Restoring balance in focal limb dystonia with botulinum toxin

Focal task-specific dystonia of the hand is rare in the general population, where it usually manifests as writer's cramp, but seems relatively common among musicians. The disability may be so severe as to prevent writing altogether or to end a professional musician's career. The cause is usually unknown but it is thought to be primarily a basal ganglia disorder with dysfunction of cortical-striatothalamic-cortical circuits. Abnormalities have been found in cortical movement preparation, intracortical inhibition, sensory and motor maps, and patterns of cortical activation during movement. Much evidence supports disordered processing of sensory information with disturbed sensorimotor integration. Underlying this may be maladaptive neural plasticity mechanisms. Treatment is difficult. Oral medications are generally ineffective and have troublesome side-effects. Intensive rehabilitation techniques based on neural plasticity theory show promise but are rarely available and are time-intensive. Botulinum toxin injections appear to be effective in writer's cramp and musician's dystonia, at least initially; long-term benefit is less common. Despite definite improvement, some patients abandon treatment because the gain is insufficient for meaningful function: this is particularly so for musicians. Much of the benefit from botulinum toxin injection comes from simply reducing muscle overactivity through muscle paralysis, restoring balance to motor control. However, some evidence suggests that botulinum toxin injections can produce transient improvement in some of the various cortical abnormalities described, probably through alteration of sensory input from the periphery, by direct and indirect means. These changes in cortical function might be usefully combined with those brought about by sensorimotor retraining programs, but such studies are awaited.     

Neurology of musical performance

Performing music at a professional level requires the integration of multimodal sensory and motor information and precise monitoring of the performance via auditory feedback. In the context of Western classical music, musicians are forced to reproduce highly controlled movements almost perfectly with a high reliability. These specialised sensorimotor skills are acquired during extensive training periods over many years. The superior skills of musicians are mirrored in functional and structural plastic adaptations of sensorimotor and auditory systems of the brain. Auditory-sensorimotor integration, for example, is accompanied by rapid modulations of neuronal connectivity in the time range of 20 minutes. Finally, dysfunctional plasticity in musicians, known as musician's dystonia, leads to deterioration of extensively trained fine motor skills. Musician's dystonia may be caused by training induced dysplasticity with pathological fusion of central nervous representations in sensorimotor cortical and subcortical brain regions.     

Brain cortical activation during guitar-induced hand dystonia studied by functional MRI

Focal hand dystonia in musicians is a strongly task-related movement disorder. Typically, symptoms become apparent only when players execute specific overpracticed skilled exercises on their instrument. We therefore examined five guitarists with functional MRI during dystonic symptom provocation by means of an adapted guitar inside the magnet. The activation patterns obtained in comparable nondystonic guitarists and in the study patients when performing normal-hand exercise served as references. A 1.5-T system equipped with echo-speed gradients and single-shot echoplanar imaging software was used. Data acquisition was centered on the cortical motor system encompassed in eight contiguous slices. Dystonic musicians compared with both control situations showed a significantly larger activation of the contralateral primary sensorimotor cortex that contrasted with a conspicuous bilateral underactivation of premotor areas. Our results coincide with studies of other dystonia types in that they show an abnormal recruitment of cortical areas involved in the control of voluntary movement. However, they do suggest that the primary sensorimotor cortex, rather than being underactive in idiopathic dystonic patients, may be overactive when tested during full expression of the task-induced movement disorder.     

书写痉挛责任肌群的认定及肉毒毒素治疗的疗效观察

目的　寻找引起患者书写痉挛 (writer scramp)并导致字迹抖动不清的主要责任肌群 ,并同时观察局部注射肉毒毒素 A (botulinumtoxin A ,BTX A)对书写痉挛病症的治疗效果及副反应发生情况。方法　通过对前臂肌群的选择性运动 ,判断各肌群对书写痉挛症状的影响 ,并初步认定责任肌群 ,然后用维库溴铵对初步确定的责任肌群进行选择性注射 ,以进一步确定引起书写痉挛的主要责任肌群 ,最后对已确定的主要责任肌群进行BTX A多点注射 ,观察其疗效及副反应发生情况。结果　本研究发现 ,当前臂旋转肌群运动时会加重书写痉挛症状 ,对该群肌肉注射维库溴铵后可消除痉挛症状。当对旋转肌群进行BTX A注射后 ,受试的 3例患者 (共 5侧患肢 )症状全部得到改善 ,无一例发生可察觉的握力减退及垂腕等副反应。结论　前臂旋转肌群是导致书写痉挛并致使字迹抖动不清的主要责任肌群 ,对其进行BTX A选择性多点注射可获得满意疗效 ,同时还可避免握力减退及垂腕等副反应的发生。     

