OnabotulinumtoxinA muscle injection patterns in adult spasticity: a systematic literature review

BACKGROUND: OnabotulinumtoxinA has demonstrated significant benefit in adult focal spasticity. This study reviews the injection patterns (i.e., muscle distribution, dosing) of onabotulinumtoxinA for treatment of adult spasticity, as reported in published studies. METHODS: A systematic review of clinical trials and observational studies published between 1990 and 2011 reporting data on muscles injected with onabotulinumtoxinA in adult patients treated for any cause of spasticity. RESULTS: 28 randomized, 5 nonrandomized, and 37 single-arm studies evaluating 2,163 adult patients were included. The most frequently injected upper-limb muscles were flexor carpi radialis (64.0% of patients), flexor carpi ulnaris (59.1%), flexor digitorum superficialis (57.2%), flexor digitorum profundus (52.5%), and biceps brachii (38.8%). The most frequently injected lower-limb muscles were the gastrocnemius (66.1% of patients), soleus (54.7%), and tibialis posterior (50.5%). The overall dose range reported was 5–200 U for upper-limb muscles and 10–400 U for lower-limb muscles. CONCLUSIONS: The reviewed evidence indicates that the muscles most frequently injected with onabotulinumtoxinA in adults with spasticity were the wrist, elbow, and finger flexors and the ankle plantar flexors. OnabotulinumtoxinA was injected over a broad range of doses per muscle among the studies included in this review, but individual practitioners should be mindful of local regulatory approvals and regulations

Objective Quantification of Neuromotor Symptoms in Parkinson's Disease: Implementation of a Portable, Computerized Measurement Tool

Quantification of neuromotor symptoms with device-based measures provides a useful supplement to clinical evaluation. Research using the CATSYS has established its utility as a computerized measurement system to quantify neuromotor function. The primary objective of this study is to provide technical guidance on the use of the CATSYS in Parkinson's disease (PD). Forty-four patients with idiopathic PD and 28 healthy controls were prospectively recruited and evaluated with CATSYS, a portable, Windows-based system consisting of a data logger and four different sensors (tremor pen, touch recording plate, reaction time handle, and force plate for balance recording) for quantification of neuromotor functions. CATSYS discriminated between PD and controls on measurements of rest/postural tremor, pronation/supination, finger tapping, simple reaction time, and postural sway intensity and velocity. CATSYS measurements using the proposed test battery were associated with relevant clinician-rated Unified Parkinson's disease rating scale (UPDRS) items assessing tremor and bradykinesia. More work is warranted to establish CATSYS as a diagnostic/monitoring instrument in movement disorders using the proposed technical approaches

SRRM2, a Potential Blood Biomarker Revealing High Alternative Splicing in Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms.We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5') exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls.The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease

Rationale and design of a prospective study: Cervical Dystonia Patient Registry for Observation of OnaBotulinumtoxinA Efficacy (CD PROBE)

<p>Abstract</p> <p>Background</p> <p>A registry of patients with cervical dystonia (Cervical Dystonia Patient Registry for Observation of onaBotulinumtoxinA Efficacy [CD PROBE]) was initiated to capture data regarding physician practices and patient outcomes with onabotulinumtoxinA (BOTOX^®, Allergan, Inc., Irvine, CA, USA). Methods and baseline demographics from an interim analysis are provided.</p> <p>Methods/Design</p> <p>This is a prospective, multicenter, clinical registry in the United States enrolling subjects with cervical dystonia (CD) who are toxin naïve and/or new to the physicians' practices, or who had been in a clinical trial but received their last injection ≥ 16 weeks prior to enrollment. Subjects are followed over 3 injection cycles of onabotulinumtoxinA, with assessments at time of injection and 4-6 weeks later. Information on physician's practice, patient demographics, CD disease history, duration of treatment intervals and neurotoxin dose, dilution, use of electromyography, and muscles injected are collected. Outcomes are assessed by physicians and subjects using various questionnaires.</p> <p>Discussion</p> <p>This ongoing registry includes 609 subjects with the following baseline data: 75.9% female, 93.6% Caucasian, mean age 57.6 ± 14.3, age at symptom onset 48.3 ± 16.2, and time to diagnosis 5.4 ± 8.6 years, with an additional 1.0 ± 3.5 years before treatment. Of those employed at the time of diagnosis, 36.6% stopped working as a result of CD. CD PROBE, the largest clinical registry of CD treatment, will provide useful data on current treatment practices with onabotulinumtoxinA, potentially leading to refinements for optimization of outcomes.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT00836017">NCT00836017</a></p

β-N-Methylamino-L-alanine Induces Neurological Deficits and Shortened Life Span in Drosophila

