8 glaser encephalitis - continuing medical education - … glaser... · · 2013-03-20scarlet...

Carol Glaser, DVM, MPVM, MD Encephalitis and Special Investigations Section

Division of Communicable Disease Control California Department of Public Health

& Department of Pediatrics

Division of Pediatric Infectious Diseases University of California, San Francisco

•  Background   Encephalitis   California Encephalitis Project (CEP)

•  Case vignettes   Highlights of agent-specific findings with focus on

diagnostics (rather than Rx)   CEP experience and lessons learned, particularly as

it relates to diagnostic testing   Present variety of cases-

  some relatively common where diagnostic problems arose and

  other rare, but important, causes   Handout slightly different > lecture

•  “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

• Not a single disease entity

• Often an uncommon presentation of a common infection

• But sometimes a rare infection

• Lots of misconceptions about diagnostic testing

•  Togavirus: EEE, VEE, WEE •  Flavivirus: SLE, WN, JV, Dengue •  Bunyaviruses: LaCrosse, •  Paramyxoviridae: mumps, measles •  Arenaviruses: LCM, Machupo, etc •  Enteroviruses: Polio, coxsacki, etc •  Reoviruses: CTF •  Rhabdovirus: rabies •  Filoviridae: Ebola, Marburg •  Retroviridae: HIV •  Herpes: HSV1/2,VZV,EBV,CMV,HHV6 •  Adenovirus

•  Rickettsial •  Bacterial •  Fungal •  Parasites •  Prion

•  Non-infectious “mimickers”

•  1998 – 2011

•  Viral and Rickettsial Disease Laboratory, State of CA

•  Funding from CDC Emerging Infections Program

•  Cases referred from MDs throughout CA   Not population-based (e.g., large sampling

throughout CA)   Biased toward more severe and diagnostically

difficult cases

•  TN and NY had similar programs

•  Hospitalized w/ encephalopathy (depressed or ALOC > 24 hours)

AND

•  1 or more of the following:   fever (38o C)   seizure(s)   focal neurological findings   CSF pleocytosis   EEG findings c/w encephalitis   abnormal neuroimaging

•  Exclusions: <6 months old or immunocompromised

•  CSF

•  Acute serum

•  Respiratory sample (NP/throat swab)

•  Convalescent serum (10-14 days > acute serum)

•  Brain tissue if available

•  Molecular, serologic, isolation

•  Multiple specimen types (CSF, sera, respiratory, brain if available)

•  Core testing:   Arboviruses (WNV, SLE, WEE)   Herpesviruses (HSV1, HSV2, VZ, EBV, HHV6)   Enteroviruses   Respiratory viruses (Flu A/B, Paraflu 1-3, adenovirus, HMPV)   Mycoplasma pneumoniae

•  Expanded testing - exposures, clinical symptomatology, laboratory

• 10 year old, previously healthy, white female

  Admitted with 2 day history fever and upper respiratory illness, increasing lethargy and somnolence

  Admission exam - inattentive, drooling, and “difficulty finding words”

•  Exposure history:   Owns dog and cat   Residence in rural area   No sick contacts   No recent travel

•  Admit labs/Neuroimaging   LP: WBC = 90 cells/mm3 (75%L, 14%M), Protein = 26 mg/ml, Glucose = 59 mg/ml   CT Scan: Left frontal lobe enhancement,

mass effect

CEP results •  CSF PCR

  HSV-1, HSV-2: Negative (HSV-1 PCR also negative outside hospital)

  VZ: Negative   Mycoplasma: Negative   Enterovirus: Negative

•  Serology:   Arboviruses/Mycoplasma/Chlamydia/ Adenovirus/EBV: Not significant

•  Respiratory PCR   Influenza A/B, Adenovirus, Mycoplasma,

Enterovirus: Negative

•  On HD#3 developed seizures

•  EEG: slowing L>R, sharp wave in left parietal

•  MRI: multifocal T2 prolongation with patchy enhancement, most pronounced in left temporal lobe

•  HD#4 LP repeated:   CSF WBC=113 WBC cells/mm3(83%L)   Protein=107 mg/dl, Glucose=57 mg/dl

1. Rabies 2. Bacterial meningitis 3. Herpes simplex

encephalitis 4. Balamuthia mandrillis 5. Non-infectious, anti-

NMDAR 6. Enterovirus

  CSF PCR HSV-1 repeated on 2nd CSF:   Hospital lab: Positive HSV-1   VRDL: Positive HSV-1

