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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.

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.

Objective To 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. Design Explorative, nonrandomized, clinical trial. Setting Patients receiving ambulatory care and control participants from the general community. Participants Volunteer 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). Interventions The 2 groups receiving injections were tested before and 3 weeks after their treatment. The group without neurological disorders received no injections. Main Outcome Measures Verbal and nonverbal reasoning scores. Results The 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). Conclusions Because of potential confounders, the results do not yet allow any conclusion on causality. Further research is needed to confirm our findings.

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.

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.

Summary Background Dystonia 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. Methods For 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. Findings We 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. Interpretation In 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. Funding Else Kroner-Fresenius-Stiftung, Technische Universitat Munchen, Helmholtz Zentrum Munchen, Medizinische Universitat Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke 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 μm/mm

Die Polyneuropathie bei Patientinnen und Patienten mit onkologischen Erkrankungen kann als paraneoplastisches Syndrom sowie infolge einer Tumorbehandlung auftreten.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the analgesic efficacy and adverse events of antipsychotics for neuropathic pain in adults.

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 (SVV). Methods SVV 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° 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° head tilt position, respectively. A moderate positive correlation between disease severity and SVV aberrations was found. When comparing within-group changes, in all participants significant aberrations occurred when the head was tilted at 30°, 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°. 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.

Die Fehlhaltung bei zervikaler Dystonie ist oft durch ein komplexes Zusammenspiel mehrerer Muskeln bedingt. Es gibt jedoch auch Falle, die durch die dystone Aktivitat eines Muskels bedingt sind. Die Inspektion und Palpation ermoglichen die einfache Identifizierung. Eine Abgrenzung gegenuber somatoformen Bewegungsstorungen und motorischen Tics sowie der Ausschluss einer sekundaren Dystonie sind wichtig, spielen aber fur die Wahl der symptomatischen Therapie (fokale Chemodenervierung mittels Botulinumtoxin) nur eine untergeordnete Rolle.

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 A precise knowledge of the spread of botulinum toxin (BoNT) in muscle tissue is required to efficiently access endplate zones and increase BoNT's therapeutic efficacy. Here, we aimed to understand the spatiotemporal dynamics of BoNT distribution in skeletal muscle and its modulating factors, such as injected volume and exercise after injection. Methods To visualize distribution in muscle tissue, sagittal, dynamic, balanced fast field echo (BFFE) MRI imaging was performed during injection of 1ml BoNT/NaCl bolus in spastic biceps brachii muscles (SBB, n =4), and 1ml NaCl in the right and 2ml NaCl in the left healthy biceps brachii (HBB, n =6), with or without successive muscle exercise. The pattern of extracellular fluid distribution was evaluated by T2-weighted and diffusion tensor imaging (DTI) sequences. Results BFFE indicated an immediate increase in hyperintensity, parallel to the muscle fibers, in the shape of a long (5.3±1.7cm) and thin (0.52±1.3cm) layer in HBB. The layer in SBB was shorter (3.25±0.6cm, p =0.01) and tended to be thicker (0.74±2.9cm, p =0.27). In HBB, an increase in volume (2ml) resulted in an increase in thickness (0.95±0.2cm, p =0.015), but a consistent length (5.67±1.3cm, p =0.54). DTI visualized a change of diffusion, which exceeded the bolus region by approximately 0.5cm. Redistribution occurred 10min after injection and was more prominent in HBB, compared to SBB. Additional muscle activity did not alter the diffusion pattern or bolus distribution. Conclusion Injecting BoNT at different depths perpendicular to the direction of the muscle fiber might optimize the efficacy of BoNT treatment. Additional sites along muscle fibers should be considered in SBB.

