WAIT FOR BRAIN IMAGING)
Acute central nervous system infection in the absence of focal
neurologic signs
LESS URGENT (WAIT FOR BRAIN IMAGING)
Vasculitis, subarachnoid hemorrhage, or cryptic process
Increased intracranial pressure in the absence of mass lesion on magnetic
resonance imaging or computed tomography
Intrathecal therapy for fungal or carcinomatous meningitis
Symptomatic treatment for headache from idiopathic intracranial
hypertension or subarachnoid hemorrhage
include known or probable intracranial or spinal mass lesion,
increased intracranial pressure as a result of mass lesions, coagu-
lopathy caused by thrombocytopenia (usually correctable), anti-
coagulant therapy, and bleeding disorders.
Rare but severe complications of lumbar puncture include
transtentorial or foramen magnum herniation, spinal epidural
hematoma, spinal abscess, herniated or infected disk, meningitis,
and adverse reaction to a local anesthetic agent. More common
and relatively benign complications include headache and
backache.
Tissue Biopsies
In selected specialty centers, a diagnostic biopsy is performed on
various tissues, including brain, peripheral nerve (see Chapter
121), muscle (see Chapter 121), and skin. Occasionally, biopsy
provides the only means of arriving at a definitive diagnosis.
Electrophysiologic Studies
Electrophysiologic studies include electroencephalography, elec-
tromyography, nerve conduction studies, and evoked potentials.
These studies are helpful in situations in which the patient cannot
be examined or interviewed adequately.
Electroencephalography is most often used to investigate sei-
zures (see Chapter 118). It can document encephalopathy, in
which case the background electrical activity of the brain is
slowed, and it is also used in the evaluation of brain death.
Electromyography is useful in the differential diagnosis of
muscle disease, neuromuscular junction disease, peripheral
nerve disease, and anterior horn cell disease (see Chapter
121). Nerve conduction studies (see Chapters 122 and 123)
may show decreased amplitude (characteristic of axonal neu-
ropathy) or decreased velocity (characteristic of demyelinating
neuropathy).
Visual-evoked potential studies are commonly used in the
evaluation of possible multiple sclerosis (see Chapter 120).
Asymmetrical slowing of the cortical response to visual pattern
stimulation suggests demyelination in the optic nerve or central
optic pathways. Brain stem auditory-evoked potential studies are
useful in the diagnosis of diseases affecting cranial nerve VIII or
its central projections. Lesions at the cerebellopontine angle and
the brain stem cause abnormal delay in conduction. Brain stem
auditory-evoked potentials are helpful in the diagnosis of deaf-
ness in infants. Somatosensory-evoked potentials are used to
identify a slowing of central sensory conduction that results from
demyelinating disease, compression, or metabolic derangements.
 964 Section XVI  Neurologic Disease
ss
TABLE 104-7  MAGNETIC RESONANCE IMAGING
VERSUS COMPUTED TOMOGRAPHY
MAGNETIC RESONANCE IMAGING (MRI)
Resolution 1-2 mm (higher with newer 3-Tesla magnets)
Gadolinium contrast relatively safe, except in severe renal insufficiency
Unaffected by bone; multiple planes of imaging available; functional
(physiologic) imaging capacity
COMPUTED TOMOGRAPHY
Resolution >5 mm
Iodine contrast associated with anaphylaxis and rash
Faster acquisition than MRI
Metallic objects such as pacemaker or aneurysm clip preclude MRI
Acute hemorrhage well visualized
Better tolerated by patients who are severely ill or claustrophobic
They are also used to evaluate spinal cord–mediated sensory
abnormalities.
Imaging Studies
Magnetic resonance imaging (MRI) and computed tomography
(CT) are high-resolution imaging techniques that provide
extraordinary diagnostic precision for central nervous system
lesions. Most neurologic diseases, however, can have normal CT
and MRI findings. Moreover, many abnormal findings on CT and
MRI bear no relation to the diagnosis responsible for the patient’s
symptoms.
Table 104-7 compares CT with MRI. MRI is used for most
purposes, although CT has the advantage of wider accessibility,
greater speed of acquisition, and better tolerability by the patient.
CT detects acute hemorrhage and is preferred for emergencies.
MRI provides more detail and simultaneously obtains images in
the horizontal, vertical, and coronal planes. Contrast media for
CT or MRI are useful in the diagnosis of tumors, abscesses, and
other processes that derange the blood-brain barrier. MRI can
be used for functional imaging and spectroscopy; both tech-
niques have great promise for the evaluation of cognitive and
metabolic disorders, epilepsy, multiple sclerosis, and many other
conditions.
MR- and CT-angiography allow noninvasive visualization of
the major vessels of the head and neck. Conventional angiogra-
phy with an intra-arterial injection of contrast agent is used for
evaluation of many intracranial vascular abnormalities, including
small aneurysms and arteriovenous malformations, and inflam-
mation of small blood vessels.
Noninvasive ultrasonography of the carotid and vertebral
arteries can define stenotic vessels. It has been supplemented by
transcranial Doppler technology, which allows characterization
of blood flow in intracranial arteries.
Single-photon emission CT (SPECT) is useful for the evalua-
tion of intracranial blood flow. The development of iodine-123
ioflupane injection (DaTscan) makes it possible to visualize the
dopamine transporter to follow cell loss in patients with Parkin-
son’s disease.
Positron-emission tomography (PET) is a functional imaging
technology that can demonstrate specific metabolic derange-
TABLE 104-8  NEUROLOGIC CONDITIONS FOR WHICH
GENETIC TESTS ARE AVAILABLE
• Neuromuscular diseases: nerve (Charcot-Marie-Tooth disease); muscle
(myotonic dystrophy, Duchenne-Becker muscular dystrophy; anterior
horn cell (spinal muscular atrophy, familial amyotrophic lateral sclerosis)
• Movement disorders: spinocerebellar ataxia, multiple types; Friedreich’s
ataxia; dystonia (DYT1 mutation); Huntington’s disease
• Mental retardation (fragile X syndrome)
• Mitochondrial diseases: mitochondrial encephalomyelopathy, lactic
acidosis, and strokelike symptoms (MELAS syndrome); myoclonus
epilepsy with ragged red fibers (MERRF syndrome).
ments. It is useful for evaluating local abnormalities of glucose
and oxygen metabolism. PET is of particular value in defining the
site of origin of focal seizures. Customized ligands may be used
to identify specific pathologic processes. Examples include flor-
betapir F-18 (Amyvid), a U.S. Food and Drug (FDA)–approved
agent for estimating β-amyloid neurotic plaque density in
Alzheimer’s disease, and fluorodopa F18, which is under FDA
review for diagnostic use in Parkinson’s disease.
Genetic and Molecular Testing
There are more neurologic diseases than diseases of all other
systems combined. Discoveries have revolutionized the diagnos-
tic approach to many of these diseases, and new genetic tests are
discovered every year. Table 104-8 outlines the tests that are com-
mercially available.
Genetic testing for a disorder requires the clinician to perform
a thoughtful and caring evaluation of the patient, usually with
input from and evaluation of the patient’s family. Important
ethical issues surround the use of genetic tests, including the
ability to ensure privacy, to ensure adequate psychological and
social support for patients who may be given devastating news,
and to address adequately the appropriateness of prenatal screen-
ing or presymptomatic testing when no treatment is available.
  PROSPECTUS FOR THE FUTURE
Novel imaging techniques and molecular diagnostic studies are
beginning to shed light on the pathogenesis of neurologic condi-
tions that have been identifiable only by clinical phenomenology.
Studies of previously untreatable neurodegenerative disorders
are now targeting presymptomatic individuals in the hope that
earlier intervention can modify disease outcomes. Despite these
and foreseeable future advances, the clinical aspects of neurologic
disease remain fundamentally important in understanding the
impact of disease on patients and their families.
SUGGESTED READINGS
Biller J, editor: Practical neurology, ed 4, Philadelphia, 2012, Lippincott Williams
& Wilkins.
Griggs RC, Jozefowicz R, Aminoff MJ: Approach to the patient with neurologic
disease. In Goldman L, Schafer AI, editors: Goldman’s Cecil medicine, ed 24,
Philadelphia, 2012, pp 2228–2235.
 105 
Disorders of Consciousness ss

Mohamad Chmayssani and Paul M. Vespa

  INTRODUCTION   PATHOPHYSIOLOGIC FACTORS

Coma is a sleeplike state in that the patient is unresponsive and
the eyes remain closed even with vigorous stimulation. A poorly
responsive state in which the eyes are open, or an agitated and
confused state, or delirium is not coma but may represent early
stages of the same disease processes and should be investigated
in the same manner.
Consciousness requires that the brainstem reticular activating
system and its cortical projections be intact and functioning. The
reticular formation begins in the midpons and ascends through
the dorsal midbrain to synapse in the thalamus; it then innervates
higher centers through thalamocortical connections. Knowledge
of this anatomic substrate provides the short list of regions to be
investigated in the search for a structural cause of coma: Brain-
stem or bihemispheric dysfunction satisfies these anatomic
requirements, whereas structural lesions elsewhere are not the
cause of the patient’s unconsciousness. In addition to structural
lesions, meningeal inflammation, metabolic encephalopathy, and
seizures diffusely affect the brain and complete the differential
diagnosis for the patient in coma.
Meningeal irritation caused by infection or blood in the subarach-
noid space is an essential early consideration in coma evaluation
because its cause requires immediate attention (especially with
purulent meningitis) and may not be diagnosed by computed
tomography (CT).
Hemispheric mass lesions result in coma either by expanding
across the midline laterally to compromise both cerebral hemi-
spheres or by impinging on the brainstem to compress the rostral
reticular formation. These processes—lateral herniation (lateral
movement of the brain) and transtentorial herniation (vertical
movement of the brain)—most commonly occur together. At the
bedside, clinical signs of an expanding hemispheric mass evolve
in a level-by-level, rostral- caudal manner (Fig. 105-1). Hemi-
spheric lesions of adequate size to produce coma are readily seen
on CT.
Brainstem mass lesions produce coma by directly affecting
the reticular formation. Because the pathways for lateral eye
movements—the pontine gaze center, medial longitudinal fas-
ciculus, and oculomotor (third nerve) nucleus)—traverse the

Pupillary light Reflex eye Motor response

response movements to pain

Early
diencephalic

Late
diencephalic

Midbrain

Pons
of upper
medulla

FIGURE 105-1  The evolution of neurologic signs in coma from a hemispheric mass lesion as the brain becomes functionally impaired in a rostral-
caudal manner. The terms early diencephalic and late diencephalic refer to levels of dysfunction just above and just below the thalamus, respectively.
(From Aminoff MJ, Greenberg DA, Simon RP: Clinical neurology, Stamford, Conn., 1996, Appleton and Lange.)

965
 966 Section XVI  Neurologic Disease

ss
TABLE 105-1  MULTIFOCAL DISORDERS INDICATING TABLE 105-2  CAUSES OF COMA WITH NORMAL
METABOLIC COMA COMPUTED TOMOGRAPHY SCAN
Disseminated intravascular Thrombotic thrombocytopenic Meningeal disorders Endogenous toxins, deficiencies,
coagulopathy purpura Subarachnoid hemorrhage derangements
Sepsis Fat emboli (uncommon) Hypoxia and ischemia
Pancreatitis Hypertensive encephalopathy Bacterial meningitis Hypoglycemia
Vasculitis Diffuse micrometastases Encephalitis Hypercalcemia
Subdural empyema
Osmolar causes
reticular activating system, impairment of reflex eye movements Exogenous toxins Hyperglycemia
Sedative drugs and barbiturates Hyponatremia
is often the critical element of diagnosis of a brainstem lesion. A Anesthetics and Hypernatremia
comatose patient without impaired reflex lateral eye movements γ-hydroxybutyrate*
Organ system failure
does not have a mass lesion compromising brainstem structures Alcohols
Hepatic encephalopathy
Stimulants
in the posterior fossa. CT is not able to show some lesions in this Uremic encephalopathy
Phencyclidine†
Pulmonary insufficiency (carbon
region. Posterior fossa lesions may block the flow of cerebrospi- Cocaine and amphetamine‡
dioxide narcosis)
nal fluid from the lateral ventricles, resulting in the dangerous Psychotropic drugs
Cyclic antidepressants Seizures
situation of noncommunicating hydrocephalus. Phenothiazines Prolonged postictal state
Metabolic abnormalities are caused by deficiency states (e.g., Lithium Spike-wave stupor
thiamine, glucose), by derangements of metabolism (e.g., hypo- Anticonvulsants Hypothermia or hyperthermia
Opioids
natremia), or by the presence of exogenous toxins (e.g., drugs) or Clonidine§ Brainstem ischemia
endogenous toxins (e.g., organ system failure). Metabolic abnor- Penicillins Basilar artery stroke
malities result in diffuse dysfunction of the nervous system; Salicylates
Anticholinergics Pituitary apoplexy
therefore, with rare exceptions, they produce no localized signs Carbon monoxide, cyanide, and Conversion or malingering
such as hemiparesis or unilateral papillary dilation. The diagnosis methemoglobinemia
of metabolic encephalopathy means that the examiner has found *General anesthetic, similar to γ-aminobutyric acid; used as a recreational drug and body
no focal anatomic features on examination or neuroimaging building aid. It has a rapid onset and rapid recovery, often with myoclonic jerking and
confusion. It causes deep coma lasting 2 to 3 hours (Glasgow Coma Scale score = 3) with
studies to explain coma but that a specific metabolic cause has maintenance of vital signs.
†
not been established. Drugs have a predilection for affecting the Coma associated with cholinergic signs: lacrimation, salivation, bronchorrhea, and
hyperthermia.
reticular formation in the brainstem and for producing paralysis ‡
Coma after seizures or status epilepticus (i.e., a prolonged postictal state).
§
of reflex eye movement on examination. Multifocal structural dis- An antihypertensive agent that is active through the opiate receptor system; overdose
is frequent when used to treat narcotic withdrawal.
orders may simulate metabolic coma (Table 105-1).
In the late stages of status epilepticus, motor movements may
be subtle even though seizure activity is continuing throughout
the brain (nonconvulsive status epilepticus). Once seizures stop, TABLE 105-3  EMERGENCY MANAGEMENT
the so-called postictal state can also cause unexplained coma. 1. Ensure airway adequacy.
2. Support ventilation and circulation.
  DIAGNOSTIC APPROACH 3. Obtain blood for glucose, electrolytes, hepatic and renal function,
prothrombin and partial thromboplastin times, complete blood count,
The history and examination are essential in the diagnosis and and drug screen.
are not replaced by brain imaging (Table 105-2). A history of 4. Administer 100 mg of thiamine intravenously (IV).
a premonitory headache supports a diagnosis of meningitis, 5. Administer 25 g of dextrose IV (typically 50 mL of 50% dextrose) to
treat possible hypoglycemic coma.*
encephalitis, or intracerebral or subarachnoid hemorrhage. A pre- 6. Treat opiate overdose with naloxone (0.4-2 mg IV repeated every
ceding period of intoxication, confusion, or delirium points to a 2-3 minutes as needed).
diffuse process such as meningitis or endogenous or exogenous 7. The specific benzodiazepine antagonist flumazenil (0.2 mg IV every
1 min, x1-5 doses; max is 1 mg) should be given for reversal of
toxins. The sudden apoplectic onset of coma is particularly sug- benzodiazepine-induced coma or conscious sedation.†
gestive of ischemic or hemorrhagic stroke affecting the brainstem *The glucose level is poorly correlated with the level of consciousness in hypoglycemia;
or of subarachnoid hemorrhage or intracerebral hemorrhage with stupor, coma, and confusion are reported with blood glucose concentrations ranging from
intraventricular rupture. Lateralized symptoms of hemiparesis or 2 to 60 mg/dL.
†
Not recommended in coma of unknown origin because seizures may be precipitated
aphasia before coma occur in patients with hemispheric masses in patients with polydrug overdoses that include benzodiazepines with tricyclic
or infarctions. antidepressants or cocaine.

The physical examination is critical, quickly accomplished,

and diagnostic. The issues are three: (1) Does the patient have
meningitis? (2) Are signs of a mass lesion present? and (3) Is this
condition a diffuse syndrome of exogenous or endogenous meta-
bolic etiology? Emergency management should then be insti-
tuted accordingly (Table 105-3).
Identification of Meningitis
Signs of meningeal irritation are not invariably present and have
differing sensitivities depending on the cause: They are extremely
common with acute pyogenic meningitis and subarachnoid hem-
orrhage and less common with indolent, fungal meningitis. Nev-
ertheless, the presence of these signs on examination is the
central clue to the diagnosis. Missing these signs results in time-
consuming additional tests such as brain imaging and the poten-
tial loss of a narrow window of opportunity for directed therapy.
Passive neck flexion should be carried out (Fig. 105-2) in all
comatose patients unless a history of head trauma exists. When
the neck is passively flexed by attempting to bring the chin within
 Chapter 105  Disorders of Consciousness 967
FIGURE 105-2  Elicitation of Brudzinski’s sign of meningeal irritation,
as seen in infectious meningitis or subarachnoid hemorrhage. (From
Aminoff MJ, Greenberg DA, Simon RP: Clinical neurology, Stamford,
Conn., 1996, Appleton and Lange.)
a few fingerbreadths of the chest, patients with irritated meninges
reflexively flex one or both knees. This sign, called Brudzinski’s
reflex, is usually asymmetrical and not dramatic, but any evidence
of knee flexion during passive neck flexion mandates that the
cerebrospinal fluid be examined.
Is CT required before lumbar puncture in this setting? In
the absence of lateralized signs (e.g., hemiparesis) supporting
a superimposed mass lesion, a spinal puncture should be per-
formed immediately. Although rare cases of herniation after
lumbar puncture have been reported in children with bacterial
meningitis, the urgency of diagnosis and treatment at the point
of coma is paramount. The time required for CT may result
in a fatal therapeutic delay. An alternative approach involves
obtaining blood cultures and immediately initiating antibiotic
therapy with subsequent lumbar puncture. With this approach,
the cerebrospinal fluid cell count, glucose determination, and
protein content are unchanged, and Gram stain and culture
often remain positive despite a short period of antibiotic treat-
ment. Bacterial antigens in the cerebrospinal fluid or blood can
also be detected.
Separation of Structural from   decerebration.
Metabolic Causes of Coma
The goal of this differential diagnosis is achieved by neurologic
examination. Because the evaluation and potential treatments for
structural and metabolic coma are widely divergent and the
disease processes in both categories are often rapidly progressive,
initiating prompt medical and surgical evaluation may be life-
saving. Identification of a structural versus a metabolic cause is
accomplished by focusing on three features of the neurologic
examination: the motor response to a painful stimulus, pupillary
function, and reflex eye movements.
Motor Response
Asymmetrical or reflex function of the motor system provides the
clearest indication of a mass lesion. Elicitation of a motor response
requires that a painful stimulus be applied, to which the patient
will react. The patient’s arms should be placed in a semiflexed
posture, and a painful stimulus should be applied to the head or
trunk. Strong pressure on the supraorbital ridge or pinching of
the skin on the anterior chest or inner arm is the most useful
method; finger nail bed pressure is also used, but it makes the
interpretation of upper limb movement difficult.
The neurologic examination of a patient with an expanding
hemispheric mass lesion is shown in Figure 105-1. Hemispheric ss
masses in their early diencephalic stage (i.e., compromising the
brain above the thalamus), produce appropriate movement of
one upper extremity—that is, movement toward the painful
stimulus. The attenuated contralateral arm movement reflects a
hemiparesis. This lateralized motor response in a comatose
patient establishes the working diagnosis of a hemispheric mass.
As the mass expands to involve the thalamus (late diencephalic
stage), the response to pain becomes reflex arm flexion associated
with extension and internal rotation of the legs (decorticate postur-
ing); asymmetry of the response in the upper extremities is seen.
With further brain compromise at the midbrain level, the reflex
posturing in the arms changes such that both arms and legs
respond by extension (decerebrate posturing); at that level, the
asymmetry tends to be lost. At this point, the pupils become
midposition in size, and the light reflex is lost, first unilaterally
and then bilaterally. With further progression to the level of the
pons, the most frequent finding is no response to painful stimula-
tion, although spinal-mediated movements of leg flexion may
occur.
The classic postures illustrated in Figure 105-1, and particu-
larly their asymmetry, strongly support the presence of a mass
lesion. However, these motor movements, especially early in
coma, are most frequently seen as fragments of the fully devel-
oped, asymmetrical flexion or extension of the arms (illustrated
as decorticate and decerebrate postures in Figure 105-1). A small
amount of asymmetrical flexion or extension of the arms in
response to a painful stimulus carries the same implications as
the full-blown postures of decortication or decerebration.
Metabolic lesions do not compromise the brain in a progres-
sive, level-by-level manner as do hemispheric masses, and they
rarely produce the asymmetrical motor signs typical of masses.
Reflex posturing may be seen, but it lacks the asymmetry of
decortication seen with a hemispheric mass, and it is not associ-
ated with the loss of pupillary reactivity at the stage of
Pupillary Reactivity
In metabolic coma, one feature is central to the examination:
Pupillary reactivity is present. This reactivity is seen both early in
metabolic coma, when an appropriate motor response to pain
may be retained, and late in coma, when no motor responses can
be elicited. The pupillary reaction in metabolic coma is lost only
when coma is so deep that the patient requires ventilatory and
blood pressure support.
Reflex Eye Movements
The presence of inducible lateral eye movements reflects the
integrity of the pons and midbrain. These reflex eye movements
(see Fig. 105-1 ) are brought about with the use of passive head
rotation to stimulate the semicircular canal input to the vestibular
system (so-called doll’s eyes maneuver) or by inhibiting the func-
tion of one semicircular canal by infusing ice water against the
tympanic membrane (caloric testing).
In metabolic coma, reflex eye movements may be lost or
retained. Lack of inducible eye movements with the doll’s eyes
maneuver, in the setting of preserved pupillary reactivity, is
 968 Section XVI  Neurologic Disease

virtually diagnostic of drug toxicity. With metabolic coma of there has been extensive work using additional means besides the
ss non–drug-induced origin, such as organ system failure, electro- physical examination to better predict prognosis. Pupillary,
lyte disorders, or osmolar disorders, reflex eye movements are corneal, and motor responses are the best clinical indicators of
preserved. prognosis that can be assessed at bedside. Such responses give
Brainstem mass lesions are most commonly caused by hemor- some indication of the functionality of the brainstem, which is
rhage or infarction. Reflex lateral eye movements, the pathways the most resilient portion of central nervous system. Any signs of
for which traverse the pons and midbrain, are particularly damage to the brainstem is strong evidence of cortical injury
affected, and the reflex postures of decortication and decerebra- (Fig 105-3).
tion typical of brainstem injury are common. Lesions restricted Current guidelines endorse the utility of EEG for predicting
to the midbrain (e.g., embolization from the heart to the top of poor outcome in comatose survivors of cardiac arrest not treated
the basilar artery) cause sluggish pupillary reflexes or their with hypothermia. The early onset of generalized myoclonic
absence, with or without impaired medial eye movements; both status is an ominous sign. Serum biomarkers have been used in
are controlled by the third cranial nerve. With lesions restricted evaluating prognosis among comatose patients after cardiac
to the pons (e.g., intrapontine hypertensive hemorrhage), pupils arrest. Neuron-specific enolase (NSE) is the most promising bio-
are reactive but very small (pinpoint or pontine pupils), reflect- marker and has been extensively studied. NSE levels of >30 ng/
ing focal impairment of sympathetic innervations; pinpoint mL or higher have been found to predict persistent coma. Simi-
pupils are rare. Ocular bobbing (spontaneous symmetrical or larly, somatosensory evoked potentials (SSEPs), as electrophysi-
asymmetrical rhythmic vertical ocular oscillations) is most often ologic markers, are most helpful for predicting which patients
a manifestation of a pontine lesion. will remain in a persistent coma. In particular, the bilateral
Seizures occurring in a patient with acute brain injury (such as absence of the N20 cortical response (a negative peak at 20 ms)
that resulting from encephalitis, hypertensive encephalopathy, to median nerve stimulation after 24 hours predicts a grave
hyponatremia, hypernatremia, hypoglycemia, or hyperglycemia) outcome. Despite tremendous potential, the role of neuroimag-
or chronic brain injury (such as dementia or mental retardation) ing as a prognostic tool after hypoxic-ischemic injury from
often result in prolonged postictal coma. The examination shows cardiac arrest has yet to be clearly defined. Severe reductions in
reactive pupils and inducible eye movements (in the absence of the apparent diffusion coefficient (ADC), as well as bilateral
overtreatment with anticonvulsants), and often up-going toes or
focal signs are often observed (Todd’s paresis).
Nonconvulsive status epilepticus should be considered as a Coma
diagnosis even if there are no obvious seizure movements. Non-
convulsive seizures can cause coma and also can complicate other Exclude major
confounders
etiologies of coma, including infectious and metabolic disorders.
Nonconvulsive seizures should be suspected in patients with (1)
No brain stem reflexes at any time Yes Brain death
a seemingly prolonged “postictal state’’ after generalized convul- (pupil, cornea, oculocephalic, cough) testing
sive seizures or prolonged alteration of alertness after an opera-
Or
tive procedure or neurologic insult; (2) acute onset of impaired
consciousness or fluctuating mentation interspersed with epi- Day 1 Yes Poor
FPR
sodes of normal awareness; (3) altered mental status or con- Myoclonus 0%
outcome
Status epilepticus (0–8.8)
sciousness associated with facial myoclonus or nystagmoid eye
Or
movements; or (4) episodic blank staring, aphasia, automatisms Yes FPR
Day 1–3 Poor
e.g., lip-smacking, fumbling with fingers), or acute-onset aphasia SSEP absent N20 responses outcome
0.7%
without an acute structural lesion. The diagnosis is made by elec- (0–3.7)
Or
troencephalography (EEG) (see Chapter 118). EEG provides FPR
Day 1–3 Yes Poor
information about brain electrical activity even when brain func- 0%
Serum NSE 33 µg/L outcome
tion is depressed and cannot be evaluated otherwise, as in coma- (0–3)
Or
tose patients. EEG is essential to detect electrical seizures and
Day 3 Yes FPR
document their duration as well as the response to therapy and Poor
Absent pupil or corneal reflexes; 0%
outcome
to improve coma prognostication. extensor or absent motor response (0–3)
Current evidence suggests that the presence of nonconvulsive
No
seizures or periodic discharges, delay to diagnosis, and duration
of nonconvulsive status in patients with or without acute brain Indeterminate outcome
injury are independent predictors of worse outcome. FIGURE 105-3  Decision algorithm for use in prognostication of
comatose survivors after cardiopulmonary resuscitation (CPR). The
  PROGNOSIS IN COMA numbers in parentheses show the exact 95% confidence intervals. FPR,
False-positive rate; N20, a negative peak at 20 ms on SSEP; NSE, neuron-
Therapeutic hypothermia has been demonstrated to improve specific enolase; SSEP, somatosensory evoked potential. (Data from
neurologic outcomes in patients who have return of spontaneous Wijdicks EFM, Hijdra A, Young GB, et al: Practice parameter: prediction
circulation but remain comatose after cardiac arrest. Historically, of outcome in comatose survivors after CPR [an evidence-based
prognostication after cardiac arrest was solely based on neuro- review]: report of the Quality Standards Subcommittee of the American
Academy of Neurology, Neurology 67:203–210, 2006.)
logic examination. Although this still holds true for the most part,
 Chapter 105  Disorders of Consciousness 969
hippocampal hyperintensities on magnetic resonance imaging
(MRI), suggests severe global damage and extensive ischemic
injury and is highly indicative of poor outcome.
The use of therapeutic hypothermia quite likely influences the
clinical examination and ancillary test findings. There is a scarcity
of data about the utility of physical examination, EEG, and
evoked potentials in predicting outcomes among cardiac arrest
patients with induced hypothermia. It is well accepted that one
should consider observation for longer than 72 hours before
prognosticating outcome in patients treated with hypothermia.
  COMA-LIKE STATES
Patients with locked-in syndrome have a lesion (usually a hemor-
rhage or an infarct) that transects the brainstem at a point below
the reticular formation (thereby sparing consciousness) but
above the ventilatory nuclei of the medulla (thereby maintaining
cardiopulmonary function) (Table 105-4). Such patients are
awake, with eye opening and sleep-wake cycles, but the descend-
ing pathways through the brainstem that are necessary for voli-
tional vocalization or limb movement have been transected.
Voluntary eye movement, especially vertically, is preserved, and
patients can open and close their eyes or produce appropriate
numbers of blinking movements in answer to questions. The
EEG is usually normal, reflecting normal cortical function.
Psychogenic unresponsiveness is a diagnosis of exclusion. The
neurologic examination shows reactive pupils and no reflex pos-
turing in response to pain. Eye movements during the doll’s eyes
maneuver show volitional override rather than the smooth, unin-
hibited reflex lateral eye movements of coma. Ice water caloric
testing either arouses the patient because of the discomfort pro-
duced or induces cortically mediated nystagmus rather than the
tonic deviation typical of coma. The slow, conjugate roving eye
movements of metabolic coma cannot be imitated and therefore
rule out psychogenic unresponsiveness. Likewise, the slow, often
asymmetrical, and incomplete eye closure seen after passive eye
opening in a comatose patient cannot be feigned and also rules
out psychogenic coma. In contrast, conscious patients usually
exhibit some voluntary muscle tone in the eyelids during passive
eye opening. The EEG in psychogenic unresponsiveness is that
of normal wakefulness, with reactive posterior rhythms on eye
opening and eye closing. In patients with catatonic stupor, loraz-
epam administration may produce awakening.
TABLE 105-4  LOCKED-IN SYNDROME
Clinical features Recovery possible
Eye opening Onset over 1-12 wk (vascular)* or
Reactive pupils Onset over 4-6 mo (nonvascular)*
Volitional vertical eye movements
Prognosis favorable
in response to command
Normal CT scan*
Muteness
Quadriparesis
Early recovery of lateral eye
movements*
Sleep-wake cycles
Causes
Pontine vascular lesions
(common)
Head injury, brainstem tumor,
pontine myelinolysis (rare)
CT, Computed tomography.
*Implications for care.
The vegetative state (VS), now also called unresponsive wakeful-
ness syndrome, is exhibited by patients with eye opening and ss
sleep-wake cycles. The reticular activating system of the brain-
stem is intact to produce wakefulness, but the connections to the
cortical mantle are interrupted, precluding awareness.
A VS is termed persistent after 3 months if the brain injury was
medical or after 12 months if the brain injury was traumatic. The
determination as to when persistent equals permanent cannot be
stated absolutely. Prediction early in VS of which patients will
remain persistently vegetative is particularly difficult in cases of
trauma. Lesions of the corpus callosum and dorsolateral brain-
stem seen on MRI 6 to 8 weeks after trauma correlated with
persistence of VS at 1 year. A combined analysis of morphologic
MRI studies and post-traumatic brainstem spectroscopy can be
a predictor of persistent vegetative states (PVS) and minimally
conscious states (MVS). In rare cases, patients show late improve-
ment, but they do not return to normal. Bilateral absence of
SSEPs in the first week predicts death or VS.
Patients in a PVS open their eyes diurnally and in response to
loud sounds; blinking occurs with bright lights. Pupils react, and
eye movements occur both spontaneously and with the doll’s
eyes maneuver. Yawning, chewing, swallowing, and, uncom-
monly, guttural vocalizations and lacrimation may be preserved.
Spontaneous roving eye movements (very slow, with constant
velocity) are particularly characteristic and distressing to the
patient’s visitors because the patient appears to be looking about
the room. The brainstem origin of the eye movements is docu-
mented by their being readily redirected by the oculocephalic
(doll’s eyes) reflex. The limbs may move, but motor responses are
only primitive; pain usually produces decorticate or decerebrate
postures or fragments of these movements.
MCS is a newly described entity in which patients do not meet
criteria for PVS. Both patients in PVS and those in MCS demon-
strate severe alteration in consciousness. In contrast to PVS, sub-
jects with MCS exhibit evidence of limited interaction with the
environment by visually tracking, following simple commands,
answering yes or no (not necessarily reliably), or having intelli-
gible verbalization or restricted purposeful behavior. It is esti-
mated that the rate of misdiagnosis between the VS and MCS is
about 40%.
Novel applications of functional neuroimaging in patients
with disorders of consciousness may aid in differential diagnosis,
prognostic assessment, and identification of pathophysiologic
mechanisms. In one study, authors prospectively evaluated corti-
cal activation in response to a familiar voice in seven patients in
VS and four subjects in MCS. All four of the MCS patients and
only two of the VS patients showed activation that extended
beyond the primary auditory cortex to hierarchically higher-
order associative temporal areas. Over the course of 3 months,
these two VS patients improved clinically to MCS.
Brain death characterizes the irreversible cessation of brain func-
tion. Therefore, death of the organism can be determined based
on death of the brain. Although local laws may dictate some
details, the standard definition permits a diagnosis of brain death
based on documentation of irreversible cessation of all brain
function, including function of the brainstem (Table 105-5).
Documentation of irreversibility requires that the cause of the
coma is known, that the cause is adequate to explain the clinical
 970 Section XVI  Neurologic Disease

findings of brain death, and that exclusionary criteria are absent

ss
TABLE 105-5  CRITERIA FOR CESSATION OF BRAIN (Table 105-6). Confirmatory tests are sometimes used but are
FUNCTION* not required for diagnosis (Table 105-7). Brain death results in
ANATOMIC REGION TESTED CONFIRMATORY SIGN asystole, usually within days (mean, 4 days), even if ventilatory
Hemispheres Unresponsive and unreceptive to support is continued. Recovery after appropriate documentation
sensory stimuli including pain† of brain death has never been reported. Removal of the ventilator
Midbrain Unreactive pupils‡
Pons Absent reflex eye movements§ results in terminal rhythms (most often complete heart block
Medulla Apnea‖ without ventricular response), junctional rhythms, or ventricular
CO2, Carbon dioxide; Pco2, partial pressure of carbon dioxide. tachycardia. Purely spinal motor movements may occur in the
*Sequential testing is necessary for a clinical diagnosis of brain death; it should be moments of terminal apnea (or during apnea testing in the
done at least every 6 hours in all cases and at least every 24 hours in the setting of
anoxic-ischemic brain injury. absence of passive administration of oxygen); these may include
†
The patient does not rouse, groan, grimace, or withdraw limbs. Purely spinal reflexes arching of the back, neck turning, stiffening of the legs, and upper
(deep tendon reflexes, plantar flexion reflex, plantar withdrawal, and tonic neck reflexes)
may be maintained. extremity flexion.
‡
Most easily assessed by the bright light of an ophthalmoscope viewed through its
magnifying lens when focused on the iris. Unreactive pupils may be either midposition, as SUGGESTED READINGS
they will be in death, or dilated, as they often are in the setting of a dopamine infusion.
§
No eye movement toward the side of irrigation of the tympanic membrane with Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-
50 mL of ice water. The oculocephalic response (doll’s eyes maneuver) is always absent in
the setting of absent oculovestibular testing. of-hospital cardiac arrest with induced hypothermia, N Engl J Med 346:557–
‖
No ventilatory movements in the setting of maximum CO2 stimulation (≥60 mm 563, 2002.
Hg); with apnea, Pco2 passively rises 2 to 3 mm Hg/min). Disconnect the ventilator from Bernat JL: Chronic disorders of consciousness, Lancet 367:1181–1192, 2006.
the endotracheal tube and insert a cannula with 6 L of oxygen per minute. Fins JJ, Master MG, Gerber LM, et al: The minimally conscious state: a diagnosis
in search of an epidemiology, Arch Neurol 64:1400–1405, 2007.
Greer DM, Scripko PD, Wu O, et al: Hippocampal magnetic resonance imaging
abnormalities in cardiac arrest are associated with poor outcome, J Stroke
TABLE 105-6  EXCLUSIONARY CRITERIA FOR Cerebrovasc Dis 22:899–905, 2013.
BRAIN DEATH Laureys S, Celesia GG, Cohadon F, et al: Unresponsive wakefulness syndrome:
Seizures Hypothermia (<32.2° C) a new name for the vegetative state or apallic syndrome, BMC Med 8:68, 2010.
Decorticate or decerebrate posturing Neuromuscular blockade Laureys S, Schiff ND: Coma and consciousness: paradigms (re)framed by
Sedative drugs Shock neuroimaging, Neuroimage 61(2):478–491, 2012.
Meaney PA, Bobrow BJ, Mancini ME: Cardiopulmonary resuscitation quality:
improving cardiac resuscitation outcomes both inside and outside the
hospital–a consensus statement From the American Heart Association,
Circulation 124:417–435, 2013.
TABLE 105-7  CONFIRMATORY TESTS FOR Peberdy MA, Callaway CW, Neumar RW, et al: Cardiac arrest care: 2010
American Heart Association guidelines for cardiopulmonary resuscitation and
BRAIN DEATH
emergency cardiovascular care, Circulation 122(18 Suppl 3):S768–S786,
EEG isoelectricity Deep coma from sedative drugs or hypothermia 2010. [Errata in Circulation 123:e237, 2011, and Circulation 124:e403,
(temperature <20° C) can produce EEG
2011.].
flattening.
Nuclear medicine The most common radionuclide modality for Plum F, Posner JB: The diagnosis of stupor and coma. Contemporary Neurology
brain imaging uses the tracer HMPAO. Absence Series, vol 71, ed 4, New York, 2007, Oxford University Press.
of isotope uptake (“hollow skull phenomenon”) Rodriguez RA, Nair S, Bussiere M, et al: Long-lasting functional disabilities in
indicates no brain perfusion and supports the patients who recover from coma after cardiac operations, Ann Thorac Surg
diagnosis of brain death. 95:884–891, 2013.
Transcranial Doppler Findings of small systolic peaks without diastolic Wijdicks EFM: The diagnosis of brain death, N Engl J Med 344:1215–1221,
flow or a reverberating flow pattern suggest high 2001.
vascular resistance and support the diagnosis of Wijdicks EFM, Hijdra A, Young GB, et al: Practice parameter: prediction of
brain death. No cerebral blood flow is the most
outcome in comatose survivors after cardiopulmonary resuscitation (an
definitive confirmatory test.
CT angiography Nonopacification of the cortical segments of evidence-based review), Neurology 67:203–210, 2006.
MCAs and ICVs appears to be highly sensitive Wu O, Soresnen AG, Benner T, et al: Comatose patients with cardiac arrest:
for confirming brain death, with a specificity of predicting clinical outcome with diffusion-weighted MR imaging, Radiology
100%. Lack of opacification of the ICVs is the 252:173–181, 2009.
most sensitive sign. Young GB: Neurologic prognosis after cardiac arrest, N Engl J Med 361:605–611,
CT, Computed tomographic; EEG, electroencephalogram; HMPAO, 99mTc-labeled 2009.
hexamethylpropyleneamineoxime; ICV, internal cerebral vein; MCA, middle cerebral Zandbergen EGJ, Hijdra A, Koelman JH, et al: Prediction of poor outcome
artery. within the first 3 days of postanoxic coma, Neurology 66:62–68, 2006.
 106 
Disorders of Sleep ss

Selim R. Benbadis

latency (i.e., latency to stage N1) is measured and sleep stages are
  INTRODUCTION determined. The MSLT is better standardized than the MWT.
Sleep disorders can be classified in various ways. The interna- Normal sleep latency is greater than 12 minutes; latency of less
tional classification uses an axial system to define three catego- than 5 minutes is evidence for severe sleepiness.
ries: dyssomnias, parasomnias, and sleep disorders associated
with mental or neurologic diseases. From a practical point of
  SLEEP-DISORDERED BREATHING
view, sleep disorders are better classified by their clinical presen-
tation, which is the approach taken here. This chapter focuses on Definition and Epidemiology
primary sleep disorders rather than sleep disturbances that result Sleep-disordered breathing encompasses a spectrum of condi-
from self-evident medical or psychiatric diseases. tions typified by the most common: obstructive sleep apnea
(OSA). The spectrum of obstructive disease extends from
primary, isolated, or trivial snoring to upper airway resistance
  DISORDERS OF EXCESSIVE DAYTIME SLEEPINESS
syndrome (i.e., compensated OSA) to OSA of mild, moderate,
History or severe degree. The degree is determined by PSG.
A careful sleep history is the starting point. It often uncovers OSA has a prevalence of about 2% to 4%. It affects more men
likely causes of excessive daytime sleepiness (EDS), such as med- than women, and the incidence increases with age. Central sleep
ications, systemic illnesses, sleep deprivation, or circadian rhythm apnea is much less well defined. It has the same definitions but
disturbances. Most of the causes of EDS (e.g., insufficient sleep has no evidence of obstruction.
time, lifestyle, circadian rhythm disorders) do not require a spe-
cialized sleep evaluation. The history can elicit symptoms that Pathophysiology
suggest specific causes such as sleep-disordered breathing (i.e., The pathophysiology of OSA is recurrent upper airway closure
sleep apnea) or narcolepsy. or collapse with resulting oxygen desaturation leading to arous-
To subjectively quantify EDS, various scales have been devel- als. Obstruction typically occurs at the level of the nasopharynx
oped. The most useful in clinical practice is the Epworth Sleepi-
ness Scale (ESS), which is an extension of the history. The ESS
consists of a brief questionnaire on the likelihood of dozing off
in eight situations. This yields a score between 0 and 24 (Table TABLE 106-1  EPWORTH SLEEPINESS SCALE
106-1). Although there is no strict cutoff, scores above 10 or 11 How likely are you to doze off or fall asleep in the following situations in
contrast to just feeling tired? The situations refer to your usual way of life.
indicate sufficiently severe EDS to warrant investigation. In addi- Even if you have not done some of these things recently, try to work out
tion to being disabling for the individual, EDS is a public health how they would have affected you. Use the following scale to choose the
concern because it impairs performance and may cause motor most appropriate number for each situation.
0 = would never doze
vehicle and industrial accidents in a way comparable to alcohol 1 = slight chance of dozing
intoxication. 2 = moderate chance of dozing
3 = high chance of dozing
Examination What is your chance of dozing in the following situations?
Sitting and reading __________________
The examination of patients with EDS should include a general Watching TV __________________
neurologic examination. If sleep-disordered breathing is sus- Sitting and inactive in a public place __________________
(theater or meeting)
pected, the upper airway should also be examined. As a passenger in a car for an hour __________________
without a break
Sleep Studies Lying down to rest in the afternoon __________________
when possible
Polysomnography (PSG) is an all-night sleep study that measures Sitting and talking to someone __________________
multiple parameters such as sleep staging, respiration, leg move- Sitting quietly after lunch (without __________________
ments, and electrocardiographic patterns. Portable or home alcohol)
In a car while stopped for a few __________________
adaptations of formal laboratory PSG are increasingly used. minutes in traffic
The multiple sleep latency test (MSLT) and the maintenance Total __________________
of wakefulness test (MWT) are used to measure and quantify Modified from Johns MW: A new method for measuring daytime sleepiness: the Epworth
EDS. They consist of a series of daytime naps during which sleep Sleepiness Scale, Sleep 14:540–545, 1991.

971
 972 Section XVI  Neurologic Disease
or oropharynx. The sleep fragmentation caused by arousal is
responsible for sleep deprivation and EDS.
ss
Clinical Manifestation
OSA typically manifests with a combination of EDS and snoring
in a patient who is overweight. Other symptoms include apneic
pauses or “choking” witnessed by the bed partner, and less spe-
cific symptoms such as morning headaches, depression, impaired
cognition, and sexual dysfunction. On examination, the body
mass index (>10 kg/m2) and neck circumference (>17 inches for
men or 16 inches for women) predict OSA. If the patient is not
obese, abnormalities of the craniofacial anatomy or upper airways
(e.g., retromicrognathia, macroglossia, tonsillar hypertrophy)
should be sought.
Diagnosis and Differential Diagnosis
Other causes of EDS should be considered, but in a typical case
of OSA, the diagnosis is usually obvious and easily confirmed by
overnight PSG. Apneas are defined as cessation (90% reduction)
of airflow, whereas hypopneas are 30% to 90% reductions of
airflow; both last 10 seconds or longer. These events are called
obstructive if they occur with respiratory effort and central if they
occur with no respiratory effort. The apnea-hypopnea index
(AHI) is the total number of apneas plus hypopneas per hour,
and an AHI score greater than 5 is considered abnormal. An AHI
score of 5 to 10 is mild, 10 to 15 is moderate, and more than 15
is severe.
Respiratory effort–related arousals are episodes of decreased
airflow with increased effort and crescendo snoring that result in
arousals, and they define upper airways resistance syndrome.
They represent a compensated degree of OSA. The PSG quanti-
fies the severity in terms of event frequency (i.e., AHI), oxygen
desaturation, sleep disturbances (i.e., arousals and fragmenta-
tion), and arrhythmias. With some limitations, diagnostic PSG
can be performed at home with portable systems if OSA is the
likely cause and there are no signs of underlying neurologic
disease.
Treatment and Prognosis
Depending on severity, treatment modalities include weight
loss, positional measures to prevent sleeping supine, oral appli-
ances for mild disease, and positive airway pressure (PAP)
modalities and surgery for moderate to severe disease. For
patients with moderate to severe OSA, the initial treatment is
PAP; its main limitation is patient compliance. Maximizing
the patient’s comfort with nasal pillows, humidification, and
attention to mask fit is important. PAP requires a titration
study to determine the type continuous positive airway pres-
sure (CPAP) (e.g., auto-CPAP, bilevel PAP) and pressure set-
tings appropriate for each patient. When PAP modalities do
not work, stimulants and wake-promoting agents can be used
as adjuncts to help EDS.
Central sleep apnea is often associated with other cardiopul-
monary abnormalities such as heart failure. It is also treated with
CPAP initially, but it often requires specialized pulmonary care.
It is important to treat OSA because it has many complica-
tions. They include hypertension, coronary artery disease, stroke,
diabetes mellitus, depression, and cognitive impairment.
  NARCOLEPSY
Definition and Epidemiology
Narcolepsy affects at least 2 in 1000 individuals. Narcolepsy
includes a tetrad of excessive sleepiness, cataplexy, sleep paralysis,
and hypnagogic hallucinations. The full tetrad occurs in approxi-
mately 1 of 5000 people.
Pathophysiology
Narcolepsy is a disorder of rapid eye movement (REM) sleep
regulation caused by disordered hypocretin neurotransmission,
likely resulting from an autoimmune loss of hypocretin neurons
in the lateral hypothalamus. It has a major genetic component, as
evidenced by strong human leukocyte antigen (HLA) associa-
tions such as HLA-DQB1*0602 in black and white populations
and HLA-DR2 in Japanese populations. The daytime symptoms
of narcolepsy are accompanied by the intrusion of REM sleep
into wakefulness.
Clinical Presentation
The mean age of onset of narcolepsy is in the mid-20s, but two
peaks occur around 15 and 35 years of age. EDS is severe and
almost constant, and the urge to sleep can be sudden and irresist-
ible (i.e., sleep attacks).
Of the three accessory symptoms, cataplexy is the most spe-
cific and helpful for diagnosis. Cataplexy without narcolepsy is
exceptional. Narcolepsy without cataplexy is more difficult to
identify, and overlaps occur with idiopathic hypersomnia. Cata-
plexy is characterized by brief (seconds to a few minutes) loss of
muscle tone (i.e., intrusion of REM atonia) triggered by emo-
tions, most commonly laughter but also elation, surprise, and
fear. If severe, the patient may fall. With milder attacks, a head
nod or slurred speech can occur.
Hypnagogic hallucinations that are vivid and dreamlike and
that occur at sleep onset are more specific for narcolepsy than
hypnopompic (i.e., sleep offset) hallucinations. Sleep paralysis is
the often frightening experience of inability to move while aware,
usually on awakening. In addition to the tetrad, patients fre-
quently have episodes of automatic behaviors with no recall,
which can resemble complex partial seizures. Nocturnal sleep is
often fragmented by frequent arousals, vivid dreams, or leg
movements.
Diagnosis and Differential Diagnosis
Other causes of EDS, especially the more common OSA, should
be sought. A PSG should be obtained the night before the MSLT.
The PSG can exclude OSA as a cause of EDS, and an MSLT with
a sleep latency of less than 8 minutes and two sleep-onset epi-
sodes of REM confirms the diagnosis. Alternatively, a CSF hypo-
cretin level less than 110 pg/mL can confirm the diagnosis. HLA
typing is more useful to exclude narcolepsy than to diagnose it
because it is sensitive but not specific.
Treatment and Prognosis
Stimulants (e.g., amphetamines, methylphenidate) are still used
for the treatment of EDS, but newer wake-promoting agents are
more widely used. They include modafinil (100 to 400 mg twice
daily) and the longer-acting, once-daily armodafinil (150 to

250 mg per day). Sodium oxybate (3 to 9 g each day) is also used
to treat EDS, cataplexy, and disrupted nocturnal sleep. It is potent
but short acting; it is typically administered at bedtime and again
a few hours later. Sodium oxybate and modafinil may be syner-
gistic in treating EDS. For cataplexy, antidepressants can be used
(Table 106-2).
Prognosis is usually good with adequate treatment. However,
narcolepsy, when severe, can remain disabling and require accom-
modations such as scheduled naps.
  IDIOPATHIC HYPERSOMNIA
Definition and Epidemiology
Idiopathic hypersomnia is a poorly characterized syndrome with
no known pathologic substrate. It is therefore a diagnosis of elim-
ination. It is much less common than narcolepsy.
Clinical Manifestation
Patients have lifelong EDS with non-REM (long and unrefresh-
ing) naps, and none of the REM-type accessory symptoms of
narcolepsy. By definition, there must be no other cause of EDS.
Patients also wake up unrefreshed (i.e., sleep inertia) from noc-
turnal sleep and long daytime naps, and they can have prolonged
states of fogginess (i.e., sleep drunkenness).
Diagnosis and Differential Diagnosis
Other causes of EDS must be excluded, and the PSG should be
normal with no sleep-disordered breathing and no sleep frag-
mentation such as seen in narcolepsy. MSLT confirm sleep
latency of less than 8 minutes but without sleep-onset REM.
Treatment and Prognosis
Treatment includes the same stimulants and wake-promoting
agents as used for narcolepsy. The response is typically less satis-
factory. The response to treatment is varies, and accommodation
in the workplace is usually necessary.
  KLEINE-LEVIN SYNDROME
Kleine-Levin syndrome is a rare, recurrent or cyclic hypersomnia
with a prevalence of 1 case per 1 million people. Its cause is
unknown. Its onset is usually in the second decade, with episodes
of hypersomnia lasting days to weeks and with associated hyper-
phagia, hypersexuality, confusion, and hallucinations. Episodes
tend to recur every few months and at least once each year. Other
symptomatic causes of EDS must be excluded.
Stimulants and wake-promoting agents and lithium are used
for treatment. With time, episodes tend to become less severe,
less prolonged, and less frequent.
TABLE 106-2  AGENTS PROMOTING WAKEFULNESS
DRUG DOSE RANGE (MG)
Amphetamine (Dexedrine, Desoxyn, Adderall, 5-60
Adderall XR)
Methylphenidate (Ritalin, Metadate, Methylin, 10-60
Concerta)
Modafinil (Provigil) 200-400
Armodafinil 150-250
Chapter 106  Disorders of Sleep 973
  PERIODIC LIMB MOVEMENT DISORDER
Definition and Epidemiology
ss
Periodic limb movement disorder (PLMD) is characterized by
repetitive movements (usually of the legs) that occur during
sleep. This can be purely a PSG finding, but it is often associated
with restless legs syndrome (RLS).
Pathophysiology
PLMD is caused by decreased dopamine neurotransmission.
Clinical Manifestations
Leg movements may be reported by the bed partner, and the
patient may report EDS, insomnia, or symptoms of RLS (i.e.,
urge to move legs or walk due to unpleasant “creepy-crawly” sen-
sations at rest). Most patients with RLS have PLMD, but the
reverse is not true.
Diagnosis and Differential Diagnosis
RLS is diagnosed by the history. PLMD is diagnosed by PSG.
Once established, the search for a cause of secondary PLMD
should investigate the same causes as RLS: polyneuropathy,
spinal cord disease, pregnancy, iron-deficiency anemia (i.e., fer-
ritin levels), B12 deficiency, uremia, medications, primary sleep
disorders, narcolepsy, or OSA.
Treatment and Prognosis
Similar to RLS, pramipexole or ropinirole is used at lower doses
than for treating Parkinson’s disease (Table 106-3). Prognosis is
usually good with treatment.
For a deeper discussion of these topics, please see Chapter
410, “Other Movement Disorders,” in Goldman-Cecil
Medicine, 25th Edition.
  INSOMNIA
Definition and Epidemiology
Insomnia is defined as difficulty initiating or maintaining sleep.
Severe, chronic insomnia can have major health consequences,
including depression, anxiety, drug or alcohol use, and overall
higher mortality rates.
Insomnia is the most common sleep complaint in the general
population. Up to one third of the population report at least
occasional difficulties sleeping. Chronic insomnia (>1 month)
affects about 10% of the population.
Pathophysiology
Insomnia can be caused by pain, medical conditions (e.g., chronic
obstructive pulmonary disease), psychiatric conditions, and
TABLE 106-3  TREATMENTS FOR RESTLESS LEGS
SYNDROME
DRUG DOSE RANGE (MG)
Levodopa or carbidopa (Sinemet) 50-200
Ropinirole (Requip) 0.25-4.0
Pramipexole (Mirapex) 0.125-0.5
 974 Section XVI  Neurologic Disease
medications. Acute or short-term insomnia is caused by identifi-
ss able factors and can become a chronic, persistent problem.
Chronic insomnia results from predisposing (genetic), precipi-
tating (environmental), and perpetuating (behaviors) factors.
With the exception of rare conditions such as the prion disease,
fatal familial insomnia, insomnia alone is almost never the
symptom of a neurologic disease.
Clinical Manifestations
Insomnia may manifest as the inability to fall asleep (i.e., onset
insomnia) or to stay asleep (i.e., maintenance insomnia). In addi-
tion to nighttime symptoms, the diagnosis demands daytime
symptoms considered to be the consequence of insomnia (e.g.,
fatigue, EDS, poor concentration, altered mood, headache).
Adjustment insomnia is an acute reaction to some type of
stress. When the trigger combines with a propensity for poor or
fragile sleep, the condition can become chronic (>1 month) and
lead to maladaptive behaviors and a conditioned arousal associ-
ated with sleep. This is known as psychophysiologic insomnia, and
it is by far the most common insomnia syndrome. A vicious cycle
is created by poor sleep habits that worsen the insomnia. Because
of its chronicity, it is typically associated with poor sleep habits,
multiple treatment trials, and anxiety about sleep. If there was no
trigger at onset, there may be a lifelong history of poor sleep (i.e.,
idiopathic insomnia) with the same end result of psychophysio-
logic insomnia.
Paradoxical insomnia and sleep-state misperception are terms
applied to patients who claim to not sleep. However, when
studied objectively, they have normal sleep amounts and
architecture.
Diagnosis and Differential Diagnosis
The diagnosis is based on the history, which should include a
sleep diary. Identifiable medical, psychiatric, or drug-related
disease and other sleep disorders (e.g., OSA) require exclusion.
Sleep studies (PSG and MSLT) are occasionally helpful.
Treatment and Prognosis
Nondrug treatments include common sense sleep hygiene rec-
ommendations (e.g., avoiding caffeine, exercising late in the day)
(Table 106-4) and behavior modifications to avoid the condi-
tioned arousal responses associated with sleep (e.g., using the
TABLE 106-4  SLEEP HYGIENE
1. Maintain a regular schedule each day.
2. Wake at the same time each morning.
3. Exposure to natural light entrains the circadian rhythm.
4. Exercise in the morning or early afternoon; avoid vigorous exercise in
the evening.
5. Avoid napping during the day, especially after 3 pm.
6. Avoid stimulants such as caffeine and nicotine and avoid alcohol close
to bedtime.
7. Avoid large meals close to bedtime.
8. Maintain regular and relaxing routines at bedtime.
9. Maintain a comfortable sleep environment.
10. Reserve the bed for sleep; avoid other activities (e.g., TV, radio,
reading).
11. Sleep only when sleepy.
12. Try to resolve worries (or list for future thought) before sleeping.
13. Get out of bed if not sleeping in 20 minutes.
bedroom only for sleep and sex). Other strategies include cogni-
tive behavior therapy specifically for insomnia (CBT-I), relax-
ation techniques, biofeedback, and behavioral changes such as
sleep restriction therapy and stimulus control therapy.
The principles of the pharmacologic treatment of insomnia
include using the lowest effective dose, intermittent (not daily)
use, using the appropriate (i.e., short or intermediate half-life)
drug based on the type of insomnia (i.e., onset or maintenance),
and limiting the duration of treatment. Treatment should be
tapered to avoid rebound. Medications should be used only in
combination with nondrug (i.e., behavioral) treatments. Behav-
ioral treatment has been effective.
Over-the-counter sleep aids (usually antihistamines) are typi-
cally safe, but use is limited by anticholinergic and hangover
effects. Melatonin may promote sleep and be used for circadian
rhythm disorders, including jet lag. The selective melatonin
agonist ramelteon is helpful for sleep-onset insomnia. Other
treatments are listed in Table 106-1.
Prognosis is usually good with the combination of drug and
nondrug treatments. Behavior modification may be limited by
the willingness of patients to participate.
  PARASOMNIAS
Parasomnias are undesirable phenomena that occur in sleep or
during transition to or from sleep. They usually consist of complex
and seemingly purposeful behaviors, sometimes dramatic, of
which the patient is not aware. They are often classified by the
sleep stage in which they arise.
Slow-Wave Sleep Parasomnias
Definition and Epidemiology
Slow-wave sleep parasomnias include disorders of arousals,
including sleep talking, night terrors (i.e., pavor nocturnus), sleep
walking (i.e., somnambulism), nocturnal wandering, and confu-
sional arousals (i.e., sleep drunkenness), with considerable
overlap among these entities.
Pathophysiology and Clinical Manifestations
Characterized by partial arousals and intermediate states between
wakefulness and sleep, slow-wave sleep parasomnias tend to
begin in childhood. A family history of similar symptoms is
common.
Episodes are often triggered by precipitants such as fever,
intercurrent illness, sleep deprivation, or alcohol. They tend to
occur in the first third of the night, when delta sleep predomi-
nates. They are characterized by typical slow-wave sleep arousals.
Patients appear confused, may have slurred speech, and take
several minutes to regain orientation. Slow-wave sleep has a
higher threshold for arousal.
Sleep talking usually consists of fragments of barely intelligible
sentences. Sleep walking and nocturnal wandering typically
include ambulation. Night terrors (i.e., sleep terrors or pavor noc-
turnus) are dramatic, with an abrupt arousal, a scream, and auto-
nomic hyperactivity (e.g., mydriasis, diaphoresis, flushing,
piloerection, tachycardia). The child appears terrified and is
inconsolable. Episodes last a few minutes and are not recalled the
next morning.

Diagnosis and Differential Diagnosis
The main differential diagnosis is nocturnal seizure, which occa-
sionally requires epilepsy monitoring (video electroencephalo-
gram) if the episodes are frequent. For episodic symptoms, the
use of home video (by cell phone) is more reliable than descrip-
tion by witnesses. Nocturnal seizures tend to be more stereo-
typed than parasomnias, and they often include tonic or clonic
motor activity.
Treatment and Prognosis
Reassurance and measures to avoid injuries usually are sufficient.
For episodes with injurious behaviors, low-dose benzodiazepines
(clonazepam, 0.5 to 1 mg) are often effective. Prognosis is good,
and most patients do not require treatment.
Rapid Eye Movement Behavior Disorder
Definition and Epidemiology
REM behavior disorder (RBD) is a disorder of REM sleep regu-
lation in which there is a dissociation of REM features with loss
of the muscle atonia, leading to patients acting out their dreams.
RBD typically affects patients after the age of 50 (usually older)
and the male-to-female ratio is 10 : 1.
Pathophysiology
REM inhibition is lost due to bilateral degeneration of REM
atonic neurons in the pons. RBD occurs with α-synucleinopathies
(i.e., Parkinson’s disease, multiple system atrophy, and dementia
with Lewy bodies), and RBD typically heralds these neurodegen-
erative diseases, sometimes by 10 to 15 years.
Clinical Manifestations
Typically, the episodes are reported by the bed partner and
consist of high-amplitude, flailing, injurious behaviors during
Chapter 106  Disorders of Sleep 975
sleep. When awakened, the patient typically recalls the dream. As
is typical of REM arousals, the patient is alert and coherent ss
immediately (unlike slow-wave sleep arousal). Medications,
especially psychotropics, can exacerbate RBD.
Diagnosis and Differential Diagnosis
The diagnosis can usually be made by the history alone, and PSG
is not needed. When performed, PSG shows a lack of REM
atonia or increased phasic and tonic REM. Like slow-wave para-
somnias, the main differential diagnosis is nocturnal seizure, and
this occasionally requires epilepsy monitoring. Home video (cell
phones) recordings can be useful.
Treatment and Prognosis
Low-dose clonazepam (0.5 to 2 mg) is usually effective. Symp-
toms initially respond to treatment, but a neurodegenerative
disease is likely to become evident.
For a deeper discussion of these topics, please see Chapter
100, “Obstructive Sleep Apnea,” and Chapter 405, “Disor-
ders of Sleep,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Buysse DJ: Insomnia, JAMA 309:706–716, 2013.
Ebisawa T: Analysis of the molecular pathophysiology of sleep disorders relevant
to a disturbed biological clock, Mol Genet Genomics 288:185–193, 2013.
Faraut B, Boudjeltia KZ, Vanhamme L, et al: Immune, inflammatory and
cardiovascular consequences of sleep restriction and recovery, Sleep Med
Rev 16:137–149, 2012.
Mignot EJ: A practical guide to the therapy of narcolepsy and hypersomnia
syndromes, Neurother 9:739–752, 2012.
Ohayon MM: From wakefulness to excessive sleepiness: what we know and still
need to know, Sleep Med Rev 12:129–141, 2008.
 107 

ss
Cortical Syndromes
Sinéad M. Murphy and Timothy J. Counihan

hemisphere is dominant for language in only between 10% and

  ANATOMY
The paired cerebral hemispheres are connected by a large band
of white matter fibers, the corpus callosum. Each hemisphere con-
sists of four anatomically and functionally distinct regions: the
frontal, temporal, parietal, and occipital lobes (Fig. 107-1). The
two cerebral hemispheres supplement each other functionally in
a variety of behavioral and sensorimotor tasks; however, certain
functions, particularly language, manual dexterity, and visuospa-
tial perception, are strongly lateralized to one hemisphere. Lan-
guage function is lateralized to the left hemisphere in 95% of the
population; although 15% of people are left-handed, the right
Parietal lobe Central sulcus Frontal lobe
A of onset of symptoms and the tempo of progression influence the
27% depending on the degree of left-handedness. Visuospatial
functions are largely subserved by the right (nondominant)
hemisphere. The Rolandic fissure separates the motor cortex
(precentral gyrus) from the sensory cortex (postcentral gyrus).
In these regions, cortical representations of the different parts of
the body are arranged as the motor (frontal lobe) and sensory
(parietal lobe) homunculi (Fig. 107-2).
  CLINICAL ASSESSMENT
Symptoms and signs caused by cortical lesions may be less con-
sistent than deficits caused by lesions of the spinal cord or more
peripheral nerves, and patients may be unaware of the extent of
their deficit. This makes a collateral history and careful examina-
tion (including cognitive assessment) important. In addition,
there is substantial individual variability among patients. The rate
extent of the clinical deficit. The homuncular arrangement of
cortical motor and sensory representation may allow for more
precise localization of a lesion. For instance, motor or sensory
signs confined to the lower extremities may suggest a parasagittal
lesion, whereas signs involving the face and upper limb may origi-
nate in laterally placed cortical lesions.

  REGIONAL SYNDROMES
Occipital lobe Table 107-1 summarizes some of the eponymous syndromes and
Lateral sulcus Temporal lobe clinical features associated with damage to individual lobes.

Aphasia
Frontal lobe Central sulcus Parietal lobe Aphasia or dysphasia refers to a loss or impairment of language
function as a result of damage to the specific language centers of
the dominant hemisphere. It is distinct from dysarthria, which is
B a disturbance in the articulation of speech. The principal types of
aphasia are summarized in Table 107-2.
Writing is almost invariably affected in patients with distur-
bances of language (Fig. 107-3). An exception to this occurs in
the syndrome of alexia without agraphia, which results from a
lesion in the dominant occipital lobe and splenium of corpus
callosum (usually caused by infarction in the territory of the pos-
terior cerebral artery). The patient’s language center is “discon-
nected” from the contralateral (unaffected) visual cortex. Such
Occipital lobe patients can write a sentence but are unable to read what they
Temporal lobe have written.
Limbic lobe Clinical assessment for aphasia requires testing of fluency,
FIGURE 107-1  Lateral (A) and medial (B) views of the cerebral hemi- comprehension, repetition, naming, reading, calculation, and
spheres. (From FitzGerald MJT, editor: Clinical neuroanatomy and neu- writing. Anomia (difficulty in recalling the names of objects) in
roscience, ed 6, Philadelphia, 2011, Saunders, Fig. 2-1.)
isolation has little localizing value.

976
 Chapter 107  Cortical Syndromes 977

ss

Hand Foot

Face Hand area

Tongue and
larynx
A

B
FIGURE 107-2  A, Homuncular arrangement shows the correlations with the primary motor cortex lying anterior to the central sulcus and the
somatosensory cortex posteriorly (B). (Modified from Kretschmann HJ, Weinrich W: Neurofunctional systems: 3D reconstructions with correlated
neuroimaging: text and CD-ROM, New York, 1998, Thieme.)

TABLE 107-1  CORTICAL SYMPTOMS AND SIGNS

DOMINANT HEMISPHERE NONDOMINANT HEMISPHERE EITHER HEMISPHERE
FRONTAL LOBE
Broca’s aphasia Motor dysprosody Contralateral spastic weakness
Transcortical motor aphasia Forced eye deviation
Pure agraphia Executive dysfunction, poor sequencing
Akinetic mutism, urinary incontinence (bilateral lesions)
Disinhibition, emotional lability, abulia
Frontal lobe release signs (pout, grasp, snout, rooting,
palmomental)
Alien hand
PARIETAL LOBE
Wernicke aphasia Contralateral sensory neglect Contralateral sensory loss
Transcortical sensory aphasia Constructional apraxia
Apraxia Anosagnosia
Gerstmann’s syndrome (acalculia, finger Dressing apraxia
agnosia, right-left disorientation, agraphia)
Conduction aphasia
TEMPORAL LOBE
Anomic or sensory aphasia Impaired recognition of facial emotional expressions Contralateral superior quadrantanopia
Verbal amnesia Visuospatial amnesia Amnesia
Transcortical sensory aphasia Sensory dysprosody/amusia Klüver-Bucy syndrome (oral-exploratory behavior, passivity,
hypersexuality) bilateral lesions
Pure word deafness Auditory hallucinations
Complex visual hallucinations
Olfactory hallucinations
Visual/experiential delusions
OCCIPITAL LOBE
Alexia without agraphia Anton’s syndrome (visual agnosia, denial of blindness)
Contralateral homonymous hemianopia
Visual hallucinations
Optic apraxia, absent optokinetic nystagmus, palinopsia
Balint’s syndrome (simultanagnosia, optic ataxia,
oculomotor apraxia); bilateral lesions, usually
occipitoparietal
 978 Section XVI  Neurologic Disease

ss
TABLE 107-2  PRINCIPAL TYPES OF APHASIA
TYPE LESION SITE FLUENCY COMPREHENSION REPETITION NAMING OTHER SIGNS
Broca’s (expressive) Inferior frontal lobe ↓ Good ↓ ↓ Contralateral weakness
Wernicke’s (receptive) Posterior superior Good ↓ ↓ ↓ Homonymous hemianopia
temporal lobe
Transcortical motor Inferior frontal gyrus ↓ Good Good May be normal May be contralateral weakness
Transcortical sensory Middle temporal gyrus, Good ↓ Good Usually normal May be normal
thalamus
Conduction Supramarginal gyrus Good Good ↓ ↓ None
Global Frontal lobe (large) ↓ ↓ ↓ ↓ Hemiplegia
↓, Reduced.

FIGURE 107-4  Attempts to draw a cube by a patient with a neuro-

degenerative disorder demonstrate constructional apraxia.

Conduction aphasia is characterized by normal comprehension

FIGURE 107-3  Neologisms written by a patient with aphasia who
was attempting to name cell phone, keys, camera, watch, pen, bag, and
boots.
and fluent speech but an inability to repeat. The responsible
lesion lies in the arcuate fasciculus connecting Broca’s and Wer-
nicke’s areas. Global aphasia results from large lesions of the
frontal lobe; all aspects of language are affected. Lesions of the
language areas of the nondominant hemisphere result in dyspros-
ody. For instance, patients with lesions in the inferior frontal lobe
of the nondominant hemisphere, analogous to Broca’s area, speak
with a monotonous voice, losing the natural cadence of speech.
In dysarthria, the language function is intact (which can be
confirmed by having the patient write a sentence), but patients
have difficulty articulating. Dysarthria can result from a lesion
anywhere along the path from the cerebral cortex to the bulbar
muscles.

Agnosia and Apraxia

Broca’s aphasia is characterized by a severe disruption in the
fluency of speech, with profound impairments of expression in
both speech and writing. Comprehension may be mildly affected.
The language disturbance is almost invariably accompanied by
contralateral face and arm weakness as a result of the proximity
of the motor homunculus to Broca’s speech area.
Wernicke’s aphasia is characterized by an inability to compre-
hend spoken or written language. Affected patients speak fluently,
but the content is meaningless; they may use words that are close
in meaning to the intended word (semantic paraphasias) or
words that sound like the intended word (literal paraphasias).
Patients may be misdiagnosed as having a psychiatric disorder
because they lack an associated hemiparesis.
Agnosia is the inability to recognize a specific sensory stimulus
despite preserved sensory function. For instance, visual agnosia
is the inability to recognize a visual stimulus despite normal
visual acuity. Other agnosia syndromes include the inability to
recognize sounds (auditory agnosia), color (color agnosia), or
familiar faces (prosopagnosia). Usually, the responsible lesions
are located in the occipitotemporal region.
Apraxia refers to an inability to perform learned motor tasks
despite sufficient sensorimotor function to physically execute the
movement; it is a disorder of motor planning (Fig. 107-4). The
responsible lesions are usually in the dominant inferior parietal
lobe. A simple test of apraxia is to ask the patient to perform a
pantomime (e.g., combing his or her hair, blowing out a candle).
 Chapter 107  Cortical Syndromes 979
Lesions of the nondominant parietal lobe often result in hemispa-
tial neglect: the patient does not attend to stimuli in the contralat-
eral (usually the left) visual field or on the contralateral side of
the body. In a milder form of neglect, called extinction, patients
can attend to stimuli contralateral to the side of the brain with the
lesion (and the lesion is usually on the right side), but when
presented with bilateral stimuli simultaneously, they respond
only on the ipsilateral (right) side. Anosognosia, or the lack of
awareness of one’s deficit, frequently accompanies hemispatial
neglect. In severe cases, patients may even deny that the affected
limb belongs to them.
  PROSPECTUS FOR THE FUTURE
There have been many advances in neuroimaging technology that
allow neuroscientists to study not only the structural and func-
tional anatomy of a particular brain structure but also its meta-
bolic activity. Functional magnetic resonance imaging (fMRI)
permits mapping of the metabolic anatomy of subcortical gray
and white matter structures, such as the basal ganglia, and their
roles in conditions such as dystonia. These modalities allow one
to study white matter tracts (tractography) in great detail, using
a technique called diffusion tensor imaging.
Similarly, modern MRI technology is now able to discriminate
brain tissue that is infarcted from tissue that is ischemic (and ss
therefore potentially still viable) in the setting of acute stroke.
Positron emission tomography (PET) and single-photon emis-
sion computed tomography (SPECT) are nuclear medicine
imaging techniques that are increasingly used in the diagnosis of
neurodegenerative disorders. It is likely that these techniques will
become increasingly available in the acute hospital setting.
SUGGESTED READINGS
Brazis PW, Masdeu JC, Biller J: Localization in clinical neurology, ed 6,
Philadelphia, 2011, Lippincott Williams & Wilkins.
Carota A, Calabrese P: The achromatic “philosophical zombie,” a syndrome of
cerebral achromatopsia with color anopsognosia, Case Rep Neurol 5:98–103,
2013.
Goldenberg G: Apraxia in left handers, Brain 136:2592–2601, 2013.
Knopman DS: Regional cerebral dysfunction: higher mental functions, chapter
408. In Goldman’s Cecil Medicine, ed 24, Philadelphia, 2012, Saunders.
Mesulam MM: Primary progsressive aphasia and the language network,
Neurology 81:456–462, 2013.
 108 
Dementia and Memory
Disturbances
ss

Frederick J. Marshall
diagnosis. The Montreal Cognitive Assessment (MoCA) (Table
  MAJOR DEMENTIA SYNDROMES 108-4) is a standard test that can be used as a bedside or office
Dementia is progressive loss of intellectual function coupled with screening tool for identifying patients with dementia. This exami-
loss of meaningful function in daily life. Memory loss is the nation is superior to the Mini-Mental Status Examination
central feature, and specific dementia syndromes characteristi- (MMSE) in that it is sensitive to abnormalities in a wider array
cally cause particular forms of memory impairment. Dementia of cognitive domains, including visual-spatial or executive
syndromes also produce specific abnormalities of cognition in
language, spatial processing, praxis (i.e., learned motor behavior),
and executive function (i.e., ability to plan and sequence events).
TABLE 108-2  ETIOLOGIC DIAGNOSIS OF
Cortical dementia and subcortical dementia, although older terms,
NEURODEGENERATIVE DEMENTIA  
remain helpful for subdividing the dementias (Table 108-1). IN ADULTS
Table 108-2 provides the differential diagnosis of neurodegen- Alzheimer’s disease*
erative causes of dementia, and Table 108-3 outlines other causes Parkinson’s disease*
of dementia. Neurodegeneration is the most common underly- Diffuse Lewy body disease*
Progressive supranuclear palsy
ing cause of dementia and is seen in Alzheimer’s disease (AD), Corticobasal ganglionic degeneration
frontotemporal dementia, and diffuse Lewy body disease. Striatonigral degeneration
Most causes of dementias are currently untreatable. Potentially Olivopontocerebellar degeneration
Huntington’s disease
correctable causes account for less than 5% of dementia cases. Frontotemporal dementias
Structural processes or infections must be considered, along with Pick’s disease
metabolic and nutritional diseases. Every patient with dementia Frontotemporal dementia without characteristic neuropathology
Frontotemporal dementia with motor neuron disease
should have tests of serum electrolytes and vitamin B12 and Hallervorden-Spatz disease
assessments of liver, renal, and thyroid function. Serologic studies
*Denotes conditions for which symptomatic treatment is available.
for syphilis and Lyme exposure should be done if risk factors are
identified. Chronic infections (see Chapter 90) and normal-
pressure hydrocephalus should be considered. Brain imaging
TABLE 108-3  OTHER CAUSES OF PROGRESSIVE
should be performed.
DEMENTIA IN ADULTS
Neuropsychological testing characterizes the pattern of cogni-
STRUCTURAL DISEASE INFECTIOUS DISEASE
tive and memory impairments and is helpful in the differential OR TRAUMA
Human immunodeficiency virus
Normal-pressure hydrocephalus* type 1*
Neoplasms* Tertiary syphilis*
Dementia pugilistica (multiple Creutzfeldt-Jakob disease
TABLE 108-1  DISTINGUISHING CHARACTERISTICS OF concussions in boxers) Progressive multifocal
CORTICAL AND SUBCORTICAL leukoencephalopathy
VASCULAR DISEASE
DEMENTIAS Whipple’s disease*
Vascular dementia† Chronic meningitis*
CORTICAL DEMENTIA
Vasculitis* Cryptococcal meningitis*
Symptoms: major changes in memory, language deficits, perceptual deficits, Others
HEREDOMETABOLIC DISEASE
praxis disturbances
Affected brain regions: temporal cortex (medial), parietal cortex, and frontal Wilson’s disease* METABOLIC OR NUTRITIONAL
lobe cortex Neuronal ceroid lipofuscinosis DISEASE
Examples: Alzheimer’s disease, diffuse Lewy body disease, vascular (Kufs’ disease) Vitamin B12 deficiency*
dementia, frontotemporal dementias Other late-onset lysosomal storage Thyroid hormone deficiency or
diseases excess*
SUBCORTICAL DEMENTIA
DEMYELINATING OR Thiamine deficiency* (Korsakoff ’s
Symptoms: behavioral changes, impaired affect and mood, motor slowing, syndrome)
DYSMYELINATING DISEASE
executive dysfunction, less severe changes in memory Alcoholism†
Affected brain regions: thalamus, striatum, midbrain, striatofrontal Multiple sclerosis†
projections Metachromatic leukodystrophy PSYCHIATRIC DISEASE
Examples: Parkinson’s disease, progressive supranuclear palsy, normal- Pseudodementia from depression*
pressure hydrocephalus, Huntington’s disease, Creutzfeldt-Jakob disease,
*Denotes conditions for which preventive or corrective treatment is available.
chronic meningitis †
Denotes conditions for which symptomatic treatment is available.

980
 Chapter 108  Dementia and Memory Disturbances 981

function, naming, attention, fluency; abstract reasoning, short- tangles. β-Amyloid (Aβ) is the major component of the plaques,
term memory encoding and retrieval, and orientation. and hyperphosphorylated tau protein is the major constituent of ss

In addition to the MoCA, patients with dementia should have the neurofibrillary tangles. The process starts in the hippocampus
tests of praxis (e.g., show how you would comb your hair; show and entorhinal cortex and spreads to involve diffuse areas of asso-
how you would blow out a match) and neglect (e.g., testing of ciation cortex in the temporal, parietal, and frontal lobes. The
double-simultaneous extinction to visual, tactile, and auditory relative deficiency of cortical acetylcholine (resulting from the
stimuli). Depending on the results of these screening procedures, loss of neurons in the nucleus basalis) provides the rationale for
more detailed neuropsychological studies can be pursued. symptomatic treatment of the disease with centrally acting ace-
tylcholinesterase inhibitors.
Alzheimer’s Disease
AD accounts for approximately 70% of dementia cases among Pathogenesis
older adults. Almost 5.3 million persons in the United States are AD is often categorized as a young-onset, hereditary or familial
affected, and this number may approach 18 million by 2050 as form, which is rare and for which three specific genetic abnor-
the population ages. AD places enormous burdens on the patient, malities have been determined, or as a common, sporadic
family, and society. The annual direct and indirect expenditures form that typically occurs in persons older than 65 years of age
are estimated to exceed $150 billion. The disease occurs in 32% (Table 108-5).
to 47% of persons older than 80 years of age. Incidence at age 65 The autosomal dominant, early-onset forms of AD have in
is one in 200 people per year. Incidence at age 80 is one case per common abnormalities of Aβ production and processing, which
10 people per year. More than 50% of caregivers develop depres- have provided clues to the molecular pathogenesis of sporadic
sion or major medical illness. AD. Abnormal processing of amyloid precursor protein into the
AD has many causes, but none is fully defined. All causes amyloidogenic peptide Aβ (1-42) is thought to be important in
produce similar clinical and pathologic findings. The disease is the pathogenesis of AD. It is thought to provoke downstream
characterized by the progressive loss of cortical neurons and the abnormalities of tau protein processing, with hyperphosphoryla-
formation of amyloid plaques and intraneuronal neurofibrillary tion of tau yielding intraneuronal tangles.
The apolipoprotein E (Apo E) gene (APOE) was found to be
a susceptibility locus for sporadic AD in late-onset familial AD
pedigrees. The gene is polymorphic (ε2, ε3, ε4), and first-degree
TABLE 108-4  ELEMENTS OF THE MONTREAL
relatives of AD patients, who inherit both ε4 alleles, have a more
COGNITIVE ASSESSMENT
than 60% lifetime risk of developing AD. Apo E-ε4 interacts
COGNITIVE
DOMAIN ITEMS SCORE selectively with Aβ and with tau protein, but how Apo E-ε4
Visual-spatial or Complete a trail-making task, copy a cube, 5
increases the risk of AD remains unknown.
executive draw a clock
Naming Name three depicted animals 3 Clinical Features
Attention Recall 5 digits forward, 3 digits backward, 6
maintain letter vigilance, subtract 7s
AD begins gradually and affects memory, orientation, language,
serially visuospatial processing, praxis, judgment, and insight. Depres-
Language Repeat two phrases, generate a list of 3 sion is common early in AD, and psychosis with agitation and
words starting with a specific letter
Abstraction Identify the similarity between nouns 2
behavioral disinhibition often occur in advanced stages. Patients
(train/bicycle; watch/ruler) become dependent on others for all activities of daily living. The
Delayed recall Recall five words rehearsed twice 5 rate of progression of AD is varies but usually takes 5 to 15 years
previously (face, velvet, church, daisy,
red)
to progress from presentation to advanced illness.
Orientation Identify the date, month, year, day, place, 6 Diagnostic criteria are outlined in Table 108-6. Although a
and city definitive diagnosis of AD requires biopsy (rarely done) or
Total possible score 30
autopsy confirmation, these diagnostic criteria establish the diag-
From Nasreddine ZS, Phillips NA, Bedirian V, et al: The Montreal Cognitive Assessment, nosis with more than 85% specificity in moderately demented
MoCA: a brief screening tool for mild cognitive impairment, J Am Geriatr Soc 53:695–699,
2005. patients. The positron emission tomography (PET) ligand

TABLE 108-5  FAMILIAL VERSUS SPORADIC ALZHEIMER’S DISEASE

CHROMOSOME AND GENE AGE AT ONSET (YR) % OF ALL FAD CASES % OF ALL SAD CASES
FAMILIAL ALZHEIMER’S DISEASE*
Chromosome 1, PSEN2 (presenilin 2) 40-80 5-10 <0.5
Chromosome 14, PSEN1 (presenilin 1) 30-60 70 <1
Chromosome 21, APP (amyloid-β precursor protein) 35-65 5 <0.5
SPORADIC ALZHEIMER’S DISEASE†
No single determinant gene‡ Usually >60 — 98
*Familial Alzheimer’s disease (FAD) has early onset and is autosomal dominant.
†
Sporadic Alzheimer’s disease (SAD) has late onset and may be polygenetic and/or environmental.
‡
Apolipoprotein E-ε4 allele on chromosome 19 increases the risk compared with the ε2 or ε3 allele.
 982 Section XVI  Neurologic Disease
ss
TABLE 108-6  DIAGNOSTIC CRITERIA FOR PROBABLE
ALZHEIMER’S DISEASE
Progressive functional decline and dementia established by clinical
examination and mental status testing and confirmed by
neuropsychological assessment
Insidious onset
Clear-cut history of worsening cognition by report or observation
Initial and most prominent cognitive deficits evident on history and
examination in one of the following categories:
Amnestic presentation (plus at least one other domain)
Nonamnestic presentations (plus deficits in other domains): language,
visuospatial, executive dysfunction
No evidence of vascular dementia, dementia with Lewy bodies,
frontotemporal dementias, or other concurrent active neurologic or
non-neurologic medical comorbidity or use of medication that could have
a substantial effect on cognition
florbetapir F 18 (Amyvid), which binds to amyloid plaques, has
been approved by the U.S. Food and Drug Administration (FDA)
for use in the clinical diagnosis of AD. It can be positive in patients
without clinical signs of dementia. Similarly, cerebrospinal fluid
(CSF) assays for Aβ, tau, and phosphorylated tau protein loads
have been commercialized as aids to diagnosis, but they are not
universally used due to the invasive nature of the testing and the
relatively good accuracy of the clinical diagnosis.
PET and CSF assays are in widespread use for stratification of
subjects in emerging large-scale, prospective, randomized studies
of individuals at risk for preclinical disease. Changes in brain
morphometry are identifiable on structural imaging many years
before onset of clinical symptoms.
Treatment
Although their benefits are modest, the cholinesterase-inhibiting
drugs donepezil (Aricept), rivastigmine (Exelon), and galan-
tamine (Razadyne) represent important advances. These drugs
may be given in once-daily formulations. Rivastigmine is also
available as a transdermal patch.
In clinical trials, cholinesterase inhibitors benefited less than
50% of patients. They have not been shown to prevent AD in
patients with mild cognitive impairment (MCI), a condition in
which the memory or another domain of cognition is impaired
in the absence of meaningful dysfunction in daily life. Approxi-
mately 12% of patients with MCI go on to develop AD per year,
with roughly two thirds of patients with MCI developing clinical
AD within 5 years of symptom onset.
Gingko biloba has no role in the treatment or prevention of
AD. The glutamate antagonist memantine (Namenda) has been
shown to prolong daily function in patients with moderate to
advanced AD.
Treatment strategies in clinical trials over the past decade
have included decreasing Aβ peptide production by blocking
α-secretase or β-secretase or upregulating cleavage of the
amyloid precursor protein at the α-secretase site. Studies of
active and passive immunization have been designed to lower
brain Aβ levels. However, these approaches have failed to deliver
on the promise of AD disease modification, necessitating a
wide-reaching reassessment of current theories of disease
pathogenesis.
There is an emerging concept of preclinical AD, with many
biomarkers showing changes years before clinical manifestations.
Several large, prospective, interventional studies targeting this
population are getting underway or are planned on the inference
that intervening later in the disease process (when symptoms of
dementia have manifested) may be too late. Novel molecular and
immunologic approaches continue to hold promise for disease-
modifying treatments in the future.
Nursing services provide oversight of hygiene, nutrition, and
medication compliance. Antipsychotics, antidepressants, and
anxiolytics are useful for patients with behavioral disturbances,
which are the most common cause of nursing home placement.
Patients and families can be referred to a local Alzheimer’s Asso-
ciation chapter for further information on available community
support.
Prevention
There is no high or even moderate level of evidence that any
intervention decreases the risk of AD. There is a low level of
evidence that a Mediterranean diet, folic acid, HMG-CoA reduc-
tase inhibitors (i.e., statins), higher levels of education, light
alcohol intake, cognitively engaging activities, and physical activ-
ity (particularly at high levels) may decrease the risk of AD.
There is a moderate level of scientific evidence that conjugated
equine estrogen with methyl-progesterone increases the risk of
AD. There is a low level of scientific evidence that some nonste-
roidal anti-inflammatory drugs, depressive disorder, diabetes
mellitus, hyperlipidemia in midlife, current tobacco use, trau-
matic brain injury, pesticide exposure, and relative social isola-
tion increase the risk of AD.
Diffuse Lewy Body Disease
Lewy bodies are pathologic inclusions that are the hallmark of
Parkinson’s disease when they are restricted to the brain stem (see
Chapter 114). Patients with diffuse Lewy body disease have clini-
cal parkinsonism (i.e., slow movement, rigidity, and balance
problems) combined with early and prominent dementia. Patho-
logically, Lewy bodies are found in the brain stem, limbic system,
and cortex. Visual hallucinations and cognitive fluctuations are
common, and patients are unusually sensitive to the adverse
effects of neuroleptic medication.
Diffuse Lewy body disease may represent the second most
common cause of dementia after AD. However, the common
concurrence of the pathologic features of diffuse Lewy body
disease with the classic neuritic plaques and neurofibrillary
tangles of AD complicates the identification of the cause of
dementia in a given patient.
Vascular Dementia
Approximately 10% to 20% of older patients with dementia have
radiographic evidence of focal stroke on magnetic resonance
imaging (MRI) or computed tomography (CT), combined with
focal signs on the neurologic examination. When the dementia
syndrome begins with a stroke and progression of the illness is
stepwise (suggesting recurrent vascular events), the diagnosis of
vascular dementia is likely.
Patients typically develop early incontinence, gait distur-
bances, and flattening of affect. A subcortical dementing process
attributed to small vessel disease in the periventricular white
matter has been referred to as Binswanger’s disease, but it may be
a radiographic finding rather than a true disease. Appropriate
 Chapter 108  Dementia and Memory Disturbances 983
treatment of risk factors for vascular disease—blood pressure
control, smoking cessation, diet modification, and anticoagula-
tion (in select settings such as atrial fibrillation)—is mandatory
and may be of benefit.
Frontotemporal Dementias
Patients with the behavioral variant of frontotemporal dementia
(FTD) are frequently socially disinhibited, but they may also be
lethargic and lack motivation and spontaneity. Patients with the
progressive nonfluent aphasia variant of FTD have loss of speech
fluency with poor articulation and syntactic errors but relative
preservation of comprehension. Those with the semantic demen-
tia variant of FTD remain fluent with normal phonation but have
progressive difficulty with naming and word comprehension.
Memory and spatial skills and praxis are relatively preserved early
on in all of these forms, whereas executive function, emotional
regulation, and conduct are relatively impaired.
There are several frontotemporal lobar degenerations
(FTLDs), including Pick’s disease (now referred to as FTLD-
tau). In some families, a mutation in the microtubule-associated
protein tau gene (MAPT) on chromosome 17 causes tau-positive
frontotemporal dementia with parkinsonism (FTDP-17). Trans-
active response DNA-binding protein (TDP-43) pathology
accounts for 40% of FTD with or without motor neuron disease.
Although mutations in the fused in sarcoma gene (FUS) had
previously been identified as a cause of familial amyotrophic
lateral sclerosis (ALS), some also give rise to 5% to 10% of clini-
cally diagnosed FTD (typically the behavioral variant). Hexa-
nucleotide repeat expansions in C9orf72 cause neurodegeneration
in FTD and ALS. RNA processing is abnormal in both
conditions.
As in AD, all forms of FTD progress for years. No intervention
slows the inevitable decline of these patients. Approximately 50%
of patients have a family history of the disease.
Parkinson’s Disease
Almost 50% of patients with Parkinson’s disease (see Chapter
114) become demented by the time they reach the age of 85
years. The dementia of Parkinson’s disease affects executive func-
tion out of proportion to its impact on language and visuospatial
processing. Thought processes appear to slow down (i.e.,
bradyphrenia), analogous to the slowing of movement (i.e.,
bradykinesia).
Because dementia occurs relatively late in the progression of
Parkinson’s disease, most patients are taking drugs to improve
their movement disorder by enhancing dopaminergic neuro-
transmission. These drugs can induce psychosis. Dose reductions
should be attempted before the diagnosis of underlying dementia
is made for these patients. Acetylcholinesterase inhibition has
been helpful for patients with dementia caused by Parkinson’s
disease, and the FDA has specifically approved rivastigmine for
this indication.
Normal-Pressure Hydrocephalus
The triad of dementia (typically subcortical), gait instability, and
urinary incontinence suggests the possibility of normal-pressure
hydrocephalus. These patients appear to walk with their feet
stuck to the floor, without lifting up the knees and with a broad
base. Symptoms evolve over the course of weeks to months, and
brain imaging reveals ventricular enlargement out of proportion
to the degree of cortical atrophy. ss
Numerous diagnostic tests have been described, including
radionuclide cisternography and MRI flow studies. The most
important test remains the clinical response to removal of large
volumes of CSF through serial lumbar punctures or the tempo-
rary placement of a lumbar drain, followed by examination of the
patient’s gait and cognitive function. Neurosurgical placement of
a permanent ventriculoperitoneal shunt may correct the problem.
Patients likely to benefit from shunt placement have a clear
response to the removal of 30 to 40 mL of spinal fluid, with
improved gait and alertness within minutes to hours of the pro-
cedure. The cause of normal-pressure hydrocephalus is a derange-
ment of the CSF hydrodynamics. Shunt placement is most likely
to be effective if normal-pressure hydrocephalus occurs after
severe head trauma or subarachnoid hemorrhage.
Prion Infection, Chronic Meningitis, and
Dementia Related to Acquired
Immunodeficiency Syndrome
Creutzfeldt-Jakob disease (CJD) is a subacute, dementing, trans-
missible illness with typical onset between 40 and 75 years of age
and an incidence of one case per 1 million people (see Chapter
90). The disease causes spongiform degeneration and gliosis in
widespread areas of the cortex. Clinical variants of the disorder
are differentiated by the relative predominance of cerebellar
symptoms, extrapyramidal hyperkinesias, or visual agnosia and
cortical blindness (i.e., Heidenhain variant).
Ninety percent of patients with CJD have myoclonus, com-
pared with 10% of patients with AD. Patients with all forms of
the disease share a relentlessly progressive dementia and disrup-
tion of personality over weeks to months. The electroencephalo-
gram shows characteristic abnormalities, including diffuse
slowing and periodic sharp waves or spikes.
The transmissible agent, a prion protein, is invulnerable to
routine modes of antisepsis. CSF can be tested for the 14-3-3
protein, although this test is not as sensitive or specific for CJD
as once hoped (see Chapter 90). Diffusion-weighted MRI images
show characteristic cortical ribbon changes.
Certain infectious agents can cause the subacute or chronic
development of subcortical dementia. These chronic meningiti-
des are discussed in Chapter 90.
Human immunodeficiency virus accesses the central nervous
system through monocytes and the microglial system and causes
associated neuronal cell loss, vacuolization, and lymphocytic
infiltration. The dementia associated with this infection is char-
acterized by bradyphrenia and bradykinesia. Patients have execu-
tive dysfunction, impaired memory, poor concentration, and
apathy. Treatment of the underlying viral infection with protease
inhibitors and reverse transcriptase inhibitors may slow the pro-
gression of the dementia (see Chapter 90).
  OTHER MEMORY DISTURBANCES
Structure of Memory
Memory function is divided into introspective processes (i.e.,
declarative, explicit, aware memories) and processes that are
not accessible to introspection (i.e., nondeclarative, implicit, pro-
cedural memories). Short-term memory (e.g., words on a list) is
 984 Section XVI  Neurologic Disease
a form of declarative memory. Other forms include the conscious
ss recall of episodes from personal experience (i.e., episodic
memory), and factual knowledge (i.e., semantic memory) that
can be consciously recalled and stated (i.e., declared). Declarative
memory involves consciously knowing that …. Patients with
amnesia resulting from lesions of the medial temporal lobes or
midline diencephalic structures have deficits of declarative
memory.
Nondeclarative memory encompasses several distinct and
neuroanatomically less clearly localized functions related to the
performance of specific learned motor, cognitive, or perceptual
tasks. Nondeclarative (procedural) memories involve uncon-
sciously knowing how …. Deficits in nondeclarative memory may
involve various areas of association neocortex, depending on the
nature of the task (e.g., parietal-temporal-occipital junction
cortex for visual perceptual tasks, frontal association cortex for
motor tasks). Patients with amnesia resulting from lesions of the
medial temporal lobes tend to perform normally on tests of non-
declarative memory.
Anterograde amnesia is the inability to learn new information.
It commonly occurs after brain injury or in association with
dementia. The inability to recollect prior information is retro-
grade amnesia. Both types of amnesia usually occur together in
brain injury syndromes, although the extent of one type or the
other may vary. The degree of anterograde amnesia after head
injury correlates with the severity of the injury.
Isolated Disorders of Memory Function
Memory can be impaired in relative isolation as a consequence
of head injury, thiamine deficiency (i.e., Korsakoff ’s syndrome),
benign forgetfulness of aging, transient global amnesia, or psy-
chogenic disease.
Head injury typically results in retrograde amnesia in excess of
anterograde amnesia, with both forms stretching out over time
from the discrete event. As time passes, these disrupted memo-
ries gradually return, although rarely to the point at which the
events immediately surrounding the trauma are recalled.
Korsakoff ’s syndrome is characterized by the near-total inabil-
ity to establish new memory. Patients often confabulate responses
when they are asked to convey the details of their current circum-
stance or to relay the content of a recently presented story. Defi-
ciency of thiamine and other nutritional deficiencies in the
context of chronic alcoholism are the most common underlying
causes. Thiamine is a necessary cofactor in the metabolism of
glucose, and thiamine must be replenished at the same time
glucose is administered whenever a comatose patient is seen in
the emergency department.
Aging is associated with mild loss of memory, exhibited by
difficulty in recalling names and by forgetfulness for dates.
Population-based assessments of neuropsychological function
have demonstrated that poor performance on delayed-recall
tasks is the most sensitive indicator of cognitive change with
advancing age. Verbal fluency, in contrast, remains intact with
advancing age, and vocabulary may increase with time, even into
old age.
Transient global amnesia is a dramatic memory disturbance
that affects older patients (>50 years). Patients usually have only
one episode; occasionally, episodes recur over the course of
several years. Patients have complete temporal and spatial disori-
entation; orientation for person is preserved. Near-total retro-
grade and anterograde amnesia persists for various periods,
typically 6 to 12 hours. Patients are often anxious and may repeat
the same question over and over again. Transient global amnesia
may be confused with psychogenic amnesia, fugue state, or
partial complex status epilepticus. Transient global amnesia is
thought to reflect underlying vascular insufficiency to the hip-
pocampus or midline thalamic projections.
Unlike patients with organic memory disturbances, patients
with psychogenic amnesia typically have inconsistent loss of
recent and remote memory, relatively more loss of emotionally
charged memory (rather than relatively less loss of such memory
in organic disease), and an apparent indifference to their own
plight; they ask few questions. Most characteristically, patients
with psychogenic amnesia tend to express disorientation to
person (asking, Who am I?), a phenomenon seldom seen in
organic memory disturbance.
Patients with severe depression may exhibit pseudodementia.
Vegetative signs, including changes in appetite, weight, and sleep
pattern, are common, whereas signs of cortical impairment, such
as aphasia, agnosia, and apraxia, are rare. Memory and brady­
phrenia improve with antidepressant therapy. Depression often
coexists with other causes of dementia, such as AD, Parkinson’s
disease, and vascular dementia.
For a deeper discussion on this topic, please see Chapter
402, “Alzheimer’s Disease and Other Dementias,” in
Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Bateman RJ, Xiong C, Benzinger TLS, et al: Clinical and biomarker changes in
dominantly inherited Alzheimer’s disease, N Engl J Med 367:795–804, 2012.
Carrillo MC, Brashear HR, Logovinsky V, et al: Can we prevent Alzheimer’s
disease? Secondary “prevention” trials in Alzheimer’s disease, Alzheimers
Dement 9:123–131, 2013.
Castellani RJ, Perry G: Pathogenesis and disease-modifying therapy in Alzheimer’s
disease: the flat line of progress, Arch Med Res 43:694–698, 2012.
Iqbal K, Flory M, Soininen H: Clinical symptoms and symptom signatures of
Alzheimer’s disease subgroups, J Alzheimers Dis 37:475–481, 2013.
Ling SC, Polymenidou M, Cleveland DW: Converging mechanisms in ALS and
FTD: disrupted RNA and protein homeostasis, Neuron 79:416–438, 2013.
McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due
to Alzheimer’s disease: recommendations from the National Institute on Aging
and the Alzheimer’s Association workgroup, Alzheimers Dement 7:263–269,
2011.
Perry DC, Miller BL: Frontotemporal dementia, Semin Neurol 33:336–341,
2013.

