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Background For many indications, BoNT/A is repetitively injected with the risk of developing neutralizing antibodies (NABs). Therefore, it is important to analyze whether there is a difference in antigenicity between the different licensed BoNT/A preparations. Methods In this cross-sectional study, the prevalence of NABs was tested by means of the sensitive mouse hemidiaphragm assay (MHDA) in 645 patients. Patients were split into those having exclusively been treated with the complex protein-free incoBoNT/A preparation (CF-MON group) and those having started BoNT/A therapy with a complex protein-containing BoNT/A preparation (CC-I group). This CC-I group was split into those patients who remained either on abo- or onaBoNT/A (CC-MON group) and those who had been treated with at least two BoNT/A preparations (CC-SWI group). To balance treatment duration, only CC-MON patients who did not start their BoNT/A therapy more than 10 years before recruitment (CC-MON-10 group) were further analyzed. The log-rank test was used to compare the prevalence of NABs in the CF-MON and CC-MON-10 group. Results In the CF-MON subgroup, no patient developed NABs. In the CC-I group, 84 patients were NAB-positive. NABs were found in 33.3% of those who switched preparations (CC-SWI) and in 5.9% of the CC-MON-10 group. Kaplan–Meier curves for remaining NAB-negative under continuous BoNT/A therapy were significantly different (p Conclusion Frequent injections of a complex protein-containing BoNT/A preparation are associated with significantly higher risks of developing NABs than injections with the same frequency using the complex protein-free incoBoNT/A preparation.

Aim of the study: To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. Patients and Methods: A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients’ charts. Results: The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. Conclusions: Patients’ drawings of their course of disease severity helps to easily detect “difficult to treat” primary and secondary nonresponders to BoNT on the one hand, but also to detect “golden responders” on the other hand.

Background Repeated injections with abo- or onabotulinumtoxin type A (aboBoNT/A, onaBoNT/A) may lead to induction of neutralizing antibodies (NABs) and/or a secondary treatment failure (STF). The relation between NABs and STF is still unclear. Aim of the study To demonstrate that a significant improvement can be observed in patients with STF after abo- or onaBoNT/A-treatment when switched to incobotulinumtoxin type A (incoBoNT/A) and that in NAB-positive patients without STF abo- or onaBoNT/A-treatment can be continued without significant worsening. Methods Paralysis times (PT) of the mouse hemidiaphragm assay (MHDA) and clinical outcome (TSUI-score) was analyzed in 60 patients with cervical dystonia (CD) and STF after abo- or onaBoNT/A-treatment (STF-group) who were switched to incobotulinumtoxin type A (incoBoNT/A). These data were compared to those of 34 patients who were exclusively treated with incoBoNT/A (INCO-group). Furthermore, PTs and TSUI-scores were followed up over 7 years in 9 patients with NABs but without STF who were switched to inco-BoNT/A (SWI-group) and 9 other patients with NABs who remained on their previous BoNT/A preparation (NO-SWI-group). Results In the STF-group, a significant improvement of TSUI-scores could be detected after switch to incoBoNT/A. This improvement was less pronounced than in the INCO-group. There was no significant difference in long-term outcome between the SWI- and NO-SWI-group. Conclusion The best strategy is to avoid the induction of NABs. A switch to incoBoNT/A may lead to improvement in patients with STF. However, in some patients with NABs without STF, BoNT/A-treatment can be continued without significant worsening.

The aim of this study was to demonstrate that pseudocholinesterase (CHE) serum level is a useful diagnostic biomarker for untreated Wilson’s disease (WD). Between 2013 and 2019, about 75 patients were referred to the outpatient department of the University of Düsseldorf with suspected Wilson’s disease. In 31 patients with suspected Wilson’s disease (WD-SUS-group), WD was excluded by means of investigations other than analysis of blood and urine. A total of 27 parameters of blood and urine in these 31 patients were compared to those of 20 de novo patients with manifest WD (WD-DEF-group), which parameter showed the highest significance level of difference between the WD-DEF-group and the WD-SUS-group. Thereafter, receiver operating characteristics (ROC-curves) were analyzed to evaluate which parameter showed the largest area under the curve (AUC) to detect WD. Finally, a logistic regression analysis was performed to analyze which combination of parameters allowed the best classification of the 51 patients either into the WD-DEF-group or into the WD-SUS-group. CHE showed the highest significance level for a difference between the WD-DEF- and WD-SUS-group, had the highest AUC, and, in combination with ceruloplasmin, allowed 100% correct classification. Without CHE, no other combination of parameters reached this level of correct classification. After the initiation of treatment, which regularly results in an improvement in CHE, the high diagnostic accuracy of this biomarker was lost. Cholinesterase turns out to be an excellent biomarker for differentiation between untreated de novo patients with manifest WD and heterozygotic gene carriers.

Recently, it was demonstrated that copper complexes and 3,4-diaminopyridine can effectively reduce the activity of the botulinum neurotoxin light chain. The aim of the present study was to indicate that treatment with an antidote may have a major influence, not only on the extremely rare disease of botulism, but also on the much more frequently occurring side effects experienced during BoNT therapy. This was a retrospective chart review of patients who were regularly treated with BoNT for various indications. The percentage of patients with clinical signs of overdosing was determined. In patients with facial dystonia, double vision and ptosis occurred as side effects. In patients with cervical dystonia, neck weakness and dysphagia were observed as the most frequent side effects. In oromandibular and oropharyngeal dystonia, abnormal tongue movements and dysphagia occurred frequently. In writer’s cramp and mild post-stroke hand spasticity, severe paresis of the injected and non-injected finger muscles was observed. Additionally, in the BoNT treatment of pain syndromes (such as tension headaches or migraines), neck weakness may occur. Across all indications for clinical BoNT applications, clinical signs of BoNT overdosing may occur in up to 5% of the BoNT-treated patients. Therefore, the development of an antidote for BoNT overdoses would be very much appreciated and would have a major influence on the management of BoNT therapy.

