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Treatment of dystonia
Review
Treatment of dystonia Joseph Jankovic Lancet Neurol 2006; 5: 864–72 Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA (Prof J Jankovic MD) [email protected]
Dystonia, defined as a neurological syndrome characterised by involuntary, patterned, sustained, or repetitive muscle contractions of opposing muscles, causing twisting movements and abnormal postures, is one of the most disabling movement disorders. Although gene mutations and other causes are increasingly recognised, most patients have primary dystonia without a specific cause. Although pathogenesis-targeted treatment is still elusive, the currently available symptomatic treatment strategies are quite effective for some types of dystonia in relieving involuntary movements, correcting abnormal posture, preventing contractures, reducing pain, and improving function and quality of life. A small portion of patients have a known cause and respond to specific treatments, such as levodopa in dopa-responsive dystonia or drugs that prevent copper accumulation in Wilson’s disease. Therapeutic options must be tailored to the needs of individual patients and include chemodenervation with botulinum toxin injections for patients with focal or segmental dystonia, and medical treatments or deep brain stimulation for patients with generalised dystonia.
Introduction Despite paucity of knowledge about the cause and pathogenesis of dystonic disorders, the symptomatic treatment of dystonia has substantially improved, especially since the introduction of botulinum toxin and deep brain stimulation. In most cases of dystonia, treatment is merely symptomatic, designed to improve posture and function and to relieve associated pain. In a few patients, however, dystonia can be so severe that it can produce not only abnormal postures and disabling movements, sometimes compromising respiration, but also a muscle breakdown and a life-threatening hyperthermia, rhabdomyolysis, and myoglobinuria. In such cases of so-called dystonic storm or status dystonicus, proper therapeutic intervention can be life saving.1 The assessment of various therapeutic interventions in dystonia is problematic for various reasons. First, dystonia and its effects on function are difficult to quantify and, therefore, most trials use crude clinical rating scales, many of which have not been properly assessed or validated. Second, dystonia is a syndrome with different causes, anatomic distributions, and heterogeneous clinical manifestations that produce variable disability. Third, some patients, perhaps up to 15%, might have spontaneous, albeit transient, remissions. Fourth, most therapeutic trials in dystonia are not randomised controlled studies. And fifth, most studies, even those that have been otherwise well designed, enrolled few patients, which makes the results difficult to interpret and generalise, which is especially important because of the large placebo effect.2 Except for botulinum toxin in patients with cervical dystonia and high-dose trihexyphenidyl in young patients with segmental and generalised dystonia (level A, class I–II), none of the other methods of pharmacological intervention has been confirmed as being effective according to evidence-based criteria.3 Cervical dystonia is the most common type of focal dystonia. Several instruments have been used to assess response in patients with cervical dystonia. The most 864
commonly used scale is the Toronto western spasmodic torticollis rating scale (TWSTRS).4 Additionally, various scales, such as the Burke-Fahn-Marsden scale (BFMS) and the unified dystonia rating scale (UDRS), have been used to assess patients with generalised dystonia.5–7 Another scale designed to capture the burden of dystonia on patients is the the cervical dystonia impact profile (CDIP-58) scale.8 The selection of a particular choice of treatment is largely guided by the age of the patient and the anatomical distribution of dystonia (panel). Although a systematic, evidence-based review of the treatment of dystonia has been published,9 most treatments have not been subjected to rigorous double-blind, controlled trials, and, therefore, the selection of the most optimum treatment option is usually based on personal clinical experience weighing knowledge of efficacy against potential adverse effects.10 This Review attempts to provide a comprehensive and balanced overview of the available and experimental therapeutic strategies, noting, whenever possible, limitations and controversial features of the various treatments. The identification of a specific cause of dystonia, such as drug-induced dystonias or Wilson’s disease,11 could lead to a treatment that is targeted to the particular cause. Discussion of the diagnostic approaches to patients with dystonia is beyond the scope of this Review and has been reviewed elsewhere.12
Physical therapy Education of patients, genetic counselling, and consideration of orthopaedic and other comorbid disorders, including depression,13 are all important parts of a comprehensive therapeutic approach to dystonia. Physical therapy and well-fitted braces are designed primarily to improve posture and to prevent contractures. Although braces are commonly poorly tolerated, especially by children, in some cases they may be used as a substitute for a so-called sensory trick. For example, some patients with cervical dystonia might benefit from specially designed neck and head braces that substitute http://neurology.thelancet.com Vol 5 October 2006
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Panel: Treatment of dystonia Focal dystonias Blepharospasm Botulinum-toxin injections Clonazepam, lorazepam Trihexyphenidyl Orbicularis oculi myectomy Oromandibular dystonia Botulinum-toxin injections Baclofen Trihexyphenidyl Spasmodic dysphonia Botulinum-toxin injections Voice and supportive therapy Cervical dystonia Botulinum-toxin injections Trihexyphenidyl Diazepam, lorazepam, clonazepam Tetrabenazine Cyclobenzaprine Carbamazepine Baclofen (oral) Peripheral surgical denervation Deep brain stimulation of the internal segment of the globus pallidus Task-specific dystonias (eg, writer’s cramp) Botulinum-toxin injections Benzatropine, trihexyphenidyl Occupational therapy Segmental and generalised dystonias Levodopa (in children and young adults) Trihexyphenidyl, benzatropine Diazepam, lorazepam, clonazepam Baclofen (oral, intrathecal) Carbamazepine Tetrabenazine Intrathecal baclofen infusion (axial and leg dystonia) Deep brain stimulation of the internal segment of the globus pallidus