  Diagnosis: Herpes Simplex Encephalitis (HSE)

• HSV-1 considered to be leading cause of encephalitis

• Acute necrotizing encephalitis • PCR: considered sensitive and

specific -  Tunkel AR et al., Clin Inf Dis, 2008

•  CEP: 80 cases --~ 20% had initial PCR negative (biased toward more difficult cases)

•  Of those with false negative 1st CSF, CSFs were relatively bland:   Initial CSF lab values:

 Median CSF WBC=17 WBCs/mm3 (range: 0-330)

 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 days5 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

•  10 year old male —  3 days prior to admission with fever, right

sided weakness, and slurred speech

  On admission   febrile   lethargy   change in behavior   confusion   somnolence

•  Exposure history —  Owns dog, cat and lizard —  Raccoons in yard —  Plays football —  No international travel, traveled to Central

Valley

•  Admit labs, neuroimaging —  LP: WBC = 27 WBCs/mm3 (100% Mo) —  Protein = 23 mg/dL, Glucose = 54 mg/ml —  1st MRI: bilateral thalamic enhancement, L>R

• CSF PCR  HSV1, HSV2: Negative  VZ: Negative  Mycoplasma: Negative  Enterovirus: Negative

Respiratory — Enterovirus: Negative — Other viruses: Negative

• Serology:  Arboviruses (SLE, WEE, WNV), Mycoplasma,

Chlamydia, adenovirus, EBV: Not significant

• Quickly deteriorated within first few days of hospitalization —  Intubated — Comatose — Non-interactive — Occasional

— Repeat MRI: area of enhancement involvement with more extensive involvement of brainstem region

• A. Rabies • B. Bacterial meningitis • C. Herpes simplex encephalitis • D. Balamuthia mandrillis • E. Non-infectious, anti-NMDAR • F. Enterovirus




• Brain biopsy —  “necrotizing encephalitis”, no

intranuclear cells, no organism

• Multiple studies done on biopsy — All negative — EXCEPT for weakly positive Entero

PCR — Prelim sequence data suggestive

EV 71

Most common infection identified:

• 26% of all confirmed etiologies:   98 patients confirmed by positive PCR in CSF

• Median age = 14.0 years (mean=20.5 years)

• 63% pediatric, 37% adult

• CSF: median WBC = 58 cells (0-2655), Protein=40 mg/dl (20-473), glucose=64 mg/dl (20-122)

• Relatively short length of stay, median= 6 days

• Most with good outcomes, however 5+ fatalities (e.g. Enterovirus 71)

Fowlkes AL et al., JID, 2008

•  57 additional cases considered probable or possible –CSF EV PCR negative but positive in respiratory and/or stool

•  CSF EV PCR good, but…not perfect

•  Important to examine for enterovirus in multiple specimens:   Brain biopsy if possible   Throat/Nasopharyngeal   Stool

•  Suspect we are missing EV cases due to unsuitable or incomplete specimens

Outbreak of Neurologic EV 71 Disease: A Diagnostic Challenge

-EV-PCR CSF ‘frequently negative’ -EV-PCR from resp and gi tract have higher yields > EV-PCR CSF

-Perez-Velez C, CID, 2007

CSF Blood Throat Rectal other

# specimens submitted

16 3 6 8 9+

# PCR positive

5 0 6 7 8

% positive

32% 0 100% 88% ~80%

Perez-Velez C, CID, 2007

• 12 year old previously healthy Hispanic male

  Presented with one week of progressively worsening headache, vomiting, decreased appetite, poor sleep, lethargy, and hallucinations

  CT concerning for brain tumor

  Intubated for increased ICP and ALOC

•  Exposure history   Bird at home   Motorcycling – dusty conditions

•  Admission laboratory results   LP: WBC = 78 cells/mm3 (78%L, 20%M),

Protein = 42 mg/ml, Glucose = 74 mg/ml   MRI suggestive of ADEM

  Negative bacterial, fungal, & AFB stains & cultures   Negative Coccidioides, Blasto, Histo, Cocci, &

Cysticercosis

•  Treatment   Decadron, Vancomycin,

Cefotaxime, Flagyl

•  Discharged one week later   At baseline on 1 week oral

prednisone taper with dx of ADEM

•  Symptoms returned   2 weeks after stopping oral prednisone   Headache, nausea, vomiting, and

lethargy •  Repeat CT

  Worsening enhancement and edema •  Recurrent ADEM?

