Chronic and Subacute Meningitis PDF

Review Article
Chronic and Subacute

Address correspondence to
Dr Joseph R. Zunt, Harborview
Medical Center, 325 Ninth Ave,
Room 3EH70, Box 359775,
Seattle, WA 98104,
jzunt@u.washington.edu.
Relationship Disclosure:
Meningitis
Dr Zunt receives funding from Joseph R. Zunt, MD, MPH; Kelly J. Baldwin, MD
the NIH for research and
training programs. Dr Baldwin
reports no disclosure.
Unlabeled Use of ABSTRACT
Products/Investigational
Use Disclosure:
Purpose of Review: This article describes the background, clinical presentation,
Drs Zunt and Baldwin report diagnosis, and treatment of selected etiologies of subacute and chronic meningitis. Key
no disclosures. diagnostic considerations when evaluating a patient presenting with chronic inflam-
* 2012, American Academy mation of the CNS are discussed, and several specific infectious, neoplastic, and au-
of Neurology.
toimmune etiologies are reviewed in detail.
Recent Findings: With recent advancement in serologic and CSF diagnostic testing,
specific infectious, neoplastic, or autoimmune etiologies of chronic meningitis can be
identified. Eliminating previous diagnostic uncertainty of chronic inflammation in the
CNS has led to rapid and specific treatment regimens that ultimately improve patient
outcomes. Recent advances in imaging have also aided clinicians in both their diagnostic
approach and the detection of inflammatory complications such as hydrocephalus,
hemorrhage, and ischemic stroke.
Summary: Meningitis is defined as inflammation involving the meninges of the brain
and spinal cord. Meningitis can be categorized as acute, subacute, or chronic based on
duration of inflammation. This article focuses on the most common causes of subacute
and chronic meningitis. Chronic meningitis is commonly defined as inflammation evolv-
ing during weeks to months without resolution of CSF abnormalities. Determining the
time course of meningitis is important for creating a differential diagnosis. Most organ-
isms causing acute meningitis rarely persist more than a few weeks. Although numerous
etiologies of subacute and chronic meningitis have been identified, this article focuses on
the most common etiologies: (1) infectious, (2) autoimmune, and (3) neoplastic.
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318.
INFECTIOUS Cryptococcus
Infectious causes of subacute and Cryptococcal meningitis is caused by the
chronic meningitis that are discussed encapsulated yeast organism Crypto-
in this article include Cryptococcus coccus neoformans. With a worldwide
species, Coccidioides immitis, Histo- distribution, C. neoformans is primarily
plasma capsulatum, Blastomyces der- found in contaminated soil, avian ex-
matitidis, Aspergillus fumigatus, crement, and the bark of several tree
Mycobacterium tuberculosis, and species. Infection usually occurs by in-
syphilis. halation of the organism, followed by a
Tables 3-1 and 3-2 summarize the respiratory infection and dissemina-
presentation, radiographic findings, and tion of the infection.1 This organism
CSF findings for the most common emerged as an important opportunistic
causes of infectious meningitis. pathogen in the 1980s with the advent of
Table 3-3 lists the recommended HIV infection. Cryptococcal meningitis
treatments for the most common infec- is most common in people with impaired
tious etiologies of chronic meningitis. cell-mediated immunity, especially HIV
1290 www.aan.com/continuum December 2012
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 3-1 Infectious Meningitis: CSF Parameters and Diagnosis
White
Blood CSF Microscopic
Opening Cell Diagnostic Appearance
Organism Pressure Count Differential Glucose Protein Testing of Organism
Cryptococcus j j@
Y Mononuclear , j India ink Encapsulated
staining fungi
Cryptococcal Yeastlike
capsular cells with budding
polysaccharide daughter cells
antigen
Capsule visualized
Fungal culture by India ink
(halo effect)
Coccidioidomycosis j@
Y j Early , j Complement- Yeast form
neutrophil fixation endosporulating
antibody spherules
Lymphocytic
testing
Branched septate
Eosinophilic
Fungal culture hyphae with
(70%)
alternating
arthroconidia
Histoplasmosis @
Y j Mononuclear , j Histoplasma Hyphae large
polysaccharide macroconidia
antigen and smaller
infectious
Fungal culture
microconidia
Yeast forms at
temperatures
G35-C (95-F)
Hyphal elements
possible
Blastomycosis j j Early , j Fungal culture Mycelium at
neutrophil room temperature
Lymphocytic Yeast phase at
37-C (98.6-F)
Conidia, yeast
cells with
multinucleate
broad budding
Aspergillosis @
Y j Early , j CSF PCR Septate hyphae
neutrophil branched at 45-
Antigen
angles with
Lymphocytic galactomannan
conidiophores
Antibody
Hyphae develop
Fungal culture terminal buds
forming small conidia
Continued on next page
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318 www.aan.com/continuum 1291

Chronic and Subacute Meningitis
TABLE 3-1 Continued
White
Blood CSF Microscopic
Opening Cell Diagnostic Appearance
Organism Pressure Count Differential Glucose Protein Testing of Organism
Mycobacterial j@
Y j Mononuclear , j Acid-fast bacillus Acid-fast
smear bacillus
Culture on
Lowenstein-
Jensen medium
PCR
Syphilis @
Y j@
Y Lymphocytic @
Y, j Venereal Disease Thin, motile
Research Laboratory corkscrew
test (serum and CSF) bacterium on
dark-field
Fluorescent treponemal microscopy
antibody absorption
test (serum and CSF)
PCR
j indicates an increase from normal values.

, indicates a decrease from normal values.
Y indicates no change from normal values.
@
*two arrows together indicate that either pattern may occur.
KEY POINTS infection; people with hematologic outbreak occurred in British Columbia
h Cryptococcal meningitis malignancies; solid-organ transplant in 1999. Most of these infections oc-
is most common in recipients; and patients on chronic cor- curred in patients with normal immune
people with impaired
ticosteroids or other immunosuppres- systems.4 Serotype D is classified as C.
cell-mediated immunity,
sive therapy; but it also occurs in neoformans neoformans, is predomi-
especially HIV
infection, hematologic
immunocompetent individuals.2 nantly found in Western Europe, and
malignancies, solid-organ Historically, the genus Cryptococcus typically affects immunocompromised
transplantation, and in was divided into four serotypes (A, B, C, patients.
patients on chronic D) using capsular assays, but recently In immunocompromised patients,
corticosteroids or other these have been reclassified. Serotype cryptococcal meningitis is the most
immunosuppressive A is now classified as C. neoformans common systemic fungal infection and
therapy, but also occurs grubii; this organism has a worldwide a frequent etiology of CNS infection,
in immunocompetent distribution and is the most common with a prevalence varying from 10% in
individuals. cause of cryptococcal meningitis in im- the United States to as high as 30% in
h In immunocompromised munocompromised patients. Serotypes sub-Saharan Africa.5 Although the in-
patients, cryptococcal B and C are classified as C. neoformans cidence of cryptococcal meningitis has
meningitis is the most gattii, and this organism causes men- decreased since the introduction of com-
common systemic ingitis in individuals with impaired cell- bination antiretroviral therapy, it contin-
fungal infection and a mediated immunity and those who are ues to be a common cause of death in
frequent cause of
immunocompetent.3 C. neoformans gattii many resource-limited countries. In
fungal CNS infections.
was previously thought to be rare and several areas of Africa, cryptococcal
limited to subtropical climates until a large meningitis is the most common cause

TABLE 3-2 Fungal Meningitis
Organism Pathogenesis CNS Features Neuroimaging Systemic Features

Cryptococcus Inhalation, fungemia Basilar meningitis, Hydrocephalus, Pulmonary, multiorgan
neoformans granuloma, vasculitis cerebral edema, involvement
leptomeningeal
enhancement, and
cryptococcomas
Coccidioides Airborne, fungemia Chronic meningitis, Hydrocephalus,
immitis cerebritis, arteritis, meningeal
abscess, granuloma enhancement,
nodular
enhancement,
basilar meningitis,
cerebral infarction
Histoplasma Airborne, fungemia Meningitis, Normal, granuloma, Acute or chronic
capsulatum granuloma meningeal pulmonary,
enhancement dissemination with
multiorgan involvement
Blastomyces Airborne, fungemia Meningitis Single or multiple Pulmonary, cutaneous
dermatitidis abscesses, granuloma,
meningeal
enhancement,
epidural extensions,
and overlying
osteomyelitis
Aspergillus Fungemia, direct Meningitis, vasculitis, Multiple abscesses, Pulmonary
fumigatus inoculation by trauma mycotic aneurysm, meningeal
or surgery, extension granuloma, abscess, enhancement,
from paranasal, spinal cord infarction, hemorrhage,
angioinvasive involvement sinusitis with extension
of meningitis, with mortality rates as high Patients with normal cellular immunity
as 100% in a study of 230 adults in generally manifest more typical signs
Zambia.6 and symptoms of meningitis. In gen-
Clinical presentation. The clinical eral, over 75% of patients present with
manifestations of infection with C. neo- headache and fever, which typically d-
formans depend largely on the host im- evelop insidiously over 2 to 4 weeks.8
mune status. Severity of infection varies Nausea, vomiting, and altered mental
from asymptomatic incidental pulmonary status occur in about half of patients.
nodules to widely disseminated disease. Signs and symptoms of meningismus
Patients with HIV and CD4+ cell counts affect less than 25% of patients. Visual
of less than 50 cells/2L are especially symptoms, such as diplopia and blind-
vulnerable to disseminated infection ness, occur in about 20% of patients,
and meningitis.7 Immunosuppressed most often in immunocompetent
patients with cryptococcal meningitis patients.9 Seizures and focal neurologic
frequently present with indolent non- deficits occur in 10% of patients and
specific symptoms and in some cases are generally caused by space-occupying
with isolated neurologic manifestations. lesions such as cryptococcomas or

TABLE 3-3 Treatments for Infectious Causes of Subacute and Chronic Meningitis
Cause Treatment Phase (Duration) Corresponding Medication(s) and Dosage(s)

Cryptococcus Induction (14 days) Amphotericin B 0.7 mg/kg/d to 1 mg/kg/d IV plus
flucytosine 100 mg/kg/d
Consolidation (8 to 10 weeks) Fluconazole 400 mg/d orally

Maintenance (for life) Fluconazole 200 mg/d orally
Primary prophylaxis Fluconazole 100 mg/d to 200 mg/d orally
Coccidioidomycosis Induction (4 weeks) Fluconazole 400 mg/d to 800 mg/d orally or
amphotericin B 0.5 mg/kg/d to 0.7 mg/kg/d
Maintenance (for life) Fluconazole 200 mg/d to 400 mg/d
Blastomycosis Induction (4 weeks) Amphotericin B 0.7 mg/kg/d to 1 mg/kg/d to
cumulative dose of 2 g
Consolidation/maintenance Fluconazole 800 mg/d orally

