Clinical Improvement After Treatment With IncobotulinumtoxinA (XEOMIN®) in Patients With Cervical Dystonia Resistant to Botulinum Toxin Preparations Containing Complexing Proteins.

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.

Long-term adherence and response to botulinum toxin in different indications.

OBJECTIVE: The objective of the study was the analysis of adherence and self-perceived treatment response to long-term botulinum neurotoxin type A (BoNT-A) treatment in different neurological indications. METHODS: In this retrospective, monocentric, observational study, cross-sectional and longitudinal data of 1351 patients documenting 20705 injection appointments at the BoNT outpatient clinic of Heinrich Heine University Duesseldorf between 1989 and 2014 were retrospectively analyzed. Patients had been treated with BoNT for neurological conditions, including cervical dystonia (CD), blepharospasm (BSP), other dystonia (ODT), hemifacial spasm (HFS), and spasticity (SPAS). The parameters longitudinally analyzed for the entire cohort were therapy duration as well as the mean and cumulative BoNT-A dose. Cross-sectionally, for subgroups of at least 721, patients' global self-perceived quality of health and life, global self-perceived reduction of symptoms by BoNT-A treatment as well as the clinical global impression were evaluated. Furthermore, mouse hemidiaphragm assay antibodies (MHDA-ABs) were analyzed in a subgroup. RESULTS: The mean treatment duration was 4.58 years (95% CI 4.32-4.84), and 678 (50.2%) therapy dropouts of 1351 patients occurred within the first 8 years. Therapy adherence and self-perceived symptom reduction in long-term BoNT-A treatment over the years were significantly longer in BSP, HFS, and CD patients than in ODT and SPAS patients. INTERPRETATION: The treatment indication determines long-term adherence and self-perceived symptom reduction in BoNT-A therapy, which are better in BSP, HFS, and CD patients than in ODT and SPAS patients. MHDA-ABs had a significant impact on global self-perceived symptom reduction, but with only a limited degree.

Transient Improvement after Switch to Low Doses of RimabotulinumtoxinB in Patients Resistant to AbobotulinumtoxinA.

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

High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy.

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

Clinical relevance of neutralizing antibodies in botulinum toxin long-term treated still-responding patients with cervical dystonia.

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 < 0.015), and had been treated for significant longer (p < 0.022) and with significantly higher doses (p < 0.001). Patient's rating of BoNT/A-treatment effect and quality of life tended to be worse in ELISA-positive compared with ELISA-negative patients. The paralysis time of ELISA-positive patients was significantly correlated with the mean dose of the last 10 injections (p < 0.027) and the pain subscore of the CDQ24 (p < 0.012). CONCLUSIONS: Presence of NABs is clinically relevant in CD, leading to a significantly worse head position, therapy with significantly higher BoNT/A doses, and a correlation between the CDQ24 pain-subscore and antibody titers.

Quality of life in long-term botulinum toxin treatment of cervical dystonia: Results of a cross sectional study.

INTRODUCTION: Patients' rating of the effectiveness of and quality of life after long-term botulinum toxin (BoNT) injection therapy up to 22 years and treating physician's rating of the therapy effect in patients with idiopathic cervical dystonia (CD) are analysed in a large monocentric cross-sectional study. PATIENTS AND METHODS: Patients (n = 221) who received uninterrupted, long-term treatment for CD (≥10 BoNT injection cycles) in a BoNT outpatient clinic underwent detailed clinical investigation, Tsui scoring, rated post-treatment CD severity as a percentage of CD severity prior to BoNT injection (patient's subjective scoring of the treatment effect (PSSTE)), and completed the CDQ-24 quality of life (QoL) questionnaire. Correlations between demographics, treatment-related data and QoL were analysed by linear regression, analysis of variance and pairwise single comparisons. RESULTS: Treating physicians and patients rated mean ongoing treatment effect as >50%. There was high variability of duration of treatment, PSSTE, Tsui score and CDQ-24 across all patients. PSSTE was significantly correlated with Tsui score (p < .001) and all CDQ-24 subscores (p < .003). Tsui score and CDQ-24 were significantly correlated (p < .001), but the correlation was lower than between PSSTE and total CDQ24. CDQ-24 revealed a significant improvement with duration of therapy. PSSTE and Tsui score did not change with duration of BoNT treatment. CONCLUSION: Patients with CD who receive up to 22 years' continuous BoNT treatment experience a >50% mean reduction of symptoms and a significant improvement of QoL with duration of treatment. A highly significant correlation exists between patients' and physicians' rating of treatment effectiveness.

