L-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: the COPARK survey.

BACKGROUND AND PURPOSE: Studies assessing the correlations between L-DOPA-induced dyskinesias (LIDs) and motor fluctuations with health-related quality of life (HRQoL) in Parkinson's disease (PD) have yielded conflicting results. This study aimed to assess the relationship between LIDs and motor fluctuations with HRQoL in patients with PD, and to assess the relative contribution of their severity and duration in a large sample of patients with PD. METHODS: A total of 683 patients with PD from the COPARK survey were evaluated. HRQoL was assessed using the 39-Item Parkinson's Disease Questionnaire (PDQ-39) (primary outcome) and 36-Item Short Form Survey (SF-36). The daily duration and severity of LIDs were obtained from Unified Parkinson's Disease Rating Scale (UPDRS) IV items 32 and 33, respectively. The daily duration of motor fluctuations was obtained from UPDRS IV item 36 and severity was estimated as the difference between the UPDRS 2 (Activities of Daily Living) score in 'OFF' versus 'ON' condition. RESULTS: A total of 235 patients with PD (35%) experienced motor fluctuations and 182 (27%) experienced LIDs. The PDQ-39 total and SF-36 physical scores were significantly worse in patients with LIDs, after adjusting for the presence of motor fluctuations. The PDQ-39 total score and SF-36 physical and mental score were significantly worse in patients with motor fluctuations, after adjusting for the presence of LIDs. The severity of LIDs and the duration of motor fluctuations significantly and independently affected PDQ-39 scores. The SF-36 physical score was affected only by the severity of motor fluctuations, whereas the mental score was not affected by any of the aforementioned variables. CONCLUSION: Our findings suggest that LIDs (mainly their severity) and motor fluctuations (mainly their duration) correlate independently with HRQoL in patients with PD.

[Continuous subcutaneous infusion of apomorphine in Parkinson's disease: retrospective analysis of a series of 81 patients]. / Le traitement par apomorphine en perfusion continue sous-cutanée dans la maladie de Parkinson : analyse rétrospective d'une série de 81 patients.

BACKGROUND: Continuous subcutaneous infusion of apomorphine (CAI) has shown efficacy in the treatment of motor fluctuations but its place in the therapeutic arsenal remains poorly defined in terms of indication, acceptability and long-term tolerance. Indeed, few studies have been carried out with a follow-up greater than 12 months. The main objective was to assess the quality of life of Parkinson's disease (PD) patients treated with CAI. We also evaluate the effectiveness on the motor fluctuations, the long-term tolerance of this treatment with its causes of discontinuation and the treatment regimens used. METHODS: We conducted a retrospective study of 81 PD patients treated with CAI between April 2003 and June 2012. Data were collected from medical records. A repeated measures analysis of variance by the linear mixed model was used (significance level: 5%). RESULTS: In August 2012, 27/81 patients were still treated with CAI with a mean duration of 28 months, 46/81 discontinued CAI (9 precociously), and 8 were lost to view. We didn't show improvement in the quality of life nor efficacy of CAI on the UPDRS IV score (P=0.54) and dyskinesia score (P=0.95). The CGI score patient also reflects this result with a majority response suggesting no significant change with CAI. We observed relative good cognitive and psychiatric tolerance. Adverse events were frequent but often benign. The average (±SD) rate of apomorphine was 3.15±1.71 mg/h and the oral dopaminergic treatment was decreased by 37.8%. DISCUSSION: The results are consistent with the literature except for the lack of efficiency on motor fluctuations which may be due to the use of too small doses of apomorphine. This seems to be a leading cause of discontinuation of CAI, especially when it is associated with side effects or important constraints. For better efficiency on motor fluctuations, we recommend the use of apomorphine at higher doses to obtain an optimal continuous dopaminergic stimulation.

[Impulse control disorders in Parkinson's disease: A cohort of 35 patients]. / Troubles du contrôle des impulsions associés à la maladie de Parkinson : étude d'une cohorte de 35 patients.

