Chronic and Recurrent Meningitis¶
Chapter 144 | Harrison's 22e · Part 5 – Infectious Diseases: Bacterial · Chapter 144
Key Clinical Points¶
- Chronic meningitis is defined by neurologic symptoms lasting >4 weeks with persistent CSF inflammation (WBC >5/μL).
- Five primary categories: meningeal infections, malignancy, autoimmune disorders, chemical meningitis, and parameningeal infections.
- Systemic manifestations (skin, eyes, mucosa) provide critical clues to etiology (e.g., erythema nodosum in sarcoidosis, uveitis in Behçet's).
- Basal meningitis often involves cranial nerves II-VI and can cause significant neurological deficits.
- CSF analysis is essential for diagnosis: infectious cases typically show elevated protein (>100 mg/dL), low glucose (<40 mg/dL), and pleocytosis (WBC >5/μL).
- MRI with contrast is critical to identify meningeal enhancement, granulomatous changes, or 'clumped' exudates.
- Recurrent meningitis may indicate monogenic autoinflammatory disorders such as Mollaret's syndrome or Complement factor I deficiency.
1. DEFINITION & OVERVIEW¶
• Definition: Chronic meningitis is characterized by persistent neurologic symptoms lasting >4 weeks with evidence of CSF inflammation (WBC >5/μL).
• Primary Categories: ◦ Meningeal infections ◦ Malignancy ◦ Autoimmune inflammatory disorders ◦ Chemical meningitis ◦ Parameningeal infections
• Recurrent Cases: May indicate monogenic autoinflammatory disorders.
1.1 Pathophysiology¶
Chronic inflammation of the meninges leads to neurologic disability via several mechanisms:
• Nociceptive Stimulation: Activation of nociceptive nerve fibers causes headache and neck/back pain. • Obsturction: Blockage of CSF pathways may produce hydrocephalus with signs of increased ICP (headache, vomiting, papilledema). • Vascular Damage: Subarachnoid inflammation causes vascular damage leading to infarction and cognitive changes. • Basal Meningitis: Inflammatory deposits localize to brainstem/cranial nerves and frontal/temporal lobes. • Spinal Involvement: Leads to radiculopathy, arachnoiditis, and myelopathy.
2. CLINICAL MANIFESTATIONS¶
Symptoms depend on the anatomic location of inflammation:
• Intracranial meningitis: Chronic headache, papilledema, cranial neuropathies (CN II-VI), and cognitive/behavioral changes. • Spinal meningitis: Radiculopathy with pain, sensory/motor deficits, bowel/bladder dysfunction, and arachnoiditis. • Systemic manifestations: Fever, malaise, anorexia; skin changes (e.g., erythema nodosum); ocular findings (uveitis); and mucosal lesions.
Table 144-1: Symptoms and Signs of Chronic Meningitis
| Symptom | Sign |
|---|---|
| Chronic headache | ± Papilledema |
| Neck or back pain/stiffness | Brudzinski’s or Kernig’s sign |
| Change in personality | Altered mental status, drowsiness, inattention, disorientation, memory loss, frontal release signs (grasp, suck, snout), perseveration |
| Double vision | Paresis of CNs III, IV, and/or VI |
| Hearing loss | Eighth CN paresis |
| Numbness in arms or legs | Myelopathy or radiculopathy |
| Clumsiness | Ataxia |
3. DIAGNOSTIC APPROACH¶
Diagnosis requires clinical suspicion and systematic investigation:
- Clinical Indications for Lumbar Puncture: Chronic headache, hydrocephalus signs, cranial/spinal neuropathy, or cognitive decline.
- CSF Analysis: • Cell Count: Pleocytosis (WBC >5/μL). • Protein: Elevated (>100 mg/dL) in infectious cases. • Glucose: Low (<40 mg/dL) in infectious cases. • Microbiology: Gram stain, culture, Tuberculin skin test, IGRA, TB PCR, cryptococcal antigen, CSF VDRL, RPR, FTA-ABS, and MHA-TP.
- Imaging (MRI with contrast): Essential to detect meningeal enhancement, localize inflammation (brainstem, cerebellar folia), and identify complications like 'clumped' exudates or granulomatous changes.
- Systemic Workup: Tuberculin skin test, chest radiograph, urine analysis, blood tests for autoimmune markers (ANCA, ANA, complement levels), and cancer screening (imaging, tumor markers).
