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Multimodal Longitudinal Neurophysiological Investigations in Dopa-Responsive Dystonia
Movement Disorders ( IF 8.6 ) Pub Date : 2021-06-11 , DOI: 10.1002/mds.28679
Anne Weissbach 1, 2 , Annika Steinmeier 1 , Martje G. Pauly 1, 2, 3 , Duha M. Al‐Shorafat 4, 5 , Gerard Saranza 4, 6 , Anthony E. Lang 4 , Norbert Brüggemann 3 , Vera Tadic 3 , Christine Klein 2 , Katja Lohmann 2 , Matt J.N. Brown 7 , Christian Beste 8 , Alexander Münchau 1 , Tobias Bäumer 1
Affiliation  

Multimodal longitudinal studies combining clinical and neurophysiological examinations in patients with dystonia are scarce but could lay the groundwork for phenotype–genotype–neurophysiology correlations and clinical and neurophysiological markers of disease progression and treatment response over time.

In this respect, dopa (l-dopa)-responsive dystonia (DRD) attributed to guanosine triphosphate cyclohydrolase 1 (GCH1) gene mutations1 might serve as a monogenic model disease for genetically undefined dystonia. However, examinations of neocortical network changes using transcranial magnetic stimulation (TMS) in DRD showed heterogenous results in only small patient groups (n = 7) and were not combined with detailed clinical investigations. Short-interval intracortical inhibition (SICI), a measure of Gamma aminobutyric acid (GABA) A-ergic–mediated primary motor cortex (M1) inhibition was either normal2 or reduced after dopaminergic drug withdrawal and normalized in one study after l-dopa substitution.3 Physiological M1 inhibition after conditioning of the dorsal premotor cortex (PMd), responsible for motor planning and shaping, was abolished in patients with DRD.4 Studies within larger groups of patients with DRD with and without dopaminergic medication, obtaining both clinical and TMS parameters in a longitudinal fashion are desirable.

Thus, in the current study, 16 GCH1 mutation-positive patients with DRD (1 man, mean age 45 years [range 15–80 years]; Table SS1), and 16 matched healthy controls (HC; four men, mean age 45 years [range 19–78 years]) underwent a video-instructed and video-recorded movement examination, rated in randomized, blinded fashion using the Movement Disorder Society–Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). In addition, TMS was used to investigate SICI and PMd-M1 interaction. Measurements were performed under dopaminergic treatment (on) and after a mean 22-hour drug withdrawal (off). Of these patients and controls, 10 were investigated longitudinally (on and off) with an interval of 5 years. The Wilcoxon signed-rank test was used for the analysis of clinical results, and an analysis of variance was used with the factors group, medication, and time for the TMS data (see the Supplementary Methods).

There was significant clinical improvement (BFMDRS on 13 points standard deviation [SD] ± 12 and off 16 points SD ± 13 [P = 0.026] and MDS-UPDRS Part III on 11 points SD ± 10 and off 16 points SD ± 15 [P = 0.01]) under dopaminergic treatment, without deterioration over 5 years. In addition, PMd-M1 interaction showed an effect for medication (F1,15 = 13.48, P = 0.002; Fig. 1), without an effect for group or time. SICI analysis did not reveal an effect for medication, time, or group. However, in the longitudinal SICI observation, there was a group effect comparing healthy controls and DRD off (F1,14 = 5.47, P = 0.035). There was no correlation between any clinical or TMS results after correction for multiple comparisons (see the Supplementary Results).

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FIG. 1
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Results of the dorsal premotor cortex (PMd)–primary motor cortex (M1) interaction transcranial magnetic stimulation paradigm. The mean PMd–M1 interaction (mean value of all transcranial magnetic stimulation conditioning intensities, eg, 80% and 90% active motor threshold and 110% resting motor threshold, and all interstimulus intervals, eg, 4, 6, and 8 milliseconds) are shown. Mutation carriers on treatment showed a loss of PMd-M1 inhibition compared with healthy controls and after dopaminergic drug withdrawal. Mean amplitudes of conditioned motor evoked potentials (MEPs) are expressed as a percentage of the mean peak-to-peak amplitude of the unconditioned MEP. Bars indicate the standard error of mean. MC, GCH1 mutation carriers; ON, measurements under standard dopaminergic medication; OFF, measurements after a mean dopaminergic drug withdrawal of 22 hours; HC, age-matched and sex-matched healthy controls.