  Initial plan was for longer course of steroids

  Changed after repeat MRI- concerning for lymphoma

•  Laboratory results   LP: WBC = 298 cells/mm3 (89%L, 5%M),

Protein = 69 mg/ml, Glucose = 40 mg/ml   Repeat infectious studies-bacterial, fungal, and

TB studies negative   Biopsy #1- angiocentric lymphoid and plasma

cell infiltrates   Full body CT, PET, & bone scans normal

•  Treatment   Prednisone





•  Symptoms returned - California Encephalitis Project contacted

•  Balamuthia mandrillaris testing positive

•  Rx with ‘cocktail’ of different Rx with initial improvement but died a few weeks later

•  Type of free-living amoeba (living single-celled organisms)  Dozen of types of free-living amoeba, few are pathogenic

•  Two distinct CNS presentations of free-living amoeba:  Fulminant, rapid progressive, fatal encephalitis — Naegleria fowlerii (diving in brackish water)  Granulomatous amoebic encephalitis

–  Acanthoemba sp., –  Balamuthia mandrillis

•  Considered to be a rare cause of encephalitis

•  Subacute to chronic presentation   Imaging: ring-enhancing, hydrocephalus, or parenchymal mass   Often lymphocytic CSF pleocytosis   Insidious onset -- headache, nausea, low-grade fever, lethargy, & confusion

•  Can mimic   Brain tumor   ADEM   Mycobacterium tuberculosis   Neurocysticercosis   Viral encephalitis

•  Found in soil and water •  Worldwide distribution •  Inhalation or direct contamination of skin lesion

•  15 confirmed cases identified by CEP since 1990: (probably additional cases but no brain tissue)

•  Positive serology often the ‘tip-off’ but brain biopsy needed for confirmation

•  Demographics

  Median age = 19 years (1-84 years)   82% Hispanic

 Is this because of exposure vs. genetic susceptibility vs. ?   91% male   Most immunocompetent

•  CSF: lymphocytic or neutrophilic predominance, normal-high protein, normal-low glucose

•  All had abnormal neuroimaging: ring-enhancing, mass lesions, hydrocephalus

•  Exposure/risk factor:   Not clear but most with soil exposure such as

gardener, construction worker, jeeping/motorcycling in dusty area

•  Most died but 2 still living (one lost-to-follow-up)

Consult with CDC National Center for Emerging and Zoonotic Infectious Diseases Waterborne Disease Prevention Branch, CDC (or if in California, consult with California State Health Dept) •  Testing

Brain material for IHC and molecular (serology can be helpful as well) •  Treatment recommendations

  Combination of Sulfadiazine, Flucytosine, Azole, Azithromycin and Pentamidine

  CEP cases survivors

Case 4

•  72 y/o male with possible encephalitis, referred to CEP

  Onset of headache/fever

  5 days later hospitalized with lethargy, somnolence and ascending paralysis

  Clinician thought it was probably a stroke but wanted to rule out encephalitis

  Exposure history:

  Born and raised in the Philippines and had been there 10 months prior to onset of illness

  US resident for 10 years

  No known mosquito bites

  No known animal exposures

  Admit labs/Neuroimaging:

  LP: WBC = 10 WBCs/mm3, Protein = 172 mg/dL, Glucose = 60 mg/dL

  MRI: mild atrophy (appropriate for age), otherwise normal

  Died 11 days after hospitalization

  No autopsy, cause of death: “cerebral vascular accident”

CEP results •  CSF PCR

 Herpes consensus: NEG  Mycoplasma: NEG   Enterovirus: NEG

•  Serology   Arboviruses/Mycoplasma/Chlamydia/Adenovirus/

EBV: Negative

•  Respiratory PCR   Influenza A/B, Adenovirus, Mycoplasma,

enterovirus: Negative





•  CEP deceased “core testing” includes rabies testing: • Rabies antibody positive and rabies PCR

positive from “throat swab” (contaminated with saliva)

• Sequenced strain: canine strain/Philippines

•  Patient originally from Philippines, was there 10 months prior to onset of illness

