The Necessity of a Locally Active Antidote in the Clinical Practice of Botulinum Neurotoxin Therapy: Short Communication.

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.

Analysis of Single-Leg Hopping in Long-Term Treated Patients with Neurological Wilson's Disease: A Controlled Pilot Study.

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.

The Use of High Initial Doses of Botulinum Toxin Therapy for Cervical Dystonia Is a Risk Factor for Neutralizing Antibody Formation-A Monocentric Cross-Sectional Pilot Study.

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.

A Novel Multiple-Cue Observational Clinical Scale for Functional Evaluation of Gait After Stroke - The Stroke Mobility Score (SMS).

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.

Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy.

BACKGROUND: Recently, we described a novel autoantibody, anti-Sj/ITPR1-IgG, that targets the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in patients with cerebellar ataxia. However, ITPR1 is expressed not only by Purkinje cells but also in the anterior horn of the spinal cord, in the substantia gelatinosa and in the motor, sensory (including the dorsal root ganglia) and autonomic peripheral nervous system, suggesting that the clinical spectrum associated with autoimmunity to ITPR1 may be broader than initially thought. Here we report on serum autoantibodies to ITPR1 (up to 1:15,000) in three patients with (radiculo)polyneuropathy, which in two cases was associated with cancer (ITPR1-expressing adenocarcinoma of the lung, multiple myeloma), suggesting a paraneoplastic aetiology. METHODS: Serological and other immunological studies, and retrospective analysis of patient records. RESULTS: The clinical findings comprised motor, sensory (including severe pain) and autonomic symptoms. While one patient presented with subacute symptoms mimicking Guillain-Barré syndrome (GBS), the symptoms progressed slowly in two other patients. Electrophysiology revealed delayed F waves; a decrease in motor and sensory action potentials and conduction velocities; delayed motor latencies; signs of denervation, indicating sensorimotor radiculopolyneuropathy of the mixed type; and no conduction blocks. ITPR1-IgG belonged to the complement-activating IgG1 subclass in the severely affected patient but exclusively to the IgG2 subclass in the two more mildly affected patients. Cerebrospinal fluid ITPR1-IgG was found to be of predominantly extrathecal origin. A 3H-thymidine-based proliferation assay confirmed the presence of ITPR1-reactive lymphocytes among peripheral blood mononuclear cells (PBMCs). Immunophenotypic profiling of PBMCs protein demonstrated predominant proliferation of B cells, CD4 T cells and CD8 memory T cells following stimulation with purified ITPR1 protein. Patient ITPR1-IgG bound both to peripheral nervous tissue and to lung tumour tissue. A nerve biopsy showed lymphocyte infiltration (including cytotoxic CD8 cells), oedema, marked axonal loss and myelin-positive macrophages, indicating florid inflammation. ITPR1-IgG serum titres declined following tumour removal, paralleled by clinical stabilization. CONCLUSIONS: Our findings expand the spectrum of clinical syndromes associated with ITPR1-IgG and suggest that autoimmunity to ITPR1 may underlie peripheral nervous system diseases (including GBS) in some patients and may be of paraneoplastic origin in a subset of cases.

Hepatobiliary malignancies in Wilson disease.

BACKGROUNDS & AIMS: Reports of hepatobiliary malignancies in Wilson disease are sparse. The aim of this study was to evaluate hepatobiliary malignancies in Wilson disease patients concerning the clinical course of tumour disease and pathological analysis of tumour tissue. METHODS: Multicenter cohort study of patients with confirmed diagnosis of Wilson disease treated at the Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland, the university hospitals Heidelberg, Duesseldorf and Dresden, Germany, and the Department of Hepatology, University Leuven, Belgium. Occurrence, treatment and outcome of hepatobiliary tumours were analysed retrospectively. RESULTS: Of a total of 1186 patients, fourteen developed hepatobiliary malignancies. Eight were hepatocellular carcinomas (HCC) and six were intrahepatic cholangiocellular carcinomas (ICC). The prevalence of hepatobiliary malignancies in the cohort was 1.2% and the incidence was 0.28 per 1000 person years. Pathological analysis of tumour material showed no abnormal copper concentration. CONCLUSIONS: The rate of hepatobiliary malignancies in Wilson disease is very low, even in cirrhotic patients. As a result of the relevant number of ICC in addition to HCC histological analysis through surgical resection or biopsy should be mandatory when a suspect liver lesion is detected. The influence of copper depletion from Wilson disease-specific medical treatment on tumour activity remains to be elucidated.

Very early reduction in efficacy of botulinum toxin therapy for cervical dystonia in patients with subsequent secondary treatment failure: a retrospective analysis.

