Sanz Leandro R D, Lejeune Nicolas, Szymkowicz Emilie, Bonin Estelle A C, Panda Rajanikant, Sala Arianna, Thibaut Aurore, Huerta-Gutierrez Rodrigo, Dardenne Nadia, Dikenstein David, Van Goethem Sébastien, Ledoux Didier, Hustinx Roland, Stender Johan, Farber Neal M, Zafonte Ross D, Schiff Nicholas D, Laureys Steven, Gosseries Olivia
Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium.
Centre du Cerveau, University Hospital of Liège, Liège, Belgium.
EClinicalMedicine. 2024 Nov 15;78:102925. doi: 10.1016/j.eclinm.2024.102925. eCollection 2024 Dec.
Apomorphine is a dopaminergic candidate therapy to improve recovery in patients with prolonged disorders of consciousness (PDoC). Behavioural improvements were previously described in non-controlled case series, but its efficacy and neural mechanisms remain largely unknown. This open-label controlled study using multimodal outcome measures investigates the action of apomorphine in severely brain-injured patients.
Thirteen PDoC patients received 30-day subcutaneous apomorphine treatment (n = 6) or standard care (control group, n = 7) in a neurological rehabilitation centre between February 2018 and January 2021. The apomorphine group was monitored 30 days before treatment initiation, during treatment and one year after treatment. Primary outcome measure was defined as changes in behavioural diagnosis using the Coma Recovery Scale-Revised (CRS-R). CRS-R index, recovery of new conscious behaviours, DoC-feeling scores, high-density electroencephalography, and fluorodeoxyglucose positron emission tomography were employed as secondary outcome measures. The control group was monitored with repeated CRS-R only. Registration: EudraCT 2018-003144-23; Clinicaltrials.govNCT03623828.
Groups (apomorphine vs. control: odds ratio 8.9, 95% CI 3.3-17.8) and study phase (treatment vs. baseline, apomorphine group only: odds ratio 3.9, 95% CI 1.5-10.1) significantly influenced positive changes in behavioural diagnosis. At one-year post-injury, 4/6 patients in the apomorphine group and 1/7 patients in the control group had improved their diagnosis. Similarly, CRS-R index was significantly influenced by study phase (treatment vs. baseline). All items on the DoC-feeling score were rated higher after treatment than before by both family and medical staff. Patients in the apomorphine group recovered more conscious behaviours than control patients. Alpha-band whole-brain connectivity and participation coefficient, as well as alpha-band parieto-temporal connectivity and frontal participation coefficient were higher after treatment than at baseline. Whole-brain metabolism increased by a relative mean of 13.8% after treatment compared to baseline, with a significant effect of timing (pre-vs. post-treatment scans) on regional SUV.
Long-lasting consciousness improvements were observed in patients treated with apomorphine, compared to controls and compared to baseline. Changes in brain connectivity and metabolism were observed after treatment, providing insights into possible neurophysiological mechanisms and target areas. This open-label study confirmed the feasibility and safety of apomorphine treatment, which may represent a key therapeutic option for PDoC.
University and University Hospital of Liege, Belgian National Funds for Scientific Research, Fund Generet of the King Baudouin Foundation, AstraZeneca Foundation, Leon Fredericq Foundation and NeuroHealing Pharmaceuticals Inc.
阿扑吗啡是一种多巴胺能候选疗法，用于改善长期意识障碍（PDoC）患者的恢复情况。此前在非对照病例系列中描述了行为改善情况，但其疗效和神经机制仍 largely 未知。本项使用多模态结局指标的开放标签对照研究调查了阿扑吗啡在重度脑损伤患者中的作用。
2018年2月至2021年1月期间，13例PDoC患者在一家神经康复中心接受了30天的皮下阿扑吗啡治疗（n = 6）或标准护理（对照组，n = 7）。阿扑吗啡组在治疗开始前30天、治疗期间和治疗后一年进行监测。主要结局指标定义为使用修订的昏迷恢复量表（CRS-R）进行行为诊断的变化。CRS-R指数、新意识行为的恢复情况、意识障碍感受评分、高密度脑电图和氟脱氧葡萄糖正电子发射断层扫描被用作次要结局指标。对照组仅通过重复的CRS-R进行监测。注册信息：欧洲药品管理局临床试验数据库编号2018-003144-23；Clinicaltrials.gov编号NCT03623828。
分组（阿扑吗啡组与对照组：优势比8.9，95%置信区间3.3 - 17.8）和研究阶段（治疗与基线，仅阿扑吗啡组：优势比3.9，95%置信区间1.5 - 10.1）对行为诊断的积极变化有显著影响。受伤一年后，阿扑吗啡组6例患者中有4例、对照组7例患者中有1例诊断得到改善。同样，CRS-R指数受研究阶段（治疗与基线）的显著影响。意识障碍感受评分的所有项目在治疗后家庭和医务人员的评分均高于治疗前。阿扑吗啡组患者比对照组患者恢复了更多的意识行为。治疗后α波段全脑连通性和参与系数，以及α波段顶颞连通性和额叶参与系数均高于基线。与基线相比，治疗后全脑代谢相对平均增加了13.8%，扫描时间（治疗前与治疗后扫描）对区域标准化摄取值有显著影响。
与对照组和基线相比，接受阿扑吗啡治疗的患者观察到了持久的意识改善。治疗后观察到脑连通性和代谢的变化，为可能的神经生理机制和靶区域提供了见解。这项开放标签研究证实了阿扑吗啡治疗的可行性和安全性，这可能是PDoC的一种关键治疗选择。
列日大学和列日大学医院、比利时国家科学研究基金、国王博杜安基金会的Generet基金、阿斯利康基金会、利昂·弗雷德里克基金会和NeuroHealing制药公司
