2006 overview: Key messages from the epilepsy literature

The year coming to an end yielded a number of important contributions in the epilepsy field. The following is a selection of findings on topics which are likely to be of particular interest to clinicians.

Advances in the Genetics of Epilepsy
Molecular genetics is contributing greatly to advancing our knowledge on the pathophysiology of many diseases, and epilepsies are no exception. Last year's overview focused on developments in pharmacogenomics. An update is now due on progresses made in elucidating genetic factors which involved in the etiology of epilepsies. 

Unravelling the genetic architecture of idiopathic epilepsies
Idiopathic partial and generalized epilepsies are characterized by recurrent unprovoked partial or generalized seizures in the absence of associated mental or neurological impairment and detectable brain lesions or metabolic abnormalities (ref. 1). Although these epilepsies are known to be genetically determined, elucidation of the genes involved in their etiology has proved to be more complex than originally thought (ref. 2).

Molecular genetic approaches did identify causative gene mutations in monogenic forms of  idiopathic epilepsies, such as autosomal dominant temporal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, benign familial neonatal convulsions, and generalized epilepsy with febrile seizures plus (ref. 2, ref. 3, ref. 4, ref. 5, ref. 6).

However, these disorders, which mechanistically turned out to be mostly channelopathies, affect collectively only a small subgroup of people with idiopathic epilepsies, and no common gene variant has been identified that impact substantially on the etiology of common idiopathic epilepsies that display a complex pattern of inheritance. It is now clear that the etiology of these epilepsies involves a large number of susceptibility genes.

A collaborative network of investigators from 7 countries explored the genetic architecture of idiopathic generalized epilepsies by performing genome-wide linkage scans in 126 families of European origin ascertained through a proband with idiopathic absence epilepsy or juvenile myoclonic epilepsy (ref. 8). Linkage analyses were conducted in family subgroups segregating either typical absence seizures or myoclonic and generalized tonic-clonic seizures on awakening.

The study provided evidence for complex and heterogeneous architectures involving linkage signals at 5q34, 6p12, 11q13, 13q22-q31, and 19q13. The composition of signal patterns differed in relation to the predominant seizure type in the families, with determinants on 11q13 and 13q22-q31 predisposing sequentially to absence seizures, and determinants on 5q34, 6p12 and 19q13 being preferentially associated with myoclonic and generalized tonic-clonic seizures on awakening.

Overall, these results suggest that the genetic substrate of the most common idiopathic generalized epilepsies is more complex and heterogeneous than initially expected. Similarly, an international study which assessed phenotypic concordance in homozygous and dizygous twins for another form of idiopathic epilepsy, benign rolandic epilepsy, came to the conclusion that for this condition "etiology and mode(s) of inheritance ... are much more complicated than initially conceptualized" (ref. 9).

Complexities in linking genes to function: Severe Myoclonic Epilepsy of Infancy (SMEI) as an example
SMEI (Dravet syndrome) is a severe disorder characterized by recurrent prolonged seizures typically beginning in the first year of life, followed by intractable epilepsy, psychomotor impairment and, at times, ataxia and other neurological abnormalities (ref. 10). Since the original report by Claes et al. (ref. 11 ) linking SMEI to de novo mutations in the sodium channel coding gene SCN1A, there has been an explosion of information on the genetics of this disorder.

The emerging data  illustrate how complex pathophysiological mechanisms can be, even for a disorder which appears to be monogenic in nature (ref. 12).

More than 100 mostly de novo mutations of the SCN1A  have now been identified in probands with SMEI (ref. 13, ref. 14). Some of the mutations are predicted to cause premature truncation of the sodium channel protein, suggesting that they will produce non-functional alleles. However, about one third of mutations are missense with no predictable effects on channel function.

To better understand the functional implications of these alterations, Ohmori et al (ref. 14) have completed the functional characterization of eight SMEI-associated SCN1A mutations, using heterologous expression of recombinant human SCN1A. Six of the mutants were non-functional, but two generated measurable sodium channel activity.

The authors suggest that SCN1A mutations associated with SMEI can be divided into two categories, functional and non-functional. In rare instances, the mutated channel may even exhibit an increased persistent sodium current. The mechanisms by which these remarkable functional differences can result in a relatively homogeneous phenotype remain to be elucidated.

While most cases of SMEI are sporadic and attributable to de novo mutations, familial cases have also been reported. At least three separate reports in 2006 described mosaic SCN1A mutations in familial cases of SMEI (ref. 15, ref. 16, ref. 17). A review of the available data highlights the importance of investigating parental mosaicism even in sporadic SMEI cases.

Different mutations of the nicotinic receptor gene cause different types of sleep-related epilepsies
A careful study identified a large pedigree segregating sleep-related epilepsy in which seizures  are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep walking (ref. 18). The condition appears to be caused  by a heterozygous missense mutation in the first transmembrane domain of the neuronal cholinergic nicotinic receptor alpha 2 subunit gene (CHRNA2).

