Clinical profile of children with cerebral palsy born term compared with late- and post-term: a retrospective cohort study.

OBJECTIVE: To determine whether cerebral palsy (CP) risks factors, neurological subtype, severity and co-morbidities differ between early/full-term-born children with CP compared with those born late/post-term. DESIGN: Retrospective cohort study. SETTING: Children with CP born between 1998 and 2014, residing in Canada, and registered in the Canadian Cerebral Palsy Registry (CCPR) (n = 1691), a database with information from 15 participating centres across six Canadian provinces. POPULATION: Children with CP from the CCPR born at 37 weeks of gestation and later (n = 802). METHODS: The clinical profile of children with CP born at 37-40 weeks of gestation was compared with those born at 41 weeks and later using the Pearson chi-square test (or Fisher's exact test) for univariate analyses of categorical data. A P value <0.05 was considered significant a priori. MAIN OUTCOME MEASURES: CP neurological subtype, Gross Motor Function Classification System (GMFCS) severity, risk factors and co-morbidities. RESULTS: Neonatal encephalopathy was found in 23.9% of children with CP born early/full-term and in 33.6% of those born late/post-term (P = 0.026). Neonatal hyperbilirubinaemia was found in 10.2% of children born in the earlier period and in 2.6% of those born in the later period (P = 0.008). Apgar score at 5 minutes, but not 10 minutes, was significantly higher in the early/full-term group (9) compared with its late/post-term counterpart (7; P = 0.046). Rates of CP subtype, severity (GMFCS) and co-morbidities did not differ significantly between the two gestational periods. CONCLUSIONS: In children with CP, neonatal encephalopathy was significantly less frequent and neonatal hyperbilirubinaemia was significantly more frequent in those born early/full-term compared with their later-born counterparts. However, clinical outcomes of CP were not significantly different between these two gestational epochs. TWEETABLE ABSTRACT: Children with cerebral palsy born early/full-term have similar outcomes to those born late/post-term.

Rehabilitation service utilization in children and youth with cerebral palsy.

AIM: To describe the pattern of use of rehabilitation services in children and adolescents with cerebral palsy (CP), and to identify factors associated with use. METHODS: In this study, parents of 91 school-age children and 167 adolescents with CP completed a questionnaire regarding educational and rehabilitation resources received within the last 6 months. Rehabilitation services included occupational therapy (OT), physical therapy (PT), speech language pathology (SLP), psychology and special education. Demographic characteristics were documented and developmental and functional status was assessed. Relationships between service utilization and sociodemographic factors, functioning and school setting were determined. RESULTS: Over half of children (53.2%) and adolescents (57.5%) were in regular schools; however, 41% of these required special education resources. The remainder (42.5-46.8%) was in special schools. The majority of children (84.6%) were receiving at least one rehabilitation service although this decreased (68.1%) in adolescence. PT and OT were most common and services were provided predominantly in the school setting. Services were primarily weekly direct interventions at school age, with weekly interventions or consultations most common for adolescents. Younger age was associated with service receipt at school age only. Children with greater motor limitations, lower IQ and greater activity limitations were more likely to receive OT, PT, SLP or special education. Children in segregated schools were significantly more likely to receive rehabilitation services, when compared with children in regular schools. CONCLUSIONS: The majority of children and youth received one or more services. Individuals with greater motor or cognitive challenges were more likely to receive a range of school-based services from rehabilitation specialists. When compared with children of school age, adolescents were less likely to receive services and when provided, services were more likely to be consultative. Services may need to be more optimally organized through childhood to enhance benefits to children with CP across activity limitation profiles.

Prevalence of cerebral palsy in Quebec: alternative approaches.

