Vol 27.4 - Neuroinfectious Diseases.2021

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AUGUST 2021
VOL. 27 NO. 4 Neuroinfectious Disease
Guest Editor: Aaron L. Berkowitz, MD, PhD
816 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
818 Approach to Neurologic Infections

Aaron L. Berkowitz, MD, PhD
836 Meningitis
Allen J. Aksamit Jr, MD, FAAN; Aaron L. Berkowitz, MD, PhD
855 Encephalitis and Brain Abscess

Arun Venkatesan, MD, PhD
887 Infections of the Spine and Spinal Cord

Shamik Bhattacharyya, MD, MS; Michael J. Bradshaw, MD
921 Infections of the Peripheral Nervous System

Samantha LoRusso, MD
943 Parasitic Infections of the Nervous System

Hector H. Garcia, MD, PhD
963 Neurologic Complications of Human Immunodeficiency Virus

Marie F. Grill, MD
992 Neurologic Complications of Tuberculosis

Deanna Saylor, MD, MHS
DENOTES CONTINUUM
AUDIO INTERVIEW
1018 Neurosyphilis
Felicia Chow, MD, MAS
1040 Neurologic Complications of Lyme Disease

Karen L. Roos, MD, FAAN
1051 Neurologic Manifestations of Severe Acute Respiratory Syndrome

Coronavirus 2 Infection
Avindra Nath, MD
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1066 Neurologic Infections in Patients on Immunomodulatory and
Immunosuppressive Therapies
Pria Anand, MD
1105 Congenital Infections of the Nervous System

Payal Patel, MD
SELF-ASSESSMENT AND CME
810 Learning Objectives and Core Competencies
1127 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
1129 Postreading Self-Assessment and CME Test
1144 Postreading Self-Assessment and CME Test—Preferred Responses
1155 Errata
1156 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
Aaron L. Berkowitz, MD, PhD, Shamik Bhattacharyya, MD, MS

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Guest Editor Assistant Professor of

Professor of Neurology and Neurology, Harvard Medical
Director of Global Health, School; Associate Neurologist,
Kaiser Permanente Brigham and Women’s Hospital,
Bernard J. Tyson School of Boston, Massachusetts
Medicine, Pasadena; Attending
Relationship Disclosure: Dr Bhattacharyya
Neurologist, Kaiser Permanente has received personal compensation for
Los Angeles Medical Center, serving on a scientific advisory board for
Alexion Pharmaceuticals, Inc, and for serving
Los Angeles, California as a consultant for Teladoc Health, Inc; has
received publishing royalties from Springer
Relationship Disclosure: Dr Berkowitz serves
Publishing Company and UpToDate, Inc; and
on the editorial board for Continuum and
has given expert testimony in a trial.
has received publishing royalties from
HarperCollins Publishers, McGraw Hill,
Unlabeled Use of Products/Investigational
MedMaster, and Oxford University Press.
Use Disclosure: Dr Bhattacharyya
discusses the unlabeled/investigational
use of IV glucocorticoids in the treatment
Use Disclosure: Dr Berkowitz reports
of certain viral infections of the spinal
no disclosure.
cord (eg, varicella-zoster myelitis) and
IV immunoglobulins in the treatment of
certain viral infections of the spinal cord
(eg, enterovirus, West Nile virus, vacuolar
Pria Anand, MD myelopathy in human immunodeficiency
Assistant Professor of Neurology, virus [HIV]).
Boston University School
of Medicine and Boston
Medical Center, Michael J. Bradshaw, MD
Boston, Massachusetts Director of Medical Education,
Neurology; Co-Director,
Relationship Disclosure: Dr Anand reports
no disclosure. Center for Rare Neuroimmune
Disorders, Billings Clinic,
Use Disclosure: Dr Anand reports
Billings, Montana; Assistant
no disclosure. Professor, Neurology, Rosalind
Franklin University of Medicine
and Science, Chicago, Illinois;
Allen J. Aksamit Jr, MD, FAAN Clinical Instructor, Neurology,
Consultant, Department University of Washington,
of Neurology, Mayo Clinic; Seattle, Washington
Professor of Neurology, Mayo Relationship Disclosure: Dr Bradshaw
Clinic College of Medicine, reports no disclosure.
Rochester, Minnesota
Relationship Disclosure: Dr Aksamit reports Use Disclosure: Dr Bradshaw discusses
no disclosure. the unlabeled/investigational use of
IV glucocorticoids in the treatment of
Unlabeled Use of Products/Investigational certain viral infections of the spinal
Use Disclosure: Dr Aksamit reports no cord (eg, varicella-zoster myelitis) and
disclosure. IV immunoglobulins in the treatment of
certain viral infections of the spinal cord
(eg, enterovirus, West Nile virus, vacuolar
myelopathy in human immunodeficiency
virus [HIV]).
812 AU G U S T 2 0 2 1

Felicia Chow, MD, MAS Marie F. Grill, MD
Associate Professor of Assistant Professor of
Neurology and Medicine Neurology, Mayo Clinic,
(Infectious Diseases), Scottsdale, Arizona
University of California,
Relationship Disclosure: Dr Grill reports no
San Francisco, California disclosure.
Relationship Disclosure: Dr Chow has Unlabeled Use of Products/Investigational

received personal compensation for Use Disclosure: Dr Grill discusses
speaking engagements from the University the unlabeled/investigational use
of California, San Francisco, for the annual of neuropathic pain medications
Recent Advances in Neurology meeting and (amitriptyline, lamotrigine, lidocaine
for serving as an expert physician for Grand gel, and topical capsaicin cream)
Rounds and has received research/grant not specifically approved for human
support from the National Institutes of Health immunodeficiency virus (HIV)-
(K23NS105575, R21TW010148, R21TW011035). associated neuropathy, as well cidofovir,
mirtazapine, and pembrolizumab for
Unlabeled Use of Products/Investigational the treatment of progressive multifocal
Use Disclosure: Dr Chow reports no leukoencephalopathy.
disclosure.
Neurologist, Colorado
Head, Cysticercosis Unit,
Permanente Medical Group,
Instituto Nacional de Ciencias
Department of Neurology,
Neurologicas; Director, Center
Denver, Colorado
for Global Health, Universidad
Peruana Cayetano Heredia, Relationship Disclosure: Dr LoRusso has
received a research education grant from
Lima, Peru the National Institute of Neurological
Disorders and Stroke (NeuroNext Fellowship;
Relationship Disclosure: Dr Garcia has
5U24NS107205-03).
served as an associate editor for the
American Journal of Tropical Medicine
and Hygiene and PLOS Neglected Tropical
Use Disclosure: Dr LoRusso reports no
Diseases and as a board member of the
disclosure.
Oxfendazole Development Group and has
received research grants from the Fogarty
International Center (D43TW001140),
National Institute of Allergy and Infectious
Disease (U19AI129909), and National
Institute of Neurological Disorders and
Stroke (U01NS086974).

Use Disclosure: Dr Garcia reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 813

CONTRIBUTORS (CONTINUED)
Avindra Nath, MD Deanna Saylor, MD, MHS

Chief, Section of Infections Assistant Professor of Neurology,
of the Nervous System, and Director, Johns Hopkins Global
Clinical Director, National Neurology Program, Johns
Institute of Neurological Hopkins University School of
Disorders and Stroke; Medicine, Baltimore, Maryland;
National Institutes of Health, Director, Post-Graduate Training
Bethesda, Maryland Program in Neurology, University
of Zambia School of Medicine,
Relationship Disclosure: Dr Nath has served
on the editorial board for Brain, as a section Lusaka, Zambia
editor for Frontiers of Neurology, and
as an associate editor for the Journal of Relationship Disclosure: Dr Saylor has
Neurovirology and has received research received research/grant support from the
grants from the National Institutes of Health American Academy of Neurology, National
(NS03130). Institute of Aging (R01 AG059504-01A),
National Institute of Mental Health
Unlabeled Use of Products/Investigational (R01 MH120693-01, P30 MH075673), National
Use Disclosure: Dr Nath reports no Institute of Neurological Disorders and
disclosure. Stroke (R01 NS094037-05S1, R21 NS118543-01),
and National Multiple Sclerosis Society.

Payal Patel, MD Use Disclosure: Dr Saylor discusses
the unlabeled/investigational use of
Acting Assistant Professor, thalidomide and nonstandard doses
University of Washington, and/or nonstandard formulations of
ethambutol, isoniazid, and rifampin for
Seattle, Washington the treatment of central nervous system
tuberculosis.
Relationship Disclosure: Dr Patel has
received compensation as an author for
MedLink, Inc, and has received research
and salary support from the National
Institutes of Health (K23MH119914). Arun Venkatesan, MD, PhD
Associate Professor; Director,
Unlabeled Use of Products/Investigational Johns Hopkins Encephalitis
Use Disclosure: Dr Patel reports no
disclosure. Center, Johns Hopkins
University School of Medicine,
Baltimore, Maryland
Karen L. Roos, MD, FAAN Relationship Disclosure: Dr Venkatesan
John and Nancy Nelson reports no disclosure.
Professor of Neurology, Indiana
University School of Medicine, Use Disclosure: Dr Venkatesan reports no
Indianapolis, Indiana disclosure.
Relationship Disclosure: Dr Roos has

received publishing royalties from Elsevier
and has given expert medical testimony
during a trial.

Use Disclosure: Dr Roos reports no
disclosure.
814 AU G U S T 2 0 2 1

Self-Assessment and CME Test Writers
James W. M. Owens Jr, MD, PhD Allison L. Weathers, MD, FAAN

Associate Professor of Neurology, Associate Chief Medical
Adjunct Associate Professor Information Officer, Cleveland
of Pediatrics, University Clinic; Assistant Professor,
of Washington School of Cleveland Clinic Lerner College
Medicine, Seattle, Washington of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Owens has Relationship Disclosure: Dr Weathers serves
served as CME co-editor for Neurology on the editorial board of Continuum and as
and has received publishing royalties from chair of the adult neurosciences specialty
UpToDate, Inc. steering board for Epic.
Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

Use Disclosure: Dr Owens reports Use Disclosure: Dr Weathers reports no
no disclosure. disclosure.

EDITOR’S PREFACE
A Topic With Culture

and Sensitivity
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This issue of Continuum is devoted to the diagnosis and management

of infections affecting the brain, meninges, spinal cord, or peripheral
nervous system. To accomplish this monumental task, I am so
pleased that Dr Aaron L. Berkowitz accepted my invitation to serve as
guest editor of this issue, assembling such a remarkable group of
experts in the field to guide us in our diagnosis and management of the wide variety of
neuroinfectious diseases that may affect our patients.
The issue begins with an article by Dr Berkowitz The next group of articles delves into details of
that describes an overall approach to the several specific categories of infections that impact
characterization and diagnosis of the broad range of the nervous system. In the first of these articles,
infections (eg, bacterial, viral, fungal, and parasitic) Dr Hector H. Garcia discusses the diagnosis and
affecting various regions of the nervous system management of parasitic infections of the nervous
and serves as an important introduction to the system, concentrating on the clinical features,
articles that follow. diagnosis, and management of cerebral malaria,
The issue then delves into infections organized toxoplasmosis, neurocysticercosis, and
by general region of the nervous system affected, neuroschistosomiasis. Dr Marie F. Grill then
starting with the article by Dr Allen J. Aksamit Jr reviews the neurologic complications of human
and Dr Berkowitz, who review the diagnosis and immunodeficiency virus (HIV), as well as its
both the empiric and the more specific associated opportunistic infections, that can affect
management of infections involving the meninges the central or peripheral nervous system.
(meningitis) from any of the wide variety of Dr Deanna Saylor next discusses the multifaceted
organisms that can invade this space. In the next neurologic complications of tuberculosis and
article, Dr Arun Venkatesan provides an extensive its management.
review of the diagnosis and management of the Dr Felicia Chow then reviews the neurologic
many potential infections of the brain parenchyma, syndromes caused by neurosyphilis and the current
whether in the form of encephalitis or as focal or and evolving diagnostic pathways and treatment
multifocal collections in the form of abscesses. regimen. Dr Karen L. Roos next provides an
Drs Shamik Bhattacharyya and Michael J. Bradshaw up-to-date review of the clinical and laboratory
then review the diagnosis and management of diagnosis and treatment recommendations of the
the many infections that affect the spinal cord or neurologic complications of Lyme disease. In the
the spine. In the final localization-based article, final article of this pathogen-based section,
Dr Samantha LoRusso discusses the clinical Dr Avindra Nath discusses the current and
diagnosis and management of the infections that still-evolving knowledge regarding the neurologic
involve the peripheral nervous system from the manifestations of severe acute respiratory syndrome
nerve roots to the muscles. coronavirus 2 infection (COVID-19).
816 AUGUST 2021

The last two articles in the issue cover specific accredited by the Royal College of Physicians and
populations of patients affected by neuroinfectious Surgeons of Canada.
disease. In the first of these articles, Dr Pria Anand This issue is included in a pilot program of
discusses the myriad neurologic infections that Continuum issues read aloud. Different from
can occur in patients on immunomodulatory and Continuum Audio, these are recordings read
immunosuppressive therapies. In the final article of verbatim from the print articles by Dr Michael
the issue, Dr Payal Patel reviews the diagnosis and Kentris, a neurologist at the Clinical Neuroscience
current management of the many congenitally Institute in Dayton, Ohio. The audio files are
acquired infections of the nervous system. available to all Continuum subscribers in the AAN’s
After reading the issue and taking the Postreading Online Learning Center at continpub.com/CME. I
Self-Assessment and CME Test written by Drs James encourage you to listen and submit the survey with
W. M. Owens Jr and Allison L. Weathers and edited your feedback on this pilot.
by Dr Joseph E. Safdieh, Associate Editor and We are also pleased to remind all readers of the
Associate Editor of Self-Assessment and CME, rollout of the new Continuum mobile experience at
readers may earn up to 20 AMA PRA Category 1 ContinuumJournal.com. Just follow the directions on
CreditsTM toward self-assessment CME or, for the inside front cover in the “Beyond the Page”
Canadian participants, a maximum of 20 hours section of this issue to save Continuum to your
toward the Self-Assessment Program (Section 3) of phone’s home screen. You will then be able to simply
the Maintenance of Certification Program of the and easily navigate content from any Continuum
Royal College of Physicians and Surgeons of Canada. issue on your mobile phone as well as read full-text
Additional credit can be obtained by listening to articles and access tables and figures wherever you
Continuum Audio interviews associated with this and are and whenever you need it, including at the point
other Continuum issues, available to all subscribers, of care.
and completing tests on the Continuum Audio web I would like to extend my sincere appreciation to
platform or mobile app. Continuum Audio is also Dr Berkowitz for his truly expert guest editorship of
this issue, including his very thoughtful and unique
organization of such an inclusive set of topics, his
gathering of such renowned experts in the field of
neuroinfectious diseases, and his skillful and
…I am so pleased that Dr Aaron L. hands-on attention to the many details throughout
Berkowitz accepted my invitation to the process of creating this issue, all to provide us
serve as guest editor of this issue, with the most up-to-date information regarding the
diagnosis and management of these potentially
assembling such a remarkable group treatable and preventable diseases, wherever in the
of experts in the field to guide us in world they may occur.
our diagnosis and management of —STEVEN L. LEWIS, MD, FAAN
the wide variety of neuroinfectious EDITOR-IN-CHIEF
diseases… © 2021 American Academy of Neurology.
CONTINUUMJOURNAL.COM 817

REVIEW ARTICLE
Approach to Neurologic
Infections

C O N T I N UU M A UD I O
INTERVIEW AVAILABLE
ONLINE
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By Aaron L. Berkowitz, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This
article provides an overview of the clinical approach
to the diagnosis of neurologic infections, focusing on the symptoms, signs,
imaging features, and laboratory findings of the major categories of
neuroinfectious diseases.
RECENT FINDINGS: Theincreased use of immunosuppressive and

immunomodulatory therapy to treat autoimmune diseases has led to an
increase in opportunistic neurologic infections. The description of
numerous causes of autoimmune antibody–mediated encephalitis over the
past decade has expanded the differential diagnosis of encephalitis
beyond infection. The emergence of metagenomic next-generation
sequencing has led to diagnoses of rare or unexpected causes of
neurologic infections and has the potential to enhance diagnostic precision
in neuroinfectious diseases.
SUMMARY: Infections of the nervous system can affect any level of the
CITE AS:
neuraxis and present over any time course. Neurologic infections may
CONTINUUM (MINNEAP MINN) present atypically with respect to clinical, radiologic, and CSF analysis
2021;27( 4 , N E U R O I NF E C T I O U S features in immunocompromised patients or older adults. A thorough
DISEASE):818–835.
evaluation including systemic features, past medical history, travel,
Address correspondence to exposures, detailed examination, neuroimaging, and CSF analysis is often
Dr Aaron L. Berkowitz, necessary to make a definitive diagnosis. It is important to be aware of the
Kaiser Permanente Bernard J. test characteristics and limitations of microbiological tests on CSF for
Tyson School of Medicine,
100 S Los Robles Ave, neurologic infections to avoid being misled by false positives or false
Pasadena, CA 91006, negatives.
aaron.l.berkowitz@kp.org.
RELATIONSHIP DISCLOSURE:
Dr Berkowitz serves on the
editorial board for Continuum
and has received publishing
INTRODUCTION
N
royalties from HarperCollins eurologic infections can affect any level of the neuraxis. Infections
Publishers, McGraw Hill, must, therefore, be considered in the differential diagnosis for any
MedMaster, and Oxford
University Press.
possible neurologic presentation: meningitis, encephalitis, focal or
multifocal brain lesions (these first three may present with
UNLABELED USE OF headache, seizures, focal deficits, encephalopathy, or coma), cranial
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE: neuropathy, myelopathy, radiculopathy, peripheral neuropathy (including
Dr Berkowitz reports no mononeuropathy, mononeuropathy multiplex, and polyneuropathy),
disclosure.
neuromuscular junction disorder, and myopathy.
Neurologic infections can be caused by any category of microbes: viruses,
© 2021 American Academy bacteria, fungi, or parasites.
of Neurology.
818 AUGUST 2021

u Viruses are composed of genetic material surrounded by a protein coat (capsid or KEY POINTS
envelope) and require the cellular machinery of another organism to replicate; they are
classified based on whether their genetic material is DNA or RNA and subsequently by ● Neurologic infections can
family according to morphologic characteristics.1 affect any level of the
u Bacteria are prokaryotic organisms (ie, unicellular without organelles or nuclear neuraxis.
membrane) classified by the staining of their cell wall (gram-positive or -negative), their
morphology (coccus, bacillus, and spiral [further distinguished as vibrio, spirillum, and ● Neurologic infections can
spirochete]), their metabolism (aerobic versus anaerobic), and other characteristics for be caused by any category
non–gram-staining organisms that are not classified by these parameters (eg, mycobacteria).2 of microbe: viruses,
bacteria, fungi, or parasites.
u Fungi are eukaryotic organisms (ie, containing organelles and a nuclear membrane)
classified as yeasts (which are unicellular), molds (which are multicellular), or dimorphic ● Infectious agents can
(fungi that can exist as either yeast or mold).3 cause disease in the nervous
u Parasites are classified as protozoa and helminths. Protozoa are unicellular organisms system by direct invasion of
including Sarcodina (amoebas), Mastigophora (flagellates), Ciliophora (ciliates), and neural tissue, production of
Sporozoa. Helminths are multicellular worms, including platyhelminths (flatworms, neurotoxins, and/or the
further divided into trematodes and cestodes), nematodes (roundworms), and immune response incited by
acanthocephalans (thorny-headed worms).4,5 the pathogen. Certain
infectious pathogens cause
a specific clinical syndrome
Infectious agents can cause nervous system disease by direct invasion of or characteristic radiologic
neural tissue, production of neurotoxins (eg, botulism, tetanus), and/or the pattern(s), but many can
immune response incited by the pathogen. Certain infectious pathogens cause a cause a wide variety of
specific clinical syndrome (eg, botulism, tetanus) or characteristic radiologic different clinical
presentations or radiologic
pattern(s) (eg, progressive multifocal leukoencephalopathy [PML] caused by the abnormalities.
JC virus; neurocysticercosis caused by Taenia solium), but many can cause a wide
variety of clinical presentations or radiologic abnormalities. Moreover, many ● In general, most viral and
microbes that cause the same clinical syndrome may be clinically and bacterial infections of the
nervous system present
radiologically indistinguishable from each other and, in some cases, acutely, emerging and
indistinguishable from noninfectious causes of the presenting syndrome. evolving over hours to days.
Definitive diagnosis requires precise microbiological diagnostic tests on CSF or a In contrast, fungal,
tissue biopsy, which may not have perfect sensitivity. mycobacterial, spirochetal,
and parasitic infections and
Therefore, practicing neurologists should be familiar with when to consider
neurosyphilis generally
infectious causes of a patient’s symptoms, signs, or radiologic abnormalities; present subacutely or
how to make a precise microbiological diagnosis and the limitations of chronically. However, many
microbiological tests; and empiric treatment strategies for potential infections exceptions to these general
principles occur.
based on the most likely pathogen(s) while awaiting the results of diagnostic
testing. In this article, a general approach to neurologic infections is provided as ● Fever is an obvious
an introduction to this issue of Continuum in which all of the topics discussed indication of an infectious
here are covered in greater depth and detail. etiology of a neurologic
presentation but may be
absent with localized
CLINICAL APPROACH central nervous system
When should a neurologic infection be considered? As with diagnostic reasoning infections (eg, brain
in any area of neurology, key considerations include syndrome identification and abscess), in
localization, time course, associated symptoms and signs, and context, including immunocompromised
patients who cannot mount
past medical history, exposures, and travel history. This article begins with a an adequate inflammatory
discussion of the features that should lead to consideration of infection in any response, and even in
presenting neurologic syndrome followed by a brief review of considerations for immunocompetent patients,
each particular localized syndrome that is discussed in greater depth in particularly infants and
older adults.
subsequent articles in this issue of Continuum.
Time Course
In general, most viral and bacterial infections of the nervous system present
acutely, emerging and evolving over hours to days. In contrast, fungal,

APPROACH TO NEUROLOGIC INFECTIONS
mycobacterial, spirochetal, and parasitic infections generally present subacutely

or chronically. However, many exceptions to these general principles occur. Viral
syndromes that may affect the nervous system nonacutely include PML caused by
the JC virus, which usually presents subacutely; human T-cell lymphotropic virus
type I (HTLV-I)-associated myelopathy (tropical spastic paraparesis), which
presents chronically; and certain direct neurologic complications of human
immunodeficiency virus (HIV), such as HIV neuropathy, HIV-associated
neurocognitive disorder, and HIV-associated vacuolar myelopathy, which present
chronically (other direct neurologic complications of HIV such as meningitis,
Guillain-Barré syndrome, and seventh nerve palsy most commonly present
acutely at the time of seroconversion). Fungal and mycobacterial infections and
neurosyphilis may present acutely if they cause seizures (as in fungal or
tuberculous meningitis) or stroke (as in meningovascular syphilis or in
fungal or tubercular meningitis). Parasitic infections that can present acutely
include neurocysticercosis (presenting with seizure) and schistosomiasis
(causing acute myelopathy).
Associated Symptoms and Signs

Fever is an obvious indication of an infectious etiology of a neurologic
presentation but may be absent with localized central nervous system (CNS)
infections (eg, brain abscess), in immunocompromised patients in whom
an inflammatory response is inadequate, and even in patients who are
immunocompetent, particularly infants and older adults.
Systemic clues to particular neurologic infections can be found in any
organ system. Skin changes associated with neurologic infections include petechial
or purpuric rash in meningococcal meningitis, dermatomal vesicular rash in
zoster, target-shaped rash in Lyme disease, and hypopigmented patches in leprosy
(Hansen disease). Otitis and sinusitis may be associated with subsequent
meningitis, and sinus involvement may also be seen in mucormycosis (generally
seen only in patients who are immunocompromised or who have uncontrolled
diabetes). Ocular findings include pupillary light-near dissociation in
neurosyphilis (Argyll Robertson pupils), retinitis in cytomegalovirus (CMV),
macular star in Bartonella henselae chorioretinitis, retinopathy in malaria, and
subconjunctival or subretinal cysts in neurocysticercosis. Pulmonary involvement
is common in endemic mycoses (coccidioidomycosis, blastomycosis,
histoplasmosis) and tuberculosis (although patients may have isolated
extrapulmonary tuberculosis affecting only the nervous system). Cardiac
involvement can be seen in Chagas disease or if brain abscess, mycotic aneurysms,
or meningitis results from endocarditis (eg, Austrian syndrome: the triad of
pneumonia, endocarditis, and meningitis due to Streptococcus pneumoniae).
Gastrointestinal symptoms such as nausea, vomiting, and abdominal cramps
commonly accompany botulism, and colitis may coexist with CMV encephalitis or
radiculitis in severely immunocompromised patients. Genital lesions may be seen
in syphilis and herpes simplex virus (HSV)-2, which may cause meningitis,
encephalitis, or lumbosacral radiculitis (Elsberg syndrome). Orchitis may be seen
with mumps, flaviviruses, lymphocytic choriomeningitis virus, and brucellosis.
Context
Although many neurologic infections can occur in otherwise healthy individuals,
a high degree of suspicion for infection must be maintained in patients who are
820 AUGUST 2021

immunocompromised due to HIV/acquired immunodeficiency syndrome (AIDS), KEY POINTS
congenital immunodeficiency, hematologic malignancy, and patients taking
● Although many neurologic
immunosuppressive/immunomodulatory medications (eg, in the setting of infections can occur in
autoimmune disease, bone marrow transplantation, or solid organ transplantation). otherwise healthy
For more information about this, refer to the article “Neurologic Infections in individuals, a high degree
Patients on Immunomodulatory and Immunosuppressive Therapies” by Pria of suspicion for infection
must be maintained in
Anand, MD,6 in this issue of Continuum. In patients with HIV, particular CD4+
patients who are
counts determine predisposition to certain neurologic infections: cryptococcal immunocompromised due to
meningitis and PML in patients with CD4+ count less than 200 cells/mm3, human immunodeficiency
toxoplasmosis and Epstein-Barr virus (EBV)-associated primary CNS lymphoma virus (HIV)/acquired
immunodeficiency
with CD4+ count less than 100 cells/mm3, and CMV encephalitis and radiculitis
syndrome (AIDS), congenital
with CD4+ count less than 50 cells/mm3. Refer to the article “Neurologic immunodeficiency,
Complications of Human Immunodeficiency Virus” by Marie F. Grill, MD,7 in this hematologic malignancy,
issue of Continuum. In immunocompromised populations, infections may present and patients taking
atypically both clinically and radiologically because of the reduced inflammatory immunosuppressive/
immunomodulatory
reaction to the infectious pathogen. In the context of immune reconstitution medications (eg, in the
resulting from treatment of HIV or withdrawal of immunomodulatory setting of autoimmune
medications, latent infections may be unmasked or active infections may disease, bone marrow
paradoxically worsen, called immune reconstitution inflammatory syndrome (IRIS). transplantation, or solid
organ transplantation).
A past medical history of prior head trauma could raise suspicion for a
CSF leak, which can predispose patients to meningitis. Patients who have ● In immunocompromised
recently undergone neurosurgery may be at risk of hospital-acquired populations, infections may
meningitis or subdural empyema with Staphylococcus species and/or present atypically both
clinically and radiologically
gram-negative rods such as Pseudomonas aeruginosa. Indwelling devices
because of the reduced
such as ventriculoperitoneal shunts can become infected, most commonly inflammatory reaction to the
with skin flora (eg, Staphylococcus epidermidis, Staphylococcus aureus, or infectious pathogen.
Cutibacterium [formerly Propionibacterium] acnes) or gram-negative bacteria.
Congenital heart disease, cardiac valvular disease, and IV drug use predispose ● Asking about place of
residence, country of origin,
to endocarditis, which can lead to neurologic infections including abscess, and travel history is
meningitis, or mycotic aneurysm. essential in the evaluation of
With increasing global travel and migration, patients may present to providers a patient with a potential
in nonendemic regions with infections acquired elsewhere. Therefore, asking neurologic infection.
about place of residence, country of origin, and travel history is essential in the ● Although infection is a
evaluation of a patient with a potential neurologic infection. Lyme disease primary consideration in the
(the most common neurologic complications of which are cranial nerve palsy, differential diagnosis of
meningitis, and radiculitis) is endemic to the northeastern and mid-Atlantic meningitis and encephalitis,
noninfectious causes must
United States as well as Europe. In the United States, the endemic fungi
be considered. Although
(which can cause meningitis or rarely brain abscess) are most common in infection is often not a
particular regions: histoplasmosis and blastomycosis in the Ohio and Mississippi primary consideration in the
River valleys (blastomycosis is also endemic in the Great Lakes region), and differential diagnosis of
myelopathy, radiculopathy,
coccidioidomycosis in the southwestern United States. Histoplasmosis is also
neuropathy, neuromuscular
endemic in Central and South America, southern Africa, and Southeast Asia; junction disorder, and
blastomycosis has been reported in Africa; coccidioidomycosis occurs in myopathy, infections can
Central and South America; and these regions are under constant evolution affect these levels of the
because of migration and climate change.8 HTLV-I (which causes tropical neuraxis and must be
considered in the
spastic paraparesis) is endemic in the Caribbean, South America, Japan, and differential diagnosis of
West Africa. Infections such as leprosy, malaria, tuberculosis, and tetanus are these conditions.
uncommon in the United States but very common worldwide and may be seen in
patients who immigrate to the United States or travelers returning from endemic
regions. Neurocysticercosis is common worldwide and commonly seen in the

United States in patients who have immigrated from or traveled to endemic

regions (Central and South America, Caribbean, Africa, and Asia).
Exposures to inquire about include animals (cats: toxoplasmosis, Bartonella;
pigs: neurocysticercosis, although direct exposure is not necessary given
fecal-oral transmission), foods (unpasteurized milk: brucellosis, Listeria;
home-canned foods: botulism), hiking/outdoor activities (Lyme disease,
arboviruses), fresh-water swimming (Naegleria fowleri; schistosomiasis in
endemic regions such as Africa, Southeast Asia, South America, Caribbean),
and subcutaneous injection of heroin also known as skin popping (wound botulism).
Localization
Although infection is a primary consideration in the differential diagnosis of
meningitis and encephalitis, noninfectious causes must be considered. Although
infection may not be a primary consideration in the differential diagnosis of
myelopathy, radiculopathy, neuropathy, neuromuscular junction disorder, and
myopathy, infections can affect these levels of the neuraxis and must be
considered in the differential diagnosis of these conditions.
MENINGITIS. Meningitis refers to inflammation of the meninges. When the brain is

involved concurrently with the meninges, the syndrome is referred to as
meningoencephalitis. Although the most common causes of meningitis are
infectious, involvement of the meninges can also occur as a result of
inflammatory disease (eg, IgG4-related disease, sarcoidosis, Behçet disease,
FIGURE 1-1
Common etiologies of meningitis by time course.
HIV = human immunodeficiency virus.
822 AUGUST 2021

Vogt-Koyanagi-Harada disease), neoplasia (carcinomatous meningitis/ KEY POINTS
leptomeningeal metastases; chemical meningitis due to rupture of epidermoid
● While the most common
cyst), and secondary to medications (eg, nonsteroidal anti-inflammatory drugs, causes of meningitis are
IV immunoglobulin [IVIg], trimethoprim-sulfamethoxazole). Infectious infectious, involvement of
meningitis may be caused by bacteria, viruses, fungi, tuberculosis, and, rarely, the meninges can also occur
parasites (eg, N. fowleri, Angiostrongylus cantonensis). as a result of inflammatory
disease (eg, IgG4-related
The time course of onset and evolution is related to the infectious organism
disease, sarcoidosis,
and classified as acute or chronic, with chronic meningitis defined as more than Behçet disease,
4 weeks of symptoms. Chronic meningitis may be progressive or recurrent. Vogt-Koyanagi-Harada
Acute infectious meningitis is most commonly bacterial or viral, whereas chronic disease), neoplasia
(carcinomatous
infectious meningitis is most commonly fungal or mycobacterial (FIGURE 1-1).
meningitis/leptomeningeal
Recurrent meningitis is often associated with HSV-2 (also known as metastases; chemical
Mollaret meningitis). meningitis due to rupture of
Characteristic symptoms of acute infectious meningitis include fever, epidermoid cyst), and
headache, neck stiffness, and altered mental status. However, these classic features secondary to medications
(eg, nonsteroidal
cannot be relied on because some may be absent, particularly in infants, older anti-inflammatory drugs, IV
adults, immunocompromised patients, and patients on anti-inflammatory immunoglobulin [IVIg],
analgesics (CASE 1-1). In one systematic review, headache was present in trimethoprim-
only 50% of patients with acute meningitis, fever in only 85%, and the triad of sulfamethoxazole).
fever, neck stiffness, and altered mental status in only 42%, although 95% of patients ● Characteristic symptoms
had two or more of these symptoms.9 Classic physical examination signs of of acute infectious
meningismus such as Kernig and Brudzinski signs are highly specific but very meningitis include fever,
insensitive.9 headache, neck stiffness,
and altered mental status.
Acute bacterial meningitis is a neurologic emergency, and delays in treatment
However, these classic
are associated with worse outcomes.10 Therefore, patients with acute meningitis features cannot be relied on
are often treated empirically for the most likely pathogens in a given patient because they may be
while awaiting CSF diagnostics to narrow coverage to the microbe ultimately absent, particularly in
infants, older adults,
diagnosed. In adults with presumed community-acquired meningitis, this
immunocompromised
coverage generally includes a third-generation cephalosporin (eg, ceftriaxone) patients, and patients on
for Neisseria meningitidis and S. pneumoniae and vancomycin to cover potentially anti-inflammatory
resistant S. pneumoniae species, with ampicillin added to cover Listeria analgesics.
monocytogenes in patients who are immunocompromised or older than 50.11 In
● Patients with acute
nosocomial meningitis, vancomycin and coverage for P. aeruginosa (with meningitis are often treated
cefepime, ceftazidime, or meropenem) are recommended as empiric empirically for the most
treatment.12 If meningoencephalitis is a concern, empiric acyclovir is likely pathogens in a given
often initiated to cover HSV until CSF analysis or MRI exonerate this patient while awaiting CSF
diagnostics to narrow
diagnosis. coverage to the microbe
In patients with acute meningitis, IV dexamethasone should be initiated with ultimately diagnosed.
or before starting antibiotics, as it reduces mortality in adults with S. pneumoniae
meningitis and decreases the risk of hearing loss in children with
Haemophilus influenzae meningitis.13 However, several studies have shown that
steroids do not appear to be beneficial in patients with acute meningitis in
low-income countries attributed to the higher likelihood of a delayed
presentation and higher burden of HIV and malnutrition.13
Nearly any virus can cause meningitis, but enteroviruses, herpesviruses, and
arboviruses are common causes.14 Acute HIV infection should also be considered
as a cause of viral meningitis, often accompanying a flulike syndrome at the time
of seroconversion.
In endemic regions, the microbiological differential diagnosis of meningitis
should be expanded to include Lyme disease (northeastern/mid-Atlantic

United States), endemic fungi (histoplasmosis blastomycosis,

coccidioidomycosis; see earlier text for endemic regions), Cryptococcus gattii
(Pacific Northwest), and tuberculosis. In patients who are
immunocompromised, Cryptococcus neoformans is a common cause of meningitis.
Fungal etiologies are treated with amphotericin and azole agents, and
tuberculosis is treated with multidrug antimycobacterial therapy (rifampicin,
isoniazid, pyrazinamide, and ethambutol) and steroids. For details of treatment
regimens for fungal meningitis, refer to the article “Meningitis” by Allen J.
Aksamit Jr, MD, FAAN, and Aaron L. Berkowitz, MD, PhD,15 in this issue of
Continuum; for information about treatment regimens for tuberculous
meningitis, see “Neurologic Complications of Tuberculosis” by Deanna Saylor,
MD, MHS,16 in this issue of Continuum.
Definitive diagnosis of the causative microbe is made through CSF analysis.
While awaiting a definitive microbiological diagnosis to narrow antimicrobial
CASE 1-1 A 56-year-old man presented with several months of headache. He

described the headache as mild but persistent, with no particular pattern
throughout the day and night. He had no associated visual loss,
weakness, sensory changes, or gait disturbance. He had a history of
pulmonary sarcoidosis in remission treated with 5 mg of prednisone daily.
He presented to a neurologist who documented a completely normal
neurologic examination, diagnosed him with tension headache, and
initiated him on amitriptyline. His headache persisted, and he sought a
second neurologic opinion.
His examination was again normal as was brain MRI. Given his history of
sarcoidosis and prednisone use, a lumbar puncture was performed. CSF
protein was 127 mg/dL, glucose was 16 mg/dL (serum glucose of
85 mg/dL), and white blood cell count was 274 cells/mm3 (96%
lymphocytes); Gram stain and India ink stain were both negative. CSF
cryptococcal antigen returned positive, and the patient was diagnosed
with cryptococcal meningitis. The patient was initiated on antifungal
therapy but had bilateral basal ganglia infarction during the course of his
illness.
COMMENT This case demonstrates how a serious neurologic infection (fungal

meningitis) can present with minimal symptoms when patients have an
abnormal immune system, blunting the inflammatory response that is
normally a major contributor to symptoms and signs. Although the dosage
of prednisone was low, sarcoidosis alone can lead to altered immunity
(most commonly the result of lymphopenia affecting T cells). This case also
underscores the importance of having a low threshold for evaluation for an
infection in patients who are immunosuppressed, as well as the
importance of heeding “red flags” in the evaluation of patients with
headache. Note that the India ink test is insensitive, and CSF cryptococcal
antigen is the most sensitive test for the diagnosis of cryptococcal
meningitis.
824 AUGUST 2021

therapy, CSF parameters can provide clues as to the most likely category of KEY POINTS
infection (see the section CSF Analysis).
● In patients with acute
Although the risk of herniation with lumbar puncture in patients with acute meningitis, IV
meningitis is thought to be low,17 CT is commonly obtained before the lumbar dexamethasone should be
puncture. The clinical features predictive of an abnormality on CT in patients initiated with or before
with meningitis are age older than 60, immunocompromise, previous history of starting antibiotics, as it
reduces mortality in adults
neurologic disease, a seizure proximate to presentation, altered level of with Streptococcus
consciousness, or focal deficits on examination.18 Neither CT nor lumbar pneumoniae meningitis and
puncture should delay initiation of empiric treatment when acute bacterial decreases the risk of hearing
meningitis is a possibility. Blood cultures obtained before antibiotics may be loss in children with
Haemophilus influenzae
diagnostic, CSF cultures do not become sterile until hours after antibiotic meningitis. However,
administration, and cellular/biochemical changes in the CSF last for up several studies have shown
to 2 to 3 days after antibiotics have been initiated.17 For further discussion, that steroids do not appear
see “Meningitis” by Allen J. Aksamit Jr, MD, FAAN, and Aaron L. Berkowitz to be beneficial in patients
with acute meningitis in
MD, PhD,15 in this issue of Continuum.
low-income countries,
attributed to the higher
ENCEPHALITIS. Encephalitis refers to inflammation of the brain parenchyma. likelihood of a delayed
Patients present with headache, altered mental status, focal neurologic deficits, presentation and higher
burden of HIV and
and/or seizures. The primary differential diagnosis for encephalitis is between
malnutrition.
infectious and immune-mediated conditions (eg, acute disseminated
encephalomyelitis and antibody-mediated autoimmune encephalitis). Infectious ● The primary differential
encephalitis is most commonly viral, with herpesviruses (most commonly diagnosis for encephalitis is
HSV-1, varicella-zoster virus [VZV]), enteroviruses, and arboviruses between infectious and
immune-mediated
(eg, West Nile virus, Eastern equine encephalitis virus) being the most frequent conditions (eg, acute
etiologies in immunocompetent patients. In immunocompromised patients, disseminated
the differential diagnosis of encephalitis expands to include CMV, human encephalomyelitis and
herpesvirus 6 (HHV-6) (most commonly in patients who have undergone antibody-mediated
autoimmune encephalitis).
hematopoietic stem cell transplantation), EBV, and adenovirus.
Characteristic MRI features and microbiological diagnosis of different ● In immunocompromised
etiologies of encephalitis are discussed in the section Neuroimaging and patients, the differential
Microbiologic Diagnosis. Specific treatment for viral encephalitis is only available diagnosis of encephalitis
expands to include
for HSV (acyclovir), VZV (acyclovir), CMV (ganciclovir, foscarnet), and
cytomegalovirus, human
HHV-6 (ganciclovir, foscarnet), and so acyclovir is often initiated empirically in herpesvirus 6 (most
patients with presumed viral encephalitis while awaiting a specific diagnosis. commonly in patients who
It is commonly reported that a definitive etiology of encephalitis is not have undergone
determined in more than half of patients.19 However, it should be noted that hematopoietic stem cell
transplantation),
cited studies preceded the characterization of many autoimmune causes of Epstein-Barr virus, and
encephalitis, which may have been the cause of previously undiagnosed cases of adenovirus.
encephalitis. Therefore, when an infectious etiology of encephalitis is not
discovered, autoimmune encephalitis should be considered and appropriate ● The spine can be affected
by infection in any of its
antibody testing obtained. compartments:
For further discussion, refer to “Encephalitis and Brain Abscess” by Arun vertebrae/discs
Venkatesan, MD, PhD,20 in this issue of Continuum. (osteomyelitis, Pott
disease), epidural/subdural
spaces (abscess), or the
FOCAL OR MULTIFOCAL BRAIN LESION(S). Focal or multifocal discrete brain lesions
spinal cord parenchyma
may cause focal or multifocal deficits or may be small enough not to cause focal (infectious myelitis).
deficits, discovered when a patient presents with headache or seizure. Causes
of focal or multifocal brain lesions include vascular, neoplastic, inflammatory,
and infectious etiologies such as bacterial or fungal abscess, toxoplasmosis,
tuberculoma, cryptococcoma, neurocysticercosis, and granulomatous amebic

encephalitis (caused by Acanthamoeba species or Balamuthia mandrillaris).

Neuroimaging features that may distinguish between these etiologies and
identify specific infections are discussed later in this article.
Multifocal infarction has a broad differential diagnosis, including
cardioembolism, endocarditis, hypercoagulable state, primary CNS vasculitis,
and intravascular lymphoma, but may also be caused by infectious vasculitis, as
can be seen with VZV, meningovascular syphilis, angioinvasive aspergillosis, or
mucormycosis or in the context of bacterial, fungal, or tuberculous meningitis.
CRANIAL NEUROPATHY. Cranial neuropathy can be caused by inflammatory,

neoplastic, or infectious disorders as well as by aneurysmal compression. Cranial
neuropathies may complicate meningitis or may occur in isolation, for example,
seventh nerve palsy in Lyme disease or due to HIV (most commonly
around the time of seroconversion).
MYELOPATHY. Pathology of the spine can present with back pain, weakness,
sensory changes, and/or bowel/bladder dysfunction. The spine can be affected
by infection in any of its compartments: vertebrae/discs (osteomyelitis, Pott
disease), epidural/subdural spaces (abscess), or the spinal cord parenchyma
(infectious myelitis). The differential diagnosis for myelopathy includes
structural, vascular, malignant, infectious, inflammatory (which may be primary
autoimmune disease or postinfectious), toxic/metabolic (eg, radiation,
vitamin B12 or copper deficiency), and hereditary causes (eg, hereditary spastic
paraplegia, adrenomyeloneuropathy).
Acute infectious myelitis may be caused by nearly any virus, with the
particular pattern of anterior horn cell involvement causing flaccid paralysis
associated with enteroviruses (enterovirus 71 [EV71], enterovirus D68 [EVD68],
poliovirus) and West Nile virus. In endemic regions, schistosomiasis can cause
an acute or subacute myelopathy. Chronic infectious myelitis can be caused by
HTLV-I (causing tropical spastic paraparesis), HIV (causing vacuolar myelopathy,
typically affecting the dorsal columns and corticospinal tracts), and syphilis
(causing tabes dorsalis, which affects the dorsal columns and dorsal roots,
causing sensory loss, lancinating pains, and imbalance due to sensory ataxia).
The unique clinical syndrome of tetanus is due to the effect of tetanus toxin on
spinal inhibitory interneurons causing diffuse tetanic spasms and autonomic
instability.
For further discussion, refer to “Infections of the Spine and Spinal Cord”
by Shamik Bhattacharyya, MD, MS, and Michael Bradshaw, MD,21 and in this
issue of Continuum.
RADICULOPATHY. Radiculopathy causes sensory and/or motor deficits in the

involved dermatomes, often accompanied by radiating pain. Nerve roots are
most commonly affected by structural disease of the spine (spondylosis, disc
disease) but may be affected in inflammatory, malignant, metabolic
(eg, diabetic thoracic radiculopathy), and rarely infectious conditions. The most
common infectious causes of radiculitis are viral (eg, VZV, HSV-2 [Elsberg
syndrome], CMV [in immunocompromised patients]), Lyme disease, and
tuberculous arachnoiditis.
PERIPHERAL NEUROPATHY. Peripheral neuropathy causes sensory, motor, and/or

autonomic symptoms in the regions supplied by the affected nerve(s). Peripheral
826 AUGUST 2021

neuropathy is divided most broadly into mononeuropathy, mononeuropathy KEY POINTS
multiplex, and polyneuropathy. The most common causes of mononeuropathy
● Acute infectious myelitis
are compression and injury, but mononeuropathy multiplex and polyneuropathy may be caused by nearly any
have more expansive differential diagnoses including toxic, metabolic, virus, with the particular
inflammatory, infectious, and hereditary causes (and in the case of pattern of anterior horn cell
mononeuropathy multiplex, vasculitis). Infections associated with involvement causing flaccid
paralysis associated with
mononeuropathy multiplex include hepatitis B–associated polyarteritis nodosa, enteroviruses (enterovirus 71
hepatitis C–associated cryoglobulinemic vasculitic neuropathy, HIV, and [EV71], enterovirus D68
leprosy. Infections that can cause polyneuropathy include HIV and diphtheria. [EVD68], poliovirus) and
Diphtheric neuropathy has a unique pattern of presentation as a postinfectious West Nile virus.
biphasic neuropathy presenting with lower cranial nerve palsies followed weeks
● The most common
later by neuropathy affecting the extremities. infectious causes of
Although Guillain-Barré syndrome is most commonly a postinfectious radiculitis are viral (eg,
syndrome, if a pleocytosis is found on CSF analysis, the possibility of HIV varicella-zoster virus,
herpes simplex virus 2
seroconversion-associated Guillain-Barré syndrome22 or Lyme polyradiculitis
[Elsberg syndrome],
should be considered. cytomegalovirus [in
immunocompromised
NEUROMUSCULAR JUNCTION DISORDERS. The neuromuscular junction is most patients]), Lyme disease,
commonly affected by immune-mediated conditions such as myasthenia gravis and tuberculous
or Lambert-Eaton myasthenic syndrome but may also be affected by congenital arachnoiditis.
disorders of the neuromuscular junction and, rarely, the infection botulism.
● Infections associated
Botulinum toxin interferes with acetylcholine release from presynaptic nerve with mononeuropathy
terminals of the neuromuscular junction, leading to an acute syndrome of multiplex include hepatitis
descending paralysis affecting the ocular motor and bulbar cranial nerves B–associated polyarteritis
followed by the extremities, often accompanied by gastrointestinal nodosa, hepatitis
C–associated
symptoms. cryoglobulinemic vasculitic
neuropathy, HIV, and
MYOPATHY. Myopathy is most commonly caused by medications, inflammatory leprosy. Infections that can
conditions, and genetic disorders but may rarely be caused by infections. cause polyneuropathy
Infectious myositis can be focal (eg, bacterial pyomyositis) or diffuse (eg, include HIV and diphtheria.
trichinosis [caused by Trichinella spiralis], HIV, HTLV-I).
● Infectious myositis can be
For further discussion of infections of the nerve roots, nerves, neuromuscular focal (eg, bacterial
junction, and muscles, refer to “Infections of the Peripheral Nervous System” by pyomyositis) or diffuse (eg,
Samantha LoRusso, MD,23 in this issue of Continuum. trichinosis [caused by
Trichinella spiralis], HIV,
DIAGNOSTIC TESTING human T-cell lymphotropic
virus type I [HTLV-I]).
Although definitive diagnosis of a neurologic infection requires
microbiological testing of CSF or tissue specimen, neuroimaging is ● Although definitive
often obtained first because it can provide important clues as to the diagnosis of a neurologic
infectious etiology24,25 and may be necessary to exclude contraindications infection requires
microbiological testing of
to lumbar puncture. CSF or tissue specimen,
neuroimaging is often
Neuroimaging obtained first because it can
MRI is more sensitive than CT for most neurologic diagnoses, but CT is rapidly provide important clues as
obtainable and may be the only neuroimaging modality available in to the infectious etiology
and may be necessary to
resource-limited settings. Although CT of the brain without contrast may be
exclude contraindications to
inadequate to distinguish most infectious lesions from neoplastic, vascular, or lumbar puncture.
inflammatory processes, it can identify the characteristic features of
neurocysticercosis in the vesicular or calcified nodular stages (although granular
and colloidal stages may be impossible to disambiguate from other hypodense
lesions) (FIGURE 1-226) (CASE 1-2). CT without contrast may also identify PML in

FIGURE 1-2
CT findings in neurocysticercosis. A, Axial noncontrast head CT showing a lesion posterior to
the occipital horn of the right lateral ventricle that is spherical with a punctate hyperdensity
consistent with neurocysticercosis in the vesicular stage. (The left frontal hypodensity is
encephalomalacia from previous head trauma.) B, Axial noncontrast head CT showing
innumerable punctate calcifications, consistent with neurocysticercosis in the calcified
nodular stage.
Panel B is reprinted with permission from Del Brutto, Continuum (Minneap Minn).26 © 2012 American
Academy of Neurology.
CASE 1-2 A 42-year-old man had a generalized tonic-clonic seizure at work. He

recovered completely and had a normal neurologic examination. He
underwent a CT scan that revealed a cystic lesion with a central
hyperdense “dot” with no surrounding edema, consistent with
neurocysticercosis in the vesicular stage (FIGURE 1-2A). The patient
reported that he had immigrated from the Caribbean several years before
and visited frequently. He was initiated on albendazole, prednisone, and
antiepileptic therapy.
COMMENT Neurocysticercosis in the vesicular stage has a characteristic neuroimaging

appearance and must be recognized to avoid unnecessary testing and
delays in appropriate treatment. Of note, although the common
misconception is that cysticercosis is caused by eating undercooked pork,
this only leads to infection with the Taenia solium tapeworm, which sheds
eggs in the patient’s stool. It is ingestion of the eggs through fecal-oral
transmission that leads to neurocysticercosis. For further discussion of
neurocysticercosis and its treatment, refer to “Parasitic Infections of the
Nervous System” by Hector H. Garcia, MD, PhD,28 in this issue of
Continuum.
828 AUGUST 2021

immunocompromised patients, given the
characteristic propensity of this infection
for the juxtacortical white matter and
middle cerebellar peduncle without mass
effect (FIGURE 1-3). Basal cistern
hyperdensity on CT without contrast and
the combination of hydrocephalus,
infarction, and basal meningeal
enhancement were both found to be 100%
specific for tuberculous meningitis in
children in South Africa, although only
46% and 41% sensitive, respectively.27
Patterns of involvement on MRI can
provide clues to the etiology of CNS
infections (FIGURE 1-4). HSV encephalitis
FIGURE 1-3 causes a characteristic MRI pattern of T2
CT findings in progressive multifocal
leukoencephalopathy. Axial
hyperintensity in limbic cortical regions
noncontrast head CT showing (medial and inferior temporal, insular,
hypodensity in the juxtacortical white inferior frontal, and orbitofrontal
matter of the right parietal lobe without regions), which may be accompanied by
mass effect in a patient with human
hemorrhagic foci, contrast enhancement,
immunodeficiency virus (HIV),
consistent with progressive multifocal and/or diffusion restriction (FIGURE 1-5).
leukoencephalopathy. HHV-6 encephalitis and autoimmune
(antibody-mediated) limbic encephalitis
most commonly cause T2 hyperintensity
in the medial temporal lobes. Arbovirus encephalitis causes T2 hyperintensities
in the deep gray matter (basal ganglia and thalamus) (FIGURE 1-629). CMV
encephalitis causes periventricular white matter changes, often accompanied by
ependymal enhancement.
Ring-enhancing lesions most commonly represent abscess or tumor, although
subacute stroke may also show a peripheral pattern of enhancement. Abscesses
FIGURE 1-4
Common radiologic findings in brain infections.
CNS = central nervous system; FLAIR = fluid-attenuated inversion recovery.

typically show diffusion restriction on

diffusion-weighted imaging sequences,
which is generally not seen in glial
tumors or metastases (although
commonly seen in CNS lymphoma).
In immunocompromised patients,
ring-enhancing lesions may be caused
by toxoplasmosis or EBV-associated
primary CNS lymphoma, which can be
challenging to distinguish from each
other radiologically. For further
discussion, refer to “Neurologic Infections
in Patients on Immunomodulatory and
Immunosuppressive Therapies” by Pria
Anand, MD,6 in this issue of Continuum.
FIGURE 1-5 Schistosomiasis of the brain causes a classic
MRI in herpes simplex virus
encephalitis. Axial fluid-attenuated “arborized” pattern of contrast
inversion recovery (FLAIR) MRI showing enhancement (FIGURE 1-730). The colloidal
T2 hyperintensity and edema of the and granular stages of neurocysticercosis
right temporal lobe consistent with demonstrate ring enhancement, although
herpes simplex virus encephalitis.
these are less commonly seen than the
characteristic vesicular and calcified stages.
The lesions of PML cause T2 hyperintensities in the juxtacortical white matter
or the middle cerebellar peduncle or both (FIGURE 1-831,32). PML lesions typically
do not cause mass effect and usually do
not enhance (although they may enhance
in the setting of IRIS). PML lesions may be
challenging to distinguish from
demyelinating plaques in patients with
multiple sclerosis being treated with
therapies such as natalizumab that carry a
risk of PML.
CSF Analysis
CSF in neurologic infections generally
shows elevations in white blood cells and
protein. Glucose is decreased in bacterial
(including mycobacterial) and fungal
infections and generally normal in viral
infections, but it may be decreased in
mumps, HSV-2, CMV, and Eastern equine
encephalitis infection, as well as in
noninfectious causes of meningitis such as FIGURE 1-6
leptomeningeal metastases and MRI in arbovirus-associated
encephalitis. Axial fluid-attenuated
sarcoidosis.33 A neutrophilic inversion recovery (FLAIR) MRI showing
predominance is generally seen in T2 hyperintensity in the bilateral basal
bacterial infections, whereas a ganglia consistent with arbovirus-
lymphocytic predominance is seen in associated encephalitis.
Reprinted with permission from Lyons JL,
viral, fungal, and mycobacterial Continuum (Minneap Minn).29 © 2018
infections. However, a neutrophilic American Academy of Neurology.
830 AUGUST 2021

predominance may be seen early in the KEY POINTS
course of viral infections and throughout
● Although CT of the brain
the course of West Nile virus without contrast may be
encephalitis.33 CSF eosinophilia is inadequate to distinguish
classically associated with parasitic most infectious lesions from
infections but may also be seen in fungal neoplastic, vascular, or
inflammatory processes, it
infections (eg, most commonly
can identify the
coccidioidomycosis), lymphoproliferative characteristic features of
diseases, idiopathic hypereosinophilic neurocysticercosis in the
syndrome, and drug-induced meningitis.34 vesicular or calcified
nodular stages (although
The degree of white blood cell and
granular and colloidal stages
protein increases and glucose decrease is may be impossible to
generally more dramatic in bacterial disambiguate from other
meningitis: a CSF white blood cell count hypodense lesions).
greater than 500 cells/mm3 is associated
FIGURE 1-7 ● Ring-enhancing lesions
with a likelihood ratio of 15 for bacterial most commonly represent
MRI in schistosomiasis. Postcontrast
meningitis, whereas a CSF white blood cell abscess or tumor, although
T1-weighted MRI showing left temporal
enhancement in an “arborized” count less than 500 cells/mm3 is associated subacute stroke may also
pattern, determined by biopsy to be with a likelihood ratio of 0.3; a CSF to show a peripheral pattern of
enhancement.
neuroschistosomiasis. blood glucose ratio of less than 0.4 is
Reprinted with permission from Cho TA,
Continuum (Minneap Minn).30 © 2018
associated with a likelihood ratio of 18 for ● CSF in neurologic
American Academy of Neurology. bacterial meningitis, whereas a CSF to infections generally shows
blood glucose ratio greater than 0.4 has a elevations in white blood
cells and protein.
likelihood ratio of 0.31.35
CSF parameters in conjunction with the clinical presentation provide an initial ● Glucose is decreased in
impression of the possible microbiological diagnoses to guide empiric therapy. bacterial (including
However, they cannot be relied on because they may change after initiation of mycobacterial) and fungal
antimicrobial therapy and over infections and generally
normal in viral infections,
the course of the illness. In but it may be decreased in
immunocompromised patients, mumps, herpes simplex
diminished capacity to mount an virus 2, cytomegalovirus,
immune response may also alter and Eastern equine
encephalitis infection, as
the CSF profile. well as in non-neurologic
causes of meningitis such as
Microbiological Diagnosis leptomeningeal metastases
Definitive microbiological and sarcoidosis.
diagnosis can be made through
● A neutrophilic
several different types of predominance is generally
laboratory tests. It is, therefore, seen in bacterial infections,
crucial to be aware of the most FIGURE 1-8 whereas a lymphocytic
MRI in progressive multifocal predominance is seen in
sensitive tests when evaluating
leukoencephalopathy (PML). A, Axial viral, fungal, and
for particular pathogens fluid-attenuated inversion recovery (FLAIR) MRI mycobacterial infections.
(TABLE 1-1). showing hyperintensity in the juxtacortical white However, a neutrophilic
Direct identification can be matter of the bilateral frontal lobes in a patient predominance may be seen
with PML. B, Axial T2-weighted MRI showing early in the course of viral
attempted with microscopy and
hyperintensity in the left middle cerebellar infections and throughout
staining (eg, Gram stain for peduncle in a patient with PML. the course of West Nile virus
bacteria, acid-fast staining for Panel A reprinted with permission from Aksamit AJ Jr, encephalitis.
mycobacteria, India ink for Continuum (Minneap Minn).31 © 2012 American Academy
of Neurology. Panel B reprinted with permission from
fungi) or culture. These methods Saylor D, Continuum (Minneap Minn).32 © 2018 American
are used most commonly for Academy of Neurology.

bacteria and fungi, but cultures often take days to grow, whereas other
techniques provide results more rapidly. CSF cultures are generally the test of
choice for gram-positive and gram-negative bacterial CNS infections, but culture
is insensitive for viruses, spirochetes, and fungi. Although culture is sensitive for
tuberculosis, it may take weeks to grow. Therefore, additional techniques are
necessary for diagnosis of these pathogens in the CSF.
Latex agglutination and immunoassays use specific antibodies to evaluate for
the presence of microbial antigens or toxins. CSF cryptococcal antigen is the most
sensitive test for diagnosing cryptococcal meningitis, and antigen tests are also
important in the diagnosis of meningitis caused by endemic mycoses.
Serology refers to the measurement of antibodies formed to the infectious
agent (IgM during acute infection, IgG with previous exposure/chronic
infection). CSF serology is considered a more sensitive test than polymerase
TABLE 1-1 Recommended CSF Diagnostic Testing for Common Neurologic Infections
Cause of infection Most sensitive CSF diagnostic tests
Bacteria
Gram-positive and gram-negative Gram stain and culture
Mycobacteria Polymerase chain reaction (PCR) (Xpert MTB/RIF), culture
Spirochetes
Lyme disease IgG
Syphilis Venereal Disease Research Laboratory (VDRL), fluorescent treponemal

antibody absorption (FTA-ABS)
Viruses
Herpesviruses
Herpes simplex virus PCR
Varicella-zoster virus PCR (meningitis, encephalitis), IgG (myelitis, vasculitis)
Human herpesvirus 6 PCR
Enteroviruses PCR
Arboviruses IgM
JC virus PCR
Fungi
Cryptococcus Antigen
Histoplasmosis, blastomycosis, Antigen and antibody

coccidioidomycosis
Candida Culture and (1,3)-β-D-glucan
Aspergillus PCR and galactomannan
CSF = cerebrospinal fluid; IgG = immunoglobulin G; IgM = immunoglobulin M.
832 AUGUST 2021

chain reaction (PCR) for certain viruses (arbovirus IgM; VZV IgG in the setting KEY POINTS
of myelitis or vasculitis), and serology is also the test of choice for Lyme disease
● CSF parameters in
(IgG) and neurosyphilis (nontreponemal: Venereal Disease Research Laboratory conjunction with the clinical
[VDRL], rapid plasma reagin [RPR]; treponemal: fluorescent treponemal presentation provide an
antibody [FTA-ABS], Treponema pallidum particle agglutination assay [TP-PA], initial impression of the
enzyme immunoassay [EIA]). possible microbiological
diagnoses to guide empiric
Nucleic acid probes evaluate for particular sequences of microbial DNA
therapy. However, they
or RNA. PCR is a technique that amplifies microbial genetic material to make it cannot be relied on because
more easily detectable (eg, 16s ribosomal RNA sequencing for bacteria; they may change after
18s or 28s ribosomal RNA for fungi; DNA or RNA PCR for viruses; DNA for initiation of antimicrobial
therapy and over the course
tuberculosis [Xpert MTB/RIF (Cepheid)]). CSF PCR is the most sensitive test for
of the illness. In
most viral infections of the nervous system, with some notable exceptions immunocompromised
(arboviruses, VZV). patients, diminished
All of these techniques generally require a targeted approach to evaluate for capacity to mount an
particular pathogens by ordering one or more specific PCR, serology, stain, or immune response may also
alter the CSF profile.
antigen tests. In contrast, multiplex PCR tests for several common causes of
meningitis simultaneously. For example, the BioFire FilmArray meningitis/ ● Definitive microbiological
encephalitis panel evaluates for six bacteria (S. pneumoniae, Streptococcus diagnosis can be made
agalactiae, N. meningitidis, L. monocytogenes, H. influenzae, Escherichia coli), seven through several different
types of laboratory tests. It
viruses (HSV-1, HSV-2, HHV-6, VZV, CMV, enterovirus, human parechovirus), is, therefore, crucial to be
and two fungi (C. neoformans and C. gattii).36 However, it should be noted that aware of the most sensitive
PCR is not the most sensitive test for Cryptococcus, so if this pathogen is tests when evaluating for
suspected, the most sensitive test (cryptococcal antigen) should be ordered in particular pathogens.
addition to the use of multiplex PCR. Additionally, both false positives
● CSF cultures are generally
(Streptococcal species) and false negatives (HSV-1, HSV-2, enteroviruses, the test of choice for
Cryptococcus) have been reported with this assay,37,38 so its results should be gram-positive and
interpreted with caution and confirmed with alternative techniques if they seem gram-negative bacterial
discrepant with the clinical presentation. CNS infections, but culture
is insensitive for viruses,
Metagenomic next-generation sequencing of CSF is an emerging spirochetes, and fungi.
unbiased, hypothesis-free technique that evaluates all genetic material in a Although sensitive for
sample to detect any nonhost sequences and identify them through tuberculosis, cultures take
computational algorithms using bioinformatic libraries.39 This technique has weeks to result. Therefore,
additional techniques are
identified novel or unexpected pathogens in patients with neurologic infections necessary for diagnosis of
that were unable to be diagnosed with conventional microbiological these pathogens in the CSF.
testing.40,41
● CSF cryptococcal antigen
is the most sensitive test for
diagnosing cryptococcal
CONCLUSION meningitis, and antigen tests
Infections are in the differential diagnosis for any neurologic syndrome, affect are also important in the
individuals of all ages, and can present in protean ways. “Classic” clinical diagnosis of meningitis
caused by endemic mycoses.
features suggestive of infection such as fever and meningeal signs may be absent
and cannot be relied on. Systemic symptoms and signs and contextual ● CSF serology is
features such as past medical history, travel history, and exposure may considered a more sensitive
provide important clues to the diagnosis of a neurologic infection. In test than polymerase chain
immunocompromised individuals, clinicians should maintain a high index of reaction (PCR) for certain
viruses (arbovirus IgM;
suspicion for an infectious cause of a neurologic syndrome, and a neurologic varicella-zoster virus IgG in
infection may be the presenting syndrome in patients with undiagnosed myelitis and vasculitis), and
immunodeficiency. serology is also the test of
Neuroimaging is often obtained in the evaluation of potential neurologic choice for Lyme disease
(IgG) and neurosyphilis.
infections. Although certain radiologic patterns for particular organisms should

KEY POINTS be recognized, atypical radiologic features may be seen in immunocompromised

individuals. Definitive microbiological diagnosis can be made by way of a
● CSF PCR is the most
sensitive test for most viral
growing number of techniques, requiring the neurologist to be aware of the most
infections of the nervous sensitive test for each pathogen under consideration.
system, with some notable
exceptions (arboviruses,
varicella-zoster virus).
ACKNOWLEDGMENTS
● Metagenomic The author would like to thank Pria Anand, MD, and Saman Nematollahi, MD,
next-generation sequencing for helpful comments and suggestions on an earlier version of this manuscript.
of CSF is an emerging
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CON.0000000000000647

REVIEW ARTICLE

Meningitis
CONTINUUM AUDIO By Allen J. Aksamit Jr, MD, FAAN; Aaron L. Berkowitz, MD, PhD
INTERVIEW AVAILABLE
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Thisarticle reviews the diagnosis and treatment of
infectious meningitis, including updates on newer molecular diagnostic
techniques for microbiological diagnosis.
RECENT FINDINGS:New polymerase chain reaction (PCR)-based molecular

diagnostic techniques have improved the timeliness of microbiological
diagnosis in meningitis, but clinicians must be aware of the limitations of
such tests. Next-generation sequencing can now be applied to CSF,
allowing for diagnosis of infections not identifiable by conventional means.
SUMMARY: Infectious meningitis can be caused by a broad range of

organisms. The clinician must be aware of the test characteristics of new
molecular techniques for microbiological diagnosis as well as traditional
techniques to tailor antimicrobial therapy appropriately in patients with
meningitis.
INTRODUCTION
T
CITE AS: he meninges are the coverings of the brain and spinal cord. From
CONTINUUM (MINNEAP MINN)
2021;27(4, NEUROINFECTIOUS
external to internal, they consist of the dura mater, arachnoid, and pia
DISEASE):836–854. mater. The dura mater is referred to as the pachymeninges, and the
arachnoid and pia mater are referred to as the leptomeninges.
Address correspondence to Meningitis is an inflammatory condition of the meninges that can be
Dr Allen J. Aksamit, Department
of Neurology, Mayo Clinic, caused by infections, autoimmune diseases, neoplasia, and medications. This
200 First St SW, Rochester, article focuses on infectious causes of meningitis, which include bacteria, viruses,
MN 55905, aksamit.allen@
fungi, and parasites. Most infectious meningitis affects the leptomeninges, but
mayo.edu.
pachymeningeal involvement can be seen in fungal, tubercular, and syphilitic
RELATIONSHIP DISCLOSURE: meningitis.
Dr Aksamit reports no disclosure.
Dr Berkowitz serves on the
Inflammation of the meninges causes symptoms of headache and neck pain,
editorial board for Continuum and signs of meningeal irritation are referred to collectively as meningismus. Signs
and has received publishing of meningismus include nuchal rigidity, the Kernig sign (pain and resistance with
royalties from HarperCollins
Publishers, McGraw Hill, passive extension of the knee with the hip flexed), and the Brudzinski sign (hip
MedMaster, and Oxford and knee flexion with passive neck flexion). Although highly specific, these signs
University Press. have very low sensitivity and may be absent in patients who are older than
UNLABELED USE OF 65 years of age, immunocompromised, or taking analgesic medications.
PRODUCTS/INVESTIGATIONAL Meningitis can also cause seizures, stroke (due to infectious vasculitis),
USE DISCLOSURE :
Drs Aksamit and Berkowitz report
hydrocephalus, cranial neuropathy (more common in tubercular and fungal
no disclosures. etiologies), and an altered level of consciousness. When meningitis causes
changes in mental status, the term meningoencephalitis is used. Focal features may
© 2021 American Academy
be seen if brain abscess, venous sinus thrombosis, or infarction due to infectious
of Neurology. vasculitis complicate meningitis.
836 AUGUST 2021

This article begins with a discussion of CSF analysis and microbiological
diagnosis of meningitis and is then divided into sections on acute meningitis and
chronic meningitis.
CSF ABNORMALITIES
Patterns of abnormalities in CSF glucose, protein, and cell counts can be helpful
in distinguishing infectious etiologies of meningitis from one another as well as
from noninfectious causes of meningitis (TABLE 2-1).
CSF Glucose
Low CSF glucose (hypoglycorrhachia) can be seen in CSF infections,
inflammatory conditions (eg, sarcoidosis), neoplastic process (carcinomatous
meningitis), chemical meningitis (eg, dermoid or craniopharyngioma rupture),
and subarachnoid hemorrhage. CSF glucose should normally be greater than
40% of serum glucose. CSF glucose level less than 40% of serum level (or less
than 40 mg/dL) is suspicious for infection, most commonly bacterial,
tuberculous, and fungal meningitis. CSF glucose is normal in most viral
meningitides; however, hypoglycorrhachia can occur with some viruses,
including mumps, lymphocytic choriomeningitis virus, West Nile virus,
enterovirus, and cytomegalovirus (CMV) ventriculitis associated with human
immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).
Ideally, serum glucose should be measured 1 hour before lumbar puncture
because complete equilibration requires that interval of time, but this is rarely
done in practice, and measurement of simultaneously obtained serum glucose is
satisfactory. CSF glucose in patients with diabetes is even more difficult to
interpret because of wide swings in serum levels. Low spinal fluid glucose in
bacterial meningitis is thought to result primarily from effects on the glucose
transporter system1,2 but may also be due to leukocyte utilization of glucose and
some contribution of bacterial consumption.3
CSF Protein
Protein is typically elevated in the spinal fluid in meningitis (TABLE 2-1).
Normal values for CSF total protein are less than 35 mg/dL and for serum total
protein 6.3 g/dL to 7.9 g/dL. Because of the large gradient between serum and
Patterns of Reaction in Spinal Fluid in Neurologic Infections TABLE 2-1
White blood
Organism Protein, mg/dL Glucose cells/mm3 Cell type predominance
Normal 1-35 >40% serum <5 Lymphocytes
Bacterial meningitis >100 <40% serum >500 Polymorphonuclear leukocytes
Viral meningitis <120 >40% seruma 10-500 Lymphocytes
Granulomatous meningitis (tuberculosis >50 <40% serum 10-1000 Lymphocytes

and noninfectious granulomatous)
a
Decreased CSF glucose may be seen in some viral infections causing meningitis.

MENINGITIS
CSF protein concentration, the degree of CSF protein elevation reflects the
degree of opening of the blood-brain barrier or blood-CSF barrier.
Protein values in CSF obtained from the ventricles during a neurosurgical
procedure or from a ventricular device (ventriculoperitoneal shunt or external
ventricular drain) must be interpreted with caution because CSF protein is
normally lower in the ventricles than in the lumbar sac. In contrast, CSF glucose
level is higher in the ventricles than in the lumbar sac (even when infection
is present).
CSF Cellularity
The type and degree of cellular reaction in the spinal fluid provide clues to the
type of infection. Acute bacterial meningitis produces a polymorphonuclear
response, usually greater than 1000 cells/mm3. Viral meningoencephalitis can
produce an early polymorphonuclear response that later transitions to a
lymphocytic response, but the cell count rarely exceeds 1000 white blood
cells/mm3. Lymphocytic reaction with low glucose suggests tuberculous or
fungal meningitis, although this pattern can occasionally be seen in viral
meningoencephalitis (see the earlier section titled “CSF Glucose”) or
noninfectious conditions. Elevated CSF eosinophils can be seen in parasitic or
fungal infections but also in other noninfectious conditions, including
hypereosinophilic syndrome, granulomatosis with polyangiitis, Hodgkin disease,
and glioblastoma invading the meninges.
MICROBIOLOGICAL DIAGNOSIS
Precise diagnosis of an infectious cause of meningitis can be achieved through
CSF culture, serology, or molecular diagnostics such as polymerase chain
reaction (PCR)-based assays and next-generation metagenomic sequencing.
Polymerase Chain Reaction–Based Assays

Previously, microbiological diagnosis of meningitis relied on Gram stain for
bacteria and culture of CSF for bacteria, fungi, and viruses. Serology is most
sensitive for some fungal infections, syphilis, and certain viral infections
(eg, arboviruses). Although culture is still important in the diagnoses of
bacterial and fungal infections, culture for viruses has largely been supplanted by
PCR. PCR is also now used in the diagnosis of bacterial and fungal causes of
meningitis.
The BioFire FilmArray Meningitis/Encephalitis (ME) Panel is a multiplex
PCR platform that evaluates for several common meningitis pathogens
simultaneously: the bacteria Escherichia coli K1, Haemophilus influenzae, Listeria
monocytogenes, Neisseria meningitidis, Streptococcus agalactiae (group B
streptococcus), and Streptococcus pneumoniae; the viruses including CMV,
enterovirus, herpes simplex virus (HSV)-1, HSV-2, human herpesvirus 6, human
parechovirus, and varicella-zoster virus (VZV); and the yeast Cryptococcus (both
Cryptococcus neoformans and Cryptococcus gattii).4
Although the FilmArray ME Panel is a fast, reliable, easy-to-implement
diagnostic tool for evaluating infectious meningitis, clinicians must be aware of
its limitations. The panel has an overall percent positive agreement of 97.5% for
bacterial pathogens and 90.1% for viruses5 when compared with stand-alone PCR
and/or culture and only 52% for C. neoformans/C. gattii when compared with
cryptococcal antigen. Additionally, the panel does not evaluate for tuberculosis
838 AUGUST 2021

(TB), syphilis, Lyme disease, or common nosocomial causes of meningitis KEY POINTS
(eg, Staphylococcus, gram-negative bacteria). Finally, even when diagnostic
● Meningitis is an
testing is accurate, antimicrobial susceptibility testing requires concurrent use of inflammatory condition of
standard culture techniques. Therefore, the FilmArray ME Panel should not be the meninges that can be
used as the only microbiological test and must be complemented by other caused by infections,
techniques.6 autoimmune diseases,
neoplasia, and medications.
Metagenomic Next-Generation Sequencing for Diagnosis of Meningitis ● Signs of meningismus

Metagenomic next-generation sequencing is an unbiased, hypothesis-free include nuchal rigidity, the
method of assessing for any microbial genetic material in the CSF.7 Using this Kernig sign (pain and
technique, a 2019 study of 204 pediatric and adult patients with meningitis or resistance with passive
extension of the knee with
encephalitis identified 13 infections not discovered through other testing the hip flexed), and the
modalities; 7 of these 13 diagnoses guided change in treatment.8 In a study of Brudzinski sign (hip and knee
patients with subacute CNS disorders concerning for infection over the course of flexion with passive neck
2 years (53 patients seen at Mayo Clinic and 27 referral specimens sent from flexion). Although highly
specific, these signs have
outside institutions), next-generation sequencing had a result rate of 15% very low sensitivity.
(12 of 80), but 58% (7 of 12) of results were interpreted as inconsistent with the
patient’s clinical presentation.7 Therefore, although next-generation sequencing ● CSF glucose level less
is becoming a more widely available clinical test, its utility in routine clinical than 40% of serum level (or
less than 40 mg/dL) is
practice remains to be determined.
suspicious for infection,
most commonly bacterial,
ACUTE MENINGITIS tuberculous, and fungal
Acute infectious meningitis is most commonly bacterial or viral, although rarely meningitis.
it can be caused by parasitic infection.
● CSF glucose is normal in
most viral meningitides;
Acute Bacterial Meningitis however, hypoglycorrhachia
The annual incidence of bacterial meningitis in the United States is can occur with some viruses,
approximately 5 to 10 per 100,000, with 3630 cases per year reported between including mumps,
lymphocytic
1997 and 2010.9 The Global Burden of Diseases, Injuries, and Risk Factors 2016 choriomeningitis virus, West
study estimated meningitis burden (caused by S. pneumoniae, N. meningitidis, H. Nile virus, enterovirus, and
influenzae, and an “other” category) to have decreased by 21% from 1990 to 2016 cytomegalovirus (CMV)
(from 403,012 to 318,400 cases per year), although progress lags substantially ventriculitis associated with
human immunodeficiency
behind that of other vaccine-preventable diseases.10 virus (HIV)/acquired
The clinical features of bacterial meningitis are fever, headache, stiff immunodeficiency
neck, and change in mental status (CASE 2-1). Approximately 45% of patients syndrome (AIDS).
have all four symptoms, and 95% have at least two of the four.11 Typically, the
● Elevated CSF eosinophils
onset of the illness is over 2 or 3 days. However, some forms of meningitis,
can be seen in parasitic or
particularly meningococcal meningitis, can present even more acutely over fungal infections but also in
24 hours. other noninfectious
Bacterial meningitis is a neurologic emergency and is universally fatal if conditions, including
untreated. Outcomes are worse with delayed treatment, so empiric antibiotics hypereosinophilic
syndrome, granulomatosis
should be initiated as soon as the diagnosis of bacterial meningitis is with polyangiitis, Hodgkin
considered, guided by age and past medical history (TABLE 2-2). Although disease, and glioblastoma
CSF analysis is necessary for precise microbiological diagnosis and antibiotic invading the meninges.
susceptibility testing, this should not delay treatment. Blood cultures are
positive in 70% of patients, as bacteremia is common in bacterial meningitis.
CT is performed before lumbar puncture if elevated intracranial pressure is a
concern. Infectious Diseases Society of America guidelines recommend CT
before lumbar puncture if the patient has focal signs on neurologic examination,
coma, papilledema, an immunocompromised state, or new-onset seizures.12

MENINGITIS
CASE 2-1 A 58-year-old man with no past medical history presented with 3 days of
fever and 1 day of confusion. Two days earlier, he had been treated with
IM penicillin for presumed pneumonia and discharged, although he
remained febrile and fatigued. He had no headache, nausea, or vomiting.
Examination revealed a temperature of 39°C (102.2°F), obtundation,
nuchal rigidity, and a positive Brudzinski sign but no focal deficits. Blood
cultures were collected. Head CT without contrast was unremarkable.
CSF examination showed protein of 435 mg/dL, 2350 white blood cells/
mm3 (68% polymorphonuclear leukocytes), and glucose of 18 mg/dL with
a serum glucose of 85 mg/dL. Empiric vancomycin, ceftriaxone, and
ampicillin were initiated along with IV dexamethasone.
COMMENT The patient has three of the four classic features of bacterial meningitis:
fever, nuchal rigidity, and reduced level of consciousness. Head CT was
performed because of the reduced level of consciousness raising concern
for increased intracranial pressure. Head CT should be performed if readily
available but should not delay initiation of empiric antibiotics and
dexamethasone. Empiric regimens should include ampicillin in patients
who are older than age 50 or immunocompromised.
TABLE 2-2 Empiric Antibiotic Therapy of Bacterial Meningitis
Clinical context Treatment
Adults
Community acquired Vancomycin 15-20 mg/kg IV every 8-12 hours (not to exceed 2 g per dose or a total
daily dose of 60 mg/kg, adjust dose based on serum drug level to target trough) until
sensitivities of organism are known AND
Ceftriaxone 2 g IV every 12 hours or cefotaxime 2 g IV every 4-6 hours AND
Dexamethasone 10 mg IV every 6 hours for 4 days
Alcohol use disorder or advanced Above treatment plus ampicillin 2 g IV every 4 hours (for Listeria) or, for patients who
age (>65 years old) or are allergic to penicillin, trimethoprim-sulfamethoxazole 10-20 mg/kg/d
immunosuppression (trimethoprim component) IV divided every 6-12 hours
Neurosurgical procedure, shunt Vancomycin (above doses) plus an antipseudomonal beta-lactam (such as cefepime
infection, or head trauma 2 g IV every 8 hours, ceftazidime 2 g IV every 8 hours, or meropenem 2 g IV every 8 hours
Children Ceftriaxone 50 mg/kg IV every 12 hours or cefotaxime 100 mg/kg IV every 8 hours AND
Vancomycin 15 mg/kg IV every 6 hours PLUS
Dexamethasone 0.15 mg/kg IV every 6 hours
IV = intravenous.
840 AUGUST 2021

MICROBIOLOGY. The most common bacterial causes of meningitis in adults and KEY POINTS
children are S. pneumoniae and N. meningitidis. H. influenzae may be seen in
● The BioFire FilmArray
children but is now rare because of widespread vaccination. L. monocytogenes may Meningitis/Encephalitis
be seen in adults older than 50 years and in patients who are (ME) Panel is a multiplex
immunocompromised.13 In infants, E. coli, S. agalactiae, and L. monocytogenes are polymerase chain reaction
the most common causes of bacterial meningitis. (PCR) assay that evaluates
for several common
S. pneumoniae is the most common cause of bacterial meningitis in adults.13
meningitis pathogens
Splenectomy and immunoglobulin defects are predisposing factors. simultaneously: the bacteria
Vaccination for pneumococcus in older individuals has reduced infections. Escherichia coli K1,
Resistant strains are common, requiring vancomycin as part of the empiric Haemophilus influenzae,
Listeria monocytogenes,
treatment regimen until a susceptibility pattern is determined.
Neisseria meningitidis,
N. meningitidis meningitis may be accompanied by purpuric rash, but this is Streptococcus agalactiae
not universally present. It is acquired by respiratory transmission, so contacts (group B streptococcus),
need antibiotic prophylaxis. The monoclonal antibody eculizumab, a complement and Streptococcus
inhibitor approved for treatment of neuromyelitis optica and myasthenia gravis, pneumoniae; the viruses
including cytomegalovirus,
is associated with a 1000-fold to 2000-fold increased incidence of meningococcal enterovirus, herpes simplex
meningitis. Therefore, administration of the meningococcal vaccine is virus 1, herpes simplex virus
recommended before beginning eculizumab treatment.14 2, human herpesvirus 6,
H. influenzae was historically the most frequent cause of meningitis in children human parechovirus, and
varicella-zoster virus; and
aged 3 months to 6 years. However, since the advent of the H. influenzae vaccine, the yeast Cryptococcus
the incidence has declined substantially. It should still be considered in (both Cryptococcus
unvaccinated populations. It can also occur in older adults if they are neoformans and
unvaccinated or immunocompromised. Cryptococcus gattii).
Staphylococcus species and gram-negative organisms can cause meningitis
● The FilmArray ME Panel
associated with surgery or trauma that allows these organisms access to the CNS has an overall percent
from the skin or environment. Staphylococcal meningitis without a history of positive agreement of 97.5%
trauma or neurosurgery suggests bacteremia from a skin breach such as from for bacterial pathogens and
90.1% for viruses when
IV drug use or an undiagnosed cranial breach such as a CSF leak.
compared with stand-alone
Group B streptococcal species, most commonly S. agalactiae, are the most PCR and/or culture, and
common cause of meningitis in infants, resulting from exposure during passage only 52% for Cryptococcus
through the birth canal. neoformans/Cryptococcus
L. monocytogenes meningitis often occurs in patients who are gattii when compared with
cryptococcal antigen.
immunosuppressed, are older than 65 years of age, or have alcohol use disorder.
Presentation may be acute or subacute. With systemic invasive listeriosis, the ● The clinical features of
mean incubation period after exposure is 11 days, with 90% of cases of meningitis bacterial meningitis are
occurring within 28 days.15 In addition to meningitis, Listeria may cause fever, headache, stiff neck,
and change in mental status.
rhombencephalitis, associated with cranial nerve palsies, ataxia and other Approximately 45% of
cerebellar signs, and a decreased level of consciousness.16 patients have all four
symptoms, and 95% have at
NEUROIMAGING. Neither CT nor MRI of the brain is specific for diagnosis of least two of the four.
bacterial meningitis, although CT is often obtained if elevated intracranial pressure
that could complicate lumbar puncture is a concern. CT in bacterial meningitis ● Bacterial meningitis is a
neurologic emergency and is
can demonstrate sulcal effacement but may be normal. MRI typically shows T2
universally fatal if untreated.
hyperintensity in the cerebral sulci. Diffusion restriction in the sulci may also be Outcomes are worse with
seen on diffusion-weighted imaging, a finding more common in bacterial meningitis delayed treatment, so
than viral meningitis, but not specific for infectious meningitis. Postcontrast empiric antibiotics should
T1-weighted MRI often reveals enhancement of the leptomeninges within the be initiated as soon as the
diagnosis of bacterial
cerebral sulci (FIGURE 2-117); delayed contrast-enhanced T2-weighted meningitis is considered,
fluid-attenuated inversion recovery (FLAIR) and delayed contrast-enhanced guided by age and past
T1-weighted sequences may be more sensitive for detection of this finding.18 medical history.

MENINGITIS
New contrast-enhanced MRI

sequences, such as modified black-blood
imaging, may improve detection of
meningeal disease. A 2020 study
compared contrast-enhanced turbo
spin-echo acquisition sequences to
conventional T1-weighted rapid
gradient-echo (MP-RAGE) sequences for
the detection of meningeal enhancement
in patients with infectious and neoplastic
meningitis compared with matched
controls. Black-blood sequences were
found to be superior for detection of
leptomeningeal enhancement but did not
FIGURE 2-1
distinguish between underlying etiologies.19
Axial postcontrast T1-weighted MRI
demonstrating leptomeningeal TREATMENT. Empiric antimicrobial
enhancement in a patient with severe treatment should be initiated immediately
bacterial meningitis. if bacterial meningitis is suspected
Reprinted with permission from Berkowitz AL,
17
McGraw-Hill Education. © 2021 McGraw-Hill
(TABLE 2-2). Treatment is then adjusted
Education. based on blood or CSF culture and
antibiotic sensitivity data, which also
determines the duration of antibiotic
therapy based on the organism
(TABLE 2-3).20 Dexamethasone should be initiated before or with the first dose
of antibiotics, but it appears to show benefit only in streptococcal meningitis
and is generally discontinued if cultures reveal an alternative etiology; benefit
of empiric steroids in patients with acute meningitis has not been demonstrated
in low-income countries, attributed to the higher likelihood of a delayed
presentation and higher burden of HIV and malnutrition.21 Although
vancomycin is thought not to penetrate the blood-brain barrier under normal
TABLE 2-3 Duration of Antibiotic Therapy for Meningitis Caused by Bacterial

Organismsa
Organism Duration of therapy (days)
Streptococcus pneumoniae 10-14
Listeria monocytogenes 21
Neisseria meningitidis 7
Staphylococcus Variable
Gram-negative bacilli 21
Group B Streptococcus 14-21
Haemophilus influenzae 7-10
a
Data from Wilson JW, Oxford University Press.20
842 AUGUST 2021

circumstances, penetration is likely improved in bacterial meningitis because of
blood-brain barrier breakdown caused by local inflammation. The theoretical
concern that steroids could close the blood-brain barrier and reduce the efficacy
of vancomycin remains controversial.
Practice guidelines developed in 2017 for nosocomial ventriculitis and
meningitis recommend empiric therapy with vancomycin plus an
antipseudomonal beta-lactam (such as cefepime, ceftazidime, or meropenem)
with the choice of empiric beta-lactam based on local in vitro susceptibility
patterns. Intraventricular antimicrobial therapy should be considered for
patients with health care–associated ventriculitis and meningitis if the infection
responds poorly to systemic antimicrobial therapy alone.22
Acute Viral Meningitis

Viral meningitis usually causes a rapidly evolving headache, fever, and stiff neck,
but symptoms are generally less severe than in bacterial meningitis. However,
distinguishing bacterial from viral meningitis is challenging on clinical grounds
alone, requiring CSF analysis for diagnosis (TABLE 2-1). In one detailed study,
34% of acute lymphocytic meningitis cases were never linked to a specific
organism, even with extensive evaluation.23
Common causes of viral meningitis and the preferred diagnostic testing for each
are given in TABLE 2-4. Although most viruses are diagnosed by PCR, some are more
sensitively diagnosed by CSF serology, such as arboviruses. The most common
causes of viral meningitis are enterovirus, HSV-2, and VZV. The FilmArray ME
Panel described earlier evaluates for these viruses but is less sensitive for HSV than
stand-alone HSV PCR.5 Epidemic arboviruses, including West Nile virus and La
Crosse encephalitis virus, are common in the summer months and often cause
meningoencephalitis. Of note, arboviruses are most sensitively diagnosed by CSF
IgM antibodies rather than PCR as for most other viral meningitides. An IgM
Some Common Causes of Viral Meningitis TABLE 2-4
Viruses best diagnosed by polymerase chain reaction (PCR) in spinal fluid

◆ Herpes simplex type 2
◆ Enteroviruses including echoviruses, coxsackieviruses, and polioviruses
◆ Human parechovirus
◆ Varicella-zoster virus (VZV)a
◆ Cytomegalovirus
◆ Lymphocytic choriomeningitis virus (with accompanying IgM in the serum)
Viruses best diagnosed by serology in spinal fluid
◆ West Nile virus (IgM)
◆ La Crosse encephalitis virus (IgM)
◆ Mumps virus (IgM)
IgM = immunoglobulin M.
a
For VZV vasculitis and myelitis, VZV IgG may be more sensitive than PCR.

MENINGITIS
response in arboviral infections may be delayed, so repeating CSF serology 5 to

7 days after presentation in unknown cases may be necessary for diagnosis.
HERPES SIMPLEX VIRUS TYPE 2. HSV-1 more commonly causes encephalitis, whereas
HSV-2 more commonly causes meningitis. HSV-2 meningitis can occur as a
complication of genital herpes or without a history of known sexual exposure or
genital infection. It can be a severe illness when it occurs in patients who are
immunocompromised. Recurrent meningitis secondary to HSV-2 can occur
(Mollaret meningitis). Diagnosis is made by CSF PCR, which is most reliable in
the first 3 days of meningitis symptoms.24
WEST NILE VIRUS MENINGITIS. This mosquito-transmitted flavivirus is now the most
common cause for summer epidemic viral meningitis in the United States.
Neuroinvasive disease may cause meningitis, encephalitis, and acute flaccid
paralysis. Meningitis can occur in any age group, whereas encephalitis is more
common in people older than 65 years of age or patients who are
immunocompromised. Diagnosis is confirmed by identification of anti–West
Nile virus IgM in CSF. Positive serum antibody confirms exposure but not
necessarily neuroinvasive disease.
LA CROSSE MENINGOENCEPHALITIS. This mosquito-borne infection is most common

in the upper Mississippi River valley area and can present as meningitis or
encephalitis in the late summer. Seizures are a common presenting symptom,
and focal neurologic signs may be present. Spinal fluid IgM is the most sensitive
diagnostic test. Seroconversion in the blood from a seronegative to seropositive
state can be presumptive for diagnosis, although it may not occur until 2 to
4 weeks after the acute illness, requiring acute and convalescent serum
comparison. Usually, the disease is self-limited and without long-term sequelae.
ENTEROVIRUS. Enterovirus meningitis has a seasonal peak in the late summer

months. Many serotypes of enterovirus, echovirus, and coxsackievirus cause
meningitis and may be preceded by a respiratory or gastrointestinal prodrome.
The condition is generally self-limited but may be more severe in patients who
are immunocompromised.
MUMPS VIRUS. Mumps virus was the most common cause of viral meningitis prior
to widespread mumps vaccination. However, given the recent trend in decreased
childhood vaccination, systemic mumps has reemerged, and more meningitis
cases may appear. Unlike most other viruses, mumps meningitis may cause low
CSF glucose. Mumps meningitis is best diagnosed by CSF IgM serology or PCR,
although sensitivities are not defined.
VARICELLA-ZOSTER VIRUS. Varicella, known as chickenpox in children, is usually a

mild infection. VZV can emerge from latency in the dorsal root ganglia and cause
shingles (painful dermatomal vesicular rash) or meningitis. Zoster meningitis
can occur with or without concurrent rash. Dissemination is more common in
patients who are immunocompromised and may be associated with stroke due to
VZV vasculitis. VZV PCR from spinal fluid is the most sensitive diagnostic test in
the acute setting of acute meningitis and myelopathy, but serology (IgG) in
spinal fluid is more sensitive in VZV vasculopathy.
844 AUGUST 2021

HUMAN IMMUNODEFICIENCY VIRUS LYMPHOCYTIC MENINGITIS. HIV can also cause KEY POINTS
viral meningitis, most commonly at or around the time of seroconversion. It may
● The most common
be accompanied by a flulike illness. Because the patient may not yet have formed bacterial causes of
antibodies, HIV antibody testing may be negative, requiring viral load for meningitis in adults and
confirmation. Patients with HIV can also develop chronic persistent headache children are S. pneumoniae
and CSF pleocytosis consistent with meningitis. and N. meningitidis. H.
influenzae may be seen in
children but is now rare
LYMPHOCYTIC CHORIOMENINGITIS VIRUS. Outbreaks of lymphocytic because of widespread
choriomeningitis virus were first reported in humans in the 1960s. Initial reports vaccination. L.
documented disease in laboratory personnel working with mice and hamsters.25 monocytogenes may be
seen in adults older than
Lymphocytic choriomeningitis virus is endemic in mice and usually infects
50 years and in patients who
humans through inhalation of aerosolized virus in urine and droppings from are immunocompromised. In
infected rodents. The presentation is usually acute to subacute, and often infants, E. coli, S. agalactiae,
preceded by a viral prodrome.26 Human-to-human transmission has been and L. monocytogenes are
reported in the context of organ transplantation.27 the most common causes of
bacterial meningitis.
SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2. Severe acute respiratory ● L. monocytogenes may be
syndrome coronavirus 2 (SARS-CoV-2) has been rarely associated with seen in adults older than
meningitis, usually occurring in the context of the typical respiratory and 50 years and in patients who
are immunocompromised.
systemic manifestations of the disease.28
● The monoclonal antibody
IMAGING OF VIRAL MENINGITIS. Neuroimaging of patients with viral meningitis is eculizumab, a complement
most commonly normal, although in one study, 14% of patients with West Nile inhibitor approved for
treatment of neuromyelitis
virus meningitis had leptomeningeal or periventricular enhancement on MRI.29
optica and myasthenia
Although MRI is generally unrevealing in viral meningitis, it should still be gravis, is associated with a
performed to evaluate for encephalitis, bacterial abscess, or noninfectious causes 1000-fold to 2000-fold
of meningitis given the overlapping clinical presentations. In viral increased incidence of
meningoencephalitis, parenchymal abnormalities are common.30 For further meningococcal meningitis.
Therefore, administration of
discussion, refer to “Encephalitis and Brain Abscess” by Arun Venkatesan, MD, the meningococcal vaccine
PhD,31 in this issue of Continuum. is recommended before
beginning eculizumab
TREATMENT OF VIRAL MENINGITIS. HSV-2 and VZV meningitis are generally treated treatment.
with acyclovir (10 mg/kg IV 3 times a day); although in patients who are ● In infectious bacterial
immunocompetent, the benefit is not clearly established. No consensus has been meningitis, postcontrast
reached on the length of IV therapy before transition to oral valacyclovir (1 g T1-weighted MRI often
orally 2 times a day) or famciclovir, but the total length of treatment is generally reveals enhancement of
the leptomeninges within
10 to 14 days.24,32 A 14-day course of IV therapy is recommended for meningitis
the cerebral sulci.
in patients who are immunocompromised.
Although West Nile virus meningitis and encephalitis have been treated with ● Empiric antimicrobial
IV immunoglobulin, a small prospective study did not demonstrate benefit.33 treatment should be
initiated immediately if
bacterial meningitis is
Parasitic Meningitis suspected.
Acute meningoencephalitis can be caused by infection with free-living amoebas
Naegleria fowleri34 and Angiostrongylus cantonensis. Naegleria is thought to enter
the CNS through the nasopharynx and cribriform plate after swimming in warm
water. Naegleria meningoencephalitis is usually rapidly fatal with few surviving
patients, but isolated reports of successful treatment have used IV and/or
intrathecal amphotericin B, IV/intrathecal miconazole, and rifampin.
Angiostrongylus (endemic in the Caribbean, Pacific Islands, and Southeast Asia) is
ingested from contaminated seafood. Diagnosis should be suspected when CSF

MENINGITIS
eosinophilia is detected, and confirmation is made by direct observation of

organisms on CSF wet mount or PCR. Angiostrongylus generally causes a
milder syndrome than Naegleria and can be managed with steroids and
supportive care.
Meningitis may be seen with granulomatous amoebic encephalitis caused by
Balamuthia mandrillaris and Acanthamoeba. One regimen reported to be
successful in treating Acanthamoeba was pentamidine, sulfadiazine, fluconazole,
and clarithromycin.35 Next-generation sequencing has been used for diagnosis of
TABLE 2-5 Infectious Causes of Chronic Meningitis and Diagnostic Tests
Cause of infection Preferred diagnostic test(s)
Bacterial
Mycobacterium tuberculosis CSF culture, polymerase chain reaction (PCR), blood interferon gamma
release assay
Listeria monocytogenes CSF culture
Borrelia burgdorferi CSF to serum serology index
Treponema pallidum CSF Venereal Disease Research Laboratory (VDRL), serum syphilis serology
Leptospira species CSF culture, serum serology
Brucella species CSF culture, serum serology
Nocardia species CSF culture, CSF staining
Fungal
Cryptococcus neoformans and Cryptococcus CSF antigen

gattii
Histoplasma capsulatum CSF serology and antigen
Blastomyces dermatitidis CSF serology and antigen
Coccidioides immitis CSF serology
Sporothrix schenckii CSF and serum serology
Aspergillus CSF culture, PCR, and galactomannan
Candida species CSF culture and 1,3-β-D-glucan
Parasitic
Taenia solium CSF and serum serology
Angiostrongylus cantonensis CSF PCR
Toxoplasma gondii CSF PCR and serology, serum serology
Viral
Human immunodeficiency virus (HIV) Serum serology, serum viral load
Enterovirus CSF PCR
CSF = cerebrospinal fluid.
846 AUGUST 2021

Balamuthia where other conventional testing has been unsuccessful.36 For KEY POINTS
further discussion, refer to “Encephalitis and Brain Abscess” by Arun
● Practice guidelines
Venkatesan, MD, PhD,31 in this issue of Continuum. developed in 2017 for
nosocomial ventriculitis and
CHRONIC MENINGITIS meningitis recommend
Chronic meningitis is defined as meningitis lasting longer than 1 month without empiric therapy with
vancomycin plus an
improvement. Most causes are chronic bacterial and fungal infections and
antipseudomonal
inflammatory disorders (eg, sarcoidosis, IgG4-related disease). beta-lactam (such as
cefepime, ceftazidime, or
Evaluation meropenem) with the choice
of empiric beta-lactam
Evaluating patients with chronic meningitis requires first distinguishing
based on local in vitro
infectious from noninfectious causes. Meningeal enhancement on neuroimaging susceptibility patterns.
occurs with all etiologies and is therefore nonspecific. CSF analysis is thus
necessary to evaluate the biochemical and cellular profile; culture, PCR, antigen, ● Although most viruses are
and/or serologic testing for infection; cytology and flow cytometry for possible diagnosed by PCR, some are
more sensitively diagnosed
malignancy; and consideration of evaluation for systemic clues to an underlying by CSF serology, such as
autoimmune, malignant, or infectious process that may be associated with the arboviruses.
development of meningitis (eg, serum autoantibodies, CT or positron emission
tomography [PET] imaging of the chest/abdomen/pelvis, ophthalmologic ● The FilmArray ME Panel
evaluates for enterovirus,
examination to evaluate for uveitis or lymphoma).
herpes simplex virus type 2,
Serum serologies for syphilis, HIV, and Lyme disease are helpful evidence of and varicella-zoster virus
systemic infection with pathogens that could cause meningitis. A purified protein but is less sensitive for
derivative (PPD) skin test or blood interferon gamma release study for TB is also herpes simplex virus than
stand-alone herpes simplex
recommended. CSF serology compared with serum serology is used for the
virus PCR.
diagnosis of meningitis caused by Lyme disease and Sporothrix schenckii, the
latter a rare cause of chronic meningitis in patients involved in agriculture, ● Positive serum antibodies
horticulture, forestry, or gardening.37 confirm exposure to West
Lumbar puncture should be repeated up to 3 times with large collection Nile virus but not necessarily
neuroinvasive disease.
volumes if the initial lumbar puncture is nondiagnostic. The most sensitive
studies to evaluate for fungal, mycobacterial, and spirochetal etiologies of ● Varicella-zoster virus PCR
meningitis are listed in TABLE 2-5. Of note, the FilmArray ME Panel discussed from spinal fluid is the most
earlier evaluates for only one fungus, Cryptococcus, but PCR is less sensitive than sensitive diagnostic test in
the acute setting of acute
cryptococcal antigen, making the panel of less clinical utility in chronic
meningitis and myelopathy,
meningitis. but serology (IgG) in spinal
If no diagnosis is made by these means, serum serologies for fungal and fluid is more sensitive in
bacterial infections such as histoplasmosis, blastomycosis, coccidioidomycosis, varicella-zoster virus
vasculopathy.
brucellosis, and leptospirosis should be considered. Serum studies for
autoimmune causes of meningitis to be considered include antibodies against ● HIV can also cause viral
cyclic citrullinated peptide (CCP) (rheumatoid arthritis), antineutrophil meningitis, most commonly
cytoplasmic antibodies (ANCA), and serum IgG4. at or around the time of
Next-generation sequencing for microbial organisms in the spinal fluid of seroconversion. It may be
accompanied by a flulike
patients with chronic meningitis may improve diagnosis in challenging cases. In a illness. Because the patient
2018 study, CSF next-generation sequencing identified the cause of chronic may not yet have formed
meningitis in seven previously undiagnosed patients (two cases of Taenia solium, antibodies, HIV antibody
one case of HIV, and one case each of C. neoformans, Aspergillus oryzae, testing may be negative,
requiring viral load for
Histoplasma capsulatum, and Candida dubliniensis).38 confirmation.
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a common cause of meningitis in low- and
lower-middle-income countries. Although rare in the United States, it can be

MENINGITIS
seen in patients who immigrate from endemic areas, have been incarcerated, or
are immunocompromised. Characterized by headache, stiff neck, and fever, TB
meningitis usually presents after a systemic prodrome of greater than 6 days.39
Cranial neuropathies are common because of the granulomatous reaction in the
basal meninges. Subcortical strokes can also occur because of the involvement of
penetrating vessels in the involved basilar meninges.
TB meningitis can occur with or without evidence of systemic TB.
Diagnosis of TB can be made by PPD skin testing or serum gamma interferon
release assay, but these can be negative in patients who are anergic or have
isolated CNS disease. The CSF shows elevated protein, decreased glucose, and
lymphocytic pleocytosis, but the values are not generally as extreme as in
bacterial meningitis.
The Xpert MTB/RIF test (Cepheid) was developed as a PCR-based, closed-
cartridge system.40 The World Health Organization (WHO) approved the
Xpert MTB/RIF in 2010 for the diagnosis of pulmonary TB after extensive
evaluation projects in six countries led by the Foundation for Innovative New
Diagnostics.41 The Xpert MTB/RIF test was subsequently evaluated on CSF in
a large cohort of patients with suspected tuberculous meningitis. Sensitivity of
Xpert MTB/RIF was 59.3% (108 of 182), but specificity was 99.5% with only
one false positive.42 WHO initially recommended Xpert MTB/RIF as the
diagnostic test of choice for tuberculous meningitis but now recommends
Xpert MTB/RIF Ultra, which detected significantly more tuberculous meningitis
than did either Xpert MTB/RIF or culture.43 Xpert MTB/RIF Ultra found higher
sensitivity (95%) compared with Xpert MTB/RIF (45%) or culture (45%) and a
negative predictive value of 93%.
Treatment is with the antimycobacterial agents isoniazid, rifampin,
pyrazinamide, and ethambutol with the addition of dexamethasone in the initial
phase of treatment.44,45 For further discussion of tuberculous meningitis see
“Neurologic Complications of Tuberculosis” by Deanna Saylor, MD, MHS,46 in
this issue of Continuum.
Borrelia burgdorferi (Lyme Disease)

Lyme disease is a tick-borne illness caused by Borrelia burgdorferi. Clinical
diagnosis of Lyme disease as the cause of meningitis is suspected in an endemic
area after tick bite and/or the classic skin lesion erythema chronicum migrans,
although the rash may be absent or escape notice. Diagnosis is established by
serum serology and CSF to serum serology antibody index in the setting of CSF
pleocytosis. Both IV ceftriaxone and oral doxycycline are considered effective
treatments for neuroborreliosis.47 For further discussion of Lyme meningitis, see
“Neurologic Complications of Lyme Disease” by Karen Roos, MD, FAAN,48 in
Treponema pallidum (Meningovascular Syphilis)

Neurosyphilis can affect the nervous system in several ways: meningovascular
syphilis, gumma (abscess), tabes dorsalis, and general paresis (dementia).
Meningovascular syphilis causes a subacute meningitis syndrome and should be
considered in patients with HIV or history of other sexually transmitted diseases
who develop chronic meningitis. CSF analysis generally demonstrates
lymphocytic pleocytosis and elevated protein, and diagnosis is confirmed by
serum nontreponemal (Venereal Disease Research Laboratory [VDRL] or rapid
848 AUGUST 2021

plasma reagin [RPR]) or treponemal (fluorescent treponemal antibody absorption KEY POINTS
[FTA-ABS] or syphilis IgG Antibody) tests. Serum nontreponemal tests are reactive
● Severe acute respiratory
in nearly all cases of neurosyphilis. The CSF VDRL test is specific for neurosyphilis syndrome coronavirus 2
but is only 30% to 70% sensitive49; if the test is negative in cases with a high index of (SARS-CoV-2) has been
suspicion, CSF FTA-ABS should be performed, although positive results can occur rarely associated with viral
in previously treated patients. Treatment is with high-dose penicillin (2 million meningitis and is usually
associated with the typical
units to 4 million units of penicillin G every 4 hours or 20 million units to
respiratory and systemic
24 million units daily by constant IV infusion for 10 days) or ceftriaxone. For manifestations of the
further discussion of neurosyphilis, refer to “Neurosyphilis” by Felicia Chow, disease.
MD, MAS,50 in this issue of Continuum.
● Chronic meningitis is
defined as meningitis lasting
Fungal Meningitis longer than 1 month without
Fungal organisms are common causes of subacute to chronic meningitis. improvement. The most
The fungi to consider depend on geography, exposure history, and immune common causes are chronic
status. The most common forms of fungal meningitis include cryptococcosis, bacterial and fungal
infections and inflammatory
coccidioidomycosis, histoplasmosis, blastomycosis, and candidiasis. Rarely, disorders (eg, sarcoidosis,
meningitis may be caused by sporotrichosis. CSF analysis in fungal meningitis IgG4-related disease).
reveals findings consistent with infection like TB (TABLE 2-1), and diagnosis is
confirmed by CSF fungal antigen assays and culture. ● TB meningitis can occur
with or without evidence of
systemic TB.
CRYPTOCOCCOSIS. Cryptococcus is the most common cause of fungal meningitis.
Case numbers of cryptococcal meningitis in the United States rival the total ● Diagnosis of Lyme
number of bacterial meningitis cases. Hospitalizations due to cryptococcal meningitis is established by
meningitis averaged 3400 annually in the United States between 1997 and 2009.51 CSF to serum serology
antibody index in the setting
Most patients with cryptococcal meningitis are immunocompromised, but 20% of CSF pleocytosis.
are immunocompetent (CASE 2-2). Most cases of cryptococcal meningitis are
caused by C. neoformans, but C. gattii, endemic in the Pacific northwest region of ● Meningovascular syphilis
the United States and Canada, can cause meningitis in patients who are causes a subacute
meningitis syndrome and
immunocompetent. should be considered in
CSF cryptococcal antigen is the most sensitive test for diagnosis. Fungal patients with HIV or history
culture can differentiate between the two common disease-causing Cryptococcus of other sexually
species (C. neoformans and C. gattii) and can be used for antifungal susceptibility transmitted diseases who
develop chronic meningitis.
testing. India ink testing is insensitive. Although both C. neoformans and C. gattii
are detected by PCR on the FilmArray ME Panel, the sensitivity is only 52% ● The CSF VDRL test is
(26 of 50) for C. neoformans/C. gattii.5 specific for neurosyphilis
Induction treatment is with amphotericin B 0.7 mg/kg/d or liposomal but is only 30% to 70%
amphotericin B 3 mg/kg/d to 4 mg/kg/d plus flucytosine 100 mg/kg/d for sensitive; if the test is
negative in cases with a high
2 weeks; this is followed by consolidation treatment with fluconazole 400 mg/d index of suspicion, CSF
to 800 mg/d for 8 weeks and then maintenance therapy with fluconazole fluorescent treponemal
200 mg/d to 400 mg/d for 1 year. Elevated intracranial pressure is a common antibody absorption should
complication, often requiring serial lumbar punctures or temporary external be performed, although
positive results can occur in
ventricular drain for CSF decompression; in severe cases, implantation of a previously treated patients.
permanent ventriculoperitoneal shunt may be necessary.
● Fungal organisms are
COCCIDIOIDOMYCOSIS. Coccidioidomycosis is endemic in the southwestern common causes of subacute
to chronic meningitis. The
United States. Coccidioidomycosis meningitis should be considered in patients
fungi to consider depend on
who live in or have traveled to this region and develop headache, altered mental geography, exposure
status, unexplained nausea or vomiting, or new focal neurologic deficit.52 Serum history, and immune status.
antibody confirms exposure and, if present, suggests this pathogen as a potential
cause of meningitis. Antibody and antigen in the CSF are diagnostic of

MENINGITIS
Coccidioides meningitis. Treatment is with fluconazole 400 mg/d to 1200 mg/d

orally although itraconazole may be substituted. Lifelong azole treatment is
recommended.
HISTOPLASMOSIS. Histoplasmosis is endemic in the Mississippi and Ohio River

valleys. When meningitis occurs, it is often accompanied by active pulmonary
disease. In patients who develop histoplasmosis meningitis, serum antibodies are
nonspecific because they are commonly present in patients residing in the
endemic region. CSF IgG antibodies are insensitive (approximately 50%), and
CSF Histoplasma antigen is a more sensitive test. Treatment is with liposomal
amphotericin B 5 mg/kg/d for a total of 175 mg/kg given over 4 to 6 weeks
followed by itraconazole 200 mg 2 or 3 times a day for at least 1 year until CSF
abnormalities have resolved, including Histoplasma antigen clearance.53
BLASTOMYCOSIS. Blastomycosis is endemic in the Mississippi and Ohio River

valleys, as is histoplasmosis, but it is also found in the Great Lakes region.
Involvement of the nervous system can be as chronic meningitis or as a focal
mass with or without meningitis. CNS disease is usually accompanied by
pulmonary infection, although pulmonary disease may be subclinical. Diagnosis
is primarily by CSF serology and antigen testing; culture is insensitive.
Recommended treatment is amphotericin B given as a lipid formulation at a
dosage of 5 mg/kg/d over 4 to 6 weeks followed by an oral azole. Possible options
CASE 2-2 A 73-year-old woman with a history of non-Hodgkin lymphoma

presented for evaluation of 7 weeks of headache and malaise and 2 days
of horizontal diplopia on left lateral gaze.
Her temperature was 38.5°C (101.3°F) and neurologic examination
demonstrated mild lethargy, nuchal rigidity, and left sixth cranial nerve
palsy. Noncontrast head CT was unrevealing. MRI demonstrated basilar
meningeal enhancement. CSF examination revealed protein of
120 mg/dL, 48 white blood cells/mm3 (89% lymphocytes, 7%
polymorphonuclear leukocytes, 4% others), and glucose of 25 mg/dL.
The patient’s lethargy and sixth nerve palsy improved after lumbar
puncture. A BioFire FilmArray Meningitis/Encephalitis panel was performed
and was negative, but CSF cryptococcal antigen returned positive.
COMMENT This patient presented with chronic meningitis in the setting of

immunocompromise due to hematologic malignancy. The presence of
fever and the CSF parameters suggest infection, but lymphoma of the
meninges should be considered and evaluated for by cytology and flow
cytometry. The meningitis/encephalitis panel polymerase chain reaction
(PCR)-based assay includes testing for Cryptococcus but is less sensitive
than the Cryptococcus antigen assay, which is the most sensitive test for
cryptococcal meningitis. The patient was treated with amphotericin and
flucytosine and had several episodes of declining level of consciousness
requiring lumbar puncture.
850 AUGUST 2021

for azole therapy include fluconazole 800 mg/d, itraconazole 200 mg 2 or 3 times KEY POINTS
a day, or voriconazole 200 mg to 400 mg 2 times a day, for at least 12 months and
● Most cases of
until resolution of CSF abnormalities.54 cryptococcal meningitis are
caused by Cryptococcus
CANDIDIASIS. Candida species can affect the nervous system in patients who are neoformans, but
Cryptococcus gattii,
immunocompromised, especially those who have neutropenia. CNS involvement
endemic in the Pacific
most commonly occurs in the setting of disseminated hematogenous candidiasis northwest region of the
and can cause encephalitis, brain abscesses, and meningitis. Candida meningitis United States and Canada,
may result from infection of a ventriculoperitoneal shunt or as a complication of can cause meningitis in
neurosurgery. Diagnosis is made by CSF culture, and CSF 1,3-β-D-glucan is patients who are
immunocompetent.
frequently positive.
The recommended initial treatment is liposomal amphotericin B 5 mg/kg/d ● CSF cryptococcal antigen
with or without oral flucytosine 25 mg/kg 4 times a day followed by is the most sensitive test for
fluconazole 400 mg/d to 800 mg/d (6 mg/kg/d to 12 mg/kg/d) after the diagnosis of cryptococcal
meningitis.
patient has responded to initial treatment. Therapy should continue until all
clinical, CSF, and radiologic abnormalities have resolved. Infected CNS ● Elevated intracranial
devices (eg, ventriculostomy drains, ventriculoperitoneal shunts, etc) should pressure is a common
be removed. For patients in whom a ventricular device cannot be removed, complication of
cryptococcal meningitis,
amphotericin B deoxycholate can be administered through the device into
often requiring serial lumbar
the ventricle at a dosage ranging from 0.01 mg to 0.5 mg in 2 mL of 5% punctures or temporary
dextrose in water.55 external ventricular drain for
CSF decompression.
SPOROTRICHOSIS. Although rare, S. schenckii can cause meningitis in patients ● Histoplasmosis is

exposed occupationally or recreationally to agriculture, horticulture, forestry, or endemic in the Mississippi
gardening. Diagnosis is made by CSF IgG to serum IgG ratio.37 and Ohio River valleys. When
Recommended treatment is liposomal amphotericin B 5 mg/kg/d for 4 to meningitis occurs, it is often
accompanied by active
6 weeks followed by itraconazole 200 mg 2 times a day for a total treatment pulmonary disease.
duration of at least 12 months, and, based on repeat spinal fluid analysis,
long-term therapy with itraconazole may be needed.56 ● Blastomycosis is endemic
in the Mississippi and Ohio
River valleys, as is
IMAGING. The most common neuroimaging findings in fungal meningitis are histoplasmosis, but it is also
thick, nodular leptomeningeal enhancement (most commonly in the basilar found in the Great Lakes
cisterns and subarachnoid space), hydrocephalus, and deep stroke(s) region. Involvement of the
nervous system can be as
(due to infectious vasculitis of small perforating arteries). These findings
chronic meningitis or as a
are like those seen in tuberculous meningitis due to a similar granulomatous focal mass with or without
pathologic reaction. Mass lesions may be seen in endemic mycoses and meningitis. CNS disease is
cryptococcal infection (cryptococcomas), and a “soap bubble” appearance usually accompanied by
pulmonary infection,
due to gelatinous pseudocysts in the Virchow-Robin spaces may also be seen in
although pulmonary disease
cryptococcal meningitis.18 may be subclinical.
● Diagnosis of Candida
meningitis is made by CSF
CONCLUSION culture, and CSF 1,3-β-D-
Infectious meningitis is a neurologic emergency. Prompt evaluation, accuracy glucan is frequently
of diagnosis, and early treatment are critical. Infectious meningitis is often positive.
treated empirically based on the time course of onset (acute versus chronic)
and patient and environmental factors that may suggest a particular pathogen.
Antimicrobial treatment is then narrowed when results of microbiological
assays on CSF become available. Bacterial, viral, and fungal meningitis
diagnoses have been aided by new molecular techniques including PCR,

MENINGITIS
KEY POINT immunoassays for antigen detection, and next-generation sequencing. The
clinician must be aware of the benefits and limitations of each test when
● The most common
neuroimaging findings in
evaluating for meningitis given the potential for false positives and false
fungal meningitis are thick, negatives.
nodular leptomeningeal
enhancement (most
commonly in the basilar
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854 AUGUST 2021

Encephalitis and Brain REVIEW ARTICLE

Abscess CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Arun Venkatesan, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article reviews infections of the brain parenchyma
and includes an overview of the epidemiology, pathogenesis, diagnostic
approach, and management of infectious encephalitis and brain abscess.
RECENT FINDINGS: Theepidemiology of infectious encephalitis and brain

abscess has changed in recent years. Vaccination has reduced the
incidence of certain viruses associated with encephalitis, while a decrease
in fulminant otogenic infections has led to fewer brain abscesses
associated with otitis media. However, changes in climate and human
population density and distribution have enabled the emergence of newer
pathogens and expanded the geographic range of others, and greater
adoption of intensive immunosuppressive regimens for autoimmune
conditions has increased the risk of opportunistic infections of the brain.
The widespread use of early neuroimaging, along with improved diagnostic
methodologies for pathogen detection, newer antimicrobial therapies with
better brain penetration, and less invasive neurosurgical techniques, has
resulted in better outcomes for patients with infectious encephalitis and
brain abscess. Novel technologies including metagenomic next-generation
sequencing are increasingly being applied to these conditions in an effort
to improve diagnosis. Nevertheless, both infectious encephalitis and brain
abscess continue to be associated with substantial mortality.
CITE AS:
SUMMARY: Infectious encephalitis and brain abscess can present as 2021;27(4, NEUROINFECTIOUS
neurologic emergencies and require rapid assessment, thorough and DISEASE):855–886.
appropriate diagnostic testing, and early initiation of empiric therapies

Address correspondence to
directed against infectious agents. Close clinical follow-up, proper Dr Arun Venkatesan, Johns
interpretation of diagnostic results, and appropriate tailoring of therapeutic Hopkins Encephalitis Center,
agents are essential to optimizing outcomes. Diagnosis and management of 600 N Wolfe St, Meyer 6-113,
Baltimore, MD 21287,
parenchymal brain infections are complex and often best achieved with a avenkat2@jhmi.edu.
multidisciplinary care team involving neurologists, neurosurgeons,
neuroradiologists, infectious disease physicians, and pathologists. RELATIONSHIP DISCLOSURE:
Dr Venkatesan reports no
disclosure.
UNLABELED USE OF
INTRODUCTION PRODUCTS/INVESTIGATIONAL
I
USE DISCLOSURE:
nfectious encephalitis and brain abscess are potentially life-threatening
Dr Venkatesan reports no
infections of the brain parenchyma with mortality rates of 10% to 20%. disclosure.
Although encephalitis typically results in fever, altered mental status,
seizures, and focal neurologic deficits, brain abscess is by definition a © 2021 American Academy
contained infection, and, thus, headache and focal neurologic deficits of Neurology.