The precise definition of prevalence of neutralizing antibodies (NABs) affords cross-sectional testing of a cohort. But in most studies, only selected patients are tested. This leads to gross underestimation of NAB-prevalence, and the opinion that induction of NABs is a rare phenomenon in botulinum neurotoxin (BoNT)/A-therapy. However, recent cross-sectional studies report annual incidences between 1 and 2% in patients being treated with a complex protein (CP)-containing preparation. This implies that NAB-prevalence above 10% has to be expected in patients being treated for more than 10 years. High dose per session and long duration of treatment are relevant risk factors for induction of NABs. In patients exclusively treated with the CP-free incobotulinumtoxin A (incoBoNT/A) preparation Xeomin® no NAB-induction has been reported so far. In patients with NABs switching to incoBoNT/A may lead to a decline of NAB-titers. In patients with NABs under treatment with a CP-containing BoNT/A-preparation it may take years of treatment until a second treatment failure (STF) becomes clinical manifest. In a cohort of 59 patients with partial STF patients’ reports on the reduction of BoNT-activity predicted the presence of NABs better than treatment related data produced by the treating physicians.

Aim of the study was to analyze the ability of long-term treated patients with Wilson’s disease (WD) to run a distance of 40 m. 30 WD-patients from a single center were consecutively recruited. All patients were able to walk a distance of 40 m without walking aids. Vertical ground reaction forces (GRF-curves) were analyzed by means of an Infotronic® gait analysis system (CDG®) and correlated with clinical and laboratory findings. Results of the WD-patients were compared to those of an age-and sex-matched control group. 25 of the 30 WD-patients were able to run. Patients being unable to run had a significantly (p < 0.03) higher non-motor score. In comparison to the controls speed of running was significantly (p < 0.02) reduced in WD-patients. Their duration of foot contact on the ground lasted significantly (p < 0.05) longer. Running was more irregular in WD and the variability of times to peak of the GRF-curves was significantly (p < 0.05) increased. All running parameters extracted from the GRF-curves of the CDG® did not correlate with severity of WD. Cadence of running was significantly (p < 0.03) negatively correlated with serum liver enzyme levels. Running appears to be rather unimpaired in long-term treated WD, only 16% of the 30 WD-patients were unable to run. This knowledge is highly relevant for the patient management, but because of the missing correlation with severity of WD, analysis of running is of minor importance for monitoring WD-therapy.

Background: The response to BoNT is not uniform; a broad spectrum of responses and side-effects usually occurs. This study aimed to show special cervical dystonia cases with therapy response very different to normal treatment course which indicate the extreme ends of therapy spectrum. Patients: Clinical data and course of treatment of five long-term treated patients with cervical dystonia out of therapy response norms are presented: a patient who was supersensitive to standard dose and has required dose adjustment to lower dose of BoNT; one patient who worsened under a standard dose, but responded excellently to twice the standard dose; one insensitive patient who responded poorly for years to a dose well above the standard dose, but responded when dose was further increased; and two patients with a totally different response pattern to BoNT/A preparation 1, but the development of a neutralizing antibody induced secondary treatment failure in both cases and a totally different response after switch to BoNT/A preparation 2. Conclusions: These five patients indicate that the response of a patient to a BoNT preparation may be unexpected. Therefore, cautious onset of BoNT therapy is recommended as well as consequent dose adjustment later on and even switch to another BoNT/A preparation when a patient has already developed NABs against BoNT/A.

Background and Objectives: The present study aims to analyze the complex patient/treating physician interaction at onset of botulinum toxin (BoNT) therapy in patients with idiopathic cervical dystonia (CD) and the influence of high initial doses on long-term outcomes. Materials and Methods: A total of 74 CD patients with well-documented courses of BoNT treatment were consecutively recruited after written informed consent. Patients had to rate the amount of improvement of CD in percent of severity of CD at onset of BoNT therapy. They had to draw the course of disease severity (CoD) of CD from the onset of symptoms until the onset of BoNT therapy and from the onset of BoNT therapy until recruitment. The remaining severity of CD was estimated by the treating physician using the TSUI score. Demographic- and treatment-related data were extracted from the charts of the patients. Seventeen patients with suspected secondary treatment failure (STF) were tested for the presence of antibodies. Results: Depending on the CoD before BoNT therapy, three patient subgroups could be distinguished: rapid onset, continuous onset and delayed onset groups. Time to BoNT therapy, increase in dose and improvement were significantly different between these three groups. In the rapid onset group, with the highest initial doses, the best improvement was reported, but the highest number of patients with an STF and with neutralizing antibodies was also observed. Conclusion: The use of high initial doses in the BoNT therapy of CD is associated with a rapid response and quick success; however, it leads to an elevated risk for the development of a secondary treatment failure and induction of neutralizing antibodies.

Abnormal gait is a common initial symptom of Wilson’s disease, which responds well to therapy, but has not been analyzed in detail so far. In a pilot study, a mild gait disturbance could be detected in long-term treated Wilson patients. The question still is what the underlying functional deficit of this gait disturbance is and how this functional deficit correlates with further clinical and laboratory findings. In 30 long-term treated Wilson patients, the vertical component of foot ground reaction forces (GRF-curves) was analyzed during free walking without aid at the preferred gait speed over a distance of 40 m. An Infotronic® gait analysis system, consisting of soft tissue shoes with solid, but flexible plates containing eight force transducers, was used to record the pressure of the feet on the floor. Parameters of the GRF-curves were correlated with clinical scores as well as laboratory findings. The results of Wilson patients were compared to those of an age- and sex-matched control group. In 24 out of 30 Wilson patients and all controls, two peaks could be distinguished: the first “heel-on” and the second “push-off” peak. The heights of these peaks above the midstance valley were significantly reduced in the patients (p < 0.05). The time differences between peaks 1 or 2 and midstance valley were significantly negatively correlated with the total impairment score (p < 0.05). Gait speed was significantly correlated with the height of the “push-off” peak above the midstance valley (p < 0.045). The GRF-curves of free walking, long-term treated patients with Wilson’s disease showed a reduced “push-off” peak as an underlying deficit to push the center of mass of the body to the contralateral side with the forefoot, explaining the reduction in gait speed during walking.

