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Clinical aspects and biological bases of drug-resistant epilepsies
Epilepsy Research 34 (1999) 109 – 122
Clinical aspects and biological bases of drug-resistant epilepsies Giovanni Regesta a,*, Paolo Tanganelli b a
Department of Neurology, Epilepsy Center, San Martino Hospital, Viale Benedetto XV, 10 -16132 Geno6a, Italy b Department of Neurology, P. A. Micone Hospital, Geno6a, Italy Received 11 February 1998; received in revised form 22 September 1998; accepted 30 September 1998
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. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy; Drug resistance; Biological bases; Clinical aspects; Genetic factors
1. Introduction * Corresponding author. Tel.: + 39 010 5552542; fax: + 39 010 5556603. e-mail: [email protected].
To investigate the clinical aspects and the biological bases of drug-resistant epilepsies (DRE) is
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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.
2. 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 seizures (CPS) misdiagnosed as absences, carbamazepine or phenytoin, in juvenile myclonic epilepsy (JME) misdiagnosed as grand mal (GM) epilepsy, etc. 2. Inappropriate assessment of response: pseudoseizures developing as a substitute for epileptic seizures, paradoxical drug intoxication. 3. Suboptimal dosing regimen: drug not tried at the highest tolerated dosage, inappropriate dosing frequency. 4. Inappropriate patient behaviour: poor compliance, detrimental lifestyle. Coming back to the difficulty in defining and assessing DRE, some controversial issues and unsolved questions may be identified.
2.1. How many years are needed before establishing drug resistance? The duration of active epilepsy before a patient might be labelled as pharmacoresistant is much debated. It is widely accepted that about 60–70% of people with epilepsy will achieve remission of seizures in a variable, generally short, period of time. The duration of active epilepsy before a patient might be labelled as pharmacoresistant is much debated. For example, Leppik (1992) proposes that DRE can be defined as seizures not completely controlled with AEDs 1 year after onset, while Loyning and Hauglie-Hanssen (1995)
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suggest at least 2 years of adequate drug trials with at least two drugs for establishing refractoriness. However, it should be considered that, in some cases, even after 10 years, seizure control may be obtained (Hauser, 1992). Furthermore, the rate of remission and the time needed for achieving it are rather different when data derived from hospital- and community-based studies are considered. Consequently, in order to answer this question, we have to consider the prognosis of the individual cases, in relation to the specific type of seizures and/or of epileptic syndrome. As regards outcome, the epileptic syndromes have been classified into four different prognostic groups (Sander, 1993). Following this grouping, the time required for establishing drug resistance cannot be an absolute value but it is related to the belonging group of the syndrome, as, for example, a case of childhood absence epilepsy not responding to treatment in the short term. Unfortunately, this classification does not offer an answer in any case. In fact, while some epileptic syndromes are clear cut, for most of them a disagreement about their precise limits exists, with possible overlaps. The possibility of different etiologies for the same syndrome, and the existence of cases not falling into the recognized syndromes, must also be considered, together with the statement that sometimes a syndromic diagnosis is made retrospectively. For these reasons, a better-defined answer requires further prospective studies focusing on the prognosis of specific epileptic syndromes (Sander, 1993).
2.2. When should a patient be considered to ha6e failed on the initially prescribed drug, and how many drugs should be tried before his/her epilepsy might be regarded as intractable? The score suggested by Schmidt (1986) for the assessment of treatment failures, admits only the possibility of primary drugs in monotherapy and does not take into account the number of drugs to be tried (Table 1). On the other hand, a certain percentage ( 40%) of patients not adequately controlled with a single drug treatment
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Table 1 Medical intractability scale (Schmidt, 1986) Index of intractability
Seizures persist despite the following treatment
0
Other than primary drug regardless of its daily dose Primary drug below the recommended daily dose Primary drug within the recommended daily dose Primary drug with plasma concentrations within the recommended ‘therapeutic range’ Primary drug with maximum tolerable daily dose More than one primary drug with maximum tolerable daily dose in subsequent single-drug therapy for at least 9 months
1 2 3
4 5
may enter remission with a combination of two or three AEDs (Mattson, 1994). A grading system for evaluating the probability of achieving future seizure freedom, based on the failure of the appropriate treatment with one or more drugs, has been proposed by Perucca (1996) (Table 2).
2.3. Should only first-line treatments or also second-line treatments be tried before establishing drug resistance? When initiating a treatment, the selection of an AED is currently based on its expected efficacy
Table 2 Grading system for drug resistance (Perucca, 1996) Grade
Definition
1
Failure on appropriate 530–35 treatment with one drug Failure with two drugs 510–15 given alone or combined Failure with three drugs 55 given alone or combined
2
3
Probability of future seizure freedom (%)
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for specific seizure type(s) and epilepsy. Therefore, therapeutic algorithms suggesting first-line and second-line drugs according to the diagnosis have been proposed. However, except for rare situations, these recommendations are not based on irrefutable data and it is well known that different drugs may show a corresponding efficacy in a given seizure type or syndrome. Comparative monotherapy trials in partial and secondarily generalized tonic – clonic seizures found no conclusive difference in efficacy among carbamazepine, phenytoin, phenobarbital, and valproate (Mattson et al., 1985, 1992). Comparing the efficacy of the new AEDs is even more uncertain because studies concerning their use in monotherapy have been limited until now. The results of a metanalysis of efficacy data from randomized placebo-controlled add-on trials of all new drugs do not allow an evidencebased choice between these agents (Marson et al., 1997). Therefore, drug selection should be based not only on the specific antiepileptic action (provided that it is thoroughly known), but also on other factors such as pharmacokinetic properties, adverse effects, and patient characteristics. Strictly related to this issue is the vexata quaestio concerning monotherapy vs polytherapy. In the 1980s, after the negative appraisal of polytherapy by Reynolds and Shorvon (1981), polytherapy became a synonym of ‘bad therapy’. Monotherapy was therefore considered a ‘dogma’. More recently, this dogma crumbled, due to the evidence of synergistic therapeutic effects of some comedications (Rowan et al., 1983; Bourgeois and Dodson, 1989). Other different favourable combinations are still under evaluation (Robinson et al., 1993; Stolarek et al., 1993). While the advantages of monotherapy in the initial management of epilepsy are universally accepted, no general agreement exists about the strategy to be used when seizures continue, despite administration of a single drug at adequate dosages. Two therapeutic alternatives can be proposed for these patients: (a) to add a second drug or (b) to substitute the initial drug with another, known to be active against the same
seizure type (Beghi and Perucca, 1995; Schmidt and Gram, 1995). The main advantages of the latter policy include the possibility of evaluating separately the effects of individual drugs, of reducing the risk of toxicity and of avoiding adverse drug interactions. On the other hand, a possible disadvantage could be represented by the longer delay in obtaining control of the seizures in those patients responding only to bitherapy, with a potentially unfavourable impact on overall prognosis (Reynolds et al., 1983). Except for two studies (Hakkarainen, 1980; Tanganelli and Regesta, 1996), no other trial has yet evaluated the risk/benefit ratio of add-on therapy in patients unresponsive to alternative monotherapy. A rational choice of therapeutic strategies in patients who failed to respond to initial monotherapy is so hampered by lack of relevant information from controlled trials. Thus, a scientific evaluation of different treatment options in epileptic patients who continue to have seizures despite adequate initial monotherapy is desirable.
