Seizure Aggravation Research Articles

Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome

In this retrospective European multicenter study we evaluated the efficacy and tolerability of rufinamide in patients with Dravet syndrome and refractory seizures. Twenty patients were included; in 16 patients a SCN1A mutation was detected. The responder rate after 6 months was 20%, and after 34 months, 5%. The retention rate was 45% after 6 months and 5% after 34 months. Rufinamide treatment was stopped because of aggravation of seizures (30%), no effect (45%), and side effects (10%). The efficacy and long-term retention rate were low in our patients with Dravet syndrome and refractory seizures, far lower than in patients with Lennox–Gastaut syndrome; one-third of our patients experienced seizure aggravation. Therefore, rufinamide does not seem to be a suitable option for long-term treatment in patients with Dravet syndrome.

1FC1.5 Interstitial radiosurgery for gelastic epilepsy due to hypothalamic hamartomas: tolerability and efficacy in childhood and adolescence

Study aim: Our objective was to examine the demography, clinical features and prognostic factors predicting developmental outcome in a United Kingdom cohort of children with Dravet Syndrome. Methods: In the study period, 12/2005 to 2/2010, we prospectively collected data on individuals with Dravet syndrome referred to the only UK centre offering genetic testing. We analysed demographic information based on UK population and birth data. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, EEG data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. Results: We identified 241 SCN1A mutation-positive Dravet syndrome cases of which 207 are UK-based. The incidence of Dravet Syndrome is at least one in every 40,900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (OR=3.1; CI=1.5−6.3; p = 0.003), interictal EEG abnormalities in the first year of life (OR=5.7; CI=1.9 16.8; p = 0.002) and motor disorder (OR=3.3; CI=1.7−6.4; p<0.001). No significant effect was seen for seizure precipitants, MRI abnormalities or mutation class (truncating vs. missense). Abnormal MRI imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes. Valproate, benzodiazepines and topiramate were reported the most helpful medications at time of referral. Aggravation of seizures was reported for carbamazepine (60%) and lamotrigine (43%). Conclusions: Identification of factors influencing prognosis both aids counselling and encourages early, syndrome specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.

Pharmacogenetics of valproic acid as unmodified risk factor of adverse drug reactions

The purpose of the research is the assessment of the role of CYP2C9 gene polymorphisms of the isoenzyme 2С9 of cytochrome Р450 of the liver as unmodified risk factor of adverse drug events development in case of intake of an average therapeutic doses of PA drugs at patients with epilepsy and epileptic syndromes. The studies was carried out within the limits of complex theme of scientific project “Epidemiological, clinical and genetics aspects of diseases of central, peripheral and autonomic neural systems and preventive health care” in 2010-2011. Sampling included 41 cases (patients with epilepsy and epileptic syndromes). Patients were from 1 up to 60 years of age, the median was 23 years. All the carriers of mutant polymorphous allelic variants CYP2C9*2 and CYP2C9*3, both homozygous and heterozygous carriers and also in case of their combination (for example, genotype CYP2C9*2/CYP2C9*3) had 100% occurrence of treatment-emergent adverse events in case of standard usage of VPA drug dosage in accordance with the Pharmacopeia (20-30 mg/kg/per day for children, 20 mg/kg/per day for adults) even during the daily dose titration (10-15 mg/kg/per day for children, 5-10 mg/kg/per day for adults). The homozygous carrier of the gene CYP2C9 of the minor allelic variant of the isoenzyme 2С9 of cytochrome Р450 had the most severe adverse drug reactions in the form of epileptic seizures aggravation, cognitive and behavioral disorders in case of standard usage of VPA drug dosage (kg/ body weight per daily). NATALIA SHNAYDER1,2, MARINA PILUGINA1, DIANA DMITRENKO1, ELENA BOCHANOVA1, EVGENIA SHAPOVALOVA1, SVETLANA ERIKALOVA1, EVGENIA SHMATOVA1, ELVIRA KHAMRAEVA1

Seizure aggravation with antiepileptic drugs in idiopathic generalized epilepsies

Seizure aggravation with antiepileptic drugs in idiopathic generalized epilepsies

Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus.