A family is described as having two recessively inherited metabolic diseases and three differently affected children. During the explantation of a drain tube grommet under general anesthesia, a prolonged resuscitation and wake-up period occurred in the key case when he was 8 years old. This led to a family screening for butyrylcholinesterase deficiency, which was confirmed not only in the key case but also in his 5-year-old sister; it was not confirmed in his 10-year-old brother. However, the key case not only had reduced serum levels of BCHE, but also elevated liver enzyme levels, which are atypical for BCHE deficiency. After the exclusion of viral and autoimmune hepatitis, Wilson’s disease (WD) was eventually diagnosed and also confirmed in his elder brother, but not in his sister. This family is presented to highlight an extremely rare WD-patient in whom a low serum level of BCHE did not occur because of WD but because of BCHE deficiency.

This study analyses the influence of the course of the disease of idiopathic cervical dystonia (CD) before botulinum toxin (BoNT) therapy on long-term outcomes. 74 CD-patients who were treated on a regular basis in the botulinum toxin outpatient department of the University of Düsseldorf and had received at least 3 injections were consecutively recruited after written informed consent. Patients were asked to rate the amount of change of CD in relation to the severity of CD at begin of BoNT therapy (IMPQ). Then they had to draw the course of disease of CD from onset of symptoms until initiation of BoNT therapy (CoDB-graph) on a sheet of paper into a square of 10 × 10 cm2 size. Remaining severity of CD was estimated by the treating physician using the TSUI-score. Demographical and treatment related data were extracted from the charts of the patients. Depending on the curvature four different types of CoDB-graphs could be distinguished. Time to BoNT therapy, increase of dose and improvement during BoNT treatment were significantly (p &lt, 0.05) different when patients were split up according to CoDB-graph types. The lower the age at onset of symptoms, the shorter was the time to therapy (p &lt, 0.02). Initial dose (p &lt, 0.04) and actual dose (p &lt, 0.009) were negatively correlated with the age of the patients at recruitment. The course of disease of CD before BoNT therapy has influence on long-term outcome. This has implications on patient management and information on the efficacy of BoNT treatment.

Background: The aim of this study was to demonstrate an increase in muscle action potentials and an enhancement of the efficacy of botulinum toxin (BoNT) after mechanical leg vibration. Methods: A 53-year-old healthy male volunteer underwent vibration ergometry training (VET) every morning and every evening for 10 min for 14 days. Compound muscle action potential (CMAP) of the right (R) and left (L) extensor digitorum brevis (EDB) muscle was analyzed by supramaximal peroneal nerve stimulation before and after VET 12 times during the 14 days. Thereafter, VET was stopped and 20 U incobotulinumtoxin (incoBoNT/A) were injected into the right EDB. During the following 10 days, CMAP of both EDBs was tested 12 times. Results: Under VET, the CMAP of both EDBs significantly increased (L: p < 0.01; R: p < 0.01). During the first 14 days, CMAP of the left EDB before VET was significantly (

Background: Wilson’s disease (WD) is an autosomal-recessive disorder of copper deposition caused by pathogenic variants in the copper-transporting ATP7B gene. There is not a clear correlation between genotype and phenotype in WD regarding symptom manifestations. This is supported by the presentation of genetically identical WD twins with phenotypic discordance and different response behavior to WD-specific therapy. Case Presentation: One of the female homozygous twins (age: 26 yrs) developed writing, speaking, swallowing and walking deficits which led to in-patient examination without conclusive results but recommended genetic testing. Both sisters were tested and were heterozygous for the C.2304dupC;p(Met769Hisf*26) and the C.3207C>A;p(His1069Gln) mutation. Self-medication of the affected sibling with 450 mg D-penicillamine (DPA) did not prevent further deterioration. She developed a juvenile parkinsonian syndrome and became wheelchair-bound and anarthric. A percutaneous endoscopic gastrostomy was applied. Her asymptomatic sister helped her with her daily life. Despite the immediate increase of the DPA dose (up to 1800 mg within 3 weeks) in the severely affected patient and the initiation of DPA therapy (up to 600 mg within 2 weeks) in the asymptomatic patient after the first visit in our institution, liver function tests further deteriorated in both patients. After 2 months, the parkinsonian patient started to improve and walk again, but experienced several falls, broke her right shoulder and underwent two necessary surgical interventions. With further consequent copper elimination therapy, liver dysfunction improved in both patients, without need for orthotopic liver transplantation (LTX) in the severely affected patient. Her excellent recovery of liver and brain dysfunction was only transiently interrupted by the development of a nephrotic syndrome which disappeared after switching to Cuprior®. Unfortunately, she died from fulminant pneumonia. Conclusion: Despite identical genetic disposition, WD symptom presentations may develop differently in monozygotic twins, and they may need to be placed on a very different therapeutical regimen. The underlying gene-environment interaction is unclear so far.

