The n e w e ng l a n d j o u r na l
case records of the massachusetts general hospital
From the Department of Neurology, Yale
University School of Medicine, New Ha-
ven, CT (D.M.G.); and the Departments
of Medicine (G.K.R.), Radiology (R.G.G.),
and Pathology (D.M.), Massachusetts
General Hospital; the Departments of
Medicine (G.K.R.), Radiology (R.G.G.),
and Pathology (D.M.), Harvard Medical
School; and the Division of Epidemiology
and Immunization, Massachusetts De-
partment of Public Health (V.L.) — all in
Boston.
This article was updated on January 17,
2013, at NEJM.org.
N Engl J Med 2013;368:172-80.
DOI: 10.1056/NEJMcpc1209935
Copyright © 2013 Massachusetts Medical Society.
172
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of m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 1-2013: A 63-Year-Old Man with
Paresthesias and Difficulty Swallowing
David M. Greer, M.D., Gregory K. Robbins, M.D., M.P.H.,
Virginia Lijewski, M.P.H., R. Gilberto Gonzalez, M.D., Ph.D.,
and Declan McGuone, M.B., B.Ch.
PR E SEN TAT ION OF C A SE
Dr. Andrew M. Brunner (Medicine): A 63-year-old man was admitted to this hospital
because of paresthesias, difficulty drinking liquids, and anxiety.
The patient had been well until 4 days before admission, when aching devel-
oped in the left elbow, which improved with ibuprofen. The next day, right-elbow
discomfort occurred, and he had decreased appetite. Two days before admission,
he noted difficulty forming words, mild light-headedness, and mild recurrent pain
in both elbows. An attempt to drink a glass of water precipitated a gagging sensa-
tion. He had difficulty breathing and could not swallow the water. The choking
sensation resolved when he spat out the water, but it recurred with subsequent
attempts. He stopped drinking liquids and became increasingly anxious. One day
before admission, he was unable to shower because of increased anxiety and
noted intermittent decreased fluency in his speech and pruritus at the nape of his
neck. He was concerned that he was having a stroke, and he drove to the emer-
gency department at a local hospital.
On examination, the temperature was 37.8°C, the blood pressure 111/81 mm Hg,
the pulse 97 beats per minute, the respiratory rate 18 breaths per minute, and the
oxygen saturation 96% while the patient was breathing ambient air. He was inter-
mittently very anxious and hyperventilating. When given a cup of water or juice,
he gagged as the cup neared his mouth and coughed while attempting to drink,
with improvement after he expectorated the liquid. He was able to swallow solids.
The remainder of the examination was normal. The blood levels of hemoglobin,
electrolytes, total protein, albumin, creatine kinase isoenzymes, and troponin T were
normal, as were the hematocrit, platelet count, and red-cell indexes; tests of co-
agulation and renal and liver function were also normal. Other test results are
shown in Table 1. An electrocardiogram (ECG) showed sinus rhythm at a rate of
87 beats per minute, left ventricular hypertrophy, and a QRS-complex duration of
134 msec, without evidence of acute ischemia. A chest radiograph was normal.
Lorazepam and intravenous fluids were administered, with some reduction in anxi-
ety. Computed tomography (CT) of the head without the administration of contrast
material was reportedly normal. The patient was transferred to this hospital.
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 case records of the massachusetts gener al hospital

