Arts, W.F.M.

Febrile seizures and behavioural and cognitive outcomes in preschool children: The Generation R Study (Article)

2012-11-01T00:00:00Z

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 3years. At the age of 3years, 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 4years 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

Frequent fever episodes and the risk of febrile seizures: The Generation R Study (Article)

2012-01-01T00:00:00Z

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.

Health perception and socioeconomic status following childhood-onset epilepsy: The Dutch study of epilepsy in childhood (Article)

2011-12-01T00:00:00Z

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.

Frequent fever episodes and the risk of febrile seizures: The Generation R Study (Article)

2011-10-05T00:00:00Z

The phenotype of the Gly94fsX222 PMP22 insertion (Article)

2011-06-01T00:00:00Z

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.

Long-term follow-up of type 1 lissencephaly: Survival is related to neuroimaging abnormalities (Article)

2011-05-01T00:00:00Z

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 14years (SD 9y 8mo). 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

CDKL5 gene-related epileptic encephalopathy: Electroclinical findings in the first year of life (Article)

2011-04-01T00:00:00Z

Medium-dose riboflavin as a prophylactic agent in children with migraine: A preliminary placebo-controlled, randomised, double-blind, cross-over trial (Article)

2010-12-01T00:00:00Z

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.

Effect of enzyme therapy in juvenile patients with Pompe disease: A three-year open-label study (Article)

2010-12-01T00:00:00Z

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.

Paroxysmal disorders in infancy and their risk factors in a population-based cohort: The Generation R Study (Article)

2010-11-01T00:00:00Z

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.

Fetal growth retardation and risk of febrile seizures (Article)

2010-10-01T00:00:00Z

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.

Long term outcome of benign childhood epilepsy with centrotemporal spikes: Dutch Study of Epilepsy in Childhood (Article)

2010-10-01T00:00:00Z

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 (TRF) of more than 5 years and 89% of more than 10 years. Mean duration of epilepsy was 2.7 years; mean age at reaching TRFwas 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.

Absence epilepsy and periventricular nodular heterotopia (Article)

2010-09-01T00:00:00Z

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.

Psychopathology in children and adolescents with migraine in clinical studies: A systematic review (Article)

2010-08-01T00:00:00Z

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.

Course and outcome of childhood epilepsy: A 15-year follow-up of the Dutch Study of Epilepsy in Childhood (Article)

2010-07-01T00:00:00Z

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 onethird 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 ∼30% and becomes intractable in ∼10%. AEDs probably do not influence epilepsy course; they merely suppress seizures. Mortality is significantly higher only in those with remote symptomatic etiology.

PRPS1 Mutations: Four Distinct Syndromes and Potential Treatment (Article)

2010-04-09T00:00:00Z

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).

Landau-Kleffner syndrome and CSWS syndrome: Treatment with intravenous immunoglobulins (Article)

2009-08-01T00:00:00Z

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.

Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood (Article)

2009-07-20T00:00:00Z

Purpose: To prospectively study cognitive deficits and predictors 3 years after diagnosis in a large series of pediatric patients treated for pilocytic astrocytoma (PA). Patients and Methods: Sixty-one of 67 children were grouped according to infratentorial, supratentorial midline, and supratentorial hemispheric site. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Included predictors were sex, age, relapse, diagnosis-assessment interval, hydrocephalus, kind of treatment, and tumor variables. Results: All children with PA had problems with sustained attention and speed. In the infratentorial group, there also were deficits in verbal intelligence, visual-spatial memory, executive functioning, and naming. Verbal intelligence and verbal memory problems occurred in the brainstem tumor group. The supratentorial hemispheric tumor group had additional problems with selective attention and executive functioning, and the supratentorial midline tumor group displayed no extra impairments. More specifically, the dorsal supratentorial midline tumor group displayed problems with language and verbal memory. Predictors for lower cognitive functioning were hydrocephalus, radiotherapy, residual tumor size, and age; predictors for better functioning were chemotherapy or treatment of hydrocephalus. Almost 60% of children had problems with academic achievement, for which risk factors were relapse and younger age at diagnosis. Conclusion: Despite normal intelligence at long-term follow-up, children treated for PA display invalidating cognitive impairments. Adequate treatment of hydrocephalus is important for a more favorable long-term cognitive outcome. Even children without initial severe deficits may develop cognitive impairments years after diagnosis, partly because of the phenomenon of growing into deficit, which has devastating implications for academic achievement and quality of life (QOL).

