Excessive psychological stress preceding the onset of idiopathic cervical dystonia.

Idiopathic cervical dystonia (ICD) is the largest subgroup of dystonia. Psychological stress as a triggering factor has long been discussed, but detailed descriptions are lacking. We report on a group of 13 patients with ICD and preceding excessive psychological stress (age at ICD onset 39.0 ± 13.9 years, 7 females, 6 males). The observation period was 7.8 ± 5.0 years. Excessive psychological stress included partner conflicts (divorce and separation, domestic violence), special familial burdens, legal disputes and migration. It started 8.3 ± 3.9 months before ICD onset. In 85% of our patients (typical cases), ICD developed within 5.8 ± 4.4 weeks, then lasted 18.5 ± 8.3 months, before it started to remit 2.7 ± 0.8 years after its onset to 54.5 ± 35.3% of its maximal severity. Idiopathic dystonia is thought to be based upon a genetic predisposition triggered by epigenetic factors. Our study suggests that excessive psychological stress could be one of them. Pathophysiologic elements are only vaguely identified, but could include the endoplasmic reticulum stress response, cerebellar 5HT-2A receptors and the metabolism of heat shock proteins. Whilst the clinical presentation of ICD preceded by excessive psychological stress is typical, its course is atypical with rapid onset and fast and substantial remission.

The natural course of idiopathic cervical dystonia.

Idiopathic cervical dystonia (ICD) is by far the largest subgroup of dystonia. Still, its natural course is largely unknown. We studied the natural course of 100 ICD patients from our botulinum toxin clinics (age at ICD onset 45.8 ± 13.5 years, female/male ratio 2.0) over a period of 17.5 ± 11.5 years with follow-ups during botulinum toxin therapy and with semi-structured interviews. Two courses of ICD could be distinguished by symptom development of more or less than 6 months. ICD-type 2 was less frequent (19% vs 81%, p < 0.001), had a more rapid onset (8.7 ± 8.0 weeks vs 3.8 ± 3.5 years), a higher remission rate (92% vs 5%, p < 0.001) and a higher prevalence of excessive psychological stress preceding ICD (63% vs 1%, p < 0.001). In both ICD-types, the plateau phase was non-progressive. Significant differences in patient age at ICD onset, latency and extent of remission, female/male ratio and prevalence of family history of dystonia could not be detected. ICD is a non-progressive disorder. ICD-type 1 represents the standard course. ICD-type 2 features rapid onset, preceding excessive psychological stress and a high remission rate. These findings will improve prognosis, treatment strategies and understanding of underlying disease mechanisms. They contradict the widespread fear of patients of a constant and continued decline of their condition. Excessive psychological stress may be an epigenetic factor triggering the manifestation of genetically predetermined dystonia.

Potency of botulinum toxin drugs: test systems and labelling.

Cell-based assays are a novel method to determine potency of botulinum toxin drugs. Manufacturers are working on their acquisition, development and implementation to reduce animal consumption during the manufacturing process. Potency labelling of botulinum toxin drugs differes principally between Ipsen and the other manufacturers. Reference to a uniform international standard would avoid this potentially dangerous situation. However, this has not been demanded by the registration authorities and has not been persued by the manufacturers for decades.

Botulinum toxin therapy: past, present and future developments.

Although botulinum toxin (BT) is now being used in a large number of different indications in numerous medical specialties, there is still dynamic and rapid development. Treatment algorithms were improved by the introduction of BT short-interval therapy, BT high-dose therapy and improved dosing guidelines. Ultrasound guidance may be helpful in special situations. New indication areas including depression and inflammatory processes are being explored. Drug development projects are mainly focusing on onabotulinumtoxinA analogues, some are addressing liquid preparations and modifications of BT's duration of action. Recombinant BT may simplify production processes. Cell-based assays for potency measurement will soon be required by registration authorities. Treatment algorithms will be further refined and indications will be expanded. New indication areas are still uncertain. BT type A will remain the drug substance of choice. Removal of complexing proteins seems logical. Whether there is a need for BT drugs with modified duration of action and for liquid preparations, is unclear. Bringing BT therapy to those who need it, is the biggest challenge. Current high-price business models need to be changed, either by employing a biosimilar registration approach or by referring to companies from countries where business models are based on different cost structures.

Botulinum toxin dosing in arm muscles: contextual factors.