Histoplasmosis Induction (4 months) Amphotericin B 0.7 mg/kg/d to 1 mg/kg/d IV to
complete 35 mg/kg total dose
Consolidation (9 to 12 months) Fluconazole 800 mg/d orally

Maintenance For relapsing disease 800 mg/d orally
Aspergillosis Induction (2 doses) Voriconazole 6 mg/kg IV twice on day 1 followed by
4 mg/kg IV twice daily
Maintenance Oral maintenance 200 mg every 12 hours

Mycobacterial Intensive four-medication Isoniazid 300 mg/d orally or IM
regimen (2 months)
Rifampin 600 mg/d orally or IV
Ethambutol or streptomycin 15 mg/kg IM
Pyrazinamide 20 mg/kg to 35 mg/kg orally

Continuation of Isoniazid 300 mg/d orally or IM
two-medication regimen
(10 months)
Rifampin 600 mg/d orally or IV
Neurosyphilis First line (10 to 14 days) Aqueous penicillin G 3 million U to 4 million U IV every
4 hours or as continuous infusion
Alternative (10 to 14 days) Procaine penicillin 2.4 million U IM once daily plus
probenecid 500 mg orally 4 times daily
granulomas. Two of the most dangerous Case 3-1 demonstrates a common

complications of cryptococcal meningi- presentation and clinical course in a
tis are elevated intracranial pressure and patient with cryptococcal meningitis.
hydrocephalus. Over half of immuno- Diagnosis. The diagnosis of crypto-
compromised patients will develop in- coccal meningitis should be considered
tracranial hypertension, and it is even more in patients presenting with a subacute
common in immunocompetent hosts.10 presentation of headache and fever,

Case 3-1
A 39-year-old woman presented with 2 weeks of progressive altered mental status, headache, and
vertigo. Neurologic examination revealed bilateral papilledema, left cranial nerve VI palsy, and diffuse
hyperreflexia. Further history revealed the patient had rescued an injured loon 10 days prior to
her presentation and continued caring for the bird. An MRI brain scan demonstrated abnormal
leptomeningeal enhancement over the bilateral frontal and occipital lobes and left cerebellar
hemisphere (Figure 3-1). Lumbar puncture revealed opening pressure of 44 cm H2O, 221 white blood
cells (WBCs)/2L (29% lymphocytes, 66% neutrophils),
15 red blood cells (RBCs)/2L, glucose concentration
of 46 mg/dL, and protein concentration of 104 mg/dL.
Empiric ampicillin, ceftriaxone, vancomycin,
and acyclovir were started for presumptive
community-acquired meningitis. On hospital day 2 the
patient began reporting diplopia, followed by lethargy
and unresponsiveness. Repeat lumbar puncture had
an opening pressure of 70 cm H2O, 40 WBCs/2L (88%
lymphocytes, 12% monocytes), 0 RBCs/2L, glucose
concentration of 46 mg/dL, and protein concentration
of 49 mg/dL. Original CSF culture was positive for C.
neoformans, and the CSF Cryptococcus antigen (CRAg)
titer was 1:512. The patient received flucytosine and
amphotericin B (AmB) lipid complex induction therapy;
this was followed by fluconazole consolidation and
maintenance therapy.
Despite declining CSF CRAg titers, the patient
FIGURE 3-1 Brain MRI showing cryptococcal continued to have persistently elevated intracranial
meningitis. Coronal T1
postcontrast image demonstrates pressure of 40 cm H2O. Several weeks of serial lumbar
abnormal leptomeningeal enhancement over the punctures and the addition of acetazolamide failed
bilateral frontal and occipital lobes and left to reduce the intracranial pressure. The patient’s
cerebellar hemisphere. The arrow points to
leptomeningeal enhancement of the frontal lobe. headache, diplopia, and papilledema persisted. A
repeat MRI of the brain revealed considerable
progression of leptomeningeal enhancement in
the posterior fossa, acute hydrocephalus, and development of early tonsillar herniation. She was
referred to neurosurgery for placement of a ventriculoperitoneal shunt.
With aggressive management of elevated intracranial pressure via shunt placement and
continued antifungal treatment, the patient had resolution of her neurologic symptoms. Follow-up
HIV antibody test results were negative, and CD4 counts were normal. The patient was diagnosed with
immunocompetent acquisition of cryptococcal meningitis, presumably from exposure to
C. neoformans in the loon feces.
Comment. Cryptococcal meningitis is a common cause of chronic meningitis in patients presenting
with signs and symptoms of elevated intracranial pressure. Patients are typically immunosuppressed
or have an environmental exposure, such as occurred in this patient who was caring for an injured
loon. This case demonstrates that fungal meningitis can initially present with a neutrophilic
pleocytosis, followed by mononuclear cellular predominance on later cerebrospinal fluid analyses.
especially in the setting of HIV infection comas. Lumbar puncture, the diagnostic
or immunosuppression. CT and MRI procedure of choice, is often notable for
are nonspecific for the diagnosis of cryp- a mild mononuclear pleocytosis as well
tococcal meningitis but may reveal as increased protein and low glucose
hydrocephalus, cerebral edema, lep- concentrations. Although India ink stain-
tomeningeal enhancement, or cryptococ- ing of centrifuged CSF is cost-efficient,

KEY POINT
h The CSF cryptococcal rapid, and 75% sensitive, the decreasing and equally effective treatment for cryp-
capsular polysaccharide use of microscopic evaluation of CSF in tococcal meningitis.13 Treatment efficacy
antigen assay is both high-income countries has led to a re- is best monitored by clinical response to
sensitive and specific for liance on antigen-based assays.8 The therapy, as CSF CRAg titer varies signifi-
cryptococcal meningitis CSF cryptococcal capsular polysaccharide cantly; however, an increasing titer has
and also provides a antigen (CRAg) assay is both sensitive been associated with ineffective treat-
quantitative titer that is and specific for cryptococcal meningitis ment. Lifelong maintenance therapy with
useful for prognostication and also provides a quantitative titer that fluconazole is no longer required after
but has limited value is useful for prognostication but has successful immune restoration in patients
for measuring response limited value for measuring response to who are HIV-positive. Several prospective
to therapy.
therapy.11 Fungal culture for the or- trials suggest it is safe to discontinue main-
ganism is 90% sensitive and can be use- tenance therapy if the patient has an
ful for both diagnosing infection and undetectable HIV viral load and CD4+
speciation. cell count greater than 100 cells/2L.14
Laboratory results, physical examina- Elevated intracranial pressure can be
tion, and neuroimaging findings may aid managed through a variety of treat-
in determining prognosis of cryptococcal ments. To date, no trials support aceta-
meningitis. Poor prognostic factors in- zolamide as an effective treatment of
clude low CSF glucose concentration, elevated intracranial pressure in crypto-
high CSF cryptococcal antigen titer coccal meningitis.15 Patients with elevated
(greater than 1:1024), high CSF lactate intracranial pressure should undergo
level, altered level of consciousness, daily lumbar punctures to reduce open-
hydrocephalus, and elevated intracra- ing pressure until normal opening pres-
nial pressure.12 sure is maintained consistently. For
Treatment. A combination of antifun- patients requiring frequent lumbar
gal medication and aggressive treatment punctures, placement of a lumbar drain
of intracranial hypertension is integral to or a ventriculostomy can serve as a tem-
successful treatment of patients with cryp- porary measure to control intracranial
tococcal meningitis. Treatment protocols pressure.16 A small case series supports
involve a three-step approach: induction, the use of ventriculoperitoneal shunting
consolidation, and maintenance ther- for patients with intracranial hyperten-
apy. Induction includes 2 weeks of AmB sion and HIV-associated cryptococcal
(0.7 mg/kg/d to 1 mg / kg/ d) plus flucy- meningitis who do not respond to serial
tosine (100 mg/kg/d). Consolidation ther- lumbar punctures or who require pro-
apy is 8 weeks of fluconazole (400 mg/d), longed lumbar drainage.17 A review of
followed by maintenance therapy with 27 patients with cryptococcal meningi-
fluconazole (200 mg/d) for life (see later tis with elevated intracranial pressure
discussion). This regimen was validated reported good outcomes in 63% of pa-
in a large double-blind randomized trial tients who underwent ventriculoperi-
that demonstrated significant benefit toneal shunting; 37% of patients had
of combined induction therapy over bad outcomes, defined as death or
AmB alone.11 A study comparing AmB persistent vegetative state. Of note,
0.7 mg/kg daily for 21 days with lip- 85% of patients with a good outcome
osomal AmB 4 mg/kg daily for 21 days did not have altered level of conscious-
detected no difference in clinical re- ness at the time of shunt placement.
sponse, although major adverse events Poor outcomes were associated with a
were less common in patients receiv- Glasgow Coma Scale score of less than
ing liposomal AmB. This study suggests 8 or duration of altered level of con-
that liposomal AmB is better tolerated sciousness longer than 48 hours.

