# Understanding Chronic Meningitis: Causes, Diagnosis, and Treatment

## Table of Contents

- Key Points
- Introduction: What is Chronic Meningitis?
- Symptoms and Clinical Manifestations
- Differential Diagnosis: Infectious and Non-Infectious Causes
- Diagnostic Evaluation and Testing
- Imaging Techniques for Detection
- Newer Diagnostic Technologies
- When Brain Biopsy Is Necessary
- Empirical Treatment Approaches
- Prognosis and Long-Term Outcomes
- Key Conclusions for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Chronic meningitis is inflammation of the meninges persisting for at least 4 weeks without improvement.
- Common symptoms include persistent headache, lethargy, mental status changes, and low-grade fever.
- Diagnosis involves CSF analysis, MRI, and sometimes brain biopsy of enhancing regions.
- Causes include infections (bacterial, fungal, viral), autoimmune diseases, and neoplasms.
- Treatment is empirical and targeted based on identified cause, with prognosis varying by etiology.

## Introduction: What is Chronic Meningitis?

Chronic meningitis is defined as inflammation of the protective membranes covering the brain and spinal cord (called meninges) that persists for at least 4 weeks without improvement. This condition differs significantly from acute meningitis, which develops rapidly and typically resolves more quickly. Since 1987, the list of known causes has expanded dramatically, making diagnosis and treatment increasingly complex for healthcare providers.

The medical landscape has changed substantially with new pathogens identified and advanced molecular testing now available. Next-generation sequencing allows doctors to detect pathogens without predetermined expectations about what they might find. Additionally, long-term immunosuppressive therapies have made opportunistic infections like cryptococcal meningitis nearly as common as bacterial meningitis in the United States.

Cryptococcal meningitis accounts for approximately 3400 hospitalizations annually in the US, while bacterial meningitis accounts for about 3600 cases per year. This review covers conditions affecting the leptomeninges (the inner two meningeal layers) or pachymeninges (the outer tough layer), but not conditions primarily involving brain tissue itself, which would be classified as encephalitis.

## Symptoms and Clinical Manifestations

Patients with chronic meningitis typically experience persistent symptoms that may fluctuate in severity but don't resolve completely. The most common symptoms include:

-
**Headache**: Usually constant but nonspecific in location, quality, and pattern
-
**Lethargy and fatigue**: Persistent tiredness that doesn't improve with rest
-
**Mental status changes**: Difficulty thinking clearly or concentrating
-
**Fever**: Often low-grade but persistent

Progressively worsening headache, especially when accompanied by mental clouding and fever, should prompt immediate medical evaluation and likely a lumbar puncture (spinal tap) to examine cerebrospinal fluid (CSF) for signs of inflammation. Cranial nerve dysfunction such as hearing loss or double vision (diplopia) can also indicate chronic meningitis, as these nerves are affected where they pass through the fluid-filled spaces around the brain.

Cognitive changes occur in approximately 40% of patients with chronic meningitis, though the incidence varies according to the specific cause. In some cases, cognitive change is the only noticeable symptom, making chronic meningitis part of the differential diagnosis in patients with rapidly progressive dementia, particularly those with a history of immunosuppression.

Neck stiffness (nuchal rigidity) occurs less commonly in chronic meningitis than in acute or subacute forms and is even less common with non-infectious causes compared to infectious ones. For example, in a review of neurosarcoidosis (a inflammatory condition), 65 of 83 patients had chronic meningitis, but none showed signs of meningeal irritation and neck stiffness.

Inflammatory changes may cause hydrocephalus (fluid buildup in the brain) and elevated intracranial pressure, particularly in cryptococcal meningitis. Seizures or stroke-like episodes can occur due to infectious or inflammatory cerebral vasculitis (blood vessel inflammation). The inflammatory process may affect cranial nerves and nerve roots, causing cranial neuropathies or radiculopathies (nerve root disorders).

## Differential Diagnosis: Infectious and Non-Infectious Causes

Chronic meningitis is broadly characterized as either infectious or non-infectious. Geographic region of residence, travel history, immune status, and underlying illnesses provide crucial clues for diagnosis. Systematic examination of the lungs, skin, liver, spleen, joints, eyes, and lymph nodes can reveal information about inflammatory and granulomatous diseases that often underlie chronic meningitis.

For example, uveitis (eye inflammation) suggests sarcoidosis, lymphoma, Behçet's disease, or rare "uveo-meningeal syndromes." Rheumatoid arthritis and sarcoidosis can cause inflammatory reactions in the meninges but also increase susceptibility to opportunistic infections. Tumors or cysts in the nervous system can induce chemical meningitis by leaking contents into the CSF, as occurs with dermoid cysts or craniopharyngiomas.

