Management ofAcute, Recurrent, andChronic Meningitidesin Adults

Tracey A. Cho, MD*, Nagagopal Venna, MD, MRCP

KEYWORDS

� Meningitis � Bacterial � Viral � Aseptic� Chronic � Management

By common usage, the term meningitis implies inflammation of the leptomeninges (thearachnoid and pia) and, by extension, involvement of the cerebrospinal fluid (CSF) inthe subarachnoid space. In the rare pachymeningitis, inflammation predominantlyaffects the dura, and its causes and course are distinct from those of leptomeningitis.This review focuses on leptomeningitis, with the understanding that many processesmay affect all 3 layers of the meninges simultaneously.

Meningitis may be further classified based on the time course. Most investigatorsdistinguish between acute meningitis (with onset over hours to days) and chronicmeningitis (syndrome persisting more than 4 weeks). Those meningitis syndromesevolving over several days but less than 4 weeks may be termed subacute, althoughthe distinction between these and the other 2 categories is arbitrary. Recurrent menin-gitis is distinguished by symptoms that appear and then resolve completely betweendistinct episodes. Although there may be some etiologic overlap, the clinical distinc-tion between acute, chronic, and recurrent meningitis is relevant because the causesand approaches to management are often different.

Meningitis typically manifests as headache, neck stiffness, light sensitivity, andvarying degrees of neurologic symptoms and signs. Acute meningitis is more oftenaccompanied by fever and mental status changes, whereas symptoms are more indo-lent in chronic meningitis. Furthermore, inflammation of the meninges sometimesextends into the parenchyma with resultant symptoms and signs of cerebral or spinalcord involvement, often termed meningoencephalitis or meningoencephalomyelitis.Viral syndromes in particular often cause a broad spectrum of neurologic disorders,

Neurology-Infectious Diseases Section, Department of Neurology, Massachusetts GeneralHospital, WACC 835, 55 Fruit Street, Boston, MA 02114, USA* Corresponding author.E-mail address: tcho@partners.org

Neurol Clin 28 (2010) 1061–1088doi:10.1016/j.ncl.2010.03.023 neurologic.theclinics.com0733-8619/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.

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but this article concentrates on those syndromes predominantly affecting themeninges.

The most common and often most severe forms of meningitis are due to infections,including bacteria, viruses, fungi, and parasites. Noninfectious causes of meningitisinclude primary inflammatory syndromes such as vasculitis and connective tissuedisease, neoplasms of solid tumor and hematologic forms, and chemical irritantsincluding certain medications, subarachnoid blood, and biologic matter spilling intothe CSF from tumors. Although a patient may present with symptoms of meningitiswithin days of onset, distinguishing acute from subacute or chronic meningitis maynot always be possible early in the course. Nevertheless, the distinction is importantbecause of the varying urgency, causes, and treatment strategy involved in eachsyndrome. Although the list of possible causes of acute, chronic, and recurrent menin-gitis is extensive, this article focuses on the most important and treatable causes.

ACUTE MENINGITIS

The most common causes of acute meningitis are bacteria and viruses. Acute menin-gitis begins with the abrupt onset of headache, fever, and neck stiffness, with varyingdegrees of mental status change. Neck stiffness may be elicited on physical examina-tion as pain and resistance to passive neck flexion, knee and hip flexion in response topassive neck flexion (Brudzinski sign), or resistance and pain to passive extension of theknee with the hip flexed (Kernig sign). However, these signs are not sensitive. Althoughpatients may not present with all of these symptoms and signs, 95% of those with acutebacterial meningitis will have at least 2 of them, and 100% will have at least 1.1–3 Addi-tional, but less reliable, symptoms and signs may include photophobia, rash, nausea,seizures, or focal neurologic signs. Caution should be taken in immunocompromised,elderly, chronic alcoholic, and severely malnourished patients because typical symp-toms may be lacking and meningitis may present with an acute confusional state orvarying degrees of decreased level of alertness.

Patients presenting with these classic symptoms should be treated as an acute andpotentially life- and brain-threatening emergency because morbidity and mortality arehigh with delayed treatment of bacterial meningitis.4 History and examination shouldtarget the symptoms and signs noted earlier, as well as review for systemic cluesand survey for rash and pulmonary consolidation. Petechial rash of the skin or oralmucosal suggests meningococcal infection. Oral, genital, and dermatomal vesicles(herpes simplex virus [HSV] and herpes zoster) offer causal clues. Blood culturesshould be obtained immediately, because they will yield the offending organism in50% to 75% of cases of bacterial meningitis.2,4,5 Lumbar puncture (LP) should beperformed as soon as possible for definitive diagnosis. Many patients will not requireneuroimaging before performing LP. In patients with features that indicate increasedrisk of uncal or tonsillar herniation with removal of spinal fluid, head computed tomog-raphy (CT) should be carried out before performing LP. Risk factors include new onsetseizure, immunocompromise, history of focal brain disease, decreased level of alert-ness, papilledema, or focal neurologic signs, in particular of cerebellar or brainstemdysfunction.6,7 In cases in which LP is delayed, empiric antibiotics should be initiatedat once as soon as blood cultures are obtained, and LP should still be attempted within2 to 3 hours. Even when CT reveals no mass lesion, there may still be a risk for herni-ation in certain cases, especially those with depressed mental status or papilledema.LP should be deferred in these cases until the mental status improves or measures canbe taken to lower the intracranial pressure.

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CSF examination is the critical test that helps distinguish bacterial, viral, and othercauses of acute meningitis. However, CSF profiles are not 100% specific, and cannotbe used in isolation to determine treatment. Although no definitive tests are availableto differentiate all cases of bacterial from viral meningitis, options are available forcertain situations. In postneurosurgical patients with clinical meningitis, CSF lactateequal to or greater than 4.0 mmol/L significantly raises the possibility of bacterialmeningitis and should prompt empiric treatment.8 In patients presenting with symp-toms and CSF patterns consistent with meningitis, normal serum C-reactive proteinhas a high negative predictive value for bacterial meningitis and may allow carefulobservation without antibiotics.9,10 When blood culture and CSF Gram stain andculture fail to reveal a bacterial pathogen, further testing may help identify the causa-tive agent. Latex agglutination for bacterial antigens in the CSF may be useful in casesin which CSF has been sterilized by antibiotics before obtaining the fluid.7 Polymerasechain reaction (PCR) is not yet widely available for bacterial causes, but may becomea useful alternative when Gram stains and cultures are negative.11 In cases of viralmeningitis, PCR is sensitive and specific for enteroviruses, HSV types 1 and 2, humanimmunodeficiency virus (HIV) type 1, and some arboviruses. Although identifyingcertain viruses may not lead to specific treatment, it can sometimes provide enoughinformation to discontinue unnecessary treatment. Specific diagnostic tests andmanagement of different causal agents are discussed later.

