Clinical Study Stereotact Funct Neurosurg DOI: 10.1159/000509317 Received: February 20, 2020 Accepted: June 10, 2020 Published online: August 26, 2020 Subthalamic Nucleus Deep Brain Stimulation in Post-Infarct Dystonia Kantharuby Tambirajoo a Luciano Furlanetti a Michael Samuel b Keyoumars Ashkan a a Department of Neurosurgery, King’s College Hospital NHS Foundation Trust, London, UK; b Department of Neurology, King’s College Hospital NHS Foundation Trust, London, UK Abstract Dystonia secondary to cerebral infarcts presents months to years after the initial insult, is usually unilateral and causes significant morbidity. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is established as the most frequent target in the management of the dystonic symptoms. We report our experience with subthalamic nucleus (STN) DBS in 3 patients with post-infarct dystonia, in whom GPi DBS was not confidently possible due to the presence of striatal infarcts. Two patients had unilateral STN DBS implantation, whereas the third patient had bilateral STN DBS implantation for bilateral dystonic symptoms. Prospectively collected preoperative and postoperative functional assessment data including imaging, medication and neuropsychology evaluations were analyzed with regard to symptom improvement. Median follow-up period was 38.3 months (range 26–43 months). All patients had clinically valuable improvements in dystonic symptoms and pain control despite variable improvements in the Burke-Fahn-Marsden dystonia rating scores. In our series, we have demonstrated that STN DBS could be an alternative in the management of post-infarct dystonia in patients with abnormal striatal anat- karger@karger.com www.karger.com/sfn © 2020 S. Karger AG, Basel omy which precludes GPi DBS. A multidisciplinary teambased approach is essential for patient selection and management. © 2020 S. Karger AG, Basel Introduction Hemidystonia is characterized by unilateral sustained or intermittent muscle contractions and involuntary, often repetitive movements involving arm, leg and/or face [1]. It is an acquired condition, usually secondary to brain lesions such as stroke, tumors or infection [1] and has been considered to be the result of aberrant reorganization of the motor network after brain injury [2]. Cerebral infarction is the most common etiology of symptomatic hemidystonia [3, 4]. Overall surgical outcomes in acquired dystonia cases are variable depending on the pathology [5–8]. Previous reports have described the globus pallidus internus (GPi) as a target for deep brain stimulation (DBS) in post-infarct hemidystonia [9–15]. In this paper, we report our experience of using subthalamic nucleus DBS (STN DBS) as an alternative target to treat 3 patients with clinically significant refractory post-infarct M.S. and K.A. are joint last authors. Kantharuby Tambirajoo Department of Neurosurgery King’s College Hospital NHS Foundation Trust Denmark Hill, London SE5 9RS (UK) Kantharuby.tambirajoo @ nhs.net Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM Keywords Post-infarct dystonia · Subthalamic nucleus · Deep brain stimulation 6 (14.3)b 7 46.5 Left Case+, 1– 0.6 V, 60 µs, 130 Hz Right Case+, 8–, 9–, 1.7 V, 60 µs,130 Hz Trihexphendryl 6 mg BD, baclofen 20 mg TDS, gabapentin 200 mg OD, co-codamol PRN, botulinum toxin injection (left arm) Infarct of the right posterior putamen and corona radiata with possible signal change within the globus pallidus. Right putamen hypometabolism on FDG-PET 0.78 18 3 years 4 Male 3 Stereotact Funct Neurosurg DOI: 10.1159/000509317 Methods Patient Selection Three patients with medically refractory dystonia due to striatal infarcts underwent STN DBS implantation. A comprehensive multi-disciplinary review, including neurological, neurosurgical, neuropsychological, nursing and neuropsychiatric assessments were completed for each patient prior to surgery. Quantification of dystonic signs and symptoms was done at baseline and at last follow-up using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) movement score and disability score [16]. Overall percentage change in BFMDRS score was calculated, and standard clinical assessments also recorded pre- and postoperatively. This study was approved by our institution’s Research Advisory Group, and informed consent was obtained from all patients. Surgical Procedure Quadripolar Medtronic 3389 DBS electrodes (Medtronic Inc., Minneapolis, MN, USA) were implanted under general anesthesia using stereotactic MRI with a Leksell G frame (Elekta Instruments AB, Stockholm, Sweden). A direct targeting technique was utilized with single-track impedance recording. Patients 1 and 2 had single electrodes targeted to the STN ipsilateral to the previous stroke, whereas patient 3 had bilateral STN electrodes implanted due to presence of bilateral symptoms. Postoperative stereotactic computed tomography was performed, and final electrode