This study documents a characteristic clinical and neurophysiological profile in patients with DRD, with PMd-M1 inhibition and clinical symptoms being responsive to l-dopa and appearing stable across time. However, the general concept of disease progression is probably too heterogeneous to assume that a 5-year period of 10 patients using our clinical and TMS paradigms is sufficient to allow firm conclusions. Therefore, a follow-up multimodal examination is planned in another 5 years.



中文翻译:

多巴反应性肌张力障碍的多模式纵向神经生理学研究

结合肌张力障碍患者的临床和神经生理学检查的多模式纵向研究很少,但可以为表型-基因型-神经生理学相关性以及疾病进展和治疗反应随时间推移的临床和神经生理学标志物奠定基础。

在这方面,归因于三磷酸鸟苷环化水解酶 1 ( GCH1 ) 基因突变1 的多巴 ( l -多巴) 反应性肌张力障碍 (DRD)可能作为遗传未定义肌张力障碍的单基因模型疾病。然而,在 DRD 中使用经颅磁刺激 (TMS) 对新皮质网络变化的检查仅在小患者组 (n = 7) 中显示出异质性结果,并且未与详细的临床调查相结合。短时间间隔内抑制(SICI)的伽马氨基丁酸的量度(GABA)A-GABA能介导的初级运动皮层(M1)的抑制要么正常2或后多巴胺能停药后降低,并且归一化在一项研究中-DOPA取代.3负责运动规划和塑造的背侧运动前皮质 (PMd) 调节后的生理 M1 抑制在 DRD 患者中被消除。4在有和没有多巴胺能药物治疗的更大组的 DRD 患者中进行研究,以纵向方式获得临床和 TMS 参数是可取的。

因此,在当前的研究中,16 名GCH1突变阳性 DRD 患者(1 名男性,平均年龄 45 岁 [范围 15-80 岁];表 SS1)和 16 名匹配的健康对照(HC;4 名男性,平均年龄 45 岁) [范围 19-78 岁]) 接受了视频指导和视频记录的运动检查,使用运动障碍协会赞助的统一帕金森病评定量表 (MDS-UPDRS) 第三部分和Burke-Fahn-Marsden 肌张力障碍评定量表 (BFMDRS)。此外,TMS 用于研究 SICI 和 PMd-M1 相互作用。测量是在多巴胺能治疗下()和平均 22 小时停药后()进行的。在这些患者和对照中,有 10 名接受了纵向调查(),间隔为 5 年。Wilcoxon 符号秩检验用于临床结果分析,方差分析用于 TMS 数据的因素组、药物和时间(参见补充方法)。

有显着的临床改善(BFMDRS13 点标准偏差 [SD] ± 12 和关闭16 点 SD ± 13 [ P  = 0.026] 和 MDS-UPDRS Part III11 点 SD ± 10 和关闭16 点 SD ± 15 [ P  = 0.01]) 在多巴胺能治疗下,5 年内没有恶化。此外,PMd-M1 相互作用显示出对药物的影响(F 1,15  = 13.48,P  = 0.002;图 1),对组或时间没有影响。SICI 分析未显示对药物、时间或组的影响。然而,在纵向 SICI 观察中,比较健康对照和 DRD off存在组效应(F 1,14  = 5.47,P  = 0.035)。多重比较校正后,任何临床或 TMS 结果之间没有相关性(见补充结果)。

形象
图。1
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背侧运动前皮层 (PMd)-初级运动皮层 (M1) 相互作用经颅磁刺激范例的结果。平均 PMd-M1 相互作用(所有经颅磁刺激调节强度的平均值,例如 80% 和 90% 活动运动阈值和 110% 静息运动阈值,以及所有刺激间隔,例如,4、6 和 8 毫秒)是显示。突变携带者治疗表现出与健康对照和多巴胺能停药后相比,PMD-M1抑制的损失。条件运动诱发电位 (MEP) 的平均幅度表示为未条件 MEP 平均峰峰值幅度的百分比。条形表示平均值的标准误差。MC、  GCH1突变携带者;ON,在标准多巴胺能药物下测量;OFF,平均多巴胺能药物停药 22 小时后的测量值;HC,年龄匹配和性别匹配的健康对照。

该研究记录了 DRD 患者的特征性临床和神经生理学特征,PMd-M1 抑制和临床症状对l-多巴有反应,并且随着时间的推移表现稳定。然而,疾病进展的一般概念可能过于异质,无法假设使用我们的临床和 TMS 范例的 10 名患者的 5 年时间足以得出明确的结论。因此,计划再过 5 年进行一次后续多模式检查。

更新日期:2021-08-19
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