Purpose Phantom pain in upper limb amputees is associated with the extent of reorganization in the primary sensorimotor cortex. Mirror visual feedback therapy has been shown to improve phantom pain. We investigated the extent of cortical reorganization in lower limb amputees and changes in neural activity induced by mirror therapy. Materials and methods Eight lower limb amputees underwent 12 sessions of MVFT and functional magnetic resonance imaging (fMRI) of the brain before the first and after the last MVFT session. FMRI sessions consisted of two runs in which subjects were instructed to perform repetitive movement of the healthy and phantom ankle. Results Before MVFT, the mean phantom pain intensity was 4.6 ± 3.1 on a visual analog scale and decreased to 1.8 ± 1.7 (p = 0.04). We did not observe a consistent pattern of cortical activation in primary sensorimotor areas during phantom limb movements. Following MVFT, increased activity was obtained in the right orbitofrontal cortex during phantom ankle movements. Comparison of cortical activity during movements of the phantom ankle and the intact ankle showed significantly higher activity in the left inferior frontal cortex (pars triangularis). Conclusion These results question the known association between phantom pain and primary sensorimotor reorganization and propose reorganizational changes involving multiple cortical areas in lower limb amputees. Finally, reduction of phantom pain after mirror visual feedback therapy was associated with increased prefrontal cortical activity during phantom ankle movements.

The non-vitamin K antagonist oral anticoagulants (NOACs) have considerably changed clinical practice and are increasingly being used as an alternative to vitamin K antagonists (VKAs) for 3 main reasons: 1) an improved benefit-risk ratio (in particular lower rates of intracranial bleeding), 2) a more predictable effect without the need for routine monitoring, and 3) fewer food and drug interactions compared with VKAs. Currently, there are four NOACs available: the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, and the thrombin inhibitor dabigatran. This consensus paper reviews the properties and usage of NOACs in a number of high-risk patient populations, such as patients with chronic kidney disease, patients ≥80 years of age and others and provides guidance for the use of NOACs in patients at risk of bleeding.

Summary Background Mouse units (mU) are used for quantification of the biological activity of botulinum A and B toxin preparations. However, in human tissue, mU values between preparations are not equivalent and lack of clarity concerning efficacy and safety remains with regard to their respective potencies, duration of drug effect and diffusion qualities. Objectives To compare short-term and long-term effects of Botox® (BOT; Allergan Inc., Irvine, CA, U.S.A.) and Neurobloc®/Myobloc® (NBC; Solstice Neurosciences Inc., Malvern, PA, U.S.A.) in different doses and dilutions in a human skin model. Methods In this prospective randomized double-blind study, 18 healthy volunteers (eight women and 10 men; mean ± SD age 28·4 ± 5·7 years) were injected intradermally with pure saline, BOT and NBC at 10 points in the abdomen in random order, using the BOT/NBC conversion ratio 1 : 75 and different dilution schemes. For an objective outcome, the ninhydrin sweat test was used to compare the anhidrotic areas (action halos). Ten measurements were taken during a time period of 54 weeks. Results Both preparations showed a peak effect at week 3, with significantly larger anhidrotic areas for NBC. Thereafter, however, the rate of decline was lower in BOT and after week 24, mean BOT areas were larger. The effect of dilution was higher in NBC and the mean dose equivalence conversion ratio (BOT/NBC) was 1 : 29 (area under the curve). Gender effects were seen in both products, with smaller action halos in women. Conclusions These results have important implications in clinical routine, especially for autonomic indications.

Klinische Berichte weisen auf eine Schmerzlinderung durch topische Applikation von Morphin auf Ulzera hin. Ziel der vorliegenden Studie war es, die Wirksamkeit von topisch appliziertem Morphin und Buprenorphin placebokontrolliert und doppelblind zu untersuchen. Die Untersuchung wurde in 2 getrennten, placebokontrollierten, doppelblinden Cross-over-Studien mit je 16 Teilnehmern durchgefuhrt. Im Studienteil A wurde Morphin in Ultrabas-Ultrasic-Creme in 3 Konzentrationen (0,1, 0,2, 0,4%), im Studienteil B Buprenorphin in den 3 Konzentrationen 0,01, 0,02 und 0,1% in einem Gel und jeweils Placebo auf 4 UVB-induzierte Erytheme am Oberschenkel fur 60 min (A) bzw. 90 min (B) appliziert. Die thermische und mechanische Hyperalgesie wurden mit quantitativ sensorischen Testungen im Erythem standardisiert bestimmt und die Opioide mit Placebo verglichen. Weder Morphin noch Buprenorphin veranderten die Hyperalgesie im Vergleich zu Placebo. Die topische Applikation von Opioiden in dieser Aufbereitung auf inflammierte Haut ist wirkungslos.

