Download Chronic and Subacute Meningitis

Review Article
Address correspondence to
Dr Joseph R. Zunt, Harborview
Medical Center, 325 Ninth Ave,
Room 3EH70, Box 359775,
Seattle, WA 98104,
[email protected].
Relationship Disclosure:
Dr Zunt receives funding from
the NIH for research and
training programs. Dr Baldwin
reports no disclosure.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Zunt and Baldwin report
no disclosures.
* 2012, American Academy
of Neurology.
Chronic and Subacute
Meningitis
Joseph R. Zunt, MD, MPH; Kelly J. Baldwin, MD
ABSTRACT
Purpose of Review: This article describes the background, clinical presentation,
diagnosis, and treatment of selected etiologies of subacute and chronic meningitis. Key
diagnostic considerations when evaluating a patient presenting with chronic inflammation of the CNS are discussed, and several specific infectious, neoplastic, and autoimmune 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 evolving during weeks to months without resolution of CSF abnormalities. Determining the
time course of meningitis is important for creating a differential diagnosis. Most organisms 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
Infectious causes of subacute and
chronic meningitis that are discussed
in this article include Cryptococcus
species, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Aspergillus fumigatus,
Mycobacterium tuberculosis, and
syphilis.
Tables 3-1 and 3-2 summarize the
presentation, radiographic findings, and
CSF findings for the most common
causes of infectious meningitis.
Table 3-3 lists the recommended
treatments for the most common infectious etiologies of chronic meningitis.
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Cryptococcus
Cryptococcal meningitis is caused by the
encapsulated yeast organism Cryptococcus neoformans. With a worldwide
distribution, C. neoformans is primarily
found in contaminated soil, avian excrement, and the bark of several tree
species. Infection usually occurs by inhalation of the organism, followed by a
respiratory infection and dissemination of the infection.1 This organism
emerged as an important opportunistic
pathogen in the 1980s with the advent of
HIV infection. Cryptococcal meningitis
is most common in people with impaired
cell-mediated immunity, especially HIV
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Infectious Meningitis: CSF Parameters and Diagnosis
TABLE 3-1
Organism
White
Blood
Opening Cell
Pressure Count
CSF
Diagnostic
Differential Glucose Protein Testing
Microscopic
Appearance
of Organism
Cryptococcus
j
Mononuclear ,
Encapsulated
fungi
j@
Y
j
India ink
staining
Yeastlike
Cryptococcal
cells with budding
capsular
polysaccharide daughter cells
antigen
Capsule visualized
Fungal culture by India ink
(halo effect)
Coccidioidomycosis j@
Y
j
Early
neutrophil
,
j
Lymphocytic
Eosinophilic
(70%)
Histoplasmosis
@
Y
j
Complementfixation
antibody
testing
Fungal culture
Mononuclear ,
j
Yeast form
endosporulating
spherules
Branched septate
hyphae with
alternating
arthroconidia
Hyphae large
Histoplasma
polysaccharide macroconidia
and smaller
antigen
infectious
Fungal culture
microconidia
Yeast forms at
temperatures
G35-C (95-F)
Hyphal elements
possible
Blastomycosis
j
j
Early
neutrophil
,
j
Fungal culture
Lymphocytic
Mycelium at
room temperature
Yeast phase at
37-C (98.6-F)
Conidia, yeast
cells with
multinucleate
broad budding
Aspergillosis
@
Y
j
Early
neutrophil
Lymphocytic
,
j
Septate hyphae
branched at 45Antigen
angles with
galactomannan
conidiophores
Antibody
Hyphae develop
Fungal culture terminal buds
forming small conidia
CSF PCR
Continued on next page
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Chronic and Subacute Meningitis
TABLE 3-1 Continued
Organism
Opening
Pressure
White
Blood
Cell
Count
CSF
Diagnostic
Differential Glucose Protein Testing
Microscopic
Appearance
of Organism
Mycobacterial
j@
Y
j
Mononuclear ,
Acid-fast
bacillus
j
Acid-fast bacillus
smear
Culture on
LowensteinJensen medium
PCR
Syphilis
@
Y
j@
Y
Lymphocytic
@
Y,
j
Thin, motile
Venereal Disease
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
h Cryptococcal meningitis
is most common in
people with impaired
cell-mediated immunity,
especially HIV
infection, hematologic
malignancies, solid-organ
transplantation, and in
patients on chronic
corticosteroids or other
immunosuppressive
therapy, but also occurs
in immunocompetent
individuals.
h In immunocompromised
patients, cryptococcal
meningitis is the most
common systemic
fungal infection and a
frequent cause of
fungal CNS infections.
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infection; people with hematologic
malignancies; solid-organ transplant
recipients; and patients on chronic corticosteroids or other immunosuppressive therapy; but it also occurs in
immunocompetent individuals.2
Historically, the genus Cryptococcus
was divided into four serotypes (A, B, C,
D) using capsular assays, but recently
these have been reclassified. Serotype
A is now classified as C. neoformans
grubii; this organism has a worldwide
distribution and is the most common
cause of cryptococcal meningitis in immunocompromised patients. Serotypes
B and C are classified as C. neoformans
gattii, and this organism causes meningitis in individuals with impaired cellmediated immunity and those who are
immunocompetent.3 C. neoformans gattii
was previously thought to be rare and
limited to subtropical climates until a large
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outbreak occurred in British Columbia
in 1999. Most of these infections occurred in patients with normal immune
systems.4 Serotype D is classified as C.
neoformans neoformans, is predominantly found in Western Europe, and
typically affects immunocompromised
patients.
In immunocompromised patients,
cryptococcal meningitis is the most
common systemic fungal infection and
a frequent etiology of CNS infection,
with a prevalence varying from 10% in
the United States to as high as 30% in
sub-Saharan Africa.5 Although the incidence of cryptococcal meningitis has
decreased since the introduction of combination antiretroviral therapy, it continues to be a common cause of death in
many resource-limited countries. In
several areas of Africa, cryptococcal
meningitis is the most common cause
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Fungal Meningitis
TABLE 3-2
Organism
Pathogenesis
CNS Features
Cryptococcus
neoformans
Inhalation, fungemia
Basilar meningitis,
Hydrocephalus,
granuloma, vasculitis cerebral edema,
leptomeningeal
enhancement, and
cryptococcomas
Coccidioides
immitis
Airborne, fungemia
Chronic meningitis,
cerebritis, arteritis,
abscess, granuloma
Hydrocephalus,
meningeal
enhancement,
nodular
enhancement,
basilar meningitis,
cerebral infarction
Histoplasma
capsulatum
Airborne, fungemia
Meningitis,
granuloma
Normal, granuloma,
meningeal
enhancement
Acute or chronic
pulmonary,
dissemination with
multiorgan involvement
Blastomyces
dermatitidis
Airborne, fungemia
Meningitis
Single or multiple
abscesses, granuloma,
meningeal
enhancement,
epidural extensions,
and overlying
osteomyelitis
Pulmonary, cutaneous
Aspergillus
fumigatus
Fungemia, direct
inoculation by trauma
or surgery, extension
from paranasal,
angioinvasive
Meningitis, vasculitis,
mycotic aneurysm,
granuloma, abscess,
spinal cord
involvement
Multiple abscesses,
meningeal
enhancement,
infarction, hemorrhage,
sinusitis with extension
Pulmonary
of meningitis, with mortality rates as high
as 100% in a study of 230 adults in
Zambia.6
Clinical presentation. The clinical
manifestations of infection with C. neoformans depend largely on the host immune status. Severity of infection varies
from asymptomatic incidental pulmonary
nodules to widely disseminated disease.
Patients with HIV and CD4+ cell counts
of less than 50 cells/2L are especially
vulnerable to disseminated infection
and meningitis.7 Immunosuppressed
patients with cryptococcal meningitis
frequently present with indolent nonspecific symptoms and in some cases
with isolated neurologic manifestations.
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Neuroimaging
Systemic Features
Pulmonary, multiorgan
involvement
Patients with normal cellular immunity
generally manifest more typical signs
and symptoms of meningitis. In general, over 75% of patients present with
headache and fever, which typically develop insidiously over 2 to 4 weeks.8
Nausea, vomiting, and altered mental
status occur in about half of 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 immunocompetent
patients.9 Seizures and focal neurologic
deficits occur in 10% of patients and
are generally caused by space-occupying
lesions such as cryptococcomas or
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Chronic and Subacute Meningitis
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
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
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
Intensive four-medication
regimen (2 months)
Isoniazid 300 mg/d orally or IM
Histoplasmosis
Aspergillosis
Mycobacterial
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
two-medication regimen
(10 months)
Isoniazid 300 mg/d orally or IM
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
complications of cryptococcal meningitis are elevated intracranial pressure and
hydrocephalus. Over half of immunocompromised patients will develop intracranial hypertension, and it is even more
common in immunocompetent hosts.10
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Case 3-1 demonstrates a common
presentation and clinical course in a
patient with cryptococcal meningitis.
