Viral encephalitis comprises a wide range of infections of the brain parenchyma, each with characteristic neuropathologic features that often allow the agent to be inferred from the tissue. The patterns range from the limbic predilection of HSV (one of the most distinctive in neurology) to the anterior horn cell destruction of polio, to the diffuse white matter involvement of arboviral infections. Modern PCR and metagenomic sequencing have revolutionized diagnosis, but the neuropathologic patterns remain clinically important for guiding workup and recognizing complications. This page covers the major viral encephalitides.

Herpes Simplex Encephalitis (HSV-1)

Pathology

  • Hemorrhagic necrotizing encephalitis with predilection for medial temporal lobes (uncus, hippocampus, amygdala), insular cortex, anterior cingulate.
  • Cowdry type A intranuclear inclusions: eosinophilic with peripheral chromatin margination, in neurons and glia.
  • Perivascular lymphocytic cuffing.
  • Microglial nodules with neuronophagia.
  • Necrosis: extensive, hemorrhagic in severe cases.
  • HSV IHC: confirms.

Clinical

  • Subacute fever, headache, confusion, behavioral change.
  • Seizures (often focal from temporal lobe).
  • Aphasia (left temporal involvement).
  • Memory impairment (hippocampal).
  • Most common sporadic encephalitis in adults.

Diagnosis

  • CSF PCR for HSV (sensitivity 96-98%, specificity >99%).
  • CSF: lymphocytic pleocytosis, mild protein elevation, often RBCs (hemorrhagic).
  • MRI: T2/FLAIR hyperintensity in medial temporal lobes (often asymmetric), insula, cingulate. Restricted diffusion early.
  • EEG: periodic lateralized epileptiform discharges (PLEDs) over temporal lobes — supportive.

Treatment

IV acyclovir 10 mg/kg q8h × 14-21 days. Empirical treatment in any suspected case — do not wait for PCR. Untreated mortality 70%; treated mortality still 20-30%, with substantial morbidity.

Other Herpesvirus Encephalitides

VZV Encephalitis

  • Acute disseminated form or focal vasculopathy with strokes.
  • Often follows shingles, especially ophthalmic zoster.
  • Treat with IV acyclovir.

CMV Encephalitis

  • Immunocompromised (HIV/AIDS, transplant).
  • Periventricular distribution (often ventriculitis).
  • “Owl’s eye” intranuclear inclusions: large central inclusion with clear halo and rim of marginated chromatin.
  • CMV IHC confirms.
  • Treat with ganciclovir.

EBV

Encephalitis usually mild; associated with PCNSL in immunocompromised.

HHV-6

Limbic encephalitis in immunocompromised, especially post-stem cell transplant. PCR diagnostic.

Arboviral Encephalitides

West Nile Virus

  • Anterior horn cell destruction: classic feature; polio-like flaccid paralysis.
  • Encephalitis with predilection for thalamus, basal ganglia, brainstem.
  • Pathology: microglial nodules, neuronophagia, perivascular lymphocytic inflammation.
  • Diagnosis: CSF IgM, PCR.

Eastern Equine Encephalitis (EEE)

Most severe arboviral encephalitis; basal ganglia and thalamus predilection. High mortality. No specific treatment.

Japanese Encephalitis

  • Most common arboviral encephalitis worldwide.
  • Thalamus, basal ganglia, substantia nigra predilection.
  • Often parkinsonian features in survivors.
  • Effective vaccine.

St. Louis Encephalitis

Older adults more affected; mortality 5-15%.

La Crosse Encephalitis

Pediatric; usually less severe.

Tick-Borne Encephalitis (TBE)

Europe and Asia. Anterior horn cells + brainstem + cerebellum.

Enteroviral Encephalitides

Poliomyelitis (now rare with vaccination)

  • Selective destruction of anterior horn motor neurons.
  • Asymmetric flaccid paralysis without sensory loss.
  • Neuronophagia of anterior horn cells.
  • Post-polio syndrome: late progressive weakness years after initial recovery.

Enterovirus 71 (EV71)

Similar anterior horn cell involvement; hand-foot-mouth disease + brainstem encephalitis. Asia outbreaks.

Coxsackievirus, Echovirus

Aseptic meningitis (more common), occasional encephalitis.

Rabies

Pathology

  • Negri bodies: eosinophilic intracytoplasmic inclusions in neurons of Purkinje cells (cerebellum), pyramidal cells of hippocampus, brainstem neurons.
  • Microglial nodules, neuronophagia.
  • Perivascular lymphocytic inflammation.
  • Brainstem and limbic system predilection.

Clinical

  • Furious (encephalitic) form: hydrophobia, aerophobia, agitation, autonomic instability.
  • Paralytic form: ascending paralysis (less common).
  • Universally fatal once symptomatic.
  • Pre-exposure or post-exposure prophylaxis is the only effective approach.

