2004 overview: Key messages from the epilepsy literature

In this overview Professor Emilio Perucca, Italy, discusses some of the issues in epilepsy that attracted special interest in 2004.

Epilepsy continues to be a hot topic for research: typing "epilepsy" into Pubmed brings up over 3,000 publications in the first 11 months of 2004. Many of these are important contributions in areas as disparate as molecular biology, genetics, pharmacology, neurophysiology, imaging, epidemiology, semiology, neurosurgery, therapeutic stategies, and outcome assessment. The following is a selection of key findings in three areas where research has been particularly active.

EPILEPSY AND LIFE EXPECTANCY

It is widely appreciated that epilepsy is associated with seizure-related mortality, including SUDEP (sudden unexpected death in epilepsy), and, partly as a result of this, overall mortality rates in people with epilepsy are 2-3 times higher than in the general population (ref. 1). The prospective, population-based UK National General Practice Study of Epilepsy has now provided an estimate of life expectancy for people with newly diagnosed epilepsy (ref. 2).

The study found that idiopathic/cryptogenic epilepsy is associated with a reduction in life expectancy of up to 2 years, whereas in symptomatic epilepsy the reduction can be up to 10 years. The greatest reduction in life expectancy is found at the time of diagnosis, and tends to diminish with time.

One weakness of this study is that there was no breakdown of mortality risk associated with the various syndromes: these have widely different outcomes in response to therapy, and some seizure types (most notably absences) have not been shown to be associated with increased mortality.

Increased seizure-related autonomic activity

Much research is now focusing on the mechanisms of SUDEP, because their elucidation could be critical for prevention. In refractory epilepsy, the incidence of SUDEP has been estimated to be as high as 1:200 to 1:300 person-years (ref. 3). Risk factors include young adult age, refractory epilepsy, tonic-clonic seizures, mental retardation, multiple antiepileptic drug (AED) therapy, and low blood AED levels.

A recent study has shown that patients who die of SUDEP exhibit, in the years preceding their death, an increased seizure-related autonomic activity (ref. 4), which could make them at high risk for deadly arrhythmias. These patients show a particularly marked increase in heart rate during seizures arising from sleep, an important observation given the high incidence of SUDEP during sleep.

Important areas for investigation

Although the study had methodological limitations (limited sample size, less than perfect comparability of patient and control groups, possible spurious findings arising from multiple comparisons), it does point to important areas for investigation.

Since the data suggest that seizure clusters occurring during sleep in a young person may be particularly dangerous, treatment strategies aimed at suppressing nocturnal seizures and clusters could be effective in reducing the risk of SUDEP.

Cardiac arrhythmias

In another study, the potential contribution of AEDs to cardiac arrhythmias was explored by looking at QTc intervals in 178 AED-treated children with epilepsy and 26 controls. There was no evidence that the AEDs most frequently used in this group (valproate, carbamazepine, oxcarbazepine and topiramate) adversely affected QTc, but the study had low statistical power due to the small size of subgroups (ref. 5).

Evidence that SUDEP could be linked to cardiac arrhythmias has led to speculate that dietary supplementation with omega-3 fatty acids could reduce seizure-related mortality (ref. 6).

Omega-3 fatty acids have been shown to reduce cardiac arrhythmias in animal studies, and to reduce sudden cardiac deaths in healthy subjects and in survivors of myocardial infarction.

A large scale study would be required to test whether SUDEP can also be reduced. The interest in such study is compounded by the fact that omega-3 fatty acids have anticonvulsant properties in animal models, and were associated with reduced seizure frequency and severity in a small clinical study (ref. 7).

The latter, however, was uncontrolled and the improvement found could be explained by regression to the mean or other confounders.

No mortality related directly to seizures

One of the few good news in this area came from a Finnish population based-study that for 2 years followed up on 86 children with convulsive seizures lasting more than 5 minutes (ref. 8). There was no mortality related directly to the acute seizure episodes; the most common sequela was epilepsy (22%), and permanent neurological sequelae were noted in only four patients (2.2%; mean seizure duration 16 minutes). The study could not clarify the role of acute seizures in the evolution of epilepsy.