for a sensory input in that, by touching certain portions of the neck or head in a fashion similar to a patient’s own sensory trick, they enable patients to maintain a desired head position. Various hand devices have been developed to help patients with writer’s cramp to use their hands more effectively and comfortably.14 In one small study of five professional musicians with focal dystonia, Candia and colleagues15 reported success with immobilisation by splints of one or more of the digits other than the dystonic finger, followed by intensive repetitive exercises of the dystonic finger. However, whether this treatment provides lasting benefits is unclear. In one study of eight patients with idiopathic occupational focal dystonia of the arm, immobilisation with a splint for 4–5 weeks resulted in a significant improvement at a 24 week follow-up visit, http://neurology.thelancet.com Vol 5 October 2006
measured with the arm dystonia disability scale (0=normal; 3=marked difficulty in playing) and the Tubiana and Champagne score (0=unable to play; 5=returns to concert performances), and was judged as substantial in four, moderate in three, and the initial improvement disappeared in one.16 The splint was applied for 24 h every day, except for 10 min once a week for brief local hygiene. Immediately upon removal of the splint, all patients reported much clumsiness and weakness, which resolved in 4 weeks. There was also some local subcutaneous and joint oedema and pain in the immobilised joint, and nail growth stopped; no patients developed contractures. Although the mechanisms of action of immobilisation are unknown, researchers have postulated that removing all motor and sensory input to a limb could allow the cortical map to reset to the previous normal topography.16 A major concern about immobilisation of a limb, especially a dystonic limb, is that such immobilisation can actually increase the risk of exacerbating or even precipitating dystonia, as has been shown in dystonia after casting and in other forms of peripherally induced dystonia.17 An alternative to the immobilisation strategy, constraint-induced movement therapy has been used successfully in rehabilitation of patients after stroke and other brain injuries as well as in dystonia.18,19 The observed benefits have been attributed to cortical or subcortical reorganisation,17 but the mechanism of this therapeutic approach is not well understood. Some patients find various muscle relaxation techniques and sensory feedback therapy useful adjuncts to medical or surgical treatments. Because some patients with dystonia have impaired sensory perception, sensory training has been postulated to relieve dystonia. In a study of ten patients with focal hand dystonia, Zeuner and colleagues20 showed that reading Braille for 30–60 min daily for 8 weeks improved spatial acuity and dystonia, an effect that was sustained for up to a year in some patients.21 Sensory training to restore sensory representation of the hand along with mirror imagery and mental practice techniques have also been reported to be useful in the treatment of focal hand dystonia.22 Various neurophysiological techniques have been used in the treatment of dystonia. By use of repetitive transcranial magnetic stimulation delivered at low frequencies (≤1 Hz) for 20 min, Siebner and colleagues23 showed that this technique might temporarily improve handwriting impaired by dystonic writer’s cramp (eight of 16 patients reported improvement that lasted longer than 3 h), presumably by increasing inhibition (and thus reducing excitability) of the underlying cortex. Finally, neck-muscle vibration of the contracting muscle could have therapeutic value in some patients with cervical dystonia. This notion was lent support by the finding of transient (minutes) improvement in head position in one patient treated for 15 min with muscle vibration.24 Transcutaneous electrical stimulation improved dystonic 865
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writer’s cramp for at least 3 weeks in a double-blind, placebo-controlled trial.25 This observation is consistent with the idea that proprioceptive sensory input affects cervical dystonia.
Medical therapy Dopaminergic drugs Although most patients with dystonia have limited or no improvement with levodopa, a small subset, possibly representing up to 5% of childhood dystonias, have substantial improvement and even complete resolution of dystonia with levodopa, hence the designation doparesponsive dystonia. This type of dystonia, characterised by childhood onset, parkinsonian features, gait and postural abnormalities, diurnal fluctuation, and autosomal dominant inheritance, is usually caused by mutations in the GTP cyclohydrolase 1 gene on chromosome 14q or abnormalities in tyrosine hydroxylase or sepiapterin reductase.26–28 GTP cyclohydrolase 1 indirectly regulates the production of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme in the synthesis of dopamine. Because the presentation of dopa-responsive dystonia is multifaceted and the disorder is wrongly attributed to cerebral palsy (eg, spastic diplegia) in many cases, levodopa should be considered in all patients with childhood-onset and young-onset dystonia. In my experience, most patients with dopa-responsive dystonia improve substantially, even with small doses of levodopa (100 mg of levodopa with 25 mg of decarboxylase inhibitor), but some patients might need doses of levodopa as high as 1000 mg per day (unpublished). By contrast with patients with juvenile Parkinson’s disease, most with dopa-responsive dystonia do not develop levodopa-induced fluctuations or dyskinesias. If no clinically evident improvement is noted after 1 month of treatment at adequate doses, the diagnosis of doparesponsive dystonia is unlikely. In addition to levodopa, patients with dopa-responsive dystonia also improve with dopamine agonists, anticholinergic drugs, and carbamazepine, but no controlled studies have been done. Modest improvements with levodopa have been reported in patients with other types of dystonia besides dopa-responsive dystonia.10
Antidopaminergic drugs Although used extensively in the past, most clinical trials have produced mixed results with dopamine-receptorblocking drugs. Because of the poor response and the possibility of undesirable side-effects, especially sedation, parkinsonism, and tardive dyskinesia, the use of these drugs in the treatment of dystonia should be discouraged. Clozapine, an atypical neuroleptic, has been reported in a small, open trial to be moderately effective in the treatment of segmental and generalised dystonia, but its usefulness was limited by potential side-effects.29 Although antidopaminergic drugs might be beneficial in 866
the treatment of dystonia, the potential clinical benefit is usually limited by the development of side-effects. Dopamine depleting drugs, however, such as tetrabenazine, have proven useful in some patients with dystonia, particularly in those with tardive dystonia.30 Tetrabenazine, an inhibitor of vesicular monoamine transporter 2, has the advantage over other antidopaminergic drugs in that it does not cause tardive dyskinesia, although it can cause transient acute dystonic reaction.31 The drug is not readily available in the USA, but it is dispensed by prescription under the trade name Nitoman or Xenazine 25 in other countries, including the UK and Canada.
