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OBJECTIVE: Follow-up data on the long-term effectiveness (efficacy and tolerability) of lamotrigine are limited. A useful though crude measure for effectiveness in daily clinical practice is the treatment retention rate determined from drug dispensing data. This study describes the baseline characteristics, the usage patterns and the retention rate of this antiepileptic drug (AED) in a population-based cohort of lamotrigine users in the Netherlands during the first 5 years after its registration in 1995. Data from this cohort are compared with those from the initial randomized clinical trials (RCTs) in patients with refractory epilepsy. METHODS: This retrospective cohort study used dispensing data from community pharmacies. Baseline characteristics and usage patterns were evaluated for first time users of lamotrigine in this study. Usage patterns were characterized as continued, add-on or discontinued use during the patient observation time window. Cox regression analysis was used to explore possible relationships between baseline characteristics and specific usage patterns defined. The baseline characteristics and discontinuation rates in this cohort study were compared with RCT data reported in medical literature. RESULTS: A total of 3598 lamotrigine users were identified. The mean age of the population was 39 years and 54% were female. On average, patients used two other AEDs at the start of lamotrigine therapy and approximately 6% of the patients had no history of prior AED use. The discontinuation rate was 25% after 1 year, and approximately 32% at the end of the 5-year study. Addition of another drug or discontinuation was seen in more than half of the population 3 years after the start of therapy. Concurrent use of valproic acid was associated with a better retention rate. Absence of AED history, use of antidepressants, or use of migraine abortive drugs resulted in an increased likelihood of discontinuing lamotrigine. The population from RCTs differed from the study cohort with respect to age, concurrent use of AEDs and length of follow-up. CONCLUSION: Data from RCTs cannot easily be extrapolated to daily clinical practice. In this large, observational study, lamotrigine therapy failed in a considerable number of patients, although the mean retention rate was better than previously reported by others. Population-based linkage of health care records can be used to further clarify the effectiveness of lamotrigine. [ABSTRACT FROM AUTHOR]

Gélineau originally described narcolepsy as a disease with an organic cause. However, the disorder had undeniable emotional triggers and psychiatric-like expressions, and soon a psychiatric etiology of narcolepsy became a seriously considered option. In fact, the psychiatric view dominated scientific thinking for a long time, not necessarily to the benefit of patients. When hypocretin (orexin) defects were proven to be the cause of narcolepsy Gélineau's original disease model was shown to be right. However, the psychiatric symptoms of the disease were not forgotten afterwards, but gained a different significance: as psychiatric expressions of a brain disease. These symptoms, such as anxiety and eating disorders, can be highly debilitating and warrant clinical attention. Here, we describe the role of psychiatry in the history of narcolepsy, showing their evolving association., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Most patients with Dravet syndrome have de novo mutations in the neuronal voltage-gated sodium channel type 1 (SCN1A) gene. We report on two unrelated fathers with severe childhood epilepsy compatible with a possible diagnosis of Dravet syndrome, who both have a child with Dravet syndrome. Analysis of the SCN1A gene revealed a pathogenic mutation in both children. One father exhibited somatic mosaicism for the mutation detected in his son. A relatively favorable cognitive outcome in patients with Dravet syndrome patients may be explained by somatic mosaicism for the SCN1A mutation in brain tissue. A mild form of Dravet syndrome in adult patients is associated with a high recurrence risk and possibly a more severe epilepsy phenotype in their offspring., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Introduction: In CLRE specific learning difficulties and motor problems may occur. The aim of this study is to examine whether CLRE or the accompanying specific learning difficulties are associated with the occurring problems in motor function., Methods: Motor functioning in 140 children with CLRE and without epilepsy, as well as with and without specific learning difficulties is compared using Chi-square., Results: In the CLRE group 35% score below the 5th percentile (poor motor function). No correlations with epilepsy variables or the occurrence of specific learning difficulties is found., Discussion: A subgroup of about one-third of children with CLRE are at risk for poor motor function. Their development is best monitored using a multi-dimensional approach, including cognitive development and motor functioning., (Copyright © 2010. Published by Elsevier Ltd.)

