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Study Design: Retrospective, cross-sectional study., Objectives: To investigate prevalence, types, and severity of fecal incontinence (FI) and constipation in adults with spina bifida (SB), in relation to self-perception and help-seeking, and to compare findings to data from a general population reference group., Setting: University Medical Center Groningen (UMCG), the Netherlands., Methods: The 294 adults with SB registered at UMCG in 2017 were invited to participate. The Groningen Defecation and Fecal Continence Questionnaire was used to assess functional outcomes for FI and constipation using Rome IV criteria. Vaizey (for FI) and Agachan (for constipation) scores were determined. Socio-demographic factors and self-perception of bowel-related problems were recorded through the questionnaire. Data were compared with an age and sex matched reference group., Results: The completed questionnaires of 112 (38%) responding participants were analyzed. FI and constipation were more prevalent in the study group (35% and 45%, respectively) than in the reference group (8.9% and 22%, respectively). In general, in participants with SB aperta (SBA; n = 75), FI was more severe than in participants with SB occulta (SBO; n = 37). However, severity of FI was higher in SBO participants than in the SBA group after the age of 61. Bowel problems in adults with SB were associated with worse self-perception regarding health., Conclusions: In adults with SB, anorectal dysfunction is often present and severe. Older persons with SBO experience more severe FI than in early age. Bowel problems should systematically and more adequately be addressed and controlled throughout adulthood in both the spina bifida groups., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Early onset cerebellar Ataxia (EOAc) comprises a large group of rare heterogeneous disorders. Determination of the underlying etiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This may change the diagnostic work-up into a time-consuming, costly and not always rewarding task. In this overview, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society (CACG-EPNS) presents a diagnostic algorithm for EOAc patients. In seven consecutive steps, the algorithm leads the clinician through the diagnostic process, including EOA identification, application of the Inventory of Non-Ataxic Signs (INAS), consideration of the family history, neuro-imaging, laboratory investigations, genetic testing by array CGH and Next Generation Sequencing (NGS). In children with EOAc, this algorithm is intended to contribute to the diagnostic process and to allow uniform data entry in EOAc databases., (Copyright © 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: Cerebral palsy (CP) can be classified as spastic, dyskinetic, ataxic or combined. Correct classification is essential for symptom-targeted treatment. This study aimed to investigate agreement among professionals on the phenotype of children with CP based on standardized videos., Methods: In a prospective, observational pilot study, videos of fifteen CP patients (8 boys, mean age 11 ± 5 y) were rated by three pediatric neurologists, three rehabilitation physicians and three movement disorder specialists. They scored the presence and severity of spasticity, ataxia or dyskinesias/dystonia. Inter- and intraobserver agreement were calculated using Cohen's and Fleiss' kappa., Results: We found a fair inter-observer (κ = 0.36) and moderate intra-observer agreement (κ = 0.51) for the predominant motor symptom. This only slightly differed within the three groups of specialists (κ = 0.33-0.55)., Conclusion: A large variability in the phenotyping of CP children was detected, not only between but also within clinicians, calling for a discussing on the operational definitions of spasticity, dystonia and ataxia. In addition, the low agreement found in our study questions the reliability of use of videos to measure intervention outcomes, such as deep brain stimulation in dystonic CP. Future studies should include functional domains to assess the true impact of management options in this highly challenging patient population., (Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years).

Background: Acute flaccid myelitis (AFM) is a relatively rare disorder affecting the anterior horn of the spinal cord and brain stem. It is characterised by rapid progressive weakness of the limbs and respiratory muscles, often combined with cranial nerve dysfunction. This used to be seen in infections with the polio virus, but in recent years, AFM has been mainly associated with enterovirus D68 infection., Case Description: A boy of nearly 4 years-old developed rapidly progressive weakness and respiratory failure after an upper airway infection. Initially, Guillain-Barré syndrome was suspected, but after further investigations enterovirus D68 was detected in the nasopharyngeal aspirate and the diagnosis of AFM was made., Conclusion: Progressive weakness after a respiratory tract infection should raise the suspicion of enterovirus-associated AFM. This syndrome can be distinguished from Guillain-Barré syndrome by its more rapid progression, asymmetrical weakness and greater involvement of the upper limbs. The diagnosis can be confirmed by typical findings on MRI and electromyography of the spinal cord and brain stem, combined with the detection of enterovirus D68 in nasopharyngeal specimens.

Objective: To examine the impact of introduction of the mid-trimester scan on pregnancy outcome in cases of open spina bifida in two regions of The Netherlands., Methods: This was a retrospective cohort study of 190 cases of open spina bifida diagnosed pre- or postnatally, with an estimated date of delivery between 2003 and 2011., Results: With implementation of the mid-trimester scan the percentage of cases of open spina bifida detected before the 24(th) week of pregnancy increased from 43% to 88%. The rise in prenatal detection rate was associated with a significant increase in the number of terminated pregnancies and a decrease in the rate of perinatal loss; the percentage of children born alive did not change significantly. In the subgroup that underwent a scan between 18 and 24 weeks of pregnancy, cranial signs were present in 94.4% of cases., Conclusion: Introduction of the mid-trimester scan has led to an increase in early identification of pregnancies complicated by open spina bifida. Pregnancies previously destined to end in perinatal loss are now terminated whilst pregnancies with a relatively good prognosis are frequently continued; the number of children with open spina bifida who are born alive has not changed significantly. Our study confirms that prenatal diagnosis is usually triggered by visualization of a lemon-shaped skull or a banana-shaped cerebellum., (Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.)