ACUTE BACTERIAL MENINGITIS

In cases of suspected acute bacterial meningitis, swift initiation of treatment is essentialin decreasing morbidity and mortality. As noted earlier, any difficulties in obtaining a CTscan should not delay the initiation of antibiotics (after obtaining blood cultures). Evenafter CSF results are obtained, the clinical presentation and initial diagnostic workupcannot always immediately distinguish between pyogenic bacterial causes and othercauses of acute meningitis. If there is any suspicion for bacterial meningitis, empirictreatment should be initiated until it is excluded. In addition, when mental status changeis present, acyclovir should be administered until CSF PCR for HSV-1 is negative,because herpes encephalitis may initially be hard to distinguish from bacterial andaseptic meningitis.

Based on the most common causes of acute bacterial meningitis in different popu-lations, empiric regimens have been established (Table 1). Factors influencing thechoice of antibiotics include age, local susceptibility patterns, immunocompromise,community versus hospital setting, and any predisposing surgical procedures orinjuries. For the purposes of this review, susceptibility patterns in the United Statesare considered. For children and adults aged 2 to 50 years, with suspected commu-nity-acquired bacterial meningitis, the most common causes include Neisseria menin-gitidis and Streptococcus pneumoniae. The recommended empiric regimen includesceftriaxone and vancomycin (see Table 1 for dosing). In adults older than 50 years, themajor community-acquired species include S pneumoniae and N meningitidis, as wellas Listeria monocytogenes and aerobic gram-negative bacilli.1,12 For better coverageof L monocytogenes, ampicillin is added to ceftriaxone and vancomycin in this agegroup.

In patients with impaired cell-mediated immunity (such as HIV, lymphoma, cortico-steroid use, or cytotoxic chemotherapy) there is an increased risk for L monocyto-genes and gram-negative bacilli.1,13 Ampicillin and ceftazidime,14,15 respectively,should be used to ensure coverage for these, in addition to vancomycin forS pneumoniae.

Table 1Empiric antibiotic regimens for acute bacterial meningitis in adults

Patient Factor Most Common Causesa Empiric Regimen

Age 2–50 y Neisseria meningitidis,Streptococcus Pneumoniae

Vancomycin 1 third-generation cephalosporinb,c

Age >50 y S pneumoniae, N meningitidis,Listeria monocytogenes,aerobic gram-negativebacilli

Vancomycin 1 ampicillin 1

third-generationcephalosporinb,c

Impaired cellularimmunity

L monocytogenes, aerobicgram-negative bacilli,S pneumoniae

Vancomycin 1 ampicillin 1

ceftazidime or cefepime

Head trauma,CSF leak, neurosurgery

Coagulase-negativestaphylococci,Staphylococcus aureus,gram-negative bacilli,S pneumoniae

Vancomycin 1 ceftazidime orcefepimed

Skull base fracture S pneumoniae, Haemophilusinfluenzae, group AB-hemolytic streptococci

Vancomycin 1 third-generation cephalosporin

a In United States.b Ceftriaxone or cefotaxime.c Consider adding rifampin if adjunctive corticosteroids are used.d Meropenem is an alternative.

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Meningitis due to penetration of the subarachnoid space (including head trauma,CSF leak, and neurosurgery) has a distinctive pattern of causative organisms. Themost common causes in these cases are aerobic gram-negative bacilli (Pseudomonasaeruginosa, Enterobacteriaceae, and Klebsiella pneumoniae) and skin flora (Staphylo-coccus aureus and coagulase-negative staphylococci).1,16 Organisms often showantibiotic resistance. Empiric regimens for nosocomial meningitis should includevancomycin and ceftazidime.7,14,15,17 The exception is skull-based fractures, in whichmeningitis is typically caused by upper respiratory tract flora.18,19 For these cases, therecommended empiric regimen is vancomycin and a third-generation cephalosporin.7

For cases of shunt infection, optimal treatment entails removing the infected hardwareand providing an external drain to monitor clearance and treat increased intracranialpressure. If shunt infection does not clear or hardware removal is not possible, antibi-otics may be administered intrathecally.20 Antibiotics should be continued for a fullcourse regardless of culture results, because perioperative antibiotics may sterilizeCSF without preventing meningitis.

Once serum or CSF culture and susceptibility data are available, antibiotics shouldbe tailored to the specific organism (Table 2). If cultures are negative but latexagglutination identifies a species, treatment should be based on the assumption ofantibiotic resistance. For S pneumoniae with susceptibility to penicillin (PCN), PCNG or ampicillin is first-line therapy. For intermediate resistance, a third-generationcephalosporin (ceftriaxone or cefotaxime) is appropriate. With high PCN resistanceor cephalosporin resistance, vancomycin is added to a third-generation cephalo-sporin. In cases of N meningitidis with low PCN resistance, PCN G or ampicillin isfirst-line treatment. For N meningitidis with intermediate resistance, a third-generationcephalosporin should be substituted. For L monocytogenes, optimal treatment isampicillin or PCN G. For specific therapy for other less-common species, as well asdosing and alternative regimens, please refer to Table 2.

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Because much of the morbidity associated with acute bacterial meningitis is due tosubarachnoid inflammation driven in part by bacterial lysis and toxic injury to parame-ningeal cerebral cortex and cranial nerves (CNs) coursing through the inflamed CSF,adjuvant corticosteroid administration in addition to antibiotics can potentially mitigatethe effects of an overly exuberant inflammatory response. Based on the results ofa large, randomized, placebo-controlled trial in Europe, patients with suspected orproven pneumococcal meningitis should receive dexamethasone 10 mg intravenously(IV) every 6 hours for 4 days, to be started before or concurrent with antibiotics.5

If blood cultures or CSF data reveal an alternative cause, steroids should be discon-tinued because they have shown no benefit in adults with meningitis due to otherorganisms. Due to an increase in the prevalence of PCN and cephalosporinresistance, vancomycin is a key component of regimens for suspected or provenpneumococcal meningitis. Because vancomycin is a large molecule, use of cortico-steroids could theoretically reduce the penetration of vancomycin into the CSFspace.21–23 Although recent evidence indicates the potential for adequate CSF pene-tration of vancomycin with concomitant steroid use,24 rifampin should be added to theempiric regimen when adjuvant corticosteroids are used, and continued if culturesreveal intermediate or high resistance to PCN or cephalosporins.

Management of the complications of acute pyogenic meningitis, including cerebralthrombophlebitis with venous infarctions and arteritic infarctions, is symptomatic.Antiepileptic drugs are often needed because bacterial meningitis frequently presentswith partial and secondarily generalized seizures. Loculated subdural or intraventric-ular empyema rarely occurs but may need prolonged antibiotic regimens. Brainabscesses are rare, except when meningitis and abscess are due to parameningealinfection from paranasal sinuses or mastoids. Rarely recognized is a delayed occlu-sive arteriopathy affecting multiple intracranial vessels but the natural course andutility of steroid management for this complication are not known.

