Old age is now the commonest time to develop epilepsy, often as a consequence of underlying cerebrovascular or neurodegenerative disease. Age-related physiological changes can affect the pharmacokinetics and pharmacodynamics of antiepileptic drugs. Only three double-blind, head-to-head, randomised, controlled trials have been undertaken in this patient population and so pharmacological treatment tends to be empirical, often based on what antiepileptic drug not to chose for an individual patient. The available evidence has tended to favour lamotrigine, and perhaps gabapentin, over carbamazepine, based on better tolerability rather than superior efficacy for newly diagnosed epilepsy in this population. Preliminary data with levetiracetam suggest that this drug will also be useful in older people as a consequence of its favourable side-effect profile and lack of idiosyncratic reactions and drug interactions. Despite the dearth of high quality trial evidence, published outcome data hint at a good prognosis with a single antiepileptic drug for the majority of elderly people with epilepsy. A few patients will require low dose combination therapy. Epilepsy surgery is also an occasional option in this population. As life expectancy rises, so will the likelihood of presenting with seizures in later life placing an increasing burden on healthcare resources.

抄録全体を表示

The goal of pharmacogenetics is to deliver safe and effective drug therapy. Genetic polymorphisms in cytochrome P450 (CYP) enzyme genes are implicated in the inter-individual variability in pharmacokinetics of anti-epileptic drugs (AEDs). However, the clinical impact of CYP polymorphisms on AED therapy remains controversial. Previous studies have shown that the defective CYP2C9 alleles affect the required dose of phenytoin and the risk of its toxicity. We have reported that the CYP2C19-deficient genotype is associated with the serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the clinical efficacy of clobazam therapy. We determined also the influence of polymorphisms in CYP genes on the population pharmacokinetic parameters of AEDs using a non-linear mixed effect modeling program, which enables us to define relevant genetic factors together with other factors, and the magnitude of the effect on variation in pharmacokinetics in patients. The defective alleles of CYP2C9 and CYP2C19 were found to have significant effects on the inter-individual differences in clearance of phenobarbital and zonisamide, respectively. Based on these recent findings, we discuss the clinical significance of AED dose adjustment according to both genetic and non-genetic factors that affect CYP activity.

抄録全体を表示

Several recent studies have reported strong genetic associations between HLA-B and susceptibility to drug hypersensitivity. The genetic associations are often drug-specific; HLA-B*1502 is associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS⁄TEN), HLA-B*5701 with abacavir hypersensitivity, and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. The genetic association can also be phenotype-specific; B*1502 is associated solely with carbamazepine-SJS⁄TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, genetic association can be ethnicity-specific; carbamazepine-SJS⁄TEN associated with B*1502 is seen in Southeast Asians but not in Caucasians or Japanese, which can be explained by the difference in allele frequencies among populations. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity, in which the HLA molecule presents an antigenic drug for T-cell activation. Pharmacogenomic study has identified an unusual form of granulysin secreted by cytotoxic T lymphocytes and natural killer cells responsible for the disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. The high sensitivity⁄specificity of some of these genetic markers provides a plausible basis for developing tests to identify individuals at risk for these life-threatening conditions in some populations. Application of HLA-B*1502 and HLA-B*5701 genotyping as a screening tool for patients taking carbamazepine and abacavir, respectively, has reduced the incidence of these adverse drug reactions.

抄録全体を表示

Drug resistance is an important clinical problem. Significant efforts have been made recently to improve understanding. Most recently, a Commission of the International League against Epilepsy has produced a document on the definition of drug resistance [1]. This is an important step forward. It must be recognised, however, that the definition of drug resistance may need to be adjusted according to the needs of a particular clinical or research question. Overall, about one in three patients who have epilepsy do not respond to currently available anti-epileptic drugs. Not only is this a significant burden on healthcare systems, but it is also associated with an increased risk of morbidity and premature mortality for patients, as well as a broad range of psycho-social consequences. One can estimate that in the United Kingdom alone, for example, the cost of the first failed anti-epileptic drug is of the order of £20 to £30 million per year. There are of course costs well beyond monetary values. Observational studies have demonstrated that some patients who have not responded to several anti-epileptic drugs in the past, and might therefore be expected to continue to have seizures despite trials of further anti-epileptic drugs [2], might in fact occasionally respond to a new anti-epileptic drug [3, 4].

