REVIEW ARTICLE
Approach to Neurologic

C O N T I N UU M A UD I O
INTERVIEW AVAILABLE
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CITE AS:
CONTINUUM (MINNEAP MINN)
2021;27( 4 , N E U R O I NF E C T I O U S
DISEASE):818–835.
Address correspondence to
Dr Aaron L. Berkowitz,
Kaiser Permanente Bernard J.
Tyson School of Medicine,
100 S Los Robles Ave,
Pasadena, CA 91006,
aaron.l.berkowitz@kp.org.
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.
© 2021 American Academy
of Neurology.
818
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Infections
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
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.
INTRODUCTION
N
eurologic infections can affect any level of the neuraxis. Infections
must, therefore, be considered in the differential diagnosis for any
possible neurologic presentation: meningitis, encephalitis, focal or
multifocal brain lesions (these first three may present with
headache, seizures, focal deficits, encephalopathy, or coma), cranial
neuropathy, myelopathy, radiculopathy, peripheral neuropathy (including
mononeuropathy, mononeuropathy multiplex, and polyneuropathy),
neuromuscular junction disorder, and myopathy.
Neurologic infections can be caused by any category of microbes: viruses,
bacteria, fungi, or parasites.
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
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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)
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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,

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 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
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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,
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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

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 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
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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
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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

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 APPROACH TO NEUROLOGIC INFECTIONS

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,
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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).
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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.

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 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
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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
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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

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 APPROACH TO NEUROLOGIC INFECTIONS

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,
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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
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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.

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 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
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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
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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

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 APPROACH TO NEUROLOGIC INFECTIONS

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
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can be seen with VZV, meningovascular syphilis, angioinvasive aspergillosis, or

mucormycosis or in the context of bacterial, fungal, or tuberculous meningitis.
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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

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 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
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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
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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

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 APPROACH TO NEUROLOGIC INFECTIONS
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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

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 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
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the combination of hydrocephalus,

infarction, and basal meningeal
enhancement were both found to be 100%
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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.

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 APPROACH TO NEUROLOGIC INFECTIONS

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,
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ring-enhancing lesions may be caused

by toxoplasmosis or EBV-associated
primary CNS lymphoma, which can be
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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

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FIGURE 1-7
MRI in schistosomiasis. Postcontrast
T1-weighted MRI showing left temporal
enhancement in an “arborized”
pattern, determined by biopsy to be
neuroschistosomiasis.
Reprinted with permission from Cho TA,
Continuum (Minneap Minn).30 © 2018
American Academy of Neurology.
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.
Microbiological Diagnosis
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
(TABLE 1-1).
Direct identification can be
attempted with microscopy and
staining (eg, Gram stain for
bacteria, acid-fast staining for
mycobacteria, India ink for
fungi) or culture. These methods
are used most commonly for
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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
● Ring-enhancing lesions
with a likelihood ratio of 15 for bacterial most commonly represent
meningitis, whereas a CSF white blood cell abscess or tumor, although
count less than 500 cells/mm3 is associated subacute stroke may also
with a likelihood ratio of 0.3; a CSF to show a peripheral pattern of
enhancement.
blood glucose ratio of less than 0.4 is
associated with a likelihood ratio of 18 for ● CSF in neurologic
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
● 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,
FIGURE 1-8 whereas a lymphocytic
MRI in progressive multifocal predominance is seen in
leukoencephalopathy (PML). A, Axial viral, fungal, and
fluid-attenuated inversion recovery (FLAIR) MRI mycobacterial infections.
showing hyperintensity in the juxtacortical white However, a neutrophilic
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
hyperintensity in the left middle cerebellar infections and throughout
peduncle in a patient with PML. the course of West Nile virus
Panel A reprinted with permission from Aksamit AJ Jr, encephalitis.
Continuum (Minneap Minn).31 © 2012 American Academy
of Neurology. Panel B reprinted with permission from
Saylor D, Continuum (Minneap Minn).32 © 2018 American
Academy of Neurology.
831
 APPROACH TO NEUROLOGIC INFECTIONS

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.
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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
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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

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 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
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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
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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