Major Disorders of Mood,
Thoughts, and Behavior
  CLASSIFICATION OF MENTAL DISORDERS
Mental (psychiatric) disorders are alterations in thoughts, feel-
ings, or behaviors that produce substantive subjective distress or
affect the patient’s functional status. Many mental disorders are
caused by the direct effects of drugs, systemic disease, or neuro-
logic disease on brain physiology. They may be broadly consid-
ered as secondary psychiatric disorders, as opposed to the
primary or idiopathic psychiatric disorders. The distinguishing
feature of neurocognitive disorders is impairment in intellectual
functions such as level of consciousness, orientation, attention,
or memory; however, these disorders also often include disrup-
tion of mood, thoughts, and behaviors similar to that seen in
other psychiatric syndromes. Neurocognitive disorders are the
focus of Chapters 105 and 108.
The noncognitive secondary syndromes by definition cause
psychiatric phenomena similar to their idiopathic counterparts.
During the evaluation of any patient with new or worsened psy-
chiatric symptoms, it is essential to conduct a thorough evalua-
tion for other medical causes, including a careful history and
physical examination (with a screening neurologic examination)
that often are supplemented by laboratory evaluations. Table
109-1 outlines important causes of psychiatric syndromes.
Although some conditions are likely to produce certain psychiat-
ric syndromes, many manifest as any of several psychiatric syn-
dromes. Conversely, a psychiatric syndrome may be caused by
any of a wide range of conditions.
Because the cause of primary psychiatric disorders is unknown,
approaches to classification depend on reliable empirical obser-
vations of phenomena clustered into recognizable syndromes.
Table 109-2 shows the most important psychiatric syndromes
TABLE 109-1  IMPORTANT CAUSES OF PSYCHIATRIC
SYNDROMES
CENTRAL NERVOUS SYSTEM SYSTEMIC DISEASES
CONDITIONS
Cardiovascular diseases
Tumor Pulmonary diseases
Toxins Cancer
Vascular disorders Infection
Seizure Nutritional disorders
Infection Endocrine disorders
Genetic disorders Metabolic disorders
Congenital malformation
DRUGS
Demyelinating conditions
Degenerative conditions Drug intoxication
Hydrocephalus Drug withdrawal
109 
ss
Jeffrey M. Lyness
and the disorders in which they may manifest. Table 109-3 shows
the major idiopathic disorders, excluding addictive disorders (see
Chapter 126). Many psychiatric disorders manifest with multiple
syndromes. For example, major depression with psychotic fea-
tures manifests with a depressive syndrome and a psychotic syn-
drome. In evaluating a patient with new or worsened psychiatric
symptoms, the clinician must construct a differential diagnosis
based on syndromes alongside the differential diagnosis based on
potential secondary causes.
  DEPRESSIVE AND BIPOLAR DISORDERS
Depressive and bipolar disorders are characterized by idiopathic
episodes of depression alone (i.e., unipolar) or mania and depres-
sion (i.e., bipolar). The core symptoms of depressive episodes
include emotional symptoms (e.g., dysphoria, irritability, anhe-
donia, loss of interests), ideational symptoms (e.g., thoughts with
hopeless, worthless, guilty, or suicidal themes), and neurovegeta-
tive symptoms and signs (e.g., anergia; psychomotor slowing or
agitation; decreased concentration; altered sleep, appetite, and
weight).
Major depressive disorder is defined by episodes of a least five
symptoms, including depressed mood, anhedonia, or loss of
interests, that occur almost every day for at least 2 consecutive
weeks, sufficient to cause significant distress and affect functional
status. Other prominent symptoms may include associated
anxiety, somatic worry, or new somatic symptoms, and in the
most severe cases, psychotic symptoms, including nihilistic or
self-deprecatory (i.e., mood-congruent) delusions.
Major depression is common, with a 12-month prevalence of
approximately 7% and a lifetime prevalence of up to 10% among
men and 20% to 25% in women. New depressive episodes have
an annual incidence of approximately 3%. First onset may occur
at any age but is most common in the third through fifth decades
of life. Whereas most episodes of major depression fully remit
spontaneously or with treatment, the lifetime risk of recurrence
is at least 50% to 70%, and up to 20% of patients may experience
chronic symptoms over many years. Major depression is a leading
correlate of disability worldwide, is an important determinant of
death by suicide, and is associated with increased risk of death
from comorbid physical illnesses. Persistent depressive disorder
(i.e., dysthymia) is a condition defined by chronic depressive
symptoms, often of insufficient severity to meet criteria for major
depression.
Depressive disorders are heterogeneous, with many potential
pathogenic mechanisms. Genetic factors, such as polymorphisms
985
 986 Section XVI  Neurologic Disease

ss
TABLE 109-2  IMPORTANT PSYCHIATRIC SYNDROMES
SYNDROME MAIN SYMPTOMS AND SIGNS DISORDERS
Neurocognitive Impairment in intellectual functions (e.g., level of consciousness, Neurocognitive disorders
orientation, attention, memory, language, praxis, visuospatial, Intellectual disability (if onset in childhood)
executive functions)
Mood Depressive: lowered mood, anhedonia, negativistic thoughts, Neurocognitive disorders
neurovegetative symptoms Mood disorders (bipolar or depressive) (primary or secondary)
Manic: elevated or irritable mood; grandiosity; goal-directed Psychotic disorders (schizoaffective disorder)
hyperactivity with increased energy; pressured speech; decreased
sleep need
Anxiety All include anxious mood and associated physiologic signs and Neurocognitive disorders
symptoms (e.g., palpitations, tremors, diaphoresis) Mood disorders (bipolar or depressive) (primary or secondary)
May include various types of dysfunctional thoughts (e.g., Psychotic disorders (primary or secondary)
catastrophic fears, obsessions, flashbacks) and behaviors (e.g., Anxiety disorders (primary or secondary)
compulsions, avoidance behaviors)
Psychotic Impairments in reality testing: hallucinations, thought process Neurocognitive disorders
derailments Mood disorders (bipolar or depressive) (primary or secondary)
Psychotic disorders
Somatic symptom Somatic symptoms with associated distressing thoughts, feelings, or Mood disorders (bipolar or depressive) (primary or secondary)
syndromes behaviors Anxiety disorders (primary or secondary)
Obsessive-compulsive and related disorders
Trauma-related disorders
Somatic symptom disorders
Personality pathology Dysfunctional enduring patterns of emotional regulation, thought Neurocognitive disorders
patterns, interpersonal behaviors, impulse regulation Personality change due to another medical condition
Personality disorders
Data from American Psychiatric Association: Diagnostic and statistical manual of mental disorders, ed 5, Washington, D.C., 2013, American Psychiatric Association.

of the serotonin transporter protein, affect vulnerability to
depressive episodes in the face of psychosocial stressors. Depres-
sion is polygenic and multifactorial, with genetic factors account-
ing for about 40% of the risk. Alterations in the functioning of
brain serotonergic and noradrenergic systems and of the
hypothalamic-pituitary-adrenal axis are found in depression.
Neuroimaging studies show smaller hippocampal volumes and
altered metabolic activity in several regions, including the ante-
rior cingulate cortex. However, the information in these studies
is not sufficient for making the clinical diagnosis, which depends
on identification of the clinical syndrome. Dysfunctional, nega-
tivistic patterns of thinking, impaired social relationships, and
stressful life events also contribute to depression.
Mild to moderate forms of major depression respond to
focused psychotherapies or antidepressant medications (level A
evidence) (Table 109-4). More severe forms of depression do not
respond to psychosocial interventions alone. Severe or refractory
depression may be treated safely and effectively with electrocon-
vulsive therapy (level A). Other evidence-based somatic thera-
pies include light therapy (for depression with a seasonal
component) and vagal nerve stimulation (levels B and C). Data
suggest that the dissociative anesthetic ketamine, an N-methyl-d-
aspartate (NMDA) receptor antagonist, may rapidly improve
patients with treatment-resistant depression, although the general
clinical applicability of ketamine remains to be determined.
Bipolar disorder (i.e., bipolar I) is characterized by recurrent
episodes of mania, usually with episodes of major depression.
Manic episodes include elevated (euphoric) or irritable mood,
goal-directed hyperactivity (often for pleasurable activities with
poor judgment leading to substantial adverse consequences such
as sexual, spending, or gambling sprees), pressured speech,
increased energy level with a decreased need for sleep, and
distractibility.
Compared with unipolar depression, bipolar disorder has a
lower 12-month prevalence (approximately 0.6%) and a younger
average age of onset (typically late teens to 20s). Unlike unipolar
depression, bipolar disorder is slightly more common among
males. Most patients return to baseline functioning between
acute mood episodes, but some have a deteriorating course, and
others have frequent debilitating episodes (i.e., rapid cycling of
four episodes per year).
Genetic factors play a greater role in the pathogenesis of
bipolar disorder than in major depressive disorder, accounting
for approximately 50% of the risk and representing a greater than
50-fold increase over the population base rate. Bipolar disorder
is polygenic and has been linked in individual families to different
loci. The pathogenesis is unclear but likely involves dysregulation
of frontostriatal systems. Structural neuroimaging studies show
increased ventricular-to-brain ratios, suggesting parenchymal
atrophy. Psychosocial stressors often play a role in precipitating
episodes of mania and depression.
The mainstay of treatment for bipolar disorder is mood stabi-
lizer medications (e.g., lithium, anticonvulsants such as valproic
acid and carbamazepine) for acute episodes and maintenance
therapy (level A evidence). The anticonvulsant lamotrigine may
be particularly useful for bipolar depression. Antipsychotic medi-
cations are useful for acute manic episodes and may have a role
in maintenance therapy. Benzodiazepines may be used to treat
acute agitation and aggression while waiting for more definitive
antimanic therapies to take effect. Antidepressants have long
been used for depressive episodes, although they may precipitate
manic episodes.
Electroconvulsive therapy is effective for refractory mania
(level B evidence) and depression (level A). Psychosocial treat-
ments alone do not effectively treat mania and may be less effec-
tive for bipolar depression, but psychoeducation and support to
 Chapter 109  Major Disorders of Mood, Thoughts, and Behavior 987

TABLE 109-3  MAJOR IDIOPATHIC (PRIMARY) TABLE 109-4  PSYCHOTHERAPIES FOR DEPRESSION ss

DISORDERS OF MOOD, THOUGHTS, AND ANTIDEPRESSANT MEDICATIONS

AND BEHAVIOR APPROACH OR
MOOD DISORDERS PERSONALITY DISORDERS NAME MECHANISM OF ACTION
Depressive (Unipolar) Cluster A: Odd Eccentric PSYCHOTHERAPY
Major depressive disorder Schizoid personality disorder Cognitive psychotherapy Identify and correct negativistic patterns
Persistent depressive disorder (detachment from social of thinking
(dysthymia) relationships, restricted emotional Interpersonal psychotherapy Identify and work through role transitions
expression) or interpersonal losses, conflicts, or
Bipolar deficits
Schizotypal personality disorder
Bipolar disorder (social and emotional deficits, Problem-solving therapy Identify and prioritize situational
Cyclothymic disorder cognitive or perceptual distortions, problems; plan and implement strategies
Bipolar II disorder (bipolar disorder eccentric behavior) to deal with top-priority problems
not otherwise specified) Paranoid personality disorder COMMONLY USED ANTIDEPRESSANTS
ANXIETY DISORDERS (pervasive distrust and
suspiciousness) Selective serotonin reuptake Inhibit presynaptic reuptake of serotonin
Panic disorder (without or with inhibitors (SSRIs)
agoraphobia) Cluster B: Dramatic or Emotional   Citalopram and escitalopram
Generalized anxiety disorder Borderline personality disorder   Fluoxetine
Social phobia (instability of interpersonal   Paroxetine
Specific phobia relationships, self-image, and   Sertraline
affects, and impulsivity) Serotonin and Inhibit presynaptic reuptake of serotonin
OTHER CONDITIONS WITH
Narcissistic personality disorder norepinephrine reuptake and norepinephrine
ANXIETY AS A PROMINENT
(grandiosity, need for admiration, inhibitors (SNRIs)
FEATURE
lack of empathy)   Duloxetine
Obsessive-compulsive disorder Antisocial personality disorder   Venlafaxine and
Acute stress disorder, posttraumatic (disregard for and violation of the desvenlafaxine
stress disorder rights of others) Tricyclic antidepressants Inhibit presynaptic reuptake of serotonin
PSYCHOTIC DISORDERS Histrionic personality disorder (TCAs) and norepinephrine (in various
  Amitriptyline proportions depending on the
Schizophrenia Cluster C: Anxious or Fearful   Desipramine specific TCA)
Schizophreniform disorder Avoidant personality disorder (social   Doxepin
Brief psychotic disorder inhibition, feelings of inadequacy,   Imipramine
Schizoaffective disorder hypersensitivity to criticism)   Nortriptyline
Delusional disorder Dependent personality disorder Monoamine oxidase Inhibit monoamine oxidase, the enzyme
SOMATIC SYMPTOM DISORDERS (pervasive and excessive need to inhibitors (MAOIs) that catalyzes oxidative metabolism of
be taken care of, leading to   Isocarboxazide monoamine neurotransmitters
Somatic symptom disorder submissive and clinging behavior   Phenelzine
Illness anxiety disorder and fears of separation)   Selegiline Selective MAO-B inhibitor
Conversion (functional neurologic Obsessive-compulsive personality   Tranylcypromine
symptom) disorder disorder (preoccupation with Other drugs
Psychological factors affecting orderliness, perfectionism, and   Bupropion Unknown, although it is weak inhibitor of
physical condition mental and interpersonal control, presynaptic reuptake of norepinephrine
Factitious disorder (i.e., at the expense of flexibility, and dopamine
Munchausen’s syndrome) openness, and efficiency)   Mirtazapine Serotonin (5-hydroxytryptamine [5-HT])
antagonist at α2 and 5-HT2 receptors
Data from American Psychiatric Association: Diagnostic and statistical manual of mental
disorders, ed 5, Washington, D.C., 2013, American Psychiatric Association.
  Trazodone Inhibits presynaptic reuptake of serotonin;
antagonist at 5-HT2 and 5-HT3
receptors
manage psychosocial stressors and encourage medication com-   Vilazodone Inhibits presynaptic reuptake of serotonin;
agonist at 5-HT1A receptors
pliance improve longer-term outcomes.
A spectrum of less severe bipolar disorders includes condi-
tions marked by episodes of hypomania (i.e., low-level manic
symptoms without psychosis or significant impairment in func- emotional sensation of anxiety. A panic attack is a transient
tioning). They include bipolar II disorder, characterized by epi- episode of crescendo anxiety, catastrophic thoughts (e.g., fears of
sodes of hypomania and major depression, and cyclothymic dying, going insane, losing self-control), and somatic symptoms.
disorder, characterized by hypomania and low-level depression If panic attacks or other clinically significant anxiety symptoms
not meeting criteria for major depression. Because patients with occur only in predictable response to environmental stimuli, the
bipolar II disorder are most likely to seek care during depressive anxiety disorder is known as a phobia, which may further be clas-
episodes, it is important to inquire about a history of manic sified as agoraphobia (i.e., anxiety about being in places from
symptoms to avoid precipitating mania with the use of antide- which escape may be difficult or embarrassing such as being
pressant medications. The pathogeneses of these less severe alone, in crowds, in tunnels, or on bridges), social phobia (i.e.,
mood disorders is unclear. anxiety in interpersonal situations); and specific phobia (i.e.,
anxiety provoked by other situations or objects such as blood,
  DISORDERS WITH ANXIETY animals, or heights). Panic disorder manifests with recurrent
AS A PROMINENT FEATURE panic attacks, some of which are unexpected and unpredictable,
The idiopathic anxiety disorders manifest with troublesome along with anticipatory anxiety (i.e., fear of having another
thoughts and somatic symptoms (Table 109-5) along with the attack) and avoidance behaviors (i.e., avoiding situations that
 988 Section XVI  Neurologic Disease
ss
TABLE 109-5  COMMON SOMATIC SYMPTOMS
OF ANXIETY
CARDIORESPIRATORY GENITOURINARY
Palpitations Urinary frequency or urgency
Chest pain
NEUROLOGIC OR AUTONOMIC
Dyspnea or sensation of being
smothered Diaphoresis
Warm flushes
GASTROINTESTINAL
Dizziness or presyncope
Sensation of choking Paresthesia
Dyspepsia Tremor
Nausea Headache
Diarrhea
Abdominal bloating or pain
may provoke a panic attack or in which having an attack is per-
ceived to be embarrassing or dangerous).
Other disorders may not cause discrete panic attacks.
Obsessive-compulsive disorder is characterized by recurrent
obsessions (i.e., thoughts, impulses, or mental images that are
anxiety-producing, perceived as intrusive and inappropriate, and
resistant to attempts to suppress or neutralize them) and compul-
sions (i.e., repetitive behaviors or mental acts performed in
response to obsessions or other rigid rules). Recognizing its dis-
tinct pathogenesis involving striatofrontal function and central
serotonergic systems, it has been classified separately from the
anxiety disorders.
Individuals exposed to severely stressful events (typically
involving the actual or threatened loss of life or limb) may
experience any of a wide variety of psychiatric sequelae. If the
sequelae include symptoms of intrusion (e.g., intrusive memo-
ries, dreams, flashbacks, intense distressing responses to remind-
ers of the trauma), avoidance of distressing memories or external
reminders, negative cognitions and mood (e.g., amnesia for
aspects of the event, negativistic thoughts about oneself in
general or self-blame for the event, diminished interests or
activities, feelings of detachment), and alterations in arousal
and reactivity, the disorder is called acute stress disorder (dura-
tion up to 1 month) or posttraumatic stress disorder (duration
is more than 1 month). Enduring anxiety symptoms that are
not captured by these diagnoses or by diagnoses of cognitive,
mood, or psychotic disorders may be diagnosed as generalized
anxiety disorder.
These disorders are common, with point prevalence of 1% to
2% each for panic disorder and obsessive-compulsive disorder
and up to 10% for phobias. Although there are fewer data on
long-term outcome than for mood disorders, many of these dis-
orders tend to have a chronic waxing and waning course. Most of
these disorders have a first onset in the teens, 20s, and 30s,
although new-onset anxiety is common in later life. The cause is
rarely a primary anxiety disorder (see Table 109-2).
The pathogeneses of most anxiety disorders may be under-
stood as inappropriate activation of the stress response system
involving a variety of neuroendocrine and autonomic outputs
and coordinated by the central nucleus of the amygdala and other
brain structures. The amygdala receives excitatory glutamatergic
inputs from cortical sensory areas and the thalamus and has
outputs to the major monoaminergic centers (e.g., noradrenergic
neurons of the locus coeruleus, dopaminergic neurons of the
ventral tegmental area, and serotonergic neurons of the raphe
nuclei), which project to the many brain regions subserving the
symptoms of anxiety.
The identification and correction of dysfunctional patterns of
thinking (i.e., cognitive therapy) and the extinction of pathologic
behaviors and positive reinforcement of more functional behav-
iors (i.e., behavior therapy) are evidence-based psychotherapies
useful in most anxiety disorders (level A evidence). They are the
sole therapies for specific phobias and may be the sole or primary
therapy for most other anxiety disorders or combined with
pharmacotherapy.
Antidepressant, anxiolytic, and other drug therapies are used
in treatment. Increasingly, antidepressant medications have
replaced anxiolytics as the mainstay of pharmacotherapy for
panic disorder, posttraumatic stress disorder, generalized social
phobia, and generalized anxiety disorder. For obsessive-
compulsive disorder, only antidepressant agents with pronounced
activity on the serotonergic system (i.e., clomipramine and selec-
tive serotonin reuptake inhibitors [SSRIs]; see Table 109-4) are
efficacious.
  PSYCHOTIC DISORDERS
Psychosis is a loss of reality testing, manifested as hallucinations
(i.e., false sensory perceptions), delusions (i.e., fixed false beliefs),
and thought process derailments. Schizophrenia is the prototypic
psychotic disorder; it includes acute episodes of psychosis (i.e.,
positive symptoms) and often declining overall functioning over
time related to the negative symptoms such as affective flattening,
abulia, apathy, and social withdrawal.
The lifetime prevalence of schizophrenia is slightly less than
1%, and its chronic, debilitating course takes a considerable toll
on patients, families, and society. Peak onset is in late adolescence
to young adulthood, with slightly younger ages for males than
females. The annual incidence is approximately 15 cases per
100,000 people, but with marked variability across study samples
and populations. The condition is slightly more common in
males than females.
The pathogenesis of schizophrenia remains unknown, but it is
clearly multifactorial. Genetic factors account for up to 50% of
the risk, with multiple loci implicated. Studies of postmortem
brains indicate a nongliotic neuropathologic process with subtle
disruptions of cortical cytoarchitecture. It is likely that psychoso-
cial factors and neurodevelopment interact with a nonlocalizable
brain lesion present at birth or acquired early in life. Dopaminer-
gic mesocortical and mesolimbic pathways are important in the
production of psychotic symptoms.
Antipsychotic medications, often with adjunctive benzodiaz-
epines, are used to treat acute psychotic episodes. Although
maintenance antipsychotic medications help reduce the severity
and frequency of acute psychotic episodes (level A evidence),
comprehensive psychosocial rehabilitation programs are required
to help patients manage interpersonal and other stressors and to
improve overall clinical outcomes. Adjunctive cognitive-
behavioral therapy also may improve outcomes for some patients
(level A). Second-generation (atypical) antipsychotic medica-
tions have replaced first-generation antipsychotics in common
U.S. practice because of their lower rates of extrapyramidal side
effects, including tardive dyskinesia. However, second-generation
drugs contribute to an increase in obesity and metabolic
syndrome.
 Chapter 109  Major Disorders of Mood, Thoughts, and Behavior 989
Schizoaffective disorder is a chronic, recurrent disorder with a
prevalence slightly lower than that of schizophrenia. It is charac-
terized by episodes of nonmood psychosis and mood episodes
(i.e., manic or depressed) with psychotic features. Its diagnosis
therefore cannot be based on the patient’s clinical findings at any
one point in time but requires knowledge of the overall course.
The outcomes of schizoaffective disorder are heterogeneous but
on average are intermediate between schizophrenia and mood
disorders. Treatment is symptomatic, using antipsychotic, mood
stabilizing, and antidepressant medications to target specific psy-
chotic and mood symptoms.
Delusional disorder is characterized by delusions in the
absence of thought process disorder, prominent hallucinations,
or the negative symptoms of schizophrenia. The delusions may
be potentially plausible (i.e., not bizarre). Delusional disorder has
a lifetime prevalence of approximately 0.2%. It often is only par-
tially responsive to antipsychotic medications, but patients’ func-
tioning may be largely unimpaired if they are able with the aid of
antipsychotics and psychotherapy to avoid acting on their delu-
sions. The pathogeneses of the nonschizophrenic primary psy-
chotic disorders remain largely unknown.
  SOMATIC SYMPTOM DISORDER AND
RELATED DISORDERS
Formerly called somatoform disorders, these conditions include
somatic symptoms and associated thoughts, feelings, or behav-
iors that are distressing and disabling. Prominent types include
somatic symptom disorder (i.e., excessive thoughts, feelings, or
behaviors associated with one or more somatic symptoms),
illness anxiety disorder (i.e., illness preoccupation and health-
related behaviors disproportionate to somatic symptoms), con-
version (i.e., functional neurologic symptom) disorder (i.e.,
neurologic somatoform symptoms incompatible with recognized
neurologic or general medical conditions), and psychological
factors affecting physical conditions. Factitious disorder (i.e.,
Munchausen’s syndrome) is a mental disorder in which patients
consciously produce stigmata of disease (e.g., simulated or artifi-
cially induced fever or hypoglycemia) for the unconscious gain
of assuming the sick role.
Although identifiable physical disease is insufficient to fully
explain the patient’s presentation, in all these conditions other
than factitious disorder, the patient’s distress and dysfunction are
not consciously produced and are just as distressing to patients as
would be similar symptoms produced by other medical condi-
tions. Malingering is the conscious feigning of illness for con-
scious gain and therefore is not a mental disorder.
  PERSONALITY DISORDERS
Personality is defined as the repertoire of enduring patterns of
inner mental experience and behavior, including affect and
impulse regulation, defense and coping mechanisms, and inter-
personal relatedness. Personality traits must be distinguished
from time-limited states. For example, a patient who exhibits
dependent features solely while acutely depressed does not have
a dependent personality.
A personality disorder is diagnosed when personality traits
lead to pervasive (if variable) subjective distress or dysfunction
in a broad range of situations. The major personality disorders are
listed in Table 109-3. Personality and personality disorders are
the result of complex interactions among genetic, environmental,
and developmental factors. Approaches to patients with person- ss
ality disorders depend on the specific type, but in most clinical
circumstances other than long-term psychotherapy, the realistic
goal is not to alter fundamental personality structure but to help
the patient maximize use of personality strengths (e.g., optimal
defense mechanisms) while minimizing the harmful effects of
emotional dysregulation, unhelpful defenses, and destructive
behaviors.
Although not the mainstay of most treatments for personality
disorders, pharmacotherapy can be useful in selected patients
(e.g., antipsychotics to target escalating paranoia in paranoid per-
sonality disorder, mood stabilizers or antidepressants to target
emotional dysregulation in borderline personality disorder).
Patients with personality disorders are also prone to mood,
anxiety, eating, addictive, and other treatable psychiatric
disorders.
  PROSPECTUS FOR THE FUTURE
Advances in neuroscience will lead to better pharmacologic or
other somatic therapies. One example, deep brain stimulation,
is being studied for severe refractory mood and anxiety dis-
orders. In the future, regimens tailored for each individual may
be based on genomic or proteomic profiles. These same advances
may help identify patients for whom evidence-based psycho-
therapies or other psychosocial interventions are most likely
to be effective. Identification of more specific and powerful
risk markers may lead to the development of preventive inter-
ventions for at-risk individuals or groups. The current U.S.
health care system, however, provides barriers that often prevent
implementation of mental health treatments, although this may
change in light of recent incentives to improve the health of
populations.
SUGGESTED READINGS
American Psychiatric Association: Diagnostic and statistical manual of mental
disorders, ed 5, Arlington, VA, 2013, American Psychiatric Association.
Anderson IM, Haddad PM, Scott J: Bipolar disorder, BMJ 345:e8508, 2012.
Bateman AW: Treating borderline personality disorder in clinical practice, Am J
Psychiatry 169:560–563, 2012.
Gask L, Evans M, Kessler D: Clinical review: personality disorder, BMJ 347:f5276,
2013.
Geddes JR, Miklowitz DJ: Treatment of bipolar disorder, Lancet 381:1672–1682,
2013.
Kupfer DJ, Frank E, Phillips ML: Major depressive disorder: new clinical,
neurobiological, and treatment perspectives, Lancet 379:1045–1055, 2012.
Leucht S, Tardy M, Komossa K, et al: Antipsychotic drugs versus placebo for
relapse prevention in schizophrenia: a systematic review and meta-analysis,
Lancet 379:2063–2071, 2012.
Leucht S, Cipriani A, Spineli L, et al: Comparative efficacy and tolerability of 15
antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis,
Lancet 382:951–962, 2013.
Murrough JW, Iosifescu DV, Chang LC, et al: Antidepressant efficacy of ketamine
in treatment-resistant major depression: a two-site randomized controlled
trial, Am J Psychiatry 170:1134–1142, 2013.
Rector NA, Beck AT: Cognitive behavioral therapy for schizophrenia: an
empirical review, J Nerv Ment Dis 200:832–839, 2012.
Tol WA, Barbui C, van Ommeren M: Management of acute stress, PTSD, and
bereavement: WHO recommendations, JAMA 310:477–478, 2013.
Wetherell JL, Petkus AJ, White KS, et al: Antidepressant medication augmented
with cognitive-behavioral therapy for generalized anxiety disorder in older
adults, Am J Psychiatry 170:782–789, 2013.
 110 
Autonomic Nervous
System Disorders
ss
William P. Cheshire, Jr.
  DEFINITION AND EPIDEMIOLOGY
The autonomic nervous system reaches throughout the body and
governs all visceral activity. Its central network and peripheral
sympathetic and parasympathetic divisions integrate complex
organ functions, maintain internal homeostasis in response to
environmental change, modulate the flight-or-fight physiologic
response to stress, and enable circulation, digestion, and
procreation.
Benign dysautonomias are common. Neurally mediated
syncope and situational reflex syncope in response to emotional
distress, carotid sinus stimulation, micturition, defecation,
coughing, straining, or other factors occur in about 20% of people
during a lifetime and account for 1% to 3% of all emergency room
visits. Hyperhidrosis of the palms and soles affects about 1% of
the population. Anhidrosis can contribute to increased mortality
rates during severe heat stress.
One of the most disabling manifestations of autonomic failure
is orthostatic hypotension, the prevalence of which increases
with age, physical inactivity, and in diseases that impair sympa-
thetic adrenergic nerves. Orthostatic hypotension affects about
5% to 20% of the elderly.
Diabetes mellitus is the most common cause of autonomic
neuropathy in industrialized nations. About 30% of diabetics
develop autonomic neuropathy, and symptomatic orthostatic
hypotension occurs in 5% of patients. Other features of auto-
nomic neuropathy include constipation in 40% to 60% of diabet-
ics, gastroparesis in 20% to 40%, bladder dysfunction in 30% to
80%, and erectile impotence in more than 30% of men.
For a deeper discussion of these topics, please see Chapter
25, “Common Clinical Sequelae of Aging,” and Chapter
229, “Diabetes Mellitus,” in Goldman-Cecil Medicine,
25th Edition.
  PATHOLOGY
Many brain, spinal cord, peripheral nerve, and systemic disorders
that impair autonomic nerves can cause autonomic dysfunction
or failure. They include a wide range of degenerative, traumatic,
cerebrovascular, autoimmune, genetic, metabolic, toxic, and
pharmacologic conditions.
Small-caliber peripheral autonomic nerves are unmyelinated
or thinly myelinated, and small-fiber peripheral neuropathies
that cause distal sensory loss may also involve sympathetic
990
or parasympathetic nerves. Diabetic autonomic neuropathy
results from microvascular damage to autonomic nerves.
Several hereditary, infectious, metabolic, toxic, and drug-
induced sensory and autonomic neuropathies are recognized
causes.
Accumulation of abnormal proteins distinguishes some of the
degenerative dysautonomias. Oligodendroglial cytoplasmic
inclusions composed of aggregates of misfolded α-synuclein are
pathognomonic of multiple system atrophy. Abnormally folded
sympathetic neuronal accumulation of α-synuclein occurs in
Lewy body disorders such as Parkinson’s disease. Peripheral auto-
nomic nerve deposition of β-pleated sheet amyloid protein
causes a severe autonomic neuropathy, which is frequently seen
in primary amyloidosis, immunoglobulin light chain–associated
disease, and hereditary amyloidosis, although rarely in reactive
amyloidosis.
Other dysautonomias have an autoimmune basis. Autonomic
instability has long been recognized in Guillain-Barré syndrome,
which is an acute inflammatory, demyelinating polyradiculoneu-
ropathy associated with antiganglioside antibodies (e.g., anti-
GM1, anti-GM3). The list of autoimmune autonomic neuropathies
includes acute autonomic ganglionopathy; patients with acute
pandysautonomia have antibodies against the nicotinic acetyl-
choline receptor in autonomic ganglia, which is sometimes asso-
ciated with lung cancer or thymoma. Additional paraneoplastic
autonomic neuropathies include those associated with antineu-
ronal nuclear antibody type 1 (i.e., ANNA-1 or anti-Hu) and
antibodies against collapsing response mediator proteins (i.e.,
CRMP-5 or anti-CV2). Lambert-Eaton myasthenic syndrome is
associated with antibodies to voltage-gated calcium channels.
Antibodies to voltage-gated potassium channels cause autoim-
mune neuromyotonia and dysautonomia with hyperhidrosis and
orthostatic intolerance.
Pharmacologic agents frequently alter autonomic function.
Diuretics, sympatholytic drugs, α-adrenoreceptor blockers, and
vasodilators can cause or contribute to orthostatic hypotension.
Anticholinergics and carbonic anhydrase inhibitors decrease
sweating, whereas opioids and selective serotonin reuptake
inhibitors increase sweating. Opioids slow intestinal transit. Anti-
cholinergics, tricyclic antidepressants, and antihistamines may
cause urinary retention.
Functional dysautonomias are medical conditions in which
autonomic function is impaired in the absence of a known struc-
tural neurologic deficit. Some psychological disorders may
 Chapter 110  Autonomic Nervous System Disorders 991
manifest with autonomic symptoms because emotional and
autonomic centers are closely linked in the limbic system.
For a deeper discussion of these topics, please see
Chapter 420, “Peripheral Neuropathies,” Chapter 188,
“Amyloidosis,” and Chapter 47, “Mechanisms of Immune-
Mediated Tissue Injury,” in Goldman-Cecil Medicine, 25th
Edition.
  CLINICAL PRESENTATION
Clinical manifestations of autonomic disorders vary according to
which nerves are involved and how severely. Autonomic signs
and symptoms may be benign or serious, paroxysmal or continu-
ous, or localized or generalized, and they may represent hypo-
function or hyperfunction.
Afferent autonomic lesions that separate central autonomic
nuclei from incoming information needed to gauge an appropri-
ate response may cause excessive or erratic autonomic outflow.
An example of afferent dysautonomia is the volatile hypertension
in carotid arterial baroreceptor failure after irradiation to treat
laryngeal carcinoma. Spinal cord injuries above the level of sym-
pathetic outflow at T5 can cause autonomic dysreflexia, a condi-
tion of paroxysmal sympathetic surges with hypertension,
diaphoresis, flushing, and headache. Catastrophic brain disorders
such as subarachnoid hemorrhage, trauma, or hydrocephalus
may also cause autonomic storms if hypothalamic circuits are
released from cortical inhibition.
More common are efferent autonomic lesions, which cause
failure of outflow to neuroeffector junctions, resulting in inade-
quate excitatory or inhibitory autonomic responses. An example
of efferent dysautonomias is autonomic peripheral neuropathy,
which may accompany distal sensory loss and decreased Achilles
tendon jerks.
Adrenergic failure impairs the cardiac and peripheral vascular
response needed to maintain blood pressure during orthostatic
stress. Typical symptoms of adrenergic failure include lighthead-
edness or fatigue on standing that is relieved by sitting.
Vagal failure impairs cardiac parasympathetic tone that may
protect against arrhythmogenic sympathetic activity. Patients
have a fixed heart rate that does not vary with respiration.
Sudomotor failure with extensive anhidrosis may coexist with
tonic pupils and areflexia (i.e., Ross syndrome), and it can
increase the risk of heat exhaustion or heat stroke. A dramatic
example of regional sudomotor failure is harlequin syndrome, in
which hemifacial cutaneous sympathetic denervation divides the
pale and dry denervated half of the face from the intact half that
flushes red in response to heat stress. Horner’s syndrome (i.e.,
unilateral ptosis, miosis, and anhidrosis) may be identified.
The clinical hallmark of generalized autonomic failure is severe
orthostatic hypotension without pulse acceleration. In at least
one half of patients, it is accompanied by supine and nocturnal
hypertension, a reversal of the normal diurnal decrease in blood
pressure during sleep. In addition to vagal and sudomotor failure,
patients with generalized autonomic failure may have constipa-
tion, gastroparesis, bladder dysfunction, male erectile dysfunc-
tion, dry mouth, or dry eyes. Some have postprandial hypotension,
in which a large meal high in carbohydrate content causes a
reduction in blood pressure.
One of the most severe autonomic disorders is multiple system
atrophy, which is a sporadic, progressive, ultimately fatal neuro- ss
degenerative disorder in which autonomic failure occurs in
combination with parkinsonism or cerebellar ataxia. Bladder
hypotonia with overflow incontinence and nocturnal respiratory
stridor may occur. The parkinsonian phenotype (i.e., Shy-Drager
syndrome) tends to respond poorly to levodopa. Orthostatic
hypotension is also common in Lewy body disorders such as
Parkinson’s disease. Pure autonomic failure consists of wide-
spread autonomic failure without other neurologic features.
In contrast to autonomic failure, neurally mediated syncope
occurs in patients with a functioning autonomic nervous system
in which there is a reversal of normal autonomic outflow. Prodro-
mal features typically include pallor, sweating, nausea, abdominal
discomfort, mydriasis, increased respiratory rate, and cognitive
slowing, which may progress to transient loss of consciousness
if the patient continues in an upright posture. Withdrawal of
peripheral sympathetic vasomotor tone (i.e., vasodepressor
syncope) or an increase in parasympathetic tone (i.e., vasovagal
syncope) causes a fall in blood pressure, heart rate, and cerebral
perfusion.
Orthostatic intolerance refers to a heterogeneous group of
conditions in which patients have difficulty sustaining the auto-
nomic outflow needed to maintain blood pressure during the
gravitational stress of prolonged standing. Some patients experi-
ence a gradual decline in blood pressure, but others experience
an abnormal increase in heart rate without a drop in blood
pressure.
For a deeper discussion of these topics, please see Chapter
62, “Approach to the Patient with Suspected Arrhythmia,”
Chapter 67, “Arterial Hypertension,” Chapter 136, “Disor-
ders of Gastrointestinal Motility,” and Chapter 409, “Par-
kinsonism,” in Goldman-Cecil Medicine, 25th Edition.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
A careful history and discerning physical examination are essen-
tial for reaching a diagnosis. The astute clinician inquires about
the time course of symptoms and the circumstances that provoke
or modify them. How long have they been present? Are they
stable, improving, or worsening? Do they occur consistently
or episodically? Orthostatic disorders are typically worse in
the early morning, in heat, and after physical exercise or a
large meal. How well the patient tolerates standing in line or
taking a warm shower are helpful clues to identifying orthostatic
intolerance.
Physical signs of autonomic dysfunction may include pupillary
asymmetry or sluggishness, ptosis, or mucosal dryness. An
acutely distended bladder may be suspected by percussion.
Asymmetrical sweating may be visible or palpable.
The most important part of the examination, but one that is
frequently omitted, is measurement of orthostatic blood pressure
(Fig. 110-1). Blood pressure and heart rate should be assessed
when the patient is resting supine and again after standing for 1
to 3 minutes or longer. Correlation with symptoms is key. Patients
with orthostatic hypotension may appear less alert, or they may
shift weight from one leg to the other to improve venous return,
lower the head to bring the cerebral circulation closer to the level
 992 Section XVI  Neurologic Disease
ss
A Normal
B Dehydration
Heart rate
C Neurogenic
orthostatic
hypotension
Blood pressure
D Postural
tachycardia
syndrome
Neurally
E mediated
syncope
Time
FIGURE 110-1  Orthostatic blood pressure profiles. A, The normal
response to standing or head-up tilt is no change or a small decrease
in blood pressure that recovers within one-half minute and a small
increase in heart rate. B, Dehydration causing intravascular hypovole-
mia may cause a fall in blood pressure accompanied by reflex tachycar-
dia. C, Neurogenic orthostatic hypotension may cause a more profound
drop in blood pressure. Hypotension occurs immediately and is sus-
tained without recovery during standing and often without adequate
compensatory tachycardia. D, Postural tachycardia syndrome and
other forms of orthostatic intolerance are characterized by an abnor-
mal increase in heart rate without orthostatic hypotension. E, Neurally
mediated syncope develops after standing for some time, may be pre-
ceded by oscillations in blood pressure, and may be accompanied by
bradycardia with loss of consciousness in about 7 seconds if cerebral
perfusion is not restored.
of the heart, or exhibit lower extremity rubor if cutaneous vaso-
motor function is impaired.
Orthostatic hypotension is a reduction in systolic blood pres-
sure of at least 20 mm Hg or a reduction in diastolic blood pres-
sure of at least 10 mm Hg, with or without symptoms, within 1
to 3 minutes of assuming an erect posture. Neurogenic ortho-
static hypotension is typically sustained with continued standing
and lacks the reflex tachycardia that may be seen if hypotension
is caused by blood loss, dehydration, or excessive venous pooling.
Orthostatic intolerance is a sustained increase in postural
heart rate of more than 30 beats per minute in adults (40 in ado-
lescents). In postural tachycardia syndrome, the standing heart
rate consistently exceeds 120 beats per minute.
Laboratory testing of autonomic responses under controlled
conditions is useful to determine the presence, severity, and dis-
tribution of autonomic failure. Clinical autonomic testing typi-
cally evaluates beat-to-beat blood pressure and heart rate
responses to the Valsalva maneuver, upright tilt, and periodic
deep breathing, along with quantitative assessment of sweating
responses. Ambulatory blood pressure testing is useful for the
assessment of episodic or postprandial hypotension, nocturnal
hypertension, and the volatile hypertension of autonomic storms.
  TREATMENT
Treatment options for orthostatic hypotension are outlined in
Table 110-1. The goal is to enable the patient to stand long
enough to engage in daily activities without symptoms. Medica-
tion is not always needed and can potentially exacerbate recum-
bent hypertension. Orthostatic intolerance was shown in a
randomized controlled trial to improve after endurance exercise
training (level A evidence).
Generalized hyperhidrosis may be reduced by oral anticholin-
ergic agents such as 1 to 2 mg of glycopyrrolate taken one to three
times daily (level B evidence). Topical glycopyrrolate reduces
regional gustatory sweating (level A). Subdermal botulinum
toxin injections are helpful for some forms of focal hyperhidrosis
(level A), and palmar hyperhidrosis may respond to tap water
iontophoresis (level B) or, in severe cases, to endoscopic thoracic
sympathotomy (level A).
For a deeper discussion of these topics, please see Chapter
418, “Autonomic Disorders and Their Management,” in
Goldman-Cecil Medicine, 25th Edition.
  PROGNOSIS
Orthostatic intolerance and neurally mediated syncope are fre-
quently benign, manageable, and improve or recover with time.
Autonomic failure, in contrast, can signify a more serious prog-
nosis, depending on the nature and extent of its pathophysiology.
Persistent or severe orthostatic hypotension carries a worse
prognosis.
Diabetic cardiovascular autonomic neuropathy doubles the
risk for silent myocardial ischemia and overall mortality. Amyloid
autonomic neuropathy is especially grave, with a median survival
of less than 1 year if the patient has orthostatic hypotension. Pure
autonomic failure may remain stable for many years, although
some patients with this phenotype eventually develop signs of
multiple system atrophy, which denotes a life expectancy of 7 to
9 years after diagnosis.
Regular physical exercise can reverse the autonomic decon-
ditioning that comes from inactivity. In the elderly, it may com-
pensate for some age-associated decline in autonomic function
(level B evidence).
For a deeper discussion of these topics, please see Chapter
418, “Autonomic Disorders and Their Management,” in
Goldman-Cecil Medicine, 25th Edition.
 Chapter 110  Autonomic Nervous System Disorders 993

TABLE 110-1  TREATMENT OF ORTHOSTATIC HYPOTENSION ss

INTERVENTION RATIONALE DOSAGE EVIDENCE LEVEL

CONSERVATIVE
Avoid prolonged bed rest and Reverses physiologic deconditioning B
increase time spent upright
Liberalize fluid intake Expand plasma volume 2-2.5 L/day B
Increase sodium intake Expand plasma volume Salt 10-20 g/day A
Compressive leg garments and Reduce venous pooling 15-20 mm Hg B
abdominal binder
Physical counter-maneuvers Tensing limb muscles augments venous Isometric contractions for 30 sec A
return
Water bolus treatment Sympathetic reflex increases blood 16 oz. plain water A
pressure for 1-2 hr
Elevate heads of bed 4 inches Decrease nocturnal natriuresis and C
nocturnal hypertension
Avoid large meals high in If patient is subject to postprandial B
carbohydrate content hypotension
PHARMACOLOGIC
Discontinue or decrease dose of A
blood pressure–lowering drugs
Midodrine α-Adrenergic agonist, constricts 5-10 mg tid A
capacitance vessels
Fludrocortisone Retains sodium and sensitizes peripheral 0.1-0.4 mg/day B
vascular α-adrenergic receptors
Pyridostigmine Stimulates sympathetic ganglionic 30-60 mg bid or tid B
transmission

SUGGESTED READINGS
Benarroch EE: Postural tachycardia syndrome: a heterogeneous and multifactorial
disorder, Mayo Clin Proc 87:1214–1225, 2012.
Feldstein C, Weder AB: Orthostatic hypotension: a common, serious and under-
recognized problem in hospitalized patients, J Am Soc Hypertens 6:27–39,
2013.
Figueroa JJ, Basford JR, Low PA: Preventing and treating orthostatic hypotension:
as easy as A, B, C, Cleve Clin J Med 77:298–306, 2010.
Freeman R, Wieling W, Axelrod FB, et al: Consensus statement on the definition
of orthostatic hypotension, neurally mediated syncope and the postural
tachycardia syndrome, Auton Neurosci 161:46–48, 2011.
Guzman JC, Armaganijan LV, Morillo CA: Treatment of neurally mediated reflex
syncope, Cardiol Clin 31:123–129, 2013.
Karayannis G, Giamouzis G, Cokkinos DV, et al: Diabetic cardiovascular
autonomic neuropathy: clinical implications, Expert Rev Cardiovasc Ther
10:747–765, 2012.
Koike H, Watanabe H, Sobue G: The spectrum of immune-mediated autonomic
neuropathies: insights from the clinicopathological features, J Neurol
Neurosurg Psychiatry 84:98–106, 2013.
Logan IC, Witham MD: Efficacy of treatments for orthostatic hypotension: a
systematic review, Age Ageing 41:587–594, 2012.
Pop-Busui R, Cleary PA, Braffett BH, et al: Association between cardiovascular
autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study
(Diabetes Control and Complications Trial/Epidemiology of Diabetes
Interventions and Complications), J Am Coll Cardiol 61:447–454, 2013.
Singer W, Sletten DM, Opfer-Gehrking TL, et al: Postural tachycardia in children
and adolescents: what is abnormal? J Pediatr 160:222–226, 2012.
Spallone V, Ziegler D, Freeman R, et al: Cardiovascular autonomic neuropathy in
diabetes: clinical impact, assessment, diagnosis, and management, Diabetes
Metab Res Rev 27:639–653, 2011.
Stewart JM: Common syndromes of orthostatic intolerance, Pediatrics 131:968–
980, 2013.
Wenning GK, Geser F, Krismer F, et al: The natural history of multiple system
atrophy: a prospective European cohort study, Lancet Neurol 12:264–274,
2013.
 111 
Headache, Neck and Back Pain,
and Cranial Neuralgias
ss

Timothy J. Counihan

  HEADACHE
Definition and Epidemiology TABLE 111-2  SECONDARY HEADACHE SYNDROMES
Post-traumatic Disordered Homeostasis
Headache is caused by irritation of pain-sensitive intracranial Vascular • Hypoxia or hypercapnia
structures, including the dural sinuses; the intracranial portions • Subarachnoid hemorrhage (e.g., obstructive sleep apnea)
• Vasculitis • Dialysis-associated headache
of the trigeminal, glossopharyngeal, vagus, and upper cervical • Hypoglycemia
• Arterial Dissection (carotid or
nerves; the large arteries; and the venous sinuses. Many struc- vertebral) Medication
tures are insensitive to pain, including the brain parenchyma, the Non-Vascular • Side effects (e.g.
ependymal lining of the ventricles, and the choroid plexuses. The • Idiopathic Intracranial dipyridamole,nitrates,
Hypertension (Pseudotumor cyclosporine)
insensitivity of the brain parenchyma to pain accounts for the • Withdrawal
cerebri)
common clinical observation of patients who, despite having • Low CSF pressure (e.g. post Syndrome of Transient
large intracerebral lesions (such as a hematoma or a brain tumor), lumbar puncture or CSF leak) Headache and Neurological
complain of little or no headache. The term “cervicogenic” head- • Tumor Deficits with CSF Lymphocytosis
• Chiari malformation (HANDL)
ache is sometimes used to indicate that the source of headache
(usually occipital in location) arises from an abnormality in the Infection Cervicogenic
• Meningitis
cervical spine. • Abscess
• Sinusitis
Classification of Headache CSF, Cerebrospinal fluid.
Headache is generally classified into primary, secondary, and
cranial neuralgia syndromes (Table 111-1; Table 111-2; Table
111-3). It is essential that the clinician make every effort to make
an accurate clinical diagnosis of the presenting headache syn- TABLE 111-3  COMMON CRANIAL NEURALGIAS
drome; Table 111-4 provides some key questions in the assess- AND RELATED DISORDERS
Trigeminal neuralgia
ment of the patient with headache. Glossopharyngeal neuralgia
Occipital neuralgia
Migraine Other cranial branch neuralgias (e.g., superior orbital neuralgia)
Central facial pain syndromes (e.g., cold-stimulus headache)
Definition
Migraine is a common episodic neurologic disorder character-
ized by disabling headache preceded in one third of patients by
various combinations of neurologic, gastrointestinal, and auto-
TABLE 111-4  KEY QUESTIONS IN THE ASSESSMENT
nomic phenomena (termed the “aura”). The diagnosis is based OF HEADACHE
on the headache’s characteristics and associated symptoms. 1. For how long have you been having headaches?
Results of the physical examination as well as the laboratory 2. What were they like when they first began? Were they intermittent, daily
studies are usually normal. persistent, or progressive from the beginning?
3. What is the length of time from the start of the headache until its peak
intensity?
4. Are there any warning symptoms (e.g., aura)?
5. Does the headache interfere significantly with normal activity (e.g., work,
school)?
TABLE 111-1  PRIMARY HEADACHE SYNDROMES 6. What aggravates the headache (e.g., light, noise, odors)?
Migraine Other primary headache syndromes 7. What do you do for relief from the headache (e.g., rest, move around,
Tension-type headache • Primary stabbing headache take medication)?
Trigeminal autonomic cephalgias • Exertional/Sex headache 8. What time of day are the headaches most likely to occur? Do they
• Cluster • Primary thunderclap headache regularly awaken you from sleep?
• Paroxysmal Hemicrania • Hemicrania continua 9. Are you aware of any specific triggers (e.g., foods, stress, lack of sleep,
• SUNCT menstrual cycle)?
10. Does anyone else in the family have headaches?
SUNCT, Sudden-onset Unilateral Neuralgiform (Headache with) Conjunctival Tearing.

994
 Chapter 111  Headache, Neck and Back Pain, and Cranial Neuralgias 995
TABLE 111-5  CLASSIFICATION OF MIGRAINE
Migraine without aura Migraine variants
Migraine with aura • Hemiplegic migraine
• Migraine with basilar aura
• Vestibular Migraine
• Retinal Migraine
The prevalence of migraine is up to 18% in women and 6% in
men. It is estimated that 28 million Americans have disabling
migraine headaches. All varieties of migraine may begin at any
age from early childhood on, although peak ages at onset are
adolescence and early adulthood.
Several subtypes of migraine are described (Table 111-5). The
two most common are migraine without aura and migraine with
aura; migraine without aura accounts for 70% of patients.
Migraine auras are focal neurologic symptoms that precede,
accompany, or, rarely, follow an attack. The aura usually develops
over 5 to 20 minutes, lasts less than 60 minutes, and can involve
visual, sensorimotor, language, or brainstem disturbances. The
most common aura is typified by positive visual phenomena
(such as scintillating scotomata) that often precede the headache.
The differential diagnosis of an aura includes a focal epileptic
seizure arising from the visual cortex of the occipital lobe, or a
transient ischemic attack (TIA). In the latter, there is no evolution
of symptoms, and the symptoms themselves are typically “nega-
tive” (such as a hemianopia) rather than the “positive” visual
phenomenon of phosphenes that is characteristic of the migrain-
ous aura. The pain of migraine is often pulsating, unilateral, and
frontotemporal in distribution and usually accompanied by
anorexia, nausea, and, occasionally, vomiting. In characteristic
attacks, patients are markedly intolerant of light (photophobia)
and seek rest in a dark room. There may also be intolerance to
sound (phonophobia) and occasionally to odors (osmophobia).
The diagnosis of migraine requires the presence of at least one of
these features, particularly in the absence of gastrointestinal
symptoms. The presence of these symptoms results in a syndrome
that is invariably disabling for the patient, to the extent that for
the duration of the attack he or she is unable to function normally.
In children, migraine is often associated with episodic abdominal
pain, motion sickness, vertigo, and sleep disturbances. Onset of
typical migraine late in life (older than age 50) is rare, although
recurrence of migraine that had been in remission is not uncom-
mon. Recurrent migraine headache associated with transient
hemiparesis or hemiplegia occurs rarely as a clearly genetically
determined (Mendelian) disease (familial hemiplegic migraine).
Migraine with basilar aura is unusual and occurs primarily in
childhood. Severe episodic headache is preceded, or accompa-
nied by, signs of bilateral occipital lobe, brainstem, or cerebellar
dysfunction (e.g., diplopia, bilateral visual field abnormalities,
ataxia, dysarthria, bilateral sensory disturbances, other cranial
nerve signs, and occasionally coma). Vestibular migraine is char-
acterized by symptoms of vertigo with or without the other
typical migraine symptoms.
Complications of Migraine
Status Migrainosus refers to a severe migraine lasting greater than
72 hours. Migrainous infarction is a rare complication of migraine
with aura. The term migralepsy has been suggested for patients in
whom an aura triggers a seizure. ss
Pathophysiology of Migraine
A migraine attack is the end result of the interaction of a number
of factors of varying importance in different individuals. These
factors include a genetic predisposition, a susceptibility of the
central nervous system to certain stimuli, hormonal factors, and
a sequence of neurovascular events. A positive family history is
reported in 65% to 91% of cases. Three distinct ion channel gene
mutations have been identified in patients with familial hemiple-
gic migraine (FHM), including a mutation in the P/Q type
calcium channel on chromosome 19 (FHM 1) and a gene encod-
ing a Na/K- ion pump on chromosome 1 (FHM 2). These find-
ings lend support to the theory that migraine may be a true
channelopathy in which mutations of diverse channels result in a
common phenotype. The etiology of migraine in the majority of
patients remains unknown.
The migrainous aura is likely caused by a “cortical spreading
depression,” corresponding to a wave of neuronal depolarization
spreading over the cortex from posterior to anterior. One of the
key structures in the mechanism of pain in migraine is the tri-
geminal vascular system. Stimulation of the trigeminal nucleus
caudalis can activate serotonin receptors and nerve endings on
small dural arteries and result in a state of neurogenic inflamma-
tion. It is postulated that these processes, in turn, stimulate
perivascular nerve endings, with resultant orthodromic stimula-
tion of trigeminal nerve and pain referred to its territory. Further-
more, positron emission tomographic (PET) studies have
demonstrated activation of brainstem neuromodulatory struc-
tures, including the periaqueductal grey matter, locus coeruleus,
and raphe nuclei during a migraine attack.
Treatment of Migraine
The goals of treatment are (1) making an accurate and confident
diagnosis of migraine to reassure the patient that there is no more
sinister cause for the headache; (2) relieving acute attacks; and
(3) preventing pain and associated symptoms of recurrent head-
aches. The first step is to inform the patient that he or she has a
migraine. The benign nature of the disorder and the patient’s
central role in the treatment plan should be emphasized. It is
important that the patient keep a headache diary, which serves to
help identify covert headache triggers, assists in monitoring
headache frequency and response to treatment, and actively
involves the patient in the management of the condition. A sus-
tained pain-free therapeutic response should aim to have the
patient pain-free at two hours with no recurrence and no need
for subsequent rescue medication.
Acute Migraine Attack
Acute attacks are best alleviated using a stratified, rather than
stepped care approach, using single agents or varying combina-
tions of drugs as well as with behavioral modification therapy.
Many attacks of migraine respond to simple analgesics, such as
acetaminophen, aspirin, or nonsteroidal anti-inflammatory
agents (NSAIDs). Opioid drugs and butalbital should not be
used in the routine management of patients with migraine.
Overuse of analgesics is particularly frequent in headache
 996 Section XVI  Neurologic Disease
patients; therefore, one of the most important aspects of therapy
ss is the monitoring of amounts of analgesic used. In patients who
are nauseated, it is often helpful to prescribe an anti-emetic
agent early in an attack. Phenothiazine drugs have antiemetic,
prokinetic, and sedative properties, but they can produce invol-
untary movements as an acute adverse effect (acute dystonic
reaction) or with prolonged use (tardive dyskinesias).
A number of migraine-specific serotonin agonist drugs have
become available. These agents, commonly referred to as “trip-
tans,” are useful in the acute treatment of migraine, having a rapid
onset of action. The increasing availability of non-oral (paren-
teral, inhaled, and transdermal) preparations has largely circum-
vented the problem of emesis and gastroparesis in migraine
patients resulting in greater efficacy. For instance, sumatriptan,
available as a subcutaneous preparation, results in a headache
response rate of close to 70% (Fig. 111-1). Although triptans are
highly effective in alleviating migraine, patients must be carefully
instructed in their appropriate use. Moreover, a response to these
medications does not confirm a diagnosis of migraine.
Treating Acute Migraine in the Emergency Room
Migraine is one of the most common reasons for emergency
room visits and presents some treatment challenges; typically
migraine is more difficult to treat once it is fully established. It is
essential to confirm that the diagnosis is accurate, even in patients
with an established history of migraine. Patients will usually be
aware that the headache will have started as their typical migraine,
although it may be more severe than usual. In patients who state
that the new headache is different to their usual headache, con-
sideration should be given to exclude a more sinister cause.
Migraine
General measures
• Confirm diagnosis accuracy
• Reassure patient
• Rehydration
• Nurse in quiet environment
Mild or moderate attack
• Aspirin 900 mg PO Analgesia
• Naproxen 550 mg PO • Diclofenac 75 mg IM
• Ketorolac 30 mg IV
• Triptan
Treatment successful?
Yes No Yes
Continue Oral Continue
treatment triptan treatment
FIGURE 111-1  Algorithm for the treatment of migraine. DHE, Dihydroergotamine; IM, intramuscular; IV, intravenous; NS, normal saline; NSAIDs,
nonsteroidal anti-inflammatory drugs; SC, subcutaneous.
Thereafter the core principles of treatment include reassurance
that the headache can be treated effectively, hydration, pain
control, and relief of accompanying symptoms such as nausea
and photophobia. The majority of patients presenting with acute
migraine as an emergency will have already tried some form of
abortive therapy, and they are likely to be dehydrated. In this
setting parenteral therapy with an NSAID, a triptan, and an anti-
emetic is often effective (Fig. 111-1)
Migraine Prevention
Several agents have a strong evidence base for efficacy in the
prevention of migraine (Table 111-6). The use of these agents
should be restricted to patients who have frequent attacks (usually
more than four per month) and who are willing to take daily
medication. With any of the medications, an adequate trial period
should be given, using adequate doses, before it is declared inef-
fective. Combination therapy is occasionally required but is not
routinely prescribed. For a preventative drug to be considered
successful, it should reduce the headache frequency rate by at
least 50%. Other medications commonly used for migraine pre-
vention include gabapentin, cyproheptadine, methysergide, and
clonidine, but these have limited evidence to support their use as
first line therapy. Magnesium supplementation, the plant extract
feverfew, butterbur, and high-dose riboflavin (vitamin B2) have
been effective in some patients.
Future of Migraine Treatment
The most significant recent advance in acute migraine treatment
relates to calcitonin gene-related peptide (CGRP) receptor
antagonists. Stimulation of trigeminal ganglia neurons results in
Severe attack
Antiemetic
• Prochlorperazine 10 mg IV/IM; 25 mg PR
• Metoclopramide 10 mg IV
• Chlorpromazine 25 mg IV/IM
Treatment successful?
No
• Sumatriptan 6 mg sc
• Dihydroergotamine 0.5–1 mg IV
• Sodium valproate 300–1200 mg IV
 Chapter 111  Headache, Neck and Back Pain, and Cranial Neuralgias 997
TABLE 111-6  PREVENTIVE THERAPIES FOR MIGRAINE
DRUG CLASS AGENT
β-adrenoceptor blockers Propranolol
Metoprolol
Timolol
Antiepileptic drugs Divalproex sodium
Topiramate
Gabapentin
Antidepressants Amitriptyline
Nortriptyline
Venlafaxine
Calcium channel blockers Verapamil
Flunarizine*
Other Onabotulinum toxin A
Level of Evidence A, Medication with established efficacy; Level B, medication probably effective; Level U, inadequate data to support use; N/A, not considered in recent evidence review.
*Not available in the US.
release of CGRP; telcagepant, a CGRP receptor antagonist has
been found to have similar efficacy to oral triptan therapy. Greater
insights into the genetic basis for migraine has enhanced our
understanding of ion channel dysfunction in this disorder, and
are likely to lead to new therapeutic targets.
Cluster Headache
Clinical Features
Cluster headache is the prototypic trigeminal autonomic cephal-
gia, entirely distinct from migraine, although there may be some
clinical overlap. It is uncommon, occurring in less than 10% of all
patients with headache. Unlike migraine, it is much more
common in men than in women, and the mean age at onset is
later in life. Also, unlike migraine, cluster headache rarely begins
in childhood, and there is less often a family history. The pain in
cluster headache is of extreme intensity, is strictly unilateral, and
is associated with congestion of the nasal mucosa and injection
of the conjunctiva on the side of the pain. Increased sweating of
the ipsilateral side of the forehead and face may occur. There may
be associated ocular signs of Horner syndrome: miosis, ptosis,
and the additional feature of eyelid edema. Attacks often awaken
patients, usually 2 to 3 hours after the onset of sleep (“alarm-clock
headache”). In contrast to migraineurs, the pain is not relieved by
resting in a dark, quiet area; on the contrary, patients sometimes
seek activity that can distract them. The duration of headache is
usually around 1 hour, although it may recur several times in a
day, paroxysmally (in clusters) for several weeks.
These periods of frequent headaches are separated by
headache-free periods of varying duration, often several months
or years. Attacks have a striking tendency to be precipitated by
even small amounts of alcohol. There are rare variants of cluster
headache: a “chronic variety” in which remissions are brief (less
than 14 days); “chronic paroxysmal hemicrania,” in which attacks
are shorter and strikingly more prevalent in women; and “hemi-
crania continua,” in which there is continuous, moderately severe,
unilateral headache. The cause of all these syndromes is unknown,
although the distribution of the pain suggests dysfunction of the
trigeminal nerve.
Treatment
Therapy for cluster headache may be abortive for acute head-
ache or prophylactic to prevent headache. Acute headache
may respond to oxygen by mask (7 to 10  L/min for 15
ss
DOSE RANGE EVIDENCE LEVEL ADVERSE EFFECTS
80-240 mg A Contraindicated in asthma, syncope
50-150 mg A
10-20 mg A
200-1500 mg A Weight gain, thrombocytopenia, tremor
25-150 mg A Renal calculi, weight loss, amnesia,
300-1800 mg U glaucoma, dysequilibrium
10-150 mg B Somnolence
25-100 mg N/A Insomnia, hypertension
37.5-150 mg B
180-480 mg U Constipation, hypotension, edema
5-10 mg N/A Weight gain, depression
Variable N/A Discomfort, ecchymosis
minutes), which is effective within several minutes in 70% of
patients. Sumatriptan and dihydroergotamine are also effective.
Preventive medications include lithium, divalproex sodium,
verapamil, methysergide, and corticosteroids. Paroxysmal hemi-
crania and related syndromes are often strikingly responsive
to indomethacin.
Tension-Type Headache
In contrast to migraine, tension-type headache is featureless. The
pain is usually not throbbing, but rather steady and often
described as a “pressure feeling” or a “viselike” sensation. It is
usually not unilateral and may be frontal, occipital, or general-
ized. There is frequently pain in the neck area, unlike in migraine.
Pain commonly lasts for long periods of time (days) and does not
rapidly appear and disappear in attacks. There is no “aura.” Pho-
tophobia and phonophobia are not prominent. Although tension-
type headache may be related by the patient to occur or be
exacerbated at times of particular emotional stress, the patho-
physiology may relate to sustained craniocervical muscle con-
traction; hence, a more useful term for this syndrome is
muscle-contraction headache.
A careful evaluation should be made of the patient’s psycho-
social milieu and the presence of anxiety or depression. The tri-
cyclic antidepressant drugs in low doses have proven the most
useful for prevention of tension-type headache. Although the
best documented is amitriptyline, newer agents with fewer side
effects may be equally effective. Nonpharmacologic therapies
such as relaxation therapy, massage, physiotherapy, or acupunc-
ture may be useful in refractory cases. Intramuscular botulinum
toxin injections have been used both in migraine and tension-
type headache, but are of established benefit only in patients with
chronic migraine.
Other Defined Primary Headache Syndromes
Other acute short-lasting headache syndromes need to be dif-
ferentiated from migraine, cluster, or tension headache. These
include primary “thunderclap” headache, primary stabbing head-
ache, primary exertional headache, and coital headache. The latter
may be indistinguishable from the headache of intracranial
aneurysm rupture and requires computed tomography (CT)
and lumbar puncture to exclude subarachnoid hemorrhage
(SAH). All of these headache syndromes are more common
in migraineurs. Two additional rare, short-lasting headache
 998 Section XVI  Neurologic Disease
syndromes deserve mention: short-lasting unilateral neuralgi-
ss form headache with conjunctival tearing (SUNCT); and hypnic
headache. The latter refers to multiple episodes of very brief
headache that awaken the patient (typically an older woman)
from sleep. The syndrome of SUNCT causes multiple very brief
(seconds to minutes) episodes of cluster-like headache and
autonomic disturbance.
Chronic daily headache is defined arbitrarily as headache
lasting for more than 4 hours on more than 15 days in the month
for more than 3 months. In clinical practice this means that the
patient has a headache more often than not. In these cases it is
important to establish whether the headache syndrome began as
an episodic disorder (as in migraine or tension-type headache)
or whether it consists of new daily persistent headaches.
New Daily Persistent Headache
New daily persistent headache needs to be distinguished from
tension-type or migraine headaches that have transformed into
chronic daily headache, and necessitates investigation to exclude
a secondary cause.
Headache may be a manifestation of underlying structural
brain disease (Table 111-2). Headache can be seen in all forms
of cerebrovascular disease, including infarction, intracerebral
hemorrhage, and SAH, although headache is rarely prominent in
cerebral infarction. In contrast, the headache in SAH is usually
extremely severe and often described by the patient as “the worst
headache of my life.” Nuchal rigidity, third nerve palsy (usually
involving the pupil), and retinal, preretinal, or subconjunctival
hemorrhages may be found. CT of the head usually shows sub-
arachnoid, intraventricular, or other intracranial blood.
Certain symptoms raise suspicion for a structural brain lesion
(Table 111-7).
The patient with headache and fever presents a common diag-
nostic problem in the emergency department. Neck stiffness is a
common symptom. Meningismus is confirmed by eliciting
Brudzinski and Kernig signs. Vomiting occurs in about 50% of
patients. Suspicion for meningitis should prompt immediate
investigation, including a lumbar puncture. If the patient shows
focal signs, papilledema, or profound alteration in level of con-
sciousness, CT of the head before lumbar puncture is required to
rule out focal disease such as an abscess or subdural empyema.
These lesions, however, are rare.
Acute Sinusitis
Head and face pain is the most prominent feature of sinusitis.
Malaise and low-grade fever are usually present. The pain is dull,
aching, and nonpulsatile; is exacerbated by movement, coughing,
or straining; and is improved with nasal decongestants. The pain
TABLE 111-7  DIFFERENTIAL DIAGNOSIS OF ACUTE
HEADACHE—MAJOR CAUSES
Migraine Acute hydrocephalus
Cluster headache Meningitis or encephalitis
Stroke Giant cell arteritis (often chronic)
• Subarachnoid hemorrhage Tumor (usually chronic)
• Intracerebral hemorrhage Trauma
• Cerebral infarction
• Arterial dissection (carotid or
vertebral)
is most pronounced on awakening or after any prolonged recum-
bency, and is diminished with maintenance of an upright posture.
The location of the pain depends on the sinus involved. Maxil-
lary sinusitis provokes ipsilateral malar, ear, and dental pain with
significant overlying facial tenderness. Frontal sinusitis produces
frontal headache that may radiate behind the eyes and to the
vertex of the skull. Tenderness to frontal palpation may be present
with point tenderness on the undersurface of the medial aspect
of the superior orbital rim. In ethmoidal sinusitis, the pain is
between or behind the eyes with radiation to the temporal area.
The eyes and orbit are often tender to palpation, and, in fact, eye
movements themselves may accentuate the pain. Sphenoidal
sinusitis causes pain in the orbit and at the vertex of the skull and
occasionally in the frontal or occipital regions. Given that the
trigeminal nerve mediates pain perception from the sinuses,
many patients who complain of “sinus headaches” are probably
suffering from the trigeminovascular disturbance of migraine,
rather than sinusitis. Chronic sinusitis is seldom a cause of
headache.
Brain Tumors
Posterior fossa tumors (particularly of the cerebellum) frequently
produce headache, especially if hydrocephalus occurs because
cerebrospinal fluid (CSF) flow is partially obstructed. Supraten-
torial tumors, however, are less likely to cause headache and are
more frequently heralded by altered mental status, focal deficits,
or seizures. Although increased intracranial pressure is often asso-
ciated with headache, it is usually not the primary mechanism
because uniform pressure elevations do not usually produce dis-
tortions of pain-sensitive structures.
Idiopathic Intracranial Hypertension
Idiopathic intracranial hypertension (IIH), also called benign
intracranial hypertension, is defined as a syndrome of elevated
intracranial pressure without evidence of focal lesions, hydro-
cephalus, or frank brain edema. It usually occurs between the
ages of 15 and 45 years and is more frequent in obese women.
The disorder is characterized by headache with features of raised
intracranial pressure. The headache is usually insidious in onset,
is typically generalized, is relatively mild in severity, and is often
worse in the morning or after exertion (e.g., straining or
coughing).
At times, patients have visual disturbances, such as restricted
peripheral visual fields, enlarged blind spots, visual blurring
(obscurations), or diplopia secondary to abducens nerve palsies.
Funduscopic examination shows papilledema, which is often
more impressive than the clinical picture. IIH is usually a benign
and self-limited disorder, but it may lead to visual loss, including
blindness.
The condition has been associated with drugs—vitamin A
intoxication, nalidixic acid, danazol (Danocrine), and isotreti-
noin (Accutane)—as well as corticosteroid withdrawal and sys-
temic disorders such as hypoparathyroidism and lupus.
CT scans are usually normal but can show small ventricles and
an “empty sella” in some cases. CSF opening pressure is elevated,
usually in the range of 250 to 450 mm of water, with the pressure
fluctuating markedly when monitoring occurs over a prolonged
period. Some cases of IIH are caused by cerebral venous sinus
 Chapter 111  Headache, Neck and Back Pain, and Cranial Neuralgias 999
occlusion. These cases can occur in hypercoagulable states,
including peripartum, in association with the combined oral con-
traceptive pill, and in association with antiphospholipid antibody
syndrome. After secondary causes of IIH have been eliminated,
the patient should have dietary counseling for weight loss. Car-
bonic anhydrase inhibitors (acetazolamide) and corticosteroids
have proved useful in headache control. As a second-line agent,
furosemide also acts to lower CSF production. Serial lumbar
punctures are understandably unpopular with patients even
though transient headache relief is obtained. CSF shunting pro-
cedures (ventriculoperitoneal shunt) are occasionally necessary.
For patients with progressive visual loss, optic nerve sheath fen-
estration preserves or restores vision in 80% to 90% of cases and
provides headache relief in a majority.
Idiopathic Intracranial Hypotension
Also known as low pressure headache, idiopathic intracranial
hypotension is commonly encountered as a sequela of lumbar
puncture, resulting from leakage of CSF through the dural sac.
Low pressure headaches may also occur spontaneously as a result
of rupture of subarachnoid cysts. The headache is initially char-
acteristically positional, being severe on standing but relieved
rapidly on lying down. Occasionally the headache is associated
with focal or “false localizing” signs, especially abducens nerve
palsies.
Post-Traumatic Headache
Headache following trauma has no specific quality and is
associated with irritability, concentration impairment, insomnia,
memory disturbance, and light-headedness. Anxiety and
depression are present to variable degrees. Multiple treatment
options are available, and amitriptyline and nonsteroidal anti-
inflammatory agents are useful. Occasionally, muscle relaxants
and anxiolytics are beneficial. Training is occasionally associated
with the onset of typical migraine.
Giant Cell Arteritis
Headache occurs in 60% of patients with giant cell arteritis, a
granulomatous vasculitis of medium and large arteries. Over 95%
of patients are 50 years of age or older. Malaise, fever, weight loss,
and jaw claudication occur early, in addition to headache. Poly-
myalgia rheumatica, a syndrome of painful stiffness of the neck,
shoulders, and pelvis, is found in half the patients (Chapter 131).
Visual impairment secondary to ischemic optic neuritis may
occur. The headache is usually described as aching and is exacer-
bated at night and after exposure to cold. The superficial temporal
artery is frequently swollen, tender, and may be pulseless. The
erythrocyte sedimentation rate is usually elevated; the mean is
100 mm/hr. Anemia is frequently present. Temporal artery
biopsy usually confirms the diagnosis, but, because the arteritis
is segmental, large or multiple sections may be required. Predni-
sone therapy is often dramatically effective and must be given
promptly to preserve vision on the affected side.
Evaluation of the patient   Onset >50 years of age
with acute headache
It is important to distinguish benign from ominous causes of
headache. A detailed history (the quality, location, duration, and
time course of the headache) helps in determination of which
patients have a symptomatic structural intracranial lesion (Table ss
111-7; Table 111-8; Table 111-4)). Pain intensity is not of much
diagnostic value, except for the patient who complains of the
acute onset of the worst headache of his or her life). The quality
of pain (“throbbing,” “pressure,” “jabbing”) and the location may
also be helpful, especially if the pain is of extracranial origin, such
as temporal in temporal arteritis. Posterior fossa lesions cause
occipitocervical pain, occasionally associated with unilateral
retro-orbital pain. In general, multifocal pain usually implies a
benign cause. It is most important to clarify the acuity of onset
of the headache; patients who describe the onset of pain as “like
being hit on the head with a bat” should be suspected of having
the sentinel headache of subarachnoid headache. Equally impor-
tant is to establish the time course of the headache. Is this parox-
ysmal, nonprogressive headache (typical of migraine or
tension-type headache)? Or is the headache daily persistent
(such as in temporal arteritis) or progressive (suggesting the pres-
ence of a structural brain lesion)? Patients should be asked about
any known triggers for the headache, such as menses, particular
foods, caffeine, alcohol, or stress. Positional headache (headache
that is maximal in the upright position and disappears rapidly on
lying down) is characteristic of intracranial hypotension (low
pressure headache). Diurnal variation in headache severity may
give a clue to cause; morning headache or headache that awakens
a patient from sleep may indicate raised intracranial pressure or
sleep apnea as a cause. The presence of associated symptoms such
as visual disturbances, nausea, or vomiting should be noted. The
history should include inquiries about medications, especially
use of analgesics and over-the-counter remedies. Information
regarding the patient’s past medical history as well as family
history should also be taken into consideration. In the majority
of patients with headache, the physical and neurologic examina-
tion findings are normal, although special attention may be
directed toward examination of the eyes for papilledema, as well
as the temporal arteries for a palpable nonpulsatile artery. Assess-
ment of the patient with acute nontraumatic headache in the
emergency room can be challenging; it is essential to establish
how the headache evolved. Acute-onset severe headache should
prompt investigation to exclude SAH, intracranial hemorrhage,
acute obstructive hydrocephalus, and meningitis (Table 111-7).
Appropriate initial investigations should include brain imaging
with CT or magnetic resonance imaging (MRI). Patients with
suspected meningitis without focal neurologic signs or impaired
consciousness should not have their lumbar puncture delayed
unnecessarily before imaging. All patients should have standard
TABLE 111-8  CLINICAL FEATURES OF HEADACHES
SUGGESTING A STRUCTURAL BRAIN
LESION
SYMPTOMS SIGNS
Worst of the patient’s life Nuchal rigidity
Progressive Fever
Papilledema
Worse in early morning—awakens
patient
Pathologic reflexes or reflex
asymmetry
Marked exacerbation with straining Altered state of consciousness
Focal neurologic dysfunction
 1000 Section XVI  Neurologic Disease
blood tests, including blood cultures if bacterial meningitis is
ss suspected.
A wide variety of systemic diseases have headache as a promi-
nent symptom; some of the more prevalent disorders are sum-
marized in Table 111-2.
  CRANIAL NEURALGIAS
Neuralgias are differentiated from other head pains by the brevity
of the attacks (usually 1 to 2 seconds or less) and by the distribu-
tion of the pain (Table 111-3).
Trigeminal Neuralgia
In trigeminal neuralgia (tic douloureux), stabbing, spasmodic
pain occurs unilaterally in one of the divisions of the trigeminal
nerve. It lasts seconds, but it may occur many times a day for
weeks at a time. It is characteristically induced by even the light-
est touch to particular areas of the face, such as the lips or gums.
Trigeminal neuralgia is the most frequent neuralgia of the elderly
and is thought to be caused by compression of the trigeminal
nerve root in the pons by an aberrant arterial loop. A small minor-
ity of cases are caused by multiple sclerosis, cerebellopontine
angle tumors, aneurysms, or arteriovenous malformations,
although in these cases (unlike “true” trigeminal neuralgia) there
are usually objective signs of neurologic deficit, such as areas of
diminished sensation. In these cases of “symptomatic” neuralgia,
the pain is often atypical. MRI is indicated in patients who have
sensory loss, those who are under 40, and those with bilateral or
atypical symptoms. Trigeminal neuralgia may be life threatening
when it interferes with eating. Neuralgic pain is often responsive
to treatment with standard doses of an anticonvulsant such as
phenytoin, carbamazepine, gabapentin, pregabalin, and, occa-
sionally, baclofen. Antidepressant drugs such as amitriptyline
and, more recently, duloxetine may also be useful in this setting.
Combination therapy, including an antidepressant, anticonvul-
sant, and opiate analgesic has been shown to have synergistic
effects.
If medical treatments are unsuccessful, surgical treatment may
be indicated: microvascular decompression or radiofrequency
lesioning of the sensory portion of the trigeminal nerve.
Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia is less common than trigeminal neu-
ralgia. Brief paroxysms of severe, stabbing, unilateral pain radiate
from the throat to the ear or vice versa and are frequently initiated
by stimulation of specific “trigger zones” (e.g., tonsillar fossa or
pharyngeal wall). Swallowing often provokes an attack; yawning,
talking, and coughing are other potential triggers. Microvascular
decompression is necessary if medical treatment is ineffective.
Postherpetic Neuralgia
Herpes zoster produces head pain by cranial nerve involvement
in one third of cases. In some cases a persistent intense burning
pain follows the initial acute illness. The discomfort may subside
after several weeks or persist (particularly in the elderly) for
months or years. The pain is localized over the distribution of the
affected nerve and associated with exquisite tenderness to even
the lightest touch. The first division of the trigeminal nerve is the
most frequent cranial nerve involved (ophthalmic herpes) and is
occasionally associated with keratoconjunctivitis. When the
seventh nerve is affected (“geniculate herpes”), the pain involves
the external auditory meatus and pinna. Occasionally, concomi-
tant facial paralysis may occur (Ramsay Hunt syndrome).
Occipital Neuralgia
Occipital neuralgia is a syndrome that includes occipital pain
starting at the base of the skull and often provoked by neck exten-
sion. Physical examination shows tenderness in the region of the
occipital nerves and altered sensation in the C2 dermatome.
Treatment includes the use of a soft collar, muscle relaxants,
physical therapy, and local injections of analgesics and anti-
inflammatory agents. The term cervicogenic headache is often used
to describe headache associated with myofascial trigger points in
the neck. Importantly, cervical spondylosis (discussed below) is
not usually typically associated with headache.
  CERVICAL SPONDYLOSIS
Cervical spondylosis is a degenerative disorder of the cervical
intervertebral disks leading to osteophyte formation and hyper-
trophy of adjacent facet joints and ligaments. In contrast to the
lumbar spine, herniation of cervical intervertebral disks (nucleus
pulposus) accounts for only 20% to 25% of cervical root irrita-
tion. Cervical spondylosis one of the most common pathologies
seen in office practice and is present radiographically in over 90%
of the population older than 60 years of age. For unknown
reasons, the degree of anatomic abnormality is not directly cor-
related with the clinical signs and symptoms. Clinical disease may
represent a combination of normal, age-related, degenerative
changes in the cervical spine and a congenital or developmental
stenosis of the cervical canal; the process may be aggravated by
trauma. Cervical spinal myelopathy results from a combination
of degenerative disc disease, spondylosis aggravated by biome-
chanical instability, as well as stiffening and buckling of the liga-
mentum flavum. It may manifest as a painful stiff neck, with or
without symptoms or signs of cervical root irritation or spinal
cord compression. Patients with root irritation (cervical radicu-
lopathy) complain of pain and paresthesias radiating down the
arm roughly in the dermatomal distribution of the affected nerve
root. More typically, the pain radiates in a myotomal pattern,
whereas numbness and paresthesias follow a dermatomal distri-
bution. Discrete sensory loss is uncommon and less prominent
than symptoms (Table 111-9). For relief, patients often adopt a
position with the arm elevated and flexed behind the head. Pain
is exacerbated by turning the head, ear down, to the side of the
pain (Spurling maneuver). Objective neurologic findings may be
limited to reflex asymmetry because weakness may be obscured
by pain. Patients who have some degree of spinal cord compres-
sion demonstrate gait and bladder disturbances and evidence of
spasticity on examination of the lower extremities. These patients
require investigation with MRI. Plain radiographs of the cervical
spine add little information except in patients with rheumatoid
arthritis in whom basilar invagination or atlantoaxial subluxation
is suspected.
Cervical spondylosis is so common in the general population
that it may be present coincidentally in a patient with another
disease of the spinal cord. Among other diseases that may mimic
cervical spondylosis are multiple sclerosis, amyotrophic lateral
 Chapter 111  Headache, Neck and Back Pain, and Cranial Neuralgias 1001
TABLE 111-9  COMMON CERVICAL ROOT SYNDROMES
DISK ROOT MUSCLES DISTRIBUTION
SPACE AFFECTED AFFECTED OF PAIN
C4-5 C5 Deltoid, biceps Medial scapula; shoulder
C5-6 C6 Wrist extensors Lateral forearm
C6-7 C7 Triceps Medial scapula
C7-T1 C8 Hand intrinsics Medial forearm
sclerosis, and, less commonly, subacute combined system disease
(vitamin B12 deficiency). Conservative treatment includes the
use of anti-inflammatory medication, cervical immobilization,
and physical therapy for isometric strengthening of neck muscles
once pain has subsided. Surgery should be considered if there is
progression of the neurologic deficit, especially the emergence of
signs of cervical cord compression. There is some evidence to
suggest that cervical spondylosis is an active degenerative disease
rather than simply the process. Furthermore, early studies with
the glutamate antagonist riluzole suggest a potential role in
reducing disease progression.
  ACUTE LOW BACK PAIN
Low back pain without sciatica (radiating radicular pain) is
common, with a reported point prevalence of up to 33%. Acute
low back pain lasting several weeks is usually self-limiting, with a
low risk for serious permanent disability. Risk factors for pro-
longed disability include psychological distress, compensation
conflict over work-related injury, and other coexistent pain syn-
dromes. The evaluation of patients with acute low back pain
should focus on distinguishing pain of mechanical origin from
neurogenic pain caused by nerve root irritation. The same patho-
logic changes that affect the cervical spine may also affect the
lumbar spine. Because the spinal cord ends at the level of the first
lumbar vertebra, lumbar canal stenosis from intervertebral disk
disease and degenerative spondylosis will affect the roots of the
cauda equina. The most common levels for lumbar degenerative
disk disease are at L4 to L5 and L5 to S1, resulting in the common
complaint of sciatica caused by irritation of the lower lumbar
roots. Pain tends to improve with sitting or lying down, in con-
trast to the pain from spinal or vertebral tumors, which is aggra-
vated by prolonged recumbency. Examination shows loss of the
normal lumbar lordosis, paraspinal muscle spasm, and exacerba-
tion of pain with straight leg rising, owing to stretching of the
lower lumbar roots. About 10% of disk herniations occurs lateral
to the spinal canal, in which case the more rostral root is com-
pressed. Percussion of the spine may elicit focal tenderness of one
of the vertebrae, suggesting bony infiltration by infection or
tumor.
Spinal stenosis of the lumbar region may manifest as “neuro-
genic claudication,” which is usually described as unilateral or
bilateral buttock pain that is worse on standing or walking and
relieved by rest or flexion at the waist. Patients may have pain that
is worse when walking downhill, in contrast to patients with vas-
cular claudication, whose pain is maximal when walking up an
incline.
ss
DISTRIBUTION OF
SENSORY SYMPTOMS REFLEX AFFECTED
Shoulder Biceps
Thumb; index finger Triceps
Middle finger Brachioradialis
Fourth and fifth fingers Finger flexion
MRI in many patients with isolated low back pain shows non-
specific findings; MRI assessment early in the course of an
episode of low back pain does not improve clinical outcome. MRI
should be limited to patients with back pain who have associated
neurologic symptoms or signs, especially new onset disturbances
of bladder or bowel continence or perineal sensory symptoms
suggestive of a cauda equina syndrome. Patients with risk factors
for malignancy, infection, or osteoporosis, as well as those with
pain maximal at rest (or nocturnal pain) require imaging. Patients
with primary and metastatic tumor can present with acute back
pain (Chapter 119). Moreover, developmental anomalies are
often associated with pain (Chapter 115).
Treatment strategies for lumbar pain are similar to those for
cervical pain, with surgery reserved for patients with neurologic
signs and clear pathologic processes seen on imaging studies.
Most cases of acute low back pain, even with rupture of an inter-
vertebral disk, can be treated conservatively with a short period
of rest, muscle relaxants, and analgesics. Prolonged bed rest is
recommended only for patients in severe pain. Patient education
regarding proper posture and appropriate back exercises is
helpful, as is a formal physical therapy program. Chiropractic
manipulation should not be performed for patients who have
evidence of neurologic injury or spine instability.
For a deeper discussion on this topic, please see
Chapter 398, “Headaches and Other Head Pain,” in
Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Bronfort G, Evans R, Anderson AV, et al: Spinal manipulation, medication, or
home exercise with advice for acute and subacute neck pain: a randomized
trial, Ann Intern Med 156:1–10, 2012.
Cherkin DC, Sherman KJ, Kahn J, et al: A comparison of the effects of 2 types of
massage and usual care on chronic low back pain: a randomized, controlled
trial, Ann Intern Med 155:1–9, 2011.
El Barzouhi A, Vleggeert-Lankamp CL, Lycklama à Nijeholt GJ, et al: Magnetic
Resonance Imaging in follow up assessment of sciatica, N Engl J Med 368:999–
1007, 2013.
Fehlings MG, Tetreault LA, Wilson JR, et al: Cervical Spondylitic Myelopathy.
Current State of the art and future directions, Spine 38:S1–S8, 2013.
Gelfand AA, Goadsby PJ: A neurologist’s guide to acute migraine treatment in
the emergency room, Neurohospitalist 2:51–59, 2012.
Headache Classification Subcommittee of the International Headache Society:
The International Classification of Headache Disorders: 3rd edition,
Cephalalgia 33:629–808, 2013. Available at: http://ihs.classification.org/en/.
Rana MV: Managing and treating headache of cervicogenic origin, Med Clin
North Am 97:267–280, 2013.
Rizzoli PB: Acute and preventive treatment of migraine, Continuum 18:764–782,
2012.
 112 
ss
Disorders of Vision and Hearing
Eavan McGovern and Timothy J. Counihan
  DISORDERS OF VISION AND EYE MOVEMENTS
Examination of the Visual System
Acuity
The clinical examination of visual function should begin with
testing visual acuity. Patients who wear corrective lenses should
wear them during testing, and testing should be performed using
a Snellen chart at a distance of 20 feet (Fig. 112-1). The smallest
line the patient can read is documented as the visual acuity; for
instance, acuity of 20/40 refers to letters that the patient sees
maximally at 20 feet, which a normal individual can see at 40 feet.
When errors of refraction are responsible for decreased visual
acuity, vision may be improved by having the patient look through
a pinhole. Corrected vision in one eye of less than 20/40 suggests
damage to the lens (cataract) or retina or a disorder of the ante-
rior visual (prechiasmal) pathway. Color vision in each eye
FIGURE 112-1  Snellen Chart.
1002
should also be tested using Ishihara color plates; even when
visual acuity is normal, patients with lesions of the optic nerve
may complain that colors appear “washed out” in the affected eye.
Visual Fields
Thorough examination of the visual fields can often localize
lesions interrupting the afferent (sensory) visual system (Fig.
112-2). Visual fields in all four quadrants should be tested by
comparing the patient’s field with that of the examiner (confron-
tation). The examiner’s head should be level with that of the
patient’s, and a white pin used to map peripheral visual fields and
a red pin to assess for the presence of a scotoma. Asking the
patient to count the number of the examiner’s extended fingers
is more sensitive than presenting moving objects in detecting
visual field deficits. The field should be tested first unilaterally and
then bilaterally because uncovering a defect (particularly in the
left hemifield) with bilateral testing only (extinction) suggests a
lesion in the contralateral parietal lobe.
Partial or complete visual loss in one eye only implies damage
to the retina or optic nerve anterior to the optic chiasm, whereas
a visual field abnormality involving both eyes implies a defect at
or posterior to the optic chiasm. Scotomas are areas of partial or
complete visual loss and may be central or peripheral. Central
scotomas result from damage to the macula. A scotoma affecting
one half of a visual field is known as a hemianopia. Field defects
are said to be homonymous if the same part of the visual field is
affected in both eyes; a homonymous hemianopia implies a post-
chiasmal lesion. A homonymous defect may be congruous (the
visual defect is identical in each hemifield) or incongruous (the
visual defect is not identical in each hemifield).
Quadrantanopias are smaller defects in the visual field and
may be superior (which suggests a temporal lobe lesion) or infe-
rior (which suggests a parietal lobe lesion). Bitemporal hemiano-
pia implies a lesion at the chiasm, such as a pituitary tumor. An
altitudinal hemianopia occurs with vascular damage to the retina.
Scintillating scotomas are hallucinations of flashing lights. If they
are monocular, they may be caused by retinal detachment; bi­
nocular scintillations suggest occipital oligemia (as in migraine)
or seizure. Any suspicious findings on bedside confrontation
testing warrant formal visual field testing using perimetry
(Fig. 112-3).
Pupils
Examination of the pupils should begin with observation of pap-
illary size and shape at rest. Pupil constriction is mediated by the
parasympathetic system of the oculomotor (third cranial) nerve,
 Chapter 112  Disorders of Vision and Hearing 1003
Temporal
Nasal
2
1 ent homonymous hemianopia.
4
2
4
3 suspected. This abnormality is referred to as an afferent pupillary
5 5
6
6 symmetrically and rapidly. Argyll-Robertson pupils are small,
7
7 neurosyphilis, diabetes, and other disorders. This so-called
Lt Rt
8(subtotal) 8
FIGURE 112-2  Visual fields that accompany damage to the visual
pathways. 1, Optic nerve: unilateral amaurosis. 2, Lateral optic chiasm:
grossly incongruous, incomplete (contralateral) homonymous hemi-
anopia. 3, Central optic chiasm: bitemporal hemianopia. 4, Optic tract:
incongruous, incomplete homonymous hemianopia. 5, Temporal
(Meyer) loop of optic radiation: congruous partial or complete (contra-
lateral) homonymous superior quadrantanopia. 6, Parietal (superior)
projection of the optic radiation: congruous partial or complete   in distortion of the eye (inferolaterally, “down and out”) and a
homonymous inferior quadrantanopia. 7, Complete parieto-occipital
interruption of optic radiation: complete congruous homonymous
hemianopia with psychophysical shift of foveal point often sparing
central vision, giving “macular sparing.” 8, Incomplete damage to visual
cortex: congruous homonymous scotomas, usually encroaching at
least acutely on central vision. (From Baloh RW: Neuro-ophthalmology.
In Goldman L, Bennett JC, editors: Cecil textbook of medicine, ed 21,
Philadelphia, 1998, WB Saunders, p 2236).
whereas dilation is mediated by the sympathetic system. If the
balance of these systems is disrupted, anisocoria (unequal pupil
size) results. The pupils should be examined in both dim and
bright light. If the anisocoria increases going from dim to bright
light, a lesion of the parasympathetic system is likely. Physiologic
anisocoria is characterized by pupillary asymmetry that is
unchanged irrespective of the ambient light intensity; this occurs
in approximately 20% of the population.
Both the direct and consensual light responses should be
noted for each eye; in the latter, when the light is shone in
one eye, both pupils should constrict. This is best tested using
the “swinging light test,” in which the light is moved quickly
from one eye to the other. When light is shone into one eye,
both eyes should constrict simultaneously. If there is dilation
of one pupil as the light is moved to it from the other side,
an abnormality of the optic nerve in that eye should be
Left eye Right eye
ss
30° 30° 30°
FIGURE 112-3  Humphrey visual fields demonstrating an incongru-
defect. The accommodative pupillary response is tested by asking
the patient to look first in the distance and then at the exam-
iner’s finger, held 12 inches away. The pupils should constrict
irregular pupils that constrict to near vision (accommodation
reflex) but not in response to light. They are associated with
light-near dissociation may also occur in rostral dorsal midbrain
lesions, in which there may be associated abnormalities of
vertical gaze, eyelid retraction, and convergence retraction nys-
tagmus (Parinaud Syndrome). This uncommon constellation of
clinical findings is frequently noted in patients with lesions of
the pineal gland.
The presence of ptosis should be noted. A large, unreactive
pupil with ptosis indicates a lesion of the oculomotor nerve (third
cranial nerve palsy) interrupting the parasympathetic nerve supply
to the pupil. The associated paralysis of the medial and inferior
rectus and inferior oblique muscles (see later discussion) results
subjective complaint of diplopia by the patient. Common causes
of a third nerve palsy include compression by an aneurysm of the
posterior communicating artery by transtentorial herniation, or
from ischemia, usually in the setting of diabetes or vasculitis. A
third nerve palsy caused by ischemia often spares the pupil but
results in complete paralysis of the oculomotor and eyelid levator
muscles. Acute painful third nerve palsy should be treated as an
emergency, with the need to investigate for an intracranial
aneurysm.
A small, poorly reactive pupil with associated ptosis is known
as Horner syndrome and results from damage to the sympathetic
fibers to the pupil, which may occur anywhere along their course
from the hypothalamus, brainstem, and ascending sympathetic
chain from the superior cervical ganglion to the orbit. There may
be associated unilateral anhidrosis resulting from damage to sym-
pathetic fibers. Horner syndrome may be the first sign of an apical
lung tumor (Pancoast) or may occur in diseases affecting the
carotid artery.
Tonic (Adie) pupils constrict slowly and incompletely in
response to light. This is usually an incidental finding on examina-
tion but may be associated with areflexia (Holmes-Adie syn-
drome). Reaction to accommodation is preserved, and it has
been suggested that the disorder is a result of parasympathetic
denervation. Hippus refers to pupillary unrest with synchronous
oscillation of the pupil size; it is considered a normal
 1004 Section XVI  Neurologic Disease

Physiological
Pupil large Reacts to light Normally
ss

anisocoria

Doesn’t react Normal Afferent pupillary

to light accommodation defect

Slowly Holmes-Adie
accommodates pupil

No + ptosis:
accommodation Probable CN III

Reacts to light Elderly Senile miosis

Horner’s
Pupil small + partial ptosis
syndrome

Doesn’t react Normal Argyll-

to light accommodation Robertson

No Miotic FIGURE 112-4  Algorithm for the approach to unequal pupils

accommodation drugs (anisocoria).

phenomenon. Figure 112-4 summarizes common pupillary
abnormalities and their associated features.
Eye Movements
The history helps in evaluating the patient with diplopia. Is the
diplopia primarily horizontal or vertical, or is it greater looking
to the right or to the left? Double vision that varies during the
day suggests myasthenia gravis. Is the diplopia maximal with near
or distant vision? Greater difficulty with near vision suggests
impairment of the medial rectus, oculomotor nerve, or conver-
gence system, whereas abducens nerve weakness results in hori-
zontal diplopia when objects are viewed at a distance. Diplopia
that worsens on going down stairs may suggest a fourth nerve
lesion. Monocular diplopia is usually caused by diseases of the
retina or lens and is corrected by having the patient look through
a pinhole, unless the cause is psychogenic.
The examination should begin by determining the position of
the head and eyes with the eyes in primary gaze. There are four
components to oculomotor function:
1. Pursuit eye movements: Smooth pursuit eye movements
allow fixation on a moving object. Ask the patient to follow
a moving target such as a pin in all directions of gaze.
2. Saccadic eye movements: These movements allow rapid
switching of gaze from one target to another. Both hori-
zontal and vertical saccadic movements should be checked.
3. Vestibulo-ocular reflex: This reflex enables fixation on an
object even if the head is moving. It is assessed by using
the Doll’s Eye Maneuver.
4. Convergence Response: This tests the ability of the eyes to
track an object as it is brought close to the limit of accom-
modation. Ask the patient to look into the distance and
then at your finger held close to their eyes.
Both smooth pursuit and (voluntary) saccadic eye movements
in horizontal and vertical directions are checked to determine
whether the movements are conjugate or disconjugate. Discon-
jugate eye movements suggest a disorder of the brainstem (at the
level of the ocular motor nuclei or their connections), the periph-
eral nerves (cranial nerves III, IV, or VI), individual eye muscles
(ocular myopathy), or the neuromuscular junction (myasthenia
gravis or botulism). A large deficit in the range of eye movements
may provide sufficient diagnostic information. However, in many
cases, although the patient complains of diplopia, no clear mis-
alignment is visible on testing eye movements. The corneal reflec-
tion test may help identify misalignment in these cases. The
patient is instructed to look at a light shining directly at the eyes.
If the eyes are normally aligned, the light reflection will be about
1 mm nasal to the center of the cornea. If one eye is deviated
medially, the reflection will be displaced outward; the reflection
will be displaced inward if the eye is deviated outward.
The abducens (sixth cranial) nerve supplies the lateral rectus
muscle. The trochlear (fourth cranial) nerve subserves the supe-
rior oblique muscle, which intorts the eye as well as depresses the
eye in adduction (such as when a patient tries to look down-
stairs). All other muscles are supplied by the oculomotor nerve
(Fig. 112-5). Abnormalities of the cranial nerves in the brainstem
are usually accompanied by other signs, such as weakness, ataxia,
or dysarthria. The abducens nerve has a long ascending course
through the posterior fossa, where it is prone to compression at
multiple sites and as a result of raised intracranial pressure; hence,
a sixth nerve palsy may be a false localizing sign. Conjugate eye
movement is regulated by supranuclear pathways from the cere-
bral hemisphere to the medial longitudinal fasciculus in the
brainstem. A lesion in the cerebral hemisphere resulting from
hemorrhage, infarction, or tumor disrupts conjugate gaze to the
contralateral side, so that the eyes “look away” from the
 Chapter 112  Disorders of Vision and Hearing 1005

Inferior oblique III Superior rectus III

ss

Medial rectus III Lateral rectus VI

Superior oblique IV Inferior rectus III

FIGURE 112-5  Movements of eye muscles and their innervation.

FIGURE 112-6  A normal optic disk on fundoscopic examination.

TABLE 112-1  MAJOR CAUSES OF ACUTE

OPHTHALMOPLEGIA non-homonymous visual defects. The term papillitis refers to
CONDITION DIAGNOSTIC FEATURES ophthalmoscopically observable changes in the optic nerve; ret-
BILATERAL robulbar neuritis refers to this condition without observable
Botulism Contaminated food; high-altitude changes in the funduscopic examination findings (“the doctor
cooking; pupils involved sees nothing and the patient sees nothing”).
Myasthenia gravis Fluctuating degree of paralysis; The patient with optic neuritis complains of difficulty with
responds to edrophonium chloride
(Tensilon) IV vision in the affected eye. Loss of vision may be insidious and
Wernicke encephalopathy Nutritional deficiency; responds to recognized only when the unaffected eye is accidentally occluded.
Acute cranial polyneuropathy thiamine IV Patients often complain of periorbital pain on eye movement on
Brainstem stroke Antecedent respiratory infection;
elevated CSF protein level presentation. The evolution of visual loss is highly variable, pro-
Other brainstem signs gressing over a period ranging from less than a day to several
UNILATERAL weeks, although most patients will have reached their maximal
P Comm aneurysm Third cranial nerve, pupil involved visual deficit in 3 to 7 days. Patients may describe their vision as
Diabetic-idiopathic Third or sixth cranial nerve, pupil blurred or dim, and colors may appear less bright than usual or
Myasthenia gravis spared “gray.” Red desaturation may occur with optic neuritis and may
Brainstem stroke As above
As above be detected using Ishihara color plates. At the time the patient is
CSF, Cerebrospinal fluid; IV, intravenous; P Comm, posterior communicating artery.
first examined, visual acuity may range from almost 20/20 to the
extreme of total blindness. Examination of the visual field shows
defects within the central 25 degrees, with central and paracentral
hemiplegia. Lesions of the brainstem cause conjugate paralysis to scotomas being the most common types. An afferent pupillary
the ipsilateral side (eyes looking toward the side of the hemiple- defect is frequently present. The funduscopic examination is
gia). Lesions of the medial longitudinal fasciculus, which con- abnormal in only about one half of the cases. The disc may appear
nects the nuclei of the oculomotor and abducens nerves, lead to hyperemic with blurred margins, and hemorrhages, when present,
internuclear ophthalmoplegia. In this case, horizontal gaze results are few and found only on the disc or in the area immediately
in failure of adduction in one eye and nystagmus in the abducting surrounding the disc. Optic neuritis should be treated acutely
eye. The lesion is on the side of failed adduction; bilateral lesions with high-dose intravenous corticosteroids because this is proven
are frequently seen in multiple sclerosis. Table 112-1 lists the to shorten time to recovery. The most common cause of optic
major causes of acute opthalmoplegia. neuritis is multiple sclerosis. Bilateral optic neuritis is much less
common and may coincide with longitudinally extensive trans-
Funduscopy verse myelitis, known as neuromyelitis optica (NMO) or Devic
The retina should be carefully examined in each patient by direct disease. The recent discovery of antibodies directed toward aqua-
ophthalmoscopy, which provides a magnified view of the fundus porin 4 (a water channel present on astrocytes and vascular endo-
without the necessity for dilation of the pupil (Fig. 112-6). thelial cells), associated with NMO, has identified this as a
separate disease entity, with a different treatment regimen emerg-
Monocular Visual Loss ing for it. The NMO antibody is the first sensitive and specific
Loss of vision in one eye may be caused by lesions of the cornea, biomarker associated with a central demyelinating disorder.
lens, vitreous, retina, or optic nerve. Careful funduscopic exami- The optic nerve may be compressed by tumors that originate
nation will usually reveal ocular and retinal lesions, but acute in the nerve itself or in the region of the optic chiasm. Pathologic
lesions of the optic nerve (optic neuritis) may not be associated processes that appear acutely as optic disc edema frequently
with abnormalities of the optic nerve head. Optic neuritis is char- result in a secondary optic atrophy, including papilledema, optic
acterized by inflammation of the optic nerve accompanied by neuritis, and ischemic optic neuropathy. Glaucoma is responsible
 1006 Section XVI  Neurologic Disease
for more cases of optic atrophy in the adult population than any
ss other cause. In young patients with inherited optic atrophy, Leber
hereditary optic neuropathy is often the cause; it is usually bilat-
eral. Foster-Kennedy syndrome is optic atrophy in one eye with
papilledema in the other eye, secondary to a tumor compressing
the atrophied optic nerve and causing raised intracranial pressure
to produce papilledema in the opposite eye.
Ischemic optic neuropathy occurs in two forms. The atheroscle-
rotic variety occurs mostly between the ages of 50 and 70 years,
and no evidence of systemic disease is present. The arteritic form
is usually a manifestation of giant cell arteritis; there may be
systemic manifestations of the disease, including headache, scalp
tenderness, and generalized myalgias. Laboratory evaluation
shows anemia and elevated erythrocyte sedimentation rate in
almost every case. Patients with arteritis should be treated with
high doses of corticosteroids to prevent permanent loss of vision.
Acute transient monocular blindness is usually the result of
embolization to the central retinal artery from an atheromatous
plaque in the carotid artery (amaurosis fugax). Any complaint of
transient visual loss constitutes an emergency, and steps must be
taken to prevent permanent loss of vision by making a prompt
diagnosis and initiating appropriate therapy. Examples of sight-
saving procedures include corticosteroid therapy for cranial arte-
ritis, reduction of intraocular pressure for acute glaucoma, and
carotid surgery, anticoagulation, or antiplatelet therapy for
embolic cerebrovascular disease.
Binocular Visual Loss
Gradual bilateral visual loss caused by optic nerve lesions is rare.
Causes include Leber hereditary optic neuropathy and a toxic
nutritional–deficiency state. Acute transient bilateral visual loss
(visual obscuration) may be a symptom of raised intracranial
pressure caused by a brain tumor or idiopathic intracranial hyper-
tension (IIH); papilledema is often severe. IIH, formerly known
as pseudotumor cerebri, requires prompt investigation and treat-
ment to prevent potential bilateral visual failure. It is often associ-
ated with a high body mass index (BMI) and is more common
in young females. Vitamin A and tetracycline ingestion have been
associated with the condition. Unilateral or bilateral lateral rectus
palsy may be present. It is one of the few situations in which,
after imaging, performance of a lumbar puncture is safe in the
setting of marked bilateral papilledema. Cerebral venous sinus
thrombosis may mimic IIH and should be screened for with
neuroimaging.
Bilateral damage to the optic radiations or visual cortex results
in cortical blindness. The pupillary light reflex is normal, as are
the funduscopic examination findings, and the patient may occa-
sionally be unaware that he or she is blind (Anton syndrome).
Patients are often misdiagnosed as having a conversion reaction.
Transient cortical blindness occurs most often in basilar artery
insufficiency but is also seen in hypertensive encephalopathy.
Positive visual phenomena (e.g., phosphenes, scintillating scoto-
mas) are characteristic of migrainous aura and probably reflect
oligemia to the occipital lobes from vasoconstriction. Arteriove-
nous malformations, tumors, and seizures may produce similar
symptoms and should be distinguished from migraine with aura
by a careful history and examination as well as by imaging in
appropriate cases.
Visual hallucinations are visual sensations independent of
external light stimulation; they may be either simple or complex,
may be localized or generalized, and may occur in patients with
a clear or clouded sensorium. Visual illusions are alterations of a
perceived external stimulus in which some features are distorted.
The simplest visual phenomena consist of flashes of light (pho-
topsias), blue lights (phosphenes), or scintillating zigzag lines,
which last a fraction of a second and recur frequently or which
appear to be in constant motion. These can arise from dysfunc-
tion within the optic pathways at any point from the eye to the
cortex. Glaucoma, incipient retinal detachment, retinal ischemia,
or macular degeneration can cause simple visual hallucinations
based on dysfunction in the eye. Lesions of the occipital lobe are
often associated with simple hallucinations; classic migraine is
by far the most common condition of this type. Complex visual
hallucinations such as seeing objects as people, animals, land-
scapes, or various indescribable scenes occur most frequently
with temporal lobe lesions or parieto-occipital association
areas. Visual hallucinations of epileptogenic origin are typically
stereotyped.
  HEARING AND ITS IMPAIRMENTS
Symptoms of Auditory Dysfunction
The main symptoms of lesions within the auditory system are
hearing loss and tinnitus. Hearing loss can be classified as con-
ductive, sensorineural, mixed, or central, based on the anatomic
site of pathology (Figs. 112-7 and 112-8). Tinnitus can be either
subjective or objective. Conductive hearing loss results from
lesions involving the external or middle ear. Patients with a con-
ductive hearing loss can hear speech in a noisy background as
well as in a quiet background, because they can understand loud
speech as well as anyone. The ear often feels full, as if it is blocked.
The Weber test localizes to the deaf ear, if the deafness is
unilateral.
Sensorineural hearing loss usually results from lesions of the
cochlea or the auditory division of the vestibulocochlear (eighth
cranial) nerve. Patients with sensorineural hearing loss often have
difficulty hearing speech that is mixed with background noise
and may be annoyed by loud speech. They usually hear low tones
better than high-frequency ones. Distortion of sounds is common
with sensorineural hearing loss. Central (retrocochlear) hearing
disorders are rare and result from bilateral lesions of the central
auditory pathways, including the cochlear and dorsal olivary
nuclear complexes, inferior colliculi, medial geniculate bodies,
and auditory cortex in the temporal lobes. Damage to both audi-
tory cortices may result in pure word deafness, in which patients
are selectively unable to discriminate language but may be able
to hear nonverbal sounds.
Tinnitus is the perception of a noise or ringing in the ear that
is usually audible only to the patient (subjective), although,
rarely, an examiner can hear the sound as well. The latter, so-called
objective tinnitus, can be heard when the examining physician
places a stethoscope against the patient’s external auditory canal.
Tinnitus that is pulsatory and synchronous with the heartbeat
suggests a vascular abnormality within the head or neck (see Fig.
120-7). Aneurysms, arteriovenous malformations, and vascular
tumors can produce this type of tinnitus.
 Chapter 112  Disorders of Vision and Hearing 1007

Hearing ss

loss Acoustic neuroma

Impacted cerumen Other C-P angle
Otitis media Abnormal tumor
Ear Abnormal Cholesteatoma Multiple sclerosis
History examination Drum perforation Brainstem infarct
Normal Trauma

Drugs
Pure tone Sensorineural
Noise exposure MR imaging
audiogram hearing loss
Hereditary factors Perilymph
Intrauterine factors fistula
Trauma
Otosclerosis
Ossicular chain Normal Labyrinthitis
Conductive dysfunction Labyrinthine infarct
hearing loss Serous otitis Meniere disease
Eustachian tube Presbycusis
dysfunction Noise induced

FIGURE 112-7  Evaluation of deafness (unilateral and bilateral). C-P, Cerebellopontine; MR, magnetic resonance. (Modified from Baloh RW: Hearing
and equilibrium. In Goldman L, Bennett JC, editors: Cecil textbook of medicine, ed 21, Philadelphia, 1998, WB Saunders, p 2250).