Anticholinergic drugs Anticholinergic drugs, such as trihexyphenidyl, are useful in the treatment of generalised and segmental dystonia.6,32 When the dose is started low and increased very slowly, anticholinergic drugs can be well tolerated. We recommend starting trihexyphenidyl, 2 mg tablet, a half tablet at bedtime and advancing up to 12 mg per day over the next 4 weeks, eventually switching to a sustained release preparation. Some patients need up to 60–100 mg per day of trihexyphenidyl, but may experience doserelated drowsiness, confusion, memory difficulty, and hallucinations. Pyridostigmine, a peripherally acting anticholinesterase, and eye drops of pilocarpine (a muscarinic agonist) commonly improve at least some of the peripheral side-effects such as urinary retention and blurred vision. Pilocarpine 5 mg four times per day, cevimeline 30 mg three times a day, and synthetic saliva have proven effective in the treatment of dry mouth.
Other pharmacological treatments Many patients with dystonia need a combination of several drugs and treatments.10 Muscle relaxants, such as benzodiazepines (diazepam, lorazepam, or clonazepam), tizanidine, cyclobenzaprine, metaxalone, carisoprodol, methocarbamol, orphenadrine, and chlorzoxazone could provide additional benefit for patients whose response to anticholinergic drugs is unsatisfactory. Clonazepam might be especially useful in patients with blepharospasm and with myoclonic dystonia.33 Oral baclofen might occasionally be helpful, particularly in the treatment of oromandibular dystonia and in levodopa-related wearingoff dystonia. Narayan and colleagues34 first suggested that intrathecal baclofen infusion could be effective in the treatment of dystonia in 1991 in a report of an 18-year-old man with dystonic storm. Subsequent reports have provided support for this form of treatment, especially in patients with dystonia associated with spasticity (spastic dystonia).35,36 There are many other drugs used in the treatment of dystonia, but their benefits have not been assessed by well-designed controlled trials. For example, slow release morphine sulfate has been reported to improve not only pain but also dystonic movements in some patients with http://neurology.thelancet.com Vol 5 October 2006
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primary and tardive dystonia.37 Besides clonazepam, gamma-hydroxybutyrate, used in the treatment of alcohol abuse, is beneficial in the treatment of myoclonusdystonia syndrome.38 Although kinesigenic paroxysmal dystonia might be well controlled with anticonvulsants (eg, carbamazepine, phenytoin), the non-kinesigenic forms of paroxysmal dystonia are less responsive to pharmacological therapy, although clonazepam and acetazolamide might be beneficial.39 Peripheral deafferentation with anaesthetic was previously reported to improve tremor, but this approach could also be useful in the treatment of focal dystonia, such as writer’s cramp,40 or oromandibular dystonia41 unresponsive to other pharmacological treatment. An injection of 5–10 mL of 0·5% lidocaine into the target muscle improved focal dystonia for up to 24 h. This short effect can be extended for up to several weeks if ethanol is simultaneously injected. Mexiletine, an oral derivative of lidocaine, has been shown to be effective in the treatment of cervical dystonia at doses ranging from 450 mg a day to 1200 mg a day.42 Two-thirds of patients, however, experience adverse effects such as heartburn, drowsiness, ataxia, and tremor. On the basis of review and rating of videotapes by a “blind” rater, Lucetti and colleagues43 reported a significant improvement in six patients with cervical dystonia treated with mexiletine. The observation that blocking of muscle-spindle afferents reduces dystonia provides additional evidence that somatosensory input is important in the pathogenesis of dystonia.44 Local electromyography-guided injections of phenol have also been proposed as a potential treatment of cervical dystonia, but the results have not been very encouraging because of pain associated with the procedure and unpredictable response.45 Chemomyectomy with muscle necrotising drugs, such as doxorubicin, has been tried in some patients with blepharospasm and hemifacial spasm,46 but because of severe local irritation, this approach is unlikely to be adopted into clinical practice. In addition to conventional forms of treatment described above, many patients with dystonia seek complementary or alternative forms of therapy. In one survey of 180 members of the German Dystonia Group, 131 (73%) patients used some form of alternative treatment, such as acupuncture (56%), relaxation techniques (44%), homoeopathy (27%), and massage (26%).47 None of these alternative therapies, however, have been subjected to careful scrutiny by well designed, controlled trials.