position confirmed by fusion of preoperative and postoperative images. A Medtronic primary cell Activa SC (Medtronic; Patient 1) or rechargeable Activa RC (Patients 2 and 3) implantable pulse generator (IPG) was placed subcutaneously in the infraclavicular region and connected to the electrode(s) in a single-stage operation. Image processing, co-registration, normalization and segmentation of the DBS leads were performed on LEAD-DBS. An ultra-high resolution single-echo multi-flip Fast Low-Angle Shot (FLASH) MRI dataset spatially normalized into MNI_ICBM_2009b_NLIN_ ASYM space [17] was used as template in Figure 1b, d and f. LeadDBS is a MATLAB-based software package whose code is available at GitHub (www.github.com/netstim/leaddbs) [18]. Results Case Reports Table 1 and Figures 1–3 show the patient characteristics, imaging and postoperative outcomes. Patient 1 was 9 years old when he sustained a traumatic left internal carotid artery dissection with a resultant stroke manifesting as aphasia and right hemiparesis. The face and speech recovered quickly but otherwise hemiparesis persisted. Dystonic symptoms started 2 months later and progressed to painful overflow dystonia affecting Tambirajoo/Furlanetti/Samuel/Ashkan Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM 8 (11.1) 9 24 (14.3) 28 Case+, 1– 3.8 V, 90 µs, 130 Hz Infarct of the right frontal region involving the putamen, Biperiden 2 mg TDS, clonazepam 0.5 mg TDS, internal capsule and globus pallidus interna baclofen 10 mg TDS, botulinum toxin injection (left arm and leg) 0.61 18 3 months 7 Female 2 BFMDRS, Burke-Fahn-Marin Dystonia Rating Scale; MS, movement score; DS, disability score; ICA, internal carotid artery; FDG-PET, fluorodeoxyglucose positron emission topography. a Proportion of life lived with dystonia calculated as ratio of dystonia duration to age at surgery. b Scores were performed at 24 months’ follow-up. 6 (33.3) 9 10 (64.2) 28 2+, 3–, 2.6 V, 90 µs, 130 Hz None at time of surgery; previously tried clonazepam, carbamazepine and tetrabenazine; unsuccessful botulinum toxin injection to right leg Infarct involving the left caudate, putamen and globus pallidus extending into the cortex and surrounding white matter with lateral ventricle enlargement, loss of left cerebral peduncle volume and narrowing of left ICA 9 Male 1 2 months 21 0.62 baseline 42 (14)b 36 months baseline 36 months BFMDRS DS (% improvement) BFMDRS MS (% improvement) Optimal stimulation settings Baseline medications Radiological findings Proportion of life lived with dystoniaa Age at Dystonia onset following surgery, years stroke Age at stroke, years Case Gender Table 1. Patient baseline characteristics and outcomes after DBS surgery 2 dystonia, 2 presenting with hemidystonia and one with bilateral manifestations, in whom the stroke-induced disturbed striatal anatomy prevented DBS of the GPi target. Fig. 1. a MRI T2 axial image of patient 1 demonstrating an infarct in the left caudate, putamen and globus pallidus. b Localization of the left deep brain stimulation electrode in patient 1. Standard space with segmentation of the subthalamic nucleus (orange) and red nucleus (red; left anterolateral view). a b a b Fig. 2. a MRI T2 axial image of patient 2 demonstrating an infarct involving the right putamen, internal capsule and globus pallidus interna. b Location of the right STN electrode in patient 2 (right anterolateral view). Standard space with segmentation of the subthalamic nucleus (orange) and red nucleus (red). Fig. 3. a MRI T2 axial image of patient 3 a b his right arm and foot with a tight fist and flexed fingers. He had no bimanual activity but was able to walk independently with a circumducting gait. The abnormal posturing reversed during sleep. Due to persistent dystonic symptoms for 12 years after his stroke and failure of medical management including botulinum toxin injections at improving his movements or pain, the patient accepted stereotactic surgery. The left GPi could not be used as a target with confidence because of the presence of an infarct involving the left caudate, putamen and globus pallidus, extending into the cortex and surrounding white matter (Fig. 1a), and so we elected for insertion of a single DBS electrode into the left STN with an Activa SC battery, at the age of 21 years (Fig. 1b). Upon activation of the DBS system, immediate ease of hand movement was noted and over the next few months, hand dexterity and subjective pain levels greatly improved with increased stimulation parameters. He unfortunately hit his head on a metal bench 9 months after surgery and rapidly lost all stimulation benefit, reverting to his preoperative state. Interrogation of the system revealed high impedances, although CT and X-ray imaging did not reveal any obvious lead fractures. Despite attempts at multiple re-programming sessions, the lost benefit was not regained, and subsequent surgical revision revealed a lead fracture. Post-revision, bipolar stimulation proved most efficacious resulting in improved ambulation and 60% improvement in foot and hand dys- STN DBS in Post-Infarct Dystonia Stereotact Funct Neurosurg DOI: 10.1159/000509317 3 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM demonstrating an infarct of the right posterior putamen and corona radiata with possible involvement of globus pallidus. b Location of bilateral STN electrodes in patient 3. Standard space with segmentation of the subthalamic nucleus (orange) and red nucleus (red; anterior view). 