Botulinum toxin (BT) has been successfully used for many years to treat various muscle hyperactivity disorders including dystonia and spasticity. Its dosing is guided by dosing tables describing target muscles and dose ranges. To refine the BT dosing, we wanted to analyse how contextual factors may influence the injector's final dosing decision.In a retrospective review of real-life data of 1170 BT treatments, we studied the influence of various contextual factors on the BT doses in 21 arm muscles of 252 patients receiving BT therapy for different muscle hyperactivity disorders.We found that BT arm doses are significantly higher in treatment of spasticity than in treatment of dystonia. We also found that spontaneous arm dystonia requires higher BT doses in a proximal application pattern, whereas task specific writer's cramp requires considerably reduced BT doses with a distal application pattern. Injections of non-arm muscles influence the BT dosing in arm muscles only marginally.Our study demonstrates that BT dosing does not only depend on the particularities of the individual target muscle injected, such as its volume and its static or phasic function. BT dosing and its application pattern rather depend on additional contextual factors such as the aetiology and pathophysiology of the muscle hyperactivity treated. These contextual factors need to be included in dosing tables and may improve the outcome of BT therapy.

Botulinum toxin therapy of dystonia.

Botulinum toxin (BT) is used to treat a large number of muscle hyperactivity syndromes. Its use in dystonia, however, is still one of the most important indications for BT therapy. When BT is injected into dystonic muscles, it produces a peripheral paresis which is localised, well controllable and follows a distinct and predictable time course of around 3 months. Adverse effects are always transient and usually mild, long-term application is safe. With this profile BT can be used to treat cranial dystonia, cervical dystonia and limb dystonia including writer's and musician's cramps. The recent introduction of BT high dose therapy also allows to treat more wide-spread dystonia including segmental and generalised dystonia. BT can easily be combined with other anti-dystonic treatments such as deep brain stimulation and intrathecal baclofen application. Best treatment results are obtained when BT therapy is integrated in the multimodal and long-term 'multilayer concept of treatment of dystonia'. The biggest challenge for the future will be to deliver state of the art BT therapy to all dystonia patients in need, regardless of whether they live in developed countries or beyond.

Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Clinical Pharmacology of Botulinum Toxin Drugs.

Botulinum toxin (BT) has changed from a deadly poison to a novel therapeutic principle for a large number of disorders in many medical areas.BT drugs are special in many ways: they are biologicals, their active ingredient BT is not patentable, their spectrum of clinical applications is extremely broad, their dose range is enormous, their mode of action is local and their life cycles are special.This review covers BT's therapeutic mode of action, time course of action, target tissues, pharmacological profile, adverse effects, interactions, potency labelling and antigenicity as well as BT's therapeutic preparations.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.

Botulinum toxin therapy in the SARS-CoV-2 pandemic: patient perceptions from a German cohort.

The SARS-CoV-2 virus pandemic has provoked drastic countermeasures including shutdowns of public services. We wanted to describe the effects of a 6 week shutdown of a large German botulinum toxin (BT) outpatient clinics on patients and their well-being. 45 patients (age 61.9 ± 9.8 years, 29 females, 16 males) receiving BT therapy (319.3 ± 201.9MU-equivalent, treatment duration 8.3 ± 5.5 years) were surveyed with a standardised questionnaire. The shutdown delayed BT therapy by 6.6 ± 2.3 weeks. 93% of the patients noticed increased muscle cramps and 82% increased pain reducing their quality of life by 40.2 ± 19.5%. For 23 patients with cervical dystonia this reduction was 41.1 ± 18.3%, for 3 patients with blepharospasm 33.3 ± 15.3%, for 9 patients with spasticity 37.8 ± 15.6%, for 4 patients with pain conditions 37.4 ± 35.7% and for 3 patients with hemifacial spasm 27.5 ± 17.1%. After the shutdown 66% of patients perceived BT therapy as more important than before, 32% perceived it as unchanged. For all patients long-term availability of BT therapy was very important or important. 98% of the patients perceived the shutdown as inadequate and felt their patient rights not respected. The shutdown confirmed the considerable burden of disease caused by dystonia, spasticity, hemifacial spasm and various pain conditions and the importance of BT therapy to treat them. Any shutdown severely affects these patients and needs to be avoided.

Dysphagia in cervical dystonia patients receiving optimised botulinum toxin therapy: a single-center retrospective cohort study.

