Effectiveness of add-on acetazolamide in children with drug-resistant CHD2-related epilepsy and in a zebrafish CHD2 model

Abstract

CHD2-related epilepsy is characterized by early-onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2-related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug-resistant CHD2-related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2-related epilepsy, ictal-like events were recorded 5 days post-fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add-on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure-free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow-up was 13 months. In the zebrafish model, ACZ exposure reduced ictal-like events by 72%. ACZ, a well-tolerated and cost-effective medication, could be a good option for CHD2-related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity. PLAIN LANGUAGE SUMMARY: Epilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic-clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.

Keywords: developmental epileptic encephalopathy; myoclonic seizures; photosensitivity; tonic–clonic seizures; zebrafish.