4 Stereotact Funct Neurosurg DOI: 10.1159/000509317 MRI scan revealed evidence of a mature infarct involving the right posterior putamen and corona radiata with possible signal change within globus pallidus (Fig. 3a). Although the signal change within the globus pallidus was not extensive, because of concerns over its proximity to the area affected by the stroke and possible functional involvement, it was decided best to opt for an alternative target. No abnormalities were seen in the left hemisphere to account for his right-sided symptoms. Nonetheless, given the bilateral nature of his symptoms, he underwent bilateral STN DBS and Activa RC IPG implantation at the age of 18 years (Fig. 3b). At 1 month, he had 30% better control of movements and transient postoperative worsening of speech which resolved. By 3 months, his pain had fully resolved with 60% improvement in bilateral dystonic movements and ability to walk faster. These positive gains were sustained at his 1- and 2-year follow-ups, and he was able to complete secondary education. BFMDRS motor and disability scores improved by 14 and 14.3%, respectively, at 2-year follow-up. Final settings were left: case+, 1–, 0.7 V, 60 µs, 130 Hz, and right: case+, 8–, 9–, 1.7 V, 60 µs, 130 Hz. Discussion The natural history of post-infarct dystonia typically consists of a period of hemiparesis and variable recovery of motor deficit followed by development of progressive dystonia a number of months later [3], which can persist. As expected, the latency in development of hemidystonia in our series ranged from 2 months to 3 years with progressive dystonic symptoms and pain. This latency period has been reported to occur even up to 40 years after the initial insult [3, 4]. The latency is longest when the insult was due to perinatal injury, either reflecting the greater ability of the developing brain to compensate for cerebral insults or the delay in recognizing the hemidystonic symptoms. Possible explanations for the delayed onset of dystonia have been attributed to aberrant neuronal sprouting, transsynaptic neuronal degeneration or receptor super-sensitivity secondary to denervation [3, 14, 19], although the mechanism(s) remain unclear. A recent functional MRI study demonstrated that patients with hemidystonia have variable motor reorganization including intra and interhemispheric patterns [20]. “Hyperkinetic” hemidystonic patients (dystonia with a prominent phasic component) exhibit decreased activation in the contralateral thalamus, globus pallidus and medial temporal cortex, with preserved postTambirajoo/Furlanetti/Samuel/Ashkan Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM tonia with minimal spasms. At 3 years’ follow-up, there was a 64.2% improvement in his BFMDRS motor score and 33.3% improvement in the disability score. Final setting was 2+, 3–, 2.6 V, 90 µs and 130 Hz. Patient 2 was 7 years old when she sustained a postvaricella encephalitis right basal ganglia infarct. Facial weakness and speech recovered within 24 h, but left sided hemiparesis otherwise persisted. Dystonic symptoms emerged 3 months later and progressed steadily. Her main symptoms were pain of the left arm affecting school attendance and dystonic movements of the left arm which caused difficulties with most activities of daily living. She had no arm spasticity which was held in adduction with incomplete elbow extension, flexion of the fingers and a fluctuating tone. There was reversal of dystonia during sleep. She also had posturing of the left toes and walked with the aid of a leg brace. Multiple oral medications conferred unsatisfactory benefit whilst botulinum injections to the left arm and leg were only short-lasting. As her MRI scan revealed an infarct of the right putamen, internal capsule and globus pallidus interna (Fig. 2a), a decision was made to offer a right sided STN DBS implantation with an Activa RC battery which was carried out at the age of 18 years (Fig. 2b). Significant micro-lesioning effect was experienced for 3 weeks with transient improvement in her gait resulting in the ability to walk without a leg brace and subjectively reduced pain levels. One year post-surgery, her pain and spasms had reduced by 100 and 90%, respectively. There was no significant functional arm improvement but with the improvement in position and