Deep brain stimulation in the treatment of Parkinson's disease: a review and update

Deep brain stimulation (DBS) is a neurosurgical treatment of severe forms of Parkinson's disease, already applied to three targets, the thalamus, the internal pallidum (GPi) and the subthalamic nucleus (STN). Thalamic DBS mainly improves contralateral tremor and is therefore restricted to a small group of patients with tremor dominant disease. STN and GPi DBS improve off-motor periods and dyskinesias. The magnitude of the improvement seems more constant with STN DBS than with GPi, but there is very little comparative data between these procedures. The DBS procedure has the unique advantage of reversibility and adjustability over time. Most authors agree that bilateral DBS is reasonably safe, which is not the case of ablation. In any event, surgery is restricted to patients disabled by their condition but still responding well at times to levodopa, who are generally fit with no behavioural, mood or cognitive impairment. DBS can have side effects. Side effects more specific to the DBS procedure are infection, disconnection and hardware failure. DBS, like ablative surgery can induce an intracranial lesion like a hematoma or a stroke. There are side effects more specific to the target like postural instability, dysarthria or paresthesia in the thalamus and dyskinesias or eyelid opening apraxia in the STN. The mechanism by which high frequency DBS mimics the effect of ablation is not fully understood.     

Comparative effects of unilateral and bilateral subthalamic nucleus deep brain stimulation.

OBJECTIVE: To compare the effects of unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) with bilateral STN DBS in advanced PD. METHODS: Our initial 10 consecutive patients with medication-refractory motor fluctuations and levodopa-induced dyskinesias undergoing chronic bilateral STN DBS underwent a standardized evaluation of unilateral and bilateral STN DBS in the medication-off state 6 to 18 months after electrode implantation. RESULTS: Bilateral STN DBS improved the mean total Unified Parkinson's Disease Rating Scale motor score by 54%, whereas unilateral stimulation improved motor scores only 23%. Unilateral STN DBS improved postural stability and gait 14%, other axial motor features 19%, and overall parkinsonism in limbs contralateral to stimulation by 46%, including an 86% improvement in contralateral tremor. However, bilateral STN DBS resulted in greater improvement in each of these domains, including limb function, i.e., the reduction in scores from the limbs on one side was greater with bilateral than with unilateral stimulation of the contralateral STN. CONCLUSIONS: Bilateral STN DBS improves parkinsonism considerably more than unilateral STN DBS; bilateral simultaneous electrode implantation may be the most appropriate surgical option for patients with significant bilateral disability. Unilateral STN DBS results in moderate improvement in all aspects of off-period parkinsonism and improves tremor as much as is typically reported with DBS of the ventral intermedius nucleus of the thalamus (Vim). For this reason, STN DBS may be a more appropriate choice than Vim DBS or thalamotomy for parkinsonian tremor. Some patients with highly asymmetric tremor-dominant PD might be appropriately treated with unilateral instead of bilateral STN DBS.     

Parkinson's disease: deep brain stimulation

The effects of deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal pallidum (GPi) on the parkinsonian triad and on levodopa-induced dyskinesias are very similar. The antiakinetic effect of STN DBS seems to be slightly better. On the contrary to pallidal DBS, stimulation of the STN allows to reduce dopaminergic treatment by more than 50p.100 on average. Moreover, the current drain is smaller in STN. Thus, the STN is a low budget target compared to the GPi. STN DBS seems to be as effective on PD tremor as stimulation of the classic thalamic target, the ventral intermediate nucleus (Vim), whereas Vim stimulation has no effect on akinesia and very little on levodopa-induced dyskinesias. Thus, the STN has become the main target nucleus for DBS in PD, which is most often performed bilaterally in one surgical procedure. There is a good correlation of the preoperative response to levodopa and postoperative effects of bilateral STN DBS and this defines the patient population. Given the large patient population, simple guidelines for patient selection are developed. The referring physician can preselect patients based mainly on age (less than 70), absence of dementia and presence of severe disability related to motor fluctuations or dyskinesias. It is the responsibility of the operating centre to determine the levodopa response, to confirm the diagnosis, to rule out contraindications and to make sure that the medical treatment cannot be further optimised. Severe surgical complications with permanent sequels are relatively rare, about 1p.100 per implanted side. The patient selection, the precision of the surgery and the quality of the postoperative follow-up are the three main determinants of success.     

