Clinical aspects and biological bases of drug-resistant epilepsies
Introduction
To investigate the clinical aspects and the biological bases of drug-resistant epilepsies (DRE) is a complex problem and it presupposes, first of all, a definition of DRE. However, a universally accepted definition of DRE does not yet exist due to some unsolved controversial issues which impede attaining a consensus about this matter.
According to Theodore (1993), we have to admit that current definitions of uncontrolled seizures are fluid. Hauser (1992) remarks that “The definition of drug resistant epilepsy is elusive and may vary with the question being asked, upon the investigator’s interest and available procedures. In some ways, all epilepsy is drug resistant in that there is no evidence that action of anti epileptic drugs (AEDs) is other than palliative (preventing seizures), but without effect on the underlying pathologic state.” Cascino (1990) considers the seizures persisting intractable, despite maximally tolerated monotherapy or combination AED therapy. Similarly, Juul-Jensen (1986) defines the presence of repeated seizures during years in a patient receiving appropriate treatment at high doses as refractory epilepsy .
All these definitions, although useful for clinical purposes, are not based on objective, clearly quantified criteria of assessment, and therefore do not permit comparison of the different studies. Furthermore, they focus on the persistence of seizures as the sole index of refractoriness, not taking into account the patient’s ability to function in everyday life and psychosocial problems related to epilepsy or therapy. This view is pointed out in the definition of Schachter (1993): a patient with refractory epilepsy is one who is unable to lead a lifestyle consistent with his capabilities because of seizures, AED side-effects, and/or psychosocial problems.
The persisting uncertainty about the definition and, consequently, the impossibility of exactly identifying these subjects, produces some important consequences, mainly concerning the selection of cases to be considered for surgery and the unavoidable heterogeneity of patients included in clinical trials of new AEDs.
In the first part of this paper, we will try to identify and discuss the issues hampering the attainment of a clear-cut definition of DRE. In the second part, the clinical features and the biological factors more frequently encountered in difficult-to-treat subjects will be analyzed.
Section snippets
Issues in defining DRE
There is no doubt that, when dealing with the problem of pharmacoresistance, one should be aware of the possibility of a false pharmacoresistance, a not always easily recognizable phenomenon that may be found in all chronic diseases. An exhaustive analysis of this important matter is beyond the scope of this article; however, it may be useful to summarize the main causes of pseudo-refractory epilepsy.
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Diagnostic errors leading to inappropriate drug selection: e.g. ethosuximide in complex partial
Possible predictors of refractoriness
Apart from these semantic and methodological considerations, intractable epilepsy constitutes a reality regarding some 20–30% of all epileptic patients (Annegers et al., 1979, Reynolds et al., 1983, Shorvon, 1984) and 5–10% of all incidental cases (Hauser, 1992).
The question arises if predictors of DRE exist. Numerous studies have been performed to identify predictive factors of intractability, with different results depending on the investigator’s interest and the type of population examined.
Is there a gene of intractability?
Genetic factors may play a role in the degree of progression associated with symptomatic epilepsy (Wada and Osawa, 1976). Data from different studies (Andermann, 1982, Levesque et al., 1991, Meencke and Veith, 1992) suggest that migration disturbances often encountered in subjects with temporal lobe epilepsy are markers for a genetic predisposition to the development of hippocampal sclerosis, and may also predispose to more serious progression of symptoms (Engel, 1992, Wieser et al., 1993).
Conclusions
Despite the development and the use of an increasing number of new AEDs, the percentage of pharmacoresistant patients remains stabilized between 20 and 25%, probably due to the multiple pathogenetic mechanisms underlying refractoriness. These may be mainly represented by the nature of the pathophysiologic process, its possible evolution over time, and the different individual sensitivity to drugs, congenital or acquired. The unsatisfactory knowledge of these mechanisms does not permit an
Acknowledgements
The authors wish to thank Rosalba Knechtlin for her assistance in the preparation of the manuscript.
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