Lack of motor symptoms progression in Parkinson's disease patients with long-term bilateral subthalamic deep brain stimulation

To evaluate the long-term progression of motor symptoms in Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS), we retrospectively analyzed data from 50 PD patients with bilateral STN-DBS. Clinical records at baseline and at several yearly intervals were reviewed. The Unified Parkinson's Disease Rating scale (UPDRS) was performed preoperatively after withholding medications for at least 12 hr (OFF) and after taking the usual dose of levodopa. Postoperative evaluations were completed in four clinical states: OFF medications—stimulators OFF (OFF/OFF); OFF medications—stimulators ON; ON medications—stimulators OFF; and ON medications—stimulators ON. The UPDRS motor scores OFF/OFF were virtually unmodified up to 5 years when compared with preoperative OFF scores. There was no significant difference between OFF/OFF score variations from baseline in patients with shorter (<11 years) and longer PD duration at the time of surgery. No consistent deterioration from untreated baseline was noted for each UPDRS motor subscore (tremor, rigidity, bradykinesia, and axial). Untreated PD motor scores did not worsen over time in patients undergoing STN-DBS, suggesting that there is no progression of motor severity. These results could be explained either by a natural stabilization of PD motor symptoms after many years or neuroprotective properties of STN-DBS.     

Staged unilateral versus bilateral subthalamic nucleus stimulator implantation in Parkinson disease.

In 17 consecutive patients with Parkinson disease (PD), bilateral subthalamic nucleus (STN) stimulators were implanted during staged surgeries. The Unified Parkinson Disease Rating Scale (UPDRS) and the Dyskinesia Disability Scale were completed both off and on medication prior to any surgery and also OFF and ON stimulation after each surgery. On-medication UPDRS activities of daily living (ADL) and motor examination scores changed little with unilateral or bilateral stimulation. Off-medication UPDRS motor examination scores improved to similar degrees after each staged STN electrode implantation. Most of the improvements in off-medication ADL scores, dyskinesia scores, complications of therapy, and medication dose reduction occurred after unilateral STN stimulation with smaller improvements after the second operation.     

Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation.

To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.     

Functional balance performance in patients with Parkinson's disease after long-term treatment with subthalamic nucleus high-frequency stimulation

The aim was to investigate if functional balance performance in patients with Parkinson's disease (PD) was affected by long-term (3 years) treatment with bilateral subthalamic nucleus (STN) high-frequency stimulation. Thirty-five patients were consecutively included, and 28 patients completed the study (mean age 62 years, SD 6.5). The Berg Balance Scale (BBS) was assessed preoperatively and 1 and 3 years postoperatively (with and without anti-PD medication and with the STN stimulation turned OFF or ON). Although the balance performance of patients with PD decreased over time, the functional balance performance was still positively affected by STN stimulation alone 3 years after surgery.     

The UPDRS-8: a brief clinical assessment scale for Parkinson's disease

We evaluated a brief, 8-item version of the Unified Parkinson's Disease Rating Scale (UPDRS) using two existing patient databases. One database included 1,445 PD patients. Spearman correlation between UPDRS-8 motor scores and full UPDRS motor scores was .765 (p < .001). Correlation between total UPDRS-8 scores and full UPDRS total scores (parts I-III) was .798 (p < .001). Correlation between total UPDRS-8 scores and total 39-item PD questionnaire (PDQ-39) scores was .629 (p < .001). In 177 patients undergoing deep brain stimulation (DBS), UPDRS-8 motor scores were similarly significantly sensitive to change as full UPDRS motor scores in assessing change from the medication OFF state to the medication ON state at baseline and from the medication OFF state at baseline to the medication OFF/stimulation ON state 1 year post-DBS. The UPDRS-8 focuses on items that are most relevant for clinical decision making. In this study, the UPDRS-8 exhibited good correlation with the full UPDRS and the PDQ-39. We therefore believe that it can provide a useful, rapid assessment of PD patients in clinical practice. Whether it might be useful in clinical trials depends on demonstrating that it is also sensitive to relatively small changes in clinical status.     

Effects of stereotactic neurosurgery on postural instability and gait in Parkinson's disease.

Postural instability and gait disability (PIGD) are disabling signs of Parkinson's disease. Stereotactic surgery aimed at the internal globus pallidus (GPi) or subthalamic nucleus (STN) might improve PIGD, but the precise effects remain unclear. We performed a systematic review of studies that examined the effects of GPi or STN surgery on PIGD. Most studies examined the effects of bilateral GPi stimulation, bilateral STN stimulation, and unilateral pallidotomy; we, therefore, only performed a meta-analysis on these studies. Bilateral GPi stimulation, bilateral STN stimulation, and to a lesser extent, unilateral pallidotomy significantly improved PIGD, and more so during the ON phase than during the OFF phase.     

