Encephalitis is inflammation of the brain parenchyma causing neurological dysfunction, most commonly due to infectious (primarily viral) or autoimmune etiologies. It is a neurological emergency requiring immediate empiric treatment with IV acyclovir while pursuing etiologic diagnosis. HSV-1 is the most common sporadic infectious cause; anti-NMDAR antibody encephalitis is the most common autoimmune cause. [1-3]
1. History
- Onset and tempo: Acute (days) vs. subacute (weeks) — infectious causes tend to present acutely; autoimmune causes may be more subacute [2]
- Prodrome: Fever, headache, malaise, upper respiratory or GI symptoms preceding neurological decline
- Neuropsychiatric symptoms: Confusion, personality/behavioral changes, hallucinations (olfactory hallucinations and déjà vu suggest HSV temporal lobe involvement), psychosis, short-term memory loss [2]
- Seizures: New-onset seizures, especially refractory — more common in autoimmune encephalitis (85% AE vs. 20% IE) [4]
- Movement disorders: Involuntary movements, orofacial dyskinesias (classic for anti-NMDAR encephalitis) [5]
- Exposure history: Season, geographic location, travel, animal/insect contact, sick contacts, sexual history, recreational water exposure [6]
- Immune status: HIV, immunosuppressive medications, transplant history, malignancy [7]
- Vaccination history: Measles, mumps, varicella, Japanese encephalitis [6]
- Occupation/hobbies: Outdoor activities (tick/mosquito exposure), animal handling
2. Alarm Features
- Rapidly declining GCS or coma — GCS ≤8 is a strong predictor of poor outcome [6]
- Status epilepticus — convulsive or non-convulsive [2]
- Signs of raised intracranial pressure: Papilledema, Cushing triad, pupillary asymmetry
- Autonomic instability: Cardiac arrhythmias, labile blood pressure, temperature dysregulation [6]
- Respiratory failure requiring intubation
- Focal neurological deficits progressing rapidly
- Hyponatremia (SIADH) — particularly associated with HSV encephalitis [8]
3. Medications
- Empiric treatment: IV acyclovir 10 mg/kg q8h (adults) — start immediately, do NOT wait for LP or imaging results [2][9]
- Pediatric (3 mo–12 yr): 20 mg/kg q8h [10]
- Duration: 14–21 days for confirmed HSV encephalitis [6]
- Requires renal dose adjustment — infuse over 1 hour; ensure adequate hydration to prevent crystalline nephropathy [9]
- VZV encephalitis: Acyclovir at higher dose; consider adjunctive corticosteroids if vasculopathy present [2]
- CMV/HHV-6: Ganciclovir or foscarnet [2]
- Autoimmune encephalitis: First-line immunotherapy — IV methylprednisolone, IVIg, or plasma exchange (PLEX); second-line — rituximab, cyclophosphamide [2]
- Adjunctive dexamethasone for HSV encephalitis: The DexEnceph trial (2026) evaluated dexamethasone 10 mg IV q6h × 4 days as adjunct to acyclovir — results should be reviewed for updated guidance [11]
- Contraindicated: Do not delay acyclovir for any reason; avoid nephrotoxic agents concurrently with acyclovir when possible
- Seizure management: Levetiracetam or other ASMs as needed; prophylactic AEDs are not routinely recommended
4. Diet
- NPO if altered consciousness or risk of aspiration
- Assess swallowing function before oral intake
- Adequate IV hydration is critical during acyclovir therapy to prevent renal toxicity
- No specific dietary triggers or long-term dietary management for encephalitis itself
5. Review of Systems
- Neurological: Headache, confusion, memory loss, speech difficulty, seizures, weakness, sensory changes, movement abnormalities
- Psychiatric: Personality change, agitation, psychosis, catatonia (especially anti-NMDAR) [12]
- Constitutional: Fever, malaise, weight loss
- Dermatologic: Rash (vesicular for VZV; maculopapular for measles, enterovirus; erythema migrans for Lyme)
- Respiratory/GI: Preceding URI or GI illness (prodromal phase)
- Genitourinary: Genital lesions (HSV-2)
