Diagnosis and Treatment of Neurological Disease from Herpesvirus infection in Neonates and Children Cheryl Jones The Children s s Hospital at Westmead, NSW University of Sydney
Overview Members of herpesvirus family that cause CNS infections in infants and children Epidemiology HSV CMV Pathogenesis VZV Diagnosis EBV Therapy HHV-6,7 HHV-8
Herpes Simplex Virus medicineworld.org Clinical CNS Syndromes HSV Encephalitis (HSE) Recurrent benign meningitis (Mollaret s) Neonatal HSV encephalitis
Epidemiology: HSV Encephalitis Commonest cause sporadic encephalitis > 6 mo No seasonal or gender variation Bimodal distribution 1/3 < 20 yrs, 1/2 > 50 yrs Infrequent : 1:250,000 population per yr USA Serotype: 96-99% HSV-1, 1-4% HSV-2 2/3 due to reactivation, 1/3 primary High incidence long term sequelae in survivors Without Rx: mortality 70% and only 9% survivors normal With Rx (IV ACV) mortality 19% at 6 mos, 30% survivors normal or mild defects
HSE: how does the virus access the CNS After Primary infection Animals: primary infection olfactory tract or trigeminal nerves to brain. In humans, pathways less clear After HSV reactivation: Sensory ganglia 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 Zhang Immunol Rev 2007 but is redundant for immunity to most other viruses.
Diagnosis of HSE I Altered LOC Clinical features CSF examination Fever CSF Headache pleocytosis and elevated protein HSV DNA in CSF detected by PCR Non invasive Personality studies change Neuroimaging :CT or MRI EEG Seizures: focal or general CSF viral culture: CSF WCC Dysphasia rarely usually positive lymphocytes in older children and adults HSE (4%) but higher yield in neonates (25-40%) Average pr Other 100mg/dl, CNS symptoms, increases as Ataxia, disease Brain biopsyprogressesautonomic dysfunction isolation of HSV, histopath, PCR CSF cell now count only for and atypical protein cases may or be immunocompromised normal early 5-10% CSF especially serologyin children for chronic disease or retrospective diagnosis: Maybe 4x elevated or > HSV CSF Ab Red in cell CSF count or serum to CSF to HSV IgG ratio: 20 usually after a month. Need albumin control to check integrity of blood brain barrier)
PCR for HSV DNA in HSE Changed understanding of symptoms/signs of HSE Monitoring of therapy Evaluate recurrence
HSE Clinical Manifestations and HSV DNA detection by PCR Dominigues et al, Clin Infect Dis 1997 Study of PCR with clinical presentations of HSE Grouped: Focal, Diffuse- dec LOC, neurobehavioural change, but no focal signs or imaging, Mild disease- GCS > 13 PCR Result Focal Patients n (%) Diffuse Mild Total HSV +ve 15 (52) 0 3 (25) 18 (37) HSV -ve 14 8 9 31 Total 29 8 12 49 (100)
HSE Bx-proven Vs PCR-proven Severity GSC >10 Personality 60% change Seizures Motor deficits Aphasia Bx-proven 35% 40% 33% 31% PCR-proven Milder cases ~ 80% 70-85% 50% 33% 75% Dominigues et al, Clin Infect Dis 1997
Duration of HSV DNA detection in HSE post onset of symptoms HSV DNA detectable for up to one week post onset of symptoms Revello et al, Clin Diag Virol 1997 False negative : V. early or late (>d 10) testing after 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 47% 21% PCR of CSF should be considered at completion of Rx Quantitative PCR Copy no/ ml >100- poorer prognosis in adult HSE Needs standardisation Lakeman et al, JID 1995
Rx and outcome HSE in children Rx intravenous aciclovir 10mg/kg/dose every 8 hours i.v. for (2 to) 3 weeks RCT 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 defects LOC at presentation Duration 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 Australia Mode of Presentation 97-07 APSU study 21% 18% 11% Jones, Isaacs, et al in prep. 3% 47% HSV-1 55% HSV-2 45% Skin, Eye, Mouth Disseminated alone Disseminated + CNS CNS alone Intrauterine 39% HSE Hydrancephaly, chorioretinitis, Scarring lesions at birth