Botulinum toxin The introduction of botulinum toxin into clinical practice in the 1980s clearly revolutionised the treatment of dystonia. As the most potent biological toxin, botulinum toxin has become a powerful therapeutic tool in the treatment of a variety of neurological, ophthalmic, and http://neurology.thelancet.com Vol 5 October 2006
other disorders manifested by abnormal, excessive, or inappropriate muscle contractions.48 In December, 1989, after extensive laboratory and clinical testing, the US Food and Drug Administration (FDA) approved botulinum toxin A (formulation BOTOX) as a therapeutic agent in patients with strabismus, blepharospasm, and other facial nerve disorders, including hemifacial spasm. In December, 2000, the FDA approved Botox and botulinum toxin B (Myobloc) as treatments for cervical dystonia. In addition to improving blepharospasm, hemifacial spasm, and cervical dystonia, botulinum toxin provides meaningful relief in other focal dystonias, including oromandibular dystonia, such as involuntary jaw-opening and trismus with bruxism,49–51 dystonic writer’s cramp, and other task-specific dystonias, such as musician’s dystonia.52 Although its widest application is still in the treatment of disorders manifested by abnormal, excessive, or inappropriate muscle contractions, the use of botulinum toxin is rapidly expanding to include treatment of various ophthalmological, gastrointestinal, urological, orthopaedic, dermatological, secretory, painful, and cosmetic disorders.48 The therapeutic benefit of botulinum toxin is mainly due to its primary mechanism of action of blocking the release of acetylcholine into the neuromuscular junction causing local temporary chemodenervation and muscle paralysis. There are seven immunologically distinct toxins that share structurally homologous subunits. Synthesised as single-chain polypetides (molecular weight of 150 kD), these toxin molecules have relatively little potency, until they are cleaved by trypsin or bacterial enzymes into a heavy chain (100 kD) and a light chain (50 kD). Botulinum toxin A enters neurons by binding to the synaptic vesicle protein SV2 (isoform C), which acts as the botulinum toxin A receptor.53,54 The neural membrane proteins synaptotagmin I and II act as receptors for botulinum toxins B and G.54 Although the heavy chain of the toxin binds to the presynaptic cholinergic terminal, the light chain acts as a zincdependent protease that selectively cleaves proteins that are critical for fusion of the presynaptic vesicle with the presynaptic membrane. Thus, the light chains of botulinum toxins A and E cleave SNAP-25 (synaptosome associated protein), a protein needed for synaptic vesicle targeting and fusion with the presynaptic membrane. The light chains of botulinum toxins B, D, and F prevent the quantal release of acetylcholine by proteolytically cleaving synaptobrevin-2, also known as VAMP (vesicle associated membrane protein), an integral protein of the synaptic vesicle membrane. Botulinum toxin C cleaves syntaxin, another plasma membrane associated protein. Botox and Myobloc (Neurobloc in Europe) are the only types of botulinum toxin currently approved for clinical use in the USA, but other formulations of botulinum toxin A, such as Dysport55 and Xeomin (NT 201),56 are available in other countries. These other formulations have similar efficacy and adverse effect profiles to Botox. 867
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Figure 1: Effects of botulinum toxin in a patient with cervical dystonia There is substantial improvement of head and neck position from before treatment (left) to 4 weeks after injection (right).
Although botulinum toxin has been used in several focal dystonias, including blepharospasm, oromandibular dystonia, dystonic writer’s cramp, and other occupational dystonia,48 its therapeutic application has been most studied in cervical dystonia. Botulinum toxin A and botulinum toxin B were directly compared in 139 patients with cervical dystonia in a randomised, double-blind, parallel-group study.57 The patients were assessed at baseline, 4 weeks, 8 weeks, and at 2 week intervals thereafter until a loss of 80% of clinical effect or completion of 20 weeks of observation. The severity of cervical dystonia was measured with the TWSTRS and adverse events were assessed by structured interview. Whereas improvement in TWSTRS score at 4 weeks after injection did not differ between the two serotypes, dysphagia and dry mouth were less common with botulinum toxin A than with botulinum toxin B (dysphagia 19% vs 48%, p=0·0005; dry mouth 41% vs 80%, p<0·0001). In clinical responders, botulinum toxin A had a modestly longer duration of benefit than did botulinum toxin B (14 weeks vs 12·1 weeks, p=0·033). The effects on drooling may be even more robust with botulinum toxin B than with botulinum toxin A. To compare autonomic effects of botulinum toxin we randomly assigned patients with cervical dystonia to receive either botulinum toxin A or botulinum toxin B in a double-blind manner.58 Efficacy and physiological questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with botulinum toxin B had significantly less saliva production (p<0·01) and greater severity of constipation (p=0·037) than did those treated with botulinum toxin A, but did not differ with respect to 868
other tests of autonomic function, including changes in blood pressure, heart rate, and ocular function. These and other studies have provided evidence that botulinum toxin is the treatment of choice for patients with cervical dystonia (figure 1). Many clinical studies have provided evidence that botulinum toxin is not only safe and effective, but also leads to meaningful improvements in quality of life,59,60 and the benefits are long-lasting.61 Although antigenicity and development of immunoresistance due to blocking antibodies with consequent loss of response to botulinum toxin was a concern with the original formulation of Botox that contained 25 ng of neurotoxin protein per 100 units, occurrence of blocking antibodies is quite rare with the current formulation, which contains only 5 ng of neurotoxin protein per 100 units.62 Of 119 patients enrolled in a multicentre study of patients treated with botulinum toxin B for cervical dystonia, 13 (26%) patients with history of exposure to botulinum toxin B had evidence of blocking antibodies to botulinum toxin B, whereas 15 (21%) of those exposed to botulinum toxin A had blocking antibodies to botulinum toxin A.63 Furthermore, 30 (32%) patients who were negative for botulinum toxin B antibodies at baseline became positive for botulinum toxin B antibodies at last visit. These studies suggest that although botulinum toxin B offers a useful alternative to patients with immunoresistance to botulinum toxin A, long-term efficacy might be limited by the development of autonomic adverse effects and blocking antibodies, probably as a result of cross-reactivity between the two serotypes. Low antigenicity has been predicted with NT 201 because it is presumably free of complexing proteins, but no long-term data exist. If http://neurology.thelancet.com Vol 5 October 2006
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detected by a reliable method, such as the mouse protection assay, the presence of blocking antibodies indicates immunoresistance; therefore, the response to subsequent injections will be substantially diminished or non-existent. Although the mouse protection assay is regarded to be the most reliable method for detecting blocking antibodies,48,62 this assay is not readily available and, therefore, a simple clinical test, known as unilateral brow injection, can ascertain whether poor or lack of response is due to immunoresistance. In this test, botulinum toxin (eg, 20 U of botulinum toxin A or 1000 U of botulinum toxin B) is injected unilaterally into one corrugator-procerus muscle complex and if, 1 week later, the patient frowns asymmetrically because of weakness of the injected muscles, this indicates absence of neutralising antibodies.