脑深部电刺激治疗帕金森病和特发性震颤的近期和远期疗效

自1987年以后,脑深部电刺激(deep brain stimulation,DBS)成为治疗难治性帕金森病和特发性震颤的主要外科手段。刺激的靶点最先为丘脑腹侧中间核(nucleus ventero-intermedius,Vim)。由于Vim DBS只能缓解震颤,而对于帕金森病的其他核心症状以及多巴长期应用后的不良反应,如运动波动和异动症疗效不显著,1990年后治疗PD的靶点转移到丘脑底核(subthalamic nucleus,STN)和苍白球内侧部(interal globus pallidus,GPi),上述问题在这两个靶点得到显著改善。Vim DBS仍然为治疗特发性震颤的位点。本文就这3个靶点的持续电刺激在治疗帕金森病和特发性震颤的近期和远期疗效等进行评述。     

Deep brain stimulation therapy for involuntary movements]

During the last decade, it has become clear that deep brain stimulation (DBS) therapy provides a dramatic improvement in the symptoms of movement disorders. We have experienced DBS in 110 patients with various types of involuntary movements, and confirmed the benefits of stimulation of the thalamic nucleus ventralis intermedius (Vim), internal globus pallidus (GPi) and subthalamic nucleus (STN) in these patients. DBS therapy affords the best effect on tremor when the Vim is selected as the stimulation site. DBS therapy is also useful for controlling rigidity when the GPi or STN is stimulated. Improvements of bradykinesia and gait disturbance are often induced by DBS therapy involving the GPi or STN. Dopa-induced dyskinesia can be attenuated effectively by the direct and/or indirect effects of DBS therapy. DBS of the Vim also provides excellent control of post-stroke involuntary movements, including hemiballism and hemichoreoathetosis. Dystonia in young patients is controlled effectively by DBS of GPi. Ablative procedures for control of involuntary movement disorders, such as thalamotomy and pallidotomy, always carry a risk associated with creating additional lesions in an already damaged brain. In contrast, there is not such a risk in DBS therapy. This modality of therapy is an important option in treating involuntary movements.     

Which Approach is Better: Bilateral Versus Unilateral Thalamic Deep Brain Stimulation in Patients with Fragile X–Associated Tremor Ataxia Syndrome

Fragile X–associated tremor ataxia syndrome (FXTAS) is a relatively recently described condition that is frequently misdiagnosed as essential tremor and then occasionally treated as such with deep brain stimulation (DBS) to the nucleus ventralis intermedius of the thalamus (Vim). Reports of ataxia worsening after bilateral Vim DBS in FXTAS patients are conflicting, and only five FXTAS patients treated with Vim DBS for intractable tremor have been reported in the literature, three of whom having undergone a bilateral procedure. We report a patient who underwent a staged Vim DBS procedure, with excellent contralateral hand tremor control and no worsening of ataxia after the first procedure, but immediate worsening of his ataxia after the second one, arguing in favor of a unilateral surgical approach for intractable tremor in FXTAS.     

Deep brain stimulation of the Vim nucleus of the thalamus in the treatment of parkinsonian tremor

Deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (Vim) has been recently introduced by Benabid and his colleagues as a new surgical procedure in the treatment of tremor-dominant Parkinson's disease (PD). The advantage of DBS Vim over lesioning (thalamotomy) is its reversibility and adjustability with the same clinical effect, but without the need to make a destructive thalamic lesion. In this procedure high-frequency stimulation is employed to simulate a thalamic lesion using an implanted electrode connected to a subcutaneously placed neuropacemaker. Four patients with tremor-dominant PD were included in the study. There were 3 men and one women. Three stimulators were implanted in the left and one in the right cerebral hemisphere. The patients were evaluated using clinical scales, before and up to 24 months after surgery. Adverse effects associated with chronic Vim stimulation were mild and reversible. Chronic thalamic stimulation is effective for drug-resistance parkinsonian tremor suppression, with few adverse side-effects. The method results in a significant improvement of function.     

