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PubMed2006

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. DATA SOURCES: Electronic databases. Drug company submissions. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model. RESULTS: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective. CONCLUSIONS: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

Anticonvulsants↗
PubMed2004

The choice of antiepileptic drugs in newly diagnosed epilepsy: a national French survey.

The choice of an antiepileptic drug (AED) in patients with epilepsy is mainly based on efficacy and safety of each drug. However, these criteria of drug selection should be further evaluated according to the epileptic syndromes, and adjusted to the sex and age of the patient. Unfortunately, very few studies have been conducted based on these latter criteria. We conducted a survey on the management of epilepsy treatment in adults. This survey was undertaken in France, and led to the establishment of a French consensus on antiepileptic drug treatment in adult patients with newly diagnosed epilepsy. Patients were grouped into 18 categories according to the epileptic syndrome (absence epilepsy, juvenile myoclonic epilepsy, undetermined idiopathic generalized epilepsy, symptomatic or cryptogenic partial epilepsy and unclassified epilepsy), and to the patient's gender and age. Our survey suggests that there is a consensus among French epileptologists for the choice of AEDs, mainly based on the epilepsy syndrome. Gender also plays a crucial role. Sodium valproate and lamotrigine are the two drugs of choice for generalized epilepsies, as well as for undetermined epilepsies. Lamotrigine is often prefered for women of childbearing age. First line AEDs in partial epilepsy are carbamazepine (particularly for men), lamotrigine (particularly for women), and gabapentin (in the elderly). In cases of failure and/or intolerance to one of these AED, the principal alternatives are oxcarbazepine, sodium valproate and topiramate.

Adolescent↗
PubMed2005

Electro-clinical phenotypes of chromosome disorders associated with epilepsy in the absence of dysmorphism.

Chromosome imbalances are associated with epilepsy but electro-clinical phenotypes are lacking for all but the best-known syndromes. Scanty information is contained in older case reports published in genetics journals that describe children with severe patterns of malformation and dysmorphism. From a larger series of children with chromosome abnormalities and epilepsy, we identified 10 patients with associated dysmorphism without malformation. Electro-clinical features are described for each patient. We found that these patients are at greater risk of delayed diagnosis, particularly when there are no learning difficulties at the onset of epilepsy, as in ring chromosome 20 syndrome. Chromosome studies should be ordered on all children with learning difficulties and epilepsy, and on children with atypical non-lesional epilepsy, even in the absence of learning difficulties or dysmorphism.

Brain↗
PubMed1999

Length variation of a polyglutamine array in the gene encoding a small-conductance, calcium-activated potassium channel (hKCa3) and susceptibility to idiopathic generalized epilepsy.

The present association study tested whether length variations of two adjacent polymorphic CAG repeats in the coding sequence of a small-conductance, calcium-activated potassium channel (hKCa3) confer susceptibility to common subtypes of idiopathic generalized epilepsy (IGE). We found no significant difference in the allelic length distribution of the CAG repeats between 290 healthy German controls and the entire sample of 126 German IGE patients (Wilcoxon rank-sum test, P = 0.44) or two subgroups, comprising either 78 patients with juvenile myoclonic epilepsy (Wilcoxon rank-sum test, P = 0.74) or 59 patients with idiopathic absence epilepsies (Wilcoxon rank-sum test, P = 0.44). Moreover, the allelic distribution in parents-child trios of 46 IGE offspring did not differ significantly between the transmitted and non-transmitted parental alleles (Wilcoxon rank-sum test, P = 0.48). Therefore, our association study provides no evidence that length variations of polyglutamine arrays in the N-terminus of the hKCa3 channel exert a frequent and relevant effect in the epileptogenesis of common subtypes of IGE.

Adult↗
PubMed1999

Evidence against the existence of a temporal lobe epilepsy personality syndrome.

The existence and specificity of a characteristic behavioral syndrome among patients with temporal lobe epilepsy (TLE) remains controversial. The behavioral pattern of many epilepsy patients differs from that of age-, sex-, and socioeconomic-matched control subjects. Patients with TLE and other forms of epilepsy can experience changes in cognitive function, personality, affect, and drive-related behavior (e.g., libido, aggression). Biologic factors (e.g., underlying brain pathology, epileptogenic process, localization and lateralization, recurrent seizures, family history), antiepileptic drugs, and psychosocial factors interact pathogenically. Their roles vary among patients and among different neurobehavioral disorders. Behavioral changes occur in some epilepsy patients. However, the question of whether specific behavioral changes occur with different seizure types or epilepsy syndromes remains unanswered. For example, behavioral changes can occur in patients with absence epilepsy, juvenile myoclonic epilepsy, frontal lobe epilepsy, and tonic-clonic seizures. Many of these behavioral changes overlap with features of the purported TLE syndrome. We lack a clear delineation of the spectrum, frequency, and severity of changes in well-characterized partial and primary generalized epilepsy syndromes. Furthermore, the relative roles and the interplay among pathogenic factors remain poorly defined.

Epilepsy, Temporal Lobe↗
PubMed1993

Animal models of inherited epilepsy.