Purpose: The purposes of this study were to explore the prevalence of sleep disturbances in a large cohort of school-aged children with partial epilepsy, to compare the findings with those in children without epilepsy of the same age and gender, and to evaluate the relationship between sleep disturbances and health-related quality of life (HRQoL)., Methods: One hundred thirty children with partial epilepsy aged 4 to 10years, who were treated in the outpatient setting of a Dutch epilepsy clinic, and 161 age- and sex-matched controls participated in this study. In addition to providing information about their child's demography and health, parents of both groups of children completed three questionnaires to measure their child's sleep [Sleep Disturbance Scale for Children (SDSC), Medical Outcomes Study-Sleep Scale (MOSS-S), and Groningen Sleep Quality Scale (GSQS)] and one questionnaire to measure quality of life (Kidscreen-27). Parents of children with epilepsy also completed the Hague Scales to measure the severity of epilepsy. The prevalence of sleep disturbances and scores on HRQoL in children with and without epilepsy were compared. Additionally, the HRQoL scores were compared between children with and without sleep disturbances in children both with and without epilepsy., Results: The answers for all three questionnaires suggested worse sleep in children with epilepsy than in children of the same age and gender without epilepsy. Pathological scores (T-value>70) for total SDSC were seen twelve times more frequently in children with epilepsy (36.92% vs. 3.01%, p<0.001). Children with epilepsy also scored significantly lower for all dimensions of HRQoL. Between subgroups of children with and without disturbed sleep, insignificant differences in quality of life were found, with the lowest scores in children with sleep disturbances in both groups., Conclusion: This study confirms the high prevalence of disturbed sleep, as well as its effect on quality of life, in a large group of children with partial epilepsy. The abnormalities are both more prevalent and more severe than in children without epilepsy., (© 2013.)

Purpose: In spina bifida aperta (SBA), the "second-hit hypothesis" addresses consequences by delayed neurological damage superimposed upon the congenital myelomeningocele (MMC). This secondary damage is postulated to underlie the disappearance of leg movements shortly after birth. Innovative fetal surgery might prevent this, but results are methodologically hard to prove in small and heterogeneous treatment groups. We reasoned that delayed postnatal alterations in muscle ultrasound density (MUD = muscle echogenicity) could quantitatively reflect consequences by "the second hit" of damage. In the present study, we investigated whether delayed postnatal leg-MUD alterations are associated with postnatal muscle function loss., Methods: We cross-sectionally assessed leg-MUD in 16 postnatally operated SBA children (MMC-L5; at 0, 6, and 12 months; in n = 11/16; 11/16, and 15/16 children, respectively) and compared outcomes with 13 healthy control children. Additionally, we assessed SBA MUD caudal and cranial to the MMC and calculated MMC-L5 impact by: dMUD((MMC-L5)) = [MUD(calf muscle/S1-2)] - [MUD(quadriceps muscle/L2-4)] and associated outcomes with leg muscle function caudal to the MMC., Results: At 0 month, clinically discernible dMUD was more often increased in SBA than in control newborns (p < .05), but a relationship between absolute quantitative differences and leg muscle dysfunction was still lacking. At 6-12 months, additionally increased dMUD outcomes coincided with SBA leg muscle dysfunction (p < .05)., Conclusions: In post-neonatal SBA, secondarily increased dMUD (i.e., MMC impact) coincides with leg muscle dysfunction. This may implicate that muscle ultrasound could provide a quantitative tool to assess the neuromuscular impact by the second hit of damage.

Differential diagnosis of facial nerve palsy in children is extensive. We report on three pediatric cases presenting with facial nerve palsy caused by hyperostosis corticalis generalisata (Van Buchem disease). This autosomal recessive disease is characterized by progressive bone overgrowth, with narrowing of the neuroforamina in the skull causing cranial neuropathies. These three new cases of Van Buchem disease are of interest because of exceptionally early presentation of symptoms. Furthermore, this is the first report describing bilateral papilledema in a child with Van Buchem disease. Head computerized tomography (CT) scan revealed thickened calvarium, skull base and mandible in all three children, with narrowed facial nerve canals. Bone mineral density (BMD) was markedly increased at all measured points and biochemical markers of bone formation were significantly elevated. Diagnosis of Van Buchem disease was genetically confirmed. The cases are unique in that these are the first well-documented pediatric cases of Van Buchem disease., (Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Opitz-Kaveggia syndrome is a rare X-linked multiple congenital anomalies and intellectual disability disorder caused by the recurrent p.R961W mutation in the MED12 gene. Twenty-three affected males from 10 families with this mutation in the MED12 gene have been described so far. Here we report on a new family with three affected cousins, in which we identified a novel MED12 mutation (p.G958E). This is the first demonstration that other mutations in this gene can also lead to Opitz-Kaveggia syndrome. The clinical phenotype of these three new cases is reviewed in detail and compared with the previous reported cases., (© 2010 John Wiley & Sons A/S.)

Dystroglycanopathies are a heterogeneous group of disorders caused by defects in the glycosylation pathway of alpha-dystroglycan. The clinical spectrum ranges from severe congenital muscular dystrophy with structural brain and eye involvement to a relatively mild adult onset limb-girdle muscular dystrophy without brain abnormalities and normal intelligence. Mutations have been identified in one of six putative or demonstrated glycosyltransferases. Many different FKRP mutations have been identified, which cover the complete clinical spectrum of dystroglycanopathies. In contrast to the other known genes involved in these disorders, genotype-phenotype correlations are not obvious for FKRP mutations. To date, no homozygous or compound heterozygous null mutations have been identified in FKRP, suggesting that null mutations in FKRP could result in embryonic lethality. We report a family with two siblings carrying a homozygous mutation in the start codon of FKRP that is likely to result in a loss of functional FKRP protein. The clinical phenotype of the patients was consistent with Walker-Warburg syndrome, the most severe disorder in the disease spectrum of dystroglycanopathies.