ENCEPHALITIS AND BRAIN ABSCESS
predominate. Encephalitis is associated with hundreds of agents, mostly viral,

and specific treatments are largely lacking for many viruses. Brain abscess, on the
other hand, most commonly results from bacterial infections, and identification
of the infectious source can help guide antimicrobial therapies. Outcomes in
encephalitis vary widely and are chiefly dependent on the specific infectious
agent and immune status of the individual, whereas outcomes after brain abscess
are largely driven by the presence or absence of complications such as
ventriculitis.
ENCEPHALITIS
Encephalitis refers to inflammation of the brain parenchyma and is caused by a
wide range of infectious and autoimmune conditions.1 The ensuing inflammation
may be focal, multifocal, or diffuse and may also involve the meninges
(meningoencephalitis) or spinal cord (encephalomyelitis).
Case Definitions
As a result of the heterogeneity in causes and manifestations, the clinical
syndrome of encephalitis is highly variable, and, hence, case definitions have
been challenging to construct. Nevertheless, a common requirement for the
diagnosis of encephalitis is altered mental status, defined as sustained alteration
in consciousness, lethargy, or personality change, typically for greater than
24 hours.2 Other supportive elements include clinical features such as fever,
TABLE 3-1 Epidemiology of the Most Common Causes of Encephalitis Worldwidea,b
Approximate annual
Cause incidence, per 100,000 Comments
Japanese encephalitis virus 10 Geographically restricted: Asia and Australia; more common in
children
Herpes simplex virus type 1 2-4 Most common cause of sporadic encephalitis
Anti–N-methyl-D-aspartate 2 Most commonly identified antineuronal antibody; more

(NMDA) receptor common in children and young adults
Tick-borne encephalitis virus 2 Geographically restricted: more common in Russia, Eastern

Europe than in Western Europe; incidence is increasing
Varicella-zoster virus 1 Incidence appears to be rising in the setting of increasing

adoption of immunosuppressive regimens
Enterovirus 1 Meningitis more common than encephalitis; outbreaks of

enterovirus D68 (EVD68) appear to occur biannually; more
common in children
Anti–leucine-rich glioma 1 Incidence may be underappreciated

inactivated protein 1 (LGI1)
Coxsackievirus 0.25 Meningitis more common than encephalitis; far more common
in children
a
Data from Venkatesan A, et al, Lancet.1
b
In the United States, the annual incidence of West Nile neuroinvasive disease varies by year from 0.4 per 100,000 to 1.0 per 100,000.
856 AUGUST 2021

seizures not attributable to a preexisting seizure disorder, or new-onset focal KEY POINTS
neurologic findings, and diagnostic findings including CSF pleocytosis,
● Encephalitis refers to
new-onset neuroimaging abnormalities, or electroencephalographic inflammation of the brain
abnormalities compatible with encephalitis. A higher number of supportive parenchyma and is caused
features raises the confidence level of the clinical diagnosis of encephalitis. by a wide range of infectious
Because a broad range of pathologic processes can cause altered mental status, and autoimmune conditions.
including metabolic derangements, toxins, and cerebrovascular disease, patients
● Because a broad range of
with suspected encephalitis must be thoroughly evaluated for alternative pathologic processes can
conditions.3 The temporal course of neurologic changes in infectious encephalitis cause altered mental status,
is typically categorized as acute to subacute (ie, days to weeks) to distinguish including metabolic
acute encephalitis from mimics, including prion disorders and tauopathies, derangements, toxins, and
cerebrovascular disease,
which can result in similar symptoms but evolve more slowly. Although this time patients with suspected
frame is characteristic of infectious encephalitides, it has been recognized that encephalitis must be
autoimmune encephalitis may develop over a longer time span and alterations in thoroughly evaluated for
mental status may consist solely of short-term memory loss or new-onset alternative conditions.
psychiatric changes; thus, alternative case definitions that better capture ● Infections account for up
autoimmune encephalitis have been proposed.2,4 to half of all cases of
encephalitis; autoimmune
Epidemiology causes are identified in 20%
to 30%, and in the remaining
The incidence of encephalitis is 5 to 10 per 100,000 individuals annually, with
20% to 30% of cases, a
rates highest in children.5–7 Infections account for up to half of all cases; specific cause is not
autoimmune causes are identified in 20% to 30%, and in the remaining 20% to ascertained.
30% of cases, a specific cause is not ascertained despite improved methodologies
for detection of pathogens and autoantibodies (TABLE 3-1).8–10 Hundreds of ● Changes in climate,
human population growth
pathogens, chiefly viruses, but including bacteria, mycobacteria, fungi, and and migration, and farming
amoebae, have been associated with encephalitis. Of the viruses, Japanese practices have resulted in
encephalitis virus is the most commonly identified cause of encephalitis the emergence and spread
worldwide but has a restricted geographical range. Herpes simplex virus (HSV) of arthropod-borne viruses
(arboviruses), such as West
is the most commonly identified sporadic cause of encephalitis, occurring Nile virus, chikungunya virus,
globally and without regard for seasonality. In recent years, several factors have and tick-borne encephalitis
altered the epidemiology of encephalitis. Changes in climate, human population virus.
growth and migration, and farming practices have resulted in the emergence and
● Herpes simplex virus
spread of arthropod-borne viruses (arboviruses), such as West Nile virus,
(HSV) most often affects the
chikungunya virus, and tick-borne encephalitis virus.11,12 Widespread use of temporal lobes and other
immunotherapeutics for rheumatologic and other autoimmune conditions has limbic areas.
resulted in a larger proportion of the population who are immunocompromised
and, thus, at risk of opportunistic infections that can cause encephalitis. In ● The deep gray matter is
commonly affected in
addition, increasing adoption of vaccination programs targeting viruses such as flaviviral infections such as
Japanese encephalitis virus and varicella-zoster virus (VZV) has resulted in fewer West Nile virus and Japanese
such infections. encephalitis virus.
● Many patients with HSV-1

Clinical Features of Selected Infections encephalitis present with
Common clinical features of infectious encephalitis include fever and headache. prodromal symptoms
The disturbance of brain function that is a core feature of encephalitis can suggesting upper respiratory
manifest in a multitude of ways, including altered level of consciousness, tract or other systemic
infection.
confusion, disorientation, amnesia, personality or behavioral change, psychiatric
symptoms, movement disorders, aphasia, other focal neurologic deficits, or
seizure. The involvement of specific central nervous system (CNS) regions may
suggest certain infectious causes (TABLE 3-2). HSV, for example, most often
affects the temporal lobes and other limbic areas. Brainstem involvement may

TABLE 3-2 Selected Pathogens by Region of Brain Involvement in Encephalitis
Brain region Neuroimaging findings
Temporal lobe
Herpes simplex virus (HSV) Asymmetric involvement is characteristic
Varicella-zoster virus Temporal lobe involvement can mimic HSV encephalitis
Treponema pallidum Bilateral mesial temporal lobe involvement has been described
Human herpesvirus 6 In posttransplant limbic encephalitis, mesial temporal lobe involvement is bilateral and
symmetric
Frontal lobe
HSV Cingulate gyrus, usually in association with temporal lobe abnormalities
Naegleria fowlerii Necrotic, hemorrhagic lesions
Deep gray (basal ganglia/thalamus)
West Nile virus Imaging may be normal in early stages
Japanese encephalitis virus Involvement of thalamus more often than the basal ganglia
Respiratory viruses Symmetric, hemorrhagic lesions can occur in the setting of acute necrotizing
encephalopathy
Rabies Ill-defined, nonenhancing lesions
Mycobacterium tuberculosis Involvement of basal ganglia more often than thalamus
Rocky Mountain spotted fever “Starry sky” appearance in children, involving deep white and gray matter
Cerebellum
Varicella-zoster virus Brain MRI may be normal despite clear cerebellar signs on examination
West Nile virus Usually in association with deep gray matter abnormalities
Powassan virus Imaging abnormalities can be multifocal and variable
Mycoplasma pneumoniae Lesions can be large with associated mass effect
Brainstem
Enteroviruses Brainstem involvement most commonly associated with enterovirus 71 (EV71) and
enterovirus D68 (EVD68)
West Nile virus Usually in association with deep gray matter abnormalities
Japanese encephalitis virus Usually in association with deep gray matter abnormalities
Rabies Ill-defined, nonenhancing lesions
Listeria monocytogenes Multiple enhancing lesions of pons and medulla is characteristic
M. pneumoniae Lesions can be large with associated mass effect
858 AUGUST 2021

suggest Listeria monocytogenes as a cause, although viruses such as enteroviruses KEY POINTS
and the herpesvirus family should also be considered. The deep gray matter is
● Early in the course, some
commonly affected in flaviviral infections such as West Nile virus and Japanese patients with encephalitis
encephalitis virus. Concomitant involvement of the spinal cord and, in may have fever and
particular, the anterior horn cells, is suggestive of enteroviruses or West Nile headaches without
virus. Systemic manifestations, such as rash, ophthalmic involvement, or encephalopathy or focal
neurologic deficits, even
hepatitis, may also accompany the neurologic features and, in some cases, can
when parenchymal brain
suggest specific causes. Clinical and radiologic features of selected viruses, involvement is
bacteria, and eukaryotic parasites are addressed later. Fungal involvement of the demonstrated by
nervous system typically manifests as meningitis or a space-occupying lesion neuroimaging or EEG.
rather than frank encephalitis and is not further discussed in this section.
● Early in the disease
course of HSV-1
HUMAN HERPESVIRUSES. The human herpesviruses (HHVs) are a family of DNA encephalitis, findings are
viruses that includes HSV, VZV, Epstein-Barr virus (EBV), and cytomegalovirus often unilateral; when
(CMV). Together, these viruses account for a substantial proportion of cases of bilateral, asymmetry may
help to distinguish HSV-1
encephalitis in humans. encephalitis from
autoimmune causes of
HERPES SIMPLEX VIRUS. HSV is acquired through mucous membranes or broken limbic encephalitis, which
skin, where the virus infects sensory neurons and subsequently travels via more commonly cause
symmetrical changes.
retrograde axonal transport to the dorsal root ganglion, establishing latency.13
Entry into the CNS may occur during primary infection or viral reactivation. ● False-negative
Retrograde transport through the olfactory or trigeminal nerves has been polymerase chain reaction
demonstrated in animal models and may play a role in the pathophysiology of (PCR) may occur early in the
course of HSV-1
CNS infection, although hematogenous dissemination is also a possible
encephalitis. Notably, in
mechanism of entry. The accompanying inflammatory cascade triggered by children and people who are
infection contributes to the marked necrosis that can occur.14 immunocompromised, the
More than 90% of cases of HSV encephalitis are caused by HSV-1, with patients clinical manifestations and
older than 50 years most commonly affected. HSV-1 is a ubiquitous virus, MRI findings are broader
and can include a more
with a seroprevalence up to 50% in those in their twenties and rising to 90% diffuse encephalitis or
in individuals older than 70 years.15 The incidence of HSV encephalitis is also meningoencephalitis with or
high in children younger than 3 years, in whom HSV-2 is the predominant cause. without temporal lobe
Many patients with HSV-1 encephalitis present with prodromal symptoms involvement.
suggesting upper respiratory tract or other systemic infection (CASE 3-1). Signs ● Rash may be absent in up
and symptoms of encephalitis, including altered mental status, behavioral to one-third of cases of
changes, and aphasia, then progress over the course of several days.16,17 varicella-zoster virus (VZV)
Alterations in mental status can range from subtle confusion to profound encephalitis.
depression of consciousness, including coma. Seizures with temporal lobe
● In contrast to HSV-1
symptomatology are a common manifestation, and olfactory hallucinations can encephalitis, the primary
also occur because of the early involvement of limbic structures. Early in the pathologic process
course, some patients may have fever and headaches without encephalopathy or associated with VZV in the
focal neurologic deficits, even when parenchymal brain involvement is central nervous system
(CNS) may be vasculopathy.
demonstrated by neuroimaging or EEG.18
On head CT, hypodensity is commonly seen in the temporal lobe, with ● Human herpesvirus 6
variable levels of contrast enhancement. Sensitivity of head CT, however, is (HHV-6) can cause
limited compared with brain MRI. In a 2014 study, CT scan was abnormal in encephalitis in adults who
are immunocompromised,
roughly half of all patients with HSV-1 encephalitis, whereas MRI was abnormal most commonly in patients
in nearly all patients.19 Brain MRI typically demonstrates T2 hyperintensity and who have undergone
swelling of limbic structures including mesiotemporal, orbitofrontal, and insular hematopoietic stem cell
regions, with associated restriction of diffusion on diffusion-weighted imaging transplantation.
(DWI) sequences.20 Early in the disease course, findings are often unilateral;

when bilateral, asymmetry may help to distinguish HSV-1 encephalitis from

autoimmune causes of limbic encephalitis, which more commonly cause
symmetrical changes. Hemorrhage has historically been reported as a common
feature of HSV-1 encephalitis. However, in studies in 2015 and 2016, hemorrhage
was not commonly observed at presentation, potentially because of earlier
imaging of patients with suspected HSV-1 encephalitis.16,21 Electroencephalographic
findings may also demonstrate abnormalities of the temporal lobe, including
lateralized periodic discharges, focal slowing, or electrographic seizures,
CASE 3-1 A 58-year-old woman was brought to the emergency department by her
husband for confusion and difficulties with language. She had been in her
usual state of good health until 1 week before, when she developed
cough, fever, and mild difficulty breathing. At that time, testing for
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and
influenza was negative, and a chest radiograph was unremarkable. She
was told that she likely had COVID-19 and was advised to isolate at home.
While at home, she continued to be febrile and developed confusion.
Oxygen saturation was normal, and she was advised to continue isolating.
After several days, her husband sought further medical attention because
of worsening neurologic function (eg, getting lost inside of her own
house, having trouble formulating sentences).
On arrival, she was febrile to 38.2°C (100.8°F) and mildly tachycardic.
On neurologic examination, she was slightly somnolent and easily
distracted; her recall was 0/3 at 3 minutes, and she could not name
low-frequency objects. Head CT showed a hypodensity in the right
temporal lobe. A lumbar puncture demonstrated 124 white blood cells/
mm3 (95% lymphocytes), 12 red blood cells/mm3, protein of 74 mg/dL,
and normal glucose. Brain MRI demonstrated abnormalities in the
temporal lobe, insula, and cingulate gyrus, more prominent on the right
than the left (FIGURE 3-1).
Given the suspicion for herpes simplex virus (HSV) encephalitis, she
was started on IV acyclovir and treated for 21 days. The CSF polymerase
chain reaction (PCR) returned positive for HSV-1, confirming the
diagnosis. At a 6-month follow-up visit, her short-term memory had
continued to be quite poor, and she had not been able to return to her job
as an auto mechanic.
COMMENT This case highlights that the systemic infectious prodrome that often
precedes neurologic manifestations of HSV encephalitis can serve to
confound or delay the diagnosis. Here, treatment with acyclovir was not
initiated until 5 days after the onset of confusion, an interval that may have
contributed to the substantial temporal lobe necrosis and poor cognitive
outcome.
860 AUGUST 2021

although evidence of more diffuse cerebral dysfunction can also be seen.22
Periodic discharges in HSV-1 encephalitis are generally observed in the first
2 weeks and may manifest before structural lesions are seen on CT.
Although the clinical presentation along with neuroimaging and
electrographic findings may strongly suggest HSV-1 encephalitis, lumbar
puncture with CSF HSV polymerase chain reaction (PCR) is required to confirm
the diagnosis. A typical CSF profile includes a moderate lymphocytic pleocytosis
(10 cells/mm3 to 200 cells/mm3), modestly elevated protein (50 mg/dL to
FIGURE 3-1
Involvement of limbic structures by herpes simplex
encephalitis in the patient in CASE 3-1. Axial fluid-
attenuated inversion recovery (FLAIR) images
(A) and diffusion-weighted images (B) during
hospital admission demonstrate asymmetric FLAIR
hyperintensity and restriction of diffusion (confirmed
by hypointensity on the apparent diffusion
coefficient map, not shown) in the temporal lobes
(A and B, left), as well as insula and cingulate gyrus
(A and B, right). On follow-up FLAIR images (C)
performed several months after discharge, areas of
necrosis (C, arrows) and gliosis are present.

100 mg/dL), and normal to slightly low glucose (although hypoglycorrhachia

may be present in a minority of patients). PCR for HSV-1 and HSV-2 has replaced
viral cultures and other studies as the test of choice. The HSV PCR exhibits high
sensitivity (96%) and specificity (99%), although false-negative PCR may occur
early in the course of illness.23 Notably, in children and people who are
immunocompromised, the clinical manifestations and MRI findings are broader
and can include a more diffuse encephalitis or meningoencephalitis with or
without temporal lobe involvement.24,25
VARICELLA-ZOSTER VIRUS. After HSV, VZV is the second most commonly reported
cause of sporadic viral encephalitis worldwide.8,26 Children with primary VZV
infection (chickenpox) can develop encephalitis, typically a cerebellitis, either
before or after onset of the rash; in rare cases, other parts of the brain can be
affected. Similar to HSV, VZV can establish latency in sensory ganglia after initial
infection, with the potential for reactivation particularly in the setting of
immunocompromise or advanced age. In such cases of VZV encephalitis, a painful
rash (known as herpes zoster or shingles) often precedes the neurologic
manifestations.27 Notably, however, rash may be absent in up to one-third of cases.
Neurologic features are variable and can include encephalopathy, focal neurologic
signs, seizures, and cranial neuropathies, although a subset of patients will have
temporal lobe signs and symptoms similar to HSV encephalitis.21 In contrast to
HSV-1 encephalitis, the primary pathologic process in the CNS may be
vasculopathy. Histopathologic studies have found evidence of infection of the walls
of both large and small cerebral arteries, and neuroimaging often demonstrates
ischemic and/or hemorrhagic lesions in addition to edema.28 Of note, although
establishment of latency and reactivation can occur from the live attenuated virus
used in vaccination, this is not a concern with the newer recombinant protein-based
vaccine.29 Sensitivity of PCR for VZV is lower than that of HSV, and, thus in some
cases, the diagnosis is made by detection of anti-VZV antibodies in the CSF.2,30,31
OTHER HERPESVIRUSES. Other herpesviruses frequently infect humans and can, in

rare instances, cause encephalitis, including EBV, CMV, and HHV-6. In people
who are immunocompetent, encephalitis associated with EBV and HHV-6
occurs more often in childhood; HHV-6 can also cause encephalitis in adults who
are immunocompromised, most commonly in patients who have undergone
hematopoietic stem cell transplantation. Encephalitis associated with EBV must
be distinguished from CNS lymphoma or lymphomatoid granulomatosis, both
of which can mimic encephalitis clinically.32 Distinct neurologic conditions such
as opercular syndrome (paresis of facial, pharyngeal, and masticatory muscles)
or Alice in Wonderland syndrome (alteration of visual perception characterized
by distorted body images) have been reported in EBV encephalitis.33,34
Symptomatic HHV-6 infection in children usually occurs before 2 years of age,
and neurologic manifestations include febrile seizures or, less commonly,
encephalitis. HHV-6 causes a limbic encephalitis that develops weeks to months
after hematopoietic stem cell transplantation.35 CMV encephalitis is an
important consideration in patients with acquired immunodeficiency syndrome
(AIDS) (particularly when CD4+ count is less than 50 cells/mm3) and may be
accompanied by retinitis, polyradiculitis, and ventriculitis. CMV encephalitis
can cause a CSF neutrophilic pleocytosis, in contrast to the more common viral
pattern of lymphocytic pleocytosis.
862 AUGUST 2021

ARBOVIRUSES. Arboviruses refer to a diverse group of viruses transmitted by KEY POINTS
arthropod vectors (eg, mosquitos, ticks, sandflies) and are represented by several
● HHV-6 causes a limbic
viral families, including flaviviruses, togaviruses, bunyaviruses, and reoviruses. encephalitis that develops
After an arthropod bite, replication and amplification of the virus occur in the weeks to months after
lymphatics with subsequent viremia and, in some cases, entry into the CNS.36 The hematopoietic stem cell
resultant human disease is quite variable, reflecting in part the heterogeneity of transplantation.
viral families. Many cases of arboviral infection are asymptomatic. In symptomatic
● Cytomegalovirus
cases, a febrile illness along with headache and myalgias is common. Potential encephalitis is an important
neurologic manifestations include meningitis, encephalitis, and myelitis. Several consideration in patients with
general principles of arboviral encephalitis have emerged. Involvement of the deep acquired immunodeficiency
gray matter is commonly seen on MRI and often accompanied clinically by syndrome (AIDS) (particularly
when CD4+ count is less than
movement disorders. Regarding diagnostics, because peak viremia typically 50 cells/mm3) and may be
precedes the onset of neurologic symptoms, viral RNA has often cleared from the accompanied by retinitis,
CSF and blood by the time laboratory investigations are performed. As a result, polyradiculitis, and
laboratory diagnosis often rests on detection of virus-specific IgM in CSF and ventriculitis; a neutrophilic
pleocytosis may be seen on
blood. In addition, interpretation of positive results must take into account the CSF analysis, in contrast to the
serologic cross-reactivity that may occur between members of each viral family.37 more common viral pattern of
lymphocytic pleocytosis.
WEST NILE VIRUS. West Nile virus has emerged as the most common epidemic
● In arboviral encephalitis,
viral encephalitis in the United States over recent decades, with prominent
involvement of the deep
outbreaks also occurring in central and southern Europe. Although most gray matter is commonly
individuals infected with West Nile virus will remain asymptomatic or develop seen on MRI and often
systemic symptoms such as fever, myalgia, and diffuse maculopapular rash a accompanied clinically by
movement disorders.
small proportion (less than 1%) will develop West Nile neuroinvasive disease in
the form of meningitis, encephalitis, or acute flaccid myelitis. Risk factors for ● As a result of the
developing West Nile neuroinvasive disease include older age, diabetes or other insensitivity of CSF PCR,
chronic illness, or an immunocompromised state.38 West Nile virus encephalitis laboratory diagnosis of
preferentially affects the basal ganglia and thalamus, and thus can present with arboviral encephalitis often
rests on detection of virus-
parkinsonism, tremors, or other movement disorders (CASE 3-2).39 Accompanying specific IgM in CSF and blood.
brainstem involvement can result in cranial neuropathies, bulbar dysfunction, or
respiratory failure. CSF studies demonstrate a neutrophilic pleocytosis in up to ● Less than 1% of people
half of patients. Approximately 90% of patients with neuroinvasive disease have infected with West Nile virus
will develop West Nile
detectable CSF IgM antibody within 10 days of symptom onset.40 However,
neuroinvasive disease in the
West Nile virus IgM may persist for prolonged periods, with detectable IgM form of meningitis,
titers for longer than 1 year, and thus, in some cases, the finding of West Nile encephalitis, or acute
virus IgM may reflect previous exposure rather than current illness. flaccid myelitis.
● West Nile virus IgM may

JAPANESE ENCEPHALITIS VIRUS. Japanese encephalitis virus is the most important persist for prolonged
cause of encephalitis in South and Southeast Asia, typically affecting children periods, with detectable
younger than 10 years. After a characteristic prodrome of fever and headache, IgM titers for longer than
mental status changes, seizures, focal neurologic deficits, and movement disorders 1 year, and thus, in some
cases, the finding of West
develop. Masklike facies, tremor, and rigidity are often present, and other features Nile virus IgM may reflect
typical of basal ganglia involvement including opsoclonus-myoclonus, dystonia, previous exposure rather
and chorea may also occur.41 Similar to West Nile virus, the encephalitis can be than current illness.
accompanied by acute flaccid myelitis.42 The encephalitis associated with Japanese
● Japanese encephalitis
encephalitis virus is often severe, with mortality of around 20%.
virus is the most important
cause of encephalitis in
OTHER ARBOVIRUSES. In the United States, other neurotropic arboviruses include South and Southeast Asia,
La Crosse virus, St. Louis encephalitis virus, Powassan virus, Jamestown Canyon typically affecting children
younger than 10.
virus, Eastern equine encephalitis, and Cache Valley virus. These infections

occur sporadically or in small outbreaks, and several have been increasing in

incidence in recent years.43 Chikungunya virus, dengue virus, and Zika virus
affect similar geographic regions including Central and South America, South
and Southeast Asia, and Africa. Of the three, chikungunya virus is believed to
have the most neurotropic potential.44 Dual infections (eg, chikungunya and
dengue) are not uncommon, and the presence of concurrent infections may
impact the neurologic phenotype.45
OTHER VIRUSES. Many other viral families have been associated with encephalitis
in humans. Several important and emerging causes are briefly described here.
ENTEROVIRUSES. Enteroviruses are a common cause of aseptic meningitis but are

less typically associated with encephalitis. Brainstem encephalitis can, however,
occur in the setting of certain enteroviral infections, particularly enterovirus 71
(EV71) and enterovirus D68 (EVD68).46 In some cases, the virus is not identified
in the CSF but can be found in other samples (eg, respiratory, stool).
CASE 3-2 A 48-year-old man was brought to the emergency department by

paramedics because of fever and unresponsiveness. He had been well
until 4 days before, when he developed intermittent fevers as high as
38.9°C (102°F), nausea, and weakness of the legs. Over the next few days,
he developed headaches, muscle aches, lethargy, and worsening
weakness. On the day of presentation, his wife could not arouse him from
bed and an ambulance was called.
He was febrile to 39.6°C (103.2°F), and his heart rate was
125 beats/min. A diffuse red maculopapular rash was noted on his trunk.
On neurologic examination, he was only arousable to deep tactile
stimulation and did not follow commands. Tone was decreased, and he
had minimal withdrawal of his extremities to pain. He was emergently
intubated for airway protection.
Head CT was unremarkable, and he was begun on ceftriaxone,
vancomycin, and acyclovir. Lumbar puncture demonstrated 482 white
blood cells/mm3 (86% neutrophils), protein of 104 mg/dL, and normal
glucose. CSF Gram stain and cultures were negative, as were polymerase
chain reactions (PCRs) for herpes simplex virus, varicella-zoster virus,
enteroviruses, and West Nile virus. Brain MRI demonstrated bilateral
basal ganglia hyperintensities (FIGURE 3-2), raising the possibility of
arboviral encephalitis, and thus, additional serologic testing from blood
and CSF was sent. West Nile virus IgM returned positive from CSF,
confirming the diagnosis of West Nile virus encephalitis. Antibiotics and
antivirals were discontinued, and over the course of the next 7 days, his
mental status gradually improved such that he began following
commands and was extubated. However, tone continued to be
decreased, and he was profoundly weak in all extremities. MRI of the
spine was unremarkable, but EMG demonstrated evidence of diffuse
lower motor neuron dysfunction. At a 6-month follow-up visit, he had no
improvement in strength.
864 AUGUST 2021

PARAMYXOVIRUSES. The paramyxoviruses measles and mumps can cause
encephalitis, and measles, in particular, can result in severe disease. Measles has
been associated with acute, subacute, and chronic brain inflammation, the last of
which is termed subacute sclerosing panencephalitis (SSPE) and results from
persistent measles virus production. Although vaccination has dramatically
reduced the incidence of paramyxovirus encephalitis, it should be noted that
prior measles vaccination does not preclude the development of SSPE because
an unrecognized measles infection may occur before immunization.47
HENIPAVIRUSES. Bats represent a reservoir for a number of pathogenic viruses

including the henipaviruses Hendra virus and Nipah virus. The former is
endemic to Australia, and the latter has been responsible for outbreaks of
encephalitis in Southeast Asia.48
RHABDOVIRUSES.Although rabies virus infection has been virtually eradicated

from most industrialized countries, approximately 50,000 deaths occur annually
FIGURE 3-2
Involvement of deep gray structures by West Nile virus encephalitis in the patient in
CASE 3-2. Axial T2-weighted (A) and fluid-attenuated inversion recovery (FLAIR) (B) MRI
sequences demonstrate symmetric hyperintensities in the caudate and putamen.
In this case of West Nile neuroinvasive disease, acute flaccid myelitis is COMMENT
present in addition to encephalitis. Once anterior horn cells have been
damaged, the scope for motor improvement is quite limited. Although West
Nile virus typically affects the thalami, occasionally lesions are initially found
in the basal ganglia. In all cases of encephalitis in which deep gray matter
lesions are present, West Nile virus and other arboviruses are strong
considerations. IgM antibodies in the CSF are usually required to confirm the
diagnosis because PCR is typically negative by the time neurologic
symptoms arise.

in regions of Africa and Asia.49 A small number of infections, typically 2 to 3 per

year, still occur in the United States, usually due to unrecognized bat bites. The
incubation time of the virus is highly variable, ranging from a few days to several
years.50 Clinical manifestations include a furious form characterized by extreme
agitation, hydrophobia, delirium, and seizures, and, in a minority of cases, a
paralytic form that presents with ascending paralysis followed by confusion and
coma. Diagnosis is made by several potential techniques, including PCR of various
tissues (salivary sample, skin biopsy, urine, or CSF), serologic tests of the serum or
CSF, or detection of rabies virus antigen from hair follicles. The disease is nearly
completely preventable with timely postexposure prophylactic immunization.51
BACTERIA. Bacterial meningitis from organisms such as Streptococcus pneumoniae and

Neisseria meningitidis can also result in associated brain parenchymal involvement,
and thus, a meningoencephalitis can ensue. Similarly, although encephalitis can
occur in the setting of tuberculosis and is often cited as one of the leading causes in
large series, the underlying process is more typically one of meningitis or abscess
with associated parenchymal involvement.8,26 In addition to causing meningitis,
CASE 3-3 A 43-year-old woman who was previously healthy was brought to the
emergency department for fever and cranial nerve abnormalities. Ten
days before presentation, she had begun to experience low-grade fevers
and dizziness; three days before presentation, she developed left-sided
facial pain, gait imbalance, and nausea; and on the day of presentation,
she noted double vision and asymmetry of her face.
She was febrile to 38.7°C (101.6°F), and other vital signs were
unremarkable. On neurologic examination, she was alert with intact
language. She had marked limitation of horizontal eye movements and
had a complete peripheral seventh nerve palsy on the right.
Head CT was unremarkable, and a lumbar puncture demonstrated
79 white blood cells/mm3 (87% lymphocytes), protein of 51 mg/dL, and
normal glucose. Gram stain was negative, as was multiplex PCR panel for
meningitis/encephalitis. She was started on acyclovir but continued to be
febrile and, by the next day, had developed weakness of the left face and
difficulty swallowing. Brain MRI demonstrated abnormalities spanning
the pons and medulla (FIGURE 3-3) compatible with a rhombencephalitis.
Blood cultures returned positive for Listeria monocytogenes, confirming
the diagnosis of listeria rhombencephalitis. Ampicillin was added to her
regimen, she began to gradually improve over the subsequent week and
was left with only mild facial weakness at 1-year follow-up.
866 AUGUST 2021

L. monocytogenes can cause rhombencephalitis. Although Listeria infections occur
more commonly in individuals who are immunocompromised, immunocompetent
individuals may also be affected; according to one review of previously reported
cases, the majority of patients who developed rhombencephalitis were
immunocompetent (CASE 3-3).52 Clinically, a biphasic disease course is observed, in
which an initial nonspecific prodrome develops and subsides, followed days to
weeks later by progressive asymmetric cranial nerve palsies, cerebellar signs, and
altered levels of consciousness. CSF abnormalities are often less pronounced than in
other bacterial CNS infections, perhaps because the organism resides intracellularly
and does not provoke as vigorous an inflammatory response.53 Intracellular
residence may also explain the fastidious nature of L. monocytogenes and the
necessity to perform multiple cultures from blood and CSF to identify it.
When the spirochetes Treponema pallidum and Borrelia burgdorferi affect the
nervous system, acute encephalitis very rarely occurs. In syphilis,
meningovascular involvement, tabes dorsalis, and general paresis are the most
common neurologic sequelae, whereas in Lyme disease, cranial neuropathies,
polyradiculitis, and meningitis are the most common neurologic manifestations.
FIGURE 3-3
Listeria rhombencephalitis in the patient in CASE 3-3. Midsagittal fluid-attenuated inversion
recovery (FLAIR) sequence demonstrates extensive, diffuse hyperintensity in the dorsal
brainstem, spanning the upper pons to lower medulla (A). Multiple enhancing lesions are
seen on the sagittal postcontrast T1-weighted image (B).
This is a classic case of listeria rhombencephalitis. The disease evolves in a COMMENT

biphasic manner over several weeks. Brain MRI usually reveals multiple
enhancing lesions, which may demonstrate nodular or rim enhancement,
and, in some cases, lesions can restrict diffusion, suggestive of abscess.
Ampicillin is the treatment of choice, and when instituted promptly,
neurologic manifestations can improve markedly.

Rickettsial disorders are an important cause of encephalitis, particularly in

children. Rocky Mountain spotted fever, caused by Rickettsia rickettsii, can cause
encephalitis that typically begins abruptly with fever, severe headache,
restlessness, and delirium.54 Ophthalmologic findings, most commonly retinal
vascular changes, are frequent,55 as is temporary loss of hearing. The distinctive
spotted rash develops about 3 to 5 days after fever onset, initially appearing on
the wrists and ankles before spreading to involve other areas and developing into
petechiae. Thrombocytopenia and vascular involvement are common, likely
accounting for the petechiae and the brain MRI findings of scattered punctate
areas of restricted diffusion and T2 hyperintensity in the deep gray and white
matter in affected children.56 Notably, rickettsial species are distributed globally
and Orientia tsutsugamushi, the causative agent of scrub typhus, is increasingly
recognized as a cause of encephalitis in South Asia. Systemic involvement in the
setting of scrub typhus is common, most frequently lymphadenopathy,
hepatomegaly, and laboratory evidence of transaminitis and
thrombocytopenia.57
EUKARYOTIC PARASITES. Helminths and amoebas are important causes of

encephalitis in the United States and worldwide. Baylisascaris procyonis, a raccoon
roundworm, causes a severe, often fatal, eosinophilic encephalitis. Infection
occurs after fecal-oral contact with raccoon roundworm eggs found in feces, dirt,
or contaminated water. Small children are typically affected because of their
propensity to place dirt and other objects in their mouths.58 Other important
neurotropic helminths associated with eosinophilic encephalitis include
Gnathostoma spinigerum and Angiostrongylus species.
Disease caused by free-living amoebas can take the form of either
granulomatous amoebic encephalitis or primary amoebic meningoencephalitis.59
Granulomatous amoebic encephalitis is caused by Balamuthia mandrillaris and
Acanthamoeba species, resulting in meningitis, hydrocephalus, and space-
occupying lesions in addition to a more diffuse encephalitis. B. mandrillaris, in
particular, can affect individuals who are immunocompetent. Mortality is high,
and many cases have been identified only postmortem; however, increased
recognition and earlier identification have resulted in rapid initiation of multidrug
treatments (eg, pentamidine, sulfadiazine, flucytosine, fluconazole, azithromycin
or clarithromycin, and miltefosine) with associated survival.60
Primary amoebic meningoencephalitis is caused by Naegleria fowleri, an agent
that has achieved notoriety as the “brain-eating amoeba.” The organism is
present in warm fresh water and soil and invades the CNS through the nasal
passages. The resulting disease is fulminant, progressing rapidly through the
brain and resulting in profound tissue necrosis. In recent years, it has been
recognized that contaminated tap water is also a potential source of transmission,
as underscored by several cases associated with the use of neti pots. Although
almost uniformly fatal, good outcomes have been reported in several patients in
whom treatment regimens have included the antileishmaniasis drug
miltefosine.61,62
Neurocysticercosis caused by the tapeworm Taenia solium is a major contributor
to the incidence of epilepsy worldwide but can rarely present as encephalitis,
most commonly in children and young women. This presumably arises in the
context of acute exposure to a large parasite burden with corresponding robust
CNS inflammatory response in previously unexposed hosts.63
868 AUGUST 2021

Although the protozoan parasite Toxoplasma gondii is a common cause of KEY POINTS
CNS infection in immunocompromised hosts, the resulting syndrome is
● In addition to causing
caused by granulomatous inflammation or abscess formation rather than meningitis, Listeria
encephalitis. monocytogenes can cause
rhombencephalitis.
Diagnostic Evaluation and Management Although Listeria infections
occur more commonly in
The evaluation and management of patients with suspected encephalitis are
individuals who are
intertwined. Encephalitis can present as a systemic and neurologic emergency, immunocompromised,
and thus, initial management is focused on stabilizing patients who are acutely ill immunocompetent
while concurrently initiating a diagnostic evaluation. Systemic issues such as individuals may also be
affected; according to one
hypotension, autonomic dysfunction, and syndrome of inappropriate secretion
review of previously
of antidiuretic hormone (SIADH) must be attended to, along with neurologic reported cases, the majority
complications such as status epilepticus, increased intracranial pressure, and, in of patients who developed
some cases, impending herniation.3 rhombencephalitis were
immunocompetent.
DIAGNOSTIC EVALUATION. The myriad etiologies of encephalitis and its mimics ● Thrombocytopenia and
necessitate a broad-based approach to the evaluation of patients. Identification of vascular involvement are
a specific infectious cause, even in the absence of available treatment, is common in Rocky Mountain
important for withdrawal of unnecessary antimicrobial agents, limiting further spotted fever, likely
accounting for the
testing, counseling regarding prognosis, and potential initiation of public health petechiae and the brain MRI
interventions. A comprehensive history encompassing travel, ill contacts, findings of scattered
occupational exposures, vector and animal exposures, outdoor activities, punctate areas of restricted
ingestions, and recent illnesses should be ascertained.3 Additionally, a diffusion and T2
hyperintensity in the deep
thorough systemic evaluation, including assessment for HIV serostatus,
gray and white matter in
eosinophilia, pulmonary infections, and ophthalmologic pathology, should affected children.
be performed.
Neuroimaging, preferably MRI because of its higher sensitivity for early or ● Balamuthia mandrillaris
subtle findings of encephalitis than CT, should also be performed urgently and is can affect individuals who
are immunocompetent.
helpful in not only suggesting potential etiologies of encephalitis but also Mortality is high, and many
excluding some mimics. cases have been identified
CSF studies are essential in confirming an inflammatory process and only postmortem; however,
identifying a specific cause. Thus, lumbar puncture should be performed in all increased recognition and
earlier identification have
patients as soon as possible unless contraindicated. Although the typical CSF resulted in rapid initiation of
profile of viral encephalitis consists of a mononuclear pleocytosis (up to multidrug treatments with
200 white blood cells/mm3), some viruses can be associated with CSF associated survival.
white blood cell counts greater than 1000 cells/mm3 (ie, mumps, lymphocytic
● In recent years, it has
choriomeningitis virus). In addition, neutrophils, which are typically present in
been recognized that
the first 24 hours of viral infection, may, in some cases, persist in the CSF for contaminated tap water is a
longer periods.64 Although the CSF glucose is typically normal in viral infections potential source of
of the CNS, several viruses, including lymphocytic choriomeningitis virus, transmission of Naegleria
fowleri, as underscored by
mumps, and HSV-2, have been associated with hypoglycorrhachia. Thus, low
several cases associated
CSF glucose does not exclude a viral process. with the use of neti pots.
It should be noted that, in clinical practice, a limited array of agents accounts
for most cases of infectious encephalitis, and therefore, assessment is typically ● Encephalitis can present
focused on these agents. To assess for common and treatable infectious as a systemic and neurologic
emergency, and thus, initial
conditions, important studies to obtain in all adults with suspected encephalitis management is focused on
include opening pressure; protein; glucose; cell count and differential; Gram stabilizing patients who are
stain; bacterial cultures; PCRs for HSV-1, HSV-2, VZV, and enterovirus; acutely ill while
cryptococcal antigen; and testing for syphilis.1,2 Arboviral IgM panel should be concurrently initiating a
diagnostic evaluation.
performed if encephalitis occurs in an endemic area or if supportive clinical

features are present. If a bacterial process is strongly suspected, targeted bacterial

PCRs or more broad-based 16S DNA-based PCR can be performed. The
BioFire FilmArray panel is a rapid multiplex PCR-based system that
provides simultaneous CSF analysis for detection of several common
infectious causes of meningitis and encephalitis. This panel has shown
some promise, although both false negatives (including HSV-1, HSV-2,
enteroviruses, and cryptococcal species) and false positives (eg, streptococcal
species and HHV-6) occur, and continued validation is needed to establish its
potential.65-67 Further testing is tailored to reflect patient-specific factors,
including age, historical elements, clinical signs, CSF results, and imaging
findings.2,68
In many cases, an infectious agent is not readily identified by conventional
means. Newer relatively unbiased methodologies for pathogen detection are
increasingly being brought to bear in cases of encephalitis, including
metagenomic next-generation sequencing of the CSF, which has demonstrated
some utility in identifying novel or unexpected pathogens.69-71 When continued
neurologic deterioration occurs, a brain biopsy may be performed because both
conventional testing (immunohistochemistry, PCR) and metagenomic
TABLE 3-3 Specific Therapies for Viral Encephalitisa
Viral infection Acute treatment Comments
Herpes simplex virus Acyclovir 10 mg/kg IV every 8 hours for Adequate hydration to avoid renal toxicity from
encephalitis 14-21 days tubular precipitation
Varicella-zoster virus Acyclovir 10 mg/kg to 15 mg/kg IV every 8 hours In cases of vasculopathy or myelitis,
encephalitis for 10-21 days (duration poorly defined) corticosteroids may be of added benefit
Epstein-Barr virus Consider corticosteroids, intravenous Generally considered a parainfectious or

encephalitis immunoglobulin (IVIG), or plasmapheresis postinfectious encephalitis, and thus, antivirals are
not typically administered
Cytomegalovirus Ganciclovir 5 mg/kg IV every 12 hours + If the patient is human immunodeficiency virus
encephalitis foscarnet 90 mg/kg IV every 12 hours for (HIV) positive, combination antiretroviral therapy
21 days, followed by maintenance should be initiated concurrently
Human herpesvirus 6 Ganciclovir 5 mg/kg IV every 12 hours or If toxicity develops to one agent, treatment may
encephalitis foscarnet 90 mg/kg IV every 12 hours for be switched to the other
21 days, followed by maintenance
Herpes B virus Ganciclovir 5 mg/kg IV every 12 hours for Treatment must be administered early to avoid
encephalitis 14-21 days, followed by valacyclovir 1 g orally fatality
every 8 hours for 1 year
HIV encephalitis Consider combination antiretroviral therapy Treatment may be associated with central nervous
initiation with input from experts system immune reconstitution inflammatory
syndrome
Rabies encephalitis Postexposure prophylaxis with rabies No effective treatment once neurologic
immunoglobulin and vaccine symptoms manifestb
a
Modified with permission from Cho TA and McKendall RR, Handb Clin Neurol.78 © 2014 Elsevier B.V.
b
Regimens such as the “Milwaukee protocol” have not been proven to be effective.80
870 AUGUST 2021

next-generation sequencing analysis of tissue may provide additional diagnostic KEY POINTS
value beyond CSF studies.72
● A comprehensive history
Because some forms of autoimmune encephalitis can present with a virallike encompassing travel, ill
prodrome and, thus, closely mimic infectious encephalitis, testing for antineural contacts, occupational
antibodies is typically also performed. Autoimmune causes are particularly exposures, vector and
suspected in the setting of limbic encephalitis and marked personality or animal exposures, outdoor
activities, ingestions, and
behavioral changes or when brain MRI is normal.4 In addition, it has been
recent illnesses should be
recently recognized that autoimmune encephalitis accounts for most cases of ascertained.
clinical relapse after HSV-1 encephalitis.73 Thus, in individuals recovering from
HSV-1 encephalitis who develop signs and symptoms of a relapse of encephalitis, ● Neuroimaging, preferably
testing for anti–N-methyl-D-aspartate (NMDA) receptor and other antineural MRI because of its higher
sensitivity for early or subtle
antibodies is typically performed. findings of encephalitis than
CT, should be performed
TREATMENT. In patients in whom the clinical picture is suggestive of HSV or VZV, urgently and is helpful in not
only suggesting potential
the nucleoside analogue acyclovir should be started as soon as possible.
etiologies of encephalitis
Treatment with IV acyclovir for 14 to 21 days has been proven to improve but also excluding some
outcomes in HSV encephalitis with early initiation of treatment providing the mimics.
most benefit.16,74-76 Adequate hydration protects against the well-known
complication of obstructive nephropathy as a result of precipitation of acyclovir ● To assess for common
and treatable infectious
in the renal tubules. Acute kidney injury occurs in up to 20% of patients, conditions, important
develops several days after initiation of acyclovir, and is generally reversible once studies to obtain in all adults
additional fluids are given and acyclovir dosing is adjusted.77 Although of with suspected encephalitis
unproven benefit, steroids are sometimes coadministered in cases of marked include opening pressure;
protein; glucose; cell count
cerebral edema in HSV-1 encephalitis and in the setting of VZV vasculopathy. and differential; Gram stain;
If testing from the first lumbar puncture does not reveal a specific cause and bacterial cultures; PCRs for
HSV-1 encephalitis is still suspected (eg, limbic encephalitis, temporal lobe HSV-1, HSV-2, VZV, and
involvement), acyclovir should be continued and a second lumbar puncture enterovirus; cryptococcal
antigen; and testing for
should be performed in several days because the HSV PCR can be falsely
syphilis.
negative, particularly early in the course of illness and in children.68,78
Aside from acyclovir for HSV-1 encephalitis, a paucity of specific therapies for ● Autoimmune causes are
viral encephalitis exists (TABLE 3-379,80). Ganciclovir and foscarnet are effective particularly suspected in the
against several herpesviruses including CMV and HHV-6 but are less well setting of limbic
encephalitis and marked
tolerated than acyclovir. personality or behavioral
Currently, no accepted treatment for West Nile virus infection is available. changes or when brain MRI
Pooled IV immunoglobulins obtained from donors in high-incidence regions is normal.
have been suggested as a therapeutic approach for West Nile virus, but efficacy
● In patients in whom the
has not been demonstrated.81 clinical picture is suggestive
Other antimicrobial therapies directed against bacterial, mycobacterial, or of HSV or VZV, acyclovir
other infectious organisms should be empirically initiated based on specific should be started as soon as
epidemiologic or clinical factors.1 Broad spectrum antibiotics, typically including a possible.
third-generation cephalosporin along with vancomycin, are used for bacterial
coverage. In cases of suspected L. monocytogenes infection, ampicillin should be
added, whereas doxycycline should be used in the setting of suspected rickettsial
disorders.68 Such treatments can be tailored further pending subsequent testing.
Outcomes
The outcome of infectious encephalitis is largely dependent on the specific cause.
Rabies, Naegleria, and SSPE are almost uniformly fatal; mortality in Nipah virus
encephalitis ranges from 30% to 70%; mortality of several arboviral
encephalitides including West Nile virus, Japanese encephalitis virus, and

Eastern equine encephalitis is around 30%; and fatality rates in HSV-1

encephalitis are less than 20% with appropriate treatment.14,38,41,59,82,83
Outcomes in children with acute VZV encephalitis in the setting of primary
infection are generally quite favorable. In adults, the mortality rate is
approximately 10% to 20%, with some survivors of VZV encephalitis
experiencing residual deficits. Notably, patients who are immunocompromised
and have a VZV infection may develop a relapsing or refractory course.84
In broad cohorts of patients with encephalitis, advanced age,
immunosuppression, and other major medical comorbidities are typically
identified as poor prognostic factors.25,26,76,85,86 In addition, thrombocytopenia
on presentation has been reported as a poor prognostic factor, whereas normal
EEG early in the admission has been reported as highly predictive of survival.22,87
Several studies have also suggested that increased levels of both glial and
neuroaxonal proteins in the CSF, likely reflecting a combination of inflammation
and neuronal damage, may serve as biomarkers of prognosis in encephalitis.88-90
The few long-term studies of patients after encephalitis suggest that a substantial
proportion of survivors are left with physical, cognitive, and behavioral
dysfunction that impact quality of life.91-93
BRAIN ABSCESS
Brain abscesses most often occur in the context of bacterial infections but can
also arise in the setting of fungal and parasitic infections.
Pathogenesis
The brain appears to be highly susceptible to the development of bacterial
abscesses once the blood-brain barrier has been breached. Minute quantities of
bacteria, when directly introduced into the brain, are needed to establish an
abscess.94 Studies in rodents and larger mammals demonstrate that bacterial
inoculation of the CNS initially results in a local area of cerebritis characterized
by early necrosis, edema, and neutrophilic accumulation (early cerebritis). Over
the ensuing days, macrophages and lymphocytes infiltrate the area, and central
necrosis (late cerebritis) develops. By several weeks, the suppurative lesion is
surrounded by a well-defined vascularized fibrotic capsule (encapsulation) that
serves to limit the extent of infection and protect the surrounding brain tissue
from additional damage, although inflammation and edema extend beyond the
capsule.95,96 Interestingly, the capsule is typically less robust on the ventricular
surface, perhaps because of differential vascularization between gray and white
matter, thus potentially explaining the preferential rupture of abscesses centrally
into the ventricular space.97
Commonly recognized sources of infection that lead to brain abscess include
direct extension from a focus adjacent to the CNS (eg, sinusitis, otitis media,
mastoiditis, or dental infection), hematogenous spread from a distant site (eg,
endocarditis, pulmonary infection, skin), or direct inoculation (eg, penetrating
head trauma, neurosurgical procedure).96,98 In the setting of contiguous spread
or direct inoculation, abscesses are typically solitary and adjacent to the initial
focus or area of penetration. Sinusitis, for example, is associated with frontal or
temporal lobe abscesses, whereas abscesses arising in the setting of otitis media or
mastoiditis frequently occur in the temporal lobe and cerebellum.99,100 In
contrast, abscesses resulting from hematogenous dissemination are often
multiple and occur at the gray-white junction.
872 AUGUST 2021

Brain abscesses are typically polymicrobial and can include both aerobic and KEY POINTS
anaerobic species. The most common pathogens in brain abscesses in individuals
● If testing from the first
who are immunocompetent are streptococcal species, including aerobic lumbar puncture does not
streptococci (eg, Streptococcus anginosus group, also known as the Streptococcus reveal a specific cause and
milleri group) and anaerobic streptococci, which are identified in more than HSV-1 encephalitis is still
half of cases and are frequently associated with sinus infections (CASE 3-4). suspected (eg, limbic
encephalitis, temporal lobe
Other commonly identified pathogens in the setting of sinus infections
involvement), acyclovir
include Staphylococcus aureus, Haemophilus species, Bacteroides species, and should be continued and a
Enterobacteriaceae (eg, Escherichia coli, Klebsiella pneumoniae, and Proteus second lumbar puncture
species). Chronic otitis media can also result in abscesses due to Pseudomonas should be performed in
several days because the
aeruginosa, whereas abscesses arising in the setting of dental infections
HSV PCR can be falsely
may also result from Fusibacterium species.101 Abscesses arising from negative, particularly early
hematogenous dissemination are most commonly of pulmonary origin, and, in in the course of illness and in
addition to streptococcal and staphylococcal species, may be caused by children.
Actinomyces species, Fusibacterium species, and Nocardia species
● Patients who are
(CASE 3-5).102 Brain abscesses in the setting of infectious endocarditis are immunocompromised and
commonly caused by Staphylococcus aureus, viridans streptococci, or have VZV infection may
enterococcus species.103 More rarely, other bacteria (eg, L. monocytogenes), develop a relapsing or
mycobacteria (eg, Mycobacterium tuberculosis), fungi (eg, Aspergillus species), refractory course.
or eukaryotic pathogens (eg, B. mandrillaris) can also result in brain abscesses
● Advanced age,
in patients with intact immune systems. immunosuppression, and
In individuals who are immunocompromised, a broader spectrum of other major medical
pathogens can cause brain abscess. Opportunistic filamentous bacteria such as comorbidities are typically
reported as poor prognostic
Nocardia species, and to a lesser extent Actinomyces species, are notable causes of
factors in patients with
brain abscess in the immunocompromised host and can be challenging to encephalitis.
distinguish histologically because of their resemblance to fungi on
histopathologic examination. Although L. monocytogenes can cause brain abscess ● Sources of infection that
in individuals who are immunocompetent and in those who are lead to brain abscess
include direct extension
immunocompromised, in the latter, a frank meningoencephalitis is more likely from a focus adjacent to the
potentially because of the relative inability of the host to mount an effective CNS (eg, sinusitis, otitis
immune response to sequester the infection.104 media, mastoiditis, or dental
Several mycobacterial species, including M. tuberculosis, are also notable infection), hematogenous
spread from a distant site
causes of abscess in immunocompromised hosts, although the more common (eg, endocarditis, pulmonary
focal CNS lesion that ensues consists of a granulomatous inflammatory core infection, skin), or direct
without frank necrosis or suppuration and is termed a tuberculoma.105 inoculation (eg, penetrating
Like mycobacteria, fungi can also cause focal brain lesions such as granulomas head trauma, neurosurgical
procedure).
and abscesses. Many fungal pathogens have been implicated in brain abscess,
including the molds (Aspergillus species, Mucorales species, Cladophialophora ● The most common
bantiana), yeasts (Candida and Cryptococcus species), and dimorphic fungi pathogens in brain
(including Blastomyces, Coccidioides, and Histoplasma species).106 abscesses in individuals who
Of the eukaryotic pathogens, T. gondii is a particularly notable cause of brain are immunocompetent are
streptococcal species,
abscess in individuals who are immunocompromised. The granulomatous including aerobic
amoebic infections, including Acanthamoeba species and B. mandrillaris, are also streptococci (eg,
associated with brain abscess59 (see the discussion of granulomatous amoebic Streptococcus anginosus
encephalitis in the earlier section titled “Eukaryotic Parasites”). group, also known as the
Streptococcus milleri group)
and anaerobic streptococci,
Epidemiology which are identified in more
Estimates of brain abscess incidence range from 0.2 per 100,000 person-years than half of cases and are
to 1.9 per 100,000 person-years, with higher rates in individuals who are frequently associated with
sinus infections.
immunocompromised.107,108 Studies have consistently found a male

predominance, typically 2:1 to 3:1, which is related to, but not fully accounted
for by, the increased propensity for penetrating cranial trauma among
males.109 Peak incidence is typically early adulthood to middle age. In the
majority of individuals, predisposing factors for brain abscess can be
identified, including HIV/AIDS, treatment with immunosuppressive
medications, or risks of contiguous or systemic infection such as penetrating
trauma or congenital heart disease. In individuals who are immunocompetent,
contiguous spread accounts for up to half of all abscesses, whereas
hematogenous dissemination is responsible for 30% to 40%. Cryptogenic
CASE 3-4 A 13-year-old boy was brought to the emergency department by his
family because of confusion progressing over several days. He had
developed headache and rhinorrhea several weeks before and had been
treated with a course of amoxicillin for possible sinusitis. However, his
headache worsened, and he then developed vomiting, confusion, and
sleepiness.
On arrival, he was afebrile and normotensive, and his heart rate was in
the 50s. On neurologic examination, he was somnolent and not following
commands. He had less movement of the right extremities than the left. A
peripheral white blood cell count was 14,000 cells/mm3. Head CT
demonstrated a large left frontal mass with associated edema and
midline shift. In addition, complete opacification of the bilateral frontal
sinuses was present with osseous erosions of the inner table of the left
frontal sinus. Brain MRI demonstrated extensive inflammatory changes in
the sinuses and a left anterior frontal lobe lesion measuring
4.3 cm × 3.7 cm × 3.7 cm with restricted diffusion and substantial
vasogenic edema (FIGURE 3-4).
He was started on ceftriaxone, metronidazole, vancomycin, and
corticosteroids and taken emergently to the operating room for bifrontal
craniotomy. Culture of the abscess fluid was positive for the
Streptococcus anginosus group, and he was continued on ceftriaxone
and metronidazole. His course was complicated by recurrence of the
abscess 1 week later, prompting redrainage. This was followed by rapid
improvement such that he was back to his baseline by 1 month after
admission.
COMMENT Although most cases of brain abscess are managed by stereotactic

aspiration, this case highlights that a role for open craniotomy remains in
selected patients, and thus, close coordination between neurology,
neurosurgery, and other services is needed. The preceding
symptomatology, imaging findings demonstrating sinus inflammation and
bony erosion, and the identified organism all point to the frontal sinus as
the source of infection.
874 AUGUST 2021

abscess, in which no source is identified, accounts for the remaining 10% to
20% of cases.101
The epidemiology of brain abscess has changed in recent years. Although
aggressive management of otitis media has led to a decrease in otogenic-related
brain abscess in many countries, it remains a prominent source of brain abscess
in low- and middle-income countries.110 It is likely that the widespread adoption
of surgical repair of congenital heart disease has also decreased the incidence of
brain abscess in association with structural cardiac defects. As some of these
conditions are more effectively treated, penetrating head trauma and
FIGURE 3-4
Streptococcus anginosus group brain abscess in
the patient in CASE 3-4. Axial fluid-attenuated
inversion recovery (FLAIR) image demonstrates
a large, circumscribed lesion (A, left) with a
hypointense rim (A, arrow) and substantial
surrounding edema. A thick rim of enhancement
is seen on postcontrast T1-weighted image
(A, right). The center of the lesion markedly
restricts diffusion, as seen on axial diffusion-
weighted imaging (B, left) and apparent diffusion
coefficient (B, right) sequences. After abscess
drainage and antimicrobial therapy for 1 month,
a residual area of gliosis (C, left) and small area
of contrast enhancement are seen (C, right).

CASE 3-5 A 68-year-old man presented to the emergency department with rapidly
worsening headache over several days, followed by confusion. He had
been healthy until 1 month before, when he developed cough and mild
shortness of breath. A chest radiograph demonstrated a lobar pneumonia
in the left middle lobe. He was treated presumptively for pneumonia with
amoxicillin, then moxifloxacin, without relief.
On presentation, he was afebrile with normal vital signs. He appeared
uncomfortable and was mildly disoriented. The remainder of his neurologic
examination was unremarkable. Head CT was unrevealing. Lumbar puncture
demonstrated 24 white blood cells/mm3 (90% polymorphonuclear cells),
a protein of 123 mg/dL, and normal glucose, and he was begun on
broad-spectrum antibiotics
for bacterial meningitis along
with acyclovir.
The next day, his neurologic
function deteriorated rapidly
such that he developed a deep
coma (Glasgow Coma Scale
score of 5), necessitating
intubation and mechanical
ventilation. Brain MRI
demonstrated multiple small
ring-enhancing supratentorial
lesions bilaterally (FIGURE 3-5).
Viral PCRs from CSF were
negative, as was testing for
HIV, syphilis, and
toxoplasmosis. Stereotactic
brain biopsy was performed,
and histopathology revealed
a filamentous, weakly
gram-positive organism that
was identified as Nocardia FIGURE 3-5
farcinica. He was treated Numerous Nocardia farcinica abscesses in the
with trimethoprim- patient in CASE 3-5. Axial postcontrast T1-weighted
MRI demonstrates multiple small ring-enhancing
sulfamethoxazole with lesions in the bilateral cerebral hemispheres,
gradual improvement over some of which are present at the cortical
many months. gray-white matter interface.
COMMENT Although most cases of CNS nocardiosis occur in individuals who are
immunocompromised, this case highlights the importance of consideration
of the Nocardia species in people who are immunocompetent. The clinical
presentation and multifocal abscesses support a pathogenic mechanism
of hematogenous dissemination, likely from a primary lung source. Further
history obtained from the patient after the diagnosis was made revealed
that he frequently enjoyed caving, a point of interest given that Nocardia
species are found worldwide in soil.
876 AUGUST 2021

neurosurgical procedures account for an increasing proportion of brain KEY POINTS
abscesses.98,109 Notably, a 2020 nationwide population-based study in Denmark
● Brain abscesses arising
found that brain abscess incidence has increased among individuals older than from hematogenous
40 years and those with an immunocompromised state; the latter may be dissemination are most
explained by novel and intensified immunosuppressive treatments used for commonly of pulmonary
malignancies, rheumatologic conditions, and autoimmune disorders.108 origin, and, in addition to
streptococcal and
staphylococcal species,
Clinical Features may be caused by
Actinomyces species,
The neurologic signs and symptoms depend on the number and location of Fusibacterium species, and
abscesses. Headache is the most frequent manifestation, occurring about 70% of Nocardia species.
the time, and focal neurologic deficits occur in about half of all cases.111 Notably,
fever may be absent in half of all cases. Indeed, the classic triad of fever, ● Opportunistic
filamentous bacteria such as
headache, and focal neurologic deficit, which may be expected in the setting of a
Nocardia species, and to a
focal infectious CNS process, exhibits poor sensitivity, with fewer than 25% of lesser extent Actinomyces
cases reporting all three.112 Nausea/vomiting, focal neurologic deficits, and species, are notable causes
altered mental status each occur in about half of cases, papilledema in one-third, of brain abscess in the
immunocompromised host
and seizures occur in one-quarter. In light of the supratentorial predominance of
and can be challenging to
brain abscesses, signs and symptoms specifically referable to the cerebellum distinguish histologically
and brainstem are not common. Symptoms may be present for 1 week or because of their
longer before the diagnosis is made, highlighting the subacute nature of resemblance to fungi on
evolution of the abscess.111 histopathologic
examination.
● Although aggressive
Evaluation
management of otitis media
Neuroimaging is critical to the diagnosis, and all patients with suspected brain has led to a decrease in
abscess should undergo either CT or MRI with contrast. MRI is preferred otogenic-related brain
because it is more sensitive during early stages of abscess formation, can more abscess in many countries, it
precisely demonstrate complications of abscess, and can help better distinguish remains a prominent source
of brain abscess in low- and
abscess from other mimics.113 The early cerebritis stage, when bacteria arrive at middle-income countries.
the brain parenchyma and initiate a host response, is characterized by an
ill-defined area of hypointensity on T1-weighted imaging with associated ● Penetrating head trauma
hyperintensity on T2-weighted imaging. Enhancement is variable but, when and neurosurgical
procedures account for an
present, is typically homogeneous. At this stage, the lesion is poorly visualized increasing proportion of
on CT, but as it begins to organize in the late cerebritis stage, a central brain abscesses.
hypodensity becomes more apparent on CT.113,114 On MRI, the central
hyperintensity becomes more intense on T2-weighted imaging, and DWI may ● Headache is the most
frequent manifestation of
begin to demonstrate some restriction of diffusion centrally. As the lesion
brain abscesses, occurring
becomes encapsulated, the enhancement shifts from a homogeneous pattern to about 70% of the time, and
one of rim enhancement surrounding the necrotic core. Diffusion of water is focal neurologic deficits
markedly restricted in the highly proteinaceous central core and is thus readily occur in about half of all
identified on DWI. Notably, the imaging findings in nonbacterial brain abscesses cases. Fever may be absent
in half of all cases.
may be more heterogeneous than in pyogenic abscess, as may be the time
course of evolution of findings.115 ● MRI is preferred over CT
The combination of rim enhancement and intense central restriction of because it is more sensitive
diffusion is highly suggestive of abscess but does not exclude other conditions. during early stages of
abscess formation, can
Indeed, high-grade neoplasms, radiation necrosis, and, in rare cases, more precisely demonstrate
demyelination, can have a similar appearance on MRI. Imaging features that complications of abscess,
support abscess, compared with metastasis or high-grade glioma, include a and can help better
smooth, thin rim of enhancement, thinning along the medial wall, and a distinguish abscess from
other mimics.
T2-hypointense rim.116 The observed T2-shortening in the rim may be explained

by the presence of free radicals produced by phagocytic macrophages that have

infiltrated the capsule wall.
Additional imaging techniques have been applied to brain abscesses in an
effort to better distinguish abscess from its mimics. Of these, nuclear magnetic
resonance spectroscopy has been most widely studied. In the capsule stage, the
necrotic center lacks normal brain metabolites, including N-acetylaspartate and
choline, and levels of lactate are elevated. However, such patterns have not yet
proven to unequivocally discriminate abscesses from brain tumors.
Studies from peripheral blood are typically of low yield. Peripheral leukocytosis
and elevated serum C-reactive protein are observed in more than half of cases and,
when present, can raise suspicion for an infectious process. However, such studies
do not effectively distinguish abscesses from mimics. Blood cultures should be
routinely collected. Although only positive in about one-quarter of patients, the
yield is higher in those with hematogenous dissemination. In addition, positive
blood cultures may eliminate the need to directly sample the brain abscess. Data
on the utility of CSF studies are somewhat limited since sampling is often
deferred because of concerns regarding potential herniation in the setting of a
space-occupying lesion. When performed, routine CSF studies range from normal
to a mild pleocytosis with modestly elevated protein. In a 2014 meta-analysis, CSF
examination was performed in fewer than one-third of patients, and cultures were
positive in about one-quarter of those.111 Clinical deterioration attributed to the
lumbar puncture was reported in 7% of patients, underscoring the need for
caution when considering CSF acquisition in such patients.
Most patients will require direct sampling of the brain abscess in an attempt to
identify the offending pathogen(s). After stereotactic-guided aspiration or, more
rarely, open surgical approaches, bacterial, mycobacterial, and fungal cultures
should be performed, and, in patients who are immunocompromised, additional
testing for T. gondii should be carried out. In up to one-quarter of cases, cultures
are negative, and the yield decreases further in patients in whom empiric
antimicrobial therapy is initiated before sample acquisition.111 However, empiric
antibiotics should never be withheld or delayed in those who are critically ill in an
attempt to improve the diagnostic yield of sampling. When strong clinical
suspicion for bacterial abscess is present and culture results are negative,
PCR-based 16S ribosomal DNA sequencing or metagenomic next-generation
sequencing may prove useful in definitively identifying the etiologic agent.117,118 In
one next-generation sequencing–based study involving abscess aspirates from 71
patients, bacterial DNA was detected in 83% of samples despite positive cultures in
only 42%.119 Notably, such techniques typically identify multiple bacterial taxa,
underscoring the complex and polymicrobial nature of brain abscesses.
Management
Management of patients consists of both medical and surgical approaches and is
best accomplished by a multidisciplinary team including neurologists,
neurosurgeons, and infectious disease physicians.
NEUROSURGICAL APPROACHES. Neurosurgery is essential for identification of the

causative pathogen if it is not already determined by other means. Even when
the causative pathogen has already been identified, neurosurgical approaches
often still play an important role in management by reducing the size of the
abscess. Abscesses that are large or cause substantial mass effect or are
878 AUGUST 2021

abutting the ventricle and thus are at risk of ventricular rupture are given KEY POINTS
particular consideration.96 However, other factors, including the anatomic
● The combination of rim
relationship of lesions to eloquent areas of the brain and the clinical condition enhancement and intense
of the patient, inform both the decision to proceed to neurosurgery and the central restriction of
specific approach to pursue. In rare cases, surgery may be deferred or withheld diffusion is highly suggestive
because of comorbidities that increase the surgical risk. of brain abscess but does
not exclude other
In recent years, minimally invasive stereotactic aspiration has largely replaced
conditions.
surgical excision because of lower rates of intracranial hemorrhage and mortality.
Aspiration can be achieved for abscesses greater than 1 cm in diameter, and deep ● Blood cultures should
brain areas can be accessed. Surgical excision is typically reserved for solitary, routinely be collected.
superficial abscesses, multiloculated abscesses with high risk of incomplete Although they are positive in
only about one-quarter of
drainage, or some posterior fossa abscesses for which acute deterioration from patients with brain
mass effect after instrumentation is a concern.120 abscesses, the yield is
Some patients with brain abscess can be managed conservatively with higher in those with
antimicrobial therapy alone.121 Such an approach may be reasonable in an otherwise hematogenous
dissemination. In addition,
healthy individual with a small abscess (ie, less than 2.5 cm in diameter). In addition, positive blood cultures may
the early cerebritis stage of infection typically responds well to antimicrobial eliminate the need to
therapy, and thus, conservative management can be considered when directly sample the brain
neuroimaging does not clearly demonstrate a central cavity within the lesion. In abscess.
individuals who are immunocompromised with a high probability of cerebral
● In about one-quarter of
toxoplasmosis, presumptive antimicrobial therapy is typically instituted even in the cases of brain abscess,
absence of a tissue diagnosis.122 In all patients who are managed conservatively, close cultures of the abscess fluid
clinical and radiologic follow-up is mandatory. In the absence of improvement are negative, and the yield
decreases further in patients
within several weeks, strong consideration should be given for surgical intervention.
in whom empiric
antimicrobial therapy is
MEDICAL THERAPY. The selection of empiric antimicrobial therapy for brain initiated before sample
abscess is informed by the presumed source of infection, host factors, local acquisition. However,
patterns of antimicrobial resistance, and ability of therapeutic agents to penetrate empiric antibiotics should
never be withheld or
the blood-brain barrier (TABLE 3-4). In recognition of the polymicrobial delayed in those who are
composition of many abscesses, empiric regimens typically provide broad critically ill in an attempt to
aerobic and anaerobic coverage. Regimens have historically consisted of improve the diagnostic yield
penicillin, chloramphenicol, and metronidazole but have largely been replaced of sampling.
by third-generation cephalosporins (eg, cefotaxime or ceftriaxone) and ● Broad-based molecular
metronidazole over the past several decades.123,124 In the setting of head trauma techniques typically identify
or neurosurgery, vancomycin is added to the initial regimen to cover multiple bacterial taxa,
methicillin-resistant staphylococcal infections, and coverage for Pseudomonas underscoring the complex
and polymicrobial nature of
species (eg, ceftazidime or cefepime as the cephalosporin) is often instituted.
brain abscesses.
Antipseudomonal coverage is also used when the abscess arises in the setting of
contiguous spread from otitis media. When standard regimens are ● Even when the causative
contraindicated, meropenem monotherapy can be used given its broad spectrum pathogen has already been
of activity against aerobic and anaerobic bacteria.125 As culture data become identified, neurosurgical
approaches often still play
available, antimicrobial therapy should be tailored accordingly. However, the an important role in
identification of an aerobic organism does not preclude the concomitant presence management by reducing
of an anaerobic organism, the latter of which can be difficult to isolate and culture. the size of the abscess.
Thus, anaerobic coverage may be maintained for the duration of therapy,
particularly in the setting of contiguous infections.124
Bacterial brain abscesses are typically treated with IV antibiotics for 6 to
8 weeks. Although some experts have advocated for a shorter duration of IV
therapy followed by a transition to oral antimicrobials, such approaches have not
been broadly incorporated into clinical practice. All patients undergoing

treatment should be followed closely. If no improvement is seen in 1 to 2 weeks,

cranial imaging should be repeated, and, if the abscess size has increased
substantially, then strong consideration for further neurosurgical intervention
should be given.96 Such decisions are typically also guided by the clinical course of
the patient because radiologic changes may lag behind clinical response. Notably,
some bacterial abscesses, such as those associated with Nocardia species, along
with mycobacterial and fungal infections, require a longer duration of therapy.124
TABLE 3-4 Common Microbes and Treatment Regimens in Intracerebral Abscess
Initial empiric antimicrobial

Source of infection Typical pathogens regimens Comments
Contiguous
Otogenic Streptococcus species, Ceftriaxone or cefotaxime plus Incidence is decreasing;

Enterobacteriaceae, Pseudomonas metronidazole; if concern for preferentially affects
aeruginosa, anaerobes Pseudomonas, use ceftazidime temporal lobes
or cefepime in place of
third-generation cephalosporin
Sinus Streptococcus species, Ceftriaxone or cefotaxime plus Preferentially affects

Staphylococcus aureus, Haemophilus metronidazole; add frontal and temporal lobes
species, anaerobes vancomycin if high risk of
Staphylococcus aureus (eg,
chronic sinusitis or recent sinus
instrumentation)
Penetrating trauma Staphylococcus aureus, Streptococcus Ceftazidime or cefepime plus Incidence may be
or pyogenes, coagulase-negative vancomycin; add increasing
postneurosurgical staphylococcus, Enterobacteriaceae, metronidazole for penetrating
Pseudomonas aeruginosa, anaerobes trauma; alternatively,
meropenem can be used
Hematogenous
Pulmonary Staphylococcus aureus, Streptococcus Ceftriaxone or cefotaxime plus May occur in the setting of
infection species, Enterococcus species, vancomycin plus lung abscess,
Nocardia species, anaerobes metronidazole; for Nocardia, bronchiectasis, or
meropenem or linezolid should empyema
be used
Infectious Staphylococcus aureus, Streptococcus See guidelines for empiric Often a single pathogen,
endocarditis species, Enterococcus species, HACEK treatment of endocarditis rather than polymicrobial
(Haemophilus species, Actinobacillus abscess
actinomycetemcomitans,
Cardiobacterium hominis, Eikenella
corrodens, and Kingella kingae)
bacteria
Dental Streptococcus milleri group, Ceftriaxone or cefotaxime plus May also cause abscess
anaerobes metronidazole via contiguous spread;
may require dental
extraction
Unknown Variable Ceftriazone or cefotaxime plus Low threshold for

vancomycin plus metronidazole initiation of
antimycobacterial or
antifungal therapy
880 AUGUST 2021

Other adjunctive treatments for brain abscess may include corticosteroids or KEY POINTS
anticonvulsants. Although data from randomized trials are lacking and, thus,
● Minimally invasive
corticosteroids should not be used routinely, they are often administered stereotactic aspiration has
during the perioperative and postoperative periods and in settings of profound largely replaced surgical
cerebral edema. Seizures may occur in up to half of all patients with brain excision of brain abscesses
abscess, and anticonvulsants are typically administered in those who seize because of lower rates of
intracranial hemorrhage and
to limit the risk of further seizures.
mortality.
Outcomes ● In recognition of the

The risk of mortality from brain abscess is high, reported to be 10% to 20%. polymicrobial composition
Mortality is associated with advanced age, comorbid conditions (eg, diabetes, of many abscesses, empiric
regimens typically provide
congenital heart disease or congestive heart failure, immunodeficiency), and broad aerobic and anaerobic
hematogenous dissemination of infection.108,112 In addition, the burden of coverage. Regimens have
abscesses has been associated with death; in one study, mortality was 12% in the historically consisted of
setting of a single abscess and increased to 50% for six abscesses.109 Several other penicillin, chloramphenicol,
and metronidazole but have
associated conditions have been consistently associated with poor outcomes and largely been replaced by
death. The concurrent presence of systemic illness (eg, pneumonia, sepsis) third-generation
portends poorer prognosis.107,112 The presence of intraventricular rupture is cephalosporins (eg,
strongly associated with in-hospital mortality; the majority of adult and pediatric cefotaxime or ceftriaxone)
and metronidazole over the
patients with ventricular rupture die.109,126 past several decades.
In-hospital outcomes from brain abscess have improved over the past
several decades, likely attributable to better general medical care, more ● The identification of an
widespread and earlier adoption of neuroimaging, improved microbial aerobic organism does not
preclude the concomitant
diagnostics (in particular, culture of anaerobic bacteria), adoption of minimally
presence of an anaerobic
invasive neurosurgical procedures, and increased effectiveness of CNS organism, the latter of which
penetrating antimicrobial agents. A 2020 population-based study in Denmark can be difficult to isolate
found that the crude 30-day mortality rate decreased almost threefold from the and culture. Thus, anaerobic
1980s to the 2010s (from 18% to 7%).108 coverage may be maintained
for the duration of therapy,
Among survivors, neurologic sequelae including focal neurologic deficits and particularly in the setting of
epilepsy have been reported in up to 40% of individuals.126,127 In one 2020 study contiguous infections.
in which the median follow-up was greater than 7 years, new-onset epilepsy
occurred in 32% of survivors of brain abscess compared with 2% of matched ● Some bacterial
abscesses, such as those
controls.128 Notably, however, robust data on functional and neuropsychological associated with Nocardia
outcomes after brain abscess are lacking. species, along with
mycobacterial and fungal
infections, require a longer
duration of therapy than the
CONCLUSION
typical 6- to 8-week course.
Despite advances in recent decades in recognition and treatment of
intraparenchymal brain infections, mortality remains substantial, and in ● Mortality due to brain
survivors long-lasting neurologic sequelae such as epilepsy and neurocognitive abscess is associated with
deficits can occur. Both encephalitis and brain abscess represent neurologic advanced age, comorbid
conditions (eg, diabetes,
emergencies, and rapid initiation of diagnostic testing and empiric therapies is congenital heart disease or
critical. Newer diagnostic methodologies such as metagenomic next-generation congestive heart failure,
sequencing are increasingly being used in both conditions, and as these immunodeficiency), and
technologies improve and their limitations are better understood, they have the hematogenous
dissemination of infection.
potential to be incorporated into the routine diagnostic workflow. Regardless of
the specific technologies used, in infections of the brain parenchyma, a
multidisciplinary approach involving neurologists, neurosurgeons, infectious
disease physicians, neuroradiologists, and pathologists will continue to be
important in providing effective diagnosis and management.

KEY POINTS
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105 Nelson CA, Zunt JR. Tuberculosis of the central 117 Kommedal Ø, Wilhelmsen MT, Skrede S, et al.
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886 AUGUST 2021

Infections of the Spine REVIEW ARTICLE

and Spinal Cord C O N T I N U UM A U D I O
INTERVIEW AVAILABLE
ONLINE
By Shamik Bhattacharyya, MD, MS; Michael J. Bradshaw, MD
ABSTRACT
PURPOSE OF REVIEW: Infections of the spine and spinal cord are associated
with a high risk of morbidity and mortality and, therefore, require prompt
clinical recognition, efficient diagnostic evaluation, and interdisciplinary
treatment. This article reviews the pathophysiology, epidemiology, clinical
manifestations, diagnosis, and treatment of infections of the spine and CITE AS:
spinal cord to help practicing clinicians recognize, evaluate, and manage
patients with such infections. DISEASE):887–920.
RECENT FINDINGS: Aging of the population, increasing use of Address correspondence

to Dr Shamik Bhattacharyya,
immunosuppressive medications, and other factors have contributed to Brigham and Women’s Hospital,
increasing rates of spinal infections. Although the most common agents Department of Neurology,
responsible for spinal infections remain bacteria and viruses, fungal 75 Francis St, Boston, MA 02115,
sbhattacharyya3@bwh.
infections occur in individuals who are immunocompromised, and parasitic harvard.edu.
infections are common in endemic regions, but patterns are in evolution
with migration and climate change. Recent outbreaks of acute flaccid
Dr Bhattacharyya has received
myelitis in children have been associated with enteroviruses A71 and D68. personal compensation for
serving on a scientific advisory
board for Alexion
SUMMARY: Infections of the spine and spinal cord can be challenging to
Pharmaceuticals, Inc, and for
diagnose, requiring a thorough history and neurologic examination, serving as a consultant for
laboratory studies of serum and CSF, neuroimaging (particularly MRI), and, Teladoc Health, Inc; has
received publishing royalties
in some instances, biopsy, to establish a diagnosis and treatment regimen. from Springer Publishing
Interdisciplinary management including collaboration with experts in Company and UpToDate, Inc;
internal medicine, infectious disease, and neurosurgery is important to and has given expert testimony
in a trial. Dr Bradshaw reports no
improve clinical outcomes. disclosure.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION Drs Bhattacharyya and
S
pinal cord dysfunction of any etiology is called myelopathy, whereas Bradshaw discuss the
myelitis refers to inflammation of the spinal cord. Myelitis can be unlabeled/investigational use of
IV glucocorticoids in the
caused directly by infection or may be parainfectious, postinfectious, treatment of certain viral
or due to a primary autoimmune process. Infection can affect the infections of the spinal cord (eg,
varicella-zoster myelitis) and IV
spinal cord in many ways: direct infection (ie, infectious myelitis),
immunoglobulins in the
compression (eg, epidural abscess, rupture of infected intervertebral disks, treatment of certain viral
spinal cord edema), or infarction due to infectious vasculitis (FIGURE 4-1). infections of the spinal cord (eg,
enterovirus, West Nile virus,
Infections of the spine and spinal cord confer a significant risk of morbidity vacuolar myelopathy in human
and possible mortality, requiring prompt recognition and treatment to immunodeficiency virus [HIV]).
optimize outcomes.1
Infections of the spine and spinal cord can be caused by bacteria, viruses, © 2021 American Academy
fungi, and parasites. This article is organized by pattern of clinical presentation, of Neurology.

INFECTIONS OF THE SPINE AND SPINAL CORD
FIGURE 4-1
Tropisms of select infectious agents.
EVA71 = enterovirus A71; EVD68 = enterovirus D68; HIV = human immunodeficiency virus; HSV = herpes
simplex virus; HTLV-I = human T-cell lymphotropic virus type I; LCMV = lymphocytic choriomeningitis virus;
M. tuberculosis = Mycobacterium tuberculosis; WNV = West Nile virus; VZV = varicella-zoster virus.
with relevant microbiology discussed for each clinical entity. Although a given
infection may produce a range of clinical syndromes, the focus here is on the
primary spinal manifestations of each microbe, which are not always the most
common neurologic manifestation of the pathogen.
SPONDYLODISCITIS
Spondylodiscitis refers to infection of the vertebrae, intervertebral joints, or
intervertebral disks. The incidence of spondylodiscitis is increasing because of
the aging of the population, higher incidence of chronic illnesses including
diabetes, increased use of immunosuppressive medications, and increasing rates
of bacteremia from the use of intravascular devices (eg, pacemakers, dialysis
fistulas).2 Additional risk factors include IV drug abuse, infective endocarditis,
and degenerative spine disease.
Spondylodiscitis is most often caused by pyogenic bacteria, which can infect
spinal structures via hematogenous spread from distant sites, direct inoculation
by instrumentation, or contiguous spread from adjacent infection.2 Most
infections are monomicrobial. Staphylococcus aureus is the single most common
infectious agent responsible for pyogenic spondylitis in high-income countries,
accounting for more than 50% of cases. Patients with urinary tract
instrumentation are at higher risk for enteric gram-negative bacilli, whereas
those with diabetes are at risk for pyogenic streptococci. IV drug use and
888 AUGUST 2021

intravascular access (eg, indwelling catheter) increase the risk for infection with KEY POINT
Pseudomonas aeruginosa and coagulase-negative staphylococci.3 Bartonella
● Spondylodiscitis is most
henselae, the infectious agent associated with catscratch disease, occasionally often caused by pyogenic
causes myelitis or spondylodiscitis (FIGURE 4-2). Mycobacterium tuberculosis and bacteria, which can infect
Brucella species are less frequently implicated infectious agents in the spinal structures via
United States but are common causes of spondylodiscitis globally.4,5 Fungal hematogenous spread from
distant sites, direct
infections are rarely associated with spondylodiscitis, with Aspergillus and
inoculation by
Candida species among the most commonly implicated fungi in the United States.6 instrumentation, or
contiguous spread from
Clinical Features adjacent infection.
Back pain is the most common clinical manifestation of pyogenic spondylitis.
Pain is usually localized to the infected segment but may radiate. Most patients
with spondylodiscitis present with back pain that worsens over weeks to months,
although both acute and more chronic presentations are possible. Fungal and
mycobacterial etiologies are more likely to present with a chronic temporal
FIGURE 4-2
Bartonella osteomyelitis. A 14-year-old boy developed slowly worsening back pain over the
course of a few weeks. Sagittal short tau inversion recovery (STIR) MRI demonstrates
abnormal T2 hyperintensity (A, arrow) involving the entire L1 vertebral body, and
heterogeneous enhancement (B, arrow) on sagittal postcontrast T1-weighted MRI.
Fine-needle aspiration of an enlarged lymph node confirmed Bartonella henselae infection.

profile than bacterial causes. The pain is often exacerbated by physical activity or
at night and can be elicited on examination by spinal percussion, although this
is a nonspecific finding. When back pain is accompanied by fever, the diagnosis
is relatively straightforward. However, fever is present only in roughly half of
patients; is less likely to develop in patients with Brucella, mycobacterial, or
fungal infections; and may be absent in patients taking antipyretic analgesics and
those who are immunosuppressed. Bowel and bladder retention and saddle
anesthesia may develop if sacral nerve roots are involved. If the infection
extends, patients may develop epidural abscesses or, rarely, spinal meningitis. In
one study including 253 patients with bacterial vertebral osteomyelitis (within
the spectrum of spondylodiscitis), epidural or paravertebral extension developed
in 43%.7 Extension to epidural abscess increases the risk of permanent neurologic
dysfunction; other risk factors for long-term sequelae include involvement of
cervical or thoracic segments, infection with Staphylococcus aureus, and
C-reactive protein (CRP) greater than 150 mg/L.8
Diagnostic Approach
Spondylodiscitis should be suspected in patients with new or worsening back
pain particularly with fever, new neurologic deficits, recent bacteremia,
endocarditis, indwelling IV catheter, or IV drug use.2 The history should assess
for the potential source of infection (eg, IV drug use; recent surgical procedure;
recent infections of the skin, soft tissue, urinary tract, or blood stream;
immunocompromise; travel; and exposure to livestock or unpasteurized milk).
Erythrocyte sedimentation rate (ESR) and CRP are valuable as screening studies
with sensitivities in the range of 94% to 100%.9,10 At least two sets of blood
cultures (both aerobic and anaerobic) as well as urine culture should be obtained
in febrile patients with back pain and may yield a microbiological diagnosis in up
to 50% to 75% of cases.11,12 When brucellosis is suspected, blood cultures should
be incubated for 2 weeks, and brucella serologies (serum IgM/IgG) should be
obtained. Fungal infections of the spine are infrequent and occur more often in
patients with risk factors such as being immunocompromised (Aspergillus
species), use of IV drugs, and presence of indwelling IV catheters (Candida
species) and in patients who live in endemic areas for dimorphic fungi (eg,
histoplasmosis, blastomycosis, or coccidioidomycosis).6 When a fungal infection
is suspected, antigen detection assays, fungal cultures, and serologies (serum
IgM/IgG) should be obtained.
MRI of the spine with contrast is the imaging modality of choice and
should be urgently pursued.13 Typical findings include T2 hyperintensity and
contrast enhancement in the intervertebral disk which may be accompanied by
surrounding involvement of the inferior and superior endplates (FIGURE 4-3) and
increased signal in the paravertebral soft tissue such as the psoas muscle. When
MRI is unavailable or contraindicated (eg, because of incompatible implanted
devices), CT with contrast or CT myelogram should be obtained. Although
fludeoxyglucose positron emission tomography (FDG-PET) imaging is
highly sensitive for infection and is useful for distinguishing pyogenic
spondylitis from degenerative changes, FDG avidity also occurs in malignancies
and is not specific. When clinical, laboratory, and imaging findings support a
diagnosis of spondylodiscitis, but a microbiological diagnosis has not been
established by blood cultures, an imaging-guided aspiration biopsy should
be performed.2
890 AUGUST 2021

KEY POINTS
● Fever is present only in

roughly half of patients with
spondylodiscitis; is less
likely to develop in patients
with Brucella,
mycobacterial, or fungal
infections; and may be
absent in patients taking
antipyretic analgesics and
those who are
immunosuppressed.
● Spondylodiscitis should
be suspected in patients
with new or worsening back
pain particularly with fever,
new neurologic deficits,
recent bacteremia,
endocarditis, hemodialysis,
IV access, or IV drug use.
● Erythrocyte
sedimentation rate and
C-reactive protein should be
included as screening
studies when
spondylodiscitis is a
possibility; they are valuable
as screening studies with
sensitivities in the range of
94% to 100%.
FIGURE 4-3
Bacterial spondylodiscitis. A 52-year-old man with nonobstructive nephrolithiasis and a
urinary tract infection developed progressive lower back pain. A, Sagittal T2-weighted MRI
with disk space erosion/T2 hyperintensity (arrow) including the paradiscal vertebral bodies.
B, Sagittal postcontrast T1-weighted MRI demonstrates contrast enhancement throughout
the L3-L4 (arrow) vertebral bodies contributing to significant spinal canal narrowing.
Enhancing signal also extended into the paraspinal muscles (not shown).
Figure courtesy of L. Taylor Davis, MD.
Management
Management includes antimicrobial therapy and neurosurgical treatment.2
Patients with hemodynamic instability, sepsis, septic shock, or progressive
neurologic deficits should be treated empirically with antimicrobials and undergo
immediate surgical intervention when a surgical target is identifiable (eg,
surgical drainage of any abscess, surgical stabilization of the spine if needed).
Antimicrobial therapy generally includes vancomycin (15 mg/kg to 20 mg/kg
IV every 8 to 12 hours adjusted for renal function) and a third-generation
cephalosporin such as ceftriaxone (2 g IV every 24 hours) to cover staphylococci
(including methicillin-resistant S. aureus), streptococci, and gram-negative
bacilli. Cefepime (2 g IV every 8 hours), ceftazidime (2 g IV every 8 hours), or
meropenem (1 g IV every 8 hours) should be added if risk factors for
Pseudomonas (eg, indwelling catheters) are present. A 6-week course of
antibiotics was found to be noninferior to 12 weeks of antibiotics in an
open-label, multicenter, noninferiority randomized trial.14

For patients who are hemodynamically stable without early signs of

impending sepsis or hemodynamic compromise and with no neurologic deficits,
it is reasonable to defer empiric antimicrobials until after diagnostic aspiration to
increase the microbiological yield.2 During the first few weeks of treatment
when deterioration may be rapid, close monitoring for worsening is crucial; any
new neurologic manifestations should be promptly investigated with
neuroimaging.
Brucellosis
Brucellosis is a zoonotic infection caused by aerobic gram-negative coccobacilli.
It is transmitted to humans primarily by infected livestock including cattle,
goats, sheep (Brucella melitensis), pigs (Brucella suis), dogs (Brucella canis),
camels, and other animals through either ingestion (eg, unpasteurized dairy
products) or direct contact with tissues or fluids such as during calving or
butchering.15 Although rare in the United States, brucellosis is the most common
bacterial zoonosis worldwide and is endemic in the Mediterranean basin, Middle
East, the Indian subcontinent, Central Asia, China, sub-Saharan Africa, and
regions of Mexico and Central and South America. Risk factors for infection are
primarily related to diet (consumption of unpasteurized animal products) and
occupation (shepherds, ranchers, slaughterhouse and dairy workers,
veterinarians, and laboratory staff ).
Because the clinical manifestations of brucellosis are protean and vary
depending on the stage of the disease and organ systems involved, a high index of
suspicion and thorough history with particular attention to epidemiologic risk
factors for exposure are important in identifying clues to the diagnosis.
The most common initial manifestations of brucellosis include fever,
arthralgias, malaise, and night sweats. Although brucellosis can affect any organ
system, osteoarticular disease is the most common, including sacroiliitis,
spondylitis, peripheral arthritis, and osteomyelitis. Neurologic involvement
develops in 6.6% of patients and includes meningoencephalitis, abscess, myelitis,
radiculitis, and/or neuritis.15–17 Myelitis is a rare manifestation and may be
longitudinally extensive (ie, spanning three or more spinal segments).18
When suspected on clinical and epidemiologic grounds, laboratory personnel
should be notified for their protection and because blood cultures should be
incubated for up to 2 weeks. Serum Brucella serologies (IgM/IgG) should
also be obtained. On MRI, Brucella spondylodiscitis causes findings similar to
those of other bacterial etiologies but is more likely to have multilevel
involvement and less likely to develop paravertebral infection.19 CSF analysis
typically demonstrates a lymphocytic pleocytosis with elevated protein and may
include hypoglycorrhachia. In patients with spondylodiscitis and potential
exposure to Brucella, initially nondiagnostic cultures and biopsy results
should prompt testing serum Brucella IgM/IgG and cultures from infected
sites.2 Brucella spondylodiscitis is treated with doxycycline and rifampin
for 3 months or streptomycin for 2 to 3 weeks and doxycycline for 3 months.
Mycobacterium tuberculosis
Mycobacterium tuberculosis is a slow-growing aerobic organism that is responsible
for a significant burden of disease worldwide: 10 million people are infected
annually, and 1.4 million people died of tuberculosis in 2019.20 The incidence of
tuberculosis is highest in Bangladesh, China, India, Indonesia, Nigeria, Pakistan,
892 AUGUST 2021

the Philippines, and South Africa. In addition to epidemiologic risk factors such KEY POINTS
as history of incarceration and country of residence/origin, risk factors include
● The most common initial
malnutrition, human immunodeficiency virus (HIV) infection, IV drug use, manifestations of
alcohol use disorder, diabetes, immunosuppression (especially biological agents brucellosis include fever,
such as tumor necrosis factor-α inhibitors), and chronic renal failure and arthralgias, malaise, and
hemodialysis. Patients with HIV are up to 5 times more likely to develop central night sweats.
nervous system (CNS) involvement than those without HIV.21
● The risk of
Skeletal tuberculosis accounts for 2% to 35% of extrapulmonary disease extrapulmonary
worldwide, with the lower rates seen in the United States. The spine is the most tuberculosis is especially
common site of osteoarticular tuberculosis, and tuberculous spondylitis is the high in patients with human
most common mechanism of myelopathy associated with tuberculosis immunodeficiency virus
(HIV) co-infection, who are
(FIGURE 4-4). Tuberculous granulomas or abscesses can affect the spine, and up to 5 times more likely to
tuberculosis can also cause syringomyelia, arachnoiditis, and myelitis often develop central nervous
accompanied by radiculitis, which may include Elsberg syndrome (discussed system involvement than
later).22 Myeloradiculitis is a common manifestation of spinal tuberculosis in those without HIV.
● The spine is the most

common site of
osteoarticular tuberculosis,
and tuberculous spondylitis
is the most common
mechanism of myelopathy
associated with
tuberculosis.
● The most common

neurologic manifestation of
tuberculosis is meningitis,
although tuberculous
granulomas or abscesses
can affect the spine, and
tuberculosis can also cause
syringomyelia, arachnoiditis,
and myelitis often
accompanied by radiculitis.
FIGURE 4-4
Tuberculous spondylodiscitis. A 24-year-old woman presented with months of worsening
back pain. A, Sagittal CT of the lumbosacral spine demonstrates sclerosis and osseous
erosion at L4-L5 (arrow). B, Sagittal postcontrast T1-weighted MRI shows an enhancing
eroded disk and prevertebral fluid collection (arrow) with an abscess. Biopsy demonstrated
acid-fast bacilli, and cultures proved infection with Mycobacterium tuberculosis.
Figure courtesy of L. Taylor Davis, MD.

areas of high HIV and tuberculosis prevalence.23 For further discussion of

neurologic manifestations of tuberculosis, refer to the article “Neurologic
Complications of Tuberculosis” by Deanna Saylor, MD, MHS,24 in this
issue of Continuum.
Tuberculous spondylitis typically presents with insidious back pain that
worsens over weeks to months, may be accompanied by muscle spasms, and is
less often associated with fever than bacterial spondylitis. The thoracolumbar
spine is affected more often than the cervical spine. The patient may walk in
short, deliberate steps to avoid jarring the spine (Alderman gait) and may be
noted to have an often sharply angulated kyphotic posture (gibbus deformity)
consequent to vertebral body collapse. Compressive myelopathy can result
from epidural abscess/granulation tissue or vertebral collapse, subluxation,
or dislocation.
Considering the possibility of tuberculosis is the most challenging element of
establishing the diagnosis, and active pulmonary infection may not be present;
therefore, a careful history emphasizing risk factors for exposure is important.
The diagnosis would be supported by a positive purified protein derivative
(PPD) test or interferon gamma release assay, although these do not differentiate
between latent and active infection. Contrast-enhanced MRI in patients with
tuberculous spondylitis typically demonstrates involvement of multiple spinal
levels; involvement of three or more contiguous or discontiguous vertebral
bodies may be a clue to the diagnosis.25 On MRI, the most common patterns of
involvement are paradiscal (abutting the vertebral body and often extending to
the intervertebral disk), central (within the center of the vertebral body), anterior
or posterior subligamentous (beneath the anterior or posterior longitudinal
ligaments), and involving the posterior arches (eg, spinous processes, lamina).26
In 1779, Percivall Pott described a pattern of disk infection and vertebral
osteomyelitis of two or more contiguous vertebrae and apposed end plates due to
tuberculosis, which now bears his name (Pott disease). Infection can spread to
the potential space between the vertebral bodies and anterior spinal ligament to
produce a large subligamentous abscess with relative sparing of the disks, which
can compromise the vertebral vascular supply. Abscess centered in the vertebral
bodies can cause vertebral collapse. If CNS involvement (eg, meningitis) is
concurrent, then CSF analysis typically reveals moderate lymphocytic
pleocytosis (100 to 500 cells/mm3), hypoglycorrhachia, and possibly strikingly
high protein concentrations, which may indicate spinal block. CSF acid-fast
stains and cultures are modestly sensitive in tuberculous meningitis (30% to 60%
and as high as 80% with high volumes and multiple specimens).27,28 Precise
diagnosis of tuberculous spondylitis can be made based on microscopy and
culture data obtained from biopsy or surgical specimens. However, in
resource-limited settings with a high prevalence of disease, diagnosis of
tuberculosis is often made clinically/radiologically and treated with monitoring
of disease response.
For most patients with tuberculous spondylodiscitis, multidrug
antimycobacterial therapy is given for 9 months.29 For regimens, refer to the
article “Neurologic Complications of Tuberculosis” by Deanna Saylor, MD,
MHS,24 in this issue of Continuum. Operative intervention should be considered
in patients who do not respond to medical therapy alone or if cord compression
or spinal instability is present. If no compressive or mechanical indication for
surgery is present, surgical debridement combined with medical therapy
894 AUGUST 2021

appears to have no additional benefit over medical therapy alone.29 Although KEY POINTS
most data addressing neurologic outcomes are derived from patients with
● Tuberculous spondylitis
tuberculous meningitis, a recent meta-analysis and systematic review including typically presents with
all forms of tuberculous infection demonstrated a mortality benefit of 17% insidious back pain that
when corticosteroids are added to usual therapy, regardless of the organ system worsens over weeks to
affected29,30 and can be considered in select patients with tuberculous myelitis or months, may be
accompanied by muscle
radiculomyelitis.
spasms, and is less often
associated with fever than
Coccidioidomycosis bacterial spondylitis.
Coccidioidomycosis is a fungal infection endemic to the southwestern
United States, parts of Mexico, and Central and South America and most ● Precise diagnosis of
tuberculous spondylitis is
often causes an asymptomatic pulmonary infection. Disseminated infection primarily based on
is rare and associated with, but not limited to, individuals who are microscopy and culture data
immunocompromised.31 Spondylodiscitis develops in 19% of patients with obtained from biopsy or
disseminated disease and is most often diagnosed in patients who are surgical specimens.
immunocompetent, with African American males disproportionately ● Patients with
overrepresented.32 Patients present most often with back pain, radiculopathy, coccidioidomycosis
and sensory disturbances and less often with weakness and/or myelopathy; fever spondylodiscitis present
is uncommon.33 The thoracic and lumbar vertebrae are most often involved. most often with back pain,
radiculopathy, and sensory
Spondylodiscitis with mechanical compression of the spinal cord is a more
disturbances and less often
frequent cause of myelopathy than myelitis, although myelitis rarely occurs. with weakness and/or
When the nervous system is directly involved, the most common manifestation myelopathy; fever is
is meningitis, and clinicians should have a low threshold for spinal imaging in uncommon.
these cases given a high frequency of concomitant spinal involvement.34 One
● Prognosis in spinal
imaging series of patients with spinal coccidioidomycosis in an endemic epidural abscess depends
region identified leptomeningeal enhancement (63%), arachnoiditis (54%), on the degree and duration
osteomyelitis-discitis (34%), cord edema (27%), and syrinx (7%) as the most of neurologic deficits before
common findings.35 Brain involvement was noted in 73% of patients in that decompression and
antimicrobial therapy;
series, most often manifesting as basilar meningitis. Initial diagnostic studies therefore, early diagnosis
include serologies (IgM/IgG) and antigen studies from the serum and/or CSF; and management are
CSF polymerase chain reaction (PCR) is more rapid than culture albeit of similar critical, and clinicians
sensitivity.36 Treatment consists of antifungal therapy and surgical should maintain a high index
of suspicion to avoid
decompression (if indicated). Most patients have a good outcome.31 potentially devastating
consequences.
SPINAL EPIDURAL ABSCESS
Spinal epidural abscess is an infectious collection in the space between the
bony spinal structures and the dura mater and is a neurologic emergency
because of the risk of cord compression (CASE 4-1). As with spondylodiscitis,
the incidence of epidural abscess is increasing because of the rising prevalence
of risk factors including diabetes, HIV, IV drug use, alcohol use disorder, and
indwelling vascular catheters.37–39 Diabetes is the most common risk factor.37
Because the clinical presentation is nonspecific and epidural abscess is
uncommon, delays in diagnosis are common, particularly in the absence of
focal neurologic deficits. Prognosis depends on the severity and duration of
neurologic deficits before decompression and antimicrobial therapy.
Therefore, early diagnosis and management are critical, requiring a high index
of suspicion to avoid potentially devastating consequences.40,41 If patients are
diagnosed and treated in the early stages when they have only back or radicular
pain, full recovery is achievable. However, patients with paralysis for 24 to
36 hours before treatment often have residual neurologic deficits.38,42,43

CASE 4-1 A 60-year-old man presented to the emergency department with

difficulty walking and urinary hesitancy. His symptoms began with back
pain that worsened despite physical
therapy, and the quality changed
from an achy low back pain to
shooting pain across his abdomen.
He continued to be treated with
physical therapy and analgesics, and
after 6 weeks he developed urinary
hesitancy and difficulty walking.
His past medical history was
notable for diabetes.
Initial examination showed that
he was afebrile. He had mild
weakness in knee flexion with
hyperreflexia in both lower extremities
with bilateral Babinski signs.
The only laboratory abnormality
was an erythrocyte sedimentation
rate (ESR) of 80 mm/h. Imaging
showed discitis with osteomyelitis
and associated epidural abscess
(FIGURE 4-5).
He underwent urgent
laminectomy with debridement. FIGURE 4-5
Surgical cultures grew Epidural abscess. Sagittal T2-weighted
Staphylococcus aureus, and MRI of the thoracic spine of the patient
in CASE 4-1 demonstrates dorsal epidural
he was treated with IV antibiotics
collection (arrow). Associated thoracic
for 6 weeks. His back pain improved, cord T2 hyperintensity (arrowhead) with
but he had persistent urinary cord edema, as well as evidence of discitis
hesitancy and mild gait instability. and osteomyelitis anteriorly, is seen.
COMMENT The patient’s history illustrates the nonspecific initial symptoms of epidural
abscess and the gradual progression from back pain to radicular symptoms
to evidence of spinal cord injury. The epidural abscess in this patient
originated from concurrent osteomyelitis. Red flag symptoms that should
have prompted earlier imaging were his older age, presence of diabetes,
and progression of symptoms despite conservative therapy. As is
frequently the case, fever was absent on initial evaluation; ESR is a more
sensitive marker.
896 AUGUST 2021

Epidural abscess can develop ventral or dorsal to the spinal cord but most KEY POINT
often affects the dorsal thoracolumbar spine (probably because the epidural
● The classic triad of
space is larger in the thoracic and lumbar segments compared with the cervical epidural abscess including
spine). As with spondylodiscitis, infections spread to the epidural space through fever, back pain, and focal
one of three mechanisms38 including hematogenous spread (most often from neurologic deficits is
skin or soft tissue infection),37 regional contiguous spread (from vertebral observed in only 2% to 33%
of patients at presentation,
osteomyelitis, paraspinal abscess, or psoas abscess), and instrumentation of the
which, therefore, has
spine (eg, spinal cord stimulator implantation, lumbar puncture, epidural inadequate sensitivity to be
catheter, or epidural steroid injections). Importantly, some patients develop considered a useful clinical
spinal epidural abscess without a clear source; hence, the absence of a clear marker.
mechanism or risk factor does not exclude the possibility of an epidural abscess.
S. aureus accounts for more than two-thirds of cases of epidural abscess,
reflecting the primary sources from skin or soft tissue infections and inoculation
from spinal intervention.37 Other pathogens include Streptococcus species and
Enterobacteriaceae species such as Escherichia coli. Unlike systemic abscesses,
most epidural abscesses are not caused by anaerobic bacteria. Mycobacterium
tuberculosis is an uncommon cause of epidural abscess in the United States, but in
other regions of the world, tuberculosis is a common cause of epidural infection
and may account for the majority of cases.44 The pathogenesis of neurologic
symptoms from epidural abscess includes mechanical compression of the spinal
cord and nerve roots, septic thrombophlebitis causing vascular injury and
consequent ischemia to the spinal cord,45 and possibly bacterial toxins and
inflammatory cytokines.
Clinical Features
The classic triad of spinal epidural abscess is back pain, fever, and neurologic
deficits referable to the spinal cord or nerve roots. The full triad is observed
in only 2% to 33% of patients at presentation.39,46,47 Back pain is the most
common symptom,37,40,41 usually evolving rapidly over the course of a few
days, although a more subacute presentation may be seen.48 Clinical symptoms
typically evolve through four stages49: pain in the back at the level of the
abscess, radicular pain in the affected dermatome(s), myelopathic symptoms,
and paralysis. The rate of progression through these stages is variable, ranging
from hours to days.
In a large meta-analysis, fever was present at some point in the disease course
in about two-thirds of patients with spinal epidural abscess38 but was present
only in about one-third at initial evaluation, perhaps because of the use of
antipyretic analgesics for back pain.46 Hence, the absence of fever should not
exclude consideration of epidural abscess. An abnormal neurologic examination
is indicative of more advanced disease and can include weakness, loss of
sensation or paresthesia, loss of rectal tone, and saddle anesthesia.46
Diagnostic Approach
When epidural abscess is suspected, imaging and laboratory studies should be
conducted urgently. MRI is the modality of choice for detecting epidural
abscess (FIGURE 4-5) and can detect epidural abscess in most patients who are
symptomatic. Epidural abscess appears hyperintense on T2 imaging with a T1-
hypointense core and peripheral enhancement with IV gadolinium.42 MRI may
also reveal adjacent areas of infection such as osteomyelitis or psoas muscle
abscess from which the infection has spread. Epidural abscesses often span

multiple spinal levels that may not be contiguous. If MRI is contraindicated,

contrast-enhanced CT of the spine can demonstrate reactive bony changes but
does not detect the epidural collection. CT myelography can demonstrate
narrowing of the vertebral canal but is less specific than MRI of the spine.
Leukocytosis is found in 60% to 80% of patients with epidural abscess.50
Elevations in ESR and CRP are highly sensitive40: ESR elevation is present in
more than 90% of patients with epidural abscess37,47,51,52 with an average of
77 mm/h in one large series.37 Blood cultures should be obtained, although as
with spondylodiscitis, the sensitivity is modest at an estimated 50% to 60%.53 If
CSF is obtained, it often demonstrates mild pleocytosis and a high protein level.38
Management
Epidural abscess is a neurologic emergency that requires urgent evaluation and
treatment to decrease the risk of permanent neurologic injury. Most patients with
acute or progressive neurologic deficits should be treated surgically unless a
strong contraindication to operative intervention is present, such as significant
medical instability or high surgical risk. Surgical management typically involves
decompressive laminectomy with debridement and culture of the epidural
collection. If axial spine instability is a preoperative concern, the spine should be
immobilized to prevent further neurologic injury.42
When epidural abscess is suspected, empiric antibiotics should be started as
soon as possible. Empiric antibiotics should cover staphylococci, streptococci,
and gram-negative bacilli with vancomycin (15 mg/kg to 20 mg/kg IV every 8 to
12 hours adjusted for renal function) and a third-generation cephalosporin such
as ceftriaxone (2 g IV every 24 hours). Patients at increased risk of pseudomonas
(eg, patients with diabetes, recent antibiotic use, spinal instrumentation,
hospitalization) should be treated with a combination of vancomycin and
cefepime (2 g IV every 8 hours), ceftazidime (2 g IV every 8 hours), or
meropenem (1 g IV every 8 hours). Once an infectious agent is identified,
antibiotics should be narrowed based on susceptibility data. The duration of
therapy is individualized based on clinical, laboratory, and radiologic response to
treatment and is typically 4 to 8 weeks.42
Whether some patients can be treated with antibiotic therapy alone without
surgical decompression is controversial. No randomized trials compare surgical
to medical management alone. In a large case series, a significant rate of failure
of medical management alone (41%) was shown, and outcomes may be worse
with delayed compared with immediate surgical management.54 Risk factors
associated with failure of medical therapy alone include age older than 65,
myelopathy or cauda equina syndrome, diabetes, infection with methicillin-resistant
S. aureus, positive blood cultures, CRP greater than 115 mg/L, and leukocytosis
greater than 12,500 cells/mm3.54–56 Imaging-guided needle aspiration may be an
alternative to surgical decompression when a dorsal abscess is amenable to
drainage and in patients who are either neurologically intact or considered high
surgical risk. If surgical management must be deferred, in addition to empiric
antibiotics, serial neurologic examinations and repeat MRI should be performed
to monitor for progression or improvement of the abscess.
SPINAL MENINGITIS/ARACHNOIDITIS
Spinal meningitis, also called arachnoiditis, refers to a heterogeneous set of
inflammatory processes that primarily affect the leptomeninges of the spinal
898 AUGUST 2021

cord and spinal nerve roots. Causes of KEY POINTS
spinal meningitis/arachnoiditis include
● Epidural abscess is a
both infectious and noninfectious neurologic emergency and
etiologies (eg, sarcoidosis, leptomeningeal requires urgent evaluation
metastases, and postsurgical adhesive and treatment to decrease
arachnoiditis). the risk of permanent
neurologic injury.
Clinically, most patients with spinal
meningitis have symptoms of ● Clinically, most patients
polyradiculitis manifesting as shooting, with spinal meningitis often
sharp pain along dermatomal have symptoms of
distributions accompanied by focal polyradiculitis manifesting
as shooting, sharp pain along
numbness or weakness in radicular dermatomal distributions
distributions. Symptoms usually evolve accompanied by focal
over the course of hours to days, although numbness or weakness in
they can be subacute in chronic infections radicular distributions.
such as tuberculosis. ● Early neuroborreliosis
Neurologic examination may be normal often involves the
for pain-predominant syndromes or peripheral nervous system,
reveal patchy dysfunction affecting and frequently encountered
manifestations include
multiple nerve roots. When spinal
cranial neuritis (most
meningitis causes myelitis, bowel/bladder commonly unilateral or
dysfunction is a common early sign. FIGURE 4-6 bilateral facial nerve palsy),
MRI with contrast usually shows Staphylococcus aureus spinal radiculoneuritis, and
meningitis. A 50-year-old woman with lymphocytic meningitis.
leptomeningeal contrast enhancement fevers and meningismus developed
and clumping of nerve roots (FIGURE 4-6). progressive lower back pain and
The enhancement can be quite subtle, incontinence. Sagittal postcontrast
especially early in the disease, and an T1-weighted MRI of the lumbar spine
demonstrates diffuse thickening and
absence of enhancement does not exclude enhancement of the spinal meninges
the diagnosis. Nerve root enhancement is including the conus medullaris and
a nonspecific finding and does not cauda equina nerve roots.
necessarily indicate active inflammation. Figure courtesy of L. Taylor Davis, MD.
Nerve conduction studies/EMG is

insensitive in isolated sensory
radiculopathy but can be more revealing when motor roots are affected. The
CSF profile depends on the etiology and is discussed in the context of specific
causes below.
Neuroborreliosis
Lyme disease is a tick-borne infection caused by species of Borrelia spirochetes.
In the United States, Borrelia burgdorferi is the primary pathogen, whereas in
Europe, two additional species Borrelia afzelii and Borrelia garinii also cause
disease.57 For a detailed discussion of Lyme disease, refer to the article
“Neurologic Complications of Lyme Disease” by Karen L. Roos, MD, FAAN,58 in
Neurologic manifestations (neuroborreliosis) are reported in approximately
3% to 12% of patients with Lyme disease in both the United States and
Europe.59,60 Early neuroborreliosis most often develops in the early disseminated
stage, during which the classic erythema migrans (target) rash may still be
present. Early neuroborreliosis often involves the peripheral nervous system, and
frequently encountered manifestations include cranial neuritis (most commonly

unilateral or bilateral facial nerve palsy), radiculoneuritis, and lymphocytic

meningitis.
Lyme radiculoneuritis is a painful disorder marked by sharp, shooting pain in
single or multiple nerve root distributions. Patients can present initially with
focal cervical or lumbosacral radiculoneuritis or with more disseminated disease.
Untreated, patients eventually develop a migrating pain syndrome with focal signs
and symptoms of radiculopathy and may also develop a lymphocytic meningitis.
The clinical syndrome of Lyme meningoradiculitis is referred to by the eponym
Bannwarth syndrome or Garin-Bujadoux-Bannwarth syndrome. Although Lyme
disease is often cited as a potential etiology of CNS parenchymal pathology
such as myelitis, neuroborreliosis involving the CNS parenchyma is
exceptionally rare.61,62
When patients develop Lyme radiculoneuritis, CSF analysis typically reveals
a lymphocytic pleocytosis, often with evidence of intrathecal synthesis of
Borrelia-specific antibodies.63 Lyme IgM/IgG from the serum is generally
positive by the time Lyme radiculoneuritis occurs in the disease course. Although
relatively straightforward to diagnose once suspected, including neuroborreliosis
in the differential diagnosis of radiculoneuritis is probably the most important
step to avoid missing this treatable disease. The authors of this article have
personally seen multiple patients with radiculopathy of unclear etiology
ultimately found to be from Lyme disease. Treatment of cranial neuritis
or radiculitis in the United States is generally with oral doxycycline or, in
severe cases, IV penicillin, ceftriaxone, or cefotaxime for 14 to 21 days.64
Cytomegalovirus
Cytomegalovirus (CMV) is a herpes virus that does not cause neurologic
disease in adults who are immunocompetent but can affect patients with
severe immunocompromise due to HIV or bone marrow transplantation.
Deficiency in CMV-specific T-cell function allows for CMV replication and organ
injury. In HIV infection, this usually occurs when the CD4+ T-cell count falls
below 50 to 100 cells/mm3.65 CMV can cause encephalitis, myelitis, and
radiculitis. The clinical syndrome can be a combination of findings related
to spinal cord dysfunction and polyradiculopathy. CSF generally demonstrates
pleocytosis, which can be neutrophilic or lymphocytic, with low glucose and
positive CMV PCR.66 Whether CMV can also cause myelitis in adults who are
immunocompetent is controversial. Scattered case reports mention
CMV-associated radiculomyelitis without apparently predisposing conditions.67
In these patients, PCR may have lower sensitivity compared with serial serologic
testing. Because CMV is a common latent infection, positive PCR or serology
alone does not definitively confirm CMV as the cause of the neurologic syndrome.
Treatment of CMV depends on the severity of disease and is based on
expert consensus rather than randomized trials comparing different regimens.
In patients with severe disease such as paraparesis or multifocal disease
including retinitis, myelitis, and colitis, dual therapy with IV ganciclovir and
foscarnet is prescribed (or monotherapy if dual therapy is not tolerated).
For patients with less severe disability, oral valganciclovir can be used
instead of parenteral therapy. In patients who are immunosuppressed, measures
to reduce the degree of immunosuppression are equally important. For
individuals infected with HIV, antiretroviral therapy is started to restore
immunity.
900 AUGUST 2021

MYELITIS KEY POINTS
Myelitis is inflammation of the spinal cord parenchyma and can be caused by
● Myelitis is inflammation
infectious or immune-mediated etiologies. Infectious myelitis may develop of the spinal cord
in isolation (eg, poliomyelitis, herpesvirus myelitis) or present as an parenchyma and can be
overlap syndrome with encephalitis (eg, fungal or parasitic myelitis), caused by infectious or
meningitis/meningoencephalitis (eg, West Nile neuroinvasive disease), immune-mediated
etiologies.
radiculitis (eg, varicella-zoster radiculomyelitis), or paraspinal infection.
An infectious or parainfectious etiology of myelitis is suggested by a history of ● The anterior horn
fever, chills, myalgia, recent upper or lower respiratory tract infection, recent syndrome consists of a
gastrointestinal infection, and exposure to particular pathogens (eg, travel lower motor neuron pattern
history). The differential diagnosis for infectious myelitis includes immune- flaccid weakness with
decreased or absent
mediated etiologies, nutritional deficiencies, malignancy, and vascular reflexes and preservation of
disease. The temporal profile for infectious myelitis varies depending on the sensory modalities (often
pathogen and spans from acute progressive to chronic progressive patterns. referred to as acute flaccid
Evidence of inflammation on history, MRI (eg, contrast enhancement), or myelitis).
laboratory analysis (eg, CSF pleocytosis) implicates an infectious or
immune-mediated etiology.
Pathogenesis
A wide range of infectious agents can cause myelitis, including bacteria,
viruses, fungi, and parasites. Intramedullary bacterial abscess is most often
associated with hematologic seeding of the CSF or spinal cord or from direct
instrumentation or trauma. Viruses can access the CNS through several
mechanisms, including hematologic dissemination, infection of host leukocytes
with invasion of the CNS via a “Trojan horse” mechanism (eg, HIV), invasion
via the olfactory nerve (eg, herpes simplex virus type 1 [HSV-1]), retrograde
axonal transport (eg, rabies, some enteroviruses, such as poliovirus), or direct
infection of microvascular endothelial cells (eg, human T-cell lymphotropic virus
type I [HTLV-I], West Nile virus). In addition to direct injury to the spinal
cord parenchyma, infectious etiologies can trigger a parainfectious
immune-mediated myelitis.68
Clinical Features
Although no clinical or radiologic patterns of myelitis are adequately specific
to establish a definite diagnosis with a particular infectious agent,
recognizable patterns and tropisms exist that can help guide focused
diagnostic evaluation. This section is organized by the pattern of spinal cord
involvement, although as with other spinal infections, most organisms can
present with a range of clinical syndromes, including overlapping
syndromes.
Anterior Horn Syndrome

The anterior horn syndrome consists of lower motor neuron pattern flaccid
weakness with decreased or absent reflexes and preservation of sensory
modalities (often referred to as acute flaccid myelitis). Many viral etiologies
exhibit a tropism for the anterior horn including enterovirus A71 (EVA71) and
enterovirus D68 (EVD68); coxsackieviruses A16, B2, B4, and A9; echovirus; and
poliovirus. Flaviviruses such as West Nile virus, St. Louis encephalitis virus,
Japanese encephalitis virus, and tick-borne encephalitis virus also have a tropism
for the anterior horn.