2.4. What is the potential role of AEDs? Recent clinical trials proved new AEDs to be effective in patients refractory to conventional drugs. However, the percentage of seizure-free patients remains to be established, as most studies report only the percentage of patients with significant reduction (more than 50%) in seizure frequency (Marson et al., 1997). Only a small minority (less than 2%) of patients refractory to old drugs is reported to become seizure free with new AEDs (Walker and Sander, 1996). The persisting lack of an acceptable model of drug-resistant seizures represents the most probable explanation for these non-striking results (Lo¨scher, 1997).
2.5. To which extent should side-effects be considered acceptable? Systemic toxicity and neurotoxicity strongly contribute to medical failure, but it must be considered that the extent to which patients complain about side-effects varies according to the severity of the side-effects and the level of functioning of
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the patient. A widely accepted, standardized assessment is lacking.
2.6. Should cases with different frequency and/or se6erity of episodes during treatment be considered unitedly in the same way? Usually, all these cases are defined as refractory. The term results here to be quite generic and not appropriate to cover this wide spectrum of situations, whose biological bases are likely to be different. An attempt to fix the boundaries has been made by Camfield and Camfield (1996), who consider intractable only the patients presenting at least one seizure every 2 months in the first 5 years, and for the longer term at least one seizure per year.
2.7. Should epilepsy whose seizures relapse after a prolonged period of remission be considered refractory? Even after a long-term remission, a small minority of patients may relapse (10% of patients in the Tunbridge study by Goodridge and Shorvon (1983)) and for a part of them the risk exists of becoming intractable (Shorvon, 1984). Isolated or sporadic seizures may be frequently related to facilitating situations such as psycophysical stress, sleep disturbances, etc., even if their exact role cannot be determined. Obviously, in these cases, the term drug resistance is not justified. It should be applied, on the contrary, to cases in which the repetitiveness of seizures suggests a progression of the epileptogenic process (see later).
2.8. The concept of temporary (age-dependent) drug resistance Population studies (Camfield and Camfield, 1996) indicate that during long-term follow-up, many children with intractable epilepsy eventually have remission of their seizure disorder. In a retrospective analysis, Huttenlocher and Hapke (1990) found that in 145 children with medically resistant seizures for 2 or more years, and with a follow-up ranging from 5 to 20 years
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after seizure onset, remission occurred at rates of 4% per year for children with borderline or normal intelligence and at 1.5% per year for retarded children. Except for myoclonic seizures, all other types were equally likely to remit over time. In a prospective study of children with medically intractable complex partial seizures of temporal lobe origin, Lindsay et al. (1979) observed that one-third of them became seizure-free adults. This phenomenon of the age-dependent drug resistance is partly related to the natural history of some types of epilepsy and partly to variations with age of some factors, i.e. drug kinetics (Cloyd et al., 1997), glial proliferation, glia/neurons ratio, CSF flow, maturation of enzymatic and neurotransmitter systems (White et al., 1983).
2.9. The 6iew of some forms of epilepsy as dynamic and/or progressi6e disorders, rather than in6ariably static conditions There is little doubt that in many individual patients, epilepsy appears to be either severe or mild at different times, under the influence of constitutional and environmental factors (Reynolds et al., 1983). On the other hand, it has been suggested that some forms of epilepsy are progressive owing to the assumption that epileptogenesis is a continuous dynamic process that could make seizures more severe (Engel, 1990, 1993; Heinemann et al., 1994). The bases for the susceptibility to progression may be attributed to some factors such as: the epileptogenic potential of the initial insult, topographic variations in epileptogenicity of some areas of the brain, adverse effects on cerebral development by early onset seizures, slow pathological changes in chronic epilepsy (re-arrangement of neuronal circuitries in the hippocampus, proliferation of mossy fibres in hippocampal sclerosis), and genetic predisposition (Jennet 1975; Wilmore et al., 1978; Andermann, 1982; Okada et al., 1984; Engel, 1990; Kim et al., 1990; Babb, 1991; Engel and Shewmon 1991; Engel, 1992; Wieser et al., 1993).Secondary foci and epilepsy-induced alterations in neural network, neuronal, and glial properties may be involved in this progression, mainly as regards temporal lobe and frontal cor-
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tex seizures. Another hypothesis concerns the kindling phenomenon, even if its occurrence in human epilepsy remains to be proven (Heinemann et al., 1994; Shinnar and Berg, 1996). The following query is strictly related to the previous issue.
2.10. Would more effecti6e therapy at the onset reduce the risk of intractable epilepsy? It is current practice not to treat after a single seizure. However, in most cases (up to 80%), patients will present further attacks, and considering that a negative association between seizure outcome and pre-treatment number of seizures has been consistently reported (Juul-Jensen, 1964a; Rodin, 1968; Okuma and Kumashiro, 1981; Elwes et al., 1984; Shorvon and Reynolds, 1986; Van Donselaar et al., 1991; Collaborative Group for the Study of Epilepsy., 1992), this attitude seems questionable. On the contrary, other authors (Shinnar and Berg, 1996) attach greater importance to the type rather than the number of seizures.
3. 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. Most studies focus on electroclinical features, some others investigate the morphological aspects. More recently, molecular and neurochemical findings have been reported that could represent a key for understanding the causes of some forms of refractoriness. The identification of animal models mimicking patterns of pharmacological resistance of the human epilepsy might represent a useful mean for
studying the mechanisms of intractability and for developing more effective drugs (Lo¨scher, 1997).
3.1. Electroclinical predictors Several factors have been associated with intractability, mostly in relation to focal epilepsy since about 60% of resistant patients suffer from partial seizures. When multiple factors are present in single case, the risk of intractability obviously increases. The most commonly reported are as follows.