Introduction: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement., Aim: In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment., Methods: During a two-year study period, 6 genetically proven FRDA children with cardiomyopathy (6-18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores., Results: In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05)., Conclusion: In FRDA children, age-related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement.

Background: In fetal spina bifida aperta (SBA), leg movements caudal to the meningomyelocele (MMC) are transiently present, but they disappear shortly after birth. Insight in the underlying mechanism could help to improve treatment strategies. In fetal SBA, the pathogenesis of neuromuscular damage prior to movement loss is still unknown. We reasoned that prenatal assessment of muscle ultrasound density (fetal-MUD) could help to reveal whether progressive neuromuscular damage is present in fetal SBA, or not., Aim: To reveal whether prenatal neuromuscular damage is progressively present in SBA., Patients/methods: In SBA fetuses (n=6; 22-37 weeks gestational age), we assessed fetal-MUD in myotomes caudal to the MMC and compared measurements between myotomes cranial to the MMC and controls (n=11; 17-36 weeks gestational age). Furthermore, we intra-individually compared MUD and muscle histology between the pre- and postnatal period., Results: Despite persistently present fetal leg movements caudal to the MMC, fetal-MUD was higher caudal to the MMC than in controls (p<0.05). Fetal-MUD caudal to the MMC did not increase with gestational age, whereas fetal-MUD in controls and cranial to the MMC increased with gestational age (p<0.05). In 5 of 6 patients assessed, comparison between pre- and postnatal MUD and/or muscle histology indicated consistent findings., Conclusions: In fetal SBA, persistent leg movements concur with stable, non-progressively increased fetal-MUD. These data may implicate that early postnatal loss of leg movements is associated with the impact of additional neuromuscular damage after the prenatal period.

Objective: To investigate the utilization of antiepileptic drugs (AEDs) in Dutch children and compare this with guidelines on the treatment of epilepsy in children., Method: From the Dutch Interaction Database (IADB.nl) we selected children aged 0-19 years who received at least one prescription for an AED (ATC-code beginning with N03A) between 1997 and 2005. We calculated cumulative incidences and prevalences per 1000 children per year, stratified by age-category, sex and type of AED, and the total number of months each patient received at least one prescription of AEDs, and we counted the number of person-months and AEDs prescribed. For each AED, proportions of person-months were calculated for mono- and combination therapy. Kaplan-Meier survival analysis was used to analyse the duration of AED use, stratified by sex., Results: The overall prevalence of the prescription of AEDs to children was constant at approximately 4.0 per 1000 children during the years of the study. The overall cumulative incidence from 1997-2005 was 0.67 per 1000 children. When stratified by age category or sex, there were no relevant differences in incidence or prevalence. Valproic acid was the most frequently prescribed drug, followed by carbamazepine and lamotrigine. In 20.3% of all person-months, patients received combination therapy; of these, 34.2% received combination therapy for 3 person-months or less. The older AEDs were prescribed more often as monotherapy than combination therapy, in contrast with the newer AEDs, for which the opposite was true. The 50% survival probability (= time period when 50% of children had stopped using AEDs) was around 2 years, with a significantly lower discontinuation of treatment for girls than boys (P = 0.04)., Conclusion: The overall cumulative incidence of AEDs was determined to be 0.67 per 1000 children, and the prevalence 4.0 per 1000 children. The most frequently prescribed drug is valproic acid, followed by carbamazepine and lamotrigine. The prescribing of AEDs seems to be in conformity with the overall recommendations of the guidelines on the treatment of epilepsy in children.

Background: In spina bifida aperta (SBA), leg movements caudal to the meningomyelocele are present in utero, but they disappear shortly after birth. It is unclear whether leg movements disappear by impact of the neuro-developmental malformation or by superimposed traumatic damage. If superimposed traumatic damage is involved, targeted fetal intervention could improve motor outcome., Aim: To characterize neuromuscular pathology in association with perinatal motor function loss in SBA., Patients/methods: In fetal SBA (n=8; 16-40 weeks GA), the median time interval between ultrasound registrations of fetal motor behavior and post-mortem histology was 1 week. Histology was assessed cranial, at and caudal to the meningomyelocele and compared with findings in fetal controls (n=4)., Results: Despite fetal movements caudal to the meningomyelocele (5/6), histology indicated muscle fiber alterations (6/6) that concurred with neuro-developmental and traumatic spinal defects [Neuro-developmental defects: spinal ependymal denudation (3/8), reduced amount of (caspase3-negative) lower motor neurons (LMNs; 8/8), aberrant spinal vascularization (8/8). Traumatic defects: gliosis (7/8), acute/fresh spinal hemorrhages near LMNs (8/8)]., Conclusion: In all delivered SBA patients, recent spinal hemorrhages were superimposed upon pre-existing defects. If early therapeutic strategies can prevent these superimposed secondary spinal hemorrhages, motor outcome may improve.