Parameningeal infections and inflammatory reactions from various sources cause a sterile inflammatory response in the CSF, appearing as chronic meningitis. Many cases previously thought to be idiopathic pachymeningitis are now understood to be due to IgG4 disease or rheumatoid arthritis involving the meninges.

**Infectious causes** vary by geographic region. In areas where tuberculosis is endemic, empirical antituberculosis treatment is often started before diagnostic evaluation is complete. Coccidioidomycosis is endemic in the southwestern United States, while histoplasmosis and blastomycosis are endemic in the upper Midwest and the Ohio and Mississippi River valleys.

Cryptococcus gattii, which has appeared on the Pacific Coast, can cause chronic meningitis in non-immunosuppressed patients. In the northeastern United States and upper Midwest, Lyme disease is a diagnostic consideration. Cryptococcal meningitis is currently the most common cause in immunocompromised persons and those with HIV infection.

Patients with agammaglobulinemia and those receiving B-cell-depleting immunotherapy are susceptible to chronic enteroviral meningitis. Contaminated glucocorticoids used for epidural injection caused an outbreak of chronic fungal meningitis in 2012 in the United States. Patients with neurosurgical history, ventriculoperitoneal shunt placement, otic surgery, or diabetes are predisposed to both bacterial and fungal causes.

**Major categories of causes include:**

1.
**Infectious causes**:

- Bacterial: Mycobacterium tuberculosis, Lyme disease, syphilis
- Fungal: Cryptococcus, Histoplasma, Blastomyces
- Parasitic: Tapeworm, Angiostrongylus cantonensis
- Viral: HIV, chronic enterovirus

1.
**Neoplastic causes**:

- Meningeal carcinomatosis (cancer spread to meninges)
- Meningeal lymphomatosis (lymphoma in meninges)
- Leukemic infiltration

1.
**Autoimmune causes**:

- Granulomatosis with polyangiitis
- Rheumatoid arthritis
- Sjögren's syndrome
- IgG4 disease
- Neurosarcoidosis

1.
**Chemical causes**:

- Craniopharyngioma leakage
- Dermoid or epidermoid cyst leakage

1.
**Parameningeal infectious causes**:

- Chronic epidural abscess
- Chronic osteomyelitis of skull or vertebrae

## Imaging Techniques for Detection

Advances in head imaging have significantly improved detection of both leptomeningitis (affecting the inner membranes and CSF-filled spaces) and pachymeningitis (affecting the outer durable membrane), and for distinguishing between them. Cranial and spinal imaging is necessary to identify focal and parameningeal infections that cause sterile chronic meningeal reactions.

A computed tomographic (CT) scan of the head can rule out masses that may cause sterile meningitis and detect hydrocephalus and mass effect before lumbar puncture. While CT may show meningeal enhancement and provide safety reassurance for lumbar puncture, it's not helpful for establishing the cause of chronic meningitis.

Magnetic resonance imaging (MRI) of the head with contrast material may be normal in chronic meningitis or may show hyperintensity in cerebral sulci and basal cisterns on specialized imaging sequences. After contrast administration, imaging frequently shows abnormally enhancing basilar subarachnoid spaces and leptomeningeal membranes.

Enhancement in the dura reflects pachymeningitis and directs attention to infections involving the dura, such as granulomatous disorders and IgG4 pachymeningitis. Smooth, diffuse enhancement of dural membranes without leptomeningeal enhancement may indicate intracranial hypotension due to spontaneous CSF leak or recent lumbar puncture, sometimes confused with chronic meningitis features. Neuroimaging with MRI is also used for selecting brain biopsy sites when needed for diagnosis.

## Diagnostic Evaluation and Testing

The CSF cell count is almost always elevated in chronic meningitis, except in severe immunosuppression or some forms of neoplastic meningitis. There's generally a lymphocyte-predominant pleocytosis (increased cell count) due to the chronic nature of the disorder. However, tuberculous meningitis and some other infections may show persistent neutrophilic meningitis, providing a diagnostic clue.

Chronic neutrophilic meningitis has also been described in autoimmune disorders like Still's disease and in cases without identified cause. Eosinophils may indicate parasitic or coccidioidal meningitis. The CSF protein concentration is nearly always elevated, though nonspecifically. Low CSF glucose (hypoglycorrhachia) commonly accompanies infectious and some non-infectious causes but may be normal with other causes.

**Recommended diagnostic approach includes:**

- Spinal tap - up to three times for fungal and mycobacterial cultures if initially negative
- CSF cytologic evaluation - twice if initially negative
- CSF test for cryptococcal antigen
- CSF bacterial culture
- CSF protein, glucose measurements, and cell count
- CSF serologic tests for syphilis and fungal infections
- MRI of head with gadolinium contrast
- Serum serologic tests for syphilis, HIV infection, Lyme disease
- Chest CT scan for lymphadenopathy, granuloma, or neoplasm
- Tuberculosis skin test or interferon-γ release assay

High-volume CSF sampling (10-20 ml per sample) may increase diagnostic sensitivity for tuberculous and fungal meningitis. Blood and CSF serologic tests and positron-emission tomography for occult systemic disorders may provide useful information in otherwise obscure cases.

