A defined method for differentiating human iPSCs into midbrain dopaminergic progenitors that safely restore motor deficits in Parkinson's disease.

Background: Parkinson's disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting human-induced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction. Methods: Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro. Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks. Results: Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions. Conclusion: This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD.

Deep brain stimulation in posterior subthalamic area for Holmes tremor: Case reports with review of the literature.

Background: Holmes tremor (HT) is a refractory tremor associated with cortico-basal ganglia loops and cerebellothalamic tract abnormalities. Various drug treatments have been attempted; however, no treatment method has yet been established. Historically, thalamic deep brain stimulation (DBS) has been performed in medically refractory cases. Recently, the posterior subthalamic area (PSA) has been used for HT. Here, we report cases of HT and review the effectiveness and safety of PSA-DBS for HT. Cases: We conducted a retrospective chart review of two patients with HT who underwent PSA-DBS. Improvement in tremors was observed 1 year after surgery without apparent complications. Literature review: We identified 12 patients who underwent PSA-DBS for HT, including our cases. In six patients, PSA was targeted alone; for the rest, the ventralis intermediate nucleus (Vim) of the thalamus and PSA were simultaneously targeted. The Fahn-Tolosa-Marin Tremor Rating Scale improvement rates were 56.8% (range, 33.9-82.1%; n = 6) and 77.8% (range, 42.6-100%; n = 5) for the PSA-DBS and PSA+Vim-DBS, respectively. Conclusion: Reasonable improvements in HT were observed after PSA-DBS. PSA might be an appropriate target for improving the symptoms of HT. Long-term observations, accumulation of cases, and randomized studies are required in future.

Short-Term Motor Outcomes in Parkinson's Disease after Subthalamic Nucleus Deep Brain Stimulation Combined with Post-Operative Rehabilitation: A Pre-Post Comparison Study.

Background: The effects of subthalamic nuclear deep brain stimulation therapy (STN-DBS) and combined postoperative rehabilitation for patients with Parkinson's disease with postural instability have yet to be well reported. This study investigated the effects of short-term postoperative rehabilitation with STN-DBS on physical function in patients with Parkinson's disease. Methods: Patients diagnosed with Parkinson's disease who were admitted to our hospital for STN-DBS surgery were included in this study. Data were prospectively collected and retrospectively analyzed. Postoperative rehabilitation consisted of muscle-strengthening exercises, stretching, and balance exercises for 40-60 minutes per day for approximately 14 days. The Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go test (TUG) seconds and steps, Trunk Impairment Scale (TIS), seconds for 10 times toe-tapping, lower limb extension torque using StrengthErgo240, and center of pressure sway in the quiet standing posture were evaluated preoperatively, postoperatively, and at discharge. Mini-BESTest changes were also evaluated in the two groups classified by the presence or absence of postural instability. One-way and two-way repeated measures analyses of variance were performed for each of the three periods of change, and paired t-tests with the Bonferroni method were performed as multiple comparison tests. A stepwise multiple regression model was used to identify factors associated with balance improvement. Results: A total of 60 patients with Parkinson's disease were included, and there were significant increases in Mini-BESTest, TIS, StrengthErgo240, and postural sway during closed-eye standing compared to pre- and postoperative conditions at discharge (p < 0.05), and they decreased significantly compared to the postoperative period (p < 0.05). On stepwise multiple regression analysis, decreased steps of TUG and improvement of TIS scores were related to improvement of the Mini-BESTest (p < 0.05). In addition, Mini-BESTest scores in both groups with and without postural instability were significantly increased at discharge compared to preoperative and postoperative conditions (p < 0.01). Conclusion: Postoperative rehabilitation combined with STN-DBS may provide short-term improvements in physical function compared with the preoperative medicated status. The improvements in gait step length and trunk function may be important factors for obtaining improvement of postoperative postural stability.

Subthalamic deep brain stimulation in Parkinson's disease with SNCA mutations: Based on the follow-up to 10 years.