pain, she was able to complete school and start a university degree. At 2 years postoperatively, she remained pain free with a 60% subjective improvement in arm dystonia and 80–90% improvement in foot dystonia, leading an independent life. BFMDRS motor and disability scores at last follow-up at 3 years had improved by 14.3 and 11.1%, respectively. Final setting was case+, 1–, 3.8 V, 90 µs and 130 Hz. Patient 3 was 4 years old when he sustained a right basal ganglia infarct which was preceded by 7–10 days of vomiting and a varicella-zoster infection 6 months earlier. Dystonic symptoms started 3 years later and were worse in the arm. His left arm was non-functioning with severe and extreme dystonic posturing causing pain and requiring a range of strategies that disturbed his concentration ability. He had mild dysarthria and walked with a stick. Interestingly, he also had subtle right-sided features manifested by cramped writing with excessive force and decreased speed, and minor posturing of the right foot. Botulinum toxin to his left arm reduced the pain for 6–8 weeks only. final outcomes at 6 1/2 years mean follow-up stated as fair or good in 4 patients [29]. A further report of 7 patients with post-traumatic hemidystonia who underwent zona incerta and/or ventrolateral thalamus thalamotomy demonstrated immediate improvement in dystonic symptoms post-surgery which then reappeared over a followup period of 3 years [30]. Transient hemiparesis was noted in 4 patients. In contrast, in another series of 3 hemidystonia patients (1 post-infarct, 2 post-traumatic) who underwent Vim or ventralis oralis interna thalamotomy, only mild or transient improvement was seen after surgery [3]. More recently in the DBS era, multi-targeting has been postulated as a means of achieving better outcomes in patients with highly disorganized motor networks as in hemidystonia. Thus, when thalamic DBS was combined with GPi DBS, better clinical improvement was reported in idiopathic [31] and post-infarct [15] hemidystonia. Clearly though, any advantage of such multi-electrode technique will need to be balanced against the surgical risks. The STN as a key component of the basal ganglia thalamo-cortical circuit, has the advantage of being further away from distorted structures after a striatal infarct and can appear structurally normal. Furthermore, unlike the thalamus, STN is amenable to direct targeting as it is readily visualized on specific MRI sequences, important when targeting the structurally distorted post-infarct brain [32]. For these reasons, in these 3 cases, STN was chosen as the most appropriate target, with the potential for conferring clinical benefit and avoiding the need for multitargeting with the added risks. Indeed, there is substantial evidence demonstrating the safety and efficacy of subthalamic DBS in inherited, acquired or idiopathic dystonia (see Table 2 for summary of studies). A long-term follow-up study of 14 patients with primary dystonia who underwent STN DBS showed a 91% improvement in BFMDRS score which was maintained long-term with improved quality of life [33]. In a randomized double-blind cross-over trial of 13 patients comparing STN and GPi stimulation in a heterogenous dystonia population, the STN was efficient in improving BFMDRS scores and improving quality of life [34]. The use of shorter pulse widths in STN stimulation in this study resulted in longer battery life compared to GPi stimulation. A matched retrospective cohort study of patients with isolated and inherited dystonias comparing GPi and STN DBS found that STN stimulation conferred a greater response at 1 month with better speech improvement and lower energy consumption [35]. GPi stimulation was noted to be more effective for axial STN DBS in Post-Infarct Dystonia Stereotact Funct Neurosurg DOI: 10.1159/000509317 5 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM pallidal structures during dystonic arm movements, supporting the role of a dysfunction in the cortico-striatalpallido-thalamic circuit in pathogenesis. Even non-dystonic arm movements were associated with abnormal activation patterns. In the “hypokinetic” subtype of patients (dystonia without a phasic component), widespread bilateral overactivity and less response to pallidal DBS was noted [20]. Generalized dystonic clinical features in patients with unilateral structural lesions as seen in our third patient are uncommon but have been previously described [14]. It is important to recognize this existence of time latency in the manifestation and evolution of the dystonia post infarct, so that a sufficient period of time is allowed to elapse before considering DBS, such that the preoperative baseline of dystonia severity, location and pain have been stabilized and established. This allows a patient to determine if he/she can manage their activities of daily living with that level of stable symptoms, or to