Tinnitus

Objective
Subjective (heard by examiner)

Hearing loss Pulsatile Non-pulsatile

Yes No AVM,
Venous hum,
vascular tumor,
palatal tremor
venous hum

Conductive Sensorineural

Lesion of Lesion of
external ear, cochlea, Idiopathic
middle ear auditory nerve
FIGURE 112-8  Algorithm for the approach to the patient with tinnitus. AVM, Arteriovenous malformation.

Subjective tinnitus, heard only by the patient, can result from
lesions involving the external ear canal, tympanic membrane,
ossicles, cochlea, auditory nerve, brainstem, and cortex. The
character of the tinnitus does not usually aid in determining the
site of the disturbance. For this, one must rely on associated
symptoms and signs. When tinnitus results from a lesion of the
external or middle ear, it is usually accompanied by a conductive
hearing loss. The patient may complain that his or her voice
sounds hollow and that other sounds are muffled. Because the
masking effect of ambient noise is lost, the patient may be dis-
turbed by normal muscular sounds such as chewing, tight closure
of the eyes, or clenching of the jaws. The characteristic tinnitus
associated with Meniere’s syndrome is low pitched and continu-
ous, although fluctuating in intensity. Often the tinnitus becomes
very loud immediately preceding an acute attack of vertigo and
then may disappear after the attack. Tinnitus resulting from
lesions within the central nervous system is usually not
associated with hearing loss but is nearly always associated with
other neurologic symptoms and signs. High-dose salicylates fre-
quently result in tinnitus.
Examination of the Auditory System
A quick test for hearing loss in the speech range is to observe the
response to spoken commands at different intensities (whisper,
conversation, and shouting). The examiner must be careful to
prevent the patient from reading his or her lip movement. A high-
frequency stimulus such as a watch tick should also be used
because sensorineural disorders often involve only the higher
frequencies. Tuning fork tests permit a rough assessment of the
hearing level for pure tones of known frequency. The Rinne test
compares the patient’s hearing by air conduction with that by
bone conduction. A 512-cps tuning fork is first held against the
mastoid process until the sound fades. It is then placed 1 inch
from the ear. Normal subjects can hear the fork about twice as
 1008 Section XVI  Neurologic Disease

long by air conduction as by bone conduction. If hearing by bone conductive hearing loss. Seventy percent of patients with clinical
ss conduction is longer than by air conduction, a conductive hearing otosclerosis notice hearing loss between the ages of 11 and 30.
loss is suggested. The Weber test compares the patient’s hearing There is a family history of otosclerosis in approximately 50% of
by bone conduction in the two ears. The fork is placed at the cases. Stapedectomy, a procedure in which the stapes is replaced
center of the forehead, and the patient is asked where he or she with a prosthesis, is effective in correcting the conductive com-
hears the tone. Normal subjects hear it in the center of the head, ponent of hearing loss.
patients with unilateral conductive loss hear it on the affected A lesion of the cerebellopontine angle, such as a vestibular
side, and patients with unilateral sensorineural loss hear it on schwannoma, often causes unilateral hearing loss that progresses
the side opposite the loss. Otoscopic examination may reveal slowly (Table 112-2); symptoms are caused by compression
impacted cerumen as a cause of conductive hearing loss. of the nerve in the narrow confines of the canal (Fig. 112-9).
The most common symptoms associated with vestibular
Causes of Hearing Loss
The bilateral hearing loss commonly associated with advancing
age is called presbycusis. Presbycusis is not a distinct disease entity TABLE 112-2  CAUSE OF ACUTE UNILATERAL
but rather represents multiple effects of aging on the auditory SENSORINEURAL DEAFNESS
system. Presbycusis may include conductive and central dysfunc- COCHLEAR RETROCOCHLEAR
tion, although the most consistent effect of aging is on the sensory Idiopathic (85%) Demyelination
Trauma Vestibular schwannoma (usually
cells and neurons of the cochlea; as a result, higher tones are lost Meniere's disease gradual onset)
early. Lyme's disease Stroke
Otosclerosis is a disease of the bony labyrinth that usually mani- Syphilis
Autoimmune disease
fests itself by immobilizing the stapes and thereby producing a

FIGURE 112-9  Magnetic resonance imaging scan of the brain showing coronal and axial views of a tumor of the left cerebellopontine angle,
consistent with a schwannoma.
 Chapter 112  Disorders of Vision and Hearing 1009
schwannomas are slowly progressive hearing loss and tinnitus
from compression of the cochlear nerve. Vertigo occurs in fewer
than 20% of patients, but approximately 50% complain of imbal-
ance or disequilibrium. Next to the auditory nerve, the cranial
nerves most commonly involved by compression are the seventh
(facial weakness) and fifth (sensory loss). Loss of the corneal
reflex on the affected side is often the first clinical sign. Treatment
in most cases is surgical removal.
Meniere’s syndrome (endolymphatic hydrops) is characterized
by fluctuating hearing loss and tinnitus, episodic vertigo, and a
sensation of fullness or pressure in the ear. Typically the patient
develops a sensation of fullness and pressure, along with decreased
hearing and tinnitus in one ear. Vertigo rapidly follows, reaching
a maximum intensity within minutes and then slowly subsiding
over the next several hours. The patient is usually left with a sense
of unsteadiness and dizziness for days after the acute vertiginous
episode. In the early stages the hearing loss is completely revers-
ible, but in later stages a residual hearing loss remains. Up to 50%
of patients with idiopathic Meniere’s syndrome frequently have a
positive family history, suggesting genetic predisposing factors.
The key to the diagnosis of Meniere’s syndrome is to document
fluctuating hearing levels in a patient with the characteristic clini-
cal history. Medical therapy for endolymphatic hydrops includes
dietary sodium restriction and oral diuretics.
Acute unilateral deafness usually results from damage to the
cochlea and may be caused by viral or bacterial labyrinthitis or
vascular occlusion in the territory of the anterior inferior cerebel-
lar artery. Perilymphatic fistulas may also cause abrupt unilateral
deafness, usually in association with tinnitus and vertigo.
Drugs that cause acute irreversible bilateral hearing loss
include aminoglycosides, cisplatin, and furosemide. Salicylates ss
may cause reversible hearing loss and tinnitus.
Treatment of Hearing Loss
The best treatment is prevention, particularly by the appropriate
use of earplugs for those working in a noisy environment. Hearing
aids help patients with conductive hearing loss, and develop-
ments with cochlear implants may help patients with sensorineu-
ral hearing loss.
Prospectus for the Future
Optical coherence tomography (OCT) is an emerging technol-
ogy in the assessment of retinal layer thickness. This technology
has been used in multiple sclerosis research. It has been used to
correlate retinal layer thickness with severity of multiple sclerosis.
This may have important implications for future research in this
field.
For a deeper discussion on this topic, please see Chapter
423, “Diseases of the Visual System,” and Chapter 424,
“Neuro-Opthalmology,” in Goldman-Cecil Medicine, 25th
Edition.
SUGGESTED READINGS
Drori T, Chapman J: Diagnosis and classification of neuromyelitis optica (Devic’s
syndrome), Autoimmune Rev 13:531–533, 2014.
Toosy AT, Mason DF, Miller DH: Optic neuritis, Lancet Neurol 13:83–99, 2014.
 113 
ss
Dizziness and Vertigo
Kevin A. Kerber
  DEFINITION/EPIDEMIOLOGY
Dizziness is a common term that is used by patients and provid-
ers to group a variety of different symptoms including a spinning
sensation, lightheadedness, disorientation, or imbalance. Other
more vague symptoms are also often labeled as “dizziness.”
Vertigo is the term used for a false sense of movement, typically
spinning. The problem with defining the type of dizziness is that
patients are often inconsistent when describing dizziness. In
addition, the type of dizziness generally does not adequately dis-
criminate among disorders. Approximately 30% of the general
population reports having had some type of bothersome
dizziness.
  PATHOLOGY
Pathology that causes dizziness can stem from many systems of
the body. Understanding the vestibular system and common
peripheral vestibular disorders is of central importance in the
evaluation of patients with dizziness. This is because the dilemma
is often discriminating a benign peripheral vestibular disorder
from a focal brain lesion. The vestibular system is a common
source of confusion. Many clinicians assume a “peripheral” cause
in the absence of motor, sensory, or language deficits, but this
approach is flawed. A more effective approach is to aim to “rule
in” a specific peripheral vestibular disorder. The three common
peripheral vestibular disorders all have highly characteristic
history and examination features, thus enabling this approach.
When a specific peripheral vestibular disorder does not fit, then
one must consider other potential etiologies.
  BASIC VESTIBULAR SYSTEM CONCEPTS
The peripheral vestibular system maintains a balanced tonic
input to the brain. The input represents the circuitry that links
the inner ear to eye movements, the vestibulo-ocular reflex
TABLE 113-1  COMMON TYPES AND PATTERNS OF NYSTAGMUS
TYPES PATTERNS
Spontaneous Unidirectional horizontal ≫ torsional
Downbeat, upbeat, or pure torsional
Gaze-evoked Unidirectional
Bidirectional
Positional Burst of upbeat torsional with DH
Horizontal with supine positional testing
Persistent downbeat
BPPV, Benign paroxysmal positional vertigo; DH, Dix-Hallpike positional test; SCC, semicircular canal; ≫, greater than.
*Most common with antiepileptic drugs.
1010
(VOR). A normal functioning VOR is important for balance
and maintaining clear vision when moving. Vertigo ensues when
an imbalance is caused by a lesion (e.g., vestibular neuritis) or
aberrant stimulation (e.g., benign paroxysmal positional vertigo).
A characteristic sign of vestibular system imbalance is nystagmus:
rhythmic slow and fast movements of the eyes in opposite direc-
tions. The location of pathology determines the pattern of nys-
tagmus (Table 113-1). Dysfunction at the semicircular canal
level leads to nystagmus in the plane of the affected canal.
Therefore problems in the vertical canals (i.e., posterior and
anterior canals) lead to vertical and torsional nystagmus, whereas
problems in the horizontal canal lead to horizontal nystagmus.
At the vestibular nerve level a mixed horizontal-torsional nys-
tagmus is generated because input from all the semicircular
canals converge at this level and the signals from the vertical
canals mostly cancel each other out. The pathways and thus the
patterns of eye movements become less predictable with lesions
of the central vestibular pathways, although some general rules
apply. Pure vertical (downbeat or upbeat) spontaneous nystag-
mus, bidirectional gaze-evoked nystagmus (look left, beats left;
look right, beats right) (Video 113-1), and persistent downbeat-
ing positional nystagmus are signs of central dysfunction (see
Table 113-1).
Another characteristic sign of vestibular disturbance is a posi-
tive head-thrust test (Video 113-2). A person with an intact VOR
will maintain gaze on a stationary, straight-ahead target after a
brief, small-amplitude, high-acceleration movement of the head
to one side. A person with vestibular impairment on one side
loses this reflex on the ipsilateral side and therefore, after the
quick head movement, will need to make a re-fixation voluntary
eye movement (i.e., a “saccade”) back to the target because the
eyes moved with the head. This so-called “catch-up” or “correc-
tive” saccade is easily appreciated at the bedside and indicates
vestibular deafferentation.
LOCALIZATION PRINCIPAL CAUSES
Vestibular nerve, or less commonly the brainstem Vestibular neuritis, or less commonly stroke
Brain Stroke
Vestibular nerve Vestibular neuritis (recovery pattern)
Brain Stroke, cerebellar syndrome, medication side
effect*
Posterior SCC BPPV
Horizontal SCC or less commonly the brainstem BPPV, brainstem lesion
Brain Chiari malformation, cerebellar degeneration

  CLINICAL PRESENTATION
Patients usually present with acute constant dizziness, recurrent
spontaneous attacks, or recurrent positional attacks. Less com-
monly, patients present with chronic constant dizziness. The
physical examination is a critical part of the assessment. If the
general examination is unrevealing, then the focus should shift
to the ocular motor examination because vestibular disorders
have highly characteristic findings, particularly regarding the
presence and pattern of nystagmus (see Table 113-1). Hearing
should be tested one ear at a time with either tuning forks or
finger rub.m
  DIFFERENTIAL DIAGNOSIS
The differential diagnosis can generally be categorized as follows:
a peripheral vestibular disorder, a central nervous system disor-
der, a general medical disorder (e.g., anemia, metabolic derange-
ment, anxiety disorder), or a chronic otherwise undefined
disorder. There are three common peripheral vestibular disor-
ders: vestibular neuritis, Meniere’s disease, and benign paroxys-
mal positional vertigo (BPPV). An understanding of these three
disorders is important because each one is the primary consider-
ation for the cause of one of the three common dizziness presen-
tation categories (Table 113-2). In addition, these disorders are
the prototypes for most pathology that involves the peripheral
vestibular system.
Vestibular neuritis manifests with the abrupt onset of severe
vertigo, nausea, and imbalance without other neurologic symp-
toms. The disorder is caused by a viral disturbance of the vestibu-
lar nerve, analogous to Bell’s palsy. On examination, the acute
peripheral vestibular pattern of nystagmus is seen (see Table
113-2; Video 113-3). A positive head-thrust test in the direction
of the affected ear (but in the direction opposite the fast phase of
nystagmus) further supports vestibular nerve localization. If the
nystagmus changes direction with gaze (i.e., look left, beat left;
then look right, beat right), then vestibular neuritis is not the
diagnosis because these findings localize to the central nervous
system. Small strokes of the cerebellum or brainstem can closely
mimic vestibular neuritis.
TABLE 113-2  COMMON CATEGORIES OF DIZZINESS PRESENTATIONS
ACUTE CONSTANT DIZZINESS
Primary consideration Vestibular neuritis
Key features Constant vertigo, unidirectional
horizontal nystagmus,* positive
head-thrust test†
Red flags Other CNS features, other patterns
of nystagmus, imbalance as the
principal symptom, chest pain,
cardiovascular risk factors
Other considerations Stroke, myocardial infarction,
metabolic disturbances,
demyelinating attack
BPPV, Benign paroxysmal positional vertigo; CNS, central nervous system; DH, Dix-Hallpike; TIA, transient ischemic attack.
*This nystagmus never changes direction. Gaze in the direction of the fast phase will increase the velocity of the nystagmus, whereas gaze in the opposite direction will decrease the
velocity of the nystagmus.
†
The head-thrust test will be positive in the direction of the affected ear, which is opposite the direction of the fast phase of nystagmus.
‡
These features apply to BPPV stemming from the posterior canal.
Chapter 113  Dizziness and Vertigo 1011
Meniere’s disease is characterized by recurrent episodes of
vertigo, nausea, and imbalance typically lasting hours; prominent ss
auditory features must be present to make the diagnosis. Early in
the course, auditory symptoms fluctuate along with vertigo
attacks, but later they become a fixed symptom. The auditory
symptoms are nearly always unilateral at the onset and consist of
hearing loss, roaring tinnitus, or severe fullness in one ear. If
attacks are brief (i.e., minutes rather than hours), then transient
ischemic attacks should be considered. The dizziness of migraine
can also closely mimic Meniere’s disease.
Patients with BPPV report very brief episodes (<1 minute) of
vertigo triggered by head movement; most often tilting the head
back to look up, getting in or out of bed, or rolling over in bed.
Dizziness from any cause may worsen after certain movements,
but the dizziness of BPPV is triggered by certain movements. The
most common form of BPPV occurs when otoliths enter the
posterior canal. Posterior canal BPPV is identified at the bedside
using the Dix-Hallpike test (Fig. 113-1). In response to the Dix-
Hallpike test, otoliths move in the canal and lead to a burst of
upbeat-torsional nystagmus lasting about 20 to 30 seconds
(Video 113-4). BPPV is less commonly caused by otoliths in the
horizontal canal and very rarely the anterior canal. When the
otoliths are in one of these other canals, the pattern of nystagmus
is different from that of posterior canal BPPV, as are the reposi-
tioning maneuvers used to treat BPPV. Positional vertigo and
nystagmus are common in patients with migraine. If a persistent
downbeating nystagmus is seen during the Dix-Hallpike test,
then a central nervous system cause (e.g., Chiari malformation,
cerebellar tumor, or cerebellar degeneration) should be
considered.
If the patient reports imbalance as the principal symptom and
has a gait disorder, then the following causes should be consid-
ered: stroke (if the onset was acute), a musculoskeletal disorder,
peripheral neuropathy, bilateral vestibulopathy (frequently
attributable to ototoxicity, particularly from gentamicin), or a
neurodegenerative disorder involving the cerebellum.
If a specific peripheral vestibular disorder is not identified and
the neurologic examination is normal, then general medical
causes should be considered. The list of medications should be
RECURRENT
SPONTANEOUS ATTACKS RECURRENT POSITIONAL ATTACKS
Meniere's disease BPPV
Vertigo lasting hours, unilateral auditory Positionally triggered, brief (<1 min)
symptoms attacks
Upbeat-torsional burst of nystagmus in
DH position, cured by Epley maneuver‡
Other CNS features, CNS patterns of Other CNS features, CNS patterns of
nystagmus, imbalance as the principal nystagmus
symptom, attacks lasting only minutes,
chest pain, cardiovascular risk factors,
recent onset, crescendo pattern
TIA, cardiac arrhythmia, migraine, panic Horizontal or anterior canal BPPV,
attacks migraine, Chiari malformation, posterior
fossa tumor, orthostatic hypotension
 1012 Section XVI  Neurologic Disease

ss

PSC
B
D C

UT E
A
E

FIGURE 113-1  Repositioning treatment for benign paroxysmal positional vertigo designed to move endolymphatic debris out of the posterior
semicircular canal (PSC) of the right ear and into the utricle (UT). The patient is seated, and the patient’s head is turned 45 degrees to the right (A).
The head is then lowered rapidly to below the horizontal (B). The examiner shifts hand positions (C), and the patient’s head is rotated rapidly 90
degrees in the opposite direction, so it now points 45 degrees to the left, where it remains for 30 seconds (D). The patient then rolls onto the left
side without turning the head in relation to the body and maintains this position for another 30 seconds (E) before sitting up. The treatment is
repeated until nystagmus is abolished. The procedure is reversed for treating the left ear. (Modified from Foster CA, Baloh RW: Episodic vertigo. In
Rakel RE, editor: Conn’s Current Therapy, Philadelphia, 1995, WB Saunders.)

carefully scrutinized because dizziness is a common medication
side effect. Dizziness can be a prominent symptom of anxiety and
panic disorders. Vestibular migraine should be on the differential
diagnosis of any dizziness presentation. When none of these
seem to fit, the examination findings are normal, and the symptom
has been present for more than several months, then the patient
likely has chronic dizziness—typically considered a benign
hypersensitivity disorder.
  TREATMENT
Vestibular rehabilitation is the treatment of choice for patients
with vestibular neuritis. If Meniere’s disease is diagnosed, then a
low-salt diet or a diuretic may alleviate the frequency of episodes.
However, neither of these treatments is of established efficacy.
Ablative surgical procedures are appropriate in refractory
Meniere’s disease. The treatment of BPPV involving the posterior
canal is the highly effective and guideline-supported reposition-
ing maneuver described by Epley (see Fig. 113-1). Patients with
chronic dizziness may benefit from lifestyle modifications (e.g.,
exercise, optimizing sleep and diet, and stress management).
Migraine prophylactic agents are reasonable to initiate, but their
effectiveness for dizziness has not been established. Acute symp-
toms can be effectively managed with an antihistamine, a benzo-
diazepine, or an antiemetic. However, these are not appropriate
long-term treatment regimens.
  PROGNOSIS
The prognosis in patients with dizziness is generally favorable.
The main goals are to identify the patients at significant probabil-
ity of having a dangerous disorder, to relieve the acute symptoms,
and to take appropriate steps to reduce the likelihood of recurrent
events.
SUGGESTED READINGS
Baloh RW, Kerber KA, Honrubia V: Clinical Neurophysiology of the Vestibular
System, ed 4, New York, 2011, Oxford University Press.
Fife TD, Iverson DJ, Lempert T, et al: Practice parameter: Therapies for benign
paroxysmal positional vertigo (an evidence-based review): Report of the
Quality Standards Subcommittee of the American Academy of Neurology,
Neurology 70:2067–2074, 2008. (Accompanying video clips are accessible at
www.aan.com/go/practice/guidelines.)

Disorders of the Motor System
  INTRODUCTION
The motor system is broadly divided into the pyramidal and
extrapyramidal systems. The pyramidal system is a single neuron
system, which originates in the primary motor cortex of the
frontal lobes and, with white matter projections, coalesces to
form the internal capsule; it then traverses the brainstem (as the
cerebral peduncles in the midbrain, the basis pontis in the pons
and the pyramids in the medulla where the majority of neurons
decussate to form the corticospinal tracts), and ultimately syn-
apses on the lower motor neurons in the anterior horn of the
spinal cord (Fig. 114-1). The extrapyramidal system consists pri-
marily of the basal ganglia and the cerebellum, and provides coor-
dinating and integrating information to the pyramidal tract
system under the influence of various afferent feedback loops.
The components and pathways of the basal ganglia (Fig. 114-2)
and cerebellum (Fig. 114-3) influence and modulate voluntary
motor activity of the motor cortex.
Disorders of the motor system affect the components of the
pyramidal and extrapyramidal systems. The approach to the
patient with motor dysfunction depends on the ability to accu-
rately localize the neuroanatomical region affected through a
careful history and focused examination.
  SYMPTOMS AND SIGNS OF
MOTOR SYSTEM DISORDERS
Table 114-1 summarizes the neuroanatomic localization of dis-
eases and the associated symptoms and signs characteristic of
dysfunction at those levels. While “weakness” is a frequent com-
plaint, it does little to help with the localization of the problem
because it can occur with any disorder of the motor system and
does not always reflect weakness on examination. In addition,
weakness of insidious onset may be completely overlooked by the
patient. Some patients may complain of feeling numb, or that the
limb is asleep, uncoordinated, or fatigued. Symptoms referable to
impaired balance and gait are common. Patients with distal weak-
ness may complain of impairment in fine motor tasks, buttoning
buttons, opening jars/doors, handwriting, stumbling, or tripping
with walking. Proximal weakness of the upper extremities will
result in difficulty performing tasks over their heads, including
washing their hair or applying makeup. Proximal weakness of the
lower extremities is often manifested as difficulty with stairs or
getting up from sitting. Bulbar weakness with dysarthria and dys-
phagia may be referable to a variety of diseases of the motor
system and can often provide important clues to the differential
diagnosis. Involuntary movements may reflect diseases of the
basal ganglia but, similar to weakness, may not be appreciable to
114 
ss
Kevin M. Biglan
the patient; therefore, information from a secondary observer is
beneficial. Complaints of diffuse motor incoordination including
deficits in speech, fine motor coordination, and gait imbalance
suggest cerebellar dysfunction.
  SIGNS OF CENTRAL MOTOR SYSTEM DYSFUNCTION
Central nervous system diseases affecting the motor system are
divided into abnormalities of pyramidal tract (upper motor
neuron), basal ganglia, and cerebellum. Each presents with dis-
tinct clinical signs; however, overlapping syndromes may occur,
which suggests more diffuse disease processes.
Upper motor lesions affecting the motor cortex and the sub-
cortical white matter prior to the medullary decussation are asso-
ciated with contralateral weakness, whereas lesions of the medulla
and corticospinal tracts in the spinal cord post-decussation cause
ipsilateral weakness. Both are associated with upper motor
neuron signs. Lesions of the spinal cord may cause mixed upper
motor neuron dysfunction below the lesion and lower motor
neuron dysfunction at the level of the lesion due to involvement
of descending corticospinal tracts and peripheral motor neurons
originating in the anterior horn. Dysfunction of upper motor
neurons traditionally causes distal greater than proximal weak-
ness, increased muscle tone with spasticity, increased muscle
stretch reflexes with clonus, and pathologic reflexes (Babinski’s
sign). There is little or no muscle atrophy. Acute lesions of
the spinal cord can initially cause a flaccid paralysis with areflexia
that eventually evolves into a typical upper motor neuron
syndrome.
The basal ganglia are important for the planning, initiation,
and execution of movements. They facilitate desired movements
while inhibiting unwanted movements through pathways that
ultimately interact with primary motor cortex. Disorders of basal
ganglia function often cause movement disorders characterized
by heterogeneous and mixed impairments in voluntary move-
ment not associated with muscle weakness, and often involuntary
movements. Disorders of tone are common and variable. Speech
and posture are often affected. Patients may have involuntary
movements when awake but, with rare exceptions, the involun-
tary movements are abolished during sleep. Gait dysfunction
with postural instability may be seen.
The cerebellum constantly monitors afferent input from
muscles, joints, and motor cortex and integrates planned move-
ments to fine tune motor control through efferent projections
that regulate motor cortex activity. Disorders causing cerebellar
signs may result from direct impairment of cerebellar function or
impairment in afferent and efferent pathways of the cerebellum.
Cerebellar disorders result in signs that reflect difficulty with
1013
 1014 Section XVI  Neurologic Disease

ss MOTOR
CORTICES

Thalamus

Internal
capsule

Red
nucleus

Reticular
formation Cortico-
cerebellar
Vestibular pathways
nucleus

Nucleus
dorsalis

Corticospinal
tract

Anterior
horn cells

Lower motor
neuron FIGURE 114-1  Normal human voluntary motor system.

Cortex

GLU
Caudate
Neostriatum
Putamen
ACH FIGURE 114-2  Anatomy of the basal
Thalamus ganglia and their connections. The feedback
GABA VL Subthalamic nucleus loop proceeds from cerebral prefrontal areas
GLU to the basal ganglia and eventually back from
GPi GPe the basal ganglia to the thalamus to the
DA motor cortex. This ultimately regulates the
GABA descending corticospinal motor system.  
Superior colliculus ACH, Acetylcholine; DA, dopamine; GABA,
GLU γ-aminobutyric acid; GLU, glutamate; GP,
globus pallidum (e, external; i, internal);  
SNr
SNc SN, substantia nigra (c, compacta; r, reticu-
late); VL, ventrolateral. (From Jankovic J: The  
Excitatory extrapyramidal disorders: Introduction. In
Inhibitory Goldman L, Bennett JC, editors: Cecil Text-
Normal
Excitatory and Inhibitory book of Medicine, ed 21, Philadelphia, 2000,
Unknown Saunders, p 2078).
 Chapter 114  Disorders of the Motor System 1015
Ventrolateral
MOTOR nucleus of
CORTEX thalamus
Red
nucleus
Cerebellar
cortex
Dentate
nucleus
Spinocerebellar
tract
FIGURE 114-3  Corticocerebellar loop. The major cerebellar input is
from the spinocerebellar tract. Outflow is to the motor cortex via the
mesencephalon and thalamus.
monitoring and regulating motor actions. Eye movement abnor-
malities include square wave jerks on ocular fixation, jerky slow
pursuit movements, hypo- and hyper-metric point-to-point sac-
cades, and nystagmus. The characteristic speech pattern, a scan-
ning dysarthria, displays an abnormal modulation of speech
volume and velocity. Speech prosody is also affected. Voluntary
movements are irregular and uncoordinated with irregularities in
amplitude, velocity, and rhythm. With sustained posture a tremor
may develop and increase in amplitude with prolonged susten-
tion. On directed movements there is an irregular placement of
the limb (i.e. dysmetria) with voluntary movements, such as
finger to nose or heel to shin testing. An intention tremor (increas-
ing amplitude of tremor as one approaches target) is characteris-
tic of cerebellar dysfunction. Patients have difficulty regulating
muscle contractions with an increase in rebound when the exam-
iner pushes against a limb and the patient is asked to keep the
limb still, or a reduced ability to check a movement when resis-
tance to muscle contraction is suddenly removed.
  SIGNS OF PERIPHERAL MOTOR
SYSTEM DYSFUNCTION
Disorders affecting the peripheral motor system reflect disease of
the motor unit: the anterior horn cell, peripheral nerve, neuro-
muscular junction, and muscles. All may be associated with weak-
ness, muscle atrophy, hypotonia, hyporeflexia, fasciculations, and
fibrillations. Anterior horn cell diseases cause a pure motor dis-
order with profound atrophy and prominent fasciculations. Para-
doxically, the most common cause of anterior horn cell disease,
amyotrophic lateral sclerosis, is associated with both upper and
lower motor neuron syndrome: individuals have weakness,
muscle wasting with spasticity, and increased muscle stretch
reflexes. The motor neuron exits the spinal cord via a nerve root,
in the limb multiple roots combine to form a plexus, and then
individual peripheral nerves innervate specific muscles. Lesions
ss
of nerve roots, plexus, and peripheral nerves are often associated
with both weakness and sensory symptoms in the regions inner-
vated by the specific roots, plexus, or nerves. Muscle stretch
reflexes are reduced or absent. The distribution of weakness,
sensory, and reflex findings assists in accurate localization.
Peripheral nerve disorders may affect single nerves, such as
median nerve in carpal tunnel syndrome, or multiple nerves,
such as polyneuropathy in diabetes. In the former setting com-
bined motor and sensory findings are the rule, whereas in the
latter, occasional pure motor neuropathies occur. Polyneuropa-
thy is usually associated with a distal gradient of both motor and
sensory abnormalities that can be slowly or rapidly ascending
depending on the underlying etiology.
Neuromuscular junction disorders are characterized by fluctu-
ating weakness and fatigability. Tone and reflexes are usually
unaffected with the exception of Lambert-Eaton Syndrome, in
which muscle stretch reflexes are reduced or absent. Muscle mass
and sensation are preserved. On examination, an individual may
demonstrate fatigable weakness with strength recovery after rest.
Bulbar symptoms and signs may be prominent with a nasal
speech pattern, various abnormalities of eye movements, ptosis,
and neck weakness.
Disorders of the muscle classically result in proximal greater
than distal limb weakness with some exceptions, such as inclu-
sion body myositis and myotonic dystrophy, in which distal
weakness predominates. Muscle diseases, especially toxic or
inflammatory conditions, may be associated with myalgia and
tenderness to muscle palpation. Muscle stretch reflexes are
normal to slightly reduced. Sensation is preserved.
  DIFFERENTIAL DIAGNOSIS OF
PYRAMIDAL TRACT DISORDERS
Any disease affecting the nervous system can cause pyramidal
tract dysfunction. Structural lesions due to stroke, tumor, infec-
tion, trauma, inflammatory and demyelinating diseases can cause
pyramidal tract dysfunction with variable presentations depend-
ing on the underlying disease process and the variable involve-
ment of non-motor systems. These disorders are discussed
elsewhere.
Hereditary spastic paraplegia (HSP) is a rare and heteroge-
neous group of inherited disorders that causes progressive pyra-
midal tract dysfunction manifest clinically by spastic paraparesis.
  DIFFERENTIAL DIAGNOSIS OF PERIPHERAL
MOTOR SYSTEM DISORDERS
Similar to pyramidal tract dysfunction, lesions resulting from
direct tumor involvement, infection, trauma, and inflammatory
and demyelinating processes may all affect the peripheral motor
system. In addition, specific inherited and acquired degenerative
disorders may affect the peripheral motor system (Chapters 121,
122, and 123).
  MOVEMENT DISORDERS
Movement disorders are a heterogeneous group of disorders
associated with basal ganglia dysfunction. Movement disorders
refer to the involuntary or abnormal movement, known as the
 1016 Section XVI  Neurologic Disease

ss
TABLE 114-1  SYMPTOMS AND SIGNS APPROACH TO NEUROANATOMIC LOCALIZATION
OF MOTOR SYSTEM DYSFUNCTION
NEUROANATOMIC
LOCALIZATION SYMPTOMS SIGNS
CENTRAL NERVOUS SYSTEM
PYRAMIDAL TRACT
Cortical Weakness Hemiparesis or focal weakness
Cortical symptoms (e.g. aphasia) Spasticity
Babinski’s sign
Other cortical findings
Subcortical Isolated weakness/clumsiness Hemiparesis of face and body
Spasticity
Babinski’s sign
Absence of cortical findings
Brainstem Weakness Crossed facial and body paresis
Bulbar symptoms Spasticity
Somnolence Babinski’s sign
Cranial nerve findings (e.g. INO)
Cerebellar signs
Impaired arousal
Spinal Cord Weakness Paraparesis > hemiparesis
Sensory loss, paresthesia/dysesthesia Sensory level
Gait imbalance and falls Absence of bulbar signs
Back pain Babinski’s sign
Bowel and bladder dysfunction Hoffman’s sign
BASAL GANGLIA Changes in gait, gait imbalance, and falls Tone abnormalities (rigidity)
Changes in voice Postural abnormalities
Impairment in voluntary motor actions Postural instability
Involuntary movements Gait disorders
Behavioral changes Akinesia/hypokinesia
Tremor
Chorea/ballism/athetosis
Dystonia
Tics
CEREBELLAR Gait imbalance and falls Oculomotor abnormalities
Slurred speech Hypotonia
Tremor with intentional tasks Gait ataxia
Incoordination Titubation
Scanning dysarthria
Dysmetria
Intention tremor
Past pointing
Dysdiadokinesis
Excessive rebound
Impaired check
PERIPHERAL NERVOUS SYSTEM
ROOTS (RADICULAR) Pain radiating into limb/trunk Combined motor and sensory deficits in a radicular distribution
Localized sensory loss, parasthesias, dysesthesias Reduced MSR in region subserved by root(s)
Localized weakness Muscle atrophy
PLEXUS Localized sensory loss, parasthesias, dysesthesias in a single limb Combined motor and sensory deficits involving multiple roots and
Localized weakness in a single limb subserving multiple nerves
Bowel and bladder symptoms in lumbosacral plexus Reduced MSR in region subserved by multiple roots
Muscle atrophy
PERIPHERAL NERVE Polyneuropathy Distal predominant weakness
Distal/bilateral sensory loss, parasthesias, dysesthesias Stocking-glove sensory loss
Distal/ascending and bilateral weakness Reduced MSR
Mononeuropathy Hypotonia
Localized pain and sensory symptoms Muscle atrophy
NEUROMUSCULAR Fluctuating weakness Bulbar weakness
JUNCTION Worsening weakness over the course of the day or with physical Normal MSR
activity Normal muscle bulk
Diplopia Fatigable weakness
Slurred speech Normal sensory exam
Absence of sensory symptoms
MUSCLE Proximal greater than distal weakness Proximal weakness
Myalgias Normal muscle tone and bulk
Absence of sensory symptoms Normal to reduced MSR
INO, Intranuclear ophthalmoplegia; MSR, muscle stretch reflexes.
 Chapter 114  Disorders of the Motor System 1017
movement phenomenon, or may be used to describe a syndromic
disorder in which involuntary or abnormalities of movement are
cardinal features of the disease. In contrast to most seizures, the
involuntary movements occur when the patient is conscious, but
are absent during sleep.
Movement disorders can be classified as either hyperkinetic or
hypokinetic. Hyperkinetic phenomena include tremor, chorea,
dystonia, tics, myoclonus, and other involuntary movements.
Hypokinetic disorders encompass the Parkinsonian disorders
characterized by a paucity of spontaneous movement (akinesia)
and low amplitude slow movements (bradykinesia). While this
classification strategy is a valuable means for approaching the
patient with abnormal movements, many movement disorders
include both hyperkinetic and hypokinetic phenomena. Idio-
pathic Parkinson’s disease is the prototypical hypokinetic move-
ment disorder, but it is associated with the hyperkinetic
phenomenon of tremor in over 60% of patients. Similarly, Hun-
tington disease, a traditionally hyperkinetic disorder, is associ-
ated with bradykinetic voluntary movements.
Parkinsonism
Parkinsonism is the most common of the extrapyramidal disor-
ders and is characterized by akinesia, rigidity, tremor, and pos-
tural instability. Parkinsonism is caused by a wide variety of
degenerative disorders, medication and toxins, and systemic dis-
eases. Table 114-2 summarizes the differential diagnosis of
Parkinsonism.
Idiopathic Parkinson’s Disease
Idiopathic Parkinson’s disease (PD) accounts for most individu-
als with Parkinsonism and is the second most common adult
onset neurodegenerative disease after Alzheimer’s disease. The
average age of onset is around 60 years with an increasing preva-
lence associated with aging and a slight male preponderance. The
motor symptoms of PD result from the selective loss of dopami-
nergic neurons in the substantia nigra-pars compacta that project
to the striatum. The pathological hallmark of PD is the presence
of eosinophilic cytoplasmic neuronal inclusions known as Lewy
bodies containing α-synuclein.
TABLE 114-2  DIFFERENTIAL DIAGNOSIS OF
PARKINSONISM
DEGENERATIVE/ Idiopathic Parkinson’s disease
INHERITED CAUSES Multiple system atrophy
Progressive supranuclear palsy
Dementia with Lewy body
Corticobasal degeneration
Frontotemporal dementia with Parkinsonism
Huntington’s disease
Wilson’s disease
Dopa-responsive dystonia
Pantothenate kinase–associated
neurodegeneration
SECONDARY CAUSES Dopamine receptor blocking medications
(e.g. antipsychotics, metoclopramide,
prochlorperazine)
Presynaptic dopamine depleting medications
(tetrabenazine)
Cerebrovascular disease
Toxins (MPTP, manganese, carbon monoxide)
MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Clinically, PD is characterized by its motor phenomenon with
asymmetric rigidity, bradykinesia, rest tremor, and postural insta- ss
bility. However, PD is also characterized by secondary, non-
motor manifestations (facial hypomimia, hypophonia, dysphagia,
micrographia, and flexed posture), autonomic dysfunction
(orthostatic hypotension, constipation, hyperactive bladder,
and impaired temperature regulation), behavioral symptoms
(depression, anxiety, psychosis), cognitive impairment and
dementia, sleep disorders (impaired sleep architecture, restless
legs syndrome, REM sleep behavior disorder), and sensory
phenomena.
Until recently the diagnosis of PD was made based on the
findings of an adult onset disorder of unilateral onset, persistent
asymmetry of motor findings, and responsiveness of motor fea-
tures to levodopa therapy. In addition, a number of “red flags” on
history or examination might suggest an atypical or secondary
cause of Parkinsonism (Table 114-3). However, Dopamine
Transporter (DAT) SPECT imaging has recently been approved
to assist in distinguishing PD from PD mimics, notably drug-
induced Parkinsonism and essential tremor with parkinsonian
features. The dopamine transporter is responsible for re-uptake
of dopamine into presynaptic terminals and is, therefore, an indi-
rect measure of nigro-striatal neuronal density. In PD, nigro-
striatal neurons are lost asymmetrically; on dopamine transporter
imaging, this is characterized by asymmetric reduction in dopa-
mine transporter signal in the striatum. Unfortunately, this
imaging method does not distinguish atypical Parkinsonism
from PD.
A number of monogenic causes of Parkinsonism have been
identified. Mutations in α-synuclein (SNCA), leucine-rich repeat
kinase 2 (LRRK2), vacuolar protein sorting 35 (VPS35), and
eukaryotic translation initiation factor 4-γ (EIF4G1) are associ-
ated with autosomal dominant Parkinsonism. Autosomal domi-
nant causes account for less than 2% of all adult onset Parkinson’s
disease cases with higher frequencies in certain populations due
to founder effects. Autosomal recessive monogenic causes
include parkin, PTEN-induced kinase 1 (PINK1), and Parkinson
protein 7 (DJ-1) and are relatively common in familial cases with
onset before the age of 45. An improved understanding of these
genetic causes suggests an important role of impairment in lyso-
somal pathways and protein degradation in PD pathogenesis.
PD is a slowly progressive disorder associated with accumulat-
ing disability. No treatments have been proven to slow progres-
sion; however, ongoing efforts continue to identify putative
TABLE 114-3  “RED FLAGS” IN THE DIAGNOSIS OF
PARKINSON’S DISEASE
CLINICAL OR HISTORICAL “RED FLAG” SUGGESTED DIAGNOSIS
Early postural instability and falls PSP, MSA, CBD, DLB,
Vascular
Early dysphagia PSP, CBD
Early or spontaneous hallucinations DLB
Early dementia or dementia predating PD DLB
Early or severe dysautonomia MSA
Pyramidal tract and/or Cerebellar signs MSA
Antipsychotic exposure Tardive or drug-induced
Acute onset and/or non-progressive Vascular
CBD, Corticobasal degeneration; DLB, dementia with Lewy body; MSA, multiple system
atrophy; PSP, progressive supranuclear palsy.
 1018 Section XVI  Neurologic Disease
ss
Table 114-4  MEDICATIONS FOR PARKINSON’S
DISEASE
ANTICHOLINERGIC AGENTS
Trihexyphenidyl (Artane)
Benztropine (Cogentin)
DOPAMINE PRECURSORS (COMBINED WITH PERIPHERAL
AROMATIC AMINO ACID DECARBOXYLASE INHIBITORS)
Carbidopa-levodopa (Sinemet, Sinemet-CR, Parcopa) (regular, controlled-
release, and orally disintegrating)
Benserazide-levodopa (Madopar) (marketed in Europe)
DOPAMINE AGONISTS
Apomorphine (Apokyn) (injectable short acting), bromocriptine (Parlodel)
Pramipexole (Mirapex)
Rotigotine (Neupro) (transdermal patch)
Ropinirole (Requip, Requip XR)
MONOAMINE OXIDASE TYPE B (MAO-B) INHIBITORS
Selegiline (deprenyl) (Carbex, Eldepryl, Zelapar)
Rasagiline (Azilect)
CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS
Tolcapone (Tasmar)
Entacapone (Comtan)
CATECHOL O-METHYLTRANSFERASE (COMT) INHIBITORS
COMBINED WITH CARBIDOPA-LEVODOPA
Entacapone-carbidopa-levodopa (Stalevo)
disease modifying therapies. Treatments of the motor symptoms
can reduce disability and improve function (Table 114-4). The
mainstay of treatment is levodopa, the precursor to dopamine,
given with a dopa-decarboxylase inhibitor to maximize CNS
penetration of levodopa and minimize systemic side effects.
Other symptomatic treatments stimulate dopamine receptors in
the brain or inhibit the breakdown of levodopa and dopamine
(Table 114-4). This approach to symptom management is effec-
tive early in the course of the disease; however, as the disease
continues to progress, it may be complicated by the development
of motor fluctuations, drug-induced dyskinesias, and psychosis.
Atypical Parkinsonism
Atypical Parkinsonism or “Parkinson plus” disorders refer to a
heterogeneous group of inherited and sporadic neurodegenera-
tive disorders characterized by Parkinsonism and a reduced or
absent response to dopaminergic therapy. The most common are
multiple system atrophy (MSA), progressive supranuclear palsy
(PSP), dementia with Lewy bodies (DLB), and corticobasal
degeneration (CBD).
MSA is a sporadic neurodegenerative disorder characterized
clinically by the variable combination of Parkinsonism, auto-
nomic dysfunction, cerebellar dysfunction, and extrapyramidal
motor signs. The term MSA was coined to encompass three pre-
viously distinct clinical entities: striatonigral degeneration with
prominent parkinsonism, olivopontocerebellar atrophy with
prominent cerebellar dysfunction, and Shy-Drager syndrome
with prominent autonomic dysfunction, particularly profound
orthostatic hypotension. The identification of a shared neuro-
pathological correlate of neuronal inclusions consisting of
α-synuclein bolstered the shared nomenclature of these disor-
ders. Currently, the preferred classification refers to either MSA-
parkinsonism type or MSA-cerebellar type depending on the
predominant clinical symptoms and signs. An MSA-autonomic
type is proposed for those with an overwhelmingly autonomic
presentation. Although relatively rare, MSA is among the most
frequently encountered of the atypical Parkinsonisms with an
overall incidence of 0.6/100,000 and an increasing incidence
with age. It is universally fatal with a mean survival of 7 to 9 years,
though longer disease duration is sometimes seen. Treatment is
challenging and largely symptomatic. Some patients may be par-
tially responsive to dopaminergic therapy and levodopa is recom-
mended for individuals with prominent parkinsonism. Autonomic
manifestations can be managed with symptomatic treatments to
address orthostatic hypotension, constipation, and bladder
symptoms (see Chapter 110).
Progressive supranuclear palsy is a relentlessly progressive dis-
order characterized by early gait instability and falls, prominent
and early dysphagia, early speech difficulties progressing to a
non-fluent aphasia, dementia, and supranuclear gaze palsy; death
occurs on average 5 years after diagnosis. Supranuclear gaze palsy,
in its fully realized form, is characterized by vertical greater than
horizontal gaze palsy with preserved oculocephalic reflexes.
Early, the gaze palsy may manifest by the presence of square wave
jerks, difficulty initiating saccades, and loss of the fast phase on
optokinetic nystagmus testing. Patients have a wide-eyed stare
and lid lag may be present. Opposed to the flexed posture and
asymmetry of PD, individuals with progressive supranuclear
palsy have extensor trunk posturing and greater axial rigidity with
relatively appendicular symmetry. Up to 20% of patients may
have a modest response to levodopa therapy.
Dementia with Lewy bodies is the second most common
degenerative cause of dementia after Alzheimer’s disease. It is
characterized clinically by Parkinsonism, dementia preceding or
within 1 year of the motor symptoms, propensity for psychosis,
early falls, and fluctuations in cognition and arousal. Motorically,
it may be indistinguishable from Parkinson’s disease. Patients
have a high risk for psychosis associated with dopaminergic
therapy and antipsychotics may cause worsening of Parkinson-
ism and even death making management of these patients
challenging.
Corticobasal degeneration is a rare and heterogenous disorder.
The characteristic Parkinsonian disorder presents with marked
asymmetric Parkinsonism, focal limb dystonia, cortical sensory
findings, alien limb phenomenon, and myoclonus. However, it
may present with primary cortical cognitive symptoms and have
features of progressive supranuclear palsy. It is a relentlessly pro-
gressive and fatal illness. Treatment is symptomatic.
Secondary Parkinsonism
There are many causes of secondary Parkinsonism, including
medications, toxins, and cerebrovascular disease. Medications
associated with Parkinsonism include any medication that
reduces dopaminergic tone in the brain, either through direct
blockade of post-synaptic dopamine receptors (e.g. antipsychot-
ics) or through depletion of pre-synaptic dopamine stores (e.g.
tetrabenazine). Metoclopramide, a medication commonly used
to treat gastroparesis, is a frequent cause because its dopamine
blocking effects may be overlooked. Drug-induced Parkinsonism
can be indistinguishable from Parkinson’s disease and is fre-
quently asymmetric. Treatment consists of withholding the
 Chapter 114  Disorders of the Motor System 1019
offending agent, recognizing that it may take months for the
symptoms to resolve. Even then, patients exposed to dopamine
blocking agents may develop a tardive Parkinsonism (i.e., a drug-
induced Parkinsonism that persists even after the offending agent
is removed). DAT SPECT imaging can be useful in distinguish-
ing drug-induced or tardive Parkinsonism from Parkinson’s
Disease.
Cerebrovascular disease is a common cause of secondary Par-
kinsonism. Tremor is uncommon in vascular Parkinsonism;
lower extremity bradykinesia and gait difficulties dominate the
clinical picture. Patients may have a history of clinical strokes
with acute deteriorations followed by plateaus; however, many
patients have vascular risk factors and a history of gradual decline.
Tremor
Tremor is a rhythmic, oscillatory movement of a body part.
Tremor is classified by its distribution (e.g., voice, limb) and
whether it is present at rest, with sustained posture (sustention),
or with action. Action tremor can further be classified as an inten-
tion tremor, in which the tremor worsens as one approaches
target. Intention tremor is characteristic of cerebellar disease.
Tremor has multiple etiologies, including medications, alcohol
and drug withdrawal, systemic disease (e.g. hyperthyroidism),
structural brain lesions, or as a component of a neurodegenera-
tive disease.
Essential tremor is among the most common movement dis-
orders and the most common cause of tremor. Essential tremor
has a worldwide prevalence of 2% to 4% with increasing inci-
dence with aging. Clinically it is characterized by postural tremor
of the upper extremities. An intention tremor develops with
disease progression and may be disabling. Involvement of the
head and voice are common. Mild Parkinsonian features (e.g.,
tremor at rest, rigidity with activation) may develop and can
make distinguishing incipient Parkinson’s disease challenging.
The condition is often familial with an autosomal dominant
pattern of inheritance and tends to improve with alcohol inges-
tion. Propranolol and primidone are of similar benefit (Table
114-5).
Chorea
Chorea is characterized by brief, irregular, random, non-rhythmic
movements that flow from one body part to another. It is often
associated with athetosis and ballism. These conditions lie on a
spectrum of choreic phenomenon with ballism characterized by
proximal large amplitude flinging movements on one end, chorea
in the middle with lower amplitude random flowing movements
TABLE 114-5  TREATMENT OPTIONS FOR ESSENTIAL
TREMOR
FIRST LINE Propranolol
Primidone
SECOND LINE Topirimate
Zonisamide
Benzodiazepines
Other beta-blockers
Gabapentin/Pregabalin
MEDICATION FAILURE Botulinum toxin injections
Deep brain stimulation
and athetosis characterized by slower distal writhing movements
on the other. Chorea is often associated with a variety of second- ss
ary clinical features detailed in Table 114-6.
There are many etiologies of choreic disorders reflecting a
wide variety of processes affecting the basal ganglia and specifi-
cally the striatum. Generally, chorea either represents the primary
manifestation of an inherited disorder or is acquired secondary
to basal ganglia insults due to various comorbid medical condi-
tions, medications or toxins, or structural abnormalities. Table
114-7 summarizes the differential diagnosis of chorea catego-
rized by genetic and acquired causes.
Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant, progres-
sively disabling, and fatal neurodegenerative disease; it is and the
most common cause of inherited adult onset chorea. The caus-
ative mutation is an expansion of an unstable cytosine-adenine-
guanine (CAG) trinucleotide repeat of the IT-15 gene on the
short arm of chromosome 4.
HD may emerge at any age, with the peak incidence between
35 and 40 years of age with death occurring 10 to 20 years after
onset. Age of onset and rate of progression of the disease are
inversely associated with CAG repeat length with the longest
repeats associated with juvenile onset disease and a more rapid
disease progression.
HD is characterized clinically by the triad of an extrapyramidal
movement disorder, progressive cognitive decline (dementia),
and an array of behavioral disturbances. Chorea is the prototypi-
cal motor manifestation of HD occurring in 90% of patients.
Cognitive impairment is invariable in HD and typically pro-
gresses from selective deficits in psychomotor, executive, and
visuospatial abilities to more global impairment with higher cor-
tical functions usually spared. Psychiatric illness has been recog-
nized as an important feature of HD since George Huntington
reported on the “tendency to insanity and suicide.”
The juvenile variant of HD, in which age of onset occurs before
20, typically has an akinetic-rigid phenotype and paternal inheri-
tance and only rarely chorea. Paternal inheritance of the HD gene
is the rule for onset before the age of 10 and paternal inheritance
predominates (about 3 : 1 paternal : maternal) for onset before
the age of 20.
TABLE 114-6  SECONDARY FEATURES ASSOCIATED
WITH CHOREA
ATHETOSIS Slow, writhing movements of
distal limbs
BALLISM Rapid, flinging movements of
proximal limbs
PARAKINESIS Incorporation of an involuntary
movement into a voluntary
movement (e.g. crossing and
uncrossing of legs, adjusting
glasses)
MOTOR IMPERSISTENCE Inability to maintain tongue
protrusion, “milk maid’s grip”
PARTIALLY SUPPRESSIBLE Brief ability to voluntary reduce the
severity of movements
DEEP TENDON REFLEX CHANGES “hung up” or “pendular” reflexes
GAIT DISORDERS Irregular or dance like gait
 1020 Section XVI  Neurologic Disease

ss
TABLE 114-7  DIFFERENTIAL DIAGNOSIS OF CHOREA
GENETIC DISORDERS Autosomal dominant Huntington’s disease
Spinocerebellar ataxia (SCA 17 >1-3)
DRPLA
Neuroferritinopathy
Benign hereditary chorea
Autosomal recessive Neuroacanthocytosis
Wilson’s disease
Ataxia (Friedreich’s, ataxia-telangiectasia, ataxia with oculomotor apraxia)
Disorders associated with brain iron accumulation (PKAN)
X-linked McLeod’s syndrome
Lesch-Nyan’s syndrome
ACQUIRED/SPORADIC Medications Direct side effects
Tardive dyskinesia
Immune mediated Sydenham’s chorea
Systemic lupus erythematosus
Anti-phospholipid antibody syndrome
Vasculitis
Paraneoplastic (CRMP5 gene, anti-Hu)
Infectious HIV/AIDS
Variant CJD
Neurosyphilis
Endocrine Hyperthyroidism
Chorea gravidarum
Metabolic Hyperglycemia
Electrolyte disturbances
Acquired hepatocerebral degeneration
Vascular Basal ganglia infarcts/hemorrhage
Miscellaneous Polycythemia vera
Post-cardiac bypass pump
Multiple sclerosis
Sporadic neurodegenerative disorders
CJD, Creutzfeld-Jakob disease; DRPLA, dentatorubropallidoluysian atrophy; PKAN, pantothenate-kinase-associated neurodegeneration; SCA, spinocerebellar ataxia.

The neuropathology of HD is characterized by selective
neuronal vulnerability, particularly involving the caudate and
putamen of the corpus striatum. Microscopically, the pathologi-
cal hallmark of the disease is the preferential loss of medium-
sized spiny neurons projecting from the striatum to the external
pallidum. While HD is associated with a variety of motoric phe-
notypes, it remains the prototypical choreiform disorder and the
most common cause of inherited adult onset chorea. In addition,
HD represents one of the most important genetic disorders of
adulthood. HD was the first disease recognized to arise from a
trinucleotide expansion and serves as a model for the experimen-
tal therapeutics of adult-onset neurodegenerative diseases.
Huntington’s Disease Phenocopies
Approximately 10% of individuals with an autosomal dominant
HD-like disorder will not carry the causative mutation for HD.
Among these “phenocopies,” only a small minority will have an
identifiable genetic mutation. The most common genetic causes
in the Caucasian population include spinocerebellar ataxia
(SCA) 17, Friedreich’s ataxia, HD-like 2, and familial prion
disease (HD-like 1). Alternative diagnoses include dentatoru-
bropallidoluysian atrophy (DRPLA), SCA 1-3, and neuroferrito-
nopathy. A benign form of an autosomal dominant chorea,
benign familial chorea, without significant behavioral or cogni-
tive impairment can occur.
Wilson’s Disease
Wilson’s disease is a rare, autosomal recessive disorder of impaired
copper metabolism with copper accumulation and neurological
and hepatic dysfunction. It causes heterogenous movement
disorder including chorea, dystonia, Parkinsonism, and tremor;
dystonia and tremor tend to predominate. Onset with movement
disorder occurs in about 50% of individuals, the others present-
ing with liver disease. The mean age of onset is 20; it rarely occurs
after the age of 40. Untreated it is invariably fatal; early treatment
is associated with better clinical outcomes; therefore, a high level
of suspicion should be maintained. Diagnosis is confirmed by the
presence of Kayser-Fleischer corneal rings in the setting of
increased urinary copper excretion or elevated copper on liver
biopsy. Although ceruloplasmin is usually low in symptomatic
patients, it is not definitive, and confirmatory testing with oph-
thalmologic screen, 24-hour urinary copper or liver biopsy is
necessary. Treatment consists of drugs that facilitate copper
excretion, such as zinc, trientine, tetrathiomolybdate, penicilla-
mine (the latter falling from favor because of its toxicities).
Sydenham’s Chorea
Sydenham’s chorea is one of the most common causes of child-
hood onset chorea and is an immune complication of group A
streptococcal infection. It presents acutely months after the strep-
tococcal infection, is frequently asymmetric, and may cause
behavioral symptoms in addition to chorea. Other features of
rheumatic fever may also be present and echocardiography
should be performed on any child with suspected Sydenham’s.
Treatment of the underlying infection, management of complica-
tions of rheumatic fever, and supportive care are generally suffi-
cient with the majority of patients having resolution of symptoms
by 1 year. A history of Sydenham’s may predispose a female
patient to adult onset chorea during pregnancy (chorea gravi-
darum) or in response to estrogen treatment.
 Chapter 114  Disorders of the Motor System 1021
Medications and Tardive Dyskinesia
Numerous medications have been associated with chorea. The
most common direct cause of drug-induced chorea is levodopa-
induced dyskinesias in individuals with Parkinson’s disease.
Tardive dyskinesia is a late complication of treatment with dopa-
mine receptor blocking agents, usually neuroleptic antipsychot-
ics, and may have chorea as a prominent feature. Advancing age,
female gender, and use of high potency antipsychotics are associ-
ated with an increased risk for this complication. While removal
of the offending agent is critical to prevent worsening, symptoms
persist in approximately two thirds of patients and treatment can
be challenging.
Dystonia
Dystonia is a heterogenous class of movement disorders char-
acterized by sustained muscle contractions that lead to twisting
movements, abnormal postures, and repetitive movements. The
classification of dystonia is challenging, having undergone
numerous revisions over time, and is based on age of onset,
distribution (focal versus generalized), association with neuro-
logical signs other than dystonia, and cause, if known. Mutations
in at least 23 different genes are associated with dystonia. In
general, the specific mutation does not reliably predict the
phenotype. Childhood onset dystonia often has an underlying
genetic cause, tends to generalize, and has a more severe course;
while adult onset focal dystonia of the neck (e.g. cervical dys-
tonia) tends to be non-progressive without a defined genetic
cause.
Adult onset focal dystonias are by far the most common dys-
tonias encountered clinically. Cervical dystonia is the most
common dystonia, followed by focal dystonias involving the face
and jaw muscles (blepharospasm, oromandibular dystonia or the
combination); laryngeal and limb dystonias are rare. Adult onset
limb dystonias are usually task-specific; dystonic contraction
only occurs during specific voluntary actions (e.g., writer’s cramp,
musician’s dystonia). This task specificity may be lost over time
and occur even at rest. Focal adult onset limb dystonia that is not
task specific can be the earliest manifestation of Parkinsonism
and Parkinson’s disease.
A mutation in the TOR1A gene is the most common cause of
early onset generalized dystonia. DYT1 is an autosomal domi-
nant disorder with reduced penetrance (30%). Onset is usually
during childhood (10 to 15 years of age) with focal limb dystonia
with action that rapidly generalizes often sparing the craniocervi-
cal muscles. It accounts for less than 50% of childhood onset
dystonia in non-Jews and approximately 80% in children of Ash-
kenazi Jewish descent.
Dopa-responsive dystonia is a rare but important cause of
childhood onset dystonia. It is inherited in autosomal dominant
fashion with reduced penetrance (30%) with females more com-
monly affected than males. It is characterized by lower extremity
dystonia, Parkinsonism, and diurnal variability with the symp-
toms worsening as the day progresses and improving with sleep.
As the name suggests, it is exquisitely sensitive to levodopa
therapy. The condition is often misdiagnosed and untreated;
therefore, patients with childhood onset dystonia should have a
trial of levodopa.
Myoclonus dystonia syndrome is an autosomal dominant dis-
order with alcohol responsive myoclonic jerks and dystonia. Dys- ss
tonia is often focal with cervical dystonia and writer’s cramp
predominating. Onset is usually prior to the age of 20 years and
psychiatric symptoms are common.
Rapid-onset dystonia Parkinsonism is a rare autosomal domi-
nant condition with reduced penetrance that presents over hours
or weeks with craniofacial and limb dystonia, dysarthria, brady-
kinesia, and postural instability. After initial progression the dis-
order stabilizes. The rapid onset and triggers, including emotional
trauma or physical exertion, often result in it being misdiagnosed
as a somatoform disorder.
Treatment of dystonia consists of a combination of oral medi-
cations and focused botulinum toxin injections. Oral medica-
tions include anticholinergics, benzodiazepines, and muscle
relaxants. Deep brain stimulation has shown recent benefit in
treating dystonia resulting from multiple causes.
Tics and Tourette’s Syndrome
Tics are rapid, stereotyped, non-rhythmic movements or vocal-
izations. They can mimic many normal motor activities and
movement disorders and occur on a background of otherwise
normal activity and motor function. The key differentiating char-
acteristics of tics are that they are associated with an irresistible
urge or sensation that is temporarily relieved with performance
of the tic. Tics are voluntarily suppressible but suppressing them
results in increasing urge and rebound exacerbation of tics. Tics
of childhood are extremely common and if transient, require no
treatment.
Tourette’s syndrome (TS) is a tic disorder, beginning in child-
hood with both motor and vocal tics persisting for more than one
year. Approximately 50% of individuals with TS will also have
features of obsessive compulsive disorder and/or attention deficit
disorder. These other features are often more disabling than the
tics themselves. In the majority of individuals there is partial or
complete resolution of symptoms by adulthood. Treatment of
tics and associated comorbidities should be reserved only for
functionally disabling symptoms. A combination of behavioral
approaches (comprehensive behavioral intervention for tics),
oral medications, and botulinum toxin injections can be effective
at minimizing the impact of symptoms. Extreme cases with per-
sistence in adulthood may respond to deep brain stimulation.
  CEREBELLAR ATAXIAS
The ataxias are a heterogeneous group of conditions reflecting
impaired cerebellar function or impairment in cerebellar afferent
and efferent pathways. Structural lesions due to abnormalities of
brain development, stroke, tumor, infection, trauma, and inflam-
matory and demyelinating diseases can frequently affect cerebel-
lar function and result in cerebellar symptoms and signs. Table
114-8 summarizes the differential diagnosis of the ataxic disor-
ders divided by genetic and acquired causes.
Inherited/Genetic Ataxias
Progressive ataxia in coordination and gait disturbance are the
cardinal features of the inherited ataxias. Autosomal dominant
spinocerebellar ataxias (SCA) may present with a pure cerebellar
syndrome or be associated with other extrapyramidal, pyramidal,
 1022 Section XVI  Neurologic Disease

pyramidal tract dysfunction is a late complication. Non-

ss
TABLE 114-8  DIFFERENTIAL DIAGNOSIS OF neurological manifestations include cardiomyopathy, diabetes
CEREBELLAR ATAXIA mellitus, and skeletal deformities, which add to the morbidity
GENETIC Autosomal Spinocerebellar Ataxias and mortality of the disease. Since identification of the muta-
DISORDERS dominant Episodic ataxia
DRPLA tion, late onset forms of the disease with less systemic involve-
Autosomal recessive Friedreich’s ataxia ment and milder symptoms have been identified. Therefore,
Ataxia-telangiectasia Friedreich’s ataxia should be considered in the differential of
Ataxia with oculomotor apraxia
Ataxia with vitamin E adult onset sporadic ataxias.
deficiency Ataxia with vitamin E deficiency is a childhood onset ataxia
X-linked Fragile X-associated tremor/ with a Friedreich’s ataxia phenotype. Treatment with high dose
ataxia syndrome
Mitochondrial Polymerase gamma (POLG) vitamin E may slow the progression of neurological symptoms.
ACQUIRED/ Medications/Toxins Alcohol Ataxia with vitamin E deficiency should be considered in any
SPORADIC Phenytoin child with signs and symptoms of Friedreich’s ataxia that do not
Fluorouracil
Heavy metals carry the Friedreich’s ataxia mutation.
Carbon monoxide
Developmental Chiari malformations Sporadic/Acquired Ataxias
Dandy-Walker malformations
Pontocerebellar hypoplasia Insidious onset of cerebellar ataxia without a family history
Immune mediated Paraneoplastic (anti-Hu/Yo/Ri) can be a diagnostic challenge. Alcohol abuse, toxins, multiple
Pediatric post-viral system atrophy, and mitochondrial disorders are diagnostic
Behçhet’s disease
Infectious HIV/AIDS considerations.
PML Acute or subacute onset ataxia is most often associated with
CJD cerebrovascular disease, demyelinating illness, or direct or indi-
Lyme disease
Metabolic Thiamine deficiency rect effects of cancer. Paraneoplastic cerebellar degeneration is
(Wernicke’s encephalopathy) one of the more common paraneoplastic syndromes usually asso-
vitamin E/B12 deficiency ciated with gynecological, breast, lung cancer, or lymphoma. A
Thyroid disease
Vascular Cerebellar stroke/hemorrhage variety of anti-neuronal antibodies have been implicated;
Neoplastic Primary and metastatic tumors however, anti-Hu/Yo/Ri are most frequently seen. The cerebellar
Paraneoplastic (anti-Hu/Yo/Ri) syndrome often predates the identification of the cancer. Treat-
Miscellaneous MSA-cerebellar
Multiple sclerosis
ment of the underlying cancer and plasma exchange are some-
times beneficial.
CJD, Cruetzfeldt-Jakob disease; DRPLA, dentatorubropallidoluysian atrophy; MSA,
multiple system atrophy; PML, progressive multifocal leukoencephalopathy. Vitamin B12 and vitamin E deficiency secondary to malab-
sorption can present with ataxic gait as a result of posterior
cognitive, or behavioral features. They are usually adult onset column sensory deficits. In the appropriate clinical situation,
with variable genetic mutations, including trinucleotide repeats, Wernicke’s encephalopathy due to thiamine deficiency needs to
mutations in noncoding regions, and point mutations. Genetic be considered as an acute cause of gait ataxia.
testing is available for many of the common spinocerebellar
ataxias and new mutations are being identified in a rapid and
ongoing basis. Currently there are no treatments to address SUGGESTED READINGS
disease progression and symptomatic treatment is limited.
Aarsland D, Påhlhagen S, Ballard CG, et al: Depression in Parkinson disease—
The fragile X mental retardation (FMR1) gene contains a
epidemiology, mechanisms and management, Nat Rev Neurol 8(1):35–47,
CCG trinucleotide repeat expansion of greater than 200 in the 2011.
fully penetrant mutation associated with mental retardation in Abdo WF, van de Warrenburg BP, Burn DJ, et al: The clinical approach to
boys. Recently a pre-mutation associated with repeats of 55-200 movement disorders, Nat Rev Neurol 6:29–37, 2010.
in the FMR1 gene has been found to be the cause of the adult Albanese A, Bhatia K, Bressman SB, et al: Phenomenology and Classification of
Dystonia: A Consensus Update, Mov Disord 28:863–873, 2013.
onset neurodegenerative disorder, fragile X–associated tremor/
Anheim M, Tranchant C, Koenig M: The autosomal recessive cerebellar ataxias,
ataxia syndrome (FXTAS). Clinically, affected males have a pro- N Engl J Med 366:636–646, 2012.
gressive cerebellar tremor and ataxia. Fragile X–associated Armstrong MJ, Miyasaki JM: Evidence-based guideline: pharmacologic treatment
tremor/ataxia syndrome has been under-recognized and may be of chorea in Huntington disease: Report of the Guideline Development
the most common genetic cause of late onset ataxia. Treatment Subcommittee of the American Academy of Neurology, Neurology 79:597–
603, 2012.
is largely symptomatic and the disease results in progressive
Barker RA, Barrett J, Mason SL, et al: Fetal dopaminergic transplantation trials
disability. and the future of neural grafting in Parkinson’s disease, Lancet Neurol
Autosomal recessive ataxias are rare conditions with onset 12(1):84–91, 2013.
in childhood. Friedreich’s ataxia (FA) is the most common Beato R, Maia DP, Teixeira AL Jr, et al: Executive functioning in adult patients
and best characterized of these disorders. It results from an with Sydenham’s chorea, Mov Disord 25:853–857, 2010.
Berardelli A, Wenning GK, Antonini A, et al: EFNS/MDS-ES/ENS
unstable GAA expansion on chromosome 9. Clinically it is
recommendations for the diagnosis of Parkinson’s disease, Eur J Neurol
characterized by childhood onset gait ataxia and clumsiness. 20(1):16–34, 2013.
The ataxia reflects a combination of spinocerebellar degenera- Charlesworth G, Bhatia KP, Wood NW: The genetics of dystonia: new twists in
tion and peripheral sensory loss. Frank weakness secondary to an old tale, Brain 136(Pt 7):2017–2037, 2013.
 Chapter 114  Disorders of the Motor System 1023
Finsterer J, Löscher W, Quasthoff S, et al: Hereditary spastic paraplegias with
autosomal dominant, recessive, X-linked, or maternal trait of inheritance,
J Neurol Sci 318(1–2):1–18, 2012.
Fox SH, Katzenschlager R, Lim SY, et al: The Movement Disorder Society
Evidence-Based Medicine Review Update: Treatments for the motor
symptoms of Parkinson’s disease, Mov Disord 26(Suppl 3):S2–S41, 2011.
Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, et al: European guidelines on
management of restless legs syndrome: report of a joint task force by the
European Federation of Neurological Societies, the European Neurological
Society and the European Sleep Research Society, Eur J Neurol 19(11):1385–
1396, 2012.
Hauser RA, Cantillon M, Pourcher E, et al: Preladenant in patients with
Parkinson’s disease and motor fluctuations: a phase 2, double-blind,
randomised trial, Lancet Neurol 10:221–229, 2011.
Jellinger KA: Neuropathology of sporadic Parkinson’s disease: evaluation and
changes of concepts, Mov Disord 27(1):8–30, 2012.
Jinnah HA, Berardelli A, Comella C, et al: The focal dystonias: Current views and
challenges for future research, Mov Disord 28(7):926–943, 2013.
Kehagia AA, Barker RA, Robbins TW: Cognitive impairment in Parkinson’s
disease: the dual syndrome hypothesis, Neurodegener Dis 11(2):79–92, 2013.
Kieburtz K, Wunderle KB: Parkinson’s disease: evidence for environmental risk
factors, Mov Disord 28(1):8–13, 2013.
Killoran A, Biglan KM, Jankovic J, et al: Characterization of the Huntington
intermediate CAG repeat expansion phenotype in PHAROS, Neurology
80(22):2022–2027, 2013.
Knight T, Steeves T, Day L, et al: Prevalence of tic disorders: a systematic review
and meta-analysis, Pediatr Neurol 47(2):77–90, 2012.
Kordower JH, Bjorklund A: Trophic factor gene therapy for Parkinson’s disease,
Mov Disord 28(1):96–109, 2013.
Lee JM, Ramos EM, Lee JH, et al: CAG repeat expansion in Huntington disease
determines age at onset in a fully dominant fashion, Neurology 78:690–695,
2012.
Lipsman N, Schwartz ML, Huang Y, et al: MR-guided focused ultrasound
thalamotomy for essential tremor: a proof-of-concept study, Lancet Neurol
12(5):462–468, 2013.
Okun MS: Deep-brain stimulation for Parkinson’s disease, N Engl J Med
367(16):1529–1538, 2012. ss
Olanow CW, Schapira AH: Therapeutic prospects for Parkinson disease, Ann
Neurol 74(3):337–347, 2013.
Parkinson MH, Boesch S, Nachbauer W, et al: Clinical features of Friedreich’s
ataxia: classical and atypical phenotypes, J Neurochem 126(Suppl 1):103–
117, 2013.
Phukan J, Albanese A, Gasser T, et al: Primary dystonia and dystonia-plus
syndromes: clinical characteristics, diagnosis, and pathogenesis, Lancet Neurol
10(12):1074–1085, 2011.
Pringsheim T, Wiltshire K, Day L, et al: The incidence and prevalence of
Huntington’s disease: a systematic review and meta-analysis, Mov Disord
27(9):1083–1091, 2012.
Sailer A, Houlden H: Recent advances in the genetics of cerebellar ataxias, Curr
Neurol Neurosci Rep 12(3):227–236, 2012.
Scahill L, Woods DW, Himle MB, et al: Current controversies on the role of
behavior therapy in Tourette syndrome, Mov Disord 28:1179–1183, 2013.
Seibyl J, Russell D, Jennings D, et  al: Neuroimaging over the course of
Parkinson’s disease: from early detection of the at-risk patient to improving
pharmacotherapy of later-stage disease, Semin Nucl Med 42:406–414, 2012.
Seppi K, Weintraub D, Coelho M, et al: The Movement Disorder Society
Evidence-Based Medicine Review Update: Treatments for the non-motor
symptoms of Parkinson’s disease, Mov Disord 26(Suppl 3):S42–S80, 2011.
Tabrizi SJ, Scahill RI, Owen G, et al: Predictors of phenotypic progression and
disease onset in premanifest and early-stage Huntington’s disease in the
TRACK-HD study: analysis of 36-month observational data, Lancet Neurol
12(7):637–649, 2013.
Trinh J, Farrer M: Advances in the genetics of Parkinson disease, Nat Rev Neurol
9(8):445–454, 2013.
Vidailhet M, Jutras MF, Grabli D, et al: Deep brain stimulation for dystonia,
J Neurol Neurosurg Psychiatry 84(9):1029–1042, 2013.
Visanji NP, Brooks PL, Hazrati L-N, et al: he prion hypothesis in Parkinson’s
disease: Braak to the future, Acta Neuropathol Commun 1:2, 2013.
Zesiewicz TA, Shaw JD, Allison KG, et al: Update on treatment of essential
tremor, Curr Treat Options Neurol 15:410–423, 2013.
 115 
Congenital, Developmental, and
Neurocutaneous Disorders
ss

Maxwell H. Sims and Jennifer M. Kwon

This chapter describes some of the most important congenital
nervous system malformations and neurodevelopmental disor-
ders. Advances in imaging and molecular genetic diagnostic tech-
nology have improved our understanding of these disorders.
Neuroimaging facilitates diagnosis and informs early manage-
ment of malformations of the brain and spinal cord. The remark-
able advances in genetic sequencing and microarray technology
are improving our understanding of the etiology and pathogen-
esis of neurodevelopmental disorders due to single genes, like
Fragile X syndrome, Rett syndrome, tuberous sclerosis, and neu-
rofibromatosis, as well as the genetically heterogeneous disorders
autism and ADHD.
  CONGENITAL MALFORMATIONS
Malformations of the central nervous system develop during fetal
life. Table 115-1 summarizes the timeline of early neural and
cortical development and the defects that may occur during these
stages. Malformations developing early in embryogenesis can be
more severe than those arising later, after the basic structures of
the nervous system are in place.
Brain Malformations
Disorders of Ventral Induction
Definition/Epidemiology
Ventral induction is the early stage of brain development where
brain vesicles and the face begin to form. Malformations that
arise during this time include holoprosencephaly (HPE), agen-
esis of the corpus callosum (ACC), and septo-optic dysplasia
(SOD). In clinical practice, ACC is the most commonly seen,
with an estimated prevalence in the general population of greater
than 0.5%, higher in those with developmental disabilities. The
estimated prevalence of HPE is 1/10,000, and SOD is even rarer,
occurring in 3/100,000.
Pathology
During ventral induction, the prosencephalon forms and under-
goes cleavage and midline formation. Abnormal prosencephalon
cleavage leads to HPE, a spectrum of abnormalities ranging from
alobar HPE (cortex with a single ventricle) to semi-lobar and
lobar HPE (cerebral hemispheres are mostly separated except for
the frontal lobes) (Figure 115-1). In all cases, there is some fusion
between the two cerebral hemispheres, often accompanied by
facial anomalies. ACC and SOD represent more discrete abnor-
malities localized to specific midline structures and occur later in
prosencephalic development.
Clinical Presentation
Children with HPE, ACC, and SOD have varying degrees of
developmental disability and other congenital anomalies. In
HPE, especially, the close timing of this defect with facial devel-
opment may lead to midline anomalies like cleft lip, hypotelorism,
or cyclopia. Children with SOD will have vision problems and
optic nerve hypoplasia on examination; they can also have pitu-
itary dysfunction. The clinical presentations range from severe—
where individuals develop multiple complications related to their
severe neurologic impairments—to nearly normal, as in the case
of ACC associated with no other defects.

TABLE 115-1  STAGES OF PRENATAL NEURAL DEVELOPMENT (SIMPLIFIED)

STAGE STRUCTURES FORMING POST-CONCEPTUAL AGE ANOMALIES SEEN*
NEURAL TUBE, BRAIN Dorsal induction Neural tube closure 18-26 days (3-5 weeks) Anencephaly, spina bifida,
VESICLE DEVELOPMENT myelomeningocele, Chiari 2
(KANEKAR) malformation
Ventral induction (ref Brain vesicle and face 5-10 weeks Holoprosencephaly agenesis of
Kanekar) development the corpus callosum,
septo-optic dysplasia
CORTICAL DEVELOPMENT Proliferation Development of neuroblasts and 2-4 months (neuroblasts) Microcephaly, megalencephaly
(REF BARKOVICH, OSBORNE) glioblasts
Migration Formation of 6 cortical layers Peak occurrence at 2-4 Lissencephaly, periventricular
months, though occurs from heterotopias
8 weeks to 8 months
Post-migrational Cortex formed Polymicrogyria, schizencephaly
organization
*NB: Some anomalies (such as microcephaly, polymicrogyria) can arise from different stages. So even though it may seem intuitive to think of microcephaly as a disorder of neuronal
proliferation, there are some forms of microcephaly that develop well after migration.

1024
 Chapter 115  Congenital, Developmental, and Neurocutaneous Disorders 1025

ss

FIGURE 115-1  Semilobar HPE. MRI (sagittal T1 image taken at midline paired with and the axial FLAIR image whose location is indicated by
the scout line) of 13 day old with hypotelorism and microcephaly. There is presence of partial fusion of the frontal lobes with lack of interhemi-
spheric fissure/falx and septum pellucidum. The body and genu of corpus callosum is likewise poorly formed. There is appropriate separation of
the thalami.

Diagnosis/Differential
Neuroimaging is the primary method of diagnosing HPE, ACC,
and SOD. MRI allows for specific anatomic diagnoses and for
delineating the full extent of brain malformations. Ophthalmol-
ogy examination can also detect hypoplastic optic nerves. HPE,
ACC, and SOD are associated with a number of genetic syn-
dromes, including trisomies and familial disorders.
Treatment
Surgical treatment can improve associated craniofacial anomalies
(e.g., cleft lip) and hormone replacement is needed for pitu-
itary dysfunction (seen in SOD). These patients can present
with a wide range of medical problems related to their under-
lying disabilities, including the development of joint contrac-
tures, hip dislocations, impaired swallowing, and respiratory
insufficiency.
Prognosis
Survival has improved for these children thanks to aggressive
treatment and management of associated medical problems.
Long-term outcome depends on the degree of neurologic impair-
ment and associated medical comorbidities.
Disorders of Neuronal Migration and Organization
Definition/Epidemiology
These disorders, including lissencephaly, schizencephaly, polymi-
crogyria and pachygyria, are caused by disrupted migration of
neuronal progenitor cells, resulting in the abnormal appearance
of cortical sulci and gyri. The more severe forms of lissencephaly
occur in approximately 1/100,000 births. Other migrational
disorders have a more variable presentation and, while their
true incidence is unknown, they are more common than
lissencephaly.
 1026 Section XVI  Neurologic Disease
Pathology
ss Neuronal migration is a complex, highly-regulated process inte-
gral to formation of normal cortical architecture that occurs
throughout gestation but peaks from 2 to 4 months. In the case
of lissencephaly and pachygyria, the brain appearance is smoother
because there are fewer convolutions of the cortical surface. In
polymicrogyria syndromes, the brain is more irregular in appear-
ance due to an increased number of abnormally small gyri. In
schizencephaly, clefts form from the surface of the brain to the
lateral ventricle; the clefts are often lined by polymicrogyri.
Clinical Presentation
Lissencephaly has a severe presentation with marked motor dis-
ability and seizures. Polymicrogyria and schizencephaly, depend-
ing on the extent and location, often result in less severe
developmental disabilities. All neuronal migration disorders are
associated with high risk of seizures.
Diagnosis/Differential
Neuroimaging is the primary method of diagnosing the neuronal
migration disorders. Further diagnostic evaluation is often done
because these disorders are heterogeneous in etiology and may
be associated with other genetic syndromes or environmental
factors, such as teratogens or intrauterine infections. Single gene
mutations are responsible for many malformation syndromes
and identification of these genes can aid in counseling and
prognosis.
Treatment
The most common medical issue in this population is intractable
epilepsy which is treated with medications and possibly by surgi-
cal resection of the abnormal epileptogenic cortex. In the case of
severe neurologic impairment, a number of medical complica-
tions can arise: orthopedic complications from immobility and
spasticity; failure to thrive and aspiration from poor oromotor
coordination; vulnerability to pulmonary infections; and compli-
cations due to respiratory insufficiency.
Prognosis
Long-term outcome depends on the degree of neurologic impair-
ment and, to a lesser extent, the etiology of the migration disor-
der. Genetic evaluation is useful for prognostic counseling and
management.
Chiari Malformation, Type 1 (CMI)
Definition/Epidemiology
Chiari malformation, type 1 (CMI) is cerebellar tonsillar ectopia
with displacement of the cerebellar tonsils more than 5 mm
below the foramen magnum, usually accompanied by deformity
of tonsils and evidence of altered CSF flow (indicated by loss of
peritonsillar CSF space or impaired CSF flow dynamics.) It is
common, likely occurring in 0.5 % of the population.
Pathology
The cerebellar tonsils are inferiorly displaced, elongated, and
compressed by the foramen magnum. This displacement can
cause increased intracranial pressure and change CSF flow
dynamics, leading to development of syringomyelia.
Clinical Presentation
In CM1 cases with severe displacement, there may be lower
cranial neuropathies, disordered sleep, headaches, and vertigo,
among other symptoms. If there is an associated syringomyelia,
this may also result in symptoms (see discussion of syringomy-
elia.) Rarely, patients may experience difficulty with balance
and gait.
Diagnosis/Differential
MRI is most useful for making the diagnosis. CSF flow studies
may be helpful to establish clinical significance of the Chiari mal-
formation. Since any cause of increased intracranial pressure can
lead to tonsillar herniation, it is important to exclude idiopathic
intracranial hypertension and CNS mass lesions.
Treatment
Surgical decompression by removing suboccipital bone and pos-
terior C1 vertebrae may be necessary when the symptoms are
severe and when syringomyelia is present, symptomatic, and
worsening. Otherwise, conservative management is sufficient.
Prognosis
CM1 is generally not disabling. Surgical decompression is gener-
ally effective and prognosis is good.
Spinal Cord Malformations
Spina Bifida
Definition/Epidemiology
Failure to completely close the neural tube during the 24th to
26th days post conception can result from defects anywhere
along the neuroaxis. These abnormalities are termed neural tube
defects (NTDs), the most common of which occur caudally, and
are collectively termed spina bifida. Spina bifida occurs in about
1 in 2800 births in the United States. The prevalence of NTDs
varies by geography and is influenced by genetic and environ-
mental factors. Use of folic acid at the time of conception and
during pregnancy can significantly reduce NTD rates.
Pathology
The neural plate folds and seals itself to form the neural tube in
a process, called neurulation, from gestation day 18 to 28. The
central portion of the neural tube closes first, then the cranial and
caudal portions. Abnormal caudal closure can be associated with
overlying bony and skin defects, leading to “open” NTDs, such
as myelomeningocele (MMC). The severe neuropathology seen
in MMC may not be due only to the lack of caudal tube closure,
but also to exposure of neural tube contents to amniotic fluid,
trauma, and the leakage of CSF leading to downward herniation
of the cerebellum. In cases of “closed” spina bifida where the
abnormal caudal cord tissue is covered by fat or skin, neurologic
function is less impaired.
Clinical Presentation
The more severe and disabling the defect, the earlier it will
present. A large MMC is clinically obvious at birth. MMC can
be diagnosed prenatally as well. MMC causes severe distal spinal
cord dysfunction, including paralysis and sensory loss in the
 Chapter 115  Congenital, Developmental, and Neurocutaneous Disorders 1027
legs, and loss of bladder control. Nearly all children with MMC
have an associated Chiari malformation, “type II” (CM2, also
called an Arnold-Chiari malformation). CM2 is characterized
by displacement of the cerebellum and lower brainstem through
the foramen magnum, usually causing obstructive hydrocepha-
lus. Spina bifida does not have to be associated with an open
defect. In cases of closed NTD, patients may present with leg
spasticity, foot deformities, and bladder abnormalities, and the
overlying skin may show nevi, lipomas, abnormal dimples, or
hairy tufts.
Diagnosis/Differential
MRI is the method of choice for evaluation of NTDs. In the case
of a child with an open caudal defect, the imaging should look
for other associated nervous system abnormalities, such as CM2
and hydrocephalus. Closed NTDs are definitively diagnosed by
MRI, but patients may present with symptoms later. Other dis-
orders that can present with gait abnormalities and deformities
include spastic diplegia, vitamin B12 deficiency, multiple sclero-
sis, and other conditions presenting with spastic paraparesis.
Treatment
Treatment is surgical repair of the MMC with subsequent shunt-
ing of the hydrocephalus. Bladder dysfunction may necessitate
intermittent catheterization and treatment of urinary tract infec-
tions and genitourinary reflux. A recent clinical trial indicated
that fetal surgery before 26 weeks gestation to repair the MMC
defect resulted in better neurologic outcomes, possibly by pre-
venting the spinal cord injury and CSF leakage that can occur
during the third trimester with an open defect.
Prognosis
Infants with open NTDs such as MMC have a much more severe
presentation and course than those born with closed defects.
Fetal surgery at qualified centers may improve MMC outcome.
Syringomyelia
Definition/Epidemiology
Syringomyelia or syrinx is a cystic cavitation of the central portion
of the spinal cord. The estimated prevalence of 8/100,000 is likely
an underestimate.
Pathology
The central canal cysts are most commonly located in the cervical
spine and consist of CSF-filled space lined by glial cells, in con-
trast to hydromyelia, where the dilated central canal is lined with
ependymal cells. The syrinx can be septated and irregular, and it
may develop in association with Chiari malformations (CM1 and
CM2), trauma, tumor, or a tethered cord.
Clinical
The classic presentation is a dissociated sensory loss (pain and
temperature loss with preservation of light touch and proprio-
ception) in the neck, arms, or legs. A cervical lesion produces a
cape-like dissociated sensory loss of the arms and shoulder, along
with atrophy of the hands and arms with increased tone and
hyperreflexia in the legs. Extension into the medulla (syringobul-
bia) may cause lower cranial neuropathies.
Diagnosis/Differential
Diagnosis is confirmed by MRI, which will also differentiate ss
the cysts from neoplasms, infections, and other spinal cord
lesions.
Treatment
If the syrinx is associated with CM1 or CM2, then posterior fossa
decompression or shunting of the hydrocephalus may improve
the symptoms. Direct evacuation or shunting of the syrinx itself
is less frequently done and not of established benefit.
Prognosis
Syringomyelia can be slowly progressive but spontaneous resolu-
tion has been seen. Therefore, conservative treatment has been
advocated, especially in children.
  DEVELOPMENTAL DISORDERS
Autism Spectrum Disorder
Definition/Epidemiology
Autism spectrum disorder (ASD) is characterized by 1) impaired
social communication and interactions and 2) restricted and
repetitive behaviors. The prevalence of ASD is 1/88 and is four
times higher in boys than girls.
Pathology
The marked social impairments that characterize ASD are not
associated with specific pathology or physical findings.
Clinical Presentation
ASD presents in early childhood with lack of interest or inclina-
tion to relate to others. Young children with autism may be physi-
cally healthy with good motor skills, but they are hard to engage,
do not reliably respond to their name being called, and are slow
to develop social and communicative gestures such pointing and
waving.
Diagnosis/Differential
The lack of a clear biologic marker or simple clinical test means
that the diagnosis of ASD relies on careful evaluation of the child
by experienced examiners. (See Table 115-2 for DSM-V criteria
for ASD). ASD may be difficult to diagnosis or distinguish from
other forms of mental retardation and psychiatric disorders. ASD
should be distinguished from acquired encephalopathies (e.g.,
epilepsy or encephalitis).
Treatment
The mainstay of treatment is prompt initiation of appropriate
behavioral and early enrichment services. The treatments for
ASD are aimed at improving social interactions and communica-
tion; not surprisingly, there is no set treatment that works for all.
Rather, treatment of this disorder often requires coordination of
medical, educational, and community services.
Prognosis
Patients with ASD respond to appropriate treatments over time,
but these may be highly resource intensive. Some children with
ASD, especially those who have normal verbal and intellectual
 1028 Section XVI  Neurologic Disease
skills and a higher level of adaptive functioning, may develop
ss skills for independent living and work.
Attention Deficit/Hyperactivity  
Disorder (ADHD)
Definition/Epidemiology
ADHD is a common neurodevelopmental disorder occurring in
about 5% of children and 2.5% of adults, worldwide. ADHD is
TABLE 115-2  DSM-5 CRITERIA FOR AUTISM
SPECTRUM DISORDER
REQUIRED DOMAIN CRITERIA
Deficits in social Problems reciprocating social or emotional
communication/ interaction, including difficulty establishing or
interaction (must maintaining back-and-forth conversations and
have all three interactions, inability to initiate an interaction,
criteria) and problems with shared attention or sharing of
emotions and interests with others.
Severe problems maintaining relationships—
ranges from lack of interest in other people to
difficulties in pretend play and engaging in
age-appropriate social activities, and problems
adjusting to different social expectations.
Nonverbal communication problems such as
abnormal eye contact, posture, facial expressions,
tone of voice and gestures, as well as an inability
to understand these.
Restricted and Stereotyped or repetitive speech, motor
Repetitive Behavior movements or use of objects.
(at least 2 criteria Excessive adherence to routines, ritualized patters
must be met) of verbal or nonverbal behavior, or excessive
resistance to change.
Highly restricted interests that are abnormal in
intensity or focus.
Hyper or hypo reactivity to sensory input or
unusual interest in sensory aspects of the
environment.
Symptoms must be present in early childhood, but may not become fully
manifest until social demands exceed capacities.
Symptoms need to be functionally impairing and not better described by
another DSM-5 diagnosis.
TABLE 115-3  DSM-5 CRITERIA FOR ADHD
Inattention: 6 or more symptoms in inattention for children up to age 16, or 5
or more symptoms in those 17 years or older; symptoms present for at least 6
months.
• Often fails to give close attention to details or makes careless mistakes
in schoolwork, at work, or with other activities.
• Often has trouble holding attention on tasks or play activities.
• Often does not seem to listen when spoken to directly.
• Often does not follow through on instructions and fails to finish
schoolwork, chores, or duties in the workplace (e.g., loses focus,
side-tracked).
• Often has trouble organizing tasks and activities.
• Often avoids, dislikes, or is reluctant to do tasks that require mental
effort over a long period of time (such as schoolwork or homework).
• Often loses things necessary for tasks and activities (e.g. school
materials, pencils, books, tools, wallets, keys, paperwork, eyeglasses,
mobile telephones).
• Is often easily distracted
• Is often forgetful in daily activities.
In addition, the following conditions must be met:
• Several inattentive or hyperactive-impulsive symptoms were present before age 12 years.
• Several symptoms are present in two or more settings, (e.g., at home, school or work; with friends or relatives; in other activities).
• There is clear evidence that the symptoms interfere with, or reduce the quality of, social, school, or work functioning.
• The symptoms do not happen only during the course of schizophrenia or another psychotic disorder. The symptoms are not better explained by another
mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).
marked by inappropriate inattention, impulsivity, and hyperac-
tivity that, in turn, cause impaired functioning, as compared to
typical same-age peers.
Pathology
Despite extensive neuroimaging studies, there are no consistent
pathologic brain findings or neurotransmitter abnormalities in
ADHD. ADHD appears to be highly heritable. The behaviors of
ADHD likely are a common phenotype caused by multiple
etiologies.
Clinical Presentation
ADHD presents before age 12 years with developmentally
inappropriate inattention, hyperactivity, and impulsivity result-
ing in significant impairment in at least two different settings
(e.g., home, school, work, with friends), by multiple observers,
and the disruptive symptoms should have persisted for at least
6 months. Table 115-3 lists the symptoms of inattention and
hyperactivity/impulsivity that fulfill diagnostic criteria for
ADHD.
Diagnosis/Differential
ADHD is a primary disorder of attention and should be distin-
guished from attentional deficits that are secondary to other dis-
orders. Causes of secondary inattention include learning
disability, hearing impairment, and psychiatric disorders. ADHD
can also coexist with autism spectrum disorders. Table 115-3
outlines the criteria used for diagnosis of ADHD.
Treatment
Stimulant medications such as methylphenidate and amphet-
amines are the primary class of medication used in ADHD. Other
nonstimulant medications such as atomoxetine and guanfacine
are also used. All children with ADHD benefit from behavioral
interventions designed to help children re-focus and stay on task.
Hyperactivity and Impulsivity: 6 or more symptoms of hyperactivity-
impulsivity inattention for children up to age 16, or 5 or more symptoms in
those 17 years or older; symptoms present for at least 6 months.
• Often fidgets with or taps hands or feet, or squirms in seat.
• Often leaves seat in situations when remaining seated is expected.
• Often runs about or climbs in situations where it is not appropriate
(adolescents or adults may be limited to feeling restless).
• Often unable to play or take part in leisure activities quietly.
• Is often “on the go” acting as if “driven by a motor.”
• Often talks excessively.
• Often blurts out an answer before a question has been completed.
• Often has trouble waiting his/her turn.
• Often interrupts or intrudes on others (e.g., butts into conversations or
games)
 Chapter 115  Congenital, Developmental, and Neurocutaneous Disorders 1029
Prognosis
ADHD generally responds to treatment, but there are often resid-
ual school difficulties. Improvement depends on age at diagnosis,
associated intelligence, and the effectiveness of clinical follow-up.
Rett Syndrome
Definition/Epidemiology
Rett Syndrome is an X-linked dominant disorder caused by a
mutation of the methyl-cytosine binding protein (MECP2), a
transcriptional repressor. The prevalence in girls is 1/10,000.
In boys, MECP2 mutations are lethal or result in severe
encephalopathy.
Pathology
Girls with Rett syndrome have a characteristic constellation of
behaviors, but there are no specific pathologic hallmarks. Micro-
cephaly is typically seen, with reduced frontotemporal brain
volume. The loss of MECP2 function prevents the protein from
regulating gene expression during critical developmental periods
in infancy.
Clinical Presentation
Patients with Rett syndrome develop normally during their first
year then lose communication skills with deceleration of head
growth. A classic feature is loss of hand function and stereotypic
hand wringing. Seizures are common.
Diagnosis/Differential
Diagnosis is confirmed by mutational testing of the MECP2
gene. Other conditions that can cause a similar presentation
include Angelman syndrome, mitochondrial disorders, and neu-
ronal ceroid lipofuscinosis.
Treatment
Girls usually required ongoing medical management of seizures,
along with therapy for their gross and fine motor delays. They
receive long-term enrichment and support for their intellectual
disability.
Prognosis
While girls survive into adulthood, most will not acquire speech
or functional skills; they will remain dependent for their care.
Fragile X Syndrome (FX)
Definition/Epidemiology
X-linked disorder caused by expanded CGG triplet repeats (>200
CGG repeats) in the first exon of the fragile X mental retardation
gene (FMR1). Considered an X-linked recessive disorder, females
can be symptomatic though they may have milder intellectual
disability compared with male. FX is the most common genetic
cause of mental retardation, affecting 1/4000 males and 1/8000
females.
Pathology
Boys with FX have a characteristic constellation of behaviors and
clinical findings on examination, but there are no specific patho-
logic hallmarks.
Clinical Presentation ss
Children with FX syndrome present with mild-to-moderate
social anxiety, shyness, distractibility, hyperactivity, stereotypic
movements, and intellectual disability. They are generally diag-
nosed before school age. Children have a distinctive appearance:
relative macrocephaly with a long narrow face, and prominent
ears, pubertal macro-orchidism, soft skin, and joint laxity. Indi-
viduals with 55 to 200 CGG repeats (the “pre-mutation” range)
develop ataxia and tremor and cognitive dysfunction (Fragile X
associated tremor/ataxia syndrome, FXTAS) in adulthood, at a
median age of onset of 60 years.
Diagnosis/Differential
Diagnosis is confirmed by testing for increased repeats in the
FMR gene. Other etiologies of intellectual disability and autism
can be mistaken for FX. Adults with FXTAS are often diagnosed
with a variety of other conditions which may present similarly
(e.g., parkinsonism, other ataxia syndromes, tremor).
Treatment
Treatment focuses on appropriate behavioral and educational
services. In older individuals with movement disorders, the treat-
ment is supportive.
Prognosis
Patients with FX respond to training and education over time,
but their intellectual disability may make it difficult for them to
live independently. FXTAS tends to cause, gradual, progressive
neurologic deterioration over many years.
  NEUROCUTANEOUS DISORDERS
Neurocutaneous disorders are congenital, often hereditary disor-
ders characterized by pathognomonic cutaneous and central
nervous system lesions that uniquely distinguish each disease.
The most important of these syndromes are neurofibromatosis 1
and 2, tuberous sclerosis complex, and Sturge-Weber syndrome.
One disorder, von Hippel-Lindau disease, is often included with
the neurocutaneous syndromes though skin findings are gener-
ally absent. Many neurocutaneous disorders are associated with
abnormal, non-cancerous growth of tissues often in a disorga-
nized manner. There is considerable variability in the spectrum
of clinical manifestations.
Neurofibromatosis 1 (NF1)
Definition/Epidemiology
Autosomal dominant disorder caused by mutation of the gene,
NF1, that encodes the protein, neurofibromin. NF1 is character-
ized by altered skin pigmentation, tumors, and abnormalities of
bones, connective tissue, and brain. This is a relatively common
disorder occurring in 1/3500 individuals.
Pathology
Neurofibromin is a tumor suppressor gene, and loss of function
can lead to dysregulated cell growth and differentiation, account-
ing for the variety of tumors—cutaneous neurofibromas, plexi-
form neurofibromas, and gliomas—that can occur in NF1.
 1030 Section XVI  Neurologic Disease
Malignant tumors can also occur, likely due to malignant
ss transformation.
Clinical Presentation
Patients can present with NF1 in a variety of ways. All NF1
patients can be identified by clinical criteria before 20 years
of age, but those with mild symptoms may not realize they
have the disorder. Diagnosis is based on clinical criteria, having
two or more of the following: (1) six or more café-au-lait
macules larger than 5  mm in prepubertal patients or more
than 15  mm in postpubertal individuals (Fig. 115-2), (2) two
or more neurofibromas of any type or one plexiform neuro-
fibroma, (3) axillary or inguinal freckling, (4) sphenoid bone
dysplasia, (5) optic nerve glioma, (6) iris Lisch nodules, and
(7) a family history of NF1. Other comorbid conditions fre-
quently seen are learning disabilities, macrocephaly, and epilepsy.
Important complications of NF1 include scoliosis, gastrointes-
tinal neurofibromas, pheochromocytomas, and renal artery
stenosis.
Diagnosis/Differential
The diagnostic criteria outlined above are highly sensitive and
specific. Neuroimaging and DNA testing can be useful as well.
There are many other disorders that present with hyperpig-
mented skin macules. Schwannomatosis and neurofibromatosis
type 2 (see Neurofibromatosis type 2) may also be mistaken
for NF1.
Treatment
Most individuals with NF1 do not require specific treatment
though ongoing periodic surveillance is recommended. Many
identified tumors can be followed without surgery. Painful sub-
cutaneous neurofibromas can be excised, though they may recur.
Genetic counseling should be provided to all patients and
families.
Prognosis
There is as much variability in disease course as there is in
clinical presentation. Even within families, some individuals
FIGURE 115-2  Multiple café-au-lait spots in a child with neurofibro-
matosis type 1. (From Shah KN: The diagnostic and clinical significant
of café-au-lait macules, Pediatr Clin N Am 57:1131-1153, 2010, Fig. 3.)
may have only skin findings with no symptoms, while others
have more complications including malignant transformation
of plexiform neurofibromas. While it is an autosomal dominant
condition, about half of the cases are sporadic due to new
mutations.
Neurofibromatosis 2 (NF2)
Definition/Epidemiology
Neurofibromatosis type 2 (NF2) is an autosomal-dominant
adult onset disease characterized by bilateral vestibular schwanno-
mas and brain tumors. It is caused by mutations in the gene, NF2,
whose protein product is merlin (schwannomin). It affects
approximately 1/30,000 individuals.
Pathology
Despite the name, the primary tumor types seen in NF2 are
schwannoma and meningioma. Merlin behaves as a tumor sup-
pressor gene.
Clinical Presentation
The diagnosis is generally made when bilateral VIII nerve tumors
are identified (often by MRI). The diagnosis can be made based
on other clinical criteria (some combination of family history
of NF2; presence of characteristic tumors—meningioma,
schwannoma, neurofibroma, or posterior subcapsular lenticular
opacities.) Symptoms of NF2 begin in the second to fourth
decades usually with onset of hearing loss. Skin lesions are
present in a minority of patients with NF2.
Diagnosis/Differential
NF2 is frequently misdiagnosed as NF1, especially if there
are café-au-lait spots. Patients with NF2 may be misdiag-
nosed as having isolated meningioma or unilateral vestibular
schwannoma if other findings are not sought. Schwanno-
matosis can be distinguished by the absence of vestibular
schwannomas.
Treatment
Eventual removal of the schwannomas and other tumors is
usually indicated, though later in life when the tumors are larger
and causing significant symptoms. There may be post-surgical
complications and tumors may recur.
Prognosis
The vestibular tumors, leading to deafness and vestibular symp-
toms contribute greatly to the morbidity of this condition. Mor-
tality is related to tumor growth.
Tuberous Sclerosis Complex (TSC)
Definition/Epidemiology
Tuberous Sclerois Complex (TSC) is an autosomal dominant
disorder of early cellular differentiation, proliferation, and migra-
tion, which results in hamartomatous lesions involving multiple
organs at different stages. Sporadic cases are frequent because of
spontaneous mutations. The incidence is 1/6000. Two genes,
TSC1 and TSC2, are known to cause TSC and account for
 Chapter 115  Congenital, Developmental, and Neurocutaneous Disorders 1031
approximately 85% of cases. TSC1 for approximately 30% and
TSC2 69% of confirmed cases.
Pathology
The gene product for TSC1 is hamartin and for TSC2, tuberin.
Both gene products interact with the mammalian target of rapa-
mycin (mTOR), which is essential in cell growth, proliferation,
and angiogenesis. Hamartin and tuberin join to form a combined
tumor suppressor complex (TSC1:TSC2 complex) that acts to
inhibit mTOR signaling. Mutations that impair function of
the TSC1:TSC2 complex lead to unregulated growth and
proliferation.
Clinical Presentation
Like NF1, TSC has variable presentation depending on the loca-
tion and extent of lesions. The organs most affected include the
brain (cortical tubers, subependymal giant cell astrocytomas
[SEGAs]), heart (cardiac rhabdomyomas), skin (facial angiofi-
bromas, hypomelanotic skin macules or “ash leaf spot,” shagreen
patches, and subungual fibromas), kidney (renal angiomyoli-
poma), eye (retinal hamartoma), and lung (pulmonary lymphan-
gioleiomyomatosis). Seizures, most commonly infantile spasms,
are the usual early clinical presentation.
Diagnosis/Differential
The spectrum of tumors seen in TSC patients can also be seen in
isolation. Biopsy may be needed to distinguish facial angiofibro-
mas from acne and other skin lesions.
Treatment
Treatment is directed toward the epilepsy, especially for infantile
spasms. A surgical approach may be necessary for intractable
epilepsy. SEGAs are slow growing tumors that may enlarge
and cause obstruction, especially during adolescence and early
adulthood. Surgical treatment of SEGAs causing hydrocephalus
can be effective but associated with significant morbidity. Evero-
limus is a pharmacologic mTOR inhibitor that is effective at
reducing the size and growth of SEGAs and is useful for delay-
ing the need for surgery or in those cases where surgery is
not an option. Renal angiomyolipomas are prone to hemor-
rhage and may need to be resected, and pulmonary lymphan-
gioleiomyomatosis may cause life-threatening complications.
These renal and pulmonary tumors may also respond to the
mTOR inhibitors, everolimus and sirolimus. Cognitive disability
may require special education.
Prognosis
The variability in outcome depends on the extent and type of
presenting symptoms. Refractory seizures, developmental delays,
and CNS lesions have poor prognoses. The development of renal
angiolipomas, especially multiple tumors, is also associated with
poorer outcome.
Sturge-Weber Syndrome (SWS)
Definition/Epidemiology
SWS is variably characterized by an upper facial vascular
nevus (port-wine stain), leptomeningeal angiomatos (cerebral
venous malformation), and glaucoma with ocular capillary mal-
formations. The disorder occurs sporadically in less than 1 in ss
20,000 births.
Pathology
The port-wine stain represent a collection of congested capil-
laries of subepidermal tissue. If there is an associated lepto-
meningeal vessel abnormality, it tends to be ipsilateral to the
port-wine stain. The leptomeningeal vascular malformation
makes the underlying brain susceptible to injury, possibly
from venous stasis and abnormal perfusion. Cortical injury
can lead to increased susceptibility to seizures, which in turn
can increase the metabolic demands of already poorly perfused
tissue.
Clinical Presentation
Clinical features include focal epilepsy, cognitive impairment,
and, less frequently, hemiparesis, hemianopia, and glaucoma.
Diagnosis/Differential
The diagnosis is usually made by observing a port-wine stain in
the cranial nerve V1 distribution with neuroimaging confirma-
tion of the intracranial abnormality. Magnetic resonance imaging
is a more reliable tool for diagnosis because calcifications on
computed tomographic scans are classic but unnecessary for the
diagnosis. However, 80% of people with a facial port-wine stain
have no associated brain involvement. SWS should be distin-
guished from other disorders involving abnormal intracranial
vessels and intractable seizures and neurologic dysfunction.
These include moyamoya disease, other vascular malformations,
and tuberous sclerosis.
Treatment
Aspirin (3-5 mg/kg/day) may reduce the frequency of stroke-
like events. Aggressive treatment of seizures is indicated as well.
If antiepileptic drugs do not control seizures, surgical excision of
epileptogenic areas may be indicated. Laser treatment of the
port-wine stain is of cosmetic benefit. Patients require regular
ophthalmologist visits to screen for and surgically treat
glaucoma.
Prognosis
Prognosis depends on the degree of underlying intellectual and
developmental disability and control of seizures.
Von Hippel-Lindau Disease (Central Nervous
System Angiomatosis)
Definition/Epidemiology
Von Hippel–Lindau (VHL) disease is an autosomal-dominant
disorder caused by a defective tumor suppressor gene, VHL,
associated with a variety of vascular tumors in multiple organs,
including cerebellar and retinal hemangioblastomas and renal
cell carcinomas. Incidence is 1/36,000.
Pathology
VHL is a tumor suppressor gene and increases susceptibility to
various vascular tumors.
 1032 Section XVI  Neurologic Disease
Clinical Presentation
ss
VHL disease is variably associated with retinal angiomas, brain
and spinal cord hemangioblastomas, renal cell carcinomas, pheo-
chromocytomas, angiomas of the liver and kidney, and cysts of
the pancreas, kidney, liver, and epididymis. Symptoms typically
begin during the third or fourth decade. Retinal inflammation
with exudates, hemorrhage, and retinal detachment may antedate
cerebellar symptoms (headache, vertigo, and vomiting) or signs
(incoordination, dysmetria, and ataxia).
Diagnosis/Differential
The diagnosis of VHL disease is suspected in individuals with
characteristic lesions such as hemangioblastomas, multiple renal
cysts and renal cell carcinoma, pheochromocytoma, and endo-
lymphatic sac tumors. Clinical diagnostic criteria have been
established. Molecular genetic testing of VHL detects mutations
in 90% to 100% of those meeting clinical criteria.
Treatment
Early evaluation and repeated imaging studies are indicated once
the diagnosis has been made, and genetically at-risk relatives
should also be evaluated. Retinal detachments and tumors are
treated by laser therapy. Surveillance for brain tumors, renal cell
carcinomas, pheochromocytomas, and epididymal tumors is
instituted and appropriated medical and surgical interventions
are provided.
Prognosis
Survival depends on management of tumors. Aggressive surveil-
lance has increased survival (where the median had been less
than 50 years).
For a deeper discussion on this topic, please see Chapter
417, “Congenital, Developmental, and Neurocutaneous
Disorders,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Adzick NS, Thom EA, Spong CY, et al: A randomized trial of prenatal versus
postnatal repair of myelomeningocele, N Engl J Med 364:993–1004, 2011.
Barkovich AJ, Guerrini R, Kuzniecky RI, et al: A developmental and genetic
classification for malformations of cortical development: update 2012, Brain
135:1348–1369, 2012.
Cuddapah VA, Pillai RB, Shekar KV, et al: Methyl-CpG-binding protein 2
(MECP2) mutation type is associated with disease severity in Rett syndrome,
J Med Genet 51:152–158, 2014.
Grzadzinski R, Huerta M, Lord C: DSM-5 and autism spectrum disorders
(ASDs): an opportunity for identifying ASD subtypes, Mol Autism 4:12–17,
2013.
Gutmann DH, Parada LF, Silva AJ, et al: Neurofibromatosis type 1: modeling
CNS dysfunction, J Neurosci 32:14087–14093, 2012.
Hagerman RJ, Berry-Kravis E, Kaufmann WE, et al: Advances in the treatment
of Fragile X syndrome, Pediatrics 123:378–390, 2009.
Kanekar S, Kaneda H, Shively A: Malformations of dorsal induction, Semin
Ultrasound CT MR 32:189–199, 2011.
Kanekar S, Shively A, Kaneda H: Malformations of ventral induction, Semin
Ultrasound CT MR 32:200–210, 2011.
Lo W, Marchuk DA, Ball KL, et al: Updates and future horizons on the
understanding, diagnosis, and treatment of Sturge-Weber syndrome brain
involvement, Dev Med Child Neurol 54:214–223, 2012.
Nigg JT: Attention-deficit/hyperactivity disorder and adverse health outcomes,
Clin Psychol Rev 33:215–228, 2013.
Richard S, Gardie B, Couvé S, et al: Von Hippel-Lindau: how a rare disease
illuminates cancer biology, Semin Cancer Biol 23:26–37, 2013.
Vaz SS, Chodirker B, Prasad C, et al: Risk factors for nonsyndromic
holoprosencephaly: a Manitoba case-control study, Am J Med Genet A
158A:751–758, 2012.
Volpe P, Campobasso G, De Robertis V, et al: Disorders of prosencephalic
development, Prenat Diagn 29:340–354, 2009.
Volkow ND, Swanson JM: Adult attention deficit – hyperactivity disorder, NEJM
369:1935–1944, 2013.
Wallingford JB, Niswander LA, Shaw GM, et al: The continuing challenge of
understanding, preventing, and treating neural tube defects, Science
339:1047–1054, 2013.
 116 
Cerebrovascular Disease ss

