The Neurohospitalist

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Evaluation and Treatment of Chronic Meningitis

Kelly J. Baldwin and Joseph R. Zunt
The Neurohospitalist 2014 4: 185 originally published online 10 April 2014
DOI: 10.1177/1941874414528940

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Review

The Neurohospitalist
2014, Vol. 4(4) 185-195
Evaluation and Treatment ª The Author(s) 2014
Reprints and permission:

of Chronic Meningitis sagepub.com/journalsPermissions.nav

DOI: 10.1177/1941874414528940
nho.sagepub.com

Kelly J. Baldwin, MD1, and Joseph R. Zunt, MD, MPH2

Abstract
Chronic meningitis is defined as an inflammatory cerebrospinal fluid (CSF) profile that persists for at least 1 month. The presentation
often includes headache, nausea, vomiting, cranial neuropathies, symptoms of elevated intracranial pressure, or focal neurologic
deficits. The most common etiologies of chronic meningitis fall into 3 broad categories: infectious, autoimmune, and neoplastic.
Evaluation of the patient with suspected chronic meningitis should include a detailed history and physical examination as well as
repeated CSF diagnostics, serologic studies, and biopsy of the brain or other abnormal tissue (eg, lymph node or lung), when
indicated. Early identification of the etiology and rapid treatment are crucial for improving morbidity and mortality, but potential
infectious and neoplastic conditions should be excluded prior to empirically starting steroids or immunosuppressive medications.

Keywords
central nervous system infections, meningoencephalitis, meningitis, encephalitis, autoimmune diseases of the nervous system

Introduction to perform complex tasks. She is generally hyperreflexic with-

out focal weakness, numbness, or cranial neuropathies. This
Chronic inflammation in the cerebrospinal fluid (CSF) can be
history would suggest a probable autoimmune etiology for
a diagnostic dilemma for the neurohospitalist. Early recogni-
chronic meningitis, such as systemic lupus erythematous
tion, diagnosis, and treatment are important for improving
(SLE) rather than an infectious or neoplastic etiology. If this
morbidity and mortality. Chronic meningitis is commonly
same young woman was admitted after a recent respiratory ill-
defined as inflammation in the CSF persisting for at least 1
ness with headache and behavioral changes, and there was a
month without spontaneous resolution. The differential diag- history of rock and cave climbing, the differential would be
nosis for chronic meningitis is long and can be divided into
quite different and an infectious etiology such as histoplasmo-
3 categories: infectious, inflammatory, and neoplastic. To
sis would be considered. Histoplasmosis is an organism that is
arrive at an accurate diagnosis, the neurohospitalist must first
transmitted via inhalation or aerosolized avian and bat popu-
acquire a detailed patient history including symptomatology,
lations. Infected patients may report cleaning chicken coups,
time course, systemic symptoms, travel history, exposures,
cave climbing, or close proximity to excavation where soil
and factors such as intravenous drug abuse, medications, and
is aerosolized.
overall immune status of the patient. These important details
of the patient history will serve as a guide for determining
workup and treatment. Approach to Initial Diagnosis and Management
When clinical history and laboratory data are suggestive of
Case Example chronic meningitis, the next step in workup should include
neuroimaging. Magnetic resonance imaging (MRI) of the
A 25-year-old woman presents to the emergency department
with 3 weeks of headache and behavioral changes. She
endorses a 12-month history of intermittent photosensitive 1
Department of Neurology, Geisinger Medical Center, Danville, PA, USA
2
rash and generalized arthralgias. Her family history is signif- Department of Neurology and Global Health, Harborview Medical Center,
icant for inflammatory bowel disease. She denies recent University of Washington School of Medicine, Seattle, WA, USA
travel, risk factors for human immunodeficiency virus (HIV)
Corresponding Author:
infection, insect bites, weight loss, or pulmonary symptoms. Kelly J. Baldwin, Department of Neurology, Geisinger Medical Center, 100 N.
Her examination is significant for a malar rash on her face, Academy Ave, Danville, PA 17822, USA.
poor attention, concentration, and abstraction with inability Email: [email protected]

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186 The Neurohospitalist 4(4)

