Therapy For Refractory Epilepsy Research Articles

Association of ABCB1 genetic variants 3435C>T and 2677G>T to ABCB1 mRNA and protein expression in brain tissue from refractory epilepsy patients

There is evidence from studies in rodents that P-glycoprotein (P-gp) overexpression is implicated in the causation of refractory epilepsy. Genetic variants in the human ABCB1 (MDR1) gene were shown to affect the expression levels of the transporter in various tissues and to be associated with refractory epilepsy. However, the effect of the genetic variants on the P-gp level in epileptogenic brain tissue is poorly investigated. In the present study, we examined the impact of putatively functional polymorphisms 3435C>T and 2677G>T in the ABCB1 gene on the ABCB1 mRNA expression and P-gp content in human brain tissue from epileptogenic foci of the patients with refractory epilepsy. Fresh brain tissue specimens were obtained from therapy-refractory epilepsy patients during neurosurgery of the epileptogenic focus. We determined the ABCB1 mRNA expression in 23 samples using 5' exonuclease-based real-time polymerase chain reaction (PCR) as well as the P-gp content in 32 samples determined by immunohistochemistry, genotyping was performed by PCR/restriction fragment length polymorphism (RFLP). There was lack of association of 3435C>T and 2677G>T as well as diplotype configurations on ABCB1 mRNA expression and P-gp content in epileptogenic brain tissues. We cannot exclude an association of ABCB1 variants on P-gp function, but our results suggest that brain ABCB1 mRNA and protein expression is not substantially influenced by major ABCB1 genetic variants thus explaining in part results from case-control studies obtaining lack of association of ABCB1 polymorphisms to the risk of refractory epilepsy.

Smooth mosaics

Lissencephaly (LIS) is a diffuse cortical malformation caused by an incomplete neuronal migration disorder in early brain development.1 There is a continuum of structural alterations ranging from complete agyria and thickened cortex to variable extent of agyria or pachygyria, and subcortical band heterotopia (SBH) as the mildest form.2 Severe phenotypes include marked mental retardation, therapy refractory epilepsy, and cerebral palsy leading to reduced life expectancy whereas milder phenotypes encompass less severe epilepsy and mild to moderate intellectual impairment. A majority of patients with a clinical and neuroradiologic manifestation of the lissencephaly spectrum harbor a mutation either in the LIS1 gene or in the doublecortin ( DCX or XLIS ) gene.3 Classic LIS (type I) is associated with mutations in the LIS1 gene whereas patients with typical SBH are prone to carry mutations in the X-chromosomal DCX …

Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia

Recent arouse of interest indicated that drug resistant proteins are markedly over-expressed in the epileptogenic tissue and they may be responsible for the one-third of the epileptic patients who were refractory to anti-epileptic drugs (AEDs). Since several AEDs may act as substrates for these drug resistant proteins, the enhanced function of such proteins may increase drug extrusion, resulting in inadequate response to drug therapy in patients with epilepsy. We studied expression of the multidrug resistance protein 1 (MDR1) and multidrug resistance-associated protein 1 (MRP1) in the epileptic tissues resected surgically in 28 patients with focal cortical dysplasia (FCD) by immunohistochemistry. The results were compared with 10 normal necropsy brain tissues. Normal brain showed no MDR1 expression in neurons and astrocytes, while MRP1 expression was very weak, which were encountered in a few samples. MDR1 expression was mainly localized on the vascular endothelial cells. In contrast to normal brain, we found intense MDR1 and MRP1 expression in both neurons and reactive astrocytes in the vast majority of dysplastic tissues. The majority of the dysplastic neurons demonstrated moderate to strong MRP1 immunoreactivity. Endothelial cells showed both MDR1 and MRP1 expression in the majority of the specimens studied. Multidrug transporters are over-expressed in the epileptogenic zone in patients with FCD. These results are concordant with previous studies, in which over-expression of multidrug proteins were shown in epileptogenic brain tissue in patients with FCD, that the over-expression of drug transport proteins in tissue from patients with refractory epilepsy may explain one possible mechanism for drug resistant in these pathologies.

Resistance to Phenobarbital Extends to Phenytoin in a Rat Model of Temporal Lobe Epilepsy