INTRODUCTION: Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated with dopamine agonist treatment. Although discontinuation of dopamine agonist is recommended, ICD management has not been precisely stated. The aims of the study were to describe demographic and clinical characteristics in a group of PD patients with ICDs and to evaluate the management of dopamine agonist treatment proposed to the same patients in order to treat the ICDs. METHODS: Thirty-five PD patients with ICD and 607 PD patients without ICD were studied. In the ICD group, demographic and clinical data were collected prospectively (ICD characteristics, motor and cognitive evaluation); demographic and clinical data were obtained retrospectively in the group without ICD. RESULTS: In the ICD group, the sex ratio was 2.9 (versus 1.2 in the absence of ICD; p<0.05), the mean age was 57.5 years (versus 66.9 years; p<0.01) and the mean age at PD onset was 48.3 years (versus 55.5 years; p<0.01). All ICD patients were receiving a dopamine agonist when the ICD started (versus 50.9 % of patients receiving a dopamine agonist in the absence of ICD; p<10(-6)). In mean, ICDs started 2.8 years before they were diagnosed. No particular dopamine agonist was associated with ICDs more frequently than the others. Discontinuation of the dopamine agonist was the treatment the more frequently associated with the recovery of ICDs (93.3 %). Dose lowering and the change of dopamine agonist resulted in complete regression of ICDs respectively in 9.1% and 33.3% of patients. CONCLUSION: Young age, male gender and young age at PD onset are frequent in PD patients developing ICDs, as already described in American or Asian cohorts. We highlighted a long diagnosis delay and confirmed the strong efficacy of dopamine agonist withdrawal.

Oro-buccal symptoms (dysphagia, dysarthria, and sialorrhea) in patients with Parkinson's disease: preliminary analysis from the French COPARK cohort.

INTRODUCTION: Abnormal oro-buccal functions including dysarthria, sialorrhea and dysphagia commonly affect patients with Parkinson's disease (PD). OBJECTIVES: To estimate the prevalence of such oro-buccal symptoms at baseline in the first 419 patients with PD included in the COPARK cohort and to analyze their correlations with patients' demographics, clinical characteristics, and drugs consumption. METHODS: Patients were assessed using the Unified PD Rating Scale, the Hospital Anxiety and Depression Scale, and the PDQ-39. Dysarthria, sialorrhea, and dysphagia were defined as UPDRS items 5, 6, or 7 ≥ 1. RESULTS: Dysarthria, sialorrhea, or dysphagia were present in 51%, 37%, or 18% out of the 419 patients, respectively. At least one of these symptom was present in 267/419 patients (65%), whilst a combination of symptoms was present in 136/419 (33%). Logistic regression showed that the presence of each of the three oro-buccal symptoms was significantly correlated with that of the two others. Other correlations included male gender, hallucinations, disease severity, levodopa use and lack of opiates consumption for dysarthria; disease severity, orthostatic hypotension and absence of antidepressants consumption for sialorrhea; female gender, motor fluctuations, and depressive symptoms for dysphagia. None of the three oro-buccal symptoms were associated with a reduced PDQ-39 score. CONCLUSION: Oro-buccal symptoms were present in two of three patients with moderate PD, the presence of each symptoms being significantly correlated with that of the two others.

Effect of bilateral subthalamic nucleus deep brain stimulation on postural adjustments during arm movement.

OBJECTIVE: Although it is well known that postural adjustment (PA) is impaired in advanced Parkinson's disease (PD), the potentially compensatory effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in this respect are less clear. METHODS: While standing on a force platform and in the absence of antiparkinsonian medication, 10 patients performed voluntary, unilateral arm movements before surgery (the 'off stim' condition) and then afterwards (the 'on stim' condition). The patients' PAs were monitored by vertical torque (Tz) and compared with those recorded in control subjects. RESULTS: Patients with STN DBS and control subjects showed similar values for PA amplitude, duration and latency. CONCLUSIONS: STN stimulation may induce better postural control during the movement preparation and execution phases. Our results argue in favour of a positive effect of STN DBS on PA. SIGNIFICANCE: The PA amplitude (provided by Tz) may be a strong marker reflecting the clinical improvement seen in stimulated PD patients.

Deregulation of the hypoxia inducible factor-1α pathway in monocytes from sporadic amyotrophic lateral sclerosis patients.

