Walter J. Koroshetz Morton N. Swartz
Chronic inflammation of the meninges (pia, arachnoid, and dura) can produce profound neurologic disability and may be fatal if not successfully treated. The condition is most commonly diagnosed when a characteristic neurologic syndrome exists for >4 weeks and is associated with a persistent inflammatory response in the cerebrospinal fluid (CSF) (white blood cell count >5/μL). The causes are varied, and appropriate treatment depends on identification of the etiology. Five categories of disease account for most cases of chronic meningitis: (1) meningeal infections, (2) malignancy, (3) noninfectious inflammatory disorders, (4) chemical meningitis, and (5) parameningeal infections.
Neurologic manifestations of chronic meningitis (Table 41-1) are determined by the anatomic location of the inflammation and its consequences. Persistent headache with or without stiff neck, hydrocephalus, cranial neuropathies, radiculopathies, and cognitive or personality changes are the cardinal features. These can occur alone or in combination. When they appear in combination, widespread dissemination of the inflammatory process along CSF pathways has occurred. In some cases, the presence of an underlying systemic illness points to a specific agent or class of agents as the probable cause. The diagnosis of chronic meningitis is usually made when the clinical presentation prompts the astute physician to examine the CSF for signs of inflammation. CSF is produced by the choroid plexus of the cerebral ventricles, exits through narrow foramina into the subarachnoid space surrounding the brain and spinal cord, circulates around the base of the brain and over the cerebral hemispheres, and is resorbed by arachnoid villi projecting into the superior sagittal sinus. CSF flow provides a pathway for rapid spread of infectious and other infiltrative processes over the brain, spinal cord, and cranial and spinal nerve roots. Spread from the subarachnoid space into brain parenchyma may occur via the arachnoid cuffs that surround blood vessels that penetrate brain tissue (Virchow-Robin spaces).
SYMPTOMS AND SIGNS OF CHRONIC MENINGITIS
Nociceptive fibers of the meninges are stimulated by the inflammatory process, resulting in headache or neck or back pain. Obstruction of CSF pathways at the foramina or arachnoid villi may produce hydrocephalus and symptoms of raised intracranial pressure (ICP), including headache, vomiting, apathy or drowsiness, gait instability, papilledema, visual loss, impaired upgaze, or palsy of the sixth cranial nerve (CN) (Chap. 34). Cognitive and behavioral changes during the course of chronic meningitis may also result from vascular damage, which may similarly produce seizures, stroke, or myelopathy. Inflammatory deposits seeded via the CSF circulation are often prominent around the brainstem and cranial nerves and along the undersurface of the frontal and temporal lobes. Such cases, termed basal meningitis, often present as multiple cranial neuropathies, with visual loss (CN II), facial weakness (CN VII), hearing loss (CN VIII), diplopia (CNs III, IV, and VI), sensory or motor abnormalities of the oropharynx (CNs IX, X, and XII), decreased olfaction (CN I), or facial sensory loss and masseter weakness (CN V).
Injury may occur to motor and sensory roots as they traverse the subarachnoid space and penetrate the meninges. These cases present as multiple radiculopathies with combinations of radicular pain, sensory loss, motor weakness, and sphincter dysfunction. Meningeal inflammation can encircle the cord, resulting in myelopathy. Patients with slowly progressive involvement of multiple cranial nerves and/or spinal nerve roots are likely to have chronic meningitis. Electrophysiologic testing (electromyography, nerve conduction studies, and evoked response testing) may be helpful in determining whether there is involvement of cranial and spinal nerve roots.
In some patients, evidence of systemic disease provides clues to the underlying cause of chronic meningitis. A careful history and physical examination are essential before embarking on a diagnostic workup, which may be costly, prolonged, and associated with risk from invasive procedures. A complete history of travel, sexual practice, and exposure to infectious agents should be sought. Infectious causes are often associated with fever, malaise, anorexia, and signs of localized or disseminated infection outside the nervous system. Infectious causes are of major concern in the immunosuppressed patient, especially in patients with AIDS, in whom chronic meningitis may present without headache or fever. Non-infectious inflammatory disorders often produce systemic manifestations, but meningitis may be the initial manifestation. Carcinomatous meningitis may or may not be accompanied by clinical evidence of the primary neoplasm.