Mitchell S.V. Elkind

are generally associated with trauma and not usually manifesta-

  INTRODUCTION tions of stroke.
Stroke is a major public health problem throughout the world A further complicating issue is that advanced imaging tech-
due to its high prevalence and mortality, and its association with niques permit the detection of abnormalities consistent with
significant disability even among survivors. Stroke is the fourth infarction or microhemorrhage that are unassociated with any
leading cause of death in the United States, and a leading cause clinical symptoms. Therefore, current definitions distinguish
of death in other countries, particularly in Asia. It is the leading between “stroke,” which involves clinical symptoms, and “cere-
cause of serious disability, and results in enormous costs mea- bral infarction,” which need not be associated with symptoms of
sured in both health care dollars and lost productivity. Major cerebral injury. However, these so-called “silent infarcts” are not
strides have been made in understanding the epidemiology, etiol- so silent; they are associated with cognitive decline, dementia,
ogy, and pathogenesis of cerebrovascular disease, which have led gait disorders, functional disability, and an increased risk of clini-
to new approaches to diagnosis and treatment. cal strokes. Because these subclinical infarcts are approximately
five times more common than clinically evident strokes, includ-
  DEFINITION AND EPIDEMIOLOGY ing them (and microbleeds) within the rubric of cerebrovascular
The term cerebrovascular disease encompasses a host of disorders disease substantially increases the recognized burden of cerebro-
that share pathology localized to the vessels of the brain and vascular disease.
spinal cord, including ischemic stroke, transient ischemic attack In the United States, there are 6.4 million stroke survivors
(TIA), intracerebral hemorrhage (ICH), subarachnoid hemor- (prevalence of 3%), and there are approximately 600,000 new
rhage (SAH), cerebral venous and sinus thrombosis, and disor- (incident) and 200,000 recurrent strokes per year. Of these
ders of the vessels themselves unassociated with cerebral injury
(Table 116-1). Strokes may also be classified as either ischemic
(i.e., due to lack of blood flow) or hemorrhagic. With widespread TABLE 116-1  COMMON FORMS OF
use of sensitive brain imaging, such as diffusion-weighted MRI CEREBROVASCULAR DISEASE
(DWI), cerebral injury from ischemia can be seen among patients Ischemic cerebrovascular disease
whose symptoms last only a few minutes. A definition from an Symptomatic
expert panel in 2013 defines an ischemic stroke as “an episode of • Ischemic stroke
• Cerebral infarction
neurological dysfunction caused by focal cerebral, spinal, or • Spinal cord infarction
retinal infarction.” A stroke due to ICH was defined as “rapidly • Retinal infarction
developing clinical signs of neurologic dysfunction due to a • Transient ischemic attack
• Transient monocular blindness (amaurosis fugax)
focal collection of blood within the brain parenchyma or ven- Asymptomatic
tricular system which is not due to trauma.” Importantly, the • Cerebral infarction/spinal cord infarction/retinal infarction
pathology, and not the duration of the symptoms, is considered Hemorrhagic cerebrovascular disease
paramount. • Intracerebral hemorrhage
• Subarachnoid hemorrhage
Ischemic strokes may be further classified into etiologic sub- • Intraventricular hemorrhage
groups, based on the mechanism of the ischemia and the type • Subdural hemorrhage
and localization of the vascular lesion. Cardioembolism as the • Epidural hemorrhage
• Cerebral microbleeds
source occurs in 15% to 30% of cases, large vessel atherosclerotic
infarction varies from 14% to 40%, and small-vessel lacunar Other forms of cerebrovascular disease
• Cerebral vein thrombosis
infarcts account for 15% to 30%. Stroke from other determined • Dural sinus thrombosis
causes, such as arteritis or dissection, account for less than 5% of Disorders of cerebral autoregulation
cases. In 30% to 40% of ischemic infarcts the cause cannot be • Posterior reversible encephalopathy syndrome
determined. Intracranial hemorrhage may also be subdivided • Hypertensive encephalopathy
• Reversible cerebral vasoconstriction syndrome
into subtypes, based on the site and vascular origin of the blood:
Vascular abnormalities
subarachnoid, when the bleeding originates in the subarachnoid • Aneurysms
spaces surrounding the brain; and intracerebral, when the hem- • Arteriovenous malformations
orrhage is into the brain parenchyma. Other forms of intracranial • Cavernous malformations
• Fibromuscular dysplasia
bleeding, such as subdural hemorrhage and epidural hemorrhage,

1033
 1034 Section XVI  Neurologic Disease

strokes, about 87% are ischemic infarctions, 10% primary hemor- strokes. Risk of stroke decreases with lower systolic and diastolic
ss rhages, and 3% SAHs. Among adults age 35 to 44, the incidence blood pressures, and this graded decrement in risk persists down
of stroke is 30 to 120/100,000 per year, and for those age 65 to to levels as low as 115/75. There is no clearly defined threshold
74, the incidence is 670 to 970/100,000 per year. Stroke inci- level below which stroke risk levels off.
dence rates are approximately twice as high for African Ameri- Cardiac disease is associated with an increased risk of isch-
cans as for whites. In northern Manhattan, Caribbean Hispanics emic stroke. Atrial fibrillation accounts for up to 24% of cerebral
had an incidence rate intermediate between that of whites and infarction in the elderly. Atrial fibrillation (AF) is the most
blacks. Temporal trends in stroke incidence suggest that stroke important cardiac cause of embolic stroke, but other cardiac
incidence rates have been declining since 1950; however, dispari- diseases, including valvular heart disease, myocardial infarction
ties in stroke incidence and mortality have increased. (MI), coronary artery disease (CAD), congestive heart failure
Stroke incidence increases with age, but strokes do occur in (CHF), and electrocardiographic evidence of left-ventricular
young adults and children, and may be missed if the diagnosis is hypertrophy are also associated with stroke risk. Recent evidence
not considered. Although stroke incidence rates are higher for also suggests that other atrial abnormalities, such as paroxysmal
men than women at most ages, among young adults the rates are supraventricular tachycardia, may also increase risk of stroke,
similar or higher among women, probably related to pregnancy, even in the absence of atrial fibrillation. Other possible sources
hormonal contraception, and other hormone-related differences. of cardiac emboli include patent foramen ovale, aortic arch
At older ages, incidence rates among women are again greater, atherosclerotic disease, atrial septal aneurysms, and valvular
and because women tend to live longer than men, overall about strands.
60,000 more women than men have a stroke each year. Hyperlipidemia is a stroke risk factor, though its relationship
to stroke is more complicated than for heart disease, primarily
  MODIFIABLE RISK FACTORS because of the many types of stroke. Lipid abnormalities, such as
Well-established modifiable stroke risk factors include hyperten- elevations in low density lipoprotein (LDL) and decreased levels
sion, cardiac disease (particularly atrial fibrillation), diabetes, of high density lipoprotein, are strongly associated with athero-
hyperlipidemia, cigarette use, physical inactivity, alcohol abuse, sclerotic stroke.
asymptomatic carotid stenosis, and a history of TIAs (Table The role of alcohol as a stroke risk factor depends on stroke
116-2). subtype and quantity consumed. Alcohol consumption has been
Hypertension is the most powerful modifiable stroke risk shown to be a risk factor for both ICH and SAH in a linear
factor and is associated with both ischemic and hemorrhagic fashion, whereas a J-shaped relationship exists between alcohol
and ischemic stroke, such that modest consumption (up to two
drinks daily in men, and one daily in women) is protective against
TABLE 116-2  STROKE RISK FACTORS stroke and heavy consumption (five or more drinks per day)
NON-MODIFIABLE RISK Age increases risk.
FACTORS Sex Asymptomatic carotid artery disease, particularly with 75% or
Race/ethnicity greater stenosis, is associated with increased stroke risk (approxi-
Family history
Genetic disorders mately 2% per year). The risk of stroke also depends, however, on
WELL-ESTABLISHED Hypertension/blood pressure the rate of progression of the stenosis, collateral circulation, and
MODIFIABLE RISK Diabetes mellitus/hyperglycemia the stability of the atherosclerotic plaque.
FACTORS Cardiac disorders TIAs are a strong predictor of subsequent stroke. The first
Atrial fibrillation
Valvular heart disease several days after a TIA have the greatest stroke risk, with recent
Recent myocardial infarction series demonstrating a 5% risk at 2 days and 10% risk at 90 days.
Cardiomyopathy/heart failure Patients with transient monocular blindness (amaurosis fugax)
Bacterial endocarditis
Hyperlipidemia have a better outcome than those with hemispheric ischemic
Cigarette smoking attacks. The stroke risk after TIA depends on the underlying
Carotid stenosis cause of the ischemia, including the presence and severity of
TIAs
Physical inactivity underlying atherosclerotic disease or atrial fibrillation. Age,
Hypercoagulable states (e.g., antiphospolipid hypertension, the presence of diabetes, clinical syndromes,
antibody syndrome, cancer-associated) including aphasia and hemiparesis, and duration of at least 10
Alcohol abuse
Substance abuse (e.g., cocaine, IV drug minutes predict patients at higher risk of stroke. Patients with
abuse) TIA with evidence of infarction on MRI are also at higher risk.
OTHER POTENTIAL RISK Migraine Other potential stroke risk factors include migraine, oral
FACTORS Sleep apnea contraceptive use, drug abuse, sleep apnea, infection, and
Cardiac disorders
Paroxymsal supraventricular tachycardia
inflammation.
Patent foramen ovale/atrial septal
aneurysm   PATHOLOGY
Aortic atheroma
Infections (e.g. varicella zoster virus,
Understanding the pathology of cerebrovascular disease requires
influenza) an appreciation of the vascular anatomy of the brain, the vascular
Inflammation pathologies that can affect brain vessels, and the response of brain
Others
tissue to ischemia and hemorrhage.
 Chapter 116  Cerebrovascular Disease 1035
Clinical Implications of Vascular Anatomy
The brain is perfused by four major vessels, the paired carotid and
vertebral arteries. These originate extracranially as branches off
the aorta and great vessels and course through the neck and base
of the skull to reach the intracranial cavity (Fig. 116-1). The
carotid and its branches constitute the anterior circulation, and
the vertebral arteries and its branches the posterior circulation.
Anterior and posterior circulations communicate with one
another through the posterior communicating arteries. The left
and right sides of the anterior circulation communicate with each
other through the anterior communicating artery. The major
vessels at the base of the brain and these communicating vessels
constitute the Circle of Willis, the anastomotic network that
allows for collateral blood flow when individual vessels are ste-
notic or occluded. Because variants in the circle of Willis are
common, collateral flow may not be sufficient in many cases of
blockage, and the risk of ischemic stroke, therefore, depends on
a patient’s individual anatomy.
The right common carotid artery usually begins as a branch
from the innominate artery, whereas the left common carotid
artery originates directly from the aortic arch. The common
carotid arteries bifurcate into the internal and external carotid
arteries, usually at the level of the fourth cervical vertebrae. The
ACA
Ant Comm
MCA
PCA
Post Comm
Basilar A
SCA
ICA
AICA
ECA
PICA
Vertebral
CCA
Subclavian A
FIGURE 116-1  Coronal view of the extracranial and intracranial arte-
rial supply to the brain. Vessels forming the circle of Willis are high-
lighted. A, Artery; ACA, anterior cerebral artery; AICA, anterior inferior
cerebellar artery; Ant Comm, anterior communicating artery; CCA,
common carotid artery; ECA, external carotid artery; ICA, internal
carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral
artery; PICA, posterior inferior cerebellar artery; Post Comm, posterior
communicating artery; SCA, superior cerebellar artery. (Modified from
Lord R: Surgery of occlusive cerebrovascular disease, St. Louis, 1986,
Mosby.)
internal carotid arteries have no branches in the neck and face,
and enter the cranium through the carotid canal. There are four ss
main segments of each internal carotid artery: cervical, petrous,
cavernous, and supraclinoid. The siphon is the term used to
describe the hairloop turn made by the cavernous and supracli-
noid segments, and it is at this level that the ophthalmic artery
originates, providing the first major branch of the internal carotid
artery and supplying blood flow to the optic nerve and retina.
Thus, internal carotid artery disease commonly causes ocular
ischemia, leading to a transient ischemic attack (amaurosis fugax)
or infarction of the optic nerve or retina, a warning sign of
impending cerebral stroke. The internal carotid arteries then give
off the superior hypophyseal, posterior communicating, and
anterior choroidal arteries, before terminating intracranially by
dividing into the middle and anterior cerebral arteries. In addi-
tion to the eye, the paired carotid systems supply approximately
80% of the hemispheric blood flow, including the frontal, pari-
etal, and anterior temporal lobes. In up to 15% of individuals, the
posterior cerebral artery (PCA) also arises directly from the
internal carotid artery (the so-called fetal origin PCA), so that
the entire hemisphere including the occipital lobe is supplied by
the internal carotid artery. The anterior choroidal artery supplies
a number of structures in addition to the choroid plexus, includ-
ing the inferior portion of the posterior limb of the internal
capsule, the hippocampus, and portions of the globus pallidus,
posterior putamen, lateral geniculate, amygdala, and ventrolateral
thalamus.
The middle cerebral artery (MCA) is the largest branch of the
internal carotid artery. Its first portion, or stem, is often referred
to as the M1 segment, and this usually bifurcates into superior
and inferior divisions or, less often, trifurcates into three major
divisions (upper, middle, and lower). The MCA stem gives rise
to the medial and lateral lenticulostriates, which supply the
extreme capsule, claustrum, putamen, most of the globus palli-
dus, part of the head and the entire body of the caudate, as well
as the superior portions of the anterior and posterior limbs of the
internal capsule. The divisions of the MCA supply almost the
entire lateral cortical surface of the brain, including the insula,
operculum, and frontal, parietal, temporal, and occipital
cortices.
The anterior cerebral artery (ACA) also has a proximal, or A1,
segment, which ends at the junction with the anterior communi-
cating artery. The ipsilateral ACA then continues as the distal, or
A2, segment. An important branch is the recurrent artery of
Heubner, which supplies the head of the caudate nucleus, and
several cortical branches supply the medial and orbital surfaces
of the frontal lobe.
The vertebral arteries generally originate from the subclavian
arteries, course through the transverse foramina of the cervical
vertebrae, pierce the dura, and enter the cranial cavity through
the foramen magnum. The two vertebral arteries join to form the
basilar artery at the level of the pontomedullary junction. Ante-
rior and posterior spinal arteries and the posterior inferior cere-
bellar artery (PICA), which supplies the inferior surface of the
cerebellum, arise from the distal segments of the vertebrals. The
lateral medulla is supplied by the multiple, perforating branches
of PICA or the direct penetrating branches of the vertebral artery.
Occlusion of the distal vertebral artery may, therefore, cause
 1036 Section XVI  Neurologic Disease
infarction of the lateral medulla (Wallenberg syndrome), charac-
ss terized by vertigo, imbalance, Horner syndrome, dysphagia, and
sensory loss.
After originating as the union of the right and left vertebral
arteries, the basilar artery travels up the ventral pons. Paramedian
and circumferential penetrating arteries exit the basilar to dive
into the pontine parenchyma. Proximally, the basilar gives off the
paired anterior inferior cerebellar arteries (AICA), and more dis-
tally the superior cerebellar arteries (SCA); these perfuse the
ventrolateral aspect of the cerebellar cortex. An internal auditory
(labyrinthine) artery arises either directly from the basilar or
from the anterior cerebellar artery to supply the cochlea, laby-
rinth, and part of the facial nerve. Ischemia in the basilar territory
may, therefore, cause hearing loss and vertigo, sometimes as an
isolated symptom.
The basilar artery terminates in the right and left posterior
cerebral arteries (PCAs). A series of penetrators arise from the
posterior communicating and posterior cerebral arteries to
supply the hypothalamus, dorsolateral midbrain, lateral genicu-
late, and thalamus. The posterior cerebral artery supplies the infe-
rior temporal lobe, and the medial and inferior surfaces of the
occipital lobe. In some patients a single large penetrating vessel
at the midline of the terminal basilar artery may supply medial
aspects of both thalami (the artery of Percheron); emboli occlud-
ing this vessel may, therefore, cause bilateral thalamic infarcts,
with a decrease in alertness and vertical gaze abnormalities,
without significant motor deficit.
The brain’s anastomotic network includes not only the con-
nections through the Circle of Willis, but also intercommu­
nicating systems extracranially and more distal connections
intracranially through meningeal anastomoses that cover the cor-
tical and cerebellar surfaces (pial-pial collaterals). These net-
works all protect the brain from ischemia by providing alternate
routes to circumvent obstructions in the main arteries.
Venous anatomy is more variable than arterial. Superficial
veins drain into the transverse, superior sagittal, and cavernous
sinuses. The deep venous drainage is via the great vein of Galen,
which drains into the straight sinus, and in turn drains into the
torcula along with the sagittal sinus. Blood drains from the torcula
to the transverse sinus, then to the sigmoid sinus, and thereafter
the jugular vein. Anterior venous drainage is via the cavernous
sinus, which communicates with the contralateral cavernous
sinus, the transverse sinus via the superior petrosal sinus, and the
inferior petrosal sinus, which drains directly into the jugular bulb.
Vascular Pathogenesis
There are multiple mechanisms leading to brain ischemia. Hemo-
dynamic infarction occurs as a result of reduced perfusion,
usually in the setting of arterial stenosis due to atherosclerosis. In
some cases, stenosis may be due to arterial dissection, vasculitis,
fibromuscular dysplasia, or other arteriopathies. Embolism
occurs when a thrombus originating from a more proximal
source (e.g., arterial or cardiac) travels through the arteries and
occludes a cerebral artery. Paradoxical embolism occurs when a
thrombus crosses from the venous circulation to the left side of
the heart through a patent foramen ovale or, less commonly, an
intrapulmonary arteriovenous shunt. Other particles that may
embolize include neoplasm, fat, air, or other foreign substances.
Air emboli can follow injuries or procedures involving the lungs,
the dural sinuses, or jugular veins. Fat embolism usually results
from a bone fracture. Septic emboli arise from bacterial
endocarditis.
Intracranial hemorrhage results from the rupture of a vessel
anywhere within the cranial cavity. Intracranial hemorrhages may
be classified by location (e.g., extradural, subdural, subarachnoid,
intracerebral, intraventricular), by the nature of the ruptured
vessel (e.g., arterial, capillary, venous), or by cause (e.g., primary,
secondary). Trauma is often involved in the generation of extra-
dural hematoma from laceration of the middle meningeal artery
or vein, and subdural hematomas from traumatic rupture of veins
that traverse the subdural space.
Intracerebral hemorrhage is characterized by bleeding into the
substance of the brain, usually originating from a small penetrat-
ing artery. Hypertension has been implicated as the cause of
weakening in the walls of arterioles and the formation of micro-
aneurysms (i.e., Charcot-Bouchard aneurysms). The most
common sites for hypertensive arterial hemorrhage are the
putamen, pons, cerebellum, and thalamus. Blood under arterial
pressures destroys or displaces brain tissue. Amyloid angiopathy,
due to the vascular deposition of β-amyloid protein similar to
that seen in Alzheimer disease has been implicated as an impor-
tant cause of lobar hemorrhage in elderly patients. Other causes
of hemorrhage include arteriovenous malformations, aneurysms,
moyamoya disease, bleeding disorders or anticoagulation,
trauma, tumors, cavernous angiomas, and illicit drug abuse.
Subarachnoid hemorrhage occurs when blood is localized to
the surrounding membranes and cerebrospinal fluid. It is most
frequently caused by leakage of blood from a cerebral aneurysm.
The combination of congenital and acquired factors leads to a
degeneration of the arterial wall and the release of blood, under
arterial pressures, into the subarachnoid space and cerebrospinal
fluid. Aneurysms may be distributed at different sites throughout
the base of the brain, particularly at the origin or bifurcations of
arteries of the circle of Willis. Other secondary causes that may
lead to SAH include trauma, arteriovenous malformations,
bleeding disorders or anticoagulation, amyloid angiopathy, or
cerebral sinus thrombosis.
The most common intrinsic disorder of the cerebral blood
vessels is atherosclerosis, which shares similarities in pathology
with atherosclerosis throughout the body. Arteriosclerotic
plaques may develop at any point along the carotid artery and the
vertebrobasilar system, but the most common sites are the bifur-
cation of the common carotid artery, the origins of the MCAs
and ACAs, and the origins of the vertebral from the subclavian
arteries (Fig. 116-2). In the past it was thought that intracranial
atherosclerotic disease required significant stenosis (>50%) to
cause symptoms. However, recent pathological and radiological
studies provide evidence that substenotic lesions can also cause
strokes due to plaque rupture and acute thrombosis, as is the case
elsewhere in the body.
Small-vessel disease refers to the occlusion of a penetrant
branch of a larger artery, usually due to microatheroma or to
lipohyalinosis, a degenerative disorder of the vessel characterized
by deposition of fatty and proteinaceous material. Hematological
disorders and coagulopathies, including leukemia, Waldenstrom
macroglobulinemia, polycythemia, primary and secondary
 Chapter 116  Cerebrovascular Disease 1037
ACA
Anterior
communicating
MCA artery
CBF (mL/100 g/min)
Posterior
PCA communicating
artery
Basilar ICA
artery
CCA
Vertebral
artery
Subclavian
artery
Artery
arch
FIGURE 116-2  Sites of predilection for atheromatous plaque. ACA,
Anterior cerebral artery; CCA, common carotid artery; ICA, internal
carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral
artery. (From Caplan LR: Stroke: a clinical approach, ed 2, Boston, 1993
Butterworth-Heinemann.)
antiphospholipid antibody syndrome, and genetic defects of the
coagulation cascade, may also lead to occlusive thrombi and
emboli.
The cerebral circulation differs from the systemic circulation.
The brain is protected by the anastomoses described above. In
addition, cerebral autoregulation maintains a constant cerebral
perfusion pressure over a range of systemic blood pressures (Fig.
116-3). Cerebral arterioles have a well-developed muscular coat
that allows constriction in response to increased blood pressure,
and dilation with hypotension. The arterioles are also exquisitely
sensitive to changes in peripheral arterial concentrations of
carbon dioxide (PaCO2) and oxygen (PaO2). When the partial
pressure of CO2 decreases, such as after hyperventilation, the
arterioles constrict and blood flow is reduced. In healthy indi-
viduals, cerebral autoregulation maintains a constant cerebral
blood flow over mean arterial pressures of 60 to 140 mm Hg. In
patients with chronic hypertension, the autoregulatory curve is
shifted to the right, so that even minor reductions in blood pres-
sure levels may not be tolerated. At blood pressures above these
limits, moreover, as in severe hypertension, autoregulatory capac-
ity may be overwhelmed, leading to breakthrough edema and
hemorrhage. In the setting of infarction or hemorrhage, cerebral
autoregulation is also impaired, resulting in cerebral dependence
on systemic blood pressure to maintain adequate perfusion.
Thus, decreasing the blood pressure in the setting of acute isch-
emia is hazardous.
ss
70
60
Normal
50 Chronic hypertension
40
30
20
10
0
50 100 150 200
Mean arterial blood pressure (mm Hg)
FIGURE 116-3  Autoregulatory cerebral blood flow (CBF) response to
changes in mean arterial pressure in normotensive and chronically
hypertensive persons. Note the shift of the curve toward higher mean
pressures with chronic hypertension. (From Pulsinelli WA: Cerebrovas-
cular diseases-principles. In Goldman L, Bennett JC, editors: Cecil text-
book of medicine, ed 21, Philadelphia, 2000, Saunders, p 2097.)
Specific disorders may originate from autoregulatory dysfunc-
tion: posterior reversible encephalopathy syndrome (PRES) and
the reversible cerebral vasoconstriction syndrome (RCVS). In
posterior reversible encephalopathy syndrome, there is loss of
autoregulatory control with leakage of fluid across the blood-
brain barrier, primarily in the posterior regions of the brain.
Patients present with elevated blood pressures, headaches, sei-
zures, and loss of visual function. Reversible cerebral vasocon-
striction syndrome, a recently recognized syndrome, remains
incompletely characterized, and shares features with posterior
reversible encephalopathy syndrome. The two disorders overlap
in 10% or more of cases. Patients with reversible cerebral vaso-
constriction syndrome are typically young women who present
with acute, severe headache, have minimal or no neurological
deficits, and may have evidence of non-aneurysmal, superficial
SAH as well as vasospasm of the cerebral arteries. Sympathetic
innervation of the vessels is also less in the posterior circulation
than anteriorly, leading to a reduced ability of the posterior cir-
culation to adapt to changes in blood pressure, and may contrib-
ute to the propensity for edema to form in the occipital lobes
during hypertensive crises.
In addition, focal cerebral activity, such as occurs when activat-
ing brain regions responsible for moving a limb, is accompanied
by accelerated metabolism in the appropriate region, and is
accommodated by slight increases in local blood flow and oxygen
delivery. Exploitation of this increased local energy demand and
delivery is what allows imaging of functional brain activity using
MRI, which can detect subtle changes in regional cerebral blood
flow.
Intracerebral capillaries also lack adventitia, with astrocytes
serving as the vascular component of the neurovascular unit.
Tight junctions at the capillary level play an important role in the
blood-brain barrier, which limits permeability between the vas-
cular compartment and the brain tissue.
 1038 Section XVI  Neurologic Disease
ss
Injury to Brain Tissue
The adult brain weighs about 1500 g, or 2% of total body weight,
but accounts for 20% of the total body oxygen consumption.
Because the brain cannot store much energy, dysfunction results
after only a few minutes of deprivation when either oxygen or
glucose content is reduced below critical levels. In the resting
state, normal total cerebral blood flow is 50 mL/min per 100 g of
brain tissue.
Neuronal dysfunction occurs at cerebral blood flow levels
below 50 mg/dL, and irreversible neuronal injury begins at levels
below 30 mg/dL. Both the degree and duration of reductions in
cerebral blood flow are related to the likelihood of permanent
neuronal injury. When blood supply is completely interrupted
for 30 seconds, brain metabolism is altered; after 1 minute, neu-
ronal function may cease. After 5 minutes, anoxia initiates a chain
of events that may result in cerebral infarction; however, if oxy-
genated blood flow is restored quickly enough, the damage may
be reversible, as with a TIA.
Research into the cellular basis of cerebral ischemia has led to
the concept of the “ischemic cascade.” As perfusion of the brain
decreases, a chain of events at the neuronal level begins with
failure of the membrane sodium/potassium (Na/K) pump, the
depolarization of the neuronal membrane, the release of excit-
atory neurotransmitters such as glutamate and glycine that hyper-
stimulate their receptors, and the opening of calcium channels.
Calcium enters the neuron through various voltage-sensitive and
receptor-mediated channels (e.g., the N-methyl-d-aspartate
receptor). The influx of calcium is at the root of further neuronal
injury, with damage to organelles and further destabilization of
neuronal metabolism and normal function resulting. These
events may lead to delayed neuronal death, even after restoration
of blood flow, and are a target of experimental neuroprotective
strategies.
Recent research has distinguished between the “core” infarct
and an “ischemic penumbra,” or shadow. The core represents
a central region of necrosis, or tissue that dies very quickly
after blood flow ceases. The penumbra represents the surround-
ing region of brain tissue, in which neurons are dysfunctional
but potentially salvageable. Recanalization of occluded vessels
with blood flow into infarcted tissue, particularly when delayed,
results in “reperfusion injury.” Increased use of MRI has shown
that petechial hemorrhagic infarction is very common, occur-
ring in the majority of strokes, even when not suspected
clinically.
  CLINICAL PRESENTATION
The signs and symptoms of strokes are varied, and depend on the
type of stroke, the region of the nervous system affected by the
lack of flow or hemorrhage, and the patient’s handedness (Table
116-3). In general, embolic ischemic strokes are characterized by
the sudden onset of a neurological deficit, generally painless.
Thrombotic strokes may have a stuttering or progressive course
due to fluctuating hypoperfusion and gradual occlusion. Arterial
dissections, as well as hemorrhages, are more often associated
with headaches than ischemic stroke. Hemorrhagic strokes and
large hemispheric infarcts can lead to decrease in consciousness
due to increased intracranial pressure.
TABLE 116-3  CLINICAL MANIFESTATIONS OF
ISCHEMIC STROKE
OCCLUDED VESSEL CLINICAL SIGNS
ICA Ipsilateral blindness (variable) MCA syndrome
MCA Contralateral hemiparesis, hemisensory loss (face
or arm more than leg)
Aphasia (dominant) or anosognosia
(nondominant)
Homonymous hemianopsia (variable)
ACA Contralateral hemiparesis, hemisensory loss (leg
more than arm)
Abulia (especially if bilateral)
VA or PICA Ipsilateral facial sensory loss, hemiataxia,
nystagmus, Horner syndrome
Contralateral loss of temperature or pain sensation
Dysphagia
SCA Gait ataxia, nausea, vertigo, dysarthria
BA Quadriparesis, dysarthria, dysphagia, diplopia,
somnolence, amnesia
PCA Contralateral homonymous hemianopsia, amnesia,
sensory loss
ACA, Anterior cerebral artery; BA, basilar artery; ICA, internal carotid artery; MCA,
middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar
artery; SCA, superior cerebellar artery; VA, vertebral artery.
Most emboli occur in the territory of the MCAs. Lesions of
the dominant (almost always left) hemisphere are characterized
by variable combinations of right hemiparesis, right hemisensory
loss, right visual loss, impaired gaze to the right side of space, and
language disturbance. When the superior division of the middle
cerebral artery is affected, the language impairment is predomi-
nantly motor: the patient either cannot speak or produces sparse,
agrammatic speech, despite an ability to fully comprehend
spoken and written material. When the inferior division is
affected, the patient may produce fluent, prosodic, but nonsensi-
cal speech and be unable to follow instructions. Larger infarcts of
the dominant hemisphere produce a total loss of language func-
tion, leaving the patient mute and uncomprehending.
Lesions of the non-dominant (right) hemisphere produce
deficits of the left side of the body. Language is preserved but the
patient may demonstrate impaired attention, particularly to the
left side of space and fail to appreciate the presence of people or
objects to their left, and may even fail to recognize the left side of
their own body (asomatagnosia). This neglect phenomenon may
extend even to an awareness of any deficit of functioning on their
part, and they may be unaware there is a problem (anosagnosia).
These patients may be found at home, lying on the floor paralyzed
yet unaware that anything is the matter; their unawareness can
delay their presentation to the hospital for treatment and simi-
larly limit their participation in rehabilitation. Lesions in the right
hemisphere may also cause dysprosody, the non-dominant equiv-
alent of aphasia, which is characterized by a lack of the emotional
and gestural components of speech, despite preservation of its
semantic content; many of these patients have a flat affect or
appear to be depressed.
Infarcts in the territory of the anterior cerebral arteries often
cause weakness limited to the legs, due to location of the repre-
sentation of the legs in the medial part of the hemispheres. They
may have incontinence, lack initiative (abulia), and have gaze
 Chapter 116  Cerebrovascular Disease 1039
palsies. In some cases their deficits may be more extensive and
mimic those of middle cerebral artery infarctions. Posterior cere-
bral artery infarcts lead to visual loss, often without any motor
deficit. With involvement of the medial temporal lobes supplied
by the PCAs, there may also be behavioral disturbances, includ-
ing delirium and amnesia.
Brainstem infarcts cause specific syndromes due to the affected
neural pathways and nuclei. Midbrain infarcts often produce ver-
tical gaze deficits and impaired consciousness if the reticular acti-
vating system is involved.
Many cerebral infarctions do not cause weakness, such as
fluent (or Wernicke’s) aphasia, cortical visual loss, and Wallen-
berg syndrome. Because the inferior division of the MCA sup-
plies the lateral temporal lobe and parietal lobes, including
Wernicke’s area, occlusion of that vessel may cause a prosodic,
fluent speech with multiple paraphasic errors and poor compre-
hension, while sparing the motor strip in the frontal lobe. Emboli
traveling up the basilar artery may cause significant infarction in
the territory of both posterior cerebral arteries, causing complete
blindness, sometimes without awareness of the deficit on the part
of the patient, due to infarction of both occipital lobes (the “top
of the basilar syndrome”). Behavioral abnormalities, memory
loss, and eye movement abnormalities may also occur, due to the
involvement of the medial temporal lobe structures and the mid-
brain eye movement centers. Small emboli to branches of the
superior division of the MCA may cause focal weakness of the
hand, particularly fine finger movements, simulating a peripheral
compression neuropathy.
In patients presenting with dizziness, it is particularly difficult
to distinguish stroke from vestibular neuronitis or Ménière’s
disease (see Chapter 113). The presence of a normal head-thrust
test, skew deviation, or direction-changing nystagmus are all
signs of stroke, rather than a peripheral cause. Patients should be
followed until they can walk without imbalance; patients with
nausea and vomiting due to cerebellar infarction may develop
fatal brainstem compression due to swelling.
The signs and symptoms of subarachnoid hemorrhage differ
from other stroke types due to the absence of focal deficits.
Instead, patients present with abrupt onset of severe headache
(i.e., “the worst headache of my life”), vomiting, altered con-
sciousness, and sometimes coma, typically without localizing
signs.
Thrombosis of cerebral veins or the larger draining dural
sinuses present with a combination of headache due to elevated
intracranial pressure, seizures, and focal deficits due to hemor-
rhage. Rarely the syndrome of thunderclap headache, or sudden
severe headache without any focal signs similar to that occur-
ring in SAH, may be due to venous thrombosis. Occlusion
of the cerebral venous sinuses may occur in association with
a hyperviscosity or hypercoagulable state, including pregnancy
or hormonal contraceptive use. Imaging findings include bilat-
eral hemorrhagic infarctions in a parasagittal distribution and
extensive white matter edema. Contrast-enhanced CT may
demonstrate the empty delta sign, indicating a filling defect
in the sagittal sinus. Magnetic resonance venography (MRV)
and T1 weighted MRI images confirm the presence of throm-
bus; cerebral angiography is seldom needed to confirm the
diagnosis.
  DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS ss
The benefit of thrombolytic therapy within 3 hours of onset of
acute ischemic stroke requires urgent differentiation of ischemic
stroke from hemorrhage and other causes of sudden neurological
symptoms. Headache, vomiting, seizures, and coma, are more
common in hemorrhagic stroke, though these are never reliable
enough to preclude imaging. The distinction is straightforward
in most cases once a head CT is performed. The hyperdense
signal of blood in the parenchyma on CT almost invariably
distinguishes hemorrhage from ischemia. In exceptional cases
the typical hyperdensity of ICH is absent owing to severe anemia
or to its subacute state, during which blood may be indistin-
guishable from brain tissue. Certain imaging findings on initial
CT further support a presumed diagnosis of infarction, such as
a hyperdense vessel sign indicative of thrombus in the vessel,
or loss of the gray-white junction and sulci in the cortex, and
loss of the demarcation of the insular cortex and deep gray
nuclei, both of which are early indicators of ischemia and edema
(Fig. 116-4). CT angiography often identifies the site of vascular
occlusion.
Imaging in the setting of suspected acute ischemia does not
definitively diagnose ischemia, but rather excludes hemorrhage;
if clinical symptoms are consistent with cerebral ischemia, then
thrombolytic treatment is indicated. Primary stroke centers must
perform and interpret CT scans within 30 minutes of the arrival
of a patient with suspected stroke. MRI can also effectively
exclude acute hemorrhage, and diffusion-weighted imaging
sequences are more sensitive to the earliest changes of ischemia
(Fig. 116-5), but the speed and availability of CT make it the
initial imaging modality of choice at most centers. MRI scanning
may then be used to provide additional information. Specific
MRI sequences have greater sensitivity to blood than CT, and
many identify hemorrhagic infarction missed by CT.
Clinical features at stroke onset may suggest a subtype of cere-
bral infarction but require confirmatory laboratory data. Cerebral
embolism is suggested by sudden onset and a syndrome of cir-
cumscribed focal signs attributable to cerebral surface infarction,
such as pure aphasia or pure hemianopia. Unless the source of
embolization is obvious on hospital admission, blood cultures,
electrocardiographic monitoring, and echocardiography are
indicated.
A diagnosis of atherosclerotic infarction is suggested if there
were previous TIAs, particularly when the symptoms are stereo-
typical. Doppler ultrasonography or MRA can usually identify
the stenosis. In equivocal cases, CT angiography or conventional
angiography may be needed. Small penetrating vessel infarcts,
lacunar infarcts, usually spare cortical functions, such as language
and cognition, but cause loss of elementary neurologic function,
such as strength, sensation, and coordination. Up to 25% of
patients with lacunar infarcts have large-vessel disease or a car-
dioembolic source, so it is important to carry out a complete etio-
logic evaluation in all stroke patients.
Up to 50% of patients with transient deficits lasting less than
24 hours have evidence of infarction on imaging, and the risk of
stroke and other vascular events is as high after TIA as after com-
pleted stroke. In the acute setting, when decisions about throm-
bolysis must be made, it is virtually impossible to know which
 1040 Section XVI  Neurologic Disease

ss

A B
FIGURE 116-4  Early signs of infarction on computed tomography of the brain. A, Hyperdense middle cerebral artery sign (red arrow), and
B, hypoattenuation of the left caudate and lentiform nuclei, loss of the insular ribbon, and sulcal effacement (outlined in red).

A B
FIGURE 116-5  Magnetic resonance imaging scan of the brain of the same patient shown in Figure 116-4. A, Diffusion-weighted image shows
bright signal in the left middle cerebral artery territory. B, Apparent diffusion coefficient shows dark signal in the same area, confirming acute
infarction.

patients with ischemia will have symptoms resolve without
infarction (thus, having a TIA) and which will have a completed
infarction. Patients with either stroke or TIA need immediate
attention to secondary prevention strategies. In terms of choos-
ing treatments, the important issue is to identify the cause of the
cerebral ischemia, rather than its duration. Entities other than
cerebral ischemia can masquerade as strokes and TIAs. Among
patients diagnosed with stroke in emergency departments, 20%
or more have a stroke mimic, including seizure, migraine, systemic
infection, brain tumor, and toxic-metabolic encephalopathy.
Other sources of misdiagnosis are listed in Table 116-4.
In patients with a prior of history cerebral infarct or hemor-
rhage, new metabolic derangements, including infections, may
precipitate a recrudescence of the original stroke syndrome.
Hypoglycemia, hyponatremia, urinary tract infection, pneumo-
nia, and starting initiation of a psychotropic medication can each
precipitate this phenomenon. The patient returns to normal over
hours to days when the new insult is treated or reversed. Such
 Chapter 116  Cerebrovascular Disease 1041
TABLE 116-4  STROKE MIMICS AND DIFFERENTIAL
DIAGNOSIS
COMMON MIMICS
Metabolic encephalopathy (hypoglycemia, hyponatremia, etc.)
Systemic infection
Seizure
Migraine
Brain tumors
OTHER MIMICS
Transient focal neurological symptoms associated with amyloid angiopathy
Positional vertigo
Cardiac events
Syncope
Trauma (especially acceleration-deceleration without evidence of external
injury)
Subdural hematoma
Herpes simplex virus encephalitis
Transient global amnesia
Dementia
Demyelinating disease
Cervical spine disease/radiculopathy/fracture
Myasthenia gravis
Parkinsonism
Hypertensive encephalopathy
Conversion disorder
Intoxication/substance abuse
metabolic and infectious causes of neurologic deterioration must
be excluded in patients with a history of earlier brain injury
before diagnosing a new stroke. Focal signs may also occur with
metabolic disturbances in patients without a prior history of
stroke.
External signs of injury are usually present in brain trauma, but
they need not be present after acceleration-deceleration injury,
such as from a motor vehicle accident. The most frequent sites of
brain contusions are the frontal and temporal poles, which are
not typical locations for strokes.
Seizures may occasionally complicate acute stroke, but they
may also mimic stroke. Unlike stroke, seizures are often charac-
terized by obtundation, an amnestic state, clonic activity, incon-
tinence, or tongue biting. The postictal deficit, often called a
Todd’s paralysis, resembles stroke and weakness or language and
other cortical deficits may occur. The deficits after seizure usually
resolve within hours after the seizure, but occasionally persist for
up to a week, making the distinction from stroke difficult. Sei-
zures may also develop months or years after an infarct or hemor-
rhage, and the postictal state in these patients may recapitulate
the initial stroke syndrome.
Migraine with persistent aura often mimics stroke or TIA. Aura
alone, without headache (i.e., acephalgic migraine), is sometimes
experienced by those who previously suffered from migraine
with aura. Migraine aura typically produces a visual disturbance
that marches across the vision of both eyes as an advancing,
enlarging blind spot that takes 20 to 30 minutes to resolve. Sub-
sequent unilateral, pounding headache suggests the diagnosis,
but may not occur. Less often, migrainous auras take the form of
sensory symptoms. The speed of the march is generally slower
than the rapid spread of symptomsin stroke.
As many as 10% of brain tumors present with acute transient
symptoms reflecting intratumoral hemorrhage or focal seizures.
Seizures often precede focal signs. CT scan usually demonstrates
an enhancing mass even when symptoms are mild.
TABLE 116-5  EVIDENCE-BASED PRIMARY ss
PREVENTION OF ISCHEMIC STROKE
RISK FACTOR TREATMENT
Hypertension Anti-hypertensives
Myocardial infarction HMG-CoA reductase inhibitors
Hyperlipidemia HMG-CoA reductase inhibitors
Atrial fibrillation Anticoagulation (warfarin, other
agents)
Diabetes mellitus/vascular disease ACE inhibitor
Diabetes mellitus type II, obesity Metformin
Aymptomatic carotid stenosis Carotid endarterectomy
(60-99%)
High vascular risk populations Antiplatelet therapy
  TREATMENT
Stroke prevention and treatment are directed toward: (1) pre-
venting the first stroke (primary prevention); (2) limiting damage
from the stroke; (3) optimizing functional recovery following
stroke; and (4) avoiding recurrence (secondary prevention). Spe-
cific measures for treatment and prevention depend on the
patient’s risk factors and stroke mechanism. The diagnostic evalu-
ation of the stroke patient dictates optimal therapy.
Primary Prevention of Stroke
Randomized trials have demonstrated that specific interven-
tions prevent first stroke among patients with specific risk
factors (Table 116-5). Treatment of hypertension, for example,
is associated with up to a 45% reduction in the risk of stroke
(Level A). Among patients with atrial fibrillation, the use of
warfarin is associated with a 60% to 70% relative reduction
in risk of stroke, though younger patients without any accom-
panying heart disease, hypertension, or diabetes may be managed
with antiplatelet agents alone (Level A). Hydroxymethylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors, or statins, have
been shown in some primary prevention studies, and in studies
of patients with heart disease, to reduce the risk of a first
stroke as well as that of heart disease (Level A). The effects
on stroke risk are more modest than the effects on heart
disease, possibly reflecting the greater heterogeneity among
causes of stroke compared to heart disease. For patients with
asymptomatic carotid stenosis of at least 60%, carotid end-
arterectomy reduces the risk of stroke, though the effect is
much more modest than in symptomatic patients, and the
number of patients needed to treat to prevent one stroke is
greater. Because many of the large randomized trials of end-
arterectomy for asymptomatic patients were conducted in the
era before the current recommended use of statins and anti-
platelet agents, it is no longer clear that surgery is superior
to medical therapy. New trials are addressing medical versus
surgical treatment.
Antiplatelet therapy is not of established benefit for prevention
of a first stroke. In a large primary prevention study, for example,
aspirin use was associated with an increased risk of both ischemic
and hemorrhagic stroke, despite reducing the risk of ischemic
heart disease. However, other studies have shown that aspirin
reduces the risk of ischemic stroke among women over the age
of 45 (Level B).
 1042 Section XVI  Neurologic Disease
Observational studies provide evidence that certain behaviors
ss prevent stroke. Smoking cessation leads to a reduction by 5 years
in stroke risk to levels similar to non-smokers. Consumption of
alcohol in moderation, up to 2 drinks daily for men and one daily
for women is associated with a lower level of stroke risk than in
those who do not drink. Physical activity, weight loss when
appropriate, and management of diabetes are recommended.
Acute Treatment of Ischemic Stroke
For patients with ischemic stroke evaluated within 3 hours of
symptom onset with no evidence of hemorrhage on a brain CT
or MRI, recombinant tissue plasminogen activator (rt-PA), a
thrombolytic agent, improves functional outcomes at 3 months
compared to placebo. Among the 624 ischemic stroke patients
treated within 3 hours in the original landmark study, the propor-
tion of patients achieving normal or near-normal neurological
and functional status by 3 months was significantly higher among
those receiving rt-PA, though there was no definite benefit at 24
hours. The proportion of patients who achieved independence in
their performance of activities of daily living was increased from
38% to 50%, an absolute benefit of 12%. The absence of an imme-
diate (24-hour) benefit, coupled with the finding of a benefit at
3 months, is consistent with the hypothesis that thrombolytic
treatment works to reduce the size of the infarct penumbra
by reperfusing tissue before permanent infarction of the entire
territory occurs, despite some irreversible injury to a core
component.
Patients treated with rt-PA had a tenfold increase in incidence
of hemorrhagic conversion of the infarction (from 0.6% in
placebo-treated patients to 6.0% in rt-PA–treated patients).
Overall, the rates of neurological deterioration and mortality
within the first day after stroke were similar between the groups.
Rt-PA was approved for patient use by the FDA in 1996, and it is
now considered standard of care for ischemic stroke patients pre-
senting within 3 hours (Level A). Specific guidelines for eligibil-
ity and exclusion must be met when using rt-PA to reduce the
risk of complications (Table 116-6).
Because of the potential to reduce cerebral perfusion below
the limits permitted by autoregulation in the setting of acute
brain injury, current guidelines recommend that blood pressure
not be reduced acutely after ischemic stroke, and systolic blood
pressure levels as high as 220 mm Hg are allowed. Before and
following thrombolytic treatment, however, systolic blood pres-
sure should be kept below 180 mm Hg to reduce the risk of hem-
orrhagic conversion. In addition, antiplatelet and anticoagulant
medications must be withheld for 24 hours after rt-PA.
Subsequent meta-analyses and individual trials have demon-
strated that the benefit of thrombolytic therapy decreases as the
time interval between symptom onset (the presumed beginning
of ischemia) and treatment increases, but that the therapeutic
time window may persist as long as 4.5 hours after stroke.
Advanced imaging techniques, such as diffusion-weighted (DWI)
and perfusion-weighted images (PWI), that can distinguish irre-
versibly injured versus underperfused or “at risk” tissue have been
investigated as a means to identify ischemically viable tissue that
may respond to revascularization. Recent trial results, however,
have not confirmed their value, at least using the imaging param-
eters under study.
TABLE 116-6  ELIGIBILITY AND EXCLUSION CRITERIA
FOR TREATMENT OF ACUTE ISCHEMIC
STROKE WITH INTRAVENOUS RT-PA
ELIGIBILITY
Age ≥18 years
Diagnosis of ischemic stroke causing measurable neurological deficit
Well-documented onset of symptoms <4.5 hours before beginning treatment
MAJOR EXCLUSION CRITERIA
Stroke or head trauma within the preceding 3 months
Major surgery within the preceding 2 weeks
History of intracerebral hemorrhage
Systolic blood pressure >185 mm Hg
Diastolic blood pressure >110 mm Hg
Rapidly improving or minor neurological symptoms and signs
Symptoms suggestive of subarachnoid hemorrhage
Gastrointestinal or urinary tract bleeding within 3 weeks
Arterial puncture at a noncompressible site within 1 week
Platelet count <100,000/mm3
INR >1.7
RELATIVE EXCLUSION CRITERIA (MUST WEIGH
RISKS AND BENEFITS)
Seizure at stroke onset
Myocardial infarction within 6 weeks
Infective endocarditis
Hemorrhagic eye disorder
Blood glucose <30 mg/dL (2.7 mmol/L)
Blood glucose >400 mg/dL (21.6 mmol/L)
Patients requiring very aggressive therapy for blood pressure reduction
Interventional techniques to revascularize occluded vessels
has promise in the management of patients with ischemic stroke.
For patients with MCA occlusions presenting up to 6 hours after
symptom onset, there is evidence that intra-arterial thrombolytic
agents delivered via catheter into the face of the occluding throm-
bus can improve functional outcomes, despite an increase in risk
of hemorrhage similar to that seen with intravenous rt-PA (Level
B). More recently, the FDA has approved the use of mechanical
devices specifically engineered to facilitate clot extraction and
dissolution in the setting of ischemic stroke. These devices are
promising in that they are associated with higher recanalization
rates of occluded vessels than occurs spontaneously, but they
have not yet been demonstrated to lead to better clinical out-
comes than standard treatment with intravenous rt-PA in ran-
domized trials. There is evidence, however, that earlier treatment
(within 2 hours) may lead to better outcomes, and further studies
are ongoing to test whether other devices used quickly enough
will improve clinical outcomes.
Treatment with heparin and various heparinoids for acute
stroke are not of benefit and are not recommended in acute
stroke. In some patients with massive hemispheric strokes, surgi-
cal decompression (hemicraniectomy) can be lifesaving with
acceptable functional outcomes, particularly for younger patients
(Level A).
Since stroke is characterized by a cascade of events that can
cause further neuronal injury for hours or days after stroke,
experimental animal stroke studies have tested strategies that
might limit this injury (i.e., neuroprotection), including drugs
targeting n-Methyl-d-Aspartate (NMDA)-receptors, glycine
receptors, calcium channels, adhesion molecules, free radicals,
albumin, inflammation, and membrane constituents. However,
none of these have been of benefit in human clinical trials.
 Chapter 116  Cerebrovascular Disease 1043
Treatment of Intracerebral Hemorrhage
Treatment of ICH is primarily supportive. Many patients require
management in the intensive care setting to manage elevated
blood pressure and secondary complications, such as respiratory
failure, aspiration, and hemodynamic instability in severely neu-
rologically compromised patients. In many cases, patients also
require management of intracranial pressure using osmotic
agents, such as mannitol or hypertonic saline, or therapeutic
hyperventilation. In some patients, surgical evacuation of hema-
tomas may be lifesaving, although trials have thus far failed to
show that most ICH patients benefit from surgical decompres-
sion. Among more than 1000 participants randomized in a large
international study, there was no evidence of benefit of surgical
over medical therapy, apart from a potential benefit in the sub-
group of patients with small superficial hemorrhages. Most hem-
orrhages that occur deep within the hemispheres probably cause
the majority of their damage immediately after the ictal hemor-
rhage, so that evacuation does not save tissue and may introduce
further damage.
One of the major recent insights into the pathogenesis of cere-
bral injury associated with ICH has been the recognition that a
large proportion of hemorrhages continue to expand during the
early hours after onset. As a result, there has been increased inter-
est in the use of prothrombotic agents to reduce this expansion
and to limit secondary cerebral injury. Though preliminary
studies on the potential benefits of infusing factor VII as a pro-
thrombogenic agent showed promise, subsequent and more
definitive studies did not confirm a benefit in the majority of
patients, although it remains possible that subgroups of patients,
including those with warfarin-associated hemorrhage, may
benefit.
For cerebellar hemorrhages, surgical decompression may be
lifesaving, and it is essential to recognize the signs and symptoms
of incipient brainstem compression and herniation (i.e., head-
ache, vertigo, nausea, vomiting, and truncal ataxia without focal
weakness, declining sensorium, and gaze-palsy). Neuroimaging
studies that support the need for surgical decompression include
hematoma greater than 3 cm, fourth ventricular shift, cisternal
obliteration, and ventricular enlargement. Lumbar puncture is
contraindicated with ICH, particularly with cerebellar hemor-
rhages because life-threatening tonsillar herniation and midbrain
compression may occur. Great caution must be taken in these
patients subjected to ventriculostomy for the purposes of reduc-
ing intracranial pressure because upward cerebellar herniation
may occur.
The management of aneurysmal SAH is complicated. Recur-
rent bleeding risks and mortality are high; therefore, definitive
therapy is elimination of the ruptured aneurysm. This may be
accomplished surgically or with interventional embolization
techniques, such as with coils deposited in the aneurysm. Even
after securing the aneurysmal site of bleeding, however, several
other complications may ensue, including vasospasm, cerebral
infarction, cerebral edema, seizures, ventricular dilatation, the
syndrome of inappropriate ADH secretion (SIADH), and cardiac
failure. Antifibrinolytic agents, such as epsilon-amino-caproic
acid, used to preserve the thrombus around an aneurysm,
and thereby preventing rebleeding, have been unsuccessful.
Transcranial Doppler screening may be used daily to detect early
changes of vasospasm; continuous EEG monitoring and multi- ss
modality monitoring of vital signs are other emerging ways to
detect cerebral dysfunction while still reversible. Vasospasm may
be minimized with the calcium channel antagonist, nimodipine,
which crosses the blood-brain barrier; use of nimodipine has
become standard of care in SAH patients for up to 3 weeks after
hemorrhage. Hydration, hyperosmolar therapy, hypertensive
therapy, and angioplasty of vascular spasm may also be used to
reduce risk of infarction. Hydrocephalus may require ventricular
shunting.
Rehabilitation and Recovery
A team approach to stroke rehabilitation, starting with a stroke
recovery unit with experienced physiatrists and physical thera-
pists, has proven beneficial for the optimum recovery of patients.
A specialized stroke unit is particularly helpful in avoiding com-
plications such as infections, contractures, decubiti, and in maxi-
mizing independence for patients. Speech and occupational
therapists help patients improve their swallowing, communica-
tion, and daily living skills.
Constraint-induced therapy is a specific type of physical
therapy that involves having a hemiparetic patient wear a large
mitt to prevent use of the unaffected limb for several hours daily,
forcing the patient to use the affected limb for most tasks. In a
randomized trial, constraint-induced therapy with intensive task-
directed therapy was associated with functional improvement
compared to standard physical therapy (Level B). Further studies
are still needed to determine whether the use of constraints or
the intensive nature of the therapy itself is responsible for
the improvements in function since it is both intensive and
expensive.
Depression is a frequent accompaniment of stroke, reflecting
both the physical disability and altered brain chemistry. Depres-
sion may respond to selective serotonin-reuptake inhibitors
(SSRIs) and tricyclic antidepressants. Escitalopram administered
prophylactically to stroke patients was effective in preventing
the development of depression, though other studies have not
confirmed this (Level B). There is also evidence from other
trials that SSRI treatment facilitates functional recovery after
stroke.
Secondary Stroke Prevention
The optimal secondary prevention strategy for an individual
patient depends on the stroke mechanism. For stroke or TIA
caused by carotid stenosis of 70% or more of the vessel diameter,
carotid endarterectomy (CEA) by a skilled surgeon with an
acceptable complication rate (<5%) is preferable to medical
therapy in good surgical candidates (Level A). For patients at
high risk of surgical complications, including those over age 80,
those with cardiac or pulmonary disease, or those with radiation-
induced arteriopathy, stenting reduces the risks of cardiac com-
plications (Level B). Trials that tested whether carotid angioplasty
and stenting are more effective or safer than carotid endarterec-
tomy in patients at low surgical risk have not demonstrated any
benefit over open surgery (Level A). Among patients with symp-
tomatic intracranial stenosis (lesions not amenable to surgery), a
recent randomized trial demonstrated that best medical therapy,
 1044 Section XVI  Neurologic Disease
including aggressive risk factor control, was associated with a
ss lower recurrence risk (Level B).
Anticoagulation is indicated in patients with definite cardio-
embolic sources of stroke, such as mechanical valves or atrial
fibrillation. In embolic strokes caused by atrial fibrillation, anti-
coagulation with warfarin was superior to aspirin, with a relative
risk reduction of about 68% (Level A). Recommended options
for secondary prevention among patients with atrial fibrillation
now include warfarin with an INR between 2.0 and 3.0, or use of
one of the newer antithrombotic agents, such as dabigatran, riva-
roxaban, edoxaban, or apixaban (Level A). For patients who
cannot tolerate anticoagulants because of a risk of ICH or bleed-
ing elsewhere, newer treatment modalities, including interven-
tions to exclude the left atrial appendage from the circulation
using devices or cinching procedures, show promise in early
trials, though they are not yet approved (Level B).
Other causes of cardiogenic emboli require different treat-
ments. Infected prosthetic valves need replacement if emboli
persist on antibiotics, or if patients develop heart failure. Emboli
from myxomatous tumors of the atria frequently require surgical
removal of tumor. The need for anticoagulation among patients
with less well-established sources of emboli, such as paradoxical
embolism through a patent foramen ovale or aortic arch emboli-
zation, is unproven, and current guidelines do not support its use
in this setting (Level A). Closure of patent foramen ovale using
umbrella-like devices may reduce the risk of recurrent stroke in
selected patients (younger patients without other stroke risk
factors), though recent trials have not proven this effect; further
trials in highly selected patients are ongoing.
All patients with ischemic stroke without a definite indication
for anticoagulation, and in whom no contraindication is present,
should receive long-term antiplatelet therapy, which reduces the
risk of recurrence by 20% to 25% (Level A). Agents currently
approved for this purpose include aspirin, dipyridamole, and
clopidogrel, a thienopyridine derivative ADP receptor inhibitor.
Head-to-head trials have failed to demonstrate a benefit of one of
these agents over another; the combination of aspirin and dipyri-
damole was more effective than either agent alone, but long-term
treatment with the combination of aspirin and clopidogrel was
no more effective than aspirin alone and increased the risk of
significant bleeding. A more recent trial in China suggested that
there may be benefit to the combination of aspirin and clopido-
grel when used for the short term after stroke or TIA, and a
similar study is ongoing in the United States. Aspirin doses as low
as 30 mg daily appear effective and have fewer side effects,
such as gastrointestinal bleeding, than higher doses. The FDA
recommends doses between 50 and 325 mg daily for stroke
prevention.
Clinical trials provide evidence for increased use of anti-
hypertensive agents in patients with stroke and TIA. There are
theoretical concerns about lowering blood pressure in patients
with existing cerebrovascular disease due to the possibility that
in patients with arterial disease of cerebral vessels and reduced
autoregulation, a reduction in blood pressure could worsen per-
fusion and precipitate clinical events or affect cognition. Ran-
domized trials like PROGRESS provide evidence, however, that
blood pressure reduction among patients with cerebrovascular
disease reduces risks of recurrent stroke by 28% independently
of a history of hypertension (Level A). Guidelines currently focus
on the use of blood pressure agents to achieve recommended
target blood pressure levels, rather than on specific agents,
which should be individualized depending on a patient’s
comorbidities.
Trials using HMG-CoA reductase inhibitors, or statins, among
cardiac and other vascular disease high-risk patients have dem-
onstrated benefits in stroke risk reduction. The Stroke Prevention
by Aggressive Reduction in Cholesterol Levels (SPARCL) trial
provides more direct evidence of the benefit of statin therapy in
secondary prevention of stroke among patients presenting with
stroke or TIA (Level A). SPARCL randomized patients with
recent stroke or TIA to atorvastatin 80 mg daily or placebo. Over
5 years, atorvastatin reduced the risk of the primary outcome,
recurrent stroke, from 13.1% to 11.2%, an absolute risk reduction
of about 2%.
Among those with diabetes, diet and exercise, oral hypoglyce-
mic drugs, and insulin are recommended to obtain glycemic
control. While glycemic control reduces risks of microvascular
complications, the benefit in reducing macrovascular complica-
tions is less certain. In one trial, tight glycemic control of a pro-
spective cohort of newly diagnosed diabetics was not found to
significantly reduce stroke risk. Ongoing trials are addressing the
use of newer agents in secondary stroke prevention among those
with insulin resistance.
Behavioral risk factors are difficult to control, but are impor-
tant. Smoking is addictive, and cessation may necessitate psycho-
logic counseling and medical aids, such as nicotine patches or
varenicline. Physical activity should be encouraged, as a seden-
tary lifestyle is associated with elevations in blood pressure and
stroke risk. Alcohol consumption in excess of 2 drinks daily
should be discouraged, though there is evidence that moderate
alcohol consumption may have protective effects against stroke
risk. It should be noted, however, that there is only Level B evi-
dence that control of these risk factors reduces recurrent stroke
risk.
  PROGNOSIS
The immediate period after an ischemic stroke carries the greatest
risk of death, with fatality rates ranging from 8% to 20% in the
first 30 days. Age and stroke severity are the most important
predictors of prognosis. Case fatality rates are worse for hemor-
rhagic strokes, ranging from 30% to 80% for intracerebral hemor-
rhage and 20% to 50% for subarachnoid hemorrhage.
Stroke survivors continue to have a three to fivefold increased
risk of death, compared with the age-matched general popula-
tion. Annual aggregate estimates of death have been 5% for minor
stroke and 8% for major stroke. Survival is influenced by age,
hypertension, cardiac disease, and diabetes. Patients with lacunar
infarcts appear to have a better long-term survival than do those
with the other infarct subtypes.
Recurrent stroke is frequent. The immediate period after a
stroke carries the greatest risk for early recurrence; rates range
from 3% to 10% during the first 30 days. Thirty-day recurrence
risks vary by infarct subtypes; the greatest rates are in patients
with atherosclerotic infarction and the lowest rates in patients
with lacunes. After the early phase, the risk of stroke recurrence
continues to threaten the quality of life of a stroke survivor.
 Chapter 116  Cerebrovascular Disease 1045
Long-term stroke recurrence rates range in different studies from
4% to 14% per year, with aggregate annual estimates of 6% for
minor stroke and 9% for major stroke. These rates have been
decreasing with the advent of the improved protection strategies
outlined above. Recurrent stroke contributes to the burden of
dementia and functional decline after stroke. Importantly, cardiac
events are also increased in stroke survivors, and pose a major
threat of death.
For a deeper discussion on this topic, please see Chapters
64, “Cardiac Arrhythmias with Supraventricular Origin,”
and 70, “Atherosclerosis, Thrombosis, and Vascular
Biology,” in Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Amarenco P, Bogousslavsky J, Callahan A 3rd, et al: The Stroke Prevention by
Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-
Dose Atorvastatin after Stroke or Transient Ischemic Attack, N Engl J Med
355:549–559, 2006.
Broderick JP, Palesch YY, Demchuk AM, et al: Endovascular therapy after
intravenous t-PA versus t-PA alone for stroke, N Engl J Med 368:893–903,
2013.
Carroll JD, Saver JL, Thaler DE, et al: Closure of patent foramen ovale versus
medical therapy after cryptogenic stroke, N Engl J Med 368:1092–1100, 2013.
Furie KL, Kasner SE, Adams RJ, et al: Guidelines for the prevention of stroke in
patients with stroke or transient ischemic attack: a guideline for healthcare
professionals from the American Heart Association/American Stroke
Association, Stroke 42:227–276, 2011.
Giugliano RP, Ruff CT, Braunwald E, et al: Edoxaban versus warfarin in patients
with atrial fibrillation, N Engl J Med 369:2093–2104, 2013.
Goldstein LB, Bushnell CD, Adams RJ, et al: Guidelines for the primary
prevention of stroke: a guideline for healthcare professionals from the
American Heart Association/American Stroke Association, Stroke 42:517–
584, 2011.
Howard G, Lackland DT, Kleindorfer DO, et al: Racial differences in the impact
of elevated systolic blood pressure on stroke risk, JAMA Intern Med 173:46–
51, 2013.
Jauch EC, Saver JL, Adams HP, et al: Guidelines for the early management of
patients with acute ischemic stroke: A Guideline for Healthcare Professionals ss
From the American Heart Association/American Stroke Association, Stroke
44:870–947, 2013.
Kamel H, Elkind MSV, Bhave PD, et al: Paroxysmal Supraventricular Tachycardia
and the Risk of Ischemic Stroke, Stroke 44:1550–1554, 2013.
Kidwell CS, Jahan R, Gornbein J, et al: A trial of imaging selection and
endovascular treatment for ischemic stroke, N Engl J Med 368:914–923, 2013.
Lackland DT, Elkind MSV, D’Agostino R, et al: Inclusion of stroke in
cardiovascular risk prediction instruments: a statement for healthcare
professionals from the American Heart Association/American Stroke
Association, Stroke 43:1998–2027, 2012.
Mayer SA, Brun NC, Begtrup K, et al: Efficacy and safety of recombinant
activated factor VII for acute intracerebral hemorrhage, N Engl J Med
358:2127–2137, 2008.
Meier B, Kalesan B, Mattle HP, et al: Percutaneous closure of patent foramen
ovale in cryptogenic embolism, N Engl J Med 368:1083–1091, 2013.
Mendelow AD, Gregson BA, Fernandes HM, et al: Early surgery versus initial
conservative treatment in patients with spontaneous supratentorial
intracerebral haematomas in the International Surgical Trial in Intracerebral
Haemorrhage (STICH): a randomised trial, Lancet 365:387–397, 2005.
Robinson RG, Jorge RE, Moser DJ, et al: Escitalopram and problem-solving
therapy for prevention of poststroke depression: a randomized controlled trial,
JAMA 299:2391–2400, 2008.
Rothwell PM, Eliasziw M, Gutnikov SA, et al: Analysis of pooled data from the
randomised controlled trials of endarterectomy for symptomatic carotid
stenosis, Lancet 361:107–116, 2003.
Rutten-Jacobs LC, Arntz RM, Maaijwee NA, et al: Long-term mortality after
stroke among adults aged 18 to 50 years, JAMA 309:1136–1144, 2013.
Saver JL, Fonarow GC, Smith EE, et al: Time to treatment with intravenous tissue
plasminogen activator and outcome from acute ischemic stroke, JAMA
309:2480–2488, 2013.
Singhal AB, Biller J, Elkind MS, et al: Recognition and management of stroke in
young adults and adolescents, Neurology 81:1089–1097, 2013.
SPS3 Study Group, Benavente OR, Coffey CS, et al: Blood-pressure targets in
patients with recent lacunar stroke: the SPS3 randomised trial, Lancet
382(9891):507–515, 2013.
Wang Y, Wang Y, Zhao X, et al: Clopidogrel with aspirin in acute minor stroke or
transient ischemic attack, N Engl J Med 369:11–19, 2013.
 117 
Traumatic Brain Injury and
Spinal Cord Injury
ss
Geoffrey S.F. Ling
Traumatic brain injury (TBI) and traumatic spinal cord injury
(TSCI) are leading causes of traumatic death and disability. Over
8 million patients suffer TBI each year; the vast majority (over
80%) are mild TBI or concussion. Approximately 52,000 patients
in the U.S. die from severe TBI as a direct consequence. An addi-
tional 11,000 patients are severely disabled by TSCI. The vast
majority are due to falls, motor vehicle accidents, sports-related
occurrences, and assaults. Among the almost 5.5 million TBI and
TSCI survivors, most require prolonged rehabilitation.
  TYPES OF INJURY
Certain lesions require neurosurgical intervention while others
do not. TBI conditions for which emergency neurosurgery are
needed are penetrating wounds, intracerebral hemorrhage with
mass effect, including subdural and epidural blood, and bony
injury, such as displaced fracture and vertebral subluxation.
However, focal, hypoxic-anoxic, diffuse axonal and diffuse micro-
vascular injuries typically do not require surgery.
  MANAGEMENT
Tramatic Brain Injury (TBI)
Patients with mild or moderate TBI typically recover quickly and
fully. It is critical to first remove the TBI victim from play or work
to prevent further injury. Diagnosis of mild TBI or concussion
begins simply with identifying affected patients. This is often dif-
ficult because these patients suffer transient alteration of con-
sciousness with only a minority completely losing consciousness.
Most have memory impairment. As a result, patients are typically
unaware that they are injured. Thus, it is important that col-
leagues, coaches, athletic trainers, parents, and other observers
have a heightened suspicion when a potential head injury event
occurs. If so, then a sideline point-of-injury screening tool should
be administered, such as a standardized assessment of concussion
(SAC) or sports concussion assessment tool version 3 (SCAT3).
SAC is a neuropsychological battery that tests orientation, imme-
diate memory, concentration, and memory recall. An abnormal
score is less than 25. If abnormal, the patient is at high risk
for having suffered a concussion and thus should be brought
to medical attention for further evaluation, diagnosis and
treatment.
In the early stage of management, it is important that a neu-
rologist or medical practitioner skilled in managing TBI perform
a detailed history, physical, and neurologic examination, espe-
cially assessment of cognitive function. In the history, the practi-
tioner should determine the duration of altered sensorium,
1046
amnesia or loss of consciousness a patient may have suffered. The
American Academy of Neurology Guidelines uses a grading scale
for concussion that is based primarily on the length of these
intervals (Table 117-1). Longer periods of abnormal sensorium
are associated with higher grades. Higher grades necessitate
longer periods of convalescence. Other clinical guides that may
be used include the Cantu Grading System and the Colorado
Medical Society Guidelines.
The decision to obtain neuroimaging is based on the index of
suspicion of intracranial hemorrhage or skull fracture. Both CT
and MRI are inadequate in ruling out mild TBI, which is a clinical
diagnosis. If a patient has lost consciousness, persistent altered
mentation, abnormal GCS score, focal neurologic deficit, or is
clinically deteriorating, then neuroimaging should be obtained.
In general, patients with mild TBI do not require major
medical intervention; almost all do well after adequate convales-
cence. It is essential that patients have adequate time for recovery;
they should not return to play or work until fully recovered. A
second head injury before full recovery may be catastrophic, the
second impact syndrome (SIS), which leads to worse clinical
outcome, including death.
The patient must be allowed to rest with minimal cognitive
burden. There are no specific medications to foster recovery.
Treatment is focused on ameliorating symptoms according to
published evidence-based guidelines, such as VA/DoD Clinical
Practice Guidelines for the Management of Concussion/mild
TBI. In general, headache, the most common complaint, can be
treated with acetaminophen or a nonsteroidal anti-inflammatory
agent. Triptans can be considered if there are features of migraine.
Dizziness can be treated with physical therapy. Meclizine should
be reserved only for symptoms that are severe enough to impair
activities of daily function. Insomnia can be treated with proper
sleep hygiene. A sedative can be used acutely and should be
TABLE 117-1  GLASGOW COMA SCORE (GCS)
BEST EYE BEST VERBAL BEST MOTOR
RESPONSE RESPONSE RESPONSE
1 = No eye opening 1 = No verbal response 1 = No motor response
2 = Eye opening to pain 2 = Incomprehensible 2 = Extension to pain
sounds
3 = Eye opening to 3 = Inappropriate 3 = Flexion to pain
verbal command words
4 = Eyes open 4 = Confused 4 = Withdrawal from
spontaneously pain
5 = Orientated 5 = Localizing pain
6 = Obeys commands
GCS, Eye Response + Verbal Response + Motor Response.
 Chapter 117  Traumatic Brain Injury and Spinal Cord Injury 1047

limited to non-benzodiazepine agents such as zolpidem. Visual should be done as soon as possible to identify lesions that will
and auditory symptoms should be evaluated by appropriate require surgery and to determine the extent of injury. ss

medical specialists. If ICP remains poorly controlled, one can consider adminis-
The patient is able to return to play or work after at least 24 tering an intravenous bolus of 23% hypertonic saline (50 mL)
hours of recovery and when cleared to do so by a neurologist or followed by continuous infusion of 2% or 3% hypertonic saline
clinical practitioner experienced in the management of concus- (75-125 mL/hr) through a central venous catheter. If these inter-
sion. In many states statutes specify these requirements. In ventions are unsuccessful, pharmacological coma or surgical
general, the patient is able to return to play when symptoms no decompression should be considered. Pharmacological coma can
longer require treatment. At this point, many practitioners will be induced with pentobarbital. This is given as a loading dose of
subject the patient to provocative testing such as performing 5 mg/kg intravenously, followed by an infusion of 1-3 mg/kg/hr.
exertion (e.g., running) followed by cognitive testing. If this does Alternatively, propofol can be used, which is administered as a
not cause symptoms to recur and the patient performs well cog- loading dose of 2mg/kg intravenously, followed by an infusion
nitively, then he or she is allowed to return to full activity. up to 200 µg/min. Continuous EEG monitoring is helpful as the
For moderate to severe TBI the initial care goals are the “ABCs” limit of drug-induced coma is achieving ICP control or cerebral
of airway, breathing, and circulation. Next is “D” for disability electrical burst-suppression. Persistently elevated ICP after all
(neurologic). Every patient should undergo a detailed neurologic these efforts is ominous. Consideration should be given to frontal
examination to ascertain the level of neurologic disability. An or temporal lobe decompression and hemicraniectomy.
initial Glasgow Coma Score (GCS) should be assigned to each To meet CPP goals, patients must first be adequately hydrated.
patient. The GCS (Table 117-2) categorizes patients with TBI The goal of TBI fluid management is to increase the osmolar
and provides a quantifiable measure of impairment. gradient between systemic vasculature and brain. For this
Patients with severe TBI are those who present with GCS purpose, hyperosmolar intravenous solutions are used, such as
scores of eight or less. To optimize outcome, medical manage- normal saline. Other options are hypertonic saline (e.g., 3%
ment should adhere to currently accepted clinical guidelines such sodium solutions). If meeting CPP goals is difficult with intrave-
as the Brain Trauma Foundation “Clinical Guidelines for Severe nous fluids alone, vasoactive pharmacologic agents such as nor-
TBI.” An important early intervention is airway protection, epinephrine and phenylephrine can be administered. These two
usually by endotracheal intubation. If elevated intracranial pres- agents are preferred because they are considered to have the least
sure (ICP) is suspected, elevate the patient’s head to 30o and keep effect on cerebral vasomotor tone. Barbiturates and propofol are
it midline, ideally with a rigid neck collar (at least until the cervi- myocardial depressants, therefore aggressive cardiovascular man-
cal spine can be evaluated for stability). Mannitol should be given agement will probably be necessary when pharmacological coma
intravenously at a dose of 0.5-1.0 gm/kg. Hyperventilation may is induced.
also be used with a goal of pCO2 34-36 mm Hg. ICP should be Agitation can be treated with lorazepam or haloperidol. If
kept less than 20 mm Hg with the cerebral perfusion pressure inadequate, then infusions of midazolam or propofol may be
(CPP) greater than 60 mm Hg. A head CT without contrast used. Pain should be controlled: acetaminophen and nonsteroi-
dal anti-inflammatory agents are adequate for mild discomfort;
however, for moderate to severe pain, narcotic analgesics such as
fentanyl or morphine should be used. A benefit of opioids is that
TABLE 117-2  AMERICAN ACADEMY OF NEUROLOGY they can be reversed by naloxone to allow reassessment of neu-
CONCUSSION MANAGEMENT rologic status.
GRADE 2 Hypoxia, seizures, and fever must be avoided. Maintaining
GRADE 1 (MILD) (MODERATE) GRADE 3 (SEVERE) pO2 at approximately 100 mm Hg is sufficient. Phenytoin is
Remove from duty/ Remove from duty for Take to emergency administered for the first 7 days after injury because it will reduce
work/play the rest of the day department early onset seizures. After 7 days it should be stopped. It can be
Examine immediately Examine frequently for Neurologic evaluation,
and at 5-minute signs of CNS including appropriate
restarted if seizures recur. Fever should be reduced with anti-
intervals deterioration neuroimaging pyretics such as acetaminophen, using a cooling blanket if
May return to duty/ Physician’s neuro exam Consider hospital needed. Other important management considerations include
work/play if clear ASAP (within 24 admission
within 15 minutes hours)
prevention of gastric stress ulcer, deep vein thrombosis (DVT),
Return to duty/work/ and decubitus ulcers. Feeding should be instituted as soon as
play after 1 full practical to maintain nutrition.
asymptomatic week
(after being cleared by
After the initial few hours, efforts should be made to reduce
physician) hyperventilation, which is indicated only for initial emergency
GRADE OF CONCUSSION RETURN TO PLAY/WORK management. After 12 hours, metabolic compensation negates
Grade 1 (first) 15 minutes
the ameliorative effects of respiratory alkalosis caused by the
Grade 1 (second injury) 1 week hypocapnic state induced by hyperventilation.
Grade 2 (first) 1 week Repeated neurologic examination and continuous ICP and
Grade 2 (second injury) 2 weeks
Grade 3 (first) (brief LOC) 1 week
CPP measurement are indicated. Generally, the peak period of
Grade 3 (first) (long LOC) 2 weeks cerebral edema is from 48 to 96 hours after TBI. Thereafter, the
Grade 3 (second injury) 1 month edema resolves spontaneously and clinical improvement should
Grade 3 (third injury) Consult a neurologist
follow.
 1048 Section XVI  Neurologic Disease
A complication of TBI is post-concussive syndrome (PCS).
ss Diagnosis can be made using the Post-Concussion Symptom
Scale (PCSS) and Graded Symptom Checklist (GSC). The most
common symptoms of PCS are headache, difficulty concentrat-
ing, appetite changes, sleep abnormalities, and irritability. PCS
has a variable presentation and duration depending on the patient
and the severity of TBI. In general, PCS lasts for a few weeks
post-injury. However, uncommonly, it can persist beyond a year
or more. Treatment is symptomatic. For headache, nonsteroidal
anti-inflammatory agents, migraine drugs, and biofeedback can
be effective. For cognitive dysfunction, neuropsychological
testing may be helpful in determining appropriate intervention,
which may include cognitive behavior therapy.
Traumatic Spinal Cord Injury (TSCI)
The emergency management of traumatic injury to the spinal
cord has greatly improved with adherence to the American Asso-
ciation of Neurological Surgeons “Guidelines for the Manage-
ment of Cervical Spine and Spinal Cord Injuries.” Therapy begins
with the “ABC” of airway, breathing, and circulation. A secure
airway is absolutely vital. For patients suffering from high cervical
lesions, spontaneous ventilation will be lost. Lesions below C5
may also impair ventilatory capability. If the airway or ventilatory
efforts are compromised, emergency intubation is required. For
a patient in whom cervical spine trauma has not been assessed,
the preferred method is nasotracheal intubation using fiberoptic
guidance. Other approaches are nasotracheal (blind) or orotra-
cheal intubation, provided that cervical spine alignment is main-
tained by traction.
Maintaining an intravasacular volume is essential in TSCI.
Hypotension may be due to either neurogenic shock or hypovo-
lemia. For neurogenic shock, vasopressive pharmacologic agents,
such as phenylephrine, may be needed. If tachycardia is present,
then hypovolemia is the more likely etiology and fluid resuscita-
tion with normal saline is the appropriate initial management.
After addressing the “ABC’s,” a neurologic history and exami-
nation should be obtained. An accompanying TBI needs be con-
sidered. Up to 50% of TSCI patients have an associated TBI.
Neuroimaging is often indicated, but not all patients need radio-
graphic study. A normal neurologic assessment obviates the need
for imaging studies; however, a complaint of burning hands or of
pain over the spine, numbness, tingling, or weakness indicates
possible spinal cord injury. The time of injury should be recorded
as accurately as possible. A detailed neurologic examination is
needed to identify the level of the injury, the completeness of any
deficits, and to document the degree of neurologic dysfunction
at the earliest time possible. The level of the injury is the lowest
spinal cord segment with intact motor and sensory function. The
prognosis for neurologic improvement is better if the lesion is
incomplete than complete. Following the acute injury, serial
examinations must be made frequently.
If spinal cord injury is suspected, the patient should be imme-
diately and appropriately immobilized with a rigid collar or back
board, or both. Radiologic evaluation should begin with plain
x-rays of the bony spine. Abnormalities on x-rays should lead
to further neuroimaging. Bony vertebrae should be examined
with CT and the spinal cord with MRI. Intervertebral and para-
vertebral soft tissue are best studied with MRI. A chest x-ray
should also be obtained in order to visualize the lower cervical
and thoracic vertebrae. Presence of a pleural effusion in the
setting of a possible thoracic spine injury suggests a hemothorax.
If the C-spine x-rays are normal but the patient complains of
neck pain, then ligamentous injury may be present. Ligamentous
injury is evaluated by flexion-extension C-spine x-rays. However,
in the acute period, pain may prevent an adequate study. These
patients should be kept in a rigid cervical collar for a few days
until the pain and neck muscle spasm resolves. At that time,
imaging may be performed. If abnormal, the patient will need
surgical evaluation.
The use of methylprednisolone for TSCI is no longer
advocated.
Spinal Cord Syndromes
There are three main spinal cord syndromes: Anterior cord,
Brown-Sequard, and Central cord. Anterior cord syndrome is
associated with deficits referable to bilateral anterior and lateral
spinal cord columns. There is loss of touch sensation, pain, tem-
perature, and motor function below the level of the lesion. The
posterior column functions of proprioception and vibratory sen-
sation remain intact. In Brown-Sequard syndrome, the deficits
are due to injury to a lateral half of the cord. There is functional
loss of ipsilateral motor, touch, proprioception and vibration, and
contralateral pain and temperature. Central cord results in a “man
in a barrel” syndrome: motor paralysis of both upper extremities
with sparing of the lower extremities. Weakness is greater proxi-
mally than distally. Pain and temperature sensations are generally
reduced, but proprioception and vibration are spared.
Spinal Shock
Spinal shock may occur after acute injury causing a temporary
loss of spinal reflexes below the level of injury. Neurologic exami-
nation will reveal loss of muscle stretch reflexes, bulbocavernosus
reflex, and the anal wink. In high cervical injuries, the lower
reflexes (bulbocavernosus and anal wink) may be preserved.
There may also be the “Schiff-Sherrington” phenomenon, in
which reflexes are affected above the level of injury. Additionally,
there may be loss of autonomic reflexes leading to neurogenic
shock and ileus and urinary retention.
Acute and Subacute Management
In the intensive care unit, the patient will need continued treat-
ment. Once methylprednisolone therapy has completed, there is
no need for further steroid use. TSCI patients require close car-
diovascular and respiratory monitoring. Other issues are genito-
urinary, bowel, infectious disease, nutrition, skin, and prophylaxis
against ulcers and deep vein thrombosis formation.
Patients suffering from spinal cord injury are at risk for neuro-
genic shock and dysautonomia with resulting peripheral vasodi-
lation and hypotension. Lesions at T3 or above compromise
sympathetic tone with hypotension accompanied by bradycar-
dia: the classic neurogenic shock triad of bradycardia, hypoten-
sion, and peripheral vasodilation.
Dysautonomia is treated by ensuring adequate circulating
volume. The goal is to fluid resuscitate to a euvolemic state. Blood
can be used if the patient is anemic (i.e., hematocrit less than
30%). If blood is not required, then either colloid (e.g., albumin
 Chapter 117  Traumatic Brain Injury and Spinal Cord Injury 1049
solutions) or crystalloid (e.g., normal saline) may be used.
Central venous pressure (CVP) should be maintained at
4-6 mm Hg. Hypervolemia should be avoided because it will
exacerbate peripheral edema. Once an adequate circulating
volume has been achieved, vasopressive agents can be used, (e.g.,
phenylephrine, norepinephine, or dopamine). The mean arterial
pressure (MAP) should be 85 mm Hg or greater. Symptomatic
bradycardia can be treated with atropine.
Patients with TSCI are at risk for ventilatory compromise.
Patients whose injuries are at C5 or higher typically require
mechanical ventilation with an appropriate tidal volume
(6-10 mL/kg), FiO2 and mandatory machine driven rate. The
FiO2 inspired oxygen concentration should give a pO2 between
80-100 mm Hg. The rate should be set to give a pCO2 of
40 mm Hg. Positive end-expiratory pressure (PEEP) should also
be used to minimize atelectasis. If the patient does not show signs
of ventilatory recovery within 2 weeks of intubation, a tracheos-
tomy should be considered. Lesions below C5 may also be associ-
ated with inadequate spontaneous ventilation. Mid-cervical
lesions may be associated with intact but compromised dia-
phragm function. If suspected, a “sniff ” test under fluoroscopy
can be performed to determine if both hemidiaphragms are func-
tioning properly. If not, intubation/tracheostomy with volume-
controlled ventilation may be needed. If intact, then pressure
support (PS) ventilation sufficient to maintain an appropriate
tidal volume with oxygenation and PEEP should be set as
described above.
Patients with cervical lesions at C6 and below, including
the thoracic cord, do not require mechanical ventilation.
However, their ventilatory effort may be inadequate because
the thoracic cord innervates intercostal muscles, which are
accessory muscles of respiration. Such patients have decreased
cough and inability to increase ventilation when needed, leading
to atelectasis and inability to clear secretions, which can cause
pneumonia. Such patients need assistance with clearing their
airway: chest percussion, suctioning, and encouragement in
coughing.
Thromboembolic disease is a leading cause of morbidity and
mortality in patients with TSCI: up to 80% will develop DVT
without prophylaxis. All patients with TSCI should receive both
anticoagulation and have mechanical compression devices
applied to their legs. Sequential compression devices (SCD) or
compression stockings should be placed as soon as possible.
When hemostasis is assured, low molecular weight heparin
(LMWH) should be initiated. Unfractionated heparin may also
be used in conjunction with SCD but LMWH is preferred. An
inferior vena cava filter may be placed in those patients in whom
anticoagulation therapy is contraindicated, but it should not be
the primary means of preventing DVT.
Mid-low thoracic spinal cord injury can lead to ileus. A naso-
gastric tube should be placed to decompress the stomach. Paren-
tal nutrition should be started as soon as possible. Enteral feeding
should be delayed until gastrointestinal motility returns, usually
between 2 to 3 weeks. Pharmacologic agents that promote motil-
ity are metoclopromide, erythromycin, and cisapride. Gastric
ulcer should be prevented with medication: H2 receptor antago-
nists, proton pump inhibitors, antacids, or sucralfate. Pancreatitis
and trauma-related bowel perforation occur: loss of abdominal
muscle tone and visceral sensation may mask usual clinical find-
ings of pain, guarding, or rigidity. ss
Bladder tone may be lost due to spinal shock. A Foley catheter
should be placed and maintained for a minimum of 5 to 7 days
to drain the bladder and to evaluate circulatory volume and renal
status. Once spinal shock resolves, autonomic dysreflexia may
occur from bladder distention: skin flushing and hypertension.
Clinical examination by palpation and percussion will reveal a
distended bladder, which can be treated with intermittent cath-
eterization or bladder training. Phenoxybenzamine may be
helpful in this condition.
Nutrition should be given. Until enteral feeding can begin,
parenteral nutrition should be used. A caloric level of 80% of the
Harris-Benedict prediction should be used for quadriplegic
patients. The full Harris-Benedict predicted amount should be
used for patients with thoracic spine injuries and below. Skin care
is essential to prevent decubitus ulcers. Mechanical kinetic beds,
regular log rolling (every 2 hours), and padded orthocics are all
useful in minimize this complication.
Orthotics, physical therapy, and occupational therapy (for cer-
vical cord injury) are useful. Therapy should begin as soon as the
spine is stabilized with the goal of minimizing contractures and
beginning the rehabilitation. Once therapy begins, energy expen-
diture will increase requiring additional nutrition. If intermittent
compression devices need to be removed during therapy, heparin
dose may need to be increased.
  PROGNOSIS
Tramatic Brain Injury (TBI)
The most useful prognostic indicator following TBI is the neuro-
logic examination at presentation. Clearly, the better the neuro-
logic examination, the higher the likelihood of improved recovery.
The initial GCS score is a very reliable prognostic indicator. The
lower the initial GCS score, the less likely a patient will have
meaningful neurologic or functional recovery.
Tramatic Spinal Cord Injury (TSCI)
For TSCI, the completeness of the injury is the most useful prog-
nosticator. The American Spine Injury Association Impairment
Scale grades spinal cord injury on the basis of completeness
(Table 117-3). A grade “A” or complete motor and sensory deficit
below the lesion is the most ominous prognosis. If such a lesion
persists longer than 24 hours, there is little reasonable likelihood
of meaningful recovery. On the other hand, partial injuries, even
severe, have substantial probability of recovery.
  FUTURE
TBI and TSCI are serious neurologic conditions with sig­nificant
implications on society. Prevention remains the most effective
way of reducing the incidences of these diseases. Introduction
of practice guidelines have contributed to improved outcome
from TBI and TSCI. Sadly, morbidity remains a serious problem.
Medical management is largely confined to supportive efforts
primarily directed towards minimizing secondary injury, opti-
mizing perfusion and oxygenation, and preventing nonneuro-
logic morbidity. Surgical intervention helps restore structural
stability, minimize further injury, and reduce the lesion. However
 1050 Section XVI  Neurologic Disease

SUGGESTED READING
ss
TABLE 117-3  AMERICAN SPINAL INJURY Centers for Disease Control (CDC): State laws governing return to play following
ASSOCIATION IMPAIRMENT SCALE traumatic brain injury. Available at www.cdc.gov/concussion/policies.html.
GRADE INJURY TYPE DEFINITION Consensus Statement on TBI. American Academy of Neurology, Neurology
A Complete No motor or sensory function below the lesion 48:581–585, 1997.
B Incomplete Sensory but no motor function Cushman JG, Agarwal N, Fabian TC, et al: EAST practice management guidelines
C Incomplete Some motor strength (<3) work group: practice management guidelines for the management of mild
D Incomplete Motor strength >3 traumatic brain injury: the EAST practice management guidelines work group,
E None Sensory & motor normal J Trauma 51:1016–1026, 2001.
Giza CC, Kutcher JS, Ashwal S, et al: Summary of evidence-based guideline
update: Evaluation and management of concussion in sports: Report of
the Guideline Development Subcommittee of the American Academy of
neither reverses neuronal death nor fully prevents secondary
Neurology, Neurology 80:2250–2257, 2013.
injury processes. There are ongoing significant medical research The Brain Trauma Foundation, The Amer Assn Neurol Surg and The Congress of
efforts to improve our understanding of the pathogenesis of Neurosurgery: Guidelines for the management of severe traumatic brain injury,
these diseases and find ways to mitigate them. As new phar- J Neurotrauma 24:S1–106, 2007.
macologic, medical, and surgical approaches are introduced, VA/DoD clinical practice guidelines for the management of concussion/mild
TBI, J Rehabil Res Dev 46:CP1–68, 2009.
there will be increasing opportunities to restore these patients.
Walters BC, Hadley MN, Hurlbert RJ, et al: Guidelines for the management of
For a deeper discussion on this topic, please see Chapter acute cervical spine and spinal cord injuries: 2013 update, Neurosurgery
60(Suppl 1):82–91, 2013.
399, “Traumatic Brain Injury and Spinal Cord Injury,” in
Goldman-Cecil Medicine, 25th Edition.