The clinical course of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) is closely related to hypoxia. The normal response to hypoxia involves two pathways in particular: the hypoxia inducible factor 1α (HIF-1α) pathway (which notably controls the synthesis of vascular endothelial growth factor (VEGF)) and the nuclear factor kappa B (NF-κb) pathway (responsible for the production of inflammatory mediators, including prostaglandin E2 (PGE2)). Defects in VEGF gene expression are known to cause motor neuron degeneration in animal models. Circulating monocytes are precursors of the microglia, which are involved in the pathogenesis of ALS. To establish whether the HIF-1 and/or NF-κB pathways are deregulated during hypoxia in early-stage, sporadic ALS, we analyzed the response to acute (1 h) and prolonged (24 h) hypoxia in monocytes from ALS and healthy controls. We measured protein expression and mRNA transcription for VEGF, HIF-1, HIF-2, prolyl hydroxylases 1 and 2 (PHD-1 and -2, part of the HIF proteasome-dependent degradation pathway) and their modulation by PGE2. Our results showed that (i) the HIF-1 (but not HIF-2) and VEGF production induced by acute and prolonged hypoxia was selectively and markedly altered in ALS patients and (ii) this defect was not compensated for by PGE2 addition. Moreover, altered HIF-1α activation was associated with low levels of proteolysis by PHD-2 in cells from sporadic ALS patients (relative to controls). For the first time, we have demonstrated clinical and functional abnormalities in the HIF-1 pathway during hypoxia in monocytes from sporadic ALS patients.

[Mechanisms of deregulated response to hypoxia in sporadic amyotrophic lateral sclerosis: a clinical study]. / Mécanismes de dérégulation de la réponse à l'hypoxie dans la sclérose latérale amyotrophique.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor kappa-B (NFkappa-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-alpha, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFkappa-B pathway since the isolated desaturation stage (IL-6, TNF-alpha, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.

Characterization of DCTN1 genetic variability in neurodegeneration.

OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Reduced levodopa-induced complications after 5 years of subthalamic stimulation in Parkinson's disease: a second honeymoon.

The purpose of this paper is to describe the effect of 5 years of subthalamic nucleus deep brain stimulation (STN DBS) on levodopa-induced complications, both in everyday life and during an acute challenge with levodopa. Thirty three patients were evaluated during an acute levodopa challenge before surgery and then 1 and 5 years afterwards (both off stim and on stim), using the UPDRS III scale and the CAPSIT-PD scales for dystonia and peak-dose dyskinesia. The UPDRS IV scale was used to assess motor complications in everyday life. The levodopa daily dose and DBS parameters were also recorded. Levodopa-induced complications in everyday life (UPDRS IV) and during an acute levodopa challenge had improved markedly after 1 year (both on and off stim) and still further at 5 years. Peak-dose dyskinesia decreased between the 1- and 5-year measurements. STN DBS decreases levodopa-induced motor complications over the long term. This phenomenon may be explained by (a) overall stabilization of the basal ganglia network and (b) striatal synaptic changes. Our results suggest that DBS leads to both qualitative and quantitative modulations in the corticostriatal loops.

Molecular analyses of the LRRK2 gene in European and North African autosomal dominant Parkinson's disease.

BACKGROUND: Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (ADPD), the most common of which is the p.G2019S substitution that has been found at varying frequencies worldwide. Because of the size of the LRRK2 gene, few studies have analysed the entire gene in large series of ADPD families. METHODS: We performed extensive mutation analyses of all 51 coding exons of the LRRK2 gene in index cases from 226 Parkinson's disease families compatible with autosomal dominant inheritance, mostly from France (n = 182) and North Africa (n = 14). RESULTS: We found 79 sequence variants, 29 of which were novel. Eight potentially or proven pathogenic mutations were found in 22 probands (9.7%). There were four novel amino acid substitutions that are potentially pathogenic (p.S52F, p.N363S, p.I810V, p.R1325Q) and two novel variants, p.H1216R and p.T1410M, that are probably not causative. The common p.G2019S mutation was identified in 13 probands (5.8%) including six from North Africa (43%). The known heterozygous p.R1441H and p.I1371V mutations were found in two probands each, and the p.E334K variant was identified in one single patient. Most potentially or proven pathogenic mutations were located in the functional domains of the Lrrk2 protein. CONCLUSION: This study leads us to conclude that LRRK2 mutations are a common cause of autosomal dominant Parkinson's disease in Europe and North Africa.