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 APPROACH TO NEUROLOGIC INFECTIONS
KEY POINTS
● CSF PCR is the most
sensitive test for most viral
infections of the nervous
system, with some notable
exceptions (arboviruses,
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varicella-zoster virus).
● Metagenomic
next-generation sequencing
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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.
834
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
be recognized, atypical radiologic features may be seen in immunocompromised
individuals. Definitive microbiological diagnosis can be made by way of a
growing number of techniques, requiring the neurologist to be aware of the most
sensitive test for each pathogen under consideration.
ACKNOWLEDGMENTS
The author would like to thank Pria Anand, MD, and Saman Nematollahi, MD,
for helpful comments and suggestions on an earlier version of this manuscript.
REFERENCES
1 Murray P, Rosenthal K, Pfaller M. Viral
classification, structure, and replication. In:
Murray PR, Rosenthal KS, Pfaller MA, editors.
Medical microbiology. 9th ed. Philadelphia, PA:
Elsevier, 2020:362-377.
2 Murray P, Rosenthal K, Pfaller M. Bacterial
classification, structure, and replication. In:
Murray PR, Rosenthal KS, Pfaller MA, editors.
Medical microbiology. 9th ed. Philadelphia:
Elsevier, 2020.
3 Murray P, Rosenthal K, Pfaller M. Fungal
classification, structure, and replication. In:
Murray PR, Rosenthal KS, Pfaller MA, editors.
Medical microbiology. 9th ed. Philadelphia, PA:
Elsevier, 2020:572-577.
4 Murray P, Rosenthal K, Pfaller M. Parasitic
classification, structure, and replication. In:
Murray PR, Rosenthal KS, Pfaller MA, editors.
Medical microbiology. 9th ed. Philadelphia, PA:
Elsevier, 2020:686-692.
5 Centers for Disease Control and Prevention.
About parasites. Accessed January 15, 2021. cdc.
gov/parasites/about.html
6 Anand P. Neurologic infections in patients on
immunomodulatory and immunosuppressive
therapies. Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):1066-1104.
7 Grill MF. Neurologic complications of human
immunodeficiency virus. Continuum (Minneap
Minn) 2021;27(4, Neuroinfectious Disease):
963-991.
8 Ashraf N, Kubat RC, Poplin V, et al. Re-drawing
the maps for endemic mycoses. Mycopathologia
2020;185(5):843-865. doi:10.1007/s11046-020-
00431-2
9 Attia J, Hatala R, Cook DJ, Wong JG. The rational
clinical examination. Does this adult patient have
acute meningitis? JAMA 1999;282(2):175-181.
doi:10.1001/jama.282.2.175
10 Bodilsen J, Dalager-Pedersen M, Schønheyder
HC, Nielsen H. Time to antibiotic therapy and
outcome in bacterial meningitis: a Danish
population-based cohort study. BMC Infect Dis
2016;16:392. doi:10.1186/s12879-016-1711-z
11 Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice
guidelines for the management of bacterial
meningitis. Clin Infect Dis 2004;39(9):1267-1284.
doi:10.1086/425368
12 Tunkel AR, Hasbun R, Bhimraj A, et al. 2017
Infectious Diseases Society of America's clinical
practice guidelines for healthcare-associated
ventriculitis and meningitis. Clin Infect Dis 2017;
64(6):e34-e65. doi:10.1093/cid/ciw861
13 Brouwer MC, McIntyre P, Prasad K, van de Beek
D. Corticosteroids for acute bacterial meningitis.
Cochrane Database Syst Rev 2015;2015(9):
CD004405. doi:10.1002/14651858.
CD004405.pub5
14 Hasbun R, Brouwer MC, Van de Beek D, Tunkel
AR. Acute meningitis. In: Bennet JE, Dolin R,
Blaser MJ, editors. Mandell, Douglas, and
Bennett's principles and practice of infectious
diseases. 9th ed. Philadelphia, PA: Elsevier, 2019.
15 Aksamit AJ Jr, Berkowitz AL. Meningitis.
Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):836-854.
16 Saylor D. Neurologic complications of
tuberculosis. Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):992-1017.
17 Joffe AR. Lumbar puncture and brain herniation
in acute bacterial meningitis: a review. J Intensive
Care Med 2007;22(4):194-207.
doi:10.1177/0885066607299516
18 Hasbun R, Abrahams J, Jekel J, Quagliarello VJ.
Computed tomography of the head before
lumbar puncture in adults with suspected
meningitis. N Engl J Med 2001;345(24):1727-1733.
doi:10.1056/NEJMoa010399
19 Granerod J, Tam CC, Crowcroft NS, Davies NWS,