AED AND PREGNANCY: MORE CLOUDS OVER VALPROATE

Compared with healthy women, women with epilepsy treated with AEDs show a 2- to 3-fold increase in the risk of giving birth to a child with major malformations. Although this increase in risk is ascribed largely to AEDs, the possible contribution of epilepsy-related factors needs to be considered.

To determine if epilepsy per se represents a teratogenic risk, a metanalysis of 10 studies was conducted to compare major malformation rates among children of treated (n=1443) or untreated (n=400) women with epilepsy and non-exposed non-epileptic controls (n=5018) (ref. 9).

No evidence for increase in risk

There was no evidence for a significant increase in risk of major malformations for the offspring of women with untreated epilepsy compared with non-epileptic controls: in fact, a moderate and non-statistically significant increase in risk (OR 1.92, 95% CI 0.92-4.00) ceased to be present after removal of publication bias (OR 0.99, 95% CI 0.49-2.01).

The offspring of AED-treated women, conversely, had higher malformation rates than controls (OR 3.26; 95% CI 2.15-4.93).

Although the authors concluded that their findings do not support the commonly held view that epilepsy per se represents a teratogenic risk, the untreated epileptic women included in this analysis were a pre-selected group with a milder form of the disease, and these conclusions may not necessarily apply to more severe forms of epilepsy, including those associated with uncontrolled seizures.

Uncertainties exist

Although an adverse effect of AEDs on fetal outcome is established, uncertainties exist as to which AED is most teratogenic and which, if any, can be regarded as safe. Preliminary findings from the North American and the UK Pregnancy Registries, together with the most recent cohort studies, suggest that teratogenic risk is higher with valproate than with other AEDs (ref. 10).

The latest study utilized data from the Swedish Medical Birth Registry to assess congenital malformation rates in infants exposed to valproate (n=264) and carbamazepine (n=703) monotherapy during early pregnancy (ref. 11 ).

The OR for congenital malformations in the valproate-exposed group compared with the carbamazepine-exposed group was 2.51 (95% CI 1.43-4.68), indicating that exposure to valproate carried a higher risk than exposure to carbamazepine.

These findings, however, like those from previous studies, need to be interpreted with great caution because none of the studies performed so far has assessed adequately the role of possible confounders such as the type of epilepsy, family history of birth defects, and exposure to other risk factors.

With time, this information will eventually become available from data from ongoing large pregnancy registries (ref. 10), including EURAP.

Registry data

Ultimately, pregnancy registries should also provide critical information on the relative risk associated with newer generation AEDs. At present, the only new generation AED for which more than trivial information is available is lamotrigine.

Small scale studies sending reassuring messages on this drug (ref. 12) are not doing a service to the medical community, as the confidence limits of such findings are too wide to allow any conclusion.

Registry data containing larger numbers of pregnancies exposed to lamotrigine monotherapy suggest a malformation rate lower than that reported for valproate, but comparable to that reported for carbamazepine and other older generation AEDs (ref. 10). The confidence limits of these estimates, however, are also relatively large, making these observations only preliminary.

Lamotrigine

Lamotrigine is now widely prescribed as a first line agent in women of childbearing potential, and its use has been further encouraged by guidelines such as those issued by the UK National Institute for Clinical Excellence (ref. 13, ref. 14). Recent findings, however, suggest that lamotrigine's profile may be less woman-friendly than originally thought.

Contrary to earlier reports stating that lamotrigine does not interact with oral contraceptives, a recent study, summarized in a manufacturer's "Dear Doctor Letter" issued in European countries in later 2004 found that lamotrigine, 300 mg/day, reduces by about 20% the blood levels of levonorgestrel and modifies the hormonal response to steroid oral contraceptives.

Whether lower dosages of lamotrigine also affect the pharmacokinetics of steroid oral contraceptives is unclear. There is also a reverse interaction, in that oral contraceptives increase lamotrigine clearance and reduce blood lamotrigine levels by more than 50% (ref. 15), with a rebound two-fold increase in lamotrigine levels during the week in which the contraceptive is not taken (Lamictal, Summary of Product Characteristics, 2004).