ACUTE VIRAL MENINGITIS

In some cases, differentiating between bacterial and other causes of acute meningitis(aseptic meningitis) can be difficult. Until bacterial meningitis can be excluded, empiricantibiotic regimens should be continued. Although bacteria cause the most severeforms of meningitis, viruses are the most common causes of acute meningitis. If basicCSF studies suggest possible viral meningitis, CSF may also be sent for viral culture,viral PCR, and virus-specific immunoglobulin M (IgM)/immunoglobulin G (IgG) anti-bodies. PCR for HSV type 2 DNA, varicella-zoster virus (VZV) DNA, HIV RNA, andenterovirus in particular may affect acute management. HSV, VZV, and HIV havespecific therapy available. Although no approved specific treatment is available forenteroviral meningitis, identification by PCR may preclude unnecessary continuationof other antibacterial and antiviral treatments. Arbovirus antibodies and serologymay provide prognostic value but typically take weeks to perform and do not usuallyaffect acute management. Empiric use of intravenous acyclovir for severe cases isreasonable until virological test results return.

Most viral meningitides are self-limiting and may be treated symptomatically. Anal-gesics such as nonsteroidal antiinflammatory drugs or acetaminophen may help withheadache and malaise. In cases with increased intracranial pressure, LP oftenprovides some relief from headache. For those with chronic headache followingaseptic meningitis, tricyclic antidepressants or other preventive headache medica-tions may be appropriate.

Table 2Specific antibiotic regimens and dosing for acute bacterial meningitis in adults

Bacteria, Susceptibility Daysa First Line Alternative

S pneumoniae 10–14

PCN MIC <0.1 PCN G 4 mU q4h or ampicillin 2g q4h Ceftriaxone, cefotaxime, or chloramphenicol

PCN MIC 0.1–1.0 Ceftriaxone 2g q12h or cefotaxime 2g q4h Cefepime or meropenem

PCN MIC R2.0 Vancomycin 1g q12h plus ceftriaxone or cefotaxime Fluoroquinolone

Ceftriaxone or cefotaxime MIC R1.0 Vancomycin 1 ceftriaxone or cefotaxime Fluoroquinolone

N meningitidis 7

PCN MIC <0.1 PCN G or ampicillin Ceftriaxone, cefotaxime, or chloramphenicol

PCN MIC 0.1–1.0 Ceftriaxone or cefotaxime Chloramphenicol, fluoroquinolone, or meropenem

L monocytogenes R21 Ampicillin or PCN Gb TMP-SMXc or meropenem

Streptococcus agalactiae 14–21 Ampicillin or PCN Gb Ceftriaxone or cefotaxime

Escherichia coli 21 Ceftriaxone or cefotaxime Aztreonam, TMP-SMX, fluoroquinolone, ampicillin,or meropenem

P aeruginosa 21 Cefepime 2g q8h or ceftazidime 2g q8h Aztreonam, ciprofloxacin, or meropenem

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H influenzae 7

b-Lactamase (�) Ampicillin Ceftriaxone, cefotaxime, cefepime, chloramphenicol,or fluoroquinolone

b-Lactamase (1) Ceftriaxone or cefotaxime Cefepime, chloramphenicol, or fluoroquinolone

S aureus

Methicillin sensitive Nafcillin 2g q4h or oxacillin 2g q4h Vancomycin or meropenem

Methicillin resistant Vancomycin TMP-SMX or linezolid

Staphylococcus epidermidis Vancomycin Linezolid

Enterococcus 21

Ampicillin sensitive Ampicillin 1 gentamicin 5mg/kg q8h

Ampicillin resistant Vancomycin 1 gentamicin

Ampicillin and vancomycinresistant

Linezolid 600mg q 12h

Abbreviations: MIC, minimum inhibitory concentration; PCN, penicillin.a Minimum duration, tailor to response and severity.b For severe cases, add aminoglycoside.c Trimethoprim-sulfamethoxazole.

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The herpes viruses are important causes of aseptic meningitis. Two in particular havethe potential to cause significant morbidity and mortality: HSV and VZV. HSV menin-gitis may be presumptively diagnosed when meningitis is accompanied by genitalherpes, or definitively when CSF PCR reveals HSV-1 or (more commonly) HSV-2DNA in association with a typical inflammatory profile. In cases accompanied byzoster or CSF evidence of VZV replication (PCR or antibody production), VZV is thelikely cause. Because these viruses have the potential for parenchymal or vascularinvasion, they should be treated with appropriate antiviral agents in addition to symp-tomatic treatment. In severe cases, including patients with advanced HIV and otherforms of immunocompromised, VZV meningitis is accompanied by encephalitis,myelitis, or lumbosacral myeloradiculitis. These patients should receive acyclovir10 mg/kg IV every 8 hours for 14 to 21 days.25 In milder cases or in which symptomsimprove, therapy may be transitioned to oral valacyclovir 1000 mg 3 times daily orfamciclovir 500 mg 3 times daily for a 10-day course. The role of antiviral drugs isuncertain in cases in which VZV and HSV infection present solely with aseptic menin-gitis without neurologic complications, and clinical practice varies from symptomatictreatment only to full courses of antiviral medications used for encephalitis or myelitis.

A more recently recognized cause of aseptic meningitis is HIV.26,27 During acuteinfection, up to 24% of patients may have clinical signs of meningitis.28 Current guide-lines offer conflicting treatment recommendations for initiation of antiretroviral therapy(ART) for aseptic meningitis, but in severe cases this may be a reasonableapproach.29,30 Later in the disease process, viral breakthrough (from poor adherence,treatment interruption, or development of resistant viral strains) may manifest as acuteor subacute meningoencephalitis. Treatment with effective ART often leads to rapidimprovement.31

ACUTE MENINGITIS DUE TO OTHER CAUSES

Many other infectious agents, including fungi, atypical bacteria, and parasites, as wellas noninfectious processes, may cause acute meningitis. However, compared withbacterial and viral meningitis, subacute and chronic meningitis are more typical ofthese causes, which are discussed later.

Chronic Meningitis

The course of subacute and chronic meningitis is more indolent than acute meningitis,occurring over days to weeks or even months. Common presenting symptoms areheadache, neck stiffness, and fever. Patients often do not present with the completeclinical spectrum, and symptoms are usually mild compared with acute meningitis.However, in time, focal neurologic deficits and hydrocephalus develop. More aggres-sive causes often lead to significant basal cerebral inflammation, manifested by CNpalsies, vasculitis of the circle of Willis, and CSF outflow obstruction (Fig. 1). In partic-ular, tuberculous, spirochetal, fungal, parasitic, sarcoid, and neoplastic meningitidesare capable of more severe basal inflammation. Another feature of these forms ofchronic meningitis is asymmetric, multifocal limb and truncal radiculopathies withcorresponding sensory, motor, and reflex changes. More focal regional neuropathiescan sometimes develop, particularly cauda equina syndrome.

