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.).

The impact of subthalamic deep-brain stimulation in restoring motor symmetry in Parkinson's disease patients: a prospective study.

BACKGROUND AND OBJECTIVES: The impact of subthalamic deep-brain stimulation (STN-DBS) on motor asymmetry and its influence on both motor and non-motor outcomes remain unclear. The present study aims at assessing the role of STN-DBS on motor asymmetry and how its modulation translates into benefits in motor function, activities of daily living (ADLs) and quality of life (QoL). METHODS: Postoperative motor asymmetry has been assessed on the multicentric, prospective Predictive Factors and Subthalamic Stimulation in Parkinson's Disease cohort. Asymmetry was evaluated at both baseline (pre-DBS) and 1 year after STN-DBS. A patient was considered asymmetric when the right-to-left MDS-UPDRS part III difference was ≥ 5. In parallel, analyses have been carried out using the absolute right-to-left difference. The proportion of asymmetric patients at baseline was compared to that in the post-surgery evaluation across different medication/stimulation conditions. RESULTS: 537 PD patients have been included. The proportion of asymmetric patients was significantly reduced after both STN-DBS and medication administration (asymmetric patients: 50% in pre-DBS MedOFF, 35% in MedOFF/StimON, 26% in MedON/StimOFF, and 12% in MedON/StimON state). Older patients at surgery and with higher baseline UPDRS II scores were significantly less likely to benefit from STN-DBS at the level of motor asymmetry. No significant correlation between motor asymmetry and ADLs (UPDRS II) or overall QoL (PDQ-39) score was observed. Asymmetric patients had significantly higher mobility, communication, and daily living PDQ-39 sub-scores. CONCLUSIONS: Both STN-DBS and levodopa lead to a reduction in motor asymmetry. Motor symmetry is associated with improvements in certain QoL sub-scores.

Personality Related to Quality-of-Life Improvement After Deep Brain Stimulation in Parkinson's Disease (PSYCHO-STIM II).

BACKGROUND: Deep brain stimulation of the sub-thalamic nucleus (DBS-STN) reduces symptoms in Parkinson's disease (PD) patients with motor fluctuations. However, some patients may not feel ameliorated afterwards, despite an objective motor improvement. It is thus important to find new predictors of patients' quality of life (QoL) amelioration after DBS-STN. We hypothesized that personality dimensions might affect QoL after DBS-STN. OBJECTIVE: To evaluate associations between personality dimensions and QoL improvement one year after DBS-STN. METHODS: DBS-STN-PD patients (n = 303) having answered the "Temperament and Character Inventory" (TCI) before surgery and the PDQ-39 before and one year after surgery were included, from the cohort study PREDI-STIM. Linear regression models were used to evaluate associations between TCI dimensions and change in PDQ-39 scores after DBS-STN. RESULTS: Novelty Seeking and Cooperativeness scores before surgery were positively associated with PDQ-39 scores improvement after DBS-STN (FDR-adjusted p < 0.01). Moreover, paradoxically unimproved patients with deterioration of their PDQ-39 scores after DBS-STN despite improvement of their MDS-UPDRS-IV scores had lower Cooperativeness scores, while paradoxically improved patients with amelioration of their PDQ-39 scores despite deterioration of their MDS-UPDRS-IV scores had higher Reward Dependence scores. CONCLUSION: Some presurgical personality dimensions were significantly associated with QoL amelioration and discrepancy between motor state and QoL changes after DBS-STN in PD. Educational programs before DBS-STN should take in account patient personality dimensions to better deal with their expectations.

Preoperative REM Sleep Behavior Disorder and Subthalamic Nucleus Deep Brain Stimulation Outcome in Parkinson Disease 1 Year After Surgery.

