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.

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.

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.

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 Impact of SARS-CoV-2 Pandemic Lockdown on a Botulinum Toxin Outpatient Clinic in Germany.

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.

Clinical Implications of Difference in Antigenicity of Different Botulinum Neurotoxin Type A Preparations: Clinical Take-Home Messages from Our Research Pool and Literature.

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.

Effective long-term treatment with incobotulinumtoxin (Xeomin®) without neutralizing antibody induction: a monocentric, cross-sectional study.

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

The Extreme Ends of the Treatment Response Spectrum to Botulinum Toxin in Cervical Dystonia.

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.