Brouwer, O.F.

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.

The process of end-of-life decision-making in pediatrics: A national survey in the Netherlands (Article)

2011-04-01T00:00:00Z

OBJECTIVE: The goal of this study was to investigate how Dutch pediatric specialists reach end-of-life decisions, how they involve parents, and how they address conflicts. METHODS: We conducted a national cross-sectional survey among pediatric intensivists, oncologists, neurologists, neurosurgeons, and metabolic pediatricians practicing in the 8 Dutch university hospitals. We collected information on respondents' overall opinions and their clinical practice. RESULTS: Of the 185 eligible pediatric specialists, 74% returned the questionnaire. All responding physicians generally discuss an end-of-life decision with colleagues before discussing it with parents. In half of the reported cases, respondents informed parents about the intended decision and asked their permission. In one-quarter of the cases, respondents informed parents without asking for their permission. In the remaining onequarter of the cases, respondents advised parents and consequently allowed them to have the decisive voice. The chosen approach is highly influenced by type of decision and type and duration of treatment. Conflicts within medical teams arose as a result of uncertainties about prognosis and treatment options. Most conflicts with parents arose because parents had a more positive view of the prognosis or had religious objections to treatment discontinuation. All conflicts were eventually resolved by a combination of strategies. In 66% of all cases, pain and symptom management were intensified before the child's death. CONCLUSIONS: Within Dutch pediatrics, end-of-life decisions are team decisions. Pediatric specialists differ considerably in how they involve parents in end-of-life decision-making, ranging from benevolent paternalism to parental autonomy. Main conflict-solving strategies are taking more time and extending discussions. Copyright

The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy (Article)

2010-12-01T00:00:00Z

Purpose: Pyridoxine-dependent epilepsy (PDE) is characterized by therapy-resistant seizures (TRS) responding to intravenous (IV) pyridoxine. PDE can be identified by increased urinary alpha-aminoadipic semialdehyde (α-AASA) concentrations and mutations in the ALDH7A1 (antiquitin) gene. Prompt recognition of PDE is important for treatment and prognosis of seizures. We aimed to determine whether immediate electroencephalography (EEG) alterations by pyridoxine-IV can identify PDE in neonates with TRS. Methods: In 10 neonates with TRS, we compared online EEG alterations by pyridoxine-IV between PDE (n = 6) and non-PDE (n = 4). EEG segments were visually and digitally analyzed for average background amplitude and total power and relative power (background activity magnitude per frequency band and contribution of the frequency band to the spectrum). Results: In 3 of 10 neonates with TRS (2 of 6 PDE and 1 of 4 non-PDE neonates), pyridoxine-IV caused flattening of the EEG amplitude and attenuation of epileptic activity. Quantitative EEG alterations by pyridoxine-IV consisted of (1) decreased central amplitude, p < 0.05 [PDE: median -30% (range -78% to -3%); non-PDE: -20% (range -45% to -12%)]; (2) unaltered relative power; (3) decreased total power, p < 0.05 [PDE: -31% (-77% to -1%); -27% (-73% to -13%); -35% (-56% to -8%) and non-PDE: -16% (-43% to -5%); -28% (-29% to -17%); -26% (-54% to -8%), in delta-, theta- and beta-frequency bands, respectively]; and (4) similar EEG responses in PDE and non-PDE. Discussion: In neonates with TRS, pyridoxine-IV induces nonspecific EEG responses that neither identify nor exclude PDE. These data suggest that neonates with TRS should receive pyridoxine until PDE is fully excluded by metabolic and/or DNA analysis.

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.

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.

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.

Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations (Article)

2009-01-01T00:00:00Z

Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3′,5-triiodothyronine (T3). Mutations in MCT8 are associated with severe psychomotor retardation, high serum T3 and low 3,3′,5′-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3-responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.

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.

Sumatriptan nasal spray in the acute treatment of migraine in adolescents and children (Article)

2007-11-01T00:00:00Z

About 4-10% of children and adolescents suffer from migraine. In the last few years, several studies have been performed to assess the efficacy and safety of triptans for the acute treatment of migraine in children and adolescents. Only sumatriptan nasal spray has been approved for the treatment of acute migraine with or without aura in adolescents aged 12-17 years in Europe. This review describes the results of the studies with sumatriptan nasal spray that have been performed in children and adolescents, including a study performed in the Netherlands.

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.

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.

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%),

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.

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.