抄録全体を表示

Despite the state-of-the-art medical treatment with antiepileptic drugs (AED), at least one-third of newly diagnosed epilepsy patients may show poor response to AED. Although the biological mechanism of diverse responses to AED is poorly understood, it is likely that multifactorial factors could be responsible for the different responses. Clinical factors such as etiology of epilepsy and pre-treatment seizure frequency can predict the different responses to AED, whereas the role of genetic variations in individuals contributing to variation in response to AED is still conflicting. The inconsistency in proving the genetic roles in different responses to AED may be partly explained by (1) diversity of the definition of response to AED, (2) heterogeneity of the subjects, and (3) lack of multigenetic approach. While we hypothesize that the genetic variations in individuals may independently contribute to different responses to AED, multigenetic interactions including both the genetic variations of pharmacokinetics and pharmacodynamics may take place.

抄録全体を表示

The number of genes underlying monogenic epilepsies in human and animal models continues to grow as the clinical syndromes for a variety of heritable epilepsies yield to neurogenetic analysis. Interestingly, the diversity of co-morbid phenotypes linked to single epilepsy gene defects is also expanding. While many rare familial idiopathic epilepsy disorders are typically defined as "pure" seizure syndromes, many occur in the context of more complex clinical symptomatology. This is not surprising, since genes that alter cortical excitability are expressed in diverse brain networks, as well as in other tissues. In this brief review, two such genes are described. The gene encoding amyloid precursor protein along with related genes contributing to the accumulation of an aberrant peptide cleavage product, Aβ42, has now been placed in a molecular pathway mediating both the dementia of Alzheimer's Disease and seizures. A second gene, KCNQ1, encoding one of the voltage-sensitive ion channels contributing to membrane repolarisation in the heart, is co-expressed in both heart and brain where mutations contribute to cardiac arrhythmias, early mortality, and seizures. KCNQ1, a member of the cardiac LQTS gene family, is the first validated candidate gene for sudden unexplained death in epilepsy (SUDEP). The new strategy of searching for epilepsy genes linked to non-epileptic co-morbidity is providing illuminating examples of the role of neuronal network hyperexcitability in explaining the clinical spectrum of complex human neurological disorders that feature seizures.

抄録全体を表示

In the past decades, several mutant genes that encode ion channel subunit proteins or their functionally-related proteins have been identified in pedigrees of idiopathic epilepsy. To explore the pathogenesis and pathophysiology of epilepsy syndrome, the functional abnormalities of transmission in genetic animal models bearing the mutant genes identified in pedigrees of idiopathic epilepsy should be analyzed. In spite of these efforts, it is important to identify the most suitable genetic animal models for exploration of epileptogenesis and ictogenesis, as well as the development of novel antiepileptic drugs. In the literature on genetic epileptic animal models, there is no systematic discussion on how to assess the validation criteria for such models. In this review, we describe the validation criteria for genetic animal models of epilepsy.

抄録全体を表示

We originally reported mutations of EFHC1 gene in patients with juvenile myoclonic epilepsy (JME). Subsequently, several other groups reported additional EFHC1 mutations in patients with JME and also in other types of idiopathic generalized epilepsy. We recently generated Efhc1-deficient mouse and found that the mouse showed spontaneous myoclonus and increased susceptibility to a convulsant, pentylenetetrazol. These results further support and confirm our proposal that EFHC1 is the gene for JME.