The neurotoxic non-protein amino acid, β-N-methylamino-L-alanine (BMAA), was first associated with the high incidence of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam. Recently, BMAA has been implicated as a fierce environmental factor that contributes to the etiology of Alzheimer’s and Parkinson’s diseases, in addition to ALS. However, the toxicity of BMAA in vivo has not been clearly demonstrated. Here we report our investigation of the neurotoxicity of BMAA in Drosophila. We found that dietary intake of BMAA reduced life span, locomotor functions, and learning and memory abilities in flies. The severity of the alterations in phenotype is correlated with the concentration of BMAA detected in flies. Interestingly, developmental exposure to BMAA had limited impact on survival rate, but reduced fertility in females, and caused delayed neurological impairment in aged adults. Our studies indicate that BMAA exposure causes chronic neurotoxicity, and that Drosophila serves as a useful model in dissecting the pathogenesis of ALS/PDC

Back to Analogue: Self-Reporting for Parkinson’s Disease.

We report the process used to create artefacts for self-reporting Parkinson's Disease symptoms. Our premise was that a technology-based approach would provide participants with an effective, flexible, and resilient technique. After testing four prototypes using Bluetooth, NFC, and a microcontroller we accomplished almost full compliance and high acceptance using a paper diary to track day-to-day fluctuations over 49 days. This diary is tailored to each patient's condition, does not require any handwriting, allows for implicit reminders, provides recording flexibility, and its answers can be encoded automatically. We share five design implications for future Parkinson's self-reporting artefacts: reduce participant completion demand, design to offset the effect of tremor on input, enable implicit reminders, design for positive and negative consequences of increased awareness of symptoms, and consider the effects of handwritten notes in compliance, encoding burden, and data quality