Slow Viral Infections

Progressive Multifocal Leukoencephalopathy (PML)

JC virus infection of oligodendrocytes — covered in separate page.

Subacute Sclerosing Panencephalitis (SSPE)

  • Persistent measles virus infection of neurons and oligodendrocytes.
  • Children/adolescents, years after measles infection.
  • Pathology: panencephalitis with neuronal inclusions (Cowdry A), demyelination, gliosis.
  • Clinical: progressive cognitive decline, myoclonus, eventually death.
  • EEG: periodic high-amplitude complexes (Radermecker pattern).

HIV (covered separately)

Limbic Encephalitis (Viral)

HSV-1 is the prototype, but other viruses cause limbic encephalitis:

  • HHV-6 (especially post-transplant).
  • VZV.
  • EBV.
  • Influenza.

Differential: autoimmune limbic encephalitis (LGI1, GABA-B, AMPA, CASPR2 antibodies — often paraneoplastic or autoimmune). CSF antibodies + tumor screen distinguish.

Acute Disseminated Encephalomyelitis (ADEM)

Post-infectious or post-vaccinal autoimmune demyelinating disease — covered in demyelinating section. Pathology: perivenous demyelination distinguishes from MS confluent plaques.

Anti-NMDA Receptor Encephalitis

Autoimmune encephalitis — covered as inflammatory disease. Often paraneoplastic (ovarian teratoma in young women). Features: psychiatric symptoms, seizures, movement disorder, autonomic dysregulation. Treatable.

Rasmussen Encephalitis

Chronic unilateral focal encephalitis in children, with progressive hemiatrophy + intractable focal seizures. T-cell mediated. Pathology: chronic lymphocytic infiltration, microglial nodules, neuronal loss, gliosis. Hemispherectomy curative for seizures.

🔍 Did You Know?

The medial temporal lobe predilection of HSV encephalitis is one of the most distinctive patterns in viral neurology. The hippocampus, amygdala, uncus, insula, and anterior cingulate are the preferred targets. The mechanism is partly explained by the route of viral entry: HSV-1 establishes latent infection in the trigeminal ganglion after primary infection, and reactivation travels along trigeminal nerve branches that distribute to the meninges of the anterior and middle cranial fossae — bringing the virus to the medial temporal lobes. The pathologic pattern, even on a single MRI sequence, is often enough to make the diagnosis: bilateral or asymmetric T2/FLAIR hyperintensity in the medial temporal lobes, often extending into the insula and cingulate. The clinical translation matters: empirical IV acyclovir should be started in any patient with subacute encephalitis and temporal lobe involvement on MRI, before HSV PCR results return. The cost of empirical treatment is trivial; the cost of waiting is irreversible cognitive damage. Untreated HSV encephalitis has 70% mortality; treated, mortality is still 20-30% with substantial morbidity. Recognition of the temporal lobe pattern and reflexive empirical treatment have transformed outcomes. The lesson: when subacute encephalitis + temporal lobe MRI changes meet at the bedside, the IV bag of acyclovir should be hanging before the PCR is back.

Pitfalls and Pearls

  • HSV encephalitis: medial temporal + insular + anterior cingulate; empirical IV acyclovir; do not wait for PCR.
  • Cowdry A inclusions: HSV.
  • Owl’s eye inclusions: CMV.
  • Negri bodies: rabies (Purkinje cells, hippocampus, brainstem).
  • Anterior horn cell destruction: polio, West Nile, EV71.
  • Thalamus + basal ganglia predilection: Japanese encephalitis, EEE.
  • VZV vasculopathy: strokes weeks-months after zoster; IV acyclovir + steroids.
  • SSPE: years after measles; myoclonus + cognitive decline + periodic EEG.
  • HHV-6 limbic encephalitis: post-transplant.
  • Limbic encephalitis differential: HSV vs autoimmune (LGI1, GABA-B, etc.).
  • Anti-NMDA receptor encephalitis: young women + ovarian teratoma + psychiatric prodrome + seizures + movement disorder.
  • Rasmussen encephalitis: chronic unilateral, refractory seizures, hemiatrophy; hemispherectomy.
  • CSF metagenomic sequencing: emerging tool when standard testing negative.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. 2006;71(2-3):141-148.
  3. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2008;47(3):303-327.
  4. Solomon T. Flavivirus encephalitis. N Engl J Med. 2004;351(4):370-378.
  5. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-851.
  6. Wilson MR, Sample HA, Zorn KC, et al. Clinical metagenomic sequencing for diagnosis of meningitis and encephalitis. N Engl J Med. 2019;380(24):2327-2340.