Kranz et al. used a ninhydrin sweat test (NST) and mouse diaphragm test (MDT) in 14 dystonic patients and 14 controls and reported subclinical neutralizing antibodies (Abs) in patients with “good clinical responses” to BoNT/A. The authors defined the responses based on a three-point decrease on modified-Tsui scale, injected-muscle atrophy, or reported BoNT/A-associated adverse events.1 Only one patient had anti-BoNT/A Abs (1 mU/mL, by MDT) and a marked anhydrotic area reduction (0.26 cm2). Seven other patients had “borderline” titers of either 0.4 or 0.8 mU/mL and reduced anhidrosis area. The study design, small sample size, and subjective clinical-response assessment precludes extension to incidence value (>40%). Mixing Botox- and Dysport-treated patients complicates analysis because these products have different immune-response rates. NST employs area, but neglects color density. NST correlation value was missing, as the anhydrotic area could vary with injection method. Hyperhidrosis effect reproducibility was also overlooked. The Results imply that NST was done with both Botox and Dysport but this contradicts the statement in the Methods that Dysport was the test agent. The observation that patients had different Ab levels after similar toxin doses is expected.2,3 Immune responses mature with time, boosters, and are genetically controlled.2,3 This means that patients responding to treatment would have different Ab levels, even after similar doses and protocols. …

Background This study was performed to elucidate preliminary observations of excessive nighttime urine excretion in idiopathic restless legs syndrome (iRLS). Methods Seventeen patients, with normal serum creatinine, blood urea nitrogen, and urate, and 11 healthy controls were examined. We measured excretory renal function parameters (urine volume, osmolarity, sodium, chloride, potassium, calcium, phosphate, microalbumin, aldosterone, creatinine) between 7:00 am and 10:00 pm and between 10:00 pm and 7:00 am. Results During the nighttime, volume ( P =0.006), sodium ( P =0.009), and chloride excretion ( P =0.001) were significantly higher, and osmolarity ( P =0.025) was significantly lower in patients as compared to controls. In comparing daytime to nighttime, controls showed the physiological reduced nocturnal excretion of volume ( P =0.009) and chloride ( P =0.023), and an increased osmolarity ( P =0.026), but patients showed similar excretion rates of these parameters (all differences ns). Conclusions These data indicate a loss of normal circadian profile of urine excretion in iRLS. The elevated nighttime excretion, with values similar to those in the daytime, hint at a possibly elevated fluid, sodium, and chloride intake during daytime.

The analysis of drug's influence on peripheral and central sensitisation can give useful information about its mode of action and can lead to more efficacy in the treatment of pain. Peripheral inflammation is associated with peripheral expression and up-regulation of cyclooxygenase 2 (COX-2) in the CNS. The relative contribution of COX-2 mediated central sensitisation may be prominent under inflammatory conditions. In this randomized, double blinded, placebo controlled cross-over trial the effects of multidoses of the COX-2 selective inhibitor rofecoxib on primary and secondary hyperalgesia were evaluated in the UVB pain model. Twenty-four hours after local UVB irradiation at the upper leg of 42 healthy volunteers heat pain perception (HPPT) and heat pain tolerance thresholds (HPTT) were assessed within the inflammation. The area of secondary hyperalgesia was determined by pin prick test. Subjects received oral rofecoxib 50, 250, 500 mg or placebo. Pain testing was repeated after 3 and 6 h. Compared to placebo, rofecoxib significantly increased HPPT (1.55 and 1.08 degrees C, P

Background: Dopaminergic and opioidergic drugs have been found to be effective in patients with restless legs syndrome (RLS). Objectives: To test the effect of apomorphine—a combined opioidergic and dopaminergic agonist—and subsequent selective antagonism by naloxone and metoclopramide on subjective and objective symptoms in patients with idiopathic RLS. Methods: Nine patients with RLS were pretreated with oral domperidone for three days. A modified suggested immobilisation test (SIT) was carried out between 8 pm and 1 am under the following conditions of intravenous drug administration: baseline–apomorphine–apomorphine plus naloxone–apomorphine plus metoclopramide. Outcome variables were a visual analogue scale (VAS) of subjective RLS symptoms and EMG documented periodic leg movements while awake (PLMW). Results: Compared with baseline, apomorphine resulted in a rapid and significant improvement in subjective RLS symptoms as measured by VAS (54.5% improvement; p = 0.011), and an almost immediate cessation of PLMW, measured by PLMW index (98.0% improvement; p = 0.012). Neither additional naloxone nor metoclopramide blocked this effect significantly. While given apomorphine with metoclopramide, there was a trend to reappearance of PLMW. Conclusions: Apomorphine may be an effective treatment for idiopathic RLS. Its effectiveness may reflect both to its dopaminergic and its opioidergic activity, and is not diminished significantly by blocking only one of these pathways. The trend to a worsening of the PLMW index with metoclopramide hints at a primarily dopaminergic effect of apomorphine in idiopathic RLS.

