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Background: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure (NAB-STF), but may stem from a “pseudo”-secondary treatment failure (PSEUDO-STF). Methods: The simulation of the outcome after BoNT long-term treatment was performed in four steps: 1. The effect of the first single BoNT injection (SI curve) was displayed as a 12-point graph, corresponding to the mean improvement from weeks 1 to 12. 2. The remaining severity of the dystonia during the nth injection cycle was calculated by subtracting the SI curve (weighted by the outcome after n − 1 cycles) from the outcome after week 12 of the (n − 1)th cycle. 3. A graph was chosen (the PRO curve), which represents the progression of the severity of the underlying disease during BoNT therapy. 4. The interaction between the outcome during the nth BoNT cycle and the PRO curve was determined. Results: When the long-term outcome after n cycles of BoNT injections (applied every 3 months) was simulated as an interactive process, subtracting the effect of the first cycle (weighted by the outcome after n − 1 cycles) and adding the progression of the disease, an initial good improvement followed by secondary worsening results. This long-term outcome depends on the steepness of the progression and the duration of action of the first injection cycle. We termed this response behavior a “pseudo”-secondary treatment failure, as it can be compensated via a dose increase. Conclusion: A secondary worsening following an initial good response in BoNT therapy of focal dystonia might not necessarily indicate neutralizing antibody induction but could stem from a “PSEUDO”-STF (a combination of good response behavior and progression of the underlying disease). Thus, an adequate dose adaptation must be conducted before diagnosing a secondary treatment failure in the strict sense.

Background: Repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A) are the treatment of choice in patients with cervical dystonia (CD). As soon as BoNT therapy is initiated, the natural course of CD cannot be observed anymore. Nevertheless, the present study focuses on the “presumed” course of disease severity under the assumption that no BoNT therapy had been performed. The “experienced” benefit is compared with the “presumed” worsening. Methods: Twenty-seven BoNT/A long-term-treated CD patients were recruited. They had to assess the remaining severity of CD in percent of its severity at the start of BoNT therapy (RS-%). Then, they had to draw the course of severity from the onset of symptoms to the start of BoNT/A therapy (CoDB graph), as well as the course of severity from the start of BoNT/A therapy until the day of recruitment (CoDA graph). Then, they were instructed to presume the development of CD severity from the day of the start of BoNT/A therapy until the day of recruitment under the assumption that no BoNT/A therapy had been performed, and to assess the maximal severity they could presume in percent of the severity at the start of BoNT therapy (IS-%). Then, they had to draw the “presumed” development of CD severity (CoDI graph). The “experienced” change in disease severity and the “presumed” change since the start of BoNT/A therapy were compared and correlated with a variety of demographical and treatment-related data, including the actual severity of CD at the day of recruitment, which was assessed using the TSUI score and the actual dose per session (ADOSE). Results: No CD patients expected an improvement without BoNT therapy. “Presumed” worsening ((IS-%)-100) was about 50% in the mean and did not correlate with the “experienced” benefit (100-(RS-%)). However, IS-% was significantly correlated with ATSUI and ADOSE. Conclusion: Obviously, CD patients have the opinion that their CD would have further progressed and worsened if no BoNT/A therapy had been performed. Thus, the total benefit of BoNT/A therapy for a patient with CD is a combination of the “experienced” benefit under BoNT/A therapy and the prevented worsening of CD that the patient expects to occur without BoNT/A therapy.

The aim of this study was to detect clinical hints regarding the development of secondary treatment failure (STF) in patients with focal dystonia who were exclusively treated with incobotulinumtoxin/A (incoBoNT/A). In total, 33 outpatients (26 with idiopathic cervical dystonia, 4 with Meige syndrome and 3 with other cranial dystonia) who were treated with repeated injections of incoBoNT/A for a mean period of 6.4 years without interruptions were recruited to draw the course of their disease severity (CoD) from the onset of symptoms to the onset of BoNT therapy (CoDB graph) and from the onset of BoNT therapy to recruitment (CoDA graph). At the time of recruitment, the patients assessed the change in severity as a percentage of the severity at the onset of BoNT therapy. Blood samples were taken to test the presence of neutralizing antibodies (NABs) using the mouse hemidiaphragm assay (MHDA). Patients reported an improvement of about 70% with respect to the mean. None of the patients tested positive for MHDA. Three different types of CoDB and three different types of CoDA graphs could be distinguished. The patients with different CoDB graphs reported different long-term outcomes, but there was no significant difference in long-term outcomes between patients with different CoDA graphs. None of the patients produced a CoDA graph with an initial improvement and a secondary worsening as a hint for the development of STF. A primary non-response was not observed in any of the patients. During long-term treatment with BoNT/A, NABs and/or STF may develop. However, in the present study on patients with incoBoNT/A long-term monotherapy, no hints for the development of NABs or STF could be detected, underlining the low antigenicity of incoBoNT/A.

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.

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.

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.

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.

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.

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.

