Background and ObjectivesASPEN-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).MethodsAdults (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.ResultsOf 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%).DiscussionThis study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD.Trial Registration InformationClinicalTrials.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 EvidenceThis study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

ObjectiveThe aim of this clinical study was to assess the impact of a non-invasive selective blue-filtering photochromic lens coating Crizal Prevencia on the treatment and response of benign essential blepharospasm (BEB).Patients and methodsTwenty-four patients were recruited in the outpatient clinic of the Medical University of Vienna in a randomized, double-blind, cross-over study design. Blink frequencies were assessed in patients with BEB before and 14 days after intervention with either a filtering ophthalmic lens or a placebo lens, respectively. Outcome parameters include sub-group analysis of a blink frequency under six different conditions: three photopic conditions, one resting condition, one reading condition, and one video game condition.ResultsFrom 24 recruited patients, 15 patients were available for final analysis. Comparing the optical blue filtering lens to placebo, showed a reduced blink frequency in specific subtests, but not compared to baseline.DiscussionIn conclusion, optical filtering glasses might have a beneficial effect on BEB and provide a non-invasive therapeutic add-on option, in addition to botulinum neurotoxin therapy, for patients with BEB and should necessarily be further investigated in a multicenter setting, resulting in larger sample sizes to gain valid information about the effect of photochromic blue filter glasses in BEB.Clinical trial registration: https://drks.de/search/en/trial/DRKS00032135, DRKS00032135.

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing poststroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually. In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n = 13 ischemic, n = 1 ischemic with hemorrhagic transformation and n = 2 hemorrhagic stroke) or transitory ischemic attacks (n = 5) within 24 h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week. Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717 mu m/mm(2), p = 0.001 and 5263 vs 6550 mu m/mm(2), p = 0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717 mu m/mm(2), p < 0.001 and 5263 vs. 6550 mu m/mm(2), p = 0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r = -0.843, p < 0.001), in patients with ischemic strokes (r = -0.82, p = 0.001) as well as in healthy volunteers (r = -0.845, p < 0.001). In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes. In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Background and Purpose Patent foramen ovale (PFO)is associated with cryptogenic stroke, especially in young adults. Transcranial Doppler (TCD) ultrasound is used as a screening tool before transesophageal echocardiography (TEE). However, the use of Valsalva maneuver (VM) to identify a right-to-left-shunt underlies interindividual variability. Here, we aimed to assess whether a pressure-controlled standardization of VM is useful to estimate PFO size. Methods We included patients aged 18-80 years with a PFO according to TEE. Subjects underwent TCD with microembolic signals (MES) counted under four pressure conditions (i.e., at rest, 15 mbar, 40 mbar, and maximum expiratory pressure). Findings were correlated with TEE-based PFO size. The predictive value of TCD at rest and VM-based TCD for PFO size estimation was assessed by stepwise multivariate linear regression models and multiple cross-tab-analyses. Results We screened 203 subjects after a cerebrovascular event, of which 78 (48 males [61.5%], median age 55 years [22-80]) with PFO were included. We found an association between MES count and expiratory pressure (p < .001). Predefined MES count categories at TCD pressure conditions correlated significantly with PFO size measured by TEE. We propose a PFO size estimation model based on TCD at rest and under VM, which classified PFO size correctly in 64.1% with the highest accuracy for small PFOs. Conclusion Our data provide evidence that TCD with step-wise barometric standardization allows an estimation of PFO size with good accuracy. Though TCD will not replace TEE in future, this might be of clinical value in circumstances where TEE cannot be easily performed.

Purely torsional spontaneous nystagmus almost always has a central vestibular cause. We describe a man with spontaneous pulse-synchronous torsional nystagmus in which the clockwise component corresponded to his pulse upswing, in keeping with a peripheral vestibular cause; following imaging we diagnosed left-sided superior canal dehiscence syndrome. Identifying pulse synchronicity of spontaneous nystagmus may help to distinguish central from peripheral vestibular torsional nystagmus, and is readily confirmed at the bedside using Frenzel’s glasses and a pulse oximeter.