Objective: Although placebo controls are a standard measure in clinical trials the mechanisms underlying placebo effects are still not fully understood. We hypothesised that information about the likelihood of receiving placebo might influence the perception of adverse effects in volunteers participating in a clinical trial. Methods: Healthy subjects received either nifedipine 20mg or placebo in an adaptive two-stage crossover study. Sixty subjects were randomised to a group given either correct (50% chance) or misleading (100% chance) information about the likelihood of receiving the active drug. A sum of the severity scores from visual analogue scales over all individual adverse effects was defined as the primary endpoint. Results: The analysis revealed no difference in the primary endpoint between the two groups. This lack of difference may in part be attributable to a conditioning effect as on the first study day higher symptom scores were reported by the participants than on the second study day. Furthermore, the day effect seemed to arise mainly when the first day treatment was the placebo. For the placebo the day effect was clearly significant (p = 0.012), with higher scores on the first day. A further explorative finding in patients given placebo was a tendency for higher scores in the group with the misleading information (p = 0.08). Nothing of that sort was found in the analysis for active treatment. The day effect collapsed and the factor information did not show any tendency of being a potential influence. Conclusions: In the present study we did not find a statistically significant effect of misleading information on reported adverse events. The large treatment and day effects observed made it difficult to detect a potential small information effect. However, this study excluded a strong and relevant effect of information on the frequency and severity of reported adverse events.

ZusammenfassungGegenstand und Ziel: Ziel dieser Pilotstudie war die Visualisierung der Primärverteilung des Botulinumtoxin(BoNT)-Bolus bei Oberarmspastik (OAS) und unterschiedlicher Volumina beim Gesunden (K) mittels Magnetresonanztomografie (MRT).Material und Methoden: Sagittale dynamische BFFE-Sequenzen überwachten die Injektion von 1 ml NaCl/BoNT-Bolus in den spastischen (n = 4), 1 ml NaCl in den rechten gesunden, bzw. 2 ml NaCl in den linken gesunden M. bizeps brachii bei K (n = 6). Ergebnisse: Eine unmittelbar zunehmende Hyperintensität parallel der Muskelfasern war in der primären Längsausdehnung (Mittel: K: 1 ml: 5,3 cm; 2 ml 5,7 cm; OAS: 3,3 cm) in OAS vs. 1 ml K signifikant niedriger (p = 0,008). Die primäre Tiefenausdehnung (Mittel: K: 1 ml: 0,5 cm; 2 ml: 0,9 cm; OAS: 0,7 cm) war in 2 ml K vs. 1 ml K signifikant (p = 0,002), und in OAS vs. 1 ml K (nicht signifikant) erhöht.Schlussfolgerungen: Im Gesunden verteilte sich der Hauptanteil längs der Muskelfasern. Im spastischen Muskel war die Längsausdehnung signifikant vermindert.Klinische Relevanz: Der BoNT-Effekt könnte durch Verteilung in verschiedene Tiefen (Stichrichtung normal zu Muskelfasern) sowie bei OAS durch zusätzliche Injektionsstellen entlang des Muskelfaserverlaufs verbessert werden.

Aims Non-steroidal anti-inflammatory drugs (NSAIDs) are believed to counteract inflammation and inflammation-induced sensitization of nociceptors by inhibiting peripheral prostaglandin synthesis. We evaluated an experimental pain model for NSAIDs, that included an inflammatory component to mimic clinical inflammatory pain conditions. Methods The study was performed in a randomized, double-blind, placebo-controlled, two-way crossover design on 32 healthy volunteers. A small skin area of the proximal upper leg was irradiated with a UVB source using three times the individually estimated minimal erythema dose. Twenty hours after irradiation skin temperature, heat pain threshold and tolerance in sunburn spot were measured using a thermal sensory testing. These measurements were repeated 2 h after medication of either 800 mg ibuprofen as single oral dose or placebo capsules. Effects of ibuprofen on outcome parameters were assessed with analyses of covariance (ancova). Results Placebo did not affect heat pain threshold or tolerance. By contrast, ibuprofen increased heat pain threshold by 1.092 °C [confidence interval (CI) 0.498, 1.695; P = 0.0008) compared with placebo. Heat pain tolerance also increased significantly by 1.618 °C (CI 1.062, 2.175; P = 0.0001). Conclusion The pain model we evaluated was well tolerated in all subjects and the effects of ibuprofen were highly significant. This model is simple, sensitive to NSAIDs’ effects and therefore has potential for future experimental pain studies.

