Deep Brain Stimulation Impact on Voice and Speech Quality in Parkinson's Disease: A Systematic Review.

OBJECTIVE: Deep brain stimulation (DBS) has considerable efficacy for the motor dysfunction of idiopathic Parkinson's disease (PD) on patient quality of life. However, the benefit of DBS on voice and speech quality remains controversial. We carried out a systematic review to understand the influence of DBS on parkinsonian dysphonia and dysarthria. DATA SOURCES: A PubMed/MEDLINE and Cochrane systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Population, Intervention, Comparison, Outcome, Timing, and Setting (PICOTS) statements. REVIEW METHODS: Three investigators screened studies published in the literature from inception to May 2022. The following data were retrieved: age, demographic, sex, disease duration, DBS duration, DBS location, speech, and voice quality measurements. RESULTS: From the 180 studies identified, 44 publications met the inclusion criteria, accounting for 866 patients. Twenty-nine studies focused on voice/speech quality in subthalamic DBS patients, and 6 included patients with stimulation of pallidal, thalamic, and zona incerta regions. Most studies (4/6) reported a deterioration of the vocal parameters on subjective voice quality evaluation. For speech, the findings were more contrasted. There was an important heterogeneity between studies regarding the voice and speech quality outcomes used to evaluate the impact of DBS on voice/speech quality. CONCLUSION: The impact of DBS on voice and speech quality significantly varies between studies. The stimulated anatomical region may have a significant role since the stimulation of the pallidal area was mainly associated with voice quality improvement, in contrast with other regions. Future controlled studies comparing all region stimulation are needed to get reliable findings. LEVEL OF EVIDENCE: Level III: evidence from evidence summaries developed from systematic reviews.

Impact of HIV impact on outcomes of deep-brain stimulation of the subthalamic nucleus for Parkinson's disease.

BACKGROUND AND PURPOSE: Middle-aged persons living with HIV (PLHIV) have a heightened risk of more concomitant age-related comorbidities that are acknowledged as signs of poorer prognosis after deep-brain stimulation of the subthalamic nucleus (STN-DBS) at younger-than-expected ages. To assess the beneficial and adverse effects of STN-DBS in PLHIV with Parkinson's disease (PD). METHODS: We retrospectively included nine PLHIV with PD who had sustained virological control. Patients were followed up for 7 ± 4 years. RESULTS: Patients' mean ages at PD onset and STN-DBS were 45 ± 15 and 53 ± 16 years, respectively. At STN-DBS, mean HIV infection and PD durations were 15 ± 12 and 8 ± 4 years, respectively. STN-DBS significantly improved 1-year Unified Parkinson's Disease Rating Scale (UPDRS)-III scores (71%), daily off-time (63%), motor fluctuations (75%) and daily levodopa-equivalent dose (68%); mean 5-year UPDRS-III score and motor fluctuation improvements remained ~45%. Impulse control disorders (affecting 6/9 patients) fully resolved after STN-DBS. Postoperative course was uneventful. No serious adverse events occurred during follow-up. CONCLUSION: Our findings indicate that STN-DBS is a safe and effective treatment for PLHIV with PD.

Long-Term Follow-Up of a Phase I/II Study of ProSavin, a Lentiviral Vector Gene Therapy for Parkinson's Disease.

Parkinson's disease is typically treated with oral dopamine replacement therapies. However, long-term use is complicated by motor fluctuations from intermittent stimulation of dopamine receptors and off-target effects. ProSavin, a lentiviral vector based gene therapy that delivers local and continuous dopamine, was previously shown to be well tolerated in a Phase I/II first-in-human study, with significant improvements in motor behavior from baseline at 1 year. Here, patients with Parkinson's disease from the open-label trial were followed up in the long term to assess the safety and efficacy of ProSavin after bilateral injection into the putamen. Fifteen patients who were previously treated with ProSavin have been followed for up to 5 years, with some having been seen for 8 years. Eight patients received deep brain stimulation at different time points, and their subsequent assessments continued to assess safety. Ninety-six drug-related adverse events were reported (87 mild, 6 moderate, 3 severe) of which more than half occurred in the first year. The most common drug-related events were dyskinesias (33 events, 11 patients) and on-off phenomena (22 events, 11 patients). A significant improvement in the defined "off" Unified Parkinson's Disease Rating Scale part III motor scores, compared to baseline, was seen at 2 years (mean score 29 · 2 vs. 38 · 4, n = 14, p < 0.05) and at 4 years in 8/15 patients. ProSavin continued to be safe and well tolerated in patients with Parkinson's disease. Moderate improvements in motor behavior over baseline continued to be reported in the majority of patients who could still be evaluated up to 5 years of follow-up.

