Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Late cortical disinhibition in focal hand dystonia.

In writer's cramp (WC), a form of focal hand dystonia, cortical GABAergic inhibitory mechanisms are altered and may cause involuntary tonic contractions while writing. The objective of this study was to explore the time course of long-interval intracortical inhibition (LICI) that involves gamma-amino butyric acid (GABA)-B transmission and late cortical disinhibition (LCD) (that combines GABA-A and GABA-B mechanisms) in patients with WC and in control subjects. A double pulse transcranial magnetic stimulation protocol was used to evoke LICI and LCD while the subjects either gripped a cylinder between their thumb and index fingers or relaxed all their upper limb muscles. We measured the ratio between primed and unprimed motor evoked potential in the first dorsal interosseous at interstimulus intervals ranging between 60 and 300 ms. Though the cortical silent period was not different between the groups, LICI lasted longer in patients with WC, that is, LCD was delayed for more than 30 ms and reached a higher level. In addition to the alteration of inhibitory mechanism mediated by GABA-B transmission, LCD which probably involves presynaptic inhibition is also modified in patients with WC with possible consequences on the activity of primary motor cortex inhibitory and excitatory circuits which control the hand muscles.caus.

Dose per muscle in cervical dystonia: pooled data from seven movement disorder centres.

AIM OF STUDY: Botulinum neurotoxin type A (BoNT/A) injections are the established treatment in cervical dystonia (CD). But clinical practice regarding the choice of muscles into which injections are made varies between centres. Until now, there have been no dose-per-muscle recommendations based on 'searching the dose' clinical trial data. CLINICAL RATIONALE FOR STUDY: We therefore examined the dosages under real world conditions at seven international movement disorders centres, using an identical clinical approach. RESULTS: We examined 305 patients with CD (55.6 ± 13.2 years, 204 female). The most commonly injected muscles were the splenius capitis (84.9%), sternocleidomastoid (80.3%), trapezius (59.7%), levator scapulae (49.8%), semispinalis capitis (39%), and obliquus capitis inferior (36.7%). The mean total dose per treatment session with aboBoNT/A was 652.5 (SD = 285.5), with onaBoNT/A it was 159.5 (SD = 62.4), and with incoBoNT/A it was 173.4 (SD = 99.2) units. The doses injected into each muscle in the ona- or incoBoNT/A groups were between 19.7 and 48.2 units, with the highest dose for the splenius capitis with 49.2 ± 26.0 units. The doses in the aboBoNT/A group were between 69.6 and 146.4 units, and the highest dose being injected into the splenius capitis (139.6 ± 80.7 units). CONCLUSIONS AND CLINICAL IMPLICATIONS: In clinical trials the doses per muscle are based on an arbitrary decision. In our study, the doses were lower than in other studies, which may be due to the number of muscles per session, the use of ultrasound guidance (and therefore more precise injections), as well as the use of the Col-Cap concept. Our results exemplify everyday practice, and may help as the basis for recommendations and further investigations.

Frequency of different subtypes of cervical dystonia: a prospective multicenter study according to Col-Cap concept.

Patients with cervical dystonia (CD) may present with head and/or neck movements in the coronal, sagittal or transverse plane. According to the Col-Cap concept, CD postures are classified in torti-, latero-, ante- and retrocollis/caput patterns. The frequency of these different subtypes has to be evaluated. Between January and June 2019, we examined 306 patients (55.5 ± 13.1 years, 67% female) with CD according to the Col-Cap concept. They were all treated with botulinum toxin. This prospective study took place in seven different movement disorder centers. The most common primary form was torticaput (49%), the second most common was laterocaput (16.7%). All other subtypes were less than 10% of the study population. Pure forms were observed in 16.3% of patients only. Torticaput was combined in 46% with laterocaput, and in 20.7% with retrocaput. Laterocaput was combined mainly with torticaput (45.1%), laterocollis (33.2%) or retrocaput (23.5%). Shift forms were found in 14.7%, but diagnosed only in 3.9%. On average, the patients had 2.51 (± SD 1.09) subtypes each. Tremor was observed in 55.6%. The mean number of injected muscles was 4.4 (SD 1.6). The most often injected muscles were splenius capitis (83%), sternocleidomatoideus (79.1%), and upper trapezius (58.5%). This is the first multicenter study to examine the frequency of different subtypes of CD according to the Col-Cap concept. The caput subforms are more common than the cervical types, with torticaput as the most common one. Shift forms were diagnosed less often than described. Pure forms are very rare, combinations of 2-6 subtypes are common (83.7%). Sternocleidomatoideus, splenius capitis and trapezius muscles were still injected most often, but the muscles rarely injected in the past such as levator scapulae (48.7%), obliquus capitis inferior (35.3%) and longissimus (16.7%) were considered quite often. Since optimal therapy results depend on the injection of the right muscles, the correct classification should optimize the treatment outcome.

