APPROACH TO THE PATIENT: Chronic Meningitis
The occurrence of chronic headache, hydrocephalus, cranial neuropathy, radiculopathy, and/or cognitive decline in a patient should prompt consideration of a lumbar puncture for evidence of meningeal inflammation. On occasion, the diagnosis is made when an imaging study (CT or MRI) shows contrast enhancement of the meninges, which is always concerning with the exception of dural enhancement after lumbar puncture, neurosurgical procedures, or spontaneous CSF leakage. Once chronic meningitis is confirmed by CSF examination, effort is focused on identifying the cause (Tables 37-2 and 37-3) by (1) further analysis of the CSF, (2) diagnosis of an underlying systemic infection or noninfectious inflammatory condition, or (3) pathologic examination of meningeal biopsy specimens.
Two clinical forms of chronic meningitis exist. In the first, the symptoms are chronic and persistent, whereas in the second there are recurrent, discrete episodes of illness. In the latter group, all symptoms, signs, and CSF parameters of meningeal inflammation resolve completely between episodes without specific therapy. In such patients, the likely etiologies include herpes simplex virus (HSV) type 2; chemical meningitis due to episodic leakage from an epidermoid tumor, craniopharyngioma, or cholesteatoma into CSF; primary autoimmune inflammatory conditions, including Vogt-Koyanagi-Harada syndrome, Behçet’s syndrome, systemic lupus erythematosus (SLE), and Mollaret’s meningitis; and drug hypersensitivity with repeated administration of the offending agent.
The epidemiologic history is of considerable importance and may provide direction for selection of laboratory studies. Pertinent features include a history of tuberculosis or exposure to a likely case; past travel to areas endemic for fungal infections (the San Joaquin Valley in California and southwestern states for coccidioidomycosis, midwestern states for histoplasmosis, southeastern states for blastomycosis); travel to the Mediterranean region or ingestion of imported unpasteurized dairy products (Brucella); time spent in wooded areas endemic for Lyme disease; exposure to sexually transmitted disease (syphilis); exposure of an immunocompromised host to pigeons and their droppings (Cryptococcus); gardening (Sporothrix schenckii); ingestion of poorly cooked meat or contact with a household cat (Toxoplasma gondii); residence in Thailand or Japan (Gnathostoma spinigerum), Latin America (Paracoccidioides brasiliensis), or the South Pacific (Angiostrongylus cantonensis); rural residence and raccoon exposure (Baylisascaris procyonis); and residence in Latin America, the Philippines, or Southeast Asia (Taenia solium/cysticercosis).
The presence of focal cerebral signs in a patient with chronic meningitis suggests the possibility of a brain abscess or other parameningeal infection; identification of a potential source of infection (chronic draining ear, sinusitis, right-to-left cardiac or pulmonary shunt, chronic pleuropulmonary infection) supports this diagnosis. In some cases, diagnosis may be established by recognition and biopsy of unusual skin lesions (Behçet’s syndrome, SLE, cryptococcosis, blastomycosis, Lyme disease, sporotrichosis, trypanosomiasis, IV drug use) or enlarged lymph nodes (lymphoma, sarcoid, tuberculosis, HIV, secondary syphilis, or Whipple’s disease). A careful ophthalmologic examination may reveal uveitis (Vogt-Koyanagi-Harada syndrome, sarcoid, or central nervous system [CNS] lymphoma), keratoconjunctivitis sicca (Sjögren’s syndrome), or iridocyclitis (Behçet’s syndrome) and is essential to assess visual loss from papilledema. Aphthous oral lesions, genital ulcers, and hypopyon suggest Behçet’s syndrome. Hepatosplenomegaly suggests lymphoma, sarcoid, tuberculosis, or brucellosis. Herpetic lesions in the genital area or on the thighs suggest HSV-2 infection. A breast nodule, a suspicious pigmented skin lesion, focal bone pain, or an abdominal mass directs attention to possible carcinomatous meningitis. IMAGING
Once the clinical syndrome is recognized as a potential manifestation of chronic meningitis, proper analysis of the CSF is essential. However, if the possibility of raised ICP exists, a brain imaging study should be performed before lumbar puncture. If ICP is elevated because of a mass lesion, brain swelling, or a block in ventricular CSF outflow (obstructive hydrocephalus), then lumbar puncture carries the potential risk of brain herniation. Obstructive hydrocephalus usually requires direct ventricular drainage. In patients with open CSF flow pathways, elevated ICP can still occur due to impaired resorption of CSF by arachnoid villi. In such patients, lumbar puncture is usually safe, but repetitive or continuous lumbar drainage may be necessary to prevent abrupt deterioration and death from raised ICP. In some patients, especially those with cryptococcal meningitis, fatal levels of raised ICP can occur without enlarged ventricles.
