may exist at the time of the first seizure or may develop later as result of the disease process. The mechanisms of these different scenarios are likely to be multifactorial, and may include alterations in brain uptake or brain targets of antiepileptic drugs. Such alterations may be constitutive (intrinsic), thus underlying de novo drug resistance in epilepsy, or induced, e.g., as a consequence of recurrent seizures or disease progression. Alterations in drug efflux (“multidrug”) transporters and drug targets, such as voltage-gated sodium channels, have been found in epileptogenic brain tissue from both patients with epilepsy, and rodent models of epilepsy. However, although the multidrug transporter and target hypotheses are biologically plausible, proof-of-principle is lacking for these hypotheses. An advantage of the multidrug transporter hypothesis is that it can be validated both experimentally and clinically by combining antiepileptic drugs with inhibitors of such transporters. Selective inhibitors of the major efflux transporter P-glycoprotein are currently in clinical trials for reversing chemotherapy resistance in oncology and may soon be used to determine whether such inhibitors can prevent or reverse drug resistance in epilepsy.
Franck Semah, Philippe Ryvlin
more difficult to control than idiopathic generalized epilepsy (IGE). Indeed, the main predictors are the presence of a brain lesion demonstrated by neuroimaging or suggested by a neurological deficit or a developmental delay, as well as electroclinical evidence of non idiopathic partial epilepsy. Little is known about the relationship between the location of the epileptogenic area and the chance of being seizure-free in patients with partial epilepsy. Some data suggest that temporal lobe epilepsy (TLE) is more difficult to control than other partial epilepsies, but this might only reflect the prognostic impact of hippocampal sclerosis. Indeed, several studies have shown that the majority of patients with MRI evidence of hippocampal sclerosis develop refractory epilepsy. This observation also applies to patients with malformation of cortical development (MCD). The response to the first AED is another early predictor of refractory epilepsy. At the time of diagnosis, several prognostic factors are available to predict drug resistance, but further studies are still needed to better delineate the specific role of each of these factors, and to offer a more accurate prediction of long term seizure outcome.
exploit at best available treatments. There are however, discrepancies between commonly held opinions on several aspects of drug therapy, and the body of scientific evidence which exists to support them. This article highlights a few examples, discussing evidence that, contrary to common belief, (i) a significant proportion of patients with newly diagnosed epilepsy respond to concentrations of AEDs below the “therapeutic range” quoted in the literature; (ii) only a small group of patients unresponsive to low to moderate AED dosages become seizure-free after increasing dosage up to the limit of tolerability; (iii) knowledge of mechanisms of AED action can aid in the rational use of AEDs in the clinic; (iv) monitoring serum levels of new generation AEDs can be usefully exploited to improve management, and (v) at least in a subgroup of patients, successful epilepsy surgery cannot be regarded as curative, because seizure control may be dependent upon continuation of AED therapy. It is hoped that increased awareness of these issues could eventually contribute not only to improved clinical outcome, but also to high quality studies in many areas where gaps in knowledge prevent application of truly evidence-based management.