抄録全体を表示

Around 30% of adults with epilepsy remain refractory to antiepileptic drug (AED) therapy despite having similar seizure semiologies and syndromes to drug responsive individuals. How, when and why do they become pharmacoresistant? Observations from the Glasgow database of newly diagnosed patients receiving their first ever AED at the Epilepsy Unit have provided fascinating insights into the natural history of treated epilepsy. Prospective analyses of this expanding cohort were undertaken in 1997 (n=470), 2003 (n=780) and, most recently, in 2008 (n=1098). Overall, around 50% of patients became seizure free on their first ever AED with diminishing numbers responding to subsequent regimens either as monotherapy or in low dose combinations. The overall prognosis has modestly improved over recent years as newer drugs with novel mechanisms of action have become available. However, from the most recent analysis, around 25% of the population never had useful period of seizure freedom despite receiving many AEDS singly and in combination. Interestingly, a similar number never had another seizure after starting treatment. Differences between these clinical phenotypes included higher seizure densities prior to initiation of therapy and concurrent psychiatric comorbidities suggesting greater brain dysfunction. The presence of a family history of epilepsy and⁄or febrile convulsions also predicted refractory epilepsy, implicating a genetic component in drug response. These observations tend to support the suggestion that drug-resistant and drug-sensitive patients are not necessarily the same.

抄録全体を表示

There is ample evidence for genetic polymorphisms of drug-metabolizing enzymes showing distinct subgroups in a population with or without the ability to transform certain drugs into polar metabolites before elimination. The polymorphic alleles lead to altered activity of these isoenzymes causing absent, decreased, or increased metabolism. An individual carrying two defective mutation alleles is categorized as a poor metabolizer (PM) and an individual carrying one or two wild-type alleles as an extensive metabolizer (EM). Like most other agents, many antiepileptic drugs (AED) are metabolized by a variety of enzymatic reactions, and the polymorphisms in the CYP family have attracted considerable attention. The CYP2D6, 2C9, and 2C19 polymorphisms account for the most frequent variations in phase I metabolism of drugs [1, 2].

抄録全体を表示

Pediatric neurotransmitter diseases are new emerging neurological diseases in children. They include tyrosine hydroxylase (TH) deficiency, aromatic L-amino acid decarboxylase (AADC) deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency, gua-nosine triphosphate cyclohydrolase I deficiency, sepiapterin reductase (SR) deficiency and cerebral folate deficiency. Of these, monoamine biosynthesis and metabolism disorders are one group of inherited disorders usually requiring specific diagnostic procedures. Children with disorders of neurotransmitters often present with psychomotor retardation, hypotonia and microcephaly. Although seizures may be more common in patients with SR deficiency, patients with TH or AADC deficiency only occasionally have non-epileptic myoclonus. However, the episodic dystonia and oculogyric crisis manifested in these patients are frequently misdiagnosed as epilepsy, and multiple anti-epileptic drugs (AEDs) may be given. In the present short review, the pathogenesis and diagnosis of these neurotransmitter disorders are discussed, with the hope that correct diagnosis of pediatric neurotransmitter diseases can reduce the unnecessary AED treatment.

抄録全体を表示

Carbamazepine (CBZ) and zonisamide (ZNS) are antiepileptic drugs (AEDs) with multiple mechanisms of action, including inhibition of voltage-dependent sodium and calcium channels, enhancement of inhibitory events mediated by GABAergic neurotransmission, and blockade of the glutamatergic neurotransmission in the brain. Recently, the intracellular signaling pathways have been implicated as the new targets of AEDs. Especially, we have investigated the functional importance of Ca2+ mobilization, composed of influx through Ca2+ channels and output through ryanodine receptor (RyR)- and inositol-triphosphate receptor (IP3R)-sensitive intracellular Ca2+-induced Ca2+ releasing systems (CICRs), in the pathogenesis of epilepsy and the pharmacological mechanism of AEDs. In this review, we discuss the actions of CBZ and ZNS on neurotransmitter exocytosis associated with RyR-sensitive CICR. Further studies on the mechanisms of action of AEDs may help to understand the clinical benefits of AEDs in the treatment of epilepsy disorders.