KEY POINTS
Coccidiomycosis domycosis in patients with HIV infec- h Coccidioides immitis is a
C. immitis is a fungus endemic to the tion produces a unique reticulonodular fungus endemic to the
southwestern United States, northern diffuse infiltrative pulmonary disease. southwestern United
Mexico, and areas of South America. This pattern can resemble Pneumocys- States, northern Mexico,
Coccidioides species are found primar- tis jiroveci pneumonia, as do the ac- and areas of South
ily in warm sandy soil and climates companying constitutional symptoms America.
characterized by hot summers, mild win- of dyspnea, fever, and night sweats. Cocci- h Disseminated
ters, and minimal rainfall. The mycelial dioidomycosis frequently disseminates in coccidioidomycosis is
phase of Coccidioides species is able patients with HIV infection, with com- more likely to occur in
to withstand extreme desert climates mon sites of dissemination including patients of African or
and, after rainfalls, will multiply to form the meninges, lymph nodes, and skin. Al- Asian descent, pregnant
arthroconidia. Infection in humans oc- though patients who are HIV-positive can women, and people
curs when aerosolized arthroconidia present with unique symptoms, studies who are
are inhaled. The organism then trans- suggest that most HIV-infected patients immunocompromised,
especially from HIV
forms into multinucleated spherules that present with symptoms similar to those
infection or long-term
eventually release endospores. Once of immunocompetent patients.20
immunosuppressive
inhaled, C. immitis usually results in a Hydrocephalus, cerebral infarction,
therapy. Meningitis
self-limited respiratory infection, com- and vasculitis are potential complica- is a devastating
monly known as valley fever. In suscep- tions of C. immitis meningitis. Commu- complication, occurring
tible populations, a pulmonary infection nicating hydrocephalus is a well-known in approximately
can progress to severe disseminated complication of basilar meningitis, sec- one-third to one-half
disease. Dissemination is more likely ondary to obstruction of CSF reabsorp- of patients with
to occur in patients of African or Asian tion, and may develop during the initial disseminated disease.
descent, pregnant women, and people or later stages of the infection. Hydro- h Meningitis due to C.
who are immunocompromised, espe- cephalus develops in about 20% to 50% immitis classically
cially from HIV infection or long-term of patients with C. immitis meningitis involves the basilar
immunosuppressive therapy. Manifesta- and is associated with a 12-fold increased meninges. The most
tions of disseminated disease include risk of mortality.21 Cerebral infarction common symptom is
cavitary pneumonia, soft tissue and bone and venous and dural thrombosis have headache, which is
infection, and meningitis.18 Meningitis been reported during initial and later present in over 75% of
stages of infection. Small and medium patients.
is a devastating complication, occurring
in approximately one-third to one-half blood vessels are typically affected. Peri-
of patients with disseminated disease. vascular inflammation is typically asso-
Rarely, central nervous system involve- ciated with infarctions of the basal ganglia,
ment will present as the first sign of thalamus, and cerebral white matter.22
infection with C. immitis. Patients with Diagnosis. Coccidioidomycosis can
disseminated C. immitis typically will be diagnosed using serologic testing, his-
also suffer from pulmonary disease. topathology, or culture. Identification of
Clinical presentation. Meningitis due C. immitis spherules in tissue, sputum,
to C. immitis classically involves the bas- bronchoalveolar lavage (BAL) fluid, or
ilar meninges. The most common other body fluid, or a positive culture
symptom is headache, which is present from any location in the body, is diag-
in over 75% of patients. Other present- nostic of coccidioidal infection. Although
ing signs and symptoms include nausea definitive diagnosis of C. immitis men-
and vomiting (40%); altered mental sta- ingitis requires identification or culture
tus (39% to 73%); focal neurologic def- of the organism from the CSF, presump-
icits, including ataxia, gait disturbance, tive diagnosis is often sufficient to initiate
diplopia, or facial palsies (33% to 80%); treatment. CSF is typically abnormal, with
and nuchal rigidity (20%).19 Coccidioi- a lymphocytic pleocytosis (20 WBCs/6L

KEY POINT
h Blastomyces to 500 WBCs/6L), early neutrophil pre- guidelines recommend high-dose induc-
dermatitidis and dominance, and low glucose concen- tion therapy with oral fluconazole 400
Histoplasma capsulatum tration. Interestingly, this pathogen mg/d to 800 mg/d, followed by 200 mg/d
are dimorphic fungi may cause a CSF eosinophilia in up to to 400 mg/d indefinitely.26 Approximately
endemic to the 70% of patients with meningitis, a find- 66% to 80% of patients treated with oral
Mississippi and Ohio ing that is relatively uncommon with azoles alone achieved initial clinical im-
river valleys, with other fungal pathogens.23 Isolation of provement or remission of meningitis.
autochthonous the organism from CSF culture occurs However, up to 75% of patients may re-
infection reported less in only about 15% of cases. Identifica- lapse; therefore, lifelong prophylaxis with
frequently in Africa, tion of spherules via CSF using cytopa- fluconazole 400 mg/d is recommended.26
Central and South
thologic Papanicolaou stain can confirm Without treatment, the outcome of pa-
America, and the
the infection.24 Rarely, CSF examination tients with C. immitis meningitis is poor.
Middle East.
may reveal hyphal forms of C. immitis. In one study, 90% of patients died with-
Detection of antibodies to C. immitis in in 1 year, and 100% died within 2 years.
the CSF using the complement-fixation Treatment of C. immitis meningitis
antibody assay is the most sensitive test with IV AmB alone is not effective. In-
for confirming meningeal infection. Re- trathecal amphotericin, via lumbar ad-
peated CSF sampling is sometimes needed ministration, intracisternal injection, or
to confirm the diagnosis, as antibody Ommaya reservoir administration, in
test results can be negative early during combination with IV AmB, was the
the course of infection (71% to 94% treatment for C. immitis meningitis
sensitive). Enzyme immunoassay for prior to the advent of azole therapy,
IgM and IgG and latex agglutination particularly fluconazole, but is no longer
tests are less sensitive in CSF samples.22 the initial treatment of choice.27 For
Although PCR assays have been used pregnant patients and those intolerant
to detect C. immitis infection, they are of azole treatment, intrathecal AmB is
not routinely available. an option. Patients for whom azole ther-
Neuroimaging with MRI is superior to apy fails, who have complicated infec-
CT for detecting abnormalities, which tions, or who worsen during initial
are present in up to 75% of patients with therapy may benefit from combined
C. immitis meningitis. The most com- use of intrathecal amphotericin with
mon radiographic abnormalities include oral azole therapy.22
hydrocephalus, basilar meningitis, and
cerebral infarction. C. immitis meningi- Blastomycosis and
tis can produce diffuse meningeal Histoplasmosis
enhancement, focal or nodular enhance- B. dermatitidis and H. capsulatum
ment, parenchymal or parameningeal are dimorphic fungi endemic to the
abscesses, and spinal arachnoiditis.25 Mississippi and Ohio river valleys, with
Patients with abnormal MRI scans have autochthonous infection reported less
a mortality rate of 20% to 30%, com- frequently in Africa, Central and South
pared with 8% in patients with normal America, and the Middle East. Although
imaging studies.21 Patients with hydro- isolated cases of infection have been
cephalus, with or without cerebral infarc- reported outside this geographic area,
tion, have the highest mortality rates. most patients reside within these areas.
Patients with normal neuroimaging have H. capsulatum and Blastomycoses spe-
significantly better prognoses. cies are ubiquitous environmental organ-
Treatment. Oral fluconazole is the isms, existing in the mycelial phase and
gold standard of treatment for patients then converting to the yeast phase at
with C. immitis meningitis. Practice body temperature. Both organisms

KEY POINTS
produce a large spectrum of disease, microscopy has been the only method h Cutaneous involvement
ranging from subclinical infection to of rapid diagnosis but has variable sen- is seen in 60% of
disseminated disease. sitivity. Lumbar puncture typically re- patients with
Blastomycosis. B. dermatitidis, a veals elevated opening pressure, and blastomycosis,
thick-walled yeast with broad-based CSF examination is notable for elevated manifesting as
budding daughter cells, is endemic protein concentration, low glucose con- verrucous or fungating
to the Great Lakes and Mississippi centration, and pleocytosis with neutro- lesions with irregular
and Ohio river valleys. Like histoplas- philic predominance early in the disease borders.
mosis, infection with blastomycosis is course followed by a lymphocytic pre- h Unlike other fungal
acquired via inhalation of spores into dominance. The gold standard for diag- CNS infections,
the lung and can manifest as pulmo- nosis remains CSF culture, which is blastomycosis is more
nary or extrapulmonary disease. Chest positive in 64% of cases of blastomyco- likely to present with
radiographs commonly demonstrate sis.30 Growth of B. dermatitidis can focal neurologic deficits,
nodular or lobar infiltrates and cavita- occur within 5 to 10 days,31 but may seizures, and altered
mental status, whereas
tions. If the organism evades nonspecific take 2 to 4 weeks for definitive identi-
symptoms of fever,
host defense mechanisms in the lungs, it fication of the organism. More invasive
headache, and
will convert into the yeast phase and procedures, such as brain biopsy and meningismus are
multiply. The organism then spreads ventricular sampling of CSF, are more less common.
hematogenously to other organs. In- likely to provide sufficient material for
flammatory pyogranulomatous reac- definitive diagnosis and are often needed
tions occur at the initial pulmonary site for intracranial disease.31 Diagnostic
and at foci of infection. Cutaneous in- modalities such as skin testing and se-
volvement is seen in 60% of patients rologic assays for detection of antibodies
with blastomycosis, manifesting as ver- have limited sensitivity and specificity for
rucous or fungating lesions with irregu- diagnosing blastomycosis.32 Commer-
lar borders. Other sites less frequently cially available enzyme immunoassay
involved include bones, joints, genito- for detection of B. dermatitidis antigen
urinary system, and the CNS.28 in urine has a sensitivity of 93% and
Clinical presentation. CNS infection specificity of 79% but is cross-reactive
with blastomycosis occurs in less than with other dimorphic fungi, particularly
10% of people with disseminated dis- H. capsulatum.33
ease and manifests as solitary or multiple Treatment. All patients with CNS
abscesses and acute or chronic menin- blastomycosis should be treated with
gitis. Unlike other fungal CNS infections, AmB (0.7 mg/kg/d to 1.0 mg/kg/d) to a
blastomycosis is more likely to present cumulative dose of at least 2 g. Once con-
with focal neurologic deficits, seizures, trol of the infection has been achieved,
and altered mental status, whereas symp- an oral azole, such as fluconazole, should
toms of fever, headache, and meningismus be administered as consolidation ther-
are less common. Although intracranial apy. Other azoles, such as voriconazole,
infection results most frequently from also have adequate CNS penetration
hematogenous seeding of the brain pa- and may become primary therapies for
renchyma from the lungs, epidural ex- CNS disease. Relapse after treatment
tensions from overlying vertebral or with AmB occurs in less than 5% of im-
skull osteomyelitis have been described.29 munocompetent patients. Patients with
Diagnosis. Diagnosis of CNS blasto- immunodeficiency due to HIV or immu-
mycosis is often delayed because of nosuppressive therapy have high rates
a lack of clinical suspicion and limited of relapse and should be maintained on
tools for establishing a rapid diagnosis. long-term secondary prophylaxis with
Direct visualization of the organism via fluconazole.34
KEY POINT
h Histoplasma capsulatum Histoplasmosis. H. capsulatum nosis of histoplasmosis is difficult; clinical
obtains nutrients from obtains nutrients from bird excrement history of exposure remains crucial. CSF
bird excrement and bat and bat guano. Infection usually requires frequently demonstrates a mononuclear
guano. Infection usually a significant inoculum of organisms or pleocytosis, increased protein concen-
requires a significant repeated exposure. People with histoplas- tration, and decreased glucose concen-
inoculum of organisms mosis often report travel to or reside in tration. CSF culture is not sensitive for
or repeated exposure. the Mississippi or Ohio river valleys and diagnosing histoplasmosis. The use of
People with have a history of cleaning chicken CSF and serum antigen titers and anti-
histoplasmosis often coops or spelunking in caves with large bodies are useful, although as with blas-
report travel to or reside bat populations. Histoplasmosis may tomycosis, significant cross-reactivity
in the Mississippi or
produce an acute pulmonary infection occurs with other dimorphic fungi. Be-
Ohio river valleys and
with fever, chills, and pulmonary opac- cause meningitis is typically a result of
have a history of
cleaning chicken coops
ities. Patients with impaired cellular disseminated infection, testing for the
or spelunking in caves immunity, such as individuals who are organism in the blood or bone marrow
with large bat HIV infected, typically present with should also be considered.
populations. chronic pulmonary symptoms with Treatment. Treatment of CNS histo-
progression to severe disseminated plasmosis is challenging. Despite treat-
disease. Infection disseminates hema- ment with AmB, 20% to 40% of patients
togenously to distant sites, such as the with meningitis die of the infection and
liver, spleen, and CNS. Bone marrow up to half of responders relapse after
involvement is common and often therapy is discontinued. The optimal
manifests as thrombocytopenia, ane- treatment for H. capsulatum meningitis
mia, or leukopenia.35 is AmB (0.7 mg/kg/d to 1.0 mg/kg d) to
Clinical presentation. Most patients complete a total dose of 35 mg/kg during
with pulmonary histoplasmosis are a 3- to 4-month period. To reduce the
asymptomatic and have resolution of risk of relapse, fluconazole (800 mg/d)
the infection without therapy. It is com- should be continued for 9 to 12 months
mon for individuals in the Mississippi after completion of AmB. Chronic fluco-
and Ohio river valleys to have asymptom- nazole maintenance therapy (800 mg/d)
atic pulmonary nodules. The organism should be considered for patients who
can become dormant in macrophages relapse after completing a full course of
and later reactivate and cause disease. therapy. Itraconazole, although more active
Dissemination occurs during both pri- against H. capsulatum than fluconazole,
mary infection and reactivation of latent does not cross the blood-brain barrier in
infection. CNS involvement occurs in less adequate amounts to treat CNS infection.
than 20% of patients with disseminated Intrathecal administration of amphoter-
infection and most frequently affects pa- icin directly into the ventricles, cisterna
tients with severely impaired cellular magna, or lumbar arachnoid space should
immunity, such as people who are HIV be reserved for severe infections that do
infected and those who have under- not respond to conventional therapy.36
gone solid-organ transplantation. Pre-
senting symptoms typically include Aspergillus
headache and altered mental status; Aspergillus species are ubiquitous soil
although less common, patients may also inhabitants that grow and survive on or-
present with focal neurologic deficits, sei- ganic debris. This organism sporulates
zures, encephalitis, ischemic stroke, abundantly, releasing conidia into the
and mass lesions. atmosphere in large quantities. The
Diagnosis. Similarly to that of blas- conidia are small in diameter, making it
tomycosis, definitive laboratory diag- possible to reach smaller areas of the