- Diagnostic Algorithm: Initial lumbar puncture → CSF analysis → Imaging (MRI/CT) → Specific testing (e.g., TB PCR, cryptococcal antigen).
3.1 Laboratory Investigation & Pathogen Identification¶
Detailed investigation based on suspected etiology:
• Bacterial Infections: ◦ Partially treated suppurative meningitis: Mononuclear or mixed mononuclear-polymorphonuclear cells. ◦ Mycobacterium tuberculosis: Mononuclear (except polymorphonuclear in early infection, <500 WBC/μL); low glucose; high protein. Tests: Tuberculin skin test, IGRA, PCR, and AFB culture. ◦ Syphilis: Mononuclear; elevated protein. Tests: CSF VDRL, serum VDRL/RPR, FTA-ABS, MHA-TP. ◦ Nocardia: Polymorphonuclear or mononuclear; often low glucose.
• Fungal Infections: ◦ Cryptococcus neoformans/gattii: Mononuclear (count may not be elevated in AIDS). Tests: India ink, antigen detection, culture. ◦ Candida species: Polymorphonuclear or mononuclear. Tests: Fungal stain and culture. ◦ Blastomyces dermatitidis: Mononuclear or polymorphonuclear. Tests: Fungal stain/culture, biopsy of skin/lung lesions. ◦ Sporothrix schenckii: Mononuclear. Tests: Antibody detection, CSF culture.
• Other Infections: ◦ Whipple’s disease: Mononuclear. Tests: Biopsy of small bowel/lymph node, CSF PCR. ◦ Viral (LCMV, Enteroviruses, HIV, Herpes): ◦ LCMV: Mononuclear; may persist 3–4 weeks. ◦ Enteroviruses: Mononuclear; potential link to γ-immunodeficiency. ◦ HIV: Mononuclear; can present as acute retroviral syndrome or in later AIDS stages. ◦ Herpes (HSV-1, HSV-2, EBV, CMV): Mononuclear. Note: HSV-2 often associated with genital herpes; EBV with myelodysplastic syndrome; CMV with polyradiculopathy.
3.2 Noninfectious Investigations¶
• Malignancy: Mononuclear or PMNs; low glucose, elevated protein. Tests: Repeated cytology of large CSF volumes, polarizing microscopy, clonal lymphocyte markers, and meningeal biopsy. ◦ CNS Sarcoidosis: Mononuclear; elevated protein; often low glucose. Tests: Serum/CSF ACE (insensitive), biopsy of extraneural tissues or brain lesions. ◦ Granulomatous Angiitis: Mononuclear; elevated protein. Tests: Angiography, meningeal biopsy. ◦ Behçet’s Syndrome: Mononuclear or PMNs; elevated protein. Clinical signs: Oral/genital ulcers, iridocyclitis. ◦ Mollaret’s Meningitis: Large endothelial cells and PMNs (early), followed by mononuclear. Test: PCR for HSV. ◦ Granulomatosis with Polyangiitis (Wegener’s): Mononuclear or PMNs. Tests: Chest/sinus radiographs, urinalysis, ANCA antibodies. ◦ IgG4-related Hypertrophic Pachymeningitis: Mild lymphocytic pleocytosis; normal to mildly increased protein; normal glucose. Test: Serum IgG4 levels.
