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.

Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects.

BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). OBJECTIVES: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. METHODS: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). RESULTS: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017). CONCLUSION: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

Safety and Discontinuation Rate of Dimethyl Fumarate (Zadiva®) in Patients with Multiple Sclerosis: An Observational Retrospective Study.

BACKGROUND: This study evaluates the real-world safety and discontinuation rate of Zadiva® (generic product of dimethyl fumarate (DMF)) in Iranian patients with relapsing-remitting multiple sclerosis (RRMS), supplementing existing clinical evidence from randomized controlled trials. METHODS: This retrospective observational study evaluated the real-world safety and discontinuation rate of DMF in RRMS patients from Amir A'lam referral hospital's neurology clinic. Data on safety, discontinuation rate, and clinical disease activity were collected retrospectively. The study aimed to assess the discontinuation rate, safety, and reasons for discontinuation, as well as the number of patients experiencing a relapse, MRI activity, and EDSS scores. RESULTS: In total, 142 RRMS patients receiving DMF were included in the study, with 15 discontinuing treatment due to adverse events, lack of efficacy, or pregnancy. Notably, a significant reduction in relapse rates was observed, with 90.8% of patients remaining relapse-free throughout the study period. After 1 year of treatment with Zadiva®, only 17.6% of patients experienced MRI activity, whereas the EDSS score remained stable. CONCLUSIONS: This study provides important real-world data on the safety and tolerability of Zadiva® in RRMS patients. The results indicate that Zadiva® is generally well tolerated and safe, with a low discontinuation rate due to adverse events or lack of efficacy. These findings suggest that Zadiva® is an effective and safe treatment option for RRMS patients in real-world practice.

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.

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.

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.

The Acute Optic Neuritis Network (ACON): Study protocol of a non-interventional prospective multicenter study on diagnosis and treatment of acute optic neuritis.

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON. Trial registration: ClinicalTrials.gov, identifier: NCT05605951.

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.

Pseudocholinesterase as a Biomarker for Untreated Wilson's Disease.

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.

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.

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.

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.

The complex relationship between antibody titers and clinical outcome in botulinum toxin type A long-term treated patients with cervical dystonia.

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.

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.

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.

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.

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.

Continuous Increase of Efficacy under Repetitive Injections of Botulinum Toxin Type/A beyond the First Treatment for Adult Spastic Foot Drop.

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.

The Impact of the Course of Disease before Botulinum Toxin Therapy on the Course of Treatment and Long-Term Outcome in Cervical Dystonia.

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.