Diazepam (DZP) and phenobarbital (PB) are extensively used as first and second line drugs to treat acute seizures in neonates and their actions are thought to be mediated by increasing the actions of GABAergic signals. Yet, their efficacy is variable with occasional failure or even aggravation of recurrent seizures questioning whether other mechanisms are not involved in their actions. We have now compared the effects of DZP and PB on ictal-like events (ILEs) in an in vitro model of mirror focus (MF). Using the three-compartment chamber with the two immature hippocampi and their commissural fibers placed in three different compartments, kainate was applied to one hippocampus and PB or DZP to the contralateral one, either after one ILE, or after many recurrent ILEs that produce an epileptogenic MF. We report that in contrast to PB, DZP aggravated propagating ILEs from the start, and did not prevent the formation of MF. PB reduced and DZP increased the network driven giant depolarizing potentials suggesting that PB may exert additional actions that are not mediated by GABA signaling. In keeping with this, PB but not DZP reduced field potentials recorded in the presence of GABA and NMDA receptor antagonists. These effects are mediated by a direct action on AMPA/kainate receptors since PB: (i) reduced AMPA/kainate receptor mediated currents induced by focal applications of glutamate; (ii) reduced the amplitude and the frequency of AMPA but not NMDA receptor mediated miniature excitatory postsynaptic currents (EPSCs); (iii) augmented the number of AMPA receptor mediated EPSCs failures evoked by minimal stimulation. These effects persisted in MF. Therefore, PB exerts its anticonvulsive actions partly by reducing AMPA/kainate receptors mediated EPSCs in addition to the pro-GABA effects. We suggest that PB may have advantage over DZP in the treatment of initial neonatal seizures since the additional reduction of glutamate receptors mediated signals may reduce the severity of neonatal seizures.

Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Nav1.1

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs. Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high-performance liquid chromatography (dHPLC) and sequencing. Whole-cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Na(v) 1.1 in tsA201 cells. Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Na(v) 1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED-induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues. Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Na(v) 1.1, which may be the basis of seizure aggravation by sodium channel-blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.

Clinical feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy

We assessed the clinical variables predicting the feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy. Thirty patients aged 15 years or older with refractory partial epilepsy, who had been treated with slow-release carbamazepine as monotherapy or in combination therapy, were switched overnight from slow-release carbamazepine (mean dose at switching, 900 mg/day) to oxcarbazepine. Of these 30 patients, 29 (96.7%) had been treated with a slow-release formulation of carbamazepine. The proportion of patients with polytherapy was 85.3%. Overall, 9 of 30 (30%) switched patients experienced clinically significant adverse events until 2 weeks after switching, including 2 with seizure aggravation. The only clinical variable related to the failure of overnight switching was the number of seizures at baseline.

Levetiracetam-induced seizure aggravation associated with continuous spikes and waves during slow sleep in children with refractory epilepsies

We present a patient with cryptogenic focal epilepsy and another with Dravet syndrome, who experienced seizure aggravation and negative myoclonus, associated with continuous spikes and waves during slow sleep, induced by levetiracetam. For both patients levetiracetam was discontinued, and there was significant improvement of this particular electroclinical picture.

RUSSIAN OBSERVATIONAL SURVEY OF THE SHORT-TERM EFFICACY AND TOLERABILITY OF SUSTAINED-RELEASE SODIUM VALPROATE (DEPAKINE CHRONOSPHERA®) AS A FIRST-LINE DRUG IN THE TREATMENT OF EPILEPSY

Objective . To have additional data on the short-term safety and efficacy of sustained-release valproate (Depakine Chronosphera®, Sanofi- Aventis, France) used as both first-line monotherapy and additional therapy in children and adolescents with epilepsy. Subjects and methods . This open-label, noncomparative, prospective, short-term survey enrolled 1010 patients aged 1 month and 72 years (mean age 10,9±12,4 years). Three hundred (29,7%) patients had unspecified epilepsy; 40 (3,96%) had idiopathic focal epilepsy; 428 (42,38%) had presumptively symptomatic and symptomatic focal epilepsy; 117 (16,93%) had idiopathic generalized epilepsy, 71 (7,03%) had epileptic encephalopathy; 52 (5,15%) had West's syndrome. The starting dose of Depakine Chronosphera® was 10-15 mg/day; the mean therapeutic dose was 20-30 mg/kg/day. When there was no adequate response, the dose might be increased up to 50-60 mg/kg/day, by meticulously monitoring a patient's status. Depakine Chronosphera® was used both alone and in combination with other antiepileptic drugs (AED). The follow-up lasted at least 2 months. Results . The most common reason for using Depakine Chronosphera® was ineffective previous treatment with AED (24,7% of cases) and easiness to use. Due to the therapy, epileptic seizures ceased in 405 (40,1%) patients; their number reduced by 75 and 50% in 248 (24,55%) and 272 (26,93%) patients, respectively; therapy failed in 55 (5,45%) patients; seizure aggravation was noted in 7 (0,69%); there was no information on changes in the frequency of seizures in 23 (2,28%). Since Depakine Chronosphera® is intended mainly for both preschool children and older patients who have difficulties in taking the drug as tablets, the study group comprised children less than 7 years of age. Nevertheless, the drug was also actively given to children over 7 years and adults. This was associated with not only with the physician's interest in the new formulation of the drug, but also with its easiness to use. Adverse reactions were observed in 8,91% of the patients. The spectrum and frequency of side effects corresponded to those in the similar studies. Conclusion . The study has indicated that the use of Depakine Chronosphera® as monotherapy and multimodality treatment for epilepsy in adults and children is effective and safe. The low discontinuance rate of the drug suggests its good tolerability and efficacy, as well as easiness to use, in early preschool children in particular. The use of Depakine Chronosphera® is promising in treating epilepsy in adults and children