A mycobacterial polymerase-chain-reaction (PCR) assay of CSF for tuberculosis has estimated sensitivity close to 95% with newer techniques. The absence of blood interferon-γ reaction against mycobacterial antigens doesn't rule out tuberculosis meningitis. Three spinal taps over several days for difficult-to-culture organisms are usually sufficient to rule out these diagnoses.

A β-D-glucan assay of CSF may help identify fungal infections from candida or exserohilum in patients with negative cultures or negative specific antigen tests. Galactomannan testing in CSF has been positive in some aspergillus meningitis cases. For situations where clinical decisions about antibiotics will be affected, PCR for bacterial 16S ribosomal RNA gene can be performed in some laboratories.

Two large-volume taps for cytologic studies are typically considered sufficient to detect neoplastic meningitis. Detailed evaluation of HIV status and immune state may be warranted when opportunistic pathogens are identified. Defects in cell-mediated immunity and immunoglobulin deficiencies are associated with infectious chronic meningitis.

## Newer Diagnostic Technologies

Many US laboratories now use commercially available, multiple-organism PCR tests of CSF for diagnosing acute meningitis and encephalitis. However, these techniques are considered less useful for chronic meningitis, with chronic enteroviral meningoencephalitis being a potential exception since it's difficult to identify without this testing.

Although these CSF panels test for cryptococcus, their sensitivity is only 52%, compared to 90-95% sensitivity with stand-alone cryptococcal antigen tests. Newer methods using metagenomic or next-generation sequencing don't limit identification to specific organisms but provide sequencing information for any bacterial, fungal, or viral nucleic acid in CSF.

The sensitivity and specificity of next-generation sequencing in chronic meningitis evaluation are still being determined. A study of seven patients with puzzling chronic meningitis identified various pathogens, though no conclusions can be drawn about diagnostic sensitivity in broader populations.

A study of metagenomic sequencing in CSF specimens from 53 Mayo Clinic patients with diagnostic uncertainty and 27 externally referred specimens over 2 years showed a diagnostic detection rate of only 15%, with more than half detected infections considered inconsistent with clinical presentation. This technology requires complex computational abilities and, though expensive, is potentially cheaper than imaging and brain biopsy.

While obstacles to next-generation sequencing use aren't insurmountable, it cannot yet be recommended for routine initial use in evaluating chronic meningitis. As technology improves, these methods may reveal more infectious meningeal disorders. New autoantibodies against neuronal antigens may point to autoimmune disorders, as has occurred with meningoencephalitis and anti-glial fibrillary acidic protein astrocytopathy.

## When Brain Biopsy Is Necessary

In patients with chronic meningitis, progressive neurologic decline, and inconclusive systemic and CSF evaluations, brain and meningeal biopsy may be considered to establish diagnosis. Limited information exists about biopsy yield across chronic meningitis patients.

A 1994 retrospective single-center study of 37 extensively evaluated patients (half with leptomeningeal abnormalities on MRI) found that biopsy specimens from non-enhancing brain or meningeal regions provided diagnosis in only 9% of patients. However, diagnosis was obtained in 80% of patients with biopsy of an enhancing region. A second biopsy was diagnostic in three of four cases.

Even in non-diagnostic cases, generic pathological changes can guide empirical therapy. Granulomatous characteristics rather than vasculitic abnormalities might point toward neurosarcoid treatment trial. Necrotizing granuloma might prompt antituberculosis or antifungal therapy trial depending on clinical circumstances. Chronic meningitis eludes diagnosis despite exhaustive testing in a large but uncertain proportion of patients.

## Empirical Treatment Approaches

If no diagnosis is established after non-invasive testing or even after brain biopsy, empirical treatment choice is generally antituberculosis therapy, antifungal therapy, or glucocorticoids. Empirical antibiotic therapy isn't recommended unless exposure history or other information suggests responsive organism presence.

In tuberculosis-prevalent regions, empirical antituberculosis therapy is considered reasonable if cryptococcal meningitis is ruled out. However, it's not recommended empirically in every case—sometimes glucocorticoid trial is initiated when neurosarcoidosis suspicion is greater than tuberculosis suspicion.

Concurrent glucocorticoid therapy is recommended for tuberculous meningitis in some instances, but if tuberculosis cannot be identified, glucocorticoids may be disadvantageous as they obscure reduction in CSF cellular response to empirical antituberculosis therapy. In regions where tuberculosis is uncommon, treatment with glucocorticoids alone with follow-up clinical assessment and imaging in 4-8 weeks is reasonable for chronic meningitis cases where no diagnosis can be established despite extensive evaluation.

