Elsevier

Epilepsy Research

Volume 34, Issues 2–3, 1 April 1999, Pages 109-122
Epilepsy Research

Clinical aspects and biological bases of drug-resistant epilepsies

https://doi.org/10.1016/S0920-1211(98)00106-5Get rights and content

Abstract

The definition of drug-resistant epilepsy (DRE) is elusive and still controversial owing to some unresolved questions such as: how many drugs should be tried before a patient is considered intractable; to which extent side-effects may be acceptable; how many years are necessary before establishing drug resistance. In some cases, the view of epilepsy as a progressive disorder constitutes another important issue. Despite the use of new antiepileptic drugs (AEDs), intractable epilepsy represents about 20–30% of all cases, probably due to the multiple pathogenetic mechanisms underlying refractoriness. Several risk factors for pharmacoresistance are well known, even if the list of clinical features and biological factors currently accepted to be associated with difficult-to-treat epilepsy is presumably incomplete and, perhaps, disputable. For some of these factors, the biological basis may be common, mainly represented by mesial temporal sclerosis or by the presence of focal lesions. In other cases, microdysgenesis or dysplastic cortex, with abnormalities in the morphology and distribution of local-circuit (inhibitory) neurons, may be responsible for the severity of seizures. The possible influence of genes in conditioning inadequate intraparenchimal drug concentration, and the role of some cytokines determining an increase in intracellular calcium levels or an excessive growth of distrophic neurites, constitute other possible mechanisms of resistance. Several hypotheses on the mechanisms involved in the generation of DRE have been indicated: (a) ontogenic abnormalities in brain maturation; (b) epilepsy-induced alterations in network, neuronal, and glial properties in seizure-prone regions such as the hippocampus; (c) kindling phenomenon; (d) reorganization of cortical tissue in response to seizure-induced disturbances in oxygen supply. Such hypotheses need to be confirmed with suitable experimental models of intractable epilepsy that are specifically dedicated, which have until now been lacking.

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.

  • 1.

    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.

References (131)

  • F. Andermann

    Multifactorial inheritance of generalized and focal epilepsy

  • F. Andermann

    Brain structure in epilepsy

  • J.F. Annegers et al.

    Remission of seizures and relapse in patients with epilepsy

    Epilepsia

    (1979)
  • U.F. Annegers et al.

    Factors prognostic of unprovoked seizures after febrile convulsions

    New Engl. J. Med.

    (1987)
  • D. Armstrong et al.

    The spectrum of histopathology of gangliogliomas in patients with complex partial epilepsy

    J. Neuropathol. Exp. Neurol.

    (1988)
  • I.A. Awas et al.

    Intractable epilepsy and structural lesions of the brain. Mapping, resection strategies, and seizure outcome

    Epilepsia

    (1991)
  • T.L. Babb

    Research on the anatomy and pathology of epileptic tissue

  • L.E. Becker

    Synaptic dysgenesis

    Can. J. Neurol. Sci.

    (1991)
  • E. Beghi et al.

    The management of epilepsy in the 1990s. Acquisitions, uncertainties and perspectives for future research

    Drugs

    (1995)
  • A.T. Berg et al.

    The prognosis of childhood onset epilepsy

  • B.F.D. Bourgeois et al.

    Antiepileptic and neurotoxic interaction between antiepileptic drugs

  • C.J. Bruton
    (1988)
  • P.R. Camfield et al.

    Febrile seizures

  • P.R. Camfield et al.

    Antiepileptic drug therapy: when is epilepsy truly intractable?

    Epilepsia

    (1996)
  • F. Cendes et al.

    Atrophy of mesial structures in patients with temporal lobe epilepsy: cause or consequence of repeated seizures

    Ann. Neurol.

    (1994)
  • J.J. Chevrie et al.

    Convulsive disorders in the first year of life: persistence of epileptic seizures

    Epilepsia

    (1979)
  • J.C. Cloyd et al.

    Pharmacokinetics in infancy, childhood and adolescence

  • Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long term course of epilepsy

    Epilepsia

    (1992)
  • Long-term management of children with fever-associated seizures

    Pediatrics

    (1980)
  • C. Cordon-Cardo et al.

    Multidrug resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites

    Proc. Natl. Acad. Sci. U.S.A.

    (1989)
  • C. Daumas-Duport et al.

    Dysembryoplastic neuroepitelial tumor: a surgically curable tumor of young patients with intractable partial seizures: report of 39 cases

    Neurosurgery

    (1988)
  • W.E. Dodson et al.

    The treatment of convulsive status epilepticus

    J. Am. Med. Assoc.

    (1993)
  • M. Duchowny

    Complex partial seizures and predictors of intractability in long-term follow-up

    Epilepsia

    (1987)
  • M. Duchowny

    Febrile seizures in childhood

  • R.D.C. Elwes et al.

    The early prognosis of epilepsy

  • R.D.C. Elwes et al.

    The prognosis for seizure control in newly diagnosed epilepsy

    New Engl. J. Med.

    (1984)
  • J. Engel

    Recent advances in surgical treatment of temporal lobe epilepsy

    Acta Neurol. Scand.

    (1992)
  • J. Engel

    The progressive nature of epilepsy

    Am. Acad. Neurol. Annu Courses

    (1993)
  • J. Engel et al.

    Impact of the kindling phenomenon on clinical epileptology

  • G. Eremberg et al.

    Febrile seizures

  • N.A. Falconer et al.

    Etiology and pathogenesis of temporal lobe epilepsy

    Arch. Neurol.

    (1964)
  • A.T. Feksi et al.

    Comprehensive primary health care antiepileptic drug treatment in rural and semiurban Kenya

    Lancet

    (1991)
  • I. Ferrer et al.

    Abnormal local-circuit neurons in epilepsia partialis continua associated with focal cortical dysplasia

    Acta. Neuropathol. (Berlin)

    (1992)
  • D. Fish et al.

    Surgical strategies in patients with complex partial seizures and small posterior or extratemporal structural lesions

    Neurology

    (1991)
  • J.M. Freeman

    Just say no! Drug and febrile seizures

    Pediatrics

    (1990)
  • J.A. French et al.

    Characteristics of mesial temporal lobe epilepsy. Results of history and physical examination

    Ann. Neurol.

    (1994)
  • D.M.G. Goodridge et al.

    Epilepsy in a population of 6000. 1. Demography, diagnosis and classification and the role of hospital services. 2. Treatment and prognosis

    Br. Med. J.

    (1983)
  • W.S.T. Griffin et al.

    Overexpression of the neurotrophic cytokine S100ß in human temporal lobe epilepsy

    J. Neurochem.

    (1995)
  • V. Gross-Tsur et al.

    Convulsive status epilepticus in children

    Epilepsia

    (1993)
  • H. Hakkarainen

    Carbamazepine vs Diphenyl-hydantoin vs their combination in adult epilepsy [Abstr]

    Neurology

    (1980)
  • Cited by (0)

    View full text