A 9-year-old boy who since 3 years had been treated with a brace for presumed idiopathic thoracic scoliosis was referred because of severe syringomyelia on MRI of the spinal cord. Neuroimaging of the spinal cord had been performed because of back pain, although the patient had no neurological signs or symptoms. Besides extensive syringomyelia, the MRI revealed a type I Chiari's malformation which we assumed to be the primary cause of the syringomyelia and the subsequent scoliosis. Surgical decompression of the Chiari's malformation led to a remarkable reduction of the syringomyelia and to stabilisation of the scoliosis. In children with structural scoliosis, ancillary investigation in the way of neuroimaging of the spinal cord should be considered to exclude underlying spinal cord pathology, even in the absence of neurological abnormalities.

Purpose: In infants with frequent therapy resistant seizures (TRS-infants), clinical detection of pyridoxine-dependency (PD) or -responsiveness (PR) occurs by empirical intravenous (IV) pyridoxine administration during recording of the EEG. However, in undiagnosed TRS-infants it is still unclear to what extent EEG alterations by pyridoxine-IV are attributable to PD/PR or to non-specific responses. Before EEG alterations by pyridoxine-IV can be ascribed to PD/PR, these non-specific responses should be excluded first., Methods: In 10 TRS-infants under 1 year of age, we determined the EEG effect by pyridoxine-IV on the EEG-recording., Results: After pyridoxine-IV administration, our data indicate declined (10-15%; p<0.05) EEG-amplitudes and total power (magnitude/frequency-band) at frontal, central and centro-temporal electrodes., Conclusion: In TRS-infants, pyridoxine-IV affects EEG-amplitude and -total power in a non-specific way, which does not identify PD/PR.

Introduction: In neonates with spina bifida aperta (SBA), leg movements by myotomes caudal to the meningomyelocele (MMC) are transiently observed. It is unclear whether these leg movements relate to functional neural conduction through the MMC. For optimal therapeutical intervention, pathophysiological insight in these transient leg movements seems relevant. If leg movements by myotomes caudal to the MMC concur with the execution of general movements (GMs), functional neural conduction through the MMC is implicated., Objective: In neonates with SBA, we aimed to determine whether the transiently present leg movements caudal to the MMC indicate functional neural conduction through the MMC., Methods: During the perinatal period, fetuses and neonates with SBA (n = 7 and n = 13, respectively) were longitudinally analysed for concurrency between leg movements caudal to the MMC and GMs. To address the integrity of the reflex arc in spinal segments (at, or) caudal to the MMC, tendon leg reflexes were assessed during the first postnatal week., Results: At postnatal day 1, leg movements caudal to the MMC concurred with GMs in 12 of 13 infants. Isolated leg movements were observed in only 3 of these 12 infants (isolated vs. concurrent; p < 0.005). Leg movements concurring with GMs lasted longer than isolated leg movements (median duration = 11 s vs. 2 s; p < 0.05). Between days 1 and 7, tendon leg reflexes (at, or) caudal to the MMC had disappeared in all but 1 neonate. However, leg movements caudal to the MMC remained concurrently present with GMs in all five neonates available for follow-up after day 7. Comparing these leg movements between days 1 and 7 indicated a decreased duration (-44%, p < 0.05)., Conclusions: In neonates with SBA, leg movements caudal to the MMC concur with GMs, indicative of functional neural conduction through the MMC. The disappearance of these leg movements is caused by lower motor neuron dysfunction at the reflex arc, whereas neural conduction through the MMC is still functional.

Four-year follow-up of children with epilepsy included in a randomized trial of early withdrawal of antiepileptic drugs showed that 51% achieved a terminal remission of at least 2 years without medication and 21% with medication; 15% had seizures during the fourth year. Early medication withdrawal is not recommended as standard practice in children with a rapid response to medication. The authors developed a model to predict outcome if withdrawal is considered.

Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited partial epilepsy syndrome of early childhood with remission before the age of 3 years. The syndrome has been linked to loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q in various families. The aim of this study was to identify the responsible locus in four unrelated Dutch families with BFIC. Two of the tested families had pure BFIC; in one family, affected individuals had BFIC followed by paroxysmal kinesigenic dyskinesias at later age, and in one family, BFIC was accompanied by later-onset focal epilepsy in older generations. Linkage analysis was performed for the known loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q. The two families with pure BFIC were linked to chromosome 16p12-q12. Using recombinants from these and other published families, the chromosome 16-candidate gene region was reduced from 21.4 Mb (4.3 cm) to 2.7 Mb (0.0 cm). For the other two families, linkage to any of the known loci was unlikely. In conclusion, we confirm the linkage of pure BFIC to chromosome 16p12-q12, with further refinement of the locus. Furthermore, the lack of involvement of the known loci in two of the families indicates further genetic heterogeneity for BFIC.

Objective: To gain insight into the reporting and assessment of active termination of life in newborns in The Netherlands. DESIGN; Retrospective., Method: Data on all cases of deliberate termination of life in newborns up to the age of 6 months, reported to the public prosecutor as from 1997 onward, were collected and compared., Results: In January 1997-June 2004, 22 cases of deliberate termination of life in newborns were reported. All cases concerned newborns with spina bifida and hydrocephalus. Deliberate termination of life was acceptable to the physicians because of the presence of hopeless suffering, with no means of alleviating the suffering. In all cases, at least 2 doctors were consulted outside the medical team. In 17 of 22 cases, a multidisciplinary spina bifida team was consulted. All parents consented to the termination of life; in 4 cases they explicitly requested it. In 14 cases a combination of analgesics, sedatives and paralyzing drugs were used, in 8 cases only analgesics and sedatives were administered. For the public prosecutor the termination of life was acceptable if 4 requirements were properly fulfilled: the presence of hopeless and unbearable suffering, consent of the parents to termination of life, consultation having taken place and a careful execution ofthe termination. The mean time between reporting of the case and the decision concerning prosecution was 5.3 months. None of the cases led to prosecution., Conclusion: Three cases of deliberate termination of life in newborns were reported in The Netherlands annually. The public prosecutor used fixed criteria to assess the case and all cases of active termination of life reported were found to be in accordance with good practice.

