| 1. |
- Devos, David, et al.
(författare)
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Trial of Deferiprone in Parkinson’s Disease
- 2022
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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| 2. |
- Grötsch, Marie Therese, et al.
(författare)
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A Modified Progressive Supranuclear Palsy Rating Scale
- 2021
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:5, s. 1203-1215
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. Objective: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. Methods: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy. Results: The modified scale retained 14 items (yielding 0–2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). Conclusions: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine.
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| 3. |
- Höglinger, Günter U, et al.
(författare)
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Clinical diagnosis of progressive supranuclear palsy : The movement disorder society criteria
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:6, s. 853-864
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Tidskriftsartikel (refereegranskat)abstract
- Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence.
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| 4. |
- Koellensperger, Martin, et al.
(författare)
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Presentation, Diagnosis, and Management of Multiple System Atrophy in Europe: Final Analysis of the European Multiple System Atrophy Registry
- 2010
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:15, s. 2604-2612
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society
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| 5. |
- Koellensperger, Martin, et al.
(författare)
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Red flags for multiple system atrophy
- 2008
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 23:8, s. 1093-1099
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Tidskriftsartikel (refereegranskat)abstract
- The clinical diagnosis Of Multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/- 7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P. (C) 2008 Movement Disorder Society.
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| 6. |
- Kühnel, Line, et al.
(författare)
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Disease Progression in Multiple System Atrophy—Novel Modeling Framework and Predictive Factors
- 2022
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 37:8, s. 1719-1727
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple system atrophy (MSA) is a rare and aggressive neurodegenerative disease that typically leads to death 6 to 10 years after symptom onset. The rapid evolution renders it crucial to understand the general disease progression and factors affecting the disease course. Objectives: The aims of this study were to develop a novel disease-progression model to estimate a population-level MSA progression trajectory and predict patient-specific continuous disease stages describing the degree of progress into the disease. Methods: The disease-progression model estimated a population-level progression trajectory of subscales of the Unified MSA Rating Scale and the Unified Parkinson's Disease Rating Scale using patients in the European MSA natural history study. The predicted disease continuum was validated via multiple analyses based on reported anchor points, and the effect of MSA subtype on the rate of disease progression was evaluated. Results: The predicted disease continuum spanned approximately 6 years, with an estimated average duration of 51 months for a patient with global disability score 0 to reach the highest level of 4. The predicted continuous disease stages were shown to be correlated with time of symptom onset and predictive of survival time. MSA motor subtype was found to significantly affect disease progression, with MSA-parkinsonian (MSA-P) type patients having an accelerated rate of progression. Conclusions: The proposed modeling framework introduces a new method of analyzing and interpreting the progression of MSA. It can provide new insights and opportunities for investigating covariate effects on the rate of progression and provide well-founded predictions of patient-level future progressions.
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| 7. |
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| 8. |
- Wenning, Gregor K., et al.
(författare)
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The natural history of multiple system atrophy: a prospective European cohort study
- 2013
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Ingår i: Lancet Neurology. - 1474-4465. ; 12:3, s. 264-274
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Tidskriftsartikel (refereegranskat)abstract
- Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56.2 (SD 8.4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9.8 years (95% CI 8.1-11.4). The parkinsonian variant of MSA (hazard ratio [HR] 2.08,95% CI 1.09-3.97; p=0.026) and incomplete bladder emptying (HR 2.10,1.02-4.30; p=0.044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9.4 [SD 5.9]), 74% (12.9 [8.5]), and 57% (21.9 [11.9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0.68, 0.5-0.9; p=0.006) and absent levodopa response (OR 3.4, 1.1-10.2; p=0.03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.
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