Thirty Years of Global Deep Brain Stimulation: "Plus ça change, plus c'est la même chose"?

BACKGROUND: The advent of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease 30 years ago has ushered a global breakthrough of DBS as a universal method for therapy and research in wide areas of neurology and psychiatry. The literature of the last three decades has described numerous concepts and practices of DBS, often branded as novelties or discoveries. However, reading the contemporary publications often elicits a sense of déjà vu in relation to several methods, attributes, and practices of DBS. Here, we review various applications and techniques of the modern-era DBS and compare them with practices of the past. SUMMARY: Compared with modern literature, publications of the old-era functional stereotactic neurosurgery, including old-era DBS, show that from the very beginning multidisciplinarity and teamwork were often prevalent and insisted upon, ethical concerns were recognized, brain circuitries and rational for brain targets were discussed, surgical indications were similar, closed-loop stimulation was attempted, evaluations of surgical results were debated, and controversies were common. Thus, it appears that virtually everything done today in the field of DBS bears resemblance to old-time practices, or has been done before, albeit with partly other tools and techniques. Movement disorders remain the main indications for modern DBS as was the case for lesional surgery and old-era DBS. The novelties today consist of the STN as the dominant target for DBS, the tremendous advances in computerized brain imaging, the sophistication and versatility of implantable DBS hardware, and the large potential for research. KEY MESSAGES: Many aspects of contemporary DBS bear strong resemblance to practices of the past. The dominant clinical indications remain movement disorders with virtually the same brain targets as in the past, with one exception: the STN. Other novel brain targets - that are so far subject to DBS trials - are the pedunculopontine nucleus for gait freezing, the anteromedial internal pallidum for Gilles de la Tourette and the fornix for Alzheimer's disease. The major innovations and novelties compared to the past concern mainly the unmatched level of research activity, its high degree of sponsorship, and the outstanding advances in technology that have enabled multimodal brain imaging and the miniaturization, versatility, and sophistication of implantable hardware. The greatest benefit for patients today, compared to the past, is the higher level of precision and safety of DBS, and of all functional stereotactic neurosurgery.

Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders.

Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.

The authors compared the DNA methylation patterns in blood from individuals with two rare neurodevelopmental disorders (childhood-onset dystonia [DYT-KMT2B] and Kabuki syndrome type 1) and healthy control samples. These two disorders are associated with pathogenic variants in KMT2B and KMT2D, which encode proteins with related functions but cause distinct inherited disorders. Comparison of the methylation patterns in the two disorders showed that most DNA regions with altered methylation patterns differed between the two disorders and controls. These findings suggest that analyzing DNA methylation patterns could improve diagnostic testing for these disorders and might provide insights into how the clinical features of these disorders are caused.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

AIM: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families. METHOD: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases. RESULTS: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure. INTERPRETATION: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.

Pallidal Deep Brain Stimulation in DYT6 Dystonia: Clinical Outcome and Predictive Factors for Motor Improvement.

Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, p = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.

Seventy Years with the Globus Pallidus: Pallidal Surgery for Movement Disorders Between 1947 and 2017.

The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid-1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa-induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience. © 2017 International Parkinson and Movement Disorder Society.

Historical developments in children's deep brain stimulation.

BACKGROUND: Heterogeneous by the underlying pathobiology and clinical presentation, childhood onset dystonia is most frequently progressive, with related disability and limitations in functions of daily living. Consequently, there is an obvious need for efficient symptomatic therapies. METHODS AND RESULTS: Following lesional surgery to basal ganglia (BG) and thalamus, deep brain stimulation (DBS) is a more conservative and adjustable intervention to and validated for internal segment of the globus pallidus (GPi), highly efficient in treating isolated "primary" dystonia and associated symptoms such as subcortical myoclonus. The role of DBS in acquired, neurometabolic and degenerative disorders with dystonia deserves further exploration to confirm as an efficient and lasting therapy. However, the pathobiological background with distribution of the sequellae over the central nervous system and related clinical features, will limit DBS efficacy in these conditions. Cumulative arguments propose DBS in severe life threatening dystonic conditions called status dystonicus as first line therapy, irrespective of the underlying cause. There are no currently available validated selection criteria for DBS in pediatric dystonia. Concurrent targets such as subthalamic nucleus (STN) and several motor nuclei of the thalamus are under exploration and only little information is available in children. DBS programming in paediatric population was adopted from experience in adults. The choice of neuromodulatory DBS parameters could influence not only the initial therapeutic outcome of dystonic symptoms but also its maintenance over time and potentially the occurrence of DBS related side effects. CONCLUSION: DBS allows efficient symptomatic treatment of severe dystonia in children and advances pathophysiological knowledge about local and distributed abnormal neural activity over the motor cortical-subcortical networks in dystonia and other movement disorders.