Reference Tables¶
TABLE 144-1 Symptoms and Signs of Chronic Meningitis SYMPTOM Chronic headache Neck or back pain/stiffness Brudzinski’s…¶
Harrison's 22e, p.1128
| SYMPTOM | SIGN |
|---|---|
| Chronic headache | ± Papilledema |
| Change in personality | Altered mental status—drowsiness, inattention, disorientation, memory loss, frontal release signs (grasp, suck, snout), perseveration |
| Double vision | Paresis of CNs III, IV, and/or VI |
| Hearing loss | Eighth CN paresis |
| Numbness in arms or legs | Myelopathy or radiculopathy |
| Clumsiness | Ataxia |
TABLE 144-2 Infectious Causes of Chronic Meningitis¶
Harrison's 22e, p.1130
| CAUSATIVE AGENT | CSF FORMULA | HELPFUL DIAGNOSTIC TESTS | RISK FACTORS AND SYSTEMIC MANIFESTATIONS |
|---|---|---|---|
| Common Bacterial Causes | |||
| Partially treated suppurative meningitis |
Mononuclear or mixed mononuclear- polymorphonuclear cells |
CSF culture and Gram’s stain; CSF 16s rRNA PCR |
History consistent with acute bacterial meningitis and incomplete treatment |
| Mononuclear or mixed mononuclear- polymorphonuclear cells |
Contrast-enhanced CT or MRI to detect parenchymal, subdural, epidural, or sinus infection |
||
| Mycobacterium tuberculosis | Mononuclear cells except polymorphonuclear cells in early infection (commonly <500 WBC/μL); low CSF glucose; high protein |
Tuberculin skin test may be negative; interferon gamma release assay; PCR and AFB culture of CSF (sputum, urine, gastric contents if indicated); identify tubercle bacillus on acid-fast stain of CSF or protein pellicle |
Exposure history; previous tuberculous illness; immunosuppressed, anti-TNF therapy or AIDS; young children; fever, meningismus, night sweats, miliary TB on x-ray or liver biopsy; stroke due to arteritis |
| Mononuclear cells; elevated protein |
Serum Lyme antibody titer; western blot confirmation; (patients with syphilis may have false-positive Lyme titer) |
||
| Syphilis (secondary, tertiary) Treponema pallidum |
Mononuclear cells; elevated protein |
CSF VDRL; serum VDRL (or RPR); fluorescent treponemal antibody- absorbed (FTA) or MHA-TP; serum VDRL and RPR may be negative in tertiary syphilis due to waning antibody levels or earlier in the disease course due to very elevated antibody levels (prozone effect) |
Appropriate exposure history; HIV-seropositive individuals at increased risk of aggressive infection; fever; lymphadenopathy; generalized, nonpruritic, mucocutaneous rash; “dementia”; cerebral infarction due to endarteritis; myelopathy |
| Uncommon Bacterial Causes | |||
| Polymorphonuclear cells | Anaerobic culture | ||
| Nocardia | Polymorphonuclear; occasionally mononuclear cells; often low glucose |
Isolation may require weeks; weakly acid fast |
Associated brain abscess may be present |
| Mononuclear cells (rarely polymorphonuclear); elevated protein; often low glucose |
CSF antibody detection; serum antibody detection |
||
| Whipple’s disease Tropheryma whipplei |
Mononuclear cells | Biopsy of small bowel or lymph node; CSF PCR for T. whipplei; brain and meningeal biopsy (with PAS stain and EM examination) |
Diarrhea, weight loss, arthralgias, fever; dementia, ataxia, paresis, ophthalmoplegia, oculomasticatory myoclonus |
| Rare Bacterial Causes | |||
| Fungal Causes | |||
| Cryptococcus neoformans and var. gattii |
Mononuclear cells; count not elevated in some patients with AIDS |
India ink or fungal wet mount of CSF (budding yeast); blood and urine cultures; antigen detection in CSF (false negatives can occur in the setting of high antigen titers [prozone effect]) |
AIDS and immune suppression; pigeon exposure for C. neoformans, decaying wood exposure for C. var. gattii; skin and other organ involvement due to disseminated infection |
| Mononuclear cells (sometimes 10–20% eosinophils); often low glucose |
Antibody detection in CSF and serum, antigen detection in CSF |
||
| Candida species | Polymorphonuclear or mononuclear |
Fungal stain and culture of CSF | IV drug abuse; postsurgery; prolonged IV therapy; disseminated candidiasis, recent epidural injection |
| Mononuclear cells; low glucose | Fungal stain and culture of large volumes of CSF; antigen detection in CSF, serum, and urine; antibody detection in serum, CSF |
||
| Blastomyces dermatitidis | Mononuclear or polymorphonuclear |
Fungal stain and culture of CSF; biopsy and culture of skin, lung lesions; antibody detection in serum |
Midwestern and southeastern United States; usually systemic infection; abscesses, draining sinus, ulcers |
