SEMINARS IN NEUKOLOGY-VO1,UME

12, NO. 3 SEPTEMBER 1992

Chronic Meningitis

T h e term "chronic meningitis" applies to many diverse disease categories, unified by the persistent presence of cerebrospinal fluid (CSF) abnormalities, and accompanied by variable symptoms of meningeal irritation and global o r focal cerebral dysfunction that may be persistent, recurrent, o r relentlessly progressive. Many of these disease processes may present diagnostic difficulties because of their rare occurrence, varying presentation, o r lack of unique historical, physical, o r laboratory features. Most physicians encountering a patient with the clinical syndrome of chronic meningitis will have little personal experience in the diagnosis o r management of many of the disease entities that must be considered; and, furthermore, the often relentless disease progression precludes a leisurcly approach to diagnosis and treatment. These diagnostic difficulties provided the impetus for previous reviews of chronic m e n i n g i t i ~ , 'in .~ which the term "chronic" implied 4 weeks of clinical observation. Diseases, mostly infectious, that present in a more acute o r fulminating fashion will already have been considered and are covered elsewhere in this issue. Nevertheless, a thorough familiarity with the diseases commonly causing chronic meningitis will allow earlier diagnosis and treatment.

HISTORY Rcccnt travel history o r place of origin can be helpful in recognizing infection by Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, o r Borrelia burgdorferi. Parasites are prevalent in less developed countries, such as Cysticercus in Mexico, South America, and Asia or Angiostrongylus cantonensis in Asia.' Brucellosis occurs in the Mediterranean region; in the United States, exposure to cattle, unpasteurized dairy products, o r vaccines may rarely result in infection with Brucella ~ r g a n i s m s . ~ Exposure to sulfonamides, isoniazid (INH), ibuprofen, tolmetin, o r iophendylate (Pantopaque) dye may provoke a hypersensitivity meningiti~.~.' Person-to-person spread is important in some infectious diseases. Ask about recent o r remote exposure to tuberculosis, history of positive purified protein derivative (PPD), skin test, o r previously treated tuberculosis.

A careful sexual history, including exposure and previous gcnital lesions or infections, may lead to a consideration of syphilis. T h e presence of risk factors for AIDS, HIV positivity, o r previous opportunistic irrfection alters the differential diagnosis (See Table 1). Infections with Candida, Aspergillus, and the Zygomycetes occur predominantly in profoundly neutropenic patients.' Meningeal involvenient typically occurs late in the .coursc of leukemia, lymphoma, cat-cinorna, blastomycosis, and Beh~et'sdisease.' In other conditions, such as sarcoidosis, spirochetal infections, o r cryptococcosis, meningitis may be a presenting o r early feature of the illness ('I'able 2). HIV infection can also causc a mild chronic meningitis characterized by headache, without encephalitis.' PHYSICAL EXAMINATION I'hysical examinatiori may indicate thc presence and extent of neurologic involvement, provide evidence of sysierriic disease, and suggcst areas for biopsy or culture. Skin rashes, nodules, abscesses, ancl sinus tracts require biopsy, culture, and histopathologic examination. Prepare an India ink slide from any cxpressed drainage. Skin tracks over blood vessels are suggestive of intravenous drug use. Hclpful rashes include erythema chronicum migrans (Lyme disease), erythema nodosurn (tuberculosis, sarcoid, histoplasmosis, coccidioidomycosis), and maculopapular (syphilis). A careful ear, nose, and throat examination may reveal evidence of invasive aspergillosis (orbits, sinuses), histoplas~nosis(palatal ulcerations o r nodules), o r Beh~et'sdisease (oral ulcers). Lymphadenopathy or hepatomegaly may provide a diagnostic biopsy site. A heart murniur may suggest eridocarditis (bacterial o r fungal [Candida]). Pulmonary evaluation may lead to a diagnosis of fungal infection, tuberculosis, sarcoiclosis, o r malignancy. Ophthalmologic exaniination may reveal choroidal tubercles (sarcoid, tuberculosis), granulomas, o r uveitis. Bitemporal herr~ianopsia (and diabetes insipidus) are typical of sellar involvernent in sarcoidosis. Papilledema and focal neurologic signs mandate head computcd tomography (CT) o r magnetic resonance imaging