KEY POINTS
lung, including the alveoli. Environmen- brain or other organs (ie, skin, kidneys, h Populations significantly
tal studies indicate that humans inhale heart, and eyes). CNS infection results at risk for invasive
several hundred conidia per day,37 but from hematogenous dissemination of aspergillosis include
inhalation of organisms rarely results the organism or by direct extension from patients undergoing
in disease because the conidia are elim- rhinosinusitis. Cerebral aspergillosis treatment for
inated efficiently by host immune mech- occurs in approximately 10% to 20% of hematologic malignancies,
anisms. Alveolar macrophages constitute patients with invasive disease.39 allogeneic hematopoietic
the first line of host defense against CNS infection can present as a solitary stem cell transplant, and
aerosolized conidia. Neutrophils are the mass lesion, cavernous sinus thrombosis, solid-organ transplant,
dominant host defense against the multiple intracranial abscesses, acute or as well as people who
are HIV infected, and
invasive hyphal stage.38 Historically, chronic basilar meningitis, vasculitis, or
individuals with chronic
disease was limited to individuals with myelitis. Pathologically, CNS aspergillosis
granulomatous disease.
repetitive exposure to pathogens, pro- has a propensity for vascular invasion,
ducing a mild condition known as farm- infarction, hemorrhage, and aneurysm h CNS aspergillosis has a
propensity for vascular
er’s lung. Aspergillus was also known to formation; as a result, the clinical presen-
invasion, infarction,
produce lung aspergillomas, character- tation may be that of cerebral vasculitis,
hemorrhage, and
ized as an overgrowth of fungus in ischemic or hemorrhagic infarction, or aneurysm formation;
preexisting cavitary lung lesions. More subarachnoid hemorrhage. Granuloma as such, the clinical
recently, the incidence and severity of formation with necrosis is also commonly presentation may be
Aspergillus infection have increased observed. An isolated abscess may be that of cerebral vasculitis,
because of a growing number of people suspicious for neoplasm and, upon bi- ischemic or hemorrhagic
living with immunosuppression, leading opsy or extirpation, reveal a yellowish infarction, or
to disease known as invasive aspergillo- fluid or fungal hyphae upon staining.41 subarachnoid
sis.39 Populations significantly at risk for Case 3-2 demonstrates a classic clin- hemorrhage.
invasive aspergillosis include patients ical presentation of disseminated CNS h In patients with
undergoing treatment for hematologic aspergillosis in a heart transplant patient. suspected CNS
malignancies, recipients of allogeneic Diagnosis. Diagnosis of aspergillo- aspergillosis, it is
hematopoietic stem cell transplant and sis in immunocompromised patients re- important to examine
solid-organ transplant, people who are mains difficult. As with many invasive the lungs and sinuses
HIV infected, and individuals with chronic fungal CNS infections, diagnosis is often for evidence of infection
and potential sites for
granulomatous disease.38 Deficits in host achieved through examination of the
obtaining biopsy or
defense mechanisms that increase sus- primary entry site of infection. Thus, in
culture material.
ceptibility to invasive aspergillosis are patients with suspected CNS aspergillo-
complex but can be broadly divided into sis, it is important to examine the lungs
three groups: (1) neutropenia, (2) qual- and sinuses for evidence of infection and
itative deficits in phagocyte function, and potential sites for obtaining biopsy or
(3) deficits in cell-mediated immunity.40 culture material. BAL cultures are nearly
Clinical presentation. A. fumigatus 50% sensitive for detecting aspergillosis
is responsible for approximately 90% of in focal pulmonary lesions. Isolation of
human infections. Other members of an Aspergillus species from sputum or
this genus that less commonly produce BAL is highly predictive of invasive dis-
human infection include A. flavus, A. ease in neutropenic patients. Chest imag-
terreus, A. niger, and A. nidulans. Four ing can be used to support diagnosis.
types of invasive aspergillosis have been During early invasive pulmonary asper-
described: (1) acute or chronic pulmo- gillosis, the most common finding on
nary aspergillosis, (2) tracheobronchi- chest CT is one or more nodules. The
tis and obstructive bronchial disease, ‘‘halo sign,’’ a haziness surrounding a
(3) acute invasive rhinosinusitis, and nodule or infiltrate on chest CT, is a
(4) disseminated infection involving the characteristic feature of angioinvasive

Case 3-2
A 63-year-old woman with a history of idiopathic hypertrophic cardiomyopathy and heart
transplantation 6 years previously, receiving tacrolimus for immunosuppression, presented with
subacute altered mental status. Initially the patient had problems with simple tasks such as operating
a remote control; this progressed to an inability to perform activities of daily living. Several days prior
to admission she began having visual hallucinations and worsening orientation, followed by acute
onset of left hemiparesis and loss of consciousness. Further history revealed the patient had been
reporting a progressive productive cough for 6 months, drenching night sweats, and a 6.8-kg (15-lb)
unintentional weight loss. Examination revealed a comatose woman intubated without sedation. Her
brainstem reflexes and cranial nerve examination were normal, with the exception of a left lower
facial droop. She had brisk withdrawal to pain in all extremities, with a left hemiparesis and diffuse
hyperreflexia. Head CT revealed hypodensity involving the left frontal and temporal lobe, right basal
ganglia, and left cerebellum. Lumbar puncture yielded purulent yellow fluid with normal opening
pressure, 1546 WBCs/2L (92% neutrophils, 2% lymphocytes, 6% monocytes), 14 RBCs/2L, glucose
concentration of 22 mg/dL, and protein concentration of 97 mg/dL.
Antibiotics were started for treatment of suspected community-acquired bacterial meningitis.
MRI of the brain revealed restricted diffusion involving the frontal, parietal, and occipital cortex,
rostrum and splenium of the corpus callosum, right thalamus, and cerebellar hemispheres (Figure 3-2).
CSF analysis was
negative for
cryptococcal
antigen, Venereal
Disease Research
Laboratory (VDRL)
testing, IgG and IgM
for Borrelia species
and Toxoplasma
gondii. PCR assays
for herpes simplex
virus types 1 and 2,
human herpesvirus
6, cytomegalovirus,
Epstein-Barr virus,
and varicella-zoster
virus were negative,
as were CSF bacterial,
mycobacterial, fungal,
and viral cultures. FIGURE 3-2 Brain MRI showing Aspergillus meningitis. A, Diffusion-weighted image reveals
restricted diffusion involving the frontal, parietal, and occipital cortex; thalamus;
Despite and corpus callosum. B, T2 fluid-attenuated inversion recovery image shows
aggressive therapy bilateral subarachnoid and cortical hyperintensities.
with antiviral and
antibiotic medications, the patient continued to decline clinically. CT of the chest revealed dense
bilateral lower lobe consolidation and diffuse lymphadenopathy. Abdominal CT revealed a moderate
amount of free fluid. BAL and paracentesis were performed. The patient rapidly progressed to septic
shock and multiorgan failure and died 7 days after presentation.
BAL and paracentesis culture grew A. fumigatus 7 days after collection. The postmortem diagnosis
was invasive aspergillosis with CNS involvement. Initial CSF analysis demonstrating neutrophilic
pleocytosis, elevated protein, and low glucose concentration was consistent with early fungal
meningitis. MRI supported angioinvasive disease by demonstrating multiple ischemic infarctions.
Comment. Aspergillus meningitis is an aggressive disease that can affect posttransplant
recipients taking immunosuppressive agents. This case demonstrates the current challenges in
rapidly identifying the organism and the importance of early treatment.

