Viral Meningitis

• Direct CNS invasion and viral replication: Neurotropic viruses reach the CNS via hematogenous dissemination, transcytosis across the blood-brain barrier, or retrograde neuronal transport. Once in the meninges and subarachnoid space, viruses replicate within meningeal fibroblasts, endothelial cells, and occasionally neurons, triggering local innate immune responses. Viral RNA and proteins are recognized by pattern recognition receptors (TLRs, RIG-I-like receptors), initiating interferons and pro-inflammatory cytokine production.

• Immune-mediated meningeal inflammation: The primary pathologic process involves recruitment of lymphocytes (predominantly CD8+ T cells and B cells) to the subarachnoid space driven by chemokines (CCL2, CXCL10, CCL5). This creates the characteristic lymphocytic pleocytosis with relative sparing of neutrophils (unlike bacterial meningitis where neutrophils predominate early). Inflammatory cytokines (TNF-α, IL-6, IL-1β) increase blood-brain barrier permeability, producing meningeal edema, protein extravasation, and symptom generation (headache, nuchal rigidity). The inflammatory response peaks when viral load declines, explaining symptom onset during the early viremic phase.

• Altered CSF dynamics and complications: Meningeal inflammation impairs CSF absorption at the arachnoid villi and increases production, potentially causing mild hydrocephalus and increased intracranial pressure. Most uncomplicated viral meningitis resolves as immune clearance eliminates virus; however, certain pathogens (enterovirus 71, HSV-2) can extend beyond meninges to involve gray matter (meningoencephalitis) or cause vasculitis with stroke risk.

Major viral causes (in order of frequency in developed countries)

• Enteroviruses (echoviruses, coxsackieviruses, enterovirus 71): Account for 50-80% of viral meningitis with identified etiology; peak summer-fall incidence in temperate climates; human-to-human fecal-oral transmission
• Arboviruses (West Nile virus, St. Louis encephalitis, dengue, Zika): Geographic and seasonal distribution; transmitted by mosquitoes; enteroviral coinfection common in endemic areas
• Herpes simplex virus-2 (HSV-2): Most common cause of recurrent viral meningitis (Mollaret meningitis when recurrent); associated with primary genital herpes or reactivation disease; immunocompetent hosts usually recover without acyclovir, unlike HSV-1 encephalitis
• Paramyxoviruses (mumps, measles): Incidence declining with MMR vaccination; mumps causes meningitis in 1-10% of infected individuals (usually in unvaccinated populations); measles more commonly causes encephalitis
• Influenza viruses (A, B, C): Seasonal incidence; often concurrent respiratory infection; associated with high fever and systemic symptoms
• Lymphocytic choriomeningitis virus (LCMV): Rodent-borne pathogen; exposure history important; can cause hydrocephalus and ventriculitis
• HIV (acute retroviral syndrome): CD4 count typically >200 cells/μL; self-limited course; may progress to opportunistic CNS infections if untreated
• Varicella-zoster virus (VZV): Usually in immunocompromised hosts; associated with dermatomal rash; vasculopathy risk with neurologic complications
• Cytomegalovirus (CMV): Immunocompromised patients (CD4 <50 cells/μL); polymorphonuclear pleocytosis unusual
• EBV, HHV-6, adenovirus, rhinovirus: Less common causes; diagnosis increasingly recognized with molecular testing

Risk factors for viral meningitis

• Host factors: Age <5 years or >65 years; immunocompromise (HIV/AIDS, malignancy, transplant, biologics); asplenia; complement deficiency; recent vaccination (especially MMR)
• Epidemiologic exposure: Close contact with infected individuals; travelers to endemic arbovirus areas; rodent exposure (LCMV); sexual contact (HSV-2)
• Season and geography: Enterovirus and arbovirus meningitis seasonal; geographic distribution correlates with vector prevalence
• Absence of meningococcal vaccination or pneumococcal vaccination (slight risk reduction for enteroviral meningitis)

• Headache: Most frequent symptom (80-90%); often severe, bifrontal-occipital, photophobic; may precede other features
• Fever: Present in 80-90%; typically moderate (38-40°C) but ranges vary by pathogen
• Neck stiffness (nuchal rigidity): Present in 50-60% at presentation; develops during first 24-48 hours; pathognomonic when present but not required for diagnosis
• Altered mental status: Confusion, lethargy, irritability in 25-40%; more common with encephalitis overlap; mild compared to bacterial meningitis
• Myalgias and malaise: Prodromal or concurrent systemic symptoms common with enterovirus and influenza

