Challenges in viral CNS infections [encephalitis] PIGS Training Course 2013 Basel November 8, 2013 Christoph Aebi christoph.aebi@insel.ch
Definition Encephalitis is defined as a syndrome of neurological dysfunction caused by inflammation of the brain parenchyma a) caused by infection (direct or indirect)* b) caused by non-infectious processes *indirect, e.g. post-infectious encephalitis, ADEM etc.
Measles Koplik spots rash face rash trunk
Epidemiology Highly variable (age, geographic area, immunization rates, epidemics ) Europe: Incidence 10.5 13,8 /100 000 in children. HSV encephalitis: 2-4 per 1 000 000. 90% of identifiable causes are HSV, VZV, EBV, enteroviruses and TBE. Jmor et al. Virol J 2001;5:1; Whitley RJ et al. Semin in Pediatr Infect Dis 2005;16:17
History Consider in particular Current or recent influenza-like illness Rash Travel history Recent vaccination Animal contact Exposure to arthropods Immunocompromized state (HIV?)* *all patients with suspected encephalitis need HIV r/o
Non-specific rashes Adenovirus Enterovirus (ECHO)
Example: Hand-foot-mouth disease HSV-I Enterovirus
Clinical manifestations Fever (very common). Mental abnormalities (consciousness, behavioural etc.). New onset of seizures.* Focal neurologic signs. * More likely if cortex is affected, which is more likely infectious, than subcortical white matter disease (ADEM etc.)
Kneen r et al. J Infect 2012;64:449
Useful algorithm by the British Infection Association (BIA) Kneen r et al. J Infect 2012;64:449
Etiology Viruses HSV1 & 2 VZV EBV CMV HHV 6,7 Enteroviruses (incl polio, EV71) Flaviviruses (TBE) Rabies Measles, mumps, respiratory viruses etc. Bacteria and other organisms Mycoplasma pneumoniae Rickettsiae Coxiella burnetti Bartonella henseae Listeria monocytogenes Borrelia burgdorferi Malaria Cryptcoccocus neoformans Trypanosoma spp. Amebic meningoencephalitis
Course of fever in TBE Biphasic fever also reported for -HSV - enteroviruses Feigin & Cherry; Textbook of Pediatric Infectious Diseases, 2010
TBE cases 2013 in Switzerland 300 30 Total unter 6 Jahren Gesamtzahl Fälle 250 200 150 100 7 7 20 10 Fälle unter 6 Jahren Since 01/01/2013 2012: 71 2013: 157 50 0 1 00 3 1 00 1 00 1 2 0 2 1 5 4 1 3 4 3 3 4 3 2 1 3 0 0 Erkrankungsjahr
TBE endemic areas in Switzerland BAG, www.bag.admin.ch
Clinical hints and caveats Agent HSV VZV manifestations may be mild Consider 3 different manifestations
Varicella Seroprevalence in CH 100 VZV Seroprevalence (%) 90 80 70 60 50 40 30 20 10 0 0.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Age (years) Vaccine 2001;19:3097
VZV encephalitis (1) Post-infective immune mediated cerebellitis (2) Acute infective viral encephalitis. (3) Arterial ischemic stroke Berger TM et al. Pediatr Infect Dis 2000;19:653
Clinical hints and caveats Agent HSV VZV EBV Respiratory agents manifestations may be mild. Consider 3 different manifestations. without clinical munonuclosis; mostly adolescents. CNS disease preceding or without respiratory signs- M. pneumoniae may present with brainstem encephalitis. Influenza Various manifestations: ADEM, ANE. Enterovirus may present with brainstem encephalitis, myelitis (EV 71). May present with hemorrhagic conjuncitivits (EV70) TBE may present as poliomyelitis-like disease. Measles 3 different manifestations. - post-infectious (ADEM) - infectious in immunocompromised hosts - SSPE in immunocompetent hosts
Diagnostic work-up 1. LP 2. Imaging (MRI, CT) 3. Additional micro tests 4. Call neuro 5. EEG* *note: PLEDS are not specific for HSV
CSF interpretation of routine data
Studies on CSF (in addition to routine) All patients HSV-1 / HSV-2 PCR VZV PCR EBV PCR Enterovirus PCR TBE serum abx upon indication EBV/CMV (especially in the immunocompromised) HHV-6, HHV-7 (in all severe cases) Adeno, influenza, rotavirus measles, mumps Parvovirus B19 Other (depending on travel/exposure, etc.) Blood serologies or other body fluid tests may be helpful VZV, CMV, enteroviruses, PB19, adeno, influenza, other respiratory viruses Measles, mumps, etc.