Table 1. Laboratory Data.*

Reference Range, On Admission,

Variable Adults† Other Hospital This Hospital 2nd Hospital Day
White-cell count (per mm3) 4500–11,000 12,000 13,200 17,200
Differential count (%)
Neutrophils 40–70 75.3 76 85
Lymphocytes 22–44 17.4 17 10
Monocytes 4–11 6.5 5 5
Eosinophils 0–8 0.6 1 0
Basophils 0–3 0.2 1 0
Sodium (mmol/liter) 135–145 141 138 143
Potassium (mmol/liter) 3.4–4.8 3.4 3.2 3.5
Chloride (mmol/liter) 100–108 100 101 107
Carbon dioxide (mmol/liter) 23.0–31.9 28 25.6 18.9
Glucose (mg/dl) 70–110 121 101 145
Total protein (g/dl) 6.0–8.3 7.9 7.5 8.1
Methemoglobin (%) 0.4–1.5 0.2
Lactic acid (mmol/liter) 0.5–2.2 4.3
Cerebrospinal fluid
Color Colorless Colorless
Turbidity Clear Clear
Xanthochromia None None
Red-cell count (per mm3)
Tube 1 (out of 4) 0 16
Tube 4 (out of 4) 0 2
3)
White-cell count (per mm
Tube 1 (out of 4) 0–5 39
Tube 4 (out of 4) 0–5 27
Tube 4 differential count (%)
Lymphocytes 69
Monocytes 31
Protein (mg/dl) 5–55 50
Glucose (mg/dl) 50–75 84
Varicella–zoster virus by PCR Negative Negative
Epstein–Barr virus DNA by PCR (copies/ml) None detected None detected
Blood gases and oximetry
Specimen Unspecified
Fraction of inspired oxygen 1.00
pH 7.32–7.45 7.20
Partial pressure of carbon dioxide (mm Hg) 35–50 48
Partial pressure of oxygen (mm Hg) 40–90 102
Base excess (mmol/liter) −9.8
Oxygen saturation (%) 96

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. PCR denotes polymerase chain reaction.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.

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 The n e w e ng l a n d j o u r na l
The patient reported intermittent tremulous-
ness during the previous 2 days, retching when
thinking about drinking water, and a transient
pruritic rash on his left shoulder 2 weeks before
this presentation, without recent fever, chills,
vomiting, diarrhea, pharyngitis, or focal motor
deficits. He had hypertension, chronic ptosis of
the right eyelid, and, 6 months earlier, a tick bite
for which doxycycline had been administered.
Medications included hydrochlorothiazide and
low-dose aspirin daily; he had received influenza
and tetanus vaccinations within the past year.
He had no allergies. He drank alcohol occasion-
ally, had stopped smoking 25 years earlier, and
did not use illicit drugs. He lived with his wife
in an old house in a semirural region of New
England. He had no history of animal bites; how-
ever, bats had been seen in his home and in a
barn where he had worked several times during
the previous year. He had not traveled interna-
tionally in the past decade. His father had had
lung cancer.
On examination, the patient appeared anxious,
with dry mucous membranes. The blood pres-
sure was 171/80 mm Hg, the pulse 86 beats per
minute, the temperature 36.4°C, the respiratory
rate 16 breaths per minute, and the oxygen satu-
ration 98% while he was breathing ambient air.
Other findings included ptosis of the right eye-
lid, mild facial twitching, postural hand tremors,
and dysmetria on finger–nose–finger and heel-
to-shin testing, without truncal ataxia. Deep-
tendon reflexes were symmetrically hyperactive
throughout; plantar reflexes were flexor. There
was mild difficulty with tandem walking. The
patient’s speech was rushed and fluent, except for
occasional slurred words and pauses for word
finding; the remainder of the general and neuro-
logic examination was normal. The hematocrit,
platelet count, erythrocyte sedimentation rate,
and levels of hemoglobin, C-reactive protein, and
troponin T were normal, as were tests of renal
and liver function; toxicologic screening and test-
ing for antibodies to Ro and La were negative.
Other test results are shown in Table 1. Loraze-
pam was administered.
Magnetic resonance imaging (MRI) of the
brain without the administration of contrast
material and magnetic resonance angiography
(MRA) of the head and neck revealed abnormal
signal hyperintensity scattered in the periventric-
ular and subcortical white matter on T2-weighted
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of m e dic i n e
and fluid-attenuated inversion recovery (FLAIR)
images and was otherwise normal. A chest ra-
diograph was normal. The patient was admitted
to the hospital.
During the first day, the patient was conver-
sant and had increasing anxiety and discomfort
from ambient noises, including hospital monitor
alarms. Evaluation by a speech and language
pathologist revealed severe anxiety related to
swallowing liquids (characterized by physically
aversive behaviors when liquids began to ap-
proach his facial area), without evidence of focal
dysphagia, dysarthria, or an anatomical contra-
indication to swallowing.
Overnight, anxiety increased. Lorazepam and
haloperidol were administered. Early in the morn-
ing of the second day, the temperature rose to
38.2°C. The patient was tremulous, agitated, ori-
ented but confused, and unable to give a clear
history. After premedication with additional lor­
azepam and haloperidol, a lumbar puncture was
performed. The opening pressure was 33 cm of
water. Results of cerebrospinal fluid (CSF) anal-
ysis and other test results are shown in Table 1.
Cytologic examination and flow cytometry of
the CSF showed no abnormalities.
Immediately after the procedure, cyanosis
developed; the systolic blood pressure was
240 mm Hg, the pulse 160 beats per minute, the
respiratory rate 40 breaths per minute, and
the oxygen saturation 40 to 49%. An ECG
showed supraventricular tachycardia at a rate of
150 beats per minute, with regular rhythm and
right bundle-branch block, without ischemic
changes. The pulse suddenly decreased from
150 beats per minute to 60, then returned to
150 beats per minute before pharmacologic inter-
vention. Oxygen was administered, and the oxy-
gen saturation rose to 95%. Metoprolol and fu-
rosemide were administered intravenously,
followed by diltiazem. A repeat chest radiograph
showed perihilar fullness and loss of definition
of the pulmonary vasculature, consistent with
pulmonary edema. The trachea was intubated,
and the patient was admitted to the cardiac care
unit. An electroencephalogram (EEG) showed
moderate generalized background slowing with-
out focal features, epileptiform activity, or cor-
relation to episodes of arm tremors and twitch-
ing. CT of the brain showed no evidence of acute
injury.
Diagnostic procedures were performed.
 case records of the massachusetts gener al hospital