抄録全体を表示

Current antiepileptic drug (AED) therapy requires trial and error in determining the most effective AED and dosage for a patient, and almost one-fourth of patients are resistant to AED therapy. The introduction of individualized medicine for epilepsy based on genetic information is a new avenue to improve current AED therapy. However, several crucial issues remain to be resolved before the development of individualized medicine for epilepsy can proceed further. The epilepsy genes responsible for common phenotypes have not yet been identified, and ongoing pharmacogenetic studies continue to search for an explanation of why 25 to 30% of patients do not respond to AEDs. There is no convincing clinical evidence indicating the impact of P-glycoprotein on prediction of clinical response. This article provides a critical review of the status and perspectives for the development of individualized medicine for epilepsy based on genetic polymorphisms/mutations in relation to core elements such as pharmacodynamic pathway, pharmacokinetic pathway, prediction of idiosyncratic reaction to AED, and mechanisms of action of AEDs.

抄録全体を表示

Purpose: To investigate the effectiveness and tolerability of topiramate (TPM) in treating children with CNS anomalies and intractable epilepsy.
Methods: We retrospectively searched the patient database in National Taiwan University Hospital for candidate children (younger than 18 years of age) with epilepsy and CNS anomalies from December 2002 to February 2004. The effectiveness and possible side effects of TPM were evaluated by questionnaire.
Results: Twenty-two children (9 males, 13 females) aged from five months to fourteen years were enrolled in the present study. Underlying CNS anomalies were proliferation disorders (n=10), migration/organization disorders (n=10), and neurocutaneous syndromes (n=2). Types of epilepsy at TPM add-on were symptomatic partial epilepsy (n=11), infantile spasms (n=7), and Lennox-Gastaut syndrome (n=4). During the follow-up periods of six to 30 months, eight patients (36%) had more than 50% reduction of seizures and four patients (18%) were seizure-free. The average dosages of TPM ranged from 2.5 to 25 mg⁄kg⁄day. Patients with proliferation disorders or infantile spasms responded better to TPM therapy. The most common side effect was oligohidrosis (n=9, 41%).
Conclusion: TPM is a safe and promising add-on anticonvulsant for epileptic children with CNS anomalies. Hypohidrosis is one of the major side effects of TPM treatment.

抄録全体を表示

We have reported that cyclins and the corresponding cyclin-dependent kinase (CDK) family are related to cell proliferation during development as well as epileptogenesis. In the present study, we used EL mice to examine how levetiracetam (Lev) controls the altered expressions of cyclins and the CDK family during development, and further, the epileptogenesis as well in the parietal cortex, the seizure initiation site of EL. Developmental changes in the expression of cyclin and the corresponding CDK families (cyclin D⁄CDK-4, cyclin E⁄CDK-2, cyclin A⁄CDK-2, cyclin A⁄CDK-1, and cyclin B⁄CDK-1) in the parietal cortex of EL mice and the control DDY mice were examined by Western blotting. At different ages, one group of mice (n = 6) were administered a single dose of Lev 160 mg/kg Lev p.o. and a treatment naïve group (n = 6) was administered vehicle, three days before sacrifice. Compared with the control DDY mice, treatment naïve EL mice showed upregulations of cell cycle-specific cyclins⁄CDK during the early developmental stages, suggesting that reentry into cell cycle is promoted prior to the beginning of seizures. Lev abolished these effects and Lev-treated EL mice showed no seizures at all. These results suggest that cyclins⁄CDK may be activated during early stages of development before exhibiting seizures, suggesting that reentry into cell cycle in the parietal cortex is a candidate mechanism for the seizure predisposition of EL mice. The antiepileptic effects of Lev may be related to regulation of cell cycle reentry.