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 abnormal 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 41-2 and 41-3) 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.
INFECTIOUS CAUSES OF CHRONIC MENINGITIS
NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS
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 leakage into CSF of contents from an epidermoid tumor, craniopharyngioma, or cholesteatoma; primary inflammatory conditions, including Vogt-Koyanagi-Harada syndrome, Behçet’s syndrome, and systemic lupus erythematosus; 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 schenkii); ingestion of poorly cooked meat or contact with a household cat (Toxoplasma gondii); residence in Thailand or Japan (Gnathostoma spinigerum), Latin America (Paracoccidioides brasiliiensis), or the South Pacific (Angiostrongylus cantonensis); rural residence and raccoon exposure (Baylisascaris procyonis); and residence in Latin America, the Philippines, or Southeast Asia when eosinophilic meningitis is present (Taenia solium).
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, cryptococcosis, blastomycosis, SLE, Lyme disease, IV drug use, sporotrichosis, trypanosomiasis) or enlarged lymph nodes (lymphoma, tuberculosis, sarcoid, infection with 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 of CSF. 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 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 or inflammation and infection), or nodular deposits on the meninges or nerve roots (malignancy or sarcoidosis) (Fig. 41-1). Imaging studies are also useful to localize areas of meningeal disease prior to meningeal biopsy.
Primary central nervous system lymphoma. A 24-year-old man, immunosuppressed due to intestinal lymphangiectasia, developed multiple cranial neuropathies. CSF findings consisted of 100 lymphocytes/μL and a protein of 2.5 g/L (250 mg/dL); cytology and cultures were negative. Gadolinium-enhanced T1 MRI revealed diffuse, multifocal meningeal enhancement surrounding the brainstem (A), spinal cord, and cauda equina (B).
Cerebral angiography may be indicated in patients with chronic meningitis and stroke to identify cerebral arteritis (granulomatous angiitis, other inflammatory arteritides, or infectious arteritis).
CEREBROSPINAL FLUID ANALYSIS The CSF pressure should be measured and samples sent for bacterial, fungal, and tuberculous culture; Venereal Disease Research Laboratory (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 41-2 and 41-3) 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 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. For instance, 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, anti-La antibody, and serum angiotensin-converting enzyme level are often indicated. Liver or bone marrow biopsy may be diagnostic in some cases of miliary tuberculosis, disseminated fungal infection, sarcoidosis, or metastatic malignancy. Abnormalities discovered on chest radiograph or chest CT can be pursued by bronchoscopy or transthoracic needle biopsy.
MENINGEAL BIOPSY 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 Cheng et al., 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 hypoglycorrhachia and sixth and other CN palsies, since untreated disease is fatal in 4–8 weeks. 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.
THE IMMUNOSUPPRESSED PATIENT
Chronic meningitis is not uncommon in the course of HIV infection. Pleocytosis and mild meningeal signs often occur at the onset of HIV infection, and occasionally low-grade meningitis persists. Toxoplasmosis commonly presents as intracranial abscesses and may also be associated with meningitis. Other important causes of chronic meningitis in AIDS include infection with Cryptococcus, Nocardia, Candida, or other fungi; syphilis; and lymphoma (Fig. 41-1). Toxoplasmosis, cryptococcosis, nocardiosis, and other fungal infections are important etiologic considerations in individuals with immunodeficiency states other than AIDS, including those due to immunosuppressive medications. Because of the increased risk of chronic meningitis and the attenuation of clinical signs of meningeal irritation in immunosuppressed individuals, CSF examination should be performed for any persistent headache or unexplained change in mental state.