- Musculoskeletal: Flaccid paralysis (West Nile virus, enterovirus) [13]
6. Collateral History and Family History
- Collateral: Witnesses to behavioral changes, seizure activity, timeline of symptom progression — essential when patient is confused or obtunded
- Psychiatric history: Distinguish new psychiatric symptoms from pre-existing illness (critical for autoimmune encephalitis vs. primary psychiatric disorder) [2]
- Family history: Autoimmune conditions, immunodeficiency syndromes
- Social context: Recent travel (arboviral endemic areas), occupation, recreational exposures, substance use, sexual history
7. Risk Factors
- Age: Bimodal distribution for HSV (children and elderly >50 years); young women for anti-NMDAR encephalitis [14]
- Immunocompromised state: HIV/AIDS, transplant recipients, chemotherapy, chronic immunosuppressive therapy — broadens differential to include CMV, HHV-6, JC virus [6-7]
- Season/geography: Summer–fall for arboviruses (West Nile, Eastern equine, La Crosse); year-round for HSV [6]
- Unvaccinated status: Measles, mumps, varicella, Japanese encephalitis
- Ovarian teratoma: Strong association with anti-NMDAR encephalitis [12]
- Prior HSV encephalitis: Risk of post-infectious autoimmune encephalitis (anti-NMDAR antibodies develop in 5–27% of cases) [15]
8. Differential Diagnosis
- Bacterial meningitis — higher CSF WBC, low glucose, positive Gram stain
- Brain abscess — ring-enhancing lesion on imaging, more indolent course
- Cerebral venous sinus thrombosis — headache, seizures, focal deficits
- CNS vasculitis — multifocal strokes, vessel wall enhancement
- Toxic-metabolic encephalopathy — hepatic, uremic, drug-induced; no CSF pleocytosis
- Status epilepticus (non-convulsive) — EEG diagnostic
- Acute disseminated encephalomyelitis (ADEM) — post-infectious demyelination, multifocal white matter lesions [2]
- Creutzfeldt-Jakob disease — rapidly progressive dementia, myoclonus, characteristic DWI restriction [16]
- CNS lymphoma or leptomeningeal carcinomatosis
- Neurosyphilis — can mimic temporal lobe encephalitis [2]
- Psychiatric disorders — especially in young patients with anti-NMDAR encephalitis presenting with isolated psychiatric symptoms [2]
Key distinguishing features: Autoimmune encephalitis is more likely with seizures, involuntary movements, memory deficits, lower CSF pleocytosis (median 6 cells/µL vs. 125 in infectious), and absence of fever. Infectious encephalitis more commonly presents with fever (72%), headache (61%), and higher CSF WBC. [4]
9. Past Medical History
- Prior episodes of encephalitis or meningitis
- History of HSV infection (oral or genital)
- Autoimmune conditions (SLE, thyroiditis)
- Malignancy — paraneoplastic encephalitis (ovarian teratoma, SCLC, thymoma) [2]
- HIV status and CD4 count
- Transplant history
- Prior immunosuppressive therapy
- Vaccination history
10. Physical Exam
- Vitals: Fever (80% in HSV, only 8% in autoimmune encephalitis); tachycardia; hypertension or hypotension (autonomic instability) [4][8]
- Mental status: GCS assessment, orientation, attention, short-term memory testing — the most critical exam component
- Cranial nerves: Olfactory hallucinations (HSV), facial weakness, dysarthria
- Motor: Focal weakness, hemiparesis, tone abnormalities
- Movement disorders: Orofacial dyskinesias, choreoathetosis, dystonic posturing (anti-NMDAR) [12]
- Meningeal signs: Nuchal rigidity (may be present with meningoencephalitis)
- Skin: Vesicular rash (VZV/HSV), maculopapular rash, petechiae (RMSF), eschar
- Fundoscopy: Papilledema (raised ICP)
- Parotid swelling: Mumps
- Lymphadenopathy: EBV, HIV, lymphoma
11. Lab Studies
CSF analysis (cornerstone of diagnosis): [7][14][17]
- Opening pressure
- Cell count with differential: Typically lymphocytic pleocytosis (10–500 cells/µL); 3–5% of HSV cases can have normal CSF [14]
- Protein: Mildly to moderately elevated