Unlabelled: Continuous amplitude-integrated electroencephalogram (aEEG) recording with a cerebral function monitor is a useful tool to evaluate prognoses following perinatal asphyxia in term infants. Drugs may change the pattern of the conventional EEG. This report presents three infants treated with midazolam for status epilepticus and repetitive seizures who proved resistant to other anticonvulsants (phenobarbitone, lidocaine). The infants developed burst suppression patterns on aEEG concurrent with high serum levels of midazolam (900-7093 microg l(-1)). Following discontinuation of midazolam treatment, serum levels normalized and background patterns returned to normal voltage traces., Conclusion: These findings indicated that midazolam can cause burst suppression on aEEG. Therefore, the prognostic value of aEEG is limited in case of high serum levels of midazolam. Serum levels of midazolam should be measured in infants who have burst suppression patterns on aEEG during midazolam treatment.

Objective: To assess the interrater agreement of the diagnosis and the classification of a first paroxysmal event in childhood., Methods: The descriptions of 100 first paroxysmal events were submitted to two panels each consisting of three experienced paediatric neurologists. Each observer independently made a diagnosis based on clinical judgment and thereafter a diagnosis based on predefined descriptive criteria. Then, the observers discussed all patients within their panel. The agreement between the six individual observers was assessed before discussion within each panel and after that, between the two panels., Results: Using their clinical judgement, the individual observers reached only fair to moderate agreement on the diagnosis of a first seizure (mean (SE) kappa 0.41 (0.03)). With use of defined descriptive criteria the mean (SE) kappa was 0.45 (0.03). The kappa for agreement between both panels after intra-panel discussion increased to 0.60 (0.06). The mean (SE) kappa for the seizure classification by individual observers was 0.46 (0.02) for clinical judgment and 0.57 (0.03) with use of criteria. After discussion within each panel the kappa between the panels was 0.69 (0.06). In 24 out of 51 children considered to have had a seizure, agreement was reached between the panels on a syndrome diagnosis. However, the epileptic syndromes were in most cases only broadly defined., Conclusions: The interrater agreement on the diagnosis of a first seizure in childhood is just moderate. This phenomenon hampers the interpretation of studies on first seizures in which the diagnosis is only made by one observer. The use of a panel increased the interrater agreement considerably. This approach is recommended at least for research purposes. Classification into clinically relevant syndromes is possible only in a very small minority of children with a single seizure.

In an unselected cohort of 282 children, serum immunoglobulin (Ig) concentrations were determined shortly after the first presentation with one or more unprovoked epileptic seizures and before the start of treatment with anti-epileptic drugs (AEDs), and after 9-18 months of AEDs use. At intake, IgA, IgG1, IgG2 and IgG4 concentrations were significantly higher than published reference values in healthy age-matched controls. In a subset of 127 children, Ig levels at intake were compared with those after AEDs use for 9-18 months. IgA and IgG4 levels had decreased significantly to normal concentrations, but IgG1 and IgG3 levels increased significantly. To determine the influence of AEDs, Ig levels in children who used carbamazepine or valproic acid monotherapy were analysed separately. The use of carbamazepine was associated with a significant decrease of IgA and IgG4 levels, and the use of valproic acid with a significant decrease of IgA and increase of IgG1 levels. In conclusion, humoral immunity is already altered in children shortly after the first presentation with epileptic seizures. Whether this is the consequence of an exogenous event, and to what extent this is related to an interaction of the central nervous system and the immune system, remains to be evaluated. Treatment with AEDs, such as carbamazepine and valproic acid, is associated with significant changes of Ig (sub)class concentrations.

Objective: To assess the accuracy of the diagnosis of epileptic seizures in children., Methods: The Dutch Study of Epilepsy in Childhood is a prospective hospital-based study of 881 children referred because of possible seizures. The diagnosis was based on predefined descriptive criteria, as applied by a panel of three pediatric neurologists. Children with a definite other diagnosis were excluded. All children with unclear events were followed up for 1 year and children with seizures were followed up for 2 years to assess the accuracy of the diagnosis., Results: In 170 of 224 children seen after a single event, the incident was classified initially as epileptic, in 54 as unclear. In none of the 170 children did the diagnosis prove to be wrong. In four of the 54 children, recurrent episodes enabled a definite diagnosis of epilepsy. In 412 of the 536 children seen with multiple events, an initial diagnosis of epilepsy was made. After follow-up, this initial diagnosis was probably incorrect in 19. In contrast, seven of 124 children with multiple unclear episodes at intake later received the diagnosis epilepsy., Conclusions: A false-positive diagnosis of epilepsy was made in 4.6%, whereas a definite diagnosis of epilepsy or seizure was delayed in 5.6% of children with multiple unclear events and in 7.4% of children with one unclear event.