ENTEROVIRAL MYELITIS. Children are at higher risk of myelitis related to

enteroviruses than adults are. EVA71 was responsible for an outbreak of acute
flaccid myelitis in Colorado in summer 2018.69 All children in that study had
fever, and 42% had skin lesions consistent with hand, foot, and mouth disease at
or before neurologic manifestations. Myoclonus, weakness, ataxia, and
autonomic instability were found to help differentiate patients with EVA71
from those with other enteroviral infections.69 Even in this cohort of patients
with neurologic disease related to enteroviral infection, enterovirus was detected
in only 20% of CSF samples compared with 94% of rectal and 79% of
oropharyngeal samples, highlighting the greater sensitivity of extraneural sites
over CSF sampling in neurologic disease associated with enteroviral infection.
EVA71 also has tropism for the brainstem, and meningoencephalitis/brainstem
encephalitis may occur with or without myelitis. IV immunoglobulin (IVIg) is
often given although this is off-label and without controlled trials. Some
clinicians also try IV glucocorticoids if the patient has no response to IVIg or offer
plasma exchange, although further disease worsening with immunodepletion is a
potential risk. The risk and benefit of immunomodulation are not clearly
established.
CASE 4-2 A 72-year-old man presented in August with abrupt onset of fever, myalgia,
headaches, and maculopapular rash across the chest and back in a
nondermatomal distribution. Within 1 day of symptom onset, he developed
decreased sensation and paresthesia in the left hand that progressed up
the arm, across the neck, and to the other arm over the course of the day in
roughly a C6-T2 distribution. He then developed flaccid weakness in the
triceps and finger abductors and presented for evaluation.
MRI of the cervical spine demonstrated T2 hyperintensity without
contrast enhancement in the spinal cord gray matter at C5-C6 (FIGURE 4-7).
CSF analysis revealed 39 nucleated cells/mm3 (50% lymphocytes, 43%
polymorphonuclear leukocytes), protein of 97 mg/dL, and normal glucose,
and a multiplex meningitis polymerase chain reaction (PCR) panel was
negative. The patient was treated with IVIg for suspected West Nile myelitis
and was provided general medical supportive care and physical therapy,
and his strength and sensory deficits improved over the course of several
weeks, although he was left with mild residual weakness in both hands.
West Nile virus IgM eventually returned positive in the CSF. He made a
modest recovery with occupational and physical therapy but did not return
to baseline function.
COMMENT This case illustrates a typical presentation of West Nile virus myelitis. The
season and the patient’s age elevate the index of suspicion for West Nile
virus infection. The acute flaccid weakness is typical of West Nile virus
myelitis, and the CSF profile with a modest pleocytosis consisting of a
mixture of neutrophils and lymphocytes is common. CSF PCR is insensitive
for West Nile virus, and the preferred diagnostic study is CSF IgM.
902 AUGUST 2021

WEST NILE MYELITIS. West Nile virus is an arbovirus transmitted by mosquitoes
and is now considered endemic in the United States with the highest incidence in
North and South Dakota, Nebraska, Montana, Colorado, Wyoming, Louisiana,
and Mississippi. Human infection typically occurs in the late spring, summer, or
early fall, when mosquitos are most active in the environment. Most patients
with West Nile virus infection are asymptomatic, but roughly 25% develop West
Nile fever with headache, rash (approximately 50%), myalgia, and asthenia, and
about 0.67% will develop West Nile neuroinvasive disease (CASE 4-2). Risk
factors for West Nile neuroinvasive disease include older age, malignancy,
chemotherapy, and organ transplantation. West Nile neuroinvasive disease most
often presents with meningitis or meningoencephalitis, which may co-occur with
myelitis. Because West Nile virus has a tropism for the deep gray matter of the
brain, West Nile virus encephalitis should be considered when a patient presents
from an endemic area in the warm months with systemic signs accompanied by
extrapyramidal signs such as tremor, rigidity, bradykinesia, and/or myoclonus,
although these are not specific, and broad-spectrum empiric antimicrobials are
indicated until the diagnosis is confirmed. Myelitis develops in an estimated
5% to 10% of cases of West Nile neuroinvasive disease and most often presents as
FIGURE 4-7
West Nile virus myelitis in the patient in CASE 4-2. Sagittal (A) and axial (B) T2-weighted MRI of
the cervical spine demonstrates a short segment of T2 hyperintensity (A, arrow) at C5-C6 in
the spinal gray matter (B, arrows). No enhancement with gadolinium contrast was present
(not shown).

an acute flaccid paralysis. Spinal MRI may be normal or demonstrate T2

hyperintensity with or without contrast enhancement in the ventral spinal cord
or gray mater (FIGURE 4-7). West Nile virus can also produce a longitudinally
extensive myelitis. CSF analysis typically reveals an early moderate neutrophilic
pleocytosis (less than 500 cells/mm3) that eventually gives way to a lymphocytic
pleocytosis. The viremic phase of West Nile virus infection is usually brief and
transient (often before symptom onset), and, therefore, while the specificity of
viral PCR is 100%, the sensitivity is low (approximately 15% for serum and
approximately 50% for CSF).70 CSF IgM is more sensitive than CSF PCR; because
IgM normally cannot cross the blood-brain barrier, the detection of West Nile
virus IgM in the CSF indicates intrathecal synthesis diagnostic of West Nile
neuroinvasive disease. PCR can be useful for patients who are
immunocompromised who may not be able to mount an adequate antibody
response. Paired acute and convalescent plasma IgM/IgG antibodies can also
assist in the diagnostic evaluation. Treatment for West Nile myelitis is primarily
supportive, and, although a single randomized clinical trial of high-titer West
Nile virus–specific IVIg failed to demonstrate benefit,71 IVIg is reasonable to
consider given theoretical benefit.
Anterior Cord Syndrome

The anterior cord syndrome is characterized by weakness (ventral
horn/corticospinal tract injury) and loss of spinothalamic tract sensory
modalities (pain and temperature) at and below the level of the lesion with
preservation of the dorsal column sensory modalities (vibration and
proprioception) and is most often caused by a vascular injury to the cord. The
anterior spinal artery supplies the anterior cord, and two posterior spinal arteries
supply the dorsal columns. Infectious vasculitis of the spinal cord may occur,
generally in association with bacterial spinal meningitis.
VARICELLA-ZOSTER VIRUS MYELITIS. The neurologic manifestations of

varicella-zoster (VZV) are protean and include encephalitis, meningitis,
myelitis, radiculitis, and peripheral neuritis. Although myelitis is an infrequent
manifestation, VZV is one of the most common causes of infectious myelitis
and is important to recognize given the availability of specific antiviral therapy.
The typical presentation is acute to subacute asymmetric weakness more
often accompanied by spinothalamic tract sensory deficits than dorsal column
dysfunction. However, pathologic involvement may be most severe in the dorsal
root entry zone, and an infectious/necrotizing vasculitis with demyelination
and neuronal inclusions has been described (CASE 4-3).72,73 Patients with VZV
myelitis often develop the characteristic zoster rash before the onset of myelitis,
but myelitis can occur without rash as well (zoster sine herpete). Myelitis may be
accompanied by encephalitis and/or radiculitis (including Elsberg syndrome; see
below in the section titled “Conus Medullaris/Cauda Equina Syndrome”), and
manifestations may be severe, particularly in patients who are immunocompromised.
CSF analysis typically demonstrates a mild lymphocyte-predominant pleocytosis and
elevated protein. Although VZV may produce an infectious vasculitis that can cause
the anterior cord syndrome, it can also produce a longitudinally extensive myelitis or
T2 hyperintensity elsewhere in the spinal cord (FIGURE 4-8). Patients who develop
myelitis and have a typical zoster rash should be empirically treated with acyclovir
while the diagnostic evaluation is underway. Unroofing of skin vesicles (when
904 AUGUST 2021

present) and testing vesicular fluid or crusts with VZV PCR can establish a KEY POINTS
presumptive diagnosis of zoster myelitis. CSF VZV PCR should be obtained, although
● In enteroviral myelitis,
CSF VZV IgM and IgG may be more sensitive than PCR to confirm the enterovirus was detected in
diagnosis.74 Treatment consists of acyclovir IV 10 mg/kg every 8 hours for 14 to only 20% of CSF samples
21 days. Some clinicians will combine this with glucocorticoids, particularly when compared with 94% of rectal
zoster vasculitis is a concern.74 and 79% of oropharyngeal
samples, highlighting the
greater sensitivity of
Central Cord Syndrome peripheral over CSF
The primary sensory neurons of the spinothalamic fibers enter the dorsal spinal cord sampling in neurologic
ipsilateral to their peripheral sensory field and ascend in the tract of Lissauer for disease associated with
enteroviral infection.
roughly two levels before synapsing on the second-order neurons in the dorsal gray
matter horn, which decussate via the anterior commissure and ascend in the ● Human infection with
spinothalamic (anterolateral) tracts. Small, centrally located lesions in the spinal West Nile virus typically
cord may only affect the pathway at its decussation via the anterior commissure, occurs in the late spring,
producing a suspended level of decreased pain and temperature sensation roughly summer, or early fall, when
mosquitos are most active in
two spinal levels below the level of the lesion. Larger lesions that expand ventrally the environment.
may also affect the ventral horns and produce a lower motor neuron pattern of
weakness at the level of the lesion in addition to the suspended spinothalamic ● West Nile neuroinvasive
deficits. The corticospinal tracts are often affected by large lesions causing arm disease most often presents
with meningitis or
weakness greater than leg weakness (the fibers of the corticospinal tracts controlling
meningoencephalitis, which
the arms travel more medially than those supplying the legs). Autonomic fibers may co-occur with myelitis
controlling bowel/bladder control descend centrally as well and may be affected early. as well.
Central cord syndrome is not specific to a particular etiology of myelitis but
can be found in many causes including pyogenic spinal cord abscess and ● Myelitis develops in an
estimated 5% to 10% of cases
immune-mediated disorders. of West Nile neuroinvasive
disease and most often
Dorsal Column Syndrome presents as an acute flaccid
The dorsal column syndrome is characterized by decreased or absent vibration paralysis.
and proprioception at and below the level of the lesion with preserved strength, ● For West Nile
pain, and temperature sensation. Syphilis and HIV (both discussed in sections neuroinvasive disease, CSF
that follow) can both produce the dorsal column syndrome, often with additional IgM is more sensitive than
findings. Epidural abscess may occasionally present primarily with deficits in CSF polymerase chain
reaction (PCR), and the
dorsal column modalities. Other noninfectious etiologies of this syndrome to
detection of West Nile virus
consider include spondylotic disease, malignancy, posterior spinal artery infarct, IgM in the CSF in the
and deficiencies in vitamin B12, copper,75 and vitamin E. appropriate clinical context
strongly indicates West Nile
neuroinvasive disease.
NEUROSYPHILIS. Syphilis is caused by the spirochete Treponema pallidum. Spinal
cord involvement occurs in meningovascular syphilis (an early complication) ● The anterior cord
and tabes dorsalis (a late complication). Meningovascular syphilis occurs as a syndrome is characterized
result of a combination of granulomatous inflammation and arteritis. The by weakness and loss of
syndrome can present as either a slowly progressive spastic paraparesis over spinothalamic tract sensory
modalities below the level
months with sensory loss in the legs76 or sudden onset myelopathy from arteritis of the lesion with
and ischemic infarct. MRI in meningovascular syphilitic myelitis is generally preservation of the dorsal
nonspecific, often consisting of T2 hyperintensity in the cord with gadolinium column sensory modalities
enhancement,77 although pachymeningeal enhancement may be seen in some and is most often caused by
a vascular injury to the cord.
patients. CSF typically shows lymphocytic pleocytosis with an average of about
40 cells/mm3.78
In patients with untreated syphilis, tertiary syphilis can develop 10 to 15 years
after primary infection and is more common in men than women.79 Tabes
dorsalis evolves through several stages, and patients may have other concurrent

features of late syphilis infection, including neuropsychiatric changes, aortitis,

and gumma formation. In the first stage, patients experience severe,
lancinating/shooting pain in the limbs in radicular distributions, abdominal pain,
and frequent urinary dysfunction. Touching painful areas may elicit the shooting
pain.76 Clinical examination during this stage often shows severe deficits in
proprioception, loss of deep pain sensation, absent reflexes, Romberg sign, and
Argyll Robertson pupils (small pupils that accommodate with convergence but
do not react to light). Untreated, patients eventually develop a sensory ataxic gait
with persistent tabetic pain. The clinical syndrome reflects involvement of the
dorsal column and dorsal roots (likely the cause of the tabetic pain syndrome). In
the final stages, patients often become immobile from sensory ataxia and
CASE 4-3 An 84-year-old woman presented to her primary care provider with
several days of right occipital burning headache and neck stiffness. The
clinician noted a vesicular and crusted rash consistent with varicella-
zoster virus (VZV) (shingles) and started treatment with valacyclovir. Two
days later, she developed paresthesia in the right hand and nausea/
vomiting and presented to the emergency department. Her past medical
history was notable only for hypertension.
Neurologic examination demonstrated neck stiffness and decreased
vibration in the right hand. Her oral valacyclovir was transitioned to
acyclovir IV 10 mg/kg every 8 hours, and CSF analysis demonstrated
159 nucleated cells/mm3 (81% lymphocytes), elevated protein at
91 mg/dL, and normal glucose. VZV polymerase chain reaction (PCR) from
the CSF was positive. MRI of the cervical spinal cord demonstrated T2
hyperintensity in the right dorsolateral spinal cord including the dorsal
horn (FIGURE 4-8). Her symptoms resolved over the course of the evening,
and she was discharged to complete a 2-week course of antivirals.
She presented again several weeks later with burning dysesthesias in
the right C2-C3 distribution, although her neurologic examination was
normal, and follow-up cervical spine MRI demonstrated resolution of the
previously identified T2 hyperintensity in the cervical cord.
COMMENT This case illustrates a typical presentation of VZV myelitis in an

immunocompetent patient with a shingles exacerbation. Although VZV
myelitis typically occurs in the context of a shingles exacerbation, myelitis
may also develop without the shingles rash (zoster sine herpete). Despite
appropriate treatment of her shingles, this patient progressed to develop
VZV meningomyelitis. When central nervous system infection with VZV is
suspected, CSF VZV PCR should be evaluated, as should CSF VZV IgM/IgG.
Although PCR is more rapidly available, given brief/transient periods of
viremia, IgM/IgG may be more sensitive.73 Transition to IV acyclovir
produced rapid resolution of her symptoms. The role of glucocorticoids in
zoster myelitis has not been clearly elucidated, although in many cases,
glucocorticoids are often offered based on case reports and expert
opinion.74
906 AUGUST 2021

autonomic dysfunction. MRI of the spine typically shows T2 hyperintensity in
the dorsal columns.
CSF in neurosyphilis generally shows evidence of elevated protein, lymphocytic
pleocytosis, and positive Venereal Disease Research Laboratory (VDRL) results.
Note that even without a positive CSF VDRL, a compatible clinical syndrome with
positive serum treponemal serology and inflammatory CSF should be treated as
evidence of neurosyphilis. Neurosyphilis is treated with parenteral penicillin G for
10 to 14 days.80 If patients cannot tolerate penicillin G, then ceftriaxone may be
used as an alternative, although it is not recommended in patients infected with
HIV or in pregnant women. For further discussion, refer to “Neurosyphilis” by
Felicia Chow, MD, MAS,81 in this issue of Continuum.
FIGURE 4-8
Varicella-zoster radiculomyelitis in the patient in CASE 4-3. A, Vesicular/crusted rash in the
right cervical and upper thoracic dermatomes typical of shingles. Sagittal (B) and axial (C)
T2-weighted MRI of the cervical spine demonstrates T2 hyperintensity (B, arrow) in the
rostral cervical spinal cord at about C1-C2 with T2 hyperintensity (C, arrow) in the dorsal
gray column. No enhancement with gadolinium contrast was present (not shown).

CASE 4-4 A 55-year-old woman developed mild stiffness in her legs. Initial
evaluation by her primary care physician did not show any weakness. She
was treated with physical therapy. Over the next few months, the
stiffness in the legs increased with
worsening spasms. She was
originally from the Caribbean
region and had immigrated to the
United States 20 years prior
to presentation.
Initial neurologic evaluation
showed mild hip flexor weakness
with decreased vibratory sense
in the feet. She had significant
spasticity and hyperreflexia in
the legs. MRI of the cervical and
thoracic spine were normal
(FIGURE 4-9). After continuing to have
symptoms following another round
of physical therapy, she had a
lumbar puncture, which showed
mild lymphocytic pleocytosis of
7 cells/mm3 with a normal protein
level. She initially was diagnosed
with transverse myelitis, but on
subsequent review by another
neurologic specialist, she was
tested for human T-cell lymphotropic
virus type I (HTLV-I) serology and FIGURE 4-9
found to be positive. She was Human T-cell lymphotropic virus type
subsequently treated with a I–associated myelopathy in the patient
3-month taper of oral prednisone in CASE 4-5. Sagittal T2-weighted MRI
of the thoracic spine demonstrates no
and oral skeletal muscle relaxants. T2 hyperintense lesions. No gadolinium
She continued to have stiffness enhancement was seen on postcontrast
in the legs. T1-weighted images (not shown).
COMMENT This patient’s experience shows the spasticity-predominant gradual

presentation with often normal initial imaging common in HTLV-I–
associated myelopathy. In geographic areas in which HTLV-I is not
endemic, diagnosis is often delayed with an initial diagnosis of transverse
myelitis or hereditary spastic paraplegia. Treatment is, at present,
supportive. When symptoms are progressive, a modest response to
corticosteroids may be seen.
908 AUGUST 2021

Longitudinally Extensive Transverse Myelitis KEY POINTS
Longitudinally extensive transverse myelitis (LETM) refers to spinal cord
● Although myelitis is an
inflammation spanning three or more spinal segments. The clinical presentation infrequent manifestation,
includes paraparesis or tetraparesis, sensory loss, bowel/bladder dysfunction, varicella-zoster virus (VZV)
and gait abnormalities. Although LETM is classically associated with neuromyelitis is one of the most common
optica spectrum disorders,82,83 this pattern may be seen in other inflammatory causes of infectious myelitis
and is important to
disorders (eg, neurosarcoidosis, Behçet disease, paraneoplastic syndrome) or from
recognize given the
noninflammatory etiologies such as nutritional deficiencies (eg, copper, vitamin availability of specific
B12), vascular or neoplastic disease, and trauma. Among infectious causes, antiviral therapy.
herpesviruses, EVA71, EVD68, West Nile virus, HIV, and HTLV-I can produce
LETM as can syphilis, intramedullary abscess, M. tuberculosis, and B. burgdorferi. ● CSF VZV PCR should be
obtained when CNS zoster is
Brucellosis may rarely cause LETM.18 suspected, although it is
also prudent to test CSF VZV
Dorsolateral Syndrome IgM/IgG, which may be more
HTLV-I–associated myelopathy and HIV vacuolar myelopathy are examples of sensitive than PCR and can
also be used to confirm the
chronic infectious myelopathies. They affect the dorsal and lateral columns, diagnosis.
producing a syndrome marked by spastic paraparesis and impaired vibration and
joint position sense. ● Small, centrally located
lesions in the spinal cord
may only affect the
HUMAN T-LYMPHOTROPIC CELL VIRUS TYPE I–ASSOCIATED MYELOPATHY/TROPICAL
spinothalamic tract as they
SPASTIC PARAPARESIS. HTLV-I is a human retrovirus associated with two diseases: decussate via the anterior
adult T-cell leukemia/lymphoma and HTLV-I–associated myelopathy (HAM). commissure and produce a
The myelopathy from HTLV-I is also known as tropical spastic paraparesis suspended level of
decreased pain and
because of the geographic regions in which the virus is endemic, although the
temperature sensation
disease can be seen in extratropical locations such as the United States. HTLV-I is roughly two spinal levels
endemic to particular zones of affected regions including southwestern Japan; below the level of the
parts of the Caribbean; South American regions such as Brazil, Colombia, and lesion.
French Guiana; areas of Africa and the Middle East; and Romania.84 Prevalence
● The dorsal column
estimates have ranged from 5 million to 20 million; because HTLV-I can remain syndrome is characterized
subclinical, the true prevalence is uncertain.84 by decreased or absent
The three primary modes of transmission of HTLV-I are vertical (mother to vibration and
child), sexual, and via blood transfusion. Vertical transmission is likely the proprioception below the
level of the lesion with
primary mechanism of spread of HTLV-I; the transmission rate is increased preserved strength, pain,
significantly by breast-feeding compared with bottle-feeding.85 Women are and temperature sensation.
more susceptible to sexual transmission than men.86 Resource-rich countries
such as the United States and Canada screen all blood products for HTLV-I ● Human T-cell
lymphotropic virus type
infection, but this may not occur in more resource-limited settings.
I–associated myelopathy
An estimated 2% of patients infected with HTLV-I develop HAM,87 characterized and HIV vacuolar
by slowly progressive spastic paraparesis over months to years (CASE 4-4).5 Bladder myelopathy often affect the
dysfunction is common as is lower lumbar pain with neuropathic pain in the legs. dorsal and lateral columns
Clinical examination usually demonstrates weakness, spasticity, hyperreflexia, producing a syndrome
marked by spastic
and impaired proprioception in the legs. Early progression may be more rapid with paraparesis and impaired
later progression more chronic, but not all patients follow this pattern.88 The vibration and joint position
prognosis is variable, with some patients remaining mildly symptomatic, whereas sense.
roughly one-third progress to wheelchair use after many years of disease.89 Older
age and higher HTLV-I proviral levels (proportion of mononuclear cells that are
infected) predict a more aggressive course. Although HTLV-I is usually associated
with chronic progressive thoracic myelopathy, some patients may infrequently
have other features, including neuropathy, motor neuron disease, myopathy,
cognitive impairment, or systemic symptoms such as sicca syndrome.

Diagnosis of HAM is made by positive IgG serology in blood and CSF. Because
of the high rate of subclinical infection, especially in endemic regions, positivity
in serology alone is not specific for the clinical disease. When available, proviral
loads can also be measured in both CSF and blood. Typically, the percentage of
HTLV-I–infected cells in the CSF is greater than 10%, and the ratio of CSF to
blood proviral load is greater than 1 in HAM compared with subclinical
infection.90 In a case series of 86 patients, the mean CSF leukocyte count was
8 cells/mm3 and protein was 41.5 mg/dL.91 MRI of the spinal cord is variable
and may be normal or show progressive atrophy of the spinal cord,92,93 dorsal
cord T2 hyperintensity, and gadolinium enhancement.94
At present, no specific therapy is approved for HAM. Care is supportive,
involving physical therapy, regular exercise, consultation with a urologist, and
treatment of spasticity and neuropathic pain. Early in the disease course when
evidence of inflammation may be seen in CSF or on MRI, many patients are
treated with corticosteroids based on modest observational data, although
randomized clinical trials are lacking.95 In a small trial, treatment with the
anti-CCR4 (chemokine receptor type 4) monoclonal antibody mogamulizumab
resulted in a dose-dependent decrease in proviral load along with a reduction in
spasticity and motor disability.96 This promising phase 1-2 study needs to be
replicated in a larger cohort before recommending use. Trials are ongoing with
other agents including raltegravir, cyclosporin, and combination of zidovudine
and lamivudine. These trials are expected to report their results soon and may
change how the disease is treated.
HUMAN IMMUNODEFICIENCY VIRUS. HIV is a retrovirus that targets multiple cell

types including CD4+ T cells, dendritic cells, macrophages, and microglia. HIV
can affect the spinal cord via different mechanisms. The most well-described
spinal cord disease with HIV is vacuolar myelopathy, named for the pathologic
changes seen in the spinal cord: spongiform degeneration affecting the lateral and
posterior columns of the thoracic spinal cord with vacuoles and intravacuolar
macrophages.97 Vacuolar myelopathy is a late manifestation of chronic HIV
infection and usually develops after the onset of acquired immunodeficiency
syndrome (AIDS). The disease is common pathologically in autopsy series, even
in asymptomatic patients, indicating the presence of subclinical disease.
Vacuolar myelopathy associated with AIDS presents with chronic progressive
lower extremity weakness, spasticity, and sensory loss predominantly affecting the
dorsal column pathway. Sensory ataxia is a prominent manifestation, and bowel,
bladder, and sexual dysfunction occur frequently.98 It is important to consider other
causes of chronic, progressive myelopathy, including HTLV-I infection and vitamin
B12 and copper deficiencies, because these can present similarly and are treated
differently. The pathogenesis of vacuolar myelopathy is unclear, but direct viral
invasion is not considered to be the cause. Significant inflammation is not present in
the CSF. MRI may be normal, show isolated cord atrophy, or demonstrate T2
hyperintensity without contrast enhancement.99 The first step is treating HIV with
antiretroviral therapy, and case reports have suggested that suppressing systemic
HIV may improve myelopathy, although this has been debated.100,101 Case reports
have suggested that IVIg is of benefit in vacuolar myelopathy, but no controlled
trials provide more compelling evidence in support of its use.102
Other less common causes of HIV-associated spinal cord injury exist. Direct
infection of the spinal cord with inflammation (HIV myelitis) can be seen on
910 AUGUST 2021

pathology.103 Detailed clinical descriptions of the pathologically observed HIV KEY POINT
myelitis are lacking but likely correlate with clinical case reports of more acute
● Elsberg syndrome is a
myelitis occurring early in the clinical course of HIV.104 Unlike vacuolar presumed infectious
myelopathy, acute HIV myelitis typically has inflammatory CSF with cord signal syndrome defined by acute
changes on MRI. Case reports of motor neuron disease associated with HIV or subacute progressive
exist,105 although it is unclear whether HIV is causative or whether concurrent bilateral lumbosacral
radiculitis or
neurodegenerative motor neuron disease is present.106 Case reports have
myeloradiculitis of the
documented reversal of apparent motor neuron disease with antiretroviral caudal spinal cord and
therapy.105 In patients with HIV developing myelitis after initiation of lumbosacral nerve roots.
antiretroviral therapy, the cause may be immune reconstitution inflammatory
syndrome (IRIS) rather than a primary infection. For further discussion, refer to
the article “Neurologic Complications of Human Immunodeficiency Virus” by
Marie F. Grill, MD,107 in this issue of Continuum.
Conus Medullaris/Cauda Equina Syndrome

Inflammation of the conus medullaris and cauda equina typically presents with
subacute progressive dysfunction of bowel and bladder control, sensory changes
in the lower extremities and perineum, and weakness in the legs. Patients may
experience a subset of these symptoms. Elsberg syndrome is defined by acute or
subacute progressive bilateral lumbosacral radiculitis or myeloradiculitis of the
caudal spinal cord and lumbosacral nerve roots. Aside from infections, other causes
of a lower cord syndrome include structural pathologies such as disk herniation,
vascular malformation, immune-mediated myelitis, and neoplasms. Diagnostic
criteria for Elsberg syndrome have been recently proposed that further subdivide
the diagnostic certainty to clinically definite, probable, and possible categories.108
HERPES SIMPLEX VIRUS. HSV-1 and HSV-2 are linear, double-stranded DNA viruses
that typically cause oral and genital herpes, respectively. After primary infection,
herpesviruses integrate into the cellular genome of the infected dorsal root
ganglia, where they may lie dormant for years but periodically reactivate to
produce cutaneous or neurologic manifestations. HSV-1 and HSV-2 can cause
encephalitis, meningitis, and radiculitis/myelitis. HSV-1 is primarily implicated
in encephalitis.109 HSV-2 can cause recurrent meningitis (Mollaret meningitis)
and lumbosacral radiculomyelitis. Less commonly, HSV-2 can cause myelitis that
may affect the gray or white matter and be longitudinally extensive and
necrotizing in its severest form.110
Radiculomyelitis from HSV can occur during primary infection or
reactivation.111 The combination of urinary retention with numbness or
weakness in the legs with a subacute onset appears to be the most common
presentation.108,112 MRI typically shows T2 hyperintensity in the caudal spinal
cord accompanied by enlargement and smooth contrast enhancement of the
affected nerve roots; a nodular pattern of contrast enhancement suggests an
alternative etiology, such as granulomatous disease or an infiltrative malignancy.
CSF findings can be variable and are likely dependent on the time of sampling in
relation to the start of the syndrome. If sampled early, CSF often shows
lymphocytic pleocytosis with an elevated protein level. CSF HSV PCR is
diagnostic but may be negative if tested outside the optimum window of 3 to
14 days from symptom onset. In such cases, CSF IgM/IgG may be used to
evaluate for intrathecal synthesis of antibodies. The presence of a vesicular
genital rash may be a clue to the diagnosis, and vesicles can also be tested for the

presence of viral DNA. Treatment is based on extrapolation from other forms of

HSV and typically consists of 10 to 14 days of IV acyclovir.111 Some clinicians also
add corticosteroids to acyclovir, but data are limited.
SCHISTOSOMIASIS. Parasitic infections of the spine can be seen in endemic areas or

in travelers returning from endemic regions.113 Flukes of the Schistosoma genus
cause schistosomiasis and are endemic to Central and South America
(Schistosoma mansoni) and sub-Saharan Africa (S. mansoni and Schistosoma
haematobium). Larvae penetrate the skin and travel via hematogenous and
lymphatic spread to the portal circulation where males and females mate and
release eggs that may lodge in the liver, spinal cord, or genitals or be excreted in
the urine and stool. Most cases of schistosomal myelopathy are caused by S.
mansoni and predominantly occur in adolescents and young adults.114 The caudal
spinal cord and cauda equina are most frequently affected. MRI typically shows
T2 hyperintensity in the spinal cord with heterogeneous contrast enhancement
of the spinal cord and nerve roots. Blood or CSF may demonstrate eosinophilia.
CASE 4-5 A 61-year-old woman presented with headaches, vertigo, and painful
truncal paresthesia. She had rheumatoid arthritis treated with rituximab
and mycophenolate mofetil and had also recently been exposed to
glucocorticoids, etanercept, and adalimumab. She lived in Tennessee.
Neurologic examination demonstrated weakness in the upper and
lower extremities, patchy loss of pinprick and vibration without a
convincing spinal level, hyperreflexia in the legs, Babinski sign bilaterally,
and an ataxic gait. MRI demonstrated multiple contrast-enhancing,
masslike lesions throughout the brain, brainstem, and spinal cord
(FIGURE 4-10117). CSF analysis demonstrated 15 nucleated cells/mm3
(lymphocyte predominant), protein elevation to 127 mg/dL, and
hypoglycorrhachia with a CSF glucose level of 30 mg/dL. Histoplasma
antigen from both serum and urine were positive, and she was treated
with liposomal amphotericin B followed by itraconazole with clinical and
radiologic resolution of her infection. She made a full recovery.
COMMENT This case illustrates the importance of a history of immunosuppression as a

risk factor for fungal infection of the central nervous system including the
spinal cord. The patient lived in Tennessee, which is near the confluence of
the Mississippi and Ohio Rivers, where histoplasmosis is endemic. She had
multiple risk factors for histoplasmosis infection, and the CSF profile was
typical of a fungal infection, although hypoglycorrhachia is not always
present. The diagnosis was confirmed with serologies and serum/urine
antigen positivity, indicating disseminated disease. In this context, as well
as with her appropriate response to treatment, biopsy could be avoided.
912 AUGUST 2021

Serum IgM/IgG can suggest infection but are of limited use in endemic areas where
prior infection is common; CSF IgM and IgG provide more convincing evidence in
the appropriate clinical-radiologic context. Identification of parasites in stool is
difficult; even with optimal sample processing, only about 50% of patients will
have positive results. Treatment consists of oral praziquantel and corticosteroids
(which may be slowly tapered over months) to decrease the host inflammatory
response.115
Focal/Multifocal Lesions of the Spinal Cord

Many infectious agents can produce focal or multifocal intramedullary
lesions. Intramedullary spinal cord abscesses are rare and most frequently
monomicrobial with Staphylococcus and Streptococcus species most common.
Tubercular, fungal, or parasitic focal or multifocal spinal cord lesions can be
seen in isolation or in the setting of disseminated disease (CASE 4-5).116 Patients
with intramedullary focal lesions generally present with subacute onset of
myelopathy with or without fever or other systemic symptoms. Diagnosis is
FIGURE 4-10
Disseminated histoplasmosis with encephalomyelitis in the patient in CASE 4-5. A, Sagittal
postcontrast T1-weighted MRI of the cervical and thoracic spine demonstrates round
contrast-enhancing lesions throughout the brainstem and spinal cord (arrows). B, Sagittal
T2-weighted MRI demonstrates T2 hyperintensity associated with the enhancing lesions
(arrows) including longitudinally extensive T2 hyperintensity in the thoracic spinal cord. Axial
postcontrast T1-weighted MRI of the brain demonstrates multiple contrast-enhancing lesions
throughout the brain parenchyma (C, arrows) associated with T2 hyperintensity (D, arrows).
Modified with permission from Bradshaw MJ, et al, Rheum Dis Clin North Am.117 © 2017 Elsevier Inc.

based on MRI evidence of one or more intramedullary T2-hyperintense

lesions with ring enhancement. Whether all patients need abscess aspiration
or whether antimicrobial therapy alone is adequate is unclear because of the
rarity of the condition, but aspiration is often necessary for precise diagnosis
(ie, to distinguish abscess from neoplasm and for microbiological diagnosis).
Many patients with intramedullary infections are left with residual deficits
even when radiologic resolution is observed after antimicrobial treatment.
NEUROCYSTICERCOSIS. Taenia solium is endemic to Central and South America,

sub-Saharan Africa, and South/Southeast Asia. Human gastrointestinal
tapeworm infection is typically via ingestion of undercooked pork, whereas
fecal-oral ingestion of eggs can lead to hematologic dissemination of larvae,
which can encyst and remain viable for years in host tissues unrecognized by the
immune system. Eventually, cysts begin to degrade and are recognized by the
host immune system, which leads to inflammation, including perivascular
lymphocytic infiltration and edema. Most CNS cysts are located in the brain
parenchyma, and focal neurologic deficits and seizures are common clinical
manifestations. Neurocysticercosis rarely involves the spinal cord,
predominantly affecting the subarachnoid space, although intramedullary cysts
can rarely develop.118 CSF analysis may demonstrate elevated protein, but
eosinophilia has not been common in the experience of the authors of this article.
The diagnosis is established with MRI demonstrating typical findings of
neurocysticercosis coupled with positive serologies. Spinal neurocysticercosis
is treated with albendazole and corticosteroids and may require surgical
decompression.
TOXOPLASMOSIS. Toxoplasma gondii is a ubiquitous obligate intracellular

protozoan parasite that most often causes an asymptomatic infection.
Reactivation of dormant cysts or primary infection in individuals who are
immunocompromised (eg, HIV and CD4+ count less than 100 cells/mm3) can
produce life-threatening disease including severe neurologic illness. Single or
multifocal brain lesions are the most common presentation, although
involvement of the spinal cord rarely occurs and is most often concomitant with
brain involvement.119 In a review of the literature including 26 cases, García-
García and colleagues119 found that neurologic manifestations most often
included limb weakness (91%), sensory loss (68%), sphincter dysfunction (54%),
and abnormal deep tendon reflexes (50%) whereas fever was present in only 36%
of patients. Although 88% of patients had known HIV, most were not adequately
treated with antiretrovirals and toxoplasmosis prophylaxis. Spinal toxoplasmosis
was the presenting manifestation of AIDS in 11% of patients, and clinical
manifestations evolved over a subacute-chronic temporal profile ranging from
days to 6 months. Most patients had serologic evidence of toxoplasmosis
exposure, and CSF analysis typically demonstrated mild mononuclear
pleocytosis with normal glucose. MRI most often revealed contrast-enhancing
lesions and/or T2 hyperintense lesions in the spinal cord, most commonly
thoracic; 65% of patients had both brain and spinal cord involvement. Although
definitive diagnosis requires biopsy, empiric treatment based on the clinical and
radiologic picture with repeat imaging to evaluate for resolution is a common
initial strategy.120 If CSF analysis is feasible, evaluation for alternative etiologies
can be performed, and toxoplasmosis PCR has a modest sensitivity (16% to 98%
914 AUGUST 2021

depending on the primers used), but high specificity and, when positive, can KEY POINT
confirm the diagnosis.121–123 Treatment consists of 6 weeks
● In toxoplasmosis,
of sulfadiazine and pyrimethamine to which leucovorin is added to prevent involvement of the spinal
pyrimethamine-induced hematologic toxicity; alternative regimens include cord rarely occurs and is
trimethoprim/sulfamethoxazole.124,125 Corticosteroids are reasonable to include most often concomitant
when mass effect is present in the brain and/or spinal cord, although they should with brain involvement.
be avoided to prevent lowering the yield of biopsy if it is ultimately needed
because primary CNS lymphoma is the principal differential diagnosis. After
completing the initial treatment phase, lower-dose pyrimethamine/sulfadiazine
or an alternative regimen such as trimethoprim/sulfamethoxazole is continued
to prevent recurrence.125
CONCLUSION
A myriad of infectious agents including bacteria, viruses, fungi, and parasites can
produce infection of the spine and spinal cord. Infections can present with
progressive pain or myelopathy that are not necessarily accompanied by signs of
systemic infection. Laboratory data including microbiological studies from
serum and CSF are important in establishing the diagnosis. Imaging, particularly
MRI, can assist with identifying patterns of disease, which, combined with the
clinical context, may indicate the most likely organisms to consider. Treatment
involves antimicrobials (with steroids for certain conditions) and, in some cases,
neurosurgical decompression.
ACKNOWLEDGMENTS
The authors would like to thank Karen Bloch MD, MPH, and Mark Piedra, MD,
for their thoughtful review of the manuscript.
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doi:10.4103/aian.AIAN_255_18
116 Berkowitz AL, Raibagkar P, Pritt BS, Mateen FJ.
103 Hénin D, Smith TW, De Girolami U, et al. Neurologic manifestations of the neglected
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117 Bradshaw MJ, Cho TA, Chow FC. Central
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doi:10.1186/1471-2334-14-149
118 Alsina GA, Johnson JP, McBride DQ, et al.
105 MacGowan DJ, Scelsa SN, Waldron M. An Spinal neurocysticercosis. Neurosurg Focus
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119 García-García C, Castillo-Álvarez F,
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Azcona-Gutierrez JM, et al. Spinal cord
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encephalitis in patients with the acquired Neurotoxoplasmosis diagnosis for HIV-1
immunodeficiency syndrome. N Engl J Med patients by real-time PCR of cerebrospinal fluid.
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NEJM199309303291403 s1413-86702009000100006
121 Lamoril J, Molina JM, de Gouvello A, et al. 124 Katlama C, De Wit S, O'Doherty E, et al.
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1346-1349. doi:10.1128/AAC.42.6.1346
920 AUGUST 2021

Infections of the REVIEW ARTICLE
Peripheral Nervous

C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
System
ONLINE
Downloaded from http://journals.lww.com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4Xuj38PhBKDAOyxDHbtzda8GcSY+/55EVFiOmihz5M3Qo0o= on 09/03/2021
By Samantha LoRusso, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes infections that affect the peripheral
nervous system, including their clinical features, differential diagnoses,
and treatments.
RECENT FINDINGS: Rates of pyomyositis have increased recently in the

United States, possibly because of an increase in risk factors such as IV
drug use, obesity, and diabetes. Other peripheral nervous system infections,
such as diphtheria, have become more common in older patients secondary
to a lack of revaccination or waning immunity. Although recommended
treatment regimens for most infections remain unchanged over recent
years, debate over the ideal dosing and route of administration continues for
some infections such as tetanus and leprosy (Hansen disease).
SUMMARY: Infections of the peripheral nervous system are varied in terms of

the type of infection, localization, and potential treatment. Nerve
conduction studies and EMG can help determine localization, which is key
to determining an initial differential diagnosis. It is important to recognize
infections quickly to minimize diagnostic delays that could lead to patient CITE AS:
morbidity and mortality. C O N T I N U U M ( M I N N E A P M I NN )
2021;27(4 , N E U R O I NF E C T I O U S
D I S E A S E ) : 9 2 1 – 9 4 2.
INTRODUCTION Address correspondence to
A
Dr LoRusso, 10240 Park
lthough infections of the peripheral nervous system (PNS) are
Meadows Dr,
rare,1 it is important for neurologists to be able to recognize their Lone Tree, CO 80124,
clinical manifestations because many are treatable. Some infections Samantha.X.LoRusso@kp.org.
affect only one component of the PNS (eg, botulism affects the RELATIONSHIP DISCLOSURE:
neuromuscular junction), whereas other infections can affect one Dr LoRusso has received a
or more levels of the PNS (eg, Lyme disease can cause radiculitis, cranial research education grant from
the National Institute of
neuropathy, or peripheral neuropathy). This article is organized by anatomic Neurological Disorders and
level of the PNS from proximal to distal: infections that primarily affect the Stroke (NeuroNext Fellowship;
anterior horn cells are discussed first, followed by those that affect the root or 5U24NS107205-03).
plexus, peripheral nerves, neuromuscular junction, and muscle. TABLE 5-1 lists UNLABELED USE OF
important infections categorized by localization within the PNS.2-4 TABLE 5-2 PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
highlights key clinical features of more common infections of the PNS. Dr LoRusso reports no
disclosure.
INFECTIONS OF THE ANTERIOR HORN CELLS
Several viruses cause inflammation of the anterior horn cells of the spinal cord © 2021 American Academy
gray matter, leading to a phenotype of acute flaccid paralysis. of Neurology.

INFECTIONS OF THE PERIPHERAL NERVOUS SYSTEM
Poliovirus is the prototypical disease in this category but is now fortunately

rare as vaccination has led to near-global eradication. Only 175 cases were
reported in 2019, mainly from Pakistan and Afghanistan.5 West Nile virus is now
the most common viral cause of acute flaccid paralysis in adults in the
United States.1 Enterovirus 71 and D68, Japanese encephalitis virus, dengue, and
tick-borne encephalitis can also affect anterior horn cells.2 Rabies can also rarely
present as a paralytic disease.1 With all of these infections, the presentation tends
to be acute, and the presence of meningoencephalitis in addition to flaccid
weakness is typical but not always present. A 2018 case report describes two
patients with West Nile virus who presented only with facial palsy and arm
TABLE 5-1 Differential Diagnosis of Infectious Conditions of the Peripheral Nervous

System by Level of the Neuraxisa
Localization or syndrome Causative organisms

Anterior horn cell2 West Nile virus, polio, Japanese encephalitis virus, St. Louis encephalitis virus,
Powassan virus, tick-borne encephalitis virus, enterovirus 71, enterovirus D68, rabies;
human immunodeficiency virus (HIV) and human T-cell lymphotropic virus type I (HTLV-I)
can cause motor neuron disease affecting both lower and upper motor neurons
Radiculopathy or plexopathy Lyme disease, cytomegalovirus (CMV), HIV, herpes simplex virus (HSV), varicella-zoster
virus (VZV), tuberculosis, cryptococcus, syphilis, schistosomiasis, spinal epidural
abscess, cysticercosis, Epstein-Barr virus (EBV), nocardiosis, brucella, dengue fever
Cranial neuropathy Leprosy, syphilis, HIV, Lyme disease, COVID-19, tuberculosis, cryptococcus, brucella,
HSV, hepatitis B virus, hepatitis C virus, VZV, West Nile virus, EBV; notably, botulism and
diphtheritic neuropathy may initially present with multiple lower cranial neuropathies
Mononeuropathy or multiple Leprosy, HIV, Lyme disease, hepatitis C virus, hepatitis B virus, CMV, VZV, rarely EBV or
mononeuropathies tuberculosis
Axonal polyneuropathy Leprosy, HIV, Lyme disease, HTLV-I, hepatitis B virus, hepatitis C virus, Chagas disease,
Whipple disease, dengue fever
Demyelinating neuropathy Diphtheria, possibly Lyme disease; associated with chronic inflammatory
demyelinating polyradiculoneuropathy: HIV, hepatitis B virus, hepatitis C virus, HTLV-I;
associated with Guillain-Barré syndrome: Campylobacter jejuni, CMV, EBV,
Mycoplasma pneumoniae, influenza, hepatitis A virus, hepatitis B virus, hepatitis C
virus, hepatitis E virus, HIV, COVID-19, dengue fever, Zika virus
Sensory neuronopathy3 HIV, VZV, EBV, HTLV-I, Zika virus, enterovirus
Peripheral autonomic dysfunction4 Chagas disease, HIV, HTLV-I, leprosy, Lyme disease, diphtheria, botulism
Motor nerve hyperexcitability Tetanusb
Neuromuscular junction Botulism

2
Myopathy Acute viral myositis: influenza, coxsackievirus, parainfluenza, hepatitis B virus, hepatitis
C virus, COVID-19, adenovirus, EBV, CMV, HSV, dengue fever; subacute or chronic viral
myositis: HIV, HTLV-I; related to pyomyositis: Staphylococcus aureus, streptococci,
Escherichia coli, Legionella; parasitic myositis: toxoplasmosis, Sarcocystis,
trypanosomiasis, cysticercosis, trichinosis; other bacterial and fungal myositis: Lyme
disease, Candida, Cryptococcus, sporotrichosis, actinomycosis, histoplasmosis
a
This table is not an exhaustive list of all possible infections affecting a particular localization.
b
Tetanus affects motor nerves, but the toxin also travels from motor nerves into the central nervous system.
922 AUGUST 2021

weakness.6 Sensory symptoms in these cases are often absent because of the KEY POINTS
anterior horn cell localization. When the presentation of motor neuron disease is
● Although infections of the
more chronic, human immunodeficiency virus (HIV) and human T-cell peripheral nervous system
lymphotropic virus type I (HTLV-I) should be considered because these can are rare, it is important for
present similarly to amyotrophic lateral sclerosis, although these infections are neurologists to be able to
not usually associated with concurrent encephalitis as in arbovirus infection. recognize their clinical
manifestations because
The most typical electrodiagnostic pattern in infectious motor neuron disease
many are treatable.
is similar to noninfectious motor neuron disease with low compound muscle
action potential (CMAP) amplitudes, normal velocities, normal sensory nerve ● West Nile virus is now the
action potential (SNAP) amplitudes, and reduced recruitment. Abnormal most common viral cause of
spontaneous activity is also likely to be seen after 2 to 3 weeks.7 acute flaccid paralysis in
adults in the United States.
INFECTIONS OF THE NERVE ROOTS OR PLEXUS ● One of the most common

Radiculopathy and polyradiculopathy secondary to infection are much more infectious causes of
common than plexopathy. One of the most common infectious causes of radiculopathy is Lyme
disease.
radiculopathy is Lyme disease.8 Clinically, Lyme disease can present similarly to
a structural radiculopathy with radiating pain, numbness, and tingling, and
sometimes weakness in a nerve root distribution.8 In addition to the presence of a
preceding rash (classically erythema migrans with a targetlike appearance), clues
to the diagnosis are enhancing nerve roots (but only 3 of 66 patients had this in
one neuroborreliosis series9) and no clear structural cause on MRI.8 CSF may
reveal a lymphocytic pleocytosis or only elevated protein but can be normal.10
For more details, refer to the article “Neurologic Complications of Lyme Disease”
by Karen Roos, MD,11 in this issue of Continuum.
Varicella-zoster virus (VZV) may also have a similar radicular presentation,
but the preceding rash is different from that of Lyme disease. The rash associated
with VZV is dermatomal, vesicular, and painful. Infection most frequently affects
the thoracic dermatomes, which may be a clue to the diagnosis.2 Weakness in the
distribution of the affected nerves or nerve roots (including the face, when
involved) occurs in a minority of patients and tends to improve over time.2 If the
diagnosis is unclear and especially if CSF is obtained after 14 days in the disease
course, VZV IgG may be compared in the serum and CSF to evaluate for
intrathecal production. Although the sensitivity of VZV IgM in the CSF is low, if
present this is suggestive of an active CNS infection.12 Polymerase chain reaction
(PCR) for VZV DNA should also be sent in the CSF but also has low sensitivity.1
Nerve root enhancement may be seen on MRI as well as concomitant spinal cord
lesions consistent with myelitis.12 VZV radiculitis is generally treated with
acyclovir.13
In addition to VZV, other herpesviruses including herpes simplex virus type 1
(HSV-1) and type 2 (HSV-2) and cytomegalovirus (CMV) can also present as a
radiculopathy. HSV-2, which causes genital herpes, can lead to an acute
lumbosacral radiculitis (Elsberg syndrome); this is thought to be a reactivation
syndrome, which usually presents with acute urinary retention, constipation,
and saddle sensory disturbance.1 Genital ulcers may or may not be present at the
time of presentation. MRI of the lumbosacral spine may show smooth nerve root
enhancement, and EMG usually shows evidence of radiculopathy.12 As with
VZV, HSV-2 PCR and HSV antibodies should be sent from the CSF but have low
sensitivity, so the diagnosis is often made on clinical grounds with supportive
MRI findings or EMG findings or both.12 Acyclovir may help shorten the course
of HSV-2 radiculitis, but recurrent disease can occur.1 CMV can cause a

lumbosacral polyradiculopathy in immunocompromised individuals,

particularly in patients with HIV.13 MRI often shows enhancement of the
cauda equina, a polymorphonuclear pleocytosis (mean white blood cell count,
651 cells/mm3), and an elevated protein level.14,15 Positive CMV PCR in the CSF is
diagnostic (sensitivity 92%), but evidence of CMV infection elsewhere (eg,
retinitis, colitis) is also supportive of the diagnosis.1 Ganciclovir and foscarnet
TABLE 5-2 Infections of the Peripheral Nervous System and Key Diagnostic Clues
Infectious disease Clinical clues
Botulism Cranial nerve dysfunction including pupillary reaction dysfunction, limb weakness, gastrointestinal
symptoms
Presynaptic neuromuscular junction transmission defect on EMG without neurogenic changes
Food contamination, drug use
Chagas disease Autonomic dysfunction
Cardiomyopathy and cardiac arrhythmia
Megacolon, megaesophagus
Cardioembolic stroke
From Latin America
Diphtheria Acute demyelinating neuropathy with cranial nerve dysfunction followed by limb weakness (biphasic
course), accommodation dysfunction, myocarditis
Preceding pharyngitis, cervical lymphadenopathy
Lack of vaccination
Hepatitis B virus Mononeuropathy or mononeuropathy multiplex
Polyarteritis nodosa
Elevated liver function tests
Risk factors: human immunodeficiency virus (HIV) infection, high-risk sexual behavior, IV drug use, lack
of vaccination, blood transfusion, hemodialysis, health care worker
Hepatitis C virus Mononeuropathy or mononeuropathy multiplex; distal axonal neuropathy, may be asymmetric
Cryoglobulinemia, elevated liver function tests
Risk factors: IV drug use, HIV infection, blood transfusion, tattoos, high-risk sexual behavior,
hemodialysis, health care worker
Leprosy Rash or other skin lesions associated with numbness
Enlarged, palpable nerves
Mononeuropathies, particularly at superficial sites including facial palsy; may appear as compression
neuropathies
Length-dependent sensorimotor neuropathy
From Brazil, Southeast Asia, Africa, Southern United States or armadillo exposure
CONTINUED ON PAGE 925
924 AUGUST 2021

can be used to treat CMV, but most patients with a CMV-related
polyradiculopathy will have residual deficits.13
Mycobacterium tuberculosis, like the infections discussed earlier, can cause a
radiculopathy due to vertebral compression from Pott disease (or a myelopathy
depending on the location) or arachnoiditis with a predilection for the cauda
equina.16-19 Tuberculosis is a special concern in patients who are
CONTINUED FROM PAGE 924
Infectious disease Clinical clues
Lyme disease Facial palsy or polyradiculopathy (EMG usually with preganglionic pattern); erythema migrans
Tick exposure
Northeast United States
Pyomyositis Focal muscle pain, edema, fever, especially in quadriceps
Risk factors: male sex, younger age, IV drug use, diabetes, trauma
Tetanus Painful muscle spasms and rigidity; trismus, risus sardonicus, opisthotonus
Recent wound, lack of vaccination, IV drug use
Trichinosis Fever, gastrointestinal symptoms, periorbital and facial edema
Ingestion of poorly cooked meat, especially pork
Eosinophilia
Varicella-zoster virus Thoracic radiculopathy
Vesicular rash in dermatomal pattern
Older or immunosuppressed
West Nile virus Flaccid paralysis, lack of sensory changes
Meningoencephalitis
EMG with preganglionic/motor neuron pattern
T2 hyperintensities on MRI, especially in anterior horn cells; nerve root enhancement
Late summer
EMG = electromyography; IV = intravenous; MRI = magnetic resonance imaging.

immunocompromised or in a high-risk population, such as those who are

incarcerated or from an endemic area. For more details, see the article
“Neurologic Complications of Tuberculosis” by Deanna Saylor, MD, MHS,20 in
INFECTIONS OF THE PERIPHERAL NERVES

The specific pattern of peripheral nerve involvement can be helpful in
identifying the most likely infectious process. Therefore, this section is
divided into infectious causes of cranial neuropathy, mononeuropathy or
mononeuropathy multiplex, length-dependent axonal neuropathy, and
demyelinating neuropathy.
Cranial Neuropathy
Many infections can present with a cranial neuropathy, in isolation, as part of
a generalized peripheral neuropathy, or due to meningeal infection. Leprosy
(Hansen disease) and diphtheria are both examples of infections that can present as
a cranial neuropathy because of their direct effect on peripheral nerves. Leprosy
typically presents with multiple mononeuropathies and skin changes, whereas
diphtheria tends to affect lower cranial nerves first and is followed by diffuse limb
weakness (see the following sections for more detailed discussions of both
infections). Botulism, although technically a disorder of the neuromuscular
junction, can also first present as multiple cranial neuropathies with a poor pupillary
response being a fairly unique finding (see the Botulism section for more details
about the clinical presentation and clues to this diagnosis). Lyme disease may cause a
cranial neuropathy, most commonly affecting cranial nerve VII, causing peripheral
pattern facial palsy. Cranial neuropathy secondary to cryptococcus, tuberculosis,
and syphilis is thought to be secondary to meningeal disease.
The facial nerve is the cranial nerve that is one of the most commonly affected
in infectious conditions. In a retrospective study of 380 patients with facial palsy,
25% of cases were secondary to infection; of these, Lyme disease (49%), VZV
(26%), and HSV (14%) were the most common infectious agents.21 In a series of
43 patients with bilateral seventh nerve palsy, five cases were secondary to
infection: two secondary to syphilis, one due to leprosy, one due to cryptococcal
meningitis in a patient with HIV, and one due to tuberculous meningitis.22
When infectious causes of one or more cranial neuropathies are considered, it
is important to take a thorough history to identify risk factors for certain
infections (eg, tick exposure in Lyme disease or coming from a leprosy-endemic
area) and perform a thorough examination to look for other signs of systemic
disease. Certain clinical features may help point to an infectious cause, such as
the presence of skin findings, such as vesicular dermatomal rash (VZV), target
rash (Lyme disease), and hypopigmented lesions (leprosy). The presence of
fever, headache, or meningismus should raise suspicion for meningitis as a cause
of cranial neuropathy. However, in one study about 50% of patients with a
unilateral facial palsy determined to be from an infectious source did not have
any unique clinical features differentiating it from an idiopathic Bell’s palsy.21
When evaluating a patient with facial palsy or other cranial neuropathy of
unclear etiology, serum Lyme antibody testing, CSF analysis, or MRI of the brain
can be considered, particularly when an infectious cause is suspected.21,23 If a
disorder such as leprosy, diphtheria, or botulism is suspected, or if findings on
examination (eg, reduced extremity sensation or reflexes, flaccid weakness)
926 AUGUST 2021

suggest a more diffuse PNS process, then nerve conduction studies and EMG KEY POINTS
should be performed (usually in addition to CSF analysis).
● If the presentation is a
mononeuropathy or multiple
Mononeuropathy or Mononeuropathy Multiplex mononeuropathies, then
Infectious causes of mononeuropathy and mononeuropathy multiplex include leprosy, hepatitis B and C
leprosy, hepatitis B and C viruses, Lyme disease, HIV, and CMV. When leprosy viruses, Lyme disease,
human immunodeficiency
and hepatitis affect the PNS, a presentation of mononeuropathy multiplex is virus (HIV), and
common (although they can also cause polyneuropathy), whereas Lyme disease, cytomegalovirus should be
HIV, and CMV rarely cause mononeuropathy multiplex. Therefore, leprosy and considered.
hepatitis are the focus of this section.
● Leprosy is predominantly
a disease of the peripheral
LEPROSY (HANSEN DISEASE). Leprosy is a chronic infectious disease caused by the nerves and skin and is still a
acid-fast bacteria Mycobacterium leprae or, less often, by Mycobacterium common cause of
lepromatosis.24 It is predominantly a disease of the peripheral nerves and skin and neuropathy in Southeast
is still a common cause of neuropathy in Southeast Asia, South America, and Asia, South America, and
Africa.
Africa.2 In contrast, leprosy is rare in the United States with fewer than 200 new
cases in 2018.25 Patients who have immigrated to the United States account for
the majority of cases, but endemic cases do occur in the southern United States.26
Droplet spread is likely the main mode of transmission,27 but disease
transmission is not fully understood. Armadillos are an animal reservoir and may
transmit the disease to humans.28,29 The incubation period is typically about
5 years, but the majority of people infected develop immunity and thus do not
develop clinical symptoms.29 Immunocompromise, low socioeconomic status,
genetic factors, and close contact with someone who has a high bacterial load all
likely contribute to the risk of developing disease.25,29-31 Bacille Calmette-Guérin
(BCG) vaccination may be at least partly protective.32
CLASSIFICATION OF LEPROSY. When clinical symptoms do occur, they include a

range of skin findings, types of neuropathy, ocular complications, bone changes,
and mucosal lesions. The variation in clinical findings depends in large part on
the cell-mediated immune response of the infected person.2,25 Two classification
schemes are used to describe the spectrum of clinical manifestations: the
Ridley-Jopling system33 and the World Health Organization (WHO)
classification.34 The Ridley-Jopling system uses a combination of clinical
findings, histopathology, and bacterial load to place patients within one of five
categories covering the spectrum of disease. Those with preserved cellular
immune response fall within the category of tuberculoid leprosy on one end of
the spectrum, whereas those with poor cellular immune response fall within the
lepromatous leprosy category on the opposite end of the spectrum.35 The WHO
classification is simpler, being divided into paucibacillary (roughly correlates to
tuberculoid leprosy) and multibacillary disease (correlates to lepromatous leprosy)
based on the number of skin lesions or skin smear findings. Paucibacillary
leprosy is indicated by one to five skin lesions and multibacillary leprosy by six
or more skin lesions.36 Because of its simplicity, this binary WHO classification
scheme has traditionally been used to determine the treatment regimen.
CLINICAL MANIFESTATIONS. Skin findings are often a clue to the diagnosis but are
variable in type and appearance. Skin changes can include hypopigmented or
erythematous patches or plaques (FIGURE 5-137), as well as nodular, ulcerated,
or edematous lesions.38 Notably, however, skin lesions may be absent in up

to 10% of patients with

leprosy-associated neuropathy,
so the absence of dermatologic
findings does not exclude the
diagnosis.35 Anesthesia may be
present within a skin lesion. The
organism commonly infiltrates
the face causing a variety of
classic features including
thickened skin, exaggeration of
skin folds, loss of eyebrows, and
saddle nose.2
Nerve damage is common,
with one study showing that at
least 66% of patients had nerve
injury at some point during their
disease.39 The mechanism is not
FIGURE 5-1 entirely understood; acid-fast
Multiple hypopigmented macules with associated bacilli may invade and modify
anesthesia in a patient with leprosy. Schwann cells, leading to an
Reprinted with permission from White C and
Franco-Paredes C, Clin Microbiol Rev.37 © 2015 American
inflammatory response.35 The
Society for Microbiology. most common types of
neuropathy in leprosy are
mononeuropathy (including
cranial neuropathy ), multiple mononeuropathies (CASE 5-1), or a generalized
40
length-dependent polyneuropathy.35 Mononeuropathies may be more common

when cell-mediated immunity is preserved, whereas a length-dependent
sensorimotor polyneuropathy may be more common when cell-mediated
immunity is impaired. The most common sites of mononeuropathy include the
greater auricular nerve, the ulnar nerve at the elbow, the median nerve proximal
to the carpal tunnel, the superficial radial nerve at the wrist or radial nerve at the
spiral groove, the fibular (peroneal) nerve at the fibular head, the facial nerve,
and the sural nerve.2,26 Mononeuropathy can present acutely and may rarely be
confused with stroke.41 Pain, paresthesia, or pruritis in the distribution of the
affected nerve may be present initially, as well as weakness depending on the
nerve affected.26 On physical examination, affected nerves are often enlarged
and palpable.2 When a symmetric polyneuropathy occurs, small fiber modalities
are usually reduced early, whereas position and vibration sensations are usually
normal except in severe cases. Along with this, reflexes usually remain intact
until late in the disease course.26,42
DIAGNOSIS AND TREATMENT. The differential diagnosis depends on the presenting

symptoms and nerve conduction study findings. Nerve conduction studies are
variable and may demonstrate an axonal, demyelinating, or mixed pattern. If the
nerve conduction studies appear as multiple compression neuropathies (such as
in CASE 5-1; eg, median neuropathy at the wrist, ulnar neuropathy at the elbow),
then considerations may include diabetes, hereditary neuropathies such as
hereditary neuropathy with liability to pressure palsy, or amyloidosis (especially
hereditary transthyretin amyloidosis or wildtype transthyretin amyloidosis). If
multifocal demyelination is seen, then multifocal acquired demyelinating
928 AUGUST 2021

sensory and motor neuropathy (MADSAM) may be a consideration. If multiple KEY POINTS
axonal mononeuropathies are present that are not located at common sites of
● Common sites of
compression, then a vasculitic neuropathy should be considered, especially if mononeuropathy in leprosy
pain is a prominent feature. include the greater auricular
Definitive diagnosis of leprosy is made by skin or nerve biopsy showing nerve, the ulnar nerve at the
acid-fast bacilli (FIGURE 5-3). However, bacteria may not be found, particularly elbow, the median nerve
proximal to the carpal
in tuberculoid leprosy, in which case diagnosis can be made by histologic tunnel, the superficial radial
features such as well-organized granulomas with dense foci of lymphocytes.43 nerve at the wrist or radial
M. leprae PCR measured in biopsy samples may be useful to support the nerve at the spiral groove,
diagnosis when atypical clinical or histologic features are present.26,44 Treatment the fibular (peroneal) nerve
at the fibular head, the facial
of leprosy involves multidrug therapy with dapsone, rifampin, and sometimes nerve, and the sural nerve.
clofazimine over a prolonged period (6 to 24 months).45 Type 1 immune-
mediated reactions, or reversal reactions, can worsen skin lesions or cause ● Peripheral neuropathy is
further nerve injury. High-dose corticosteroids, given either prophylactically or thought to occur in about
10% of patients with
after clinical worsening, have been the mainstay of treatment.46-48 Type 2
hepatitis C virus and may be
mediated reactions, or erythema nodosum leprosum, is another the presenting symptom.
treatment-related reaction characterized by erythematous, painful,
subcutaneous nodules that can be associated with worsening neuropathy or other
manifestations. The treatment is also with corticosteroids, although thalidomide
and clofazimine are often used as well.46-48 Overall, because of the complexity of
treatment options and potential for serious treatment-related reactions,
consultation with an infectious disease specialist or dedicated leprosy center
should be considered.49
HEPATITIS B AND C. Hepatitis viruses are associated with a mononeuropathy

multiplex or length-dependent neuropathy. Peripheral neuropathy is thought to
occur in about 10% of patients with hepatitis C virus50 and may be the presenting
symptom.51 In a study of 30 patients with neuropathy related to hepatitis C virus,
83% had a distal axonal sensory or sensorimotor polyneuropathy phenotype
(symmetric or slightly asymmetric), 10% had a mononeuropathy multiplex, and
about 7% had a demyelinating polyneuropathy.52 Pain was a clinical feature in the
majority of patients. On physical examination, distal motor weakness was
observed in 6 of 25 patients with a distal polyneuropathy. A mixed
cryoglobulinemia was found in 63% of patients, and nerve biopsy revealed
evidence of vascular inflammation in 87%.50 The treatment of peripheral nerve
vasculitis associated with hepatitis C virus is focused on the treatment of the
hepatitis C virus infection, although some providers add rituximab.52,53 The use of
other immunomodulatory treatments such as plasma exchange may also be
helpful, but data on its use are limited.2
Hepatitis B virus has also been associated with neuropathy, particularly
vasculitic neuropathy and rarely chronic inflammatory demyelinating
polyradiculoneuropathy.54,55 As with hepatitis C virus, neuropathy may be the
initial manifestation of hepatitis B virus infection, but the exact incidence of
this is not known.56 The association of hepatitis B virus with vasculitic
neuropathy is related to the association of hepatitis B virus and polyarteritis
nodosa with 33% of polyarteritis nodosa cases associated with hepatitis B
antigenemia.57 Polyarteritis nodosa is a small and medium vessel necrotizing
vasculitis associated with mononeuritis multiplex, arthralgias, skin lesions,
liver and kidney failure, abdominal pain, and gastrointestinal bleeding.54 Of
note, polyarteritis nodosa is also less commonly associated with hepatitis C

virus and HIV (and mixed cryoglobulinemia can also less commonly be
associated with hepatitis B virus and HIV). Rarely, a mononeuritis multiplex
associated with hepatitis B virus infection has been reported in the absence of
polyarteritis nodosa.54 For the treatment of hepatitis B virus–related
vasculitis, the use of an antiviral, a 2-week course of corticosteroids, and
plasma exchange may be considered.58
Length-Dependent Axonal Polyneuropathy

Infectious causes of length-dependent axonal sensory or sensorimotor
polyneuropathy include HIV, hepatitis C virus, leprosy, and HTLV-I. This type
of neuropathy is the most common peripheral manifestation of HIV, but it is still
important to rule out other common causes of peripheral neuropathy in patients
with HIV59; for more details, refer to the article “Neurologic Complications of
Human Immunodeficiency Virus” by Marie F. Grill, MD,60 in this issue of
Continuum. Lyme disease has also been cited to cause a chronic, distal,
CASE 5-1 A 60-year-old man presented for neurologic evaluation of 3 years of

bilateral hand numbness. He was originally from Thailand but had been
living in the United States for more than 5 years. A nerve conduction study
and EMG had been performed at the time of his initial presentation to a
physician 3 months after his symptoms began, which showed a right ulnar
neuropathy at the elbow and bilateral carpal tunnel syndrome, which led
to bilateral carpal tunnel release surgery and right cubital tunnel surgery.
About 3 months after the surgery, he noticed increased weakness of his
right hand and a new nonhealing blister on his right index finger. A biopsy
of the skin lesion was performed but was indeterminate. Then, about
1 year after the surgery, he developed a new rash on his face and one on
his left foot, both erythematous plaques associated with numbness. Soon
after developing these symptoms, he visited Thailand where a biopsy of
his earlobe was consistent with leprosy. He was then treated with
multidrug therapy and ultimately seen in neurologic consultation in a
subspecialty neuromuscular clinic for evaluation of continued hand
weakness despite treatment.
Skin examination showed multiple erythematous plaques on his
face with associated numbness and cutaneous nodules on the dorsum
of his hands, most notable on the right thumb (FIGURE 5-2). Neurologic
examination showed 5/5 strength throughout except in his hands
where his strength was 3/5 to 4/5 but weaker on the right. He had distal
loss to pinprick sensation in his hands and feet in a length-dependent
pattern, but vibration sensation remained intact. Reflexes were 2+
throughout.
Repeat nerve conduction studies and EMG showed absent sensory
responses throughout, including in bilateral sural nerves and superficial
radial nerves. The right ulnar motor response was absent, and the left
ulnar motor response had a low compound muscle action potential
930 AUGUST 2021

symmetric, axonal polyneuropathy, although some authors question the
association given the quality of evidence.61 Epidemiologic context, as well as systemic
and dermatologic findings, may suggest when to consider an infectious cause of
length-dependent axonal neuropathy. However, even in the context of a known
infection that could cause a peripheral neuropathy, it is important to evaluate for
more common causes of neuropathy such as diabetes and vitamin B12 deficiency.
Demyelinating Neuropathy
Many infections lead to parainfectious or postinfectious demyelinating
neuropathy (ie, Guillain-Barré syndrome). Infections (eg, HIV, hepatitis B virus,
hepatitis C virus, HTLV-I) have also been associated with chronic inflammatory
demyelinating polyradiculoneuropathy, but this is thought to occur because
of postinfectious inflammatory mechanisms rather than directly from the
infection. Diphtheria can cause a demyelinating neuropathy with a unique
biphasic course and is the focus of this section.
(CMAP) amplitude and slow conduction

velocity (30 m/s in the forearm and
20 m/s across the elbow). The right
median motor response showed a
prolonged distal motor latency, normal
CMAP amplitude, and slow conduction
velocity (42 m/s). Bilateral fibular
(peroneal) motor responses were
normal. Needle EMG was normal with
the exception of abnormal
spontaneous activity and chronic
FIGURE 5-2
Photo of the hands of the patient
neurogenic changes in bilateral ulnar
in CASE 5-1. Cutaneous nodules innervated muscles, reflecting residual
present on the dorsum of his hands, deficits. His residual deficits were felt
particularly notable at the right thumb to be due to his longstanding leprosy,
with associated deformity. First
dorsal interosseous atrophy is also
for which appropriate treatment had
notable in his right more than already been completed. Occupational
left hand. therapy was recommended.
Multiple entrapment neuropathies with associated skin lesions in a patient COMMENT

from an endemic area were clues to the diagnosis of leprosy. This case
illustrates the diagnostic delay that can often occur with leprosy,
particularly in the United States where it is no longer commonly seen.
Unfortunately, this patient had permanent nerve damage despite
completing multidrug therapy, which highlights the importance of early
diagnosis. It is also important to understand the limitations of skin biopsy
and to ensure the biopsy is performed by someone familiar with the
diagnosis of leprosy when it is suspected.

DIPHTHERITIC NEUROPATHY.
Diphtheritic neuropathy is
caused by release of diphtheria
exotoxin, produced by
Corynebacterium diphtheriae,
which invades Schwann cells and
inhibits the synthesis of myelin
proteolipid and myelin basic
protein.62 The incidence of
diphtheria has decreased with
expanded access to vaccination,
but large outbreaks have still
occurred within the last 5 years.63
Infection occurs predominantly
in children and young adults, but
a demographic shift to older
patients has been observed in
some regions because of lack of
revaccination or waning
immunity.64 Patients typically
present with flulike symptoms,
cervical lymphadenopathy, and
an exudative pharyngitis that can
FIGURE 5-3 lead to airway obstruction.63
Sural nerve biopsy and skin findings in a patient
About 3 weeks after the initial
with leprosy. A, Section from the sural nerve
shows an enlarged fascicle with infiltration by symptoms (with a range of about
foamy histiocytes (arrows) (hematoxylin and eosin 10 days to 3 months), a variable
staining [H&E], 200× magnification). B, Section percentage of people will
from the sural nerve shows singly lying and globi develop a peripheral
(arrow) of Mycobacterium leprae bacilli
(Wade-Fite stain, 1000× magnification).
neuropathy.62 In one study, 7.6%
Figure courtesy of Ravindra Kumar Garg, MD. of all patients with diphtheria
developed a peripheral
neuropathy, but in those with
“severe” disease, 76% developed peripheral neuropathy.65 The neuropathy is
biphasic and typically starts with a “craniofacial stage,” affecting the cranial
nerves with symptoms of numbness in the tongue and gingivae, dysarthria,
dysphagia, pupillary accommodation dysfunction, and occasionally ocular motor
palsy. Respiratory failure may also occur.66,67 After the initial bulbar symptoms,
a more diffuse neuropathy occurs in more than 80% of patients, affecting sensory,
motor, and autonomic nerves.66,67 Diphtheritic neuropathy has occurred in
vaccinated individuals; however, in one case series, the presentation was milder
with less significant extremity weakness, and bulbar symptoms were less
common.68
DIAGNOSIS AND TREATMENT. A throat culture can confirm the diagnosis of

diphtheria, especially in the pharyngeal stage of the illness, but may be negative.
No specific test to diagnose diphtheritic neuropathy exists. Findings on nerve
conduction studies and CSF analysis may appear similar to Guillain-Barré
syndrome. Features that may distinguish diphtheria from Guillain-Barré
syndrome include the biphasic time course of craniofacial dysfunction followed
932 AUGUST 2021

by diffuse limb weakness and the presence of accommodation dysfunction.66 KEY POINTS
Cardiac dysfunction related to diphtheritic myocarditis and renal impairment
● A length-dependent
are also diagnostic clues if present.66,67 sensory or sensorimotor
Treatment with antitoxin and antibiotics should occur as soon as possible.66 axonal neuropathy is the
No specific treatment exists for the neuropathy itself, and the benefit of giving most common peripheral
the antitoxin after the development of neuropathy is unclear.63 Diphtheritic nervous system
manifestation of HIV.
neuropathy usually has a good prognosis with recovery of neurologic
function; however, death occurs in a small percentage because of disease ● Diphtheritic neuropathy is
complications.62,69 the prototypical infection
leading to a demyelinating
Autonomic Dysfunction neuropathy with a
presentation that resembles
Several infections have been associated with peripheral autonomic dysfunction Guillain-Barré Syndrome.
and even more associated with central autonomic dysfunction. Chagas disease,
caused by the parasite Trypanosoma cruzi, can cause autonomic neuropathy, ● Chagas disease, caused
particularly affecting cardiac and gastrointestinal function. It is endemic in Latin by the parasite
Trypanosoma cruzi, can
America with more than 8 million people estimated to be infected in the cause autonomic
Americas.4 HIV, HTLV-I, leprosy, diphtheria, botulism, and Lyme disease have neuropathy, particularly
also been associated with peripheral autonomic dysfunction; however, it is much affecting cardiac and
less commonly a sole PNS manifestation.4,35,70-72 Although tetanus, HSV, gastrointestinal function.
tick-borne encephalitis virus, West Nile virus, rabies, and enterovirus 71 can all
have PNS manifestations, autonomic dysfunction in these infections is likely due
to central involvement.
Motor Nerve Hyperexcitability

Tetanus is an important infection affecting both the PNS and central nervous
system. It does not fit well into any specific localization category but most
closely represents a motor nerve hyperexcitability syndrome, so it is
discussed here.
TETANUS. Tetanus is a disease of motor nerve hyperexcitability characterized by

muscle rigidity and spasms that are caused by the tetanus toxin, which is
produced by Clostridium tetani. The spores of C. tetani are present in soil and
feces73 and can germinate in wounds or minor abrasions.74 However, in 20% to
50% of cases, no obvious wound or infectious source is found.74 The toxin enters
the presynaptic motor neuron axon terminals through endocytosis near the
wound, and through retrograde transport, enters the cell body of motor neurons
in the spinal cord and brainstem, and impairs inhibitory neurotransmission.75
This leads to the motor nerve hyperexcitability observed clinically.2,75 One study
estimates more than 56,000 deaths from tetanus occurred worldwide in 2015,
with 79% of those occurring in South Asia and sub-Saharan Africa, and 35% of
the total representing deaths in neonates.76 Neonatal tetanus is usually secondary
to infection of the umbilical stump, which can occur as a result of unsanitary
birth practices (eg, the use of unsterilized instruments or applying cow dung or
soil to the stump).73 Lack of maternal vaccination, unsanitary birth or abortion
practices, and poverty are risk factors for neonatal and maternal tetanus.77 In
countries where vaccination is common, typically fewer than 100 cases occur
per year.74
CLINICAL PRESENTATION. Symptoms usually begin 7 to 10 days after infection and

progress for 2 weeks, with recovery beginning after about 1 month. Symptoms

begin at the wound site but almost always become generalized. The painful
muscle spasms and rigidity are usually stimulus-induced.2 Trismus (lockjaw), is
present in more than 95% of patients.73 A positive “spatula test,” in which
attempting to elicit the gag reflex results in the patient biting down, is sensitive
and specific.78 Another typical finding is an abnormal facial posture called risus
sardonicus, caused by facial muscle spasm. Laryngospasm can lead to aspiration,
airway obstruction, and dysphagia.74 Generalized rigidity and muscle spasms can
result in opisthotonus, which is a dramatic arching of the back (FIGURE 5-479).
Autonomic symptoms are also common.74
DIAGNOSIS AND TREATMENT. Tetanus is a clinical diagnosis because both false

negatives and false positives can occur from wound cultures.80 Nerve conduction
studies and EMG may be helpful to rule out other diseases, but no sensitive
or specific pattern is observed.2 The most common finding is continuous firing
of normal motor unit potentials in agonist and antagonist muscles.2 This is
similar to what is seen in stiff person syndrome. CSF in tetanus may be normal
or show elevated protein and immunoglobulins. Other diagnoses to consider
are drug-induced dystonia, neuroleptic malignant syndrome, strychnine
poisoning, meningoencephalitis, and paraneoplastic brainstem encephalitis.2
If trismus is the main feature, then a local dental infection rather than tetanus
should be considered. Management involves treating the infected wound,
administration of tetanus immunoglobulin, treatment of spasms, and supportive
intensive care including early intubation, possible early tracheostomy, and enteral
feeding tube placement as placement may become technically difficult later in
the disease.2
INFECTIONS AFFECTING THE NEUROMUSCULAR JUNCTION

Infections of the neuromuscular junction are extremely rare, with botulism being
the most common (albeit still rare). Other nonimmune-mediated neuromuscular
junction disorders include those caused by toxins or envenomations.
Botulism
Botulism causes a presynaptic neuromuscular transmission defect leading to
acute bulbar, respiratory, and limb weakness. It occurs from infection with
spores of Clostridium botulinum
or secondary to exposure to
botulinum toxin.81 Botulinum
toxin interferes with the soluble
N-ethylmaleimide–
sensitive factor attachment
protein receptor (SNARE)
polypeptide complex, preventing
fusion of acetylcholine vesicles
with the presynaptic
membrane.82 Clinically, botulism
is classified into five categories:
FIGURE 5-4 (1) infant botulism, (2) foodborne
Generalized rigidity and muscle spasms in tetanus
botulism, (3) wound botulism,
can result in opisthotonus, which is a dramatic
arching of the back. (4) adult intestinal colonization
Reprinted from the Immunization Action Coalition.79
botulism, and (5) iatrogenic
934 AUGUST 2021

botulism.73 In 2017, 182 confirmed cases of botulism in the United States were KEY POINTS
reported to the Centers for Disease Control and Prevention: 77% of cases were
● A positive “spatula test,”
infant botulism, 10% foodborne, 10% wound, 1% intestinal colonization, and 1% in which attempting to elicit
iatrogenic.83 the gag reflex results in the
patient biting down, is both
INFANT BOTULISM. Infant botulism is caused by the ingestion of spores that sensitive and specific for
tetanus.
multiply in the gastrointestinal tract and release botulinum toxin.84 Infant
botulism can be secondary to honey ingestion, although the source is not ● Wound botulism can
identified in most cases. Symptoms include constipation, hypotonia, lethargy, occur after trauma but is
weak cry, poor suck, dysphagia, and ultimately respiratory failure in about more commonly seen in
50% of patients.84 Cranial nerve abnormalities including dilated pupils, ptosis, relation to recreational drug
use, especially IV drugs and
ophthalmoplegia, and facial weakness also occur, as well as autonomic dysfunction.84 subcutaneous heroin.
Most infants have a complete recovery; the mortality rate is less than 1%.84
● Nerve conduction
FOODBORNE BOTULISM. Foodborne botulism occurs when Clostridium toxin is studies/EMG is important in
aiding the clinical diagnosis
ingested because of food contamination. Outbreaks in the United States are of botulism because it can
most commonly caused by home-canned foods.83 Symptoms start several help confirm the diagnosis
hours to days after ingestion. Gastrointestinal symptoms usually precede cranial before laboratory testing
nerve and autonomic dysfunction. Respiratory weakness is common; 30% to results and make other
diagnoses less likely.
67% of patients require intubation.2 Descending muscle weakness is classic,
beginning in the cranial nerve–innervated muscles and descending to the
extremities. Deep tendon reflexes may be normal or reduced.85 Symptoms are
bilateral but may be asymmetric.81 Sensation is typically unaffected because this
is a disorder of neuromuscular junction transmission, but rarely paresthesia is
reported.81,85
WOUND BOTULISM. Wound botulism occurs when spores enter a wound and the
toxin is produced. It can occur after trauma but is more commonly seen in
relation to illicit drug use (CASE 5-2), especially IV drugs86 and subcutaneous
heroin.87 It has also been associated with cocaine injection and intranasal cocaine,
with the cases reported from intranasal cocaine having a more mild clinical
course.88 The mechanism is unclear in the inhalation cases but may be related to
the development of sinusitis.88
ADULT INTESTINAL COLONIZATION BOTULISM. Adult intestinal colonization botulism

is extremely rare and thought to occur as a result of gastrointestinal tract
colonization with C. botulinum or Clostridium baratii. It is reported in patients
with an abnormal gastrointestinal microbiome due to gastrointestinal anatomic
abnormalities, gastric surgery, inflammatory bowel disease, and antimicrobial use.89
IATROGENIC BOTULISM. Iatrogenic botulism has rarely been reported in patients

treated with botulinum toxin. Some case series describe the occurrence of
botulism after overdose with botulinum toxin A.90 Other case series describe the
development of generalized weakness after being given therapeutic doses.91
DIAGNOSIS AND TREATMENT. The laboratory evaluation of botulism focuses on the

detection of botulinum toxin in serum, in stool, from a wound if present, or from
contaminated food samples. In infant or adult intestinal colonization botulism,
sampling stool has a higher yield.73,84 However, the sensitivity may be low, and it
takes 1 to 4 days to receive results.92,93 Nerve conduction studies/EMG is

important in aiding the clinical diagnosis of botulism because it can help confirm
the diagnosis before laboratory testing results and make other diagnoses less
likely. The EMG pattern is one of a presynaptic neuromuscular junction defect.
Although the findings can be variable, one expects normal SNAPs, normal
conduction velocities and latencies, reduced CMAP amplitudes, myopathic or
normal-appearing motor unit potentials, and a possible increment on
high-frequency repetitive nerve stimulation. These findings, particularly the
notable lack of neurogenic (decreased) recruitment, can help localize the
lesion to the presynaptic neuromuscular junction rather than to the peripheral
nerves or motor neurons.
In addition to supportive management, in adults, heptavalent botulinum
antitoxin, which binds to circulating toxin, should be administered as soon as the
CASE 5-2 A 25-year-old man presented with 3 days of worsening double vision,
slurred speech, difficulty swallowing, and facial weakness. He denied
sensory changes, shortness of breath, fever, and abdominal symptoms.
He specifically denied food exposures for botulism and IV drug use at
presentation. He did not require intubation but failed a swallow
evaluation requiring tube feeding.
Examination showed asymmetric bilateral ptosis, bilateral
ophthalmoparesis with an abnormal pupillary response, bilateral facial
weakness, weak gag, and dysarthria. Neck flexion and extremity strength
were normal with 1+ reflexes. Sensation was normal.
CSF evaluation and brain MRI were normal. Nerve conduction studies
and EMG showed normal sensory nerve action potentials (SNAPs), and
compound muscle action potential (CMAP) amplitudes were borderline
normal with normal conduction velocities and latencies (FIGURE 5-5).
Median and ulnar CMAP amplitudes showed a nearly 100% increment
after 10 seconds of isometric exercise. No decrement was seen with 3-Hz
repetitive nerve stimulation. Needle EMG was normal with the exception
of small-amplitude, short-duration motor unit potentials with early
recruitment in a facial muscle.
Given the EMG results, the patient was asked again about IV drug use
and admitted to heroin injection 2 days before the start of symptoms. He
was subsequently treated with botulinum antitoxin. Serum and stool
were negative for botulinum toxin. Infectious disease consultants
recommended a 2-week course of penicillin because of the patient’s
source of infection (thought to be direct injection of botulism spores);
however, no “wound” was present. The patient improved over 6 to 8 weeks.
936 AUGUST 2021

diagnosis is suspected. Earlier heptavalent botulinum antitoxin administration
may reduce the length of hospital stay and time on mechanical ventilation.94,95
For infants, IV botulism immunoglobulin is the treatment of choice.84 It was
found to significantly decrease the length of the hospital stay and time on
mechanical ventilation.96 For wound botulism, wound debridement and
antibiotics are usually also given.2
INFECTIONS OF MUSCLE
Infectious myopathy may present acutely or chronically. Acute causes of
myopathy include viral infections, bacterial pyomyositis, and trichinosis.
An acute, self-limited myositis may occur secondary to viral infections,
particularly influenza. In children, this can present as severe pain and swelling in
FIGURE 5-5
Median nerve compound muscle
action potential (CMAP) from the
patient in CASE 5-2 at baseline and
after 10 seconds of isometric
exercise. Amplitude increased from
4 mV to 8.2 mV.
APB = abductor pollicis brevis; NCS = nerve
conduction study.
In an acute presentation of bulbar weakness, botulism should be considered COMMENT

and risk factors assessed, including careful questioning about food exposures
and drug use. Nerve conduction studies and EMG can help to confirm the
diagnosis when clinically suspected and should be performed urgently. EMG
findings are variable and sometimes lack classic findings of presynaptic
neuromuscular junction disorders, such as low CMAP amplitudes and a
decrement on slow repetitive nerve stimulation. An increment after
isometric exercise or high-frequency repetitive nerve stimulation may not
be present and may be less pronounced (usually less than 100%) compared
with that observed in Lambert-Eaton myasthenic syndrome. This case
demonstrates the importance of the clinical diagnosis and not relying on
diagnostic tests that may be negative or take days to return.

the calves and, in adults, tends to present with less severe pain and proximal
weakness. Myoglobinuria can occur in children or adults, and symptoms are
usually self-limited, resolving within a couple of weeks.2
Pyomyositis is a term used to describe a focal or multifocal muscle infection,
often a bacterial abscess. Pyomyositis classically occurs in otherwise healthy young
men in tropical regions but has become more common in the United States.97 Risk
factors include younger age, male sex, HIV, IV drug use, diabetes, hematologic
malignancy, transplantation, malnutrition, chronic kidney disease, obesity, and
rheumatologic disease.2,97 Staphylococcus aureus (either methicillin-susceptible
S. aureus or methicillin-resistant S. aureus) causes more than 75% of cases,
followed by streptococcal species.97 The pathophysiology is unclear but likely
requires transient bacteremia in the setting of muscle injury, such as from
trauma or overuse.98 Patients usually present with acute focal muscle pain,
swelling, and sometimes erythema and fever. This can progress to a disseminated
infection leading to multiple abscesses and potentially septic shock and
death.98 The most frequently affected muscles are the quadriceps and other
large muscles of the extremities. A single muscle is affected in the majority of
patients, but 12% to 40% of patients have multiple muscles involved.98
Muscle MRI is the most sensitive and specific modality for identifying the
infection.98,99 Antibiotic therapy should be given as soon as the diagnosis
is confirmed, and, if an abscess is present, then it should be drained
emergently.
Trichinosis, caused by the nematode Trichinella spiralis, is the most common
cause of parasitic myositis. An estimated 10,000 cases of trichinosis occur each
year worldwide mostly secondary to ingestion of undercooked meat, typically
pork.100 Symptoms usually begin with gastrointestinal discomfort and evolve to
myalgia and generalized weakness over 1 to 2 weeks, but recovery may take
several months. Periorbital and facial edema is a unique finding.100 In one case
series of 92 infected patients, 100% had myalgia and fever, 84% had facial edema,
42% had gastrointestinal symptoms, 5% had conjunctival hemorrhage, and 2%
had rash.101 Early diagnosis is important because larvae may be more resistant to
treatment later in the disease course.100 Elevated serum creatine kinase,
leukocytosis, and eosinophilia (usually more than 1000 eosinophils/mm3) are
clues to the diagnosis. X-rays may reveal calcifications in the muscles. Serum
antibody tests, usually using enzyme-linked immunosorbent assay (ELISA)
followed by Western blot can help confirm the diagnosis but may not be positive
until about 3 to 4 weeks after a patient is infected. Muscle biopsy (usually of the
deltoid) is also typically performed but is not 100% sensitive to make the
diagnosis because of sampling error. It can reveal prominent cellular infiltrates as
well as larvae and cysts.100 In addition to supportive care, a course of either
albendazole or mebendazole is given in addition to a 2-week course of prednisone
(30 mg/d to 60 mg/d) in severe cases. Treatment may not eliminate Trichinella
when it is already encapsulated in muscle, leading some patients to have chronic
myalgia after resolution of their illness.100,101
Infectious causes of subacute or chronic myositis include HIV and HTLV-I.
Patients with HIV may develop an inflammatory myositis similar to polymyositis
that presents with subacute or chronic proximal weakness. Muscle biopsies can
demonstrate a range of findings, and these myopathies may respond to
immunotherapy. In patients with HIV, one must also consider muscle disease
associated with opportunistic infection (eg, S. aureus pyomyositis, CMV,
938 AUGUST 2021

Cryptococcus, Mycobacterium avium-intracellulare, Toxoplasma, HTLV-I), KEY POINTS
microsporidiosis,102 treatment toxicity (eg, mitochondrial myopathy associated
● An acute, self-limited
with zidovudine treatment), or other conditions associated with HIV itself such myositis may occur
as HIV wasting syndrome.102 Muscle biopsy is especially important in the secondary to viral
evaluation of patients with HIV because of the large differential diagnosis. infections, particularly
HTLV-I has also been associated with myositis but is usually accompanied by influenza.
HTLV-I myelopathy, which has not been found to respond to immunotherapy.103
● Pyomyositis classically
occurs in otherwise healthy
young men in tropical
CONCLUSION regions but has become
A thorough history and examination are key to localization and the diagnosis of more common in the
United States.
PNS infections. Although infections are a rare cause of peripheral disease, clues
to PNS infections include specific risk factors and exposures; examination
findings and nerve conduction studies and EMG can help localize the site of
pathology. A timely diagnosis is essential to assure rapid initiation of appropriate
treatment to improve clinical outcomes.
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942 AUGUST 2021

Parasitic Infections of the REVIEW ARTICLE
Nervous System

INTERVIEW AVAILABLE
ONLINE
By Hector H. Garcia, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article reviews how parasites affect the human
nervous system, with a focus on four parasitic infections of major public
health importance worldwide, two caused by protozoa (malaria and
toxoplasmosis) and two by helminths (neurocysticercosis and
schistosomiasis).
RECENT FINDINGS:Parasitic infections in humans are common, and many can

affect the central nervous system where they may survive unnoticed or
may cause significant pathology that can even lead to the death of the
host. Neuroparasitoses should be considered in the differential diagnosis
of neurologic lesions, particularly in individuals from endemic regions or CITE AS:
those with a history of travel to endemic regions. 2021;27(4, NEUROINFECTIOUS
DISEASE):943–962.
SUMMARY: Cerebral malaria is a significant cause of mortality, particularly in

African children, in whom infected red blood cells affect the cerebral
Dr Hector H. Garcia,
vessels, causing severe encephalopathy. Neurocysticercosis is the most Cysticercosis Unit, Instituto
common cause of acquired epilepsy worldwide and has varied clinical Nacional de Ciencias
Neurologicas, Jr. Ancash 1271,
presentations, depending on the number, size, and location of the Barrios Altos, Lima, Peru,
parasites in the nervous system as well as on the host’s inflammatory hgarcia@jhsph.edu.
response. Toxoplasmosis is distributed worldwide, affecting a significant
proportion of the population, and may reactivate in patients who are Dr Garcia has served as an
immunosuppressed, causing encephalitis and focal abscesses. associate editor for the
Schistosomiasis causes granulomatous lesions in the brain or the American Journal of Tropical
Medicine and Hygiene and
spinal cord. PLOS Neglected Tropical
Diseases and as a board
member of the Oxfendazole
Development Group and has
received research grants from
INTRODUCTION the Fogarty International Center
A
parasite is an organism that lives on or in another organism from a (D43TW001140), National
different species, taking its nourishment from the host. Parasites do Institute of Allergy and
Infectious Disease
not always harm the host, and a typical vertebrate is the host of (U19AI129909), and National
many species of parasites. The human nervous system can be Institute of Neurological
Disorders and Stroke
invaded by multiple parasite species, which, in some cases, cause a
(U01NS086974).
significant burden of morbidity and mortality.
Endoparasites (those living inside the host) are classified as protozoa or UNLABELED USE OF
helminths. Protozoa are unicellular microscopic species, whereas helminths are USE DISCLOSURE:
more complex organisms and may reach several meters in length. Some parasites Dr Garcia reports no disclosure.
(such as Toxoplasma gondii or Toxocara canis) are distributed worldwide,
whereas others (such as Plasmodium, Schistosoma, and Taenia solium) occur in © 2021 American Academy
particular endemic regions but may be diagnosed in nonendemic areas because of of Neurology.

PARASITIC INFECTIONS OF THE NERVOUS SYSTEM
travel and migration of infected individuals.1 This article reviews how parasites
affect the human nervous system and the types of pathology they cause, focusing
on four parasitic infections of major public health importance worldwide, two
caused by protozoa (malaria and toxoplasmosis) and two by helminths
(neurocysticercosis and schistosomiasis). Other parasitic infections that can
rarely be seen in neurologic practice are also briefly discussed.
MECHANISMS OF PARASITE INVASION AND PATHOLOGY

Parasites use multiple mechanisms to overcome the physical and immunologic
barriers that vertebrates have evolved to protect their nervous systems. Some
parasites, such as free-living amoebas, can enter the central nervous system
(CNS) via the olfactory nerve.2 Others, such as most nematodes and cestodes,
enter the host via the bloodstream and thus require prior successful breaching
of the skin or mucosa3 either by the bite of a vector organism or secretion of
proteolytic enzymes. To enter the CNS, parasites must then traverse the blood-
brain barrier via a paracellular or transcellular route from the bloodstream or by
being transported in a macrophagic cell.3 Once the parasite enters the host, the
host immune system will attempt to destroy it; the parasite will try to avoid
destruction using mechanisms such as molecular mimicry, invasion of host cells,
and secretion of agents able to modulate the host immune response.
Entry of a parasite into the CNS does not necessarily mean CNS damage,
although, in most cases, it does result in pathology. CNS damage by parasites may
occur in diverse forms. Tissue damage may result from the presence of the
parasite, parasite products (ie, parasite proteases), or the host inflammatory
response to these products, for example, to dying and degenerating T. solium
cysts in neurocysticercosis. Larval and adult nematodes or cestodes may also
cause pathology by actively migrating through the host tissues, as in Gnathostoma
infections or other eosinophilic meningitis.
CNS parasitoses can result in a variety of lesions, including granulomatous or
cystic lesions, abscesses, encephalitis, meningitis, or myelitis, any of which may
occur alone or in combination. These can present with diverse clinical
manifestations, including seizures, focal deficits, mass effect, and intracranial
hypertension, and can also cause complications such as vasculitis, stroke, and
hydrocephalus.4
CEREBRAL MALARIA
Malaria is the most common parasitic disease of humans and the most common
parasitic cause of mortality and morbidity worldwide. Annually, malaria causes
more than 400,000 deaths in endemic regions, mostly in African children.5
Although it is usually considered a “tropical” disease, it is not restricted to the
tropics, and approximately 10,000 cases are diagnosed every year in travelers.6
Although four species of Plasmodium can cause human malaria, only Plasmodium
falciparum affects the CNS, resulting in the most severe form of disease, cerebral
malaria. Cerebral malaria may be the most common cause of nontraumatic
encephalopathy in the world.6,7
Life Cycle
Transmission of P. falciparum to humans occurs through the bite of an infected
Anopheles species mosquito. The parasite has a very complex life cycle. After
being injected under the skin, the infective sporozoites reach the liver and infect
944 AUGUST 2021

hepatocytes. In hepatocytes, they reproduce to significant numbers to form a KEY POINTS
hepatic schizont, after which the cell breaks and releases merozoites. Merozoites
● The human nervous
infect red blood cells and alter their shape and function. In the red blood cell, the system can be invaded by
parasites (now in the trophozoite stage) reproduce again to form schizonts and multiple parasite species,
rupture the erythrocyte, releasing a new generation of merozoites that infect new which, in some cases, cause
erythrocytes and continue the blood cycle. Synchronization of this blood cycle a significant burden of
morbidity and mortality.
and erythrocyte rupture causes the characteristic cyclical fever and malaise
(FIGURE 6-18). ● Parasites use multiple
mechanisms to overcome
Clinical Presentation the physical and
Severe malaria is defined by one or more of the following: impaired consciousness, immunologic barriers that
vertebrates have evolved to
prostration, multiple seizures, acidotic breathing, acute pulmonary edema and protect their nervous
acute respiratory distress syndrome, circulatory collapse or shock, low systolic systems.
blood pressure, acute kidney injury, clinical jaundice plus evidence of other vital
organ dysfunction, or abnormal bleeding.9,10 Cerebral malaria and severe malarial ● Malaria is the most
common parasitic disease of
anemia are the major causes of mortality in severe malaria. Cerebral malaria humans and the most
primarily affects children and nonimmune adults (such as travelers to endemic common parasitic cause of
regions). In children, cerebral malaria manifests as a febrile encephalopathy with mortality and morbidity
seizures (in more than 70%), with the usual case definition involving coma worldwide. Annually,
malaria causes more than
associated with acute infection with P. falciparum in the absence of other
400,000 deaths in endemic
identifiable causes.6 The most vulnerable age group is between 6 months and regions, mostly in African
children.
FIGURE 6-1
Life cycle of the malaria parasite.
Modified from JHSPH Open Courseware.8 © 2021 Johns Hopkins Bloomberg School of Public Health.

