Encephalitis

Definition

• Rheumatology (2022, Elsevier), p. 6392

Etiology

Infectious Causes

• Herpes simplex virus (HSV-1 and HSV-2) - most common cause of fatal sporadic encephalitis in the United States (~1-2 cases per 500,000/year)
• Arboviruses (arthropod-borne): Japanese encephalitis virus, West Nile virus (WNV), tick-borne encephalitis virus (TBEV), Eastern equine encephalitis (EEE), Western equine encephalitis (WEE), St. Louis encephalitis
• Enteroviruses (~20% of identifiable viral causes); ~75% of cases in patients under 20 years old
• Enterovirus A71 (EV-A71) - causes severe brainstem encephalitis (rhombencephalitis), mainly in children
• Varicella-zoster virus (VZV) - via reactivation
• Rabies virus
• Cytomegalovirus (CMV), Epstein-Barr virus (EBV)

• Listeria monocytogenes
• Mycobacterium tuberculosis
• Fungi (in immunocompromised)

• Harrison's 22E, p. 1713; Goldman-Cecil, p. (block51)

Non-Infectious / Autoimmune Causes

• Anti-NMDA receptor encephalitis (most common autoimmune encephalitis; associated with ovarian teratoma in young women)
• Anti-LGI1 antibody encephalitis (often presents with faciobrachial dystonic seizures; usually normal CSF and MRI)
• Anti-AMPA receptor, Anti-GABA-B receptor, Anti-VGKC complex antibodies
• Paraneoplastic syndromes (anti-Yo, anti-Ri - associated with breast/ovarian cancer, SCLC)
• Systemic autoimmune diseases: SLE, Sjogren syndrome, sarcoidosis, Behcet's disease
• Steroid-responsive encephalopathy associated with thyroid disease (Hashimoto encephalopathy)
• Acute disseminated encephalomyelitis (ADEM)
• Rheumatology (2022, Elsevier), Table 40.8; Bradley & Daroff, p. 856-857

Pathogenesis

Viral

1. Infection of olfactory neuroepithelium and passage through the cribriform plate via infected macrophages
2. Infection of brain capillary endothelial cells

• Focal neuronal necrosis
• Inflammatory glial nodules
• Perivascular lymphoid cuffing
• "Luxury perfusion" phenomenon - normal or increased blood flow with low oxygen extraction
• Harrison's 22E, p. 1713

HSV Encephalitis Specifics

• HSV-1 (>90% of adult cases) reaches the temporal lobe via ascending neural pathways (trigeminal tracts, olfactory nerves)
• Causes hemorrhagic necrosis of the temporal lobe - initially unilateral, can spread contralaterally
• Defects in toll-like receptor 3 (TLR3) pathway genes increase susceptibility
• Goldman-Cecil Medicine, p. 3226

Clinical Features

Prodrome (all encephalitides)

• Fever, headache, malaise, myalgia
• Upper respiratory symptoms, nausea, vomiting, abdominal pain

Neurological Manifestations

• Altered consciousness: somnolence, lethargy, confusion, coma
• Behavioral/psychiatric changes: irritability, personality change, hallucinations
• Seizures: generalized or focal; in up to 30% of patients
• Meningismus: neck stiffness, photophobia
• Focal deficits: hemiplegia, hemichorea, aphasia, cranial nerve palsies (~30% of patients)
• Tremors, ataxia, loss of abdominal reflexes
• Frontal lobe signs, limb-girdle syndrome

Virus-Specific Features

• Rosen's Emergency Medicine, p. 2270; Harrison's 22E; Goldman-Cecil

Diagnosis

Approach

1. History: travel exposures, insect bites, immunization status, animal contact (rabies), sexual history, immunocompromise
2. Examine: febrile patient with signs of CNS dysfunction; search for skin/mucosal herpetic lesions
3. Exclude: intoxication, metabolic causes (hyperammonemia, liver failure), oncologic/paraneoplastic causes

CSF Analysis (Lumbar Puncture)