BACKGROUNDS: Although the short-term efficacy of bilateral subthalamic deep brain stimulation (DBS) has been reported in a limited number of Parkinson's disease (PD) patients with SNCA mutations, there are no data for long-term outcome. METHODS: This multicenter retrospective study investigated previously reported PD patients with SNCA mutations, implanted with bilateral subthalamic DBS. We compared demographic and clinical data at baseline and last follow-up. Clinical data of motor and nonmotor symptoms and motor fluctuation were collected up to 10 years from DBS surgery. RESULTS: Among four subjects, three had SNCA duplication and one had c.158C.A (p.A53E) mutation. The mean post-implantation follow-up duration was 5.4 ± 3.7 years. All patients with SNCA duplication showed favorable outcome, although one died from breast cancer 1.5 years after DBS. The patient with the missense mutation became wheelchair-bound due to progressed axial, cognitive and psychiatric symptoms after 3.5 years from DBS despite the benefit on motor fluctuation. CONCLUSION: Based on findings in our small cohort, subthalamic DBS could be beneficial for motor fluctuation in PD patients with SNCA mutations, especially those with SNCA duplication, and cognitive and psychiatric symptoms are important for the long-term outcome of subthalamic DBS.

New modalities and directions for dystonia care.

Dystonia is an abnormal involuntary movement or posture owing to sustained or intermittent muscle contraction. Standard treatment for dystonia includes medications, such as levodopa, anticholinergic and antiepileptic drugs, botulinum toxin, and baclofen pump, and surgeries, such as lesioning surgery and deep-brain stimulation. New treatment modalities aimed toward improving dystonia care in the future are under investigation. There are two main axes to improve dystonia care; one is non-invasive neuromodulation, such as transcranial magnetic stimulation, transcranial electrical stimulation, and transcutaneous electrical nerve stimulation. The other is a quantitative evaluation of dystonia using a wearable device and motion-capturing system, which can be empowered by artificial intelligence. In this article, the current status of these axes will be reviewed.

Technique and outcome of percutaneous endoscopic transgastric jejunostomy for continuous infusion of levodopa-carbidopa intestinal gel for treatment of Parkinson's disease.

Objective: A new method of drug delivery via the small bowel, continuous infusion of levodopa-carbidopa intestinal gel (LCIG), for patients with advanced Parkinson's disease (PD) has been developed and shown to improve patients' quality of life. Levodopa is infused directly and continuously into the proximal jejunum via a percutaneous endoscopic transgastric jejunostomy (PEG-J) tube that is connected to a portable infusion pump. The aim of this study was to evaluate the safety and outcomes of our PEG-J technique performed in advance of LCIG therapy in patients with advanced PD. Material and methods: We reviewed the cases of 37 patients who underwent PEG-J for LCIG therapy at our hospital between November 2016 and May 2018. Pull-through percutaneous endoscopic gastrostomy (PEG) and gastropexy were performed in all patients. The J-tube was inserted through the PEG tube and placed beyond the ligament of Treitz endoscopically under fluoroscopic guidance. After two weeks, the gastropexy sutures were removed. Results: PEG-J with placement of the tube beyond the ligament of Treitz was successful in all 37 patients. Median procedure time was 26.4 min. Median hospital stay after the procedure was 16 days. Median follow-up with the PEG-J tube in place was 11 months. There were five procedure-related complications (13.5%) and 13 device-related complications (35.1%). There was no death related to the procedure. Conclusions: Our PEG-J technique can be performed safely in patients with advanced PD, and favorable outcomes have been achieved to date.

Dopamine transporter imaging predicts motor responsiveness to levodopa challenge in patients with Parkinson's disease: A pilot study of DATSCAN for subthalamic deep brain stimulation.

