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

Bathypelagic particle flux signatures from a suboxic eddy in the oligotrophic tropical North Atlantic: production, sedimentation and preservation

Particle fluxes at the Cape Verde Ocean Observatory (CVOO) in the eastern tropical North Atlantic for the period December 2009 until May 2011 are discussed based on bathypelagic sediment trap time-series data collected at 1290 and 3439 m water depth. The typically oligotrophic particle flux pattern with weak seasonality is modified by the appearance of a highly productive and low oxygen (minimum concentration below 2 µmol kg−1 at 40 m depth) anticyclonic modewater eddy (ACME) in winter 2010. The eddy passage was accompanied by unusually high mass fluxes of up to 151 mg m−2 d−1, lasting from December 2009 to May 2010. Distinct biogenic silica (BSi) and organic carbon flux peaks of ∼ 15 and 13.3 mg m−2 d−1, respectively, were observed in February–March 2010 when the eddy approached the CVOO. The flux of the lithogenic component, mostly mineral dust, was well correlated with that of organic carbon, in particular in the deep trap samples, suggesting a tight coupling. The lithogenic ballasting obviously resulted in high particle settling rates and, thus, a fast transfer of epi-/meso-pelagic signatures to the bathypelagic traps. We suspect that the two- to three-fold increase in particle fluxes with depth as well as the tight coupling of mineral dust and organic carbon in the deep trap samples might be explained by particle focusing processes within the deeper part of the eddy. Molar C : N ratios of organic matter during the ACME passage were around 18 and 25 for the upper and lower trap samples, respectively. This suggests that some productivity under nutrient (nitrate) limitation occurred in the euphotic zone of the eddy in the beginning of 2010 or that a local nitrogen recycling took place. The δ15N record showed a decrease from 5.21 to 3.11 ‰ from January to March 2010, while the organic carbon and nitrogen fluxes increased. The causes of enhanced sedimentation from the eddy in February/March 2010 remain elusive, but nutrient depletion and/or an increased availability of dust as a ballast mineral for organic-rich aggregates might have contributed. Rapid remineralisation of sinking organic-rich particles could have contributed to oxygen depletion at shallow depth. Although the eddy formed in the West African coastal area in summer 2009, no indications of coastal flux signatures (e.g. from diatoms) were found in the sediment trap samples, confirming the assumption that the suboxia developed within the eddy en route. However, we could not detect biomarkers indicative of the presence of anammox (anaerobic ammonia oxidation) bacteria or green sulfur bacteria thriving in photic zone suboxia/hypoxia, i.e. ladderane fatty acids and isorenieratene derivatives, respectively. This could indicate that suboxic conditions in the eddy had recently developed and/or the respective bacterial stocks had not yet reached detection thresholds. Another explanation is that the fast-sinking organic-rich particles produced in the surface layer did not interact with bacteria from the suboxic zone below. Carbonate fluxes dropped from ∼ 52 to 21.4 mg m−2 d−1 from January to February 2010, respectively, mainly due to reduced contribution of shallow-dwelling planktonic foraminifera and pteropods. The deep-dwelling foraminifera Globorotalia menardii, however, showed a major flux peak in February 2010, most probably due to the suboxia/hypoxia. The low oxygen conditions forced at least some zooplankton to reduce diel vertical migration. Reduced “flux feeding” by zooplankton in the epipelagic could have contributed to the enhanced fluxes of organic materials to the bathypelagic traps during the eddy passage. Further studies are required on eddy-induced particle production and preservation processes and particle focusin

Training skill and will of argumentative thinking

Hefter MH. Training skill and will of argumentative thinking. Bielefeld: Universitätsbibliothek Bielefeld; 2015

Preventive effects of botulinum neurotoxin long-term therapy: comparison of the ‘experienced’ benefits and ‘suspected’ worsening across disease entities

Background: Repetitive intramuscular injections of botulinum neurotoxin (BoNT) have become the treatment of choice for a variety of disease entities. But with the onset of BoNT therapy, the natural course of a disease is obscured. Nevertheless, the present study tries to analyze patients' "suspected" course of disease severity under the assumption that no BoNT therapy had been performed and compares that with the "experienced" improvement during BoNT treatment. Methods: For this cross-sectional study, all 112 BoNT long-term treated patients in a botulinum toxin out-patient department were recruited who did not interrupt their BoNT/A therapy for more than two injection cycles during the last ten years. Patients had to assess the remaining severity of their disease as a percentage of the severity at onset of BoNT therapy and to draw three different graphs: (i) the CoDB-graph showing the course of severity of patient's disease from onset of symptoms to onset of BoNT/A therapy, (ii) the CoDA-graph illustrating the course of severity from onset of BoNT/A therapy until recruitment, and (iii) the CoDS-graph visualizing the suspected development of disease severity from onset of BoNT/A therapy until recruitment under the assumption that no BoNT/A therapy had been performed. Three different types of graphs were distinguished: the R-type indicated a rapid manifestation or improvement, the C-type a continuous worsening or improvement, and the D-type a delayed manifestation or response to BoNT therapy. Four patient subgroups (cervical dystonia, other cranial dystonia, hemifacial spasm, and the migraine subgroup) comprised 91 patients who produced a complete set of graphs which were further analyzed. The "experienced" improvement and "suspected" worsening of disease severity since the onset of BoNT/A therapy were compared and correlated with demographical and treatment related data. Results: Improvement was significant (p < 0.05) and varied between 45 and 70% in all four patient subgroups, the "suspected" worsening was also significantly (p < 0.05) larger than 0, except in the migraine patients and varied between 10 and 70%. The "total benefit" (sum of improvement and prevented "suspected" worsening) was the highest in the other cranial dystonia group and the lowest in the migraine subgroup. The distributions of R-,C-,D-type graphs across CoDB-, CoDS-, and CoDB-graphs and across the four patient subgroups were significantly different. Conclusions: (i) Most BoNT long-term treated patients have the opinion that their disease would have further progressed and worsened if no BoNT/A therapy had been performed, (ii) The type of response to BoNT/A is different across different subgroups of BoNT/A long-term treated patients

