PIGS Training Course 2013BaselNovember 8, 2013

Christoph Aebichristoph.aebi@insel.ch

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.

Koplik spots rash face rash trunk

Measles

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

Enterovirus

HSV-I

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 InfectionAssociation (BIA)

Kneen r et al. J Infect 2012;64:449

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

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Totalunter 6 Jahren

Since 01/01/20132012: 712013: 157

TBE – cases 2013 in Switzerland

BAG, www.bag.admin.ch

TBE – endemic areas in Switzerland

Clinical hints and caveats

Agent manifestationsHSV may be mildVZV Consider 3 different manifestations

Varicella – Seroprevalence in CH

Age (years)

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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

CSF interpretation of routine data

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

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;30:185Thomson 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 …

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 ?

BAG, www.bag.admin.ch

TBE- immunization rates < 16 yrs2008-2010 (3 doses)

28

5

2424

58

25

40

2440 27

41

2511

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 !