Regional cerebral blood flow correlates of the severity of writer's cramp symptoms

Writer's cramp is a type of idiopathic focal dystonia with incompletely understood pathophysiology. Recent studies provide evidence that one element might be a sensory processing defect. We performed a PET study with O(15) H(2)O to find out in which brain areas activity correlates with the severity of writer's cramp symptoms. METHODS: We studied 10 patients with writer's cramp and 10 age- and gender-matched control subjects. There were seven conditions, each repeated twice: rest, writing, tapping with index finger for 2, 3, 4, and 5 min. For each scan, we obtained EMG recordings from the flexor digitorum superficialis (FDS), extensor indicis proprius (EIP) muscles, and a subjective score of severity of dystonia. Scans were realigned, normalized, smoothed, and analyzed using SPM99. Analysis included both intra- and intergroup comparisons and a correlation analysis where we used EMG recordings and subjective dystonia score as covariates. RESULTS: Random effect analysis of the writing task showed overactivity of the primary sensory cortex and no significant underactivity. Correlation analysis of dystonia patients showed activation of SI when we used the subjective dystonia score as a covariate, and activation of both the SI and primary motor cortex when the normalized EMG score of FDS was used. CONCLUSION: While some overactivity of MI is not surprising, overactivity of SI is more dramatic and suggests a primary deficit in processing sensory feedback. Writer's cramp may arise in part as a dysfunction of sensory circuits, which causes defective sensorimotor integration resulting in co-contractions of muscles and overflow phenomena.     

Focal dystonia, with special reference to writer's cramp

If focal dystonia affects the hand muscles writer's cramp will result, but also other types of activity when the task involves repetitive movements such as typing and playing the piano. Writer's cramp is described, both simple and dystonic, and also the possibility of genetic causes, especially in the latter group. The characteristics of the electromyogram in this condition are discussed. The possible causes of focal dystonia and writer's cramp are reviewed: both the role of excitatory and inhibitory mechanisms and how these may influence treatment. Various treatments have been tried, and the most effective seems to be the use of botulinum toxin. However, if this does not relieve the symptoms, operations such as stereotactic lesions of the basal ganglia may be justified.     

Treatment of focal dystonia with botulinum toxin A

Local injections with Botulinum toxin A (BtxA) are safe and effective in the treatment of focal dystonia. In cervical dystonia and blepharospasm, BtxA injections have become the treatment of choice. However, good results have also been reported with oromandibular dystonia, spasmodic dysphonia and writer's cramp. In cervical dystonia, muscles for injection are selected by clinical presentation or in complex forms with EMG guidance. Several studies have shown that 500 units Dysport are safe and effective in the treatment of cervical dystonia. In blepharospasm, injections are performed in the periorbital part of the orbicularis oculi muscle with good results for 12-14 weeks. The most frequently employed starting dose is 120 units Dysport per eye, divided in three periorbital injection sites. In case of levator inhibition, the pretarsal part of the orbicularis oculi muscle should be injected in a lower dose. EMG guidance is not necessary. By contrast, BtxA treatment of spasmodic dysphonia and writer's cramp require EMG-guided injections in order to avoid side-effects. Dose recommendations for the various types of dystonia are given in the text. In up to 5% of patients with dystonia, the development of neutralising antibodies is reported following repetitive injections with BtxA. Patients with antibodies had a shorter interval between injections, more "boosters", a higher dose per 3-month interval, and a higher total dose injected. In case of neutralizing antibodies against the A toxin, the treatment with Botulinum toxin B (Neurobloc) is a possible alternative.     