| Mononuclear or polymorphonuclear |
CSF culture | ||
| Sporothrix schenckii | Mononuclear cells | Antibody detection in CSF and serum; CSF culture |
Traumatic inoculation; IV drug use; ulcerated skin lesion |
| Rare Fungal Causes |
TABLE 144-3 Noninfectious Causes of Chronic Meningitis¶
Harrison's 22e, p.1132
| CAUSATIVE AGENTS | CSF FORMULA | HELPFUL DIAGNOSTIC TESTS | RISK FACTORS AND SYSTEMIC MANIFESTATIONS |
|---|---|---|---|
| Malignancy | Mononuclear cells; elevated protein; low glucose |
Repeated cytologic examination of large volumes of CSF; CSF exam by polarizing microscopy; clonal lymphocyte markers; deposits on nerve roots or meninges seen on myelogram or contrast-enhanced MRI; meningeal biopsy |
Metastatic cancer of breast, lung, stomach, or pancreas; melanoma, lymphoma, leukemia; meningeal gliomatosis; sarcoma; cerebral dysgerminoma |
| Mononuclear or PMNs; low glucose, elevated protein; xanthochromia from subarachnoid hemorrhage in week prior to presentation with “meningitis” |
Contrast-enhanced CT scan or MRI; cerebral angiogram to detect aneurysm. Enhancement and clumping of nerve roots of the cauda equina in arachnoiditis/ pachymeningitis |
||
| Primary Inflammation | |||
| CNS sarcoidosis | Mononuclear cells; elevated protein; often low glucose |
Serum and CSF angiotensin-converting enzyme levels (insensitive); biopsy of extraneural affected tissues or brain lesion/meningeal biopsy, nodular meningeal and parenchymal enhancement |
CN palsy, especially CN VII and CN II, including optic chiasm; hypothalamic dysfunction, especially diabetes insipidus; abnormal chest radiograph; peripheral neuropathy or myopathy; longitudinally extensive transverse myelitis |
| Mononuclear cells | |||
| Isolated granulomatous angiitis of the nervous system |
Mononuclear cells; elevated protein |
Angiography (often normal with small vessel angiitis); meningeal biopsy may be necessary if confined to small vessels. VZV PCR in blood, CSF, and biopsy tissue; microhemorrhages with amyloid beta– related angiitis |
Subacute dementia; multiple cerebral infarctions; recent zoster ophthalmicus |
| Mononuclear or PMNs | Anti-dsDNA antibody, antinuclear antibodies |
||
| Behçet’s syndrome (recurrent meningitis) |
Mononuclear or PMNs; elevated protein |
Rhombencephalitis | Oral and genital aphthous ulcers; iridocyclitis; retinal hemorrhages; pathergic lesions at site of skin puncture |
| Mononuclear cells | |||
| Mollaret’s meningitis (recurrent meningitis) |
Large endothelial cells and PMNs in first hours, followed by mononuclear cells |
PCR for HSV; MRI/CT to rule out epidermoid tumor or dural cyst |
Recurrent meningitis; exclude HSV-2; rare cases due to HSV-1; occasional case associated with dural cyst |
| PMNs; occasionally mononuclear cells or eosinophils |
Complete blood count (eosinophilia) | ||
| Granulomatosis with polyangiitis (Wegener’s) |
Mononuclear cells | Chest and sinus radiographs; urinalysis; ANCA antibodies in serum; pachymeningitis on contrast-enhanced MRI |
Associated sinus, pulmonary, or renal lesions; CN palsies; skin lesions; peripheral neuropathy |
| Mononuclear and PMNs | Gain-of-function mutation in NLRP3 gene leading to elevated IL-1β |
||
| IgG4-related hypertrophic pachymeningitis |
Mild lymphocytic pleocytosis in some cases; normal to mildly increased protein; normal glucose |
Serum IgG4 levels frequently elevated; ESR and C-reactive protein; pachymeningitis on contrast-enhanced MRI; meningeal biopsy shows swirling “storiform” fibrosis with lymphocytic infiltrates, obliterative phlebitis and IgG4+ plasma cells |
Headache; seizures; focal symptoms from dural involvement in spinal cord/nerve roots, clivus, periorbital, vestibular, and brainstem structures. Systemic IgG4-related disease can involve many tissues including pancreas, thyroid, lungs, retroperitoneum, lacrimal, parotid and submandibular glands, orbits, kidney, aorta, liver |
| Mononuclear cells | Mutation in TNFRSF1A gene leading to elevated TNF |
||
| Complement factor I deficiency |
PMNs | Mutation in complement factor I gene leading to low serum levels of factor I (or dysfunctional factor I) and C3 |
Recurrent, steroid-responsive, aseptic, neutrophilic meningitis with or without encephalitis; increased risk for systemic infections with encapsulated bacteria, glomerulonephritis, systemic lupus erythematosus and leukocytoclastic vasculitis |
| Mononuclear cells | Heterozygous gain-of-function mutations within the NLRP3 gene |