John Libbey Eurotext

Can we predict refractory epilepsy at the time of diagnosis? Volume 7, supplément 1, Supplement 1, September 2005

Auteur(s) : Franck Semah1,2, Philippe Ryvlin3

1Service hospitalier F. Joliot, CEA, Orsay
2Neurology Department, Sainte-Anne Hospital, Paris
3Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Université Claude Bernard Lyon 1, Lyon, France

Up to 30% of patients with epilepsy do not undergo remission despite adequate antiepileptic drug treatment (AED) (Hauser et al. 1998, Kwan and Brodie 2000, Hart et al. 1990). The early identification of this population remains a major issue, even though a number of risk factors have been previously delineated. The main predictors for seizure relapse in adults are the presence of an abnormal EEG, an abnormal neurological examination, partial seizures, a known etiology, an abnormal CT scan or MRI, Todd’s paralysis, and a developmental delay (Hart et al. 1990, Elwes et al. 1984, Sillanpää 1993, Sander 1993, Berg and Shinnar 1991, Hauser et al. 1990). Most of these factors reflect the presence of a localized-related form of epilepsy (Mattson et al. 1996). The prognostic value of other factors such as age at onset is controversial. A more precise delineation of early risk factor in the different groups of patients with epilepsy is still needed, provided the heterogeneity of epileptic syndromes and of their respective prognosis (Kwan and Brodie 2000, Sander 1993, Semah et al. 1998).

Role of the epileptic syndrome

Epileptic syndromes carry various prognosis in adults and children. For example, the majority of patients with juvenile myoclonic epilepsy (JME) are seizure-free when treated with adequate AEDs (Wolf and Inoue 2002), such as valproate or lamotrigine (Prasad et al. 2003), whereas the majority of patients with mesial temporal lobe epilepsy (MTLE) remained refractory to most antiepileptic drugs (Semah et al. 1998). There is however a subset of patients with drug resistant IGE. In a study conducted in 155 patients with newly diagnosed JME, Gelisse et al. reported that 10% continued to suffer seizures despite adequate therapy and lifestyle (Gelisse et al. 2001). Unfortunately, they could not find any significant prognostic factor of drug resistance in that population (Gelisse et al. 2001). In patients with partial epilepsy, response to treatment might evolve over time, with approximately half of refractory patients who will develop drug resistance after at least five years of treatment (Berg et al. 2003). When looking at the prognostic criteria of intractability hitherto described, such as age at onset, remote symptomatic epilepsy, status epilepticus, focal EEG abnormalities, abnormal CT scan or MRI, Todd’s paralysis, complex partial seizures, and an abnormal neurological examination (Cockerell et al. 1997, Berg et al. 1996, Berg et al. 2001), one could conclude that most of these predictors reflect the presence of a symptomatic or cryptogenic epilepsy. Accordingly, in a large prospective hospital-based study conducted in 2200 patients, we found that the chance of being seizure-free significantly depended on the epileptic syndrome, i.e. 82% in idiopathic generalized epilepsy, 45% in cryptogenic partial epilepsy, and 35% in symptomatic partial epilepsy (Semah et al. 1998).

Role of the etiology of partial epilepsy

A few studies have focused on this issue, showing a clear relationship between the etiology of the epilepsy, or of the associated brain lesion, and the likelihood of seizure control with AEDs (Semah et al. 1998, Semah et al. 2002, Stephen et al. 2001). These findings largely rely on the development of MRI, accounting for the fact that studies performed prior to the systematic use of optimal MR images did not find correlation between the etiology and the prognosis of partial epilepsy (Hauser et al. 1998). Results from our own serie suggested that the prognosis of partial epilepsy was more closely related to the type of lesion than to the lobar localization of the epileptogenic zone (Semah et al. 1998). Drug resistance was observed in 97% of patients with HS and an associated malformation of cortical development (MCD) in the temporal lobe, 89% of patients with HS only, 76% of those with MCD only, 65% of patients with brain injury, 50% of those with a vascular malformation, and only 46% of patients with post-stroke epilepsy. In patients with TLE and isolated hippocampal abnormalities, those with HS were more likely to develop drug resistance than those with hippocampal malformations (Semah et al. 2002). Another study of 550 adult patients with epilepsy, including 43% with recurrent seizures, demonstrated the same findings (Stephen et al. 2001). HS and MCD were associated with the poorest prognosis, with 58% and 46% rates of drug resistance, respectively, followed by tumor (37%), stroke (33%), and arteriovenous malformations (22%). Van Paesschen and colleagues also clearly showed that patients with newly diagnosed epilepsy and HS had a worse prognosis than those with other MRI abnormalities or normal findings (Van Paesschen et al. 1997). Some isolated case reports also suggest that the type of MCD influences the prognosis of epilepsy but this needs to be confirmed by controlled studies. For instance, seizures associated with focal cortical dysplasia and dysembryoplasic neuroepithelial tumors seem to be more difficult to control than those symptomatic of other malformations, such as heterotopia. In line with the results of previous series, patients with post-stroke epilepsy were found to present a two fold higher rate of 5 years-remission than patients with brain tumors (Cockerell et al. 1997). In a recent series of 581 stroke patients aged 18 to 55, including 20 with a first late seizure, only 11 experienced seizure recurrence while on AED treatment, most of whom became eventually seizure free (Lamy et al. 2003).

