Deep brain stimulation and refractory freezing of gait in Parkinson’s disease: Improvement with high-frequency current steering co-stimulation of subthalamic nucleus and substantia Nigra

Abstract

Axial and gait disorders in Parkinson’s Disease (PD) are considered signs of disease progression with involvement of the extra nigrostriatal system. In PD patients treated with subthalamic nucleus (STN) deep brain stimulation (DBS), these symptoms may also occur from spread of the electric field outside the STN [[1]Gilat M. Lígia Silva de Lima A. Bloem B.R. Shine J.M. Nonnekes J. Lewis S.J.G. Freezing of gait: promising avenues for future treatment.Park Relat Disord. 2018; 52: 7-16https://doi.org/10.1016/j.parkreldis.2018.03.009Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. Various approaches have been suggested to manage gait disturbances [1Gilat M. Lígia Silva de Lima A. Bloem B.R. Shine J.M. Nonnekes J. Lewis S.J.G. Freezing of gait: promising avenues for future treatment.Park Relat Disord. 2018; 52: 7-16https://doi.org/10.1016/j.parkreldis.2018.03.009Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 2Moreau C. Defebvre L. Destee A. Bleuse S. Clement F. Blatt J.L. et al.STN-DBS frequency effects on freezing of gait in advanced Parkinson disease.Neurology. 2008; 71: 80-84https://doi.org/10.1212/01.wnl.0000303972.16279.46Crossref PubMed Scopus (249) Google Scholar, 3Fasano A. Herzog J. Seifert E. Stolze H. Falk D. Reese R. et al.Modulation of gait coordination by subthalamic stimulation improves freezing of gait.Mov Disord. 2011; 26: 844-851https://doi.org/10.1002/mds.23583Crossref PubMed Scopus (72) Google Scholar] and substantia nigra pars reticulata (SNr) DBS has recently been reported to improve resistant freezing of gait (FoG) [[4]Weiss D. Breit S. Wächter T. Plewnia C. Gharabaghi A. Krüger R. Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson’s disease.J Neurol. 2011; 258: 1183-1185https://doi.org/10.1007/s00415-011-5906-3Crossref PubMed Scopus (36) Google Scholar,[5]Chastan N. Westby G.W.M. Yelnik J. Bardinet E. Do M.C. Agid Y. et al.Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson’s disease.Brain. 2008; 132: 172-184https://doi.org/10.1093/brain/awn294Crossref PubMed Scopus (97) Google Scholar]. We describe the case of a young-onset PD patient who developed left arm tremor at the age of 34 years. In 2005, after 10 years of disease progression, with troublesome wearing-off, resistant tremor and disabling dyskinesias, he underwent bilateral STN-DBS (3389 leads, Medtronic, Minneapolis, MN, USA). Satisfactory control of motor symptoms was achieved with DBS and optimization of oral therapy with rotigotine (16 mg/day) and levodopa (500 mg/day). Postoperative MRI and initial stimulation parameters are shown in Fig. 1A. The implantable pulse generator (IPG) was replaced in 2009 with Kinetra® (Medtronic, Minneapolis, MN, USA) and in 2013 with a Libra XP™ hybrid system (Abbott-St Jude Medical, Saint Paul, USA). Stimulation parameters were not changed but switched from constant voltage (3.0 V) to constant current stimulation (3.6 mA) in both electrodes, to maintain good control of motor symptoms. Dopaminergic oral therapy was not modified. In 2015, the patient developed rare FoG episodes. After overnight withdrawal, several observations in this practical OFF medication condition suggested a major contribution of left leg in triggering FoG. These FoG episodes were unresponsive to optimization of both best medical treatment (levodopa [800 mg/day] and rotigotine [16 mg/day]) and modification of stimulation parameters during an updated monopolar review in the right hemisphere testing the ventral and dorsal contacts (9- and 12-). In addition, asymmetric stimulation by lowering the stimulation amplitude contralaterally to the side with longer step length did not resolve FoG. Because of battery depletion, a rechargeable IPG (Vercise™, Boston Scientific, Marlborough, USA) was implanted in 2017, keeping the stimulation parameters constant (Fig. 1B). Over the following months, FoG became progressively disabling with occasional falls and marked turn hesitation in the left leg (Video 1, segment 1). He scored 23/64 on the Gait and Falls Questionnaire and 20/28 on the Tinetti scale (Table 1). Cognitive evaluation was normal.Table 1Summary of stimulation settings and respective outcomes. Regarding Gait and Falls Questionnaire, the higher the