抄録全体を表示

Positron emission tomography with fluorine-18 fluorodeoxyglucose ([¹⁸F]FDG-PET) usually shows ganglioglioma as hypometabolic, in the absence of malignant transformation or high grade. We report a case of benign ganglioglioma in the left precentral gyrus showing hypermetabolism on [¹⁸F]FDG-PET, which was associated with intractable focal motor seizures. An 11-year-old girl started having simple partial seizures refractory to anti-epileptogenic medication since 4 years of age. Magnetic resonance imaging revealed a tumorous lesion in the left precentral gyrus. Interictal [¹⁸F]FDG-PET showed high [¹⁸F]FDG uptake in the lesion. Gross total resection was carried out. The histological diagnosis was low-grade ganglioglioma. The hypermetabolism on [¹⁸F]FDG-PET may be associated with epileptogenic activity of the ganglioglioma.

抄録全体を表示

We report two cases of localization-related epilepsy manifesting frequent brief atonia. The patients were assumed to have epileptic negative myoclonus (ENM), and were successfully treated with ethosuximide (ESM). Both exhibited hemi-orofacial twitches during sleep, and interictal electroencephalography (EEG) showed paroxysms over the contralateral posterior-temporal and centroparietal regions. Incessant atonia appeared at nine and 10 years of age accompanied by motor paresis. Ictal EEG showed irregular high-voltage spike-waves predominantly over bilateral centroparietal regions. Carbamazepine and zonisamide were ineffective in controlling, or even aggravated ENM. The addition of ESM resulted in immediate and complete disappearance of ENM and partial motor seizures along with an improvement of motor paresis. The first case was assumed to have idiopathic etiology because of normal development before the onset of epilepsy, while the second case was considered to have cryptogenic etiology based on a pre-existing intellectual disability. Hence, we recommend that ESM should be considered for the treatment of ENM that develops during the course of localization-related epilepsy, regardless of the etiology. However, further studies are still needed to evaluate the effects of ESM in the treatment of ENM.

抄録全体を表示

We report a case of lesional medial temporal lobe epilepsy (TLE) associated with cortical dysplasia extending from the right medial temporal lobe to the fornix via the basal and medial aspects of the frontal lobe and septum pellucidum. A 23-year-old man had had medically intractable psychomotor seizures since 11 years of age. Interictal EEG demonstrated paroxysmal activities in the right temporal region, and functional imaging by positron emission tomography with [18F] fluorodeoxyglucose revealed a functional deficit zone in the apex and medial part of the right temporal lobe. An intraoperative electrocorticogram demonstrated frequent paroxysmal activities in the medial temporal lobe. An anterior temporal lobectomy was performed, with an additional hippocampectomy including the focus of the paroxysmal activities on the intraoperative hippocampal EEG. Postoperatively, he became seizure-free. The surgical strategies for intractable TLE with widely distributed cortical dysplasia lesion are discussed.

抄録全体を表示

We report a case of a 41-year-old man who showed thoracocervicofacial purpura after generalized tonic-clonic convulsion. The patient also had hypoxemia with chest CT findings of non-homogeneous high density in the posterior areas in both lungs, without signs of infection or heart failure. The purpura suggested that strong valsalva maneuver during airway closure and the resultant increase in systemic arterial and pulmonary vascular pressure may have led to pulmonary congestion.

抄録全体を表示

We presented an 11-month-old-girl with subcortical band heterotopia who had focal epilepsy detected by subtraction single photon emission computed tomography (SPECT) coregistered to magnetic resonance (MR) imaging (SISCOM) and ictal electroencephalogram. She manifested cluster of partial seizures composed of asymmetric tonic posturing accompanied by head rotation to the right side. Ictal electroencephalogram showed that paroxysmal discharges were generated from the right parieto-occipital area and spread to surrounding areas. SISCOM revealed hyperperfusion in the overlying cortex of the right superior temporal gyrus, which corresponded to the onset area of ictal epileptiform discharges. These neurofunctional findings corresponded to her clinical seizures. Her seizures were controlled by high-dose phenobarbital therapy. We considered that the patient had focal epilepsy and that the epileptic focus might be in the overlying cortex, but not in the subcortical band.

抄録全体を表示