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Introduction: Narcolepsy is a primary sleeping disorder with excessive daytime sleepiness and cataplexy as core symptoms. There is increasing interest in the psychiatric phenotype of narcolepsy. Although many authors suggest an overrepresentation of mood disorders, few systematic studies have been performed and conflicting results have been reported. Anxiety disorders in narcolepsy have only received little attention., Methods: We performed a case-control study in 60 narcolepsy patients and 120 age- and sex-matched controls from a previous population study. The Schedules for Clinical Assessment in Neuropsychiatry were used to assess symptoms and diagnostic classifications of mood and anxiety disorders., Results: Symptoms of mood disorders were reported by about one third of patients. However, the prevalence of formal mood disorder diagnoses - including major depression - was not increased. In contrast, more than half of the narcolepsy patients had anxiety or panic attacks. Thirty-five percent of the patients could be diagnosed with anxiety disorder (odds ratio=15.6), with social phobia being the most important diagnosis. There was no influence of age, sex, duration of illness or medication use on the prevalence of mood or anxiety symptoms and disorders., Discussion: Anxiety disorders, especially panic attacks and social phobias, often affect patients with narcolepsy. Although symptoms of mood disorders are present in many patients, the prevalence of major depression is not increased. Anxiety and mood symptoms could be secondary complications of the chronic symptoms of narcolepsy. Recent studies have shown that narcolepsy is caused by defective hypocretin signaling. As hypocretin neurotransmission is also involved in stress regulation and addiction, this raises the possibility that mood and anxiety symptoms are primary disease phenomena in narcolepsy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: Patients with narcolepsy often experience pervasive hypnagogic hallucinations, sometimes even leading to confusion with schizophrenia. We aimed to provide a detailed qualitative description of hypnagogic hallucinations and other "psychotic" symptoms in patients with narcolepsy and contrast these with schizophrenia patients and healthy controls. We also compared the prevalence of formal psychotic disorders between narcolepsy patients and controls., Methods: We used SCAN 2.1 interviews to compare psychotic symptoms between 60 patients with narcolepsy, 102 with schizophrenia and 120 matched population controls. In addition, qualitative data was collected to enable a detailed description of hypnagogic hallucinations in narcolepsy., Results: There were clear differences in the pattern of hallucinatory experiences in narcolepsy vs. schizophrenia patients. Narcoleptics reported multisensory "holistic" hallucinations rather than the predominantly verbal-auditory sensory mode of schizophrenia patients. Psychotic symptoms such as delusions were not more frequent in narcolepsy compared to population controls. In addition, the prevalence of formal psychotic disorders was not increased in patients with narcolepsy. Almost half of narcoleptics reported moderate interference with functioning due to hypnagogic hallucinations, mostly due to related anxiety., Conclusions: Hypnagogic hallucinations in narcolepsy can be differentiated on a phenomenological basis from hallucinations in schizophrenia which is useful in differential diagnostic dilemmas.

Introduction: One-third of children with epilepsy are classified as having a cryptogenic localization related epilepsy (CLRE). In cohort studies CLRE is often grouped together with either symptomatic localization related epilepsy (SLRE) or idiopathic generalized epilepsy (IGE). Therefore, this categorization is not specific enough and will not lead to prognostic or treatment information. We objectified the classification differences between these categories., Methods: A total of 114 children admitted to our epilepsy centre underwent a standardized clinical analysis, which yielded age at onset, duration of the epilepsy, seizure frequency, seizure type, percentage of interictal epileptiform activity on EEG (IEA), type of treatment, and full scale IQ. These variables are regarded the characteristics of the epilepsy, and used in a discriminant function analysis., Results: IEA was found to be the only variable to distinguish between groups of epilepsy. SLRE could easily be distinguished significantly from IGE and CLRE, while the latter two did not differ significantly. Discriminant function analysis combined the variables into two functions, applicable to classify the children. By applying this statistical analysis method, the groups clinically classified as SLRE and IGE were mostly classified as SLRE (71.4%) and IGE (57.9%). However, CLRE appeared difficult to classify (49.2%), and most children were classified as either SLRE (19%) or IGE (31.7%)., Conclusion: The current opinion that CLRE is 'probably symptomatic' cannot be confirmed in all cases in this study. It is most likely that the current CLRE population consists of both children with eventually SLRE, as well as yet to be described syndromes to be classified as idiopathic epilepsies. We emphasize the need for separate studies regarding children with 'probably symptomatic' (cryptogenic) localization related epilepsy, as this will maximally help children, caretakers and treating physicians to achieve the best possible outcome.

Objectives: Up to one-third of the children with epilepsy are diagnosed with cryptogenic localization related epilepsy (CLRE). As yet, there is a lack of studies that specify the short- and long-term prognosis for this group. In this study, we systematically established neurological outcome (represented by seizure frequency) as well as neuropsychological outcome in a cohort of 68 children with CLRE who had been referred to our tertiary outpatient clinic. Also, we analysed correlations with risk and prognostic factors., Patients and Methods: A systematic cross-sectional open clinical and non-randomized design was used including 68 children admitted to our epilepsy centre in a child neurological programme between January 1999 and December 2004. A model was defined, distinguishing risk factors with a potential effect on epileptogenesis (history of febrile seizures, family history of epilepsy, history of early mild development delay and serious diagnostic delay) and prognostic factors, with a potential effect on the course of the epilepsy (neurological symptoms or soft signs, age at onset, duration of epilepsy, seizure type, percentage of time with epileptiform activity, localization of epileptiform activity, treatment history and treatment duration). Seizure frequency was used as the primary outcome variable, whereas three neuropsychological outcomes (IQ, psychomotor delay and educational delay) were used as secondary outcome variables., Results: The children experienced a broad range of seizure types with the 'absence-like' complex partial seizure as the most commonly occurring seizure type. Almost half of the children of the study sample had a high seizure frequency. They experienced several seizures per month, week or even daily seizures. Also a substantial impact on neuropsychological outcome was observed. Mean full scale IQ was 87.7, mean academic delay was almost 1 school year and 27 children showed psychomotor delay on the Movement ABC. Only 'having more than one seizure type' showed a prognostic value for seizure frequency, and no factors were found to be correlated with the secondary outcome measures. None of the risk factors show a differential impact on seizure outcome., Conclusion: CLRE has a non-predictable course; clinical variability is high and prognosis in many children with CLRE is obscure. Having more than one seizure type was the only factor correlated to seizure frequency. Further longitudinal studies are needed.

