Cheung Steven W, Racine Caroline A, Henderson-Sabes Jennifer, Demopoulos Carly, Molinaro Annette M, Heath Susan, Nagarajan Srikantan S, Bourne Andrea L, Rietcheck John E, Wang Sarah S, Larson Paul S
1Department of Otolaryngology-Head and Neck Surgery, UCSF.
2Surgical Services, Veterans Affairs Health Care System, San Francisco.
J Neurosurg. 2019 Sep 24;133(4):992-1001. doi: 10.3171/2019.4.JNS19347. Print 2020 Oct 1.
The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.
Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.
The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.
Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).
本开放性、非随机试验的目的是评估双侧尾状核深部脑刺激（DBS）治疗难治性耳鸣的疗效和安全性。
6名参与者接受了DBS电极植入。1名参与者因与脑刺激无关的自杀倾向退出研究。参与者经历了5至13个月的刺激优化期，在此期间确定了每个个体最有希望减少耳鸣的刺激参数。然后在24周的连续尾状核刺激期间使用这些个体最佳刺激参数以达到终点。疗效的主要结局是耳鸣功能指数（TFI），执行功能（EF）安全性是多项神经心理学测试的综合z评分（EF评分）。疗效的次要结局是耳鸣障碍量表（THI）；神经精神安全性方面是额叶系统行为量表（FrSBe），听力安全性方面是0.5、1、2、3、4和6kHz的纯音听力测定及单词识别分数（WRS）。其他监测结局包括手术和设备相关不良事件（AE）。5名参与者提供了完整的可分析数据集。主要和次要结局基于基线和终点测量值的差异。
通过TFI[均值（标准误），23.3（12.4）]和THI[30.8（10.4）]评分评估尾状核DBS治疗耳鸣的治疗效应大小，两者均具有统计学意义（Wilcoxon符号秩检验，单尾；α=0.05）。基于具有临床意义的治疗反应分类分析，由TFI确定有3名反应者（降低≥13分），由THI确定有4名反应者（降低≥20分）。根据EF评分、FrSBe、听力阈值和WRS的安全性结局显示，连续尾状核刺激无显著变化。手术相关和设备相关AE是预期的、短暂的且可逆的。只有1例严重AE，是1名参与者的自杀未遂，该事件发生前其刺激已关闭2个月，与尾状核神经调节无关。
在这项I期试验中，DBS对严重难治性耳鸣进行双侧尾状核神经调节显示出非常令人鼓舞的结果。主要和次要结局显示治疗效应大小高度可变，临床显著获益的治疗反应率为60%-80%，且无安全问题。II期试验的设计可能受益于最终DBS电极放置的靶向优化，以缩短刺激优化期的持续时间并提高治疗效应大小的一致性。临床试验注册号：NCT01988688（clinicaltrials.gov）。
