Paradoxical Benzodiazepine Response: A Rationale for Bumetanide in Neurodevelopmental Disorders?

Abstract

The diuretic agent bumetanide has recently been put forward as a novel, promising treatment of behavioral symptoms in autism spectrum disorder (ASD) and related conditions. Bumetanide can decrease neuronal chloride concentrations and may thereby reinstate γ-aminobutyric acid (GABA)-ergic inhibition in patients with neurodevelopmental disorders. However, strategies to select appropriate candidates for bumetanide treatment are lacking. We hypothesized that a paradoxical response to GABA-enforcing agents such as benzodiazepines may predict the efficacy of bumetanide treatment in neurodevelopmental disorders. We describe a case of a 10-year-old girl with ASD, epilepsy, cortical dysplasia, and a 15q11.2 duplication who had exhibited marked behavioral arousal after previous treatment with clobazam, a benzodiazepine. We hypothesized that this response indicated the presence of depolarizing excitatory GABA and started bumetanide treatment with monitoring of behavior, cognition, and EEG. The treatment resulted in a marked clinical improvement in sensory behaviors, rigidity, and memory performance, which was substantiated by questionnaires and cognitive assessments. At baseline, the girl's EEG showed a depression in absolute α power, an electrographic sign previously related to ASD, which was normalized with bumetanide treatment. The effects of bumetanide on cognition and EEG seemed to mirror the "nonparadoxical" responses to benzodiazepines in healthy subjects. In addition, temporal lobe epilepsy and cortical dysplasia have both been linked to disturbed chloride homeostasis and seem to support our assumption that the observed paradoxical response was due to GABA-mediated excitation. This case highlights that a paradoxical behavioral response to GABA-enforcing drugs may constitute a framework for targeted treatment with bumetanide.

• Authors: Hilgo Bruining, Laurien Passtoors, Natalia Goriounova, Floor Jansen, Britt Hakvoort, Maretha de Jonge, Simon-Shlomo Poil
• Journal: Pediatrics (Pediatrics) Vol. 136 Issue 2 Pg. e539-43 (Aug 2015) ISSN: 1098-4275 [Electronic] United States
• PMID: 26216321 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Academy of Pediatrics.

Chemical References

• Bumetanide
• Benzodiazepines

Topics

• Benzodiazepines (therapeutic use)
• Bumetanide (therapeutic use)
• Child
• Developmental Disabilities (complications, drug therapy)
• Female
• Humans
• Nervous System Diseases (complications, drug therapy)
• Treatment Outcome