Associated symptoms by pathogen

• Enterovirus: Exanthem (maculopapular or vesicular) in 25-50%; pleurodynia; orchitis; rarely myocarditis
• Mumps: Parotitis in 50-70% (though meningitis can occur without parotitis); bilateral salivary gland enlargement
• HSV-2: Genital vesicles or prodromal symptoms; may have sacral radiculomyelitis or autonomic dysfunction
• West Nile virus: Rash (trunk/extremities), weakness, flaccid paralysis in severe cases
• Arboviruses: Concurrent arthralgia/arthritis (dengue, Zika); rash common

Physical examination findings

• Meningismus: Neck stiffness (nuchal rigidity), Kernig sign (resistance to knee extension with hip flexed 90°), Brudzinski sign (spontaneous hip flexion with neck flexion); collectively present in 50% but highly specific when present
• Rash: Maculopapular or petechial; non-blanching petechiae should raise concern for meningococcemia but occurs in enterovirus and measles meningitis
• Neurologic exam: Typically normal cognitive function early; cranial nerve palsies rare; focal neurologic deficits suggest encephalitis, vasculitis, or stroke
• Vital signs: Fever typically 38-40°C; tachycardia, tachypnea variable
• Skin findings: Exanthem location varies (flexural with coxsackievirus, trunk with West Nile); oral vesicles with enterovirus

Red flags requiring urgent imaging and aggressive investigation

• Seizures (suggest encephalitis)
• Focal neurologic deficits
• Altered consciousness/obtundation
• Papilledema or signs of increased ICP
• Immunocompromise

• Cell count and differential: Pleocytosis 10-1000 cells/μL (range 5-10,000); lymphocytic predominance (>50% lymphocytes) is hallmark but not absolute—early meningitis (<24 hours) or certain viruses (enterovirus 71, HSV-1) may show initial neutrophilic predominance with leftward shift, gradually shifting to lymphocytic over 24-48 hours. Normal CSF may be seen early in illness. Red blood cells may be present, particularly with HSV-1 or VZV encephalitis.

• Protein and glucose: Protein mildly elevated (50-200 mg/dL; range 40-500); glucose typically normal or mildly low (>40 mg/dL; CSF:serum glucose ratio >0.4). Significant hypoglycorrhachia (<40 mg/dL, ratio <0.4) suggests bacterial or tuberculous meningitis, not typical viral meningitis (HSV-1 encephalitis may be exception).

• Gram stain and bacterial culture: NEGATIVE (diagnostic criterion for aseptic meningitis); performed to exclude bacterial meningitis; sensitivity of Gram stain ~80% in untreated bacterial meningitis

• Viral culture: Low sensitivity (10-30%); enterovirus culture of stool and throat more sensitive than CSF; results take days, limiting clinical utility

• Molecular diagnosis (PCR-based assays): GOLD STANDARD for specific viral diagnosis
• Enterovirus PCR: Sensitivity/specificity 95-100%; available in 24-48 hours
• HSV-1 and HSV-2 PCR: Sensitivity 95-100%; HSV-2 meningitis often culture-negative
• VZV PCR: Sensitivity/specificity 98-100%
• Arbovirus testing: Serology (IgM antibodies); PCR of serum/CSF in acute phase (variable sensitivity)
• Multiplex respiratory viral PCR: Increasing availability; detects influenza, rhinovirus, parainfluenza, adenovirus, RSV
• Mumps serology: IgM antibodies develop within 3-4 days; culture of saliva, CSF possible

• Serology: Less useful acutely; useful for retrospective diagnosis and epidemiologic investigation (West Nile IgM, dengue, Zika)

Imaging (CT or MRI)

• CT head: Indicated before LP if papilledema, focal neurologic signs, immunocompromise, or concern for increased ICP; normal in uncomplicated viral meningitis
• MRI brain with contrast: Enhances meninges (diffuse, thin enhancement in viral vs. thick, loculated in bacterial); useful if encephalitis suspected; may show signal abnormalities in gray matter (enterovirus 71, West Nile encephalitis)
• Purpose: Exclude mass lesion, hydrocephalus, or focal infection before LP