AIM: To provide an estimate of the period prevalence of cerebral palsy (CP) in the province of Quebec. METHODS: Children with CP were identified from three consecutive birth cohorts (1999-2001) from the Quebec CP Registry, covering 6 of the 17 administrative health regions of the province. Two inferential approaches were applied for period prevalence estimation, frequentist and bayesian. RESULTS: 228 children were identified with CP. Using a frequentist approach, the overall prevalence of CP was 1.84 per 1,000 children aged 9-11 years living in those areas in 2010 (95% CI 1.60-2.08). Using a bayesian approach taking into account the uncertainty about the registry's sensitivity in capturing all cases, the overall prevalence is higher at 2.30 per 1,000 children with a 95% CI (1.99-2.65). CONCLUSION: Using a bayesian approach to adjust for the registry's known high specificity and lower sensitivity, the prevalence estimate is in concordance with worldwide estimates and estimates using administrative databases in western Canadian provinces. Future studies are needed to validate the diagnosis of CP within administrative databases and to evaluate possible regional trends across Canada in both prevalence and health service utilization, which may highlight disparities in healthcare delivery.

Respect for autonomy in the healthcare context: observations from a qualitative study of young adults with cerebral palsy.

BACKGROUND: Respect for patient autonomy is a cornerstone of contemporary medical ethics and clinical practice. In its different shapes and forms (e.g. being informed, being engaged in discussions and decisions about medical care and being supported in developing healthcare preferences and choices), patient autonomy has been fostered by both paediatric and adult professional societies. The transition from paediatric to adult care creates a complex situation where autonomy for medical decisions shifts to the developing adolescent. More specific challenges to respect for autonomy may be experienced by young adults with cerebral palsy in the transition period where, for example, language and motor impairments may affect communication skills and this may be conflated with cognitive disability. AIM: To characterize perspectives towards autonomy in the healthcare context for young adults with cerebral palsy. METHOD: We carried out semi-structured interviews with 14 young adults (aged 18-25) with cerebral palsy. The audiotaped interviews were transcribed verbatim and analysed using a conventional thematic qualitative content analysis. RESULTS: Participants displayed a range of attitudes towards autonomy, suggesting that the value of autonomy is considered in light of competing values and of context. Testimonials from participants demonstrated that both contextual (e.g. ill-adapted health care, lack of specialized public transport) and relational (e.g. attitudes towards parental involvement in decision making) factors negatively or positively impact autonomy. CONCLUSION: We observed that there were four key elements interwoven in participants' characterization of autonomy: the coupling of decisional and physical autonomy, the influences of family and society on autonomy, the influence of healthcare professionals on autonomy and the need for preparation for autonomy.

Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.

Genetically determined leukoencephalopathies comprise a group of rare inherited white matter disorders. The majority are progressive diseases resulting in early death. We performed a cross-sectional pilot study including 55 parents from 36 families to assess the level of stress experienced by parents of patients with genetically determined leukoencephalopathies, aged 1 month to 12 years. Thirty-four mothers and 21 fathers completed the Parenting Stress Index-4th Edition. One demographic questionnaire was completed per family. Detailed clinical data was gathered on all patients. Statistical analysis was performed with total stress percentile score as the primary outcome. Mothers and fathers had significantly higher stress levels compared with the normative sample; 20% of parents had high levels of stress whereas 11% had clinically significant levels of stress. Mothers and fathers had comparable total stress percentile scores. We identified pediatric behavioral difficulties and gross motor function to be factors influencing stress in mothers. Our study is the first to examine parental stress in this population and highlights the need for parental support early in the disease course. In this pilot study, we demonstrated that using the Parenting Stress Index-4th Edition to assess stress levels in parents of patients with genetically determined leukoencephalopathies is feasible, leads to valuable and actionable results, and should be used in larger, prospective studies.

Childhood absence epilepsy requiring more than one medication for seizure control.

