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Context: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model.Objective: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1.Design, Setting, and Participants: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital.Intervention: Simvastatin or placebo treatment once daily for 12 weeks.Main Outcome Measures: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex.Results: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment.Conclusion: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707. [ABSTRACT FROM AUTHOR]

The reliability of visual interpretation of electroencephalograms (EEG) is of great importance in assessing the value of this diagnostic tool. We prospectively obtained 50 standard EEGs and 61 EEGs after partial sleep deprivation from 93 children (56 males, 37 females) with a mean age of 6 years 10 months (SE 5mo; range 4mo-15y 7mo) with one or more newly diagnosed, unprovoked seizures. Two clinical neurophysiologists independently classified the background pattern and the presence of epileptiform discharges or focal non-epileptiform abnormalities of each EEG. The agreement was substantial for the interpretation of the EEG as normal or abnormal (kappa 0.66), almost perfect for the presence of epileptiform discharges (kappa 0.83), substantial for the occurrence of an abnormal background pattern (kappa 0.73), and moderate for the presence of focal non-epileptiform discharges (kappa 0.54). In conclusion, the reliability of the visual interpretation of EEGs in children is almost perfect as regards the presence of epileptiform abnormalities, and moderate to substantial for the presence of other abnormalities. [ABSTRACT FROM AUTHOR]

It is unknown whether treatment with antiepileptic drugs in children with epilepsy with a presumed good prognosis is always necessary. We aimed to study the course of newly diagnosed epilepsy in children with a presumed good prognosis who are managed without AED treatment. A total of 151 children (one month to 12 years of age) with two to five lifetime unprovoked seizures (excluding febrile convulsions), were followed for three years. Treatment was initially withheld. Children with symptomatic epilepsy, or absence or myoclonic epilepsy, were excluded. AED treatment was started after >10 lifetime seizures or an episode of status epilepticus during follow-up, or if the parents or treating physician deemed it otherwise necessary. During follow-up, 113 children continued to meet our criteria for refraining from treatment with antiepileptic drugs, yet 30 started treatment at the request of the parents. Thirty-eight children at some time met the criteria to start treatment, but the parents of 16 declined treatment. In all, 99 (66%) children maintained the no-treatment regime. Ninety-eight children (65% of 151) reached terminal remission for at least one year, including 83 who did not receive antiepileptic drug treatment (84% of the untreated 99). Mean terminal remission was significantly longer in the group with a total of <10 seizures compared to those with >10 seizures. Treatment did not increase the length of terminal remission. Adverse events, including traumatic injury, occurred equally in the treated and untreated children. Measures of quality of life suggested a better outcome in those without treatment. Children with newly diagnosed epilepsy with a presumed good prognosis may not need immediate AED treatment. Postponing treatment does not alter the chance of remission or the risk of accidents and adverse events and appears to be associated with a good quality of life.

Background: The ketogenic diet (KD) can be effective in reducing seizures in children. Predictors of success have not been identified yet., Aims: To evaluate efficacy of KD treatment and to search for child- or diet-related factors that can predict its efficacy at 12 months follow-up. In addition we wish to determine the usefulness of a 3-month KD trial period., Methods: Single center retrospective study in a university paediatric hospital of children with refractory epilepsy in which the KD had been initiated. Patient and diet characteristics as well as seizure reduction data were obtained from medical records and parental review. Efficacy of the KD was defined as ≥ 50% seizure reduction. Variables were evaluated in their relation to a successful treatment at three and 12 months after diet initiation., Results: During a 9.5-year period, the KD was initiated in 59 children with refractory epilepsy. Twenty-four children were still on the KD after 12 months, and 21 experienced ≥50% seizure reduction. Success of the KD at three months was significantly related to a successful response to KD treatment at 12 months (p < 0.001)., Conclusions: The KD can be an effective treatment in reducing seizures in children with refractory epilepsy. No significant relationships between variables and efficacy at 12 months were revealed. Children with a successful response at 3 months were significantly more likely to achieve success at 12 months of KD treatment., (Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Neuropsychological deficits after treatment of paediatric brain tumour are well known, but not the role of hydrocephalus in these deficits., Aims: To study long-term neurological, cognitive, and behavioural deficits in children with a low grade tectal tumour and acquired obstructive hydrocephalus., Methods: In a consecutive series of 12 children with low-grade tectal tumour diagnosed in our hospital between 1994 and 2008, neurologic, neuropsychological, and radiologic data were prospectively collected. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Median follow-up was 2 years and 9 months., Results: At follow-up, most frequent neurologic disability was fatigue in children with a low-grade tectal tumour. They scored lower on sustained attention, long-term memory and had more behavioural problems. Factor influencing cognition was persisting severe hydrocephalus at time of assessment. The cognitive problems resulted in 60% of children needing assistances of special services at school., Conclusions: At long-term, children with a low-grade tectal tumour display invalidating neuropsychological impairments resulting in educational problems. Adequate treatment of hydrocephalus may result in better cognitive functioning. Our findings suggest that part of the symptoms of the cerebellar cognitive affective syndrome may not have resulted from a cerebellar lesion itself but rather from a cerebral dysfunction or compression of supratentorial structures in the cerebello-cortical circuitry due to the obstructive hydrocephalus., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