DIFFER EN T I A L DI AGNOSIS Infection with Corynebacterium diphtheriae results

in a toxin-mediated illness that causes an acute
Dr. David M. Greer: May we see the imaging studies? demyelinating polyneuropathy. Diphtheria usually
Dr. R. Gilberto Gonzalez: MRI of the brain with- affects the oropharynx and larynx, and palatal
out the administration of contrast material, paralysis occurs in more than 10% of cases.
along with MRA of the head and neck, revealed Bulbar dysfunction can occur early in the disease
abnormal signal hyperintensity scattered in the process, and weakness in the trunk and ex-
periventricular and subcortical white matter on tremities later. Perioral numbness, nasal speech,
T2-weighted and FLAIR images and was other- nasal regurgitation, diplopia, anisocoria, ptosis,
wise normal. No vascular abnormalities were mydriasis, dysphagia, and weakness of the tongue
identified. A chest radiograph was normal. and sternocleidomastoid muscle are common.2
Dr. Greer: The approach to a patient with an Later in the disease course, patients have a gen-
altered sensorium involves a careful history tak- eralized peripheral neuropathy, with sensory, mo-
ing, with particular attention to the time course. tor, and autonomic features. Although this pa-
This patient had a subacute but rapidly progres- tient has difficulty swallowing, he does not have
sive deterioration over a period of 4 days. Envi- cranial neuropathies or evidence of other neu-
ronmental exposure was possible owing to the ropathy, which makes diphtheria unlikely.
bats in his house and the history of a tick bite. Botulism, another toxin-mediated infection, is
Psychiatric features were prominent, including caused by blocking the transmission of acetyl-
agitation, anxiety, and confusion. He had sys- choline across cholinergic synapses of the pe-
temic features, including aching in the elbows, ripheral nervous system, which results in a de-
a previous rash, low-grade fever, and later, auto- scending, flaccid, symmetric pattern of paralysis,
nomic dysfunction. Other than chronic ptosis of with prominent bulbar palsies. Loss of ocular
the right eyelid, the neurologic examination did accommodation, blurred vision, diplopia, dysar-
not reveal any focal features (e.g., brain-stem thria, dysphonia, and facial weakness are also
dysfunction or lateralizing weakness), sensory seen.3 The sensorium is unaffected, sensation is
changes, or abnormalities in coordination. Most normal, and hyperthermia is unusual.4 In the
important, the patient had severe hydrophobia absence of bulbar palsies or paralysis, it is un-
without an anatomical cause. likely that this patient has botulism.
There are several considerations in the formu-
lation of the differential diagnosis. These include Alcohol Withdrawal
tetanus, diphtheria, botulism, delirium tremens, Patients with delirium tremens present with gen-
drug intoxication or reaction, and rabies. eralized tremulousness, agitation, delirium, and
visual or auditory hallucinations. Autonomic hy-
Bacterial toxins peractivity is the rule, with tachycardia, hyper-
Does this patient have tetanus? Patients who have tension, hyperthermia, and sweating. Seizures
tetanus present with muscle rigidity (with early can occur.5 Delirium tremens typically manifests
involvement of the masseter and facial muscles) 6 to 8 hours after the last exposure to alcohol
and can have laryngospasm, which can cause dif- and is most pronounced at 24 to 72 hours. Pa-
ficulty swallowing. Trismus and spasms of de- tients with chronic alcoholism have a sensorimo-
glutition muscles may result in difficulty with tor polyneuropathy, with prominent distal pares-
swallowing and verbal expression. Patients with thesias. This patient does not have a history of
tetanus commonly have autonomic instability and alcohol consumption or evidence of chronic alco-
a hyperadrenergic state,1 and the disease can oc- hol exposure (e.g., neuropathy), and he did not
cur after an animal bite. However, this patient had respond to medications, such as lorazepam, that
recently received a tetanus vaccine. Furthermore, would commonly treat delirium tremens.
the absence of the generalized muscle rigidity
characteristic of tetanus and of laryngospasm or Drug Reactions
another anatomical or physical explanation for Occasionally, the administration of a drug such
the hydrophobia makes tetanus less likely. The as a phenothiazine may cause an acute dystonic
alteration in mental status, a prominent feature reaction that is characterized by involuntary, sus-
in this case, is not consistent with tetanus. tained muscle contractions, typically involving the

