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PIGS Training Course 2013BaselNovember 8, 2013
Christoph [email protected]
Challenges in viral CNS infections[encephalitis]
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.
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
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.)
Etiology
VirusesHSV1 & 2VZVEBVCMVHHV 6,7Enteroviruses (incl polio, EV71)Flaviviruses (TBE)RabiesMeasles, mumps, respiratory virusesetc.
…
Bacteria and other organismsMycoplasma pneumoniaeRickettsiaeCoxiella burnettiBartonella henseaeListeria monocytogenesBorrelia burgdorferi
MalariaCryptcoccocus neoformansTrypanosoma spp.Amebic meningoencephalitis
Feigin & Cherry; Textbook of Pediatric Infectious Diseases, 2010
Course of fever in TBE
Biphasic fever also reportedfor- HSV- enteroviruses
10 0
3
10 0
10 0
12
0
21
54
1
34
3
7
34
32
1
3
0
7
0
10
20
30
0
50
100
150
200
250
300
Fälle
unt
er 6
Jah
ren
Ges
amtz
ahl F
älle
Erkrankungsjahr
Totalunter 6 Jahren
Since 01/01/20132012: 712013: 157
TBE – cases 2013 in Switzerland
Clinical hints and caveats
Agent manifestationsHSV may be mildVZV Consider 3 different manifestations
Varicella – Seroprevalence in CH
Age (years)
0
10
20
30
40
50
60
70
80
90
100
0.5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
VZV
Sero
prev
alen
ce(%
)
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 manifestationsHSV may be mild.VZV Consider 3 different manifestations.EBV without clinical munonuclosis; mostly adolescents.Respiratory agents 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. LP2. Imaging (MRI, CT)3. Additional micro tests4. Call neuro5. EEG*
*note: PLEDS are not specific for HSV
Studies on CSF (in addition to routine)
All patients upon indicationHSV-1 / HSV-2 PCR EBV/CMV (especially in the immunocompromised)VZV PCR HHV-6, HHV-7 (in all severe cases)EBV PCR Adeno, influenza, rotavirusEnterovirus PCR measles, mumpsTBE serum abx Parvovirus B19
Other (depending on travel/exposure, etc.)
Blood serologies or other body fluid tests may be helpfulVZV, CMV, enteroviruses, PB19, adeno, influenza, other respiratory virusesMeasles, 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 multifocalleukoencephalopathy]
(4) Enterovirusus: generalized parenchymaldestruction; brain stem involvement
Gilden DH et al. N Engl J Med 2000;342:1245; Bitnun A et al, Clin Infect Dis 2001;32:1674
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;30:185Thomson C et al. Arch Dis Child 2001, ePub 21715390
When to stop acyclovir ?
• Case confirmed: s. above
• Case not confirmed ► STOP acyclovir ifa) 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 TherapyCerebellitis No antiviral therapyAcute encephalitis Acyclovir 15 mg/kg/dose q8h for ≥14 daysStroke Acyclovir (duration ???)
Steroids (duration ???)
Subacute and chronic encephalitis
• Typically managed primarily by neurologists
• Role of ID specialist – bring up differentials
Immunocompromized immunocompetentMeasles (inclusion body) JC/BK (PML)VZV (multifocal) Measles (SSPE)CMVHSV-2EnterovirusJC/BK (PML)HIV
The returning traveller
• THINK MALARIA
• Think TB, typhoid encephalopathy, trypanosomiasis
• Think amebic meningoencephalitis
• Consider viruses
Viral encephalitis in children returningfrom abroad
Area
Dengue Endemic areas worldwideRabies Indian subcontinent et al.Japanese encephalitis Southeast asiaWest Nile and other flaviviruses where the bugs fly …
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 !
BAG, www.bag.admin.ch
TBE- immunization rates < 16 yrs2008-2010 (3 doses)
28
5
2424
58
25
40
2440 27
41
2511
Encephalitis – TREAT THE TREATABLE
• HSV, VZV ► Acyclovir
• CMV, HHV ► Gancicovir, Foscarnet
• Enterovirus ► consider IVIG, [pleconaril]
• Adeno ► consider cidofovir, [ribavirin]
ALL REQUIRE EARLY ONSET NEUROREHABILITATION