3.1.1. Early seizure onset There is general agreement that an early onset of seizures within the first year of life carries an adverse prognosis, being associated with a high rate of seizure persistence (Annegers et al., 1979; Sofijanov, 1982). The risk increases if early onset is combined with high seizure frequency (Duchowny, 1987). 3.1.2. Length of the history before treatment For some authors, length of time from first seizure and number of seizures before onset of therapy are unfavourable prognostic factors (Juul-Jensen, 1964a; Rodin, 1968; Shorvon and Reynolds, 1982; Elwes et al., 1984; Van Donselaar et al., 1991; Collaborative Group for the Study of Epilepsy., 1992). This association is denied in other studies (Sillanpa¨a¨, 1993; Camfield and Camfield, 1996). Shinnar and Berg (1996), reviewing the data from the paper of Shorvon and Reynolds (1986), observe that the outcome was only correlated with the number of complex partial seizures and not with the number of tonic–clonic seizures. Similarly, in a randomized trial comparing two AEDs in drug-naive patients in Kenya, subjects with longer duration of epilepsy and those with a history of more than 100 generalized tonic–clonic seizures responded equally well to medication, as did those with epilepsy of briefer duration and fewer seizures (Feksi et al., 1991). 3.1.3. High seizure frequency Daily or weekly seizures constitute a risk fac-
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tor for intractability especially in infancy (JuulJensen, 1964b; Oller-Daurella et al., 1976; Aicardi, 1988; Sillanpa¨a¨, 1993; Camfield and Camfield, 1996).
3.1.4. History of febrile seizures Febrile seizures, particularly complex febrile seizures and febrile status epilepticus, have been hypothesized as one cause of hippocampal sclerosis (Falconer et al., 1964; Sagar and Oxbury, 1987; Cendes et al., 1994; French et al., 1994). Yet, the incidence of hippocampal sclerosis following childhood febrile seizures is low (Eremberg and Morris, 1987; Duchowny, 1997; Offringa et al., 1994) and epidemiologic studies have shown that the prognosis of febrile seizures is generally benign (Nelson and Ellenberg, 1978; Consensus Development Panel., 1980; Annegers et al., 1987; Freeman, 1990; Verity and Golding, 1991; Camfield and Camfield, 1995). Randomized trials of treatment to prevent febrile seizures provided further evidence against a relationship between febrile seizures and later epilepsy (Wolf and Forsythe, 1989; Rosman et al., 1993; Knudsen et al., 1995). 3.1.5. Type of seizures About 60% of patients with intractable epilepsy suffer from partial seizures (Reynolds et al., 1983), mainly of complex type. The presence of multiple seizure type generally constitutes a predictor of reduced probability of remission (Hauser, 1992). However, for other authors, seizure type is not an influential predictor of intractability (Huttenlocher and Hapke, 1990; Sillanpa¨a¨, 1993; Camfield et al., 1993), particularly if epilepsy begins in infancy. 3.1.6. Persistence of seizures The longer the seizures continue on treatment, the less likely is remission to occur (Reynolds et al., 1983; Sillanpa¨a¨, 1993). In cases of seizures remaining uncontrolled for more than 4 years, the probability of remission is low (Annegers et al., 1979; Loiseau, 1986; Hauser, 1992).
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3.1.7. Status epilepticus Occurrence of status epilepticus constitutes one of the main predictors of intractability for some authors (Sillanpa¨a¨, 1993), while for others the prognosis depends also on the underlying cause and the pre-existing neurological status of the patient (Maytal et al., 1989; Shinnar et al., 1992; Hauser, 1990; Gross-Tsur and Shinnar, 1993; Dodson et al., 1993; Verity et al., 1993; Towne et al., 1994). Epilepsia partialis continua, mainly type 2, generally represents a regional lesion involving the cortex, with poor prognosis in most cases (Rasmussen’s encephalitis). 3.1.8. Epilepsy syndromes The type of epileptic syndrome is important in determining prognosis. However, as previously reported, in a large proportion of patients, a specific syndrome cannot be identified at the time of diagnosis and, in many cases, a syndromic diagnosis can be made only retrospectively (Sander, 1993; Shinnar and Berg, 1996). In some patients, particularly in those with few seizures, the assignment to a specific syndrome cannot be made even after several years of treatment (Shinnar and Berg, 1996). 3.1.9. Abnormal neurological status Patients with brain damage are less likely to go into remission than do neurologically normal patients (Aicardi, 1990; Berg et al., 1995). The more severe the neurologic impairment, the greater the chances of medical intractability (Trevathan et al., 1988; Uvenbrandt, 1988), particularly when associated with high seizure frequency (Chevrie and Aicardi, 1979). 3.1.10. Electroencephalography abnormalities The significance of electroencephalography (EEG) as a predictor of prognosis has been variably interpreted (Rodin, 1968; HolowachThurston et al., 1982; Todt, 1984; Shinnar et al., 1985). Gross EEG abnormality in a patient with epilepsy generally implies a poor prognosis for becoming seizure free (Rodin, 1968; Rowan et al., 1980). The presence of multifocal paroxysms would be the only EEG-significant risk factor for negative outcome (Satishandra et al., 1987). In
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Table 3 Structural lesions associated with epilepsy (Vinters et al., 1993) Malformati6e Cortical dysplasia Microdysgenesis (Meencke) Focal dysplasia Cortical dysplasia with hamartomatous proliferation of neuroectodermal cells Polymicrogyria Lissencephaly/Pachygyria Hemimegalencephaly Vascular malformations Arteriovenous malformation Cavernous hemangioma Neoplastic Gliomas Gangliogliomas Metastatic tumors Dysembryoplastic neuroepithelial tumor Others Familial and metabolic With focal lesions; phacomatosis Tuberous sclerosis Neurofibromatosis Encephalotrigeminal angiomatosis, Sturge–Weber disease With diffuse lesions Lysosomal enzyme deficiencies Peroxisomal disorders Mitochondrial enzyme disorders Unknown etiology, e.g. Alexander’s disease, lipofuscinosis, myelinopathies Lafora body disease Miscellaneous myoclonic epilepsies Cerebro6ascular disease and trauma Ischemic Hemorrhagic Post-traumatic Inflammatory/infectious Fulminant encephalitis, e.g. due to herpes virus Chronic: e.g. parasitic Rasmussen’s encephalitis Ammon’s horn (hippocampal) sclerosis
focal epilepsy with complex partial seizures, bilateral temporal slow wave foci in the initial EEG and development of bilateral temporal slow wave foci during treatment seem also to constitute negative prognostic factors (Runge, 1996).