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 The n e w e ng l a n d j o u r na l
cranial and cervical muscles. The head may be
flexed, extended, or rotated, and the jaw, tongue,
and face are commonly involved, affecting the
ability to swallow. This patient has no history of
exposure to phenothiazines or similarly acting
drugs, and he does not have sustained focal mus-
cle contractions.
This patient has no history of amphetamine
use. Amphetamines commonly cause anxiety,
hyperactivity, bruxism, tachycardia, hyperten-
sion, word-finding difficulties, and tremors and
would not have resulted in this patient’s pro-
gressive and fulminant course.
Rabies
Does this patient have rabies? Although a dog
bite is responsible for most rabies infections in
humans in the developing world, bats are re-
sponsible for most infections in humans in the
United States. Transmission is usually through a
bite, which is often unrecognized. Rabies can
also be transmitted by aerosolized exposure, such
as could occur in a cave with a very large density
of bats,6 and there have also been reports of the
transmission of rabies in association with organ
or tissue transplantation.7
Disease progression occurs in five stages: in-
cubation, prodrome, acute neurologic phase, coma,
and death (or, rarely, survival). There are two
varieties of rabies: encephalitic (or “furious,” ac-
counting for 80% of cases and consistent with
this case) and paralytic (or “dumb,” accounting
for 20% of cases).8 On the basis of the patient’s
history, it appears that he has a classic rabies
prodrome consisting of malaise and irritability,
as well as paresthesias, pain, and pruritus. We
are told that he had pruritus at the nape of his
neck. Although he has no known history of an
animal bite, pruritus due to rabies typically oc-
curs at the site of infection. The prodrome may
last a few days to weeks. This patient also pre-
sented with signs and symptoms that commonly
occur in the encephalitic phase of rabies, includ-
ing hyperexcitability, agitation, and hydropho-
bia, which is a fear of swallowing liquids. Hy-
drophobia is unique to rabies, and conditioning
can occur, in which the sight of liquids can trig-
ger laryngeal, pharyngeal, or diaphragmatic
spasms. I suspect that this patient also has aero-
phobia, or fear of air, in which the force of air
on the face or airway can trigger spasms.9 In
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of m e dic i n e
addition, hallucinations and excessive salivation
may occur in this phase of infection, although
these findings were not reported in this patient.
Death typically occurs within 5 days after the
start of the acute neurologic phase. Autonomic
dysfunction is common, with hypertension, car-
diac dysrhythmias, priapism, sweating, and fever.
This patient has classic autonomic dysfunction,
most prominent immediately after the lumbar
puncture.
Since rabies is rare in the United States, one
must have a strong suspicion that rabies is the
diagnosis. The diagnosis can usually be con-
firmed by the patient’s clinical history, presenta-
tion, and supporting information. Although this
patient did not report an animal bite, his history
of possible exposure to bats and his distinctive
clinical presentation are sufficient to lead one to
think of rabies. MRI can reveal increased T2-
weighted signal in the brain stem, hippocam-
pus, basal ganglia, hypothalamus, and thalamus,
or it can be normal.10 In this case, imaging stud-
ies are consistent with the diagnosis of rabies.
The presence of abnormal signal enhancement
is a worrisome prognostic sign, since this occurs
late in the course of the disease.11 In persons
infected with rabies, the CSF may reveal a mild-
ly increased protein level but a normal glucose
level; a mononuclear-predominant pleocytosis is
commonly seen, typically fewer than 100 white
cells per cubic millimeter.12 This patient’s CSF
formula falls neatly within these ranges and is
consistent with rabies, but it is not diagnostic.
The presence of rabies-specific neutralizing an-
tibodies in the serum and CSF of unvaccinated
patients is useful in confirming the diagnosis.
Rabies virus antigen can be detected on skin-
biopsy specimens,13 and reverse-transcription or
real-time polymerase chain reaction (PCR) test-
ing of saliva, tears, or skin-biopsy specimens can
provide supporting evidence.14
This patient’s history and clinical presentation,
especially the severe hydrophobia, are consistent
with a diagnosis of rabies. Furthermore, the lack
of a plausible alternative diagnosis makes rabies
the most likely diagnosis in this case.
Dr. Anne M. Neilan (Infectious Diseases): The