Centrosomal cohesion deficits as cellular biomarker in lymphoblastoid cell lines from LRRK2 Parkinson's disease patients.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD), and orally bioavailable, brain penetrant and highly potent LRRK2 kinase inhibitors are in early stages of clinical testing. Detection of LRRK2 phosphorylation, as well as phosphorylation of Rab10, a LRRK2 kinase substrate, have been proposed as target engagement biomarkers for LRRK2 inhibitor clinical trials. However, these readouts do not seem able to stratify patients based on enhanced LRRK2 kinase activity. Here, we describe a robust cell biological assay based on centrosomal cohesion alterations which were observed in peripheral blood mononuclear cell-derived lymphoblastoid cell lines (LCLs) from patients with G2019S LRRK2 mutations as compared with healthy controls, and could also be detected in a subset of sporadic PD patient samples. We suggest that LCLs may be a valuable resource for LRRK2 research, and that determination of centrosomal cohesion deficits may assist in the stratification of a subset of sporadic PD patients.

Preferred muscles in cervical dystonia.

The classification of abnormal posture and the assessment of the affected muscles in cervical dystonia (CD) have changed in recent years. To determine the frequency of injected muscles, we studied 306 patients with CD. The mean age was 55.5 ± 13.1 years (range 21-90), 67% were female. Splenius capitis was the most commonly injected muscle (83%), followed by sternocleidomastoid (79.1%), and trapezius muscles (58.5%). The three next most common were the levator scapulae, semispinalis capitis, and obliquus capitis inferior muscles. The study shows that the most commonly injected muscles have remained unchanged over the past few decades, although the concept has changed. However, several new muscles have been added that were previously never, or hardly ever, considered.

Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 ± 8 vs 63 ± 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. © 2018 International Parkinson and Movement Disorder Society.

Translation initiator EIF4G1 mutations in familial Parkinson disease.

Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3e binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.

Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial.

BACKGROUND: Even with optimal dopaminergic treatments, many patients with Parkinson's disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine's ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. METHODS: We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. FINDING: 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from -11.5 (-15/-7) at baseline to -20 (-25/-12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: -0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. INTERPRETATION: Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. REGISTRATION: Clinicaltrials.gov reference: NCT00767091.

The Use of Image Guided Programming to Improve Deep Brain Stimulation Workflows with Directional Leads in Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for parkinsonian patients with severe motor fluctuations. Proper targeting of the STN sensorimotor segment appears to be a crucial factor for success of the procedure. The recent introduction of directional leads theoretically increases stimulation specificity in this challenging area but also requires more precise stimulation parameters. OBJECTIVE: We investigated whether commercially available software for image guided programming (IGP) could maximize the benefits of DBS by informing the clinical standard care (CSC) and improving programming workflows. METHODS: We prospectively analyzed 32 consecutive parkinsonian patients implanted with bilateral directional leads in the STN. Double blind stimulation parameters determined by CSC and IGP were assessed and compared at three months post-surgery. IGP was used to adjust stimulation parameters if further clinical refinement was required. Overall clinical efficacy was evaluated one-year post-surgery. RESULTS: We observed 78% concordance between the two electrode levels selected by the blinded IGP prediction and CSC assessments. In 64% of cases requiring refinement, IGP improved clinical efficacy or reduced mild side effects, predominantly by facilitating the use of directional stimulation (93% of refinements). CONCLUSIONS: The use of image guided programming saves time and assists clinical refinement, which may be beneficial to the clinical standard care for STN-DBS and further improve the outcomes of DBS for PD patients.

Prognosis of impulse control disorders in Parkinson's disease: a prospective controlled study.

