Aseptic Meningitis

Definition

Aseptic meningitis is a clinical syndrome of meningeal irritation, fever, and altered consciousness with an acute onset, in the absence of organisms detectable by routine bacterial culture. The term was originally applied because cultures were sterile ("aseptic"), but it is now recognized as a symptom complex with many possible etiologies. The clinical course is typically less fulminant than bacterial (pyogenic) meningitis, and the CSF pattern differs accordingly.

Adams and Victor's Principles of Neurology, 12th Ed.

Epidemiology

Annual incidence: approximately 20 cases per 100,000 population
Most cases are viral; a specific etiology is established in only about two-thirds of cases even with thorough testing
Peak incidence of enteroviral infections is August-September
Mumps meningitis peaks in late winter and spring; males are affected 3x more often than females

Etiology

Viral (most common, ~80% of identified cases)

Virus	Notes
Enteroviruses (echovirus, Coxsackievirus)	Most common overall; fecal-oral spread; family outbreaks; childhood predominance
HSV-2	Most common in adults after enteroviruses; also causes recurrent Mollaret meningitis
Varicella-Zoster (VZV)	Can mildly lower CSF glucose
HIV	Acute seroconversion illness (infectious mononucleosis-like)
Mumps	Now rare with vaccination; orchitis, parotitis may co-occur
LCM (lymphocytic choriomeningitis)	Rodent-associated; late fall/winter; mild glucose depression
Adenovirus, HSV-1, EBV, CMV, West Nile	Less common but recognized
HSV-1	Associated with recurrent benign aseptic meningitis (Mollaret)

Non-viral Infectious

Atypical/fastidious bacteria: Mycoplasma, Rickettsia, Q fever
Treponema pallidum (syphilis), Borrelia burgdorferi (Lyme), Brucella, Nocardia
Fungi: Cryptococcus, Coccidioides, Histoplasma, Aspergillus
Parameningeal infections: brain abscess, sinusitis, otitis, epidural abscess (LP contraindicated if brain abscess is suspected - herniation risk)

Non-infectious Causes (4 principal categories - Goldman-Cecil)

Drug hypersensitivity
- NSAIDs (especially ibuprofen - associated with SLE)
- Trimethoprim-sulfamethoxazole
- IV immunoglobulin (IVIg)
- Intrathecal agents (methotrexate)
- Vaccines (MMR)
- CSF pleocytosis is typically neutrophilic (exception to the usual lymphocytic pattern)
- Diagnosis of exclusion; responds to drug withdrawal; may be confirmed by supervised re-challenge
Systemic/rheumatologic diseases
- SLE, Behçet's disease, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, ANCA-associated vasculitis, mixed connective tissue disease
- Pleocytosis: mild (<500 cells/µL), usually lymphocytic; glucose typically normal
- Hypoglycorrhachia (low glucose) suggests sarcoidosis or malignancy
Neoplastic (leptomeningeal involvement)
- Leukemia, lymphoma, breast cancer, lung cancer, melanoma, GI cancer
- Opening pressure elevated in ~50%; cytology is diagnostic (sensitivity improved with >10.5 mL, prompt processing, repeat LP)
Inflammatory CNS processes
- Granulomatous cerebral vasculitis, Vogt-Koyanagi-Harada syndrome, IgG-4 pachymeningitis, Wegener granulomatosis

Clinical Features

Classic triad: fever, headache, meningismus (neck stiffness)

Feature	Detail
Onset	Acute
Fever	38-40°C (100.4-104°F)
Headache	Severe; most frequent symptom
Meningismus	Neck/spine stiffness on forward bending; initially may be subtle
Photophobia	Common
Mentation	Mild lethargy, irritability, drowsiness - not the severe obtundation of bacterial meningitis
Neurologic signs	Mild/fleeting: paresthesias, wavering Babinski signs

Systemic features (virus-dependent):

Sore throat, nausea/vomiting, diarrhea, myalgia, cough
Rash: erythematous papulomacular (echovirus, Coxsackie) - in children especially
Enanthem (herpangina): vesiculoulcerative buccal eruption with Coxsackie infections
Childhood exanthems (varicella, rubella, mumps) carry their own rashes
Orchitis, pericarditis, pleurodynia (group B Coxsackie)
Hepatomegaly, splenomegaly, adenopathy