organisms and is highly suggestive of sive fungal infections, including candi-
invasive aspergillosis. Neuroimaging can diasis, fusariosis, trichosporonosis, and
be helpful in the evaluation of CNS asper- aspergillosis.45
gillosis. MRI of the brain can demonstrate Several PCR assays can detect Asper-
a variety of lesions, including cerebral in- gillus in blood and BAL fluid samples,
farction, on diffusion-weighted imaging, but experience with PCR to detect Asper-
hemorrhagic lesions, solid-enhancing as- gillus species in CSF samples is limited.
pergillomas, or ring-enhancing abscesses. A recent study using nested PCR assay
Dural enhancement is usually seen in detected Aspergillus DNA in samples from
lesions adjacent to infected paranasal six of six patients with CNS aspergillosis.
sinuses and indicates direct extension of In all patients, samples obtained at the
disease.42 initial manifestation of CNS aspergillosis
In patients with Aspergillus sinusitis, were positive by PCR. In patients with se-
endoscopy may reveal sentinel eschars rial CSF sampling, follow-up samples ob-
along the nasal turbinates. Direct smear tained during antifungal treatment and
of brushings or biopsies of these lesions after clinical improvement tested nega-
may reveal hyphae, and culture is often tive, suggesting this assay may be useful
positive. Involvement of the ethmoid si- for determining response to therapy.46
nuses carries a particularly high risk of Treatment. Unfortunately, CNS as-
extension to the cavernous sinus. Oph- pergillosis, especially in an immunocom-
thalmoplegia is often an early sign of cav- promised patient, is difficult to treat and
ernous sinus thrombosis that precedes has a high mortality rate. The newer an-
radiologic confirmation. Biopsy of nasal tifungal agent voriconazole has reduced
tissue or brain biopsy of solitary lesions mortality in an infection previously asso-
can provide histopathologic evidence of ciated with almost universal mortality.
Aspergillus species infection and remains Clinical trials have demonstrated that
critical to establishing a diagnosis of sinus voriconazole is more effective than AmB
and intracranial disease. as initial therapy for invasive aspergillosis
Several valuable serum laboratory and is associated with significantly im-
markers can aid in the diagnosis of in- proved survival (71% versus 58%, respec-
vasive Aspergillus. ELISA testing for tively).47 More recently, clinicians have
galactomannan and "-glucan, fungal cell combined voriconazole with caspofun-
wall constituents, should be considered. gin (an echinocandin) as salvage therapy
In 170 patients hospitalized in North in patients with invasive aspergillosis,
American cancer centers at high risk for resulting in a favorable response in 37 of
invasive mold infection, the serum galac- 83 patients (45%). Significant interest has
tomannan assay identified 25 of 31 developed in combining an echinocandin
patients with invasive aspergillosis (81% with either an AmB preparation or a mold-
sensitivity) and had a specificity of 89%. In active azole. Marra and colleagues
another study, the sensitivity was only reported improved survival rates in
64.5% in cases of definite invasive asper- patients treated with voriconazole plus
gillosis.43 CSF galactomannan assay using caspofungin compared to those treated
latex agglutination or ELISA is a useful with voriconazole alone.48
adjunct to serum testing. The sensitivity Surgical debulking of CNS aspergillo-
of serial CSF testing is 70% to 90% and mas has produced long-term survival; in
specificity is 86% to 71%.44 In patients combination with systemic antifungal che-
with acute myeloid leukemia and myelo- motherapy, extirpation or aspiration of ce-
dysplastic syndrome, the "-glucan assay rebral aspergillomas can be curative. In
is highly sensitive for detecting early inva- patients with a solitary abscess, lobectomy
KEY POINTS
h Tuberculous meningitis has been performed when noneloquent ing tuberculous meningitis include pov-
is an aggressive form of areas of the brain are involved.49 erty, poor education, alcoholism, diabetes
extrapulmonary disease mellitus, immunosuppressive medications,
that is more common in Mycobacterium Tuberculosis and malignancy.
patients coinfected Tuberculous meningitis is caused by M. Clinical presentation. Tuberculous
with HIV. tuberculosis, an aerobic gram-positive meningitis is typically preceded by nonspeci-
h In patients with HIV acid-fast pleomorphic bacilli. M. tuber- fic symptoms of malaise, anorexia, fatigue,
infection with low culosis is an intracellular pathogen that weight loss, fever, myalgia, and headache.
CD4 cell counts, survives within the phagosome of host In immunocompetent patients, head-
manifestations of macrophages. Apoptosis of infected mac- ache, vomiting, meningeal signs, focal
tuberculous meningitis rophages is an effective host mechanism deficits, vision loss, cranial nerve palsies,
are subtle and less against tuberculous bacilli. Virulent strains and raised intracranial pressure are char-
specific and typically of M. tuberculosis have evolved sev- acteristic clinical features. Vision loss may
present late in the eral genetic mechanisms to evade occur secondary to optic nerve involve-
course of the disease
host immune mechanisms.50 Transmis- ment. Cerebral vessels may be affected by
after a prolonged
sion occurs primarily by inhalation of adjacent meningeal inflammation, pro-
duration of
severe illness.
airborne droplet nuclei into the lungs. ducing vasospasm, constriction, and
M. tuberculosis multiplies in alveolar eventually thrombosis with cerebral
h The hallmark pathologic macrophages, and within weeks the ba- infarction. Infarcts are most often located
feature of tuberculous
cilli can hematogenously disseminate to within the internal capsule, basal ganglia,
meningitis is the
presence of a thick
extrapulmonary sites. In distant organs, and thalamus.54 In a series of 101 adult
exudate most including the meninges and adjacent patients, presenting neurologic features
prominent in the brain parenchyma, M. tuberculosis typi- included headache (96.0%), fever
basilar meninges. cally produces small granulomas. Gran- (91.1%), nuchal rigidity (91.1%), vomiting
ulomatous foci can remain dormant for (81.2%), meningismus (79.2%), and
years, and the mechanism of reactiva- abnormal mental state (72.3%).55
tion is not well understood. Tuberculous In patients with HIV infection with low
meningitis develops when a caseating CD4 cell counts, manifestations of tuber-
focus discharges its contents into the culous meningitis are subtle and less
subarachnoid space.51 Microglial cells specific and typically present late in the
are the principal targets of M. tuber- course of the disease after a prolonged
culosis. Tumor necrosis factor " released duration of severe illness. The most
from these cells plays a critical role in common clinical manifestations include
containing the infection, granuloma for- fever and altered mental status.54,56
mation, alteration of blood-brain barrier The hallmark pathologic feature of
permeability, and CSF leukocytosis.52 tuberculous meningitis is the presence
Tuberculous meningitis is an aggres- of a thick exudate most prominent in
sive form of extrapulmonary disease that the basilar meninges. This exudate can
is more common in patients coinfected block the flow of CSF and result in
with HIV. Although the exact incidence hydrocephalus. The entrapment of in-
and prevalence of tuberculosis meningi- tracranial vessels within exudates often
tis in many countries is not well defined, produces cerebral infarction. Cranial
India, China, Indonesia, Nigeria, and nervesVmost often cranial nerves VII
South Africa have high rates of infection. and VIIIVare also similarly affected, re-
Compared to people without HIV in- sulting in cranial nerve palsies. If the
fection, those with HIV infection more basal inflammatory process affects the
commonly progress to have extrapul- brain parenchyma, it can result in ence-
monary infection, including meningitis.53 phalopathy. Cerebral tuberculomas are
Other predisposing factors for develop- also common.