Although pyogenic bacteria and viruses are the most common causes of acutemeningitis, chronic meningitis has a wider differential including many forms of infec-tious and noninfectious diseases (Box 1). The same properties that lead to a moreindolent course also make the infectious causes of chronic meningitis more difficultto identify by routine methods, namely lower colony counts in the CSF and fastidious

Fig. 1. Fluid-attenuated inversion recovery (A) and T1 postcontrast axial (B), coronal (C), andsagittal (D) magnetic resonance imaging (MRI) showing basal T2 hyperintensity and lepto-meningeal enhancement, as well as hydrocephalus, in a patient with subacute granuloma-tous meningitis.

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organisms that are difficult to grow in culture. Often historical or indirect evidencesuggests the diagnosis. Host factors, including geographic origin or travel, unusualexposures, and especially immunocompromised states, are important clues thatnarrow or broaden the differential. Many of the causes of chronic meningitis also affectother organs, so review of systems and physical examination should target specificsystemic symptoms and signs associated with particular infectious and noninfectiouscauses (Table 3). In particular, evaluation of eyes, lymph nodes, lungs, joints, and skinare essential. Likewise, in addition to CSF studies and neuroimaging, which are oftennonspecific, laboratory and radiographic studies directed at systemic manifestationsoften provide indirect evidence for certain causes or an extra-CNS source for biopsy.

Box 1

Causes of chronic meningitis

Infectious

Bacteria

Parameningeal infections

Partially treated acute bacterial meningitis

Endocarditis with CSF seeding

Mycobacterium tuberculosisa,b

Borrelia burgdoferia

Treponema palliduma

Ehrlichia chaffensisa

Leptospira spp

L monocytogenes

Anaplasma phagocytophila

Babesia spp

Brucella spp

Rickettsia typhi

Rickettsia prowazekii

Rickettsia rickettsii

Viruses

HIVa

Enterovirus (agammaglobulinemia)

Cytomegalovirus

Herpes simplex type 2

Lymphocytic choriomeningitis virus

Mumps

VZV

Fungi

Cryptococcus neoformansa,b

Coccidioides immitisa,b

Histoplasma capsulatuma,b

Blastomyces dermatitidisa,b

Aspergillus spp

Candida sppa

Parasites

Taenia soliuma,b

Acanthamoeba spp

Angiostrongylus cantonensis

Toxoplasma gondii

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Noninfectious

Vasculitis

Primary central nervous system vasculitisb

Churg-Strauss syndromeb

Wegener granulomatosisb

Cogan syndrome

Paraneoplastic central nervous system vasculitis

Connective Tissue Disease

Systemic lupus erythematosusa

Rheumatoid arthritis

Sjogren syndrome

Other inflammatory

Neurosarcoidosisa

Hypertrophic pachymeningitisb

Behcet disease

Chronic benign lymphocytic meningitis

Persistent neutrophilic meningitis

Vogt-Koyanagi-Harada (VKH) syndrome

Chemical

Dermoid cysta

Craniopharyngioma

Embryonal tumors

Epidermoid cyst

Teratoma

Craniotomya

Subarachnoid hemorrhage

Intravenous immunoglobulina

Trimethoprim-sulfamethoxazolea

Intrathecal agents (including contrast dye)

Nonsteroidal antiinflammatory drugs (ibuprofen)

Monoclonal antibodies (OKT3)

Neoplasticb

Breasta

Lunga

Melanomaa

Gastrointestinal

Non-Hodgkin lymphoma

Hodgkin lymphoma

Leukemiaa

Angiocentric lymphoma

a More common causes in the United States.b More severe forms.

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Table 3Diagnostic clues for select causes of chronic meningitis

Disease History/Exposures Examination Studies Comments

Tuberculosis Any developing country;incarceration; HIV; previouspulmonary TB

Lymphadenopathy; cranial nerveII and VI palsies

PPD, interferon-g assay, chestradiography; CSF AFB smear,mycobacterial culture, PCRall insensitive

Multiple large-volume (R10 mL[10 cc]) LPs increases yield onculture; paradoxic worseningmay occur early in treatment

Lyme disease Northeastern, mid-Atlantic,northern Midwest; northernEurope; wooded areas; ticks;summer, fall; previous rash

Erythema migrans; cranial nerveVII palsy (may be bilateral),radiculopathy with atrophy;arthritis

Serum ELISA screen, Western blotconfirmation; CSF EIA withpaired serum; EKG forconduction block

Usually occurs in earlydisseminated disease, but rarelyserology is negative; repeat ifhigh suspicion

Syphilis Prostitution, male sex with men,HIV; previous chancre

Papular rash on palms and soles;lymphadenopathy; opticneuritis

Serum RPR, TPPA or FTA-ABS;CSF VDRL, FTA-ABS

CSF VDRL is specific but insensitive;if high suspicion and serum ispositive, consider treatmenteven if CSF VDRL is negative

Cryptococcosis HIV or other immunosuppression Focal neurologic signsif granuloma

CSF India ink, culture, Ag (LAor EIA); serum, urine, BAL Ag(LA or EIA); blood culture

CSF may be bland, especiallyin HIV; increased intracranialpressure often requiresrepeated LP or shunting

Coccidioisis Arid regions including southernCalifornia and Arizona

Focal neurologic signsif infarctions

MRI for basal vasculitis andinfarctions; serum and CSF Ab(CF or ID); eosinophilicpleiocytosis

Requires treatment for life

Histoplasmosis Ohio and Mississippi River valleys,southeastern Africa, and SouthAmerica; work with soil, caves;HIV or otherimmunocompromise

Respiratory sounds, retinitis CSF culture, Ag testing, Ab (CF);blood fungal cultures; serumAg (ELISA) and Ab testing, PCR;urine Ag

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Blastomycosis Ohio and Mississippi River valleys,Great Lakes; forested areas;immunocompromise

Respiratory sounds; papules orpustules on face, neck,extremities

CSF culture, wet preparation,cytolog (although all lowyield); utum culture, Abtesting y RIA, biopsy

Rare, difficult to identify directly

Candidiasis Head trauma or surgery;indwelling vascular catheter;intensive care unit

Thrush CSF stain culture; blood culture,serum ,3)-b-D-glucan

Usually nosocomial

Sarcoidosis Higher incidence in blacks;previous pulmonary, skin,or eye involvement; endocrineabnormalities; ankle arthritis

Erythema nodosum,lymphadenopathy, parotitis,uveitis; bitemporal visual-fielddefects; cranial nerve VII palsy(may be bilateral)

CSF gluco e may be low; MRIwith n dular and infiltratingenhan ment, T2 changes,especia ly in hypothalamus;PET to entify extra-CNS sitesfor bio sy

Meningeal biopsy is definitive, buthigh morbidity so extra-CNSsites are preferred; ACE is nothelpful in diagnosis but issometimes used to monitordisease activity

Neoplasm Known cancer; weight loss, nightsweats; numb chin

Cranial nerve III, IV, VI palsy;cranial nerve V lesion

CSF cytol gy and flow cytometry;MRI wi nodular enhancement;periph ral flow cytometryor PET- T body may discloseprimar

Large-volume CSF, repeat LP, andimmediate analysis increaseyield for cytology; poorprognosis

Abbreviations: Ab, antibody; ACE, angiotensin converting enzyme; AFB, acid-fast bacilli; Ag, antig n; BAL, bronchoalveolar lavage; CF, complement fixation; EIA,enzyme immunoassay; EKG, electrocardiogram; ELISA, enzyme-linked immunosorbent assay; FTA- BS, fluorescent treponemal antibody absorption; ID, immuno-diffusion; LA, latex agglutination; PCR, polymerase chain reaction; PET, positron emission tomogr phy; PPD, purified protein derivative; RAI, radioimmunoassay;RPR, rapid plasma reagin; TB, tuberculosis; TPPA, Treponema pallidum particle agglutination; VD L, venereal disease research laboratory.