A significant proportion of the childhood epilepsies have a genetic component. Therefore, animal models that can be bred for seizure expression may provide important information regarding the mechanisms by which molecular defects result in the neuronal hyperexcitability states collectively termed "epilepsy." Because of the rate and ease of breeding, rodent models are the most commonly used. The genetically epilepsy-prone rat has motor seizures in response to auditory stimuli. It is likely that the seizures are generated in the inferior colliculus because of an abnormality in the noradrenergic system. The seizure predisposition is inherited as an autosomal dominant trait. The genetic absence epilepsy rat has age-related spontaneous seizures characterized by motor arrest and head drops that are correlated with generalized spike-wave on the electroencephalogram (EEG). The seizure generating mechanism appears to be located in the lateral thalamic nuclei. The epileptic mongolian gerbil demonstrates behavioral arrest followed by myoclonic, tonic, and tonic-clonic seizures in response to unfamiliar environments. The underlying neuroanatomy involves hippocampal-cortical interactions indicative of a partial epilepsy. The tottering mouse has absence and myoclonic seizures, a 6- to 7-Hz ictal spike-wave EEG, and noradrenergic hyperinnervation that are linked to a mutation on chromosome 8. Hippocampal network hyperexcitability has been found with normal neuronal intrinsic properties. Stargazer is a mouse mutant with almost identical clinical and electrographic features as found in tottering. However, the genetic defect is located on chromosome 15 and no abnormalities of norepinephrine have been discovered. The El mouse demonstrates ictal automatisms in response to vestibular stimulation. Metabolic and structural abnormalities have been found in the hippocampus. Linkage to chromosomes 9 and 2 have been reported recently. The dilute brown agouiti mouse demonstrates motor seizures in response to auditory stimuli. Chromosomes 4 and 17 are linked to seizure expression. Thus, a variety of models exist to study the genetic, biochemical, structural and electrophysiological mechanisms that underlie the predisposition and expression of the inherited epilepsies.

Animals↗
PubMed2005

Evidence-based treatment of idiopathic generalized epilepsies with older antiepileptic drugs.

Older antiepileptic drugs continue to play a major role in the treatment of the idiopathic generalized epilepsies. Comparative studies of ethosuximide and valproate have demonstrated equivalence in the treatment of childhood absence epilepsy. Valproate can be regarded as the recommended first-line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic-clonic seizures have not separated out idiopathic from secondary generalized events. Treatment for the other idiopathic generalized epilepsy syndromes lacks evidence other than a few case reports and diverse expert opinion. Further randomized controlled trials of older antiepileptic drugs are recommended to solidify the evidence-based treatment of the idiopathic generalized epilepsies.

Anticonvulsants↗
PubMed1993

Nonconvulsive status epilepticus in adults and children.

Nonconvulsive status epilepticus (SE) accounts for approximately one-quarter of all cases of SE. The actual proportion may be higher because patients with nonconvulsive SE may go unidentified. This disorder may be divided into generalized (absence) or partial (complex partial) forms. Nonconvulsive SE may occur de novo or in patients with epilepsy. Absence SE is considered more frequent and is characterized by a continuous neurocognitive alteration. Complex partial SE may be associated with recurrent seizure activity and a cycling of the clinical states. Treatment includes antiepileptic drug(s) (AEDs) and avoidance of seizure precipitants. Electrophysiological studies are necessary to confirm the diagnosis of nonconvulsive SE and to monitor the response to AED therapy. Prompt recognition and treatment may be necessary to avoid neurological morbidity in select patients. Epilepsy with continuous spikes and waves during slow sleep (ESES) and the Landau-Kleffner syndrome are two rare childhood disorders that are difficult to classify but may be appropriate to include in a discussion of nonconvulsive SE.

Adult↗
PubMed1977

Genetic factors in childhood epilepsy with focal sharp waves. I. Clinical data and familial morbidity for seizures.

203 epileptic children (127 boys, 76 girls), who had demonstrated at least once focal sharp waves in the EEG during the course were investigated regarding clinical and historical data as well as familial morbidity for seizures. Expectedly, the seizure symptomatology was multiform: focal seizures of different type, especially secondarily generalized, grand mal, psychomotor fits, infantile spasms etc. Organic brain lesions play an important role. In 23% of cases a familial seizure affliction can be registered. The morbidity (close family) is significantly lower than in families of patients with spike wave absences (2.5 and 4.4% resp., Doose et al. 1973). Like in spike wave absence epilepsies mothers and mothers' siblings are more often affected than fathers and fathers' siblings. Among the affected relatives grand mal epilepsies predominate. The increase of febrile convulsions and spike wave absences observed in the families of absence epileptics is not present. In probands with onset of epilepsy during early childhood a significantly increased familial affliction can be observed. A more extensive discussion of the results will follow in a second paper deeling with EEG findings in probands and siblings.

Child↗
PubMed2003

Divalproex and epilepsy.

