Twenty-five years of deep brain stimulation: celebrations and apprehensions

The year 2012 marks the 25th anniversary of the birth of modern deep brain stimulation (DBS), which was introduced by Benabid et al in 1987, initially to treat tremor with DBS of the ventral intermediate nucleus of the thalamus. The subsequent extension of DBS to the subthalamic nucleus (STN), demonstrating its efficacy on virtually all symptoms of advanced Parkinson's disease (PD), sparked an era of intense clinical and research activities, eventually transcending PD and movement disorders to encompass mood and mind. Investigations of the role of DBS in a variety of neurological, psychiatric, cognitive, and behavioral conditions is ongoing. Serendipitous discoveries and advances in functional imaging are providing "new" brain targets for an increasing number of pathologies. Toward the end of this quarter of a century of DBS, there have been some indications that the field may be at risk of gliding down a slippery slope, reminiscent of the excesses of the old-era DBS. Although there are many reasons this year to celebrate the achievements of 25 years of modern DBS, there are also reasons to fear the opening of a new Pandora's box.     

Deep Brain Stimulation for Early-Stage Parkinson’s Disease: An Illustrative Case

Objectives: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinson's disease (PD), but its efficacy and safety in early PD are unknown. We are conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN‐DBS. Materials and Methods: Thirty subjects have been randomized to either optimal drug therapy (ODT) or DBS + ODT. Microelectrode recordings from the STN and substantia nigra are collected at implantation. The Unified Parkinson's Disease Rating Scale Motor Subscale (UPDRS‐III) is administered in the ON and OFF states semi‐annually and neuropsychological function and quality of life are assessed annually. We describe a 54‐year‐old man with a two‐year history of PD who was randomized to DBS + ODT and followed for two years. Results: The subject showed a lower STN to substantia nigra ratio of neuronal activity than advanced PD patients, and higher firing rate than non‐PD patients. The subject's total UPDRS and UPDRS‐III scores improved during the two‐year follow‐up, while his OFF UPDRS‐III score and levodopa equivalent daily dose increased. Quality of life, verbal fluency, and verbal learning improved. He did not experience any serious adverse events. Conclusions: This report details the first successful application of bilateral STN‐DBS for early‐stage PD during a clinical trial.     

Deep brain stimulation for movement disorders before DBS for movement disorders

Deep brain stimulation (DBS) is an established surgical treatment for Parkinson’s disease (PD), essential tremor and dystonia. It is generally acknowledged that the development of DBS as we know it today started with the publication of Benabid, Pollak et al in 1987 on thalamic DBS for tremor. This technique gained momentum in the mid-Nineties after that Pollak and Benabid introduced the subthalamic nucleus as a target in advanced PD.This paper reviews the gestational pre-natal era of deep brain stimulation, before 1987. The origin of DBS can be traced back to the practice of intra-operative electrical stimulation, used for target exploration prior to lesioning, during the early years of stereotactic functional neurosurgery. During the 60s, Sem-Jacobsen and others implanted externalised electrodes which were used for intermittent stimulation and evaluation during weeks or months, prior to subsequent ablation of thalamic and other basal ganglia targets. In the early 70s Bechtereva treated PD patients using “therapeutic electrical stimulation” through electrodes implanted for up to 1.5 years. In the late 70s and early 80s the term Deep Brain Stimulation was coined and few groups attempted treatment of Parkinson’s disease, non-Parkinsonian tremor and dystonia with high-frequency stimulation using chronically implanted DBS systems. Cumbersome, un-sophisticated DBS hardware, together with the general decline of all surgery for PD following the introduction of levodopa, may have contributed to the lack of popularity of old-times DBS. It is to the credit of the Grenoble Group to have reinvented, modernised and expanded modern DBS in surgical treatment of movement disorders.     