Contrast-enhanced MRI or CT studies of the brain and spinal cord can identify meningeal enhancement, parameningeal infections (including brain abscess), encasement of the spinal cord (malignancy, inflammation or infection), or nodular deposits on the meninges or nerve roots (malignancy or sarcoidosis) (Fig. 37-1). Imaging studies are also useful to localize areas of meningeal disease prior to meningeal biopsy.
Angiographic studies can identify evidence of cerebral arteritis in patients with chronic meningitis and stroke. CEREBROSPINAL FLUID ANALYSIS
The CSF pressure should be measured and samples sent for bacterial, fungal, and tuberculous culture; Venereal Disease Research Laboratories (VDRL) test; cell count and differential; Gram’s stain; and measurement of glucose and protein. Wet mount for fungus and parasites, india ink preparation and culture, culture for fastidious bacteria and fungi, assays for cryptococcal antigen and oligoclonal immunoglobulin bands, and cytology should be performed. Other specific CSF tests (Tables 37-2 and 37-3) or blood tests and cultures should be ordered as indicated on the basis of the history, physical examination, or preliminary CSF results (i.e., eosinophilic, mononuclear, or polymorphonuclear meningitis). Rapid diagnosis may be facilitated by serologic tests and polymerase chain reaction (PCR) testing to identify DNA sequences in the CSF that are specific for the suspected pathogen. In patients with suspected fungal infections, when other tests are negative, assays for beta-glucans may be a useful adjunct in establishing the diagnosis.
In most categories of chronic (not recurrent) meningitis, mononuclear cells predominate in the CSF. When neutrophils predominate after 3 weeks of illness, the principal etiologic considerations are Nocardia asteroides, Actinomyces israelii, Brucella, Mycobacterium tuberculosis (5–10% of early cases only), various fungi (Blastomyces dermatitidis, Candida albicans, Histoplasma capsulatum, Aspergillus spp., Pseudallescheria boydii, Cladophialophora bantiana), and noninfectious causes (SLE, exogenous chemical meningitis). When eosinophils predominate or are present in limited numbers in a primarily mononuclear cell response in the CSF, the differential diagnosis includes parasitic diseases (A. cantonensis, G. spinigerum, B. procyonis, or Toxocara canis infection, cysticercosis, schistosomiasis, echinococcal disease, T. gondii infection), fungal infections (6–20% eosinophils along with a predominantly lymphocyte pleocytosis, particularly with coccidioidal meningitis), neoplastic disease (lymphoma, leukemia, metastatic carcinoma), or other inflammatory processes (sarcoidosis, hypereosinophilic syndrome).