High Botulinum Toxin-Neutralizing Antibody Prevalence Under Long-Term Cervical Dystonia Treatment.

BACKGROUND: The aim of this study was to determine the prevalence of neutralizing antibodies in a large cohort of long-term treated patients with cervical dystonia (CD) still responding to repetitive injections with botulinum toxin (BoNT). METHODS: Consecutively recruited CD patients (n = 221) under long-term BoNT treatment (≥2-21 years) underwent a clinical examination at the same time blood samples were taken for neutralizing antibody determination. Collected data included demographics, mean dose of the last 10 botulinum injections, treatment duration, Tsui score for CD severity, and patients' subjective impression of treatment effect. Blood samples were screened for antibody presence by ELISA; positive samples were further analyzed by mouse hemidiaphragm test. The two laboratories performing antibody testing were blinded to the coded samples. RESULTS: Antibody status could be determined for 212 patients; 39 (18.4%) were ELISA positive and 31 (14.6%) additionally positive in the mouse hemidiaphragm test. Patients with positive neutralizing antibody titers had significantly higher Tsui scores and were treated for a significantly longer time with significantly higher doses. There were no differences between male and female patients and between onabotulinumtoxinA- and abobotulinumtoxinA-treated patients. When BoNT preparations had been switched during the last 10 injections, a significantly higher proportion of neutralizing antibody-positive patients was detected. CONCLUSIONS: Neutralizing antibody prevalence in long-term treated, still responding CD patients is substantially higher than suggested by follow-up studies with a shorter time frame. It should therefore be emphasized that antigenicity of BoTN preparations is still a relevant problem and should be taken into account in long-term treatment decisions.

Prospective analysis of neutralising antibody titres in secondary non-responders under continuous treatment with a botulinumtoxin type A preparation free of complexing proteins--a single cohort 4-year follow-up study.

OBJECTIVES: In long-term botulinum neurotoxin treatment, loss of therapeutic efficacy may occur due to neutralising antibody formation. Preliminary results with incobotulinumtoxinA, a preparation free of complexing/accessory proteins, have indicated a low antigenicity. We hypothesised that continuous treatment with this botulinum neurotoxin preparation would not result in an increase in neutralising antibody titres (NABTs) in patients with pre-existing NABTs. DESIGN: Prospective, blinded cohort study. SETTING: Single centre in Germany. PARTICIPANTS: Thirty-seven cervical dystonia patients with NABTs and partial secondary non-responsiveness to their previous botulinum neurotoxin type A treatment. INTERVENTION: Three-monthly intramuscular injections of incobotulinumtoxinA with a constant dose of 200 MU per injection during the first year; thereafter up to 500 MU for the next 36 months. PRIMARY OUTCOME MEASURE: number of patients in whom NABTs declined below the initial titre after 48 months of incobotulinumtoxinA treatment or in whom titres had become negative within the 48 months. SECONDARY OUTCOME MEASURE: steepness of changes in NABT. NABTs were determined by mouse hemidiaphragm assay. Findings were compared to long-term data from 24 cervical dystonia patients who had developed NABTs and in whom treatment had been discontinued. RESULTS: Following a transient increase in the first 24 months under incobotulinumtoxinA treatment in some patients, NABTs declined well below the initial titre in the majority of patients. Test assay results were negative in most of the patients followed for more than 36 months. NABTs seemed to decline into the negative detection range as rapidly under incobotulinumtoxinA treatment as after cessation of botulinum neurotoxin therapy. CONCLUSIONS: The reduction of NABTs despite continuous treatment with incobotulinumtoxinA indicates low antigenicity of incobotulinumtoxinA. This might have implications on restrictions such as minimum injection intervals of ≥10 weeks currently in place for maintaining successful long-term application of botulinum neurotoxin.