Diagnosis. Although CSF acid-fast ba- initially suspected, as the organism grows
cillus smear and culture are crucial for slowly, speciation can take weeks, and
making a diagnosis of tuberculous men- earlier treatment is associated with bet-
ingitis, both have low sensitivity and pre- ter outcomes. First-line antituberculous
sumptive treatment is often initiated when medications include rifampicin, isoni-
the clinical suspicion is high. Charac- azid, pyrazinamide, ethambutol (RIPE),
teristic CSF abnormalities include a mono- and streptomycin. Most of the first-line
nuclear cell pleocytosis, low glucose antituberculous drugs (except ethambu-
concentrations, and elevated protein tol) achieve satisfactory levels in the CSF.
concentrations. Unfortunately, acid-fast Antituberculosis treatment for meningitis
bacillus smear is positive in only 5% to is divided into two phases: an intensive
30% of patients. Conventional CSF culture (initial) phase and a continuation phase.
for M. tuberculosis on Lowenstein-Jensen In the intensive phase, therapy includes a
medium is positive in approximately 45% combination of four first-line medica-
to 90% of cases but usually takes several tions: isoniazid, rifampicin, streptomycin,
weeks for a positive result. Sensitivity is and pyrazinamide. The intensive phase
higher for patients with HIV infection continues for 2 months. In the continu-
(69% sensitivity for smear and 87.9% for ation phase, the treatment regimen is
culture). CSF may be normal in 5% of reduced to two medications (isoniazid
HIV-positive patients with tuberculous and rifampicin), and the continuation
meningitis. Detection of M. tuberculosis phase is usually extended to a total
DNA in CSF by PCR assay is a useful treatment period of 12 to 14 months.58
ancillary diagnostic test, with a sensitivity Treatment of multi- and extremely drug-
that varies between 30% and 50% and resistant tuberculosis requires prolonged
specificity of 98%. The likelihood of intensive and continuation phases and,
detecting M. tuberculosis is increased depending on sensitivity, may require
if a combination of tests is performed additional medications. A recent Cochrane
on serial CSF samples.57 review recommended that corticoste-
Chest CT is sensitive for detecting roids be used routinely for patients with
pulmonary abnormalities in patients with tuberculous meningitis because they
tuberculous meningitis. Mediastinal and significantly reduced death and dis-
hilar lymphadenopathy, miliary pattern, abling residual neurologic deficits among
and bronchopneumonic infiltrate are survivors.59 In addition, a random-
the most frequent abnormalities. Both ized trial demonstrated significantly im-
CT and MRI of the brain are valuable proved survival at 9 months in patients
for diagnosing tuberculous meningitis receiving dexamethasone, as well as de-
and evaluating for complications. Char- creased adverse effects of antituber-
acteristic abnormalities include en- culosis medications.60
hancement of the basilar meninges, Neurosurgical intervention is often
exudates, hydrocephalus, and periven- needed when hydrocephalus develops.
tricular infarcts. MRI is considered more Ventriculoperitoneal shunting is most
sensitive than CT, and gadolinium- frequently used, although other options
enhanced imaging can detect meningeal include temporary external ventricular
enhancement early in the course of drainage and endoscopic third ventricu-
illness. Focal meningeal enhancement lostomy.54 Early neurosurgical proce-
is more common than diffuse meningeal dures are also important for managing
enhancement. tuberculous brain abscesses. Stereotac-
Treatment. Treatment should be ini- tic drainage or evacuation can reduce
tiated when tuberculous meningitis is the size of space-occupying lesions, lower
KEY POINTS
h Treponema intracranial pressure, and improve erad- symptoms during this time. About one-
pallidum spreads ication of the microorganism.61 third of patients with untreated latent
hematogenously to syphilis will progress to develop late
the CNS early in the Syphilis or tertiary syphilis, which can affect any
course of disease. Syphilis is caused by the thin, motile organ in the body, particularly the ner-
Clinical signs and corkscrew bacterium Treponema pal- vous system.62
symptoms of CNS lidum. This organism cannot be rou- Clinical presentation of neurosyphilis.
involvement are evident tinely cultured in the laboratory and is T. pallidum spreads hematogenously to
throughout the course difficult to visualize using traditional light the CNS early in the course of disease.
of disease and not Clinical signs and symptoms of CNS
microscopy. Transmission is primarily
limited by stage.
via sexual contact with an infected in- involvement are evident throughout the
h The first step in dividual or by vertical transmission from course of disease and not limited by
diagnosis of mother to fetus. Without treatment, the stage. Neurosyphilis can be either early
neurosyphilis is or late disease. The early stage typically
disease will inevitably progress through
performing serologic
a series of clinical stages. In general, manifests as asymptomatic or sympto-
testing for syphilis using
syphilis can be classified as early or late matic meningitis and meningovascular
Venereal Diseases
Research Laboratory infection. Early infection encompasses disease. Late disease more often affects
testing and rapid primary, secondary, and early latent syph- the brain parenchyma or spinal cord,
plasma reagin assays. ilis. Late infection refers to tertiary syphilis. leading to general paresis, psychiatric
After sexual exposure to the organ- illness, memory deficits, tabes dorsales,
ism, an asymptomatic incubation period and gummatous masses.48
of approximately 3 weeks occurs, fol- Although neurosyphilis has several
lowed by development of a painless manifestations, this article will limit the
genital ulceration or chancre. The chan- discussion to syphilitic meningitis. Syph-
cre and corresponding generalized lym- ilitic meningitis typically presents in
phadenopathy are considered by most the secondary stage of syphilis, within
clinicians as primary syphilis. If left 2 years of acquiring infection. Although
untreated, the chancre will resolve in less common than other forms of neuro-
3 to 5 weeks and likely progress to sec- syphilis, meningitis occurs in up to 25% of
ondary syphilis. Secondary syphilis is a patients. The most common presenting
syndrome of fever, lymphadenopathy, symptoms include headache, photopho-
headache, malaise, myalgia, and a mac- bia, nausea and vomiting, meningismus,
ular or pustular rash of the palms and and cranial nerve deficits. Although
soles. It is during this stage when involve- every cranial nerve can be affected,
ment of other organ systems produces cranial nerves VII and VIII are most
clinical symptoms, including mucosal commonly affected.
lesions, renal failure, hepatitis, and neu- Diagnosis. The diagnosis of neu-
rologic symptoms. The signs and symp- rosyphilis is typically made through a
toms of secondary syphilis typically combination of history, physical exami-
resolve in 4 to 10 weeks, and the patient nation, and results of serologic and CSF
is deemed latently infected. During this analyses. The first step in diagnosis is
phase, patients are asymptomatic; how- performing serologic testing for syphilis
ever, they have serologic evidence of using VDRL and rapid plasma reagin
infection. Latent syphilis is typically sub- assays. These assays detect IgG and IgM
divided into early and late disease. Early antibodies to a cardiolipin-lecithin-
latent syphilis is typically diagnosed cholesterol antigen and are always positive
within 1 year of acquiring disease. Al- in patients with neurosyphilis. They also
though usually asymptomatic, patients provide quantitative titers that can be
may experience recurrence of clinical used to monitor response to treatment.

KEY POINT
These assays are valuable for diagnos- the CNS have a negative PCR. Rolfs and h Prognosis of
ing early syphilis and early neurosyphi- colleagues reported that 32 of 131 CSF neurosyphilis is largely
lis. Treponemal assays, including the specimens (24%) were positive for T. determined by the stage
fluorescent treponemal antibody ab- pallidum by PCR assay, but a positive of the illness. Early
sorbed and T. pallidum particle ag- PCR result did not correlate with CSF stages of disease, such
glutination tests, measure treponemal abnormalities or CSF VDRL reactivity.64 as syphilitic meningitis,
antibodies and are used for confir- Studies suggest that HIV-positive pa- respond much better to
matory testing. Treponemal assays tients are more likely to have leukocy- therapy than tertiary
should also be positive in patients with tosis, elevated protein concentration, syndromes.
neurosyphilis. and low glucose concentration than
Abnormal CSF is present in 70% of HIV-negative patients.65
patients with early syphilis. In later dis- Treatment. Penicillin is first-line
ease, these abnormalities are less com- therapy for neurosyphilis. The Centers
mon, suggesting that some patients may for Disease Control and Prevention
spontaneously clear the organism from (CDC) recommends 18 million units
the CSF without treatment. Persistent CSF to 24 million units of aqueous penicillin
abnormalities can occur and are indica- G per day administered as 3 million
tive of persistent infection. Although the units to 4 million units IV every 4 hours
significance of abnormal CSF findings for or as continuous infusion for 10 to 14
diagnosis, treatment, and prognosis in days.66 An alternative is procaine pen-
the asymptomatic patient is not certain, icillin 2.4 million units IM daily with
patients with abnormal CSF studies are at probenecid 500 mg orally 4 times daily
increased risk of progression to sympto- for 10 to 14 days. In patients with pen-
matic neurosyphilis.48 icillin allergy, most experts recommend
In active neurosyphilis, CSF typically substitution with ceftriaxone 2 g IV daily
has a lymphocytic pleocytosis and ele- for 10 to 14 days. Marra and colleagues
vated protein concentration; however, found that ceftriaxone therapy led to
in late disease, CSF studies may be nor- resolution of CSF abnormalities at a
mal. In syphilitic meningitis, CSF typi- rate similar to patients receiving pen-
cally has a mononuclear predominant icillin G treatment.48
pleocytosis (greater than 10 cells/2L), Prognosis of neurosyphilis is largely
elevated protein concentration (greater determined by the stage of the illness.
than 45 mg/dL), and normal or decreased Early stages of disease, such as syphilitic
glucose concentration. CSF immuno- meningitis, respond much better to ther-
logic tests, such as VDRL, are usually apy than tertiary syndromes. Treatment
abnormal in syphilitic meningitis; how- of tabes dorsales and general paresis is
ever, because CSF VDRL assay has a not as effective. The CDC recommends
sensitivity of less than 30% for detection reexamination of CSF every 6 months to
of neurosyphilis, a negative result does monitor response to therapy until the
not rule out neurosyphilis. CSF fluores- CSF cell count is normal and the CSF
cent treponemal antibody absorption VDRL is nonreactive. Retreatment
testing is less specific but more sensitive should be considered if the cell count
than CSF VDRL and may be used to has not decreased at 6 months or if the
exclude the diagnosis. Dark-field micro- CSF is not normal by 2 years.
scopy for organism visualization in the Although most clinical presentations
CSF is insensitive.63 More recently, PCR of syphilis have not been shown to vary
assays have been developed to detect significantly by HIV status, early menin-
T. pallidum in the CSF, but 50% of geal neurosyphilis occurs more fre-
patients with syphilitic involvement of quently among HIV-positive patients.
HIV-positive patients with early neuro- therapy are 4 times more likely to dem-
syphilis are at increased risk of early onstrate normalized CSF studies, 13 times
neurologic complications and have slightly more likely to have clinical improve-
higher rates of treatment failure. The ment, and less likely to have serologic
existing literature does not demonstrate failure of treatment.62
a more effective treatment regimen in
preventing neurosyphilis in HIV-positive AUTOIMMUNE DISEASE
patients when compared to existing rec- Nervous system involvement has been
ommendations for HIV-negative patients. described with virtually every autoim-
HIV-positive patients with neurosyphilis mune disease. Chronic meningitis may
should have repeat serologic follow-up occur in a subset of these diseases. This
at 3, 6, 9, 12, and 24 months after ther- section discusses the clinical presenta-
apy. Although patients with HIV may tion, diagnosis, and treatment of the most
continue to have abnormal CSF pleocy- common autoimmune diseases associ-
tosis at 6 months after neurosyphilis ated with chronic meningitis, including
treatment, retreatment should be con- sarcoidosis, systemic lupus erythemato-
sidered in patients with CSF VDRL or sus, Behçet disease, and CNS angiitis.
serum VDRL titers that have failed to Table 3-4 provides a comprehensive
decline. Immune reconstitution using list of autoimmune diseases reported
antiviral therapy is essential in the to cause chronic meningitis with asso-
treatment of coexisting neurosyphilis. ciated clinical symptoms and diagnos-
HIV-positive patients receiving antiviral tic recommendations.
TABLE 3-4 Noninfectious Causes of Meningitis
Causes and Other Special Laboratory

Clinical Findings Tests
Leptomeningeal Cranial nerve deficitsa CSF: cytology and flow
carcinomatosis cytometry
Behçet disease Oral and genital ulcers, Human leukocyte antigen
uveitis, iridocyclitis B51
Systemic lupus antinuclear antibody,
erythematosus American College of
Rheumatology criteria
Wegener Glomerulonephritis and Antineutrophil
granulomatosis pulmonary necrosis cytoplasmic antibody
Sarcoidosis Lungb Serum angiotensin-
Skin: erythema nodosum converting enzyme
Ophthalmic: iritis, uveitis
Cranial nerve deficits
Sjögren Sjögren syndrome, Sjögren syndrome A and
syndrome Raynaud syndrome Sjögren syndrome B
antibodies
Chemical Drug history
a
An MRI with contrast of brain and spinal cord should be performed.
b
A chest CT to check for bilateral hilar lymphadenopathy should be performed.

