ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson's disease.

BACKGROUND: NMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson's disease (PD). METHODS: Patients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations. RESULTS: 310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa. CONCLUSIONS: This is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.

Orthostatic hypotension: Review and expert position statement.

Orthostatic hypotension is defined as a drop in systolic blood pressure of at least 20mmHg or a drop in diastolic blood pressure of at least 10mmHg within 3minutes of standing. It is a common disorder, especially in high-risk populations such as elderly subjects and patients with neurological diseases, and is associated with markedly increased morbidity and mortality. Its management can be challenging, particularly in cases where supine hypertension is associated with severe orthostatic hypotension. Education of the patient, non-pharmacological measures, and drug adaptation are the cornerstones of treatment. Pharmacological treatment should be individualized according to the severity, underlying cause, 24-hour blood pressure profile, and associated coexisting conditions. First-line therapies are midodrine and fludrocortisone, which may need to be combined for optimal care of severe cases.

Brain FDG-PET correlates of saccadic disorders in early PSP.

BACKGROUND: New diagnostic criteria of Progressive Supranuclear Palsy (PSP) have highlighted the interest of Eye Movement Records (EMR) at the early stage of the disease. OBJECTIVES: To investigate the metabolic brain correlates of ocular motor dysfunction using [18F] Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in early PSP. METHODS: Retrospective observational descriptive study on longitudinal data with patients who underwent EMR and FDG-PET at the stage of suggestive and possible PSP according to Movement Disorders Society criteria. Longitudinal follow-up enables to confirm diagnosis of probable PSP. Using the Statistical Parametric Mapping software, we performed whole-brain voxel-based correlations between oculomotor variables and FDG-PET metabolism. RESULTS: Thirty-seven patients with early PSP who fulfilled criteria of probable PSP during the follow-up were included. Decrease in the gain of vertical saccades correlated with reduced metabolism in Superior Colliculi (SC). We also found a positive correlation between mean velocity of horizontal saccades and SC metabolism as well as dorsal nuclei in the pons. Finally, increase in horizontal saccades latencies correlated with decrease of posterior parietal metabolism. CONCLUSIONS: These findings suggest the early involvement of SC in saccadic dysfunction in the course of PSP.

Molecular imaging in Parkinsonism: The essential for clinical practice and future perspectives.

Nuclear medicine with positron emission tomography (PET) and single photon emission computed tomography (SPECT) develops powerful tools in molecular imaging to help clinicians in the challenging diagnosis of parkinsonism. These techniques can provide biomarkers for neurodegenerative parkinsonism and to distinguish Parkinson disease (PD) from atypical parkinsonism. This review summarizes the main SPECT and PET contributions to the diagnosis of parkinsonism. We will also discuss new technologies in the field of nuclear imaging and their potential contribution to the diagnosis of parkinsonian syndromes.

[Promoting responsible self-medication in the context of Parkinson's disease: Development of a practical guide for drug-drug interactions and assessment by patients and community pharmacy professionals]. / Sensibilisation à l'automédication responsable au cours de la maladie de Parkinson : réalisation de fiche sur les interactions médicamenteuses et évaluation par les patients et les professionnels de l'officine.

CONTEXT: Parkinson disease is a neurodegenerative disorder characterized by motor and non-motor symptoms. Symptomatic treatment is based on dopaminergic medications. In case of self-medication practices, there may be drug-drug interactions between over-the-counter medication and dopaminergic medications. Thus, the aim of our work was to develop a practical guide summarizing drug-drug interactions and assess it by patients and community pharmacy professionals. METHODS: We performed a systematic analysis of drug-drug interactions between OTC medications available in France and antiparkinsonians (ATC Class N04) using Theriaque® and Drugs® databases, and summarized the results in a practical guide. We assessed patients' satisfaction by a questionnaire administered to hospitalized patients in a French expert center for Parkinson's disease. We estimated the impact of the guide on community pharmacy professionals through a survey online, by satisfaction, knowledge acquisition and estimated awareness in professional context. RESULTS: We identified 16 OTC medication, related to seven symptoms, interacting with antiparkinsonians. We obtained 67 responses from patients, expressing high satisfaction. We obtained 101 responses from professionals, reporting high satisfaction, knowledge acquisition and increased awareness in professional context. CONCLUSION: Our results highlight the relevance of the guide and suggest that we may increase its dissemination to patients and community pharmacies.

Validation of a non-motor fluctuations questionnaire in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.

A randomized controlled double-blind study of rotigotine on neuropsychiatric symptoms in de novo PD.

