Cytomegalovirus and Herpes Simplex Virus Infections in the Fetus And
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Thesis for doctoral degree (Ph.D.) 2010 Thesis for doctoral degree (Ph.D.) 2010 Cytomegalovirus and herpes simplex virus infections in the fetus and newborn infant, with regard to neurodevelopmental disabilities Cytomegalovirus and herpes simplex virus infections in the fetus and newborn and infant. in the virusfetus herpes infections and simplex Cytomegalovirus Mona-Lisa Engman Mona-Lisa Engman From Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden Cytomegalovirus and herpes simplex virus infections in the fetus and newborn infant, with regard to neurodevelopmental disabilities Mona-Lisa Engman Stockholm 2010 All previously published papers were reproduced with permission from the publisher. Cover: Picture published with permission from Dr Hong Zhou, Deartment of Pathology, Texas University, Houston, USA. Published by Karolinska Institutet. Printed by Reproprint AB © Mona-Lisa Engman, 2010 ISBN 978-91-7409-922-5 Printed by 2010 Gårdsvägen 4, 169 70 Solna To my beloved son Andreas ABSTRACT The congenital cytomegalovirus infection (CMV) is the most common congenital infection causing childhood morbidity. The majority (85%) of infected infants have no signs of infection in the newborn period, and when sequelae such as a hearing deficit or neurological impairment manifest themselves, the possibility of a CMV infection is easily overlooked. Neonatal herpes simplex virus (HSV) infection is a rare but devastating infection. Improvements with regard to outcome have been achieved by antiviral treatment, but the morbidity remains unacceptably high in children following neonatal HSV encephalitis. The general aim of the thesis is to increase the knowledge of childhood morbidity related to CMV and HSV infections. In the first study the prevalence of congenital CMV infection in a Swedish cohort and the increased risk of hearing deficit in infants with congenital CMV infection compared to uninfected infants were investigated. The results revealed that two infants of 1000 were born with congenital CMV infection and that the risk of congenital hearing deficit in infected infants was 21 times higher than in uninfected ones in this cohort. In study II neurological morbidity associated with a congenital CMV infection is studied by retrospectively performed diagnosis in children with neurological morbidity on the basis of cerebral cortical malformations. The results revealed that four out of 26 children had a congenital CMV infection but only one had any symptoms suggesting a congenital infection in the neonatal period. Two of the children developed severe disabilities with mental retardation, autism, spastic cerebral palsy and deafness. A third child had epilepsy and unilateral cerebral palsy, while the fourth had a coordination dysfunction and hearing deficit. Parental reactions in conjunction with screening was evaluated and the results showed that parents of infants with a false positive screening test remained worried about the child’s current and future health after receiving a normal confirmatory test. No difference was found for anxiety and traumatic stress comparing parents to true positive infants, false positive infants and controls. In study IV, the neuropsychological outcome after neonatal HSV encephalitis was evaluated. The findings revealed that a considerable proportion of the children had cognitive impairments in combination with attention deficits and difficulties with expressive speech. In addition one child with a low average intellectual function suffered a relapse and was subsequently found to have severe mental retardation. We conclude that congenital CMV infection should be considered in children with hearing deficit or cerebral cortical malformations of unknown origin. If treatment options improve and hearing can be preserved by antiviral treatment, screening could be an option to identify infants at risk. The parents of infants with a false positive screening have been identified as a vulnerable group that requires follow-up as well as parents of true positive infants. Neuropsychological assessment is essential in the habilitation of the child with neonatal HSV encephalitis and is a tool to monitor deterioration of cerebral function related to relapses. LIST OF PUBLICATIONS I. Engman M-L, Malm G, Engström L, Petersson K, Karltorp E, Teär- Fahnehjelm K, Uhlén I, Guthenberg C, Lewensohn-Fuchs I. Congenital CMV infection: Prevalence in newborns and the impact on hearing deficit. Scandinavian Journal of Infectious Diseases 2008;40:935-942. II. Engman M-L, Lewensohn-Fuchs I, Mosskin M, Malm G. Congenital cytomegalovirus infection, the impact of cerebral cortical malformations. Submitted. III. Engman M-L, Malm G, Lewensohn-Fuchs I, Boman K. Parental psychological reactions in response to neonatal screening for congenital cytomegalovirus infection. Submitted. IV. Engman M-L, Adolfsson I, Lewensohn-Fuchs I, Forsgren M, Mosskin M, Malm G. Neuropsychologic outcomes in children with neonatal herpes encephalitis. Pediatr Neurol 2008,38.398-405. CONTENTS 1 Introduction ................................................................................................... 1 1.1 TORCH infections .............................................................................. 1 1.1.1 Congenital toxoplasmosis ...................................................... 1 1.1.2 Congenital rubella .................................................................. 1 1.1.3 Congenital cytomegalovirus infection ................................... 2 1.1.4 Neonatal herpes simplex virus infection ................................ 2 1.2 Herpes viruses ..................................................................................... 2 1.3 Immune defence .................................................................................. 4 1.3.1 Innate immune defence .......................................................... 4 1.3.2 Adaptive immune defence...................................................... 4 1.3.3 Immune defence against viral brain infections ...................... 5 1.4 Brain development .............................................................................. 5 1.5 Cerebral cortical malformation .......................................................... 7 1.6 Neurological dysfunction ................................................................... 8 1.7 Hearing deficit .................................................................................... 8 1.8 Cytomegalovirus infections ................................................................ 9 1.8.1 Epidemiology ......................................................................... 9 1.8.2 Clinical manifestations in pregnant mothers ....................... 10 1.8.3 Clinical manifestations in the neonate ................................. 10 1.8.4 Permanent disabilities........................................................... 10 1.8.5 Diagnosis .............................................................................. 11 1.8.6 Treatment .............................................................................. 13 1.8.7 Prevention ............................................................................. 14 1.8.8 Screening .............................................................................. 15 1.9 Herpes simplex virus infections ....................................................... 15 1.9.1 Epidemiology ....................................................................... 15 1.9.2 Clinical manifestations in pregnant mothers ....................... 16 1.9.3 Clinical manifestations in the neonate ................................. 16 1.9.4 Permanent disabilities........................................................... 17 1.9.5 Diagnosis .............................................................................. 18 1.9.6 Treatment .............................................................................. 19 1.9.7 Prevention ............................................................................. 20 2 Aim .............................................................................................................. 21 2.1 General aim ....................................................................................... 21 2.2 Specific aims ..................................................................................... 21 3 Methods....................................................................................................... 22 3.1 Design and subjects .......................................................................... 22 3.1.1 Studies I and III .................................................................... 22 3.1.2 Study II ................................................................................. 24 3.1.3 Study IV ................................................................................ 24 3.2 Assessments ...................................................................................... 25 3.2.1 Studies I and II ...................................................................... 25 3.2.2 Study I ................................................................................... 26 3.2.3 Study III ................................................................................ 27 3.2.4 Study IV ................................................................................ 30 3.3 Statistics ............................................................................................. 31 3.4 Ethical