This international study investigated caregiver perspectives on ASMs used by 399 children and adults with CDD registered in the ICDD by 2022. The most common of the 23 unique ASMs used were levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam. The median age of first use for medications varied, with phenobarbital, levetiracetam and steroids/ACTH being used earliest, and lamotrigine and clobazam later. Cannabidiol was reported as highly beneficial with few side effects, while vigabatrin, sodium valproate, and lamotrigine were also beneficial but had some side effects. Polytherapy, such as sodium valproate and levetiracetam, showed potential for reduced seizure activity with fewer side effects, though other combinations had more frequent side effects. Overall, polytherapy was associated with a greater likelihood of reported side effects and only a slight improvement in benefits compared with monotherapy.

In the face of the refractory epilepsy occurring in CDD, it is difficult to provide clinicians with clear recommendations as to what best to prescribe and, as we acknowledge, prescribing may have to be tailored to the types of epilepsy, information not available to us in our study. The findings we report represent a caregiver perspective, but when we compare side-effect profiles with those identified in the few meta-analyses in the literature [21,22,23] our findings are similar, providing some validity to our results. In an attempt to present any guidance on the efficacy of different ASMs, we considered the frequency of use, as well as the likelihood of benefits, side effects and duration of use. Of those ASMs commonly used (> 100), valproate and lamotrigine would appear to be those with the greatest benefits and fewest side effects with a current duration of use (> 30 months), suggesting good tolerability and acceptance. Topiramate and levetiracetam were slightly less beneficial although they had similar durations of use. Of the third-generation ASMs, as would be expected, both perampanel and lacosamide had been used by fewer individuals, but perampanel was rated as particularly beneficial although side effects were more common. More time and data are probably required for the assessment of this group of newer ASMs. Caregivers also rated cannabidiol very highly, but it was not commonly used (n = 61), and there is likely significant variation in the types of products available, which range from pharmaceutically produced options such as Epidiolex® in the USA to those purchased from licensed dispensaries.

This study has many strengths, including the large sample size provided by the ICDD, which has been collecting data for over 10 years. Importantly, all individuals have a pathogenic or likely pathogenic variant, and the benefits and side effects are provided directly by the caregivers. Another strength is that our results demonstrate that CDD remains one of the most medically refractory epilepsies worldwide, regardless of whether certain ASMs are available in different countries and throughout different periods. A unique aspect of our study was reporting the prevalence of side effects, as presented graphically in our figures, as an important contributing factor to the acceptability of an ASM. We also reported on the duration of ASM use. Perhaps surprisingly, phenobarbital had been used the longest despite its high side-effect profile, possibly because it was the first to be used and likely to be continued because of concerns about withdrawal symptoms, including seizure recurrence. The side-effect profiles we identified were in keeping with a 2014 review suggesting that phenobarbital, valproate and levetiracetam were particularly likely to aggravate daytime sleepiness [21]. In contrast, a more recent review focussing on developmental epileptic encephalopathies [23] reported that the effects of valproate on sleep were mixed, and evidence was limited by studies with small sample sizes (n = 20–40) in comparison to ours (n = 218 who provided side-effect data). Nevertheless, the findings of their review with respect to the sedating effects of ASMs (what we described as fatigue) were very consistent [23]. Relationships with irritability were a little less consistent, although for both of the studies, irritability was associated with levetiracetam and zonisamide and insomnia with lamotrigine. It is clear from this recent review [23] and the one undertaken in 2014 [21] that the relationship between epilepsy, the side effects of ASMs, night-time sleep disturbances and daytime sleepiness is highly complex and challenging to unravel. Moreover, we have previously shown that daytime sleepiness is associated with a poorer quality of life [24].

Regarding weaknesses, our study lacked information about which specific seizure type was targeted when an ASM was commenced. We do know that the most typical types of seizures at first initiation of treatment were tonic seizures, followed by epileptic spasms, generalised tonic-clonic seizures and finally focal seizures, and, overall, the most common seizure types were epileptic spasms, followed by tonic, myoclonic and then generalised tonic-clonic seizures [1]. Another limitation is that we did not have information about the exact seizure frequency before introducing a new medication and the subsequent change in frequency other than the caregiver’s assessment of the new medication. Notably, some but not all caregivers may have referred to seizure diaries to provide their information. While also a benefit, the multinational nature of this study has the shortcoming of the data representing the availability of ASMs in different regions of the world and at different periods, as well as the influence of the prescription preferences of different treating physicians given the absence of treatment guidelines for the management of seizures in CDD. For example, perampanel was only US Food and Drug Administration approved for the management of seizures in 2014, which would account for the relatively low number of uses. Similarly, cannabidiol was only approved in 2018, while felbamate has not yet been approved in Canada. Limited use of ganaxolone in the USA during the study period prevented us from including this potentially effective ASM in our analysis [25]. A recently completed clinical trial has demonstrated that the 28-day major motor seizure frequency was reduced in those taking ganaxolone compared with placebo [25]. The latest results from an open-label extension study of 88 patients showed reductions at 22–24 months from baseline in major motor seizure frequency of ≥ 25%, ≥ 50%, ≥ 75% and 100% to be 66% (33/50), 46% (23/50), 24% (12/50) and 6% (3/50), respectively [26]. After including those for which medication was not continued (n = 38) for various reasons, including a lack of efficacy, withdrawal by caregivers and adverse events, the corresponding percentages were 38%, 26%, 16% and 3%, respectively. With the increasing availability of ganaxolone in the USA and elsewhere, subsequent to its being the first US Food and Drug Administration-approved ASM for CDD, it will be important to continue monitoring its ongoing use through the ICDD.