The reorganization of motor network in hemidystonia from the perspective of deep brain stimulation.

Hemidystonia is usually 'secondary' to structural lesions within the cortico-striato-pallido-thalamic or the cerebello-thalamo-cortical loops. Globus pallidus internus Deep Brain Stimulation (GPi DBS) is a validated technique in the treatment of primary dystonia and still under assessment for secondary dystonia. Results of DBS in hemidystonia are limited and heterogeneous. Further knowledge concerning motor network organization after focal brain lesions might contribute to the understanding of this mitigated response to DBS and to the refinement of DBS indications and techniques in secondary dystonia. This study aimed to identify movement-related functional magnetic resonance imaging (fMRI) activation patterns in a group of hemidystonic patients in comparison to healthy controls (HC). Further analysis assessed recruitment pattern in different patient subgroups defined according to clinical and radiological criteria relevant to GPi DBS eligibility (hyperkinetic/hypokinetic and prepallidal/postpallidal). Eleven patients and nine HC underwent fMRI with a block-design alternating active and rest conditions. The motor paradigm consisted of self-paced elbow flexion-extension movements. The main results were as follows: single-subject studies revealed several activation patterns involving motor-related network regions; both ipsilesional and contralesional hemispheres showed abnormal patterns of activity; compared with HC, hemidystonic patients showed decreased brain activity in ipsilesional thalamus, pallidal and temporal areas during affected arm task execution; 'hypokinetic' subgroup was commonly related to widespread bilateral overactivity. This study provides additional arguments for case-by-case assessment of DBS surgery indication and target selection in hemidystonia. Single-lead approach might be unable to modulate a highly disorganized network activity in certain patients with this clinical syndrome.

Staged implantation of multiple electrodes in the internal globus pallidus in the treatment of primary generalized dystonia.

OBJECT: Deep brain stimulation (DBS) is used for treating various types of dystonia. Multiple electrodes could be proposed to improve the therapeutic outcome enabling the targeting of specific neuronal populations not reached by the electrical field generated by the initially implanted electrode. The authors address the question of the feasibility and safety of staged multiple lead implantations in the sensorimotor internal globus pallidus (GPi) in primary generalized dystonia (PGD). Criteria for patient selection, surgical technique, target selection, electrical settings management, and clinical outcome are presented. METHODS: Sixteen patients (8 harbored the DYT1 gene mutation) presented with PGD and were enrolled in this study. Patients underwent clinical assessment using the Burke-Fahn-Marsden Dystonia Rating Scale preoperatively and during follow-up with DBS. Prior to the addition of electrodes, the authors confirmed, by turning off stimulation, that the patient was still benefiting from DBS and that DBS settings adjustment did not provide further improvement. The second target was defined according to the position of the first electrode, to the residual volume within the sensorimotor GPi, and according to residual symptoms. The second surgery followed the same protocol as the first and the new electrode were inserted using the same bur hole as the first electrode. RESULTS: The addition of a new pair of electrodes was followed by significant improvement in the whole population (p = 0.005), as well as in the DYT1-negative subgroup (p = 0.012) but not in the DYT1 subgroup (p = not significant). Nevertheless, some patients did not exhibit significant additional benefit. Seven hardware-related complications occurred during the entire follow-up, 3 prior to it, and 4 after the addition of the second pair of electrodes. CONCLUSIONS: The addition of a second pair of electrodes in the GPi in patients with PGD with suboptimal or decaying benefit following the first surgery seems to be a safe procedure and is not followed by an increase in surgery-related complications. This staged procedure may provide further clinical improvement in patients with PGD in whom DBS effect is initially incomplete or when disease progression occurs over time. The position of the additional electrode within the GPi is determined by the available volume within the posteroventral GPi and by the distribution of the dystonic symptoms that need to be controlled.

A target-specific electrode and lead design for internal globus pallidus deep brain stimulation.