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Chest radiography is especially important because many causes of chronic meningitisare transmitted through or affect the respiratory system. Based on host factors andsystemic symptoms and signs, studies should be tailored to assess the most likelycauses, but expanded as needed.

Tuberculous Meningitis

Tuberculosis (TB) remains the leading cause of chronic meningitis in developingcountries and an important, but less common, cause in industrialized countries.Risk factors for tuberculous meningitis (TM) in adults include emigration from devel-oping countries, advanced age, alcoholism, immunosuppressive medications, malig-nancy, and HIV.32–40 Although bacteria typically spread hematogenously duringsystemic infection to seed the meninges in acute bacterial meningitis, foci of myco-bacteria in the subependymal lining of the brain and meninges serve as a source ofslow dissemination within the CSF in TM, so-called Rich foci.41 This often occursduring primary infection in developing countries, where immune responses in under-nourished children fail to control the initial proliferation. In developed countries, mostcases occur during reactivation of disease.33 Typical clinical features includesubacute course (more than 5 days), headache, fever, depressed mental status,and focal neurologic deficits including CN palsies (especially CN II and VI, followedby CN III and VII).35,40,42–44 Vomiting, night sweats, and weight loss are nonspecific,but common, findings.43,45 HIV does not seem to affect the clinical presentation ofTM, although CSF tends to be less inflammatory and survival is decreased.46–50

Laboratory screening often reveals hyponatremia, which may be due to a syndromeof inappropriate diuretic hormone or cerebral salt wasting. Chest radiograph isabnormal in around 50% of patients, and lung disease can sometimes provide anextra-CNS source for bacteriologic diagnosis.40,42,43 The tuberculin skin test is notreliable in TM; only half of adult patients will manifest a positive skin reaction, likelyrelated to the general immune state that predisposes to TM.40,43 A whole-bloodassay is now available that detects interferon-g release in response to exposure tosynthetic proteins similar to mycobacterial antigens. Commercially available asQuantiFERON-TB gold and T-SPOT.TB, these assays have sensitivities comparablewith the tuberculin skin test for detection of latent TB, but are not approved fordetection of active infection.44,51–53 Although their reliability in immunocompromisedpatients has not been fully assessed, they may add to discrimination of TB exposurein patients who have received prior bacille Calmette-Gu�erin (BCG) vaccination.51

Neuroimaging with CT or magnetic resonance imaging (MRI) is useful to assess forbasal leptomeningeal thickening and enhancement, hydrocephalus, infarcts, orenhancing mass lesions, but these findings are not specific to TM.54–58 The typicalCSF pattern is also nonspecific: increased opening pressure, low glucose, moder-ately increased protein, and a moderate lymphocytic pleocytosis.38,42,59,60 Definitivediagnosis of TM is achieved by visualization on CSF acid-fast bacilli (AFB) smear orgrowth of mycobacteria on CSF culture. The sensitivity of these methods is depen-dent on laboratory technique, with published sensitivities for AFB staining rangingfrom less than 20% to around 90%. Larger and repeated CSF samples (even duringthe first 2 weeks after initiating empiric treatment), centrifugation of CSF, and stainingthe CSF pellet have been documented to increase the yield of AFB staining.35,38,42,61

Culture is the gold standard for diagnosis and provides important antimicrobialsusceptibility data. However, cultures take several weeks to grow and even multiplelarge-volume CSF samples improve sensitivity from 30% in a single sample to only80% with 3 large-volume (30 mL) samples. Taking larger volumes (at least 6 mL),using the last collection tube, concentrating CSF through centrifugation, and

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culturing in liquid media improves yield.35,37,38,42,61 More recently, identification ofmycobacteria through nucleic acid amplification (NAA) has been used for rapid diag-nosis, with 2 US Food and Drug Administration (FDA)–approved assays for use inrespiratory samples, but its sensitivity in CSF (56% in one meta-analysis) is similarto culture.62,63 It may have advantages in cases in which antimicrobial treatment isinitiated before CSF sampling, but it is not yet widely available in developing coun-tries.64 Biopsy of affected tissue, such as enlarged lymph nodes or abnormal andaccessible thickened meninges seen by brain MRI, may occasionally be neededand helps by revealing caseating granulomas and showing AFB in tissue stainingor culture.

No randomized controlled trials have been performed to define optimal treatment ofTM, but guidelines are extrapolated from the treatment of pulmonary TB.44,65,66 Initialinduction includes isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months(see Table 4 for dosing). Most experts recommend an additional 10 months of isoni-azid and rifampin, with length adjusted based on clinical scenario.44,65,66 As in acutebacterial meningitis, corticosteroids have a role in adjunctive treatment of TM forreducing mortality and morbidity. In patients not infected with HIV but with TM of allgrades of severity, corticosteroids should be given in the form of dexamethasone12 to 16 mg daily in divided doses for 3 weeks, followed by a 3-week taper.44,65,67

However, current evidence does not support the use of corticosteroids in patientswith TM and HIV.67 For patients with communicating hydrocephalus, diureticsincluding acetazolamide (10–20 mg/kg/d) and furosemide (40 mg daily) constitutefirst-line treatment.44,68 For those who fail medical management or with noncommuni-cating hydrocephalus, surgical shunt procedures are indicated, usually with a ventricu-loperitoneal diversion.69 Monitoring for response to treatment often revealsa paradoxic response in CSF parameters: protein levels increase, neutrophilicpredominance develops, and bacilli become apparent in smears that were previouslynegative. Effective treatment may unmask an underlying tuberculoma. These earlyparadoxic responses do not necessarily indicate failure of antimycobacterial therapy,but represent effective lysis and secondary inflammation. However, as the incidenceof multiple drug resistant (MDR) TB increases, careful monitoring for response anddrug sensitivity will be important. The treatment of MDR TM requires expert infectiousdisease consultation and is beyond the scope of this review. In patients with sus-pected TM, empiric therapy should be initiated as early as possible becauseoutcomes are significantly worse with delayed treatment. Given the insensitivemethods for detection and common worsening that can occur with effective treat-ment, therapy should be continued for a full course unless an alternative cause isdiscovered.44

Table 4Antibiotic regimen for TM

Agent Dose Duration Comments

Isoniazid 300 mg daily 12 mo Give pyridoxine to prevent neuropathy;monitor liver toxicity

Rifampin 600 mg daily 12 mo Monitor liver toxicity; interacts with PIsand NNRTs for HIV; substitute rifabutin

Pyrazinamide 15–30 mg/kg (max 2 g) 2 mo Monitor liver toxicity

Ethambutol 15–25 mg/kg (max 2.5 g) 2 mo Monitor optic neuropathy

Abbreviations: NNRTs, nonnucleoside reverse transcriptase inhibitors; PIs, protease inhibitors.

