Clinical and neurodevelopmental features in children with cerebral palsy and probable congenital Zika.

OBJECTIVE: To describe the neurological and neurodevelopmental features at 1 year of age in children with cerebral palsy (CP) related to probable congenital Zika (CZ), followed in a referral neurorehabilitation hospital. METHODS: Data on 82 children with CP associated with probable CZ, who consecutively attended the neurodevelopmental and neurological assessment around one year of age, were collected. For neurodevelopmental evaluation, Bayley-III Scales of Infant and Toddler Development was used. Descriptive statistical analysis was performed. RESULTS: The children were admitted into the rehabilitation program at a young age (mean age: 4.8 months, SD 3.1), followed beyond the first year of life (mean age of follow up: 13.2 months, SD 2.1), born to young mothers (mean age: 28.1 years, SD 5.9), in their first pregnancy (62.2%). The majority had severe congenital microcephaly (62.0%), spastic CP (96.3%), epilepsy (63.4%), absent expected postural reactions (93.2%), abnormal persistence of primitive reflexes (94.7%), and severe neuroimaging abnormalities, predominantly calcifications (97.6%). Extremely low performances on cognitive (95.1%), language (97.6%) and motor (97.6%) developmental composite scores were observed. There was a correlation between the cognitive score with the birth head circumference (HC) (r = 0.3, p = 0.01) and with the follow up HC (r = 0.4, p < 0.01), as well as between the follow up HC with the motor score (r = 0.2, p = 0.03). CONCLUSION: Congenital Zika may be associated with a severe form of CP, mainly bilateral spastic, with a severe global neurodevelopmental impairment and early signs of a poor prognosis for independent walking. Head circumference may be a prognostic marker among those children. These results may help establish goals for the rehabilitation program and identify priority health services.

Economic cost of congenital CMV in the UK.

OBJECTIVE: Congenital cytomegalovirus (cCMV) is the most common infectious cause of congenital disability. It can disrupt neurodevelopment, causing lifelong impairments including sensorineural hearing loss and developmental delay. This study aimed, for the first time, to estimate the annual economic burden of managing cCMV and its sequelae in the UK. DESIGN: The study collated available secondary data to develop a static cost model. SETTING: The model aimed to estimate costs of cCMV in the UK for the year 2016. PATIENTS: Individuals of all ages with cCMV. MAIN OUTCOME MEASURES: Direct (incurred by the public sector) and indirect (incurred personally or by society) costs associated with management of cCMV and its sequelae. RESULTS: The model estimated that the total cost of cCMV to the UK in 2016 was £732 million (lower and upper estimates were between £495 and £942 million). Approximately 40% of the costs were directly incurred by the public sector, with the remaining 60% being indirect costs, including lost productivity. Long-term impairments caused by the virus had a higher financial burden than the acute management of cCMV. CONCLUSIONS: The cost of cCMV is substantial, predominantly stemming from long-term impairments. Costs should be compared against investment in educational strategies and vaccine development programmes that aim to prevent virus transmission, as well as the value of introducing universal screening for cCMV to both increase detection of children who would benefit from treatment, and to build a more robust evidence base for future research.

Congenital Cytomegalovirus among Children with Cerebral Palsy.