In nearly all deep brain stimulation (DBS) applications, the same quadripolar electrode design is used for different anatomical targets even if shape and volume differences exist between nuclei. Taking into account the electrode location within the internal globus pallidus (GPi) and the size of the GPi, 2 electrodes were designed in order to improve the therapeutic benefit, to minimize side effects from DBS and to obtain a more homogeneous electric field distribution. The electrodes were evaluated numerically by using a stereotactic model measuring the correlation between the electric field and the GPi. The model was applied to 26 dystonodyskinetic patients who underwent surgery for a bilateral lead implantation into the posteroventral part of the GPi. The designed electrodes produced a more homogeneous distribution of the electric field than the quadripolar electrode.

Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation: an open-label study.

Long-term efficacy of internal globus pallidus (GPi) deep-brain stimulation (DBS) in DYT1 dystonia and disease progression under DBS was studied. Twenty-six patients of this open-label study were divided into two groups: (A) with single bilateral GPi lead, (B) with a second bilateral GPi lead implanted owning to subsequent worsening of symptomatology. Dystonia was assessed with the Burke Scale. Appearance of new symptoms and distribution according to body region were recorded. In the whole cohort, significant decreases in motor and disability subscores (P < 0.0001) were observed at 1 year and maintained up to 10 years. Group B showed worsening of the symptoms. At 1 year, there were no significant differences between Groups A (without subsequent worsening) and B; at 5 years, a significant difference was found for motor and disability scores. Within Group B, four patients exhibited additional improvement after the second DBS surgery. In the 26 patients, significant difference (P = 0.001) was found between the number of body regions affected by dystonia preoperatively and over the whole follow-up. DBS efficacy in DYT1 dystonia can be maintained up to 10 years (two patients). New symptoms appear with long-term follow-up and may improve with additional leads in a subgroup of patients.

Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation.

Despite the beneficial effects of Globus Pallidus internus (GPi) deep brain stimulation (DBS) in patients with primary generalized dystonia (PGD), the degree of improvement varies from one patient to another. The objective of this study was to examine the effects of clinical, anatomical (volume of the GPi), and electrical variables on the postoperative Burke-Fahn-Marsden Dystonia rating scale (BFMDRS) motor score to identify which factors may be predictive of the degree of improvement. We reviewed retrospectively the clinical records of 40 steady-state patients with PGD who had been treated by bilateral GPi lead implantation. The follow-up period was 2 to 8 years. The correlation between the electrical parameters (voltage, impedance, and current) and the clinical outcome was studied. An analysis of covariance was performed to identify factors predictive of the magnitude of improvement. The most influential factors according to the model are as follows: the preoperative BFMDRS score (P < 0.0001); age at surgery (P < 0.0001); the right GPi volume (P = 0.002); the left stimulated GPi volume (P = 0.005). No significant correlation was found between the electrical parameters used and the mean motor scores in steady state.

Stereotactic coregistration of 201Tl SPECT and MRI applied to brain tumor biopsies.

UNLABELLED: The aim of the present study was to determine the clinical feasibility of integration of stereotactic SPECT (sSPECT) with 201Tl in the stereotactic MRI (sMRI)-based planning of brain tumor biopsy. Furthermore, the predictive value of the integrated techniques was analyzed by comparison with the corresponding histologically determined metabolic activity. METHODS: Ten patients underwent combined 201Tl SPECT- and MRI-guided stereotactic biopsy of intracranial lesions according to a previously described technique. An area of abnormal 201Tl uptake was used to guide the stereotactic biopsy trajectory. Several samples were taken along the trajectory above and beneath the target. An extensive histologic diagnosis (tumor grade, mitotic index [MI], and Ki67 index) and the 201Tl index were obtained for all samples and compared statistically. RESULTS: Combined 201Tl sSPECT- and sMRI-guided biopsy could be performed on all patients. Ki67 index, MI, and tumor grade correlated significantly. The correlations between MI or Ki67 index and 201Tl index were not significant (0.18 and 0.09, respectively). A trend to significance existed between tumor grade and 201Tl index (R = 0.31; P = 0.06). Mean 201Tl index for grade III tumors (3.27 +/- 1.89 [SD]) was significantly different from that for grade IV tumors (4.34 +/- 1.29). The sample position on the trajectory correlated with the MI (R = 0.39; P = 0.01). In 4 of the 10 patients, a variation in tumor grade could be observed along the trajectory. In all patients, the highest proliferative activity was within 5-10 mm of the target. CONCLUSION: These results support the view that 201Tl SPECT may contribute to the successful management of brain tumor patients requiring stereotactic biopsy, without causing a significant increase in discomfort or morbidity. The development of similar techniques integrating sSPECT data in the planning of stereotactic biopsy should be considered by centers performing stereotactic surgery and having access to SPECT technology. In the long term, this technique could become a support for focused gene therapy and cell transfer.