BOLD-based functional MRI (fMRI) can be used to explicitly measure hemodynamic aspects and functions of human neuro-physiology. As fMRI measures changes in regional cerebral blood flow and volume as well as blood oxygenation, rather than neuronal brain activity directly, other processes that may change the above parameters have to be examined closely to assess sensitivity and specificity of fMRI results. Physiological processes that can cause artifacts include cardiac action, breathing and vasomotion. Although there has been substantial research on physiological artifacts and appropriate compensation methods, controversy still remains on the mechanisms that cause the fMRI signal fluctuations. Respiratory-correlated fluctuations may either be induced by changes of the magnetic field homogeneity due to moving organs, intra-thoracic pressure differences, respiration-dependent vasodilation or oxygenation differences. The aim of this study was to characterize the impact of different breathing patterns by varying respiration frequency and/or tidal volume on EPI time courses of the resting human brain. The amount of respiration-related oscillations during three respiration patterns was quantified, and statistically significant differences were obtained in white matter only: p < 0.03 between 6 vs. 12 ml/kg body weight end tidal volume at a respiration frequency of 15/min, p < 0.03 between 12 vs. 6 ml/kg body weight and 15 vs. 10 respiration cycles/min. There was no significant difference between 15 vs. 10 respiration cycles/min at an end tidal volume of 6 ml/kg body weight (p = 0.917). In addition, the respiration-affected brain regions were very similar with EPI readout in the a-p and l-r direction. Based on our results and published literature we hypothesize that venous oxygenation oscillations due to changing intra-thoracic pressure represent a major factor for respiration-related signal fluctuations and increase significantly with increasing end tidal volume in white matter only.

Meningeal involvement of multiple myeloma is rare. A patient with multiple myeloma presented with bilateral abducens nerve palsies. In the MRI neither lytic skull lesions nor meningeal enhancement could be found. The diagnosis was based on CSF studies and cytology. A neurologic remission was achieved with intrathecal chemotherapy.

Introduction Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting. Methods In this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM). Results A total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint. Conclusions Early treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis. Trial registration Clinicaltrials.gov: NCT01867645

We describe two linked cases of botulinum toxin intoxication to provide the clinician with a better idea about how botulism cases may present since early diagnosis and treatment are crucial in botulism. Botulinum toxin is the strongest neurotoxin known.Methods:We review the available literature, the compiled clinical data, and observations.Results:After a slow onset of clinical signs a married couple living in Vienna presented with dysphagia, difficulties in accommodation, inability to sweat, urinary and stool retention, dizziness, and nausea. They suffered intoxication with botulinum toxin type B. Botulism is a rarely occurring disease in Austria. In the last 21 years there were only twelve reported cases.Conclusion:Both patients went to a general practitioner as well as several specialists before they were sent to and correctly diagnosed at our outpatient department. To avoid long delays between intoxication and diagnosis we think it is crucial to advert to the complex symptoms a nonsevere intoxication with botulinum toxin can produce, especially since intoxications have become rare occurrences in the industrialized societies due to the high quality of industrial food production.

