Yu-Yan Poon

A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease

Subthalamic nucleus deep brain stimulation improves motor symptoms and quality of life in advanced Parkinsons disease. As after other life-altering surgeries, suicides have been reported following deep brain stimulation for movement disorders. We sought to determine the suicide rate following subthalamic nucleus deep brain stimulation for Parkinsons disease by conducting an international multicentre retrospective survey of movement disorder and surgical centres. We further sought to determine factors associated with suicide attempts through a nested case-control study. In the survey of suicide rate, 55/75 centres participated. The completed suicide percentage was 0.45% (24/5311) and attempted suicide percentage was 0.90% (48/5311). Observed suicide rates in the first postoperative year (263/100,000/year) (0.26%) were higher than the lowest and the highest expected age-, gender- and country-adjusted World Health Organization suicide rates (Standardized Mortality Ratio for suicide: SMR 12.63-15.64; P < 0.001) and remained elevated at the fourth postoperative year (38/100,000/year) (0.04%) (SMR 1.81-2.31; P < 0.05). The excess number of deaths was 13 for the first postoperative year and one for the fourth postoperative year. In the case-control study of associated factors, 10 centres participated. Twenty-seven attempted suicides and nine completed suicides were compared with 70 controls. Postoperative depression (P < 0.001), being single (P = 0.007) and a previous history of impulse control disorders or compulsive medication use (P = 0.005) were independent associated factors accounting for 51% of the variance for attempted suicide risk. Attempted suicides were also associated (P < 0.05) with being younger, younger Parkinsons disease onset and a previous suicide attempt. Completed suicides were associated with postoperative depression (P < 0.001). Postoperative depression remained a significant factor associated with attempted and completed suicides after correction for multiple comparisons using the stringent Bonferroni correction. Mortality in the first year following subthalamic nucleus deep brain stimulation has been reported at 0.4%. Suicide is thus one of the most important potentially preventable risks for mortality following subthalamic nucleus deep brain stimulation for Parkinsons disease. Postoperative depression should be carefully assessed and treated. A multidisciplinary assessment and follow-up is recommended.

Unilateral pedunculopontine stimulation improves falls in Parkinson's disease

Postural instability and falls are a major source of disability in patients with advanced Parkinsons disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinsons disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinsons Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinsons Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinsons Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinsons disease but that further evaluation of this procedure is required.

Ten-Year Outcome of Subthalamic Stimulation in Parkinson Disease: A Blinded Evaluation

OBJECTIVE To assess the 10-year motor outcome of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson disease (PD). DESIGN Patients with PD with bilateral STN-DBS were assessed according to the Core Assessment Program for Surgical Interventional Therapies in Parkinsons Disease protocol and videotaped at baseline and 1, 5, and 10 years after surgery. An independent rater blinded to stimulation and medication condition scored the 10-year video assessments. SETTING Movement Disorders Centre, Toronto Western Hospital, University Health Network, University of Toronto. PATIENTS Eighteen patients with advanced PD and 10-year follow-up of STN-DBS. INTERVENTION Bilateral STN-DBS surgery. MAIN OUTCOME MEASURES The primary outcome was the change in blinded Unified Parkinsons Disease Rating Scale (UPDRS) motor scores/subscores between the no medication/stimulation condition vs the no medication/no stimulation condition at 10 years. Secondary outcomes were the changes in blinded UPDRS motor scores between the medication/no stimulation and medication/stimulation conditions, UPDRS II scores, UPDRS IV dyskinesia and motor fluctuations scores, and anti-PD medication dose (levodopa equivalent daily dose) at different points. RESULTS In the 18 patients available for follow-up at 10 years, STN-DBS still significantly improved the UPDRS total motor score (P = .007) and resting and action tremor (P < .01 and P = .02, respectively) and bradykinesia (P = .01) subscores. The UPDRS II scores in the medication and no medication conditions, UPDRS IV dyskinesia and motor fluctuations scores, and the levodopa equivalent daily dose were also significantly reduced compared with baseline. Axial signs showed the most progressive decline in stimulation and levodopa response over the years. CONCLUSION This class III study provides evidence that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time.

Pallidal deep brain stimulation in cervical dystonia: Clinical outcome in four cases

OBJECTIVE Report on the clinical results following bilateral globus pallidus interna deep brain stimulation in four patients (one female and three males) with severe cervical dystonia, mean age 48 years (range 37-67). METHODS All four patients had failed extensive medical and botulinum toxin treatment. The mean duration of the disease was nine years (range 4-15 years). Patients were assessed pre and postoperatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Pre-operatively, the mean TWSTRS total score was 43.2 (range 28-60.5). Posteroventral pallidal deep brain stimulators were inserted using MRI and microelectrode recording guidance. Last follow-up was 15 months for the four patients. RESULTS Mean reduction in the TWSTRS total scores at last follow- up was 73% (range 61- 85%). Improvement in pain occurred soon after deep brain stimulation surgery. Motor improvement was delayed and prolonged over several months. Frequent adjustment in the stimulation parameters was necessary in the first three months. CONCLUSION Bilateral pallidal stimulation is effective in management of selected cases of intractable cervical dystonia.

Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years

The local injection of botulinum toxin is accepted as the first-line treatment of primary cervical dystonia. This approach provides adequate symptomatic relief for most patients, but up to one-third will have an unsatisfactory response. Deep brain stimulation of the globus pallidus internus has been increasingly used in dystonic syndromes that are refractory to best pharmacological approaches. Although cervical dystonia is the most common idiopathic focal dystonia, evidence for long-term responsiveness to pallidal stimulation is limited. The primary objective of this study was to prospectively collect outcome data from baseline to last clinical follow-up on patients with idiopathic cervical dystonia treated with bilateral pallidal stimulation. Blinded video assessment of examinations performed preoperatively and at last video assessment were performed. Ten patients had complete prospective clinical follow-up. Baseline total Toronto Western Spasmodic Torticollis Rating Scale score (±standard deviation) was 54.5 ± 12.4 (range, 35.0-70.3). Comparison of the blinded severity sub-score on baseline video and at last video assessment at a mean of 7.7 years postoperatively demonstrated a mean improvement of 47.6% (P = 0.002) and strong inter-observer correlation between blinded raters (Spearman r = 0.78, 95% confidence interval 0.49-0.92, P = 0.0001). All 10 patients had 5 years of open prospective follow-up, documenting a 47.4 ± 26.4% (P < 0.01) mean improvement with respect to baseline. This was maintained at a mean of 7.8 years at last follow-up after surgery (range, 4.9-10.7 years) with a 54.4 ± 27.4% mean improvement (P < 0.01). Deep brain stimulation of the globus pallidus is an effective and long-lasting second-line treatment of cervical dystonia, with benefit in some of our patients extending to >10 years. More data are needed to explain variations in individual responses and to guide individual programming parameters.

rCBF Changes Associated with PPN Stimulation in a Patient with Parkinson's disease : A PET Study

Gait disturbances and akinesia are disabling symptoms in advanced Parkinsons disease (PD). The pedunculopontine nucleus (PPN) is involved in locomotion, control of posture, and behavioral states [i.e. wakefulness, rapid eye movement (REM) sleep]. Some reports have suggested that modulation of the activity of the PPN with deep brain stimulation (DBS) may be beneficial in the treatment of gait dysfunction and akinesia. To gain some insights on effects of PPN‐DBS in the human brain, we used [15O] H2O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) at rest during Off and On stimulation in an advanced PD patient with unilateral PPN‐DBS. PPN‐DBS increased rCBF in different subcortical areas most notably the thalamus, bilaterally. Double‐blinded clinical evaluation revealed an improvement in motor function by ∼20%. The PET changes provide for the first time evidence in the human brain that PPN‐DBS may be able to influence and modify rCBF of closely connected subcortical structures. Given the importance of the PPN in locomotion, control of posture, and behavioral states, DBS may have significant implication for more complicated forms of movement disorders where deterioration of gait, postural instability, and REM sleep behavior disorders are very disabling.

Involvement of the human pedunculopontine nucleus region in voluntary movements

Objective: The pedunculopontine nucleus region (PPNR) is being investigated as a target for deep brain stimulation (DBS) in Parkinson disease (PD), particularly for gait and postural impairment. A greater understanding of how PPNR activities and oscillations are modulated with voluntary movements is crucial to the development of neuromodulation strategies. Methods: We studied 7 patients with PD who underwent DBS electrode implantations in the PPNR. PPNR local field potential and EEG were recorded while patients performed self-paced wrist and ankle movements. Results: Back-averaging of the PPNR recording showed movement-related potentials before electromyography onset. Frequency analysis showed 2 discrete movement-related frequency bands in the theta (6- to 10-Hz) and beta (14- to 30-Hz) ranges. The PPNR theta band showed greater event-related desynchronization with movements in the ON than in the OFF medication state and was coupled with the sensorimotor cortices in the ON state only. Beta event-related desynchronization was observed in the PPNR during the premovement and movement execution phases in the OFF state. In contrast, premovement PPNR beta event-related synchronization occurred in the ON state. Moreover, beta band coherence between the PPNR and the midline prefrontal region was observed during movement preparation in the ON but not the OFF state. Conclusions: Activities of PPNR change during movement preparation and execution in patients with PD. Dopaminergic medications modulate PPNR activities and promote the interactions between the cortex and PPNR. Beta oscillations may have different functions in the basal ganglia and PPNR, and may be prokinetic rather than antikinetic in the PPNR.

Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia

Objectives: Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in treatment-refractory dystonia, and the identification of factors predicting surgical outcome is needed to optimize patient selection. Methods: In this retrospective multicenter study, GPi-DBS outcome of 8 patients with DYT6, 9 with DYT1, and 38 with isolated dystonia without known monogenic cause (non-DYT) was assessed at early (1–16 months) and late (22–92 months) follow-up using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. Results: At early follow-up, mean reduction of dystonia severity was greater in patients with DYT1 (BFMDRS score: −60%) and non-DYT dystonia (−52%) than in patients with DYT6 dystonia (−32%; p = 0.046). Accordingly, the rate of responders was considerably lower in the latter group (57% vs >90%; p = 0.017). At late follow-up, however, GPi-DBS resulted in comparable improvement in all 3 groups (DYT6, −42%; DYT1, −44; non-DYT, −61%). Additional DBS of the same or another brain target was performed in 3 of 8 patients with DYT6 dystonia with varying results. Regardless of the genotype, patients with a shorter duration from onset of dystonia to surgery had better control of dystonia postoperatively. Conclusions: Long-term GPi-DBS is effective in patients with DYT6, DYT1, and non-DYT dystonia. However, the effect of DBS appears to be less predictable in patients with DYT6, suggesting that pre-DBS genetic testing and counseling for known dystonia gene mutations may be indicated. GPi-DBS should probably be considered earlier in the disease course. Classification of evidence: This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

LOCATION OF ACTIVE CONTACTS IN PATIENTS WITH PRIMARY DYSTONIA TREATED WITH GLOBUS PALLIDUS DEEP BRAIN STIMULATION

OBJECTIVE Deep brain stimulation of the globus pallidus internus has been used for the treatment of various forms of dystonia, but the factors influencing postoperative outcomes remain unknown. We compared the location of the contacts being used for stimulation (active contacts) in patients with cervical dystonia, generalized dystonia, and Parkinsons disease and correlated the results with clinical outcome. METHODS Postoperative magnetic resonance scans of 13 patients with cervical dystonia, six patients with generalized dystonia, and five patients with Parkinsons disease who underwent globus pallidus internus deep brain stimulation were analyzed. We assessed the location of the active contacts relative to the midcommisural point and in relation to the anteroposterior and mediolateral boundaries of the pallidum. Postoperative outcome was measured with the Toronto Western Spasmodic Torticollis Rating Scale (for cervical dystonia) and the Burke-Fahn-Marsden Dystonia Rating Scale (for generalized dystonia) during the last follow-up. RESULTS We found that the location of the active contacts relative to the midcommisural point and the internal boundaries of the pallidum was similar across the groups. In our series, the contacts used for stimulation were clustered in the posterolateral region of the pallidum. Within that region, we found no correlation between the location of the contacts and postoperative outcome. CONCLUSION The location of the active contacts used for globus pallidus internus deep brain stimulation was similar in patients with cervical dystonia, generalized dystonia, and Parkinsons disease.

Measuring quality of life in PSP: the PSP-QoL.

Objective: To develop a new patient-reported outcome measure for progressive supranuclear palsy (PSP) and to test its psychometric properties. Methods: First, the authors generated a pool of potential scale items from in-depth patient interviews. Second, the authors administered these items, in the form of a questionnaire, to a sample of people with PSP and traditional psychometric methods were used to develop a rating scale satisfying standard criteria for reliability and validity. Third, the authors examined the psychometric properties of the rating scale in a second sample. Results: In stage 1, a pool of 87 items was generated from 27 patient interviews. In stage 2, a scale with two subscales (physical, 22 items; mental, 23 items), satisfying standard criteria for reliability and validity, was developed from the response data of 225 patients with PSP. In stage 3, the scale was examined in 188 people with PSP. Missing data were low, scores in both subscales were evenly distributed, floor and ceiling effects were small. Reliability was high (Cronbach’s alpha 0.93, 0.95; test-retest 0.95, 0.92). Validity was supported by the interscale intercorrelation (0.60), factor analysis, and the magnitude and pattern of correlations with four other rating scales, disease severity, and disease duration. The psychometric properties of the new scale were similar in the United Kingdom and North America, and in clinic- and community-based samples studied. Conclusions: The Progressive Supranuclear Palsy Quality of Life scale (PSP-QoL) may be a helpful patient-reported scale for clinical trials and studies in PSP.