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

Complete improvement of severe forearm complex regional pain syndrome with six high-dose incobotulinumtoxin A injections: clinical implications with respect to the literature

There is some evidence that injections of botulinum neurotoxin effectively reduce pain in complex regional pain syndromes (CRPSs). But no or little experience appears to exist for the application of incobotulinum neurotoxin type A (incoBoNT/A) in complex pain disorders. Here, a case of CRPS type I, characterized by severe symptoms in the left forearm is presented, showed significant continuous improvement following a series of six repetitive (painful) injections into the finger, hand, and forearm muscles of incoBoNT/A every 3 months, administered at declining doses varying between 500 and 100 U. Remarkably, this treatment regimen led to the complete resolution of pain, vaso- and sudomotor symptoms, and hand dystonia. This highlights the possible efficacy of incoBoNT/A in the treatment of CRPS and encourages the further exploration of incoBoNT/A's role in the successful management of complex pain disorders

Do female and male patients with cervical dystonia respond differently to long-term botulinum neurotoxin therapy?

BACKGROUND: Idiopathic cervical dystonia (CD) affects more female than male patients. This sex-based influence on the clinical manifestation of CD may also affect outcomes after long-term BoNT therapy. METHODS: To analyze the potential differential influence of sex on the efficacy of BoNT therapy, a cross-sectional study was conducted with 135 female and 85 male patients with idiopathic cervical dystonia. Demographic and treatment-related data were extracted from patient charts. The 24-item Cervical Dystonia Questionnaire (CDQ24), patients' self-assessment of CD severity (PAS), and the TSUI score were used as outcome measures. On the day of recruitment, blood samples were collected to analyze neutralizing antibody (NAB) formation using an ELISA, with confirmation by the mouse hemidiaphragm assay (MHDA) test. RESULTS: Male patients had significantly (p < 0.02) lower mean age and age at symptom onset and received significantly (p < 0.02) higher BoNT doses per session. Female patients had significantly worse PAS and CDQ24 scores (p < 0.006), though the TSUI score showed no significant difference (p = 0.19). Despite receiving lower BoNT doses, female patients exhibited a significantly (p < 0.006) higher risk of NAB induction. CONCLUSION: This reanalysis of previously published data reveals that female and male patients in this cohort were treated and responded differently to long-term BoNT therapy, a discrepancy that remained unnoticed by their treating physicians over more than 10 years of treatment

"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

Effects of combined vibration ergometry and botulinum toxin on gait improvement in asymmetric lower limb spasticity: a pilot study

OBJECTIVE: Botulinum neurotoxin type A (BoNT/A) injections and the new vibration ergometry training (VET) are studied for their combined effect on improving functional mobility in patients with asymmetric lower limb spasticity. METHOD: Gait was analyzed using the Infotronic® system, which measures ground reaction forces and foot contact patterns by means of special force-sensitive shoes strapped over feet or street shoes. Gait was measured several times, depending on the protocol patients underwent. Seven patients with asymmetric lower limb spasticity were analyzed according to the control protocol (CG-group): after a baseline walk of 20 m (NV-W1) patients received their routine BoNT/A injection and had to walk the same distance a second time (NV-W2). Approximately 3-5 weeks later, they had to walk a third time (NV-W3). A further seven patients (VG-group) were analyzed according to the vibration protocol: after a baseline walk (V-W1), patients underwent a first vibration training (VET1), walked a second time (V-W2), received their routine BoNT/A injection, and walked a third time (V-W3). About four weeks later, they had to walk again (V-W4), received another vibration training (VET3), and walked a fifth time (V-W5). At least six months after the analysis according to the vibration protocol, these patients were also analyzed according to the control protocol. Eleven gait parameters were compared between the CG- and VG-group, and within the VG-group. RESULT: Patients in the VG-group experienced a significant improvement in gait four weeks after BoNT/A injection, unlike the patients in the CG-group. VG-patients also showed improved gait after two VET sessions. However, there was no further functional improvement of gait when BoNT/A injections and VET sessions were combined. CONCLUSIONS: BoNT/A injections enhance functional mobility in patients with mild asymmetric leg spasticity. VET also induces an immediate gait improvement and offers a further treatment approach for leg spasticity. Whether combining BoNT treatment and vibration training offers superior outcomes compared to either treatment alone requires further investigation