Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Predicting Current Thresholds for Pyramidal Tract Activation Using Volume of Activated Tissue Modeling in Patients Undergoing Deep Brain Stimulation Surgery.

BACKGROUND: The volume of activated tissue (VTA) model attempts to represent in 3 dimensions the diffusion of the current provided by the deep brain stimulation lead on brain structures. The objective of the present study was to assess the correlations among the VTA, activation of the corticospinal tract, and the intraoperative side effect (ISE) threshold. METHODS: This double-blind, single-center study was performed between September 2016 and July 2017. We identified 2 groups for statistical analysis: the entire study population and a subset of patients with additional diffusion tensor imaging (DTI) data for determining the location of the pyramidal tract. We determined the intensity threshold at which the VTA reached the border of the target nucleus (referred to as the VTAn) and the intensity threshold when the VTA reached the pyramidal tract (VTAndti). In each group of patients, we studied the correlations between the ISE threshold and the VTAn or VTAndti threshold. RESULTS: Fifteen patients were included in the study. In both groups, there was a significant correlation between the VTA intensity threshold and the ISE threshold (P = 0.018; r = 0.31 for VTAn in the entire study population). The correlation was stronger in the subset of patients with valid tractography data (P = 0.002; r = 0.5 for VTAndti). CONCLUSIONS: The present study is the first to show a relationship between the intensity threshold as determined by the use of the VTA and the ISE threshold. The correlation between the clinical features and the VTA appears to be stronger in the model based on a combination of high-resolution anatomic data and interpretable DTI data.

Asleep Robot-Assisted Surgery for the Implantation of Subthalamic Electrodes Provides the Same Clinical Improvement and Therapeutic Window as Awake Surgery.

OBJECTIVE: To study the impact of not performing awake clinical evaluation during the robot-assisted implantation of subthalamic nucleus deep brain stimulation (STN-DBS) electrodes on the stimulation parameters and clinical outcomes in patients with Parkinson disease (PD). METHODS: A total of 23 patients with PD underwent robot-assisted surgery for the bilateral implantation of STN-DBS electrodes. Thirteen patients received general anesthesia (GA) and a limited intraoperative evaluation (side effects only), and the other 10 patients received local anesthesia (LA) and a full evaluation. The primary endpoint was the therapeutic window (TW), defined as the difference between the mean voltage threshold for motor improvement and the mean voltage threshold for side effects in the active contacts at 12 months after surgery. Motor scores were measured as well. RESULTS: The TW was similar in the LA and GA groups, with mean ± standard deviation values of 2.06 ± 0.53 V and 2.28 ± 0.99 V, respectively (P = 0.32). In the short term, the Unified Parkinson Disease Rating Scale (UPDRS) III score in the "off-drug, on-stim" condition fell to a similar extent in the LA and GA groups (by 40.3% and 49%, respectively; P = 0.336), as did the UPDRS III score in the "on-stim, on-drug" condition (by 57% and 70.7%, respectively; P = 0.36). CONCLUSIONS: Asleep, robot-assisted implantation of STN-DBS electrodes (with accurate identification of the STN and positioning of the DBS lead) produced the same motor results and TW as awake surgery.

A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease.

BACKGROUND: Cysteamine has been demonstrated as potentially effective in numerous animal models of Huntington's disease. METHODS: Ninety-six patients with early-stage Huntington's disease were randomized to 1200 mg delayed-release cysteamine bitartrate or placebo daily for 18 months. The primary end point was the change from baseline in the UHDRS Total Motor Score. A linear mixed-effects model for repeated measures was used to assess treatment effect, expressed as the least-squares mean difference of cysteamine minus placebo, with negative values indicating less deterioration relative to placebo. RESULTS: At 18 months, the treatment effect was not statistically significant - least-squares mean difference, -1.5 ± 1.71 (P = 0.385) - although this did represent less mean deterioration from baseline for the treated group relative to placebo. Treatment with cysteamine was safe and well tolerated. CONCLUSIONS: Efficacy of cysteamine was not demonstrated in this study population of patients with Huntington's disease. Post hoc analyses indicate the need for definitive future studies. © 2017 International Parkinson and Movement Disorder Society.