Objective: To establish cost-effectiveness of antiepileptic drug (AED) treatment strategies of newly diagnosed patients with epilepsy., Methods: A decision analysis was carried out comparing effectiveness and treatment cost of six treatment strategies comprising carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA) as first-line and second-line drugs. Three outcome groups were defined: complete success, partial success, and failure. Data on seizure control and failure due to adverse effects were derived from the literature. Data on resource use and costs were collected for each outcome group by means of a patient survey., Results: Cost data were obtained from 71 patients. Cost increased from complete success to failure outcome groups. The probability of obtaining complete success varied from 64% (VPA-CBZ strategy) to 74% (LTG-VPA strategy). The strategy LTG-VPA was more effective than the least expensive strategy CBZ-VPA, but at higher costs per additional effectively treated patient. Probabilistic sensitivity analysis confirmed these findings to be robust. Subsequent analysis showed that changing inclusion criteria used in the selection of the studies from the literature had a major effect on cost-effectiveness ratios of the various strategies. The probability that LTG first-line therapy is the most cost-effective option remains small, even defining a high cost-effectiveness threshold. Nevertheless, LTG second-line strategies can be cost-effective depending on the willingness to pay for patient improvement., Conclusions: Only a few studies satisfied our inclusion criteria for employment in our decision model. Our model supports the use of conventional AEDs as first-line options for patients with newly diagnosed epilepsy. LTG second-line therapy is likely to be the most cost-effective option in case society is willing to pay more than Euro 6000 for an additional successfully treated patient. This study also illustrates that, with the data presently available, the outcome of decision analysis for AED treatment choice depends on the inclusion criteria used to select trials. Prospective real-life studies are needed in which first- and second-line treatment strategies are compared with respect to both effectiveness and costs.

A 40-year-old, previously healthy man presented with a subacute coordination disorder and intermittent paraesthesias of the right arm that had begun several months before and had disappeared spontaneously within a few weeks. Neurological examination showed a mildly flattened nasolabial fold on the right side and subtle hypertonia of the right arm. A CT-scan of the brain revealed calcifications in the left caudate nucleus and putamen. Cerebral MRI showed markedly enlarged Virchow-Robin spaces bilaterally in the basal ganglia and extensive periventricular white matter lesions. The differential diagnosis of these radiological findings included carbon monoxide intoxication. Ancillary investigations excluded other causes for the radiological abnormalities, and a defective gas stove that produced carbon monoxide was found in the patient's house. Although carbon monoxide poisoning is relatively rare in the Netherlands, it remains important to be alert to the possibility of such exposure. Radiological findings, notably bilateral lesions of the basal ganglia, may point in the direction of the proper diagnosis.

Background: Up to one-third of children with epilepsy are diagnosed with cryptogenic localization-related epilepsy (CLRE). CLRE is a large nonspecific category within the ILAE classification. For this population no unequivocal prognosis exists., Methods: Twenty-five articles describing aspects of CLRE were included in this review., Results: As a result of the progress in epilepsy research, as well as more advanced investigation in individual cases, the population with CLRE constantly changes. Also, disagreement on interpretation of the classification has resulted in striking differences between the populations described. High remission rates are reported, but relapse occurs frequently, leaving the long-term prognosis unforeseeable. This is reflected in academic and psychosocial prognosis, which is described to be problematic in CLRE specifically. Possible prognostic factors of CLRE in children have been identified: age at onset, seizure semiology, seizure frequency, intractability, interictal epileptiform activity on EEG, and premorbid IQ. These factors are explored to define subgroups within the CLRE population., Discussion: Prospective studies on well-defined CLRE cohorts are needed to identify factors that distinguish various prognostic subgroups. Specific attention should be focused on course of the epilepsy, scholastic achievement, and psychosocial outcome.

Introduction: We developed structured descriptions of signs and symptoms for specific seizure types (called Diagnostic Reference Frames-DRFs-by us) that can serve as a frame of reference in the process of classifying patients with epileptic seizures. In this study the validity of the DRFs for clinical use is evaluated and described., Material and Methods: In this study we use a decision support system based on the DRFs and using Bayes's rule for the validation of the DRFs. Patient's manifestations are entered in the decision support system and by successively applying Bayes's rule posterior probabilities are calculated. The DRFs with the highest posterior probability gives an indication of the classification of the seizure. The validation of the DRFs was performed by comparing the seizure type with the highest posterior probability with the classification of experienced epileptologists on a series of test cases with known epileptic seizures. In this way we assessed the accuracy of the DRFs in classifying patients with epileptic seizures., Results: We included sixty-six patients in this efficacy study. The patients and/or their relatives described the manifestations occurring during a seizure. Sixty cases (91%) were correctly classified using the decision support system., Discussion: The accuracy of 91 % indicates that the knowledge encoded in the DRFs for the included seizure types is valid. The next step is to test the DRFs in a clinical setting to evaluate the applicability in daily practice.