Etiology •  Family: Rhabdoviridae

  Negative-stranded RNA genome •  Genus: Lyssavirus •  Envelope virus, bullet-shaped

Epidemiology

• Only 1-2 recognized cases/year in the United States…so why is it so important?   “uniformly fatal” without vaccine [until

recently]   Tremendous ‘angst’ : ~40,000 persons

receive post-exposure prophylaxis (PEP) in the US

  Many encephalitis cases are ‘rule out’ rabies …on the other hand, cases are missed

  World: 50,000-100,000 cases/year

Rabies Reservoirs

•  All mammals are susceptible

•  However some species much more important > others, e.g., canine rabies, raccoon rabies, bat rabies, skunk, etc.

•  Humans generally “dead-end” hosts

Bats (non-terrestrial) and Rabies

• Most common source of human infection in US

• Since 1990, > 90% of endemically acquired rabies in the US

• Exposure to bat not always recognized, especially bites

Bites from bats may be overlooked

-Jackson A, Lancet, 2001

•  Most cases of rabies in India, China, SE Asia, Iran, Africa and South America

•  Most are canine rabies •  Estimated 50,000 cases/year

Clinical

•  Incubation period ranges from few days to >1 year   Most cases present between 2 and 16

weeks •  Pleomorphic manifestations, often mistaken

for other CNS diseases [e.g., case 2] •  Initial symptoms are nonspecific:

  Fever, malaise, fatigue, anxiety, headache

  Half of patients have pain, itching or paresthesias at site of the bite

  Lasts 2-10 days

Clinical

After prodrome: • Furious form (aka “mad dog”) Increasing agitation, hyperactivity, seizures, hallucinations, aggressive behavior, hydrophobia (spasm of respiratory muscles when attempting to drink)

  Coma develops, then death

• Paralytic form (aka dumb rabies) Progressive lethargy, incoordination and ascending paralysis

  Respiratory muscle paralysis may occur   Coma, then death

Diagnosis of Rabies

•  Always consider in case of acute onset, rapidly progressive encephalitis

•  Diagnosis before death is ‘tricky’, testing includes:   Testing for viral antigen by DFA in nuchal skin or corneal

cells   Testing for viral RNA by PCR of saliva, neural tissue, or

CSF   Serology for antibodies in the blood   Growing virus isolated from saliva or CSF in cell culture

•  Testing after death includes:   Testing for viral antigen by DFA in brain tissue

Prevention and Treatment issues these issues often confused…note the differences

•  Rabies Pre-exposure prophylaxis   Given to ‘high risk’ individuals such as veterinarians,

animal control workers, spleunkers before exposure   3 doses vaccine

•  Rabies Post-exposure prophylaxis (PEP)   Given following a bite from rabid (or suspected rabid)

animal   Rabies Immune globulin (RIG) and 4 doses vaccine (day

0,3,7,14)

 Highly effective for prevention •  Rabies “Treatment”

  No known effective Rx; once symptoms develop; vaccine and RIG of no benefit

  Experimental treatment

PEP - Yes or No?

•  Type of exposure (bite, non-bite)   If bite: provoked vs. unprovoked   Assess other circumstances of exposure,

e.g., behavior of animal •  Severity of wound •  Animal species involved •  Animal health and vaccination history •  Local animal rabies epidemiology •  Animal available for observation / testing •  Urgent but not “emergency”, consult local public

health c

22 y/o Asian female, •  Admitted to psychiatric unit for odd behavior, “completely out of her mind” •  Abnormal movements •  High heart rate, hypotension

• California Encephalitis Project contacted because clinicians were concerned about rabies

•  CSF PCR   HSV 1&2 (-)   VZV (-)   HHV6 (-)   Enterovirus (-)

•  Parvo B19 DNA (-) •  IgG 5.3 IgM <0.1

•  West Nile (-) •  HIV-1 PCR <50 •  CMV IgG (+), IgM (-) •  EBV IgM <0.90, IgG

3.27 •  VRDL NR

•  Strongyloides Ab 0.29 •  Schistosoma Ab 0.0 •  G. lamblia Ag (-) •  Tropheryma whipplei (-) •  Bartonella panel (-) •  Cryptococus (-) •  C. immitis (-) •  RPR NR •  HBc IgM NR •  HBV DNA <40 •  HBc Ab (+) •  HCV Ab NR •  HAV IgG (+) •  Mumps Ab (+)

