Littérature scientifique sur le sujet « Drug-resistance epilepsy »

Drug Resistance in Epilepsy: Expression of Drug-resistance Proteins in Common Causes of Refractory Epilepsy Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Brain 2002;125(Pt 1):22–31 Epilepsy is resistant to drug treatment in about one third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Among the various resistance mechanisms, overexpression of drug-resistance proteins, such as multidrug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance–associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 also may be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurons, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumors (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases), and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumor nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression also was noted in dysplastic neurons. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein–positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 also may do so. The overexpression of these drug-resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins reduce the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs. P-Glycoprotein and Multidrug Resistance–associated Protein Are Involved in the Regulation of Extracellular Levels of the Major Antiepileptic Drug Carbamazepine in the Brain Potschka H, Fedrowitz M, Loscher W. Neuroreport 2001;12:3557–3560 Despite considerable advances in the pharmacotherapy of epilepsy, about 30% of epilepsy patients are refractory to antiepileptic drugs (AEDs). In most cases, a patient who is resistant to one major AED also is refractory to other AEDs, although these drugs act by different mechanisms. The mechanisms that lead to drug resistance in epilepsy are not known. Recently, overexpression of multidrug transporters, such as P-glycoprotein (PGP) and multidrug resistance–associated protein (MRP), has been reported in surgically resected epileptogenic human brain tissue and suggested to contribute to the drug resistance of epilepsy. However, it is not known to what extent multidrug transporters such as PGP or MRP are involved in transport of AEDs. In the present study, we used in vivo microdialysis in rats to study whether the concentration of carbamazepine in the extracellular fluid of the cerebral cortex can be enhanced by inhibition of PGP or MRP, using the PGP inhibitor verapamil and the MRP inhibitor probenecid. Local perfusion with verapamil or probenecid via the microdialysis probe increased the extracellular concentration of carbamazepine. The data indicate that both PGP and MRP participate in the regulation of extracellular brain concentrations of the major AED carbamazepine.

SUMMARY Background. Early identification of potential epilepsy surgery candidates is essential to the treatment process. Aim. To evaluate the clinical applicability of the ILAE definition of drug resistant epilepsy and its potential in identifying surgical candidates earlier compared to three established “older” definitions of drug resistant epilepsy. Material and Methods. Retrospective analysis of 174 patients who underwent epilepsy surgery between 1998 and 2009. Clinical factors and course of disease were extracted from patients' charts. Drug resistant epilepsy was classified according to four definitions and the time until fulfillment of criteria compared. Results. Mean time to fulfillment of criteria of drug resistant epilepsy ranged from 11.8 (standard deviation (SD) 9.8) to 15.6 years (SD 11.3). Time to drug resistance was significantly longer applying the only definition, requiring failure of three antiepileptic drugs (AEDs) (Canada definition), whereas time to fulfillment of all other definitions did not differ. Fifty percent of all patients experienced a seizure free period of ≥1 year prior to being classified as drug resistant, 13% entered another 1-year remission after fulfilling any criteria for drug resistance. Conclusion. We conclude that the ILAE definition identifies drug resistant epilepsy, with similar latency like two of three formerly used definitions. It is an easy applicable tool to minimize the delay of referral to a specialized center. Intermittent remissions delay assessment of drug resistance for all definitions and 13% of patients enter a remission despite established drug resistance.

Pharmacotherapy is the first-line treatment modality for epilepsy. However, in 20-40% of patients, epilepsy is resistant to pharmacotherapy. These numbers have not changed for decades despite the development and use of antiepileptic drugs with novel mechanisms of action. Drug-resistant epilepsy is now considered a separate pathophysiologic and clinical entity. The existing hypotheses on its pathogenesis could be divided in two groups. Firstly, drug-resistance might be caused by an abnormal pharmacokinetics or pharmacodynamics of antiepileptic drugs as a result of congenital or acquired dysfunction of the transporter or receptor proteins. Secondly, it might be a consequence of inherent features of epilepsy per se, such as the so-called “intrinsic severity” or some disorder of the connectome. Taking into account the complexity of this phenomenon, the issue of drug resistance continues to remain in the focus of the current research efforts.

