Accepted Manuscript Dentate nucleus stimulation in a patient with cerebellar ataxia and tremor after cerebellar stroke: A long-term follow-up Rubens Gisbert Cury, Carina França, Egberto Reis Barbosa, Ricardo Galhardoni, Guilherme Lepski, Manoel J. Teixeira, Daniel Ciampi de Andrade PII: S1353-8020(18)30434-6 DOI: 10.1016/j.parkreldis.2018.10.001 Reference: PRD 3799 To appear in: Parkinsonism and Related Disorders Received Date: 22 July 2018 Revised Date: 21 September 2018 Accepted Date: 1 October 2018 Please cite this article as: Cury RG, França C, Barbosa ER, Galhardoni R, Lepski G, Teixeira MJ, Ciampi de Andrade D, Dentate nucleus stimulation in a patient with cerebellar ataxia and tremor after cerebellar stroke: A long-term follow-up, Parkinsonism and Related Disorders (2018), doi: https:// doi.org/10.1016/j.parkreldis.2018.10.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Dentate nucleus stimulation in a patient with cerebellar ataxia and tremor after 2 cerebellar stroke: a long-term follow-up 3 Rubens Gisbert Cury, MD, PhD1; Carina França, MD1; Egberto Reis Barbosa, MD, PhD1; 4 Ricardo Galhardoni, PhD2; Guilherme Lepski, MD, PhD3,5; Manoel J. Teixeira, MD, PhD2,3; 5 Daniel Ciampi de Andrade, MD, PhD2,4 6 1 7 São Paulo, São Paulo, Brazil 8 2 9 Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil. RI PT 1 Movement Disorders Center, Department of Neurology, School of Medicine, University of SC Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), 10 3 11 of São Paulo, São Paulo, Brazil 12 4 Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira, São Paulo, Brazil 13 5 Department of Neurosurgery, University of Tübingen, Germany 14 Corresponding author 15 Rubens Gisbert Cury, MD, PhD 16 Address: Av. Dr. Enéas de Carvalho Aguiar, 255, 5º andar, sala 5084 – Cerqueira César, 05403- 17 900 – São Paulo – SP - Brazil 18 Phone/ Fax: +55 11 26 61 71 52 19 rubens_cury@usp.br 20 Conflict of Interest 21 The authors report no conflict of interest involved in this article. 22 Funding sources for study 23 This project was funded by the Pain Center, University of São Paulo. AC C EP TE D M AN U Functional Neurosurgery Division, Department of Neurology, School of Medicine, University 24 25 26 27 28 1 ACCEPTED MANUSCRIPT Cerebellar modulation has emerged as a promise therapy in the movement 2 disorders field, as cerebellum pathways present connections with critical cortical areas. 3 We have previously reported the short-term outcome in a patient with unilateral 4 cerebellar stroke who improved the ataxia after cerebellar neuromodulation [1,2]. The 5 rational hypothesis lies on the fact that unilateral chronic cerebellar ischemic lesions 6 were linked with a decrease in intracortical inhibition in the contralateral motor cortex, 7 culminating to inter-hemispheric asymmetry in cortical excitability, which could 8 contribute to the motor impairment [3]. Then, modulating the healthy dentate nucleus 9 could increase contralateral intracortical facilitation, restoring cortical excitability 10 symmetry (figure) [2]. We report here the 4-year results of this patient using a single- 11 blinded evaluation. M AN U SC RI PT 1 A 53-year-old female patient underwent a resection of acoustic neuroma, 13 complicated by stroke of the right cerebellar hemisphere. Due to the refractoriness of 14 her ataxia, we conducted double-blind trial of 1 Hz, transcranial magnetic stimulation 15 (TMS) to the left (“healthy”) dentate nucleus (DN). Based on her clear response to 16 TMS, after consent of the patient, she underwent DBS of the left DN. A double-blind 17 assessment 12 months after surgery showed tremor improvement by 37% and ataxia by 18 33%. Motor cortex excitability showed restoration of the asymmetry between both 19 hemispheres during on-condition (supplementary file 1). Details about the procedure 20 have been described [1,2]. AC C EP TE D 12 21 Four years after surgery, the patient (unware to DBS status) was