The objective of this study was to estimate the probability of development of partial secondary treatment failure (PSTF) in patients with cervical dystonia (CD) who had been treated over up to 9 years with repetitive intramuscular injections of botulinum neurotoxin type A (BoNT/A). The temporal course of treatment response in patients in whom PSTF was detected retrospectively was compared to patients with a normal clinical response. For this purpose, charts of all CD patients treated in our outpatient clinic between 1988 and 2001 were retrospectively analyzed. Extracted data included time of all injections, dose per visit, disease severity measured by TSUI scores, and time of determination of neutralizing antibodies. Final data analysis using a special formal definition of PSTF was based on charts of 568 patients having exclusively been treated with abobotulinumtoxinA. PSTF onset was observed in our CD cohort during the entire treatment period analyzed, with no clustering at any time point. Probability to develop PSTF was 14.5 % in 9 years. Thus, mean PSTF incidence was 1.6 % per year. The mean TSUI score of patients with retrospectively defined PSTF (n = 33) became already significantly worse after the second injection when compared with the group without PSTF (n = 535). Our data indicate that clinical response in patients developing PSTF later on differs from that of patients without PSTF already very early in the course of botulinum neurotoxin type A treatment, and that PSTF remains undetected at this early stage. Reduced response may therefore be present in a number of CD patients who think they still respond normally to continuous BoNT/A treatment.

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.

Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.

Efficacy and safety of oral chelators in treatment of patients with Wilson disease.

BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. METHODS: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). RESULTS: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). CONCLUSIONS: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.

Rating scales for cervical dystonia: a critical evaluation of tools for outcome assessment of botulinum toxin therapy.

Botulinum neurotoxin is the therapy of choice for all forms of cervical dystonia (CD), but treatment regimens still vary considerably. The interpretation of treatment outcome is mainly based on the clinical experience and on the scientific value of the rating scales applied. The aim of this review is to describe the historical development of rating scales for the assessment of CD and to provide an appraisal of their advantages and drawbacks. The Tsui score and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) have been widely employed in numerous clinical studies as specific instruments for CD. The obvious advantage of the Tsui score is its simplicity so that it can be easily implemented in clinical routine. The TWSTRS allows a more sophisticated assessment of functional features of CD, but only the Tsui score includes a rating for tremor. Other benefits of the TWSTRS are the disability and pain subscales, but despite its value in clinical trials, it might be too complex for routine clinical practice. None of the rating scales used at present has been rigorously tested for responsiveness to detect significant changes in clinical status after therapeutic interventions. Moreover, clinical data support a new classification of CD leading to a differentiation between head and neck subtypes. As the current rating scales are not able to cover all these aspects of the disorder, further research is needed to develop a valid and reliable instrument which considers the most current classification of CD.

Exploring the Interplay between the Clinical and Presumed Effect of Botulinum Injections for Cervical Dystonia: A Pilot Study.

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.

"Pseudo"-Secondary Treatment Failure Explained via Disease Progression and Effective Botulinum Toxin Therapy: A Pilot Simulation Study.

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.

No Secondary Treatment Failure during Incobotulinumtoxin-A Long-Term Treatment Demonstrated by the Drawing of Disease Severity.

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.

Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study.

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.

Differences in the Time Course of Recovery from Brain and Liver Dysfunction in Conventional Long-Term Treatment of Wilson Disease.

BACKGROUND: The aim of this study was to demonstrate that both neurological and hepatic symptoms respond to copper chelation therapy in Wilson disease (WD). However, the time course of their recovery is different. METHODS: Eighteen patients with neurological WD from a single specialized center who had been listed for liver transplantation during the last ten years and two newly diagnosed homozygous twins were recruited for this retrospective study. The mean duration of conventional treatment was 7.3 years (range: 0.25 to 36.2 years). A custom Wilson disease score with seven motor items, three non-motor items, and 33 biochemical parameters of the blood and urine, as well as the MELD score, was determined at various checkup visits during treatment. These data were extracted from the charts of the patients. RESULTS: Treatment was initiated with severity-dependent doses (≥900 mg) of D-penicillamine (DPA) or triethylene-tetramin-dihydrochloride (TRIEN). The motor score improved in 10 and remained constant in 8 patients. Worsening of neurological symptoms was observed only in two patients who developed comorbidities (myasthenia gravis or hemispheric stroke). The neurological symptoms continuously improved over the years until the majority of patients became only mildly affected. In contrast to this slow recovery of the neurological symptoms, the MELD score and liver enzymes had already started to improve after 1 month and rapidly improved over the next 6 months in 19 patients. The cholinesterase levels continued to increase significantly (p < 0.0074) even further. One patient whose MELD score indicated further progression of liver disease received an orthotopic liver transplantation 3 months after the diagnosis of WD and the onset of DPA treatment. CONCLUSIONS: Neurological and hepatic symptoms both respond to copper chelation therapy. For patients with acute liver failure, the first 4 months are critical. This is the time span in which patients have to wait either for a donor organ or until significant improvement has occurred under conventional therapy. For patients with severe neurological symptoms, it is important that they are treated with fairly high doses over several years.

Significantly lower antigenicity of incobotulinumtoxin than abo- or onabotulinumtoxin.

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 < 0.035) between the CF-MON and CC-MON-10 group. 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.

Analysis of Running in Wilson's Disease.

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.

Different Response Behavior to Therapeutic Approaches in Homozygotic Wilson's Disease Twins with Clinical Phenotypic Variability: Case Report and Literature Review.

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.

Cholinesterase Deficiency Syndrome-A Pitfall in the Use of Butyrylcholinesterase as a Biomarker for Wilson's Disease.

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.

Significant Long-Lasting Improvement after Switch to Incobotulinum Toxin in Cervical Dystonia Patients with Secondary Treatment Failure.

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.