A distinct neuromelanin magnetic resonance imaging pattern in parkinsonian multiple system atrophy.

BACKGROUND: Parkinsonian variant of multiple system atrophy is a neurodegenerative disorder frequently misdiagnosed as Parkinson's disease. No early imaging biomarkers currently differentiate these disorders. METHODS: Simple visual imaging analysis of the substantia nigra and locus coeruleus in neuromelanin-sensitive magnetic resonance imaging and nigrosome 1 in susceptibility-weighted sequences was performed in thirty patients with parkinsonian variant of multiple system atrophy fulfilling possible/probable second consensus diagnostic criteria. The neuromelanin visual pattern was compared to patients with Parkinson's disease with the same disease duration (n = 10) and healthy controls (n = 10). Substantia nigra semi-automated neuromelanin area/signal intensity was compared to the visual data. RESULTS: Groups were similar in age, sex, disease duration, and levodopa equivalent dose. Hoehn & Yahr stage was higher in parkinsonian multiple system atrophy patients, 69% of whom had normal neuromelanin size/signal, significantly different from Parkinson's disease patients, and similar to controls. Nigrosome 1 signal was lost in 74% of parkinsonian multiple system atrophy patients. Semi-automated neuromelanin substantia nigra signal, but not area, measurements were able to differentiate groups. CONCLUSIONS: In patients with parkinsonism, simple visual magnetic resonance imaging analysis showing normal neuromelanin substantia nigra and locus coeruleus, combined with nigrosome 1 loss, allowed the distinction of the parkinsonian variant of multiple system atrophy from Parkinson's disease and healthy controls. This easy and widely available method was superior to semi-automated measurements in identifying specific imaging changes in substantia nigra and locus coeruleus.

Anterior Limb of Internal Capsule and Bed Nucleus of Stria Terminalis Stimulation for Gilles de la Tourette Syndrome with Obsessive-Compulsive Disorder in Adolescence: A Case of Success.

Gilles de la Tourette syndrome (GTS) is a neurobehavioral disorder comprising motor and vocal tics. In most cases it is associated with other disorders such as obsessive-compulsive disorder (OCD). In refractory cases deep brain stimulation (DBS) is a valid treatment option. This paper describes the case of a 15-year-old adolescent with an extremely refractory GTS with associated OCD. The patient developed catatonia associated with OCD, which partially remitted after electroconvulsive therapy. At the peak of the disease the Yale Global Tic Severity Scale (YGTSS) was 100 and the patient required sedation and intubation. All medical treatment options were unsuccessful. Bilateral DBS of the anterior limb of internal capsule (ALIC)/bed nucleus of stria terminalis (BST) region was performed, using a target below the BST and a trajectory through the ALIC, with stimulation of contacts 0 and 3. Two weeks after surgery sedatives were suspended and the patient was successfully extubated. One year after surgery the patient reached a YGTSS of 19, representing an 81% improvement. OCD completely resolved. Adverse events were a superficial infection and weight gain. In conclusion, this ALIC/BST stimulation appears to have been an effective and safe treatment for GTS with OCD in this case. Young age should not be an exclusion criterion for DBS in severe GTS and OCD. Further studies should be pursued for this target.

Critical appraisal of clinical trials in multiple system atrophy: Toward better quality.

Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause. Although many clinical trials have been conducted, there is still no treatment that cures the disease or slows its progression. We sought to assess the clinical trials, methodology, and quality of reporting of clinical trails conducted in MSA patients. We conducted a systematic review of all trials with at least 1 MSA patient subject to any pharmacological/nonpharmacological interventions. Two independent reviewers evaluated the methodological characteristics and quality of reporting of trials. A total of 60 clinical trials were identified, including 1375 MSA patients. Of the trials, 51% (n = 31) were single-arm studies. A total of 28% (n = 17) had a parallel design, half of which (n = 13) were placebo controlled. Of the studies, 8 (13.3%) were conducted in a multicenter setting, 3 of which were responsible for 49.3% (n = 678) of the total included MSA patients. The description of primary outcomes was unclear in 60% (n = 40) of trials. Only 10 (16.7%) clinical trials clearly described the randomization process. Blinding of the participants, personnel, and outcome assessments were at high risk of bias in the majority of studies. The number of dropouts/withdrawals was high (n = 326, 23.4% among the included patients). Overall, the design and quality of reporting of the reviewed studies is unsatisfactory. The most frequent clinical trials were small and single centered. Inadequate reporting was related to the information on the randomization process, sequence generation, allocation concealment, blinding of participants, and sample size calculations. Although improved during the recent years, methodological quality and trial design need to be optimized to generate more informative results. © 2017 International Parkinson and Movement Disorder Society.

Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study.

BACKGROUND: Pantothenate kinase-associated neurodegeneration is a progressive neurological disorder occurring in both childhood and adulthood. The objective of this study was to design and pilot-test a disease-specific clinical rating scale for the assessment of patients with pantothenate kinase-associated neurodegeneration. METHODS: In this international cross-sectional study, patients were examined at the referral centers following a standardized protocol. The motor examination was filmed, allowing 3 independent specialists in movement disorders to analyze 28 patients for interrater reliability assessment. The scale included 34 items (maximal score, 135) encompassing 6 subscales for cognition, behavior, disability, parkinsonism, dystonia, and other neurological signs. RESULTS: Forty-seven genetically confirmed patients (30 ± 17 years; range, 6-77 years) were examined with the scale (mean score, 62 ± 21; range, 20-106). Dystonia with prominent cranial involvement and atypical parkinsonian features were present in all patients. Other common signs were cognitive impairment, psychiatric features, and slow and hypometric saccades. Dystonia, parkinsonism, and other neurological features had a moderate to strong correlation with disability. The scale showed good internal consistency for the total scale (Cronbach's α = 0.87). On interrater analysis, weighted kappa values (0.30-0.93) showed substantial or excellent agreement in 85% of the items. The scale also discriminated a subgroup of homozygous c.1583C>T patients with lower scores, supporting construct validity for the scale. CONCLUSIONS: The proposed scale seems to be a reliable and valid instrument for the assessment of pediatric and adult patients with pantothenate kinase-associated neurodegeneration. Additional validation studies with a larger sample size will be required to confirm the present results and to complete the scale validation testing. © 2017 International Parkinson and Movement Disorder Society.

Cerebral Amyloid Angiopathy Associated with Inflammation: Report of 3 Cases and Systematic Review.

INTRODUCTION: Cerebral amyloid angiopathy associated with inflammatory process (CAA-I) is a rare potentially treatable encephalopathy, characterized by an inflammatory response to vascular deposits of ß-amyloid. We aimed to describe 3 clinical cases and perform a systematic review of all neuropathologically proved CAA-I case reports to describe its clinical and pathologic features and outcome under different treatments. METHODS: We searched PubMed and Cochrane Library and screened references of included studies and review articles for additional citations. Outcome was classified at the last available follow-up by the modified Rankin Scale (mRS). RESULTS: A total of 67 publications, reporting on 155 patients, were included. Mean age was 66.9 years, and 53.5% were men. The most common clinical presentation was cognitive dysfunction (48.0%) followed by headaches (38.7%), seizures (36.7%), and pyramidal signs (20.0%). Perivascular and vasculitic inflammation with granuloma was the most common pathologic pattern (27.5%). Eighty-six percent were treated with corticosteroids and 33.9% with cyclophosphamide. Forty-two percent regained independence (mRS score 0-2), whereas 20.5% were left with a severe handicap (mRS score 3-5) and 37.5% died. There were no statistically significant differences in outcome between patients treated with therapy with corticosteroids alone comparing with those treated with combination corticosteroids with cytostatic agents. CONCLUSIONS: The most common clinical manifestation of CAA-I was cognitive dysfunction. The functional outcome was unfavorable in the majority of the patients, with death or severe disability in almost two third of the cases, despite treatment. No differences in outcome could be detected between patients treated with corticosteroids versus patients treated with cytostatics, combined with corticosteroids.

Inhaled levodopa for intermittent treatment of OFF episodes in patients with Parkinson's disease.

Introduction: Many patients with advanced Parkinson's disease (PD) have inadequate control of motor symptoms despite optimized treatment. Predictable and unpredictable OFF periods severely interfere with the quality of life. A drug that easily and rapidly reverts the OFF state is still needed. Subcutaneous apomorphine, the only approved drug for this indication, although efficacious, is not widely used probably due to its potential side effects and complicated administration.Levodopa is the most efficacious drug for the treatment of PD motor symptoms. However, issues related to the oral route and intestinal absorption in later disease stages render this route lengthy and inefficacious.Areas covered: Literature on the development of an inhaled formulation of levodopa has been reviewed. Significant advances in the field of pulmonary delivery systems and in dry powders have enabled the development of a new formulation of levodopa that can be inhaled and adequate blood levels rapidly achieved, bypassing intestinal absorption. Several clinical trials have reported efficacy, safety, and tolerability data. Some pulmonary-related adverse events have been reported but are mostly mild.Expert opinion: This new way of administering levodopa is likely to be very welcome and may fill a gap for OFF rescue treatments, at least for some patients.

