Encephalitis

Viral-mediated mechanisms

• Direct viral neurotoxicity: Virus enters CNS through hematogenous dissemination, circumventing blood-brain barrier (BBB) via infected endothelial cells or leukocytes; replication within neurons and glia causes cytopathic effect, neuronal apoptosis via caspase activation, and cellular lysis
• Innate immune activation: Viral double-stranded RNA triggers pattern recognition receptors (TLRs, RIG-I); activation of microglia and astrocytes produces pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and chemokines (CCL2, CXCL10), recruiting CD8+ T lymphocytes that perpetuate inflammation even after viral clearance
• BBB disruption: Inflammatory mediators increase vascular permeability through endothelial tight junction dysfunction, allowing leukocyte infiltration and cerebral edema; cytotoxic edema (from cellular swelling) and vasogenic edema (from extracellular fluid accumulation) increase intracranial pressure and risk of herniation

Autoimmune-mediated mechanisms

• Antibodies against neural surface antigens (NMDA receptors, AMPA receptors, GABA-B receptors, LGI1) or intracellular antigens (Hu, Yo) cause complement-mediated neuronal destruction, antibody-dependent cellular cytotoxicity, or receptor internalization and functional impairment
• Some viral infections (particularly HSV-1, VZV, enterovirus) trigger cross-reactive immune responses recognizing structurally similar epitopes on neuronal proteins

Organ-level consequences

• Inflammation localizes to gray matter but may affect white matter; temporal lobe involvement particularly common with HSV-1
• Increased ICP from edema causes decreased cerebral perfusion, secondary ischemia, and potential transtentorial or uncal herniation
• Seizure activity from altered neuronal excitability and inhibition of GABAergic transmission

Viral etiologies (most common, 60–80% of identified cases)

• Herpes simplex virus-1 (HSV-1): Most common cause of sporadic encephalitis in developed countries; accounts for 10–20% of all encephalitis cases; often presents with hemorrhagic necrosis of temporal lobes
• Enteroviruses (coxsackievirus, echovirus, enterovirus 71): Seasonal predominance (summer/fall); typically mild, self-limited illness; EV-D68 emerging cause with severe neurologic complications
• Arboviruses: West Nile Virus (most common arthropod-borne cause in North America; older age, immunocompromised status increase severity), Japanese encephalitis (endemic Asia), dengue, tick-borne encephalitis (Eastern Europe, Russia), La Crosse virus (pediatric cases in Midwest USA)
• Varicella-zoster virus (VZV): Post-varicella or disseminated zoster; risk increases with immunosuppression and advancing age
• Epstein-Barr virus (EBV): Immunocompromised hosts, particularly post-transplant; can cause limbic encephalitis
• Cytomegalovirus (CMV): Predominantly in severely immunocompromised (CD4 <50 cells/μL in AIDS, post-transplant); presents with ventriculoencephalitis or polyradiculitis
• Human immunodeficiency virus (HIV): Acute HIV meningoencephalitis in primary infection; chronic HIV-associated dementia; increased risk of opportunistic infections (CMV, toxoplasmosis, progressive multifocal leukoencephalopathy)
• Measles, mumps, rubella: Rare in vaccinated populations; mumps causes ependymitis and ventriculitis

Bacterial etiologies (10–20%)

• Treponema pallidum (neurosyphilis): General paresis of insane (GPI), tabes dorsalis; increasing incidence with HIV co-infection
• Mycobacterium tuberculosis: Tuberculous meningitis with encephalitic component; basilar involvement, vasculitis
• Partially treated bacterial meningitis: Organisms viable despite antibiotic therapy; evolves into encephalitis
• Mycoplasma pneumoniae: Post-infectious immune-mediated rather than direct invasion

Fungal etiologies (1–5%)

• Cryptococcus neoformans: Immunocompromised patients, particularly CD4 <100 cells/μL
• Coccidioides immitis: Southwest USA endemic; may disseminate to CNS
• Histoplasma capsulatum: Immunocompromised, travel history

Parasitic etiologies

• Plasmodium falciparum: Cerebral malaria with severe encephalopathy
• Toxoplasma gondii: CD4 <100 cells/μL; ring-enhancing lesions on imaging
• Naegleria fowleri: Freshwater exposure; fulminant course, nearly uniformly fatal

Autoimmune/inflammatory etiologies (15–20%)

