2005 overview: Key messages from the epilepsy literature

2005 yielded a number of important contributions in the epilepsy fiend. The following selection deals mostly with topics falling within my special areas of expertise.

A new and controversial definition of epilepsy

The International League against Epilepsy (ILAE) and the International Epilepsy Bureau (IBE) came up with new definitions of epileptic seizures and epilepsy (ref. 1). They now define an epileptic seizure as "a transient occurrence of signs and/or symptoms due to abnormal excessive and synchronous neuronal activity in the brain", and epilepsy as "a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological and social consequences of the condition".

While the definition of an epileptic seizure is congruent with that which has been in use for decades, the proposed definition of epilepsy is not, and represents a deviation from the previous, almost universally accepted definition of epilepsy as a condition characterized by recurrent unprovoked seizures (ref. 2). 

Hot debate

The new definition has sparkled a hot debate (ref. 3; ref. 4; ref. 5). Many experts object to provoked seizures (e.g., febrile seizures, acute symptomatic seizures, single unprovoked seizures) qualifying for a diagnosis of epilepsy, and they are reluctant to accept that a single seizure may be sufficient for diagnosis.

There are also queries on how an enduring predisposition to generate epileptic seizures should be defined. Arguably, the best operationally workableindication of an enduring predisposition would be the occurrence of a second unprovoked seizure, a requirement which would bring us back to the earlier definition and diagnostic criteria. Including associated medical and social conditions in the definition of epilepsy has also been questioned.

Implications

Concern has been voiced that the new definition will lead to reclassify as epilepsy many situations previously not considered to be epilepsy. It has been estimated that this may lead to a three-fold increase in the incidence of the disorder and an even greater increase in prevalence, with potential adverse consequences in terms of exposure of people to stigma, life restrictions and, perhaps, inappropriate management (ref. 2).

Although a response to these concerns has been given (ref. 6), the debate is likely to continue. The most likely outcome is that in the future more than one definition will be used, depending on context and objectives. This would be a sensible development, though the concurrent use of different definitions is potentially a source of confusion.

Pharmacogenomics coming of age?

It has been known for a long time that variability in drug response can be affected markedly by genetic influences (ref. 7). For most of the past decades, research in this area has been limited to the effects of mutations in individual genes on drug kinetics and response (the so-called discipline of pharmagenetics).

It is only lately that advances in medical genetics led to the birth of pharmacogenomics, i.e. the science which explores and describes the relationship between the whole genome and the pharmacology of specific drugs. Compared with other therapeutic areas, pharmacogenomics has not yet impacted on epilepsy therapy, but this is likely to change in the future. 

Genetic influences on antiepileptic drug (AED) metabolism

The activity of drug metabolizing enzymes is under genetic control, and genetic polymorphisms exist for all the major phase 1 and phase 2 enzyme systems, including the cytochrome P450 (CYP) family of mixed function oxidases, N-acetyltransferases, sulfatases, glucuronidases, and glutathione synthetase (ref. 8; ref. 9).

Although the majority of these polymorphic enzymes do not play a major role in AED metabolism, there are exceptions, the most notable being the CYP2C9 and CYP2C19 enzymes. About 2-5% of Caucasians and 18-23% of Chinese and Japanese exhibit deficient CYP2C19 activity, and metabolize CYP2C19 substrates such as mephenytoin and mephobarbital at a slower rate, resulting in reduced dosage requirements for these drugs (ref. 9).

A similar metabolic defect has also been described for phenytoin, which is a substrate of two genetically polymorphic enzymes (CYP2C9 and CYP2C19). Subjects carrying defective alleles for CYP2C9 and, to a greater extent, those with defective alleles for both CYP2C9 and CYP2C19 eliminate phenytoin at a slower rate (ref 10; ref. 11), and the importance of this for endpoints of clinical responsiveness has been demonstrated (ref 11; ref. 12).

Evidence for the importance of the CYP2C9 genotype in affecting phenytoin response was reinforced by a recent pharmagenomic study which demonstrated a significant association between the presence of the CYP2C9*3 allele and reduced phenytoin dose requirements in 281 patients with epilepsy (ref. 14).

On the other hand, no association has been found in a separate study between CYP2C9 and CYP2C19 genotypes and gingival hyperplasia (ref. 15). 

Idiosyncratic reactions to carbamazepine may be genetically modulated. An association has been described between tumour necrosis factor (TNF) alpha promoter region gene polymorphisms and carbamazepine hypersensitivity (ref. 16).

It has also been suggested that carbamazepine hypersensitivity may be related to mutations in the gene coding for epoxide hydrolase, but early studies failed to provide evidence for the role of any specific mutation (ref. 17; ref. 18).