Diagnosis. The diagnosis of cryptococcal meningitis should be considered
in patients presenting with a subacute
presentation of headache and fever,
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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
continued to have persistently elevated intracranial
FIGURE 3-1 Brain MRI showing cryptococcal
meningitis. Coronal T1
pressure of 40 cm H2O. Several weeks of serial lumbar
postcontrast image demonstrates
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
headache, diplopia, and papilledema persisted. A
leptomeningeal enhancement of the frontal lobe.
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
or immunosuppression. CT and MRI
are nonspecific for the diagnosis of cryptococcal meningitis but may reveal
hydrocephalus, cerebral edema, leptomeningeal enhancement, or cryptococContinuum Lifelong Learning Neurol 2012;18(6):1290–1318
comas. Lumbar puncture, the diagnostic
procedure of choice, is often notable for
a mild mononuclear pleocytosis as well
as increased protein and low glucose
concentrations. Although India ink staining of centrifuged CSF is cost-efficient,
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Chronic and Subacute Meningitis
KEY POINT
h The CSF cryptococcal
capsular polysaccharide
antigen assay is both
sensitive and specific for
cryptococcal meningitis
and also provides a
quantitative titer that is
useful for prognostication
but has limited value
for measuring response
to therapy.
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rapid, and 75% sensitive, the decreasing
use of microscopic evaluation of CSF in
high-income countries has led to a reliance on antigen-based assays.8 The
CSF cryptococcal capsular polysaccharide
antigen (CRAg) assay is both sensitive
and specific for cryptococcal meningitis
and also provides a quantitative titer that
is useful for prognostication but has
limited value for measuring response to
therapy.11 Fungal culture for the organism is 90% sensitive and can be useful for both diagnosing infection and
speciation.
Laboratory results, physical examination, and neuroimaging findings may aid
in determining prognosis of cryptococcal
meningitis. Poor prognostic factors include low CSF glucose concentration,
high CSF cryptococcal antigen titer
(greater than 1:1024), high CSF lactate
level, altered level of consciousness,
hydrocephalus, and elevated intracranial pressure.12
Treatment. A combination of antifungal medication and aggressive treatment
of intracranial hypertension is integral to
successful treatment of patients with cryptococcal meningitis. Treatment protocols
involve a three-step approach: induction,
consolidation, and maintenance therapy. Induction includes 2 weeks of AmB
(0.7 mg/kg/d to 1 mg / kg/ d) plus flucytosine (100 mg/kg/d). Consolidation therapy is 8 weeks of fluconazole (400 mg/d),
followed by maintenance therapy with
fluconazole (200 mg/d) for life (see later
discussion). This regimen was validated
in a large double-blind randomized trial
that demonstrated significant benefit
of combined induction therapy over
AmB alone.11 A study comparing AmB
0.7 mg/kg daily for 21 days with liposomal AmB 4 mg/kg daily for 21 days
detected no difference in clinical response, although major adverse events
were less common in patients receiving liposomal AmB. This study suggests
that liposomal AmB is better tolerated
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and equally effective treatment for cryptococcal meningitis.13 Treatment efficacy
is best monitored by clinical response to
therapy, as CSF CRAg titer varies significantly; however, an increasing titer has
been associated with ineffective treatment. Lifelong maintenance therapy with
fluconazole is no longer required after
successful immune restoration in patients
who are HIV-positive. Several prospective
trials suggest it is safe to discontinue maintenance therapy if the patient has an
undetectable HIV viral load and CD4+
cell count greater than 100 cells/2L.14
Elevated intracranial pressure can be
managed through a variety of treatments. To date, no trials support acetazolamide as an effective treatment of
elevated intracranial pressure in cryptococcal meningitis.15 Patients with elevated
intracranial pressure should undergo
daily lumbar punctures to reduce opening pressure until normal opening pressure is maintained consistently. For
patients requiring frequent lumbar
punctures, placement of a lumbar drain
or a ventriculostomy can serve as a temporary measure to control intracranial
pressure.16 A small case series supports
the use of ventriculoperitoneal shunting
for patients with intracranial hypertension and HIV-associated cryptococcal
meningitis who do not respond to serial
lumbar punctures or who require prolonged lumbar drainage.17 A review of
27 patients with cryptococcal meningitis with elevated intracranial pressure
reported good outcomes in 63% of patients who underwent ventriculoperitoneal shunting; 37% of patients had
bad outcomes, defined as death or
persistent vegetative state. Of note,
85% of patients with a good outcome
did not have altered level of consciousness at the time of shunt placement.
Poor outcomes were associated with a
Glasgow Coma Scale score of less than
8 or duration of altered level of consciousness longer than 48 hours.
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Coccidiomycosis
C. immitis is a fungus endemic to the
southwestern United States, northern
Mexico, and areas of South America.
Coccidioides species are found primarily in warm sandy soil and climates
characterized by hot summers, mild winters, and minimal rainfall. The mycelial
phase of Coccidioides species is able
to withstand extreme desert climates
and, after rainfalls, will multiply to form
arthroconidia. Infection in humans occurs when aerosolized arthroconidia
are inhaled. The organism then transforms into multinucleated spherules that
eventually release endospores. Once
inhaled, C. immitis usually results in a
self-limited respiratory infection, commonly known as valley fever. In susceptible populations, a pulmonary infection
can progress to severe disseminated
disease. Dissemination is more likely
to occur in patients of African or Asian
descent, pregnant women, and people
who are immunocompromised, especially from HIV infection or long-term
immunosuppressive therapy. Manifestations of disseminated disease include
cavitary pneumonia, soft tissue and bone
infection, and meningitis.18 Meningitis
is a devastating complication, occurring
in approximately one-third to one-half
of patients with disseminated disease.
Rarely, central nervous system involvement will present as the first sign of
infection with C. immitis. Patients with
disseminated C. immitis typically will
also suffer from pulmonary disease.
Clinical presentation. Meningitis due
to C. immitis classically involves the basilar meninges. The most common
symptom is headache, which is present
in over 75% of patients. Other presenting signs and symptoms include nausea
and vomiting (40%); altered mental status (39% to 73%); focal neurologic deficits, including ataxia, gait disturbance,
diplopia, or facial palsies (33% to 80%);
and nuchal rigidity (20%).19 CoccidioiContinuum Lifelong Learning Neurol 2012;18(6):1290–1318
domycosis in patients with HIV infection produces a unique reticulonodular
diffuse infiltrative pulmonary disease.
This pattern can resemble Pneumocystis jiroveci pneumonia, as do the accompanying constitutional symptoms
of dyspnea, fever, and night sweats. Coccidioidomycosis frequently disseminates in
patients with HIV infection, with common sites of dissemination including
the meninges, lymph nodes, and skin. Although patients who are HIV-positive can
present with unique symptoms, studies
suggest that most HIV-infected patients
present with symptoms similar to those
of immunocompetent patients.20
Hydrocephalus, cerebral infarction,
and vasculitis are potential complications of C. immitis meningitis. Communicating hydrocephalus is a well-known
complication of basilar meningitis, secondary to obstruction of CSF reabsorption, and may develop during the initial
or later stages of the infection. Hydrocephalus develops in about 20% to 50%
of patients with C. immitis meningitis
and is associated with a 12-fold increased
risk of mortality.21 Cerebral infarction
and venous and dural thrombosis have
been reported during initial and later
stages of infection. Small and medium
blood vessels are typically affected. Perivascular inflammation is typically associated with infarctions of the basal ganglia,
thalamus, and cerebral white matter.22
Diagnosis. Coccidioidomycosis can
be diagnosed using serologic testing, histopathology, or culture. Identification of
C. immitis spherules in tissue, sputum,
bronchoalveolar lavage (BAL) fluid, or
other body fluid, or a positive culture
from any location in the body, is diagnostic of coccidioidal infection. Although
definitive diagnosis of C. immitis meningitis requires identification or culture
of the organism from the CSF, presumptive diagnosis is often sufficient to initiate
treatment. CSF is typically abnormal, with
a lymphocytic pleocytosis (20 WBCs/6L
KEY POINTS
h Coccidioides immitis is a
fungus endemic to the
southwestern United
States, northern Mexico,
and areas of South
America.
h Disseminated
coccidioidomycosis is
more likely to occur in
patients of African or
Asian descent, pregnant
women, and people
who are
immunocompromised,
especially from HIV
infection or long-term
immunosuppressive
therapy. Meningitis
is a devastating
complication, occurring
in approximately
one-third to one-half
of patients with
disseminated disease.
h Meningitis due to C.
immitis classically
involves the basilar
meninges. The most
common symptom is
headache, which is
present in over 75% of
patients.