• Anti-NMDA receptor encephalitis: Predominantly young women; movement disorder, psychiatric symptoms, seizures; ~50% have underlying teratoma (ovarian most common)
• Anti-AMPA receptor encephalitis: Older patients; seizures, cognitive decline; associated with small cell lung cancer, thymoma
• Anti-LGI1 encephalitis: Limbic encephalitis pattern; prominent seizures, memory impairment
• Anti-GABA-B receptor encephalitis: Small cell lung cancer association; seizures, encephalopathy
• Paraneoplastic encephalitis: Anti-Hu (SCLC), anti-Yo (ovarian/breast cancer), anti-CV2
• Hashimoto's encephalitis: Associated with Hashimoto's thyroiditis; steroid-responsive
• ADEM (Acute Disseminated Encephalomyelitis): Post-viral or post-vaccination; multifocal white matter involvement

Risk factors

• Immunosuppression: HIV/AIDS, malignancy, transplantation, chronic corticosteroid use, immunosuppressive medications
• Age: Infants <2 months (enteroviruses), elderly (arboviruses, VZV), specific age peaks for particular etiologies
• Geographic/occupational exposure: Mosquito/tick exposure, freshwater exposure, bird contact (histoplasmosis)
• Vaccination status: Unvaccinated against measles, mumps, rubella
• Season: Summer/fall for vector-borne illnesses

Cardinal symptoms

• Fever: Present in 80–90% of cases; may be absent in severe immunosuppression or autoimmune etiologies
• Altered mental status/encephalopathy: Ranging from subtle personality changes and confusion to delirium, stupor, or coma; cardinal distinguishing feature from meningitis alone
• Headache: Present in majority; typically severe, diffuse
• Seizures: Occur in 30–75% depending on etiology; range from focal to generalized; particularly common with HSV-1 (>80%), anti-NMDA receptor encephalitis
• Behavioral/psychiatric changes: Personality alteration, hallucinations, inappropriate affect, agitation; particularly prominent in HSV-1 temporal lobe involvement and anti-NMDA receptor disease

Neurologic findings

• Altered consciousness: Disorientation, drowsiness, progressive decrease in Glasgow Coma Scale
• Focal neurologic deficits: Depend on areas of inflammation; HSV-1 causes temporal lobe sign (receptive language abnormalities with dominant lobe involvement, visual field defects, behavioral changes); cranial nerve palsies (particularly CN VII, VIII); hemiparesis
• Movement disorders: Dystonia, choreoathetosis, tremor (particularly anti-NMDA receptor encephalitis causing distinctive orofacial dyskinesias, limb choreiform movements, autonomic instability)
• Signs of meningeal irritation: Neck stiffness, photophobia, Kernig's sign, Brudzinski's sign (present in 25–50% of viral encephalitis, less specific than in meningitis)
• Ataxia: Cerebellar involvement; present in some arboviral infections
• Autonomic instability: Fluctuating vital signs, temperature dysregulation, labile blood pressure; particularly severe in anti-NMDA receptor disease and fulminant cases

Disease pattern

• Prodromal phase: Non-specific viral symptoms (upper respiratory infection, gastroenteritis) for 1–7 days preceding neurologic manifestation
• Rapid progression: Neurologic symptoms typically evolve over hours to days; severe cases deteriorate over hours with rapid development of altered mental status and seizures

Laboratory studies

• Cerebrospinal fluid (CSF) analysis—Gold standard diagnostic test:
• Lumbar puncture (LP) with opening pressure measurement (elevated in 50–60%), cell count with differential, glucose, protein, Gram stain, bacterial culture, viral PCR
• Typical viral encephalitis pattern: Lymphocytic pleocytosis (10–1000 cells/μL, often higher in early infection), normal or mildly elevated glucose (>40% CSF:serum glucose ratio), elevated protein (usually <200 mg/dL), negative Gram stain and bacterial culture
• HSV-1 specific: CSF may show predominant lymphocytes (can have early PMN predominance), RBCs common (hemorrhagic component), protein often >100 mg/dL, glucose typically normal to mildly low
• Bacterial encephalitis pattern: Marked pleocytosis (often >1000 cells/μL predominantly PMN), low glucose (<40% of serum), high protein (>100 mg/dL), positive Gram stain/culture
• Autoimmune pattern: Variable; anti-NMDA may show lymphocytic pleocytosis, elevated protein; some cases have relatively normal CSF ("seronegative" presentation)
• Tuberculosis: Lymphocytic pleocytosis, low glucose (<25% of serum), very high protein (100–500 mg/dL), AFB smear often negative early
• Viral PCR (HSV-1, HSV-2, VZV, EBV, CMV, enterovirus, HHV-6): 80–95% sensitivity, >95% specificity; can identify pathogen within 24 hours; crucial for guiding targeted therapy