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Fungal Meningitis

Fungal meningitis is typically a disease of immunocompromised patients, and the inci-dence has increased as a result of HIV, posttransplantation immunosuppression,corticosteroid use, and cancer chemotherapy.70 The most common fungal causesof meningitis are C neoformans and Candida spp, and both are ubiquitous. Lesscommon but important pathogens (and their endemic areas) include the dimorphicfungi C immitis (desert Southwest), H capsulatum (Ohio and Mississippi River Valleys),and B dermatitidis (Midwest, Southeast, and mid-Atlantic). Several other fungalspecies may cause meningitis, but usually with other predominant manifestationssuch as encephalitis or abscess. Most of these fungi cause primary pulmonary infec-tion with secondary seeding to the CNS; Candida spp are normal human flora that gainaccess to the CNS, most commonly through trauma or surgery. The clinical presenta-tion of fungal meningitis is nonspecific, although certain pathogens have a predilectionfor certain manifestations: basal vasculitis and infarctions with Coccidioides (Fig. 2),and basal granulomas with Cryptococcus (cryptococcoma). Neuroimaging by MRIis also nonspecific, but may reveal leptomeningeal enhancement, hydrocephalus,infarcts at the base of the brain, or cystic granulomas in the basal ganglia and cerebralpeduncles as a result of the spread of Cryptococcus along Virchow-Robin perivascu-lar spaces. The CSF pattern is often indistinguishable from tuberculous and othercauses of chronic meningitis (Table 5), with low glucose, increased protein, andlymphocytic pleocytosis. However, a polymorphonuclear predominance may occurwith Blastomyces and a prominent eosinophilia with Coccidioides. In patients infectedwith HIV with cryptococcal meningitis, some or all of these parameters may be normal,whereas the CSF has abundant organisms. With the exception of Cryptococcus,which may be identified on India ink stain or grown in culture in most cases, mostfungal pathogens are difficult to isolate. As with TB, larger CSF samples and centrifu-gation may increase the yield. In some cases, CSF obtained from C1-C2 puncture byinterventional neuroradiology may yield the organism, whereas the CSF from LPproves negative; the adhesive meningitis at the base of the brain may prevent theorganisms from reaching the lumbar thecal sac in large numbers. By a similar mech-anism, ventricular fluid obtained from ventricular drainage necessitated by severe

Fig. 2. T1 postcontrast (A) and diffusion-weighted (B) MRI showing basal leptomeningealenhancement and a focus of restricted diffusion in the pons of a patient with coccidioidalmeningitis and secondary vasculitis.

Table 5Treatment of fungal meningitis

Fungus Treatment

C neoformans Amphotericin B 0.7–1 mg/kg/d 1 flucytosine 100 mg/kg/d � 2 wk, thenfluconazole 400 mg/d � 10 wk; then fluconazole 200 mg/d indefinitely

C immitis Fluconazole 400 mg/d for life

H capsulatum Liposomal amphotericin B 5 mg/kg/d � 4–6 wk, then itraconazole 200 mg2–3�d � 1 ya

B dermatitidis Liposomal amphotericin B 5 mg/kg/d � 4–6 wk, then azole for 1 ya

(fluconazole 800 mg/d, itraconazole 200 mg 2–3�d, or voriconazole200–400 mg 2�d)

Candida spp Liposomal amphotericin B 3–5 mg/kg/d 1 flucytosine 100 mg/kg/d �2 wk,then fluconazole 400–800 mg/d � 4–6 wkb

a Continue indefinitely in patients with HIV who do not reconstitute immune function withcombined antiretroviral therapy (cART).b Removal of any indwelling device is recommended.

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obstructive hydrocephalus may be deceptively normal. In such cases, spinal fluidobtained from LP may reveal the abnormalities.

Treatment of most fungal meningitides involves induction with amphotericinfollowed by maintenance with an azole for prolonged periods (see Table 5). CSF diver-sion may be necessary, especially with Cryptococcus. In patients with HIV who arebeginning combined antiretroviral therapy (cART), clinical worsening or new onset ofcryptococcal meningitis may occur with immune reconstitution inflammatorysyndrome (IRIS). This condition may be difficult to distinguish from primary crypto-coccal meningitis, but usually HIV parameters are improving rapidly and CSForganism burden is low or undetectable. Corticosteroids may be considered in severecases once IRIS is identified.

Lyme Meningitis

The spirochete B burgdorferi is the causal agent of Lyme disease. The Ixodes genus ofticks serve as the vector, and the predominant animal reservoirs include deer andsmall rodents. Thus, Lyme disease is more prevalent in temperate wooded andsuburban areas. In the United States, endemic areas include the Northeast,mid-Atlantic, and northern Midwest regions; the Pacific Northwest has a lower butsignificant incidence. Lyme disease is also endemic to Northern Europe. Originfrom, or travel to, these regions increases the risk for Lyme disease. Early localizeddisease occurs within days to weeks of infection and manifests as erythema migrans,a red and warm expanding rash, classically with central clearing. In early disseminateddisease, patients may develop multiple skin lesions, atrioventricular block, and neuro-logic manifestations. The most common neurologic syndromes are subacute tochronic lymphocytic meningitis, facial nerve palsy, and painful radiculitis. Meningitistypically occurs weeks after erythema migrans, but not all patients have precedingrash. By far the most common symptom is headache, and fewer patients experienceneck stiffness, photophobia, or nausea.71 Meningitis may be accompanied by CNdeficits, 80% to 90% of which are facial palsy, which can be bilateral in a significantminority.72 A painful, burning radiculitis (as well as plexitis or mononeuritis) may alsooccur, typically leading to weakness and atrophy in the distribution of the nerve rootaffected. This constellation of symptoms with lymphocytic pleocytosis on CSF exam-ination in a patient exposed to an endemic area is highly suggestive of Lyme disease.

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Because isolation of Borrelia is difficult, indirect assays are used to make the labora-tory diagnosis. The serum enzyme-linked immunosorbent assays (ELISA) antibody isbased on detection of IgM and IgG to whole organism. It is highly sensitive but notspecific, and so is used for screening. Serum Western blot is more specific and canconfirm exposure and timing of infection based on IgM and IgG to antigens derivedfrom specific bacterial components.73 CSF examination typically reveals normalglucose, mildly increased protein, and a lymphocytic pleocytosis. Intrathecal produc-tion of antibody can be measured by capture enzyme immunoassay of CSF and pairedserum, comparing the ratio of specific and total IgG in serum and CSF.74,75

In the United States, patients with Lyme meningitis should be treated with ceftriax-one 2 g IV daily for 14 to 28 days. In Europe, studies have shown equivalence betweenparenteral ceftriaxone and oral doxycycline at a dose of 100 mg twice daily for neuro-logic Lyme disease.75,76 Despite the persistence of vague symptoms in some patientsfollowing effective treatment (post-Lyme syndrome), there is no evidence for effective-ness of any additional antibiotic course.