It is often necessary to broaden the number of diagnostic tests if the initial workup does not reveal the cause. In addition, repeated samples of large volumes of CSF may be required to diagnose certain infectious and malignant causes of chronic meningitis. Flow cytometry for malignant cells may be useful in patients with suspected carcinomatous meningitis. Lymphomatous or carcinomatous meningitis may be diagnosed by examination of sections cut from a cell block formed by spinning down the sediment from a large volume of CSF. The diagnosis of fungal meningitis may require large volumes of CSF for culture of sediment. If standard lumbar puncture is unrewarding, a cervical cisternal tap to sample CSF near to the basal meninges may be fruitful. LABORATORY INVESTIGATION
In addition to the CSF examination, an attempt should be made to uncover pertinent underlying illnesses. Tuberculin skin test, chest radiograph, urine analysis and culture, blood count and differential, renal and liver function tests, alkaline phosphatase, sedimentation rate, antinuclear antibody, anti-Ro antibody, anti-La antibody, and serum angiotensin-converting enzyme level are often indicated. In some cases, a thorough search for a systemic site of infection is indicated. Pulmonary foci of infection may be present, particularly with fungal or tuberculous disease. Hence a CT or MRI of the chest and a sputum examination may be helpful. Abnormalities can be pursued by bronchoscopy or transthoracic needle biopsy. A tuberculin skin test is often placed, although the test has limited specificity and sensitivity for diagnosis of active disease. Liver or bone marrow biopsy may be diagnostic in some cases of miliary tuberculosis, disseminated fungal infection, sarcoidosis, or metastatic malignancy. Positron emission tomography with fluorodeoxyglucose may be useful in identifying a systemic site for biopsy in patients with suspected carcinomatous meningitis or sarcoidosis when other tests are unrevealing. Genetic testing can identify mutations that cause rare monogenic autoinflammatory disorders. MENINGEAL BIOPSY
If CSF is not diagnostic then a meningeal biopsy should be strongly considered in patients who are severely disabled, who need chronic ventricular decompression, or whose illness is progressing rapidly. The activities of the surgeon, pathologist, microbiologist, and cytologist should be coordinated so that a large enough sample is obtained and the appropriate cultures and histologic and molecular studies, including electron-microscopic and PCR studies, are performed. The diagnostic yield of meningeal biopsy can be increased by targeting regions that enhance with contrast on MRI or CT. With current microsurgical techniques, most areas of the basal meninges can be accessed for biopsy via a limited craniotomy. In a series from the Mayo Clinic reported by TM Cheng et al. (Neurosurgery 34:590, 1994), MRI demonstrated meningeal enhancement in 47% of patients undergoing meningeal biopsy. Biopsy of an enhancing region was diagnostic in 80% of cases; biopsy of nonenhancing regions was diagnostic in only 9%; sarcoid (31%) and metastatic adenocarcinoma (25%) were the most common conditions identified. Tuberculosis is the most common condition identified in many reports from outside the United States. APPROACH TO THE ENIGMATIC CASE
In approximately one-third of cases, the diagnosis is not known despite careful evaluation of CSF and potential extraneural sites of disease. A number of the organisms that cause chronic meningitis may take weeks to be identified by cultures. In enigmatic cases, several options are available, determined by the extent of the clinical deficits and rate of progression. It is prudent to wait until cultures are finalized if the patient is asymptomatic or symptoms are mild and not progressive. Unfortunately, in many cases progressive neurologic deterioration occurs, and rapid treatment is required. Ventricular-peritoneal shunts may be placed to relieve hydrocephalus, but the risk of disseminating the undiagnosed inflammatory process into the abdomen must be considered. Empirical Treatment
Diagnosis of the causative agent is essential because effective therapies exist for many etiologies of chronic meningitis, but if the condition is left untreated, progressive damage to the CNS and cranial nerves and roots is likely to occur. Occasionally, empirical therapy must be initiated when all attempts at diagnosis fail. In general, empirical therapy in the United States consists of antimycobacterial agents, amphotericin for fungal infection, or glucocorticoids for noninfectious inflammatory causes. It is important to direct empirical therapy of lymphocytic meningitis at tuberculosis, particularly if the condition is associated with low CSF glucose and sixth and other CN palsies, since untreated disease can be devastating within weeks. Patients on prolonged anti–tumor necrosis factor therapy who develop chronic meningitis also should be treated empirically with antituberculous therapy if the etiology is uncertain. In the Mayo Clinic series, the most useful empirical therapy was administration of glucocorticoids rather than antituberculous therapy. Carcinomatous or lymphomatous meningitis may be difficult to diagnose initially, but the diagnosis becomes evident with time.