Three-dimensional SPACE fluid-attenuated inversion recovery at 3 T to improve subthalamic nucleus lead placement for deep brain stimulation in Parkinson's disease: from preclinical to clinical studies.

OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for motor symptoms in patients with pharmacoresistant Parkinson's disease (PD). However, the procedure, which requires multimodal perioperative exploration such as imaging, electrophysiology, or clinical examination during macrostimulation to secure lead positioning, remains challenging because the STN cannot be reliably visualized using the gold standard, T2-weighted imaging (T2WI) at 1.5 T. Thus, there is a need to improve imaging tools to better visualize the STN, optimize DBS lead implantation, and enlarge DBS diffusion. METHODS Gradient-echo sequences such as those used in T2WI suffer from higher distortions at higher magnetic fields than spin-echo sequences. First, a spin-echo 3D SPACE (sampling perfection with application-optimized contrasts using different flip angle evolutions) FLAIR sequence at 3 T was designed, validated histologically in 2 nonhuman primates, and applied to 10 patients with PD; their data were clinically compared in a double-blind manner with those of a control group of 10 other patients with PD in whom STN targeting was performed using T2WI. RESULTS Overlap between the nonhuman primate STNs segmented on 3D-histological and on 3D-SPACE-FLAIR volumes was high for the 3 most anterior quarters (mean [± SD] Dice scores 0.73 ± 0.11, 0.74 ± 0.06, and 0.60 ± 0.09). STN limits determined by the 3D-SPACE-FLAIR sequence were more consistent with electrophysiological edges than those determined by T2WI (0.9 vs 1.4 mm, respectively). The imaging contrast of the STN on the 3D-SPACE-FLAIR sequence was 4 times higher (p < 0.05). Improvement in the Unified Parkinson's Disease Rating Scale Part III score (off medication, on stimulation) 12 months after the operation was higher for patients who underwent 3D-SPACE-FLAIR-guided implantation than for those in whom T2WI was used (62.2% vs 43.6%, respectively; p < 0.05). The total electrical energy delivered decreased by 36.3% with the 3D-SPACE-FLAIR sequence (p < 0.05). CONCLUSIONS 3D-SPACE-FLAIR sequences at 3 T improved STN lead placement under stereotactic conditions, improved the clinical outcome of patients with PD, and increased the benefit/risk ratio of STN-DBS surgery.

Spinal stimulation for movement disorders.

Epidural spinal cord stimulation (SCS) is currently proposed to treat intractable neuropathic pain. Since the 1970s, isolated cases and small cohorts of patients suffering from dystonia, tremor, painful leg and moving toes (PLMT), or Parkinson's disease were also treated with SCS in the context of exploratory clinical studies. Despite the safety profile of SCS observed in these various types of movement disorders, the degree of improvement of abnormal movements following SCS has been heterogeneous among patients and across centers in open-label trials, stressing the need for larger, randomized, double-blind studies. This article provides a comprehensive review of both experimental and clinical studies of SCS application in movement disorders.

Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial.

BACKGROUND: Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease. METHODS: We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×10(7) transducing units [TU]); mid dose (4·0×10(7) TU); and high dose (1×10(8) TU). Inclusion criteria were age 48-65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439. FINDINGS: 15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on-off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline. INTERPRETATION: ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients. FUNDING: Oxford BioMedica.

Depression and coping as predictors of change after deep brain stimulation in Parkinson's disease.

BACKGROUND: This study examined changes in motor function and quality of life (QoL) after subthalamic nuclei deep brain stimulation (STN-DBS) in patients with Parkinson disease (PD) and the role of psychosocial predictors on individual changes. METHODS: Forty-one patients with advanced PD (29 men and 12 women; mean age: 62.0 ± 8.0; disease duration: 14.5 ± 5.7) completed self-report questionnaires before surgery and at 6 and 12 months after surgery. Psychosocial measures assessed coping strategies (Ways of Coping Checklist-Revised), symptoms of depression (Beck Depression Inventory version II), anxiety (State-Trait Anxiety Inventory), and QoL (Parkinson Disease Questionnaire 39 Items, Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: After surgery, motor function (Unified Parkinson Disease Rating Scale III and IV), global QoL (Parkinson Disease Questionnaire 39 Items) and Physical Component Summary of the Medical Outcome Study Short Form 36-items Health Survey improved, whereas the Mental Component Summary tended to deteriorate. Depression and anxiety were stable. Improvements in motor function and QoL were associated with younger age, shorter duration of illness, higher baseline distress (depression and anxiety), and changes in problem-focused coping. Improvements in mental QoL were associated with a less frequent use of coping focused on seeking social support. CONCLUSIONS: STN-DBS is associated with major positive changes in PD affecting motor function and QoL. These changes are related to psychological variables, including emotional distress and coping. A better focus on these individual characteristics is necessary to improve care of patients with PD who undertake STN-DBS.