Deficient "sensory" beta synchronization in Parkinson's disease.

OBJECTIVE: Beta rhythm movement-related synchronization (beta synchronization) reflects motor cortex deactivation and sensory afference processing. In Parkinson's disease (PD), decreased beta synchronization after active movement reflects abnormal motor cortex idling and may be involved in the pathophysiology of akinesia. The objectives of the present study were to (i) compare event-related synchronization after active and passive movement and electrical nerve stimulation in PD patients and healthy, age-matched volunteers and (ii) evaluate the effect of levodopa. METHODS: Using a 128-electrode EEG system, we studied beta synchronization after active and passive index finger movement and electrical median nerve stimulation in 13 patients and 12 control subjects. Patients were recorded before and after 150% of their usual morning dose of levodopa. RESULTS: The peak beta synchronization magnitude in the contralateral primary sensorimotor (PSM) cortex was significantly lower in PD patients after active movement, passive movement and electrical median nerve stimulation, compared with controls. Levodopa partially reversed the drop in beta synchronization after active movement but not after passive movement or electrical median nerve stimulation. DISCUSSION: If one considers that beta synchronization reflects sensory processing, our results suggest that integration of somaesthetic afferences in the PSM cortex is abnormal in PD during active and passive movement execution and after simple electrical median nerve stimulation. SIGNIFICANCE: Better understanding of the mechanisms involved in the deficient beta synchronization observed here could prompt the development of new therapeutic approaches aimed at strengthening defective processes. The lack of full beta synchronization restoration by levodopa might be related to the involvement of non-dopaminergic pathways.

[Classification of parkinsonian syndromes via factorial discriminant analysis of brain SPECT data]. / Intérêt de l'analyse factorielle discriminante pour classer les syndromes parkinsoniens à partir de la tomoscintigraphie d'émission monophotonique.

INTRODUCTION: The objective was to assess the value of single photon emission computerized tomography (SPECT) and factorial discriminant analysis (FDA) in the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). PATIENTS AND METHODS: Sixty-two patients with clinical diagnoses of either CBD, PSP or PD were studied using brain HmPaO-SPECT. Thirteen pairs of regions of interest (ROIs) were drawn on the slices located 50mm and 90mm above the canthomeatal plane. Twenty-six uptake indices and 13 asymmetry indices were determined. FDA was performed in order to determine whether or not the patients could be classified into the correct clinical group on the basis of SPECT data alone. The most discriminant parameters were used to generate two predictive scores, which were tested in a second group of 15 patients. RESULTS: FDA of all 39 variables correctly classified all the patients. A subset of 10 variables was used to build predictive scores, which correctly classified 90% of PD patients, 100% of PSP patients and 86% of CBD patients. When tested in the validation group of 15 patients, these predictive scores correctly classified 87% of the individuals. The frontal medial, temporoparietal and parietal regions were the most discriminant. CONCLUSION: Using SPECT data alone, this study enabled us to distinguish between PD, PSP and CBD in patients with clear clinical presentations of the diseases in question. This novel, statistical approach provides reliable information. However, a prospective study dealing with de novo parkinsonian syndromes will be necessary.

[Continuous dopaminergic stimulation by Duodopa in advanced Parkinson's disease: Efficacy and safety]. / Intérêts de la stimulation dopaminergique continue par Duodopa((R)) dans la maladie de Parkinson évoluée : efficacité et tolérance.