OBJECTIVES: To determine the proportion of children with cerebral palsy (CP) and cytomegalovirus (CMV) DNA detected retrospectively in their newborn screening cards (NBSC), to compare the proportion of children with CMV DNA in their NBSC across spastic subtypes of CP, and to compare the sex and other characteristics of children with CP and CMV detected on their NSBC with those in whom CMV DNA was not detected. STUDY DESIGN: Retrospective observational study. Data were extracted from patient records on children with CP (birth years 1996-2014) from 2 Australian state CP registers and state-wide paediatric rehabilitation services with consent. NBSCs were retrospectively analyzed for CMV DNA by nested polymerase chain reaction (PCR) using primers against gB. Positive samples were validated using real time PCR for CMV UL83. RESULTS: Of 401 children recruited, 323 (80.5%) had an available NBSC. Of these, 31 (9.6%; 95% CI, 6.8-13.3) tested positive for CMV DNA by nested PCR for CMV gB, of whom 28 (8.7%; 95% CI, 6.1-12.2) also had CMV DNA detected by real-time PCR for CMV UL83. Detection of CMV DNA was significantly associated with epilepsy, but not with clinical or epidemiologic characteristics, including sex and pattern of spasticity. CONCLUSIONS: CMV viremia in the newborn period, indicating congenital CMV infection, is highly prevalent among children with CP. Further research is needed to investigate the mechanisms and contribution of congenital CMV to the causal pathways to CP.

Clinical features of cerebral palsy in children with symptomatic congenital cytomegalovirus infection.

BACKGROUND: Human cytomegalovirus is the most common cause of vertically transmitted viral infection, affecting around 1% of liveborns. Infection is symptomatic in nearly 10% of infected children who are at higher risk of development of severe neurological disorders, including cerebral palsy. AIMS: To study the clinical profile of children with cerebral palsy caused by symptomatic congenital cytomegalovirus infection in a multicenter study involving six countries from the Surveillance of Cerebral Palsy in Europe (SCPE) Network. METHODS: Data on 35 children (13 males, 22 females; mean age at last assessment 12y 6mo, age range 14y 6mo, min 4y, max 18y 6mo) on pre/peri/neonatal history and last clinical assessment were collected. Classification of cerebral palsy and associated impairments was performed according to SCPE criteria. RESULTS: The majority of children had bilateral spastic cerebral palsy, 85.7%, with a confidence interval (CI) [69.7-95.2], and 71.4% [CI 53.7-85.4] were unable to walk (GMFCS levels IV-V) while fine motor function was severely affected in 62.8% [CI 44.9-78.5] (BFMF levels IV and V). Most of the children with severe CP had severe associated impairments. 11.4% of children had severe visual and 42.8% severe hearing impairment, 77.1% [CI 59.9-89.6] suffered from epilepsy, also 77.1% had severe intellectual impairment, and speech was undeveloped in 71.4%. Female:male ratio was 1.69:1 and 80% of children were term born. CONCLUSIONS: Cerebral palsy following symptomatic congenital cytomegalovirus infection seems to be in most cases a severe condition and associated impairments are overrepresented.

Spastic diplegia in children with HIV encephalopathy: first description of gait and physical status.

AIM: The aim of this study was to explore the physical status and gait patterns of children with spastic diplegia secondary to human immunodeficiency virus encephalopathy (HIVE). METHOD: A cross-sectional study was conducted on children diagnosed with HIVE and spastic diplegia. Sociodemographic and clinical background information was obtained, followed by three-dimensional gait analysis (3DGA) and a physical examination including assessments of muscle tone, strength, motor control, contractures, and bony deformities of the lower extremities. RESULTS: Fourteen children (eight males, six females; mean age 5 y 8 mo [SD 9 mo], range 4 y 4 mo-6 y 10 mo) were studied. The cohort was divided into two groups based on distinctive gait patterns. Nine participants in group I showed only limited abnormalities. Group II displayed a more pathological gait pattern including stiff knee and equinus ankle abnormalities. Results of 3DGA, as with the physical examination outcomes, showed increased impairments from proximal to distal (except for hip extension). INTERPRETATION: This study provides a first description of distinctive gait patterns and related physical characteristics of children with HIVE and spastic diplegia. Further research is necessary.

The role of parvovirus in the etiology of somatic pathology.