Valproic acid, a branched chain carboxylic acid, has a broad spectrum of action as an antiepilepsy drug. While effective in myoclonus syndromes and absence epilepsy, the drug has efficacy for patients with generalized convulsive and partial seizures as well. Mechanisms of action are similar to other drugs used to treat epilepsy, in that valproate limits sustained repetitive firing by actions on the voltage sensitive sodium channel. However, the drug facilitates the removal of glutamate from synaptic regions by up regulating glial glutamate transporters while prolonging the action of GABA by limiting production of inhibitory transmitter transporter proteins. Adverse effects include hepatotoxicity that requires informing patients and establishing clinical monitoring plans. Teratogenicity occurs with valproate and requires informing patients and careful monitoring in women during pregnancy.

Anticonvulsants↗
PubMed2001

Optimisation of methods for selecting candidate genes from cDNA array screens: application to rat brain punches and pineal.

DNA arrays are potentially powerful experimental tools within neuroscience but application of this technology to in vivo paradigms may, in practice, be limited by the sensitivity of transcript detection and inter-screen variation. Here we describe the use of brain punch micro-sampling, used in combination with commercially available cDNA arrays, for profiling brain gene expression in a mutant strain of rat (GAERS model of absence epilepsy). Furthermore, we describe a multi-step optimisation of analysis methods which provides for improved sensitivity and absence of bias in the selection of candidate genes which may be differentially expressed in the mutant. Our method has been validated through application to a second paradigm, rhythmic gene expression in the rat pineal gland. Our experimental design, and analysis method should therefore be generally applicable to subtle discriminations of transcript abundance within discrete brain areas.

Animals↗
PubMed1992

A preliminary observation on auto-cholinergic synapse dysfunction in patients with different types of epilepsy.

Serum anti-acetylcholine receptor antibodies (A AchR Ab) and anti-synaptic premembrane antibodies (A PrM Ab) were measured in 21 patients with absence epilepsy, 21 cases with benign childhood epilepsy with centro-temporal spikes (BCECTs) and 13 cases with atypical epilepsy. Respectively, in five (23.8%), eleven (51.2%) and eight (66.7%) of the above mentioned groups of patients both A AchR Ab and A PrM Ab were found.

Adolescent↗
PubMed2005

Sacred disease secrets revealed: the genetics of human epilepsy.

Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the 'sacred' disease. Genes underlying the 'malevolent' forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.

Calcium Channels↗
PubMed2005

Sacred disease secrets revealed: the genetics of human epilepsy.

Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the 'sacred' disease. Genes underlying the 'malevolent' forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.

Calcium Channels↗
PubMed2000

Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.

Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21.

Amino Acid Sequence↗
PubMed2001

Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells.

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. The ducky gene was mapped previously to distal mouse chromosome 9. High-resolution genetic and physical mapping has resulted in the identification of the Cacna2d2 gene encoding the alpha2delta2 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were found to underlie the ducky phenotype in the original ducky (du) strain and in a newly identified strain (du(2J)). Both mutations are predicted to result in loss of the full-length alpha2delta2 protein. Functional analysis shows that the alpha2delta2 subunit increases the maximum conductance of the alpha1A/beta4 channel combination when coexpressed in vitro in Xenopus oocytes. The Ca(2+) channel current in acutely dissociated du/du cerebellar Purkinje cells was reduced, with no change in single-channel conductance. In contrast, no effect on Ca(2+) channel current was seen in cerebellar granule cells, results consistent with the high level of expression of the Cacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian alpha2delta mutation and complete the association of each of the major classes of voltage-dependent Ca(2+) channel subunits with a phenotype of ataxia and epilepsy in the mouse.

Animals↗
PubMed2005

Antiepileptic drug monotherapy: pediatric concerns.

Selecting the optimal antiepileptic drug (AED) begins with accurate epilepsy classification, including seizure type and epilepsy syndrome if possible. Based on the available data, children with focal epilepsy, with or without secondary generalization, can be treated with a traditional or newer narrow-spectrum or broad-spectrum AED. Children with generalized convulsive epilepsy, mixed epilepsy, or seizures of an unknown type are best treated with a broad-spectrum AED. Children with childhood absence epilepsy can be treated with ethosuximide, valproate, or lamotrigine. In all cases, the best choice among the various AED options requires consideration of factors such as seizure frequency, seizure severity, AED adverse event profile, AED titration schedule, patient comorbidities, prescription plan coverage, and cost. Most children with epilepsy achieve the goal of "no seizures and no side effects" and most children eventually become seizure free without AEDs. If accurate epilepsy classification is made, clear differences in efficacy are not evident among the multiple available AEDs. Better comparative data emphasizing adverse event profiles, comorbidities and longer-term outcome are needed between the traditional and newer AEDs.

Adolescent↗
PubMed1998

Concomitance of childhood absence and Rolandic epilepsy.

Five children (3 girls and 2 boys) who showed generalized synchronous 3/sec spike and wave complexes as well as centrotemporal spikes in the same EEG or in different EEGs are described. Among these five patients only 1 boy and 1 girl showed clinically both absence seizures and partial motor seizures with or without secondary generalization. One girl and 1 boy have only absences and the other girl only partial motor seizures. A concomitance of generalized synchronous 3/sec spike and wave discharges and centrotemporal spikes in the same patient is rarely found. The clinical manifestation of absences and partial motor seizures in the same patient is extremely rare.

Child↗