Long‐term outcomes of surgical therapies for Parkinson's disease

The surgical lesion of different brain structures has been used as a treatment for Parkinson's disease (PD) for several decades. More recently, the favored therapeutic approach has involved the administration of levodopa and the use of DBS. These two major therapeutic advances have greatly modified both the clinical condition of patients and the history of the disease. With the introduction of L ‐dopa in 1967, patients could regain mobility, because their akinesia, tremor, and rigidity were greatly improved, with consequent significant improvement in quality of life and increased life expectancy. However, after the so‐called “honeymoon” period in which the disease seemed to be controlled, motor fluctuations and L ‐dopa‐induced dyskinesias mitigated the initial enthusiasm. In the 1990s, unilateral pallidotomy and DBS of the globus palllidus internus and STN reduced these motor fluctuations and dyskinesias remarkably, thereby inaugurating a new era in the surgical treatment of PD. Short‐ and medium‐term follow‐up studies of patients who underwent surgery have documented sustained, significant motor benefits. However, given the progressive nature of PD and the purely symptomatic effects of pallidotomy and DBS, the long‐term clinical evolution of these surgical patients currently seems to be associated with a new PD phenotype, mainly characterized by axial motor problems and cognitive impairment. Here, we analyze the long‐term clinical outcomes of surgical PD patients with at least 5‐year follow‐up, focusing on the long‐term motor symptoms that were initially responsive to surgery. © 2012 Movement Disorder Society     

Deep brain stimulation in Parkinson’s disease

Throughout the past decade, there has been a marked increase in surgical therapies, primarily deep brain stimulation (DBS), for the treatment of advanced Parkinson’s disease (PD). DBS of the thalamus has been shown to be effective in reducing parkinsonian tremor; however, it is not the treatment of choice for PD given the progression of other symptoms such as rigidity and bradykinesia. Stimulation of the globus pallidus or the subthalamic nucleus is safe and efficacious in the long-term treatment of all cardinal symptoms of PD, and they are currently the surgeries of choice. Serious adverse events with DBS can occur in 1% to 2% of patients, infection in 5% to 8% of patients, and hardware complications in approximately 25% of patients. Complications associated with DBS are related to the experience of the surgical center. Referring physicians and patients should be aware of the number of surgical procedures and complication rates of any prospective surgical center.     

MDS-UPDRS to assess non-motor symptoms after STN DBS for Parkinson's disease

Objective: To determine if the non-motor sections of the Movement Disorder Society's (MDS) version of the Unified Parkinson's Disease Rating Scale (UPDRS) could supplement the original UPDRS as a patient completed assessment of changes in non-motor symptoms in Parkinson's disease (PD) patients after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS). Methods: Thirty PD patients who underwent bilateral STN DBS were assessed using the total UPDRS and the non-motor sections of the MDS-UPDRS prior to surgery and one year following surgery. This study focuses on non-motor symptoms as assessed by Part I of the UPDRS and Part 1A and 1B of the MDS-UPDRS. Results: One year following surgery, no individual non-motor symptoms or the total mentation score of the UPDRS were significantly changed. In comparison, the MDS-UPDRS showed significant improvements in sleep and urinary problems and a trend towards improvement in anxiety, constipation, daytime sleepiness, fatigue and pain. Conclusions: This study provides evidence that the MDS-UPDRS non-motor sections, when completed by the patients, can supplement the original version of the UPDRS as an effective method of measuring changes in non-motor symptoms after DBS. It also reinforces the benefits of bilateral STN DBS on non-motor symptoms of PD.     

Long‐term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group. © 2010 Movement Disorder Society     

Deep brain stimulation effects on gait variability in Parkinson's disease

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on fall risk in patients with Parkinson's disease (PD) currently remain unclear. Although several gait parameters, such as gait speed, have shown improvement with DBS, some studies have reported an increased fall risk following DBS. The purpose of this study was to examine the effect of bilateral DBS on gait variability, a marker of fall risk. The gait of 13 patients with idiopathic PD was analyzed to determine the influence of DBS, levodopa and both therapies together. Following treatment with both levodopa and STN DBS, subjects displayed improved gait speed, reduced gait variability (enhanced stability), and lower Unified Parkinson's Disease Rating Scale (UPDRS) scores. Although UPDRS scores improved with STN DBS alone, parallel improvements were not seen for gait variability. These findings suggest that different mechanisms may contribute to performance on UPDRS motor testing and gait stability in response to DBS. © 2009 Movement Disorder Society     

Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review

Pedunculopontine nucleus region deep brain stimulation (DBS) is a promising but experimental therapy for axial motor deficits in Parkinson's disease (PD), particularly gait freezing and falls. Here, we summarise the clinical application and outcomes reported during the past 10 years. The published dataset is limited, comprising fewer than 100 cases. Furthermore, there is great variability in clinical methodology between and within surgical centers. The most common indication has been severe medication refractory gait freezing (often associated with postural instability). Some patients received lone pedunculopontine nucleus DBS (unilateral or bilateral) and some received costimulation of the subthalamic nucleus or internal pallidum. Both rostral and caudal pedunculopontine nucleus subregions have been targeted. However, the spread of stimulation and variance in targeting means that neighboring brain stem regions may be implicated in any response. Low stimulation frequencies are typically employed (20‐80 Hertz). The fluctuating nature of gait freezing can confound programming and outcome assessments. Although firm conclusions cannot be drawn on therapeutic efficacy, the literature suggests that medication refractory gait freezing and falls can improve. The impact on postural instability is unclear. Most groups report a lack of benefit on gait or limb akinesia or dopaminergic medication requirements. The key question is whether pedunculopontine nucleus DBS can improve quality of life in PD. So far, the evidence supporting such an effect is minimal. Development of pedunculopontine nucleus DBS to become a reliable, established therapy would likely require a collaborative effort between experienced centres to clarify biomarkers predictive of response and the optimal clinical methodology. © 2017 International Parkinson and Movement Disorder Society     

Parkinson's disease motor subtypes and bilateral GPi deep brain stimulation: One-year outcomes

ObjectiveWe aimed to explore the differences in motor symptoms and quality of life (QOL) outcomes following bilateral globus pallidus internus deep brain stimulation (GPi DBS), across well-defined motor subtypes of Parkinson's disease (PD), to improve clinical decision making.MethodsThis single-center retrospective study investigated bilateral GPi DBS outcomes in 65 PD patients. Outcome measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire (PDQ-39) before and one year after surgery. Outcomes were compared between the tremor-dominant (TD) and postural instability and gait difficulty (PIGD) subtypes and between the TD and akinetic-rigid (AR) subtypes.ResultsFor the entire cohort, motor function (UPDRS III) in the Off-medication state, motor complications (UPDRS IV), activities of daily living (ADL, UPDRS II), and the ADL and discomfort domains of PDQ-39 significantly improved one year following GPi implantation compared to baseline (effect size = 1.32, 1.15, 0.25, 0.45, and 0.34, respectively). GPi DBS improved the Off-medication UPDRS III scores regardless of the motor subtypes. However, compared to the PIGD and AR patients, the TD patients showed greater improvement in overall UPDRS III postoperatively primarily due to greater tremor improvement in the Off-medication state. The outcomes in akinesia, rigidity, axial symptoms and QOL were similar among all subtypes.ConclusionBilateral GPi DBS was effective for advanced PD patients regardless of motor subtypes. Greater tremor improvement in the TD patients accounted for greater Off-medication motor improvement. Longer-term GPi DBS outcomes across different motor subtypes and brain targets should be further studied.     

Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinson's disease (PD) and essential tremor (ET). However, there are few reports on its long-term efficacy. We studied the efficacy of DBS at 2 years and 6-7 years after electrode implantations in the ventrointermediate nucleus of the thalamus in 39 patients (20 PD, 19 ET) with severe tremor. Twenty-five of the patients completed the study. Evaluations were done in a double-blind manner with the Unified Parkinson's Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P < 0.025) compared to the preoperative baseline (median, 7; Q25-75, 6-9) both at 2 years (median, 2; Q25-75, 2-3.5; n = 16) and at 6 to 7 years (median, 2.5; Q25-75, 0.5-3; n = 12). Stimulation on improved tremor sum as well as sub scores (P < 0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P < 0.025) kinetic and positional tremor at both follow-up periods (n = 18 and n = 13, respectively) with significant improvements (P < 0.025) in hand-function tests. PD but not ET patients showed a general disease progression. Stimulation parameters were remarkably stable over time. We conclude that high-frequency electric thalamic stimulation can efficiently suppress severe tremor in PD and ET more than 6 years after permanent implantation of brain electrodes.     

Cognitive change on the repeatable battery of neuropsychological status (RBANS) in parkinson's disease with and without bilateral subthalamic nucleus deep brain stimulation surgery

Cognitive change following bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery in those with Parkinson's disease (PD) has led to equivocal results. The current study applied a standardized regression-based (SRB) method based on 20 medically managed PD patients and 20 STN DBS PD surgical patients who were administered the Repeatable Battery of Neuropsychological Status (RBANS). Of the medically managed PD participants, 94% remained stable compared to 73% of the DBS group. In the DBS group cognitive change was noted on the Total scale and the Immediate Memory Index. A secondary analysis also revealed reliable change on several subtest scores. Although preliminary, the current study provides change parameters for post DBS surgery on this brief battery.     

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: long-term follow-up

Neurological Sciences - Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective therapy for the treatment of advanced Parkinson's disease (PD)....     

Deep brain stimulation outcomes in the malignant end of Parkinson's disease spectrum

BackgroundHeterogeneity of Parkinson's Disease (PD) phenotype may influence deep brain stimulation (DBS) outcome. However, DBS response in the malignant end of the PD spectrum has been poorly investigated.ObjectiveTo evaluate and compare DBS outcomes in malignant and benign PD patients, defined according to motor and non-motor symptom presentation at the presurgical selection.MethodsWe categorized a cohort of 154 parkinsonian patients fulfilling criteria for subthalamic nucleus (STN)-DBS into malignant, benign, and intermediate subtypes, according to a recently validated clinical PD classification. DBS efficacy on daily living independence (Schwab and England –S&E-score ≥70%), motor symptoms, and motor fluctuations (Unified Parkinson's Disease Rating Scale -UPDRS- part-III and -IV, and Ambulatory Capacity Measure) were compared between malignant and benign patients, using corrected binary logistic regressions and repeated measure general linear model.ResultsOne year after surgery, the probability of losing daily life independence was 16-fold higher in malignant patients, even after adjusting for age at PD onset, PD duration, and percentage of motor improvement after STN-DBS (OR: 16.233; p: 0.035). Conversely, malignant and benign patients showed a similar extent of improvement after STN-DBS (p > 0.05) in motor symptoms, motor fluctuations, and ambulatory capacity, both in medication-ON and medication-OFF conditions.ConclusionDBS candidates in the malignant end of the PD spectrum may profit from a similar improvement of motor symptoms and fluctuations after STN-DBS when compared to benign PD. However, patients of the malignant group have a lower probability of maintaining independence in daily life early after surgery.     

Caregiver burden worsens in the second year after subthalamic nucleus deep brain stimulation for Parkinson's disease

BackgroundCaregiver burden (CB) in Parkinson's disease (PD) does not improve in the short term after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), despite motor improvement. This may be due to increased caregiver demands after surgery or the possibility that DBS unresponsive non-motor factors, such as executive dysfunction, contribute to CB.ObjectiveTo evaluate the trajectory of CB in year 2 following bilateral STN DBS surgery for PD, and to test whether post-operative CB changes correlate with changes in executive function in a subgroup with available neuropsychological testing.MethodsThis retrospective analysis included 35 patients with PD whose caregivers completed the Caregiver Burden Inventory (CBI) at baseline and between 9 and 24 months after bilateral STN DBS. 14 of these patients had neuropsychological testing both at baseline and within 6 months of their follow up CBI assessment.ResultsCBI scores showed worsened CB from baseline to follow-up (16.4–21.5, p = 0.006). There was no correlation between change in executive function and change in CBI in the smaller subsample.ConclusionCB worsens in the 2 years after bilateral STN DBS despite improvement in motor symptoms and is not associated with change in executive dysfunction in the setting of advancing PD. These findings have implications on pre-operative counselling for patients and caregivers considering DBS for PD.     