The scope of the present research was to study parvovirus circulation in Tbilisi population and its role in etiology of somatic pathologies. Parvovirus circulation in persons with autism and disorder of the nervous system was examined. Blood of 110 patients was examined. Among them 35 were children (up to 15 years old) and 75 adults, mainly with different somatic pathologies such as mineral metabolism disorder, allergic reactions, cystic fibrosis, cerebral palsy and autism. Almost all the children came from the so called frequently ill category and suffered from disbacteriosis. Among adults, 16 were parents of the ill children, while the rest came with hepatitis, mineral metabolism disorder of different type and psoriasis. Blood serum of 30 adults was taken as an adult control group. Their age varied from 18 to 25 years. 10 children aged 2-15 constituted a children control group. Preventive examination was made and there were practically, absolutely healthy persons. A total of 150 persons were involved in the research. Frequency of parvoviral antibody detection in the ill children and adults is much higher than in healthy individuals. Consequently, positive results for the presence of M and G immunoglobulins in children equals to 54% and 85% respectively. In adults these indicator stand at 24% and 60% respectively. At the same time in 25% and 70% of parents of positive children were found to be positive for M immunoglobulin and G immunoglobulin respectively. Thus our investigation made it clear that parvoviral infection actively circulates in Georgia. The present research did not study manifested parvoviral infection, i.e. 5th disease. If it had than the number of positive results probably would have been much higher. In autistic children presence of parvoviral infection is consistent with the literature data.

Influenza-B associated rhabdomyolysis and acute renal failure.

We present a 15 year old boy who developed severe rhabdomyolysis and acute renal failure following influenza B infection. His renal function was restored after appropriate therapy for rhabdomyolysis. Although rapidly progressive pneumonia, respiratory failure, and acute respiratory distress syndrome are the most common severe complications of influenza B infection, clinicians should be aware that influenza B may be complicated with rhabdomyolysis and acute renal failure in children.

Cytomegalovirus and Epstein-Barr virus may be associated with some cases of cerebral palsy.

OBJECTIVE: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. METHODS: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. RESULTS: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71-2.76)]. CONCLUSION: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.

Genetic susceptibility to viral exposure may increase the risk of cerebral palsy.

AIM: Cytokine polymorphisms may alter the fetal inflammatory response, increasing susceptibility to cerebral palsy (CP). This study investigates associations between selected inflammatory mediator and cytokine gene polymorphisms (Toll-like receptor-4 (TLR-4) Asp299Gly, interleukin-6 G-174C and interleukin-4 C-589T) and CP from 443 CP infants and 883 control infants. Results were correlated with viral nucleic acids in the same samples. RESULTS: At all gestational ages (GA), TLR-4 was associated with a decreased risk of developing CP (homozygous/heterozygous odds ratio (OR) 0.70, 95% confidence interval (CI) 0.50-0.98) and interleukin (IL)-6 was associated with an increased risk of developing hemiplegia (OR 1.38, 95% CI 1.05-1.83). For infants born 32-36 weeks GA, there was a tenfold increase in the risk of quadriplegic CP with homozygous/heterozygous IL-6 (OR 10.42, 95% CI 1.34-80.82). Viral exposure in combination with IL-4 in preterm infants was associated with a fourfold increased risk of quadriplegia (homozygous/heterozygous OR 4.25, 95% CI 1.21-14.95). In very preterm infants, the absence of detectable viral exposure in combination with IL-4 decreased the risk of developing CP (homozygous/heterozygous OR 0.31, 95% CI 0.13-0.76). CONCLUSION: Polymorphisms in TLR-4 may be associated with a decreased risk of CP. Polymorphisms in IL-6 or IL-4 may act as susceptibility genes, in the presence of viral exposure, for the development of hemiplegic and quadriplegic CP. These associations require confirmation but they suggest a hypothesis for CP causation due to double jeopardy from neurotropic viral exposure and genetic susceptibility to infection.

Association between Apolipoprotein E genotype and cerebral palsy is not confirmed in a Caucasian population.

Apolipoprotein E (APOE) plays a significant role in lipid metabolism and has been implicated in the growth and repair of injured neurons. Two small studies have suggested an association between APOE genotype and cerebral palsy. We investigated if APOE genotype is associated with an increased risk for cerebral palsy, influences the type of cerebral palsy or interacts with prenatal viral infection to influence risk of cerebral palsy. The population-based case-control study comprised newborn screening cards of 443 Caucasian patients with cerebral palsy and 883 Caucasian matched controls. APOE genotyping was performed on DNA extracted from dried blood spots. Allelic and genotypic frequencies did not differ between cases and controls and combined frequencies were 0.10 (epsilon2), 0.76 (epsilon3), 0.14 (epsilon4), 0.03 (epsilon2/epsilon2), 0.10 (epsilon2/epsilon3), 0.03 (epsilon2/epsilon4), 0.02 (epsilon4/epsilon4), 0.21 (epsilon3/epsilon4), 0.61 (epsilon3/epsilon3). APOE genotype was correlated with cerebral palsy, type of cerebral palsy, gestation at birth and the presence of viral nucleic acids detected in previous work. Analysis by gestational age (all gestational ages, >/=37, 32-36 and <32 weeks) and type of cerebral palsy (all types, diplegia, hemiplegia and quadriplegia) showed no association between APOE genotype and cerebral palsy in this Caucasian population. An association between prenatal viral infection, APOE genotype and cerebral palsy was not demonstrated. These results did not confirm an association between APOE genotype, cerebral palsy, type of cerebral palsy and prenatal infection in a Caucasian population. Given the low frequency of APOE epsilon2 and some of the heterozygote and homozygote combinations in this study, a larger study is assessing this further.

Secondary cytomegalovirus infection can cause severe fetal sequelae despite maternal preconceptional immunity.

OBJECTIVES: To describe our experience in cases with sonographic signs of fetal infection and with maternal serological 'immunity' to cytomegalovirus (CMV) infection. METHODS: This was a bicenter study of six pregnant women referred for evaluation of suspected fetal infection. All cases had confirmed maternal serology for past exposure to CMV but no evidence of recent secondary CMV infection. All underwent sonographic evaluation as well as complete investigation for CMV infection. RESULTS: The mean age of the women was 29 (range, 23-35) years and the mean gestational age at diagnosis was 23.5 weeks (range, 20-31) weeks. Sonographic findings included microcephaly, ventriculomegaly, periventricular calcifications and cystic lesions, echogenic bowel, hydrops and hepatosplenomegaly. Amniocentesis was performed in all cases for fetal karyotyping and viral assessment, and all were found by polymerase chain reaction to be positive for CMV infection. Four pregnancies were terminated following the parents' request. One pregnancy continued until intrauterine fetal death occurred 2 weeks after diagnosis. Postmortem was denied in all cases but one. One infant was delivered with evidence of severe cerebral palsy. CONCLUSION: In the presence of sonographic findings suggestive of fetal CMV infection, prompt investigation of amniotic fluid should follow even if maternal serology does not support recent maternal seroconversion.

Neurotropic viruses and cerebral palsy: population based case-control study.

OBJECTIVE: To investigate the association between cerebral palsy and direct evidence for perinatal exposure to neurotropic viruses. DESIGN: Population based case-control study. SETTING: Adelaide Women's and Children's Hospital Research Laboratory. PARTICIPANTS AND MAIN OUTCOME MEASURES: Newborn screening cards of 443 white case patients with cerebral palsy and 883 white controls were tested for viral nucleic acids from enteroviruses and herpes viruses by using polymerase chain reaction. Herpes group A viruses included herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 8 (HHV-8), and herpes group B viruses included varicella zoster virus (VZV) and human herpes viruses 6 and 7 (HHV-6 and HHV-7). RESULTS: The prevalence of viral nucleic acids in the control population was high: 39.8% of controls tested positive, and the prevalence was highest in preterm babies. The detection of herpes group B viral nucleic acids increased the risk of developing cerebral palsy (odds ratio 1.68, 95% confidence interval 1.09 to 2.59). CONCLUSIONS: Perinatal exposure to neurotropic viruses is associated with preterm delivery and cerebral palsy.