Some treatments cause seizure aggravation in idiopathic epilepsies (especially absence epilepsy)

Seizure aggravation by antiepileptic drugs (AEDs) is a rare phenomenon, occurring mostly in generalized epilepsies treated with drugs that are more efficacious against partial seizures. Its frequency is greatly overestimated by doctors and especially by patients. There are many other reasons for seizures to deteriorate but they are often not considered. Seizure aggravation by AEDs is important to recognize but equally important not to overdiagnose. It can largely be prevented by accurate syndromic diagnosis and the treatment of generalized epilepsies with drugs that are effective against primary generalized seizures and avoiding those that are not.

Introduction—Annual Course 2008: American Epilepsy Society

Introduction—Annual Course 2008: American Epilepsy Society

Attention-Deficit Disorders and Epilepsy in Childhood: Incidence, Causative Relations and Treatment Possibilities

At least 20% of children with epilepsy have clinical attention-deficit hyperactivity disorder (ADHD) compared to 3% to 7% of the general pediatric population. Several mechanisms may account for the high prevalence, such as a common genetic propensity, noradrenergic system dysregulation, subclinical epileptiform discharges, or even seizures, antiepileptic drug effects, and psychosocial factors. At the same time, children with attention-deficit hyperactivity disorder have a higher than normal rate of electroencephalography abnormalities (5.6-30.1% vs. 3.5%). Methylphenidate treatment is equally efficient in children with isolated attention-deficit hyperactivity disorder and in children with attention-deficit hyperactivity disorder and epilepsy (70%-77%). Electroencephalography screening in patients with attention-deficit hyperactivity disorder in the absence of other clinical indications or before starting methylphenidate treatment is not currently indicated. Methylphenidate is considered safe for use in children who are seizure-free. However, the few reports of seizure aggravation in methylphenidate-treated children with uncontrolled epilepsy have raised concern.

Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin

The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.

Oxcarbazepine, not its active metabolite, potentiates GABAA activation and aggravates absence seizures

Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of gamma aminobutyric acid (GABA(A)) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA(A) receptor current and aggravate seizures. In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA(A) receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration. OXC potentiated GABA(A) receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA(A) receptor current and did not aggravate seizures. A hydroxyl group at the C-10 position on the CBZ tricyclic structure in MHD reduces GABA(A) receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.

The pharmacological treatment of depression in adults with epilepsy

Background: Comorbid mood disorders may affect quality of life in people with epilepsy. Objective: To review available data on the use of antidepressant drugs in epilepsy taking into account major concerns that may be encountered by clinicians, namely pharmacokinetic interactions with antiepileptic medications and seizure aggravation. Results: Data on pharmacotherapy of depression in epilepsy are limited with no controlled clinical trials investigating efficacy and safety of antidepressants. Data on seizure risk come from psychiatric samples, thus limiting the general applicability to people with epilepsy. Conclusions: Antidepressant drug doses need to be used and adjusted according to individual clinical needs. Within the therapeutic range, the incidence of seizures in psychiatric populations is low for most antidepressants.

Greater response to placebo in children than in adults: a systematic review and meta-analysis in drug-resistant partial epilepsy.

BackgroundDespite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs).Methods and FindingsThree electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51–0.89]; p = 0.02 by meta-regression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p = 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43–0.98], p = 0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies.ConclusionsChildren with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.

