Patrick Kwan

Early Identification of Refractory Epilepsy

BACKGROUND More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures. METHODS We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year. RESULTS Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent). CONCLUSIONS Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.

Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies.

To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two “hierarchical” levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided.

Drug-Resistant Epilepsy

Nearly a quarter of patients with seizures have drug-resistant epilepsy. This review examines how this diagnosis should be established and how to recognize pseudoresistance. It explains possible mechanisms of drug-resistant epilepsy and presents treatment strategies.

Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese.

Summary:  A previous study conducted in Taiwan found a 100% association between HLA‐B*1502 allele and carbamazepine‐induced Stevens‐Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine‐tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED‐tolerant controls. HLA‐B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED‐induced SCR offers the possibility of avoiding these high‐risk drugs in genetically susceptible individuals.

Patterns of treatment response in newly diagnosed epilepsy.

Objective: To delineate the temporal patterns of outcome and to determine the probability of seizure freedom with successive antiepileptic drug regimens in newly diagnosed epilepsy. Methods: Patients in whom epilepsy was diagnosed and the first antiepileptic drug prescribed between July 1, 1982, and April 1, 2006, were followed up until March 31, 2008. Outcomes were categorized into 4 patterns: A) early and sustained seizure freedom; B) delayed but sustained seizure freedom; C) fluctuation between periods of seizure freedom and relapse; and D) seizure freedom never attained. Probability of seizure freedom with successive drug regimens was compared. Seizure freedom was defined as no seizures for ≥1 year. Results: A total of 1,098 patients were included (median age 32 years, range 9–93). At the last clinic visit, 749 (68%) patients were seizure-free, 678 (62%) on monotherapy. Outcome pattern A was observed in 408 (37%), pattern B in 246 (22%), pattern C in 172 (16%), and pattern D in 272 (25%) patients. There was a higher probability of seizure freedom in patients receiving 1 compared to 2 drug regimens, and 2 compared to 3 regimens (p < 0.001). The difference was greater among patients with symptomatic or cryptogenic than with idiopathic epilepsy. Less than 2% of patients became seizure-free on subsequent regimens but a few did so on their sixth or seventh regimen. Conclusions: Most patients with newly diagnosed epilepsy had a constant course which could usually be predicted early. The chance of seizure freedom declined with successive drug regimens, most markedly from the first to the third and among patients with localization-related epilepsies.

Neuropsychological effects of epilepsy and antiepileptic drugs

Epilepsy and its treatment can have deleterious cognitive and behavioural consequences. Affected individuals have a higher prevalence of neuropsychological dysfunction than the general population because of complex interactions among several multifaceted and overlapping influences--for example, underlying neuropathologies, ictal and interictal neuronal discharges, a plethora of antiepileptic drugs, and numerous psychosocial issues. Research into the clinical relevance of these factors has been dogged by a range of methodological pitfalls including lack of standardisation of neuropsychological tests, small numbers and multiple testing, and statistical failure to appreciate differential effects of interactive elements in individual patients. Although antiepileptic drugs can impair neuropsychological functioning, their positive effect on seizure control might improve cognition and behaviour. Each person should be assessed individually with respect to factors unique to his or her seizure disorder and its treatment.

Effectiveness of First Antiepileptic Drug

Summary:  Purpose: To investigate the interaction among efficacy, tolerability, and overall effectiveness of the first antiepileptic drug (AED) in patients with newly diagnosed epilepsy.

Potential Role of Drug Transporters in the Pathogenesis of Medically Intractable Epilepsy

Summary:  The pathogenesis underlying pharmacoresistance in epilepsy is unclear. One of the candidate mechanisms that has attracted growing interest is the limitation of antiepileptic drug (AED) access to the seizure focus by a range of efflux transporters, the prototype of which is P‐glycoprotein (P‐gp). P‐gp is encoded by the multidrug resistance (MDR1 or ABCB1) gene. Predominantly expressed in organs with excretory functions and at blood–tissue barriers, P‐gp is thought to act as a physiologic defense by extruding xenobiotics from mammalian cells and affording protection of sensitive organs. The high level of P‐gp in the cerebrovascular endothelium is believed to contribute to the functionality of the blood–brain barrier. Overexpression of P‐gp causes multidrug resistance in certain cancers. It has been hypothesized that overexpression of P‐gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug‐resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates. Conflicting reports suggest a possible association between variants of the MDR1 gene and medical intractability in epilepsy. Further studies to delineate the exact role, if any, of P‐gp and other efflux transporters in drug‐resistant epilepsy are warranted.

The mechanisms of action of commonly used antiepileptic drugs.

In the past decade, nine new drugs have been licensed for the treatment of epilepsy. With limited clinical experience of these agents, the mechanisms of action of antiepileptic drugs may be an important criterion in the selection of the most suitable treatment regimens for individual patients. At the cellular level, three basic mechanisms are recognised: modulation of voltage-dependent ion channels, enhancement of inhibitory neurotransmission, and attenuation of excitatory transmission. In this review, we will attempt to introduce the concepts of ion channel and neurotransmitter modulation and, thereafter, group currently used antiepileptic drugs according to their principal mechanisms of action.

Phenobarbital for the treatment of epilepsy in the 21st century: a critical review.

Summary:  Phenobarbital (PB) is the most widely used antiepileptic drug (AED) in the developing world and remains a popular choice in many industrialized countries. Meta‐analyses of randomized controlled trials suggest that few differences in efficacy exist between PB and other established AEDs, but its possible deleterious cognitive and behavioral side effects remain a concern in the developed world. In contrast, high degrees of efficacy and tolerability in everyday clinical use have been demonstrated consistently in observational studies in developing countries. We propose that a pragmatic, comprehensive outcomes program be carried out, perhaps under the aegis of the Global Campaign Against Epilepsy, to optimize the conditions of the use of PB, so that more people around the world can benefit from this cost‐effective medication and live more fulfilling lives.