Our patient, with a rare genetic DEE, besides a noteworthy reduction in seizure frequency, presented substantial improvement in language, social behavior and sleep after the authorized off-label introduction of CBD. She is affected by a balanced parental translocation between chromosome 2 and 12, with monosomy for the segment 2q37.3-2qter and trisomy for the segment 12q24.31-12qter. This condition is typically associated with severely retarded growth, intellectual disability and distinctive facial features, speech, communication and behavioural problems [6]. Lautaro Plaza-Benhumea and colleagues recently published the first case of a patient with a 12q24.21-12q24.33 duplication and drug-resistance epilepsy, which had been previously rarely described in patients with 12q trisomy [7].

According to current ILAE definition, in patients with DEEs seizures, both interictal epileptiform activity and the whole neurobiological process underlying epilepsy are involved in the establishment of patients’ cognitive profile, thus it is mandatory to introduce an aggressive treatment to reduce the overall burden of epilepsy and mitigate the EEG anomalies [2].

The underlying mechanism of CBD in humans is still partially unknown: it is supposed to be multimodal, involving also non-cannabinoid pathways, which may explain its strong anti-inflammatory and neuroprotective activity. So far, around 56 different neurological molecular targets of CBD including enzymes, ion channels, ionotropic, and metabotropic receptors have been identified [8], [9]. Besides molecular changes, some important variations in the brain connectivity profile had also been observed. These involved in particular modifications of brain resting-state functional connectivity, with stronger changes in the inter-regional connections between the vermis, amygdala, hippocampus and frontal cortex [10]. Similarly, CBD have been proved to modulate the attention processing by influencing the functional connectivity between the superior frontal gyrus and insula/middle frontal gyrus [11]. In our patient, unfortunately, we do not dispose of neuro-functional data to confirm these preliminary observations, due to her limited cooperation.

Evidence on the clinical benefits of CBD beyond its antiepileptic properties is still scarce, although there is growing scientific interest in this topic. To date, CBD has been authorized by EMA only for treatment of DS, LGS, and TSC [12], [13], [14]. However, several studies, mainly case reports and open-label studies, suggest the existence of neurological benefits also beyond these three epileptic syndromes [13], [15], [16], [17], [18]. Rosemberg et al. published in 2017 an open-label clinical study showing a significative improvement in the caregiver-reported QoLCE (Quality Of Life of Childhood Epilepsy; 8.2 +/− 9.9 points of difference) in a subset of 48 children and young adults affected by severe drug-resistant epilepsy after 12 weeks of therapy with CBD [19], [20]. Similarly, another clinical trial reported positive results on quality of life and mood after one year of treatment, regardless of changes in seizure frequency, in an adult cohort of 53 patients affected by treatment-refractory epilepsy [21]. Moreover, in a large multicentric cohort study involving 311 patients, of whom 206 children and adolescents treated with CBD off −label due to epilepsy subtype, beyond a reduction in seizure frequency, patients experienced improvements in mood, sleep, development and concentration, as well as an increase in appetite and a reduction in spasticity. Interestingly, the results for patients with LGS, DS and TCS were not significantly different from other epilepsy subtypes [15]. Finally, a recently published systematic review analyzing 42 studies on the use of CBD in patients with epileptic syndromes other than those mentioned above, including rare genetic epileptic and developmental encephalopathies, showed that a good treatment response can be seen in patients across a broad range of epilepsy disorders and DEEs [12], [16] (Table 1). In this review, the sustained seizures’ reduction and stable EEG improvement suggested a protracted efficacy of the drug.

Our patient experienced a great amelioration in her behavior, mood and cognitive performances, with striking improvement in her interaction with people (see box 1 on patient experience), together with seizure improvement and EEG amelioration, with no relevant side effects. We believe that her clinical course may be representative of the complexity of DEEs in adults, given the co-existence of epileptiform disturbances with severe cognitive and behavioral disorders, associated with a rare genetic mutation. The off-label utilization of CBD lead to a massive global improvement and seizure reduction, that lasted up to 12 months of observation. Molecular genetics and neurobiology will play a pivotal role in the comprehension of the pathophysiological mechanisms involved in several DEEs paving the way to new targeted therapies [9]. Meanwhile, growing knowledge on drugs’ efficacy and underlying genetic mechanisms in specific DEEs might help to better understand the pharmacodynamic properties of new drugs which in some cases is still unclear [22].