3.1.11. Family history for epilepsy No complete agreement exists about the importance of a family history of epilepsy in determining prognosis. For some authors, it may constitute an adverse factor of risk (Satishandra et al., 1987; Shafer et al., 1988; Elwes and Reynolds, 1990). 3.2. Biological predictors Biologic factors influencing prognosis refer almost exclusively to symptomatic epilepsy that may be the result of a structural lesion including a wide variety of pathologic conditions (inflammatory, neoplastic, metabolic, etc.) or disorders of neuronal development and migration (Table 3), and other situations presumed to be symptomatic but of unknown etiology or cryptogenous. Remote symptomatic seizure etiology seems to be one of the most important predictors of seizure intractability (Sillanpa¨a¨, 1993). Neuropathology of refractory epilepsy mainly derives from surgical resected brain tissue. However, the exact causative role of the lesion cannot be always established, mainly in cases of dual pathology. The risk for intractability varies with the different conditions (Vinters et al., 1993). Intractable focal epilepsy is often associated with structural lesions of the cerebral cortex, particularly with cortical dysplasia (Awas et al., 1991; Fish et al., 1991; Palmini et al., 1995), in relation to the high and intrinsic epileptogenicity of these lesions (Palmini et al., 1995; Mattia et al., 1995) often involving an area more extended than seen on magnetic resonance imaging or in operation (Palmini et al., 1991; Andermann, 1994). Decreases of GABAergic interneurons (Ferrer et al., 1992) or anomalies in synaptogenesis (Becker, 1991) have been reported. Hippocampal sclerosis is another cause of refractoriness and the most common pathological finding in temporal lobe epilepsy in surgical studies (Mathern et al., 1995a,b, 1996a). However, despite the large number of studies suggesting that hippocampal sclerosis leads to epilepsy, it is still possible that repeated seizures can produce or aggravate sclerosis (Swanson, 1995). Whether early childhood seizures may be one cause of this particular hippocampal damage with a conse-
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quent increase in mossy fiber sprouting and neuron loss, which may be critical in the pathophysiology of seizures, is still under debate (Munari et al., 1994; Salmenpera¨ et al., 1998). The recent finding that aberrant hippocampal mossy fiber sprouting is associated with an increase in NMDAR2 receptors further supports this hypothesis (Mathern et al., 1996b). In some cases, hippocampal sclerosis is associated with another extrahippocampal abnormality (e.g. cortical scar, glial malformation, neuronal heterotopias). This dual pathology represents 7% of the temporal lobectomy material in a retrospective study at the Maudsley Hospital (Bruton, 1988). Consequently, the outcome after lobectomy was worse in this group. Meningitis and encephalitis constitute another important cause of refractory epilepsy, producing mesial temporal sclerosis or neocortical foci in relation to age of onset of the illness (Marks et al., 1982). Pathological conditions that may influence a susceptibility to progression of the epileptogenic process, such as severe brain injuries with extravasation of blood products, are frequently responsible for drug-resistant seizures (Willmore, 1992). Brain tumours are a frequent etiologic structural lesion observed in patients with refractory seizures, especially with CPS (Bruton, 1988; Daumas-Duport et al., 1988) and low-grade tumours have been identified in 15% of intractable epilepsies. Among them, gangliogliomas represent the second common lesion associated with temporal lobe epilepsy (Bruton, 1988; Armstrong et al., 1988). Another type of primary neoplasm that is a frequent cause of epilepsy is the dysembryoplastic neuroepithelial tumour (Daumas-Duport et al., 1988). Neurocutaneos disorders (phacomatoses) are generally associated with early-onset seizures and, in some cases, very severe epilepsy develops, especially in case of Sturge – Weber syndrome and of tuberous sclerosis, in relation to the presence of vascular abnormalities and cortical dysplasias in the former and of meningocortical hamartomas and other structural lesions (including neoplasms) in the latter.
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An interesting hypothesis regarding patients with intractable temporal lobe epilepsy concerns the possible role of the astrocytes derived cytokines. A significant increase in the levels of the cytokine S100b in neocortical temporal lobe surgical specimens from these patients has been reported (Griffin et al., 1995). These abnormally high levels (up to threefold more than in controls) could determine damage to neurons by induction of an increase in intracellular free calcium levels or of excessive growth of dystrophic neurites. The mechanism underlying the increase is probably related to an induction by highly regulated feedback systems and might reflect a homeostatic attempt to suppress the epileptic activity.
4. 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). Recent data seem to indicate the possibility of a more direct role of genetic factors in determining drug resistance. Endothelial walls of human capillary blood vessels at the blood–brain barrier site express a membrane glycoprotein (P-glycoprotein) encoded by the multidrug-resistance gene (MDR1) (Riordan and Ling, 1985; Ueda et al., 1986) believed to function as an efflux pump, regulating the entry of certain molecules into the central nervous system. High levels of MDR1 expression have been found in some tumour types known to be unresponsive to chemotherapy. They have also been reported in astrocytomas (Matsumoto et al., 1991) but not in normal astrocytes (Cordon-Cardo et al., 1989). The results of a recent study suggest that MDR1 expression is increased in brain of many patients with medically intractable epilepsy (Tishler et al., 1995). In fact,
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many AEDs, including phenytoin, phenobarnital and carbamazepine, present chemical structures consistent with their being substrates for the Pglycoprotein (Morrow and Cowan, 1988), so determining an inadequate intraparenchimal drug accumulation.
els of intractable epilepsy, which have been lacking until now, even if some interesting potential animal models (Lo¨scher, 1997) have recently been proposed. Acknowledgements
5. 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 exhaustive identification of clinical and biological markers for the early detection of these subjects. It also accounts for the difficulties in defining the concept of DRE. Consequently, the list of clinical features and biological factors currently accepted to be associated with difficult-to-treat epilepsy is presumably incomplete and perhaps disputable. In fact, for a part of them, the association is denied by some authors and for other factors (e.g. mesial temporal sclerosis), their role as a cause of pharmacoresistance or a consequence of repeated seizures is debated. Furthermore, the reason why patients with seemingly identical seizure types respond to treatment in some cases while develop a different grade of drug resistance in others, is still unexplained. 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 (Heinemann et al., 1994). Such hypotheses need to be confirmed with suitable specifically dedicated experimental mod-
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Clinical aspects and biological bases of drug-resistant epilepsies Giovanni Regesta a,*, Paolo Tanganelli b a
Department of Neurology, Epilepsy Center, San Martino Hospital, Viale Benedetto XV, 10 -16132 Geno6a, Italy b Department of Neurology, P. A. Micone Hospital, Geno6a, Italy Received 11 February 1998; received in revised form 22 September 1998; accepted 30 September 1998
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. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy; Drug resistance; Biological bases; Clinical aspects; Genetic factors
1. Introduction * Corresponding author. Tel.: + 39 010 5552542; fax: + 39 010 5556603. e-mail: [email protected].
To investigate the clinical aspects and the biological bases of drug-resistant epilepsies (DRE) is
0920-1211/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 9 8 ) 0 0 1 0 6 - 5
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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.