Most patients who are resistant to the first antiepileptic drug (AED) treatment are also resistant to a treatment with a second or third AED, indicating that patients who have an inadequate response to initial treatment with AEDs are likely to have refractory epilepsy. Animal models of refractory epilepsy are important tools to study mechanisms of AED resistance and develop new treatment strategies for counteracting resistance. We have recently described a rat model of temporal lobe epilepsy (TLE), in which spontaneous recurrent seizures (SRS) develop after a status epilepticus induced by sustained electrical stimulation of the basolateral amygdala. Prolonged treatment of epileptic rats with phenobarbital (PB) resulted in two subgroups, PB responders and PB nonresponders. In the present study we examined if rats with PB-resistant seizures are also resistant to phenytoin (PHT), using continuous EEG/video recording of spontaneous seizures. First, a new group of 15 epileptic rats was produced and selected by treatment with PB into responders (8 rats) and nonresponders (6 rats), respectively. During subsequent treatment with PHT, the doses of PHT had to be individually adjusted for each rat to avoid toxicity. Treatment with PHT led to complete seizure control in two animals and a >50% reduction of seizure frequency in three other rats, which were considered PHT responders. In nine of the remaining rats, PHT did not exert any clear anticonvulsant effect, so that these rats were considered nonresponders. Plasma levels of PHT did not differ significantly between responders and nonresponders. When comparing the PB and PHT nonresponder groups, five of the six PB-resistant rats (83%) were also resistant to PHT, demonstrating that rats that have an inadequate response to initial treatment with PB are likely to be also resistant to treatment with a second AED. The AED-resistant rats of our model meet the definition of pharmacoresistance in animal models, that is, persistent seizure activity not responding to at least two AEDs at maximum tolerated doses. This new model of pharmacoresistant TLE may be useful in the targeted development of new therapies for refractory epilepsy.

Pharmacokinetics and Drug Interactions with Zonisamide

Polypharmacy is a widely employed treatment strategy in epilepsy, particularly for individuals with poorly controlled seizures. Drug combinations should be carefully considered to minimize the potential for unfavorable interactions. Older-generation antiepileptic drugs (AEDs) are well known for their pharmacokinetic interaction potential, which generally results from alterations in the metabolism of concomitant drugs due to effects on the cytochrome P450 (CYP) and uridine glucuronyl transferase enzyme systems. Newer agents, such as zonisamide, are less likely to cause adverse drug interactions. A series of interaction studies has revealed zonisamide to be without effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, zonisamide is principally inactivate by CY3A4-dependent reduction. Consequently, carbamazepine, phenytoin, and phenobarbital all increase its clearance, an interaction that may necessitate a dosage increase, but which will also permit more rapid attainment of steady-state zonisamide concentrations. Otherwise, zonisamide is essentially devoid of clinically significant interactions with other AEDs, oral contraceptives and, indeed, all other classes of therapeutic agents investigated to date. As a result, it is reasonable to conclude that zonisamide has a favorable pharmacokinetic profile and that it may be a useful and uncomplicated agent when employed as adjunctive therapy in refractory epilepsy.

Changes of coping strategies in patients with therapy refractory epilepsy in the course of a ward based treatment with a holistic therapeutic approach

In this study we examined whether individual coping strategies improve in the course of a ward based treatment with a holistic therapeutic approach. An increase in problem-focussed coping and a decrease in emotion-focussed coping or avoidance-oriented coping were considered as improvement. As a part of a comprehensive therapy monitoring 65 patients with therapy refractory epilepsy were studied with the Freiburg Questionnaire of coping with Illness (FKV) on the day after admittance to a specialized epilepsy ward. A second investigation with the FKV was performed on the day before discharge. A decrease in depressive coping and cognitive avoidance and an increase in problem focussed coping could be documented. These changes could not be interpreted as an effect of better seizure control or antidepressive drugs. This may be a hint for the efficacy of a holistic treatment approach to increase the patient's resources for a successful psychosocial adjustment to therapy refractory epilepsy.

Far field potentials from the brain stem after transcutaneous vagus nerve stimulation.

Recently, the vagus nerve has gained particular interest in neuropsychiatry, as neurodegenerative diseases like Alzheimer's and Parkinson's disease are supposed to affect the brainstem nuclei of the vagus nerve early in their course. In addition, electric stimulation of the vagus nerve has therapeutic effects in otherwise therapy-refractory epilepsies and depressions. So far, no method is available to assess vagus nerve function in this context. On this background and based on the established techniques of early acoustic evoked potentials we investigated if a transcutaneous electric stimulation of the sensory auricular branch of the vagus nerve innervating parts of the outer ear is feasible in healthy subjects using this hypothesis-generated approach. We were able to record a clear, reproducible Vagus Sensory Evoked Potential (VSEP) measured as far field potential probably originating in vagus nuclei in the brainstem. Further studies are needed to test the interindividual stability and test-retest reliability of this new method before potential diagnostic and therapeutic applications might be evaluated.

Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study.