On the other hand, genetically determined variations in epoxide hydrolase activity do have functional significance in affecting carbamazepine disposition, as shown in a recent Japanese study which identified a relationship between carbamazepine diol/carbamazepine-epoxide ratios and some haplotype structures of the EPHX2 gene (ref. 19). 

Genetic influences on transporter systems

A number of AEDs are transported across the blood-brain barrier, and between cellular and extracellular compartments in the brain, by a variety of transporter proteins, the most extensively studied of which belong to the ATP-binding cassette (ABC) family (ref. 20).

An attractive hypothesis, supported mostly by indirect evidence (ref. 21; ref. 22) holds that increased expression of such transporter proteins, including multiple drug resistance 1 (MDR1) p-glycoprotein, may limit access of AEDs to their site of action in the brain, and thereby represent an important mechanism of drug resistance.

In 2003, a reported association between a polymorphism of the ABCB1 gene, which codes for MDR1, and drug resistance in a population of patients with epilepsy sparkled great excitement in the scientific community (ref. 23). Excitement, however, largely subsided when more recent studies (ref. 14; ref. 24; ref. 25; ref. 26)  failed to report the same association.

In at least one other study, however, an association of ABCB1 gene haplotype with pharmacoresistance was described for a subpopulation with temporal lobe epilepsy (ref. 27).

These controversial findings highlight the difficulties of conducting and interpreting genetic association studies in epilepsy: advantages and limitations of these studies are discussed beautifully by Tan et al. (ref. 28).

Genetic influences on drug targets: A first breakthrough?

In recent years, major advances have been made in understanding the mechanisms responsible for genetically determined epilepsies, and channelopathies have emerged as an important group among such disorders (ref. 29; ref. 30).

Because a large number of AEDs, including carbamazepine, phenytoin and lamotrigine, act primarily by blocking voltage-activated sodium currents, the possibility of mutations in sodium channel genes affecting response to AEDs should be considered.

In that respect, 2005 saw a potentially important breaktrough when Tate et al. (ref. 14) identified a significant association between an intronic polymorphism of the SCN1A gene and maximum prescribed doses of phenytoin in 281 patients and carbamazepine in 425 patients.

In brain surgical specimens from temporal lobe epilepsy patients, this polymorphism disrupts the consensus sequence of the 5’ splice donor site of a highly conserved alternative exon, and affects the proportions of the alternative transcripts. These findings, if confirmed, would represent the first reported genetic association between an AED and a pharmacodynamic target protein, and may herald the beginning of a new era in the pharmacogenomics of epilepsy.

On the other hand, enthusiasm must be tempered, because this study had a number of shortcomings (see commented article May 2005) and left many questions unanswered. Researchers all over the world are busy exploring potential associations between drug response and single nucleotide polymorphisms (SNPs) associated with a variety of AED targets, including sodium, potassium and calcium channels, GABA and glutamate receptors, carbonic anhydrases, synaptic vesicle proteins, and other targets.

Updated lists of such genes, their locus position, number of SNPs and other details have been compiled by Ferraro and Buono (ref. 9).

Update on adverse effects of foetal exposure to AEDS

Although this topic was extensively discussed in the CNSForum December 2004 overview, important new data became available in 2005. An updated and comprehensive review of latest studies has been published very recently (ref. 31).

New registry data: Valproate

Three large pregnancy registries from Finland (ref. 32), North America (ref. 33) and the U.K (ref. 34), in addition to the manufacturer’s lamotrigine registry (ref. 35), have reported their data. Although differences in methodology and results exist, all registries seem to agree on a main finding, i.e. that exposure to valproic acid during the first trimester of pregnancy is associated with a greater risk of major congenital malformations than exposure to carbamazepine and, probably, some other AEDs. An additional important finding is that valproate teratogenicity appears to be dose-related (ref. 31; ref. 32; ref. 34; ref. 36).

Two small scale studies also reinforced concerns about potential detrimental effects of prenatal valproate exposure on postnatal mental development (ref. 37; ref. 38). Intriguingly, one of these (ref. 38) seems to have reported basically the same cases and the same analysis as an earlier article by the same group (ref. 39), which was discussed on CNSforum in November 2004.

New registry data: Lamotrigine

In the manufacturer’s registry, malformation rates after exposure to lamotrigine monotherapy were similar to rates after exposure to lamotrigine in combination with other AEDs not including valproate (ref. 35).