Objective: This retrospective study addresses the cost-effectiveness of add-on therapy with lamotrigine in clinical practice., Methods: Two years' observational data of 165 patients were used. Seizure frequency, adverse effects and direct medical costs were recorded for the year before and the year after the start of lamotrigine add-on therapy. Therapy effectiveness was measured by: (1) reduction in seizure frequency and (2) retention time. The incremental cost-effectiveness ratio expressed the direct medical cost per patient treated effectively with lamotrigine., Results: The cost of medication was 492 (95% CI: 399-583) higher after the start of lamotrigine therapy. The extra cost of lamotrigine therapy (622) was partly offset by a reduction of the cost of co-medication (-130; 95% CI: -210 to -50). Overall, the total medical cost was 453 higher in the first year of lamotrigine therapy than in the year before the start of lamotrigine. Lamotrigine was effective in 47% of all the patients, making the resultant incremental cost-effectiveness ratio 954 per year., Discussion: Add-on therapy of lamotrigine for patients with uncontrolled epilepsy offers improved health outcomes. Lamotrigine therapy is associated with increased cost (453) and an annual incremental cost-effectiveness ratio of 954. These data, together with utility data published in the literature, support the notion that lamotrigine should be considered as an add-on therapy in for patients with refractory epilepsy.

Background: Pyridoxine dependent epilepsy is a rare cause of seizures in childhood. The diagnosis is made on clinical criteria, that in many cases are never met. Therefore, epidemiological data on pyridoxine dependency are scarce., Aims: To study the epidemiology of pyridoxine dependent epilepsy in the Netherlands, and to determine whether the diagnosis is based on the appropriate criteria., Methods: Nationwide all departments of paediatrics (n = 113) and of paediatric or neonatal neurology (n = 17) were asked to report cases of pyridoxine dependent seizures. Birth incidences were calculated using national data on live births from 1991 to 2003., Results: Response was received from 67% of paediatric departments, including all university hospitals and 94% of child neurology departments. Thirteen patients were reported. Four definite (31%), three probable (23%), and four possible cases (31%) were identified. Two cases (15%) did not meet criteria for either of these groups. The birth incidence was 1:396,000 for definite and probable cases and 1:252,000 when possible cases are included., Conclusions: Thus far, epidemiological data on pyridoxine dependent seizures were only available from the UK and Ireland. A higher incidence was found in the Netherlands, in accordance with earlier suggestions of a regional difference. The study shows that the diagnosis is often made without performance of a formal trial of withdrawal. The importance of confirming the diagnosis, concerning the consequences as for individual prognosis, the potential side effects of prolonged pyridoxine substitution, and the possibility of treating the mother in case of future pregnancies are emphasised.

During her first pregnancy, a 37-year-old woman with idiopathic generalised epilepsy that was adequately controlled with lamotrigine experienced a series of epileptic seizures following an elective caesarean section. The attacks were terminated with diazepam. The following day, she developed EEG-confirmed status epilepticus, for which midazolam was administered intravenously. No further attacks were observed and the patient was later discharged in good condition with a healthy newborn son. She remained on lamotrigine therapy. At the end of her second pregnancy, the patient again experienced tonic-clonic seizures. The dosage of lamotrigine was increased and the patient received clonazepam intravenously, but a new seizure quickly occurred. Following an emergency caesarean section with midazolam treatment, a healthy daughter was born. No further attacks were observed. This case history illustrates the occurrence of adult idiopathic generalised epilepsy and highlights the problems that can arise late in pregnancy and during childbirth.

Objective: Evaluation of the effectiveness of lamotrigine in a population-based cohort of epilepsy patients., Methods: Medical charts of 360 patients treated in 37 centres in The Netherlands were reviewed. Effectiveness of lamotrigine therapy was assessed during the first year of use, with patients serving as their own controls. Effectiveness was measured by reduction in seizure frequency and retention time., Results: Effectiveness could only be assessed in 165 patients; assessment in remaining patients was not possible due to various reasons, such as insufficient medical chart information. Lamotrigine was effective in 40% of patients who had been prescribed lamotrigine because of insufficient seizure control (n=112), and 14% of these 112 patients became seizure free. Duration of epilepsy, baseline seizure frequency, valproate use, drug load and number of antiepileptic drugs (AED) used were related to effectiveness of lamotrigine. In this group, 36% continued lamotrigine (LTG) throughout the first year without experiencing a >50% seizure reduction. Lamotrigine was effective in 63% of patients who received the drug because of poor tolerability of other antiepileptic drugs (n=53)., Discussion: Lamotrigine is an effective drug in clinical practice. Use of retention time measures only may not correctly reflect the efficacy of antiepileptic drugs.

We describe two adult patients with epilepsy who received long-term antiepileptic drug therapy, a woman aged 39 years and a man aged 38 years, in whom severe osteopenia and osteoporosis, respectively, were diagnosed. Both had had epilepsy since childhood, both were seizure free and off medication for several years before the epilepsy started again. The female patient first sustained a complicated pelvis fracture after minor trauma. Next, both patients had infractions of several thoracic vertebrae after a generalised tonic-clonic seizure. Dual-energy X-ray absorptiometry for measurement of the bone mineral density revealed osteopenia in both. Bone biopsy was only performed in the male patient and showed moderate osteoporosis. Taking into consideration the young age for osteopenia and osteoporosis and the absence of other underlying causes, the long-term anticonvulsant therapy is the most likely cause of the development of osteopenia and osteoporosis in these patients. Reviewing recent literature data, advice from healthcare organisations and medical guidelines, the authors were surprised by the lack of protocols and preventive measures for patients with epilepsy who have been on antiepileptic drug therapy for many years. With this article we stress the urgent need to develop protocols and guidelines for preventive interventions.