brain with and without gadolinium contrast is more sensitive Case Example
for detecting leptomeningeal enhancement than computerized
A 30-year-old female with history of HIV infection, who is
tomography (CT). In patients for whom there is suspicion for a
noncompliant with antiretroviral therapy, presents with
mass occupying lesion, neuroimaging is essential prior to lum-
4 weeks of headache, vomiting, and diplopia. She lives in New
bar puncture. Following neuroimaging, the clinician should
York City and has daily exposure to pigeons that nest in her
proceed with lumbar puncture to assess for inflammation in
building. On presentation, she is afebrile with a CD4 count
the CSF. Initial CSF testing should include measurement of
of 20 cells/mL. She has nuchal rigidity and bilateral cranial
opening pressure, cell count with differential, glucose, pro-
nerve 6 palsies.
tein, bacterial culture, and Gram stain. Further testing should
In determining the etiology and treatment plan for this
be tailored to potential exposures elicited during the clinic
patient, the clinician can utilize the proposed 3-step algorithm.
history.
Step 1 is to determine the immunologic status; this patient
would fall into severe T-cell deficiency. The second step is
to incorporate her history of elevated ICP manifested primar-
Empiric Therapy ily by the presence of bilateral cranial nerve 6 palsies, which
As opposed to the patient who presents acutely with signs would raise your concern for fungal or mycobacterial organ-
and symptoms of meningitis who should be started on isms that are notorious for presenting with elevated ICP. Spe-
empiric antibiotics, antivirals, and steroids, patients present- cifically this HIV-positive patient with a CD4 count less than
ing with protracted mild symptoms consistent with chronic 50 cells/mL would be at risk of cryptococcal meningitis, tox-
meningitis do not necessarily warrant broad spectrum oplasma encephalitis, syphilis, and tuberculous meningitis.
empiric coverage. In general, processes that cause chronic The final step is to incorporate neuroimaging, which in this
meningitis do not respond to traditional empiric antibiotic case revealed diffuse leptomeningeal enhancement with
and antiviral treatment. The decision to initiate empiric ther- hydrocephalus; there was no evidence of mass lesion—as seen
apy should be considered on a case-by-case basis and should with toxoplasmosis—or of a basilar predilection for meningi-
consider factors such as abnormalities detected on clinical tis—as seen in tuberculosis (TB). Antifungal coverage was
examination, immune status, recent exposures, most likely initiated with amphotericin B to cover for suspected fungal
etiologies, and potential risks of treatment. A bacterial etiol- meningitis. Finally, lumbar puncture revealed opening pres-
ogy of meningitis should always be considered in patients sure of 40 mm H2O, 40 white blood cell/mL with a mixed
who are pregnant or patients with neutropenia or recent monocytic and neutrophilic predominance, normal glucose,
transplantation. Patients suspected of having acute bacterial and protein of 200 mg/dL. Cryptococcal antigen was positive
meningitis should be treated empirically with broad spec- in the CSF, confirming the diagnosis of cryptococcal
trum antibiotics. meningitis.

Infectious Causes of Chronic Meningitis

Approach to Infectious Causes of Chronic Meningitis
Fungal, bacterial, viral, and parasitic pathogens can invade the
Patients with infectious etiologies of chronic meningitis central nervous system (CNS) and present clinically as
may present with signs and symptoms of elevated intracranial chronic meningitis. Increasing use of immunosuppressant
pressure (ICP), particularly when caused by Cryptococcus medications for autoimmune disease and posttransplantation
neoformans subsp. Previously described as a disease isolated immunosuppression, as well as predisposing conditions such
to people with HIV infection or a hematologic malignancy, as impaired cellular and humoral immunity, have led to a
fungal meningitis is now recognized in immunocompetent larger population at risk of chronic meningitis. This section
patients, and those with immunologic conditions receiving will review the most common causes of chronic infectious
immunosuppressant medications or monoclonal antibodies meningitis, including Cryptococcus species, Aspergillus fumi-
such as rituximab. Identification of the organism causing gatus, Mycobacterium tuberculosis, and syphilis (Table 1).
chronic meningitis is often challenging; a proposed algo-
rithm is shown in Figure 1. Clinicians should initially con-
sider the underlying immune status of the patient.
Cryptococcus
Typically patients will fit into 1 of the 3 categories: neutro- Cryptococcal meningitis is most often caused by the encap-
penic, B-cell or immunoglobulin deficient, or T-cell defi- sulated yeast organism C neoformans, but other species of
cient. By identifying the immunodeficiency, clinicians Cryptococcus, such as Cryptococcus gattii, are emerging as
can narrow down the potential organisms of concern. The pathogens that can affect immunocompetent and immuno-
second step to diagnosis is incorporating the clinical his- compromised people. Cryptococcus neoformans is primar-
tory and examination. The final step is advanced neuroima- ily found in contaminated soil and avian excrement.
ging, CSF testing, and potentially brain biopsy to confirm Infection usually occurs by inhalation of the organism.1
the diagnosis. Cryptococcal meningitis is most common in people with

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Baldwin and Zunt 187

Immunologic Deficiency of the Patient

Immunocompetent Patient

Impaired B lymphocyte immunity or

Neutropenia Impaired T lymphocyte immunity
immunoglobulin deficiency
Bacterial:
Treponema pallidum

Bacterial: Bacterial: Fungal:

Bacterial:
Staphylococcus aureus Listeria monocytogenes Cryptococcus neoformans
Streptococcus pneumoniae
Streptococcus pneumoniae Nocardia asteriods Cryptococcus gattii
Haemophilus influenzae
Pseudomonas aeruginosa Treponema pallidum Histoplasma capsulatum
Klebsiella pneumoniae
Escherichia coli Pseudomonas aeruginosa Coccidioides immitis
Fungal: Blastomyces dermatitidis
Fungal: Mucoraceae
Viral:
Aspergillus fumigatus Cryptococcus neoformans Viral:
Measles
Candida albicans Histoplasma capsulatum HIV
Enterovirus
Mucoraceae Coccidioides immitis Varicella Zoster virus
JC Virus
Blastomyces dermatitidis
Viral: Aspergillus fumigatus Neoplastic
Cytomegalovirus
Herpes simplex virus Viral: Autoimmune:
Human herpes virus types 6 and 7 HIV Neurosarcoidosis
Adenovirus Cytomegalovirus SLE
West Nile Virus Herpes simplex virus Behcets
Varicella zoster virus
JC Virus
Epstein Barr virus
Human herpes virus 6 and 7
Adenovirus

Parasitic:
Toxoplasma gondii
Strongyloides stercoralis

Neoplastic

Narrow Organism by

Clinical Presentation, Signs, and Symptoms

Narrow Organism by

Imaging Characteristics

White Matter Stroke or vascular Meningeal Mass lesions Brainstem Bi-temporal lesions
Disease findings enhancement

Bacterial (Nocardia, Listeria Herpes Viruses

Fungal Bacterial Tuberculosis)
Viral
Varicella Paraneoplastic
(Aspergillus, Fungal Cryptococcoma
(CMV, EBV, VZV,
PML
PML) Cryptococcus,
Autoimmune Toxoplasmosis
Mucor)
WNV
Neoplastic Lymphoma
Varicella Zoster

Lumbar Puncture

Serology

Figure 1. Approach to chronic meningitis based on immune status of the patient, clinical presentation, and neuroimaging findings. Modified
from Pruitt A. CNS infections in patients with cancer. Continuum (Minneap Minn). 2012;18(2):384-405; Table 8-1 and Figure 8-1.

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 188
Table 1. Infectious Etiologies of Chronic Meningitis; CSF Findings, Serologic Testing, Clinical Presentation, Imaging Characteristics, and Systemic Features.
Infectious Meningitis: CSF Parameters and Diagnosis

Opening CSF Diagnostic Microscopic Appearance

Organism Pressure WBC Differential Glucose Protein Testing of Organism Pathogenesis CNS Features Neuroimaging Systemic Features

Cryptococcus " "$ Mononuclear # " India ink staining Encapsulated fungi; yeast-like Inhalation, fungemia Basilar meningitis, Hydrocephalus, cerebral Pulmonary, multiorgan
Cryptococcal capsular cells with budding daughter granuloma, edema, leptomeningeal involvement
polysaccharide antigen cells. Capsule visualized by vasculitis enhancement, and
Fungal culture India ink (halo effect) cryptococcomas
Coccidioidomycosis "$ " Early neutrophil # " Complement fixation Yeast form endosporulating Airborne, fungemia Chronic meningitis, Hydrocephalus, meningeal
Mononuclear antibody testing spherules. Branched cerebritis, enhancement, nodular
Eosinophilic Fungal culture septate hyphae with arteritis, abscess, enhancement, basilar
(70%) alternating arthroconidia. granuloma meningitis, cerebral
infarction.
Histoplasmosis $ " Mononuclear # " Histoplasma polysaccharide Hyphae large macroconidia Airborne, fungemia Meningitis, Normal, granuloma, Acute or chronic
antigen and smaller infectious granuloma meningeal enhancement pulmonary,
Fungal culture microconidia. At dissemination with
Urine histoplasmosis temperatures <35 C yeast multiorgan
antigen form. Hyphal elements
possible.
Blastomycosis " " Early neutrophil # " Fungal culture Mycelium at room Airborne, fungemia Meningitis Single or multiple Pulmonary, cutaneous
Mononuclear temperature; yeast phase at abscesses, granuloma,
37 C. Conidia, yeast cells meningeal
with multinucleate broad enhancement, epidural
budding. extensions and
overlying osteomyelitis
Aspergillosis $ " Early neutrophil # " CSF-PCR Septate hyphae branched at Fungemia, direct Meningitis, Multiple abscesses, Pulmonary
Mononuclear Antigen galactomannan 45 angles with inoculation by vasculitis, meningeal
Antibody conidiophores. Hyphae trauma or surgery, mycotic enhancement,
Fungal culture develop terminal buds extension from aneurysm, infarction, hemorrhage,
forming small conidia. paranasal, granuloma, sinusitis with extension
angioinvasive abscess spinal
cord