Role of the localization of the epileptogenic zone

In our study conducted in 2200 patients, those with TLE were more frequently drug-resistant than patients with frontal, occipital or parietal lobe epilepsy (Semah et al. 1998). However, multivariate analysis showed that the main predictor of intractability was the presence of hippocampal sclerosis, rather than the temporal lobe origin of seizures per se.

Role of the initial response to AED

An accurate prediction of intractability is probably easier to perform a few months after the initiation of treatment than at the time of the first visit, due to additional available data regarding the type and aetiology of the epileptic syndrome, as well as the efficacy of the first AED. Indeed, a recent study in children has demonstrated that failure to respond to the first antiepileptic drug predicts the development of refractory epilepsy (Dlugos et al. 2001). The large National General Practice Study of Epilepsy (NGPSE) in the UK has also shown that one of the major prognostic factor was the number of seizures in the early months after presentation (MacDonald et al. 2000). In addition, some authors have suggested that the time elapsing between the onset of epilepsy and the first treatment, as well as the number of seizures before treatment, predicted the development of drug resistance (Hauser et al. 1998, MacDonald et al. 2000). However, these data remain controversial. In a study including 479 children in Nova Scottia, Camfield et al. reported that the number of seizures before treatment, if less than 10, did not influence the chance of seizure control (Camfield et al. 1996).

Two large controlled studies have also demonstrated that introducing AED treatment after the first or the second seizure resulted in similar rates of long term seizure freedom (Musicco et al. 1997, Marson et al. 2005). Thus, early treatment does not seem to influence the prognosis of epilepsy, but response to first AED helps to predict the risk of further drug resistance.

Potential role of genetic predictors

Despite the sporadic and non idiopathic origin of the majority of refractory epilepsies, genetic susceptibility factors might participate to the development of this condition. In particular, gene polymorphisms could explain why apparently similar brain lesions will result in the development of drug resistance in some patients, but not in others. Two gene polymorphisms have been associated with AEDs refractoriness. They involve the GABAB receptor and the glycoprotein P170 (Pgp or MDR1 for multi-drug-resistance protein 1), respectively (Gambardella et al. 2003, Siddiqui et al. 2003). Regarding the GABAB receptor, an A/G polymorphism at position 1465 is responsible for a Gly489Ser substitution in a highly conserved region of the receptor, which thus might have functional consequences. Gambardella et al. reported that 17% of TLE patients have an A/G genotype, versus only 0,5% in their normal population (Gambardella et al. 2003). In addition, the A/G genotype was associated with a 6,47 odds ratio for developing drug resistance in this study (Gambardella et al. 2003). However, these findings could not be replicated in three recent independent studies (Ma et al. 2005, Tan et al. 2005, Salzmann et al. 2005). Regarding the Pgp gene, or ABCB1 gene (for ATP binding cassette subfamily B 1 gene), most studies have concentrated on the 3435C-T polymorphism, though other genetic variants were also described (1236C-T, 2677G-T). The 3435C-T polymorphism is silent, but associated with higher level of Pgp expression in various cell lines (enterocytes, CD56+). A C/C genotype at position 3435 was found to be associated with higher risk of drug resistance in two studies (Siddiqui et al. 2003, Zimprich et al. 2004), but again, this result could not be replicated in two other series (Tan et al. 2004, Sills et al. 2005). Thus, alike in many other fields, studies of gene polymorphism have yet failed to provide consistent results regarding the genetic susceptibility to develop refractory epilepsy. This remains however an exciting field of research which might proved fruitful in the future.