  DEFINITION/EPIDEMIOLOGY
Epileptic seizures are defined as a transient occurrence of signs
and/or symptoms due to abnormal excessive or synchronous
neuronal activity in the brain. Seizures are a common sign of
brain dysfunction. A wide variety of symptoms can occur depend-
ing on the brain networks involved including involuntary
movements, abnormal sensations and behaviors, and impaired
consciousness.
Seizures often occur during the course of medical or neuro-
logical illnesses in which brain function is temporarily deranged
(symptomatic seizures) (Table 118-1). The most common sec-
ondary causes of seizures are metabolic derangements (such as
hypoglycemia or hyponatremia), intoxications (alcohol, cocaine),
acute head trauma, and hypoxic-ischemic conditions (cardiac
arrest, syncope, embolic stroke). Symptomatic seizures are
usually self-limited and recurrent seizures do not occur after the
underlying disorder is corrected. Thus, symptomatic seizures do
not constitute epilepsy.
Epilepsy is a chronic disease of the brain characterized by an
enduring predisposition to generate epileptic seizures. The diag-
nosis of epilepsy requires the occurrence of at least one epileptic
seizure, but typically is not applied unless there are at least two
unprovoked seizures occurring more than 24 hours apart or one
unprovoked seizure and a high probability of further seizures
TABLE 118-1  CAUSES OF SYMPTOMATIC SEIZURES*
ACUTE ELECTROLYTE DISORDERS
Acute hyponatremia (<120 mEq/L)
Acute hypernatremia (>155 mEq/L)
Hyperosmolality (>310 mOsm/L)
Hypocalcemia (<7 mg/dL)
Hypoglycemia (<30 mg/dL)
DRUGS
Quinolone antibiotics, isoniazid, penicillins (in renal insufficiency)
Theophylline, aminophylline, ephedrine, phenylpropanolamine, terbutaline
Tramadol, lidocaine, meperidine (in renal insufficiency)
Tricyclic antidepressants
Cyclosporine
Cocaine (crack), phencyclidine, amphetamines; alcohol withdrawal
CENTRAL NERVOUS SYSTEM DISEASE
Hypertensive encephalopathy, eclampsia
Hepatic and uremic encephalopathy
Sickle cell disease, thrombotic thrombocytopenic purpura
Systemic lupus erythematosus
Meningitis, encephalitis, brain abscess
Acute head trauma, stroke, brain tumor
*The metabolic derangements and drugs listed in Table 118-1 also lower the seizure
threshold in people with epilepsy.
118 
Epilepsy ss
Michel J. Berg
based on additional data such as an epileptiform EEG. The phrase
seizure disorder is synonymous with the word, epilepsy. Individu-
als with epilepsy have increased seizure susceptibility (lowered
seizure threshold). Genetic factors and prior brain injury (from
a multitude of causes) are the major contributors to this suscep-
tibility. The diagnosis of epilepsy encompasses the neurobiologi-
cal, cognitive, psychological, and social consequences of this
condition.
There are many different epilepsy syndromes (the epilepsies)
with the three major categories being focal epilepsy, idiopathic
(genetic) generalized epilepsy, and symptomatic generalized
epilepsy (discussed later). Classification of the epilepsy syn-
drome depends on a number of factors, including the seizure
type, etiology, genetic mutations, neuroimaging, and response
to therapy.
The care of people with seizures suffers from imprecise termi-
nology usage. The word “epilepsy” is a noun, as in, “a person with
epilepsy.” The word “epileptic” is an adjective, as in, “an epileptic
seizure.” An individual with epilepsy should not be labeled as an
“epileptic.” That is, from the psychosocial perspective, people
with epilepsy are more than just an enduring predisposition to
seizures and their consequences. Epilepsy is thought of as a dis-
order, but, to emphasize the impact of the recurrent seizures,
epilepsy should be considered a disease. Epileptic seizures, also
referred to as electrical seizures, are distinct from nonepileptic
(or nonelectrical) seizures, which have a psychological basis and
are best referred to as psychogenic nonepileptic attacks (less
appropriately termed pseudoseizures; see later). Most seizures in
someone with epilepsy occur in an unpredictable fashion. It is
this unpredictable timing that results in the major negative
impact of epilepsy on quality of life. If functionally impairing
seizures occur during waking hours (diurnal seizures) then activ-
ity restrictions are required, including restriction from driving,
operating heavy machinery, climbing heights, and unobserved
swimming or bathing (showering with a good drain should be
advised). These activity restrictions lead to loss of independence.
The psychological impact of having intermittent involuntary loss
of body control and the dependency imposed by the activity
restrictions are major contributors to the increased incidence of
comorbid depression in people with epilepsy (up to 50%).
In many people with epilepsy there are more seizures during
sleep due to increased synchronization of neuronal activity. Sei-
zures that occur exclusively in sleep constitute nocturnal epilepsy.
In women with epilepsy (WWE), seizures sometimes occur more
often during the week around menses or at ovulation (catamenial
epilepsy). Sleep deprivation, alcohol consumption, infectious ill-
nesses, certain medications, and severe emotional stressors can
1051
 1052 Section XVI  Neurologic Disease
further lower the seizure threshold and are associated with more
ss seizures in people with epilepsy (Table 118-1).
Seizures can occur at any time. Ten percent of the population
in developed countries has a seizure at some time during their
life. In contrast, 0.7% to 1% has current epilepsy (prevalence) and
3% to 4% has epilepsy at some time during their life (lifetime
prevalence). In the United States, there are approximately
125,000 new cases of epilepsy diagnosed each year (incidence).
The incidence and prevalence are biphasic, with epilepsy being
more common in childhood (primarily because of perinatal
injury, infections, and genetic factors) and in old age (because of
stroke, tumors, and dementia) (Fig. 118-1). In developing coun-
tries the frequency of epilepsy is higher because of factors
such as increased brain infections with organisms such as
cysticercosis.
  PATHOLOGY
Prior to the 1990s, the underlying cause was not determined in
most people with epilepsy. The advent of MRI and, more recently,
genetic analysis has substantially improved our ability to identify
the cause of many types of epilepsy. About 70% of adults and 40%
of children with new-onset epilepsy have partial (focal) seizures
implying a cerebral injury or lesion. The most common lesions
are hippocampal sclerosis, neuronal and glial tumors, vascular
malformations, neuronal migration disorders (e.g., cortical
dysplasia), hamartomas, encephalitis, autoimmunity, cerebral
trauma, embolic stroke, and hemorrhage. Hippocampal sclerosis
Congenital 20.0%
Trauma 4.7%
Vascular 1.5% Idiopathic/
Neoplastic 1.5% cryptogenic
Infection 4.0% 67.6%
Degenerative 0.7%
CHILDREN
Congenital 3.3%
Trauma 9.9%
Vascular 15.5%
Idiopathic/
cryptogenic
55.2%
Neoplastic 10.5%
Infection 2.2%
Degenerative 3.3%
ADULTS
FIGURE 118-1  Etiology of epilepsy, according to age, in all newly
diagnosed cases in Rochester, Minnesota, 1935–1984. (Modified from
Hauser WA, Annegers JF, Kurland LT: Incidence of epilepsy and unpro-
voked seizures in Rochester, Minnesota: 1935–1984, Epilepsia 34:453–
468, 1993.)
(sometimes referred to as mesial temporal sclerosis) is particu-
larly common and can occur in isolation or secondary to another
epileptogenic lesion (dual pathology). It consists of loss of pyra-
midal cells and gliosis in several hippocampal subfields. Hippo-
campal sclerosis is associated with temporal lobe epilepsy and
short-term memory dysfunction. Not all patients with cerebral
lesions develop epilepsy; how or why a particular lesion becomes
epileptogenic is poorly understood.
Hereditary influences have long been associated with epilepsy.
During the past several decades, a number of gene mutations
have been associated with specific epilepsy syndromes, both focal
and generalized. Many of the mutations occur in ion channels,
which, not surprisingly, lead to neuronal dysfunction and epi-
lepsy. Two important phenotypic examples of channelopathies
are genetic (generalized) epilepsy with febrile seizures plus
(GEFS+) and Dravet syndrome (also known as severe myoclonic
epilepsy of infancy). GEFS+ is typically associated with a partial
loss of function mutation in the voltage-gated sodium channel
gene, SCN1A, whereas a complete loss of function mutation in
the same gene results in Dravet syndrome. Less commonly, muta-
tions in other ion channel genes can lead to the same phenotypic
expressions. GEFS+ can begin at any age, although is usually
evident in childhood, with various seizure types in different
affected family members; some may have febrile seizures after age
6 years (febrile seizures plus), whereas others may have myo-
clonic, absence, or partial seizures. In contrast, Dravet syndrome
typically presents at 6 to 8 months of age with prolonged hemi-
clonic seizures associated with an intercurrent fever. Adults with
Dravet syndrome are typically mentally retarded with spasticity
or ataxia, gait dysfunction, and occasion nocturnal clonic seizures
as well as other seizure types. Recognition of Dravet syndrome
is important because certain antiepileptic drugs (AEDs) can
cause permanent clinical deterioration (e.g., lamotrigine, phe-
nytoin), whereas others are particularly beneficial (e.g., topira-
mate, levetiracetam, valproate, benzodiazepines).
  CLINICAL PRESENTATION
Classification and Clinical Manifestations
Seizures are classified by their clinical symptoms and signs. The
manifestations of a seizure depend on whether its onset includes
most or only a part of the cerebral cortex, on the functions of the
involved cortical areas, and on the subsequent pattern of spread
within the brain. Seizures are of two broad types: those with
onset limited to a specific region of cerebral cortex (partial or
focal seizures) and those with onset that involves the cerebral
cortex diffusely (generalized seizures). Seizures are dynamic with
an evolving electrical discharge. Thus, highly focal (simple partial)
seizures can progress into more widespread (complex partial) sei-
zures and partial seizures can evolve into secondarily generalized
tonic-clonic seizures.
In an individual, seizures are typically stereotyped, although a
person can have more than one seizure type and a specific seizure
type can have varying intensities. The behaviors that occur during
the seizure are termed the seizure semiology. The seizure itself is
referred to as the ictus and the period of time during which the
seizure occurs is termed the ictal phase. The time after the seizure,
until the patient is fully recovered, is the postictal phase and the
 Chapter 118  Epilepsy 1053

time between seizures (which can be seconds to years) is the

interictal phase. TABLE 118-2  LOCALIZATION OF SEIZURES BY ss

The epilepsy syndromes can be divided into three major catego- SYMPTOMS AND ICTAL
ries: focal epilepsy, idiopathic (primary) generalized epilepsy, and MANIFESTATIONS
symptomatic generalized epilepsy. This classification is based on the LOCUS MANIFESTATION
widely used scheme of the International League against Epilepsy. TEMPORAL LOBE
This scheme is undergoing revision. In the future, the epilepsies Uncus/amygdala Foul odor
may be classified as genetic, structural/metabolic, and unknown Middle/inferior temporal gyrus Visual changes: micropsia, macropsia
Parahippocampal-hippocampal area Déjà vu; jamais vu
cause. The current classification of the epilepsy syndromes Amygdala-septal area Fear, pleasure, anger, dreamy
closely follows the classification of the seizures. In the following sensation
paragraphs, the specific seizure types are described followed by a Auditory association cortex Voices, music
Insular, anterior temporal cortex Lip smacking, drooling, abdominal
description of the attendant epilepsy syndromes. symptoms, cardiac arrhythmia
FRONTAL LOBE
Partial Seizures (Seizure Types)
Motor cortex Contralateral clonic movements of
In partial seizures (also known as localization-related or focal sei- face, fingers, hand, foot
zures) a localized region of the brain has abnormal neurons that Premotor cortex Contralateral arm extension,
intermittently fire hypersynchronously, recruiting the surround- hypermotor behaviors
Language areas Speech arrest, aphasia
ing, otherwise normal neurons, generating a seizure. If the Lateral cortex Contralateral eye deviation
ab­normal neuronal firing is confined, there may be no clinical Bifrontal Absence-like seizure
manifestation and the event, which can only be detected with Parietal lobe cortex Sensory symptoms
Occipital lobe cortex Visual hallucinations (often in
EEG, is termed a subclinical or electrical seizure. color), teichopsias,
metamorphopsias
Simple Partial Seizures
If the electrical discharge involves a clinically functional small seizure characteristically reflect the location of seizure onset
area, a simple partial seizure (SPS) occurs and manifests as a (Table 118-2). The location of the focus is important because it
symptom without impairment of consciousness. The symptom can predict the nature of the pathology and directs diagnostic
may be a sensation, autonomic function (e.g., nausea or another testing. Both medical and surgical treatment is determined, in
epigastric sensation), abnormal thought (e.g., fear, dèjá vu), or part, by focus location.
involuntary movement. An SPS is commonly called an aura and Psychomotor, temporal lobe, and limbic seizures are terms that
can serve as a warning that a more intense seizure is about to have been used in the past to describe a variety of ictal behaviors
occur. Auras occur in about 60% of patients with focal epilepsy. now classified as CPSs, but they are not synonymous. Not all
During an SPS the patient can interact normally with their complex partial seizures arise from the temporal lobe, nor do all
environment except for limitations imposed by the seizure itself involve the limbic system. Similarly, certain temporal lobe and
on specific functions. Thus, SPSs are divided into SPS without limbic phenomena may not be associated with the alteration in
impairment, which do not interfere with function (e.g., just an awareness that is required to term it a CPS.
internal sensation) and SPS with impairment, which can interfere
with function (e.g., a jerking limb that would disrupt the ability Secondarily Generalized Convulsive Seizures
to drive safely). A focal-onset seizure that spreads throughout the brain results in
The motor signs of a seizure can be clonic (rhythmic jerking) a secondarily generalized seizure. Typically there is a tonic phase
or tonic (stiffening) movements of a discrete body part. An SPS that consists of extensor posturing lasting 20 to 60 seconds fol-
restricted to the precentral (Rolandic) gyrus that spreads to lowed by progressively longer periods of inhibition manifesting
involve adjacent areas of the primary motor cortex, is expressed as a clonic phase that lasts up to another minute: hence the
as clonic movements that progress in an orderly sequence (Jack- descriptive name generalized tonic-clonic (GTC) seizure. The
sonian march) that reflects the motor cortex homunculus topo- terms convulsion, GTC, grand-mal, and major-motor seizure are
graphic organization (e.g., mouth to hand to arm to leg). often used interchangeably, although GTC is a specific phenom-
enological description of the behavior. In some patients, a few
Complex Partial Seizures clonic jerks precede the tonic-clonic sequence; in others, only a
A complex partial seizure (CPS) is a focal-onset seizure with tonic or clonic phase is present.
impairment of consciousness. The degree of consciousness As a partial seizure transitions into a secondarily generalized
impairment ranges from minimal to complete unresponsiveness. convulsion the arm contralateral to the seizure focus may extend
The patient’s eyes are almost always open during the ictus indicat- first, while the ipsilateral arm is flexed at the elbow. This is termed
ing an awake state (albeit impaired). The eyes may close after the the figure-4 sign and is useful for lateralizing the seizure focus. A
seizure ends and the patient typically experiences some degree loud tonic-cry may occur at the onset of a convulsion as air is
of postictal confusion, fatigue, and sometimes headache (with forcibly expelled through tightly contracted vocal cords. The eyes
the head pain often ipsilateral to the seizure focus due to the are open and commonly described to roll upward. During a con-
increased metabolic demand). An CPS typically lasts 1 to 3 vulsion, breathing stops and cyanosis may develop. Foaming
minutes with a postictal state of a few minutes to hours. at the mouth may be present. Oral trauma, especially biting
The specific signs and symptoms that occur during a partial the tongue, is typical. Urinary incontinence is common. Fecal
 1054 Section XVI  Neurologic Disease
incontinence is rare. First aid involves turning the patient onto a
ss side as the seizure ends to allow the saliva to drool out the mouth,
decreasing the likelihood of aspiration. Witnesses commonly
describe a GTC as lasting 5 to 10 minutes or longer; however,
the GTC phase rarely lasts longer than 2 minutes. The postictal
phase is marked by transient deep stupor, followed in 15 to 30
minutes by a lethargic, confused state, sometimes with automatic
behaviors. As recovery progresses, many patients complain of
headache, muscle soreness, mental dulling, lack of energy, or
mood changes lasting for hours to days. Convulsions result in a
number of striking, but transient, physiologic changes, including
hypoxemia, lactic acidosis, elevated catecholamine levels, and
increased serum concentrations of creatine kinase, prolactin, cor-
ticotropin, and cortisol. Complications include oral trauma, ver-
tebral compression fractures, shoulder dislocation, aspiration
pneumonia, and, very rarely, sudden death, which may be related
to acute pulmonary edema, cardiac arrhythmia, or suffocation.
Sudden Unexplained Death in Epilepsy (SUDEP) has garnered
increased attention during the past decade, but remains poorly
understood.
Partial seizures of all intensities may be followed by a transient
neurological abnormality reflecting postictal depression of the
epileptogenic cortical area. Thus, focal weakness may follow a
partial motor seizure or numbness a sensory seizure. These
reversible neurological deficits are referred to as Todd’s paralysis
and last minutes to hours, rarely more than 48 hours. Examina-
tion of a patient immediately after a seizure may show transient
focal abnormalities that indicate the site or at least the side of
seizure origin.
Focal Epilepsy (Epilepsy Syndrome)
Focal (localization-related, partial) epilepsy is characterized by
recurrent partial seizures. It is divided into two main groups,
idiopathic and symptomatic.
Idiopathic Focal Epilepsy
The idiopathic focal epilepsies are thought to be due to subtle
genetic developmental anomalies that manifest in childhood and
remit during puberty. There are several syndromes including
occipital, frontal, and the most common type, benign epilepsy with
central midtemporal spikes (BECTS), which is also known as
benign Rolandic epilepsy (BRE). BECTS represents about 15% of
all pediatric epilepsies. In BECTS, seizures usually begin between
the ages of 3 and 12 years in an otherwise normal child. The
seizures consist of brief simple partial hemifacial motor or
sensory events. There is typically twitching of one side of the face,
speech arrest, drooling, and paresthesias of the face, gums,
tongue, or inner cheeks. These signs may be so minor that they
escape notice, although the affected child often points to his face
and goes to a parent and holds on until it is over; the child then
quickly resumes normal activity. Seizures may progress to include
hemiclonic movements or hemitonic posturing. Secondarily gen-
eralized tonic-clonic seizures occasionally occur, usually during
sleep. The parents may report only the convulsions; the focal
signature can be missed unless the child is carefully questioned.
The EEG reveals distinctive, stereotyped epileptiform discharges
over the central and midtemporal regions that are dramatically
activated by sleep with a normal underlying background.
Prognosis for BECTS is invariably good, as it is for most of the
other benign focal epilepsy syndromes; the seizures disappear
and the EEG normalizes by mid to late adolescence. Outcome is
not affected by treatment, but AEDs prevent recurrent attacks.
Symptomatic Focal Epilepsy
The symptomatic focal epilepsies are the most common type of
epilepsy and are classified based on the cerebral lobe involved
during the initial phase of the seizure. Temporal lobe epilepsy is
the most frequent, followed by frontal, with rarer cases of parietal
and occipital. Although sometimes not identified in life, all cases
of symptomatic focal epilepsy have an underlying focal abnor-
mality in the cerebral cortex such as a scar, malformation, growth,
or abnormal gene expression. An individual patient with symp-
tomatic focal epilepsy usually has a single focus. However, the
focus can involve a large, multilobar circuit. Some patients have
multiple foci, each with different seizure manifestations.
Temporal lobe epilepsy (TLE) is the most common epilepsy
syndrome of adults, accounting for at least 40% of epilepsy cases.
Habitual seizures typically begin in childhood or adolescence
although onset in adulthood occurs. There may be a history of
childhood febrile seizures. Most patients have complex partial
seizures, some of which secondarily generalize. Medial temporal
lobe seizures involve the hippocampal and amygdalar areas. A
rising epigastric sensation or vague cephalic sensation is the most
common aura symptom. Less frequently, the classical symptom
of a foul smell, déjà vu, or other odd thinking occurs. Olfactory
auras are referred to as uncinate seizures because of their origin in
or near the uncus of the medial temporal lobe. In lateral (neocorti-
cal) temporal lobe seizures language impairment (dominant hemi-
sphere), recurring vocalizations (nondominant hemisphere), eye
blinking, or formed visual or auditory hallucinations can occur.
As a temporal lobe seizure spreads to involve the dominant tem-
poral lobe or bilateral temporal lobe structures, including the
limbic system, the seizure becomes complex. A blank stare is
often described by witnesses. Automatic motor behaviors, termed
automatisms, are common in seizures that involve the limbic
system (usually in the temporal lobe). Automatisms include oro-
alimentary signs (e.g., lip-smacking, repetitive swallowing) and
repetitive hand movements (manual automatisms).
Frontal lobe epilepsy (FLE) can be difficult to diagnose because
the scalp EEG may be normal or not reveal a classic epileptic
discharge, even during seizures. Depending on the area involved
there are at least four different premotor frontal lobe seizure
semiological patterns. Supplementary motor seizures (superior
frontal gyri, posterior aspect) consist of contralateral versive
posturing of the head and arms such that a fencing posture is
assumed; the contralateral arm is extended, the head is turned
strongly to that side, and the ipsilateral arm is flexed and held
either up above the head or across the chest. Lateral frontal sei-
zures manifest as contralateral head and eye deviation. Hypermo-
tor seizures (frontal, poorly localized) can be dramatic and consist
of wild asynchronous movements and are often confused with
psychogenic nonepileptic attacks; thus, they are sometimes
termed pseudo-pseudoseizures. Almost all hypermotor seizures
last less than 40 seconds and typically occur 1 to 5 times a night
during sleep and less often during waking. Obscene verbal exple-
tives are commonly uttered loudly during hypermotor seizures.

Frontal absence seizures are rare and are due to diffuse, bisynchro-
nous frontal epileptic activity. These consist of staring and mimic
typical or atypical absence seizures (see later). Seizures arising in
the posterior frontal lobe motor cortex (precentral gyrus) are
classically clonic with a Jacksonian march.
Parietal and occipital lobe epilepsy involve sensory structures
and at least initially, have only subjective symptoms. Parietal lobe
seizures consist of somatosensory sensations or higher cognitive
function disruption. The somatosensory sensations can have a
Jacksonian march with sensory symptoms progressing along the
sensory homunculus. Occipital lobe seizures involve unformed or
poorly formed visual hallucinations that are often in color (in
contrast to the visual aura of migraine, which is black, gray, and
white). Forced eye deviation can occur with occipital seizures.
Occipital seizures can have a prolonged discharge lasting tens of
minutes that is subclinical or minimally clinical before propagat-
ing. Parietal and occipital seizures do not become complex until
propagating to the temporal lobes or limbic system. Reflex sei-
zures are precipitated by a specific stimulus, such as touch, a
musical tune, a particular movement, reading, flashing lights, or
certain complex visual images. With the exception of the photo-
sensitive response in juvenile myoclonic epilepsy (see later)
which is relatively common, reflex seizures are rare and classified
as a type of parietal or occipital lobe epilepsy because these
regions mediate sensory functions.
Posttraumatic epilepsy is a type of symptomatic focal epilepsy
distinguished by its etiology. The likelihood of developing post-
traumatic epilepsy relates directly to the severity of the head
injury. The relative risk for developing epilepsy after a penetrating
wound to the brain (e.g., bullet or shrapnel) is up to six hundred
times that in the general population. Severe closed head injuries
result in epilepsy in 20% of patients. Severe closed head injuries
are defined by the presence of an intracranial hemorrhage (sub-
dural, epidural, subarachnoid, or cerebral contusion), uncon-
sciousness or amnesia lasting more than 24 hours, or persistent
abnormalities on neurological examination, such as hemiparesis
FP1-F3
F3-C3
C3-P3
P3-O1
FZ-CZ
CZ-PZ
FP2-F4
600 µV
F4-C4
1 sec
C4-P4
Stare
P4-O2 Normal
unresponsive
EKGL-EKGR
FIGURE 118-2  Absence (petit mal) epilepsy. The electroencephalogram shows the typical pattern of generalized 3-Hz spike-wave complexes
associated with a clinical absence seizure.
Chapter 118  Epilepsy 1055
or aphasia. Although the majority of the patients with a severe
head injury develop seizures within 1 to 2 years, new-onset epi- ss
lepsy may appear after 20 years or longer. Mild closed head inju-
ries (uncomplicated brief loss of consciousness, no skull fracture,
absence of focal neurological signs, and no contusion or hema-
toma) may minimally increase the risk of seizures. Posttraumatic
epilepsy is always focal or multifocal, although only convulsions
may be clinically evident, especially with multifocal injury.
Several early seizures within a week of a head injury do not neces-
sarily predict that future epilepsy will be present.
Primary Generalized Seizures (Seizure Types)
Primary generalized seizures begin diffusely and involve both
cerebral hemispheres simultaneously from the outset. Primary
generalized seizures should be distinguished from partial seizures
because in some cases they have similar clinical features, yet
respond to different treatments.
Absence seizures (historically termed petit mal) occur mainly
in children and are characterized by sudden, momentary lapses
in awareness with staring. Sometimes rhythmic blinking occurs
with a slight loss of neck tone. Most absence seizures last less than
10 seconds. If the absence lasts longer than 20 seconds, automa-
tisms are usually present, making differentiation from partial sei-
zures based on clinical observation difficult. The EEG has a
characteristic pattern of generalized 3 per second spike and slow
waves (Fig. 118-2) during an absence seizure. Behavior and
awareness return to normal immediately after the seizure ends,
although brief confusion may be present if the surroundings
changed during the seizure. There is no postictal period and
usually no recollection that a seizure occurred.
Myoclonic seizures manifest as rapid, recurrent, brief muscle
jerks that can occur unilaterally or bilaterally, synchronously or
asynchronously, without loss of consciousness. To be a seizure,
the myoclonus must have a corresponding discharge on EEG.
Other types of myoclonus, such as benign nocturnal (hypnic)
jerks, or subcortical and spinal myoclonus related to lesions,
Normal
 1056 Section XVI  Neurologic Disease
which do not have an EEG correlate, are not considered epileptic
ss seizures. The jerks of myoclonic seizures range from small move-
ments of the face or hands to massive bilateral spasms that simul-
taneously affect the head, limbs, and trunk. Repeated myoclonic
seizures may crescendo and evolve into a generalized tonic-clonic
seizure. Although myoclonic seizures can occur at any time, clus-
ters shortly after awakening are typical.
Primary generalized tonic-clonic seizures may begin with a few
myoclonic jerks or abruptly with a tonic phase lasting 20 to 60
seconds and then a clonic phase of similar duration followed by
a postictal state. Although there are usually no focal features,
sometimes head turning occurs; this movement does not suggest
a specific localization. If the onset is missed, it is often not pos-
sible to distinguish a primary generalized convulsion from a sec-
ondarily generalized one due to focal epilepsy.
Idiopathic Generalized Epilepsy   Drop seizures can be either or both tonic and atonic. “Drop”
(Epilepsy Syndrome)
The idiopathic (primary) generalized epilepsies (IGEs) are likely
polygenic resulting from a combination of mutations and poly-
morphisms in genes involved in thalamocortical circuitry. Differ-
ent members of the same family often have dissimilar phenotypes.
However, only rare IGE genes have been identified. A person
with IGE has a 10% chance of passing the condition to a child.
Most people with IGE have normal intelligence.
Childhood absence epilepsy (CAE; pyknolepsy, petit mal epi-
lepsy) is the most common type of childhood epilepsy. It begins
between 3 to 12 years of age with a peak at 7 years. Children
with CAE have frequent absences (often hundreds per day)
and are sometimes initially thought to have attention problems
or to be daydreamers. Parents tend to report more absences at
meal times, but that is due to closer observation; the absences
are present throughout the day. One half of children with CAE
have occasional GTC seizures. CAE is self-limited and seizures
and the EEG abnormalities resolve by young adulthood. The
absence seizures of CAE are typically provoked by hyperven­
tilation, a useful procedure in the office setting and during
an EEG.
Juvenile myoclonic epilepsy (JME) begins between age 8 and
20 years old. It is characterized by clusters of myoclonic sei-
zures in the morning, starting shortly after awakening. The
clusters typically persist for several to 30 minutes. The jerks
are predominantly in the arms and last less than one second
each. Consciousness is preserved. An affected teenager often
fails to mention the morning jerks unless specifically asked.
Sometimes there is a history of throwing breakfast utensils or
toothbrushes due to the jerks. JME is often diagnosed after a
morning GTC seizure. In JME, GTC seizures are particularly
common after sleep deprivation or alcohol consumption during
the prior night. People with JME are usually photic sensitive.
That is, the seizures and EEG discharges are activated by flick-
ering lights between 5 to 20  Hz (photic-paroxysmal or photic-
convulsive response). This is a type of reflex seizure. Some
people with JME also have absence seizures. The EEG is similar
to that seen in CAE, but the generalized spike and slow wave
discharges are slightly faster (3 to 4  Hz) and often have poly-
spike components. In contrast to CAE, the seizures in JME
persist into adulthood and can be lifelong, although they lessen
with age.
Less common IGE phenotypes include juvenile absence epilepsy
(JAE) and generalized tonic-clonic seizures alone (GTCA). In JAE
the predominant seizure type is absence with onset in the teenage
years and, like JME, persists into adulthood. In GTCA the pre-
dominant seizure type is a convulsion, sometimes with a predi-
lection for the morning. Less frequent absences or myoclonic
seizures can occur in GTCA. Although onset of IGE is typically
during childhood or teenage years, rare cases occur with onset in
all ages of adulthood and are called adult absence epilepsy (AAE).
Symptomatic Generalized Seizures
(Seizure Types)
Symptomatic generalized seizures involve rapidly synchronized
abnormal brain activity across the corpus callosum or involving
midbrain structures occurring in brains with diffuse or multifocal
dysfunction usually from early life.
implies that if the patient is upright they fall with no protective
reflexes. Patients with drop seizures often suffer head injuries and
should wear a helmet except when they are directly attended by
a care provider, in a secure chair, or lying down. During a tonic
seizure, the arms abruptly thrust forward at a 90 degree angle to
the body and the entire body stiffens. Classically the fall is back-
wards. During an atonic seizure, tone is abruptly lost in the pos-
tural muscles and the patient falls forward.
Atypical absence seizures manifest as staring or mental slowing
associated with a slow generalized spike and slow wave discharge
(2.5 Hz or less) on the EEG. They may last minutes or even
hours. Fluctuating levels of awareness and gradual onset and
offset is described with atypical absences.
Symptomatic Generalized Epilepsies  
(Epilepsy Syndrome)
Symptomatic generalized epilepsies occur in people with multi-
focal or diffuse brain dysfunction from early in life. There is
usually an associated encephalopathy with some degree of devel-
opmental delay. In addition to all of the seizure types that occur
in focal and idiopathic generalized epilepsy, people with symp-
tomatic generalized epilepsies have tonic and atonic drop sei-
zures and atypical absence seizures.
There are several unrelated types of epilepsy under the Symp-
tomatic Generalized Epilepsy syndrome classification, with the
most common being the Lennox-Gastaut syndrome (LGS).
The LGS is a common form of symptomatic generalized epi-
lepsy due to diffuse or multifocal brain dysfunction. LGS pres-
ents from 2 to 10 years of age. Sixty percent have preexisting
encephalopathy and developmental delay and 20% had infantile
spasms (see later). LGS is responsible for 5% to 10% of child-
hood epilepsy. It is characterized by the combination of tonic or
atonic seizures, myoclonic seizures, and atypical absences with
the characteristic EEG pattern of 2.5 Hz or slower generalized
spike and slow waves. During sleep there are bursts of diffuse fast
rhythms on the EEG consistent with tonic or atonic seizures
often with minimal clinical expression. Tonic-clonic and partial
seizures also occur. Almost all people with LGS have develop-
mental delay with associated behavioral disorders. LGS is a
chronic condition requiring supervision; many ultimately live in
group homes. If drop seizures are present, and the patient is
ambulatory, a helmet should be prescribed for protection.

Infantile Spasms are often a precursor of the LGS, although
not formally classified as symptomatic generalized epilepsy. By
definition, infantile spasms begin during the first year of life.
They affect approximately 1 in 5000 children. The epileptic
spasms manifest as flexor or extensor tonus, myoclonus, or a
mixed pattern. The spasms last 1 to 20 seconds each and occur
in clusters for up to 20 minutes. West Syndrome is the combi-
nation of epileptic spasms, hypsarrhythmia (a chaotic, disor-
ganized epileptiform EEG pattern), and mental retardation. It
is common for the term infantile spasms to be used synony-
mously with West syndrome. Infantile spasms have a poor
prognosis with over 90% developing mental retardation and
most progressing to symptomatic generalized epilepsy; a small
percent of cryptogenic cases recover. There are many causes
of infantile spasms including perinatal insults, cerebral malfor-
mations, CNS infections, tuberous sclerosis, and inborn errors
of metabolism.
Other Seizure Conditions
Febrile seizures affect between 3% and 5% of children younger
than the age of 6 years. About 30% of children have more than
one episode; the likelihood of recurrence is greater if the first
seizure occurs before 1 year of age or there is a family history of
febrile seizures. There are a number of genes that, when mutated,
predispose to febrile seizures. Although most affected children
have no long-term consequences, febrile seizures increase the risk
of developing epilepsy later in life. This risk is low for most chil-
dren (2% to 3%), but is 10% to 15% in those who had prolonged
or focal febrile seizures (complicated febrile seizures), a family
history of nonfebrile seizures, or neurological abnormalities
before the first febrile seizure.
  DIAGNOSIS
Accurate diagnosis is the cornerstone of epilepsy treatment. The
diagnostic evaluation has three objectives: to determine that the
events are epileptic seizures, to identify a specific underlying
cause, and to establish if the seizures are symptomatic and iso-
lated or if epilepsy is present and, if so, to determine the specific
epilepsy syndrome.
History and Examination
The patient’s and witnesses’ descriptions of the events are central
to diagnosis. Extra attention should be given to exploring details
of the behavior during the seizure. The setting of the seizure
can suggest acute causes such as drug withdrawal, central nervous
system infection, trauma, or stroke. Recent-onset seizures in
an adult suggest a new intracranial lesion. A remote history
of seizures suggests epilepsy. Any focal feature before, during,
or after the seizure suggests a structural brain lesion requiring
appropriate investigation. The pattern of the seizures and the
patient’s age are often important clues to the seizure and epi-
lepsy type.
The physical examination is normal in most patients with epi-
lepsy. Examination should seek overt or subtle focal neurological
signs: slight unilateral lower facial paresis, clumsy fine finger
movements, or mild hyperreflexia. These can be present in focal
epilepsy with a contralateral seizure focus. Careful skin examina-
tion is indicated to detect features of neurocutaneous syndromes
such as a facial port-wine stain involving the upper eyelid
Chapter 118  Epilepsy 1057
in Sturge-Weber syndrome, hypopigmented macules (ash-leaf
spots), shagreen patch, facial angiofibromas in tuberous sclerosis, ss
and café-au-lait spots and axillary freckling in neurofibromatosis.
Asymmetry in the size of the hands, feet, or face signifies a long-
standing abnormality of the cerebral hemisphere contralateral to
the smaller side. Absence seizures can be triggered in untreated
children with hyperventilation for 2 to 3 minutes.
Laboratory Tests—EEG
Electroencephalography (EEG) is the most helpful diagnostic test
for seizures and epilepsy. EEG findings help establish the diagno-
sis, classify the seizures correctly, identify the epilepsy syndrome,
and make therapeutic decisions. In combination with suitable
clinical findings, epileptiform EEG discharges, termed spikes or
sharp waves, strongly support a diagnosis of epilepsy. In patients
with recurrent seizures, focal epileptiform discharges are consis-
tent with focal epilepsy, whereas generalized epileptiform activity
usually indicates a generalized form of epilepsy. However, most
EEGs are obtained between seizures, and interictal abnormalities
alone cannot prove or disprove a diagnosis of epilepsy. Up to 50%
of patients with epilepsy show epileptiform abnormalities on
their initial EEG. The chance of capturing epileptiform activity is
enhanced by sleep deprivation the night before the test so that
the patient sleeps during a portion of the EEG recording. Serial
EEGs increase the yield of positive tracings. A small proportion
of patients with epilepsy have normal interictal EEGs despite all
efforts to record an abnormality.
The interpretation of the interictal EEG is confounded by two
factors. Epileptiform discharges occur in about 2% of normal
people; many of these may be asymptomatic markers of a genetic
trait, especially in children. Also, the interpretation of the EEG is
subjective. Normal benign variant waveforms and artifacts can be
misinterpreted as epileptiform activity and erroneously consid-
ered to be evidence of seizure susceptibility.
Epilepsy can be definitively established by recording a charac-
teristic ictal discharge during a representative clinical attack. This
is uncommon during routine EEG recordings, but can be accom-
plished with inpatient video–EEG long-term monitoring performed
at many epilepsy centers throughout the world. Inpatient video-
EEG monitoring is indicated in people who have ongoing
seizures despite being treated with appropriate antiseizure medi-
cations. About one third of patients admitted for long-term moni-
toring are found to not have epilepsy; these patients have
psychogenic nonepileptic attacks. In the 25 to 30% of people
with focal epilepsy who continue to have disabling seizures
despite trials with multiple AEDs, inpatient video-EEG monitor-
ing to define the seizure focus is a critical test for determining
candidacy for resective epilepsy surgery.
Laboratory Tests—Neuroimaging
Brain MRI complements EEG findings by identifying structural
pathology that is causally related to the development of epilepsy.
MRI is the best test to detect epileptogenic cerebral lesions
including hippocampal sclerosis, neuronal migration disorders,
tumors, focal atrophy, arteriovenous malformations, and cavern-
ous malformations. It is important to obtain a complete
imaging study that includes T1-weighted, T2-weighted, and
inversion-recovery sequences in coronal and axial planes with
and without contrast. Imaging in the coronal plane perpendicular
 1058 Section XVI  Neurologic Disease
to the long axis of the hippocampus has improved detection of
ss hippocampal atrophy and hippocampal high T2 signal; findings
that correlate with the pathological finding of hippocampal scle-
rosis and an epileptogenic temporal lobe. Additional sequences
that should be routine include T2-weighted gradient-echo
(GRE), to detect hemosiderin indicating old hemorrhage associ-
ated with vascular malformations or trauma, and diffusion-
weighted images (DWI) for cytotoxic edema sometimes present
with acute cerebral injury from prolonged seizures.
An MRI should be obtained in all patients suspected of having
epilepsy except those with definite benign epilepsy with centro-
temporal spikes (BECTS) or definite idiopathic generalized epi-
lepsy (e.g., CAE and JME). CT scan with contrast is an alternate
study for those who cannot have MRI, but is not as good at
detecting small lesions. Any patient with seizures and abnormal
neurological findings or focal slow-wave abnormalities on EEG
should have neuroimaging. Repeat neuroimaging should be con-
sidered if there is an unexplained change in seizure pattern to
evaluate for a new lesion.
Positron emission tomography (PET) and single-photon
emission computed tomography (SPECT) use physiologically
active, radio-labeled tracers to image the brain’s metabolic activ-
ity (PET) or blood flow (SPECT). SPECT is most useful when
an ictal and interictal study are combined to identify an extratem-
poral seizure focus. Abnormalities on PET or SPECT can be
present when brain structure on MRI is normal.
Other Tests
Routine blood tests rarely offer diagnostic assistance in otherwise
healthy patients with epilepsy. Serum electrolytes, liver function
tests, and complete blood count are useful with acute new onset
seizures and as baseline studies before antiepileptic drug therapy
is started. Adolescents and young adults with unexplained sei-
zures should be screened for substance abuse (especially cocaine)
with blood or urine studies. Genetic testing should be considered
in specific cases with suspected phenotypes, especially if a posi-
tive genetic test would alter therapy, such as in SCN1A associated
epilepsies (e.g., Dravet syndrome). Lumbar puncture is indicated
only if there is a suspicion of meningitis, encephalitis, or a CNS
glucose transporter abnormality. Repeated generalized seizures
and status epilepticus can increase cerebrospinal fluid protein
content slightly and produce a mild pleocytosis for 24 to 48
hours; cerebrospinal fluid pleocytosis should be attributed to sei-
zures only in retrospect after excluding an intracranial inflamma-
tory process. An electrocardiogram (ECG) should be obtained
in any young person with a first generalized seizure if there is a
family history of arrhythmia, sudden unexplained death, or epi-
sodic unconsciousness. An ECG should also be obtained in any
patient with a personal history of cardiac arrhythmia or valvular
disease.
  DIFFERENTIAL DIAGNOSIS
Not every paroxysmal event is a seizure, and misidentification of
other conditions leads to ineffective, unnecessary, and potentially
harmful treatment. Misdiagnosis accounts for patients who have
not responded to antiepileptic drug treatment. The conditions
confused with epilepsy depend on the age of the patient
and the nature and circumstances of the attacks (Table 118-3).
TABLE 118-3  NONEPILEPTIC EPISODIC DISORDERS
THAT MAY RESEMBLE SEIZURES
Movement disorders: subcortical myoclonus, paroxysmal choreoathetosis,
episodic ataxias, hyperekplexia (startle disease)
Migraine: confusional, vertebrobasilar, visual auras
Syncope
Behavioral and psychiatric: psychogenic nonepileptic attacks
(pseudoseizures), hyperventilation syndrome, panic/anxiety disorder,
dissociative states
Cataplexy (usually associated with narcolepsy)
Transient ischemic attack
Alcoholic blackouts
Hypoglycemia
Nonepileptic paroxysmal disorders that are confused with epi-
leptic seizures have sudden, discrete abnormal behaviors, vari-
able responsiveness, changes in muscle tone, and various postures
or movements.
Psychogenic nonepileptic attacks (PNEA), such as pseudosei-
zures and psychogenic nonelectrical seizures, frequently cause
intractable “epilepsy” in adults. PNEA are due to the unconscious
mind converting emotional conflicts or stressors into a physical
state, mimicking a seizure. Some patients with psychogenic sei-
zures also have epilepsy. Definitive diagnosis requires video-EEG
documentation, although a history of atypical and nonstereo-
typed attacks, emotional or psychological precipitants, psychiat-
ric illness, lack of response to antiepileptic drugs, and repeatedly
normal interictal EEGs suggest psychogenic attacks. About 80%
of patients with PNEA have been the victims of physical or sexual
abuse. PNEA are more common in females.
Panic attacks (anxiety attacks) with hyperventilation can
superficially resemble partial seizures with affective, autonomic,
or special sensory symptoms. Hyperventilation typically causes
perioral and finger tingling. Prolonged hyperventilation results in
muscle twitching or spasms (tetany); affected patients may faint.
Syncope (see Chapter 9) refers to the symptom complex that
occurs when there is a transient global reduction in cerebral per-
fusion associated with cardiovascular dysfunction. Loss of con-
sciousness lasts only a few seconds, uncommonly a minute or
more, and recovery is usually rapid. If the cerebral ischemia is
sufficiently severe, the syncopal episode may include tonic pos-
turing of the trunk or clonic jerks of the arms and legs and incon-
tinence (convulsive syncope).
Some forms of migraine can be mistaken for seizures, espe-
cially if the headache is atypical or mild. The visual aura, present
in some migraineurs, is typically black, gray, and white; a colored
aura almost always indicates an epileptic seizure. Basilar artery
migraine, usually in children and young adults, can include leth-
argy, mood changes, confusion, disorientation, vertigo, bilateral
visual disturbances, and loss of consciousness.
  TREATMENT
If the cause of symptomatic seizures is corrected, AEDs are
usually not necessary. Adults with a single, unprovoked seizure
and normal clinical and laboratory findings frequently do not
have subsequent seizures; AEDs are usually not indicated if
only one seizure has occurred. However, patients with focal
neurological findings on clinical, radiological, or EEG examina-
tions are more likely to have repeated seizures. In individual

patients, social considerations may dictate treatment after a single
seizure.
Medication Therapy
If seizures are recurrent, the goal of treatment is complete seizure
freedom. In the United States, as of 2013, there were 25 AEDs in
standard use to treat epilepsy with several other medications
sometimes used as adjuncts. There is no perfect AED; all have
potential toxic side effects and idiosyncratic reactions. For over
one half of people with epilepsy the appropriate AED for their
type of seizures can be completely effective and well tolerated.
However, for about one quarter of people with epilepsy, no AED
or combination of AEDs is completely effective. Once the seizure
type and epilepsy syndrome is determined, an initial and, if
needed, subsequent AED, should be chosen based on both its
anticipated efficacy and toxicity profile. All AEDs can cause seda-
tion, cognitive dysfunction, and incoordination in some patients,
especially at high levels. Various rare, sometimes life threatening,
reactions can occur with all of the AEDs. Commonly encoun-
tered situations are:
Idiopathic generalized epilepsy (CAE, JME, others)
• In all idiopathic generalized epilepsies, valproate or lamotrig-
ine are the first line agents and result in complete seizure
control in 85% to 90% of patients.
• Valproate tends to cause weight gain and has been associated
with the development of polycystic ovary syndrome, par-
ticularly in adolescent females. It results in hair loss in about
5%. It has an increased risk of teratogenicity.
• Lamotrigine has a small but significant risk of a severe rash
(e.g., toxic epidermal necrolysis, Stevens Johnson syn-
drome) for about the first 2 months after starting. A slow
dose escalation substantially lowers this risk. Lamotrigine’s
metabolism is substantially inhibited by valproate, so in
combination, lower doses of lamotrigine are required. Occa-
sionally lamotrigine worsens myoclonus, but it is effective in
most cases of JME.
• Second line options include clobazam, topiramate, levetirace-
tam, and zonisamide.
• In childhood absence epilepsy with exclusively absence sei-
zures, ethosuximide should be the first choice. If any convul-
sions have occurred, valproate or lamotrigine should be used.
• If there is a history of more than 5 minutes of crescendo
absences or myoclonus (often described as a “foggy” state)
culminating in a convulsion, then oral benzodiazepines (loraz-
epam or diazepam) can abort the cluster and prevent a
convulsion.
• Absences and myoclonus can be exacerbated by carbamaze-
pine, oxcarbazepine, and GABAergic compounds including
gabapentin, pregabalin, and tiagabine. These AEDs should be
avoided in idiopathic generalized epilepsy.
Focal Epilepsy
• Almost all of the AEDs (except ethosuximide) can be effective
in focal epilepsy. The choice of the first AED should be guided
by side effect concerns and pharmacokinetics.
• Phenytoin is the most commonly used AED in focal epilepsy
in developed countries. It is typically loaded in the emergency
room after the initial seizures and subsequently continued.
Chapter 118  Epilepsy 1059
However, phenytoin has substantial short- and long-term tox-
icity and its levels are difficult to regulate due to saturation ss
kinetics and multiple drug interactions. Its toxicities include
hirsuitism, coarsening of features, and gingival hyperplasia,
especially in children and adolescents. Long-term toxicities
include osteomalacia, peripheral neuropathy, and cerebellar
degeneration with permanent incoordination. Peak level tox-
icities include nystagmus, gait instability, ataxia and, if the level
rises above 50, acute cerebellar degeneration and cardiac
arrhythmias.
• Carbamazepine, oxcarbazepine, topiramate, levetiracetam,
lamotrigine, and zonisamide are currently used as first line
therapy for partial seizures. Carbamazepine and oxcarbazepine
can cause hyponatremia. Topiramate can lead to weight loss
(often desired), but also has undesirable cognitive side effects
and predisposes to renal stones. Levetiracetam can cause
severe mood changes and marked sedation, but is usually well
tolerated. Lamotrigine needs to be titrated slowly due to the
rash risk. Zonisamide, which also predisposes to renal stones,
has a long half-life (48 to 72 hours) so is a good option for
intermittently noncompliant patients.
• Patients of Asian ancestry should be tested for the HLA-
B*1502 allele and patients of Northern European ancestry
tested for the HLA-A*3101 allele prior to initiating treatment
with carbamazepine, oxcarbazepine, and eslicarbazepine.
Patients with these alleles are at increased risk of Stevens
Johnson syndrome and toxic epidermal necrolysis when
exposed to these drugs.
• Adjunctive treatment for partial seizures includes clobazam,
valproate, pregabalin, lacosamide, gabapentin, perampanel,
and primidone. The proportion of gabapentin absorbed
decreases with increasing dose, which limits its effectiveness.
For most, pregabalin is a better choice. Primidone is rapidly
converted to phenobarbital by some people, limiting its use.
• Phenobarbital is the most widely used AED in the world due
to its low cost. However, it causes sedation and cognitive
impairment, and it should be avoided except in difficult to
control epilepsy. The exception is neonatal seizures where it is
the most commonly accepted AED.
Symptomatic generalized epilepsy (LGS, others)
• All AEDs have a role in the treatment of symptomatic general-
ized epilepsy, but seizure freedom is rarely achieved. At a
minimum, control of the more severe seizures, including drop
seizures and convulsions should be the target of therapy. Poly-
therapy is usually required.
• Valproate is commonly the initial medication instituted.
• Added efficacy can occur with clobazam, lamotrigine, topira-
mate, levetiracetam, rufinamide, and zonisamide.
• Felbamate may be effective, but its use should be limited to
epileptologists due to the significant risk of fatal aplastic
anemia and liver failure.
• The vagus nerve stimulator (see later) has a specific role in
reducing the severity of seizures in this condition.
• Dravet syndrome and possibly the related syndrome of GEFS+
respond best to topiramate, levetiracetam, and benzodiaze-
pines. Some drugs, including lamotrigine and phenytoin,
worsen Dravet syndrome.
 1060 Section XVI  Neurologic Disease

Dosing of AEDs must be done with care. Only a few of the
ss AEDs are safe to load or start at a full therapeutic dose. Most
should be started with a gradual dose escalation. Management
guidelines are: (1) The type of seizures and epilepsy should
be defined and the preferred medication should be given in
usual doses and then increased until seizure control is complete
or side effects occur (Table 118-4); (2) If seizures persist at
toxic levels, or if major side effects occur, another agent should
be tried; (3) Do not stop one agent until another has been
added. Otherwise, status epilepticus may occur; (4) If seizures
persist after two agents have been given to toxic levels, consider
referral to a specialized epilepsy center for complex combination
therapy and video-EEG long-term monitoring; (5) Toxic levels
of some AEDs (e.g., phenytoin and carbamazepine) can cause
seizures; (6) Extended release and longer acting AEDs are pre-
ferred for most patients; (7) Patients should be counseled to
adhere to the medication regimen. Pill boxes should be encour-
aged. Medication noncompliance is a leading cause of poor
seizure control.
Epilepsy Surgery
In most patients, epilepsy is controlled with medication. When
seizures cannot be controlled by adequate trials of two appro-
priate single agents or by the combination of two agents, the
epilepsy is termed medically intractable (or refractory), a situation
encountered in approximately 25% of patients with symptomatic
focal epilepsy. Such patients are at risk for the consequences
of seizures: inability to drive; stigmatization by schools, employ-
ers, and families; and threats to personal educational and occu-
pational goals. In appropriately selected cases, epilepsy surgery
can abolish seizures with restoration of normal neurological
function. The accurate localization of a small, safely resectable
seizure focus requires intensive investigation at a specialized
center.
Dietary Therapy
The ketogenic diet is a very high fat diet with restricted carbohy-
drates and protein carefully designed to cause a ketotic state
mimicking starvation, but supplying adequate nutrition. It is
mainly used in developmentally delayed children with severe
symptomatic generalized epilepsy. The ketogenic diet can be
effective in this most refractory form of epilepsy, resulting in
seizure-freedom in 15% to 20%. However, the diet is hard to
maintain and requires a dedicated, cooperative caregiver and a
specially trained dietician.
The modified Atkins diet (MAD) and low glycemic-index diet are
scaled-down versions of the ketogenic diet with mainly carbohy-
drate restriction. These diets are more palatable than the keto-
genic diet and can be tolerated by adults. The slight ketosis
achieved sometimes results in a dramatic seizure reduction in any
form of epilepsy.
Neurostimulators
The vagus nerve stimulator is an implanted device similar in
appearance to a cardiac pacemaker. The stimulating electrode is
placed on the left vagus nerve in the neck and programmed to
stimulate the nerve for 30 seconds every 3 to 5 minutes. Swiping
a magnet over the device gives an extra stimulation that can
sometimes abort a seizure. In up to two thirds of patients, partial
seizures are reduced by 50% or more and seizure intensity
decreases.
Another strategy in medically refractory focal epilepsy is the
responsive neurostimulator. Chronically implanted electrodes at
the seizure foci are used to rapidly detect seizure onset and abort
the seizure within a few seconds by delivering an electrical stimu-
lation directly to the seizure focus. Deep brain stimulation to the
bilateral anterior nuclei of the thalami may also improve seizure
control.
Status Epilepticus
Status epilepticus can occur with partial or generalized epilepsy
and is defined as prolonged or rapidly recurring seizures without
full intervening recovery. Acute repetitive seizures are defined as a
cluster of seizures over minutes to hours with intervening
recovery.
Convulsive status epilepticus (Grand mal, major-motor) is a
medical emergency. Continuous generalized epileptic activity
can damage the brain permanently. The most frequent cause is
abrupt withdrawal of AEDs (e.g., noncompliance) in a person
with known epilepsy. Other precipitants include withdrawal of
alcohol or drugs in a habitual user, cerebral infection, trauma,
hemorrhage, and brain tumor.

TABLE 118-4  FREQUENTLY PRESCRIBED ANTIEPILEPTIC DRUGS

DOSE FREQUENCY “THERAPEUTIC”
NONPROPRIETARY AED NAME ADULT TOTAL DOSE PER DAY (IN HOURS) CONCENTRATIONS
Carbamazepine 800-1600 mg 6-8 (12 for sustained release) 6-12 µg/mL
Ethosuximide 750-1500 mg 8-12 40-100 µg/mL
Gabapentin 900-3600 mg 6-8 Uncertain
Lacosamide 200-600 mg 12 Uncertain
Lamotrigine* 100-800 mg 12 2-15 µg/mL
Levetiracetam 500-3000 mg 12 15-45µg/mL
Clobazam 20-60 mg 12 Uncertain
Oxcarbazepine 600-2400 mg 8-12 15-45µg/mL
Phenobarbital 60-240 mg 24 15-40 µg/mL
Phenytoin 200-600 mg 24 10-20 µg/mL
Pregabalin 100-600 mg 8-12 Uncertain
Topiramate 50-600 mg 12 2-20 µg/mL
Valproate 500-6000 mg 8 (12-24 for sustained release) 50-120 µg/mL
Zonisamide 100-600 mg 24 Uncertain
*Slow initial dose titration mandatory for lamotrigine and often indicated for other agents.

Complex partial status epilepticus manifests as a sustained state
of confusion often associated with motor and autonomic autom-
atisms. Some attacks produce bizarre behavior or stupor. Patients
may resist assistance due to their abnormal state, which can last
for hours or even days. The EEG usually shows nearly continuous
discharging activity predominating in one or both temporal
regions.
Absence status epilepticus (petit mal status) resembles complex
partial status and consists of a confused state with some auto-
matic behaviors. The EEG is characteristic with continuous runs
of generalized 3 to 4 Hz spike and slow wave activity. The condi-
tion occurs in children or young adults with known absence epi-
lepsy. Rarely, absence status occurs as the first manifestation of
epilepsy in adults with no history of seizures. Atypical absence
status with fluctuating confusion lasting for hours or longer
occurs in patients with symptomatic generalized epilepsy (e.g.,
Lennox-Gastaut syndrome) and is accompanied by a generalized
spike and slow wave pattern of 2.5 Hz or slower on the EEG.
Partial motor status, also known as epilepsy partialis continua,
ranges from highly focal, clonic movements of the face or hand
to jerks that involve most of the limb or half the body. The clonus
frequency can vary from one every three seconds to three per
second. It is relatively uncommon. Its causes include stroke,
trauma, neoplasms, encephalitis, and hyperglycemia; sometimes
the cause never becomes clear. Epilepsy partialis continua often
resist all efforts at treatment and neurosurgical removal of the
causative lesion is sometimes required.
Physicians infrequently witness seizures; most of the time they
learn about the semiology during the history. Merely observing
a patient in the midst of a seizure does not indicate that the
patient should be treated for status epilepticus. However, once
status epilepticus is diagnosed, treatment is urgent. The longer
status epilepticus lasts, the more difficult it is to terminate and
the more likely it is to cause brain damage. Aggressive therapy is
mandatory for convulsive status epilepticus (Table 118-5). If
initial therapy is not rapidly effective, anesthetic agents requiring
intubation and ventilation should be used within an hour of
onset. Complex partial status can also result in permanent neu-
ronal injury and should similarly be treated aggressively, although
therapeutic decisions are often made to try to stop complex
partial status with agents that do not cause respiratory depression
to avoid intubation. Absence status is unlikely to result in perma-
nent sequelae and usually responds promptly to benzodiazepine
treatment. Investigation of the cause of the status epilepticus
should be undertaken during the treatment and continued after
the seizures stop. Severe hyperglycemia can produce refractory
partial motor and complex partial status; seizures stop once
hyperglycemia is corrected.
Postanoxic status myoclonus is accompanied by generalized
polyspike epileptiform discharges on the EEG but is usually
unresponsive to treatment for status epilepticus. It typically indi-
cates an irreversible condition with a poor prognosis.
  GENETIC COUNSELING AND PREGNANCY
Heredity
Patients with epilepsy should be advised about the hereditary
risks to their offspring, although in most people with epilepsy it
does not influence their decision about having children. The
Chapter 118  Epilepsy 1061
TABLE 118-5  TREATMENT OF CONVULSIVE STATUS ss
EPILEPTICUS
TIME (MIN) STEPS
0-5 Give O2; ensure adequate ventilation
(ABCs) Monitor: vital signs, ECG, oximetry
Establish intravenous access; obtain blood samples
for glucose level, complete blood cell count,
electrolytes, Ca, Mg, toxins, and AED levels
6-9 Give glucose if blood glucose level is low or
(glucose) unavailable. In adults give 100 mg thiamine as well.
(benzodiazepine) Intravenously administer 1-2 mg of lorazepam or
midazolam or 5-10 mg of diazepam as initial
therapy. Alternatively use rectal diazepam gel
0.2 mg/kg.
10-20 If the initial dose of benzodiazepine is not effective,
then continue to intravenously administer either
lorazepam 1-2 mg every 5 minutes up to a
maximum of 0.1 mg/kg or diazepam 5-10 mg every
5 minutes up to a maximum of 30 mg in patients
over 12 years old. If diazepam or midazolam is
used and the status epilepticus stops, phenytoin
(or another AED) should be administered
promptly to prevent recurrence of seizures as
diazepam and midazolam’s duration of action
against seizures can be less than 30 minutes.
21-40 If status epilepticus persists, administer 20 mg/kg
(phenytoin) of fosphenytoin* intravenously no faster than
3 mg/kg/min up to 150 mg/min in adults.
(Alternatively use phenytoin at maximum 1mg/kg/
min up to 50 mg/min in adults in a proximal IV.)
Monitor carefully for hypotension, arrhythmia,
local extravasation.
>40 If the seizures do not stop after fosphenytoin/
(phenobarbital) phenytoin, give 20 mg/kg of phenobarbital
(intubate) intravenously at maximum 100 mg/min. When
phenobarbital is given after a benzodiazepine,
ventilatory assistance is usually required.
(general anesthesia) If status epilepticus persists, give general anesthesia
(e.g., propofol, midazolam, or lorazepam drip) to
induce a burst suppression pattern (EEG
monitoring, if available, should be instituted).
Vasopressors or supplemental IV fluids are often
necessary.
(alternatives) Alternative/additional treatments include IV
valproate (30 mg/kg) load, levetiracetam, and
lacosamide.
ABCs, Airway, breathing, and circulation; AED, antiepileptic drug.
*Always dosed in phenytoin-equivalents (PE).
idiopathic epilepsies have complex inheritance with about 10%
of children of an affected parent developing seizures. There are
over 200 Mendelian-inherited syndromes with epilepsy, all rare.
Teratogenicity
Children of mothers taking antiseizure medications have a birth
defect rate of 6% to 9%, which is two to three times that of the
general population. Convulsions, however, pose a substantial risk
to the mother and fetus. Thus, AEDs should not be stopped
during pregnancy. Two AEDs, valproate and carbamazepine,
have been incriminated in neural tube closure defects. Since the
neural tube closes by 28 days of fetal development, this defect
develops before the mother is aware she is pregnant. Phenytoin,
phenobarbital, and primidone have been associated with a spec-
trum of neurodevelopmental abnormalities. All five of these
older AEDs are classified as pregnancy category D by the FDA
and should be avoided if possible. Large registries suggest that
the newer AEDs have less teratogenicity, but the data are
 1062 Section XVI  Neurologic Disease
incomplete. Use of two or more AEDs (polytherapy) increases
ss the teratogenic risk. Pregnancies in women with epilepsy should
be planned. During the year prior to conception, an attempt
should be made to minimize the teratogenic potential of the
AEDs by changing to a newer AED, to monotherapy from poly-
therapy, or tapering off the AEDs, if there are reasons to believe
that seizures will not recur (see later). The lowest effective dose
of the AEDs should be used, but this must be balanced with the
risk of a breakthrough seizure. Folic acid deficiency is a well-
established factor in neural tube closure defects in the general
population. There is little evidence that additional folic acid in a
well-nourished woman with epilepsy decreases the AED effects
on neural tube closure. However, it is common practice to place
women with epilepsy of childbearing age on supplemental folic
acid (1 mg) as prophylaxis against a neural tube closure defect.
Once pregnancy is planned or recognized, the dose of folic acid
is commonly increased to 4 mg per day.
Management during and after Pregnancy
Women with epilepsy have a 1.5- to 3-fold increased rate of com-
plications of pregnancy, including bleeding, toxemia, abruptio
placentae, and premature labor. They should be managed as high
risk pregnancies. High-quality (focused or type 2) ultrasound,
maternal serum alpha-fetoprotein level (elevated in neural tube
closure defects), and amniocentesis for chromosomal analysis are
used to identify fetal malformations.
During pregnancy AED concentrations decrease due to
increased hepatic and renal clearance and increased plasma
volume. The free fraction of highly protein-bound AEDs (e.g.,
phenytoin and valproate) typically increases due to decreased
albumin concentration and increased competition for binding
sites by sex steroids. Thus, it is essential to monitor drug levels
(free levels for highly protein-bound AEDs) prior to conception
and at regular intervals throughout pregnancy. Hepatic induction
of glucuronidation can dramatically reduce lamotrigine levels,
sometimes requiring doubling or tripling of the lamotrigine dose
to maintain prepregnancy levels. Lamotrigine levels should be
measured at least every month throughout pregnancy. Similarly,
oxcarbazepine levels fall by about one third beginning in the first
trimester and, thus, the dose should be increased and the level
checked at least each trimester.
Emesis, a common problem during early pregnancy, can result
in missed and partial doses of AEDs. The expectant mother
should have specific instructions to retake a full or partial dose
of her AEDs if vomiting occurs after medications are taken.
After the child is born, the dose of AEDs should be tapered
to the pre-pregnancy amount within days to weeks. The AED
levels can be checked 1 to 2 weeks after completing the taper
to confirm they are at the patient’s baseline. In general, breast-
feeding is not contraindicated in women taking antiepileptic
drugs.
During the postpartum period the mother with epilepsy may
be at increased risk of seizures, especially if her seizures are acti-
vated by lack of sleep. To decrease this risk, a support person
should perform at least one of the nighttime feedings. Patients
whose seizure semiology would put the infant at risk (e.g., drop-
ping or excessively clutching the baby) require childcare modifi-
cation or supervision.
  PSYCHOSOCIAL CONCERNS
Ongoing epileptic seizures often have major emotional conse-
quences for the patient and family. Comorbid depression is
present in up to 50% of patients with refractory epilepsy and 20%
of patients with controlled epilepsy. Anxiety disorders are also
common. Both are often unrecognized and untreated. In people
with epilepsy, quality of life impairment is better correlated with
depression than seizure frequency. The unpredictable nature of
seizures and the necessary activity restrictions cause dependence,
decreased self-worth, embarrassment, underemployment, and
helplessness. Reduced libido and hyposexuality are common in
patients with epilepsy and are often unrecognized.
Family dynamics are often disrupted by the presence of
epilepsy. Both families and patients often fear seizures (seizure
phobia). Family members may think their loved one is dying
when they have a convulsion, especially for the first time.
Patients with epilepsy are helped most by complete seizure
control, but reassurance and optimistic social guidance can
aid immeasurably. Once seizure control is achieved, affected
persons should be encouraged to live a near normal life, using
common sense as a guide. Although activity restrictions may
eventually be lifted, patients with past epilepsy (with the excep-
tion of CAE and benign epilepsy with centro-temporal spikes,
which completely remit) should be advised to avoid head
contact sports, high alpine climbing, scuba diving, and profes-
sions requiring work at heights, large amounts of driving, or
weapon use.
All states grant automobile driver’s licenses to patients with
epilepsy provided that no seizures have occurred for specified
periods (typically six months to one year). Life and health insur-
ance policies can generally be obtained. Epilepsy foundations
and local social service organizations can assist patients with case
coordination, including social and vocational considerations.
  PROGNOSIS
Sixty to 70% of people with epilepsy achieve a 5-year remission
of seizures within 10 years of diagnosis. About half of these
patients are eventually seizure-free without AEDs. Factors favor-
ing remission include an idiopathic form of epilepsy, a normal
neurological examination, and onset in early to middle childhood
(excluding neonatal seizures). Approximately thirty percent of
patients continue to have seizures and never achieve a permanent
remission with medications. In the United States, the prevalence
of intractable epilepsy is 1 to 2 per 1000 population. Such patients
should be evaluated at an epilepsy center. Injuries due to seizures
are common. Advising patients not to cook, or to use back
burners or microwave ovens, can prevent some serious burns. A
helmet is advisable for those with drop seizures.
Sudden unexplained death in epilepsy (SUDEP) occurs in 1 per
1000 patients per year taking all forms of epilepsy together. In the
most refractory epilepsies, the SUDEP rate is greater than 1 per
200 patients per year. SUDEP may be due to excessive autonomic
nervous system sympathetic tone during an unwitnessed seizure
with resultant cardiac arrhythmia or pulmonary edema. Suffoca-
tion can occur after an unwitnessed convulsion if the patient ends
up face down in a pillow. Accidental deaths related to seizures
(e.g., motor vehicle collisions) further increase the death rate.

Aspiration with convulsions is common, but can be prevented by
turning the head to one side as the convulsion ends.
  DISCONTINUING ANTIEPILEPTIC DRUGS
Many patients with epilepsy become seizure-free on medication
for an extended period of time. Some patients can discontinue
antiepileptic drugs without a relapse. Successful drug withdrawal
is most likely if initial seizure control was readily achieved using
monotherapy, there were relatively few seizures before remission,
and the EEG and neurological examination are normal just
before the AEDs are tapered off. A seizure-free interval of at least
2 years is important to reduce the likelihood of relapse; some
advocate that seizure-freedom should be present for at least 5
years unless the epilepsy syndrome is known to remit (e.g., CAE
or BECTS). Conversely, risk of relapse is high if seizure control
was difficult to establish and required polytherapy, if there were
frequent convulsions before control was achieved, a focal abnor-
mality is present on neurological examination, or if the EEG
demonstrates focal disturbances of background activity or epi-
leptiform activity at the time AED withdrawal is considered.
For a deeper discussion of this topic, please see Chapter
403, “The Epilepsies,” in Goldman-Cecil Medicine, 25th
Edition.
Chapter 118  Epilepsy 1063
SUGGESTED READINGS
Berg AT, Scheffer IE: New concepts in classification of the epilepsies: Entering ss
the 21st century, Epilepsia 52:1058–1062, 2011.
Christensen J, Grønborg TK, Sørensen MJ, et al: Prenatal valproate exposure
and risk of autism spectrum disorders and childhood autism, JAMA
309(16):1696–1703, 2013.
Fazel S, Wolf A, Langstrom N, et al: Premature mortality in epilepsy and the role
of psychiatric comorbidity: a total population study, Lancet 382:1646–1654,
2013.
French JA, Pedley TA: Clinical Practice. Initial Management of Epilepsy, N Engl
J Med 359:166–176, 2008.
Krumholz A, Wiebe S, Gronseth G, et al: Practice Parameter: Evaluating an
apparent unprovoked first seizure in adults (in evidence-based review): report
of the Quality Standards Subcommittee of the American Academy of
Neurology and the American Epilepsy Society, Neurology 69:1996–2007,
2007.
Kumada T, Miyajima T, Hiejima I, et al: Modified Atkins Diet and Low Glycemic
Index Treatment for Medication-Resistant Epilepsy: Current Trends in
Ketogenic Diet, J Neurol Neurophysiol S2:007, 2013.
Manjunath R, Paradis PE, Parisé H, et al: Burden of uncontrolled epilepsy in
patients requiring an emergency room visit or hospitalization, Neurology
79(18):1908–1916, 2012.
Petit-Pedrol M, Armangue T, Peng X, et al: Encephalitis with refractory seizures,
status epilepticus, and antibodies to the GABAA receptor: a case series,
characterization of the antigen, and analysis of the effects of antibodies, Lancet
Neurol 13:276–286, 2014.
 119 
ss
Central Nervous System Tumors
Bryan J. Bonder and Lisa R. Rogers
  DEFINITION/EPIDEMIOLOGY
Central nervous system (CNS) tumors are of two types, primary
or metastatic. Primary tumors arise from a variety of cell types
within the parenchyma of the brain or spinal cord or the menin-
ges adjacent to the brain or spinal cord. Metastatic tumors result
from spread of systemic cancer to the brain, spinal cord, or
meninges. This chapter considers both primary and metastatic
brain tumors.
The incidence of primary malignant and nonmalignant brain
tumors in the United States is 14.8/100,000. Approximately
20,500 individuals were diagnosed with primary malignant
brain tumors in 2007 in the United States. High-grade gliomas
and meningiomas are the most common types of adult primary
brain tumors. The incidence of primary brain tumors is low
in young adults but increases with advancing age and reaches
a plateau between the ages of 65 and 79 years. There is a
recent rise in the incidence of primary brain tumors among
elderly patients, but part of this increase is due to improved
detection methods. Meningiomas are the most common benign
intracranial tumor and account for up to one third of benign
brain tumors. The incidence of primary CNS lymphoma
(PCNSL) is increasing in all age groups, accounted for only
in part by CNS lymphoma associated with the acquired immu-
nodeficiency syndrome (AIDS). Population-based studies
suggest an incidence rate of 10/100,000 population with brain
metastasis, but brain metastatic tumors are more common
than primary CNS tumors. Because incidence rates are based
on tumor registries and many patients with brain metastasis
do not undergo surgery, they are underrepresented in these
statistics.
Primary brain tumors are the second most common cancers
in children. Medulloblastomas are the most common malignant
pediatric brain tumor. In the United States, between 350 and 500
new cases of pediatric and adult medulloblastomas are diagnosed
each year, and the majority of these are pediatric.
The cause of most CNS tumors is unknown. Aside from expo-
sure to ionizing radiation, no environmental agents are known to
be causative. Hereditary syndromes that are associated with an
increased risk of CNS tumors include neurofibromatosis 1 and
2, tuberous sclerosis, von Hippel-Lindau disease, Li-Fraumeni
syndrome, and Turcot’s syndrome, but account for less than 1%
of primary CNS tumors. Although the chromosomal abnormali-
ties associated with many of these syndromes is known, the
specific mechanisms leading to CNS neoplasia have not been
defined.
1064
  PATHOLOGY
The World Health Organization classification defines brain
tumors based on the cell of origin and includes a grading system,
which is of use in predicting the biological behavior of the tumor.
Most adult primary brain tumors are of neuroepithelial origin
and result from neoplastic transformation of astrocytes, oligo-
dendrocytes, or ependymocytes. Astrocytomas are the most
common primary brain tumor in adults. Meningiomas derive
from arachnoidal cap cells in the meningeal covering of the brain.
Common locations of meningioma are the cerebral convexity,
falx and parasagittal area, olfactory groove, sphenoid wing, and
posterior fossa. They are comprised of heterogeneous histopa-
thology patterns and careful neuropathological assessment is
needed for accurate grading.
PCNSL is a rare form of non-Hodgkin lymphoma, typically of
B cell origin. It presents within the white matter of the cerebral
hemispheres, often in a periventricular location, and is often mul-
tiple, especially in AIDS patients. Brain metastasis develops when
tumor cells gain access to the systemic circulation and embolize
to the brain. Metastases occur most commonly from solid tumors
arising in the breast, lung, colon, and skin (melanoma). Lung
cancer, both non-small and small cell type, is the most common
tumor overall to metastasize to the brain and constitutes up to
50% of cases of brain metastasis. In women, breast cancer is the
most common source of brain metastasis. Malignant melanoma
is a much less common systemic cancer but carries a high risk of
brain metastasis; up to 50% of stage IV melanoma patients
develop brain metastasis. Colon and renal cell carcinoma are also
common underlying tumors. Other solid tumors are less fre-
quent. Medulloblastomas are of primitive neuro-ectodermal
origin and are highly cellular. Homer Wright rosettes can be
found in up to 40% of cases. Medulloblastomas are grade IV
tumors as they are invasive and rapidly growing, with a tendency
to disseminate through the CSF.
  CLINICAL PRESENTATION
Symptoms and signs caused by brain tumors typically result from
compression or invasion of adjacent neural tissue by the tumor
or from vasogenic edema resulting from disruption of the blood-
brain barrier caused by vessel compression or invasion from
tumor or from “leaky” blood vessels present within tumors. Neo-
angiogenesis associated with tumor growth typically results in
embryonic vessels that lack a normal blood-brain barrier. Because
of the uncompromising rigidity of the cranial vault, both histo-
logically benign and malignant tumors may cause symptoms
 Chapter 119  Central Nervous System Tumors 1065

even when they are small. Symptoms caused by low-grade

primary brain tumors tend to be slowly progressive whereas ss

those in mid-grade and high-grade histology are acute or sub-

acute (over weeks to months). The exception is the clinical pre-
sentation of a low-grade glioma with seizure. Metastatic tumors
often present in a subacute fashion but may present acutely when
hemorrhage into the tumor occurs. Hemorrhage into metastatic
brain tumors is most common with renal cell, melanoma, lung,
and choriocarcinomas.
The clinical symptoms and signs depend on the location of
tumor. In most pediatric patients with brain tumor, tumors arise
in the posterior fossa and result in diplopia, ataxia, dysphagia, or
nausea/vomiting. Most of adult brain tumors arise in the cerebral
hemispheres and present with symptoms and signs related or
supratentorial structure involved: unilateral limb weakness,
aphasia, and memory loss are common. Tumors in either loca-
tion may present with generalized symptoms arising from
increased intracranial pressure or meningeal irritation. Headache
occurs in up to two thirds of patients as a presenting sign. There
are no characteristics unique to this headache, but useful clinical
clues include a new or different headache pattern, a progressively
worsening headache, and one that occurs at night or on awaken- FIGURE 119-1  Contrast-enhanced T1-weighted MRI demonstrates
ing. The pain may localize to the side of the tumor in patients with irregular contrast enhancement with central necrosis in the left tempo-
supratentorial tumors, whereas patients with infratentorial ral lobe. There is adjacent vasogenic edema and mass effect on midline
tumors frequently describe pain in the retro-orbital, retroauricu- structures.
lar, or occipital region. Other generalized symptoms include
changes in mood or personality, a decrease in appetite, and
nausea. Projectile vomiting, common in children with posterior
fossa tumors, is rare in adults. Meningiomas generally grow
slowly; they may also be found incidentally during the evaluation
of unrelated neurologic symptoms. Seizures are a frequent pre-
senting sign of low-grade gliomas. Seizures may develop over the
course of the illness in a high percentage of other patients with
glioma, often in association with tumor progression.

  DIAGNOSIS/DIFFERENTIAL
All patients suspected of having a brain tumor should undergo a
contrast-enhanced magnetic resonance imaging (MRI) brain
scan. If MRI is not available or is contraindicated because of a
pacemaker or other condition, brain computed tomography
(CT) should be obtained. Brain MRI is preferred because it is
more useful in imaging the temporal and posterior fossae and it
is more sensitive in detecting the extent of parenchymal involve-
ment by tumor of any type. In addition, advanced sequences such
as diffusion, perfusion, and spectroscopy add to the diagnostic
accuracy of imaging. Vasogenic edema resulting from leakage of FIGURE 119-2  Coronal T-weighted MRI following contrast injection
intravascular fluid through a disrupted blood-brain barrier can in a low-grade astrocytoma shows low attenuation and no contrast
enhancement, typical of a low-grade glioma.
accompany any type of brain tumor and is easily visible on MRI.
High-grade gliomas typically appear as irregularly shaped
contrast-enhancing masses surrounded by edema. Central necro-
sis is characteristic of glioblastoma (Fig. 119-1). Anaplastic instances do not show contrast enhancement. Brain metastases
gliomas appear similar, except for less frequent tumor necrosis. are often located at the grey-white junction of the brain and dem-
Although there are exceptions, most low-grade gliomas do not onstrate homogeneous enhancement or peripheral enhancement
enhance after intravenous contrast injection (Fig. 119-2). Menin- surrounding a necrotic center. When single, a brain metastasis
giomas typically demonstrate smooth and homogeneous cannot be accurately distinguished from other neoplasm or non-
enhancement originating from the extra-axial space and may also neoplastic entities. Medulloblastomas are usually large by the
compress adjacent brain. PCNSLs typically present as multiple time they are identified and demonstrate homogeneous
contrast-enhancing lesions within the white matter but in rare enhancement within or superior to the floor of the fourth
 1066 Section XVI  Neurologic Disease
ss
FIGURE 119-3  Contrast-enhanced T1-weighted MRI shows a large
enhancing tumor in the midline of the cerebellum with compression
of the fourth ventricle.
ventricle location (Fig. 119-3). They are often accompanied by
hydrocephalus. The desmoplastic variant of medulloblastomas
can be located lateral to the fourth ventricle.
The differential diagnosis of contrast-enhancing lesions
includes brain abscess, but infection is a consideration only in
rare clinical situations. Diffusion-weighted magnetic resonance
images can be useful in distinguishing tumor from infection.
Low-grade gliomas can be misdiagnosed as cerebral infarction,
especially on brain CT. Periventricular enhancement in PCNSL
can sometimes be confused with active multiple sclerosis lesions
or with brain metastasis. Dural pathologies such as sarcoidosis,
meningeal infection, or dural metastasis can mimic a meningi-
oma. Posterior fossa ependymomas in children can mimic
medulloblastomas.
Biopsy or resection is the preferred method to establish the
histology and grade of primary brain tumors. Exceptions include
PCNSL in which malignant cells are identified in the CSF or by
vitreous biopsy to establish the diagnosis, and brainstem gliomas
in which the MRI appearance is characteristic and biopsy is con-
sidered dangerous.
  TREATMENT
Maximal surgical resection is the goal for patients with benign
and malignant primary brain tumors with the exception of
PCNSL in which clinical deterioration can result from resection,
and biopsy alone is recommended for diagnosis. Surgical resec-
tion provides tissue for analysis and often relieves neurological
symptoms; maximal surgical resection improves outcome. Surgi-
cal resection is also indicated in patients with a single brain
metastasis and who have limited systemic disease with a progno-
sis of at least 3 months. Small patient series also indicate that
resection of up to three brain metastases can be beneficial in
extending overall survival and improving quality of life. More
than three metastases are typically treated with radiation therapy
without surgery.
Standard therapy for newly diagnosed glioblastoma is maximal
resection and external beam radiation of 60Gy over 6 weeks in
combination with daily temozolomide followed by temozolo-
mide for 6 months. In a prospective randomized trial of newly
diagnosed glioblastoma patients, the median survival with radia-
tion and temozolomide was 14.6 months versus 12.1 months
with radiation alone. In addition, the 2-year survival rate was
superior with the combined regimen (26.5%) versus radiation
alone (10.4%). O-6-methylguanine DNA methyltransferase
(MGMT) is a DNA repair gene that reduces the efficacy of
temozolomide and other DNA-damaging treatments for cancer.
Methylation of the MGMT promoter in tumor tissue silences
this gene and results in improved survival in glioblastoma. Deter-
mination of the promoter status of MGMT is often obtained as
a part of clinical research trials but is rarely used in clinical
practice.
The introduction of “targeted agents” that are designed to
deactivate oncogenic pathways is a major advance in cancer treat-
ment, including glioblastoma. Bevacizumab, a monoclonal anti-
body to vascular endothelial growth factor, is associated with a
high response rate (6 month progression-free survival of 46%) in
recurrent glioblastoma, although the effect on overall survival is
not significant. Molecular markers in glioblastoma that are pre-
dictive and prognostic of outcome have not yet been identified.
There is some evidence that tissues harboring IDH1 mutations
are correlated with a superior outcome compared with wild type
IDH1. The discovery of molecular “drivers” may lead to identifi-
cation of targets for therapy.
Anaplastic gliomas are treated by maximal surgical resection,
followed by external beam radiation. Despite the overall better
prognosis for anaplastic gliomas, chemotherapy is frequently rec-
ommended but of uncertain benefit. One anaplastic glioma
exquisitely sensitive to chemotherapy is the AO with codeletions
of 1p and 19q. Small clinical trials have evaluated the benefit of
chemotherapy alone in these patients. Deferring radiation until
the time of tumor progression may reduce the CNS toxicity asso-
ciated with brain radiation.
The long-term progression-free survival and overall survival of
low-grade glioma patients is better than those with glioblastoma
or anaplastic glioma, but malignant transformation occurs in up
to 50% of such patients and close monitoring is required. Patients
with low-grade gliomas should be treated initially with surgical
resection. Postsurgical management of low-grade gliomas remains
controversial, specifically whether radiation should be adminis-
tered at diagnosis or delayed until the time of progression. The
only prospective clinical trial to compare early versus delayed
radiation therapy demonstrated that early radiation does not
improve survival but does delay the time to tumor progression.
In general, radiation therapy is deferred for patients younger than
40 years of age who have undergone complete resection. An
ongoing cooperative group trial seeks to determine if temozolo-
mide chemotherapy added to radiation offers a survival advan-
tage over radiation alone.
Maximal surgical resection is important in patients with
meningioma to reduce the risk of relapse. When complete
removal is not possible, radiation therapy should be considered,
depending upon the location of the tumor and regardless of
grade. Radiation therapy is recommended regardless of the
 Chapter 119  Central Nervous System Tumors 1067
extent of resection for malignant meningioma. Chemotherapy
for this disease has been disappointing.
Symptoms and imaging abnormalities associated with PCNSL
often improve with the administration of corticosteroids because
of the cytotoxic effects of steroids on lymphoma cells. However,
administration of steroids before brain biopsy reduces the yield
of tissue biopsy. Surgical biopsy, but not resection, is the recom-
mended method for diagnosis. The treatment for this tumor is
currently evolving as new treatments emerge. Methotrexate che-
motherapy is the most effective treatment. Combining high-dose
methotrexate with standard-dose brain radiation carries a risk of
neurotoxicity, especially in elderly patients, but reduced-dose
whole brain radiation following methotrexate chemotherapy is
currently under study.
Standard therapy for patients with a single brain metastasis is
complete resection if the tumor is in a noneloquent part of the
brain and if the extent of systemic disease predicts a survival of
at least 4 to 6 months. In addition, some patients with limited
systemic cancer show a survival benefit with resection of up to
three metastatic tumors. Resection is typically followed by whole
brain radiation or stereotactic surgery to the tumor margin. If the
patient does not receive whole brain radiation, close observation
with periodic MRI scans is indicated to assess for recurrence at
the original site or at other sites in the brain. For patients present-
ing with more than three metastases, whole brain radiation as
indicated. A meta-analysis of the addition of stereotactic radio-
surgery and whole brain radiation did not identify a survival
benefit when compared with whole brain radiation therapy
alone, except for patients with a single brain metastasis (6.5
versus 4.9 months). A variety of systemic chemotherapies show
therapeutic efficacy in newly diagnosed and recurrent brain
metastasis, depending upon the sensitivity of the brain metastasis
to the agent, rather than to delivery of the drug to the lesion.
The extent of resection is prognostic in medulloblastomas.
Staging evaluations for the extent of disease include postopera-
tive MRI of the brain and spine and lumbar CSF sampling. Pro-
spective randomized trials and single-arm trials suggest that
adjuvant chemotherapy administered during and after craniospi-
nal radiation improves the progression-free survival and overall
survival in both average and poor risk groups. The therapy for
children younger than 3 years of age excludes craniospinal radia-
tion therapy because of the long-term deleterious effects and
includes surgery and chemotherapy alone. Distinct subgroups of
medulloblastomas have been identified, and profiling of these
subgroups reveals distinct genomic events, several of which rep-
resent actionable targets for therapy.
Vasogenic edema associated with parenchymal and meningeal
tumor causes neurological symptoms and signs, and it can be
life-threatening. Treatment with corticosteroids often reduces
edema and improves neurologic function. Dexamethasone is the
preferred steroid because of its long half-life. Patients with symp-
toms related to vasogenic edema often improve within 48 hours
of dexamethasone administration. Doses used for treatment of
tumor-related edema are typically 4-24 mg/day given in divided
doses (2 to 4 times daily). Because steroids can be associated
with a variety of adverse effects, the lowest dose and duration of
administration should be sought. In patients with severe neuro-
logic signs related to brain edema, an intravenous bolus of 10 to
20 mg dexamethasone should be considered. If the neurologic
signs are life-threatening, including signs of brain herniation, ss
mannitol and dexamethasone should be administered and urgent
neurosurgical consultation obtained. Seizures should be aggres-
sively managed with antiepileptic drugs. Nonenzyme inducing
antiepileptic drugs are generally favored because of a better safety
profile than enzyme-inducing drugs and because of the lack of
interaction with other medications prescribed to treat the tumor,
including steroids and chemotherapy. Prophylactic antiepileptic
drugs are generally not recommended for patients with a primary
or metastatic brain tumor when there is no history of seizure.
  PROGNOSIS
The histology of high-grade glioma, performance status, and
age are important predictors of prognosis. Glioblastoma has
the worst prognosis, with a median survival of just over 1 year
even with aggressive therapy. Good prognosis patients can live
more than 2 years. Data from the nationwide Surveillance,
Epidemiology, and End Results registry identified an overall
median survival of 15 months and 42 months for patients with
anaplastic astrocytomas and anaplastic oligodendrogliomas,
respectively. This analysis did not include the status of 1p19q
chromosomal loss, and the more favorable survival of patients
with codeletions was not demonstrated. Low-grade gliomas
have a median survival of approximately 5 years, but there is
individual variation depending on age, size of tumor, and extent
of resection.
Recurrence rates in meningioma depend upon grade and vary
from greater than 25% in grade 1 to greater than 90% in grade 3.
Risk factors for recurrence include incomplete resection, tumor
grade, young age, specific subtypes, brain infiltration, and high
proliferative rate.
Five-year survival rates in meningioma are approximately 69%
overall but vary significantly with tumor grade. Survival in
PCNSL ranges from 1 to several years, depending on patient age
and treatment modality. Performance status, age, status of the
extracranial tumor, and number of brain metastases are factors
that predict prognosis in patients with brain metastasis. The
median survival ranges from 3 to 6 months in patients with mul-
tiple metastases treated with whole brain radiation therapy.
Patients with a single metastasis with limited extracranial disease
who undergo surgical resection and whole brain radiation therapy
have significantly improved survival (40 weeks) as compared
with those who undergo whole brain radiation therapy alone (15
weeks). Importantly, the improved survival is accompanied by a
longer period of functional independence. The 5-year progression-
free survival in medulloblastomas is 70% to 85%. However, more
than one third of patients experience recurrence, and there is no
standard therapy at the time of recurrence. Median survival after
recurrence is usually less than 1 year. For children less than 3
years of age at diagnosis, 5-year progression-free survival ranges
between 30% and 70%, depending on the extent of dissemination
at diagnosis.
SUGGESTED READINGS
American Cancer Society: www.cancer.org. Accessed October 22, 2013.
Backer-Grøndahl T, Moen BH, Torp SH: The histopathological spectrum of
human meningiomas, Int J Clin Exp Pathol 5:231–242, 2012.
 1068 Section XVI  Neurologic Disease
Barnholtz-Sloan JS, Yu C, Sloan AE, et al: A nomogram for individualized
ss
estimation of survival among patients with brain metastasis, Neuro-Oncol
14:910–918, 2012.
CBTRUS: Primary brain and central nervous system tumors diagnosed in the
United States in 2004–2007, Central Brain Tumor Registry of the United
States Statistical Report 2011.
De Braganca KC, Packer RJ: Treatment options for medulloblastoma and CNS
primitive neuroectodermal tumor (PNET), Curr Treat Options Neurol
15:593–606, 2013.
Nuño M, Birch K, Mukherjee D, et al: Survival and prognostic factors in
anaplastic gliomas, Neurosurgery 73:458–465, 2013.
Patil CG, Pricola K, Sarmiento JM, et al: Whole brain radiation therapy (WBRT)
alone versus WBRT and radiosurgery for the treatment of brain metastases,
Cochrane Database Syst Rev (9):CD006121, 2012.
Rutkowski S, von Hoff K, Emser A, et al: Survival and prognostic factors of early
childhood medulloblastoma: an international meta-analysis, J Clin Oncol
28:4961–4968, 2010.
Taylor M, Northcott P, Korshunov A, et al: Molecular subgroups of
medulloblastoma: the current consensus, Acta Neuropathol 123:465–472,
2012.
van den Bent MJ, Brandes AA, Taphoorn MJ, et al: Adjuvant procarbazine,
lomustine, and vincristine chemotherapy in newly diagnosed anaplastic
oligodendroglioma: long-term follow-up of EORTC brain tumor group study
26951, J Clin Oncol 31:344–350, 2013.
Wang Z, Bao Z, Yan W, et al: Isocitrate dehydrogenase 1 (IDH1) mutation-
specific microRNA signature predicts favorable prognosis in glioblastoma
patients with IDH1 wild type, J Exp Clin Cancer Res 32:59, 2013.

Demyelinating and
Inflammatory Disorders
  INTRODUCTION
In demyelinating CNS disorders, previously normal myelin is lost
due to an acquired, typically inflammatory disease. The proto-
typic CNS demyelinating disorder is multiple sclerosis (MS).
Other disorders of this type include neuromyelitis optica
(NMO), acute disseminated encephalomyelitis (ADEM), acute
transverse myelitis (TM), and optic neuritis (ON).
  MULTIPLE SCLEROSIS
Definition/Epidemiology
According to the National Multiple Sclerosis Society, MS affects
over 2 million people worldwide. It is a presumed autoimmune
disorder, although the exact etiology is still not fully understood.
MS begins as a relapsing remitting disease in greater than 80% of
patients and ultimately becomes progressive in greater than 50%
of untreated patients. Patients with progressive MS accumulate
neurologic disability, with or without discrete relapses. MS is
more common in females, with the current female to male ratio
in North America and in Europe estimated at 2-4 : 1. An excep-
tion is primary progressive MS (see Clinical Presentation), where
the female to male ratio is 1 : 1.
MS is most common in persons of northern European ances-
try. Recent genome-wide association studies indicate that many
genes affect the risk of MS, although most confer only a small risk
of disease (odds ratios less than 1.5). Alleles within the HLA-DR
region (DRB1*15:01 > DRB1*13:03 > DRB1*03:01) are the
most well-established and confer the greatest risk with odds
ratios between 1.5 and 4 for most populations of northern Euro-
pean ancestry.
Environmental factors can also confer risk for MS. Modifi-
able factors include low vitamin D blood level, high body mass
index during adolescence/young adulthood, and smoking ciga-
rettes. Seropositivity to the Epstein Barr virus increases the
risk of MS; a symptomatic case of infectious mononucleosis
confers greater risk than seropositivity alone. Though relatively
high at 1/1000 to 1/500, the incidence of MS appears relatively
stable in North America, the United Kingdom, and Europe.
Incidence of MS may be increasing in several regions where
MS was not previously prevalent, such as Iran, Turkey, Sicily,
and South Africa. These reports of increasing incidence may
reflect a real increase or just improved recognition and
diagnosis.
120 
ss
Anne Haney Cross
Pathology
Classically, MS causes demyelinating CNS white matter lesions
with relative sparing of axons. The most common pathology of
active lesions in white matter is perivascular mononuclear cell
infiltration (monocyte/macrophages, lymphocytes), with a vari-
able presence of antibody and activated complement. Acutely
active white matter lesions display blood-brain barrier break-
down, which is manifest on MRI by gadolinium enhancement.
Despite its categorization as a “white matter disease,” gray matter
is frequently damaged in MS. Gray matter lesions have been
under-recognized because they are difficult to see by MRI, and
are often not appreciated pathologically without special stains.
Such gray matter lesions may occur in the white matter tracts
within deep gray structures such as the thalamus or be within
gray matter itself, such as in the cerebral cortex. Cortical gray
matter lesions can be subpial, extend into cortex from underlying
white matter (leukocortical), or be wholly within the cortex.
Cortical lesions are characterized by activated microglia and rela-
tively fewer infiltrating lymphocytes and macrophages when
compared with white matter MS lesions. Ectopic lymphoid tissue
containing B cells, a finding associated with chronic inflamma-
tion, has also been observed in meninges of progressive MS
subjects.
Clinical Presentation
MS may manifest with a variety of symptoms and signs.
Common presentations include: optic neuritis, diplopia (often
caused by internuclear ophthalmoplegia due to a propensity of
MS to affect the medial longitudinal fasciculus), TM, brainstem
syndromes, sensory disturbances, and weakness. Less frequent
presentations include seizures, cognitive problems, bladder
control problems, and pain. Clinically isolated syndrome (CIS)
refers to a single attack that is likely due to CNS demyelination.
CIS may be acute or subacute in onset, and may involve a single
or more than one CNS region. CIS presentations may look
identical to MS attacks, but a formal diagnosis of MS cannot
be made until the occurrence of separation of lesions in time.
Ultimately, most CIS patients do develop MS. In one study, over
85% of CIS patients with even one silent abnormality on brain
or spinal cord magnetic resonance imaging (MRI) eventually
developed clinically definite MS. On the other hand, only about
20% of those without any other MRI abnormalities developed
clinically definite MS.
1069
 1070 Section XVI  Neurologic Disease

Three main clinical subtypes of MS are defined based on clini-

ss cal course: relapsing remitting, secondary progressive, and TABLE 120-1  THE 2010 REVISED MCDONALD
primary progressive. Relapsing remitting MS is characterized by CRITERIA
clinical stability between individual attacks from which the ADDITIONAL DATA
CLINICAL NEEDED FOR MS
patient may or may not fully recover. Secondary progressive MS PRESENTATION LESIONS DIAGNOSIS*
patients have gradual neurologic deterioration and may also have
≥2 attacks Objective clinical None
superimposed attacks. Secondary progressive MS develops fol- evidence of ≥2
lowing an initial relapsing-remitting course in a substantial pro- lesions or objective
portion of relapsing remitting patients, although this proportion clinical evidence of 1
lesion and reasonable
may be declining with the advent of disease-modifying therapies. historical evidence of
About 10% of MS patients have primary progressive MS, which a prior attack
is characterized by gradual downhill progression from onset ≥2 attacks Objective clinical DIS demonstrated by >1
evidence of 1 lesion T2w lesion in at least 2 of
without any clinical attacks. It has been proposed to discontinue 4 MS-typical regions of
the uncommon fourth clinical designation, progressive relapsing CNS, or 2nd clinical attack
MS, in favor of primary progressive MS with activity. at alternate site in CNS
1 attack Objective clinical DIT demonstrated by
evidence of ≥2 simultaneous presence of
Diagnosis lesions asymptomatic gad+ lesion
The diagnosis of MS requires dissemination of CNS disease in and non-enhancing lesions
or a new T2w and/or
time and in space. No other disease should provide a better expla- gad+ lesion on follow-up
nation. MRI, spinal fluid analyses, evoked potentials (EPs) and MRI after a baseline scan,
ocular coherence tomography (OCT) are tools that may aid in or 2nd clinical attack
1 attack Objective clinical For DIS, ≥1 T2w lesion in at
the diagnosis. The McDonald criteria (Table 120-1) allow new evidence of 1 lesion least 2 of 4 MS-typical
MRI lesions to be used to define disease in time after an initial (CIS) regions of CNS; For DIT,
first attack (clinically isolated syndrome). These criteria have as above; or await a 2nd
clinical attack implicating
made diagnosis easier, without losing significant specificity. different CNS region
Gradual 1 year or more of disease progression plus 2 of 3 of
MRI neurologic following criteria:
progression evidence for DIS in the brain based on ≥1 T2w lesions
Classic features seen on brain and spinal cord MRI greatly aid in suggestive of characteristic of MS, evidence of DIS in the spinal
the certainty of diagnosis. MS lesions are characterized by MS (PPMS) cord ≥2 T2w cord lesions positive CSF (elevated IgG
increased intensity on T2-weighted (T2w) and T2-FLAIR (fluid index or oligoclonal bands not present in serum)
attenuated inversion recovery) images (Fig. 120-1A). Lesions are (Modified from Polman CH, Reingold SC, Banwell B, et al: Diagnostic criteria for multiple
sclerosis: 2010 revisions to the McDonald criteria, Ann Neurol 69(2): 292–302, 2011,
usually ovoid, and often localize to the periventricular or subcor- Table 4.)
tical regions, the corpus callosum, the brainstem, and the cervical DIS, Dissemination in space; DIT, dissemination in time.
*These criteria were developed using CIS presentations and are therefore most
spinal cord. Periventricular lesions are typically at right angles to applicable in patients who present with a typical CIS suggestive of CNS inflammatory
the lateral ventricles and bear the moniker “Dawson’s fingers.” On demyelinating disease. Alternative diagnoses that might better explain the disorder must
be considered and reasonably excluded.
sagittal images, lesions in the corpus callosum are usually flame-
shaped (Fig 120-1C). On T1w images, MS lesions may be isoin-
tense or hypointense. T1w hypointensity in a chronic inactive Evoked Potentials
lesion denotes underlying tissue damage, including axonal loss Evoked potentials (EPs) detected by surface electrode recording
(Fig.120-1D). Enhancement of lesions following administration have in the past been useful in detecting subclinical demyelin-
of gadolinium containing contrast agents indicates blood-brain ation in the brainstem (auditory EPs), spinal cord (somatosen-
barrier breakdown, and that a lesion is active (Fig. 120-1B). sory EPs), and optic nerves (visual EPs). The advent of high
Enhancing lesions are also often T1w hypointense, but the resolution MRI has made these tests less useful.
hypointensity resolves more than 50% of the time. A ring pattern
of enhancement is common. Most enhancing MS lesions display Optical Coherence Tomography
no edema or mass effect, but occasional “tumefactive” MS lesions Optical coherence tomography (OCT) is a safe and rapid means
have significant edema on MRI and may require biopsy for to image the retina and detect evidence of prior optic neuritis.
diagnosis. OCT uses safe infrared light to provide images of the retinal
layers, including the retinal nerve fiber layer (RNFL) which con-
Spinal Fluid Analysis tains axons that form the optic nerve. The RNFL is thinner than
Evidence of increased intrathecal immunoglobulin synthesis is normal in those with remote optic neuritis. Also, RNFL thickness
present in more than 90% of MS patients. Elevated concentra- correlates with neurodegenerative aspects of MS, such as brain
tions of CSF IgG and IgM, CSF-restricted oligoclonal bands of atrophy.
immunoglobulin (Fig. 120-2), and a high intrathecal IgG synthe-
sis rate are seen. The IgG index, which is derived from the ratio Differential Diagnosis
of CSF to serum IgG and takes BBB integrity into account, is The diagnosis of MS requires the exclusion of diseases that might
elevated. A mild lymphocytic pleocytosis is frequently seen in better explain the clinical scenario. The differential diagnosis of
CSF during MS relapses. MS is broad (Table 120-2). Some diseases that can mimic MS
 Chapter 120  Demyelinating and Inflammatory Disorders 1071

ss

A B

C D
FIGURE 120-1  A, Axial fluid-attenuated inversion recovery (FLAIR) image of the brain from a patient with MS revealing classical periventricular
and deep white matter high-signal intensity lesions. B, Axial T1-weighted image following gadolinium contrast administration in the same patient
as A. Enhancing lesions after gadolinium contrast administration, indicating loss of integrity of the blood-brain barrier that is seen with active MS
lesions. One enhancing lesion in the right parietal region is ring enhancing. C, Sagittal FLAIR image of the brain of an MS patient demonstrating
classical flame-shaped pericallosal lesions radiating outward from the ventricle. D, Axial T1-weighted image showing areas of T1 low signal intensity
(“black holes”).

have relapses and others display progressive courses. “Red flags”

that are atypical for MS, such as non-CNS symptoms (arthritis,
rash, pulmonary, or GI symptoms), bilateral hearing loss, periph-
CSF eral neuropathy, or atypical time of onset (early childhood or
after age 50) should lead the clinician to question the diagnosis
of MS.
For a deeper discussion of these topics, please see Chapter
411, “Multiple Sclerosis and Demyelinating Conditions of
Serum the Central Nervous System,” in Goldman-Cecil Medicine,
25th Edition.

Anodal Cathodal Treatment

pH 8.0
FIGURE 120-2  Isoelectric focusing gel of cerebrospinal fluid (CSF)
and serum of a patient with multiple sclerosis. The CSF (upper lane)
shows oligoclonal bands cathodal to the pH 8.0, which are not seen in
the serum (lower lane).
MS treatment can be divided into three categories: treatment of
symptoms (e.g. spasticity, fatigue, or depression), treatment of
acute relapses, and disease-modifying therapies. This discussion
will be largely limited to the latter two categories. Table 120-3
lists some major symptoms and their therapies in MS.
 1072 Section XVI  Neurologic Disease

ss
TABLE 120-2  DIFFERENTIAL DIAGNOSIS OF DEMYELINATING DISEASES
DISEASE CATEGORY* EXAMPLES OF DISORDERS†
Immune-mediated /autoimmune Multiple sclerosis, neuromyelitis optica (NMO), acute demyelinating encephalomyelitis (ADEM), idiopathic optic neuritis,
CRION, idiopathic transverse myelitis, Behçet’s disease
Infectious Progressive multifocal leukoencephalopathy (PML), HTLV-I, HIV, CNS abscess, Lyme disease, Whipple disease,
neurosyphilis
Metabolic Vitamin B12, vitamin E or copper deficiency, central pontine and extrapontine myelinolysis
Neurodegenerative spinocerebellar ataxias, spine disease (e.g. compressive cervical spondylopathy)
Rheumatologic Sarcoidosis, systemic lupus erythematosus, antiphospholipid antibody syndrome, Sjögren syndrome
Genetic Disorders Adrenomyeloleukodystrophy/adrenomyeloneuropathy, hereditary spastic paraparesis, CADASIL, Leber’s optic neuropathy,
Perlizeus-Merzbacher, Wilson’s disease
Neoplastic/Paraneoplastic CNS Lymphoma, meningeal carcinomatosis, paraneoplastic CRMP-5 IgG, anti-Amphiphysin-1 Abs
Vascular CNS vasculitis (e.g., giant cell arteritis, primary CNS vasculitis, etc.), spinal dural fistula, Susac syndrome
Iatrogenic TNF inhibitors, CNS irradiation
*Several of the disorders listed could be placed in more than one category.
†
This list is not comprehensive.