5 years old (other age groups are protected by maternal immunity or previous
exposure to the parasite). In the initial days of infection, nonspecific symptoms
develop (eg, fever, cough, and vomiting), with the child subsequently falling into
a deep coma with associated seizures. In adults, the progression to coma is gradual,
seizures are less frequently observed (in 15% to 20%), and multiorgan system
failure develops.11
Untreated cerebral malaria is lethal in all cases. Even under appropriate care,
short-term mortality may approach 15% to 30%. Approximately 30% of survivors
of cerebral malaria develop neurologic complications, such as epilepsy, cognitive
and behavioral disorders, or neurologic deficits.12,13 Adult survivors generally have
fewer neurologic complications but can rarely develop postmalaria neurologic
syndrome, which is similar to acute disseminated encephalomyelitis (ADEM).
Although the disease is called cerebral malaria, the parasite never invades the
brain tissues. The pathogenesis is not completely understood, but the principal
factor is the obstruction of blood vessels caused by intravascular sequestration of
infected red blood cells, with subsequent cytokine release, blood-brain barrier
disruption, brain edema, and metabolic alterations (FIGURE 6-214).6,15,16
Diagnosis
The diagnosis of malaria is based on the demonstration of parasite forms on blood
microscopy. However, a significant proportion of people in endemic regions
have asymptomatic parasitemia, and thus, the coexistence of parasitemia and
neurologic disease may be falsely diagnosed as cerebral malaria. Detection of
malaria retinopathy is highly sensitive (95%) and specific (90%) in identifying
children whose comas are due to cerebral malaria; therefore, funduscopy should
be performed in all suspected cases to look for retinal whitening, retinal
hemorrhages, papilledema, and vascular changes (FIGURE 6-3).10 CSF examination
is usually normal but helps to exclude other causes of encephalopathy, such as
bacterial meningitis in cases with increased CSF white blood cell counts.17 Lumbar
puncture does not increase the risk of mortality in clinically stable patients with
cerebral malaria despite evidence of brain edema.18 MRI can demonstrate increased
brain volume as well as abnormal T2 signal intensity and diffusion-weighted
FIGURE 6-2
Pathology of cerebral malaria. A, Macroscopic pathology of cerebral malaria (right)
compared to a normal brain (left). B, Close-up view of the brain demonstrating the typical
“flea-bitten” appearance resulting from multiple ring hemorrhages in the white matter.
Reprinted with permission from Román GC, J Neurol Sci.14 © 1991 Elsevier Inc.
946 AUGUST 2021

KEY POINTS
● Untreated cerebral
malaria is lethal in all cases.
Even under appropriate
care, short-term mortality
may approach 15% to 30%.
● Up to one-third of the
world’s population is
infected with latent
toxoplasmosis (usually
asymptomatic), and disease
FIGURE 6-3 occurs when latent brain
Malarial retinopathy in pediatric patients from Malawi showing white-centered hemorrhages infections are reactivated in
(A), vessel discoloration (B), and perimacular whitening (C, circle). patients who become
Reprinted with permission from Taylor TT and Molyneux ME, Ann NY Acad Sci.11 © 2015 New York Academy of
immunocompromised.
Sciences.
imaging abnormalities in the cortical, deep gray, and white matter structures.19
Unfortunately, the availability of MRI is limited in malaria-endemic regions.
Treatment
Treatment of cerebral malaria requires IV antimalarials, with artesunate performing
better than quinine.10,20 Side effects of artesunate are infrequent, although delayed
hemolysis may occur a week after treatment.15 Seizures are usually managed with
phenobarbital and benzodiazepines, with respiratory suppression a common
complication. Enteral levetiracetam may provide an effective and safe alternative,21
although availability is limited in endemic areas. Otherwise, treatment is supportive,
with patients often requiring intensive care unit–level care.
TOXOPLASMOSIS
Toxoplasmosis is seen worldwide and is likely the most common parasitic infection of
the human CNS. Up to one-third of the world’s population is infected with latent
toxoplasmosis (usually asymptomatic), and disease occurs when latent brain infections
are reactivated in patients who become immunocompromised. Toxoplasmosis is the
most common opportunistic infection in patients with human immunodeficiency virus
(HIV), with highest risk when CD4+ counts are less than 100 cells/mm3.22,23
Life Cycle
Toxoplasmosis infection is caused by the ingestion of the tissue cysts or oocysts of
T. gondii in contaminated food or water. Cats are definitive hosts for Toxoplasma.
Oocysts are shed in the cat’s stools but are not infectious immediately (they
become infectious 1 to 5 days after being shed). Considering the risks of primary
nfections during pregnancy, it is recommended that pregnant women do not clean
litter boxes to avoid exposure. Primary infections in other immunocompetent
individuals are usually asymptomatic. In low-income countries, the majority of the
population has specific antibodies, compared to 10% to 50% of the population in
high-income countries.24,25 Before the antiretroviral treatment era, toxoplasmosis
reactivation rates in the United States and United Kingdom varied between 16%
and 40%, whereas in Brazil, France, and Spain, rates were even higher. Although
neurotoxoplasmosis is still a frequent cause of morbidity and mortality among

patients infected with HIV, especially in lower-income countries, mortality has

decreased substantially since the introduction of antiretroviral therapy.26
Clinical Presentation
The clinical manifestations of cerebral toxoplasmosis are usually subacute and
depend on the topography and number of lesions. The main symptoms are fever,
CASE 6-1 A 49-year-old man presented with a generalized seizure after a week
of headache. He reported a history of weight loss in the past 3 months.
On examination, the patient had normal mental status but left
hemiparesis with left-sided hyperreflexia.
Contrast-enhanced brain CT revealed three low-attenuation
parenchymal lesions. The largest lesion was in the right basal ganglia
associated with perilesional edema (FIGURE 6-4A). The results of a serum
enzyme-linked immunosorbent assay (ELISA) and Western blot for human
immunodeficiency virus (HIV)
were positive. Serum
ELISA for Toxoplasma
gondii was positive, and
the CD4+ count was
84 cells/mm3. Trimethoprim-
sulfamethoxazole,
dexamethasone, and
valproic acid were
initiated. After 2 weeks of
treatment, the patient had
complete neurologic FIGURE 6-4
recovery and showed Imaging of the patient in CASE 6-1. Axial CT shows a
partial resolution of his large rim-enhancing lesion in the right basal
ganglia associated with perilesional edema and
lesion burden on brain CT
midline shift (A) with marked improvement seen
(FIGURE 6-4B); antiretroviral after 2 weeks of anti-Toxoplasma treatment (B).
therapy was started. Images courtesy of Jose Vidal, MD.
COMMENT Cerebral toxoplasmosis is the most common cause of expansile brain

lesions in people living with HIV/acquired immunodeficiency syndrome
(AIDS) and continues to cause high morbidity and mortality in individuals
who are severely immunosuppressed. The most common characteristics
are focal subacute neurologic deficits and ring-enhancing brain lesions in
the basal ganglia, but the spectrum of clinical and neuroradiologic
manifestations is broad. Early initiation of anti-Toxoplasma therapy defines
the outcome. Trimethoprim-sulfamethoxazole and pyrimethamine-based
regimens seem to have similar efficacy, but trimethoprim-
sulfamethoxazole shows potential practical advantages. Most experts wait
for approximately 2 weeks after initiation of antiparasitic therapy before
starting antiretroviral therapy in this setting to decrease the risk of immune
reconstitution inflammatory syndrome.
948 AUGUST 2021

headache, seizures, focal deficits, confusion, lethargy, and visual alterations KEY POINT
related to retinal toxoplasmosis. Less frequent symptoms can include persistent
● The clinical
cognitive impairment and movement disorders.1 manifestations of cerebral
toxoplasmosis are usually
Diagnosis subacute and depend on the
On neuroimaging, cerebral Toxoplasma lesions can be unifocal or multifocal and topography and number of
lesions. The main symptoms
are most commonly located in the basal ganglia or subcortical white matter. On are fever, headache,
CT, they usually appear as hypodense ring-enhancing lesions with significant seizures, focal deficits,
perilesional edema (CASE 6-1), whereas on MRI they appear as T1-hypointense, confusion, lethargy, and
T2-hyperintense lesions with ring enhancement. These lesions may have small visual alterations related to
retinal toxoplasmosis.
hemorrhagic foci, or, more rarely, toxoplasmosis may present as an isolated
single or multiple cerebral hemorrhagic lesions. Two radiologic signs are highly
specific for the diagnosis. One is the eccentric target sign (a ring-shaped zone of
peripheral enhancement with a small eccentric nodule along the wall, observed
in <30% of cases)(FIGURE 6-527,28), and the other is the concentric target sign
(concentric alternating zones of hypointensity and hyperintensity seen on
T2-weighted MRI).29 These need to be distinguished from the target sign, which
has been described as a central nidus of calcification or central enhancement
surrounded by a ring of enhancement and is considered characteristic of CNS
tuberculoma.
Given the frequency of toxoplasmosis in the general population, a positive
IgG serology does not confirm the diagnosis. Acutely rising serum IgG
antibodies or a positive IgM serology suggests acute infection. IgM serology is
less specific as it may cross-react with other protozoa and may be positive in
patients with autoimmune disease. Negative serology in a patient with HIV
makes the diagnosis of toxoplasmosis unlikely. However, negative serology
does not exclude the diagnosis, especially in the presence of compatible clinical
and radiologic findings. Negative serology may represent a low titer below
the test cutoff and so does not exclude latent infection and risk of reactivation
in the setting of immune reconstitution; this is not common and occurs in
about 5% of cases. CSF polymerase chain reaction (PCR) is a useful tool for
diagnosis of T. gondii, with specificity between 96% and 100%. However, lumbar
FIGURE 6-5
Eccentric target sign. The eccentric target sign (A, arrow) in neurotoxoplasmosis shown in
coronal postcontrast T1-weighted MRI (A) and the target sign caused by tuberculoma shown
in axial CT before (B) and after (C) contrast.
Panel A reprinted with permission from Kumar GG, et al, J Magn Reson Imaging.27 © 2010 Wiley-Liss, Inc.
Panels B and C reprinted with permission from Van Dyk A, Neuroradiology.28 © 1988 Springer Nature.

puncture is not advisable for patients with cerebral lesions with significant
edema.30,31
The diagnosis of toxoplasmosis is usually confirmed with a favorable response
to anti-Toxoplasma treatment. Within 14 days of specific treatment, a good
clinical and neuroimaging response is expected. If patients do not respond to
therapy, a biopsy of the lesion is indicated to look for an alternative diagnosis,
although nuclear imaging studies (eg, positron emission tomography [PET] or
single-photon emission computed tomography [SPECT]) may be considered to
differentiate toxoplasmosis from primary CNS lymphoma.
The most common differential diagnosis of neurotoxoplasmosis in
lower-income countries is tuberculoma, whereas in higher-income countries
primary CNS lymphoma should be considered. In patients infected with HIV,
other infections, such as cryptococcosis, aspergillosis, microsporidiosis, and
Chagas disease, should also be considered in the differential diagnosis of single or
multifocal brain lesions.23 Individuals who are immunocompetent may very
rarely develop neurotoxoplasmosis, mostly as an acute diffuse encephalitis due to
overwhelming primary infection. This is extremely rare, and such patients
should be carefully evaluated for undiagnosed immunodeficiency.
Treatment
Therapy with pyrimethamine-based treatment or trimethoprim-sulfamethoxazole is
usually effective, with clinical and radiologic improvement in 80% to 90%
of patients receiving one of these regimens. In patients with sulfa allergy,
either clindamycin or atovaquone can be used in combination with
pyrimethamine. Treatment is continued for at least 6 weeks; if immunosuppression
is present, secondary prophylaxis with trimethoprim-sulfamethoxazole or
pyrimethamine-sulfadiazine is continued indefinitely. Recent data suggest that
trimethoprim-sulfamethoxazole can be used for primary therapy in place of
pyrimethamine-sulfadiazine with good outcomes.22 Potential advantages of
trimethoprim-sulfamethoxazole over pyrimethamine-based protocols include lower
pill burden and less-frequent dosing, the availability of IV formulations (important
for patients who are critically ill), the availability of multiple generic formulations
with the consequent impact on cost, and increased accessibility in poor regions.
Additionally, trimethoprim-sulfamethoxazole prevents Pneumocystis jirovecii
pneumonia, other bacterial infections, and malaria and simplifies the early initiation
of combination antiretroviral therapy. Steroids may be useful if the lesions have
mass effect or when diffuse or significant cerebral edema is seen.22,32
NEUROCYSTICERCOSIS
Cysticercosis is the most common helminthic infection of the CNS, affecting
patients in not only lower-income countries but also higher-income countries
because of migration and travel. Neurocysticercosis represents a significant cause
of morbidity and mortality, causing approximately 30% of cases of epilepsy in
endemic regions,33-35 making it the most common preventable risk factor for
acquired epilepsy in adults.13
Life Cycle
Cysticercosis is caused by the cystic larval form of the pork tapeworm T. solium,
the life cycle of which involves pigs as the usual intermediate host (cysticercosis,
larval infection) and humans as the sole definitive host, harboring the adult
950 AUGUST 2021

tapeworm in the small intestine when acquired from eating undercooked pork KEY POINTS
(taeniasis). Humans develop neurocysticercosis when ingesting the eggs of the
● Therapy with
tapeworm via fecal-oral transmission. Although the immune response of the host pyrimethamine-based
works to destroy the infective embryos that are distributed in diverse tissues, treatment or trimethoprim-
cysticerci have developed a series of immune evasion mechanisms, including sulfamethoxazole is
localizing in protected sites (such as the cerebral parenchyma, protected by the usually effective for
neurotoxoplasmosis, with
blood-brain barrier), secreting molecules able to block the complement system,
clinical and radiologic
affecting the cellular response, degrading attacking immunoglobulins, or even improvement in 80% to 90%
covering themselves with host immunoglobulins. Established cysts may survive of patients receiving one of
for years or even decades in the human brain, but they eventually begin to these regimens.
degrade, losing their ability to evade the host’s immune response. The evolution
● Neurocysticercosis
of the cyst goes from a quiescent viable state to a degenerating cyst and then to represents a significant
complete resolution or calcification, generating focal inflammation throughout source of morbidity and
the process.36,37 mortality, causing
approximately 30% of cases
of epilepsy in endemic
Clinical Presentation regions, making it the most
Neurocysticercosis varies in clinical and radiologic presentation depending on the common preventable risk
location, size, and number of lesions and host immune response (FIGURE 6-638). factor in the world for adult
Seizures and headaches are the most common symptoms in neurocysticercosis and acquired epilepsy.
may occur with parenchymal cysts in any stage (CASE 6-2). Extraparenchymal cysts
● Neurocysticercosis varies
in the cerebral ventricles or in the subarachnoid spaces (racemose cysts) can cause in clinical and radiologic
mass effect, hydrocephalus, intracranial hypertension, and chronic arachnoiditis presentation depending on
(CASE 6-3)39 and are associated with a poorer prognosis.33 Spinal cord cysticercosis the location, size, and
number of lesions and host
occurs less commonly but may be an underrecognized cause of myelopathy in
immune response.
endemic regions because of limited access to neuroimaging. Asymptomatic
involvement of the muscle and subcutaneous tissue also occurs.
Diagnosis
The diagnosis of neurocysticercosis is based on neuroimaging and is supported
by immunodiagnostic tests.40 Neuroimaging is key for the diagnosis and
provides data on the number, size, localization, and stage of lesions as well as
perilesional inflammation. Guidelines published by the Infectious Disease
Society of America and the American Society of Tropical Medicine and Hygiene
for the diagnosis of neurocysticercosis recommend that patients should be
assessed with both CT and MRI.41 Brain CT provides clinicians the capacity to
visualize lesions in the brain parenchyma, and MRI represents a more sensitive
technique that improves imaging definition for parenchymal lesions and
sensitivity for extraparenchymal lesions, although its sensitivity to detect
calcified lesions is limited. Parenchymal cysts go through a series of evolutive
(involutive) stages, beginning with a viable, noninflamed cyst (vesicular stage)
that later demonstrates degenerative changes, including increased density of its
fluid contents (colloidal stage), local inflammation with edema, and contrast
enhancement, and ultimately collapse into an inflammatory nodule (granular-
nodular stage) and disappear, followed by subsequent reappearance as a calcified
scar (nodular calcified stage) in 30% to 40% of cases. The tapeworm head
(scolex) is frequently seen as an eccentric nodule in the interior of the cyst.
Rarely, some patients (particularly young women) may present with hundreds
or thousands of cysts with a diffuse inflammatory reaction and brain edema, a
condition called cysticercotic encephalitis. Subarachnoid lesions frequently grow
and infiltrate neighboring spaces; uncontrolled growth of the parasitic

FIGURE 6-6
Types and stages of neurocysticercosis. A, Axial T1-weighted MRI shows multiple viable
parenchymal cysts. B, Axial postcontrast T1-weighted MRI shows a large occipital cyst with
contrast enhancement. C, Sagittal postcontrast T1-weighted MRI shows an enhancing lesion
with contrast enhancement and edema. D, Axial noncontrast CT shows multiple parenchymal
calcifications. E, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows cysticercotic
encephalitis. F, Axial FLAIR MRI shows a cyst in the left lateral ventricle. G, Axial postcontrast
CT shows subarachnoid neurocysticercosis of the sylvian fissure. H, Axial T1-weighted MRI
shows subarachnoid neurocysticercosis in the basal cisterns.
Modified with permission from García HH, et al, Clin Microbiol Rev.38 © 2002 American Society for
Microbiology.
membrane in subarachnoid neurocysticercosis leads to large parasite clusters that

resemble a bunch of grapes called racemose neurocysticercosis (FIGURE 6-6H).
Routine hematologic tests are mostly noncontributory, and eosinophilia is
infrequent. CSF cellularity and biochemistry findings are also nonspecific,
including moderate pleocytosis with lymphomononuclear predominance,
increased protein, and, in severe cases, low glucose.
When neuroimaging tests are not conclusive, specific serology plays a major
role in confirming the diagnosis. Antibody detection is frequently used because
of its higher sensitivity, whereas antigen detection provides information on the
presence of living parasites. The enzyme-linked immunoelectrotransfer blot
(EITB) assay using lentil-lectin purified glycoprotein parasitic antigens in serum
is the assay of choice for antibody detection, with 98% sensitivity in those with
more than one live brain cyst and a specificity close to 100%. In patients with a
single brain cyst, the sensitivity drops and may be as low as 70%. No advantage is
seen in using CSF for EITB antibody detection. The viability of the lesion is a
major factor affecting antibody responses. Antigen detection is less sensitive than
antibody detection on EITB, but when it is positive, it confirms the presence of
living parasites and helps monitor the efficacy of antiparasitic treatment.42,43
952 AUGUST 2021

A 25-year-old man presented because of an episode that occurred CASE 6-2
while he was teaching a class when he developed sudden loss of
consciousness, fell to the ground, and developed a rigid posture
followed by involuntary movements of all four limbs for approximately
3 minutes. After the episode, he regained consciousness but was still
drowsy when brought to the emergency department. He had a 2-year
history of sporadic episodes of visualization of multiple colored lights
followed by headache. He lived in a major city in Peru and rarely traveled;
however, his family from the highlands regularly visited and stayed at
his house.
On examination, he was awake and oriented in time, place, and person.
He had a bite wound on his tongue. He had generalized muscle
weakness but no focal findings or any other neurologic finding.
Brain MRI showed one
left occipital cystic lesion
with surrounding edema
(FIGURE 6-7A). Two additional
cystic lesions without edema
were also observed,
suggesting cysticercosis cysts
and scoleces (FIGURE 6-7B).
Serum enzyme-linked
immunoelectrotransfer blot
(EITB) assay for Taenia solium
was positive. Levetiracetam FIGURE 6-7
Imaging of the patient in CASE 6-2. A, Coronal
was started, and after a few T2-weighted MRI shows a cortical cystic lesion
days, a 2-week course of with surrounding edema in the left occipital lobe.
albendazole and praziquantel B, Axial fast imaging employing steady state
with concomitant acquisition (FIESTA) MRI demonstrates two
additional cysts, one juxtacortically in the right
dexamethasone was initiated. frontal lobe and another near the convexity, both
Over 2 years of follow-up, no with a hyperintense liquid content and a central
relapses occurred. hypointense scolex.
Intraparenchymal neurocysticercosis is a common cause of adult-onset COMMENT

epilepsy in endemic regions. EITB is highly sensitive in patients with more
than one cyst. Cases in urban areas outside endemic regions are not
uncommon because of the high influx of migration and complex population
dynamics. After infection, patients are usually asymptomatic for long
periods of time before presenting with symptoms, and symptoms
frequently occur at the time one or more of the cysts begin to degenerate
because of local inflammation. Corticosteroids are recommended along
with antiparasitic treatment to control inflammation and its complications.

CASE 6-3 A 55-year-old woman presented with a 1-year history of headaches that
partially improved with analgesics. One week earlier, the headache had
worsened, did not improve with oral analgesics, and was accompanied by
nausea and vomiting. On the morning of the day of admission, she was
somnolent and did not recognize her husband, so she was brought to the
hospital.
On examination, she was lethargic and disoriented with respect to
person, place, and time. She had no focal neurologic deficits, and her
vital signs were normal.
Initial brain CT showed ventriculomegaly with transependymal edema,
suggesting acute hydrocephalus. Ventriculoperitoneal shunt placement
was performed. The patient recovered, and follow-up MRI demonstrated
resolution of hydrocephalus but revealed anterior temporal,
pontocerebellar, and pontine
cystic mass subarachnoid
lesions (FIGURE 6-8).
Serum enzyme-linked
immunoelectrotransfer
blot (EITB) assay
for Taenia solium was
strongly positive. A
monoclonal antibody–
based enzyme-linked
immunosorbent assay (ELISA)
FIGURE 6-8
for circulating antigen
Imaging of the patient in CASE 6-3. A, Initial
was also strongly head CT reveals diffuse ventriculomegaly
positive. She received with transependymal edema. B, Axial fast
a 30-day course imaging employing steady state acquisition
(FIESTA) MRI reveals cystic lesions in the right
of albendazole and
perimesencephalic cistern and the left sylvian
dexamethasone with slow fissure. The lesions seen here are poorly defined
tapering of steroids. on CT.
COMMENT Subarachnoid neurocysticercosis can be life-threatening because of

intracranial hypertension with or without hydrocephalus by direct mass
effect or arachnoiditis, or both. Serology commonly shows very high
antigen levels and antibody responses. MRI is usually required for the
diagnosis because CT may only show enlarged or distorted ventricles or
subarachnoid spaces without a clear demonstration of parasitic lesions.
Management requires long-term antiparasitic treatment but may also
require surgical excision of large lesion conglomerates. Higher doses of
steroids help to reduce complications before, during, and following
antiparasitic treatment.
954 AUGUST 2021

Standard diagnostic criteria for neurocysticercosis were first developed in 1996 KEY POINTS
and last updated in 2017 (TABLE 6-1)40,44; they include absolute (confirmatory
● The enzyme-linked
by itself ), neuroimaging, and clinical/exposure criteria, prioritizing neuroimaging immunoelectrotransfer blot
as the key tool for establishing the diagnosis.40 assay using lentil-lectin
purified glycoprotein
Treatment parasitic antigens in serum is
the assay of choice for
Therapy for neurocysticercosis includes treatment of seizures and elevated
antibody detection of
intracranial pressure, if present, and antiparasitic drugs (often with steroids) if viable neurocysticercosis.
or degenerating cysts are present. Based on studies in pigs and human pathology
samples, a cyst is considered viable if it has liquid contents, and these appear similar to ● For a single parenchymal
CSF on MRI (hypointense on T1-weighted and fluid-attenuated inversion recovery cyst in neurocysticercosis,
albendazole at 15 mg/kg/d
[FLAIR] sequences, hyperintense on T2-weighted images). Degenerating cysts may for 7 to 15 days is the
have lost their ability to produce an adult tapeworm, but these lesions still contain live regimen of choice. In cases
parasitic tissue and cells. After a long controversy regarding whether the use of with multiple viable cysts,
antiparasitic treatment was of benefit or whether it was unnecessary,45 most experts the combination of
albendazole plus
now agree that it destroys parasitic cysts and results in fewer seizure recurrences46,47; praziquantel at 50 mg/kg/d
therefore, it is of benefit in most patients with neurocysticercosis. Antiparasitic for 10 days has
treatment, however, may temporarily worsen neurologic symptoms because of demonstrated superior
the resulting inflammation around a damaged cyst. It is contraindicated in patients efficacy.
with uncontrolled elevated intracranial pressure and is usually administered with
● Schistosomal infection of
concomitant steroid therapy. For a single parenchymal cyst, albendazole at the central nervous system
15 mg/kg/d for 7 to 15 days is the regimen of choice. In cases with multiple viable (neuroschistosomiasis) is a
cysts, the combination of albendazole plus praziquantel at 50 mg/kg/d for 10 days rare complication of
schistosomiasis presenting
has demonstrated superior efficacy.41,46-49 Surgical management is limited to the
with myelopathy or
placement of ventriculoperitoneal shunts in patients with hydrocephalus and encephalopathy; it can
neuroendoscopic removal of intraventricular cysts, and occasionally large cysts or present months to years
cystic masses are surgically excised.50 after exposure.
Neurocysticercosis represents a significant burden worldwide and accounts for
tens of thousands of deaths per year. Significant advances have been achieved in
the past decade, including the demonstration that active interventions, such as
antiparasitic treatment of the human and porcine population as well as pig
vaccination, can interrupt transmission and lead to focal elimination.51 Larger
elimination efforts should demonstrate the feasibility of sustained elimination and
potential eradication.
SCHISTOSOMIASIS
Schistosomiasis is a chronic parasitic disease caused by trematode blood flukes of
the genus Schistosoma. It is endemic to sub-Saharan Africa, South America, the
Caribbean, Southwest Asia, and the Middle East.4,52,53 Three species of the
Schistosoma genus account for most cases of human schistosomiasis: Schistosoma
mansoni (Africa; Southeast Asia; and parts of Brazil, Venezuela, and the
Caribbean), Schistosoma haematobium (Africa, Southeast Asia, and the Middle
East), and Schistosoma japonicum (China, Indonesia, and the Philippines).1,17
Schistosomal infection of the CNS (neuroschistosomiasis) is a rare complication of
schistosomiasis presenting with myelopathy or encephalopathy; it can present
months to years after exposure.
Life Cycle
Humans are the definitive hosts for schistosomes. Infection occurs when the skin
of the individual is penetrated by cercariae, the free-swimming larval form of the

parasite, following exposure to fresh water infested with these parasites.52,53

Cercariae then migrate through capillaries and lymphatics to the portal venous
system, where they mature to adult worms over a few weeks. These then migrate
to the venous system of either the gastrointestinal tract (S. mansoni, S. japonicum)
or bladder (S. haematobium), and in 4 to 12 weeks, the adult parasites begin to
lay eggs, which typically lodge in the intestine or bladder mucosa and are shed in
the feces or urine, respectively. Neuroschistosomiasis is caused by ectopic
deposition of eggs in the brain and spinal cord by retrograde flow from the iliac
veins and inferior vena cava through the valveless Batson venous plexus
into the spinal cord. The eggs are immunogenic, and the host response leads to
granulomatous inflammation, with local edema, congestion, and varying degrees
of fibrosis.17,53 Cerebral schistosomiasis is more common with S. japonicum, as it has
smaller eggs that are able to migrate to the brain. The eggs of S. mansoni and
TABLE 6-1 Revised Diagnostic Criteria and Degrees of Diagnostic Certainty for
Neurocysticercosisa
Diagnostic criteria
◆ Absolute criteria
◇ Histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion
◇ Visualization of subretinal cysticercus
◇ Conclusive demonstration of a scolex within a cystic lesion on neuroimaging studies
◆ Neuroimaging criteria
◇ Major neuroimaging criteria
→ Cystic lesions without a discernible scolex
→ Enhancing lesionsb
→ Multilobulated cystic lesions in the subarachnoid space
→ Typical parenchymal brain calcificationsb
◇ Confirmative neuroimaging criteria
→ Resolution of cystic lesions after cysticidal drug therapy
→ Spontaneous resolution of single small enhancing lesionsc
→ Migration of ventricular cysts documented on sequential neuroimaging studiesb
◇ Minor neuroimaging criteria
→ Obstructive hydrocephalus (symmetric or asymmetric) or abnormal enhancement of
basal leptomeninges
◆ Clinical/exposure criteria
◇ Major clinical/exposure
→ Detection of specific anticysticercal antibodies or cysticercal antigens by
well-standardized immunodiagnostic testsb
→ Cysticercosis outside the central nervous systemb
→ Evidence of a household contact with Taenia solium infection.
956 AUGUST 2021

S. haematobium are larger and more frequently migrate to the lumbosacral spinal
cord, although they may occasionally affect the brain.1
Acute cerebral neuroschistosomiasis may produce a nonspecific encephalopathy
that generally resolves within a few days or weeks. Chronic infection can present
as a slowly expanding intracranial mass (pseudotumor), which can be a solitary
mass or multiple mass lesions because of the development of parenchymal brain
granulomas.1,17,53 The most common manifestation of neuroschistosomiasis is
headache, and other symptoms vary depending on the location of the lesion in
the brain (motor deficits, visual abnormalities, seizures, altered mental status,
vertigo, sensory impairment, speech disturbances, cognitive impairment,
vomiting, and ataxia). Parenchymal brain and subarachnoid hemorrhages may
◇ Minor clinical/exposure
→ Clinical manifestations suggestive of neurocysticercosisb
→ Individuals coming from or living in an area where cysticercosis is endemicb
Degree of diagnostic certainty
◆ Definitive diagnosis
◇ One absolute criterion
◇ Two major neuroimaging criteria plus any clinical/exposure criteria
◇ One major and one confirmative neuroimaging criterion plus any clinical/exposure criteria
◇ One major neuroimaging criterion plus two clinical/exposure criteria (including at least one
major clinical/exposure criterion), together with the exclusion of other pathologies
producing similar neuroimaging findings
◆ Probable diagnosis
◇ One major neuroimaging criterion plus any two clinical/exposure criteria
◇ One minor neuroimaging criterion plus at least one major clinical/exposure criterion
a
Reprinted with permission from Del Brutto OH, et al, J Neurol Sci.44 © 1996 Elsevier Science B.V.
b
Operational definitions. Cystic lesions: rounded, well-defined lesions with liquid contents of signal similar
to that of CSF on CT or MRI; enhancing lesions: single or multiple, ring- or nodular-enhancing lesions of
10 mm to 20 mm in diameter, with or without surrounding edema, but not displacing midline structures;
typical parenchymal brain calcifications: single or multiple, solid, and most usually <10 mm in diameter;
migration of ventricular cyst: demonstration of a different location of ventricular cystic lesions on
sequential CTs or MRIs; well-standardized immunodiagnostic tests: so far, antibody detection by
enzyme-linked immunoelectrotransfer blot assay using lentil lectin-purified T. solium antigens, and
detection of cysticercal antigens by monoclonal antibody-based enzyme-linked immunosorbent assay
(ELISA); cysticercosis outside the central nervous system: demonstration of cysticerci from biopsy of
subcutaneous nodules, x-ray films or CT showing cigar-shaped calcifications in soft tissues, or visualization
of the parasite in the anterior chamber of the eye; suggestive clinical manifestations: mainly seizures
(often starting in individuals aged 20 to 49 years; the diagnosis of seizures in this context is not excluded if
patients are outside of the typical age range), but other manifestations include chronic headaches, focal
neurologic deficits, intracranial hypertension and cognitive decline; cysticercosis-endemic area:
a place where active transmission is documented.
c
The use of corticosteroids makes this criterion invalid.

KEY POINT occur in some cases and are related to segmental damage of small leptomeningeal
or parenchymal blood vessels induced by the parasites. Signs of systemic
● Transverse myelitis is
the most common
schistosomiasis are typically absent.1,17,54,55
presentation of spinal On CT and MRI, cerebral neuroschistosomiasis lesions appear as solitary or
neuroschistosomiasis and is multiple subcortical mass lesions surrounded by hypodense or T2-hyperintense
related to granulomatous edema, with heterogeneous contrast enhancement and irregular borders. A linear
lesions with inflammatory
enhancement pattern surrounded by multiple enhancing nodules (the arborized
necrosis of the spinal cord.
pattern) is suggestive but nonspecific for neuroschistosomiasis (FIGURE 6-9).1,2,4,53-57
Transverse myelitis is the most common presentation of spinal
neuroschistosomiasis and is related to granulomatous lesions with inflammatory
necrosis of the spinal cord. Symptoms usually progress in an acute to subacute time
course, with a peak at 15 days after the onset of symptoms. Granulomas may form in
the spinal cord, nerve roots, or, most commonly, both. The lower spinal cord is most
frequently affected, specifically at the levels of T11 through L1, possibly because of
increased anastomoses between the Batson venous plexus with the portal venous
system at this location.52,53,58 The most common initial symptoms are low back pain (in
79% to 100% of individuals) or pain in the lower limbs, which can be symmetric or
asymmetric. Lower spinal cord or cauda equina or conus medullaris involvement is
common, causing weakness of the lower limbs (CASE 6-4), lower limb sensory
disturbance, sphincter dysfunction, sexual dysfunction, and abnormal reflexes.1,53,58
In some patients, acute paraplegia may result from occlusion of the anterior spinal
artery by the parasites. CSF analysis usually reveals mild mononuclear pleocytosis and
an increased protein level. MRI typically reveals enlargement of the lower spinal cord
or the conus medullaris on T1-weighted images, signal hyperintensity on T2-weighted
images, and heterogeneous nerve root patterns of contrast enhancement.1,52,53
Neuroschistosomiasis should be suspected in patients who live in or traveled to an
endemic area and who present with a compatible clinical syndrome.
Diagnosis
Diagnosis requires evidence of active
Schistosoma infection. Direct visualization
of eggs in stool or urine, punch biopsy from
the rectal mucosa (higher sensitivity),52 or
indirect assays measuring antibodies against
schistosomal antigens have variable
sensitivity depending on the timing and
burden of infection. Serologic testing is
not useful in individuals from endemic
regions because schistosomiasis may cause
asymptomatic infection and schistosomal
antibodies may persist for years. Since the
radiographic pattern in cerebral
schistosomiasis is nonspecific, brain
biopsy may be required to confirm the
FIGURE 6-9
Axial postcontrast T1-weighted MRI diagnosis.52,53
shows patchy enhancement in an
arborized pattern in the left temporal Treatment
lobe in cerebral schistosomiasis. Both cerebral and spinal cord
Reprinted with permission from Cho T,
Continuum (Minneap Minn).53 © 2018 neuroschistosomiasis are managed almost
American Academy of Neurology. exclusively medically and only rarely
958 AUGUST 2021

require surgical intervention (eg, decompressive laminectomy, mass excision,
liberation of roots for larger granulomas in spinal cord neuroschistosomiasis).
Praziquantel is effective in patients with brain or spinal cord involvement, but
dosing and timing lack evidence-based guidelines (recommended dose varies by
species).53,54 Some investigators have reported improved outcomes from
maximal surgical resection followed by praziquantel. Steroids should be initiated
if neuroschistosomiasis is suspected, followed by praziquantel once the diagnosis is
confirmed. Corticosteroids can mitigate the process of endarteritis, which can lead to
progressive brain and spinal cord damage. In general, the outcome tends to be worse
for spinal cord neuroschistosomiasis than cerebral neuroschistosomiasis.1,53
A 22-year-old man traveled to Malawi. Three months after returning to CASE 6-4
the United States, he noticed back pain and weakness in both legs that
progressively worsened. A spinal MRI demonstrated an intramedullary
lesion at the T11-T12 level (FIGURE 6-10A59). Serum laboratory evaluation
including comprehensive metabolic panel, liver function tests, and
complete blood cell count were normal, and no parasite eggs were found
in stools or urine. Surgery was performed, and pathologic examination of
the excised tissue revealed an inflammatory granuloma around a
crenated Schistosoma egg (FIGURE 6-10B). Postsurgical evolution was
favorable with complete recovery.
FIGURE 6-10
Imaging of the patient in CASE 6-4 with spinal schistosomiasis. A, Sagittal postcontrast
T1-weighted MRI of the spine shows an intramedullary lesion in the lower thoracic spine. B,
Pathologic (hematoxylin and eosin [H&E]) specimen from the same lesion shows a
granuloma around a Schistosoma egg.
Images courtesy of Christina Coyle, MD. Reprinted from Coyle CM, Handb Clin Neurol.59 © 2013 Elsevier B.V.
Spinal schistosomiasis should be suspected in travelers to endemic regions COMMENT

who develop compatible neurologic, particularly spinal, manifestations.
The finding of Schistosoma eggs in feces or urine establishes the diagnosis,
although the sensitivity of parasitologic diagnosis is limited.

KEY POINT OTHER PARASITIC INFECTIONS THAT MAY AFFECT THE HUMAN
NERVOUS SYSTEM
● A variety of parasitic
infections may affect the
A variety of parasitic infections may affect the human CNS less frequently.
human central nervous Epidemiologic suspicion based on country of origin or travel history, particularly
system less frequently. in the setting of atypical clinical presentations of neurologic disease, should alert
Epidemiologic suspicion, the clinician to consider parasitic infections of the CNS. Parasites that may cause
particularly in the settings of
encephalitis, meningoencephalitis, and multiple brain abscesses include
atypical clinical
presentations of neurologic free-living amoebas (Acanthamoeba species, Balamuthia mandrillaris, Naegleria
disease, should help to fowleri), Trypanosoma (sleeping sickness in African trypanosomiasis),
detect parasitic infections Angiostrongylus cantonensis (eosinophilic meningitis); Gnathostoma spinigerum
of the central nervous
(gnathostomiasis), Strongyloides stercoralis (disseminated strongyloidiasis),
system.
Trichinella spiralis (trichinosis), and Paragonimus (paragonimiasis). Focal
noncystic lesions can be found in Chagas disease (American trypanosomiasis);
toxocariasis (T. canis, Toxocara cati), paragonimiasis (Paragonimus species) or
sparganosis (Spirometra species), whereas cystic lesions occur in coenuriasis
(Taenia multiceps) and hydatid disease (Echinococcus granulosus). Hemorrhagic or
ischemic stroke can be caused by gnathostomiasis (G. spinigerum), disseminated
strongyloidiasis (S. stercoralis), and trichinosis (T. spiralis). Spinal disease can be
caused by toxocariasis and gnathostomiasis.
CONCLUSION
Parasitic infections affect the human CNS with relative frequency and should be
considered in the differential diagnosis of neurologic lesions, particularly in
individuals from endemic regions or those with a history of travel. Cerebral
malaria, toxoplasmosis, neurocysticercosis, and neuroschistosomiasis are among
the most common parasitic infections of the nervous system, but many other
diseases are caused by pathogenic parasites in the human host.
ACKNOWLEDGMENTS
The author is deeply grateful to Christina Coyle, MD (Einstein Medical College,
NY); Jose Vidal, MD (Instituto de Infectologia Emilio Ribas, Sao Paulo); and
Jesus Abanto, MD; Carolina Andrade, MD; Carolina Guzman, MD; Sofia Sanchez,
MD; and Luz Toribio, MSc (Universidad Cayetano Heredia, Lima) for their help in
providing material and reviewing and organizing the literature and cases.
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962 AUGUST 2021

Neurologic REVIEW ARTICLE

Complications of Human C O N T I N U UM A U D I O
ONLINE
Immunodeficiency Virus
By Marie F. Grill, MD
ABSTRACT
PURPOSE OF REVIEW: This article reviews the neurologic complications
associated with human immunodeficiency virus (HIV) infection.
RECENT FINDINGS: Neurologic complications of HIV may be caused by direct

virally mediated pathology, immune-mediated phenomena in response to
viral infection, or opportunistic infections secondary to depletion of
lymphocytes. These neurologic disorders may be influenced by the degree
of immunosuppression (ie, CD4+ T-cell lymphocyte count) and stage of
infection (early versus late), as well as use of antiretroviral therapy, and
may manifest as a variety of central and peripheral neurologic syndromes,
including the more commonly encountered HIV-associated cognitive
disorders and length-dependent sensorimotor polyneuropathy, respectively. CITE AS:
Immune dysregulation underlies the majority of these neurologic phenomena, CONTINUUM (MINNEAP MINN)
as well as other HIV-associated conditions including immune reconstitution DISEASE):963–991.
inflammatory syndrome (IRIS), CD8 lymphocytosis, and potentially the
development of compartmentalized infection within the CSF, also referred Address correspondence to
to as CSF escape. Dr Marie F. Grill, Mayo Clinic,
Department of Neurology, 13400
E Shea Blvd, Scottsdale, AZ
SUMMARY: This article reviews a spectrum of clinical syndromes and related 85259, Grill.Marie@mayo.edu.
neuropathologic states associated with HIV infection.
Dr Grill reports no disclosure.
UNLABELED USE OF
INTRODUCTION PRODUCTS/INVESTIGATIONAL
H
uman immunodeficiency virus (HIV) is a retrovirus that infects USE DISCLOSURE:
Dr Grill discusses the
T cells, resulting in immunodeficiency. HIV falls under the genus unlabeled/investigational use of
Lentivirus, meaning “slow” virus, reflecting the chronicity of neuropathic pain medications
infection. Evidence of HIV RNA and inflammation in the CSF has (amitriptyline, lamotrigine,
lidocaine gel, and topical
been identified from the time of acute infection through the entire capsaicin cream) not
course of the disease, correlating with the clinical observation that nervous specifically approved for human
system manifestations of HIV can occur throughout the course of infection.1,2 immunodeficiency virus (HIV)-
associated neuropathy, as well
Although markers of intrathecal inflammation have been shown to decrease with cidofovir, mirtazapine, and
the initiation of antiretroviral therapy (ART), evidence suggests that some pembrolizumab for the
treatment of progressive
intrathecal inflammation persists and correlates with CSF viral load, as may be multifocal
seen with CSF compartmentalization/escape in which neurologic symptoms may leukoencephalopathy.
be seen despite plasma virologic suppression.3
Neurologic complications of HIV may result from direct viral complications, © 2021 American Academy
immune-mediated complications, opportunistic infections, and ART-associated of Neurology.

NEUROLOGIC COMPLICATIONS OF HIV
TABLE 7-1 Human Immunodeficiency Virus–Associated Neurologic Syndromes of the

Central Nervous System
Cerebrovascular disease
◆ Stroke: ischemic and hemorrhagic
◆ Vascular lesions: vasculitis/vasculopathy (infectious: varicella-zoster virus [VZV], syphilis,
tuberculosis [TB]), fusiform aneurysms
Meningitis
◆ Acute human immunodeficiency virus (HIV) seroconversion
◆ Opportunistic infections/co-infections
◇ Cryptococcus neoformans (CD4+ count <100 cells/mm3)
◇ Neurosyphilis (any CD4+ count)
◇ TB (CD4+ count <100 cells/mm3)
Encephalitis
◆ HIV encephalitis
◆ HIV-associated dementia
◆ CD8+ encephalitis
◆ Opportunistic infections/co-infections
◇ Cytomegalovirus (CMV) (CD4+ count <50 cells/mm3); may also be associated with
ventriculitis
◇ Herpesviruses: human herpesvirus 6, herpes simplex virus, CMV, VZV
Intracranial mass/focal lesions
◆ Opportunistic infections
◇ JC virus: progressive multifocal leukoencephalopathy (CD4+ count <200 cells/mm3); JC
virus encephalopathy and granule cell neuronopathy variants
◇ Toxoplasmosis (CD4+ count <100 cells/mm3)
◇ Primary central nervous system lymphoma (CD4+ count <50 cells/mm3)
◇ Tuberculoma
◇ Cryptococcoma
◇ Other fungal pathogens including endemic mycoses
◇ Nocardia species abscess
◆ Abscesses
◇ Fungal, Nocardia species, pyogenic bacteria
◆ Acute disseminated encephalomyelitis (ADEM) in acute HIV seroconversion
Myelitis
◆ Transverse myelitis: HIV acute seroconversion
◆ HIV vacuolar myelopathy
◆ Opportunistic infection: CMV, VZV; rarely toxoplasmosis
964 AUGUST 2021

toxicities. In general, early in HIV infection, acute seroconversion syndrome and KEY POINTS
autoimmune phenomena are most likely to be seen, whereas in middle to late
● Evidence of human
HIV infection, opportunistic infections, malignancies, and long-term immunodeficiency virus
complications of HIV are more frequently encountered. When evaluating a (HIV) RNA and inflammation
patient with HIV infection, the history should include the duration of infection, in the CSF has been
ART use history, history of previous opportunistic infections, other medical identified from the time of
acute infection through the
comorbidities, CD4+ nadir and most recent CD4+ count, and HIV plasma viral
entire course of the disease,
load. Neurologic examination should focus on localization and syndrome correlating with the clinical
characterization to guide further diagnostic studies, which may include MRI of observation that nervous
the brain and/or spinal cord, CSF studies, detailed neuropsychologic testing, system manifestations of
HIV can occur throughout
and/or nerve conduction studies and EMG.
the course of infection.
DIRECT VIRAL NEUROLOGIC COMPLICATIONS OF HIV ● Neurologic complications

HIV complications specific to the virus itself manifest within both the central and of HIV may result from
peripheral nervous system and include acute seroconversion syndromes as well direct viral complications,
immune-mediated
as HIV-associated neurocognitive disorders, vacuolar myelopathy, and complications,
peripheral neuropathy (TABLE 7-1 and TABLE 7-2). opportunistic infections,
and antiretroviral therapy
Acute Seroconversion Syndromes (ART)-associated toxicities.
Aseptic meningitis with or without concomitant cranial nerve involvement may
● Early in HIV infection,
occur at the time of initial HIV infection. Unilateral or bilateral facial paralysis acute seroconversion
has been described at a median of 15 days after the onset of clinical disease and syndrome and other
may actually precede HIV type 1 (HIV-1) seroconversion with postulated autoimmune-mediated
phenomena are most likely
mechanisms including a systemically triggered immune-mediated cranial
to be seen, whereas in
neuropathy, although a direct virally induced lesion of nerve or ganglion cannot middle to late HIV infection,
be excluded. A preceding febrile illness with rash before or accompanying the opportunistic infections,
onset of meningitis or facial palsy should raise suspicion for acute HIV infection.4 malignancies, and long-term
Of note, HIV testing may initially be negative at the time of acute complications of HIV are
more frequently
seroconversion, thus HIV viral load should be obtained if HIV seroconversion is encountered.
suspected, and plasma antigen/antibody should be retested after several weeks
(ie, beginning 45 days after possible HIV exposure per Centers for Disease ● Patients with acute HIV
Control and Prevention [CDC] recommendations).5 seroconversion have also
presented with Guillain-
Other acute HIV seroconversion syndromes include Guillain-Barré syndrome Barré type syndrome/acute
(typically with a CSF pleocytosis) and, less frequently, transverse myelitis, acute inflammatory demyelinating
disseminated encephalomyelitis (ADEM), a multiple sclerosis–like illness, and polyradiculoneuropathy.
bilateral brachial plexus neuritis.6-11 These entities may be virally mediated, Other rarely observed
neurologic conditions that
parainfectious/immune-mediated, or a combination of the two. Other neurologic
may be seen at the time of
symptoms self-reported at the time of acute HIV infection (as defined as the first seroconversion include
12 weeks after HIV diagnosis with a median estimated HIV infection duration of transverse myelitis, acute
19 days at study entry for the participants evaluated) include memory and disseminated
encephalomyelitis (ADEM), a
concentration difficulties; speech, gait, and upper extremity coordination
multiple sclerosis–like
deficits; and involuntary movements.12 illness, and bilateral brachial
plexus neuritis.
Chronic Neurologic Complications of HIV
Neurologic complications of chronic HIV infection include HIV-associated
neurocognitive disorders (HAND), vacuolar myelopathy, and peripheral
neuropathy.
HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS. HAND includes asymptomatic

neurocognitive impairment, minor or mild neurocognitive disorder, and

HIV-associated dementia, entities distinguished by severity of symptomatology

and functional impairment, as well as neuropsychologic test performance
(TABLE 7-3).13 This classification has replaced older terminology, with
HIV-associated dementia now subsuming what was previously referred to as
acquired immunodeficiency syndrome (AIDS) dementia complex, the term used for
a subacute or chronic encephalitis presenting in later stages of HIV infection and
characterized by progressive dementia often accompanied by associated motor
and behavioral abnormalities (FIGURE 7-1).14 HAND refers to the clinical
spectrum of HIV-associated cognitive impairment per the research consensus
criteria from Antinori and colleagues,15 which rely on neuropsychologic testing.
TABLE 7-2 Human Immunodeficiency Virus–Associated Neurologic Syndromes of the

Peripheral Nervous System
Disorders of nerve and nerve root

◆ Peripheral neuropathy
◇ Human immunodeficiency virus (HIV) distal symmetric polyneuropathy
◇ Antiretroviral–associated neuropathy (typically with nucleoside reverse transcription
inhibitors)
◇ Diffuse infiltrative lymphocytosis syndrome–associated multifocal symmetric axonal
neuropathy
◆ Mononeuritis multiplex
◇ Immune-mediated
◆ Poly(radiculo)neuropathy
◇ Acute inflammatory demyelinating polyradiculoneuropathy/Guillain-Barré syndrome
→ Acute HIV seroconversion
→ Immune-mediated
◇ Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
→ Immune-mediated, relapsing-remitting, or chronic
◇ Diffuse infiltrative lymphocytosis syndrome–associated lumbosacral radiculoplexus
neuropathy
◆ Radiculitis/radiculopathy
◇ Cytomegalovirus (CD4+ count <50 cells/mm3), herpes simplex virus
◆ Plexopathy
◇ Lumbosacral radiculoplexus neuropathy
◇ Brachial plexus neuritis
→ Acute HIV seroconversion
→ Immune-mediated
Motor neuronopathy
HIV-associated neuromuscular syndrome
Myasthenia gravis
Myositis
◆ Toxoplasmosis
966 AUGUST 2021

The HAND terminology refers specifically to HIV-specific cognitive impairment
and excludes cognitive impairment due to opportunistic infections. This is in
contrast to terms such as HIV encephalitis and HIV encephalopathy that have been
used to describe neurocognitive dysfunction in HIV more broadly and which
may be caused by numerous factors including opportunistic infections.15,16
Asymptomatic neurocognitive impairment is asymptomatic/subclinical,
identified only with neuropsychologic testing and used in research settings. Minor
or mild neurocognitive disorder and HIV-associated dementia exist on a spectrum
of clinically manifest neuropsychological impairment of varying severity,
primarily affecting executive functioning, memory, learning, and attention.17 The
most significant risk factor for HAND is lack of treatment with ART and low CD4+
T-cell nadir, although other factors such as advanced age; comorbid vascular
risk factors such as hypertension, dyslipidemia, and hypertension; hepatitis C
co-infection; and illicit drug use also confer increased risk.
As part of the clinical evaluation, screening questions should assess memory,
attention, and concentration by asking about the ability to multitask, recall what
one has previously read, and keep appointments. It can be helpful to obtain
collateral information from family and friends with respect to changes in
cognition, behavior, mood, and functional status because self-assessment may be
unreliable. Cognitive dysfunction may also be accompanied by psychomotor
slowing and impaired motor control, with severity typically correlating with the
degree of cognitive dysfunction. Bedside mental status tests such as the Montreal
Definitions of Human Immunodeficiency Virus–Related Central Nervous TABLE 7-3

System Diseasesa
Clinical designations and acquired

immunodeficiency syndrome (AIDS) dementia
Frascati HAND research criteria complex equivalents
Human immunodeficiency
virus (HIV)-associated Symptoms and
neurocognitive disorders functional Neuropsychological Symptoms and
(HAND) diagnosis status test performance functional status Stage and descriptors
HIV-associated dementia Major Below 2 SD in ≥2 of 5-7 Major functional Stages 1-4: difficulty with
functional domains impairment: usually demanding activities to
impairment cognitive and motor severe cognitive motor
dysfunction deficits
Minor neurocognitive Mild symptoms Below 1 SD in ≥2 of 5-7 Mild but distinct Stages 0.5-1: minimal to
disorderb and/or domains functional distinct symptoms and
functional impairment verified difficulty with activities
impairment by examination
Asymptomatic No symptoms Below 1 SD in ≥2 of 5-7 Not applicable to Stage 0.5: signs of

neurocognitive impairment or functional domains bedside clinical cognitive or motor
impairment diagnosis dysfunction without
symptoms or evident
impairment in activities
SD = standard deviation.
a
Reprinted with permission from Grill MF and Price RW, Handb Clin Neurol.13 © 2014 Elsevier B.V.
b
Also referred to as mild neurocognitive disorder (MND).

Cognitive Assessment (MoCA) may be

helpful in screening for cognitive
disorders (and preferred to the
Mini-Mental Status Examination
[MMSE], which weights orientation more
heavily), but their sensitivity may be
limited in patients infected with HIV, who
are often younger and have less severe
cognitive impairment than the population
in which the MMSE and MoCA tests have
been validated.18 Even HIV-specific
screening tests such as the HIV-associated
dementia screen and the International HIV
Dementia Scale (IHDS) lack sensitivity for
less severe HAND, although the latter scale
has been validated internationally in HIV
FIGURE 7-1 infection and considered preferable to
Axial fluid-attenuated inversion recovery other bedside screening tools. The IHDS
(FLAIR) MRI of the brain demonstrates
diffuse leukoencephalopathy (white
consists of timed finger-tapping with the
matter changes) consistent with human nondominant hand (graded per the Unified
immunodeficiency virus (HIV) Parkinson Disease Rating Scale),
encephalitis. psychomotor speed test with alternating
sequence test (the three-step Luria) also
with the nondominant hand, and recall of
18,19
four items at 2 minutes. Detailed neuropsychologic testing is recommended as
part of the diagnostic evaluation of HAND if feasible, although this is often
unavailable in resource-limited settings.
HIV-associated dementia was initially described as having a subcortical
dementia phenotype characterized by decreased cognitive processing speed,
mood and motivation disturbances, and possible associated movement
disorder.20 On neuropsychological testing, impairments were predominant in
speed of information processing tests (eg, Wechsler Adult Intelligence Scale-III
Digit Symbol Test and Trail Making Test Part A) and motor tests (eg, grooved
pegboard test). Some common presenting symptoms are outlined in CASE 7-1.
In the ART era, however, a cortical phenotype is seen with greater frequency,
characterized by more severe memory dysfunction with additional difficulties in
language, calculation, abstraction, and other cortical functions.20 In studies using
neuropsychological testing, patients in the ART era tended to have been infected
longer than those in a pre-ART cohort and were found to have more difficulty
with memory tests (eg, story memory test and figure memory test), as well as
executive functioning tasks (eg, Wisconsin Card Sorting Test); although verbal
fluency deficits were more commonly encountered in the pre-ART cohort,
the testing battery was not structured to make the distinction between cortical
and subcortical phenotypes due to limited language (as well as visuospatial
function) testing.21
The differential diagnosis for HAND includes central nervous system (CNS)
opportunistic infections and co-infections (eg, neurosyphilis). As with cognitive
disorders in patients not infected with HIV, it is also important to evaluate for
toxic, metabolic, and vascular causes (accelerated atherosclerosis is common in
HIV) as well as comorbid sleep and psychiatric disorders, which are also often
968 AUGUST 2021

encountered in this patient population. As patients with HIV live into older age, KEY POINTS
degenerative dementia may also be considered.
● HIV-associated
Neuroimaging in HIV-associated dementia may demonstrate cerebral atrophy neurocognitive disorders
(volume loss out of proportion to age-related changes) as well as T2/fluid- include asymptomatic
attenuated inversion recovery (FLAIR) hyperintense changes within the deep neurocognitive impairment,
white matter, typically sparing U fibers, that can be widespread and are often minor or mild neurocognitive
disorder, and
asymmetric.22 These changes may not always be present, however, particularly
HIV-associated dementia,
in patients with milder forms of HAND in whom less specific scattered white distinguished by the degree
matter abnormalities may be seen in comparison with more confluent bilateral of symptomatology and
symmetric white matter changes (particularly periventricular and semiovale functional impairment, as
well as neuropsychologic
regions with relative sparing of subcortical white matter) seen in advanced
test performance.
infection. Progression of T2 hyperintense changes has been shown to be
associated with lower CD4+ count; basal ganglia involvement is also more often ● Asymptomatic
seen in those with CD4+ count less than 200 cells/mm3.23 Brain MRI is also neurocognitive impairment
essential in evaluating for other potential causes of altered cognition in this is asymptomatic/subclinical,
identified only with
population, such as opportunistic infections (FIGURE 7-3). neuropsychologic testing
Advanced imaging techniques in research settings have demonstrated and used in research
additional characteristics associated with HAND. Volumetric analysis has settings. Minor or mild
demonstrated volume loss in more advanced HAND/HIV-associated dementia, neurocognitive disorder and
HIV-associated dementia
including specifically within white matter, posterior cortex, and basal ganglia exist on a spectrum of
in patients infected with HIV in the pre-ART era.24,25 Diffusion tensor imaging clinically manifest
has revealed decreased fractional anisotropy and increased mean diffusivity of neuropsychological
white matter tracts within the corpus callosum.25,26 Magnetic resonance impairment of varying
severity, primarily affecting
spectroscopy has demonstrated reduced N-acetylneuraminic acid (a neuronal
executive functioning,
marker), increased choline (a marker of inflammation and cellular proliferation), memory, learning, and
and increased myo-inositol (a marker of gliosis) in patients infected with HIV attention.
compared with controls, with the greatest change seen in patients with more
severe HAND.25,27 Functional MRI (fMRI) has shown impairment in frontostriatal
networks.28 Positron emission tomography (PET) has demonstrated glucose
hypometabolism in subcortical areas as well as in the mesial frontal lobes in
patients on combination ART; PET techniques examining ligands targeting
microglial activation, neurotransmitter metabolism, and amyloid deposition are
under investigation.25,29,30
CSF studies are also helpful in excluding alternative diagnoses such as
neurosyphilis, cytomegalovirus (CMV) encephalitis, and cryptococcal
meningitis, among others. CSF profiles are often unremarkable in HAND,
although lymphocytic predominant pleocytosis (up to 20 white blood cells/mm3)
and mildly elevated protein levels may be present in HIV infection (although
they are not specific to HAND).31 Checking viral load in the CSF can be helpful in
the less common scenario of compartmentalized CNS infection. Several potential
biomarkers have been evaluated in the research setting, including markers of
immune (macrophage/monocyte) activation (eg, plasma and CSF cytokines
including monocyte chemotactic protein-1 and CSF neopterin), neuronal
injury/protection (eg, CSF neurofilament light chain), cell stress, oxidative
stress, energy metabolism, and glutamate regulation.32-34
Institution of ART to achieve virologic suppression is the primary treatment
for HAND. Given cognitive deficits, a strategy to manage medications is crucial
to assure adherence to ART. Studies demonstrating an association of
neurocognitive impairment with nadir CD4+ suggest that prevention of more
severe immunosuppressed states may play a role in the prevention of HAND,

and, accordingly, the incidence of HIV-associated dementia has decreased

significantly in the ART era.35 Although the use of ART regimens with improved
CNS penetration has been associated with decreased CNS replication, this has not
consistently translated to improved neuropsychological testing performance.
Compartmentalized CNS infection may explain some of this. In addition, some
neuropsychological dysfunction may be driven by downstream effects of chronic
inflammatory responses to the virus that persist despite adequate virologic
suppression in the CNS (eg, release of HIV-associated viral products driving
proinflammatory pathways that lead to neuronal injury). The role of
inflammation in HAND is further supported by research demonstrating that
increased markers of CD4+ and CD8+ T-cell lymphocyte activation in the CSF
CASE 7-1 A 53-year-old man presented with several months of short-term memory
difficulties; his partner described him as increasingly withdrawn and
noted that he had been misplacing items. He reported difficulties
planning and being overwhelmed when tasked with more than one thing.
He endorsed word-finding difficulties and having to reread information to
comprehend it. He denied any headaches or focal neurologic symptoms.
Past medical history was notable for human immunodeficiency virus (HIV)
diagnosed 2 years before with a CD4+ nadir of 65 cells/mm3 at that time.
He reported adherence to antiretroviral therapy (ART) since that time.
Recent laboratory values showed a CD4+ count of 300 cells/mm3 and
plasma viral load detected at 400 copies/mL.
On examination, he had a flat affect. He scored 28 of 30 on the
Mini-Mental Status Examination, missing 2 points for attention. Some
slowness was noted on finger-tapping. Neurologic examination was
otherwise unremarkable. He was referred for neuropsychological testing,
which demonstrated some difficulties on tests of attention and executive
functioning; memory function was intact. He also had elevated scores on
self-reported measures of depression as well as anxiety. Brain MRI was
remarkable only for nonspecific white matter changes (FIGURE 7-2). Basic
laboratory testing including vitamin B12 level and rapid plasma reagin (RPR)
were within normal ranges. Lumbar puncture showed a white blood cell
count of 5 cells/mm3 (100% lymphocytes) and mildly elevated protein of
60 mg/dL; infectious studies in CSF including Venereal Disease Research
Laboratory (VDRL), varicella-zoster antibody, and cryptococcal antigen
were negative.
His clinical syndrome was felt to be most consistent with HIV-associated
neurocognitive impairment, specifically minor or mild neurocognitive
disorder. He was initiated on an antidepressant for comorbid depression,
and the importance of adherence to combination ART was emphasized;
continued clinical monitoring over time was planned.
970 AUGUST 2021

was associated with neurocognitive decline as measured by neuropsychologic
testing performance in patients on combination ART with virologic suppression.36
The pathologic hallmark of HAND is postulated to be microglial activation
resulting in the release of cytokines, viral proteins such as Tat, and other
neurotoxic products that directly and indirectly (via astrocyte-induced
neuroinflammation) lead to neuronal injury and cell death; further, microglial
cells may serve as a possible chronic reservoir within the CNS compartment.36,37
These features have differential distribution in cases in the pre-ART versus ART
eras, with the former demonstrating predominance within subcortical structures
and the latter in the hippocampus and temporal regions.38 Amyloidβ (Aβ)
plaques have also been reported in patients with HAND.39
FIGURE 7-2
Axial fluid-attenuated inversion
recovery (FLAIR) MRI of the brain of
the patient in CASE 7-1 showing some
scattered nonspecific white matter
signal abnormalities.
Difficulties with attention and executive functioning are characteristic of COMMENT

the cognitive deficits that patients experience in HIV-associated
neurocognitive impairment. The slowed finger-tapping reflects motor
impairment. The detailed neuropsychological testing allowed for further
characterization of this patient’s cognitive difficulties, as well as
supporting localization to frontosubcortical circuitry. A low CD4+ count is
associated with development of HIV-associated neurocognitive disorders
(HAND). Reinforcing adherence to ART is important in preventing further
progression of cognitive decline. Mood disorders such as depression may
be comorbid; thus, it is important to screen for these and address them
accordingly.

HIV-ASSOCIATED VACUOLAR MYELOPATHY.

HIV-associated vacuolar myelopathy is
most often seen in advanced AIDS, and
concurrent HIV-associated dementia is
common. This condition has become rare
since the advent of ART. Patients develop
a slowly progressive spastic paraparesis
with associated gait disturbance, impaired
bladder control, and sensory dysfunction.
Examination demonstrates weakness and
impaired vibratory and proprioceptive
sense with myelopathic signs including
brisk deep tendon reflexes and lower
extremity spasticity. MRI of the spinal
FIGURE 7-3
cord may show atrophy and T2
Axial fluid-attenuated inversion recovery hyperintensities in the posterior and
(FLAIR) MRI of the brain demonstrating lateral columns diffusely, although this is
periventricular white matter changes usually most severe in the mid lower
in a patient with long-standing human
immunodeficiency virus (HIV)
thoracic spinal cord.40 Pathologically,
infection. vacuolation of the white matter is seen,
as suggested by the name, and in autopsy
studies this entity appeared to be more
widespread than is clinically recognized.41 Other causes of myelopathy to
consider in patients with HIV include metabolic etiologies (eg, vitamin B 12
or copper deficiency) and infections including syphilis, CMV,
varicella-zoster virus (VZV), tuberculosis, and human T-cell lymphotropic
virus type II. As with HIV-associated dementia, ART is the mainstay of
therapy. Although there is limited benefit in slowing progression once
this condition has developed, cases of improvement have been
reported.42,43
COMPARTMENTALIZED CENTRAL NERVOUS SYSTEM INFECTION (CSF ESCAPE). CSF

escape refers to the presence of ongoing viral replication within the CNS
despite relative virologic suppression in the blood with ART use. Reported
presentations have included acute meningoencephalitis and a variety of clinical
signs and symptoms including cognitive impairment and focal and multifocal
neurologic deficits arising acutely or subacutely. In reported cases, CSF viral
loads have been elevated despite the absence of elevated plasma HIV viral
loads, and symptom improvement and reduction in CSF HIV viral load were
observed after adjustments to ART.44,45 Although checking CSF viral load may
be considered in individual cases, the benefit of using ART with higher CNS
penetration remains unclear, with general recommendations for treatment
based on adopting the most potent ART with the least amount of toxicity
because, ultimately, plasma virologic suppression is paramount in the
treatment approach.17,46 The ART regimen may not be the only factor that
contributes to CSF escape; significant inflammation is present in the CSF
even with a low CSF viral load, suggesting that local immune responses may
play a significant role, as occurs in immune reconstitution inflammatory
syndrome (IRIS) (discussed later), because a low CD4+ nadir is a risk factor
for both.47
972 AUGUST 2021

HIV-ASSOCIATED PERIPHERAL NEUROPATHY. The most commonly encountered KEY POINTS
neurologic complication of HIV is distal symmetric polyneuropathy.48 Although
● CSF escape refers to the
ART has both decreased the incidence of neuropathy and slowed disease presence of ongoing viral
progression in patients with distal symmetric polyneuropathy, asymptomatic replication within the
peripheral neuropathy (as defined by mild impairment in vibratory sensation in central nervous system
the great toes or diminished ankle reflexes bilaterally on examination in the compartment despite
relative virologic
absence of clinical symptoms) may be present despite virologic control. Older
suppression in the blood
age, history of impaired glucose tolerance, and neurotoxic ART use (specifically with antiretroviral therapy
protease inhibitors) have been found to be associated with an increased risk of use.
symptomatic peripheral neuropathy in patients infected with HIV, but the
mechanisms of pathogenesis are varied.49 Macrophage activation has been ● Perhaps the most
common clinically
identified in the epineurium in association with axonal degeneration and nerve encountered HIV-related
fiber loss on nerve biopsy examinations, suggesting an immune-mediated neurologic complication is
mechanism, although the precise pathogenesis of HIV-associated distal distal symmetric
symmetric polyneuropathy is unclear.50,51 Peripheral neuropathy has also been polyneuropathy. ART has
both decreased the
associated with the presence of elevated CSF inflammatory markers (neopterin incidence of this condition
and monocyte chemotactic protein-1 levels) in primary HIV infection (less than and slowed disease
1 year after HIV transmission). This may reflect the correlation between immune progression in patients with
activation in both CNS and peripheral nervous system (PNS) compartments as a distal symmetric
polyneuropathy, although
result of synchronous infection, although it is also possible that proinflammatory asymptomatic peripheral
molecules released from peripheral nerves may induce CNS changes by altering neuropathy (as defined by
cell trafficking.52 mild impairment in vibratory
Distal symmetric polyneuropathy is typically sensory predominant with sensation in the great toes or
diminished ankle reflexes
mixed small and large fiber involvement, causing pain, paresthesia, and
bilaterally on examination in
hypersensitivity in the feet (CASE 7-2). Examination demonstrates alterations in the absence of clinical
pain and temperature sensation, reduced vibratory sensation to a lesser degree, symptoms) may be present
diminished or absent Achilles deep tendon reflexes, and a normal motor despite virologic control.
examination. Nerve conduction studies demonstrate reduced or absent sensory
nerve action potentials (SNAPs) consistent with axonal polyneuropathy, and
needle EMG may demonstrate partial denervation of distal leg muscles.53 The
differential diagnosis includes ART toxicity (specifically the use of antiretroviral
nucleoside reverse transcription inhibitors including didanosine and stavudine)
and other causes of peripheral neuropathy seen in patients not infected with
HIV, such as vitamin B12 deficiency, impaired glucose tolerance, and toxins such
as alcohol.54
Treatment of distal symmetric polyneuropathy comprises ART to achieve
virological suppression as previous studies have demonstrated plasma HIV-1
RNA levels are associated with increased severity of neuropathy.55 Medications
for symptomatic management of neuropathic pain include antidepressants and
antiepileptic drugs, as well as topical analgesics. Treatment rationale is based
on extrapolation of data for use of such agents for diabetic and postherpetic
neuropathy because data are limited and conflicting for use specifically in
HIV-associated neuropathic pain for agents such as lamotrigine, amitriptyline,
lidocaine gel, and topical capsaicin cream.56-64 When selecting therapy, specific
attention should be given to avoidance of interactions with ART medications.
Immune-Mediated Complications of HIV

Some HIV-related neurologic complications result from immunologic response
to viral infection as well as from reconstitution of the immune system after ART
has been initiated.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME. IRIS is a clinical worsening

that occurs when the immune system reconstitutes. In patients with HIV, this
can follow initiation of ART when the CD4+ T-cell lymphocyte count increases
and HIV plasma viral load decreases, leading to an inflammatory rebound. This
typically occurs between 2 and 25 weeks after initiation of ART. The main risk
factors for development of IRIS are the presence of underlying opportunistic
infection and a lower CD4+ nadir, and patients with the sharpest rises in CD4+
count are most likely to develop IRIS.65 Paradoxical IRIS refers to a worsening
of a previously diagnosed infection, whereas unmasking IRIS refers to the
emergence of a previously unidentified infection.66 Worsening of neurologic
impairment, as well as new-onset neurologic decline, may be seen in neuro-IRIS,
which is most frequently associated with cryptococcal meningitis and progressive
multifocal leukoencephalopathy (PML), although it may also be seen with
toxoplasmosis and tuberculosis. For this reason, evaluation for (and induction
treatment of) underlying comorbid infections such as Cryptococcus, toxoplasmosis,
CASE 7-2 A 59-year-old woman presented with numbness and tingling in her feet,
noticeable for at least the past several years and gradually worsening over
time. Both lower extremities were equally involved and greatest in the
distal half of her feet. She denied any gait impairment, focal weakness, or
back pain. She had a history of human immunodeficiency virus (HIV)
infection for 10 years on combination antiretroviral therapy (ART).
Neurologic examination demonstrated reduced sensation to
temperature and pinprick distally extending just proximal to the ankles, as
well as mildly reduced vibratory sensation at the great toes bilaterally.
Motor examination was normal. Deep tendon reflexes were reduced at the
ankles but otherwise normal. Gait examination was unremarkable. She was
referred for electrodiagnostic studies. Nerve conduction studies of the
right arm were normal; nerve conduction studies of the right leg
demonstrated reduced fibular (peroneal) and tibial motor amplitudes with
slowed conduction velocities and absent sural sensory response; needle
EMG of the right leg was normal. Findings were consistent with length-
dependent axonal sensorimotor peripheral neuropathy. Laboratory
studies including glucose tolerance test and vitamin B12 level were
normal. Symptomatic management with topical analgesics was discussed
if symptoms were to become bothersome. Continued adherence to ART
was emphasized.
COMMENT HIV-associated distal sensorimotor peripheral neuropathy is one of the

most common HIV-associated neurologic disorders and presents in a
characteristic length-dependent stocking-glove distribution. It is important
to assess for other potential metabolic factors that may contribute to
peripheral neuropathy, including impaired glucose tolerance. Topical
neuropathic creams and oral neuropathic pain medications may be used
alone or in combination symptomatically, but clinicians should remain
mindful of potential medication interactions with the patient's ART regimen.
974 AUGUST 2021

and tuberculosis is necessary before initiating ART in HIV infection. In one KEY POINTS
nested epidemiologic study, 7 of 461 patients developed neuro-IRIS over an
● Immune reconstitution
8-year period with six of seven surviving and only one of those six with fixed inflammatory syndrome
neurologic deficit.67 Immune reconstitution is only rarely associated with PNS (IRIS) is a worsening of
pathology, with several case reports of Guillain-Barré syndrome described 4 to symptoms when the immune
6 weeks after a significant increase in CD4+ count.68,69 If IRIS occurs, treatment system rebuilds (ie, when
the CD4+ T-cell lymphocyte
is with corticosteroids.
count increases and HIV
plasma viral load decreases)
CD8+ ENCEPHALITIS. CD8+ encephalitis is a rare, recently recognized cause of after initiation of ART
encephalopathy seen in patients who are HIV positive and have a normal therein reflecting an
inflammatory rebound
CD4+ count stable on ART, although on occasion CD8+ encephalitis may be
phenomenon.
seen briefly after initiation of ART. Patients present with acute to subacute
encephalopathy that may be accompanied by seizures and headaches. Brain ● Worsening of neurologic
MRI demonstrates diffuse T2 hyperintensities in the white matter, although gray impairment, as well as
matter involvement may be observed, with perivascular contrast enhancement new-onset neurologic
decline, may be seen in
and corresponding diffusion restriction. CSF escape may contribute to the neuro-IRIS, which is most
pathogenesis. Although CSF viral loads are not as elevated as would be expected frequently associated with
with CNS compartmentalization and prominent CD8+ infiltrate is present, cryptococcal meningitis and
transient CSF escape may serve to trigger a CNS inflammatory response. The progressive multifocal
leukoencephalopathy,
absence of an elevated HIV plasma viral load helps distinguish CD8+ encephalitis although it may also be seen
from brain changes related to primary HIV infection itself. The CD8+ encephalitis with toxoplasmosis
syndrome is reported to respond favorably to corticosteroid therapy.70 encephalitis and other
Although both CD8+ encephalitis and neuro-IRIS are characterized opportunistic infections.
pathologically by CD8+ T-cell infiltrates and CD68+ macrophages, their clinical
● CD8+ encephalitis is a
and radiologic features differ. Neuro-IRIS typically occurs shortly after the rare, recently recognized
initiation of ART and is associated with contrast enhancement on neuroimaging cause of encephalopathy
studies, whereas CD8+ encephalitis typically occurs in patients who have been seen in patients who are HIV
stable on ART for a period of time and typically does not demonstrate contrast positive and have a normal
CD4+ count stable on ART
enhancement.71 (although on occasion may
be seen briefly after
PERIPHERAL NERVOUS SYSTEM PATHOLOGY. Although they are uncommon, initiation of ART). Patients
immune-mediated acute and chronic inflammatory demyelinating polyneuropathies present with acute to
subacute encephalopathy
occur more frequently in individuals who are HIV positive compared with those who that may be accompanied by
are HIV negative.48 Acute inflammatory demyelinating polyradiculoneuropathy seizures and headaches.
(AIDP) presents identically clinically and electrophysiologically as in patients who
are not infected with HIV, although CSF lymphocytic pleocytosis is commonly ● Although they are
uncommon, immune-
observed in contrast to the cytoalbuminologic dissociation seen in classic AIDP.71
mediated acute and
Treatment with IVIg or plasma exchange is appropriate in these cases as in chronic inflammatory
individuals not infected with HIV. Chronic inflammatory demyelinating demyelinating
polyradiculoneuropathies may also be seen in HIV-1 infection in either polyradiculoneuropathies
occur more frequently in
relapsing-remitting or progressive forms, with symptoms progressing over more
individuals who are HIV
than 8 weeks. Patients typically have elevated protein levels within the CSF, positive compared with
although mild lymphocytic predominant pleocytosis may also be seen.72 Treatment those who are HIV negative.
strategies are the same as for individuals not infected with HIV and include oral
prednisone along with IVIg or plasma exchange for acute exacerbations or
recurrences.
Mononeuritis multiplex is characterized by sequential multifocal,
noncontiguous typically painful sensory and motor nerve dysfunction and may
occur in the setting of HIV as a vasculitic phenomenon as supported by the
presence of perivascular inflammation and epineural microvascular necrosis.48

Although initially patchy and asymmetric, this may evolve to mimic a distal
symmetric peripheral neuropathy pattern. Reduced evoked sensory and
compound motor action potentials (CMAPs) on nerve conduction studies and
EMG support this diagnosis. Corticosteroids and/or IVIg is used for treatment.
The main differential diagnosis in patients infected with HIV is CMV radiculitis,
which most commonly occurs when the CD4+ count is less than 50 cells/mm3.
Plexopathies have been described in association with HIV, including brachial
plexitis as previously mentioned.
Diffuse infiltrative lymphocytosis syndrome is a rare hyperimmune syndrome
characterized by persistent peripheral blood polyclonal CD8+ lymphocytosis
with infiltration in several organs including the peripheral nerves. In the PNS,
this is characterized as a painful, multifocal symmetric axonal neuropathy. A
Sjögren syndrome–like picture with parotid gland inflammation and xerostomia
secondary to salivary gland infiltration may be seen. Diffuse infiltrative
lymphocytosis syndrome has also manifested clinically as a painful lumbosacral
radiculoplexus neuropathy.73 ART is the cornerstone of treatment, although
steroids may be necessary in some cases.74
Myasthenia gravis (MG) has been described in association with HIV, with the
majority of cases associated with acetylcholine receptor antibodies and a few
associated with muscle-specific kinase (MuSK) antibodies. This neuromuscular
disorder is uncommon in HIV, although numerous cases have been reported in
the literature and include patients with MG before HIV infection, those who
developed MG after HIV infection (most of whom had normal CD4+ counts),
and several rare cases of simultaneous diagnoses of both HIV and MG.75
Recommendations are that treatment should be considered as it would be for
patients not infected with HIV with the added nuance that monitoring is needed
because worsening of MG symptoms may be seen in the first 6 months of
initiating ART. In addition, one should remain mindful of potential drug
interactions, as well as potential reactivation of latent viral infections
(in a case review of 16 patients treated for HIV and MG, none developed
an opportunistic infection, and one had reactivation of varicella-zoster rash).75
MOTOR NEURONOPATHY. An amyotrophic lateral sclerosis (ALS)-like syndrome/

motor neuron disease has been described in some individuals infected with HIV.
Patients tended to be younger than 40 at the onset of neurologic symptoms in
contrast to sporadic ALS and primarily male. Although rare, identification of
this ALS-like syndrome seen in the setting of HIV is critical because initiation of
early ART has been associated with a potential reversal of neurologic disability
with this entity, in contrast to ALS.76 The pathologic relationship between
retroviruses and ALS is an area of ongoing research interest, as is the role that
retroviruses may play in contributing to motor neuron degeneration through
neuroinflammatory and apoptotic regulatory pathways.77
Cerebrovascular Disease in HIV

Increased incidence of cerebrovascular disease may arise in patients with HIV
because of multiple potential mechanisms. Risk factors for ischemic stroke
include accelerated atherosclerotic disease and other microangiopathic changes,
altered vascular reactivity/endothelial changes secondary to HIV-induced
inflammatory changes, HIV-associated hyperviscosity and coagulopathy (eg,
antiphospholipid antibody syndrome), effects of combination ART, comorbid
976 AUGUST 2021

substance use (including tobacco use and stimulants), and cardioembolic KEY POINTS
phenomena (including both bacterial and marantic endocarditis, as well as
● Risk factors for ischemic
cardiac dysfunction).78 Comorbid opportunistic infections such as stroke include accelerated
VZV-associated vasculitis, meningovascular syphilis, and tuberculous and atherosclerotic disease and
cryptococcal meningitis are additional specific risk factors for stroke in HIV, other microangiopathic
as is intravascular lymphoma, albeit less commonly. HIV-associated changes, altered vascular
reactivity/endothelial
thrombocytopenia, vasculopathy, and mycotic aneurysms are associated with changes secondary to
an increased risk of hemorrhagic stroke.78 One study of 6298 individuals HIV-induced inflammatory
infected with HIV identified 38.2% as having imaging evidence of cerebral changes, HIV-associated
vasculopathy, including 13.9% with vessel dolichoectasia with or without hyperviscosity and
coagulopathy (eg,
intracranial aneurysm formation; tobacco use and ART use were antiphospholipid antibody
independently associated with the development of coagulopathy in this syndrome), effects of
cohort.79 Reactivation of VZV may also contribute to the subsequent combination ART, comorbid
development of fusiform aneurysms.80 In a study of adults infected with HIV, substance use (including
tobacco use and stimulants),
younger patients and women were found to have significantly increased
and cardioembolic
stroke rates, independent of typical vascular risk factors.81 phenomena (including both
bacterial and marantic
OPPORTUNISTIC INFECTIONS AND CO-INFECTIONS IN HIV endocarditis, as well as
cardiac dysfunction).
Opportunistic infections occur in the setting of HIV due to impairments in
cell-mediated immunity. The risk of opportunistic infections correlates with the ● Comorbid opportunistic
degree of immunodeficiency; thus, patients with lower CD4+ counts are at infections such as
higher risk. The mortality associated with opportunistic infections is high if left varicella-zoster
untreated, and timely diagnosis and treatment are key to decreasing morbidity virus–associated vasculitis,
meningovascular syphilis,
and mortality. Restoration of immune function with combination ART is also of and tuberculous and
critical importance, although the risk of IRIS must be considered and may cryptococcal meningitis are
influence the timing of ART initiation. Syphilis is another infection that additional specific risk
commonly occurs in patients with HIV infection, and the presence of HIV factors for stroke in HIV, as
is intravascular lymphoma
infection is one of the main risk factors for neurosyphilis.82 albeit less commonly.
HIV-associated
Intracranial Focal/Multifocal Lesions thrombocytopenia,
HIV-associated lesions may be solitary or multifocal in distribution; differential vasculopathy, and mycotic
aneurysms are associated
diagnoses include opportunistic infections, such as toxoplasmosis and PML, and
with an increased risk of
malignancies such as CNS lymphoma. hemorrhagic stroke.
TOXOPLASMOSIS. Toxoplasmosis is the most common cause of intracranial mass ● Timely recognition,
lesions in patients with HIV, typically those with a CD4+ count less than diagnosis, and treatment are
key to decreasing morbidity
200 cells/mm3, most often with less than 100 cells/mm3. Reactivation of latent and mortality risk associated
infection by Toxoplasma gondii, an intracellular obligate protozoan parasite, with opportunistic
occurs in the setting of impaired cell–mediated immunity because cytokines infections. Restoration of
(including interleukin-12), interferon gamma activity, and T cells are immune function with
combination ART is also of
necessary to keep the infection quiescent.83 Clinically, patients present with critical importance,
subacute focal neurologic signs (eg, hemiparesis, unilateral movement although the risk of IRIS must
disorder, gait disturbance, or speech abnormalities) and with headache, fever, be considered and may
and altered mental status. CT of the head demonstrates one or more influence the timing of ART
initiation.
hypodense ring-enhancing lesions often with perilesional edema, most often
located in the basal ganglia or cortical gray matter; ring enhancement or nodular
enhancement may also be apparent on postcontrast brain MRI (CASE 7-3). The
differential diagnosis of ring-enhancing lesions in patients infected with HIV
includes primary CNS lymphoma, tuberculoma, fungal mass lesions (eg,
cryptococcoma), Nocardia species, bacterial brain abscess, and primary brain

tumor. The presence of a small asymmetric nodule abutting the wall of ring
enhancement (ie, the eccentric target sign) is an uncommon but reportedly
highly specific sign to distinguish toxoplasmosis from other causes of
ring-enhancing lesions, and diffusion restriction is not typically seen in
toxoplasmosis, although it is common with other infectious brain abscesses and
primary CNS lymphoma.84 Although not entirely specific, nuclear imaging
modalities such as PET may aid in distinguishing intracranial lesions in patients
infected with HIV as increased metabolic activity is typically observed in
primary CNS lymphoma but may be lacking in toxoplasmosis lesions.85,86
CASE 7-3 A 23-year-old man presented to the emergency department after a

new-onset generalized tonic-clonic seizure. He had a history of
human immunodeficiency virus (HIV) but was not on antiretroviral
therapy (ART).
Neurologic examination was notable for drowsiness as well as a
mild left hemiparesis. Brain
MRI was ultimately pursued
for further characterization of
the lesion and demonstrated
several T2/fluid-attenuated
inversion recovery (FLAIR)
hyperintensities, with
postcontrast enhancement
of a right frontal lesion
(FIGURE 7-487). Serum
Toxoplasma gondii IgG
antibody was positive. FIGURE 7-4
Empiric treatment of MRI of the patient with toxoplasmosis in
toxoplasmosis with CASE 7-3. A, Axial fluid-attenuated inversion
pyrimethamine was initiated. recovery (FLAIR) brain MRI demonstrating

hyperintense signal change in the right frontal
The patient’s CD4+ count region, as well as some periventricular white matter
was 78 cells/mm3. He changes including asymmetric hyperintense focus
underwent repeat brain MRI abutting the left lateral ventricle. B, Axial
postcontrast MRI showing some enhancement of
2 weeks later, which
the right frontal lesion.
demonstrated improvement Panel B reprinted with permission from Continuum
of some lesions. (Minneap Minn).87 2000 © American Academy of Neurology.
COMMENT The most common cause of an intracranial mass in a patient with HIV/
acquired immunodeficiency syndrome (AIDS) is toxoplasmosis. Empiric
treatment for toxoplasmosis should be initiated in this setting with a
close follow-up scan (ie, 10 to 14 days) to ensure a response to treatment.
Assuming clinical response and tolerance to treatment, ART would be
initiated 2 to 3 weeks later. A lack of clinical and/or radiologic response
should lead to consideration of primary central nervous system
lymphoma.
978 AUGUST 2021

The presence of elevated T. gondii IgG antibodies suggests chronic or KEY POINTS
secondary reactivation of latent infection, but many individuals may have
● Toxoplasmosis is the most
antibodies from exposure and remain asymptomatic (an estimated 11% of the US common cause of
population aged 6 years and older), so the test is more helpful in ruling out intracranial mass lesions in
toxoplasmosis if negative.88 Pyrimethamine is a mainstay of therapy along with patients with HIV, typically
leucovorin (folinic acid to prevent bone marrow–suppressive effect of with a CD4+ count less than
200 cells/mm3, most often
pyrimethamine) plus sulfadiazine; trimethoprim-sulfamethoxazole may be used
with less than 100 cells/mm3.
if pyrimethamine is not available and/or the patient is not able to tolerate it.
Because of the high frequency of toxoplasmosis in individuals with AIDS, ● Clinically, patients with
recommendations are to initiate antiparasitic therapy early in the setting of toxoplasmosis often present
intracranial mass lesion with positive serologies and limit biopsy to patients who with subacute focal
neurologic signs (eg,
have no response to therapy clinically and radiologically after 2 weeks.89 IRIS hemiparesis, unilateral
occurs much less commonly with toxoplasmosis than with other opportunistic movement disorder, gait
infections. disturbance, or speech
In addition to encephalitis, toxoplasmosis may also cause myositis with abnormalities) and with
headache, fever, and
Toxoplasma cysts within muscles, and, much more rarely, myelopathy may also altered mental status.
be seen.90 Outside the nervous system, chorioretinitis, pneumonitis, and a
sepsislike syndrome in the case of systemically disseminated disease may be seen. ● Nuclear imaging
modalities such as positron
emission tomography (PET)
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. Malignancies occur at higher
may be helpful in making the
frequency in patients with HIV/AIDS as a result of reduced immune surveillance distinction (ie, no increase in
directed against oncogenic viruses and cancer cells infected with viruses (often metabolic activity of lesions
herpesviruses) as seen with human herpes virus 8–associated Kaposi sarcoma and in toxoplasmosis whereas
increased metabolic activity
Epstein-Barr virus (EBV)-associated Hodgkin and non-Hodgkin lymphomas.91
is suggestive of primary CNS
Primary CNS lymphoma is a diffuse large B-cell lymphoma restricted to lymphoma).
the brain, meninges, spinal cord, cranial nerves, and eyes. It is associated with
EBV in individuals infected with HIV and encountered in advanced
immunodeficiency most often when the CD4+ count is less than 50 cells/mm3
but can occur in patients with higher CD4+ counts, even greater than
200 cells/mm3.92,93 Clinical presentations are varied and may include focal
neurologic deficits, neurocognitive impairment, and headaches and other
features of elevated intracranial pressure in addition to constitutional
symptoms.94 Radiographically, lesions are most often masslike, enhancing,
solitary or multifocal lesions that are hyperintense on diffusion-weighted
imaging and hypointense on apparent diffusion coefficient sequences and
accompanied by surrounding vasogenic edema.95 Neuroimaging findings in
primary CNS lymphoma in individuals who are immunocompromised may not
show the characteristic uniform enhancement associated with primary CNS
lymphoma in people who are immunocompetent (FIGURE 7-5). Rather, primary
CNS lymphoma lesions in patients infected with HIV may take on a more
heterogeneous appearance due to central necrosis and are more often multiple in
number and smaller in size compared with radiologic findings in individuals who
are immunocompetent. The most commonly involved areas are the
supratentorial white matter of both cerebral hemispheres, basal ganglia, corpus
callosum, and periventricular subependymal region.96 Nuclear imaging
modalities such as PET may aid in distinguishing between toxoplasmosis and
primary CNS lymphoma as discussed earlier.
Also characteristic of lymphoma is a dramatic imaging response to the
initiation of corticosteroids; it may be even complete resolution, described as
“vanishing tumor,” and thus, steroids should be avoided when possible while

attempting to ascertain
diagnosis.97 If lumbar puncture
can be safely performed, CSF
EBV polymerase chain reaction
(PCR) should be obtained
because it is highly sensitive for
primary CNS lymphoma in
individuals who are
immunocompromised.
Treatment consists of systemic
chemotherapy with high-dose IV
methotrexate and corticosteroids
in addition to ART initiation;
historically, whole-brain
radiation therapy was also used,
although, given concerns for CNS
toxicity, this has evolved to an
adjuvant role in cases of relapsed
FIGURE 7-5 disease and consolidation
Axial brain MRI of primary central nervous system therapy. Recent data support
(CNS) lymphoma. A, Axial fluid-attenuated rituximab as an effective
inversion recovery MRI showing left hemisphere–
radiation-sparing agent without
predominant diffuse white matter lesion in
primary CNS lymphoma. B, Postcontrast associated neurocognitive
T1-weighted image of primary CNS lymphoma dysfunction that may be used in
showing a lack of significant enhancement. combination with high-dose
Although CNS lymphoma is characteristically
methotrexate and ART.98 Primary
homogeneously enhancing on postcontrast MRI, in
individuals who are human immunodeficiency virus CNS lymphoma is a particularly
(HIV) infected (immunocompromised), the lesions aggressive malignancy in patients
may take on a more heterogeneous appearance infected with HIV, with a median
and may not enhance as they do in those who are survival of less than 2 months
immunocompetent and thus may be misdiagnosed
(ie, as a diffuse nonspecific leukoencephalopathy) without treatment.
as might be in this case. C, Diffusion-weighted
imaging demonstrating CNS lymphoma with some PROGRESSIVE MULTIFOCAL
diffusion restriction. D, Apparent diffusion LEUKOENCEPHALOPATHY. PML
coefficient correlate.
results from reactivation of
latent JC virus infection in the
setting of immunosuppression;
in patients infected with HIV, this is seen most often with CD4+ cell count less
than 200 cells/mm3.99 Affected individuals may present with visual dysfunction,
neuropsychological changes, focal motor or sensory impairment, ataxia or other
gait disturbance, and speech difficulties. MRI demonstrates asymmetric,
nonenhancing T2/FLAIR hyperintense lesions most commonly involving the
juxtacortical white matter within parieto-occipital regions and the middle
cerebellar peduncle (FIGURE 7-6).100 Asymmetry and involvement of the U
fibers distinguishes PML from advanced HIV-associated dementia, which tends
to be symmetric and spare the U fibers, although more focal subcortical white
matter changes have also been associated with HAND and, thus, at times may be
challenging to distinguish radiographically (FIGURE 7-5). The barbell sign refers to
confluent T2/FLAIR signal changes in the parieto-occipital region crossing the
splenium; clinically, these patients present with visual disturbances.101 The basal
980 AUGUST 2021

ganglia, brainstem, and cerebellum may be KEY POINT
involved (FIGURE 7-6). Restricted diffusion
● Progressive multifocal
may be seen at the leading edge of leukoencephalopathy is one
expansive lesions and has been attributed of the opportunistic
to swelling secondary to oligodendrocyte infections more commonly
and astrocyte death (FIGURE 7-7).102 associated with IRIS, which
can appear on imaging as
The presence of JC virus PCR in the CSF
edema, mass effect, and
supports the diagnosis of PML. Autopsy contrast enhancement.
studies suggest pathologic evolution of
infection in three proposed steps: (1)
initiation of early, small lesions in
blood-supply-rich regions, followed by (2)
extension distally via axonal spread and
expansion locally (associated with more
tissue destruction), and then (3) fusion of FIGURE 7-6
demyelinating lesions to form larger Axial fluid-attenuated inversion
lesions leading to axonal destruction.103 recovery (FLAIR) MRI of a patient with
Immune restoration with combination progressive multifocal
leukoencephalopathy shows a
ART is the fundamental management prominent lesion in the left middle
strategy. PML is one of the opportunistic cerebellar peduncle, without
infections more commonly associated associated mass effect or
with IRIS, which can appear on enhancement (not shown).
neuroimaging as edema,
mass effect, and contrast
enhancement.104 Steroids are
used for treatment based on
case reports.105
Several medications have
been studied with some in vitro
efficacy, although no significant
clinical benefit has been found.
These include mirtazapine, an
antidepressant medication that
targets the 5-HT2A receptor,
which the JC virus uses to infect
oligodendrocytes, although
support for its use is lacking.106
Cidofovir, a medication thought
to have some activity against
polyoma viruses and considered
as a possible treatment in case
reports, was also found to be FIGURE 7-7
ineffective for PML in patients Axial fluid-attenuated inversion recovery (FLAIR)
MRI of the brain (A and B) demonstrates confluent
with AIDS treated with cidofovir and nonconfluent areas of subcortical and
and antiretrovirals versus periventricular white matter hyperintensity without
antiretrovirals alone.107 associated mass effect in a patient with
Allogeneic BK virus–specific T progressive multifocal leukoencephalopathy.
C, Sagittal T1-weighted brain MRI demonstrates
cells were used in the treatment hypointensity within the lesions. D, Axial
of three patients who were diffusion-weighted image shows restricted
immunocompromised and had diffusion at the leading edge of the lesion.

PML (one with AIDS) with clinical improvement seen in two and stabilization
seen in the third patient.108 Most recently, the checkpoint inhibitor
pembrolizumab was shown to reduce JC viral load in CSF with accompanying
clinical improvement or stabilization in five of eight patients who were
immunocompromised (two of whom were HIV positive); the putative
mechanism suggested is that by inducing programmed cell-death inhibition,
improved viral clearance occurs.109
Rarer JC virus–associated CNS disorders include granule cell neuronopathy in
which cerebellar granule cell neurons are infected and JC virus encephalopathy in
which cortical gray matter pyramidal neurons are infected.110,111
OTHER INTRACRANIAL LESIONS. Additional intracranial infections in patients with HIV/

AIDS that can cause focal or multifocal lesions include Nocardia species, pyogenic
bacteria, tuberculosis, cryptococcus, and other fungal abscesses. For further
discussion, refer to the articles “Encephalitis and Brain Abscess” by Arun Venkatesan,
MD, PhD,112 and “Neurologic Infections in Patients on Immunomodulatory and
Immunosuppressive Therapies” by Pria Anand, MD,113 in this issue of Continuum.
Meningitis/Encephalitis
When performing CSF analysis in patients infected with HIV and who have a
possible intracranial infection, it should be noted that a lymphocytic pleocytosis of up
to 20 white blood cells/mm3 (primarily T cells, with some monocytes) and mild
elevation of protein may be seen in the absence of opportunistic infection.31 That said,
due diligence should be made in attempting to exclude opportunistic/co-infections.
CRYPTOCOCCAL MENINGITIS. Cryptococcal meningitis is one of the most commonly

encountered opportunistic infections in patients with HIV, most commonly
with CD4+ counts less than 100 cells/mm3.114 Cryptococcus neoformans is an
encapsulated yeast that is typically acquired via inhalation and may disseminate
systemically, most commonly to the CNS. Patients with cryptococcal meningitis
typically present with subacute progressive headache and fever. Other symptoms
may manifest from complications relating to meningitis including altered mental
status, blurred vision, and cranial nerve palsies secondary to elevated intracranial
pressure with or without accompanying hydrocephalus. Much less commonly,
focal masslike lesions known as cryptococcomas may be seen. Formation of
gelatinous cysts may develop in increasingly dilated perivascular spaces, referred
to as a soap bubble appearance on brain MRI, and is more commonly seen in
patients with cryptococcal disease who are infected with HIV in contrast to
patients who are not infected with HIV. The basal ganglia are most commonly
involved, although these “soap bubbles” (which are characteristically lacking
in significant vasogenic edema and enhancement) may also be found in the
cerebral white matter, brainstem, and cerebellum. Other imaging findings
include basilar enhancement and supratentorial leptomeningeal enhancement,
as well as subcortical infarcts (FIGURE 7-8).115,116 Lumbar puncture often reveals
markedly elevated opening pressures (greater than 20 cm H2O in 70%
of patients), elevated white blood cell count, elevated protein, and
hypoglycorrhachia. However, normal CSF findings may be seen in 26% of
patients with cryptococcal meningitis, so the diagnosis cannot be excluded by
normal CSF parameters. CSF cryptococcal antigen is the most sensitive test
(greater than 93% sensitivity) for diagnosis, although data are lacking with
982 AUGUST 2021

respect to checking serial CSF KEY POINTS
cryptococcal antigen during
● Other novel JC
ongoing management/disease virus–associated CNS
monitoring.117,118 disorders are caused by JC
Treatment consists of induction virus variants and include
therapy with amphotericin B in granule cell neuronopathy in
which cerebellar granule
combination with flucytosine cell neurons are infected, as
followed by fluconazole for well as JC virus
consolidation therapy. Serial encephalopathy in which
FIGURE 7-8 lumbar punctures are often cortical gray matter
Cryptococcal meningoencephalitis. Axial pyramidal neurons are
necessary to manage persistently
fluid-attenuated inversion recovery (FLAIR) MRI of infected.
the brain (A) shows abnormal hyperintensity in
elevated intracranial pressure, with
bilateral lentiform nuclei, and axial postcontrast shunting procedures (ie, lumbar ● Patients with
T1-weighted MRI (B) demonstrates subtle drain or ventriculoperitoneal cryptococcal meningitis
enhancement of these structures. Imaging shunt) considered in refractory typically present with
represents symmetrically increased signal in basal subacute progressive
ganglia reflective of parenchymal (basal) edema
cases. Cryptococcal disease has headache and fever. Other
due to the fungal material within this region, been associated with cases of IRIS; symptoms may manifest
consistent with what has been called “hazy brain thus, initiation of ART should be from complications relating
base,” thought to represent fungal involvement of delayed to decrease this risk (2 to to meningitis including
the perivascular spaces.115 altered mental status,
10 weeks per Infectious Diseases blurred vision, and cranial
Society of America guidelines nerve palsies secondary to
given some uncertainty on precise timing).119 Very low CD4+ count, higher CSF elevated intracranial
cryptococcal antigen titers, previously undiagnosed HIV infection, lack of previous pressure with or without
accompanying
ART use, and initiation of ART within 2 months of initial diagnosis have been hydrocephalus.
associated with increased risk of IRIS.120,121
● Formation of gelatinous
CYTOMEGALOVIRUS. CMV infection is seen almost exclusively in individuals cysts may develop in
increasingly dilated
who are immunocompromised; in patients infected with HIV, this is typically
perivascular spaces,
seen when CD4+ counts are less than 50 cells/mm3. It may be associated with referred to as a soap bubble
meningitis, encephalitis, myelitis, and radiculitis. Clinically, it manifests as appearance on brain MRI,
an encephalitic syndrome with acute onset and rapid progression, in contrast and is more commonly seen
to other conditions such as PML and HIV-associated leukoencephalopathy. in patients with
cryptococcal disease
CMV-associated ventriculitis is another CNS manifestation, and mass lesions infected with HIV in contrast
may also be seen uncommonly. CMV retinitis and colitis may be seen in to patients who are not
association with neurologic manifestations of CMV. Brain MRI most commonly infected with HIV.
demonstrates periventricular T2-hyperintense signal changes, although
● Cytomegalovirus
ventricular enhancement may be seen in cases of ventriculitis, and signal infection is seen almost
changes within the brainstem may be seen in cases of CMV-associated exclusively in
rhombencephalitis.122 MRI of the spinal cord may be normal in up to 50% of individuals who are
cases of CMV-associated myelitis; nerve root enhancement of the cauda equina immunocompromised; in
patients infected with HIV,
may be seen in patients with a polyradiculitis syndrome.123 CSF may show a
this is typically seen when
neutrophil-predominant pleocytosis and mild hypoglycorrhachia. Diagnosis CD4+ counts are less than
is ascertained by confirming the presence of CMV PCR in the CSF. IV ganciclovir 50 cells/mm3. It may be
and foscarnet is the preferred treatment for induction therapy for CNS disease. associated with meningitis,
encephalitis, myelitis, and
Given the risk of IRIS in patients with CMV infection of the nervous system,
radiculitis.
initiation of ART should be delayed, but generally no longer than 2 weeks.124
TUBERCULOSIS. In patients infected with HIV, Mycobacterium tuberculosis is

most commonly encountered when the CD4+ count is less than 100 cells/mm3,
although it may occur at any stage of HIV infection, with increasing risk of

extrapulmonary disease correlating with a decreasing CD4+ count.125 It is the

most frequently encountered opportunistic infection globally and is a leading
cause of death in AIDS; ART use longer than 6 months has been associated with
lowered risks of illness and death, underscoring the importance of ART.126 HIV
co-infection is associated with an increased risk of tuberculosis infection, as well as
progression from latent to active tuberculosis; conversely, co-infection with
tuberculosis is associated with an increased rate of HIV/AIDS progression.125,127
Numerous potential medication interactions and drug toxicities are associated with
the combined use of ART and tuberculosis treatment (eg, rifamycins such as
rifampin have several significant drug-drug interactions with non-nucleoside
transcriptase inhibitors and protease inhibitors).128 Tuberculosis is one of the
opportunistic infections more frequently associated with IRIS, with some studies
citing a nearly 50% incidence in some cohorts.129 In patients with CNS tuberculosis
and HIV who are not yet on ART, the CDC recommends delaying initiation of ART
for 8 weeks after initiation of anti-tuberculosis treatment to decrease the risk of
tuberculosis CNS IRIS.130 Clinical trials are ongoing with respect to whether an
adjunctive course of corticosteroids is beneficial.131
VARICELLA-ZOSTER VIRUS. VZV infection may be associated with meningitis,
encephalitis, vasculitis, cranial nerve dysfunction, radiculitis, and myelitis.
Neurologic complications of VZV may be encountered in individuals infected
with HIV who have a broad range of CD4+ counts, although they can also be seen
in individuals who are immunocompetent. CSF typically shows mild pleocytosis,
although it may be normal. CSF VZV IgG is considered more sensitive than PCR,
particularly in those with a latency of weeks to months since rash or in cases of
zoster sin herpete.132 Treatment consists of IV acyclovir, as well as steroids in the
setting of VZV-associated vasculitis.
NEUROSYPHILIS. Neurosyphilis should be considered in all individuals infected

with HIV who have neurologic symptoms given considerable rates of co-infection, with
a serum rapid plasma reagin (RPR) titer of at least 1:32 associated with an increased
likelihood of neurosyphilis.133 Early symptomatic neurosyphilis syndromes (acute
meningitis and meningovascular neurosyphilis) rather than late syndromes are
more commonly encountered and may develop despite routine antibiotic
treatment for syphilis in patients infected with HIV.134,135 Furthermore,
neurosyphilis may be asymptomatic and, given that mild pleocytosis may be seen
in the setting of HIV infection itself, this may render the diagnosis more
challenging. Although CDC guidelines do not recommend lumbar puncture for
individuals infected with HIV and co-infected with syphilis in the absence of
neurologic symptoms given limited outcomes data to support benefit, some
experts recommend lumbar puncture even in asymptomatic individuals,
particularly if serum RPR is greater than or equal to 1:32 and/or CD4+ T-cell count
is less than or equal to 350 cells/mm3.133,136 For further discussion, refer to the
article “Neurosyphilis” by Felicia Chow, MD, MS,137 in this issue of Continuum.
OTHER CO-INFECTIONS. Endemic mycotic infections including coccidioidomycosis

and histoplasmosis may also result in extrapulmonary dissemination to the CNS
in patients who are HIV positive and manifest most commonly as chronic
meningitis; additional complications such as hydrocephalus may also develop.
Consideration should be given for potential medication interactions between
triazole antifungals (which are mainstays of treatment) and ART.
984 AUGUST 2021

Antiretroviral Therapy–Related Complications KEY POINTS
Nucleoside reverse transcriptase inhibitors such as didanosine, zalcitabine, and
● The Centers for Disease
stavudine can cause a toxic peripheral neuropathy; mitochondrial toxicity is Control and Prevention
postulated to be the underlying mechanism.138 recommends delaying the
HIV-associated neuromuscular weakness syndrome is characterized by the rapid initiation of ART for 8 weeks
progression of severe sensory and motor dysfunction over days to weeks in after initiation of
antituberculosis treatment
association with elevated serum lactate. Systemic symptoms including nausea and
to decrease the risk of
vomiting, hepatomegaly, and hepatic steatosis are seen in more than half of affected tuberculosis CNS IRIS.
patients. Electrodiagnostic findings demonstrate sensorimotor neuropathy or
myopathy. A spectrum of pathologic changes has been demonstrated in biopsy of ● CSF varicella-zoster
nerve (demyelination, axonal degeneration, and inflammation) and muscle (VZV) IgG is considered
more sensitive than PCR,
(inflammation and mitochondrial abnormalities).139 Nucleoside reverse transcriptase particularly in those with a
inhibitor–mediated neurotoxicity is suspected to play a role, given the majority of latency of weeks to months
patients described had exposure to stavudine as part of their ART regimen. However, since rash or in cases of
with the spectrum of pathologic changes as well as the observation that many patients zoster sin herpete.
Treatment consists of IV
developed symptoms after discontinuation of ART, immune-mediated factors may acyclovir, as well as steroids
contribute in addition to possible mitochondrial toxicity. in the setting of
Given the neurotoxicity of these older agents, they are generally avoided with VZV-associated vasculitis.
preference given to newer alternatives when available. Protease inhibitors
● Neurosyphilis should be
including ritonavir, indinavir, and saquinavir may be associated with a small
considered in all individuals
increased risk of peripheral neuropathy although data are conflicting.140,141 The infected with HIV who have
non-nucleoside reverse transcriptase inhibitor efavirenz is associated with vivid neurologic symptoms.
dreams, mood and anxiety disturbances, and rarely psychosis—symptoms that Serum rapid plasma reagin
(RPR) titer of at least 1:32 is
may reflect its excellent CNS penetration—and should thus be avoided in
associated with an
patients with neurocognitive impairment.142 One should remain mindful of increased likelihood of
drug-drug interactions and the potential overlapping side effect profiles of neurosyphilis, both in
medications used in combination with ART. patients who are not
infected with HIV and in
those who are, with an even
higher risk in the latter
CONCLUSION group.
HIV-associated neurologic disorders can be caused by HIV infection of the
nervous system, immune response to the virus, and opportunistic infections. ● Nucleoside reverse
transcriptase inhibitors such
Some antiretroviral medications (particularly older ones) have also been as didanosine and
associated with neurotoxicity, and significant potential exists for drug-drug zalcitabine, as well as
interactions. Initiation and adherence to ART are paramount in the prevention stavudine, can cause
and treatment of neurologic complications of HIV, although the initiation of ART peripheral neuropathy with
mitochondrial toxicity
in ART-naïve patients may need to be delayed to avoid the risk of IRIS with
postulated to be the
certain opportunistic infections. underlying mechanism.
USEFUL WEBSITES
AMERICAN ACADEMY OF NEUROLOGY HIV.GOV
The AAN and International League Against Epilepsy This site offers information on HIV/AIDS treatment,
provide guidelines for antiepileptic drug selection prevention, and research.
for people with HIV/AIDS. clinicalinfo.hiv.gov/
n.neurology.org/content/78/2/139
HIV INSITE
This site provides comprehensive, up-to-date
information on HIV/AIDS treatment and prevention
from the University of California, San Francisco.
hivinsite.ucsf.edu

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Pembrolizumab treatment for progressive
neoformans disease in the era of highly active
antiretroviral therapy. Clin Infect Dis 2005;40(7):
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1049-1052. doi:10.1086/428618
NEJMoa1815039
121 Lortholary O, Fontanet A, Memain N, et al.
110 Koralnik IJ, Wuthrich C, Dang X, et al. JC virus
Incidence and risk factors of immune
granule cell neuronopathy: a novel clinical
reconstitution inflammatory syndrome
syndrome distinct from progressive multifocal
complicating HIV-associated cryptococcosis in
leukoencephalopathy. Ann Neurol 2005;57(4):
France. AIDS 2005;19(10):1043-1049. doi:10.1097/
576-580. doi:10.1002/ana.20431
01.aids.0000174450.70874.30
111 Wüthrich C, Dang X, Westmoreland S, et al.
122 Silva CA, Penalva de Oliveira AC, Vilas-Boas L,
Fulminant JC virus encephalopathy with
et al. Neurologic cytomegalovirus complications
productive infection of cortical pyramidal
in patients with AIDS: retrospective review of
neurons. Ann Neurol 2009;65(6):742-748.
13 cases and review of the literature. Rev Inst
doi:10.1002/ana.21619
Med Trop Sao Paulo 2010;52(6):305-310.
112 Venkatesan A. Encephalitis and brain abscess. doi:10.1590/s0036-46652010000600004
123 Tselis AC. Cytomegalovirus infections of the
adult human nervous system. Handb Clin Neurol
113 Anand P. Neurologic infections in patients on 2014;123:307-318. doi:10.1016/B978-0-444-53488-
immunomodulatory and immunosuppressive 0.00014-6
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124 Panel on Opportunistic Infections in Adults and 132 Nagel MA, Gilden D. Neurological complications
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prevention and treatment of opportunistic Neurol 2014;27(3):356-360. doi:10.1097/
infections in adults and adolescents with HIV: WCO.0000000000000092
recommendations from the Centers for Disease
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Control and Prevention, the National Institutes
Cerebrospinal fluid abnormalities in patients
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with syphilis: association with clinical and
the Infectious Diseases Society of America.
laboratory features. J Infect Dis 2004;189(3):
Accessed July 19, 2021. clinicalinfo.hiv.gov/
369-376. doi:10.1086/381227
sites/default/files/guidelines/documents/
Adult_OI.pdf 134 Flood JM, Weinstock HS, Guroy ME, et al.
Neurosyphilis during the AIDS epidemic, San
125 Moore D, Liechty C, Ekwaru P, et al. Prevalence,
Francisco, 1985-1992. J Infect Dis 1998;177(4):
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tuberculosis in HIV-infected patients initiating
antiretroviral therapy in rural Uganda. AIDS 2007; 135 Centers for Disease Control and Prevention
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cities, United States, January 2002-June 2004.
126 World Health Organization. Global tuberculosis
MMWR Morb Mortal Wkly Rep 2007;56(25):
report 2019. Accessed April 25, 2021. who.int/
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report-2019#:~:text=The%202019%20edition% 136 Workowski KA, Bolan GA, Centers for Disease
20of%20the%20global%20TB%20report,latest% Control and Prevention. Sexually transmitted
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%20not%20appropriate Recomm Rep 2015;64(RR-03):1-137.
127 Badri M, Ehrlich R, Wood R, et al. Association 137 Chow F. Neurosyphilis. Continuum (Minneap
between tuberculosis and HIV disease Minn) 2021;27(4, Neuroinfectious Disease):
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area. Int J Tuberc Lung Dis 2001;5(3):225-232.
138 Lewis W, Dalakas MC. Mitochondrial toxicity of
128 Vinnard C, Macgregor RR. Tuberculous antiviral drugs. Nat Med 1995;1:417-422.
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HIV/AIDS Rep 2009;6(3):139-145. doi:10.1007/
139 HIV Neuromuscular Syndrome Study Group.
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HIV-associated neuromuscular weakness
129 Torok ME, Yen NTB, Chau TTH, et al. Timing of syndrome. AIDS 2004;18(10):1403-1412. doi:
initiation of antiretroviral therapy in human 10.1097/01.aids.0000131309.70451.fe
immunodeficiency virus (HIV)–associated
140 Crabb C. Protease inhibitors and risk of
tuberculous meningitis. Clin Infect Dis 2011;52(11):
developing HIV-related sensory neuropathy.
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AIDS 2004;18(14):N10. doi:10.1097/00002030-
130 Centers for Disease Control and Prevention. 200409240-00001
Guidelines for the use of antiretroviral agents in
141 Ellis RJ, Marquie-Beck J, Delaney P, et al. Human
adults and adolescents living with HIV.
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Accessed May 5, 2021. clinicalinfo.hiv.gov/en/
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tuberculosishiv-coinfection
142 Clifford DB, Evans S, Yang Y, et al. Impact of
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February 24, 2021. Accessed April 25, 2021.
clinicaltrials.gov/ct2/show/NCT03092817?
term=ACT-HIV+trial&draw=2&rank=1

REVIEW ARTICLE
Neurologic Complications
of Tuberculosis

C O N T I N UU M A UD I O
INTERVIEW AVAILABLE
ONLINE
By Deanna Saylor, MD, MHS
ABSTRACT
PURPOSE OF REVIEW: This article describes the current epidemiology, common
clinical characteristics, and up-to-date evidence-based approaches to
the diagnosis and management of the most common neurologic
complications of tuberculosis (TB): tuberculous meningitis, intracranial
tuberculoma, and spinal TB.
RECENT FINDINGS:Central nervous system (CNS) TB remains common and

associated with significant mortality and neurologic sequelae worldwide.
Human immunodeficiency virus (HIV) co-infection is strongly associated
with both the development of and mortality due to CNS TB. Strongyloides
CITE AS: co-infection is associated with reduced CNS inflammation and improved
outcomes in the setting of tuberculous meningitis. Stroke remains a
DISEASE):992–1017. common complication of tuberculous meningitis, and emerging evidence
suggests aspirin may be used in this context. Although a recent nucleic acid
amplification test has demonstrated suboptimal sensitivity in the diagnosis
Dr Deanna Saylor, Meyer 6-113,
600 N Wolfe St, Baltimore, MD of CNS TB, emerging diagnostic techniques include cell-free DNA, peripheral
21287, deanna@jhmi.edu. blood microRNA, metagenomic next-generation sequencing, and advanced
imaging techniques, but these are not yet well validated. CNS TB is associated
Dr Saylor has received with high mortality even with current treatment regimens, although novel,
research/grant support from promising strategies for treatment are under investigation, including a
the American Academy of
Neurology, National Institute of combination of IV isoniazid and ethambutol and high-dose rifampicin.
Aging (R01 AG059504-01A),
National Institute of Mental SUMMARY: TB can affect the nervous system in various ways and is
Health (R01 MH120693-01,
P30 MH075673), National associated with high mortality. Diagnosis remains challenging in endemic
Institute of Neurological settings, with empiric treatment often initiated without a definitive
Disorders and Stroke
(R01 NS094037-05S1,
diagnosis. Furthermore, optimal treatment regimens remain uncertain
R21 NS118543-01), and National because current treatment for all forms of CNS TB is extrapolated from
Multiple Sclerosis Society. trials of tuberculous meningitis whereas the role of steroids in people with
UNLABELED USE OF
HIV and tuberculous meningitis remains controversial.
USE DISCLOSURE:
Dr Saylor discusses the
unlabeled/investigational use of INTRODUCTION
thalidomide and nonstandard
T
doses and/or nonstandard uberculosis (TB) is caused by the acid-fast bacillus Mycobacterium
formulations of ethambutol, tuberculosis and is one of the oldest documented infectious diseases
isoniazid, and rifampin for the
treatment of central nervous
of humans. TB is the leading cause of death from an infectious
system tuberculosis. etiology and remains in the top 10 causes of death globally. In 2019
alone, TB accounted for 10 million new symptomatic infections
(1.2 million symptomatic infections in children) and 1.4 million deaths
of Neurology. globally, with a global prevalence estimated at 25% of the world’s population.1
992 AUGUST 2021

Eight countries (India, Indonesia, China, Philippines, Pakistan, Nigeria,
Bangladesh, and South Africa) account for two-thirds of the world’s
infections, and 90% of global infections are found in 30 high-TB-burden
countries (FIGURE 8-1). Although TB occurs in every country in the world,
variations in its worldwide prevalence reflect its strong association with
poverty, malnutrition, and human immunodeficiency virus (HIV)/acquired
immunodeficiency syndrome (AIDS). In the United States, TB cases have
been declining since 1993 with approximately 10,000 cases reported annually
since 2015. More than two-thirds of these cases are among individuals born
outside the United States. Incarceration, housing insecurity, and employment
in a health care setting are other common risk factors for TB acquisition in the
United States.2
The majority of TB infections remain latent throughout an individual’s lifetime
with only 5% to 10% of infections leading to active disease. The majority of active
infections (approximately 90%) represent reactivation of latent infection rather
than symptomatic presentations of primary infection. Risk factors for active
disease include co-infection with HIV, other immunocompromised states, chronic
lung disease, tobacco use, malnutrition, diabetes, heavy alcohol use, indoor
pollution, silicosis, end-stage renal disease, intestinal bypass surgery or
gastrectomy, and chronic malabsorptive states.3
FIGURE 8-1
Estimated TB incidence rates by country in 2019.1
Reprinted with permission from the World Health Organization.1 © 2020 World Health Organization.
License: CC BY-NC-SA 3.0 IGO.

