Viral Meningitis and Encephalitis

• Viral entry and CNS invasion: Most neurotropic viruses reach the CNS through hematogenous dissemination following primary viral replication in the respiratory tract, gastrointestinal tract, or other portal of entry. Some viruses (particularly arboviruses) undergo amplification in vector-associated tissues before viremia. Viral crossing of the blood-brain barrier (BBB) occurs through several mechanisms: (1) direct infection of endothelial cells compromising tight junction integrity, (2) transcytosis across infected endothelial cells, (3) leukocyte-mediated viral transport ("Trojan horse" mechanism), and (4) increased BBB permeability secondary to inflammatory mediators. Once in the CNS, viruses reach the meninges via the cerebrospinal fluid (CSF) or directly infect meningeal vasculature, whereas encephalitis results from direct parenchymal invasion of neurons and glial cells.

• Meningeal inflammation and CSF pleocytosis: Viral invasion of the meninges and choroid plexus triggers activation of resident microglia and perivascular macrophages, which produce interferon-alpha/beta (IFN-α/β) and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8). These cytokines upregulate adhesion molecules (ICAM-1, VCAM-1) on endothelial cells and promote infiltration of peripheral lymphocytes and monocytes into the subarachnoid space. In early viral meningitis (first 24–48 hours), polymorphonuclear (PMN) leukocytes may predominate due to IL-8 production, creating potential diagnostic confusion with bacterial meningitis; however, the shift toward lymphocytic predominance occurs within days in viral disease. The inflammatory cascade increases vascular permeability, leading to elevated CSF protein and opening of the BBB. Prostaglandins, leukotrienes, and complement activation further amplify inflammation, increasing CSF pressure and meningeal irritation.

• Encephalitis pathophysiology - direct parenchymal infection: In encephalitis, viral neuroinvasion results in direct infection of neurons and astrocytes, followed by local viral replication and cell lysis. Infected neurons undergo apoptosis through mechanisms including viral protease activation of caspase pathways (particularly in picornavirus infections) and mitochondrial damage leading to cytochrome c release. Activated microglia and infiltrating lymphocytes produce cytotoxic mediators (TNF-α, perforin, granzyme) that additionally damage infected and bystander neurons. Depending on the virus, encephalitis may present as focal disease (e.g., herpes simplex encephalitis preferentially affecting temporal lobes via direct invasion of trigeminal nerve neurons and transneuronal spread) or diffuse disease. The blood-brain barrier disruption in encephalitis is more pronounced than in meningitis alone, resulting in greater CSF pleocytosis and protein elevation. Cerebral edema develops from cytotoxic edema (intracellular swelling from Na+/K+ ATPase dysfunction and cellular injury) and vasogenic edema (extracellular fluid accumulation from BBB breakdown), potentially leading to increased intracranial pressure and herniation.

• Immune response and viral clearance: Innate immunity is initiated through pattern recognition receptors (TLRs, RIG-I, NOD-like receptors) on microglia and dendritic cells, producing type I interferons crucial for antiviral defense. Type I IFNs induce expression of 2'5'-oligoadenylate synthetase and protein kinase R, which inhibit viral translation and promote apoptosis of infected cells. Adaptive immunity develops with CD8+ T cell infiltration (recognizing viral peptide-MHC class I complexes) and B cell production of neutralizing antibodies, with antibody appearance in CSF marking transition to recovery phase. In immunocompetent hosts, viral clearance typically occurs within 7–10 days for most enteroviral meningitis, though some viruses (particularly herpes simplex virus) may require specific antiviral therapy to prevent severe neuronal damage.

• Seizure mechanisms: Viral encephalitis can trigger seizures through multiple mechanisms: (1) direct viral infection of cortical neurons disrupting normal electrical activity, (2) inflammatory mediators (cytokines, chemokines) lowering seizure threshold, (3) alterations in inhibitory GABA neurotransmission, (4) increased excitatory glutamate signaling, and (5) cerebral edema causing mass effect and increased intracranial pressure. HSV encephalitis carries particularly high seizure risk due to necrotizing temporal lobe involvement.

• Enteroviral meningitis (most common viral etiology): Coxsackievirus (particularly groups A and B) and echovirus are responsible for 50–80% of viral meningitis cases with identified etiology in developed countries. These non-enveloped, single-stranded RNA viruses belong to the Picornaviridae family and are transmitted via fecal-oral route. Peak incidence occurs in summer and fall months. Classic presentation is benign meningitis with excellent prognosis, though some coxsackievirus strains can cause more severe disease. Risk factors include young age (<5 years), immunosuppression, and male gender (slight male predominance). Enterovirus D68 has emerged as a cause of meningoencephalitis and acute flaccid paralysis.