Patients' rating of the effectiveness of and quality of life after long-term botulinum toxin (BoNT) injection therapy up to 22 years and treating physician's rating of the therapy effect in patients with idiopathic cervical dystonia (CD) are analysed in a large monocentric cross-sectional study.Patients (n = 221) who received uninterrupted, long-term treatment for CD (≥10 BoNT injection cycles) in a BoNT outpatient clinic underwent detailed clinical investigation, Tsui scoring, rated post-treatment CD severity as a percentage of CD severity prior to BoNT injection (patient's subjective scoring of the treatment effect (PSSTE)), and completed the CDQ-24 quality of life (QoL) questionnaire. Correlations between demographics, treatment-related data and QoL were analysed by linear regression, analysis of variance and pairwise single comparisons.Treating physicians and patients rated mean ongoing treatment effect as50%. There was high variability of duration of treatment, PSSTE, Tsui score and CDQ-24 across all patients. PSSTE was significantly correlated with Tsui score (p .001) and all CDQ-24 subscores (p .003). Tsui score and CDQ-24 were significantly correlated (p .001), but the correlation was lower than between PSSTE and total CDQ24. CDQ-24 revealed a significant improvement with duration of therapy. PSSTE and Tsui score did not change with duration of BoNT treatment.Patients with CD who receive up to 22 years' continuous BoNT treatment experience a50% mean reduction of symptoms and a significant improvement of QoL with duration of treatment. A highly significant correlation exists between patients' and physicians' rating of treatment effectiveness.

Objective Outcome differences between selective abobotulinumtoxin type A (aboBoNT/A) injections into the soleus (SOL) and gastrocnemius (GAS) muscles were investigated in post-stroke patients with spastic foot drop. Methods A monocentric observational study was conducted at a university hospital botulinum toxin clinic including 24 free-walking adult, botulinum toxin-naive patients with post-stroke hemiplegia. AboBoNT/A (800 MU in 4 mL saline) was injected into the SOL or GAS muscle under electromyographic guidance. After 30 days post-injection, the effect of aboBoNT/A injection was assessed by patients. The treating physician scored spasticity and measured angles at the knee and ankle joint and gait speed. Results After 30 days, significant improvements of subjective and objective outcome measures were observed. No significant difference was observed in the modified Ashworth scale, gait speed, ankle and knee angles, or their angle combinations between the SOL and GAS groups. Tendencies toward greater active range of motion (RoM) improvement in the SOL group and passive RoM improvement in the GAS group were observed. The difference between active and passive ankle extensions plus knee flexions was significantly larger in the SOL group. Conclusions Selective 800 MU aboBoNT/A injections into the SOL or GAS muscle were effective but without relevant clinical difference.

This study investigated the clinical long-term effect of incobotulinumtoxinA (incoBoNT/A) in 33 cervical dystonia (CD) patients who had developed partial secondary therapy failure (PSTF) under previous long-term botulinum toxin (BoNT) treatment. Patients were treated four times every 12 weeks with incoBoNT/A injections. Physicians assessed treatment efficacy using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the baseline visit, week 12 and 48. Patients rated quality of life of CD with the Craniocervical Dystonia Questionnaire (CDQ-24). Titres of neutralizing antibodies(NAB) were determined at start of the study and after 48 weeks. All patients had experienced significant and progressive worsening of symptoms in the last 6 months of previous BoNT treatment. Repeated incoBoNT/A injections resulted in a significant reduction in mean TWSTRS at week 12 and 48. Patients' rating of quality of life was highly correlated with TWSTRS but did not change significantly over 48 weeks. During the 48 weeks -period of incoBoNT/A treatment NAB titres decreased in 32.2%, did not change in 45.2%, and only increased in 22.6% of the patients. Thus, repeated treatment with the low dose of 200 MU incoBoNT/A over 48 weeks provided a beneficial clinical long-term effect in PSTF and did not booster titres of NAB.

Botulinum neurotoxin type A (BoNT/A) injections have to be administered repeatedly to achieve a rather stable, high level of improvement. This study aimed to take a look at changes in the daily routine of a BoNT/A outpatient clinic due to the SARS-CoV-2 pandemic lockdown, analyze the impact of SARS-CoV-2-induced re-injection delay on outcomes in patients with cervical dystonia (CD) (n = 36) and four other disease entities (n = 58), and study the influence of covariables, including previous injections and doses. For the present observational study, the first 100 patients who were scheduled to have an appointment between April 20 and May 18 during the partial lockdown and also had been treated regularly before the lockdown were recruited. Clinical and demographical characteristics and treatment-related data from the previous visits were extracted from charts. Time delay, symptom severity assessment, and TSUI score (if applicable) were gathered at the first coronavirus pandemic lockdown emergency visit for each patient. Of the 94 patients who could come to the clinic, 48 reported a delay and 44 reported worsening during the delay. Delays ranged from 1 to 63 days, the mean delay was 23 days, and the mean worsening was 26% compared to the previous visit. A significant correlation was found between the duration of the delay and the patient’s rating of worsening (PwP). In CD patients, the physician´s rating of CD worsening by the TSUI score (ATUSI-PTSUI) was significantly correlated with general worsening (DwP) and the TSUI at the last visit (PTSUI). A small delay of a few weeks led to a similar worsening of symptoms in CD and all other disease entities and to relapse on a higher level of severity. This relapse can only be compensated by continuous treatment up to at least 1 year until patients reach the same level of treatment efficacy as that before the SARS-CoV-2 pandemic.

Aim of the Study: To demonstrate general progression of symptoms in cervical dystonia (CD) on the one hand and improvement of some special symptoms on the other hand after botulinum toxin (BoNT) therapy. Methods: 74 patients with idiopathic CD under continuous treatment in a BoNT outpatient department with at least three injections, completed a short questionnaire. They were asked whether pain, increased muscle tone and tension, reduced mobility of the head, abnormal head position, head tremor, or other symptoms had been present at the onset of BoNT-therapy and which symptoms were present at the time of recruitment. Patients had to rate actual severity of CD in percent of the severity of CD at the onset of BoNT-therapy. The TSUI score was determined by the treating physician. Blood samples were taken to analyze induction of neutralizing antibodies. Results: Mean improvement of CD reported by the patients and scored by the physician was about 50%. The frequency of all symptoms increased with duration of therapy. The symptom most frequently improved was abnormal head position. The longer the time span between onset of symptoms and onset of BoNT-therapy was, the higher was the actual TSUI score and the lower the improvement reported. Twelve patients had positive antibody tests. Conclusions: Patients experience a progression of CD, but recognize improvement of abnormal head position due to BoNT-therapy. The longer patients have been without BoNT- therapy, the poorer is the long-term outcome independent on duration of BoNT treatment. Therefore BoNT-therapy should be initiated as early as possible.