To explore the correlations of botulinum toxin (BT) therapy with dysphagia, we wanted to study a group of cervical dystonia (CD) patients with optimised BT therapy during a prolonged period of time to record their dysphagia frequency, severity and duration, to study potential risk factors and try to avoid it by BT application with ultrasound guidance. BT therapy of 75 CD patients (23 males, 52 females, age 60 ± 12 years, BT total dose 303.5 ± 101.5 uMU) was retrospectively analysed for 1 year. BT therapy was optimised prior to the observation period. Dysphagia was noticed by one fifth of the patients. In those patients, it only occurred in about one third of the injection series. It was never associated with a functional deficit and lasted several days to 2 weeks. It was not related to patient age or gender, BT total dose, BT dose in the sternocleidomastoid muscle, BT dose in the sternocleidomastoid and scalenii muscles, by BT therapy with bilateral sternocleidomastoid muscle injections or BT therapy with abobotulinumtoxinA. Ultrasound guidance was not able to prevent it. Further prospective studies will be necessary to study underlying dystonia associated swallowing abnormalities as a potentially predisposing factor.

Botulinum neurotoxin injections for muscle-based (dystonia and spasticity) and non-muscle-based (neuropathic pain) pain disorders: a meta-analytic study.

Apart from the known efficacy of Botulinum Neurotoxin Type A (BoNT/A) in hyperactive striated and smooth muscles, different pain states have become potential targets of toxin effects. This present study determined the comparative toxin effectiveness in pain reduction among those patients injected with BoNT/A in muscle-based and in non-muscle-based conditions. Randomized controlled trials (RCTs) on the effect of BoNT/A on selected pain conditions were included. The conditions were spasticity and dystonia for muscle-based pain. For non-muscle-based pain, conditions included were painful diabetic neuropathy (PDN), post-herpetic neuralgia (PHN), trigeminal neuralgia (TN), complex regional pain syndrome (CRPS), and spinal cord injury (SCI). In view of possibly differing pathophysiology, myofascial pain, temporomandibular joint (TMJ), other joint or tendon pains, cervicogenic and lumbar pains, migraine and visceral pain syndromes were excluded. Standardized mean difference was used as the effect measure and computed with STATA. 25 RCTs were analyzed. Pooled estimates showed significantly lower pain score in the Treatment group (z = 5.23, p < 0.01, 95% CI = - 0.75, - 0.34). Subgroup analyses showed that BoNT/A significantly reduced both muscle-based (z = 3.78, p < 0.01, 95% CI = - 0.72, - 0.23) and non-muscle-based (z = 3.37, p = 0.001, 95% CI = - 1.00, - 0.27) pain. Meta-regression using four covariates namely dosage, route, frequency and duration was done which revealed that dosage significantly affects standardized mean differences, while the other three covariates were insignificant. The joint F-test was found to be insignificant (p value = 0.1182). The application of the model with these covariates does not significantly explain the derived heterogeneity of standardized mean differences. In conclusion, BoNT/A can be effectively used in muscle-based and non-muscle-based pain disorders. We detected no difference between the presence and magnitude of pain relief favoring muscle-based compared to non-muscle-based pain. Thus, we cannot say whether or not there might be independent mechanisms of toxin-induced pain relief for pain generated from either muscle or nerve hyperactivity.

Quality of life in subjects with upper- and lower-limb spasticity treated with incobotulinumtoxinA.

BACKGROUND: We evaluated quality of life among subjects with upper- and lower-limb spasticity who received escalating doses of incobotulinumtoxinA (total body doses up to 800 U) in the prospective, single-arm, dose-titration TOWER study. METHODS: In this exploratory trial, subjects (N = 155; 18-80 years of age) with upper- and lower-limb spasticity due to cerebral causes who were deemed to require total body doses of up to 800 U incobotulinumtoxinA received three consecutive injection cycles of incobotulinumtoxinA (400, 600, and up to 800 U), each with 12 to 16 weeks' follow-up. QoL was assessed using the EuroQol 5-dimensions questionnaire, three-level (EQ-5D), before and 4 weeks post-injection in each injection cycle and at the end of injection cycle 3. RESULTS: The mean EQ-5D visual analog scale scores of 155 participants continuously improved from study baseline to 4 weeks post-injection in all injection cycles (mean [standard deviation] change 6.7 [14.1], 9.6 [16.3], and 8.6 [17.0] for injection cycles 1, 2, and 3, respectively; p < 0.0001 for all, paired sample t-test). In general, among those with a change in the EQ-5D rating of their condition, the proportion of subjects with 'improvement' was greater than that with 'worsening' for individual EQ-5D dimensions across all injection cycles. At the end of injection cycle 3, the proportion of subjects rating their condition as 'normal' increased from study baseline for all dimensions, and there was a ≥ 46% reduction in the proportion of subjects with a rating of 'severe impairment'. CONCLUSION: These preliminary results suggest that escalating incobotulinumtoxinA doses up to 800 U are associated with improvement in quality of life ratings in subjects with multifocal upper- and lower-limb spasticity, and form a basis for future comparator studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01603459. Date of registration: May 22, 2012.