score, the more severe the symptoms, while for the Tinetti scale, the higher the score, the less severe the symptoms. Gait and Falls Questionnaire: maximum score = 64. Tinetti Scale maximum score = 28.Right Electrode. Contacts (% of current distribution)Amplitude (mA)Pulse width (μsec)Frequency (Hz)Gait and Falls QuestionnaireTinetti scale10- (50%), 11- (50%)3.66013023209- (50%), 10- (31%), 11- (19%)4.5608019239- (50%), 10- (31%), 11- (19%)3.6601301428 Open table in a new tab Therefore, we decided to use the same contacts (10- and 11-) but lowered the stimulation frequency to 80 Hz and increased the amplitude to 4.5 mA to maintain the same total electrical energy delivered (TEED) bilaterally. This attempt was unsuccessful because of worsening of cardinal motor symptoms in the left hemibody without sufficient improvement of FoG. We next shaped the electric field vertically by activating the lowest contact 9 (9- [50%], 10- [31%], 11 – [19%]). A 4-week trial using the same setting at 80 Hz improved FoG slightly but worsened PD segmental symptoms, especially bradykinesia (Video 1, segment 2 and Table 1). Since the volume of tissue activated (VTA) with this DBS setting (GUIDETM XT software, Boston Scientific, Valencia, CA, USA), seemed to simultaneously involve the STN and SNr, we decided to stimulate both of these nuclei with high-frequency DBS, as suggested by others [[4]Weiss D. Breit S. Wächter T. Plewnia C. Gharabaghi A. Krüger R. Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson’s disease.J Neurol. 2011; 258: 1183-1185https://doi.org/10.1007/s00415-011-5906-3Crossref PubMed Scopus (36) Google Scholar,[5]Chastan N. Westby G.W.M. Yelnik J. Bardinet E. Do M.C. Agid Y. et al.Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson’s disease.Brain. 2008; 132: 172-184https://doi.org/10.1093/brain/awn294Crossref PubMed Scopus (97) Google Scholar]. Current amplitude and frequency were respectively changed to 3.6 mA and 130 Hz (Fig. 1C), obtaining remarkable FoG relief (Video 1, segment 3). The patient reported satisfactory control of PD cardinal symptoms, with significant reduction of FoG episodes at the 6- and 9- month follow-up. The patient had no further falls, and gait scales improved by 39% and 40% (Gait and Falls Questionnaire and Tinetti scales, respectively), with items related to turn hesitation being most improved (Table 1). The following is the supplementary data related to this article:eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0NDcyZDA3MTJmNjFmNWI2YmE1YTdkZDVhMTZjYzE4NyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjM2Nzk5OTc4fQ.BMb4QA04_ftgdk8EkLzJPFzBgeHcJBMSZj7PF5SdCAkefj5eYhiJ_nmp4Oxmxvcrlf2yYccUdctVlw2dw9bem3aTvI-9-UEVBsPpIm1ovuBq0FshCUL4ML0FzQNABHJmnnO7flfug7l9BUQggQMo5VxeZ9kKGKxbtKhbmQwNyDTG2ysVDTPaRMdkZpeY7MMDaFX4PUU3q4pMBxFwIJx-vlzTNbJd31_9FgHZUY61EOD18arZYMl7bhPxXZRR7O2Adr2vhc1l636wynCHQu9i-foxTO0q5E7la2fDQ-RdtwpqrjB4ZMp_OzT_uQ8S-KuPmBH2QZoZQl7LAJhslu3iAQ(mp4, (14.09 MB) Download video eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0NDcyZDA3MTJmNjFmNWI2YmE1YTdkZDVhMTZjYzE4NyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjM2Nzk5OTc4fQ.BMb4QA04_ftgdk8EkLzJPFzBgeHcJBMSZj7PF5SdCAkefj5eYhiJ_nmp4Oxmxvcrlf2yYccUdctVlw2dw9bem3aTvI-9-UEVBsPpIm1ovuBq0FshCUL4ML0FzQNABHJmnnO7flfug7l9BUQggQMo5VxeZ9kKGKxbtKhbmQwNyDTG2ysVDTPaRMdkZpeY7MMDaFX4PUU3q4pMBxFwIJx-vlzTNbJd31_9FgHZUY61EOD18arZYMl7bhPxXZRR7O2Adr2vhc1l636wynCHQu9i-foxTO0q5E7la2fDQ-RdtwpqrjB4ZMp_OzT_uQ8S-KuPmBH2QZoZQl7LAJhslu3iAQ(mp4, (14.09 MB) Download video To our knowledge, this is the first description of a patient affected by FoG resistant to changes in both medication and conventional DBS paradigms who has benefited from a hybrid system. Indeed, IPG replacement using a device with multiple independent current control (MICC) allowed fine tuning of stimulation parameters; in particular, we were able to ventrally steer the current with probable co-modulation of STN and SNr activity, as suggested by Guide™ XT software (Fig. 1C). Regarding FoG in STN-DBS implanted patients, the literature suggests reducing the stimulation frequency [[2]Moreau C. Defebvre L. Destee A. Bleuse S. Clement F. Blatt J.L. et al.STN-DBS frequency effects on freezing of gait in advanced Parkinson disease.Neurology. 