NEUROLOGIC COMPLICATIONS OF TUBERCULOSIS
Although pulmonary TB is the most common site of active disease,

extrapulmonary TB is not uncommon, accounting for 10% to 40% of cases
globally.1,4 However, this may be an underestimate because some classifications
limit the “extrapulmonary TB” designation to only patients with exclusively
extrapulmonary disease and no pulmonary disease, thus missing patients with
concurrent pulmonary and extrapulmonary disease.4 Risk factors for
development of extrapulmonary TB include older age, female sex, lower
education level, urban residence, HIV co-infection, other immunocompromised
states, diabetes, and end-stage renal disease.5 Although nervous system
involvement is less common than involvement of other extrapulmonary sites,
nonstandard reporting and diagnostic criteria make robust estimates of its
prevalence difficult. In addition, it is one of the most severe forms of TB and is
associated with high mortality, especially among people with HIV.5
HIV is strongly associated with both TB infection overall and central nervous
system (CNS) TB in particular. People with HIV are at significantly increased
risk of acquiring TB infection and progressing from having latent infection to
active disease. People with HIV are also 3 times as likely to die while on TB
treatment such that TB accounted for 35% of global mortality among people with
HIV in 2015.1 Furthermore, CNS TB is up to 5 times more common in people with
HIV, which may account for the higher mortality rates seen with HIV and TB
co-infection.6
This article focuses on the clinical presentations and approach to diagnosis and
management of the most common forms of CNS TB: tuberculous meningitis,
tuberculoma, and spinal manifestations of TB including spondylitis,
radiculomyelitis, spinal arachnoiditis, intramedullary tuberculoma, and myelitis.
TUBERCULOUS MENINGITIS
The most common form of CNS TB is tuberculous meningitis, which can present
as either insidious chronic meningitis or acute fulminant meningitis. Its
presentation, diagnosis, and treatment are discussed here.
The most common symptoms of tuberculous meningitis include fever, headache,
and alterations in consciousness. Cranial neuropathies are also common because
TABLE 8-1 Modified British Medical Research Council Criteria for Grading Severity of
Tuberculous Meningitisa,b
Grade Criteria
Grade I Glasgow Coma Scale (GCS) 15, no focal neurologic deficits
Grade II GCS 11-14
GCS 15 and focal neurologic deficit(s)
Grade III GCS ≤10
a
Data from Marais BJ, et al, Clin Infect Dis.8
b
Higher Medical Research Council (MRC) stage is correlated with higher mortality rates.
994 AUGUST 2021

of thick purulent exudates frequently found in the basal cisterns. However, KEY POINTS
clinical presentations are highly variable. Patients may present with strokes,
● Tuberculosis (TB) is the
seizures, focal deficits due to the development of tuberculomas, and symptoms leading cause of death from
of hydrocephalus. They then may further develop new symptoms, signs, and an infectious etiology and
neuroimaging findings after initiation of appropriate treatment. A systematic remains in the top 10 causes
review of global tuberculous meningitis cases found that the only features of death globally. In 2019, TB
accounted for 10 million new
present in at least 80% of cases were fever and a low CSF to serum glucose ratio.7
symptomatic infections
Overall clinical severity is most often graded by using the modified British (1.2 million symptomatic
Medical Research Council (MRC) criteria (TABLE 8-1), with higher grades infections in children) and
associated with higher mortality.8 1.4 million deaths globally,
and 25% of the world’s
Stroke is one of the most common complications of tuberculous meningitis,
population is thought to be
occurring in approximately 30% to 60% of cases.9,10 In one study from China, infected with TB.
infarcts occurred in approximately one-quarter of otherwise healthy young
adults (those 50 years old and younger) with tuberculous meningitis.11 These ● Central nervous system
strokes are usually found in the basal ganglia because of involvement of small (CNS) TB is one of the most
severe forms of TB and is
penetrating arteries that are surrounded by exudates in the basal cisterns, but associated with high
abnormalities of the large anterior circulation arteries are also common as the result mortality, especially among
of tuberculous vasculopathy.9,10,12 Hypothesized stroke mechanisms include people with human
endothelial reactions to inflammatory exudates, proliferative and necrotizing immunodeficiency
virus (HIV).
arteritis, and hypercoagulable states.9 More recently, tuberculous
meningitis–associated stroke was found to be associated with multiple abnormal ● The most common form
platelet parameters including mean platelet volume, platelet distribution of CNS TB is tuberculous
width, platelet–large cell ratio, and platelet aggregometry but not with other meningitis, which can
present either as an
hematologic parameters, suggesting primary platelet dysfunction may play a role
insidious chronic meningitis
in strokes.13 or as an acute fulminant
Predictors of stroke among individuals with tuberculous meningitis include meningitis with the most
more advanced disease stage, HIV co-infection, presence of basal exudates, common symptoms being
optochiasmatic arachnoiditis, focal neurologic deficits, cranial nerve palsy, fever, headache, and
alterations in
hydrocephalus, meningeal enhancement, and vision impairment.11,12,14 High CSF consciousness.
white blood cell count and the absence of a tuberculoma were also associated
with an increased stroke risk among young adults in China.11 Furthermore, stroke ● Stroke, usually in the
is associated with poorer tuberculous meningitis outcomes, including 2.6 times basal ganglia, is one of the
most common
higher odds of any poor outcome, 4.5 times higher odds of a longer hospital stay, complications of
and 8.8 times higher odds of requiring multiple hospitalizations.11,12,14 tuberculous meningitis,
Seizures are also common in tuberculous meningitis, occurring in 34% of occurring in approximately
individuals in a 2018 Indian case series.15 In this cohort, 30% of seizures occurred 30% to 60% of cases.
within 1 month of the onset of meningitis, and 70% occurred late (more than
● Seizures are common in
1 month after onset). The majority were focal onset, and nearly one-quarter tuberculous meningitis,
presented with status epilepticus. Early seizures were associated with meningeal occurring in approximately
irritation, whereas late seizures were more common in those with tuberculomas, one-third of individuals and
infarcts, and hyponatremia. Seizures were also associated with poorer outcomes most often occurring more
than 1 month after the onset
but not with mortality in this series, but recurrent new-onset seizures and status of meningitis symptoms.
epilepticus were associated with nearly 3 times higher mortality among
individuals with tuberculous meningitis in China.15,16
In addition to the higher mortality associated with HIV infection, other
co-infections may also modulate the severity of tuberculous meningitis. For
example, among a large cohort of Vietnamese adults with tuberculous
meningitis, 9% had evidence of Strongyloides stercoralis co-infection. Those with
co-infections had lower levels of pretreatment CSF neutrophils, interferon
gamma, and tumor necrosis factor-α concentrations and fewer neurologic

complications at 3 months after treatment than those without co-infection. This

suggests Strongyloides may modify the CNS inflammatory response to TB and
improve outcomes.17
Finally, paradoxical worsening in people with HIV initiating antiretroviral
therapy can also be seen and is known as immune reconstitution inflammatory
syndrome (IRIS). This can take two forms: (1) unmasking IRIS, which is an
immune response to a previously unknown infection; and (2) paradoxical IRIS,
which is an immune response to residual antigens after a known and previously
treated infection.
Diagnosis
Despite its worldwide distribution and severity, diagnosis of tuberculous
meningitis remains challenging. Neuroimaging is part of the standard
evaluation for suspected cases and can further increase clinical suspicion for the
diagnosis. Brain MRI obtained at the time of presentation of 90 adults with
tuberculous meningitis in India revealed tuberculomas in 100% of the patients,
leptomeningeal enhancement in 84%, infarcts in 58%, and hydrocephalus in
29%.10 However, in many high-TB-burden settings, MRI is often unavailable;
CT is the most accessible imaging modality. Typical CT findings in both
adults and children include hydrocephalus, deep infarcts, basal meningeal
enhancement, tuberculomas, and precontrast basal hyperdensity, the
combination of which is specific but not sensitive for a diagnosis of tuberculous
meningitis.18
The most common pattern of CSF abnormalities in tuberculous meningitis is
a mononuclear (ie, lymphocytic or monocytic) pleocytosis, low glucose, and
markedly elevated protein. However, these findings are not specific and may not
be present in individuals who are immunocompromised who may have normal
or only mildly abnormal CSF findings. The primary microbiological tools for
CNS diagnosis include CSF acid-fast bacilli stain, Mycobacterium culture, and
nucleic acid amplification tests such as the polymerase chain reaction (PCR)-
based assays Xpert MTB/RIF and Xpert MTB/RIF Ultra (Cepheid). All of these
modalities are limited in their sensitivity, which results in higher than acceptable
rates of false-negative results. CSF culture is often used as the gold standard for
definitive diagnosis, but it can take up to 6 weeks to grow M. tuberculosis, thus
necessitating that critical clinical decisions be made before its results are available
(CASE 8-1). The introduction of the Xpert MTB/RIF nucleic acid amplification
test in 2010 and, more recently, the second-generation Xpert MTB/RIF Ultra
assay in 2017 brought hopes of more sensitive CSF assays for CNS TB. However,
their sensitivity has varied widely in different populations. In tuberculous
meningitis cases from India, CSF MTB/RIF Xpert, Xpert MTB/RIF Ultra, and
multiplex PCR all demonstrated 100% specificity (meaning no false positives
were reported) but 71%, 28%, and 88% sensitivity, respectively.19 In tuberculous
meningitis cases from Zambia, CSF Xpert MTB/RIF demonstrated 53%
sensitivity and 94% specificity, and the introduction of Xpert MTB/RIF into
routine clinical practice did not lead to improved outcomes among individuals
with tuberculous meningitis.20 CSF Xpert MTB/RIF Ultra has been found to be
more sensitive than Xpert MTB/RIF in several cohorts, but the sensitivity of both
assays remains suboptimal.21 Overall, a systematic review of all nucleic acid
amplification tests revealed 82% sensitivity and 99% specificity when utilized in
CSF samples.22
996 AUGUST 2021

Given the imperfect sensitivity of current diagnostic tests, novel and KEY POINTS
adjunctive methods have been developed in hopes of improving the accuracy of
● Immune reconstitution
CNS TB diagnosis. CSF cell-free DNA is more sensitive than both culture and inflammatory syndrome is
Xpert MTB/RIF Ultra in identifying CNS TB but demonstrates only 53% paradoxical worsening of an
sensitivity when compared with a clinical diagnosis of tuberculous meningitis.21 individual’s clinical and
CSF adenosine deaminase levels have been purported to discriminate between radiographic presentations
that occurs in people with
tuberculous meningitis and other causes of meningitis in some populations, but
HIV initiating antiretroviral
the results have been inconsistent between populations, thus limiting its therapy.
uptake.23 Lateral flow assays to detect mycobacteria lipoarabinomannan antigen,
a polysaccharide chain found on mycobacterial cell walls, in the urine have been ● The primary
used as a point-of-care test to detect disseminated TB infection, especially in microbiological tools for
CNS diagnosis include
people with HIV with severe immunocompromise. However, efforts to utilize acid-fast bacilli stain,
this assay on CSF for tuberculous meningitis have been suboptimal with poor Mycobacterium culture, and
sensitivity, although a positive CSF lipoarabinomannan antigen in people with nucleic acid amplification
HIV and tuberculous meningitis was correlated with higher mortality compared tests. All of these modalities
are limited in their
with patients with negative CSF lipoarabinomannan antigen.20,24 sensitivity, which results in
Interferon gamma release assays are blood tests for detecting levels of higher than acceptable rates
interferon gamma released by T cells when exposed to TB antigens and are of false-negative results.
widely used to diagnose systemic TB. These assays include QuantiFERON
● Novel and adjunctive
(Qiagen), TB Gold (Qiagen), and T-Spot.TB (Oxford Immunotec). Applying
assays have been developed
these assays to the CSF has resulted in suboptimal sensitivities between 70% and in hopes of improving the
80% with no significant difference in sensitivity to detect tuberculous meningitis ability to accurately
between blood and CSF specimens.25 Furthermore, these assays are negative in diagnose CNS TB but, thus
far, continue to demonstrate
up to two-thirds of tuberculous meningitis cases.26 Peripheral blood microRNA
suboptimal sensitivity or
and CSF metagenomic next-generation sequencing have also been proposed as have not been widely
diagnostic assays but are not yet well validated.27,28 Advanced imaging validated.
techniques such as fludeoxyglucose positron emission tomography (FDG-PET)
and magnetization transfer imaging may also be useful in diagnosing tuberculous ● Investigating
combinations of diagnostic
meningitis.29,30 However, these techniques have not been widely validated, and tests may lead to the highest
their applicability in resource-limited settings that bear the highest burden of utility for diagnosing
CNS TB would be very limited. tuberculous meningitis.
Optic nerve sheath diameter ultrasonography, which is relatively inexpensive
● Given the difficulty of
and does have the potential for widespread use even in resource-limited settings,
obtaining a microbiologically
has been investigated in Vietnam in a cohort of adults with tuberculous meningitis confirmed diagnosis of
as a potential proxy indicator of increased intracranial pressure. Among study tuberculous meningitis,
participants, a higher optic nerve sheath diameter was associated with increased clinical case definitions such
as the Uniform Case
disease severity, the presence of brain imaging abnormalities, and increased
Definition and the Thwaites
mortality at 3 months after diagnosis.31 As a result of imperfect diagnostic tools, Score are often used in
many authors have begun investigating combinations of diagnostic tests that may high-TB-burden regions to
lead to the highest utility in diagnosing tuberculous meningitis.25 make presumptive diagnoses
Given the difficulty of obtaining a microbiologically confirmed diagnosis of to initiate empiric treatment.
tuberculous meningitis, clinical case definitions, CSF parameters, and radiologic

findings (if available) are often used in high-TB-burden regions to make
presumptive diagnoses and initiate empiric treatment. The most commonly used
definition is the uniform case definition, which divides cases into definite,
probable, and possible tuberculous meningitis based on a scoring system by using
clinical, CSF, and neuroimaging characteristics (TABLE 8-2).18 Although
commonly used, however, this score also has poor sensitivity in differentiating
tuberculous meningitis from other causes of meningitis even in TB-endemic
regions.32 Other clinical prediction scores have also been developed, including

the Thwaites score from Vietnam33; however, these, too, show higher sensitivity
but lower specificity than microbiological standards.32
In practice, a combination of clinical and laboratory parameters is used to
make clinical decisions in high-TB-burden settings, which often lack extensive
CSF diagnostic testing. In these settings, a high degree of suspicion for TB is
maintained even in the absence of confirmatory microbiological evidence from
the CSF. In patients with clinical presentations that could be compatible with
tuberculous meningitis in whom alternative diagnoses have been excluded (eg,
negative Gram stain and bacterial culture, negative cryptococcal antigen), the
threshold to initiate early empiric therapy for tuberculous meningitis is low,
especially when evidence of systemic TB infection and/or compatible CSF and
neuroimaging findings are present. It is essential, however, in these situations to
CASE 8-1 A 40-year-old previously healthy man presented with decreased

consciousness. He developed headaches 1 month before that were
intermittent and then became more frequent and severe. One week
before presentation, he developed facial droop and seemed intermittently
confused, which progressed to constant confusion and then decreased
arousability. Additional history included a 4.5-kg (10-lb) unintentional weight
loss, night sweats, and intermittent fevers over the preceding month. He
lived in Zambia but had no known close contacts with tuberculosis (TB).
On examination, he grimaced to sternal rub but did not open his eyes, did
not track, and was nonverbal. He had bilateral papilledema, bilateral sixth
nerve palsies, and weakness of eye closure and grimace on the right.
Laboratory evaluation revealed serum sodium of 129 mmol/L, white blood
cell count of 2500 cells/mm3, reactive rapid human immunodeficiency virus
(HIV) test, and CD4+ T-cell count of 154 cells/mm3. Chest x-ray was normal,
and urine mycobacteria lipoarabinomannan antigen was negative. Brain MRI
(FIGURE 8-2) revealed thick exudates in the basal cisterns and frontotemporal
regions and communicating hydrocephalus. EEG showed diffuse slowing but
no epileptiform discharges. CSF white blood cell count was 8 cells/mm3
(70% lymphocytes), glucose was 50 mg/dL, and protein was greater than
200 mg/dL (the upper limit of detection for the available assay). Acid-fast
bacillus stain, Gram stain, and India ink were unrevealing. Cryptococcal
antigen test was negative, as was Xpert MTB/RIF nucleic acid amplification.
Despite the lack of microbiological confirmation, the clinical,
radiographic, and laboratory presentations were thought to be consistent
with tuberculous meningitis. The patient was initiated empirically on
standard antituberculous therapy and IV dexamethasone. Antiretroviral
therapy for HIV was begun 1 week later per guidelines in HIV and TB
co-infection designed to balance the mortality benefit of early antiretroviral
therapy initiation with prevention of immune reconstitution inflammatory
syndrome. Within 1 week of initiating TB treatment, his mental status began
to improve, and he was discharged home after 3 weeks. His TB culture
returned positive 5 weeks after it was obtained and 2 weeks after the
patient’s hospital discharge.
998 AUGUST 2021

continue close follow-up of these patients to ensure an appropriate response to
empiric therapy and reevaluation of the diagnosis if such a response is not
demonstrated.
Treatment
The World Health Organization recommends treatment of tuberculous
meningitis in two stages, which are (1) the intensive phase: rifampicin, isoniazid,
pyrazinamide, and ethambutol for 2 months followed by (2) the continuation
phase: rifampicin and isoniazid for an additional 7 to 10 months (9 to 12 months
of total treatment).34 Antimicrobial sensitivity data are also important, when
available, to detect drug resistance. This can be obtained either from a positive
culture or, at least for rifampicin, from Xpert MTB/RIF and Xpert MTB/RIF
FIGURE 8-2
Axial (A) and coronal (B) postcontrast T1-weighted MRIs from the patient in CASE 8-1
reveal a thick basal exudate (A, green arrow) in the basal cisterns and leptomeningeal
enhancement (B, yellow arrows) in the frontotemporal regions bilaterally as well as a
communicating hydrocephalus.
This case illustrates the difficulty of obtaining a confirmed diagnosis of COMMENT

tuberculous meningitis in a clinically relevant timeframe. Especially in
TB-endemic regions, a high suspicion and initiation of empiric therapy are
often required after exclusion of other common etiologies. In these
settings, a markedly elevated CSF protein in the absence of other
significant abnormalities is suggestive of tuberculous meningitis, and the
basal exudates seen on this patient’s imaging were also very typical.

Ultra assays. Multidrug-resistant and extremely drug-resistant TB infections are

becoming more common, especially in high-TB-burden regions, and usually
require prolonged treatment with additional antituberculous agents such as
levofloxacin, bedaquiline, linezolid, clofazimine, cycloserine, and amikacin.
In addition to antituberculous agents, concomitant steroids tapered over 6 to
8 weeks have also been shown to reduce mortality, severe disability, and disease
relapse.35,36 Of note, the benefit of steroids in people with HIV and individuals
with MRC stage 3 disease on presentation remains controversial.36 One protocol
from Vietnam suggests 2 weeks of IV dexamethasone for MRC stage 1 disease and
4 weeks of IV dexamethasone for MRC stage 2 and 3 disease followed by a 4-week
oral prednisone taper for all stages.35 However, this approach requires prolonged
hospital stays. A study from India found IV steroids may be safely transitioned to
oral steroids after 48 hours of sustained clinical improvement on IV steroids,
especially among individuals with basal exudates, tuberculomas, and/or higher
functional status.37
TABLE 8-2 Uniform Case Definition for Tuberculous Meningitisa,b
Criteria Score
Clinical criteria
Symptom duration >5 days 4
Systemic symptoms suggestive of tuberculosis (TB), including weight loss, night 2

sweats, or cough lasting >2 weeks
Close contact with someone with TB in the past year 2
Focal neurologic deficits (excluding cranial nerve palsies) 1
Cranial nerve palsy 1
Altered consciousness 1
Maximum score 6
CSF criteria
Clear appearance 1
10-500 cells/mm3 1
Lymphocytic predominance 1
Protein >1 g/L 1
CSF to plasma glucose ratio <50% or absolute CSF glucose <40 mg/dL 1
Maximum score 4
Neuroimaging criteria
Hydrocephalus 1
Basal meningeal enhancement 2
1000 AUGUST 2021

Several other treatment considerations unique to individuals with TB and
HIV co-infection also exist. For people with HIV who are either newly
diagnosed with HIV or have not yet initiated HIV treatment, early initiation of
antiretroviral therapy (less than 8 weeks after commencement of TB treatment)
results in a mortality benefit. If the CD4+ T-cell count is less than 50 cells/mm3,
antiretroviral therapy should be commenced within 2 weeks of TB treatment
as this confers an additional survival benefit.38,39 These considerations are
designed to reduce the risk of IRIS while maximizing the mortality benefit of
antiretroviral therapy. If IRIS does occur, treatment depends on which form
of IRIS is present. In unmasking IRIS, treatment involves both corticosteroids
and treatment of the underlying infection; in paradoxical IRIS, it usually involves
only corticosteroids.
Given high mortality rates in all populations despite standard therapy, efforts
continue to identify new, more effective therapies. The addition of a
fluoroquinolone to standard therapy did not improve outcomes in a retrospective
Criteria Score
Tuberculoma 2
Infarct 1
Precontrast basal hyperdensity 2
Maximum score 6
Evidence of TB elsewhere
Chest x-ray suggestive of active TB
Signs of TB 2
Miliary TB 4
Imaging evidence of TB outside of the central nervous system 2
Acid-fast bacilli identified or Mycobacterium tuberculosis cultured from another 4

source (eg, sputum, lymph node)
Positive TB nucleic acid amplification test from a source outside of the central 4
nervous system
Maximum score 4
CSF = cerebrospinal fluid.

a
Data from Marais S, et al, Lancet Infect Dis.18
b
To apply this score, individuals must have symptoms and signs of meningitis, including one or more of the
following: headache, irritability, vomiting, fever, meningismus, seizures, focal neurologic deficits, lethargy,
and/or altered consciousness. In addition, alternative diagnoses, including bacterial, viral, fungal, and
parasitic meningitides, should be excluded. If these criteria are met, the case definition can be applied to
the individual as follows: Definite tuberculous meningitis requires microbiological confirmation of M.
tuberculosis. Probable tuberculous meningitis requires a score ≥10 if neuroimaging is unavailable and a score
≥12 if neuroimaging is available. Possible tuberculous meningitis requires a score of 6-9 if neuroimaging is
unavailable and 6-11 if neuroimaging is available.

cohort of HIV-uninfected adults with tuberculous meningitis in China.40

However, thalidomide as an adjunctive anti-inflammatory treatment has shown
promise in animal models and case reports, but its toxicity may limit widespread
use.41 Nevertheless, a 2020 retrospective study of 38 children presenting with
CNS TB complications who were treated with thalidomide found the drug was
safe, well tolerated, and very efficacious with 37 of 38 children showing a
satisfactory clinical and radiologic response.42 A retrospective review of clinical
trial data from Indonesia suggested a higher rifampicin dosage (either oral or IV
formulations) resulted in improved survival.43 Therefore, a randomized
controlled trial of high-dose oral and IV rifampicin is being launched to
investigate whether this dosage achieves a higher CSF rifampicin concentration
and improves outcomes.44 Furthermore, a 2020 trial of replacing oral isoniazid
and ethambutol with IV formulations resulted in significant clinical and
radiographic improvement and higher rates of sputum conversion after 2 months
of treatment in people with HIV with tuberculous meningitis compared with
those treated with standard oral treatment.45 However, these results have not
been verified in larger populations.
Another area of controversy concerns the addition of aspirin to standard
treatment regimens. In a small randomized controlled trial of adults with
tuberculous meningitis in India, aspirin reduced the risk of stroke by 19% and
overall mortality by 50%.46 However, studies have shown inconsistent results,
and a systematic review found aspirin reduced stroke risk in tuberculous
meningitis and was safe but had no effect on overall mortality.47
In addition to pharmacologic therapy against M. tuberculosis, other complications
of the disease must be addressed, including hyponatremia, hydrocephalus,
increased intracranial pressure, and paradoxical reactions (eg, IRIS among people
with HIV or the development of tuberculomas in people with HIV or
HIV-uninfected individuals after treatment of tuberculous meningitis is initiated),
all of which often result in critical illness. For example, hyponatremia may occur
because of cerebral salt wasting or the syndrome of inappropriate secretion of
antidiuretic hormone, each of which needs to be accurately identified to be
appropriately and aggressively managed. From a neurosurgical perspective,
endoscopic third ventriculostomies may be useful for hydrocephalus, but success
rates are estimated to be less than 60%, and the patient population most likely to
benefit is unknown.48 The evidence base for determining appropriate
management strategies of these complications is quite limited, especially in
resource-limited settings with high TB burdens where access to critical care
facilities is often extremely limited.49 Daily checklists have been proposed as a
systematic method to approach the comprehensive management of individuals
with tuberculous meningitis but have not yet been validated.50
Outcomes
A worldwide systematic review of adults with tuberculous meningitis identified
a 23% mortality rate and 29% risk of neurologic sequelae.7 However, outcomes
vary widely with mortality rates as high as 60% in lower-resource settings and
less than 20% in higher-resource settings with greater access to critical care
facilities.51,52 In addition to physical disability, neurocognitive impairment occurs
in 10% to 55% of adult survivors, and approximately half of child survivors have
long-term neurodevelopmental consequences.53 Risk factors for death include
advanced MRC disease stage, hydrocephalus, altered consciousness, older age,
1002 AUGUST 2021

HIV co-infection, low CSF white blood cell count, positive CSF culture, and KEY POINTS
infarct.7,52,54 Several bedside prediction scores have been developed to identify
● The World Health
individuals at the highest risk of mortality to target them for more aggressive Organization recommends
clinical management, but these have not yet been validated in more diverse treatment of tuberculous
populations.55,56 meningitis in two stages,
which are (1) the intensive
phase: rifampicin, isoniazid,
TUBERCULOMAS AND TUBERCULOUS ABSCESSES
pyrazinamide, and
Tuberculomas are space-occupying lesions consisting of granulomatous reactions ethambutol for 2 months
to M. tuberculosis infection that are believed to arise from the hematogenous and (2) the continuation
spread of mycobacteria to the brain parenchyma. Microscopic granulomatous phase: rifampicin and
isoniazid for 9 to 12 months.
foci, called Rich foci, develop over time, organizing into encapsulated
granulomatous mass lesions. Tuberculomas are similar to tuberculous abscesses, ● Concomitant steroids in
but abscesses are often larger and have a pus-filled cavitary center. Tuberculomas addition to antitubercular
and tuberculous abscesses are considered together here because their clinical therapy tapered over 6 to
presentation, radiologic findings, diagnosis, and treatment are similar, and they 8 weeks have also been
shown to reduce mortality,
are ultimately only definitively differentiated based on pathologic features. severe disability, and
disease relapse.
Approximately 10% of individuals with tuberculous meningitis have concomitant ● A systematic review
found that the addition of
tuberculomas, but tuberculomas can also occur in the absence of meningitis and
aspirin to standard
without evidence of TB infection outside the CNS.57,58 Tuberculomas can develop treatment regimens for
anywhere within the CNS including the brain parenchyma, spinal cord, or tuberculous meningitis
subdural, epidural, subependymal, or subarachnoid spaces. Overall, tuberculomas reduced the risk of stroke
and was safe but had no
are more common in children, in whom they tend to be infratentorial, but are
effect on overall mortality.
more commonly supratentorial in adults.59 Lesions are solitary in one-third of
cases and multiple, with an average of approximately five, in the remainder.60 ● A systematic review of
Clinical presentation typically consists of focal neurologic deficits corresponding tuberculous meningitis
to the site of the lesion, accompanied by headaches, fever, and, often, seizures. among adults worldwide
identified a 23% mortality
Examination frequently reveals papilledema. risk and 29% risk of
Of note, paradoxical expansion of tuberculomas, defined as the development neurologic sequelae.
of a new tuberculoma or enlargement of an existing tuberculoma while on However, outcomes vary
appropriate TB treatment, is not uncommon and usually occurs within 3 months widely with mortality rates
as high as 60% in
of initiating TB treatment. This is more common in people with HIV, especially lower-resource settings and
in those initiating antiretroviral therapy for the first time, in which case it is a less than 20% in
manifestation of IRIS. However, it can also occur in HIV-uninfected individuals, higher-resource settings
with up to one-third of patients with tuberculous meningitis developing with greater access to
critical care facilities.
tuberculomas during treatment despite no neuroimaging evidence of tuberculoma
at the time of antituberculous treatment initiation. This may be predicted by ● Approximately 10% of
serial CSF studies showing worsening white blood cell counts and neutrophils individuals with tuberculous
within the first 2 weeks of treatment. However, development of paradoxical meningitis have concomitant
tuberculomas does not seem to be related to outcome, including mortality.61 tuberculomas, but
tuberculomas can also occur
in the absence of meningitis
Diagnosis and without evidence of TB
Like tuberculous meningitis, definitive diagnosis of tuberculomas is often infection outside of the CNS.
challenging. A presumptive diagnosis of tuberculoma is usually made on the basis
of neuroimaging findings in combination with a compatible clinical history,
supportive evidence of TB outside the CNS, and response to treatment.62
Radiographic features depend on the stage of the granuloma, which can be
noncaseating, caseating, caseating with central liquefication, or calcified
(TABLE 8-363). The majority of tuberculomas are less than 1 cm in diameter with

about 10% of lesions measuring 1 cm to 3 cm in diameter, although larger lesions

are possible. Approximately 10% of tuberculomas also have associated
calcification, and one-third demonstrate perilesional edema (CASE 8-2).64 The
“target sign,” a central nidus of calcification surrounded by a rim of enhancement
(CASE 8-2), is found more commonly in children than in adults and is nearly
pathognomonic for tuberculoma, although it is occasionally seen in other
infections and neoplasms.65
Differentiating tuberculomas from metastatic lesions and gliomas can also be
challenging, but unique patterns on noncontrast arterial spin labeling, diffusion
tensor imaging, susceptibility-weighted imaging (SWI), and magnetic resonance
spectroscopy may be useful.67,68 Additionally, differentiating tuberculomas from
some stages of neurocysticercosis can be difficult in many regions where both
infections are endemic. However, the addition of perfusion MRI to conventional
MRI sequences can be especially helpful in this regard because relative cerebral
blood volume is significantly higher in the wall of tuberculomas than in
neurocysticercosis lesions.69
In addition to the absence of pathognomonic radiographic findings, CSF
findings are also often nonspecific. Both the basic CSF profile and
microbiological tests for TB are usually normal in the absence of a concurrent
tuberculous meningitis, and the only definitive diagnostic test is a brain biopsy.
In a retrospective cohort of people with HIV in Argentina presenting with
space-occupying lesions, brain biopsy revealed a definitive etiology in 93% of
cases and changed management in 75%.70 However, biopsy is often not possible
in resource-limited settings where TB is most common, thus necessitating a
presumptive diagnosis based on clinical and radiographic characteristics to
initiate empiric antimicrobial therapy.
Further complicating this scenario is that the differential diagnosis for
space-occupying lesions is broad in both people with HIV and HIV-uninfected
TABLE 8-3 MRI Features of Tuberculomas by Stagea
Fluid-attenuated Diffusion-
Tuberculoma inversion recovery weighted
stage T1 T2 (FLAIR) imaging T1 + gadolinium
Noncaseous Iso/hypointense Hyperintense Hyperintense No restriction Homogenous

granuloma enhancement
Caseous Iso/hypointense Hypointense Hyperintense No restriction Homogenous or

granuloma with hyperintense ringlike
peripheral ring enhancement
Noncaseous Iso/hypointense Hyperintense Predominantly Heterogenous Ringlike

granuloma with with hyperintense peripheral ring with hyperintense hyperintensity enhancement
liquefied center peripheral ring hyperintense
center
Calcified Iso/hypointense Hypointense Hypointense No restriction No enhancement

granuloma
MRI = magnetic resonance imaging.

a
Modified with permission from Salvador GLO, et al, Neuroradiology.63 © 2020 Elsevier Inc.
1004 AUGUST 2021

individuals. In South Africa, a retrospective study of people with HIV presenting KEY POINTS
with space-occupying lesions found that more than 80% of the lesions were
● In the absence of
felt to be caused by either toxoplasmosis or tuberculoma, and difficulty meningitis, CSF is usually
differentiating between the two led to the initiation of empiric treatment for normal in patients with
both infections simultaneously; individuals in whom cotreatment was initiated tuberculoma, and the only
earlier had better outcomes than those in whom treatment was delayed.71 definitive diagnostic test is a
brain biopsy. As such, a
presumptive diagnosis
Treatment based on clinical and
Tuberculoma treatment largely mirrors recommendations for tuberculous radiographic characteristics
meningitis with most guidelines recommending a total of 9 to 12 months of is often made to facilitate
standard TB treatment (ie, 2 months of intensive phase followed by 7 to the initiation of empiric TB
treatment.
10 months of continuation phase therapy) along with adjuvant corticosteroids.
However, these guidelines are largely based on expert opinion rather than ● Tuberculoma treatment
evidence because few clinical trials have been conducted. Duration of TB largely mirrors
treatment is one area of significant controversy with some experts recommendations for
tuberculous meningitis with
recommending prolonged treatment until contrast enhancement has resolved
most guidelines
on neuroimaging. Whether persistent enhancement represents persistent recommending 9 to
infection or an inflammatory response to a sterilized lesion is unclear.62 Persistent 12 months of standard TB
tuberculomas are, however, associated with persistent neurologic deficits, and larger treatment along with
tuberculomas are more likely to persist despite treatment.72 Still, most experts do not adjuvant corticosteroids.
recommend prolonged treatment for persistent enhancement, but evidence-based

clinical data are not yet available to definitively answer this question.62
Optimal corticosteroid dose and duration are also unknown and should be
tailored to lesion size and clinical and radiologic response. Corticosteroids are
more likely to be helpful in tuberculomas with significant perilesional edema and
in the setting of paradoxical worsening during treatment, and they may not be
beneficial in TB abscesses whereas thalidomide may.73,74 Furthermore,
prolonged duration of treatment may be necessary for some individuals in whom
tapering steroids leads to clinical deterioration. The role of surgical management
is less clear but primarily includes biopsy in the setting of indeterminate lesions
or poor response to empiric therapy. Neurosurgical resection is reserved for
life-threatening complications of the mass lesion such as obstructive
hydrocephalus.
SPINAL TUBERCULOSIS
As with the varied manifestations of intracranial TB, TB can involve every
compartment of the spine including bony structures, intradural and extradural
spaces, the spinal cord, and nerve roots. The thoracic and lumbar regions are
most commonly involved, but cervical involvement occurs in more than one-
quarter of affected individuals and is associated with more frequent neurologic
sequelae than other locations.75 Worldwide, 150,000 new cases of spinal TB are
estimated annually, and its incidence may be rising.75,77 Although concurrent
presentations with pulmonary TB occur, the majority of cases of spinal TB occur
in the absence of pulmonary disease.77 The most common manifestations of
spinal TB are spondylitis and intradural tuberculous spinal infections including
radiculomyelitis, spinal arachnoiditis, intramedullary tuberculomas, and myelitis.
Spondylitis
Spondylitis, also known as Pott disease, is the most common form of spinal TB
and accounts for 50% of cases of skeletal TB.78 It presents with insidiously

CASE 8-2 A 24-year-old woman with human immunodeficiency virus (HIV) infection
presented with new-onset seizures and headache. She had been unwell
for 2 months with generalized malaise, intermittent low-grade fevers,
night sweats, and productive cough. She had been on antiretroviral
therapy for more than 15 years but had stopped taking her medication
1 year before presentation. She lived in Zambia and had no known
tuberculosis (TB) exposures.
On examination, she was oriented to person and place, could follow
only simple commands, and had 2/5 left leg weakness with a Babinski
sign. Her strength and mental status improved over the next 24 hours.
Investigations revealed a white blood cell count of 14,000 cells/mm3
(92% neutrophils) that normalized within 24 hours, CD4+ T-cell count of
178 cells/mm3, HIV viral load of 152,000 copies/mL, EEG with focal
slowing and intermittent epileptiform discharges in the right frontal
region, chest x-ray with a cavitary lesion in the left upper lobe, and
positive urine mycobacterial lipoarabinomannan antigen. Head CT
showed a well-circumscribed lesion in the right frontal lobe with a
hyperdense ring, internal calcification, and surrounding vasogenic edema
(FIGURE 8-3). Lumbar puncture was deemed unsafe because of mass
effect.
Given the compatible clinical history, chest x-ray findings, and positive
urine lipoarabinomannan antigen, a presumptive diagnosis of pulmonary
TB with intracranial tuberculoma was made. The patient was initiated on
standard antituberculous therapy with IV dexamethasone for 1 week,
which was transitioned to oral prednisolone and tapered over 5 weeks.
She was started on carbamazepine, and antiretroviral therapy was
reinitiated.
The patient had no further seizures and regained full strength in her
right leg 3 days later. She was discharged home and completed 12 months
of antituberculous treatment. Repeat brain imaging revealed resolution
of the previously seen lesion. Carbamazepine was discontinued after
18 months without a seizure.66
1006 AUGUST 2021

FIGURE 8-3
Axial noncontrast CT of the patient in
CASE 8-2 demonstrates a well-
circumscribed lesion with an area of
central calcification and surrounding
hyperdense ring. Marked associated
vasogenic edema is seen with
resultant compression of the right
lateral ventricle. Of note, if
postcontrast images had been
obtained, they would have likely
demonstrated central enhancement
surrounded by a ring of enhancement.
This case illustrates a typical presentation of an intracranial tuberculoma COMMENT

with headache, focal deficits, and seizures. In the absence of
microbiological confirmation of Mycobacterium tuberculosis, evidence
of extracranial TB infection (eg, chest x-ray findings) and a positive urine
lipoarabinomannan antigen (indicative of disseminated TB; see the
Diagnosis portion of the section titled Tuberculous Meningitis), was felt
to be strongly supportive of a diagnosis of tuberculoma. Furthermore,
the imaging findings in this case are an example of the 10% of
tuberculomas that show internal calcification. This case demonstrates a
central calcification and a hyperdense rim, features of the target sign
(which can include ring enhancement), a nearly pathognomonic finding
for central nervous system TB.

CASE 8-3 A 47-year-old previously healthy man presented with a new-onset dull,
global headache that was increasing in intensity. He was treated with
over-the-counter analgesics. Four months later, he presented again with
night sweats and a 5.4-kg (12-lb) weight loss. Chest x-ray was suggestive
of pulmonary tuberculosis (TB). He was newly diagnosed with human
immunodeficiency virus (HIV) and initiated on antituberculous treatment
and antiretroviral therapy. One month later, he returned with worsening
headache.
Examination was notable only for mild meningismus and papilledema
bilaterally. Basic laboratory results were notable for lymphopenia (white
blood cell count of 3700 cells/mm3), anemia (hemoglobin 7.8 g/dL), and
elevated inflammatory markers (erythrocyte sedimentation rate of
131 mm/h and C-reactive protein level of 41 mg/L). CT scan of the brain
was normal. Lumbar puncture revealed 30 white blood cells/mm3 (100%
lymphocytes), glucose of 32 mg/dL (serum glucose of 85 mg/dL), and
protein of 134 mg/dL. Gram stain, bacterial culture, cryptococcal antigen,
India ink, Xpert MTB/RIF nucleic acid amplification test, acid-fast bacilli
stain, and TB culture were negative.
Given the clinical picture, a presumptive diagnosis of tuberculous
meningitis with possible immune reconstitution inflammatory syndrome
(IRIS) was made. Dexamethasone was added, and the planned duration of
TB treatment was increased to 1 year. His headache began to improve,
and he was discharged home. One month later, he presented again with
an inability to walk preceded by 1 week of symmetric paresthesia and
bowel and bladder incontinence. Neurologic examination was notable
for spastic paraplegia, hyperreflexia, extensor plantar responses, loss of
all sensory modalities in the lower extremities, and a T6 sensory level.
MRI of the spine demonstrated three subdural ring-enhancing lesions
with associated cord compression and signal change in the thoracic
region (FIGURE 8-4) consistent with subdural spinal tuberculomas. Spine
surgeons were consulted but recommended no surgical intervention.
Prednisolone dosage was increased to 80 mg daily with a planned taper
over 8 weeks, and he was discharged home. One year later, he continued
to have a mild spastic paraparesis but was able to ambulate
independently.
COMMENT This case demonstrates two important concepts regarding central nervous
system (CNS) TB in people with HIV. First, the patient’s worsening
headache after initiation of TB treatment and antiretroviral therapy was
likely a manifestation of unmasking IRIS in which his previously
unrecognized tuberculous meningitis worsened in the setting of immune
restoration. Second, this case also demonstrates the paradoxical
development of spinal tuberculomas during appropriate CNS TB
treatment.
1008 AUGUST 2021

FIGURE 8-4
Sagittal postcontrast T1-weighted MRI
from the patient in CASE 8-3
demonstrates three thin-walled
ring-enhancing lesions in the thoracic
subdural region with associated mass
effect on the spinal cord causing cord
compression.

evolving nonspecific back pain that is then followed by kyphosis (which

can often be detected clinically as a gibbus formation on the back), sensory
symptoms, bowel and bladder symptoms, and, finally, paraparesis. Progression
through these stages occurs over the course of months to more than 1 year.77
Acute presentations of neurologic deficits are not uncommon because
of vertebral fracture or abscess formation with subsequent spinal cord
compression. Imaging classically shows edema and bony destruction of the
vertebral body with paravertebral granulomatous exudates or abscess. The
thoracic cord is the most common location, and spondylitis often involves
three or more consecutive vertebral bodies while sparing the intervertebral
disks.79 More severe vertebral body destruction and kyphosis have been reported
in HIV-uninfected adults with spondylitis whereas people with HIV are more
likely to develop epidural abscesses anterior to the vertebral body.80
Intradural Tuberculous Spinal Infections

Intradural tuberculous spinal infections, including radiculomyelitis, spinal
arachnoiditis, intramedullary tuberculomas, and myelitis, are seen most
commonly in the setting of tuberculous meningitis because of the spread of
inflammatory exudates from the cranial to the spinal compartment. These
inflammatory exudates often settle in the lumbosacral subarachnoid space and
present with a conus medullaris or cauda equina syndrome. Areflexic paraparesis
with prominent bladder symptoms and neuropathic pain are common. The
subarachnoid space may also become irregularly obstructed because of these
exudates, resulting in the formation of CSF loculations. Syrinx is a frequent late
complication of tuberculous meningitis and spinal TB.81
Tubercular radiculomyelitis is the most common intradural spinal manifestation
of TB, occurring in nearly 40% of individuals with tuberculous meningitis.
Intradural extramedullary tuberculomas, intramedullary tuberculomas, and
tuberculous abscesses occur in 20%, 9%, and 7% of patients, respectively.82
Intradural spinal infections are most often symptomatic during illness with
tuberculous meningitis, but they can occasionally be asymptomatic or present
many years after resolution of the meningitis (CASE 8-3).83 In addition, paradoxical
worsening of spinal tuberculosis during treatment is common and often responds
to increased dosages or repeated courses of corticosteroids. Uncommon
complications of these infections include spinal cord vasculitis and infarcts.
Diagnosis
For Pott disease, initial investigations usually include spinal imaging, which, in
many high-TB-burden settings, may be limited to plain x-rays. If oblique views
are obtained as part of the spine series, plain radiographs can demonstrate
sensitivity as high as 70% for the diagnosis of spondylitis, although they may be
normal early in the disease.84 Radiolucencies and loss of definition of plate margins
are the earliest findings in spondylitis followed by vertebral body destruction
(most commonly involving the anterior portion of the vertebral body), endplate
erosion, loss of normal disk height, sclerosis, and paravertebral masses. Where
MRI is available, the combination of subligamentous spread, vertebral collapse,
and large abscess collection with a thin wall was comparable to biopsy-obtained
tissue studies in discriminating TB from non-TB etiologies (FIGURE 8-5).85
In cases of spinal arachnoiditis, CSF loculations are often visualized on MRI
(FIGURE 8-5). Laboratory confirmation should be sought in suspected cases of
1010 AUGUST 2021

TB of the spine whenever possible. With intradural spinal tuberculosis, CSF is KEY POINTS
often abnormal and shows a profile similar to tuberculous meningitis. In Pott
● Tuberculous spondylitis
disease, however, CSF is often normal, and bone biopsy, which is the gold presents insidiously over the
standard to exclude alternative infectious and neoplastic etiologies, is often course of months to more
difficult in resource-limited settings. than 1 year, first with
nonspecific back pain that is
then followed by kyphosis,
Treatment sensory symptoms, bowel
Similar to tuberculomas, a presumptive diagnosis based on clinical presentation and bladder symptoms, and,
and x-ray findings (or other neuroimaging findings if available) is often required finally, paraparesis.
for all forms of TB of the spine and is followed by initiation of empiric TB
● Intradural tuberculous
treatment. TB treatment for 9 to 12 months (ie, intensive phase therapy for
spinal infections, including
2 months followed by 7 to 10 months of continuation phase therapy) with adjuvant radiculomyelitis, spinal
corticosteroids is recommended, but the optimal dose and duration of these arachnoiditis,
treatments are not based on evidence from clinical trials and remain controversial. intramedullary
Of note, clinical improvement often precedes radiographic improvement in Pott tuberculomas, and myelitis,
are seen most commonly in
disease and may even occur despite radiographic worsening. This limits the utility the setting of tuberculous
of serial imaging in informing decisions regarding treatment duration.86 meningitis because of the
Among individuals with spondylitis, surgical options, including decompression, spread of inflammatory
stabilization, and correction of kyphotic deformities, are considered on a exudates from the cranial to
the spinal compartment.
case-by-case basis.76 Predictors of neurologic decline in individuals with spinal TB
include signal change within the spinal cord on MRI and severe deviation of the
spine (ie, scoliosis), so these individuals should be targeted for early surgical
FIGURE 8-5
Sagittal T2-weighted (A) image from thoracic spine MRI demonstrating vertebral body
destruction, loss of disk height, erosion, and paravertebral masses consistent with
tuberculous spondylitis. Sagittal T2-weighted (B) and T1-weighted (C) images from another
patient’s thoracic spine MRI demonstrating CSF loculations with resultant spinal cord
compression consistent with spinal arachnoiditis. Of note, postcontrast images were not
available for these patients, but spinal arachnoiditis is often associated with abnormal
enhancement.
Panel A courtesy of Omar Siddiqi, MD, MPH.

intervention to prevent the development of more severe neurologic deficits.87 Still,

delayed decompression may be beneficial with significant neurologic
improvement reported with decompression occurring up to 3 to 4 weeks after
development of progressive neurologic deficits.88
With appropriate treatment, more than half of people with spinal tuberculosis
have a favorable outcome, but 14% develop postinfectious complications, 10%
experience no improvement, and 18% die despite treatment.82
OTHER CENTRAL NERVOUS SYSTEM TUBERCULOSIS MANIFESTATIONS

Although the most common manifestations of CNS TB have been detailed here,
TB has a myriad of uncommon CNS manifestations including optic neuropathy,
optochiasmatic arachnoiditis, tuberculous encephalopathy, subarachnoid
TABLE 8-4 Less Common Neurologic Manifestations of Tuberculosis
Syndrome Description
Optic neuritis/optic Most optic neuropathies are secondary to chronic increased intracranial pressure, mass effect
neuropathy from tuberculomas, or drug-associated toxicities. However, primary optic neuropathies have also
been reported and can be the presenting sign of central nervous system (CNS) tuberculosis (TB).
In these cases, optic neuritis occurs because of tubercular perineuritis, endarteritis of the optic
nerve, or arachnoiditis of the optic nerve and/or chiasm.89
Optochiasmatic Occurs in conjunction with tuberculous meningitis when accumulation of exudates in the basal
arachnoiditis cisterns leads to arachnoiditis of the optic nerves and chiasm, which manifests as slowly
progressive vision loss and most commonly occurs in younger individuals, including children.90 In
addition, this entity commonly occurs as part of a paradoxical reaction after initiation of
antituberculous treatment.90
Tuberculous A rare clinical manifestation of CNS TB that occurs most commonly in the pediatric population. Its
encephalopathy clinical presentation ranges from focal neurologic deficits or confusion to seizures or coma. MRI
shows extensive white matter changes, usually with contrast enhancement and sometimes
diffuse cerebral edema, but CSF is usually normal or only mildly abnormal. The mechanism for this
entity is thought not to be caused by direct infection of the CNS by TB but to be an
immune-mediated reaction. Two mechanisms have been postulated: (1) an acute disseminated
encephalomyelitis (ADEM)-like mechanism; and (2) an allergic (type IV hypersensitivity) reaction
within the nervous system to systemic TB protein. Early diagnosis and initiation of antituberculous
treatment and steroids is imperative to reduce associated morbidity and mortality.91-93
Subarachnoid Occurs as a result of rupture of tuberculous cerebral aneurysms that develop in the setting of
hemorrhage tuberculous meningitis.94
Limbic encephalitis Described in association with systemic TB infection, including mediastinal lymphadenopathy,95 or
in association with tuberculous meningitis.96 In high-TB-burden regions, TB accounts for a
nonsignificant proportion of limbic encephalitis cases.97
Neuromyelitis optica Some studies have suggested a potential unproven link between pulmonary tuberculosis and
neuromyelitis optica. For example, a study from South Africa described three patients with optic
neuritis and longitudinally extensive myelopathy and active pulmonary TB but no evidence of CNS
TB whereas another South African study found nearly 80% of patients with neuromyelitis optica
had a preceding or simultaneous diagnosis of pulmonary TB.98 However, a study from China did
not show any significant increase in TB prevalence among patients with neuromyelitis optica
compared with controls.99 Whether these reports represent the coincidental simultaneous
occurrence of two not uncommon disorders in the same person or whether a mechanistic link
exists between these conditions remains undetermined.
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
1012 AUGUST 2021

hemorrhage, limbic encephalitis, and a possible unproven association with
neuromyelitis optica (TABLE 8-4).89-99 Therefore, especially in TB-endemic
regions and in people with HIV, TB should be considered in the differential
diagnosis of a wide array of neurologic manifestations.
COMPLICATIONS OF ANTITUBERCULOUS THERAPY

Of note, several antituberculous medications have important neurologic side
effects for which one must also monitor. Ethambutol can cause optic neuropathy,
so visual function should be carefully monitored during the intensive phase of
therapy. Isoniazid can cause a painful peripheral neuropathy through depletion
of pyridoxine, so supplementation with 50 mg of pyridoxine daily should be
prescribed to prevent this complication. Isoniazid overdose can also lead to
seizures, which are most effectively treated with pyridoxine supplementation.100
Finally, isoniazid is a potent cytochrome P450 inhibitor whereas rifampicin is a
potent cytochrome P450 inducer such that both have significant interactions
with many antiretroviral medications and antiepileptic drugs, necessitating
careful antiepileptic drug level monitoring throughout the course of therapy.101
CONCLUSION
TB remains one of the most common infections worldwide and the leading
infectious cause of deaths globally. TB and HIV co-infections are common
because of geographic overlap, and the risk of CNS TB and mortality are higher
among people with HIV than HIV-uninfected individuals. Tuberculous
meningitis and tuberculomas are the most common forms of intracranial TB and
often occur concurrently whereas Pott disease and radiculomyelitis are the most
common forms of spinal TB. Despite being one of the oldest infections known to
humankind, much remains uncertain about the optimal diagnosis and
management of CNS TB. TB culture is the most sensitive diagnostic test, but a
positive result often requires weeks, thus limiting its day-to-day clinical
application whereas the limited sensitivity of other diagnostic modalities and
poor specificity of clinical definitions limit their widespread use. Furthermore,
large-scale clinical trials to determine optimal drug combinations, dosages, and
durations of treatment for CNS TB are lacking. The emergence of multidrug-
resistant and extremely drug-resistant strains of M. tuberculosis worldwide now
poses additional challenges and demonstrates an urgent need for research into
diagnostic and treatment innovations to improve outcomes for all forms of CNS TB.
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REVIEW ARTICLE

Neurosyphilis
C O N T I N UU M A UD I O By Felicia Chow, MD, MAS
I NT E R V I E W A V AI L A B L E
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This
article focuses on the epidemiology, clinical
presentation, diagnosis, and management of neurosyphilis, with an
emphasis on clinically relevant issues faced by the practicing neurologist.
RECENT FINDINGS: The incidence of primary and secondary syphilis, the

sexually transmissible stages of infection, has been on the rise for the past
2 decades. A concerning recent trend is the surge in cases of syphilis in
women and of congenital syphilis. Neurosyphilis remains a relatively
common complication that can occur at any stage of syphilis. Along with
meningitis, meningovascular syphilis, which has been historically
described as a late presentation of neurosyphilis, now frequently occurs as
a manifestation of early infection. Late forms of neurosyphilis, including
tabes dorsalis and general paresis, are less prevalent in the era of
widespread penicillin use. As more laboratories adopt the
CITE AS:
reverse-sequence algorithm for syphilis testing, patients with
CONTINUUM (MINNEAP MINN) serodiscordant results (ie, a reactive serum treponemal test with a
2021;27(4, NEUROINFECTIOUS nonreactive nontreponemal test) may present an increasingly encountered
DISEASE):1018–1039.
diagnostic challenge for neurologists. Although the CSF Venereal Disease
Address correspondence to Research Laboratory (VDRL) remains a mainstay of diagnostic testing for
Dr Felicia Chow, University of neurosyphilis, using a higher titer cutoff (greater than 1:320) for the
California, San Francisco at
Zuckerberg San Francisco
Treponema pallidum particle agglutination assay (TPPA) from the CSF may
General Hospital, 1001 Potrero improve the utility of the TPPA as a supporting criterion for the diagnosis of
Ave, Bldg 1, Room 101, neurosyphilis. Penicillin G is the treatment of choice for neurosyphilis,
San Francisco, CA 94110,
felicia.chow@ucsf.edu.
although ceftriaxone may be a reasonable alternative therapy.
RELATIONSHIP DISCLOSURE: SUMMARY: A high index of suspicion and awareness of the variable clinical
Dr Chow has received personal
compensation for speaking presentations of neurosyphilis are essential to the approach to this
engagements from the treatable infection. Neurologists should be mindful of the limitations of
University of California, San
serologic testing in the diagnosis of neurosyphilis and exercise clinical
Francisco, for the annual Recent
Advances in Neurology meeting judgment to determine the likelihood of the diagnosis.
and for serving as an expert
physician for Grand Rounds and
has received research/grant
support from the National
Institutes of Health INTRODUCTION
A
(K23NS105575, R21TW010148, common misconception among neurologists and other health care
R21TW011035).
providers is that all presentations of neurosyphilis, an infection of
UNLABELED USE OF the nervous system by the spirochete Treponema pallidum
subspecies pallidum, are late, or tertiary, manifestations of
USE DISCLOSURE:
Dr Chow reports no disclosure. infection. In fact, neurosyphilis can occur at any stage of syphilis
and now appears to be most frequently seen in individuals with secondary
syphilis1-3; secondary syphilis, along with primary and early latent infection (ie,
of Neurology. asymptomatic infection acquired within the preceding 12 months), is referred to
1018 AUGUST 2021

as early syphilis. The lack of a single, perfectly sensitive and specific test that can KEY POINTS
either definitively exclude or clinch the diagnosis of neurosyphilis requires
● Symptomatic
clinicians to use their judgment in interpreting serologic testing and the CSF neurosyphilis can occur at
profile, alongside a careful history and neurologic examination. This article any stage of syphilis and, in
reviews the epidemiology, clinical presentation, diagnosis, and management of fact, is now diagnosed most
neurosyphilis. commonly in early syphilis.
● Although the syphilis

EPIDEMIOLOGY epidemic in the
The incidence of primary and secondary syphilis, the sexually transmissible United States is centered on
stages of infection, reached an all-time low in the United States in the year 2000 young men who have sex
with 2.1 cases per 100,000 population, the lowest rate since reporting began in with men, syphilis rates are
on the rise in women and
the United States in 1941. With a year-over-year decline in rates in the 1990s, newborns.
public health officials at the turn of the 21st century considered eradication of
syphilis to be an attainable goal. The goal, however, has proven to be elusive, ● The prevalence of
with syphilis rates consistently on the rise since the nadir in 2000. Data from 2018 neurosyphilis is higher in
men, particularly men who
demonstrated a fivefold higher incidence of primary and secondary syphilis have sex with men, along
compared with data from the year 2000 at 10.8 cases per 100,000 population,4 a with people with HIV
far cry from syphilis elimination, which had seemed achievable a mere 2 decades infection.
earlier. Of the 35,063 reported primary and secondary syphilis cases in the
United States in 2018, men accounted for 86% of cases, with 53.5% in men who
have sex with men, 15.4% in men who have sex with women, and 16.7% in men
without information about the sex of sex partners. Rates were highest among
young men 20 to 34 years old.4
Although men account for the majority of syphilis cases in the United States,
an alarming trend that has surfaced more recently is the subepidemic affecting
women, with rates of primary and secondary infection in this demographic
doubling from 2014 to 2018.4,5 Substance use, including methamphetamine and
heroin use, may be driving part of the increase in infections in women.4 Other
factors, including incarceration and lack of access to health care and housing,
may also be contributing to this surge in cases in women of reproductive age and
the serious threat that it poses to newborns.6 Mother-to-child transmission and
infant mortality and neurologic disability associated with congenital syphilis,
which is entirely preventable with adequate screening and treatment of pregnant
women, are emerging public health concerns in the United States. For further
discussion of congenital syphilis, refer to the article “Congenital Infections of the
Nervous System” by Payal Patel, MD,7 in this issue of Continuum.
Epidemiology of Neurosyphilis
Although syphilis is a reportable condition, surveillance of neurosyphilis as a
complication of syphilis is inconsistent. As a result, population-based data on
the epidemiology of neurosyphilis are scarce. In a cross-sectional analysis of
national data on primary, secondary, and early latent syphilis (collectively
referred to as early syphilis) reported to the Centers for Disease Control and
Prevention (CDC) in 2015, 403 of 48,045 cases (0.8%) involved confirmed or
probable neurosyphilis.2 Between 2009 and 2015, the period prevalence of
neurosyphilis based on 10 states with more complete neurosyphilis reporting
was 1.8%. The annual prevalence ranged from 0.8% to 2.5%, comparable
to prevalence estimates from retrospective studies of urban US health
department records.8,9 The prevalence of neurosyphilis was nearly twofold
higher in men and in people with human immunodeficiency virus (HIV). Men

NEUROSYPHILIS
who have sex with men were more likely to have neurosyphilis than men who
have sex with women only.
These data must be interpreted in the context of several limitations, including
ascertainment bias, passive case-based surveillance methods, and variability in
screening and diagnosis of neurosyphilis, including the threshold to obtain a
lumbar puncture. The expected effect of these limitations would be to bias
toward an underestimate of the true burden of neurosyphilis. In two
contemporary studies, the estimated prevalence of neurosyphilis was higher. In a
retrospective registry of all adults with HIV diagnosed with syphilis in
Copenhagen, Denmark, between 2004 and 2016, 6% met the criteria for
neurosyphilis.1 In a review of 567 syphilis cases in both people with HIV and
HIV-uninfected individuals from King County, Washington, between 2012 and
2013, 3.5% met the criteria for confirmed symptomatic neurosyphilis.3 When
interpreting neurosyphilis studies, the definition of neurosyphilis, which can
impact reported results, should be noted. In the former Danish study,
neurosyphilis was defined as a seroreactive test in the CSF, regardless of the
presence of symptoms, or CSF pleocytosis combined with neurologic signs and
symptoms compatible with neurosyphilis. In contrast, in the latter study in
Washington, which had a lower prevalence estimate, neurosyphilis was more
strictly defined as visual or hearing symptoms with either abnormal CSF testing
or an ophthalmologic examination consistent with ocular syphilis.
In sum, as rates of primary and secondary syphilis steadily rise nationwide,
these prevalence estimates suggest that neurosyphilis remains a relatively
common complication of the infection.
CLINICAL PRESENTATION
Neurosyphilis can occur at any stage of infection. A clinically useful approach is
to consider whether a patient is presenting early or late after primary infection,
although this critical piece of information may not always be straightforward
to ascertain.
Asymptomatic Neurosyphilis
Early in infection, T. pallidum disseminates widely throughout the body,
including in the central nervous system (CNS). Studies from the modern
treatment era using rabbit inoculation and polymerase chain reaction (PCR)
have found that 20% to 40% of individuals with untreated primary, secondary,
or early latent syphilis have detectable T. pallidum in the CSF,10,11 a proportion
comparable to studies from the pre-penicillin era. An inflammatory CSF profile,
reactive Venereal Disease Research Laboratory (VDRL), or some combination of
these CSF abnormalities may also be present. Some individuals with evidence of
early neuroinvasion have accompanying neurologic symptoms (eg, headache);
however, the majority are asymptomatic.10
Although neuroinvasion and the presence of CSF abnormalities in early
syphilis are common, their clinical and prognostic relevance in neurologically
asymptomatic individuals is unknown.12 Neuroinvasion may resolve
spontaneously, whereas for some patients, T. pallidum is not successfully
“cleared” from the CSF, and persistent inflammation may occur. HIV status does
not appear to impact the likelihood of detecting T. pallidum in the CSF in early
syphilis10,11; however, once present, HIV infection may impede the ability to
clear the infection from the nervous system. Cases of neurosyphilis have been
1020 AUGUST 2021

diagnosed after people with HIV received appropriate treatment for early KEY POINTS
uncomplicated syphilis with a single IM injection of benzathine penicillin G,13
● In early neurosyphilis, the
which does not reach treponemicidal concentrations in the CSF.14 These CSF, meninges, and cerebral
examples of treatment failure suggest that immune-mediated clearance of T. blood vessels are typically
pallidum from the CSF, and by extension, the nervous system, may be impaired affected, leading to
by HIV infection, making people with HIV potentially more vulnerable to syphilitic meningitis and
meningovascular disease,
progression to symptomatic neurosyphilis. This raises the question of whether
whereas late forms of
obtaining a lumbar puncture in neurologically asymptomatic individuals with neurosyphilis tend to cause
HIV and syphilis is warranted, particularly in people with untreated HIV, lower injury to the brain and spinal
CD4+ count, and higher nontreponemal (eg, rapid plasma reagin [RPR]) titers, cord parenchyma.
which have been shown to increase the risk of neurosyphilis.15-18 However,
● Patients with
because of the lack of evidence that tailoring therapy in early syphilis based on a symptomatic early
CSF examination in neurologically asymptomatic individuals impacts long-term neurosyphilis typically
outcomes, the current CDC Sexually Transmitted Diseases Treatment Guidelines present with signs and
do not recommend routine CSF analysis in people with primary or secondary symptoms of a meningitis
(eg, headache,
syphilis, including people with HIV regardless of CD4+ count or RPR titer, unless photophobia, neck
clinical signs of neurosyphilis, ocular syphilis, or otosyphilis are present.12 Results stiffness, confusion) with or
of a clinical trial investigating whether immediate lumbar puncture followed by without cranial nerve
therapy based on CSF evaluation leads to better serologic and functional outcomes involvement.
in patients with syphilis at high risk of neuroinvasion are eagerly awaited.19
Symptomatic Neurosyphilis
Early neurologic involvement in syphilis can present concomitantly with
primary, secondary, or otherwise asymptomatic (ie, latent) syphilis and usually
occurs within the first weeks to 1 year of infection. Late neurologic
manifestations tend to present years, even decades, after infection. In early
neurosyphilis, the CSF, meninges, and cerebral blood vessels are typically
affected, leading to syphilitic meningitis and meningovascular disease, whereas
late forms of neurosyphilis more often affect the brain and spinal cord
parenchyma.
Early Neurosyphilis
Patients with symptomatic early neurosyphilis typically present with meningitis.
Cranial neuropathies, most frequently involving cranial nerves II, VII, or VIII,
may accompany the meningitis. Typical signs and symptoms include headache,
photophobia, neck stiffness, and confusion. Ocular and auditory symptoms,
including decreased visual acuity and hearing loss, are common presenting
features of neurosyphilis1 and may occur in isolation.
Syphilitic meningitis can be complicated by a vasculitis that affects both
small arteries (ie, Nissl-Alzheimer arteritis) and medium and large arteries
(ie, Heubner arteritis) of the CNS, leading to focal cerebral and, less commonly,
spinal cord infarcts.20,21 Strokes in the distribution of the middle cerebral arteries
are classically seen, although any vascular territory, including the vertebrobasilar
system, can be involved.22-25 Angiography may reveal segmental narrowing or
occlusion of one or more vessels, although radiologic evidence of vasculopathy
may be absent. High-resolution vessel wall imaging may demonstrate concentric
wall enhancement.26,27 Infarcts in multiple vascular territories,25 as often occurs
with vasculitis, can serve as an important clue to consider other causes of stroke
beyond traditional mechanisms. Although meningovascular syphilis is described
as a late form of neurosyphilis,22,28 cerebrovascular disease is now predominantly

NEUROSYPHILIS
observed during early syphilis,29 usually weeks to months after primary

infection. Patients with meningovascular syphilis present with an acute stroke
syndrome that may follow a prodrome of symptoms of meningitis and/or
encephalitis.22,30 In some cases, infarcts are “silent” and noted incidentally on
neuroimaging obtained in a patient with meningitis (CASE 9-1).
Several studies have proposed obtaining a serum serologic test for syphilis in
all patients presenting with an acute ischemic stroke in an area where the
prevalence of syphilis is high. In a tertiary hospital in Brazil in an area with a high
prevalence of syphilis (101 cases per 100,000 people), neurosyphilis was
diagnosed in 1% to 4.7% of 1119 patients with acute stroke, depending on the
definition of neurosyphilis used.31 In a study from Thailand, also with a reported
high local prevalence of syphilis, 2.5% of 284 patients presenting with an acute
stroke were diagnosed with neurosyphilis based on serum and CSF testing; among
CASE 9-1 A 41-year-old man presented to the emergency department with 1 day of
right arm and leg weakness. He endorsed several weeks of headaches
and neck stiffness. About 1 week before presentation, he noted left face
numbness and “drooping”; he was seen by his primary care provider, who
diagnosed him with Bell’s palsy and prescribed prednisone. He was on
daily tenofovir/emtricitabine for preexposure prophylaxis to prevent HIV
infection and was sexually active with men and did not use condoms.
In the emergency department, he was febrile to 39.2°C (102.5°F). He
had generalized lymphadenopathy and a mildly pruritic, maculopapular
rash on his palms and soles. His neurologic examination was notable for
left lower motor neuron facial weakness and mild weakness of the right
upper and lower extremity in a pyramidal pattern.
Brain MRI showed multiple areas of restricted diffusion (FIGURE 9-1),
including in the right basal ganglia, left caudate head, genu of the internal
capsule bilaterally, left thalamus, right anterior insula, and bilateral
corona radiata. Magnetic resonance angiography (MRA) demonstrated
irregularity and diffuse narrowing of the bilateral supraclinoid internal
carotid arteries and the proximal middle and anterior cerebral arteries.
Serum treponemal chemiluminescent immunoassay was reactive, and
serum rapid plasma reagin (RPR) was reactive at a titer of 1:128. (He had
had a nonreactive serum RPR 4 months before presentation.) HIV testing
was negative. CSF had 121 white blood cells/mm3 and an elevated protein
concentration of 94 mg/dL. CSF Venereal Disease Research Laboratory
(VDRL) was reactive at 1:8.
He was treated with a 2-week course of high-dose IV penicillin G. His
headaches resolved within 1 month of treatment, although he continued
to have mild right-sided weakness. On repeat lumbar puncture 6 months
after completing IV penicillin G, CSF pleocytosis and elevated protein
concentration were no longer present, and a CSF VDRL was nonreactive.
Serum RPR obtained at the same time as the repeat lumbar puncture was
1:16 and was nonreactive at 12 months.
1022 AUGUST 2021

people younger than 50 years of age presenting with stroke, 4.4% met the definition
for having neurosyphilis.25 Although syphilis testing in cases of acute stroke may
not be practical for every patient population, red flags that should raise the
suspicion for meningovascular syphilis include stroke with concomitant or
preceding symptoms of meningitis or encephalitis; stroke in young, sexually
active individuals, especially in the absence of traditional cerebrovascular risk
factors32; and recurrent, unexplained strokes.33 Obtaining a detailed social
history, including sexual history, to uncover potential epidemiologic exposures is
critically important and should not be shied away from by neurologists.
Late Neurosyphilis
Widespread antibiotic use has altered the clinical landscape of neurosyphilis,
with substantially lower rates of late forms of neurosyphilis in the penicillin era.
FIGURE 9-1
Multifocal infarcts in the patient in CASE 9-1, who had meningovascular syphilis.
Hyperintense signal on axial diffusion-weighted imaging (A, B, and C) and hypointense
signal on apparent diffusion coefficient imaging (not shown) are consistent with acute
infarcts involving the right basal ganglia, left caudate head, genu of the internal capsule
bilaterally, left thalamus, right anterior insula, and bilateral corona radiata.
This was a case of meningovascular syphilis that occurred during early COMMENT
infection with clinical evidence at presentation of secondary syphilis.
Because the patient was on preexposure prophylaxis to prevent HIV
infection, he was regularly tested for sexually transmitted infections and
had had a nonreactive serum RPR 4 months before presentation. Although
cerebrovascular complications of syphilis have historically been described
as a late form of neurosyphilis, meningovascular syphilis is now often
diagnosed in early syphilis (ie, within 1 year of infection). The patient’s
young age, lack of cardiovascular risk factors, and prodrome of headaches
raised suspicion for an atypical cause of stroke, prompting serum syphilis
testing and then lumbar puncture to confirm the diagnosis of neurosyphilis.

NEUROSYPHILIS
Tabes dorsalis, one of the prototypical late manifestations of neurosyphilis

along with general paresis, is a spinal cord disorder that results from
demyelination of the posterior columns, dorsal roots, and dorsal root ganglia. The
classic presentation of tabes dorsalis, which usually occurs decades after primary
infection, is a sensory gait ataxia with profoundly impaired proprioception,
diminished reflexes, bowel and bladder dysfunction, and lancinating pains in the
abdomen and extremities. Although tabes dorsalis was the dominant manifestation
of neurosyphilis in the prepenicillin era, it is now an uncommon diagnosis.34,35
In a series of 43 HIV-uninfected individuals with neurosyphilis seen between 1991
and 2001 in the Canary Islands, 63% had early neurosyphilis compared with 28%
with late neurosyphilis36; tabes dorsalis was observed in only one patient. In a
retrospective review of 161 patients with neurosyphilis between 1990 and 1999
in Cape Town, South Africa, only two presented with tabes dorsalis.34
General paresis, also known as syphilitic dementia or dementia paralytica, is a
chronic encephalitic form of neurosyphilis that presents with neuropsychiatric
symptoms years to decades after primary infection. Patients develop gradually
progressive personality and behavioral changes (eg, irritability, emotional
lability), cognitive impairment, psychiatric symptoms (eg, depression,
psychosis, delusions, hallucinations), seizures, and sleep disturbance.35,37,38 As
with other forms of dementia, patients can become bedbound and incontinent in
advanced disease.39 Aphasia, speech impairment, tremor, myoclonus, ataxia,
hyperreflexia, corticospinal tract signs, and primitive reflexes40-43 may be found
on examination. Argyll Robertson pupils, pupils that react poorly to light but
constrict briskly to accommodation, can be seen in both general paresis38,42 and
tabes dorsalis, although this finding is reportedly noted more frequently in
patients with tabes dorsalis.44
In late forms of neurosyphilis, CSF pleocytosis has been reported in modern
series to be absent in as many as half of cases.38,42 In one study of 85 patients
without HIV diagnosed with general paresis, 55% had a CSF pleocytosis (defined
as more than 10 white blood cells/mm3), whereas 25% had a normal CSF white
blood cell count and protein concentration (defined as protein less than
50 mg/dL).38 Atrophy, often of the frontal and temporal lobes, and subcortical
T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities may be present
on MRI,37,40,42,45 whereas in some patients neuroimaging may be normal or may
detect only minimal atrophy.45 The presence of more severe atrophy on imaging,
likely reflecting later-stage disease, portends a lower likelihood of clinical
improvement after treatment.41,45 Serologic testing for syphilis should be
considered in the evaluation of patients with new-onset neuropsychiatric
symptoms, which may be a harbinger of late neurosyphilis. In one retrospective
review of 85 patients with general paresis presenting over a 9-year period in
Zhongshan, China, 64% were initially misdiagnosed, most commonly with other
causes of dementia, primary psychiatric illnesses, or cerebrovascular disease.38
Syphilitic Gummas
Syphilitic gummas are granulomatous lesions that can develop in any tissue,
including in the CNS. These intracranial and spinal mass lesions46 typically arise
from the pia mater, most commonly in the region of the cerebral convexities,47
and are often mistaken for tumors because of direct extension into the
parenchyma. Presenting symptoms (eg, headache, seizures, focal weakness) are
related to the location of the lesion and associated mass effect and
1024 AUGUST 2021

inflammation.47 On MRI, gummas are typically T1 hypointense and T2 hyperintense KEY POINTS
with associated contrast enhancement and perilesional edema. Gummas are
● Red flags that should
traditionally described as a tertiary manifestation of syphilis, although they can raise the suspicion for
occur in early infection, including in HIV-uninfected individuals.48,49 meningovascular syphilis
include stroke with
The “Great Imitator” concurrent or preceding
symptoms of meningitis or
If all cases of neurosyphilis followed these textbook presentations, it would not
encephalitis and stroke in
live up to its well-deserved reputation as the “great imitator.” In daily practice, young, sexually active
the wide-ranging clinical presentations of this treatable infection, including individuals, especially in the
with lesser-known manifestations such as syphilitic amyotrophy (CASE 9-2) or a absence of traditional
cerebrovascular risk
pure cerebellar ataxia,52 or atypical presentations of more classic syndromes
factors.
(eg, general paresis masquerading as Parkinson disease53) argue for
maintaining a high index of suspicion and low threshold for testing for syphilis. ● Late forms of
However, as with any testing, before ordering syphilis testing, careful neurosyphilis (eg, tabes
consideration of the pretest probability for neurosyphilis and how test results dorsalis and general paresis)
are much less common in
will inform decision making is essential, particularly in light of challenges in the the era of penicillin.
interpretation of diagnostic testing, as outlined in CASE 9-3.
● The classic presentation
DIAGNOSIS of tabes dorsalis, which
usually occurs decades after
The diagnosis of neurosyphilis relies on interpretation of serologic testing from
primary infection, is a
the serum and CSF, along with the CSF profile, the patient’s exposure and sensory gait ataxia with
treatment history, current symptoms, and neurologic examination. Because of profoundly impaired
the limitations of culture and methods to detect T. pallidum directly from lesion proprioception, diminished
reflexes, bowel and bladder
exudate or tissue, serologic testing, which refers to detection of antibodies, is the
dysfunction, and lancinating
mainstay of the laboratory diagnosis of syphilis. All patients with neurosyphilis pains in the abdomen and
should have evidence of current or previous syphilis with reactive serologic extremities.
testing from serum (ie, a reactive serum treponemal test at a minimum; most will
have both a reactive serum treponemal and nontreponemal test) (FIGURE 9-3). ● General paresis is a
chronic encephalitic form of
Although serologic testing from CSF is crucial, no one test can definitively neurosyphilis that presents
confirm or exclude the diagnosis of neurosyphilis. The highly specific CSF VDRL is with neuropsychiatric
erroneously regarded as a gold standard test, but its low sensitivity limits symptoms years to decades
its utility in ruling out neurosyphilis in individuals with a high pretest probability. after primary infection.
In contrast, CSF treponemal tests are less specific than the VDRL and do not
● All patients with
distinguish between previously treated neurosyphilis and active infection. neurosyphilis should have
evidence of current or
Serum Nontreponemal Tests previous syphilis with a
reactive serum treponemal
Serologic testing for syphilis is divided into nontreponemal and treponemal tests.
test.
Both types of tests are required to make a presumptive diagnosis of syphilis, and
either can serve as an initial screen followed by the other as a confirmatory test. ● Serologic testing for
Nontreponemal tests, including the RPR and VDRL tests, measure nonspecific syphilis is divided into
antibodies made in response to a synthetic cardiolipin, cholesterol, and lecithin nontreponemal and
treponemal tests. Both
antigen complex. The sensitivity of nontreponemal testing varies by stage of types of tests, one as an
syphilis (TABLE 9-154-58), with higher false-negative rates from serum in primary initial screen followed by
and late (ie, tertiary and late latent) syphilis.54 False-negative results have also the other as a confirmatory
been reported in people with HIV59 and with the prozone phenomenon, which is test, are required to make a
presumptive diagnosis of
most common in secondary syphilis and occurs when a high antibody syphilis.
concentration interferes with flocculation. In cases of the prozone reaction, the
reactive test will be missed unless the sample is diluted. Serum false-positive tests
can be seen in a variety of clinical situations, including in HIV infection,
autoimmune disorders, pregnancy, and injection drug use.60 These false-positive

NEUROSYPHILIS
results are generally low titer (less than 1:8)61 and underscore the importance of
obtaining a confirmatory treponemal test in all patients with a reactive serum
nontreponemal test (FIGURE 9-462,63).
Nontreponemal test results are reported as a titer that largely correlates
with disease activity. Titers of nontreponemal tests decline in response
to treatment but can wane over time even in the absence of treatment.
CASE 9-2 A 33-year-old man presented to neurology clinic with a 2-year history of
slowly progressive bilateral weakness and gradual wasting of his hand
muscles. He denied sensory changes, neck or shoulder pain, bowel/
bladder incontinence, or bulbar symptoms.
Three years before presentation, he had a reactive serum rapid plasma
reagin (RPR) but was lost to follow-up. Two years before presentation, he
noted decreased visual acuity of the right eye. Six months before
presentation, he reported progressive vision loss. Ophthalmologic
examination revealed bilateral panuveitis with chronic retinal
detachments. A serum RPR was reactive at 1:256. HIV testing was
negative. CSF demonstrated 80 white blood cells/mm3, protein
concentration of 60 mg/dL, and reactive CSF Venereal Disease Research
Laboratory (VDRL) at 1:4. He was treated at that time with high-dose IV
penicillin G for 14 days. His past medical history was notable for
methamphetamine use disorder.
On examination, he had marked atrophy of the intrinsic hand muscles
with associated weakness. Reflexes were preserved in the upper and
lower extremities. Sensation was intact to all modalities in the hands. Gait
was normal, and Romberg testing was negative.
Spine MRI demonstrated abnormal cervical cord signal from C6 to C7,
with focal T2 hyperintensities in the ventral gray matter (FIGURE 9-2).
Repeat RPR titer (6 months after completing treatment with IV penicillin
G) was 1:64. CSF demonstrated 4 white blood cells/mm3, protein
concentration of 57 mg/dL, and nonreactive CSF VDRL. Herpes simplex
and varicella-zoster virus testing from CSF was negative, as was West Nile
and human T-cell lymphotropic virus types I and II. Vitamin B12 level was
normal. Nerve conduction studies and EMG showed chronic reinnervation
changes in bilateral C7, C8, and T1 innervated muscles with preserved
sensory responses, localizing most likely to the nerve roots and/or
anterior horn cells.
His symptoms and neurologic examination remained stable over 3 years
of follow-up. Repeat RPR titer 3.5 years after IV penicillin G was 1:16, down
from 1:256 before treatment.
1026 AUGUST 2021

A minimum fourfold decrease in titer, which represents a change of two dilutions
(eg, from 1:32 to 1:8), is one criterion used to demonstrate a successful response
to treatment. RPR and VDRL test results are not interchangeable; because the
two results are not comparable, the same testing method (ideally performed in
the same laboratory) should be used for successive testing to gauge treatment
response.
FIGURE 9-2
Cervical spinal cord involvement in the patient in CASE 9-2, with late neurosyphilis. A,
Sagittal T2-weighted image showing hyperintense cord signal abnormality spanning C6 to
C7 with mild cord volume loss. B, Axial T2-weighted image demonstrates that the cord
signal abnormality predominantly affected the ventral gray matter, also known as the
owl-eyes sign in which bilaterally symmetric ovoid foci of T2 hyperintensity are observed
in the anterior horn cells. The cervical cord lesion did not enhance after administration of
gadolinium on T1-weighted MRI (not shown).
This case was thought to be an example of syphilitic amyotrophy (ie, muscular COMMENT
atrophy due to syphilis).50 Progressive degeneration of anterior horn cells
results in insidious onset of muscular atrophy, typically of the hands, shoulder
girdle, or legs.50 Other lower motor neuron signs, including hypotonicity,
decreased tendon reflexes, and fasciculation potentials, may be observed. As
with this patient, syphilitic amyotrophy is a motor-predominant syndrome.
Weakness is the chief presenting symptom, followed by neck or shoulder
pain.50 Bulbar symptoms are uncommon, and sensation remains intact.
Syphilitic amyotrophy is a form of late neurosyphilis that can present with
tabes dorsalis or general paresis but often occurs in isolation.50,51 The
duration of syphilis was unknown when this patient began to develop hand
weakness 2 years before he presented for evaluation. Although his
presentation was consistent with syphilitic amyotrophy, no test can establish
the diagnosis with complete confidence. However, the lack of progression or
development of new neurologic symptoms over the 3 years after IV penicillin
G treatment supported the diagnosis of syphilitic amyotrophy.

NEUROSYPHILIS
Serum Treponemal Tests

In general, treponemal tests are more sensitive than nontreponemal tests but lack
specificity for active syphilis. Manual treponemal tests, which include the T.
pallidum particle agglutination assay (TPPA) and the fluorescent treponemal
antibody absorption (FTA-ABS) test, measure antibodies to T. pallidum organisms,
whereas automated enzyme and chemiluminescent immunoassays measure
antibodies to recombinant T. pallidum proteins. Similar to nontreponemal tests, the
sensitivity of treponemal tests differs by syphilis stage (TABLE 9-1). The majority of
treponemal assays performed on serum have greater than 95% sensitivity when
considering all stages of syphilis combined.64 Unlike nontreponemal tests,
treponemal test positivity tends to persist for life, even after treatment, making it
less specific for active syphilis infection. However, in individuals treated early in
infection and in those with advanced HIV infection, seroreversion of treponemal
testing to nonreactive has been observed.64-67
Serodiscordant Results
In the traditional syphilis testing algorithm, a nontreponemal test (eg, RPR) is
used as the initial screen followed, as needed, by a confirmatory treponemal test.
The diagnosis for patients with primary or latent syphilis may be missed by the
traditional algorithm because of the lower sensitivity of nontreponemal tests for
those stages of syphilis (TABLE 9-1).68 Given the growing availability and
CASE 9-3 An 82-year-old woman with hypertension presented to clinic with a

3-year history of mild cognitive decline. As part of the evaluation, a serum
treponemal enzyme immunoassay was obtained, which was reactive,
whereas the confirmatory serum rapid plasma reagin (RPR) was
nonreactive. A serum Treponema pallidum particle agglutination assay
(TPPA) sent to resolve the discrepancy was reactive. The patient denied a
previous history of syphilis exposure, diagnosis, or treatment. She had
never traveled outside the United States. Her neurologic examination was
normal, aside from mild impairment on delayed recall memory testing.
COMMENT This is a fairly common clinical scenario that neurologists may encounter. If
the patient has no history of previously treated syphilis, the question arises
as to whether her cognitive decline is due to untreated late neurosyphilis
with a spontaneous decline in RPR over time. In general, neurosyphilis is
unlikely, albeit not impossible, in this scenario. To evaluate further, most
neurologists, including this author, would continue on the diagnostic
pathway for possible untreated neurosyphilis and perform a CSF examination
to rule out neurosyphilis. Although cognitive changes due to late neurosyphilis
may be permanent, treatment could prevent further cognitive decline. The
primary issue with CSF examination is that no test can definitively exclude
neurosyphilis if the clinical suspicion is high. However, in this case, given the
low pretest probability, this author would be reassured by a bland CSF profile
and nonreactive CSF Venereal Disease Research Laboratory (VDRL). If the
history, neurologic examination, or an abnormal CSF profile raised the pretest
1028 AUGUST 2021

affordability of automated treponemal testing, a reverse-sequence algorithm
may also be used, in which an automated treponemal immunoassay is the initial
screen followed by a nontreponemal test. The reverse algorithm can lead to
serodiscordant results, whereby a patient has a reactive treponemal
immunoassay but a nonreactive nontreponemal test. In these situations, a
second, usually manual treponemal test is used to adjudicate serodiscordant
results, with the more sensitive and specific TPPA preferred over the
FTA-ABS.64 If the second treponemal test is also reactive, confirming the
serodiscordant results, one of three scenarios is most likely: (1) previously treated
syphilis with the expected fall in nontreponemal titers to nonreactive, (2)
previously untreated late syphilis with a decline in nontreponemal titers over
time, or (3) early infection before nontreponemal antibodies have developed
(FIGURE 9-4). Serodiscordant results may also be seen in patients with other
treponemal infections, such as yaws (endemic in Asia, Africa, and Central and
South America) or pinta (endemic predominantly in Central and South America
and the Caribbean).
As more laboratories adopt the reverse-sequence algorithm, patients with
serodiscordant results present an increasingly common diagnostic challenge
(CASE 9-3). The probability of neurosyphilis in people with serodiscordant
serologies (ie, reactive serum treponemal test and confirmatory treponemal test
with a nonreactive RPR) is thought to be low overall, although it has been
probability for neurosyphilis, then this author would obtain a CSF treponemal
test if the CSF VDRL were nonreactive.
If the pretest probability for neurosyphilis is low in an older patient
presenting with mild cognitive impairment and no other neuropsychiatric
symptoms, some clinicians may be less inclined to pursue a CSF examination,
in part because of the risks of lumbar puncture, low as they may be. Infectious
disease physicians in this camp may opt instead to treat for late latent syphilis
with three doses of weekly IM benzathine penicillin G followed by close
observation. This rationale highlights the importance of consideration of the
pretest probability for neurosyphilis before sending syphilis testing, which
could circumvent unnecessary testing. Finally, some clinicians might make the
argument that no further evaluation or treatment is warranted. With the
traditional screening algorithm, syphilis would have been ruled out by a
nonreactive serum RPR and, additional testing (eg, CSF examination) would
only have been pursued if a high pretest probability were present, which was
not the case with this patient.
Ultimately, the likelihood of neurosyphilis in a patient with serodiscordant
results presenting with cognitive decline or another nonspecific neurologic
symptom should be considered on a case-by-case basis, taking into account
the clinical presentation, indication for lumbar puncture and other workup,
the results of these evaluations, and the plausibility of other diagnoses. In this
case, the patient had a lumbar puncture with a bland CSF profile and
nonreactive CSF VDRL, which were felt to be adequate to exclude
neurosyphilis. She was treated with three doses of weekly IM benzathine
penicillin G for presumed late latent syphilis.

NEUROSYPHILIS
KEY POINTS
● The sensitivity of
nontreponemal and
treponemal testing varies by
stage of syphilis.
● Serum false-positive
nontreponemal tests, which
are usually low titer (less
than 1:8) can be seen in a
variety of clinical situations,
including in HIV infection,
autoimmune disorders,
pregnancy, and injection
drug use.
● Nontreponemal test
results are reported as a
titer that correlates with
disease activity. A minimum
fourfold decrease in titer,
which represents a change FIGURE 9-3
of two dilutions (eg, from Approach to the diagnosis of symptomatic neurosyphilis.
1:32 to 1:8), is one criterion CSF = cerebrospinal fluid; c/w = consistent with; VDRL = Venereal Disease Research Laboratory;
used to demonstrate a WBC = white blood cells.
successful response to a
Most patients with neurosyphilis will have a reactive serum treponemal and nontreponemal test. See the
treatment. text (Serodiscordant Results) for additional discussion, including the approach to serodiscordant results (ie,
reactive serum treponemal test with a nonreactive treponemal test).
● Treponemal tests b
Human immunodeficiency virus (HIV) itself can cause a CSF pleocytosis up to 20 WBCs/mm3, especially in
typically remain positive for people not on antiretroviral therapy, with detectable HIV RNA, or with CD4+ greater than 200 cells/mm3.
life, even after appropriate This should be considered when interpreting the CSF profile of a person with HIV, although it is less relevant
treatment, making them less when making a diagnosis of symptomatic (in contrast to asymptomatic) neurosyphilis.
c
specific for active infection. In some situations of a nonreactive CSF VDRL with a CSF pleocytosis or elevated protein in which the
clinical suspicion for neurosyphilis is only moderate (eg, an alternative explanation for the CSF abnormalities is
● The probability of available), a CSF treponemal test may help guide the diagnostic decision making.
d
A reactive CSF treponemal test does not distinguish between active and previously treated neurosyphilis.
neurosyphilis in people with e
In very rare cases in which the clinical suspicion is extremely high, a nonreactive CSF treponemal test may
serodiscordant serologies
not rule out symptomatic neurosyphilis.
(ie, reactive serum
treponemal test with a
nonreactive RPR) is thought
to be low overall.
reported in data of variable quality.69 A retrospective analysis of patients
● The CSF pleocytosis in identified by at least one reactive serum treponemal test who had paired serum
early neurosyphilis tends to and CSF syphilis testing found that the 43 patients who met laboratory criteria
be more robust than in late
for neurosyphilis all had a reactive serum nontreponemal test. Furthermore,
neurosyphilis.
none of the 265 patients (including both people with HIV and HIV-uninfected
individuals) with a negative serum nontreponemal test met the criteria for
neurosyphilis, leading the authors to conclude that neurosyphilis in patients with
serodiscordant results is extremely unlikely.15 In a retrospective single-center
chart review of patients with serodiscordant results who underwent lumbar
puncture, no definitive cases of neurosyphilis were identified.69 These limited
data provide some reassurance that neurosyphilis is unlikely in people with a
reactive treponemal assay and nonreactive RPR. Ultimately, the probability of
neurosyphilis in patients with serodiscordant results has to be determined on an
individual basis, taking into account the presenting neurologic signs and
symptoms, whether a lumbar puncture and neuroimaging are indicated and, if
so, their respective results, alongside the weight of alternative diagnoses.
1030 AUGUST 2021

CSF Testing
In most forms of symptomatic neurosyphilis, the CSF profile demonstrates a
mild to moderate (greater than 5 white blood cells/mm3) lymphocyte-
predominant pleocytosis with elevated protein. The pleocytosis in early
neurosyphilis tends to be more robust than in late neurosyphilis. Interpretation
of the CSF profile can be confounded by HIV co-infection (FIGURE 9-3), as a mild
CSF pleocytosis (up to 20 white blood cells/mm3) is common in people with HIV
without neurosyphilis, especially in those with untreated HIV infection,
detectable plasma HIV RNA, and CD4+ greater than 200 cells/mm3.70
One question that arises in clinical practice is the likelihood of neurosyphilis
in the setting of bland CSF. Certainly, up to half of individuals with ocular
Performance Characteristics of Syphilis Serologic Tests From Serum TABLE 9-1

and CSFa
Nontreponemal test Treponemal test
Sensitivity Specificity Sensitivity Specificity
Serum RPR or VDRL Serum treponemal testing

b
Primary 62-78% Primary
FTA-ABS + TPPA 78-100%
Very limited data; Immunoassays 82-100%c
false positives can
Secondary 97-100% occur in 1-2% of Secondary
92-100%d; see
the population and FTA-ABS 93-100% FIGURE 9-4 for
are usually low titer potential causes
(<1:8); see FIGURE 9-4 TPPA + immunoassays 100%
of false-positive
for potential causes results
Early latent 82-100% Early latent 94-100%
of false-positive
Late latent or 61-64% results Late latent or unknown 85-100%
unknown duration duration
Tertiary 47-64% All stages combined

Immunoassays 95-100%
CSF VDRL 74-100%; false CSF treponemal testing 55-100%; false

e positives can f positives can
Neurosyphilis 49-88% Neurosyphilis 76-100%
occur with CNS occur with blood
Ocular syphilis ≤50% malignancy or blood contamination;
contamination higher TPPA titer
cutoff can improve
specificity
CSF = cerebrospinal fluid; FTA-ABS = fluorescent treponemal antibody absorption; RPR = rapid plasma reagin; TPPA = Treponema pallidum
particle agglutination; VDRL = Venereal Disease Research Laboratory.
a
Data from Tuddenham S, et al, Clin Infect Dis54; Park IU, et al, Clin Infect Dis55; and Harding AS, Sex Transm Dis.56
b
The sensitivity of nontreponemal testing for primary syphilis has been shown to be 50% and 93% in two outlier studies.54
c
The sensitivity of a treponemal immunoassay for primary syphilis in one study was 54%.57
d
Specificities as low as 83% to 87% have been reported.55
e
The sensitivity of CSF VDRL for neurosyphilis may be as low as 30%.58
f
The performance characteristics of treponemal and nontreponemal testing in the CSF are highly dependent on the criteria used to define
neurosyphilis and the non-neurosyphilis comparative population. The sensitivity of CSF treponemal testing for neurosyphilis is generally higher
when a reactive CSF VDRL is used to define neurosyphilis.

NEUROSYPHILIS
FIGURE 9-4
Interpretation of possible permutations of syphilis serologic test results.
FTA-ABS = fluorescent treponemal antibody absorption; HIV = human immunodeficiency virus; RPR =
rapid plasma reagin; TPPA = Treponema pallidum particle agglutination.
a
For reverse-sequence algorithm testing, assume both initial treponemal and second confirmatory tests
are reactive.
syphilis71-73 and an even higher proportion of individuals with otologic

syphilis74 may have a normal CSF examination. However, although reports of
“burned out” tabes dorsalis with normal CSF have been described,75 as has
normal CSF in a relatively high proportion of patients with general paresis in
modern case series,38 this clinical scenario should still be viewed as atypical
for neurosyphilis.
Serologic Testing From CSF

The performance characteristics of treponemal and nontreponemal testing in the
CSF depend on the non-neurosyphilis population included for comparison and
the criteria used to define neurosyphilis. Furthermore, studies investigating the
utility of syphilis testing to diagnose neurosyphilis can suffer from incorporation
bias, in which the laboratory test being evaluated is actually used in the gold
standard definition of neurosyphilis. Two 2020 systematic reviews on syphilis
laboratory diagnostics provide discerning assessments of the methods
used in studies evaluating syphilis test performance characteristics
(summarized in TABLE 9-1).54,55
The CSF VDRL is regarded as a mainstay of diagnostic testing for
neurosyphilis. A reactive CSF VDRL is highly specific and considered diagnostic
for neurosyphilis. False positives have been described infrequently in the context
of CNS malignancy or of CSF with visible blood contamination if the serum
1032 AUGUST 2021

nontreponemal titer is high.54,76,77 However, the variable sensitivity of the CSF KEY POINTS
VDRL, which may be as low as 30%,58 is a major drawback of its use. A 2020
● Although reports of
review of the performance characteristics of nontreponemal testing in the “burned out” tabes dorsalis
diagnosis of neurosyphilis found that the sensitivity of CSF VDRL ranged with normal CSF have been
from 49% to 88%.54 The high specificity but variable sensitivity of the described, as has normal
CSF VDRL (TABLE 9-1) makes it a clinically informative test when CSF in a relatively high
proportion of patients with
reactive, whereas a nonreactive test does not exclude the diagnosis of
general paresis in modern
neurosyphilis. case series, this clinical
In addition to the limitations of the CSF VDRL as a gold standard test for scenario should be viewed
neurosyphilis, it is also logistically challenging to perform because of specific as atypical for neurosyphilis.
resource requirements and, thus, may not be readily available in resource-limited
● The high specificity but
regions of the world.78 Data comparing the performance of the CSF VDRL with variable sensitivity of the
other nontreponemal tests that are often more accessible outside the CSF Venereal Disease
United States (eg, RPR, toluidine red unheated serum test [TRUST]) are limited. Research Laboratory (VDRL)
The CSF RPR and CSF TRUST may be more specific but less sensitive than the makes it a clinically
informative test when
already flawed sensitivity of the CSF VDRL.79,80 Point-of-care syphilis tests, reactive, whereas a
which require minimal training and no special equipment or refrigeration, may nonreactive test does not
overcome some of the challenges of neurosyphilis diagnosis in resource-limited exclude the diagnosis of
settings. One study found the sensitivity and specificity of a point-of-care test neurosyphilis.
from the CSF to diagnose neurosyphilis was comparable to the CSF VDRL.78
● CSF treponemal tests are
These point-of-care tests, most of which are treponemal tests, may have a role in less specific than the VDRL
neurosyphilis diagnosis in low- and middle-income countries where CSF VDRL is and do not distinguish
inaccessible, although further evaluation is needed. between previously treated
neurosyphilis and active
Compared with the CSF VDRL, CSF treponemal tests are more sensitive but
infection.
less specific for neurosyphilis (TABLE 9-1). If the CSF VDRL is nonreactive in a
patient for whom the clinical suspicion for neurosyphilis is high, obtaining a CSF ● If the CSF VDRL is
treponemal assay is a reasonable next step (FIGURE 9-3). A nonreactive CSF nonreactive in a patient for
treponemal test is highly reassuring against neurosyphilis, although it may not whom the clinical suspicion
for neurosyphilis is high,
always rule out symptomatic neurosyphilis if the pretest probability is high.55,56 obtaining a CSF treponemal
Similar to the CSF VDRL, the specificity of treponemal testing is reduced in CSF assay is a reasonable next
contaminated by blood.81 As with serum testing, a reactive CSF treponemal test step.
often remains reactive even after appropriate treatment, although seroreversion
to nonreactive may occur in a proportion of patients treated early in infection.
Thus, a reactive CSF treponemal test does not differentiate between previously
treated and untreated neurosyphilis.
One explanation of the lower specificity of treponemal assays for
neurosyphilis is passive diffusion of treponemal antibodies from blood into the
CSF. Using a higher cutoff in the CSF to establish a positive treponemal test,
which would presumably capture intrathecal production and not just passive
diffusion of antibodies, may circumvent this issue and improve specificity. A
2017 study found that using a CSF TPPA titer cutoff greater than 1:320 enhanced
specificity for neurosyphilis.82 In a validation data set of 380 participants, the
specificity of a CSF TPPA 1:640 or greater was more than 90% (97%, 93.8%, and
93.3%) for three different definitions used for neurosyphilis and did not differ by
HIV status. Ten CSF samples that were nonreactive by VDRL were reactive using
TPPA 1:640 or greater. These findings argue for the utility of a higher treponemal
titer cutoff value in the CSF to establish the diagnosis of neurosyphilis. The
enhanced specificity of a higher cutoff coupled with the superior sensitivity of
treponemal testing could result in a single test that outperforms the CSF VDRL,
at least for patients with a first-time diagnosis of neurosyphilis. At the least, a

NEUROSYPHILIS
CSF TPPA could be obtained if the CSF VDRL is negative in a patient for
whom the clinical suspicion for neurosyphilis is high. Although additional
confirmatory studies are needed, the United Kingdom’s British Association
for Sexual Health and HIV national guidelines already include a CSF TPPA
titer greater than 1:320 as a supporting criterion for the diagnosis of
neurosyphilis.83
In summary, the diagnosis of neurosyphilis requires neurologists to interpret
serologic testing from both serum and CSF in the appropriate clinical and
epidemiologic context. This includes judicious consideration of the pretest
probability and prevalence of syphilis both before ordering testing and on return
of the results, along with appraisal of presenting neurologic signs and
symptoms and the associated CSF profile. A suggested diagnostic approach to
symptomatic neurosyphilis is outlined in FIGURE 9-3.
TREATMENT AND FOLLOW-UP

High-dose IV penicillin G administered for 10 to 14 days is the treatment of
choice for neurosyphilis. IM procaine penicillin G with oral probenecid 4 times a
day for 10 to 14 days is considered a potential alternative first-line regimen in the
CDC guidelines.12 Because no treatments are established as alternatives to
penicillin for the treatment of neurosyphilis, skin testing and desensitization
are recommended in patients with a penicillin allergy, followed by treatment
with a first-line regimen. IV ceftriaxone 2 grams daily may be an acceptable
alternative for the treatment of neurosyphilis based on limited data.12,84 The
CDC guidelines include ceftriaxone as a treatment option for patients with a
penicillin allergy, whereas the most recent European and UK guidelines
consider ceftriaxone to be an acceptable alternative regimen for any patient
with neurosyphilis.83,85 Other discrepancies between the CDC and UK
guidelines include the use of doxycycline and steroids. No stand-alone oral
antibiotic regimen is recommended by the CDC for neurosyphilis, whereas oral
doxycycline is included as an alternative regimen in the UK guidelines. In
addition, steroids are not routinely recommended in the approach to the
treatment of neurosyphilis in the United States, whereas they are part of the
UK guidelines.83
After appropriate treatment, patients with neurosyphilis should experience
improvement in symptoms and, at the least, clinical stabilization. In general,
patients with early neurosyphilis are more likely to respond to treatment, both in
terms of clinical recovery and resolution of CSF abnormalities. In contrast, in late
neurosyphilis, clinical manifestations due to long-standing parenchymal injury
may be irreversible. In a single-center retrospective study investigating the
clinical course of 29 patients with neurosyphilis without HIV who were seen in
follow-up between 6 months and more than 2 years after initial diagnosis, 42%
with early neurosyphilis recovered completely compared with none of the
patients with late neurosyphilis. One-third of patients with late neurosyphilis
experienced no improvement in their clinical status.36
Syphilis cure is defined as a fourfold decline from a serum nontreponemal titer
documented at the time of treatment. However, even with appropriate treatment,
nontreponemal titers may not serorevert to nonreactive; this clinical scenario,
known as a serofast state, may occur in more than one-third of patients treated for
syphilis.86 The CDC guidelines suggest that the expected serologic response of a
fourfold decline in titer should occur by 12 months after treatment for primary,
1034 AUGUST 2021

secondary, or early latent syphilis, and by 24 months for late latent syphilis or KEY POINTS
syphilis of unknown duration.12 After appropriate therapy for neurosyphilis,
● High-dose IV penicillin G
repeat serum nontreponemal tests are typically performed at 3 months, 6 months, for 10 to 14 days is the
12 months, and 24 months. Although a fourfold decrease in the serum treatment of choice for
nontreponemal titer has been shown to be an accurate predictor of concomitant neurosyphilis. IV ceftriaxone
normalization of CSF pleocytosis and VDRL in patients with neurosyphilis (with 2 grams daily may be an
acceptable alternative
the exception of people with untreated HIV),87 the CDC guidelines recommend
therapy, especially for those
serial CSF examinations every 6 months until normalization of the pleocytosis and with a penicillin allergy.
reduction in the CSF VDRL by a factor of four (or seroreversion of a VDRL of 1:2
or less to nonreactive).12 A decline in the CSF white blood cell count is expected at ● Patients with early
6 months, with normalization in all CSF parameters by 2 years. One caveat to this neurosyphilis are more likely
to respond to treatment
is the CSF protein concentration, which can remain elevated after treatment and than those with late
does not necessarily signal treatment failure.16 neurosyphilis, both in terms
Treatment failure and retreatment should be considered in patients who are of clinical recovery and
noted to have a persistent CSF pleocytosis or failure of the serum RPR or CSF resolution of CSF
abnormalities.
VDRL to decline fourfold within 12 to 24 months of therapy. However, in clinical
practice, the serologic response to therapy, including time to cure,88 can vary
from patient to patient. Early syphilis and higher serum nontreponemal titers
have been associated with a greater likelihood of both serologic response and
seroreversion to nonreactive.88-90 The biological and clinical relevance of
serologic treatment failure (ie, failure to achieve a fourfold decline in serum
nontreponemal titers) is unclear, and retreatment does not necessarily lead to
higher rates of cure.90
CONCLUSION
Symptomatic neurosyphilis can occur at any stage of infection. Although serum
and CSF laboratory testing provides valuable information, neurologists should be
aware of the limitations of serologic testing in the diagnosis of neurosyphilis and
exercise clinical judgment to determine the likelihood of the diagnosis. To avoid
missing the diagnosis of this treatable infection, a high index of suspicion should
be maintained based on an understanding of the protean manifestations of
neurosyphilis. With appropriate and timely treatment with high-dose IV
penicillin, patients with early neurosyphilis typically have a complete clinical
recovery unless ischemic injury has occurred in the setting of meningovascular
disease, and in those with late neurosyphilis, further disease progression
may be prevented.
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doi:10.1186/s12879-015-1209-0

REVIEW ARTICLE
Neurologic Complications
of Lyme Disease

CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Karen L. Roos, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: This article reviews the symptomatology, diagnosis, and
treatment of neuroborreliosis.
RECENT FINDINGS: The most recent guidelines for the diagnosis and treatment
of Lyme disease were published in 2020 by the Infectious Diseases Society
of America, the American Academy of Neurology, and the American
College of Rheumatology.
SUMMARY: The most common neurologic complications of Lyme disease are

cranial neuritis (most often a unilateral or bilateral facial nerve palsy),
meningitis, and radiculoneuritis/mononeuropathy multiplex. Testing for
Lyme disease begins with an enzyme-linked immunosorbent assay (ELISA).
If the ELISA is positive or borderline, Western blots should be performed
for both IgM and IgG antibodies. As a general rule, in infectious diseases,
an IgM antibody response is followed by an IgG antibody response. A
central nervous system infection has either a CSF pleocytosis or
pathogen-specific intrathecal antibody production. Lyme meningitis, cranial
neuropathy, radiculoneuropathy, or other peripheral nervous system
manifestations are treated with oral doxycycline or IV ceftriaxone,
cefotaxime, or penicillin G. No additional antibiotic therapy is indicated for
patients with posttreatment Lyme disease syndrome or patients with
CITE AS:
concern for chronic Lyme disease with no evidence of previous or current
2021;27(4, NEUROINFECTIOUS Lyme infection.
DISEASE):1040–1050.
Dr Karen Roos, IU Health INTRODUCTION
L
Neuroscience Center, 355 W
16th St, Indianapolis, IN 46202,
yme disease, named for Lyme, Connecticut, where the disease
kroos@iupui.edu. was first definitively identified, is caused by infection with
spirochetes of the genus Borrelia acquired from a bite of an infected
Dr Roos has received publishing
Ixodes tick. In North America, only one spirochete in the genus
royalties from Elsevier and has Borrelia causes Lyme disease, Borrelia burgdorferi.1 In addition to
given expert medical testimony B. burgdorferi, other Borrelia species causing Lyme Disease in Europe include
during a trial.
Borrelia afzelii and Borrelia garinii (and the much rarer Borrelia spielmanii and
UNLABELED USE OF Borrelia bavariensis).
The most recent map of the incidence of Lyme disease in the United States is
USE DISCLOSURE:
Dr Roos reports no disclosure. presented in FIGURE 10-1.2 The states with the highest incidence are Connecticut,
Vermont, Maine, Delaware, Massachusetts, New Hampshire, Rhode Island,
New Jersey, Maryland, Pennsylvania, New York, Virginia, West Virginia,
of Neurology. Minnesota, and Wisconsin.
1040 AUGUST 2021

KEY POINTS
● In North America, only

one spirochete in the genus
Borrelia causes Lyme
disease, Borrelia
burgdorferi.
● The most common

neurologic complications of
Lyme disease are cranial
neuritis (most often cranial
nerve VII), meningitis, and
FIGURE 10-1 radiculoneuritis.
The most recent map of the incidence of Lyme disease in the United States (2018).
Reprinted from Centers for Disease Control and Prevention.2 ● An Ixodes tick typically
must remain attached for 24
to 48 hours to transmit
Borrelia to the host.
The neurologic manifestations of Lyme disease are collectively referred to as
neuroborreliosis. The focus of this article is on the most common neurologic ● The initial sign of infection
complications of Lyme disease, which are cranial neuritis (most often cranial with Borrelia burgdorferi is a
nerve VII), meningitis, and radiculoneuritis; rarer neurologic manifestations and nonpruritic targetoid skin
lesion called erythema
posttreatment Lyme disease syndrome are also mentioned. Serologic diagnosis
migrans that develops at the
and its importance in understanding the contentious topic of “chronic Lyme site of the tick bite.
disease” are also reviewed.
LIFE CYCLE OF IXODES TICKS AND TRANSMISSION OF BORRELIA

An Ixodes tick typically must remain attached for 24 to 48 hours to transmit Borrelia
to the host.3 Most humans are infected through the bites of nymphs, which are
smaller than 2 mm in length. Although adult ticks can also transmit infection, they
are much larger and thus more readily seen and removed before they are able to
transmit infection. As the tick ingests the host’s blood, the spirochetes can multiply
in the tick’s gut and migrate to the tick’s salivary glands where they are subsequently
injected into the host as the tick continues to feed on the host.4
The life cycle of Ixodes scapularis ticks lasts approximately 2 years. During this
time, they go through four life stages: eggs, six-legged larva, eight-legged nymph,
and adult. After the eggs hatch, the ticks must have a blood meal at every stage
from a new host (mammals, birds, reptiles, and amphibians) to survive
(FIGURE 10-25). Rodents and deer are the most common intermediate hosts
before human exposure.
SYSTEMIC MANIFESTATIONS OF LYME DISEASE

The initial sign of infection is a nonpruritic targetoid skin lesion called erythema
migrans that develops at the site of the tick bite (FIGURE 10-36). This is a slowly
enlarging erythematous lesion that classically appears as a target as the erythema
in the center of the lesion clears. Central clearing does not always occur, in which
case the rash appears as an enlarging erythematous lesion. The skin lesion is a site
of active spirochete proliferation from which hematogenous dissemination of the
spirochetes leads to systemic involvement.4 In approximately one-fourth of
patients, more than one skin lesion is present, believed to result from
hematogenous dissemination of spirochetes from the site of the initial tick bite.5
Because the rash is nonpruritic, it is possible that it is missed when it occurs on
areas of the body that are difficult to see, such as the back. Erythema migrans is

NEUROLOGIC COMPLICATIONS OF LYME DISEASE
FIGURE 10-2
The life cycle of Ixodes scapularis ticks goes through four stages: egg, six-legged larva,
eight-legged nymph, and adult. After the eggs hatch, the ticks must have a blood meal at
every stage from a new host. Humans are most commonly infected by a nymph.
Reprinted from Centers for Disease Control and Prevention.5
reported to occur in 90% of infected children because they are typically closely
examined by their parents.4
In addition to the cutaneous manifestations of Lyme disease, a monarthritis
or oligoarthritis may occur; the knee is the most frequently involved joint.
Cardiac complications may also be present, of which atrioventricular conduction
defects are most commonly reported.