Different effects of unilateral versus bilateral subthalamic nucleus stimulation on walking and reaching in Parkinson's disease.

The purpose of this study was to determine the effects of unilateral versus bilateral subthalamic nucleus (STN) stimulation on quantitative measures of walking and reaching in Parkinson's disease (PD). We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 6 people with PD who had bilateral STN stimulators implanted for at least 6 months and withheld their anti-parkinson medication for at least 8 hours. Subjects were studied with both stimulators off, one on, and both on. Kinematic data were collected as subjects walked, reached to a target, and were rated using the UPDRS motor subscale. STN stimulation improved walking speed and stride length, with the greatest benefit from bilateral stimulation. Reaching speed was improved by unilateral STN stimulation alone, with no additive effect of bilateral stimulation. UPDRS motor subscale ratings paralleled the kinematic findings. STN stimulation did not restore PD subjects' movements to the level of age-matched controls. Overall, these results provide further evidence that the basal ganglia pathways involved in control of walking and reaching may be distinct. We speculate that basal ganglia may influence walking through bilateral pedunculopontine projections and reaching through ipsilateral thalamocortical projections. Our findings also suggest that maximal improvement of walking requires bilateral rather than unilateral STN stimulation.     

脑深部电刺激治疗帕金森病的程控

目的探讨丘脑底核脑深部电刺激术治疗帕金森病(PD)的手术方法和脉冲发生器程控调节。方法自2000年1月～2004年2月用脑深部电刺激丘脑底核(STN)治疗帕金森病61例,其中单侧30例,双侧31例。采用磁共振扫描结合微电极记录技术进行靶点定位。术后用帕金森病评定量表(UPDRS)运动评分评价刺激效果。结果61例PD患者术后随访6～36个月,平均11．3个月。脉冲发生器开启时,在“关”状态下,UPDRS运动评分改善率45．2％;在“开”状态下,UPDRS运动评分改善率20．7％,未发现任何并发症。结论脑深部刺激(DBS)能有效控制帕金森病患者的症状,手术并发症少,术后可根据患者的症状调节参数,丘脑底核(STN)已成为治疗帕金森病的最佳靶点。     

Subthalamic deep brain stimulation in patients with a previous pallidotomy.

The safety and efficacy of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients who have had a previous unilateral pallidotomy is not clear. We identified 10 patients (9 male) at the Baylor College of Medicine Parkinson's Disease Center who underwent STN DBS after prior unilateral pallidotomy. Demographics, efficacy as determined by off Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, and levodopa equivalent dosing were analyzed. We then compared these to an age- and sex-matched group of 25 DBS patients who had no prior pallidotomy. After their initial pallidotomy (mean age, 51.8 +/- 10.8 years), the mean UPDRS motor off medicine scores improved from 51.3 +/- 14.3 to 34.9 +/- 12.8, and the UPDRS dyskinesia score improved from 1.8 +/- 1.0 to 0.8 +/- 0.7. Their STN DBS off UPDRS motor scores (mean age, 56.0 +/- 10.2 years) improved by 16.0% from 53.1 +/- 9.7 (range, 42-68) to 44.6 +/- 11.1 (range, 25-67). In contrast, the UPDRS off motor scores in a control group of 25 DBS patients improved by 49.9%, from 49.7 +/- 11.1 to 25.7 +/- 18.9, (16.0% vs. 49.9%; P < 0.001). Changes in UPDRS dyskinesia scores were similar in both groups. AE thought to be related to the STN DBS following pallidotomy included worse dysarthria (three) and worse balance (two). STN DBS patients with prior pallidotomy had less improvement in UPDRS off motor score compared to other STN DBS patients, despite relatively good outcomes immediately after their pallidotomy. This may be partially due to a selection bias, but it may also indicate that prior pallidotomy is a negative predictor of outcome of STN DBS and should be considered in patient selection.     

Evaluation of timed tests in advanced Parkinsonian patients who were candidates for subthalamic stimulation

The evaluation of Parkinson disease relies on the use of clinical scales, mainly the UPDRS. However, especially for those candidates for functional surgery, other objective methods are also considered, including the use of timed tests. METHODS: The authors studied the motor performance of 33 patients with advanced Parkinson disease (PD) who were candidates for subthalamic nucleus (STN) stimulation. Presurgical motor evaluation included UPDRS and the 4 timed tests of the CAPIT protocol, including pronation-supination (PS), finger dexterity (FD), movement between 2 points (MTP), and the walking test (WT). A clinical evaluation was performed during patients' OFF condition and during their best ON state. Fifteen patients were implanted with STN stimulation and were evaluated at 6 months with the same protocol described for the presurgical evaluation. RESULTS: At baseline, all 4 timed tests significantly correlated with total and motor UPDRS scores, in the OFF and ON states, especially MTP. All timed tests, save WT, significantly improved after surgery in the OFF state (especially MTP; P = 0.002). After surgery, all timed tests, save FD, significantly correlated with total and motor UPDRS scores in the OFF state. Timed tests, especially MTP, maintained an excellent correlation with UPDRS in both OFF and ON states before and after surgery.     