The objective of this study was to examine the validity of the diagnosis of "febrile seizure" as reported by parents. The study was embedded in a population-based prospective cohort study. Information on paroxysmal events was obtained by screening questions at ages 1, 2, and 3 years. One of these questions was the following: "Did your child have a febrile seizure?" If a screen-positive result was found, an additional questionnaire was sent and the medical record was consulted. Based on this information, paroxysmal events were classified by a pediatric neurologist as febrile seizure or other event. The validity of a positive reply to the screening question on febrile seizures was assessed, taking this classification as reference standard. Analyses were based on participants who reported at least one paroxysmal event (n = 610). The sensitivity of the positive reply to the question, "Did your child have a febrile seizure?", for the diagnosis of febrile seizures was 92%, the specificity 72%, the positive predictive value 41%, and the negative predictive value 98%. In conclusion, the sensitivity of the question, "Did your child have a febrile seizure?", is high. The positive predictive value is only 41%. Although this question may be appropriate as a screening instrument for febrile seizures, a second stage of evaluation is necessary to identify true cases., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Estimate the causes and risk of death, specifically seizure related, in children followed from onset of epilepsy and to contrast the risk of seizure-related death with other common causes of death in the population., Methods: Mortality experiences from 4 pediatric cohorts of newly diagnosed patients were combined. Causes of death were classified as seizure related (including sudden unexpected death [SUDEP]), natural causes, nonnatural causes, and unknown., Results: Of 2239 subjects followed up for >30 000 person-years, 79 died. Ten subjects with lethal neurometabolic conditions were ultimately excluded. The overall death rate (per 100 000 person-years) was 228; 743 in complicated epilepsy (with associated neurodisability or underlying brain condition) and 36 in uncomplicated epilepsy. Thirteen deaths were seizure-related (10 SUDEP, 3 other), accounting for 19% of all deaths. Seizure-related death rates were 43 overall, 122 for complicated epilepsy, and 14 for uncomplicated epilepsy. Death rates from other natural causes were 159, 561, and 9, respectively. Of 48 deaths from other natural causes, 37 were due to pneumonia or other respiratory complications., Conclusions: Most excess death in young people with epilepsy is not seizure-related. Mortality is significantly higher compared with the general population in children with complicated epilepsy but not uncomplicated epilepsy. The SUDEP rate was similar to or higher than sudden infant death syndrome rates. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to or higher than rates for other common causes of death in young people (eg, accidents, suicides, homicides). Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with patients and families.

Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.

Objective: Monocarboxylate transporter 8 (MCT8) is an essential thyroid hormone (TH) transporter as humans with MCT8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block-and-replace treatment in an MCT8 patient., Design: The TOP-R study is a cross-sectional nation-wide multicentre study., Patients: Subjects with unexplained mental retardation (MR) were screened for MCT8 mutations., Results: We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block-and-replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU, and eventually their complete normalization by administration of LT4 with PTU but not with methimazole. The frequency of MCT8 mutations in males with X-linked MR approximately 3·9%., Conclusions: We identified several MCT8 mutations in a cohort of subjects with unexplained MR. We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block-and-replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT8 mutations. Our study indicates that MCT8 mutations are a relatively frequent cause of X-linked MR., (© 2012 Blackwell Publishing Ltd.)

Aim: General developmental outcome is known to be good in school-aged children who experienced febrile seizures. We examined cognitive and behavioural outcomes in preschool children with febrile seizures, including language and executive functioning outcomes., Method: This work was performed in the Generation R Study, a population-based cohort study in Rotterdam from early fetal life onwards. Information about the occurrence of febrile seizures was collected by questionnaires at the ages of 1, 2, and 3 years. At the age of 3 years, behaviour and emotion were assessed using the Child Behavior Checklist. Information on expressive language development was obtained by the Language Development Survey at the age of 2 years 6 months. To assess executive functioning, parents completed the Behaviour Rating Inventory of Executive Function - Preschool Version when their children were 4 years old. Final analyses were based on 3157 children., Results: No associations were found between febrile seizures and the risk of behavioural problems or executive functioning. In contrast to single febrile seizures, recurrent febrile seizures were significantly associated with an increased risk of delayed vocabulary development (odds ratio 3.22, [95% confidence interval 1.30-7.94])., Interpretation: Febrile seizures are not associated with problem behaviour or executive functioning in preschool children, but the results suggest that children with recurrent febrile seizures might be at risk for delayed language development., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Objective: Classic infantile Pompe disease affects many tissues, including the brain. Untreated infants die within their first year. Although enzyme-replacement therapy (ERT) significantly increases survival, its potential limitation is that the drug cannot cross the blood-brain barrier. We therefore investigated long-term cognitive development in patients treated with ERT., Methods: We prospectively assessed cognitive functioning in 10 children with classic infantile Pompe disease who had been treated with ERT since 1999. Brain imaging was performed in 6 children., Results: During the first 4 years of life, developmental scores in 10 children ranged from above-average development to severe developmental delay; they were influenced by the type of intelligence test used, severity of motor problems, speech/language difficulties, and age at start of therapy. Five of the children were also tested from 5 years onward. Among them were 2 tetraplegic children whose earlier scores had indicated severe developmental delay. These scores now ranged between normal and mild developmental delay and indicated that at young age poor motor functioning may interfere with proper assessment of cognition. We found delayed processing speed in 2 children. Brain imaging revealed periventricular white matter abnormalities in 4 children., Conclusions: Cognitive development at school age ranged between normal and mildly delayed in our long-term survivors with classic infantile Pompe disease treated with ERT. The oldest was 12 years. We found that cognition is easily underestimated in children younger than 5 years with poor motor functioning.