2008; 71: 80-84https://doi.org/10.1212/01.wnl.0000303972.16279.46Crossref PubMed Scopus (249) Google Scholar]. However, this was not effective in our patient. Similarly, decreasing stimulation amplitude on the side contralateral to the leg with longer step length, as suggested by others [[3]Fasano A. Herzog J. Seifert E. Stolze H. Falk D. Reese R. et al.Modulation of gait coordination by subthalamic stimulation improves freezing of gait.Mov Disord. 2011; 26: 844-851https://doi.org/10.1002/mds.23583Crossref PubMed Scopus (72) Google Scholar,[6]Meoni S. Debȗ B. Pelissier P. Scelzo E. Castrioto A. Seigneuret E. et al.Asymmetric STN DBS for FOG in Parkinson’s disease: a pilot trial.Park Relat Disord. 2019; https://doi.org/10.1016/j.parkreldis.2019.02.032Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar], was unsuccessful. We observed remarkable improvement in FoG with SNr high-frequency stimulation (HFS), as reported by others [[4]Weiss D. Breit S. Wächter T. Plewnia C. Gharabaghi A. Krüger R. Combined stimulation of the substantia nigra pars reticulata and the subthalamic nucleus is effective in hypokinetic gait disturbance in Parkinson’s disease.J Neurol. 2011; 258: 1183-1185https://doi.org/10.1007/s00415-011-5906-3Crossref PubMed Scopus (36) Google Scholar,[5]Chastan N. Westby G.W.M. Yelnik J. Bardinet E. Do M.C. Agid Y. et al.Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson’s disease.Brain. 2008; 132: 172-184https://doi.org/10.1093/brain/awn294Crossref PubMed Scopus (97) Google Scholar,[7]Lewis S.J.G. Shine J.M. The next step: a common neural mechanism for freezing of gait.Neurosci. 2016; 22: 72-82https://doi.org/10.1177/1073858414559101Crossref Scopus (72) Google Scholar]. An animal model of HFS in PD suppressed the hyperactive SNr outflow, resulting in FoG reduction [[8]Sutton A.C. Yu W. Calos M.E. Smith A.B. Ramirez-Zamora A. Molho E.S. et al.Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat.J Neurophysiol. 2013; 109: 363-374https://doi.org/10.1152/jn.00311.2012Crossref PubMed Scopus (30) Google Scholar]. It is conceivable that HFS inhibits the GABAergic projections directed from the globus pallidus pars interna and SNr to the mesencephalic locomotor region, considered the most important generator for gait automaticity [[7]Lewis S.J.G. Shine J.M. The next step: a common neural mechanism for freezing of gait.Neurosci. 2016; 22: 72-82https://doi.org/10.1177/1073858414559101Crossref Scopus (72) Google Scholar]. Furthermore, electrophysiological experiments in a microstimulation study have suggested that the higher the stimulation frequency, the longer the SNr inhibition [[9]Lafreniere-Roula M. Kim E. Hutchison W.D. Lozano A.M. Hodaie M. Dostrovsky J.O. High-frequency microstimulation in human globus pallidus and substantia nigra.Exp Brain Res. 2010; 205: 251-261https://doi.org/10.1007/s00221-010-2362-8Crossref PubMed Scopus (44) Google Scholar]. In summary, this case highlights three key points. (1) High-frequency co-modulation of the STN and SNr was essential to improve disabling FoG without negatively affecting other PD cardinal symptoms. (2) This approach was only feasible by using a hybrid system with a MICC IPG. (3) Fine tuning of DBS was possible through the volumetric estimation of the electric field spreading to both the SNr and STN using proprietary software. Combined with recent literature, our case highlights the need to further study the effects of the SNr-DBS in advanced PD patients. The anatomical proximity of the SNr to the STN allows simultaneous stimulation of both targets, now achievable with newer stimulation systems. This approach might be considered as a rescue therapy for resistant FoG in STN-DBS. 1. Clinical Follow-up of the patient: A. Conception, B. Organization, C. Execution;2. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;3. Final approval. NGA: Conception, Organization, Execution, Writing of the first draft, Final approval; VR: Conception, Organization, Execution, Writing of the first draft, Review and Critique, Final approval; EC: Execution, Writing of the first draft, Review and Critique, Final approval; FC: Execution, Review and Critique, Final approval; ML: Review and Critique, Final approval; MAC: Conception, Review and Critique, Final approval; MS: Conception, Organization, Execution, Review and Critique, Final approval. The patient gave his informed consent prior the inclusion in the study and written informed consent was obtained for videotaping and to use the videos for scientific purposes. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.