- Glucose: Usually normal (low glucose suggests bacterial, TB, or fungal etiology)
- HSV-1/2 PCR — sensitivity/specificity >95%; if negative but clinical suspicion high, repeat in 3–7 days [7]
- VZV PCR (~60% sensitivity) + VZV IgM [7]
- Enterovirus PCR — sensitivity >95% [7]
- West Nile virus CSF IgM (preferred over PCR, which has <60% sensitivity in immunocompetent hosts) [7]
- Anti-NMDAR antibodies (CSF more sensitive than serum) [1]
- Oligoclonal bands, IgG index
Serum labs
- CBC, CMP (hyponatremia from SIADH), LFTs, coagulation studies
- HIV testing
- Blood cultures
- Serum autoimmune encephalitis antibody panel (NMDAR, LGI1, CASPR2, GABA-B, AMPA)
- Inflammatory markers (CRP, ESR — nonspecific)
The tiered virologic testing approach is summarized in the following table from Tyler (2018):
12. Imaging
- MRI brain with contrast is the gold standard — far superior to CT in sensitivity and specificity [2]
- HSV: Asymmetric T2/FLAIR hyperintensity in temporal lobes, orbitofrontal cortex, insular cortex, and cingulate gyrus; often with diffusion restriction and contrast enhancement; may show hemorrhagic changes [2][6]
- Autoimmune limbic encephalitis: Bilateral, symmetric mesial temporal lobe T2/FLAIR hyperintensity, confined to hippocampus/amygdala, without diffusion restriction or contrast enhancement [2][16]
- Arboviral (West Nile, Japanese encephalitis): Deep grey matter involvement — thalami, basal ganglia, brainstem [13]
- CT head: Useful primarily to rule out mass effect before LP; low sensitivity for early encephalitis
- MRI may be normal early in disease — does not exclude encephalitis [2]
The following figures illustrate characteristic MRI patterns across viral and autoimmune encephalitides:
13. Special Tests
- Lumbar puncture: Essential — should not be delayed unless signs of impending herniation; CT before LP only if focal deficits, papilledema, immunocompromised, or GCS concern [19]
- EEG: Indicated in all patients [2][20]
- HSV: Periodic lateralized epileptiform discharges (PLEDs) and focal temporal slowing — highly suggestive [14][20]
- Anti-NMDAR: Extreme delta brush pattern (pathognomonic when present), generalized slowing [2][21]
- Autoimmune encephalitis shows greater spatial and temporal EEG variability than HSV [22]
- Detects non-convulsive status epilepticus
- Normal EEG is the strongest predictor of survival [20]
- Autoimmune antibody panels: CSF and serum (NMDAR, LGI1, CASPR2, GABA-B, GABA-A, AMPA, DPPX, GAD65)
- Next-generation sequencing (metagenomic NGS): Consider when standard testing is negative [1][17]
- CT body (chest/abdomen/pelvis) or pelvic ultrasound: Screen for ovarian teratoma in suspected anti-NMDAR encephalitis [1]
- Brain biopsy: Reserved for diagnostically difficult cases unresponsive to empiric therapy [19]
14. ECG
- Obtain baseline ECG — encephalitis can cause autonomic instability with cardiac arrhythmias [6]
- Monitor for QTc prolongation if using antipsychotics for agitation
- Myocarditis may coexist with certain viral etiologies (enterovirus, influenza)
- Continuous telemetry monitoring recommended for ICU patients
15. Assessment
Severity stratification: [6][23]
- Poor prognostic indicators: Age >65, GCS ≤8, immunocompromised state, need for mechanical ventilation, restricted diffusion on MRI, delay in acyclovir >24 hours, acute thrombocytopenia
- Mortality: Overall 5–15%; HSV encephalitis 10–15% even with acyclovir; West Nile 10%; Japanese encephalitis 20–30% [2]
- Morbidity: Severe neuropsychiatric sequelae in 43–67% of HSV survivors; <20% return to work [2][11]
- Autoimmune encephalitis: Lower mortality but prolonged recovery; better long-term trajectory, especially with early immunotherapy [2][24]
- An etiologic agent is identified in only ~50% of cases despite comprehensive testing [7][17]
16. Treatment Plan
Initial stabilization: [2][6]