The most common neurologic complications of Lyme disease are cranial neuritis
(most often a unilateral or bilateral facial nerve palsy), meningitis, and
radiculoneuritis. These may occur independently or concurrently.
Cranial Neuritis
Unilateral or bilateral cranial nerve VII palsy is one of the most common
neurologic manifestations of Lyme disease. Patients develop lower motor neuron
facial weakness. In a series of 559 patients presenting with a facial nerve palsy in a
Lyme disease–endemic area, Lyme disease was the etiology in 4.7% of patients.1
The majority of patients with facial nerve palsy due to Lyme disease presented in
the months of July to September, and most had headache.1
Less commonly, cranial nerves III, IV, VI, and VIII may be involved. The
mechanism of cranial neuritis in Lyme disease is thought to be due to mild
meningitis based on the finding of CSF lymphocytic pleocytosis in spinal fluid
1042 AUGUST 2021

from patients presenting with a KEY POINT
cranial neuritis.4 However, CSF
● The Centers for Disease
analysis is generally unnecessary Control and Prevention
for diagnosis in patients who recommends a two-step
develop facial nerve palsy in a serologic testing procedure
Lyme disease–endemic region for Lyme disease. First, an
enzyme-linked immunosorbent
and have positive serum
assay (ELISA) for antibodies
serology (see FIGURE 10-1 for to B. burgdorferi should be
FIGURE 10-3 the endemic regions). obtained. If the ELISA is
Erythema migrans on the left anterior chest wall of negative, the patient does
a patient with Lyme disease. not have Lyme disease. If
Courtesy of Robert Nadelman, MD. Reprinted with
Meningitis
the ELISA is positive or
The most common symptom in
permission from Halperin JJ, Continuum (Minneap Minn).6 borderline, a Western blot
© 2018 American Academy of Neurology. Lyme meningitis is headache for both IgM and IgG
(CASE 10-1). Patients may have antibodies is performed.
photo- and phonosensitivity,4
but fever and meningismus may be mild or absent.8 Analysis of the CSF
demonstrates a lymphocytic pleocytosis, a mildly increased protein
concentration, and a normal glucose concentration. Papilledema due to
intracranial hypertension has been reported in children with Lyme meningitis
and may rarely occur in adults.8
Radiculoneuritis
Nervous system Lyme disease may present with pain and weakness in one or
more limbs. This was initially attributed to a radiculitis or a plexitis, but in
electrophysiologic studies and in the experimentally infected rhesus macaque
monkey, this has been demonstrated to be a mononeuropathy multiplex.9,10
Lyme Neuroborreliosis in Europe

In the United States, it is rare for patients with Lyme disease to develop brain
parenchymal or spinal cord involvement. In Europe, infection of the central
nervous system (CNS) occurs in 2% to 4% of patients with Lyme
neuroborreliosis, manifesting as encephalitis or a myelitis with a spastic gait and
bladder dysfunction. Much more commonly, the spinal nerve roots or cranial
nerves are involved. If the meninges are involved as well (ie,
meningoradiculoneuritis), that is called Garin-Bujadoux-Bannwarth syndrome, or
Bannwarth syndrome for short.11 Stroke as a result of vasculitis has also been
described in the European literature in case reports and small case series.11-13
DIAGNOSIS
The Centers for Disease Control and Prevention (CDC) recommends a
two-step serologic testing procedure for Lyme disease. First, an enzyme-linked
immunosorbent assay (ELISA) for antibodies to B. burgdorferi should be
obtained. If the ELISA is negative, the patient does not have Lyme disease. If
the ELISA is positive or borderline, a Western blot for both IgM and IgG
antibodies is performed. IgM antibodies are useful only in patients whose
illness is shorter than 3 to 6 weeks in duration. Beyond this time period,
isolated IgM antibodies are more likely to represent nonspecific
cross-reactivity and cannot be interpreted as evidence of B. burgdorferi
infection.4 IgG antibodies are positive in all patients with Lyme disease,
except in the earliest period of infection, in which case spinal fluid analysis

may be necessary to make the diagnosis of neuroborreliosis (CASE 10-2).

FIGURE 10-4 provides an algorithm for treatment decisions based on the
presence or absence of erythema migrans, duration of symptoms, and results
of IgM and IgG if ELISA is positive or borderline.14
Patients with active neuroborreliosis have a CSF pleocytosis. Because
Borrelia antibodies can be passively transferred from serum to CSF, CSF
antibodies do not necessarily indicate CNS infection. Therefore, the CSF to
serum antibody index is used to determine if intrathecal production of
antibodies to Borrelia has occurred. The antibody index is defined in the
following equation:
anti-Borrelia IgG in CSF=anti-Borrelia IgG in serum

total IgG in CSF=total IgG in serum
CASE 10-1 A 39-year-old man and his 18-year old daughter presented for neurologic
consultation after vacationing at their Cape Cod, Massachusetts, home in
early June. They were aware they were in a Lyme disease–endemic area
and used tick repellant, wore long sleeve shirts and long pants when
hiking, and examined themselves frequently for ticks. During their trip,
they were visited by a family member and his golden retriever. Shortly
after returning home, the father developed headache with
photosensitivity, and his daughter accompanied him to the visit because
she woke up with mild right facial weakness.
On examination, the father had mild meningismus but was afebrile. His
daughter was unable to smile on the right side and had weakness of eye
closure with Bell’s phenomenon. She recalled a nonpruritic targetoid skin
lesion, but he did not. Lumbar puncture and CSF analysis was obtained on
the father because he had symptoms and signs of meningitis, and it
revealed a lymphocytic pleocytosis of 100 cells/mm3, protein of
70 mg/dL, glucose of 45 mg/dL, and oligoclonal bands. Lumbar puncture
was not performed on his daughter.
They were both treated with doxycycline 100 mg orally 2 times a day
for 28 days. Serum enzyme-linked immunosorbent assay (ELISA) for
Borrelia burgdorferi antibody returned positive 48 hours later for both the
father and daughter; confirmatory testing with Western blot IgM was
positive on initial testing, and IgG was positive on subsequent testing
4 weeks later. Ixodes ticks were identified on the dog during the time the
family was together in the Cape Cod home.
COMMENT The patients were in a Lyme disease–endemic area, and both had signs and
symptoms of neurologic complications of Lyme disease. Cranial nerve VII
palsy is treated with doxycycline. Either oral doxycycline or IV ceftriaxone
is considered acceptable treatment for Lyme meningitis, and the decision
about which is used for treatment should be based on the severity of the
meningitis.
1044 AUGUST 2021

The antibody index is considered positive when the result is greater than
1.3 to 1.5.
Spinal fluid analysis is especially helpful in patients who develop
neuroborreliosis symptoms in an endemic area for Lyme disease in whom
serology is negative. The absence of CSF lymphocytic pleocytosis is evidence
against CNS Lyme infection (CASE 10-3).
TREATMENT
The most recent guidelines for the diagnosis and treatment of Lyme disease
were published in 2020 by the Infectious Diseases Society of America, the
American Academy of Neurology (AAN), and the American College of
Rheumatology.15
These guidelines recommend prophylactic therapy for a high-risk tick bite
with doxycycline given as a single oral dose of 200 mg for adults and 4.4 mg/kg
(up to a maximum dose of 200 mg) for children. A high-risk tick bite is defined
as a bite from an Ixodes species tick that was attached for 36 hours or longer in an
area highly endemic for Lyme disease.
The 2020 guidelines recommend that patients with Lyme meningitis, cranial
neuropathy, or radiculoneuropathy be treated with IV ceftriaxone, IV
cefotaxime, IV penicillin G, or oral doxycycline. Numerous European studies
have shown that oral doxycycline is as effective as IV antibiotics for
neuroborreliosis,16,17 and it has excellent CNS penetration.7 Doxycycline is not
recommended in pregnant women, women who are breast-feeding, and children
younger than 8 years of age, although a short course of doxycycline is not likely to
stain teeth. Doxycycline is dosed 100 mg orally, 2 times a day, for 2 to 4 weeks. IV
antibiotics are recommended in patients with severe neurologic manifestations
such as the extremely rare Lyme encephalitis, myelitis, or encephalomyelitis.17
A 26-year-old man presented with a 4-month history of pain in the lateral CASE 10-2
area of his left thigh. He worked as a lineman repairing electrical power
lines and wore a heavy tool belt. He did not live in nor had he traveled to
an area endemic for Lyme disease. He had not had a lesion that
resembled erythema migrans. He asked to be tested for Lyme disease.
The enzyme-linked immunosorbent assay (ELISA) was borderline,
Western blot IgM was positive, and Western Blot IgG was negative. The
patient was counseled that his symptoms were not due to Lyme disease
based on these results and that he most likely had meralgia paresthetica
from his toolbelt.
Western blot IgMs are useful only in patients whose illness is shorter than COMMENT
3 weeks or at most 6 weeks in duration. In a patient with symptoms longer
than this period and due to Lyme disease, an IgG antibody response should
be observed. Patients regularly ask to be tested for Lyme disease. This is
entirely reasonable if they live in or have traveled to an area endemic for
Lyme disease and have symptoms consistent with neuroborreliosis such as
headache, facial nerve palsy, or radiculoneuritis/mononeuropathy multiplex.

KEY POINTS
● The CSF to serum

antibody index is used to
determine if intrathecal
production of antibodies to
Borrelia has occurred.
● Doxycycline is not
recommended in pregnant
women, women who are
breast-feeding, and
children younger than
8 years of age, although a
short course of doxycycline
is not likely to stain teeth.
● No rationale exists for

managing posttreatment
Lyme disease syndrome
with long-term antibiotic
therapy; convincing
biological and clinical
evidence is lacking for the FIGURE 10-4
existence of chronic B. An algorithm for treatment decisions based on the presence or absence of erythema migrans,
burgdorferi infection after duration of symptoms, and results of Western blots for immunoglobulin M (IgM) and
the recommended immunoglobulin G (IgG) if the enzyme-linked immunosorbent assay (ELISA) is positive or
treatment regimens for borderline.
Lyme disease are Reprinted with permission from Halperin JJ, Continuum (Minneap Minn).14 © 2012 American Academy of
completed. Neurology.
● Lyme disease IgM

Western blots have a high
false-positive rate and must Ceftriaxone is dosed 2 g once a day for 14 to 28 days for adults and children,
be followed by IgG testing.
cefotaxime 2 g every 8 hours for 14 to 28 days, and penicillin G 20 million units
daily in divided doses every 4 hours for 2 to 4 weeks.8
POSTTREATMENT LYME DISEASE SYNDROME AND CHRONIC LYME DISEASE

Posttreatment Lyme disease syndrome is not synonymous with chronic Lyme disease.
Posttreatment Lyme disease syndrome requires a history of symptomatology of
Lyme disease, laboratory proof that the patient had Lyme disease, and treatment
with one of the earlier-mentioned recommended antimicrobial therapies. The
CDC lists pain, fatigue, and difficulty thinking as symptoms in posttreatment Lyme
disease syndrome that can persist for months to years.18 The CDC states that
prolonged antibiotic therapy provides no benefit to patients who have these
symptoms.8,18 The Infectious Diseases Society of America and the European
Federation of Neurological Associations “assert that while some patients report
postinfection sequelae, there is no rationale for the use of long-term antibiotic therapy
for [posttreatment Lyme disease syndrome] given the consistent lack of convincing
biologic or clinical evidence for the existence of chronic B. burgdorferi infection after
completion of recommended treatment regimens for Lyme disease.”19
A recent review of posttreatment Lyme disease included the following
symptoms: fatigue, chronic pain, cognitive concerns, paresthesia, and poor
sleep.20 The authors suggest that the symptoms of posttreatment Lyme disease
may be caused by a dysregulated host immune response or nonspecific immune
activation.20
1046 AUGUST 2021

“Chronic Lyme disease” is a controversial entity in which fatigue, depression,
pain, and cognitive concerns are attributed to Lyme disease without a history of
characteristic symptoms or a legitimate laboratory diagnosis of Lyme disease.8
See CASE 10-4 for discussion of the approach to this scenario.
CHEMOKINES AND CYTOKINES

Even before severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
cytokines and chemokines were frequently written about by those of us who are
interested in dexamethasone in the prevention of the neurologic complications of
bacterial meningitis. The SARS-CoV-2 pandemic has again focused research and
therapeutic trials on cytokines and chemokines.
In meningitis complicating Lyme disease, infection of the CNS with B.
burgdorferi is followed by a rapid increase in CSF CXCL13 (a B cell–attracting
chemokine) and intrathecal B. burgdorferi antibody production.7 Elevated levels
of CXCL13 are also present in the CSF of patients with neurosyphilis, human
immunodeficiency virus (HIV), aseptic meningitis, and CNS lymphoma.8,17,25,26
The significance of this observation is unclear at this time, but the concentration
of this chemokine falls rapidly after initiation of antibiotic therapy.17
Chemokines and cytokines may have a role in patients who develop cognitive
symptoms during an acute infectious disease that persist after the disease despite
eradication of the pathogen. However, what is not understood is how chronic
cognitive symptoms could be caused by chemokines and cytokines when an
encephalopathy or stroke did not develop during the acute illness.
A 32-year-old woman presented in October with a 3-day history of a CASE 10-3

facial nerve palsy on the right side. She had been hiking in a Lyme
disease–endemic area and every evening examined her skin closely for
ticks. She had not found a tick attached to her skin or had a lesion of
erythema migrans. On review of systems, she acknowledged she had a
headache but stated she often had headaches. She had no fever or
weight loss.
Lyme disease enzyme-linked immunosorbent assay (ELISA) was
negative. Because it may have been too early for her to have a measurable
antibody response, spinal fluid analysis was performed. No evidence of a
CSF pleocytosis or intrathecal antibody production was found. The
patient was reassured that she did not have Lyme disease and was
treated with steroids for Bell’s palsy.
Spinal fluid analysis may be considered in patients with facial nerve palsy COMMENT
and negative Lyme disease serology in a Lyme disease–endemic area when
they have headache and present during tick season, even if they have no
history of a recent tick bite or the appearance of a lesion of erythema
migrans.1 Alternative approaches to obtaining CSF analysis would be to
treat with corticosteroids and repeat serology several weeks later or treat
with corticosteroids and doxycycline (see the section titled “Treatment”)
while awaiting repeat Lyme disease serology.

CONCLUSION
In North America, Lyme disease is caused by infection with the spirochete,
B. burgdorferi, which occurs from the bite of an infected Ixodes tick that has
been attached for 24 to 48 hours. The most common neurologic complications of
Lyme disease are cranial neuritis (most often a unilateral or bilateral facial nerve
palsy), meningitis, and radiculoneuritis/mononeuropathy multiplex. Testing for
Lyme disease begins with an ELISA. If the ELISA is positive or borderline,
Western blots should be performed for both IgM and IgG antibodies. IgM
antibodies are useful only in patients whose illness is shorter than 3 weeks or at
most 6 weeks in duration. Beyond this time period, IgM antibodies are more
likely to represent nonspecific cross-reactivity and cannot be interpreted as
evidence of acute infection.4 As a general rule, in infectious diseases, an IgM
antibody response is followed by an IgG antibody response. A CNS infection has
either a CSF pleocytosis or pathogen-specific intrathecal antibody production.
Lyme meningitis, cranial neuropathy, radiculoneuropathy, or other peripheral
nervous system manifestations are treated with oral doxycycline or IV
ceftriaxone, cefotaxime, or penicillin G. No additional antibiotic therapy is
indicated for patients with posttreatment Lyme disease syndrome or patients
with concern for chronic Lyme disease with no evidence of previous or current
Lyme infection.
CASE 10-4 A 46-year-old woman was referred by her primary care physician for
“chronic Lyme disease.” She had been treated for 8 months with IV
ceftriaxone for fatigue, pain, and “brain fog.” She had not been to a Lyme
disease–endemic area and never had a nonpruritic targetoid skin lesion,
joint pain, a seventh cranial nerve palsy, meningitis, or radiculitis. She
brought her medical records with her, including a laboratory record that
stated, “Lyme Western blot IgM positive.”
A Western blot IgG was sent and returned negative. The patient was
counseled at her subsequent visit that she did not have Lyme disease, that
she did not need to continue antibiotic treatment, and that antibiotics may
be harmful to her.21,22 She was reassured that, although the cause of her
symptoms was unclear, she did not have a chronic infection in her brain.
She was offered to undergo a lumbar puncture with the explanation that,
if infection and inflammation were present in the brain, the spinal fluid
would be abnormal. She was told to expect that the results would be
normal, but if it would give her peace of mind, she could go ahead with a
lumbar puncture. She was not anxious to undergo the procedure but was
comforted by knowing about a possible way to determine if she had a
chronic infection in her brain.
COMMENT Chronic Lyme disease is a controversial entity that is not considered to have
a scientific basis. Lyme disease IgM Western blots have a high false-positive
rate and must be followed by IgG testing.23,24 Chronic antibiotic therapy is
not indicated for chronic fatigue, pain, and brain fog, and it can be harmful.
1048 AUGUST 2021

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15 Lantos PM, Rumbaugh J, Bockenstedt LK, et al.
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3 Piesman J, Dolan MC. Protection against Lyme
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Biller J, Ferro JM, eds. Handbook of clinical
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17 Kullberg BJ, Vrijmoeth HD, van de Schoor F,
Hovius JW. Lyme borreliosis: diagnosis and
Lyme disease maps: most recent year. Accessed
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6 Halperin JJ. Neuroborreliosis and neurosyphilis.
Post-treatment Lyme disease syndrome.
Accessed March 22, 2012. cdc.gov/Lyme/
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19 Goodlet KJ, Fairman KA. Adverse events
7 Halperin JJ. Neuroborreliosis. Neurol Clin 2018;
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36(4):821-830. doi:10.1016/j.ncl.2018.06.006
therapies for post-Lyme disease syndrome in a
8 Garcia-Monco JC, Benach JL. Lyme commercially insured sample. Clin Infect Dis
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20 Rebman AW, Aucott JN. Post-treatment Lyme
Ann Neurol 2019;85(1):21-31. doi:10.1002/
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ana.25389
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9 Halperin JJ, Luft BJ, Volkman DJ, Dattwyler RJ. doi:10.3389/fmed.2020.00057
Lyme neuroborreliosis. Peripheral nervous
21 Berende AB, ter Hofstede HJM, Vos FJ, et al.
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Randomized trial of longer-term therapy for
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Mononeuropathy multiplex in rhesus monkeys NEJMoa1505425
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12 Zajkowska J, Garkowski A, Moniuszko A, et al.
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24 Seriburi V, Ndukwe N, Chang Z, et al. High 26 Fujimori MC, Nakashima I, Kuroda H, et al.
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25 Marra CM, Tantalo LC, Sahi SK, et al. CXCL13 as a
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OLQ.0b013e3181d877a1
1050 AUGUST 2021

Neurologic REVIEW ARTICLE

Manifestations of Severe C O N T I N U UM A U D I O
ONLINE
Acute Respiratory
Syndrome Coronavirus 2
Infection
By Avindra Nath, MD
ABSTRACT
PURPOSE OF REVIEW: This article describes the spectrum of neurologic
complications associated with severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2) infection, their underlying pathology and pathogenic
mechanisms, gaps in knowledge, and current therapeutic strategies.
RECENT FINDINGS: COVID-19 is the clinical syndrome caused by the novel

coronavirus SARS-CoV-2. It can affect the entire neuraxis, and
presentations in the acute phase are variable, although anosmia is a common
manifestation. Encephalopathy is common in patients who are hospitalized
and is often associated with multiorgan involvement. Immune-mediated
CITE AS:
encephalitis is probably underrecognized; however, viral encephalitis is CONTINUUM (MINNEAP MINN)
rare. Other manifestations include stroke, seizures, myelitis, and peripheral 2021;27(4, NEUROINFECTIOUS
DISEASE):1051–1065.
neuropathies, including Guillain-Barré syndrome, which sometimes has
atypical manifestations. Treatment is symptomatic, and immunotherapies Address correspondence to
have been used successfully in some patients. Long-term complications Dr Avindra Nath, Bldg 10, Room
include dysautonomia, exercise intolerance, malaise, sleep disturbances, 7C-103, 10 Center Dr, Bethesda,
MD 20892, natha@ninds.nih.
cognitive impairment, and mood disorders. gov.
SUMMARY: Neurologic manifestations of COVID-19 may occur in the acute
Dr Nath has served on the
setting and may be independent of respiratory manifestations. editorial board for Brain, as a
Immune-mediated syndromes and cerebrovascular complications are section editor for Frontiers of
Neurology, and as an associate
common. Large populations of patients are expected to have long-term editor for the Journal of
neurologic complications of COVID-19, many of which may emerge only Neurovirology and has received
after recovery from the acute illness. research grants from the
National Institutes of Health
(NS03130).
INTRODUCTION UNLABELED USE OF
C
oronaviruses are known causes of respiratory, enteric, and systemic
USE DISCLOSURE:
infections. Most human coronaviruses cause mild symptoms that Dr Nath reports no disclosure.
resolve spontaneously. Coronaviruses are enveloped viruses with a
positive-sense single-stranded RNA genome. The Latin word corona © 2021 American Academy
means “crown” and describes the spikelike proteins projecting from of Neurology.

NEUROLOGIC MANIFESTATIONS OF SARS-C O V-2 INFECTION
the surface of the virus. Coronaviruses are classified into four genera:
Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.
Alphacoronavirus, Betacoronavirus, and Deltacoronavirus infect mammals.
Deltacoronavirus and Gammacoronavirus infect avian species. However, the virus is
able to jump between species with dire consequences, causing the emergence of
Middle East respiratory syndrome (MERS) coronavirus, severe acute respiratory
syndrome coronavirus (SARS-CoV)-1, and SARS-CoV-2.1 To date, seven human
coronaviruses have been identified. SARS-CoV-1 and SARS-CoV-2 originated from
bats. Both these viruses use spike proteins to attach to angiotensin-converting enzyme
receptor type 2 (ACE2), which is highly expressed in the respiratory tract.2 Neuropilin
acts as a coreceptor for the virus. The virus has four major structural proteins. Spike
(S) protein is a trimeric protein and is made up of two separate polypeptides, S1
(binding domain) and S2 (stalk). The membrane protein is the most abundant
structural protein in the virion. The envelope protein facilitates assembly and release
of the virus. The ion channel activity in the envelope protein plays a critical role in
pathogenesis. The N protein is the nucleocapsid that binds the viral RNA.
The SARS-CoV-2 virus was first discovered in December 2019 and emerged in
Wuhan, China. Within a few months, it had spread to every country in the world,
causing paralysis of the global economy, devastation of health care systems, and
isolation of large populations. COVID-19, the clinical syndrome caused by
SARS-CoV-2, is the biggest challenge that humanity has faced in over a century,
TABLE 11-1 Neurologic Complications of Coronavirus Infections
Parainfectious syndromes
◆ Anosmia and ageusia
◆ Encephalopathy (metabolic/hypoxic)
◆ Viral meningoencephalitis
◆ Central hypoventilation
◆ Stroke
◆ Acute necrotizing hemorrhagic encephalopathy
◆ Myositis
Postinfectious syndromes
◆ Acute disseminated encephalomyelitis (ADEM)
◆ Brainstem encephalitis
◆ Myelitis
◇ Transverse myelitis
◇ Acute flaccid myelopathy
◇ Necrotizing myelitis
◆ Guillain-Barré syndrome
◇ Miller Fisher syndrome
◇ Cranial neuropathies
◆ Long-haul COVID
◇ Multi-systemic inflammatory syndrome
1052 AUGUST 2021

affecting every aspect of society. History teaches us that many prior pandemics have KEY POINTS
each killed more people on the planet than all wars combined. For example, in the
● Coronaviruses are
1300s, the plague is said to have killed 25 million people in Europe. In the 1600s, enveloped viruses with a
smallpox killed 20 million indigenous people in North America. The influenza positive-sense
epidemic of 1918-1919 killed about 30 million to 50 million people. Similarly, millions single-stranded RNA
of people have been killed by yellow fever, polio, measles, and acquired genome.
immunodeficiency syndrome (AIDS). Unfortunately, SARS-CoV-2 is following the
● Although effective
same pattern of devastation, with the number of infections and deaths rising vaccines have been
exponentially. As of January 1, 2021, the United States was seeing nearly 200,000 new developed for COVID-19 and
infections per day and nearly 400,000 people had died, but the rate of new infections are being distributed,
in the United States has steadily declined as vaccination rates have increased. It is millions of people will have
long-term complications
estimated that more than 800,000 people have died from the infection in United from the infection, some of
States.3 Nearly 10% to 35% of survivors have persistent and disabling neurologic which will be neurologic.
symptoms. With nearly 200 million people infected worldwide, the long-term
socioeconomic consequences are unfathomable. Although effective vaccines ● Myalgia and fatigue are
seen in about 50% of
have been developed and are being distributed, millions of people will have patients with COVID-19 and
long-term complications from the infection, some of which will be neurologic. may persist even after
The burden of care for these patients will be the responsibility of neurologists; recovery from the other
hence, we must be prepared to take care of them. symptoms. Headache
occurs in 8% of patients.
Symptoms of COVID-19 infection may initially resemble influenza. Fever is
present in almost 90% of patients, and cough is present in approximately 70%. ● Anosmia and ageusia may
The median incubation period is 4 to 7 days,4 during which the patients may be be heralding manifestations
infectious. Myalgia and fatigue are seen in about 50% of patients and may persist of COVID-19.
even after recovery from other symptoms. Headache occurs in 8% of patients
● Mortality in COVID-19 is
Diarrhea occurs in less than 5% of patients and, in some patients, might be the higher with advanced age
major symptom.4 Anosmia and ageusia may be heralding manifestations.4 On CT and underlying
of the chest, more than 50% of patients have a ground-glass opacity. Many comorbidities, including
patients develop superimposed bacterial pneumonia. Older patients have more diabetes, cardiac and
respiratory disorders, and
severe disease. In a study from China, mechanical ventilation was required in immunosuppressed states.
6% of patients.4 In patients who are hospitalized, rates of acute respiratory
distress syndrome are as high as 29%. A study of 262 confirmed cases revealed ● The neurologic
that 18% had severe disease, 73% were mild, 4% were nonpneumonic, and 5% manifestations of COVID-19
can be broadly divided into
were asymptomatic5; widespread antibody testing will likely show far higher
two categories: those that
numbers of asymptomatic or mildly symptomatic people. Lymphopenia is occur during the acute
common in patients who are critically ill.6 Mortality is higher with advanced phase of the infection
age and underlying comorbidities, including diabetes, cardiac and respiratory (parainfectious
disorders, and immunosuppressed states. Several acute neurologic syndromes complications) and the
postviral manifestations that
have been associated with coronaviruses (TABLE 11-1). About 13.5% of occur following the acute
hospitalized patients have neurologic manifestations. Of these, nearly half phase (post–acute phase
have metabolic abnormalities or hypoxic brain injury.7 complications).
● Anosmia and ageusia are

NEUROLOGIC COMPLICATIONS OF COVID-19 the most common early
The neurologic manifestations of COVID-19 can be broadly divided into two symptoms of COVID-19
categories: those that occur during the acute phase of the infection infection. Nearly 40% to 60%
(parainfectious complications) and the postviral manifestations that occur of patients develop loss of
smell, and, upon testing,
following the acute phase (post–acute phase complications).
nearly 90% have alteration of
smell.
Anosmia
Anosmia and ageusia are the most common early symptoms of the infection.
Nearly 40% to 60% of patients develop loss of smell,8 and, upon testing, nearly

90% have an alteration of smell.9 The loss of taste is secondary to anosmia but can
lead to anorexia and weight loss. Many patients recover their sense of smell; others
may develop hyposmia, parosmia, or permanent anosmia. The virus is thought to
invade the sustentacular (also called support) cells in the vicinity of the olfactory
nerve endings in the nasal mucosa, which express the SARS-CoV-2 receptor
ACE2.10 Transient obstruction of the olfactory clefts11 and olfactory bulb edema
have been seen on MRI in patients with COVID-19–associated anosmia.12 To date,
no direct evidence of infection of the olfactory nerve has been seen.
Encephalopathy
Encephalopathy is the most common neurologic manifestation in patients who are
hospitalized with COVID-19, with nearly one-third of patients who are
hospitalized developing encephalopathic symptoms ranging from alteration in
consciousness to delirium and seizures. Patients with encephalopathy have
prolonged hospitalization, and two-thirds are unable to manage activities of daily
living at the time of discharge.13 Encephalopathy is more common in older adults.
The underlying causes of encephalopathy are complex and require careful
evaluation and investigation (CASE 11-1). In patients who have significant
pulmonary or multiorgan involvement, hypoxic or metabolic abnormalities should
be considered as major contributors to the encephalopathy. In some critically ill
patients, the MRI may show diffuse, bilaterally symmetrical high-signal-intensity
lesions suggestive of a delayed posthypoxic leukoencephalopathy. This may be
associated with microhemorrhagic lesions in the corpus callosum and juxtacortical
regions.14 Delirium in patients hospitalized with COVID-19 has been commonly
described. Rarely, it is present at onset and may be associated with sepsis. In the
critical care setting, the causes are multifactorial. In one series, 84% of patients
CASE 11-1 A 32-year-old woman developed a low-grade fever for 2 days with a
stuffy nose and hyposmia. She tested positive for SARS-CoV-2 but was
sent home. The next day she developed visual hallucinations and became
agitated. Upon admission, her oxygen saturation was 88%. She appeared
delirious but could follow commands. Only a partial neurologic
assessment could be performed, but it did not show any focal deficits.
The patient had to be sedated for an MRI of the brain, which was normal.
EEG showed some focal slowing in the left temporal lobe. CSF was
normal, including polymerase chain reaction (PCR) for SARS-CoV-2.
Chest CT showed bilateral infiltrates in the lower lobes of the lungs.
COMMENT A broad differential diagnosis should be considered in hospitalized

patients with COVID-19 who are encephalopathic. Metabolic abnormalities
should be corrected, and medications and drugs of abuse should be
considered as potential etiologies; psychosocial aspects, including social
isolation, can be contributory factors. Neurologic etiologies to consider
include posterior reversible encephalopathy syndrome (PRES) or
autoimmune encephalitis, as a wide variety of autoantibody syndromes are
being reported in this patient population.
1054 AUGUST 2021

with COVID-19 in the critical care unit had delirium with impairment of attention, KEY POINTS
awareness, and cognition.15 In this setting, delirium may also arise from
● Encephalopathy is the
medications such as sedative-hypnotics, anticholinergics, and corticosteroids. most common neurologic
Prolonged mechanical ventilation and isolation from the health care team and manifestation in patients
family members may also be contributory factors. who are hospitalized with
COVID-19, with nearly
one-third of patients who
Viral Encephalitis
are hospitalized developing
Direct viral invasion of the brain in COVID-19 is rare. A case of SARS-CoV-2 encephalopathic symptoms
meningoencephalitis was reported in Japan; the patient presented with ranging from alteration in
generalized seizures and was found to have lesions of the temporal lobe with consciousness to delirium
and seizures.
adjoining ventriculitis as well as paranasal sinusitis. The virus was detected in the
CSF but not by nasal swab. CSF showed a mild pleocytosis with 12 cells/mm3.16 ● Direct viral invasion of the
Other case reports of encephalitis with confirmed SARS-CoV-2 in CSF have been brain in COVID-19 is rare.
rare,17,18 so it does not seem to be a common manifestation of infection. Most
autopsy studies have been unable to detect the virus in the brain.19-21 Although ● Acute necrotizing
hemorrhagic
low copy numbers of the virus have been detected in the medulla and frontal lobe encephalopathy is a feared
of an occasional patient, they were considered a blood contaminant.20 A complication of several
postmortem neuropathologic study of 43 patients found evidence of viruses, most notably
SARS-CoV-2 RNA and proteins in the brain tissue of 53% of patients, but rare influenza. It is thought to
result from cytokine release
infected cells with low copy numbers of the virus were detected and the presence
syndrome rather than direct
of the virus was not associated with the severity of neuropathologic changes, viral invasion of brain
such as astrogliosis, ischemic lesions, and inflammatory lesions.22 parenchyma, which is
especially salient given the
propensity of SARS-CoV-2
Acute Necrotizing Hemorrhagic Encephalopathy
for causing similar cytokine
Acute necrotizing hemorrhagic encephalopathy is a feared complication of storms in the lungs.
several viruses, most notably influenza. It is thought to result from cytokine
release syndrome rather than direct viral invasion of brain parenchyma,23 which is ● Acute disseminated
especially salient given the propensity of SARS-CoV-2 for causing similar cytokine encephalomyelitis is a rare
demyelinating disease; it is
storms in the lungs. Patients with this condition develop bilateral symmetric often postviral and is more
lesions of the thalami with hemorrhagic foci; the temporal lobes, brainstem, and common in children than
other regions of the brain may also be involved. Usually, no contrast enhancement adults. However, in patients
is seen. Patients present with several days of altered mental status in addition to with COVID-19, it has been
described mainly in adults.
more typical COVID-19 symptoms.24 Acute necrotizing hemorrhagic
encephalopathy does not respond to corticosteroids,25,26 but response to plasma
exchange and IV immunoglobulin (IVIg) has been described.27
Another cytokine release neurologic syndrome has been described with
COVID-19 in which patients develop confusion, tremor, cerebellar ataxia,
behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy,
dysautonomia, and central hypothyroidism. This syndrome has responded to
corticosteroid therapy or IVIg in some patients.28
Acute Disseminated Encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease;
it is often postviral and is more common in children than adults. However, in
patients with COVID-19, it has been mainly described in adults.29,30 Clinically,
the presentation is heterogeneous, usually causing an encephalopathy and
multifocal deficits. It has been described following a mild flulike illness31,32 and
following severe COVID-19 requiring admission to the critical care unit.29,33,34
MRI typically demonstrates T2/fluid-attenuated inversion recovery (FLAIR)
hyperintensities in deep white matter and at the gray-white matter interface.

Contrast enhancement is not always present; when seen, it may be punctate or

ring-enhancing or have an open-ring pattern. Hemorrhagic changes with ADEM
have been a striking observation in some patients.30 Virus has not been detected
in the CSF of patients with COVID-19 who develop ADEM.30 ADEM in patients
with COVID-19 generally responds to treatment with high-dose corticosteroids.35
ADEM pathology is characterized by perivenular sleeves of demyelination
associated with inflammatory infiltrates. Eventually, larger areas of demyelination
may occur secondary to coalescence of perivenous demyelinating lesions.
Postmortem neuropathologic findings in one patient with COVID-19 with ADEM
revealed features suggestive of combined demyelinating and vascular
mechanisms; hemorrhagic white matter lesions, aggregates of macrophages
associated with axonal injury, and an ADEM-like appearance were present in the
subcortical white matter.36 Congested blood vessels are a common finding in these
patients, may give the appearance of punctate lesions on the MRI, and may
represent perivascular leakage of red blood cells (FIGURE 11-1). Hemorrhagic
transformation may occur with ADEM, which may complicate treatment with
anticoagulants for coexisting hypercoagulable states. In autopsy of some patients,
infiltration of macrophages and lymphocytes were also seen (FIGURE 11-2). These
clinical and pathologic observations suggest that inflammatory syndromes are
common in patients with COVID-19 and may respond to immunotherapies.
Ondine’s Curse
Some patients report forgetting to breathe (unpublished observations), and
many others have decreased oxygen saturation levels but are not breathless and
have normal respiratory rates. Sudden death has also been reported with
COVID-19, although this has been most often attributed to cardiac disease.37
These symptoms suggest the possibility of central hypoxia or Ondine’s curse.38
However, to date, objective evidence is lacking. Autopsy studies suggest that the
pathology is particularly prominent in the olfactory system and the brainstem.22
The author’s own observations show the presence of brainstem lesions in patients
with sudden death.39 Although concrete evidence for neuroinvasion by
FIGURE 11-1
Microvascular disease in a patient with COVID-19. A, Autopsy tissue from the patient shows
congested blood vessels in the cortical white matter. B, Postmortem MRI of the same tissue
shows a hyperintense signal in the blood vessels. C, Microscopic examination shows blood
vessels full of red blood cells in the lumen and periluminal region.
Figure courtesy of Rebecca Folkerth, MD (provided autopsy tissue), Govind Nair, PhD (performed MRI), and
Myounghwa Lee, PhD (performed immunostaining).
1056 AUGUST 2021

FIGURE 11-2
Central nervous system inflammation in COVID-19. Autopsy brain tissue was stained with
monoclonal antibodies to immune cellular markers. Diaminobenzidine was used as a
chromogen, which gives a brown-colored precipitate. Panel A shows infiltration of
macrophages staining for CD68 in the perivascular region and parenchyma, and panel B
shows infiltration of CD3 T cells in foci around the blood vessels and the parenchyma.
Figure courtesy of Rebecca Folkerth, MD (provided autopsy tissue) and Myounghwa Lee, PhD
(performed immunostaining).
SARS-CoV-2 is lacking, it is intriguing to consider the possibility of viral

brainstem invasion via transneuronal spread (as has been shown in mouse
models with other coronaviruses), either via the olfactory system or the vagus
nerve as it innervates the respiratory and gastrointestinal tracts.40
Stroke
Patients with COVID-19 develop a hypercoagulable syndrome causing both arterial
and venous occlusions in the brain vasculature (TABLE 11-2). In a single-center case
series of 219 hospitalized patients, 4.6% developed an ischemic stroke and 0.5%
Strokes in Patients With COVID-19 TABLE 11-2
Presentation
◆ Cerebral venous thrombosis
◆ Ischemic stroke with multiple arterial occlusions
◆ Microhemorrhages
Pathophysiology
◆ Coagulopathy
◆ Antiphospholipid antibodies
◆ Cardiac embolism
◆ Endothelitis
Risk factors
◆ Myocarditis
◆ Known vascular risk factors
◆ Acute respiratory distress syndrome
◆ Multiorgan impairment

developed intracerebral hemorrhage.41 Ischemic stroke, hemorrhagic stroke, and

cerebral venous sinus thrombosis have all been reported.42,43 Some patients may
develop microhemorrhages44,45 and have other signs of microvascular injury.46
Spinal cord infarcts have also been reported.47,48
Cerebrovascular complications of COVID-19 are likely due to altered
coagulation pathways, as demonstrated by observations of elevated D-dimer,
increased prothrombin time, and activated partial thromboplastin time, and
disseminated intravascular coagulation49; anticoagulants are frequently used in
hospitalized patients with elevated D-dimer levels (CASE 11-2). The Virchow
triad consists of endothelial cell injury, hypercoagulable state, and immobility. All
three states are applicable to patients with COVID-19, putting them at risk for
strokes. Older patients with preexisting cardiovascular risk factors are at risk
of developing vascular occlusive syndromes, including ischemic strokes, deep vein
thrombosis, and pulmonary embolism.50 Some patients may develop myocarditis,
which may be an added risk factor for stroke.51,52 In severe cases that require
extracorporeal membrane oxygenation (ECMO) support with continuous
anticoagulation, intraparenchymal hemorrhage with a poor prognosis may occur.53
Strokes may also occur in individuals who have no risk factor other than
COVID-19. Potential causes include interaction between the virus and ACE2
receptor on endothelial cells, including the cerebral vasculature and
antiphospholipid antibodies.54 In patients with COVID-19 with acute stroke who
are eligible for thrombolysis, some practitioners may prefer tenecteplase over
alteplase given the rapidity of effect and shorter infusion time that minimizes the
risk of health care workers’ exposure.
CASE 11-2 A 60-year-old man with long-standing well-controlled hypertension

presented to the emergency department with fever, loss of smell, and
shortness of breath. Chest CT showed bilateral infiltrates in the lungs,
and he tested positive for SARS-CoV-2 by polymerase chain reaction
(PCR) from a nasal swab. Over the next 12 hours, his respiratory status
decreased further, requiring treatment with extracorporeal membrane
oxygenation (ECMO). His D-dimer level was elevated to 620 ng/mL, and
serum creatinine was 3.4 mg/dL. The patient was treated with heparin.
However, the next day he developed Broca aphasia with right-sided
hemiparesis. He underwent a thrombectomy of the left internal carotid
and had good neurologic recovery.
COMMENT Early in the pandemic, strokes were often missed in patients admitted to
the critical care unit, since the focus was primarily on respiratory
symptoms. As awareness of the hypercoagulable state induced by
COVID-19 has increased, prophylactic anticoagulation is now provided to
patients with highly elevated D-dimer levels. However, this carries the risk
of hemorrhagic cerebral complications since patients with COVID-19 often
have inflammation and microvascular disease in the brain with
microhemorrhages. Hence, careful monitoring of these patients is
necessary.
1058 AUGUST 2021

Neurodegenerative Diseases KEY POINTS
Rare cases of acute parkinsonism and a single case of Creutzfeldt-Jakob disease
● Patients with COVID-19
have been reported in patients with COVID-19 infection.55,56 It remains unclear if develop a hypercoagulable
this co-occurrence is coincidental or causative or whether the infection and syndrome causing both
associated inflammatory response led to precipitation or acceleration of a arterial and venous
preexisting underlying neurodegenerative condition. occlusions in the brain
vasculature. Ischemic
stroke, hemorrhagic stroke,
Myelitis and cerebral venous sinus
Several forms of myelitis have been described with COVID-19, and reports of thrombosis have all been
transverse myelitis are the most common. These patients have involvement of at reported.
least three segments of the spinal cord that includes the gray and white matter,
● Cerebrovascular
although not all patients had neuroimaging.57,58 In some patients, the clinical complications of COVID-19
presentation was consistent with transverse myelitis, although the MRI was are likely due to altered
normal59; this has been reported in both adults and children.60 An isolated report coagulation pathways as
described a longitudinally extensive acute necrotizing myelitis with an acute demonstrated by
observations of elevated
motor axonal neuropathy that responded to high-dose steroids and plasma D-dimer, increased
exchange.61 A case of acute flaccid myelitis with MRI hyperintensity on prothrombin time and
T2-weighted images involving the ventral gray matter of the thoracic cord has activated partial
been described, which occurred during the acute phase of the illness. This patient thromboplastin time, and
disseminated intravascular
had a lymphocytic pleocytosis in the CSF, but the virus was not detected in the coagulation.
CSF by PCR.62
● Variants of Guillain-Barré
Guillain-Barré Syndrome syndrome seem to be more
common when associated
A report from Italy described five patients with Guillain-Barré syndrome
with preceding COVID-19
(GBS) symptom onset 5 to 10 days after they first developed COVID-19 infection.
symptoms.63 The virus could not be detected in the CSF of any of the
patients, and two did not have albuminocytologic dissociation in the CSF. ● Myositis can occur at any
Neurophysiologic features were consistent with the axonal variant in three of the time during the course of
COVID-19; it can be quite
patients and with the demyelinating variant in the other two. Two patients extensive and associated
required mechanical ventilation, two had flaccid paraplegia, and one was able with myalgia and muscle
to walk independently. A subsequent review of 73 cases reported that the weakness that can persist
age range for GBS with COVID-19 was 11 to 94 years; 68.5% of cases were in after recovery of the other
symptoms.
male patients. Most patients had symptoms of COVID-19 with pulmonary
involvement. The distribution of clinical variants resembled those of classic GBS.
CSF albuminocytologic dissociation was present in 71% of cases, and CSF
SARS-CoV-2 was absent by PCR in all patients tested. Seventy percent of cases
had a good outcome with the use of IVIg.64 Several patients with the Miller
Fisher variant of GBS with ophthalmoparesis have been described.65,66 Other
patients with cranial neuropathies have also been reported.65 Such variants of
GBS seem to be more common when associated with preceding COVID-19
infection.
Myositis
Myositis can occur at any time during the course of the illness and can be quite
extensive, associated with myalgia and muscle weakness that can persist after
recovery of other symptoms.67 It can involve the paraspinal muscles, causing
patients to report back or chest pain.68 MRI may show evidence of myonecrosis,
and inflammatory infiltrates have been described on histology, which responded
to treatment with IV corticosteroids67; some have argued that these reports
represent dermatomyositis.69 Occasionally, rhabdomyolysis may occur,

increasing the risk for renal toxicity.70,71 Patients with rhabdomyolysis require
careful monitoring and treatment with hydration.
Long-Haul COVID or Post–acute COVID Syndrome

A distinct postviral syndrome that is independent of the severity of the acute phase
of the illness is seen in some patients with COVID-19. This syndrome
can emerge even in patients who have relatively mild symptoms during the
acute phase. This syndrome has been termed long-haul COVID or long COVID,72
and its manifestations overlap with myalgic encephalomyelitis/chronic fatigue
syndrome. Often these symptoms first manifest after the acute phase of the illness.
These manifestations are 4 times more common in women and young adults.
Long-haul COVID can be broadly divided into three clinical subtypes.
The first subtype manifests predominantly with dysautonomia, which may
include palpitations, tachycardia upon mild exercise or standing, hypotension
or hypertension, gastroparesis, constipation or loose stools, and peripheral
vasoconstriction (CASE 11-3). Some patients report low-grade fever, which is
also thought to be due to autonomic dysfunction. Patients with the second subtype
CASE 11-3 A 35-year-old woman developed a sore throat, loss of smell, and pain in
the supraorbital regions over a period of 2 days. This was followed by
nausea, diarrhea, and a feeling of extreme fatigue. She did not develop
any cough, dyspnea, or a drop in oxygen saturation levels. Polymerase
chain reaction (PCR) by nasal swab was positive for SARS-CoV-2. These
symptoms gradually improved over the next 5 days. However, at the
same time, she developed orthostatic hypotension and became almost
bedbound. She also had palpitations and decreased sweating but no new
urinary symptoms. Over the next few days, she developed burning pain in
the face, chest, and trunk, sparing the distal extremities.
Neurologic evaluation confirmed a drop in blood pressure with
tachycardia upon standing for 2 minutes. The rest of the examination was
normal. MRI brain, CSF analysis, EMG, and nerve conduction velocities
were normal. Complete blood cell count and chemistry profile were
normal. A course of treatment with IV immunoglobulin (IVIg) and
high-dose corticosteroids with a prolonged taper showed only a mild
improvement in symptoms.
COMMENT This patient has a postural tachycardia syndrome (POTS)–like presentation

following COVID-19 due to dysautonomia. The palpitations are a
compensatory phenomenon caused by the drop in blood pressure from
pooling of the blood in the abdomen, pelvis, and lower limbs. The use of
β-adrenergic receptor blockers can make the symptoms worse. Increased
fluid intake, abdominal binders, and tight stockings should be considered.
Mineralocorticoids may also help. Her pain may represent a small fiber
neuropathy. Many patients report a similar pain syndrome after COVID-19.
It is currently unknown whether this is an immune-mediated phenomenon
involving the nerves or the sensory ganglia.
1060 AUGUST 2021

have extreme exercise intolerance, and those with the third subtype have cognitive KEY POINTS
dysfunction. In some patients, the cognitive dysfunction may be related to
● Long-haul COVID is a
postural hypotension, as some have noticed that their ability to think and distinct postviral syndrome
concentrate is better when they are lying down. Others may develop symptoms of that is independent of the
distortion of time, short-term memory loss, and depression. Sleep disturbance is severity of the acute phase
also a common symptom. Although some patients improve spontaneously over of the illness. This syndrome
can emerge even in patients
several weeks, it is anticipated that 10% to 30% of individuals may have persistent
who have relatively mild
symptoms. A distinction needs to be made between patients with long-haul symptoms during the acute
COVID and patients who were hospitalized, who often have a large number of phase.
lingering symptoms from respiratory disease, other organ damage, and prolonged
hospitalization that may overlap with the syndrome described above.73 The full ● A distinction needs to be
made between patients with
extent of this syndrome, including its prevalence and the duration of symptoms, long-haul COVID and
remains unknown. More research is needed to understand the complete nature of patients who were
the infection and its lasting effects. Because the majority of these patients had hospitalized, who often
relatively mild symptoms during the acute phase of the illness and did not have a large number of
lingering symptoms from
require hospitalization, it is possible that they may not have cleared the virus respiratory disease, other
completely and may have a persistent or restricted viral replication that could be organ damage, and
driving the syndrome. In support of this hypothesis, viral RNA but not viable virus prolonged hospitalization.
has been recovered from seminal fluid, and sexual transmission of SARS-CoV-2
has not been documented.74 Similarly, viral RNA has been detected in tears,
vomitus, and bile fluid, but its clinical significance has yet to be determined.75,76,77
Viral antigen has also been found in intestinal mucosa 3 months after infection.78
Multisystem Inflammatory Syndrome in Children

It is being increasingly recognized that some children can develop systemic
symptoms including neurologic manifestations about 2 to 3 weeks after recovery
from the acute syndrome. These may manifest as an encephalopathy and
generalized weakness and dysarthria and dysphagia. MRI may show restricted
diffusion on diffusion-weighted imaging in the splenium of the corpus callosum.
CSF is normal; however, blood may show signs of acute inflammation such as
elevated CRP, D-dimer, and ferritin. The pathophysiology of this postviral
syndrome is not entirely clear, but the patients show response to treatment with
IVIg and corticosteroids.79
NEUROLOGIC COMPLICATIONS OF SARS-COV-2 VACCINES

Several different types of vaccines have been developed against the virus. Most of
them are based on immunization against the spike protein of the virus delivered
as DNA in a viral vector, mRNA, or protein. The first two mRNA-based vaccines
to be approved have excellent safety profiles. However, several cases of Bell’s palsy
and a few cases of anaphylaxislike reactions have been reported. Few cases of
stroke, transverse myelitis, acute disseminated encephalomyelitis, GBS, vertigo,
and unilateral facial paresthesia have also occurred.80 Currently, it is unclear
whether these side effects are related to the mRNA vaccines or coincidental.
Another vaccine delivered in an adeno-associated virus vector resulted in transient
myelopathic symptoms in two patients, and clinical trials were temporarily halted for
this reason.81 The major difference between the mRNA and the adeno-associated
virus vaccines is the sequence of the spike protein used. It remains unknown if some
homology might exist between the spike protein and central nervous system
antigens. If so, it would have to be a conformational-based homology since no
sequence homology has been identified. Several cases of cerebral venous thrombosis

and splanchnic vein thrombosis have been reported with the two vaccines that use
the adeno-associated viral vector for delivery. These patients have a vaccine-
induced thrombotic thrombocytopenia with antibodies to platelet factor 4. These
patients should not be treated with heparin because heparin can induce such
immune phenomena. IVIg and nonheparin anticoagulation should be used.
ETHICAL DILEMMA
The COVID-19 pandemic has brought to light numerous ethical issues involving
neurologists and their patients. Notably, many of our patients may be unable
to advocate for themselves because of neurologic disease and, as a result, could
be denied rationed health care resources. For example, patients with COVID-19
and comorbid dementia could be unable to advocate for themselves and thus
may be more likely to be deprived of scarce resources such as ventilator
support.84 As neurologists, our role is certainly to continue to advocate for our
patients, especially when they are at their most vulnerable.
CONCLUSION
Neurologic complications of SARS-CoV-2 infection can occur during the acute
phase of the illness from multiorgan involvement presenting as an
encephalopathy. These patients often have a prothrombotic state and can
develop occlusion of multiple arteries and the venous system simultaneously.
This can be further complicated with hemorrhagic lesions. Viral encephalitis is
rare; however, some may develop immune-mediated syndromes such as ADEM,
transverse myelitis, GBS, or myositis. Some patients are developing a constellation
of chronic symptoms, termed long-haul COVID, that resembles myalgic
encephalomyelitis/chronic fatigue syndrome. Even though most children develop
mild symptoms from the infection, a multisystemic inflammatory syndrome that
includes neurologic manifestations is being recognized. Early recognition and
treatment are key to effective management of these patients.
ACKNOWLEDGMENTS
Funding/Support: This article was supported by intramural funding from the
National Institute of Neurological Disorders and Stroke at the National Institutes
of Health (NS03130).
Disclaimer: This article was written by Dr Avindra Nath in his personal capacity.
The views expressed are his own and do not necessarily represent the views of
the National Institutes of Health, the Department of Health and Human Services,
or the United States government.
USEFUL WEBSITES AND RESOURCES

NEUROLOGY PODCAST JOHNS HOPKINS UNIVERSITY & MEDICINE’S
This provides a discussion of the neurologic CORONAVIRUS RESOURCE CENTER GLOBAL MAP
complications of COVID-19 and the various forms This provides up-to-date information on the
of COVID-19 vaccines. worldwide incidence of COVID-19.
http://neurology.libsyn.com/website/special- coronavirus.jhu.edu/map.html
report-looking-ahead-at-covid-in-2021-with-avi-
nath-part-1
http://neurology.libsyn.com/website/special-
report-looking-ahead-at-covid-in-2021-with-dr-
avi-nath-part-2
1062 AUGUST 2021

US CENTERS FOR DISEASE CONTROL AND PREVENTION BRAIN INFECTIONS GLOBAL COVID-NEURO NETWORK
COVID-19 INFORMATION PAGE This provides a comprehensive collection of the
This provides the epidemiology of COVID-19 in the published literature of neurologic manifestations of
United States and guidelines for prevention and COVID-19 and tools for collection of data for
treatment. epidemiological studies.
cdc.gov/coronavirus/2019-ncov/index.html braininfectionsglobal.tghn.org/covid-neuro-network/
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REVIEW ARTICLE

Neurologic Infections
CONTINUUM AUDIO
I NT E R V I E W A V AI L A B L E
ONLINE
in Patients on
Immunomodulatory and
Immunosuppressive
Therapies
By Pria Anand, MD
ABSTRACT
PURPOSE OF REVIEW: Both broadly immunosuppressive medications and
selective immunomodulatory agents that act on particular
components of the immune system are increasingly used in the treatment
of neurologic and non-neurologic diseases. These therapies predispose
patients to particular infections, some of which may affect the
nervous system. Therefore, familiarity with the clinical and radiologic
features of neurologic infections associated with specific
immunomodulatory therapies is of importance for the practicing
neurologist. This article reviews these neuroinfectious conditions,
as well as other neurologic complications unique to transplant
recipients and other patients who are immunocompromised.
RECENT FINDINGS:Diagnosis of infectious pathogens in patients

who are immunocompromised may be particularly challenging
because a decreased immune response can lead to atypical imaging or
CITE AS: laboratory findings. Next-generation sequencing and other novel
diagnostic modalities may improve the rate of early identification
DISEASE):1066–1104. of neurologic infections in patients who are immunocompromised
and ultimately ameliorate outcomes in this vulnerable
Address correspondence to population.
Dr Pria Anand, Department of
Neurology, Boston University
School of Medicine, 72 E SUMMARY: A broad range of bacterial, viral, fungal, and parasitic infections
Concord St, Boston, MA 02118,
pria.anand@bmc.org.
of the nervous system can complicate solid organ and hematopoietic cell
transplantation as well as other forms of immunocompromise. In addition
RELATIONSHIP DISCLOSURE: to neurologic infections, such patients are at risk of neurotoxic and
Dr Anand reports no disclosure.
neuroinflammatory complications related to immunomodulatory and
UNLABELED USE OF immunosuppressive therapies. Early recognition of infectious and
noninfectious complications of immunocompromise is essential to guide
USE DISCLOSURE:
Dr Anand reports no disclosure. appropriate treatment, which can include antimicrobial therapy and, in
some cases, withdrawal of the predisposing medication with a transition to
an alternative regimen.
of Neurology.
1066 AUGUST 2021

KEY POINTS
INTRODUCTION
I
mmunosuppressive or immunomodulatory therapies are used to treat ● The term
patients undergoing solid organ and hematopoietic stem cell transplant, immunocompromise spans
patients with rheumatologic diseases, patients with immune-mediated the effects of both broadly
immunosuppressive
neurologic diseases (eg, multiple sclerosis, neuromyelitis optica, myasthenia therapies used to treat
gravis, autoimmune encephalitis), and patients with hematologic autoimmune and neoplastic
malignancies. Treatments that lead to altered immunity include broadly conditions (eg,
immunosuppressive therapies used to treat autoimmune and neoplastic cyclophosphamide,
methotrexate, azathioprine,
conditions (eg, cyclophosphamide, methotrexate, azathioprine, mycophenolate mycophenolate mofetil,
mofetil, cyclosporine, and tacrolimus) and immunomodulatory therapies cyclosporine, and
such as natalizumab or fingolimod, which act selectively on part of the immune tacrolimus) and
system. Although immunosuppressive therapies predispose patients to a wide immunomodulatory
therapies such as
range of opportunistic infectious pathogens, the risk profile in patients on natalizumab or fingolimod,
immunomodulatory therapies may be limited to specific pathogens or infectious which act selectively on part
syndromes (TABLE 12-1). For instance, corticosteroids can inhibit the production of the immune system.
of multiple inflammatory mediators, including the cytokines interleukin 1,
● Although
interleukin 6, and tumor necrosis factor-a (TNF-a); they can reduce macrophage immunosuppressive
motility and response to interferon gamma, downregulate adhesion molecules, therapies predispose
inhibit IgE-dependent degranulation, and induce eosinophil apoptosis. As a patients to a wide range of
result of these broad effects on the immune system, patients on prolonged opportunistic infectious
pathogens, the risk profile in
corticosteroids are at risk of a wide range of infectious pathogens, including patients on
pyogenic bacteria, Listeria monocytogenes, Mycobacterium tuberculosis, immunomodulatory
herpesviruses, fungal infections, and certain parasites. By contrast, natalizumab, therapies may be limited to
which blocks the passage of leukocytes across the blood-brain barrier by specific pathogens or
infectious syndromes.
inhibiting α4 integrin, has limited effects on adaptive immunity. Exposure to
natalizumab carries an increased risk of a more restricted set of microorganisms, ● The immunosuppressive
including JC virus, the cause of progressive multifocal leukoencephalopathy or immunomodulatory
(PML). The immunosuppressive or immunomodulatory effects of a medication effects of a medication may
persist for weeks or even
may persist for weeks or even months after it is discontinued. months after it is
A thorough understanding of the evaluation and management of neurologic discontinued.
infections in immunocompromised populations is critical because increasing
numbers of patients are exposed to new and repurposed therapies for a range of ● When neurologic
infections that can also
autoimmune and oncologic conditions and the frequency of organ transplantation affect immunocompetent
continues to rise worldwide. When neurologic infections that can also affect hosts occur in patients who
immunocompetent hosts occur in those who are immunocompromised, atypical are immunocompromised,
clinical presentations, imaging, and laboratory findings may be seen (TABLE 12-21-5). atypical clinical
presentations, imaging, and
For instance, when herpes simplex encephalitis occurs in patients who are laboratory findings may be
immunocompromised, the presentation may be more insidious, with fewer seen.
prodromal and focal symptoms. Imaging can demonstrate more brainstem
involvement or more widespread cortical abnormalities beyond the classic limbic
changes typically seen in those who are immunocompetent, and CSF white blood
cell count may be normal or only mildly elevated.6 These atypical presentations can
lead to underdiagnosis, delays in treatment, and increased morbidity and mortality.
Although this article focuses on infectious complications of immunocompromise,
neurologic disease in patients who are immunocompromised has a broad
differential diagnosis, including medication-induced neurotoxic syndromes
(eg, posterior reversible encephalopathy syndrome [PRES]), inflammatory
conditions (eg, immune reconstitution inflammatory syndrome [IRIS]),
neoplasia (eg, posttransplantation lymphoproliferative disorder), and, in

NEUROLOGIC INFECTIONS IN PATIENTS ON IMMUNOMODULATORY AND IMMUNOSUPPRESSIVE THERAPIES
transplant recipients, neurologic graft versus host disease (GVHD). Early

recognition of infectious and noninfectious complications of immunocompromise
is essential to guide appropriate treatment, which can include antimicrobial
therapy and, in some patients, withdrawal of the predisposing medication with a
transition to an alternative regimen. The neuroinfectious conditions discussed
here often overlap with infections seen in patients who are immunocompromised
TABLE 12-1 Risk of Neurologic Infections Associated With Selected

Immunosuppressive and Immunomodulatory Medications
Pathogen
Medication Therapeutic class Virus Bacteria Fungus Parasite
Central nervous system demyelinating disease-modifying therapies
Alemtuzumab Monoclonal Cytomegalovirus Listeria None None

antibody (target: (CMV), herpes simplex monocytogenes,
CD52) virus (HSV), Mycobacterium
varicella-zoster virus tuberculosis,
(VZV) Nocardia species
Dimethyl fumarate Transcription factor JC virus (particularly in None None None

activator patients with
lymphopenia), VZV
Eculizumab Monoclonal None Neisseria None None

antibody (target: meningitides
complement
component C5)
Fingolimod Sphingosine-1- HSV, JC virus, VZV None Cryptococcus None

phosphate receptor neoformans
modulator
Natalizumab Monoclonal HSV, JC virus, VZV None None None

antibody (target: α4
integrin)
Ocrelizumab and Monoclonal CMV, Epstein-Barr virus None C. neoformans Toxoplasma

rituximab antibodies (target: (EBV) (with associated gondii
CD20) primary central nervous
system [CNS]
neoplasm), JC virus
(more often seen in
patients on rituximab
with underlying
predisposing
conditions, although
cases have been
reported in patients on
ocrelizumab previously
treated with other
immunosuppressive
medications), VZV,
West Nile virus
1068 AUGUST 2021

due to infection with human immunodeficiency virus (HIV); refer to the article
“Neurologic Complications of Human Immunodeficiency Virus” by Marie F. Grill,
MD,7 in this issue of Continuum.
This article first reviews the neuroinfectious considerations in selected
populations of patients who are immunocompromised. Following this, topics
including meningitis, encephalitis, focal brain lesions, and spinal infectious
Pathogen
Medication Therapeutic class Virus Bacteria Fungus Parasite
Teriflunomide Pyrimidine synthesis JC virus (in one patient M. tuberculosis None None
inhibitor previously treated with
natalizumab)
Posttransplant medications
Azathioprine Purine analogue None None None None
Cyclosporine, Calcineurin BK virus, CMV, EBV M. tuberculosis, Aspergillus T. gondii,

everolimus, inhibitors (with associated L. monocytogenes, fumigatus, granulomatous
sirolimus, and primary CNS Nocardia species Candida amebic
tacrolimus neoplasm), human species, C. encephalitis
herpesvirus 6, HSV, JC neoformans,
virus, lymphocytic Histoplasma
choriomeningitis virus, capsulatum
lyssaviruses (rabies),
VZV, West Nile virus
Methotrexate Folate analogue EBV (with associated None None T. gondii

inhibitor primary CNS neoplasm)
Mycophenolate Inosine EBV (with associated None None T. gondii

mofetil 50-monophosphate primary CNS
dehydrogenase neoplasm), JC virus
inhibitor
Other
immunomodulatory
medications
Cyclophosphamide Alkylating agent None Nocardia species C. neoformans None
Adalimumab, Tumor necrosis HSV L. monocytogenes, A. fumigatus, None

etanercept, factor-α inhibitors M. tuberculosis, Candida
golimumab, and Nocardia species species, C.
infliximab neoformans,
H. capsulatum

TABLE 12-2 Cerebral Infections in Patients on Immunomodulatory and

Immunosuppressive Therapiesa
Entity CSF and serologic diagnostics Imaging characteristics

Cytomegalovirus CSF polymerase chain reaction (PCR) is more Enhancing multifocal periventricular and
(CMV) encephalitis sensitive and specific than IgM and IgG testing ependymal lesions without mass effect;
or viral culture (86-94% sensitivity and 87-94% variably T2 hyperintense and diffusion-
specificity, depending on the specific assay restricting
used); higher serum cytomegalovirus PCR
correlates with a greater likelihood of invasive
infection
Human herpesvirus CSF HHV-6 PCR, although false positives Nonenhancing T2 hyperintensity or diffusion
(HHV) 6 encephalitis may be seen in patients who are restriction of the bilateral medial temporal
immunocompetent with a low pretest lobes and limbic structures without mass
probability; viremia may be seen with effect; MRI is normal in up to 30% of patients,
elevated serum HHV-6 PCR particularly early in infection
Herpes simplex virus CSF HSV PCR is highly sensitive and specific MRI is abnormal in up to 95% of patients; T1-
(HSV) encephalitis (98% sensitivity and 94% specificity or isointense or -hypointense and T2-hyperintense
higher); CSF HSV IgG and IgM may be seen lesions of the temporal lobes, limbic system, and
later in the course of infection orbital frontal lobe with associated diffusion
restriction; patients who are immunocompromised
may have brainstem involvement; hemorrhage may be
seen on susceptibility-weighted imaging (SWI)
BK virus CSF BK virus PCR or PCR of cerebral tissue is T2 hyperintensities involving the limbic system,
encephalitis used for diagnosis sometimes with associated diffusion restriction
Granulomatous CSF culture has a low sensitivity; diagnosis is Single (38% at presentation) or multifocal (75%
amebic encephalitis more often by brain biopsy with examination for during the course of illness) T2-hyperintense
cysts and trophozoites, culture, or molecular lesions throughout the brain; 80% with
assays; Balamuthia or Acanthamoeba antibodies associated contrast enhancement
or DNA may be detected in the serum
Varicella-zoster CSF VZV PCR is incompletely sensitive (30% T2-hyperintense lesions involving the gray-white matter
virus (VZV) sensitivity and seen more reliably early in junction with associated diffusion restriction in the event
encephalitis and the course of infection); reduced ratio of of stroke, often with associated contrast enhancement;
vasculitis serum to CSF VZV IgG is preferred for strokes involving white matter more often than gray
diagnosis (93% sensitivity and 100% matter, multiple vascular territories; angiography may
specificity) show vascular occlusions, stenoses, or typical beading
Progressive multifocal CSF JC virus PCR is incompletely sensitive Confluent and asymmetric T2-hyperintense, T1-
leukoencephalopathy (74-93% sensitivity and 92-100% specificity); hypointense lesions in subcortical white matter,
(PML) serum JC virus antibody index predicts risk subcortical U fibers, corpus callosum, and cerebellar
of PML in patients on natalizumab; peduncles; rare contrast enhancement, more common in
histopathologic triad includes multifocal patients with immune reconstitution inflammatory
demyelination, enlarged oligodendroglial syndrome; patchy diffusion restriction may be seen,
nuclei, and bizarre astrocytes particularly on periphery of active lesions
Cerebral CSF Toxoplasma gondii PCR is incompletely Multifocal more often than single T1-hypointense,
toxoplasmosis sensitive (PCR targeting B1 gene sequence is T2-hyperintense lesions involving the basal ganglia
30-55% sensitive and 100% specific, whereas and corticomedullary junction; ring-enhancing,
PCR targeting repeated sequences [529–base often with an “eccentric target sign” of nodular
pair repeat] improves sensitivity to 80%); enhancement; marked mass effect and
serum T. gondii IgG is highly sensitive but not perilesional edema, often with associated
specific (positive in >90% of affected hemorrhage on SWI
patients, with rates varying based on
seroprevalence)
1070 AUGUST 2021

Entity CSF and serologic diagnostics Imaging characteristics

Cerebral CSF Aspergillus PCR and fungal culture are Strokes involve territories supplied by small
aspergillosis incompletely sensitive (75% sensitivity and perforator vessels (basal ganglia, thalamus, and
98.3% specificity); CSF galactomannan has corpus callosum), sometimes with associated
improved performance (88.2% sensitivity and subarachnoid or parenchymal hemorrhage on SWI;
96.3% specificity); serum galactomannan is abscesses typically have associated ring
highly specific for invasive aspergillosis enhancement and diffusion restriction, sometimes
(50-80% sensitivity, 94% specificity for invasive some hemorrhagic SWI component; rhinosinusitis
aspergillosis); diagnosis is often made by is associated with dural and optic nerve sheath
biopsy enhancement
Nocardia brain Diagnosis is rarely made by CSF bacterial Multifocal or single T1-hypointense, T2-
abscess culture, more often by biopsy or aspiration of hyperintense, diffusion-restricting lesions; thick
abscess with culture, PCR, or genetic wall of ring enhancement with rare meningeal
sequencing enhancement
Listeria meningitis, CSF bacterial culture, Gram stain, and PCR are Abscesses are ring-enhancing, diffusion-
encephalitis, and incompletely sensitive (15-40% sensitivity); restricting, and more often solitary (69%) than
abscesses blood cultures may be positive, but sensitivity multifocal (31%); meningitis is associated with
decreases with antibiotic administration nonspecific leptomeningeal enhancement;
(50-80% sensitivity, 100% specificity for Listeria encephalitis often involves the brainstem, with T2
bacteremia) hyperintensity; neuroimaging is normal in up to half
of cases of encephalitis
Candida meningitis CSF fungal culture may aid in diagnosis of Hydrocephalus is seen in up to 20% of cases;
encephalitis but is less sensitive in cases of typical findings include multiple diffusion-
isolated abscess; Blood cultures and 1,3-β-D- restricting microabscesses in gray-white junction,
glucan may aid in diagnosis (sensitivity of 80%, basal ganglia, and cerebellum, often with a
specificity of 82% for invasive fungal hemorrhagic component on SWI; associated
infections) leptomeningeal enhancement; may have
associated mycotic aneurysms, subarachnoid
hemorrhage, or vasculitic infarcts
Cryptococcal Serum and CSF antigen testing are highly Hydrocephalus common; T1-hypointense,
meningitis sensitive (serum testing has 83-97% T2-hyperintense gelatinous pseudocysts with a
sensitivity, 93-100% specificity for “soap-bubble” appearance commonly involve the
cryptococcal antigenemia); CSF PCR has basal ganglia; nodular leptomeningeal
low sensitivity enhancement particularly involves the basal
meninges; dilated perivascular spaces around
perforating vessels; cryptococcomas are
T1-hypointense and T2-hyperintense lesions with
variable enhancement
Tuberculous Detection of acid-fast bacilli and Hydrocephalus is particularly common in children;

meningitis mycobacterial culture are incompletely basilar meningitis manifests with leptomeningeal
sensitive, and results are often delayed enhancement with basal enhancing exudates;
(sensitivity 10-80% and technique dependent); tuberculomas are nodular or ring-enhancing
Other modalities include PCR-based lesions without associated diffusion restriction;
molecular assay in blood, CSF, or other fluid ischemic strokes seen in 25-50% of cases, often
(60% sensitivity and 100% specificity); periventricular or basal ganglia, may show beading,
diagnosis may require biopsy segmental stenosis, or occlusion of vessels on
angiography
CSF = cerebrospinal fluid; DNA = deoxyribonucleic acid; MRI = magnetic resonance imaging.
a
Data from Ogata M, et al1; Nagel MA, et al2; Anagnostou T, et al3; Garg RK, et al4; and Mylonakis E, et al.5

complications of immunocompromise are presented, covering populations at

risk for each pathogen, clinical presentation, neuroimaging, laboratory diagnosis,
treatment, and prognosis.
IMMUNOCOMPROMISED POPULATIONS
Specific immunocompromised populations, including hematopoietic stem cell
and solid organ transplant recipients and patients with central nervous system
(CNS) demyelinating disease, are each at risk of a distinct array of neurologic
infections and require a tailored approach to evaluation and management.
Hematopoietic Stem Cell and Solid Organ Transplant Recipients

Hematopoietic stem cell and solid organ transplant recipients are at particular
risk of neurologic infections in the setting of both treatment-related
immunocompromise and underlying immunocompromise. This includes
pretransplantation bone marrow ablation with high doses of chemotherapy and
sometimes radiotherapy in hematopoietic stem cell recipients, high-dose
induction immunosuppression in recipients of solid organ transplants, and
subsequent immunosuppressive and immunomodulatory medications to prevent
rejection and GVHD in both populations. Neurologic complications after
transplantation affect as many as 11% to 19% of hematopoietic stem cell
transplant recipients8 and approximately one-third of recipients of solid organ
transplants,9 with variable incidence based on the underlying condition
prompting transplantation, immunosuppressive regimen used, and donor- and
recipient-specific factors. The occurrence of specific infectious and
noninfectious complications also varies based on the time elapsed after
transplant (TABLE 12-310).
In the first month after hematopoietic cell transplantation, patients may
develop pancytopenia as a consequence of pretransplantation conditioning,
immunosuppressive therapy, and while awaiting engraftment, which begins at
2 to 4 weeks after transplantation, with complete recovery at 1 year. Recipients in
this phase are at particular risk of drug-resistant hospital-acquired infections,
donor-derived infections, and reactivation of preexisting latent infections such
as cytomegalovirus (CMV) and other herpesviruses. Between months 2 and
6 after transplant, impaired cellular immunity due to immunosuppressive
therapy and ongoing immune reconstitution puts recipients at risk of opportunistic
pathogens such as Aspergillus and JC virus, although delayed reactivation of CMV
and other herpesviruses can also occur in this timeframe. Among solid organ
transplant recipients, liver transplant recipients, particularly those with fulminant
hepatic failure, often have serious medical problems at the time of their transplant
and may be at higher risk of early CNS infections, whereas heart, intestinal, and
pancreas transplant recipients are chronically immunosuppressed and may be most
prone to late infectious complications.
Solid organ transplant recipients are at particular risk of donor organ–derived
infections, including rabies, West Nile virus, Balamuthia mandrillaris
(granulomatous amebic encephalitis), and lymphocytic choriomeningitis virus;
they are also at risk of CNS fungal infections, most often Cryptococcus but
also endemic mycoses with Histoplasma and Coccidioides depending on
geographic exposures.
The frequency, timing, and morbidity of infectious complications also
differ between solid organ and hematopoietic stem cell transplant recipients.
1072 AUGUST 2021

For instance, the median time to PML occurrence is 27 months after solid KEY POINTS
organ transplantation versus 11 months after hematopoietic stem cell
● Early recognition of
transplantation, with a survival after diagnosis of PML of 6.4 months among infectious and noninfectious
solid organ transplant recipients versus 19.5 months among hematopoietic cell complications of
transplant recipients.11 IRIS, an exuberant and dysfunctional host immunocompromise is
inflammatory response to a recent infection triggered by immune recovery, essential to guide
appropriate treatment,
can involve the CNS in both solid organ and hematopoietic cell transplant
which can include
recipients. In the latter population, CNS IRIS may occur during engraftment, antimicrobial therapy and, in
but it has also been reported later after transplant and even several months some cases, withdrawal of
after discontinuation of immunosuppression. the predisposing medication
with a transition to an
Infections associated with IRIS include those caused by mycobacteria,
alternative regimen.
Cryptococcus neoformans, CMV, JC virus, and Candida.
Early noninfectious neurologic syndromes seen in transplant recipients ● Neurologic complications
include PRES, whereas late noninfectious complications include GVHD, after transplantation affect
which can affect the CNS (eg, mass lesions, cerebral angiitis, optic neuritis, or a as many as 11% to 19% of
hematopoietic stem cell
multiple sclerosis–like relapsing-remitting demyelinating syndrome) and PNS transplant recipients and
(eg, acute inflammatory demyelinating polyradiculoneuropathy or myasthenia approximately one-third of
gravis). solid organ transplant
recipients.
Patients With Central Nervous System Demyelinating Disease
● Among solid organ
The earliest multiple sclerosis therapies, glatiramer acetate and interferons, were transplant recipients, liver
not associated with a significant risk of neurologic infections. However, a host transplant recipients,
of immunomodulatory therapies have been repurposed for the treatment of particularly those with
fulminant hepatic failure,
multiple sclerosis in recent decades, and these carry an increased risk of
often have serious medical
infection. Neurologic infections may be particularly challenging to recognize and problems at the time of their
diagnose in patients with concomitant neurologic disorders because it may be transplant and may be at
difficult to distinguish between the clinical and radiographic features of multiple higher risk of early central
sclerosis and those of an infection. In particular, PML may develop in some nervous system infections,
whereas heart, intestinal,
patients with multiple sclerosis, particularly those on natalizumab, and can share and pancreas transplant
clinical and neuroimaging features with multiple sclerosis. Clinical progression recipients are chronically
may help distinguish between the two; patients with PML typically present with immunosuppressed and may
a slower, progressive symptom onset, with more frequent cognitive and be most prone to late
infectious complications.
behavioral symptoms,12 whereas multiple sclerosis lesions are more likely to
cause focal deficits with short-term recovery following a relapse. Brain MRI in ● Immune reconstitution
patients with PML may also demonstrate larger, more diffuse, and less inflammatory syndrome, an
well-demarcated T2-hyperintense lesions that tend to occupy the juxtacortical exuberant and dysfunctional
host inflammatory response to
areas, with relative sparing of the periventricular region commonly affected in
a recent infection triggered by
multiple sclerosis. Compared with the homogeneous or open-ring enhancement immune recovery, can involve
frequently seen in multiple sclerosis lesions, PML lesions enhance less frequently the central nervous system in
and generally in a sparse peripheral pattern, often in the context of IRIS. both solid organ and
hematopoietic cell transplant
In a comparative study, monosymptomatic presentations were more common
recipients. In the latter
in relapsing-remitting multiple sclerosis than in PML (85% versus 47%).13 On population, central nervous
MRI, large, confluent T2-hyperintense lesions (74% versus 2%) and deep gray system immune reconstitution
matter lesions (31% versus 7%) were more frequent in patients with PML than inflammatory syndrome may
in patients with multiple sclerosis, whereas crescentic cerebellar lesions were occur during engraftment, but
it has also been reported later
seen only in patients with PML. Spinal cord and optic nerve involvement was after transplant and even
seen only in multiple sclerosis, and brainstem involvement was more common in several months after
multiple sclerosis (18% versus 2%). By contrast, patients with PML presented discontinuation of
more often with hemiparesis (24% versus 5%) and altered mentation immunosuppression.
(19% versus 0%).

RITUXIMAB AND OCRELIZUMAB. Rituximab is a chimeric monoclonal antibody that

binds to the CD20 antigen present on all peripheral B cells. It is used to treat
B-cell lymphoma and autoimmune disorders, including neuromyelitis optica,
myasthenia gravis, autoimmune encephalitis, and myositis. Treatment with
rituximab causes a rapid depletion of pre-B cells and mature B cells, which
remain at low or undetectable levels for 2 to 6 months before returning to
pretreatment levels, generally within 12 months. Rituximab may also influence
T-cell immunity and, particularly in the setting of prolonged use, can cause
cytopenias and hypogammaglobulinemia. Rituximab can predispose patients to
Epstein-Barr virus (EBV)-associated primary CNS lymphoma and several
opportunistic CNS pathogens, including Toxoplasma and JC virus. The role of
rituximab in the development of PML remains unclear, given that the majority of
cases are seen in patients with underlying lymphoproliferative or rheumatologic
disorders that may independently predispose patients to JC virus reactivation.
Ocrelizumab, a humanized anti-CD20 monoclonal antibody used in the treatment
TABLE 12-3 Infections in Transplant Recipientsa
Time from
transplant Infectious conditions Noninfectious conditions
Conditioning and Drug-related encephalopathy (busulfan,
infusion etoposide, ifosfamide, methotrexate,
(hematopoietic cell cytarabine), dimethyl sulfoxide (DMSO)-related
transplantation) stroke,b posterior reversible encephalopathy
syndrome (PRES), seizures, low intracranial
pressure after lumbar puncture
<1 Month Cytomegalovirus, human herpesvirus 6,b Engraftment syndromeb; metabolic delirium
neutropenic period Aspergillus, Toxoplasma gondii (organ failure); seizures; PRES (tacrolimusc and
cyclosporine more than sirolimus); other
Donor organ–acquired pathogens: lymphocytic
calcineurin inhibitor complications; parkinsonism
choriomeningitis virus, West Nile virus, rabies,
(amphotericin B); subdural hematoma,
adenovirus, coxsackievirus B4, human T-cell
intracranial hemorrhage, or subarachnoid
lymphotropic virus type 1 (HTLV-I) myelitis
hemorrhage due to coagulopathy
Candida (IV lines)
Nosocomial bacterial sepsis
1–6 Months Aspergillus, human herpesvirus 6,b herpes simplex Acute disseminated encephalomyelitis (ADEM),
virus, progressive multifocal leukoencephalopathy, osmotic demyelination syndrome, immune
Epstein-Barr virus (posttransplantation reconstitution inflammatory syndrome (IRIS),
lymphoproliferative disorder), T. gondii, graft versus host disease (GVHD)
varicella-zoster virus
>6 Months Varicella-zoster virus, cytomegalovirus, progressive Secondary malignancy, disease relapse, Graves
multifocal leukoencephalopathy, Epstein-Barr virus disease, sarcoidosis, demyelination, IRIS, GVHD
(posttransplantation lymphoproliferative disorder), (polymyositis, myasthenia, chronic inflammatory
Aspergillus, Mucoraceae demyelinating polyradiculoneuropathy [CIDP])
a
Reprinted with permission from Pruitt AA, Continuum (Minneap Minn).10 © 2018 American Academy of Neurology.
b
Predominantly in hematopoietic cell transplantation recipients.
c
Numerous complications are associated with tacrolimus not necessarily related to level and at any time after transplantation, including akinetic
mutism, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), demyelinating optic neuropathy, and delayed leukoencephalopathy.
1074 AUGUST 2021

of multiple sclerosis, has also been associated with PML, primarily in KEY POINTS
patients previously treated with rituximab, fingolimod, or natalizumab,
● On MRI, large, confluent
although a case of ocrelizumab-associated PML was described in 2020 in the T2-hyperintense lesions
setting of lymphopenia in a patient with primary progressive multiple sclerosis and deep gray matter
who had not received previous immunomodulatory or immunosuppressive lesions were more frequent
medication.14 in patients with
progressive multifocal
leukoencephalopathy (PML)
NATALIZUMAB. First introduced in 2005 as a promising therapy for multiple than in patients with
sclerosis, natalizumab is a monoclonal antibody that blocks leukocyte passage multiple sclerosis, whereas
across the blood-brain barrier by inhibiting α4 integrin. In the years since it was crescentic cerebellar
lesions were seen only in
introduced, roughly 4.2 cases of PML have been identified for every 1,000
patients with PML.
treated patients, with a survival rate of 70% to 75%.15 Risk factors for the
development of PML in patients on natalizumab include elevated serum levels of ● Ocrelizumab, a
anti–JC virus antibodies, the use of immunosuppressant or immunomodulatory humanized anti-CD20
therapies before natalizumab initiation, and the duration of natalizumab monoclonal antibody used in
the treatment of multiple
treatment, with a median time from treatment initiation to onset of PML sclerosis, has also been
symptoms of 25 months.16 PML can also occur up to 6 months after cessation of associated with PML,
natalizumab, and cessation of natalizumab may be associated with the primarily in patients
development of PML-IRIS (discussed in greater depth in the later section titled previously treated with
rituximab, fingolimod, or
“Progressive Multifocal Leukoencephalopathy”). natalizumab, although a
Monitoring for PML in patients on natalizumab should consist of brain MRI case of ocrelizumab-
every 12 months and serologic JC virus monitoring every 6 months. Alternative associated PML was
therapies are preferred in patients who are seropositive for anti–JC virus described in 2020 in the
setting of lymphopenia in a
antibodies, in whom the risk of PML is estimated at 1 in 932 in the first 24 months patient with primary
(1 in 330 if the patient has received prior immunosuppressive treatment; 1 in 1375 progressive multiple
if the patient has not received prior immunosuppressive treatment) and 1 in 88 sclerosis who had not
beyond 24 months (1 in 31 if the patient has received prior immunosuppressive received previous
immunomodulatory or
treatment; 1 in 129 if the patient has not received prior immunosuppresive
immunosuppressive
treatment).17 The anti–JC virus antibody index compares the titer of anti–JC medication.
virus antibodies in serum to a standard control serum and may also be used for
monitoring patients who seroconvert during natalizumab treatment. With an ● Risk factors for the
anti–JC virus antibody index of less than 0.9 in a patient who has not received development of PML in
patients on natalizumab
prior immunosuppressive or immunomodulatory therapies, the estimated risk of include elevated serum
developing PML is less than 1 in 10,000 within the first 24 months of natalizumab levels of anti–JC virus
therapy and 1 in 748 beyond 24 months.17 In patients who have an anti–JC virus antibodies, the use of
antibody index of 0.9 or greater and have not received prior immunosuppressive immunosuppressant or
immunomodulatory
or immunomodulatory therapies, natalizumab should be discontinued in favor of therapies before
an alternative disease-modifying therapy at 24 months because of the increasing natalizumab initiation, and
risk of PML (estimated at 1 in 1062 in the first 24 months, but 1 in 101 beyond the duration of natalizumab
that period).17 treatment, with a median
time from treatment
In addition to PML, cases of varicella-zoster virus (VZV) encephalitis and initiation to onset of PML
herpes simplex virus (HSV) meningitis have been reported in patients treated symptoms of 25 months.
with natalizumab.
ECULIZUMAB. Eculizumab is a monoclonal antibody against the complement

component C5 that was first approved for the treatment of hematologic disorders
in 2007 and is now used to treat neuromyelitis optica. Eculizumab treatment
carries a particular risk of infection with encapsulated organisms such as Neisseria
meningitidis. Although meningococcal vaccination is recommended for all
patients before initiating eculizumab, infections with nontypable strains not

included in the vaccine have been reported in vaccinated patients, and antibiotic
prophylaxis with penicillin or a macrolide is warranted for the duration of therapy.18
ALEMTUZUMAB. Alemtuzumab binds CD52 and significantly depletes B cells,

T cells, natural killer cells, and monocytes. Treatment with alemtuzumab carries a risk
of both autoimmune conditions and opportunistic CNS infections with herpesviruses,
Listeria, and Nocardia. Acyclovir prophylaxis for 1 month after treatment is warranted
to prevent herpesvirus reactivation. Although acyclovir prophylaxis was found to
reduce the incidence of herpetic infections during the first month after treatment,
HSV and VZV infections have been reported in patients on alemtuzumab despite
prophylaxis (4.9% without prophylaxis versus 0.5% with prophylaxis after the first
course of the drug and 2.4% versus 0.8% after the second).19
OTHER DISEASE-MODIFYING THERAPIES. Cases of shingles, herpesvirus vasculitis and

encephalitis, and cryptococcal meningoencephalitis, including fatalities, have
been reported in patients treated with fingolimod. Herpesvirus infections have
not been reported in patients treated with siponimod, a sphingosine-1-phosphate
receptor modulator that is thought to act more selectively than fingolimod.20
VZV immune status should be checked before initiation of fingolimod therapy;
VZV vaccination is recommended in at-risk patients, and patients on either
fingolimod or dimethyl fumarate should be monitored closely for the
development of lymphopenia. Although treatment with natalizumab confers the
highest risk of development of PML among disease-modifying therapies for
multiple sclerosis, PML has also been reported in patients on dimethyl fumarate,
particularly those with moderate or severe lymphopenia,21 and in 15 patients on
fingolimod.22 Alternative disease-modifying therapy should be considered in
patients who are anti–JC virus antibody positive who develop lymphopenia,
particularly those with a high anti–JC virus antibody index.
EVALUATION AND MANAGEMENT OF SPECIFIC INFECTIOUS SYNDROMES

Patients who are immunocompromised are at risk of a range of neuroinfectious
syndromes, including meningitis, encephalitis, focal brain lesions, and spinal
infectious complications.
Meningitis
Patients who are immunocompromised are at risk of both common bacterial
pathogens and other causes of meningitis, representing one-fourth of patients
with Streptococcus pneumoniae bacterial meningitis. Transplant recipients and
others with impaired cell-mediated immunity are at risk of fungal and
mycobacterial meningitis.23 For additional guidance on the evaluation and
management of meningitis in patients who are immunocompetent, refer to the
article “Meningitis” by Allen Aksamit, MD, and Aaron L. Berkowitz, MD, PhD,24
in this issue of Continuum.
CRYPTOCOCCUS. C. neoformans is a fungal species that can cause meningitis in the

posttransplant setting and in other patients with defects in cell-mediated
immunity, including those on steroids, fingolimod, or TNF-α inhibitors or in
those with underlying autoimmune diseases (CASE 12-1).
Clinical manifestations of cryptococcal infection may vary depending on
degree and type of immunocompromise; however, headache may be the initial
1076 AUGUST 2021

symptom in as many as 86.1% of patients, and nausea, vomiting, and fever are KEY POINTS
also frequently seen.26 Other clinical manifestations of cryptococcal meningitis
● In patients who have an
include cranial nerve abnormalities, meningismus, visual changes, and other anti–JC virus antibody index
symptoms associated with elevated intracranial pressure. Pulmonary involvement, of 0.9 or greater,
dermatologic manifestations, and positive blood cultures may provide a clue natalizumab should be
regarding the diagnosis of meningitis in patients with disseminated cryptococcosis. discontinued in favor of an
alternative disease-
Brain MRI is often normal but may reveal abnormal findings such as
modifying therapy at
leptomeningeal enhancement, ventricular dilatation, ependymal or choroidal 24 months because of the
enhancement, strokes, and dilated perivascular spaces. In some cases, dilated increasing risk of PML.
perivascular spaces can coalesce into gelatinous pseudocysts with a “soap
bubble” appearance, most often involving the basal ganglia. Patients may also ● Although meningococcal
vaccination is
develop parenchymal space-occupying intracranial lesions called recommended for all
cryptococcomas. Cryptococcal meningitis often causes elevated intracranial patients before initiating
pressure and hydrocephalus even in the absence of such space-occupying lesions. eculizumab, infections with
Diagnosis of cryptococcal meningitis is typically established via lumbar nontypable strains not
included in the vaccine have
puncture, which demonstrates elevated opening pressure, hypoglycorrhachia, been reported in vaccinated
lymphocytic pleocytosis, and elevated total protein; in rare cases, CSF may be patients, and antibiotic
normal. The gold standard for diagnosis has traditionally been the isolation of C. prophylaxis with penicillin
neoformans in fungal culture, although sensitivity is variable depending on the or a macrolide is warranted
for the duration of therapy.
stage of infection and volume of CSF, and diagnosis may be delayed for more
than 7 days. India ink staining has been largely supplanted by serum and CSF ● Treatment with
cryptococcal antigen, which has sensitivity and specificity greater than 97%.25 alemtuzumab carries a risk
Much of the morbidity and mortality associated with cryptococcal of both autoimmune
conditions and
meningoencephalitis result from the increased intracranial pressure, and
opportunistic central
worsened headache or other symptoms should prompt consideration of repeat nervous system infections
imaging, possible repeat lumbar puncture, and, in refractory cases, CSF with herpesviruses, Listeria,
diversion. Treatment of cryptococcal meningitis is typically amphotericin B and and Nocardia.
flucytosine for at least 2 weeks followed by fluconazole maintenance therapy; a
longer duration of maintenance therapy may be considered in patients who are immunocompromised
heavily immunosuppressed. Prognosis after cryptococcal meningitis varies based represent one-fourth of
on population; mortality may be particularly high in patients with an underlying patients with
malignancy, with one study reporting a median survival of 2 months in patients Streptococcus pneumoniae
bacterial meningitis, and
with cancer compared with 9 months in patients with acquired immunodeficiency transplant recipients and
syndrome (AIDS).27 Among solid organ transplant recipients, survival at 6 months others with impaired
was lower in patients who had persistently positive CSF fungal cultures at 2 weeks, cell-mediated immunity are
and relapse after treatment was documented in just 1 of 79 patients.28 at risk of fungal and
mycobacterial meningitis.
TUBERCULOSIS. Posttransplant status and treatment with immunomodulatory ● India ink staining has been
medications, particularly TNF-α inhibitors, are significant risk factors for the largely supplanted by serum
development of tuberculous meningitis as a result of either reactivation or new and CSF cryptococcal
infection. The most common presenting clinical features of tuberculous antigen, which has
sensitivity and specificity
meningitis include headache (50% to 80%), fever (60% to 95%), neck stiffness greater than 97%.
(40% to 80%), cranial nerve palsies (30% to 50%), coma (30% to 60%),
seizures (5% to 50%), and confusion (10% to 30%).29 Tuberculous exudates ● Ischemic strokes are a
cause CSF obstruction and hydrocephalus, leading to compression of cranial significant cause of
long-term morbidity in
nerves as they leave the brainstem. Cranial nerve VI is most commonly tuberculous meningitis and
affected (30% to 40%), followed by cranial nerves VII (10% to 20%) and III affect 25% to 50% of
(5% to 15%).29 Hyponatremia attributable to cerebral salt wasting or syndrome of infected patients.
inappropriate secretion of antidiuretic hormone (SIADH) occurs in 40% to
50% of patients with tuberculous meningitis.30 Ischemic strokes are also a

CASE 12-1 A 45-year-old woman presented with 2 months of nausea and headaches.
She had a history of granulomatosis with polyangiitis and was on
prednisone and cyclophosphamide. Her vital signs were remarkable for
an elevated temperature of 39.3°C (102.7°F). During her hospitalization,
she developed acute-onset left-sided weakness, with neurologic
examination demonstrating left face, arm, and leg weakness and
left-sided hemisensory loss to pinprick and temperature.
Brain MRI (FIGURES 12-1A and 12-1B) showed multiple foci of restricted
diffusion involving the bilateral corona radiata, left insular gyrus, right
temporal lobe, and posterior limb of the right internal capsule, whereas
magnetic resonance angiography (MRA) of the brain (FIGURE 12-1C)
demonstrated a “beaded” appearance of the bilateral middle cerebral
arteries, posterior cerebral arteries, and anterior cerebral arteries in the
setting of multifocal narrowing.
CSF analysis revealed an opening pressure of 18 cm H2O, an elevated
protein of 422 mg/dL, hypoglycorrhachia of 12 mg/dL, and a positive
cryptococcal antigen with a corresponding positive serum cryptococcal
antigen. She was treated with liposomal amphotericin and flucytosine.
FIGURE 12-1
Stroke secondary to cryptococcal meningitis. Brain MRI (A and B) shows multiple foci of
restricted diffusion involving the bilateral corona radiata, left insular gyrus, right temporal
lobe, and posterior limb of the right internal capsule, whereas magnetic resonance
angiography (MRA) of the head (C) demonstrates a “beaded” appearance of the bilateral
middle cerebral arteries, posterior cerebral arteries, and anterior cerebral arteries.
COMMENT Ischemic stroke is a common complication of cryptococcal

meningoencephalitis in patients who are immunocompromised. Lumbar
puncture typically demonstrates an elevated opening pressure and often
reveals hypoglycorrhachia, lymphocytic pleocytosis, and elevated total
protein, although in rare cases, CSF may be normal. Diagnosis is established
via serum and CSF cryptococcal antigen testing, which have sensitivities
and specificities greater than 97%.25
1078 AUGUST 2021

significant cause of long-term morbidity in tuberculous meningitis and affect
25% to 50% of infected patients.31,32 Basal ganglia infarctions are particularly
common and may manifest with movement disorders such as tremor, chorea,
or dystonia.33
Neuroimaging findings particularly suggestive of tuberculous meningitis
include hydrocephalus, basal meningeal exudates, periventricular infarcts, and
nodular or rim-enhancing lesions representing tuberculomas.4 CSF sampling
reveals an elevated opening pressure in more than 50% of patients, a lymphocytic
pleocytosis (although cell count may rarely be normal in patients with severe
immunosuppression), hypoglycorrhachia, and elevated protein levels. Specific
diagnostic tests include large-volume CSF microscopy with identification of
acid-fast bacilli on a stained smear or M. tuberculosis growing in cell culture, as
well as polymerase chain reaction (PCR)-based molecular assays. Cell culture
and acid-fast bacilli smear performance characteristics are variable depending on
the quality and size of the sample as well as laboratory expertise. The CSF
molecular assays are more readily available as point-of-care tests and have
excellent specificity but variable sensitivity.34,35 Standard management of
tuberculous meningitis consists of rifampicin, isoniazid, pyrazinamide, and
ethambutol, consideration of adjunctive steroids, and surgical measures to treat
hydrocephalus, if present. However, treatment of CNS tuberculosis in transplant
recipients is especially challenging because many antituberculosis medications
interact with immunosuppressive agents.36 Rifampicin may accelerate the
metabolism of cyclosporine, tacrolimus, and corticosteroids and can lead to
allograft rejection and higher mortality, whereas isoniazid and rifampin can both
lead to hepatotoxicity, which is of particular concern in liver transplant
recipients.37 Rifabutin is a less potent cytochrome P450 inducer and may be used
as an alternative to rifampicin in patients on calcineurin inhibitors.37 Mortality
from tuberculosis in transplant recipients is high, ranging from 13% to 40%.38
For further discussion of tuberculosis, refer to the article “Neurologic
Complications of Tuberculosis” by Deanna Saylor, MD, MHS,39 in this issue of
Continuum.
LISTERIA. L. monocytogenes is a foodborne gram-positive facultative intracellular

bacterium that is one of the few causes of bacterial meningitis to preferentially
affect patients who are immunocompromised. Significant risk factors for Listeria
infection include advanced age, malignancy (particularly hematologic
malignancy), transplantation, alcohol use disorder or liver disease, autoimmune
conditions, and immunocompromise with TNF-α inhibitors, steroids, or
alemtuzumab. The most common presenting symptoms of Listeria meningitis
are fever (91% to 100%), altered mental status (64% to 87%), and headache
(45% to 87%).5,40 Focal neurologic signs, seizures, brainstem or cerebellar
involvement (rhombencephalitis), and cerebrovascular complications including
hemorrhage or ischemia may also be seen.5,40 Listeria also rarely causes brain
abscesses, particularly in immunocompromised hosts. Blood cultures are key to
the diagnosis because bacteremia is seen in up to 80% of patients with Listeria,
compared with just 11% of patients with other etiologies of brain abscess.41
Neuroimaging is normal in up to half of cases. In the remaining cases, imaging
is variable and depends on the manifestation of infection, which can include
cerebral abscesses, meningitis, meningoencephalitis, or rhombencephalitis
(more often seen in patients who are immunocompetent).5 CSF profiles in

patients with Listeria meningitis are similar to the profiles found in other patients
with bacterial meningitis, with prominent polymorphonuclear pleocytosis
(greater than 100 cells/mm3), elevated total protein, and hypoglycorrhachia,
although the pleocytosis and hypoglycorrhachia may be less pronounced than
with other etiologies of bacterial meningitis. Diagnosis is established via CSF
Listeria PCR or culture, or by blood cultures with a compatible CSF profile
and clinical picture; Gram stain has low sensitivity. Treatment consists of
ampicillin or penicillin in conjunction with gentamicin, although trimethoprim-
sulfamethoxazole may be used in patients on cyclosporine or other nephrotoxic
medications who cannot tolerate aminoglycosides.42 The duration of therapy
should be prolonged in patients who are immunocompromised, with at least
FIGURE 12-2
Cytomegalovirus ventriculoencephalitis. Axial T1-weighted (A) and T2-weighted
(B) MRI sequences show mild ventricular dilatation and multiple tiny nodular T2 high-signal-
intensity lesions in the basal ganglia and right frontal subcortical white matter. C, Axial
fluid-attenuated inversion recovery (FLAIR) image shows thin curvilinear high signal
intensities along the walls of both lateral ventricles and multifocal faint high signal
intensities at right frontal and basal ganglia regions. D, Axial postcontrast T1-weighted
image shows subtle subependymal enhancement (arrow). E and F, Diffusion-weighted
images show striking curvilinear high signal intensities along the ventricular wall with a
subtle low apparent diffusion coefficient value (F, arrows).
Reprinted with permission from Seok JH, et al, Br J Radiol.47 © 2011 The British Institute of Radiology.
1080 AUGUST 2021

4 to 8 weeks of therapy in patients with meningitis and longer durations in KEY POINTS
patients with CNS abscesses, and immunosuppressive medications should be
● Infectious etiologies of
decreased if possible. Neuroimaging can be used to monitor for improvement encephalitis unique to
and to guide the duration of therapy. patients who are
The prognosis of CNS listeriosis is worse in patients who are immunosuppressed include
immunocompromised. In a nationwide prospective observational cohort study in viruses such as
cytomegalovirus, human
France, 3-month mortality after CNS listeriosis was 30%, with underlying cancer
herpesvirus 6, BK virus, and
or cytopenias increasing the greatest risk of mortality.42 Neurologic sequelae are varicella-zoster virus.
common among survivors.43,44
● In patients who do not
Encephalitis respond to antiviral therapy,
transplant guidelines
Encephalitis is characterized by inflammation of the brain parenchyma due to regarding general
infectious or immune-mediated conditions. Patients typically present with fever, management of
altered mental status, seizures, or focal neurologic signs such as aphasia. cytomegalovirus infection
For an in-depth discussion of encephalitis, refer to the article “Encephalitis and suggest that dose reduction
of immunosuppressive
Brain Abscess” by Arun Venkatesan, MD,45 in this issue of Continuum; unique therapies may be beneficial.
considerations in patients who are immunocompromised are discussed here.
For many patients with encephalitis, no definitive diagnosis is ever
established. Infectious etiologies of encephalitis unique to patients who are
immunosuppressed include viruses such as CMV, human herpesvirus
6 (HHV-6), BK virus, and VZV.
CYTOMEGALOVIRUS. CMV encephalitis presents in those with severe or

protracted immunodeficiency, such as transplant recipients within months of
their transplant. Symptoms are variable but typically include subacute cognitive
changes over weeks, sometimes accompanied by cranial nerve palsies, ataxia,
and other focal neurologic deficits. CMV encephalitis may occur in conjunction
with CMV-associated colitis, esophagitis, or retinitis. CMV viremia, routinely
assessed in the posttransplant population, has been identified as a risk factor
for the development of CMV encephalitis.46 CMV encephalitis may cause a
ventriculoencephalitis or ventriculitis, characterized by periventricular
subependymal and ependymal enhancement (FIGURE 12-247), but it has
also been described in association with diffuse, nonspecific T2-hyperintense
lesions throughout the hippocampus, brainstem, basal ganglia, and cerebellum
with occasional rim enhancement. Focal mass lesions are rare but have also been
reported.46,48,49 CSF findings are typically nonspecific but may include
mononuclear or polymorphonuclear pleocytosis, elevated total protein, and
rarely hypoglycorrhachia, which has also been infrequently described in patients
with other CNS herpesvirus infections.50,51 Diagnosis is confirmed by
identification of CMV DNA in the CSF by PCR.
Existing guidelines for CMV treatment in both solid organ and hematopoietic
stem cell transplant recipients do not specifically address the management of
CMV encephalitis,52,53 and much of the existing data on CMV encephalitis come
from literature on AIDS. Guidelines for the treatment of CMV encephalitis in
patients with AIDS suggest the use of either ganciclovir or foscarnet, with
consideration of cidofovir in patients who cannot tolerate either medication and
combined therapy in patients who have previously been treated with antivirals.54
This approach is recommended both because of the possibility of resistant
infection and to overcome decreased drug levels in the CSF due to inconsistent
blood-brain barrier penetration.55 In patients who do not respond to antiviral

therapy, transplant guidelines regarding general management of CMV

infection suggest that dose reduction of immunosuppressive therapies may be
beneficial.56,57 In solid organ transplant recipients with hypogammaglobulinemia
and recurrent CMV infection after treatment, IV immunoglobulin (IVIg) may be
beneficial for some patients.58-60 After infection, prophylaxis with valganciclovir
is warranted in patients who remain on immunosuppression. Case reports also
describe the use of donor CMV-specific cytotoxic T lymphocytes to treat
drug-resistant CMV encephalitis, although the data are limited regarding
the utility of this approach.61 Although the incidence of CMV encephalitis in
patients who are immunocompromised has been reduced in the setting of
ganciclovir prophylaxis, the mortality remains high because of antiviral
drug resistance and reduced efficacy of antiviral therapy due to poor CSF
penetration.61
HUMAN HERPESVIRUS 6. HHV-6 reactivation in the posttransplant population may

present with a classic limbic encephalitis, also sometimes called posttransplant acute
limbic encephalitis (PALE). Although HHV-6 encephalitis has been rarely described
in solid organ transplant recipients,62,63 reactivation of HHV-6 primarily affects
stem cell transplant recipients, with higher rates in human leukocyte antigen–
mismatched unrelated donor recipients and cord blood recipients.1 PALE
typically presents 2 to 6 weeks after transplantation and is often associated with
amnesia, headaches, confusion, seizures, and subclinical epileptic abnormalities,
as well as either hyponatremia or, more rarely, hypernatremia. Brain MRI may
show abnormalities of the bilateral medial temporal lobes, including diffusion
restriction and subsequent T2/fluid-attenuated inversion recovery (FLAIR)
hyperintensities without contrast enhancement (FIGURE 12-364). Hippocampal
atrophy may develop several weeks after the initial infection.
Diagnosis is typically made by positive CSF HHV-6 PCR, and often an
associated mild lymphocytic pleocytosis is present. CSF HHV-6 PCR has a
sensitivity of greater than 95% in patients with PALE.65 However, estimates
of specificity vary, with some evidence suggesting that it may also be detected
in the CSF of between 0.9% and 30% of transplant recipients without
encephalitis.66,67
HHV-6 encephalitis in transplant recipients is treated with foscarnet or
ganciclovir. Patients whose condition worsens on monotherapy may be switched
from foscarnet to ganciclovir or vice versa, with consideration of combination
therapy in severe cases for patients who do not improve. Cidofovir may be
used in patients who cannot tolerate or do not respond to these agents. A
CSF HHV-6 viral load can be rechecked in patients with ongoing symptoms and
may help guide the duration of therapy. Given the involvement of the limbic
system and the possibility of electrolyte depletion secondary to foscarnet
therapy, patients with PALE are at high risk of seizures, and clinicians should
maintain a low threshold for EEG monitoring. Levetiracetam is often favored
for antiepileptic therapy in these patients to avoid interactions with other
medications included in the posttransplant regimen, and electrolytes should
be monitored and repleted in patients on foscarnet to reduce the risk of
seizure.
Outcomes after HHV-6 encephalitis are variable, with a mortality rate of 10%
to 25% within the first month of symptoms and persistent neurologic dysfunction
observed in more than half of survivors.68-70
1082 AUGUST 2021

KEY POINTS
● Although the incidence

of CMV encephalitis
in patients who are
immunocompromised has
been reduced in the setting
of ganciclovir prophylaxis,
the mortality remains high
because of antiviral drug
resistance and reduced
efficacy of antiviral therapy
due to poor CSF
penetration.
● Human herpesvirus 6
reactivation in the
posttransplant population
may present with a classic
limbic encephalitis, also
sometimes called
posttransplant acute limbic
encephalitis.
● Given the involvement of

the limbic system and the
possibility of electrolyte
depletion secondary to
foscarnet therapy, patients
with posttransplant acute
FIGURE 12-3
limbic encephalitis are at
Posttransplant acute limbic encephalitis. Coronal fluid-attenuation inversion recovery (FLAIR)
high risk of seizures, and
MRI demonstrates the focality of human herpesvirus 6–associated encephalitis, which can
clinicians should maintain a
be traced bilaterally from the uncus through the hippocampal body and into the fornix. The
low threshold for EEG
amygdala is partly affected, and the parahippocampal gyrus is conspicuously spared.
monitoring.
Reprinted with permission from Seeley WW, et al, Neurology.64 © 2007 American Academy of Neurology.
BK VIRUS. BK virus is a ubiquitous polyomavirus most commonly associated with

posttransplant polyomavirus-associated nephropathy or hemorrhagic cystitis in
renal transplant recipients. It can also reactivate in patients who are
immunocompromised and cause meningoencephalitis, which has been described
in solid organ transplant recipients, stem cell transplant recipients, and a small
number of patients who are immunocompetent without a clear predisposing
condition. Brain MRI may be normal or show nonspecific T2/FLAIR
hyperintensities, and CSF studies may show a mild pleocytosis. BK virus
encephalitis is typically diagnosed via CSF PCR testing for BK virus and may
occur without associated viremia.
No guidelines have been published regarding the treatment of BK virus
encephalitis in patients who are immunocompromised. Agents including IVIg,
leflunomide, and cidofovir have been used with variable results, and reduction of
immunosuppression may be beneficial.71-73 Mortality after BK virus encephalitis
is high; a review of 13 cases of BK virus encephalitis in the literature in which
outcome was reported found that eight patients died as a result of the disease.74
VARICELLA-ZOSTER VIRUS. VZV

encephalitis affects a range of patients who are
immunocompromised, including transplant recipients, patients with

hematologic malignancies, and patients with rheumatologic diseases who are on

high-dose steroids or other immunosuppressive medications. Clinical
presentations of VZV encephalitis are heterogeneous, and the syndrome may
present with concomitant cerebellitis, cranial neuropathies, meningitis, myelitis
(discussed in greater depth in the paragraph about VZV in the later section titled
“Myelopathy and Radiculopathy”), or vasculopathy.
People who are immunocompromised are at a significantly higher risk of
developing VZV vasculopathy, which should be considered in any patient with
recurrent strokes who is immunocompromised. VZV vasculopathy can affect
both large and small cerebral arteries, leading to transient ischemic attacks,
ischemic strokes, or, more rarely, dissections, aneurysms, cerebral venous sinus
thrombosis, and hemorrhages due to direct viral infection of cerebral
vasculature. In those who are immunocompromised, VZV vasculopathy more
often affects small vessels, whereas in older patients who are immunocompetent,
it typically causes a large vessel vasculopathy several weeks after trigeminal
zoster.75 On MRI, VZV-related infarctions may involve the gray or white
matter and are atypical-appearing in that they favor the gray-white matter
junction, may involve multiple vascular territories, and are frequently
contrast-enhancing. Angiography may show vascular occlusions, stenoses,
or the typical beading appearance of vasculitis. However, in cases with
predominant involvement of small vessels, angiography may be normal.
Diagnosis of CNS VZV is established via abnormal imaging findings and
detection of CSF VZV IgG antibodies, with an increased CSF to serum
VZV IgG ratio. VZV DNA in the CSF is highly specific and helpful if positive but has
only 30% sensitivity in patients with isolated vasculopathy.75 Other criteria
supportive of this diagnosis include CSF pleocytosis (although only seen in
67% in a retrospective study of 30 patients), a preceding rash (seen in 63%, and
often many months before strokes), and abnormalities such as narrowing or
beading on angiography (seen in 70%).2 Patients who are immunocompromised do
not have significantly different rates of pleocytosis, rash, or angiographic
abnormalities compared with those who are immunocompetent.2,75,76
Typically, IV acyclovir is used in the treatment of VZV vasculitis or encephalitis,
often with a short course of oral corticosteroids with the goal of reducing vascular
inflammation. In a study of both immunocompromised and immunocompetent
patients with any neurologic manifestation of VZV, severe and multisite disease was
more common in those who were immunocompromised, but mortality was not
affected by immunologic status and was generally low, with death occurring in 3%
of the cohort overall, complete neurologic recovery occurring in 71%, and persistent
neurologic symptoms seen in 24%.77
Focal Brain Lesions

The differential diagnosis for infectious focal brain lesions in patients who are
immunocompromised is broad, including PML, toxoplasmosis, EBV-associated
lymphoproliferative disorders, and abscesses with microbiology unique to this
population.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. PML is an opportunistic

infection caused by reactivation of latent JC virus in patients who are
immunocompromised, resulting in an infection of oligodendrocytes. PML was
first reported in 1958 in a patient with chronic lymphocytic lymphoma.78 By 1982,
1084 AUGUST 2021

the syndrome had been characterized in patients infected with HIV,79 and in KEY POINTS
2005, PML was first reported in patients treated with natalizumab.80,81 More
● Clinical presentations of
recently, PML has been reported in association with underlying rheumatologic varicella-zoster virus
diseases, lymphoreticular malignancies, and both solid organ and hematopoietic encephalitis are
cell transplantation, as well as a host of medications in addition to natalizumab, heterogeneous, and the
including dimethyl fumarate, fingolimod, rituximab, cyclophosphamide, syndrome may present with
concomitant cerebellitis,
methotrexate, mycophenolate mofetil, adalimumab, and cyclosporine. PML
cranial neuropathies,
usually progresses subacutely over weeks to months and may present with meningitis, myelitis, or
cognitive or personality changes, aphasia, weakness or sensory changes, seizures, vasculopathy.
or ataxia.12 Visual processing deficits including homonymous hemianopia, visual
agnosia, visual hallucinations, hemineglect, and other visuospatial deficits may ● In patients who are
immunocompromised,
be the presenting symptom in 20% of patients with PML and occur at some point varicella-zoster virus
during the disease in up to half of patients with PML.82 vasculopathy more often
On neuroimaging, PML lesions are typically large, confluent, and asymmetric. affects small vessels,
They most often involve the subcortical white matter and are T2 hyperintense whereas in older patients
who are immunocompetent,
and T1 hypointense (CASE 12-2). They classically lack mass effect and may it typically causes a large
not contrast enhance, although punctate contrast enhancement has been vessel vasculopathy several
described, and PML-IRIS may also be associated with enhancement. The cerebellar weeks after trigeminal
peduncles and deep gray matter may also be affected. The diagnosis of PML is zoster.
established when characteristic MRI findings are supported by positive CSF JC virus
● Varicella-zoster virus
PCR or histopathology. In some patients who are immunocompromised, JC virus DNA in the CSF is highly
may cause a granule cell neuronopathy, characterized by infection of the granule specific and helpful if
cells of the cerebellum and presenting with slowly progressive cerebellar atrophy positive, but it has only 30%
sensitivity in patients with
without white matter lesions.83 Although this entity was first described in patients
isolated vasculopathy.
with HIV, it has since been reported in patients who are iatrogenically
immunocompromised, including those with myelofibrosis who are receiving ● Visual processing deficits
ruxolitinib and a patient with systemic lupus erythematosus on methotrexate, including homonymous
corticosteroids, and hydroxychloroquine.83-85 hemianopia, visual agnosia,
visual hallucinations,
Immune reconstitution through reduction or discontinuation of hemineglect, and other
immunosuppressive medications is the mainstay of treatment of PML, visuospatial deficits may be
with some reports in the literature describing favorable outcomes and others the presenting symptom in
reporting complications such as organ rejection in transplant recipients. 20% of patients with PML
and occur at some point
In patients with natalizumab-associated PML, natalizumab should be during the disease in up to
immediately discontinued on the development of PML. Although the use of half of patients.
plasmapheresis has been reported to eliminate circulating natalizumab because
of its long duration of action, a review of published natalizumab-associated PML ● In some patients who are
immunocompromised, JC
cases that compared patients who received plasmapheresis with those who did
virus may cause a granule
not found no improvement in mortality or other outcomes.86 Patients who cell neuronopathy,
discontinue or reduce immunosuppressive medications are at risk of developing characterized by infection
PML-IRIS, particularly patients on natalizumab, who can develop the syndrome of the granule cells of the
weeks or even months after discontinuing natalizumab. Early high-dose cerebellum and presenting
with slowly progressive
corticosteroid therapy followed by a prolonged taper may be beneficial in cerebellar atrophy without
these patients.87,88 white matter lesions.
Other medications that have been used anecdotally for PML or on the basis of
theoretical or in vitro efficacy include cytarabine, cidofovir, topotecan,
mirtazapine, and mefloquine, none of which has been demonstrated to have
clinical benefit.89 Early, small reports have suggested favorable outcomes in
patients treated with immune checkpoint inhibitors such as pembrolizumab or
nivolumab and in those treated with virus-specific cytotoxic T cells.90,91 These
therapies remain under ongoing investigation.