Vagus nerve stimulation (VNS) is an established treatment method for therapy-refractory epilepsy and, in Europe, for treatment-resistant depression also. Clinical and experimental investigations have also shown positive effects of VNS on cognition in epilepsy and depression. The purpose of the present pilot study was to investigate the effect of VNS on cognition in patients with Alzheimer's disease. All the included patients (N = 10) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for the diagnosis of Alzheimer's disease. Before the implantation of the vagus stimulator (NeuroCybernetic Prosthesis), the patients underwent neuropsychological tests (e.g., Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-cog] and Mini-Mental State Examination [MMSE]), computerized tomography of the brain, medical/neurologic and psychological examinations (status evaluation), and lumbar puncture with investigation of the cerebrospinal fluid. The presence of depressive symptoms was rated using the Montgomery-Asberg Depression Rating Scale. The VNS was initiated 2 weeks after the implantation, and the patients were followed up with regular investigations and tests over 6 months. Response was defined as improvement or absence of impairment in ADAS-cog and MMSE scores after 3 and 6 months. After 3 months of treatment, 7 of 10 patients were responders according to the ADAS-cog (median improvement of 3.0 points), and 9 of 10 patients were responders according to the MMSE (median improvement of 1.5 points). After 6 months of treatment, 7 patients were responders on the ADAS-cog (median improvement of 2.5 points), and 7 patients were responders on the MMSE (median improvement of 2.5 points). VNS was well tolerated, and its side effects were mild and transient. The results of this open-label pilot study suggest a positive effect of VNS on cognition in patients with Alzheimer's disease. Further studies are warranted.

Monotherapy trials: prerequisite data

Is it possible for an antiepileptic drug (AED) to be effective as add-on therapy in refractory epilepsy but ineffective as monotherapy for the same seizure type(s)? If the answer is ‘no’, why not award a new AED a monotherapy licence once it has been shown to be effective as adjunctive treatment in placebo controlled, dose-ranging studies in patients with difficult-to-control epilepsy? The recent comparative study between carbamazepine and remacemide, however, suggests that subtle pharmacokinetic/pharmacodynamic interactions between established and new AEDs can indicate efficacy in add-on studies that does not necessarily transfer to monotherapy. There is some evidence that an AED whose primary mechanism of action does not involve blockade of voltage-dependent sodium channels may do less well than carbamazepine in terms of efficacy end-points in a double-blind, head-to-head comparison. These observations lead to the conclusion that monotherapy trials are, indeed, required. They should be undertaken after proof of efficacy has been obtained using a single short presurgical AED withdrawal study backed up by a substantive dose-ranging phase III efficacy trial. There is no reason to recommend earlier assessment since the clinical need for new AEDs is in refractory epilepsy. The subsequent monotherapy trial programme should contain elements utilising comparative and withdrawal designs. Sponsors should be able to seek a licence for their drug either as a first choice treatment in newly diagnosed epilepsy or as substitution monotherapy once treatment with at least one other AED has failed.

Lamotrigina en epilepsia parcial y generalizada refractarias

Lamotrigine (LTG) is a new antiepileptic drug that it has proved to be efficacious in treating patients with partial and generalized tonic-clonic seizures in adjunctive and monotherapy. It has similar efficacy in comparison with carbamazepine and phenytoin with a minor number of adverse experiences. We report the use of LTG in adjunctive therapy in 106 adults patients with refractory epilepsy (efficacy and safety) with partial and generalized seizures, with follow-up to 3.4 years. The LTG mean doses used was 273 mg/day. 66% of patients experienced a > or = 50% reduction in seizure frequency, with 30% in remission. Both partial, secondarily generalized and generalized seizures showed significant reductions with LTG treatment. LTG was well tolerated in our patients. Side effects were minor. No case of rash was seen. LTG is a excellent agent for adjunctive therapy in refractory epilepsy.

Animal models of the ketogenic diet: what have we learned, what can we learn?

Despite its clinical use as a therapy for refractory epilepsy for more than 75 years, the ketogenic diet (KD) remains a therapy in search of an explanation. The mechanism of action of the KD is unclear and the optimal indications for its clinical use are incompletely defined. Animal models could help to elucidate these questions. Surprisingly, there have been very few animal studies of the KD, and those that have been performed are difficult to compare because of wide discrepancies in experimental methods. Earlier models concentrated on the effect of the KD on acute seizure threshold in normal (i.e. nonepileptic) animals. Recent studies are beginning to examine the longer term effects of the KD and its role in epileptogenesis. Some features of clinical experience have been replicated in animal models, including the role of ketosis, elevation of seizure threshold by both classic ketogenic and medium chain triglyceride diets, better effectiveness at younger ages, and rapid reversal of the seizure protective effect when the diet is discontinued. These parallels raise hope that pertinent clinical questions can be addressed in the more controlled setting of the research laboratory. As in the clinical arena, there has been a recent resurgence of interest in pursuing basic questions related to the ketogenic diet, using techniques of modern neuroscience. Experimental approaches such as brain slice neurophysiology, genetic models, dissection of metabolic pathways, and neurohistological techniques hold much promise in the effort to understand this intriguing alternative to standard anticonvulsants.

Electrophysiological characterization of Na+ currents in acutely isolated human hippocampal dentate granule cells.