Background: Botulinum toxin type B (BoNT/B) has been recommended as an alternative for patients who have become resistant to botulinum toxin type A (BoNT/A). This study aimed to compare the clinical effect, within a patient, of four injections with low doses of rimabotulinumtoxinB with the effect of the preceding abobotulinumtoxinA (aboBoNT/A) injections. Methods: In 17 patients with cervical dystonia (CD) who had become resistant to aboBoNT/A, the clinical effect of the first four rimabotulinumtoxinB (rimaBoNT/B) injections was compared to the effect of the first four aboBoNT/A injections using a global assessment scale and the TSUI score. Results: After the first two BoNT/B injections, all 17 patients responded well and to a similar extent as to the first two BoNT/A injections, but with more side effects such as dry mouth and constipation. After the next BoNT/B injection, the improvement started to decline. The response to the fourth BoNT/B injection was significant (p &lt, 0.048) lower than the fourth BoNT/A injection. Only three patients developed a complete secondary treatment failure (CSTF) and five patients a partial secondary treatment failure (PSTF) after four BoNT/B injections. In nine patients, the usual response persisted. Conclusion: With the use of low rimaBoNT/B doses, the induction of CSTF and PSTF to BoNT/B could not be avoided but was delayed in comparison to the use of higher doses. In contrast to aboBoNT/A injections, PSTF and CSTF occurred much earlier, although low doses of rimaBoNT/B had been applied.

Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.

BACKGROUND For future development of machine learning tools for gait impairment assessment after stroke, simple observational whole-body clinical scales are required. Current observational scales regard either only leg movement or discrete overall parameters, neglecting dysfunctions in the trunk and arms. The purpose of this study was to introduce a new multiple-cue observational scale, called the stroke mobility score (SMS). MATERIAL AND METHODS In a group of 131 patients, we developed a 1-page manual involving 6 subscores by Delphi method using the video-based SMS: trunk posture, leg movement of the most affected side, arm movement of the most affected side, walking speed, gait fluency and stability/risk of falling. Six medical raters then validated the SMS on a sample of 60 additional stroke patients. Conventional scales (NIHSS, Timed-Up-And-Go-Test, 10-Meter-Walk-Test, Berg Balance Scale, FIM-Item L, Barthel Index) were also applied. RESULTS (1) High consistency and excellent inter-rater reliability of the SMS were verified (Cronbach's alpha >0.9). (2) The SMS subscores are non-redundant and reveal much more nuanced whole-body dysfunction details than conventional scores, although evident correlations as e.g. between 10-Meter-Walk-Test and subscore "gait speed" are verified. (3) The analysis of cross-correlations between SMS subscores unveils new functional interrelationships for stroke profiling. CONCLUSIONS The SMS proves to be an easy-to-use, tele-applicable, robust, consistent, reliable, and nuanced functional scale of gait impairments after stroke. Due to its sensitivity to whole-body motion criteria, it is ideally suited for machine learning algorithms and for development of new therapy strategies based on instrumented gait analysis. CA Raab

Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.

Background The aim of study was to demonstrate that the first three injections of botulinum neurotoxin type A (BoNT/A) appear to be less effective in botulinum toxin naïve patients with idiopathic cervical dystonia (CD) with mild symptoms and low severity scores (TSUI-scores) at onset of BoNT/A-therapy compared to patients with full-blown CD and high initial TSUI-scores. Methods In 337 patients with CD who started BoNT/A-therapy in the BoNT-outpatient clinic of the university hospital in Düsseldorf during the last 12 years, demographical and treatment-related data as well as outcome measures (TSUI-scores) of the first four visits were extracted from the treatment ACCESS data bank. Results Distribution of the severity of CD scored using the TSUI-score significantly changed with the first three injections. In patients with a high baseline severity (TSUI-score > 10), mean TSUI-score continuously decreased (p p Conclusion Clinical response to the first three BoNT/A-injections in severely affected de novo CD-patients is different from the response to BoNT/A in mildly affected de novo CD-patients. This has implications for further scientific studies and the patient management of mildly affected de novo patients with cervical dystonia.

Poster-Abstract

Background and Objectives: In long-term treated patients with neurological Wilson’s disease, the ability to perform single-leg hopping was analyzed to quantify motor deficits. Materials and Methods: Twenty-nine long-term treated Wilson patients had to stand on one leg for at least 3 s and then perform at least five consecutive hops on this leg. Ground reaction forces and temporal patterns of hopping were recorded using an Infotronic® walking system, which consists of soft tissue shoes with a solid, but flexible plate containing eight force transducers allowing measurement of ground reaction forces (GRF) and temporal patterns of foot ground contact. Parameters of hopping were correlated with clinical scores and parameters of copper metabolism and liver enzymes. Patients’ hopping data were compared with those of an age- and sex-matched control group. Results: Five severely affected Wilson patients were unable to hop. Time to the peak was significantly (p < 0.03) shorter in the remaining 24 patients compared to controls, but there was no difference in hopping frequency, the amplitude of ground forces and duration of foot contact. Twelve patients produced a second, sharp, initial “impact” force peak during ground contact in addition to the usual “active” force peak. Variability of the amplitude of the “active” peak was significantly inversely correlated with urinary copper elimination. Conclusions: The majority of long-term treated patients with neurological Wilson’s disease was able to perform single-leg hopping. The presence of a sharp initial “impact” peak in the GRF-curves of hopping may indicate a mild deficit of limb/trunk coordination and subclinical cerebellar impairment.