Route of neonatal HSV infection http://www.spineguys.com/images/160w/52.gif www.irishhealth.com Intrauterine 3-5% HSV entry to CNS? Encephalitis alone: neuronal entry Disseminated disease: blood borne During delivery 85% Risk transmission 30-60% with 1º genital herpes www.thematrona.com/ practice.html Postnatal: 10%
Age at Presentation? CATEGORY All cases Mean (days) 8.0 RANGE 0-47 Skin, eye, mouth CNS alone Disseminated 3.6 12.0 3.5 0-28 10-28 1-13 Jones et al, unpublished observations. Neonatal APSU HSV study 1997-2007
Neonatal HSV Encephalitis Clinical 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 normal Mortality usually due to brain stem involvement, un Rx 50%. Good Response to Rx. Predictors: decreased LOC, prematurity, seizures Sequelae 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 Jones et al, unpublished observations, APSU 2005 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
Recommended Antiviral Rx Neonatal HSV Disease Aciclovir 20mg/kg/dose given 8 th 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 Not routinely recommended. Consider: preterm, frequent HSV- 2 recurrence Role of chronic suppressive antiviral therapy to prevent long term CNS sequelae under evaluation Ph II:Kimberlin PIDJ 1996 300 mg/m 2 3x/d 46% neutropenia (<1000x10 3 )
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 outcome Microcephaly (adjusted) most specific predictor, Abnormal head CT most sensitive predictor Long term motor disability Abnormal head CT strong, sensitive predictor chorioretinitis 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 CMV Long Term CNS Outcome? If no CNS abnormality by one year, unlikely to be at increased risk for subsequent neurodevel/cns impairment Prospective mother/infant studies Sweden Ivarsson et al, Pediatr 1997; Scand Infect Dis J 1999 USA 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%? Chorioretinitis Mild Late onset learning defects
Diagnosis CNS sequelae congenital CMV Newborn CMV isolation or PCR on specimens obtained in 1 st 3 weeks of life CMV IgM Neuroimaging Hearing screen Eye exam Dx after newborn period Retrospective dx CMV PCR on newborn screening card Neuroimaging, hearing, eye exam
Treatment Congenital CMV Infection Recommended for life or sightthreatening 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 VZV vascular Acute cerebellar syndromes-large and small vessel ataxia VZV vascular Large vessel wks/months after syndromes cutaneous syndrome, VZV encephalitis Rare- mostly in elderly but isolate CNS sequelae reports in infants/children post varicella from Congenital Dx: varicella CT/MRI syndrome shows infarct Pleocytosis, VZV PCR/Ab on CSF www.rch.org.au
VZV Acute cerebellar ataxia Rare: about 1:4000 children with VZV < 15 yrs Usually within 1 wk of rash, has occurred prior to onset of rash Viral replication vs immune mediated? VZV DNA in 3/5 children in one series VZV Ab usually negative CSF mild changes only, MRI usually normal Recovery the norm. Rare reports of persistent cerebellar defects Role of antiviral Rx unclear: if Rx IV aciclovir 500mg/m 2 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. IgG usually positive, and IgM neg
Summary HSV Encephalitis Immunogenetic markers in future PCR directed therapy Neonatal HSV disease High dose Rx for 3 weeks PCR directed Rx CMV Predictive factors at birth of poor CNS outcome More research needed to define use of ganciclovir to decrease CNS sequelae VZV Acute cerebellar ataxia: usually self limiting
Acknowledgements Neonatal HSV APSU study: Coinvestigators: D. Isaacs, A. Cunningham, S. Garland, P. McIntyre Contributors to the APSU APSU staff and sponsors