Little House on the Prairie author wrote that her sister Mary was - PDF document

• Background Encephalitis   California Encephalitis Project (CEP) • Case vignettes Highlights of agent-specific findings with focus on  diagnostics (rather than Rx) Carol Glaser, DVM, MPVM, MD  CEP experience and lessons learned, particularly as it relates to diagnostic testing Encephalitis and Special Investigations Section Present variety of cases-  Division of Communicable Disease Control  some relatively common where diagnostic problems California Department of Public Health arose and &  other rare, but important, causes Department of Pediatrics  Handout slightly different > lecture Division of Pediatric Infectious Diseases University of California, San Francisco • “Little House on the Prairie” author wrote that her sister Mary was robbed of her sight by scarlet fever • The journal Pediatrics asserts that it wasn’t scarlet fever, it was viral meningoencephalitis Mary’s meningoencephalitis likely caused optic neuritis, inflammation of her optic nerves, which resulted in her vision loss

• Wide range of incidence rates depending on country, age-group etc., • 0.7-13.8/100,000 • Generally higher pediatric population > adults • Higher in tropical areas > “Western” countries • Comparable to ‘purulent meningitis’ Jmor F et al., Jour Virol 2008 Granerod J et al., Lancet Infect Dis 2010 Michael BD et al., Epilepsia, 2010 One of the most challenging syndromes for clinicians to diagnose and manage: • Severity of syndrome with high morbidity/ mortality • Vast number of infectious agents • Large number of non-infectious mimickers • Specific pathogen/underlying cause is identified < 50% of cases

• Togavirus: EEE, VEE, WEE • Flavivirus: SLE, WN, JV, Dengue • Not a single disease entity • Bunyaviruses: LaCrosse, • Paramyxoviridae: mumps, measles • Often an uncommon presentation of a • Arenaviruses: LCM, Machupo, etc • Enteroviruses: Polio, coxsacki, etc common infection • Reoviruses: CTF • But sometimes a rare infection • Rhabdovirus: rabies • Filoviridae: Ebola, Marburg • Lots of misconceptions about diagnostic • Retroviridae: HIV • Herpes: HSV1/2,VZV,EBV,CMV,HHV6 testing • Adenovirus • Rickettsial • Bacterial • Fungal • Parasites • Prion • Non-infectious “ mimickers ”

• Hospitalized w/ encephalopathy (depressed or ALOC > • 1998 – 2011 24 hours) • Viral and Rickettsial Disease Laboratory, AND State of CA • 1 or more of the following: • Funding from CDC Emerging Infections  fever (38 o C) Program  seizure(s)  focal neurological findings • Cases referred from MDs throughout CA  CSF pleocytosis  EEG findings c/w encephalitis Not population-based (e.g., large sampling   abnormal neuroimaging throughout CA)  Biased toward more severe and diagnostically • Exclusions: <6 months old or immunocompromised difficult cases • TN and NY had similar programs • CSF • Molecular, serologic, isolation • Acute serum • Multiple specimen types (CSF, sera, • Respiratory sample respiratory, brain if available) (NP/throat swab) • Core testing: Arboviruses (WNV, SLE, WEE) • Convalescent serum  Herpesviruses (HSV1, HSV2, VZ, EBV, HHV6)  (10-14 days > acute Enteroviruses  serum) Respiratory viruses (Flu A/B, Paraflu 1-3, adenovirus, HMPV)   Mycoplasma pneumoniae • Brain tissue if available • Expanded testing - exposures, clinical symptomatology, laboratory

• Exposure history: • 10 year old, previously healthy,  Owns dog and cat white female Residence in rural area  No sick contacts  No recent travel   Admitted with 2 day history fever and upper respiratory illness, increasing • Admit labs/Neuroimaging lethargy and somnolence LP: WBC = 90 cells/mm 3 (75%L, 14%M),  Protein = 26 mg/ml, Glucose = 59 mg/ml  Admission exam - inattentive, drooling,  CT Scan: Left frontal lobe enhancement, and “ difficulty finding words ” mass effect

CEP results • On HD#3 developed seizures • CSF PCR  HSV-1, HSV-2: Negative (HSV-1 PCR also negative • EEG: slowing L>R, sharp wave in left parietal outside hospital)  VZ: Negative  Mycoplasma : Negative • MRI: multifocal T2 prolongation with patchy  Enterovirus: Negative enhancement, most pronounced in left • Serology : temporal lobe  Arboviruses/ Mycoplasma /Chlamydia/ Adenovirus/EBV: Not significant • HD#4 LP repeated: • Respiratory PCR CSF WBC=113 WBC cells/mm 3 (83%L)   Influenza A/B, Adenovirus, Mycoplasma ,  Protein=107 mg/dl, Glucose=57 mg/dl Enterovirus: Negative 1. Rabies 2. Bacterial meningitis  CSF PCR HSV-1 repeated on 2 nd CSF: 3. Herpes simplex  Hospital lab: Positive HSV-1 encephalitis  VRDL: Positive HSV-1 4. Balamuthia mandrillis  Diagnosis: Herpes Simplex 5. Non-infectious, anti- Encephalitis (HSE) NMDAR 6. Enterovirus