Imaging studies are necessary prior to subthalamic deep brain stimulation (STN-DBS). Dopamine transporter (DAT) imaging is a powerful tool for visualizing dopamine terminals in the striatum, but its usefulness in STN-DBS is unclear. Here, we retrospectively investigated the relationship between motor symptoms and the specific binding ratio (SBR) on DAT imaging in patients with Parkinson's disease (PD). We included 23 consecutive patients (9 female; 14 male) who were evaluated for DBS eligibility between October 2013 and October 2014 and subsequently received bilateral STN-DBS. Correlation and simple regression analyses were performed on SBR values and clinical parameters before and after surgery. SBR value was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the "ON" state before surgery (rs=-0.637, p=0.001) and positively correlated with the reduction of the levodopa equivalent daily dose by surgery (r=0.422, p=0.045). A simple regression analysis revealed that SBR value was positively correlated with UPDRS motor score improvement after levodopa challenge before surgery (p=0.001, R2=0.423). DAT imaging may be useful in STN-DBS candidate selection and the identification of the therapeutic mechanism of STN-DBS in patients with advanced PD and motor symptom fluctuations.

Postoperative lead migration in deep brain stimulation surgery: Incidence, risk factors, and clinical impact.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for multiple movement disorders and shows substantial promise for the treatment of some neuropsychiatric and other disorders of brain neurocircuitry. Optimal neuroanatomical lead position is a critical determinant of clinical outcomes in DBS surgery. Lead migration, defined as an unintended post-operative displacement of the DBS lead, has been previously reported. Despite several reports, however, there have been no systematic investigations of this issue. This study aimed to: 1) quantify the incidence of lead migration in a large series of DBS patients, 2) identify potential risk factors contributing to DBS lead migration, and 3) investigate the practical importance of this complication by correlating its occurrence with clinical outcomes. METHODS: A database of all DBS procedures performed at UF was queried for patients who had undergone multiple post-operative DBS lead localization imaging studies separated by at least two months. Bilateral DBS implantation has commonly been performed as a staged procedure at UF, with an interval of six or more months between sides. To localize the position of each DBS lead, a head CT is acquired ~4 weeks after lead implantation and fused to the pre-operative targeting MRI. The fused targeting images (MR + stereotactic CT) acquired in preparation for the delayed second side lead implantation provide an opportunity to repeat the localization of the first implanted lead. This paradigm offers an ideal patient population for the study of delayed DBS lead migration because it provides a large cohort of patients with localization of the same implanted DBS lead at two time points. The position of the tip of each implanted DBS lead was measured on both the initial post-operative lead localization CT and the delayed CT. Lead tip displacement, intracranial lead length, and ventricular indices were collected and analyzed. Clinical outcomes were characterized with validated rating scales for all cases, and a comparison was made between outcomes of cases with lead migration versus those where migration of the lead did not occur. RESULTS: Data from 138 leads in 132 patients with initial and delayed lead localization CT scans were analyzed. The mean distance between initial and delayed DBS lead tip position was 2.2 mm and the mean change in intracranial lead length was 0.45 mm. Significant delayed migration (>3 mm) was observed in 17 leads in 16 patients (12.3% of leads, 12.1% of patients). Factors associated with lead migration were: technical error, repetitive dystonic head movement, and twiddler's syndrome. Outcomes were worse in dystonia patients with lead migration (p = 0.035). In the PD group, worse clinical outcomes trended in cases with lead migration. CONCLUSIONS: Over 10% of DBS leads in this large single center cohort were displaced by greater than 3 mm on delayed measurement, adversely affecting outcomes. Multiple risk factors emerged, including technical error during implantation of the DBS pulse generator and failure of lead fixation at the burr hole site. We hypothesize that a change in surgical technique and a more effective lead fixation device might mitigate this problem.

Deep brain stimulation for Parkinson's disease.

There is a long history of surgical treatment for Parkinson's disease (PD). After pioneering trials and errors, the current primary surgical treatment for PD is deep brain stimulation (DBS). DBS is a promising treatment option for patients with medically refractory PD. In this review, we summarize accumulated findings concerning patient selection, clinical outcomes, complications, target selection, long-term outcomes, manage- ment of axial symptoms, and timing of surgery in DBS for PD. We also describe new technologies of DBS device.

Current Topics in Deep Brain Stimulation for Parkinson Disease.