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: 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.

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.

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.

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: 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

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.

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 < 0.006) increased with time and significantly correlated with all parameters measured. The best correlation (r = 0.927; p < 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; p < 0.00001) compared to aRoMs (r = 0.567; p < 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.

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 < 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 < 0.02). Initial dose (p < 0.04) and actual dose (p < 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 (p < 0.0001) decreased during the first 48 h by about 90%, from a level of about 14 mV down to a plateau of around 1.5 mV. Conclusion: Local mechanical leg vibration has a short- and long-term training effect. Compared to other studies analyzing the reduction in EDB CMAPs after BoNT injections, the reduction of EDB CMAPs in the present study observed after combined application of BoNT and VET was much faster and more pronounced.

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. 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. BoNT/A injection therapy is a rare (

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.

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.

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. 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. 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 < 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. 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.

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.

The diagnosis of Legg-Calvé-Perthes disease (LCPD) has a considerable influence on the daily life of the patients with restrictions in their leisure time activities. This might influence their mood. Until now this aspect of the disease has been neglected. Therefore the objective of the study was to evaluate the health related quality of life (HRQoL) of children with severe LCPD who had an extensive surgery with pelvic/femoral osteotomy. The KIDSCREEN-10 and the modified Modified Harris Hip Score (mHHS)-questionnaire were administered to 17 children (16 boys and 1 girl) aged 5 to 11 years at the time of surgery. Analyses of mHHS were made preoperatively and at the time of the follow-up examination at least 2 years postoperatively. KIDSCREEN-analyses were made postoperatively. The follow-up results were compared to an age-matched normal control group. Correlations were computed between KIDSCREEN-10 and mHHS pre- and post-operatively. The postoperative calculated KIDSCREEN-10-T-value [70.2 (SD 12.7)] was higher than the mean T-value of the control-group [56.6 (SD 10.4)]. The mHHS improved from 54.4 (SD 19.9) to a score of 99.5 (SD 1.5) postoperatively. A strong correlation was found between the preoperative mHHS and the postoperative KIDSCREEN-10- T-value (Spearman’s-rho 0.67, P=0.003). After containment improving surgery and a mean follow-up period of 4.2 years the HRQoL-status is even better compared with a healthy age-matched control group. As well an excellent clinical function could be achieved.

BACKGROUND/OBJECTIVE: In addition to cirrhosis of the liver, Wilson's disease leads to copper accumulation and widespread degeneration of the nervous system. Delayed visual evoked potentials (VEPs) suggest changes to the visual system and potential structural changes of the retina. METHODS: We used the latest generation of spectral domain optical coherence tomography to assess the retinal morphology of 42 patients with Wilson's disease and 76 age- and sex-matched controls. We measured peripapillary retinal nerve fiber layer (RNFL) thickness and total macular thickness and manually segmented all retinal layers in foveal scans of 42 patients with Wilson's disease and 76 age- and sex-matched controls. The results were compared with VEPs and clinical parameters. RESULTS: The mean thickness of the RNFL, paramacular region, retinal ganglion cell/inner plexiform layer and inner nuclear layer was reduced in Wilson's disease. VEPs were altered with delayed N75 and P100 latencies, but the N140 latency and amplitude was unchanged. An analysis of the laboratory parameters indicated that the serum concentrations of copper and caeruloplasmin positively correlated with the thickness of the outer plexiform layer and with N75 and P100 VEP latencies. CONCLUSION: Neuronal degeneration in Wilson's disease involves the retina and changes can be quantified by optical coherence tomography. While the VEPs and the thickness of the outer plexiform layer appear to reflect the current copper metabolism, the thicknesses of the RNFL, ganglion cell/inner plexiform layer, inner nuclear layer and the total paramacular thickness may be the best indicators of chronic neuronal degeneration.

Although Dysport® (botulinum toxin type A) has been used as a first-line therapy for cervical dystonia (CD) for many years, there are only few studies available on dose, efficacy and safety in the treatment of heterogeneous forms of CD. The aim of this study was to analyse effectiveness and safety in the treatment of the most frequent forms of CD, rotational torticollis and predominantly laterocollis with a standard initial dose of 500U Dysport® in a large representative group of patients as presented in typical dystonia clinics. Between November 2004 and January 2008, 514 de novo patients with CD were recruited by 81 study sites in Germany and Austria. Muscle selection for injection was based on clinical assessment taking into account direction of head deviation and occurrence of the additional components shoulder elevation and/or tremor, evaluated using the Tsui rating scale. These ratings permitted the desired individual treatment of the muscles affected and at the same time provided a structure of twelve CD subgroups for intra-individual first treatment. Results of a data monitoring analysis on the baseline values of different study criteria of the first 200 patients will be presented, showing the demographic characteristics, the proportions of the different subgroups and the mean Tsui score across these subgroups. This study with a large patient population will provide valuable insights for optimal initial treatment of heterogeneous forms of CD. [Copyright &y& Elsevier]