Outcomes after PML vary based on the etiology of underlying

immunocompromise. In a review of 107 cases of PML in patients with
hematologic malignancies treated with either chemotherapy or hematopoietic
stem cell transplant, transplant recipients had a lower mortality rate (56% versus
88%) and a longer median survival (8 months versus 2 months), with favorable
outcomes attributed to immune reconstitution among transplant recipients
whose immunosuppressive therapies are reduced or discontinued.92 Studies
of natalizumab-associated PML report a survival rate of 70% to 80% at
CASE 12-2 A 47-year-old man presented with dysphagia and falls. He had a history
of pulmonary sarcoidosis in remission and was not taking immunotherapy.
He had previously been treated with corticosteroids 10 years before
presentation. His neurologic examination revealed dysarthria, bilateral
dysmetria of the upper and lower extremities, bilateral
dysdiadochokinesia, and a wide-based, ataxic gait.
Brain MRI revealed T2/fluid-attenuated inversion recovery (FLAIR)
hyperintensities of the bilateral cerebellar peduncles, extending into
the cerebellar hemispheres and sparing the dentate nuclei (FIGURE 12-4A),
with associated T1 hypointensity (FIGURE 12-4B), as well as extensive
asymmetric, confluent supratentorial T2/FLAIR hyperintensities
(FIGURES 12-4C and 12-4D). No enhancement was seen after contrast
administration. CSF revealed a positive JC virus polymerase chain
reaction (PCR).
COMMENT In addition to immunosuppressive and immunomodulatory medications

such as natalizumab, progressive multifocal leukoencephalopathy (PML)
has been reported in patients with sarcoidosis and other systemic
rheumatologic conditions without immunomodulatory or
immunosuppressive therapies. The diagnosis of PML is established via
compatible brain MRI findings with typical neuropathologic findings or CSF
JC virus PCR positivity.
1086 AUGUST 2021

6 months, although the majority of survivors may have moderate to severe
disability.10,93
TOXOPLASMA. Caused by the parasite Toxoplasma gondii, toxoplasmosis is seen in

both solid organ and hematopoietic stem cell transplant recipients. Clinical
manifestations include headache, fever, seizures, confusion, and focal neurologic
signs, particularly weakness. T. gondii also has a predilection for the basal
ganglia and may cause hyperkinetic movement disorders.
FIGURE 12-4
Brain MRI from the patient in CASE 12-2. A, Fluid-attenuated inversion recovery (FLAIR)
sequence shows hyperintensities in the bilateral cerebellar peduncles, extending into the
cerebellar hemispheres and sparing the dentate nuclei. B, Associated T1 hypointensity. C and
D, Extensive asymmetric, confluent supratentorial FLAIR hyperintensities involving the
cerebral white matter. No associated enhancement was seen after contrast administration
(not shown).

Cerebral toxoplasmosis should be considered in the patient who is

immunocompromised, presents with one or more cerebral ring-enhancing
lesions, and is seropositive for toxoplasma IgG, which is present in more
than 90% of patients with cerebral toxoplasmosis.94 A large number of
ring-enhancing lesions on CT or MRI is highly suggestive of toxoplasmosis,
although as many as one-quarter of patients may present with only a single
visible lesion on CT.95,96 Toxoplasmosis on MRI is typically T1 hypointense
and T2/FLAIR hyperintense, with associated perilesional edema (CASE 12-3),
and may have a pathognomonic “eccentric target sign” enhancement
pattern. Cerebral toxoplasmosis also frequently involves intralesional foci of
susceptibility. The main clinical-radiologic differential diagnosis for cerebral
toxoplasmosis is primary CNS lymphoma; the challenging distinction between
these two entities is discussed further in the primary CNS lymphoma portion
of the later section titled “Epstein-Barr Virus–Associated Malignancies.”
CSF PCR for T. gondii is highly specific, although sensitivity is lower and varies
from roughly 55% to 80% depending on the type of PCR assay that is used.98
Availability of CSF is often limited in the setting of significant mass effect from
parenchymal lesions, which may prevent safe lumbar puncture.
The combination of sulfadiazine and pyrimethamine in conjunction with
leucovorin to prevent hematologic toxicity is the preferred first-line treatment.
In 2015, the cost of pyrimethamine was increased from $13.50 per tablet to $750
after US marketing rights to the drug were acquired by a pharmaceutical
company, severely limiting access for the majority of patients. Trimethoprim-
sulfamethoxazole or atovaquone may be used if pyrimethamine is not readily
available; however, a generic version of pyrimethamine was approved by the US
Food and Drug Administration (FDA) in 2020.99 The majority of patients have
radiographic and clinical improvement after 2 weeks of empiric treatment; in
patients who show no improvement, biopsy may be necessary to evaluate for
primary CNS lymphoma.
Limited data exist regarding outcomes after cerebral toxoplasmosis in patients
who are immunocompromised. One European study of transplant recipients
found a survival rate of 38%, with decreased survival in hematopoietic stem cell
transplant recipients compared with solid organ transplant recipients and in
those not receiving trimethoprim-sulfamethoxazole prophylaxis at the time of
their infection.100
EPSTEIN-BARR VIRUS–ASSOCIATED LYMPHOPROLIFERATIVE DISORDERS. EBV is

associated with a wide range of B-cell–derived lymphoid neoplasms, particularly
in immunocompromised hosts. In the nervous system, these include primary
CNS lymphoma and primary CNS posttransplant lymphoproliferative disorder.
EBV-associated malignancies may be difficult to differentiate from other
infectious complications in patients who are immunocompromised and may
require biopsy to aid in diagnosis.
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA. Primary CNS lymphoma is a type of

non-Hodgkin lymphoma confined to the brain and spine that is typically
associated with EBV in those who are immunocompromised. Primary CNS
lymphoma is difficult to distinguish from toxoplasmosis in patients who are
immunocompromised because it has a similar clinical presentation with elevated
intracranial pressure, headache, altered mental status, focal neurologic deficits,
1088 AUGUST 2021

and seizures. Detailed ocular evaluation with slit-lamp examination may reveal KEY POINTS
either Toxoplasma chorioretinitis or vitreoretinal lymphoma, providing a clue to
● Patients who discontinue
the ultimate neurologic diagnosis. or reduce
Primary CNS lymphoma typically presents with a single, large lesion that can immunosuppressive
have homogeneous, patchy, or rim enhancement with associated restricted medications are at risk of
diffusion and rarely has associated susceptibility artifact. Multifocal lesions are developing progressive
multifocal
also common, and although toxoplasmosis is more likely to present with multiple
leukoencephalopathy–
lesions, this cannot be used to reliably distinguish the two conditions. immune reconstitution
Single-photon emission computed tomography (SPECT) and positron emission inflammatory syndrome,
tomography (PET) may be used to help distinguish toxoplasmosis from particularly patients on
natalizumab, who can
primary CNS lymphoma, with primary CNS lymphoma lesions more commonly
develop the syndrome
hypermetabolic and toxoplasmosis hypometabolic. After neuroimaging evaluation weeks or even months after
for mass effect, lumbar puncture should be performed in all patients with primary discontinuing natalizumab.
CNS lymphoma who can safely undergo the procedure. CSF analyses should
include cytology, flow cytometry, EBV PCR, and immunoglobulin heavy chain ● Early, small reports have
suggested favorable
gene rearrangement studies. Serial large-volume CSF sampling may improve outcomes in patients with
diagnostic yield. No large studies exist on the diagnostic utility of CSF testing in PML treated with immune
patients with primary CNS lymphoma who are iatrogenically immunocompromised. checkpoint inhibitors such
However, EBV PCR testing has demonstrated particular utility in patients who are as pembrolizumab or
nivolumab and in those
infected with HIV.101 In a study of patients who are immunocompetent and have treated with virus-specific
primary CNS lymphoma, immunoglobulin heavy chain gene rearrangement studies cytotoxic T cells.
and cytology were frequently found to be discordant, suggesting that the two tests
may be complementary in making a diagnosis of primary CNS lymphoma.102 Brain ● Toxoplasma gondii has a
predilection for the basal
biopsy is often necessary for definitive diagnosis of primary CNS lymphoma. Because
ganglia and may cause
corticosteroids can greatly decrease diagnostic yield, they should be avoided when hyperkinetic movement
primary CNS lymphoma is under consideration. disorders.
High-dose methotrexate is the backbone of initial treatment, and
corticosteroids may be added after diagnosis is made to treat symptomatic edema ● The majority of patients
with toxoplasmosis have
or increased intracranial pressure. Much of the data regarding outcomes after radiographic and clinical
primary CNS lymphoma in patients who are immunocompromised come from improvement after 2 weeks
HIV-infected patients. However, one study using data from the US Transplant of empiric treatment; in
Registry and multiple cancer registries found that the 5-year survival after primary patients who show no
improvement, biopsy may
CNS lymphoma in solid organ transplant recipients was 35%, with a median be necessary to evaluate for
survival time of 1.1 years.103 primary central nervous
system lymphoma.
PRIMARY CENTRAL NERVOUS SYSTEM POSTTRANSPLANT LYMPHOPROLIFERATIVE
● In a study of patients who
DISORDERS. Primary CNS posttransplant lymphoproliferative disorder is a rare
are immunocompetent and
malignancy that occurs in both solid organ and hematopoietic stem cell have primary central
transplant recipients and is commonly associated with EBV. It may occur as nervous system lymphoma,
early as 6 weeks after transplantation but more typically develops several years immunoglobulin heavy chain
after transplantation, with a median time to occurrence of 4 to 5 years.104 The gene rearrangement studies
and cytology were
vast majority of these malignancies are diffuse large B-cell lymphomas; frequently found to be
however, T-cell lymphomas have also been described. Clinical presentation discordant, suggesting that
depends on lesion location and includes headache (34%), mental status changes the two tests may be
(36%), hemiparesis (33%), ataxia (29%), and seizures (26%).104,105 CNS complementary in making a
diagnosis of primary central
posttransplant lymphoproliferative disorder lesions tend to be multifocal, nervous system lymphoma.
ring-enhancing, or homogeneously enhancing lesions with mass effect and with
associated restricted diffusion. CSF positivity for EBV PCR with a compatible
clinical picture is highly suggestive of the diagnosis, and cytology or flow
cytometry, if positive, may also help confirm the diagnosis of posttransplant

CASE 12-3 A 53-year-old man presented with fever, headaches, and altered mental
status 45 days after allogeneic hematopoietic cell transplant. His
neurologic examination revealed left-sided dysmetria with finger-nose
and heel-knee-shin testing and left-sided dysdiadochokinesia with rapid
alternating movements.
MRI revealed multiple peripherally enhancing lesions involving the
cerebellum and cerebral hemispheres (FIGURES 12-5A, 12-5B, and 12-5C) with
extensive surrounding edema, effacement of the fourth ventricle, and
ventriculomegaly with transependymal CSF flow (FIGURES 12-5D, 12-5E,
and 12-5F).
CSF analysis revealed a mild lymphocytic pleocytosis and elevated
protein. CSF Toxoplasma gondii polymerase chain reaction (PCR) testing
was negative, but T. gondii–specific IgG levels were elevated in both
serum and CSF.
The patient was diagnosed with cerebral toxoplasmosis and treated
with sulfadiazine, pyrimethamine, and leucovorin. Follow-up imaging
revealed marked improvement in both enhancement
(FIGURES 12-5G, 12-5H, and 12-5I) and edema (FIGURES 12-5J, 12-5K, and 12-5L), with
resolution of transependymal CSF flow and ventricular effacement.
COMMENT Cerebral toxoplasmosis should be considered in transplant recipients

presenting with fever, headaches, altered mental status, and other
neurologic symptoms. Brain MRI is significantly more sensitive than CT for
diagnosis and typically reveals multiple ring-enhancing lesions with
associated edema. The differential diagnosis for such lesions includes
primary central nervous system lymphoma and cryptococcoma. T. gondii
PCR testing is highly specific but incompletely sensitive for cerebral
toxoplasmosis, and a negative result does not exclude this diagnosis.97
1090 AUGUST 2021

FIGURE 12-5
MRI from the patient in CASE 12-3. Initial brain MRI reveals multiple peripherally enhancing
lesions involving the cerebellum and cerebral hemispheres on postcontrast T1-weighted
images (A through C) with extensive surrounding edema, effacement of the fourth ventricle,
and ventriculomegaly with transependymal CSF flow on fluid-attenuated inversion recovery
(FLAIR) images (D through F). Follow-up imaging reveals marked improvement in both
enhancement on postcontrast T1-weighted images (G through I) and edema on FLAIR images
(J through L), with resolution of transependymal CSF flow and ventricular effacement.

lymphoproliferative disorder. However, brain biopsy with histopathologic

evaluation is often required.
Treatment is multifaceted and may include a reduction of immunosuppression,
anti-CD20 therapy, chemotherapy, radiation therapy, or a combination of these.
Adoptive immunotherapy with EBV-specific cytotoxic T cells may have utility in
refractory cases. Although antiviral prophylaxis may decrease the incidence of
posttransplant lymphoproliferative disorder, no convincing evidence suggests
efficacy of antiviral therapy in the treatment of posttransplant
lymphoproliferative disorder. Immunotherapy has improved prognosis in
patients with CNS posttransplant lymphoproliferative disorder, with one 2015
study reporting an overall survival rate of 62% of patients with CNS
posttransplant lymphoproliferative disorder and worse outcomes among older
patients or those with poor baseline performance status.106
INTRACRANIAL ABSCESS. Brain abscesses are a rare complication of

immunocompromise and are most often seen in patients who have undergone
neurosurgical procedures or have concomitant mastoiditis, sinusitis, endocarditis,
or bacteremia. Patients who are immunocompromised are at particular risk of
fungal brain abscesses, with 86% of abscesses in solid organ transplant recipients
and 92% of brain abscesses in bone marrow transplant recipients resulting from
fungal pathogens including Aspergillus, Mucor, Candida, Nocardia, and
Cryptococcus (cryptococcomas).107,108 Infection with Listeria species and M.
tuberculosis (tuberculomas) may also occur in this population. Intracranial
abscesses due to more common bacterial pathogens such as Klebsiella pneumoniae,
Staphylococcus aureus, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia
are notably rare in patients who are immunocompromised, accounting for just
0.61% of brain abscesses in liver transplant recipients and 0.65% of those in bone
marrow transplant recipients.109-111 For more information about intracranial
abscesses in patients who are immunocompetent, refer to the article “Encephalitis
and Brain Abscess” by Arun Venkatesan, MD,45 in this issue of Continuum.
ASPERGILLUS. Aspergillus fumigatus is a ubiquitous fungus and an important cause

of neurologic disease in people who are immunocompromised. A large review
of invasive aspergillosis cases found that 6% of patients with invasive aspergillosis
developed CNS involvement (34 patients) and that patients with CNS
aspergillosis almost always had predisposing conditions, including bone marrow
transplant (32%), solid organ transplant (9%), hematologic malignancies (29%),
AIDS (8%), solid organ tumors (4%), chronic granulomatous disease (2%), or
other underlying pulmonary disease (9%), with no predisposing factors identified
in just 2% of patients.112 Clinical findings of CNS aspergillosis in several large
series included nonspecific manifestations such as fever (64% to 96%), altered
mental status (35% to 64%), hemiplegia (21% to 41%), and seizures (18% to 35%),
whereas headache, nausea, vomiting, and meningismus occurred more rarely.112,
113
These clinical features may help distinguish CNS aspergillosis from related
pathologies, including cryptococcal meningitis.
Neuroimaging findings are variable and often depend on the patient’s
degree of underlying immunosuppression. Characteristic findings include
multiple brain abscesses, as well as infarcts or hemorrhages in the basal
ganglia and thalami due to angioinvasion with a predilection for small perforator
vessels (CASE 12-4).
1092 AUGUST 2021

CSF analysis is typically normal or may demonstrate mildly elevated protein, KEY POINTS
and Aspergillus antigen and fungal cultures are rarely positive and therefore have
● Primary central nervous
limited utility. CSF galactomannan antigen testing has a sensitivity of 88% and system posttransplant
specificity of greater than 96%,114 and Aspergillus PCR has a 75% sensitivity and lymphoproliferative
98.3% specificity.115 However, definitive diagnosis of CNS aspergillosis may disorder may occur as early
require histopathologic confirmation. as 6 weeks after
transplantation but more
CNS aspergillosis is treated with voriconazole, with or without neurosurgical
typically develops several
management depending on the extent and accessibility of the lesion. If possible, years after transplantation,
doses of immunosuppressive medications should be reduced. CNS aspergillosis with a median time to
has a poor prognosis in the vast majority of affected patients, with a case fatality occurrence of 4 to 5 years.
rate approaching 100%.116
immunocompromised are at
MUCOR. Cerebral mucormycosis is most often seen in patients who are particular risk of fungal brain
immunocompromised, typically those with diabetes mellitus or hematologic abscesses, with 86% of
malignancy. Cerebral mucormycosis most often occurs secondary to sinonasal abscesses in solid organ
transplant recipients and
infection with subsequent extension into the CNS, although fungemia 92% of brain abscesses in
causing isolated cerebral mucormycosis has also been reported. Like cerebral bone marrow transplant
aspergillosis, the majority of cases of isolated cerebral mucormycosis involve the recipients resulting from
basal ganglia, and MRI frequently reveals basal ganglia abnormalities such as fungal pathogens including
Aspergillus, Mucor,
thrombotic infarcts, mycotic emboli, and abscesses. Serum studies may disclose Candida, Nocardia, and
a metabolic acidosis and hyperglycemia, although blood culture is typically Cryptococcus
negative. CSF may show an increased opening pressure, modest neutrophilic (cryptococcomas).
pleocytosis, normal or slightly elevated protein levels, or low glucose levels,
● Clinical findings of central
and PCR-based analyses of RNA isolated from CSF may facilitate early
nervous system aspergillosis
detection. However, in most cases, basic CSF studies are normal, and biopsy is in several large series
necessary for diagnosis. Early tissue diagnosis followed by surgical excision included nonspecific
of the necrotic tissue and aggressive antifungal therapy with amphotericin manifestations such as
B can reduce morbidity and mortality. One study of patients with hematologic fever, altered mental status,
hemiplegia, and seizures,
malignancy who presented with mucormycosis infection showed that delay of whereas headache, nausea,
treatment by 6 days or more doubled mortality at 12 weeks after diagnosis when vomiting, and meningismus
compared with early treatment (82.9% versus 48.6%).117 occurred more rarely.
● Early tissue diagnosis

CANDIDA. Although Candida species frequently cause systemic infection in followed by surgical
patients with hematologic malignancies or after transplant, CNS candidiasis is excision of the necrotic
rare and almost always occurs in the setting of invasive or disseminated tissue and aggressive
candidiasis. As with other fungal pathogens, meningitis and vascular antifungal therapy with
amphotericin B can reduce
complications such as infarcts, subarachnoid hemorrhage, or mycotic aneurysms
morbidity and mortality
may occur. Radiologic findings vary but may include multiple small, enhancing from cerebral
lesions in the deep gray or white matter that correlate pathologically with mucormycosis.
abscesses. Diagnosis is most often established via confirmation of systemic
candidemia. CSF chemistry and CSF cell counts may also be abnormal in the
setting of meningitis or large abscesses, and elevated CSF 1,3-b-D-glucan is
suggestive of CNS infection. CNS Candida infections are treated with
amphotericin B and flucytosine followed by an azole for maintenance, with
serial MRI and lumbar puncture to monitor for disease resolution. Echinocandins
(eg, caspofungin or micafungin) should be avoided given poor CNS penetration.
Much of the published data on outcomes after CNS Candida infections focus on
neonates; however, a review of adult patients in the literature with and without
underlying risk factors (including hematologic and solid malignancies) found a
mortality rate of 53% in patients with chronic Candida meningitis.118

NOCARDIA. Nocardia species are aerobic, gram-positive bacteria that cause disease
mostly in patients who are immunocompromised, although approximately
119
one-third of infections occur in patients who are immunocompetent. Infection
typically occurs after prolonged immunosuppression; in posttransplant patients,
it most commonly occurs 1 to 6 months after transplant. CNS nocardiosis most
often presents with headache (45%), focal neurologic abnormalities (51%), fever
3
(40%), altered mental status (36%), seizures 28%, or meningismus (9%). The
disease is often multifocal, with pulmonary, ocular, and skin manifestations such
CASE 12-4 A 67-year-old man presented with fevers and altered mental status 1 year
after renal transplant. He was taking tacrolimus, prednisone, and
mycophenolate mofetil. His neurologic examination revealed weakness
of the left face, arm, and leg. Brain MRI showed restricted diffusion
involving the right basal ganglia (FIGURES 12-6A and 12-6B) and right corona
radiata and right parietal lobe (FIGURES 12-6C and 12-6D). Subsequent imaging
revealed an enhancing lesion involving the right lateral sphenoid sinus.
Pathology from the sphenoid mass revealed aggregates of septated
fungal hyphae forming fungal balls, morphologically suggestive of
aspergillosis, with a diagnosis of Aspergillus fumigatus confirmed on
tissue culture. He was treated with voriconazole and micafungin and was
discharged from the hospital with improved motor function. He died
15 months later of complications related to his renal transplant.
COMMENT A. fumigatus is a ubiquitous fungus and an important cause of neurologic

disease in patients who are immunocompromised. Unlike other fungal
central nervous system infections, Aspergillus rarely presents with
headaches or meningismus and more often presents with nonspecific
findings such as fever and altered mental status. Because of its
angioinvasive potential and predilection for small perforator vessels,
Aspergillus can cause infarcts or hemorrhages in the basal ganglia and
thalami. Aspergillus antigen and fungal cultures are rarely positive and have
limited utility, although CSF galactomannan antigen testing and Aspergillus
PCR may aid in diagnosis.114,115 Definitive diagnosis often requires
histopathologic confirmation, either with brain biopsy or on postmortem
analysis.
1094 AUGUST 2021

as subcutaneous nodules or abscesses providing clues to the diagnosis, although
single-organ CNS infection can also occur. Neuroimaging shows either single or
multiple ring-enhancing lesions consistent with cerebral abscesses in the vast
majority of cases (93% in one review), and meningeal enhancement can rarely be
119
seen, as well. CSF may be normal, although it rarely may be consistent with
bacterial meningitis or grow Nocardia species in culture when meningitis and brain
abscesses coexist. Diagnosis is more typically established by surgical aspiration or
biopsy. Trimethoprim-sulfamethoxazole readily penetrates the CNS and is usually
FIGURE 12-6
MRI of the patient in CASE 12-4. Initial brain MRI shows restricted diffusion involving the right
basal ganglia (A, diffusion-weighted image; B, apparent diffusion coefficient sequence), right
corona radiata, and right parietal lobe (C, diffusion-weighted image; D, apparent diffusion
coefficient sequence). Subsequent imaging (not shown) revealed an enhancing lesion
involving the right lateral sphenoid sinus.

combined with imipenem or amikacin. Prompt treatment with combined

neurosurgical and medical management leads to recovery in the majority of
3
cases, including those who are immunocompromised.
ACANTHAMOEBA AND BALAMUTHIA MANDRILLARIS. Acanthamoeba species and

B. mandrillaris are both known causes of granulomatous amebic encephalitis
(GAE), characterized by a progressive, subacute encephalopathy. These
organisms are ubiquitous protozoans found in soil, air, and water. Acanthamoeba
typically causes encephalitis in transplant recipients, patients undergoing cancer
treatments, or those with autoimmune conditions, although patients who are
immunocompetent are rarely affected as well. B. mandrillaris is more commonly
seen in immunocompetent hosts, although it has recently been associated with
clusters of donor-derived infections in transplant recipients.120
Clinical presentation of GAE is variable and may include progressive
altered mental status, seizures, cranial neuropathies, and various other focal
neurologic signs, headache, fever, and signs of progressive increased
intracranial pressure. MRI may show single or multifocal necrotic
space-occupying mass lesions with or without associated contrast
enhancement, and CSF studies often reveal a lymphocytic pleocytosis,
although both of these findings are nonspecific. Diagnosis requires CSF PCR
for Acanthamoeba or B. mandrillaris, identification of trophozoites on wet
mount preparations (although these are very rarely seen), or histopathologic
evaluation of skin, lung, sinus, or brain tissue biopsy. However, diagnosis remains
challenging and is unfortunately often made postmortem.
Given its rarity and the lack of clinical data, no published guidelines exist on the
treatment of GAE, although limited data suggest that single CNS lesions should be
surgically resected, followed by medical therapy.121,122 In the United States, seven
cases of survival after B. mandrillaris infection have been reported.121,123,124 Six
patients were treated with a combination of pentamidine, flucytosine, fluconazole,
and either clarithromycin or azithromycin, plus either sulfadiazine, miltefosine,
thioridazine, or liposomal amphotericin B, and a seventh patient was treated with
fluconazole, azithromycin, trimethoprim-sulfamethoxazole, and miltefosine. Cases
in the literature report successful treatment of Acanthamoeba with variable
combinations of rifampicin, fluconazole, itraconazole, voriconazole, pentamidine
isethionate, sulfadiazine, flucytosine, azithromycin, miltefosine, caspofungin,
trimethoprim-sulfamethoxazole, amphotericin B, and metronidazole, including in
patients who are immunocompromised. Prognosis remains poor, and GAE is fatal in
more than 90% of patients.125
MYELOPATHY AND RADICULOPATHY

Several infectious pathogens have a particular predilection for the spinal cord and
nerve roots and should be considered in the differential diagnosis for a patient who
is immunocompromised and presenting with new-onset numbness or weakness.
For additional considerations in patients who are immunocompetent, refer to the
articles “Infections of the Spine and Spinal Cord” by Shamik Bhattacharyya, MD,
MS, and Michael J. Bradshaw, MD,126 and “Infections of the Peripheral Nervous
System” by Samantha LoRusso, MD,127 in this issue of Continuum.
Varicella-zoster Virus
VZV may cause a myelopathy in patients on natalizumab and other
immunomodulatory agents through several mechanisms, including VZV
1096 AUGUST 2021

vasculopathy causing spinal cord infarction, direct viral infection of the spinal KEY POINTS
cord, or a postinfectious inflammatory process. MRI may show findings
● Neuroimaging in patients
suggestive of myelitis, with T2-hyperintense, contrast-enhancing lesions. with Nocardia infection
Lumbar puncture typically reveals a mild CSF lymphocytic pleocytosis, and shows either single or
diagnosis is established via CSF VZV PCR or VZV IgG. VZV myelopathy may multiple ring-enhancing
also exist concurrently with VZV cerebral vasculopathy, VZV encephalitis, lesions consistent with
cerebral abscesses in the
ocular disease, or meningoradicular disease, so careful investigation for
vast majority of cases, and
other sites of infection is important once the diagnosis is established.76 rare cases may show
Reactivation of the virus in the dorsal root ganglia may also cause a meningeal enhancement as
radiculopathy, plexopathy, or ganglionopathy, with or without an associated well.
zoster rash. Although no standardized treatment regimen exists, anecdotal
● Prognosis for patients
evidence supports the use of acyclovir and corticosteroids.128 Data regarding with granulomatous amebic
prognosis are limited by the rarity of this condition; although the majority of encephalitis remains poor
patients in the literature recover, a small number of fatalities have been and the disease is fatal in
reported.129 more than 90% of cases.
● Varicella-zoster virus may

Cytomegalovirus cause a myelopathy in
CMV polyradiculitis or polyradiculomyelitis occurs in patients who are severely patients on natalizumab and
immunocompromised, including hematopoietic cell and solid organ other immunomodulatory
agents through several
transplant recipients, typically more than 100 days after transplant. The
mechanisms, including
syndrome typically presents with early bowel and bladder dysfunction, pain, varicella-zoster virus
paresthesia, hypotonic weakness, and reduced reflexes, but clinical vasculopathy causing spinal
presentation may be similar to other radicular pathologies. Concurrent cord infarction, direct viral
infection of the spinal cord,
encephalitis or subacute cognitive changes, cranial nerve palsies, visual
or a postinfectious
changes due to retinitis, or extraneural manifestations such as pulmonary or inflammatory process.
gastrointestinal CMV infections may provide clues to the diagnosis. Nerve
conduction studies and EMG are helpful for confirming the localization in ● Cytomegalovirus
patients who may have multiple reasons for weakness or paresthesia. MRI of polyradiculitis or
polyradiculomyelitis occurs
the lumbosacral spine is neither sensitive nor specific for CMV infection but in patients who are severely
can show thickening of the cauda equina, leptomeningeal or nerve root immunocompromised,
enhancement, or transverse T2-hyperinense lesions of the spinal cord in including hematopoietic cell
patients with concomitant myelitis. Additional details regarding diagnosis, and solid organ transplant
recipients, typically more
treatment, and outcomes of neurologic CMV infections are included in the than 100 days after
cytomegalovirus portion of the earlier section titled “Evaluation and transplant.
Management of Specific Infections Syndromes.”
● MRI in patients with
Elsberg syndrome (herpes
Herpes Simplex Virus
simplex virus-2
Spinal cord involvement is seen more often with HSV-2 than HSV-1. The virus myeloradiculitis) typically
can reactivate in the sacral spinal ganglia causing acute inflammation of the shows T2 hyperintensities of
corresponding dorsal roots and adjacent spinal cord (Elsberg syndrome). the cord and contrast
Compared with patients who are immunocompetent, those who are enhancement of both the
spinal cord and nerve roots,
immunocompromised are at greater risk of severe complications from HSV-2, sometimes with
and Elsberg syndrome has been described in solid organ transplant recipients. cervicothoracic extension.
In most cases, symptomatic HSV-2 infections in transplant recipients result from
reactivation of latent virus, although donor-derived infections and primary
infections in the setting of interpersonal transmission have also been reported.130
MRI typically shows T2 hyperintensities of the cord and contrast enhancement
of both the spinal cord and nerve roots, sometimes with cervicothoracic
extension. Elsberg syndrome is typically accompanied by a CSF pleocytosis,
which may be lymphocytic early in the course of the illness. CSF HSV PCR is

KEY POINT the gold standard for diagnosis. HSV-1 and HSV-2 can both cause a transverse
myelitis, typically mild and self-resolving in patients who are immunocompetent
● Next-generation but occasionally recurrent or fulminant and necrotic in immunocompromised
sequencing of the CSF is a
hosts.131 Treatment of HSV myeloradiculitis is with IV acyclovir with or
promising approach for
unbiased diagnostic without high-dose corticosteroids to reduce the risk of progression.
evaluation and organism Although data on outcomes are limited, a case series describing 13 patients
identification in central with HSV myeloradiculitis for whom follow-up data were available reported
nervous system infections
that 1 patient died of encephalomyelitis, 3 patients had no neurologic
and may be used more
commonly in clinical recovery, 8 had moderate neurologic recovery, and 1 had complete recovery,
practice in the coming years. whereas 2 patients relapsed 2 or more years after the initial onset of
symptoms.132
FUTURE TRENDS
As new and repurposed immunomodulatory and immunosuppressive medications
are increasingly used in the treatment of both neurologic and systemic autoimmune
disorders, familiarity with the spectrum of neurologic infections in patients who are
immunocompromised is of critical importance to the practicing neurologist.
However, diagnosis of infectious pathogens in patients who are
immunocompromised may be particularly challenging because a decreased
immune response can lead to atypical imaging or laboratory findings.
Next-generation sequencing of the CSF is a promising approach for unbiased
diagnostic evaluation and organism identification in CNS infections and may be
used more commonly in clinical practice in the coming years. A 2019 study in 204
patients with meningitis or encephalitis in which 58 definitive diagnoses were
established found that 13 (22%) additional organisms were detected by using
next-generation sequencing that were not found with standard clinical
evaluation.133 Next-generation sequencing has the potential to be helpful in many
cases where active pathogen is present in the CSF, but it is less sensitive with a
longer duration of infection or in conditions more dependent on serology for
diagnosis. Next-generation sequencing of the CSF in patients who are
immunocompromised has also identified unusual pathogens such as Leptospira
and astrovirus species in addition to more common organisms such as T. gondii
and L. monocytogenes. Next-generation sequencing and other novel diagnostic
modalities may improve the rate of early identification of infectious
complications of immunocompromise and ultimately ameliorate outcomes
in this vulnerable population.
CONCLUSION
Neurologic complications in patients who are immunocompromised, including
transplant recipients and patients on immunomodulatory medications, are
common and often have significant morbidity. Although some conditions are
specific to transplantation or specific immunotherapies, many infectious and
noninfectious neurologic conditions may occur in association with multiple types
of immunosuppressed states. In addition to lumbar puncture, neuroimaging, and
EEG, careful investigation for associated pulmonary, dermatologic, ocular, or
other systemic findings is often critical to establishing a neurologic diagnosis.
Awareness of these conditions is key because many may be treatable or reversible
with early recognition.
1098 AUGUST 2021

ACKNOWLEDGMENTS
The author would like to thank Anastasia Vishnevetsky, MD, and Anna M.
Cervantes-Arslanian, MD, for their insights and invaluable contributions in the
preparation of this manuscript.
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1104 AUGUST 2021

Congenital Infections of REVIEW ARTICLE
the Nervous System


INTERVIEW AVAILABLE
ONLINE
By Payal Patel, MD
ABSTRACT
PURPOSE OF REVIEW: Thisarticle provides an overview of congenital infections
affecting the central nervous system (CNS), discussing the epidemiology,
clinical features, diagnostic tools, and preventive and treatment measures
for a variety of pathogens with the potential to infect the developing
fetal brain.
RECENT FINDINGS: Contrary to popular belief, many congenital CNS infections

are preventable and treatable. Treatment options exist for congenital
cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex
virus, toxoplasmosis, and syphilis, although the efficacy of these
treatments and the populations that may benefit from treatment are
variable. Zika virus has recently emerged as a pathogen affecting the fetal
brain, and new data suggest that the pathogenesis of Zika virus involves
direct infection of neuronal progenitor cells leading to destruction of CNS
tissue. The incidence of congenital syphilis has been increasing in the
United States over the past decade as a direct result of new syphilis cases
among adults and poor access to adequate maternal health care.
SUMMARY: Congenital CNS infections often result in significant neurologic

morbidity in pediatric patients. Therefore, early identification of maternal CITE AS:
illness and implementation of preventive measures are important in CONTINUUM (MINNEAP MINN)
improving developmental outcomes and quality of life. 2021;27(4, NEUROINFECTIOUS
DISEASE):1105–1126.
Dr Payal Patel, 4800 Sand Point
INTRODUCTION Way, MB.7.420, PO Box 5371,
I
nfections of the central nervous system (CNS) occurring before or during Seattle, WA 98145,
pbp22@uw.edu.
birth may cause significant neurologic injury to the developing brain.
Historically, the most common pathogens known to cause CNS injury in RELATIONSHIP DISCLOSURE:
neonates have been toxoplasmosis, rubella, cytomegalovirus (CMV), human Dr Patel has received
compensation as an author for
immunodeficiency virus (HIV), and herpes simplex virus (HSV), designated MedLink, Inc, and has received
by the acronym TORCH with the O standing for other infections; recently research and salary support
emerging and reemerging pathogens, including Zika virus and syphilis, should be from the National Institutes of
Health (K23MH119914).
added to this list. These pathogens cross the placenta either through direct
extension or through transmission via the placental-fetal blood barrier resulting UNLABELED USE OF
in fetal infection.1 Several mechanisms of injury to the developing brain often PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
coexist for each microorganism, the most common being direct infection of Dr Patel reports no disclosure.
neuronal progenitor cells.2 Therefore, gestational age at the time of infection is of
clinical importance because early fetal infections result in the most severe © 2021 American Academy
disease.3 Animal fetal infection models have shown that localized inflammatory of Neurology.

CONGENITAL INFECTIONS OF THE NERVOUS SYSTEM
responses to invading pathogens can also result in neuronal injury.1 Congenital

CNS infections often present with similar symptoms in the newborn period,
including sensorineural hearing loss, chorioretinitis, cerebral malformations,
petechiae/purpura, and hepatosplenomegaly; all can also result in long-term
neurologic disability.4 Understanding modes of transmission and preventive and
treatment measures may help reduce the risk of exposure and the subsequent
development of neurologic sequelae. Importantly, advances in medicine over the
past decade have resulted in improved treatments for these congenital infections,
and therefore, we now have the potential to reduce the burden of these diseases
worldwide.
This article summarizes the epidemiology (TABLE 13-1), diagnosis, and
potential preventive and treatment options (TABLE 13-2) for CNS infections
acquired in the perinatal period. Although congenital acquisition of infections
occurs most often through transplacental transmission, newborns are also at risk
of perinatal exposure to many of these same pathogens as they pass through the
birth canal and may acquire some of these infections through exposure during
breast-feeding. Evidence of neurologic injury may be present at birth or may not
manifest for many years, making retrospective diagnoses of the pathogenic agent
TABLE 13-1 Prevalence and Incidence Data for Congenital Central Nervous System
Infections
Disease Worldwide United States Important epidemiologic notes

4
Toxoplasmosis 201,000 cases 1 in 3000 to 1 in 10,000 live births Highest prevalence in South America
per year
Rubella5 100,000 Eliminated with universal vaccination Highest prevalence in Africa

cases/yr
Cytomegalovirus6 Unknown 30,000 cases/yr Highest rates occur in low- and

middle-income countries
Human 150,000 162 cases/yr (as of 2010) Highest burden in sub-Saharan Africa
immunodeficiency cases/yr
virus (HIV)7
Herpes simplex Unknown 1 in every 3200 live births Most maternal herpes simplex virus type 2
virus8,9 infections are diagnosed following
transmission to neonates after birth
Zika10 Unknown 144 confirmed cases of congenital Zika True prevalence rates are difficult to
syndrome occurred between February ascertain given the lack of specific
2015 and February 2017; 203 infants diagnostic tests and universal criteria for
born to 1450 mothers with suspected congenital Zika syndrome
or confirmed Zika virus infection
developed anomalies (central nervous
system and non–central nervous
system–related birth defects)
Syphilis11 661,000 300 cases/yr A 2020 Centers for Disease Control and
cases/yr Prevention publication highlights how
disparities in maternal care result in higher
rates of congenital syphilis among racial/
ethnic minority groups12
1106 AUGUST 2021

difficult. Early recognition is key to improved outcomes because many of these KEY POINTS
infections are preventable and treatable.
● Many congenital
infections affecting the
TOXOPLASMOSIS central nervous system
Toxoplasma gondii, the cause of toxoplasmosis, is an obligate intracellular (CNS) are preventable and
pathogen that predominantly infects birds and mammals. treatable. Therefore,
anticipatory guidance
regarding preventive
Epidemiology measures and early
In high-income countries, cats are the primary reservoir with exposure to feline detection are important.
feces being the most common source of transmission. In lower-income countries,
● Transmission of
exposure to undercooked meats is a leading cause of transmission as well.
congenital acquisition of
Maternal-fetal transmission varies depending on gestational age and timing of infections most often occurs
maternal infection with risk being higher during the second and third trimesters transplacentally but may
(FIGURE 13-1).13 Parasite load during acute maternal infection may be an also occur as infants pass
important factor in determining the risk of transmission and fetal disease through the birth canal or
may be acquired through
severity.29 Prevalence rates vary based on geographic factors. In the United States, breast-feeding.
congenital toxoplasmosis infection estimates range from 1 in 3000 to 1 in 10,000
live births.4 ● CNS involvement is
common in congenital
toxoplasmosis infection
Clinical Presentation presenting as
Congenital toxoplasmosis infection is frequently asymptomatic with only 25% of macrocephaly, cerebral
infections presenting with clinical signs.4 Severity is indirectly related to calcifications, hearing loss,
gestational age at the time of transmission; infections occurring in the first and seizures.
trimester present with the most severe manifestations. CNS involvement
frequently occurs in congenital toxoplasmosis infection manifesting as
macrocephaly, cerebral calcifications, hearing loss, and seizures. Systemic signs
include hepatosplenomegaly, petechial rash, and chorioretinitis. If untreated,
infants with congenital toxoplasmosis are also at risk of developing
chorioretinitis in childhood or even into adulthood.14
Diagnosis
IgM antibodies do not cross the maternal blood-placenta barrier and, therefore,
are useful in diagnosing congenital infections if amniocentesis is performed in
mothers with suspected Toxoplasma infection. Toxoplasma polymerase chain
reaction (PCR) also has high sensitivity and specificity for diagnosis of congenital
toxoplasmosis in utero. The presence of IgM antibodies to Toxoplasma in
amniotic fluid (for suspected fetal infection) or suggestive clinical manifestations
and positive Toxoplasma serologies or PCR in a newborn are diagnostic of
congenital toxoplasmosis.
Prevention and Treatment

Prevention of maternal-fetal transmission of toxoplasmosis is essential. Pregnant
women or those planning on becoming pregnant are advised to not handle cat
litter and to avoid consuming undercooked meat. Protecting the fetus through
early detection and treatment is of utmost importance. Therefore, routine
screening for acute toxoplasmosis in pregnant women is recommended.
However, universal guidelines have not been developed because accurately
identifying maternal infections is difficult as many infections are asymptomatic.
If maternal infection is suspected, spiramycin can be administered in the first or
early second trimester, or pyrimethamine/sulfadiazine (with leucovorin to

TABLE 13-2 Clinical Features and Treatment of Congenital Central Nervous System
Infections by Pathogen
Timing of Clinical neurologic

Disease transmission features Diagnosis Treatment
Toxoplasmosis Can occur during any Common neurologic Polymerase chain Spiramycin can be
trimester, highest risk manifestations include reaction (PCR) or titers administered in the first
in second and third macrocephaly, cerebral on newborn serum or early second
trimesters13 calcifications, hearing (can be tested on trimester, or
loss, and seizures14 amniotic fluid for in pyrimethamine/
utero diagnosis)14 sulfadiazine (with
leucovorin to prevent
toxicity) can be given in
the late second or third
trimester15
Rubella Most commonly Sensorineural hearing Viral isolation or PCR Prevention through
transmitted from loss and cataracts are from bodily fluids universal vaccination is
mother to fetus in the the most common (nasal swab, blood, recommended
first trimester5 manifestations of urine, or CSF) at birth
congenital rubella or positive serum
syndrome; imaging rubella-specific IgM
features often and confirmation with
demonstrate intracranial avidity testing of
calcifications and white rubella-specific IgG to
matter hyperintensities4 document recent
exposure
Cytomegalovirus Can occur during any Intracranial PCR of the infant’s Valganciclovir is
trimester, highest risk calcifications, urine or saliva, which recommended for
occurring in the first hydranencephaly, has 95% sensitivity16 6 months in infants with
trimester16 atrophy, moderate or severe
schizencephaly, symptomatic congenital
cerebellar hypoplasia, cytomegalovirus
and sensorineural infection; universal
hearing loss are recommendations have
common17,18 not been established for
infants with mild or
asymptomatic
infection19
Human Transmission Neurologic Either HIV DNA or RNA Combination

immunodeficiency commonly occurs manifestations of PCR should be antiretroviral therapy is
virus (HIV) during birth perinatally acquired HIV performed at birth and recommended with early
occurs in childhood for then again at 6 months initiation being
treated children, for infants born to potentially protective
particularly those with a mothers living with HIV against neurologic
history of acquired sequelae23,24
immunodeficiency
syndrome (AIDS)-
defining illnesses, and
commonly manifests as
cognitive deficits20-22
1108 AUGUST 2021


Herpes simplex HSV-1 is typically Early signs of HSV PCR on CSF or High-dose IV acyclovir is
virus (HSV) transmitted encephalitis include vesicular lesions (if the recommended
postnatally, and poor feeding, lethargy, present) is the gold treatment for HSV
HSV-2 is transmitted and irritability and can standard for encephalitis
perinatally precede the diagnosis25
development of skin and
eye manifestations;
classically, HSV
encephalitis affects the
temporal lobe, but
neonates with exposure
to HSV at birth often
present with diffuse
cerebral involvement4
Zika virus Can occur during all Five features are Serologies are the No treatment available
trimesters; most considered mainstay of diagnosis,
severe clinical characteristic of but high false-positive
manifestations occur congenital Zika rates occur because of
when fetal infection syndrome and cross-reactivity with
occurs during the distinguish congenital other flavivirus
first trimester Zika syndrome from infections
other congenital central
nervous system
infections: (1) severe
microcephaly with
partially collapsed skull,
(2) thin cerebral cortex
with subcortical
calcifications, (3)
macular scarring and
focal pigmentary retinal
mottling, (4) congenital
contractures, and (5)
marked early
hypertonia26



Syphilis Maternal-fetal Neurologic Infants born to IV or IM penicillin G for
transmission of manifestations present mothers diagnosed 10-15 days is the
syphilis occurs in after decades of with syphilis should be recommended
utero with the untreated infection as screened with a treatment for infants
highest risk of meningitis, infarcts, quantitative with congenital syphilis28
transmission hydrocephalus, and nontreponemal test
occurring in the first hearing loss. (rapid plasma reagin
and second [RPR] or Venereal
trimesters and in Disease Research
pregnant women Laboratory [VDRL]);
who are in their evaluation of infants
primary or secondary with positive
stage of maternal screening tests for
syphilis infection clinical signs of
congenital syphilis is
recommended,
although the lack of
clinical findings does
not exclude the
diagnosis of
congenital syphilis;
diagnosis of
congenital syphilis is
considered proven if
one or more of the
following are true in
infants with reactive
RPR or VDRL27: (1)
clinical signs
characteristic of
congenital syphilis, (2)
serum quantitative
nontreponemal titers
that are fourfold
higher than maternal
titers, and (3) a positive
darkfield test or PCR
of lesions, placenta, or
infant bodily fluids
CSF = cerebrospinal fluid, DNA = deoxyribonucleic acid; IgG = immunoglobulin G; RNA = ribonucleic acid.
1110 AUGUST 2021

KEY POINT
● If in utero toxoplasmosis
exposure is suspected,
spiramycin can be
administered in the first or
early second trimester, or
pyrimethamine/sulfadiazine
or leucovorin can be given in
the late second or third
trimester. Treatment with
antimicrobial therapy should
be continued for 1 year after
delivery and has been shown
to improve neurologic
outcomes in neonates born
with congenital
toxoplasmosis.
FIGURE 13-1
Risk of maternal-fetal transmission of Toxoplasma gondii by gestational age at maternal
seroconversion (n = 1721).
Reprinted with permission from SYROCOT Study Group, Lancet.13 © 2007 Elsevier Ltd.
prevent toxicity) can be given in the late second or third trimester. These
antimicrobial agents have been shown to reduce the risk of clinical sequelae in
the developing fetus after in utero Toxoplasma exposure. Treatment of the infant
with pyrimethamine, sulfadiazine, and leucovorin is often continued for 1 year
after birth and has been shown to reduce the risk of neurologic sequelae.15
RUBELLA
The rubella virus is a single-stranded RNA virus enclosed by a capsid and is
primarily transmitted through respiratory droplets.
Epidemiology
Because of the introduction and widespread use of the measles-mumps-
rubella (MMR) vaccine in the United States, no cases of congenital rubella have
been reported in the United States since 2000. In countries without universal
vaccination programs, congenital rubella remains prevalent, with approximately
100,000 infants born with congenital rubella globally each year.5 Rubella is most
commonly transmitted from mother to fetus if the mother is acutely infected
during the first trimester. The risk of transmission is significantly lower (10% to
20%) after 20 weeks of gestational age. Maternal-fetal transmission occurs only
in nonimmune mothers, and therefore, universal screening for rubella immunity
is recommended for all pregnant women.5
Sensorineural hearing loss and cataracts are the most common manifestations
of congenital rubella syndrome. Imaging features include intracranial
calcifications and white matter hyperintensities. Similar to other congenital
infections, rubella infections have multiorgan involvement, including cardiac

defects, hepatosplenomegaly,
petechial (“blueberry muffin”)
rash (FIGURE 13-230),
microphthalmia, glaucoma, and
chorioretinitis.4
Diagnosis
Congenital rubella syndrome can
be confirmed by viral isolation or
PCR from bodily fluids (nasal
swab, blood, urine, or CSF) at FIGURE 13-2
Blueberry muffin rash in congenital rubella syndrome.
birth or positive serum rubella
Reprinted with permission from Centers for Disease Control
IgM and confirmation with and Prevention.30
avidity testing of rubella IgG to
document recent exposure.
Avidity describes the strength with which a multivalent antibody binds to the
antigen of interest; lower avidity is seen after recent infections, and higher
avidity is seen with maturation of the immune response.

No treatment exists for congenital rubella syndrome. Therefore, prevention through
universal vaccination is important. The rubella vaccine provides lifelong immunity
to multiple viral strains and is recommended for women who are considering
pregnancy and have not had exposure to rubella. Through the Global Vaccine Action
Plan, the World Health Organization is pursuing the elimination of congenital
rubella syndrome, rubella, and measles.31 As of 2020, the Americas have eliminated
congenital rubella syndrome. In Europe and Asia, congenital rubella syndrome has
been mostly eliminated with a few countries reporting approximately 5 cases per
month. The predominant disease burden is in Africa, where resource constraints in
some regions have stalled the elimination of congenital rubella syndrome.32
CYTOMEGALOVIRUS
CMV is a double-stranded DNA virus belonging to the herpesvirus family; it is
known to cause infections in immunocompromised hosts in addition to
congenital infections described here.
Epidemiology
The true prevalence of CMV transmission from mother to child is difficult to
estimate because approximately 90% of infants born with exposure to CMV in
utero are asymptomatic. Nevertheless, CMV is the leading cause of congenital
viral infections, affecting approximately 30,000 infants in the United States
annually,6 and is the most common nongenetic cause of sensorineural hearing
loss and developmental delay.17 CMV has a variable geographic distribution with
higher infection rates occurring in low-income and middle-income countries,
particularly in populations affected by crowding and lack of resources for proper
hygiene. Young children are the most likely age group to acquire new infections
and shed the virus at higher rates. Therefore, pregnant women who work with or
live with young children, especially children attending school, are at highest risk
of becoming infected. When a seronegative pregnant woman is exposed to CMV,
1112 AUGUST 2021

she has a 40% chance of acquiring CMV and an approximately 10% risk of KEY POINTS
transmitting the infection to her fetus. The risk of transmission varies based on
● Positive cytomegalovirus
gestational age with the highest risk occurring in the first trimester.16 Women (CMV) titers do not indicate
who are seropositive are also at risk of becoming infected with a different strain of protection against
CMV or reactivation of latent virus during pregnancy.33 The incidence of acquisition of the virus by
reactivation of maternal CMV during pregnancy resulting in congenital CMV pregnant women, and
transmission to their fetus,
infection varies among different racial and ethnic populations in the United States.
given that multiple strains of
According to a 2020 study, Black patients experience higher rates of congenital CMV exist globally, and
CMV infection compared with Hispanic patients despite similar rates of baseline reactivation of latent
seroprevalence.33 Additionally, for pregnant women, exposure to young disease can occur.
school-aged children is a risk factor for reinfection with a different strain of
● Cerebral manifestations
CMV.33 Therefore, positive CMV titers do not indicate protection against maternal of congenital CMV infection
infection with the risk of subsequent intrauterine transmission leading to include intracranial
congenital CMV infection.33 Based on universal screening studies, approximately calcifications,
half of infants with symptomatic CMV infection at birth develop auditory and/or hydranencephaly, atrophy,
schizencephaly, and
neurologic sequelae, and 13.5% of infants with asymptomatic disease develop a cerebellar hypoplasia. Of
permanent neurologic deficit at follow-up visits spanning 1 to 5 years.17 the 10% of infants who
Larger-scale cohort studies, which include longer-term follow-up after applying present with symptomatic
universal screening measures to identify infants with asymptomatic CMV CMV disease at birth,
one-third will experience
infections, are needed to determine the true prevalence of the neurologic sensorineural hearing loss
morbidity of congenital CMV. and two-thirds will have
persistent neurologic
Clinical Presentation deficits.
Systemic clinical features of symptomatic CMV are similar to the manifestations
of other congenital infections and include petechial rash, thrombocytopenia,
anemia, and hepatosplenomegaly
with associated hyperbilirubinemia
and elevated transaminases.
Cerebral manifestations of
congenital CMV infection
include intracranial
calcifications, hydranencephaly,
atrophy, schizencephaly, and
cerebellar hypoplasia18
(FIGURE 13-334). Of the 10% of
infants who present with
symptomatic disease at birth,
one-third will experience
sensorineural hearing loss and
two-thirds will have persistent
neurologic deficits.17 Hearing
loss can be progressive; 24% of
all infants with congenital CMV
infection develop sensorineural FIGURE 13-3
hearing loss by 4 years of age.35 Imaging findings in congenital CMV infection. Axial
CT of the brain at day 1 of life shows extensive
Diagnosis periventricular calcifications (A, arrow),
ventriculomegaly (B, arrow), reduced cortical sulcation
Diagnosis of congenital CMV (C, arrow), and cerebellar hypoplasia (D, arrow).
infection is established through Reprinted with permission from Dhamija R, Neurology.34
PCR of the infant’s urine or © 2011 American Academy of Neurology.

saliva, which has 95% sensitivity.16 Because many infants with CMV infection
are asymptomatic at birth, retrospective diagnosis is challenging when
late-onset neurologic sequelae develop, which occurs in approximately 10% of
cases. PCR of dried blood spots may be useful in these cases, but the sensitivity
of this method is only 72%.36

Unfortunately, no vaccine exists for CMV. The global presence of multiple
strains, viral mutagenicity, and lack of persistent immunologic response to viral
exposure make developing a single universal vaccine against CMV difficult.37
Nevertheless, antiviral agents ganciclovir and valganciclovir are treatment
options for infants with symptomatic CMV infection at birth. In a randomized
controlled trial, IV ganciclovir was shown to reduce the risk of sensorineural
hearing loss at 6-month follow-up. Some infants were also evaluated for
developmental outcomes by using the Denver Developmental Test II at 6 weeks,
6 months, and 12 months of age. The treatment group attained significantly more
milestones than the placebo group.38 Importantly, all infants experienced
developmental delays at all three time points, so treatment did not prevent
neurologic injury. Significant neutropenia was experienced by the treatment
group.
Valganciclovir, the oral form of ganciclovir, is usually well tolerated and a
more feasible medication option for at-home treatment. One study randomly
assigned infants with symptomatic CMV infection to 6 weeks or 6 months of
treatment with valganciclovir and found that auditory and developmental
outcomes were improved in the group on the longer duration of therapy. A
placebo control group was not included in this study, limiting the interpretation
of results. Of note, infants in the 6-week treatment group developed neutropenia
over the following 4.5 months at the same rate as the 6-month treatment group,
indicating that CMV infection itself may be the primary cause of neutropenia in
treated infants. As demonstrated in previous cohort studies, most children had
lower scores on developmental measures compared with normative means.39 An
international expert panel published consensus guidelines that recommended
treatment with valganciclovir for 6 months in infants with moderate or severe
symptomatic congenital CMV infection.19 In infants with asymptomatic or
mildly symptomatic congenital CMV, the risks and benefits of valganciclovir
remain to be determined.
HUMAN IMMUNODEFICIENCY VIRUS

HIV is a single-stranded RNA virus that is part of the Retroviridae viral family.
Epidemiology
Globally, more than 2 million children younger than 15 years are living with
perinatally acquired HIV, with 150,000 new infections occurring every year.7 In
the United States, the rate of new perinatally acquired HIV infections has fallen
dramatically because of universal testing and treatment for HIV in pregnancy to
prevent maternal-fetal transmission.40 Additionally, survival of adolescents and
young adults living with perinatally acquired HIV has improved because of
increased access to combination antiretroviral therapy (ART). These factors have
led to an increased global prevalence of neurologic sequelae in people aged
21 years or younger living with perinatally acquired HIV.
1114 AUGUST 2021

Clinical Presentation KEY POINTS
Clinical manifestations of HIV infection are not present at birth. Before the availability
● Valganciclovir has been
of combination ART, perinatal HIV infection had an 80% mortality rate in the first shown to improve
2 years of life, but survival rates have significantly improved over the past few decades neurologic outcomes in
because of better access to and newer pediatric formulations of combination ART. infants born with
Neurologic manifestations of HIV in pediatric patients include cerebrovascular disease, symptomatic congenital
CMV infection.
epilepsy, and, most commonly, cognitive impairment.20 Cognitive deficits in children
with HIV usually encompass multiple domains including working memory and ● Cognitive impairment in
executive function.21 Cognition is more severely affected in children with a history of children with human
acquired immunodeficiency syndrome (AIDS)-defining illnesses.22 immunodeficiency virus
(HIV) usually encompasses
multiple domains and is
Diagnosis more severe in children with
For infants born to mothers with HIV, screening at birth is recommended with either a history of acquired
HIV DNA or RNA PCR. In cases in which maternal HIV status is unknown at birth, immunodeficiency
further testing is recommended at 2 weeks of life, 4 to 6 weeks of life, and 4 to syndrome (AIDS)-defining
illnesses.
6 months of life. Newborns with unknown HIV status should be initiated on
combination ART at birth, which may affect the sensitivity of HIV DNA PCR results. ● Early identification and
Therefore, follow-up testing after cessation of combination ART is recommended. initiation of treatment for
children living with
perinatally acquired HIV
may be neuroprotective,
Maternal viral suppression with combination ART has successfully reduced the particularly for the
incidence of perinatally acquired HIV. Therefore, screening for maternal HIV prevention of opportunistic
infection during pregnancy and initiating ART early is important for the prevention CNS infections.
of maternal-fetal transmission of perinatally acquired HIV. Management of
neurologic complications of perinatally acquired HIV revolves around early
initiation of combination ART and prevention of AIDS-defining illnesses and CNS
opportunistic infections. The CHER (Children with HIV Early Antiretroviral
Treatment) trial randomly assigned infants with perinatally acquired HIV in
South Africa to early initiation of combination ART (mean age at initiation,
1.5 months) or deferred treatment until the emergence of immunocompromise
(mean age at initiation, 6.8 months) as was the national clinical guidance at the
time. Although locomotor delay was observed in the deferred treatment arm at
1 year, children with perinatally acquired HIV who initiated combination ART in
both groups had developmental outcomes similar to uninfected controls at 5-year
follow-up.23 In contrast, a randomized trial of early versus deferred treatment
initiation in children older than 1 year of age living with perinatally acquired HIV in
Thailand and Cambodia did not demonstrate a benefit to early initiation of
combination ART compared with delayed initiation; children with perinatally
acquired HIV in this cohort demonstrated poor cognitive performance compared
with healthy controls regardless of the timing of combination ART initiation.24
These findings suggest that a window of opportunity may exist to preserve some
cerebral function through early initiation of combination ART in the first year of
life for infants with perinatal HIV infection.
HERPES SIMPLEX VIRUS

HSV is a double-stranded DNA virus encased in a capsid.
Epidemiology
The majority of adults and a substantial number of children older than 5 years
demonstrate serologic evidence of HSV type 1 (HSV-1) infection, whereas 20%

of adults in the United States are seropositive for HSV type 2 (HSV-2).41 HSV-2
infections are usually asymptomatic in adults with up to 70% of mothers with
neonates diagnosed with perinatally acquired HSV-2 being unaware of their
infection status.8 HSV-2 transmission to neonates most often occurs during the
birth process.25 HSV-1, in contrast, is usually transmitted to infants through oral
secretions postnatally. HSV-1 accounts for 10% of all neonatal HSV infections.
Perinatal infections with either HSV-1 or HSV-2 occur in 1 of 3200 live births
with an estimated 5% to 10% of HSV-2 infections occurring through intrauterine
transmission.8,9
HSV infection, similar to other TORCH infections, manifests as a combination of
brain, eye, and skin findings. Microcephaly, hydranencephaly, vesicles with
scarring, and chorioretinitis are classic features of congenitally acquired HSV.
The most common manifestation of HSV infection in neonates with peripartum
transmission is a vesicular rash occurring in up to 70% of infants with HSV. CNS
disease occurs in approximately half of all infants with HSV infection.8
Symptomatic presentation of HSV infection in neonates with peripartum
transmission occurs between 5 days and 2 weeks after birth.25 Early signs of HSV
encephalitis include poor feeding, lethargy, and irritability and can precede the
development of skin and eye manifestations. Classically, HSV encephalitis affects
the temporal lobe, but neonates with exposure to HSV at birth often present with
diffuse cerebral involvement (FIGURE 13-4).
FIGURE 13-4
Imaging findings in neonatal herpes simplex virus (HSV) infection. A, Axial postcontrast
T1-weighted brain MRI in an infant with neonatal HSV encephalitis. Cortical enhancement
(arrows) is observed diffusely in both cerebral hemispheres. The circles indicate areas of
parenchymal hypointensity. B, Axial T2-weighted brain MRI of the infant with neonatal HSV
encephalitis shown in panel A. The arrow points to disruption of the normal cortical ribbon
indicative of HSV-induced neuronal necrosis. The circles indicate areas of signal
hyperintensity compatible with HSV-related cerebral edema.
Reprinted with permission from Ostrander B and Bale J, Handb Clin Neurol.4 © 2019 Elsevier Science B.V.
1116 AUGUST 2021

MRI and EEG studies are useful to determine the extent of the disease process KEY POINTS
and to evaluate for the presence of seizure activity.
● Classically, herpes
simplex virus (HSV)
Diagnosis encephalitis affects the
HSV PCR performed on CSF or vesicular lesions (if present) is the gold standard temporal lobe, but neonates
for diagnosis. In neonates with HSV encephalitis, CSF HSV PCR has a 75% often present with diffuse
cerebral involvement.
positive predictive rate with most false negatives occurring early (within
24 hours of onset) in the disease process.25 Therefore, if HSV infection is ● In neonates with HSV
suspected based on clinical suspicion, acyclovir should be started immediately, encephalitis, CSF HSV
and repeat CSF testing should be performed within the next 24 to 48 hours. polymerase chain reaction
(PCR) has a 75% positive
predictive rate with most
Prevention and Treatment false negatives occurring
Before the discovery of antiviral therapy, half of infants with HSV encephalitis early (within 24 hours of
died, and the majority of survivors were left with significant developmental onset) in the disease
delays.42 With high-dose IV acyclovir, the mortality rate of HSV encephalitis process. Therefore, if HSV
infection is suspected based
dropped to 4%, but the morbidity of HSV encephalitis remains high: Only about on clinical suspicion,
one-third of infants with HSV encephalitis have normal developmental acyclovir should be started
outcomes.43 Early initiation of treatment may be protective, but large-scale immediately, and repeat
randomized studies are not feasible for definitive confirmation because of the CSF testing should be
performed within the next
unethical nature of delaying approved treatment for HSV encephalitis. 24 to 48 hours.
Retrospective studies that evaluated the time to initiation of antiviral therapy and
long-term neurologic outcomes did not demonstrate a benefit from early ● The rate of CNS morbidity
treatment in neonates. More studies are needed to determine which factors, such after HSV encephalitis
remains high (two-thirds of
as immunologic or genetic variables, significantly influence the development of
infants with a history of HSV
poor neurologic outcomes following neonatal HSV encephalitis. encephalitis experience
developmental delay)
ZIKA VIRUS despite adequate
Zika virus is a single-stranded RNA virus primarily spread by the Aedes treatment.
species of mosquitos.
Epidemiology
Zika virus was endemic to Africa and certain regions of Asia from the 1950s
until recently, and these strains were not known to cause neurologic disease. In
2013, a regional outbreak in French Polynesia resulted in an estimated 39,000
cases; although the disease burden was likely higher given the high rate of
asymptomatic disease.44 Then in 2014 and 2015, a large-scale outbreak of
Zika virus occurred in multiple states across Brazil and South America, resulting
in approximately 1 million individuals becoming infected.45 Shortly after the
onset of the epidemic, the virus spread to other parts of Central and
North America and reached mainland United States in 2016.46 Epidemiologists
noted a sudden increase in infants born with microcephaly and other CNS
malformations in the months after the Zika virus outbreaks in Brazil and
French Polynesia.47
Approximately 80% of Zika virus infections in adults are asymptomatic with
the remaining 20% causing fever and maculopapular rash as the most
common symptoms. A prospective study of mothers with confirmed Zika virus
infections during pregnancy was conducted by the Centers for Disease
Control and Prevention (CDC) and demonstrated a 5% birth defect rate

(51 in 972) in infants born to this cohort. Among infants born to women who
experienced Zika infection during the first trimester, 15% developed birth
defects, and 75% of these infants had CNS involvement.10 Zika virus can infect
neuronal progenitor cells after crossing into the fetal bloodstream through
the placenta.2 Transmission of infection during the first trimester results
in the most significant neurologic injury. Five features are considered
CASE 13-1 A 4-month-old girl who recently immigrated from Brazil presented for
evaluation of episodes of arm raising and appearing to be startled. For the
past 3 days, she had intermittent events consisting of bilateral arm
stiffening, which clustered 2 to 3 times per event and occurred at least 2
times per day. She appeared to be startled by these events afterward and
cried for her mother. Per history, she had mild motor delay with the
recent acquisition of the ability to hold her head up unassisted. She did
not roll.
Notably, on examination, she had microcephaly with overhanging
scalp folds and exhibited hypertonicity in all four extremities.
Ophthalmologic examination demonstrated chorioretinal scarring and
focal pigmentary changes in the macula. Brain MRI (FIGURE 13-550) showed
severe microcephaly with polymicrogyria predominantly involving
bilateral frontal, perisylvian, and parietal cortical regions, and numerous
foci of cerebral calcification in bilateral subcortical white matter and
gray-white matter interfaces were seen across multiple cerebral imaging
modalities.
Based on her history, examination, and imaging findings, the diagnosis
of congenital Zika syndrome was confirmed. Her EEG was notable for
hypsarrhythmia, and her seizures were classic for infantile spasms.
Vigabatrin was initiated as opposed to first-line therapy with steroidal
agents to avoid the potential side effect of insomnia and subsequent
worsening of the patient’s underlying sleep issues. She responded well to
vigabatrin but within a few months developed a new seizure type of tonic
stiffening of upper and lower extremities occurring for longer than
1 minute. Clobazam was started, and her epilepsy remained under control
at her next follow-up visit. She continued to make developmental gains
while receiving physical, occupational, and speech therapy, although
motor and verbal skills remained below average.
COMMENT This patient presented with classic features of congenital Zika syndrome,26
including severe microcephaly, thin cerebral cortex with subcortical
calcifications, and marked early hypertonia on examination. The diagnosis
of congenital Zika syndrome can be made outside the neonatal period
based on clinical presentation and supportive history. Ophthalmologic
evaluation should be considered to evaluate for features that may support
the diagnosis. Serum laboratory evaluation is of limited value for this
patient given the late presentation to care and high rate of cross-reactivity
of Zika virus titers with other flaviviruses.
1118 AUGUST 2021

characteristic of congenital Zika syndrome and distinguish congenital Zika
syndrome from other congenital CNS infections: (1) severe microcephaly with
partially collapsed skull, (2) thin cerebral cortex with subcortical calcifications, (3)
macular scarring and focal pigmentary retinal mottling, (4) congenital
contractures, and (5) marked early hypertonia.26 Fetal and postnatal imaging
often demonstrates cerebral atrophy, subcortical calcifications, posterior fossa
FIGURE 13-5
Imaging findings in congenital Zika infection.
Prenatal sagittal T2-weighted MRI (A and C) and
postnatal axial CT (B) and axial T2-weighted MRI
(D) of congenital Zika infection. The following
characteristics can be seen in the images:
microcephaly and reduced brain volume,
craniofacial disproportion with a decreased
vertical size of the skull, and prominent
occipital bone (A and C, thick arrow); enlarged
torcula filled with heterogeneous material
probably related to thrombus presence
(A, white asterisk); hypoplastic corpus callosum
(A and C, thin arrow) and brainstem (C, long
gray arrow); shallow sulci and Sylvian fissure
with hypodeveloped opercula and insular cortex
(B and D, white arrowheads); cortico-subcortical
hypointensity with thickened blurred borders
(B and D, curved arrow); ventriculomegaly with
dilated occipital horns (D, black asterisks) and
intraventricular septations (D, black arrowheads);
cerebral atrophy (D, star); and brain calcifications
as hyperdense foci on CT scan (B, black star).
Reprinted with permission from de Souza AS, et al,
Childs Nerv Syst.50 © 2018 Springer-Verlag.

abnormalities, and abnormal cortical development, including pachygyria and

lissencephaly.48 Ocular manifestations include pigmented retinopathy and optic
disc hypoplasia and are common in infants with congenital Zika syndrome.49
CASE 13-1 describes a typical example of congenital Zika syndrome.
Diagnosis
Maternal infection can be diagnosed via serum titers documenting a recent
infection with positive IgM antibodies or positive PCR detecting Zika virus RNA.
Notably, serologic assays have considerable cross-reactivity to other flaviviruses
(eg, dengue), which are often endemic to areas where Zika virus outbreaks
commonly occur. Therefore, false positives are common, hindering accurate
CASE 13-2 A neonate was born at 32 weeks of gestational age via emergency
cesarean delivery for fetal distress to a mother who did not have access
to prenatal care. At birth, the infant was noted to have
hepatosplenomegaly, ascites, and a petechial rash, and was intubated
for persistently low Apgar scores despite positive pressure ventilation.
Laboratory values were notable for elevated aspartate transaminase
(AST) and alanine transaminase (ALT), direct bilirubin of 2.0 mg/dL, and
thrombocytopenia. She was started on penicillin G, gentamicin, and
acyclovir pending the results from her infectious workup.
A neurologist was consulted on the fourth day of life when the patient
developed twitching of the right upper extremity. Routine EEG showed
evidence of multifocal spike-and-wave discharge arising from the left
central region. Multiple seizures were captured. Additionally, evidence
of a severe, diffuse, nonspecific encephalopathy with slow background
for age was seen. She was treated with IV phenobarbital with a loading
dose followed by maintenance dosing. Brain MRI
(FIGURE 13-6) demonstrated evolving bilateral intraventricular hemorrhage
with moderate dilation of the lateral and third ventricles.
Maternal rapid plasma reagin (RPR) titers returned at 1:8, and infant
RPR titers were reactive. Maternal quantitative Venereal Disease
Research Laboratory (VDRL) was 1:16 dilution, and the infant’s
quantitative VDRL was 1:64 dilution. The fourfold difference in syphilis
titers between infant and mother and the infant’s clinical examination
were consistent with a diagnosis of congenital syphilis. Treatment with
penicillin G was continued, and the patient was monitored for clinical
improvement of multiorgan dysfunction. The family was counseled
regarding a guarded prognosis about the long-term neurocognitive
development of their child.
1120 AUGUST 2021

diagnoses and prevalence estimates of primary maternal Zika viral infections and
resultant congenital Zika syndrome.

No known antiviral agent is effective for treatment of Zika virus infection.
Vaccine studies are currently in development for the prevention of congenital
Zika syndrome. Mosquito abatement programs, governmental programs that
target areas where mosquito populations are likely to breed through the use of
pesticides, nets, and traps, have played an important role in the reduction of the
incidence of flavivirus infections, including mosquito-to-human transmission of
Zika virus.51
FIGURE 13-6
Susceptibility-weighted imaging (SWI)
from the patient in CASE 13-2
demonstrates intraventricular
hemorrhage with ventricular dilation.
Early initiation of broad-spectrum antimicrobial agents in infants with COMMENT

presentations concerning for neonatal sepsis is an important first step in
clinical care. Premature birth is a common consequence of congenital central
nervous system infections. A fourfold difference in serum quantitative
nontreponemal serologic tests between mother and child is diagnostic of
congenital syphilis, especially in the setting of the clinical presentation noted
here. Direct treponemal tests (eg, serum fluorescent treponemal antibody
absorption [FTA-ABS]) are not recommended because of low sensitivity and
specificity for congenital syphilis. Lumbar puncture is recommended to
evaluate the extent of the disease process. CSF results should be interpreted
with caution because healthy neonates often have a high white blood cell
count at baseline given the increased permeability of the blood-brain barrier.
IV or IM penicillin G is the recommended treatment for congenital syphilis.

SYPHILIS
Syphilis infection is caused by the bacterium Treponema pallidum and is
primarily spread through sexual transmission.
Epidemiology
Global prevalence rates of congenital syphilis are estimated to be 473 per
100,000 live births with approximately 661,000 infants diagnosed with clinically
apparent congenital syphilis worldwide annually. Congenital syphilis incidence
coincides with rates of new adult cases. Improved access to prenatal care and
national screening and treatment guidelines have led to a reduction in the
incidence of congenital syphilis cases in certain countries. In the United States,
maternal-fetal transmission of syphilis had been decreasing up until 2013.
From 2013 to 2018, congenital syphilis rates tripled from 362 annually to
1300 annually.11 According to the CDC, the Southern United States has the
highest rate of congenital syphilis cases compared with other regions in the
United States, and a quality-of-care study discovered that inadequate treatment
of maternal syphilis is the primary cause of high case rates in the South.12 In
other regions in the United States, the lack of access to timely prenatal care or
repeat testing after seroconversion during pregnancy play a significant role in
maternal-fetal transmission of syphilis. Racial disparities were highlighted in
these findings as Black and Hispanic mothers were more likely to receive
inadequate treatment for syphilis infections compared with White mothers,
predominantly in the South.12
Maternal-fetal transmission of syphilis occurs in utero; the highest risk of
transmission occurs in the first and second trimesters and in pregnant women
who are in their primary or secondary stages of syphilis infection.
Diagnosis
Poor prenatal outcomes are commonly observed in infants born to mothers
with untreated syphilis and include stillbirths, prematurity, and low
birth weight in addition to common clinical manifestations of congenital
syphilis.52,53 Early manifestations of congenital syphilis include maculopapular
rash, hepatosplenomegaly, nasal secretions (snuffles), pneumonia, and
osteochondritis. CNS symptoms of congenital syphilis can present in
early adolescence or adulthood as meningitis, infarcts, hydrocephalus, and
hearing loss after 10 to 40 years of untreated infection. Ocular manifestations
of chorioretinitis or glaucoma or both can co-occur with neurologic
symptoms.
Infants born to mothers diagnosed with syphilis should be screened with a
quantitative serum nontreponemal test (rapid plasma reagin [RPR] or Venereal
Disease Research Laboratory [VDRL]). In infants with positive screening
tests, evaluation for clinical signs of congenital syphilis is recommended,
although the lack of clinical findings does not exclude the diagnosis.27 Direct
detection methods, such as dark field microscopy, immunofluorescence, or
PCR, may be useful when performed on fresh skin lesions. However, these
methods have low sensitivity and specificity on neonatal samples. Special
equipment and experienced technicians are required to perform direct detection
laboratory tests, and therefore, these methods may not be feasible in
resource-limited settings.
1122 AUGUST 2021

In infants with reactive serum RPR or VDRL, diagnosis of congenital syphilis KEY POINTS
is made if one or more of the following are present27:
● Five features are
considered characteristic of
u Clinical signs characteristic of congenital syphilis
congenital Zika syndrome
u Serum quantitative nontreponemal titers that are fourfold higher than maternal titers and distinguish congenital
Zika syndrome from other
u A positive dark field test or PCR of lesions, placenta, or infant bodily fluids
congenital CNS infections:
(1) severe microcephaly with
Per CDC recommendations, infants meeting these criteria should undergo a partially collapsed skull, (2)
lumbar puncture with CSF VDRL testing, screening for clinical manifestations of thin cerebral cortex with
congenital syphilis with hearing test and ocular examination, and brain MRI.27 subcortical calcifications,
(3) macular scarring and
See CASE 13-2 for an example of congenital syphilis. focal pigmentary retinal
mottling, (4) congenital
Prevention and Treatment contractures, and (5)
marked early hypertonia.
An important aspect of the treatment of syphilis is prevention through early
diagnosis and treatment of maternal syphilis. The World Health Organization ● False-positive rates are
and most national guidelines recommend screening for maternal syphilis during high for serum Zika titers
the first trimester with follow-up screening recommended in high-risk given cross-reactivity with
other flaviviruses. These
populations.54 A systematic review of data from countries implementing national viruses often coexist in the
screening guidelines indicated that universal testing reduced rates of congenital same geographic area.
syphilis and adverse neonatal outcomes by more than 50%.55 Therefore, accurate
IV or IM penicillin G for 10 to 15 days is the recommended treatment for prevalence data are difficult
to ascertain after endemic
infants with congenital syphilis.28 All infants born to mothers with syphilis
outbreaks.
should be followed for at least 6 months with nontreponemal titers to ensure that
titers become nonreactive.27 Infants with positive nontreponemal titers after ● Neurologic
6 months should be reevaluated with repeat CSF testing and treated with a manifestations of congenital
second course of IV penicillin G.56 syphilis present late after
decades of untreated
infection and include
meningitis, infarcts,
CONCLUSION hydrocephalus, and hearing
Many congenital CNS infections are preventable and treatable, making early loss.
maternal and fetal diagnosis essential in protecting the integrity of the ● Congenital syphilis is
developing brain. This article summarizes current prevalence, clinical features, diagnosed if one or more of
diagnostic criteria, and treatment guidelines for congenitally acquired CNS the following are true in
infections to aid neurologists in the management of infants after congenital or infants with reactive serum
rapid plasma reagin (RPR) or
perinatal exposure to pathogens that have the potential to cause neurologic injury.
Venereal Disease Research
Laboratory (VDRL): (1)
clinical signs characteristic
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serum quantitative
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maternal titers, and (3) a
positive dark field test or
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1126 AUGUST 2021

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POSTREADING TEST
ARTICLE 1: APPROACH TO NEUROLOGIC INFECTIONS
1 A macular star seen on ophthalmoscopy is associated with an infection

caused by which of the following agents?
A Bartonella henselae
B cytomegalovirus
C Plasmodium malariae
D Taenia solium
E Treponema pallidum
2 Consumption of unpasteurized milk risks exposure to which of the

following infectious agents?
A Bartonella henselae
B Borrelia burgdorferi
C Clostridium botulinum
D Leptospira interrogans
E Listeria monocytogenes
3 Empiric treatment of community-acquired meningitis in adults at

risk for Listeria monocytogenes should include which of the following
antibiotics?
A ampicillin
B cefepime
C ceftriaxone
D meropenem
E vancomycin
ARTICLE 2: MENINGITIS
4 Limitations of metagenomic next-generation sequencing include

which of the following?
A it does not evaluate for common nosocomial causes of meningitis

B it does not evaluate for syphilis
C it has no value in patients with subacute or chronic meningitis
D positive predictive value is low for Cryptococcus neoformans/
Cryptococcus gattii when compared with testing for cryptococcal
antigen
E results may not necessarily explain the patient’s clinical
presentation
1130 AUGUST 2021

5 The meningococcal vaccine should be administered before initiation of
treatment with which of the following monoclonal antibodies?
A eculizumab
B galcanezumab
C natalizumab
D ocrelizumab
E rituximab
6 Serial lumbar punctures are often required as part of the management

for meningitis caused by which of the following infections?
A blastomycosis
B coccidiomycosis
C cryptococcosis
D histoplasmosis
E sporotrichosis
ARTICLE 3: ENCEPHALITIS AND BRAIN ABSCESS
7 A 17-year-old boy is brought to the emergency department with a

fever, rash, and altered mentation. He developed a painful vesicular
rash over his right cheek extending to the nose 1 week ago. Yesterday,
he seemed sleepy and somewhat confused throughout the day; this
morning, the family noted that the lower right side of his face did not
elevate when he smiled. His examination in the emergency department
is significant for lethargy, a right upper motor neuron pattern of facial
weakness, and brisk reflexes and an upgoing toe on the right. An MRI
of the brain reveals patchy areas of T2 hyperintensity in the left
subcortical white matter with restricted diffusion. A lumbar puncture
demonstrates moderate lymphocytic predominance, modestly
elevated protein, and a normal glucose level. Polymerase chain
reaction (PCR) for herpes simplex virus (HSV) and varicella-zoster
virus (VZV) is negative. Which of the following tests would be most
helpful to do next?
A repeat HSV PCR

B repeat VZV PCR
C test for anti-HSV antibodies in CSF
D test for anti-HSV antibodies in serum
E test for anti-VZV antibodies in CSF

POSTREADING TEST
8 Brain MRI T2 hyperintensity in which of the following regions would

best support West Nile virus neuroinvasive disease?
A bilateral basal ganglia

B bilateral frontopolar and orbitofrontal cortex
C bilateral occipital cortex and juxtacortical white matter
D patchy subcortical white matter
E unilateral mesial temporal
9 An otherwise healthy 30-year-old woman comes to the emergency

department with low-grade subjective fevers, mild dizziness, and
nausea; is diagnosed with a viral syndrome; and is sent home. She
continues to have fevers and, 5 days later, begins to have gait
imbalance followed by the onset of diplopia the next day. She returns
to the emergency department and is found to have a fever to 39°C
(102.2°F). Her examination is notable for decreased abduction of the
right eye and mild weakness of the orbicularis oculi and oris on the
right. A CT scan is unremarkable, and a lumbar puncture
demonstrates a mild lymphocytic pleocytosis with normal protein and
glucose levels. Brain MRI demonstrates T2 hyperintensities in the
brainstem most prominently at the pontomedullary junction. Which
of the following organisms is most likely the cause of her illness?
A Borrelia burgdorferi
B Listeria monocytogenes
C Neisseria meningitidis
D Rickettsia rickettsii
E Treponema pallidum
10 A 28-year-old woman with polymerase chain reaction (PCR)-

established herpes simplex virus (HSV) encephalitis was slowly
improving but then experiences a return of her previous confusion
and somnolence, as well as worsening of focal seizures. Which of the
following tests would be most likely to uncover the cause of her
relapse?
A anti–myelin oligodendrocyte glycoprotein antibody testing

B anti–N-methyl-D-aspartate (NMDA) receptor antibody testing
C HSV PCR
D metagenomic next-generation sequencing of CSF
E varicella-zoster virus PCR
1132 AUGUST 2021

ARTICLE 4: INFECTIONS OF THE SPINE AND SPINAL CORD
11 A 65-year-old man with diabetes who began hemodialysis 6 months

ago presents with several weeks of back pain and night sweats. Over
the past 24 hours, he developed fever prompting his presentation to
the emergency department. He meets criteria for sepsis. MRI of the
spine with contrast revealed T2 hyperintensity and contrast
enhancement of the T3 and T4 intervertebral discs with surrounding
involvement of the inferior and superior endplates and increased
signal of the paravertebral soft tissue with severe cord compression.
He has leukocytosis and an elevated erythrocyte sedimentation rate to
85 mm/h. Blood cultures and CSF studies are pending. Which of the
following best describes the optimal timing of surgical intervention in
this patient?
A defer until the patient has been shown to have no response to

medical management
B defer until the results of the pending cultures are known
C delay for 24 to 48 hours after initiation of IV antibiotics
D immediate intervention is warranted
E surgical intervention is not indicated
12 A 70-year-old woman who had chemotherapy and autologous stem

cell transplant 5 years ago presents to her local emergency department
in Denver, Colorado, in August with fever, myalgias, headaches, a
maculopapular rash, and an acute flaccid paraparesis that progressed
over the past several days. On examination, she also has tremor,
rigidity, and bradykinesia. Spinal MRI demonstrates multilevel T2
hyperintensity without contrast enhancement. CSF analysis
demonstrates a neutrophilic-predominant pleocytosis of 75 cells/mm3,
protein of 85 mg/dL, and normal glucose. Which of the following
studies has the greatest sensitivity given the probable diagnosis?
A CSF IgM
B CSF polymerase chain reaction (PCR)
C serum IgM
D serum PCR
E throat swab IgA

POSTREADING TEST
ARTICLE 5: INFECTIONS OF THE PERIPHERAL NERVOUS SYSTEM
13 A 45-year-old man living with human immunodeficiency virus (HIV)

presents with lumbar paraspinal pain, pain and numbness affecting
his legs, and bilateral lower extremity weakness. The symptoms have
developed over the past 2 weeks and were initially associated with
fever and malaise without rash. In addition to his sensorimotor
symptoms, his examination reveals decreased patellar and ankle
reflexes and evidence of retinitis on fundoscopy. A nerve conduction
study and EMG confirms a lumbosacral radiculopathy, and MRI
shows enhancement of the cauda equina. A lumbar puncture,
obtained after the MRI, reveals elevated protein and a
polymorphonuclear pleocytosis. Which of the following infectious
agents is most likely responsible for this patient’s radiculopathy?
A cytomegalovirus
B Epstein-Barr virus
C herpes simplex virus type 2
D human immunodeficiency virus (HIV)
E varicella-zoster virus
14 A 54-year-old woman presents to clinic with numbness and tingling in

her right fourth and fifth fingers. These symptoms have been present
for several months and have gradually worsened in intensity. She has
experienced no other symptoms of being ill and has been otherwise
healthy. She was born and raised in Brazil. On examination, she has
mild wasting of the hypothenar eminence, a palpably enlarged nerve
at the right cubital tunnel, and four scattered erythematous rough
ovoid plaques over her arms. Sensation is decreased over these
plaques. Which of the following infectious agents is most likely
responsible for her symptoms?
A Corynebacterium diphtheriae
B hepatitis B virus
C human immunodeficiency virus (HIV)
D Mycobacterium leprae
E Mycobacterium tuberculosis
1134 AUGUST 2021

15 A 12-year-old boy is brought to the emergency department with the
recent onset of numbness of the tongue and gums as well as difficulty
with articulation and swallowing. Three weeks before these
symptoms, the patient had a flulike illness with fever and a sore
throat. Which of the following agents is most likely responsible?
A Borrelia burgdorferi
B Corynebacterium diphtheriae
C cytomegalovirus
D group A streptococcus
E human T-cell lymphotropic virus type I (HTLV-I)
16 A 4-month-old girl is brought to the emergency department with poor

oral intake and lethargy. She has had no fever or rash and no emesis,
but she has been constipated over the past week. On examination, she
has dilated pupils, ptosis, and facial muscle weakness, as well as
reduced appendicular muscle tone. Which of the following
treatments is most appropriate?
A ceftriaxone
B heptavalent botulinum antitoxin
C IV botulism immunoglobulin
D IV immunoglobulin
E plasma exchange
ARTICLE 6: PARASITIC INFECTIONS OF THE NERVOUS SYSTEM
17 The neurologic deficits in cerebral malaria occur through which of

the following mechanisms?
A chronic arachnoiditis from infiltration of the subarachnoid spaces

B direct intraparenchymal infiltration
C hydrocephalus due to ventricular obstruction
D intravascular sequestration of infected erythrocytes
E subarachnoid hemorrhage

POSTREADING TEST
18 A 28-year-old woman presents to the emergency department after

having a witnessed seizure. On history and examination, she is mildly
confused but able to report that she has had several weeks of fever
and headaches. She has right hemiparesis and right-sided
hyperreflexia. CT reveals multiple parenchymal lesions, including
several in the basal ganglia with significant perilesional edema. MRI
shows an even greater lesion load with T1-hypointense and
T2-hyperintense lesions with ring enhancement. Serum enzyme-linked
immunoabsorbent assay and Western blot for human
immunodeficiency (HIV) are positive and CD4+ count is 92 cells/mm3.
Which of the following is the most appropriate next step?
A antiretroviral therapy
B brain biopsy
C high-dose IV methotrexate
D lumbar puncture
E trimethoprim-sulfamethoxazole therapy
19 Which of the following testing modalities is most beneficial for

monitoring the efficacy of antiparasitic treatment in a patient with
neurocysticercosis?
A CSF antibody detection

B CSF antigen detection
C serum antibody detection
D serum antigen detection
E urine antibody detection
ARTICLE 7: NEUROLOGIC COMPLICATIONS OF HUMAN IMMUNODEFICIENCY

VIRUS
20 A 56-year-old man with advanced acquired immunodeficiency

syndrome (AIDS) and human immunodeficiency virus
(HIV)-associated dementia develops a slowly progressive spastic
paraparesis, impaired bladder control, and sensory dysfunction.
On his examination, deep tendon reflexes are brisk, and he has
velocity-dependent increased tone of the lower extremities. After
death, examination of the spinal cord at autopsy is most likely to
demonstrate which of the following findings?
A extensive microhemorrhages
B grey matter liquefactive necrosis
C patchy demyelination
D wallerian degeneration of descending tracts
E white matter vacuolization
1136 AUGUST 2021

21 What is the most commonly encountered neurologic complication of
human immunodeficiency virus (HIV)?
A cryptococcal meningitis
B distal symmetric polyneuropathy
C HIV-associated dementia
D immune reconstitution inflammatory syndrome
E progressive multifocal leukoencephalopathy
22 A 46-year-old man with human immunodeficiency virus (HIV)

taking stavudine as part of his regimen develops severe sensory and
motor dysfunction with nausea and vomiting over the course of
3 days. On examination, he appears ill and has clear hepatomegaly.
His neurologic examination is notable for significant appendicular
sensory loss, weakness of arms and legs, and decreased reflexes.
Blood work reveals an elevated serum lactate. Which of the following
conditions is most likely in this patient?
A diffuse infiltrative lymphocytosis syndrome

B HIV vacuolar myelopathy
C HIV-associated neuromuscular syndrome
D toxic peripheral neuropathy
E toxoplasma myositis
ARTICLE 8: NEUROLOGIC COMPLICATIONS OF TUBERCULOSIS
23 Which of the following limitations is shared by all of the current

primary microbiological testing used for central nervous system
diagnosis of tuberculous meningitis?
A impacted by immunosuppression/immunocompromise
B low sensitivity
C low specificity
D not well-validated
E time to availability of the result

POSTREADING TEST
24 A 45-year-old man presents with altered consciousness. His

symptoms were preceded by 3 weeks of headache and 2 months of
unintentional weight loss, night sweats, and intermittent fevers. On
examination, he is minimally arousable to sternal rub (would grimace
and grunt) but would not track the examiner or follow other
commands and is otherwise nonverbal. He has bilateral papilledema.
Chest x-ray shows a cavitary left upper lobe lesion, and he has a
positive urine lipoarabinomannan antigen. His human
immunodeficiency virus (HIV) viral load is elevated, and his CD4+
T-cell count is 48 cells/mm3. MRI reveals basal leptomeningeal
enhancement, bilateral deep infarcts, and several well-circumscribed
lesions with extensive surrounding vasogenic edema. Which of the
following are the most appropriate next steps in the management of
this patient?
A initiate treatment with IV dexamethasone and perform a lumbar

puncture to obtain CSF acid-fast bacilli stain with the plan to
initiate antituberculous therapy once the specimen is collected
B initiate treatment with IV dexamethasone and perform a lumbar
puncture to send CSF acid-fast bacilli stain with the plan to start
antituberculous management if positive
C initiate treatment with standard antituberculous therapy and add
IV dexamethasone and antiretroviral therapy if repeat MRI does
not show improvement after 2 weeks
D initiate treatment with standard antituberculous therapy and IV
dexamethasone and add antiretroviral therapy after 1 week
E initiate treatment with standard antituberculous therapy and IV
dexamethasone and perform a lumbar puncture to obtain
baseline CSF studies to trend effectiveness of therapy
ARTICLE 9: NEUROSYPHILIS
25 Which of the following syphilitic manifestations can commonly be

seen in early infection?
A general paresis
B meningovascular disease
C syphilitic amyotrophy
D syphilitic cerebellar ataxia
E tabes dorsalis
1138 AUGUST 2021

26 A 63-year-old man being evaluated for memory impairment has a
positive fluorescent treponemal antibody absorption test and a
negative rapid plasma reagin (RPR). His neurologic examination is
unremarkable, and he reports no history of sexually transmitted
diseases. What would be the most appropriate next step in his
evaluation and management?
A begin empiric treatment with penicillin G

B brain MRI with and without contrast
C continued observation
D lumbar puncture and CSF analysis
E repeat serum nontreponemal test
27 In a patient with a serious penicillin allergy, which of the following

regimens would be the appropriate treatment for neurosyphilis
according to the Centers for Disease Control and Prevention
guidelines?
A cefotaxime
B ceftriaxone
C cephalexin
D doxycycline
E penicillin G and steroids
ARTICLE 10: NEUROLOGIC COMPLICATIONS OF LYME DISEASE
28 Which of the following examination findings is more common in

children with Lyme meningitis than in adults?
A bilateral facial weakness

B hearing loss
C papilledema
D spastic gait
E urinary retention
29 Pain and weakness in one or more limbs in the setting of acute Lyme
disease are caused by which of the following peripheral nerve
disorders?
A amyotrophy
B mononeuropathy multiplex
C peripheral polyneuropathy
D plexitis
E radiculitis

POSTREADING TEST
30 An isolated positive Lyme IgM Western blot in a patient with greater

than 6 weeks of symptoms is consistent with which of the following
infection statuses?
A active ongoing infection that is not yet treated

B chronic Lyme disease
C exposure to Lyme disease in the past without active infection
D history of a previous infection, now resolved after treatment
E nonspecific cross-reactivity without evidence of infection
ARTICLE 11: NEUROLOGIC MANIFESTATIONS OF SEVERE ACUTE

RESPIRATORY SYNDROME CORONAVIRUS 2 INFECTION
31 Which of the following proteins acts as the receptor for severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2)?
A angiotensin-converting enzyme receptor type 2 (ACE2)

B intercellular adhesion molecule 1
C junctional adhesion molecule A
D spike protein S1 polypeptide
E spike protein S2 polypeptide
32 A 25-year-old man is diagnosed with a severe acute respiratory

syndrome coronavirus 2 (SARS-CoV-2) infection after developing
anosmia, low-grade fever, and malaise. Over the next 4 days, while
quarantining at home, he becomes increasingly somnolent and
confused and is brought back to the emergency department for
evaluation. MRI reveals bilateral symmetric hemorrhagic lesions in
the thalami as well as in the temporal poles without contrast
enhancement. Which of the following conditions is most likely
present in this patient?
A acute disseminated encephalomyelitis

B acute necrotizing hemorrhagic encephalopathy
C antiphospholipid autoimmune encephalitis
D intracerebral hemorrhage
E SARS-CoV-2 meningoencephalitis
33 Which of the following syndromes is the most common neurologic

manifestation of COVID-19 in hospitalized patients?
A encephalopathy
B Guillain-Barré syndrome
C myelitis
D myositis
E stroke
1140 AUGUST 2021

ARTICLE 12: NEUROLOGIC INFECTIONS IN PATIENTS ON IMMUNOMODULATORY
AND IMMUNOSUPPRESSIVE THERAPIES
34 After hematopoietic cell transplantation, when are patients most at

risk of illness secondary to reactivation of preexisting latent
infections?
A within the first month

B between months 2 and 6
C after 1 year
D at 5 years or later
E the risk is equal throughout the time the patient remains on
immunosuppression
35 Which of the following regimens is most appropriate for the

monitoring for the development of progressive multifocal
leukoencephalopathy in patients on natalizumab?
A brain MRI and serologic JC virus testing every 6 months

B brain MRI and serologic JC virus testing every 12 months
C brain MRI every 6 months and serologic JC virus testing every
12 months
D brain MRI every 12 months and serologic JC virus testing every
6 months
E brain MRI every 2 years and serologic JC virus testing every
12 months
36 Prophylactic acyclovir for 1 month is indicated after treatment with

which of the following medications?
A alemtuzumab
B eculizumab
C natalizumab
D rituximab
E siponimod

POSTREADING TEST
37 A 65-year-old woman with long-standing rheumatoid arthritis

managed over the years on various immunosuppressive agents,
including methotrexate and corticosteroids, presents with her third
stroke in the past 7 months. MRI reveals several infarctions of
different ages, involving different vascular territories,
predominantly located at the gray-white matter junction with the
most acute one being contrast enhancing. The patient likely has a
vasculopathy related to which of the following infections?
A BK virus
B cytomegalovirus
C herpes simplex virus
D human herpesvirus 6
E varicella-zoster virus
ARTICLE 13: CONGENITAL INFECTIONS OF THE NERVOUS SYSTEM
38 A 6-month-old infant is evaluated for seizures is found on

examination to have chorioretinitis, macrocephaly, and concern for
hearing loss. His general examination reveals hepatomegaly, and
imaging demonstrates cerebral calcifications. The pregnancy and
exposure history are significant only for maternal consumption of
raw meat early in the first trimester. Which of the following
strategies could have prevented or treated this congenital infection?
A full maternal immunization with standard vaccines

B maternal combination antiretroviral therapy
C maternal treatment with IM penicillin G
D neonatal IV ganciclovir
E spiramycin given in the first trimester
39 A 12-month-old being evaluated for progressive sensorineural

hearing loss was born at term after an uncomplicated pregnancy with
a normal neonatal course and no perinatal concerns. Hearing loss was
first detected at 2 months and has been progressively worsening. He
has also been falling behind developmentally although his early
milestones were met on time. Which of the following congenital
infections is most likely the cause of the patient’s illness?
A cytomegalovirus
B human immunodeficiency virus (HIV)
C rubella
D syphilis
E toxoplasmosis
1142 AUGUST 2021

40 Which of the following clinical features or imaging findings is
characteristic of congenital Zika syndrome?
A cerebral calcifications
B chorioretinitis
C maculopapular rash
D partially collapsed skull
E white matter hyperintensities

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By James W. M. Owens Jr, MD, PhD; Allison L. Weathers, MD, FAAN
NEUROINFECTIOUS DISEASE
Following are the preferred responses to the questions in the Postreading
Self-Assessment and CME Test in this Continuum issue. The preferred
response is followed by an explanation and a reference with which you
may seek more specific information. You are encouraged to review the
responses and explanations carefully to evaluate your general
understanding of the article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon completion of the Postreading Self-Assessment and

CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the University of Calgary Office of Continuing Medical
Education and Professional Development. Refer to the CME tab on
ContinuumJournal.com for dates of accreditation. Canadian participants
should visit MAINPORT (www.mainport.org) to record learning and
outcomes. Canadian participants can claim a maximum of 20 hours per
1144 AUGUST 2021

ARTICLE 1: APPROACH TO NEUROLOGIC INFECTIONS
1 The preferred response is A (Bartonella henselae). A macular star is

associated with Bartonella henselae infections. Cytomegalovirus can
cause retinitis, malaria can be associated with retinopathy, and
neurocysticercosis can cause subconjunctival or subretinal cysts.
Neurosyphillis is associated with light-near dissociation but not with
structural ocular findings. For more information, refer to page 820 of the
Continuum article, “Approach to Neurologic Infections.”
2 The preferred response is E (Listeria monocytogenes). Drinking

unpasteurized milk is a risk factor for infection with L. monocytogenes.
For more information, refer to page 822 of the Continuum article,
“Approach to Neurologic Infections.”
3 The preferred response is A (ampicillin). Ampicillin should be used in the

empiric treatment of meningitis when Listeria monocytogenes is a
concern. For more information, refer to page 823 of the Continuum
article, “Approach to Neurologic Infections.”
4 The preferred response is E (results may not necessarily explain the

patient’s clinical presentation). Metagenomic next-generation
sequencing may have utility in the evaluation of patients with subacute
and chronic meningitis, especially in cases in which initial studies have
been negative, because it may increase the chance of detecting an
organism without the bias of a specific target. However, results should
be correlated with the patient’s clinical presentation, because organisms
may be detected that are not relevant to the patient’s clinical state. For
more information, refer to page 833 of the Continuum article,
“Meningitis.”
5 The preferred response is A (eculizumab). Eculizumab is a complement

inhibitor used in the treatment of neuromyelitis optica and myasthenia
gravis. Its use is associated with a 1000-fold to 2,000-fold increased
incidence of meningococcal meningitis, so administration of the
meningococcal vaccine is recommended before initiation of treatment.
“Meningitis.”

POSTREADING TEST—PREFERRED RESPONSES
6 The preferred response is C (cryptococcosis). Elevated intracranial

pressure is a frequent complication of cryptococcus meningitis, and
serial lumbar punctures or temporary external ventricular drain
placement is often required as part of the management. Severe cases
may require permanent ventriculoperitoneal shunt placement. Although
serial lumbar punctures are not routinely part of the management of
coccidiomycosis, lifelong azole treatment is recommended. Treatment
with antifungal agents is required for at least 1 year for blastomycosis,
histoplasmosis, and sporotrichosis. For more information, refer to
page 849 of the Continuum article, “Meningitis.”
ARTICLE 3: ENCEPHALITIS AND BRAIN ABSCESS
7 The preferred response is E (test for anti–varicella-zoster virus [VZV]

antibodies in CSF). This patient’s presentation is most consistent with
VZV encephalitis accompanied by vasculopathy and, in light of the
relatively low sensitivity of VZV polymerase chain reaction (PCR), testing
for anti-VZV antibodies in the CSF is most likely to be diagnostic. For
“Encephalitis and Brain Abscess.”
8 The preferred response is A (bilateral basal ganglia). West Nile virus

neuroinvasive disease tends to affect the basal ganglia and thalamus.
“Encephalitis and Brain Abscess.”
9 The preferred response is B (Listeria monocytogenes). This patient’s

biphasic course with development of a rhombencephalitis would be
most consistent with an infection by L. monocytogenes. For more
information, refer to page 867 of the Continuum article, “Encephalitis
and Brain Abscess.”
10 The preferred response is B (anti–N-methyl-D-aspartate [NMDA]

receptor antibody testing). Anti-NMDA receptor autoimmune
encephalitis accounts for most cases of relapse in herpes simplex virus
encephalitis and should be tested for in this patient. For more
information, refer to page 871 of the Continuum article, “Encephalitis and
Brain Abscess.”
1146 AUGUST 2021

ARTICLE 4: INFECTIONS OF THE SPINE AND SPINAL CORD
11 The preferred response is D (immediate intervention is warranted).

This patient’s presentation and imaging findings are consistent with a
diagnosis of infectious spondylodiscitis. Because the patient is
hemodynamically stable but meets sepsis criteria and MRI reveals cord
compression with an identifiable surgical target, immediate surgical
intervention is indicated. Surgery should not be deferred until blood
cultures or CSF studies have returned or until medical management has
failed. For more information, refer to page 892 of the Continuum article,
“Infections of the Spine and Spinal Cord.”
12 The preferred response is A (CSF IgM). The patient’s presentation

and workup are consistent with a probable diagnosis of West Nile
neuroinvasive disease. CSF IgM is more sensitive than CSF polymerase
chain reaction (PCR). As the viremic phase of West Nile infection usually
occurs before symptom onset, the sensitivity of serum studies is lower.
The presence of West Nile virus IgM in the CSF indicates intrathecal
synthesis and is diagnostic of West Nile neuroinvasive disease. For more
information, refer to page 904 of the Continuum article, “Infections of
the Spine and Spinal Cord.”
ARTICLE 5: INFECTIONS OF THE PERIPHERAL NERVOUS SYSTEM
13 The preferred response is A (cytomegalovirus). This patient’s constellation

of findings would be most consistent with a cytomegalovirus lumbosacral
polyradiculopathy. Varicella-zoster virus infection would often be
accompanied by a painful dermatomal and vesicular rash as well as nerve
root enhancement on MRI. The MRI in herpes simplex virus type 2 may show
smooth nerve root enhancement, different from what is seen here. Human
immunodeficiency virus (HIV) is more likely to cause a length-dependent
axonal neuropathy. For more information, refer to pages 923-925 of the
Continuum article, “Infections of the Peripheral Nervous System.”
14 The preferred response is D (Mycobacterium leprae). This patient’s

constellation of findings is most consistent with leprosy, an infection by
Mycobacterium leprae. Hepatitis B virus usually is associated with a
vasculitic neuropathy. Diphtheritic neuropathy would typically be
associated with constitutional symptoms of illness, most commonly a
pharyngitis, preceding the onset of neuropathic symptoms. Tuberculosis
can cause a radiculitis in patients who are immunocompromised. For
more information, refer to pages 927-928 of the Continuum article,
“Infections of the Peripheral Nervous System.”

15 The preferred response is B (Corynebacterium diphtheriae). The age of the

patient, the preceding flulike symptoms with pharyngitis, and the cranial
neuropathy would all be most consistent with a diphtheritic neuropathy.
Most patients will then go on to develop a more diffuse neuropathy but will
also eventually fully recover. For more information, refer to page 932 of
the Continuum article, “Infections of the Peripheral Nervous System.”
16 The preferred response is C (IV botulism immunoglobulin). This patient

has infant botulism, which would be most appropriately treated with IV
botulism immunoglobulin. For more information, refer to pages 935-937
of the Continuum article, “Infections of the Peripheral Nervous System.”
ARTICLE 6: PARASITIC INFECTIONS OF THE NERVOUS SYSTEM
17 The preferred response is D (intravascular sequestration of infected

erythrocytes). In cerebral malaria, the parasite does not actually
infiltrate the brain parenchyma or subarachnoid space directly. Injury
occurs through intravascular sequestration of infected erythrocytes with
resultant cytokine release, blood-brain barrier disruption, brain edema,
and metabolic alterations. For more information, refer to page 946 of the
Continuum article, “Parasitic Infections of the Nervous System.”
18 The preferred response is E (trimethoprim-sulfamethoxazole therapy).

The patient’s presentation and imaging findings are consistent with a
diagnosis of toxoplasmosis. As cerebral toxoplasmosis is the most common
etiology of expansive brain lesions in patients with human immunodeficiency
virus (HIV) and acquired immunodeficiency syndrome (AIDS) and the chance
of a good outcome is improved with the early initiation of anti-Toxoplasma,
therapy should be initiated with trimethoprim-sulfamethoxazole
without delay. It is generally recommended that antiretroviral therapy
not be started until approximately 2 weeks of anti-Toxoplasma therapy
have been completed to decrease the risk of immune reconstitution
inflammatory syndrome. For more information, refer to page 948 of the
Continuum article, “Parasitic Infections of the Nervous System.”
19 The preferred response is D (serum antigen detection). Although

antigen detection is less sensitive than antibody detection and,
therefore, less useful in the diagnosis of neurocysticercosis, it confirms
the presence of living parasites and is also a much more useful tool
than antibody measurements regarding monitoring treatment effects.
Antibody levels take a long time to become negative. Antibody testing
has a high sensitivity (98%) and specificity (near 100%) in patients with
multiple live brain cysts, but the sensitivity drops to as low as 70% in
1148 AUGUST 2021

patients with only a single cyst. In terms of diagnosis, CSF testing does
not provide any benefits over serum testing, and the advantages of
serum versus CSF collection make it the sample of choice. However, it
is unclear whether CSF antigen assessments could be more sensitive
than serum for early detection of late relapses. For more information,
refer to page 952 of the Continuum article, “Parasitic Infections of the
Nervous System.”
ARTICLE 7: NEUROLOGIC COMPLICATIONS OF HUMAN IMMUNODEFICIENCY

VIRUS
20 The preferred response is E (white matter vacuolization). This patient

most likely has human immunodeficiency virus (HIV)-associated
vacuolar myelopathy, which is pathologically characterized by white
matter vacuolization. For more information, refer to pages 971-972 of
the Continuum article, “Neurologic Complications of Human
Immunodeficiency Virus.”
21 The preferred response B (distal symmetric polyneuropathy). The most

commonly encountered neurologic complication of human
immunodeficiency virus (HIV) is distal symmetric polyneuropathy. For
“Neurologic Complications of Human Immunodeficiency Virus.”
22 The preferred response is C (human immunodeficiency virus [HIV]-

associated neuromuscular syndrome). This patient’s constellation of
findings would best fit with HIV-associated neuromuscular weakness
syndrome. Diffuse infiltrative lymphocytosis syndrome presents as a
painful multifocal symmetric axonal neuropathy. HIV vacuolar
myelopathy would be associated with subacute progressive spastic
paraparesis and loss of bladder control. Nucleoside reverse
transcriptase inhibitors such as stavudine can be associated with a toxic
peripheral neuropathy, but this would not explain the patient’s systemic
findings, nor would toxoplasma myositis. For more information, refer to
page 985 of the Continuum article, “Neurologic Complications of Human
Immunodeficiency Virus.”
ARTICLE 8: NEUROLOGIC COMPLICATIONS OF TUBERCULOSIS
23 The preferred response is B (low sensitivity). Current primary testing

used for the central nervous system diagnosis of tuberculous
meningitis includes CSF stain for acid-fast bacilli, Mycobacterium

culture, and nucleic acid amplification tests. All of these studies have
high specificity but are limited by low sensitivity. CSF parameters such
as cell counts, glucose, and protein are nonspecific findings and may
not be present in patients with immunosuppression or who are
immunocompromised. CSF Mycobacterium cultures have the highest
sensitivity of the tests listed but can take several weeks for results,
limiting their use in making urgent clinical decisions regarding
management. CSF metagenomic next-generation sequencing has not
been well-validated. For more information, refer to page 996 of the
Continuum article, “Neurologic Complications of Tuberculosis.”
24 The preferred response is D (initiate treatment with standard

antituberculous therapy and IV dexamethasone and add antiretroviral
therapy after 1 week). Standard treatment for tuberculous meningitis
consists of an intensive phase of rifampicin, isoniazid, pyrazinamide,
and ethambutol for 2 months, followed by a prolonged continuation
phase of rifampicin and isoniazid for an additional 7 to 10 months.
Additional agents may be indicated if the patient is found to have a
drug-resistant tuberculosis infection. Steroids should be administered
concomitantly because this has been shown to have positive benefits on
outcome with reduced mortality, severe disability, and disease relapse.
Empiric treatment should be initiated if a high level of suspicion exists
based on the clinical and neuroimaging characteristics, and lumbar
puncture should not be performed if mass effect is evident. In patients
with newly diagnosed co-infection with human immunodeficiency
virus (HIV) or those who have not yet started antiretroviral therapy at
the time of diagnosis, early initiation of antiretroviral therapy has been
associated with increased survival benefit. In patients with CD4+ T-cell
count less than 50 cells/mm3, antiretroviral therapy for HIV infection
should be started within 2 weeks of the initiation of tuberculosis
treatment. For more information, refer to page 1001 of the Continuum
article, “Neurologic Complications of Tuberculosis.”
25 The preferred response is B (meningovascular disease). Of the listed

options, only meningovascular disease (along with meningitis) is
commonly seen in early infection. For more information, refer to
page 1021 of the Continuum article, “Neurosyphilis.”
26 The preferred response is D (lumbar puncture and CSF analysis).

