Clinical Approach To Aseptic Meningitis and Encephalitis

Clinical Approach To Aseptic Meningitis and Encephalitis

Virology Rotation (R2) , Clinical Microbiology Residency
King Fahd Hospital of The University

23/4/2019

1. Clinical Approach To Aseptic Meningitis and Encephalitis Clinical Microbiology Resident. King Fahd Hospital of the University. Teaching Assistant, Department of Microbiology, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia. Abdullatif Sami Al Rashed

2. Objectives Encephalitis Introduction Causes Approach to a case of viral encephalitis Risk factors Investigations Treatment Details of specific viral types CNS Syndromic Panels Aseptic Meningitis

3. Encephalitis

4. INTRODUCTION Encephalitis is defined by the presence of an inflammatory process of the brain parenchyma in association with clinical evidence of neurologic dysfunction. (IDSA encephalitis guidelines, 2008) It is a Strictly pathological diagnosis; but surrogate clinical markers often used, including inflammatory change in the cerebrospinal fluid or parenchyma inflammation on imaging and others. (BIA encephalitis guidelines, 2012).

5. CAUSES

6. (BIA encephalitis guidelines, 2012).

7. (BIA encephalitis guidelines, 2012).

8. Bacteria Parasites Fungi Mycoplasma pneumoniae Trypanosoma brucei Coccidioidomycosis Bartonella hensellae Naegleria fowleri Histoplasmosis Chlamydophila Balamuthia mandrillaris Blastomycosis Rickettsiae Angiostrongylus cantonensis Brucella spp. Coxiella burnetti Tropheryma whipplei Listeria monocytogenes Trepenoma pallidum Borrelia burgdorferi Borrelia recurrentis Ehrlichiosis Mycobacterium tuberculosis (BIA encephalitis guidelines, 2012).

9. (BIA encephalitis guidelines, 2012).

10. (BIA encephalitis guidelines, 2012).

11. Approach to a case of viral encephalitis

12. In the approach to the patient with encephalitis, an attempt should be made to establish an etiologic diagnosis. Although there are no definitive effective treatments in many cases of encephalitis, identification of a specific agent may be important for: Prognosis, Potential prophylaxis, Counseling of patients and family members, and Public health interventions. Approach (IDSA encephalitis guidelines, 2008)

13. Epidemiologic clues may help in directing the investigations for an etiologic diagnosis include: season of the year, geographic locale, prevalence of disease in the local community, travel history, recreational activities, occupational exposure, insect contact, animal contact, vaccination history, immune status of the patient. Various clinical clues may also be helpful to physicians in considering specific etiologies. (IDSA encephalitis guidelines, 2008)

14. Investigations Body fluid specimens: Cultures and analysis (i.e., antigen detection and nucleic acid amplification tests). Biopsy of specific tissues: With culture, antigen detection, PCR, and histopathologic evaluation, Serologic testing: for specific IgM and acute-and-convalescent-phase IgG antibody titers. (IDSA encephalitis guidelines, 2008)

15. Investigations MRI of the brain should be performed in all patients, with CT used only if: MRI is unavailable, unreliable, or cannot be performed. Neuroimaging findings may also suggest disease caused by specific etiologic agents. (IDSA encephalitis guidelines, 2008)

16. Risk Factors Let’s do our exercise!

17. Age Neonates HSV-2 Rubella CMV Infants & Children HHV 6 and 7 & Influenza Eastern equine encephalitis virus. Japanese encephalitis virus Murray Valley encephalitis virus Elderly Eastern equine encephalitis virus West Nile virus (IDSA encephalitis guidelines, 2008)

18. Insect contact Mosquitoes Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus, Murray Valley encephalitis virus, Japanese encephalitis virus, West Nile virus, La Crosse virus Ticks Tickborne encephalitis virus Powassan virus (IDSA encephalitis guidelines, 2008)

19. Immunocompromised patient Varicella zoster virus, cytomegalovirus, human herpesvirus 6, West Nile virus, HIV, JC virus (IDSA encephalitis guidelines, 2008)

20. Animal Contacts Rabies virus Nipah virus Rabies virus Rabies virus Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan equine encephalitis virus Hendra virus (IDSA encephalitis guidelines, 2008)

21. Animal Contacts Japanese encephalitis virus Nipah virus West Nile virus Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan equine encephalitis virus St. Louis encephalitis virus Murray Valley encephalitis virus Japanese encephalitis virus (IDSA encephalitis guidelines, 2008)

22. Ingestion items Unpasteurized milk: Tickborne encephalitis virus (IDSA encephalitis guidelines, 2008)

23. Occupation Occupation Type of Virus Lab workers West Nile virus, HIV Physicians and Health Care Workers Varicella zoster virus, HIV, Influenza virus, Measles virus Veterinarians Rabies (IDSA encephalitis guidelines, 2008)

24. Person-to-person transmission Type of Virus Comment Herpes simplex virus In neonates specially Varicella zoster virus Measles virus Venezuelan equine encephalitis virus Rare Mumps virus Rubella virus Human herpesvirus 6 Epstein-Barr virus Rabies virus With organ transplantation West Nile virus With transfusion, transplantation, breast feeding Influenza virus & HIV (IDSA encephalitis guidelines, 2008)