Purpose: Intractability in epilepsy is difficult to define, and little is known about its onset, course, and duration. We investigated these aspects (as well as the occurrence of intractability) during long-term follow-up in patients with epilepsy, focusing on possible explanations for the variation in time of onset and duration of intractability., Methods: After diagnosis, 453 patients with childhood-onset epilepsy had a 5-year follow-up with regular visits and data collection. Ten years later they received a questionnaire with items concerning epilepsy, which was completed by 413 patients resulting in a mean follow-up of 15 years. Intractability during the first 5 years was compared with that in the last year of follow-up. Intractability was defined as having no 3-month remission during a 1-year period despite adequate medical treatment., Key Findings: At least 12.1% of the cohort had a period of intractability during the 15-year follow-up, and 8.5% were intractable in the final year. Of the patients with idiopathic etiology 4.3% had a period of intractability versus 17.0% for those with cryptogenic, and 22.6% for those with remote symptomatic etiology (p < 0.001). Other risk factors at baseline were younger age at first seizure, generalized cryptogenic/symptomatic or localization-related symptomatic epilepsy, mental retardation, and febrile convulsions before enrollment. The cumulative risk of a period of intractability was 6.1% (95% confidence interval [CI] 3.7-8.5) at 2 years follow-up and 8.2% (95% CI 5.4-11.0) at 5 years. The mean time to onset of intractability during the first 5 years of follow-up was 1.6 (95% CI 1.3-2.0; median 1.0) years and the mean duration of intractability during these 5 years was 3.3 (95% CI 2.8-3.8; median 3.6) years. Fifteen patients were intractable only during the first 5 years of follow-up (group A), and 19 subjects were intractable both during the first 5 years and the last year of follow-up (group B). Compared with group A, group B had shorter remission and a longer time to intractability during the first 5 years and more were intractable in the fifth year of follow-up. Sixteen other patients had a late onset of intractability after 5 years of follow-up, sometimes after long periods of remission (group C). No significant differences in baseline characteristics were found among groups A, B, and C, but slightly more children in groups B and C became mentally retarded during the follow-up. In all groups, antiepileptic drugs were of little use in preventing and ending intractability., Significance: There is a large unpredictable variation in time of onset, course, and duration of intractability, with a higher chance of final intractability after a poor course during the first 5 years of follow-up. The natural course of epilepsy probably best explains the variable course of intractability. The effect of medication seems to be minor., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Aim: To examine the association between the number of fever episodes and the risk of febrile seizures., Methods: This study was embedded in a population-based prospective cohort study from early foetal life onwards. Information about the occurrence of febrile seizures and fever episodes was collected by questionnaires at the ages of 12, 24 and 36 months. Analyses were based on 3033 subjects. The risk of febrile seizures was compared between children with frequent fever episodes (>2 per year), and children with only 1 or 2 fever episodes per year., Results: The frequency of fever episodes was not associated with the risk of febrile seizures in the age range of 6-12 months. In the second and third year of life, having more than 2 fever episodes was associated with an increased risk of febrile seizures (odds ratios 2.02 [95% confidence interval 1.13-3.62] and 2.29 [95% confidence interval 1.00-5.24], respectively). In the age range between 6 and 36 months, we observed a significant trend between the frequency of fever episodes (<2, 3-4 or >4 per year) and the risk of febrile seizures (p-value for trend < 0.001). The association between the number of fever episodes and the occurrence of febrile seizures was stronger for children with recurrent febrile seizures., Conclusion: Frequent fever episodes are associated with an increased risk of febrile seizures in the second and third years of life. Further studies are needed to identify the mechanisms underlying this association., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: Epilepsy may have far-reaching consequences for patients, other than having seizures and medication. At 15 years after diagnosis, this study investigates health perception, restrictions due to epilepsy, living arrangements (including marital status and offspring), and the educational and occupational attainment of patients with childhood-onset epilepsy., Methods: A total of 453 patients with epilepsy had a 5-year follow-up since diagnosis with regular visits and data collection. Ten years later, a questionnaire addressing epilepsy was completed by 413 patients, resulting in a mean follow-up of 15 years. Subjects were compared with age peers of the Dutch population for each etiologic group separately, and also for subjects with/without a 5-year terminal remission regardless of treatment. Age-adjusted standardized incidence rates were calculated for each variable., Key Findings: Subjects with normal intelligence had a health perception comparable with that of the general population, but significantly more subjects without remission had a worse health perception, especially those still using medication. Restrictions and symptoms due to epilepsy were reported by 14% of the subjects, mainly by those without remission or with ongoing medication. The living arrangement of subjects with idiopathic or cryptogenic etiology was similar to that of Dutch persons of the same age (age peers). Subjects with remote symptomatic etiology less often lived independently or with a partner, and more frequently resided in an institution or living group for the disabled. Those with and without remission were more often part of another household, mainly due (in both groups) to having a remote symptomatic etiology. Rates of having a partner and offspring were significantly reduced only for subjects with remote symptomatic etiology. Fewer students with idiopathic/remote symptomatic etiology and students in remission followed higher vocational or scientific education. In these latter groups, the highest attained education of employees was lower than expected. The employment status of subjects with idiopathic or cryptogenic etiology was comparable with that of their Dutch age peers, but fewer subjects with remote symptomatic etiology were employed and more of them were part of the dependent population. However, for those in the labor force (employed/unemployed) all employment rates were ≥90%, even for those with remote symptomatic etiology. Nevertheless, fewer employees than expected had a higher vocational or scientific level of occupation, even those with idiopathic etiology and those in remission., Significance: Health perception, living arrangement, and socioeconomic status were influenced by epilepsy, comorbidities, or treatment, particularly for subjects with remote symptomatic etiology or no remission. The group in remission fared less well than expected, mainly due to the numbers of subjects with remote symptomatic etiology in this group. In line with others, we conclude that childhood-onset epilepsy is associated with lower educational attainment, even for subjects with idiopathic etiology and subjects in remission; probably related to this, their occupational level was also lower than expected., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Point mutations in PMP22 are relatively rare and the phenotype may vary from mild hereditary neuropathy with liability to pressure palsies (HNPP) to severe Charcot-Marie-Tooth type 1 (CMT1). We describe the phenotype of the Gly94fsX222 mutation in the PMP22 gene. Medical records of all patients were reviewed and 11 patients were re-examined. EMG was carried out in nine patients and nerve biopsy in one. Thirteen patients originating from seven families with a Gly94fsX222 mutation were included and consisted of 10 women and 3 men with a median age of 41 years (range 7-67). Five index patients were originally suspected of CMT1. Ten patients had abnormal motor skills during childhood. Nine patients had a history of pressure palsies. Involvement of the olfactory, trigeminal, facial, and pudendal nerves occurred in three patients. Twelve patients had pes cavus and one scoliosis. Distal anterior leg and distal arm weakness were found in 12 and 4 patients, respectively. Twelve patients had distal leg sensory abnormalities. Electrophysiological examination revealed a demyelinating sensorimotor neuropathy, both resembling CMT1 and HNPP. Sural nerve biopsy showed demyelinating neuropathy with presence of tomacula. More than three-fourths of the patients with Gly94fsX222 mutation demonstrated a CMT1 phenotype combined with transient deficits. Clinicians should test for this mutation in those patients exhibiting a generalised neuropathy combined with compressive like episodes., (© 2011 Peripheral Nerve Society.)