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

High-resolution 3-dimensional T2*-weighted angiography (HR 3-D SWAN): an optimized 3-T magnetic resonance imaging sequence for targeting the subthalamic nucleus.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for Parkinson's disease. OBJECTIVE: To characterize an optimized magnetic resonance imaging (MRI) sequence (high-resolution 3-dimensional T2*-weighted angiography [HR 3-D SWAN]) for direct STN targeting. METHODS: Sequence distortions were measured using the Leksell stereotactic phantom. Eight consecutive candidates for STN-DBS underwent HR 3-D SWAN MRI for direct identification of the 16 STN. Two senior neurosurgeons independently determined the boundaries of STN on a semiquantitative scale (ranging from 1 [identification very easy] to 4 [identification very difficult]) and the anatomic target within the nucleus. The anatomic data were compared with electrophysiological recordings (48 microrecordings). We examined the anatomic location of the active contacts on MRI. RESULTS: The mean distortion error over the phantom was 0.16 mm. For the 16 STNs, identification of the upper, internal, anterior, and external edges was considered to be easy (scores of 1 or 2). The distinction between the substantia nigra and the STN was rated 1 or 2 for all but 6 nuclei. In the mediolateral axis, electrophysiological recordings covered perfectly anatomic data. In the craniocaudal axis, the mean differences between the electrophysiological data and the anatomic data were 0.8 mm and 0.19 mm for the "entry" and "exit" of the STN, respectively. All active contacts were located within the STN on MRI. CONCLUSION: HR 3-D SWAN allows easy visualization of the STN. Adapted to stereotactic requirement, the sequence simplifies direct targeting in STN-DBS surgery.

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification.

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.

Association between caffeine intake and age at onset in Huntington's disease.

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinson's and Alzheimer's diseases. Experimental evidence support that ARs play a role in Huntington's disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.

Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification.

OBJECTIVES: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene. METHODS: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes. RESULTS: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1. CONCLUSION: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology.

A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease.

Based on the pathophysiological role of adenosine A(2A) receptors in HD, we have evaluated the association of the 1976C/T single-nucleotide polymorphism in the ADORA2A gene (rs5751876) with residual age at onset (AAO) in HD. The study population consisted of 791 unrelated patients belonging to the Huntington French Speaking Network. The variability in AAO attributable to the CAG repeats number was calculated by linear regression using the log (AAO) as the dependent variable, and the respective rs5751876 genotypes as independent variables. We show that the rs5751876 variant significantly influences the variability in AAO. The R(2) statistic rose slightly but significantly (p=0.019) when rs5751876 T/T genotype was added to the regression model. Patients harbouring T/T genotype have an earlier AAO of 3.8 years as compared to C/C genotype (p=0.02). Our data thus strengthens the pathophysiological role of A(2A) receptors in Huntington's disease.

Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study.

BACKGROUND: Cerebral palsy (CP) with dystonia-choreoathetosis is a common cause of disability in children and in adults, and responds poorly to medical treatment. Bilateral pallidal deep brain stimulation (BP-DBS) of the globus pallidus internus (GPi) is an effective treatment for primary dystonia, but the effect of this reversible surgical procedure on dystonia-choreoathetosis CP, which is a subtype of secondary dystonia, is unknown. Our aim was to test the effectiveness of BP-DBS in adults with dystonia-choreoathetosis CP. METHODS: We did a multicentre prospective pilot study of BP-DBS in 13 adults with dystonia-choreoathetosis CP who had no cognitive impairment, little spasticity, and only slight abnormalities of the basal ganglia on MRI. The primary endpoint was change in the severity of dystonia-choreoathetosis after 1 year of neurostimulation, as assessed with the Burke-Fahn-Marsden dystonia rating scale. The accuracy of surgical targeting to the GPi was assessed masked to the results of neurostimulation. Analysis was by intention to treat. FINDINGS: The mean Burke-Fahn-Marsden dystonia rating scale movement score improved from 44.2 (SD 21.1) before surgery to 34.7 (21.9) at 1 year post-operatively (p=0.009; mean improvement 24.4 [21.1]%, 95% CI 11.6-37.1). Functional disability, pain, and mental health-related quality of life were significantly improved. There was no worsening of cognition or mood. Adverse events were related to stimulation (arrest of the stimulator in one patient, and an adjustment to the current intensity in four patients). The optimum therapeutic target was the posterolateroventral region of the GPi. Little improvement was seen when the neurostimulation diffused to adjacent structures (mainly to the globus pallidus externus [GPe]). INTERPRETATION: Bilateral pallidal neurostimulation could be an effective treatment option for patients with dystonia-choreoathetosis CP. However, given the heterogeneity of motor outcomes and the small sample size, results should be interpreted with caution. The optimum placement of the leads seemed to be a crucial, but not exclusive, factor that could affect a good outcome. FUNDING: National PHRC; Cerebral Palsy Foundation: Fondation Motrice/APETREIMC; French INSERM Dystonia National Network; Medtronic.