2. 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 seizures (CPS) misdiagnosed as absences, carbamazepine or phenytoin, in juvenile myclonic epilepsy (JME) misdiagnosed as grand mal (GM) epilepsy, etc. 2. Inappropriate assessment of response: pseudoseizures developing as a substitute for epileptic seizures, paradoxical drug intoxication. 3. Suboptimal dosing regimen: drug not tried at the highest tolerated dosage, inappropriate dosing frequency. 4. Inappropriate patient behaviour: poor compliance, detrimental lifestyle. Coming back to the difficulty in defining and assessing DRE, some controversial issues and unsolved questions may be identified.
2.1. How many years are needed before establishing drug resistance? The duration of active epilepsy before a patient might be labelled as pharmacoresistant is much debated. It is widely accepted that about 60–70% of people with epilepsy will achieve remission of seizures in a variable, generally short, period of time. The duration of active epilepsy before a patient might be labelled as pharmacoresistant is much debated. For example, Leppik (1992) proposes that DRE can be defined as seizures not completely controlled with AEDs 1 year after onset, while Loyning and Hauglie-Hanssen (1995)
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suggest at least 2 years of adequate drug trials with at least two drugs for establishing refractoriness. However, it should be considered that, in some cases, even after 10 years, seizure control may be obtained (Hauser, 1992). Furthermore, the rate of remission and the time needed for achieving it are rather different when data derived from hospital- and community-based studies are considered. Consequently, in order to answer this question, we have to consider the prognosis of the individual cases, in relation to the specific type of seizures and/or of epileptic syndrome. As regards outcome, the epileptic syndromes have been classified into four different prognostic groups (Sander, 1993). Following this grouping, the time required for establishing drug resistance cannot be an absolute value but it is related to the belonging group of the syndrome, as, for example, a case of childhood absence epilepsy not responding to treatment in the short term. Unfortunately, this classification does not offer an answer in any case. In fact, while some epileptic syndromes are clear cut, for most of them a disagreement about their precise limits exists, with possible overlaps. The possibility of different etiologies for the same syndrome, and the existence of cases not falling into the recognized syndromes, must also be considered, together with the statement that sometimes a syndromic diagnosis is made retrospectively. For these reasons, a better-defined answer requires further prospective studies focusing on the prognosis of specific epileptic syndromes (Sander, 1993).
2.2. When should a patient be considered to ha6e failed on the initially prescribed drug, and how many drugs should be tried before his/her epilepsy might be regarded as intractable? The score suggested by Schmidt (1986) for the assessment of treatment failures, admits only the possibility of primary drugs in monotherapy and does not take into account the number of drugs to be tried (Table 1). On the other hand, a certain percentage ( 40%) of patients not adequately controlled with a single drug treatment
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Table 1 Medical intractability scale (Schmidt, 1986) Index of intractability
Seizures persist despite the following treatment
0
Other than primary drug regardless of its daily dose Primary drug below the recommended daily dose Primary drug within the recommended daily dose Primary drug with plasma concentrations within the recommended ‘therapeutic range’ Primary drug with maximum tolerable daily dose More than one primary drug with maximum tolerable daily dose in subsequent single-drug therapy for at least 9 months
1 2 3
4 5
may enter remission with a combination of two or three AEDs (Mattson, 1994). A grading system for evaluating the probability of achieving future seizure freedom, based on the failure of the appropriate treatment with one or more drugs, has been proposed by Perucca (1996) (Table 2).
2.3. Should only first-line treatments or also second-line treatments be tried before establishing drug resistance? When initiating a treatment, the selection of an AED is currently based on its expected efficacy
Table 2 Grading system for drug resistance (Perucca, 1996) Grade
Definition
1
Failure on appropriate 530–35 treatment with one drug Failure with two drugs 510–15 given alone or combined Failure with three drugs 55 given alone or combined
2
3
Probability of future seizure freedom (%)
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for specific seizure type(s) and epilepsy. Therefore, therapeutic algorithms suggesting first-line and second-line drugs according to the diagnosis have been proposed. However, except for rare situations, these recommendations are not based on irrefutable data and it is well known that different drugs may show a corresponding efficacy in a given seizure type or syndrome. Comparative monotherapy trials in partial and secondarily generalized tonic – clonic seizures found no conclusive difference in efficacy among carbamazepine, phenytoin, phenobarbital, and valproate (Mattson et al., 1985, 1992). Comparing the efficacy of the new AEDs is even more uncertain because studies concerning their use in monotherapy have been limited until now. The results of a metanalysis of efficacy data from randomized placebo-controlled add-on trials of all new drugs do not allow an evidencebased choice between these agents (Marson et al., 1997). Therefore, drug selection should be based not only on the specific antiepileptic action (provided that it is thoroughly known), but also on other factors such as pharmacokinetic properties, adverse effects, and patient characteristics. Strictly related to this issue is the vexata quaestio concerning monotherapy vs polytherapy. In the 1980s, after the negative appraisal of polytherapy by Reynolds and Shorvon (1981), polytherapy became a synonym of ‘bad therapy’. Monotherapy was therefore considered a ‘dogma’. More recently, this dogma crumbled, due to the evidence of synergistic therapeutic effects of some comedications (Rowan et al., 1983; Bourgeois and Dodson, 1989). Other different favourable combinations are still under evaluation (Robinson et al., 1993; Stolarek et al., 1993). While the advantages of monotherapy in the initial management of epilepsy are universally accepted, no general agreement exists about the strategy to be used when seizures continue, despite administration of a single drug at adequate dosages. Two therapeutic alternatives can be proposed for these patients: (a) to add a second drug or (b) to substitute the initial drug with another, known to be active against the same
seizure type (Beghi and Perucca, 1995; Schmidt and Gram, 1995). The main advantages of the latter policy include the possibility of evaluating separately the effects of individual drugs, of reducing the risk of toxicity and of avoiding adverse drug interactions. On the other hand, a possible disadvantage could be represented by the longer delay in obtaining control of the seizures in those patients responding only to bitherapy, with a potentially unfavourable impact on overall prognosis (Reynolds et al., 1983). Except for two studies (Hakkarainen, 1980; Tanganelli and Regesta, 1996), no other trial has yet evaluated the risk/benefit ratio of add-on therapy in patients unresponsive to alternative monotherapy. A rational choice of therapeutic strategies in patients who failed to respond to initial monotherapy is so hampered by lack of relevant information from controlled trials. Thus, a scientific evaluation of different treatment options in epileptic patients who continue to have seizures despite adequate initial monotherapy is desirable.