Neurosarcoidosis including the nervous system, can be
Sarcoidosis is a multisystem granuloma- affected. Neurosarcoidosis was first de-
tous disease affecting the CNS in up to scribed in the 1900s by Heerford as ‘‘uveo-
25% of patients. Although sarcoidosis has parotid fever’’ with cranial neuropathies.
a predilection for the lungs, anterior uvea, Clinical presentation. The clinical fea-
lymphatic system, and skin, any organ, tures of neurosarcoidosis can involve
Case 3-3
A 32-year-old man presented with 1 month of headache, progressive
alteration in mental status, and disinhibited behavior. He noted several
months of polydipsia, during which he consumed about 3 gallons of water
per day. On examination, the patient was alert with fluent speech and
normal comprehension. His disinhibited behavior was manifest as foul
language and sexual referencing. The patient demonstrated concrete
thinking to proverb interpretation. The cranial nerve examination was
normal. His motor examination revealed spasticity of bilateral lower
extremities with gegenhalten in the right upper extremity; he was
diffusely hyperreflexic with bilateral upgoing toes.
A T2-weighted fluid-attenuated inversion recovery MRI sequence
demonstrated diffuse hyperintensities involving the subcortical and gray
matter of the bilateral frontal and parietal lobes, hypothalamus, midbrain,
pons, medulla, and cerebellum (Figure 3-3A). MRI of the cervical spinal cord
FIGURE 3-3 Brain MRI showing neurosarcoidosis. A, Sagittal T2-weighted

fluid-attenuated inversion recovery MRI sequence demonstrates diffuse
hyperintensities involving the subcortical and gray matter of the bilateral
frontal and parietal lobes, hypothalamus, midbrain, pons, medulla, and cerebellum (arrows).
B, Sagittal T1 postcontrast of the cervical spinal cord displays large areas of T2-weighted
hyperintensity with patchy gadolinium enhancement (arrows).
displayed large areas of T2-weighted hyperintensity with patchy gadolinium

enhancement (Figure 3-3B). Lumbar puncture had normal opening pressure,
13 WBCs/2L (99% lymphocytes), glucose concentration 22 mg/dL, and
protein concentration 428 mg/dL. Endocrinologic evaluation revealed
Continued on page 1310

Continued from page 1309
undetectable testosterone, low luteinizing hormone, low follicle-stimulating

hormone, hyponatremia, and central hypothyroidism. All studies were
consistent with hypothalamic dysfunction.
The patient declined clinically during the following month of
hospitalization, with worsening spasticity, new incoordination, and
progressive hyperreflexia with nonsustained clonus of the bilateral
lower extremities. A repeat lumbar puncture displayed 41 WBCs/2L
(64% lymphocytes, 9% neutrophils, 26% monocytes), glucose concentration
23 mg/dL, and protein concentration 357 mg/dL. CSF fungal and bacterial
cultures were negative; CSF cryptococcal antigen, cytology, and PCR assays
for human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, varicella-zoster
virus, and herpes simplex virus types 1 and 2 were negative. IgG index was
normal at 0.69 (normal is less than 0.7) with no oligoclonal banding. Serology
was negative for Borrelia burgdorferi IgM and IgG, HIV antibody, Bartonella
species IgG and IgM, and VDRL. Autoimmune workup was negative for
neuromyelitis optica antibody, thyroglobulin antibody, thyroid peroxidase
antibody, antineutrophil cytoplasmic antibody, antinuclear antibody,
angiotensin-converting enzyme (ACE) (serum and CSF), erythrocyte
sedimentation rate, C-reactive protein, and Sjögren syndrome antigens A
and B. In light of the patient’s declining neurologic examination and the
negative infectious and neoplastic workup, empiric IV methylprednisolone
sodium succinate was started. Definitive diagnosis was ultimately made via
conjunctival biopsy. Pathology results indicated noncaseating granulomatous
conjunctivitis consistent with sarcoidosis (Figure 3-4). The patient was
ultimately diagnosed with systemic sarcoidosis with neurologic involvement.
He was maintained on prednisone and improved both clinically and
radiologically.
Comment. This case of neurosarcoidosis highlights the unique hypothalamic
involvement of disease presenting with multiple endocrine abnormalities.
Despite advanced methods of CSF testing and imaging, ultimate diagnosis was
made using systemic biopsy.
FIGURE 3-4 Conjunctival biopsy. Medium (A) and high power (B) view of conjunctival
biopsy demonstrating a large noncaseating granuloma.

KEY POINTS
almost any part of the nervous system. Dural enhancement is present in up to h The most common
The most common clinical presentations 30% of cases. Intraparenchymal mass le- clinical presentations of
include cranial neuropathies, seizures, sions or granulomas may be solitary neurosarcoidosis include
meningitis, mass lesions, hypothalamic or multiple and typically enhance with cranial neuropathies,
or pituitary involvement, spinal cord lesions, gadolinium. Pituitary and hypothalamic seizures, meningitis,
psychiatric manifestations, movement masses, enhancement, or thickening are mass lesions,
disorders, peripheral neuropathy, and present in 18% of patients with neuro- hypothalamic or
myopathies. Cranial neuropathies occur sarcoidosis. Although the facial nerve pituitary involvement,
in 50% to 75% of patients and are most is the most common clinical manifes- spinal cord lesions,
often the result of elevated intracranial tation of cranial neuropathy, on MRI, the psychiatric
manifestations,
pressure, granulomas, or basilar menin- optic nerve is most frequently abnormal,
movement disorders,
gitis. The most common cranial neuro- displaying enhancement and thickening.
peripheral neuropathy,
pathy is unilateral or bilateral facial Other nonspecific findings include hydro- and myopathies.
palsy. Acute and chronic meningitis cephalus, cavernous sinus involvement,
occurs in up to 26% of patients with lacrimal gland enlargement, osseous h The diagnosis of
systemic sarcoidosis is
neurosarcoidosis. Case 3-3 demon- lesions, intramedullary spinal lesions,
typically made through
strates a classic case of neurosarcoidosis. and spinal nerve root enhancement.68 biopsy of lymph nodes,
Diagnosis. Diagnosis of neurosar- Treatment. Corticosteroids are the lung, liver, skin, or
coidosis is difficult and often requires a mainstay of treatment for sarcoidosis, conjunctiva with
combination of medical history with with recommended doses of 40 mg/d to histologic demonstration
neuroimaging, serologic and CSF data, 60 mg/d followed by a slow taper. Pa- of noncaseating
and tissue biopsy. The diagnosis of tients with severe symptoms may be granulomas consisting
systemic sarcoidosis is typically made treated with high-dose methylpredniso- of epithelioid cells
through biopsy of lymph nodes, lung, lone (1 g IV for 3 to 5 days) followed by and macrophages.
liver, skin, or conjunctiva with histologic oral prednisone. Steroid-sparing immu-
demonstration of noncaseating granulo- nosuppressive medications, including my-
mas consisting of epithelioid cells and cophenolate, azathioprine, methotrexate,
macrophages. Brain biopsy may be use- cyclophosphamide, infliximab, and hydro-
ful when meningeal or cerebral abnor- xychloroquine, have been used with vary-
malities are easily accessible but is not ing degrees of success; these medications
routine. Serum ACE levels are elevated in are often used for long-term suppression.
50% of patients with neurosarcoidosis.67
CSF analysis typically reveals a lym- Systemic Lupus Erythematosus
phocytic pleocytosis (10 cells/2L to 200 Adult and pediatric systemic lupus eryth-
cells/2L) with significantly elevated pro- ematosus (SLE) commonly may affect any
tein concentration (2 g/L or greater) and part of the nervous system and has been
low glucose concentration. Opening pres- termed neuropsychiatric lupus. The
sure is often elevated. CSF tests for American College of Rheumatology es-
oligoclonal bands may be positive, most tablished case definitions for 19 central
often in the setting of an elevated and peripheral nervous system syndromes
protein concentration. Additional useful in neuropsychiatric SLE, including cog-
CSF markers include CSF lysosome, "2- nitive and psychiatric disorders, demy-
microglobulin, and T-cell lymphocyte elination, seizures, transverse myelitis,
ratios. CSF ACE levels are nonspecific but headache, movement disorders, vasculi-
can be elevated with neurosarcoidosis. tis, aseptic meningitis, and peripheral
MRI with gadolinium reveals lepto- neuropathy. The pathogenesis of CNS
meningeal enhancement in up to 40% of manifestations is multifactorial and may
patients with neurosarcoidosis, with the involve autoantibodies against the ner-
basilar meninges most often involved. vous system, microangiopathy, intrathecal
KEY POINTS
h Infectious meningitis production of proinflammatory cyto- antibody (82%), antiYdouble-stranded
should be considered in kines, and premature atherosclerosis. DNA (79%), antiribosomal (61%), anticar-
patients with systemic Antiphospholipid antibodies are the diolipin IgG (15%), antiY" 2 glycoprotein
lupus erythematosus most frequently observed autoanti- IgG (65%), and anti-NMDA receptor
who have been body in SLE and have been associated (35%). These antibodies did not change
treated with with stroke and cognitive decline. Dis- with resolution of symptoms. The fol-
immunosuppressive ruption of the integrity of the blood- lowing CSF autoantibodies were de-
therapy and present brain barrier is essential for SLE-related tected: antinuclear antibody (57%),
with fever, altered neuropathology to develop. Abnormal antiYdouble-stranded DNA (77%), anti-
mental status, endothelial cell interactions may be ribosomal (46%), anticardiolipin IgG
meningeal signs, and
involved in allowing proteins and lym- (11%), antiY" 2 glycoprotein I (0%), and
nausea or vomiting.
phocytes to gain access into the CNS.69 antiYNMDA receptor antibody (41%).
h CSF examination is Clinical presentation. Meningitis asso- Similar to serum values, CSF autoanti-
crucial for excluding the ciated with SLE is typically aseptic,70 but bodies did not resolve with improve-
diagnosis of infectious
because many patients are treated with ment of symptoms. The role of serum
meningitis prior to
chronic immunosuppressive therapy, and CSF autoantibody detection in
initiating
immunosuppressive
they are at risk for developing infectious patients with lupus is not clear.72 Aseptic
therapy for meningitis. Infectious meningitis should meningitis associated with SLE is typi-
neurosarcoidosis. be considered in patients with SLE who cally self-limited.
have been treated with immunosup-
pressive therapy and present with fever, Behçet Disease
altered mental status, meningeal signs, Behçet disease, a multisystem disease
and nausea or vomiting. Compared to characterized by recurrent oral aphthous
SLE-associated aseptic meningitis, pa- ulcers, genital ulcers, and uveitis, typi-
tients with infectious meningitis are cally presents between 20 and 40 years
typically older, develop mental status of age. Men are affected more com-
changes, and have plasma leukocytosis monly than women. This disease can af-
with neutrophilia, as well as a marked fect almost any organ, including the eye;
CSF pleocytosis and hypoglycemia. Non- skin; major vessels; and cardiac, pulmo-
steroidal anti-inflammatory medications nary, musculoskeletal, and gastrointestinal
have been implicated as a causative factor systems. Neurologic involvement occurs
in aseptic meningitis associated with SLE.71 in 5% to 10% of patients with Behçet
Diagnosis and treatment. No single disease and can be parenchymal or non-
diagnostic test that is sensitive and specific parenchymal. Parenchymal disease, or
for SLE-related neurologic disease is avail- meningoencephalitis, occurs in 70% of
able. Assessment should include neu- patients with neuroYBehçet disease and
rologic and rheumatologic evaluations, typically involves a massive inflammatory
serologic testing of immune parameters, infiltration of polymorphonuclear lym-
and neuroimaging. CSF examination is phocytes, eosinophils, lymphocytes, and
crucial for excluding the diagnosis of in- macrophages into the brainstem, dien-
fectious meningitis prior to initiating cephalon, and small vessels; fibrinoid
immunosuppressive therapy. A recent necrosis is typically absent. Nonparen-
study evaluated the presence of autoan- chymal disease typically manifests as
tibodies in the serum and CSF in patients cerebral venous thrombosis. Other rare
with lupus and neurologic symptoms. presentations include spinal cord lesions,
Antibodies were checked again at 6 months arteritis, optic neuritis, aseptic meningitis,
when clinical manifestations of disease and peripheral neuropathies.
had resolved. The following serum auto- NeuroYBehçet disease typically pres-
antibodies were detected: antinuclear ents subacutely with a constellation of