INTRODUCTION: Absence epilepsy is the most common primary generalized epilepsy syndrome encountered in pediatric practice. Treatment is pharmacologically specific and usually successful with a single medication. The objective of this study was to identify any clinical or electroencephalographic features at initial presentation in a consecutive cohort of children with absence epilepsy that may be associated with the need for a second medication. METHODS: A computerized pediatric neurology database (1991-2007 inclusive) was retrospectively searched for all patients with typical absence seizures, 3 Hz spike and wave on EEG and no apparent symptomatic etiology who were over the age of two years at seizure onset with at least one year of follow-up. All such children were then divided into two groups; a) those requiring a single medication for seizure control (Group 1), and b) those requiring two medications for seizure control despite optimal management with the initial medication as determined by serum drug monitoring (Group 2). Clinical and electrographic features evident at diagnosis were then contrasted between Group 1 and 2. RESULTS: Seventy-five children with absence seizures were initially identified with 52 meeting the study's inclusion and none of the exclusion criteria. Of these 52 children, 43 required a single medication for seizure control (Group 1), while 9 required two or more medications for seizure control (Group 2). A significant difference (p < 0.05) was apparent between Group 1 and 2 with respect to gender (16/43 males vs 8/9 males) and mean age of diagnosis (8.19 years +/- 3.00 vs 6.06 years +/- 2.22). Age of onset of seizures, interval duration of seizures prior to treatment initiation, duration of seizures, presence of automatisms, family history, presence of co-morbid conditions and EEG findings were not found to be significantly different between the two Groups. CONCLUSIONS: Male gender and an earlier age of diagnosis is associated with the need for two medications for seizure control in children with absence epilepsy. This observation may suggest the need for more intensive early programmatic follow-up for young male children with newly diagnosed absence epilepsy to effect more rapid attainment of seizure control.

Array comparative genomic hybridization in global developmental delay.

OBJECTIVE: Array-based comparative genomic hybridization (array CGH) is an emerging technology that allows for the genome-wide detection of DNA copy number changes (CNC) such as deletions or duplications. In this study, array-based CGH was applied to a consecutive series of children with previously undiagnosed non-syndromal global developmental delay (GDD) to assess potential etiologic yield. METHODS: The children in this study were drawn from a previously reported consecutive series of children with well-defined GDD. Almost all subjects had undergone prior karyotyping and neuroimaging studies with non-diagnostic results. Array-based CGH was undertaken using the SignatureChip(R) (1887 BACs representing 622 loci) with abnormalities verified by subsequent FISH analysis and testing of parents to distinguish between pathogenic and familial non-pathogenic variants. RESULTS: On CGH analysis in our study, 6 of 94 children (6.4%) had a causally related pathogenic CNC. Three were sub-telomeric in location. An analysis of a variety of clinical factors revealed that only the presence of minor dysmorphic features (<3) was predictive of etiologic yield on CGH analysis (4/26 vs. 2/68, P = 0.05). Severity of delay was not found to be predictive. INTERPRETATION: In children with non-syndromal GDD, array-based CGH has an etiologic yield of 6.4%. This suggests that this emerging technology may be of diagnostic value when applied subsequent to detailed history, physical examination, and targeted laboratory testing. Array CGH may merit consideration as a first-tier test in the context of a child with unexplained GDD.

Children born at 32 to 35 weeks with birth asphyxia and later cerebral palsy are different from those born after 35 weeks.