2.4. What is the potential role of AEDs? Recent clinical trials proved new AEDs to be effective in patients refractory to conventional drugs. However, the percentage of seizure-free patients remains to be established, as most studies report only the percentage of patients with significant reduction (more than 50%) in seizure frequency (Marson et al., 1997). Only a small minority (less than 2%) of patients refractory to old drugs is reported to become seizure free with new AEDs (Walker and Sander, 1996). The persisting lack of an acceptable model of drug-resistant seizures represents the most probable explanation for these non-striking results (Lo¨scher, 1997).
2.5. To which extent should side-effects be considered acceptable? Systemic toxicity and neurotoxicity strongly contribute to medical failure, but it must be considered that the extent to which patients complain about side-effects varies according to the severity of the side-effects and the level of functioning of
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the patient. A widely accepted, standardized assessment is lacking.
2.6. Should cases with different frequency and/or se6erity of episodes during treatment be considered unitedly in the same way? Usually, all these cases are defined as refractory. The term results here to be quite generic and not appropriate to cover this wide spectrum of situations, whose biological bases are likely to be different. An attempt to fix the boundaries has been made by Camfield and Camfield (1996), who consider intractable only the patients presenting at least one seizure every 2 months in the first 5 years, and for the longer term at least one seizure per year.
2.7. Should epilepsy whose seizures relapse after a prolonged period of remission be considered refractory? Even after a long-term remission, a small minority of patients may relapse (10% of patients in the Tunbridge study by Goodridge and Shorvon (1983)) and for a part of them the risk exists of becoming intractable (Shorvon, 1984). Isolated or sporadic seizures may be frequently related to facilitating situations such as psycophysical stress, sleep disturbances, etc., even if their exact role cannot be determined. Obviously, in these cases, the term drug resistance is not justified. It should be applied, on the contrary, to cases in which the repetitiveness of seizures suggests a progression of the epileptogenic process (see later).
2.8. The concept of temporary (age-dependent) drug resistance Population studies (Camfield and Camfield, 1996) indicate that during long-term follow-up, many children with intractable epilepsy eventually have remission of their seizure disorder. In a retrospective analysis, Huttenlocher and Hapke (1990) found that in 145 children with medically resistant seizures for 2 or more years, and with a follow-up ranging from 5 to 20 years
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after seizure onset, remission occurred at rates of 4% per year for children with borderline or normal intelligence and at 1.5% per year for retarded children. Except for myoclonic seizures, all other types were equally likely to remit over time. In a prospective study of children with medically intractable complex partial seizures of temporal lobe origin, Lindsay et al. (1979) observed that one-third of them became seizure-free adults. This phenomenon of the age-dependent drug resistance is partly related to the natural history of some types of epilepsy and partly to variations with age of some factors, i.e. drug kinetics (Cloyd et al., 1997), glial proliferation, glia/neurons ratio, CSF flow, maturation of enzymatic and neurotransmitter systems (White et al., 1983).
2.9. The 6iew of some forms of epilepsy as dynamic and/or progressi6e disorders, rather than in6ariably static conditions There is little doubt that in many individual patients, epilepsy appears to be either severe or mild at different times, under the influence of constitutional and environmental factors (Reynolds et al., 1983). On the other hand, it has been suggested that some forms of epilepsy are progressive owing to the assumption that epileptogenesis is a continuous dynamic process that could make seizures more severe (Engel, 1990, 1993; Heinemann et al., 1994). The bases for the susceptibility to progression may be attributed to some factors such as: the epileptogenic potential of the initial insult, topographic variations in epileptogenicity of some areas of the brain, adverse effects on cerebral development by early onset seizures, slow pathological changes in chronic epilepsy (re-arrangement of neuronal circuitries in the hippocampus, proliferation of mossy fibres in hippocampal sclerosis), and genetic predisposition (Jennet 1975; Wilmore et al., 1978; Andermann, 1982; Okada et al., 1984; Engel, 1990; Kim et al., 1990; Babb, 1991; Engel and Shewmon 1991; Engel, 1992; Wieser et al., 1993).Secondary foci and epilepsy-induced alterations in neural network, neuronal, and glial properties may be involved in this progression, mainly as regards temporal lobe and frontal cor-
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tex seizures. Another hypothesis concerns the kindling phenomenon, even if its occurrence in human epilepsy remains to be proven (Heinemann et al., 1994; Shinnar and Berg, 1996). The following query is strictly related to the previous issue.
2.10. Would more effecti6e therapy at the onset reduce the risk of intractable epilepsy? It is current practice not to treat after a single seizure. However, in most cases (up to 80%), patients will present further attacks, and considering that a negative association between seizure outcome and pre-treatment number of seizures has been consistently reported (Juul-Jensen, 1964a; Rodin, 1968; Okuma and Kumashiro, 1981; Elwes et al., 1984; Shorvon and Reynolds, 1986; Van Donselaar et al., 1991; Collaborative Group for the Study of Epilepsy., 1992), this attitude seems questionable. On the contrary, other authors (Shinnar and Berg, 1996) attach greater importance to the type rather than the number of seizures.
3. 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. Most studies focus on electroclinical features, some others investigate the morphological aspects. More recently, molecular and neurochemical findings have been reported that could represent a key for understanding the causes of some forms of refractoriness. The identification of animal models mimicking patterns of pharmacological resistance of the human epilepsy might represent a useful mean for
studying the mechanisms of intractability and for developing more effective drugs (Lo¨scher, 1997).
3.1. Electroclinical predictors Several factors have been associated with intractability, mostly in relation to focal epilepsy since about 60% of resistant patients suffer from partial seizures. When multiple factors are present in single case, the risk of intractability obviously increases. The most commonly reported are as follows.