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involvement
Mycobacterial "$ " Mononuclear # " AFB smear Acid fast bacilli Inhalation, Basliar meningitis, Hydrocephalus, meningeal Pulmonary
Culture on Lowenstein- hematologic vasculitis, enhancement, basilar
Jensen medium dissemination abscess meningitis, cerebral
PCR infarction,
tuberculomas
Syphilis $ "$ Mononuclear $# " VDRL (serum and CSF) Thin motile corkscrew Genitourinary, Meningitis, Normal, meningeal Genital lesions,
FTA-ABS (serum and CSF) bacterium on dark field hematologic myelopathy, enhancement, myelitis, cutaneous
PCR microscopy dissemination neuropsychiatric brain atrophy

Abbreviations: AFB, acid-fast bacillus; CNS, central nervous system; CSF, cerebrospinal fluid; FTA-ABS, fluorescent treponemal antibody absorption; PCR, polymerase chain reaction; VDRL, venereal disease research
laboratory; WBC, white blood count.
Baldwin and Zunt 189

impaired cell-mediated immunity, especially HIV infection,

people with hematologic malignancies, solid-organ trans-
plant recipients, and patients on chronic corticosteroids or
other immunosuppressive therapy. In patients infected with
HIV, cryptococcal meningitis is the most common systemic
fungal infection and a frequent etiology of CNS infection.2
The clinical manifestations of infection with C neoformans
depend largely on the host immune status. Severity of infec-
tion varies from asymptomatic incidental pulmonary nodules
to widely disseminated disease. Patients with HIV and CD4þ
cell counts of less than 50 cells/mL are especially vulnerable to
disseminated infection and meningitis.3 Immunosuppressed
patients with cryptococcal meningitis frequently present with
indolent nonspecific symptoms and in some cases with iso-
lated neurologic manifestations. In general, over 75% of
patients present with headache and fever, which typically
develop insidiously over 2 to 4 weeks.4 Nausea, vomiting, and
altered mental status occur in about half of the patients. Signs
and symptoms of meningismus affect less than 25% of
patients. Visual symptoms, such as diplopia and blindness,
occur in about 20% of patients, most often in immunocompe-
tent patients. Seizures and focal neurologic deficits occur in
10% of patients and are generally caused by space- Figure 2. Magnetic resonance imaging of the brain of cryptococcal
meningitis. A, B, and D, Magnetic resonance imaging T1 postcontrast
occupying lesions such as cryptococcomas or granulomas. imaging shows avid leptomeningeal enhancement from fungal
Two of the most dangerous complications of cryptococcal meningitis. C, Magnetic resonance imaging diffusion-weighted imaging
meningitis are elevated ICP and hydrocephalus.5,6 (DWI) demonstrates cortical areas of restricted diffusion indicating
The diagnosis of cryptococcal meningitis should be consid- acute ischemic strokes, likely secondary to inflammation and infarc-
ered in patients presenting with a subacute presentation of tion of end arteries.
headache and fever, especially in the setting of HIV infection
or immunosuppression. Computerized tomography and MRI punctures. For those patients requiring frequent lumbar punc-
are nonspecific for the diagnosis of cryptococcal meningitis tures, placement of a lumbar drain or a ventriculostomy can
but may reveal hydrocephalus, cerebral edema, leptomenin- serve as a temporary measure to control ICP.10,11 A recent ret-
geal enhancement, or cryptococcomas (Figure 2). Lumbar rospective study suggests elevated ICP in patients with cryp-
puncture, the diagnostic procedure of choice, is often notable tococcal meningitis is associated with higher mortality and
for increased opening pressure, a mild mononuclear pleocyto- aggressive management of ICP during the initial 5 days was
sis, increased protein, and low glucose concentrations. The more important than initial antifungal management alone for
CSF cryptococcal capsular polysaccharide antigen (CRAg) survival.12
assay is both sensitive and specific for cryptococcal meningi-
tis and also provides a quantitative titer that is useful for prog-
nostication.7 The CRAg is not useful for determining response
to therapy. Because the cryptococcal antigen (CRAg) lateral Aspergillus
flow assay has nearly 100% sensitivity and specificity on CSF Historically, disease from A fumigatus was limited to individ-
samples, it is considered for point-of-care diagnosis of crypto- uals with repetitive exposure to pathogens, producing a mild
coccal meningitis.8 Fungal culture for the organism is 90% condition known as farmer’s lung. Aspergillus subsp were also
sensitive and can also be useful for speciation. known to produce lung aspergillomas, characterized as an
A combination of antifungal medication and aggressive overgrowth of fungus in preexisting cavitary lung lesions.
treatment of hydrocephalus is integral to the successful treat- More recently, the incidence and severity of Aspergillus subsp
ment of patients with cryptococcal meningitis. Amphotericin infection have increased due to a growing number of people
B (AmB) plus flucytosine, as compared with AmB alone, is living with immunosuppression, leading to more cases of
associated with improved survival of patients with cryptococ- invasive aspergillosis. Populations significantly at risk of
cal meningitis.9 Hydrocephalus causing elevated ICP can be invasive aspergillosis include patients undergoing treatment
managed through a variety of treatments. Patients with ele- for hematologic malignancies, recipients of allogeneic hema-
vated ICP should undergo daily lumbar punctures to reduce topoietic stem cell or solid-organ transplantation, people who
opening pressure until normal opening pressure is maintained are HIV infected, and individuals with chronic granulomatous
consistently; some patients may require multiple daily lumbar disease.13