There is a long history of surgical treatment for Parkinson disease (PD). After pioneering trials and errors, the current primary surgical treatment for PD is deep brain stimulation (DBS). DBS is a promising treatment option for patients with medically refractory PD. However, there are still many problems and controversies associated with DBS. In this review, we discuss current issues in DBS for PD, including patient selection, clinical outcomes, complications, target selection, long-term outcomes, management of axial symptoms, timing of surgery, surgical procedures, cost-effectiveness, and new technology.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

Brittle Dyskinesia Following STN but not GPi Deep Brain Stimulation.

BACKGROUND: The aim was to describe the prevalence and characteristics of difficult to manage dyskinesia associated with subthalamic nucleus (STN) deep brain stimulation (DBS). A small subset of STN DBS patients experience troublesome dyskinesia despite optimal programming and medication adjustments. This group of patients has been referred to by some practitioners as brittle STN DBS-induced dyskinesia, drawing on comparisons with brittle diabetics experiencing severe blood sugar regulation issues and on a single description by McLellan in 1982. We sought to describe, and also to investigate how often the "brittle" phenomenon occurs in a relatively large DBS practice. METHODS: An Institutional Review Board-approved patient database was reviewed, and all STN and globus pallidus internus (GPi) DBS patients who had surgery at the University of Florida from July 2002 to July 2012 were extracted for analysis. RESULTS: There were 179 total STN DBS patients and, of those, four STN DBS (2.2%) cases were identified as having dyskinesia that could not be managed without the induction of an "off state," or by the precipitation of a severe dyskinesia despite vigorous stimulation and medication adjustments. Of 75 GPi DBS cases reviewed, none (0%) was identified as having brittle dyskinesia. One STN DBS patient was successfully rescued by bilateral GPi DBS. DISCUSSION: Understanding the potential risk factors for postoperative troublesome and brittle dyskinesia may have an impact on the initial surgical target selection (STN vs. GPI) in DBS therapy. Rescue GPi DBS therapy may be a viable treatment option, though more cases will be required to verify this observation.

Deep brain stimulation may improve quality of life in people with Parkinson's disease without affecting caregiver burden.

OBJECTIVE: This study aims to investigate the influence of deep brain stimulation (DBS) on caregiver burden and quality of life in Parkinson's disease. METHODS: A cross-sectional retrospective study utilizing the National Parkinson Foundation Quality Improvement Initiative clinical study was conducted. A group of 275 patients who had undergone DBS for Parkinson's disease were extracted from 2916 subjects who were included in this data base. The data were compared to an age, sex, and disease severity matched control group. A secondary analysis was then performed on two more control groups that were matched to account for presence or absence of motor fluctuations. The multidimensional caregiver strain index and Parkinson's disease quality-of-life questionnaire 39 summary index were compared. RESULTS: The multidimensional caregiver strain index did not differ between the DBS group (16.9 ± 11.8) and a matched non-DBS group (16.1 ± 17.6, p = 0.618). The quality-of-life index was, however, significantly better in the DBS group (28.9 ± 15.6) than in the non-DBS group (32.3 ± 17.6, p = 0.034). A secondary analysis revealed that the total caregiver strain score was lower in the no motor fluctuation control group than the other two groups (p < 0.05). Regression analysis revealed significant relationships between the quality-of-life index and caregiver strain index total scores (p < 0.001), between caregiver strain index total score and age at surgery (p = 0.027), and also between the interval since surgery (p = 0.048). CONCLUSIONS: Although there were several limitations to this study, DBS seems to improve quality of life without significantly increasing caregiver burden.

[Update on deep brain stimulation for movement disorders].