assessed during 22 on-stimulation (1.9 mA, 60 µs, 20 Hz) and 30 minutes after the DBS has been switched 23 off. The tremor continued to further improve (Fahn, Tolosa, Marin Tremor Rating Scale 24 [FTMRS] baseline=38, after=19/144 [50% reduction]) and the ataxia improvement 25 stabilized (scale for the assessment and rating of ataxia [SARA] baseline=25, 2 ACCEPTED MANUSCRIPT 1 after=17/40 [33% reduction]) in the on-stimulation (video, supplementary file 2). When 2 the DBS was switched off, the patient spontaneously reported worsening the symptoms, 3 and the SARA worsened to 30/40 (supplementary file 3). No adverse events were 4 reported. The patient’s global impression of change was 6 (moderately improved). The present case is the first prospective long-term report of DN-DBS in a patient 6 with cerebellar stroke assessed in a blinded fashion. The findings suggest an initial and 7 sustained benefit in tremor and ataxia of unilateral DN-DBS along with long-term safety 8 and a good tolerability profile. SC RI PT 5 To date, only few studies have been designed to assess the effects of cerebellar 9 modulation. A recent study showed that stimulation of dentate nucleus in rats with 11 cortical stroke was associated with motor recovery, probably via intensification of 12 perilesional excitability [4]. Two trials reported improvement in posture and gait in 13 patients with cerebellar ataxia due to stroke after repetitive-TMS stimulation [4]. In 14 regard to cerebellar DBS, there is no study focusing exclusively in ataxia outcomes. 15 In addition to the evidence that cerebellar modulation could restore the altered TE D M AN U 10 cortical excitability asymmetry seen between both motor cortices after a chronic 17 cerebellar stroke, structural changes in brain blood flow and metabolism can also be 18 involved in the pathophysiology [4]. Patients with spinocerebellar degeneration showed 19 increased brain blood flow in the cerebellum, putamen, and pons after sessions of 20 cerebellar TMS. A reduction in cerebellar metabolism after 5 sessions of cerebellar TBS 21 in parkinsonian patients was observed through positron emission tomography imaging 22 [5]. 23 AC C EP 16 Despite the consistent result described in the present case, and a reasonable 24 explanation for the improvement, at least in part, based on the restored cortical 25 excitability, the hypothesis on why cerebellar stimulation could change motor 3 ACCEPTED MANUSCRIPT symptoms after cerebellar lesions is still theoretical. This is the index case, and larger 2 prospective studies are obviously necessary. The best target into the cerebellum (DN or 3 the dentate-rubro-thalamic tracts or both), the stimulation parameters, and the baseline 4 clinical characteristics predictive of response should be further explored. Interestingly, 5 during the off-stimulation in the last follow-up (4 years) the SARA worsened when 6 compared to the preoperative score, i.e., after the stimulation has been switched off, the 7 worsening of symptoms exceeded the baseline levels, probably reflecting a rebound 8 phenomena. Defining whether the sudden interruption of stimulation affects the 9 cerebellar-cortical circuitry and whether these rebound symptoms also occur when 10 stimulation is tapered off slowly could help explain the mechanism behind the effects of 11 cerebellar modulation SC M AN U 12 RI PT 1 Continuous progress in our understanding of brain pathology, connectivity and biomarkers will certainly contribute to the field of movement disorders research, 14 especially regarding new brain targets for neuromodulation. We showed that DN-DBS 15 improved tremor and ataxia in a single patient with cerebellar stroke, and this effect is 16 sustainable over time. The study protocol was safe and well tolerated. Additional 17 comprehensive studies are required to bring evidences for its application in clinical 18 practice. 