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190 The Neurohospitalist 4(4)

may be useful adjunct to serum testing; however, data are lim-

ited to small sample sizes with variable performance and relia-
bility (sensitivity of 70%-90%).17 Several polymerase chain
reaction (PCR) assays can detect Aspergillus subsp in blood
and bronchoalveolar lavage (BAL) fluid samples; a recent
study to detect Aspergillus subsp in fresh tissue and BAL fluid
reported a sensitivity and specificity values of 86% and
100%.18 Experience with PCR to detect Aspergillus subsp in
CSF samples is limited.
Unfortunately, cerebral aspergillosis, especially in an
immunocompromised patient, is difficult to treat and has a
high mortality rate. The use of voriconazole, a newer antifun-
gal agent, has reduced the mortality of an infection that was
previously associated with almost universal mortality. Clini-
cal trials have demonstrated that voriconazole is more effec-
tive than AmB as initial therapy for invasive aspergillosis
and is associated with significantly improved survival (71%
vs 58%, respectively).19 In vitro studies evaluating combina-
tion therapy with voriconazole and caspofungin for Aspergil-
lus subsp have provided promising results in patients with
invasive aspergillosis.20,21

Mycobacterium
Figure 3. Magnetic resonance imaging of the brain of central ner-
vous system aspergillosis. A, Magnetic resonance imaging T2 fluid Tuberculous meningitis is an aggressive form of extrapulmon-
attenuation inversion recovery (FLAIR) image demonstrates diffuse ary disease that is more common in patients coinfected with
leptomeningeal hyperintensity with parenchymal involvement of the HIV. Meningitis is typically preceded by nonspecific symp-
bilateral frontal and parietal lobes. B-D, Magnetic resonance imaging toms of malaise, anorexia, fatigue, weight loss, fever, myalgia,
diffusion-weighted imaging (DWI) sequence shows multiple areas of and headache. In immunocompetent patients, headache,
restricted diffusion indicating acute ischemic infarctions caused by vomiting, meningeal signs, focal deficits, vision loss, cranial
angioinvasion of the organism.
nerve palsies, and raised ICP are characteristic clinical fea-
tures. Cerebral vessels may be affected by adjacent meningeal
Cerebral aspergillosis occurs in approximately 10% to 20% inflammation, producing vasospasm, constriction, and eventu-
of patients with invasive disease and results from hematogen- ally thrombosis with cerebral infarction.22 The hallmark
ous dissemination of the organism or direct extension from pathologic feature of tuberculous meningitis is the presence
rhinosinusitis.14 Central nervous system infection can present of a thick exudate most prominent in the basilar meninges
as a solitary mass lesion, cavernous sinus thrombosis, multiple (Figure 4). This exudate can block the flow of CSF and result
intracranial abscesses, acute or chronic basilar meningitis, in hydrocephalus and multiple cranial neuropathies. Chest CT
vasculitis, or myelitis.15 Pathologically, cerebral aspergillosis is sensitive for detecting pulmonary abnormalities in patients
has a propensity for vascular invasion, infarction, hemorrhage, with tuberculous meningitis. Mediastinal and hilar lymphade-
and aneurysm formation; as a result, the clinical presentation nopathy, miliary pattern, and bronchopneumonic infiltrate are
may mimic cerebral vasculitis, ischemic or hemorrhagic frequently noted.
infarction, or subarachnoid hemorrhage (Figure 3). In patients Although CSF acid-fast bacillus (AFB) smear and culture
with suspected cerebral aspergillosis, it is important to are crucial for making a diagnosis of tuberculous meningitis,
examine the lungs and sinuses for evidence of infection there is a wide range of reported sensitivities for AFB smear;
and potential sites for obtaining biopsy or culture material. sensitivities can reach as high as 52% with large volume of
Neuroimaging can be helpful in the evaluation of cerebral CSF samples (>6 mL), and microscopic examination for at
aspergillosis. Magnetic resonance imaging of the brain may least 30 minutes.23 Conventional CSF culture for M tubercu-
demonstrate dural enhancement adjacent to infected para- losis on Lowenstein-Jensen medium is positive in approxi-
nasal sinuses, indicating direct extension of infection.16 mately 45% to 90% of cases but usually takes several
Several serum laboratory markers can aid in the diagnosis weeks for a positive result.24 Characteristic CSF abnormal-
of invasive aspergillosis. Enzyme-linked immunosorbent ities include a mononuclear cell pleocytosis, low glucose
assay (ELISA) testing for the fungal cell wall constituents concentration, and elevated protein concentration. The CSF
galactomannan and b-D-glucan should be considered. The pleocytosis can be lower in HIV-infected patients.25 Of note,
CSF galactomannan assay using latex agglutination or ELISA 16% of patients with confirmed Cryptococcus, 5% with TB,