Exhaustive, one-year follow-up of subthalamic nucleus deep brain stimulation in a large, single-center cohort of parkinsonian patients.

OBJECTIVE: To prospectively assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) at 12 months after surgery in a series of 100 consecutive patients treated in a single center. The primary objective was to describe the clinical outcome in terms of efficacy and tolerance in STN-DBS patients. A secondary objective was to discuss presurgery clinical characteristics a posteriori as a function of outcome. METHODS: One hundred and three consecutive patients with severe Parkinson's disease received bilateral STN-DBS in our clinic between May 1998 and March 2003. Clinical assessment was performed before and 12 months after surgery and was based on the Unified Parkinson's Disease Rating Scale, Parts II, III, and IV A; the Schwab and England Scale; and cognitive evaluation. Patient-rated overall improvement was also evaluated. RESULTS: Twelve months after surgery, the Unified Parkinson's Disease Rating Scale Part III score decreased by 43%, the Unified Parkinson's Disease Rating Scale Part II score (activities of daily living) fell by 34%, and the severity of dyskinesia-related disability decreased by 61%. The main surgical complications after STN-DBS were as follows: infection (n = 7), intracerebral hematoma (n = 5), electrode fracture (n = 4), and incorrect lead placement (n = 8). We observed cognitive decline and depression in 7.7 and 18% of the patients, respectively. The mean patient-rated overall improvement score was 70.7%. CONCLUSION: The efficacy and safety of STN-DBS in our center's large cohort of Parkinsonian patients are generally similar to the results obtained by other groups, albeit at the lower limit of the range of reported values. In contrast to efficacy, the occurrence of adverse events cannot be predicted. Younger patients with Parkinson's disease (i.e., those younger than 60 yr) often show an excellent response to levodopa. However, in view of our data on overall patient satisfaction and the occurrence of adverse events, we suggest that older patients (but not those older than 70 yr) and less dopa-sensitive patients (but not those with a response <50%) should still be offered the option of STN-DBS.

Effects of pulse width variations in pallidal stimulation for primary generalized dystonia.

BACKGROUND: Various pulse widths (from 60-450 mus) have been used for bilateral pallidal stimulation in generalized dystonia but, to date, no comparison of this parameter's effects is available. OBJECTIVE: To provide an analysis of the differential effects of bilateral short, medium and long stimulus pulse width (PW) on clinical improvement in primary generalized dystonia. METHODS: The most effective therapeutic stimulation parameters were recorded in 22 patients using bilateral pallidal stimulation. Six months after surgery, the effects of bilateral pallidal short (60-90 micros), medium (120-150 micros) and long (450 micros) PWs were studied in 20 of those patients. The effect of the stimulation was assessed by reviewing videotaped sessions by an observer blinded to treatment status (Burke-Fahn-Marsden movement score). Patients were tested on separate days, in random order, for the stimulation conditions (acute effect with the stimulation condition lasting 10 hours). The same contact was used for each stimulation condition. All the electrodes were set at 130 Hz (monopolar stimulation) and the intensity was set individually 10% below the side effect threshold. RESULTS: Median PWs of 60 (short), 120 (medium) and 450 micros (long) were compared,with a mean intensity of 4.46, 3.45 and 2.47 V, respectively. This study failed to demonstrate any significant difference in the movement scale dystonia mean scores depending on PW. CONCLUSION: According to our findings, short duration stimulus PWs are as effective as longer ones during a 10 hour period of observation. Confirmation of this finding for chronic use could be of importance in saving stimulator energy. Moreover, the use of smaller stimulus pulse widths are said to reduce charge injection and increase the therapeutic window between therapeutic effects and side effects.

Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study.