Laboratory studies

• Blood cultures: Negative in viral meningitis (positive in bacterial meningitis in 60-80%)
• CBC: Normal or mild lymphocytosis; not specific
• Metabolic panel: Assess for hyponatremia (SIADH in viral meningitis)
• Blood PCR: Enterovirus and arbovirus detection in early viremic phase; HSV-1/2 rarely positive in blood

• Acute meningitis syndrome (fever, headache, meningismus or altered mental status) with CSF pleocytosis (typically lymphocytic >10 cells/μL)
• Negative bacterial cultures and Gram stain
• No parameningeal focus (e.g., abscess, ventriculitis) on imaging
• Absence of alternative diagnosis (fungal, tuberculous, malignant, drug-induced meningitis)

Diagnostic challenges and mimics

• Early bacterial meningitis may present with lymphocytic CSF; empiric antibiotics given until cultures negative (48-72 hours)
• Aseptic meningitis from bacteria (partially treated, Listeria, Brucella, Leptospira, TB early, Lyme disease)
• Non-infectious causes: Medications (NSAIDs, antibiotics, chemotherapy); malignancy (lymphomatous, carcinomatous meningitis); inflammatory (SLE, sarcoidosis); post-vaccination

• Isolation precautions: Contact precautions for enteroviruses and paramyxoviruses; respiratory precautions for suspected arbovirus or influenza if concurrent respiratory illness
• Fluid management: IV hydration for fever/vomiting; avoid hyponatremia from SIADH (restrict free water, cautious NS use); monitor sodium
• Pain and fever management: Acetaminophen or NSAIDs for headache and fever (no evidence of harm in viral meningitis unlike bacterial meningitis); avoid morphine early (complicates exam)
• Antiemetics: Ondansetron or metoclopramide for vomiting
• Rest and supportive care: Most patients improve with conservative management; discharge home after 24-48 hours observation if improving clinically and alternate diagnoses excluded
• Monitoring: Repeat LP if inadequate improvement, deterioration, or diagnostic uncertainty

• Cannot distinguish viral from bacterial at presentation; therefore empiric antibiotics + acyclovir initiated if meningitis presumed:
• Ceftriaxone 2 g IV Q12H (or cefotaxime 2 g Q4-6H)
• Vancomycin 15-20 mg/kg IV Q8-12H (for penicillin-resistant Streptococcus pneumoniae)
• Acyclovir 10 mg/kg IV Q8H (covers HSV-1/2 and partially VZV; HSV-1 encephalitis differs from meningitis and requires full treatment)
• Ampicillin 2 g IV Q4H added if Listeria suspected (age >50, immunocompromise, pregnancy)

• Discontinue antibiotics after 48-72 hours if CSF cultures remain negative, Gram stain negative, and clinical picture consistent with viral (improving symptoms, CSF profile compatible)

Pathogen-specific antiviral therapy

• HSV-1 encephalitis (not meningitis): Acyclovir 10 mg/kg IV Q8H continued for 10-14 days (essential; encephalitis has higher mortality without treatment). Viral meningitis from HSV-2 typically resolves without acyclovir in immunocompetent hosts, though some experts treat to reduce recurrence risk and symptom duration.

• HSV-2 meningitis (immunocompetent): Acyclovir 800 mg PO 5x daily or IV dosing considered for severe disease or immunocompromise; reduces symptom duration and recurrence but not universally required

• VZV meningitis/encephalitis: Acyclovir 10-15 mg/kg IV Q8H for 7-10 days (immunocompetent); higher doses/longer duration for immunocompromised

• Enterovirus meningitis: Supportive care only (no antiviral effective); pleconaril (investigational) reduces symptom duration if given early but not standard; IV immunoglobulin considered in severe neonatal disease

• Mumps meningitis: Supportive care; no antiviral; consider MMR vaccination for unvaccinated contacts

• West Nile virus, other arboviruses: Supportive care only; no effective antivirals; interferon-α, ribavirin studied without proven benefit

• Influenza meningitis: Neuraminidase inhibitors (oseltamivir 75 mg PO BID) if respiratory infection suspected; unclear benefit for CNS disease but standard for systemic influenza; acyclovir covers only if HSV coinfection suspected

• CMV meningitis (immunocompromised): Ganciclovir or cidofovir depending on CD4 count and organ involvement

• Benefit established in bacterial meningitis; limited evidence in viral meningitis
• Some data suggest

Neurologic complications (mechanism → signal)