patient’s wife and I stood outside the patient’s
room. His wife handed me a sheet of paper with
a message that the patient had typed 24 hours
before admission that described his inability to
 case records of the massachusetts gener al hospital
swallow. He wrote, “While I ate breakfast and
drank coffee without incident, at midday, an at-
tempt to drink a glass of water resulted in an
immediate gagging sensation, with a sensation
that I couldn’t breathe. I could not swallow the
water. This sensation went away when I spit it
out, but happened again repeatedly on subse-
quent attempts.” And later in the day he wrote,
“Just bringing a glass of water to my lips starts
the gagging sensation.” His wife recalled that
2 to 3 months before this admission, she and
her husband had awakened in the night to a bat
flapping around the room. On the morning of
the lumbar puncture, the patient seemed wor-
ried about rabies and had written a list of all
the animals he had seen in the neighborhood,
although he did not report any animal bites. We
initially considered atypical Guillain–Barré syn-
drome and infectious causes of encephalitis,
including West Nile virus, arboviruses, herpes
simplex virus, influenza virus, Lyme disease,
and Mycoplasma pneumoniae. No cases of rabies
have been described as endemic in Massachu-
setts for more than 80 years. Nevertheless, we
were concerned about rabies and called the Mas-
sachusetts Department of Public Health (MDPH)
and the Centers for Disease Control and Preven-
tion (CDC) immediately after evaluating the pa-
tient.
CL INIC A L DI AGNOSIS
Human rabies.
Dr . Dav id M. Gr eer’s Di agnosis
Human rabies.
PATHOL O GIC A L DISCUSSION
Dr. Declan McGuone: The diagnostic test was a bi-
opsy of nuchal skin. Rabies virus antigen was
detected on direct fluorescence antibody testing
of the biopsy specimen, and sequence analysis
identified a variant found in insectivorous bats in
the myotis (mouse-eared) species. Rabies virus
nucleic acids were detected by heminested PCR.
Rabies virus IgM and IgG antibodies were pres-
ent in the patient’s serum and CSF, and a small,
neutralizing antibody response was detected in
the serum but not in the CSF. His saliva remained
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PCR-positive for rabies throughout the disease
course. All tests were performed by the CDC.
DISCUSSION OF M A NAGEMEN T
Dr. Gregory K. Robbins: Postexposure prophylaxis is
highly efficacious, but once rabies encephalitis has
begun, there is unfortunately no proven treat-
ment and the mortality rate approaches 100%.
Therefore, for most patients with symptomatic
rabies, the standard of care is palliation. However,
in this patient, after discussing treatment op-
tions (including palliative care) with his family,
we elected to pursue a more aggressive approach.
In collaboration with the CDC and investigators
at the Medical College of Wisconsin, we began
treatment according to the Milwaukee protocol
(www.chw.org/display/PPF/DocID/33223/router
.asp), a strategy developed to minimize brain in-
jury while allowing the patient’s immune response
to eradicate the virus. Key features of the proto-
col are sedation and other supportive measures
designed to suppress brain activity and minimize
injury from catecholamine storm and cerebral
vasospasm. In addition, it is important to avoid
the administration of glucocorticoids, rabies IgG,
and the rabies vaccine.
This patient was intubated and sedated with
ketamine and midazolam to induce coma. He
had a hectic hospital course notable for cerebral
vasospasms, fluctuating blood pressure, flash pul-
monary edema, diabetes insipidus, and unex-
plained fevers. Rabies-neutralizing antibodies
were detected in the serum on hospital day 18
but not in the CSF. On hospital day 27, neutral-
izing antibodies were still absent in the CSF, and
interferon beta was administered to stimulate
the development of antibody. Three days later,
the patient had fixed pupils, progressive multisys-
tem organ failure, and a flat EEG while not under
sedation. The patient’s family and caregivers
agreed to withdraw care, and he died on hospital
day 30.
Dr. McGuone: An autopsy limited to the cranial
cavity revealed a swollen, dusky-gray brain weigh-
ing 1535 g. Coronal slicing revealed a diffusely
thin, dark, soft granular cortex with blurring of
the white-matter interface (Fig. 1A). The hippo-
campi and the amygdalae were small. The cere-
bral white matter and basal ganglia were soft.
The periventricular medial thalamus, hypothala-
177
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 1. Pathological Examination of the Brain.