Aim: To evaluate survival, clinical, and genetic characteristics of all patients with classic or type 1 lissencephaly born between 1972 and 1990 in the Netherlands, who at the time were enrolled in an observational study., Method: We re-evaluated 24 patients (11 males, 13 females) for long-term follow-up and survival information., Results: Mean length of follow-up was 14 years (SD 9 y 8 mo). Eleven patients were alive at follow-up. All patients showed severe intellectual disability, intractable epilepsy, and complete dependency on care. Life expectancy was related to the severity of the lissencephaly on neuroimaging. Molecular analysis of the LIS1 gene was not possible at the time of the original study and was now requested by eight parents. This revealed a pathogenic nonsense mutation or deletion in seven patients., Interpretation: Our study provides information about the long-term course of lissencephaly and the relationship between lissencephaly severity and prognosis. It also shows that renewed attention to genetic counselling remains valued by families of patients with a severe congenital neurological disease., (© The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.)

Pompe disease is a rare neuromuscular disorder caused by deficiency of acid α-glucosidase. Treatment with recombinant human α-glucosidase recently received marketing approval based on prolonged survival of affected infants. The current open-label study was performed to evaluate the response in older children (age 5.9-15.2 years). The five patients that we studied had limb-girdle muscle weakness and three of them also had decreased pulmonary function in upright and supine position. They received 20-mg/kg recombinant human α-glucosidase every two weeks over a 3-year period. No infusion-associated reactions were observed. Pulmonary function remained stable (n = 4) or improved slightly (n = 1). Muscle strength increased. Only one patient approached the normal range. Patients obtained higher scores on the Quick Motor Function Test. None of the patients deteriorated. Follow-up data of two unmatched historical cohorts of adults and children with Pompe disease were used for comparison. They showed an average decline in pulmonary function of 1.6% and 5% per year. Data on muscle strength and function of untreated children were not available. Further studies are required., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Riboflavin seems to have a promising effect on migraine in adults. The present study examines whether riboflavin has a prophylactic effect on migraine in children., Objective: To investigate whether riboflavin in a dosage of 50 mg/day has a prophylactic effect on migraine attacks in young children., Subjects and Methods: This randomised, placebo-controlled, double-blind, cross-over trial included 42 children (aged 6-13 years) with migraine of whom 14 children were also suffering from tension-type headache. Following a 4-week baseline period, all children received placebo for 16 weeks then riboflavin for 16 weeks (or vice versa) with a washout period of 4 weeks in between. The primary outcome measure was reduction in mean frequency of migraine attacks and tension-type headache in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period. Secondary outcome measures were mean severity and mean duration of migraine and tension-type headaches in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period., Results: No significant difference in the reduction of mean frequency of migraine attacks in the last month of treatment was found between placebo and riboflavin (P = 0.44). However, a significant difference in reduction of mean frequency of headaches with a tension-type phenotype was found in favour of the riboflavin treatment (P = 0.04)., Conclusions: In this group of children with migraine, there is no evidence that 50 mg riboflavin has a prophylactic effect on migraine attacks. We found some evidence that 50 mg riboflavin may have a prophylactic effect on interval headaches that may correspond to mild migraine attacks or tension-type headache attacks in children with migraine.

Aim: To examine the incidence of paroxysmal epileptic and non-epileptic disorders and the associated prenatal and perinatal factors that might predict them in the first year of life in a population-based cohort., Method: This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Information about the occurrence of paroxysmal events, defined as suddenly occurring episodes with an altered consciousness, altered behaviour, involuntary movements, altered muscle tone, and/or a changed breathing pattern, was collected by questionnaires at the ages of 2, 6, and 12 months. Information on possible prenatal and perinatal determinants was obtained by measurements and questionnaires during pregnancy and after birth., Results: Information about paroxysmal events in the first year of life was available in 2860 participants (1410 males, 1450 females). We found an incidence of paroxysmal disorders of 8.9% (n=255) in the first year of life. Of these participants, 17 were diagnosed with febrile seizures and two with epilepsy. Non-epileptic events included physiological events, apnoeic spells, loss of consciousness by causes other than epileptic seizures or apnoeic spells, parasomnias, and other events. Preterm birth (p<0.001) and low Apgar score at 1 minute (p<0.05) were significantly associated with paroxysmal disorders in the first year of life. Continued maternal smoking during pregnancy and preterm birth were significantly associated with febrile seizures in the first year of life (p<0.05)., Interpretation: Paroxysmal disorders are frequent in infancy. They are associated with preterm birth and a low Apgar score. Epileptic seizures only form a minority of the paroxysmal events in infancy. In this study, children whose mothers continued smoking during pregnancy had a higher reported incidence of febrile seizures in the first year of life. These findings may generate various hypotheses for further investigations., (© The Authors. Journal compilation © Mac Keith Press 2010.)

Purpose: To determine long-term outcome in a cohort of children with newly diagnosed benign childhood epilepsy with centrotemporal spikes (BECTS)., Methods: 29 children with BECTS were included in the Dutch Study of Epilepsy in Childhood. Each child was followed for 5 years, and subsequently contacted 12-17 years after enrolment to complete a structured questionnaire. Twenty children had typical BECTS, nine had atypical BECTS (age at onset <4 years, developmental delay or learning difficulties at inclusion, other seizure types, atypical EEG abnormalities)., Results: Mean age at onset of epilepsy was 8.0 years with slight male preponderance. Most common seizure-types before enrolment were generalized tonic-clonic seizures (GTCS) and simple partial seizures; in 86% of the children seizures occurred during sleep. After 12-17 years, 96% had a terminal remission (TR(F)) of more than 5 years and 89% of more than 10 years. Mean duration of epilepsy was 2.7 years; mean age at reaching TR(F) was 10.6 years. Many children (63%) had experienced one or more (secondary) GTCS. Antiepileptic drugs were used by 79% of the children with a mean duration of 3.0 years. None of the children seemed to have developed learning problems or an arrest of cognitive development during follow-up. No significant differences were observed in patient characteristics or outcome between children with typical BECTS and children with atypical BECTS., Conclusions: All children in our cohort, both those with typical and atypical BECTS, had a very good prognosis with high remission rates after 12-17 years. None of the predictive factors for disease course and outcome observed in earlier studies (other seizure types, age at onset, multiple seizures at onset) were prognostic in our cohort., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: The goal was to examine the associations between fetal growth characteristics in different trimesters of pregnancy and the occurrence of febrile seizures in early childhood., Methods: This study was embedded in a population-based, prospective, cohort study from early fetal life onward. Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) were measured with ultrasonography in the second and third trimesters of pregnancy. Information on the occurrence of febrile seizures was collected with questionnaires at the ages of 12 and 24 months. Analyses were based on data for 3372 subjects., Results: In the second trimester, children in the lowest tertile of TCDs were at increased risk of developing febrile seizures, compared with children in the highest tertile (odds ratio 2.87 [95% confidence interval: 1.31-6.28]). In the third trimester, children in the lowest tertile of all general growth characteristics (femur length, abdominal circumference, and estimated fetal weight) were at increased risk of developing febrile seizures. This association was strongest for children in the lowest tertile of estimated fetal weight (odds ratio: 2.57 [95% confidence interval: 1.34-4.96]). Children in the lowest tertile of biparietal diameter in the third trimester also were at increased risk of febrile seizures. Similar but not statistically significant tendencies were observed for head circumference and TCD., Conclusions: Fetal growth retardation is associated with increased risk of febrile seizures in the first 2 years of life. Adverse environmental and genetic factors during pregnancy may be important in the development of febrile seizures.