The GLUT-1 deficiency is a metabolic disorder caused by a defect in glucose transport across the blood-brain barrier as a result of a defect in the glucose-transport protein. Patients present with epileptic seizures, delayed development, ataxia and hypotonia, and in many cases acquired microcephaly. In most patients, treatment with a ketogenic diet proved to be successful in controlling the epilepsy. We report a 9-year-old boy with retardation and ataxia, but without epilepsy, caused by GLUT-1 deficiency, proven biochemically and by DNA analysis. Treatment with a medium-chain triglyceride ketogenic diet had a beneficial effect.

Objective: To study the outcome of pregnancies with a prenatally diagnosed central nervous system (CNS) malformation., Methods: Leiden University Medical Centre is a tertiary referral center for fetal ultrasound and invasive prenatal diagnosis. Maternal and neonatal records of prenatally diagnosed CNS malformations were retrospectively reviewed over a 6-year period (1993-1998). Information on current development of surviving children was obtained by contacting the care-giving pediatric neurologist., Results: During the study period 124 fetuses were diagnosed with a CNS malformation. Data on pregnancy and delivery were available for 118 pregnancies. Additional malformations were present in 47% of fetuses (55/118). A total of 46% of pregnancies (54/118) were terminated, and 15% (18/118) ended in spontaneous intrauterine death. A total of 39% of pregnancies (46/118) resulted in live birth, and 29 of the infants were still alive at the age of 3 months. One child was lost to follow-up, one infant died at the age of 4 months, and two children died at the age of 3 years. Psychomotor development of the remaining 25 children was normal for five, slightly disabled for seven, moderately disabled for five and severely disabled for eight., Conclusion: Due to the high rate of termination of pregnancy and to the frequent association with other anomalies, the survival rate of pregnancies in which a CNS defect had been diagnosed prenatally was only 25%. More than 50% of surviving children were moderately or severely disabled., (Copyright 2002 ISUOG. Published by John Wiley & Sons, Ltd.)

Duchenne muscular dystrophy is clinically characterised by progressive muscle weakness and a gradual increase in the size of some affected muscles, especially calf muscles. The extent of calf enlargement is usually determined by subjective visual assessment. The purpose of this study was to determine the extent of calf muscle enlargement in Duchenne muscular dystrophy (DMD) patients compared with healthy age matched boys by quantifying calf circumference. Calf circumference in the group of DMD patients is significantly increased. However, in individual patients calf enlargement can be feigned by a discrepancy between calf circumference and circumference of the upper leg and arm muscles as part of a general muscle atrophy.

Purpose: To assess the prognosis and the accuracy of the epilepsy classification in young children with nonsymptomatic generalized epilepsy., Methods: Of the cohort of the Dutch Study of Epilepsy in Childhood (n = 466), all children younger than 6 years with a diagnosis of idiopathic (IGE) or cryptogenic (CGE) generalized epilepsy either at intake (n = 108) and/or after 2 years of follow-up (n = 102) were included. The number of reclassifications after 2 years was determined, and the reasons for reclassification were analyzed. All children receiving a diagnosis of IGE or CGE at 2 years were followed up for 5 years to study their outcome in terms of terminal remission (TR). Data on their level of intellectual functioning were collected at the start of this analysis., Results: The epilepsy syndrome was reclassified in 17 children. In 14 of them, the seizure type also was reclassified, and in three, the course of the epilepsy determined the new epilepsy type. Two other children had a reclassification of their seizure types without a change of the epilepsy type. Many children were categorized as having IGE not otherwise specified. In all probability, this is a heterogeneous group, containing patients with various epilepsy syndromes, with generalized tonic-clonic seizures as a common hallmark. Of the 102 children with IGE or CGE at 2 years of follow-up, 75% had a TR of >6 months after 2 years, and 85% a TR of >or=1 year after 5 years., Conclusions: In a fair proportion of children with nonsymptomatic generalized epilepsy in this age group, it is not possible to classify firmly the epilepsy and/or the seizures immediately after the intake. Instead, they are reclassified during the course of the disease. This and the apparent heterogeneity of the category IGE not otherwise specified point to inherent drawbacks of the current International League Against Epilepsy (ILAE) classification of epilepsy and epileptic syndromes. The prognosis of IGE at this young age is generally excellent.

Objective: To explore the course of epilepsy following relapse after antiepileptic drug (AED) withdrawal., Methods: Forty two patients were identified with onset of epilepsy in childhood in whom AEDs had been withdrawn after at least 2 years of seizure freedom, and in whom a relapse had occurred. Two patients were lost to follow up., Results: Median follow up after AED withdrawal was 5.9 years (range 1.6-13.2 years). Relapse occurred in more than half of the patients within 6 months of AED withdrawal. At the end of follow up, 12 patients (30%) were seizure free for at least 1 year (mean 10.4 years) without medication; 16 (40%) were seizure free for at least 1 year (mean 5.3 years) with ongoing medication; and 12 patients (30%) were seizure free for less than 1 year with medication. No status epilepticus occurred in any patient after withdrawal. Age at onset, if over the age of 5, combined with normal intelligence were predictive of an excellent outcome; presence of a neurological disorder, and hence symptomatic aetiology, was predictive of poor outcome after a relapse., Conclusions: Fears that premature withdrawal of AEDs might result in uncontrollable seizures were unsubstantiated in this study. The current practice of withdrawing AEDs in children who have been seizure free for 2 years can be beneficial to most of these patients.