The BIFNs and GA all reduced annualized relapse rate by about

TABLE 120-3  SELECTED MS SYMPTOMS AND THEIR 30% in early pivotal studies. Most have also been shown to delay
MANAGEMENT progression to definite MS in patients with clinically isolated syn-
SYMPTOM/SIGN TREATMENT(S) drome who are at high risk for developing MS.
Stiffness/cramps/spasms/spasticity baclofen, tizanidine (evidence level As of 2015, twelve different DMTs with seven different
A) mechanisms of action are available for MS (Table 120-4). The
Fatigue Amantadine, modafanil, armodafinil,
amphetamines approved agents have distinct and variable risk profiles. As
Depression Selective serotonin reuptake there are currently no biomarkers that direct the choice of
inhibitors, cognitive behavior disease modifying therapies for an individual patient, selection
therapy
Pain/paresthesias/trigeminal gabapentin, carbamazepine, of the disease modifying therapy for an individual is based on
neuralgia oxcarbazepine, pregabalin, disease course and severity, patient comorbidities, and individual
amitriptyline preferences.
Gait impairment Fampridine SR (Evidence level A)
Nystagmus, with visual impairment Gabapentin Five BIFNs are approved for use in relapsing remitting MS and
Dizziness/Vertigo Meclizine, dimenhydrinate, clinically isolated syndrome in the United States. They differ in
benzodiazepines dosage, side effects, and incidence of neutralizing antibody
Urinary urgency/incontinence/ Oxybutynin, tolterodine, other
neurogenic bladder anticholinergics, BOTOX injection induction. Three BIFNs are identical to endogenous human
Impotence/erectile dysfunction Sildenafil, tadalafil, testosterone BIFN-1a (poly ethyleneglycol has been covalently attached to
supplementation if low one of the three for longer duration of effect); the other two are
Tonic spasms Phenytoin, carbamazepine
BIFN-1b, which differs by one amino acid. BIFNs are immuno-
modulators, though their exact mechanism of action in MS is not
Relapses that alter function or cause pain are typically treated fully established. BIFN therapy is associated with increased cir-
with corticosteroids. Severe relapses are usually managed with culating soluble VCAM-1, which could produce an effect similar
intravenous methylprednisolone at 500-1000 mg daily for 3 to 5 to that of the monoclonal antibody natalizumab. Patients taking
doses, followed by a short oral corticosteroid taper (usually pred- BIFNs require monitoring of hepatic transaminases and CBC;
nisone). Oral corticosteroid tapering courses may be used for elevation of transaminases is uncommon, but may require dose
mild relapses. Blood pressure, serum electrolytes and glucose, adjustment or discontinuation. Common side effects include a
and patient mood should be monitored during corticosteroid “flu-like” feeling for several hours after a dose, which is usually
therapy. Based on the multi-center Optic Neuritis Treatment improved by nonsteroidal anti-inflammatory medications or
Trial (ONTT), this regimen will lead to more rapid recovery from acetaminophen. BIFNs are given by injection and, as with any
the attack, but is unlikely to alter the degree of eventual recovery injectable drug, skin infection can occur. BIFNs are rated Preg-
(evidence level A). nancy Category C; the BIFNs should be discontinued before
For severe relapses that do not respond to high-dose IV corti- conception.
costeroids, a small randomized study showed that plasma Glatiramer acetate is given as a daily 20 mg subcutaneous injec-
exchange can be effective. Plasma exchange was followed by rapid tion, or 40 mg SQ three times per week. The drug is a random
functional improvement in over 40%, with early initiation of polymer of four amino acids that are abundant within myelin
plasma exchange treatment the single factor most associated with basic protein, a major protein in CNS myelin. It is considered
significant improvement (level A). Subjects in this trial likely immunomodulatory not immunosuppressive, although its mech-
included patients with neuromyelitis optica (NMO) and acute anism of action is not fully understood. Glatiramer acetate has no
disseminated encephalomyelitis (ADEM), in addition to MS. known drug interactions, and laboratory monitoring is not
Relapsing remitting MS (RRMS) is one of only a handful of needed. Side effects include injection site reactions and an
chronic neurologic disorders with effective disease modifying uncommon transient tachycardia reaction that occurs soon after
therapies. The beta-interferons (BIFNs) and glatiramer acetate an injection. Lipoatrophy at injection sites may develop with pro-
(GA) are FDA-approved for relapsing remitting MS (level A). longed use. Glatiramer acetate is pregnancy category B, and is
 Chapter 120  Demyelinating and Inflammatory Disorders 1073
TABLE 120-4  DISEASE MODIFYING MEDICATIONS FOR MS
DRUG (BRAND NAME), DOSING APPROVED
Interferon beta 1b (Betaseron, Extavia), 250ug SQ qod 1993, 2009
Interferon beta 1a (Avonex) 30ug IM weekly 1996
Interferon beta 1a (Rebif) 22 or 44ug SQ 3x /wk. 2002
Interferon beta 1a (Plegridy) 125ug SQ every 14 days 2014
Glatiramer acetate (Copaxone) 20mg SQ daily, 1996
or 40mg SQ 3x/wk 2014
Mitoxantrone (Novantrone) 12mg/m2 IV q 3 months 2000
Natalizumab (Tysabri) 300mg IV q 4 weeks 2004/2006
Fingolimod (Gilenya) 0.5mg po daily 2010
Teriflunomide (Aubagio) 7mg or 14mg po daily 2012
Dimethyl fumarate (Tecfidera) 240mg po BID 2013
Alemtuzumab (Lemtrada) IV infusion, SQ in 2014
development
considered the safest MS disease modifying therapy to use in
women who may become pregnant.
Mitoxantrone is an anthracenedione chemotherapeutic agent
that is FDA approved for secondary progressive MS, progressive
relapsing MS, or worsening relapsing-remitting MS. It is admin-
istered by IV infusion every 3 months and has a lifetime dose
limit due to dose-related cardiotoxicity. In a prospective random-
ized 2-year study enrolling worsening relapsing-remitting or
secondary progressive MS patients, those that received mitoxan-
trone had longer time to first treated relapse and improved level
of disability compared with those randomized to placebo (level
A). Beneficial effects were still measurable 12 months after treat-
ment discontinuation. In addition to dose-limiting cardiotoxicity,
mitoxantrone is associated with leukemia in approximately 1%
of MS patients. Because of these risks and with the advent of
more targeted medications, mitoxantrone is not commonly used
in the United States.
Natalizumab is a humanized monoclonal antibody targeting
the α-4-integrins, part of the VLA-4 adhesion-related heterodi-
mer. The dose is 300 mg given intravenously every 4 weeks. A
2-year phase 3 trial of natalizumab showed 68% reduction in
annualized relapse rate, 42% reduction in sustained disability, and
over 90% reduction in gadolinium-enhancing lesions compared
with placebo (level A). Natalizumab was temporarily removed
from the market in 2005 due to an association with progressive
multifocal leukoencephalopathy, a severe viral disorder caused by
the JC virus. Because of its association with progressive multifo-
cal leukoencephalopathy, this drug is generally recommended in
cases of an inadequate response or intolerance of an alternate MS
therapy. Patients receiving it must take part in a risk-mitigation
program and can only be infused at certified infusion centers.
Natalizumab is pregnancy category C.
Fingolimod was the first oral disease modifying therapy to
be approved for relapse rate reduction in MS. This once daily
0.5  mg capsule reduces annualized relapse rate by about 50%
and disability progression by about 25% versus placebo (level
A). Fingolimod has several risks, including macular edema,
pulmonary dysfunction, bradycardia, and herpetic infections.
ss
MS INDICATION MECHANISM OF ACTION
RRMS, CIS Inhibits “pro-inflammatory” cytokines, such as interferon
RRMS, CIS (IFN)-gamma, tumor necrosis factor alpha, and
RRMS lymphotoxin. Increases IL-10.
Relapsing forms of MS Adhesion molecule and class II MHC induction reduced.
RRMS, CIS Alters T cell cytokine profile toward that of Th2
immunomodulatory cells.
Worsening RRMS, Anthracenedione chemotherapeutic agent
relapsing SPMS PRMS
Relapsing MS* Monoclonal antibody targeting the alpha-4-integrins, part
of the VLA-4 adhesion molecule.
Relapsing MS, approved for Down-modulates sphingosine-1-phosphate receptors,
treatment naïve patients lymphocytes unable to migrate out of lymphoid tissue.
May have direct effects in CNS
Relapsing MS, approved for Inhibits dihydroorotate dehydrogenase, thus inhibiting
treatment naïve patient proliferation of activated lymphocytes
Relapsing MS, approved for Activates nuclear factor erythroid 2-related factor 2
treatment naïve patients (Nrf2) pathway which enhances response to oxidative
stress
Relapsing forms of MS Monoclonal antibody that lyses cells expressing CD52
It is contraindicated in some settings, such as recent myocardial
infarction or uncontrolled heart failure, and with certain medi-
cations (such as class IA and class III anti-arrhythmic drugs).
Medical monitoring for potential bradycardia for at least 6
hours is necessary for the first dose. Fingolimod is pregnancy
category C.
Teriflunomide is a once daily oral tablet of 7 mg/day or 14 
mg/day. Two phase 3 studies in relapsing patients with relapsing
forms of MS found that the 14 mg/day dose significantly reduced
annualized relapse rate by over 30% and disability progression by
around 30% (level A). The 7 mg dose had a lesser beneficial
effect. Thus, the 14 mg daily dose is favored by many clinicians.
Teriflunomide can cause hepatotoxicity, and it is contraindicated
in pregnancy (pregnancy category X). If necessary, teriflunomide
can be rapidly eliminated from the body using cholestyramine,
otherwise it persists for long periods. Teriflunomide is closely
related to the drug leflunomide, approved for rheumatoid arthri-
tis in 1998.
Dimethyl fumarate is a capsule taken orally twice daily. In phase
3 trials, it reduced MS relapse rates by 44 to 53% and also
improved MRI outcomes (level A). The white blood cell count
may drop and should be monitored. As of late 2014, one fatal case
of PML in a person taking the medication and with persistent low
lymphocyte counts has occurred. Adverse effects include flush-
ing, gastrointestinal side effects, and rash. Dimethyl fumarate is
pregnancy category C.
Alemtuzumab is a monoclonal antibody targeting cells express-
ing CD52, which includes T and B lymphocytes, monocytes, and
other mononuclear white blood cells. In the CARE-MS I and II
studies in RRMS patients, alemtuzumab was compared not to
placebo, but instead to 44 µg BIFN-1a given subcutaneously
three times per week. Patients treated with alemtuzumab had
lower annualized relapse rate (by 49% and 53.8%) and disability
progression (by 28% and 42%). Alemtuzumab leads to a pro-
found drop in the white blood cell count, which may last for
months or even years. In trials, secondary autoimmune diseases
developed in a sizeable proportion of alemtuzumab-treated sub-
jects, with autoimmune thyroid disease being most common.
 1074 Section XVI  Neurologic Disease
ss
Prognosis
MS is highly variable. It is occasionally “benign” in which case
the disease has little impact on quality of life. It can also be severe
with considerable disability or early death. Most patients fall in
between these extremes. Poor prognostic indicators at onset of
MS include primary progressive course, male gender, frequent
attacks, prominent motor or cerebellar findings, and high initial
MRI lesion burden. Expected lifespan of people with MS is
reduced overall by 7 to 14 years. Suicide rate is 1.7 to 7.5 times
that of the general population. Albeit controversial, the use of
disease modifying therapies (BIFNs and GA) likely improves not
only relapse rate but long-term disability and even mortality. In
one non-randomized study, early initiation of disease modifying
therapies within a year of symptom onset was associated with
better long-term outcomes.
  NEUROMYELITIS OPTICA (DEVIC’S DISEASE)
Definition/Epidemiology
Neuromyelitis optica (NMO), also called Devic’s Disease, is an
inflammatory CNS disorder causing both demyelination and
necrosis. NMO can be monophasic, but is more often character-
ized by attacks of optic neuritis and longitudinally extensive TM
that are not necessarily concurrent. NMO was once believed to
be a subtype of MS, but now is known to be a different disorder
associated in most cases with autoantibodies to the aquaporin 4
(AQP4) water channels, which are strongly expressed by astro-
cytes. Histopathological changes in NMO are mostly in the
spinal cord and optic nerve; the brain is less involved. AQP4 is
expressed outside of the CNS in the kidney, stomach, and other
tissues, but curiously no pathology has been recognized in the
non-CNS organs expressing AQP4.
NMO is much less common than MS, with estimates by the
Guthy-Jackson Charitable Foundation of 4,000 patients in the
FIGURE 120-3  A, Sagittal T2w image of the upper spinal cord in a 37-year-old female with NMO. She developed quadriparesis over several days,
and was AQP4-IgG seropositive. Two years later she had right eye optic neuritis, which left her with visual acuity of only 20/200. The spinal cord lesion
(arrows) had mild mass effect and was contiguous over 6 vertebral segments. B, Sagittal T2w image of the upper spinal cord in a 24-year-old male
with MS shows a lesion (arrow) in the posterior cord at C2. This patient had moderate vibration loss in the legs but was otherwise asymptomatic.
United States, and a half million worldwide. It is even more
female-preponderant than MS, with female to male ratio esti-
mated from 4 : 1 to 8 : 1. Children and adults both develop NMO.
Unlike MS, NMO is not associated with HLA-DRB1*15:01,
and it affects those of Asian, African, and Hispanic ancestry
disproportionately.
Clinical Presentation
NMO presents clinically as an acute attack of optic neuritis
and/or TM; it often takes a relapsing course. Gradually pro-
gressive NMO has not been described (helping to distinguish
it from progressive MS). Other autoimmune diseases often
occur together with NMO including Sjögren’s syndrome, sys-
temic lupus erythematosis, Hashimoto’s disease, and myasthenia
gravis.
Diagnosis/Differential
In 2004, researchers first reported the presence of a serum
IgG autoantibody to cerebral vessels in NMO; this was later
found to target aquaporin 4. NMO-IgG/ AQP4-IgG is highly
specific (>90%) and relatively sensitive (~75%) for NMO.
Fulfilling two out of three of the following criteria is reported
to be 99% sensitive and 90% specific for NMO in the set-
ting of optic neuritis and TM: (1) longitudinally extensive
spinal cord lesion, which is greater than or equal to 3 seg-
ments in length (Figure 120-3); (2) NMO-IgG positivity;
and (3) brain MRI not typical or diagnostic for MS. NMO-
IgG seropositive patients with isolated optic neuritis or lon-
gitudinally exten­sive TM are currently described as having
“NMO spectrum disorder.”
For a deeper discussion of these topics, please see Chapter
411, “Multiple Sclerosis and Demyelinating Conditions of
the Central Nervous System,” in Goldman-Cecil Medicine,
25th Edition.
 Chapter 120  Demyelinating and Inflammatory Disorders 1075
Pathology
NMO lesions affect both white and gray matter and are located
mainly in the spinal cord and optic nerves. In the brain, they are
most common in the hypothalamus and around the fourth
ventricle. NMO lesions center on blood vessels, where IgG, IgM,
and complement activation products are seen. The vessels are
abnormally thickened and hyalinized. Active NMO lesions show
infiltration by mononuclear cells (lymphocytes, monocytes),
neutrophils, and eosinophils. Older lesions display demyelin-
ation, axon loss, and death of oligodendroglia and neurons. In
vitro and animal studies indicate that AQP4-IgG itself is patho-
genic, causing complement- and antibody-mediated damage.
Treatment
Acute relapses are treated with high-dose corticosteroids. If these
are not effective, plasma exchange is usually tried.
Because NMO is a rare disease, large multi-center randomized,
controlled trials of disease modifying therapies are lacking.
Several short case series have pointed toward possible efficacy of
azathioprine plus prednisone, rituximab, and mycophenolate
mofetil for prevention of future attacks (level C). Eculizumab, a
monoclonal antibody that inhibits the complement cascade, was
used in a small open-label trial in AQP4-IgG positive NMO
patients. Over one year, 85% had no relapses and no patient pro-
gressed in disability (level B). Of note, beta-interferons are not
effective for NMO and may actually increase the rate of attacks.
Prognosis
The necrotic nature of NMO results in worse outcomes than MS.
Seropositive NMO patients tend to have more frequent and
severe relapses than AQP4-IgG negative patients. Death can be a
consequence and is often due to respiratory failure. The death
rate in a retrospective study covering 1950-1997 was over 30%.
Less than 10% mortality was reported in a more recent retrospec-
tive study of Caucasian NMO patients.
  ACUTE DISSEMINATED ENCEPHALOMYELITIS
Acute disseminated encephalomyelitis (ADEM) is an acute,
inflammatory, presumed immune-mediated disorder of the CNS
that is encountered primarily in children but may occur in adults.
An antecedent viral infection, or occasionally a vaccination, is
common. ADEM presents with multifocal neurologic symptoms
and signs. These can include encephalopathy, which may mani-
fest as reduced level of consciousness (even coma), or as behav-
ioral changes (e.g. confusion or irritability). Fever is common.
Seizures, optic neuritis, and spinal cord involvement can all
occur. Males and females are about equally affected. ADEM is
usually monophasic, although relapsing ADEM has been
described. On MRI, both white and gray matter CNS regions are
affected. Gray matter involvement can include the basal ganglia,
a region not typically affected in MS. The periventricular white
matter region is often spared, unlike MS. When present, enhance-
ment with gadolinium occurs in all lesions simultaneously. CSF
often shows pleocytosis and an elevated protein, but no infection.
Findings typical of MS, such as oligoclonal bands, are not usual.
No randomized prospective treatment trials for acute dissemi-
nated encephalomyelitis are reported. Intravenous methylpred-
nisolone followed by a prednisone taper is typically administered,
and the response is usually good (level D). Over 80% of cases
recover well. As ADEM is only rarely recurrent, long-term ss
immunomodulatory/immunosuppressive therapy is not indi-
cated. A rare hemorrhagic form of ADEM (Weston Hurst
syndrome) is more severe and can lead to death or severe
disability.
  ACUTE TRANSVERSE MYELITIS
Transverse myelitis (TM) is an inflammatory spinal cord syn-
drome presenting with abrupt or subacute onset of motor and/
or sensory loss below a specific spinal level. Control of bladder
and bowel is often affected, as is autonomic function below the
level. Back pain and paresthesias may be prominent. Many cases
of acute TM are idiopathic, but treatable causes must be ruled
out. An urgent MRI with and without gadolinium should be
obtained to look for compressive etiologies needing immediate
treatment. After a compressive etiology has been ruled out, a
lumbar puncture to assess CSF for cell count, glucose, and
protein, and cultures and PCRs for infectious causes should be
done. The usual tests for MS should be performed, and CSF
should be analyzed for evidence of neoplastic etiology. Serum
AQP4-IgG, paraneoplastic panels and chest CT should be con-
sidered. CSF may also be tested for NMO-IgG, angiotensin con-
verting enzyme, and paraneoplastic antibodies when no etiology
is forthcoming.
Acute TM can be the presenting episode for MS (where the
TM is generally incomplete and asymmetric) or NMO (where
the TM affects ≥3 spinal cord segments). Acute TM can also be
caused by spinal cord infarction due to occlusion of the anterior
spinal artery. Infections by viruses can cause acute or subacute
TM. The most common viruses associated with acute TM are
varicella zoster, herpes virus type 2, and cytomegalovirus. The
retroviruses HTLV-I and HIV can each cause a myelopathy that
is usually subacute. West Nile virus can cause a myelopathy that
resembles poliomyelitis, with flaccid paralysis due to infection
and death of anterior horn cells. Subacute TM may be caused by
vitamin B12 or copper deficiency, or infiltrating or compressive
syndromes such as tumors or abscesses. Nitrous oxide anesthesia
can precipitate an acute onset myelopathy in the case of border-
line vitamin B12 deficiency. Rheumatologic disorders such as
Sjögren’s disease, systemic lupus erythematosus, and Behçet’s
disease can all cause TM. Paraneoplastic syndromes associated
with anti-CRMP-5 and anti-amphiphysin can cause a tract-
specific myelopathy. The history and physical examination should
be performed with these disorders in mind.
Treatment is determined by the most likely etiology. Idio-
pathic TM is treated much like TM in MS or NMO, with intra-
venous methylprednisolone at 500 mg to 1000 mg/day, usually
followed by a short oral prednisone taper (evidence level D).
When response to intravenous methylprednisolone is subopti-
mal, plasma exchange should be considered.
  IDIOPATHIC ACUTE OPTIC NEURITIS
Inflammatory demyelinating optic neuritis can occur as part of
MS or NMO, or as an idiopathic entity. Classically, optic neuritis
presents over hours with loss of vision together with pain exac-
erbated by eye movement. Vision loss may range from subclinical
to frank blindness. Color vision and contrast sensitivity are
disproportionately affected. On examination, a relative afferent
 1076 Section XVI  Neurologic Disease
pupillary defect is seen in unilateral optic neuritis. Acute demy-
ss elinating optic neuritis is often retrobulbar without papillitis.
On MRI, the optic nerve can be swollen and enhance after gado-
linium contrast. After recovery from the acute episode, the optic
disk may appear pale, and the relative afferent pupillary defect
may persist. Transient worsening of vision when the body tem-
perature rises due to exercise or fever (Uhthoff ’s phenomenon)
may occur following recovery. The differential diagnosis includes
other causes of acute monocular or binocular vision loss, such as
Leber’s hereditary optic neuropathy, giant cell arteritis, and acute
non-arteritic anterior ischemic optic neuropathy.
The Optic Neuritis Treatment Trial studied patients with acute
optic neuritis (either idiopathic or due to MS) who were random-
ized to one of three treatments, intravenous methylprednisolone
versus oral prednisone taper versus oral placebo. Visual acuity
initially recovered faster in the intravenous methylprednisolone
group, but by 6 months later there was no difference among the
three groups (level A). Recovery of vision was good. Patients
from this trial were examined 10 years later and acuity in the
affected eyes was 20/20 or better in 74% and less than 20/200 in
only 3%. However, recurrence of optic neuritis was common, and
had occurred in either eye in 35% of the patients. Recurrences
were more frequent in those who had MS than those with idio-
pathic optic neuritis (P < .001).
  CHRONIC RELAPSING INFLAMMATORY
OPTIC NEUROPATHY
First described in 2003, chronic relapsing inflammatory optic
neuropathy (CRION) is an inflammatory optic neuropathy char-
acterized by acute relapses, but often with more severe visual loss
than idiopathic optic neuritis or optic neuritis associated with
MS. Patients with CRION can have onset at any age and the
entity has been described worldwide. Prevalence rates and epide-
miology are still unclear. As in other types of optic neuritis, eye
pain at onset is frequent. Return of pain can herald a relapse.
Uveitis is present in a small percentage of cases. Five diagnostic
criteria for CRION have been suggested: (1) optic neuritis with
at least one relapse, (2) objective visual loss, (3) AQP4-IgG sero-
negative, (4) contrast enhancement on MRI of acutely inflamed
optic nerve, and (5) response to immunosuppressive treatment
and relapse on withdrawal. Other diseases that might present
similarly, such as sarcoidosis and giant cell arteritis, should be
ruled out. Treatment for acute CRION is similar to that for other
causes of optic neuritis, using intravenous methylprednisolone
followed by oral corticosteroids. Relapses are common upon cor-
ticosteroid discontinuation. Successful long-term treatment with
“steroid sparing” agents such as methotrexate, azathioprine, or
mycophenolate mofetil has been reported. The underlying
pathology is not yet known, but the disease appears inflamma-
tory based on clinical presentation, imaging, and specific medica-
tion response. Eventual visual outcomes are often poor. One
report indicated that visual acuity was less than 20/200 in one
third of CRION patients.
SUGGESTED READINGS
Kim SH, Huh SY, Lee SJ: A 5-Year Follow-up of Rituximab Treatment in Patients
with Neuromyelitis Optica Spectrum Disorder, JAMA Neurol 70:1110–1117,
2013.
Klaver R, De Vries HE, Schenk GJ, et al: Grey matter damage in multiple sclerosis:
a pathology perspective, Prion 7:66–75, 2013.
Langer-Gould A, Brara SM, Beaber BE, et al: Incidence of multiple sclerosis in
multiple racial and ethnic groups, Neurology 80:1734–1739, 2013.
Petzold A, Plant GT: Chronic relapsing inflammatory optic neuropathy: a
systematic review of 122 cases reported, J Neurol 261:17–26, 2014.
Polman CH, Reingold SC, Banwell B, et al: Diagnostic criteria for multiple
sclerosis: 2010 revisions to the McDonald criteria, Ann Neurol 69(2):292–
302, 2011.
West TW, Hess C, Cree BA: Acute transverse myelitis: demyelinating,
inflammatory, and infectious myelopathies, Semin Neurol 32(2):97–113,
2012.
Wootla B, Watzlawik JO, Denic A, et al: The road to remyelination in demyelinating
diseases: current status and prospects for clinical treatment, Expert Rev Clin
Immunol 9(6):535–549, 2013.
 121 
Neuromuscular Diseases:
Disorders of the Motor
ss

Neuron and Plexus and

Peripheral Nerve Disease
Carlayne E. Jackson

toms, reflex abnormalities, and specific associated clinical

  INTRODUCTION features (Table 121-2).
Neuromuscular diseases are classified into four groups, accord-
ing to which portion of the motor unit is involved (Table Electromyography and Nerve  
121-1). Motor neuron and peripheral nerve diseases are con- Conduction Studies
sidered in this chapter; myopathies are considered in Chapter Electromyography (EMG) and nerve conduction studies can
122, and neuromuscular junction diseases are considered in also be useful diagnostic tools in localizing the lesion in a patient
Chapter 123. The symptoms and signs of the neuromuscular with a suspected neuromuscular disease. The measurement of
diseases are at times indistinguishable. However, some useful electrical activity arising from muscle fibers is performed by
general rules apply to assist with localization based on the inserting a needle electrode percutaneously into a muscle.
distribution of weakness, presence or absence of sensory symp- Normal muscle is electrically silent at rest. Spontaneous activity
during complete relaxation occurs in myotonic disorders, in
inflammatory myopathies, and in denervated muscles. Spontane-
ous activity of a single muscle fiber is called a fibrillation, and
TABLE 121-1  CLASSIFICATION OF NEUROMUSCULAR such activity of part of or an entire motor unit is called a fas-
DISEASES ciculation. In myotonia, repeated muscle depolarization and
SITE OF INVOLVEMENT TYPICAL EXAMPLES contraction occur despite voluntary relaxation. Abnormalities
ANTERIOR HORN CELL in motor unit potentials occur during the course of denervation;
Without upper motor neuron Spinal muscular atrophy with the development of reinnervation, the remaining motor
involvement Progressive muscular atrophy units increase in amplitude and become longer in duration and
Bulbospinal muscular atrophy
Poliomyelitis
polyphasic (E-Fig. 121-1). Conversely, in muscle diseases such
West Nile virus as the muscular dystrophies and other diseases that destroy
With upper motor neuron Amyotrophic lateral sclerosis scattered fibers within a motor unit, the motor unit action
involvement Primary lateral sclerosis
potentials are of lower amplitude and shorter duration and are
PERIPHERAL NERVE polyphasic. A reduced recruitment (interference) pattern from
Mononeuropathy Carpal tunnel syndrome maximum voluntary effort occurs in denervation. Conversely,
Ulnar palsy
Meralgia paresthetica in patients with primary muscle disease, submaximal voluntary
Multiple mononeuropathies Mononeuritis multiplex (e.g., effort produces a full recruitment pattern despite marked
polyarteritis nodosa), leprosy, weakness.
sarcoidosis, amyloidosis
Polyneuropathies Diabetic neuropathy Nerve conduction is studied by stimulating a peripheral nerve
Charcot-Marie-Tooth disease (e.g., the ulnar) with surface electrodes placed over the nerve.
Guillain-Barré syndrome The resulting action potential is recorded by electrodes placed
NEUROMUSCULAR JUNCTION over the nerve more proximally in the case of large sensory nerve
Myasthenia gravis fibers and over the muscle distally in the case of motor nerve
Lambert-Eaton syndrome fibers in a mixed motor sensory nerve. For sensory nerves, the
MUSCLE sensory nerve action potential (SNAP) is quantitated, and for
Duchenne muscular dystrophy motor nerves, the compound muscle action potential (CMAP)
Dermatomyositis
is quantitated.

1077
 Chapter 121  Neuromuscular Diseases 1077.e1

ss

E-FIGURE 121-1  Motor unit potentials. The shaded muscle fibers are
functional members of the motor unit; the axon, which enters from the
upper left, branches terminally to innervate the appropriate muscle
fibers. The motor unit action potential produced by each motor unit is
seen at the upper right; its duration is measured between the two small
vertical lines. The normal-appearing but unshaded fibers belong to
other motor units. A, The normal situation, with five muscle fibers in
the active unit. B, In this myopathic unit, only two fibers remain active;
the other three (shrunken and unshaded) have been destroyed by a
muscle disease. C, Four fibers that belonged to other motor units and
had been denervated have now been reinnervated by terminal axon
sprouting from the healthy motor unit. Both the motor unit and its
action potential are now larger than normal. Note that only under these
abnormal circumstances do fibers in the same unit lie next to one
another. (From Griggs RC, Bradley WG: Approach to the patient with
neuromuscular disease. In Isselbacher KJ, Braunwald E, Wilson JD, et al,
editors: Harrison’s textbook of internal medicine, ed 13, New York, 1994,
McGraw-Hill, p 2364.)
 1078 Section XVI  Neurologic Disease

ss
TABLE 121-2  CLINICAL FEATURES OF THE NEUROMUSCULAR DISEASES
CLINICAL FEATURE ANTERIOR HORN CELL PERIPHERAL NERVE NEUROMUSCULAR JUNCTION MUSCLE
DISTRIBUTION OF Asymmetrical limb or Symmetrical, usually distal Extraocular, bulbar, Symmetrical, proximal
WEAKNESS bulbar proximal limb limb
ATROPHY Marked and early Mild, distal None (or very late) Slight early; marked later
SENSORY INVOLVEMENT None Dysesthesias, loss of sensation None None
REFLEXES Variable (depending on Decreased out of proportion Normal in myasthenia gravis, Decreased in proportion
degree of upper motor to weakness depressed in Lambert-Eaton to weakness
neuron involvement) syndrome
CHARACTERISTIC Fasciculations, cramps Combined sensory and motor Fatigability Usually painless
FEATURES abnormalities

  DISEASES OF THE MOTOR NEURON

(ANTERIOR HORN CELL)
Amyotrophic Lateral Sclerosis
Definition and Epidemiology
The most common acquired motor neuron disease, amyotrophic
lateral sclerosis (ALS), is a progressive, typically fatal disorder.
The incidence is approximately 2 per 100,000 population, and
there is a slight male predominance. The peak age of onset is in
the sixth decade, although the disease can occur at any time
throughout adulthood. Epidemiologic studies have incriminated
risk factors for ALS including exposure to insecticides, smoking,
participation in varsity athletics, and military service in the Gulf
War. The cause of ALS is largely unknown, with 95% of cases
considered “sporadic,” and 5% related to an autosomal dominant
disease (familial ALS [FALS]). FALS is an adult-onset disease
that is clinically and pathologically indistinguishable from spo-
radic ALS. FALS is caused by mutations in many genes, including
the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and
VAPB genes. Mutations in C9orf72 can also cause sporadic ALS.
(E-Table 121-1).
Pathology
ALS results from degeneration of the cortical motor neurons
originating in layer five of the motor cortex and descending via
the pyramidal tract (resulting in upper motor neuron signs and
symptoms) and from degeneration of the anterior horn cells in
the spinal cord and their brainstem homologues innervating
bulbar muscles (resulting in lower motor neuron signs and symp-
toms) (Table 121-3).
Clinical Presentation
Clinical symptoms relating to the upper motor neuron degen-
eration include loss of dexterity, slowed movements, muscle
weakness, stiffness, and emotional lability. Signs on neurologic
examination that confirm an upper motor neuron lesion include
pathologic hyperreflexia, spasticity, and extensor plantar
responses (Babinski’s sign). Lower motor neuron signs and
symptoms caused by anterior horn cell degeneration include
weakness, muscle atrophy, fasciculation, and cramps. Fascicula-
tions in the absence of associated muscle atrophy or weakness
are usually benign and may be aggravated by sleep deprivation,
stress, and excessive caffeine ingestion. Muscle weakness in
patients with ALS usually begins distally and asymmetrically
and may manifest as a monoparesis, hemiparesis, paraparesis,
TABLE 121-3  SYMPTOMS AND SIGNS ASSOCIATED
WITH AMYOTROPHIC LATERAL
SCLEROSIS
SYMPTOMS SIGNS
UPPER MOTOR NEURON DEGENERATION
Loss of dexterity Pathologic hyperreflexia
Slowed movements Babinski’s sign
Weakness Hoffman’s sign
Stiffness Jaw jerk
Pseudobulbar affect Spasticity
LOWER MOTOR NEURON DEGENERATION
Weakness Muscle atrophy
Fasciculations Fibrillation potentials on electromyography
Cramps Neurogenic atrophy on muscle biopsy
or quadriparesis. It may also be limited initially to the bulbar
region, resulting in difficulty with swallowing, speech, and move-
ments of the face and tongue. For unclear reasons, ocular motility
is spared until the very late stages of the illness. Bowel and
bladder function and sensation remain spared throughout the
course of the disease. Degeneration of the corticobulbar projec-
tions innervating the brainstem can lead to pseudobular affect
causing difficulty controlling laughter and/or tearfulness. Up to
50% of patients with ALS may also have a component of fron-
totemporal dementia characterized by executive dysfunction,
poor insight, personality changes (disinhibition, impulsivity, and
apathy), abnormal eating habits, poor hygiene, and language
dysfunction.
Diagnosis and Differential Diagnosis
The diagnosis of ALS remains one of “exclusion,” in which other
potential causes must be ruled out through a variety of neuroim-
aging, laboratory, and electrodiagnostic investigations (E-Table
121-2). For example, compression of the cervical spinal cord or
cervicomedullary junction from tumors or cervical spondylosis
can produce weakness, atrophy, and fasciculations in the upper
extremities and spasticity in the lower extremities, closely resem-
bling ALS.
Treatment
Specialized multidisciplinary clinic referral should be considered
for patients with ALS to optimize health care delivery (Level
B) and prolong survival (Level B). The only current U.S. Food
and Drug Administration (FDA)–approved therapy for ALS is
riluzole 50  mg twice per day, which in clinical trials prolonged
 Chapter 121  Neuromuscular Diseases 1078.e1

E-TABLE 121-1  HEREDITARY MOTOR NEURON E-TABLE 121-2  DIFFERENTIAL DIAGNOSIS AND ss

DISEASES DIAGNOSTIC EVALUATION FOR

LOCUS GENE PATIENTS WITH SUSPECTED MOTOR
AUTOSOMAL DOMINANT NEURON DISEASE
DIFFERENTIAL DIAGNOSIS DIAGNOSTIC EVALUATION
ALS 1 21q Superoxide dismutase
ALS 4 9q34 Senataxin TOXINS—LEAD, MERCURY 24-hr urine collection for heavy
ALS 6 16p11 FUS metals
ALS 8 20q Vesicle-associated protein B METABOLIC DISORDERS
ALS 9 14q11 Angiogenin
ALS 10 1p36 TDP-43 Hypoglycemia Serum chemistry
ALS 11 6q21 FIG4 Hyperparathyroidism Parathyroid hormone level, calcium
ALS 12 10p15 OPTN Hyperthyroidism Thyroid function studies
ALS 13 12q24 Ataxin-2 PARANEOPLASTIC DISORDER MRI scan, anti-Hu antibody
ALS 14 9p13 VCP
ALS 18 17p13 PFN1 IMMUNOLOGIC MECHANISM Complete blood count,
ALS-FTD 9p21 C9orf72 sedimentation rate, anti-nuclear
antibody, rheumatoid factor, serum
AUTOSOMAL RECESSIVE protein electropheresis, anti-GM1
ALS 2 2q33 Alsin antibodies
ALS 5 15q21 Spatacsin VITAMIN/MINERAL Copper, vitamin B12, folate levels
ALS 6 16p11 FUS DEFICIENCIES
ALS 12 10p15 OPTN
ALS 16 9p13 SIGMAR1 BACTERIAL/VIRAL INFECTION HIV, HTLV-1, Lyme titers, CSF
Spinal muscular atrophy 5q Survival motor neuron protein exam/culture
X-LINKED STRUCTURAL LESION
Spinobulbar muscular atrophy Xq 11-12 Androgen receptor Cervical spondylosis MRI of brain and cervical spine
ALS15 Xp11 UBQLN2 Chiari malformation or syrinx
Spinal cord arteriovenous
malformation
Parasagittal or foramen magnum
tumor
 Chapter 121  Neuromuscular Diseases 1079
TABLE 121-4  SYMPTOM MANAGEMENT FOR MOTOR
NEURON DISEASES
RESPIRATORY INSUFFICIENCY SPASTICITY
Noninvasive positive pressure Baclofen 10-20 mg qid
ventilation Dantrium 25-100 mg qid
Cough-assist devices
PSEUDOBULBAR AFFECT
DYSARTHRIA
Serotonin reuptake inhibitors
Augmentative speech device Amitriptyline 25-75 mg qhs
DYSPHAGIA Dextromethorphan/Quinidine
20/10 mg bid
Percutaneous endoscopic
gastrostomy placement WEAKNESS
Suction machine Ankle foot orthosis
Wheelchair
SIALORRHEA
Elevated toilet seat
Amitriptyline 25-75 mg qhs
Glycopyrrolate 1-2 mg q8h
Botulinum toxin
survival by 2 to 3 months (Level A). The mechanism of this
effect is not known with certainty; however, riluzole may reduce
excitotoxicity by diminishing presynaptic glutamate release.
Initiation of noninvasive positive pressure ventilation (NPPV)
on a spontaneous timed mode has also been shown to prolong
survival up to 20 months, slow the rate of forced vital capacity
(FVC) decline (Level B), and improve quality of life (Level
C). NPPV should be initiated when the forced vital capacity
(FVC) is less than 50%, the maximal inspiratory pressure is
less than 60  cm, or when patients report symptoms that suggest
nocturnal hypoventilation (e.g., daytime fatigue, frequent arous-
als, supine dyspnea, morning headaches). A cough-assist device
can be used to assist with clearing upper airway secretions and
has been shown to minimize the risk of pneumonia in clinical
trials (Level C). A percutaneous gastrostomy (PEG) tube should
be considered for prolonging survival and stabilizing body weight
(Level B) in patients with impaired oral food intake. Symp-
tomatic therapy for spasticity, pseudobulbar affect, muscle
cramping, and sialorrhea is also essential in maintaining patient
dignity and quality of life (Table 121-4). Augmentative speech
devices can assist patients with communication and computer
access.
Prognosis
Mean survival from onset of symptoms is 2 to 5 years, with 10%
of patients surviving beyond 10 years. The majority of deaths are
related to respiratory muscle failure and aspiration pneumonia.
Other Acquired Motor Neuron Diseases
Other motor neuron diseases involve only particular subsets of
motor neurons (Table 121-5). Progressive muscular atrophy
(PMA) is a pure lower motor neuron disease that accounts for
8% to 10% of patients with motor neuron disease. Weakness is
typically distal and asymmetrical, and bulbar involvement is rare.
Patients with PMA generally have a better prognosis than those
with ALS, with a survival of 3 to 14 years. Primary lateral sclerosis
(PLS) is a pure upper motor neuron syndrome in which patients
demonstrate either a slowly progressive spastic paralysis or dys-
arthria. This is a rare disorder, accounting for 2% of all motor
neuron cases. Survival is generally years to decades.
TABLE 121-5  CLINICAL SPECTRUM OF MOTOR ss
NEURON DISEASES*
UPPER AND LOWER MOTOR LOWER MOTOR NEURON
NEURON INVOLVEMENT INVOLVEMENT
Sporadic amyotrophic lateral Motor neuronopathy related to
sclerosis malignancy or paraproteinemia
Familial amyotrophic lateral sclerosis Poliomyelitis
West Nile virus
UPPER MOTOR NEURON
Postpolio syndrome
INVOLVEMENT
Hexosaminidase deficiency
Primary lateral sclerosis Progressive muscular atrophy
Familial spastic paraparesis Spinal muscular atrophy
Type I: Infantile onset (Werdnig-
Hoffmann disease)
Type II: Late infantile onset
Type III: Juvenile onset (Kugelberg-
Welander disease)
*Italicized disorders are hereditary.
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a hereditary form of motor
neuron disease in which only the lower motor neuron is affected.
The SMAs may begin in utero, in infancy, in childhood, or in
adult life and represent the first class of neurologic disorders in
which a developmental defect in neuronal apoptosis most likely
produces the disease. Two genes are involved in SMA types 1 to
3: the neuronal apoptosis inhibitor protein (NAIP) and survival
motor neuron (SMN) genes.
Bulbospinal muscular atrophy (BSMA) or Kennedy’s disease
is an X-linked recessive disorder in which the mean age at onset
is 30 years; the range is from 15 to 60 years. BSMA is a trinucleo-
tide repeat disorder with a CAG expansion encoding for a poly-
glutamine tract in the first exon of the androgen receptor gene,
on chromosome Xq11-12. The mechanism by which disruption
of the androgen receptor gene alters the function of bulbar and
spinal motor neurons is not known. An inverse correlation exists
between the number of CAG repeats and the age of onset of the
disease. Affected individuals exhibit chin fasciculations, midline
furrowing and atrophy of the tongue, and proximal weakness.
Dysphagia and dysarthria are common, and up to 90% of patients
demonstrate gynecomastia and infertility. Two findings distin-
guishing this disorder from ALS are the absence of upper motor
neuron signs and in some patients the presence of a subtle
sensory neuropathy.
  DISORDERS OF THE BRACHIAL
AND LUMBOSACRAL PLEXUS
The roots within the cervical, lumbar, and sacral regions organize
into the cervical, lumbar, and sacral plexuses before giving rise to
individual peripheral nerves. Diseases of these plexuses (plexop-
athies) tend to be focal in symptoms and signs, whereas many
diseases of the peripheral nerves and muscles are generalized.
Brachial Plexopathy
The brachial plexus is constituted by mixed nerve roots from C5
to T1 that fuse into upper, middle, and lower trunks above the
level of the clavicle and redistribute into lateral, posterior, and
medial cords below that landmark (E-Fig. 121-2). Symptoms
include weakness, pain, and sensory loss in the shoulders or arms.
 Chapter 121  Neuromuscular Diseases 1079.e1

ss

E-FIGURE 121-2  The brachial plexus is comprised of mixed nerve

roots from C5 to T1 that fuse into upper, middle, and lower trunks
above the level of the clavicle and redistribute into lateral, posterior,
and medial cords. (From Morton D, Peterson KD, Albertine KH: Gray’s
dissection guide for human anatomy, ed 2, Philadelphia, 2006, Churchill
Livingstone.)
 1080 Section XVI  Neurologic Disease
Upper trunk lesions may be due to trauma and idiopathic brachial
ss plexitis (see later discussion). Lower trunk lesions may result
from malignant tumor invasion, thoracic outlet syndrome, or as
a complication of sternotomy. If the entire plexus is involved,
radiation injury, trauma, and late metastatic disease are the most
common causes.
Acute Autoimmune Brachial Neuritis
Acute autoimmune brachial neuritis is characterized by the
abrupt onset of severe pain, usually over the lateral shoulder, but
at times extending into the neck or entire arm. The acute pain
generally subsides after a few days to a week; by this time, weak-
ness of the proximal arm becomes apparent. The serratus ante-
rior, deltoid, and supraspinatus are the most commonly affected
muscles, but other muscles of the shoulder girdle may also be
affected. In rare cases, most of the patient’s arm and even the
ipsilateral diaphragm are involved. Sensory loss is usually slight
and generally involves the axillary nerve distribution. Weakness
lasts weeks to months and be accompanied by severe atrophy of
the shoulder girdle. No therapy has been shown to alter or
shorten the clinical course, although steroids and analgesics may
reduce pain. Most patients recover within several months to 3
years. The disorder frequently follows an upper respiratory infec-
tion or an immunization, but in many instances no antecedent
illness occurs. It is bilateral in one third of cases but is always
asymmetrical; it may recur in 5% of patients. Recurrent brachial
plexopathies that are painless may be related to an autosomal
dominant disorder, hereditary neuropathy with liability to pres-
sure palsies (HNPP), caused by a deletion, or point mutation of
PMP-22 protein (chromosome 17p).
Lumbosacral Plexopathy
The lumbosacral plexus is formed from the ventral rami of spinal
nerves T12 to S4. These divide within the plexus into ventral and
dorsal branches that form the femoral, sciatic, and obturator
nerves. The plexus is located within the substance of the psoas
major muscle. Clinical features include proximal pain and weak-
ness in anterior thigh muscles (femoral) or posterior thigh
muscles and the buttocks. Bowel and bladder dysfunction may
also occur. Diabetes, malignant invasion, radiation therapy, infec-
tion (herpes zoster), psoas abscess, trauma, and retroperitoneal
hemorrhage are common causes. An autoimmune form is much
less frequent than brachial neuritis.
  DISORDERS OF THE PERIPHERAL NERVES
Definition and Epidemiology
Peripheral neuropathy refers to a large group of disorders that can
produce focal (mononeuropathy or multiple mononeuropathies)
or generalized nerve dysfunction (polyneuropathies) (Table
121-6). Peripheral neuropathies are prevalent neurologic condi-
tions, affecting 2% to 8% of adults, with the incidence increasing
with age. They range in severity from mild sensory abnormalities,
found in up to 70% of patients with long-standing diabetes, to
fulminant, life-threatening paralytic disorders such as Guillain-
Barré syndrome (GBS).
Mononeuropathies are disorders in which only a single periph-
eral nerve is affected. The most common cause is nerve
TABLE 121-6  CLASSIFICATION AND CAUSES OF
PERIPHERAL NEUROPATHY
TYPE OF NEUROPATHY EXAMPLES
MONONEUROPATHIES
Compressive Carpal tunnel syndrome, ulnar palsy
Hereditary Hereditary neuropathy with predisposition
to pressure palsies
Inflammatory Bell’s palsy
Multiple mononeuropathies Vasculitis (mononeuritis multiplex),
diabetes, leprosy, sarcoidosis, amyloidosis
POLYNEUROPATHIES
Hereditary Charcot-Marie-Tooth disease
Endocrine Diabetes, hypothyroidism
Metabolic Uremia, liver failure
Infections Leprosy, diphtheria, human
immunodeficiency virus, Lyme disease
Immune mediated Guillain-Barré syndrome, chronic
inflammatory demyelinating
polyneuropathy
Toxic Lead, arsenic, alcohol, drug induced
Paraneoplastic Lung cancer
entrapment such as median nerve compression resulting in carpal
tunnel syndrome or peroneal nerve injury causing footdrop
(Table 121-7). When more than one peripheral nerve is involved,
the term mononeuropathy multiplex or multiple mononeuropathies
is often used. Multiple mononeuropathies are most commonly
seen in diabetes mellitus and vasculitis but also occur in leprosy,
vasculitis, sarcoidosis, hereditary neuropathy with predisposition
to pressure palsies, and amyloidosis.
Polyneuropathies are a group of disorders affecting the motor,
sensory, and autonomic nerves. These disorders may predomi-
nantly affect the nerve axon (axonal neuropathies), myelin sheath
(demyelinating neuropathies), or the small- to medium-sized
blood vessels supplying the nerves (vasculitic neuropathies). The
clinical features of the polyneuropathies reflect the pathology of
the underlying process.
Pathology
In the symmetrical axonal polyneuropathies, the underlying
pathology is usually a slowly evolving type of axonal degenera-
tion that involves the ends of long nerve fibers first and preferen-
tially. With time, the degenerative process involves more proximal
regions of long fibers, and shorter fibers are affected. This pattern
of distal axonal degeneration or dying back of nerve fibers results
from a wide variety of metabolic, toxic, and endocrinologic
causes.
In the demyelinating polyneuropathies, the underlying pathol-
ogy involves the myelin sheath.
Demyelination of a peripheral nerve at even a single site can
block conduction, resulting in a functional deficit identical to
that seen after axonal degeneration. In contrast to repair by regen-
eration, however, repair by remyelination can be rapid. Autoim-
mune attack on the myelin sheath occurs in the inflammatory
demyelinating neuropathies (GBS and chronic inflammatory
demyelinating polyneuropathy [CIDP]) and some neuropathies
associated with paraproteinemias (see later discussion). Inher-
ited disorders of myelin such as Charcot-Marie-Tooth (CMT)
disease comprise the other major category of demyelinating
neuropathies. Other causes include toxic, mechanical, and
 Chapter 121  Neuromuscular Diseases 1081

TABLE 121-7  COMMON MONONEUROPATHIES ss

SENSORY SIGNS AND

PRECIPITATING FACTORS
Entrapment at the Repetitive wrist flexion or
wrist (carpal tunnel sleep
syndrome)
Entrapment at the External compression in
elbow condylar groove, fracture of
humerus
Entrapment at the Prolonged sleeping on arm
spiral groove after drinking excessive
amounts of alcohol:
“Saturday night palsy”
Abdominal hysterectomy,
hematoma, prolonged
lithotomy position, diabetes
Meralgia paresthetica Obesity, pregnancy, diabetes,
constrictive belts
Entrapment at the Habitual leg crossing, knee
fibular head casts, prolonged squatting,
profound weight loss
Injection injury, fracture or
dislocation of hip
Entrapment in tarsal External compression from
tunnel tight shoes, trauma,
tenosynovitis
MOTOR SIGNS AND SYMPTOMS
MEDIAN NERVE
Weakness in thenar muscle; inability
to make a circle with the thumb and
index fingers
ULNAR NERVE
Weakness or atrophy of the interossei
and thumb adductor
RADIAL NERVE
Wrist drop with sparing of elbow
extension; weakness of finger and
thumb extensors
FEMORAL NERVE
Weakness and atrophy of quadriceps
LATERAL FEMORAL CUTANEOUS NERVE
None
PERONEAL NERVE
Weakness of ankle dorsiflexors or
evertors and toe extensors
SCIATIC NERVE
Weakness of hamstrings, ankle plantar
flexors or dorsiflexors
TIBIAL NERVE
None
SYMPTOMS TREATMENT
Numbness, tingling, and/or pain Neutral wrist splint, carpal
in thumb, index finger, middle tunnel injections or
finger, and medial half of ring surgery
finger. Tinel and Phalen signs
Sensory loss in the little finger and Elbow pads; ulnar nerve
contiguous half of the ring finger transposition or
decompression of
cubital tunnel
Sensory loss on dorsum of hand Spontaneous recovery;
wrist splint
Sensory loss in anterior thigh and Physical therapy
medial calf
Sensory loss, pain, or tingling over Weight loss; spontaneous
anterolateral thigh recovery
Sensory loss in anterolateral leg Ankle-foot orthosis;
and dorsum of foot remove source of
compression
Sensory loss in buttock, lateral calf Ankle-foot orthosis;
and foot physical therapy
Sensory loss and tingling in sole of Tarsal tunnel injection,
foot eliminate source of
compression, medial
arch support

physical injuries to nerves. Although these examples have nearly
pure demyelination, many neuropathies have both axonal degen-
eration and demyelination. This mixed pathologic abnormality
reflects the mutual interdependency of the axons and the myelin-
forming Schwann cells. Vasculitic neuropathies occur as a result
of disease of the small- or medium-sized blood vessels that leads
to ischemia and infarction of isolated peripheral nerves. The term
mononeuritis multiplex is also used to describe this clinical situ-
ation, in which there is multifocal involvement of individual
nerves.
distribution. Truncal and abdominal dysesthesias may develop
once the sensory abnormalities ascend to the level of the elbows.
The prominent clinical feature of an acquired demyelinating
polyneuropathy is weakness that affects not only the distal
muscles, but also the proximal and facial muscles. Unlike in an
axonal neuropathy, sensory loss is rarely the presenting symptom.
Patients generally have diffuse hyporeflexia or areflexia.
Vasculitic neuropathies typically present with acute or sub-
acute asymmetrical, predominantly distal weakness and sensory
loss associated with severe pain.

Clinical Presentation Diagnosis and Differential Diagnosis

The clinical picture of an axonal polyneuropathy includes early
loss of muscle stretch reflexes at the ankle and weakness that
initially involves the intrinsic muscles of the feet, the extensors of
the toes, and the dorsiflexors at the ankle. The motor signs are
usually mild in contrast to the sensory abnormalities, which may
include numbness, tingling, and burning sensations (dysesthe-
sias). The sensory symptoms usually begin symmetrically in the
toes and feet and then ascend proximally to the legs in a “stock-
ing” distribution. When the sensory abnormalities reach the level
of the knees, the symptoms begin in the hands, in a “glove”
Neuropathic disorders can be broadly divided into those that are
acquired and those that are hereditary (Table 121-8). Acquired
disorders are the more common and have many causes: meta-
bolic or endocrine disorders (diabetes mellitus, renal failure, por-
phyria); immune-mediated disorders (GBS, CIDP, multifocal
motor neuropathy, antimyelin-associated glycoprotein neuropa-
thy); infectious causes (human immunodeficiency virus [HIV],
Lyme disease, cytomegalovirus [CMV], syphilis, leprosy, diph-
theria); medications (HIV drugs, chemotherapies); environmen-
tal toxins (heavy metals); or paraneoplastic processes. Diabetes
 1082 Section XVI  Neurologic Disease

ss
TABLE 121-8  HEREDITARY NEUROPATHIC DISORDERS
INHERITANCE PATTERN GENETIC DEFECT CLINICAL FEATURES
Hereditary sensorimotor neuropathies AR, AD, or X-linked See E-Table 121-4 Pes cavus, distal atrophy and weakness, hammer toes
Familial amyloid polyneuropathy AD Transthyretin Pain, autonomic dysfunction
Gelsolin
Apolipoprotein Al
Fabry disease X-linked α-Galactosidase Cardiac ischemia, renal disease, stroke, cutaneous
angiokeratomas
Tangier disease AR Apolipoprotein A Low HDL levels, orange tonsils
Refsum disease AR Phytanic acid oxidase Retinitis pigmentosa, cardiomyopathy, deafness, ichthyosis
AD, Autosomal dominant; AR, autosomal recessive; HDL, high-density lipoprotein.

mellitus and alcoholism are the most common causes of polyneu-

ropathy in developed countries. As many as one third of acquired TABLE 121-9  DIFFERENTIAL DIAGNOSIS OF
neuropathies are cryptogenic in which the etiology can never be NEUROPATHIC DISORDERS BASED  
identified. Causes of monneuritis multiplex include systemic vas- ON SYMPTOMS
culitis (rheumatoid arthritis, systemic lupus erythematosus, MOTOR SENSORY AUTONOMIC
SYMPTOMS ONLY SYMPTOMS ONLY SYMPTOMS
Wegener’s granulomatosis, Churg-Strauss syndrome, polyarteri-
tis nodosa) and primary peripheral system vasculitis (25% of Porphyria Cryptogenic sensory Amyloid neuropathy
Charcot-Marie-Tooth polyneuropathy Diabetic neuropathy
cases). Chronic inflammatory Metabolic, drug-related, Fabry disease
Because of the many causes, it is important to approach the demyelinating or toxic neuropathy Guillain-Barré
patient with neuropathy systematically, beginning with the polyneuropathy Paraneoplastic sensory syndrome
Guillain-Barré neuropathy Hereditary sensory or
patient’s history and physical examination. It is essential to deter- syndrome autonomic
mine which nerves are involved (motor, sensory, or autonomic) Lead neuropathy neuropathy
and in what specific combination (Table 121-9). Small-fiber neu- Motor neuron disease Porphyria
ropathies often manifest with unpleasant or abnormal sensations
such as a burning pain, electric shock-like sensations, cramping,
tingling, pins and needles, or prickly feelings such as the limb
“feeling asleep.” Large-fiber neuropathies can manifest as numb- TABLE 121-10  NEUROPATHIES ASSOCIATED
ness, tingling, or as gait ataxia. Symptoms suggesting motor nerve WITH PAIN
involvement include muscle weakness that typically involves the Alcoholic neuropathy Heavy metal toxicity (arsenic,
distal foot muscles. Autonomic nerve involvement is suggested Amyloidosis thallium)
Cryptogenic sensorimotor Hereditary sensory or autonomic
by symptoms of orthostatic hypotension, impotence, cardiac neuropathy neuropathy
arrhythmia, or bladder dysfunction. Diabetic neuropathy HIV sensorimotor neuropathy
The distribution of muscle weakness is important. In axonal Fabry disease Radiculopathy or plexopathy
Guillain-Barré syndrome Vasculitis
neuropathies, the weakness predominantly involves the distal
HIV, Human immunodeficiency virus.
lower extremity muscles, and in demyelinating neuropathies the
weakness can involve both proximal and distal muscles as well as
facial muscles. Most neuropathies result in symmetrical weakness.
If asymmetry is present, motor neuron disease, radiculopathy, a viral illness, immunization, or a surgical procedure. The neu-
plexopathy, compressive mononeuropathies, or mononeuritis rologic history must thoroughly explore potential toxic expo-
multiplex should be considered. The intensity and distribution of sures such as prior medications and alcohol use (E-Table
painful dysesthesias can be informative. Although many axonal 121-3).
neuropathies are associated with a burning sensation in the feet, Because many neuropathies are hereditary, it is essential to
pain as the chief complaint suggests specific causes of neuropathy obtain a detailed family history, specifically inquiring about a
(Table 121-10). A neuropathy that manifests with acute, asym- history of gait instability, use of adaptive equipment, or skeletal
metrical weakness, and severe pain suggests vasculitis. deformities of the feet. Hereditary neuropathies may be autoso-
In patients with severe, asymmetrical proprioceptive deficits, mal recessive, autosomal dominant, or X-linked. In some situa-
with sparing of motor function, the site of the lesion is usually tions it may be helpful to actually examine family members
the sensory neuron. This specific syndrome has a relatively because the severity of disease may vary considerably from one
limited differential diagnosis, including paraneoplastic process, generation to the next. The most common hereditary neuropathy
Sjögren’s syndrome, cisplatinum toxicity, vitamin B6 toxicity, and is CMT disease (see later discussion).
HIV infection. A complete neurologic examination should always be per-
Most neuropathies are relatively insidious in onset, particu- formed in a patient complaining of numbness. If the patient
larly those associated with metabolic or endocrine disorders. shows evidence of upper motor neuron involvement in addition
Acute neuropathies may be caused by a vasculitic process, toxin to the sensory loss, vitamin B12 or copper deficiency should be
exposure, porphyria, or GBS. GBS is commonly preceded by considered, even in the absence of apparent anemia. An elevated
 Chapter 121  Neuromuscular Diseases 1082.e1

E-TABLE 121-3  ETIOLOGY OF NEUROPATHIC DISORDERS: TOXIC AGENTS ss

AXONAL DEMYELINATING MIXED

SENSORY SENSORY & MOTOR MOTOR
Chloramphenicol Acrylamide Β-bungarotoxin Buckthorn Amiodarone
Doxorubicin Alcohol (Ethanol) Botulism Chloroquine Diethylene glycol
Ethambutol Allyl chloride Gangliosides Diphtheria Ethylene glycol
Ethionamide Arsenic Latrotoxin FK506 (Tacrolimus) I,I′-Ethylidinebis (tryptophan)
Etoposide (VP-16) Carbon disulfide Black widow Hexachlorophene Gold Hexacarbons
Flecanide Chlorphenoxy Lead Mercury Procainamide n-Hexane
Gemcitabine Ciguatoxin Misoprostol TNF-α antagonists Na+ Cyanate Suramin
Glutethimide Cobalt Tetanus
Hydralazine Colchicine Tick paralysis
Interferon-α Cyanide
Isoniazid Dapsone
Lead Dichloroacetate
Lefluonomide Dinitrophenol
Metronidazole Disulfiram
Misonidazole Ethylene oxide
Nitrous oxide Heroin
Nucleosides Lithium
ddC; ddI; Methyl bromide
d4T; 3TC Nitrofurantoin
Phenytoin Organophosphates
Platinum analogs Taxol
Pyridoxine Tetrodotoxin
Statins Thallium
Thalidomide Trichloroethylene
Vacor (PNU)
Vinca alkaloids
 Chapter 121  Neuromuscular Diseases 1083
methylmalonic acid or homocystine level can also help confirm
this diagnosis in patients with borderline B12 levels. The presence
of weakness and upper motor neuron signs without associated
sensory loss suggests ALS.
If the neuropathy is associated with mental status abnormali-
ties, then pyridoxine intoxication or deficiencies of thiamine,
niacin (“dementia, diarrhea, dermatitis”), and vitamin B12 should
be considered in the differential diagnosis. Lyme disease (see
Chapter 90) may result in both peripheral nervous system symp-
toms (facial nerve palsies, paresthesias, weakness) and central
nervous system symptoms (dementia, headache). Acquired
immunodeficiency syndrome (AIDS) can also affect both the
central and the peripheral nervous systems. GBS and CIDP
usually occur at the time of HIV seroconversion, whereas sensory
neuropathy, mononeuritis multiplex, and CMV polyradiculopa-
thy generally occur in the context of low CD4 counts in the ter-
minal stages of the disease.
Once a preliminary differential diagnosis is developed based
on the history and neurologic examination findings, laboratory
studies can confirm the diagnosis. Laboratory tests to identify
potentially treatable causes of neuropathy are included in Table
121-11. Additional studies can be ordered based on the sus-
pected diagnosis. An impaired glucose tolerance test is found in
more than half of patients with cryptogenic sensory peripheral
neuropathy and is more sensitive than tests of fasting glucose or
hemoglobin A1c (HbA1c). In a patient with acute, asymmetrical
weakness and sensory loss, screening for an inflammatory process
(ESR, ANA, RA, SS-A, SS-B) is appropriate. In addition, genetic
testing is now available for most patients with CMT disease. If a
monoclonal protein is identified on serum protein electrophore-
sis, a skeletal survey, urine immunofixation electrophoresis, and
bone marrow biopsy should be ordered to rule out an underlying
lymphoproliferative disorder. If the patient has a monoclonal
protein associated with autonomic dysfunction, congestive heart
failure, or renal insufficiency, a biopsy (rectal, abdominal fat, or
sural nerve) should be considered for diagnosis of amyloidosis.
CIDP can be associated with a monoclonal gammopathy, and in
this situation patients should be treated with immunosuppressive
therapy. Monoclonal gammopathies observed in patients with an
axonal peripheral neuropathy are frequently benign (monoclonal
TABLE 121-11  PERIPHERAL NEUROPATHY
LABORATORY STUDIES
STANDARD TESTS TESTS INDICATED IN SELECTED CASES
B12 Anti-Hu antibody
Complete blood count ESR, ANA, RF, SS-A, SS-B
Glucose tolerance test Genetic studies for Charcot-Marie-Tooth
Rapid plasmin reagin Human immunodeficiency virus
SMA20 Lyme antibody
Serum protein Phytanic acid
electrophoresis and
immunofixation
electrophoresis
Thyroid function tests 24-hr urine for heavy metals
Nerve conduction studies or Quantitative sensory testing
electromyogram Lumbar puncture
Nerve biopsy
Skin biopsy
Tilt table testing
gammopathy of unknown significance) and do not necessarily
warrant therapy. ss
A lumbar puncture is indicated only if an acquired demyelinat-
ing neuropathy such as GBS or CIDP is being considered. In
these cases one expects to find “albuminocytologic dissociation”
with an elevation in cerebrospinal fluid (CSF) protein and a rela-
tively normal white blood cell (WBC) count. If the CSF WBC
count is greater than 50/mm3, Lyme disease, HIV-associated
disease, or a paraneoplastic process must be considered.
Electrodiagnostic studies consisting of nerve conduction
testing and EMG can be a helpful extension of the physical exam-
ination. These studies are useful in defining whether the neuro-
pathic process is caused by a primarily axonal or demyelinating
process. In general, axonal degeneration decreases the amplitude
of the compound muscle action potential out of proportion to
the degree of reduction in peripheral nerve conduction velocity,
whereas demyelination produces prominent reduction in con-
duction velocities. Nerve conduction testing can help determine,
in the case of a demyelinating neuropathy, whether the process
has an acquired or hereditary cause. A uniform slowing of nerve
conduction usually suggests a hereditary cause. Electrodiagnostic
studies can identify subclinical neuropathy (in patients receiving
potentially neurotoxic medications) and can quantitate the
extent of axon loss. Finally, these studies can localize the lesion
in the case of radiculopathies, plexopathies, and multiple
mononeuropathies.
Sensory nerve biopsies should be obtained for diagnosis of a
vasculitic neuropathy because treatment involves potentially
toxic medications. Performing a muscle biopsy in addition to the
nerve biopsy may improve the diagnostic yield and should be
considered because the inflammation is random and focal and
easily missed. Nerve biopsies are not indicated in “cryptogenic”
neuropathies, diabetic neuropathy, or motor neuron disease. If
nerve conduction studies are normal, skin biopsies allow quanti-
fication of the number of epidermal nerve fibers. A length-
dependent decrease in the number of these fibers can help
confirm a small fiber neuropathy.
Treatment
Despite a very thorough history, examination, and laboratory
studies, the cause of as many as one third of neourpathics
remain unknown. In this situation, the focus of management
is pain control. Patients with neuropathy frequently report a
burning, searing, and aching sensation in their feet and hands
that interferes with sleep. Neuropathic pain is difficult to treat
but may respond to various medications having different mecha-
nisms of action (Table 121-12). It is important to “start low
and taper slow” and to treat for a minimum of 4 weeks before
concluding that an agent is ineffective. In patients with a vas-
culitic neuropathy, therapy with corticosteroids in addition to
a cytotoxic agent can stabilize and in some cases improve the
neuropathy.
Prognosis
Peripheral neuropathies caused by axonal degeneration are gen-
erally progressive unless the underlying cause can be identified
and treated. Recovery from axonal degeneration requires nerve
regeneration, a process that often requires 2 to 3 years. Prognosis
 1084 Section XVI  Neurologic Disease
ss
TABLE 121-12  SYMPTOMATIC TREATMENT FOR
NEUROPATHIC PAIN
TRICYCLIC ANTIDEPRESSANTS Topiramate 150-200 mg bid
(Level U)
Amitriptyline 10-150 mg qhs
Duloxetine 60-120 mg qd (Level B)
(Level B)
Nortriptyline 10-150 mg qhs Pregabalin 150-600 mg qd (Level A)
(Level U) Sodium valproate 250-500 mg BID
(Level B)
Imipramine 10-150 mg qhs
(Level U) ALTERNATIVE TREATMENTS
Desipramine 10-150 mg qhs
Tramadol 50-100 mg qid (Level B)
(Level U)
Lidoderm patches (Level C)
Venlafaxine 75-225 mg qd (Level B)
Capsaicin cream (Level B)
ANTICONVULSANTS Transcutaneous nerve stimulation
Gabapentin 300-1200 mg tid Acupuncture
(Level B)
Carbamazepine 100-200 mg tid
(Level U)
of demyelinating and vasculitic neuropathies is extremely vari-
able, depending on the cause.
  COMMON MONONEUROPATHIES
Common mononeuropathies are explored in Table 121-7.
Carpal Tunnel Syndrome
Carpal tunnel syndrome results from compression of the median
nerve at the wrist as it passes beneath the flexor retinaculum.
Precipitating factors include activities that require repetitive
wrist movements, such as mechanical work, gardening, house
painting, and typing. Predisposing causes include pregnancy, dia-
betes, acromegaly, rheumatoid arthritis, chronic renal failure,
thyroid disorders, and primary amyloidosis.
Symptoms usually begin in the dominant hand but commonly
involve both hands over time. Patients typically report numb-
ness, tingling, and burning sensations in the palm and in the
fingers supplied by the median nerve: the thumb, index finger,
middle finger, and medial one half of the ring finger. Some
patients report that all fingers become numb. Pain and paresthe-
sias are most prominent at night and often interrupt sleep. The
pain is prominent at the wrist but may radiate to the forearm and
occasionally to the shoulder. Shaking the hand relieves both pain
and paresthesias. Percussion of the median nerve at the wrist
provokes paresthesias in a median nerve distribution in 60% of
patients (Tinel sign), and flexion of the wrist for 30 to 60 seconds
provokes pain or paresthesias in 75% of cases (Phalen sign).
The diagnosis is based on clinical symptoms and signs. Elec-
trodiagnostic studies may demonstrate prolongation of the
sensory or motor latencies across the wrist in up to 85% of
patients. In more severe cases, EMG may demonstrate evidence
of denervation in the abductor pollicis brevis.
Treatment initially includes avoidance of repetitive wrist activ-
ities and the use of a neutral wrist splint. If these conservative
measures fail, injections of lidocaine and methylprednisolone can
be given into the carpal tunnel or surgical treatment by section
of the transverse carpal ligament can effectively decompress the
nerve. Indicators that have been shown to predict failure with
conservative management include age greater than 50 years,
disease duration greater than 10 months, constant paresthesias,
and a positive Phalen sign in less than 10 seconds.
Ulnar Palsy
The ulnar nerve may become entrapped at the elbow because of
external compression in the condylar groove. Injury may also
occur years after a malunited supracondylar fracture of the
humerus with bony overgrowth. Contrary to the findings in
carpal tunnel syndrome, muscle weakness and atrophy character-
istically predominate over sensory symptoms and signs. Patients
notice atrophy of the first dorsal interosseous muscle and diffi-
culty performing fine manipulations of the fingers. Numbness of
the little finger, the contiguous one half of the ring finger, and the
ulnar border of the hand may be present. Ulnar nerve compres-
sion can be confirmed with electrodiagnostic studies demon-
strating slowed motor conduction velocity across the elbow.
Treatment includes the use of elbow pads to avoid compression
or surgical procedures including transposition of the ulnar nerve
or decompression of the cubital tunnel.
Peroneal Neuropathy
The peroneal nerve can become compressed as it wraps around
the fibular head and passes into the fibular tunnel between the
peroneus longus muscle and the fibula. Compression may occur
as a result of habitual leg crossing, prolonged bedrest, knee casts,
prolonged squatting, anesthesia, or profound weight loss. The
nerve can also be compressed as a result of Baker cysts, fibular
fractures, blunt trauma, tumors, or hematomas at the knee.
Symptoms include “footdrop” with selective weakness of the
ankle dorsiflexors and evertors as well as the toe extensors.
Reflexes remain normal, and sensory loss generally involves the
anterolateral leg and dorsum of the foot. Electrodiagnostic
studies demonstrate slowing of the peroneal conduction velocity
across the fibular head and may demonstrate denervation if
axonal injury is present. Compressive injuries usually resolve
spontaneously within weeks to months. Magnetic resonance
imaging (MRI) and surgical exploration should be considered if
symptoms are progressive.
  SPECIFIC ACQUIRED POLYNEUROPATHIES
Guillain-Barré Syndrome: Acute
Inflammatory Demyelinating
Polyneuropathy
Since the advent of polio vaccination, Guillian-Barré (GBS) has
become the most frequent cause of acute flaccid paralysis
throughout the world. GBS is an immune-mediated disorder that
follows an identifiable infectious disorder in approximately 60%
of patients. The best-documented antecedents include infection
with Campylobacter jejuni, infectious mononucleosis, CMV, her-
pesvirus, and mycoplasma. C. jejuni is often associated with more
severe axonal cases.
The initial symptoms of GBS often consist of tingling and pins-
and-needles sensations in the feet and may be associated with
dull low back pain. By the time of presentation, which occurs
hours to 1 to 2 days after the first symptoms, weakness has usually
developed. The weakness is usually most prominent in the legs,
but the arms or cranial musculature may be involved first. Muscle
stretch reflexes are lost early, even in regions where strength
is retained. Cutaneous sensory deficits (loss of pain and
 Chapter 121  Neuromuscular Diseases 1085
temperature) are relatively mild; however, large fiber function
(vibration and proprioception) is more severely impaired. Other
clinical features include pain (20%), paresthesias (50%), auto-
nomic symptoms (20%), facial weakness (50%), ophthalmopa-
resis (9%), bulbar weakness, and respiratory failure (25%).
Symptoms associated with GBS typically evolve over a 2- to
4-week period, with approximately 90% of patients showing no
evidence of progression beyond 4 weeks. For this reason, patients
who are seen within several weeks from onset continue to require
hospitalization for close observation. Respiratory muscle strength
should be monitored with bedside measurements of the forced
vital capacity. Intubation should be initiated when the forced vital
capacity falls below 15 mL/kg.
Treatment may include either intravenous gammaglobulin
(0.4 g/kg/day for 5 days) or plasmapheresis (the exchange of the
patient’s plasma for albumin) (200 mL/kg over 7 to 10 days).
Clinical studies have confirmed equal efficacy between these two
therapies, with no additional benefit conferred with combination
therapy. Corticosteroids are not effective in GBS. Indications for
therapy include inability to ambulate independently, impaired
respiratory function, or rapidly progressive weakness.
Clinical features predicting a poor prognosis or prolonged
recovery time include rapidly progressive weakness, need for
mechanical ventilation, and low-amplitude compound muscle
action potentials. The mortality rate remains 5% to 10%, usually
because of respiratory complications, cardiac arrhythmia, or pul-
monary embolism. With appropriate supportive care and reha-
bilitation, 80% to 90% of patients recover with little or no
disability.
Chronic Inflammatory Demyelinating
Polyneuropathy
Chronic inflammatory demyelinating polyneuropathy (CIDP)
has been considered the “chronic form” of GBS, because by defi-
nition the symptoms must progress for at least 8 weeks. The
clinical features include proximal and distal weakness, areflexia,
and distal sensory loss. Autonomic dysfunction, respiratory
insufficiency, and cranial nerve involvement can occur but are
much less common than in GBS. Treatment for CIDP includes
the use of oral immunosuppressive agents such as prednisone,
cyclosporine, mycophenolate mofetil, and azathioprine. Intrave-
nous immune globulin and plasmapheresis are also indicated for
severe or refractory cases.
Diabetic Neuropathy
Diabetes mellitus is the most frequent cause of peripheral neu-
ropathy worldwide. The diabetic neuropathies take many clinical
forms, including symmetrical polyneuropathies and a wide
variety of individual plexus or nerve disorders.
Diabetes mellitus often causes a slowly progressive, distal,
symmetrical sensorimotor polyneuropathy (DSPN). DSPN is
uncommon at the time of diagnosis of diabetes, but its preva-
lence increases with duration of diabetes with a lifetime preva-
lence of 55% for type 1 and 45% for type 2. The precise
pathogenesis is not defined, but, similar to the ocular and renal
complications, diabetic neuropathy can be reduced in incidence
and in severity by maintaining blood glucose levels close to
normal.
Initial symptoms may consist of numbness, tingling, burning,
or prickling sensations affecting the feet and toes. Mild distal ss
weakness and gait instability may subsequently develop. The
sensory symptoms can then slowly progress to involve a
“stocking-glove pattern.” The small-fiber dysfunction often pro-
duces spontaneous neuropathic pain in which unpleasant sensa-
tions can be evoked by normally innocuous stimuli, such as the
bed sheets on the toes at night. Continuous burning or throbbing
pain may occur, and prolonged walking is often distressing. In
severe cases, patients may develop foot ulcers in insensitive areas
that necessitate amputation. Autonomic dysfunction is also fre-
quently associated with DSPN including impotence, nocturnal
diarrhea, sweating abnormalities, orthostatic hypotension, and
gastroparesis.
Other less common neuropathies associated with diabetes
include cranial neuropathies (the sixth, third, and rarely fourth
nerves), mononeuropathies, mononeuropathy multiplex, radicu-
lopathies, and plexopathies. Diabetic amyotrophy (also known as
diabetic lumbosacral polyradiculopathy) is a distinctive disorder
characterized by severe thigh pain followed by proximal greater
than distal lower extremity weakness that progresses over a
period of months. The onset is invariably unilateral, but the con-
dition may progress to involve both lower extremities. Physical
therapy and effective pain management are essential; treatment
with immune modulators is controversial.
Toxic-Induced Neuropathies
Toxic-induced neuropathies constitute a large number of dis-
orders caused by alcohol, drugs, heavy metals, and environ-
mental substances (E-Table 121-3). The majority of toxic
neuropathies manifest as a distal sensorimotor axonal neu-
ropathy that chronically progresses over time unless the offend-
ing agent is eliminated. Clinical evaluation should focus on
the temporal relationship between exposure and the onset of
sensory or motor symptoms as well as symptoms of systemic
toxicity.
Critical Illness Polyneuropathy
Critical illness polyneuropathy (CIP) is a common cause of
failure to wean from a ventilator in a patient with associated
sepsis and multi-organ failure. Clinical features include general-
ized or distal flaccid paralysis, especially involving the lower
extremities, depressed or absent reflexes, and distal sensory loss
with relative sparing of cranial nerve function. The diagnosis can
be confirmed with nerve conduction studies showing evidence
of a severe, generalized axonal neuropathy. CSF protein should
be normal and, in addition to conduction studies, distinguishes
CIP from GBS.
  SPECIFIC HEREDITARY POLYNEUROPATHIES
Charcot-Marie-Tooth Disease
The eponym Charcot-Marie-Tooth (CMT) identifies a group of
heritable disorders of peripheral nerves that share clinical fea-
tures but differ in their pathologic mechanisms and the specific
genetic abnormalities (E-Table 121-4). CMT is the most
common heritable neuromuscular disorder, with an incidence of
17 to 40 cases per 100,000.
 Chapter 121  Neuromuscular Diseases 1085.e1

E-TABLE 121-4  CHARCOT-MARIE-TOOTH DISEASE ss

DISORDER LOCUS/PROTEIN INHERITANCE USUAL ONSET SPECIFIC CLINICAL FEATURES

CMT1: DEMYELINATING
CMT1A 17p11.2 AD 1st decade Distal weakness
Peripheral myelin protein 22 (PMP22)
CMT1B 1q22 AD 1st decade Distal weakness
Myelin protein zero (P0) More severe
CMT1C 16p13.1-p12.3 AD 2nd decade Distal weakness
LITAF
CMT1D 10q21.1-q22.1 AD 2nd decade Distal weakness
Early growth response protein 2 (EGR2) Ptosis
CMT1F 8p21 AD 1 to 40 years Distal weakness
NF-68 Ataxia
CMTX Xq13.1 X-linked 2nd decade Distal weakness
Connexin 32 Hearing loss
Encephalopathy
HNPP 17p11.2 AD 3rd decade Focal episodic weakness
Peripheral myelin protein 22 (PMP22)
Dejerine-Sottas 8q23,17p11,10q21 AD 2 yrs Severe weakness
(HSMN3) Early growth response protein 2 (EGR2)
Peripheral myelin protein 22 (PMP22)
CMT2: DOMINANT; AXONAL
CMT2A 1p36.2 AD 10 years Distal weakness
Kinesin-like protein (KIF1B)
CMT2A2 1p36 AD 10 years Distal weakness
Mitofusin 2 (MFN2) Hearing loss
CMT2B 3q21 AD 2nd decade Distal weakness
RAB7 Sensory loss
Acromutilation
CMT2C 12q23-24 AD 1st decade Vocal cord and distal weakness
TRPV4
CMT2D 7p15 AD 16 to 30 years Distal weakness arms > legs
Glycyl-tRNA (GARS)
CMT2E 8p21 AD 1 to 40 years Distal weakness
Synthetase Neurofilament triplet L protein (NEFL
Sequencing)
CMT2F 7q11-21 AD 2nd decade Difficulty walking
HSPB1
CMT2G 12q12 AD 15 to 25 years Distal weakness
CMT2K 8q21 AD Infant Distal weakness
GDAP1 Vocal cord
CMT2L 12q24 AD 15 to 33 years Distal weakness
HSPB8
CMT2M 19p13 AD 0 to 50 years Distal weakness, legs > arms,
DNM2 ophthalmoparesis
CMT2N 16q22 AD 6 to 54 years Distal leg weakness
AARS Asymmetric
CMT4: RECESSIVE; DEMYELINATING
CMT4A 8q13-q21.1 AR Childhood Distal weakness
Ganglioside-induced differentiation protein-1 (GDAP1) Vocal cord
CMT4B1 11q22 AR 2 to 4 yrs Distal and proximal weakness
Myotubularin-related protein 2 (MTMR2)
CMT4B2 11p15 AR 1st 2 decades Distal weakness
Set binding factor 2 (SBF2) Sensory loss
Glaucoma
CMT4C 5q32 AR 5 to 15 yrs Delayed walking
SH3TC2
CMT4D 8q24.3 AR 1 to 10 yrs Gait disorder
NDRG1 protein Hearing loss
CMT4E 10q21.1-q22.1 AR Birth Infant hypotonia
Early growth response protein 2 (EGR2) Arthrogryposis
Respiratory failure
CMT4F 19q13.1-q13.2 AR 1 to 3 yrs Motor delay
Periaxin (PRX) Sensory loss
CMT4H 12p11.21 AR 10 to 24 mo Walking delay
FGD4 Scoliosis
CMT4J 6q21 AR Congenital to adult Asymmetric proximal and distal weakness
FIG4
CMT3 P0, PMP-22, EGR2, Periaxin AR 2 years Severe weakness
(Dejerine-
Sottas)
 1086 Section XVI  Neurologic Disease
CMT disease usually manifests during the first to second
ss decades with symptoms related to insidious footdrop: frequent
tripping and inability to jump well or run as fast as other children.
Over time, distal upper extremity weakness develops, resulting in
difficulty with buttoning, handling keys, and opening jars. Exami-
nation reveals distal weakness and wasting of the intrinsic muscles
of the feet, the peroneal muscles, the anterior tibial muscles, and
the calves (inverted champagne bottle legs). A variable degree of
impaired large-fiber sensory function is reflected in reduced
vibratory sensation at the toes. Muscle stretch reflexes are lost,
first at the ankles. Typically, a foot deformity exists, with high
arches (pes cavus) and hammer toes, reflecting long-standing
muscle imbalance in the feet. Most patients with CMT disease
have nearly normal occupational and daily activities, and they
have a normal life span. Although no specific treatment has been
developed, the foot drop can be treated by appropriate bracing
of the ankle with ankle-foot orthoses. Genetic counseling and
education of affected patients and their families are important,
both for reassurance and to preclude unnecessary diagnostic
evaluation of affected members in future generations.
Demyelinating forms of CMT are classified as CMT1 and
axonal forms as CMT2. CMT is usually transmitted as an auto-
somal dominant trait; however, X-linked dominant transmission
is responsible for approximately 10% of cases. Rare autosomal
recessive forms are designated CMT4, and these patients tend to
have an earlier onset and more severe phenotype. CMT1A is the
most common form and accounts for 90% of CMT1 and 50% of
all CMT cases. CMT1A is associated with the 17p11.2-p12
duplication in the PMP22 gene expressed by Schwann cells. A
deletion or a point mutation of the PMP22 gene produces a dif-
ferent phenotype: HNPP, which is characterized by recurrent
episodes of focal entrapment with attacks of weakness and numb-
ness in the peroneal, ulnar, radial, and median nerves (in descend-
ing order of frequency) or in a brachial plexus distribution.
  FAMILIAL AMYLOID NEUROPATHIES
Amyloid neuropathy is an autosomal dominant disorder caused
by extracellular deposition of the fibrillary protein amyloid in
peripheral nerve and sensory and autonomic ganglia, as well as
around blood vessels in nerves and other tissues. The age of onset
varies from 18 to 83 years. In all forms of amyloidosis, the initial
and major abnormalities affect the small sensory and autonomic
fibers. Involvement of small fibers responsible for pain and tem-
perature sensibilities leads to loss of the ability to perceive
mechanical and thermal injuries and to an increased risk of tissue
damage. As a result, painless injuries present a major hazard of
this disorder; in advanced stages, they can lead to chronic infec-
tions or osteomyelitis of the feet or hands and the necessity for
amputation. Amyloid deposition in the heart can lead to cardio-
myopathy. Mutations in transthyretin, apolipoprotein A1, or gel-
solin are responsible. Early recognition is essential, as liver
transplantation has been shown to halt disease progression.
For a deeper discussion on this topic, please see Chapter
420, “Peripheral Neuropathies,” in Goldman-Cecil Medi-
cine, 25th Edition.
SUGGESTED READINGS
Barohn RJ: Approach to peripheral neuropathy and neuronopathy, Sem Neurol
18:7–18, 1998.
Bril V, England J, Franklin GM, et al: Evidence-based guideline: Treatment
of painful diabetic neuropathy–report of the American Association of
Neuromuscular and Electrodiagnostic Medicine, the American Academy
of Neurology, and the American Academy of Physical Medicine &
Rehabilitation, Muscle Nerve 43:910–917, 2011.
Dyck PJ, Thomas PK, editors: Peripheral Neuropathy, ed 4, Philadelphia, 2005,
WB Saunders.
Feldman EL: Amyotrophic lateral sclerosis and other motor neuron diseases. In
Goldman L, Ausiello DA, editors: Cecil Textbook of Medicine, ed 23,
Philadelphia, 2007, WB Saunders.
Jackson CE, Bryan WW: Amyotrophic lateral sclerosis, Sem Neurol 18:27–40,
1998.
Miller RG, Jackson CE, Kasarkis EJ, et al: Practice parameter update: The care of
the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory
therapies (an evidence-based review):report of the Quality Standards
Subcommittee of the American Academy of Neurology, Neurology
73(15):1218–1226, 2009.
Miller RG, Jackson CE, Kasarksi EJ, et al: Practice parameter update: The care of
the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom
management, and cognitive/behavioral impairment (an evidence-based
review): report of the Quality Standards Subcommittee of the American
Academy of Neurology, Neurology 73(15):1227–1233, 2009.
Shy M: Peripheral neuropathies. In Goldman L, Ausiello DA, editors: Cecil
Textbook of Medicine, ed 23, Philadelphia, 2007, WB Saunders.
Wolfe GI, Baker NS, Amato AA, et al: Chronic cryptogenic sensory
polyneuropathy: clinical and laboratory characteristics, Arch Neurol 56:540–
547, 1999.

Muscle Diseases
Jeffrey M. Statland and Robert C. Griggs
  INTRODUCTION
Skeletal muscle fibers are the effector cells of the nervous system,
turn thoughts into actions, and are the means by which we inter-
act with our environment. Myopathies are primary diseases
of the muscle and can be both inherited and acquired
(Table 122-1). Myopathies can result in weakness and muscle
wasting, myalgias, cramps, muscle breakdown, or contractures.
Inherited disorders affect muscle proteins involved in transmis-
sion of signals from the neuromuscular junction, proteins
involved in energy production or metabolism, or structural pro-
teins that anchor and transmit force from the contractile appara-
tus to the extracellular matrix. Acquired myopathies are caused
by external factors and can be due to metabolic derangements,
toxic exposures or drugs, infections, or autoimmune dysfunction
causing inflammation in the muscle. Acquired myopathies often
improve with treatments geared towards eliminating or amelio-
rating the precipitating factors. To date, there have not been spe-
cific treatments for most inherited disorders of muscle, but as our
understanding of the molecular pathological mechanisms of
these disorders advances, new disease-directed therapies are
entering clinical trials.
  ORGANIZATION AND STRUCTURE OF MUSCLE
Each muscle is enclosed in a connective tissue sheath made up of
collagen and extracellular matrix proteins called the epimyseum,
which merges at either end to form the tendons, which attach
muscle to bone. The epimyseum divides internally into the peri-
mysium, which separates the muscle into individual bundles of
muscle fibers called fascicles. The endomyseum surrounds and
provides support for the individual fibers. Each muscle fiber is a
single multi-nucleated syncytial cell and can be as long as 10 cm.
On cross section, muscle fibers appear polygonal in shape and in
adults range from 40 to 80 micrometers in diameter. Medium size
arterioles and veins run in the perimysium, with capillaries
between the individual muscle fibers. On hematoxylin and eosin
stains, cytoplasm appears pink and the nuclei blue, with a thin
rim of white, the epimyseum, between fibers (Fig. 122-1A). Each
TABLE 122-1  OVERVIEW OF MYOPATHIES
HEREDITARY MYOPATHIES ACQUIRED MYOPATHIES
Muscular dystrophies Inflammatory myopathies
Congenital myopathies
Metabolic/Mitochondrial
Endocrine myopathies
Systemic illness/infectious
myopathies myopathies
Channelopathies Toxic/Drug-induced myopathies
122 
ss
individual muscle fiber has multiple nuclei, which are found
beneath the sarcolemma membrane on the periphery of the cell.
The amount of connective tissue between fibers, the position and
number of myonuclei, and the amount and distribution of mito-
chondria can all be indicators of disease.
The plasma membrane around the muscle fiber is called the
sarcolemma, and inside there are a large number of myofibrils
made of thick (myosin) and thin (actin) filaments, which make
up 70% to 80% of the volume of the cell, and when activated,
create force. Electrochemical signals carry the signal from the
nerve, through the neuromuscular junction, into the muscle fiber
along the sarcolemma and t-tubule system. Muscle ion channels
line this network and carry electrochemical signals. Mitochon-
dria and enzymes involved in glycolysis and fatty acid metabo-
lism provide energy for muscle. A network of proteins, the
dystrophin-glycoprotein complex (DGC), anchors the myofi-
brils to the subsarcolema cytoskeleton and connects to the extra-
cellular matrix (Fig. 122-2). Many inherited myopathies are due
to mutations in these ion channels, metabolic enzymes, or struc-
tural anchoring proteins.
  ASSESSMENT
The work-up of a patient with a suspected myopathy is a staged
process and involves a history and physical examination, followed
by laboratory studies, electrodiagnostic testing, muscle biopsy,
and genetic testing (Table 122-2). The family history is impor-
tant because muscle disease can run in the family and may not
have been previously diagnosed. Questions about whether family
members require assistive devices to walk or wheelchairs, and
concerning common extra muscular manifestation of muscular
dystrophies can be useful. The genetic myopathies can be inher-
ited in an autosomal dominant or recessive fashion, be X-linked,
show maternal inheritance, or be sporadic (Table 122-3).
The most common symptom of a patient with muscle disease
is a loss of function caused by weakness (see Table 122-2). Other
common symptoms, like fatigue or myalgias (muscle pain), are
less specific than muscle weakness. Muscle cramping is most
often benign, and can be secondary to neuropathic changes.
Muscle contractures are sustained contractions that are distin-
guished from cramping on electrodiagnostic testing, where con-
tractures are electrically silent. Tendon contractures, on the other
hand, are a fixed shortening of the tendon, and associated with
long-standing disuse.
  EXAMINATION
The physical examination uses a standard modified Medical
Research Council scale of motor strength to determine the
1087
 1088 Section XVI  Neurologic Disease

ss

A B

C D
FIGURE 122-1  Muscle biopsies hematoxylin and eosin staining. A, Normal adult muscle medium power. Notice polygonal muscle fibers arranged
in fascicles with blue staining nuclei on the periphery. A small arteriole is visible (white arrow). B, Duchenne muscular dystrophy low power. Note the
variability in fiber size with rounding of fibers, increase in connective tissue, and fatty deposition. C, Centronuclear congenital myopathy. Notice
variability in fiber size, large rounded fibers, and characteristic central nuclei in most fibers (white arrow). D, Dermatomyositis on low power. Notice
the prominent perifascicular atrophy of fibers, with inflammatory infiltrates (white arrow).

Extracellular Collagen VI → Ullrich/Bethlam myopathy

α2

Basal lamina
β1 γ1

Laminin → Congenital muscular dystrophy

Congenital
muscular ← Dystroglycan
dystrophy
Integrin

Dgα

Plasma membrane Iα Iβ
Sα Sβ Sδ Sγ
Dgβ

α
C Sarcoglycan → LGMD 2C-F
β1
Syntrophin β2

N Caveolin-3 → LGMD 1C

Intracellular
Dystrophin → DMD/BMD
F-actin
LGMD 2A → Calpain
Dysferlin → LGMD 2B
FIGURE 122-2  The dystrophin-glycoprotein complex. Muscle structural proteins connect the contractile apparatus to the internal cytoskeleton
and the extracellular matrix. Mutations in proteins from the extracellular matrix to the anchoring proteins, which connect the extracellular matrix to
the internal cytoskeleton to proteins, which attach the internal cytoskeleton to the contractile apparatus are all involved in the inherited muscular
dystrophies and myopathies.

TABLE 122-2  WORK UP FOR A PATIENT WITH
SUSPECTED MYOPATHY
FEATURE DESCRIPTION
HISTORY
Age of onset Congenital, childhood, adult
Chronic, progressive, or Dystrophies are usually progressive; congenital
episodic static; metabolic/channelopathies episodic
Triggers Exercise, foods, temperatures
FAMILY HISTORY Dominant, recessive, or no family history
WEAKNESS ON EXAM
Proximal Difficulty lifting objects, climbing stairs, getting
up from chair, scapular winging, waddling
gait, Gower’s sign
Distal Difficulty making a tight fist, fastening buttons,
opening jars, wrist drop, foot drop
Facial Difficulty squeezing the eyes shut, transvers
smile, inability to pucker or blow out cheeks,
inability to whistle
Oculopharyngeal Ptosis, restricted extra ocular movements,
coughing after drinking, and difficulty
swallowing
Cardiac Cardiac conduction defects, cardiomyopathy
Respiratory Using accessory muscles, difficulty lying flat
LABORATORY
CK Dystrophies/inflammatory myopathy increased
>10x normal; congenital 3-5x normal;
metabolic >10x normal during attacks
Thyroid / Parathyroid High TSH, low T4, low PTH, Ca2+
ELECTRODIAGNOSTIC Irritated muscle shows fibrillations and positive
STUDIES sharp waves; myopathic motor units are brief,
low amplitude, and polyphasic; myotonia
spontaneous waxing and waning motor unit
amplitude and frequency
MUSCLE BIOPSY Changes in muscle fiber shape and composition
of fiber types, amount of connective tissue,
presence of inflammatory cells, necrotic
muscle fibers, regenerating fibers, number or
morphology of mitochondria, or abnormal
deposits of fat or glycogen
GENETIC TESTING Confirmatory for inherited myopathies
TABLE 122-3  INHERITANCE PATTERN IN GENETIC
MYOPATHIES
X-LINKED Oculopharyngeal muscular
dystrophy
Duchenne/Becker muscular
dystrophy Channelopathies
Emory-Dreifuss muscular dystrophy Central core myopathy
AUTOSOMAL DOMINANT AUTOSOMAL RECESSIVE
Myotonic dystrophy types 1 and 2 Limb-girdle muscular dystrophy
(2A-2S)
Facioscapulohumeral muscular
Metabolic myopathies
dystrophy
Limb-girdle muscular dystrophy Recessive myotonia congenita
(1A-1H) MATERNAL TRANSMISSION
Mitochondrial myopathies
pattern and degree of involvement of various muscles
(Table 122-4). But just as important as isolated strength testing
are functional motor tasks, particularly in children. Patients may
have difficulty climbing stairs, rising from a low chair or toilet,
getting up from the floor, trouble lifting objects over their heads
and washing or brushing their hair, or difficulty opening jar tops
and fastening buttons. Muscles should be inspected for atrophy
or hypertrophy and range of motion around the joints for evi-
dence of tendon contractures. Ten broad patterns of muscle
Chapter 122  Muscle Diseases 1089
TABLE 122-4  MODIFIED MEDICAL RESEARCH ss
COUNCIL MOTOR STRENGTH TESTING
SCALE
GRADE DEGREE OF STRENGTH
5 Normal strength through entire range of motion and against
resistance
5- Equivocal, barely detectable weakness
4+ Able to move against gravity and resistance, but examiner can
break
4 Able to move against gravity and some resistance
4- Able to resist gravity but only minimal resistance
3+ Able to overcome gravity and transient resistance, but then
quickly gives out
3 Able to overcome gravity but no resistance
3- Able to resist gravity but not through full range of motion
2 Able to move through range of motion with gravity eliminated
1 Trace muscle contraction
0 No contraction
weakness occur in myopathies (Table 122-5). Most myopathies
have the proximal, limb-girdle pattern. There are other, highly
distinctive, patterns. Weakness that is asymmetric and includes
the face, proximal arms and shoulders, and distal lower extremi-
ties is characteristic of facioscapulohumeral muscular dystrophy.
Weakness that starts in the distal finger flexors (patients cannot
curl fingers when making a fist) and proximal lower extremities
(the quadriceps) is virtually pathognomonic for sporadic inclu-
sion body myositis. A patient in middle age who presents with
ptosis and difficulty swallowing is highly characteristic for oculo-
pharyngeal muscular dystrophy. In all cases these patterns need
to be distinguished from other diseases of the nervous system
causing similar patterns of weakness (see Chapters 121
and 123.).
  DIAGNOSTIC TESTING
The most useful initial laboratory study is the serum creatine
kinase (CK), which is commonly elevated in both inherited and
acquired myopathies. Despite the obvious localizing value of
elevated muscle enzymes it is important to remember not all
elevations in serum CK are due to myopathy (Table 122-6).
Electrodiagnostic testing can help distinguish between neuro-
genic and myopathic causes for weakness. In muscle disease
nerve conduction studies are normal. Changes on electromyog-
raphy characteristic for muscle disease include: chronic changes
characterized by small, brief duration, polyphasic motor units;
and more acute changes (irritable myopathic changes), which
include fibrillations or positive sharp waves.
Muscle biopsies can be an important diagnostic test in patients
whose family history and physical examination does not suggest
a particular myopathic diagnosis. Characteristic morphological
changes are hallmarks of the congenital myopathies (e.g., central
core disease, or centronuclear myopathy), inflammatory myopa-
thies (dermatomyositis and polymyositis), and metabolic myop-
athies (glycogen storage disorders), but most myopathies result
in nonspecific muscle changes including rounding of muscle
fibers, variation in fiber size, and increased number of internal
nuclei.
In patients for whom the family history is suggestive of an
inherited myopathy or in which the diagnosis is important to help
guide surveillance or treatment, genetic testing is confirmatory.
 1090 Section XVI  Neurologic Disease

ss
TABLE 122-5  CHARACTERISTIC PATTERNS OF MUSCLE WEAKNESS AND ASSOCIATED MYOPATHIES
PATTERN
Proximal limb-girdle
Distal
Proximal arm/distal leg
Distal arm/proximal leg
Ptosis ± ophthalmoparesis
Neck extensor weakness
Bulbar weakness
Episodic pain, weakness, and
myoglobinuria
Episodic weakness delayed or
unrelated to exercise
Stiffness and decreased ability
to relax
Modified from Jackson CE, Barohn RJ: A pattern recognition approach to myopathy, Continuum (Minneap Minn) 19(6 Muscle Diseases):1674-1697, 2013.
WEAKNESS
Symmetrical, pelvic and shoulder girdle muscles.
Distal muscles to lesser extent. ± Neck flexor/
extensor.
Symmetrical, distal upper or lower extremity.
Proximal muscles to lesser degree.
Scapuloperoneal distribution: periscapular
muscles (proximal arm) and anterior
compartment distal leg (tibialis anterior).
Scapular winging. Can be asymmetrical.
Distal forearm muscles (distal finger flexors)
and proximal leg (quadriceps). Other muscles
variable. Often asymmetrical.
Ocular weakness at presentation. Restriction of
eye movements often without diplopia.
Occasionally followed by pharyngeal weakness.
Variable extremity weakness
Neck extensors, “dropped head syndrome.”
Variable neck flexor. ± extremity weakness.
Tongue and pharyngeal weakness
May be triggered by exercise or metabolic stress
May be triggered by food, stress, rest after
exercise
May be episodic, triggered by cold
DISEASES
Nonspecific: Duchenne muscular dystrophy; limb-girdle muscular
dystrophy; inflammatory myopathies; certain autoimmune neuropathies
Nonspecific: Miyoshi myopathy (calves); Welander myopathy (wrist and
finger extensors); Nonaka and Markesbery/Udd myopathy (tibialis
anterior); rule out neuropathy
When face involved highly suggestive of facioscapulohumeral muscular
dystrophy; with elbow contractures Emory-Dreifuss dystrophy;
scapuloperoneal dystrophies; certain limb-girdle dystrophies; congenital
myopathies
Highly suggestive of sporadic inclusion body myositis; also consider
myotonic dystrophy
Ocular and pharyngeal weakness highly suggestive of oculopharyngeal
muscular dystrophy; ptosis and ophthalmoplegia without pharyngeal
involvement mitochondrial myopathies
In isolation consider isolated neck extensor myopathy; rule out
amyotrophic lateral sclerosis and myasthenia gravis
Certain myopathies (e.g., oculopharyngeal muscular dystrophy); significant
overlap with neuromuscular junction and motor neuron disease
Metabolic myopathies; may also occur in deconditioning
Characteristic of periodic paralyses
Characteristic of myotonic disorders; but may be seen in other myopathies;
acquired conditions (e.g. stiff person syndrome)

MRI, include congenital muscular dystrophies (see Table 122-8;

TABLE 122-6  CAUSES FOR ELEVATED SERUM CK not discussed in text). The traditional distinction between dys-
MYOPATHIES MEDICATIONS trophies and other inherited myopathies is becoming blurred as
Muscular dystrophies/carrier state Statins our genetic understanding advances because mutations for differ-
Congenital myopathies Fibric acid derivatives ent diseases are often allelic.
Metabolic myopathies Chloroquin
Inflammatory myopathies Colchicine
CHANNELOPATHIES ENDOCRINE ABNORMALITIES Dystrophinopathies
(THYROID/PARATHYROID)
MOTOR NEURON DISEASE Definition and Epidemiology
(ALS, SMA) SURGERY
Dystrophinopathies are X-linked recessive disorders resulting
NEUROPATHIES (GBS, CIDP) TRAUMA
from mutations of the large dystrophin gene located at Xp21. The
VIRAL ILLNESS STRENUOUS EXERCISE
incidence of Duchenne muscular dystrophy is 1 in 5300 male
INCREASED MUSCLE MASS
births; one third of the cases result from a new mutation. Becker
IDIOPATHIC muscular dystrophy is a milder form of dystrophinopathy and is
less common than the Duchenne form, with an incidence of 5
per 100,000.
  INHERITED MYOPATHIES Pathology
Muscular Dystrophies Dystrophin is a large subsarcolemmal cytoskeletal protein that,
The muscular dystrophies are inherited myopathies characterized along with the other components of the dystrophin-glycoprotein
by progressive weakness and mutations in genes coding for struc- complex, provides support to the muscle membrane during con-
tural and other muscle proteins. Typically the muscular dystro- traction. Muscle biopsies are typically not required for diagnosis
phies are divided into the dystrophinopathies, the myotonic but show variability in fiber size; active and chronic changes,
dystrophies, facioscapulohumeral muscular dystrophy, Emery- including necrotic and regenerating fibers; and, later in the
Dreifuss muscular dystrophy, and the limb-girdle dystrophies disease, increased connective tissue and deposition of fat
(Tables 122-7, 122-8, and E-Table 122-1). The limb-girdle mus- (Fig. 122-1B).
cular dystrophies (LGMD) are a diverse group of diseases due to
mutations in more than 20 genes. The LBMDs are inherited in Clinical Presentation
either autosomal dominant or recessive fashion, and present any- Mutations in dystrophin result in a spectrum of disorders reflect-
where from childhood to later in life, having as the name implies, ing variations in the amount of functional dystrophin still
a limb-girdle pattern of weakness (E-Table 122-1). Another expressed—from Duchenne muscular dystrophy and Becker’s on
group of patients who have dystrophic changes in the muscle the severe end, to isolated quadriceps weakness and isolated car-
from birth, often with accompanying changes in the brain on diomyopathy in the middle, and to cramps and myalgias with
 Chapter 122  Muscle Diseases 1090.e1

E-TABLE 122-1  LIMB-GIRDLE MUSCULAR DYSTROPHIES—ABBREVIATED LIST ss

INHERITANCE NOMENCLATURE MUTATION AGE CK PHENOTYPES SURVEILLANCE

Autosomal 1A 5q31; MYOT (myotilin) 18-40 Normal to 15x limb-girdle pattern; tight Respiratory
dominant* Achilles tendons; involvement; trouble
dysarthria swallowing
1B 1q21; LMNA (lamin Variable; birth Normal to Limb-girdle pattern; Significant cardiac
A/C) to adulthood mildly elevated contractures involvement
1C 3p25 CAV3 (caveolin 3) 5-adulthood 3x-40x Limb-girdle pattern; Cardiac involvement
rippling muscle disease;
elevated CK and
cramping; distal
myopathy (hand/foot)
1D 2q35; DES (desmin) Teens to 2x-4x Limb-girdle pattern Cardiac involvement
adulthood
1E 7q36 DNAJB6 ( 30s-60s Normal to 5x Limb-girdle pattern; lower Trouble swallowing
> upper
Autosomal 2A 15q15 CAPN3(Calpain-3) 2-40s Normal to 80x Limb-girdle pattern;
recessive† scapular winging;
paraspinal involvement/
scoliosis
2B 2p13 DYSF (dysferlin) Teens to 20s 10x to 72x Limb-girdle pattern; Respiratory late
Miyoshi distal myopathy
(calf wasting); tibialis
anterior
2C-2F 13q12 (γ- sarcoglycan); 3-15 >10x Limb-girdle pattern; mild to Respiratory and
17q12 (α- sarcoglycan); severe phenotype; cardiac involvement;
4q12 (β -sarcoglycan); contractures/scoliosis; orthopedics
5q33 (δ- sarcoglycan) calf pseudo-hypertrophy
2G 17q12 TCAP (telethonin) 9-15 3x-30x Limb-girdle pattern; distal
tibialis anterior
2I 19q13 FKRP (fukutin Birth to 20s 10x to 30x Limb-girdle pattern; upper Respiratory
related protein) > lower involvement
*Other autosomal dominant mutations: 1F 7q32 TNPO3; 1G 4q21; 1H 3p23.
†
Other recessive mutations: 2H 9q33 TRIM32; 2J 2q24 Titin; 2L 11p14 ANO5.
 Chapter 122  Muscle Diseases 1091

TABLE 122-7  PREVALENT MUSCULAR DYSTROPHIES ss

DISEASE INHERITANCE MUTATIONS AGE OF ONSET PHENOTYPES TREATMENT

Dystrophinopathies X-linked recessive Xp21; ~75% deletion Duchenne diagnosis by Limb-girdle pattern. Duchenne: Prednisone (or deflazacort)
or duplication; age 4; Becker variable severe progressive and life for Duchenne; ACE
remaining sequence limiting. Becker progressive β-blocker for afterload
variant but not as severe, more reduction in
variable. Calf pseudo- cardiomyopathy; yearly to
hypertrophy; isolated biannual surveillance for
quadriceps weakness; isolated respiratory, cardiac and
cardiomyopathy orthopedic problems
Myotonic dystrophy Autosomal 19q13; CTG expansion Classic 20-30s; Limb-girdle, can have distal Mexiletine for symptomatic
type 1 dominant > 50 repeats congenital at birth weakness. Classic: myotonia myotonia; Yearly
and muscle wasting, temporal surveillance for cataracts,
wasting, frontal balding; cardiac conduction deficits,
cataracts; cardiac conduction and respiratory
deficits; and diabetes. involvement.
Congenital: severe and
progressive, respiratory
deficits, intellectual disability,
and death ~45 years if survive
neonatal period
Myotonic dystrophy Autosomal 3q13; CCGT 30s Limb-girdle pattern; multi- Mexiletine for symptomatic
type 2 dominant expansion > 75 system involvement cataracts, myotonia; Yearly
repeats cardiac conduction deficits; surveillance for ocular,
diabetes cardiac, and respiratory
involvement
Facioscapulohumeral Autosomal 4q35; ~95% between 20s Scapuloperoneal pattern with Supportive; screening dilated
muscular dominant 1-10 D4Z4 repeats; facial involvement; can have eye exam; hearing studies
dystrophy ~5% decreased marked asymmetry; as indicated clinically;
methylation <20% significant axial involvement respiratory studies once
D4Z4 region wheelchair bound
Emery-Dreifuss X-linked recessive; ~70% Xq28 Emerin or Joint contractures Scapuloperoneal pattern; joint Yearly surveillance for cardiac
muscular autosomal FHL1 mutation; childhood; contractures, particularly at and respiratory
dystrophy dominant or 1q21 lamin A/C, progressive weakness elbows, significant cardiac involvement; orthopedic
recessive both dominant and 20s-30s involvement evaluation for symptomatic
recessive mutations contractures
reported
Oculopharyngeal Autosomal 14q11 PABPN1 40s (range 20s-60s) Typically ptosis 2-3 years before Swallow study; consider
muscular dominant and (Polyadenylate- dysphagia; limb-girdle pattern blepharoplasty for ptosis,
dystrophy recessive binding protein) weakness consider cricopharyngeal
GCG repeats 7-13 myotomy for severe
swallowing difficulty

TABLE 122-8  CONGENITAL MUSCULAR DYSTROPHIES

NAME / AKA GENE
Merosin-deficient 6q22; laminin alpha-2
Bethlam myopathy / 21q22; 2q37; COL6 (collagen
Ullrich muscular 6 spectrum disorders)
dystrophy
Dystroglycanopathy 9q34 (POMT1); 14q24
(POMT2); 9q31 (fukutin);
19q13 (FKRP); 22q12
(LARGE); 1q32
(POMGnT1); 7p21 (ISPD)
SEPN1 related myopathy 1q36 (SEPN1)
LMNA related 1q22 (lamin A/C
INHERITANCE PHENOTYPE CNS INVOLVEMENT
Autosomal recessive Hypotonia; contractures; scoliosis MRI diffuse white matter changes;
or rigid spine; respiratory 20-30% seizures
involvement; external
ophthalmoplegia
Autosomal dominant Hypotonia; contractures; distal
or recessive joint laxity; keloid; respiratory
involvement
Autosomal recessive Spectrum of disorders but Walker Warburg Syndrome: severe
characteristic intellectual, eye, and eye involvement, cobblestone
brain involvement; motor early lissencephaly, hypoplastic
death, to acquiring ambulation cerebellum and brainstem.
Muscle eye Brain Syndrome:
common eye involvement,
pachygyri/polymicrogyri,
hypoplastic cerebellum and
brainstem. Fukuyama: mild eye
involvement, cortex mild changes,
hypoplastic cerebellum but
normal brainstem
Autosomal recessive Cervicoaxial weakness, rigid spine
syndrome, early nocturnal
hypoventilation, medial thigh
wasting
Autosomal dominant Cervicoaxial weakness, dropped
and recessive head, rigid spine syndrome,
respiratory and cardiac
involvement
 1092 Section XVI  Neurologic Disease
elevated serum CK on the mild end. Duchenne muscular dystro-
ss phy manifests as early as age 2 to 3 years with delays in motor
milestones and difficulty running. Patients can have marked
pseudo-hypertrophy of the calf muscles. And when asked to get
up from the floor, boys use a Gower’s maneuver (use hands to
push up). The average age of diagnosis is around 4 years of age.
The proximal muscles are the most severely affected, and the
course is relentlessly progressive. Patients begin to fall frequently
by age 5 to 6, have difficulty climbing stairs by age 8 years, and
are usually confined to a wheelchair in their early teens. The
smooth muscle of the gastrointestinal tract is involved and may
cause intestinal pseudo-obstruction. The average IQ of boys with
Duchenne muscular dystrophy is low, reflecting central nervous
system involvement.
Diagnosis and Differential Diganosis
Diagnosis is based on clinical history, physical examination,
serum CK, and is confirmed by genetic testing. The majority of
patients have deletions or duplications in the dystrophin gene. In
the remaining patients, mutations can be small insertions or dele-
tions, point mutations, or splicing errors. Other differential con-
siderations are congenital myopathies and muscular dystrophies,
and limb-girdle muscular dystrophies.
Treatment
Duchenne muscular dystrophy is a combination of surveillance
for respiratory, orthopedic, and cardiac involvement, and the use
of prednisone. Prednisone and deflazacort (a synthetic derivative
of prednisolone available in other countries) improve strength
and motor function in boys with Duchenne muscular dystrophy.
Cardiac evaluation should begin at the time of diagnosis and, if
cardiac involvement is found, afterload reduction is recom-
mended (ACE inhibitor, β-blocker). Respiratory function should
be monitored beginning prior to wheelchair use or when the
forced vital capacity drops below 80%. Regular orthopedic
screening for scoliosis and bone health is recommended. New
investigational strategies for treatment include gene therapy,
exon skipping strategies, and readthrough of premature stop
mutations, all of which are designed to make the cell produce
some form of dystrophin. There are no guidelines for the treat-
ment of Becker muscular dystrophy and clinical presentation is
highly variable, but monitoring for cardiac and respiratory
involvement is warranted. Some female carriers of dystrophin
mutations may become symptomatic later in life, and may have
severe cardiomyopathy.
Prognosis
Patients with Duchenne muscular dystrophy die of respiratory
complications in their 20s unless they are provided with respira-
tory support. Congestive heart failure and arrhythmias can occur
late in the disease. The disease course for other dystrophinopa-
thies is highly variable.
Myotonic Dystrophy
Definition and Epidemiology
Myotonic dystrophies are autosomal dominant diseases charac-
terized by muscle wasting and myotonia. There are two types and
both are due to expanded DNA repeats: type 1 (DM-1) due to
CTG expansion on chromosome 19; and type 2 (DM-2) to
CCGT expansion on chromosome 3. DM-1 is the most prevalent
adult muscular dystrophy, with an incidence of 13.5 per 100,000
live births.
Pathology
In both myotonic dystrophy types 1 and 2, accumulation of aber-
rant RNA in the nucleus binds regulatory proteins and causes
aberrant splicing of a variety of proteins. Both disorders are mul-
tisystem diseases, affecting skeletal, cardiac, smooth muscle, and
other organs, including the eyes, the endocrine system, and the
brain. Muscle biopsies are not required for diagnosis but charac-
teristic findings include rows of internal nuclei (boxcar appear-
ance), ring fibers, type 1 fiber predominance, and later, fibrosis
and fatty infiltration.
Clinical Presentation
DM-1 can present at any age, with the usual onset of symptoms
in the late second or third decade. However, some affected indi-
viduals may remain symptom-free their entire lives. A severe
form of DM-1 with onset in infancy is known as congenital myo-
tonic dystrophy. The severity of DM-1 generally worsens from
one generation to the next (anticipation). Typical patients
exhibit facial weakness with temporalis muscle wasting, frontal
balding, ptosis, and neck flexor weakness. Extremity weakness
usually begins distally and progresses slowly to affect the proxi-
mal limb-girdle muscles. Percussion myotonia can be elicited on
examination in most patients, especially in thenar and wrist
extensor muscles. DM-2 is typically milder but can present in
an identical fashion to DM-1; however, some patients can only
have a mild proximal limb-girdle pattern of weakness. Associated
manifestations in the myotonic dystrophies include cataracts,
testicular atrophy and impotence, intellectual impairment, and
hypersomnia associated with both central and obstructive sleep
apnea.
Diagnosis and Differential Diagnosis
The diagnosis is based on clinical examination, demonstration
of myotonia on electromyography, and is confirmed by genetic
testing. Myotonic dystrophy needs to be distinguished from
other adult onset muscular dystrophies and non-dystrophic myo-
tonic disorders.
Treatment
Yearly surveillance for cardiac and respiratory involvement is
recommended. Mexiletine, a type IB anti-arrhythmic medica-
tion, can be used for symptomatic myotonia. There is currently
no treatment to halt disease progression but many therapies tar-
geting the interaction between RNA accumulations and regula-
tory proteins, or RNA accumulations themselves, are under
investigation.
Prognosis
Respiratory muscle weakness may be severe, with impairment of
ventilatory drive. Chronic hypoxia can lead to cor pulmonale.
Cardiac conduction defects are common and can produce sudden
death. Pacemakers may be necessary.