Quality of life in children with primary headache in a general hospital (Article)

2009-06-01T00:00:00Z

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.

When to start drug treatment for childhood epilepsy: The clinical-epidemiological evidence (Article)

2009-03-01T00:00:00Z

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.

Long-term outcome of childhood absence epilepsy: Dutch Study of Epilepsy in Childhood (Article)

2009-02-01T00:00:00Z

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.

Impact of neurofibromatosis type 1 on school performance (Article)

2008-09-03T00:00:00Z

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.

Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: A randomized controlled trial (Article)

2008-07-16T00:00:00Z

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 (β=0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (β=-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 (β=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 (β=0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (β=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

Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study (Article)

2008-07-01T00:00:00Z

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.

Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease (Article)

2008-06-01T00:00:00Z

Pompe disease (type 2 glycogenosis, acid maltase deficiency) is a disorder affecting skeletal and cardiac muscle, caused by deficiency of acid α-glucosidase. In 2006 enzyme therapy with recombinant human α-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.

Status epilepticus in children with epilepsy: Dutch study of epilepsy in childhood (Article)

2007-09-01T00:00:00Z

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.

Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine (Article)

2007-06-01T00:00:00Z

Context: T3action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3levels. Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3. Design: MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T3uptake, 2) T3metabolism 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 T3levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3in central neurons. Copyright

Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression [2] (Article)

2007-03-01T00:00:00Z

Medical end-of-life decisions for children in the Netherlands. (Article)

2005-09-01T00:00:00Z

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.

Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood. (Article)

2004-08-01T00:00:00Z

Knowing the prognosis of epilepsy will undoubtedly influence the treatment strategy. This study aimed to define the prospects of newly diagnosed childhood epilepsy, assess the dynamics of its course, identify relevant variables and develop models to assess the individual prognosis. Four hundred and fifty-three children with newly diagnosed epilepsy were followed for 5 years. Terminal remission at 5 years (TR5) was compared with terminal remission at 2 years (TR2) and with the longest remission during follow-up. Variables defined at intake and at 6 months of follow-up were analysed for their prognostic relevance. In multivariate analyses, combinations of variables were tested to develop reliable models for the calculation of the individual prognosis. Data on treatment, course during follow-up and epilepsy syndromes were also studied. Three hundred and forty-five children (76%) had a TR5 >1 year, 290 (64%) >2 years and 65 (14%) had not had any seizure during the entire follow-up. Out of 108 children (24%) with TR5 <1 year, 27 were actually intractable at 5 years. Medication was started in 388 children (86%). In 227 of these (59%), anti-epileptic drugs (AEDs) could be withdrawn. A TR5 >1 year was attained by 46% on one AED, on the second AED by 19%, and by 9% on all additional AED regimes. Almost 60% of the children treated with a second or additional AED regime had a TR5 >1 year. Variables predicting the outcome at intake were aetiology, history of febrile seizures and age. For intake and 6-month variables combined, sex, aetiology, postictal signs, history of febrile seizures and TR at 6 months were significant. The model derived from intake variables only predicted TR5 <1 year correctly in 36% and TR5 >1 year in 85% (sensitivity 0.65, specificity 0.64). The corresponding values for the model derived from intake and 6-month variables were 43 and 88% (sensitivity 0.69, specificity 0.71). The course of the epilepsy was constantly favourable in 51%, steadily poor in 17%, improving in 25% and deteriorating in 6%. Intractability was in part only a temporary phenomenon. The outcome at 5 years in this cohort of children with newly diagnosed epilepsy was favourable in 76%; 64% were off medication at that time. Almost a third of the children had a fluctuating course; improvement was clearly more common than deterioration. After failure of the first AED, treatment can still be successful. Models predicting the outcome have fewer misclassifications when predicting a long terminal remission than when predicting continuing seizures.