Finally, a major decrease in blood lamotrigine levels occurs during pregnancy, potentially complicating clinical management (ref. 16).

Children's IQ scores

Teratogenic risk is not the only concern for women taking AEDs during pregnancy. An earlier retrospective study from the U.K. found that children exposed in utero to valproate required additional educational aid more frequently than children exposed in utero to carbamazepine (ref. 17).

These findings have been reinforced by two recent studies, one from Finland (ref. 18) and the other from the UK. (ref. 19). In the Finnish study, which was prospective, verbal and nonverbal IQ scores in children exposed in utero to carbamazepine monotherapy did not differ from unexposed control subjects, whereas significantly reduced verbal IQ scores were found in children exposed to valproate and to polytherapy.

An independent effect of valproate, however, could not be confirmed in this study because results were confounded by low maternal education and polytherapy. In the UK study, which was retrospective, verbal IQ was lower in children exposed in utero to valproate than in unexposed control children or children exposed in utero to carbamazepine or phenytoin.

Not conclusive

Again, the latter results cannot be regarded as conclusive (ref. 20) because of potential bias associated with the retrospective design, the lack of details about critical variables (e.g., paternal IQ, parental ethnic group, gestational age of probands, etc.) and the intriguing nature of some findings, particularly the observation that children exposed to carbamazepine tended to have a higher verbal IQ than unexposed controls (a more detailed discussion of this study was presented in the November update of CNSforum).

Well designed prospective studies are sorely needed to determine whether in utero exposure to valproate and/or other AEDs does affect postnatal mental devopment, and the practical relevance of any such effect on long-term outcome. Unfortunately, an answer to these concerns is not likely become available until some years from now.

NEWEST AEDs

The new generation of AEDs has enlarged our options for the management of epilepsy, allowing for improved tailoring of drug therapy. However, the contribution of these drugs to solving the plague of drug resistant epilepsy has been modest. Research into development of newer AEDs is continuing, even though recognition of difficulties involved in rational AED discovery and increasing development costs are hampering much needed investment into this area.

Pregabalin

Pregabalin is the newest addition to the antiepileptic armamentarium, having been licensed in 2004 in some European countries as adjunctive treatment for refractory partial onset seizures, with or without secondary generalisation.

Pregabalin shares the same action as gabapentin in that it modulates neuronal excitability through an interaction with the alpha2-delta recognition site of P/Q and N calcium channels (ref. 21).

It also shares with gabapentin a renal, non-metabolic route of elimination, and the lack of pharmacokinetic drug interactions. Pregabalin differs from gabapentin in having greater affinity for the alpha2-delta site and a virtually complete oral bioavailability.

This results in better access to the site action, and may explain why pregabalin produced higher response rates than gabapentin in placebo-controlled adjunctive therapy trials in refractory partial epilepsy.

The latest of the published trials demonstrated pregabalin's efficacy at doses of 150 and 600 mg/day (ref. 22). Seizure reduction rates were 20.6% and 47.8% at the lower and at the higher dose respectively, compared with a 1.8% increase in the placebo group.

Dose-related adverse events, which included somnolence, dizziness, ataxia, diplopia, and weight gain, led to withdrawal in 10% of patients at 150 mg/day and 18.5% of patients at 600 mg/day, compared with 6.2% on placebo.

Conference on new AEDs

Potential drugs at earlier stages of development were discussed at the VII Eilat Conference on New AEDs which took place in Villasimius, Italy from 9th to 13th May, 2004.

A summary of the latest information on BIA-2-093 , fluorofelbamate, retigabine (D-23129), safinamide, SPM 927, stiripentol, talampanel, ucb 34714 and valrocemide (TV 1901) is provided in the conference proceedings (ref. 23).

Data are still insufficient to make a qualified judgement on any of those compounds, though some have produced encouraging preliminary results.

Ultimately, a truly major breakthrough will emerge when a trial will have to be stopped because so many refractory patients become seizure free as to make continuation oif placebo treatment no longer ethical. This scenario, regrettably, has not yet materialized in any of the trials conducted to date.

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