• Note: Normal CSF does not exclude autoimmune encephalitis (e.g., anti-LGI1 often has normal CSF)
• CSF PCR for HSV DNA is the gold standard for HSV encephalitis

Neuroimaging

• MRI is more sensitive than CT
• May be normal early; imaging abnormalities appear as disease evolves
• HSV: T2/FLAIR signal abnormality in temporal lobes (unilateral early, bilateral later)
• TBEV: thalamic lesions
• EEE: focal cortical/subcortical abnormalities
• Japanese encephalitis: bilateral thalamic hemorrhagic lesions
• FDG-PET is superior to MRI in depicting CNS involvement in autoimmune encephalitis (abnormal in 78-100% vs 42-63% for MRI), especially anti-NMDA-R encephalitis

Serology / Molecular Testing

• RT-PCR of CSF for arboviruses (Japanese encephalitis virus can be isolated from CSF in severe disease)
• Serum and CSF antibody panels for autoimmune encephalitis (NMDA-R, LGI1, AMPA-R, GABA-B, VGKC)
• Enteroviruses: frequently detectable by nucleic acid amplification of CSF
• Brain biopsy: considered in patients with focal MRI abnormalities, no autoimmune serology, progressive deterioration despite acyclovir + supportive therapy
• Harrison's 22E; Goldman-Cecil; Bradley & Daroff

Management

Empirical Treatment (Before Etiology Confirmed)

• IV Acyclovir (10 mg/kg every 8 hours) should be started empirically for all suspected encephalitis until HSV is excluded by CSF PCR
• Empirical antibiotics should be given until bacterial meningitis is ruled out

HSV Encephalitis Treatment

• IV Acyclovir 10 mg/kg every 8 hours for 14-21 days
• Without treatment: mortality >70%, <10% return to neurologic baseline
• With treatment: mortality reduced to 10-25%, 40-55% can resume daily activities
• Long-term oral valacyclovir after IV acyclovir confers no additional benefit

Arboviral Encephalitis

• No specific antivirals are approved
• Supportive care: management of elevated intracranial pressure, SIADH, respiratory failure, seizures
• IVIg role remains under investigation (for some arboviruses)
• Prevention: vector control, personal protective measures; vaccines available for Japanese encephalitis and TBEV (in specific circumstances)

Autoimmune Encephalitis

• Immunosuppressive therapy: corticosteroids, IVIg, plasmapheresis (first line)
• Rituximab, cyclophosphamide (second line)
• Remove underlying tumor (teratoma in anti-NMDA-R encephalitis)
• A 2025 meta-analysis (PMID: 40472799) highlights the urgent need for high-quality evidence in anti-NMDAR encephalitis treatment, noting ongoing equipoise about optimal immunotherapy regimens

Enteroviral Encephalitis

• Management is primarily supportive; ~50% of patients require intensive care
• Median hospitalization <1 week; mortality <10% (but severe EV-A71 rhombencephalitis carries ~70% mortality)
• Empirical acyclovir until HSV is excluded in patients with focal neurologic findings
• Goldman-Cecil, p. 3239; Harrison's 22E; Rosen's Emergency Medicine

Prognosis

Key Points Summary

1. Always treat empirically with IV acyclovir while awaiting CSF results
2. HSV encephalitis = temporal lobe hemorrhagic necrosis; may present with psychiatric symptoms
3. Autoimmune encephalitis (especially anti-NMDA-R) is common in "unexplained" cases; normal CSF does not exclude it
4. MRI may be normal early; FDG-PET may be more sensitive for autoimmune encephalitis
5. Arboviruses are seasonal and geographically clustered; no specific antivirals exist
6. EV-A71 causes uniquely severe brainstem encephalitis in children (rhombencephalitis)
7. Brain biopsy is reserved for progressive unexplained cases despite empirical therapy

Recent Evidence Note: A 2025 meta-analysis on anti-NMDA receptor encephalitis treatment (PMID: 40472799, J Neuroimmunol) highlights that treatment evidence remains largely anecdotal with urgent need for controlled trials. The current answer on autoimmune encephalitis reflects established practice but this area is rapidly evolving.