• Herpes simplex virus (HSV) encephalitis: HSV-1 accounts for 10–20% of sporadic encephalitis in developed countries and is the most common cause of fatal encephalitis. HSV-2 causes neonatal herpes with CNS involvement in disseminated infection. HSV reaches the CNS either through hematogenous dissemination during primary infection or, more commonly, through retrograde neuronal transport from latent infection in the trigeminal ganglion (explaining the predilection for temporal lobe involvement). Risk factors include primary HSV infection, immunosuppression (particularly HIV with CD4 <50 cells/μL), and reactivation in latently infected individuals. HSV encephalitis is a medical emergency requiring immediate acyclovir therapy to prevent permanent neurologic sequelae.

• Varicella-zoster virus (VZV) encephalitis: VZV causes meningitis, encephalitis, and vasculopathy through direct viral invasion and immune-mediated mechanisms. Encephalitis typically occurs 1–2 weeks after rash onset but may occur without rash (zoster sine herpete). Risk factors include advanced age (>50 years) and immunosuppression. VZV can cause multifocal inflammatory leukoencephalitis presenting with cognitive decline, ataxia, and seizures, or vasculopathy leading to stroke. CSF analysis often shows lymphocytic pleocytosis with elevated protein; VZV PCR of CSF is diagnostic.

• Arboviruses (arthropod-borne): West Nile virus (WNV), transmitted by Culex mosquitoes, causes most arboviral CNS infections in North America, with estimated 1 in 150 viremic individuals developing neuroinvasive disease. Other significant arboviruses include St. Louis encephalitis virus, Japanese encephalitis virus, dengue, chikungunya, and Zika virus (associated with congenital CNS malformations). Arboviral transmission is seasonal and geographically dependent. Risk factors include age >60 years, immunosuppression, and geographic exposure during transmission season. West Nile virus neuroinvasive disease manifests as meningitis, encephalitis, or acute flaccid paralysis; mortality approaches 10% in severe cases.

• Mumps virus meningitis: Though less common in vaccinated populations, mumps causes meningitis without parotitis in approximately 15% of infected individuals. Mumps meningitis typically presents as benign, self-limited meningitis 3–10 days after respiratory symptoms. The incidence has dramatically decreased in countries with routine MMR vaccination, but outbreaks occur in unvaccinated populations.

• Measles encephalitis: Measles causes post-infectious encephalitis 7–10 days after rash onset (immune-mediated pathology) or subacute sclerosing panencephalitis (SSPE), a chronic progressive encephalitis months to years after infection. Risk is increased in immunocompromised hosts and unvaccinated individuals.

• Epstein-Barr virus (EBV) meningitis: Primarily occurs during acute infectious mononucleosis, presenting as aseptic meningitis with lymphocytic CSF pleocytosis. More serious manifestations include encephalitis and meningoencephalitis.

• Influenza virus meningitis and encephalitis: Influenza rarely causes direct CNS infection but can trigger post-infectious immune-mediated encephalitis. Increased risk during pandemic years.

• Immunosuppression-specific viruses: Immunocompromised patients (HIV with CD4 <100 cells/μL, post-transplant, on immunosuppressive therapy) are susceptible to cytomegalovirus (CMV) ventriculoencephalitis presenting with dementia and ventriculomegaly; progressive multifocal leukoencephalopathy (PML) from JC virus causing demyelination; and severe enteroviral infections. Immunosuppression is a major risk factor for increased severity and atypical presentations.

• Geographic and vector-related risk factors: Residence or travel to endemic areas increases risk of specific arboviruses (WNV in North America, JEV in Asia, dengue in tropical regions) and other geographically restricted pathogens.

Viral Meningitis - Cardinal Features

• Headache: Usually severe, frontal or occipital, exacerbated by neck movement or Valsalva maneuver. Results from meningeal irritation and inflammatory mediator-induced pain fiber activation. Typically accompanied by photophobia and phonophobia due to heightened sensory perception.

• Fever: Low to moderate grade (38–40°C), reflecting the body's response to viral infection. Unlike bacterial meningitis, fever may be less prominent in viral disease.

• Meningismus (meningeal signs): Neck stiffness (nuchal rigidity) is classic, resulting from irritation of the posterior cervical muscles and meningeal inflammation. Kernig's sign (pain or resistance with knee extension when hip is flexed) and Brudzinski's sign (involuntary knee flexion when neck is passively flexed) reflect meningeal irritation. However, these signs are absent in up to 50% of viral meningitis cases and are not sensitive in very young children or elderly patients.

Viral Encephalitis - Cardinal Features (often more severe than meningitis alone)

• Altered mental status: Ranges from mild confusion and personality changes to profound lethargy, unresponsiveness, and coma. Results from direct neuronal infection, inflammation, cerebral edema, and increased intracranial pressure. Confusion and behavioral changes may be more prominent than in meningitis.