Facioscapulohumeral Muscular Dystrophy
Definition and Epidemiology
The majority of patients with facioscapulohumeral muscular dys-
trophy (FSHD) have disease inherited in an autosomal dominant
fashion due to a deletion of a large repetitive element on chromo-
some 4 (FSHD-1). An additional 5% of patients (FSHD-2) will
have disease with digenic inheritance, which occurs through a
deletion-independent pathway. The prevalence of FSHD is
1 : 15,000.
Pathology
Both forms of FSHD lead to changes in methylation on chromo-
some 4 leading to the de-repression of the gene, DUX4, which is
typically silenced in adult muscle; it is believed to cause disease
in a toxic gain-of-function fashion. Muscle biopsy is typically not
required for the diagnosis, but shows nonspecific myopathic
changes. Up to 30% of biopsies can show inflammatory
infiltrates.
Clinical Presentation
Patients typically present in their late teens or early twenties with
weakness in a characteristic pattern, often with dramatic side-to-
side asymmetry: typically first in the face, shoulders, and arms,
later involving the trunk and distal lower extremities. Patients are
unable to squeeze their eyes shut, have a transverse smile, scapu-
lar winging, loss of proximal muscle mass with often preserved
forearm muscles, and a positive Beevor’s sign (movement of the
umbilicus up or down when asked to tense the abdominal
muscles). Extramuscular manifestations of FSHD are rare: retinal
vascular changes, which can occasionally lead to symptomatic
retinal vasculopathy termed Coat’s syndrome, high frequency
hearing loss, and often asymptomatic atrial arrhythmias.
Diagnosis and Differential Diagnosis
Diagnosis is based on clinical examination, family history, and is
confirmed by genetic testing. The differential diagnosis includes
other myopathies or neuropathies with a scapuloperoneal pattern
of weakness.
Treatment
There is no treatment for the weakness of FSHD. A dilated eye
examination is indicated at the time of diagnosis, and surveillance
for respiratory involvement for patients with pelvic girdle weak-
ness or who are confined to wheelchair.
Prognosis
FSHD is not life limiting, but approximately 20% over the age of
50 will require a wheelchair.
  CONGENITAL MYOPATHIES
Congenital myopathies are defined by their appearance on
biopsy (see E-Table 122-2; Fig. 122-1C), and have a large number
of genetic mutations associated with them. They are usually
present at birth with hypotonia and subsequent delayed motor
development. If the child survives the perinatal period, most
congenital myopathies are relatively nonprogressive and may not
be diagnosed until the second or third decade. Clinical findings
Chapter 122  Muscle Diseases 1093
common in the congenital myopathies are reduced muscle bulk,
slender body build, a long and narrow face, skeletal abnormalities
ss
(high-arched palate, pectus excavatum, kyphoscoliosis, dislo-
cated hips, and pes cavus), and absent or reduced muscle stretch
reflexes.
  METABOLIC MYOPATHIES
Metabolic myopathies are muscle diseases due to mutations
in enzymes responsible for energy production including gly-
cogen, lipid, and mitochondrial metabolism (see E-Table
122-3). Classically, these disorders present in older children
or adults with episodes of exercise intolerance, muscle cramp-
ing, or pain associated with myoglobinuria. Newborn and
infants present with severe multisystem disorders that are
often fatal.
Glucose and Glycogen Metabolism Disorders
Definition and Epidemiology
Glucose, and its storage form glycogen, is essential for the
short-term, predominantly anaerobic energy requirements of
muscle (see E-Table 122-3). Disorders of glucose and glycogen
metabolism (called glycogenesis) have two distinct syndromes:
static symptoms of fixed weakness without exercise intolerance
or myoglobinuria, and dynamic symptoms of exercise intoler-
ance, pain, cramps, and myoglobinuria. Acid maltase deficiency
(Pompe disease) is an example of the first and is notable for
enzyme replacement therapy, which is life extending for
the childhood variant. McArdle’s disease is an example of the
second. These are rare disorders with incidence rates for the
individual disorders of around 1 : 100,000. The incidence varies
between region and ethnic group. For example, acid maltase
deficiency has an incidence as high as 1 : 14,000 in African
Americans. The prevalence of McArdle’s disease is approximately
1 : 100,000.
Pathology
All are due to mutations in enzymes responsible for glucose or
glycogen metabolism. Muscle biopsies usually show subsarco-
lemmal accumulation of glycogen.
Clinical Presentation
Acid maltase disease typically has a severe infantile form with
respiratory and cardiac involvement and a slowly progressive
adult myopathy, which can affect the diaphragm, so surveillance
for respiratory involvement is important. However, McArdle’s
disease presents with severe episodes of muscle cramping and
contractures associated with exercise and a fixed myopathy later
in life. Many patients note a “second wind” phenomenon after a
period of brief rest so that they can continue the exercise at the
previous level of activity.
Diagnosis and Differential Diagnosis
Diagnosis is made by characteristic appearance on muscle biopsy
with subsequent study of the enzyme activity or by searching for
specific genetic mutations. The differential diagnosis includes
other glycogen storage disorders, disorders of lipid metabolism,
or mitochondrial disorders.

E-TABLE 122-2  CONGENITAL MYOPATHIES
PATHOLOGICAL FINDING ASSOCIATED GENES
Central cores, multicore 19q13 RYR1 (ryanodine receptor); 1q36
SEPN1; 14q11 MYH7
Nemaline rod Sarcomeric thin filament genes: 1q42
ACTA1; 1q21 TPM3; 9p13 TPM2; 2q23
NEB; 19q13 TNNT1; 14q13 CFN2;
3p22 KCHL40
Centronuclear Myotubular: Xq28 XMTM1; 19p13
DNM2; 12q21 MYF6; 2q14 BIN1;
19q13 RYR1; 2q31 TTN
Fiber type disproportion (type 1) See nemaline rod; plus Xq13, 1p36 SEPN1;
Reducing body Xq26 FHL1
Sarcotubular 9q31 TRIM32
Myofibrillar Desmin-storage: 2q35 Desmin; 11q22 alpha
beta crystalline; 5q31 myotilin; 10q23
ZASP; 2q32 filamin C; 10q25 BAG3
Chapter 122  Muscle Diseases 1093.e1
PHENOTYPE
limb-girdle pattern weakness; scoliosis;
respiratory involvement; malignant
hyperthermia susceptibility
Limb-girdle pattern, Hypotonia, absent
tendon reflexes, facial weakness, neck
flexors
Limb-girdle pattern; hypotonia;
respiratory involvement; cardiac rarely
Limb-girdle pattern, scoliosis,
hypotonia, respiratory involvement
Limb-girdle pattern, scoliosis,
hypotonia, respiratory involvement
Limb-girdle pattern, scapular winging
Limb-girdle pattern, cardiomyopathy
ss
SURVEILLANCE
Caution with anesthesia
Respiratory involvement;
independent ambulation by 18
months predictive of survival
Respiratory involvement
Respiratory involvement
Respiratory involvement; cardiac
late
Cardiac involvement
 1093.e2 Section XVI  Neurologic Disease

ss
E-TABLE 122-3  SELECTED METABOLIC MYOPATHIES
CLASS NAME ENZYME/GENE PHENOTYPE TESTING
GLYCOGEN STORAGE
Type II Pompe’s disease Acid maltase / GAA, Infantile: hypotonia, cardiomegaly, Muscle biopsy with non-rimmed
17q21 hepatomegaly, fatal in 1st year without vacuoles, and PAS positive material.
treatment. Adult: limb-girdle Decreased enzyme activity in
weakness, respiratory failure muscle, lymphocytes, or fibroblasts
Type III Cori-Forbes disease Debrancher / AGL, Infantile: hypotonia. Adult: Limb-girdle Muscle biopsy PAS positive glycogen
1p21 pattern with distal weakness, deposits. Decreased enzyme activity
respiratory involvement in fibroblasts or lymphocytes
Type IV Andersen disease Branching / GBE1, 3p12 Infantile: hypotonia. Adult: limb-girdle PAS-positive, diastase-resistant
pattern, ± distal filamentous polysaccharides
(polyglucosan bodies); decreased
enzyme activity in skin fibroblasts,
muscle or liver.
Type V McArdle’s disease Myophosphorylase / Infantile: profound weakness. Adult: Electrically silent muscle contractures;
PYGM, 11q13 Exercise intolerance, cramps, fatigue, Subsarcollemal glycogen deposits;
limb-girdle pattern, second wind Decreased enzyme activity from
phenomenon muscle;
Type VII Tauri’s disease Phosphofructokinase / Childhood: cramps, fatigue, exercise Accumulation of free glycogen in
PFKM, 12q13 intolerance muscle; hemolytic anemia; enzyme
deficiency in muscle, erythrocytes
LIPID METABOLISM
Carnitine CPT II, 1p32 Neonatal/infantile: severe, fatal. Adult: Low total serum carnitine; increased
palmitoyltransferase exercise or illness related, cramping, acylcarnitine fraction; reduced
II deficiency myoglobinuria, usually no fixed enzyme activity in skeletal muscle
weakness
Very long chain ACADVL, 17p13 Childhood: nonketotic hypoglycemia Reduced VLCAD activity in
acylcoenzyme A can have severe form with fibroblasts; increased lipid staining
dehydrogenase cardiomyopathy. Adult: rare, exercise/ in muscle
deficiency fasting induced myalgias or
myoglobinuria.
Long chain ACADL, 2q34 Infancy: failure to thrive, nonketotic Reduced total and free carnitine
acylcoenzyme A hypoglycemia, cardiomegaly, levels; increased long chain
dehydrogenase encephalopathy. Adult: myopathy with acylcarnitine esters; reduced
deficiency cramps and myoglobinuria enzyme activity in fibroblasts
Medium chain ACADM, 1p31 Infancy: failure to thrive, nonketotic Reduced total and free carnitine;
acylcoenzyme A hypoglycemia, cardiomegaly, decreased enzyme activity in
dehydrogenase encephalopathy. Adult: mild myopathy lymphocytes, fibroblasts, and liver;
deficiency later in life. excess lipid in muscle
MITOCHONDRIAL
Myoclonic Epilepsy Mitochondrial Onset usually childhood, epilepsy, Muscle biopsy ragged red fibers;
associated with mutations, ~80% myoclonus, ataxia, dementia, short elevated lactic acid; mitochondrial
Ragged Red Fibers m.8344 A>G; stature, optic atrophy, wolf Parkinson sequencing;
(MERRF) white syndrome
Mitochondrial Mitochondrial Childhood onset, normal psychomotor Muscle biopsy ragged red fibers;
encephalopathy, lactic mutations, ~80% m. development, then episodes of elevated lactic acid; mitochondrial
acidosis, and 3243 A>G encephalopathy, migraine, seizures, sequencing;
stroke-like episodes stroke like symptoms, anorexia and
(MELAS) vomiting, short stature, deafness,
myopathy with exercise intolerance
Mitochondrial Genomic mutations, Onset childhood/teenage, visceral Muscle biopsy ragged red fibers;
neurogastrointestinal TYMP, 22q13 neuropathy (gastroparesis, obstipation, elevated lactic acid; mitochondrial
encephalopathy diarrhea), ptosis, external sequencing
(MNGIE) ophthalmoplegia, sensory > motor
neuropathy, hearing loss, myopathy
Kearns-Sayre Syndrome Single large Onset less than 20 years; external Muscle biopsy ragged red fibers;
mitochondrial ophthalmoplegia; pigmentary elevated lactic acid; mitochondrial
deletion (~80%); also degeneration of retina; heart block; sequencing
individual mutations myopathy
Leigh Syndrome Many genes nuclear Typical: Onset 1st year; hypotonia; Muscle normal histology but COX
(complex I-IV); episodic vomiting, ataxia; negative; elevated lactate (CSF
SURF-1, 9q34; encephalopathy; hearing loss; visual >blood); MRI high T2 in lentiform
mitochondrial loss; death often within 2 years of and caudate nuclei
onset. Mitochondrial: variable age of
onset; less severe;
Progressive External Nuclear: POLG 15q25; Onset variable typically >20 years; Muscle biopsy ragged red fibers;
Ophthalmoplegia ANT1 4q35; Twinkle ptosis; ophthalmoparesis often without genetic testing or mitochondrial
(PEO) 10q23; POLG2 17q. double vision; plus syndromes have sequencing;
Mitochondrial: myopathy and variable organ
deletions or depletion involvement.
GAA, Acid α-glucosidase; GBE1, glycogen branching enzyme 1.
 1094 Section XVI  Neurologic Disease
ss
Treatment
The only glycogen storage disorder with a therapy approved by
the U.S. Federal Drug Administration is enzyme replacement for
infantile or adult-onset acid maltase deficiency. Treatment for the
other glycogen storage disorders is supportive.
Prognosis
Severe infantile forms of most these disorders can often involve
multiple organs and be fatal. A less severe adult myopathic phe-
notype is also common.
  DISORDERS OF FATTY ACID METABOLISM
Disorders of lipid metabolism differ from glucose and glycogen
disorders in that the metabolic derangement is in the enzymatic
breakdown of fatty acids (see E-Table 122-3). Many present in
childhood with episodes of encephalopathy precipitated by
fasting with hypoketotic hypoglycemia. Serum fatty acid profiles
often show reduced carnitine and increased longer chain frac-
tions, depending on whether the mutation is in very long chain,
long chain, or medium chain fatty acid metabolism. Adults typi-
cally show exercise intolerance and myoglobinuria and may
developed a mild limb-girdle pattern myopathy. The most preva-
lent disorder of fatty acid metabolism is carnitine palmitoyltrans-
ferase II deficiency. This disease ranges from a lethal neonatal
form to an adult form with muscle pain and recurrent myoglo-
binuria, often precipitated by intense exercise, febrile illness, or
fasting. The diagnosis is usually made by detection of reduced
carnatine palmitoyltransferase enzyme activity in skeletal muscle.
Mitochondrial Myopathies
Definition and Epidemiology
Mitochondrial myopathies can present at any age, with varying
degrees of severity or weakness, affect multiple organ systems,
and have any pattern of inheritance (see E-Table 122-3). Muta-
tions affect enzymes necessary for normal mitochondrial func-
tion, and can be mitochondrial or nuclear. The overall prevalence
for mitochondrial disorders is thought to be approximately
1 : 8500; however, the prevalence of individual mitochondrial
syndromes is much lower and ranges from just a handful of cases,
to 1to 6 per 100,000.
Pathology
Mutations can occur in both mitochondrial DNA (in which case
inheritance is maternal) and nuclear DNA (autosomal dominant,
recessive, or x-linked). Mitochondrial disorders produce bio-
chemical defects proximal to the respiratory chain (involving
substrate transport and usage) or within the respiratory chain.
On muscle biopsy, muscle fibers contain abnormal mitochon-
dria. Pathologically these fibers have a “ragged red” appearance
on biopsy stains (trichrome) and may fail to react for cytochrome
c oxidase.
Clinical Presentation
Despite the diversity, there are certain patterns that are character-
istic for mitochondrial disorders, including slowly progressive
myopathy and myalgias, which worsen with exertion or illness,
and ptosis and/or ophthalmoplegia. E-Table 122-3 lists common
clinical mitochondrial syndromes.
Diagnosis and Differential Diagnosis
The diagnosis is based on clinical history, serum lactate levels,
which are often elevated at rest, and characteristic findings on
muscle biopsy. Diagnosis is confirmed by mitochondrial or
nuclear genetic testing.
Treatment
Treatment is largely supportive, and includes identification of
other multisystem involvement, including diabetes, cardiac and
ophthalmological involvement, and hearing loss. Many agents
have been tried in mitochondrial diseases, including coenzyme
Q10, creatine, and carnitine; however, a meta-analysis showed no
clear evidence for benefit for any treatment. Aerobic exercise may
reduce fatigue and improve muscle function, although there are
no large trials of efficacy.
Prognosis
The severity and prognosis depends partially on the load of
abnormal mitochondrial DNA as well as the degree of multisys-
tem involvement. Certain clinical syndromes with more predict-
able prognosis have been described (see E-Table 122-3).
  MUSCLE CHANNELOPATHIES
The muscle channelopathies are a spectrum of disorders due to
mutations in muscle ion channels commonly divided into the
nondystrophic myotonias and periodic paralyses. Most are inher-
ited in an autosomal dominant fashion, with episodic symptoms,
often triggered by temperature or certain foods.
Nondystrophic Myotonias
Definition and Epidemiology
Nondystrophic myotonias are due to mutations in muscle chlo-
ride (CLCN1 on chromosome 7) or sodium (SCN4A on chro-
mosome 17) channels resulting in hyperexcitable muscle and
myotonia. The overall worldwide prevalence for nondystrophic
myotonias is 1 : 100,000.
Pathology
Mutations in chloride channels cause a loss of function. Loss
of hyperpolarizing chloride conductance cannot counteract a
buildup of potassium in the t-tubule system during repetitive
contractions, which results in a depolarized sarcolemma. Sodium
mutations, on the other hand, cause anomalous depolarizing
sodium currents due to alterations in fast or slow channel inacti-
vation, or hyperpolarizing shifts in channel activation curves.
Clinical presentation
The nondystrophic myotonias have myotonia in common; on
examination this can be seen as delayed muscle relaxation after
contraction. Patients have trouble opening their eyes or fist when
instructed to squeeze them shut. On percussion of the thenar
eminence or wrist extensors there is a catch then delay in the
relaxation phase. Electromyography shows a characteristic
waxing and waning motor unit amplitude and frequency that

when amplified sounds like a dive bomber or motorcycle revving.
Symptoms usually start in the first decade, and patients can have
a characteristic muscular build. Chloride channel mutations can
be both dominantly and recessively inherited and have a charac-
teristic warmup of myotonia with repetition. Sodium channel
myotonias typically have more myotonia on eye closure and can
demonstrate a paradoxical worsening of myotonia with activity
(paramyotonia).
Diagnosis and Differential Diagnosis
Diagnosis is based on family history, myotonia on clinical exami-
nation, and electrodiagnostic testing. It is confirmed by genetic
testing. The differential diagnosis includes myotonic dystrophy
and secondary causes of myotonia (other myopathies and drugs
associated with myotonia—e.g., statins, fibric acid derivatives,
and colchicine).
Treatment
Treatment for nondystrophic myotonias consists of non-
mutation–specific sodium channel blockade: mexiletine, a class
IB antiarrhythmic, is the first line therapy but phenytoin, pro-
cainamide, and flecainide have also been used. Certain sodium
channel myotonias respond to the carbonic anhydrase inhibitor
acetazolamide.
Periodic Paralyses
Definition and Epidemiology
The periodic paralyses are disorders due to mutations in the
calcium (CACN1AS on chromosome 1), sodium (SCN4A on
chromosome 17), and potassium channels (KCNJ2 on chromo-
some 17) that result in depolarized but inexcitable sarcolemma
and episodes of paralysis. Overall prevalence for the primary
periodic paralyses is greater than 1 : 100,000 and varies between
conditions from 1 : 100,000 to 1 : 1,000,000.
Pathology
Hyperkalemic periodic paralysis is due to sodium mutations that
lead to persistent inward sodium current causing both myotonia
and paralysis depending on the relationship of depolarization to
the sodium channel inactivation potential. Hypokalemic peri-
odic paralysis is due to an anomalous gating pore current that, in
low potassium conditions, produces a depolarizing current larger
than hyperpolarizing potassium currents. Andersen Tawil syn-
drome is due to loss of function in a potassium inward rectifier.
Clinical Presentation
Common to all is attacks of flaccid tetraplegia, often brought on
by rest after exercise, or in the mornings, and is associated with
changes in extracellular potassium. Hyperkalemic periodic paral-
ysis is due to mutations in sodium channels and is associated with
either high or normal extracellular potassium. Triggers include
potassium-rich foods. In hypokalemic periodic paralysis attacks
are associated with low extracellular potassium, and are triggered
by carbohydrates, stress, alcohol, or rest after exercise. Andersen-
Tawil syndrome is due to mutations in a potassium inward recti-
fier and is characterized by the clinical triad of attacks of flaccid
paralysis, dysmorphic features (wide-set eyes, narrow mandible,
Chapter 122  Muscle Diseases 1095
low-set ears, bent fifth finger, and common origin for the second
and third toes), and polymorphic ventricular tachyarrhythmias. ss
Diagnosis and Differential Diagnosis
Diagnosis is based in family history and clinical history, sup-
ported by electrodiagnostic testing and confirmed by genetic
testing.
Treatment
In all of the periodic paralyses disorders mild exercise at onset of
weakness can abort attacks of paralysis. Treatment for acute
attacks consists of carbohydrates (hyperkalemic periodic paraly-
sis) or potassium supplementation (hypokalemic periodic paral-
ysis). Prophylactic treatment for all the periodic paralyses consists
of carbonic anhydrase inhibitor acetazolamide.
  ACQUIRED MYOPATHIES
Unlike the inherited myopathies, the acquired myopathies are
typically secondary to another process: toxic, inflammatory, or
infectious. Pathological changes can be distinctive and are not
due to mutations in muscle-related proteins. Clinically, symp-
toms appear acutely or subacutely. Treatment often includes
eliminating the precipitating factor.
Inflammatory Myopathies
The idiopathic inflammatory myopathies can be divided into
dermatomyositis/polymyositis and sporadic inclusion body
myositis (Table 122-9).
Dermatomyositis/Polymyositis
Definition and Epidemiology
Dermatomyositis/Polymyositis (DM/PM) are acquired idio-
pathic diseases of muscle characterized by inflammation and vari-
able symmetrical proximal muscle weakness, associated with
elevated serum creatine kinase and irritable features on electro-
myography. The overall annual incidence is approximately 1 in
100,000.
Pathology
Dermatomyositis shows a characteristic pattern on muscle biopsy
of perifascicular atrophy with perivascular inflammatory infil-
trates and positive pericapillary membrane attack complex stain-
ing (Fig. 122-1D). In contrast, polymyositis shows endomyseal
inflammatory infiltrates with invasion of non-necrotic fibers,
without other pathological changes.
Clinical Presentation
Dermatomyositis has a bimodal age of onset with peaks in child-
hood and adulthood, with an acute to insidiously progressive
onset of painless symmetrical proximal muscle weakness with
characteristic skin changes, which include heliotrope rash, shawl
sign (maculopapular violaceous rash in v-shape around neck),
Gottron’s nodules (erythematous papular rash on the extensor
surfaces of the hands or fingers), and mechanic’s hands (dry,
cracked skin on the dorsal or ventral hands). In contrast, Polymy-
ositis is largely a diagnosis of exclusion, occurring in adults and
not associated with skin changes. Myalgias are more common in
polymyositis. In both DM/PM can be associated with respiratory
 1096 Section XVI  Neurologic Disease

ss
TABLE 122-9  IDIOPATHIC INFLAMMATORY MYOPATHIES
RESPONSE TO
TYPICAL AGE PATTERN OF CREATINE IMMUNOSUPPRESSIVE
MYOPATHY SEX AT ONSET WEAKNESS KINASE MUSCLE BIOPSY THERAPY
Dermatomyositis Women > men Childhood and adult Proximal > distal Increased (up to Perifascicular atrophy, Yes
50× normal) inflammation,
complement deposition
on capillaries
Polymyositis Women > men Adult Proximal > distal Increased (up to Endomyseal Yes
50× normal) inflammation; invasion
of non-necrotic fibers
Sporadic Inclusion Men > women Elderly (>50 yr) Proximal and distal; Increased (<10× Endomyseal No
Body Myositis predilection for normal) inflammation, rimmed
finger and wrist vacuoles; electron
flexors, knee microscopy: 15- to
extensors 18-nm tubulofilaments

involvement, difficulty swallowing, or cardiomyopathy. Both
DM/PM can be associated with underlying malignancy (derma-
tomyositis more frequently than polymyositis), so screening for
malignancy is recommended especially in patients over age 40.
Diagnosis and Differential Diagnosis
Diagnosis is based on clinical history and examination findings
in conjunction with irritable changes on electromyography (e.g.,
fibrillation potentials and positive sharp waves) and characteristic
muscle biopsy. Both can be associated with autoantibodies (e.g.,
ANA). The most useful is the anti-Jo-1 antibody, which can be
seen more frequently in patients with pulmonary involvement.
Treatment
For both DM/PM the first line of treatment is prednisone. Ste-
roid-sparing immunosuppressive therapies (e.g., methotrexate,
azathioprine) are often added for those patients requiring long-
term therapy in order to reduce the required dose of prednisone
or to replace prednisone completely. In patients who do not
respond to conventional therapy, intravenous immunoglobulin
or rituximab may be effective.
Prognosis
Most patients respond to immunosuppressive therapies.
Sporadic Inclusion Body Myositis
Definition and Epidemiology
Sporadic inclusion body myositis (s-IBM) is an idiopathic, slowly
progressive muscle condition in older adults (occurring in more
men than women), associated with inflammation and character-
istic pathological changes on muscle biopsy. It is the most
common inflammatory muscle disease in patients over 50, affect-
ing 3.5 per 100,000.
Pathology
Muscle biopsies resemble polymyositis with endomyseal inflam-
matory infiltrates and invasion of non-necrotic fibers. Distinctive
for IBM are vacuoles rimmed by mitochondria and electron
microscopy, which shows 15 to 18 nm tubulofilamentous
inclusions.
Clinical Presentation
S-IBM is a slowly progressive, often asymmetric weakness occur-
ring usually after 50 years of age initially in a distinctive pattern,
including distal forearm muscles (distal finger flexors) and quad-
riceps wasting and weakness. This can progress to involve almost
any muscle and can affect swallowing in up to 70% of patients.
Diagnosis and Differential Diagnosis
Diagnosis is based on clinical history and examination and char-
acteristic muscle pathology. The main differential diagnosis is
other idiopathic inflammatory myopathies or late-onset inherited
myopathies, including a hereditary form of IBM.
Treatment
Unlike the other inflammatory myopathies, IBM does not
respond to immunosuppression. Treatment is supportive.
Prognosis
Most patients with s-IBM progress to need a wheelchair over 10
to 15 years. Swallowing difficulty can be life threatening.
Infectious Myositis
An acute viral myositis can occur in the setting of an influenza
viral upper respiratory tract infection. In addition to typical
influenza-associated myalgias, affected patients develop muscle
pain, proximal weakness, and elevated CK levels. The disorder is
self-limited, but when severe it is often associated with myoglo-
binuria and occasionally with renal failure. A similar syndrome
can complicate infections with other viruses.
An inflammatory myopathy can occur in the setting of
human immunodeficiency virus infection, either in early or in
later acquired immunodeficiency syndrome. The clinical pre-
sentation resembles polymyositis. The patient’s condition may
improve with corticosteroid therapy. The disorder must be
distinguished from the toxic myopathy caused by zidovudine,
which responds to dose reduction. Although rarely seen, tuber-
culosis can present with muscle abscess (pyomyositis) either
in the setting of pulmonary or disseminated disease or in
isolation.
Myopathies Caused by Endocrine  
and Systemic Disorders
Thyroid studies should be obtained in any adult coming in with
a new complaint of muscle weakness. Patients with hyperthyroid-
ism often have some degree of proximal weakness but this is
rarely the presenting manifestation of thyrotoxicosis. Hypothy-
roid myopathy is associated with proximal weakness and

myalgias, muscle enlargement, slow relaxation of the reflexes, and
marked (up to 100-fold) increase of the serum CK level.
Excess corticosteroids can result from endogenous Cushing’s
syndrome or can be caused by exogenous glucocorticoid admin-
istration. Iatrogenic corticosteroid myopathy (or atrophy) is the
most common endocrine-related myopathy. However, muscle
weakness is rarely the presenting manifestation of Cushing’s syn-
drome and, in virtually all instances of corticosteroid myopathy,
other factors contributing to weakness are also present. Therapy
consists of reducing the corticosteroid dose to the lowest possible
level. Exercise and adequate nutrition prevent and may improve
weakness.
Toxic Myopathies
Many drugs have been associated with muscle damage, proximal
weakness, elevated CK levels, myopathic EMG readings, and
abnormalities on muscle biopsy. Symptoms generally improve
after stopping the medication. Some drugs can produce acute,
rapidly progressive muscle destruction and myoglobinuria, par-
ticularly the hypocholesterolemic drugs, including the statins and
fibric acid derivatives. In some patients statin use has been associ-
ated with a subsequent autoimmune necrotizing myopathy asso-
ciated with antibodies to HMG-CoA.
Critical illness myopathy (CIM), also termed, acute quadriple-
gic myopathy, develops in a patient in the intensive care setting
and is often discovered when a patient is unable to be weaned off
a ventilator. The cause of the diffuse weakness is the prolonged
daily use of either high-dose intravenous glucocorticoids or non-
depolarizing neuromuscular blocking agents, often both. Patients
Chapter 122  Muscle Diseases 1097
often have had sepsis and multi-organ failure. The diagnosis of
critical illness myopathy can be confirmed by muscle biopsy, ss
which shows the loss of myosin-thick filaments on electron
microscopic examination. Treatment is supportive after discon-
tinuation of the offending agents.
SUGGESTED READING
Amato AA, Griggs RC: Overview of the muscular dystrophies, Handb Clin
Neurol 101:1–9, 2011.
Jackson CE, Barohn RJ: A pattern recognition approach to myopathy, Continuum
(Minneap Minn) 19(6 Muscle Disease):1674–1697, 2013.
Lemmers RJ, Tawil R, Petek LM, et al: Digenic inheritance of an SMCHD1
mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral
muscular dystrophy type 2, Nat Genet 44(12):1370–1374, 2012.
Matthews E, Fialho D, Tan SV, et al: The non-dystrophic myotonias: molecular
pathogenesis, diagnosis and treatment, Brain 133(Pt 1):9–22, 2010.
Pfeffer G, Majamaa K, Turnbull DM, et al: Treatment for mitochondrial disorders,
Cochrane Database Syst Rev (4):CD004426, 2012.
Statland JM, Bundy BN, et al: Mexiletine for symptoms and signs of myotonia in
nondystrophic myotonia: a randomized controlled trial, JAMA 308(13):1357–
1365, 2012.
Statland JM, Tawil R: Facioscapulohumeral muscular dystrophy: molecular
pathological advances and future directions, Curr Opin Neurol 24(5):423–
428, 2011.
Wheeler TM, Leger AJ, Pander SK, et al: Targeting nuclear RNA for in vivo
correction of myotonic dystrophy, Nature 488(7409):111–115, 2012.
Wu F, Mi W, Burns DK, et al: A sodium channel knockin mutant (NaV1.4-
R669H) mouse model of hypokalemic periodic paralysis, J Clin Invest
121(10):4082–4094, 2011.
Wu F, Mi W, Hernández-Ochoa EO, et al: A calcium channel mutant mouse
model of hypokalemic periodic paralysis, J Clin Invest 122(12):4580–4591,
2012.
 123 
ss
Neuromuscular Junction Disease
Emma Ciafaloni
Neuromuscular junction diseases are caused by abnormal neuro­
muscular transmission of the action potential from the nerve
terminal to the muscle, and they can be autoimmune (myasthenia
gravis, Lambert Eaton Syndrome), hereditary (congenital my­
asthenic syndromes), or toxic (botulism, organophosphate
intoxication).
  MYASTHENIA GRAVIS
Definition/Epidemiology/Pathology
Myasthenia gravis (MG) is a rare autoimmune disease caused by
antibodies against the postsynaptic acetylcholine receptors
(AChR Ab) in the neuromuscular junction. All ages are affected
but incidence is higher in women younger than 40, and in men
older than 50. Prevalence is approximately 20 in 100,000. Tran­
sient neonatal MG occurs in about 12% of newborns of myas­
thenic mothers and is caused by transplacental passive transfer of
antibodies from the mother to the fetus. Thymoma is found in
10% of patients with MG and thymic hyperplasia is present in
65%.
Clinical Presentation
MG is characterized by fluctuating, fatigable weakness either iso­
lated to the ocular muscles (ocular MG), or involving ocular as
well as limb, bulbar, and respiratory muscles (generalized MG).
The majority of patients present first with ocular symptoms
(blurred vision, double vision, droopy eyelids), but about 15% of
cases present with bulbar symptoms first (dysarthria, dysphagia,
shortness of breath), or limb weakness. Ptosis is usually asym­
metric. Myasthenia crisis is a true neurological emergency that
occurs in 15% to 20% of patients and consists of severe dysphagia
or respiratory failure requiring ventilator support and/or tube
feeding in an ICU setting.
Diagnosis and Differential Diagnosis
The diagnosis of MG is based on a combination of clinical history,
physical examination, and confirmatory tests. The ice pack test is
a simple and relatively sensitive test to differentiate ptosis caused
by MG from other causes of ptosis. In this test an ice pack is
applied to the ptotic eye for 2 minutes and an improvement of
2 mm or more in ptosis supports MG.
Edrophonium chloride (Tensilon) is a short-acting acethyl­
cholinesterase inhibitor administered IV to demonstrate
symptom improvement in patients with MG. A positive Tensilon
test is defined as an unequivocal improvement in strength in an
affected muscle after 2 to 5 minutes from administration of 2 mg
incremental doses up to 10 mg. Atropine should be available
1098
during a tensilon test because bradychardia and hypotension are
possible side effects. Edrophonium testing can be positive in
other disorders.
Electrodiagnostic testing with 3 Hz repetitive nerve stimula­
tion (RNS) demonstrates a compound muscle action potential
(CMAP) decrement more than10% in about 50% to 75% of
patients with generalized MG, but is abnormal in less than 50%
of patients with purely ocular symptoms. Single fiber electromy­
ography (SFEMG) is the most sensitive test in the diagnosis of
MG and reveals increased jitter and blocking in 99% of patients
with generalized MG, and in 97% of those with purely ocular MG
when a weak muscle is tested. SFEMG is usually available only
in specialized EMG laboratories.
Serum antibody testing for AchR Ab (binding antibody) is
positive in about 80% of patients with generalized MG, and 50%
of patients with purely ocular symptoms. Anti MuSK antibody is
detected in a portion of seronegative patients, usually men.
Chest CT should be performed to rule out thymoma. Thyroid
function should be evaluated because thyroid disease is com­
monly associated with MG. Electrodiagnostic and serum anti­
body testing help with differentiating MG from motor neuron
disease, Lambert-Eaton myasthenic syndrome (LEMS), and
Guillain-Barre syndrome (GBS).
Treatment
Pyridostigmine 30 to 60 mg every 4 hours improves symptoms
in most patients with MG; it is used alone to treat purely ocular
and generalized cases with only minimal or mild weakness, or in
combination with immunosuppressant drugs in patients with
more severe manifestations. Prednisone is effective in improving
muscle weakness in a short period of time, but long-term use is
associated with side effects. Azathioprine and mycophenolate
mofetil are used for long-term treatment and as steroids-sparing
agents. Plasmapheresis and IVIG are used for cases with severe
bulbar or generalized weakness, respiratory crisis, and in refrac­
tory patients who do not respond to oral immunomodulating
medications. Thymoma resection is indicated in all patients with
MG and thymoma. Thymectomy is also recommended as an
option in patients with nonthymomatous autoimmune MG to
increase the probability of remission or improvement. Thymec­
tomy is usually not recommended in patients over age 60. Some
medications may exacerbate the symptoms of MG or precipitate
the initial signs and symptoms of the disease (Table 123-1).
Prognosis
Most patients with MG who are optimally treated experience
improvement or remission of their symptoms. About 10% of
 Chapter 123  Neuromuscular Junction Disease 1099
TABLE 123-1  DRUGS TO BE AVOIDED OR USED WITH
CAUTION IN MYASTHENIA GRAVIS
DRUGS TO BE AVOIDED
• D-penicillamine and α-interferon should not be used in myasthenic
patients because they can cause Myasthenia Gravis (MG)
• Botulinum toxin treatment should be avoided as it blocks NMT
DRUGS TO USE ONLY WITH CAUTION AND MONITOR FOR
EXACERBATION OF MG SYMPTOMS
• Selected antibiotics, particularly aminogylcosides, telithromycin
(Ketek) and ciprofloxacin (many other antibiotics have been
reported to increase weakness in occasional patients with MG)
• Magnesium, magnesium salts contained in some laxatives and
antacids
• Neuromuscular blocking agents such as succinylcholine and
vecuronium should only be used by an anesthesiologist familiar with
MG
• Quinine, quinidine or procainamide
• Beta-blockers (propranolol; timolol maleate eyedrops)
• Calcium channel blockers
• Iodinated contrast agents
patients with MG experience refractory symptoms despite
optimal treatment. Mortality is currently less than 5%.
  LAMBERT-EATON MYASTHENIC SYNDROME (LEMS)
Definition/Epidemiology/Pathology
Lambert-Easton myasthenic syndrome (LEMS) is an acquired,
presynaptic neuromuscular transmission disorder caused by anti­
bodies against the P/Q type voltage-gated calcium channel
(VGCC). P/Q VGCC antibodies cause reduced Ca+ influx into
the presynaptic nerve terminal resulting in decreased acetylcho­
line release and neuromuscular transmission failure. LEMS is
associated with cancer, usually small cell lung carcinoma, in 60%
of cases. LEMS may predate tumor detection by up to 3 years.
LEMS is very rare and more common in men (3 : 1).
Clinical Presentation
LEMS should be suspected whenever the triad of muscle weak­
ness, dry mouth, and decreased or absent reflexes is present.
Patients have fluctuating weakness and fatigability of proximal
limb and trunk muscles, with the lower limbs more severely
affected than the upper ones. Difficulty walking is a common
symptom. Dysphagia, dysarthria, and ocular symptoms (ptosis,
blurred vision, and diplopia) are less common than in MG.
Tendon reflexes are hypoactive or absent and may increase fol­
lowing short exercise of the muscle. Autonomic manifestations
(dry mouth, impotence, decreased sweating, orthostatic hypo­
tension, and slow pupillary reflexes) occur in 75% of patients.
Diagnosis and Differential Diagnosis
Serum antibodies against P/Q VGCCs are found in nearly all
cases of paraneoplastic LEMS, and in about 90% of non-
paraneoplastic cases. Electrodiagnostic testing can help confirm
the diagnosis by demonstrating reduced CMAP amplitudes in
distal hand muscles; CMAP facilitation of at least 100% after
10" maximal voluntary contraction or high frequency RNS
(posttetanic facilitation); and CMAP decrement greater than
10% with low frequency RNS. Patients diagnosed with LEMS
should be screened and monitored with chest CT for lung
cancer, especially if they are smokers and over age 50. LEMS ss
and MG can be differentiated with electrodiagnostic and anti­
body testing.
Treatment
Symptomatic treatment with 3,4-DAP 5 to 10 mg every 3 to 4
hours and up to a maximum daily dose of 80 to 100 mg is most
effective in improving muscle strength in patients with LEMS.
Side effects at doses up to 60 mg per day are rare. Acral and peri­
oral paresthesias occur within minutes from a dose and resolve
in about 15 minutes. It is contraindicated in patients with sei­
zures. 3,4-DAP is not currently FDA approved in the United
States, but it can be obtained in specialized neuromuscular
centers. Pyridostigmine 60 mg every 4 hours is also used to
improve symptoms. In patients in whom symptoms are not ade­
quately controlled with 3,4-DAP and pyridostigmine, immuno­
modulation with prednisone, azathioprine, or mycophenolate
mofetil is used. Severe weakness is treated with plasmapheresis
or IVIG. The underlying cancer should be treated.
Prognosis
In paraneoplastic LEMS the prognosis is determined by the
underlying cancer. The presence of LEMS in patients with small
cell lung cancer (SCLC) is associated with longer survival from
the malignancy. Non-paraneoplastic LEMS, when optimally
treated, has an excellent prognosis and normal life expectancy,
although patients may continue to experience various degrees of
muscle weakness.
  BOTULISM
Definition/Epidemiology/Pathology
Botulism is a rare, potentially lethal, paralytic illness caused by
the neurotoxin produced by the anaerobic, spore-forming bacte­
rium Clostridium botulinum. Botulinum toxin blocks voluntary
and autonomic cholinergic neuromuscular junctions by binding
irreversibly to the presynaptic nerve endings where it inhibits the
release of acetylcholine. Human forms of the disease include
foodborne botulism most commonly caused by home-canned
food, wound botulism with most cases occurring among “black
tar” heroin users, and infant botulism occurring usually in the
second month of life due to intestinal colonization. Outbreaks of
foodborne botulism occur in prison inmates due to ingestion of
pruno, an alcoholic drink made illicitly in prison. About 145
botulism cases are reported each year in the United States;
approximately 15% are foodborne, 65% are infant, and 20% are
wound botulism.
Clinical Presentation
The disease is characterized by symmetric descending flaccid
paralysis starting with blurred or double vision, ptosis, dysphagia,
dry mouth, dysarthria, and muscle weakness. Symptoms usually
start 18 to 36 hours after ingesting contaminated food.
Botulism should be suspected in any infant with poor feeding
and sucking, constipation, dilated pupils, weak cry, poor tone,
and respiratory distress. Sensory examination and mental status
are normal.
 1100 Section XVI  Neurologic Disease
ss
Diagnosis and Differential Diagnosis
All suspected cases of botulism need to be reported to public
health authorities immediately. Local health department and
CDC laboratories can confirm the diagnosis by detecting the
toxin in serum, stool, or gastric or wound aspirate specimens.
Electrodiagnostic testing can also confirm the diagnosis by dem­
onstrating persistent post-tetanic facilitation of CMAP of at least
20%, a decremental response greater than 10% with slow RNS,
and increased jitter and blocking on SFEMG. Electrodiagnostic
tests are also helpful in differentiating botulism from Guillain-
Barré syndrome and myasthenia gravis.
Treatment
Prompt intensive care support with mechanical ventilation and
parenteral feeding as needed are crucial in reducing mortality.
Timely administration of equine antitoxin within the first 24
hours may arrest the progression of paralysis and decrease the
duration of illness. The antitoxin is provided by the CDC through
the local health departments. Children less than 12 months old
should not be fed honey because it can contain Clostridium
botulinum.
Prognosis
The proportion of patients with botulism who die has fallen from
50% to between 3% and 5% in the past 50 years. Recovery of
muscle strength may take several months. Mortality in untreated
botulism is 60%.
  ORGANOPHOSPHATE POISONING
Organophosphorus compounds (OPs) are used as pesticides
and developed for chemical warfare. Exposure to even small
amounts of an OP can be fatal and death is usually caused by
respiratory failure. OPs cause inhibition of acetylcholinesterase
(AChE) accumulation of acetylcholine at the cholinergic recep­
tor sites, producing continuous stimulation of cholinergic fibers
throughout the nervous system. A combination of an antimus­
carinic agent (e.g., atropine), AChE reactivator, such as one of
the pyridinium oximes (i.e., pralidoxime, trimedoxime, obidox­
ime, and HI-6), and diazepam are used for the treatment of
OP  poisoning  in humans.
For a deeper discussion on this topic, please see Chapter
422, “Disorders of Neuromuscular Transmission,” in
Goldman-Cecil Medicine, 25th Edition.
SUGGESTED READINGS
Gronseth GS, Barohn RJ: Practice parameter: Thymectomy for autoimmune
myasthenia gravis (an evidence-based review), Neurology 55:7–15, 2000.
Palace J, Newsom-Davis J, Lecky B: A randomized double-blind trial of
prednisolone alone or with azathioprine in myasthenia gravis, Neurology
50:1778–1783, 1998.
Passaro DJ, Werner SB, McGee J: Wound botulism associated with black tar
heroin among injecting drug users, JAMA 279(11):859–863, 1998.
Pascuzzi RM, Coslett HB, Johns TR: Long-term corticosteroid treatment of
myasthenia gravis: report of 116 patients, Ann Neurol 515:291–298, 1984.
Sobel J, Tucker N, Sulka A: Foodborne botulism in the United States, 1990-2000,
Emerg Infect Dis 10:1606–1611, 2004.
Tim R, Massey J, Sanders D: Lambert-Eaton mysthenic syndrome:
electrodiagnostic findings and response to treatment, Neurology 54:2176–
2178, 2000.
Underwood K, Rubin S, Deakers T: Infant botulism: a 30 year experience
spanning the introduction of botulism immune globulin intravenous in the
intensive care unit at Children’s Hospital Los Angeles, Pediatrics 120(6):1380–
1385, 2007.
Vugia DJ, Mase SR, Cole B: Botulism from drinking pruno, Emerg Infect Dis
15:69–71, 2009.
Wirtz P, Lang B, Graus F: P/Q-type calcium channel antibodies, Lambert-Eaton
myasthenic syndrome and survival in small cell lung cancer, J Neuroimmunol
164:161–165, 2005.
XVII
ESSENTIALS

Geriatrics
124  The Aging Patient
Mitchell T. Heflin and Harvey Jay Cohen

1101
 124 
The Aging Patient
Mitchell T. Heflin and Harvey Jay Cohen

predisposition to certain conditions, identification of goals of

  INTRODUCTION
Over the last century, the number of Americans over the age of
65 years increased from 3 million to nearly 45 million in 2013,
accounting for 13% of the population. During the same period
the population over age 85 grew rapidly, expanding from 100,000
in 1900 to nearly 6 million in 2013. By 2030, the number of adults
over age 65 will likely reach 72 million, or just over 20% of the
total population. Ten million of those people will be over age 85
(Fig. 124-1). A report from the National Institute on Aging and
the U.S. State Department points out that this phenomenon is
not isolated to the United States. Around the globe, the percent-
age of the population over 65 years of age will increase by 25%
to 50% over the next 25 years and by 140% in developing nations.
The aging of the world’s population compels virtually all health
care providers to gain competency in geriatrics, the clinical
science of assessment, prevention, and treatment of illness in
older adults. A basic grasp of geriatrics requires understanding
at epidemiologic, biologic, and clinical levels. The provider
must appreciate the impact of aging on presentation of and
care, and selection of treatment strategies. Moreover, care of
older adults demands a multifaceted approach, accounting for
individual, family, and community resources for caregiving.
Finally, the practice of geriatrics requires an appreciation for
systems of care that include interprofessional teams working in a
variety of settings ranging from home to hospital to long-term
care. This chapter will provide an introduction to geriatrics and
the essentials of caring for older adults.
  EPIDEMIOLOGY OF AGING
Most experts believe that the rapid growth of the population of
older adults reflects the many health care successes of the twen-
tieth century. Fries, in his landmark paper, attributes the exten-
sion of the human lifespan to “the elimination of premature
death, particularly neonatal mortality.” Improvements in other
aspects of public health, including adequate nutrition and
housing, safe drinking water, immunizations, and antibiotics,
have led to lower rates of mortality throughout childhood and
early adulthood, affording an opportunity for more people to

Population Age 65 and Over and Age 85 and Over, Selected Years 1900–2010 and Projected 2010–2050
100
Projected

80

60
Millions

40

65 and over
20

85 and over
0
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050
Reference population: These data refer to the resident population.
FIGURE 124-1  Number of people aged 65 years and older, by age group, for selected years 1900 to 2010 and projected years 2010 to 2050. (From
Federal Interagency Forum on Aging-Related Statistics: Older Americans 2012: key indicators of well-being. Federal Interagency Forum on Aging-
Related Statistics, Washington, D.C., 2012, U.S. Government Printing Office.)

1102

100
80
Percent surviving
60
40
1999–2001
1949–1951
20 1900–1902
0 FIGURE 124-3  Classic schematic representation of decreased
0 10 20 30 40 50 60 70 80 90 100
Age
FIGURE 124-2  Percent surviving by age. Deaths tracked by state
registries, 1900 to 1902, and by national registry, 1949 to 1951 and 1999
to 2001. (From Arias E, Curtin LR, Wei R, et al: U.S. decennial life tables
for 1999-2001, United States life tables, Natl Vital Stat Rep 57:1–10,
2008.)
survive to late life. Examination of survival curves across the
twentieth century demonstrates a marked change in the shape of
the overall graph from nearly linear in 1900 to rectangular in the
1990s, with much of the mortality compressed into late life (Fig.
124-2). Although the life expectancy at birth over the same
period has risen dramatically from 47 years to nearly 77 years
with up to 10% of the birth cohort surviving to age 95, the
maximum lifespan defined as the age of the oldest surviving
humans has remained remarkably stable.
  THE BIOLOGY OF AGING
The relatively static nature of the maximum lifespan reflects the
human body’s limits at the cellular, tissue, and organ level in
dealing with the stresses of aging. Across cell types and organ
systems, certain consistent age-related alterations in function
exist. Variability in tissue and organ function decreases, as evi-
denced by less fluctuation in heart rate or hormone secretion.
Organ systems also exhibit predictable declines in function over
time. These changes are most evident at times of stress, and ulti-
mately these systems are slower to react and recover. The overall
result is an impaired ability to deal with any demands beyond a
narrow range outside the normal. This progressive restriction in
the capacity to maintain homeostasis can be depicted as a steady
tapering in the reserve available in multiple organ systems as time
progresses (Fig. 124-3). In this situation an individual may func-
tion within the normal range in the absence of crisis, but stress
such as acute illness may exceed his or her capacity to restore
function and recover health. The result at best may be a decline
in health and ability, and at worst, death.
  THEORIES OF AGING
Scientific research provides a number of plausible theories of
aging, which can be grouped into two major categories. Error or
Chapter 124  The Aging Patient 1103
e
es erv
yr
ne
Kid
Heart reserve
Normal
Age homeostasis
cylinder
homeostatic reserve. (From Fries J, Crapo LM: Vitality and aging: impli-
cations of the rectangular curve, San Francisco, 1981, WH Freeman.)
damage theories propose that aging occurs because of persistent
threats from damaging agents and an ever-declining ability to
respond to or repair this damage. Program theories postulate that
genetic and developmental factors most significantly determine
the biologic life course and the maximal age of the organism. In
actuality, biologic aging may reflect a complex combination of
many types of events.
The free radical theory of aging proposes that oxidative metab-
olism results in an excess of highly reactive byproducts, called
oxygen free radicals, which damage proteins, DNA, and lipids.
Molecular injury eventually leads to cell dysfunction and ulti-
mately to tissue and organ disrepair. A second theory asserts that
the accumulation of glucose-related molecules on proteins con-
tributes to their dysfunction and degradation. These “glycosyl-
ated” molecules become more abundant over time and lead to
impaired function at the tissue and organ level. Theory propo-
nents point to the many chronic problems that routinely arise in
patients with diabetes mellitus as proof of the significance of this
phenomenon.
A different line of reasoning asserts that human lifespan and
aging result from genetic-based timing mechanisms. Older theo-
ries suggest that evolutionary pressures are biased for traits that
promote health and reproduction in early adulthood, possibly at
the expense of health and function in late life. Furthermore, little
selective pressure exists against negative traits that emerge in late
life, leaving humans prone to the ill effects of aging. Geneticists
have identified, among species of fruit flies and certain nema-
todes, specific genes that result in a significant prolongation in
the organism’s lifespan. Work is ongoing to discover similar
genetic sequences among mammalian models.
Study of the enzyme telomerase has also generated much
interest among theorists on aging. In a process called apoptosis,
cells undergo programmed death to be replaced by younger cells.
These divisions and replacements are limited by the number of
generations intrinsic to a specific cell line (the Hayflick phenom-
enon). As telomeres located on the ends of chromosomes are
depleted, cell aging and demise eventually occur. The enzyme
telomerase prevents telomere shortening and may increase a cell’s
number of allotted replications and thereby extend the lifespan
1104 Section XVII  Geriatrics

of the organism. Of course, this advantage must be weighed

against the price of “immortality,” namely the increased risk of   THE FRAILTY PHENOTYPE
malignancy. Biologic changes of aging portend the increased vulnerability of
Caloric restriction (CR), or the purposeful reduction of food humans to illness and functional decline in late life—a state com-
intake, is the only intervention that has been shown to reproduc- monly referred to as “frailty.” Recent research has established a
ibly extend maximal lifespan in certain laboratory animal models. definition of frailty that moves beyond traditional components
In rats, lifespan increases an average of 20 months with a 40% of chronologic age, comorbidity, and disability to identify a
reduction in calories. Rhesus monkeys enrolled in a trial of unique clinical entity with independent predictive capacity. Two
caloric restriction appear to have improvements in metabolic prevailing models of frailty have emerged—one focused more
markers and a lower disease burden than controls after 15 years exclusively on a set of physiologic changes occurring in a cyclical
but have had no definitive extension in lifespan. The mechanism pattern and the other that includes measures of both physiologic
is not well understood but may be metabolically mediated. In markers as well as disease burden. The “cycle of frailty” ties
observational studies in humans, those with lower average body together the individual system-specific changes and identifies key
temperature, lower insulin levels, and higher dehydroepiandros- events or clinical presentations that create a specific phenotype,
terone sulfate (DHEAS) levels (all changes found in calorically including weight loss, weakness, poor endurance, slowness, and
restricted monkeys) appeared to survive longer. Current research inactivity (Fig. 124-4).
is focused on reproducing this phenomenon in human subjects Frailty, defined as three or more of these conditions, inde-
and discovering chemical agents that mimic or mediate these pendently predicts falls, declines in mobility, loss of ability to
metabolic effects, including resveratrol and sirtuins. perform activities of daily living (ADLs), hospitalization, and
To understand the changes in the individual’s ability to cope death. This definition seems to provide a defined link between
with physiologic stress with age, one must also examine the aging-related disease and disability and, perhaps, a target for
changes at the level of the organ system. Table 124-1 provides an interventions to prevent the onset of functional decline. Many
overview of these changes by system. As will be evident, although believe, however, that this model remains difficult to recognize
normal aging is not itself a diagnosis, it is, indeed, fertile ground or measure in the clinical setting. The other definition conceives
for disease and disability. of frailty as a result of accumulation of problems (or deficits)
that ultimately exceeds an individual’s ability to maintain func-
tion and health. This count of deficits generates an index
TABLE 124-1  CHANGES IN PHYSIOLOGIC FUNCTION predictive of disability and death. To some degree both models
WITH AGE capture different aspects of complex and heterogeneous phe-
ORGAN SYSTEM AGE-RELATED DECLINE IN FUNCTION nomenon of vulnerability to declines in health and function
Special senses Presbyopia with aging.
Lens opacification
Decreased hearing   CLINICAL CARE OF OLDER ADULTS
Decreased taste, smell
Cardiovascular Impaired intrinsic contractile function Caring for older adults requires a strong foundation in the basics
Increased ventricular stiffness and impaired filling of internal medicine integrated with an appreciation for the com-
Decreased conductivity plexity and heterogeneity of the impact of aging on health and
Increased systolic blood pressure
Impaired baroreceptor function well-being. The clinician must possess strong diagnostic skills,
Respiratory Decreased lung elasticity given that older adults may have atypical presentations or mul-
Decreased maximal breathing capacity tiple comorbid conditions and functional decline. In addition,
Decreased mucus clearance
Decreased arterial PO2 the clinician must monitor for a number of nonspecific condi-
Gastrointestinal Decreased esophageal and colonic motility tions, such as problems with mobility, mood, or mentation that
Renal Decreased glomerular filtration rate affect self-care capacity and safety. Treatment strategies present
Immune Decreased cell-mediated immunity
Decreased T-cell number unique challenges as well, often requiring a balance of pharmaco-
Increased T-suppressor cells logic and nonpharmacologic interventions with careful consider-
Decreased T-helper cells ation of the individual’s goals for care. This section presents the
Loss of memory cells
Decline in antibody titers to known antigens core components of the comprehensive assessment of the older
Increased autoimmunity patient.
Endocrine Decreased hormonal responses to stimulation
Impaired glucose tolerance   COMORBID CONDITIONS,
Decreased androgens and estrogens
Impaired norepinephrine responses FUNCTION, AND LIFE EXPECTANCY
Autonomic nervous Impaired response to fluid deprivation With advancing age and declines in reserve, older adults experi-
Decline in baroreceptor reflex
Increased susceptibility to hypothermia ence high rates of chronic illness and related functional decline.
Peripheral nervous Decreased vibratory sense Eighty percent of those over age 65 years have at least one chronic
Decreased proprioception illness, and 50% have two or more comorbid conditions. Some
Central nervous Slowed speed of processing and reaction time
Decreased verbal fluency of these conditions contribute directly to increased rates of mor-
Increased difficulty learning new information tality, including the leading causes of death among older adults—
Musculoskeletal Decreased muscle mass heart disease, cancer, stroke, lung disease, and Alzheimer’s
Po2, Partial pressure of oxygen. disease. Many common diseases, however, primarily threaten

Weight
loss
Chronic undernutrition
(Inadequate intake of protein
and energy; micronutrient
deficiencies)
↓ Total energy Cycle of Frailty
expenditure
↓ Resting
metabolic
rate
↓ Activity
↓ Walking
speed
Disability Immobilization
Dependency
FIGURE 124-4  Cycle of frailty. (From Xue QL, Bendeen-Roche K, Varadhan R, et al: Initial manifestations of frailty criteria and the development of
frailty phenotype in the Women’s Health and Aging Study II, J Gerontol A Biol Sci Med Sci 63:984–990, 2008.)
function and result in disability and institutionalization. Arthri-
tis, hearing loss, and vision impairment are all important prob-
lems in this respect. The presence of multiple comorbid
conditions compounds the disabling effects of individual dis-
eases and further complicates management. In the era of evi-
dence and guidelines, a provider caring for a patient with several
common chronic conditions, such as diabetes mellitus, coronary
artery disease, and osteoporosis, may feel compelled to prescribe
six or seven medications to remain in compliance with current
recommendations. This practice can result in significant cost to
the patient and with limited accounting for risks, benefits, and
individual preferences. In addition to considering the discrete
management of individual diseases, care of the older adult
requires assessment of the overall impact of treatment on symp-
toms, function, and life expectancy. To address this common
clinical challenge, the American Geriatrics Society has recently
published guiding principles on care of older persons with mul-
tiple comorbid conditions that highlights the importance of
accounting for complex interactions between conditions, risks
and benefits of various treatment options, overall prognosis, and
patient goals and preferences.
Function, defined formally by Reuben et al, is “a person’s
ability to perform tasks and fulfill social roles across a broad range
of complexity”—more succinctly, self-care capacity. Assessing
this ability provides the clinician with a means of understanding
Chapter 124  The Aging Patient 1105
Sarcopenia
↓ VO2max/
↓ Energy/
↓ Strength Exhaustion
Impaired
balance
Falls and
injuries
the impact of illness, assessing quality of life, identifying care
needs, and estimating progress and prognosis. Comprehensive
assessment of function should include questions about self-care
capacity as well as objective measures of cognition and mobility
(see later sections for details about the latter two). Self-care
capacity is most often divided into basic, instrumental, and
advanced ADLs. Basic ADLs include those actions that maintain
personal health and hygiene, including transferring, bathing, toi-
leting, dressing, and eating. Instrumental ADLs (IADLs) include
activities necessary for living independently, specifically driving
or using public transportation, cooking, shopping, managing
medications and finances, using the telephone (or other com-
munication device), and doing housework. Advanced ADLs
include social or occupational functions associated with activities
such as hobbies, employment, or caregiving. Approximately 30%
of adults over age 65 and 78% of those over age 85 have difficulty
with IADLs or one or more basic ADLs. Predictably, as the inci-
dence of disability rises, so does the rate of dependence and
nursing home residence. Long-term care in skilled facilities
increases from 2% among those aged 65 to 74, to 14% among
those older than 85 years. Impairment in ADLs is also associated
with an increased risk of falls, depression, and death in the
affected elder. Among older adults the assessment of self-care
capacity provides key health status information independent of
age and comorbid conditions.
1106 Section XVII  Geriatrics

For clinicians, navigating the myriad options for management
of multiple chronic conditions requires individualized assess-
ment of risks, benefits, and specific goals of various therapies.
Estimates of life expectancy, integrating the impact of age, comor-
bid illness, and function, have been generated to assist in medical
decision making. These estimates assist providers in predicting
median survival and thus can help in estimating the potential life
remaining in which one might benefit from a given procedure or
therapy (Fig. 124-5). For example, the options offered to a frail
85-year-old man with less than 3 years left to live may be quite
different from those presented to his healthy counterpart of the
same age with a median life expectancy of 5 to 7 years. In addi-
tion, any decision should take into account the individual patient’s
goals and preferences. A variety of prognostic tools exist to assist
clinicians with estimating survival in different populations and
care circumstances. These tools can be accessed online in an
interactive fashion for clinicians at http://eprognosis.ucsf.edu/.
  PRESENTATION OF DISEASE IN THE OLDER ADULT
Competent care of the frail older adult starts with recognition of
disease, even in the absence of typical signs and symptoms. Pre-
sentation of disease among older adults may differ dramatically
from that expected in younger patients; manifestations of distress
may be subtle or nonspecific, and improvement is less obvious
and slower. These phenomena occur for a number of reasons. As
noted previously, older adults experience high rates of comorbid
illness, which may confound the clinician’s ability to diagnose a
problem accurately. For example, a patient with heart disease and
chronic obstructive pulmonary disease who visits the office
because of dyspnea may be experiencing a flare of his or her
pulmonary disease or an atypical presentation of ischemic heart
disease or both. Reporting of symptoms may also be affected by
psychosocial factors, including limited access to the health care
system, cognitive problems, or minimization of symptoms as
“normal aging.” Likewise, health care providers may minimize
complaints by older adults with complex medical illness or frail
health.
The alert clinician may anticipate “geriatric” presentations
for certain conditions (Table 124-2). Hyperthyroidism can
manifest with apathy, malaise, depression, and fatigue, while
lacking classic symptoms of tremor, tachycardia, or sweating.
It can also manifest with heart failure and is highly prevalent
among older adults with new-onset atrial fibrillation. Likewise,
older patients with hypothyroidism may atypically demonstrate

LIFE EXPECTANCY FOR WOMEN

25
21.3 Top 25th percentile
20 50th percentile
17 Lowest 25th percentile
15.7
15
13
Years

11.9
9.5 9.6
10 8.6
6.8 6.8
5.9
4.6 4.8
5 3.9
2.9 2.7
1.8 1.1
0
A 70 75 80 85 90 95

LIFE EXPECTANCY FOR MEN

25

20
18

15 14.2
12.4
Years

10.8
10 9.3
7.9
6.7 6.7
5.8
4.9 4.7
5 4.3
3.3 3.2
2.2 2.3
1.5 1.0
0
B 70 75 80 85 90 95
Age (yr)

FIGURE 124-5  Upper, middle, and lower quartiles of life expectancy for women and men at selected ages. (From Walter LC, Covinsky KE: Cancer
screening in elderly patients: a framework for individualized decision making, JAMA 285:2750–2756, 2001.)
 Chapter 124  The Aging Patient 1107

TABLE 124-2  PRESENTATIONS OF DISEASE IN OLDER   MEDICATIONS

ADULTS* Medication-related problems are very common in older adults. In
POTENTIAL PRESENTING the United States, outpatients over age 65 take, on average, three
DIAGNOSIS SYMPTOMS AND SIGNS
to five medications. Although medications may be indicated for
Myocardial infarction Altered mental status specific medical conditions, use of multiple medications increases
Fatigue
Fever the risk for drug-drug interactions and associated adverse drug
Functional decline events. Altered pharmacokinetics and pharmacodynamics con-
Infection Altered mental status tribute to adverse drug events, which are a common cause of hos-
Functional decline
Hypothermia pitalization and morbidity in older persons. Common changes in
Hyperthyroidism Altered mental status pharmacokinetics include changes in body composition, with
Anorexia increased fat stores and decreased body water. Fat-soluble medi-
Atrial fibrillation
Chest pain cations, such as benzodiazepines, have a prolonged duration of
Constipation effect because of this phenomenon. Age-related declines in glo-
Fatigue merular filtration rates result in decreased clearance of many
Weight gain
Depression Cognitive impairment medications, including such drugs as atenolol, digoxin, and
Failure to thrive lithium. Accurate calculations of creatinine clearance will inform
Functional decline drug choice and dosing and improve prescribing safety. Pharma-
Electrolyte disturbance Altered mental status
Falls codynamic changes include decreased sensitivity to certain com-
Fatigue monly prescribed drugs, such as β-blockers, and increased
Personality changes sensitivity to other agents, such as narcotics and warfarin.
Malignancy Altered mental status
Fever Given the risks of medication use in older adults, health care
Pathologic fracture providers and systems must employ strategies to improve both
Pulmonary embolus Altered mental status the effectiveness and safety of prescribing. Evidence-based rec-
Fatigue
Fever ommendations include the following:
Syncope • Maintain an up-to-date medication list, including over-the-
Vitamin deficiency Altered mental status counter medications and herbal supplements.
Ataxia
Dementia • Comprehensively review medications at least once annually
Fatigue (if not at every visit) and, in particular, at the time of transi-
Fecal impaction Altered mental status tions between care settings (e.g., after hospitalization). A
Chest pain
Diarrhea clear indication for each medication, and documentation of
Urinary incontinence response to therapy (particularly for chronic conditions)
Aortic stenosis Altered mental status should be included.
Fatigue
• Assess for duplication and drug-drug or drug-disease inter-
*This table represents only a limited list of select disease processes and presentations; it is
not meant to serve as an exhaustive reference for use during patient care activities.
actions. Using a drug information database will help with
this process.
• Assess adherence and affordability and inquire about
failure to thrive, weight loss, cognitive decline, or depression. the patient’s system for administering medications (e.g., a
In the presence of infection, older adults may not reliably mount pillbox).
fever or experience localized symptoms. Studies have demon- • Assess for specific classes of medications commonly associ-
strated that lowering the threshold definition of fever can ated with adverse events: warfarin, analgesics (particularly
improve the diagnostic utility of body temperature as a sign of narcotics and nonsteroidal anti-inflammatory drugs
bacterial infection. Although chest pain remains the most [NSAIDs]), antihypertensives (particularly angiotensin-
common and important symptom of ischemic heart disease, converting enzyme [ACE] inhibitors and diuretics), insulin
dyspnea in the absence of chest pain is a commonly reported and hypoglycemic agents, and psychotropics.
symptom, particularly in older adults and those with multiple • Be suspicious that new symptoms arise from adverse effects
comorbidities. of current drugs, not new disease.
In truth, any medical illness may manifest nonspecifically • Minimize or avoid use of anticholinergic medications, which
among older adults, particularly those in frail health. Nonspecific present specific risks.
symptoms related to an underlying illness include changes in In addition to following these general principles, prescribing
mentation, difficulty with balance and falls, new urinary inconti- providers also benefit from consulting lists of potentially inap-
nence (UI), and a general change in functional ability. These propriate medications. The Beers List of Potentially Inappropri-
presentations are often referred to as the “geriatric syndromes” ate Medications (PIMs) provides an evidence-based guide to
and are detailed later. A lack of understanding of how disease drugs that should be avoided if possible or used with caution in
presentation differs among older adults can lead to delays in older adults. A clear and rational approach to prescribing and
diagnosis and treatment and result in worse outcomes. Research ongoing management of medications that accounts for indica-
indicates that altered presentation predicts not only suboptimal tion, interactions, and adherence may reduce the risk of common
care, but future functional decline and increased mortality. adverse events.
1108 Section XVII  Geriatrics
  COGNITION
Dementia
The prevalence of dementia increases with age, with estimates
ranging from 20% to 50% after age 85. The most common forms
of dementia include Alzheimer’s disease, Lewy body dementia,
and vascular dementia. The latter is commonly present in combi-
nation with Alzheimer’s disease in a condition termed mixed etiol-
ogy dementia. Dementia is characterized by impairment in one or
more cognitive domains severe enough to disrupt function or
occupation. Mild cognitive impairment (MCI) is present when
an individual has discernible cognitive limitations without appar-
ent functional impact. Patients with MCI develop dementia at a
rate of approximately 15% per year. Dementia is associated with
a higher risk of falls, functional impairment, institutionalization,
and death. Caregivers of demented individuals also face increased
rates of stress and health problems. Clinicians diagnose dementia
through symptom and functional history (often including the
input of caregivers), cognitive assessment, and physical examina-
tion. A number of instruments, including the MOCA (see
Chapter 108), clock-drawing test, and the Mini-Cog, are vali-
dated screening tools. The time-tested Mini Mental State Exami-
nation (MMSE) offers an assessment of multiple cognitive
domains but does not provide adequate measure of executive
function and is prone to lack of sensitivity in individuals with
high premorbid intelligence and lack of specificity in those with
low levels of education. Validated assessments of executive func-
tion include the clock-drawing test, verbal fluency test, and the
Trail B test. Instruments also exist for collecting data regarding
patient function from a relative or caregiver. In patients suspected
of having dementia, personal safety with respect to firearms,
driving, and the home environment should be assessed. A careful
medication review and physical examination, including vital
signs, complete neurologic assessment, including gait and
balance, are, of course, essential in dementia to reveal findings
that point to a specific cause (see Chapter 116).
Delirium
The differential diagnosis for cognitive problems other than
dementia is broad, and includes delirium, mood disturbance, and
drug effects. The differentiation of dementia and delirium may
present the most significant challenge, particularly in hospital-
ized elders (Table 124-3). Delirium is characterized by its acuity
and alteration in global cognitive function, whereas dementia is
chronic and affects specific cognitive domains. Differentiation
often hinges on history, which may be lacking at presentation.
Delirium affects more than 2 million hospitalized persons each
year. Its incidence is variably estimated at 25% to 60% among
patients in acute care settings and results in extra hospital days
and related expenditures. Delirium is also associated with pro-
longed hospital stay, increased costs, increased readmission rates
to the hospital (12% to 65% at 6 months), higher in-hospital and
1-year mortality, and incident dementia. The Confusion Assess-
ment Method (CAM) offers a validated tool to diagnose delir-
ium. Per the CAM, delirium is likely present if the patient has
both an acute onset of confusion with fluctuating course and
inattention, and either disorganized thinking or altered level of
consciousness. Key risk factors for delirium include older age,
TABLE 124-3  FEATURES OF DELIRIUM VERSUS
DEMENTIA
FEATURE DELIRIUM DEMENTIA
Onset Acute Insidious
Course Fluctuating, lucid at Generally stable
times
Duration Hours to weeks Months to years
Alertness Abnormally low or high Usually normal
Perception Illusions and Usually normal
hallucinations
common
Memory Immediate and recent Recent and remote
impaired impaired
Thought Disorganized Impoverished
Speech Incoherent, slow, or Word-finding difficulty
rapid
Physical illness or Frequently Usually absent
medication causative
cognitive impairment, comorbid illness, and impairments in
vision and hearing. Precipitating factors related to acute illness
include hypoxia, electrolyte abnormalities, dehydration, and mal-
nutrition as well as medications and alcohol withdrawal. Although
treatment of delirium is difficult and revolves around the underly-
ing medical issues, controlled trials have demonstrated that a
multi-modal intervention is effective in reducing rates of delirium
in high-risk patients. There is evidence that the use of restraints
in combative or confused older adults leads to increased morbid-
ity and mortality. Nonpharmacologic management strategies
include reorientation and preservation of sleep patterns, family
or caregiver presence at the bedside, and early mobilization. The
use of pharmacologic agents, specifically neuroleptics, should be
reserved for patients in whom nonpharmacologic strategies do
not help and the patient presents a risk of harm to self or others.
  MOOD
Older adults commonly experience depressive symptoms, with
prevalence estimates as high as 15% to 19% among those over age
75, although in community-dwelling elders, major depressive
disorder is actually less common than in younger adults. The
presence of comorbid illness and grief often confound the pre-
sentation of depression. As a result, it can remain undetected
despite its significant adverse impact on quality of life, morbidity,
and mortality. Suicide rates are almost twice as high among older
persons when compared with the general population, with the
rate highest for white men over 85 years of age. Among older
adults, depression can manifest atypically with cognitive, func-
tional, or sleep problems, as well as complaints of fatigue or low
energy. Several instruments have been developed and validated
for screening for depression in elders. Asking two simple ques-
tions about mood and anhedonia (“Over the past 2 weeks have
you felt down, depressed, or hopeless?” and “Over the past 2
weeks have you felt little interest or pleasure in doing things?”)
may be as effective as using longer instruments. Longer screening
questionnaires, such as the Geriatric Depression Screen (GDS)
or Patient Health Questionnaire (PHQ-9), are also useful tools
in the ambulatory setting. Any positive screening test result
should trigger a full diagnostic interview. When screening
for depression in elders, it is particularly important to have
systems in place to provide feedback of screening results, a readily

accessible means of making an accurate diagnosis, and a mecha-
nism for providing treatment and careful follow-up. Recent trials
indicate that the addition of counseling to pharmacologic therapy
confers additional benefit for older, frail patients with depression.
Anxiety is more common than depression among older adults
and may similarly result in physical and cognitive symptoms,
insomnia, agitation, psychosis, and isolation. Clinicians should
consider a diagnosis of generalized anxiety, panic, or agoraphobia
in older adult patients with any of these symptoms.
  MOBILITY
Problems with mobility are common among older persons.
Among those over age 65, 20% of men and 32% of women report
difficulty with one or more of five specific physical activities
(stooping or kneeling, reaching overhead, writing, lifting 10
pounds, or walking two to three blocks). Among these, respon-
dents cite problems with walking most commonly. Difficulties
with balance and gait present significant risks for older adults.
Approximately 30% of community-dwelling elders fall each year.
The annual incidence of falls approaches 50% in patients over 80
years of age. Five percent of falls in older adults result in fracture
or hospitalization. Risk factors for falls include a history of falls,
fear of falling, decreased vision, cognitive impairment, medica-
tions (particularly anticholinergic, psychotropic, and cardiovas-
cular medications), diseases causing problems with strength and
coordination, and environmental factors. Effective interventions
for people with a history of falls or who are at risk for falling
involve addressing multiple contributing factors. Providers
should regularly inquire about recent falls or a fear of falling in
older patients. For patients who report falling, the assessment
should include review of circumstances of the fall(s), measure of
orthostatic vital signs, visual acuity testing, cognitive evaluation,
and gait and balance assessment. A brief physical examination
maneuver called the “timed get up and go” has the patient arise
from a sitting position, walk 10 feet, turn, and return to the chair
to sit. A time of more than 12 seconds to complete the process,
or observation of postural instability or gait impairment, suggests
an increased risk of falling. Gait speed, an additional measure of
mobility, predicts changes in ability and health status in older
adults. Gait speed is measured over a 10-meter span with the
patient walking at a comfortable pace. A speed of less than
1.0 m/sec is associated with increased mortality; 0.8 m/sec pre-
dicts difficulty navigating outside the home, and a speed of less
than 0.6 m/sec predicts a high risk of falls and functional decline.
For those found to be at risk for falls, providers should also review
all medications for possible causative agents and inquire about
home safety. High-risk patients should be evaluated for assistive
devices and a supervised exercise program (Table 124-4).
  VISION AND HEARING
Problems with vision and hearing are very common among older
adults and frequently complicate the management of comorbid
conditions and accelerate functional decline. Significant vision
loss occurs in 16% to 18% of adults over age 65. Common causes
include glaucoma, cataracts, age-related macular degeneration,
and retinopathy from hypertension and diabetes. Decreased
visual acuity increases fall risk and has been associated with all-
cause mortality. Such problems may be detectable with regular
Chapter 124  The Aging Patient 1109
testing via bedside tools such as the Snellen or Jaeger eye chart.
Given the implications of vision loss for function and safety, a
general ophthalmologic examination every 1 to 2 years is recom-
mended for all older adults. Furthermore, ophthalmologic
centers have recognized the multifaceted challenges faced by
older adults with vision impairment and have developed special-
ized low vision clinics offering evaluation by optometrists, occu-
pational therapists, and social workers with a focus on improving
quality of life and maintaining independence.
Hearing loss is the third most common ailment in older adults
(behind hypertension and arthritis), affecting an estimated 40%
to 66% of those over age 75. It is associated with depression,
social isolation, poor self-esteem, cognitive decline and func-
tional disability. Pure tone audiometry is the reference standard
for screening for hearing loss, but a simple whispered voice test
is also highly sensitive and specific. Ideally all older adults would
undergo annual hearing screen by questionnaire and handheld
audiometry. Unfortunately, the lack of reimbursement for hear-
ings aids under most insurance plans, including Medicare, pres-
ents a major barrier for many older adults.
  CONTINENCE
UI affects up to 30% of community-dwelling older adults and at
least half of those residing in skilled nursing facilities. It occurs
more frequently in women, but this gender disparity narrows as
the rate of UI in men increases after age 85. The impact of UI on
health ranges from increased risk of skin irritation, pressure
wounds, and falls, to social isolation, functional decline, and
depression. For caregivers of older adults, UI complicates physi-
cal care and can contribute to decisions for placement in skilled
nursing facilities. Common comorbid conditions include diabe-
tes mellitus, heart failure, arthritis, and dementia.
A systematic approach to the investigation of UI can often
reveal a cause and potential solution. It is important to first deter-
mine if the incontinence is acute or chronic in nature. Acute
causes of incontinence are often attributable to specific medical
problems, including infection, metabolic disturbance, or medica-
tion effects. The pneumonic DIAPERS recalls the various poten-
tial acute causes of UI (D, delirium; I, infection; A, atrophic
vaginitis; P, pharmaceuticals; E, excess urine output from conges-
tive heart failure [CHF] or hyperglycemia; R, restricted mobility;
and S, stool impaction). If the UI is chronic, then further history
can characterize the nature of the symptoms from among four
types. Urge incontinence from detrusor overactivity is the most
common type. Patients with this problem will complain of
urinary frequency, nocturia, and a sudden onset of urge to void.
Stress incontinence occurs with incompetence of pelvic muscu-
lature or urethral sphincter, and is characterized by small amounts
of leakage with laughing, sneezing, coughing, or even standing.
Overflow incontinence results from urinary retention, often
related to prostatic hyperplasia in men or bladder atony in
patients with diabetes or spinal cord injury. Patients often have
constant dribbling or leakage without a true sense of needing to
void. Finally, functional incontinence results from comorbid con-
ditions that limit a patient’s ability to act on or interpret the need
to void, mobility problems such as arthritis, and weakness or
cognitive problems. Table 124-5 describes the various types of
incontinence and suggested approaches. Of course, older adults
1110 Section XVII  Geriatrics

TABLE 124-4  RECOMMENDED COMPONENTS OF CLINICAL ASSESSMENT AND MANAGEMENT FOR OLDER
PERSONS LIVING IN THE COMMUNITY WHO ARE AT RISK FOR FALLING
ASSESSMENT AND RISK FACTOR MANAGEMENT
Circumstances of previous falls* Change in environment and activity to reduce the likelihood of recurrent falls
Medication use Review and reduction of medications
• High-risk medications (e.g., benzodiazepines, other sleep medications,
neuroleptics, antidepressants, anticonvulsives, or Class IA
antiarrhythmics—including Quinidien, Procainamide, and
Disopyramide)*†‡
• Four or more medications‡
Vision* Ample lighting without glare; avoidance of multifocal glasses while walking;
• Acuity <20/60 referral to an ophthalmologist
• Decreased depth perception
• Decreased contrast sensitivity
• Cataracts
Postural blood pressure (after ≥5 min in a supine position, immediately after Diagnosis and treatment of underlying cause, if possible; review and reduction
standing, and 2 min after standing)‡ of medications; modification of salt restriction; adequate hydration;
• ≥20 mm Hg (or ≥20%) drop in systolic pressure, with or without compensatory strategies (e.g., elevating head of bed, rising slowly, or
symptoms, either immediately or after 2 min of standing performing dorsiflexion exercises); pressure stockings; pharmacologic therapy
if the above strategies fail
Balance and gait†‡ Diagnosis and treatment of underlying cause, if possible; reduction of
• Patient’s report or observation of unsteadiness medications that impair balance; environmental interventions; referral to
• Impairment on brief assessment (e.g., the “get up and go” test or physical therapist for assistive devices and for gait, balance, and strength
performance-oriented assessment of mobility) training
Targeted neurologic examinations Diagnosis and treatment of underlying cause, if possible; increase in
• Impaired proprioception* proprioceptive input (with an assistive device or appropriate footwear that
• Impaired cognition* encases the foot and has a low heel and thin sole); reduction of medications
• Decreased muscle strength†‡ that impair cognition; awareness on the part of caregivers of cognitive deficits;
reduction of environmental risk factors; referral to physical therapist for gait,
balance, and strength training
Targeted musculoskeletal examinations of legs (joints and range of motion) and Diagnosis and treatment of underlying cause, if possible; referral to physical
examination of feet* therapist for strength, range-of-motion, and gait and balance training, and for
assistive devices; use of appropriate footwear; referral to podiatrist
Targeted cardiovascular examination† Referral to cardiologist; carotid-sinus massage (in case of syncope)
• Syncope
• Arrhythmia (if there is known cardiac disease, abnormal
electrocardiogram, and syncope
Home-hazard evaluations after hospital discharge†‡ Removal of loose rugs and use of nightlights, nonslip bathmats, and stair rails;
other interventions as necessary
From Tinetti ME: Clinical practice. Preventing falls in elderly persons, N Engl J Med 348(1):42–49, 2003.
*Recommendation of this assessment is based on observations that the finding is associated with an increased risk of falling.
†
Recommendation of this assessment is based on one or more randomized controlled trials of a single intervention.
‡
Recommendation of this assessment is based on one or more randomized controlled trials of a multifactorial intervention strategy that included this component.

TABLE 124-5  CAUSES, TYPES, AND TREATMENT OF URINARY INCONTINENCE

TYPE DEFINITION CAUSE TREATMENT
Stress Leakage associated with increased Hypermobility of the bladder base, frequently caused by Pelvic muscle exercise, timed voiding,
intra-abdominal pressure lax perineal muscles α-adrenergic drugs, estrogens, surgery
(coughing, sneezing)
Urge Leakage associated with a Detrusor hyperactivity (outflow obstruction, bladder Bladder training, pelvic muscle exercise,
precipitous urge to void tumor, detrusor instability), idiopathic (poor bladder), bladder-relaxant drugs (anticholinergics,
compliance (radiation cystitis), hypersensitive bladder oxybutynin, tolterodine, imipramine)
Overflow Leakage from a mechanically Outflow obstruction, enlarged prostate, stricture, prolapsed Surgical correction of obstruction,
distended bladder cystocele, acontractile bladder (idiopathic, neurologic intermittent catheter drainage
[spinal cord injury, stroke, diabetes])
Functional Inability or unwillingness to void Cognitive impairment, physical impairment, environmental Prompted voiding, garment and padding,
barriers (physical restraints, inaccessible toilets), external collection devices
psychological problems (depression, anger, hostility)

with multiple comorbid conditions often have incontinence that
results from a combination of chronic and/or acute causes.
Continence problems are frequently treatable but are often not
raised by patients as a concern. A targeted history and physical
examination can often identify the cause of UI and lead to appro-
priate intervention. Asking about and documenting the presence
or absence of UI should be done biannually, as well as determin-
ing whether the UI, if present, is bothersome to the patient or
caregiver. In addition to a history of acute and chronic causes, a
targeted physical examination should include an assessment for
fluid overload, genital and rectal examination, and neurologic
evaluation. Urine and blood tests are indicated to evaluate for
infection, metabolic causes, and renal dysfunction. In addition,
for patients suspected of having urinary retention, catheterization
or ultrasound can help define the postvoid residual and deter-
mine any need for catheter placement and further urologic
evaluation. Many institutions now offer more specialized evalua-
tion and care through incontinence clinics, which offer a

multidisciplinary approach to management, addressing both
pharmacologic and nonpharmacologic options. Effective non-
pharmacologic options include scheduled toileting, bladder
training, and biofeedback. Use of these strategies may avoid the
use of medications with frequent adverse effects, such as anticho-
linergic medications for detrusor overactivity.
  NUTRITION
Older adults experience high rates of malnutrition related to mul-
tiple causes, including medical illness, dental problems, or access
issues related to limited mobility, cost, or cognitive problems.
Approximately 15% of older outpatients and half of hospitalized
elders are malnourished, and have associated increases in mor-
bidity and mortality. The utility of general laboratory testing is
limited, but a combination of serial weight measurements and
inquiries about changing appetite can reveal nutritional problems
in the older adults. Vulnerable elders with an involuntary weight
loss of 10% or more in 1 year or less should undergo further
evaluation for undernutrition, including assessment of medical
or medication-related causes, dental status, problems with acquir-
ing or preparing food, appetite and intake, swallowing ability, and
previous directions for dietary restrictions.
  SOCIAL AND LEGAL ISSUES
The social history for older persons includes assessment of
resources for direct caregiving and financial support available.
These issues become particularly important for frail older adults,
given their physical and economic vulnerability.
Caregiving
The clinician should always inquire about who is providing care
for the older patient, including both personal care with ADLs and
help with IADLs, such as transportation, medications, food prep-
aration, finances, and housekeeping. This list should include both
formal caregivers, such as home health professionals or hired
aides, and informal caregivers, such as family members, neigh-
bors, or friends. The majority of elder care provided in the United
States is delivered by informal caregivers. Over 34 million people
in the United States provide informal care for older adults and,
of these, 8.9 million are caring for persons suffering from demen-
tia. The majority of informal caregivers are women and elderly
themselves, with an average age of 63 years. The stress of provid-
ing daily care can have serious deleterious effects on the care-
giver’s health. Studies have demonstrated adverse effects on
blood pressure and immune function, and increased rates of car-
diovascular disease and death. In addition, caregivers have alarm-
ingly high rates of psychological illness, with symptoms of
depression reported in up to 50%. This problem is particularly
prevalent in those providing care for patients with dementia. The
presence of mental illness further raises the risk of verbal or
physical abuse or neglect of the patient. The clinician must rec-
ognize caregiver problems early and consider referral to a social
worker, patient resource manager, or, when available, a geriatric
assessment team. Key risk factors for stress include a frail family
caregiver; a patient with cognitive impairment, emotional distur-
bance, substance abuse, sleep disruption, or behavioral problems;
low income or financial strain; and acute illness or hospitaliza-
tion. Providers should recognize signs and symptoms of physical
Chapter 124  The Aging Patient 1111
or mental strain, and regularly inquire about caregiver burden
with an offer to talk apart from the patient if need be.
A number of resources exist to support caregivers and provide
strategies for problem solving and self-care. Community-based
programs provide assistance with meals, transportation, and
respite care options through volunteer organizations or subsi-
dized programs. Counseling on both the physical and emotional
aspects of care has been demonstrated to reduce health risks to
the caregiver and delay institutionalization, including in-home or
institutional respite stays to provide caregivers with precious
time off. Studies consistently demonstrate that such services are
underused by caregivers.
Mistreatment
Older adults are particularly vulnerable to mistreatment due to
poor health, functional dependence, and social isolation. Mis-
treatment is defined as either elder abuse (harm caused by
others) or self-neglect. Self-neglect is thought to be the most
common form of mistreatment, but true rates are difficult to esti-
mate. Risk factors include cognitive impairment and recent func-
tional decline. Elder abuse has been reported in 3% to 8% of the
older adult population in the United States, although this is likely
an underestimate due to underreporting by patients and lack of
recognition by health care providers. Abuse assumes many forms
including psychological, financial, physical, sexual abuse, and
neglect. Studies have demonstrated that neglect and abuse are
associated with higher rates of nursing home placement and mor-
tality among older adults. Signs of physical abuse include contu-
sions, burns, bite marks, genital or rectal trauma, pressure ulcers,
or unexplained weight loss. Other forms of abuse may be more
difficult to discern on examination, but can be improved with
direct questions such as “Has anybody hurt you?”; “Are you afraid
of anybody?”; or “Is anyone taking or using your money without
your permission?” Any suspicion of abuse or neglect should be
reported to Adult Protective Services. Of note, 44 states and the
District of Columbia have laws mandating reporting of suspected
elder abuse.
Finances
The older adult population in the United States varies widely in
measures of wealth. Although the overall rate of poverty among
adults over age 65 has declined over the last 50 years, 10% of
older adults still live at or below the poverty line, and the percent-
age is higher among African Americans (24%) and Hispanics
(21%). Providers should screen for financial problems because
these issues have direct implications for health status and well-
being. Older adults with limited means are more prone likely to
have problems affording medications, meals, and basic amenities.
Referrals to community resource networks can help identify
options for help with basic needs, including housing options and
congregate meals. Information on agencies and services in spe-
cific locales can be identified at www.eldercare.org.
Advance Directives
Advance directives come in a number of different forms and serve
a variety of purposes. Ideally these documents articulate a
person’s preferences for care in the event of serious illness or
incapacitation. Often they will describe limits on care and
1112 Section XVII  Geriatrics
circumstances in which life sustaining or restoring measures may
be withheld or even withdrawn. Traditionally, advance directives
have included a living will and health care power of attorney. The
living will often addresses situations in which the patient has a
terminal illness, persistent vegetative state, or progressive neuro-
logic condition and can include explicit directions for care man-
agement including withdrawal or withholding of specific
measures, including artificial nutrition and hydration. Living
wills are ideally paired with a companion document, the health
care power of attorney, which designates the person’s preferred
decision maker, or proxy, in the event of an incapacitating illness.
For patients who have not created a health care power of attorney,
typically the spouse or other first-degree relative is the default
decision maker. If no proxy is designated and no next of kin is
available, guardianship may be obtained. Guardianship is a legal
proceeding whereby the court appoints a surrogate decision
maker. The physician’s responsibility includes determination of a
person’s capacity for independent decision making in the event
of altered sensorium or progressive cognitive impairment. This
involves an assessment of his or her ability to understand the situ-
ation, ask questions, weigh options and render an opinion and,
in certain situations, may require a full geriatric or neuropsycho-
logical assessment. Traditional advance directives, particularly
the living will, have been criticized as having limited utility in
conveying specific preferences. Recently, more detailed forms
have emerged to record very specific preferences and limits for
measures such as hydration, nutrition, hospitalization, and resus-
citation. Examples include the Medical Orders for Scope of
Treatment (MOST) and Physician’s Orders for Life Sustaining
Treatment (POLST) forms. Of course, effective completion and
application of any of these forms should include a goals of care
conversation conducted with the primary care provider ideally
involving family caregivers. In addition, as preferences change
over time depending on health status, health care providers
should encourage older adults to revisit and renew their advance
directives on an annual basis.
  HIGH-RISK CIRCUMSTANCES
The Hospitalized Patient
Millions of older adults are hospitalized in the United States each
year for a variety of acute illnesses and elective procedures. For-
tunately, in the United States, Medicare Part A covers much of
the cost associated with acute care, including hospitalization and
follow-up rehabilitation. While in the hospital, however, older
adults are vulnerable to myriad complications related to both
their compromised health state and problems inherent to the
acute care environment itself. As noted previously, delirium
afflicts hospitalized elders at a very high rate and increases risk of
prolonged hospital stays, nursing home admission, and death.
Hospitalized older adults also experience the effects of immobi-
lization, with loss of muscle strength and deconditioning. Acutely,
these factors increase the risk of falls and impair function and
ability to provide self-care. In addition, poor oral intake may
result in malnutrition, and illness-related fluid losses cause dehy-
dration. As a result, hypotension and protein-calorie malnutri-
tion are common problems. Immobility and malnutrition both
predispose the acutely ill patient to the development of pressure
wounds, which can develop in under 2 hours. All these problems
worsen in the presence of delirium or depressed mood. Environ-
mental factors also contribute to problems, including tethers
such as catheters and intravenous lines (which increase risk of
falls), noisy wards, and frequent tests and procedures that further
disrupt diurnal rhythms and sleep. Up to one third of hospitalized
older adults experience a decline in their ability to perform ADLs
in the course of their hospitalization. Patients who experience
declines in function during hospitalization have higher rates of
rehospitalization, prolonged institutionalization, and mortality
after discharge, and many (41%) never return to their preadmis-
sion level of function. To combat these problems, some hospitals
have created specialized inpatient geriatric care units, often
termed acute care for elders (ACE) units. These units incorporate
adaptations in the physical environment and specially trained
staff to provide safe, patient-centered care designed to maximize
restoration of function and prevent common complications of
hospitalization. In randomized trials, ACE units and their consul-
tative counterpart, the Mobile ACE (or MACE), have reduced
lengths of stay, improved care transitions, and lowered readmis-
sions. Likewise, geriatric evaluation and management (GEM)
units (described later) offer specialized, team-based post-acute
care with an emphasis on rehabilitation and return to prior level
of function.
Care Transitions
As noted previously, older adults experience high rates of com-
plications during acute illness and require prolonged periods of
time to recover. For this reason, management in the post-acute
period represents a critical and complex time in their care. Spe-
cifically, older adults with acute illness often find themselves
transferred among different care settings and providers. Nearly
one quarter of hospitalized older adults are discharged to skilled
nursing facilities, and another 12% are discharged with home
health care. Of those discharged to skilled facilities, about one
fifth will return to the hospital within 30 days. Transitions in care
represent high-risk episodes, and evidence shows that patients
and caregivers frequently experience miscommunication, medi-
cation errors, and missed essential laboratory tests or appoint-
ments during this period. Recent trials have demonstrated a
reduction in rehospitalization through a structured discharge and
transition plan that includes medication reconciliation before
and after discharge, careful planning for laboratory and appoint-
ment follow-up, communication with patients and caregivers
about expectations and preferences, and specific coaching for
patients and caregivers in symptom management and care. More
information on care management in transitions is available at
www.caretransitions.org.
  SYSTEMS OF CARE
Ambulatory and Home Care
The majority of care for older adults occurs in the outpatient
setting. Much of the cost of this care, including visit fees, labora-
tory tests, x-ray studies, and vaccinations, is covered under Medi-
care Part B, for which patients pay a monthly premium. Outpatient
visits may occur with the physician, physician assistant, nurse
practitioner, or clinical nurse specialists, depending on the nature

of the problem and the structure of the setting. Other key
members of the care team include social workers, pharmacists,
psychologists, and physical and occupational therapists. Most
assessments discussed in this chapter can be performed in outpa-
tient settings, including functional assessments, cognitive and
mood screening, gait and balance assessment, medication review,
eye and ear examinations, and continence evaluations. Interview
of a caregiver can augment the information collected. Care in this
setting can be complicated, though, by problems with transporta-
tion and ineffective or inefficient communication among multi-
ple providers, particularly for patients with multiple specialists.
Over the last several years, home care has reemerged as an
effective means of providing health care for older adults. As with
the outpatient setting, Medicare Part B will reimburse providers
in part for services rendered in the home. In addition, if a reha-
bilitative or skilled service is needed, Medicare Part A provides
coverage. Patients receiving services in the home must be “home-
bound,” implying that they are significantly functionally impaired
and travel with assistance out of the home infrequently and
usually only for medical purposes. Services rendered in the home
include a full range of evaluations by teams of providers from a
variety of health professions depending on needs. Social workers
often lead these visits and perform case management, assessing
financial and other resource needs. Nurses, clinical nurse special-
ists, and/or nurse practitioners provide skilled services when
necessary, including health education, symptom monitoring, or
wound care. Physical and occupational therapy can assess mobil-
ity and home safety and greatly enhance function and indepen-
dence. Furthermore, examination of a person’s home environment
can reveal much about his or her safety and nutrition, and can
facilitate education or intervention in these areas. Physicians may
serve as medical directors of such programs, but may also
perform visits themselves to learn more about a given patient’s
health status. If significant concerns exist about a patient’s safety,
particularly in the setting of cognitive impairment, a home visit
may provide information about the need for more urgent inter-
ventions, including referrals to Adult Protective Services.
Research has demonstrated that coordinated home care pro-
grams can improve management of chronic disease, including
dementia, diabetes mellitus, and congestive heart failure, as well
as to reduce rehospitalization in patients with congestive heart
failure.
Long-Term Care
The phrase long-term care describes the array of services available
to provide care for patients with disability from chronic and acute
conditions. This definition includes the services offered in the
outpatient and home settings described previously. Most associ-
ate the term, however, with the system of nursing facilities pro-
viding personal and medical care for disabled adults of all ages.
Skilled nursing facilities provide long-term care for those with
permanent disabilities from chronic illness or short rehabilitative
stays after acute illness (e.g., stroke) or procedures (e.g., joint
replacement). The scope of services may also include end-of-life
care in conjunction with a hospice care team. Facility staff
includes licensed nurses who give 24-hour supervision, with
much of the personal care provided by certified nursing assis-
tants. Each facility also has a medical director overseeing various
Chapter 124  The Aging Patient 1113
aspects of medical care. An attending physician, who may or may
not be the medical director, performs patient visits every 30 to
60 days. Most SNFs also employ physical, occupational, and
speech therapists for rehabilitation care, dietitians, social workers,
and recreational therapists. Patients with moderate or severe
dementia constitute approximately 60% of patients living in
skilled nursing facilities. Although Medicare Part A provides
payment for rehabilitative stays of 100 days or less (with a copay-
ment for days 21 to 100), it does not finance long-term stays.
Such patients pay out of pocket, through long-term care insur-
ance, or through Medicaid, a joint federal and state assistance
program. Medicaid constitutes 47% of all payment sources for
skilled nursing facilitie care.
For patients with less complex care needs, assisted living
facilities or domiciliary care homes provide an alternative
arrangement for long-term care. Although these facilities vary
dramatically in their size and structure, most provide nonskilled
care for patients who need some assistance with activities of
daily living. Licensed nurses may be present during some speci-
fied periods of time, and other professions may visit the facility
intermittently to provide services such as physical therapy. Facili-
ties do not have medical directors, and patients normally con-
tinue to see a primary care provider in the outpatient setting.
Unlicensed staff, including nursing aides, provides most of the
personal care and assistance. Medicaid provides some reimburse-
ment for this type of care, but the majority of residents pay out
of pocket or through other assistance programs, such as Social
Security. For those with adequate means, a living option has
emerged that combines independent living, assisted living and
skilled care in one location. Continuing care retirement com-
munities allow residents to live within the same community
while moving through or between levels of care. They offer
residents convenient central resources, such as recreational and
dining facilities, transportation, and onsite health care.
  PACE
In the 1970s, a group providing care for older Chinese adults in
San Francisco developed a model of long-term care centered in
the community. Proponents of this model, entitled the Program
of All-inclusive Care for the Elderly (PACE), believed that the
community (rather than the institution) provided a better loca-
tion to meet the chronic care needs of older adults. From its start
as a community-based effort in California, the PACE model has
grown with the support of private foundations and Medicare
demonstration projects; now PACE is a benefit for elders who
qualify for both Medicare and Medicaid. Reimbursement is at
95% of the cost of nursing home care in the area where the patient
lives. Participants must be over 55 and certified by the state to be
eligible for nursing home care. The PACE program then uses
combined Medicare and Medicaid funds otherwise slated to pay
for the individual’s long-term care to provide care in the com-
munity; much of it coordinated through senior centers offering
an array of resources and services, including the following*:
• Adult day care, offering nursing; physical, occupational, and
recreational therapies; meals; nutritional counseling; social
work; and personal care
*Information from the National PACE Association website at www.npaonline.org.
1114 Section XVII  Geriatrics
• Medical care provided by a PACE physician familiar with
the history, needs, and preferences of each participant
• Home health care and personal care
• All necessary prescription drugs
• Social services
• Medical specialists such as audiology, dentistry, optometry,
podiatry, and speech therapy
• Respite care
When necessary, PACE participants are admitted to the hos-
pital or nursing home. These services are provided under the
auspices of the PACE program as part of the care package, and
the program bears full financial risk. The benefits of care for older
adults, particularly those of limited means, appear to be
substantial.
Geriatric Care
In caring for frail older adults with complex care needs, consulta-
tion with a geriatrician or geriatrics-focused team can often
provide highly useful information. The geriatrician can assist in
the assessment and management of the specific conditions or
situations described earlier. He or she can help with difficult deci-
sions regarding treatment options in the context of multiple
comorbidities and limited life expectancy, and offer advice on
appropriate level or setting of care for an older adult. Geriatri-
cians complete a minimum of 1 year of fellowship after residency
training in internal medicine or family practice. After training
they are eligible for board certification and qualified to work in a
number of different settings, including the hospital, long-term
care, home care, and outpatient clinics. Comprehensive assess-
ment by a geriatrician or geriatrics team includes components
detailed previously, including evaluation of the patient’s medical
condition, function, and social support. Normally the consultant
will work with an interdisciplinary team that may include a nurse
case manager, physician’s assistant, social worker, physical or
occupation therapist, pharmacist, psychologist and others. The
outcome of the geriatric assessment is a comprehensive plan for
safely restoring the patient to optimal function with mutually
agreeable and realistic goals of care.
In the setting of acute illness, geriatricians also provide impor-
tant services. As described earlier, acute-care-for-elders units can
improve patient care and prevent iatrogenic complications. Simi-
larly, once patients are medically stable, transfer to a specialized
geriatrics care unit, often termed a geriatric evaluation and man-
agement unit, may be possible, to provide a comprehensive
medical assessment and plan for transition of care. Early consul-
tation with a geriatrician and an interdisciplinary team in the
acute care setting can help in the management of complex medical
illness and with communication with patients and caregivers
about post-hospitalization options. Subsequent to hospitaliza-
tion, locating facilities or services that offer comprehensive care
by a geriatrician and interdisciplinary team would be ideal,
including a coordinated approach that uses specific strategies to
manage transitions of care.
For a deeper discussion on this topic, please see Section IV,
“Aging and Geriatric Medicine,” in Goldman-Cecil Medi-
cine, 25th Edition.
SUGGESTED READINGS
American Geriatrics Society 2012 Beers Criteria Update Expert Panel: American
Geriatrics Society Updated Beers Criteria for Potentially Inappropriate
Medication Use in Older Adults, J Amer Geriatr Soc 2012. http://
www.americangeriatrics.org/files/documents/beers/2012BeersCriteria
_JAGS.pdf.
American Geriatrics Society Expert Panel on the Care of Older Adults with
Multimorbidity: Guiding Principles for the Care of Older Adults with
Multimorbidity: An Approach for Clinicians, J Am Geriatr Soc 2012. http://
americangeriatrics.org/files/documents/MCC.principles.pdf.
Boyd CM, Darer J, Boult C, et al: Clinical practice guidelines and quality of care
for older patients with multiple comorbid diseases: Implications for pay for
performance, JAMA 294:716–724, 2005.
Campisi J: Aging, Cellular Senescence, and Cancer, Annu Rev Physiol 75:685–
705, 2013.
Covinsky KE, Pierluissi E, Johnston B: Hospitalization-Associated Disability:
“She Was Probably Able to Ambulate, but I’m Not Sure,” JAMA 306:93–2011,
1782.
Eckstrom E, Feeny DH, Walter LC, et al: Individualizing Cancer Screening in
Older Adults: A Narrative Review and Framework for Future Research, J Gen
Intern Med 28:292–298, 2012.
Federal Interagency Forum on Aging-Related Statistics: Older Americans
2012:Key Indicators of Well-Being. Federal Interagency Forum on Aging-
Related Statistics, Washington, DC, June 2012, U.S. Government Printing
Office. http://www.agingstats.gov/main_site/data/2012_documents/docs/
entirechartbook.pdf.
Flood KL, Maclennan PA, McGrew D, et al: Effects of an Acute Care for Elders
unit on costs and 30-day readmissions, JAMA Intern Med 173:981–987, 2013.
Fries JF: Aging, natural death, and the compression of morbidity, N Engl J Med
303:130–135, 1980.
Goode PS, Burgio KL, Richter HE, et al: Incontinence in Older Women, JAMA
303:2172–2181, 2010.
Hung WW, Ross JS, Farber J, et al: Evaluation of a Mobile Acute Care of the
Elderly (MACE) service, JAMA Intern Med 173:990–996, 2013.
Kim CS, Flanders SA: In the Clinic: transitions of Care, Ann Intern Med
158:ITC3-1, 2013.
Li RM, Iadarola AC, Maisano CC, editors: Why Population Aging Matters: A
Global Perspective. A booklet prepared in follow-up to the 2007 Summit on
Global Aging hosted by the U.S. State Department and the National Institute
on Aging, March 2007, National Institute on Aging and the National Institutes
of Health.
Libert S, Guarente L: Metabolic and Neuropsychiatric Effects of Calorie
Restriction and Sirtuins, Annual Rev Physiol 75:669–684, 2013.
Marcantonio ER: In the Clinic. Delirium, Ann Intern Med 154:ITC6-1, 2011.
Mosqueda L, Dong X: Elder Abuse and Self-neglect: “I Don’t Care Anything
About Going to the Doctor, to Be Honest…,” JAMA 306:532–540, 2011.
Pacala JT, Yueh B: Hearing Deficits in the Older Patient: “I Didn’t Notice
Anything,” JAMA 307:1185–1194, 2012.
Reuben DB: Medical Care for the Final Years of Life: “When You’re 83, It’s Not
Going to Be 20 Years,” JAMA 302:2686–2694, 2009.
Reuben DB, Wieland DL, Rubenstein LZ: Functional status assessment of older
persons: concepts and implications, Facts Res Gerontol 7:232, 1993.
Steinman MA, Hanlon JT: Managing Medications in Clinically Complex Elders:
“There’s Got to Be a Happy Medium,” JAMA 304:1592–1601, 2010.
Tinetti ME, Kumar C: The Patient Who Falls: “It’s Always a Trade-off,” JAMA
303:258–266, 2010.
Xue QL: The Frailty Syndrome: Definition and Natural History, Clin Geriatr Med
27:1–15, 2011.
XVIII
ESSENTIALS