ObjectiveTo investigate higher cognitive functions after mimicry changes after facial botulinum toxin (BTX) injections, we tested verbal and nonverbal reasoning in patients with blepharospasm or hemifacial spasm before and after their long-term botulinum toxin treatment.DesignExplorative, nonrandomized, clinical trial.SettingPatients receiving ambulatory care and control participants from the general community.ParticipantsVolunteer sample (N=84) of patients (n=21) with blepharospasm or hemifacial spasm who received facial BTX injections. Control participants included patients (n=30) with cervical dystonia who received cervical BTX injections and individuals without neurological disorders (n=33).InterventionsThe 2 groups receiving injections were tested before and 3 weeks after their treatment. The group without neurological disorders received no injections.Main Outcome MeasuresVerbal and nonverbal reasoning scores.ResultsThe key unexpected finding was that patients who received facial BTX injections perform significantly worse in nonverbal reasoning tasks, when compared with those who did not receive injections (P=.022). There was no significant difference in the baseline reasoning scores and at follow-up for verbal reasoning between the 3 groups. There was no correlation between toxin dose and reasoning scores (verbal: P=.132; nonverbal: P=.294).ConclusionsBecause of potential confounders, the results do not yet allow any conclusion on causality. Further research is needed to confirm our findings.

Obwohl Botulinumtoxin‑A (BoNT-A) von Leitlinien als First-line-Therapie der fokalen zervikalen Dystonie (ZD) empfohlen wird, existieren kaum Langzeitdaten zu den Behandlungsmodalitaten in der klinischen Routine. Die vorliegende Subgruppenanalyse untersuchte Patientenzufriedenheit und Symptomkontrolle unter Berucksichtigung von Behandlungsmodalitaten der BoNT-A-Therapie zwischen ZD-Patienten in Deutschland und Osterreich (DE/AT, n = 79) und der internationalen Gesamtkohorte (n = 995). INTEREST-IN-CD2 war eine prospektive, multizentrische, longitudinale Beobachtungsstudie, die uber 3 Jahre der Therapie erwachsener Patienten mit idiopathischer ZD unter BoNT-A-Behandlung folgte. Primarer Endpunkt war die Patientenzufriedenheit mit der Therapie gemessen an der maximalen Zufriedenheit zwischen 2 Injektionen und der Zufriedenheit zum Zeitpunkt der Reinjektion. Die Therapiezufriedenheit im Wirkmaximum war in beiden Populationen im Studienverlauf stabil und vergleichbar gut (82,3–92,7 % bzw. 85,0–89,9 %). Mit nachlassender BoNT-A-Wirkung zum Ende des Behandlungsintervalls sank die Zufriedenheit ab: Zu Studienbeginn in beiden Gruppen ahnlich (54,2 % vs. 51,4 %), fiel sie numerisch in der der DE/AT-Gruppe bis auf 32,7 % ab, blieb dagegen in der Gesamtpopulation stabil. Die Toronto Western Spasmodic Torticollis Rating Scale(TWSTRS)- und Tsui-Scores zeigten keine wesentlichen Unterschiede zwischen der DE/AT-Gruppe und der Gesamtpopulation. Die Studie bestatigt insgesamt eine gute klinische Symptomkontrolle durch BoNT‑A. Die im Vergleich von DE/AT zur internationalen Gesamtkohorte gesehenen numerischen Unterschiede in der aktuellen Zufriedenheit sind moglicherweise bedingt durch abweichende Anteile BoNT-A-naiver Patienten beider Gruppen, da diese unterschiedliche Zufriedenheit als vorbehandelte Patienten auserten.

Introduction: Botulinumtoxin associated muscle denervation (BNTMD) can be detected by magnet resonance imaging (MRI), MRI may provide further insights into the exact timeline of BNTMD and the potential impact and timing of physical exercise. We aimed to assess the time interval until detection of BNTMD by MRI and whether immediate physical exercise after intramuscular BNT injection has a measurable effect on clinical parameters and the intramuscular denervation dynamics illustrated by MRI.Materials and Methods: Eleven age-matched patients were randomized to an “exercise” or “no-exercise” group. Eighty mouse-units of incobotulinumtoxin were injected into the spastic biceps muscle. MRI of the injected region, hand-held dynamometry of elbow flexor strength and clinical rating scales (mAS, CGI-I) were conducted in predefined intervals.Results: We could not detect BNTMD within 24 h but 7 days after injection independent of group allocation (exercise n = 6, no-exercise n = 5). Denervation signs were more diffuse and spread into adjacent muscles in patients having received exercise. We could not detect differences concerning clinical measures between the two groups.Conclusions: Physical exercise might influence BNTMD dynamics and promote propagation of T2-MR muscle denervation signs from the injected site into adjacent muscles.Trial registration:clinicaltrialsregister.eu, Identifier 2017-003117-25.