OBJECTIVE: The objectives of this study were to (1) establish the proportion of cerebral palsy (CP) that occurs with a history suggestive of birth asphyxia in children born at 32 to 35 weeks and (2) evaluate their characteristics in comparison with children with CP born at ⩾36 weeks with such a history. STUDY DESIGN: Using the Canadian CP Registry, children born at 32 to 35 weeks of gestation with CP with a history suggestive of birth asphyxia were compared with corresponding ⩾36 weeks of gestation children. RESULTS: Of the 163 children with CP born at 32 to 35 weeks and 738 born at ⩾36 weeks, 26 (16%) and 105 (14%) had a history suggestive of birth asphyxia, respectively. The children born at 32 to 35 weeks had more frequent abruptio placenta (35% vs 12%; odds ratio (OR) 4.1, 95% confidence interval (CI) 1.5 to 11.2), less frequent neonatal seizures (35% vs 72%; OR 0.20, 95% CI 0.08 to 0.52), more frequent white matter injury (47% vs 17%; OR 4.3, 95% CI 1.3 to 14.0), more frequent intraventricular hemorrhage (IVH) (40% vs 6%; OR 11.2, 95% CI 3.4 to 37.4) and more frequent spastic diplegia (24% vs 8%; OR 1.8, 95% CI 1.2 to 12.2) than the corresponding ⩾36 weeks of gestation children. CONCLUSIONS: Approximately 1 in 7 children with CP born at 32 to 35 weeks had a history suggestive of birth asphyxia. They had different magnetic resonance imaging patterns of injury from those born at ⩾36 weeks and a higher frequency of IVH. Importantly, when considering hypothermia in preterm neonates with suspected birth asphyxia, prospective surveillance for IVH will be essential.

Injury to the Cerebellum in Term Asphyxiated Newborns Treated with Hypothermia.

BACKGROUND AND PURPOSE: Until now, most studies of brain injury related to term neonatal encephalopathy have focused on the cerebrum and ignored the cerebellum. We sought to evaluate whether cerebellar injury occurs in term asphyxiated neonates. MATERIALS AND METHODS: Asphyxiated neonates treated with hypothermia were enrolled prospectively. Severity of brain injury in the cerebrum was scored on each MR imaging obtained during the first month of life; cerebellar injury was recorded when mentioned in the imaging or autopsy report. In addition, for some of the neonates, the ADC and fractional anisotropy were measured in 4 regions of interest in the cerebellum. RESULTS: One hundred seventy-two asphyxiated neonates met the criteria for hypothermia. Cerebellar injury was visible only on conventional imaging of 4% of the neonates for whom brain imaging was available, but it was reported in the autopsy report of 72% of the neonates who died. In addition, 41 of the asphyxiated neonates had a total of 84 ADC and fractional anisotropy maps. Neonates with brain injury described only in the cerebrum demonstrated ADC and fractional anisotropy changes similar to those of the neonates with brain injury in the cerebrum and cerebellum--increased ADC around day 10 of life and decreased fractional anisotropy on day 2-3 of life, around day 10 of life, and around 1 month of age. CONCLUSIONS: The cerebellum may be injured in term neonates after birth asphyxia. These cerebellar injuries are only rarely visible on conventional imaging, but advanced neuroimaging techniques may help to identify them.

Searching for human epilepsy genes: a progress report.

Application of new genetic techniques has brought remarkable discoveries in the study of genetic diseases. The potential benefits from applying such technology to idiopathic epilepsies include improved understanding of cellular mechanisms and potential new methods of prevention and treatment. The complex problems involved in studying the hereditary epilepsies include: defining of specific phenotypes; detecting genetic and non-genetic heterogeneity; and specifying the appropriate mode of inheritance and penetrance. The gene loci for three primary epilepsies have been localized to specific chromosomal regions, and serve to demonstrate the process used in generalized linkage studies of hereditary epilepsy syndromes. Benign familial neonatal convulsions (BFNC) and Unverricht-Lundborg progressive myoclonus epilepsy are rare single-gene disorders that are sufficiently localized to chromosomal regions that positional cloning studies are likely to succeed. Juvenile myoclonic epilepsy (JME), a common hereditary syndrome with an uncertain mode of inheritance, has been reported to be linked to chromosome 6p. JME presents a challenge for generalized linkage methodology that may be overcome by attending to potential problems reviewed here. The candidate-gene method, combined with studies using animal models, holds promise for understanding these as well as other hereditary epilepsies.

Congenital inflammatory myopathy.