The pathogenesis of intractable epilepsy is not fully clear. In recent years, both animal and clinical trials have shown that the expression of ATP-binding cassette (ABC) transporters is increased in patients with intractable epilepsy; additionally, epileptic seizures can lead to an increase in the number of sites that express ABC transporters. These findings suggest that ABC transporters play an important role in the drug resistance mechanism of epilepsy. ABC transporters can perform the funcions of a drug efflux pump, which can reduce the effective drug concentration at epilepsy lesions by reducing the permeability of the blood brain barrier to antiepileptic drugs, thus causing resistance to antiepileptic drugs. Given the important role of ABC transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of ABC transporters were used to obtain ABC transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for long-term use; therefore, these drugs can be used for future clinical treatment of intractable epilepsy.

About 30% of epileptic subjects is “drug resistant” (DR) to mono and multiple treatments. The risk of sudden unexpected death (SUDEP) is more than 20 times higher in epileptic patients than that in the general population; SUDEP represents the main cause of death in patients with refractory epilepsy. Several mechanisms probably exist, but most research has focused on seizure related cardiac arrhythmia. No evidence-based intervention to prevent SUDEP exists. Biological basis of DR are still unclear and applying innovative diagnostic techniques for prediction of outcome in the pharmacotherapy of epilepsy is a mission with important social and economical aspects. Genomic and proteomic are not able to depict the holistic approach that is fundamental for a complete description of phenotiping in human physiology. Metabolomic responses, as integration of genomic and proteomic expressions with the environmental solicitations, can give us the possibility to investigate about complex interactions in the metabolic networks induced by pathologies or by drugs. Data presented in this paper are 1H-NMR spectroscopy measurements performed by our team in our Clinical Metabolomic Labs, University of Cagliari, on blood samples of epileptic patients, previously classified by us as drug-responders or not. Using supervised models we are extracting a metabolic characterization, higher in specificity and sensibility with increasing of number of patient, to realize a profile of drug resistance in epilepsy. In this study we present a PLS_DA model. This is a preliminary model of metabolic alterations in our cohort of DR patients, which could represent a new and non-invasive method for early detection of epileptic patients at risk of sudden death and simultaneously help to clarify the pathophysiological mechanisms of DR and SUDEP.