We report a case of a girl who presented with typical absence seizures at age of 4.5 years. EEG showed absence seizures of sudden onset with 3 Hz spike-and-waves that also correlated with the clinical absences. The seizure semiology included subtle deviation of the eyes which prompted MRI investigation of the brain. This showed a periventricular nodular heterotopia in the mid to anterior horn of the right lateral ventricle. Although possibly coincidental, periventricular heterotopia are considered to be epileptogenic and this association has been reported once before. Migration disorders, such as in the periventricular heterotopia of our patient, may influence the formation and excitability of the striato-thalamo-cortical network involved in the generation of 3 Hz spike-waves., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: In past decades, numerous population- and hospital-based studies have revealed a relationship between migraine or headache and psychopathology in children., Objective: To describe and assess all clinical studies on the prevalence and manifestations of psychological functioning and psychiatric comorbidity in children with migraine and to provide recommendations for its diagnosis and treatment., Methods: A literature search was performed in Medline, Embase, PsycINFO, and the Cochrane Database to identify clinical studies that assessed psychological functioning and/or psychiatric comorbidity in children with migraine. Trial quality was assessed according to a standardized and validated set of criteria., Results: Seven studies met our inclusion criteria. Evidence assessment was performed by using the best-evidence synthesis method of Slavin. On the basis of this method, we found strong evidence that children with migraine in a clinical setting do not exhibit more withdrawn behavior, do not have more thought problems, do not have more social problems, and do not exhibit more delinquent or aggressive behavior than healthy children. Furthermore, there is strong evidence that children with migraine have more somatic complaints and exhibit internalizing behavior which is, given the construct of the outcome measure used, a consequence of the nature of their disease rather than a sign of psychological dysfunctioning. Finally, compared with healthy children, there is limited evidence that children with migraine in a clinical setting are more frequently diagnosed with oppositional defiant disorder, and they are not more frequently diagnosed with attention-deficit/hyperactivity disorder, conduct disorder, dysthymia, or depression., Conclusions: On the basis of this review, we conclude that children with migraine at referral to a specialist do not exhibit more psychological dysfunctioning and (to a lesser extent) do not exhibit more psychiatric comorbidity compared with healthy controls.

Purpose: To study the course and outcome of childhood-onset epilepsy during 15-year follow-up (FU)., Methods: We extended FU in 413 of 494 children with new-onset epilepsy recruited in a previously described prospective hospital-based study by questionnaire., Results: Mean FU was 14.8 years (range 11.6-17.5 years). Five-year terminal remission (TR) was reached by 71% of the cohort. Course during FU was favorable in 50%, improving in 29%, and poor or deteriorating in 16%. Mean duration of seizure activity was 6.0 years (range 0-21.5 years), strongly depending on etiology and epilepsy type. Duration was <1 year in 25% of the cohort and exceeded 12 years in another 25%. Antiepileptic drugs (AEDs) were used by 86% during a mean of 7.4 years: one-third had their last seizure within 1 year of treatment, and one-third continued treatment at the end, although some had a 5-year TR. At last contact, 9% of the cohort was intractable. In multivariate analysis, predictors were nonidiopathic etiology, febrile seizures, no 3-month remission, and early intractability. Eighteen patients died; 17 had remote symptomatic etiology. Standardized mortality ratio for remote symptomatic etiology was 31.6 [95% confidence interval (CI) 18.4-50.6], versus 0.8 [95% CI 0.02-4.2] for idiopathic/cryptogenic etiology., Discussion: In most children with newly diagnosed epilepsy, the long-term prognosis of epilepsy is favorable, and in particular, patients with idiopathic etiology will eventually reach remission. In contrast, epilepsy remains active in approximately 30% and becomes intractable in approximately 10%. AEDs probably do not influence epilepsy course; they merely suppress seizures. Mortality is significantly higher only in those with remote symptomatic etiology.

Phosphoribosylpyrophosphate synthetases (PRSs) catalyze the first step of nucleotide synthesis. Nucleotides are central to cell function, being the building blocks of nucleic acids and serving as cofactors in cellular signaling and metabolism. With this in mind, it is remarkable that mutations in phosphoribosylpyrophosphate synthetase 1 (PRPS1), which is the most ubiquitously expressed gene of the three PRS genes, are compatible with life. Mutations described thus far in PRPS1 are all missense mutations that result in PRS-I superactivity or in variable levels of decreased activity, resulting in X-linked Charcot-Marie-Tooth disease-5 (CMTX5), Arts syndrome, and X-linked nonsyndromic sensorineural deafness (DFN2). Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment. Postlingual progressive hearing loss is found as an isolated feature in DFN2 patients. Patients with CMTX5 and Arts syndrome have peripheral neuropathy, including hearing impairment and optic atrophy. However, patients with Arts syndrome are more severely affected because they also have central neuropathy and an impaired immune system. The neurological phenotype in all four PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in two Arts syndrome patients show improvement of their condition, indicating that SAM supplementation in the diet could alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides (J.C., unpublished data)., ((c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

