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Sodium channel blockers are not to be dismissed for the treatment of seizures in CDKL5 deficiency disorder

Over the last decade, both the repurposing of already commercialized antiseizure medications and the development of new molecules, are starting to redesign the management of patients with developmental and epileptic encephalopathies (DEEs) of genetic origin [1].

Studies on the therapy of patients with CDKL5 deficiency disorder (CDD) are scarce and absent of solid methodologies. Hence, targeted recommendations or concrete guidelines for managing these patients, beyond the common guidance for patients with DEEs, are lacking [2]. This is crucial since the proportion of people with CDD who develops refractory epilepsy is huge. Nevertheless, research in this field is currently active, leading to some milestones worthy of mentioning such as the designation of ganaxolone as an orphan drug for the treatment of CDD, the phase-3 randomized controlled trial evaluating this molecule as adjunctive therapy for the treatment of seizures in CDD (the Marigold study, NCT03572933), among other studies, such as those with soticlestat, fenfluramine, or cannabidiol.

Along these lines, sodium channel blockers (SCBs) are a group of widespread and solidly established antiseizure medications with value for treating concrete types of seizures, syndromes, and patients. Patients diagnosed with certain DEEs such as KCNQ2, KCNQ3, PRRT2, InvDup 15, and a subgroup of patients with SCN2A-related genetic epilepsies may benefit from this from their use. On the contrary, most patients diagnosed with SCN1A-related disorders will not be recommended their employment [3].

Specifically concerning CDD, the effectiveness of SCBs is still controversial. The idea of carrying out a study that addressed this topic came from the interaction with the CDD Spanish Association, which provided notification of some patients becoming seizure-free after treatment using SCBs.

The present study [4] was published in April 2021, intending to elucidate a hypothesis about the effectiveness of SCBs in patients with CDD. It displays an observational and retrospective design performed at three epilepsy reference centers in Spain, two in Madrid and one in Barcelona. All patients with CDD evaluated between June 2016 and December 2019 were assessed using medical records and updating with telemedicine. Carbamazepine, eslicarbazepine, lacosamide, lamotrigine, oxcarbazepine, phenytoin and rufinamide were drugs considered as SCBs in this work.

Nineteen patients diagnosed with CDD and epilepsy were finally included. Six of them (31.6%) were considered as “responders” to SCBs (>50% improvement in seizure frequency), and among them, four were seizure-free, in the majority of cases with just one drug. Amongst responders, two patients presented mild and transient adverse events, and regarding the group of thirteen non-responders, three had worsened after the onset of SCBs.

When comparing demographic and clinical features of both groups, responders, and non-responders, we found that the age at epilepsy onset was significantly lower, the onset of SCBs had been significantly earlier, and focal epileptiform activity was significantly more frequent in the responders than in the non-responders group. Furthermore, non-responders showed higher frequencies of precedent West and Lennox-Gastaut Syndromes throughout their history.

Although this study is small and presents limitations and biases, it suggests that there might exist a subset of well-selected patients with CDD, particularly those with lower age, predominant focal epileptiform activity, and absence of epileptic encephalopathy history, which could safely benefit from early therapy with SCBs. While a well-defined plausible biological explanation for this finding is lacking, it is worth remarking that some patients with CDD shares characteristics with patients with focal epilepsy. In this subgroup, SCBs are extensively employed. This study underlines the relevance of the interaction between patient advocacy groups and researchers, generating new hypotheses and studies that might open new treatment possibilities in the near future.

In conclusion, sodium channel blockers might be effective for seizure control in determined patients with CDD displaying the above-mentioned demographic and electroclinical features. However, further investigation and more robust studies are warranted to confirm or disregard this consideration.

References

1.- Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol. 2020 Dec;16(12):674-688.

2.- Olson HE, Daniels CI, Haviland I, Swanson LC, Greene CA, Denny AMM et al. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. J Neurodev Disord. 2021 Sep 16;13(1):40.

3.- Bayat A, Bayat M, Rubboli G, MØller RS. Epilepsy syndromes in the first year of life and genetic testing for precision therapy. Genes. 2021 Jul 8;12(7):1051.

4.- Aledo-Serrano Á, Gómez-Iglesias P, Toledano R, García-Peñas JJ, García-Morales I, Anciones C, et al. Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort. Epilepsy Behav. 2021 May;118:107946.