BACKGROUND: The long-term prognosis of impulsive compulsive disorders (ICD) remains poorly studied in Parkinson's disease (PD). OBJECTIVE: Evaluating the natural history of ICD and its impact on PD symptoms including cognition and treatment adjustments. MATERIALS AND METHODS: We assessed PD patients at baseline (BL) with (BL-ICD+) or without (BL-ICD-) ICD despite dopamine agonist (DA) exposure of > 300 mg levodopa-equivalent daily dose for > 12 months at baseline and after more than two years of follow-up. ICD were assessed using the Ardouin's Scale of Behaviors in PD (ASBPD), cognition using the Mattis scale, and PD symptoms using the UPDRS score. Treatment adjustments, DA withdrawal-associated symptoms, and ICDs social consequences were recorded. RESULTS: 149 patients were included (78 cases and 71 controls), mean duration of follow-up was 4.4 ± 1 years. At baseline, psychiatric disorders were more common among BL-ICD + (42.3 vs 12.3% among BL-ICD-, p < 0.01). At follow-up, 53.8% of BL-ICD + were not ICD-free while 21.1% of BL-ICD- had developed ICD. BL-ICD + more frequently experienced akinesia (21.8 vs 8.5%, p = 0.043) and rigidity worsening (11.5 vs 1.4%, p = 0.019) following therapeutic modifications. Decision to decrease > 50% DA doses (12.8 vs 1.4%, p = 0.019) or to withdraw DA (19.2 vs 5.6%, p = 0.025) was more frequently considered among BL-ICD+ . At follow-up, the prevalence of cognitive decline was lower among BL-ICD + (19.2 vs 37.1%, p = 0.025). CONCLUSION: ICDs were associated with increased psychiatric burden at baseline and better cognitive prognosis. Most patients were still showing ICDs at the follow-up visit, suggesting ICD to be considered as a chronic, neuropsychiatric disorder.

Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson's disease and pharmacodynamic biomarkers.

Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.

Accuracy of non-guided versus ultrasound-guided injections in cervical muscles: a cadaver study.

INTRODUCTION: The col-cap concept encouraged neurologists to inject a large group of muscles in the treatment of cervical dystonia. This includes deep muscles such as the obliquus capitis inferior or the semispinalis capitis, and muscles close to vascular or neurological structures such as scalene muscles. Our aim was to determine the accuracy of injections in cervical muscles using ultrasonography (US) or palpation of anatomical landmarks. METHODS: A mix of paint, gelatin and iodized contrast agent was injected in nine pairs of cervical muscles of human cadavers, according to two injection techniques: US-guided and non-guided. The dye was localized on 1 cm-thick, frozen slices. RESULTS: A total of 102 muscles was injected in the US-guided group (n = 8). The global accuracy was 88.2%. The lowest accuracy was in the OCI (41.7%); trying to avoid the vertebral artery, injections were too medial. A total of 54 muscles was injected in the non-guided group (n = 3). The global accuracy was 48.0%; moreover, some dye was found in four blood vessels. The embalming process produced texture changes, making difficult the palpation of bony landmarks. CONCLUSIONS: Our results indicate that US-guided injections are more accurate than non-guided injections in most cervical muscles.

Differing short-term neuroprotective effects of the fibrates fenofibrate and bezafibrate in MPTP and 6-OHDA experimental models of Parkinson's disease.

Earlier study from our group indicated that the peroxisome proliferator-activated receptor-alpha agonist fenofibrate prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss in C57Bl/6 mice. Our objective was to determine whether or not fibratescan improve motor activity in two experimental models of Parkinson's disease: the MPTP C57Bl/6 mouse and the 6-hydroxydopamine (6-OHDA) Wistar rat. Six groups of mice were set up: sham, sham-fenofibrate, sham-bezafibrate, MPTP, MPTP-fenofibrate and MPTP-bezafibrate. Mice were fed a diet containing 0.2% fenofibrate, 0.2% bezafibrate or no hypolipidaemic agent for 2 weeks. Four groups of rats were set up: sham, sham-fenofibrate, 6-OHDA and 6-OHDA-fenofibrate. Rats were fed a diet containing 0.2% fenofibrate or no hypolipidaemic agent for 4 weeks. In mice, motor activity was quantified using actimetry. Nine parameters were recorded. The results were analyzed with a mixed linear model. In rats, behavioural sensitization was studied with repetitive injections of apomorphine. All the actimetry parameters indicated a decrease of locomotion the day after MPTP injections and eight parameters improved in MPTP mice treated with fenofibrate or bezafibrate. The apomorphine-induced rotation behaviour mildly decreased in 6-OHDA rats treated with fenofibrate, but behavioural sensitization was unchanged. The 6-OHDA and MPTP compounds have different toxicity mechanisms, which could explain why we did not observe the same effect in 6-OHDA rats as in MPTP mice. These data suggest that the protective effect of fibrates can be carried through inhibition of inflammation rather than oxidative stress.

Tremor in Idiopathic Cervical Dystonia - Possible Implications for Botulinum Toxin Treatment Considering the Col-Cap Classification.