BACKGROUND: We have previously reported the efficacy and safety of bilateral pallidal stimulation for primary generalised dystonia in a prospective, controlled, multicentre study with 1 year of follow-up. Although long-term results have been reported by other groups, no controlled assessment of motor and non-motor results is available. In this prospective multicentre 3 year follow-up study, involving the same patients as those enrolled in the 1 year follow-up study, we assessed the effect of bilateral pallidal stimulation on motor impairment, disability, quality of life, cognitive performance, and mood. METHODS: We studied 22 patients with primary generalised dystonia after 3 years of bilateral pallidal stimulation. We compared outcome at 3 years with their status preoperatively and after 1 year of treatment. Standardised video recordings were scored by an independent expert. Data were analysed on an intention-to-treat basis. FINDINGS: Motor improvement observed at 1 year (51%) was maintained at 3 years (58%). The improvement in quality of life (SF-36 questionnaire) was similar to that observed at 1 year. Relative to baseline and to the 1 year assessment, cognition and mood were unchanged 3 years after surgery, but slight improvements were noted in concept formation, reasoning, and executive functions. Pallidal stimulation was stopped bilaterally in three patients because of lack of improvement, technical dysfunction, and infection, and unilaterally in two patients because of electrode breakage and stimulation-induced contracture. No permanent adverse effects were observed. INTERPRETATION: Bilateral pallidal stimulation provides sustained motor benefit after 3 years. Mild long-term improvements in quality of life and attention were also observed.

Reliability of the Burke-Fahn-Marsden scale in a multicenter trial for dystonia.

BACKGROUND: The multicenter SPIDY trial (pallidal stimulation for generalized, idiopathic dystonia) recently reported a marked improvement in dystonia which was assessed by the Burke-Fahn-Marsden (BFM) scale. However, the reliability of this tool has rarely been evaluated and its use in a multicenter study has never been assessed prospectively. PURPOSE: To evaluate the concordance between three unblinded clinical raters and one single-blinded rater for 10 prospective series of ratings on the BFM scale in 22 dystonic patients of the SPIDY study. METHODS: Ten assessments on the BFM scale were performed under various stimulation conditions at different time points (before surgery and 1, 3, 6, and 12 months afterwards). Patients were first evaluated by three unblinded clinical raters (one per center). All assessments were videotaped and sent to a blinded rater. Intra- and inter-rater reliability was assessed using intraclass correlation coefficients. RESULTS: The intra-rater reliability at inclusion was better for the blinded rater than for the clinical raters. The inter-rater reliability (comparing the blinded rater with each clinical rater) was "very good" at inclusion, "fair" at month 1 and was "good" at month 3, month 6, and month 12. CONCLUSION: Blinding (rather than video) is probably the key factor in better intra-rater reliability and can produce more accurate rating than clinical rating. Consequently, a blind procedure should be performed systematically in multicenter studies. As inter-rater reliability is good in trained unblinded raters, the BFM scale may also be used in the follow up of dystonic patients in movement disorders centers, in clinical practice.

Alloimmunisation to donor antigens and immune rejection following foetal neural grafts to the brain in patients with Huntington's disease.

BACKGROUND: The brain is deemed "immunologically privileged" due to sparse professional antigen-presenting cells and lymphatic drainage, and to the blood-brain barrier. Although the actual extent of this privilege is controversial, there is general consensus about the limited need in intracerebral neural grafts for immunosuppressive regimens comparable to those used in other cases of allotransplantation. This has led over the past fifteen years to the use of either short-term or even no immunosuppression in most clinical trials with foetal neural transplant in patients with Parkinson's and Huntington's disease. METHODOLOGY/PRINCIPAL FINDINGS: We report biological demonstration of alloimmunisation without signs of rejection in four grafted patients out of 13 studied during the course of a clinical trial involving fetal neural transplantation in patients with Huntington's Disease. Biological, radiological and clinical demonstration of an ongoing rejection process was observed in a fifth transplanted patient. The rejection process was, however, fully reversible under immunosuppressive treatment and graft activity recovered within six months. CONCLUSIONS/SIGNIFICANCE: There had been, up to date, no report of documented cases that could have cast a doubt on those procedures. Our results underline the need for a reconsideration of the extent of the so-called immune privilege of the brain and of the follow-up protocols of patients with intracerebral grafts. It also suggests that some of the results obtained in past studies with foetal neural transplants may have been biased by an unrecognized immune response to donor cells.

Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia.