• Serum and CSF antibody studies:
• Acute and convalescent serum titers for arboviruses (4-fold rise diagnostic), Mycoplasma, syphilis (RPR/VDRL), Lyme disease serology (two-tier testing)
• CSF-specific IgM for arboviruses, VZV
• Autoimmune encephalitis: Serum and CSF testing for anti-NMDA receptor antibodies, anti-AMPA receptor, anti-LGI1, anti-GABA-B, anti-CASPR2, paraneoplastic markers (anti-Hu, anti-Yo, anti-CV2)

• Blood cultures: Before antibiotics if bacterial infection suspected; positive in 50–80% of untreated bacterial meningitis

• PCR and other molecular studies:
• Respiratory viral PCR: Influenza, parainfluenza, respiratory syncytial virus (RSV), rhinovirus, adenovirus; identifies community-acquired respiratory infections
• Enterovirus and parechovirus PCR: Particularly in pediatric cases
• Arboviral PCR and IgM: In endemic areas or travel history

• Metabolic/inflammatory markers:
• Procalcitonin, CRP: More elevated in bacterial versus viral encephalitis but overlap exists; not diagnostic alone
• Serum electrolytes, glucose, kidney function, liver function: Baseline and monitoring for complications and drug toxicity
• Blood glucose: Hypoglycorrhachia (CSF glucose <40 mg/dL) particularly concerning; check serum glucose contemporaneously for comparison

Imaging studies

• Magnetic resonance imaging (MRI) brain with contrast—Most sensitive imaging:
• Fluid-attenuated inversion recovery (FLAIR): Most sensitive for early encephalitis; shows increased signal in affected brain parenchyma
• T2-weighted/proton density images: Show signal abnormalities in gray and/or white matter
• Contrast enhancement: Variable; may show meningeal enhancement (dura, pia), parenchymal enhancement, or enhancement of affected structures
• HSV-1 characteristic findings: Temporal lobe abnormalities (80–90% of cases with classic presentation); may be unilateral or bilateral; T2 hyperintensity, contrast enhancement; hemorrhage may be seen on susceptibility-weighted imaging (SWI); insular cortex, orbitofrontal cortex involvement also characteristic
• Autoimmune encephalitis: Often temporal lobe involvement (limbic encephalitis); may appear normal early; T2/FLAIR hyperintensity of mesial temporal lobes, amygdala, hippocampus
• Arboviral infections: Gray matter involvement particularly in basal ganglia, thalamus, brainstem; less dramatic enhancement than HSV
• Japanese encephalitis: Distinctive basal ganglia, thalamic, brainstem involvement
• Tuberculosis: Basilar meningeal enhancement, infarction in territory of perforating vessels, tuberculomas (ring-enhancing lesions)
• Cryptococcal meningitis: Often minimal enhancement despite severe disease; may have cryptococcomas

• Computed tomography (CT) head (without and with contrast):
• Less sensitive than MRI but faster; useful for initial assessment, evaluating for mass effect, hemorrhage, or structural abnormalities
• May be normal early in viral encephalitis
• Identifies edema, herniation risk, hydrocephalus requiring intervention
• Essential before LP to exclude mass effect/increased ICP (papilledema, focal neurologic signs, altered consciousness)

Diagnostic criteria and diagnostic algorithms

• Clinical diagnosis of encephalitis requires:
• Fever OR altered mental status (either may be subtle)
• PLUS evidence of CNS inflammation (CSF pleocytosis >4 WBC/μL, abnormal MRI, EEG findings)
• PLUS absence of other explanations (metabolic encephalopathy, toxic ingestion, seizure disorder, structural lesion)

• International encephalitis consortium case definitions:
• Definite encephalitis: Core features + CSF or brain inflammation + ≥1 confirmatory test (CSF viral PCR positive, arboviral serology, electroencephalography [EEG] consistent with encephalitis, brain MRI findings consistent)
• Probable encephalitis: Core features + CSF or MRI showing inflammation + no alternative diagnosis

• Temporal lobe involvement on imaging or EEG in setting of fever + altered mental status = presume HSV-1 until proven otherwise

Electroencephalography (EEG)

• Periodic sharp wave complexes (PSWCs): Distinctive 2–3 Hz sharp waves typically in temporal regions; highly specific for HSV-1 encephalitis; present in ~80% of confirmed cases (though may develop over first week)
• Generalized slowing: Low-amplitude theta or delta activity reflecting diffuse encephalopathy
• Seizure activity: Spike-and-wave discharges, electrographic seizures (may be subclinical)
• Extreme delta brush pattern: Seen in anti-NMDA receptor encephalitis; bursts of delta activity with superimposed 20–30 Hz activity