Outcome Measures for Evaluating the Effect of a Multidisciplinary Intervention on Axial Symptoms of Parkinson's Disease.

Introduction: The satisfactory symptomatic control of the axial symptoms of Parkinson's disease (PD) remains challenging. As these symptoms are an important cause of disability, new therapeutic strategies should be developed and evaluated. To do this, it is necessary to select the outcomes to be measured and reported in a clinical trial. In this study, we sought to identify the most responsive outcome measures for assessing the efficacy of a multidisciplinary intervention on the axial symptoms of PD. Methods: An exploratory prospective clinical study was conducted. PD patients engaged in a pre-defined multidisciplinary intervention program for parkinsonian patients were assessed at admission and discharge by a multidisciplinary team. The responsiveness to intervention was evaluated and the smallest sample size needed to enable statistically significant results for an expected 30% change from baseline for each outcome was calculated. Results: Twenty-two patients were included in the study. The effect size detected varied between 0.04 and 0.83. The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score and each subsection, the N-FOG questionnaire, the 10-m walk test, and Frenchay Dysarthria Assessment-2 Edition (FDA-2) showed a medium to large effect size. Sample size calculations for 90% power and assuming 30% change from baseline ranged from eight to 180 participants. The outcome measures that require a small number of participants to enable statistically significant results were the FDA-2 rating scale (n = 4 participants), the MDS-UPDRS total score (n = 9), the 10-m walk test (n = 9), and the MDS-UPDRS motor examination (n = 10). Conclusions: The MDS-UPDRS part III and total score and the 10-m walk test were the outcomes with the best responsiveness to a multidisciplinary intervention and required a small number of participants to enable statistically significant results. Further studies are needed to clarify the suitability of the Timed Up and Go test.

Physical Activity, Exercise, and Physiotherapy in Parkinson's Disease: Defining the Concepts.

BACKGROUND: Exercise is gaining extreme relevancy as a new therapeutic intervention for Parkinson's disease (PD). However, the frequent misuse of the concepts exercise, physiotherapy, and physical activity limits the possibility of summarizing research findings. This review aims to clarify these concepts and summarize the evidence on exercise in PD. METHODS: We critically appraised physical activity-related concepts and conducted a systematic review of clinical trials evaluating exercise interventions in PD. Additionally, we discussed the implications for PD clinical practice and research. RESULTS: Exercise is a subset of physical activity, and a major component of physiotherapy for PD management, having as the main goal to improve physical fitness. The appraisal of the 83 identified clinical trials found high variability in exercise interventions. Multimodal exercise was the most studied, and 60 minutes, two times/week for 12 weeks, the most reported prescription parameters. CONCLUSION: The best available evidence recommends increasing physical activity levels in PD. Exercise and physiotherapy programs seem the most efficacious strategies to achieve this goal. As a result of the heterogeneity in the type and manner exercise is prescribed, it is not possible to propose strong recommendations for exercise in PD. We believe that, in addition to the clarification of concepts here presented, a collaborative and rigorous work of different areas of knowledge is needed.

Measurement Instruments to Assess Functional Mobility in Parkinson's Disease: A Systematic Review.

BACKGROUND: Functional mobility (FM) is a person's ability to move to accomplish activities of daily living; it bridges the concepts of mobility and functional ability. There is frequently a loss of FM in Parkinson's disease (PD). Several instruments have been used to assess this concept in PD; however, there is no consensus on which are the most appropriate. OBJECTIVE: We aimed to identify and critically appraise which measurement instruments have been used to assess FM. METHODS: A systematic review was conducted using the databases CENTRAL, MEDLINE, Embase, and PEDro from their inception to January 2019 to identify all observational and experimental studies conducted in PD or atypical parkinsonism that included an FM assessment. Two reviewers independently screened citations, extracted data, and assessed clinimetric properties. RESULTS: We included 95 studies that assessed FM in PD. Fifty-five (57.9%) studies mentioned FM in the article, and 39 (41.1%) specified the measurement tools used to evaluate FM. FM was the primary outcome in 12 (12.6%) studies. The Timed Up and Go test was the most frequently used measurement tool. Only one study presented a definition of FM. Several overlapping terms were used, the most common being mobility. CONCLUSION: Several studies reported the use of FM measurement tools in PD, though with frequent misconceptions, an inadequate context of use, or suboptimal assessment. We propose the establishment of the concept of FM applied to PD, followed by the adequate clinimetric validation of existing measurement tools to provide a comprehensive and reliable evaluation of FM in PD.