This study reports results of therapy with immunoglobulin in children with Landau-Kleffner syndrome (LKS) or the syndrome of continuous spikes and waves during sleep (CSWS syndrome). In a prospective study, children diagnosed between 2002 and 2006 with either LKS or CSWS syndrome were treated soon after diagnosis with intravenous courses of immunoglobulin (IVIg). We compared the results with those reported in the literature and with data from a retrospective survey of our earlier patients. Six children (two girls), aged 4-9 years, were included. Three had LKS, and three had CSWS syndrome. One child-with typical LKS-had been treated with prednisone before (without response). No patient had seizures during IVIg treatment and follow-up. Their electroencephalography (EEG) findings did not improve. Neuropsychological improvement occurred in one child with CSWS syndrome. Three children did not show any beneficial effect; they were subsequently treated with steroids, one with a clearly positive result. We conclude that successful treatment of LKS and CSWS syndrome with IVIg occurs occasionally. However, the improvement cannot always be clearly attributed to this. It might also reflect the natural course of the disease. Although the temporal relation between IVIg treatment and clinical improvement cannot be denied in individual patients, its real value remains to be determined.

Knowledge on the quality of life of children with headache is lacking. Until now only a few studies in this field have provided information on a limited number of life domains. The aim of this study was to assess the quality of life in a comprehensive number of life domains in children with primary headache presenting at an out-patient paediatric department in a general hospital. From October 2003 to October 2005 all children referred to the out-patient paediatric department of the Vlietland Hospital because of primary headache were investigated by protocol. A thorough history was taken and a general physical and neurological examination was performed. The International Headache Society criteria were used for classification. Quality of life (QoL) was measured using the Dutch version of the Child Health Questionnaire (CHQ-PF50 Dutch edition) and compared with data from a previously investigated cohort of healthy children from the same region, and with data from a cohort of children from the USA with asthma or with attention deficit hyperactivity disorder (ADHD), investigated with the CHQ-PF50. A total of 70 primary headache patients were included in the study (25 with tension-type headache, 36 with migraine, seven with chronic tension-type headache, two with both tension-type headache and migraine). Their mean age was 10.6 years (range 4-17 years); 37 children were male. On all but one subscale (self-esteem) the QoL of the children with primary headache was decreased compared with the cohort of healthy children, especially on the domains of mental health, parental impact time and family cohesion. Compared with the cohort of children with asthma the QoL was significantly worse for our headache group on seven subscales and significantly better on one subscale (general health perception). Compared with the cohort of children with ADHD, the QoL was significantly worse on six subscales but significantly better on three subscales. There were no significant differences on any QoL subscale between children with tension-type headache and children with migraine. We conclude that the QoL in children with primary headache presenting at the out-patient paediatric department of a general hospital seems to be considerably diminished. Furthermore, we conclude that, in this population there is no difference in QoL between children with tension-type headache and those with migraine.

Introduction: Many data on the course and prognosis after provoked and unprovoked single and multiple seizures in childhood have been collected in the past decennia by prospective, large-scale, long-term observational cohort studies. These data may serve to guide treatment decisions and help to design controlled trials investigating treatment strategies in childhood epilepsy., Methods: The results of the Dutch study of epilepsy in childhood will be compared with those of other studies. We will also discuss the potential consequences of these results for the "why" and "when" of the decision to start treatment., Results: Recurrence after a solitary unprovoked seizure in childhood is about 50%. Those with a recurrence have a similar outcome of their epilepsy compared to children presenting with multiple seizures, regardless whether they were treated after the first seizure or not. This argues in favour of postponing anti-epileptic drug (AED) treatment until at least a second seizure has occurred. After an unprovoked status epilepticus (SE), later outcome is not worse than after presentation with a short seizure. Therefore, long-term AED treatment after a single unprovoked SE may not be necessary either. The same holds true for children presenting with a short (less than one week) burst of unprovoked seizures. One quarter of them do not have recurrences and the final prognosis of children with recurrences does again not differ from the prognosis of the entire cohort. Findings in new-onset epilepsy further indicate that AED treatment can be safely omitted or at least postponed in about 15%, especially those with only a small number of seizures before presentation, those with benign partial epilepsy and those with sporadic generalised tonic-clonic seizures. On the reverse side, three considerations might lead to the decision to start early and aggressive treatment: the dangers of the seizures, the chance of intractability and the possibility of intellectual decline caused by recurrent seizures or epileptic activity. In idiopathic generalised absence epilepsy, the risks of accidents and learning problems indeed prompt early AED treatment. A self-propagating mechanism of seizures promoting the occurrence of more seizures, in the end causing intractable epilepsy (Gowers), occurs only rarely. Real intractability is seen in only 5-15% of the children with new-onset epilepsy. The chance of intractability is increased by variables like symptomatic aetiology, localisation-related epilepsy, and an early unfavourable course. Landau-Kleffner or continuous spikes and waves during sleep (CSWS) syndrome cause cognitive decline and syndromes like West, Lennox-Gastaut or Dravet's induce both psychomotor regression and intractability. In such cases, early aggressive treatment is indicated, including early consideration of the ketogenic diet, immunotherapy, vagus nerve stimulation and, if possible, referral for epilepsy surgery., Conclusions: Omitting or postponing treatment after a solitary seizure, an unprovoked SE, a single burst of seizures or multiple infrequent seizures usually does not worsen the prognosis. A poor prognosis and the consequent indication for early and aggressive treatment are dependent mainly upon the presence of variables like symptomatic aetiology, certain epilepsy types and syndromes, and the early evolution of the epilepsy in that particular child. Intellectual decline caused by seizures or epilepsy is rare and may be confined to certain specific and readily recognizable syndromes.