Although the overall likelihood of neurosyphilis is low in this patient,
a lumbar puncture with CSF Venereal Disease Research Laboratory
(VDRL) is warranted given that the patient has a reactive serum
treponemal test and neurologic symptoms. If neurosyphilis were
1150 AUGUST 2021

confirmed, treatment could arrest further cognitive decline. For
“Neurosyphilis.”
27 The preferred response is B (ceftriaxone). According to the Centers for

Disease Control and Prevention guidelines, either ceftriaxone or
desensitization followed by penicillin G would be the appropriate
treatment for patients with a penicillin allergy and neurosyphilis. For
“Neurosyphilis.”
ARTICLE 10: NEUROLOGIC COMPLICATIONS OF LYME DISEASE
28 The preferred response is C (papilledema). Papilledema secondary

to idiopathic intracranial hypertension has been reported in children
with Lyme meningitis, but it only rarely occurs in adults. Facial
weakness, either bilateral or unilateral, is one of the most common
neurologic complications of Lyme disease with cranial nerve VIII
involvement, as well as cranial nerves III, IV, and VI, occurring less
commonly. Although spinal cord involvement is rare in the United States,
it is more common in Europe and can present with a spastic gait and
bladder dysfunction. For more information, refer to page 1043 of the
Continuum article, “Neurologic Complications of Lyme Disease.”
29 The preferred response is B (mononeuropathy multiplex). Based on

electrophysiologic studies in humans as well as animal studies, pain and
weakness in one or more limbs in the setting of acute Lyme disease are
now known to be caused by mononeuropathy multiplex rather than
radiculitis or plexitis as was previously thought. For more information,
refer to page 1043 of the Continuum article, “Neurologic Complications
of Lyme Disease.”
30 The preferred response is E (nonspecific cross-reactivity without

evidence of infection). Serologic testing for Lyme disease is a two-step
procedure, involving an enzyme-linked immunosorbent assay (ELISA)
for antibodies against Borrelia burgdorferi as the initial step. If this is
positive or borderline, an IgM and an IgG Western blot should be
performed. IgM testing is useful only in patients whose symptoms
are shorter than 6 weeks in duration. After 6 weeks, isolated IgM
antibodies cannot be interpreted as evidence of infection and are
more likely due to cross-reactivity. Chronic Lyme disease is distinct
from posttreatment Lyme disease syndrome and is a debated diagnosis
in which vague symptoms including fatigue and pain are attributed to
Lyme disease without a preceding history of classic symptoms or

laboratory confirmation. Isolated positive IgM Western blot should not

be used to make this diagnosis. For more information, refer to page 1043
of the Continuum article, “Neurologic Complications of Lyme Disease.”
ARTICLE 11: NEUROLOGIC MANIFESTATIONS OF SEVERE ACUTE

RESPIRATORY SYNDROME CORONAVIRUS 2 INFECTION
31 The preferred response is A (angiotensin-converting enzyme receptor

type 2 [ACE2]). ACE2 and neuropilin are the receptors for the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2); the proteins
are highly expressed in the respiratory tract. For more information, refer
to page 1052 of the Continuum article, “Neurologic Manifestations of
Severe Acute Respiratory Syndrome Coronavirus 2 Infection.”
32 The preferred response is B (acute necrotizing hemorrhagic

encephalopathy). This patient developed a progressive
encephalopathy over several days in the context of a COVID-19
infection with imaging findings supporting the diagnosis of acute
necrotizing hemorrhagic encephalopathy. The presence of hemorrhage
and absence of demyelinating lesions would argue against acute
disseminated encephalomyelitis, whereas the distribution of the
hemorrhages would be atypical for primary intracerebral hemorrhage.
Meningoencephalitis would not be expected to have these imaging
findings. For more information, refer to page 1055 of the Continuum
article, “Neurologic Manifestations of Severe Acute Respiratory
Syndrome Coronavirus 2 Infection.”
33 The preferred response is A (encephalopathy). Encephalopathy is the

most common neurologic manifestation of COVID-19 in hospitalized
patients. Stroke is seen in approximately 5% of patients, and 0.5% of
patients develop an intracerebral hemorrhage. Guillain-Barré
syndrome, myelitis, and myositis have all been reported but are less
commonly seen. For more information, refer to page 1054 of the
Continuum article, “Neurologic Manifestations of Severe Acute
Respiratory Syndrome Coronavirus 2 Infection.”
ARTICLE 12: NEUROLOGIC INFECTIONS IN PATIENTS ON IMMUNOMODULATORY

34 The preferred response is A (within the first month). Pancytopenia

may develop in the first month as a complication of pretransplantation
conditioning and immunosuppressive therapy. As engraftment does not
1152 AUGUST 2021

start until 2 to 4 weeks after transplantation, patients are at the greatest
risk of illness secondary to reactivation of preexisting latent infections
during this time. In addition to reactivation of preexisting latent
infections, patients are also at risk of drug-resistant hospital-acquired
infections and donor-derived infections. Patients 2 to 6 months out from
transplant are at risk of infection from opportunistic pathogens, although
delayed reactivation of latent infections can occur during this period as
well. Progressive multifocal leukoencephalopathy occurs, on average,
11 months after hematopoietic cell transplantation. For more information,
refer to page 1072 of the Continuum article, “Neurologic Infections in
Patients on Immunomodulatory and Immunosuppresive Therapies.”
35 The preferred response is D (brain MRI every 12 months and serologic

JC virus testing every 6 months). Patients should be screened before
the initiation of treatment, and natalizumab should not be started for
patients who are seropositive for anti–JC virus antibodies. Once
treatment is started, ongoing monitoring should take place with yearly
brain MRI and serologic testing every 6 months. For more information,
refer to page 1075 of the Continuum article, “Neurologic Infections in
Patients on Immunomodulatory and Immunosuppressive Therapies.”
36 The preferred response is A (alemtuzumab). Alemtuzumab binds

CD52 and depletes B cells, T cells, natural killer cells, and monocytes.
Prophylaxis reduces the incidence of herpesvirus reactivation but
does not fully prevent this; several patients still develop herpes
simplex virus and varicella-zoster virus infections. For more
information, refer to page 1076 of the Continuum article, “Neurologic
Infections in Patients on Immunomodulatory and Immunosuppresive
Therapies.”
37 The preferred response is E (varicella-zoster virus). Varicella-zoster

virus (VZV) is associated with the development of a varicella
vasculopathy in patients who are immunocompromised. This process
can affect large or small cerebral arteries through direct viral infection
of the vasculature. The vasculopathy can result in transient ischemic
attacks, ischemic or hemorrhagic strokes, dissections, aneurysms, and
cerebral venous sinus thrombosis. VZV vasculopathy–related
infarctions may involve multiple vascular territories and are often
contrast enhancing and located at the gray-white matter junction on
MRI. Vascular occlusions, stenosis, or the classic beading appearance
of vasculitis may be seen on vessel imaging. For more information, refer
to page 1084 of the Continuum article, “Neurologic Infections in
Patients on Immunomodulatory and Immunosuppressive Therapies.”

ARTICLE 13: CONGENITAL INFECTIONS OF THE NERVOUS SYSTEM
38 The preferred response is E (spiramycin given in the first trimester).

This constellation of clinical findings together with the mother’s history
of eating undercooked meat would be most consistent with congenital
toxoplasmosis, and spiramycin given in the first trimester could
decrease clinical sequelae. Full maternal immunization would be
protective against rubella, whereas maternal combination antiretroviral
therapy decreases human immunodeficiency virus (HIV) transmission.
Maternal treatment with penicillin G treats syphilis, whereas neonatal IV
ganciclovir may be helpful with congenital cytomegalovirus infection.
For more information, refer to pages 1107 and 1111 of the Continuum
article, “Congenital Infections of the Nervous System.”
39 The preferred response is A (cytomegalovirus). The finding of progressive

hearing loss and developmental delay in a patient asymptomatic at
birth would be most consistent with congenital cytomegalovirus.
Toxoplasmosis, rubella, and syphilis can be associated with hearing
loss but would be much less likely to be asymptomatic at birth; syphilitic
hearing loss shows up later in life. For more information, refer to page 1113
of the Continuum article, “Congenital Infections of the Nervous System.”
40 The preferred response is D (partially collapsed skull). Congenital Zika

syndrome is associated with several characteristic features that can be
useful in differentiating this diagnosis from other congenital infections.
Although microcephaly can be seen in other congenital infections, it
can be particularly severe in Zika syndrome and occur in association
with a partially collapsed skull. The other options provided are shared
by multiple congenital infections or are characteristic of ones that are
not Zika syndrome. For more information, refer to pages 1118-1120 of the
Continuum article, “Congenital Infections of the Nervous System.”
1154 AUGUST 2021

ERRATA
In the June 2021 issue of Continuum In question 11 of “Postreading Self-Assessment and

(Headache, Vol. 27, No. 3), the following CME Test–Preferred Responses” by Adam G. Kelly,
errors occurred: MD, FAAN, and Allison L. Weathers, MD, FAAN
(Continuum: Lifelong Learning in Neurology
In “False Claims Act Overview and Implications for 2021;27:779), the preferred response was incorrectly
Neurologists” by Rachel V. Rose, JD, MBA, and labeled as “D (option for repeat dosing)” when it should
Joseph S. Kass, MD, JD, FAAN (Continuum: Lifelong have been listed as “C (option for repeat dosing).”
Learning in Neurology 2021:27:769), the amount of
the False Claims Act allegations settlement against See the corrected question below.
Alaska Neurology Center LLC was incorrectly stated
as “June 5, 2020: Alaska Neurology Center LLC and Kelly AG, Weathers, AL. Postreading self-assessment and CME
test–preferred responses. Continuum (Minneap Minn) 2021;
its owner settled False Claims Act allegations related 27(3, Headache):788–799.
to the knowing submission of false billing claims to
the government for $2 billion.” The corrected 11 Which of the following characteristics
settlement amount is shown below: differentiates between rimegepant and ubrogepant?
“June 5, 2020: Alaska Neurology Center LLC and its A efficacy

owner settled False Claims Act allegations related B IV versus oral route of administration
to the knowing submission of false billing claims to C option for repeat dosing
the government for $2 million.” D side effect profile
E tolerability
Rose RV, Kass JS. False claims act overview and implications for
neurologists. Continuum (Minneap Minn) 2021;27(3, Headache):
767-772. doi:10.1212/CON.0000000000000976 The preferred response is C (option for repeat
dosing). Calcitonin gene-related peptide antagonists,
known as gepants, are a novel treatment class for
acute migraine. Thus far, two gepants (ubrogepant
and rimegepant) have received US Food and Drug
Administration (FDA) approval for the acute
treatment of migraine in adults. As they are part of
the same drug class, these medications are very
similar, especially in efficacy and tolerability, but
they differ in availability of formulation (rimegepant
comes in an orally disintegrating tablet) and in the
option for repeat dosing (ubrogepant). For more
information, refer to pages 605-606 of the
Continuum article “Acute Migraine Treatment.
The error has been corrected in the online version of

the test.

LEARNING OBJECTIVES AND CORE COMPETENCIES
Learning Objectives Core Competencies

Upon completion of this Continuum: Lifelong This Continuum: Lifelong Learning in Neurology
Learning in Neurology Neuroinfectious Disease Neuroinfectious Disease issue covers the

issue, participants will be able to: following core competencies:
◆ Discuss the symptoms, signs, radiologic features, ◆ Patient Care

and laboratory diagnosis of neurologic infections
◆ Medical Knowledge
◆ Diagnose and treat infectious causes of meningitis,
including understanding the role of newer molecular ◆ Practice-Based Learning and Improvement
diagnostic techniques
◆ Interpersonal and Communication Skills
◆ Describe the approach to diagnosis and management
of intracerebral infections ◆ Professionalism
◆ Recognize, diagnose, and manage a range of infections ◆ Systems-Based Practice

of the spine and spinal cord
◆ Recognize the key features of infections that

affect the peripheral nervous system and describe
the appropriate differential diagnosis based on
localization within the peripheral nervous system
◆ Discuss the epidemiology, pathophysiology,

and management of neurologic parasitoses, especially
the more frequent parasitic infections affecting the
human nervous system
◆ Diagnose and treat human immunodeficiency

virus (HIV)-associated neurologic disorders and
opportunistic infections that can occur in patients
with HIV
◆ Describe the epidemiology, clinical characteristics,

and approach to the diagnosis and management of
neurologic complications of tuberculosis
◆ Diagnose and manage early and late clinical

presentations of neurosyphilis and recognize
the limitations of serologic testing in the diagnosis
of neurosyphilis
◆ Discuss the symptomatology, diagnosis, and treatment

of Lyme disease
◆ Describe the spectrum of acute and chronic neurologic

manifestations of COVID-19 caused by SARS-CoV-2
◆ Diagnose and manage neuroinfectious complications

in patients who are immunocompromised
◆ Discuss the neurologic presentation and management

of congenitally acquired infections affecting the
central nervous system
810 AU G U S T 2 0 2 1

LIST OF ABBREVIATIONS
Neuroinfectious Disease IgE Immunoglobulin E

IgG Immunoglobulin G
IgM Immunoglobulin M
IHDS International HIV Dementia Scale
Aβ Amyloid-
Amyloid-β
IM Intramuscular
ACE2 Angiotensin-converting enzyme receptor type 2
IRIS Immune reconstitution inflammatory syndrome
ADEM Acute disseminated encephalomyelitis
IV Intravenous
AIDP Acute inflammatory demyelinating
polyradiculoneuropathy IVIg Intravenous immunoglobulin
AIDS Acquired immunodeficiency syndrome LETM Longitudinally extensive transverse myelitis
ALS Amyotrophic lateral sclerosis MADSAM Multifocal acquired demyelinating sensory
and motor neuropathy
ANCA Antineutrophil cytoplasmic antibodies
MG Myasthenia gravis
ART Antiretroviral therapy
MMR Measles-mumps-rubella
BCG Bacille Calmette-Guérin
MMSE Mini-Mental Status Examination
CCP Cyclic citrullinated peptide
MoCA Montreal Cognitive Assessment
CDC Centers for Disease Control and Prevention
MRA Magnetic resonance angiography
CMAP Compound muscle action potential
MRC Medical Research Council
CMV Cytomegalovirus
MRI Magnetic resonance imaging
CNS Central nervous system
MRSA Methicillin-resistant Staphylococcus aureus
CRP C-reactive protein
PALE Posttransplant acute limbic encephalitis
CSF Cerebrospinal fluid
PCR Polymerase chain reaction
CT Computed tomography
PET Positron emission tomography
DNA Deoxyribonucleic acid
PML Progressive multifocal leukoencephalopathy
EBV Epstein-Barr virus
PNS Peripheral nervous system
ECMO Extracorporeal membrane oxygenation
PPD Purified protein derivative
EEG Electroencephalography
PPP Purified protein derivative
EIA Enzyme immunoassay
PRES Posterior reversible encephalopathy syndrome
EITB Enzyme-linked immunoelectrotransfer blot
RNA Ribonucleic acid
ELISA Enzyme-linked immunosorbent assay
RPR Rapid plasma reagin
EMG Electromyography
SIADH Syndrome of inappropriate secretion of
ESR Erythrocyte sedimentation rate antidiuretic hormone
EV Enterovirus SNAP Sensory nerve action potential
FDA US Food and Drug Administration SNARE Soluble N-ethylmaleimide–sensitive
-ethylmaleimide–sensitive factor
FDG-PET Fludeoxyglucose positron emission tomography attachment protein receptor
FIESTA Fast imaging employing steady state acquisition SPECT Single-photon emission computed tomography
FLAIR Fluid-attenuated inversion recovery SSPE Subacute sclerosing panencephalitis
fMRI Functional magnetic resonance imaging SWI Susceptibility-weighted imaging
FTA-ABS Fluorescent treponemal antibody absorption TB Tuberculosis
GBS Guillain-Barré syndrome TNF-a Tumor necrosis factor-a
HAM Human T-lymphotropic virus type I–associated TORCH Toxoplasmosis, other infections, rubella,
myelopathy cytomegalovirus, human immunodeficiency virus,
HAND Human immunodeficiency virus–associated and herpes
neurocognitive disorders TPPA Treponema pallidum particle agglutination assay
HHV Human herpesvirus TRUST Toluidine red unheated serum test
HIV Human immunodeficiency virus VDRL Venereal Disease Research Laboratory
HSV Herpes simplex virus VZV Varicella-zoster virus
HTLV-I Human T-cell lymphotropic virus type I WHO World Health Organization
© 2021 American Academy of Neurology.

NEUROINFECTIOUS DISEASES
ARTICLE 1: APPROACH TO
NEUROLOGIC INFECTIONS
Aaron L. Berkowitz, MD, PhD. Continuum (Minneap Minn). August 2021;
27 (4 Neuroinfectious Disease):818–835.
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of the clinical approach to the diagnosis of neurologic
infections, focusing on the symptoms, signs, imaging features, and laboratory findings of the
major categories of neuroinfectious diseases.
RECENT FINDINGS:
The increased use of immunosuppressive and immunomodulatory therapy to treat autoimmune
diseases has led to an increase in opportunistic neurologic infections. The description of
numerous causes of autoimmune antibody–mediated encephalitis over the past decade has
expanded the differential diagnosis of encephalitis beyond infection. The emergence of
metagenomic next-generation sequencing has led to diagnoses of rare or unexpected causes
of neurologic infections and has the potential to enhance diagnostic precision in
neuroinfectious diseases.
SUMMARY:
Infections of the nervous system can affect any level of the neuraxis and present over any time
course. Neurologic infections may present atypically with respect to clinical, radiologic, and
CSF analysis features in immunocompromised patients or older adults. A thorough evaluation
including systemic features, past medical history, travel, exposures, detailed examination,
neuroimaging, and CSF analysis is often necessary to make a definitive diagnosis. It is important
to be aware of the test characteristics and limitations of microbiological tests on CSF for
neurologic infections to avoid being misled by false positives or false negatives.
KEY POINTS
• Neurologic infections can affect any level of the neuraxis.
• Neurologic infections can be caused by any category of microbe: viruses, bacteria, fungi, or parasites.
• Infectious agents can cause disease in the nervous system by direct invasion of neural tissue, production of
neurotoxins, and/or the immune response incited by the pathogen. Certain infectious pathogens cause a
specific clinical syndrome or characteristic radiologic pattern(s), but many can cause a wide variety of
different clinical presentations or radiologic abnormalities.

• In general, most viral and bacterial infections of the nervous system present acutely, emerging and evolving
over hours to days. In contrast, fungal, mycobacterial, spirochetal, and parasitic infections and neurosyphilis
generally present subacutely or chronically. However, many exceptions to these general principles occur.
• Fever is an obvious indication of an infectious etiology of a neurologic presentation but may be absent with
localized central nervous system infections (eg, brain abscess), in immunocompromised patients who
cannot mount an adequate inflammatory response, and even in immunocompetent patients, particularly
infants and older adults.
• Although many neurologic infections can occur in otherwise healthy individuals, a high degree of suspicion
for infection must be maintained in patients who are immunocompromised due to human immunodeficiency
virus (HIV)/acquired immunodeficiency syndrome (AIDS), congenital immunodeficiency, hematologic
malignancy, and patients taking immunosuppressive/immunomodulatory medications (eg, in the setting of
autoimmune disease, bone marrow transplantation, or solid organ transplantation).
• In immunocompromised populations, infections may present atypically both clinically and radiologically
because of the reduced inflammatory reaction to the infectious pathogen.
• Asking about place of residence, country of origin, and travel history is essential in the evaluation of a patient
with a potential neurologic infection.
• Although infection is a primary consideration in the differential diagnosis of meningitis and encephalitis,
noninfectious causes must be considered. Although infection is often not a primary consideration in the
differential diagnosis of myelopathy, radiculopathy, neuropathy, neuromuscular junction disorder,
and myopathy, infections can affect these levels of the neuraxis and must be considered in the
differential diagnosis of these conditions.
• While the most common causes of meningitis are infectious, involvement of the meninges can also occur as a
result of inflammatory disease (eg, IgG4-related disease, sarcoidosis, Behçet disease,
Vogt-Koyanagi-Harada disease), neoplasia (carcinomatous meningitis/leptomeningeal metastases; chemical
meningitis due to rupture of epidermoid cyst), and secondary to medications (eg, nonsteroidal
anti-inflammatory drugs, IV immunoglobulin [IVIg], trimethoprim-sulfamethoxazole).
• Characteristic symptoms of acute infectious meningitis include fever, headache, neck stiffness, and altered
mental status. However, these classic features cannot be relied on because they may be absent, particularly
in infants, older adults, immunocompromised patients, and patients on anti-inflammatory analgesics.
• Patients with acute meningitis are often treated empirically for the most likely pathogens in a given patient
while awaiting CSF diagnostics to narrow coverage to the microbe ultimately diagnosed.
• In patients with acute meningitis, IV dexamethasone should be initiated with or before starting antibiotics, as
it reduces mortality in adults with Streptococcus pneumoniae meningitis and decreases the risk of hearing
loss in children with Haemophilus influenzae meningitis. However, several studies have shown that steroids
do not appear to be beneficial in patients with acute meningitis in low-income countries, attributed to the
higher likelihood of a delayed presentation and higher burden of HIV and malnutrition.
• The primary differential diagnosis for encephalitis is between infectious and immune-mediated conditions
(eg, acute disseminated encephalomyelitis and antibody-mediated autoimmune encephalitis).
• In immunocompromised patients, the differential diagnosis of encephalitis expands to include
cytomegalovirus, human herpesvirus 6 (most commonly in patients who have undergone hematopoietic stem
cell transplantation), Epstein-Barr virus, and adenovirus.
• The spine can be affected by infection in any of its compartments: vertebrae/discs (osteomyelitis, Pott
disease), epidural/subdural spaces (abscess), or the spinal cord parenchyma (infectious myelitis).
• Acute infectious myelitis may be caused by nearly any virus, with the particular pattern of anterior horn cell
involvement causing flaccid paralysis associated with enteroviruses (enterovirus 71 [EV71], enterovirus D68
[EVD68], poliovirus) and West Nile virus.
• The most common infectious causes of radiculitis are viral (eg, varicella-zoster virus, herpes simplex virus 2
[Elsberg syndrome], cytomegalovirus [in immunocompromised patients]), Lyme disease, and tuberculous
arachnoiditis.
• Infections associated with mononeuropathy multiplex include hepatitis B–associated polyarteritis nodosa,

hepatitis C–associated cryoglobulinemic vasculitic neuropathy, HIV, and leprosy. Infections that can cause
polyneuropathy include HIV and diphtheria.
• Infectious myositis can be focal (eg, bacterial pyomyositis) or diffuse (eg, trichinosis [caused by Trichinella
spiralis], HIV, human T-cell lymphotropic virus type I [HTLV-I]).
• Although definitive diagnosis of a neurologic infection requires microbiological testing of CSF or tissue
specimen, neuroimaging is often obtained first because it can provide important clues as to the infectious
etiology and may be necessary to exclude contraindications to lumbar puncture.
• Although CT of the brain without contrast may be inadequate to distinguish most infectious lesions from
neoplastic, vascular, or inflammatory processes, it can identify the characteristic features of
neurocysticercosis in the vesicular or calcified nodular stages (although granular and colloidal stages may be
impossible to disambiguate from other hypodense lesions).
• Ring-enhancing lesions most commonly represent abscess or tumor, although subacute stroke may also
show a peripheral pattern of enhancement.
• CSF in neurologic infections generally shows elevations in white blood cells and protein.
• Glucose is decreased in bacterial (including mycobacterial) and fungal infections and generally normal in viral
infections, but it may be decreased in mumps, herpes simplex virus 2, cytomegalovirus, and Eastern equine
encephalitis infection, as well as in non-neurologic causes of meningitis such as leptomeningeal metastases
and sarcoidosis.
• A neutrophilic predominance is generally seen in bacterial infections, whereas a lymphocytic predominance
is seen in viral, fungal, and mycobacterial infections. However, a neutrophilic predominance may be seen
early in the course of viral infections and throughout the course of West Nile virus encephalitis.
• CSF parameters in conjunction with the clinical presentation provide an initial impression of the possible
microbiological diagnoses to guide empiric therapy. However, they cannot be relied on because they may
change after initiation of antimicrobial therapy and over the course of the illness. In immunocompromised
patients, diminished capacity to mount an immune response may also alter the CSF profile.
• Definitive microbiological diagnosis can be made through several different types of laboratory tests. It is,
therefore, crucial to be aware of the most sensitive tests when evaluating for particular pathogens.
• CSF cultures are generally the test of choice for gram-positive and gram-negative bacterial CNS infections,
but culture is insensitive for viruses, spirochetes, and fungi. Although sensitive for tuberculosis, cultures take
weeks to result. Therefore, additional techniques are necessary for diagnosis of these pathogens in the CSF.
• CSF cryptococcal antigen is the most sensitive test for diagnosing cryptococcal meningitis, and antigen tests
are also important in the diagnosis of meningitis caused by endemic mycoses.
• CSF serology is considered a more sensitive test than polymerase chain reaction (PCR) for certain viruses
(arbovirus IgM; varicella-zoster virus IgG in myelitis and vasculitis), and serology is also the test of choice for
Lyme disease (IgG) and neurosyphilis.
• CSF PCR is the most sensitive test for most viral infections of the nervous system, with some notable
exceptions (arboviruses, varicella-zoster virus).
• Metagenomic next-generation sequencing of CSF is an emerging unbiased, hypothesis-free technique that
evaluates all genetic material in a sample to detect any nonhost sequences and identify them through
computational algorithms using bioinformatic libraries. This technique has identified novel or unexpected
pathogens in patients with neurologic infections that were unable to be diagnosed with conventional
microbiological testing.

Allen J. Aksamit Jr, MD, FAAN; Aaron L. Berkowitz, MD, PhD. Continuum
(Minneap Minn). August 2021; 27 (4 Neuroinfectious Disease):836–854.
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the diagnosis and treatment of infectious meningitis, including updates on
newer molecular diagnostic techniques for microbiological diagnosis.
RECENT FINDINGS:
New polymerase chain reaction (PCR)-based molecular diagnostic techniques have improved
the timeliness of microbiological diagnosis in meningitis, but clinicians must be aware of the
limitations of such tests. Next-generation sequencing can now be applied to CSF, allowing for
diagnosis of infections not identifiable by conventional means.
SUMMARY:
Infectious meningitis can be caused by a broad range of organisms. The clinician must be aware
of the test characteristics of new molecular techniques for microbiological diagnosis as well as
traditional techniques to tailor antimicrobial therapy appropriately in patients with meningitis.
KEY POINTS
• Meningitis is an inflammatory condition of the meninges that can be caused by infections, autoimmune
diseases, neoplasia, and medications.
• Signs of meningismus include nuchal rigidity, the Kernig sign (pain and resistance with passive extension of
the knee with the hip flexed), and the Brudzinski sign (hip and knee flexion with passive neck flexion).
Although highly specific, these signs have very low sensitivity.
• CSF glucose level less than 40% of serum level (or less than 40 mg/dL) is suspicious for infection, most
commonly bacterial, tuberculous, and fungal meningitis.
• CSF glucose is normal in most viral meningitides; however, hypoglycorrhachia can occur with some viruses,
including mumps, lymphocytic choriomeningitis virus, West Nile virus, enterovirus, and cytomegalovirus
(CMV) ventriculitis associated with human immunodeficiency virus (HIV)/acquired immunodeficiency
syndrome (AIDS).
• Elevated CSF eosinophils can be seen in parasitic or fungal infections but also in other noninfectious
conditions, including hypereosinophilic syndrome, granulomatosis with polyangiitis, Hodgkin disease, and
glioblastoma invading the meninges.
• The BioFire FilmArray Meningitis/Encephalitis (ME) Panel is a multiplex polymerase chain reaction (PCR)
assay that evaluates for several common meningitis pathogens simultaneously: the bacteria Escherichia coli
K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae
(group B streptococcus), and Streptococcus pneumoniae; the viruses including cytomegalovirus,
enterovirus, herpes simplex virus 1, herpes simplex virus 2, human herpesvirus 6, human parechovirus, and
varicella-zoster virus; and the yeast Cryptococcus (both Cryptococcus neoformans and Cryptococcus gattii).
• The FilmArray ME Panel has an overall percent positive agreement of 97.5% for bacterial pathogens and 90.1%
for viruses when compared with stand-alone PCR and/or culture, and only 52% for Cryptococcus
neoformans/Cryptococcus gattii when compared with cryptococcal antigen.
• The clinical features of bacterial meningitis are fever, headache, stiff neck, and change in mental status.
Approximately 45% of patients have all four symptoms, and 95% have at least two of the four.
• Bacterial meningitis is a neurologic emergency and is universally fatal if untreated. Outcomes are worse with

delayed treatment, so empiric antibiotics should be initiated as soon as the diagnosis of bacterial meningitis
is considered, guided by age and past medical history.
• The most common bacterial causes of meningitis in adults and children are S. pneumoniae and N.
meningitidis. H. influenzae may be seen in children but is now rare because of widespread vaccination.
L. monocytogenes may be seen in adults older than 50 years and in patients who are immunocompromised. In
infants, E. coli, S. agalactiae, and L. monocytogenes are the most common causes of bacterial meningitis.
• L. monocytogenes may be seen in adults older than 50 years and in patients who are immunocompromised.
• The monoclonal antibody eculizumab, a complement inhibitor approved for treatment of neuromyelitis
optica and myasthenia gravis, is associated with a 1000-fold to 2000-fold increased incidence of
meningococcal meningitis. Therefore, administration of the meningococcal vaccine is recommended before
beginning eculizumab treatment.
• In infectious bacterial meningitis, postcontrast T1-weighted MRI often reveals enhancement of the
leptomeninges within the cerebral sulci.
• Empiric antimicrobial treatment should be initiated immediately if bacterial meningitis is suspected.
• Practice guidelines developed in 2017 for nosocomial ventriculitis and meningitis recommend empiric
therapy with vancomycin plus an antipseudomonal beta-lactam (such as cefepime, ceftazidime, or
meropenem) with the choice of empiric beta-lactam based on local in vitro susceptibility patterns.
• Although most viruses are diagnosed by PCR, some are more sensitively diagnosed by CSF serology, such as
arboviruses.
• The FilmArray ME Panel evaluates for enterovirus, herpes simplex virus type 2, and varicella-zoster virus but
is less sensitive for herpes simplex virus than stand-alone herpes simplex virus PCR.
• Positive serum antibodies confirm exposure to West Nile virus but not necessarily neuroinvasive disease.
• Varicella-zoster virus PCR from spinal fluid is the most sensitive diagnostic test in the acute setting of acute
meningitis and myelopathy, but serology (IgG) in spinal fluid is more sensitive in varicella-zoster virus
vasculopathy.
• HIV can also cause viral meningitis, most commonly at or around the time of seroconversion. It may be
accompanied by a flulike illness. Because the patient may not yet have formed antibodies, HIV antibody
testing may be negative, requiring viral load for confirmation.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been rarely associated with viral
meningitis and is usually associated with the typical respiratory and systemic manifestations of the disease.
• Chronic meningitis is defined as meningitis lasting longer than 1 month without improvement. The most
common causes are chronic bacterial and fungal infections and inflammatory disorders (eg, sarcoidosis,
IgG4-related disease).
• TB meningitis can occur with or without evidence of systemic TB.
• Diagnosis of Lyme meningitis is established by CSF to serum serology antibody index in the setting of CSF
pleocytosis.
• Meningovascular syphilis causes a subacute meningitis syndrome and should be considered in patients with
HIV or history of other sexually transmitted diseases who develop chronic meningitis.
• The CSF VDRL test is specific for neurosyphilis but is only 30% to 70% sensitive; if the test is negative in cases
with a high index of suspicion, CSF fluorescent treponemal antibody absorption should be performed,
although positive results can occur in previously treated patients.
• Fungal organisms are common causes of subacute to chronic meningitis. The fungi to consider depend on
geography, exposure history, and immune status.
• Most cases of cryptococcal meningitis are caused by Cryptococcus neoformans, but Cryptococcus gattii,
endemic in the Pacific northwest region of the United States and Canada, can cause meningitis in patients
who are immunocompetent.
• CSF cryptococcal antigen is the most sensitive test for diagnosis of cryptococcal meningitis.
• Elevated intracranial pressure is a common complication of cryptococcal meningitis, often requiring serial
lumbar punctures or temporary external ventricular drain for CSF decompression.

• Histoplasmosis is endemic in the Mississippi and Ohio River valleys. When meningitis occurs, it is often
accompanied by active pulmonary disease.
• Blastomycosis is endemic in the Mississippi and Ohio River valleys, as is histoplasmosis, but it is also found in
the Great Lakes region. Involvement of the nervous system can be as chronic meningitis or as a focal mass
with or without meningitis. CNS disease is usually accompanied by pulmonary infection, although pulmonary
disease may be subclinical.
• Diagnosis of Candida meningitis is made by CSF culture, and CSF 1,3-b-D-glucan is frequently positive.
• The most common neuroimaging findings in fungal meningitis are thick, nodular leptomeningeal
enhancement (most commonly in the basilar cisterns and subarachnoid space), hydrocephalus, and deep
stroke(s) (due to infectious vasculitis of small perforating arteries).
ARTICLE 3: ENCEPHALITIS AND

BRAIN ABSCESS
Arun Venkatesan, MD, PhD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews infections of the brain parenchyma and includes an overview of the
epidemiology, pathogenesis, diagnostic approach, and management of infectious encephalitis
and brain abscess.
RECENT FINDINGS:
The epidemiology of infectious encephalitis and brain abscess has changed in recent years.
Vaccination has reduced the incidence of certain viruses associated with encephalitis, while a
decrease in fulminant otogenic infections has led to fewer brain abscesses associated with otitis
media. However, changes in climate and human population density and distribution have
enabled the emergence of newer pathogens and expanded the geographic range of others, and
greater adoption of intensive immunosuppressive regimens for autoimmune conditions has
increased the risk of opportunistic infections of the brain. The widespread use of early
neuroimaging, along with improved diagnostic methodologies for pathogen detection, newer
antimicrobial therapies with better brain penetration, and less invasive neurosurgical
techniques, has resulted in better outcomes for patients with infectious encephalitis and brain
abscess. Novel technologies including metagenomic next-generation sequencing are
increasingly being applied to these conditions in an effort to improve diagnosis. Nevertheless,
both infectious encephalitis and brain abscess continue to be associated with substantial
mortality.
SUMMARY:
Infectious encephalitis and brain abscess can present as neurologic emergencies and require
rapid assessment, thorough and appropriate diagnostic testing, and early initiation of empiric
therapies directed against infectious agents. Close clinical follow-up, proper interpretation of
diagnostic results, and appropriate tailoring of therapeutic agents are essential to optimizing
outcomes. Diagnosis and management of parenchymal brain infections are complex and often
best achieved with a multidisciplinary care team involving neurologists, neurosurgeons,
neuroradiologists, infectious disease physicians, and pathologists.

KEY POINTS
• Encephalitis refers to inflammation of the brain parenchyma and is caused by a wide range of infectious and
autoimmune conditions.
• Because a broad range of pathologic processes can cause altered mental status, including metabolic
derangements, toxins, and cerebrovascular disease, patients with suspected encephalitis must be
thoroughly evaluated for alternative conditions.
• Infections account for up to half of all cases of encephalitis; autoimmune causes are identified in 20% to 30%,
and in the remaining 20% to 30% of cases, a specific cause is not ascertained.
• Changes in climate, human population growth and migration, and farming practices have resulted in the
emergence and spread of arthropod-borne viruses (arboviruses), such as West Nile virus, chikungunya virus,
and tick-borne encephalitis virus.
• Herpes simplex virus (HSV) most often affects the temporal lobes and other limbic areas.
• The deep gray matter is commonly affected in flaviviral infections such as West Nile virus and Japanese
encephalitis virus.
• Many patients with HSV-1 encephalitis present with prodromal symptoms suggesting upper respiratory tract
or other systemic infection.
• Early in the course, some patients with encephalitis may have fever and headaches without encephalopathy
or focal neurologic deficits, even when parenchymal brain involvement is demonstrated by neuroimaging
or EEG.
• Early in the disease course of HSV-1 encephalitis, findings are often unilateral; when bilateral, asymmetry
may help to distinguish HSV-1 encephalitis from autoimmune causes of limbic encephalitis, which more
commonly cause symmetrical changes.
• False-negative polymerase chain reaction (PCR) may occur early in the course of HSV-1 encephalitis. Notably,
in children and people who are immunocompromised, the clinical manifestations and MRI findings are
broader and can include a more diffuse encephalitis or meningoencephalitis with or without temporal lobe
involvement.
• Rash may be absent in up to one-third of cases of varicella-zoster virus (VZV) encephalitis.
• In contrast to HSV-1 encephalitis, the primary pathologic process associated with VZV in the central nervous
system (CNS) may be vasculopathy.
• Human herpesvirus 6 (HHV-6) can cause encephalitis in adults who are immunocompromised, most
commonly in patients who have undergone hematopoietic stem cell transplantation.
• HHV-6 causes a limbic encephalitis that develops weeks to months after hematopoietic stem cell
transplantation.
• Cytomegalovirus encephalitis is an important consideration in patients with acquired immunodeficiency
syndrome (AIDS) (particularly when CD4+ count is less than 50 cells/mm3) and may be accompanied by
retinitis, polyradiculitis, and ventriculitis; a neutrophilic pleocytosis may be seen on CSF analysis, in contrast
to the more common viral pattern of lymphocytic pleocytosis.
• In arboviral encephalitis, involvement of the deep gray matter is commonly seen on MRI and often
accompanied clinically by movement disorders.
• As a result of the insensitivity of CSF PCR, laboratory diagnosis of arboviral encephalitis often rests on
detection of virus-specific IgM in CSF and blood.
• Less than 1% of people infected with West Nile virus will develop West Nile neuroinvasive disease in the form
of meningitis, encephalitis, or acute flaccid myelitis.
• West Nile virus IgM may persist for prolonged periods, with detectable IgM titers for longer than 1year,
and thus, in some cases, the finding of West Nile virus IgM may reflect previous exposure rather than
current illness.
• Japanese encephalitis virus is the most important cause of encephalitis in South and Southeast Asia, typically
affecting children younger than 10.
• In addition to causing meningitis, Listeria monocytogenes can cause rhombencephalitis. Although Listeria
infections occur more commonly in individuals who are immunocompromised, immunocompetent individuals

may also be affected; according to one review of previously reported cases, the majority of patients who
developed rhombencephalitis were immunocompetent.
• Thrombocytopenia and vascular involvement are common in Rocky Mountain spotted fever, likely
accounting for the petechiae and the brain MRI findings of scattered punctate areas of restricted diffusion
and T2 hyperintensity in the deep gray and white matter in affected children.
• Balamuthia mandrillaris can affect individuals who are immunocompetent. Mortality is high, and many cases
have been identified only postmortem; however, increased recognition and earlier identification have
resulted in rapid initiation of multidrug treatments with associated survival.
• In recent years, it has been recognized that contaminated tap water is a potential source of transmission of
Naegleria fowleri, as underscored by several cases associated with the use of neti pots.
• Encephalitis can present as a systemic and neurologic emergency, and thus, initial management is focused on
stabilizing patients who are acutely ill while concurrently initiating a diagnostic evaluation.
• A comprehensive history encompassing travel, ill contacts, occupational exposures, vector and animal
exposures, outdoor activities, ingestions, and recent illnesses should be ascertained.
• Neuroimaging, preferably MRI because of its higher sensitivity for early or subtle findings of encephalitis than
CT, should be performed urgently and is helpful in not only suggesting potential etiologies of encephalitis but
also excluding some mimics.
• To assess for common and treatable infectious conditions, important studies to obtain in all adults with
suspected encephalitis include opening pressure; protein; glucose; cell count and differential; Gram stain;
bacterial cultures; PCRs for HSV-1, HSV-2, VZV, and enterovirus; cryptococcal antigen; and testing
for syphilis.
• Autoimmune causes are particularly suspected in the setting of limbic encephalitis and marked personality or
behavioral changes or when brain MRI is normal.
• In patients in whom the clinical picture is suggestive of HSV or VZV, acyclovir should be started as soon as
possible.
• If testing from the first lumbar puncture does not reveal a specific cause and HSV-1 encephalitis is still
suspected (eg, limbic encephalitis, temporal lobe involvement), acyclovir should be continued and a second
lumbar puncture should be performed in several days because the HSV PCR can be falsely negative,
particularly early in the course of illness and in children.
• Patients who are immunocompromised and have VZV infection may develop a relapsing or refractory course.
• Advanced age, immunosuppression, and other major medical comorbidities are typically reported as poor
prognostic factors in patients with encephalitis.
• Sources of infection that lead to brain abscess include direct extension from a focus adjacent to the CNS
(eg, sinusitis, otitis media, mastoiditis, or dental infection), hematogenous spread from a distant site
(eg, endocarditis, pulmonary infection, skin), or direct inoculation (eg, penetrating head trauma,
neurosurgical procedure).
• The most common pathogens in brain abscesses in individuals who are immunocompetent are streptococcal
species, including aerobic streptococci (eg, Streptococcus anginosus group, also known as the
Streptococcus milleri group) and anaerobic streptococci, which are identified in more than half of cases and
are frequently associated with sinus infections.
• Brain abscesses arising from hematogenous dissemination are most commonly of pulmonary origin, and, in
addition to streptococcal and staphylococcal species, may be caused by Actinomyces species,
Fusibacterium species, and Nocardia species.
• Opportunistic filamentous bacteria such as Nocardia species, and to a lesser extent Actinomyces species,
are notable causes of brain abscess in the immunocompromised host and can be challenging to distinguish
histologically because of their resemblance to fungi on histopathologic examination.
• Although aggressive management of otitis media has led to a decrease in otogenic-related brain abscess in
many countries, it remains a prominent source of brain abscess in low- and middle-income countries.
• Penetrating head trauma and neurosurgical procedures account for an increasing proportion of brain
abscesses.

• Headache is the most frequent manifestation of brain abscesses, occurring about 70% of the time, and focal
neurologic deficits occur in about half of all cases. Fever may be absent in half of all cases.
• MRI is preferred over CT because it is more sensitive during early stages of abscess formation, can more
precisely demonstrate complications of abscess, and can help better distinguish abscess from other mimics.
• The combination of rim enhancement and intense central restriction of diffusion is highly suggestive of brain
abscess but does not exclude other conditions.
• Blood cultures should routinely be collected. Although they are positive in only about one-quarter of patients
with brain abscesses, the yield is higher in those with hematogenous dissemination. In addition, positive
blood cultures may eliminate the need to directly sample the brain abscess.
• In about one-quarter of cases of brain abscess, cultures of the abscess fluid are negative, and the yield
decreases further in patients in whom empiric antimicrobial therapy is initiated before sample acquisition.
However, empiric antibiotics should never be withheld or delayed in those who are critically ill in an attempt
to improve the diagnostic yield of sampling.
• Broad-based molecular techniques typically identify multiple bacterial taxa, underscoring the complex and
polymicrobial nature of brain abscesses.
• Even when the causative pathogen has already been identified, neurosurgical approaches often still play an
important role in management by reducing the size of the abscess.
• Minimally invasive stereotactic aspiration has largely replaced surgical excision of brain abscesses because
of lower rates of intracranial hemorrhage and mortality.
• In recognition of the polymicrobial composition of many abscesses, empiric regimens typically provide broad
aerobic and anaerobic coverage. Regimens have historically consisted of penicillin, chloramphenicol, and
metronidazole but have largely been replaced by third-generation cephalosporins (eg, cefotaxime or
ceftriaxone) and metronidazole over the past several decades.
• The identification of an aerobic organism does not preclude the concomitant presence of an anaerobic
organism, the latter of which can be difficult to isolate and culture. Thus, anaerobic coverage may be
maintained for the duration of therapy, particularly in the setting of contiguous infections.
• Some bacterial abscesses, such as those associated with Nocardia species, along with mycobacterial and
fungal infections, require a longer duration of therapy than the typical 6- to 8-week course.
• Mortality due to brain abscess is associated with advanced age, comorbid conditions (eg, diabetes,
congenital heart disease or congestive heart failure, immunodeficiency), and hematogenous dissemination
of infection.
• The presence of intraventricular rupture is strongly associated with in-hospital mortality; the majority of
adult and pediatric patients with ventricular rupture die.
• In-hospital outcomes from brain abscess have improved over the past several decades, likely attributable to
better general medical care, more widespread and earlier adoption of neuroimaging, improved microbial
diagnostics, adoption of minimally invasive neurosurgical procedures, and increased effectiveness of CNS
penetrating antimicrobial agents.

ARTICLE 4: INFECTIONS OF THE SPINE
AND SPINAL CORD
Shamik Bhattacharyya, MD, MS; Michael J. Bradshaw, MD. Continuum (Minneap Minn).
August 2021; 27 (4 Neuroinfectious Disease):887–920.
ABSTRACT
PURPOSE OF REVIEW:
Infections of the spine and spinal cord are associated with a high risk of morbidity and mortality
and, therefore, require prompt clinical recognition, efficient diagnostic evaluation, and
interdisciplinary treatment. This article reviews the pathophysiology, epidemiology, clinical
manifestations, diagnosis, and treatment of infections of the spine and spinal cord to help
practicing clinicians recognize, evaluate, and manage patients with such infections.
RECENT FINDINGS:
Aging of the population, increasing use of immunosuppressive medications, and other factors
have contributed to increasing rates of spinal infections. Although the most common agents
responsible for spinal infections remain bacteria and viruses, fungal infections occur in
individuals who are immunocompromised, and parasitic infections are common in endemic
regions, but patterns are in evolution with migration and climate change. Recent outbreaks of
acute flaccid myelitis in children have been associated with enteroviruses A71 and D68.
SUMMARY:
Infections of the spine and spinal cord can be challenging to diagnose, requiring a thorough
history and neurologic examination, laboratory studies of serum and CSF, neuroimaging
(particularly MRI), and, in some instances, biopsy, to establish a diagnosis and treatment
regimen. Interdisciplinary management including collaboration with experts in internal
medicine, infectious disease, and neurosurgery is important to improve clinical outcomes.
KEY POINTS
• Spondylodiscitis is most often caused by pyogenic bacteria, which can infect spinal structures via
hematogenous spread from distant sites, direct inoculation by instrumentation, or contiguous spread from
adjacent infection.
• Fever is present only in roughly half of patients with spondylodiscitis; is less likely to develop in patients with
Brucella, mycobacterial, or fungal infections; and may be absent in patients taking antipyretic analgesics and
those who are immunosuppressed.
• Spondylodiscitis should be suspected in patients with new or worsening back pain particularly with fever,
new neurologic deficits, recent bacteremia, endocarditis, hemodialysis, IV access, or IV drug use.
• Erythrocyte sedimentation rate and C-reactive protein should be included as screening studies when
spondylodiscitis is a possibility; they are valuable as screening studies with sensitivities in the range of
94% to 100%.
• The most common initial manifestations of brucellosis include fever, arthralgias, malaise, and night sweats.
• The risk of extrapulmonary tuberculosis is especially high in patients with human immunodeficiency virus
(HIV) co-infection, who are up to 5 times more likely to develop central nervous system involvement than
those without HIV.
• The spine is the most common site of osteoarticular tuberculosis, and tuberculous spondylitis is the most
common mechanism of myelopathy associated with tuberculosis.
• The most common neurologic manifestation of tuberculosis is meningitis, although tuberculous granulomas

or abscesses can affect the spine, and tuberculosis can also cause syringomyelia, arachnoiditis, and myelitis
often accompanied by radiculitis.
• Tuberculous spondylitis typically presents with insidious back pain that worsens over weeks to months, may
be accompanied by muscle spasms, and is less often associated with fever than bacterial spondylitis.
• Precise diagnosis of tuberculous spondylitis is primarily based on microscopy and culture data obtained from
biopsy or surgical specimens.
• Patients with coccidioidomycosis spondylodiscitis present most often with back pain, radiculopathy, and
sensory disturbances and less often with weakness and/or myelopathy; fever is uncommon.
• Prognosis in spinal epidural abscess depends on the degree and duration of neurologic deficits before
decompression and antimicrobial therapy; therefore, early diagnosis and management are critical, and
clinicians should maintain a high index of suspicion to avoid potentially devastating consequences.
• The classic triad of epidural abscess including fever, back pain, and focal neurologic deficits is observed in
only 2% to 33% of patients at presentation, which, therefore, has inadequate sensitivity to be considered a
useful clinical marker.
• Epidural abscess is a neurologic emergency and requires urgent evaluation and treatment to decrease the
risk of permanent neurologic injury.
• Clinically, most patients with spinal meningitis often have symptoms of polyradiculitis manifesting as
shooting, sharp pain along dermatomal distributions accompanied by focal numbness or weakness in
radicular distributions.
• Early neuroborreliosis often involves the peripheral nervous system, and frequently encountered
manifestations include cranial neuritis (most commonly unilateral or bilateral facial nerve palsy),
radiculoneuritis, and lymphocytic meningitis.
• Myelitis is inflammation of the spinal cord parenchyma and can be caused by infectious or immune-mediated
etiologies.
• The anterior horn syndrome consists of a lower motor neuron pattern flaccid weakness with decreased or
absent reflexes and preservation of sensory modalities (often referred to as acute flaccid myelitis).
• In enteroviral myelitis, enterovirus was detected in only 20% of CSF samples compared with 94% of rectal and
79% of oropharyngeal samples, highlighting the greater sensitivity of peripheral over CSF sampling in
neurologic disease associated with enteroviral infection.
• Human infection with West Nile virus typically occurs in the late spring, summer, or early fall, when
mosquitos are most active in the environment.
• West Nile neuroinvasive disease most often presents with meningitis or meningoencephalitis, which may
co-occur with myelitis as well.
• Myelitis develops in an estimated 5% to 10% of cases of West Nile neuroinvasive disease and most often
presents as an acute flaccid paralysis.
• For West Nile neuroinvasive disease, CSF IgM is more sensitive than CSF polymerase chain reaction (PCR),
and the detection of West Nile virus IgM in the CSF in the appropriate clinical context strongly indicates West
Nile neuroinvasive disease.
• The anterior cord syndrome is characterized by weakness and loss of spinothalamic tract sensory modalities
below the level of the lesion with preservation of the dorsal column sensory modalities and is most often
caused by a vascular injury to the cord.
• Although myelitis is an infrequent manifestation, varicella-zoster virus (VZV) is one of the most common
causes of infectious myelitis and is important to recognize given the availability of specific antiviral therapy.
• CSF VZV PCR should be obtained when CNS zoster is suspected, although it is also prudent to test CSF VZV
IgM/IgG, which may be more sensitive than PCR and can also be used to confirm the diagnosis.
• Small, centrally located lesions in the spinal cord may only affect the spinothalamic tract as they decussate
via the anterior commissure and produce a suspended level of decreased pain and temperature sensation
roughly two spinal levels below the level of the lesion.
• The dorsal column syndrome is characterized by decreased or absent vibration and proprioception below
the level of the lesion with preserved strength, pain, and temperature sensation.

• Human T-cell lymphotropic virus type I–associated myelopathy and HIV vacuolar myelopathy often affect
the dorsal and lateral columns producing a syndrome marked by spastic paraparesis and impaired vibration
and joint position sense.
• Elsberg syndrome is a presumed infectious syndrome defined by acute or subacute progressive bilateral
lumbosacral radiculitis or myeloradiculitis of the caudal spinal cord and lumbosacral nerve roots.
• In toxoplasmosis, involvement of the spinal cord rarely occurs and is most often concomitant with
brain involvement.
ARTICLE 5: INFECTIONS OF THE

PERIPHERAL NERVOUS SYSTEM
Samantha LoRusso, MD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article describes infections that affect the peripheral nervous system, including their
clinical features, differential diagnoses, and treatments.
RECENT FINDINGS:
Rates of pyomyositis have increased recently in the United States, possibly because of an
increase in risk factors such as IV drug use, obesity, and diabetes. Other peripheral nervous
system infections, such as diphtheria, have become more common in older patients secondary
to a lack of revaccination or waning immunity. Although recommended treatment regimens for
most infections remain unchanged over recent years, debate over the ideal dosing and route of
administration continues for some infections such as tetanus and leprosy (Hansen disease).
SUMMARY:
Infections of the peripheral nervous system are varied in terms of the type of infection,
localization, and potential treatment. Nerve conduction studies and EMG can help determine
localization, which is key to determining an initial differential diagnosis. It is important to
recognize infections quickly to minimize diagnostic delays that could lead to patient morbidity
and mortality.
KEY POINTS
• Although infections of the peripheral nervous system are rare, it is important for neurologists to be able to
recognize their clinical manifestations because many are treatable.
• West Nile virus is now the most common viral cause of acute flaccid paralysis in adults in the United States.
• One of the most common infectious causes of radiculopathy is Lyme disease.
• If the presentation is a mononeuropathy or multiple mononeuropathies, then leprosy, hepatitis B and C
viruses, Lyme disease, human immunodeficiency virus (HIV), and cytomegalovirus should be considered.
• Leprosy is predominantly a disease of the peripheral nerves and skin and is still a common cause of
neuropathy in Southeast Asia, South America, and Africa.
• Common sites of mononeuropathy in leprosy include the greater auricular nerve, the ulnar nerve at the
elbow, the median nerve proximal to the carpal tunnel, the superficial radial nerve at the wrist or radial nerve
at the spiral groove, the fibular (peroneal) nerve at the fibular head, the facial nerve, and the sural nerve.
• Peripheral neuropathy is thought to occur in about 10% of patients with hepatitis C virus and may be the
presenting symptom.

• A length-dependent sensory or sensorimotor axonal neuropathy is the most common peripheral nervous
system manifestation of HIV.
• Diphtheritic neuropathy is the prototypical infection leading to a demyelinating neuropathy with a
presentation that resembles Guillain-Barré Syndrome.
• Chagas disease, caused by the parasite Trypanosoma cruzi, can cause autonomic neuropathy, particularly
affecting cardiac and gastrointestinal function.
• A positive “spatula test,” in which attempting to elicit the gag reflex results in the patient biting down, is both
sensitive and specific for tetanus.
• Wound botulism can occur after trauma but is more commonly seen in relation to recreational drug use,
especially IV drugs and subcutaneous heroin.
• Nerve conduction studies/EMG is important in aiding the clinical diagnosis of botulism because it can help
confirm the diagnosis before laboratory testing results and make other diagnoses less likely.
• An acute, self-limited myositis may occur secondary to viral infections, particularly influenza.
• Pyomyositis classically occurs in otherwise healthy young men in tropical regions but has become more
common in the United States.
ARTICLE 6: PARASITIC INFECTIONS OF

THE NERVOUS SYSTEM
Hector H. Garcia, MD, PhD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews how parasites affect the human nervous system, with a focus on four
parasitic infections of major public health importance worldwide, two caused by protozoa
(malaria and toxoplasmosis) and two by helminths (neurocysticercosis and schistosomiasis).
RECENT FINDINGS:
Parasitic infections in humans are common, and many can affect the central nervous system
where they may survive unnoticed or may cause significant pathology that can even lead to the
death of the host. Neuroparasitoses should be considered in the differential diagnosis of
neurologic lesions, particularly in individuals from endemic regions or those with a history of
travel to endemic regions.
SUMMARY:
Cerebral malaria is a significant cause of mortality, particularly in African children, in whom
infected red blood cells affect the cerebral vessels, causing severe encephalopathy.
Neurocysticercosis is the most common cause of acquired epilepsy worldwide and has varied
clinical presentations, depending on the number, size, and location of the parasites in the
nervous system as well as on the host’s inflammatory response. Toxoplasmosis is distributed
worldwide, affecting a significant proportion of the population, and may reactivate in patients
who are immunosuppressed, causing encephalitis and focal abscesses. Schistosomiasis causes
granulomatous lesions in the brain or the spinal cord.
KEY POINTS
• The human nervous system can be invaded by multiple parasite species, which, in some cases, cause a
significant burden of morbidity and mortality.

• Parasites use multiple mechanisms to overcome the physical and immunologic barriers that vertebrates have
evolved to protect their nervous systems.
• Malaria is the most common parasitic disease of humans and the most common parasitic cause of mortality
and morbidity worldwide. Annually, malaria causes more than 400,000 deaths in endemic regions, mostly in
African children.
• Untreated cerebral malaria is lethal in all cases. Even under appropriate care, short-term mortality may
approach 15% to 30%.
• Up to one-third of the world’s population is infected with latent toxoplasmosis (usually asymptomatic), and
disease occurs when latent brain infections are reactivated in patients who become immunocompromised.
• The clinical manifestations of cerebral toxoplasmosis are usually subacute and depend on the topography
and number of lesions. The main symptoms are fever, headache, seizures, focal deficits, confusion,
lethargy, and visual alterations related to retinal toxoplasmosis.
• Therapy with pyrimethamine-based treatment or trimethoprim-sulfamethoxazole is usually effective for
neurotoxoplasmosis, with clinical and radiologic improvement in 80% to 90% of patients receiving one of
these regimens.
• Neurocysticercosis represents a significant source of morbidity and mortality, causing approximately 30% of
cases of epilepsy in endemic regions, making it the most common preventable risk factor in the world for
adult acquired epilepsy.
• Neurocysticercosis varies in clinical and radiologic presentation depending on the location, size, and number
of lesions and host immune response.
• The enzyme-linked immunoelectrotransfer blot assay using lentil-lectin purified glycoprotein parasitic
antigens in serum is the assay of choice for antibody detection of neurocysticercosis.
• For a single parenchymal cyst in neurocysticercosis, albendazole at 15 mg/kg/d for 7 to 15 days is the
regimen of choice. In cases with multiple viable cysts, the combination of albendazole plus praziquantel at
50 mg/kg/d for 10 days has demonstrated superior efficacy.
• Schistosomal infection of the central nervous system (neuroschistosomiasis) is a rare complication of
schistosomiasis presenting with myelopathy or encephalopathy; it can present months to years after
exposure.
• Transverse myelitis is the most common presentation of spinal neuroschistosomiasis and is related to
granulomatous lesions with inflammatory necrosis of the spinal cord.
• A variety of parasitic infections may affect the human central nervous system less frequently. Epidemiologic
suspicion, particularly in the settings of atypical clinical presentations of neurologic disease, should help to
detect parasitic infections of the central nervous system.
ARTICLE 7: NEUROLOGIC
COMPLICATIONS OF HUMAN
IMMUNODEFICIENCY VIRUS
Marie F. Grill, MD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the neurologic complications associated with human immunodeficiency virus
(HIV) infection.

RECENT FINDINGS:
Neurologic complications of HIV may be caused by direct virally mediated pathology,
immune-mediated phenomena in response to viral infection, or opportunistic infections
secondary to depletion of lymphocytes. These neurologic disorders may be influenced by the
degree of immunosuppression (ie, CD4+ T-cell lymphocyte count) and stage of infection
(early versus late), as well as use of antiretroviral therapy, and may manifest as a variety of
central and peripheral neurologic syndromes, including the more commonly encountered
HIV-associated cognitive disorders and length-dependent sensorimotor polyneuropathy,
respectively. Immune dysregulation underlies the majority of these neurologic phenomena, as
well as other HIV-associated conditions including immune reconstitution inflammatory
syndrome (IRIS), CD8 lymphocytosis, and potentially the development of compartmentalized
infection within the CSF, also referred to as CSF escape.
SUMMARY:
This article reviews a spectrum of clinical syndromes and related neuropathologic states
associated with HIV infection.
KEY POINTS
• Evidence of human immunodeficiency virus (HIV) RNA and inflammation in the CSF has been identified
from the time of acute infection through the entire course of the disease, correlating with the clinical
observation that nervous system manifestations of HIV can occur throughout the course of infection.
• Neurologic complications of HIV may result from direct viral complications, immune-mediated
complications, opportunistic infections, and antiretroviral therapy (ART)-associated toxicities.
• Early in HIV infection, acute seroconversion syndrome and other autoimmune-mediated phenomena are
most likely to be seen, whereas in middle to late HIV infection, opportunistic infections, malignancies,
and long-term complications of HIV are more frequently encountered.
• Patients with acute HIV seroconversion have also presented with Guillain-Barré type syndrome/acute
inflammatory demyelinating polyradiculoneuropathy. Other rarely observed neurologic conditions that may
be seen at the time of seroconversion include transverse myelitis, acute disseminated encephalomyelitis
(ADEM), a multiple sclerosis–like illness, and bilateral brachial plexus neuritis.
• HIV-associated neurocognitive disorders include asymptomatic neurocognitive impairment, minor or mild
neurocognitive disorder, and HIV-associated dementia, distinguished by the degree of symptomatology and
functional impairment, as well as neuropsychologic test performance.
• Asymptomatic neurocognitive impairment is asymptomatic/subclinical, identified only with
neuropsychologic testing and used in research settings. Minor or mild neurocognitive disorder and
HIV-associated dementia exist on a spectrum of clinically manifest neuropsychological impairment of
varying severity, primarily affecting executive functioning, memory, learning, and attention.
• CSF escape refers to the presence of ongoing viral replication within the central nervous system
compartment despite relative virologic suppression in the blood with antiretroviral therapy use.
• Perhaps the most common clinically encountered HIV-related neurologic complication is distal symmetric
polyneuropathy. ART has both decreased the incidence of this condition and slowed disease progression in
patients with distal symmetric polyneuropathy, although asymptomatic peripheral neuropathy (as defined by
mild impairment in vibratory sensation in the great toes or diminished ankle reflexes bilaterally on
examination in the absence of clinical symptoms) may be present despite virologic control.
• Immune reconstitution inflammatory syndrome (IRIS) is a worsening of symptoms when the immune system
rebuilds (ie, when the CD4+ T-cell lymphocyte count increases and HIV plasma viral load decreases) after
initiation of ART therein reflecting an inflammatory rebound phenomenon.
• Worsening of neurologic impairment, as well as new-onset neurologic decline, may be seen in neuro-IRIS,
which is most frequently associated with cryptococcal meningitis and progressive multifocal

leukoencephalopathy, although it may also be seen with toxoplasmosis encephalitis and other
opportunistic infections.
• CD8+ encephalitis is a rare, recently recognized cause of encephalopathy seen in patients who are HIV
positive and have a normal CD4+ count stable on ART (although on occasion may be seen briefly after
initiation of ART). Patients present with acute to subacute encephalopathy that may be accompanied by
seizures and headaches.
• Although they are uncommon, immune-mediated acute and chronic inflammatory demyelinating
polyradiculoneuropathies occur more frequently in individuals who are HIV positive compared with those
who are HIV negative.
• Risk factors for ischemic stroke include accelerated atherosclerotic disease and other microangiopathic
changes, altered vascular reactivity/endothelial changes secondary to HIV-induced inflammatory changes,
HIV-associated hyperviscosity and coagulopathy (eg, antiphospholipid antibody syndrome), effects of
combination ART, comorbid substance use (including tobacco use and stimulants), and cardioembolic
phenomena (including both bacterial and marantic endocarditis, as well as cardiac dysfunction).
• Comorbid opportunistic infections such as varicella-zoster virus–associated vasculitis, meningovascular
syphilis, and tuberculous and cryptococcal meningitis are additional specific risk factors for stroke in HIV, as
is intravascular lymphoma albeit less commonly. HIV-associated thrombocytopenia, vasculopathy, and
mycotic aneurysms are associated with an increased risk of hemorrhagic stroke.
• Timely recognition, diagnosis, and treatment are key to decreasing morbidity and mortality risk associated
with opportunistic infections. Restoration of immune function with combination ART is also of critical
importance, although the risk of IRIS must be considered and may influence the timing of ART initiation.
• Toxoplasmosis is the most common cause of intracranial mass lesions in patients with HIV, typically with a
CD4+ count less than 200 cells/mm3, most often with less than 100 cells/mm3.
• Clinically, patients with toxoplasmosis often present with subacute focal neurologic signs (eg, hemiparesis,
unilateral movement disorder, gait disturbance, or speech abnormalities) and with headache, fever, and
altered mental status.
• Nuclear imaging modalities such as positron emission tomography (PET) may be helpful in making the
distinction (ie, no increase in metabolic activity of lesions in toxoplasmosis whereas increased metabolic
activity is suggestive of primary CNS lymphoma).
• Progressive multifocal leukoencephalopathy is one of the opportunistic infections more commonly
associated with IRIS, which can appear on imaging as edema, mass effect, and contrast enhancement.
• Other novel JC virus–associated CNS disorders are caused by JC virus variants and include granule cell
neuronopathy in which cerebellar granule cell neurons are infected, as well as JC virus encephalopathy in
which cortical gray matter pyramidal neurons are infected.
• Patients with cryptococcal meningitis typically present with subacute progressive headache and fever.
Other symptoms may manifest from complications relating to meningitis including altered mental status,
blurred vision, and cranial nerve palsies secondary to elevated intracranial pressure with or without
accompanying hydrocephalus.
• Formation of gelatinous cysts may develop in increasingly dilated perivascular spaces, referred to as a soap
bubble appearance on brain MRI, and is more commonly seen in patients with cryptococcal disease infected
with HIV in contrast to patients who are not infected with HIV.
• Cytomegalovirus infection is seen almost exclusively in individuals who are immunocompromised; in patients
infected with HIV, this is typically seen when CD4+ counts are less than 50 cells/mm3. It may be associated
with meningitis, encephalitis, myelitis, and radiculitis.
• The Centers for Disease Control and Prevention recommends delaying the initiation of ART for 8 weeks after
initiation of antituberculosis treatment to decrease the risk of tuberculosis CNS IRIS.
• CSF varicella-zoster (VZV) IgG is considered more sensitive than PCR, particularly in those with a latency of
weeks to months since rash or in cases of zoster sin herpete. Treatment consists of IV acyclovir, as well
as steroids in the setting of VZV-associated vasculitis.
• Neurosyphilis should be considered in all individuals infected with HIV who have neurologic symptoms.

Serum rapid plasma reagin (RPR) titer of at least 1:32 is associated with an increased likelihood of
neurosyphilis, both in patients who are not infected with HIV and in those who are, with an even higher risk in
the latter group.
• Nucleoside reverse transcriptase inhibitors such as didanosine and zalcitabine, as well as stavudine, can
cause peripheral neuropathy with mitochondrial toxicity postulated to be the underlying mechanism.
COMPLICATIONS OF TUBERCULOSIS
Deanna Saylor, MD, MHS. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article describes the current epidemiology, common clinical characteristics, and
up-to-date evidence-based approaches to the diagnosis and management of the most common
neurologic complications of tuberculosis (TB): tuberculous meningitis, intracranial tuberculoma,
and spinal TB.
RECENT FINDINGS:
Central nervous system (CNS) TB remains common and associated with significant mortality and
neurologic sequelae worldwide. Human immunodeficiency virus (HIV) co-infection is strongly
associated with both the development of and mortality due to CNS TB. Strongyloides
co-infection is associated with reduced CNS inflammation and improved outcomes in the setting
of tuberculous meningitis. Stroke remains a common complication of tuberculous meningitis,
and emerging evidence suggests aspirin may be used in this context. Although a recent nucleic
acid amplification test has demonstrated suboptimal sensitivity in the diagnosis of CNS TB,
emerging diagnostic techniques include cell-free DNA, peripheral blood microRNA,
metagenomic next-generation sequencing, and advanced imaging techniques, but these are not
yet well validated. CNS TB is associated with high mortality even with current treatment
regimens, although novel, promising strategies for treatment are under investigation, including a
combination of IV isoniazid and ethambutol and high-dose rifampicin.
SUMMARY:
TB can affect the nervous system in various ways and is associated with high mortality. Diagnosis
remains challenging in endemic settings, with empiric treatment often initiated without a
definitive diagnosis. Furthermore, optimal treatment regimens remain uncertain because current
treatment for all forms of CNS TB is extrapolated from trials of tuberculous meningitis whereas
the role of steroids in people with HIV and tuberculous meningitis remains controversial.
KEY POINTS
• Tuberculosis (TB) is the leading cause of death from an infectious etiology and remains in the top 10 causes of
death globally. In 2019, TB accounted for 10million new symptomatic infections (1.2 million symptomatic
infections in children) and 1.4 million deaths globally, and 25% of the world’s population is thought to be
infected with TB.
• Central nervous system (CNS) TB is one of the most severe forms of TB and is associated with high mortality,
especially among people with human immunodeficiency virus (HIV).
• The most common form of CNS TB is tuberculous meningitis, which can present either as an insidious chronic

meningitis or as an acute fulminant meningitis with the most common symptoms being fever, headache, and
alterations in consciousness.
• Stroke, usually in the basal ganglia, is one of the most common complications of tuberculous meningitis,
occurring in approximately 30% to 60% of cases.
• Seizures are common in tuberculous meningitis, occurring in approximately one-third of individuals and most
often occurring more than 1month after the onset of meningitis symptoms.
• Immune reconstitution inflammatory syndrome is paradoxical worsening of an individual’s clinical and
radiographic presentations that occurs in people with HIV initiating antiretroviral therapy.
• The primary microbiological tools for CNS diagnosis include acid-fast bacilli stain, Mycobacterium culture,
and nucleic acid amplification tests. All of these modalities are limited in their sensitivity, which results in
higher than acceptable rates of false-negative results.
• Novel and adjunctive assays have been developed in hopes of improving the ability to accurately diagnose
CNS TB but, thus far, continue to demonstrate suboptimal sensitivity or have not been widely validated.
• Investigating combinations of diagnostic tests may lead to the highest utility for diagnosing tuberculous
meningitis.
• Given the difficulty of obtaining a microbiologically confirmed diagnosis of tuberculous meningitis, clinical
case definitions such as the Uniform Case Definition and the Thwaites Score are often used in high-TB-burden
regions to make presumptive diagnoses to initiate empiric treatment.
• The World Health Organization recommends treatment of tuberculous meningitis in two stages, which are (1)
the intensive phase: rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months and (2) the
continuation phase: rifampicin and isoniazid for 9 to 12 months.
• Concomitant steroids in addition to antitubercular therapy tapered over 6 to 8 weeks have also been shown
to reduce mortality, severe disability, and disease relapse.
• A systematic review found that the addition of aspirin to standard treatment regimens for tuberculous
meningitis reduced the risk of stroke and was safe but had no effect on overall mortality.
• A systematic review of tuberculous meningitis among adults worldwide identified a 23% mortality risk and
29% risk of neurologic sequelae. However, outcomes vary widely with mortality rates as high as 60% in
lower-resource settings and less than 20% in higher-resource settings with greater access to critical care
facilities.
• Approximately 10% of individuals with tuberculous meningitis have concomitant tuberculomas, but
tuberculomas can also occur in the absence of meningitis and without evidence of TB infection outside
of the CNS.
• In the absence of meningitis, CSF is usually normal in patients with tuberculoma, and the only definitive
diagnostic test is a brain biopsy. As such, a presumptive diagnosis based on clinical and radiographic
characteristics is often made to facilitate the initiation of empiric TB treatment.
• Tuberculoma treatment largely mirrors recommendations for tuberculous meningitis with most guidelines
recommending 9 to 12 months of standard TB treatment along with adjuvant corticosteroids.
• Tuberculous spondylitis presents insidiously over the course of months to more than 1 year, first with
nonspecific back pain that is then followed by kyphosis, sensory symptoms, bowel and bladder symptoms,
and, finally, paraparesis.
• Intradural tuberculous spinal infections, including radiculomyelitis, spinal arachnoiditis, intramedullary
tuberculomas, and myelitis, are seen most commonly in the setting of tuberculous meningitis because of
the spread of inflammatory exudates from the cranial to the spinal compartment.

Felicia Chow, MD, MAS. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article focuses on the epidemiology, clinical presentation, diagnosis, and management of
neurosyphilis, with an emphasis on clinically relevant issues faced by the practicing neurologist.
RECENT FINDINGS:
The incidence of primary and secondary syphilis, the sexually transmissible stages of infection,
has been on the rise for the past 2 decades. A concerning recent trend is the surge in cases
of syphilis in women and of congenital syphilis. Neurosyphilis remains a relatively common
complication that can occur at any stage of syphilis. Along with meningitis, meningovascular
syphilis, which has been historically described as a late presentation of neurosyphilis, now
frequently occurs as a manifestation of early infection. Late forms of neurosyphilis, including
tabes dorsalis and general paresis, are less prevalent in the era of widespread penicillin use. As
more laboratories adopt the reverse-sequence algorithm for syphilis testing, patients with
serodiscordant results (ie, a reactive serum treponemal test with a nonreactive nontreponemal
test) may present an increasingly encountered diagnostic challenge for neurologists. Although
the CSF Venereal Disease Research Laboratory (VDRL) remains a mainstay of diagnostic testing
for neurosyphilis, using a higher titer cutoff (greater than 1:320) for the Treponema pallidum
particle agglutination assay (TPPA) from the CSF may improve the utility of the TPPA as a
supporting criterion for the diagnosis of neurosyphilis. Penicillin G is the treatment of choice for
neurosyphilis, although ceftriaxone may be a reasonable alternative therapy.
SUMMARY:
A high index of suspicion and awareness of the variable clinical presentations of neurosyphilis
are essential to the approach to this treatable infection. Neurologists should be mindful of the
limitations of serologic testing in the diagnosis of neurosyphilis and exercise clinical judgment to
determine the likelihood of the diagnosis.
KEY POINTS
• Symptomatic neurosyphilis can occur at any stage of syphilis and, in fact, is now diagnosed most commonly in
early syphilis.
• Although the syphilis epidemic in the United States is centered on young men who have sex with men, syphilis
rates are on the rise in women and newborns.
• The prevalence of neurosyphilis is higher in men, particularly men who have sex with men, along with people
with HIV infection.
• In early neurosyphilis, the CSF, meninges, and cerebral blood vessels are typically affected, leading to
syphilitic meningitis and meningovascular disease, whereas late forms of neurosyphilis tend to cause injury to
the brain and spinal cord parenchyma.
• Patients with symptomatic early neurosyphilis typically present with signs and symptoms of a meningitis
(eg, headache, photophobia, neck stiffness, confusion) with or without cranial nerve involvement.
• Red flags that should raise the suspicion for meningovascular syphilis include stroke with concurrent or
preceding symptoms of meningitis or encephalitis and stroke in young, sexually active individuals, especially
in the absence of traditional cerebrovascular risk factors.

• Late forms of neurosyphilis (eg, tabes dorsalis and general paresis) are much less common in the era of
penicillin.
• The classic presentation of tabes dorsalis, which usually occurs decades after primary infection, is a sensory
gait ataxia with profoundly impaired proprioception, diminished reflexes, bowel and bladder dysfunction,
and lancinating pains in the abdomen and extremities.
• General paresis is a chronic encephalitic form of neurosyphilis that presents with neuropsychiatric symptoms
years to decades after primary infection.
• All patients with neurosyphilis should have evidence of current or previous syphilis with a reactive serum
treponemal test.
• Serologic testing for syphilis is divided into nontreponemal and treponemal tests. Both types of tests, one
as an initial screen followed by the other as a confirmatory test, are required to make a presumptive
diagnosis of syphilis.
• The sensitivity of nontreponemal and treponemal testing varies by stage of syphilis.
• Serum false-positive nontreponemal tests, which are usually low titer (less than 1:8) can be seen in a variety
of clinical situations, including in HIV infection, autoimmune disorders, pregnancy, and injection drug use.
• Nontreponemal test results are reported as a titer that correlates with disease activity. A minimum fourfold
decrease in titer, which represents a change of two dilutions (eg, from 1:32 to 1:8), is one criterion used to
demonstrate a successful response to treatment.
• Treponemal tests typically remain positive for life, even after appropriate treatment, making them less
specific for active infection.
• The probability of neurosyphilis in people with serodiscordant serologies (ie, reactive serum treponemal test
with a nonreactive RPR) is thought to be low overall.
• The CSF pleocytosis in early neurosyphilis tends to be more robust than in late neurosyphilis.
• Although reports of “burned out” tabes dorsalis with normal CSF have been described, as has normal CSF in a
relatively high proportion of patients with general paresis in modern case series, this clinical scenario should
be viewed as atypical for neurosyphilis.
• The high specificity but variable sensitivity of the CSF Venereal Disease Research Laboratory (VDRL) makes it
a clinically informative test when reactive, whereas a nonreactive test does not exclude the diagnosis of
neurosyphilis.
• CSF treponemal tests are less specific than the VDRL and do not distinguish between previously treated
neurosyphilis and active infection.
• If the CSF VDRL is nonreactive in a patient for whom the clinical suspicion for neurosyphilis is high, obtaining a
CSF treponemal assay is a reasonable next step.
• High-dose IV penicillin G for 10 to 14 days is the treatment of choice for neurosyphilis. IV ceftriaxone 2 grams
daily may be an acceptable alternative therapy, especially for those with a penicillin allergy.
• Patients with early neurosyphilis are more likely to respond to treatment than those with late neurosyphilis,
both in terms of clinical recovery and resolution of CSF abnormalities.

COMPLICATIONS OF LYME DISEASE
Karen L. Roos, MD, FAAN. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article reviews the symptomatology, diagnosis, and treatment of neuroborreliosis.

RECENT FINDINGS:
The most recent guidelines for the diagnosis and treatment of Lyme disease were published in
2020 by the Infectious Diseases Society of America, the American Academy of Neurology,
and the American College of Rheumatology.
SUMMARY:
The most common neurologic complications of Lyme disease are cranial neuritis (most often a
unilateral or bilateral facial nerve palsy), meningitis, and radiculoneuritis/mononeuropathy
multiplex. Testing for Lyme disease begins with an enzyme-linked immunosorbent assay (ELISA).
If the ELISA is positive or borderline, Western blots should be performed for both IgM and IgG
antibodies. As a general rule, in infectious diseases, an IgM antibody response is followed by an
IgG antibody response. A central nervous system infection has either a CSF pleocytosis or
pathogen-specific intrathecal antibody production. Lyme meningitis, cranial neuropathy,
radiculoneuropathy, or other peripheral nervous system manifestations are treated with oral
doxycycline or IV ceftriaxone, cefotaxime, or penicillin G. No additional antibiotic therapy is
indicated for patients with posttreatment Lyme disease syndrome or patients with concern for
chronic Lyme disease with no evidence of previous or current Lyme infection.
KEY POINTS
• In North America, only one spirochete in the genus Borrelia causes Lyme disease, Borrelia burgdorferi.
• The most common neurologic complications of Lyme disease are cranial neuritis (most often cranial nerve
VII), meningitis, and radiculoneuritis.
• An Ixodes tick typically must remain attached for 24 to 48 hours to transmit Borrelia to the host.
• The initial sign of infection with Borrelia burgdorferi is a nonpruritic targetoid skin lesion called erythema
migrans that develops at the site of the tick bite.
• The Centers for Disease Control and Prevention recommends a two-step serologic testing procedure for
Lyme disease. First, an enzyme-linked immunosorbent assay (ELISA) for antibodies to B. burgdorferi should
be obtained. If the ELISA is negative, the patient does not have Lyme disease. If the ELISA is positive or
borderline, a Western blot for both IgM and IgG antibodies is performed.
• The CSF to serum antibody index is used to determine if intrathecal production of antibodies to Borrelia
has occurred.
• Doxycycline is not recommended in pregnant women, women who are breast-feeding, and children younger
than 8 years of age, although a short course of doxycycline is not likely to stain teeth.
• No rationale exists for managing posttreatment Lyme disease syndrome with long-term antibiotic therapy;
convincing biological and clinical evidence is lacking for the existence of chronic B. burgdorferi infection
after the recommended treatment regimens for Lyme disease are completed.
• Lyme disease IgM Western blots have a high false-positive rate and must be followed by IgG testing.

MANIFESTATIONS OF SEVERE ACUTE
RESPIRATORY SYNDROME
CORONAVIRUS 2 INFECTION
Avindra Nath, MD. Continuum (Minneap Minn). August 2021;

ABSTRACT
PURPOSE OF REVIEW:
This article describes the spectrum of neurologic complications associated with severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, their underlying pathology and
pathogenic mechanisms, gaps in knowledge, and current therapeutic strategies.
RECENT FINDINGS:
COVID-19 is the clinical syndrome caused by the novel coronavirus SARS-CoV-2. It can affect the
entire neuraxis, and presentations in the acute phase are variable, although anosmia is a
common manifestation. Encephalopathy is common in patients who are hospitalized and is often
associated with multiorgan involvement. Immune-mediated encephalitis is probably
underrecognized; however, viral encephalitis is rare. Other manifestations include stroke,
seizures, myelitis, and peripheral neuropathies, including Guillain-Barré syndrome, which
sometimes has atypical manifestations. Treatment is symptomatic, and immunotherapies have
been used successfully in some patients. Long-term complications include dysautonomia,
exercise intolerance, malaise, sleep disturbances, cognitive impairment, and mood disorders.
SUMMARY:
Neurologic manifestations of COVID-19 may occur in the acute setting and may be independent
of respiratory manifestations. Immune-mediated syndromes and cerebrovascular complications
are common. Large populations of patients are expected to have long-term neurologic
complications of COVID-19, many of which may emerge only after recovery from the
acute illness.
KEY POINTS
• Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome.
• Although effective vaccines have been developed for COVID-19 and are being distributed, millions of people
will have long-term complications from the infection, some of which will be neurologic.
• Myalgia and fatigue are seen in about 50% of patients with COVID-19 and may persist even after recovery from
the other symptoms. Headache occurs in 8% of patients.
• Anosmia and ageusia may be heralding manifestations of COVID-19.
• Mortality in COVID-19 is higher with advanced age and underlying comorbidities, including diabetes, cardiac
and respiratory disorders, and immunosuppressed states.
• The neurologic manifestations of COVID-19 can be broadly divided into two categories: those that occur
during the acute phase of the infection (parainfectious complications) and the postviral manifestations that
occur following the acute phase (post–acute phase complications).
• Anosmia and ageusia are the most common early symptoms of COVID-19 infection. Nearly 40% to 60% of
patients develop loss of smell, and, upon testing, nearly 90% have alteration of smell.
• Encephalopathy is the most common neurologic manifestation in patients who are hospitalized with
COVID-19, with nearly one-third of patients who are hospitalized developing encephalopathic symptoms
ranging from alteration in consciousness to delirium and seizures.
• Direct viral invasion of the brain in COVID-19 is rare.
• Acute necrotizing hemorrhagic encephalopathy is a feared complication of several viruses, most notably
influenza. It is thought to result from cytokine release syndrome rather than direct viral invasion of brain
parenchyma, which is especially salient given the propensity of SARS-CoV-2 for causing similar cytokine
storms in the lungs.
• Acute disseminated encephalomyelitis is a rare demyelinating disease; it is often postviral and is more
common in children than adults. However, in patients with COVID-19, it has been described mainly in adults.
• Patients with COVID-19 develop a hypercoagulable syndrome causing both arterial and venous occlusions in
the brain vasculature. Ischemic stroke, hemorrhagic stroke, and cerebral venous sinus thrombosis have all
been reported.

• Cerebrovascular complications of COVID-19 are likely due to altered coagulation pathways as demonstrated
by observations of elevated D-dimer, increased prothrombin time and activated partial thromboplastin
time, and disseminated intravascular coagulation.
• Variants of Guillain-Barré syndrome seem to be more common when associated with preceding
COVID-19 infection.
• Myositis can occur at any time during the course of COVID-19; it can be quite extensive and associated with
myalgia and muscle weakness that can persist after recovery of the other symptoms.
• Long-haul COVID is a distinct postviral syndrome that is independent of the severity of the acute phase of
the illness. This syndrome can emerge even in patients who have relatively mild symptoms during the
acute phase.
• A distinction needs to be made between patients with long-haul COVID and patients who were hospitalized,
who often have a large number of lingering symptoms from respiratory disease, other organ damage,
and prolonged hospitalization.
ARTICLE 12: NEUROLOGIC INFECTIONS

IN PATIENTS ON IMMUNOMODULATORY
Pria Anand, MD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
Both broadly immunosuppressive medications and selective immunomodulatory agents that act
on particular components of the immune system are increasingly used in the treatment of
neurologic and non-neurologic diseases. These therapies predispose patients to particular
infections, some of which may affect the nervous system. Therefore, familiarity with the clinical
and radiologic features of neurologic infections associated with specific immunomodulatory
therapies is of importance for the practicing neurologist. This article reviews these
neuroinfectious conditions, as well as other neurologic complications unique to transplant
recipients and other patients who are immunocompromised.
RECENT FINDINGS:
Diagnosis of infectious pathogens in patients who are immunocompromised may be particularly
challenging because a decreased immune response can lead to atypical imaging or laboratory
findings. Next-generation sequencing and other novel diagnostic modalities may improve the
rate of early identification of neurologic infections in patients who are immunocompromised
and ultimately ameliorate outcomes in this vulnerable population.
SUMMARY:
A broad range of bacterial, viral, fungal, and parasitic infections of the nervous system can
complicate solid organ and hematopoietic cell transplantation as well as other forms of
immunocompromise. In addition to neurologic infections, such patients are at risk of neurotoxic
and neuroinflammatory complications related to immunomodulatory and immunosuppressive
therapies. Early recognition of infectious and noninfectious complications of
immunocompromise is essential to guide appropriate treatment, which can include antimicrobial

therapy and, in some cases, withdrawal of the predisposing medication with a transition to an
alternative regimen.
KEY POINTS
• The term immunocompromise spans the effects of both broadly immunosuppressive therapies used to
treat autoimmune and neoplastic conditions (eg, cyclophosphamide, methotrexate, azathioprine,
mycophenolate mofetil, cyclosporine, and tacrolimus) and immunomodulatory therapies such as
natalizumab or fingolimod, which act selectively on part of the immune system.
• Although immunosuppressive therapies predispose patients to a wide range of opportunistic infectious
pathogens, the risk profile in patients on immunomodulatory therapies may be limited to specific
pathogens or infectious syndromes.
• The immunosuppressive or immunomodulatory effects of a medication may persist for weeks or even months
after it is discontinued.
• When neurologic infections that can also affect immunocompetent hosts occur in patients who are
immunocompromised, atypical clinical presentations, imaging, and laboratory findings may be seen.
• Early recognition of infectious and noninfectious complications of immunocompromise is essential to guide
appropriate treatment, which can include antimicrobial therapy and, in some cases, withdrawal of the
predisposing medication with a transition to an alternative regimen.
• Neurologic complications after transplantation affect as many as 11% to 19% of hematopoietic stem cell
transplant recipients and approximately one-third of solid organ transplant recipients.
• Among solid organ transplant recipients, liver transplant recipients, particularly those with fulminant hepatic
failure, often have serious medical problems at the time of their transplant and may be at higher risk of early
central nervous system infections, whereas heart, intestinal, and pancreas transplant recipients are
chronically immunosuppressed and may be most prone to late infectious complications.
• Immune reconstitution inflammatory syndrome, an exuberant and dysfunctional host inflammatory response
to a recent infection triggered by immune recovery, can involve the central nervous system in both solid
organ and hematopoietic cell transplant recipients. In the latter population, central nervous system immune
reconstitution inflammatory syndrome may occur during engraftment, but it has also been reported later
after transplant and even several months after discontinuation of immunosuppression.
• On MRI, large, confluent T2-hyperintense lesions and deep gray matter lesions were more frequent in
patients with progressive multifocal leukoencephalopathy (PML) than in patients with multiple sclerosis,
whereas crescentic cerebellar lesions were seen only in patients with PML.
• Ocrelizumab, a humanized anti-CD20 monoclonal antibody used in the treatment of multiple sclerosis, has
also been associated with PML, primarily in patients previously treated with rituximab, fingolimod, or
natalizumab, although a case of ocrelizumab-associated PML was described in 2020 in the setting of
lymphopenia in a patient with primary progressive multiple sclerosis who had not received previous
immunomodulatory or immunosuppressive medication.
• Risk factors for the development of PML in patients on natalizumab include elevated serum levels of anti–JC
virus antibodies, the use of immunosuppressant or immunomodulatory therapies before natalizumab
initiation, and the duration of natalizumab treatment, with a median time from treatment initiation to onset of
PML symptoms of 25 months.
• In patients who have an anti–JC virus antibody index of 0.9 or greater, natalizumab should be discontinued in
favor of an alternative disease-modifying therapy at 24 months because of the increasing risk of PML.
• Although meningococcal vaccination is recommended for all patients before initiating eculizumab, infections
with nontypable strains not included in the vaccine have been reported in vaccinated patients, and antibiotic
prophylaxis with penicillin or a macrolide is warranted for the duration of therapy.
• Treatment with alemtuzumab carries a risk of both autoimmune conditions and opportunistic central nervous
system infections with herpesviruses, Listeria, and Nocardia.
• Patients who are immunocompromised represent one-fourth of patients with Streptococcus pneumoniae

bacterial meningitis, and transplant recipients and others with impaired cell-mediated immunity are at risk of
fungal and mycobacterial meningitis.
• India ink staining has been largely supplanted by serum and CSF cryptococcal antigen, which has sensitivity
and specificity greater than 97%.
• Ischemic strokes are a significant cause of long-term morbidity in tuberculous meningitis and affect
25% to 50% of infected patients.
• Infectious etiologies of encephalitis unique to patients who are immunosuppressed include viruses such
as cytomegalovirus, human herpesvirus 6, BK virus, and varicella-zoster virus.
• In patients who do not respond to antiviral therapy, transplant guidelines regarding general management of
cytomegalovirus infection suggest that dose reduction of immunosuppressive therapies may be beneficial.
• Although the incidence of CMV encephalitis in patients who are immunocompromised has been reduced in
the setting of ganciclovir prophylaxis, the mortality remains high because of antiviral drug resistance and
reduced efficacy of antiviral therapy due to poor CSF penetration.
• Human herpesvirus 6 reactivation in the posttransplant population may present with a classic limbic
encephalitis, also sometimes called posttransplant acute limbic encephalitis.
• Given the involvement of the limbic system and the possibility of electrolyte depletion secondary to
foscarnet therapy, patients with posttransplant acute limbic encephalitis are at high risk of seizures, and
clinicians should maintain a low threshold for EEG monitoring.
• Clinical presentations of varicella-zoster virus encephalitis are heterogeneous, and the syndrome may
present with concomitant cerebellitis, cranial neuropathies, meningitis, myelitis, or vasculopathy.
• In patients who are immunocompromised, varicella-zoster virus vasculopathy more often affects small
vessels, whereas in older patients who are immunocompetent, it typically causes a large vessel vasculopathy
several weeks after trigeminal zoster.
• Varicella-zoster virus DNA in the CSF is highly specific and helpful if positive, but it has only 30% sensitivity in
patients with isolated vasculopathy.
• Visual processing deficits including homonymous hemianopia, visual agnosia, visual hallucinations,
hemineglect, and other visuospatial deficits may be the presenting symptom in 20% of patients with PML and
occur at some point during the disease in up to half of patients.
• In some patients who are immunocompromised, JC virus may cause a granule cell neuronopathy,
characterized by infection of the granule cells of the cerebellum and presenting with slowly progressive
cerebellar atrophy without white matter lesions.
• Patients who discontinue or reduce immunosuppressive medications are at risk of developing progressive
multifocal leukoencephalopathy–immune reconstitution inflammatory syndrome, particularly patients on
natalizumab, who can develop the syndrome weeks or even months after discontinuing natalizumab.
• Early, small reports have suggested favorable outcomes in patients with PML treated with immune
checkpoint inhibitors such as pembrolizumab or nivolumab and in those treated with virus-specific
cytotoxic T cells.
• Toxoplasma gondii has a predilection for the basal ganglia and may cause hyperkinetic movement disorders.
• The majority of patients with toxoplasmosis have radiographic and clinical improvement after 2 weeks of
empiric treatment; in patients who show no improvement, biopsy may be necessary to evaluate for primary
central nervous system lymphoma.
• In a study of patients who are immunocompetent and have primary central nervous system lymphoma,
immunoglobulin heavy chain gene rearrangement studies and cytology were frequently found to be
discordant, suggesting that the two tests may be complementary in making a diagnosis of primary central
nervous system lymphoma.
• Primary central nervous system posttransplant lymphoproliferative disorder may occur as early as 6 weeks
after transplantation but more typically develops several years after transplantation, with a median time
to occurrence of 4 to 5 years.
• Patients who are immunocompromised are at particular risk of fungal brain abscesses, with 86% of abscesses
in solid organ transplant recipients and 92% of brain abscesses in bone marrow transplant recipients

resulting from fungal pathogens including Aspergillus, Mucor, Candida, Nocardia, and Cryptococcus
(cryptococcomas).
• Clinical findings of central nervous system aspergillosis in several large series included nonspecific
manifestations such as fever, altered mental status, hemiplegia, and seizures, whereas headache, nausea,
vomiting, and meningismus occurred more rarely.
• Early tissue diagnosis followed by surgical excision of the necrotic tissue and aggressive antifungal therapy
with amphotericin B can reduce morbidity and mortality from cerebral mucormycosis.
• Neuroimaging in patients with Nocardia infection shows either single or multiple ring-enhancing lesions
consistent with cerebral abscesses in the vast majority of cases, and rare cases may show meningeal
enhancement as well.
• Prognosis for patients with granulomatous amebic encephalitis remains poor and the disease is fatal in
more than 90% of cases.
• Varicella-zoster virus may cause a myelopathy in patients on natalizumab and other immunomodulatory
agents through several mechanisms, including varicella-zoster virus vasculopathy causing spinal cord
infarction, direct viral infection of the spinal cord, or a postinfectious inflammatory process.
• Cytomegalovirus polyradiculitis or polyradiculomyelitis occurs in patients who are severely
immunocompromised, including hematopoietic cell and solid organ transplant recipients, typically more
than 100 days after transplant.
• MRI in patients with Elsberg syndrome (herpes simplex virus-2 myeloradiculitis) typically shows T2
hyperintensities of the cord and contrast enhancement of both the spinal cord and nerve roots, sometimes
with cervicothoracic extension.
• Next-generation sequencing of the CSF is a promising approach for unbiased diagnostic evaluation and
organism identification in central nervous system infections and may be used more commonly in clinical
practice in the coming years.
ARTICLE 13: CONGENITAL INFECTIONS

OF THE NERVOUS SYSTEM
Payal Patel, MD. Continuum (Minneap Minn). August 2021;
ABSTRACT
PURPOSE OF REVIEW:
This article provides an overview of congenital infections affecting the central nervous system
(CNS), discussing the epidemiology, clinical features, diagnostic tools, and preventive and
treatment measures for a variety of pathogens with the potential to infect the developing
fetal brain.
RECENT FINDINGS:
Contrary to popular belief, many congenital CNS infections are preventable and treatable.
Treatment options exist for congenital cytomegalovirus, human immunodeficiency virus (HIV),
herpes simplex virus, toxoplasmosis, and syphilis, although the efficacy of these treatments and
the populations that may benefit from treatment are variable. Zika virus has recently emerged as
a pathogen affecting the fetal brain, and new data suggest that the pathogenesis of Zika virus
involves direct infection of neuronal progenitor cells leading to destruction of CNS tissue.
The incidence of congenital syphilis has been increasing in the United States over the past

decade as a direct result of new syphilis cases among adults and poor access to adequate
maternal health care.
SUMMARY:
Congenital CNS infections often result in significant neurologic morbidity in pediatric patients.
Therefore, early identification of maternal illness and implementation of preventive measures
are important in improving developmental outcomes and quality of life.
KEY POINTS
• Many congenital infections affecting the central nervous system (CNS) are preventable and treatable.
Therefore, anticipatory guidance regarding preventive measures and early detection are important.
• Transmission of congenital acquisition of infections most often occurs transplacentally but may also occur as
infants pass through the birth canal or may be acquired through breast-feeding.
• CNS involvement is common in congenital toxoplasmosis infection presenting as macrocephaly, cerebral
calcifications, hearing loss, and seizures.
• If in utero toxoplasmosis exposure is suspected, spiramycin can be administered in the first or early second
trimester, or pyrimethamine/sulfadiazine or leucovorin can be given in the late second or third trimester.
Treatment with antimicrobial therapy should be continued for 1 year after delivery and has been shown to
improve neurologic outcomes in neonates born with congenital toxoplasmosis.
• Positive cytomegalovirus (CMV) titers do not indicate protection against acquisition of the virus by pregnant
women, and transmission to their fetus, given that multiple strains of CMV exist globally, and reactivation of
latent disease can occur.
• Cerebral manifestations of congenital CMV infection include intracranial calcifications, hydranencephaly,
atrophy, schizencephaly, and cerebellar hypoplasia. Of the 10% of infants who present with symptomatic
CMV disease at birth, one-third will experience sensorineural hearing loss and two-thirds will have persistent
neurologic deficits.
• Valganciclovir has been shown to improve neurologic outcomes in infants born with symptomatic congenital
CMV infection.
• Cognitive impairment in children with human immunodeficiency virus (HIV) usually encompasses multiple
domains and is more severe in children with a history of acquired immunodeficiency syndrome
(AIDS)-defining illnesses.
• Early identification and initiation of treatment for children living with perinatally acquired HIV may be
neuroprotective, particularly for the prevention of opportunistic CNS infections.
• Classically, herpes simplex virus (HSV) encephalitis affects the temporal lobe, but neonates often present
with diffuse cerebral involvement.
• In neonates with HSV encephalitis, CSF HSV polymerase chain reaction (PCR) has a 75% positive predictive
rate with most false negatives occurring early (within 24 hours of onset) in the disease process. Therefore,
if HSV infection is suspected based on clinical suspicion, acyclovir should be started immediately, and
repeat CSF testing should be performed within the next 24 to 48 hours.
• The rate of CNS morbidity after HSV encephalitis remains high (two-thirds of infants with a history of HSV
encephalitis experience developmental delay) despite adequate treatment.
• Five features are considered characteristic of congenital Zika syndrome and distinguish congenital Zika
syndrome from other congenital CNS infections: (1) severe microcephaly with partially collapsed skull,
(2) thin cerebral cortex with subcortical calcifications, (3) macular scarring and focal pigmentary retinal
mottling, (4) congenital contractures, and (5) marked early hypertonia.
• False-positive rates are high for serum Zika titers given cross-reactivity with other flaviviruses. These viruses
often coexist in the same geographic area. Therefore, accurate prevalence data are difficult to ascertain
after endemic outbreaks.
• Neurologic manifestations of congenital syphilis present late after decades of untreated infection and
include meningitis, infarcts, hydrocephalus, and hearing loss.

• Congenital syphilis is diagnosed if one or more of the following are true in infants with reactive serum rapid
plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL): (1) clinical signs characteristic of
congenital syphilis, (2) serum quantitative nontreponemal titers that are fourfold higher than maternal titers,
and (3) a positive dark field test or PCR of lesions, placenta, or infant bodily fluids.

Issue Overview
Neuroinfectious Disease, Volume 27, Number 4, August 2021
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills.
Learning Objectives
Upon completion of this Continuum: Lifelong Learning in Neurology Neuroinfectious Disease

issue, participants will be able to:
 Discuss the symptoms, signs, radiologic features, and laboratory diagnosis of neurologic
infections
 Diagnose and treat infectious causes of meningitis, including understanding the role of
newer molecular diagnostic techniques
 Describe the approach to diagnosis and management of intracerebral infections
 Recognize, diagnose, and manage a range of infections of the spine and spinal cord
 Recognize the key features of infections that affect the peripheral nervous system and
describe the appropriate differential diagnosis based on localization within the peripheral
nervous system
 Discuss the epidemiology, pathophysiology, and management of neurologic parasitoses,

especially the more frequent parasitic infections affecting the human nervous system
 Diagnose and treat human immunodeficiency virus (HIV)-associated neurologic

disorders and opportunistic infections that can occur in patients with HIV
 Describe the epidemiology, clinical characteristics, and approach to the diagnosis and
management of neurologic complications of tuberculosis
 Diagnose and manage early and late clinical presentations of neurosyphilis and recognize
the limitations of serologic testing in the diagnosis of neurosyphilis
 Discuss the symptomatology, diagnosis, and treatment of Lyme disease
 Describe the spectrum of acute and chronic neurologic manifestations of COVID-19

caused by SARS-CoV-2

 Diagnose and manage neuroinfectious complications in patients who are
immunocompromised
 Discuss the neurologic presentation and management of congenitally acquired infections

affecting the central nervous system

Core Competencies
This Continuum: Lifelong Learning in Neurology Neuroinfectious Disease issue covers the
following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Aaron L. Berkowitz, MD, PhD, Guest Editor

Professor of Neurology and Director of Global Health, Kaiser Permanente Bernard J. Tyson
School of Medicine, Pasadena; Attending Neurologist, Kaiser Permanente Los Angeles Medical
Center, Los Angeles, California
Relationship Disclosure: Dr Berkowitz serves on the editorial board for Continuum and has received publishing
royalties from HarperCollins Publishers, McGraw Hill, MedMaster, and Oxford University Press.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Berkowitz reports no disclosure.
Pria Anand, MD
Assistant Professor of Neurology, Boston University School of Medicine and Boston Medical
Center, Boston, Massachusetts
Relationship Disclosure: Dr Anand reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Anand reports no disclosure.
Allen J. Aksamit Jr, MD, FAAN

Consultant, Department of Neurology, Mayo Clinic; Professor of Neurology, Mayo Clinic
College of Medicine, Rochester, Minnesota
Relationship Disclosure: Dr Aksamit reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Aksamit reports no disclosure.
Shamik Bhattacharyya, MD, MS

Assistant Professor of Neurology, Harvard Medical School; Associate Neurologist, Brigham and
Women’s Hospital, Boston, Massachusetts
Relationship Disclosure: Dr Bhattacharyya has received personal compensation for serving on a scientific advisory
board for Alexion Pharmaceuticals, Inc, and for serving as a consultant for Teladoc Health, Inc; has received
publishing royalties from Springer Publishing Company and UpToDate, Inc; and has given expert testimony in a
trial.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bhattacharyya discusses the unlabeled/investigational

use of IV glucocorticoids in the treatment of certain viral infections of the spinal cord (eg, varicella-zoster myelitis)
and IV immunoglobulins in the treatment of certain viral infections of the spinal cord (eg, enterovirus, West Nile
virus, vacuolar myelopathy in human immunodeficiency virus [HIV]).
Michael J. Bradshaw, MD
Director of Medical Education, Neurology; Co-Director, Center for Rare Neuroimmune
Disorders, Billings Clinic, Billings, Montana; Assistant Professor, Neurology, Rosalind Franklin
University of Medicine and Science, Chicago, Illinois; Clinical Instructor, Neurology, University
of Washington, Seattle, Washington
Relationship Disclosure: Dr Bradshaw reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Bradshaw discusses the unlabeled/investigational use
of IV glucocorticoids in the treatment of certain viral infections of the spinal cord (eg, varicella-zoster myelitis) and
IV immunoglobulins in the treatment of certain viral infections of the spinal cord (eg, enterovirus, West Nile virus,
vacuolar myelopathy in human immunodeficiency virus [HIV]).

Felicia Chow, MD, MAS
Associate Professor of Neurology and Medicine (Infectious Diseases), University of California,
San Francisco, California
Relationship Disclosure: Dr Chow has received personal compensation for speaking engagements from the
University of California, San Francisco, for the annual Recent Advances in Neurology meeting and for serving as an
expert physician for Grand Rounds and has received research/grant support from the National Institutes of Health
(K23NS105575, R21TW010148, R21TW011035).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Chow reports no disclosure.

Head, Cysticercosis Unit, Instituto Nacional de Ciencias Neurologicas; Director, Center for
Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru
Relationship Disclosure: Dr Garcia has served as an associate editor for the American Journal of Tropical Medicine
and Hygiene and PLOS Neglected Tropical Diseases and as a board member of the Oxfendazole Development
Group and has received research grants from the Fogarty International Center (D43TW001140), National Institute of
Allergy and Infectious Disease (U19AI129909), and National Institute of Neurological Disorders and Stroke
(U01NS086974).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Garcia reports no disclosure.
Marie F. Grill, MD
Assistant Professor of Neurology, Mayo Clinic, Scottsdale, Arizona
Relationship Disclosure: Dr Grill reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Grill discusses the unlabeled/investigational use of
neuropathic pain medications (amitriptyline, lamotrigine, lidocaine gel, and topical capsaicin cream) not specifically
approved for human immunodeficiency virus (HIV)-associated neuropathy, as well cidofovir, mirtazapine, and
pembrolizumab for the treatment of progressive multifocal leukoencephalopathy.
Neurologist, Colorado Permanente Medical Group, Department of Neurology, Denver, Colorado
Relationship Disclosure: Dr LoRusso has received a research education grant from the National Institute of
Neurological Disorders and Stroke (NeuroNext Fellowship; 5U24NS107205-03).
Unlabeled Use of Products/Investigational Use Disclosure: Dr LoRusso reports no disclosure.
Avindra Nath, MD
Chief, Section of Infections of the Nervous System, and Clinical Director, National Institute of
Neurological Disorders and Stroke; National Institutes of Health, Bethesda, Maryland
Relationship Disclosure: Dr Nath has served on the editorial board for Brain, as a section editor for Frontiers of
Neurology, and as an associate editor for the Journal of Neurovirology and has received research grants from the
National Institutes of Health (NS03130).
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nath reports no disclosure.
Payal Patel, MD
Acting Assistant Professor, University of Washington, Seattle, Washington
Relationship Disclosure: Dr Patel has received compensation as an author for MedLink, Inc, and has received
research and salary support from the National Institutes of Health (K23MH119914).

Unlabeled Use of Products/Investigational Use Disclosure: Dr Patel reports no disclosure.
Karen L. Roos, MD, FAAN

John and Nancy Nelson Professor of Neurology, Indiana University School of Medicine,
Indianapolis, Indiana
Relationship Disclosure: Dr Roos has received publishing royalties from Elsevier and has given expert medical
testimony during a trial.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Roos reports no disclosure.
Deanna Saylor, MD, MHS

Assistant Professor of Neurology, Director, Johns Hopkins Global Neurology Program, Johns
Hopkins University School of Medicine, Baltimore, Maryland; Director, Post-Graduate Training
Program in Neurology, University of Zambia School of Medicine, Lusaka, Zambia
Relationship Disclosure: Dr Saylor has received research/grant support from the American Academy of Neurology,
National Institute of Aging (R01 AG059504-01A), National Institute of Mental Health (R01 MH120693-01, P30
MH075673), National Institute of Neurological Disorders and Stroke (R01 NS094037-05S1, R21 NS118543-01),
and National Multiple Sclerosis Society.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Saylor discusses the unlabeled/investigational use of
thalidomide and nonstandard doses and/or nonstandard formulations of ethambutol, isoniazid, and rifampin for the
treatment of central nervous system tuberculosis.
Arun Venkatesan, MD, PhD

Associate Professor; Director, Johns Hopkins Encephalitis Center, Johns Hopkins University
School of Medicine, Baltimore, Maryland
Relationship Disclosure: Dr Venkatesan reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Venkatesan reports no disclosure.

Self-Assessment and CME Test Writers
James W. M. Owens Jr, MD, PhD

Associate Professor of Neurology, Adjunct Associate Professor of Pediatrics, University of
Washington School of Medicine, Seattle, Washington
Relationship Disclosure: Dr Owens has served as CME co-editor for Neurology and has received publishing
royalties from UpToDate, Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Owens reports no disclosure.
Allison L. Weathers, MD, FAAN

Associate Chief Medical Information Officer, Cleveland Clinic; Assistant Professor, Cleveland
Clinic Lerner College of Medicine, Cleveland, Ohio
Relationship Disclosure: Dr Weathers serves on the editorial board of Continuum and as chair of the adult
neurosciences specialty steering board for Epic.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Weathers reports no disclosure.

Methods of Participation and Instructions for Use
Continuum: Lifelong Learning in Neurology® is designed to help practicing neurologists stay
abreast of advances in the field while simultaneously developing lifelong self-directed learning
skills. In Continuum, the process of absorbing, integrating, and applying the material presented is
as important as, if not more important than, the material itself.
The goals of Continuum include disseminating up-to-date information to the practicing
neurologist in a lively, interactive format; fostering self-assessment and lifelong study skills;
encouraging critical thinking; and, in the final analysis, strengthening and improving patient
care.
Each Continuum issue is prepared by distinguished authors who are acknowledged leaders in
their respective fields. Six issues are published annually and are composed of review articles,
case-based discussions on ethical and practice issues related to the issue topic, coding
information, and comprehensive continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and video material relating to the
issue topic accompanies issues when applicable.
The text can be reviewed and digested most effectively by establishing a regular schedule of
study in the office or at home, either alone or in an interactive group. If subscribers use such
regular and perhaps new study habits, Continuum’s goal of establishing lifelong learning patterns
can be met.

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com/continuum by juGL3SikQGgPeJhlsy5S2tR2Je1+DSLxXM5+5U0pNQ/o8Sr9B6vmzj4RAT1RqJBz5vmQ6bjYts4rZHominWNXy0H3U65GuTdNee3fZ5dQ+6XNmvYCGaBTods9Wqj4Xuj38PhBKDAOyxDHbtzda8GcRokJZqQbumdttFhFmAeKsA= on 09/03/2021

816 Editor’s Preface

818 Approach to Neurologic Infections

855 Encephalitis and Brain Abscess

887 Infections of the Spine and Spinal Cord

921 Infections of the Peripheral Nervous System

943 Parasitic Infections of the Nervous System

963 Neurologic Complications of Human Immunodeﬁciency Virus

992 Neurologic Complications of Tuberculosis

1040 Neurologic Complications of Lyme Disease

1051 Neurologic Manifestations of Severe Acute Respiratory Syndrome

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1105 Congenital Infections of the Nervous System

SELF-ASSESSMENT AND CME

810 Learning Objectives and Core Competencies

1127 Instructions for Completing Postreading Self-Assessment and CME

1129 Postreading Self-Assessment and CME Test

1144 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Aaron L. Berkowitz, MD, PhD, Shamik Bhattacharyya, MD, MS

Guest Editor Assistant Professor of

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Relationship Disclosure: Dr Chow has Unlabeled Use of Products/Investigational

Unlabeled Use of Products/Investigational

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Avindra Nath, MD Deanna Saylor, MD, MHS

Unlabeled Use of Products/Investigational

Relationship Disclosure: Dr Roos has

Unlabeled Use of Products/Investigational

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James W. M. Owens Jr, MD, PhD Allison L. Weathers, MD, FAAN

Unlabeled Use of Products/Investigational Unlabeled Use of Products/Investigational

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A Topic With Culture

This issue of Continuum is devoted to the diagnosis and management

816 AUGUST 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

By Aaron L. Berkowitz, MD, PhD

RECENT FINDINGS: Theincreased use of immunosuppressive and

818 AUGUST 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mycobacterial, spirochetal, and parasitic infections generally present subacutely

Associated Symptoms and Signs

820 AUGUST 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

United States in patients who have immigrated from or traveled to endemic

MENINGITIS. Meningitis refers to inflammation of the meninges. When the brain is

822 AUGUST 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

United States), endemic fungi (histoplasmosis blastomycosis,

CASE 1-1 A 56-year-old man presented with several months of headache. He

COMMENT This case demonstrates how a serious neurologic infection (fungal

824 AUGUST 2021

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

encephalitis (caused by Acanthamoeba species or Balamuthia mandrillaris).

CRANIAL NEUROPATHY. Cranial neuropathy can be caused by inflammatory,