We present 3 patients with congenital inflammatory myopathy and summarize the literature. CNS involvement (microcephaly/intellectual delay) may or may not be present. Serum creatine kinase activity is elevated, the EMG is myopathic, and the muscle biopsy reveals inflammatory infiltrates, muscle fiber damage, and class I major histocompatibility complex products in muscle sarcolemma. Possible etiologies include intrauterine viral infection or an autoimmune process. Treatment with steroids may result in some motor improvement but has no effect on the CNS involvement. Despite a common time of presentation, these patients have a heterogeneous clinical profile, often suggesting a congenital muscular dystrophy syndrome.

Septo-optic dysplasia plus: a spectrum of malformations of cortical development.

The authors describe three children with septo-optic dysplasia (SOD)-plus: SOD and an associated malformation of cortical development. All three children had developmental delay, and two of the children had significant associated motor deficits. The associated cortical malformations with SOD include a spectrum of disorders of neuronal organization, not limited, as previously described, to schizencephaly. SOD-plus should be suspected in children with SOD and developmental delay.

Congenital bilateral perisylvian polymicrogyria presenting as congenital hemiplegia.

We report three children with pure congenital hemiplegia found to have congenital bilateral perisylvian polymicrogyria (CBPP). None of our patients had the seizures, oromotor dysfunction, or cognitive impairment usually associated with CBPP. CBPP may be more common and heterogeneous than previously thought, is easily recognized by MRI, and should be included in the differential diagnosis of the young child presenting with congenital hemiplegia.

Genetic mapping of the cleidocranial dysplasia (CCD) locus on chromosome band 6p21 to include a microdeletion.

Cleidocranial dysplasia (CCD) is a generalized skeletal dysplasia with autosomal dominant inheritance. Recently, the CCD disease locus was localized to 23 [Mundlos et al., 1995] and 17 cM regions [Feldman et al., 1995], of chromosome band 6p21 by linkage studies of seven affected families. Of note, the 23 cM region contained a microdeletion detected in one family at D6S459, an interval that was excluded in the 17 cM overlapping region. Here, linkage of CCD to 6p21 was independently confirmed with a maximal two-point LOD score of Z = 5.12 with marker D6S452 at theta = 0.00. Recombinant events in two affected individuals defined a CCD region of 7 cM from D6S465 to D6S282, which overlapped with the CCD region containing the microdeletion but did not overlap with the 17 cM critical region from D6S282 to D6S291. These results suggest the refined localization of the CCD region to 6 cM spanning markers D6S438 to D6S282, thereby reviving the possibility that the CCD gene lies within the microdeletion at D6S459.

Varying neurological phenotypes among muto and mut- patients with methylmalonylCoA mutase deficiency.

MethylmalonylCoA mutase (MCM) is a mitochondrial homodimer responsible for the isomerization of methylmalonylCoA to succinylCoA. Apomutase defects are traditionally divided into muto and mut- classes on the basis of residual mutase activity. Clinical findings were reviewed in 20 patients with methylmalonic aciduria secondary to MCM deficiency. All 11 muto patients had an early neonatal presentation; 6 of these patients died in infancy and 3 of 5 survivors had a poor neurological outcome as evidenced by severe delay or spastic quadriparesis with dystonia. The 2 other survivors include a 27-month-old child with a mild delay in verbal and fine motor skills and an adolescent with low normal intelligence. Of the 9 mut- patients, 7 became symptomatic in late infancy or childhood and 2 were picked up on screening. Two of the 9 patients have never had an episode of metabolic decompensation yet both are neurologically compromised; one severely retarded and autistic, the other mildly delayed. Four mut- patients have had episodic acidosis and are neurologically moderately affected, while 3 have had episodic acidosis and are neurologically intact. These results confirm phenotypic pleomorphism without a consistent pattern of neurological injury and suggest some broad correlation between mutase class and phenotype. Survival with good outcome is possible among muto patients as is significant morbidity among mut- patients. Acidosis and metabolic imbalance are not necessary preconditions for significant morbidity.