3.1.1. Early seizure onset There is general agreement that an early onset of seizures within the first year of life carries an adverse prognosis, being associated with a high rate of seizure persistence (Annegers et al., 1979; Sofijanov, 1982). The risk increases if early onset is combined with high seizure frequency (Duchowny, 1987). 3.1.2. Length of the history before treatment For some authors, length of time from first seizure and number of seizures before onset of therapy are unfavourable prognostic factors (Juul-Jensen, 1964a; Rodin, 1968; Shorvon and Reynolds, 1982; Elwes et al., 1984; Van Donselaar et al., 1991; Collaborative Group for the Study of Epilepsy., 1992). This association is denied in other studies (Sillanpa¨a¨, 1993; Camfield and Camfield, 1996). Shinnar and Berg (1996), reviewing the data from the paper of Shorvon and Reynolds (1986), observe that the outcome was only correlated with the number of complex partial seizures and not with the number of tonic–clonic seizures. Similarly, in a randomized trial comparing two AEDs in drug-naive patients in Kenya, subjects with longer duration of epilepsy and those with a history of more than 100 generalized tonic–clonic seizures responded equally well to medication, as did those with epilepsy of briefer duration and fewer seizures (Feksi et al., 1991). 3.1.3. High seizure frequency Daily or weekly seizures constitute a risk fac-
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tor for intractability especially in infancy (JuulJensen, 1964b; Oller-Daurella et al., 1976; Aicardi, 1988; Sillanpa¨a¨, 1993; Camfield and Camfield, 1996).
3.1.4. History of febrile seizures Febrile seizures, particularly complex febrile seizures and febrile status epilepticus, have been hypothesized as one cause of hippocampal sclerosis (Falconer et al., 1964; Sagar and Oxbury, 1987; Cendes et al., 1994; French et al., 1994). Yet, the incidence of hippocampal sclerosis following childhood febrile seizures is low (Eremberg and Morris, 1987; Duchowny, 1997; Offringa et al., 1994) and epidemiologic studies have shown that the prognosis of febrile seizures is generally benign (Nelson and Ellenberg, 1978; Consensus Development Panel., 1980; Annegers et al., 1987; Freeman, 1990; Verity and Golding, 1991; Camfield and Camfield, 1995). Randomized trials of treatment to prevent febrile seizures provided further evidence against a relationship between febrile seizures and later epilepsy (Wolf and Forsythe, 1989; Rosman et al., 1993; Knudsen et al., 1995). 3.1.5. Type of seizures About 60% of patients with intractable epilepsy suffer from partial seizures (Reynolds et al., 1983), mainly of complex type. The presence of multiple seizure type generally constitutes a predictor of reduced probability of remission (Hauser, 1992). However, for other authors, seizure type is not an influential predictor of intractability (Huttenlocher and Hapke, 1990; Sillanpa¨a¨, 1993; Camfield et al., 1993), particularly if epilepsy begins in infancy. 3.1.6. Persistence of seizures The longer the seizures continue on treatment, the less likely is remission to occur (Reynolds et al., 1983; Sillanpa¨a¨, 1993). In cases of seizures remaining uncontrolled for more than 4 years, the probability of remission is low (Annegers et al., 1979; Loiseau, 1986; Hauser, 1992).
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3.1.7. Status epilepticus Occurrence of status epilepticus constitutes one of the main predictors of intractability for some authors (Sillanpa¨a¨, 1993), while for others the prognosis depends also on the underlying cause and the pre-existing neurological status of the patient (Maytal et al., 1989; Shinnar et al., 1992; Hauser, 1990; Gross-Tsur and Shinnar, 1993; Dodson et al., 1993; Verity et al., 1993; Towne et al., 1994). Epilepsia partialis continua, mainly type 2, generally represents a regional lesion involving the cortex, with poor prognosis in most cases (Rasmussen’s encephalitis). 3.1.8. Epilepsy syndromes The type of epileptic syndrome is important in determining prognosis. However, as previously reported, in a large proportion of patients, a specific syndrome cannot be identified at the time of diagnosis and, in many cases, a syndromic diagnosis can be made only retrospectively (Sander, 1993; Shinnar and Berg, 1996). In some patients, particularly in those with few seizures, the assignment to a specific syndrome cannot be made even after several years of treatment (Shinnar and Berg, 1996). 3.1.9. Abnormal neurological status Patients with brain damage are less likely to go into remission than do neurologically normal patients (Aicardi, 1990; Berg et al., 1995). The more severe the neurologic impairment, the greater the chances of medical intractability (Trevathan et al., 1988; Uvenbrandt, 1988), particularly when associated with high seizure frequency (Chevrie and Aicardi, 1979). 3.1.10. Electroencephalography abnormalities The significance of electroencephalography (EEG) as a predictor of prognosis has been variably interpreted (Rodin, 1968; HolowachThurston et al., 1982; Todt, 1984; Shinnar et al., 1985). Gross EEG abnormality in a patient with epilepsy generally implies a poor prognosis for becoming seizure free (Rodin, 1968; Rowan et al., 1980). The presence of multifocal paroxysms would be the only EEG-significant risk factor for negative outcome (Satishandra et al., 1987). In
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Table 3 Structural lesions associated with epilepsy (Vinters et al., 1993) Malformati6e Cortical dysplasia Microdysgenesis (Meencke) Focal dysplasia Cortical dysplasia with hamartomatous proliferation of neuroectodermal cells Polymicrogyria Lissencephaly/Pachygyria Hemimegalencephaly Vascular malformations Arteriovenous malformation Cavernous hemangioma Neoplastic Gliomas Gangliogliomas Metastatic tumors Dysembryoplastic neuroepithelial tumor Others Familial and metabolic With focal lesions; phacomatosis Tuberous sclerosis Neurofibromatosis Encephalotrigeminal angiomatosis, Sturge–Weber disease With diffuse lesions Lysosomal enzyme deficiencies Peroxisomal disorders Mitochondrial enzyme disorders Unknown etiology, e.g. Alexander’s disease, lipofuscinosis, myelinopathies Lafora body disease Miscellaneous myoclonic epilepsies Cerebro6ascular disease and trauma Ischemic Hemorrhagic Post-traumatic Inflammatory/infectious Fulminant encephalitis, e.g. due to herpes virus Chronic: e.g. parasitic Rasmussen’s encephalitis Ammon’s horn (hippocampal) sclerosis
focal epilepsy with complex partial seizures, bilateral temporal slow wave foci in the initial EEG and development of bilateral temporal slow wave foci during treatment seem also to constitute negative prognostic factors (Runge, 1996).