INTRODUCTION: When advanced Parkinson's disease (PD) patients experience motor complications (fluctuations and dyskinesias) despite standard oral treatment, two treatment options are available: deep brain stimulation and subcutaneous apomorphine infusion with respects of indications for each strategy. Continuous intraduodenal infusion of levodopa (Duodopa) via a gastrojejunal tube may be proposed at this stage of the disease and the study of indications and clinical results with Duodopa may develop this new therapeutic alternative. PATIENTS AND METHODS: Seven patients with advanced PD (dementia for all and psychiatric disorders for some of them, axial signs) were treated with Duodopa. We evaluated neuropsychological functions, all UPDRS scales, gait and quality-of-life just before Duodopa onset and six months after treatment end. Moreover, we described all adverse events (early and late) and studied daily levodopa doses before and 6 months after treatment. RESULTS: We demonstrated an improvement in motor UPDRS (44%), in axial signs (40% for UPDRS part III axial subscore and 12% for gait) and a reduction of fluctuations (37.5%) and in UPDRS part IV dyskinesia (20%). These significant results are observed without any change in the quality-of-life. Adverse events were due to PEG positioning for four patients, the equipment (pump, connection, inner tube) for all patients and levodopa for four patients. Daily levodopa dose had to be increased 13.5%. CONCLUSION: Duodopa can be considered as a new treatment strategy providing significant improvements in motor fluctuations, dyskinesia and severe axial signs. These results were demonstrated in very advanced PD patients, who had been excluded from previous studies, with cognitive disorders and for some of them dopaminergic psychosis well controlled by medications.

[Issues of France's "Leonetti Act": Involvement of amyotrophic lateral sclerosis patients in prior discussions concerning respiratory support and end-of-life care]. / Les enjeux de la loi Leonetti: participation des patients atteints de sclérose latérale amyotrophique à une discussion anticipée sur la réanimation respiratoire et les soins de fin de vie.

In accordance with the principle of personal autonomy, expert consensus statements on amyotrophic lateral sclerosis (ALS) recommend early engagement with terminal-phase patients on the type of symptomatic treatment to be administered in the event of respiratory failure, since decompensation progresses too rapidly to allow time for a discussion. The French Parliamentary Act on Patients' Rights and End-of-Life Care (dated 22 April 2005) grants individuals the right to refuse unreasonable treatment and obliges physicians to take account of any prior instructions given by a person before he/she became incapable of communicating. The provision of prior instructions is a very reassuring situation for the physician: the autonomous patient indicates his or her choice of end-of-life care. However, there are two pitfalls which must be avoided: (i) holding a discussion for the sole purpose of obtaining prior instructions and (ii) not acknowledging the patient's vulnerability. The present study dealt with 35 ALS patients for whom the question of either intensive care or palliative end-of-life care remained open. Even though the great majority of these individuals were keen to know their exact state of health, 48% refused to consider this circumstance and only 20% expressed prior instructions. These results prompted us to question the ethical dimension of the concept of autonomy beyond its founding formulation: can one envisage an incapacity to confront oneself with the existential question of possible death? In 80% of cases, the physician will have to take a care decision in the absence of any prior instructions from the patient. This amounts to more than respecting a person's autonomy and involves exercising medical responsibility.

Externally provoked freezing of gait in open runways in advanced Parkinson's disease results from motor and mental collapse.

Freezing of gait (FOG) in Parkinson's disease (PD) is defined as a sudden inability to maintain effective stepping movements. However, its pathophysiology remains unclear. The objectives are: (1) To assess the contribution of both spatial (walking speed, stride length) and temporal parameters (cadence, stride time) and their coefficients of variation to the genesis of FOG in PD. (2) To evaluate whether and how externally imposed modifications of self-determined gait would elicit FOG. We included ten patients with advanced PD, and with daily off drug FOG episodes. We focused on walking in an open runway. For each subject, we manipulated gait by externally imposing four changes in walking speed and four changes in cadence. FOG episodes, often with a long duration of more than 5-s, were observed mostly under conditions with a high imposed cadence. The steps that immediately preceded these episodes were mainly characterized by an increase in cadence and an increase in stride length variability. The results also underscore that FOG can be elicited in a laboratory setting when patients are placed under considerable strain, at least in advanced stages of PD. Patients were unable to adequately negotiate the extreme imposed cadence condition, and this resulted in frequent FOG episodes, even while walking in an open runway. Placing advanced PD patients into extreme imposed conditions leads to a motor wise and mental collapse response, culminating in FOG. Future work should establish the relevance of these findings for the more common forms of FOG, including brief episodes during turning or gait initiation.

Seizure after use of almotriptan.

We report the case of a young woman who suffered from a seizure after use of almotriptan. There was a recurrence with ergotamine. We discuss possible link with susceptibility genes.