Familial Parkinson's disease

Objective An Ala53Thr mutation of the a-synuclein has been recently identified as a rare cause of autosomal Parkinson's Disease (PD). We set out to study the clinical characteristics of 15 Parkinson's disease patients living in Greece with the Ala53Thr a-synucleinmutation (α-synPD) and to compare them to sporadic Parkinson's disease (sPD) and familial (fPD) patients who do not carry the Ala53Thr α-synuclein mutation.Methods An investigator blind to the results of the genetic analysis examined 15 a-synPD, 43fPD and 52 consecutive sPD patients. Demographic data, age at onset of the illness,modality of presentation and duration of PD were carefully collected. The Unified Parkinson's Disease Rating Scale, including the Hoehn & Yahr and Schwab-Englandscales were completed. Results Patients with α-synuclein mutation were significantly younger (average 7.6 years), showed the first sign of the disease significantly earlier in life (average 10.8 years) and had significantly longer duration of the disease compared to sPD patients. Tremor at onset of the disease was present in only one (6.7%) of the α-synPD patients, whilst it was present in 32 (61.5%) of the sPD patients. (p=0.0006). During the course of the disease one patient of the α-synPD group went on to develop tremor compared to 6 patients of the sPD group. Rigidity, bradykinesia, postural instability, orthostatic hypotension, intellectual impairment, depression, complications of therapy, and clinical severity of the disease at the time of examination did not differ significantly between α-synPD and sPD patients, or between α-synPD and MsPD patients. When compared to fPD patients α-synPD patients were significantly younger (mean difference 11.8 years) and showed the first sign of the disease earlier in life (mean difference 12,7 years). Tremor at onset was present in only one (6.7%) of the α-synPD patients compared with 18 (41.9%) of the fPD patients (p=0.01). At the time of examination rigidity, postural instability, orthostatic hypotension and the overall clinical seventy did not differ significantly either between α-synPD and fPD or between α-synPD and MfPD groups. Nevertheless, some clinically relevant trends concerning the psychiatric symptoms and complications of therapy were recognized. ConclusionThe younger age at onset of the illness, the much lower prevalence of tremor and the longer duration of the disease characterize the clinical phenotype in this sample of asynPD patients. The other symptoms and signs of the illness did not appear to differentiate the α-synPD patients from the other group of patients.ΣΚΟΠΟΣ ΤΗΣ ΕΡΓΑΣΙΑΣ Πρόσφατα μια μετάλλαξη (Ala53Thr) στο εξόνιο 4 του γονιδίου της α-συνουκλεΐνηςενοχοποιήθηκε σαν αιτιολογικός παράγοντας μιας σπάνιας μορφής κληρονομικής νόσου του Parkinson (α-συνΝΡ). Σκοπός της παρούσας εργασίας είναι η μελέτη του κλινικού φαινοτύπου της α-συν ΝΡ και η σύγκριση του με τον αντίστοιχο της σποραδικής (σπΝΡ) και της κληρονομικής χωρίς Ala53Thr μετάλλαξη (κΝΡ) μορφής της νόσου.Υλικό και Μέθοδος Ο ίδιος ερευνητής χωρίς να γνωρίζει τα αποτελέσματα της γενετικής ανάλυσης εξέτασε 15 α-συνΝΡ ασθενείς, 52σπΝΡ και 43 κΝΡ συνεχείς ασθενείς και κατέγραψε τα δημογραφικά στοιχεία, την ηλικία και τα συμπτώματα ενάρξεως και τη διάρκεια της ΝΡ. Επίσης συμπληρώθηκαν η Ενοποιημένη Κλίμακα Βαθμολόγησης της Νόσου του Parkinson (Unified Parkinson's Disease Rating Scale-UPDRS), η οποία περιλαμβάνει και τις κλίμακες Hoehn & Yahr και Swab & England.Ταιριάξαμε (matching) 32 από τους 52 σπΝΡ ασθενείς με τους α-συν ασθενείς ως προς την διάρκεια της νόσου (ΤσπΝΡ). Αποτελέσματα Οι α-συνΝΡ ασθενείς ήταν σημαντικά νεώτεροι από τους σπΝΡ (μ.ο. 7,6 χρ.) αλλά και από τους κΝΡ (μ.ο. 11,8 χρ.), παρουσίασαν το πρώτο σύμπτωμα της νόσου αρκετά νωρίτερα από τις άλλες ομάδες ασθενών (μ.ο. 10,8 χρ. πριν από σπΝΡ και μ.ο.10,7 χρ. πριν από κΝΡ) και είχαν μεγαλύτερη διάρκεια νόσου. Μόνο ένας α-συνΝΡ ασθενής (6,7%) παρουσίασε τρόμο στην έναρξη της νόσου σε σύγκριση με 32 σπΝΡ ασθενείς (41,8%) και 18 κΝΡ ασθενείς (42%). Κατά τη διάρκεια της νόσου μόνο ένας επιπλέον ασθενής με α-συνΝΡ παρουσίασε τρόμο σε σύγκριση με 6 σπΝΡ και 6κλΝΡασθενείς. Τα άλλα χαρακτηριστικά της νόσου (δυσκαμψία, βραδυκινησία, διαταραχές αντανακλαστικών στάσεως, ορθοστατική υπόταση,διανοητικές διαταραχές, παρενέργειες της θεραπεία και η βαρύτητα της νόσου τη στιγμή της εξέτασης) δεν παρουσίασαν στατιστικά σημαντικές διαφορές μεταξύ των α-συν ασθενών και των άλλων ομάδων. ΣΥΜΠΕΡΑΣΜΑΤΑ Ο κλινικός φαινότυπος των α-συνΝΡ ασθενών χαρακτηρίζεται από μικρότερη ηλικία ενάρξεως και σχεδόν ολική έλλειψη τρόμου σε σύγκριση με τους σπΝΡ και κΝΡ ασθενείς καθώς και από ηπιότερη συμπτωματολογία σε σύγκριση με τους σπΝΡ. Από τις λοιπές συγκρίσεις δεν προκύπτουν άλλες διαφορές μεταξύ των α-συνΝΡ και των άλλων ομάδων ασθενών

Descriptive Epidemiology of Cervical Dystonia

Background: Cervical dystonia (CD), the most common form of adult‐onset focal dystonia, has a heterogeneous clinical presentation with variable clinical features, leading to difficulties and delays in diagnosis. Owing to the lack of reviews specifically focusing on the frequency of primary CD in the general population, we performed a systematic literature search to examine its prevalence/incidence and analyze methodological differences among studies. Methods: We performed a systematic literature search to examine the prevalence data of primary focal CD. Sixteen articles met our methodological criteria. Because the reported prevalence estimates were found to vary widely across studies, we analyzed methodological differences and other factors to determine whether true differences exist in prevalence rates among geographic areas (and by gender and age distributions), as well as to facilitate recommendations for future studies.Results: Prevalence estimates ranged from 20&ndash;4,100 cases/million. Generally, studies that relied on service‐based and record‐linkage system data likely underestimated the prevalence of CD, whereas population‐based studies suffered from over‐ascertainment. The more methodologically robust studies yielded a range of estimates of 28&ndash;183 cases/million. Despite the varying prevalence estimates, an approximate 2:1 female:male ratio was consistent among many studies. Three studies estimated incidence, ranging from 8&ndash;12 cases/million person‐years. Discussion: Although several studies have attempted to estimate the prevalence and incidence of CD, there is a need for additional well‐designed epidemiological studies on primary CD that include large populations; use defined CD diagnostic criteria; and stratify for factors such as age, gender, and ethnicity.</p