Michael Shevell

Practice Parameter: Diagnostic assessment of the child with cerebral palsy Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. For this parameter the authors reviewed available evidence on the assessment of a child suspected of having cerebral palsy (CP), a nonprogressive disorder of posture or movement due to a lesion of the developing brain. Methods: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. Results: CP is a common problem, occurring in about 2 to 2.5 per 1,000 live births. In order to establish that a brain abnormality exists in children with CP that may, in turn, suggest an etiology and prognosis, neuroimaging is recommended with MRI preferred to CT (Level A). Metabolic and genetic studies should not be routinely obtained in the evaluation of the child with CP (Level B). If the clinical history or findings on neuroimaging do not determine a specific structural abnormality or if there are additional and atypical features in the history or clinical examination, metabolic and genetic testing should be considered (Level C). Detection of a brain malformation in a child with CP warrants consideration of an underlying genetic or metabolic etiology. Because the incidence of cerebral infarction is high in children with hemiplegic CP, diagnostic testing for coagulation disorders should be considered (Level B). However, there is insufficient evidence at present to be precise as to what studies should be ordered. An EEG is not recommended unless there are features suggestive of epilepsy or a specific epileptic syndrome (Level A). Because children with CP may have associated deficits of mental retardation, ophthalmologic and hearing impairments, speech and language disorders, and oral-motor dysfunction, screening for these conditions should be part of the initial assessment (Level A). Conclusions: Neuroimaging results in children with CP are commonly abnormal and may help determine the etiology. Screening for associated conditions is warranted as part of the initial evaluation.

Sodium-channel defects in benign familial neonatal-infantile seizures

Ion-channel gene defects are associated with a range of paroxysmal disorders, including several monogenic epilepsy syndromes. Two autosomal dominant disorders present in the first year of life: benign familial neonatal seizures, which is associated with potassium-channel gene defects; and benign familial infantile seizures, for which no genes have been identified. Here, we describe a clinically intermediate variant, benign familial neonatal-infantile seizures, with mutations in the sodium-channel subunit gene SCN2A. This clinico-molecular correlation defines a new benign familial epilepsy syndrome beginning in early infancy, an age at which seizure disorders frequently have a sombre prognosis.

Participation and Enjoyment of Leisure Activities in School-Aged Children with Cerebral Palsy.

The objective of this study was to characterize participation in leisure activities in children with cerebral palsy (CP) and identify determinants of greater involvement. Ninety‐five children of school age (9y 7mo [SD 2y 1mo]) with CP were recruited, and participation was evaluated with the Children’s Assessment of Participation and Enjoyment in a subset (67/95; 42 males, 25 females) who could actively participate in completion of the assessment. Most had mild motor dysfunction (Gross Motor Function Classification System: 59% level I, 23% level II, 18% levels III–V) and had a spastic subtype of CP (23 hemiplegia, 17 diplegia, 16 quadriplegia, 11 other). Biomedical, child, family and environmental predictor variables were considered in the analysis. Results demonstrated that these children were actively involved in a wide range of leisure activities and experienced a high level of enjoyment. However, involvement was lower in skill‐based and active physical activities as well as community‐based activities. Mastery motivation and involvement in rehabilitation services enhanced involvement (intensity and diversity) in particular leisure activities, whereas cognitive and behavioral difficulties, activity limitations, and parental stress were obstacles to participation.

Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.

Clinical Genetic Evaluation of the Child With Mental Retardation or Developmental Delays

This clinical report describes the clinical genetic evaluation of the child with developmental delays or mental retardation. The purpose of this report is to describe the optimal clinical genetics diagnostic evaluation to assist pediatricians in providing a medical home for children with developmental delays or mental retardation and their families. The literature supports the benefit of expert clinical judgment by a consulting clinical geneticist in the diagnostic evaluation. However, it is recognized that local factors may preclude this particular option. No single approach to the diagnostic process is supported by the literature. This report addresses the diagnostic importance of clinical history, 3-generation family history, dysmorphologic examination, neurologic examination, chromosome analysis (≥650 bands), fragile X molecular genetic testing, fluorescence in situ hybridization studies for subtelomere chromosome rearrangements, molecular genetic testing for typical and atypical presentations of known syndromes, computed tomography and/or magnetic resonance brain imaging, and targeted studies for metabolic disorders.

