Drug Resistant Epilepsies: News and Challenges

A task force of the International League Against Epilepsy (ILAE) proposed that drug-resistant be defined as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure drugs (whether as monotherapy or in combination) to achieve seizure freedom. Approximately ⅓ of patients with epilepsy are drug refractory (Between 30 to 40 percent). This is obviously a very significant challenge in managing a patient with drug-resistant epilepsy. Neurologists try to use combinations of different medications, typically with different mechanisms of action, hopefully to achieve the best effectiveness in terms of seizure control. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis) and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the transporter , target , network , and intrinsic severity hypotheses. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses.Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is often a significant delay in referring to epilepsy surgery centers. Optimization of AEDs, identification and treatment of comorbidities, patient education to promote adherence to treatment, and avoidance of triggers should be periodically performed. Identifying those individuals who are most at risk of seizure relapse and development of DRE remains a challenge. Intrinsic factorsCertain pediatric epilepsy syndromes, including Lennox–Gastaut syndrome, Rasmussen encephalitis, and early infantile epileptic encephalopathy among others, are almost invariably drug refractory. Similarly, underlying structural abnormalities in non-idiopathic localization-related epilepsies, which account for > 50% of adult cases of DRE, must be considered. A common observation is that epilepsy from an underlying vascular lesion is more treatment responsive than that due to mesial temporal sclerosis (MTS), cortical dysplasia, or dual pathology. In fact, it has been observed that up to 80% of individuals with MTS develop DRE and these individuals are unlikely to benefit from ongoing medication trials alone. Another consistently identified risk factor for DRE is having a high number of seizures prior to diagnosis and treatment. Management of patients with DRE is challenging because the mechanism underlying it is not completely understood nor do we understand why pharmacoresistance develops in some individuals and not others. The pathogenesis underlying DRE is likely to be multifactorial and variable with both genetic and environmental factors implicated and several theories for how DRE develops. The transporter hypothesis is based on findings of overexpression of multidrug efflux genes and concomitant proteins in human epileptic brain tissue and in animal models of DRE. the extent that these transporters contribute to drug resistance is still relatively unknown.In contrast, the alternative target hypothesis suggests an epilepsy-induced alteration of cellular targets of AEDs, leading to a reduction in sensitivity. These targets include various receptors and ion channels, but this hypothesis is principally based on studies with carbamazepine (CBZ) on voltage-gated sodium channels in hippocampal neurons. Sodium channels of hippocampal CA1 neurons from patients with MTS were studied and compared with neocortical neurons from patients without MTS. The mechanism of action of CBZ, use-dependent block of voltage-dependent sodium channels, was completely lost in these DRE patients. Similarly, a loss of drug-target sensitivity has also been found in rat models of temporal lobe epilepsy.Other hypotheses have emerged more recently, born from findings in patients and animal models of DRE. The network hypothesis proposes that seizure-induced structural brain alterations such as axonal sprouting, synaptic reorganization, neurogenesis, and gliosis can contribute to the formation of an abnormal neural network.Traditionally, there are a few options available for people with medically refractory epilepsy. The most common one is epilepsy surgery, which has been performed since the 1940s. It is a very mature procedure, very reliable, but most of the surgical treatment is still open brain surgery. Somewhere between 60 and 70 percent of patients with drug-resistant epilepsy who have surgery become seizure-free, which is the standard of care if the medications were not to work So, any patient who has drug-resistant epilepsy should be evaluated for surgery. Open brain surgery is effective but also carries higher risk for complications, pain and psychological impacts. Recently, minimally invasive epilepsy brain surgery has advanced quite significantly, particularly a procedure called laser ablation for patients with epilepsy.Are there other options besides surgery Vagus nerve stimulation (VNS) has been shown to decrease the frequency and intensity of seizures, with 30%–40% of patients achieving a > 50% reduction in seizure frequency. Another device gaining attention is deep brain stimulation, with open-label and some small controlled studies finding a reduction in seizure frequency by ≥50%.Diet therapy: The ketogenic diet was proposed as a treatment for seizures prior to introduction of modern AEDs. The There is demonstrated efficacy in children with DRE, with more than one-third experiencing a ≥50% reduction in seizures.Alternative diets to consider are the modified Atkins diet and low-glycemic-index diet.Cannabis: Recently, there has been intense interest regarding the potential of medical cannabis to treat seizures, due to mounting anecdotal reports and media coverage of its success.Conclusion: Management of DRE requires a multidisciplinary and often multitreatment approach with timely referral to specialist epilepsy centers for prompt evaluation. Selection of the patients and treatment modality are the most challengeable facts that must be considered as the first and the most important step in the management.