Risk of Developing Parkinson Disease in Bipolar Disorder: A Systematic Review and Meta-analysis.

Importance: Parkinson disease (PD) manifests by motor and nonmotor symptoms, which may be preceded by mood disorders by more than a decade. Bipolar disorder (BD) is characterized by cyclic episodes of depression and mania. It is also suggested that dopamine might be relevant in the pathophysiology of BD. Objective: To assess the association of BD with a later diagnosis of idiopathic PD. Data Sources: An electronic literature search was performed of Cochrane Controlled Register of Trials, MEDLINE, Embase, and PsycINFO from database inception to May 2019 using the terms Parkinson disease, bipolar disorder, and mania, with no constraints applied. Study Selection: Studies that reported data on the likelihood of developing PD in BD vs non-BD populations were included. Two review authors independently conducted the study selection. Data Extraction and Synthesis: Two review authors independently extracted study data. Data were pooled using a random-effects model, results were abstracted as odds ratios and 95% CIs, and heterogeneity was reported as I2. Main Outcome and Measures: Odds ratios of PD. Results: Seven studies were eligible for inclusion and included 4 374 211 participants overall. A previous diagnosis of BD increased the likelihood of a subsequent diagnosis of idiopathic PD (odds ratio, 3.35; 95% CI, 2.00-5.60; I2 = 92%). A sensitivity analysis was performed by removing the studies that had a high risk of bias and also showed an increased risk of PD in people with BD (odds ratio, 3.21; 95% CI, 1.89-5.45; I2 = 94%). Preplanned subgroup analyses according to study design and diagnostic certainty failed to show a significant effect. Conclusions and Relevance: This review suggests that patients with BD have a significantly increased risk of developing PD compared with the general population. Subgroup analyses suggested a possible overestimation in the magnitude of the associations. These findings highlight the probability that BD may be associated with a later development of PD and the importance of the differential diagnosis of parkinsonism features in people with BD.

The launch of opicapone for Parkinson's disease: negatives versus positives.

INTRODUCTION: Opicapone is a novel, third generation COMT inhibitor approved for the treatment of Parkinson's disease. Safety and tolerability data is critical to determine the benefit-harm balance and anticipate therapeutic adherence. Areas covered: This review evaluates the tolerability and safety profile of opicapone. These data were extracted from all published clinical trials, including preclinical, phase I, phase II and phase III studies as well as postmarketing data. Opicapone was safe and well tolerated, with frequencies of treatment-emergent adverse events similar to placebo. Expert opinion: Opicapone have shown a good safety and tolerability profile. This adds to its proven efficacy and convenient once-daily administration, supporting a role of opicapone as a first-line therapy for motor complications in Parkinson's disease patients.

Pharmacological interventions for daytime sleepiness and sleep disorders in Parkinson's disease: Systematic review and meta-analysis.

BACKGROUND: Daytime sleepiness and sleep disorders are frequently reported in Parkinson's disease (PD). However, their impact on quality of life has been underestimated and few clinical trials have been performed. OBJECTIVES: We aimed to assess the efficacy and safety of pharmacological interventions for daytime sleepiness and sleep disorders in PD. METHODS: Systematic review of randomized controlled trials comparing any pharmacological intervention with no intervention or placebo for the treatment of daytime sleepiness and sleep problems in PD patients. RESULTS: Ten studies (n = 338 patients) were included. Four trials addressed interventions for excessive daytime sleepiness. Meta-analysis of the three trials evaluating modafinil showed a significant reduction in sleepiness, as assessed by the Epworth Sleepiness Scale (ESS) (- 2.24 points, 95% CI - 3.90 to - 0.57, p < 0.05). In one study, treatment with caffeine was associated with a non-significant improvement of 1.71 points in ESS (95% CI, - 3.57 to 0.13). The six remaining trials assessed interventions for insomnia and REM sleep Behaviour Disorder (RBD). Single study results suggest that doxepin and YXQN granules might be efficacious, while pergolide may be deleterious for insomnia and that rivastigmine may be used to treat RBD in PD patients. However, there is insufficient evidence to support or refute the efficacy of any of these interventions. No relevant side effects were reported. CONCLUSIONS: Whilst providing recommendations, this systematic review depicts the lack of a body of evidence regarding the treatment of sleep disorders in PD patients; hence, further studies are warranted.