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Diagnosis and Treatment of Neurological Disease from
Herpesvirus infection in Neonates and ChildrenCheryl JonesCheryl Jones
The ChildrenThe Children’’s Hospital at Westmead, NSWs Hospital at Westmead, NSWUniversity of SydneyUniversity of Sydney
C Jones- University of Sydney Viruses in May 2009
Overview
Members of herpesvirus family that cause CNS infections in infants and children
HSVCMVVZVEBVHHV-6,7HHV-8
Epidemiology
Pathogenesis
Diagnosis
Therapy
C Jones- University of Sydney Viruses in May 2009
Herpes Simplex Virus
Clinical CNS SyndromesHSV Encephalitis (HSE)
Recurrent benign meningitis (Mollaret’s)
Neonatal HSV encephalitis
medicineworld.org
C Jones- University of Sydney Viruses in May 2009
Epidemiology: HSV Encephalitis
Commonest cause sporadic encephalitis > 6 moNo seasonal or gender variationBimodal distribution
1/3 < 20 yrs, 1/2 > 50 yrsInfrequent : 1:250,000 populationper yr USASerotype: 96-99% HSV-1, 1-4% HSV-22/3 due to reactivation, 1/3 primaryHigh incidence long term sequelae in survivorsWithout Rx: mortality 70% and only 9% survivors normal With Rx (IV ACV) mortality 19% at 6 mos, 30% survivors normal or mild defects
Sensory ganglia
HSE: how does the virus access the CNSAfter Primary infection
•Animals: primary infection olfactory tract or trigeminal nerves to brain. In humans, pathways less clear
After HSV reactivation:
•From periphery (TG, olfactory n) or
•Latent HSV in brain ? PM asymp seropositive adults: 1/3 HSV Cx & DNA from br. stem, olfact. bulbs, gyrus rectus and limbic areas.
C Jones- University of Sydney Viruses in May 2009
HSE Pathogenesis – direct damage from virus versus role of host response
Neuronal apoptosis- mechanism of neuronal injury in HSE
DeBiasis et al, JID 2002; 186: 1547-57
Immunogenetics:
UNC-93B–TLR3–IFN pathway important for primary HSV-1 CNS in children
but is redundant for immunity to most other viruses.
Zhang Immunol Rev 2007
C Jones- University of Sydney Viruses in May 2009
Diagnosis of HSE IClinical featuresCSF examination
CSF pleocytosis and elevated proteinHSV DNA in CSF detected by PCR
Non invasive studiesNeuroimaging :CT or MRIEEG
CSF viral culture: rarely positive in older children and adults HSE (4%) but higher yield in neonates (25-40%)
Brain biopsy-isolation of HSV , histopath, PCRnow only for atypical cases or immunocompromised
CSF serologyfor chronic disease or retrospective diagnosis: 4x or > HSV Ab in CSF or serum to CSF to HSV IgGratio: ≤ 20 – usually after a month.Need albumin control to check integrity of blood brain barrier)
•Altered LOC
•Fever
•Headache
•Personality change
•Seizures: focal or general
•Dysphasia
•Other CNS symptoms, Ataxia, Autonomic dysfunction
•CSF WCC usually lymphocytes
•Average pr 100mg/dl, increases as disease progresses
•CSF cell count and protein may be normal early 5-10% especially in children
•Maybe elevated CSF Red cell count
C Jones- University of Sydney Viruses in May 2009
PCR for HSV DNA in HSE
Changed understanding of symptoms/signs of HSEMonitoring of therapyEvaluate recurrence
C Jones- University of Sydney Viruses in May 2009
HSE Clinical Manifestations and HSV DNA detection by PCR
Study of PCR with clinical presentations of HSEGrouped:
Focal, Diffuse- dec LOC, neurobehavioural change, but no focal signs or imaging, Mild disease- GCS > 13
49 (100)12829Total
319814HSV -ve
18 (37)3 (25)015 (52)HSV +ve
TotalMildDiffuseFocal
Patients n (%)PCRResult
Dominigues et al, Clin Infect Dis 1997
C Jones- University of Sydney Viruses in May 2009
HSE Bx-proven Vs PCR-proven
75%31%Aphasia
33%33%Motor deficits
50%40%Seizures
70-85%60%Personality change
Milder cases
~ 80%35%Severity GSC >10
PCR-provenBx-proven
Dominigues et al, Clin Infect Dis 1997
C Jones- University of Sydney Viruses in May 2009
Duration of HSV DNA detection in HSE post onset of symptoms
Revello et al, Clin Diag Virol 1997