Borchert M, Thomas SL. Challenge of the
unknown. A systematic review of acute
encephalitis in non-outbreak situations.
Neurology 2010;75(10):924-932. doi:10.1212/
WNL.0b013e3181f11d65
20 Venkatesan A. Encephalitis and brain abscess.
Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):855-886.
AUGUST 2021
 21 Bhattacharyya S, Bradshaw M. Infections of the
spine and spinal cord. Continuum (Minneap
Minn) 2021;27(4, Neuroinfectious Disease):
887-920.
22 Brannagan TH, Zhou Y. HIV-associated
Guillain-Barré syndrome. J Neurol Sci 2003;
208(1-2):39-42. doi:10.1016/s0022-
510x(02)00418-5
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw
23 LoRusso S. Infections of the peripheral nervous
system. Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):921-942.
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 03/16/2023
24 Raibagkar P, Neagu MR, Lyons JL, Klein JP.
Imaging in neurologic infections I: bacterial and
parasitic diseases. Curr Infect Dis Rep 2014;16(13):
443. doi:10.1007/s11908-014-0443-8
25 Neagu MR, Raibagkar P, Lyons JL, Klein JP.
Imaging in neurologic infections II: fungal and
viral diseases. Curr Infect Dis Rep 2015;17(4):474.
doi:10.1007/s11908-015-0474-9
26 Del Brutto OH. Neurocysticerosis. Continuum
(Minneap Minn) 2012;18(6):1392-1416.
27 Andronikou S, Smith B, Hatherhill M, Douis H,
Wilmshurst J. Definitive neuroradiological
diagnostic features of tuberculous meningitis in
children. Pediatr Radiol 2004;34(11):876-885.
doi:10.1007/s00247-004-1237-1
28 Garcia HH. Parasitic infections of the nervous
system. Continuum (Minneap Minn) 2021;
27(4, Neuroinfectious Disease):943-962.
29 Lyons JL. Viral meningitis and encephalitis.
Continuum (Minneap Minn) 2018;
25(5, Neuroinfectious Disease):1284-1297.
doi:10.1212/CON.0000000000000650
30 Cho TA. Helminthic infections of the central
nervous system. Continuum (Minneap Minn)
2018;24(5, Neuroinfectious Disease):1489-1511.
doi: 10.1212/CON.0000000000000646
31 Aksamit AJ Jr. Progressive multifocal
leukoencephalopathy. Continuum (Minneap
Minn) 2012;18(6, Infectious Disease):1374-1391.
32 Saylor D. Neurologic complications of human
immunodeficiency virus infection. Continuum
(Minneap Minn) 2018; (5, Neuroinfectious
Disease):1397-1421. doi:10.1212/
CON.0000000000000647
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
33 Beckham JD, Tyler KL. Encephalitis. In: Bennet JE,
Dolin R, Blaser MJ, editors. Mandell, Douglas, and
Bennett's principles and practice of infectious
diseases. 9th ed. Philadelphia, PA: Elsevier, 2019.
34 Graeff-Teixeira C, Arámburu da Silva AC,
Yoshimura K. Update on eosinophilic
meningoencephalitis and its clinical relevance.
Clin Microbiol Rev 2009;22(2):322-348. doi:
10.1128/CMR.00044-08
35 Strauss SE, Thorpe KE, Holroyd-Leduc J. How do I
perform a lumbar puncture and analyze the
results to diagnose bacterial meningitis? JAMA
2006;296(16):2012-2022. doi:10.1001/
jama.296.16.2012
36 Leber AL, Everhart K, Balada-Llasat J-M, et al.
Multicenter evaluation of BioFire FilmArray
Meningitis/Encephalitis Panel for Detection of
Bacteria, Viruses, and Yeast in Cerebrospinal
Fluid Specimens. J Clin Microbiol 2016;54(9):
2251-2261. doi:10.1128/JCM.00730-16
37 Tansarli GC, Chapin KC. Diagnostic test accuracy
of the BioFire® FilmArray® meningitis/
encephalitis panel: a systematic review and
meta-analysis. Clin Microbiol Infect 2020;26(3):
281-290. doi:10.1016/j.cmi.2019.11.016
38 Liesman RM, Strasburg AP, Heitman AK, Theel ES,
Patel R, Binnicker MJ. Evaluation of a commercial
multiplex molecular panel for diagnosis of
infectious meningitis and encephalitis. J Clin
Microbiol 2018;56(4):e01927-17. doi:10.1128/
JCM.01927-17
39 Ramachandran PS, Wilson MR. Metagenomics for
neurological infections—expanding our
imagination. Nat Rev Neurol 2020;16:547-556.
40 Wilson MR, Sample HA, Zorn KC, et al. Clinical
metagenomic sequencing for diagnosis of
meningitis and encephalitis. N Engl J Med 2019;
380(24):2327-2340. doi:10.1056/NEJMoa1803396
41 Wilson MR, O'Donovan BD, Gelfand JM, et al.
Chronic meningitis investigated via metagenomic
next-generation sequencing. JAMA Neuro 2018;
75(8):947-955. doi:10.1001/jamaneurol.2018.0463
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