A coronal slice of the right cerebral hemisphere at the level of the thalamus (Panel A) shows gray discoloration of
the cortex and deep nuclei and loss of the usual sharp junction of the gray matter and white matter, as well as necrosis
around the third ventricle (Panel A, arrow). The temporal horn of the lateral ventricle is mildly dilated, reflecting loss
of brain substance. A section of frontal cortex shows loss of neurons, macrophage infiltration, and gliosis (Panel B,
Luxol fast blue–hematoxylin and eosin). There are Negri bodies in the neuron (inset, arrow). Panel C shows tegmental
infarction in the pons (upper inset), with neuronal necrosis and macrophage infiltration in the basis pontis (lower
inset) (arrows indicate higher magnification). The cerebellum has relative preservation of neurons in the granule-cell
layer of the cerebellar cortex, as compared with the neurons of the cerebral cortex, and loss of Purkinje cells (Panel D).

mus, and cerebellar dentate nuclei were dark gray
(Fig. 1A). The mammillary bodies were normal.
The descending white-matter tracts of the basis
pontis and the medulla lacked differentiation.
The substantia nigra of the midbrain was pale.
The cerebellum was mildly atrophic. Cranial nerves
and trigeminal ganglia were grossly normal.
Neurohistologic examination confirmed viral
encephalitis, with widespread microglial activa-
tion, microglial nodules, perivascular lymphocyt-
ic inflammation, and frequent Negri bodies in
the brain stem, confirming the antemortem di-
agnosis of rabies encephalitis (Fig. 1B). There
was diffuse neuronal necrosis and a macrophage
response throughout the cortical ribbon, hippo-
campus, basal ganglia, thalamus, and brain stem.
Neurons of the lateral geniculate nucleus and a
lateral thalamic nucleus were relatively preserved.