Aim of the study was to analyze the ability of long-term treated patients with Wilson’s disease (WD) to run a distance of 40 m. 30 WD-patients from a single center were consecutively recruited. All patients were able to walk a distance of 40 m without walking aids. Vertical ground reaction forces (GRF-curves) were analyzed by means of an Infotronic® gait analysis system (CDG®) and correlated with clinical and laboratory findings. Results of the WD-patients were compared to those of an age-and sex-matched control group. 25 of the 30 WD-patients were able to run. Patients being unable to run had a significantly (p < 0.03) higher non-motor score. In comparison to the controls speed of running was significantly (p < 0.02) reduced in WD-patients. Their duration of foot contact on the ground lasted significantly (p < 0.05) longer. Running was more irregular in WD and the variability of times to peak of the GRF-curves was significantly (p < 0.05) increased. All running parameters extracted from the GRF-curves of the CDG® did not correlate with severity of WD. Cadence of running was significantly (p < 0.03) negatively correlated with serum liver enzyme levels. Running appears to be rather unimpaired in long-term treated WD, only 16% of the 30 WD-patients were unable to run. This knowledge is highly relevant for the patient management, but because of the missing correlation with severity of WD, analysis of running is of minor importance for monitoring WD-therapy.

Under continuous long-term treatment with abo- or onabotulinum toxin type A (BoNT/A), ~10 to 15% of patients with cervical dystonia (CD) will develop neutralizing antibodies and reduced responsiveness over an ~10-year treatment period. Among the botulinum neurotoxin type A preparations so far licensed for CD, incobotulinum toxin A (incoBoNT/A; Xeomin®) is the only one without complex proteins. Whether CD patients with treatment failure under abo- or onaBoNT/A may still respond to incoBoNT/A is unknown. In this cross-sectional, retrospective study, 64 CD patients with secondary treatment failure after abo- or onaBoNT/A therapy who were switched to incoBoNT/A were compared to 34 CD patients exclusively treated with incoBoNT/A. The initial clinical severity of CD, best outcome during abo- or onaBoNT/A therapy, severity at the time of switching to incoBoNT/A and severity at recruitment, as well as all corresponding doses, were analyzed. Furthermore, the impact of neutralizing antibodies (NABs) on the long-term outcome of incoBoNT/A therapy was evaluated. Patients significantly improved after the switch to incoBoNT/A (p < 0.001) but did not reach the improvement level obtained before the development of partial secondary treatment failure or that of patients who were exclusively treated with incoBoNT/A. No difference between abo- and onaBoNT/A pretreatments or between the long-term outcomes of NAB-positive and NAB-negative patients was found. The present study demonstrates significant long-term improvement after a switch to incoBoNT/A in patients with preceding secondary treatment failure after abo- or onaBoNT/A therapy and confirms the low antigenicity of incoBoNT/A.

Background: Recent studies of botulinum toxin for post-stroke spasticity indicate potential benefits of early treatment (i. e., first 6 months) in terms of developing hypertonicity, pain and passive function limitations. This non-interventional, longitudinal study aimed to assess the impact of disease duration on the effectiveness of abobotulinumtoxinA treatment for upper limb spasticity. Methods: The early-BIRD study (NCT01840475) was conducted between February 2013 and 2018 in 43 centers across Germany, France, Austria, Netherlands and Switzerland. Adult patients with post-stroke upper limb spasticity undergoing routine abobotulinumtoxinA treatment were followed for up to four treatment cycles. Patients were categorized by time from stroke event to first botulinum toxin-A treatment in the study (as defined by the 1st and 3rd quartiles time distribution) into early-, medium- and late- start groups. We hypothesized that the early-start group would show a larger benefit (decrease) as assessed by the modified Ashworth scale (MAS, primary endpoint) on elbow plus wrist flexors compared with the late-start group. Results: Of the 303 patients enrolled, 292 (96.4%) received ≥1 treatment and 186 (61.4%) received 4 injection cycles and completed the study. Patients in all groups showed a reduction in MAS scores from baseline over the consecutive injection visits (i.e., at end of each cycle). Although reductions in MAS scores descriptively favored the early treatment group, the difference compared to the late group did not reach statistical significance at the last study visit (ANCOVA: difference in adjusted means of 0.15, p = 0.546). Conclusions: In this observational, routine-practice study, patients in all groups displayed a benefit from abobotulinumtoxinA treatment, supporting the effectiveness of treatment for patients at various disease stages. Although the data revealed some trends in favor of early vs. late treatment, we did not find strong evidence for a significant benefit of early vs. late start of treatment in terms of reduction in MAS scores.

Die Digitalisierung der Medizin hat zur Beschleunigung der Ablaufe und nahezu universellen Verfugbarkeit von Informationen gefuhrt. Verkurzte stationare Verweildauern erfordern nun auch intelligente und praxistaugliche Systeme in der Rehabilitation und Pravention. Hierzu gehoren u. a. die Optimierung von Bewegungsanalysen durch innovative Techniken, z. B. Detektoren mit Druckmessfolien, portable Monitorsysteme, robotergestutzte Assistenzsysteme sowie professionelle Praventionsprogramme, die auf reliablen Daten beruhen. Nicht zuletzt bedarf es allerdings auch klinischer Strukturen, um die Moglichkeiten kunstlicher Intelligenz (AI) und maschinellen Lernens in der Rehabilitation optimal zu nutzen. Einen Beitrag hierzu konnen inter- und transdisziplinare Behandlungsteams wie z. B. das RehaBoard liefern. Durch die zunehmende Einfuhrung von AI in der rehabilitativen Orthopadie und Unfallchirurgie mit der Unterstutzung sektorenubergreifender Behandlungspfade hat diese im Gegensatz zu anderen kostenintensiven Bereichen wie beispielsweise der Onkologie, sehr gute Chancen, bei einem Wettbewerb um den grosten Patientennutzen („value-based competition“) vergleichsweise gut abzuschneiden.