ABSTRACT INTRODUCTION. Epilepsy is one of the most common chronic neurological disorders characterized by the presence of spontaneous and recurrent seizures and it affects 1% of the population worldwide. Up to 30% of patients continue to have seizures despite an adequate and well-tolerated treatment with antiepileptic drugs (ASMs), used singularly or in combination. These individuals are regarded as having refractory or drug- resistant epilepsy. In 2010, an Internationally accepted definition of refractory epilepsy was proposed by a Task Force of International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules to achieve sustained seizure freedom”. Regardless of the advances in the field of epilepsy and the acquisition of new antiepileptic drugs, the proportion of drug-resistant patients remain unchanged. Dravet syndrome (DS) is a rare, drug-resistant, developmental epileptic encephalopathy with onset in infancy characterized by multiple types of frequent, disabling epileptic seizures, developmental delay/cognitive impairment and an increased risk of sudden unexpected death in epilepsy (SUDEP). In more than 80% of patients, a sodium voltage-gated channel alpha subunit 1 gene (SCN1A) genetic variant can be demonstrated, although diagnosis is based on clinical criteria. Idiopathic generalized epilepsies (IGEs) are the most common group of epilepsies in children and adolescents and include four well-characterized epilepsy syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and IGE with generalized tonic–clonic seizures only. Distinctive features of IGE syndromes are typical age of onset, specific generalized seizures type, normal background EEG activity and interictal generalized spike-and-wave (GSW) discharges in the absence of any brain lesion and with normal developmental skills. Lacosamide (LCM) is a third generation ASM approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA) as both monotherapy and adjunctive therapy in treatment of focal seizures, with or without bilateral tonic-clonic seizures, in patient older than 16 (EMA) or 17 (FDA) years old. Stiripentol (STP) is a third generation ASM indicated as adjunctive therapy in Dravet syndrome, whose seizures are not adequately controlled with clobazam and valproate. Fenfluramine (FFA) Hydrochloride is fourth generation ASMs, recently noticed as effective for the treatment of convulsive seizures and non-convulsive SE in DS. In the 2019, Zogenix supported an EAP of FFA in patients with a clinical diagnosis of DS, without echocardiographic signs of cardiac valve disfunction and pulmonary arterial hypertension and in June 2020 FDA approved FFA for the treatment of seizures in DS. Levetiracetam (LEV) is one of the most widely used ASMs for both adults and children. It is approved by EMA and FDA as adjunctive therapy in IGEs with myoclonic or tonic-clonic seizures in patients >12 years, as monotherapy in focal seizures in patients >16 years and as add-on therapy in focal or focal to bilateral tonic- clonic seizures in children and adults. AIM OF THE STUDY. To evaluate efficacy, long-term efficacy and tolerability of LCM, STP, FFA, or LEV in a cohort of children, adolescents and young adults with different types of refractory epilepsies, including focal and generalized forms and epileptic encephalopathies such as DS. METHODS. Patients treated with Study Drugs as therapy for different, refractory, types of epilepsy and seen at the Neuroscience Center of Excellence-Meyer Children Hospital in different period time were included in our studies. Data were retrospectively reviewed. Responder rate, relapse free survival and retention rate were calculated. Tolerability was assessed by reporting adverse events. RESULTS. Lacosamide: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11). Stiripentol first study: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with DS. The median follow-up was 14.8 months (range=4 months-18 years, interquartile range=25.72). Twenty-nine individuals (22%) received more than two ASMs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. Stiripentol second study: We expanded our analysis to a larger cohort of 196 patients with long-term follow-up. We observed a responder rate of 53% including seizure freedom in 9%. Etiology was associated with sustained response over time, with DS being the etiology with the highest responder rate (64%) at 48 months compared with syndromes with other genetic causes (13%) or unknown etiology (38%). A higher responder rate over time was also observed in patients with generalized (44%) and combined focal and generalized epilepsies (28%) than in patients with focal epilepsies (20%). The highest relapse free-survival was observed when STP was initiated at the youngest age (0-4 years) or in adulthood. Fenfluramine: Levetiracetam: A total of 88 patients with IGEs aged from 3.4 to 33.8 years, started LEV as monotherapy or add-on therapy. The median follow-up was 7.3 months (range=0.5-106 months). Thirty-four individuals (46.6%) received more than two ASMs. Thirty-five patients (39.8%) were responders, and 26 of them (29.5%) were seizure-free. The median time to LEV failure was 42 months and the median retention time was 10 months in all 88 individuals. A higher retention time was observed in patient older than 14 years. Fifty- Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. seven patients changed their therapy regimen by replacing LEV with another ASMs. Fourty-two (73.4%) remained responders at the last evaluation. About patients that replaced LEV with VPA or ETS, 23/27 (85.2%) or 9/12 (75%) were responders, respectively (p=0.19). neurological/psychiatric (17/18). CONCLUSIONS. Lacosamide: This study documents a real-world progressive and significant loss Stiripentol: suggest that STP is an effective and well-tolerated therapeutic option not only in DS but also in other epilepsy syndromes with or without an established genetic etiology, with sustained response over time. Fenfluramine: Levetiracetam: This study suggests that LEV did not result in a satisfactory clinical response in IGEs, considering their known good prognosis The most frequent adverse events were of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time. These studies In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated. Further confirmations based on prospectively or controlled designed studies with larger population are required to confirm our data.

It is well recognized that both Intellectual Disability (ID) and epilepsy individually have higher rates of premature mortality. Thus, the two conditions in combination will be more likely to lead to premature mortality than either individually. People with ID and epilepsy have a higher likelihood of communication, psychiatric, behavioural, and drug sensitivity problems that makes their treatment difficult. This is not a homogenous group. At one end of the spectrum are patients with mild ID, 10–12% of who have epilepsy and treatment is mainly focused on areas like compliance and risky behaviours. At the other end are patients with severe ID, up to 50% of who have epilepsy and treatment is more focused on factors such as the co-morbidity, impact of medications, recognition of side effects, treatment resistance, and informed consent. This chapter looks to collate and provide an overview of epilepsy diagnosis and management and the current good practice on its applicability to people with ID.