Bilateral Implantation in Globus Pallidus Internus and in Subthalamic Nucleus in Parkinson's Disease

Introduction . Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and of the pars interna of Globus Pallidus (GPi) is used to improve parkinsonian symptoms and attenuate levodopa‐induced motor complications in Parkinson's disease (PD) (DBS for PD study group, 2001). It is still not clear what the best anatomic structures to stimulate are or what the physiologic effects of DBS are. Most of the studies regarding DBS for parkinsonian symptoms have been conducted in patients with STN implantation, and these studies reported significant improvement in motor function with a relatively low rate of complication. The large experience of ablative surgery associated with the DBS experience of some groups worldwide indicate that GPi is a possible and very promising target for the management of parkinsonian symptoms. Surgical procedures have become safer and it is now possible, in selected cases, to target both structures in the same patient by means of the stereotactic system, “3P Maranello” (CLS‐SRL, Italy). Using this system we were able to evaluate the clinical effects of simultaneous stimulation of both STN and GPi as well as evaluate the effects of isolated stimulation of each target. As it is known that there is a high intersubject variability of DBS, it seems relevant to test all different combinations of DBS in the same patient. Methods . We assessed the effects of DBS in 13 cases of PD, immediately after (30 min) stimulation and during chronic stimulation (weeks or months). Patients fell into two groups. The first (n = 7) responded to both GPi and STN stimulation equally. The second group (n = 6) was preferentially stimulated with only one target (STN = 5, GPi = 1). Results . There was a good reduction in levodopa treatment following surgery. Most patients remained were chronically treated with bilateral stimulation of both targets. Conclusion . We conclude that DBS of STN and GPi was effective, with most patients treated chronically with both targets stimulated.     

Deep brain stimulation in the treatment of movement disorders]

The introduction of deep brain stimulation (DBS) was a historical step forward for the treatment of advanced and medically intractable movement disorders that include Parkinson's disease, dystonias, essential tremor, and Holmes' tremor. DBS is able to modulate the target region electrically in a reversible and adjustable fashion in contrast to an irreversible and destructive lesioning procedure. In the treatment of movement disorders, the potential targets are the thalamic ventral intermediate nucleus (Vim), globus pallidus internus (GPi), subthalamic nucleus (STN), pedunculopontine nucleus (PPN), and thalamic Vo-complex nucleus. With the development of DBS technology and stereotactic neurosurgical techniques, its therapeutic efficacy has been increased while reducing surgical complications. DBS has become an established therapy for disabling movement disorders and is currently being used to treat neuropsychiatric disorders.     

Advances in neurostimulation for movement disorders

In just 12 years since its introduction, deep brain stimulation (DBS) has become well established as a safe and effective therapy in the treatment of medically refractory movement disorders. Ventralis intermedius (Vim) DBS has virtually replaced thalamotomy in the routine clinical treatment of essential tremor, affording relief to thousands of patients who previously would not have undergone surgery, and there is increasing usage of Vim DBS in other tremors of intention (e.g., multiple sclerosis). Subthalamic nucleus (STN) and globus pallidus internus (GPi) DBS have revolutionized the treatment of advanced stage Parkinson's disease, improving all cardinal disease features and increasing 'on' time without dyskinesias. Finally, DBS of various sub-cortical structures is being developed and tested in other less prevalent movement disorders such as dystonia. Future developments in this rapidly advancing area will no doubt include widening indications for this relatively safe surgical procedure, elucidation of the mechanisms of action of electrical stimulation, and technological advancements improving effectiveness and convenience.     