Comparing lanbotulinumtoxinA (Hengli®) with onabotulinumtoxinA (Botox®) and incobotulinumtoxinA (Xeomin®) in the mouse hemidiaphragm assay.

LanbotulinumtoxinA (LAN) is manufactured and registered in China since 1994. Despite its widespread use in China and its increasing use in other Asian countries and in South America, it is not yet well known elsewhere. We wanted to compare its potency labelling using the mouse diaphragm assay (MDA), an isolated muscle model for botulinum toxin (BT) potency measurements, which is superior to clinical tests and which was recently refined as an alternative batch release assay for BT manufacturing. We also wanted to estimate LAN manufacturing quality by testing its inter-batch potency consistency. Potencies of 20, 60 and 100 MU of LAN, onabotulinumtoxinA (ONA) and incobotulinumtoxinA (INCO) were measured by the inversely related paresis time (PT) in the MDA. The PT (M ± SD) of all doses of LAN, ONA and INCO was 90.4 ± 27.0 min, 114.9 ± 46.5 min and 94.3 ± 29.9 min, respectively. Statistical analysis demonstrated indistinguishable potency labelling of LAN and INCO, but revealed a slightly lower potency of ONA compared to LAN and INCO. PT of LAN batch 1 and LAN batch 2 was 86.9 ± 21.2 min and 94.0 ± 32.8 min, respectively (no statistically significant difference), suggesting an adequate LAN manufacturing consistency. The MDA is an appropriate instrument for potency testing of BT drugs, including new ones currently under development. Our results allow comparing therapeutic effects, adverse effects and economics of LAN, ONA and INCO. They also suggest adequate manufacturing consistency of LAN.

Botulinum neurotoxin a therapy efficacy and safety for oromandibular dystonia: a meta-analysis.

Oromandibular dystonia (OMD) is a focal dystonia involving the mouth, jaw, and tongue. Botulinum neurotoxin (BoNT) therapy might be one form of treatment in OMD. Systematic pooling of BoNT studies in OMD remains wanting, as the derived data could provide useful information in regard to efficacy and safety issues. This meta-analysis determined the effects of botulinum neurotoxin type A (BoNT/A) on the reduction of dystonic movement and its safety among patients with OMD. A systematic search of the literature that met the following eligibility criteria were done: (1) patients treated with BoNT/A for OMD, (2) studies of high methodological quality and (3) outcome criteria specified as regard to efficacy. Risk of unresolved dystonia was computed before and after BoNT/A intervention. Random effect size (p < 0.05ɑ) and test of heterogeneity (< I2 50%) were computed as meta-analysis tool using REVMAN ver 5.3 program. Safety data, where available, were systematically reviewed. Nine studies involved 387 cases in total of OMD. The pooled risk ratio is 0.607 with a confidence interval of 0.371-0.783, a z value of 3.85, and a p value of 0.0001. Results indicate that risk of dystonic movements is lower by 39.30% in the treatment group than in the control group. A total of 105/387 patients (27.1%) experienced adverse events most commonly dysphagia. Whilst cited literatures have inherent weaknesses, results show that BoNT/A is efficacious in reducing dystonic movements of patients with OMD. Majority of studies employed electromyography (EMG) guidance in muscle targeting. Given the potential adverse event of dysphagia, one may take a cautious stand while delivering injections to target muscles. These findings are congruent with what has been published in regard to efficacy of BoNT/A in focal dystonia.

IncobotulinumtoxinA for hypersalivation in patients with amyotrophic lateral sclerosis: an open-label single-centre study.

The objective of this study is to discover whether incobotulinumtoxinA (inco) can reduce relative hypersalivation in patients with amyotrophic lateral sclerosis (ALS). 14 patients with ALS (8 males and 6 females, age 55.4 ± 16.3 years) received ultrasound-guided injection of inco 100 MU in both parotid glands and inco 50 MU in both submandibular glands. Saliva production was gravimetrically measured with three cotton rolls placed in the mouth. Weight increase after 5 min was measured on an electronic scale. Subjective saliva production was registered with drooling frequency scale (DFS) and drooling severity scale (DSS). Saliva production was gravimetrically reduced at week 4 (p = 0.04), week 8 (p = 0.01) but not after week 12 after BT application. DFS was reduced at week 4 (p = 0.04), week 8 (p = 0.02), but not after week 12. DSS was reduced at week 4 (p = 0.03), week 8 (p = 0.04) and week 12 (p = 0.04). Patients in our study did not experience changes in their swallowing patterns or any other safety-relevant events. Inco is effective and well tolerated for saliva reduction in patients with ALS for 8-12 weeks.