Aim of the study was to characterize the clinical spectrum of long-term treated patients with Wilson's disease (WD) and to identify risk factors influencing long-term outcome.In a cross-sectional study 30 WD-patients being treated for at least 2.5 and up to 31 years underwent a detailed clinical investigation, scoring of clinical findings yielding 7 motor and 3 non-motor subscores as well as laboratory testing. A factor analysis of these subscores and laboratory parameters was performed to detect those items with the highest influence on outcome, an ANOVA and subgroup analysis tested the influence of age, age at onset of diagnosis and duration of treatment on outcome. A correlation analysis was performed between clinical subscores and laboratory findings.Three factors (F1-F3) characterized the clinical outcome (F1: tremor and pathological reflexes; F2: dystonia and dysarthria; F3: cerebellar abnormalities and gait), and three factors the laboratory findings (LF1: serum level of ceruloplasmin; LF2: liver enzymes; LF3: INR). Mildly affected patients had an elevated 24 h urinary copper excretion, more affected patients presented with elevated liver enzymes. Six of the 7 motor subscores did not change with duration of treatment, whereas tremor (p .04), the total score (p .02) and especially the non-motor items (p .001) significantly increased with duration of treatment. The outcome of patients with neuropsychiatric abnormalities was significantly worse (p .01) compared to the rest of the patients.Long-term outcome in WD is influenced by patient's compliance and neurological comorbidity.

The objective of this study was to quantify the increase in efficacy during the first four cycles of treatment with botulinum toxin type/A (BoNT/A) in 24 free-walking BoNT/A naïve adult patients with post-stroke hemispasticity and spastic foot drop. Patients were followed over 390 days and received five injections of 800 U aboBoNT/A every three months. Patients assessed the treatment effect at eight visits using a global assessment scale, physicians scored the muscle tone at the ankle joint, measured active and passive ranges of motion (aRoMs, pRoMs) at the knee and ankle joint and determined the distance patients succeeded to walk during a minute. Patients’ assessments significantly (p &lt, 0.006) increased with time and significantly correlated with all parameters measured. The best correlation (r = 0.927, p &lt, 0.0001) was found with the sum of the aRoMs of knee and ankle joint. After one year of treatment outcome measures were better than and significantly correlated with the peak effect of the first injection. This correlation was higher for pRoMs (r = 0.855, 0.00001) compared to aRoMs (r = 0.567, 0.009). When BoNT/A treatment of the spastic foot in chronic hemispasticity is performed regularly every three months for at least one year, patients will experience a significant increase of benefit beyond the first treatment, but have to learn how to adapt to and use the new degree of freedom induced by the injections.

Background Among the spectrum of licensed botulinum neurotoxin preparations incobotulinumtoxin (incoBoNT/A; Xeomin®) is the only one which does not contain complex proteins. Therefore, incoBoNT/A has been suggested to have a low antigenicity, but precise estimations on incidence and prevalence of neutralizing antibody formation during long-term treatment are outstanding so far. Methods For the present cross-sectional study, 59 patients having exclusively been treated with incoBoNT/A (mono group) and 32 patients having been treated with other BoNT/A preparations less than nine times and who were then switched to at least 14 sessions of incoBoNT/A treatment (switch group) were recruited from one botulinum toxin outpatient clinic. Side effects and doses were extracted from the charts, and the efficacy of treatment was assessed by the patients using a visual analogue scale (0–100). The prevalence of neutralizing antibodies was tested by means of the mouse hemi-diaphragm assay (MHDA). Findings None of the patients in the mono and only two in the switch group had a positive MHDA-test. Across all indications and patients, mean improvement exceeded 67%. Improvement did not depend on age at onset, sex, change of dose or duration of treatment, but on disease entity. In patients with cervical dystonia, improvement was about the same in the mono and switch subgroup, but the last dose was different. Conclusions The present study confirms the low antigenicity of incoBoNT/A, which has immediate consequences for patient management, and the use of higher doses and shorter durations of reinjection intervals in botulinum toxin therapy.

Background: Abnormal gait is a frequently observed initial symptom of Wilson’s disease (WD), which responds well to therapy, but has not been analyzed quantitatively so far. The question therefore is whether abnormalities can be detected by simple quantitative gait measurements in long-term treated Wilson-patients and whether these have a relation to clinical and laboratory findings. Methods: In 30 long-term treated Wilson-patients, walking without aid at the preferred gait speed over a distance of 40 meters was analyzed. An Infotronic ® gait analysis system which consists of soft tissue shoes with two solid, but flexible plates each containing 8 force transducers was used to record the vertical component of the ground forces and the temporal patterns of foot ground contact. Gait parameters were correlated with clinical scores as well as laboratory findings. Results of Wilson-patients were compared to those of an age- and sex-matched control group. Results: Wilson-patients walked significantly (P

