Multimodal Longitudinal Neurophysiological Investigations in Dopa‐Responsive Dystonia

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). 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. This study was supported by the Else Kröner-Fresenius Foundation (2018_A55) and the German Research Foundation (WE 5919/2-1, SFB936 project C5, and FOR2488). Support by the European Reference Network–Rare Neurological Diseases (Project 739510) is also gratefully acknowledged. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. A.W.: 1A, 1B, 1C, 2A, 2B, 3A A.S.: 1C, 2B, 3B M.G.P.: 1C, 2C, 3B D.M.A.: 1C, 2C, 3B G.S.: 1C, 2C, 3B A.E.L.: 1C, 2C, 3B N.B.: 1C, 2C, 3B V.T.: 1C, 2C, 3B C.K.: 1C, 2C, 3B K.L.: 1C, 2C, 3B M.J.N.B.: 1C, 2A, 3B C.B.: 1C, 2A, 3B A.M.: 1A, 2A, 2C, 3B T.B.: 1A, 2A, 2B, 2C, 3B A.W. reports the following: Else Kröner-Fresenius grant (EKFS, 2018_A55), German Research Foundation (DFG, WE5919/2–1), and Edmond J. Safra Fellowship in Movement Disorders from The Michael J. Fox Foundation and employment at the University Medical Center Schleswig-Holstein, Campus Lübeck. A.S. has nothing to report. M.G.P. reports the following: employment at the University Medical Center Schleswig-Holstein, Campus Lübeck. D.M.A. reports the following: employment at the Jordan University of Science and Technology, Irbid, Jordan and a scholarship from Jordan University of Science and Technology. G.S. reports the following: employment at Toronto Western Hospital, Toronto, Ontario, Canada and fellowship training supported by the Parkinson's Foundation. A.E.L. reports the following: employment at Toronto Western Hospital, Toronto, Ontario, Canada. N.B. reports the following: consultancies with Centogene and Bridgebio; grants from the German Research Foundation (BR4328/2–2, GRK1957), Collaborative Center for X-linked Dystonia-Parkinsonism, and Else-Kröner Fresenius-Stiftung (HA17_2017); and employment at the University Medical Center Schleswig-Holstein, Campus Lübeck. V.T. reports the following: employment at University Medical Center Schleswig-Holstein, Campus Lübeck. C.K. reports the following: consultancies with Centogene, honorarium for speaking from Desitin; grants from the German Research Foundation (SFB936 project C5 and FOR2488), and employment at theUniversity Medical Center Schleswig-Holstein, Campus Lübeck. K.L. reports the following: grants from the German Research Foundation, Damp Foundation, International Parkinson and Movement Disorder Society, and The Michael J. Fox Foundation (GP2 consortium) and employment at University of Lübeck. M.J.N.B. reports the following: employment at California State University Sacramento, Sacramento, CA. C.B. reports the following: honoraria from Genzyme, Bayer, Novartis, and Teva; a grant from the German Research Foundation (FOR 2698); and employment at the Technical University Dresden, Dresden, Germany. A.M. reports the following: consultancies with Desitin, Merz Pharmaceuticals, and Admedicum; advisory boards of German Tourette Syndrome Association and Alliance of Patients With Chronic Rare Diseases; honoraria from Pharm Allergan, Ipsen, Merz Pharmaceuticals, Actelion, GlaxoSmithKline, Desitin, Teva, and Takeda; grants from Possehl-Stiftung (Lübeck, Germany), Margot und Jürgen Wessel Stiftung (Lübeck, Germany), Tourette Syndrome Association (Germany), Interessenverband Tourette Syndrom (Germany), Cure Huntington Disease Initiative (CHDI), and Damp-Stiftung (Kiel, Germany); academic research support from Deutsche Forschungsgemeinschaft Projects 1692/3–1, 4–1, SFB 936, and FOR 2698 (project numbers 396, 914, 663, 396, 577, 296, 396, 474, 989) and European Reference Network–Rare Neurological Diseases (Project 739510) employment at the University of Lübeck and University Medical Center Schleswig-Holstein, Campus Lübeck; and royalties for the book Neurogenetics (Oxford University Press). T.B. reports the following: advisory boards of Ipsen Pharma, Allergan, and Merz Pharmaceuticals; honoraria from Ipsen Pharma, Allergan, and Merz Pharmaceuticals; Grants, Research Group, DFG FOR 2698; and employment with the University Medical Center Schleswig-Holstein, Campus Lübeck. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Clinical information of 16 GCH1 mutation-positive dopa-responsive dystonia patients. Table S2a. TMS thresholds and test pulse intensities of mutation carriers ON and OFF treatment and healthy controls. Table S2b. TMS thresholds and test pulse intensities of mutation carriers ON and OFF treatment and healthy controls in 2014 and 2019. Table S3a. Results of repeated measures ANOVA comparing SICI of mutation carriers ON and OFF. Table S3b. Results of repeated measures ANOVA comparing SICI of mutation carriers OFF and healthy controls. Table S3c. Results of repeated measures ANOVA comparing SICI of mutation carriers ON and healthy controls. Table S3d. Results of repeated measures ANOVA comparing PMd-M1 interaction of mutation carriers ON vs. OFF. Table S3e. Results of repeated measures ANOVA comparing PMd-M1 interaction of mutation carriers OFF and healthy controls. Table S3f. Results of repeated measures ANOVA comparing PMd-M1 interaction of mutation carriers ON and healthy controls. Table S4a. Results of repeated measures ANOVA comparing longitudinally SICI results of mutation carriers OFF and healthy controls. Table S4b. Results of repeated measures ANOVA comparing longitudinally SICI results of mutation carriers ON vs. OFF. Table S4c. Results of repeated measures ANOVA comparing longitudinally SICI results of mutation carriers ON vs. healthy controls. Table S4d. Results of repeated measures ANOVA comparing longitudinal PMd-M1 results of mutation carriers ON and healthy controls. Table S4e. Results of repeated measures ANOVA comparing longitudinal PMd-M1 results of mutation carriers OFF and healthy controls. Table S4f. Results of repeated measures ANOVA comparing longitudinal PMd-M1 results of mutation carriers ON vs. OFF. Figure S1. Localization of anatomical stimulations sites (MNI coordinates) of the primary motor cortex (posterior spheres: blue indicates GCH1 mutation carriers, dark blue indicates healthy controls) and the dorsal premotor cortex (anterior spheres: white indicates GCH1 mutation carriers, light blue indicates healthy controls) in a 3-D brain using BrainNet Viewer.1 Figure S2. Results of the dorsal premotor cortex (PMd)-primary motor cortex (M1) interaction transcranial magnetic stimulation (TMS) paradigm of 10 longitudinal mutation carriers (DRD) under chronic dopaminergic treatment (ON), after drug withdrawal (OFF) and 10 healthy controls (HC) measured in 2014 and 2019. 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. Mean PMd–M1 interactions averaged across all three conditioning intensities (80% AMT, 90% AMT, and 110% RMT) and three interstimulus intervals (4, 6, and 8 ms) are shown. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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