25. Recreational activities Rabies virus Enteroviruses All agents transmitted by mosquitoes and ticks (IDSA encephalitis guidelines, 2008)

26. Travel Africa: Rabies virus, West Nile virus Australia: Murray Valley encephalitis virus, Japanese encephalitis virus, Hendra virus. Central America: Rabies virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus. (IDSA encephalitis guidelines, 2008)

27. Travel Europe: West Nile virus, tickborne encephalitis virus, India, Nepal: Rabies virus, Japanese encephalitis virus Middle East: West Nile virus. South America: Rabies virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, St. Louis encephalitis virus. (IDSA encephalitis guidelines, 2008)

28. Unvaccinated status Varicella zoster virus, Japanese encephalitis virus, Poliovirus, Measles virus, Mumps virus, Rubella virus (IDSA encephalitis guidelines, 2008)

29. Investigations

30. CNS Studies Outside CNS studies Neuroradiology CSF analysis Culture of blood, stool, nasopharynx, sputum, skin.. ex MRI is the most sensitive neuroimaging test to evaluate patients with encephalitis Viral specific IgM in CSF Biopsy of specific tissues for culture, antigen detection, NAAT, and histopathology CT Scan NAAT (HSV, VSV, Enterovirus, and parechovirus should be studied in all patients) BIA Detection of IgM antibodies in serum FDG-PET Viral Culture (limited use) acute- and convalescent-phase serum samples EEG Brain biopsy (for difficult to diagnose cases and failure of ttt )

31. CNS Syndromic Panels

32. BIOFIRE® FILMARRAY® ME Panel

33. Overall, the FilmArray ME panel demonstrated a PPA with routine testing of 85.6% (249/291)  Viral targets. Of these 161 specimens, the FilmArray ME panel correctly identified the virus in 145 (90.1%).  The FilmArray ME Panel detected 114 targets, and 21.1% (24/114) were considered false positives; false positives were observed for all of the viral targets. A total of five false-negative results were also observed (two for EV and three for HHV-6).

34. Liesman RM, Strasburg AP, Heitman AK, Theel ES, Patel R, Binnicker MJ. 2018. Evaluation of a commercial multiplex molecular panel for diagnosis of infectious meningitis and encephalitis. J Clin Microbiol 56:e01927-17

35. Leber AL, Everhart K, Balada-Llasat J-M, Cullison J, Daly J, Holt S, Lephart P, Salimnia H, Schreckenberger PC, DesJarlais S, Reed SL, Chapin KC, LeBlanc L, Johnson JK, Soliven NL, Carroll KC, Miller J-A, Dien Bard J, Mestas J, Bankowski M, Enomoto T, Hemmert AC, Bourzac KM. 2016. Multicenter evaluation of BioFire FilmArray Meningitis/Encephalitis Panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol 54:2251–2261.

36. Cephied Gene Xpert EV ARUP® Laboratory Developed Test FilmArray ® Meningitis/Encephalitis System VS VS

37. BIOFIRE® FILMARRAY® ME Panel – KFHU experience

38. BIOFIRE® FILMARRAY® ME Panel – KFHU experience

39. BIOFIRE® FILMARRAY® ME Panel – KFHU experience

40. Treatment

41. Empirical Treatment Acyclovir should be initiated in all patients with suspected encephalitis, pending results of diagnostic studies Other empirical antimicrobial agents should be initiated on the basis of specific epidemiologic or clinical factors including appropriate therapy for presumed bacterial meningitis, if clinically indicated. In patients with clinical clues suggestive of rickettsial or ehrlichial infection during the appropriate season, doxycycline should be added to empirical treatment regimens (IDSA encephalitis guidelines, 2008) & (BIA encephalitis guidelines, 2012).

42. Targeted Treatment Virus Treatment Herpes simplex virus Acyclovir Varicella-zoster virus Acyclovir, ganciclovir can be considered an alternative; adjunctive steroids to be considered Cytomegalovirus the combination of ganciclovir plus foscarnet is recommended. Cidofovir is not recommended (Poor BBB penetration) Epstein-Barr virus Acyclovir is not recommended, the use of corticosteroids may be beneficial Human herpesvirus 6 Ganciclovir or foscarnet B virus valacyclovir is recommended Influenza virus oseltamivir Measles and Nipah virus ribavirin West Nile virus ribavirin is not recommended Japanese encephalitis virus IFN-a is not recommended. St. Louis encephalitis virus IFN-2a can be considered HIV HAART JC virus reversal of immunosuppression (IDSA encephalitis guidelines, 2008) & (BIA encephalitis guidelines, 2012).