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Baldwin and Zunt 191

Figure 4. Magnetic resonance imaging of the brain of tuberculosis meningitis. A and B, Magnetic resonance imaging T1 postcontrast imaging
demonstrates diffuse leptomeningeal enhancement and hydrocephalus. C and D, Magnetic resonance imaging T1 postcontrast with discrete
areas of parenchymal infiltration and the presence of tuberculomas located primarily in the deep gray matter. D-F, Magnetic resonance imaging
T1 postcontrast imaging displays the predilection for the basilar meninges.

and 4% with bacterial meningitis will have normal CSF cell Syphilis
counts and biochemistry.26 Detection of M tuberculosis Although neurosyphilis can produce protean manifestations,
DNA in CSF by PCR assay may be a useful ancillary diag- this article will limit the discussion to syphilitic meningitis.
nostic test, with a nearly 100% specificity but a sensitivity Syphilitic meningitis typically presents in the secondary
that varies between 30% and 50%, thus limiting its useful- stage of syphilis, within 2 years of acquiring infection.
ness. The likelihood of detecting M tuberculosis is increased Although less common than other forms of neurosyphilis,
if repeat smear, culture, and PCR are performed on serial abnormal CSF with leukocytosis and elevated protein occur
CSF samples.27 in up to 25% of patients.31,32 The most common presenting
Both CT and MRI of the brain are valuable for diagnosing symptoms include headache, photophobia, nausea and
tuberculous meningitis and evaluating complications. Charac- vomiting, meningismus, and cranial nerve deficits. Although
teristic abnormalities include enhancement of the basilar any cranial nerve can be affected, cranial nerves VII and VIII
meninges, exudates, hydrocephalus, and periventricular are most commonly affected.
infarcts. Empiric treatment should be initiated when tubercu- In syphilitic meningitis, CSF typically has a mononuclear
lous meningitis is initially suspected, as the organism grows predominant pleocytosis (greater than 10 cells/2 L), elevated
slowly, speciation can take weeks, and earlier treatment is protein concentration (greater than 45 mg/dL), and normal or
associated with better outcomes. First-line antituberculous decreased glucose concentration. Although CSF immunologic
medications include rifampicin, isoniazid, pyrazinamide, tests, such as venereal disease research laboratory (VDRL), are
ethambutol, and streptomycin. Most first-line anti-TB drugs usually abnormal in syphilitic meningitis (70%-80% sensitiv-
(except ethambutol) achieve satisfactory levels in the CSF.22 ity33), a negative result does not rule out neurosyphilis. The
Adjunctive corticosteroids result in significantly reduced CSF fluorescent treponemal antibody absorption testing is less
death and disabling residual neurologic deficits and should specific but more sensitive than CSF-VDRL and may be used to
be used regardless of HIV status, although evidence for added exclude the diagnosis. More recently, PCR assays have been
benefit for HIV-infected patients is inconclusive.28-30 developed to detect Treponema pallidum in the CSF, but 50%

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192 The Neurohospitalist 4(4)