Strategies for controlling dystonia. Overview of therapies that may alleviate symptoms

Dystonia is an involuntary movement disorder characterized by twisting, turning, and posturing. This disorder may affect a single body part or may be more generalized, but the pathophysiology remains unclear. The treatment of choice for most of the focal dystonias is botulinum toxin injections, although oral medications occasionally may be beneficial. Surgical treatment of dystonia may be performed peripherally or centrally but is usually reserved for patients in whom other forms of therapy fail.     

Focal dystonia in musicians

In conclusion, musicians' focal dystonia is a significant and potentially career-ending neurological condition of which physiatrists and other performing arts medicine clinicians should be aware. Pathology has been identified in the somatosensory cortex, and in the motor cortex and basal ganglia. Although advances have been made in the elucidating some of the pathologic changes in focal dystonia, better understanding is needed. Current treatments such as retraining, splinting, oral medications, and botulinum toxin injections are limited. Therefore, the ultimate goal for focal dystonia is to prevent this disabling disorder of instrumental musicians.     

Use of botulinum toxin type A in neuro-ORL]

Dystonia is the result of abnormal contractions of muscles, which may disturb activities between agonist and antagonist muscles. Since synchronization of laryngeal and masticatory muscles is highly necessary to allow opening and closure of the larynx or the mouth, expression of dystonia is especially exhibited. Focal laryngeal dystonia may disturb phonation, but also breathing or swallowing, which may be difficult to identify. In ORL, the botulinum toxin is used to treat focal dystonias, especially laryngeal (spamodic dysphonia being predominant) and oromandibular dystonias. Beside these indications, intracutaneous injections of botulinum toxin may be helpful in Frey's syndrome in patients with gustatory sweating; injections in the upper esophageal sphincter are also performed in cricopharyngeal dysphagia although this indication is mainly controversial.     

Neuroplasticity of semantic representations for musical instruments in professional musicians

Professional musicians constitute a model par excellence for understanding experience-dependent plasticity in the human brain, particularly in the auditory domain. Their intensive sensorimotor experience with musical instruments has been shown to entail plastic brain alterations in cortical perceptual and motor maps. It remains an important question whether this neuroplasticity might extend beyond basic perceptual and motor functions and even shape higher-level conceptualizations by which we conceive our physical and social world. Here we show using functional magnetic resonance imaging (fMRI) that conceptual processing of visually presented musical instruments activates auditory association cortex encompassing right posterior superior temporal gyrus, as well as adjacent areas in the superior temporal sulcus and the upper part of middle temporal gyrus (pSTG/MTG) only in musicians, but not in musical laypersons. These areas in and adjacent to auditory association cortex were not only recruited by conceptual processing of musical instruments during visual object recognition, but also by auditory perception of real sounds. Hence, the unique intensive experience of musicians with musical instruments establishes a link between auditory perceptual and conceptual brain systems. Experience-driven neuroplasticity in musicians is thus not confined to alterations of perceptual and motor maps, but even leads to the establishment of higher-level semantic representations for musical instruments in and adjacent to auditory association cortex. These findings highlight the eminent importance of sensory and motor experience for acquiring rich concepts.     

Movement disorders and botulinum toxin in neurology

Botulinum toxin has been a useful treatment in many movement disorders and more recently in other non-neurological motor dysfunctions for more than 15 years. Here, we review the various indications in neurology, mainly in the field of movement disorders. From 1973 to 2002, we searched the Medline database on this topic. We selected the most useful and relevant papers, with a special interest in dystonia. We summarized the results in the main indications (spasmodic torticollis, bleparospasm, hemifacial spasm) and in other manifestations such as writer's cramp, oromandibular dystonia, tremor, tics and myoclonus. We discuss the data of literature and compare them with the experience of the French movement disorders groups.     

Botulinum toxin treatment of axial and cervical dystonia

Axial truncal dystonia is characterized by an abnormal trunk posture often superimposed by myoclonic motor activities. Cervical dystonia is a motor syndrome characterized by abnormal head and neck posture due to tonic involuntary contractions in a certain set of muscles often superimposed by myoclonic or tremolous movements. Intramuscular injection of botulinum toxin is the first line treatment in cervical dystonia, in axial truncal dystonias botulinum toxin therapy is used only in mild forms. In this review the theoretical background, practical aspects and efficacy results especially in cervical dystonia are presented. Treatment of axial trunk dystonia is only briefly discussed at the beginning of this review.     