Palliative Care
125  Palliative Care
Robert G. Holloway and Timothy E. Quill

1115
 125 
Palliative Care
Robert G. Holloway and Timothy E. Quill
  INTRODUCTION
Palliative care is both a philosophy of care and an area of special-
ization within several medical fields. The primary goal of pallia-
tive care is to minimize suffering and to support the best possible
quality of life for patients and their families. Patients with serious
and debilitating illness need and deserve excellent symptom
control, assistance with difficult medical decisions, effective com-
munication and collaboration among their providers, addressing
of psychosocial problems, and an empathetic presence that
fosters hope and healing relationships. Palliative care affirms life
by supporting the patient’s goals for the future in light of a full
understanding of their medical condition, potentially including
their hopes for cure, life-prolongation, relief from suffering, as
well as preparation for death when time is short. This process
includes exploring what would be left undone if treatment does
not go as hoped, who should make medical decisions for the
patient if decision-making capacity is lost, and what, if any, limits
might be set on aggressive therapy.
Palliative care provides an organized, highly structured system
for delivering care by an interdisciplinary team, including physi-
cians, nurses, social workers, chaplains, counselors, as well as
other health care professionals. Palliative care should be inte-
grated within various health care settings including the hospital,
emergency department, nursing home, home care, assisted living
facilities, and outpatient settings. Palliative care remains very
unevenly available, so many patients and families needlessly
suffer having either no, limited, or delayed access to appropriate
palliative care. Basic palliative care should be part of the tool kit
for all physicians who care for seriously ill patients, and specialty
palliative care should be available for the more challenging
symptom management and complex and often conflictual
medical decision making.
The integration of palliative care into the experiences of
patients and families is designed to meet several objectives. First,
to ensure that pain and symptom control, psychosocial distress,
spiritual issues, and practical needs are addressed throughout the
continuum of care. Second, to make certain that patients and
families obtain the information they need in an ongoing and
comprehensible manner to understand their prognosis and treat-
ment options. This process incorporates their values and prefer-
ences and is sensitive to changes in the patient’s condition over
time. Third, palliative care seeks to provide seamless care coordi-
nation across settings with high-quality communication among
providers. Finally, for those patients who are not going to recover,
palliative care prepares patients and families, to the extent pos-
sible, for the dying process and for death, including options for
1116
hospice care and opportunities for personal growth and bereave-
ment support.
  COMMON ILLNESS TRAJECTORIES
AND PALLIATIVE CARE
There are four distinct trajectories of functional decline before
dying (E-Fig. 125-1). These trajectories have major implications
for palliative care and health care delivery. Patients and families
likely have different physical, psychological, social, and spiritual
needs depending on the trajectory of their illness before they die.
Being aware of these trajectories can help providers deliver
appropriate care that integrates both disease-directed and pallia-
tive treatments.
Trajectory 1: Short Period of  
Evident Decline before Death
Cancer typifies this trajectory. Function is preserved until rather
late, followed by a predictable and precipitous decline over weeks
to months. The onset of decline usually suggests metastatic
tumor. A more predictable decline in function can assist in antici-
pating care needs, transitioning away from curative treatments
toward a more exclusive emphasis on palliation, and eventually
into hospice care. Not all malignancies follow this trajectory (e.g.,
prostate, breast) and some non-malignant conditions may follow
this course.
Trajectory 2: Chronic Illness with
Exacerbations and Sudden Dying
Congestive heart failure (CHF), chronic obstructive pulmonary
disease (COPD), end-stage liver disease, and AIDS typify this
trajectory. These organ system diseases represent chronic ill-
nesses with occasional, acute exacerbations (e.g., physiological
stress that overwhelms the body’s reserves), often requiring hos-
pital admission. Patients can have a return of function after an
exacerbation, but often not to the level of their baseline. They also
may die suddenly during an exacerbation, but it is difficult to
predict in advance. Prognosticating is very challenging in this
trajectory. When patients choose to forego or stop aggressive life
support, planning for aggressive symptom relief during a future
exacerbation is essential.
Trajectory 3: Prolonged Dwindling
Dementia and frailty typify this trajectory. These patients have a
prolonged course of physical and cognitive decline and become
increasingly frail. Additional diagnoses include other neurode-
generative conditions (e.g., Parkinson’s disease, amyotrophic
lateral sclerosis) and patients with multiple moderate to severe
 Chapter 125  Palliative Care 1116.e1

Cancer Organ System Failure

High
Function

Low

Death Death
A Time B Time

Dementia/Frailty Stroke/Hypoxic Ischemic Encephalopathy

Death Death
C Time D Time
E-FIGURE 125-1  In patients with cancer, function typically remains high until the very late stages of disease (A); this is the model of illness for
which hospice care was developed. Patients with chronic organ system failure such as heart failure or obstructive lung disease are often ill for pro-
longed periods, with frequent exacerbations followed by recovery of function (B). Patients with dementia also follow a chronic course, with dwindling
reserve over time (C). Sudden neurological injury (stroke, hypoxic ischemic injury, traumatic brain injury) often results in a sudden decrement of
well-being and function associated with a high mortality (D). Recovery is prolonged and slow with frequent setback and accumulating disability over
time. (Modified from Murray SA, Kendall M, Boyd K, et al: Illness trajectories and palliative care, BMJ 330:1007–1011, 2005.)

comorbidities (e.g., arthritis, visual impairment, past mild strokes,
diabetes with neuropathy). Gradual decline in function, weight
loss, fatigue, and low levels of activity are core features. Caregiver
burden is usually immense. Prognosticating survival is difficult
and complications, such a pneumonia and fractures, may be ter-
minal events. The benefits and burdens of artificial nutrition and
hydration must be balanced in the late stages.
Trajectory 4: Sudden, Severe   (e.g., “I am afraid I have some difficult news to share with you”) is a
Neurological Injury
Sudden impairment trajectories are those that stem from sudden
neurological injury that can lead to profound cognitive and func-
tional impairment. These include stroke, hypoxic ischemic
encephalopathy, and traumatic brain injury. The vast majority of
deaths occur either early after the event when treatments are
withheld or withdrawn, or in the chronic stage in survivors who
have accumulating debility (these events represent the leading
cause of adult disability). At the extremes of impairment are per-
sistent vegetative states, minimally conscious states, and locked-in
syndrome. But there is a vast spectrum of severe impairments
short of these extremes that raise questions about how to manage
potentially severe debility with little or uncertain chances of
improvement. This trajectory requires a health care system
responsive to negotiating goals of treatment with patients and
surrogates who may consider these future health states to be
“worse than death.”
  COMMUNICATION SKILLS AND
NEGOTIATING GOALS OF TREATMENT
Excellent communication skills are central to palliative care:
communication with patients, family, other physicians, nurses,
and other members of the health care team. The overarching aim
is to assist the patient and family in establishing the goals of
current and future treatment in a process of shared decision
making. When negotiating goals of treatment in palliative care,
the focus is often to assist with the following decisions: to
help decide types and aggressiveness of disease-directed thera-
pies; to ensure optimum palliation of symptoms; to assist in
hospice determinations; to discuss initiating, withholding or
withdrawing therapies; to facilitate advance care planning; and to
initiate surrogate decision-making if the patient lacks capacity.
These discussions occur at various time points in the course of
advancing illness when new and important information is learned
and needs to be communicated to the patient and family. The
need to renegotiate goals should also be anticipated when trig-
gers of advancing disease suggest limited life expectancy or exces-
sive suffering. These discussions are almost always variants of
“bad news” discussions.
The overall approach to communication and negotiating goals
of care in each of these scenarios is similar (Table 125-1). This
includes running an effective family meeting with or without the
patient present. Initial elements include establishing the proper
setting, identifying key stakeholders, and “doing your home-
work” (i.e., discussing potential plans with all relevant subspecial-
ties who may have communicated with the patient and families).
When the meeting begins, find out what the patient and family
understand about the medical condition and ask about what
added information they want. Keeping an open mind and trying
Chapter 125  Palliative Care 1117
to hold back on a fixed agenda (e.g., to “get the DNR” or to “stop
futile care”) helps clinicians allow patients and families sufficient
time to “tell their stories” and provides the context within which
effective decision making can occur. In general, the more patients
and families speak in the early parts of such meetings, the better.
The provider then needs to share prognostic information and
discuss the benefits and burdens of the available treatment
options. Alerting the patient or family of impending bad news
useful initial communication strategy. The amount of informa-
tion should be paced with frequent pauses to allow time for emo-
tional responses. Comprehension should be frequently checked,
and questions should be encouraged using an “ask-tell-ask” strat-
egy. The skilled clinician can flexibly assess, probe, and pace the
content and depth of the discussion in an emotionally responsive
(acknowledge, explore, empathize, and legitimize) and culturally
competent manner. This includes the ability to understand and
respect diverse religious practices and differing preferences about
degree of truth telling. When appropriate, the clinician should
make recommendations based on scientific knowledge as well as
awareness of a patient’s values and preferences, and be prepared
to help resolve conflicts among patient, family members, and
providers. Finally, providers need to develop strategies to pre-
serve and potentially reframe hope, including ways to “hope for
the best” and simultaneously “prepare for the worst.” Commit-
ments to minimize suffering and to not abandon the patient and
family are essential. At the end of the discussions, the provider
should summarize key aspects of what was reviewed and establish
a follow-up plan for future communications and treatments.
Estimating and Communicating Prognosis
A core component of information shared in the palliative care
setting is prognosis. Understanding prognosis is central to making
decisions (e.g., treatment, comfort measures, hospice). Prognosis
is a prediction of possible future outcomes of a disease (e.g.,
TABLE 125-1  GENERAL STRATEGY FOR
COMMUNICATING AND NEGOTIATING
GOALS OF CARE IN COMMON
PALLIATIVE CARE SETTINGS
Step 1 Prepare and establish setting
Do not have a rigid preset agenda
Step 2 Ask patient and family what they know and understand
Provide sufficient time for patients and families to “tell
their story”
Active listening skills
Step 3 Find out how much patient and family want to know
Acknowledge and explore emotions
Step 4 Give information in small amounts, and frequently
check understanding
Discuss prognosis and benefits and burdens of
treatment options
Be mindful of overly optimistic and pessimistic
predictions
Be prepared to make recommendations
Step 5 Respond to emotions and empathetic response
Convey honesty and reframe hope
Use “I wish” statements
Step 6 Summarize, establish and implement plan, follow-up
Possible time-limited trial
1118 Section XVIII  Palliative Care
survival, symptoms, function, quality of life, family and financial
impact) with or without treatment. Most patients and families
want to know prognosis. Since there are some patients and fami-
lies that may not want to know prognosis or want it communi-
cated in a particular way, it is essential to begin by finding out
what the patient and family knows and wants to know.
Inaccurate predictions may lead to poor decision making.
Indeed, physicians tend to overestimate survival in patients with
advanced cancer by about 30%, and the bias is more pronounced
the longer the physician-patient relationship. Overly optimistic
predictions can lead to overuse of ineffective or unwanted
disease-directed treatment, delay in hospice referrals, false expec-
tations, unnecessary tests and procedures, and poor symptom
control. Therefore, accurately estimating and communicating
prognosis is central to optimal decision making in advanced
illness and at the end of life.
In advanced illnesses, common factors found to be predictive
of short-term survival (i.e., less than 6 months) include perfor-
mance status, anorexia-cachexia syndrome, delirium, and
dyspnea. In addition to a physician’s subjective predictions of
survival, there exist models to assist with prognostic estimates,
including generic models for particular populations (e.g., hospice
enrollees) as well as disease-specific models (e.g., cancers, heart
failure, liver disease, stroke, AIDS, spinal cord compression).
Hospice eligibility criteria also differ for specific diseases. While
not uniformly reliable, they can be useful in formulating esti-
mates where prognosis might be 6 months or less if the disease
is allowed to run its natural course (a prognostic criterion).
For an individual patient, however, prognostic uncertainty
remains the rule. Therefore, it is important to integrate both evi-
dence and experience-based medicine, and present the informa-
tion in formats tailored to the particular patient (verbal
descriptions, numeric, frequencies, or graphics). Prognostic esti-
mates should be bounded with ranges to convey realistic uncer-
tainty, being sure to allow for exceptions in both directions. For
example, “in my experience, patients with your condition live on
average a few weeks to a few months. It could be longer, but it could
also be shorter.” For survival-predominate prognoses (e.g., “How
long do I have?”), be mindful of overly optimistic prognoses,
remembering to think of and convey the lower bound (e.g., “some
may live longer, but others may, unfortunately, live shorter”). For
outcome-predominant prognoses (e.g., “What will life be like?”),
be mindful of overly pessimistic predictions, remembering the
power of adaptation and engendering hope by helping patients
and families find new meaning.
  SUFFERING AND SYMPTOM MANAGEMENT
Palliative care aims to relieve suffering, which is defined as severe
distress related to events that threaten the stability of personhood
or interconnectedness of the physical, psychological, spiritual
and social aspects of self. Beginning with simple, open-ended
screening questions, such as “In what ways are you suffering most?”
and following with more domain-related screening questions
(e.g., physical, psychological, spiritual, social) may allow for more
probing and multidimensional inquiries to better understand the
various sources of and contributions to an individual’s suffering.
One of the first steps in the care of any seriously ill patient is
to control pain and other forms of physical suffering. There are
striking similarities between the burden of symptoms experi-
enced in patients dying of cancer and non-cancer conditions.
Although the profile of symptoms may differ, each disease carries
with it troubling symptoms that can potentially be addressed and
managed.
Physical Symptoms
Pain
Uncontrolled pain dominates all other experiences, and most
pain can be relieved using basic pain management strategies. This
includes a detailed history and physical examination, categoriz-
ing the likely type or types (i.e., somatic, visceral, neuropathic)
and severity (rated on a 0-10 scale) of pain, knowledge about
proper opioid dosing strategies, and judicious use of consulta-
tions and invasive interventions (e.g., nerve blocks, epidural anal-
gesia). The overarching three-tiered approach is to use nonopioids
(e.g., acetaminophen, nonsteroidal anti-inflammatory drugs) for
mild pain, weak opioids (e.g., hydrocodone or codeine) for mild-
to-moderate pain, and strong opioids (e.g., morphine, hydromor-
phine, fentanyl, methadone) for moderate to severe pain.
Risk factors for potential opioid abuse or misuse should be
screened for even in the presence of clearly defined terminal
illness, including any lifetime personal or family history of opioid,
alcohol, or other substance abuse. If risk factors are present
(about 20% of the population), special precautions should be
taken to minimize the risk of abuse, including clearly defined and
adhered to prescribing contracts and strict limits and expecta-
tions about renewals and dose alteration processes. One single
prescriber should be responsible for all opioid prescriptions and
renewals, and one pharmacy should be used. If clinicians are
inexperienced with such prescribing, formal consultation with
specialists in palliative care and/or addiction medicine should be
considered.
Most seriously ill patients with chronic moderate to severe
pain should be initially started on around-the-clock dosing using
a short-acting opioid. Table 125-2 shows the equianalgesic
dosing, usual starting doses, half-life, and duration for the com-
monly available opioid agents. Once the total daily dosing has
been determined (sum of all scheduled and “as needed” doses),
the patient may be switched to a long-acting opioid to cover the
baseline requirements. As needed opioids for breakthrough pain
should be approximately 10% of the total daily dose every 1 to 2
hours orally or every 30 to 60 minutes subcutaneously or intra-
venously. If a patient is requiring more than 4 to 6 breakthrough
doses per day, he should be in contact with the prescribing clini-
cian for re-evaluation of dosing. Continuous intravenous or sub-
cutaneous infusions of opioids may be needed for rapid control
of severe pain. Methadone is useful in palliative care because of
its excellent oral bioavailability, lack of active metabolites in renal
impairment, low cost, flexible route of administration (PO, IV,
SC), and possible effect on both neuropathic and somatic pain.
However, it does have a dose-dependent, progressively long half-
life and arrhythmogenic potential.
Constipation occurs with all opioids, and it should be antici-
pated and treated. Other predictable but less common side
effects include nausea, myoclonus, urinary retention, pruritis,
and delirium. Some of these side effects are time-limited with


TABLE 125-2  EQUIANALGESIC TABLE FOR ADULTS

USUAL STARTING DOSES
ADULT > 50 KG; FOR OPIOID NAÏVE
PATIENTS
EQUIANALGESIC DOSE (♦ ½ dose for elderly, or severe renal
(for chronic dosing) or liver disease)
IM/IV
onset PO
PAIN MEDICATION 15-30 min onset 30-60 min PARENTERAL PO HALF-LIFE DURATION RELATIVE GENERIC COST
Moderate to Morphine 10 mg 30 mg 2.5-5 mg IV/SC 5-15 mg q3-4h 1.5-2 h 3-7 h $ (IR tablet)
Severe q3-4h (IR or Oral (includes active $$ (solution)
(♦1.25-2.5 mg) Solution) metabolites) $$ (ER generic)
(♦2.5-7.5 mg) $$$$ (ER brand)
Oxycodone Not Available 20 mg Not Available 5-10 mg q3-4h 3-4 h 4-6 h $$ (comb. w/APAP)
(♦2.5 mg) $$ (IR tablet)
$$$ (solution)
$$$ (ER brand)
Hydromorphone 1.5 mg 7.5 mg 0.2-0.6 mg IV/SC 1-2 mg q3-4h 2-3 h 4-5 h $ (tablet)
q2-3h (♦0.5-1 mg) $$$ (solution)
(♦0.2 mg) $$$$ (ER tablet)
Methadone Oral: IV 24 hr oral Oral morphine :  1.25-2.5 mg q8h 2.5-5 mg q8h 15-190 h 6-12 h $ (tablet)
2 : 1 morphine dose methadone ratio (♦1.25 mg) (♦1.25-2.5 mg) (N.B. large $ (solution)
<30 mg 2 : 1 variation)
31-99 mg 4 : 1
100-299 mg 8 : 1
300-499 mg 12 : 1
500-999 mg 15 : 1
1000-1200 mg 20 : 1
>1200 mg Consider consult
Fentanyl 100 µg 24 hr oral morphine Initial patch dose 25-50 µg IV q1-3h 12.5 µg/hr q72h 7 h (lozenge) 60+ min (lozenge) $$$ (transdermal)
(Duragesic Patch) (single dose) dose (♦12.5-25 µg) (transdermal) 12-22 h (buccal) 120+ min (buccal; $$$$ (buccal)
(T1/2 life and 30-59 mg 12.5 µg/hr (♦Not 13-22 h not well studied) $$$$ (buccal)
duration of 60-134 mg 25 µg/hr recommended for (transdermal) 48-72 h
parenteral doses 135-224 mg 50 µg/hr opioid naïve) (transdermal)
variable) 225-314 mg 75 µg/hr
315-404 mg 100 µg/hr
Chapter 125  Palliative Care

Mild to Codeine 130 mg 200 mg 15-30 mg IM/SC 30-60 mg q3-4h 3 h 4-6 h $$ (combination with APAP)
Moderate (IM only) q4h (♦15-30 mg) $$$ (tablet)
(♦7.5-15 mg)
IV Contraindicated
Hydrocodone Not Available 30 mg Not Available 5 mg q3-4h 3 h 4-6 h $$ (comb. with ibuprofen)
(♦2.5 mg) $ (combination with APAP)
1119
1120 Section XVIII  Palliative Care
initiation (e.g., nausea), while others can be managed by dose
reduction or opioid rotation (e.g., myoclonus, delirium). Major
respiratory depression is extremely rare if the opioid is dosed
appropriately and proportionate to the severity of symptoms.
In the absence of a prior personal or family history of drug
and alcohol abuse, addiction is rare in the presence of serious
illness, but physical dependence (i.e., withdrawal symptoms
upon abrupt cessation) and tolerance (i.e., decrease in drug
effect over time) should be expected. Naloxone should be rarely
used unless a clear overdose is suspected, or if life-threatening
complications occur. Special caution about opioid prescribing
is needed in the elderly and debilitated patients, and recom-
mended starting doses should be reduced by approximately
50%. There are additional opioid selection recommendations
for patients with renal insufficiency (avoid morphine and
codeine; use hydromorphone and oxycodone with caution;
methadone and fentanyl (optimal) and hepatic insufficiency
(cautiously use fentanyl, hydromorphone, oxycodone, or metha-
done; avoid or decrease dose of morphine).
Non-pain
There are numerous non-pain physical symptoms that can domi-
nate and overwhelm the clinical picture in any given patient.
These include dyspnea, nausea and vomiting, constipation,
anorexia-cachexia, fatigue, bleeding, agitation, apathy, myoclo-
nus, pruritis, and specific functional deficits. Each symptom
requires a structured approach to the history and physical exami-
nation with a full exploration of the potential etiologies and treat-
ment options; informed by the prognosis and preferences of the
patient and family. (For practical information geared to basic pal-
liative management of pain and other symptoms, see Quill TE,
Holloway RG, Shah MS, et al: Primer of Palliative Care, ed 5,
Illinois, 2010, American Academy of Hospice and Palliative
Medicine.)
Psychological Distress
Depression, anxiety, and delirium are all common in the palliative
care setting. They are frequently under-recognized and under-
treated. Appropriate diagnosis and treatment can improve quality
of life.
Nearly all patients in palliative care and their families experi-
ence sadness, preparatory grief, and transient anxiety as illness
advances. Grief or normal sadness is often experienced in waves
with retained capacity for pleasure. Depression is more endur-
ing, persistent and intense, and may be associated with hope-
lessness, helplessness, worthlessness, and guilt. Two screening
questions assessing depressed mood and anhedonia include:
“Are you depressed?” and “Do you have much interest and pleasure
in doing things?” One should be cautious about overusing somatic
symptoms to diagnose depression (e.g., fatigue, anorexia, sleep
disturbance) because they frequently overlap with physiological
changes associated with advanced disease. For depression and
anxiety, consider and rule out contributions from physical
symptoms (e.g., uncontrolled pain), medical causes (e.g., hypo-
thyroidism, hyperthyroidism), and medications. Effective phar-
macological and non-pharmacological treatments exist for both
depression and anxiety, though treatment selection depends
on symptom intensity, patient prognosis, and treatment benefits
and burdens. Other members of the interdisciplinary team
(social worker, chaplain, and psychologist) often play a critical
role in assessment and ongoing management.
Delirium, an acquired and fluctuating disorder of conscious-
ness and cognition, occurs commonly in the palliative care
setting. The level of psychomotor activity can vary from hyperac-
tive (“agitated” delirium) to hypoactive (“quiet” delirium). Nearly
80% of the delirium in the palliative care setting is the hypoactive
variant. As a result, it is often under-diagnosed or misdiagnosed
as depression and fatigue. The most common causes of delirium
in palliative care include medications (e.g., opioids), metabolic
disorders due to progressive organ failure, and infection. Meticu-
lous attention to the history from collateral sources (e.g., nurses,
caregiver) and a detailed medication history are essential for an
accurate diagnosis. While delirium may reverse if an obvious
cause is identified and removed, frequently it represents an
important marker of progressive illness so cognitive improve-
ments may be transient and incomplete. In addition to etiology-
specific treatment (e.g., change or stop medications, treat
infection, oxygen, hydration, biphosphonates), environmental
interventions are recommended for all patients (e.g., quiet reas-
surance, gentle re-orientation, optimize sensory input, minimize
night disruptions). Pharmacological management should be used
sparingly and cautiously, and may include antipsychotic medica-
tions, benzodiazepines, and pyschostimulants (for the hypoac-
tive variant).
Spiritual and Existential Pain
Spiritual and existential distress is prevalent in patients and fami-
lies with serious illness, especially at the end of life. Spirituality
is about one’s relationship with and responses to transcendent
questions that confront one as a human being (e.g., search for
meaning and purpose in life). Religion is a set of texts, practices,
and beliefs about the transcendence shared by a community.
Spirituality is broader than religion. The spiritual issues of seri-
ously ill and dying patients often center on questions of meaning,
value, and relationships. Dying patients want to be assured of
their value in the face of actual or perceived threats to their intact-
ness as a human being (e.g., physical and cognitive declines,
altered appearances). Spirituality can help people find hope in
despair and help restore purpose.
One of the goals of palliative care is to relieve spiritual and
existential distress. Patients and families often welcome such dis-
cussions. Examples of open-ended questions to facilitate this
dialogue include: “Are you at peace with all of this?” and “Is faith
(religion, spirituality) important to you?” Acknowledgement and
empathetic listening are the most important responses for most
clinicians, as opposed to trying to provide “correct answers.”
Other strategies for fostering hope and meaning include devel-
oping caring relationships, setting attainable goals, involving the
patient in the decision-making process, affirming the patient’s
worth, using lighthearted humor (when appropriate), and remi-
niscing with life review. It is important, however, to know one’s
professional boundaries and refer to chaplains or clergy from the
patient’s faith traditions if questions move beyond the realm of
general exploration (e.g., “It sounds like it would be good to explore
this with someone with more experience than I have. Would it be okay
for me to send our chaplain in to discuss this with you?”).

The Role and Use Of Diagnostic Tests   Request for Hastened Death
and Invasive Procedures
Several questions should be considered in determining the
appropriateness of aggressive medical or palliative interventions
near the end of life: What is the goal or expected outcome of the
proposed intervention? What is the probable efficacy of the inter-
vention? What is the patient’s baseline level of function and life
expectancy? What are the potential side effects and burdens of
the intervention? What are the patient’s and family’s wishes,
values, and preferences?
The range of medical and palliative options available is huge,
so the challenge is to determine what makes sense to enhance the
well-being of this patient at this particular stage of illness. Pallia-
tive interventions range from pure symptom management and
support to invasive options, such as chemotherapy, radiotherapy,
surgical/endoscopic interventions, stenting procedures, thora-
centisis, paracentesis, pericardiocentesis, home inotropic therapy,
non-invasive ventilation, antibiotics, or transfusions. The chal-
lenge is to individualize discussions, so that patients can take full
advantage of treatments that will help them meet their goals
without having their experience dominated by near futile inva-
sive interventions.
The Role of Hospice
Hospice care is a specialized form of palliative care aimed
at those patients and families in the terminal stages of illness.
In 2011, 1.65 million patients were served by hospice pro-
grams in the United States. Median length of stay on hospice
is less than 3 weeks. In order to qualify for the Medicare
Hospice Benefit, two physicians must sign a statement cer-
tifying that the patient’s prognosis for survival, if the disease
runs its natural course, is likely to be 6 months or less.
Hospice criteria exist to assist in making these determina-
tions for common medical conditions. Hospice care can be
delivered in hospitals, patient’s homes, nursing homes, or
dedicated “hospice houses.” The Medicare Hospice Benefit
covers most costs related to terminal care without a deduct-
ible, which includes palliative medications, nursing oversight,
supplies, and bereavement care. Hospice also covers up to
4 hours of custodial caregiver services per day; however,
family and/or friends must provide the remaining care if
the patient is to stay at home. Hospice it does not cover
custodial caregiver serives if the patient is admitted to a
nursing facility.
Cancer continues to be the most common diagnosis for
patients dying in hospice programs. However, the prevalence
of non-cancer diagnoses is increasing and now represents
more than 50% of all hospice admissions. Discussing hospice
with patients and families can be challenging. First, it is often
initially viewed as a “bad news” discussion given that patients
and families need to confront the fact that disease-directed
treatment is no longer effective and that prognosis is likely
to be 6 months or less. Second, given the reimbursement
restrictions, patients may also need to forgo particular types
of treatment that are important to them (e.g., acute hospital
or ICU-level care, dialysis, chemotherapy, milrinone for heart
failure).
Chapter 125  Palliative Care 1121
 
and Last Resort Options
The prevalence of suicidal ideation and suicide attempts is higher
in patients with advanced life-limiting illness compared to those
without serious disease. In Oregon where physician-assisted
suicide is legally permitted (subject to safeguards), the preva-
lence of a patient’s wanting to explore a health care professional’s
willingness to help hasten death is about 1/50, whereas only
about 1/500 die using physician-assisted suicide. The motivation
behind such initial explorations may relate to relentless physical
suffering, disfigurement, hopelessness, loss of dignity, fear of
being a burden, or a “cry for help.” Most enduring requests from
patients with progressive medical illnesses, however, arise not
from inadequate symptom control, but from a patient’s belief
about dignity, meaning, and control over the circumstances of
death. Although some providers might be uncomfortable with
exploring such requests, they need to be approached systemati-
cally with a diligent search to understand the root causes before
responding.
A careful evaluation includes a precise clarification and explo-
ration as to exactly what the patient is asking and why. Is the
request based on transient thoughts about ending life (common)
or a serious appeal for assistance (relatively rare)? Does the
request occur in the context of intense physical suffering, psycho-
logical despair, an existential crisis, or a combination of factors?
Does the patient have full decision-making capacity? Is the
request proportionate to the level of suffering? Evaluating such
requests can be emotionally fatiguing and conflicting, and clini-
cians need self-awareness in distinguishing their emotions from
the patient’s, including tending to one’s own support by sharing
the burden of such requests with trusted colleagues.
Responding to such a request should first include intensifica-
tion of a search for potentially reversible contributions to suffer-
ing. This will often include treating physical and psychological
symptoms, aggressive attempts to foster hope, consulting psy-
chiatrists or spiritual counselors, and creative brainstorming with
trusted colleagues and team members. Some requests for has-
tened death persist, despite optimal palliative care. In such cir-
cumstances, the clinician should seek out a second opinion and
confront the possibilities. These possibilities include withdrawal
of life-sustaining interventions, palliative sedation, voluntary ces-
sation of oral intake, and assisted suicide (illegal in the United
States except for the states of Oregon, Washington, Vermont, and
Montana). While it is important to support the patient, the clini-
cian must balance integrity and non-abandonment. This may
include drawing specific boundaries of what the clinician can and
cannot do, while still searching in earnest for a mutually accept-
able solution.
  COMMON ETHICAL CHALLENGES
IN PALLIATIVE CARE
Inadequate Treatment of Pain and the Myth
that Pain Medication Hastens Death
Evidence abounds that pain is under-treated in many medical
settings, including those patients who are severely and even ter-
minally ill (especially women, the elderly, minorities and those
1122 Section XVIII  Palliative Care
who are cognitively impaired). Some under-treatment stems
from fears about addiction as well as concerns about the possibil-
ity of hastening death. When patients with prior addiction prob-
lems are excluded, the incidence of new addictive behavior when
opioids are used to treat pain in those with a well-defined, serious
illness is rare. Similarly, there is very little data to suggest that
properly prescribed opioids hasten death. In fact, current evi-
dence supports the idea that opioids may prolong life in these
patients and enhance quality of life in those with advanced illness
and major pain or dyspnea.
Addiction and diversion exist in medically ill populations.
Alcoholism and substance abuse exist in medically ill populations
as they do in all other parts of society. When patients with such
risk factors develop painful, potentially life-limiting medical con-
ditions, they deserve adequate pain treatment, but with extreme
caution because of the risk of reactivating or aggravating abuse
behavior, including diversion of prescription drugs for recre-
ational purposes. Prescribing contracts that specify one single
medical prescriber, set amounts around the clock and as needed
limits, face-to-face encounters for all renewals, and dose adjust-
ments only after direct conversation with the prescriber, are all
essential parts of the plan. Consultations with experts in palliative
care and/or substance abuse should be requested if there is any
difficulty adhering to the contract.
When Patients and Families   Caregivers will frequently ask about intravenous hydration. In
Want Near Futile Treatment
The patient autonomy movement in medicine has led to patients
and families taking an active role in their own medical decision
making. This is generally a positive development except in two
circumstances: 1) when physicians stop taking an active role
using their expertise to guide patients in their decision making,
thereby abdicating their professional responsibility of advocating
for the best possible treatment based on the patient’s medical
condition and personal values, and 2) when patients or their
families want and even demand near futile treatment toward the
end of their lives despite physician’s advice that treatment has
much more burden than benefit. Physicians might try to respond
to patients who want “everything” by suggesting that they want
to try everything that is “more likely to help than harm,” but avoid
any treatment that is most likely to “do more harm than good.”
However, some patients and families will accept no limits on
treatment no matter what the burden and the improbability of
success. Of course, truly futile treatment should not be offered or
provided upon request, but absolute futility has been difficult to
define in many cases.
Feeding Tube Questions When Patients   ness of breath is relatively uncommon, but can be treated with
Stop Eating and Drinking
Many patients gradually stop eating and drinking as a natural part
of the dying process, but this can be very hard for patients and
families to accept in light of fears about “starving to death” and
in view of seemingly simple technologies that can potentially
combat and even reverse the problem. In fact, with few excep-
tions, feeding tubes have not been show to prolong life in most
advanced illnesses such as metastatic cancer or advanced
Alzheimer disease. It is important to know about the exceptions
(e.g. esophageal and oropharyngeal cancers, amyotrophic lateral
sclerosis, acute stroke), but also to have an open discussion about
the naturalness of diminished eating and drinking as many ill-
nesses progress. If there is uncertainty about whether a particular
patient might benefit from a feeding tube, and patient and family
are clear about wanting to give it a try, the clinician can frame the
decision as a “time-limited trial” to see how the patient tolerates
tube feeding psychologically as well as physiologically in a speci-
fied timeframe. A nasogastric tube has a built-in time limit of
about a month before a PEG tube needs to be inserted as a poten-
tial framework for such a trial. Explaining to patients and families
about the positive aspects of natural feeding, even in small
amounts, of real food (smell, taste, and enjoyment) may help
focus the decision on important quality of life issues (that may
otherwise be ignored), rather than more technical, physiological
issues.
  LAST HOURS AND DAYS OF LIVING
An integral aspect of palliative care is preparing and guiding the
patient and caregivers through the dying process. When progno-
sis is measured in hours to days there are typical signs and symp-
toms that usually occur. Patients become weak and fatigued and
gradually lose mobility. There is also a gradual and predictable
decrease in food and fluid intake. Most patients do not experi-
ence hunger and thirst, and the associated mouth dryness that
occurs is easily palliated with small sips or sponges of cold water.
rare instances, intravenous or subcutaneous fluids may temporar-
ily improve mental status and energy in the final days of life. Most
of the time, however, the benefits are difficult to discern and the
excessive fluids may contribute to end-of-life physiologic condi-
tions (edema, ascites, effusions, and pulmonary secretions) that
do not improve longevity and may worsen comfort.
As patients become weaker, there is a predictable decrease in
the level of consciousness with increasing periods of somnolence
eventually giving way to a comatose state. Education about this
process should include associated changes in respiratory patterns
and to anticipate progressive periods of apnea, interspersed with
episodes of hyperpnea and deep breathing (Cheyne-Stokes res-
pirations). During this process caregivers often feel they are on
“a roller-coaster ride” and gentle guidance on what to expect can
allay concerns. As consciousness wanes, swallowing slows and
the cough reflex weakens. As a result, saliva pools in the oropha-
ynx and can result in noisy respiration (“death rattle”), which
can usually be palliated to some degree with transdermal scopol-
amine, gylcopyrrolate (PO, IV, SC) or sublingual atropine oph-
thalmic drops. Families should be reminded that these symptoms
are a natural part of the dying process, and that persistent short-
opiates and benzodiazepines, if needed.
As death approaches, reduced perfusion causes cooling and
cyanosis of the extremities and a decrease and darkening of the
urine. Most deaths are relatively peaceful, but a few can be pre-
ceded by periods of intense agitation and restlessness (hyperac-
tive terminal delirium). Antipsychotic medications and
conventional doses of benzodiazepines can usually treat terminal
delirium. Prior to and when death occurs, families should be
encouraged to carry out cultural or religious rituals that are
important to them. Providers should express condolences, be

available for questions and responsive to intense emotional reac-
tions that sometimes occur. A short condolence card or letter is
almost always appreciated. If possible, efforts should be made to
follow-up with family members and caregivers deemed at risk for
complicated bereavement and grief.
  PROSPECTUS FOR THE FUTURE
Palliative care became an officially recognized subspecialty
within the United States in 2006. Physicians from 10 specialties
can be board certified in hospice and palliative medicine includ-
ing: family medicine, internal medicine, emergency medicine,
pediatrics, physical medicine and rehabilitation, anesthesiology,
psychiatry, neurology, radiology, and surgery. As patients live
longer with chronic illness, there will be an increasing need to
fully integrate palliative care providers and programs within hos-
pitals, nursing homes, and the outpatient setting; and to ensure
that all primary care providers and non-palliative specialists
develop the skill sets needed to provide basic palliative care.
Chapter 125  Palliative Care 1123
There is a compelling need for research to better define the
optimal timing, setting, and delivery of palliative care to improve
the quality of life and lessen the suffering of patients and families
with advanced illness.
SUGGESTED READINGS
Goldstein NE, Morrison RS, editors: Evidence-Based Practice of Palliative
Medicine, Philadelphia, 2013, Elsevier.
Moryl N, Coyle N, Foley KM: Managing an acute pain crisis in a patient with
advanced cancer: “This is as much of a crisis as a code”, JAMA 299:1457–1467,
2008.
National Consensus Project for Quality Palliative Care: Clinical Practice
Guidelines for Quality Palliative Care, ed 3, Pittsburgh, PA, 2013. http://
www.nationalconsensusproject.org.
Quill TE, Abernethy AP: Generalist plus specialist palliative care–creating a more
sustainable model, N Engl J Med 368:1173–1175, 2013.
Quill TE, Holloway RG, Shah MS, et al: Primer of Palliative Care, ed 5, Glenview,
2010, American Academy of Hospice and Palliative Medicine.
XIX
ESSENTIALS

Alcohol and Substance Abuse

126  Alcohol and Substance Abuse
Richard A. Lange and L. David Hillis

1125
 126 
Alcohol and Substance Abuse
Richard A. Lange and L. David Hillis
  ALCOHOL ABUSE
Alcohol abuse is a major public health problem. In 2010, an esti-
mated 2,735,511 deaths worldwide were attributable to alcohol
use. About 58.3 million people in the United States (nearly one
quarter of persons aged 12 years or older) participate in binge
drinking, and almost 16 million (6.2% of the population aged 12
or older) report heavy drinking, defined as binge drinking on at
least 5 days in the past month. Alcohol use is the third leading
preventable cause of death in the United States (exceeded only
by cigarette smoking and obesity) and claims over 80,000 lives
annually. In 2011, an estimated 11% of persons aged 12 years or
older drove under the influence of alcohol at least once. Alcohol
use contributes to roughly 31% of all fatalities caused by motor
vehicle accidents, or approximately 10,000 vehicular deaths
annually, and is a major contributor to risky sexual behavior,
domestic violence, homicide, and suicide. For the year 2006, the
estimated economic cost of excessive drinking in the United
States was $223.5 billion: 72% from lost productivity, 11% from
healthcare costs, 9% from criminal justice costs, and 7.5% from
other effects.
  DEFINITION AND EPIDEMIOLOGY
The American Psychiatric Association has specific criteria for the
diagnosis of alcohol use disorder; these 11 criteria are described in
the Diagnostic and Statistical Manual of Mental Disorders, fifth
edition, and are listed in Table 126-1. Alcohol use disorder is
further characterized as mild, moderate, or severe, based on the
number of criteria the individual meets; 2 to 3 criteria indicate a
mild disorder, 4 to 5 criteria a moderate disorder, and 6 or more
a severe disorder. The so-called binge drinker is defined as one
who typically consumes five or more drinks on a single
occasion.
Among individuals aged 12 or older, whites are more likely to
report current alcohol use than other racial groups (Fig. 126-1),
and men are more likely than women to be drinkers (57% versus
47%, respectively). The average age at first alcohol use is 17 years;
65% of college students currently use alcohol (Fig. 126-2); and
more than half of all college students admit to heavy episodic
drinking. Although the prevalence of ethanol use is highest in
individuals younger than 30 years of age, survey data suggest that
about two thirds of persons over age 30 consume it.
  PHARMACOLOGIC AND METABOLIC FACTORS
After oral ingestion, alcohol is absorbed predominantly in the
small intestine, and its rate of intestinal absorption is accelerated
by the simultaneous ingestion of carbohydrates and carbonated
1126
beverages. Prolonged retention of alcohol in the stomach, as
occurs when food is consumed before drinking, delays alcohol
absorption because absorption in the stomach is considerably
slower than in the duodenum. Once in the blood, alcohol equili-
brates rapidly across all membranes, including the blood-brain
barrier, thereby accounting for the prompt onset of its euphoric
effects. Maximal blood alcohol concentrations are reached 45 to
75 minutes after alcohol is ingested.
The liver metabolizes approximately 90% of ethanol to acetal-
dehyde via the alcohol dehydrogenase pathway; subsequently,
acetaldehyde is converted by aldehyde dehydrogenase to acetate,
which enters the Krebs cycle. At low or moderate serum concen-
trations of ethanol, the alcohol dehydrogenase pathway functions
almost exclusively in metabolizing ethanol. At high concentra-
tions, the microsomal ethanol oxidizing system (CYP2E1) con-
tributes to metabolism. Less than 10% of ethanol is excreted
unchanged through the skin, kidneys, and lungs. Elimination of
alcohol from the body is affected by obesity, food intake, previous
exposure to alcohol, and variability among individuals in the effi-
ciency of the alcohol and aldehyde dehydrogenase systems.
TABLE 126-1  CRITERIA FOR THE DIAGNOSIS OF
ALCOHOL USE DISORDER
TWO OR MORE OF THE FOLLOWING IN THE PREVIOUS 12 MONTHS
Recurrent alcohol use resulting in a failure to fulfill major obligations at
work, school, or home
Recurrent alcohol use in situations in which it is physically hazardous
Continued alcohol use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of alcohol
Tolerance, as defined by:
• need for markedly increased amounts of alcohol to achieve intoxication
or desired effect; and/or
• markedly diminished effect with continued use of the same amount of
alcohol
Withdrawal, as manifested by:
• characteristic alcohol withdrawal syndrome; and/or
• alcohol is taken to relieve or avoid withdrawal symptoms
Alcohol is often taken in larger amounts or over a longer period than was
intended
Persistent desire or unsuccessful efforts to diminish or to control
alcohol use
A great deal of time is spent in activities necessary to obtain, use, or recover
from the effects of alcohol
Important social, occupational, or recreational activities are relinquished
or reduced because of alcohol use
Alcohol use is continued despite knowledge of having a persistent or
recurrent physical or psychological problem that is likely to have been
caused or exacerbated by alcohol use
Craving or a strong desire or urge to use a specific type of alcohol
Modified from the American Psychiatric Association: Diagnostic and statistical manual of
mental disorders, ed 5, Washington, D.C., 2013, American Psychiatric Press.
 Chapter 126  Alcohol and Substance Abuse 1127

60 These enzymatic variations also influence a person’s risk of devel-

oping an alcohol use disorder. The mechanism is thought to
50 involve elevated acetaldehyde levels resulting from a more rapid
Percent using in past month

conversion of ethanol (in cases of alcohol dehydrogenase variants

40 with higher enzymatic activity) or slower elimination of acetal-
dehyde oxidation (in cases of aldehyde dehydrogenase variants
30 with reduced enzymatic activity). Acetaldehyde causes facial
flushing, nausea, and tachycardia, which make individuals reduce
20 their intake of alcohol.

10   MECHANISMS OF ALCOHOL-INDUCED
ORGAN DAMAGE
0 The major organs that are susceptible to damage by alcohol are
White Black or American Asian Two or Hispanic
African Indian or more or Latino the liver, pancreas, heart, brain, and bone (Table 126-2). Several
American Alaska races alcohol-related medical disorders are caused by various nutri-
Native tional deficiencies; ethanol is deficient in proteins, minerals, and
Current use (not binge) vitamins. Therefore, the initial management of the alcoholic
Binge use (not heavy) patient must attend to suggested dietary deficiencies (e.g., thia-
Heavy alcohol use
mine) and electrolyte deficiencies, including potassium, magne-
FIGURE 126-1  Current, binge, and heavy alcohol use among persons sium, calcium, and zinc.
aged 12 or older, by race and ethnicity, according to the National
Alcohol-related liver disease is the leading preventable cause
Survey on Drug Use and Health (2011). Binge drinking is defined as
having five or more drinks on a single occasion. Heavy alcohol use is of hepatic failure in the industrialized world. Genetic factors are
defined as having had five or more drinks on the same occasion on thought to play a role in susceptibility to this disorder, since
each of five or more days in the previous 30 days. (From Substance alcoholic liver disease is more prevalent in whites than in other
Abuse and Mental Health Services Administration: Results from the ethnic groups (despite a similar magnitude of ethanol consump-
2011 National Survey on Drug Use and Health: Summary of National
tion). The histopathologic features of alcoholic liver disease
Findings, NSDUH Series H-44, HHS Publication No. [SMA] 12-4713,
Rockville, Md., 2012, Substance Abuse and Mental Health Services
Administration.)
TABLE 126-2  MEDICAL COMPLICATIONS OF
ALCOHOL ABUSE
80 NEUROLOGIC ELECTROLYTE OR NUTRITIONAL
Encephalopathy (Wernicke, with Thiamine deficiency
70 oculomotor dysfunction; gait Niacin deficiency
Percent using in past month

ataxia) Folate deficiency

60 Marchifava-Bignami disease Vitamin B12 deficiency
(demyelination of corpus Vitamin D deficiency
50 callosum) Zinc deficiency
Central pontine myelinosis Hypokalemia
40 Cognitive dysfunction Hypomagnesaemia
Amnesia (i.e., Korsakoff syndrome) Hypocalcaemia
30 Dementia Ketoacidosis
Cerebellar degeneration Hypoglycemia
20 Peripheral neuropathy Hypertriglyceridemia
Seizures Malnutrition
10
HEMATOLOGIC ENDOCRINE
0 Anemia (often with macrocytosis) Diabetes mellitus
14–15 18–20 26–29 35–39 45–49 55–59 65+
Leukopenia Gynecomastia
12–13 16–17 21–25 30–34 40–44 50–54 60–64 Thrombocytopenia
MUSCULOSKELETAL
Age in years GASTROINTESTINAL
Myopathy
Current use (not binge) Esophagitis Osteoporosis
Binge use (not heavy) Esophageal varices Testicular atrophy
Heavy alcohol use Gastritis Amenorrhea
Gastrointestinal bleeding Infertility
FIGURE 126-2  Current, binge, and heavy alcohol use among persons Pancreatitis
MISCELLANEOUS
aged 12 or older, by age, according to the National Survey on Drug Use Hepatitis
and Health (2007). Binge drinking is defined as having five or more Cirrhosis Spontaneous abortion
drinks on a single occasion. Heavy alcohol use is defined as having had Splenomegaly Fetal alcohol syndrome
five or more drinks on the same occasion on each of five or more days Increased risk of cancer (breast,
CARDIOVASCULAR
oropharyngeal, esophageal,
in the previous 30 days. (From Substance Abuse and Mental Health
Hypertension hepatocellular, colorectal)
Services Administration: Results from the 2011 National Survey on Cardiomyopathy Accidents, trauma, violence, suicide
Drug Use and Health: Summary of National Findings, NSDUH Series Stroke
H-44, HHS Publication No. [SMA] 12-4713, Rockville, Md., 2012, Sub- Arrhythmias (especially atrial
stance Abuse and Mental Health Services Administration.) fibrillation)
1128 Section XIX  Alcohol and Substance Abuse
include fatty infiltration, hepatitis, fibrosis, and end-stage
cirrhosis.
  CLINICAL PRESENTATION
Acute Alcohol Intoxication
Mild ethanol intoxication produces slurred speech, ataxia, irregu-
lar eye movements, and poor coordination. Signs of CNS depres-
sion and associated cerebellar or vestibular dysfunction include
dysarthria, ataxia, and nystagmus. Although blood alcohol con-
centrations are not precisely correlated with the degree of intoxi-
cation and the clinical effect of ethanol widely varies among
individuals, stupor and coma usually develop at blood concentra-
tions approaching 400 mg/dL. Blood levels of 500 mg/dL often
are fatal; however, it is important to understand that death may
occur even when the blood alcohol concentration is as low as
300 mg/dL.
Withdrawal Syndrome (Convulsions)
Alcohol withdrawal occurs in three stages. The signs of minor
withdrawal usually appear 6 to 12 hours after the discontinuation
of ethanol and are caused by central adrenergic hyperexcitability;
they consist of anxiety, tremors, sweating, tachycardia, diarrhea,
and insomnia. Additional evidence of autonomic nervous system
hyperactivity often appears within 12 to 24 hours and includes
increased startle response, nightmares, and visual hallucinations.
Alcohol withdrawal seizures (so-called rum fits) are generalized
clonic-tonic convulsions that occur 12 to 48 hours after the dis-
continuation of ethanol and are estimated to occur in 2% to 5%
of alcoholics.
Delirium Tremens
Delirium tremens (DTs) is characterized by delirium (a confused
state with varying levels of consciousness), hallucinations, disori-
entation, agitation, tremor (caused by marked autonomic nervous
system over activity), tachycardia, hypertension, fever, and dia-
phoresis. It occurs in approximately 5% of alcoholics, most often
in chronic heavy abusers with underlying neurologic damage. If
unrecognized and untreated, the in-hospital mortality rate of DTs
approaches 25%; with early recognition and treatment the mor-
tality is only 5%.
  TREATMENT
Intervention strategies in alcohol abusers are designed to modify
the individual’s attitudes, knowledge, and skills to prevent alcohol
misuse. In the outpatient setting, increased frequency of contact
between the primary care physician and the patient increases the
likelihood of detection, intervention, and prevention of heavy
alcohol consumption. All scheduled office visits should include
alcohol screening, assessment, and brief attempts at intervention
(one or more discussions lasting 10 to 15 minutes), if indicated,
as studies show that this approach decreases alcohol intake and
its consequences. Behavioral or pharmacologic treatment should
be considered because two thirds of treated patients have a reduc-
tion in the amount of consumption (by more than 50%) as well
as the consequences of consumption (e.g., alcohol-related injury
or job loss). A year after treatment, one third of patients are either
abstinent or drink moderately without consequences.
Screening and Intervention Strategies
The National Institute on Alcohol Abuse and Alcoho­lism
(NIAAA) provides several web-based guidelines for alcohol
screening during the routine health examination (www.niaaa
.nih.gov). A four-step plan exists with which physicians can (1)
screen patients for alcohol use, (2) assess for the presence of
alcohol-related problems, (3) provide advice concerning appro-
priate action, and (4) monitor the patient’s progress. For the
current drinker, the physician should inquire about the number
of drinks consumed per day, number of days per week on which
ethanol is consumed, and total number of drinks consumed per
month. Alcohol consumption that exceeds 14 drinks per week or
three drinks per day should trigger an in-depth assessment of
alcohol-related problems. The physician should ascertain if the
individual is at risk for alcohol-related problems, has an existing
problem, or may be alcohol-dependent. Difficulties with work-
related, interpersonal, or family relationships and/or evidence of
high-risk behavior despite self-reported low-risk consumption
indicate that the individual is at risk for alcohol use disorder.
The CAGE questionnaire (each of the letters in the acronym
refers to one of the questions) (Table 126-3) is a useful screening
tool for identifying alcohol-dependent individuals. A positive
response to two or more of the four questions is indicative of a
potential alcohol problem and should prompt questions regard-
ing the quantity and frequency of consumption. The Alcohol Use
Disorders Identification Test (AUDIT) (Table 126-4) is the
most widely validated instrument for use in primary care settings.
Utilizing 10 items and taking two to three minutes to complete,
it is better suited to settings where visit times are longer or when
it can be completed and scored before a clinician visit. On
physical examination, evidence of alcoholic liver disease may
be exhibited as jaundice, hepatomegaly, palmar erythema, male
gynecomastia, spider angiomata, and ascites. The serum
γ-glutamyltransferase concentration typically is elevated in indi-
viduals who drink excessively.
Low-Risk Drinking
A standard drink contains 12 g of alcohol, an amount similar to
that found in one 12-oz bottle of beer or wine cooler, one 5-oz
glass of wine, or 1.5 oz. of distilled (e.g., 80 proof) spirits. In men
older than age 64 years and in women older than 21 years, the
limit for moderate drinking is one drink per day. For younger
men, moderate drinking is defined as no more than two drinks
per day. For the same amount of ingested ethanol, women and
older adult men achieve a higher blood concentration of ethanol
than younger men owing to their smaller volume of body water.
A reasonable blood alcohol level should not exceed 50 mg/dL.
A blood-alcohol level as low as 80 mg/dL may exceed the legal
definition for driving under the influence (DUI) or driving while
TABLE 126-3  CAGE: AN ALCOHOLISM
SCREENING TEST
1. Have you ever felt you should cut down on your drinking?
2. Have people annoyed you by criticizing your drinking?
3. Have you felt guilty about your drinking?
4. Have you ever had a drink first thing in the morning to steady your
nerves or to get rid of a hangover (i.e., as an eye-opener)?
 Chapter 126  Alcohol and Substance Abuse 1129

TABLE 126-4  COMMONLY ABUSED DRUGS

SUBSTANCE: EXAMPLES OF COMMERCIAL HOW INTOXICATION EFFECTS AND
CATEGORY AND NAME AND STREET NAMES ADMINISTERED* POTENTIAL HEALTH CONSEQUENCES
CANNABINOIDS Euphoria, slowed thinking and reaction time,
drowsiness, inattention, confusion, impaired
balance and coordination, enhanced
perception, cough, frequent respiratory
infections, impaired memory and learning,
increased heart rate, anxiety, panic attacks,
tolerance, addiction
Hashish Boom, gangster, hash, hash oil, hemp Smoked, swallowed
Marijuana Blunt, dope, ganja, grass, herb, joint, bud, Smoked, swallowed
Mary Jane, pot, reefer, green trees, smoke,
sinsemilla, skunk, weed
K2/Synthetic Marijuana Spice, K2, fake weed, Yucatan fire, skunk, Smoked, swallowed Vomiting, agitation, hallucinations,
moon rocks, hypertension, myocardial infarction, death,
withdrawal and addiction symptoms.
SEDATIVE-HYPNOTICS (CNS Reduced pain and anxiety, feeling of well-being,
DEPRESSANTS) lowered inhibitions, labile mood, impaired
judgment, poor concentration, fatigue,
confusion, impaired coordination and
memory, respiratory depression and arrest,
addiction
Benzodiazepines (Other Than Ativan, Halcion, Klonopin, Librium, ProSom, Swallowed Sedation, drowsiness, dizziness
Flunitrazepam) Restoril, Serax, Tranxene, Valium, Xanax,
Doral; candy, downers, sleeping pills, tranks
Flunitrazepam† Rohypnol; forget-me pill, Mexican Valium, Swallowed, snorted Visual and gastrointestinal disturbances, urinary
R2, roach, Roche, roofies, roofinol, rope, retention, amnesia while under drug’s effects
rophies
Sleep Medications Ambien (zolpidem), Sonata (zaleplon), Swallowed Sedation, drowsiness, dizziness
Lunesta (eszopicline)
Barbiturates Amytal, Nembutal, phenobarbital, Seconal; Injected, swallowed Sedation, drowsiness, depression, unusual
barbs, reds, red birds, phennies, tooies, excitement, fever, irritability, poor judgment,
yellows, yellow jackets slurred speech, dizziness
GHB† γ-hydroxybutyrate; G, Georgia home boy, Swallowed Drowsiness, dizziness, nausea and vomiting,
grievous bodily harm, liquid ecstasy, soap, headache, loss of consciousness,
scoop, goop, liquid X hallucinations, peripheral vision loss,
nystagmus, loss of reflexes, seizures, coma,
death
DISSOCIATIVE DRUGS Increased heart rate and blood pressure,
impaired function, memory motor loss,
numbness, nausea and vomiting
PCP and Analogues Phencyclidine; angel dust, boat, hog, love Injected, smoked, Possible decrease in blood pressure and heart
boat, peace pill swallowed rate, panic, aggression, violence, suicidal
ideation; loss of appetite, depression
Ketamine* Ketalar SV; cat Valiums, K, Special K, vitamin Injected, smoked, At high doses: delirium, depression, respiratory
K snorted depression and arrest, amnesia while under
drug’s effects
Salvia Divinorum Salvia, shepherdess’s herb, maria pastora, Chewed, smoked
magic mint, sally-d swallowed
Dextromethorphan (DXM) Found in some cough and cold medications: Swallowed Euphoria, slurred speech, confusion, dizziness,
Robo, Robotripping, Triple C distorted visual perceptions
HALLUCINOGENS Altered states of perception and feeling, nausea,
chronic mental disorders, persisting
perception disorder (flashbacks)
LSD Lysergic acid diethylamide; acid, blotter, Swallowed, absorbed LSD: flashbacks, hallucinogen persisting
cubes, microdot, yellow sunshines, blue through mouth tissues perception disorder
heaven LSD and mescaline: increased body
temperature, heart rate, blood pressure, loss
of appetite, sleeplessness, numbness,
weakness, tremors, impulsive behavior, rapid
shift in emotion
Mescaline Buttons, cactus, mesc, peyote Smoked, swallowed,
Psilocybin Magic mushrooms, purple passion, shrooms, Swallowed nervousness, paranoia, panic
little smoke
OPIOIDS AND MORPHINE Pain relief, euphoria, drowsiness, respiratory
DERIVATIVES depression and arrest, pinpoint pupils,
nausea, confusion, constipation, sedation,
unconsciousness, seizures, coma, tolerance,
addiction
Codeine Empirin with Codeine, Fiorinal with Codeine, Injected, swallowed Less analgesia, sedation, and respiratory
Robitussin A-C, Tylenol with Codeine, depression than morphine
OxyContin, Roxicodone, Vicodin; Captain
Cody, Cody, schoolboy
(with glutethimide: doors and fours, loads,
pancakes and syrup)
Continued
1130 Section XIX  Alcohol and Substance Abuse
TABLE 126-4  COMMONLY ABUSED DRUGS—cont’d
SUBSTANCE: EXAMPLES OF COMMERCIAL
CATEGORY AND NAME AND STREET NAMES
Other Opioid Pain Relievers
Oxycodone, hydrocodone bitartrate Tylox, Oxycontin, Percodan, Percocet; Oxy,
hydromorphone, oxymorphone, O.C., oxycotton, oxycet, hillbilly, heroin,
meperidine, propoxyphene percs
Vicodin, Lortab, Lorcet; vike, Watson-387
Dilaudid; juice, smack, D, footballs, dillies
Opana, Numorphan, Numorphone; biscuits,
blue heaven, blues, Mrs. O, octagons, stop
signs, O bomb
Demerol, meperidine hydrochloride;
demmies, pain killer
Darvon, Darvocet
Fentanyl Actiq, Duragesic, Sublimaze; apache, China
girl, China white, dance fever, friend,
goodfella, jackpot, murder 8, TNT, Tango
and Cash
Heroin Diacetylmorphine; brown sugar, dope, H,
horse, junk, skag, skunk, smack, white
horse, China white, cheese (with OTC cold
medicine and antihistamine)
Morphine Roxanol, Duramorph, M, Miss Emma,
monkey, white stuff
Opium Laudanum, paregoric; big O, black stuff,
block, gum, hop
STIMULANTS
Amphetamine Adderall, Biphetamine, Dexedrine; bennies,
black beauties, crosses, hearts, LA
turnaround, speed, truck drivers, uppers
Methamphetamine Desoxyn; chalk, crank, crystal, fire, glass, go
fast, ice, meth, speed, yaba, fire, tina, tweak,
uppers, trash, yellow barn, methlies quick,
stove top, go fast
Methylphenidate Ritalin, Concerta; JIF, MPH, R-ball, Skippy,
the smart drug, vitamin R
Cocaine Cocaine hydrochloride; blow, bump, C,
candy, Charlie, coke, crack, flake, rock,
snow, toot
MDMA† (Methylenedioxymetha Adam, clarity, ecstasy, Eve, lover’s speed,
mphetamine) peace, uppers, Molly
Synthetic Cathinone Bath salts, drone, meph, meow meow, ivory
(Methylenedioxypyrovalerone wave, bloom, cloud nine, lunar wave, vanilla
(MDPV), Mephedrone (“Drone,” sky, white lightning, scarface
“Meph,” or “Meow Meow”), and
Methylone)
OTHER COMPOUNDS
Inhalants Solvents (paint thinners, gasoline), glues,
gases (butane, propane, aerosol propellants,
nitrous oxide), nitrites (isoamyl, isobutyl,
cyclohexyl); laughing gas, poppers,
snappers, whippets
Anabolic Steroids Anadrol, Oxandrin, Durabolin, Depo-
Testosterone, Equipoise; roids, juice, gym
candy, pumpers
CNS, Central nervous system.
*Taking drugs by injection can increase the risk of infection through needle contamination with staphylococci, human immunodeficiency virus, hepatitis, and other organisms.
†
Associated with sexual assaults (e.g., date rapes).
HOW INTOXICATION EFFECTS AND
ADMINISTERED* POTENTIAL HEALTH CONSEQUENCES
Chewed, injected, For oxycodone—muscle relaxation/twice as
snorted, suppositories, potent an analgesic as morphine; high abuse
swallowed potential
Injected, smoked, 80-100 times more potent an analgesic than
snorted morphine
Injected, smoked, Staggering gait
snorted
Injected, smoked,
swallowed
Smoked, swallowed
Increased heart rate, blood pressure, body
temperature; feelings of exhilaration,
increased energy and mental alertness,
tremors, rapid or irregular heart beat; reduced
appetite, irritability, anxiety, panic, paranoia,
violent behavior, psychosis, weight loss,
insomnia, heart failure, seizures, coma
Injected, smoked, Rapid breathing, hallucinations, loss of
snorted, swallowed coordination, restlessness, delirium, panic,
impulsive behavior, Parkinson’s disease,
tolerance, addiction
Injected, smoked, Memory loss, cardiac and neurologic damage,
snorted, swallowed impaired memory and learning, tolerance,
addiction, severe dental problems
Injected, snorted Increase or decrease in blood pressure,
swallowed psychotic episodes, digestive problems,
Injected, smoked, Chest pain, respiratory failure, nausea,
snorted abdominal pain, stroke, malnutrition, nasal
damage from snorting
Injected, snorted, Mild hallucinogenic effects, increased tactile
swallowed sensitivity, empathic feelings, chills, sweating,
nystagmus, ataxia, teeth clenching, muscle
cramping, impaired memory and learning,
lowered inhibition
Injected, smoked, Chest pain, paranoia, hallucinations, panic
swallowed attacks, excited delirium, rhabdomyolysis,
renal failure, high abuse and addiction
potential
Inhaled through nose or Stimulation, loss of inhibition, headache,
mouth nausea or vomiting, slurred speech, loss of
motor coordination, wheezing,
unconsciousness, cramps, weight loss, muscle
weakness, depression, memory impairment,
damage to cardiovascular and nervous
systems, sudden death
Injected, swallowed, No intoxication effects. Hypertension, blood
topical clotting and cholesterol changes, hostility and
aggression, acne, prostate cancer, reduced
sperm production, shrunken testicles, breast
enlargement. In females: menstrual
irregularities, beard development, and other
masculine characteristics
 Chapter 126  Alcohol and Substance Abuse 1131
intoxicated (DWI). In national surveys, the strategy of the desig-
nated driver appears to be effective at preventing unsafe driving
by drinkers at risk for DWI. Complete abstinence is recom-
mended for people with a history of alcohol use disorder, other
serious medical conditions (e.g., liver disease), and pregnancy.
Nonpharmacologic Therapies
Pharmacologic agents are complementary and adjunctive to
the traditional approaches of abstinence, group therapy, coping
mechanisms, and behavior modification. The most widely
employed behavioral approach is the 12-step program admin-
istered by Alcoholics Anonymous (AA), with which the
recovering alcoholic moves through 12 specific steps aided
by his or her attendance at regular meetings within a self-
help peer group. Cognitive behavioral therapy is based on
the principle that the alcoholic first must identify the internal
and external cues to drinking so that he or she can develop
effective countermeasures for drinking behavior. Motivation
enhancement therapy is a four-session, brief contact interven-
tion program that encourages self-awareness and behavioral
changes in the alcoholic. These therapies provide similar
efficacy.
Considerations for Drug Interventions
If desired, medications can be administered in conjunction with
behavioral modification. Disulfiram, naltrexone, and acampro-
sate have been approved by the U.S. Food and Drug Administra-
tion (FDA) for adjunctive therapy.
Disulfiram (Antabuse) inhibits aldehyde dehydrogenase (i.e.,
the enzyme that converts acetaldehyde to acetate), resulting in a
5- to 10-fold increase in serum acetaldehyde concentrations
when alcohol is consumed. This produces uncomfortable symp-
toms (e.g., facial flushing, tachycardia, nausea, vomiting, and
headache), which act to deter alcohol consumption. Because of
low medication compliance and limited efficacy, disulfiram is
rarely prescribed.
Naltrexone is an opioid receptor antagonist. In clinical trials, a
combination of naltrexone and psychosocial intervention
reduced the number of drinking days, induced a longer period of
abstinence from ethanol, and decreased the relapse rate in heavy
drinkers when compared with psychosocial intervention alone.
Naltrexone is administered orally in a dose of 50 mg daily for 12
weeks, although larger doses (i.e., 100 to 150 mg daily) and a
longer duration of administration may improve its success in pre-
venting relapse. In 2006, the FDA approved a once-a-month
injectable form of naltrexone (380 mg) for the treatment of
alcohol use disorders; this form appears to be more effective than
the pill form at maintaining abstinence, since it eliminates the
problem of medication compliance.
Naltrexone can be initiated while the individual is still drink-
ing, thereby permitting treatment to be provided in a community-
based setting without the need for enforced abstinence or
detoxification. Some recovering alcoholics develop nausea when
it is initiated. Because hepatic toxicity may occur at high doses
(≥300 mg), periodic testing of liver function is recommended.
Naltrexone is contraindicated in subjects receiving opioids,
given that opiate withdrawal is an unintended adverse effect of
the drug.
Acamprosate (Campral), a structural analog of γ-amino butyric
acid (GABA), decreases excitatory glutamatergic neurotransmis-
sion during alcohol withdrawal. The recommended dosage is 666
to 1000 mg 3 times daily, and its most common side effects are
diarrhea and intestinal cramping. In placebo-controlled trials
involving almost 7000 alcoholic patients, acamprosate reduced
relapse rates and increased abstinence from ethanol. In compara-
tive trials, it did not appear to be as efficacious as naltrexone.
Acamprosate should be used once abstinence is achieved; since
it is not metabolized by the liver, it can be given safely to individu-
als with alcoholic liver disease.
The use of several other pharmacologic agents has been associ-
ated with a reduction in alcohol consumption, including ondan-
setron (a selective serotonin reuptake inhibitor), topiramate (an
anticonvulsant), baclofen (a GABA agonist), nalmefene (an
opioid antagonist), and varenicline (a nicotinic acetylcholine-
receptor and dopamine partial agonist), but none of these agents
has been approved by the FDA for treatment of alcohol
dependence.
Fetal Alcohol Spectrum Disorders
Alcohol freely crosses the placenta and is teratogenic. It is a
leading preventable cause of birth defects with mental deficiency,
with up to 1 in 100 children in the United States being born with
fetal alcohol spectrum disorders (FASDs). The scope of disabili-
ties and malformations varies and depends on the amount of
alcohol consumed, the frequency of exposure, the stage of fetal
development when alcohol is present, maternal parity, nutrition,
genetic susceptibility, and individual variation in maternal and
fetal alcohol metabolism.
The term fetal alcohol spectrum disorder (FASD) is used to char-
acterize the full range of prenatal alcohol damage, varying from
mild to severe and encompassing a broad array of physical defects
and cognitive, behavioral, and emotional deficits. It includes con-
ditions such as fetal alcohol syndrome (FAS), alcohol-related
neurodevelopmental disorder (ARND), and alcohol-related
birth defects (ARBDs).
FAS, the most severe form of FASD, is characterized by
(a) growth retardation (i.e., height or weight ≥10th percentile);
(b) neurodevelopmental abnormalities (i.e., microcephaly,
hyperactivity, irritability, altered motor skills, learning disabili-
ties, seizure disorders, and mental retardation), and (c) dys-
morphic facial features (i.e., short palpebral fissures, smooth
philtrum, and a thin upper lip). Children with typical dys-
morphic facial features who lack the other features have partial
FAS. Children with ARBDs have typical facies associated with
FAS as well as anomalies in other organs (i.e., cardiac, renal,
skeletal, auditory) but no growth retardation or neurodevel-
opmental abnormalities. Children with ARND exhibit behav-
ioral or cognitive abnormalities in the absence of dysmorphic
facial features.
Although the damage from prenatal exposure to alcohol
cannot be reversed, children with FASDs benefit from early diag-
nosis and aggressive intervention with physical, occupational,
speech and language, and educational therapies. Early recogni-
tion can also benefit the impaired mother, resulting in access to
alcohol treatment and a better social situation for the entire
family.
1132 Section XIX  Alcohol and Substance Abuse
Although the recognition of FASD is important, its prevention
is essential. Given that no safely established level of alcohol con-
sumption in pregnancy exists, recommendations suggest that
pregnant women maintain abstinence. In addition, women who
are considering pregnancy or are already pregnant must be coun-
seled about the effects of alcohol on the fetus.
Medical Management of Alcohol Withdrawal
and Delirium Tremens
For the patient with probable alcohol withdrawal, comorbid con-
ditions that may coexist or mimic the symptoms of withdrawal
(e.g., infection, trauma, hepatic encephalopathy, drug overdose,
gastrointestinal bleeding, and metabolic derangements) should
be excluded. Once this has been accomplished, the patient
should be placed in a quiet and protective environment and
should receive parenteral thiamine and multivitamins to decrease
the risk of Wernicke encephalopathy or Korsakoff amnestic
syndrome.
The Revised Clinical Institute for Withdrawal Assessment for
Alcohol (CIWA-Ar) scale (available at https://umem.org/files/
uploads/1104212257_CIWA-Ar.pdf), a measure of withdrawal
severity, is useful in guiding symptom-triggered therapy in medi-
cally stable (i.e., non ICU or postoperative) patients. Benzodiaz-
epines are the only medications proved to ameliorate symptoms
and to decrease the risk of seizures and DTs in patients with
alcohol withdrawal. Typically, diazepam (5 to 20 mg), chlordiaz-
epoxide (50 to 100 mg), or lorazepam (1 to 2 mg) is adminis-
tered intravenously every 5 to 10 minutes until symptoms
subside, with the last of these medications preferred in patients
with advanced cirrhosis, considering that the liver minimally
metabolizes it. All benzodiazepines appear to be similarly effica-
cious in treating alcohol withdrawal, but long-acting agents may
be more effective in preventing withdrawal seizures and are asso-
ciated with fewer rebound symptoms. Conversely, short-acting
agents may offer a lower risk of oversedation. For the patient who
is resistant to benzodiazepines, intravenous phenobarbital (130
to 260 mg administered intravenously every 15 minutes until
symptoms are controlled) may be given.
  PRESCRIPTION DRUG ABUSE
According to the National Survey on Drug Use and Health, an
estimated 6.1 million Americans aged 12 years or older used
prescription-type psychotherapeutic drugs nonmedically in the
past month (Fig. 126-3). This estimate represents 2.4% of the
population aged 12 years or older. In 2011, the illicit drug cate-
gory with the largest number of recent initiates was marijuana use
(2.6 million), followed by nonmedical use of pain relievers (1.9
million) and nonmedical use of tranquilizers (1.2 million). More
people in the United States now die of prescription drug over-
dose (i.e., the nonmedical use of prescription-type pain relievers,
tranquilizers, stimulants, and sedatives) than accidental vehicular
trauma.
Sedatives and Hypnotics
Benzodiazepines and barbiturates are the major sedative-
hypnotic drugs among the commonly abused agents that are
listed in Table 126-4. The patient with sedative-hypnotic intoxi-
cation may have slurred speech, incoordination, unsteady gait,
Past Month Illicit Drug Use among
Persons Aged 12 or Older: 2011
Illicit drugs 22.5
Marijuana 18.1
Psychotherapeutics 6.1
Cocaine 1.4
Hallucinogens 1.0
Inhalants 0.6
Heroin 0.3
0 5 10 15 20 25
Numbers in millions
FIGURE 126-3  Past-month illicit drug use among persons aged 12
or older, according to the National Survey on Drug Use and Health
(2011). (From Substance Abuse and Mental Health Services Administra-
tion: Results from the 2011 National Survey on Drug Use and Health:
Summary of National Findings, NSDUH Series H-44, HHS Publication
No. [SMA] 12-4713, Rockville, Md., 2012, Substance Abuse and Mental
Health Services Administration.)
impaired attention or memory, stupor, and coma. The psychiatric
manifestations of intoxication include inappropriate behavior,
labile mood, and impaired judgment and social functioning. On
physical examination, the person may have respiratory depres-
sion or even arrest, nystagmus, and hyper-reflexia. Although ben-
zodiazepines rarely depress respiration to the extent that
barbiturates do (and, as a result, have a much wider margin of
safety), the effects of these drugs are additive with those of other
CNS depressants, such as ethanol. Chronic use may produce
physical and psychological dependence and a potentially danger-
ous withdrawal syndrome.
Benzodiazepines potentiate the effects of GABA, which inhib-
its neurotransmission. They are available as short-acting agents
(temazepam [Restoril] and triazolam [Halcion]), intermediate-
acting agents (alprazolam [Xanax], chlordiazepoxide [Librium],
estazolam [ProSom], lorazepam [Ativan], and oxazepam
[Serax]), and long-acting agents (clorazepate [Tranxene], clon-
azepam [Klonopin], diazepam [Valium], flurazepam [Dalmane],
halazepam [Paxipam], Prazepam [Centrax], and quazepam
[Doral]). Flunitrazepam (Rohypnol, also known as roach, roofies,
circles, Mexican valium, or rope) is a popularly abused benzodiaz-
epine that is not legally available in the United States but is often
smuggled here from other countries. It has been implicated in
cases of date rape and is known as a club drug because adoles-
cents and young adults often use it at nightclubs and bars or
during all-night dance parties called raves.
In persons with an acute benzodiazepine overdose, respiratory
depression is the major danger. Flumazenil (Romazicon), a com-
petitive antagonist of benzodiazepines, can be given intrave-
nously for acute overdose. Although it reverses the sedative
effects of benzodiazepines, flumazenil may not completely reverse
respiratory depression, and it may cause seizures in patients with
 Chapter 126  Alcohol and Substance Abuse 1133
physical dependence or concurrent tricyclic antidepressant
poisoning.
Benzodiazepine cessation may precipitate withdrawal symp-
toms, depending on the half-life of the specific agent, the dura-
tion of use, and the dose. Such withdrawal is characterized
by intense anxiety, insomnia, irritability, perceptual changes,
hypersensitivity to light and sound, psychosis, hallucinations,
palpitations, hyperthermia, tachypnea, diarrhea, muscle spasms,
tremors, and seizures. Withdrawal symptoms usually peak 2 to
4 days after the discontinuation of a short-acting agent and 5
to 6 days after discontinuation of a longer-acting one; however,
panic attacks and nightmares may recur for months. In general,
agents with shorter half-lives produce more intense withdrawal
symptoms compared with agents with longer half-lives. Detoxi-
fication requires a change to a longer-acting benzodiazepine
(e.g., clonazepam, diazepam) or phenobarbital and a tapering
regimen of 7 to 10 days for short-acting agents or 10 to 14
days for longer-acting ones. For hemodynamically unstable
patients who require very rapid medication titration to control
withdrawal symptoms and for those with severe hepatic failure,
short-acting medications are indicated in lieu of phenobarbital.
Propranolol can be given to decrease tachycardia, hypertension,
and anxiety.
Barbiturates may be short acting (pentobarbital and secobar-
bital), intermediate acting (amobarbital, aprobarbital, and but-
abarbital), or long acting (mephobarbital and phenobarbital).
The symptoms of acute intoxication with the withdrawal from
barbiturates are similar to those of benzodiazepines. For acute
barbiturate overdose, oral charcoal and alkalinization of the urine
(to a pH >7.5) with forced diuresis are effective in lowering the
blood concentration. For patients with hemodynamic compro-
mise refractory to aggressive supportive therapy, barbiturate
elimination can be increased by hemodialysis or charcoal hemo-
perfusion. The effective treatment of withdrawal symptoms
requires estimating the daily dose of the abused drug and substi-
tuting an equivalent phenobarbital dose to stabilize the patient,
after which the dose of phenobarbital is tapered over 4 to 14 days,
depending on the half-life of the abused drug. Benzodiazepines
may also be used for detoxification, and propranolol and cloni-
dine may help reduce symptoms.
Abuse of γ-hydroxybutyrate (GHB) has increased substan-
tially over the last decade in the United States. This drug is abused
for its sedative, euphoric, and bodybuilding effects. GHB is a
metabolite of the neurotransmitter GABA, and it also influences
the dopaminergic system. It potentiates the effects of endoge-
nous or exogenous opiates. The ingestion of GHB results in
immediate drowsiness and dizziness, with the feeling of a high.
These effects can be potentiated by the concomitant use of
alcohol or benzodiazepines. Similar to flunitrazepam and ket-
amine, GHB is a popular club drug, and it has been implicated in
cases of date rape. Its street names include G, liquid E, liquid X,
fantasy, Georgia home boy, and grievous bodily harm. Adverse
effects that may occur within 15 to 60 minutes of its ingestion
include headache, nausea, vomiting, hallucinations, loss of
peripheral vision, nystagmus, hypoventilation, cardiac dysrhyth-
mias, seizures, and coma. In rare instances, these adverse effects
have led to death. The withdrawal from GHB becomes clinically
apparent within 12 hours and may last up to 12 days.
Opioids
Opioids include the natural and semisynthetic alkaloid deriva-
tives of opium as well as the purely synthetic drugs that mimic
heroin. They bind to opioid receptors in the brain, spinal cord,
and gastrointestinal tract; in addition, they act on several other
CNS neurotransmitter systems, including dopamine, GABA, and
glutamate, to produce analgesia, CNS depression, and euphoria.
With continued opioid use, tolerance and physical dependence
develop. As a result, the user must use larger amounts of the drug
to obtain the desired effect, and withdrawal symptoms may occur
if use is discontinued. The commonly abused opioids include
heroin, morphine, codeine, oxycodone (OxyContin, OxyIR,
Oxectya, Roxicodone, or combination products, such as Perco-
cet, Percodan, Tylox, Combunox), meperidine (Demerol), pro-
poxyphene (Darvon), hydrocodone (Vicodin, Lortab, Lorcet),
hydromorphone (Dilaudid), buprenorphine (Temgesic) and
fentanyl (Sublimaze). In 2000, retail pharmacies dispensed 174
million prescriptions for opioids; by 2009, 257 million prescrip-
tions were dispensed, an increase of 48%. The 2011 National
Survey on Drug Use and Health reported that over 70% of sub-
jects who abused prescription pain relievers obtained them from
friends or relatives, whereas approximately 5 percent procured
them from a drug dealer or over the internet.
Acute opioid overdose produces pulmonary congestion, with
resultant cyanosis and respiratory distress, and changes in mental
status that may progress to coma. Other manifestations include
fever, pinpoint pupils, and seizures. Unsterile intravenous prac-
tices can lead to skin abscesses, cellulitis, thrombophlebitis,
wound botulism, meningitis, rhabdomyolysis, endocarditis, hep-
atitis, or human immunodeficiency virus (HIV) infection. Neu-
rologic complications from intravenous heroin use include
transverse myelitis, inflammatory polyneuropathy, and periph-
eral nerve lesions.
For acute opioid overdose, the patient’s respiratory status must
be assessed and supported. Naloxone should be administered
intravenously and repeated at 2- to 3-minute intervals, often in
escalating doses; the patient should respond within minutes with
increases in pupil size, respiratory rate, and level of alertness. If
no response occurs, opioid overdose is excluded, and other
causes of somnolence and respiratory depression must be con-
sidered. Naloxone should be titrated carefully, since it may pre-
cipitate acute withdrawal symptoms in opioid-dependent
patients.
Withdrawal symptoms may appear as early as 6 to 10 hours
after the last injection of heroin. Initially the individual often has
feelings of drug craving, anxiety, restlessness, irritability, rhinor-
rhea, lacrimation, diaphoresis, and yawning; these signs are fol-
lowed by dilated pupils, piloerection, anorexia, nausea, vomiting,
diarrhea, abdominal cramps, bone pain, myalgia, tremors, muscle
spasms, and, in rare cases, seizures. These symptoms and signs
peak at 36 to 48 hours and then subside over 5 to 10 days, if
untreated. A protracted abstinence syndrome characterized by
bradycardia, hypotension, mild anxiety, sleep disturbance, and
decreased responsiveness may occur for up to 5 months.
Withdrawal from opioids can be managed with methadone, a
long-acting synthetic agonist drug; withdrawal symptoms of
methadone develop more slowly and are less severe than those
1134 Section XIX  Alcohol and Substance Abuse
caused by heroin. Methadone can be given twice daily and
tapered over 7 to 10 days. Methadone use, in both therapeutic
doses and overdoses, has been associated with QTc interval pro-
longation and torsade de pointes, which, in some cases, has been
fatal. Alternatively, buprenorphine, a partial agonist, can be given;
it is combined with naloxone in a formulation (Suboxone) devel-
oped to decrease the potential for abuse. Clonidine reduces auto-
nomic hyperactivity and is particularly effective if combined with
a benzodiazepine. Patients with repeated relapses can be main-
tained on methadone or buprenorphine.
Naltrexone, a long-acting opioid antagonist that blocks impul-
sive opioid use, is an option for maintenance treatment to prevent
relapse. It can be given orally daily or via injectable depot and
implantable formulations every 60 to 90 days. It should only be
administered after the patient is thoroughly detoxified because it
may precipitate withdrawal. Pharmacotherapy must be com-
bined with psychotherapy and structured rehabilitation to
achieve an optimal outcome.
Amphetamines
Amphetamines have been used therapeutically for weight reduc-
tion and treatment of attention-deficit disorder and narcolepsy.
Similar to cocaine, they cause a release of monoamine neu-
rotransmitters (dopamine, norepinephrine, and serotonin) from
presynaptic neurons. In addition, however, they have neurotoxic
effects on dopaminergic and serotonergic neurons. Their
euphoric and reinforcing effects are mediated through dopamine
and the mesolimbic system, whereas their cardiovascular effects
are caused by the release of norepinephrine. Chronic use leads to
neuronal degeneration in dopamine-rich areas of the brain, which
may increase the risk for the eventual development of Parkinson’s
disease.
Amphetamines can be abused orally, intranasaly, intrave-
nously, or by smoking. The most frequently used drugs are dex-
troamphetamine (Dexedrine), methamphetamine (Desoxyn),
and methylphenidate (Ritalin). Methamphetamine is known on
the street as ice, crank, meth, crystal, tina, glass, and yaba. Illicit use
of amphetamines has increased substantially, in part because (a)
it is easily and quickly synthesized from ephedrine or pseudo-
ephedrine (Fig. 126-4), and (b) its psychotropic effects persist
for up to 24 hours. The anorexiants, phenmetrazine and phenter-
mine, which are structurally and pharmacologically similar to
amphetamine, also have been used illicitly.
Tolerance to the stimulant effects of amphetamines develops
rapidly, and toxic effects can occur with higher doses. Acute
amphetamine toxicity is characterized by excessive sympathomi-
metic effects, including tachycardia, hypertension, hyperthermia,
cardiac tachyarrhythmia, tremors, seizures, and coma. The patient
may experience irritability, hypervigilance, paranoia, stereotyped
compulsive behavior, and tactile, visual, or auditory hallucina-
tions. The clinical picture may simulate an acute schizophrenic
psychosis. The symptoms of withdrawal are similar to those seen
with cocaine (see discussion of cocaine), but the acute psychosis
and paranoia are often pronounced.
The treatment of amphetamine abuse centers on a quiet envi-
ronment, benzodiazepines for anxiety, and sodium nitroprusside
for severe hypertension. Antipsychotics, such as haloperidol, can
reduce the agitation and psychosis by blocking the effect of
Ephedrine Pseudoephedrine
OH OH
H H
N N
Amphetamine Methamphetamine
H
NH2 N
FIGURE 126-4  The chemical structures of amphetamine and meth-
amphetamine, which can be easily manufactured from ephedrine or
pseudoephedrine given that they are structurally similar and widely
available.
dopamine on the CNS receptor. Urine acidification with ammo-
nium chloride accelerates amphetamine excretion.
  ILLICIT DRUG ABUSE
Cocaine
Among individuals 12 years old or older in 2011, 1.4 million had
used cocaine within the previous month, and 670,000 had used
it for the first time within the previous 12 months. Cocaine can
be taken orally or intravenously; alternatively, because it is well
absorbed through all mucous membranes, abusers may achieve a
high blood concentration after intranasal, sublingual, vaginal, or
rectal administration. Its freebase form (called crack because of
the popping sound it makes when heated) is heat stable, and it
can be smoked. Crack cocaine is considered to be the most
potent and addictive form of the drug. Euphoria occurs within
seconds after crack cocaine is smoked, and is short lived. Com-
pared with smoking crack cocaine or intravenous injection of the
drug, mucosal administration results in a slower onset of action,
a later peak effect, and a longer duration of action. The blood
half-life is approximately 1 hour. The drug’s major metabolite is
benzoylecgonine, which can be detected in the urine for 2 to 3
days after a single dose.
An intense, pleasurable reaction lasting 20 to 30 minutes
occurs after cocaine use, after which rebound depression, agita-
tion, insomnia, and anorexia occur, which are then followed by
fatigue, hypersomnolence, and hyperphagia (the crash). This
crash usually lasts 9 to 12 hours but occasionally may last up to
4 days. Users often ingest the drug repetitively at relatively short
intervals to recapture the euphoric state and to avoid the crash.
On occasion, sedatives or alcohol are ingested concomitantly to
reduce the intensity of anxiety and irritability associated with the
crash. The combination of cocaine and intravenously adminis-
tered heroin (so-called speedball, snowball, blanco, boy-girl,
Bombita, Belushi, or dynamite) is often used so that the abuser can
experience the cocaine-induced euphoria and then float down on
the opiate. Unfortunately, this combination has been reported to
cause sudden death. People who use cocaine in temporal
 Chapter 126  Alcohol and Substance Abuse 1135
proximity to the ingestion of ethanol produce the metabolite
cocaethylene, which has also been implicated in cocaine-related
deaths.
Cocaine blocks the presynaptic reuptake of norepinephrine
and dopamine, producing an excess of these neurotransmitters at
the site of the postsynaptic receptor. Thus, cocaine acts as a pow-
erful sympathomimetic agent, resulting in tachycardia, hyperten-
sion, tachypnea, hyperthermia, agitation, pupillary dilation,
peripheral vasoconstriction, and seizures. Cocaine causes potent
vasoconstriction of cerebral arteries and, therefore, may result in
a stroke. It is associated with myocardial ischemia and arrhyth-
mias and, in rare cases, with myocardial infarction in young
persons with normal or only minimally diseased coronary
arteries. The principal mechanisms of ischemia and infarction
are coronary arterial vasoconstriction, thrombosis, platelet
aggregation, tissue plasminogen activator inhibition, increased
myocardial oxygen demand, and accelerated atherosclerosis
(Fig. 126-5).
For patients with cocaine-induced hypertension or tachycar-
dia, labetalol and benzodiazepines are usually effective in lower-
ing systemic arterial pressure and heart rate. Patients with acute
myocardial infarction should receive aspirin, heparin, nitroglyc-
erin, and, if indicated, reperfusion therapy (with a thrombolytic
agent or primary coronary intervention). The use of β-adrenergic
blockers should be avoided, since ischemia may be worsened by
unopposed α-adrenergically mediated coronary arterial vasocon-
Increased heart rate
Increased blood pressure
Increased myocardial contractility
Increased α-adrenergic stimulation
Increased endothelin production
Increased nitric oxide production
Increased plasminogen-activator inhibitor
Increased platelet activation and aggregability
Increased endothelial permeability
FIGURE 126-5  The mechanisms by which cocaine may induce myocardial ischemia or infarction. Cocaine may cause increases in the determinants
of myocardial oxygen demand when oxygen supply is limited (top), when intense vasoconstriction of the coronary arteries occurs (middle), or when
accelerated atherosclerosis and thrombosis are present (bottom).
striction. Patients with a normal electrocardiogram or nonspe-
cific changes can be managed safely with observation.
The immediate treatment of acute cocaine intoxication
includes obtaining vascular and airway access, if needed, and
careful electrocardiographic monitoring. Benzodiazepines can be
given to control CNS agitation; haloperidol or risperidone can
be used in the severely agitated patient. A supportive environ-
ment is needed, but detoxification is not required, given that few
physical signs of true dependence are present.
Most chronic cocaine abusers have psychological dependence
and an intense craving for cocaine. Personal and group therapies
are important adjuncts to pharmacologic treatment, but relapse
is common and is difficult to manage. Although no medication is
FDA approved for treatment of cocaine addiction, disulfiram,
modafinil, anticonvulsants (e.g., topiramate and tiagabine), sero-
tonin reuptake inhibitors (e.g., citalopram), serotonin receptor
antagonists (e.g., ondansetron), and GABA receptor agonists
(e.g., baclofen) have shown some promise in promoting cocaine
abstinence.
Cannabis
The cannabinoid drugs include marijuana (the dried flowering
tops and stems of the hemp plant) and hashish (a resinous extract
of the hemp plant). Marijuana is the most commonly used illicit
drug in the United States. (It has been recently legalized for rec-
reational use in Alaska, Colorado, Oregon, and Washington.) In
Increased
myocardial oxygen
demand with
limited oxygen
supply
Atherosclerotic
plaque
Vasoconstriction
Smooth muscle
cell
Platelets
Fibrin
Accelerated
atherosclerosis
and thrombosis
Atherosclerotic
plaque
1136 Section XIX  Alcohol and Substance Abuse
2011, an estimated 18.1 million Americans had used it in the past
month. Between 2007 and 2011, the rate of use increased from
5.8 to 7.0%, and the number of users increased from 14.5 million
to 18.1 million. Nearly 5.0 million persons used marijuana on a
daily or almost daily basis over a 12-month period. Marijuana
and hashish are among the drugs most commonly used by ado-
lescents, with approximately one half of 12th graders admitting
use at least once and 20% reporting that they are current users.
Most of their pharmacologic effects come from metabolites of
δ-9-tetrahydrocannabinol, which bind to specific cannabinoid
receptors located in the CNS, spinal cord, and peripheral nervous
system. The primary mode of use is smoking, with mood-altering
and intoxicating effects noted within 3 minutes and peak effects
in approximately 1 hour. The acute physiologic effects are dose-
related and often include increased heart rate, conjunctival con-
gestion, dry mouth, fine tremor, muscle weakness, and ataxia.
Psychoactive effects include euphoria, enhanced perception of
colors and sounds, drowsiness, inattentiveness, and inability to
learn new facts. Tolerance and physical dependence occur, and
chronic users may experience mild withdrawal symptoms of irri-
tability, restlessness, anorexia, insomnia, or mild hyperthermia.
Rarely, acute psychosis with panic reactions occurs. The treat-
ment of withdrawal is supportive and includes reassurance;
benzodiazepines may be used in severely agitated patients. Can-
nabinoids have been used as antiemetic agents in patients with
cancer receiving chemotherapy, for weight stimulation (in
patients with cancer or HIV infection), and in the treatment of
glaucoma.
Synthetic marijuana is a psychoactive designer drug composed
of a mixture of herbs, spices, or shredded plant material that is
sprayed with synthetic chemicals that mimic the effects of can-
nabis when smoked or prepared as a tea. They have been sold
widely in “head shops” as well as through the internet and are
best known by the brand names K2 and Spice. Spice products
are popular among young people; of the illicit drugs most used
by high school seniors, they are second only to marijuana. Syn-
thetic cannabis can precipitate acute psychosis or a worsening
of previously stable psychotic disorders; they also may trigger a
chronic (long-term) psychotic disorder among vulnerable indi-
viduals, such as those with a family history of mental illness. K2
ingestion has been associated with myocardial infarction and
death. Regular users may experience withdrawal and addiction
symptoms.
Hallucinogens and Dissociative Drugs
Hallucinogens (drugs that cause hallucinations) include lysergic
acid diethylamide (LSD), mescaline, psilocybin, and ibogaine.
Dissociative drugs distort perceptions of sight and sound
and produce feelings of detachment (dissociation) without
causing hallucinations. They include phencyclidine (PCP),
ketamine, salvia, and dextromethorphan (a widely available
cough suppressant).
LSD is the most potent of the hallucinogenic drugs. Although
it is known to interact with serotonin receptors in the cerebral
cortex and locus ceruleus, its precise psychoactive mechanism is
unknown. Within 30 minutes of its oral ingestion, sympathomi-
metic effects appear, including mydriasis, hyperthermia, tachy-
cardia, elevated blood pressure, diaphoresis, dry mouth, increased
alertness, tremors, and nausea. Within 2 hours, the psychoactive
effects become apparent, with heightened perceptions (highly
intensified colors, smells, sounds, and other sensations), body
distortions, mood variations, and visual hallucinations. An acute
panic reaction may occur, sometimes leading to self-injury or
suicide. After approximately 12 hours, the syndrome begins to
subside, but fatigue and tension may persist for another day.
Flashbacks (brief recurrences of the hallucinations) may occur
days or even weeks after the last dose but tend to disappear
without treatment. Acute panic reactions are best treated in a
supportive environment; benzodiazepines can be given to
severely agitated patients.
PCP is a potent, addictive hallucinogen that produces a
prompt stimulant effect similar to that of amphetamines, with
feelings of euphoria, power, and invincibility. Patients may have
hypertension, tachycardia, hyperthermia, bidirectional nystag-
mus, slurred speech, ataxia, hallucinations, extreme agitation,
and rhabdomyolysis. With more severe reactions, patients may
be brought to medical attention in a coma-like state, with open
eyes and pupils that are partially dilated, a decreased pain
response, brief periods of excitation, and muscle rigidity. On
occasion, PCP users may have hypertensive urgency, seizures,
and bizarre (often violent) behavior, which lead to suicide or
extreme violence toward others. Tolerance and mild withdrawal
symptoms have been seen in daily users, but the major problem
is drug craving. Treatment entails a quiet environment, sedation
with benzodiazepines, hydration, haloperidol for terrifying hal-
lucinations, and suicide precautions. Continuous gastric suction
and acidification of the urine with intravenous ammonium chlo-
ride or ascorbic acid may aid in the drug’s excretion, but acidifica-
tion may increase the risk of renal failure if rhabdomyolysis is
present.
Ketamine is a rapidly acting general anesthetic; unlike most
anesthetics, it produces only mild respiratory depression and
appears to stimulate the cardiovascular system. Adverse effects,
including delirium and hallucinations, limit its use as a general
anesthetic in humans. Similar to PCP, ketamine is a dissociative
anesthetic. In addition, it has both analgesic and amnestic prop-
erties and is associated with less confusion, irrationality, and
violent behavior than PCP. Ketamine is one of the club drugs that
have been implicated in date rape.
Inhalants
The inhalants may be classified as (1) organic solvents, including
toluene (airplane glue and spray paint), paint thinners, kerosene,
gasoline, carbon tetrachloride, shoe polish, acetone (nail polish
removers and Liquid Paper), xylene (permanent markers), and
degreasers (dry cleaning fluids); (2) gases, such as butane,
propane, aerosol propellants, and anesthetics (ether, chloroform,
halothane, and nitrous oxide); and (3) nitrites, such as cyclohexyl
nitrite, amyl nitrite, and butyl nitrite (room deodorizer). These
substances are most often inhaled by children or young adoles-
cents, after which they produce dizziness and intoxication within
minutes. Prolonged exposure or daily use may lead to hearing
loss, bone marrow depression, cardiac arrhythmias, cerebral
degeneration, peripheral neuropathies, and damage to the liver,
kidneys, or lungs. A characteristic “glue sniffer’s rash” around the
nose and mouth is sometimes seen after prolonged use. In rare
 Chapter 126  Alcohol and Substance Abuse 1137
instances, death may occur, most likely from hypoxemia, cardiac
arrhythmias, pneumonia, or aspiration of vomit while uncon-
scious. Detoxification is rarely required for the patient who has
abused these substances, but psychiatric treatment may be
needed to prevent relapse.
Designer Drugs
The term designer drug refers to illicit synthetic drugs, many of
which have increased potency in comparison with their parent
compounds. The most common designer drugs include analogs
of fentanyl, meperidine, piperazine, and methamphetamines. The
best-known fentanyl derivatives are α-methyl fentanyl (China
white), parafluorofentanyl, and 3-methyl fentanyl. Because these
drugs are approximately 1000 times as potent as heroin, it is not
surprising that fatal overdoses from respiratory depression have
been reported.
The major meperidine derivatives are 1-methyl-4-phenyl-4-
propionoxypiperidene (MPPP) and 1-methyl-4-phenyl-1, 2, 3,
6-tetrahydropyridine (MPTP), each of which produces euphoria
similar to that caused by heroin. In some users, MPTP causes
neuronal degeneration in the substantia nigra, which produces an
irreversible form of Parkinson’s disease.
Piperazines, a new class of designer drugs of abuse, are com-
monly sold as party pills in the form of tablets, capsules, or
powders on the drug black market and in so-called head shops or
over the internet under the names of Frenzy, Bliss, Charge,
Herbal ecstasy, A2, Legal X and Legal E. 1-Benzylpiperazine
(BZP) is the most prevalent of these compounds. Aside from
BZP and 1-(3,4-methylenedioxybenzyl) piperazine (MDBP),
the phenylpiperazine derivatives 1-(3-trifluoromethylphenyl)
piperazine (TFMPP), 1-(3-chloro phenyl) piperazine (mCPP),
and 1-(4-methoxyphenyl) piperazine (MeOPP) are often
abused. Because piperazines and amphetamines cause similar
pharmacologic symptoms, piperazine poisoning can easily be
wrongly diagnosed as amphetamine poisoning. Furthermore,
piperazines are not detected by routinely used immunochemical
screening procedures for drugs of abuse, but they require an
appropriate toxicologic analysis (e.g., by gas chromatography-
mass spectrometry). The methylenedioxy synthetic derivatives of
amphetamine and methamphetamine are generally referred to as
ecstasy and include 3, 4-methylenedioxy methamphetamine
(MDMA, also known as Adam); 3, 4-methylenedioxy-ethylam-
phetamine (MDEA, also known as Eve); and N-methyl-1-
(3, 4-methylenedioxyphenyl)-2-butanamine (MBDB, also
known as Methyl-J or Eden). These drugs have CNS stimulant and
hallucinogenic properties. They produce elevated mood and
increased self-esteem and may cause acute panic, anxiety, para-
noia, hallucinations, tachycardia, nystagmus, ataxia, and tremor.
Deaths in some users have been attributed to cardiac arrhyth-
mias, hyperthermia with seizures, and intracranial hemorrhage.
Prospectus for the Future
Recent research is focused on so-called vaccine strategies,
whereby protein-conjugated analogues of cocaine would be
administered to produce anti-cocaine antibodies that bind
cocaine, thereby preventing its passage across the blood-brain
barrier. A novel pharmacokinetic approach to the treatment of
drug toxicity involves the development of compounds that can
be administered safely to humans and that accelerate the metabo-
lism of the drug to inactive components. For example, catalytic
antibodies have been developed to accelerate cocaine metabo-
lism and are administered parentally. In experimental animals,
mutations of human butyrylcholinesterase (one of the enzymes
responsible for the metabolism of cocaine) accelerate cocaine
metabolism and antagonize cocaine’s behavioral and toxic effects.
SUGGESTED READINGS
Amato L, Minozzi S, Davoli M: Efficacy and safety of pharmacological
interventions for the treatment of the Alcohol Withdrawal Syndrome,
Cochrane Database Syst Rev (6):CD008537, 2011.
Anton RF: Naltrexone for the management of alcohol dependence, N Engl J Med
359:715–721, 2008.
Arbo MD, Bastos ML, Carmo HF: Piperazine compounds as drugs of abuse,
Drug Alcohol Dep 122:174–185, 2012.
Capriola M: Synthetic cathinone abuse, Clin Pharm Adv Appl 5:109–115, 2013.
Centers for Disease Control and Prevention: Alcohol Related Disease Impact
(ARDI) application, 2012. Available at: http://apps.nccd.cdc.gov/DACH_
ARDI/Default.aspx. Accessed November 2014.
Edenberg HJ: The genetics of alcohol metabolism: role of alcohol dehydrogenase
and aldehyde dehydrogenase variants. Available at: http://pubs.niaaa.nih.gov/
publications/arh301/5-13.htm. Accessed October 2014.
Ferri MMF, Amato L, Davoli M: Alcoholics Anonymous and other 12-step
programs for alcohol dependence, Cochrane Database Syst Rev 4:1–26, 2008.
Jonas DE, Garbutt JC, Amick HR, et al: Behavioral counseling after screening for
alcohol misuse in primary care: a systematic review and meta-analysis for the
U.S. Preventive Services Task Force, Ann Intern Med 157:645–654, 2012.
Kao D, Bartelson BB, Khatir V, et al: Trends in reporting methadone-associated
arrhythmia, 1997-2011, Ann Int Med 158:735–740, 2013.
Lim SS, Vos T, Flaxman AD: A comparative risk assessment of burden of disease
and injury attributable to 67 risk factors and risk factor clusters in 21 regions,
1990–2010: a systematic analysis for the Global Burden of Disease Study 2010,
Lancet 380:2224, 2012.
Pruett D, Waterman EH, Caughey AB: Fetal alcohol exposure; consequences,
diagnosis, and treatment, Obstet Gynecol Surv 68:62–69, 2013.
Rosner R, Hackl-Herrwerth A, Leucht P, et al: Acamprosate for alcohol
dependence, Cochrane Database Syst Rev (9):CD004332, 2010.
Schindler CW, Goldberg SR: Accelerating cocaine metabolism as an approach to
the treatment of cocaine abuse and toxicity, Futuer Med Chem 4:163–175,
2012.
Substance Abuse and Mental Health Services Administration: Results from the
2011 National Survey on Drug Use and Health: Summary of National
Findings, NSDUH Series H-44, HHS Publication No. (SMA) 12-4713,
Rockville, Md., 2012, Substance Abuse and Mental Health Services
Administration. Available at http://store.samhsa.gov/product/Results-from
-the-2011-National-Survey-on-Drug-Use-and-Health-NSDUH-/SMA12
-4713. Accessed November 2014.
Warner M, Chen LH, Makuc DM, et al: Drug poisoning deaths in the United
States, 1980-2008, NCHS Data Brief 1–8, 2011.