The results of long-term follow-up of 10 children with global or specific cognitive deterioration and, on the electroencephalogram, electrical status epilepticus during sleep (ESES) are described. They were referred because of cognitive deterioration and underwent repeated neurological and neuropsychological examinations and all-night electroencephalography. A previous cognitive level was known or could be estimated in all. Seven children had a continuous spikes and waves during sleep (CSWS) syndrome, with global cognitive deterioration in four and more specific cognitive decline in three, and another three children had Landau-Kleffner syndrome (LKS). Of the last three, two children never had seizures, while the other had localization-related epilepsy. No children experienced aggravation of clinical seizures. However, therapy was disappointing. Cognitive dysfunction did not respond to valproate and/or benzodiazepines in 9 of the 10 children. A frontal epileptic focus was found in 5 of 7 children with CSWS, and a left temporal focus in 2 of 3 children with LKS. The ESES persisted in CSWS for 5-9 years and in LKS for 1-5 years, and disappeared at puberty. Good cognitive recovery after disappearance of ESES occurred in only one child, and partial recovery in four. An unfavorable prognosis of cognitive deterioration seems to be related to long-duration ESES and/or early onset epileptic activity. The authors are of the opinion that cognitive deterioration in children, with or without manifest epileptic seizures, should mandate electroencephalographic investigation during sleep.

Objective: Community pharmacists may function as intermediaries in the recruitment of a population-based cohort of patients using specific drugs. In this study, baseline characteristics and the retention rate of patients that gave informed consent, refused and did not answer were compared., Methods: A total of 1819 patients using the new antiepileptic drug (AED) lamotrigine were asked to provide informed consent for a retrospective chart study via their individual pharmacist. Four possible reactions resulted from the consent question: active consent, active refusal, passive refusal and non-informed. Patient characteristics and lamotrigine retention rate of the different groups were compared., Results: Pharmacists did not inform a total of 183 patients (10%). Of the remaining patients, a total of 968 (59%) gave consent; 101 (6%) actively refused and 567 (35%) did not respond. Age, burden of illness, psychotropic co-medication and continuation of lamotrigine therapy were related to active consent. Lamotrigine retention rate in patients that gave consent was higher than in other patients., Conclusions: Patient recruitment with community pharmacists as intermediaries for observational studies on the effects of (new) drugs is feasible, and allows access to a broad population of patients. The recruitment procedure, however, may lead to selection bias.

Purpose: To establish the long-term efficacy and tolerability of vagus nerve stimulation (VNS) in children with a Lennox-like syndrome., Method: This study was a longitudinal observational prospective cohort analysis. Baseline: 6 months., Follow-Up: 24 months. Screening (baseline and every 6 months): MRI (baseline only), EEG, neuropsychological evaluation, ECG and blood sampling for antiepileptic drug levels. Nineteen children are included., Results: A seizure frequency reduction of 20.6% was found at the end of the follow-up period. No relationship was detected between the length of the stimulation period and the reduction in the seizure frequency. 21% of the patients showed a reduction in seizure frequency of 50% or more. The seizure severity showed improvement in the first 12 months of treatment. The largest seizure reduction was found in the patients with highest frequency of background activity at the baseline EEG. Neuropsychological findings: no negative impact on behaviour, moderate improvement in function, behaviour and mood. Largest seizure reduction was found in the group with the highest baseline mental function. The scores for mental age improved independently of the seizure control. Twelve patients (63%) experienced minor side effects, which subsided after 1 month., Conclusion: (1) There was a significant reduction in seizure frequency and severity. (2) No serious side effects were recorded. (3) No negative effects on cognition or quality of life were apparent. (4) Patients with highest baseline mental functioning showed the highest seizure reduction. (5) Those patients with less disturbed EEG (high background activity and less interictal epileptic activity) showed the highest seizure reduction.

Introduction: Lamotrigine is one of the recently introduced antiepileptic drugs (AEDs) licensed in the Netherlands in 1995. The objective of this study was to examine the diffusion of lamotrigine into clinical practice. Three different aspects of this diffusion process were examined: incidence of use, patient characteristics and changes in prescription patterns in the first 5 years following its introduction., Methods: A retrospective follow-up study has been conducted using drug prescription data from the database of the Dutch Drug Information Project (GIP database). Patients were included who started with lamotrigine, carbamazepine, phenytoin or valproate in the period between January 1996 and December 2000. Incidence of use was calculated for the four drugs. Multiple logistic regression analysis was used to determine differences in baseline characteristics. The Chi-square test was used to analyse changes in the usage patterns of lamotrigine., Results: The study population consisted of a total of 29,718 patients who were prescribed carbamazepine, phenytoin, valproate or lamotrigine for the first time in the study period. Carbamazepine and valproate accounted for the majority of all new prescriptions; the incidence of lamotrigine use remained stable with 4.4 patients per 100,000 per year. Baseline characteristics of lamotrigine differed depending on the patient's age and gender (OR 3.7, 95% CI 3.3-4.2; OR 1.4, 95% CI 1.3-1.5) relative to the conventional AEDs. In a large majority of cases, lamotrigine was used as a second-line or third-line AED. Physicians prescribing lamotrigine were predominantly neurologists, in contrast to prescribers of conventional AEDs. The prevalence of psychotropic medication and migraine-abortive drugs was significantly lower in users of lamotrigine than in users of conventional AEDs. During follow-up, several significant trends were noticed in the prescribing of lamotrigine with regard to age groups, gender, antiepileptic history and off-label use., Discussion: Lamotrigine is prescribed to a population different from that using conventional AEDs. The uptake of lamotrigine in clinical practice is slow, for reasons probably related to characteristics of the drug itself and the prescribers. During the observation period, lamotrigine diffused gradually towards more first-line use as an AED and more off-label use.