Surgical treatment Although surgery has been used for a long time in the treatment of dystonia, there has been a recent resurgence in this approach, largely because of improved understanding of the functional anatomy of the basal ganglia and of physiological mechanisms underlying dystonia, coupled with refinements in imaging and surgical techniques.64–70 Intraoperative recordings in patients with dystonia have shown not only abnormal discharge rates but also, more importantly, abnormal patterns of discharge in the various portions of the basal ganglia, particularly in the external and internal portions of the globus pallidus (GPe and GPi).71 On the basis of various physiological and functional imaging studies, a model of basal ganglia circuitry has been proposed suggesting an overactivity of both direct (striatum–GPi) and indirect (striatum–GPe–GPi) pathways. Therefore, ablative surgery (pallidotomy) and high-frequency stimulation of the main basal ganglia outflow nucleus, GPi, seem to be rational strategies in patients with dystonia, perhaps because they disrupt the abnormal discharge pattern in the GPi and thus reduce cortical overactivation, a characteristic of dystonia. Deep-brain stimulation of the GPi is now the preferred surgical treatment for dystonia because it has a lower risk of complications than does pallidotomy, and the stimulation parameters can be customised for each individual patient. Primary generalised dystonia seems to respond better than secondary dystonia to GPi deep-brain stimulation, although uncontrolled evidence also suggests that patients with cervical dystonia,72 pantothenate kinaseassociated neurodegeneration,65,67,70 and tardive dystonia73 also substantially improve. In a prospective, multicentre study of 22 patients with generalised dystonia, seven of whom had mutations in DYT1, the mean BFMS score improved after bilateral GPi deep-brain stimulation from 46·3 (SD 21·3) to 21·0 (14·1) at 12 months (p<0·001).70 A “blinded” review of the videos at 3 months showed improvement with stimulation in mean BFMS from 34·63 (12·3) to 24·6 (17·7; p<0·001). The improvement http://neurology.thelancet.com Vol 5 October 2006
in mean dystonia motor scores was 51% and a third of the patients improved more than 75% compared with preoperative scores. Additionally, there was a significant improvement in health-related quality of life as measured by the SF-36, but there was no change in cognition or mood. The sample was rather small and the authors were not able to find any predictors of response, such as DYT1 gene status, anatomic distribution of the dystonia, or exact location of the electrodes. Patients with phasic form of dystonia improved more than those with tonic contractions and posturing. The maximum benefit was not achieved in some patients until 3–6 months after surgery. These findings are consistent with those in our study of patients undergoing bilateral GPi deep-brain stimulation.66 We showed significant improvements (p≤0·05) in mean total UDRS score, especially in the subscores for neck, trunk, arm, and leg, and a 23·6% (p=0·008) improvement in walking. The mean voltage was 3·5 V (SD 0·9), the frequency was 150·8 Hz (29·9), and the pulse width was 151·5 μsec (98) at the most recent follow-up. Most studies of deep-brain stimulation in dystonia have reported very low frequency of complications and no serious adverse effects on cognitive and neuropsychiatric functions.69 However, in one series of 16 patients treated for dystonia with GPi deep brain stimulation, two patients committed suicide, although a clear association with deep brain simulation could not be established.68 In addition to stereotactic procedures targeting thalamus and basal ganglia, peripheral denervation procedures have been used extensively before the advent of botulinum toxin, especially for focal and segmental dystonias. Three procedures have been used in the treatment of cervical dystonia: extradural selective sectioning of posterior (dorsal) rami (posterior ramisectomy) with or without myotomy; intradural sectioning of anterior cervical roots (anterior cervical rhizotomy); and microvascular decompression of the spinal accessory nerve. Although the first procedure, championed by Bertrand and MolinaNegro,74 is regarded by many clinicians to be the procedure of choice, no study has compared the different surgical approaches. Bertrand and Molina-Negro74 reported that 97 of 111 (87%) patients had “excellent” or “very good” results. We reported the effects of 70 intradural or extradural approaches in 46 patients with severe cervical dystonia.75 During a mean duration of follow-up of 6·5 years, 21 patients (46%) reported excellent or marked improvement on a global outcome scale. There was no difference when patients who still responded to botulinum toxin were compared with the botulinum toxin nonresponders. By use of the modified TWSTRS scale, we found significant improvements not only in the severity of dystonia, but also in occupational and domestic work, as well as in various activities of daily living. Our results were comparable to those of Ford and colleagues76 who reported an open-label, retrospective study of a selective denervation for severe cervical dystonia in 16 patients 869
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Dystonia
Oral drugs
Levodopa
Chemodenervation
Botulinum toxin A
Botulinum toxin B
Anticholinergics
Surgical therapies
Peripheral surgery
Selective peripheral denervation
Other treatments
Central surgery
Myectomy
Deep brain stimulation (globus pallidus)
Physical and occupational therapy
Immobilisation, constraint-induced therapy
Pallidotomy
Baclofen
Benzodiazepines
Tizanidine, tetrabenazine, etc
Figure 2: Algorithm for the treatment of dystonia
refractory to injections with botulinum toxin A. By use of functional capacity scales, they concluded that six patients (38%) had “a moderate or complete return of normal neck function”. Despite some improvement in 12 of 14 (86%) patients on the TWSTRS dystonia rating scale applied to “blinded” ratings of videotaped examinations, the surgery did not return patients to their occupations. These and other studies suggest that surgical treatment tailored to the specific pattern of dystonic activity in the individual patient is an effective alternative in the long-term management of cervical dystonia. Surgical treatments, such as facial nerve lysis and orbicularis oculi myectomy, once used extensively in the treatment of blepharospasm, have been essentially abandoned because botulinum-toxin treatment is very effective in most cases and without frequent postoperative complications such as ectropion, exposure keratitis, facial droop, and postoperative swelling and scarring.77 Likewise, recurrent laryngeal nerve section, once used in the treatment of spasmodic dysphonia,78 is rarely used currently and only when botulinum toxin fails to provide a satisfactory relief. Another once popular procedure, namely spinal-cord stimulation for cervical dystonia, was ineffective in a controlled trial.79
Experimental therapeutics Inhibition of expression of mutant torsin A could be a powerful therapeutic strategy in DYT1 dystonia. Gonzalez-Alegre and colleagues80 successfully suppressed expression of this abnormal protein in transfected cells, which was allele-specific, with small interfering RNA. This strategy is being tested in animal models of the 870
disease.81 As new dystonia-causing genes are being discovered and the understanding of mechanisms of dystonia is improving, there is hope that more pathogenesis-targeted, rather than merely symptomatic treatments, will become available in the future.
