Diagnosis and Treatment of Neurological Disease from ......varicella syndrome VZV vascular syndromes-Large and small vessel •Large vessel wks/months after cutaneous syndrome, •Rare-

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


Herpes Simplex Virus

Clinical CNS SyndromesHSV Encephalitis (HSE)

Recurrent benign meningitis (Mollaret’s)

Neonatal HSV encephalitis

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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.


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


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


PCR for HSV DNA in HSE

Changed understanding of symptoms/signs of HSEMonitoring of therapyEvaluate recurrence


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


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


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


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%


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


“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…


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


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


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


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


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


Congenital CMV Infection…


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


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


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


CNS Sequelae after ASYMPTOMATIC INFECTION AS NEWBORN

Sensorineural hearing loss 10-15% ? ChorioretinitisMild Late onset learning defects


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


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


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


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


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


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

Documents

Diagnosis and Treatment of Neurological Disease from ......varicella syndrome VZV vascular syndromes-Large and small vessel •Large vessel wks/months after cutaneous syndrome, •Rare-