Neurologic emergencies

• Cerebral edema with herniation (emergency): cytotoxic plus vasogenic edema in a fixed cranial vault; signaled by declining GCS, new anisocoria, Cushing reflex (hypertension with bradycardia), or extensor posturing. Requires head-of-bed elevation, osmotherapy (hypertonic saline or mannitol), airway protection, and neurosurgical consultation; the IDSA encephalitis guideline advises against routine LP when imaging shows mass effect.
• Status epilepticus (emergency): cortical irritation from necrotizing temporal inflammation; suspect when altered mentation fails to improve — nonconvulsive status is common and requires continuous EEG. Benzodiazepine (lorazepam) followed by a second-line antiseizure drug (levetiracetam, fosphenytoin, or valproate) per Neurocritical Care Society guidance.
• Hemorrhagic necrosis of the temporal lobe: HSV-1 tropism for limbic cortex; RBCs or xanthochromia in CSF and susceptibility-weighted MRI blooming are the tip-off. Rapid expansion can produce uncal herniation.
• Central hypoventilation and autonomic storm (emergency): classic in anti-NMDA receptor encephalitis; labile blood pressure, hyperthermia, bradyarrhythmias, and apnea mandate ICU monitoring.

Systemic and delayed complications

• SIADH with hyponatremia: inflammatory ADH release; a falling sodium worsens cerebral edema and lowers seizure threshold.
• Post-HSV relapse with NMDA receptor antibodies: biphasic course — recovery, then choreoathetosis and psychiatric decline weeks later; re-test for autoantibodies rather than assuming viral relapse.
• Persistent sequelae: anterograde amnesia (hippocampal loss), aphasia with dominant temporal injury, epilepsy, and rarely Klüver–Bucy syndrome (hyperorality, hypersexuality, placidity) after bilateral temporal damage.

Treatment-related

• Acyclovir crystalline nephropathy: drug precipitation in tubules; rising creatinine — prevent with aggressive IV hydration and slow infusion, and dose-adjust for renal function.
• Acyclovir neurotoxicity: accumulated metabolite in renal impairment causing tremor, myoclonus, confusion — the classic mimic of "worsening encephalitis."
• Immunotherapy risks: corticosteroid hyperglycemia and infection, IVIG aseptic meningitis and thrombosis, rituximab-associated hepatitis B reactivation.

• Start IV acyclovir before the workup is complete: in any febrile patient with altered mental status, the single best next step is empiric IV acyclovir (plus empiric bacterial meningitis coverage) — do not wait for LP, MRI, or PCR. The IDSA encephalitis guideline emphasizes that delay to acyclovir is the strongest modifiable predictor of poor outcome.
• Temporal lobe = HSV-1 until proven otherwise: unilateral or asymmetric T2/FLAIR hyperintensity of medial temporal and orbitofrontal cortex, RBCs in CSF, and temporal periodic sharp wave complexes or lateralized periodic discharges on EEG form the classic triad. CSF HSV PCR is the confirmatory test — brain biopsy is now rarely needed.
• A negative HSV PCR in the first ~72 hours does not exclude disease: continue acyclovir and repeat the PCR if clinical suspicion is high; sensitivity rises after the first days of symptoms.
• Young woman + psychiatric prodrome + orofacial dyskinesias + seizures + autonomic instability = anti-NMDA receptor encephalitis. The association examiners test is ovarian teratoma — pelvic ultrasound or MRI is mandatory, and tumor resection plus immunotherapy (steroids, IVIG or plasma exchange, then rituximab) is the treatment. Extreme delta brush on EEG is the buzzword.
• Encephalitis vs meningitis: altered mental status/focal deficits define encephalitis; a fully alert patient with fever, headache, and nuchal rigidity has meningitis. Both may share a lymphocytic CSF.
• West Nile virus: asymmetric flaccid paralysis (anterior horn cell involvement) with encephalitis in an older adult after mosquito exposure; diagnosis is CSF IgM, and treatment is supportive — acyclovir will not help.
• Common distractors: adjunctive dexamethasone is not established therapy for HSV encephalitis (unlike pneumococcal meningitis); ganciclovir/foscarnet are for CMV or acyclovir-resistant HSV, not first-line HSV; and a normal head CT never excludes encephalitis — MRI is far more sensitive.