Everett Neurological Center, Everett, Washington, and Division of Neurology, Univel-sity of Washington School of Medicine, Harborview Medical Center, Scattlc, Washington Reprint requests: Dr. Wilhelm, Everett Neurological Ckntcr, 2320 Ruckcr Avcnuc, Evcrctt, C$A ' 9820 1 Copyright 0 1992 by Thierne Medical Publishers, Inc., 381 Park Avenue South, New York, K Y 100 16. All rights reserved.

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Crispin S. Wilhelm, M.D., and Christina M . Marm, M.D.

CHRONIC MENINGITIS-WILHELM, MARRA

Common

Rare

Mycobacterium tuberculosis' Cryptococcus neoformans* Coccidioides immitis' Histoplasma capsulatum* Candida sp.* Aspergillus sp.*t Blastomyces dermatitidist Treponema pallidum* Borrelia burgdorferi Brucella sp. Toxoplasma gondii*t Nocardia asteroidest Actinomyces sp.t Streptococcus sp. (infective endocarditis) Cysticercust Human immunodeficiency virus'

Sporothrix schenckii

Zygomycetes (mucormycosis) Cladosporium trichoides (xylohypha bantiana) Phialophora sp. (chromoblastomycosis) Leptospira icterohaemorrhagiae Paracoccidioides brasiliensis Pseudoallescheria boydii Taenia solium Coenurus cerebralis Angiostrongylus cantonensis Enteroviruses*

Table 3. Laboratory Tests Available in Chronic Meningitis 1. Screening: complete blood count; erythrocyte sedimentation rate; chemistry profile, antinuclear antibody; rheumatoid factor; Sjogren's syndrome antigens A and 9; C3, C4, C1Q binding assay; serum protein electrophoresis; HIV 2. Serologies: antibody titer for Brucella, Toxoplasma, T. pallidum (FTA-ABS) B. Burgdorferi, Blastomyces, Histoplasma, Coccidioides, Sporothrix, measles, leptospirosis 3. Antigen assays: Cryptococcus (serum, CSF), Histoplasma antigen (serum, urine, CSF), tuberculostearic acid (CSF) 4. CSF studies: routine studies, culture (bacterial, fungal, rnycobacterial) India ink, AFB, VDRL, antibody titers for 9. burgdorferi, Histoplasma, Coccidioides, Sporothrix, cytopathology, cell surface markers (lymphoma), beta-glucuronidase, carcinoembryonic antigen (carcinoma), glial fibrillary acidic protein (gliomatosis) 5. Cultures (see text): blood, urine (prostatic massage), sputum, gastric, skin, bone marrow, nodes, liver for fungi, tuberculosis.) CSF: large volumes, prolonged incubation, 5-10% CO, (Brucella), anaerobic (Actinomyces), Sabouraud's (fungi) 6. Skin tests: intermediate strength PPD, repeat in 2 weeks if negative, second strength PPD, anergy testing, Coccidioides (prognosis). Avoid Histoplasma skin test: alters serology 7. Radiographic: Chest x-ray, spine, skull, sinus films, head CT or MRI, spine MRI, cerebral arteriogram, myelogram

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Table 1. Infectious Causes of Chronic Meningitis

*Occurs in HIV infection. tMore commonly occurs as abscess or focal lesion. *Occurs in patients with agammaglobulinemia

(MKI), looking for abscess, granuloma, or mass effect, prior to lurnbar puncture. Signs of hydrocephalus, with o r without cranial neuropathies, are found in basilar meningitis (granulomatous infection, sarcoid), but niay also indicate infiltration bv tumor. Proximal muscle weakness, tenderness, or nodularity suggests sarcoidosis. Neuropathy may be present in sarcoidosis, systeniatic lu1x1s ery~hernatosi~s, vasculitis, brucellosis, or I.yme disease, or as a remote effect of malignancy.