Screening for Developmental Delay in the Setting of a Community Pediatric Clinic: A Prospective Assessment of Parent-Report Questionnaires

OBJECTIVES. Our goal for this study was to prospectively test whether parent-completed questionnaires can be effectively used in the setting of a busy ambulatory pediatric clinic to accurately screen for developmental impairments. Specific objectives included (1) assessing the feasibility of using parent-report instruments in the setting of a community pediatric clinic, (2) evaluating the accuracy of 2 available screening tests (the Ages and Stages Questionnaire and Child Development Inventory), and (3) ascertaining if the pediatricians clinical judgment could be used as a potential modifier. METHODS. Subjects were recruited from the patient population of a community clinic providing primary ambulatory pediatric care. Subjects without previous developmental delay or concerns noted were contacted at the time of their routine 18-month-old visit. Those subjects who agreed to participate were randomly assigned to 1 of 2 groups and completed either the Ages and Stages Questionnaire or Child Development Inventory. The childs pediatrician also completed a brief questionnaire regarding his or her opinion of the childs development. Those children for whom concerns were identified by either questionnaire underwent additional detailed testing by the Battelle Development Inventory, the “gold standard” for the purposes of this study. An equal number of children scoring within the norms of the screening measures also underwent testing with the Battelle Development Inventory. RESULTS. Of the 356 parents contacted, 317 parents (90%) agreed to participate. Most parents correctly completed the Ages and Stages Questionnaire (81%) and the Child Development Inventory (75%). Predictive values were calculated for the Ages and Stages Questionnaire and the Child Development Inventory (sensitivity: 0.67 and 0.50; specificity: 0.39 and 0.86; positive predictive value: 34% and 50%; negative predictive value: 71% and 86%, respectively). Incorporating the physicians opinion regarding the developmental status of the child did not improve the accuracy of the screening questionnaires. CONCLUSIONS. Three important conclusions were reached: (1) parent-completed questionnaires can be feasibly used in the setting of a pediatric clinic; (2) the pediatricians opinion had little effect in ameliorating the accuracy of either questionnaire; and (3) single-point accuracy of these screening instruments in a community setting did not meet the requisite standard for development screening tests as set by current recommendations. This study raises important questions about how developmental screening can be performed, and we recommend additional research to elucidate a successful screening procedure.

Topical Review: Long-Term Developmental Outcome of Asphyxiated Term Neonates

Asphyxia remains one of the main causes of later disability in term infants. Despite many publications identifying possible predictors of outcome in this population of interest, little is known of the long-term developmental outcome of asphyxiated term neonates. Observational studies have largely focused on short-term outcomes, with an emphasis on significant neurologic sequelae and intellectual impairments. This article reviews the literature that has described the developmental outcome of asphyxiated term newborns. As part of this review, we have also highlighted the evolution of the definition of asphyxia and delineated appropriate markers that should be used in future research on this population. (J Child Neurol 2001;16:781—792).

Diagnostic yield of the neurologic assessment of the developmentally delayed child.