Brachial amyotrophic diplegia in a patient with human immunodeficiency virus infection: widening the spectrum of motor neuron diseases occurring with the human immunodeficiency virus.

Although amyotrophic lateral sclerosis and progressive spinal muscular atrophy have been recognized to occur in association with human immunodeficiency virus infection, to our knowledge, brachial amyotrophic diplegia, a form of segmental motor neuron disease, has not been previously reported. Brachial amyotrophic diplegia results in severe lower motor neuron weakness and atrophy of the upper extremities in the absence of bulbar or lower extremity involvement, pyramidal features, bowel and bladder incontinence, and sensory loss. We describe a human immunodeficiency virus-seropositive man without severe immunosuppression or prior AIDS-defining illnesses who had brachial amyotrophic diplegia. This disorder may represent one end of a spectrum of motor neuron diseases occurring with this retrovirus infection.

Intrapartum fetal heart rate monitoring in cases of cytomegalovirus infection.

OBJECTIVE: Several studies have shown that abnormal intrapartum fetal heart rate patterns are the results from pre-existing fetal brain damage. We evaluated intrapartum fetal heart rate pattern of cytomegalovirus-infected fetuses and correlated the patterns with neurologic outcomes. STUDY DESIGN: Between 1991 and 2001, there were 20 cytomegalovirus-infected fetuses. We selected 40 fetuses as control subjects that were matched for gestational age and birth weight. Fetal heart rate was interpreted according to the guidelines of the National Institute for Child and Human Development. The incidence of abnormal fetal heart rate pattern and umbilical blood gases were compared between both groups. We also investigated the factors that contributed to abnormal fetal heart rate pattern in the cytomegalovirus group. RESULTS: Nonreassuring fetal heart rate patterns (prolonged deceleration and recurrent late deceleration) were observed in 8 of 20 fetuses (prolonged deceleration, 7 fetuses; recurrent late deceleration, 1 fetus) in the cytomegalovirus group and in 3 of 41 fetuses (prolonged deceleration, 1 fetus; recurrent late deceleration, 2 fetuses) in the control group (P<.05, Fisher test). Baseline fetal heart rate variability was minimal in 4 of the 7 prolonged deceleration cases in the cytomegalovirus group. Umbilical pH <7.1 was found for 1 fetus in the cytomegalovirus group. The average umbilical arterial pH values were similar in both the groups. In the cytomegalovirus group, there were no differences in the incidence of contributing factors between 8 fetuses with abnormal fetal heart rate pattern (prolonged deceleration and recurrent late deceleration) and 8 fetuses with no change. There were 3 fetuses with cerebral palsy: 2 fetuses in the no change group and 1 fetus in the prolonged deceleration group. Antigenemia was positive exclusively in 4 cases with abnormal fetal heart rate pattern (P<.05). CONCLUSION: Cytomegalovirus-infected fetuses are more likely to show abnormal intrapartum fetal heart rate patterns than low-risk control fetuses, which suggests that the perinatal detection of cytomegalovirus is necessary to distinguish hypoxic-ischemic encephalopathy.

Unselected low-risk pregnancies and the effect of continuous intrapartum fetal heart rate monitoring on umbilical blood gases and cerebral palsy.