proceed to invasive therapies such as DBS. This will also help in managing patient expectations, especially important given that the outcome of DBS for acquired dystonias is generally less readily demonstrable than for primary dystonias. There are no established criteria to guide DBS therapy in post-infarct dystonia, although a few general principles seem reasonable: (i) having a relative preservation of the pyramidal system, (ii) “hyperkinetic” dystonic clinical presentations responding better than “hypokinetic” dystonia, and (iii) existence of a suitable DBS target, which is usually GPi but can include others such as STN as demonstrated in our series [20–26]. The latter is particularly important as pallidal anatomy can be severely distorted by the striatal infarcts. Alternative targets could include ventralis intermedius/ventralis oralis anterior (Vim/Voa) thalamus, especially for dystonia which has a tremor component. In fact, there is an extensive literature on the use of thalamus for hemidystonia, including for post-infract dystonia, primarily in the pre-DBS era following the seminal work of Cooper [27]. In a series of 12 patients with hemidystonia from various etiologies, unilateral lesioning of the Vim and ventralis caudalis externus-ventralis caudalis internus (Vce-Vci) nuclei was reported to result in functional improvement even without complete abolition of dystonic movements in all patients [28]. Another series of 5 hemidystonic patients (4 post-infarct and 1 perinatal trauma) who underwent thalamotomy (ventralis oralis anterior and posterior of thalamus and zona incerta targets) had immediate significant improvement of dystonic symptoms which subsequently worsened with 6 Stereotact Funct Neurosurg DOI: 10.1159/000509317 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM Tambirajoo/Furlanetti/Samuel/Ashkan 110–150 Hz 2.4±0.4 V 150 Hz 30 µs 1.8–2.0 mA 14.8±5.4 BFMDRS-D: BFMDRS-M: 46.6±16.5 Modified Rankin score 5 1.7±1.8 BFMDRS-D: 4.0±3.9 BFMDRS-M: Modified Rankin score 4 BFMDRS-D: 3 BFMDRS-D: 9 BFMDRS-D: 88.5% BFMDRS-M: 91.4% NA 77.8% Total BFMDRS: 56.7– 152 (mean) 48 BFMDRS-D: 66.7–76.5% BFMDRS-M: 10 BFMDRS-M: 21 125–160 Hz BFMDRS-M: 52.4–78.6% 18 (mean) stimulation BFMDRS-D: 4 STN: 45.3% GPi: 54.7% BFMDRS Total: STN: 51.7% for STN 12 months for trial 10–14 days (mean) 14.8±4.0 14.6 (mean) 12 36 120 32 (mean) months Follow-up, BFMDRS-M: 6 BFMDRS-D: 17 BFMDRS-M: 28 60–90 µs dystonia Bilateral STN Bilateral STN Bilateral STN 2.15–3.3 V BFMDRS-D: 2.8±2.6 BFMDRS-D: 5.8±3.6 Unilateral STN BFMDRS-M: 8.6±5.0 BFMDRS-M: 15.3±6.9 60-90 µs Idiopathic GNA01 mutation MMA Post-traumatic GPi 65.5% STN: STN: BFMDRS Total: 21.2±10.2 BFMDRS Total: 11.6±7.4 BFMDRS-D: BFMDRS Total: 21.2±10.2 BFMDRS Total: 9.6±5.5 GPi STN: 43.7% BFMDRS-D: 2.0±1.4 GPi: 50.6% BFMDRS-M: 70.9% 100% overall) Mean 45% (–43.3 to BFMDRS-D: 5.8±3.6 GPi: NA BFMDRS-D: 0–3 BFMDRS-M: 0–66 80% tation was 1 STN and 7 STN: 1.9–2.8 V GPi: NA BFMDRS-D: 0–10 BFMDRS-M: 9–66 Mean BFMDRS: 9.18 Pain: 0–2 Mean BFDRS: 41.53 Pain: 4–12 BFMDRS-M: 7.6±4.2 130 Hz, 60 µs 130–150 Hz 50–170 µs 1.7–3.3 V 90–180 Hz 60-80 µs 1.1–3.15 V 130–175 Hz 60–120 µs 1.7–3.25 V Disability: 4–7 Disability: 28 and STN – final implan- GPi: 2.9 V (2.2–4.00 BFMDRS-M: 15.3±6.9 Cross-over trial of GPi Bilateral STN Bilateral STN (16 vs. 14 patients) STN vs GPi generalized isolated Focal, segmental and Deng 14 cus) 2019 [33], 2018 dystonia (status dystoni- Generalized isolated 1 [70], Benato Hemidystonia Generalized dystonia 2 [39], 2019 Li tal isolated dystonia Generalized and segmen- Idiopathic 8 Liu [36], 2019 nia [55], 2019 Segmental isolated dysto- Meige syndrome Yao 14 9 unknowns dystonia Segmental isolated dysto- Meige syndrome 1 DYT1 positive tal, generalized isolated Focal, multifocal, segmen- 6 idiopathic nia 15 16 130–160 Hz Severity: 4–7 Overall 74–84.3% Severity: 19–23 TWSTR TWSTR (12 months) 2.8–3.5 V pallidotomies in 1 patient Bilateral STN BFMDRS-D: 86.5±13.9% BFMDRS-D: 1.5 BFMDRS-D: 14 BMFDRS-M: 90.4±10.4% BFMDRS-M: 2.25 BFMDRS-M: 49.5 89.3±11.2% BFMDRS total: BFMDRS-D: 19.6% BFMDRS-M: 30.8% at last follow-up Improvement 115–165 Hz BFMDRS total: 3.5 Mean scores BFMDRS-D: 6–8 BFMDRS-M: 10–42 severity score Postoperative BFMDRS total: 64 Mean scores BFMDRS-D: 7–9 BFMDRS-M: 28–46.5 severity score Preoperative 60–110 µs 60–90 µs Idiopathic Bilateral STN with previous bilateral [54], 2019 Wang [35], 2019 Lin 2 Focal cervical dystonia [42], 2020 Gupta 2 DYT1 positive 7 idiopathic 2.15–3.5 V dystonia Generalized isolated [51], 2020 9 0.6–3.8 V Xu STN mean/range parameters, Stimulation 130 Hz Post-infarct DBS target 2020 Hemidystonia Axis II: etiology 60–90 µs 3 Patients, n Axis I: clinical features (this paper), Tambirajoo [Ref.], year First author Table 2. Summary of STN studies in idiopathic, acquired and isolated dystonias STN DBS in Post-Infarct Dystonia Stereotact Funct Neurosurg DOI: 10.1159/000509317 