We report on a patient with a bradycardia followed by an asystole as expression of a complex partial seizure arising from a cerebral neoplasm in the medial part of the left temporal lobe. Previously published papers have shown that cardiac asystole and bradycardia as manifestation of epilepsy originate from the temporal lobe. Although seizures are a common presenting symptom of a cerebral neoplasm, bradycardia and cardiac asystole of epileptic origin as first sign of a cerebral neoplasm is only sporadically documented in literature. Many different regions of the central nervous system are involved in the cardiovascular control. When a patient with a collapse is admitted to the emergency room it often is difficult to differentiate between cardiological and neurological aetiologies. However, it is important to identify the origin of a collapse in order to start the right treatment and give correct information to the patient and his family. Therefore, in patients with a non-typical cardiac syncope, a primary neurological cause should be considered.

Spitting as a seizure manifestation is described in an autistic child with a mild expression of epilepsy. Spitting became a predominant automatism of in seizure manifestation. In contrast to most cases in the literature, the epileptic discharges were localized in the left temporal lobe, an uncommon side to cause spitting seizures. By increasing the dose of carbamazepine, spitting behaviour disappeared.

Objectives: To describe, validate and demonstrate an approach for knowledge base construction based on expert opinions., Methods: A knowledge base containing the frequency of occurrence of manifestations in epileptic seizures is constructed based on information provided by neurologists/epileptologists. The reliability of the responses is determined with the inter-rater intraclass correlation coefficient (ICC). If the ICC is not large enough the Spearman-Brown prophecy formula can be used to predict the number of additional experts. We propose a method to assess whether an additional expert provides information consistent with the already acquired data as well as a method to detect experts with deviating opinions. The power of the first method was determined., Results: Data were collected for five seizure types. The ICCs determined from the responses for the various seizure types after inclusion of the additional experts was in all cases almost equal to 0.9, the target value. Yet one expert with diverging opinions concerning the frequency of occurrence of manifestations for different seizure types could be identified. Excluding this participant improved the reliability of the data. The power of the methods was good (> or =0.75)., Conclusions: It is shown that human experts can provide reliable information about the frequency of occurrence of manifestations in epileptic seizures. In addition, the described approach correctly identified neurologists/epileptologists with both consistent and diverging opinions about the frequency of occurrence of manifestations in a number of seizure types.

The human cerebellum develops over a long time, extending from the early embryonic period until the first postnatal years. This protracted development makes the cerebellum vulnerable to a broad spectrum of developmental disorders. The development of the cerebellum occurs in four basic steps: 1) characterization of the cerebellar territory at the midbrain-hindbrain boundary; 2) formation of two compartments for cell proliferation: first, the Purkinje cells and the deep cerebellar nuclei arise from the ventricular zone of the metencephalic alar plate; second, granule cell precursors are formed from a second compartment of proliferation, i. e. the upper rhombic lip; 3) inward migration of the granule cells: granule precursor cells form the external granular layer, from which (and continuing into the first postnatal year), granule cells migrate inwards to their definite position in the internal granular layer, and 4) formation of cerebellar circuitry and further differentiation. The precerebellar nuclei, i. e. the pontine nuclei and the inferior olive, arise from the lower rhombic lip. Developmental disorders of the cerebellum are often accompanied by malformations of the precerebellar nuclei. In this review the development of the cerebellum and some of its more frequent developmental disorders, such as the Dandy-Walker and related midline malformations, and the pontocerebellar hypoplasias, are discussed.

Objective: To determine whether the seizure descriptions given by a group of neurologists/epileptologists are discriminative., Method: We constructed templates for various seizure types describing how often symptoms were selected by the participants. We defined a matching score to indicate the match between such a template and the symptoms selected by each neurologist/epileptologist individually and computed the scores for each of the sets of selected symptoms with all templates. Correlation coefficients were calculated between the templates., Results: Data were collected from 24 participants. The matching scores and the correlation coefficients both show that participants provide discriminative descriptions of the seizure types. Descriptions of aggregated seizure types, such as primary generalized seizures, are less discriminatory than the descriptions of more specific seizure types., Conclusion: We concluded that the participants in our study selected symptoms that result in discriminative descriptions of the seizure types. This indicates that knowledge elicitation by using the opinions of a group of clinical experts is possible. The study also indicates that the design of the study could be ameliorated in several ways. These findings will be taken into account when designing the final study.

Objective: Our aim is to develop reliable descriptions of various seizure types, which will be used as a basis for decision support. We use expert opinions in this process. In this contribution we evaluate the inter-participant agreement in the selection of frequently occurring symptoms for the description of seizure types., Method: We compared the actual agreement among participants with the agreement that would result from random symptom selection as well as with the maximal agreement attainable. For each seizure type we calculated the reliability coefficients of the responses., Results: For all seizure types we found that the agreement in symptom selection among the participants is significantly higher than expected by chance, but not reaching the maximum agreement attainable. The reliability coefficients varied between 0.56 and 0.74 for the various seizure types., Conclusion: Although the participants do not reach the maximum agreement attainable in the selection of symptoms, the majority agreement on characteristic frequently occurring symptoms for the different seizure types does approach the maximum agreement attainable. Therefore, we conclude that expert opinions can be used for building descriptions of seizure types. However, to derive a reliable set of symptoms for the construction of the diagnostic reference frames (DRFs) more participants are needed.