Objective: Long-term follow-up studies of patients with epilepsy have revealed an increased mortality risk compared with the general population. Mortality of children who have epilepsy in modern times is as yet unknown. Therefore, the objective of this study was to determine mortality of children who have epilepsy in comparison with the general population., Methods: Between August 1988 and August 1992, 472 children, aged 1 month to 16 years, who presented in 1 of the participating hospitals with 2 or more newly diagnosed unprovoked seizures or at least 1 status epilepticus were enrolled in the study. All children were followed for 5 years or until death. The number of deaths observed during follow-up was compared with the expected number of deaths in the same age group in the general population in the Netherlands., Results: Nine children died during follow-up, amounting to a mortality rate of 3.8/1000 person-years, which is sevenfold higher than expected (95% confidence interval = 2.4-11.5). No deaths were observed among the 328 children who had epilepsy of nonsymptomatic cause. All deceased children had epilepsy that was caused by a static or progressive neurologic disorder (mortality risk = 22.9; 95% confidence interval = 7.9-37.9). None of them died from sudden unexpected and unexplained death of epilepsy., Conclusions: In our cohort, we found no indication that children who have nonsymptomatic epilepsy have an increased mortality risk compared with the general population, whereas children who have symptomatic epilepsy have a 20-fold increased mortality risk. These data provide guidance for counseling parents of children who have epilepsy.

A diagnostic lumbar puncture was performed in a 12-year-old male with acute lymphoblastic leukemia. Because of thrombocytopenia (platelet count 42,000/mm(3)), a platelet transfusion was given immediately before the lumbar puncture. However, the platelet count was not re-examined. The patient developed progressive paraparesis shortly after the lumbar puncture. Magnetic resonance imaging revealed an extensive spinal subdural hematoma from the T2 to S2 level. This case report illustrates the sometimes dramatic consequences of lumbar puncture in patients with childhood leukemia. Guidelines for the examination of the platelet count and correction of thrombocytopenia before lumbar puncture are discussed.

This paper reviews Angelman syndrome (AS) with regard to the clinical features in childhood and adulthood, epileptic seizures and EEG findings, neuroimaging studies and the present knowledge on the genetic mechanisms underlying this syndrome. Different clinical phenotypes and genotypes of AS are described, including chromosome 15q11-13 deletion, uniparental disomy, methylation imprinting abnormalities and mutations in the UBE3A gene.

Progressive walking difficulties and bladder dysfunction may be attributed to Alzheimer disease or atlanto-axial subluxation in people with Down's syndrome (DS). The present authors describe five patients with DS suffering from the above symptoms as a result of cervical spondylarthrotic myelopathy. Clinical and radiological data were collected from all patients with DS who underwent surgery for cervical spondylarthrotic myelopathy at the Leiden University Medical Centre during the period between 1991 and 1995. Five patients with DS (four males and one female) were identified. Their mean age at diagnosis was 42 years. The main clinical features were weakness of the arms and legs, ataxic gait, hyperreflexia and bilateral Babinski signs. Radiological examination showed spondylarthrosis, compression of the spinal cord and myelomalacia. The mean delay in diagnosis was 3 years. All five individuals showed clinical stabilization after laminectomy. Cervical spondylarthrotic myelopathy seems a rather frequent disorder in DS, occurring at a relatively young age. Early diagnosis may prevent irreversible neurological deficits.

Four previously healthy children, two boys aged 5 and one boy and one girl aged 4 more or less acutely developed a stumbling gait. The causes varied from benign such as postviral acute cerebellar ataxia and benign paroxysmal vertigo to potentially life-threatening such as intoxication with benzodiazepines and medulloblastoma. Treatment led to complete or partial recovery. (Sub)acute balance disorders in previously healthy children can be due to cerebellar ataxia, vestibular disorders and abnormal proprioception. Ancillary investigations are warranted in case of gradually developing ataxia, accompanying neurological deficits, suspicion of intoxication, recurrent or familial ataxia, no spontaneous remission or even progression. In children with an isolated cerebellar ataxia without these features, ancillary investigations may be avoided, although in such cases careful follow-up remains necessary.

Purpose: To examine which variables available early in the course of childhood epilepsy are associated with a poor short-term outcome and to develop models to predict such an outcome., Methods: We prospectively followed up 466 children with newly diagnosed epilepsy for 2 years. Variables were collected at intake and after 6 months. Outcome was defined as the duration of the terminal remission (TR): poor (<6 months) and not poor (> or =6 months)., Results: Of the subjects, 31% had a poor outcome. Multivariate analysis based on the intake variables identified number of seizures, seizure type, and etiology as risk factors for a poor outcome. With the intake and 6-month variables combined, seizure type, etiology, the number of seizures, and not attaining a 3-month remission during these 6 months, and the EEG at 6 months were predictive variables. A predictive model based on the multivariate logistic-regression analysis with the intake variables was correct in 56% of the children in whom it predicted a poor outcome and in 73% of the children in whom it predicted a not-poor outcome. With the intake and 6-month variables together, these percentages were 66 and 79%, respectively. The sensitivity of these models was low (29 and 47%, respectively); the specificity was good (90 and 89%)., Conclusions: The 2-year outcome of childhood epilepsy is closely related to its early course. The prognosis is poor in approximately 30% of patients. By using our data, the prediction of a poor outcome is correct in almost two thirds of the patients; however, the models produce many false-negative predictions.

