Herpes simplex encephalitis

Definition

Herpes simplex encephalitis (HSE) is an acute, usually necrotizing inflammation of the brain parenchyma caused by herpes simplex viruses, in adults and older children almost always HSV-1. It preferentially affects the temporal lobes and orbitofrontal regions and is the most common cause of sporadic, potentially fatal viral encephalitis worldwide.

Classification

• HSE in adults and children: predominantly HSV-1, due to primary infection or – more commonly in adults – reactivation of latent virus.
• Neonatal HSV encephalitis: almost always HSV-2, usually acquired during birth, onset between the 1st and 4th week of life.
• HSV-2 encephalitis in immunodeficiency: more common than usual in immunocompromised adults.
• Autoimmune encephalitis after HSE: secondary, antibody-mediated encephalitis (mainly anti-NMDA receptor) weeks after the viral encephalitis.

Occurrence & epidemiology

• Global incidence about 1 in 250,000 to 1 in 500,000 people per year.
• Occurs at any age and in any season; bimodal age distribution: about one third children and adolescents, about half over 50 years.
• HSV-1 is very widespread: in 2016 about 67 % of people aged 0–49 years worldwide were infected; 80–85 % of young adults are seropositive.

Aetiopathogenesis

• Pathogen: herpes simplex virus type 1 (human herpesvirus 1), less often type 2. After primary infection, HSV persists latently in nerve ganglia for life and can reactivate.
• Routes into the brain: probably retrograde trans-synaptic spread via the trigeminal nerve or via the olfactory tract to frontal and mesiotemporal brain regions.
• Pathogenesis: direct viral invasion damages neurons (sometimes with inclusion bodies) and triggers inflammation with edema; in severe courses, hemorrhagic necrosis develops. The innate immune response via Toll-like receptor 3 (TLR3) and interferons is central; genetic defects in this pathway predispose children to HSE.
• Post-HSE autoimmunity: the viral infection can trigger autoantibodies against neuronal surface proteins, most often against the GluN1 subunit of the NMDA receptor.

Clinical features

• Leading symptoms: fever, headache and altered mental status, often with behavioral and personality changes, seizures and focal neurologic deficits (e.g. aphasia, hemiparesis); sometimes a gastrointestinal or respiratory prodrome. Meningeal signs are usually mild.
• Suggestive: olfactory seizures with an aura of unpleasant smells (rotten eggs, burnt meat) as a sign of temporal lobe involvement; multiple early seizures are characteristic.
• Severe courses: status epilepticus, coma, cerebral edema with raised intracranial pressure.
• Sequelae: frequently persistent neurologic impairment, especially of verbal memory, as well as impaired concentration, processing speed and executive function.
• Renewed deterioration: in 5–27 % of patients, mostly within the first 2 months and often without renewed virus detection; frequently due to autoimmune encephalitis (median about 30 days after HSE) with behavioral changes, new seizures, movement disorders and encephalopathy, particularly marked in young children.
• Neonates: among others lethargy, temperature instability, hypotonia, respiratory distress up to apnea, and seizures; skin vesicles are common but may be absent.

Histology

Inflammation and edema with neuronal damage, sometimes intranuclear inclusion bodies and petechial hemorrhages; in severe cases hemorrhagic necrosis, mainly temporal and orbitofrontal. Brain biopsy is rarely needed today and is informative only if taken from an area abnormal on MRI or CT.

Diagnosis

• Cerebrospinal fluid: abnormal in about 90 %, typically lymphocytic pleocytosis, moderately elevated protein (above 0.5 g/L) and normal glucose; in severe cases also neutrophils. Hemorrhagic necrosis introduces red blood cells into the CSF. Changes may still be absent in the first 8–24 hours.
• HSV PCR of CSF: highly sensitive and specific and the central method of pathogen detection; false-negative results are possible early in the course, and testing is repeated after 48–72 hours if suspicion persists. Multiplex PCR panels provide results within a few hours. CSF viral cultures no longer play a role.
• Contrast-enhanced MRI: abnormal in 80–100 %; sensitive early on, with high signal and edema in the mesial temporal, insular, cingulate and orbitofrontal regions; also excludes other causes (e.g. brain abscess, cerebral venous sinus thrombosis).
• CT: much less sensitive than MRI but rapidly available to exclude a mass lesion, hydrocephalus or cerebral edema before lumbar puncture.
• Intrathecal antibodies: HSV-specific IgG in CSF may remain detectable for years, even with a negative PCR.
• Autoimmune encephalitis after HSE: detection of neuronal autoantibodies (mainly against the NMDA receptor) in CSF and serum; new or progressive MRI changes in about 30–40 %.

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Further reading (open access)

1. MSD Manual Professional: Encephalitis
2. MSD Manual Professional: Herpes Simplex Virus (HSV) Infections
3. PMC-Übersichtsarbeit: The immunobiology of herpes simplex virus encephalitis and post-viral autoimmunity (2024)
4. MSD Manual Professional: Neonatal Herpes Simplex Virus (HSV) Infection

Cross-references