We performed a case-control analysis on 418 patients pooled from 2 large prospective studies of new-onset seizures to quantify the extent to which AE reporting as measured by a validated screening instrument, the AEP, can be reliably attributed to AED treatment, and to investigate which variables contribute to the different AEs reported.
In line with prior observations on similar samples,26
we found low AEP scores in individuals newly started on AED treatment. The vast majority of these subjects were taking a single AED at low daily doses. When compared to a control group with new-onset seizures in which AED treatment was withheld, no significant difference was found in the AEP total score or in each of the 6 factor scores. Moreover, a comparison of AEP scores across the 5 most commonly used AEDs and untreated controls did not yield any significant between-group difference. These findings suggest that when an AED is started at low daily doses in patients with new-onset seizures, it is generally well-tolerated. Considering that almost 50% of people with newly diagnosed epilepsy become seizure-free on the first-ever prescribed AED,27
and that more than 90% of these do so at low or moderate doses,25
the desirable goal of epilepsy medical management—“no seizures–no AEs”—may be accomplished in a relevant proportion of patients. These subjects may largely account for those seizure-free individuals who have quality of life ratings similar to the general population.28
Overall, these findings have important implications for better patient counseling regarding initiation of AED treatment.
We identified several variables contributing to AE reporting. Depression emerged as the strongest predictor of worst AEP total scores and worst scores for 3 of 6 factors (cognition/coordination, sleep, and tegument/mucosa), its effect being on average 2-fold greater than that of other predictors. This effect remained after performing the analyses separately on MESS and NMS samples, confirming the strong contribution of depression to AE reporting, which is independent of measures used to assess it. Similar findings have been reported in previous studies using the AEP26,29
or other measures of AEs,30
and may be interpreted as result of a substantial overlapping between epilepsy-associated depression and AED-related toxicity. In fact, some symptoms of depression can be utterly indistinguishable from AEs of AEDs, particularly cognitive impairment and sleep disturbances. In the absence of overt depressed mood, these symptoms may be erroneously attributed to AED treatment, possibly in part accounting for the common failure to recognize and subsequently treat depression in epilepsy.31
This is exceptionally insidious in newly treated epilepsy, where attention typically focuses on AEs rather than the increased risk of depression.32
Therefore, mood assessment should always complement adverse AED effects screening.33
Although compelling evidence exists that pharmacokinetic and pharmacodynamic drug properties are influenced by gender, leading to a higher incidence of AEs in females than in males across a variety of drug classes, including AEDs,34
we found that female gender predicts AE reporting independently of drug exposure. This effect could not be explained by the well-known interaction between female gender and mood dysfunction, as more men in our study were depressed compared to women (9.5% vs 3.4%, p
< 0.05); this is not an unprecedented finding.35
Future research should elucidate potential mechanisms, and whether this association is limited to women with seizures.
Younger age at seizure onset, symptomatic etiology, and a history of febrile seizures impacted negatively on AEP scores. The association between earlier seizure onset age and AE reporting is unclear; it could be related to a higher propensity in younger patients to report subtle adverse experiences. Prior studies described higher rates of AEs in symptomatic epilepsy compared to other epilepsy types, possibly because patients with symptomatic epilepsy usually require higher AED loads.27
However, our findings suggest that CNS insults may lead to neurologic sequelae increasing patients' self-perception of AEs. The effect of history of febrile seizures on worst cephalgia scores is intriguing, particularly in light of recent evidence that certain genotypes, e.g., mutations in the Na+
-ATPase pump gene ATP1A2
, may predispose to febrile seizures, epilepsy, and migraine.36
AE reporting increased with the increasing number of prior seizures, and for AEP total, cognition/coordination, and sleep scores, this effect was more pronounced in subjects taking AEDs than in untreated controls. These findings reinforce existing evidence on the deleterious consequences of seizure recurrence,37,38
and suggest that more severe brain dysfunction associated with the increasing number of seizures may predispose to greater AED-related toxicity.