OBJECTIVE The aim of this study was to determine the etiologic yield of the neurologic assessment of a consecutive cohort of developmentally delayed children. STUDY DESIGN A retrospective chart review was carried out on all patients referred to a single university-based pediatric neurologist for evaluation of global developmental delay from July 1991 to December 1993. Patients referred because of isolated speech or motor delay or autism or those who had been previously evaluated by another neurologist were excluded. RESULTS A total of 77 patients were identified; 47 were male, and 62 were referred by a pediatrician. Neurologic evaluation did not confirm global delay in 10, and 8 did not complete diagnostic evaluation; one child was included in both groups. Of the remaining 60, an etiologic diagnosis was suspected by the referring physician at the time of referral in 13. Although parents suspected a delay at a mean age of 0.66 (+/- 0.69) year, children were examined by the neurologist at a mean age of 3.58 (+/- 2.42) years. Twenty-five were mildly delayed, 23 were moderately delayed, and 12 were severely delayed. Diagnostic studies (history, physical examination, and selected investigations, including screens for metabolic disease, karyotype, fragile X testing, electroencephalography, and neuroimaging) yielded an etiologic diagnosis in 38 (63.3%) of the 60 patients. Etiologic categories included cerebral dysgenesis (16.7%), hypoxic-ischemic encephalopathy (10.0%), chromosomal abnormalities (10%), toxins (8.3%), metabolic disorders (5.0%), and neurocutaneous (3.3%), neuromuscular (3.3%), genetic/dysmorphic (3.3%), and epileptic (3.3%) syndromes. Etiologic yield was equivalent across categories and degree of developmental delay. CONCLUSION Referral to a pediatric neurologist and application of a selected battery of investigations yield etiologic findings with important implications with respect to management, prognosis, and recurrence risk estimate in a significant portion of globally delayed children.

Evidence Report: Genetic and metabolic testing on children with global developmental delay Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society

Objective: To systematically review the evidence concerning the diagnostic yield of genetic and metabolic evaluation of children with global developmental delay or intellectual disability (GDD/ID). Methods: Relevant literature was reviewed, abstracted, and classified according to the 4-tiered American Academy of Neurology classification of evidence scheme. Results and Conclusions: In patients with GDD/ID, microarray testing is diagnostic on average in 7.8% (Class III), G-banded karyotyping is abnormal in at least 4% (Class II and III), and subtelomeric fluorescence in situ hybridization is positive in 3.5% (Class I, II, and III). Testing for X-linked ID genes has a yield of up to 42% in males with an appropriate family history (Class III). FMR1 testing shows full expansion in at least 2% of patients with mild to moderate GDD/ID (Class II and III), and MeCP2 testing is diagnostic in 1.5% of females with moderate to severe GDD/ID (Class III). Tests for metabolic disorders have a yield of up to 5%, and tests for congenital disorders of glycosylation and cerebral creatine disorders have yields of up to 2.8% (Class III). Several genetic and metabolic screening tests have been shown to have a better than 1% diagnostic yield in selected populations of children with GDD/ID. These values should be among the many factors considered in planning the laboratory evaluation of such children.

Pediatric migraine equivalents: occurrence and clinical features in practice.

Migraine equivalents of infancy, childhood, and adolescence are recognized periodic, paroxysmal syndromes without associated headache that are thought to be migrainous in etiology. Five such equivalents are presently recognized. Their clinical features and relative frequency in ambulatory pediatric neurology practice have not been well documented. Utilizing a comprehensive, standardized computer database, the occurrence of these migraine equivalents in a single pediatric neurology practice together with their observed clinical features were documented over an 8-year period. Of a total of 5,848 patients in the database, of whom 1,106 were migraineurs, 108 patients (1.8% of total, 9.8% of migraineurs) were identified to have migraine equivalents. The following distribution among migraine equivalents was observed: benign paroxysmal torticollis 11 (10.2% of patients with migraine equivalents), benign paroxysmal vertigo 41 (38%), abdominal migraine/cyclical vomiting 20 (18.5%), acephalgic migraine 31 (28.7%), and acute confusional migraine 5 (4.6%). In each type, with the exception of benign paroxysmal torticollis and acute confusional migraine, females clearly predominated, and in all types a strong positive family history of migraine was elicited (68%-100%). There was variation in the age of onset of a particular equivalent with considerable overlap observed. Coexisting more typical migraines were observed in from 10% (benign paroxysmal torticollis) to 70% (abdominal migraines/cyclical vomiting) of the cases. In conclusion, pediatric migraine equivalents occur with relative frequency in ambulatory practice, possessing discrete clinical features that have a clear relationship to more typical migrainous phenomena.