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM 7 dystonia and bibrachial isolated Cervical, craniocervical 7 Ostrem [52], 2014 dystonia Generalized isolated 1 [58], 2016 Meng Segmental isolated dystonia 2 5 idiopathic 2 DYT1 positive Tardive dystonia Meige syndrome high-frequency STN Low-frequency vs. Bilateral STN Bilateral STN 131.5±0.27 Hz 66.9±1.3 µs 2.7±0.1 V NA 185 Hz 90–120 µs 3.2–3.6 V 129.3±30.1 Hz dystonia 2.5±1.2 V 146.7±12.5 Hz 65.5±13.4 µs Bilateral STN 91.7±21.9 µs 2.65±0.45 V 130 Hz 60 µs 0 (6 years) BFMDRS-D: 28 TWSTR-S: 214 BFMDRS-D: 5.6 (mean) (at 6 months) TWSTR-S: 7.7 BFMDRS-D: 3.6 BFMDRS-M: 6.6 High frequency: TSWST-S: 12.7 BFMDRS-D: 3 BFMDRS-M: 11.5 BFMDRS-M: 13.8 (mean) Low frequency: 0 (12 years) 3 (9 years) 8 (6 months) BFMDRS total: BFMDRS-D: 5.5 BFMDRS-M: 9.5 TWSTR 13.7±17.9 BFMDRS-M: 5.3±5.6 BFMDRS: 9–45 BFMDRS: 15 BFMDRS: 72 AIMS: 2.1±4.6 BFMDRS-D: 2.6±6.9 BFMDRS-M: 7.6±21.2 BFMDRS-D: 6.1±3.5 BFMDRS-M: 5.5 TWSTR: 14 BFMDRS-M: 38 BFMDRS-M: 29 severity score Postoperative BFMDRS-M: 70.5 BFMDRS total: 98.5 BFMDRS-D: 9.5 BFMDRS-M: 20.5 TWSTR 41.0±18.9 BFMDRS-M: 17.9±8.5 BFMDRS: 23–77 BFMDRS: 40 BFMDRS: 100 AIMS: 18.0±10.0 110–175 Hz 2.5 V BFMDRS-D: 10.4±8.2 BFMDRS-M: 36.1±29.4 BFMDRS-D: 15.6±4.9 BFMDRS-M: 19.3±7.6 TWSTR: 29 BFMDRS-M: 118 BFMDRS-M: 68 severity score Preoperative 60–120 µs 1.5–3.25 V 135–185 Hz 60–120 µs 1.95–3.75 V 130 Hz 60 µs 1.5–1.7 V al and generalized isolated [57], 2016 Wang [48], 2017 Focal, segmental, bibrachi- Idiopathic tion positive) Ostrem 20 Unilateral STN Bilateral STN Bilateral STN Bilateral STN Vo thalamotomy STN + unilateral Vim- PKAN (2 PANK2 muta- Bilateral STN dystonia Generalized isolated 3 Liu Post-traumatic Post-anoxic Tardive dystonia [45], 2017 Hemidystonia [53], 2017 Generalized dystonia Margolesky 2 dystonia [41], 2017 Generalized isolated Deng 10 nia Segmental isolated dysto- Meige syndrome 15 [56], 2018 Zhan Generalized isolated Idiopathic 130 Hz omy (status dystonicus) DBS and bilateral pallidot- 2.4–3.0 V mean/range parameters, Stimulation 60–110 µs Bilateral STN DBS target tonia with previous GPi Generalized isolated dys- Idiopathic Axis II: etiology dystonia 1 1 Patients, n Axis I: clinical features [44], 2018 Lin [69], 2018 Barbosa [Ref.], year First author Table 2 (continued) 28.5±16.5 7 10 months Follow-up, TWSTR-S: 56.0% BFMDRS-M: 51.8% 100% at 12 years 42.1% 53.7% TSWTR: 66.6% BFMDRS-M: 70.4% 45–73.1% 62.5% 28% AIMS: 93.6±12.4% 12 144 patients) 36 (14 30 (mean) 9 3 BFMDRS-D: 84.3±22.9% (mean) BFMDRS-M: 88.3±21.6% 65.6±30.4 BFMDRS-D: 61% BFMDRS-M: 74% TWSTR: 52% BFMSRS-M: 68% 57% at last follow-up Improvement 8 Stereotact Funct Neurosurg DOI: 10.1159/000509317 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM Tambirajoo/Furlanetti/Samuel/Ashkan 2011 9 dystonia Focal isolated cervical [47], Ostrem Bilateral STN Bilateral STN Bilateral STN (autosomal recessive) hydroxylase deficiency nia due to thyroxine Idiopathic BFMDRS-M: 24 UDRS: 69–116 UPDRS III: 18 GPi: GDS: 6 NA UDRS motor: 74% UPDRS III: 67% Bilateral STN Bilateral STN 130 145 Hz 63.3±3.3 µs 3.1±0.3V 160 Hz 2.4–2.7 V, 210 µs, TWSTR: 53.1±2.57 TSWTR: 19.6±5.48 BFMDRS: 18 skills than right, improved social 62.9% 84% ments bilaterally, left more and crawls with ease 130 Hz BFMDRS: 114 UDRS motor: 57% UPDRS III: 11 NA UPDRS III: 67% UDRS motor: 11 at the end NA BFMDRS-M: 69% BFMDRS-M: 76% STN: BFMDRS-M: 8 UDRS: 69.2% BFMDRS: 65.3% TWSTR: 87.5% BFMDRS-D: 73.1% BFMDRS-M: 91.7% score not matched by change in Clinical improvements NA with GPi) TWSTR: 50.9% (4.8% (8% with GPi) BFMDRS: 44% 79% at 3–10 years 77% at 1 year 55% at 1 month 52% at last follow-up Improvement With both GPi and STN: UDRS: 18–57 BFMDRS: 18–65 TWSTR: 14 BFMDRS-D: 7 BFMDRS-M: 4 At 12 months: NA TWSTR: 1–26 13.8±4.2 points BFMDRS improved by BFMDRS-D: 4.2±3.2 BFMDRS-M: 10.3±8.6 BFMDRS-M: 44 severity score Postoperative Improved dystonic move- Continent, pulls to stand 2.6 V 3.0 V, 60 µs, 130 Hz GDS: 13 STN: 3.2 V, 210 µs, 130 Hz UDRS motor: 24 GPi: 130 Hz 210 µs BFMDRS: 78–108 TWSTR: 59 185 Hz 1.7–3.4 V BFMDRS-D: 26 BFMDRS-M: 48 BFMDRS-D: 30 90 µs 3.0–3.2 V 130 Hz 60 µs BFMDRS-M: 103 TWSTRS: 14–29 BFMDRS-D: 1–28 BFMDRS-M: 7.5–78.5 BFMDRS-D: 13.9±4.7 BFMDRS-M: 49.2±19.6 BFMSRS-M: 91 severity score Preoperative side used for stimulation 90 µs Dopa-responsive dysto- Bilateral STN; only left Dystonia-parkinsonism Bilateral STN and GPi Generalized dystonia with NBIA1 dystonia Generalized isolated previous pallidotomy 1 1 [66], 2011 Ge 2011 [50], Tormenti 2012 dystonia Generalized combined Wohrle 1 omies 2012 [60], previous bilateral pallidot- 1 tardive dystonia Generalized dystonia with 3 idiopathic 4 [68], Fonoff Fahr’s disease dystonia Segmental isolated Ma 1 pallidotomy 2013 MMA [46], 2013 dystonia with auto [67], Generalized isolated 0.9–1.2 V 1 60 µs 2.6±0.12 V Chakraborti vs. STN Cross-over trial of GPi 135–185 Hz 90–120 µs 2.0–3.6 