Do complexing proteins provide mechanical protection for botulinum neurotoxins?

Botulinum toxin (BT) consists of botulinum neurotoxin and complexing proteins (CPs). CPs might provide mechanical protection for botulinum neurotoxin. As incobotulinumtoxinA (INCO, Xeomin®) does not contain CPs, we wanted to compare its mechanical stability to that of onabotulinumtoxinA (ONA, Botox®) containing CPs. For this, ONA and INCO were reconstituted without mechanical stress (NS) and with mechanical stress (WS) generated by a recently introduced stress test. Potencies were then measured by the paralysis times (PTs) in the mouse diaphragm assay. ONA-PT was 75.8 ± 10.3 min (n = 6) under NS and 116.7 ± 29.8 min (n = 6) under WS (two-tailed t test, p = 0.002). Mechanical stress increased the ONA-PT by 35.0% on the Growth Percentage Index. INCO-PT was 66.0 ± 7.0 min for NS and 76.0 ± 1.0 min for WS (t test, p = 0.129). Mechanical stress increased the INCO-PT by 13.2% on the Growth Percentage Index. Our data show that mechanical stress inactivates a CP-containing BT drug, but not a CP-free BT drug. We conclude that CPs do not provide protection against mechanical stress, supporting the view that CPs are not necessary for therapeutic purposes.

Botulinum toxin type D blocks autonomic cholinergic synapses in humans: discussion of a potential therapeutic use.

Based on epidemiological data it was believed that botulinumtoxin type D (BT-D) may not block human cholinergic synapses. We wanted to investigate BT-D's effect on the autonomic cholinergic synapse in humans. For this, we compared in four volunteers intraindividually the hypohidrotic effect of intradermal BT-D and BT-A in Minor's iodine starch sweat test. Altogether, we studied BT-D in doses of 4, 8, 16 and 32MU and BT-A in doses of 2, 4, 8 and 16MU at weekly intervals throughout a period of 13 weeks. All BT doses were diluted in 0.2 ml 0.9% NaCl/H2O. Overall 704 data points were collected. Combined over all four subjects and all four doses BT-D's hypohidrotic effect intensity was half of BT-A's. BT-D's effect peaked around 5 weeks, BT-A's around 7 weeks. BT-D's effect duration was around 12 weeks, of BT-A's was around 14 weeks. For both BT types the hypohidrotic effect was dose dependent. BT-D, when injected intradermally, can block autonomic cholinergic synapses in humans. Compared to BT-A, BT-D's effect intensity was half and its effect duration was some 2 weeks shorter. With its weaker and shorter effect BT-D does not seem to promise therapeutic effects superior to BT-A.

Antibody-induced failure of botulinum toxin therapy: re-start with low-antigenicity drugs offers a new treatment opportunity.

Botulinum toxin (BT) can stimulate formation of BT antibodies (BTAB) thus producing Antibody-Induced Therapy Failure (ABTF). BTAB titres may drop eventually. When BT therapy is then re-started with conventional BT drugs, BTAB titres re-increase promptly. We wanted to study whether the use of the low-antigenicity BT drug incobotulinumtoxinA (INCO) can prevent this re-increase. 8 patients with cervical dystonia and ABTF with maximal BTAB titres (6 women, 2 men, age 41.4 ± 12.1 years, disease duration 6.6 ± 4.7 years) were studied. ABTF ocurred under onabotulinumtoxinA (ONA) in five patients and under abobotulinumtoxinA (ABO) in 3 after 8.8 ± 3.8 injection series and a treatment time of 962.0 ± 473.2 days. After 3881.5 ± 2468.3 days without BT, all BTAB titres had dropped to insignificant levels before BT therapy was re-started with INCO. Treatment parameters before and after re-start were as follows: single dose 219.2 ± 90.7 MU vs 252.6 ± 109.0 MU (ns), interinjection interval 119.7 ± 18.4 vs 104.5 ± 14.7 days (ns), cumulative dose 1893.8 ± 1161.6 MU vs 5130.4 ± 3602.5 MU (ns), treatment time 962.0 ± 505.9 vs 1895.4 ± 1211.4 days (ns) and number of injection series 8.8 ± 3.8 vs 19.3 ± 11.8 (ns). Repeated BTAB measurements and clinical examinations did not reveal any signs of ABTF after re-start. INCO offers a new and long-term treatment opportunity for ABTF patients when their BTAB titres have dropped. Our observations also confirm lower antigenicity of INCO compared to conventional BT drugs.