Few other studies have investigated responses to specific ASMs, and the case numbers have been generally small. In 2012, a group from the Mayo Clinic reported a reduction in seizure frequency in six patients with CDD treated with topiramate, vigabatrin and a ketogenic diet [27]. A second study from Germany with aggregated individual responses from 39 patients showed that a small number of commonly prescribed medications (felbamate, vigabatrin, clobazam and valproate) initially reduced seizure frequency by 50% or more [17]. However, this improvement was generally unsustained. In our much larger study, vigabatrin and sodium valproate were ASMs that appeared to provide a more permanent benefit, but the benefit-to-side-effect ratio was less favourable for felbamate and clobazam. In a Georgian case series (n = 8), five patients with CDD responded positively to a combination of vigabatrin and zonisamide, providing the best outcome in reducing seizure frequency [28]. We were unable to report the latter combination because of insufficient cases. However, we found that zonisamide and levetiracetam provided reasonable seizure control but with side effects. After the Georgian case series, a Spanish study reported a reduction in seizure frequency of more than 50% among six of the 19 patients with CDD treated with sodium channel blockers, of which the most frequent were oxcarbazepine, carbamazepine and lacosamide [29]. In the German-based study, seizures were aggravated by carbamazepine in four patients, although one patient had a long period of seizure freedom [17]. Although lacosamide appeared relatively beneficial in our study, oxcarbazepine and carbamazepine appeared less so. Thus, there are contraindicatory data on whether sodium channel blockade ASMs are beneficial or detrimental for seizure control, also considering oxcarbazepine is primarily of value for focal seizures.

In the most recent US study (n = 168), information on a 2-week response to medications was available for 86 patients [14]. Similar to our observations, levetiracetam, topiramate, clobazam, and phenobarbital were frequently used, as were vigabatrin and sodium valproate. In both studies, the responses to these two latter medications were fair to good, as was the response to lamotrigine. In contrast, the response to levetiracetam, as in our study, was considerably poorer. This may be of concern given that levetiracetam was the most frequently used ASM in both studies. In a recently published US study, the response of epileptic spasms to first-line treatments (ACTH, oral corticosteroids and vigabatrin) was 26% at 14 days and sustained response only 4% at 3 months, both significantly worse compared with individuals with spasms of other aetiology from the National Infantile Spasms Consortium [30]. However, in our study, despite apparent benefits from steroids/ACTH, there was a high prevalence of reported side effects. The side-effect profile we saw, predominantly Cushingoid features and obesity, was very similar to that found in a systematic review of the use of steroids/ACTH in epilepsies other than infantile spasms where there was an overall 50% reduction in seizures but which tended not to be universally sustained [31]. Both ours and the earlier US study [14] reported on responses to cannabis derivatives, but in our study, we were unable to separate CBD only (Epidiolex®) from other cannabis derivatives. The 2-week response in the US study was 29%, but it was rated highly beneficial in our study with the least side effects. This was consistent with results from our previous study on the use of medical cannabis in CDD, where, despite favourable reporting, we were unable to identify any definite improvement in seizure frequency [32]. It is gratifying to see the similarities between the findings in our and the US study despite data in the latter being sourced from physician chart reviews. Although our study was international and had mostly non-US participants, some US participants may have also contributed to the published US study [14].

Unlike the US study [14], our analysis was limited to ASM therapy, and data on the use of the ketogenic diet and vagus nerve stimulation were not presented, as we have previously published separately on these [33, 34]. However, we did present data on the number of ASMs currently being used, finding that just over 40% were on three or more. This is of concern given that we had previously found that quality of life was adversely affected by polytherapy [12]. We also presented data on the outcomes of different ASM combinations. The combination with the greatest benefit and fewest side effects appeared to be levetiracetam and sodium valproate despite the less favourable findings for levetiracetam in the single medication analysis. Although the numbers were necessarily small, we consider this an important contribution.