KEY POINTS
fever, malaise, orogenital ulcerations, who have progression of symptoms h Diagnosis involves
skin lesions, or uveitis. Over weeks, or cannot tolerate azathioprine, myco- fulfilling the diagnostic
patients develop a progressive head- phenolate mofetil is an alternative criteria for systemic
ache, followed by a variety of potential treatment.74 Behçet disease plus
accompanying symptoms, including neurologic symptoms
altered mental status, dysarthria, oph- Primary Angiitis of the CNS not explained by other
thalmoplegia, ataxia, and hemiparesis. Primary angiitis of the CNS (PACNS) is conditions or infections.
The course of illness may be notable for characterized by inflammation and de- h CSF analysis is
recurrent attacks, secondary progressive struction of cerebral vessels without abnormal in over
disease, or a primary progressive de- systemic involvement. PACNS consists of 90% of patients and
cline. Diagnosis involves fulfilling the several subtypes grouped into typical usually demonstrates a
diagnostic criteria for systemic Behçet and atypical forms. Typical PACNS is the modest lymphocytic
disease plus neurologic symptoms not granulomatous type. Atypical forms in- pleocytosis (less than
explained by other conditions or infec- clude lymphocytic, angiographically de- 20 cells/2L), elevated
protein concentration
tions. Typical radiographic and CSF fined, mass lesions, and amyloid "Yrelated
(median less than
analysis are also useful. Early in the cerebral angiitis.
120 mg/dL), and normal
disease course, CSF has a polymorpho- Granulomatous angiitis, the classic glucose concentration.
nuclear pleocytosis followed by a lym- form of PACNS, is characterized by
phocytic predominance. The cell count chronic meningitis with an insidious
ranges from 0 cells/2L to 400 cells/2L with onset of symptoms. Patients may pres-
elevated protein concentration (greater t- ent with a history of years of headache,
han 1 g/dL) and normal glucose concen- encephalopathy, seizures, cognitive and
tration. MRI of the brain typically behavioral changes, ataxia, recurrent
demonstrates a large asymmetric lesion TIAs, or focal neurologic deficits. Symp-
involving the midbrain, pons, thalamus, toms of chronic meningitis can precede
or basal ganglia. These lesions are gen- diagnosis by several years. Granuloma-
erally hyperintense on T2-weighted im- tous angiitis of the CNS is diagnosed by
ages and hypointense on T1-weighted pathologic findings of small and medium
images. Gadolinium enhancement leptomeningeal and cortical artery infil-
and small hemorrhages may be pres- tration of giant cells, which can be seg-
ent. Chronically, MRI often demon- mental with necrotizing or lymphocytic
strates widespread subcortical white involvement.75
matter lesions with brainstem atrophy.73 Diagnostic criteria proposed in 1988
No standard treatment is available for includes the presence of acquired and
neuroYBehçet disease. Most commonly, unexplained neurologic or psychiatric
glucocorticoids are administered to treat deficits, presence of angiographic or his-
acute exacerbations, with an initial pulse topathologic evidence of angiitis in the
of high-dose IV steroids followed by grad- CNS, and no evidence of systemic or
ual taper. Many medications used to treat other disorders that may mimic the dis-
systemic Behçet disease, including aza- ease. Primary angiitis of the CNS peaks
thioprine, colchicine, cyclosporine, cyclo- in the fifth and sixth decades of life and is
phosphamide, methotrexate, interferon more common in men. The combina-
alpha, and antiYtumor necrosis factor tion of serologic studies, CSF analysis,
agents, have been used as adjunctive angiography, MRI, and brain biopsy are
treatment of neuroYBehçet disease. Some essential for diagnosing PACNS. Biopsy
experts suggest starting azathioprine is the gold standard for diagnosis but has
with steroids at the first attack. Low-dose low sensitivity. More importantly, biopsy
steroids should be continued for 5 weeks is useful in identifying lesions that may
until azathioprine is active. In patients mimic PACNS, such as infection or
KEY POINTS
h Diagnostic criteria for malignancy, which are found in up to neurologic examinations and MRI
primary angiitis of the 40% of patients. Serum erythrocyte scans.76
CNS proposed in 1988 sedimentation rate and C-reactive pro-
include the presence tein are typically normal in PACNS and NEOPLASTIC
of acquired and elevated in conditions that mimic Neoplastic involvement of the CNS
unexplained neurologic PACNS. CSF analysis is abnormal in over should be considered in the differential
or psychiatric deficits, 90% of patients and usually demon- diagnosis for patients presenting with
presence of strates a modest lymphocytic pleocyto- signs and symptoms of chronic menin-
angiographic or sis (less than 20 cells/2L), elevated gitis. Leptomeningeal carcinomatosis
histopathologic protein concentration (median less or carcinomatous meningitis is defined
evidence of angiitis
than 120 mg/dL), and normal glucose as malignant seeding or infiltration of
in the CNS, and
concentration. CSF examination is cru- the leptomeninges. Leptomeningeal
no evidence of systemic
or other disorders that
cial for excluding infectious and neo- carcinomatosis is most commonly asso-
may mimic the disease. plastic mimics of PACNS. Cranial MRI ciated with hematologic malignancies, but
may reveal infarction in up to half of solid tumors and primary brain tumors
h Neoplastic involvement
patients, and nonspecific subcortical infiltrate the meninges in up to 5% of pa-
of the CNS should
be considered in the
white matter, deep white matter, and tients. Patients classically present with signs
differential diagnosis for cortical T2-weighted hyperintensities are and symptoms of multifocal involvement
patients presenting with often present. Mass lesions are present of the neuraxis due to involvement of the
signs and symptoms of in 5% of patients with PACNS and are p- cerebral hemispheres, brainstem, cranial
chronic meningitis. otential sites for biopsy to confirm the nerves, spinal cord, or nerve roots. The
h CSF cytology should diagnosis of PACNS and exclude other most common presenting symptoms in-
be sent for all patients potential etiologies. Gadolinium enhance- clude headache, encephalopathy, nuchal
with CSF pleocytosis of ment of the leptomeninges occurs in 8% rigidity, diplopia, weakness, and radic-
unknown etiology to of patients. Cerebral angiography is com- ular pain. Cranial neuropathies may
evaluate for monly used to aid in the diagnosis of include trigeminal neuropathy, facial
neoplastic cells. PACNS and classically demonstrates al- weakness, and hearing loss.77
ternating areas of dilation and stenosis Diagnosis of leptomeningeal carcino-
that can be smooth or irregular. These matosis is made by clinical examination,
findings are nonspecific for PACNS and can CSF analysis, and gadolinium-enhanced
be seen with other disorders, including MRI. Lumbar puncture typically reveals
infection, radiation, atherosclerosis, and elevated opening pressure, leukocytosis,
vasospasm. Sensitivity of angiography and elevated protein and low glucose
varies from 40% to 90%. Although the concentrations. CSF cytology should be
diagnosis of PACNS can be difficult to sent for all patients with CSF pleocytosis
confirm, patients with normal CSF, an- of unknown etiology to evaluate for neo-
giography, and MRI are extremely un- plastic cells. The sensitivity of a single
likely to have PACNS.76 large volume CSF sample is 38% to 66%;
Treatment of PACNS includes immu- if three large volume CSF samples are
nosuppression with a combination of gluco- performed, the sensitivity increases to
corticosteroids and cyclophosphamide. 90%.78 Gadolinium-enhanced MRI is the
High-dose oral prednisone (1 mg/kg/d) imaging modality of choice and typically
or IV pulse methylprednisolone for 3 displays contrast enhancement of the
days, followed by oral prednisone, is meninges, cortical convexities, basilar
recommended. Cyclophosphamide, cistern, and cauda equina.79 Meningeal
azathioprine, or mycophenolate mofe- biopsy of contrast-enhancing lesions
til are most commonly used for long- remains the gold standard for de-
term immunosuppression. Disease finitive diagnosis of leptomeningeal
activity can be monitored with serial carcinomatosis.77

Early diagnosis and treatment of lep- Treatment Groups. Clin Infect Dis 2000;30(1):
47Y54.
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Review Article

Chronic and Subacute

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TABLE 3-1 Continued

j indicates an increase from normal values.

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Organism Pathogenesis CNS Features Neuroimaging Systemic Features

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Cause Treatment Phase (Duration) Corresponding Medication(s) and Dosage(s)

Consolidation (8 to 10 weeks) Fluconazole 400 mg/d orally

Consolidation/maintenance Fluconazole 800 mg/d orally

Consolidation (9 to 12 months) Fluconazole 800 mg/d orally

Maintenance Oral maintenance 200 mg every 12 hours

Pyrazinamide 20 mg/kg to 35 mg/kg orally

granulomas. Two of the most dangerous Case 3-1 demonstrates a common

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TABLE 3-4 Noninfectious Causes of Meningitis

Causes and Other Special Laboratory

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FIGURE 3-3 Brain MRI showing neurosarcoidosis. A, Sagittal T2-weighted

displayed large areas of T2-weighted hyperintensity with patchy gadolinium

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Continued from page 1309

undetectable testosterone, low luteinizing hormone, low follicle-stimulating

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