Management of apathy, depression and anxiety in Parkinson's disease (PD) represents a challenge. Dopamine agonists have been suggested to be effective. This multicenter, randomized (1:1), double-blind study assessed the 6-month effect of rotigotine versus placebo on apathy, depression and anxiety in de novo PD. The primary outcome was the change of apathy, measured with the LARS. The secondary outcomes were the change in depression and anxiety, measured with BDI-2 and STAI-trait and state. Forty-eight drug-naive PD patients were included. The primary outcome was not reached, with a surprisingly high placebo effect on apathy (60%). There was no significant difference in the change of depression at 6 months between rotigotine and placebo. Trait-anxiety was significantly improved by rotigotine compared to placebo (p = 0.04). Compared to placebo, low dose rotigotine significantly improved trait anxiety, but not apathy and depression. The major placebo effect on apathy points towards the importance of a multidisciplinary and tight follow-up in the management of neuropsychiatric symptoms.

Subthalamic Deep Brain Stimulation Modulates Proprioceptive Integration in Parkinson's Disease During a Postural Task.

Defective proprioceptive integration may play a role in the pathophysiology of motor symptoms in Parkinson's disease (PD). Dysfunction related to proprioceptively-evoked postural reactions in PD patients is still a controversial issue, with only a limited number of studies to date and mostly discordant results. The aims of the present study were (1) to determine whether or not the proprioceptive defect in PD underlies postural impairment and (2) whether or not deep brain stimulation of the subthalamic nucleus (STN-DBS) affects proprioceptive integration. We examined proprioceptive integration during a postural task in 13 PD patients and 12 age-matched control subjects, using a muscle-tendon vibration paradigm. Analysis of the center of pressure displacement and kinematic data indicates a greater degree of postural destabilization and a reduced ability to maintain a vertical orientation in PD. We found a significant positive effect of STN-DBS on these postural features. Our findings indicate that Parkinson patients, even in the absence of any clinical evidence of instability, falls, or freezing, use proprioceptive information for postural control less efficiently than healthy subjects. Furthermore, STN-DBS was found to improve proprioceptive integration, with positive impacts on postural orientation and balance.

Prevalence and characterisation of vocal fold motion impairment (VFMI) in patients with Multiple system atrophy compared with Parkinson's disease.

INTRODUCTION: Multiple system atrophy (MSA) is a neurodegenerative disorder in which vocal fold mobility can be affected, sometimes leading to life-threatening situations. Our aim was to know if laryngeal examination could help differentiate MSA from Parkinson's disease (PD). MATERIALS AND METHODS: Between 2004 to 2014, all consecutive patients diagnosed with probable MSA were included in this retrospective, monocentric study. Flexible laryngoscopy was obtained in 51 MSA patients and compared with 27 patients with Parkinson's disease (PD). Laryngeal muscles EMG was available in 6 MSA patients. RESULTS: Vocal fold motion impairments (VFMI) was found in 35 (68.6%) MSA patients: 15 (29.4%) had uni- or bilateral vocal fold abnormal movement (VFAM), 13 (25.5%) had uni- or bilateral vocal fold abductor paresis (VFABP), 4 (7.8%) had uni- or bilateral vocal fold adductor paresis (VFADP), 10 (19.6%) had bilateral vocal fold paralysis (BVFP). VFMI was found in 13 PD patients (48.1%) all of whom had VFADP. Presence of BVFP was found associated with stridor (P<0.001) and dysphagia (P=0.002). In all muscles examined in 6 MSA patients, the EMG showed neuropathic patterns. CONCLUSIONS: Our data support that VFMI may be encountered in two-thirds of MSA with a variable degree of gravity. Laryngological examination should be considered as a supplementary tool for the diagnosis and prognosis of MSA. VFMI in particular VFAM, VFABD and BVFP should be discussed as an additional possible red flag even at an early stage of MSA and could help discriminate MSA from PD.

Parkinson's disease associated with 22q11.2 deletion: Clinical characteristics and response to treatment.

BACKGROUND: While it is known that 22q11.2 microdeletions (22q11.2-del) increase the risk of Parkinson's disease (PD), the characteristics of PD associated with 22q11.2-del have not been specifically explored. OBJECTIVE: This report aimed to assess the clinical characteristics and treatment responses of PD patients with 22q11.2-del, and to describe any features that might lead neurologists to investigate the comorbidity. METHODS: Nine PD patients (eight men, one woman) with 22q11.2-del were followed at seven centers of the French PD Expert Network (Ns-Park). RESULTS: PD diagnosis was made before 22q11.2-del diagnosis in seven cases; their main characteristics were early onset (32-48 years) and good initial levodopa sensitivity, but with a course characterized by severe and early-onset levodopa-induced motor complications and psychiatric manifestations. Three patients received deep brain stimulation (DBS) that was effective. CONCLUSION: Searching for 22q11.2-del in PD patients presenting with suggestive features is relevant as the clinical presentation is similar to idiopathic PD, but with other associated characteristics, including a severe evolution. Results with DBS are similar to those reported for idiopathic PD.