Syphilitic Meningitis

Chronic meningitis is a frequent feature of syphilis, which is caused by another andancient spirochete, T pallidum Neurosyphilis warrants consideration in the differentialdiagnosis of chronic lymphocytic meningitis, even in these times. Most commonly, it isdetected as an asymptomatic meningeal reaction when CSF is tested in a personfound to have positive serology for syphilis but no neurologic abnormalities; a conditiontermed asymptomatic neurosyphilis. Chronic lymphocytic meningitis also underliesmeningovascular syphilis. Clinically, this is dominated by stroke syndromes due toinfarctions in the middle and anterior cerebral artery distributions, as well as lacunarsyndromes of the basal ganglia and brainstem due to endarteritis obliterans. It occursup to 10 years after primary infection. Similar chronic meningitis accompanies the rareprogressive dementia of frontotemporal type due to treponemal encephalitis, some-times with MRI abnormalities predominating in the temporal lobes.77 A more robustCSF response occurs in syphilitic meningitis, especially during secondary syphiliswithin the first 2 years of infection. This condition presents as a subacute illnesswith headache, neck stiffness, and skin rash, characteristically affecting the palmsand soles of feet. As with Lyme meningitis, the predominant presenting symptom ofsyphilitic meningitis is headache; but neck stiffness, fever, and CN deficits (especiallyCN II, VII, VIII, and III) occur frequently. In patients coinfected with HIV, ocular andoptic nerve involvement is particularly common and aggressive.78 Risk factors forsyphilis in the United States include crack cocaine abuse associated with prostitutionand male sex with men. Patients with HIV are at increased risk for syphilis, as well asprogressing to neurosyphilis, and HIV should be tested in anyone diagnosed withsyphilis.78–80 Because T pallidum cannot be grown in culture, diagnosis rests on indi-rect evidence. Symptomatic or suspected syphilis is screened for with a nontrepone-mal test such as rapid plasma reagin (RPR) or venereal disease research laboratory(VDRL) and confirmed with treponema-specific tests including fluorescent treponemalantibody absorption (FTA-ABS) or T pallidum particle agglutination (TPPA). Basic CSFstudies show nonspecific mild lymphocytic pleocytosis, normal glucose, and mildlyincreased protein. An increased white blood cell (WBC) count in a patient with positiveserum testing and clinical meningitis is suggestive, but patients with HIV in particularmay have an increased CSF WBC count from HIV itself. The gold standard for diag-nosis is VDRL from CSF, which is highly specific but only 30% to 70% sensitive forneurosyphilis.81–83 CSF FTA-ABS is more sensitive but not specific, because false-positives are common, especially with high serum levels.84–86

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Syphilitic meningitis, as with any manifestation of neurosyphilis, should be treatedwith aqueous crystalline PCN G 2 to 4 million units IV every 4 hours for 10 to 14days.75 Follow-up CSF studies should be performed every 6 months to confirmdecrease in WBC and CSF VDRL. Those in whom WBC do not decline should beretreated.

Neurosarcoidosis

Sarcoidosis is a systemic disease characterized by noncaseating granulomatousinflammation, most commonly affecting the lungs, eyes, lymph nodes, and skin.Neurologic involvement occurs in 5% to 15% of cases, often as the presenting mani-festation.87–90 Its predilection for the meninges and parenchyma at the base of thebrain explains the most common symptoms of neurosarcoidosis. CN palsies, espe-cially of the facial nerve, are the most frequent manifestation of neurosarcoidosis,occurring in 50% to 75% of cases. Aseptic meningitis commonly accompanies CNdeficits, but may occur in isolation in up to 30%.88 Patients often present with head-ache, but only a minority display signs of meningismus.91 In this context, accompa-nying ankle arthritis is particularly suggestive. The typical CSF profile consists ofmoderately increased opening pressure, mild lymphocytic pleocytosis, moderatelyincreased protein, and normal to low (occasionally very low) glucose.89–92 Granuloma-tous involvement of the basal meninges may also lead to hypothalamic and pituitaryinvolvement, presenting as neuroendocrine disorders, chiasmal visual impairment,or hydrocephalus. In addition to brain, spinal cord is frequently involved and may beextra- or intramedullary.89–92 MRI most commonly shows nonspecific periventricularwhite matter T2 foci, but may also reveal leptomeningeal enhancement at the baseof the brain with infiltration and T2 changes in hypothalamus or other affected paren-chyma.93–95 Definitive diagnosis can be made with biopsy of meninges or other CNSmaterial showing noncaseating granuloma, but the morbidity associated with thisdiagnostic procedure precludes its routine use. More typically, CT and sometimespositron emission tomography scan will disclose an extra-CNS focus of granulomawhich is more amenable to biopsy.96

There are no large studies focused on the treatment of neurosarcoidosis specificallywith meningitis as the cardinal manifestation, particularly regarding the long-termoutcomes and need for long-term treatment with immunosuppressive drugs. Initialtreatment consists of corticosteroids: the meningitis typically responds well to thetreatment with resolution of CN palsies and improvement in the hydrocephalus.However, severe obstructive hydrocephalus may require ventricular drainage untilimprovement occurs in response to steroid treatment. Most patients eventuallybecome steroid-dependent or -resistant, so additional steroid-sparing immunomodu-latory treatments should be started early. Methotrexate is commonly used to helplower steroid dosing, but many newer immunomodulators have shown anecdotalsuccess.90,92,97

Neoplastic Meningitis

Infiltration of the subarachnoid space by neoplastic cells leads to neoplastic menin-gitis, which may be carcinomatous, lymphomatous, or leukemic. Although mostpatients have a known metastatic process at the time of diagnosis, meningitis maybe the presenting symptom of malignancy in 5% to 20% of cases.98–100 Longerduration of symptoms and prior diagnosis of malignancy are more likely with solidtumors than with hematologic malignancies, in which meningitis is frequently diag-nosed with or before the underlying malignancy.99,101 Presenting symptoms aremost commonly related to increased intracranial pressure (headache), CN infiltration