Botulinum toxin treatment of axial and cervical dystonia

Axial truncal dystonia is characterized by an abnormal trunk posture often superimposed by myoclonic motor activities. Cervical dystonia is a motor syndrome characterized by abnormal head and neck posture due to tonic involuntary contractions in a certain set of muscles often superimposed by myoclonic or tremulous movements. Intramuscular injection of botulinum toxin is the first line treatment in cervical dystonia, in axial truncal dystonias botulinum toxin therapy is used only in mild forms. In this review the theoretical background, practical aspects and efficacy results especially in cervical dystonia are presented. Treatment of axial trunk dystonia is only briefly discussed at the beginning of this review.     

Evaluation and treatment of dystonia

BACKGROUND: Dystonia is a neurologic disorder that interferes with normal motor control, causing development of bizarre postures and writhing, twisting movements. METHODS: The patient database of the Duke Movement Disorders Clinic was searched to identify and characterize all cases of dystonia evaluated during the 3 1/2 year period between July 1995 and December 1998. RESULTS: Of the 68 patients identified, 44% had focal dystonia, 10% segmental dystonia, 9% hemidystonia, 7% generalized dystonia, 4% multifocal dystonia, 12% psychogenic dystonia, and 9% tardive dystonia. The remainder had either paroxysmal or pseudodystonia. Twenty-five patients had improvement with botulinum toxin injections, 16 with anticholinergics, benzodiazepines and/or baclofen, and 2 with tetrabenazine. CONCLUSION: A variety of treatments can give symptomatic benefit in dystonia, but appropriate treatment requires proper diagnosis of the condition.     

Treatment of cervical dystonia and focal hand dystonia by high cervical continuously infused intrathecal baclofen: a report of 2 cases

We describe 2 patients, one with cervical dystonia (CD) combined with focal hand dystonia (writer's cramp) and another with idiopathic CD, who were unresponsive to oral medications and became resistant to botulinum toxin type A and B injections. Both patients were successfully treated with high cervical (C1-3) continuously infused intrathecal baclofen (ITB). Neck range of motion (ROM) was measured by using a 3-dimensional electromagnetic cervical ROM system. Pain, disability, and severity were assessed by using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The patient with CD and writer's cramp did well on a continuous baclofen dose of 186.1 microg/d. Her total TWSTRS score improved significantly, her electromagnetic measurements showed an increased in total neck flexion and extension, and her handwriting improved. Unfortunately, this patient (a heavy smoker) developed small cell carcinoma of the lung and died 9 months after her pump was placed. Total TWSTRS score and electromagnetic measurements also significantly improved after pump implant in the patient with CD. He continues to do well on a periodic bolus dose using a combination of 50 microg of baclofen and 25 microg of hydromorphone (Dilaudid) every 4 hours. Our findings suggest the potential usefulness of this therapy in other patients with focal dystonia. To our knowledge, this is the first reported successful treatment of CD and CD combined with writer's cramp with high cervical continuously infused ITB.     

Botulinum toxin for the treatment of musculoskeletal pain and spasm

The impressive pain relief experienced by sufferers of dystonia and spasticity from intramuscular injections of botulinum toxin suggested that patients with other chronic, musculoskeletal pain conditions also may benefit. However, there have been relatively few placebo-controlled studies of botulinum toxin in such non-neurologic conditions as myofascial pain syndrome, chronic neck and low back pain, and fibromyalgia; the results of these studies have not been impressive. One explanation for the lack of positive findings may be the lack of clinically evident muscle spasms (overactivity), despite the presence of muscle tenderness, tightness, or trigger points. Clinical observations of pain relief from injections of botulinum toxin for dystonia and spasticity and its apparent efficacy in treating migraine suggest an anti-nociceptive action independent of its neuromuscular junction-blocking action. Evidence from animal experiments supports this notion, and other data provide plausible physiologic mechanisms in the periphery and central nervous systems. These involve modulation of the activity of the neurotransmitters glutamate, substance P, calcitonin gene-related peptide, enkephalins, and others. However, even if botulinum toxin is firmly established as an analgesic, there is insufficient clinical evidence of its efficacy in treating non-neurologic, chronic, musculoskeletal pain conditions.     