CSF Findings

Parameter	Aseptic Meningitis	Bacterial Meningitis
Opening pressure	Normal (<18 cm H₂O) or mildly elevated	Elevated
WBC/µL	5-1,000	>1,000 (often >10,000)
Cell type	Lymphocytes (early may be neutrophils)	Neutrophils
Glucose	Normal	Decreased (<45 mg/dL)
Protein	<100 mg/dL (mild elevation)	Markedly elevated
Gram stain/culture	Negative	Often positive

Important exceptions (glucose can be mildly low): mumps, HSV-2, LCM, VZV (rarely below 25 mg/dL).

Early disease caveat: In the first hours, CSF may be entirely normal; early cases can mimic migraine.

Drug-induced exception: Pleocytosis is typically neutrophilic, not lymphocytic.

Differential Diagnosis

Key diagnostic challenge is distinguishing aseptic meningitis from:

Partially treated bacterial meningitis - prior antibiotics can convert neutrophilic to lymphocytic pleocytosis and sterile cultures; glucose may normalize
Bacterial meningitis - clinical course is more fulminant; CSF glucose decreased
Migraine - early aseptic meningitis with normal CSF can mimic migraine
Tuberculous meningitis - chronic course; strikingly elevated protein; moderate glucose reduction

Clues to viral etiology: season (late summer for enteroviruses), age (children), family outbreaks, rash, accompanying parotitis/orchitis, geographic/exposure history, prior immunizations.

Mollaret Meningitis (Recurrent Aseptic Meningitis)

Recurrent episodes of benign aseptic meningitis
Now associated with HSV-2 (most common) and HSV-1
Virus has been isolated from CSF during acute episodes
Large "Mollaret cells" (endothelial-appearing cells) may be seen in CSF

Diagnosis

Lumbar puncture - essential (see CSF profile above)
PCR of CSF - method of choice for enteroviruses, HSV; increasingly, next-generation DNA sequencing allows identification of obscure organisms
Serology - useful for some agents (e.g., mumps, LCM, HIV seroconversion); note HIV antibodies may still be negative at the time of acute meningitis
Viral culture - lower sensitivity; still used for enteroviruses
Neuroimaging - CT/MRI before LP if focal signs, papilledema, or immunocompromised state; MRI also useful for leptomeningeal malignancy
CSF cytology - for suspected leptomeningeal malignancy

A specific cause cannot be established with conventional testing in >1/3 of presumed viral cases.

Treatment

Etiology	Management
Viral (most cases)	Symptomatic/supportive - analgesics, antipyretics, fluids; self-limited
HSV (HSV-1/HSV-2)	IV acyclovir - one of the few actionable viral causes; controversy remains on indications for uncomplicated HSV-2 meningitis
HIV acute meningitis	Antiretroviral therapy
Drug-induced	Withdraw offending agent; full recovery expected without sequelae
Autoimmune/connective tissue disease	Treat underlying condition; corticosteroids
Neoplastic (leptomeningeal)	Intrathecal chemotherapy ± craniospinal radiation
Partially treated bacterial meningitis	Empirical antibiotics must be maintained/added if cannot exclude

Key principle: Because most viral cases are self-limited, extensive etiologic workup is generally unnecessary - but HSV should be covered empirically if clinically uncertain, given its treatability.

Prognosis

Viral aseptic meningitis: excellent; fully self-limited in the vast majority
Complete recovery is the rule
Minor neurologic signs (paresthesias, Babinski signs) are transient
Drug-induced: full recovery after withdrawal of agent
Non-infectious (lupus, malignancy): prognosis depends on underlying disease

Sources:

Adams and Victor's Principles of Neurology, 12th Ed., Chapter 32
Robbins & Kumar Basic Pathology, Chapter 21
Goldman-Cecil Medicine, Chapter 381
Frameworks for Internal Medicine, Chapter on Meningitis

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