Indications for MRI (1) All patients should receive MRI (with diffusion weighted imaging) within 24-48 post admission (2) Superior sensitivity for HSV vs. CT [90% sens p 48 h in Gyrus cinguli, medial temporal lobe]. (3) Superior sensitivity in VZV [large vessel vasculitis or multifocal leukoencephalopathy] (4) Enterovirusus: generalized parenchymal destruction; brain stem involvement Gilden DH et al. N Engl J Med 2000;342:1245; Bitnun A et al, Clin Infect Dis 2001;32:1674
Treatment Kneen r et al. J Infect 2012;64:449
Evidence for acyclovir in HSV encephalitis Nucleoside analogue with antiviral activity against HSV. Reduces case-fatality rate (70 to 20%). Should be started within 6-48 h of admission. CSF PCR remains positive up to 7-10 d post starting therapy. Relapse common if duration of therapy is < 14 d (up to 30%). Some evidence that relapses are most common between 3 months and 12 yrs of age. Tunkel AR et al. Clin Infect Dis 2008;47:303; Ito Y et al. Clin Infect Dis 2000;30:185 Thomson C et al. Arch Dis Child 2001, epub 21715390
When to stop acyclovir? Case confirmed: s. above Case not confirmed STOP acyclovir if a) PCR negative on 2 occasions within 24-48 hours PLUS MRI not characteristic OR b) PCR negative once > 72 hours after onset of symptoms PLUS LP normal PLUS MRI normal. Tyler KL. Rev Neurol Dis 2004;1:169
Evidence for acyclovir in VZV encephalitis No hard evidence Entity Cerebellitis Acute encephalitis Therapy No antiviral therapy Acyclovir 15 mg/kg/dose q8h for 14 days Stroke Acyclovir (duration???) Steroids (duration???)
Subacute and chronic encephalitis Typically managed primarily by neurologists Role of ID specialist bring up differentials Immunocompromized Measles (inclusion body) VZV (multifocal) CMV HSV-2 Enterovirus JC/BK (PML) HIV immunocompetent JC/BK (PML) Measles (SSPE)
The returning traveller THINK MALARIA Think TB, typhoid encephalopathy, trypanosomiasis Think amebic meningoencephalitis Consider viruses Viral encephalitis in children returning from abroad Dengue Rabies Japanese encephalitis West Nile and other flaviviruses Area Endemic areas worldwide Indian subcontinent et al. Southeast asia where the bugs fly
Dengue endemic areas
JE endemic areas
Encephalitis - PREVENT Stay out of risk areas! Immunize with MMR(V) Immunize against TBE (Encepur, FSME-Immun ) Immunize against rabies (Rabipur, Tollwut-Mérieux ) Immunize against JapE (Ixiaro ) Immunize against polio for endemic areas (Poliorix ) and immunize against Influenza!
Encephalitis - PREVENT Genetic counselling of families with infant with HSV encephalitis?
TBE- immunization rates < 16 yrs 2008-2010 (3 doses) 11 25 28 40 40 27 41 25 5 58 24 24 24 BAG, www.bag.admin.ch
Poliomyelitis
Encephalitis TREAT THE TREATABLE HSV, VZV Acyclovir CMV, HHV Gancicovir, Foscarnet Enterovirus consider IVIG, [pleconaril] Adeno consider cidofovir, [ribavirin] ALL REQUIRE EARLY ONSET NEUROREHABILITATION
THANK YOU!