刺激术和毁损术在双侧立体定向手术治疗帕金森病中的比较

目的比较脑深部刺激术和毁损术在双侧立体定向手术治疗帕金森病中的优缺点。方法69例帕金森病病人进行了双侧手术治疗,其中同期双侧丘脑底核(STN)脑深部刺激术(DBS)11例,同期一侧苍白球腹后部毁损术(PVP),另一侧STNDBS3例,分期一侧PVP或腹中间核(Vim)毁损术、另一侧STN或VimDBS9例;分期双侧PVP或Vim毁损术41例,同期双侧PVP5例。平均随访9.3个月。结果UPDRS评分显示刺激术和毁损术均能显著改善对侧肢体震颤、僵硬和运动迟缓症状,双侧刺激术还能改善步态和姿势症状,但双侧毁损术可加重语言、吞咽及流涎等症状,并发症较高。结论双侧DBS是具有双侧症状的帕金森病病人手术治疗的最佳术式,双侧毁损术并发症较高,应严格慎重采用。     

Surgical targets for dystonic tremor: Considerations between the globus pallidus and ventral intermediate thalamic nucleus

Dystonic tremor (DT) is characterized by coexisting tremor and abnormal dystonic posturing in the same segment. DT is often medically refractory and DBS is an important therapeutic option. However, the optimal surgical target for DT remains uncertain with Vim, GPi and zona incerta previously reported as effective. We retrospectively reviewed the outcome data from all patients with DT involving at least one upper extremity who underwent DBS at Vanderbilt University from July 2006 to July 2010. We evaluated the improvement of tremor and dystonia after their response to DBS was judged to be maximal. Ten patients met the inclusion criteria. Vim was targeted in four patients and three had unilateral procedure and one bilateral Vim DBS. GPi was targeted in four patients with bilateral DBS procedure in every patient from this subgroup. A combined bilateral GPi and unilateral Vim DBS was performed in two patients. The best results for tremor control were observed in patients with Vim DBS but they had persisting mild dystonia. Patients with GPi DBS had average DT improvement by approximately 50% but their dystonia symptoms were markedly improved. We propose that the patients with DT with a mild dystonia should be considered for Vim DBS procedure and the coexistence of severe DT and dystonia may be successfully controlled by combined GPi and Vim DBS surgeries.     

双侧丘脑底核脑深部电刺激治疗帕金森病

目的 应用双侧丘脑底核脑深部电刺激（DBS）治疗难治性帕金森病（PD），并对其疗效作出评价。方法 对7例帕金森病患者采用磁共振导向立体定向及术中电生理验证方法，将刺激电极分别植入丘脑底核，采用同期或分期植入刺激发生器。术后1周用程控计算机在体外调速刺激参数，以达到最佳疗效。结果 6例患者术后均获得了显著的疗效。震颤完全消失，肌强直、步态、姿障碍以及药物所致的并发症明显,面时多巴胺类药物用量明显减少，1例曾接爱双侧丘脑腹中间核及一侧苍白球毁损后的患者只得到了轻度改善。结论 DBS法治疗中晚期PD，具有安全，副作用可逆转的优点，且可根据患者的不同状况及病情发展调节刺激参数达到最佳症状控制，完全控制震颤，明显改善肌张力障碍、步态、资势等运动障碍及药物所致的并发症，另外多巴胺类药物的用量也明显减少。     

Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor

BACKGROUND: The preferred surgical target for the treatment of Parkinson disease (PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the target for treatment of essential tremor (ET) is the thalamic subnucleus ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the identification of a single surgical target to treat both parkinsonian motor symptoms and ET would be of practical importance. OBJECTIVE: To describe the use of the STN target in deep brain stimulator (DBS) surgery to treat PD motor symptoms and the action-postural tremor of ET. DESIGN: Case report. PATIENT: A 62-year-old man had a greater than 30-year history of action-postural tremor in both hands, well controlled with beta-blockers for more than 20 years. He developed resting tremor, bradykinesia, and rigidity on his right side that progressed to his left side during the past 10 years. Dopaminergic medication improved his rigidity and bradykinesia, with only mild improvement of his resting tremor and no effect on his action-postural tremor. INTERVENTIONS: Left pallidotomy followed by placement of a left DBS in the Vim and subsequent placement of a right STN DBS. MAIN OUTCOME MEASURES: Control of symptoms of PD and ET. RESULTS: The left pallidotomy controlled the patient's parkinsonian motor symptoms on the right side of his body, but did not affect the action-postural component of his tremor. The symptoms on the left side of the body, including both an action-postural and a resting tremor (as well as the rigidity and bradykinesia), improved after placement of a single right STN DBS. CONCLUSION: Placement of an STN DBS should be considered as the procedure of choice for surgical treatment of patients with a combination of PD and ET.     

