Congenital Infectious Encephalopathies Sarah B. Mulkey, M.D., Ph.D. Fetal-Neonatal Neurologist Fetal Medicine Institute, Children’s National Health System Assistant Professor of Pediatrics and Neurology George Washington University School of Medicine and Health Sciences Roberta L. DeBiasi, M.D., M. S. Chief, Division of Pediatric Infectious Diseases Co-Director Congenital Zika Program Children’s National Medical Center/ Children’s Research Institute Professor of Pediatrics and Microbiology, Immunology and Tropical Medicine George Washington University School of Medicine Disclosures • We have no conflicts of interest to report • Financial relationships: – Thrasher Foundation Award (Zika) – CDC Contract (Zika) – Ikaria Fund (Zika) – NIH/NIAD Collaborative Antiviral Study Group (CMV, HSV) Objectives 1. Discuss the term “TORCH” 2. Describe congenital infections from presentation, evaluation, diagnosis, and discuss prognosis 1. Cytomegalovirus 2. Lymphocytic Choriomeningitis Virus (LCMV) 3. Parvovirus B19 4. Toxoplasma 5. Zika virus 3. Recognize emerging infectious threats to the mother/fetus and infant Congenital infections • Are likely under-recognized • May not get treated • May be preventable in some cases • Can contribute to substantial abnormalities of the developing brain – Destructive lesions- intracranial hemorrhage, calcifications, reduced cerebral growth – Malformative lesions- schizencephaly, polymicrogyria, cortical dysplasia 100 120 2016 Top 25 Neurology Diagnoses Neurology 25 Top 2016 20 40 60 80 0 Ventriculomegaly Microcephaly/Small Head Absent Septum… Agenesis of the Corpus… etiologies infectious which in = Cases 5 ZIKV should be considered mega cisterna magna choroid plexus cysts Total cerebellar hypoplasia Intracranial Cyst Diagnosis by Cases Assymetric Ventricles Posterior Fossa… NTD, unspecified Macrocephaly Hypoplastic Vermis Dandy-Walker… Intraventricular… Spine Abnormality Holoprosencephaly Hypoplastic Corpus… Arachnoid Cyst Abnormal Brain Stem Delayed Cerebral… Myelomeningocele Aqueductal Stenosis Colpocephaly Perinatal Infection: “TORCH”- No longer works! • Toxoplasmosis • Term “TORCH” coined in • Other Agents 1971 – Hepatitis B – HIV • Introduction of “TORCH- – Parvovirus titers” – Varicella Zoster Virus (VZV) • Since then, new infectious – Lymphocytic Choriomeningitis Virus etiologies appreciated (LCMV) • “Other” list is very long – Enterovirus (EV) – Syphilis • TORCH is no longer – Zika virus (ZIKV) accurate since 2014! • Rubella • Cytomegalovirus (CMV) • Herpes Simplex Sequelae of Congenital Infections Sequelae Toxo Rubella CMV HSV EV Syphilis VZV HIV LCMV Zika Mental X X X X X X X X X X retardation Seizures X X X X X X X X X Blindness X X X X X X X X X X Deafness X X X X X X X Motor disability X X X X X X X X Learning X X X X X X X disability Limb deformity X X X Cardiac X X dysfunction Hepatic X dysfunction Endocrine X X dysfunction Discriminating CNS Abnormalities Sign Toxo Rub- CMV HSV EV Syph VZV Par HIV LCMV Zika ella -ilis -vo Microcephaly + + ++ + + + ++ Hydrocephaly ++ + + + + Calcifications ++5 ++6 + ++7 + ++8 Hearing loss + ++ ++ ++ + 5diffuse 6periventricular 7basal ganglia 8subcortical Comparison of cerebral calcifications in congenital infections Infection Cerebral Widely Periventricular Basal Gray white Cortical calcifications spread ganglia matter junction ZIKV +++ + +++ Toxo + +++ + Rubella Rare + CMV +++ ++ + ++ + = infrequent ++ = common finding +++ = Frequently reported and severe Levine D et al, 2017 Periventricular vs. Gray-white matter junction calcifications Congenital CMV Congenital ZIKV November 7, 2018 Case 1: Three week old infant with failed newborn hearing screen presents to ID clinic • CC: Evaluate for congenital CMV • HPI: . Born at term with birth weight 3.14kg by SVD. No complications of pregnancy or delivery. Failed hearing screen in right ear by ABR testing . Mother requested testing for congenital CMV infection Testing results - Infant • CMV PCR in urine at 2 weeks of age- positive (>1,000,000 copies) • CBC normal (no thrombocytopenia), CMP normal • Ophthalmology- normal exam with no evidence of chorioretinitis. • Repeat ABR performed- failure of right ear • Cranial US- multiple bilateral periventricular cysts and calcifications c/w congenital CMV infection • Brain MRI- subependymal cyst of the temporal horns of the lateral ventricles. Suspicious for polymicrogyria Imaging findings of congenital CMV Sagittal Cranial US- periventricular cysts (upper left image) and linear echogenic calcification (lower left image) Brain MRI- subependymal temporal horn cysts, also suspicious areas of polymicrogyria (upper right image-axial T2 and lower right coronal T1). Additional history • Father diagnosed with CMV infection when mother was pregnant at 8 weeks gestation – Asymptomatic – Elevated transaminases noted on routine lipid screening – CMV IgM positive and CMV IgG negative • Maternal testing results: (at 8 and 15 weeks gestation) – CMV IgM negative and CMV IgG positive – Mother was told she could not have CMV infection – No CMV IgG avidity testing performed in mother . Rubella immune/RPR NR/GBS/HIV/HepB/GC/Chlamydia negative Treatment - Infant • Oral valganciclovir 16mg/kg bid for 6 months – Kimberlin and NIH Collaborative Antiviral Study Group randomized trial, NEJM 2015 • Monitor for toxicity with CBC and CMP – Initially weekly, then spaced to monthly if no toxicities • F0rmal audiology evaluation to better evaluate hearing loss, to be repeated at least every 6 months • Neurology clinic evaluation • Follow up eye exam in 6 months CMV: Transmission • Passed from person to person through close contact with body fluids – Saliva – Semen, Vaginal fluid – Blood – Urine – Tears – Breast milk • Transmitted by contact with infected fluids by inoculation via mucous membranes (eyes, nose or mouth) • CMV also transmitted via sex, breastfeeding, blood transfusions and organ transplantation CMV Epidemiology • 50-80 % of adults in the United States have acquired CMV infection (seropositive) by age 40 – 40-60% in higher SES – 80% in lower SES • Most people who acquire primary CMV infection (adults and children post-natal) are completely asymptomatic • If symptomatic – Immunocompetent: • Mononucleosis syndrome, flu-like illness • Retinitis rare – Immunocompromised - severe • Bone marrow suppression, colitis (HIV) , retinitis, pneumonia CMV Exposure for Seronegative Pregnant Women • Daycare centers are a significant source of CMV infection. – Up to 70% excretion rates in children 1-3 years of age – Children <3 years of age with postnatally acquired CMV infection excrete CMV in their urine/saliva for 6 -42 months! • Seronegative mothers with children in group daycare are at significant risk of acquiring CMV infection • At least 50% seroconvert within 1 year of their child’s CMV infection • Preventative measures: – Hand Hygiene after diaper changes – Pregnant personnel should use universal precautions Congenital CMV: Epidemiology • Most common intrauterine/congenital infection – 1% of all live births affected – 9,000 infants per year in US – Economic burden > $2 billion annually US • Vertical transmission to fetus at any stage of gestation – Highest risk in first ½ of gestation – Primary maternal infection: • 50% transmission to fetus – Reactivation of infection: • 1% transmission to fetus • Pre-existing maternal immunity confers significant, but not full protection against congenital infection or disease Congenital CMV: Clinical Significance • Symptomatic at birth (10% of infected infants) – 40-60% with severe neurologic sequelae • Sensorineural deafness • Seizures • Mental retardation • Chorioretinitis, optic neuritis, micropthalmia • Microcephaly, polymicrogyria – 10% fatal in early infancy • Asymptomatic at birth (90% of infected infants) – 10-15% present later with neurological sequelae • Developmental Delay • Progressive sensorineuronal hearing loss • Congenital CMV infection is responsible for 20-25% of all cases of hearing loss in young children Congenital CMV: CNS malformation • Most critical period for malformations and disruptions is the third to eighth week of gestation – Microcephaly – Polymicrogyria • CMV infection in the third trimester can Microcephaly, abnormal gyral pattern cause encephalitis CNS Manifestations of Congenital CMV Infection ThinHydrocephalus cortical mantle, periventricular Periventricular calcifications calcifications Atrophic cortex, dilated ventricles, perventricular calcifications CNS Manifestations: Ocular CMV Chorioretinitis Cataract “Blueberry Muffin” Rash: Extramedullary Hematopoesis Congenital Cytomegalovirus: Lab Diagnosis • Must be diagnosed in first 3 weeks of life • CMV culture, shell vial, or PCR – Urine – Blood – CSF • Serology- less helpful – CMV IgG - maternal transfer – CMV IgM Screening for CMV in Pregnant Women • Still controversial in US • Neither ACOG or CDC recommend universal screening • Why? – Seropositivity does not rule out risk of infection to fetus • Reactivation, Infection with new strain – Dx of in utero CMV infection (using amniotic fluid PCR) does not necessarily predict symptomatic disease or sequelae – No established evidence in randomized trials for efficacy of preventing fetal CMV infection in pregnant patients – Maternal screening may cause undue anxiety – Not cost-effective unless treatment, such as CMV- specific hyperimmune IVIG, could result in >50% reduction of symptomatic infection Maniklal et al, CMR, 2013 Prenatal Serologic Dx of CMV in Mother • Knowing serostatus PRIOR to pregnancy is ideal • If CMV IgG and