• CEP: 80 cases --~ 20% had initial PCR • HSV-1 considered to be leading negative (biased toward more difficult cases) cause of encephalitis • Of those with false negative 1 st CSF, CSFs • Acute necrotizing encephalitis were relatively bland: • PCR: considered sensitive and  Initial CSF lab values: specific  Median CSF WBC=17 WBCs/mm 3 (range: 0-330) - Tunkel AR et al., Clin Inf Dis, 2008  Median CSF Protein=34 mg/dL (range: 22-87) • False negative PCRs tend to occur early in course of illness (e.g., w/in 72 hours of onset) or CSF fluid relatively “ bland ’’  3/11 (27%) patients tested within 72 hours: negative-  repeat LP 5-11 day later positive - Weil AA et al, CID, 2002  8/33 (24%) negative first 3 days  5 cases repeat LP and 4 were positive - De Tiege X et al, CID, 2003  2/15 (13%) of HSE cases were initially negative HSV CSF PCR but results became positive in repeat CSF analyses - Elbers JM et al, Pediatrics, 2007

• Exposure history • 10 year old male — Owns dog, cat and lizard — 3 days prior to admission with fever, right — Raccoons in yard sided weakness, and slurred speech — Plays football — No international travel, traveled to Central  On admission Valley  febrile  lethargy • Admit labs, neuroimaging  change in behavior — LP: WBC = 27 WBCs/mm 3 (100% Mo)  confusion — Protein = 23 mg/dL, Glucose = 54 mg/ml  somnolence — 1 st MRI: bilateral thalamic enhancement, L>R • Quickly deteriorated within first few • CSF PCR days of hospitalization  HSV1, HSV2: Negative  VZ: Negative — Intubated  Mycoplasma : Negative — Comatose  Enterovirus: Negative — Non-interactive Respiratory — Occasional — Enterovirus: Negative — Other viruses: Negative — Repeat MRI: area of enhancement • Serology: involvement with more extensive  Arboviruses (SLE, WEE, WNV), Mycoplasma , involvement of brainstem region Chlamydia, adenovirus, EBV: Not significant

1. Rabies • A. Rabies 2. Bacterial meningitis • B. Bacterial meningitis • C. Herpes simplex encephalitis 3. Herpes simplex • D. Balamuthia mandrillis encephalitis • E. Non-infectious, anti-NMDAR 4. Balamuthia mandrillis • F. Enterovirus 5. Non-infectious, anti- NMDAR 6. Enterovirus Most common infection identified : • Brain biopsy — “necrotizing encephalitis”, no • 26% of all confirmed etiologies: intranuclear cells, no organism 98 patients confirmed by positive PCR in CSF  • Median age = 14.0 years (mean=20.5 years) • Multiple studies done on biopsy • 63% pediatric, 37% adult — All negative — EXCEPT for weakly positive Entero • CSF: median WBC = 58 cells (0-2655), Protein=40 mg/dl (20-473), glucose=64 mg/dl (20-122) PCR — Prelim sequence data suggestive • Relatively short length of stay, median= 6 days EV 71 • Most with good outcomes, however 5+ fatalities (e.g. Enterovirus 71) Fowlkes AL et al., JID, 2008

• 57 additional cases considered probable or Outbreak of Neurologic EV 71 possible –CSF EV PCR negative but positive in Disease: A Diagnostic Challenge respiratory and/or stool • CSF EV PCR good, but…not perfect -EV-PCR CSF ‘frequently negative’ -EV-PCR from resp and gi tract • Important to examine for enterovirus in have higher yields > EV-PCR CSF multiple specimens: Brain biopsy if possible  Throat/Nasopharyngeal  - Perez-Velez C, CID, 2007  Stool • Suspect we are missing EV cases due to unsuitable or incomplete specimens CSF Blood Throat Rectal other # specimens 16 3 6 8 9+ submitted # PCR 5 0 6 7 8 positive % 32% 0 100% 88% ~80% positive Perez-Velez C, CID, 2007

• 12 year old previously healthy • Exposure history Bird at home Hispanic male   Motorcycling – dusty conditions  Presented with one week of progressively worsening headache, • Admission laboratory results vomiting, decreased appetite, poor  LP: WBC = 78 cells/mm 3 (78%L, 20%M), sleep, lethargy, and hallucinations Protein = 42 mg/ml, Glucose = 74 mg/ml  MRI suggestive of ADEM  CT concerning for brain tumor  Negative bacterial, fungal, & AFB stains & cultures  Intubated for increased ICP and ALOC Negative Coccidioides, Blasto, Histo, Cocci, &  Cysticercosis • Treatment • Symptoms returned  Decadron, Vancomycin, 2 weeks after stopping oral prednisone  Cefotaxime, Flagyl Headache, nausea, vomiting, and  lethargy • Repeat CT Worsening enhancement and edema  • Discharged one week later • Recurrent ADEM?  At baseline on 1 week oral Initial plan was for longer course of  prednisone taper with dx of ADEM steroids Changed after repeat MRI- concerning  for lymphoma