Background: Tremor is an important phenotypic feature of dystonia. Using the new concept (Col-Cap) of classification we examined the frequency of tremor in cervical dystonia (CD) patients, their main subtypes and muscles injected. Methods: In this large study conducted at multiple movement disorder centres in Europe and India, between January and June 2019, we examined 293 patients with idiopathic CD who were all treated with botulinum toxin (BTX). Results: The dystonic head tremor (DHT+) was present in 57.6 % of CD patients and they had a significantly longer duration of symptoms than patients without head tremor (DHT-). In DHT+ patients torticaput was the most common subtype and the majority (63.3%) had one or two subtypes only. There was no significant difference between the number of unilateral injections for any of the muscles in the DHT+ and DHT- groups, while the number of patients receiving bilateral injections in splenius capitis (78 vs 25; p = 0.00001), sternocleidomastoid (31 vs 6; p = 0.0005), trapezius (28 vs 9; p = 0.01), and obliquus capitis inferior (15 vs 2; p = 0.008) were significantly more in the DHT+ group. The mean doses of all three types of BTX/A were not significantly different between the two groups. Conclusions: The frequency of head tremor was 57.6% in our CD patients and torticaput was the most common dystonic subtype associated with tremor. Simple forms of CD seemed more likely associated with head tremor, than complex forms of CD. Most of the DHT+ patients received bilateral injections. The use of 'Col-Cap' classification was helpful in the identification of muscles likely to be involved in tremor in CD patients.

Myoclonus of peripheral origin: two case reports.

The concept of peripheral myoclonus is not yet fully accepted by the medical community because of the difficulty in establishing a cause-and-effect relationship between trauma and subsequent movement disorders. Here, we report two cases of patients suffering from peripheral myoclonus after nerve injury. The first patient experienced myoclonus of the 4th dorsal interosseous muscle several days after trauma to the elbow. The second patient presented myoclonus of the arm stump (combined with phantom-limb pain) 1 year after amputation. In both cases, central nervous system function (spine and brain imaging, somesthetic evoked potentials, EEG back-averaging) was normal. For the second patient, local infiltration of xylocaine and botulinum toxin into the stump scar rapidly stopped myoclonus and pain. Nerve injury induces ephaptic transmission and ectopic excitation. The physiopathological mechanisms of this type of myoclonus involve a peripheral generator that induces central (spinal) generator activity.

Lipid-lowering drugs are associated with delayed onset and slower course of Parkinson's disease.

Fibrates and statins activate the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). This nuclear receptor regulates genes governing inflammation, apoptosis and oxidative stress, three important mechanisms of neuronal death in Parkinson's disease (PD). We retrospectively studied the effect of statins and fibrates in a cohort of 419 patients with PD. In PD patients receiving either a statin or a fibrate, the mean age of disease onset was delayed by nearly 9 years, when compared with (control) PD patients not taking a lipid-lowering treatment. According to a mixed linear model, the increase in the levodopa-equivalent daily dose over 2 years was significantly smaller in the group taking a statin (+24 mg) than in the matched control group (+212 mg) (p=0.004), whereas the Unified Parkinson's Disease Rating Scale motor score progression was similar. The course of the disease in patients taking a fibrate did not differ from the controls. These data suggest that lipid-lowering drugs may have a disease modifier effect, with a stronger action for statins than for fibrates.

Treatment with Botulinum Neurotoxin Improves Activities of Daily Living and Quality of Life in Patients with Upper Limb Tremor.

Background: Botulinum neurotoxin's degree of effectiveness on upper limb tremor is subject to debate; although this treatment reduces the tremor's amplitude, a clear functional benefit has not been demonstrated. The objective of this study was to assess the effect of botulinum neurotoxin type A treatment on activities of daily living and quality of life in patients with upper limb tremor. Methods: We retrospectively examined the medical records of 50 consecutive patients treated with botulinum neurotoxin for upper limb tremor that was refractory to oral medication. One month after the injection, the patient was evaluated according to the Quality of Life in Essential Tremor Questionnaire, and the Essential Tremor Embarrassment Assessment. Results: Full data sets were available for 38 patients suffering variously from essential tremor (n = 21), Holmes tremor secondary to a focal brain lesion (n = 8), idiopathic dystonic tremor (n = 4), primary writing tremor (n = 4), and Parkinson's disease (n = 1). The Quality of Life Essential Tremor Questionnaire and the Essential Tremor Embarrassment Assessment scores improved significantly (p < 0.001) in the study population as a whole, and in the essential tremor and Holmes tremor subgroups. Discussion: Botulinum neurotoxin treatment of patients with upper limb tremor is associated with improved quality of life and activities of daily living, irrespective of the tremor's etiology. Long-term treatment enables the physician to adjust the injection strategy to the patient's needs. Our study was limited by its retrospective design. The results must therefore be confirmed in a prospective, double-blind, placebo-controlled, randomized clinical trial.