A 10-year-old girl developed a progressive rash and high fever more than a month after the start of lamotrigine as add-on medication for therapy-resistant epilepsy. A skin biopsy indicated toxic epidermal necrolysis (Lyell syndrome). Because her situation deteriorated and the lesions of the skin and mucosa progressed, she was transferred to a specialised centre for burn patients. Despite maximal supportive treatment, she died 3 weeks after the first skin lesions. Even with a low initial dosage of lamotrigine followed by a slow increase, a fatal toxic epidermal necrolysis is still possible. This should be kept in mind, especially in case of concurrent administration of valproic acid.

In recent years, several new antiepileptic drugs (AEDs) have been licensed: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide. These drugs have proven efficacy as add-on therapy in patients with difficult-to-treat partial epilepsy, as 20-50% of patients treated in add-on trials experienced a seizure reduction of >or=50%. Relatively few trials have been conducted to evaluate these drugs as monotherapy for patients with newly diagnosed epilepsy. In the monotherapy trials that have been conducted, the newer drugs were often as efficacious as conventional drugs, and their tolerability was often better. However, the methodology of these trials can be criticised. Because of the relative lack of robust data for the newer agents, the conventional drugs have thus far maintained their status as first-line monotherapy. However, when first-line monotherapy fails, an alternative drug has to be chosen from the available conventional and newer drugs. This article aims to give detailed background information on the newer AEDs in order to enable physicians to make a rational choice from the available drugs for individual patients. Data are provided for the different newer AEDs on mechanisms of action; efficacy in refractory partial epilepsy, newly diagnosed epilepsy in adults and generalised seizure types; adverse effects; pharmacokinetics; and use in special patient categories.

We are developing seizure descriptions as a basis for decision support. Based on an existing dataset we used the Spearman-Brown prophecy formula to estimate how many neurologist/epileptologists are needed to obtain reliable seizure descriptions (rho = 0.9). By extending the number of participants to the required level we found that the number of participants needed to obtain a reliability coefficient of 0.9 were in accordance with the number of participants determined from the Spearman-Brown prophecy formula. Systematic differences between the participants were minor and not statistically significant.

The long-term effects of vagus nerve stimulation (VNS) on behaviour were studied in 19 children with Lennox-Gastaut syndrome. We used the following stimulation parameters: output current: 112 to 2mA; signal frequency: 30Hz frequency; signal pulse width: 500&mgr;s; signal 'on and off' time: 30s 'on,' 3min 'off.' The test battery consisted of cognitive tests assessing mental age and quality of life measurements assessing independency, behavioural problems, and mood. The results show relatively small changes in the behavioural outcomes, concurrent with the modest effects of VNS on seizure frequency (an average of 20.6% seizure reduction). When baseline measurements are compared with the follow-up measures, neither the cognitive measure nor the quality of life measures show any deterioration and the cognitive measure (mental age) showed mild positive changes (gain of 4.2 months mental age during the follow-up period). None of the changes were statistically significant. Treatment effect was most prominent in the group with the highest mental age at baseline, which suggests that mental retardation is a negative prognostic factor for VNS treatment. Moreover, in this specific patient group, treatment effect did not increase with treatment duration. Some evidence during follow-up suggests a direct positive effect of VNS on behavioural function, independent of changes in seizure frequency. Long-term treatment with VNS is not associated with adverse behavioural effects. Mental retardation is a negative prognostic factor for the efficacy of VNS.

Isolated sulfite oxidase deficiency is an autosomal recessive, neurological disorder resulting from a defect in SUOX, the gene encoding the enzyme that catalyzes the terminal reaction in the sulfur amino acid degradation pathway. In its classical, severe form, sulfite oxidase deficiency leads to intractable seizures, severe and progressive brain pathology and death at an early age. We report here on clinical features and mutational analysis of the genetic defect in a newborn with sulfite oxidase deficiency. Cultured fibroblasts from this patient exhibited no detectable sulfite oxidase activity, and a unique four base pair deletion was present in the cDNA isolated from the same source. Identification of the same genetic defect in a heterozygous state in each of the parents and the monitoring of subsequent pregnancies in this family by DNA-based prenatal diagnosis are also described. The deletion mutation was identified in a homozygous state in uncultured chorionic villus tissue from the second pregnancy that was subsequently terminated. In the third pregnancy, the presence of sulfite oxidase activity and identification of the mutation in a heterozygous state suggested that the fetus was not affected. This pregnancy resulted in the birth of a normal child., (Copyright 2002 John Wiley & Sons, Ltd.)

Although the eponym "West syndrome" is used widely for infantile spasms, the originators of the term and the time frame of its initial use are not well known. This article provides historical details about Dr. West, about his son who had infantile spasms, and about the circumstances leading to the coining of the term West syndrome.