V 130 Hz 2 tardive dystonia Bilateral STN 2013 alized isolated dystonia Focal, multifocal or gener- 11 idiopathic [34], 12 Isolated Schjerling Generalized idiopathic 130 Hz 2.8–3.0 V bilateral pallidotomies Bilateral STN mean/range parameters, Stimulation 90 µs Isolated DBS target dystonia with previous Generalized idiopathic Axis II: etiology dystonia 27 1 Patients, n Axis I: clinical features [40], 2013 Cao [65], 2014 Dec [Ref.], year First author Table 2 (continued) 12 36 14 12 31 (mean) 24 6 6 36–120 24 months Follow-up, STN DBS in Post-Infarct Dystonia Stereotact Funct Neurosurg DOI: 10.1159/000509317 Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM 9 Craniofacial dystonia 120 µs 3.0 V Bilateral STN 1 STN-GPi 2 unilateral STN 6 bilateral STN tial tremor Family history of essen- Bilateral STN Tardive dystonia 2 unknown 1 neonatal jaundice 3 perinatal anoxia 1 post-traumatic 2 tardive dystonia Bilateral STN Bilateral STN TWSTR: 26.6% BFMDRS-D: –25% BFMDRS-M: 24.6% Mean 35.7% 100% 58.5% at last follow-up Improvement On 0 Off 20 TWSTR disability On 3 185 Hz TWSTR severity BFMDRS: 8 UDRS: 38 matic) BFMDRS: 7 (post-trau- N/A BFMDRS: 91.8% UDRS: 59.6% 90.8% (post-traumatic) BFMDRS: 8 and 2 (tardive) 91.25% (tardive) Off 14 NA BFMDRS: 98.5 UDRS: 94 matic) BFMDRS: 76 (post-trau- (tardive) BFMDRS: 98.5 and 26.6 TWSTR: 41.3±11.8 90 µs 2.0–3.2 V 185 Hz 90 µs 1.5–3.0 V NA TWSTR: 56.2±9.4 100–185 Hz BFMDRS-M: 33.3±13.7 BFMDRS-D: 10.0±4.0 UDRS: 12.5 BFMDRS-M: 44.2±8.3 BFMDRS-D: 8.0±3.0 GDS: 28 UDRS: 24.5 BFMDRS-D: 4 BFMDRS-M: 23 BFMDRS: 0 TWSTR: 22 (mean) severity score Postoperative GDS: 43 BFMDRS-D: 7 BFMDRS-M: 30 BFMDRS: 12 90–150 µs 1.5–2.5 V 145 Hz 270 µs 2.5 m 2.9 V 185 Hz 60–90 µs TWSTR: 53 (mean) severity score Preoperative 6 3 6 12 29 16 36 months Follow-up, Rating Scale; NBIA1, neurodegeneration with brain iron accumulation type 1; NA, not available; GDS, Global Dystonia Severity Rating Scale; MMA, methylmalonic acidemia. Movement Scale; PKAN, panthotenate kinase-associated neurodegeneration; Vim, ventralis intermedius nucleus; Vo, ventralis oralis nucleus; UDRS, Unified Dystonia Rating Scale; TWSTR, Toronto Western Spasmodic Torticollis GPi, globus pallidus internus; STN, subthalamic nucleus; BFMDRS, Burke-Fahn-Marsden Dystonia Rating Scale; BFMDRS-M, BFMDRS movement score; BFMDRS-D, BFMDRS disability score; AIMS, Abnormal Involuntary tremor head tremor from essential 2005 Focal combined cervical dystonia Generalized isolated and hemidystonia Generalized, multifocal dystonia with dystonic 1 1 9 isolated dystonia [62], Chou 2006 [59], Zhang 2006 [63], Zhang 2007 [43], Fisman Segmental and generalized Idiopathic Kleiner- 4 ral pallidotomy 2008 Segmental isolated dysto- Idiopathic nia with previous unilate- 1 drome with Parkinson’s syn- [64], Novak 2010 dystonia Bilateral STN 1 unilateral STN 1 bilateral STN mean/range parameters, Stimulation 3.5 V [61], Segmental combined Idiopathic DBS target Lyons dystonia Focal isolated cervical Axis II: etiology 185 Hz 1 2 Patients, n Axis I: clinical features 2010 [49], Pahapill [Ref.], year First author Table 2 (continued) 10 Stereotact Funct Neurosurg DOI: 10.1159/000509317 In terms of programming settings, there is wide variation in the programming practice for GPi DBS [71, 72]. Most variation seem to be for pulse width, with some centers using 60 μs and others 450 μs. In Parkinson’s disease, where STN DBS has been used much more extensively, typical pulse widths are 60–90 μs, and so we felt that this should be the starting point in our cohort of dystonic patients, bearing in mind that STN is a much smaller structure than GPi. It is unclear why STN modulation could improve dystonia, particularly when GPi is damaged. Motor improvements seen with STN stimulation may be due to a downstream glutamatergic innervation of the GPi via remnants of viable GPi tissue or by a putative alternative pathway bypassing the GPi en-route to the thalamus and subsequent motor outflow tracts [53]. It is also postulated that the motor outputs of GPi can be enhanced by the STN [33] or that STN DBS may independently activate motor pathways [73]. There is a significant variability in the postoperative BFMDRS scores in our cohort. Our first patient demonstrated a remarkable 64% improvement in his motor score and a 33% improvement in his disability score. Our second patient had modest improvements in both her motor and disability scores at 3 years. Our third patient also had a modest change in his BFMDRS scores despite achieving significant positive gains in alertness, patientreported dystonia control and school performance. Lack of improvement in the BFMDRS score could be explained by the inadequate sensitivity of the scales for measuring subtle but clinically meaningful changes [74]. Some examples of clinically meaningful aspects of improvements not represented in the BFMDRS score include reduced frequency of dystonic