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Chronic and Subacute Meningitis
KEY POINT
h Blastomyces
dermatitidis and
Histoplasma capsulatum
are dimorphic fungi
endemic to the
Mississippi and Ohio
river valleys, with
autochthonous
infection reported less
frequently in Africa,
Central and South
America, and the
Middle East.
1298
to 500 WBCs/6L), early neutrophil predominance, and low glucose concentration. Interestingly, this pathogen
may cause a CSF eosinophilia in up to
70% of patients with meningitis, a finding that is relatively uncommon with
other fungal pathogens.23 Isolation of
the organism from CSF culture occurs
in only about 15% of cases. Identification of spherules via CSF using cytopathologic Papanicolaou stain can confirm
the infection.24 Rarely, CSF examination
may reveal hyphal forms of C. immitis.
Detection of antibodies to C. immitis in
the CSF using the complement-fixation
antibody assay is the most sensitive test
for confirming meningeal infection. Repeated CSF sampling is sometimes needed
to confirm the diagnosis, as antibody
test results can be negative early during
the course of infection (71% to 94%
sensitive). Enzyme immunoassay for
IgM and IgG and latex agglutination
tests are less sensitive in CSF samples.22
Although PCR assays have been used
to detect C. immitis infection, they are
not routinely available.
Neuroimaging with MRI is superior to
CT for detecting abnormalities, which
are present in up to 75% of patients with
C. immitis meningitis. The most common radiographic abnormalities include
hydrocephalus, basilar meningitis, and
cerebral infarction. C. immitis meningitis can produce diffuse meningeal
enhancement, focal or nodular enhancement, parenchymal or parameningeal
abscesses, and spinal arachnoiditis.25
Patients with abnormal MRI scans have
a mortality rate of 20% to 30%, compared with 8% in patients with normal
imaging studies.21 Patients with hydrocephalus, with or without cerebral infarction, have the highest mortality rates.
Patients with normal neuroimaging have
significantly better prognoses.
Treatment. Oral fluconazole is the
gold standard of treatment for patients
with C. immitis meningitis. Practice
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guidelines recommend high-dose induction therapy with oral fluconazole 400
mg/d to 800 mg/d, followed by 200 mg/d
to 400 mg/d indefinitely.26 Approximately
66% to 80% of patients treated with oral
azoles alone achieved initial clinical improvement or remission of meningitis.
However, up to 75% of patients may relapse; therefore, lifelong prophylaxis with
fluconazole 400 mg/d is recommended.26
Without treatment, the outcome of patients with C. immitis meningitis is poor.
In one study, 90% of patients died within 1 year, and 100% died within 2 years.
Treatment of C. immitis meningitis
with IV AmB alone is not effective. Intrathecal amphotericin, via lumbar administration, intracisternal injection, or
Ommaya reservoir administration, in
combination with IV AmB, was the
treatment for C. immitis meningitis
prior to the advent of azole therapy,
particularly fluconazole, but is no longer
the initial treatment of choice.27 For
pregnant patients and those intolerant
of azole treatment, intrathecal AmB is
an option. Patients for whom azole therapy fails, who have complicated infections, or who worsen during initial
therapy may benefit from combined
use of intrathecal amphotericin with
oral azole therapy.22
Blastomycosis and
Histoplasmosis
B. dermatitidis and H. capsulatum
are dimorphic fungi endemic to the
Mississippi and Ohio river valleys, with
autochthonous infection reported less
frequently in Africa, Central and South
America, and the Middle East. Although
isolated cases of infection have been
reported outside this geographic area,
most patients reside within these areas.
H. capsulatum and Blastomycoses species are ubiquitous environmental organisms, existing in the mycelial phase and
then converting to the yeast phase at
body temperature. Both organisms
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produce a large spectrum of disease,
ranging from subclinical infection to
disseminated disease.
Blastomycosis. B. dermatitidis, a
thick-walled yeast with broad-based
budding daughter cells, is endemic
to the Great Lakes and Mississippi
and Ohio river valleys. Like histoplasmosis, infection with blastomycosis is
acquired via inhalation of spores into
the lung and can manifest as pulmonary or extrapulmonary disease. Chest
radiographs commonly demonstrate
nodular or lobar infiltrates and cavitations. If the organism evades nonspecific
host defense mechanisms in the lungs, it
will convert into the yeast phase and
multiply. The organism then spreads
hematogenously to other organs. Inflammatory pyogranulomatous reactions occur at the initial pulmonary site
and at foci of infection. Cutaneous involvement is seen in 60% of patients
with blastomycosis, manifesting as verrucous or fungating lesions with irregular borders. Other sites less frequently
involved include bones, joints, genitourinary system, and the CNS.28
Clinical presentation. CNS infection
with blastomycosis occurs in less than
10% of people with disseminated disease and manifests as solitary or multiple
abscesses and acute or chronic meningitis. Unlike other fungal CNS infections,
blastomycosis is more likely to present
with focal neurologic deficits, seizures,
and altered mental status, whereas symptoms of fever, headache, and meningismus
are less common. Although intracranial
infection results most frequently from
hematogenous seeding of the brain parenchyma from the lungs, epidural extensions from overlying vertebral or
skull osteomyelitis have been described.29
Diagnosis. Diagnosis of CNS blastomycosis is often delayed because of
a lack of clinical suspicion and limited
tools for establishing a rapid diagnosis.
Direct visualization of the organism via
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318
microscopy has been the only method
of rapid diagnosis but has variable sensitivity. Lumbar puncture typically reveals elevated opening pressure, and
CSF examination is notable for elevated
protein concentration, low glucose concentration, and pleocytosis with neutrophilic predominance early in the disease
course followed by a lymphocytic predominance. The gold standard for diagnosis remains CSF culture, which is
positive in 64% of cases of blastomycosis.30 Growth of B. dermatitidis can
occur within 5 to 10 days,31 but may
take 2 to 4 weeks for definitive identification of the organism. More invasive
procedures, such as brain biopsy and
ventricular sampling of CSF, are more
likely to provide sufficient material for
definitive diagnosis and are often needed
for intracranial disease.31 Diagnostic
modalities such as skin testing and serologic assays for detection of antibodies
have limited sensitivity and specificity for
diagnosing blastomycosis.32 Commercially available enzyme immunoassay
for detection of B. dermatitidis antigen
in urine has a sensitivity of 93% and
specificity of 79% but is cross-reactive
with other dimorphic fungi, particularly
H. capsulatum.33
Treatment. All patients with CNS
blastomycosis should be treated with
AmB (0.7 mg/kg/d to 1.0 mg/kg/d) to a
cumulative dose of at least 2 g. Once control of the infection has been achieved,
an oral azole, such as fluconazole, should
be administered as consolidation therapy. Other azoles, such as voriconazole,
also have adequate CNS penetration
and may become primary therapies for
CNS disease. Relapse after treatment
with AmB occurs in less than 5% of immunocompetent patients. Patients with
immunodeficiency due to HIV or immunosuppressive therapy have high rates
of relapse and should be maintained on
long-term secondary prophylaxis with
fluconazole.34
KEY POINTS
h Cutaneous involvement
is seen in 60% of
patients with
blastomycosis,
manifesting as
verrucous or fungating
lesions with irregular
borders.
h Unlike other fungal
CNS infections,
blastomycosis is more
likely to present with
focal neurologic deficits,
seizures, and altered
mental status, whereas
symptoms of fever,
headache, and
meningismus are
less common.
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1299
Chronic and Subacute Meningitis
KEY POINT
h Histoplasma capsulatum
obtains nutrients from
bird excrement and bat
guano. Infection usually
requires a significant
inoculum of organisms
or repeated exposure.
People with
histoplasmosis often
report travel to or reside
in the Mississippi or
Ohio river valleys and
have a history of
cleaning chicken coops
or spelunking in caves
with large bat
populations.
1300
Histoplasmosis. H. capsulatum
obtains nutrients from bird excrement
and bat guano. Infection usually requires
a significant inoculum of organisms or
repeated exposure. People with histoplasmosis often report travel to or reside in
the Mississippi or Ohio river valleys and
have a history of cleaning chicken
coops or spelunking in caves with large
bat populations. Histoplasmosis may
produce an acute pulmonary infection
with fever, chills, and pulmonary opacities. Patients with impaired cellular
immunity, such as individuals who are
HIV infected, typically present with
chronic pulmonary symptoms with
progression to severe disseminated
disease. Infection disseminates hematogenously to distant sites, such as the
liver, spleen, and CNS. Bone marrow
involvement is common and often
manifests as thrombocytopenia, anemia, or leukopenia.35
Clinical presentation. Most patients
with pulmonary histoplasmosis are
asymptomatic and have resolution of
the infection without therapy. It is common for individuals in the Mississippi
and Ohio river valleys to have asymptomatic pulmonary nodules. The organism
can become dormant in macrophages
and later reactivate and cause disease.