• Seizures: Occur in 30–50% of encephalitis cases (particularly HSV encephalitis) compared to <5% in uncomplicated meningitis. Reflect cortical irritability from inflammation and direct infection.

• Focal neurologic deficits: Including aphasia, hemiparesis, hemianopsia, or ataxia, indicate focal brain involvement and are uncommon in simple meningitis. HSV encephalitis characteristically presents with temporal lobe dysfunction (olfactory hallucinations, memory disturbance, complex partial seizures).

• Headache and fever: Present but often overshadowed by encephalopathic features.

General Systemic Features

• Myalgias and arthralgias: Particularly prominent in enteroviral and arboviruses, reflecting systemic viral infection.

• Rash: Enterovirus can present with vesicular or maculopapular exanthem; arboviruses (dengue, Zika, chikungunya) characteristically present with rash; VZV presents with dermatomal distribution in zoster.

• Respiratory symptoms: Upper respiratory infection symptoms may precede meningitis by several days.

Age-Specific and Population-Specific Presentations

• Neonates and infants (<3 months): May present with fever, irritability, poor feeding, high-pitched cry, bulging fontanelle, and seizures. Classic meningeal signs are unreliable in this age group.

• Elderly patients: Often present with subtle findings: minimal fever, no meningeal signs, altered mental status as primary complaint. This leads to diagnostic delays and increased morbidity.

• Immunocompromised patients: May present with atypical or minimal CSF findings despite severe encephalitis. CMV ventriculoencephalitis in AIDS presents with dementia, cranial nerve palsies, and ventriculomegaly without prominent CSF pleocytosis.

Specific Viral Syndromes

• HSV encephalitis: Acute presentation with fever, headache, seizures (80% of cases), altered mental status, and focal neurologic signs. Temporal lobe involvement produces olfactory hallucinations (gustatory, visual, or olfactory sensations), memory disturbance, and complex partial seizures. Herpetic vesicles may be present on lips or genitals in some cases.

• Arboviruses (WNV, JEV): Fever, headache, myalgias (particularly with chikungunya), progressing to meningitis or encephalitis. WNV neuroinvasive disease can present with acute flaccid paralysis (WNV poliomyelitis-like syndrome) due to anterior horn cell involvement.

• Mumps meningitis: Typically occurs 3–10 days after parotitis onset (though may occur without parotitis). Presents as relatively benign aseptic meningitis with excellent prognosis.

Clinical Assessment and History

Physical Examination Pearls

Lumbar Puncture and CSF Analysis (Cornerstone of Diagnosis)

Absolute CSF findings in viral meningitis

• Cell count and differential: CSF pleocytosis with 100–500 white blood cells/μL is typical, though can range from

Immediate stabilisation (before any etiologic certainty)

• Airway, seizure, and ICP control: obtunded patients with encephalitis may need intubation for airway protection. Seizures are terminated with a benzodiazepine (lorazepam) followed by a maintenance agent (levetiracetam or fosphenytoin); status epilepticus and clinical herniation (posturing, blown pupil, Cushing reflex) are emergencies treated with head-of-bed elevation, osmotherapy (hypertonic saline or mannitol), and neurosurgical consultation.
• Do not delay therapy for imaging or LP. The IDSA bacterial meningitis guideline advises obtaining blood cultures and giving empiric drugs first when CT is indicated (immunocompromise, focal deficit, new seizure, papilledema, depressed consciousness, prior CNS disease).

Empiric therapy while awaiting CSF PCR (IDSA encephalitis guideline)

• Acyclovir (nucleoside analog): IV acyclovir 10 mg/kg every 8 hours is started in every adult with encephalitis until HSV is excluded — the mechanism (viral thymidine kinase–dependent activation, then chain termination) means it only works before neurons are lost, so empiric use is the standard.
• Antibacterials: vancomycin plus a third-generation cephalosporin (ceftriaxone), with ampicillin added for Listeria coverage at the extremes of age, immunocompromise, or pregnancy. Vancomycin is dosed to a 24-hour AUC/MIC of 400–600 per the 2020 IDSA/ASHP consensus. Adjunctive dexamethasone is given with or just before the first antibiotic dose only when pneumococcal meningitis is suspected, and stopped once viral etiology is confirmed.