Seizure Aggravation—Evidence that Oxcarbazepine Requires Monitoring

Aggravation of Seizures and/or EEG Features in Children Treated with Oxcarbazepine Monotherapy. Vendrame M, Khurana DS, Cruz M, Melvin J, Valencia I, Legido A, Kothare SV. Epilepsia 2007;48(11):2116–2120. Epub 2007 Jul 21. PURPOSE: Exacerbation of epilepsy may occur following initiation of therapy with antiepileptic drugs (AEDs). The aim of this study is to analyze the clinical and EEG characteristics of a group of pediatric patients with worsening of seizures and/or EEG deterioration while on oxcarbazepine (OXC). METHODS: A retrospective analysis of a clinical database was performed to identify patients with epilepsy treated with OXC over the past 3 years. History, neurological examination, and EEG findings were reviewed to identify any who had developed exacerbation of seizures or new abnormalities on EEG. RESULTS: Of 290 patients on OXC, we identified 12 patients with new onset seizures, all with initial normal neurological exam and normal EEG, who developed either worsening of preexisting seizures, new seizure types, and/or EEG deterioration following introduction of OXC monotherapy. EEG changes were primarily characterized by new onset of generalized epileptiform activity not reported on the initial baseline EEG. Following substitution of OXC with a broad spectrum AED, significant improvement of seizure control and improvement in the EEG was observed. CONCLUSIONS: These findings suggest that OXC can aggravate seizures and/or worsen EEG features in children. Following initiation of therapy with OXC, monitoring of patients with follow-up EEGs may be important, especially in patients who do not show adequate response to therapy.

A study on epileptic negative myoclonus in atypical benign partial epilepsy of childhood

Objective. To investigate the clinical and neurophysiological characteristics, particularly therapeutic considerations, of epileptic negative myoclonus (ENM) in atypical benign partial epilepsy (ABPE) of childhood. Methods. From 1998 to 2006, 14/242 patients with benign children epilepsy with centrotemporal spikes (BECTS) were diagnosed as having ABPE with ENM. In all 14 patients, we performed video-EEG monitoring along with tests with the patient’s arms outstretched; 6/14 patients were also simultaneously underwent surface electromyogram (EMG). ENM manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. Results. In all cases, ENM developed after the onset of epilepsy and during antiepileptic drug therapy, and the appearance of ENM were corresponding to EEG findings of high-amplitude spikes followed by a slow wave in the contralateral motor areas with secondary generalization. This was further confirmed by time-locked silent EMG. During ENM occurrence or recurrence, habitual seizures and interictal discharges were exaggerated. In some patients, the changes in antiepileptic drug regimens in relation to ENM appearance included add-on therapy with carbamazepine, oxcarbazepine, and phenobarbital or withdrawal of valproate. ENM was controlled in most cases by administration of various combinations of valproate, clonazepam, and corticosteroids. Conclusion. The incidence of ENM or ABPE in our center was approximately 5.79%. A combination of video-EEG monitoring with the patient’s arms outstretched and EMG is essential to identify ENM. The aggravation of habitual seizures and interictal discharges indicate ENM. Some antiepileptic drugs, such as carbamazepine, oxcarbazepine, and phenobarbital, may be related to ENM occurrence during spontaneous aggravation of ABPE. Various combinations of valproate, benzodiazepines, and corticosteroids are relatively effective for treating ENM that occurs in ABPE.

Provocation and aggravation of seizures with patients suffering from SCN1A-mutation

Provocation and aggravation of seizures with patients suffering from SCN1A-mutation

Dramatic Aggravation of Partial Seizures Induced by Gabapentin Overdose

Dramatic aggravation of partial seizures, unreported until now, was observed in association with gabapentin (GBP) overdose in an 18-year-old man with symptomatic localization-related epilepsy accompanying focal cortical dysplasia in the right occipital lobe. The patient compulsively took 13400 mg GBP in a single dose one evening. The next morning he was ataxic and had very frequent simple partial seizures with eye deviation to the left, which appeared similar to his habitual seizure. The patient's blood level of GBP was 17.62 μg/ml, and laboratory examinations detected no abnormalities. Ictal EEG, however, showed that the origin of the induced seizures was different from that of his habitual seizures. His ataxia and seizures subsided immediately after cessation of GBP and hydration, with no sequel. This case shows that occasional induction of seizures by GBP is not limited to myoclonus or absence seizures but may involve partial seizures in case of overdose.