Deletion of 22q11 in two brothers with different phenotype.

We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.

Adenylosuccinate lyase (ADSL) and infantile autism: absence of previously reported point mutation.

Autism is a heterogeneous neuropsychiatric syndrome of unknown etiology. There is evidence that a deficiency in the enzyme adenylosuccinate lyase (ADSL), essential for de novo purine biosynthesis, could be involved in the pathogenesis of certain cases. A point mutation in the ADSL gene, resulting in a predicted serine-to-proline substitution and conferring structural instability to the mutant enzyme, has been reported previously in 3 affected siblings. In order to determine the prevalence of the mutation, we PCR-amplified the exon spanning the site of this mutation from the genomic DNA of patients fulfilling DSM-III-R criteria for autistic disorder. None of the 119 patients tested were found to have this mutation. Furthermore, on preliminary screening using singlestrand conformation polymorphism (SSCP), no novel mutations were detected in the coding sequence of four ADSL exons, spanning approximately 50% of the cDNA. In light of these findings, it appears that mutations in the ADSL gene represent a distinctly uncommon cause of autism.

The 'first to perish'. Child euthanasia in the Third Reich.

In an attempt to improve racial fitness, racial policy in the Third Reich targeted many groups, including physically and mentally handicapped children. An early program identified disabled children who were systematically selected and then transferred to various hospital centers where they were actively euthanatized. The program, directed by mainstream German physicians, was begun on the eve of war and was a harbinger of the evils to come. This article highlights the "scientific thought" that provided the rationale for this policy together with the details of implementation of the active euthanasia program and profiles one of the major participants, Werner Catel, DrMed, who was a distinguished pediatrician.

Restricted unilateral Sydenham's chorea: reversible contralateral striatal hypermetabolism demonstrated on single photon emission computed tomographic scanning.

Sydenham's chorea results from group A streptococcus infection and subsequent generation of antineuronal antibodies directed at the caudate nucleus and putamen. Predominantly bilateral, in up to 30% of cases the chorea can be unilaterally restricted. Imaging studies, both structural (magnetic resonance imaging) and functional (positron emission tomography), in patients with bilateral Sydenham's chorea have suggested reversible striatal abnormalities. Two patients with unilateral Sydenham's chorea are presented. Computed tomographic and magnetic resonance imaging were normal in both. However, hexamethylpropylenamine oxime single photon emission tomographic (HMPAO SPECT) studies demonstrated hypermetabolism in the contralateral basal ganglia. Resolution of symptoms in one of the patients coincided with normalization of the SPECT scan. Thus, unilateral striatal hypermetabolism appears to underlie the contralateral chorea observed. A SPECT scan probably should be included in the work-up of new-onset chorea.

Neurologic perspectives of Crigler-Najjar syndrome type I.

Limited information exists on the neurologic sequelae of Crigler-Najjar syndrome type I despite this being the major morbidity of this rare autosomal recessive disorder of bilirubin conjugation that results in chronic unconjugated hyperbilirubinemia. Two patients with identical underlying genetic mutations resulting in Crigler-Najjar syndrome type I were assessed from a neurodevelopmental perspective in late childhood using age appropriate standardized measures. In addition, the English language literature of case reports and series describing the outcomes of patients with this disorder was reviewed (descriptive meta-analysis) and summarized with particular reference to neurologic symptomatology, pattern of neurologic disability, age of onset of symptoms, and therapeutic interventions. Despite radically different therapeutic interventions, our two patients did not differ in outcome measures. Review of the literature reveals distinct, often age-related, patterns of neurologic sequelae reflecting injury to basal ganglia, cerebellar, and likely hippocampal structures. Definitive prevention of the neurologic sequelae that often occur within the context of Crigler-Najjar syndrome type I requires that curative treatment (hepatic transplantation, presently, and gene therapy in the future) be applied prior to the possible onset of neurologic symptoms in adolescence.