Treatment guidelines Any form of treatment should be preceded by a thorough assessment designed to rule out secondary causes of dystonia. Before considering pharmacological treatment for dystonia, comorbities such as depression and secondary orthopaedic problems should be addressed and physical and occupational therapies should be considered (figure 2). Besides abnormal movement, posture, pain, depression, anxiety, and other psychological comorbidities could have important effects on the quality of life of patients with dystonia and must be appropriately treated.13 Patients with segmental or generalised dystonia beginning in childhood or adolescence should be initially tried with levodopa up to 1000 mg per day. If this treatment is successful, it should be maintained at the lowest possible dose. If ineffective after 1 month, highdose anticholinergic treatment (eg, trihexyphenidyl, diphenhydramine) may be considered. In most patients with adult-onset dystonia, the distribution is focal and, therefore, botulinum-toxin injections are the treatment of choice. Botulinum toxin might also be helpful in controlling the most disabling symptoms of segmental or generalised dystonia. Peripheral denervation for cervical dystonia or myectomy for blepharospasm are seldom needed as these forms of focal dystonia usually respond well to botulinum toxin. Surgical treatment with http://neurology.thelancet.com Vol 5 October 2006
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Search strategy and selection criteria References for this review were identified by searches of PubMed from 1980 to June 2006, with the terms “dystonia”, “blepharospasm”, “torticollis”, “levodopa”, “anticholinergics”, “BTX”, and “deep brain stimulation”. Articles were also identified through searches of the author’s own files. Only papers published in English were reviewed. Books on dystonia and other movement disorders published during the same period, personal experience and judgment, and comments from the reviewers were also used in preparation of this review.
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GPi deep brain stimulation should be reserved only for patients whose symptoms continue to be disabling despite optimum medical treatment.
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Conflicts of interest I have no conflicts of interest.
26
References 1 Manji H, Howard RS, Miller DH, et al. Status dystonicus: the syndrome and its management. Brain 1998; 121: 243–52. 2 Lindeboom R, de Haan RJ, Brans JWM, Speelman JD. Treatment outcomes in cervical dystonia: a clinimetric study. Mov Disord 1996; 11: 371–76. 3 Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of BTX and other cure options. Eur J Neurol 2004; 11: 361–70. 4 Consky ES, Lang AE. Clinical assessments of patients with cervical dystonia. In: Jankovic J, Hallett M, eds. Therapy with botulinum toxin. New York, USA: Marcel Dekker, 1994: 211–37. 5 Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986; 36: 160–64. 6 Ondo WG, Desaloms M, Jankovic J, Grossman R. Surgical pallidotomy for the treatment of generalized dystonia. Mov Disord 1998; 13: 693–98. 7 Comella CL, Leurgans S, Wuu J, Stebbins GT, Chmura T; Dystonia Study Group. Rating scales for dystonia: a multicenter assessment. Mov Disord 2003; 18: 303–12. 8 Cano SJ, Warner TT, Linacre JM, et al. Capturing the true burden of dystonia on patients: the Cervical Dystonia Impact Profile (CDIP58). Neurology 2004; 63: 1629–33. 9 Albanese A, Barnes MP, Bhatia KP, et al. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force. Eur J Neurol 2006; 13: 433–44. 10 Jankovic J. Dystonia: medical therapy and botulinum toxin. In: Fahn S, Hallett M, DeLong DR, eds. Dystonia 4: advances in neurology voume 94. Philadelphia: Lippincott, Williams & Wilkins, 2004: 275–86. 11 Svetel M, Kozic D, Stefanoval E, et al. Dystonia in Wilson’s disease. Mov Disord 2001; 16: 719–23. 12 Jankovic J, Fahn S. Dystonic disorders. In: Jankovic J, Tolosa E, eds. Parkinson’s disease and movement disorders, 4th edn. Philadelphia, USA: Lippincott Williams and Wilkins, 2002: 331–57. 13 Ben-Shlomo Y, Camfield L, Warner T. What are the determinants of quality of life in people with cervical dystonia? J Neurol Neurosurg Psychiatry 2002; 72: 608–14. 14 Tas N, Karatas K, Sepici V. Hand orthosis as a writing aid in writer’s cramp. Mov Disord 2001; 16: 1185–89. 15 Candia V, Elbert T, Altenmüller E, et al. Constraint-induced movement therapy for focal hand dystonia in musicians. Lancet 1999; 53: 42. 16 Priori A, Pesenti A, Cappellari A, et al. Limb immobilisation for the treatment of focal occupational dystonia. Neurology 2001; 57: 405–09. 17 Jankovic J. Can peripheral trauma induce dystonia and other movement disorders? Yes! Mov Disord 2001; 16: 7–12.
