Residency · Residency · Neurology
Viral Encephalitis: HSV and Beyond
Introduction
Viral encephalitis is an inflammation of the brain parenchyma caused by viral infection, presenting with fever, altered mental status, and focal neurological deficits. Herpes simplex virus (HSV) encephalitis is the most common cause of sporadic fatal encephalitis and is treatable, making early recognition and empiric acyclovir administration a neurological imperative. A broad differential of viral etiologies must be considered based on clinical context, geography, and immune status.
Herpes Simplex Encephalitis (HSE)
Epidemiology and Pathogenesis
HSE is the most common cause of sporadic viral encephalitis, with an incidence of 2-4 per million per year. HSV-1 accounts for more than 90% of cases in adults, while HSV-2 predominantly causes neonatal encephalitis and meningitis. The pathogenesis involves reactivation of latent virus in the trigeminal ganglion with retrograde spread along the trigeminal nerve to the temporal lobes, or primary infection with hematogenous spread. There is a characteristic predilection for the medial temporal lobes, orbitofrontal cortex, and insular cortex due to viral tropism.
Clinical Presentation
HSE presents with acute onset of fever, headache, and altered mental status evolving over days. Temporal lobe signs are prominent and include personality changes, behavioral disturbances, olfactory and gustatory hallucinations, aphasia when the dominant hemisphere is involved, and memory impairment. Seizures occur in 40-60% of patients and are often focal with temporal lobe semiology. Focal neurological deficits such as hemiparesis, visual field deficits, and cranial nerve palsies may develop. Without treatment, mortality exceeds 70%, and even with treatment mortality remains 15-20% with significant morbidity common among survivors.
Diagnosis
CSF analysis typically shows lymphocytic pleocytosis (10-500 cells/mcL), elevated protein, normal or mildly decreased glucose, and red blood cells may be present reflecting the hemorrhagic necrotizing nature of the encephalitis. CSF HSV PCR is the gold standard for diagnosis with a sensitivity of 96-98% and specificity greater than 99%, though it may be negative in the first 24-72 hours; if clinical suspicion is high, LP should be repeated in 3-7 days. MRI brain shows T2/FLAIR hyperintensity and restricted diffusion in the medial temporal lobes, insular cortex, and orbitofrontal regions, often asymmetric, with hemorrhagic transformation common. EEG may show periodic lateralized epileptiform discharges (PLEDs) or temporal periodic discharges with diffuse slowing.
Treatment
Acyclovir 10 mg/kg IV every 8 hours for 14-21 days must be initiated empirically at the first suspicion of HSE. Adequate hydration prevents acyclovir crystalluria and nephrotoxicity, and renal function should be monitored with dose adjustment for renal impairment. Seizures are managed with antiseizure medications. CSF HSV PCR should be repeated at the end of treatment to confirm viral clearance, with therapy extended if the result remains positive. The role of corticosteroids is debated, with some evidence suggesting benefit in reducing edema but no definitive trial data.
Other Important Viral Encephalitides
| Virus | Key Features | Diagnosis | Treatment |
|---|---|---|---|
| HSV-1 | Medial temporal lobe predilection; seizures; hemorrhagic necrosis | CSF HSV PCR (may be negative <72 hrs) | Acyclovir 10 mg/kg IV q8h x 14-21 days |
| VZV | Cerebellitis, vasculopathy/stroke, myelitis; ± rash | CSF VZV PCR or IgG antibody index | Acyclovir 10-15 mg/kg IV q8h ± steroids |
| West Nile virus | Acute flaccid paralysis (anterior horn cells); encephalitis | CSF WNV IgM | Supportive only |
| Japanese encephalitis | Thalamic involvement on MRI; endemic in Asia | Serology | Supportive; vaccination available |
| EEE | High mortality (30-70%); ring-enhancing basal ganglia lesions | Serology | Supportive only |
| Enterovirus D68 | Acute flaccid myelitis; children | CSF enterovirus PCR | Supportive |
| CMV (immunocompromised) | Ventriculoencephalitis; periventricular enhancement | CSF CMV PCR | Ganciclovir + foscarnet |
| HHV-6 (post-transplant) | Limbic encephalitis; medial temporal lobe | CSF HHV-6 PCR | Ganciclovir or foscarnet |
Varicella-Zoster Virus (VZV)
VZV is the second most common cause of viral encephalitis in immunocompetent adults and can occur with or without concurrent zoster rash (zoster sine herpete). Manifestations include cerebellitis (especially in children), vasculopathy causing stroke, myelitis, and cranial nerve palsies. CSF shows lymphocytic pleocytosis, and diagnosis relies on VZV PCR or VZV IgG antibody index in CSF. Treatment is acyclovir 10-15 mg/kg IV every 8 hours, with corticosteroids often added for vasculopathy.