LABORATORY EVALUATION In enigmatic cases, a systematic and thorough collection of laboratory data is essential and should include applicable tests listed in Table 3. Many of these are also discussed under specific disease headings. A thorough pul~nonaryevaluation, including chest radiograph, possibly leading to bronchoscopy with cytologic study and biopsy, o r transthoracic biopsy, will be friritfi~li r i marly disseniiriated diseases. Body fluids that include blood, urine (after prostatic massage), gastric wasliirigs, spirturn for tubercle bacilli and fungi, and stool tor fungi require careful culturing.

Table 2.

Noninfectious Causes of Chronic Meningitis

Neoplasm Sarcoidosis Vasculitis Systemic lupus erythematosus Behqet's disease Vogt-Koyanagi-Harada syndrome Chronic benign lymphocytic meningitis Fabry's disease

T h e laboratory examination of CSF should be carefully rnorritored. I h e CSF formula may suggest a subset of diseases (Table 4). Cytologic preparations should be processed promptly, even when the cell count is normal, and repeated with adequate volumes u p to three times. In cases of suspected fungal infection, cultures of large volumes of CSF (more than 10 ml) should be hand carried to the laboratory with instructions to culture the entire amount without centrifugation (concentrated specinierls are more useful for smears than cultures). Inoculating the bottom of' an Erlenmeyer flask coated with Sabouraud's agar with a large volume of CSF may preverlt desiccation. In infectious o r carcinomatous meningitis, cisternal o r ventricular puncture for CSF culture and cytology rnay yield rnore than lumbar puncture. India ink preparations require 3 to 5 ml of CSF sedinierit (newspaper should be readable through the slide) and should be completely scanned. Irrlagirig of the neuraxis with CI' o r MKI may reveal granulomas, abscesses, infarcts, hydrocephalus, sellar processes, meningeal enhancement, hyclrocephalus, spinal cord involvement, or parameningeal foci. T h e subject is covered elsewhere in this issue of Srminurs. All biopsies of skin lesions, nodes, paranasal sinuses, liver, bone marrow, testes, or lung should be cultured for bacteria, fungi, and mycobacteria and should be examiued histopathologically. Grariuloma formation with or without caseation limits the differerltial diagnosis. When cerebral abscesses or granulomas are biopsied, both rr~eningealand brain tissue should be obtained; when it is feasible, obtain ventricular fluid. Blind meningeal biopsy and brain biopsy are also indicated in undiagnosed progressive meningitis, following cerebral arteriographv in most cases. Specific diseases causing chronic meningitis are reviewed below and elsewhere in this issue.

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Table 4.

CSF Abnormalities in Chronic Meningitis of Specific Cause

Cells - 5 0 Sarcoidosis Carcinoma Beh~et'sdisease Vasculitis Primary HIV infection Parameningeal focus Neutrophilic predominance Chemical meningitis Systemic lupus Nocardia, Actinomyces, Brucella* Aspergillus, Candida, Zygomycetes Tuberculosis* Eosinophilic pred~rninance'~~ Angiostrongylus cantonensis Taenia soliurn (cysticercosis) Gnathostoma spinigerum Schistosorna sp. Paragonimus Fasciola hepatica Coccidioides Lymphoma (especially Hodgkin's) Chemical (ibuprofen, iophendylate dye) Syphilis, tuberculosis(rare) Low CSF glucose Carcinoma Sarcoidosis Subarachnoid hemorrhage Tuberculosis Fungal infection Bacterial infection (Actinomyces, Nocardia) Syphilis Viral infection (mumps, LCM) Cysticercosis Culture negative Parasites Fungal infection (especially Coccidioides, Histoplasma, Sporothrix, Blastomyces) Infective endocarditis Lyme disease Syphilis See noninfectious causes *Persists less than 2 weeks, usually mononuclear.

INFECTIOUS CAUSES OF CHRONIC MENINGITIS TUBERCULOSIS In the preantibiotic era, tuberculosis was a common disease, although it predominantly affected children. In 1972, this held true in many parts of the developing world, where 40 to 80% of children below the age of 14 years had been exposed to Mycobacterium tuberculosis." In the US, case rates of tuberculosis fell steadily from the 1930s; the decline was accelerated by the advent of effective antituberculous therapy in 1950. Although the incidence of tuberculous meningitis has fallen concornitantly, recent case rates are still estimated to be 0. I I per 100,000.!' Furthermore, 75% of new cases occur in adults; blacks, hispanics, alcoholics, drug users, and the homeless are overrepresented in the US."'