•  Rickettsia panel IFA   Typhus IgG (-)   RMS IgG (-)   E. chaffeensis IgG (-)   A. phagocytophilla IgG (-)   Q fever phase I and II IgG (-)

•  Arbo Panel pending •  M. pneumo IgM 307, IgG 1.24 •  H. capsulatum Ab <8 •  pANCA (-) •  cANCA (-) •  Heavy metal screen (WNL)

•  β-HCG (-) •  α-fetoprotein 1.5 •  VGCC Ab •  Pemphigus Ab Screen •  ANNA titers •  GAD 65 Ab <0.5 •  Neuroimm •  Thyroid Peroxidase Ab

<10 •  TSH 2.93 T4 1.65 •  DS DNA Ab (-) •  ANA (-)





• Suggested:   Anti-N-methyl-D-aspartate receptor

(anti-NMDAR) testing   Abdominal/pelvic ultrasound

  Results:   U/S – teratoma   Antibody positive for anti-NMDAR

antibody

•  Initially recognized ~ 7 years ago in young Asian females, often with teratoma

•  Initially considered a ‘paraneoplastic syndrome’

•  Immune form of encephalitis • Some have teratomas, but the

young children and males generally do not

Comparison to Viral Agents CEP data (2007-2011)

0

5

10

15

20

25

30

35

EV WNV HSV-1 VZV NMDAR

< 30 years of age

-Gable M et al, CID, 2012

•  Herpes simplex:   Limitations of CSF PCR testing, consider

re-tap if temporal lobe involvement

•  Enterovirus   Another leading cause of encephalitis   More often in pediatrics but still important

in adults   Multiple specimen types needed to

optimize yield

•  Balamuthia mandrillis

  Although not common, probably not so rare   Consider testing in patients with parenchymal

lesions especially if CSF profile “MTB/fungal-ish”

•  Rabies

  Should be considered in any rapidly progressive encephalitis

  Probably also being missed   Changing paradigm-not all fatal

• Bacterial meningitis — Prior antibiotics influence culture,

role for PCR in these cases

•  Anti-NMDAR encephalitis

  THE leading entity in CEP, consider in patients with movement disorders, seizures and/or autonomic instability

11 year old female — Fever — Upper respiratory illness for a few

days — Seen by PMD, Rx Amoxicillin

• A few days later presented to ER — Lethargy and confusion — Aphasia — Stiff neck

Laboratory: CSF: 1700 WBCs (70P/30Mo) Protein=120 mg/dl G= 50 mg/dl

• Routine bacterial & Blood cultures: negative • Referred to CEP

• Because of ‘bacterial’-looking CSF profile — PCRs for Strep pneumo and

Neisseria meningitis peformed • Postive Strep pneumo

Organism Incidence (cases per 100,000)

1986 1995 2006-2007

H. influenzae 2.9 0.2 0.08

S. pneumoniae 1.1 1.1 0.81

N. meningitidis 0.9 0.6 0.19

Group B streptococcus

0.4 0.3 0.25

L. monocytogenes 0.2 0.2 0.05

1986: Wenger et al. J Infect Dis 1990;162:1316-23 1995: Schuchat A, et al. NEJM 1997;337:970-7

2006-7: Thigpen M, et al. NEJM 2011; 364:2016-25.

• Estimated 3,000–6,000 cases per year in U.S.

• #1 cause of bacterial meningitis in US

• Case-fatality rate ~30%, up to 80% in the elderly

• Neurologic sequelae common among survivors

• Gram-positive bacteria • At >90 known serotypes • Polysaccharide capsule important

virulence factor • Type-specific antibody is

protective

“Treatment” Human Rabies Survivors - Prior Experiences in US

•  Recovery without rabies PEP   15 year old female, Wisconsin, 2004Milwaukee protocol   17 year old female, Texas, 2009 (“Abortive Case”)

•  Both met case definition for human rabies based on clinical manifestations and rabies virus specific antibodies in serum and CSF

•  Rabies virus, antigen, nucleic acid not detected from these patients

•  Antibody identified “early”

-Willoughby et al., New Eng J Med, 2005 -CDC, MMWR, 2010

Controversial whether this was really a case or not…

8 glaser encephalitis - continuing medical education - … glaser... · · 2013-03-20scarlet...

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