BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

• MeSH
• botulotoxiny typu A * škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• dystonické poruchy * farmakoterapie   MeSH
• injekce intramuskulární MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nervosvalové látky * škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tortikolis * farmakoterapie   chemicky indukované   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• botulotoxiny typu A * MeSH
• nervosvalové látky * MeSH

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

• Klíčová slova
• Botulinum toxin, Consensus guidelines, Dose limits, Dose variability, Dosing tables, Dystonia, Spasticity, Target muscles, Therapy, Total dose, Treatment algorithms, Typical dose,
• MeSH
• algoritmy MeSH
• botulotoxiny typu A * MeSH
• botulotoxiny * MeSH
• dystonické poruchy * farmakoterapie   MeSH
• dystonie * farmakoterapie   MeSH
• lidé MeSH
• svalová spasticita farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• botulotoxiny typu A * MeSH
• botulotoxiny * MeSH

Cognitive control is relevant when distracting information induces behavioral conflicts. Such conflicts can be produced consciously and by subliminally processed information. Interestingly, both sources of conflict interact suggesting that they share neural mechanisms. Here, we ask whether conjoint effects between different sources of conflict are modulated by microstructural basal ganglia dysfunction. To this end, we carried out an electroencephalography study and examined event-related potentials (ERPs) including source localization using a combined flanker-subliminal priming task in patients with X-linked dystonia Parkinsonism (XDP) and a group of healthy controls. XDP in its early stages is known to predominantly affect the basal ganglia striosomes. The results suggest that conjoint effects between subliminal and conscious sources of conflicts are modulated by the striosomes and were stronger in XDP patients. The neurophysiological data indicate that this effect is related to modulations in conflict monitoring and response selection (N2 ERP) mechanisms engaging the anterior cingulate cortex. Bottom-up perceptual gating, attentional selection, and motor response activation processes in response to the stimuli (P1, N1, and lateralized readiness potential ERPs) were unaffected. Taken together, these data indicate that striosomes modulate the processing of conscious and subliminal sources of conflict suggesting that microstructural basal ganglia properties are relevant for cognitive control.

• MeSH
• analýza rozptylu MeSH
• antiparkinsonika terapeutické užití   MeSH
• bazální ganglia patofyziologie   MeSH
• dospělí MeSH
• dystonické poruchy farmakoterapie   patologie   patofyziologie   psychologie   MeSH
• elektroencefalografie MeSH
• evokované potenciály fyziologie   MeSH
• funkční lateralita MeSH
• genetické nemoci vázané na chromozom X farmakoterapie   patologie   patofyziologie   psychologie   MeSH
• konflikt (psychologie) * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mapování mozku MeSH
• mozkové vlny fyziologie   MeSH
• psychomotorický výkon fyziologie   MeSH
• reakční čas fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiparkinsonika MeSH

OBJECTIVE: Patients with writer's cramp (WC) were studied for differences in cortical activation during movements likely to induce WC (complex movements) and movements which rarely lead to dystonia (simple movements). METHODS: Eleven WC patients (10F, 1M, mean age 41.5 ± (SD)7.2 years) and eleven age matched controls were examined for Blood oxygenation-level dependent (BOLD) 1.5 T fMRI. The complex task consisted of writing a single letter or random drawing using an especially adapted joystick with the line of trajectory visualized or hidden. The simple task consisted of self-initiated fingers flexion/extension using the affected hand. RESULTS: Unlike the controls, WC patients performing complex movements exhibited a lower BOLD signal in the primary sensorimotor cortex and in the posterior parietal cortex bilaterally. A hypoactivation was also observed in the right secondary somatosensory area, in the right anterior insula and in the left premotor cortex (p < 0.05 corrected). No significant inter-group differences were found for simple movements. CONCLUSIONS: Although WC patients' complex movements during fMRI were never associated with dystonic cramp, they exhibited an abnormally low cortical activity. This phenomenon was not observed in simple movements and was unrelated to the character of handwriting or to visual feedback. SIGNIFICANCE: Our results support the dualistic behavior in the sensorimotor system in WC.

• MeSH
• algoritmy MeSH
• antidyskinetické látky terapeutické užití   MeSH
• biomechanika MeSH
• botulotoxiny terapeutické užití   MeSH
• dospělí MeSH
• dystonické poruchy farmakoterapie   patofyziologie   MeSH
• feedback psychologický MeSH
• kyslík krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• motorické korové centrum patofyziologie   MeSH
• mozková kůra patofyziologie   MeSH
• počítačové zpracování obrazu MeSH
• pohyb fyziologie   MeSH
• psaní rukou MeSH
• psychomotorický výkon fyziologie   MeSH
• somatosenzorické korové centrum patofyziologie   MeSH
• světelná stimulace MeSH
• temenní lalok patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antidyskinetické látky MeSH
• botulotoxiny MeSH
• kyslík MeSH