43. Herpes simplex virus encephalitis

44. Epidemiology Clinical Features Diagnosis Treatment 5%–10% Of all cases Fever & seizures CSF PCR for HSV-1 & 2 (& Quantification) Acyclovir is the treatment of choice One of the most common causes of identified sporadic encephalitis worldwide Hemicranial headache CSF antibodies (may be – ve after 1 week of TTT) HSV-1 > in adults Language and behavioral abnormalities MRI: temporal and/or inferior frontal lobe edema with high signal intensity on FLAIR and T2-weighted images; bilateral temporal lobe involvement is nearly pathognomonic HSV-2 > in neonates Memory impairment Viral culture and antigen detection in brain biopsy specimen, if needed Less commonly, a brainstem syndrome and SIADH (IDSA encephalitis guidelines, 2008) & (BIA encephalitis guidelines, 2012).

45. HHV-6 Encephalitis

46. Epidemiology Clinical Features Diagnosis Treatment Immunocompromised, particularly in transplant recipients Resent exanthum Serologic testing Acyclovir is the treatment of choice No seasonal predilection Seizures CSF PCR Ganciclovir or foscarnet In children Febrile convulsions in children (after roseola) MRI: hyperintense T2-weighted signal in white matter of frontal and partial lobes to edema of temporal lobes and limbic system Viral culture and antigen detection in brain biopsy specimen, if needed (IDSA encephalitis guidelines, 2008) & (BIA encephalitis guidelines, 2012).

47. Measles Encephalitis

48. Epidemiology Clinical Features Diagnosis Treatment Unvaccinated children and adults Decline of consciousness; focal neurologic signs and seizures are common Serologic testing for recent measles Ribavirin SSPE has variable incubation, with most cases seen 4–8 years after primary infection SSPE has insidious onset, with subtle personality changes and declining intellectual performance progressing to mental deterioration, seizures, myoclonic jerks, motor signs, coma, and death Culture of nasopharynx and urine specimens RT-PCR of nasopharynx and urine specimens for viral RNA Intrathecal ribavirin for SSPE CSF antibodies; CSF PCR Detection of viral RNA in brain tissue (IDSA encephalitis guidelines, 2008) & (BIA encephalitis guidelines, 2012).

49. CASE A 8-year-old boy, medically free, he was in his usual state of health till 3 weeks back when he started to have fever, left ear pain without discharge. Parents sought medical help at another hospital and they prescribed Abx for him for 2 weeks. After 4 days of Abx, the fever subsides and the pain disappeared. 4 days later, he developed fever again with the same ear pain and sore throat. He went back to the same hospital and was discharged on Augmentin for 7 days. The fever and the symptoms subsides. After 2 days, the fever reappeared with sore throat, runny nose, cough with yellow sputum so they went to the same hospital and was discharged on azithromycin. The patient didn’t improve so he came to the KFHU ER with headache, photophobia, and 3 episodes of vomiting.

50. CASE No hx of Loss of Consciousness, No hx of diarrhea, No hx of abdominal pain, No hx of skin rash, No hx of contact with sick patients or animals. No hx of decreased level of activity or feeding. Physical Examinations: Vital signs: temp: 39.3 (route Tympanic), Pulse: 129, RR: 18, BP: 115/74. GCS: 15/15 Other examinations: Unremarkable.

51. The patient was started on ceftriaxone, vancomycin and acyclovir and admitted as a case of partially treated meningitis

52. BIOFIRE® FILMARRAY® ME Panel treatment was discontinued and the patient was discharged after 3 days

53. Aseptic Meningitis

54. The term aseptic meningitis refers to patients who have clinical and laboratory evidence for meningeal inflammation with negative routine bacterial cultures.  (Parasuraman TV et al, 2001)

55. MENINGITIS VERSUS ENCEPHALITIS The presence or absence of normal brain function is the important distinguishing feature between encephalitis and meningitis. Patients with meningitis may be lethargic or distracted by headache, but their cerebral function remains normal. In contrast, patients with encephalitis commonly present with abnormalities in brain function such as altered mental status, motor or sensory deficits, altered behavior and personality changes, and speech or movement disorders. Seizures and postictal states can be seen with meningitis so should not be construed as definitive evidence of encephalitis.

56. MENINGITIS VERSUS ENCEPHALITIS The distinction between the two entities is frequently blurred since some patients may have both a parenchymal and meningeal process with clinical features of both. 

57. The same approach of viral encephalitis should be followed Approach

58. References Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases. 2008 Aug 1;47(3):303-27. Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, Holland M, Easton A, Buckley C, Kneen R, Beeching NJ. Management of suspected viral encephalitis in adults–association of British Neurologists and British Infection Association National Gu Parasuraman TV, Frenia K, Romero J. Enteroviral Meningitis. Pharmacoeconomics. 2001 Jan 1;19(1):3-12. Leber AL, Everhart K, Balada-Llasat JM, Cullison J, Daly J, Holt S, Lephart P, Salimnia H, Schreckenberger PC, DesJarlais S, Reed SL. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. Journal of clinical microbiology. 2016 Sep 1;54(9):2251-61. Liesman RM, Strasburg AP, Heitman AK, Theel ES, Patel R, Binnicker MJ. Evaluation of a commercial multiplex molecular panel for diagnosis of infectious meningitis and encephalitis. Journal of clinical microbiology. 2018 Apr 1;56(4):e01927-17. https://www.biomerieux-diagnostics.com/filmarray-meningitis-encephalitis-me-panel

59. THANK YOU