John Lynch MD MPH Harborview Medical Center & University of Washington

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

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

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

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

6. CNS Infections • Physical examination • Identify contraindications to LP • mass lesion with midline shift • infected lumbar area • disordered coagulation (PLT <50K, INR >1.5) • Identify concomitant sites of pathology • Define the site and the syndrome

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

8. 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.

9. 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

10. Neuroimaging in Encephalitis • Normal • Focal inflammation • Diffuse inflammation

11. 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

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

13. Encephalitis etiology? Underlying medical problems • HIV: toxoplasmosis (CD4 <200) • Transplant: LCMV, WNV, rabies • Immunosuppression: VZV, HHV6, WNV, toxoplasmosis

14. More clues • Rash: VZV, JJV6, WNV, borrelia, erlichia, anaplasma • Retinitis: WNV, B henselae, syphilis • Parkinsonism: WNV, SLEV, JEV • Flaccid paralysis: WNV, JEV, tick-borne encephalitis virus

15. Case Ongoing abnormal mental status leading to admission to psychiatric floor. Two weeks later develops seizures and is transferred to the neurology service at the local university hospital. Unresponsive, eyes closed, hyperventilating, resists passive eye opening, no response to visual threat.

16. Case EEG with EDs Head CT normal CSF WBC 58 per microliter (all WBCs) Glucose 53 mg/dl Protein 48 mg/dl

17. Selected Causes of Encephalitis-Viral

18. Selected Causes of Encephalitis-Bacterial

19. Selected Causes of Encephalitis- Non-infectious

20. Case Subsequently developed high fever, hypertension, tachycardia CSF and serum with NMDAR antibodies Ovarian US showed “dermoid” (teratoma)

21. Question What is the most likely diagnosis? • Herpes encephalitis • HHV6 encephalitis • Leucine rich glioma inactivated 1 encephalitis • Rhomboencephalitis 2nd to L monocytogenes • NMDA receptor encephalitis

22. Anti-NMDAR Encephalitis Population-based study of encephalitis in England = 4% of all cases California Encephalitis Project = most common cause of encephalitis in those under 30 years of age

23. 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

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

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

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

27. 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

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

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

30. 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

31. 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

32. 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

33. Question What is the most likely diagnosis? • Herpes encephalitis • HHV6 encephalitis • Leucine rich glioma inactivate 1 encephalitis • Rhomboencephalitis due to L monocytogenes • NMDA receptor encephalitis

34. HSV Encephalitis Most common cause of sporadic encephalitis in US Occurs any time of year Bimodal age distribution • 25-30% <20yo • 50-70% >40 yo Most due to HSV-1 • Primary ~30% • Reactivation ~60% HSV-2 in immunosuppressed (Mollaret’s?) Steroids, TNF-alpha blockers are risk factors

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

36. 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

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

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

40. 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.

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

42. 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.

43. Question What is the most likely etiology? • S pneumoniae • Naegleriafowleri • N meningococcus • L monocytogenes • B henselae • MRSA

44. 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

45. 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

46. 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 <1 month old and immunocompromised

47. HSV-2 Meningitis More commonly associated with aseptic meningitis Can be recurrent (Mollaret’s syndrome) • Prophylactic valacyclovir RCT • Slightly higher recurrence rates on tx • 3x higher recurrence after stopping prophy Aurelius CID 2012

48. Case 4 20 yo male, sexually active and daily IC drug use, in the ED with 2 days of fever and HA. He has photophobia, mild meningismus and a normal neurological exam.

49. IDSA Meningitis Treatment Guidelines

50. Question What is the most likely etiology? • S pneumoniae • Naegleriafowleri • N meningococcus • L monocytogenes • B henselae • MRSA