1. Properties of voltage-dependent Na+ currents were investigated in forty-two dentate granule cells (DGCs) acutely isolated from the resected hippocampus of twenty patients with therapy-refractory temporal lobe epilepsy (TLE) using the whole-cell patch-clamp technique. 2. Depolarizing voltage commands elicited large, rapidly activating and inactivating Na+ currents (140 pS microm-2; 163 mM extracellular Na+) that were reduced in amplitude by lowering the Na+ gradient (43 mM extracellular Na+). At low temperatures (8-12 C), the time course of Na+ currents slowed and could be well described by the model of Hodgkin & Huxley. 3. Na+ currents were reversibly blocked by tetrodotoxin (TTX) and saxitoxin (STX) with a half-maximal block of 4.7 and 2.6 nM, respectively. In order to reduce series resistance errors, the Na+ current was partially blocked by low toxin concentrations (10-15 nM) in the experiments described below. Under these conditions, Na+ currents showed a threshold of activation of about -50 mV, and the voltages of half-maximal activation and inactivation were -29 and -55 mV, respectively. 4. The time course of recovery from inactivation could be described with a double-exponential function (time constants, 3-20 and 60-200 ms). The rapid and slow time constants showed a distinct voltage dependence with maximal values around -55 and -80 mV, respectively. These properties contributed to a reduction of the Na+ currents during repetitive stimulation that was more pronounced with higher stimulation frequencies and also showed a dependence on the holding potential. 5. In summary, the most striking features of DGC Na+ currents were the large current density and the presence of a current component showing a slow recovery from inactivation. Our data provide a basis for comparison with properties of Na+ currents in animal models of epilepsy, and for the study of drug actions in therapy-refractory epilepsy.

Flunarizine as add-on therapy in refractory epilepsy: An open trial

We evaluated flunarizine as add-on therapy for control of refractory epilepsy in an open trial in 17 patients. Children received 10 mg/day and adults received 20 mg/day of flunarizine for 6 months. In eight patients, antiepileptic drug (AED) serum levels at baseline and at 3 months of flunarizine therapy were available. Six of the 17 patients had seizure reduction ⩾50%. Three of six had generalized tonic-clonic seizures (GTCS). Most of remaining patients were unchanged or had increased complex partial seizures (CPS). Three of the six patients with ⩾50% seizure reduction were treated with phenobarbital (PB) and phenytoin (PHT) combination. Addition of flunarizine caused no significant alteration in baseline serum AED levels. With the addition of flunarizine, seizure control in patients with GTCS was better than that of patients with CPS. Patients receiving combination PB and PHT treatment responded better with the addition of flunarizine than did those receiving other AED combinations. We conclude that flunarizine had some antiepileptic property as add-on therapy in 35% of our cases with refractory epilepsy.

The place of clobazam in the treatment of epilepsy: An update

The 1,4-benzodiazepines have a recognized place in the treatment of epilepsy, mainly in status epilepticus, as adjunctive therapy in refractory epilepsy, in hypsarrythmia and in myoclonic epilepsy. Clobazam, the only marketed 1,5-benzodiazepine, has been shown in eight controlled studies involving 291 patients to be significantly superior to placebo, while in 35 open studies embracing 2259 patients, it has produced an overall reduction in seizure frequency of 65 per cent, with some 18 per cent of patients being rendered seizure free. The main indication for its use is as oral adjunctive therapy in refractory epilepsy. It has a rapid onset of action, is well tolerated, and many studies indicate it has a psychotropic action and/or produces minimal, or no cognitive impairment. The most common side-effect reported is transient sedation, while the overall incidence of adverse effects in the open studies is 38 per cent. In the controlled investigations 4 per cent of patients had to be withdrawn because of adverse side-effects, while in the open studies the figure was 9 per cent. In general, there are no significant interactions with other antiepileptic drugs, although changes in a few have been described. Withdrawal seizures can occur and require gradual termination of clobazam. The main disadvantage of clobazam is the development of tolerance, which develops in approximately 32 per cent of patients, and there is no way of predicting when the phenomenon is likely to occur nor in which individuals. A dose of 20 to 30 mg given preferably at night is recommended, possibly commencing at 10 mg.

Gabapentin is safe and effective add-on therapy in refractory epilepsy

Gabapentin is safe and effective add-on therapy in refractory epilepsy

Factors relating to dramatic response to clobazam therapy in refractory epilepsy

Twenty-five out of 41 (61%) patients with drug-resistant complex partial seizures showed an initial dramatic response to clobazam. Sixteen of these responders developed tolerance to the effects of clobazam so that only 9 (22%) maintained a dramatic response for 1 year. Factors which appeared important in predicting a dramatic response to treatment were a known aetiology for the epilepsy, the occurrence of complex partial seizures alone (i.e., without secondary generalisation) and the absence of mental retardation.