Dissemination occurs during both primary infection and reactivation of latent
infection. CNS involvement occurs in less
than 20% of patients with disseminated
infection and most frequently affects patients with severely impaired cellular
immunity, such as people who are HIV
infected and those who have undergone solid-organ transplantation. Presenting symptoms typically include
headache and altered mental status;
although less common, patients may also
present with focal neurologic deficits, seizures, encephalitis, ischemic stroke,
and mass lesions.
Diagnosis. Similarly to that of blastomycosis, definitive laboratory diag-
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nosis of histoplasmosis is difficult; clinical
history of exposure remains crucial. CSF
frequently demonstrates a mononuclear
pleocytosis, increased protein concentration, and decreased glucose concentration. CSF culture is not sensitive for
diagnosing histoplasmosis. The use of
CSF and serum antigen titers and antibodies are useful, although as with blastomycosis, significant cross-reactivity
occurs with other dimorphic fungi. Because meningitis is typically a result of
disseminated infection, testing for the
organism in the blood or bone marrow
should also be considered.
Treatment. Treatment of CNS histoplasmosis is challenging. Despite treatment with AmB, 20% to 40% of patients
with meningitis die of the infection and
up to half of responders relapse after
therapy is discontinued. The optimal
treatment for H. capsulatum meningitis
is AmB (0.7 mg/kg/d to 1.0 mg/kg d) to
complete a total dose of 35 mg/kg during
a 3- to 4-month period. To reduce the
risk of relapse, fluconazole (800 mg/d)
should be continued for 9 to 12 months
after completion of AmB. Chronic fluconazole maintenance therapy (800 mg/d)
should be considered for patients who
relapse after completing a full course of
therapy. Itraconazole, although more active
against H. capsulatum than fluconazole,
does not cross the blood-brain barrier in
adequate amounts to treat CNS infection.
Intrathecal administration of amphotericin directly into the ventricles, cisterna
magna, or lumbar arachnoid space should
be reserved for severe infections that do
not respond to conventional therapy.36
Aspergillus
Aspergillus species are ubiquitous soil
inhabitants that grow and survive on organic debris. This organism sporulates
abundantly, releasing conidia into the
atmosphere in large quantities. The
conidia are small in diameter, making it
possible to reach smaller areas of the
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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
lung, including the alveoli. Environmental studies indicate that humans inhale
several hundred conidia per day,37 but
inhalation of organisms rarely results
in disease because the conidia are eliminated efficiently by host immune mechanisms. Alveolar macrophages constitute
the first line of host defense against
aerosolized conidia. Neutrophils are the
dominant host defense against the
invasive hyphal stage.38 Historically,
disease was limited to individuals with
repetitive exposure to pathogens, producing a mild condition known as farmer’s lung. Aspergillus was also known to
produce lung aspergillomas, characterized as an overgrowth of fungus in
preexisting cavitary lung lesions. More
recently, the incidence and severity of
Aspergillus infection have increased
because of a growing number of people
living with immunosuppression, leading
to disease known as invasive aspergillosis.39 Populations significantly at risk for
invasive aspergillosis include patients
undergoing treatment for hematologic
malignancies, recipients of allogeneic
hematopoietic stem cell transplant and
solid-organ transplant, people who are
HIV infected, and individuals with chronic
granulomatous disease.38 Deficits in host
defense mechanisms that increase susceptibility to invasive aspergillosis are
complex but can be broadly divided into
three groups: (1) neutropenia, (2) qualitative deficits in phagocyte function, and
(3) deficits in cell-mediated immunity.40
Clinical presentation. A. fumigatus
is responsible for approximately 90% of
human infections. Other members of
this genus that less commonly produce
human infection include A. flavus, A.
terreus, A. niger, and A. nidulans. Four
types of invasive aspergillosis have been
described: (1) acute or chronic pulmonary aspergillosis, (2) tracheobronchitis and obstructive bronchial disease,
(3) acute invasive rhinosinusitis, and
(4) disseminated infection involving the
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318
brain or other organs (ie, skin, kidneys,
heart, and eyes). CNS infection results
from hematogenous dissemination of
the organism or by direct extension from
rhinosinusitis. Cerebral aspergillosis
occurs in approximately 10% to 20% of
patients with invasive disease.39
CNS infection can present as a solitary
mass lesion, cavernous sinus thrombosis,
multiple intracranial abscesses, acute or
chronic basilar meningitis, vasculitis, or
myelitis. Pathologically, CNS aspergillosis
has a propensity for vascular invasion,
infarction, hemorrhage, and aneurysm
formation; as a result, the clinical presentation may be that of cerebral vasculitis,
ischemic or hemorrhagic infarction, or
subarachnoid hemorrhage. Granuloma
formation with necrosis is also commonly
observed. An isolated abscess may be
suspicious for neoplasm and, upon biopsy or extirpation, reveal a yellowish
fluid or fungal hyphae upon staining.41
Case 3-2 demonstrates a classic clinical presentation of disseminated CNS
aspergillosis in a heart transplant patient.
Diagnosis. Diagnosis of aspergillosis in immunocompromised patients remains difficult. As with many invasive
fungal CNS infections, diagnosis is often
achieved through examination of the
primary entry site of infection. Thus, in
patients with suspected CNS aspergillosis, it is important to examine the lungs
and sinuses for evidence of infection and
potential sites for obtaining biopsy or
culture material. BAL cultures are nearly
50% sensitive for detecting aspergillosis
in focal pulmonary lesions. Isolation of
an Aspergillus species from sputum or
BAL is highly predictive of invasive disease in neutropenic patients. Chest imaging can be used to support diagnosis.
During early invasive pulmonary aspergillosis, the most common finding on
chest CT is one or more nodules. The
‘‘halo sign,’’ a haziness surrounding a
nodule or infiltrate on chest CT, is a
characteristic feature of angioinvasive
KEY POINTS
h Populations significantly
at risk for invasive
aspergillosis include
patients undergoing
treatment for
hematologic malignancies,
allogeneic hematopoietic
stem cell transplant, and
solid-organ transplant,
as well as people who
are HIV infected, and
individuals with chronic
granulomatous disease.
h CNS aspergillosis has a
propensity for vascular
invasion, infarction,
hemorrhage, and
aneurysm formation;
as such, the clinical
presentation may be
that of cerebral vasculitis,
ischemic or hemorrhagic
infarction, or
subarachnoid
hemorrhage.
h In patients with
suspected CNS
aspergillosis, it is
important to examine
the lungs and sinuses
for evidence of infection
and potential sites for
obtaining biopsy or
culture material.
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1301
Chronic and Subacute Meningitis
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.
1302
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organisms and is highly suggestive of
invasive aspergillosis. Neuroimaging can
be helpful in the evaluation of CNS aspergillosis. MRI of the brain can demonstrate
a variety of lesions, including cerebral infarction, on diffusion-weighted imaging,
hemorrhagic lesions, solid-enhancing aspergillomas, or ring-enhancing abscesses.
Dural enhancement is usually seen in
lesions adjacent to infected paranasal
sinuses and indicates direct extension of
disease.42
In patients with Aspergillus sinusitis,
endoscopy may reveal sentinel eschars
along the nasal turbinates. Direct smear
of brushings or biopsies of these lesions
may reveal hyphae, and culture is often
positive. Involvement of the ethmoid sinuses carries a particularly high risk of
extension to the cavernous sinus. Ophthalmoplegia is often an early sign of cavernous sinus thrombosis that precedes
radiologic confirmation. Biopsy of nasal
tissue or brain biopsy of solitary lesions
can provide histopathologic evidence of
Aspergillus species infection and remains
critical to establishing a diagnosis of sinus
and intracranial disease.
Several valuable serum laboratory
markers can aid in the diagnosis of invasive Aspergillus. ELISA testing for
galactomannan and "-glucan, fungal cell
wall constituents, should be considered.
In 170 patients hospitalized in North
American cancer centers at high risk for
invasive mold infection, the serum galactomannan assay identified 25 of 31
patients with invasive aspergillosis (81%
sensitivity) and had a specificity of 89%. In
another study, the sensitivity was only
64.5% in cases of definite invasive aspergillosis.43 CSF galactomannan assay using
latex agglutination or ELISA is a useful
adjunct to serum testing. The sensitivity
of serial CSF testing is 70% to 90% and
specificity is 86% to 71%.44 In patients
with acute myeloid leukemia and myelodysplastic syndrome, the "-glucan assay
is highly sensitive for detecting early invaContinuum Lifelong Learning Neurol 2012;18(6):1290–1318
sive fungal infections, including candidiasis, fusariosis, trichosporonosis, and
aspergillosis.45
Several PCR assays can detect Aspergillus in blood and BAL fluid samples,
but experience with PCR to detect Aspergillus species in CSF samples is limited.
A recent study using nested PCR assay
detected Aspergillus DNA in samples from
six of six patients with CNS aspergillosis.