Subthalamic nucleus deep brain stimulation for parkinson's disease after successful pallidotomy: clinical and electrophysiological observations.

Unilateral pallidotomy is an effective treatment for contralateral parkinsonism and dyskinesia, yet symptoms progress in many patients. Little is known about whether such patients obtain a useful response to subsequent bilateral subthalamic nucleus deep brain stimulation (STN DBS). Changes in Unified Parkinson's Disease Rating Scale (UPDRS) Motor and Activities of Daily Living (ADL) scores, medication requirements, and dyskinesias were measured. Clinical outcomes were compared to patients with de novo STN DBS. Neuronal recordings were performed. STN DBS resulted in a significant reduction in UPDRS Motor scores (42.1%; 95% confidence interval [CI], 26.9-57.4; P = 0.03), comparable with de novo STN DBS surgery (41%; 95% CI, 26-46%; P < 0.001). There was also less change in dyskinesia duration and disability scores (P = 0.017, 0.005). There were no side-to-side differences clinically or in the STN neuronal firing rates and patterns. Bilateral STN DBS is safe and efficacious in improving motor symptoms in patients with prior pallidotomy.     

Acute Changes in Mood Induced by Subthalamic Deep Brain Stimulation in Parkinson Disease Are Modulated by Psychiatric Diagnosis

BackgroundDeep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood.ObjectiveThe study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS.MethodsThirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal.ResultsSTN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS.ConclusionsPD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group.     

Unilateral subthalamic nucleus deep brain stimulation contralateral to thalamic stimulation in Parkinson disease

The effects of unilateral subthalamic nucleus (STN) stimulation contralateral to thalamic stimulation in Parkinson disease (PD) have not been previously reported. We are reporting a patient who developed left arm tremor in 1994, at age 62, as her first PD symptom. She underwent right thalamic DBS surgery in 1999 that resulted in complete resolution of left arm tremor. Her PD symptoms progressed and she developed severe motor fluctuations and disabling dyskinesias. In 2003, she underwent left STN electrode implantation. Left STN stimulation improved contralateral motor scores in the medication OFF state, and allowed for reduced medication doses and less dyskinesia. However, there was no significant improvement in activities of daily living (ADL), motor scores in the medication ON state, gait, or postural stability.     

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     

Effects of pallidotomy and levodopa on walking and reaching movements in Parkinson's disease.

We examined the effects of levodopa and unilateral pallidotomy on quantitative measures of walking and reaching in Parkinson's disease (PD). We also compared quantitative measures of movement with standard clinical rating scales. We used kinematic measures and the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale (subscale III) to evaluate the movement of 10 people with PD. Subjects were tested after withholding PD medications for at least 8 hours and again 30 to 45 minutes after taking the first morning dose of levodopa. They were studied in this manner before unilateral pallidotomy and then 3.5 to 10 months after surgery. The UPDRS motor subscale was performed in each state. Kinematic data were collected as subjects reached to a target and walked. The UPDRS motor subscale ratings were similar to those reported in the literature: pallidotomy improved the overall motor score and the contralateral bradykinesia + rigidity score, but not the gait + posture score. In contrast, kinematic measures demonstrated that levodopa and pallidotomy had different effects on walking and reaching speed. Both treatments improved walking speed, and the effect was additive. Levodopa improved reaching speed before pallidotomy but did not improve it as much after pallidotomy. Additionally, pallidotomy had inconsistent effects on reaching; some subjects were faster and others were slower. The subjects who initially reached more slowly improved after pallidotomy; the subjects who initially reached more normally (faster) worsened after pallidotomy. On the basis of our results, we speculate that basal ganglia output pathways that control walking and reaching may be distinct, such that bilateral projections to the pedunculopontine area influence walking, whereas ipsilateral thalamocortical projections influence reaching.     

Effects of bilateral stimulation of the subthalamic nucleus in patients with severe Parkinson's disease and motor fluctuations.