Long-term intravenous treatment of Pompe disease with recombinant human alpha-glucosidase from milk (Article)

2004-01-01T00:00:00Z

OBJECTIVE: Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human -glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40,000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of alpha-glucosidase activity and presence of fully deleterious mutations in the alpha-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of alpha-glucosidase. METHODS: In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week. RESULTS: Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of alpha-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35S-methionine incorporation, we could detect low-level synthesis of -glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The alpha-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection (<2% of normal). The rhAGLU was tolerated well by the patients during >3 years of treatment. Anti-rhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIM-positive patients. Muscle alpha-glucosidase activity increased from <2% to 10% to 20% of normal in all patients during the first 12 weeks of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal alpha-glucosidase activity levels, which were maintained until the last measurement in week 72. Importantly, all 4 patients, including the patient without any endogenous alpha-glucosidase (CRIM negative), revealed mature 76- and 70-kDa forms of -glucosidase on Western blot. Conversion of the 110-kDa precursor from milk to mature 76/70-kDa alpha-glucosidase provides evidence that the enzyme is targeted to lysosomes, where this proteolytic processing occurs. At baseline, patients had severe glycogen storage in the quadriceps muscle as revealed by strong periodic acid-Schiff--positive staining and lacework patterns in hematoxylin and eosin--stained tissue sections. The muscle pathology correlated at each time point with severity of signs. Periodic acid-Schiff intensity diminished and number of vacuoles increased during the first 12 weeks of treatment. Twelve weeks after dose elevation, we observed signs of muscle regeneration in 3 of the 4 patients. Obvious improvement of muscular architecture was seen only in the patient who learned to walk. Clinical effects were significant. All patients survived beyond the age of 4 years, whereas untreated patients succumb at a median age of 6 to 8 months. The characteristic cardiac hypertrophy present at start of treatment diminished significantly. The left ventricular mass index decreased from 171 to 599 g/m2 (upper limit of normal 86.6 g/m2 for infants from 0 to 1 year) to 70 to 160 g/m2 during 84 weeks of treatment. In addition, we found a significant change of slope for the diastolic thickness of the left ventricular posterior wall against time at t = 0 for each separate patient. Remarkably, the younger patients (patients 1 and 3) showed no significant respiratory problems during the first 2 years of life. One of the younger patients recovered from a life-threatening bronchiolitis at the age of 1 year without sequelae, despite borderline oxygen saturations at inclusion. At the age of 2, however, she became ventilator dependent after surgical removal of an infected Port-A-Cath. She died at the age of 4 years and 3 months suddenly after a short period of intractable fever of >42 degrees C, unstable blood pressure, and coma. The respiratory course of patient 1 remained uneventful. The 2 older patients, who both were hypercapnic (partial pressure of carbon dioxide: 10.6 and 9.8 kPa; normal range: 4.5-6.8 kPa) at start of treatment, became ventilator dependent before the first infusion (patient 2) and after 10 weeks of therapy (patient 4). Patient 4 was gradually weaned from the ventilator after 1 year of high-dose treatment and was eventually completely ventilator-free for 5 days, but this situation could not be maintained. Currently, both patients are completely ventilator dependent. The most remarkable progress in motor function was seen in the younger patients (patients 1 and 3). They achieved motor milestones that are unmet in infantile Pompe disease. Patient 1 learned to crawl (12 months), walk (16 months), squat (18 months), and climb stairs (22 months), and patient 3 learned to sit unsupported. The Alberta Infant Motor Scale score for patients 2, 3, and 4 remained far below p5. Patient 1 followed the p5 of normal. CONCLUSION: Our study shows that a safe and effective medicine can be produced in the milk of mammals and encourages additional development of enzyme replacement therapy for the several forms of Pompe disease. Restoration of skeletal muscle function and prevention of pulmonary insufficiency require dosing in the range of 20 to 40 mg/kg/week. The effect depends on residual muscle function at the start of treatment. Early start of treatment is required.

Mutations in TITF-1 are associated with benign hereditary chorea (Article)

2002-01-01T00:00:00Z

Benign hereditary chorea (BHC) (MIM 118700) is an autosomal dominant movement disorder. The early onset of symptoms (usually before the age of 5 years) and the observation that in some BHC families the symptoms tend to decrease in adulthood suggests that the disorder results from a developmental disturbance of the brain. In contrast to Huntington disease (MIM 143100), BHC is non-progressive and patients have normal or slightly below normal intelligence. There is considerable inter- and intrafamilial variability, including dysarthria, axial dystonia and gait disturbances. Previously, we identified a locus for BHC on chromosome 14 and subsequently identified additional independent families linked to the same locus. Recombination analysis of all chromosome 14-linked families resulted initially in a reduction of the critical interval for the BHC gene to 8.4 cM between markers D14S49 and D14S278. More detailed analysis of the critical region in a small BHC family revealed a de novo deletion of 1.2 Mb harboring the TITF-1 gene, a homeodomain-containing transcription factor essential for the organogenesis of the lung, thyroid and the basal ganglia. Here we report evidence that mutations in TITF-1 are associated with BHC.