Partial rescue of the perfusion deficit area by thrombolysis.

PURPOSE: To investigate the evolution of the perfusion deficit area following systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) in a clinical study on acute cerebral ischemia. MATERIALS AND METHODS: We performed volumetric measurements of the acute ischemic lesions in MR images of perfusion (TTP, MTT, and rCBV) and in diffusion-weighted (DW) images, as well as the manifest stroke lesions in T2-weighted MR images on day 8. We compared the data of 29 patients who were subjected to systemic thrombolysis with those of 18 patients who were not eligible for thrombolysis. RESULTS: In the treated patients there were prominent MTT/DWI and TTP/DWI mismatches (P < 0.0006). The acute TTP volumes were smaller than the acute MTT volumes, but as large as the T2 lesions on day 8. The MTT/T2 lesion volume reduction was significant (P < 0.03) in patients who received the GPIIb/IIIa receptor antagonist tirofiban (N = 13) in addition to the low-dose rtPA. This corresponded to a greater neurological improvement compared to patients who received rtPA alone (P < 0.05). In contrast, in the nontreated patients the initial MTT and TTP lesion volumes were of similar magnitude and predicted the T2 lesions on day 8. In the treated and nontreated patients the TTP lesion signified the viability threshold of acute ischemia, which corresponded to a rCBF of 25 +/- 11 mL/100 g/min. CONCLUSION: The perfusion deficit area comprises the ischemic core that is destined to undergo necrosis, and an ischemic rim that is salvageable by systemic thrombolysis.

Perilesional pathological oscillatory activity in the magnetoencephalogram of patients with cortical brain lesions.

In the surrounding of focal ischemic brain lesions dysfunctional neuronal zones emerge often resulting in pathological oscillatory activity. Using whole-head magnetoencephalography we recorded brain activity during rest in 23 patients with ischemic cortical lesions to find out whether we can localise and characterise low-frequency oscillatory activity. We measured patients at different times after stroke and partly in a follow-up approach to determine the time course of slow-wave activity. Using the analysis tool Dynamic Imaging of Coherent Sources we computed tomographic maps of oscillatory power in the delta-band (0.5-3 Hz). Fifteen of 23 patients with cortical strokes showed delta-activity, which was localised in an area not more than 2 cm away from the lesion. We found this perilesional low-frequency activity in the acute as well as in the chronic stage of stroke. Follow-up measurements of individual patients revealed persistence of perilesional low-frequency activity for months and even years. No consistent relation between perilesional activity and clinical symptoms was observed. Our results indicate that perilesional delta activity is common after ischemic cortical stroke. However, the functional significance remains to be elucidated.

Rapid mapping of finger representations in human primary somatosensory cortex applying neuromagnetic steady-state responses.

We analyzed somatosensory evoked steady-state fields in order to localize finger representations in the hand area of the primary somatosensory cortex (S1). Using a 122-channel whole-head neuromagnetometer we recorded in six healthy subjects neuromagnetic responses to high frequency electrical stimuli delivered simultaneously to digit I, II, III and V at 22, 24, 27 and 30 Hz, respectively, and to transient stimulation of each single digit with a frequency of 3 Hz. Responses were averaged separately for each digit and were modeled by single equivalent current dipoles. Both conditions yielded the typical somatotopic finger representations within S1 hand area. Dipole locations did not differ significantly between the transient and the steady-state stimulation. Therefore, simultaneous high-frequency stimulation of the digits seems to be a reliable method for rapid and detailed mapping of the S1 hand area. This procedure has potential advantages over recording of transient responses. With simultaneous steady-state stimulation the measurement times are reduced to 2 min for mapping the whole hand area. Because of this our method probably increases spatial accuracy and permits repeated short interval recordings, e.g. in experiments studying short term plasticity.