1. HSV Encephalitis Jack Kuritzky, PGY-2 UNC Internal Medicine August 31, 2009

2. HSV Encephalitis: General Encephalitis: 20,000 cases/year Encephalitis: 20,000 cases/year HSV accounts for 10-20% HSV accounts for 10-20% HSV-1 causes encephalitis in adults HSV-1 causes encephalitis in adults HSV-1 or HSV-2 in neonates HSV-1 or HSV-2 in neonates HSV-1 and 2 associated w/Mollaret’s meningitis HSV-1 and 2 associated w/Mollaret’s meningitis Benign recurrent lymphocytic meningitis Benign recurrent lymphocytic meningitis Preferentially affects temporal lobe Preferentially affects temporal lobe Can rarely cause recurrent brainstem encephalitis Can rarely cause recurrent brainstem encephalitis HSV-2 tends to cause global encephalitis HSV-2 tends to cause global encephalitis 1/3 cases 50 yrs 1/3 cases 50 yrs

3. HSV Encephalitis: Pathogenesis Infiltrates CNS via 3 routes Infiltrates CNS via 3 routes 1. Trigeminal nerve or olfactory tract 1. Trigeminal nerve or olfactory tract Typically after primary infection Typically after primary infection <18yrs old <18yrs old 2. CNS invasion after recurrent infection 2. CNS invasion after recurrent infection Viral reactivation w/subsequent spread Viral reactivation w/subsequent spread 3. CNS infection w/o primary or recurrent HSV-1 3. CNS infection w/o primary or recurrent HSV-1 Latent HSV in situ within CNS Latent HSV in situ within CNS Invades and replicates in neurons and glia Invades and replicates in neurons and glia Causes necrotizing encephalitis Causes necrotizing encephalitis Widespread hemorrhagic necrosis throughout parenchyma Widespread hemorrhagic necrosis throughout parenchyma

4. HSV Encephalitis: Pathogenesis Necrosis of temporal lobe Necrosis of temporal lobe

5. HSV Encephalitis: Pathogenesis Necrosis of temporal lobe Necrosis of temporal lobe Immune mediated Immune mediated Not more common in immunosuppressed Not more common in immunosuppressed Small studies suggest HSV viral load does not correlate with degree of temporal lobe damage Small studies suggest HSV viral load does not correlate with degree of temporal lobe damage

6. HSV Encephalitis: Presentation Fever Fever Altered mental status Altered mental status Altered level of consciousness Altered level of consciousness Focal cranial nerve deficits Focal cranial nerve deficits Hemiparesis Hemiparesis Dysphasia/aphasia Dysphasia/aphasia Ataxia Ataxia Focal seizures Focal seizures

7. HSV Encephalitis: Presentation Fever Fever Altered mental status Altered mental status Altered level of consciousness Altered level of consciousness Focal cranial nerve deficits Focal cranial nerve deficits Hemiparesis Hemiparesis Dysphasia/aphasia Dysphasia/aphasia Ataxia Ataxia Focal seizures Focal seizures

8. HSV Encephalitis: Presentation More on AMS – consequences of temporal lobe damage More on AMS – consequences of temporal lobe damage Hypomania - elevated mood, excessive animation, decreased need for sleep, inflated self-esteem, and hypersexuality Hypomania - elevated mood, excessive animation, decreased need for sleep, inflated self-esteem, and hypersexuality Kluver-Bucy syndrome (KBS) Kluver-Bucy syndrome (KBS) Initially seen in Rhesus monkeys Initially seen in Rhesus monkeys Loss of normal anger and fear responses Loss of normal anger and fear responses Increased sexual activity Increased sexual activity Amnesia Amnesia

9. HSV Encephalitis: Diagnosis CSF CSF Lymphocytic pleocytosis Lymphocytic pleocytosis Erythrocytosis (84% of patients) Erythrocytosis (84% of patients) Elevated protein Elevated protein Low glucose uncommon Low glucose uncommon CSF PCR now diagnostic test of choice CSF PCR now diagnostic test of choice Quickest, sensitive, and specific Quickest, sensitive, and specific HSV culture out of favor HSV culture out of favor Brain biopsies previously performed Brain biopsies previously performed

10. HSV Encephalitis: Diagnosis Imaging Imaging Temporal lobe injury Temporal lobe injury

11. HSV Encephalitis: Diagnosis Imaging – Temporal lobe injury Imaging – Temporal lobe injury Usually unilateral Usually unilateral May have mass effect May have mass effect MRI much more sensitive/specific MRI much more sensitive/specific EEG – focal findings in >80% cases EEG – focal findings in >80% cases High amplitude slow waves (delta and theta slowing) High amplitude slow waves (delta and theta slowing) Continuous periodic lateralized epileptiform discharges in the affected region Continuous periodic lateralized epileptiform discharges in the affected region

12. HSV Encephalitis: Treatment EARLY TREATMENT IMPERATIVE! EARLY TREATMENT IMPERATIVE! Before loss of consciousness Before loss of consciousness Within 24 hours of the onset of symptoms Within 24 hours of the onset of symptoms Glasgow Coma Scale score of 9 to 15 Glasgow Coma Scale score of 9 to 15 Acyclovir 10 mg/kg IV Q 8h (infuse slowly to prevent crystalluria/renal failure) Acyclovir 10 mg/kg IV Q 8h (infuse slowly to prevent crystalluria/renal failure) Mortality 19-28% vs. 50-58% w/vidarabine Mortality 19-28% vs. 50-58% w/vidarabine 6 month functional status significantly better w/acyclovir 6 month functional status significantly better w/acyclovir Treat 14-21 days Treat 14-21 days Future treatment  steroids? (non-randomized, retrospective study) Future treatment  steroids? (non-randomized, retrospective study)

13. HSV Encephalitis: Prognosis Untreated, mortality 70% Untreated, mortality 70% Survivors with severe neurologic damage Survivors with severe neurologic damage With treatment—mortality ~20%! With treatment—mortality ~20%! Severe disability in 20% Severe disability in 20% Simplified Acute Physiology Score II >/=27 Simplified Acute Physiology Score II >/=27 Delay >2 days b/w admission and acyclovir Delay >2 days b/w admission and acyclovir GCS <6 GCS <6 Age>30 Age>30 62% of survivors have neurologic sequelae 62% of survivors have neurologic sequelae

14. REFERENCES Kimberline, DW. Management of HSV Encephalitis in Adults and Neonates: Diagnosis, Prognosis, and treatment. Herpes. (14)1. 2007. Klein, R. “Clinical manifestations and diagnosis of herpes simplex virus type 1 infection”. UpToDate, version 17.2. Jan 2009. Klein, R. “Herpes Simplex Type 1 Encephalitis”. UpToDate, version 17.2. Feb 2009. Shandera, WX and H Koo. “Infectious Diseases: Viral & Rickettsial”. 2007 Current Medical Diagnosis & Treatment. 46 th ed. The McGraw Hill Companies: USA. 2007.

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