BACKGROUND AND OBJECTIVES: To determine whether patients with Parkinson disease (PD) eligible for subthalamic nucleus deep brain stimulation (STN-DBS) with probable REM sleep behavior disorder (RBD) preoperatively could be more at risk of poorer motor, nonmotor, and quality of life outcomes 12 months after surgery compared to those without RBD. METHODS: We analyzed the preoperative clinical profile of 448 patients with PD from a French multicentric prospective study (PREDISTIM) according to the presence or absence of probable RBD based on the RBD Single Question and RBD Screening Questionnaire. Among the 215 patients with PD with 12 months of follow-up after STN-DBS, we compared motor, cognitive, psycho-behavioral profile, and quality of life outcomes in patients with (pre-opRBD+) or without (pre-opRBD-) probable RBD preoperatively. RESULTS: At preoperative evaluation, pre-opRBD+ patients were older (61 ± 7.2 vs 59.5 ± 7.7 years; p = 0.02), had less motor impairment (Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] III "off": 38.7 ± 16.2 vs 43.4 ± 7.1; p = 0.03) but more nonmotor symptoms on daily living activities (MDS-UPDRS I: 12.6 ± 5.5 vs 10.7 ± 5.3; p < 0.001), had more psychobehavioral manifestations (Ardouin Scale of Behavior in Parkinson's Disease total: 7.7 ± 5.1 vs 5.1 ± 0.4; p = 0.003), and had worse quality of life (Parkinson's Disease Questionnaire-39: 33 ± 12 vs 29 ± 12; p = 0.03), as compared to pre-opRBD- patients. Both pre-opRBD+ and pre-opRBD- patients had significant MDS-UPDRS IV score decrease (-37% and -33%, respectively), MDS-UPDRS III "med 'off'/stim 'on'" score decrease (-52% and -54%), and dopaminergic treatment decrease (-52% and -49%) after surgery, with no between-group difference. There was no between-group difference for cognitive and global quality of life outcomes. CONCLUSIONS: In patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with a different clinical outcome 1 year after neurosurgery. TRIAL REGISTRATION INFORMATION: NCT02360683. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with poorer outcomes 1 year post surgery.

Increased Risk of Parkinson's Disease in Women after Bilateral Oophorectomy.

BACKGROUND: Results regarding the association between hormonal exposure and risk of Parkinson's disease (PD) are heterogeneous. OBJECTIVES: To investigate the association of reproductive life characteristics with PD among postmenopausal women. METHODS: The PARTAGE case-control included 130 female cases and 255 age-matched female controls. Information on gynecological history was obtained from a standardized questionnaire and PD was validated by neurological examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. RESULTS: After adjustment for education level, smoking status, professional exposure to pesticides, and coffee and alcohol drinking, bilateral oophorectomy (OR = 3.55, 95%CI = 1.75-7.20), but neither menopause before age 50 years (OR = 1.24, 95%CI = 0.74-2.09) nor hormone therapy (HT; OR = 1.07, 95%CI = 0.62-1.86), was associated with PD. CONCLUSION: Our findings suggest that bilateral oophorectomy is associated with increased risk of PD. © 2021 International Parkinson and Movement Disorder Society.

[Trends in stroke incidence and case-fatality rates over a 20-year period (1985-2004) in Dijon, France]. / Evolution sur vingt ans des taux d'incidence et de mortalité des AVC au sein de la population de dijon intra-muros: 1985-2004.

With progress in stroke prevention it is important to evaluate epidemiological trends over a long period and in an unselected population. We estimated changes in stroke incidence, the case-fatality rate, risk factors, and the use of primary prevention, based on a continuous registry of a well-defined population, from 1985 to 2004. We recorded 3142 ischemic strokes, 341 primary cerebral hemorrhages and 74 subarachnoid hemorrhages. During the 20-year study period, age at first stroke increased by 5 years in men and 8 years in women. Comparing the periods 1985-1989 and 2000-2004, the age - and sex-adjusted incidence rates of first-ever strokes were stable, except for lacunar strokes, the incidence of which increased significantly (p = 0.05), and also cardio-embolic stroke, the incidence of which fell significantly (p = 0.01). Twenty-eight-day case-fatality rates fell significantly, especially for lacunar stroke (p = 0.05) and primary cerebral hemorrhage (p = 0.03). The frequency of hypercholesterolemia and diabetes increased significantly (p < 0.01). In contrast, the frequency of myocardial infarction fell significantly (p = 0.02). The frequency of smoking and diastolic blood pressure J 90 mmHg also fell, but the difference was not significant because of missing data. The frequency of pre-stroke antiplatelet and anticoagulant treatment increased significantly (p < 0.01). The age - and sex-adjusted incidence rates of stroke in Dijon, France, have thus been stable for the past 20 years. Age at stroke onset has increased, the case-fatality rate has fallen, antiplatelet treatment is more frequent, and the frequency of some pre-stroke risk factors has fallen.

Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: three years follow-up.