paroxysms, reduction in proximal appendage rigidity and dystonia, and marked improvement in alertness [53, 75]. Duration of dystonic symptoms does have an influence on improvements after DBS. A shorter duration of dystonic symptoms correlates with greater improvements from DBS in both inherited and acquired dystonia in children [76]. The best time for DBS is unknown. When schooling time is paramount, it has been suggested that children with acquired dystonia be offered DBS therapy within 5 years of onset but with realistic goals and expectations setting to reflect a less satisfactory outcome compared to inherited dystonia. Poorer outcome in acquired dystonia also coincides with the absence of a period of normal motor development [76]. Irrespective of target chosen for stimulation, timing needs careful individual consideration. Tambirajoo/Furlanetti/Samuel/Ashkan Downloaded by: Auckland University of Technology 156.62.3.11 - 10/25/2020 3:38:55 AM symptoms, and both targets improved quality of life. A recent randomized study compared the short-term outcomes of GPi and STN stimulation in 8 patients with primary dystonia implanted with bilateral double electrodes. Significant improvement in motor scores were noted with both targets but with higher rates of stimulation-related side effects with STN DBS [36]. Two recent meta-analyses of GPi and STN DBS in cervical dystonia and isolated dystonia confirmed that stimulation of either target conferred substantial clinical improvement with no difference at the short and long term [37, 38]. Shorter disease duration correlated positively with larger DBS treatment efficacy, with a more persistent improvement and larger treatment potential with STN stimulation. Similar experience has been described by others [39–53]. STN DBS has also been successfully used in the management of Meige syndrome with motor score improvements in the range of 42.1–74% [54–57] and in tardive dystonia with improvements of 88–100% at up to 12-year follow-up periods [41, 58, 59]. STN DBS has been utilized in selected cases of combined dystonia (dystonia with Parkinson’s disease or essential tremor) with good results [60–62]. Specifically, in hemidystonias, STN DBS has been used successfully as described in 3 case reports with a 62.5–91% improvement when compared to baseline scores [39, 53, 63]. Of note, STN DBS has also been used as a salvage treatment in a range of dystonias previously treated with pallidotomy or GPi DBS with good results as well as in status dystonicus [42, 64–70]. These reports therefore supported our choice of STN as a target in this cohort of patients with post stroke dystonia and a structurally normal STN in whom the GPi could not be targeted confidently, either because of its direct damage as shown on the MRI or its close proximity to the infarct raising concern about potential functional involvement. Given the presence of postulated bilaterally disorganized motor circuits, one could suggest that bilateral DBS should be theoretically considered even for hemidystonia, but these data need confirmation and minimizing risks of surgery is paramount. Therefore, unilateral electrode insertion under direct anatomical guidance was deemed adequate for 2 patients with hemidystonia, aiming to modulate enough of the complex reorganization of the cortico-striato-pallido-thalamo-cortical circuits to provide clinical improvement. In the third patient, we elected for bilateral STN DBS as he had bilateral symptoms although they were very asymmetrical, similar to a previous report [14]. Conflict of Interest Statement Conclusion This is the largest case series describing the use of subthalamic DBS in the treatment of post-infarct dystonia. In the absence of large prospective studies, given the rare nature of stroke-related dystonia, the heterogenous nature of the condition and its natural history, these cases do add to the growing body of knowledge on STN DBS use in post-stroke dystonias. M.S. and K.A. have received educational support from Medtronic (paid to the institution), act as consultants for Abbott Medical, and received honoraria from The Movement Disorders Society. No potential conflict of interest was reported by the authors. Funding Sources This study did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors. Statement of Ethics This study was approved by our institution’s Research Advisory Group and carried out in accordance with the principles of the Declaration of Helsinki. Informed consent was obtained from all patients prior to study commencement. Author Contributions K.T. collected and analyzed the data, wrote the first draft and critically revised the manuscript. L.F. analyzed the data and critically revised the manuscript. M.S. and K.A. conceptualized the study and critically revised the manuscript. All authors approved the final version to be published. 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