Progressive supranuclear palsy and corticobasal degeneration: Diagnostic challenges and clinicopathological considerations.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are two atypical parkinsonian syndromes first described half a century ago. The spectrum of these conditions as well as, more generally, the concept of tauopathy have dramatically changed over the past decade and especially in recent years. In particular, clinicopathological correlations have led to the description of several subtypes of these diseases and the features they share with other neurodegenerative diseases. The present paper is a review of how the concepts of PSP and CBD have evolved over time. In particular, it focuses on the different presentations of the disease and the overlapping syndromes that can complicate the differential diagnoses. Also discussed are some of the tools that may prove useful in making a diagnosis. Indeed, differential diagnosis issues are of particular importance in light of the likely emergence of pathology-specific disease-modifying therapies in the near future.

Essential tremor: Update of therapeutic strategies (medical treatment and gamma knife thalamotomy).

Tremor is a highly prevalent movement disorder that markedly reduces quality of life. The management of severe tremor is particularly challenging. Pharmacological treatment is available, but no real breakthrough has emerged recently. Propranolol and primidone are still the two most recommended agents, followed by topiramate. However, surgical treatments for medically refractory tremors are expanding. Gamma knife (GK) thalamotomy is an option particularly suitable for patients who are not candidates for deep brain stimulation. Owing to the fact that it is a non-invasive procedure without craniotomy, GK radiosurgery has almost no contraindications. Since the late 1990s, more than 250 case reports and patient series have been published. Most of these studies show that unilateral GK thalamotomy is well tolerated and reduces tremor disability. A recent study with prospective blinded assessment has confirmed its safety, together with significant improvements in tremor scores and activities of daily living.

French consensus procedure for assessing cognitive function in Parkinson's disease.

INTRODUCTION: One of the objectives of the French expert centers for Parkinson's disease (NS-Park) network was to determine a consensus procedure for assessing cognitive function in patients with Parkinson's. This article presents this procedure and briefly describes the selected tests. METHODS: A group of 13 experts used the Delphi method for consensus building to define the overall structure and components of the assessment procedure. For inclusion in the battery, tests had to be validated in the French language, require little motor participation, have normative data and be recognized by the international community. Experimental tasks and tests requiring specific devices were excluded. RESULTS: Two possibilities were identified, depending on whether an abbreviated or comprehensive assessment of cognitive function was necessary. For an abbreviated assessment, the experts recommended the Montreal Cognitive Assessment (MoCA) as a screening test for cognitive impairment or dementia. For a comprehensive neuropsychological assessment, the experts recommended assessing global efficiency plus the five main cognitive domains (attention and working memory, executive function, episodic memory, visuospatial function and language) that may be impaired in Parkinson's disease, using two tests for each domain. DISCUSSION AND CONCLUSION: A common procedure for assessing cognitive function is now available across the French network dedicated to Parkinson's disease, and is recommended for both research and clinical practice. It will also help to promote standardization of the neuropsychological assessment of Parkinson's disease.

A combined pharmacokinetic/pharmacodynamic model of levodopa motor response and dyskinesia in Parkinson's disease patients.

PURPOSE: Levodopa is the reference treatment for Parkinson's disease. However, after several years of treatment, dyskinesia may occur and strategies to overcome this side effect still need to be explored. We identified a unique population pharmacokinetic/pharmacodynamic model in Parkinson's disease to investigate the relationship and dissociability of motor response and dyskinesia. METHODS: Thirty parkinsonian patients (Hoehn and Yahr stages 3-4), treated with levodopa and suffering from peak-dose dyskinesia, were included in a prospective open-label study. They received a single dose of levodopa equal to 150 % of their usual daily dose. Blood samples, motor evaluations (UPDRS III scale) and peak-dose dyskinesia (Goetz scale) were examined after administration. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed using NONMEM software. RESULTS: Pharmacokinetic analysis identified a one-compartment model with the following parameter values [bootstrap 95 % CI]: absorption rate constant (KA) 1.86 1/h [1.08-3.25], clearance 36.6 L/h [31.3-42.8], and volume of distribution 42.9 L [34.3-52.3]. Between-subject variability was 122 % [71-183] and 38 % [26-47] for KA and clearance, respectively. Residual variability was 1120 µg/L [886-1290]. UPDRS III and dyskinesia were best described with an effect compartment and similar KE0 values of 1.37 1/h [1.01-1.77]. For UPDRS III, the E0, EC50, Emax, and Hill coefficient were 31.4 [28.4-35.3], 1410 µg/L [1200-1700], 0.72 [0.71-0.75], and 4.26 [3.20-5.58], respectively. For dyskinesia, the EC50 and Emax were 6280 µg/L [3420-37,900] and 17.9 [12.3-80.8], respectively. Residual variability was 3.15 [2.75-3.53] for UPDRS III and 2.66 [1.94-3.51] for dyskinesia. No covariates influenced the parameters. CONCLUSIONS: In patients treated with levodopa and suffering from dyskinesia, the motor response and dyskinesia have close onsets and duration effects. Maximal motor response tends to be inevitably associated with dyskinesia.