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SEPTEMBER 1992

T h e AIDS epidemic that began in the 1980s has led to a resurgence of tuberculosis: 5 to 10% of patients with AIDS in urban centers have active tuberculosis, many cases probably due to reactivation rather than new infection.ll HIV-positive patients without AIDS present similarly to HIV-negative patients; however, disseminated disease, irlcludirig rrienir~gitis(often without concomitant pulmonary disease) is more common in advanced HIV infection and may present before AIDS is diagnosed."-" Tuberculous meningitis typically presents with fever, headache, and change in n~entalstatus, because of the rupture of' a parameningeal tuberculoma (Rich focus) irlto the subarachnoid space. Most patients have had symptonis of central nervous system (CNS) involvement tbr less than 1 month. Meningeal involvement is preceded by fever, weight loss, malaise, and pulmonary symptoms in one third of patients.15 Chest radiographs are norrrlal arid PPDs are initially nonrcactivc in 25% of cases. T h e presence of' a lateral rectus palsy is the most corrlrrlori sign of a basilar meningeal exudate. Unilateral or bilateral involvement of cranial nerves 11, 111, IV, and VII, as well as hydrocephalus, also commonly occurs. Hemiparesis, coma, or convulsions occur less frequently; they indicate advanced CNS tuberculosis. Hypothalamic inflammation or infarction may cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH). C:horoidal tubercles are more common in miliary tuberculosis. Mortalily and neurologic sequelae arc due in part to a f'ibrocollagenous reaction that leads to vascular inf'arctiorr, cranial neuropathy, demcntia, and seizures. Mortality is related to extent of infection before initiation of'therapy, and age greater than 50.15.11' I he C:SI; is usually i ~ n d e rincreased prcssurc. A moderate pleocytosis may initially be neutrophilic, b u ~ will become mononuclear within several weeks.'" Progressive hypoglycorrhachia occurs in untreated cases. Smears fbr acid-fist bacilli (AFB) are positive less than 25% of the tirrle (Fig. 1). T h e sensitivity of the AFB smear may be increased by auraniine-rhodamine staining o r by repeated sampling, and staining the pcllicle that forms whcn tuberculous CSF is left standing. CSF cultures are positive in 25 to 70% of cases of clinically apparent tuberculous meningitis. Multiple cultures are recommended hut obtaining them should not prevent prompt therapy. Sterile meningitis may rcsult from the rupture of a tubercle that releases tuberculoprotein without viable mycobactcria." CSF tuberculostearic acicl assay may be obtained f'rom the Centers for Disease Control (J.B. Brooks, Mail Stop 0 6 , CDC, Room 308-Bldg 5, Atlanta, GA 30333). Elevated levels have a high sensitivity (95%) arid specificity (99%).17Kadiolabeled bromide partition ratios also carry sensitivities and specificities of nearly 90%. CSF adenosine deaminase levels, mycobacterial antigen and arltibody, a r ~ dpolyn~erasechain reactiorl to detect M. tuberclilosis DNA have all been investigated for the rapid diagnosis of smear-negative tuberculous meningitis, and providc potentially sensitive and specific tests."IH-" C'I' or MKI scanriirrg often reveals hydrocephalus, basilar enhancement, or lucencies consistent with edema or infarction (Fig. 2). Angiography may demonstrate evidcnce of vascular darnage in the form of occlusion, narrowing, "beading," or arleurysrn formation. 7

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VOL,IJME 12, NUMBER 3

SEMINARS IN NEURO1,OGY

CHRONIC MENIN

Chronic meningitis.

SEMINARS IN NEUKOLOGY-VO1,UME 12, NO. 3 SEPTEMBER 1992 Chronic Meningitis T h e term "chronic meningitis" applies to many diverse disease categorie...
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