Deep brain stimulation for dystonia confirming a somatotopic organization in the globus pallidus internus.

OBJECT: In patients with dystonia, symptoms vary greatly in their extent and severity. The efficacy of pallidal stimulation is now established, but an interindividual variability in the responses to this treatment exists. A retrospective analysis of postoperative magnetic resonance (MR) images demonstrated millimetric variations in the positions of electrode contacts inside the posterolateroventral portion of the globus pallidus internus (GPi). It therefore seemed very likely that there is a somatotopic organization within the GPi. The goal of this study was to examine the positions of specific electrode contacts according to patients' clinical evolution, so that a somatotopic organization within the GPi could be defined. METHODS: This study included 19 patients (17 of whom were right handed) with generalized dystonia who were treated by bilateral stimulation of the GPi. Patients were examined pre- and postoperatively by using the Burke-Fahn-Marsden Dystonia Rating Scale. Dividing the patient's body into three parts--cervicoaxial area, superior limb, and inferior limb--we determined the following: 1) where the dystonic symptoms started; 2) where symptoms predominated at the time of surgery; and 3) where the highest postoperative improvement was observed. Variations in clinical response were correlated to the positions of the electrode contacts. All activated electrode contacts were in the posterolateroventral portion of the GPi (Laitinen target). A correlation between the contact location measured longitudinally and the part of the body in which the highest improvement was observed (three different areas; p = 0.004) showed that a location more anterior for the inferior limb and one more posterior for the superior limb were delineated for the right side, but not for the left side. CONCLUSIONS: Inside the posterolateroventral subvolume of the GPi on the right side, three statistically different locations of electrode contacts were determined to be primary deep brain stimulation treatment sites for particular body parts in cases of dystonia.

Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results.

OBJECT: Primary generalized dystonia (PGD) is a medically refractory disease of the brain causing twisting or spasmodic movements and abnormal postures. In more than 30% of cases it is associated with the autosomal DYT1 mutation. Continuous electrical stimulation of the globus pallidus internus (GPi) has been used successfully in the treatment of PGD. The aim of this study was to examine the long-term efficacy and safety of deep brain stimulation (DBS) in the treatment of PGD in children and adults with and without the DYT1 mutation. METHODS: Thirty-one patients with PGD were selected for surgery. Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulators that were inserted subcutaneously. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) before and after implantation. The efficacy of stimulation improved with time. After 2 years, compared with preoperative values, the mean (+/- standard deviation) clinical and functional BFMDRS scores had improved by 79 +/- 19% and 65 +/- 33%, respectively. At the 2-year follow-up examination the improvement was comparable in patients with and without the DYT1 mutation in both the functional (p = 0.12) and clinical (p = 0.33) scores. Children displayed greater improvements in the clinical score than adult patients (p = 0.04) at 2 years of follow up. In contrast, there was no significant difference in functional scores between children and adults (p = 0.95). CONCLUSIONS: Electrical stimulation of the GPi is an effective, reversible, and adaptable treatment for PGD and should be considered for conditions refractory to pharmaceutical therapies.

Deep brain stimulation for dystonia. Surgical technique.

Stimulation electrodes are implanted under general anesthesia, without intra-operative electrophysiology or clinical testing, based only on stereotactic MRI and direct anatomical localization of the postero-ventro-basal GPi. We retrospectively analyzed the surgical procedure that has been designed and implemented in our center, using the Leksell G frame, for initiating deep brain stimulation in 65 dystonic patients. We report the surgical technique and the hardware and software complications. We recommend immediate postoperative stereotactic MRI under general anesthesia as a prerequisite to check the reliability of MR acquisition (magnet stability) and the exact localization of each electrode. This technique allowed us to reduce the duration of the operation to 4 h, including general anesthesia, frame fixation, MRI acquisition, implantation of two electrodes under radioscopic control, immediate postoperative stereotactic MRI and frame removal. Surgery-related morbidity was very low with a 0% hemorrhage rate and three delayed unilateral infections re-operated 6 months later. Hardware and software complications were rare. The advances in 3D-MR imaging permit the electrode implantation for deep brain stimulation without resorting to intraoperative localization techniques, which is especially helpful in children and for treating dystonia. The maximum follow-up period is 58 months (first case: November 1996). GPi stimulation has proven to be an effective treatment for most dystonic syndromes with particular efficacy in the disease due to the DYT1 mutation.