In all patients, samples obtained at the
initial manifestation of CNS aspergillosis
were positive by PCR. In patients with serial CSF sampling, follow-up samples obtained during antifungal treatment and
after clinical improvement tested negative, suggesting this assay may be useful
for determining response to therapy.46
Treatment. Unfortunately, CNS aspergillosis, especially in an immunocompromised patient, is difficult to treat and
has a high mortality rate. The newer antifungal agent voriconazole has reduced
mortality in an infection previously associated with almost universal mortality.
Clinical trials have demonstrated that
voriconazole is more effective than AmB
as initial therapy for invasive aspergillosis
and is associated with significantly improved survival (71% versus 58%, respectively).47 More recently, clinicians have
combined voriconazole with caspofungin (an echinocandin) as salvage therapy
in patients with invasive aspergillosis,
resulting in a favorable response in 37 of
83 patients (45%). Significant interest has
developed in combining an echinocandin
with either an AmB preparation or a moldactive azole. Marra and colleagues
reported improved survival rates in
patients treated with voriconazole plus
caspofungin compared to those treated
with voriconazole alone.48
Surgical debulking of CNS aspergillomas has produced long-term survival; in
combination with systemic antifungal chemotherapy, extirpation or aspiration of cerebral aspergillomas can be curative. In
patients with a solitary abscess, lobectomy
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1303
Chronic and Subacute Meningitis
KEY POINTS
h Tuberculous meningitis
is an aggressive form of
extrapulmonary disease
that is more common in
patients coinfected
with HIV.
h In patients with HIV
infection with low
CD4 cell counts,
manifestations of
tuberculous meningitis
are subtle and less
specific and typically
present late in the
course of the disease
after a prolonged
duration of
severe illness.
h The hallmark pathologic
feature of tuberculous
meningitis is the
presence of a thick
exudate most
prominent in the
basilar meninges.
1304
has been performed when noneloquent
areas of the brain are involved.49
Mycobacterium Tuberculosis
Tuberculous meningitis is caused by M.
tuberculosis, an aerobic gram-positive
acid-fast pleomorphic bacilli. M. tuberculosis is an intracellular pathogen that
survives within the phagosome of host
macrophages. Apoptosis of infected macrophages is an effective host mechanism
against tuberculous bacilli. Virulent strains
of M. tuberculosis have evolved several genetic mechanisms to evade
host immune mechanisms.50 Transmission occurs primarily by inhalation of
airborne droplet nuclei into the lungs.
M. tuberculosis multiplies in alveolar
macrophages, and within weeks the bacilli can hematogenously disseminate to
extrapulmonary sites. In distant organs,
including the meninges and adjacent
brain parenchyma, M. tuberculosis typically produces small granulomas. Granulomatous foci can remain dormant for
years, and the mechanism of reactivation is not well understood. Tuberculous
meningitis develops when a caseating
focus discharges its contents into the
subarachnoid space.51 Microglial cells
are the principal targets of M. tuberculosis. Tumor necrosis factor " released
from these cells plays a critical role in
containing the infection, granuloma formation, alteration of blood-brain barrier
permeability, and CSF leukocytosis.52
Tuberculous meningitis is an aggressive form of extrapulmonary disease that
is more common in patients coinfected
with HIV. Although the exact incidence
and prevalence of tuberculosis meningitis in many countries is not well defined,
India, China, Indonesia, Nigeria, and
South Africa have high rates of infection.
Compared to people without HIV infection, those with HIV infection more
commonly progress to have extrapulmonary infection, including meningitis.53
Other predisposing factors for develop-
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ing tuberculous meningitis include poverty, poor education, alcoholism, diabetes
mellitus, immunosuppressive medications,
and malignancy.
Clinical presentation. Tuberculous
meningitis is typically preceded by nonspecific symptoms of malaise, anorexia, fatigue,
weight loss, fever, myalgia, and headache.
In immunocompetent patients, headache, vomiting, meningeal signs, focal
deficits, vision loss, cranial nerve palsies,
and raised intracranial pressure are characteristic clinical features. Vision loss may
occur secondary to optic nerve involvement. Cerebral vessels may be affected by
adjacent meningeal inflammation, producing vasospasm, constriction, and
eventually thrombosis with cerebral
infarction. Infarcts are most often located
within the internal capsule, basal ganglia,
and thalamus.54 In a series of 101 adult
patients, presenting neurologic features
included headache (96.0%), fever
(91.1%), nuchal rigidity (91.1%), vomiting
(81.2%), meningismus (79.2%), and
abnormal mental state (72.3%).55
In patients with HIV infection with low
CD4 cell counts, manifestations of tuberculous meningitis are subtle and less
specific and typically present late in the
course of the disease after a prolonged
duration of severe illness. The most
common clinical manifestations include
fever and altered mental status.54,56
The hallmark pathologic feature of
tuberculous meningitis is the presence
of a thick exudate most prominent in
the basilar meninges. This exudate can
block the flow of CSF and result in
hydrocephalus. The entrapment of intracranial vessels within exudates often
produces cerebral infarction. Cranial
nervesVmost often cranial nerves VII
and VIIIVare also similarly affected, resulting in cranial nerve palsies. If the
basal inflammatory process affects the
brain parenchyma, it can result in encephalopathy. Cerebral tuberculomas are
also common.
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Diagnosis. Although CSF acid-fast bacillus smear and culture are crucial for
making a diagnosis of tuberculous meningitis, both have low sensitivity and presumptive treatment is often initiated when
the clinical suspicion is high. Characteristic CSF abnormalities include a mononuclear cell pleocytosis, low glucose
concentrations, and elevated protein
concentrations. Unfortunately, acid-fast
bacillus smear is positive in only 5% to
30% of patients. Conventional CSF culture
for M. tuberculosis on Lowenstein-Jensen
medium is positive in approximately 45%
to 90% of cases but usually takes several
weeks for a positive result. Sensitivity is
higher for patients with HIV infection
(69% sensitivity for smear and 87.9% for
culture). CSF may be normal in 5% of
HIV-positive patients with tuberculous
meningitis. Detection of M. tuberculosis
DNA in CSF by PCR assay is a useful
ancillary diagnostic test, with a sensitivity
that varies between 30% and 50% and
specificity of 98%. The likelihood of
detecting M. tuberculosis is increased
if a combination of tests is performed
on serial CSF samples.57
Chest CT is sensitive for detecting
pulmonary abnormalities in patients with
tuberculous meningitis. Mediastinal and
hilar lymphadenopathy, miliary pattern,
and bronchopneumonic infiltrate are
the most frequent abnormalities. Both
CT and MRI of the brain are valuable
for diagnosing tuberculous meningitis
and evaluating for complications. Characteristic abnormalities include enhancement of the basilar meninges,
exudates, hydrocephalus, and periventricular infarcts. MRI is considered more
sensitive than CT, and gadoliniumenhanced imaging can detect meningeal
enhancement early in the course of
illness. Focal meningeal enhancement
is more common than diffuse meningeal
enhancement.
Treatment. Treatment should be initiated when tuberculous meningitis is
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318
initially suspected, as the organism grows
slowly, speciation can take weeks, and
earlier treatment is associated with better outcomes. First-line antituberculous
medications include rifampicin, isoniazid, pyrazinamide, ethambutol (RIPE),
and streptomycin. Most of the first-line
antituberculous drugs (except ethambutol) achieve satisfactory levels in the CSF.
Antituberculosis treatment for meningitis
is divided into two phases: an intensive
(initial) phase and a continuation phase.
In the intensive phase, therapy includes a
combination of four first-line medications: isoniazid, rifampicin, streptomycin,
and pyrazinamide. The intensive phase
continues for 2 months. In the continuation phase, the treatment regimen is
reduced to two medications (isoniazid
and rifampicin), and the continuation
phase is usually extended to a total
treatment period of 12 to 14 months.58
Treatment of multi- and extremely drugresistant tuberculosis requires prolonged
intensive and continuation phases and,
depending on sensitivity, may require
additional medications. A recent Cochrane
review recommended that corticosteroids be used routinely for patients with
tuberculous meningitis because they
significantly reduced death and disabling residual neurologic deficits among
survivors.59 In addition, a randomized trial demonstrated significantly improved survival at 9 months in patients
receiving dexamethasone, as well as decreased adverse effects of antituberculosis medications.60
Neurosurgical intervention is often
needed when hydrocephalus develops.
Ventriculoperitoneal shunting is most
frequently used, although other options
include temporary external ventricular
drainage and endoscopic third ventriculostomy.54 Early neurosurgical procedures are also important for managing
tuberculous brain abscesses. Stereotactic drainage or evacuation can reduce
the size of space-occupying lesions, lower
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1305
Chronic and Subacute Meningitis
KEY POINTS
h Treponema
pallidum spreads
hematogenously to
the CNS early in the
course of disease.
