Botulinum toxin injections reduce associative plasticity in patients with primary dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long‐term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation‐evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short‐interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Cervical dystonia: Improved treatment response to botulinum toxin after referral to a tertiary centre and the use of polymyography

RationaleCervical dystonia is the most common form of (primary) dystonia. The first line of treatment for cervical dystonia is intramuscular injections with botulinum toxin. To optimise the response to botulinum toxin proper muscles selection is required. Pre-treatment polymyographic EMG in addition to clinical evaluation is hypothesised to be a good tool to improve muscle selection and treatment outcome.ObjectiveTo determine the efficacy of botulinum toxin treatment after adjacent polymyographic EMG in cervical dystonia patients referred to our tertiary referral centre with an unsatisfactory response to botulinum toxin treatment elsewhere.MethodsWe performed a retrospective analysis of 40 consecutive second opinion cervical dystonia patients. Standard polymyographic EMG was performed before treatment. We retrieved the Tsui scores and subjective evaluations from the first visit, after 12 weeks and after one year of treatment. In addition, we assessed the final outcome of treatment in our centre based on the records and asked the patients for their personal opinion about the effect of referral to our centre on their treatment response.ResultsAfter one year of treatment there was a significant improvement on both the Tsui scores (p < 0.01) and the subjective treatment evaluation (p < 0.001.) On their last visit 60% of the patients still continued treatment with a reasonable to good response.ConclusionA substantial amount of CD patients with an unsatisfactory response to botulinum toxin improved after polymyography and subsequent treatment with botulinum toxin in a tertiary referral centre.     

Change in the pattern of cervical dystonia might be the cause of benefit loss during botulinum toxin treatment

The muscular patterns of cervical dystonia were identified by polymyographic recordings in 76 patients before botulinum toxin treatment. The leading muscles were considered to be those which started dystonic movement and which showed constant and maximal activity during all dystonic movements. The dystonic muscles were repeatedly treated by local Injections of botulinum toxin. Sixteen patients showed (after repeated injections) loss of the benefit of local applications of botulinum toxin after various periods of time. Repeated polymyographic recordings were performed in these patients during the loss of the benefit of injected botulinum toxin. In four patients repeated polymyographic recordings showed an Identical pattern of cervical dystonia, but the activity of previously injected muscles was apparently decreased. In 12 patients only minimum or no activity was recorded in muscles which had previously been treated with botulinum toxin, but the pattern of cervical dystonia was changed. Different patterns of cervical dystonia with different leading muscles, but with identical directions of head deviation, were observed in six patients. In another six patients, the head deviation direction was to the opposite side and was accompanied by a change of the leading muscle and a change of the muscular pattern of dystonia. These results suggest either that dystonic activity from the cerebral generator changes to new effectors during the peripheral blockade of primary dystonic muscles, or that a change of generators at different levels of the CNS occurs. It may be neccessary to carry out repeated polymyographic recordings throughout the period of loss of benefit of previously successful local botulinum toxin injections.     

Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia

To find out whether botulinum toxin alters the excitability of cortical motor areas, we studied intracortical inhibition with transcranial magnetic stimulation in patients with upper limb dystonia before, 1 month after, and 3 months after the injection of botulinum toxin type A in the affected muscles. Eleven normal subjects and 12 patients with dystonia involving the upper limbs (7 with generalized dystonia, 2 with segmental dystonia, and 3 with focal dystonia) were studied. Patients were assessed clinically with the Dystonia Movement Scale. Paired magnetic stimuli were delivered by two Magstim 200 magnetic stimulators connected through a Bistim module to a figure-of-eight coil placed over the motor area of the forearm muscles. Paired stimulation was given at rest. A subthreshold (80% of motor threshold) conditioning stimulus was delivered 3 and 5 msec before the suprathreshold (120% of motor threshold) test stimulus. Electromyographic signals were recorded over the flexor or extensor muscles of the forearm on the affected side. We measured the amplitude of the test motor evoked potential (expressed as a percentage of the unconditioned motor evoked potential). All results were compared using ANOVA. In all patients, a botulinum toxin type A injection (50-100 mouse units) reduced dystonic movements in the arm. In normal subjects, electromyographic recordings showed significant inhibition of the test response. Before botulinum toxin injection, patients had less test response inhibition than normal subjects. One month after injection, patients had test response inhibition similar to that of normal subjects. At 3 months after injection, they again had less inhibition than normal subjects or patients at 1 month after injection. In conclusion, our data suggest that botulinum toxin can transiently alter the excitability of the cortical motor areas by reorganizing the inhibitory and excitatory intracortical circuits. The cortical changes probably originate through peripheral mechanisms.     

Treatment of cervical dystonia hand spasms and laryngeal dystonia with botulinum toxin

Summary One hundred and twenty-six patients with different forms of focal dystonia (89 with cervical dystonia, 12 with hand cramps and 25 with laryngeal dystonia) were treated with localised injections of botulinum toxin. Mean doses per muscle were 200 mouse units (m.u.) for treating cervical dystonia, 40–120 m.u. for forearm muscles in writers' cramp and 3.7 m. u. for the thyroarytenoid muscle in laryngeal dystonia. Responder rates have been above 80% in all patient groups and beneficial effects could be reproduced over follow-up periods of up to 4 years. The commonest side-effects were dysphagia after treatment of spasmodic torticollis, weakness of neighbouring muscles after injections for hand cramps and breathiness and hypophonia following laryngeal injections. All these were transient and generally well tolerated. It is concluded that botulinum toxin injections are a safe and effective treatment in all three types of focal dystonia.     

The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A -- initial experiences.

The increasing use of botulinum toxin type-A, especially for focal dystonia and spasticity has highlighted the issue of secondary non-responsiveness. Within the last few years botulinum toxin type-B (Myobloc/Neurobloc) has become commercially available as an alternative to type-A. This paper discusses our initial experience of botulinum toxin type-B in a total of 63 individuals who attended our botulinum clinic. Thirty-six patients had cervical dystonia and a secondary non-response to type-A toxin. Thirteen of these patients (36%) had a reasonable clinical response to Neurobloc and continue to have injections. The other 23 patients either had no response, or a poor response, or had unacceptable side effects and ceased treatment. A small number of people with blepharospasm, hemifacial spasm and foot dystonia also had a disappointing response to injection. Twenty patients with spasticity were also type-A resistant. Seven of these show some continuing response to type-B, without unacceptable side effects. These findings demonstrate that botulinum toxin type-B has a place in the management of patients who have become non-responsive to type-A, but overall the responses to type-B toxin were disappointing.     

Muscle selection for treatment of cervical dystonia with botulinum toxin--a systematic review

RationaleCervical dystonia, also called spasmodic torticollis, is the most common form of (primary) dystonia. Intramuscular injections with botulinum toxin are the first line of treatment for cervical dystonia. To optimise the treatment response to botulinum toxin correct muscles should be selected. Clinical evaluation is important for muscle selection but the value of additional tests to identify dystonic muscles remains unclear.ObjectiveTo evaluate all relevant literature regarding the best approach to select dystonic muscles for treatment with botulinum toxin.MethodsWe conducted a systematic review of studies that had investigated methods of selecting muscles for treatment with botulinum toxin. In addition, we compared all prospective botulinum toxin trials using either clinical evaluation or polymyographic electromyography for muscle selection.ResultsForty relevant studies were included and polymyographic electromyography recordings were most often employed. In several studies, polymyographic electromyography revealed a different pattern of muscle involvement compared to that found during clinical evaluation. In one randomized controlled trial polymyographic electromyography significantly improved the outcome of botulinum toxin treatment. A limited number of studies used positron emission tomography – computed tomography imaging or frequency analysis of the electromyography signal to identify dystonic muscles but their effect on the outcome of treatment has never been studied.ConclusionPolymyographic electromyography may improve the outcome of botulinum toxin treatment in cervical dystonia, but evidence is limited and larger studies are needed.     

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.     

Long-term botulinum toxin treatment of cervical dystonia--EMG changes in injected and noninjected muscles.

OBJECTIVE: To evaluate changes in quantitative EMG of injected and noninjected sternocleidomastoid muscles following long-term unilateral botulinum toxin treatment of cervical dystonia. METHODS: We investigated 27 patients with cervical dystonia, who received repeated unilateral botulinum toxin injections of the sternocleidomastoid muscle, with quantitative EMG at rest and at maximal voluntary contraction. The patients had on the average 7.1 botulinum toxin treatments and the follow-up period was on the average 31 months (SD 16). RESULTS: After the first treatment, the injected sternocleidomastoid muscles showed a significant decrease in turns/s (mean 45%) and amplitude (mean 52%) at rest, and in amplitude at maximal flexion (mean 24%) and rotation (mean 39%). Except for a reduction in turns/s at rotation (mean 19%) no further reductions in EMG parameters were seen after long-term treatment. The contralateral noninjected sternocleidomastoid muscles showed no significant change in EMG activity after the first BT treatment, but after long-term treatment a significant reduction in turns/s and amplitude at both maximal flexion (turns: mean 28%; amplitude: mean 25%) and rotation (turns/s: mean 32%; amplitude: mean 25%) were seen as compared to pretreatment values. CONCLUSION: The results indicate that there seems to be no cumulative chemodenervation by repeated botulinum toxin injections of sternocleidomastoid muscles measured by quantitative EMG. Contralateral noninjected sternocleidomastoid muscles however, seem to be affected following long-term treatment. The mechanism behind this finding is unknown.     

Tiefe Hirnstimulation bei zervikaler Dystonie

BACKGROUND: Cervical dystonia results in severe disability and cannot be effectively treated with medication. Repeat injections of botulinum toxin into the dystonic neck muscles can relieve the symptoms in most patients. When this treatment fails (mostly due to antibody formation), deep brain stimulation can be considered. PATIENTS AND METHODS: We report our experiences with eight patients who were treated with bilateral deep brain stimulation of the globus pallidus interna for cervical dystonia. The mean observation period was 31 months. RESULTS: Six of eight patients experienced relief from symptoms a few days after the implantation. Improvement of symptoms was a mean of 60% during the 1st year. There were no complications. CONCLUSION: In this and in other studies with small numbers of patients, deep brain stimulation has shown a good effect on cervical dystonia. According to our results, the patients who benefit most are those with no dystonic shoulder involvement and who have a tonic rather than clonic symptomatology. It seems probable that deep brain stimulation will become the therapy of choice for otherwise intractable cervical dystonia.     

Fluoroscopic, EMG-guided injection of botulinum toxin into the longus colli for the treatment of anterocollis

BackgroundAnterocollis is a form of cervical dystonia characterized by forward neck flexion. While botulinum toxin is the treatment of choice for cervical dystonia, patients with anterocollis, who receive injections into the sternocleidomastoid and anterior scalene muscles, represent a disproportionate number of treatment failures. Deep cervical muscles such as the longus colli likely play an important role in neck flexion but are not routinely injected.ObjectiveTo describe a technique for longus colli injection in cases of anterocollis and to report the clinical outcomes of 10 such injections of botulinum toxin.MethodsThree patients were referred for evaluation and treatment of anterocollis. All had previous treatment failures with sternocleidomastoid/anterior scalene injections or no activity noted on needle EMG investigation of these muscles. All patients received injections of botulinum toxin into the longus colli under fluoroscopic and EMG guidance.ResultsAll patients experienced symptomatic improvement (eight of 10 injections). Two patients reported mild dysphagia without serious complications after dose increases in botulinum toxin.ConclusionsIncomplete muscle selection may be one cause of treatment failures in anterocollis. Deep cervical flexors such as the longus colli represent an under-recognized potential target for symptomatic treatment of anterocollis.     

Use of botulinum toxin in the treatment of laryngeal dystonia (spasmodic dysphonia): preliminary study of twelve patients

Laryngeal dystonia (spasmodic dysphonia) is a movement disorder characterized by involuntary contractions of laryngeal muscles involved with vocalization. The introduction of botulinum toxin in the treatment of laryngeal dystonia had a major clinical impact due to the striking improvement of symptoms. We report the preliminary results of therapeutical use of botulinum toxin in the treatment of twelve patients with laryngeal dystonia. After an extensive clinical evaluation, the patients underwent a videostroboscopic exam for diagnostic confirmation. Botulinum toxin was injected in the cricothyreoid membrane, directed towards the thyreoaritenoid muscle, with the aid of eletromyography needles. Most of patients who underwent botulinum toxin injection had a significant improvement of their symptoms (83%), with effects lasting for four months in average and without important side effects.     

Treatment of hip adductor spasticity with botulinum toxin type B

For the treatment of focal spasticity using botulinum toxin, only studies using type A have been published.Botulinum toxin type B (Neurobloc) is registered for cervical dystonia, but there is increasing interest in ist effectiveness for treating other diseases. Four patients, each with seriously disabling hip adductor spasticity of different origins, were treated with botulinum toxin type B following the failure of other therapeutic options.Total doses of 10,000 IU to 22,000 IU were injected bilaterally into the hip adductor muscles. A reduction in muscle tone or painful spasms was observed in all patients within 2 weeks, leading to an improvement in gait and increased ease of nursing care. Therefore, botulinum toxin type B may be a more cost-effective treatment for hip adductor spasticity than botulinum toxin type A.     

Botulinum toxin injections for cervical dystonia

We followed 205 of 232 patients with medically intractable cervical dystonia for at least 3 months and up to 4 years, during which time they received 1,074 injections in 505 visits. One hundred forty-five of the 205 patients (71%) improved substantially (global rating greater than or equal to 2; from 0 = no response to 4 = marked improvement in severity and function) after 1 or more visits. Of the 89 patients who reported pain, 68 (76%) had almost complete relief of their pain. While most patients noted improvement within the 1st week after injection, some had a latency of up to 8.5 weeks. Duration of maximum benefit lasted up to 12.5 months in some, but the average was 11.2 weeks. Only 58 of 205 (28%) patients, seen in 76 of 505 visits (15% of all visits), had complications, primarily mild dysphagia (35 patients) or neck weakness (17 patients). We conclude that botulinum toxin is a safe and effective therapy for most patients with cervical dystonia.     

Utility of an EMG mapping study in treating cervical dystonia

Intramuscular injections of botulinum toxin are the cornerstone of treatment for cervical dystonia. Controversy exists regarding the necessity for EMG-guided injections. We compared the clinical examination of four movement disorder specialists to an electromyographic (EMG) mapping study. Clinical predictions of individual muscle involvement were only 59% sensitive and 75% specific. Muscle hypertrophy, shoulder elevation, and dominant head vector did not bolster clinical accuracy. An EMG mapping study facilitates identification of dystonic muscles in cervical dystonia, which may enhance botulinum toxin therapy.     

Five-year experience in the treatment of focal movement disorders with low-dose dysportTM botulinum toxin

We report the results of botulinum toxin type A (Dysport^TM, Porton Products, UK) treatment over 5 years in 107 patients with blepharospasm, Meige's syndrome, oromandibular dystonia, hemifacial spasm, cervical dystonia, and writer's cramp. Electromyography was used to localize dystonic muscles and guide Dysport^TM injections in Meige's syndrome, oromandibular dystonia, cervical dystonia, and writer's cramp. All but 2 Meige's syndrome and 2 writer's cramp patients responded to treatment. Improvement was dramatic in blepharospasm (79%) and hemifacial spasm (90%); pronounced in cervical dystonia (74%); and moderate in Meige's syndrome (53%), oromandibular dystonia (57%), and writer's cramp (34%). Although Dysport^TM doses were 50–75% lower than usually reported, response and improvement rates as well as relapse intervals were similar to those of others. To treat cervical dystonia relapses, only 50% of the initial dose was required for continued optimal relief of symptoms. Low-dose Dysport^TM was associated with a very low incidence of dysphagia in cervical dystonia. © 1995 John Wiley & Sons, Inc.     

Evidence-based medicine in botulinum toxin therapy for cervical dystonia

Early controlled studies of botulinum toxin (BTX) in cervical dystonia were unblinded and indicated that BTX injections are more successful than medication. In this article, the use of botulinum toxin (BTX) in cervical dystonia is reviewed according to evidence-based medicine. To document the efficacy of BTX, there have been a number of prospective, placebo-controlled studies of the use of BTX in cervical dystonia. Most were double-blind, some included videotapes to provide blinded objective assessments. The more recent studies of BTX in cervical dystonia focused on particular issues such as utility of EMG guidance, comparison to anti-cholinergic treatment, BTX serotype B in BTX type A resistant and non-resistant patients and different dosages. Despite the wealth of data generated with prospective placebo-controlled studies on the effectiveness of BTX in cervical dystonia, there is uncertainty on which outcome measures to use to express the efficacy of treatments for cervical dystonia. Disease specific instruments to measure quality of life in cervical dystonia have not been used so far. Data on the use of BTX for cervical dystonia have long been restricted to small series of patients reflecting exclusively the experience of individual specialized centers.     

Polyradiculoneuritis after botulinum toxin therapy for cervical dystonia

A 40-year-old man with cervical dystonia developed an acute inflammatory demyelinating polyradiculoneuritis after botulinum toxin type A treatment. Some cases of idiopathic brachial plexopathy and polyradiculoneuritis have been reported to date. Although a causal relationship is not firmly established, the clinical temporal profile suggests a pathogenic relationship. In patients with cervical dystonia, further use of type A botulinum toxin should be considered contraindicated, and the use of another type of botulinum toxin should be taken into consideration.     

Localized injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm

Medical treatment of dystonia usually results in an incomplete response and is frequently unsuccessful. Peripheral surgical therapy is available for some focal dystonias, but may only offer temporary relief and may have unacceptable complications. We have used local injections of botulinum toxin into the appropriate muscles for treatment of disabling focal or segmental dystonia in 93 patients with torticollis, blepharospasm, oromandibular dystonia (OMD), limb dystonia, lingual dystonia, and dystonia adductor dysphonia, in addition to four patients with hemifacial spasm. Significant relief of motor symptoms was seen in 69% of the patients with blepharospasm and 64% of patients with torticollis; 74% of the latter group with pain experience relief. Relief of symptoms was noted in most patients with OMD and limb dystonia, and all with lingual dystonia, dystonic adductor spastic dysphonia, and those with hemifacial spasm. Benefit averaged 2 1/2-3 months initially; however some patients experienced longer relief with subsequent injections. Adverse effects were transient, although 2 patients developed antibodies against the toxin, and we documented evidence for distant effects in others. This approach of chemically weakening contracting muscles in focal dystonia offers many advantages over pharmacotherapy and surgical therapy. Additional experience is needed to explore the proper doses, and potential for long term adverse effects.     

Evidence-based medicine in botulinum toxin therapy for cervical dystonia

Early controlled studies of botulinum toxin (BTX) in cervical dystonia were unblinded and indicated that BTX injections are more successful than medication. In this article, the use of botulinum toxin (BTX) in cervical dystonia is reviewed according to evidence-based medicine. To document the efficacy of BTX, there have been a number of prospective, placebo-controlled studies of the use of BTX in cervical dystonia. Most were double-blind, some included videotapes to provide blinded objective assessments. The more recent studies of BTX in cervical dystonia focused on particular issues such as utility of EMG guidance, comparison to anticholinergic treatment, BTX serotype B in BTX type A resistant and non-resistant patients and different dosages. Despite the wealth of data generated with prospective placebo-controlled studies on the effectiveness of BTX in cervical dystonia, there is uncertainty on which outcome measures to use to express the efficacy of treatments for cervical dystonia. Disease specific instruments to measure quality of life in cervical dystonia have not been used so far. Data on the use of BTX for cervical dystonia have long been restricted to small series of patients reflecting exclusively the experience of individual specialized centers.