HSV DNA detectable for up to one week post onset of symptoms
False negative : • V. early or late (>d 10) testingafter onset of symptoms• After Antiviral Rx: detection reduced by 5-7 days Rx, in most• Presence of inhibitors eg blood• Poor sensitivity in an individual lab
C Jones- University of Sydney Viruses in May 2009
PCR Monitoring of Therapy
Frequency HSV DNA declines after antiviral Rx:
by 5-7 days Rx in most;sharp decline after two weeks. (Lakeman JID ’95)
Persistence HSV DNA at end 2-3 weeks Rx poor prognostic indicator (Adult studies) e.g. Wildman 1997
PCR of CSF should be considered at completion of Rx
Quantitative PCRCopy no/ ml >100- poorer prognosis in adult HSENeeds standardisation
Lakeman et al, JID 1995
47%
21%
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Rx and outcome HSE in children
Rx intravenous aciclovir 10mg/kg/dose every 8 hours i.v. for (2 to) 3 weeksRCT of valaciclovir for HSE underway (IV Rx followed by VACV or Placebo for 90 days)Outcome influenced by
Age- sl. Lower mortality in children than adults, but 70% survivors have residual defectsLOC at presentationDuration of encephalitis
C Jones- University of Sydney Viruses in May 2009
“Recurrent” HSV Encephalitis
Up to 20% will have recurrence of neurological symptoms
? Role of viral reactivation or immunological phenomenon
Limited data on role of antiviral Rx/ suppressive therapy
Antiviral Rx: if repeat +ve HSV DNA in CSF, or if using corticosteroids
Neonatal HSV Encephalitis…
C Jones- University of Sydney Viruses in May 2009
Neonatal HSV in AustraliaMode of Presentation ‘97-’07 APSU study
47%
11%
21%3%
18%
Skin, Eye, Mouth
Disseminated alone
Disseminated + CNS
CNS alone
Intrauterine
Jones, Isaacs, et al in prep.
39%
HSE
HSV-1 55%
HSV-2 45%Hydrancephaly, chorioretinitis,Scarring lesions at birth
C Jones- University of Sydney Viruses in May 2009
Route of neonatal HSV infectionhttp://www.spineguys.com/images/160w/52.gif
www.thematrona.com/ practice.html
Intrauterine 3-5%During delivery 85%
Risk transmission 30-60% with 1ºgenital herpes
Postnatal: 10%
www.irishhealth.com
HSV entry to CNS?
•Encephalitis alone: neuronal entry
•Disseminated disease: blood borne
C Jones- University of Sydney Viruses in May 2009
Age at Presentation?
1 - 133.5Disseminated
10-2812.0CNS alone
0 - 283.6Skin, eye, mouth
0 - 478.0All cases
RANGEMean (days)
CATEGORY
Jones et al, unpublished observations. Neonatal APSU HSV study 1997-2007
Neonatal HSV EncephalitisClinical signs non specific; seizures, poor feeding, irritability, lethargy, temp instability; if disseminated: shock, tachypnoea, DIC, elevated LFTs,Cutaneous vesicles may be absent (40%)HSV DNA PCR as for older children but Virus cultured from CSF more readily than in older children/adults (25-40%). CSF pleocytosis, increased protein in most, but CSF WCC/Protein may be normalMortality usually due to brain stem involvement, un Rx 50%. Good Response to Rx. Predictors: decreased LOC, prematurity, seizuresSequelae in70% survivors: associated with seizures at presentation, HSV-2 in CNS, PCR positive at end of 21 days Rx
C Jones- University of Sydney Viruses in May 2009
Survival – APSU study?
21.6% (22/102) acute mortality
Category of disease
SEM *1/22
Disseminated 20/22 +/- CNS
I/uterine death 1/22
CNS alone 1/22
*1 Death of preterm infant at 56 days ? due
to other cause
Jones et al, unpublished observations, APSU 2005
Recommended Antiviral RxNeonatal HSV Disease
Aciclovir 20mg/kg/dose given 8th hourly
21 days if encephalitis/ disseminated infection or LP not performed
14 days for disease localised to skin, eye or mouth
Kimberlin et al, Pediatrics 2003
C Jones- University of Sydney Viruses in May 2009
Recurrent Herpes Post Neonatal HSV Disease
• Role of chronic suppressive antiviral therapy to prevent long term CNS sequelae under evaluation
•Ph II:Kimberlin PIDJ 1996
•300 mg/m2 3x/d
•46% neutropenia (<1000x103)
Not routinely recommended.