Clinical signs and
symptoms of CNS
involvement are evident
throughout the course
of disease and not
limited by stage.
h The first step in
diagnosis of
neurosyphilis is
performing serologic
testing for syphilis using
Venereal Diseases
Research Laboratory
testing and rapid
plasma reagin assays.
1306
intracranial pressure, and improve eradication of the microorganism.61
Syphilis
Syphilis is caused by the thin, motile
corkscrew bacterium Treponema pallidum. This organism cannot be routinely cultured in the laboratory and is
difficult to visualize using traditional light
microscopy. Transmission is primarily
via sexual contact with an infected individual or by vertical transmission from
mother to fetus. Without treatment, the
disease will inevitably progress through
a series of clinical stages. In general,
syphilis can be classified as early or late
infection. Early infection encompasses
primary, secondary, and early latent syphilis. Late infection refers to tertiary syphilis.
After sexual exposure to the organism, an asymptomatic incubation period
of approximately 3 weeks occurs, followed by development of a painless
genital ulceration or chancre. The chancre and corresponding generalized lymphadenopathy are considered by most
clinicians as primary syphilis. If left
untreated, the chancre will resolve in
3 to 5 weeks and likely progress to secondary syphilis. Secondary syphilis is a
syndrome of fever, lymphadenopathy,
headache, malaise, myalgia, and a macular or pustular rash of the palms and
soles. It is during this stage when involvement of other organ systems produces
clinical symptoms, including mucosal
lesions, renal failure, hepatitis, and neurologic symptoms. The signs and symptoms of secondary syphilis typically
resolve in 4 to 10 weeks, and the patient
is deemed latently infected. During this
phase, patients are asymptomatic; however, they have serologic evidence of
infection. Latent syphilis is typically subdivided into early and late disease. Early
latent syphilis is typically diagnosed
within 1 year of acquiring disease. Although usually asymptomatic, patients
may experience recurrence of clinical
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symptoms during this time. About onethird of patients with untreated latent
syphilis will progress to develop late
or tertiary syphilis, which can affect any
organ in the body, particularly the nervous system.62
Clinical presentation of neurosyphilis.
T. pallidum spreads hematogenously to
the CNS early in the course of disease.
Clinical signs and symptoms of CNS
involvement are evident throughout the
course of disease and not limited by
stage. Neurosyphilis can be either early
or late disease. The early stage typically
manifests as asymptomatic or symptomatic meningitis and meningovascular
disease. Late disease more often affects
the brain parenchyma or spinal cord,
leading to general paresis, psychiatric
illness, memory deficits, tabes dorsales,
and gummatous masses.48
Although neurosyphilis has several
manifestations, this article will limit the
discussion to syphilitic meningitis. Syphilitic meningitis typically presents in
the secondary stage of syphilis, within
2 years of acquiring infection. Although
less common than other forms of neurosyphilis, meningitis occurs in up to 25% of
patients. The most common presenting
symptoms include headache, photophobia, nausea and vomiting, meningismus,
and cranial nerve deficits. Although
every cranial nerve can be affected,
cranial nerves VII and VIII are most
commonly affected.
Diagnosis. The diagnosis of neurosyphilis is typically made through a
combination of history, physical examination, and results of serologic and CSF
analyses. The first step in diagnosis is
performing serologic testing for syphilis
using VDRL and rapid plasma reagin
assays. These assays detect IgG and IgM
antibodies to a cardiolipin-lecithincholesterol antigen and are always positive
in patients with neurosyphilis. They also
provide quantitative titers that can be
used to monitor response to treatment.
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These assays are valuable for diagnosing early syphilis and early neurosyphilis. Treponemal assays, including the
fluorescent treponemal antibody absorbed and T. pallidum particle agglutination tests, measure treponemal
antibodies and are used for confirmatory testing. Treponemal assays
should also be positive in patients with
neurosyphilis.
Abnormal CSF is present in 70% of
patients with early syphilis. In later disease, these abnormalities are less common, suggesting that some patients may
spontaneously clear the organism from
the CSF without treatment. Persistent CSF
abnormalities can occur and are indicative of persistent infection. Although the
significance of abnormal CSF findings for
diagnosis, treatment, and prognosis in
the asymptomatic patient is not certain,
patients with abnormal CSF studies are at
increased risk of progression to symptomatic neurosyphilis.48
In active neurosyphilis, CSF typically
has a lymphocytic pleocytosis and elevated protein concentration; however,
in late disease, CSF studies may be normal. In syphilitic meningitis, CSF typically has a mononuclear predominant
pleocytosis (greater than 10 cells/2L),
elevated protein concentration (greater
than 45 mg/dL), and normal or decreased
glucose concentration. CSF immunologic tests, such as VDRL, are usually
abnormal in syphilitic meningitis; however, because CSF VDRL assay has a
sensitivity of less than 30% for detection
of neurosyphilis, a negative result does
not rule out neurosyphilis. CSF fluorescent treponemal antibody absorption
testing is less specific but more sensitive
than CSF VDRL and may be used to
exclude the diagnosis. Dark-field microscopy for organism visualization in the
CSF is insensitive.63 More recently, PCR
assays have been developed to detect
T. pallidum in the CSF, but 50% of
patients with syphilitic involvement of
Continuum Lifelong Learning Neurol 2012;18(6):1290–1318
the CNS have a negative PCR. Rolfs and
colleagues reported that 32 of 131 CSF
specimens (24%) were positive for T.
pallidum by PCR assay, but a positive
PCR result did not correlate with CSF
abnormalities or CSF VDRL reactivity.64
Studies suggest that HIV-positive patients are more likely to have leukocytosis, elevated protein concentration,
and low glucose concentration than
HIV-negative patients.65
Treatment. Penicillin is first-line
therapy for neurosyphilis. The Centers
for Disease Control and Prevention
(CDC) recommends 18 million units
to 24 million units of aqueous penicillin
G per day administered as 3 million
units to 4 million units IV every 4 hours
or as continuous infusion for 10 to 14
days.66 An alternative is procaine penicillin 2.4 million units IM daily with
probenecid 500 mg orally 4 times daily
for 10 to 14 days. In patients with penicillin allergy, most experts recommend
substitution with ceftriaxone 2 g IV daily
for 10 to 14 days. Marra and colleagues
found that ceftriaxone therapy led to
resolution of CSF abnormalities at a
rate similar to patients receiving penicillin G treatment.48
Prognosis of neurosyphilis is largely
determined by the stage of the illness.
Early stages of disease, such as syphilitic
meningitis, respond much better to therapy than tertiary syndromes. Treatment
of tabes dorsales and general paresis is
not as effective. The CDC recommends
reexamination of CSF every 6 months to
monitor response to therapy until the
CSF cell count is normal and the CSF
VDRL is nonreactive. Retreatment
should be considered if the cell count
has not decreased at 6 months or if the
CSF is not normal by 2 years.
Although most clinical presentations
of syphilis have not been shown to vary
significantly by HIV status, early meningeal neurosyphilis occurs more frequently among HIV-positive patients.
KEY POINT
h Prognosis of
neurosyphilis is largely
determined by the stage
of the illness. Early
stages of disease, such
as syphilitic meningitis,
respond much better to
therapy than tertiary
syndromes.
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1307
Chronic and Subacute Meningitis
HIV-positive patients with early neurosyphilis are at increased risk of early
neurologic complications and have slightly
higher rates of treatment failure. The
existing literature does not demonstrate
a more effective treatment regimen in
preventing neurosyphilis in HIV-positive
patients when compared to existing recommendations for HIV-negative patients.
HIV-positive patients with neurosyphilis
should have repeat serologic follow-up
at 3, 6, 9, 12, and 24 months after therapy. Although patients with HIV may
continue to have abnormal CSF pleocytosis at 6 months after neurosyphilis
treatment, retreatment should be considered in patients with CSF VDRL or
serum VDRL titers that have failed to
decline. Immune reconstitution using
antiviral therapy is essential in the
treatment of coexisting neurosyphilis.
HIV-positive patients receiving antiviral
therapy are 4 times more likely to demonstrate normalized CSF studies, 13 times
more likely to have clinical improvement, and less likely to have serologic
failure of treatment.62
AUTOIMMUNE DISEASE
Nervous system involvement has been
described with virtually every autoimmune disease. Chronic meningitis may
occur in a subset of these diseases. This
section discusses the clinical presentation, diagnosis, and treatment of the most
common autoimmune diseases associated with chronic meningitis, including
sarcoidosis, systemic lupus erythematosus, Behçet disease, and CNS angiitis.
Table 3-4 provides a comprehensive
list of autoimmune diseases reported
to cause chronic meningitis with associated clinical symptoms and diagnostic recommendations.
