Immunological mechanisms in the aetiology of epilepsy: implications for treatment.

About 30 years ago, an autoimmune reaction was hypothesised in animal models of epilepsy and for the genesis of the 'mirror focus' in some patients with refractory epilepsy. However, this hypothesis did not attract attention among clinicians. During the 1950s, cortisone and corticotropin appeared to be efficacious in some epileptic syndromes, but the link with the immune system was not made. Furthermore, controlled studies were not rigorously planned and the best dosage and schedule still remain unknown. Later, immune deficits were described in patients with epilepsy, but the origin (disease-related or treatment-related) of these deficits is still open. An immunogenetic predisposition was also described in these patients, but results were often contradictory. During the 1980s, the successful use of intravenous immunoglobulin (IVIg) in childhood epilepsies again suggested a possible autoimmune process in some patients. During the last few years, specific autoantibodies have been found in Rasmussen disease and other epileptic syndromes. Immunomodulatory treatments (IVIg, plasmapheresis) have been used with significant success in refractory epilepsies, and IVIg is considered by most epileptologists as the first-choice treatment in Rasmussen syndrome. Recent work has shown that autoantibodies directed against some brain components might interact with ion-gated channels or neurotransmitters and therefore affect the stability of neuronal membranes. Autoimmune mechanisms are considered possible in the process of epileptogenesis. Taking this hypothesis further, immunomodulatory treatment at the time of brain injury (such as by trauma, prolonged seizures or stroke) could offer a preventive approach against epileptogenesis and therefore prevent recurrent seizures

Medical treatment of newly diagnosed epilepsy.

The first step in the treatment of epilepsy is the confirmation of the diagnosis. A correct diagnosis not only includes the epileptic origin of the event, but also the diagnosis of the seizure type and the epileptic syndrome. The second step is to try to find the aetiology of the seizures. Some papers have shown that the prognosis of epilepsy is better if the seizures are treated earlier, but other papers did not find any difference in the long-term prognosis between patients treated after the first seizure or after several seizures. Therefore, one of the most difficult points, after confirmation of the diagnosis, with a first or few seizures will be to identify the risks of relapse in some patients and to immediately treat them and to avoid treating the others who will have only one or rare seizures during their lives without any damage. In most cases, the first treatment will be the prescription of an antiepileptic drug (AED) in monotherapy. If the cause is treatable, it will be treated concomitantly. In generalised epilepsies, especially in idiopathic syndromes, valproate will be the first choice, most of the classic AEDs may worsen some seizure types in these syndromes. In partial epilepsies, there are no statistically significant differences in efficacy between the 4 classic major AEDs (carbamazepine, phenytoin, phenobarbitone and valproate) in pooled data. The choice of the drug should be more influenced by considerations of safety profile, dosing frequency, and costs for equivalent advantages. Accordingly, valproate is a good first choice in patients in whom the epilepsy syndrome is not clearly defined. Efficacy of newer AEDs is similar to old AEDs but most are better tolerated. However, some studies including seizure control, side effects, medical consultation, inpatient, accidental injuries, and laboratory investigations showed that newer AEDs are more expensive in newly diagnosed patients, compared to classic major AEDs and this notion should be taken into account for the prescription

Cognitive problems related to epilepsy syndromes, especially malignant epilepsies.

Neurocognitive impairment is frequent in epilepsy patients. Causes are multiple, and may be influenced by several factors including the epilepsy syndrome. Most cognitive complaints in adult patients are mental slowness, memory difficulties and attention deficits. In children, cognitive problems are more diffuse, responsible for language troubles, learning difficulties, poor academic outcome, behavior problems and finally unfortunate socio-professional prognosis. The most devastating epilepsy syndromes such as epileptic encephalopathies are nearly exclusively described in infancy and childhood. This paper will review the major cognitive complaints in relation to the epilepsy syndrome, with a more detailed interest for the malignant epilepsies in infancy and childhood such as Ohtahara and West syndrome, Lennox-Gastaut syndrome and epileptic encephalopathis with continuous spike-and-wase during slow wave sleep. The impact of surgery on cognition will be briefly discussed in adults and youger patients