Background and purpose The UV-B model is an established pain model of different types of hyperalgesia in animal and human pain research. Beside the skin region of the sunburn in human volunteers pinprick hyperalgesia has been described in a large zone of non-inflamed skin adjacent to the sunburn. However, there are opposing results on the existence of pinprick hyperalgesia and most notably a controversial discussion is still on-going whether this mechanical hyperalgesia in the undamaged tissue adjacent to and at some distance from the site of inflammation is of peripheral or central origin. We therefore addressed this in our study by hypothesising that pinprick hyperalgesia around a circular spot of UV-B inflamed skin is not reduced by a superficial local anaesthetic block and therefore underlies centrally mediated mechanisms. Methods This exploratory study was conducted in a prospective, controlled, randomised, single-blinded fashion in relation to the study hypothesis in 12 healthy volunteers. Before circular irradiation with UV-B light (3-times the individual minimal erythema dose at both thighs), a strip of continuous intradermal local anaesthetic block with lidocaine 2% was established via two single plasmaphoresis hollow fibres. These were positioned perpendicular to one thigh overlapping on the midline of the leg at the distal part of the planned irradiation site, and compared with the contralateral control side without anaesthetic block. The local anaesthetic block was established and then maintained via a syringe pump. The area of pinprick hyperalgesia was measured by pricking on a large skin surface including 360° around the circular irradiation site. This was done with a slightly painful pin (256 mN) until 8h after irradiation. Primary outcome was the area of pinprick hyperalgesia in the skin adjacent to the sunburn at 8h. Results Large areas of mechanical hyperalgesia to pinprick surrounding the adjacent skin of the sunburn developed on both sides after 8h without any significant difference between the side of the anaesthetic strip showing an area of 72.6±39.7 cm2 (mean±SD) and the control side (59.1±20.1 cm2); p = 0.24. Moreover, mechanical hyperalgesia to various pin stimuli of different strength was unchanged by the anaesthetic block. Conclusion This trial provides evidence that the development of mechanical hyperalgesia surrounding an experimental sunburn was not influenced by continuous peripheral afferent blockade with local anaesthetic at 8h after UV-B irradiation. Our data support the hypothesis that in the UV-B model peripheral nociceptive afferent input of inflamed skin may enhance central hypersensitivity of mechanosensitive nociceptors in a larger receptive field far beyond the inflamed skin. Furthermore, these findings are in line with other pain models demonstrating comparable central hypersensitivity around the site of injury. Implications As for other pain models this finding provides further evidence that the UV-B model offers secondary mechanical hyperalgesia in addition to its known primary hyperalgesia. Consequently, this is a further validation for the utilisation of the UV-B model in human pain research.

The ultraviolet B (UVB) sunburn model was characterized with a comprehensive battery of quantitative sensory testing (QST). Primary hyperalgesia in UVB-irradiated skin and secondary hyperalgesia in adjacent nonirradiated skin were studied in 22 healthy subjects 24h after irradiation with UVB at 3-fold minimal erythema dose of a skin area 5 cm in diameter at the thigh and compared to mirror-image contralateral control areas. The time course of hyperalgesia over 96 h was studied in a subgroup of 12 subjects. Within the sunburn area, cold hyperesthesia (P=.01), profound generalized hyperalgesia to heat (P.001), cold (P.05), pinprick and pressure (P.001), and mild dynamic mechanical allodynia (P.001) were present. The finding of cold hyperalgesia and cold hyperesthesia is new in this model. The sunburn was surrounded by large areas of pinprick hyperalgesia (mean±SEM, 218±32 cm(2)) and a small rim of dynamic mechanical allodynia but no other sensory changes. Although of smaller magnitude, secondary hyperalgesia and dynamic mechanical allodynia adjacent to the UVB-irradiated area were statistically highly significant. Primary and secondary hyperalgesia developed in parallel within hours, peaked after 24-32 h, and lasted for more than 96 h. These data reveal that the UVB sunburn model activates a broad spectrum of peripheral and central sensitization mechanisms and hence is a useful human surrogate model to be used as a screening tool for target engagement in phases 1 and 2a of drug development.

Neuropathische Schmerzsyndrome sind durch Lasionen oder Funktionsstorungen im Bereich des peripheren oder zentralen Nervensystems bedingt. Als Ursachen kommen Druckschadigungen (Beispiel: Bandscheibenvorfalle), entzundliche Veranderungen (Beispiele: Gurtelrose, Borreliose), Schadigungen durch Stoffwechselerkrankungen (Beispiel: Diabetes) Gifteinwirkungen (Beispiel: Alkohol) aber auch Durchblutungsstorungen in Frage.

