Treatment Responsiveness in KCNT1-Related Epilepsy

Abstract

Pathogenic variants in KCNT1 represent an important cause of treatment-resistant epilepsy, for which an effective therapy has been elusive. Reports about the effectiveness of quinidine, a candidate precision therapy, have been mixed. We sought to evaluate the treatment responsiveness of patients with KCNT1-related epilepsy. We performed an observational study of 43 patients using a collaborative KCNT1 patient registry. We assessed treatment efficacy based upon clinical seizure reduction, side effects of quinidine therapy, and variant-specific responsiveness to treatment. Quinidine treatment resulted in a > 50% seizure reduction in 20% of patients, with rare patients achieving transient seizure freedom. Multiple other therapies demonstrated some success in reducing seizure frequency, including the ketogenic diet and vigabatrin, the latter particularly in patients with epileptic spasms. Patients with the best quinidine response had variants that clustered distal to the NADP domain within the RCK2 domain of the protein. Half of patients did not receive a quinidine trial. In those who did, nearly half did not achieve therapeutic blood levels. More favorable response to quinidine in patients with KCNT1 variants distal to the NADP domain within the RCK2 domain may suggest a variant-specific response.

KCNT1‐related epilepsy: An international multicenter cohort of 27 pediatric cases

“…As previously reported by different authors, KCNT1 pathogenic variants are highly pleiotropic and associated with a variety of phenotypes . In our study, two‐thirds of patients presented with EIMFS; however, unclassified EOEE, West syndrome, and ADSHE were also present, similar to previous reports.…”

“…Twenty‐seven percent (3/11) reported >50% seizure reduction, and 18.1% (2/11) reported from 25% to 50% seizure reduction. Our findings were similar to those from the largest cohort of KCNT1‐related epilepsy, which evaluated 20 patients taking quinidine and found nearly 50% (9/20) of patients with some response, including 20% of patients having at least 50% seizure reduction . Neither seizure freedom nor worsening of seizures was reported in our patients.…”

“…Poor response to AEDs is a common characteristic among KCNT1‐related epilepsy patients regardless of the phenotype. Not different from other studies, our patients were exposed to several AEDs over time (mean = 7.4, SD = 3.1), with no seizure freedom achieved. Moreover, more than one‐half (55%, 15/27) reported >50 seizures monthly.…”

“…Analyzing the response to the ketogenic diet (not including the low glycemic index diet), half of the patients (6/12) had >50% seizure reduction. Reasonable response to the ketogenic diet has also been reported, with a response rate of 31% (9/29) as per caregivers and physicians . For those who responded well to CBD, two of three were previously on the ketogenic diet, making any conclusions on the CBD efficacy merely speculative.…”

“…Unblinded assessment of seizure reduction may range from complete to no response . Overall, half of EIMFS or EOEE patients will have no response to quinidine, and only 20% may benefit with at least a 50% seizure reduction . The main adverse effect attributed to quinidine therapy is cardiotoxicity with prolonged QTc interval and arrhythmias, but sedation, elevated liver function tests, rash, and skin discoloration have also been described …”