Pathogen-directed and second-line therapy

• HSV-1/VZV encephalitis: continue IV acyclovir 14–21 days; adequate hydration prevents crystal nephropathy.
• Neonatal HSV: high-dose IV acyclovir 20 mg/kg every 8 hours for 21 days in CNS/disseminated disease, followed by oral suppressive acyclovir (AAP Red Book).
• CMV encephalitis in advanced HIV/transplant: ganciclovir with or without foscarnet, plus antiretroviral therapy or reduced immunosuppression.
• Enterovirus, mumps, West Nile: supportive care only; IVIG is used for chronic enteroviral CNS infection in agammaglobulinemia. PML: immune reconstitution (ART) is the only effective intervention.

Neurologic emergencies

• Cerebral edema with herniation (emergency): combined cytotoxic and vasogenic edema from necrotising parenchymal infection, most often HSV temporal lobe disease. Signalled by declining GCS, unilateral fixed pupil, hypertension with bradycardia, or new posturing; uncal herniation from a swollen temporal lobe is the classic mechanism of death in HSV encephalitis.
• Status epilepticus (emergency): cortical neuronal infection plus cytokine-mediated lowering of seizure threshold. Suspect it in any encephalitic patient who fails to wake up — nonconvulsive status requires urgent EEG.
• Post-HSV anti-NMDA receptor autoimmune encephalitis (emergency): neuronal destruction exposes NMDA receptor epitopes, provoking autoantibodies weeks after apparent recovery. Signalled by relapsing psychiatric symptoms, orofacial dyskinesias, and choreoathetosis with a negative repeat CSF HSV PCR — the treatment is immunotherapy, not more acyclovir.

Disease complications

• SIADH: hypothalamic/inflammatory ADH release causing euvolemic hyponatremia; signalled by falling serum sodium with concentrated urine, and it can itself precipitate seizures.
• Permanent cognitive and behavioural sequelae: bilateral medial temporal/limbic necrosis produces anterograde amnesia, aphasia, and rarely Klüver-Bucy syndrome (hyperorality, hypersexuality, placidity).
• Acute flaccid paralysis: anterior horn cell infection by West Nile virus or enterovirus D68; asymmetric weakness with preserved sensation and areflexia.
• Sensorineural hearing loss: classically unilateral after mumps; obtain audiometry in children after recovery.
• Communicating hydrocephalus: arachnoid granulation inflammation impairing CSF resorption; signalled by ventriculomegaly with progressive gait apraxia or somnolence.
• SSPE: delayed measles complication with myoclonus, dementia, and periodic EEG complexes.

Treatment complications

• Acyclovir crystal nephropathy: poorly soluble drug precipitates in tubules; signalled by rising creatinine days into therapy — prevented by generous IV hydration and slow infusion.
• Acyclovir neurotoxicity: accumulation of metabolites in renal impairment causing tremor, myoclonus, hallucinations, and confusion — easily mistaken for worsening encephalitis.
• Vancomycin-associated AKI, and ceftriaxone-related biliary sludging or drug rash, from empiric antibacterials continued longer than needed.

• The single best next step in suspected encephalitis is empiric IV acyclovir, started before CSF PCR, MRI, or EEG results return. Untreated HSV encephalitis mortality is very high; treated, most survivors still have deficits, and outcome tracks with time-to-acyclovir.
• Temporal lobe = HSV-1. MRI showing hemorrhagic necrosis of the medial temporal and inferior frontal lobes and EEG showing periodic lateralised epileptiform discharges (PLEDs/LPDs) over a temporal lead are the classic buzzwords. CSF often has red blood cells or xanthochromia without a traumatic tap.
• CSF profile is the discriminator: viral disease gives lymphocytic pleocytosis, mildly elevated protein, and a normal glucose. Low CSF glucose points away from a simple viral cause (bacterial, TB, fungal). Remember that early enteroviral meningitis can be neutrophil-predominant — that is a deliberate distractor, not evidence of bacterial disease.
• CSF HSV PCR is the diagnostic test of choice, but a PCR obtained within the first ~72 hours can be falsely negative — continue acyclovir and repeat the PCR rather than stopping therapy.
• Enterovirus (coxsackievirus, echovirus) is the most common cause of viral meningitis, peaks in late summer/fall, and needs supportive care only — no antiviral. Do not "treat" it with acyclovir.
• The association examiners love: Mollaret meningitis (recurrent benign lymphocytic meningitis) is caused by HSV-2, whereas encephalitis in adults is HSV-1; neonatal CNS herpes is usually HSV-2 acquired peripartum.
• Acute HIV can present as aseptic meningitis; a fourth-generation antigen/antibody test may be negative, so order HIV RNA viral load in the right stem.
• Common distractors to avoid: a new relapse of psychiatric symptoms after treated HSV encephalitis is anti-NMDA receptor autoimmune encephalitis, not acyclovir failure; rising creatinine on therapy is acyclovir crystal nephropathy, not sepsis; and dexamethasone is for suspected pneumococcal meningitis, not routine HSV encephalitis.