Zusammenfassung Hintergrund Obwohl Botulinumtoxin‑A (BoNT-A) von Leitlinien als First-line-Therapie der fokalen zervikalen Dystonie (ZD) empfohlen wird, existieren kaum Langzeitdaten zu den Behandlungsmodalitäten in der klinischen Routine. Fragestellung Die vorliegende Subgruppenanalyse untersuchte Patientenzufriedenheit und Symptomkontrolle unter Berücksichtigung von Behandlungsmodalitäten der BoNT-A-Therapie zwischen ZD-Patienten in Deutschland und Österreich (DE/AT, n = 79) und der internationalen Gesamtkohorte ( n = 995). Material und Methoden INTEREST-IN-CD2 war eine prospektive, multizentrische, longitudinale Beobachtungsstudie, die über 3 Jahre der Therapie erwachsener Patienten mit idiopathischer ZD unter BoNT-A-Behandlung folgte. Primärer Endpunkt war die Patientenzufriedenheit mit der Therapie gemessen an der maximalen Zufriedenheit zwischen 2 Injektionen und der Zufriedenheit zum Zeitpunkt der Reinjektion. Ergebnisse Die Therapiezufriedenheit im Wirkmaximum war in beiden Populationen im Studienverlauf stabil und vergleichbar gut (82,3–92,7 % bzw. 85,0–89,9 %). Mit nachlassender BoNT-A-Wirkung zum Ende des Behandlungsintervalls sank die Zufriedenheit ab: Zu Studienbeginn in beiden Gruppen ähnlich (54,2 % vs. 51,4 %), fiel sie numerisch in der der DE/AT-Gruppe bis auf 32,7 % ab, blieb dagegen in der Gesamtpopulation stabil. Die Toronto Western Spasmodic Torticollis Rating Scale(TWSTRS)- und Tsui-Scores zeigten keine wesentlichen Unterschiede zwischen der DE/AT-Gruppe und der Gesamtpopulation. Schlussfolgerungen Die Studie bestätigt insgesamt eine gute klinische Symptomkontrolle durch BoNT‑A. Die im Vergleich von DE/AT zur internationalen Gesamtkohorte gesehenen numerischen Unterschiede in der aktuellen Zufriedenheit sind möglicherweise bedingt durch abweichende Anteile BoNT-A-naiver Patienten beider Gruppen, da diese unterschiedliche Zufriedenheit als vorbehandelte Patienten äußerten.

BackgroundDystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.MethodsFor this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.FindingsWe sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.InterpretationIn this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.FundingElse Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Die Fehlhaltung bei zervikaler Dystonie ist oft durch ein komplexes Zusammenspiel mehrerer Muskeln bedingt. Es gibt jedoch auch Fälle, die durch die dystone Aktivität eines Muskels bedingt sind. Die Inspektion und Palpation ermöglichen die einfache Identifizierung. Eine Abgrenzung gegenüber somatoformen Bewegungsstörungen und motorischen Tics sowie der Ausschluss einer sekundären Dystonie sind wichtig, spielen aber für die Wahl der symptomatischen Therapie (fokale Chemodenervierung mittels Botulinumtoxin) nur eine untergeordnete Rolle.

Correction to: Wien Klin Wochenschr 2018 https://doi.org/10.1007/s00508-018-1381-5 Unfortunately, the original version of this article contained two mistakes.The text passage "It should be mentioned here that in the case of apixaban, dose adjustment is not based on GFR. A lower dosage of apixaban ….

Anecdotal oculomotor disturbances have been described in spastic paraplegia type 7 (SPG7). We investigated oculomotor and vestibular dysfunction in five patients with genetically verified SPG7. All five patients exhibited significantly slower velocities of vertical saccades compared to controls, but significantly faster than in progressive supranuclear palsy, with upward saccades being particularly affected. Horizontal saccades, cerebellar oculomotor markers, and vestibuloocular reflex seem to be variably affected. Thus, albeit subclinical in some cases, slowing of the vertical saccades may belong to the phenotype of SPG7 and may serve as a valuable biomarker for differentiation from spastic ataxias and atypical parkinsonism.