TABLE 3-4 Noninfectious Causes of Meningitis
Causes and Other
Clinical Findings
Special Laboratory
Tests
Leptomeningeal
carcinomatosis
Cranial nerve deficitsa
CSF: cytology and flow
cytometry
Behçet disease
Oral and genital ulcers,
uveitis, iridocyclitis
Human leukocyte antigen
B51
Systemic lupus
erythematosus
antinuclear antibody,
American College of
Rheumatology criteria
Wegener
granulomatosis
Glomerulonephritis and
pulmonary necrosis
Antineutrophil
cytoplasmic antibody
Sarcoidosis
Lungb
Skin: erythema nodosum
Ophthalmic: iritis, uveitis
Cranial nerve deficits
Serum angiotensinconverting enzyme
Sjögren
syndrome
Sjögren syndrome,
Raynaud syndrome
Sjögren syndrome A and
Sjögren syndrome B
antibodies
Chemical
Drug history
a
b
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An MRI with contrast of brain and spinal cord should be performed.
A chest CT to check for bilateral hilar lymphadenopathy should be performed.
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Neurosarcoidosis
Sarcoidosis is a multisystem granulomatous disease affecting the CNS in up to
25% of patients. Although sarcoidosis has
a predilection for the lungs, anterior uvea,
lymphatic system, and skin, any organ,
including the nervous system, can be
affected. Neurosarcoidosis was first described in the 1900s by Heerford as ‘‘uveoparotid fever’’ with cranial neuropathies.
Clinical presentation. The clinical features 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
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).
FIGURE 3-3
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
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1309
Chronic and Subacute Meningitis
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
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Conjunctival biopsy. Medium (A) and high power (B) view of conjunctival
biopsy demonstrating a large noncaseating granuloma.
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almost any part of the nervous system.
The most common clinical presentations
include cranial neuropathies, seizures,
meningitis, mass lesions, hypothalamic
or pituitary involvement, spinal cord lesions,
psychiatric manifestations, movement
disorders, peripheral neuropathy, and
myopathies. Cranial neuropathies occur
in 50% to 75% of patients and are most
often the result of elevated intracranial
pressure, granulomas, or basilar meningitis. The most common cranial neuropathy is unilateral or bilateral facial
palsy. Acute and chronic meningitis
occurs in up to 26% of patients with
neurosarcoidosis. Case 3-3 demonstrates a classic case of neurosarcoidosis.
Diagnosis. Diagnosis of neurosarcoidosis is difficult and often requires a
combination of medical history with
neuroimaging, serologic and CSF data,
and tissue biopsy. The diagnosis of
systemic sarcoidosis is typically made
through biopsy of lymph nodes, lung,
liver, skin, or conjunctiva with histologic
demonstration of noncaseating granulomas consisting of epithelioid cells and
macrophages. Brain biopsy may be useful when meningeal or cerebral abnormalities are easily accessible but is not
routine. Serum ACE levels are elevated in
50% of patients with neurosarcoidosis.67
CSF analysis typically reveals a lymphocytic pleocytosis (10 cells/2L to 200
cells/2L) with significantly elevated protein concentration (2 g/L or greater) and
low glucose concentration. Opening pressure is often elevated. CSF tests for
oligoclonal bands may be positive, most
often in the setting of an elevated
protein concentration. Additional useful
CSF markers include CSF lysosome, "2microglobulin, and T-cell lymphocyte
ratios. CSF ACE levels are nonspecific but
can be elevated with neurosarcoidosis.
MRI with gadolinium reveals leptomeningeal enhancement in up to 40% of
patients with neurosarcoidosis, with the
basilar meninges most often involved.
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Dural enhancement is present in up to
30% of cases. Intraparenchymal mass lesions or granulomas may be solitary
or multiple and typically enhance with
gadolinium. Pituitary and hypothalamic
masses, enhancement, or thickening are
present in 18% of patients with neurosarcoidosis. Although the facial nerve
is the most common clinical manifestation of cranial neuropathy, on MRI, the
optic nerve is most frequently abnormal,
displaying enhancement and thickening.
Other nonspecific findings include hydrocephalus, cavernous sinus involvement,
lacrimal gland enlargement, osseous
lesions, intramedullary spinal lesions,
and spinal nerve root enhancement.68
Treatment. Corticosteroids are the
mainstay of treatment for sarcoidosis,
with recommended doses of 40 mg/d to
60 mg/d followed by a slow taper. Patients with severe symptoms may be
treated with high-dose methylprednisolone (1 g IV for 3 to 5 days) followed by
oral prednisone. Steroid-sparing immunosuppressive medications, including mycophenolate, azathioprine, methotrexate,
cyclophosphamide, infliximab, and hydroxychloroquine, have been used with varying degrees of success; these medications
are often used for long-term suppression.
KEY POINTS
h The most common
clinical presentations of
neurosarcoidosis include
cranial neuropathies,
seizures, meningitis,
mass lesions,
hypothalamic or
pituitary involvement,
spinal cord lesions,
psychiatric
manifestations,
movement disorders,
peripheral neuropathy,
and myopathies.
h The diagnosis of
systemic sarcoidosis is
typically made through
biopsy of lymph nodes,
lung, liver, skin, or
conjunctiva with
histologic demonstration
of noncaseating
granulomas consisting
of epithelioid cells
and macrophages.
Systemic Lupus Erythematosus
Adult and pediatric systemic lupus erythematosus (SLE) commonly may affect any
part of the nervous system and has been
termed neuropsychiatric lupus. The
American College of Rheumatology established case definitions for 19 central
and peripheral nervous system syndromes
in neuropsychiatric SLE, including cognitive and psychiatric disorders, demyelination, seizures, transverse myelitis,
headache, movement disorders, vasculitis, aseptic meningitis, and peripheral
neuropathy. The pathogenesis of CNS
manifestations is multifactorial and may
involve autoantibodies against the nervous system, microangiopathy, intrathecal
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1311
Chronic and Subacute Meningitis
KEY POINTS
h Infectious meningitis
should be considered in
patients with systemic
lupus erythematosus
who have been
treated with
immunosuppressive
therapy and present
with fever, altered
mental status,
meningeal signs, and
nausea or vomiting.
h CSF examination is
crucial for excluding the
diagnosis of infectious
meningitis prior to
initiating
immunosuppressive
therapy for
neurosarcoidosis.
1312
production of proinflammatory cytokines, and premature atherosclerosis.
Antiphospholipid antibodies are the
most frequently observed autoantibody in SLE and have been associated
with stroke and cognitive decline. Disruption of the integrity of the bloodbrain barrier is essential for SLE-related
neuropathology to develop. Abnormal
endothelial cell interactions may be
involved in allowing proteins and lymphocytes to gain access into the CNS.69
Clinical presentation. Meningitis associated with SLE is typically aseptic,70 but
because many patients are treated with
chronic immunosuppressive therapy,
they are at risk for developing infectious
meningitis. Infectious meningitis should
be considered in patients with SLE who
have been treated with immunosuppressive therapy and present with fever,
altered mental status, meningeal signs,
and nausea or vomiting. Compared to
SLE-associated aseptic meningitis, patients with infectious meningitis are
typically older, develop mental status
changes, and have plasma leukocytosis
with neutrophilia, as well as a marked
CSF pleocytosis and hypoglycemia. Nonsteroidal anti-inflammatory medications
have been implicated as a causative factor
in aseptic meningitis associated with SLE.71
Diagnosis and treatment. No single
diagnostic test that is sensitive and specific
for SLE-related neurologic disease is available. Assessment should include neurologic and rheumatologic evaluations,
serologic testing of immune parameters,
and neuroimaging. CSF examination is
crucial for excluding the diagnosis of infectious meningitis prior to initiating
immunosuppressive therapy. A recent
study evaluated the presence of autoantibodies in the serum and CSF in patients
with lupus and neurologic symptoms.
Antibodies were checked again at 6 months
when clinical manifestations of disease
had resolved. The following serum autoantibodies were detected: antinuclear
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antibody (82%), antiYdouble-stranded
DNA (79%), antiribosomal (61%), anticardiolipin IgG (15%), antiY" 2 glycoprotein
IgG (65%), and anti-NMDA receptor
(35%). These antibodies did not change
with resolution of symptoms. The following CSF autoantibodies were detected: antinuclear antibody (57%),
antiYdouble-stranded DNA (77%), antiribosomal (46%), anticardiolipin IgG
(11%), antiY" 2 glycoprotein I (0%), and
antiYNMDA receptor antibody (41%).
Similar to serum values, CSF autoantibodies did not resolve with improvement of symptoms. The role of serum
and CSF autoantibody detection in
patients with lupus is not clear.72 Aseptic
meningitis associated with SLE is typically self-limited.