Deep brain stimulation (DBS) has been widely performed for various medically refractory movement disorders. For Parkinson disease (PD), target of DBS is subthalamic nucleus (STN) or globus pallidus internus (GPi). There are some evidences to demonstrate its effectiveness on motor function and QOL. DBS effectively improves levodopa-responsive motor symptoms, and significantly reduces dyskinesia and motor fluctuations. STN DBS particularly decreases the need for dopaminergic medication. A combination of medical treatment and DBS would provide longer relief of motor symptoms than medical treatment only. Currently new evidence supporting early introduction of DBS for better future outcome is published. DBS of Vim thalamus has been indicated for intractable tremor with various etiologies. Recently posterior subthalamic area (PSA) is introduced as an alternative target to Vim for tremor. GPi DBS is also effective treatment option for generalized dystonia.

Validity of single tract microelectrode recording in subthalamic nucleus stimulation.

In surgery for subthalamic nucleus (STN) deep brain stimulation (DBS), precise implantation of the lead into the STN is essential. Physiological refinement with microelectrode recording (MER) is the gold standard for identifying STN. We studied single tract MER findings and surgical outcomes and verified our surgical method using single tract MER. The number of trajectories in MER and the final position of lead placement were retrospectively analyzed in 440 sides of STN DBS in 221 patients. Bilateral STN DBS yielded marked improvement in the motor score, dyskinesia/fluctuation score, and reduced requirement of dopaminergic medication in this series. The number of trajectories required to obtain sufficient activity of the STN was one in 79.0%, two in 18.2%, and three or more in 2.5% of 440 sides. In 92 sides requiring altered trajectory, the final direction of trajectory movement was posterior in 73.9%, anterior in 13.0%, lateral in 5.4%, and medial in 4.3%. In 18 patients, posterior moves were required due to significant brain shift with intracranial air caused by outflow of CSF during the second side procedure. Sufficient STN activity is obtained with minimum trajectories by proper targeting and precise interpretation of MER findings even in the single tract method. Anterior-posterior moves rather than medial-lateral moves should be attempted first in cases with insufficient recording of STN activity.

Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant and progressive neurodegenerative syndrome characterized by motor, cognitive and psychiatric manifestations. Chorea and dystonia are features that may be troublesome to some patients and may potentially prove unresponsive to pharmacological treatments. There are several reports on the results of globus pallidus internus deep brain stimulation (DBS) surgery for HD. In these published cases, DBS was utilized mainly to treat disabling chorea. We report our experience with 2 HD cases treated with DBS. The cases illustrate a differential response with a better outcome in the choreic presentation compared to the dystonic presentation. Additionally, DBS worsened gait features in both cases.

Taking a better history for behavioral issues pre- and post-deep brain stimulation: issues missed by standardized scales.

OBJECTIVES: To screen for potentially underreported behavioral changes in patients with idiopathic Parkinson's disease (PD) pre- and post-deep brain stimulation (DBS), a retrospective data base review was performed. METHODS: In total, 113 patients who underwent unilateral or bilateral DBS at the University of Florida in either subthalamic nucleus or globus pallidus internus for PD were screened for behavioral issues by asking about the presence or absence of seven neuropsychiatric symptoms (panic, fear, paranoia, anger, suicidal flashes, crying, and laughing). RESULTS: There was a high prevalence of fear (16.3%), panic (14.0%), and anger (11.6%) at baseline in this cohort. In the first six months following DBS implantation, anger (32.6%), fear (26.7%), and uncontrollable crying (26.7%) were the most frequent symptoms reported. Those symptoms also were present following six months of DBS surgery (30.2%, 29.1%, and 19.8%, respectively). New uncontrollable crying occurred more in the acute postoperative stage (less than or equal to six months) (p = 0.033), while new anger occurred more in the chronic postoperative stage (greater than six months) (p = 0.017). The frequency of uncontrollable laughing significantly increased with bilateral DBS (p = 0.033). CONCLUSIONS: Many of the neuropsychiatric issues were identified at preoperative baseline and their overall occurrence was more than expected. There was a potential for worsening of these issues post-DBS. There were subtle differences in time course, and in unilateral vs. bilateral implantations. Clinicians should be aware of these potential behavioral issues that may emerge following DBS therapy, and should consider including screening questions in preoperative and postoperative interviews. Standardized scales may miss the presence or absence of these clinically relevant issues.