OBJECTIVE: To assess the long-term efficacy and safety of chronic bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson's disease (PD). METHODS: 36 consecutive patients with idiopathic Parkinson's disease treated with bilateral stimulation of the STN were studied. Parkinsonian status was assessed preoperatively and at 1 and 3 years postoperatively using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological evaluation in on and off-medication / on and off stimulation conditions. RESULTS: At 3 years follow-up, STN stimulation reduced the UPDRS motor score by 54.2 % compared to baseline in the off-medication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 72.2 %, 62.4 %, 56.8 %, 40.5 % and 45.3 %, respectively. UPDRS part II scores were reduced by 41.4 %. The overall dopaminergic drugs dose was reduced by 48.6 % after surgery and four patients were no longer taking antiparkinsonian medication at three years. However, axial dopa-unresponsive signs worsened in some patients. The most frequent transient adverse event consisted in mood disorders in 23 patients. CONCLUSIONS: Our data demonstrate that: 1) bilateral STN stimulation is relatively safe, improves the motor symptoms and drug-related motor complications of PD, and reduces the daily dosage of medication; 2) this benefit is sustained over time despite the occurrence of axial doparesistant signs in some patients.

[Epidemiology of strokes. Impact on the treatment decision]. / Epidémiologie des accidents vasculaires cérébraux. Impacts sur la décision thérapeutique.

The development of several population stroke registries has improved our knowledge of the epidemiology of strokes, their natural history, and their trends over time and place. In Europe, stroke incidence decreases from east to west and from north to south. Incidence and mortality have also been decreasing regularly over time. The diagnostic tools created with the arrival of computed tomography (CT), magnetic resonance imaging (MRI), and other forms of vascular and cardiac imaging have improved the identification of risk factors for stroke according to its mechanism--hemorrhagic or ischemic--and according to the subtype of ischemic stroke. Hypertension is the leading risk factor for both ischemic and hemorrhagic strokes. New independent stroke risk factors have been confirmed, including elevated cholesterol and homocysteine levels. The regular decline of the incidence of some types of stroke and of mortality is partly due to the positive effects of prevention and confirms the usefulness of screening and early treatment of stroke risk factors. Development of new treatments during the acute phase and in the field of primary and secondary stroke prevention (such as statins) is necessary to improve prognosis, which remains too serious, especially in women.

Trends in the incidence of transient ischemic attacks, premorbid risk factors and the use of preventive treatments in the population of Dijon, France from 1985 to 2004.

BACKGROUND: We describe the epidemiological trends of transient ischemic attack (TIA) in a 20-year population-based pilot study. METHODS: Trends in the incidence, risk factors and pre-TIA use of preventive treatments for TIA were observed from 1985 to 2004 according to the classic definition in the population of the city of Dijon, France (150,000 inhabitants). RESULTS: The raw and standardized incidence of TIA were stable over time. We observed a significant increase in the mean age at TIA onset in women only. The prevalence of hypercholesterolemia and diastolic blood pressure > or =90 mm Hg among patients with TIA increased significantly. This contrasts with falls in smoking and in history of previous myocardial infarction. CONCLUSION: The stability of classic TIA incidence, despite the rise in the proportion of elderly people, and the increase in the mean age at onset in women may be considered as a medical progress.

[Air pollution and cardiovascular and cerebrovascular disease. Pathophysiologic basis and groups at risk]. / Pollution de l'air et pathologie athérothrombotique cardiaque et cérébrale. Bases physiopathologiques et groupes à risque.

The pathophysiologic basis of the harmful action of air pollutants rests principally on their proinflammatory and prothrombotic effects. The principal pollutants currently identified as responsible for these effects are fine suspended particles (PM2.5) and ozone. Inflammatory effects, initially localized in the lungs, then become systemic. Analysis of groups at the highest risk of atherothrombotic events suggests the elderly may be most sensitive to the effects of air pollution.

Stable stroke incidence rates but improved case-fatality in Dijon, France, from 1985 to 2004.

BACKGROUND AND PURPOSE: With the progress in stroke prevention, it is important to evaluate the epidemiological trends of strokes over a long period and from a nonselected population-based perspective. METHODS: We estimated changes in incidence, case-fatality rates, severity, risk factors and prestroke use of preventive treatments for first-ever strokes, from a continuous 20-year well-defined population-based registry, from 1985 to 2004. RESULTS: We recorded 3142 ischemic strokes, 341 primary cerebral hemorrhages and 74 subarachnoid hemorrhages. During the 20-year study, the age at first stroke onset increased by 5 years in men and 8 years in women. Comparing the 1985 to 1989 and the 2000 to 2004 periods, age- and sex-standardized incidences of first-ever strokes were stable except for lacunar strokes whose incidence significantly increased (P=0.01) and for cardioembolic stroke whose incidence significantly decreased (P=0.01). Twenty-eight-day case-fatality rates decreased significantly mainly for lacunar strokes (P=0.05) and for primary cerebral hemorrhages (P=0.03). The proportion of hypercholesterolemia and diabetes significantly increased (P<0.01). In contrast, the proportion of myocardial infarction significantly decreased (P=0.02). Prestroke antiplatelets and anticoagulants treatment significantly increased (P<0.01). CONCLUSIONS: The age- and sex-standardized incidences of first strokes in Dijon have been stable over the past 20 years and were associated with an increase in age at stroke onset, a decrease in case-fatality rates, and an increased use of antiplatelet treatments.

