Key Facts

Encephalitis is inflammation of the brain parenchyma causing neurological dysfunction. HSV encephalitis is the most treatable cause and must be suspected and treated empirically. Autoimmune encephalitis is an increasingly recognised entity requiring immunotherapy.

Epidemiology

Incidence ~5-8 per 100,000/year (all causes). HSV encephalitis: ~1 per 250,000/year but accounts for ~20% of identified viral encephalitis. Anti-NMDAR encephalitis: increasingly recognised; ~1.5 per million/year.

Aetiology

Viral (most common):

• HSV-1: commonest sporadic (adults); temporal lobe predilection
• HSV-2: neonatal encephalitis; recurrent lymphocytic meningitis (Mollaret)
• VZV: immunocompromised, cerebellitis, vasculopathy
• Enterovirus, influenza, measles, mumps, EBV, CMV, HHV-6

Autoimmune:

• Anti-NMDA receptor: young women; psychiatric → seizures → movement disorder → autonomic instability → coma; ovarian teratoma in ~50%
• Anti-LGI1: limbic encephalitis; faciobrachial dystonic seizures; hyponatraemia; older men
• Anti-CASPR2, anti-AMPAR, anti-GABA-B

Other: TB, fungal, parasitic (rare in UK)

Pathophysiology

HSV-1: reactivation from latency in trigeminal ganglion → retrograde spread to temporal lobe → necrotising haemorrhagic encephalitis. The temporal lobe predilection is due to the virus travelling along the olfactory or trigeminal nerves. Autoimmune: antibodies target surface neuronal antigens → synaptic dysfunction; anti-NMDAR antibodies cause receptor internalisation → NMDA receptor hypofunction.

HSV Encephalitis

• Fever + altered consciousness (confusion, disorientation, reduced GCS)
• Personality/behavioural changes (temporal lobe → disinhibition, aggression)
• Seizures (focal or generalised — ~60%)
• Dysphasia (dominant temporal lobe)
• Temporal lobe signs: olfactory hallucinations, memory disturbance
• Focal weakness, cranial nerve palsies

Anti-NMDA Receptor Encephalitis

• Prodrome: headache, fever (viral-like)
• Psychiatric phase: psychosis, hallucinations, agitation, paranoia, catatonia
• Seizures: often refractory
• Movement disorder: orofacial dyskinesias, choreoathetosis
• Autonomic instability: tachycardia, hypo/hypertension, central hypoventilation
• Decreased consciousness: may require prolonged ITU

Red Flags

• New-onset seizures with fever and confusion → encephalitis until proven otherwise
• Personality/behavioural change with fever → temporal lobe encephalitis (HSV)
• Young woman with psychiatric symptoms → consider anti-NMDAR encephalitis
• Rapid deterioration → ITU referral

CSF (Lumbar Puncture)

• Viral pattern: lymphocytic pleocytosis (10-500 cells/μL), mildly raised protein (0.4-1 g/L), normal glucose
• HSV PCR: gold standard (sensitivity >95% after 48-72 hours; may be negative in first 24-48 hours — repeat LP if initially negative and suspicion persists)
• VZV, enterovirus PCR: if HSV negative
• CSF antibodies: anti-NMDAR, anti-LGI1, anti-CASPR2 (send if autoimmune suspected)
• CSF may be normal early in HSV encephalitis — does NOT exclude diagnosis

Imaging

• MRI brain: investigation of choice
  • HSV: temporal lobe oedema/haemorrhage (T2/FLAIR hyperintensity), often asymmetric, DWI restriction
  • Anti-NMDAR: may be normal (~50%) or show medial temporal/cortical signal change
• CT head: less sensitive than MRI; may show temporal lobe low density/haemorrhage

EEG

• Periodic lateralised epileptiform discharges (PLEDs): characteristic but not specific for HSV encephalitis
• Background slowing; seizure activity

Bloods

• FBC, CRP, U&Es, LFTs, glucose, coagulation
• Blood cultures: exclude bacterial infection
• Autoimmune encephalitis panel: serum anti-NMDAR, anti-LGI1, anti-CASPR2
• Tumour markers / pelvic USS/CT: ovarian teratoma screening in anti-NMDAR encephalitis

Other

• HIV test: if risk factors or atypical presentation

Empirical Treatment (Do NOT Delay)

• IV aciclovir 10mg/kg TDS: start IMMEDIATELY in all suspected encephalitis; continue until HSV PCR result available
• HSV confirmed: complete 14-21 days IV aciclovir
• HSV excluded: consider stopping aciclovir; investigate for other causes

Autoimmune Encephalitis

• First-line immunotherapy: IV methylprednisolone 1g × 5 days + IVIg 0.4g/kg × 5 days + plasma exchange
• Second-line: rituximab, cyclophosphamide
• Ovarian teratoma: surgical removal in anti-NMDAR encephalitis (essential for recovery)
• Anti-LGI1: steroids + immunosuppression; often good response

Supportive

• ITU if GCS deteriorating, seizures, autonomic instability
• Seizure management: IV levetiracetam, phenytoin; AVOID carbamazepine in hyponatraemia (anti-LGI1)
• ICP management if raised
• Nutritional support
• Rehabilitation: neuropsychology, physiotherapy, occupational therapy

Referral Criteria

• All suspected encephalitis: emergency admission, neurology
• ITU: declining GCS, refractory seizures, autonomic instability
• Neurology: all cases for investigation and management
• Gynaecology: ovarian teratoma removal in anti-NMDAR encephalitis

HSV encephalitis: mortality ~70% untreated; ~10-20% with IV aciclovir; ~50% of survivors have significant cognitive/neurological sequelae (memory impairment, personality change, seizures). Delay in treatment is the strongest predictor of poor outcome. Anti-NMDAR encephalitis: ~80% make good recovery with immunotherapy ± tumour removal; recovery may take months; relapses occur in ~12-25%. Anti-LGI1: generally good response to immunosuppression.

Meningitis vs Encephalitis

Autoimmune Encephalitis Antibodies