Congenital TORCH and Zika Infections Dorothy Bulas MD, FACR, FAAP Professor of Pediatrics and Radiology Children’s National Health Systems Disclosures: None
Learning Objectives
• Review the clinical presentation and imaging characteristics of various congenital CNS infections pre and postnatally • Discuss advances in radiologic evaluation of fetal and neonatal infections • Provide the latest updates regarding ZIKA virus • Understand unique imaging features to facilitate early diagnosis that may lead to prompt initiation of therapy
Congenital CNS Infections • TORCH = perinatal infections classically presenting with rash in mother and newborn ocular abn (cataracts, microphthalmia, chorioretinitis) • Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex Virus. • ‘Other’ - Syphilis, enteroviruses, varicella zoster , parvovirus B19. • Zika Virus, arthropod-borne flavivirus • intensely neurotropic targeting neural progenitor cells • severe CNS disorders; relative sparing of other organs
TORCH • Transmission rates vary among virus/parasite • Risk of Damage differs in-utero vs child/adulthood • Vertical transmission in 1st trimester differs from later transmission • ZIKA/RUBELLA high rate of 1st tri infection w/ severe neurologic abnormalities • By 12 wks GA when uteroplacental circulation established, placenta is sole barrier preventing microorganisms to access fetus.
TORCH - Nonspecific Findings
• IUGR, demise • Fetal Anemia, Heart Failure, Hydrops • Hepatosplenomegaly, hepatic calcifications (CMV) • Echogenic bowel
• Well seen by US TORCH - CNS Injury
• Developing brain sensitive to neurotropic organisms. • Tissue damage related to 1o insult- pathogen specific endotoxins & host inflammatory response. • If acquired 1st - early 2nd tri, can result in migration abnormalities, cortical disorganization, altered white matter myelination, microcephaly. • Destruction can lead to calcifications, cerebral volume loss. • Microcephaly particularly in 1st tri (However, up to 80% of HC<3% due to noninfectious etiology)
Calcifications
• Location can help distinguish types of infection • CMV - periventricular or cortical • ZIKA - grey white junction • TOXO - echogenic nodules on US • CMV, Rubella, Zika - Lenticulostriate vasculitis in basal ganglia US Evaluation Prenatal - Assess growth, hydrops, calcifications • May not be present early - calcifications • May not be detectable - cortical dysplasia • FU important – microcephaly evolution
Postnatal – • Germinolytic cysts, LS vasculopathy • Calcifications Fetal/ Neonatal MRI Evaluation
• T2w workhorse, EPI, T1, DWI, Volumetrics
• Different pathogen’s predilection for specific anatomic regions help narrow differential
• MRI effective in dx CNS infection plus suggesting specific agent
Cytomegalovirus • Most common intrauterine infection across the placenta. • 1% of newborns + serology, only 5-11% have findings of dz at birth. • Of those infected, 20% have cognitive disabilities or deafness. • Risk higher when acquired during pregnancy (10) than those prior to pregnancy (non1o/ reactivation). • Risk increases with inc GA but malformations greatest in 1st tri.
• 35,000 /yr asymptomatic. • 3-4000 /yr symptomatic = congenital CMV disease. • Risk - epilepsy, neurodev delay, CP, vision/sensorineural hearing loss • If asymptomatic, up to 25% still develop sequelae by 2 yo - sensorineural hearing loss. CMV Diagnosis
• Prenatal amniocentesis – after 6 wks of maternal infection and after 21 wks GA. • Postnatal - before 3 wks of age by urine or saliva CMV • After 3 wks - challenging dx as either congenital or postnatal. • • Rx Ganciclovir first 30 days - improves long-term audiologic and neurodevelopmental outcomes
CMV Neurotropic virus
• Hematogenously seeds choroid plexus • Replicates in ependyma, germinal matrix, capillary endothelium. • Germinal matrix involvement disrupts neuronal migration. Capillary involvement can lead to thrombosis, brain ischemia. • Cerebral calcification, ventriculomegaly, white matter disease, neuronal migrational disorders, microcephaly.
• Presence /severity vary based on timing.
CMV – in utero infection
• Early 2nd Trimester - agyria/pachygyria, cbl hypoplasia, VM. • Late 2nd Trimester - polymicrogyria, schizencephaly, mild VM • 3rd Trimester - no migrational abnormalities. • But myelin delay/destruction. WM focal, patchy, confluent. • WM abn signal posterior distribution, anterior temporal lobes, spare periventricular & subcortical WM • Periventricular cysts. • Cysts around ventricular system 2o to germinal matrix necrosis /hemorrhage.