[Consultation after cerebral infarction or intracerebral hematoma]. / Consultation après un infarctus ou un hématome cérébral.

Hypertension is the principal risk factor for cerebral infarctions and intracerebral hematoma. The brain is the principal target of hypertension. The brain is the principal target of antihypertensive drugs. Controlling blood pressure and stopping smoking reduces the risk of cerebral infarction by 40%. Objectives of a consultation after cerebral infarction or intracerebral hematoma: validate diagnosis and cause, identify risk factors for recurrent cerebral infarction but also for myocardial infarction and lower limb arterial disease, begin treatment of the risk factors for recurrence, begin prevention of atherothrombotic complications and embolic heart disease, identify complications of cerebral infarction and intracerebral hematoma.

Trends in utilization of antithrombotic therapy in patients with atrial fibrillation before stroke onset in a community-based study, from 1985 through 1997. From scientific evidence to practice.

BACKGROUND: Despite the significant beneficial effects of antithrombotic therapy in primary prevention of stroke in patients with chronic nonvalvular atrial arrhythmia, this prevention therapy is underutilized. We conducted this population-based study to determine the rates and the trends of utilization of antithrombotic therapy for stroke patients with atrial fibrillation before stroke onset, and to evaluate indirectly the impact of medical recommendations on physician practice. Our aim was not to evaluate the efficacy of such prevention therapy. METHODS: From 2,330 men and women of any age registered for a first-ever stroke from 1985 to 1997 in a community-based study, we selected 599 patients admitted for ischemic stroke or TIA, associated with prior atrial fibrillation. Previous antithrombotic treatment before stroke onset was recorded and we evaluated the ratio of stroke patients who had received antithrombotic treatment for atrial fibrillation, from 1985 through 1997. RESULTS: Our study was performed to evaluate the practice of physicians in the prevention of stroke, and not to evaluate the efficacy of the anticoagulants in the prevention of stroke. Atrial fibrillation before stroke onset was identified in 599 patients. Of these, 222 (37%) received no antithrombotic therapy, 65 (10.8%) received an anticoagulant alone, 147 (24.5%) received an antiplatelet agent alone and 10 (1.7%) received both anticoagulation and antiplatelet treatment. From 1985 to 1988, the proportion of treated atrial fibrillation before stroke was small (14.6%). This increased to 21.5% within the period 1989-1991, to 40.3% within the period 1992-1994 and then to 47.6% within the period 1995-1997. It appears that the most significant change occurred within the period 1992-1994 (14.6% of treated atrial fibrillation within the period 1985-1987 constituted to 40.3% within the period 1992-1994) (P < 0.05), with a current rate of utilization of antithrombotic therapy close to 50%. The logistic regression analysis concerning anticoagulant therapy before stroke onset as a dependent variable, found that the factors independently associated with the use of anticoagulants before stroke were the lack of arterial hypertension and a history of smoking. The factors independently associated with the use of aspirin before stroke were arterial hypertension and lower limb peripheral vascular disease. CONCLUSION: For primary prevention of stroke onset in patients with atrial fibrillation, therapeutic trials have changed medical practices although not to ideal levels because close to 50% of patients with atrial fibrillation experiencing an acute stroke or TIA received antithrombotic treatment. Therefore, clinical practice is inconsistent with the guidelines resulting from therapeutic trials. It is necessary to know the reasons for this inconsistency and to improve medical information about the cerebrovascular risk of atrial fibrillation and the efficacy of anticoagulants in stroke prevention in this condition.

Atypical propriospinal myoclonus with possible relationship to alpha interferon therapy.

We report on a man who received interferon-alpha 2a therapy for kidney cancer and who subsequently developed propriospinal myoclonus. The myoclonus was noted at rest and during movement. The jerks were reinforced by cutaneous stimuli and tendon taps and spread to the spinal cord via polysynaptic propriospinal pathways. Cerebrospinal fluid analysis, spinal cord magnetic resonance imaging, electroencephalogram with back-averaging, and somatosensory-evoked potentials were normal. No antineuronal antibodies were found. Although the mechanism of interferon neurotoxicity remains unclear, the possible responsibility of interferon was considered, as no focal lesion or paraneoplastic pathology were disclosed.