Electrophysiological studies in cells expressing either the mutant or the wild-type receptor showed that the newly discovered mutation markedly increases the sensitivity of the receptor to acetylcholine. Since previous studies had shown that another form of sleep-related epilepsy, autosomal dominant nocturnal lobe epilepsy (ADNFLE), is associated with mutations of the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor, CHRNA2 appears to be the third nicotinic receptor gene associated with familial sleep-related epilepsies.

Compared with the CHRNA4 and CHRNB2 mutations associated with ADNFLE, CHRNA2 mutations appear to cause a more complex and finalized ictal behavior. This new type of epilepsy should be considered in the differential diagnosis between sleep related epilepsies and parasomnias.

Post-vaccine encephalopathy or genetically determined epilepsy?
One of the most intriguing findings reported in 2006 in the field of epilepsy genetics came from a retrospective but careful study of 14 patients with alleged vaccine-induced encephalopathy and epilepsy in whom the first seizure occurred within 72 h of vaccination (ref. 19). Mutations in in the SCN1A gene were identified in all 8 cases with phenotypes of SMEI and in 3 of 4 with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome.

In the 11 patients with SCN1A mutations, the mutations predicted truncation of the protein in 5 cases, while the other cases had missense mutations in conserved regions of the molecule. For 9 cases in whom parenteral DNA could be assessed, mutations arose de novo. These data suggest that many cases of alleged vaccine encephalopathy may in fact be a genetically determined epileptic encephalopathy which arose de novo. As pointed out by the authors, these findings, if confirmed in other cohorts, could have major societal implications for the general acceptance of vaccination.

Epilepsy and Depression: An Underestimated Comorbidity
Many studies have shown that major depression is a common comorbidity in epilepsy. It was found to occur in >30% of patients in a comunity-based study (ref. 20) and in 20-55% of patients in tertiary referral clinics (ref. 21, ref. 22, ref. 23). Recent findings confirmed (ref. 24, ref. 25) earlier reports that depression correlates strongly with quality of life in people with epilepsy (ref. 26, ref. 27). Therefore, its recognition and management should be part of  the routine standard of care in epilepsy clinics.

Etiological factors
Many factors can contribute to depressed mood in people with epilepsy. These include the medical and psycho-social impact of having seizures, the physical disabilities associated with various types of epilepsy (ref. 28), a probable common pathophysiological mechanism predisposing to depression and to some forms of epilepsy, particularly temporal lobe epilepsy (ref. 29, ref. 30) and, finally, the potential ability of some antiepileptic medications to cause depression (ref. 31).

In a recent  study in adults with epilepsy assessed at a specialized referral center, 100 out of 203 patients (49.2%) were found to suffer from concurrent depression, which was severe in 76 cases (37.4%) (ref. 32). Significant risk  factors for depression in this population included  complex partial seizures and absence of secondary generalized tonic-clonic seizures, treatment with clonazepam, frequent hospitalizations (drug resistance) and lack of occupational and social activity.

Most studies on the comorbidity of epilepsy and depression did not assess the temporal relationship of the two disorders. Increasing evidence, however, suggests that in some patients depression pre-dates the onset of a seizure disorder. In a population-based study from Sweden that included 83 adults with incident unprovoked seizures and 130 control subjects, a history of depression was found to be associated with a 7-fold increase in risk of developing unprovoked seizures (ref. 33).

A similar population-based case-control study from the U.S. also found that prior depression was 4-fold more common among 145 adults with incident unprovoked seizures than in 290 controls. These findings have now been confirmed and supplemented by a larger population-based study in Iceland that included both adults and children older than 10 years (ref. 29). The 324 cases were matched to the next two same-sex births from the population registry.

There was a 1.7-fold increase in the occurrence of a positive history of major depression  among cases compared with controls. More interestingly, a history of attempted sucide was 5.1-fold more common among cases than among controls, and the statistical significance of this association persisted after adjusting for several other variables, including cumulative alcohol intake, major depression and number of symptoms of depression.

The authors concluded that depression and attempted suicide are independent risk factors for unprovoked seizures. Overall, these data are consistent with the suggestion that there may be a common neurochemical abnormality leading to the occurrence of epilepsy and depression. Since many antidepressant drugs reduce seizure threshold (ref. 35), use of antidepressants may also contribute to the higher susceptibility to seizures among people with a history of depression.

Screening for depression in people with epilepsy
The comorbidity of epilepsy and depression is underestimated because, contrary to all recommendations, depression is not routinely assessed in neurology clinics (ref. 36). A novel screening tool for epilepsy-associated depression, the Neurological Depression Inventory for Epilepsy (NDDI-E), has been developed (ref. 37). This tool, which is discussed in detail in one of the 2006 CNSForum Commented Articles, appears  to have a number of advantages:

1. it is simple, being based on a brief set of symptoms;
2. its positive predictive value, sensitivity and specificity compare favorably with other available instruments for people with epilepsy, such as the Beck’s Depression Inventory (BDI) and the Center for Epidemiological Studies Depression Scale (CES-D);
3. unlike the BDI and the CES-D, it  does not include common adverse effects of  antiepileptic drugs which mimic symptoms of depression.