We present the efficacy and side effects of bilateral deep brain stimulation (DBS) of the subthalamic nuclei (STN) performed with a more simplified surgical procedure than described by the Grenoble group. A consecutive series of 26 patients with advanced and levodopa-responsive Parkinson's disease and motor complications was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) part I-VI, timed tests, and a patient diary for 2 days concerning on-off phenomenon and dyskinesias. At 3 months, evaluation of stimulation by the UPDRS motor score was performed in a double-blind manner and a significant improvement of 57% was found. The results 12 months after surgery off medication showed significant improvement in both UPDRS motor score and activities of daily living of 64% and, on medication, a significant reduction of 86% in duration of dyskinesias and 83% in duration of off-periods. Reduction in medication was less than for other groups, probably because we used smaller doses of levodopa before the operation. No serious side effects were encountered. When the patients are carefully selected and followed up, bilateral DBS of STN is a significant progress in treatment of advanced idiopathic Parkinson's disease with levodopa-induced motor complications.     

Chronic inhibition of the subthalamic nucleus in Parkinson's disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a popular treatment option for patients suffering from severe Parkinson's disease (PD). Yet the long-term outcome of subthalamic DBS is unknown. A total of 27 patients suffering from severe PD underwent bilateral stereotactic implantation of high-frequency stimulators in the STN. Before surgery and at least annually after surgery they were examined with the Unified Parkinson's Disease Rating Scale (UPDRS). This study presents the results of a mean 30 months (range 23 to 55) follow-up of these patients. We found stable and significant off medication improvement of motor function by DBS (between 40% and 44% in the UPDRS part III). While on medication there was no significant change in the motor function by DBS. UPDRS part III worsened gradually during the follow-up period, suggesting disease progression. Thirty months postsurgery the UPDRS part II (ADL) was still improved by 17%. There was a lasting decrease in fluctuations by more than 50%, and dyskinesias were reduced by about 70%. Freezing was reduced significantly from 2.2 in the UPDRS part II to 1.2 at the endpoint. The daily levodopa-equivalent dose was reduced by 39% at 12 months and by 30% at 30 months after STN stimulator implantation. Subthalamic DBS improves sustainable motor function in patients with severe Parkinson's disease and leads to a lasting reduction of medication. Limitations of this procedure were found for disturbances of speech and swallowing.     

Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect or selection bias?

BACKGROUND: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. OBJECTIVE: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. METHODS: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). RESULTS: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. CONCLUSION: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.     

Effects of subthalamic nucleus stimulation on motor cortex excitability in Parkinson's disease

BACKGROUND: Transcranial magnetic stimulation (TMS) studies have found abnormalities in several excitatory and inhibitory circuits in the motor cortex in PD. These include motor evoked potential (MEP) recruitment curve, silent period duration (SP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI). METHODS: The authors studied the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on these circuits in 12 patients with PD treated with STN DBS. Data from nine patients who completed the study were analyzed. Patients remained on their usual medications. The stimulators were set at the optimal parameters (ON), half the optimal amplitude (HALF), and switched off (OFF) in random order. RESULTS: The Unified PD Rating Scale motor scores were significantly lower in the ON compared to the HALF and OFF conditions. Resting SICI, studied with paired-pulse TMS at interstimulus interval of 2 ms, was reduced in the OFF and HALF conditions compared to normal subjects. STN stimulation restored SICI to normal levels. STN stimulation had no effect on motor threshold, MEP recruitment curve, SP, active SICI, ICF, and LICI. CONCLUSIONS: Although restoration of short-interval intracortical inhibition by STN stimulation is similar to the effects of dopaminergic drugs, it has no effect on silent period duration and long-interval intracortical inhibition, which are also influenced by dopaminergic drugs. A previous study found that internal globus pallidus (GPi) stimulation reduced SP but did not change SICI. Thus, GPi and STN stimulation may affect different circuits in the motor cortex.     

Extradural motor cortex stimulation in Parkinson's disease.

Extradural motor cortex stimulation (EMCS) is a surgical procedure proposed for patients with advanced Parkinson's disease (PD) who cannot undergo deep brain stimulation (DBS). Five PD patients with motor fluctuations and dyskinesia underwent EMCS of the left hemisphere. All fulfilled CAPSIT criteria for DBS, with the exception of age > 70 years. Patients were assessed preoperatively and 6 months after surgery on and off medications, with stimulator on, and 2 weeks later with stimulator off. Outcome measures included changes in mean medication dosage (levodopa and dopamine agonists), Unified Parkinson's Disease Rating Scale (UPDRS Parts II-III and Item 39), and dyskinesias (Abnormal Involuntary Movements Scale [AIMS]). We found no significant mean changes following EMCS. However, there was a trend for a reduction of mean daily medication intake (-30%) and AIMS (-19%). There were 3 patients who reported reduced OFF time (UPDRS Item 39) and 4 of 5 who felt a subjective benefit in stability and gait. In our PD cohort, EMCS induced no objective benefit, although some subjective improvement was reported mostly on axial symptoms.