Background and Objective The possible interference of combined laser hair removal and Botulinum toxin A (BoNT/A) injections in the treatment of axillary hyperhidrosis has not previously been explored. In order to examine this potential interference, we assessed the effect of BoNT/A on axillary hyperhidrosis with and without concomitant diode laser axillary hair removal. Study Design/Materials and Methods In a prospective, double blind, randomized cross over trial, nine patients suffering from primary axillary hyperhidrosis were laser-treated on one randomly assigned axilla. One week later, both axillas were injected intradermally with BoNT/A (100 MU per axilla). During the same session, the previously untreated axilla was lasered. Axillary sweat rates (in g/5 minutes.) were determined by gravimetry and compared at rest, during mental exercise, and during physical exercise. Additionally, subjective outcome measures were assessed by a visual analogue scale, Dermatology Life Quality Index, and Global Clinical Impression score. Results No differences were found regarding the effect of BoNT/A on previously laser-treated and laser co-treated sides over time course for any of the outcome parameters. Sweat production was reduced 3 weeks after BoNT/A treatment by 93.5% at rest, 96.5% during mental exercise, and 67% during physical exercise. Conclusions Concomitant laser hair removal does not interfere with BoNT/A treatment on axillary hyperhidrosis. Lasers Surg. Med. 42:211–214, 2010. © 2010 Wiley-Liss, Inc.

Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well.The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma.Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001.This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma.Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results.According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported.In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma.

Background Posterior capsule opacification (PCO) remains the most common long-term complication after cataract surgery. It can be treated by Nd:YAG laser capsulotomy, however, this may lead to other complications and laser treatment is not available in large parts of the developing world. Therefore, many studies try to find factors influencing the development of PCO. Objectives To summarise the effects of different interventions to inhibit PCO. These include modifications of surgical technique and intraocular lens (IOL) design, implantation of additional devices and pharmacological interventions. Search strategy We searched CENTRAL, MEDLINE, EMBASE, LILACS in January 2007 and reference lists of identified trial reports. Selection criteria We included only prospective, randomised and controlled trials with a follow-up time of at least 12 months. Interventions included modifications in surgical technique explicitly to inhibit PCO, modifications in IOL design (material and geometry), implantation of additional devices, and pharmacological therapy, compared to each other, placebo or standard treatment. Data collection and analysis Data were extracted and entered into Review Manager. Visual acuity data, PCO score and YAG capsulotomy rates were compared and a meta-analysis was performed when possible. Main results Fifty three studies were included in the review. The review was divided into three parts. (1) Influence of IOL optic material on the development of PCO. Compared to other materials, the meta-analysis of the included studies showed a significantly higher PCO score (overall effect: 12.39 (95% confidence interval: 9.82 to 14.95), scale 0 to 100) and YAG rate (odds ratio: 8.37 (3.74 to 20.36)) only in hydrogel IOLs. (2) Influence of IOL optic design on the development of PCO. There was a significantly lower PCO score (-8.65 (-10.72 to -6.59), scale 0 to 100) and YAG rate (0.19 (0.11 to 0.35)) in sharp edged than in round edged IOLs, however, not between 1-piece and 3-piece IOLs. (3) Influence of surgical technique and drugs on the development of PCO. There was no significant difference between different types of intra-/postoperative anti-inflammatory treatment except for treatment with an immunotoxin (MDX-A) leading to a significantly lower PCO rate. Authors' conclusions Due to the highly significant difference between round and sharp edge IOL optics, IOLs with sharp (posterior) optic edges should be preferred. There is no clear difference between optic materials, except for hydrogel IOLs, that showed more PCO than the other materials. The choice of postoperative anti-inflammatory treatment does not seem to influence PCO development.