Experience with the use of this instrument, however, is limited, and further data are needed to fully assess its value.

Preventing depression in adolescents with epilepsy
In a pilot study from Serbia, 30 adolescents with newly diagnosed epilepsy found to be at risk for depression at screening were randomized to a cognitive-behavioral intervention or to treatment with counseling as usual (ref. 38). After a 9-month follow-up, subthreshold depressive disorder was found to be significantly improved in the intervention group compared with the "counseling as usual" group. These data reinforce the value for careful assessment of depression and risk for depression in people with newly diagnosed epilepsy.

Antiepileptic drugs and depression
Antiepileptic drugs differ in their ability to influence mood (ref. 31). Some drugs, such as barbiturates, tiagabine, and vigabatrin, are more frequently associated with depressed mood. Conversely, among newer generation anticonvulsants, lamotrigine has been associated in some studies with a relatively favorable effect on mood. The latest of these studies was a secondary analysis of a randomized, double-blind, placebo-controlled in 70 patients with primary generalized tonic-clonic seizures (ref. 39).

Overall, the findings suggested that lamotrigine may improve mood symptoms independently of seizure reduction. These data, however, require confirmation in a controlled trial specifically focused on mood effects in epilepsy patients with comorbid depression.

Interactions between Oral Contraceptives and Antiepileptic Drugs: New Data
A recent study looked at potential effects of lamotrigine on the kinetics of an oral contraceptive (ref. 40). Lamotrigine (300 mg/day) was found to decrease moderately the serum concentration of levonorgestrel, but not that of ethinylestradiol. Whether the magnitude of interaction is sufficient to impair the efficacy of the contraceptive is unclear, but this possibility cannot be excluded. It is also unclear whether the same interaction will occur at lower dosages of lamotrigine.

While the effect of antiepileptic drugs on the pharmacokinetics of oral contraceptives is mostly known (ref. 41),  the potential effects of contraceptive steroids on the pharmacokinetics of antiepileptics has been little investigated. Separate studies have now demonstrated that combined contraceptive steroids can stimulate markedly lamotrigine metabolism, particularly in patients on lamotrigine monotherapy, resulting in a reduction of serum lamotrigine levels by 50% or more (ref. 40, ref. 42, ref. 43, ref. 44).

Interestingly, this interaction does not appear to occur (or is greatly reduced) in women receiving lamotrigine in combination with valproate. Valproate also reduces the extent of stimulation of lamotrigine metabolism which takes place during pregnancy (ref. 44).
The reduction in serum lamotrigine levels by combined contraceptive steroids may result in loss of seizure control when women stabilized on lamotrigine are started on a contraceptive, or in adverse effects when the contraceptive is discontinued (ref. 42).

The interaction follows a biphasic pattern, with a gradual decrease in serum lamotrigine levels during the 21 days of contraceptive intake and a rebound increase in lamotrigine levels during the 7-day contraceptive-free interval (ref. 40, ref. 43). The stimulation of lamotrigine metabolism by contraceptive steroids seems to be caused by the estrogen component, which acts as inducer of the enzymes responsible for glucuronide conjugation (ref. 45).

Valproic acid is also partly metabolized by glucuronidation, and two preliminary reports suggest that serum valproic acid levels may also be decreased by co-administration of contraceptive steroids (ref. 46, ref. 47).
 
More Guidelines
The year coming to an end saw the publication of  the much awaited therapeutic guidelines by the ad hoc  Subcommittee of the Commission on Therapeutic Strategies of the International League against Epilepsy (ref. 48). The term "guidelines" for this work is rather misleading. The document  is not a guide to treatment choices – instead, it is a rigorous assessment of the quality of the evidence concerning the efficacy and effectiveness of antiepileptic drugs in newly diagnosed epilepsy.

For this reason, the drugs which are given the highest grade in this document are not necessarily those with the best efficacy and effectiveness - they are simply those with the best evidence for efficacy and effectiveness.

As discussed in more detail in the relevant CNSForum Commented Article, the major usefulness of the work is in highlighting the paucity of well designed trials in this area: out of 50 randomized trials, only 6 provided Class I or II evidence based on a reasonable set of criteria. Because there are no fully objective criteria to rate adverse effect profiles, these were not addressed in the guidelines.

Yet, they are a major consideration in chosing antiepileptic drugs in everyday's practice. As acknowledged in the guidelines, "it must ultimately remain for the individual physician to use his judgement and expertise when deciding on the most appropriate antiepileptic drug for a specific patient … This document is only the first attempt to create a working framework rather than a rulebook about the treatment of new onset epilepsy."

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