Consider: preterm, frequent HSV-2 recurrence
C Jones- University of Sydney Viruses in May 2009
Congenital CMV Infection…
C Jones- University of Sydney Viruses in May 2009
CNS Sequelae in Infants With Signs of Congenital CMV Infection at Birth
Sensorineural hearing loss ~59%Severe Motor Deficit ~49%Mental retardation (IQ <70) ~47%Chorioretinitis ~12%Seizures ~11%
Boppana et al , Pediatrics 1997
C Jones- University of Sydney Viruses in May 2009
Early Predictors of Poor CNS Outcome?
Poor cognitive outcomeMicrocephaly (adjusted) most specific predictor,Abnormal head CT most sensitive predictor
Long term motor disabilityAbnormal head CT strong, sensitive predictorchorioretinitis insensitive, but specific predictor
Not predictive SN hearing loss, jaundice,↓ platelets, increased LFTs, hepatosplenomegaly, growth retardation
Boppana et al, Pediatr 1997
Noyola et al, J Pediatr 2001
C Jones- University of Sydney Viruses in May 2009
Congenital CMVLong Term CNS Outcome?
If no CNS abnormality by one year, unlikely to be at increased risk for subsequent neurodevel/CNS impairment
Prospective mother/infant studiesSweden
Ivarsson et al, Pediatr 1997; Scand Infect Dis J 1999USA
Fowler et al, NEJM 1992; Temple et al, J Dev Behav Ped 2000
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CNS Sequelae after ASYMPTOMATIC INFECTION AS NEWBORN
Sensorineural hearing loss 10-15% ? ChorioretinitisMild Late onset learning defects
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Diagnosis CNS sequelae congenital CMV
NewbornCMV isolation or PCR on specimens obtained in 1st 3 weeks of lifeCMV IgMNeuroimagingHearing screenEye exam
Dx after newborn periodRetrospective dx CMV PCR on newborn screening cardNeuroimaging, hearing, eye exam
C Jones- University of Sydney Viruses in May 2009
TreatmentCongenital CMV Infection
Recommended for life or sight-threatening disease
IV ganciclovir: dose? duration?5mg/kg/dose IV q12h
Treatment of symptomatic infant to reduce long term neurological sequelae?
Kimberlin et al, Pediatrics 2003 IV Ganciclovir for 6 weeks
C Jones- University of Sydney Viruses in May 2009
Varicella Zoster- CNS syndromes
Acute cerebellarataxiaVZV vascular
syndromesVZV encephalitisCNS sequelae
from Congenital varicella syndrome
www.rch.org.au
VZV vascular syndromes-Large and small vessel
•Large vessel wks/months after cutaneous syndrome,
•Rare- mostly in elderly but isolate reports in infants/children post varicella
•Dx: CT/MRI shows infarct
•Pleocytosis, VZV PCR/Ab on CSF
C Jones- University of Sydney Viruses in May 2009
VZV Acute cerebellar ataxia
Rare: about 1:4000 children with VZV < 15 yrsUsually within 1 wk of rash, has occurred prior to onset of rashViral replication vs immune mediated?
VZV DNA in 3/5 children in one seriesVZV Ab usually negative
CSF mild changes only, MRI usually normalRecovery the norm. Rare reports of persistent cerebellar defectsRole of antiviral Rx unclear: if Rx IV aciclovir 500mg/m2 every 8 hours
Connolly et al, Ann Neurol, 1994
C Jones- University of Sydney Viruses in May 2009
CNS sequelae of congenital Varicella
Skin scars ~80%Eye defects 60% Limb abnormalities ~70% Cortical atrophy, Low IQ 46%Poor sphincter control 32%
Also: Prematurity, LBW 50%, Early death 29%
DX; Hx varicella inmother during pregnancy. VZV PCR negative. IgGusually positive, and IgM neg
C Jones- University of Sydney Viruses in May 2009
SummaryHSV
EncephalitisImmunogenetic markers in futurePCR directed therapy
Neonatal HSV diseaseHigh dose Rx for 3 weeksPCR directed Rx
CMVPredictive factors at birth of poor CNS outcomeMore research needed to define use of ganciclovir to decrease CNS sequelae
VZVAcute cerebellar ataxia: usually self limiting
Acknowledgements
• Neonatal HSV APSU study: Co-investigators: D. Isaacs, A. Cunningham, S. Garland, P. McIntyre
• Contributors to the APSU• APSU staff and sponsors