CMV Calcifications
• 70% - CT- thick chunky, periventricular regions. • BUT can be fine/punctate any parenchyma, deep gray nuclei. • Nonspecific - other infections, ischemia, metabolic disorders.
• In isolation- cerebral calcifications, migrational abnormalities, white matter disease, and anterior temporal cysts are nonspecific • In combination- findings raise concern for CMV
ZIKA
• arthropod-borne Flavivirus - infected mosquito (Aedes species) • The first case identified in 1952. • Outbreaks since occurred throughout Africa, Latin America, Southeast Asia, and the Pacific Islands. • 2016 declared a global health emergency by WHO
ZIKA
• Maternal-fetal transmission any time throughout pregnancy • Greatest risk 1st trimester. • Neurotropic, gliotropic, targets neural progenitor cells • Neuronal growth, proliferation, migration, & differentiation disrupted • Microcephaly, hypertonia, hyperreflexia, seizures, arthrogryposis, ocular,sensorineural hearing loss. ZIKA
• Dx RNA infant serum, urine, or CSF collected w/in 2 days of life. • no specific Rx, vaccine being developed. • current outbreak has dissipated - no longer considered a global health emergency • remains important pathogen with serious complications ZIKA Imaging
• Disrupt normal brain development at any stage. - SPECTRUM • Microcephaly early; but observed in 3rd trimester and postnatally • atrophy, VM, subependymal pseudocysts occipital horns • polymicrogyria, gyral simplification, pachygyria-lissencephaly, opercular dysplasia • Cbl, vermian hypoplasia, large cisterna magna. • Corpus callosum - thin, dysgenesis, hypoplasia, absence • WM - delayed myelination or dysmyelination Zika Imaging
• Intraparenchymal calcifications -corticomedullary junction frontal parietal, thalamus, basal ganglia, cortex, periventricular • Calcifications at gray-white matter junction NOT described in other infections, ? vascular pathophysiology. • microphthalmia, cataracts, herniation of orbital fat
• normal HC doesn’t exclude infection Toxoplasmosis
• Protozoan parasite infects humans via ingestion of undercooked/cured meats containing viable tissue cysts; direct from cats, contaminated soil/water source • Present in every country. Seropositive 10 - 90% • 1 in 10,000 USA births ; 1 in 1000 births in endemic areas
• Often asymptomatic in immuno competent hosts. • Disease - immunosuppressed or transmission to fetus following 1o maternal infection.
Toxoplasmosis
• Risk of fetal infection inc w/ advancing GA, • but clinical severity decreases w/ advancing GA. • Triad - chorioretinitis, hydrocephalus, calcifications • triad RARE <10 %. • 70-90% have subclinical infection w/ normal neonatal exam. • Few have symptoms - hepatosplenomegaly, jaundice, seizures, lymphadenopathy, abnormal CSF, anemia. • BUT Ophthalmologic and CSF abnormal in 40%.
Toxoplasmosis
• Congenital Toxo (vs CMV) - higher incidence of chorioretinitis (85%), hydrocephalus. • Without Rx, symptomatic patients - 12% mortality. • High rate of intellectual disability, seizures, spasticity/palsies
• Need Serial samples, comparison with maternal serology. • Rx Pyrimethamine sulphonamide or spiamycin but variable efficacy • Timely dx facilitates early Rx may improve long term prognosis
Toxoplasmosis
• Calcifications - Focal regions of brain necrosis • nodular rather than punctate • (vs CMV periventricular/ZIKA gray white junction)
• Calcifications, VM, macro/microcephalus • parenchymal destruction/volume loss
• Periaqueductal and periventricular vasculitis and necrosis Hydrocephalus Toxoplasmosis Imaging
• Severity dependent on timing • Early 2nd Trimester - hydrocephalus, volume loss/ porencephaly, in utero necrosis result in dystrophic calcification • 3rd Trimester - mild atrophy, rare HC, smaller calcifications periventricular/parenchymal may resolve with Rx • In contrast to CMV, hydrocephalus frequently associated with toxoplasmosis, while migrational abnormality rare. Herpes Simplex Virus
• 1 : 3 -10,000 births, 1500/yr USA • Herpesviridae family, with properties of latency and reactivation. • Enters host through mucosal surfaces/skin breaks to infect sensory nerve endings, lifelong latent virus in dorsal root ganglia. • Both HSV-1 and HSV-2 can cause neonatal infection • Dx : HSV DNA in serum or CSF.