of patients with syphilitic involvement of the CNS have a significantly elevated protein concentration (2 g/L or greater)
negative PCR. Other new techniques include using CSF- and low glucose concentration. The CSF abnormalities in neu-
fluorescent treponemal antibody and percentage of CSF-B cells rosarcoidosis are most pronounced in patients with diffuse
when CSF-VDRL is negative to aid in establishing the diagno- leptomeningeal enhancement on MRI.39 Opening pressure is
sis of neurosyphilis.34 often elevated. The CSF oligoclonal bands may be present,
Penicillin is the first-line therapy for neurosyphilis. The most often in the setting of an elevated protein concentration.
Centers for Disease Control and Prevention recommends The CSF-ACE levels are nonspecific but can be elevated with
18 million units to 24 million units of aqueous penicillin G per neurosarcoidosis. Magnetic resonance imaging with gadoli-
day administered as 3 million units to 4 million units intrave- nium reveals leptomeningeal enhancement in up to 40% of
nously (IV) every 4 hours or as continuous infusion for 10 to patients with neurosarcoidosis, with the basilar meninges most
14 days. An alternative is procaine penicillin 2.4 million units often involved. Dural enhancement is present in up to 30% of
intramuscularly daily with probenecid 500 mg orally 4 times cases. Intraparenchymal mass lesions or granulomas may be
daily for 10 to 14 days.35,36 solitary or multiple and typically enhance with gadolinium.
Brain biopsy is not routine but may be useful when meningeal
or cerebral abnormalities are easily accessible. Enhancement
Autoimmune Causes of Chronic Meningitis or thickening of the pituitary or hypothalamic masses are pres-
Central nervous system involvement has been associated ent in 18% of patients with neurosarcoidosis. Although the
with nearly every autoimmune disease. Chronic meningitis facial nerve is the most common cranial neuropathy, on MRI,
is a presenting constellation of symptoms for a select group the optic nerve is most frequently abnormal, displaying
of diseases including sarcoidosis, lupus, Behçet disease, and enhancement and thickening.40
vasculitis. Many patients with autoimmune disease are man- Corticosteroids are the mainstay of treatment for neurosar-
aged with immunosuppressant medications and are thus at coidosis, with recommended initial doses of 40 to 60 mg/d,
increased risk of acquiring infectious meningitis. It is critical followed by a slow taper. Patients with severe symptoms may
to carefully evaluate patients for potential infectious and be treated with high-dose methylprednisolone (1 g IV for
neoplastic etiologies prior to administering immunosuppres- 3-5 days) followed by oral prednisone. Steroid-sparing
sive medications or steroids for the treatment of suspected immunosuppressive medications, including mycophenolate,
autoimmune meningitis. If needed, serologic testing and azathioprine, methotrexate, cyclophosphamide, infliximab,
brain biopsy should be obtained to confirm the diagnosis and hydroxychloroquine, have been used with varying
prior to empiric treatment. degrees of success; these medications are often used for
long-term suppression.41
Neurosarcoidosis
Sarcoidosis is a multisystem granulomatous disease affecting
Systemic Lupus Erythematous
the CNS in up to 25% of patients. Although sarcoidosis has a Meningitis associated with SLE is typically associated with
predilection for the lungs, anterior uvea, lymphatic system, aseptic CSF. However, as many patients are treated with
and skin, any organ, including the nervous system, can be chronic immunosuppressive therapy, infectious meningitis
affected. The most common clinical presentations of neurosar- should be considered in patients with SLE who have been
coidosis include cranial neuropathies, seizures, meningitis, treated with immunosuppressive therapy and develop fever,
mass lesions, hypothalamic or pituitary involvement, and altered mental status, meningeal signs, and nausea or
spinal cord lesions. Cranial neuropathies occur in 50% to vomiting. Compared to SLE-associated aseptic meningitis,
75% of patients and are most often the result of elevated ICP, patients with infectious meningitis are typically older,
granulomas, or basilar meningitis. The most common cranial develop mental status changes, and have plasma leukocyto-
neuropathy is unilateral or bilateral facial palsy, hearing loss, sis with neutrophilia, as well as a marked CSF pleocytosis
or optic neuropathy. Acute and chronic meningitis occur in up and hypoglycorrhachia.42
to 26% of patients with neurosarcoidosis.37,38 Common manifestations of SLE affecting the CNS include
Diagnosis of neurosarcoidosis is difficult and often cerebrovascular disease (CVD) and seizures. Neuropsychia-
requires a combination of medical history with neuroimaging, tric manifestations are relatively uncommon (1%-5%) but can
serologic and CSF data, and tissue biopsy. The diagnosis of produce severe cognitive dysfunction, major depression, acute
systemic sarcoidosis is typically made through biopsy of confusional state (ACS), or psychosis. Risk factors for CNS
lymph nodes, lung, liver, skin, or conjunctiva with histologic involvement are previous or concurrent severe neuropsychia-
demonstration of noncaseating granulomas consisting of tric lupus (for cognitive dysfunction and seizures) and anti-
epithelioid cells and macrophages. Serum angiotensin- phospholipid antibodies (for CVD, seizures, and chorea).43
converting enzyme (ACE) level is elevated in 50% of patients No single diagnostic test is both sensitive and specific for CNS
with neurosarcoidosis.38 Cerebrospinal fluid analysis typically SLE. Assessment should include neurologic and rheumatolo-
reveals a lymphocytic pleocytosis (10-200 cells/2 L) with gic evaluations, serologic testing of immune parameters, and