Elinor Ben-Menachem, Jacqueline A. French
has a right to expect that they have a greater chance of a good outcome with an invasive therapy than with a non-invasive one. The main question is when, if ever, this becomes the case when comparing implantation of a VNS Therapy System versus adding an antiepileptic drug (AED)? After the first drug? The second? After all AEDs have failed? To date, no randomized trial comparing the addition of an AED against vagus nerve stimulation (VNS Therapy) has been undertaken, although several are currently being contemplated. Without this information, it is more difficult to make a case for early implementation of VNS Therapy. Unfortunately, few data are available regarding the potential for patients to become seizure-free after implantation of a VNS Therapy System. Another issue is side effects. It is important to remember that VNS Therapy also produces adverse events, albeit very different in character than those associated with AEDs, to which physicians have become accustomed. These include cough, dyspnea, pharyngitis, voice alteration and sleep apnea. A less frequently discussed, potentially negative consequence of VNS Therapy relates to the ability to obtain imaging of the patient. Patients who have undergone VNS Therapy System implantation are not candidates for imaging of the chest, breast, or abdomen. A second issue is that imaging of the brain can only be performed with MRI scanners that meet certain requirements, and as MRI technology develops, scanners meeting these requirements may become harder to find. However, to summarize, VNS Therapy is an excellent and useful treatment choice. Fortunately, the choice between AEDs and VNS Therapy is not an “either/or” decision. Each has a role in the treatment of patients with epilepsy, and the advantages and disadvantages of each should be kept in perspective. Pro VNS Therapy: VNS Therapy is no longer a new treatment for patients with refractory epilepsy. The first implant was performed in l988, and since then more than 30,000 patients have received this therapy. It is no longer considered an unusual or dangerous procedure, but it is still used almost exclusively for refractory epilepsy patients and it has not been generally accepted for use as a first line or even second line therapy. However, compared to the new AEDs, VNS Therapy has similar efficacy results in clinical trials and in many epilepsy syndromes and the long-term efficacy results are even more positive, with continued improvement in seizure reduction for up to two years. Two of the major reasons for not using VNS Therapy early are that it is a surgical procedure, and its safety during MRI procedures, especially with 3 Tesla, has not yet been elucidated. The safety profile of VNS Therapy is very favorable; the side effects being totally different from those seen with AEDs. The most important aspects are that there have been no pharmacological interactions, cognitive or sedative side effects reported, and it is safe for use in all age groups. Side effects are restricted to local irritation, hoarseness, coughing and, in a few cases, swallowing difficulties when the stimulator is on, but these tend to disappear with time. No idiosyncratic side effect has emerged during the 16 years of use. Compliance is guaranteed. The cost of the implantation of the VNS Therapy System, when spread out over 8 years (battery life), is actually less than the cost of using a new AED over an eight-year period, and real savings as regards hospital costs due to seizures can be expected.
Steven C Schachter
and to be “concerned not only with turbulent brain waves but with disturbed emotions”. Indeed, while seizure frequency and severity correlate with quality of life and psychosocial outcomes for patients with drug-resistant epilepsy, numerous other epilepsy-related factors may also be significant determinants. These factors include medical and psychiatric co-morbidities, side effects of therapy, stigma, parental anxiety, employment status, seizure worry, self-esteem and self-mastery. Importantly, these epilepsy-related factors may be amenable to educational or therapeutic interventions, which if successful may benefit patients even without a concomitant reduction in seizure frequency or severity. Therefore, while further research is needed, physicians and other health care providers should comprehensively attend to these factors and refer patients with treatment-resistant seizures, when appropriate, for further evaluation and treatment to improve their quality of life beyond seizure control.
Philippe Ryvlin, Alexandra Montavont, Philippe Kahane
avoided by surgical cure of the epilepsy. Several series have addressed this issue by comparing the mortality rate between medically and surgically treated drug resistant populations, as well as between patients, seizure free and non seizure free post-operatively. Results from some studies suggest that successful temporal lobe surgery reduced the risk of death to that observed in the normal population, whereas patients who continue to suffer recurrent seizures still present an increased standardized mortality ratio (SMR). However, other series have failed to replicate this finding, or found no difference in the overall mortality and SUDEP rates between operated and medically treated patients. All the above studies suffer various types of methodological limitations, hampering any definite conclusion regarding the impact of epilepsy surgery on mortality. However, part of the apparently discordant reported findings might be reconciled through the following framework. Patients who will eventually respond favourably or unfavourably to an anterior temporal lobectomy might already differ in the risk of seizure-related death, pre-operatively. Specifically, patients whose temporal lobe epileptogenic network extends to the perisylvian region (temporal plus epilepsy) appear to be at higher risk of failed TLE surgery, secondary generalised tonic-clonic seizures, ictal apnoea or insula-driven severe cardiac arrhytmias. This population might carry most of the SUDEP burden, both pre- and post-operatively, accounting for the lack of an obvious net reduction of seizure related deaths after temporal lobe surgery. A multicentric study has recently been launched in order to test this hypothesis, and will hopefully help to conclude on the impact of epilepsy surgery on mortality outcome.