## Prognosis and Long-Term Outcomes

No general prognosis statement is possible given the variety of disorders causing chronic meningitis. Future improved and more widely available PCR tests (like those for tuberculosis) and next-generation sequencing may reveal more infectious meningeal disorders.

Few studies have followed patients longitudinally to assess chronic meningitis outcomes. A 1994 study (before PCR and next-generation sequencing) followed 49 patients with undiagnosed chronic meningitis for mean 50 months. Diagnosis was eventually established in 10 patients (8 had neoplastic meningitis, 2 had histoplasma meningitis), and 33 of remaining 39 patients had good outcomes despite prolonged illness. Two patients died without diagnosis.

Empirical antituberculosis therapy, administered mainly in upper midwestern US patients, didn't appear to alter illness course. The impression was that glucocorticoid therapy relieved symptoms, highlighting the complex nature of treatment decisions for this condition.

## Key Conclusions for Patients

Chronic meningitis represents a challenging diagnostic entity that differs from acute meningitis in causes, diagnostic process, and treatment approach. The condition is associated with numerous potential underlying infectious and non-infectious inflammatory disorders that require diligent and persistent follow-up.

Patients should understand that diagnosis often requires multiple tests and procedures, including repeated spinal taps, advanced imaging, and sometimes even brain biopsy. Treatment must be tailored to the specific cause when identified, and empirical treatment may be necessary when causes cannot be determined despite extensive testing.

As newer diagnostic technologies like next-generation sequencing become more refined and accessible, diagnosis rates may improve. Patients with persistent headaches, cognitive changes, or other neurological symptoms lasting more than four weeks should seek thorough neurological evaluation to rule out this serious condition.

## Frequently Asked Questions

### What are the first symptoms of chronic meningitis?

The most common symptoms include a constant but nonspecific headache, persistent lethargy and fatigue, difficulty thinking clearly or concentrating, and often a low-grade fever. Progressively worsening headache with mental clouding and fever should prompt immediate medical evaluation. Cognitive changes occur in about 40% of patients and may be the only symptom in some cases.

### How is chronic meningitis diagnosed?

Diagnosis typically begins with a lumbar puncture to examine cerebrospinal fluid (CSF) for elevated cell count, protein, and low glucose. MRI of the head with contrast can show meningeal enhancement. Blood and CSF tests for infections like syphilis, HIV, Lyme disease, and fungi are performed. If initial tests are inconclusive, brain biopsy of an enhancing region may be considered.

### Why does chronic meningitis come back after treatment?

Chronic meningitis may persist or recur if the underlying cause is not fully treated or if the treatment is not appropriate for the specific etiology. For example, fungal or mycobacterial infections require prolonged therapy. In some cases, the cause may be autoimmune or neoplastic, requiring immunosuppressive or oncologic treatment. Incomplete diagnostic evaluation can lead to inadequate treatment.

### What causes chronic meningitis?

Chronic meningitis can be caused by infectious agents such as tuberculosis, cryptococcus, Lyme disease, and HIV, or by non-infectious conditions like sarcoidosis, rheumatoid arthritis, lupus, and cancers that spread to the meninges. Geographic location, immune status, and underlying illnesses provide important clues. Some cases are due to chemical irritation from cysts or tumors.

### How long does chronic meningitis last?

Chronic meningitis is defined as inflammation of the meninges that persists for at least 4 weeks without improvement. The duration can vary widely depending on the underlying cause. Some patients may have prolonged illness, but outcomes can be good even without a specific diagnosis. In one study, 33 of 39 patients with undiagnosed chronic meningitis had good outcomes after a mean follow-up of 50 months.

### What is the difference between chronic and acute meningitis?

Chronic meningitis differs from acute meningitis in that it persists for at least 4 weeks without improvement, whereas acute meningitis develops rapidly and typically resolves more quickly. The causes, diagnostic process, and treatment approach also differ. Chronic meningitis often requires extensive testing, including repeated spinal taps and advanced imaging, to identify the underlying cause.

### What tests are done to diagnose chronic meningitis?

Diagnosis typically involves a spinal tap to examine cerebrospinal fluid, including cell count, protein, glucose, and cultures. MRI of the head with contrast is often performed. Blood tests for syphilis, HIV, and Lyme disease may be done. Chest CT and tuberculosis tests are also common. If initial tests are inconclusive, repeated spinal taps or brain biopsy may be necessary.

## Source Information

**Original Article Title:** Chronic Meningitis

**Authors:** Allen J. Aksamit, M.D.

**Publication:** The New England Journal of Medicine, September 2, 2021

**DOI:** 10.1056/NEJMra2032996

*This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine and has been developed to help patients understand complex medical information about chronic meningitis. Always consult with healthcare providers for personal medical advice.*


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