20 21 EP AC C 19 TE D 13 22 23 24 25 4 ACCEPTED MANUSCRIPT 1 Acknowledgement 2 None. 3 4 RI PT 5 6 7 SC 8 9 M AN U 10 11 12 13 17 18 19 20 21 EP 16 AC C 15 TE D 14 22 23 24 25 5 ACCEPTED MANUSCRIPT References: 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 [1] R.G. Cury, M.J. Teixeira, R. Galhardoni, V.R. Barboza, E. Alho, C.M. Seixas, G. Lepski, D. Ciampi de Andrade, Neuronavigation-guided transcranial magnetic stimulation of the dentate nucleus improves cerebellar ataxia: A shamcontrolled, double-blind n = 1 study, Parkinsonism Relat. Disord. (2015). doi:10.1016/j.parkreldis.2015.05.010. [2] M.J. Teixeira, R.G. Cury, R. Galhardoni, V.R. Barboza, A.R. Brunoni, E. Alho, G. Lepski, D. Ciampi de Andrade, Deep brain stimulation of the dentate nucleus improves cerebellar ataxia after cerebellar stroke, Neurology. 85 (2015) 2075– 2076. doi:10.1212/WNL.0000000000002204. [3] S.N. Farias da Guarda, L.G. Cohen, M. da Cunha Pinho, F.I. Yamamoto, P.E. Marchiori, M. Scaff, A.B. Conforto, Interhemispheric asymmetry of corticomotor excitability after chronic cerebellar infarcts, Cerebellum Lond. Engl. 9 (2010) 398–404. doi:10.1007/s12311-010-0176-7. [4] C. França, D.C. de Andrade, M.J. Teixeira, R. Galhardoni, V. Silva, E.R. Barbosa, R.G. Cury, Effects of cerebellar neuromodulation in movement disorders: A systematic review, Brain Stimulat. 11 (2018) 249–260. doi:10.1016/j.brs.2017.11.015. [5] L. Brusa, R. Ceravolo, L. Kiferle, F. Monteleone, C. Iani, O. Schillaci, P. Stanzione, G. Koch, Metabolic changes induced by theta burst stimulation of the cerebellum in dyskinetic Parkinson’s disease patients, Parkinsonism Relat. Disord. 18 (2012) 59–62. doi:10.1016/j.parkreldis.2011.08.019. 29 30 31 32 33 SC M AN U TE D 28 EP 27 AC C 24 25 26 RI PT 1 34 35 36 37 6 ACCEPTED MANUSCRIPT Figure. Representation of the physiology of cerebellar cortical pathway and the 2 effect of the dentate-deep brain stimulation after unilateral lesion of the 3 cerebellum. 4 Legend. Panel A displays the excitatory cerebellum-cortico pathway passing through 5 the rubro nucleus and thalamus. There is an ICI between both M1 cortices that is related 6 to preserving the integrity of limbs coordination (panel B). Panel C shows a progression 7 of changes in intracortical motor function over time following a contralateral cerebellar 8 lesion leading toward progressive disinhibition of the primary motor cortex (the ICI of 9 contralesional M1 decreases). Panel D shows the restoration of the interhemispheric 10 asymmetry after DBS of the left DN (ICF of the ipsilesional M1 and ICI of the 11 contralesional M1 both increase). DN = Dentate Nucleus, R = Rubro Nucleus, Th = 12 Thalamus, M1 = Motor Cortex, ICI = Intracortical Inhibition, ICF = Intracortical 13 Facilitation, Green arrow = Excitatory projection, Red arrow = Inhibitory projection 14 (adapted from Teixeira et al., 2015). 18 19 20 21 SC M AN U TE D 17 EP 16 AC C 15 RI PT 1 22 23 24 25 7 ACCEPTED MANUSCRIPT Supplementary File 1. Cortical excitability parameters during on- and off-stimulation 2 according to the brain hemisphere. 3 Legend. During the on-stimulation condition, the ipsilesional M1 (right hemisphere) 4 intracortical facilitation (ICF) was increased (bold). CE = cortical excitability; ICF = 5 Intracortical Facilitation; MEP = Motor evoked potentials. RI PT 1 6 Supplementary File 2. Video. At baseline, the patient had cerebellar ataxia, action 8 tremor, dysmetria, and impaired handwriting. She had difficulty performing manual 9 tests such as drawing an Archimedes' spiral. One year and four years after DBS of the 10 healthy DN there is a clinical improvement in terms of dysmetria, writing, drinking. M AN U SC 7 11 Supplementary File 3. Evolution of ataxia and tremor over time. 13 Legend. DBS = deep brain stimulation; FTMTRS = Fahn Tolosa Marin Tremor Rating 14 Scale; m = months; SARA = Scale for the assessment and rating of ataxia. 17 EP 16 AC C 15 TE D 12 8 AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT