Treatment of occupational cramp with botulinum toxin: Diffusion of toxin to adjacent noninjected muscles

Over a 5-year period, 40 patients, 11 with musician's and 29 with writer's cramp, were treated with botulinum toxin A using a precise injection technique in which the hollow-bore electromyography (EMG) needle was positioned by both standard EMG and by muscle twitch evoked by stimulating current passed through it. Moderate to complete improvement in dystonia occurred in 28 patients (70%) after the first injection and in 34 patients (85%) after the second injection with better outcome in nonmusicians than in musicians. Of note, weakness of uninjected muscles, immediately adjacent to those injected, was found in 25/40 patients (63%). The most common patterns of toxin spread were from flexor digitorum sublimis to profundus, extensor carpi radialis to extensor digitorum communis, and extensor indicis proprius to extensor pollicis brevis. Spread to, and weakness of, adjacent uninjected muscles was a major factor contributing to suboptimal outcome in 6/39 (15%) such patients. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 593–598, 1997.     

Remote effects of chronic botulinum toxin treatment: electrophysiologic results Do not indicate subclinical remodelling of noninjected muscles

This study investigates the remote effects of botulinum toxin injections by examining the motor unit architecture of noninjected distant muscles. In 21 dystonia patients treated with botulinum toxin (n = 11, mean cumulative dose = 815 mU; n = 10, mean cumulative dose = 7,207 mU) and 10 control individuals, a blinded single-fiber electromyography of the vastus lateralis muscle was performed. The main outcome measure was fiber density (FD), thus measuring the effect of different cumulative doses on remote reinnervation. FD was normal in all patients treated with botulinum toxin. FD did not differ between the three groups studied. No relationship was found between FD and cumulative dose. Therefore, in this specific patient population, muscles remote to the site of injection showed no FD change months after the injection. We conclude that there was no evidence of remote reinnervation and remodelling of motor units with cumulative chemodenervation.     

Long-term botulinum toxin treatment increases employment rate in patients with cervical dystonia.

We examined the impact of cervical dystonia (CD) and long-term botulinum toxin (BTX) treatment on employment status. Data on employment status at onset of CD, at initiation of BTX treatment, and at evaluation of long-term treatment were obtained from 62 CD patients aged 31-66 years (median, 53 years; 61% females) who had been treated for a median of 5 years (range, 1.5-10 years). The employment rate fell from 84% at the onset of CD to 47% before initiation of BTX treatment. With long-term BTX treatment, 72% of those who worked at the initiation of treatment stayed employed, and 67% of those on sick leave returned to work. A younger age and a higher level of education increased the probability of being employed and avoiding disability benefits. Among those who were younger than 55 years at evaluation of BTX treatment (n = 40), the employment rate increased from 47% to 65% with treatment, and among the male patients, it reached the level of the general population (86%). About half of the 34% who received disability benefits did so already before the BTX treatment was initiated.     

Long-term remission of idiopathic cervical dystonia after treatment with botulinum toxin

Botulinum toxin type A (BTX-A) treatment for cervical dystonia is traditionally considered a purely symptomatic treatment. BTX-A blocks acetyl choline exocytosis for 3-6 months and most patients require reinjection after this period. We report on 6 patients (mean age 41.6 years, range 18-69) with idiopathic cervical dystonia who were treated with BTX-A injections and became asymptomatic for 2-4 years. Four patients showed remission after the first BTX-A treatment, 1 patient after the second set of injections and 1 after the third session. Amelioration of neck dystonia was observed within 1-4 weeks after the last BTX-A treatment and all 6 patients are symptom-free, off antidystonic medications for over 2 years. The possibility that BTX-A treatment may increase the chances of development of clinical remission in patients with idiopathic cervical dystonia is discussed.     

Long-term follow-up of cervical dystonia patients treated with botulinum toxin A.

We followed the course in 100 consecutive patients with cervical dystonia (CD) after they were initially treated with botulinum toxin (BTX) in the form of Dysport 10 to 12 years ago. A total of 4 patients had died, and 6 were lost to follow-up. Of the remaining 90 patients, 57 (63%) were still treated with BTX. In the patients treated at one centre over the whole period with Dysport, mean dose used during each treatment session was 833 (SD +/- 339) units Dysport with a cumulative dose of 20,943 (SD +/- 9462) units Dysport over a mean of 26.8 (SD +/- 8.6) treatment cycles. Secondary nonresponse was detected in 3 of the 90 patients. During follow-up, 12 patients developed blepharospasm, 13 oromandibular dystonia, and 17 patients writer's cramp. We conclude that BTX remains effective and safe for approximately 60% of CD patients for more than 10 years.     

Electromyographic guidance of botulinum toxin treatment in cervical dystonia

We report the results of electromyographic (EMG) guidance in the treatment of cervical dystonia with botulinum toxin. Eight-four patients received a total of 225 injection sessions. Overall there was moderate objective improvement in 78.7%. The mean dose of toxin was 269 +/- 39 mouse lethal units and the mean duration of maximum effect was 107 +/- 49 days. Complications included excessive neck weakness in 16.0% and dysphagia in 11.1% of the injection sessions. We conclude that EMG guidance is a safe and effective method of administering botulinum toxin in the treatment of cervical dystonia.     

Muscle fiber orientation in muscles commonly injected with botulinum toxin: An anatomical pilot study

The endplate zone is assumed to be at about the midpoint of a muscle fiber. This study was designed to locate the middle of the muscle fibers of commonly injected muscles, thus identifying the endplate zone of these muscles. The proximal and distal musculotendinous junctions in muscles of the upper and lower extremities were identified. Orientation of muscle fibers was determined. Measurements using common surface landmarks were used to determine the relationship of these muscles with the landmarks (e.g., biceps muscle bulk extends from the upper fourth to the lower fourth of the humerus). Figures were developed using these measurements so as to be able to extrapolate these measurements to other patients of varying sizes. Illustrations of muscle fiber orientation were done and the assumed location of motor endplate bands marked. Color illustrations will be shown. With the thought that the endplate zone is at the middle of the muscle fiber, this detailed study of muscle fibers helps identify assumed location of motor endplates of specific muscles, thereby improving technique and efficacy of botulinum toxin injections.     

Long-term follow-up by video of cervical dystonia treated with botulinum toxin

We have analysed video recordings of 21 patients with cervical dystonia treated with botulinum toxin. Fourteen patients have a record both of their response shortly after injections were commenced and between four years five months and six years seven months later. Our analysis shows that the long term outcome is often better than the initial response. We suggest that chronic treatment with botulinum toxin allows different muscles to those initially injected to be identified as contributors to the dystonia. Subsequent injection of these muscles leads to further improvement. It implies that cervical dystonia is a more widespread disorder of motor control, rather than simply limited to a few muscles.     

Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency

Data from 616 patients suffering from idiopathic cervical dystonia were analyzed to determine the efficacy and safety of treatment with botulinum neurotoxin type A (BoNT/A). Since the specific purpose of this study was to determine the long-term effects of this treatment, the analysis focused specifically on the patients (n = 303) having received six or more injections. Statistical analysis of a standardized documentation showed sustained significant benefit as measured by a disease severity score independent of the type of cervical dystonia. Furthermore, pronounced individual differences were found in response to this treatment although initial clinical scores and doses of BoNT/A were similar. There was no indication of previously unknown adverse events, the only risk being the development of serum antibodies against the toxin. As in previous studies on short-term effects of BoNT/A treatment, the most frequent adverse event was dysphagia, which occurred on average 9.7 days after injection and lasted on average 3.5 weeks. While secondary nonresponse was seen in approx. 5% of patients, antibody tests revealed neutralizing serum antibodies in only 2%. On the basis of the present data, therapy of cervical dystonia with BoNT/A seems to be safe and yields good stable results even after 5 years of treatment. Received: 26 June 1997 Received in revised form: 17 July 1998 Accepted: 4 August 1998     

A new treatment for cervical vertigo with botulinum toxin

A new and unique treatment for cervical vertigo with botulinum toxin is presented for a woman who sustained neck trauma from being hit by a wave. A diagnosis of cervical vertigo and cervical dystonia was confirmed by history, physical exam, dystonia on EMG exam, and a negative test for benign paroxysmal positional vertigo.She experienced consistent resolution of her vertigo symptoms and pain after each treatment for a total of 5 treatments with botulinum toxin to the upper cervical muscles. This report appears to be the first to demonstrate the missing link between vertigo and cervical dystonia with pain. Chemodenervation was effective in treating cervical vertigo and is likely to have altered the cervical proprioceptive input by relaxing the overactive muscles and/or by decompression of cervical nerves.     

Clinical changes of cervical dystonia pattern in long-term botulinum toxin treated patients

Cervical dystonia (CD) is a complex disorder but the response to long-term botulinum toxin (BTX) therapy is satisfactory in most cases. Bad results are attributed by some authors to changes in muscle activation. Our purpose is to verify if the change in head deviation affects negatively the response to BTX therapy in a long-term follow-up, and if there are any differences in clinical parameters of these patients in comparison to those with stable pattern. From a total of 88 patients evaluated at the Movement Disorders Clinics of Hospital das Clinicas – University of São Paulo School of Medicine between January 1993 and December 2005, 67 were included. In 24 (35.8%) change in pattern of CD was observed, in a medium follow-up period of 80 months. The time between onset of dystonia and the diagnosis of pattern change was 9.7 years. Comparing with patients with no changes in CD pattern, there were no significant statistical differences. Improvement of symptoms around 60% was reported in both groups. In conclusion, the change in head deviation observed in CD was not responsible for bad response to therapy with BTX and there were no significant differences between both groups.     

Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia

The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administration of botulinum toxin type A (Dysport^®, Ipsen Biopharm Ltd.) for the treatment of cervical dystonia (CD) and the long-term safety and efficacy of repeated treatments. During the randomized, double-blind, placebo-controlled phase patients were randomized to 500 units Dysport (n = 55) or placebo (n = 61). Efficacy assessments included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total and subscale scores, visual analogue scale (VAS) for pain, subject/investigator’s VAS for symptom assessments. Patients completing the double-blind treatment could enter an open-label extension phase and receive up to 4 additional Dysport treatments. Dysport produced a significant decrease from baseline in mean (±SE) TWSTRS total scores compared with placebo at Week 4 (primary efficacy endpoint; −15.6 ± 2.0 vs. −6.7 ± 2.0; p < 0.001) with significant improvements sustained to Week 12 (p = 0.019). Dysport also produced significant improvements in TWSTRS subscale scores, VAS pain scores, and subject/investigator’s VAS symptom assessments compared to placebo. The mean duration of open-label study participation was 51.9 weeks (range 3.9–94.0 weeks). During open-label treatment, all treatment cycles resulted in improvements in mean TWSTRS total and subscale scores at Week 4 post-treatment; greatest improvement was seen in cycle 1. The mean duration between treatment cycles was 15–17 weeks. Dysport demonstrated a good long-term safety profile; most adverse events were mild or moderate and typical of the known safety profile of Dysport in this indication. These results confirm that Dysport (500 units) is safe, effective, and well-tolerated in patients with CD.     

Muscle activity changes in spasmodic torticollis after botulinum toxin treatment

We assessed electromyographic (EMG) activity in neck muscles before and after botulinum toxin injections in 28 patients with spasmodic torticollis (ST) to investigate possible changes in muscle activation after treatment. A six-channel EMG with surface electrodes was used to record activity of sternocleiodomastoid, trapezius and splenius capitis bilaterally. Objective benefit (>25% reduction in Tsui's score) occurred in 22 patients (78%). Of the 168 muscles studied before botulinum toxin injections, 90 presented EMG activity. Sixty-eight of these muscles were injected and a decrease in EMG activity occurred in 44 (65%) of them. A decrease in EMG activity was also detected in 15 (68%) of those which were not injected. On the other hand, 70 of the 78 muscles without pre-botulinum toxin EMG activity were not injected. However, after treatment, EMG activity increased in 37 (52%) of these muscles. These changes involved 18 patients and occurred without concomitant change in the main direction of head deviation despite the improvement observed in most cases. These results suggest that in ST head turning results from an abnormal central motor program which results in non-specific neck muscle activation.     

Long-term botulinum toxin efficacy, safety, and immunogenicity.

To determine the long-term efficacy of botulinum toxin (BTX) treatments, we analyzed longitudinal follow-up data on 45 patients (32 women; mean age, 68.8 years) currently followed in the Baylor College of Medicine Movement Disorders Clinic, who have received BTX treatments continuously for at least 12 years (mean 15.8 +/- 1.5 years). Their mean response rating after the last injection, based one a previously described scale 0-to-4 scale (0 = no effect; 4 = marked improvement) was 3.7 +/- 0.6 and the mean total duration of response was 15.4 +/- 3.4 weeks. Although the latency and total duration of the response to treatment have not changed over time, the peak duration of response (P < 0.005) and dose per visit (P < 0.0001) have increased since the initial visit. Furthermore, global rating (P < 0.02) and peak effect (P < 0.05) have improved. In total, 20 adverse events occurred in 16 of 45 (35.6%) patients after their initial visit and 11 adverse events in 10 of 45 (22.2%) patients at their most recent injection visit. Antibody (Ab) testing was carried out in 22 patients due to nonresponsiveness; blocking Abs were confirmed by the mouse protection assay in 4 of 22 (18%) patients. Of the Ab-negative patients, 16 resumed responsiveness after dose adjustments and 2 persisted as nonrespondents. Except for 1 patient, the 4 Ab-positive and the 2 clinical nonresponders are being treated with BTX-B. This longest reported follow-up of BTX injections confirms the long-term efficacy and safety of this treatment.     

Treatment recommendations and practical applications of botulinum toxin treatment of cervical dystonia

CD is a complex disorder that can have significant impact on a patient's quality of life and physical well-being. BoNTs are a very effective and well-tolerated first-line therapy in relieving CD symptoms over long-term treatment. BoNT treatment should be administered at the lowest effective dose with a minimum of 3 months between treatments. As the incidence of immunoresistance is low, a reassessment of muscle selection, dosing, and diagnosis should take place in the event of suboptimal patient response. Optimal treatment may involve a combination of oral pharmacologic treatment with BoNTs to maintain the use of lowest possible dosing and to extend effectiveness to the recommended 3-month dosing interval. Physical therapy in conjunction with BoNT treatment can also extend treatment efficacy as well. Comorbidities such as insomnia, depression, and anxiety can interfere with successful CD treatment and should be actively managed along with the symptoms of CD. Although our understanding of CD is incomplete, it is ever expanding. As a deeper understanding of disease pathophysiology and disease progression is gained, treatment efforts will be refined for optimal outcome and patient satisfaction.     

Long-term safety of therapeutic botulinum toxin A

For more than 20 years, therapeutic botulinum toxin A has been applied with success. With this long experience, the substance can viewed as safe and low in side effects. This was confirmed by a recent meta-analysis of placebo-controlled clinical studies. The side effects documented were light to moderate, temporary, and local. In respect to the frequently needed long-term therapy, it is necessary that botulinum toxin A be safe and cause no disturbance. The development of neutralizing antibodies to botulinum toxin A is very rare and no longer has an appreciable effect on its clinical application.