OBJECTIVE: Our purpose was to evaluate the clinical validity of electronic fetal heart rate monitoring to detect fetal acidemia and to evaluate the prevalence of cerebral palsy in unselected low-risk pregnancies. STUDY DESIGN: We selected two secondary and two tertiary level institutions in which 10,030 infants were born. Among them, 5546 of the pregnancies were low-risk pregnancies by antepartum evaluation. The fetal heart rate patterns were interpreted according to the guidelines of the National Institute of Child Health and Human Development. The correlations between the fetal heart rate pattern and umbilical blood gases and the fetal heart rate pattern and cerebral palsy were studied. Spastic cerebral palsy was diagnosed at > or =1 year by pediatric neurologists. Statistics included unpaired t test, contingency table with chi(2) and Fisher tests, and one-way analysis of variance with Bonferroni/Dunn test. RESULTS: On the basis of the severity of decelerations, frequency of decelerations, and decreased variability, umbilical pH, and Po(2) level were decreased accordingly, and incidence of pH<7.1 was increased. Sensitivity and false-positive rate of nonreassuring fetal heart rate patterns for fetal acidemia were 63% and 89%. There were nine cerebral palsy cases: six of the cases were preexisting asphyxia before monitoring was initiated, two of the cases were cytomegaloviral infections, and one of the cases was a maternal amniotic fluid embolism. CONCLUSION: In low-risk pregnancies, intrapartum fetal heart rate monitoring was useful to detect fetal acidemia. Cerebral palsy caused by intrapartum asphyxia was restricted to unavoidable accidents under continuous fetal heart rate monitoring.

Children with human immunodeficiency virus admitted to a paediatric intensive care unit in the United Kingdom over a 10-year period.

OBJECTIVE: There is little published experience regarding the outcome of children with human immunodeficiency virus (HIV) infection treated on a paediatric intensive care unit (PICU). We describe the outcome of children with HIV infection in our hospital over a 10-year period. METHOD: We performed a retrospective analysis of all children with HIV infection admitted to our PICU between August 1992 and July 2002. Their ages ranged from 2 months to 11 years (median 4 months). Information collected included demographic data, clinical presentation, investigations, treatment and outcome. RESULTS: There were 42 children with HIV infection admitted to PICU during the study period, with 66 admission episodes. Sixteen (38%) children died in PICU, and 26 (62%) survived their last PICU admission. Of these, 5 died at a later date (between 1 and 32 months after discharge from PICU) and 21 survived to the time of reporting. The most frequent reason for PICU admission was respiratory failure, due either to Pneumocystis carinii pneumonia (45% of admissions) or to other respiratory pathogens (32%). Over 80% of current survivors had good outcomes in terms of growth and development; 6 children had evidence of spastic diplegia. CONCLUSIONS: Although there is significant mortality among children with HIV infection admitted to PICU, many of them survive their admission, and over 80% of the survivors have good outcomes with the currently available highly active anti-retroviral therapy. This provides evidence that intensive care treatment is appropriate for this group of patients in the United Kingdom.

Early predictors of neurodevelopmental outcome in symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To determine the ability of neonatal clinical, audiologic, and computed tomography (CT) findings to predict long-term neurodevelopmental outcome in children with symptomatic congenital cytomegalovirus (CMV) infection. METHODS: Longitudinal cohort study of children (n = 41) with symptomatic congenital CMV infection evaluated at birth and followed up with serial age-appropriate neurodevelopmental testing. The performance of birth characteristics as predictors of long-term outcome were determined, and clinical and CT scoring systems were developed and correlated with intellectual outcome. RESULTS: Microcephaly was the most specific predictor of mental retardation (100%; 95% CI 84.5-100) and major motor disability (92.3%; 95% CI 74.8-99). An abnormality detected by CT was the most sensitive predictor for mental retardation (100%; 95% CI 82.3-100) and motor disability (100%; 95% CI 78.2-100). A highly significant (P <.001) positive correlation was found between head size at birth and the intelligence/developmental quotient (IQ/DQ). Approximately 29% of children had an IQ/DQ >90. There was no association between sensorineural hearing loss at birth and cognitive outcome. However, children with sensorineural hearing loss on follow-up (congenital and late-onset) had a lower IQ/DQ (P =.006) than those with normal hearing. CONCLUSIONS: The presence of microcephaly at birth was the most specific predictor of poor cognitive outcome in children with symptomatic congenital CMV infection, whereas children with normal findings on head CT and head circumference proportional to weight exhibited a good cognitive outcome.