Traitement de l'épilepsie réfractaire par stimulation du nerf vague

La stimulation du nerf vague est un traitement non pharmacologique de l’épilepsie pharmaco résistante. Plusieurs études ont démontré une efficacité clinique chez environ un tiers des patients implantés (> 50% moins de crises). Les mécanismes d’actions ne sont pas encore tout à fait élucidés. Presque tous les types d’épilepsie pharmaco résistantes sont susceptibles d’être améliorés. Une meilleure connaissance des mécanismes antiépileptiques mis en jeu, permettrait de mieux sélectionner les patients potentiellement répondeursEpilepsy is a chronic neurological disorder that is characterized by recurrent epileptic seizures. Its prevalence is estimated at 0.5 to 1[%] of the population. About 30[%] of epileptic patients are considered refractory, meaning that they do not respond to anti-epileptic drugs. For these patients, alternative treatment modalities such as epilepsy surgery or vagus nerve stimulation (VNS) may be useful. However, there are no predictive factors that enable us to identify VNS responders at an early stage. VNS is generally considered to be cost-efficient, and advancements in VNS technologies are developing rapidly

Effect of levetiracetam in patients with epilepsy and interictal epileptiform discharges

The effect of acute treatment with the new antiepileptic drug (AED) levetiracetam (Keppra(R)) on the frequency of interictal epileptiform discharges (IEDs) was evaluated in a double- blind, placebo-controlled, crossover study with therapeutic drug monitoring and serial electroencephalographic (EEG) observations. Acute (500 mg twice daily) and chronic (individualized, 500-1000 mg twice daily) doses of levetiracetam were administered as an add-on to current AED treatment. Efficacy was tested by measuring the frequency of IEDs in EEG recordings and the number of seizures. A single acute dose of levetiracetam induced a reduction of IEDs in eight out of ten patients. During the acute phase, an insufficient number of seizures occurred for analysis. During chronic treatment over 8 weeks, seven patients showed a reduction in seizure frequency (responder rate), and one patient remained seizure free. No correlation was seen between levetiracetam levels and IED frequency. Doses of levetiracetam of up to 2000 mg/day were well tolerated, and no interactions were seen with concomitant AEDs. (C) 2001 BEA Trading Ltd

Clinical and EEG findings in six patients with altered mental status receiving tiagabine therapy.

Tiagabine (TGB), a novel GABA reuptake inhibitor antiepileptic drug, has been reported to induce nonconvulsive status epilepticus (NCSE) in patients with generalized or partial onset seizures. We describe six patients with refractory partial epilepsy treated with add-on TGB. They developed acute intermittent or progressive chronic confusion associated with diffuse slowing of the electroencephalogram (EEG), shortly after an increase in dose of TGB. This remitted in each situation after reduction of the daily dose. The possibility of nonconvulsive status epilepticus or toxic encephalopathy is discussed

Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy

Few comparative clinical trials of newer antiepileptic drugs (AEDs) in patients with refractory partial epilepsy are available. Therefore, meta-analysis is a widely used and useful method for comparing them. Despite the limitations of indirect comparisons, and recognizing that these drugs were tested at different doses, such comparisons can be helpful to physicians making practical treatment decisions. The purposes of this study were to present newer meta-analysis results for add-on levetiracetam compared with placebo and to estimate its efficacy and tolerability compared with other new AEDs (gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide) in a meta-analysis using methods for making indirect comparisons. Randomized placebo-controlled clinical trials of add-on therapy with levetiracetam, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide in patients with refractory partial epilepsy were identified in the Cochrane Library 2002. A fixed effects model was used to estimate Mantel-Haenszel odds ratios for the responder rate (efficacy measure) and withdrawal rate (mainly tolerability measure) of levetiracetam and other new AEDs versus placebo. Because no head-to-head clinical trials comparing these new AEDs exist, adjusted indirect comparisons were then made between levetiracetam and each other AED using the meta-analysis results. At the doses tested, levetiracetam was more effective in terms of responder rate than gabapentin (odds ratio 2.64 with 95% CI 1.514.63) and lamotrigine (odds ratio 1.86 with 95% CI 1.04-3.34) and equally well tolerated. Levetiracetam had a significantly lower withdrawal rate than topiramate (odds ratio 0.52 with 95% CI 0.290.93) and oxcarbazepine (odds ratio 0.55 with 95% CI 0.33-0.92), with comparable efficacy. Although levetiracetam did not differ significantly from the other AEDs, numerical trends favoring levetiracetam were obtained in response rate and in withdrawal rate (tiagabine, zonisamide). Indirect comparisons based on meta-analysis suggest that add-on therapy with levetiracetam has a favorable responder and/or withdrawal rate relative to several AEDs in patients with partial epilepsy with doses used in clinical trials. These meta-analyses give only short-term efficacy and safety data. Comparative clinical trials and long-term studies of these agents are needed to confirm these findings