• Progression to meningoencephalitis: viral spread from meninges into cortical gray matter; heralded by seizures, focal deficits, or persistent altered mentation rather than isolated headache. This is an emergency — obtain MRI and CSF HSV PCR and continue empiric IV acyclovir per the IDSA encephalitis guideline until HSV is excluded.
• Raised intracranial pressure and hydrocephalus: inflammatory obstruction of arachnoid villi impairs CSF resorption; signaled by vomiting, obtundation, papilledema, or cranial nerve VI palsy. Herniation is an emergency; image before LP when red flags are present.
• Acute flaccid paralysis: West Nile virus (and enterovirus D68/71) targets anterior horn motor neurons, producing asymmetric, areflexic weakness with preserved sensation — a polio-like syndrome. Diaphragmatic involvement causing respiratory failure is an emergency.
• Brainstem rhombencephalitis (enterovirus 71): myoclonus, ataxia, and autonomic instability progressing to neurogenic pulmonary edema and cardiovascular collapse — an emergency in young children.
• Elsberg syndrome / sacral radiculitis (HSV-2): lumbosacral root inflammation causing urinary retention and saddle anesthesia.
• **Recurrent (Mollaret) meningitis**: HSV-2 reactivation with repeated self-limited episodes and large mononuclear "Mollaret cells" on cytology.
• SIADH with hyponatremia: inflammatory ADH release; signaled by falling serum sodium with concentrated urine; symptomatic hyponatremic seizures are an emergency.

Systemic and pathogen-specific

• Mumps: sensorineural hearing loss, orchitis, pancreatitis; hearing loss is often unilateral and permanent — a key argument for MMR vaccination (ACIP/CDC).
• Neonatal enteroviral disseminated disease: hepatic necrosis, myocarditis, coagulopathy — high-mortality emergency.

Treatment-related

• Acyclovir crystalline nephropathy and neurotoxicity: tubular crystal precipitation with bolus dosing; signals are rising creatinine or confusion/tremor in renal impairment — prevent with hydration and renal dosing.
• Vancomycin nephrotoxicity: mitigated by AUC-guided dosing (AUC/MIC 400–600, 2020 IDSA/ASHP consensus), not trough-only targeting.
• Missed or partially treated bacterial meningitis: premature antibiotic discontinuation in a decompensating patient is an emergency — repeat LP.

• Enterovirus in late summer/early fall is the answer: a previously well child or young adult with headache, fever, nuchal rigidity, and a nonspecific exanthem after fecal–oral exposure. Lymphocytic pleocytosis, normal glucose, mildly elevated protein, negative Gram stain is the classic CSF triad.
• Single best next step is lumbar puncture — but obtain head CT first only if there are focal deficits, seizures, papilledema, immunocompromise, or depressed consciousness (IDSA bacterial meningitis guideline). If imaging will delay LP, draw blood cultures and give empiric antimicrobials first; do not wait.
• Treat as bacterial until proven otherwise: empiric ceftriaxone plus vancomycin (AUC-guided per 2020 IDSA/ASHP), add ampicillin for Listeria risk (age >50, pregnancy, immunocompromise), and IV acyclovir if encephalitic features are present. Dexamethasone belongs to the suspected pneumococcal bacterial pathway, given before or with the first antibiotic dose — not to routine viral meningitis.
• The association examiners test: HSV-2 causes recurrent benign lymphocytic meningitis (Mollaret meningitis); HSV-1 causes temporal-lobe hemorrhagic encephalitis with RBCs in CSF and personality change. Do not conflate them — HSV-2 meningitis in an immunocompetent host is usually self-limited, whereas HSV-1 encephalitis mandates prompt acyclovir.
• Neutrophils early do not equal bacteria: enteroviral CSF within the first 24 hours can be neutrophil-predominant and shifts to lymphocytes over 24–48 hours. The discriminating value is glucose — hypoglycorrhachia points to bacterial, tuberculous, or fungal disease, not typical viral meningitis.
• Mumps meningitis with parotitis in an unvaccinated patient; meningitis can precede or occur without parotid swelling. West Nile classically adds asymmetric flaccid paralysis.
• Common distractor: drug-induced aseptic meningitis (NSAIDs, TMP-SMX, IVIG), especially in SLE — stem gives recent drug exposure and a sterile lymphocytic CSF that resolves on withdrawal.
• Watch the sodium: SIADH-driven hyponatremia is the quiet cause of in-hospital seizures.