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(diplopia or numb chin syndrome), or spinal cord and nerve root infiltration (caudaequina syndrome).98–101 Any of these symptoms in the setting of known malignancyshould prompt strong suspicion for neoplastic meningitis. MRI most often showsdiffuse or focal nodular leptomeningeal enhancement, sometimes tracking intosulci.102,103 Because of gravity and slower CSF flow, the most common locationsfor metastatic deposition are the sylvian fissures, the base of the brain, and the caudaequina. MRI should be performed before LP, because removal of CSF can causeartifactual meningeal enhancement. The typical CSF pattern in neoplastic meningitisis nonspecific and includes increased opening pressure, low glucose, increasedprotein, and mild lymphocytic pleocytosis.99–101,104 In suspected cases, at least10 mL (10 cc) of CSF should be sent for cytology for immediate processing. InitialLP is positive in around 50% of cases, but a second LP increases the yield to 75%.When disease is limited to the brain, LP is less sensitive than cisternal or ventriculartap. In hematologic malignancies, flow cytometry increases sensitivity beyondcytology alone.105 Tumor markers, when present in concentrations greater than thoseexpected from serum contamination, can give clues to the diagnosis. For cases inwhich meningitis is the presenting symptom, a systemic search for tumor should besought with CT of the chest, abdomen, and pelvis, and other studies targeted at thepatient population (eg, testicular ultrasound for young men). Although dependent ontype of presentation and systemic burden, leptomeningeal involvement generallyportends a poor outcome, with most untreated patients dying within weeks to monthsof diagnosis. As a rule, neurologic deficits are permanent.98,100,106

The treatment of neoplastic meningitis includes intrathecal and systemic chemo-therapy, radiation, and surgery directed at relief of increased intracranial pressureand debulking of any solid component. Specific therapies require oncology consulta-tion and are beyond the scope of this review.106

RECURRENT MENINGITIS

Rarely, meningitis may recur after complete resolution, in some cases several times inmany years. As with acute meningitis, recurrent meningitis may be bacterial or aseptic,with correspondingly varied causes and treatments (Table 6).

Recurrent Pyogenic Meningitis

Recurrent pyogenic meningitis is characterized by episodes of neutrophilic pleiocyto-sis and CSF inflammation due to pyogenic bacteria. Patients present with typicalsymptoms and signs of acute bacterial meningitis. Most commonly this is due toCSF leak; an anatomic communication between the subarachnoid space and a non-sterile cavity or skin. Defects in the CSF barrier may be congenital or acquired

Table 6Select causes of recurrent meningitis

Infectious Noninfectious

Viral (especially HSV-2, rarely HSV-1) Chemical (cholesterol leakage from dermoid cystor craniopharyngioma)

Pyogenic bacteria (anatomic defect) Drug-induced (ibuprofen, TMP-SMX, IVIG, OKT3)Chronic inflammatory diseases (VKH, sarcoidosis,

SLE, vasculitis, Behcet)

Abbreviations: IVIG, intravenous immune globulin; SLE, systemic lupus erythematosus; TMP-SMX,trimethoprim-sulfamethoxazole; VKH, Vogt-Koyanagi-Harada.

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(traumatic or iatrogenic). Common pathogens include those bacteria associated withnosocomial acute bacterial meningitis. Less commonly, patients with immune defi-ciency (agammaglobulinemia or complement deficiency) may experience recurrentmeningococcal meningitis. A parameningeal source of recurrent meningitis in theform of sinus tracks due to dysraphism should be sought in the midline over the lumbarregion or over the occiput. The abnormality can be subtle, but a tuft of hair or nevus inthe region should raise suspicion of an associated sinus track continuous with the CSFspace. In all patients with recurrent pyogenic meningitis, a source of CSF leak shouldbe sought. In patients with CSF rhinorrhea, a sample can be tested for b-2 transferrin,confirming the fluid as CSF. If high-resolution CT of the skull base and MRI are unre-vealing, CT contrast myelocisternography or radiotracer cisternography may be help-ful in detecting the CSF leak and location. The initial treatment approach is the sameas for acute bacterial meningitis. Definitive treatment is repair of the CSF leak whenpossible.

Recurrent Aseptic Meningitis

Often termed Mollaret meningitis after the French neurologist who described 3 casesin 1944, recurrent aseptic meningitis typically has a benign course of multiple self-resolving episodes of lymphocytic meningitis. Patients usually present acutely withheadache, fever, and neck stiffness, but focal neurologic deficits or seizures mayoccur. Symptoms resolve over days, and recurrences may be separated by monthsor years before winding down. Basic CSF studies reveal a profile similar to viral menin-gitis. Cytologic examination of CSF, especially when conducted early in the course ofan episode, may reveal atypical monocytes, so-called Mollaret cells, which may havea ghostlike or footprint appearance.107 Although these are not pathognomonic, theyare characteristic of recurrent aseptic meningitis. Historically, most cases of recurrentaseptic meningitis have been idiopathic, but, more recently, HSV-2 has been the mostcommonly identified causal agent.108–110 CSF should be analyzed immediately afterLP and as early as possible in the course of an episode, with specific consultationwith the cytology department to assess for Mollaret cells. PCR should also be sentfor HSV DNA. Although no controlled treatment trials have been performed, mostexperts recommend acute or suppressive antiviral treatment in proven or suspectedHSV-2 recurrent meningitis.108,109,111–113

In addition to infectious causes, recurrent chemical meningitis may occur withrupture of contents from an epidermoid (usually in children) or dermoid cyst, or froma craniopharyngioma.114–118 CSF often shows a more prominent polymorphonuclearpleiocytosis than in viral meningitis. Examination of CSF under polarized light mayshow cholesterol crystals in cases resulting from the rupture of contents of cranio-pharyngioma and dermoid cyst. In cases of recurrent aseptic meningitis in which noother cause is found, contrast-enhanced MRI of the entire neuroaxis should be per-formed to exclude these possibilities. Rupture can sometimes be visualized assubarachnoid lipid deposits on MRI.119 Case reports have documented resolution ofmeningitis with surgical removal of the lesions. Rarely, idiopathic inflammatory condi-tions may be associated with recurrent aseptic meningitis, including VKH syndrome,defined by inflammation directed at melanocytes and manifested as uveitis, skinand hair depigmentation, and lymphocytic meningitis. Treatment consists ofcorticosteroids.

Drug-induced aseptic meningitis, although rare, warrants consideration in cases ofrecurrent aseptic meningitis because this cause can be easily overlooked. Nonste-roidal antiinflammatory drugs (especially ibuprofen), antibiotics (especially sulfame-thoxazole-trimethoprim), therapeutic monoclonal antibodies (especially OKT3), and

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intravenous immune globulin are the best-documented causes of drug-inducedmeningitis. This rare drug reaction should be suspected, particularly in patients withunderlying autoimmune connective tissue diseases like systemic lupus erythemato-sus. Typical CSF parameters include a moderate polymorphonuclear predominantpleiocytosis and mildly increased protein but normal glucose.120 Careful history oftemporal relationship to use of the drug, recurrences with inadvertent rechallengewith the medication, and eosinophilia in the CSF (if present) suggest the diagnosis.It is essential to rule out other causes of the meningitis because the diagnosis isone of exclusion, but recognizing this cause is important to prevent recurrent bouts.Cessation of the medication typically leads to resolution without other sequelae.

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