Purpose: Monotherapy has been the gold standard in epilepsy treatment for the last 20 years, partly because of the reputation for increased toxicity of polytherapy. However, monotherapy and polytherapy have not been compared in a double-blind clinical trial. Open trials that compared the two treatments were not optimally designed and compared the two at unequal drug loads (i.e., at nonequivalent dosages). We report on a double-blind clinical trial in which a combination of carbamazepine (CBZ) and valproate (VPA) was compared with CBZ monotherapy. Patients started with equal drug loads, and neurotoxicity was the primary outcome measure., Methods: The 130 adult patients with untreated generalized tonic-clonic and/or partial seizures were randomized to equal drug loads of either monotherapy (400 mg CBZ per day) or polytherapy (200 mg CBZ plus 300 mg VPA per day). Outcome was measured by seizure counts, clinimetric epilepsy scales, and neuropsychological tests at baseline, at 2 and 12 months, and irregularly between 2 and 12 months., Results: No statistical differences were found between the two treatments in the reduction of seizure frequencies, in overall neurotoxicity, or in overall systemic toxicity. The frequencies and clinimetric scores of certain adverse effects did differ (e.g., more monotherapy patients remained sedated, and more polytherapy patients gained weight). Fewer polytherapy patients withdrew because of adverse effects (14 vs. 22%), although this did not reach statistical significance (p=0.15). Neuropsychological assessment did not show significant differences., Conclusions: No differences were found in overall neurotoxicity between monotherapy and polytherapy.

We studied the clinical efficacy and tolerability, neuropsychological effects, and cost-effectiveness (direct medical costs, direct nonmedical costs, and indirect costs) of vagus nerve stimulation (VNS) in children with Lennox-like syndrome (n = 16). The situation 6 months before implantation of the device is compared with that 6 months after surgery. Seizure frequency and severity are significantly reduced during VNS: 25% of the patients show a reduction in seizure frequency of 50% or greater; overall seizure reduction is 26.9%. Measures of neuropsychological outcome show a moderate improvement in mental functioning, behavior, and mood. The scores for mood and mental age improve independently of seizure control. Side effects are minor and transient. There is a significant reduction in direct non-health care costs, ergotherapy, and the number of days of sub-optimal functioning of the child. The costs during the 6 postoperative months are 2,876.06 Euros less than the costs during the 6 months before VNS; the payback period is 2.3 years.

The effect of vagus nerve stimulation (VNS) on behavior outcomes was studied in 16 children with Lennox-Gastaut syndrome. We used the following stimulation parameters: output current, 11 2 to 2 mA; signal frequency, 30 Hz; signal pulse width, 500 microseconds; signal on and off times, 30 seconds on and 3 minutes off. The test battery consisted of cognitive tests measuring mental age, attention, language, psychomotor function, and cognitive style, and quality-of-life measurements assessing independence, behavioral problems, symptoms of pervasive development disorders (PDDs) and mood. The results show relatively small changes in behavioral outcomes concurrently with modest effects on seizure frequency (an average of 26.9% seizure reduction). When baseline and endpoint measurements are compared none of the cognitive measures show any deterioration and three of five cognitive measures show slight positive changes. Among the quality-of-life measures, one measure showed a slight worsening of scores and three showed slight improvement. When the group is divided into subgroups on the basis of treatment effect the most prominent improvements are observed in the group without any effects of VNS on seizure frequency. These patients gained, on average, 9.5 months in mental age and showed more independent behavior, mood improvements and fewer PDD symptoms. This suggests an effect of VNS on behavioral function independent of changes in seizure frequency.

Neuronal migration disorders of the cerebral cortex form a heterogeneous group of abnormalities, characterised by mental retardation, epilepsy and hypotonia. They are prevalent in 1% of the population and in 20-40% of the untreatable forms of epilepsy. Disorders at the start of the migration result in nodular heterotopias. Bilateral periventricular nodular heterotopias are X-linked disorders, in which cortical neurons are unable to leave their position at the ventricular surface due to the absence of filamin 1. The large group of lissencephalies can be divided into a number of syndromes, each of which is characterised by a gene mutation (LIS1, DCX, RELN). These mutations result in agyria and pachygyria, which are characteristic for this group. A number of these abnormalities, especially the smaller nodular heterotopias and focal cortical dysplasia, may be treated by neurosurgical excision.

In the development of the cerebral cortex, two phases can be distinguished: (a) the formation of the preplate, a superficial layer essential for a normal lamination of the cerebral cortex; (b) the formation of the cortical plate. The cortical plate divides the preplate into a superficial marginal zone (the future layer I) and the subplate. The transient subplate is important for the formation of thalamocortical projections. Most cortical neurons arise in the ventricular zone of the pallium and migrate along radial glial cells (radial migration) to the cortical plate. The gamma-aminobutyric acid (GABA)ergic cortical interneurons, however, originate from the ganglionic eminences and reach the cerebral cortex through tangential migration.

The recent discovery of many genes that regulate brain development is revolutionizing our knowledge of neuroembryology and, moreover, our understanding of how gene defects cause human birth defects. The first 8 weeks of the development of the cerebrum can be subdivided into 23 stages, with early development of mostly the spinal cord and the brain stem. Regionalization of the brain has been related to genes that play a part in it. A characteristic developmental disorder for this early phase in the development of the forebrain is holoprosencephaly, a brain patterning disorder. Numerous genes play a part in its occurrence; abnormal function of signal factors as well as of transcription factors may lead to holoprosencephaly.