Benign hereditary chorea of early onset maps to chromosome 14q (Article)

2000-01-01T00:00:00Z

Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by an early-onset nonprogressive chorea. The early onset and the benign course distinguishes BHC from the more common Huntington disease (HD). Previous studies on families with BHC have shown that BHC and HD are not allelic. We studied a large Dutch kindred with BHC and obtained strong evidence for linkage between the disorder and markers on chromosome 14q (maximum LOD score 6.32 at recombination fraction 0). The BHC locus in this family was located between markers D14S49 and D14S1064, a region spanning approximately 20.6 cM that contains several interesting candidate genes involved in the development and/or maintenance of the CNS: glia maturation factor-beta, GTP cyclohydrolase 1 and the survival of motor neurons (SMN)-interacting protein 1. The mapping of the BHC locus to 14q is a first step toward identification of the gene involved, which might, subsequently, shed light on the pathogenesis of this and other choreatic disorders.

Epilepsy in childhood: an audit of clinical practice. (Article)

1998-05-01T00:00:00Z

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.

The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood. (Article)

1998-01-01T00:00:00Z

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%),

The first unprovoked, untreated seizure in childhood: a hospital based study of the accuracy of the diagnosis, rate of recurrence, and long term outcome after recurrence. Dutch study of epilepsy in childhood (Article)

1998-01-01T00:00:00Z

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%),

Een lelijk eendje? (Inaugural Lecture)

1997-10-24T00:00:00Z

Clinical course of untreated tonic-clonic seizures in childhood: prospective, hospital based study. (Article)

1997-01-01T00:00:00Z

To assess declaration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children's hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly evolve into a progressive disease should not be used as an argument in favour of early drug treatment in children with epilepsy.

Outcome assessment in epilepsy: available rating scales for adults and methodological issues pertaining to the development of scales for childhood epilepsy. (Article)

1996-07-01T00:00:00Z

During the past decade, several scales have been developed to improve the assessment of outcome in epilepsy. These scales were developed for adults and their reliability, validity and usefulness have been established. However, there is also a need for alternative measures of outcome in childhood epilepsy, especially a measure of seizure severity (SS) and measures pertaining to quality of life (QoL). Four of these adult scales are reviewed and compared to examine their applicability in childhood epilepsy. Two important methodological differences between them are discussed: (a) patient self-report vs. physician-based scales and (b) generic vs. disease-specific instruments. QoL in epilepsy is briefly reviewed. Severity of seizures and severity of side-effects are relatively neglected areas of importance to QoL in epilepsy. The existing instruments for adults are not appropriate for children in their present form. Some specific methodological issues, which are relevant for the development of scales for children with epilepsy, are subsequently discussed. New scales pertaining to physical and psychosocial aspects of QoL in childhood epilepsy are being developed. In the near future, data on their reliability, validity and usefulness will become available. A combination of scales focusing on specific aspects of QoL, including SS and severity of adverse effects, and more traditional clinical data may provide a more complete assessment of outcome in childhood epilepsy.

Parent-completed scales for measuring seizure severity and severity of side-effects of antiepileptic drugs in childhood epilepsy: development and psychometric analysis. (Article)

1996-07-01T00:00:00Z

We have developed two outcome measures for childhood epilepsy: a seizure severity (SS) scale and a side-effects (SE) scale. Both scales have been designed for completion by parents. The scales were tested in two pilot phases and the results of this stepwise analysis are described here. The final scales' psychometric properties were assessed in a group of 80 children with active epilepsy, representative of the population at whom the scales were aimed: children with chronic epilepsy, aged 4-16 years, including all seizure types and epilepsies, as well as children with neurological comorbidity. The SS scale and SE scale showed good internal consistency and test-retest stability. Although there was a significant positive correlation between the SS scale and the SE scale, this was low, indicating that the scales measure a different clinical trait. The SE scale consisted of two subscales: a Toxic subscale, measuring the severity of dose-related side-effects, and a Chronic subscale, measuring the severity of long-term behavioural and cognitive side-effects. These subscales for side-effects showed a high correlation and can be used as a joint scale. These scales have the potential to improve outcome assessment in childhood epilepsy and they can be used to assess important aspects of quality of life in this population.