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Wirtschafeter JD. Clinical doxorubicin chemomyectomy: an experimental treatment for benign essential blepharospasm and hemifacial spasm. Ophthalmology 1991; 98: 357–66. Junker J, Oberwittler C, Jackson D, Berger K. Utilization and perceived effectiveness of complementary and alternative medicine in patients with dystonia. Mov Disord 2004; 19: 158–61. Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004; 75: 951–57. Tan E-K, Jankovic J. Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up. Neurology 1999; 53: 2102–05. Tan E-K, Jankovic J. Treating severe bruxism with botulinum toxin. J Am Dent Assoc 2000; 131: 211–16. Restivo DA, Maimone D, Patti F, et al. Trismus after stroke/TBI: botulinum toxin benefit and use pre-PEG placement. Neurology 2005; 64: 2152–53. Schuele S, Jabusch HC, Lederman RJ, Altenmuller E. Botulinum toxin injections in the treatment of musician’s dystonia. Neurology 2005; 64: 341–43. Dong M, Yeh F, Tepp WH, et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312: 592–96. Mahrhold S, Rummel A, Bigalke H, Davletov B, Binz T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett 2006; 580: 2011–14. Truong D, Duane DD, Jankovic J, et al. Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study. Mov Disord 2005; 20: 783–91. Benecke R, Jost WH, Kanovsky P, Ruzicka E, Comes G, Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005; 64: 1949–51. Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 2005; 65: 1423–29. Tintner R, Gross R, Winzer UF, Smalky KA, Jankovic J. Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial. Neurology 2005; 65: 765–67. Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 2004; 20: 981–90. Jankovic J, Esquenazi A, Fehling D, Freitag F, Lang AM, Naumann M. Evidence-based review of patient reported outcomes with botulinum toxin type A. Clin Neuropharmacol 2004; 27: 234–44. Mejia NI, Vuong KD, Jankovic J. Long-term botulinum toxin efficacy, safety and immunogenicity. Mov Disord 2005; 20: 592–97. Jankovic J, Vuong KD, Ahsan J. Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology 2003; 60: 1186–88. Jankovic J, Hunter C, Atassi MZ. Botulinum toxin type B observational study (BOS). Mov Disord 2005; 20 (suppl 10): S31. Ondo WG, Desalom JM, Jankovic J, Grossman RG. Pallidotomy and thalamotomy for dystonia. In: Krauss JK, Jankovic J, Grossman RG, eds. Surgery for Parkinson’s disease and movement disorders. Philadelphia, USA: Lippincott Williams and Wilkins, 2001: 299–306. Coubes P, Cif L, El Fertit H, et al. Electrical stimulation of the globus pallidus internus in patients with primary generalized dystonia: long-term results. J Neurosurg 2004; 101: 189–94.
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Treatment of dystonia Joseph Jankovic Lancet Neurol 2006; 5: 864–72 Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA (Prof J Jankovic MD) [email protected]
Dystonia, defined as a neurological syndrome characterised by involuntary, patterned, sustained, or repetitive muscle contractions of opposing muscles, causing twisting movements and abnormal postures, is one of the most disabling movement disorders. Although gene mutations and other causes are increasingly recognised, most patients have primary dystonia without a specific cause. Although pathogenesis-targeted treatment is still elusive, the currently available symptomatic treatment strategies are quite effective for some types of dystonia in relieving involuntary movements, correcting abnormal posture, preventing contractures, reducing pain, and improving function and quality of life. A small portion of patients have a known cause and respond to specific treatments, such as levodopa in dopa-responsive dystonia or drugs that prevent copper accumulation in Wilson’s disease. Therapeutic options must be tailored to the needs of individual patients and include chemodenervation with botulinum toxin injections for patients with focal or segmental dystonia, and medical treatments or deep brain stimulation for patients with generalised dystonia.
