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John Lynch MD MPH Harborview Medical Center & University of Washington Encephalitis and Meningitis

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http://bit.ly/1wb7KOz

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Case 25 year old woman with a headache and change in mental status. LP finds WBC 88 per microliter.

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Central Nervous System Infections Signs and symptoms Fever Headache Altered mental status Focal neurological findings Nonspecific Infectious and noninfectious etiologies

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CNS Infections Risk factors Geographic location, travel Time of year Environments (dormitories, barracks) Concomitant illness (HIV, diabetes, alcoholism) Medications (immunosuppressants, chemo, prophylactic medications)

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CNS Infections Physical examination Identify contraindications to LP mass lesion with midline shift infected lumbar area disordered coagulation (PLT 1.5) Identify concomitant sites of pathology Define the site and the syndrome

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CNS Infection Syndromes Acute meningitis Subacute or chronic meningitis Acute encephalitis Chronic encephalitis Space occupying lesion Toxin mediated Encephalopathy with systemic infection Postinfectious

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Case 25 year old woman with a headache and change in mental status. LP finds WBC 88 per microliter, HSV PCR negative. D/c to home, improved on topiramate after 5 days.

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Encephalitis Inflammation of the brain Pathological diagnosis +/- neurons infected Cardinal features Altered mental status Can mimic psychiatric disease Other features Headache, fever, nausea, vomiting Seizures, focal neurological deficits

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Neuroimaging in Encephalitis Normal Focal inflammation Diffuse inflammation

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Encephalitis Etiology Infectious More than 100 infectious etiologies identified Most commonly viruses Para- or post-infectious Etiology not established in ~50% of cases Diagnostics not adequate Emergence of new etiologies

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Encephalitis etiology? Season: late summer, early fall enteroviruses parechoviruses tick and mosquito-borne agents Geographic exposure Relapsing fever vs Borreliosis JEV in Asia/SE Asia Consult public health

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Encephalitis etiology? Underlying medical problems HIV: toxoplasmosis (CD4

Anti-NMDAR Encephalitis 80% of patients are female Associated with ovarian teratoma Females >11 yrs More common in people of African and Asian ancestry Prominent psychiatric symptoms early (can resemble phencyclidine or ketamine intox) Patients often require ICU care and prolonged hospitalization

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Clinical Findings in NMDARE-1 Prodrome Headache Fever Nausea and vomiting Diarrhea URI symptoms

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Clinical Findings in NMDARE-1 Early Seizures Psychiatric symptoms Short-term memory loss Language abnormalities

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Clinical Findings in NMDARE-1 Late Involuntary movements Catatonia Coma Autonomic and breathing instability

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Diagnosis NMDARE Serum: antibodies to N-terminal domain of NR1 subunit of NMDAR CSF Mild to moderate mononuclear pleocytosis OCBs in 60% Antibodies to NMDAR, more sensitive than serum antibodies

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Diagnosis NMDARE MRI: non-specific abnormalities EEG: slowing, electrographic seizures Pelvic and transvaginal ultrasound: teratoma

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NMDARE Treatment Immunotherapy Corticosteroids Rituximab +/- cyclophosphamide Identification and removal of tumor (empiric oophorectomy)

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NMDARE Prognosis Recover or mild sequelae ~75%, can take >18 months Severely disabled ~20% Die ~4% Relapse ~20-25% No tumor identified Not treated with immunosuppression Rapid taper of immunosuppression

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Case 2 70 yo man with CAD, AF on warfarin. Comes into the ED ill x 3-4 days (fever, MS changes, nausea, vomiting, diarrhea). Neurological examination: confused and left facial weakness

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Case 2 70 yo man with CAD, AF on warfarin. Comes into the ED ill x 3-4 days (fever, MS changes, nausea, vomiting, diarrhea). Neurological examination: confused and left facial weakness WBC 17,000, head CT normal CSF: 28 WBCs (40% polys), glucose 57, protein 56

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Question What is the most likely diagnosis? A.Herpes encephalitis B.HHV6 encephalitis C.Leucine rich glioma inactivate 1 encephalitis D.Rhomboencephalitis due to L monocytogenes E.NMDA receptor encephalitis

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HSV Encephalitis Most common cause of sporadic encephalitis in US Occurs any time of year Bimodal age distribution 25-30% 40 yo Most due to HSV-1 Primary ~30% Reactivation ~60% HSV-2 in immunosuppressed (Mollarets?) Steroids, TNF-alpha blockers are risk factors

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Clinical Findings in HSVE Fever Headache Change in level of consciousness Dysphasia Personality changes Seizures Mild or atypical cases in PCR era

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HSVE Treatment Acyclovir 10mg/kg IV q8hrs 14-21 days course Continue till CSF HSV PCR negative Prolonged PO treatment after IV? Study in adults pending Study in neonates found better neurodevelopmental outcomes after 6 months of treatment

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HSVE Prognosis Mortality Untreated 70% Treated 28% Neurological, neuropsychiatric sequelae in more than 50%

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Diagnostic Algorithm Metabolic Evaluation and Directed Physical Exam CT FIRST? YES CT Empiric Acyclovir LP MR Not OKOK Continue treatment NO

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Meningitis Inflammation of the leptomeninges (the pia, arachnoid, and dura mater). Meningitis reflects inflammation of the arachnoid mater and the cerebrospinal fluid (CSF) in both the subarachnoid space and in the cerebral ventricles.

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Types of Meningitis Bacterial (N meningitidis, S pneumoniae) Viral (enteroviruses, arbovirus, HSV) Fungal (cryptococcus, histoplasma) Parasitic (A cantonensis) Non-infectious (SLE, vancer, drugs, injury)

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Case 3 12 yo male living in Alabama with headache, neck stiffness, nausea, vomiting x 1. Only medical history is sinusitis treated with home remedies. Started on broad empiric antibiotics and acyclovir. The next day he started to hallucinate and soon became unresponsive and died a day later.

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Question What is the most likely etiology? A. S pneumoniae B.Naegleria fowleri C.N meningococcus D.L monocytogenes E.B henselae F.MRSA

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Primary Amebic Meningoencephalitis (PAM) Very rare form of parasitic meningitis (31 US cases/10 yrs) The ameba is found worldwide in warm freshwater, hot springs, water heaters and warm industrial waters The ameba enters the body through the nose (cannot infect by drinking water) Uniformly fatal in 1-12 days

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Fungal Meningitis Cryptococcus- inhalation of soil contaminated with bird droppings Histoplasma- environments with heavy contamination of bird/bat droppings, Ohio and Mississippi Rivers Blastomyces- soil with rich decaying matter, northern Midwest Coccidioides- SW US, Central and S America (and E Washington), African Americans, Filipinos, pregnant women, immunocompromised at higher risk Candida- usually hospital acquired

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Viral Meningitis Summer and fall months = enteroviruses Fecal contamination and respiratory secretions Person to person spread Others: mumps, EBV, HSV, VZV, measles, influenza, arboviruses, LCMV Risk groups: Infants