Severity and impact of xerostomia in patients treated with botulinum toxin type b for cervical dystonia: Observations on the quality of life of patients with xerostomia

Background: Although dry mouth (xerostomia) has been reported with botulinum toxin type B used as treatment for cervical dystonia, the impact of this adverse effect (AE) on patients' activities of daily living (ADLs) has not been assessed.tObjective: The aim of this study was to examine the severity, duration, and impact of xerostomia in patients with cervical dystonia who reported this AE in routine clinical practice following treatment with botulinum toxin type B.Methods: In this uncontrolled study, investigators at 5 study centers across the United States retrospectively identified patients who were diagnosed with cervical dystonia and had received ≥ 1 treatment with botulinum toxin type B injection and who had reported xerostomia, based on patients' charts. These patients were mailed a survey that included questions about their treatment history, disease severity, and xerostomia (severity, onset, duration, change with subsequent injections, and effects on dental and oral health), as well as an 8-item Patient Benefit Questionnaire (PBQ), which was designed to assess the impact of xerostomia symptoms on patients' ADLs.Results: A total of 45 patients received a mean of 2.91 injections with botulinum toxin type B (mean dose per injection, 11,958 U), with a total of 131 injections. The mean severity of patient-rated xerostomia following the first injection of botulinum toxin type B was 3.88 on a scale of 1 (mild) to 5 (severe), and this rating did not change for patients who received subsequent injections (mean, 3.76). Following atypical injection of botulinum toxin type B, xerostomia began a mean (SD) of 4.82 (3.32) days later and persisted for a mean (SD) duration of 5.56 (3.57) weeks. The overall mean score on the 10-point PBQ prior to botulinum toxin treatment was 8.89, which decreased to 5.42 following botulinum toxin type B injection (lower scores indicate more severe xerostomia).Conclusions: This study of patients with cervical dystonia suggests that patients who experience xerostomia following treatment with botulinum toxin type B injection, on average, rate their symptoms as moderate to severe and exhibit reduced scores on the PBQ—a questionnaire on which lower scores indicate greater negative impact of xerostomia on patients' ADLs.     

Extensive sensorimotor training enhances nociceptive cortical responses in healthy individuals

Background

Prolonged and repeated sensorimotor training is a crucial driver for promoting use-dependent plasticity, but also a main risk factor for developing musculoskeletal pain syndromes, yet the neural underpinnings that link repetitive movements to abnormal pain processing are unknown.

Methods

Twenty healthy musicians, one of the best in vivo models to study use-dependent plasticity, and 20 healthy non-musicians were recruited. Perceptual thresholds, reaction times (RTs) and event-related potentials (ERPs) were recorded using nociceptive intra-epidermal and non-nociceptive transcutaneous electrical stimulation.

Results

In response to comparable stimulus intensities, musicians compared to non-musicians showed larger non-nociceptive N140 (associated with higher activation of regions within the salience network), higher nociceptive N200 ERPs (associated with higher activation of regions within the sensorimotor network) and faster RTs to both stimuli. Non-musicians showed larger non-nociceptive P200 ERP. Notably, a similar P200 component prominently emerged during nociceptive stimulation in non-musicians. Across participants, larger N140 and N200 ERPs were associated with RTs, whereas the amount of daily practice in musicians explained non-nociceptive P200 and nociceptive P300 ERPs.

Conclusions

These novel findings indicate that the mechanisms by which extensive sensorimotor training promotes use-dependent plasticity in multisensory neural structures may also shape the neural signatures of nociceptive processing in healthy individuals.

Significance

Repetitive sensorimotor training may increase the responsiveness of nociceptive evoked potentials. These novel data highlight the importance of repetitive sensorimotor practice as a contributing factor to the interindividual variability of nociceptive-related potentials.     

The importance of electromyographic guidance and electrical stimulation for injection of botulinum toxin

The importance of EMG or electrical stimulation for guiding injections of botulinum toxin in limb muscles to treat dystonia or spasticity is based more on theoretical and preclinical data than on controlled clinical trials. Questions remain about the preferred administration of botulinum toxin for these conditions. Future clinical research is necessary to show clearly functional benefit of any particular injection localization method.