The effects of subthalamic nucleus deep brain stimulation on parkinsonian tremor

Deep brain stimulation (DBS) of the ventral intermediate (Vim) nucleus of the thalamus has been the target of choice for patients with disabling essential tremor or medication refractory parkinsonian tremor. Recently there is evidence that the subthalamic nucleus (STN) should be the targets for patients with tremor associated with Parkinson's disease (PD). To assess the effects of STN DBS on parkinsonian tremor, eight consecutive patients with PD and disabling tremor were videotaped using a standardized tremor protocol. Evaluations were performed at least 12 h after last dose of medication with the DBS turned off followed by optimal DBS on state. A rater blinded to DBS status evaluated randomized video segments with the tremor components of the Unified Parkinson Disease Rating Scale (UPDRS) and Tremor Rating Scale (TRS). Compared with DBS off state there were significant improvements in mean UPDRS tremor score 79.4% (p = 0.008), total TRS score 69.9% (p = 0.008) and upper extremity 92.5% (p = 0.008) TRS subscore. Functional improvement was noted with pouring liquids. Our findings provide support that STN DBS is an effective treatment of tremor associated with PD.     

Pallidal stimulation in advanced Parkinson's patients with contraindications for subthalamic stimulation

The aim of this study was to evaluate the efficacy and safety of bilateral pallidal (GPi) deep brain stimulation (DBS) 6 months after surgery in advanced parkinsonian patients whose dopa‐resistant axial motor signs or cognitive decline constituted contraindications for subthalamic nucleus (STN) DBS. Seventeen patients with a mean age of 59.3 ± 7.1 years (range, 45–70), mean disease duration of 12.5 ± 4.3 years (range, 7–20), and contraindications for STN DBS, underwent bilateral GPi DBS. They were evaluated before surgery and 6 months afterward, in accordance with Core Assessment Program for Intracerebral Transplantation recommendations. There were mean improvements of 41.1% in the UPDRS III motor score in the off‐dopa condition and 20.3% in the activities of daily living score. Motor fluctuations were reduced by 22.9% and dyskinesias by 68.6%. Axial motor signs improved in the off‐dopa condition by 34.2%. Neuropsychological performances remained unchanged at the 6‐month assessment. Bilateral GPi DBS is both safe and effective in advanced parkinsonian patients with untreatable motor fluctuations, for whom STN DBS is contraindicated due to dopa‐resistant axial motor signs or cognitive decline. As such, it should be regarded as a viable option for these patients. © 2010 Movement Disorder Society     

脑深部电刺激治疗肌张力障碍

目的 探讨脑深部电刺激术(deep brain stimulation, DBS)治疗全身性、偏身性和节段性肌张力障碍的有效性和安全性,肌张力障碍患者治疗和术后程控的策略.方法 采用微电极记录下丘脑底核(subthalamic nucleus, STN)、苍白球内侧部(globus pallidus intemus, GPi)和丘脑腹中间核(ventrointermediate nucleus, Vim)埋置脑深部刺激器治疗肌张力障碍患者15例,同时记录患者对侧受累肌肉的电活动.其中13例患者的刺激靶点为STN(11例为双侧,2例为单侧),1例刺激靶点为单侧GPi,1例为Vim.结果 除1例严重全身肌张力障碍患者外,其余患者因随访时间长短,均有不同程度改善,改善率从22.0%～95.8%不等.其中随访时间超过12个月的患者症状改善率均大于48.6%.1例因全身扭动造成电极外露,颈、胸腹部切口感染,最终将DBS装置取出.另有1例患者因双侧上端的两个触点断路,再次手术将电极位置上移.所有患者均未出现因穿刺造成的颅内出血的永久并发症.结论 通过对现有DBS治疗肌张力障碍病例资料有效性和安全性的总结,DBS成为治疗肌张力障碍的一种新方法.     

Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery

Before the introduction of high frequency stimulation of the subthalamic nucleus (STN), many disabled tremor dominant parkinsonian patients underwent lesioning or chronic electrical stimulation of the thalamus. We studied the effects of STN stimulation in patients with previous ventral intermediate nucleus (VIM) surgery whose motor state worsened. Fifteen parkinsonian patients were included in this study: nine with unilateral and two with bilateral VIM stimulation, three with unilateral thalamotomy, and one with both unilateral thalamotomy and contralateral VIM stimulation. The clinical evaluation consisted of a formal motor assessment using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests encompassing a 50 point frontal scale, the Mattis Dementia Rating Scale, and the Beck Depression Inventory. The first surgical procedure was performed a mean (SD) of 8 (5) years after the onset of disease. STN implantation was carried out 10 (4) years later, and duration of follow up after beginning STN stimulation was 24 (20) months. The UPDRS motor score, tremor score, difficulties in performance of activities of daily living, and levodopa equivalent daily dose significantly decreased after STN stimulation. Neither axial symptoms nor neuropsychological status significantly worsened after the implantation of the STN electrodes. The parkinsonian motor state is greatly improved by bilateral STN stimulation even in patients with previous thalamic surgery, and STN stimulation is more effective than VIM stimulation in tremor dominant parkinsonian patients.     

Deep brain stimulation for Parkinson’s disease

The surgical treatment of Parkinson’s disease has been through a revival phase over the last 20 years with the development of deep brain stimulation (DBS). Thalamic DBS was developed first and has proven to be a very effective treatment for tremor. The limitation is the lack of effect on other symptoms. Other targets were therefore investigated, and the procedure was applied to the subthalamic nucleus (STN) and the internal globus pallidus (GPi). STN stimulation can improve a wide range of symptoms and is currently the preferred target for many patients. Nevertheless, the morbidity seems higher than with other targets, and the selection criteria have to be quite strict. When STN DBS is not advised, thalamic DBS remains an option for patients with severe tremor, and GPi stimulation for those with severe dyskinesias. DBS remains a symptomatic treatment for a limited number of patients; it does not seem to alter the disease progression, and many patients are not suitable. There is, therefore, the need for further research into other targets and other approaches.     

Motor outcomes and adverse effects of deep brain stimulation for dystonic tremor: A systematic review

Dystonic tremor (DT) is defined as the tremor in body parts affected by dystonia. Although deep brain stimulation (DBS) has been used to manage medically-refractory DT patients, its efficacy has not been well established. The objective of this study is to provide an up-to-date systematic review of DBS outcomes for DT patients. We conducted a literature search using Medline, Embase, and Cochrane Library databases in February 2020 according to the PRISMA guidelines. From 858 publications, we identified 30 articles involving 89 DT patients who received DBS of different targets. Thalamic DBS was the most common (n = 39) and improved tremor by 40–50% potentially in the long-term over five years with variable effects on dystonic symptoms. Globus pallidus internus (GPi), subthalamic, and subthalamic nucleus (STN) DBS improved both tremor and dystonic symptoms; however, data were limited. A few studies have reported better tremor and dystonia outcomes with combinations of different targets. Concerning adverse effects, gait/balance disorders, and ataxia seemed to be more common among patients treated with thalamic or subthalamic DBS, whereas parkinsonian adverse effects were observed only in patients treated with subthalamic or GPi DBS. Comparative benefits and limitations of these targets remain unclear because of the lack of randomized controlled trials. In conclusion, DBS of these targets may improve tremor with a variable effect on dystonia with different adverse effect profiles. The shortcomings in the literature include long-term motor outcomes, quality of life outcomes, optimal DBS targeting, and DBS programming strategy.