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 case records of the massachusetts gener al hospital

Neuronal necrosis was particularly severe in the prophylaxis. Nine health care workers were con-
basis pontis, with an associated macrophage sidered to have had sufficient exposure to warrant
response (Fig. 1C). In the cerebellum, there was postexposure prophylaxis. Twenty-one of the pa-
prominent loss of Purkinje cells, with a striking tient’s close contacts were questioned about po-
preservation of neurons in the granule-cell layer tential exposure (e.g., through kissing or shar-
(Fig. 1D). The dentate nucleus had an occasional ing food, drinks, or cigarettes), and five received
Negri body. This pattern of pontocerebellar dam- postexposure prophylaxis.
age is not easily explained by global hypoxic– A Physician: If well patients report seeing a bat
ischemic injury and is much more suggestive of flying around the house, what should they do?
a direct viral cytolytic effect. The distribution of Ms. Lijewski: We recommend postexposure pro-
the gray-matter necrosis (i.e., in the medial thala- phylaxis only in situations in which contact with
mus, hypothalamus, and periaqueductal region) a bat cannot be ruled out, such as when a person
also suggests a superimposed nutritional defi- awakens to find a bat in the room they are sleep-
ciency. There was mild chronic trigeminal gan- ing in. That is what happened in this case.
glionitis with dropout of occasional ganglion Dr. Eric S. Rosenberg (Pathology): If we encounter
cells. No Negri bodies in the trigeminal ganglia a patient with symptomatic rabies, should we
were identified. One branch of the trigeminal implement the Milwaukee protocol?
nerve showed marked wallerian degeneration. Dr. Robbins: There have been several reports of
patients who survived rabies,16 although none
DISCUSSION OF EPIDEMIOL O GY had detectable rabies antigen or virus. Of these,
the most tantalizing case was a 15-year-old teen-
Ms. Virginia Lijewski (Massachusetts Department of ager from Wisconsin who survived after she was
Public Health): In 2011 in Massachusetts, 110 ani- treated according to the Milwaukee protocol.17,18
mals with rabies were identified. Bats accounted Subsequent reports of the use of this strategy
for 20 (18%) of the animals that tested positive. have not shown similar success,19 and there is
Most of the bats with rabies were identified in no good evidence to support the use of the pro-
the summer and early fall, which was when this tocol, although there are no other reasonable
patient was probably exposed. alternatives outside of palliative care. This pro-
The MDPH received more than 1000 calls tocol should be considered only for persons
about potential rabies exposures in 2011. Expo- early in the course of symptomatic disease who
sures are assessed individually, and management are otherwise in good health. It is critically im-
recommendations are made on the basis of cur- portant that patients and family members un-
rent guidelines published by the Advisory Com- derstand that this approach is unlikely to be
mittee on Immunization Practices (ACIP).15 In successful and that there is a high risk of neuro-
this patient, exposure information was obtained logic sequelae if the patient survives.
from the family after diagnosis. It was reported
that several weeks before the onset of symptoms, A NAT OMIC A L DI AGNOSIS
the patient had awoken to a bat flying around
his face during the night and that he had direct Rabies encephalitis.
contact with the bat. The reported exposure sce- This case was presented at Medical Grand Rounds.
nario meets the ACIP criteria for the recommen- No potential conflict of interest relevant to this article was re-
dation of the administration of postexposure ported.
Disclosure forms provided by the authors are available with
prophylaxis. the full text of this article at NEJM.org.
The patient was seen at two health care fa- We thank Dr. E. Tessa Hedley-Whyte for review of an earlier
cilities, and 122 health care workers involved in version of the manuscript; Drs. Ann Neilan, James Kimo
Takayesu, Stephen Neil Gomperts, Nicholas A. Morris, and Eyal
his care were assessed. Any person with expo- Kimchi and Ms. Rebecca Santos for their assistance with the
sure to the patient’s saliva, CSF, or brain tissue, case history; Dr. Catherine Brown of the MDPH; Dr. Rodney E.
through the mucous membranes or through open Willoughby of the Medical College of Wisconsin for assistance
with implementation of the Milwaukee protocol; and Dr.
wounds, within 10 days before the onset of symp- Charles E. Rupprecht of the CDC. All rabies diagnostic testing
toms is considered a candidate for postexposure was performed at the CDC.

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 case records of the massachusetts gener al hospital

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