Bumetanide to Ameliorate Hyperexcitable Behavior in Tuberous Sclerosis Complex
Selective treatment in Autism Spectrum Disorder (ASD) may be based on genetic or molecular information. Here we present a rational treatment for tuberous sclerosis complex (TSC), a monogenetic disorder strongly associated with ASD. Preclinical studies have identified signs of excitatory GABAAR transmission in tubers and perituberal cortex of TSC patients indicating disturbed chloride homeostasis. These imbalances may be a common mechanistic pathway and underlie the observed (hyper)excitability in these neurodevelopmental disorders. Bumetanide, a selective NKCC1 antagonist, may enhance GABAergic transmission by correcting intracellular chloride concentration. We present results of an open-label trial testing the effect of bumetanide on behavior, cognition, resting state EEG and event related potentials (ERP) in a sample of children with TSC with and without formal ASD diagnosis.
Open label trial testing bumetanide to improve behavioral, cognitive and neurophysiological adaptation in TSC patients.
Add-on open-label trial in which 12 TSC patients (aged 8-21) were treated with bumetanide for 3 months, followed by a 1-month wash-out phase. Treatment effect was evaluated by a broad range of behavioral and cognitive endpoints, including autism symptom questionnaires. Novel advanced electroencephalography (EEG) markers were where possible used to objectify treatment effect and to identify candidate prognostic biomarkers.
An overall beneficial effect on behavioral functioning was obtained, that could be substantiated by individual EEG parameters in several cases. Improvements were analyzed in relation to EEG markers of hyperexcitability and sensory processing abnormalities.
(Add on) bumetanide treatment is a novel treatment consideration to improve daily functioning for patients with TSC. Improvement in neural imbalances and sensory reactivity may indicate overlap in common treatment targets between TSC and idiopathic ASD.