BACKGROUND: Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversible neurosurgical procedure that has been used for the treatment of dystonia, but assessment of its efficacy has been limited to open studies. METHODS: We performed a prospective, controlled, multicenter study assessing the efficacy and safety of bilateral pallidal stimulation in 22 patients with primary generalized dystonia. The severity of dystonia was evaluated before surgery and 3, 6, and 12 months postoperatively during neurostimulation, with the use of the movement and disability subscores of the Burke-Fahn-Marsden Dystonia Scale (range, 0 to 120 and 0 to 30, respectively, with higher scores indicating greater impairment). Movement scores were assessed by a review of videotaped sessions performed by an observer who was unaware of treatment status. At three months, patients underwent a double-blind evaluation in the presence and absence of neurostimulation. We also assessed the patients' quality of life, cognition, and mood at baseline and 12 months. RESULTS: The dystonia movement score improved from a mean (+/-SD) of 46.3+/-21.3 before surgery to 21.0+/-14.1 at 12 months (P<0.001). The disability score improved from 11.6+/-5.5 before surgery to 6.5+/-4.9 at 12 months (P<0.001). General health and physical functioning were significantly improved at month 12; there were no significant changes in measures of mood and cognition. At the three-month evaluation, dystonia movement scores were significantly better with neurostimulation than without neurostimulation (24.6+/-17.7 vs. 34.6+/-12.3, P<0.001). There were five adverse events (in three patients); all resolved without permanent sequelae. CONCLUSIONS: These findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.

Effects of subthalamic nucleus stimulation on parkinsonian dysarthria and speech intelligibility.

Subthalamic stimulation is known to improve tremor, akinesia and rigidity in Parkinson's disease. However, other signs such as hypophonia and swallowing disorders can be relatively resistant to this technique. The effect on dysarthria remains unclear. The aim of this study was to investigate the effects of implantation of electrode and stimulation of the subthalamic nucleus (STN) on parkinsonian dysarthria. Seven patients were prospectively included. Electrodes (Medtronic) were implanted in both STN. The electrode contacts and stimulation parameters were adjusted to provide best relief of symptoms with fewest side effects. Assessment used global scales (Unified Parkinson Disease Rating Scale, UPDRS II and III), dyskinesia scale, exhaustive dysarthria assessment (bucco-facial movements, voice, articulation, intelligibility) and the 'dysarthria' item from the UPDRS III. Evaluations were performed in six conditions: before and three months after surgery (pre-op, post-op) stimulation turned off or on (off-stim, onstim), and without or with a suprathreshold levodopa dose (offdrug, on-drug). Performance level on the UPDRS III significantly improved following electrode implantation and stimulation. For dysarthria, modest beneficial effects were observed on several motor parameters, especially lip movements. Voice mildly improved, especially for the modulation in loudness and pitch. Articulation was not affected. Furthermore, intelligibility was slightly reduced in the on-stimulation condition, especially when patients received levodopa. At an individual level, negative effects on intelligibility were observed in two patients, and this was associated with a discrete increase in facial and trunk dyskinesias, but not with the electrode position or stimulation parameters. In conclusion, surgery had weak effects on dysarthria. Intelligibility can be worsened, especially in the on-drug condition. Thus, adaptation of the stimulation parameters can be difficult.

Effects of subthalamic nucleus stimulation and levodopa treatment on gait abnormalities in Parkinson disease.

BACKGROUND: Stimulation of the subthalamic nucleus is proposed for the treatment of patients presenting with severe Parkinson disease. The effect on gait is not clearly established. OBJECTIVES: To evaluate objectively the influence of bilateral subthalamic nucleus stimulation on gait in Parkinson disease and to compare it with the effects of levodopa treatment. METHODS: Ten patients underwent bilateral subthalamic nucleus stimulation. The preoperative and postoperative (3 months after surgery) clinical gait disturbances, as well as spatial and temporal gait parameters, were analyzed in off and on-drug conditions. The gait analysis was performed using a video motion analysis system (optoelectronic VICON system; Oxford Metrics, Oxford, England). RESULTS: In the off condition, there was an improvement after surgery for the total motor score and the gait subscore. In the on-drug condition, there was an improvement in levodopa-induced dyskinesias and the motor score, whereas the gait subscore was unchanged. For the gait parameters measured by the video motion analysis system system, there was also an improvement in the off condition and to a lesser extent in the on-drug condition. CONCLUSIONS: Our method allowed exact quantification of the benefit of surgery on gait parameters. Compared with the levodopa treatment, the effect of stimulation on gait kinematic parameters seems to be qualitatively similar but quantitatively different with a lower benefit on gait velocity and stride length. Concerning the pathophysiology of gait troubles in Parkinson disease, the deficit in control of stride length would be the fundamental deficit. The study underlines the possible role of the subthalamic nucleus on the stride length regulation.