Patients with subacute or chronic meningitis typically have fluctuating but slowly progressive symptoms of fever, headache, neck pain or stiffness, vomiting, and/or cognitive changes over four or more weeks. Meningitis can also lead to focal neurologic deficits including cranial neuropathies such as facial palsy, radiculopathies, or seizures from focal cortical irritation. The persistence of symptoms is important, as there are forms of benign recurrent aseptic meningitis (such as Mollaret meningitis due to herpes simplex virus) in which symptoms resolve in between attacks even if they occur close together.
Lumbar puncture (LP) is necessary to establish that meningitis is present. Brain imaging to exclude a mass lesion should be considered prior to LP, particularly in patients age 60 years or older and those with focal neurologic deficits, seizures, known central nervous system disease, or who are immunocompromised. The majority of patients with a chronic meningitis will have normal brain imaging. Serum human immunodeficiency virus (HIV) testing should be performed on all patients. HIV seroconversion can present as a lymphocytic meningitis, and the range of infectious causes is significantly broader in immunocompromised patients. Cerebrospinal fluid (CSF) should be tested for cryptococcal antigen, venereal disease research laboratory (VDRL) test, cytology, and flow cytometry, as these will quickly identify more typical causes of a subacute meningitis.
An elevated CSF white blood cell count with neutrophilic predominance should raise concern for specific infections. In immunocompromised patients, a serum 1,3-beta-D-glucan assay and CSF fungal culture should be performed to assess for fungal infections such as aspergillus and candida. Some fungi, such as cryptoccocus and blastomycosis, have low levels of 1,3-beta-D-glucan in their cell walls, and thus will test negative. Nocardia should also be considered. Immunocompetent patients should be asked about exposure to unpasteurized milk for potential brucellosis (serology, blood culture), as well as recent oral trauma for actinomycosis (serology, culture).
Eosinophilia raises concern for parasitic meningitis. A thorough travel history should be obtained. Cysticercosis, strongyloidiasis, schistosomiasis, and trypanosomiasis can all be tested for by serologic tests. Coccidioides may also cause an eosinophilic meningitis.
The majority of patients with subacute or chronic meningitis will demonstrate a lymphocytic pleocytosis.
The CSF glucose is typically greater than two-thirds of the serum glucose, though this ratio may change in the setting of hypoglycemia. Low CSF glucose, defined as < 50% of serum glucose, in the setting of subacute or chronic meningitis suggests fungal infection, tuberculosis, sarcoidosis, or neoplastic meningitis.
If the patient has a history of malignancy or systemic signs such as fever, night sweats, or weight loss that suggest malignancy, meningeal involvement should be suspected and assessed with CSF cytology and flow cytometry. To reduce the likelihood of a false-negative result, LP should be repeated if initial cytology is negative; compared to a single study, three serial LPs increases the diagnostic yield from ~ 70% to ~ 85%–90%. Primary central nervous system lymphoma can also be considered; lymphocytic pleocytosis may be absent in this scenario.
Iatrogenic causes of lymphocytic pleocytosis include recent spinal intervention (including epidural steroid injection), intravenous immunoglobulin, and nonsteroidal antiinflammatory drugs.
Travel to the northeast or midwest part of the United States (US), European countries (especially Austria, Estonia, Lithuania, the Netherlands, Slovenia), as well as Russia, China, and Japan, may indicate exposure to Lyme disease. Histoplasma capsulatum is found in the United States (Ohio River Valley), the Caribbean, southern Mexico, Central and South America, Africa, and Asia. Most cases of blastomycosis occur in people who have traveled to the southeastern or south central United States, Canada (bordering the Great Lakes), and Africa. Exposure to Coccidiodes immitis is restricted mostly to the southwestern United States and parts of Central and South America. Each of these infectious etiologies can be tested by serologies. If a patient has known exposure to tuberculosis or a positive screening test, CSF should be sent for acid-fast bacilli stains and mycobacterial culture, and consideration should be made for serial LPs.
Systemic signs may suggest an underlying autoimmune condition such as sarcoidosis, granulomatosis with polyangiitis, Behçet disease, or systemic lupus erythematosus.
Despite extensive focused serologic and CSF testing, a specific cause will not be identified in up to one-third of patients with a subacute/chronic meningitis. CSF from these patients can be assessed with unbiased next generation sequencing to identify nonhuman viral or parasitic genetic material. If a coexistent parenchymal lesion is identified, this lesion may be amenable to biopsy if an extensive evaluation is unrevealing and the patient is not responding to standard treatment.