- ABCs — airway protection if GCS declining; intubation for GCS ≤8
- IV access, continuous monitoring, ICU admission for moderate-severe cases
- Treat seizures aggressively (benzodiazepines → levetiracetam or other ASMs)
- Manage raised ICP: Head elevation, osmotic therapy (mannitol/hypertonic saline), consider neurosurgical decompression for refractory cases [19]
Empiric antimicrobials — start immediately
- IV acyclovir 10 mg/kg q8h (adults) — do NOT delay for LP or imaging [1-2][6]
- Continue until HSV PCR negative; if strong clinical suspicion persists despite negative initial PCR, continue acyclovir and repeat LP in 3–7 days [2][7]
- Consider empiric antibiotics (ceftriaxone + vancomycin + dexamethasone) if bacterial meningitis cannot be excluded
Etiology-specific treatment
- HSV: IV acyclovir 14–21 days [6]
- VZV: IV acyclovir (higher dose) ± corticosteroids [2]
- CMV/HHV-6: Ganciclovir ± foscarnet [2]
- Autoimmune: First-line — IV methylprednisolone (1g/day × 3–5 days), IVIg (0.4 g/kg/day × 5 days), or PLEX; second-line — rituximab or cyclophosphamide [2]
- Arboviruses: Supportive care only; no proven antiviral therapy [2]
Supportive care: Antipyretics, DVT prophylaxis, stress ulcer prophylaxis, nutrition, rehabilitation planning [6]
17. Disposition
- All patients with suspected encephalitis require hospital admission [19]
- ICU admission criteria: GCS ≤12, status epilepticus, hemodynamic instability, respiratory failure, signs of raised ICP, rapidly deteriorating neurological exam [6][24]
- Ward admission: Stable patients with mild encephalopathy, no seizures, stable vitals — still require close neurological monitoring
- Neurology consultation: All cases
- Infectious disease consultation: All cases
- Neurosurgery: If signs of herniation or refractory ICP
- Psychiatry: If prominent psychiatric features (especially suspected anti-NMDAR encephalitis)
- Gynecology/oncology: If ovarian teratoma identified
The ENCEPHALITICA cohort study demonstrated that functional independence at 3 months was achieved in only ~50% of ICU-admitted patients, with autoimmune encephalitis patients showing the most favorable long-term recovery trajectories. [24]
18. Follow Up / Return Precautions
Follow-up timing
- Neurology follow-up within 1–2 weeks of discharge
- Repeat MRI at 2–4 weeks and as clinically indicated [1]
- Neuropsychological testing at 3–6 months — cognitive deficits (especially verbal memory) are common even in "recovered" patients [2][11]
- Monitor for post-HSV autoimmune encephalitis (anti-NMDAR antibodies) — occurs in 5–27% of cases, typically within 2 months of completing acyclovir [15]
Return precautions — instruct patients/families to return immediately for:
- New or worsening confusion, personality changes, or memory problems
- New seizures or recurrence of seizures
- Worsening headache, fever, or neck stiffness
- New weakness, speech difficulty, or vision changes
- Decreased level of consciousness
Patient counseling
- Recovery is often prolonged (months to years); multidisciplinary rehabilitation is frequently needed [25]
- Cognitive, behavioral, and psychiatric sequelae are common even after apparent clinical recovery [2]
- Driving restrictions until seizure-free per local guidelines
- Emotional and psychological support for patients and caregivers
References
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2. Acute Encephalitis in Immunocompetent Adults. — Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T. Lancet. 2019.
3. Encephalitis: Diagnosis, Management and Recent Advances in the Field of Encephalitides. — Alam AM, Easton A, Nicholson TR, et al. Postgraduate Medical Journal. 2023.
4. Autoimmune and Infectious Encephalitis: Development of a Discriminative Tool for Early Diagnosis and Initiation of Therapy. — Moser T, Gruber J, Mylonaki E, et al. Journal of Neurology. 2024.
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