3.1.11. Family history for epilepsy No complete agreement exists about the importance of a family history of epilepsy in determining prognosis. For some authors, it may constitute an adverse factor of risk (Satishandra et al., 1987; Shafer et al., 1988; Elwes and Reynolds, 1990). 3.2. Biological predictors Biologic factors influencing prognosis refer almost exclusively to symptomatic epilepsy that may be the result of a structural lesion including a wide variety of pathologic conditions (inflammatory, neoplastic, metabolic, etc.) or disorders of neuronal development and migration (Table 3), and other situations presumed to be symptomatic but of unknown etiology or cryptogenous. Remote symptomatic seizure etiology seems to be one of the most important predictors of seizure intractability (Sillanpa¨a¨, 1993). Neuropathology of refractory epilepsy mainly derives from surgical resected brain tissue. However, the exact causative role of the lesion cannot be always established, mainly in cases of dual pathology. The risk for intractability varies with the different conditions (Vinters et al., 1993). Intractable focal epilepsy is often associated with structural lesions of the cerebral cortex, particularly with cortical dysplasia (Awas et al., 1991; Fish et al., 1991; Palmini et al., 1995), in relation to the high and intrinsic epileptogenicity of these lesions (Palmini et al., 1995; Mattia et al., 1995) often involving an area more extended than seen on magnetic resonance imaging or in operation (Palmini et al., 1991; Andermann, 1994). Decreases of GABAergic interneurons (Ferrer et al., 1992) or anomalies in synaptogenesis (Becker, 1991) have been reported. Hippocampal sclerosis is another cause of refractoriness and the most common pathological finding in temporal lobe epilepsy in surgical studies (Mathern et al., 1995a,b, 1996a). However, despite the large number of studies suggesting that hippocampal sclerosis leads to epilepsy, it is still possible that repeated seizures can produce or aggravate sclerosis (Swanson, 1995). Whether early childhood seizures may be one cause of this particular hippocampal damage with a conse-
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quent increase in mossy fiber sprouting and neuron loss, which may be critical in the pathophysiology of seizures, is still under debate (Munari et al., 1994; Salmenpera¨ et al., 1998). The recent finding that aberrant hippocampal mossy fiber sprouting is associated with an increase in NMDAR2 receptors further supports this hypothesis (Mathern et al., 1996b). In some cases, hippocampal sclerosis is associated with another extrahippocampal abnormality (e.g. cortical scar, glial malformation, neuronal heterotopias). This dual pathology represents 7% of the temporal lobectomy material in a retrospective study at the Maudsley Hospital (Bruton, 1988). Consequently, the outcome after lobectomy was worse in this group. Meningitis and encephalitis constitute another important cause of refractory epilepsy, producing mesial temporal sclerosis or neocortical foci in relation to age of onset of the illness (Marks et al., 1982). Pathological conditions that may influence a susceptibility to progression of the epileptogenic process, such as severe brain injuries with extravasation of blood products, are frequently responsible for drug-resistant seizures (Willmore, 1992). Brain tumours are a frequent etiologic structural lesion observed in patients with refractory seizures, especially with CPS (Bruton, 1988; Daumas-Duport et al., 1988) and low-grade tumours have been identified in 15% of intractable epilepsies. Among them, gangliogliomas represent the second common lesion associated with temporal lobe epilepsy (Bruton, 1988; Armstrong et al., 1988). Another type of primary neoplasm that is a frequent cause of epilepsy is the dysembryoplastic neuroepithelial tumour (Daumas-Duport et al., 1988). Neurocutaneos disorders (phacomatoses) are generally associated with early-onset seizures and, in some cases, very severe epilepsy develops, especially in case of Sturge – Weber syndrome and of tuberous sclerosis, in relation to the presence of vascular abnormalities and cortical dysplasias in the former and of meningocortical hamartomas and other structural lesions (including neoplasms) in the latter.
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An interesting hypothesis regarding patients with intractable temporal lobe epilepsy concerns the possible role of the astrocytes derived cytokines. A significant increase in the levels of the cytokine S100b in neocortical temporal lobe surgical specimens from these patients has been reported (Griffin et al., 1995). These abnormally high levels (up to threefold more than in controls) could determine damage to neurons by induction of an increase in intracellular free calcium levels or of excessive growth of dystrophic neurites. The mechanism underlying the increase is probably related to an induction by highly regulated feedback systems and might reflect a homeostatic attempt to suppress the epileptic activity.
4. 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). Recent data seem to indicate the possibility of a more direct role of genetic factors in determining drug resistance. Endothelial walls of human capillary blood vessels at the blood–brain barrier site express a membrane glycoprotein (P-glycoprotein) encoded by the multidrug-resistance gene (MDR1) (Riordan and Ling, 1985; Ueda et al., 1986) believed to function as an efflux pump, regulating the entry of certain molecules into the central nervous system. High levels of MDR1 expression have been found in some tumour types known to be unresponsive to chemotherapy. They have also been reported in astrocytomas (Matsumoto et al., 1991) but not in normal astrocytes (Cordon-Cardo et al., 1989). The results of a recent study suggest that MDR1 expression is increased in brain of many patients with medically intractable epilepsy (Tishler et al., 1995). In fact,
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many AEDs, including phenytoin, phenobarnital and carbamazepine, present chemical structures consistent with their being substrates for the Pglycoprotein (Morrow and Cowan, 1988), so determining an inadequate intraparenchimal drug accumulation.
els of intractable epilepsy, which have been lacking until now, even if some interesting potential animal models (Lo¨scher, 1997) have recently been proposed. Acknowledgements
5. 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 exhaustive identification of clinical and biological markers for the early detection of these subjects. It also accounts for the difficulties in defining the concept of DRE. Consequently, the list of clinical features and biological factors currently accepted to be associated with difficult-to-treat epilepsy is presumably incomplete and perhaps disputable. In fact, for a part of them, the association is denied by some authors and for other factors (e.g. mesial temporal sclerosis), their role as a cause of pharmacoresistance or a consequence of repeated seizures is debated. Furthermore, the reason why patients with seemingly identical seizure types respond to treatment in some cases while develop a different grade of drug resistance in others, is still unexplained. 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 (Heinemann et al., 1994). Such hypotheses need to be confirmed with suitable specifically dedicated experimental mod-
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