Arboviruses
West Nile virus is the most common arboviral encephalitis in North America, presenting with asymmetric acute flaccid paralysis from anterior horn cell involvement, encephalitis, or meningitis. Diagnosis is made by CSF WNV IgM, and there is no specific treatment. Japanese encephalitis is the leading cause of viral encephalitis worldwide, with characteristic thalamic involvement on MRI, and vaccination is available. Eastern equine encephalitis (EEE) carries high mortality of 30-70% with no specific therapy. La Crosse virus primarily affects children and generally has a good prognosis.
Enteroviral Encephalitis
Enteroviruses including coxsackievirus, echovirus, enterovirus A71, and D68 cause meningoencephalitis especially in children and neonates. Enterovirus D68 is associated with acute flaccid myelitis. CSF enterovirus PCR provides diagnosis, and management is supportive with no proven antiviral therapy.
Autoimmune Encephalitis (Important Mimic)
Autoimmune encephalitis must always be considered in the differential of suspected viral encephalitis when CSF PCR is negative. Anti-NMDA receptor encephalitis can present with psychiatric symptoms, seizures, movement disorders, and autonomic instability. CSF may show lymphocytic pleocytosis, and anti-neuronal antibody testing is essential. MRI may be normal or show subtle T2/FLAIR changes.
Diagnostic Approach
The diagnostic evaluation includes CSF analysis with cell count, protein, glucose, Gram stain, and bacterial culture. A broad CSF PCR panel should test for HSV-1/2, VZV, enterovirus, CMV, EBV, HHV-6, and West Nile virus. CSF cytology and flow cytometry are indicated if lymphoma or carcinomatous meningitis is considered. Arboviral serology (IgM) in CSF and serum should be obtained during appropriate season and geography. Anti-neuronal antibody panels in serum and CSF evaluate for autoimmune encephalitis. MRI brain with contrast and DWI sequences and EEG for seizure detection and encephalopathy assessment complete the workup.
Immunocompromised Hosts
CMV encephalitis presents subacutely as ventriculoencephalitis with periventricular enhancement on MRI and is treated with ganciclovir plus foscarnet. HHV-6 encephalitis causes limbic encephalitis especially post-transplant, with medial temporal lobe involvement on MRI, and is treated with ganciclovir or foscarnet. JC virus causes progressive multifocal leukoencephalopathy (PML) with white matter lesions without mass effect; there is no proven antiviral therapy, and immune reconstitution is key. EBV-associated CNS lymphoma must be distinguished from encephalitis.
Clinical Pearls
Acyclovir should be started empirically in any patient with fever, altered mental status, and CSF pleocytosis without waiting for PCR results, as delay in treatment worsens outcomes dramatically. CSF HSV PCR can be negative in the first 72 hours, so if clinical suspicion remains high, the LP should be repeated. Asymmetric medial temporal lobe involvement on MRI is highly suggestive of HSV encephalitis but can also be seen in autoimmune encephalitis, especially anti-LGI1. Anti-neuronal antibodies should always be sent when viral PCR is negative, as autoimmune encephalitis is a treatable mimic. West Nile virus encephalitis with acute flaccid paralysis mimics poliomyelitis and carries a poor motor prognosis.
References
- Tyler KL. Acute viral encephalitis. N Engl J Med. 2018;379(6):557-566.
- Gnann JW Jr, Whitley RJ. Herpes simplex encephalitis: an update. Curr Infect Dis Rep. 2017;19(3):13.
- Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the International Encephalitis Consortium. Clin Infect Dis. 2013;57(8):1114-1128.
- Granerod J, Ambrose HE, Davies NWS, et al. Causes of encephalitis and differences in their clinical presentations in England. Lancet Infect Dis. 2010;10(12):835-844.