Die Wiedergewinnung und der Erhalt der Mobilitat stellen aufgrund der demografischen Entwicklung eine wachsende medizinische und soziale Problematik dar, deren Meisterung neue, moderne Losungsstrategien aus der interdisziplinaren Zusammenarbeit zwischen Arzten, Therapeuten und Ingenieurwissenschaftlern erfordert. Wahrend bei der Therapieauswahl zur Behandlung von Gangstorungen, insbesondere bei neurologischen Erkrankungen, bisher hauptsachlich semiquantitative und teils „intuitive“ Diagnosemethoden von Arzten und Therapeuten zum Tragen kommen, bieten moderne Methoden der Bewegungssimulation neue Ansatze, die eine evidenzbasierte Therapieplanung ermoglichen. In dem Forschungsprojekt ReHabX wurde die Technologie der Bewegungssimulation genutzt, um innovative Methoden fur die personalisierte Therapiesteuerung in der Schlaganfallrehabilitation zu entwickeln. Dies umfasste (1) die Formulierung von klinischen Kenngrosen, welche eine reproduzierbare Bestimmung der funktionell erforderlichen Rehabilitationsmasnahmen unterstutzen, (2) eine Methodik, um die Masnahmenempfehlungen von klinischen Experten zu objektivieren, und (3) ein Softwaretool, das es Arzten und Therapeuten ermoglicht, aufgrund objektivierter Kriterien unterschiedliche Masnahmen fur die Rehabilitation der Gangfahigkeit nach einem Schlaganfall zu vergleichen und eine Empfehlung fur die Behandlung zu erhalten. Durch die Weiterentwicklung der Methoden konnten innovative, auf den Patienten zugeschnittene „Multi“-Therapien personalisiert gestaltet werden und aus den daraus resultierenden Therapieerfolgen konnte die Teilhabe der Patienten am gesellschaftlichen Leben deutlich verbessert werden.

Background: Recent cell-based and animal experiments have demonstrated an effective reduction in botulinum neurotoxin A (BoNT/A) by copper. Aim: We aimed to analyze whether the successful symptomatic BoNT/A treatment of patients with Wilson’s disease (WD) corresponds with unusually high doses per session. Methods: Among the 156 WD patients regularly seen at the outpatient department of the university hospital in Düsseldorf (Germany), only 6 patients had been treated with BoNT/A during the past 5 years. The laboratory findings, indications for BoNT treatment, preparations, and doses per session were extracted retrospectively from the charts. These parameters were compared with those of 13 other patients described in the literature. Results: BoNT/A injection therapy is a rare (

The three different botulinum toxin type A (BoNT/A) preparations being licensed in Europe and the U.S. differ in protein content, which seems to be a major factor influencing the antigenicity of BoNT/A. In the present study, several arguments out of our research pool were collected to demonstrate that the clinical response and antigenicity were different for the three BoNT/A preparations: some results of (1) a cross-sectional study on clinical outcome and antibody formation of 212 patients with cervical dystonia (CD) being treated between 2 and 22 years; (2) another cross-sectional study on the clinical aspects and neutralizing antibody (NAB) induction of 63 patients having developed partial secondary treatment under abobotulinum (aboBoNT/A) onabotulinumtoxin (onaBoNT/A) who were switched to incobotulinumtoxin (incoBoNT/A) in comparison to 32 patients being exclusively treated with incoBoNT/A. These results imply that (1) the presence of NAB cannot be concluded from the course of treatment, that (2) an increase in the dose and variability of outcome with treatment duration indicates the ongoing induction of NABs over time, that (3) the higher protein load of BoNT/A goes along with a higher incidence and prevalence of NAB induction and that (4) the best response to a BoNT/A is also dependent on the protein load of the preparation.

ObjectiveTo investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications.MethodsIn this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAb-positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs.ResultsOverall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, while all other factors analyzed, including disease entity and treatment duration, had no additional influence.ConclusionsWe present the largest study to date of the prevalence of BoNT/A NAbs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NAbs. However, in addition to avoiding booster injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAb induction independently of the indication for which BoNT/A is used.

Residual deformity of the femoral head after slipped capital femoral epiphysis (SCFE) may be accompanied by a loss of femoral offset and lead to femoro-acetabular impingement (FAI), especially during hip flexion. It is hypothesized that during phases of the gait cycle, when the hip is flexed, the offset-loss is compensated by an increased external rotation. The gait pattern of 36 patients suffering from SCFE, who were treated by pinning-in-situ, were compared to a control group of 40 healthy adults by an instrumented 3D-gait analysis. Total patient group was subdivided into 3 subgroups in dependence on the offset (offset groups (OG)) quantified by the angle α according to Nötzli: OG1: α-angle55°, OG2: α-angle between 55 and 75°, OG3: α-angle75°. Comparisons were made at 3 instants: initial foot contact (0% gait cycle (GC)), 40-60% GC and 90-100% GC. Patients showed an increased external hip rotation during all 3 periods of the GC with a tendency of increasing external rotation in association with offset-loss. Only during hip extension (40-60% GC) there was a weak correlation between angle α and hip rotation (r=-0.375, p=0.024). In conclusion, the offset-loss does not lead to a functional relevant impingement during walking which needs compensation strategies like increasing external rotation during periods of hip flexion.

Background: The aim of the study was to test the clinical relevance of neutralizing antibodies (NABs) in patients with cervical dystonia (CD) still responding to repeat injections with botulinum toxin type A (BoNT/A). Methods: Enzyme-linked immunosorbent assay (ELISA)-test evidence from a cross-sectional study on 221 CD-patients with treatment durations of between 2 and 21 years and still responding to repeat BoNT/A-injections showed the presence of antibodies against BoNT/A in 39 patients. A mouse hemi-diaphragm (MHDA) confirmation test was performed in these 39 ELISA-positive patients, and demographic (age, sex, age at onset of CD) and treatment-related (duration of treatment, mean dose of the last 10 injections, TSUI-score, patient’s subjective scoring of the treatment effect, patient’s scoring of quality of life by means of the CDQ24-questionnaire) data from these 39 patients were compared with data from ELISA-negative patients. Paralysis time, the MHDA outcome measure, was correlated with clinical data. Results: The ELISA-positive CD-patients had significantly higher TSUI-scores ( p Conclusions: Presence of NABs is clinically relevant in CD, leading to a significantly worse head position, therapy with significantly higher BoNT/A doses, and a correlation between the CDQ24 pain-subscore and antibody titers.