Normal tension glaucoma is a clinical condition in which the optic nerve is pathologically excavated and the visual field is disturbed. Nevertheless it has been assumed that intraocular pressure plays a role in the progression of visual field defects in this disease, but other, mainly vascular factors, have been discussed as well.The objective of this review is to assess the effects of medical and surgical treatments for normal tension glaucoma.Trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group trials register), MEDLINE, EMBASE and BIOSIS Previews. Bibliographies of identified trials were searched to find additional trials. In addition, investigators and pharmaceutical companies were contacted. Date of last search: January 2001.This review includes randomised controlled trials in which medical or surgical interventions were compared to no treatment, placebo or other treatment in people with normal tension glaucoma. Two reviewers independently assessed the full text copies of the possibly relevant trials. Trial quality was assessed according to the methods set out in Section 6 of the Cochrane Reviewers' Handbook (Clarke 2000).Data were extracted by two reviewers and results were compared for differences. Discrepancies were resolved by discussion. The heterogeneity of interventions, follow-up periods and outcomes did not allow for statistical combinations of the study results.According to the selection criteria on visual field loss, eight studies were included in this review. Only three studies focussed on patient relevant outcomes. In one trial a beneficial effect of lowering intraocular pressure was found, but only if data were corrected for cataract development. In two small studies a beneficial effect on visual field loss of brovincamine, a calcium antagonist was reported.In one study the effect of intraocular pressure lowering on visual field outcome was only significant when data were corrected for cataract development. The results for calcium antagonists are promising, but larger trials have to be performed. Studies that focussed on reduction of intraocular pressure or haemodynamic variables are not necessarily relevant for the outcome in people with normal tension glaucoma.

BACKGROUND: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice. METHODS: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A--Dysport (Dp) and Botox (Bx). RESULTS: Four key areas of evidence were identified: nonclinical and preclinical studies; studies exploring the diffusion characteristics and effects of complexing proteins; comparative experimental data from human studies; and clinical studies. Nonclinical data indicate that the principal reasons for differences in unit potency between the two products are dilution artefacts in the mouse assay. Use of saline as a diluent, at high dilutions, results in significant loss of potency in the Bx assay, whereas use of gelatin phosphate buffer in the Dp assay procedure protects the toxin during dilution. The published data on mouse assays show a Dp : Bx unit ratio range of 2.3-2.5 : 1 in saline and 1.8-3.2 : 1 in gelatin phosphate buffer. Data indicate that complexing proteins or size of the complex, which is highly pH sensitive, play no role in toxin diffusion and that Dp and Bx have similar diffusion characteristics when used at comparable doses. Randomized, controlled clinical studies indicate that 3 : 1 is more appropriate than 4 : 1, but the two products are not equivalent at this ratio. Comparative human experimental studies using the extensor digitorum brevis test, facial lines and anhidrotic action halo tests support dose-conversion ratios less than 3 : 1. LIMITATIONS: Data comparing dose equivalence ratios from the non-clinical setting should be extrapolated into the clinical setting with some caution. CONCLUSIONS: Dose-conversion ratios between Dp and Bx of 4 : 1 and greater are not supported by the recent literature.

The aim of this review was to evaluate the evidence for the treatment of phantom limb pain with mirror therapy.Randomised controlled studies were identified by a systematic search strategy in the databases "Medline" and "The Cochrane Library". The studies were evaluated using the quality criteria of the JADAD-scale.Three small-sized randomised controlled studies were identified. Unfortunately, these studies lacked methodological quality. One of them found a significant decrease of phantom pain after four weeks of daily mirror therapy sessions. Two other studies could not find a significant difference in the reduction of phantom limb pain between intervention- and control-groups. To date, there is only circumstantial evidence for mirror therapy in phantom pain. Hence, no firm recommendations regarding this treatment option are possible.More sufficiently powered randomised controlled studies with high methodological quality are mandatory to investigate the analgesic effect of mirror therapy in phantom limb pain.

Mouse units used to quantify the activity of botulinum A toxin preparations are not equivalent and issues concerning efficacy and safety remain with regard to their respective potencies and diffusion qualities in human tissue. We compared the effects of Botox (BOT) and Dysport (DYS) in different doses and dilutions in a human skin model. Eighteen (8 women, 10 men) healthy volunteers, aged 28.4 years +/- 5.7 years were injected intradermally with pure saline, BOT and DYS at 16 points in the abdomen in random order and in a double-blind condition, using two conversion ratios (1:3 and 1:4) and three different dilution schemes. For an objective outcome, the Ninhydrin sweat test was used to compare the anhidrotic areas. Both preparations showed a linear dose and dilution relationship with similar variances of responses for anhidrosis and hypohidrosis, indicating the same reliability of response. The dose equivalence conversion ratios (BOT: DYS) were 1:1.3 for anhidrosis and 1:1.6 for hypohidrosis (1:1.1-1.5 and 1:1.4-1.8 95% confidence intervals). The diffusion characteristics of both products were similar. A dose equivalence factor of more than 1:2 (BOT:DYS) is not supported by these objective and reproducible data.