Summary: We determined long-term outcome and the predictive value of baseline and EEG characteristics on seizure activity evolution in 47 children with newly diagnosed childhood absence epilepsy (CAE) included in the Dutch Study of Epilepsy in Childhood. All children were followed for 12-17 years. The children were subdivided in three groups for the analyses: those becoming seizure-free (I) within 1 month after enrolment; (II) 1-6 months after enrolment; and (III) more than 6 months after enrolment or having seizures continuing during follow-up. No significant differences were observed between groups in sex, age at onset, occurrence of febrile seizures, and positive first-degree family history for epilepsy. All groups had high remission rates after 12-17 years. Significantly more relapses occurred in group III than in group I. Total duration of epilepsy and mean age at final remission were 3.9 and 9.5 years, respectively, being significantly longer and higher in group III than in groups I and II. In all groups only a small number of children (total 13%) developed generalized tonic-clonic seizures. In conclusion, our children with CAE had an overall good prognosis with few children (7%) still having seizures after 12-17 years. Remission rate in children with CAE cannot be predicted on the basis of baseline and EEG characteristics. The early clinical course (i.e. the first 6 months) has some predictive value with respect to the total duration of absence epilepsy.

Background: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome., Methods: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI., Results: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates., Conclusions: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis.

School functioning of 86 Dutch neurofibromatosis type 1 children (7-17 years) using teacher questionnaires was analyzed to determine the impact of neurofibromatosis type 1 on school performance. In all, 75% of the neurofibromatosis type 1 children performed more than 1 standard deviation below grade peers in at least one of the domains of spelling, mathematics, technical reading or comprehensive reading. Furthermore, neurofibromatosis type 1 children had a 4-fold increased risk for attending special education and a 6-fold increased risk for receiving remedial teaching for learning, behavior, speech, or motor problems. Children without apparent learning disabilities still frequently displayed neuropsychological deficits. Only 10% of the children did not show any school-functioning problems. Finally, it was found that the clinical severity of neurofibromatosis type 1 correlated with the cognitive deficits. Taken together, it was shown that neurofibromatosis type 1 has profound impact on school performance. Awareness of these problems may facilitate timely recognition and appropriate support.

Purpose: To study the efficacy and tolerability of add-on levetiracetam in children and adolescents with refractory epilepsy., Methods: In this prospective multi-centre, open-label, add-on study, 33 children aged 4-16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day., Results: Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of 22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Compared to their baseline seizure frequency, 13 children (39.4%) had a >50% seizure reduction 12 weeks after initiation of levetiracetam, and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizure-free for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use., Conclusion: Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy.

Pompe disease (type 2 glycogenosis, acid maltase deficiency) is a disorder affecting skeletal and cardiac muscle, caused by deficiency of acid alpha-glucosidase. In 2006 enzyme therapy with recombinant human alpha-glucosidase received marketing approval based on studies in infants. Results in older children and adults are awaited. Earlier we reported on the 3-year follow-up data of enzyme therapy in two adolescents and one adult. In the present study these patients were followed for another 5 years. Two severely affected patients, wheelchair and ventilator dependent, who had shown stabilization of pulmonary and muscle function in the first 3 years, maintained this stabilization over the 5-year extension period. In addition patients became more independent in daily life activities and quality of life improved. The third moderately affected patient had shown a remarkable improvement in muscle strength and regained the ability to walk over the first period. He showed further improvement of strength and reached normal values for age during the extension phase. The results indicate that both long-term follow-up and timing of treatment are important topics for future studies.

Purpose: To study course and outcome of epilepsy in children having had a status epilepticus (SE) as the presenting sign or after the diagnosis., Methods: A total of 494 children with newly diagnosed epilepsy, aged 1 month through 15 years, were followed prospectively for 5 years., Results: A total of 47 Children had SE. Forty-one of them had SE when epilepsy was diagnosed. For 32 (78%), SE was the first seizure. SE recurred in 13 out of 41 (32%). Terminal remission at 5 years (TR5) was not significantly worse for these 41 children: 31.7% had a TR5 <1 year versus 21.2% of 447 children without SE. They were not more often intractable. Five out of six children with first SE after diagnosis had a TR5 <1 year. Mortality was not significantly increased for children with SE. Independent factors associated with SE at presentation were remote symptomatic and cryptogenic etiology, and a history of febrile convulsions. Children with first SE after inclusion more often had symptomatic etiology., Conclusions: Although we find a trend for shorter TR5 in children with SE at presentation, outcome and mortality are not significantly worse. Etiology is an important factor for prognosis. Children with SE during the course of their epilepsy have a worse prognosis and a high recurrence rate of SE. This outcome is not due to the SE itself, but related to the etiology and type of epilepsy. The occurrence of SE is just an indicator of the severity of the disease.

Context: T(3) action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T(3) uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T(3) levels., Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3)., Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T(3) uptake, 2) T(3) metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry., Results: The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8., Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.

Purpose: To validate two prognostic models for childhood-onset epilepsy designed to predict a terminal remission of <6 months at 2 years after diagnosis in children referred to the hospital., Methods: A hospital-based cohort of children with newly diagnosed epilepsy was recruited and followed up for 2 years to validate previously developed models. One model was based on variables collected at intake, and the other was based on intake variables plus variables collected during the first 6 months of follow-up. The accuracy of both models was estimated by measuring the area under the receiver-operant-characteristic curves (ROC area)., Results: The ROC area of the model developed with intake variables was 0.69 [95% confidence interval (CI), 0.64-0.74] for the original cohort and 0.62 (95% CI, 0.55-0.69) for the validation cohort. The best combination of sensitivity and specificity for the original cohort was 61.6% and 69.1%, whereas it was 60.0% and 61.4% for the validation cohort. For the model with intake and 6-month variables combined, the ROC area was 0.78 (95% CI, 0.73-0.82) for the original cohort and 0.71 (95% CI, 0.64-0.78) for the validation cohort. The sensitivity and specificity were 72.6% and 73.1%, respectively, for the original cohort and 67.4% and 60.2%, respectively, for the validation cohort., Conclusions: Although both models predict outcome better than chance, they are insufficiently accurate to be of practical value. Both models performed marginally less well with the validation cohort than with the original cohort, but in both instances, the model based on intake and 6-month variables was more accurate.