Assessing accuracy of the magnetic resonance imaging-computed tomography fusion images to evaluate the electrode positions in subthalamic nucleus after deep-brain stimulation.

BACKGROUND: Accurate evaluation of the electrode position in subthalamic nucleus (STN) after deep-brain stimulation (DBS) has rarely been verified before. OBJECTIVE: We superimposed the postoperative thin-sliced computed tomography (CT) on the preoperative magnetic resonance imaging (MRI), and the positional information of the implanted electrodes with electrophysiological data was reflected on MRI. The accuracy of this method was assessed by comparing STN demarcated on this method (M-STN) with the electrophysiologically defined STN (E-STN) and with STN on the Schaltenbrand-Wahlen atlas (SW-STN). METHODS: In 16 patients, T2-weighted MRI was obtained before surgery and STN boundary was demarcated. Seven days after surgery, the position of the implanted electrodes was localized on thin-sliced CT and superimposed on the preoperative MRI. Their accordance with E-STN and compatibility of M-STN or SW-STN with E-STN were statistically assessed. RESULTS: In all patients, postoperative CT corresponded well with the preoperative MRI. Between inside and outside the boundaries of M-STN, the mean amplitude levels of multiunit neuronal activities were significantly different on both the rostral and caudal sides (P < .0001), and the marginal errors between M- and E-STN were 0.388 +/- 0.755 mm (mean +/- standard deviation) at the rostral margin and 0.271 +/- 0.738 mm at the caudal margin. Statistical comparison disclosed that M-STN was more similar to E-STN than SW-STN on the axial and coronal images. CONCLUSION: M-STN corresponded well with the high-amplitude area on the electrophysiological data, and the MRI-CT fusion method allowed sufficiently accurate assessment of the electrode position after DBS surgery.

Outcome of bilateral subthalamic nucleus stimulation in the treatment of Parkinson's disease: correlation with intra-operative multi-unit recordings but not with the type of anaesthesia.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) gained general acceptance in the treatment of Parkinson's disease (PD). OBJECTIVE: To study the clinical outcome and the predicting factors of efficacy of chronic STN stimulation, while DBS electrodes were implanted under local or general anaesthesia with intra-operative electrophysiological guidance based on multi-unit recordings. METHODS: We included a large single-centre cohort of 54 patients with advanced PD (mean age: 59 years; disease duration: 14 years). Clinical evaluation was performed by the Unified Parkinson's Disease Rating Scale (UPDRS) before and 1 year after surgical placement of DBS electrodes. RESULTS: In the on-stimulation and off-medication condition, the UPDRS part III score was reduced by 56% compared to the off-stimulation condition or pre-operative off-drug score. In the on-stimulation and on-medication condition, this score was reduced by 73%. The severity of motor fluctuations and dyskinesia (UPDRS part IV) and the activities of daily living (UPDRS part II) were reduced by 65 and 80%, respectively, in the on-stimulation/on-medication condition compared to the pre-operative baseline. The daily dose of antiparkinsonian treatment was diminished by 72%. Among the various pre- and intra-operative data, the most important predictive factor for clinical efficacy of STN stimulation was the length of hyperactivity along the best track observed in intra-operative multi-unit recordings. Other predictive factors included age, disease duration and pre-operative levodopa responsiveness or baseline off-drug values of the Hoehn and Yahr and UPDRS part III scores. In contrast, the type of anaesthesia (local vs. general) did not significantly influence the clinical outcome. CONCLUSION: The present results are in the average of previously published results, but they have been obtained from a large single-centre cohort of patients with important reductions in the daily dose of antiparkinsonian drugs. This study confirmed the efficacy of the STN-DBS technique and emphasized the value of an original intra-operative electrophysiological approach based on multi-unit and not single-unit quantified recordings. This method allows DBS electrode implantation to be safely performed under general anaesthesia without lessening the rate of efficacy of the procedure.

Transplantation in Parkinson's disease: PET changes correlate with the amount of grafted tissue.

We compared the striatal uptake of [(18)F]fluorodopa with [(76)Br]-FE-CBT, a positron emission tomography (PET) ligand of the dopamine transporter (DAT), which estimates the density of dopamine nerve terminals, in 6 patients with Parkinson's disease grafted with fetal mesencephalic cells. There was no change in DAT ligand binding in the grafted putamen, despite a significant increase of [(18)F]fluorodopa uptake. This finding suggests that the clinical benefit induced by the graft is more related to increased dopaminergic activity than improved dopaminergic innervation in the host striatum and, therefore, that [(18)F]fluorodopa remains the optimal tracer to evaluate grafted PD patients. Further analysis showed that the clinical and [(18)F]fluorodopa uptake changes after the grafts were correlated with the number of ventral mesencephalae used for implantation.