Herpes Simplex Virus • Can be acquired intrauterine, perinatal, postnatal. • Intrauterine - 5%, greatest risk during 1o maternal infection - fetal hydrops and demise. • Perinatal - 85% fetal contact via infected maternal genital tract
Herpes Simplex Virus
• Neonatal - presents in 1st 3 weeks of life • 3 forms: (1) skin, eyes,mouth (SEM) (2) CNS w/ without SEM (3) disseminated disease • SEM 45% may progress to disseminated dz if untreated, better outcome if Dx and Rx early. • CNS w / without SEM (30%) - encephalitis, seizures, lethargy, irritability, tremors, poor feeding, temperature lability. • Disseminated - sepsis-like (25%), multi-organ failure. Mortality if untreated > 80%
Herpes Simplex Virus
• Acyclovir therapy started empirically, early Rx improves survival outcomes • Even with Rx, survivors, have significant neurologic sequelae, including cerebral palsy, epilepsy, and developmental delay.
Herpes Simplex Virus Imaging
• Intrauterine – encephalomalacia, VM, scattered Ca++, microcephaly • Perinatal - Early US/MR may be normal. Underestimates injury • 1st week- MR edema, multifocal diffusion restriction, +/- hemorrhage • Later severe parenchymal destruction, cystic encephalomalacia, cortical thinning, atrophy, scattered Ca++, VM • Neonatal - NO predilection for temporal lobe and insular cortex (Unlike older pts), • Variable multifocal WM, cortical gray matter, basal ganglia, temporal lobe, watershed, rare brainstem and cerebellum. • Patchy parenchymal and meningeal enhancement Human Immunodeficiency Virus
• Decreasing in US, only 107 new dx in 2013. • But in Sub-Saharan Africa: 240,000 diagnosed. • Most acquired during delivery, Vertical transmission at any time during gestation, breastfeeding. • Prevent mother to child transmission via universal screening, reduce maternal viral load, administer neonatal antiretroviral prophylaxis, eliminate breastfeeding • Decreases risk of transmission from 25% to 1% Human Immunodeficiency Virus
• Often asymptomatic at birth. • Lymphadenopathy, hepatomegaly, oral candidiasis, FTT , developmental delay after 3 mos to 10 yrs of age • Opportunistic infections less frequent – pneumocystis, CMV • HIV encephalitis - spasticity, extremity weakness, microcephaly, seizures. • If untreated, developmental delay and milestone regression • High mortality rates, most die by 5 yo
HIV - Imaging
• Calcifications correlate w/ viral load - frontal lobe subcortical white matter (esp in-utero). • Late - fusiform vasculopathy, intracranial arterial ectasia, fusiform aneurysmal dilation. Hemorrhage / infarction, 1% stroke • 2O infections less common- CMV encephalitis, fungal, varicella zoster virus, progressive multifocal leukoencephalopathy (PML). • Rare Intracranial neoplasms - <5%.
Rubella
• Prior to vaccine, rubella world-wide pandemics. • Now rare in developed countries, decreasing in developing countries • Via blood-placental barrier during maternal viremia • Highest severity in 1st trimester. Miscarriage • If survives - Hearing loss, cataracts/glaucoma, cardiac, “blueberry muffin” rash, extramedullary hematopoiesis. • No directed therapy exists Rubella Imaging
• Brain imaging not specific - ischemia, microcephaly, sequelae of meningoencephalitis and vasculitis. • Early infection - near total brain destruction microcephaly. • Later infections VM, myelination abn, patchy frontal periventricular signal abnormality, similar to congenital CMV • Periventricular, basal ganglia calcifications,cystic change. • Abnormal skeletal metaphysis
Don’t forget MIMICS
If serology negative for TORCH (or other) congenital infection • Pseudo-TORCH syndrome (OCLN gene mutation) • Cockayne Syndrome, • Metabolic disorders (Biotinidase deficiency, Carbonic Anhydrase II deficiency) • Aicardi-Goutiéres syndrome. • Microcephaly - 80% due to noninfectious etiologies, toxic chemical/heavy metals, alcohol, smoking, genetic, IUGR