Departments of Translational Neuroscience, Psychiatry, and
Psychiatry, and.
Pediatrics. 2015 Aug;136(2):e539-43. doi: 10.1542/peds.2014-4133.
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.
利尿剂布美他尼最近被提出作为一种新颖的、有前途的治疗自闭症谱系障碍（ASD）和相关疾病的行为症状的方法。布美他尼可以降低神经元氯离子浓度，从而恢复神经发育障碍患者的γ-氨基丁酸（GABA）能抑制。然而，缺乏选择布美他尼治疗合适候选者的策略。我们假设，对 GABA 增强剂（如苯二氮䓬类药物）的矛盾反应可能预测布美他尼在神经发育障碍中的治疗效果。我们描述了一例 10 岁女孩，患有 ASD、癫痫、皮质发育不良和 15q11.2 重复，她在之前使用苯二氮䓬类药物氯巴占治疗后表现出明显的行为觉醒。我们假设这种反应表明存在去极化兴奋性 GABA，并开始使用布美他尼治疗，并监测行为、认知和 EEG。治疗导致感觉行为、僵硬和记忆表现的明显临床改善，这通过问卷调查和认知评估得到证实。在基线时，女孩的 EEG 显示绝对 α 功率降低，这是与 ASD 相关的电描记法标志，用布美他尼治疗后得到正常化。布美他尼对认知和 EEG 的影响似乎反映了健康受试者对苯二氮䓬类药物的“非矛盾”反应。此外，颞叶癫痫和皮质发育不良都与氯离子稳态紊乱有关，这似乎支持我们的假设，即观察到的矛盾反应是由于 GABA 介导的兴奋。该病例强调，对 GABA 增强药物的矛盾行为反应可能构成布美他尼靶向治疗的框架。