Background: Porencephaly (cystic cavities of the brain) is caused by perinatal vascular accidents from various causes. Several familial cases have been described and autosomal dominant inheritance linked to chromosome 13q has been suggested. COL4A1 is an essential component in basal membrane stability. Mouse mutants bearing an in-frame deletion of exon 40 of Col4a1 either die from haemorrhage in the perinatal period or have porencephaly in survivors. A report of inherited mutations in COL4A1 in two families has shown that familial porencephaly may have the same cause in humans., Objective: To describe three novel COL4A1 mutations., Results: The three mutations occurred in three unrelated Dutch families. There were two missense mutations of glycine residues predicted to result in abnormal collagen IV assembly, and one mutation predicted to abolish the traditional COL4A1 start codon. The last mutation was also present in an asymptomatic obligate carrier with white matter abnormalities on brain magnetic resonance imaging., Conclusions: This observation confirms COL4A1 as a major locus for genetic predisposition to perinatal cerebral haemorrhage and porencephaly and suggests variable expression of COL4A1 mutations.

Background: The relatively high survival rate of patients with low-grade astrocytoma necessitates increasing attention to physical and psychosocial outcomes. The objective of the current study was to investigate functional outcomes among children who were treated for low-grade or pilocytic astrocytoma in different areas of the brain., Methods: Functional outcomes were evaluated in the following domains: impairments, disabilities, handicaps, and quality of life (QOL). In a consecutive series, 38 children were included. Follow-up ranged from 3 years and 7 months to 11 years and 4 months after diagnosis., Results: Approximately 61% of children had impairments and 10% had a severe disability. Handicaps were found in the domains of relationships, school, and behavior. Children who were treated for supratentorial tumors required significantly more special education, and children who were treated for infratentorial tumors had significantly more behavioral and social problems. QOL was decreased significantly in all domains except emotions. Children who had a diagnosis in adolescence reported a lower QOL in social functioning compared with younger children. Data analysis revealed that some deficits suddenly became apparent years after diagnosis., Conclusions: At long-term follow-up, children who had low-grade or pilocytic astrocytomas were found to have poor functional outcomes, depending on tumor site, age, and recurrence. Children without deficits may develop severe cognitive, social, and behavioral deficits years after diagnosis, because of the phenomenon of "growing into deficit." Therefore, the authors suggest a long-term follow-up of children who are treated for low-grade or pilocytic astrocytomas at a young age to detect and subsequently offer support focused on the medical and cognitive impairments as well as on the behavioral and social consequences of their disease.

Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.

The diagnosis of a first seizure or epilepsy may be subject to interobserver variation and inaccuracy with possibly far-reaching consequences for the patients involved. We reviewed the current literature. Studies on the interobserver variation of the diagnosis of a first seizure show that such a diagnosis is subject to considerable interobserver disagreement. Interpretation of the electroencephalogram (EEG) findings is also subject to interobserver disagreement and is influenced by the threshold of the reader to classify EEG findings as epileptiform. The accuracy of the diagnosis of epilepsy varies from a misdiagnosis rate of 5% in a prospective childhood epilepsy study in which the diagnosis was made by a panel of three experienced pediatric neurologists to at least 23% in a British population-based study, and may be even higher in everyday practice. The level of experience of the treating physician plays an important role. The EEG may be helpful but one should be reluctant to make a diagnosis of epilepsy mainly on the EEG findings without a reasonable clinical suspicion based on the history. Being aware of the possible interobserver variation and inaccuracy, adopting a systematic approach to the diagnostic process, and timely referral to specialized care may be helpful to prevent the misdiagnosis of epilepsy.

Is 'hopeless and unbearable suffering' a just criterion for the deliberate termination of life of newborns with spina bifida? Hopeless suffering, with no means of alleviation, is not applicable in the acute phase of spina bifida in newborns, but to the chronic suffering that comes later on as the result of pain and discomfort experienced by the patient. There is a need for a nationwide discussion on (a) how can we determine when acute or chronic suffering become hopeless and unbearable, and on what basis should a given situation be regarded as an 'emergency situation'?; (b) what qualifies as a very severe form of spina bifida?; (c) what kind of care should be provided after the decision to withhold active care?

Background: Most end-of-life decision-making studies have, until now, involved either the general population or newborn infants., Objective: To assess the frequency of end-of-life decisions preceding child death and the characteristics of the decision-making process in the Netherlands., Methods: Two studies were performed. The first was a death certificate study in which all 129 physicians reporting the death of a child aged between 1 and 17 years in the period August to December 2001 received a written questionnaire; the second was an interview study in which face-to-face interviews were held with 63 physicians working in pediatric hospital departments., Results: Some 36% of all deaths of children between the ages of 1 and 17 years during the relevant period were preceded by an end-of-life decision: 12% by a decision to refrain from potentially life-prolonging treatment; 21% by the alleviation of pain or symptoms with a possible life-shortening effect; and 2.7% by the use of drugs with the explicit intention of hastening death. The latter decision was made at the child's request in 0.7% and at the request of the family in 2% of cases. The interview study examined 76 cases of end-of-life decision making. End-of-life decisions were discussed with all 9 competent and 3 partly competent children, with the parents in all cases, with other physicians in 75 cases, and with nurses in 66 cases., Conclusions: While not inconsiderable, the percentage of end-of-life decisions was lower for children than for adults and newborn infants. Most children are not considered to be able to participate in the decision-making process. Decisions are generally discussed with parents and other caregivers and, if possible, with the child.

Incontinentia pigmenti (IP; MIM308310) is a rare neurocutaneous X-dominant inherited disorder. Besides skin and neurological abnormalities, there is also ophthalmologic and dental involvement. The first stage is characterised by inflammation and apoptosis of the skin and central nervous system. The first stage consists of vesicles and the second of verrucous elements; the third stage is characterised by hyperpigmentation while the fourth is characterised by slightly atrophic hypopigmentations. The skin abnormalities follow the lines of Blaschko. The disorder is observed almost exclusively in girls, but diseased boys are more seriously affected. The IP gene is localised on chromosome Xq28. Mutations in the NEMO-gene are responsible for IP. This gene codes for the nuclear factor-KB essential modulator protein (NEMO; synonym: inhibitor kappaB kinase (IKK)y). In the absence of serious neurological symptoms, the prognosis is not poor.

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.