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Baldwin and Zunt 193

neuroimaging. Serum antibodies detected in patients with CNS- mofetil is most commonly used for long-term immunosuppres-
SLE include antinuclear antibody (82%), antidouble-stranded sion. Disease activity can be monitored with serial neurologic
DNA (79%), antiribosomal P antibodies (61%), anticardiolipin examinations and MRI scans.46
immunoglobulin G (IgG; 15%), anti-b2 glycoprotein IgG
(65%), and anti-N-methyl-D-aspartate receptor (35%). Low
serum complement (C3 and C4) and elevation of sedimentation Neoplastic Causes of Chronic Meningitis
rate may be supportive of disease; however, normal values do
Neoplastic involvement of the CNS should be considered in
not exclude CNS SLE. These antibody titers do not typically
the differential diagnosis for patients presenting with signs
change with treatment or with resolution of symptoms.44,45
and symptoms of chronic meningitis. Leptomeningeal carci-
nomatosis (LMC), or carcinomatous meningitis, is defined
Primary Angiitis of the CNS as malignant seeding or infiltration of the leptomeninges. Lep-
tomeningeal carcinomatosis is most commonly associated
Primary angiitis of the CNS (PACNS) is characterized by
with hematologic malignancies, but solid tumors and primary
inflammation and destruction of cerebral vessels without sys-
brain tumors can infiltrate the meninges in up to 5% of
temic involvement. Patients may present with a history of
patients. Autopsy studies reveal that up to 19% of patients who
years of headache, encephalopathy, seizures, cognitive and
have cancer with neurologic symptoms also have LMC.49
behavioral changes, ataxia, recurrent TIAs, or focal neurolo-
Patients classically present with signs and symptoms of
gic deficits.46 Symptoms of chronic meningitis can precede
multifocal involvement of the neuraxis due to involvement
diagnosis by several years. Diagnostic criteria include the
of the cerebral hemispheres, brain stem, cranial nerves, spinal
presence of acquired and unexplained neurologic or psychia-
cord, or nerve roots. The most common presenting symptoms
tric deficits, presence of angiographic or histopathologic evi-
include headache, encephalopathy, nuchal rigidity, diplopia,
dence of angiitis in the CNS, and no evidence of systemic or
weakness, and radicular pain. Cranial neuropathies may
other disorders that may mimic the disease.
include trigeminal neuropathy, facial weakness, and hearing
The combination of serologic studies, CSF analysis, angio-
loss. Leptomeningeal carcinomatosis may precipitate obstruc-
graphy, MRI, and brain biopsy are essential for diagnosing
tive hydrocephalus, and radionuclide scans reveal impaired
PACNS. Biopsy is the gold standard for diagnosis but has low
CSF flow in 70% of patients with LMC.50
sensitivity. More importantly, biopsy is useful in identifying
Diagnosis of LMC is made by clinical examination, CSF
lesions that may mimic PACNS, such as infection or malig-
analysis, and gadolinium-enhanced MRI. Lumbar puncture
nancy, which are found in up to 40% of patients.47 Serum ery-
typically reveals elevated opening pressure, leukocytosis, and
throcyte sedimentation rate and C-reactive protein are
elevated protein and low glucose concentrations. The CSF
typically normal in PACNS and elevated in conditions that
cytology should be sent to evaluate for neoplastic cells. The
mimic PACNS. The CSF analysis is abnormal in over 90%
sensitivity of a single, large volume CSF sample is 38% to
of patients and usually demonstrates a modest lymphocytic
66%; if 3 large volume CSF samples are performed, the sen-
pleocytosis (less than 20 cells/2 L), elevated protein concen-
sitivity increases to 90%.49 Gadolinium-enhanced MRI is the
tration (median less than 120 mg/dL), and normal glucose
imaging modality of choice and typically reveals contrast
concentration. The CSF examination is crucial for excluding
enhancement of the meninges, cortical convexities, basilar
infectious and neoplastic mimics of PACNS.
cistern, and cauda equina (Figure 5). Meningeal biopsy of
Cranial MRI may reveal infarction in up to half of the
contrast-enhancing lesions remains the gold standard for defi-
patients, and nonspecific subcortical white matter, deep white
nitive diagnosis of LMC.
matter, and cortical T2-weighted hyperintensities are often
present. Gadolinium enhancement of the leptomeninges occurs
in 8% of patients. Cerebral angiography is commonly used to
aid in the diagnosis of PACNS and classically demonstrates
Idiopathic Chronic Meningitis
alternating areas of dilation and stenosis that can be smooth Despite a clinician’s best effort, there remain a large number
or irregular. These findings are nonspecific for PACNS and can of patients who remain undiagnosed. A retrospective review
be seen with other disorders, including infection, radiation, of 49 patients with chronic idiopathic meningitis evaluated
atherosclerosis, and vasospasm. Sensitivity of angiography var- at Mayo Clinic identified an etiology in 10 patients, with 8
ies from 40% to 90%. Although the diagnosis of PACNS can be of the 10 having a neoplastic cause. Overall, 24% of brain
difficult to confirm, patients with normal CSF, angiography, biopsies in this population yielded a diagnosis. Of the 39
and MRI are extremely unlikely to have PACNS.48 undiagnosed cases, 85% of patients had a good outcome
Treatment of PACNS includes immunosuppression with a despite a prolonged illness. Corticosteroid therapy was effec-
combination of glucocorticosteroids and cyclophosphamide. tive in 52% of the patients treated but did not influence the
High-dose oral prednisone (1 mg/kg/d) or IV pulse methylpred- outcome.51 In those cases where history, examination, CSF
nisolone for 3 days, followed by oral prednisone, is recom- analysis, novel testing, and biopsy fail to yield answers, clin-
mended. Cyclophosphamide, azathioprine, or mycophenolate icians may choose to offer empiric steroids.

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194 The Neurohospitalist 4(4)

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