Ramez Morkous MS4 Medical University Of the Americas April 29, 2016 Internal Medicine Conference 04/29/16 Encephalitis Ramez Morkous MS4 Medical University Of the Americas April 29, 2016

A 57-year-old woman is admitted to the hospital with a 2-day history of fever and confusion. Medical history is significant for hypertension treated with metoprolol. On physical examination, temperature is 39.0 °C (102.2 °F); other vital signs are normal. The patient is alert but lethargic and answers questions with one-word responses. She is oriented to person only. Passive flexion of the neck elicits mild nuchal rigidity. Remaining physical examination findings are unremarkable. Lumbar puncture is performed. Opening pressure is 21 mm H2O. The cerebrospinal fluid (CSF) leukocyte count is 147/microliter (147 × 106/L) with 77% lymphocytes. CSF glucose and protein levels are normal. An MRI of the brain is normal. Treatment with empiric acyclovir, 10 mg/kg intravenously every 8 hours, is initiated. By hospital day 3, the patient's fever has resolved and her mental status has normalized. Results of a CSF herpes simplex virus (HSV) polymerase chain reaction (PCR) performed at admission are negative.

Which of the following is the most appropriate management of this patient's acyclovir therapy? A-Change intravenous acyclovir to oral acyclovir to complete a 14-day course B-Continue intravenous acyclovir pending results of repeat HSV PCR C-Continue intravenous acyclovir to complete a 14-day course D-Discontinue intravenous acyclovir In patients with a low clinical suspicion for herpes simplex encephalitis, empiric acyclovir therapy may be discontinued when herpes simplex virus polymerase chain reaction results are negative.

Introduction Meningitis vs. Encephalitis The clinical distinction between meningitis and encephalitis is based upon the state of brain function and presence of meningeal irritation Seizures and postictal states can be seen with meningitis alone and should not be construed as definitive evidence of encephalitis

Introduction Encephalitis is an acute inflammatory process affecting the brain Viral infection is the most common and important cause, with over 100 viruses implicated worldwide Symptoms Fever Headache Behavioral changes Altered level of consciousness Focal neurologic deficits Seizures Incidence of 3.5-7.4 per 100,000 persons per year

Initial Signs Headache Malaise Anorexia Nausea and Vomiting Abdominal pain

Developing Signs Altered LOC – mild lethargy to deep coma. AMS – confused, delirious, disoriented. Mental aberrations: hallucinations agitation personality change behavioral disorders occasionally frank psychosis Focal or general seizures in >50% severe cases. Severe focused neurologic deficits.

Neurologic Signs Virtually every possible focal neurological disturbance has been reported. Most Common Aphasia Ataxia Hemiparesis with hyperactive tendon reflexes Involuntary movements Cranial nerve deficits (ocular palsies, facial weakness)

Differential Diagnosis

HSV Encephalitis HSV-1 causes encephalitis in adults HSV-1 or HSV-2 in neonates HSV-1 and 2 associated w/Mollaret’s meningitis Benign recurrent lymphocytic meningitis Preferentially affects temporal lobe Can rarely cause recurrent brainstem encephalitis HSV-2 tends to cause global encephalitis 1/3 cases <20yrs and 1/2 cases >50 yrs Most common cause of encephalitis at any time of the year HSV-1 causes more than 95% of cases age distribution is biphasic: peaks at 5 to 30 and > 50 years of age

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

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

Presentation Fever Altered level of consciousness Focal cranial nerve deficits Hemiparesis Dysphasia/aphasia Ataxia Focal seizures Altered mental status :consequences of temporal lobe damage Hypomania - elevated mood, excessive animation, decreased need for sleep, inflated self-esteem, and hypersexuality Kluver-Bucy syndrome (KBS) Initially seen in Rhesus monkeys Loss of normal anger and fear responses Increased sexual activity Amnesia

CSF CSF CSF PCR now diagnostic test of choice Lymphocytic pleocytosis Erythrocytosis (84% of patients) Elevated protein Low glucose uncommon CSF PCR now diagnostic test of choice Quickest, sensitive, and specific HSV culture out of favor Brain biopsies previously performed The most helpful finding on standard tests is CSF red blood cells in the absence of a traumatic lumbar puncture CSF PCR for viral DNA is highly accurate: 98% sensitive and 100% specific. May be negative in first 72h

Imaging Imaging – Temporal lobe injury Usually unilateral May have mass effect MRI much more sensitive/specific

EEG EEG – focal findings in >80% cases High amplitude slow waves (delta and theta slowing) Continuous periodic lateralized epileptiform discharges in the affected region

Disease Progression Worsening neurologic symptoms Vascular collapse and shock May be due to adrenal insufficiency. Loss of tissue fluid may be equally important. Homeostatic failure Decreased respiratory drive Untreated, mortality 70% Survivors with severe neurologic damage With treatment—mortality ~20%! Severe disability in 20% Simplified Acute Physiology Score II >/=27 Delay >2 days b/w admission and acyclovir GCS <6 Age>30 62% of survivors have neurologic sequelae

Treatment

Supportive Therapy Fever, dehydration, electrolyte imbalances, and convulsions require treatment. For cerebral edema severe enough to produce herniation, controlled hyperventilation, mannitol, and dexamethasone. Patients with cerebral edema must not be overhydrated. If these measures are used, monitoring ICP should be considered. If there is evidence of ventricular enlargement, intracranial pressure may be monitored in conjunction with CSF drainage. Outcome is usually poor. For infants with subdural effusion, repeated daily subdural taps through the sutures usually helps. No more than 20 mL/day of CSF should be removed from one side to prevent sudden shifts in intracranial contents. If the effusion persists after 3 to 4 weeks of taps, surgical exploration for possible excision of a subdural membrane is indicated.