HSV Encephalitis

Risk factors

• No major host risk factors in most cases (immunocompetent patients are affected)
• Neonatal HSE: maternal genital HSV (especially primary infection near delivery)
• Rare familial defects in TLR3 / UNC93B / TRIF pathway (impaired innate immunity to HSV in CNS)
• Immunocompromise can produce atypical presentations but is NOT required

Pathophysiology

Primary or reactivated HSV-1 in the trigeminal ganglion is thought to spread from the ganglion along trigeminal nerve fibers to the meninges of the anterior and middle cranial fossae (an olfactory-tract route is an alternative hypothesis), producing necrotizing, hemorrhagic encephalitis of the orbitofrontal and medial temporal lobes. HSV-2 is the principal cause of neonatal HSE (transmitted during delivery) and may cause Mollaret recurrent lymphocytic meningitis in adults.

Clinical presentation

Differential diagnosis

• Bacterial meningitis — Neutrophil-predominant CSF, low glucose, positive Gram stain/culture; more prominent meningismus, less prominent personality/temporal-lobe symptoms
• Other viral encephalitides (arbovirus — West Nile, EEE, La Crosse; enterovirus; influenza-associated) — Seasonal/geographic clues; serology and PCR
• Autoimmune encephalitis (anti-NMDA receptor, LGI1, CASPR2) — Subacute psychiatric symptoms, dyskinesias, autonomic instability; antibody testing; HSE can TRIGGER post-HSV anti-NMDA encephalitis weeks later
• Limbic encephalitis (paraneoplastic, e.g., anti-Hu, anti-Ma2) — Subacute memory loss, seizures; underlying malignancy
• Brain abscess — Ring-enhancing lesion, mass effect, source of infection; surgical drainage
• Status epilepticus / postictal state — Witnessed seizure, EEG; HSE often causes seizures itself
• Neurosyphilis — Tabes dorsalis, general paresis, Argyll Robertson pupils; CSF VDRL
• Drug toxicity / metabolic encephalopathy — Medication review, ammonia, BMP, LFTs

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A["Fever + AMS<br/>± focal Sx, seizure"] --> B["Empiric acyclovir<br/>10 mg/kg IV q8h<br/>+ broad antibiotics"]
  B --> L["MRI brain (preferred) early<br/>T2/FLAIR + DWI temporal lobe<br/>± EEG PLEDs"]
  B --> C["CT head first<br/>if mass effect risk or no MRI"]
  C --> D["Lumbar puncture"]
  L --> D
  D --> E{CSF}
  E --> F["Lymphocytic pleocytosis<br/>+ RBCs<br/>+ elevated protein<br/>± normal glucose"]
  F --> G["CSF HSV PCR"]
  G --> H{PCR result}
  H -->|Positive| I["Continue acyclovir<br/>14-21 days"]
  H -->|Negative + high suspicion| J["Repeat PCR in 3-7 d<br/>continue acyclovir"]
  H -->|Negative + alternative dx| K["Stop acyclovir<br/>treat underlying cause"]
  I --> M["Monitor for relapse<br/>anti-NMDA encephalitis"]

Treatment

Complications

• Persistent cognitive impairment (especially memory — Klüver-Bucy-like syndromes after bilateral temporal damage)
• Aphasia (Wernicke-type)
• Epilepsy (temporal lobe, often medically refractory)
• Personality and behavioral changes
• Post-HSE anti-NMDA receptor autoimmune encephalitis (occurs in up to 20-30% of pediatric and ~10% adult cases, typically 2-12 weeks after recovery)
• Hydrocephalus from inflammation
• Death (~20-30% even with treatment)
• Neonatal HSE — disseminated disease (SEM/CNS/disseminated forms), high mortality and severe disability

PANCE pearls

• Start IV acyclovir EMPIRICALLY for any patient with encephalitis and lymphocytic CSF — do not wait for PCR. Empiric treatment costs little; delayed treatment costs lives.
• RBCs in CSF without trauma + lymphocytic pleocytosis + temporal-lobe symptoms = HSE until proven otherwise.
• Early CSF HSV PCR (<72 hours) can be falsely negative; REPEAT if clinical suspicion remains.
• MRI is more sensitive than CT for early HSE — request T2/FLAIR and DWI.
• Late behavioral relapse after HSE recovery — think anti-NMDA receptor encephalitis (HSV triggers autoimmunity).
• HSE is NOT preventable by valacyclovir prophylaxis in immunocompetent patients; in neonates, cesarean delivery for genital lesions or prodromal symptoms at the onset of labor reduces risk, and suppressive acyclovir or valacyclovir from 36 weeks in women with recurrent genital herpes reduces lesions at term.
• Acyclovir nephrotoxicity (crystal-induced) — maintain hydration; monitor creatinine.
• After HSE, expect significant memory and personality changes — neuropsychiatric rehabilitation is essential.

References

• IDSA 2008 — Management of Encephalitis: Clinical Practice Guidelines (Tunkel et al., Clin Infect Dis 2008)
• Whitley NEJM 1986 — Vidarabine versus Acyclovir Therapy in HSE (Whitley et al., NEJM 1986)
• Armangue Lancet Neurol 2018 — Frequency and Symptoms of Anti-NMDAR Encephalitis After HSV Encephalitis (Armangue et al., Lancet Neurol 2018)