Fluoxetine Treatment in Epilepsy of Infancy with Migrating Focal Seizures Due to KCNT1 Variants: An Open Label Study

Abstract

Objective: Gain-of-function (GoF) variants in KCNT1 encoding for potassium channels are associated with different epilepsy phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), other early infantile developmental and epileptic encephalopathies, and focal epilepsy. Fluoxetine blocks currents from both wild-type (WT) and mutant KCNT1 channels with GoF in vitro features. In this study, we tested the hypothesis that treatment with fluoxetine might improve clinical outcome in patients with EIMFS carrying GoF variants in KCNT1 channels showing in vitro sensitivity to fluoxetine blockade.

Methods: We enrolled three pediatric patients carring de novo KCNT1 genetic variants linked to EIMFS. Functional and pharmacological studies to assess fluoxetine's ability to counteract in vitro variant-induced functional effects were performed with patch-clamp electrophysiology on heterologous channel expression in mammalian Chinese hamster ovary cells. Neuropsychological assessment, electroencephalogram and seizure diary were evaluated at baseline and every 3 months during the study. Electrocardiography and blood levels of medications were monitored for safety.

Results: All 3 KCNT1 variants displayed GoF effects in vitro. Exposure to fluoxetine (10μM) blocked both WT and mutant KCNT1 channels, therefore, counteracting variant-induced functional effects. Treatment with fluoxetine caused a variable reduction of seizure frequency (25-75%). Improvement in visual attention, participation, and muscle tone was also reported. No adverse events were reported except for transient dyskinesia in 1 patient, which was probably related to an increase in fluoxetine plasma level.

Interpretation: Fluoxetine may be a potential targeted medication in EIMFS caused by KCNT1 GoF variants. Further research is needed to assess its long-term efficacy and safety. ANN NEUROL 2025;98:48-61.

FIGURE 1

Study design. The study was divided into 3 phases: the baseline period, the titration period, and the maintenance period. The in vitro study was performed during the baseline period. The graph shows the scheme of fluoxetine dose titration and which investigations were performed at each visit. Symbols indicate the time points at which the study procedures were conducted. w = week; m = months; ASMs = anti‐seizure medications; ADEs = adverse drug events; EEG = electroencephalogram; EKG = electrocardiogram. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Functional and pharmacological characterization of wild‐type (WT) and mutant KCNT1 channels. Topological representation of a KCNT1 subunit and localization of R356W, R398Q, and R474H variants identified in this study (A). Partial alignment of KCNT1 subunits of different species (h = human, r = rat, m = mouse, g = chicken, x = Xenopus laevis, s = sheep, z = zebrafish). (B) Representative current traces recorded in Chinese hamster ovary (CHO) cells encoding the indicated channels in response to the voltage protocol shown below the leftmost traces. Current scale = 1nA; time scale = 50 milliseconds (C). Average of current densities (D), IINST/ISTEADY‐STATE ratios (E), and conductance/voltage curves (F) measured in cells expressing the indicated channels. (G) Representative traces recorded in response to the ramp protocol shown below the leftmost traces in CHO cells expressing the indicated channels in control solution (C), after 1–3 minutes exposure to 10μM fluoxetine (FLX), or on drug washout (W). Current scale = 500 pA; time scale = 200 milliseconds. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Blood levels of fluoxetine and desmetilfluoxetine during the study. The graphs illustrate the fluoxetine titration for each patient (A, B, C, respectively for patient 1, 2, and 3) and the corresponding increase in blood levels of fluoxetine and desmetilfluoxetine. Plasma levels were measured weekly during the titration period and every 3 months during the maintenance period.

FIGURE 4

Developmental profiles trajectories for each patient. The graphs illustrate the developmental profiles trajectories for each patient (A, B, C, respectively for patient 1, 2, and 3). Griffiths Mental Development Scale (GMDS) age equivalent values are expressed in months. V0 represents the evaluation made at baseline visit, before the start of fluoxetine. V3, V6, V9, and V12 represent the evaluations respectively done at 3, 6, 9, and 12 months during the administration of fluoxetine. Patient 1 had the greater improvement of equivalent age in different subdomains. Patient 2 and 3 had a lower improvement with an evident roof effect in patient 2. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 5

Pediatric Quality of Life Inventory (PedsQL) Family Impact Module scores. The PedsQL Family Impact Module was designed to measure the impact of pediatric chronic health conditions on parents and the family. A 5‐point response scale is used (0 = never a problem; 4 = always a problem). Items are reverse‐scored and linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better functioning (less negative impact). Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). [Color figure can be viewed at www.annalsofneurology.org]