At June 2019, this protocol has been withdrawn as the full review did not meet the expectations of Cochrane or PaPaS.

Congenital fiber-type disproportion is a rare condition, histologically characterized by a relative type 1 fiber hypotrophy. The main clinical feature is mild-to-severe muscle weakness. In this report, we present the case of a 21-year-old patient with congenital fiber-type disproportion in an outpatient rehabilitative setting to evaluate the feasibility and results of an assessment battery, including bioimpedance analysis (BIA), dynamometry, 3D gait analysis, 6‑min walk test (6MWT), and the timed up and go test (TUG). The patient had a notable decrease in all functional scores. BIA: lean body mass, 38.4 kg (50.2 ± 5.3), body fat, 1.6% (12.4 ± 4.4); hand dynamometry: 18.5 kg left/20.0 kg right (44.8 ± 6.6); walking speed, 58 cm/s (122.7 ± 11.1), step length, 43.0 cm (61.6 ± 3.5); 6MWT: 478.5 m (638 ± 44); TUG: 9.4 s (8.1 ± 1.0). No adverse events were reported. The tests used were easily applicable in clinical routine and well tolerated by our patient.

Objective: Botulinum toxin (BoNT) is effective in improving abnormal head posture in cervical dystonia (CD) within a period of several weeks to an upright position. These dynamic alterations over time represent a unique model to study the plasticity of static graviceptive function in CD by assessing the subjective visual vertical (SW).Methods: SW was assessed in 30 CD patients and 13 controls, in their habitual head posture and with fixed head positions at different angles of head tilt. The patients were tested before and 3 weeks after BoNT administration.Results: At baseline, the patient's estimates in their habitual head posture and at forced head tilt angle of 30 degrees differed significantly from those of controls. This effect was no longer visible after BoNT injection, or when the patient's head was fixed in an upright, and at a 15 degrees head tilt position, respectively. A moderate positive correlation between disease severity and SW aberrations was found. When comparing within-group changes, in all participants significant aberrations occurred when the head was tilted at 30 degrees, which may be explained by the physiological E-effect.Conclusion: Our findings demonstrate that patients with CD exhibit altered static graviceptive perception when tested in their habitual head posture and an overshooting E-effect at the major forced head tilt of 30 degrees. This graviceptive perceptual deficit can be reversed by modification of the somatosensory input (i.e. head fixation) as a short-term effect, and by changes in the proprioceptive input (i.e. BoNT injections) as a long-term effect. (C) 2017 Elsevier B.V. All rights reserved.

Summary Congenital fiber-type disproportion is a rare condition, histologically characterized by a relative type 1 fiber hypotrophy. The main clinical feature is mild-to-severe muscle weakness. In this report, we present the case of a 21-year-old patient with congenital fiber-type disproportion in an outpatient rehabilitative setting to evaluate the feasibility and results of an assessment battery, including bioimpedance analysis (BIA), dynamometry, 3D gait analysis, 6‑min walk test (6MWT), and the timed up and go test (TUG). The patient had a notable decrease in all functional scores. BIA: lean body mass, 38.4 kg (50.2 ± 5.3), body fat, 1.6% (12.4 ± 4.4); hand dynamometry: 18.5 kg left/20.0 kg right (44.8 ± 6.6); walking speed, 58 cm/s (122.7 ± 11.1), step length, 43.0 cm (61.6 ± 3.5); 6MWT: 478.5 m (638 ± 44); TUG: 9.4 s (8.1 ± 1.0). No adverse events were reported. The tests used were easily applicable in clinical routine and well tolerated by our patient.

Die chronische Migräne ist mit einer Prävalenz von zirka 0,5–2,2 % deutlich seltener als die episodische Migräne. Botox® ist – basierend auf wissenschaftlichen Daten eines umfangreichen Studienprogramms – in Österreich seit 2012 als Prophylaxe zugelassen. Die übrigen medikamentösen Prophylaxen sind zumeist von limitierter Wirksamkeit und mit deutlichen Nebenwirkungen assoziiert. Voraussetzung für eine erfolgreiche Prophylaxe und Therapie sind die Patientencompliance sowie die Entzugsbehandlung eines häufig den Analgetikaübergebrauch begleitenden Kopfschmerzes.