This is the first survey on clinical experience and attitudes toward use of cannabinoid therapy for refractory epilepsy among neuropediatricians in North-Europe. A recent, similar online survey reported data from 155 physicians treating children or adolescents for epilepsy within eight countries in Central- and South-Europe (7). In that survey 45% of the respondents prescribed off-label cannabinoids (mainly CBD) for epilepsy, but the response rate was not presented (5). Moreover, the authors reported that individual experience with cannabinoid therapy among responders was limited, and there were diverse opinions about the use of CBD and how to manage the CBD treatment (7).

The main finding of the current survey was that very few neuropediatricians in Scandinavia and Germany had prescribed off-label cannabinoid therapy for pediatric epilepsy. However, those who had prescribed this therapy followed the indications used in recent clinical trials on CBD-based therapy for refractory epilepsies (3–5).

Respondents that had not prescribed cannabinoid-based therapy gave different reasons. Concerns about law regulations and lack of an available product (off-label use) was commonly cited. This may change since a purified CBD-formulation (Epidiolex®/Epidyolex®, GW Pharma) is approved by both the American Food and Drug Administration (June 2018) and the European Medicine Agency (September 2019). Recent clinical trials support a possible adjunctive role of CBD-based therapy for selected refractory epilepsies such as Dravet syndrome and LGS, two of the most severe and difficult-to-treat forms of childhood onset epilepsy (3–5). Long-term CBD treatment has showed an acceptable safety profile and a sustained reductions in seizure frequency in patients with these two epileptic encephalopathies (2, 8–10). This was confirmed in two recently published systematic reviews on CBD therapy including nearly 800 patients (children and adults) with Dravet syndrome (2) and LGS (9). These systematic reviews concluded that adjunctive add-on CBD therapy resulted in a significant reduction in seizure frequency compared to placebo, but also in a higher rate of adverse events (AEs). Typical AEs were somnolence, sedation, decreased appetite, pneumonia, diarrhea, and increased liver enzymes. Nevertheless, the overall conclusion was that add-on CBD is an efficacious long-term treatment option for these group of patients and that CBD is well-tolerated. CBD has relatively few side effects, but interactions with other medications should be monitored carefully (2, 9, 10). It also has to be acknowledged that only a purified, pharmaceutical formulation of cannabidiol has been authorized, and data from RCTs included in these systematic reviews cannot be extrapolated to other cannabinoid products.

The lack of clinical experience, but also theoretical knowledge, with CBD therapy for epilepsy in children was striking in our survey. In other countries, and in particular in the USA, off-label use of cannabinoids has increased over the last decade (1). Before initiating CBD-therapy clinicians must be aware of the most common side effects such as gastrointestinal problems, drowsiness, and liver function abnormalities (1, 3–5, 7, 8). Moreover, it is of great importance that interactions with commonly used anti-epileptic drugs (AEDs) are appreciated by doctors prescribing CBD-based therapy (1, 5, 6, 11). It has been shown that CBD may exhibit numerous interactions with other AEDs, both enzyme inducers (such as carbamazepine or phenytoin) and inhibitors (such as valproic acid), even if the clinical significance not yet is clear. CBD may have an impact on liver metabolism with significant elevation of liver enzymes in up to 10% of treated patients, of whom more than three quarter had received concomitant valproic acid therapy. In addition, there are clinically significant interaction between CBD and clobazam, an AED widely used in patients with both Dravet and LGS. The use of CBD (by inhibition of CYP2C19) may lead to a significant increase in clobazam metabolites, leading to toxicity. At the same time, clobazam may increase an active metabolite of CBD, which could lead to better seizure control. Overall, there are still many unanswered questions regarding the impact of interactions between CBD and other AEDs. However, due to an increased risk of side effects such as somnolence and increased liver enzymes, close clinical and biochemical monitoring is recommended (6, 10, 11). Moreover, it has to be emphasized that clinicians need to report all possible severe side effects, preferably by enrolling patients in post-authorization Phase IV safety studies.

The greatest limitation with our survey, and the one published by Klotz et al. (7), is that that we do not have the exact number of neuropediatricians that received the survey. We can therefore not give an exact response rate. Certainly many neuropediatricians on our email lists may in their daily practice focus on other pediatric neurology subspecialties (e.g., congenital neuromuscular disorders, cerebral palsy, and neurohabilitation) and thus do not have the same focused interest in or experience with therapy of refractory epilepsies. However, those who responded were overall very experienced neuropediatricians and around 2/3 were treating children with epilepsy on a weekly basis. We speculate that many of those who did not respond were less interested or familiar with the topic of CBD therapy and refractory epilepsies.

In conclusion, this survey indicates that off-label cannabinoid-based therapy for pediatric epilepsy in children was not widely prescribed by neuropediatricians in Scandinavia and Germany in 2018. However, self-medication and parental request for this therapy was common. This may reflect a previously reported disparity in opinion on the use of cannabinoids in epilepsy treatment with fewer medical specialists supporting its use compared with patients and the public (12). Evidence from recent clinical trials and improved availability of an approved CBD formulation will most likely change the situation regarding CBD-based therapy for pediatric refractory epilepsy in the future.