The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson's disease

Objective

To evaluate the impact of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on the prevalence of non-motor symptoms reported by Parkinson's disease (PD) patients one year following surgery and to examine whether there was an association between number of non-motor symptoms reported and quality of life (QoL).

Methods

Twenty-four patients who received bilateral STN DBS and had follow-up evaluations one year after surgery were included in this study. Patients’ motor function was evaluated with the Unified Parkinson’s Disease Rating Scale, non-motor symptoms were assessed with the Non-Motor Symptom questionnaire (NMSQuest) and quality of life was assessed with the PDQ-39.

Results

There was a mean of 12 non-motor symptoms reported prior to surgery which was significantly reduced to a mean of 7 symptoms one year after surgery. Autonomic symptoms were the most frequently reported and demonstrated the greatest reductions following surgery. Twenty-seven of the 30 items represented in the NMSQuest were reported less frequently one year after surgery compared to before surgery. The reduction in non-motor symptoms was significantly correlated with total QoL scores and the subscales of mobility, activities of daily living, cognition and bodily discomfort.

Conclusions

Non-motor symptoms are common in patients with advanced PD. The number of non-motor symptoms was significantly decreased one year following bilateral STN DBS which was associated with a significant improvement in QoL. Further studies focused on specific non-motor symptoms are warranted in order to fully understand the impact and mechanisms of STN DBS on these symptoms.     

Seventy years of pallidotomy for movement disorders

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     

Speed effects of deep brain stimulation for Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) accelerates reaction time (RT) in patients with Parkinson's disease (PD), particularly in tasks in which decisions on the response side have to be made. This might indicate that DBS speeds up both motor and nonmotor operations. Therefore, we studied the extent to which modifications of different processing streams could explain changes of RT under subthalamic DBS. Ten PD patients on‐DBS and off‐DBS and 10 healthy subjects performed a choice‐response task (CRT), requiring either right or left finger button presses. At the same time, EEG recordings were performed, so that RTs could be assessed together with lateralized readiness potentials (LRP), indicative of movement preparation. Additionally, an oddball task (OT) was run, in which right finger responses to target stimuli were recorded along with cognitive P300 responses. Generally, PD patients off‐DBS had longer RTs than controls. Subthalamic DBS accelerated RT only in CRT. This could largely be explained by analog shortenings of LRP. No DBS‐dependent changes were identified in OT, neither on the level of RT nor on the level of P300 latencies. It follows that RT accelerations under DBS of the STN are predominantly due to effects on the timing of motor instead of nonmotor processes. This starting point explains why DBS gains of response speed are low in tasks in which reactions are initiated from an advanced level of movement preparation (as in OT), and high whenever motor responses have to be raised from scratch (as in CRT). © 2010 Movement Disorder Society     

Combined deep brain stimulation and thalamotomy for tremor-dominant Parkinson’s disease

Although deep brain stimulation (DBS) is an established treatment for Parkinson’s disease, the long-term suppression of tremor is still a challenging issue. We report two patients with tremor-dominant Parkinson’s disease (PD) treated with unilateral thalamotomy of the ventralis intermedius nucleus (Vim) combined with the subthalamic nucleus (STN)-DBS or the posterior subthalamic area (PSA)-DBS. One year after the surgery, thalamotomy of the area from the Vim to the PSA showed improvement not only in tremor but also in rigidity and akinesia. PSA- or STN-DBS with low intensity stimulation eliminated residual PD symptoms. Combined DBS and thalamotomy may provide long-term improvement of the majority of PD symptoms using lower therapeutic stimulation voltages.