Behçet Disease
Behçet disease, a multisystem disease
characterized by recurrent oral aphthous
ulcers, genital ulcers, and uveitis, typically presents between 20 and 40 years
of age. Men are affected more commonly than women. This disease can affect almost any organ, including the eye;
skin; major vessels; and cardiac, pulmonary, musculoskeletal, and gastrointestinal
systems. Neurologic involvement occurs
in 5% to 10% of patients with Behçet
disease and can be parenchymal or nonparenchymal. Parenchymal disease, or
meningoencephalitis, occurs in 70% of
patients with neuroYBehçet disease and
typically involves a massive inflammatory
infiltration of polymorphonuclear lymphocytes, eosinophils, lymphocytes, and
macrophages into the brainstem, diencephalon, and small vessels; fibrinoid
necrosis is typically absent. Nonparenchymal disease typically manifests as
cerebral venous thrombosis. Other rare
presentations include spinal cord lesions,
arteritis, optic neuritis, aseptic meningitis,
and peripheral neuropathies.
NeuroYBehçet disease typically presents subacutely with a constellation of
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fever, malaise, orogenital ulcerations,
skin lesions, or uveitis. Over weeks,
patients develop a progressive headache, followed by a variety of potential
accompanying symptoms, including
altered mental status, dysarthria, ophthalmoplegia, ataxia, and hemiparesis.
The course of illness may be notable for
recurrent attacks, secondary progressive
disease, or a primary progressive decline. Diagnosis involves fulfilling the
diagnostic criteria for systemic Behçet
disease plus neurologic symptoms not
explained by other conditions or infections. Typical radiographic and CSF
analysis are also useful. Early in the
disease course, CSF has a polymorphonuclear pleocytosis followed by a lymphocytic predominance. The cell count
ranges from 0 cells/2L to 400 cells/2L with
elevated protein concentration (greater than 1 g/dL) and normal glucose concentration. MRI of the brain typically
demonstrates a large asymmetric lesion
involving the midbrain, pons, thalamus,
or basal ganglia. These lesions are generally hyperintense on T2-weighted images and hypointense on T1-weighted
images. Gadolinium enhancement
and small hemorrhages may be present. Chronically, MRI often demonstrates widespread subcortical white
matter lesions with brainstem atrophy.73
No standard treatment is available for
neuroYBehçet disease. Most commonly,
glucocorticoids are administered to treat
acute exacerbations, with an initial pulse
of high-dose IV steroids followed by gradual taper. Many medications used to treat
systemic Behçet disease, including azathioprine, colchicine, cyclosporine, cyclophosphamide, methotrexate, interferon
alpha, and antiYtumor necrosis factor
agents, have been used as adjunctive
treatment of neuroYBehçet disease. Some
experts suggest starting azathioprine
with steroids at the first attack. Low-dose
steroids should be continued for 5 weeks
until azathioprine is active. In patients
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who have progression of symptoms
or cannot tolerate azathioprine, mycophenolate mofetil is an alternative
treatment.74
Primary Angiitis of the CNS
Primary angiitis of the CNS (PACNS) is
characterized by inflammation and destruction of cerebral vessels without
systemic involvement. PACNS consists of
several subtypes grouped into typical
and atypical forms. Typical PACNS is the
granulomatous type. Atypical forms include lymphocytic, angiographically defined, mass lesions, and amyloid "Yrelated
cerebral angiitis.
Granulomatous angiitis, the classic
form of PACNS, is characterized by
chronic meningitis with an insidious
onset of symptoms. Patients may present with a history of years of headache,
encephalopathy, seizures, cognitive and
behavioral changes, ataxia, recurrent
TIAs, or focal neurologic deficits. Symptoms of chronic meningitis can precede
diagnosis by several years. Granulomatous angiitis of the CNS is diagnosed by
pathologic findings of small and medium
leptomeningeal and cortical artery infiltration of giant cells, which can be segmental with necrotizing or lymphocytic
involvement.75
Diagnostic criteria proposed in 1988
includes the presence of acquired and
unexplained neurologic or psychiatric
deficits, presence of angiographic or histopathologic evidence of angiitis in the
CNS, and no evidence of systemic or
other disorders that may mimic the disease. Primary angiitis of the CNS peaks
in the fifth and sixth decades of life and is
more common in men. The combination of serologic studies, CSF analysis,
angiography, MRI, and brain biopsy are
essential for diagnosing PACNS. Biopsy
is the gold standard for diagnosis but has
low sensitivity. More importantly, biopsy
is useful in identifying lesions that may
mimic PACNS, such as infection or
KEY POINTS
h Diagnosis involves
fulfilling the diagnostic
criteria for systemic
Behçet disease plus
neurologic symptoms
not explained by other
conditions or infections.
h CSF analysis is
abnormal in over
90% of patients and
usually demonstrates a
modest lymphocytic
pleocytosis (less than
20 cells/2L), elevated
protein concentration
(median less than
120 mg/dL), and normal
glucose concentration.
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1313
Chronic and Subacute Meningitis
KEY POINTS
h Diagnostic criteria for
primary angiitis of the
CNS proposed in 1988
include the presence
of acquired and
unexplained neurologic
or psychiatric deficits,
presence of
angiographic or
histopathologic
evidence of angiitis
in the CNS, and
no evidence of systemic
or other disorders that
may mimic the disease.
h Neoplastic involvement
of the CNS should
be considered in the
differential diagnosis for
patients presenting with
signs and symptoms of
chronic meningitis.
h CSF cytology should
be sent for all patients
with CSF pleocytosis of
unknown etiology to
evaluate for
neoplastic cells.
1314
malignancy, which are found in up to
40% of patients. Serum erythrocyte
sedimentation rate and C-reactive protein are typically normal in PACNS and
elevated in conditions that mimic
PACNS. CSF analysis is abnormal in over
90% of patients and usually demonstrates a modest lymphocytic pleocytosis (less than 20 cells/2L), elevated
protein concentration (median less
than 120 mg/dL), and normal glucose
concentration. CSF examination is crucial for excluding infectious and neoplastic mimics of PACNS. Cranial MRI
may reveal infarction in up to half of
patients, and nonspecific subcortical
white matter, deep white matter, and
cortical T2-weighted hyperintensities are
often present. Mass lesions are present
in 5% of patients with PACNS and are potential sites for biopsy to confirm the
diagnosis of PACNS and exclude other
potential etiologies. 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 alternating areas of dilation and stenosis
that can be smooth or irregular. These
findings are nonspecific for PACNS and can
be seen with other disorders, including
infection, radiation, atherosclerosis, and
vasospasm. Sensitivity of angiography
varies from 40% to 90%. Although the
diagnosis of PACNS can be difficult to
confirm, patients with normal CSF, angiography, and MRI are extremely unlikely to have PACNS.76
Treatment of PACNS includes immunosuppression with a combination of glucocorticosteroids and cyclophosphamide.
High-dose oral prednisone (1 mg/kg/d)
or IV pulse methylprednisolone for 3
days, followed by oral prednisone, is
recommended. Cyclophosphamide,
azathioprine, or mycophenolate mofetil are most commonly used for longterm immunosuppression. Disease
activity can be monitored with serial
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neurologic examinations and MRI
scans.76
NEOPLASTIC
Neoplastic involvement of the CNS
should be considered in the differential
diagnosis for patients presenting with
signs and symptoms of chronic meningitis. Leptomeningeal carcinomatosis
or carcinomatous meningitis is defined
as malignant seeding or infiltration of
the leptomeninges. Leptomeningeal
carcinomatosis is most commonly associated with hematologic malignancies, but
solid tumors and primary brain tumors
infiltrate the meninges in up to 5% of patients. Patients classically present with signs
and symptoms of multifocal involvement
of the neuraxis due to involvement of the
cerebral hemispheres, brainstem, cranial
nerves, spinal cord, or nerve roots. The
most common presenting symptoms include headache, encephalopathy, nuchal
rigidity, diplopia, weakness, and radicular pain. Cranial neuropathies may
include trigeminal neuropathy, facial
weakness, and hearing loss.77
Diagnosis of leptomeningeal carcinomatosis is made by clinical examination,
CSF analysis, and gadolinium-enhanced
MRI. Lumbar puncture typically reveals
elevated opening pressure, leukocytosis,
and elevated protein and low glucose
concentrations. CSF cytology should be
sent for all patients with CSF pleocytosis
of unknown etiology to evaluate for neoplastic cells. The sensitivity of a single
large volume CSF sample is 38% to 66%;
if three large volume CSF samples are
performed, the sensitivity increases to
90%.78 Gadolinium-enhanced MRI is the
imaging modality of choice and typically
displays contrast enhancement of the
meninges, cortical convexities, basilar
cistern, and cauda equina.79 Meningeal
biopsy of contrast-enhancing lesions
remains the gold standard for definitive diagnosis of leptomeningeal
carcinomatosis.77
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Early diagnosis and treatment of leptomeningeal carcinomatosis is important
for symptomatic relief and prognostic implications, but long-term prognosis is
poor. Without treatment, overall survival
is typically 4 to 6 weeks. Treatment for leptomeningeal carcinomatosis includes focal
radiotherapy for bulky disease, local chemotherapy, and systemic chemotherapy.80
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