The authors’ conclusion that malformation rates with lamotrigine monotherapy are similar to those expected for the general population are unconvincing, because the methodology used to ascertain and classify malformations in the lamotrigine registry were not fully comparable to those used for the general population studies quoted.

The U.K. registry included monotherapy data for 647 lamotrigine exposures, compared with 900 carbamazepine exposures and 715 valproate exposures (ref. 34). The methodology of this registry is less than ideal, and the fact that in this study the offspring of untreated women with epilepsy had comparable malformation rates (3.5%) to the offspring of many AED-treated groups is intriguing.

Overall malformation rates for lamotrigine exposures were 3.2%, compared with 2.2% for carbamazepine and 6.2% for valproate. Comparison of malformation rates at different dosages of lamotrigine and valproate led to interesting findings, even though due to limited sample size differences between doses were not statistically significant.

With valproate, malformation rates were 4.1% at <600 mg/day, 6.1% at 600-1000 mg/day, and 9.1% at >1000 mg/day, whereas corresponding figures for lamotrigine were 1.3% at <100 mg/day, 1.9% at 100-200 mg/day and 5.4% at >200 mg/day.

The dose relationship reported for lamotrigine is not necessarily indicative of a cause-effect relation, because it cannot be excluded that women on high lamotrigine dosages had more severe seizure disorders which, by themselves, could have affected adversely foetal outcome.

In any case, the observation that the estimated risk with valproate </= 1000 mg/day was similar to that with lamotrigine > 200 mg/day, if confirmed, would have important implications for management decisions.

New registry data: Oxcarbazepine

In the retrospective population-based Finnish registry, there was one case with a urogenital malformation among 99 monotherapy exposures to oxcarbazepine (ref. 32). In another study from Argentina, there was one malformed offspring among 55 oxcarbazepine exposures (35 as monotherapy) (ref. 40).

In a review that included the Argentinian and some of the Finnish data, there were 6 malformations (2.4%) in a total of 248 pregnancies exposed to oxcarbazpine monotherapy and 4 malformations (6.6%) among 61 exposures to polytherapies including oxcarbazepine (ref. 41). These data do not suggest that oxcarbazepine causes higher risk than other AEDs, but the relatively small denominators require caution in interpreting these data.

Management implications

Keeping seizures under control in pregnancy remains an important goal. Among widely used AEDs, valproate appears to be associated with higher risks to the foetus. In one study, a greater risk compared with other common monotherapies was also reported for phenobarbital (ref. 42), though this has not been found in other studies (ref. 31). 

In partial epilepsies, carbamazepine is often the drug of choice and it appears to be safer than valproate (ref. 31). In generalized epilepsies, high-dose lamotrigine may not carry lower teratogenic risks than </= 1000 mg/day valproate. Further data to guide treatment decisions are needed, including more information on additional concerns related to valproate exposure, particularly the possibility of impaired postnatal intellectual development.

An evidence-based approach to AED choice in the elderly?

Major trial completed

The largest randomized double-blind therapeutic trial ever conducted in elderly patients with newly diagnosed seizure disorders has been reported (ref. 43). The trial compared the effectiveness of carbamazepine, lamotrigine and gabapentin in 593 patients aged 60 or older.

In terms of 12-month retention on the allocated treatment, carbamazepine-treated patients did worse than those treated with lamotrigine or gabapentin: this was ascribed to differences in tolerability rather than efficacy, and there were no significant differences in seizure-free rates among drugs.

Unfortunately, the study methodology was less than desirable, due to questionable inclusion criteria (e.g., patients who only had only one seizure could enter, and almost one half-half had been treated previously, mostly with phenytoin, possibly leading to selection bias), use of an immediate-release carbamazepine formulation and, arguably, suboptimal target dosages and titration rates.

Other studies

A superior tolerability of lamotrigine over carbamazepine in the elderly had also been reported in an earlier trial (ref. 44), but again an immediate-release carbamazepine formulation was used. On the other hand, preliminary analysis of a recently completed 40-week European randomized double-blind trial that compared lamotrigine with sustained-release carbamazepine in 184 elderly patients failed to identify differences in seizure freedom rates between the two drugs (ref. 45).

Implications for management

Overall, outcome data from the randomized trials in elderly populations conducted so far could reflect more differences in study design (including choice of formulations and dosing schedules) than actual differences in effectiveness between the different drugs. While this limitation should be kept in mind, available evidence does seem to favour lamotrigine as treatment of choice for epilepsy in new age.

Elderly patients often respond to lower AED doses than younger subjects, and appear to be also more sensitive to adverse drug effects (ref. 46). Better designed comparative trials are needed in these patients, though no such studies are likely to be completed in the near future.

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