CNS nontumor


Acute viral infections

Herpes simplex encephalitis

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Last staff update: 4 December 2020

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PubMed Search: Herpes simplex encephalitis [title] CNS

Mark Cohen, M.D.
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Cite this page: Cohen M. Herpes simplex encephalitis. website. Accessed March 26th, 2023.
Definition / general
  • Herpes simplex (HSV) encephalitis is a severe necrotizing viral infection preferentially involving the medial temporal and frontal lobes of the brain
  • Most commonly identified etiology of nonepidemic viral encephalitis, ~10% of all encephalitis
  • Annual incidence ~3 cases per million population
  • No sex predominance or seasonal variation
  • All ages are affected but most common and most severe in children (~1/3 of cases) and elderly adults
  • ~50% > age 50 years (Arch Dis Child 2012;97:162)
  • Asymmetric limbic system (medial temporal and frontal lobes) localization is seen in nearly all cases and is virtually diagnostic once noninfectious etiologies are excluded
  • Appears to arise independently of herpetic infections elsewhere in body (including herpes labialis)
    • In patients with oral herpes infection, the viral strain responsible for the encephalitis differs from that responsible for cold sores
  • Experimental and anatomical evidence supports brain invasion via the olfactory system
  • Herpes simplex virus 1 (HSV1) causes > 90% of cases
  • Herpes simplex virus 2 (HSV2) is primarily responsible for disseminated neonatal encephalitis although rare cases have been described in elderly, immunocompromised patients
Clinical features
  • Typically, follows a prodromal flu-like illness (including fever and headache) and manifests as superimposed behavioral changes, seizures, focal neurological signs and cognitive impairment
  • Increased risk of herpes encephalitis in patients treated with monoclonal antibodies to tumor necrosis factor (Clin Infect Dis 2009;49:924)
  • In children, herpes simplex encephalitis may result from inborn errors of toll-like receptor 3 (TLR3) immunity (Curr Opin Virol 2011;1:487, J Exp Med 2012;209:1567)
  • Immediate administration of intravenous acyclovir is recommended if the diagnosis is suspected, as high morbidity and mortality of untreated herpes encephalitis far outweighs drug's toxicity (J Clin Microbiol 2011;49:3576)
  • CSF analysis typically demonstrates lymphocytosis (10 - 500x106/L, average 100x106/L) with or without red cells or xanthochromia, mildly elevated protein and normal or mildly decreased glucose
  • Definite diagnosis is by PCR based detection of viral nucleic acid, which may be undetectable early in disease but almost always can be found within a week of presentation, even after starting antiviral therapy (Am J Clin Pathol 2009;132:687)
Radiology description
  • Magnetic resonance imaging is abnormal in 90% of patients at presentation, typically demonstrating asymmetric high signal within the medial temporal lobes, insular cortex and orbitofrontal and cingulate cortex (Br J Radiol 2012;85:e782)
Radiology images

Contributed by Mark Cohen, M.D.

Diffusion weighted MRI


Images hosted on other servers

FLAIR hyperintensities

Bilateral FLAIR

Abnormal enhancement

Hemorrhages in both temporal lobes

Bilateral symmetric cortical swelling

High signal intensity lesions

  • Although neuronal nuclear staining of affected cortex with antibodies to HSV may be seen during the second week or so of infection, brain biopsies are only performed in cases where the diagnosis of herpes encephalitis is considered unlikely
Prognostic factors
  • Untreated, mortality is ~70% and nearly all survivors have severe neurological deficits
  • Treatment with acyclovir reduces mortality to < 20% and markedly improves the likelihood of preserving neurological function
  • Immunocompromised patients often present with atypical manifestations and poor outcomes (Neurology 2012;79:2125)
Case reports
  • IV acyclovir
  • Utility of concomitant corticosteroid administration is currently under investigation
Gross images

Contributed by Mark Cohen, M.D.


Dusky discoloration

Microscopic (histologic) description
  • Viral inclusions are rarely seen
  • Immunostaining characteristics are similar to HSV of liver or other sites
Microscopic (histologic) images

Contributed by Mark Cohen, M.D.


Cerebral edema

Scant meningeal lymphocytic infiltration


HSV encephalitis
Differential diagnosis
  • Autoimmune or paraneoplastic limbic encephalitis:
    • Onset and evolution tends to be more subacute than acute, which correlates with the nonnecrotizing histopathology consisting of perivascular lymphocytic infiltrates and microglia nodules
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