Since occult spinal dysraphism can lead to irreversible neurological complications, early diagnosis and treatment are necessary. We retrospectively studied the presenting clinical signs and symptoms in all 47 cases of occult spinal dysraphism identified in two university hospitals in The Netherlands since 1965. Dermal sinus had been diagnosed in 12, lipomyelomeningocele in nine, and diastematomyelia in eight patients. Thirty-three patients had symptoms due to tethering of the spinal cord, leading to a clinical suspicion of occult spinal dysraphism in only eight cases. Twenty-eight patients had cutaneous back lesions that led to further investigation in eight cases. Nineteen patients had a small backmass leading to further examination in 13 cases. Three patients with dermal sinus presented with meningitis caused by an unusual aetiological agent. This study stresses the importance of identification of neurological dysfunction due to tethered cord syndrome, cutaneous back lesions, a small backmass and meningitis caused by an unusual aetiological agent for the early diagnosis of occult spinal dysraphism.

Three neonates had diverse kinds of central apnoea. The first child, a girl aged 3 weeks, had an upper respiratory tract infection caused by the respiratory syncytial virus; she was intubated and needed ventilatory support for three days. The second patient, a boy of 17 days, had an Arnold-Chiari-malformation with apnoeas treated with a carbonic anhydrase inhibitor (acetazolamide). The third patient, a boy of 5 days, had central apnoeas of epileptic origin and was treated with phenobarbital. All three recovered well. If in an infant with apnoeas no paediatric explanation is found, and the child is neurologically at risk, it is advisable to make an EEG to determine if an epileptic substrate is present, even in the absence of motor phenomena.

There exist various types of epilepsy in children, which can be classified on the basis of nature and severity of the impairment of consciousness and the motor phenomena. The anamnesis is the main aid in distinguishing a seizure from a non-epileptic convulsion. Convulsions may have a number of causes, which may or may not be acute, while several factors may provoke attacks. The extent and necessity of supplementary investigation depend mostly on the child's clinical condition at presentation and on the nature of the seizure(s). The electro-encephalogram is important for the classification of the type of seizure. Anti-epileptic medication should not be started after a single epileptic seizure; whether it will be started after several attacks depends on the frequency and severity of the seizures, and on the syndrome diagnosis made. The long-term prognosis depends mostly on the syndrome diagnosis.

Background: It is not known how many children with epilepsy may not need treatment with antiepileptic drugs (AEDs), how many respond unsatisfactorily to subsequent treatment regimens, and how many achieve "acceptable control" despite lack of remission., Methods: In a prospective multicenter hospital-based study, 494 children with a broad range of seizure types and types of epilepsy were followed up for at least 2 years. There was no standard treatment protocol. We describe the treatment strategies applied to these children by the neurologists in charge and outcome with respect to remission from seizures., Results: Treatment was initially withheld in 29% of the children, and after 2 years 17% still had not received any AEDs. There were no serious complications caused by withholding treatment. Of the children treated with AEDs, 60% were still using the first AED after 2 years; 80% received monotherapy and 20%, polytherapy. Children with severe symptomatic epilepsies, such as the West or Lennox-Gastaut syndrome, received polytherapy early on in the course of treatment. When 3 regimens had failed, the chance of achieving a remission of more than 1 year with subsequent regimens was 10%. Nevertheless, 15 of 50 children receiving AEDs in whom the "longest remission ever" was less than 6 months did achieve acceptable seizure control according to the neurologist in charge of treatment. Hence, of 494 children, only 35 (7%) developed an intractable form of epilepsy, defined as failure to bring seizures under acceptable control., Conclusions: A substantial percentage of children with new-onset epilepsy did not need treatment with AEDs. Chances of achieving a good outcome declined with subsequent treatment regimens. Not all children with recurrent seizures were suffering from intractable epilepsy; some had achieved acceptable control of seizures.

We determined the diagnostic value of the EEG in young children with Angelman syndrome (AS) and Rett syndrome (RS). EEGs, recorded before 5 years of age, of 10 patients with AS, 10 with RS and 10 with mental retardation of other origin were studied blindly by two examiners for the presence of the following items: (A) 4-6 Hz rhythmic activity of over 200 microV; (B) 2-3 Hz frontal activity of 200-500 microV; (C) posterior spikes; (D) triphasic frontal waves; (E) central and/or centro-temporal spike-wave complexes; and (F) other epileptic discharges. Based on these items the EEGs were scored as AS (A-D); RS (E-F); or other. Examiners never made a mistake between AS and RS. One examiner labeled 6 of 10 AS cases correctly, the other 5; 4 (5) were characterized as 'other.' In RS cases 5 were labeled as 'other' by the first examiner and 3 by the second one. We conclude that EEG patterns of AS and RS are sufficiently different to help differentiate between AS and RS at a young age, which has a bearing on genetic counseling.

Objective: To assess the accuracy of the diagnosis of a first unprovoked seizure in childhood, the recurrence rate within two years, the risk factors for recurrence, and the long term outcome two years after recurrence., Methods: One hundred and fifty six children aged 1 month to 16 years after a first seizure, and 51 children with a single disputable event were followed up. The diagnosis of a seizure was confirmed by a panel of three child neurologists on the basis of predescribed diagnostic criteria. None of the children was treated after the first episode., Results: Five children with a disputable event developed epileptic seizures during follow up. The diagnosis did not have to be revised in any of the 156 children with a first seizure. The overall recurrence rate after two years was 54%. Significant risk factors were an epileptiform EEG (recurrence rate 71%) and remote symptomatic aetiology and/or mental retardation (recurrence rate 74%). For the 85 children with one or more recurrences, terminal remission irrespective of treatment two years after the first recurrence was >12 months in 50 (59%),