Introduction Despite paucity of knowledge about the cause and pathogenesis of dystonic disorders, the symptomatic treatment of dystonia has substantially improved, especially since the introduction of botulinum toxin and deep brain stimulation. In most cases of dystonia, treatment is merely symptomatic, designed to improve posture and function and to relieve associated pain. In a few patients, however, dystonia can be so severe that it can produce not only abnormal postures and disabling movements, sometimes compromising respiration, but also a muscle breakdown and a life-threatening hyperthermia, rhabdomyolysis, and myoglobinuria. In such cases of so-called dystonic storm or status dystonicus, proper therapeutic intervention can be life saving.1 The assessment of various therapeutic interventions in dystonia is problematic for various reasons. First, dystonia and its effects on function are difficult to quantify and, therefore, most trials use crude clinical rating scales, many of which have not been properly assessed or validated. Second, dystonia is a syndrome with different causes, anatomic distributions, and heterogeneous clinical manifestations that produce variable disability. Third, some patients, perhaps up to 15%, might have spontaneous, albeit transient, remissions. Fourth, most therapeutic trials in dystonia are not randomised controlled studies. And fifth, most studies, even those that have been otherwise well designed, enrolled few patients, which makes the results difficult to interpret and generalise, which is especially important because of the large placebo effect.2 Except for botulinum toxin in patients with cervical dystonia and high-dose trihexyphenidyl in young patients with segmental and generalised dystonia (level A, class I–II), none of the other methods of pharmacological intervention has been confirmed as being effective according to evidence-based criteria.3 Cervical dystonia is the most common type of focal dystonia. Several instruments have been used to assess response in patients with cervical dystonia. The most 864
commonly used scale is the Toronto western spasmodic torticollis rating scale (TWSTRS).4 Additionally, various scales, such as the Burke-Fahn-Marsden scale (BFMS) and the unified dystonia rating scale (UDRS), have been used to assess patients with generalised dystonia.5–7 Another scale designed to capture the burden of dystonia on patients is the the cervical dystonia impact profile (CDIP-58) scale.8 The selection of a particular choice of treatment is largely guided by the age of the patient and the anatomical distribution of dystonia (panel). Although a systematic, evidence-based review of the treatment of dystonia has been published,9 most treatments have not been subjected to rigorous double-blind, controlled trials, and, therefore, the selection of the most optimum treatment option is usually based on personal clinical experience weighing knowledge of efficacy against potential adverse effects.10 This Review attempts to provide a comprehensive and balanced overview of the available and experimental therapeutic strategies, noting, whenever possible, limitations and controversial features of the various treatments. The identification of a specific cause of dystonia, such as drug-induced dystonias or Wilson’s disease,11 could lead to a treatment that is targeted to the particular cause. Discussion of the diagnostic approaches to patients with dystonia is beyond the scope of this Review and has been reviewed elsewhere.12
Physical therapy Education of patients, genetic counselling, and consideration of orthopaedic and other comorbid disorders, including depression,13 are all important parts of a comprehensive therapeutic approach to dystonia. Physical therapy and well-fitted braces are designed primarily to improve posture and to prevent contractures. Although braces are commonly poorly tolerated, especially by children, in some cases they may be used as a substitute for a so-called sensory trick. For example, some patients with cervical dystonia might benefit from specially designed neck and head braces that substitute http://neurology.thelancet.com Vol 5 October 2006
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Panel: Treatment of dystonia Focal dystonias Blepharospasm Botulinum-toxin injections Clonazepam, lorazepam Trihexyphenidyl Orbicularis oculi myectomy Oromandibular dystonia Botulinum-toxin injections Baclofen Trihexyphenidyl Spasmodic dysphonia Botulinum-toxin injections Voice and supportive therapy Cervical dystonia Botulinum-toxin injections Trihexyphenidyl Diazepam, lorazepam, clonazepam Tetrabenazine Cyclobenzaprine Carbamazepine Baclofen (oral) Peripheral surgical denervation Deep brain stimulation of the internal segment of the globus pallidus Task-specific dystonias (eg, writer’s cramp) Botulinum-toxin injections Benzatropine, trihexyphenidyl Occupational therapy Segmental and generalised dystonias Levodopa (in children and young adults) Trihexyphenidyl, benzatropine Diazepam, lorazepam, clonazepam Baclofen (oral, intrathecal) Carbamazepine Tetrabenazine Intrathecal baclofen infusion (axial and leg dystonia) Deep brain stimulation of the internal segment of the globus pallidus
for a sensory input in that, by touching certain portions of the neck or head in a fashion similar to a patient’s own sensory trick, they enable patients to maintain a desired head position. Various hand devices have been developed to help patients with writer’s cramp to use their hands more effectively and comfortably.14 In one small study of five professional musicians with focal dystonia, Candia and colleagues15 reported success with immobilisation by splints of one or more of the digits other than the dystonic finger, followed by intensive repetitive exercises of the dystonic finger. However, whether this treatment provides lasting benefits is unclear. In one study of eight patients with idiopathic occupational focal dystonia of the arm, immobilisation with a splint for 4–5 weeks resulted in a significant improvement at a 24 week follow-up visit, http://neurology.thelancet.com Vol 5 October 2006
measured with the arm dystonia disability scale (0=normal; 3=marked difficulty in playing) and the Tubiana and Champagne score (0=unable to play; 5=returns to concert performances), and was judged as substantial in four, moderate in three, and the initial improvement disappeared in one.16 The splint was applied for 24 h every day, except for 10 min once a week for brief local hygiene. Immediately upon removal of the splint, all patients reported much clumsiness and weakness, which resolved in 4 weeks. There was also some local subcutaneous and joint oedema and pain in the immobilised joint, and nail growth stopped; no patients developed contractures. Although the mechanisms of action of immobilisation are unknown, researchers have postulated that removing all motor and sensory input to a limb could allow the cortical map to reset to the previous normal topography.16 A major concern about immobilisation of a limb, especially a dystonic limb, is that such immobilisation can actually increase the risk of exacerbating or even precipitating dystonia, as has been shown in dystonia after casting and in other forms of peripherally induced dystonia.17 An alternative to the immobilisation strategy, constraint-induced movement therapy has been used successfully in rehabilitation of patients after stroke and other brain injuries as well as in dystonia.18,19 The observed benefits have been attributed to cortical or subcortical reorganisation,17 but the mechanism of this therapeutic approach is not well understood. Some patients find various muscle relaxation techniques and sensory feedback therapy useful adjuncts to medical or surgical treatments. Because some patients with dystonia have impaired sensory perception, sensory training has been postulated to relieve dystonia. In a study of ten patients with focal hand dystonia, Zeuner and colleagues20 showed that reading Braille for 30–60 min daily for 8 weeks improved spatial acuity and dystonia, an effect that was sustained for up to a year in some patients.21 Sensory training to restore sensory representation of the hand along with mirror imagery and mental practice techniques have also been reported to be useful in the treatment of focal hand dystonia.22 Various neurophysiological techniques have been used in the treatment of dystonia. By use of repetitive transcranial magnetic stimulation delivered at low frequencies (≤1 Hz) for 20 min, Siebner and colleagues23 showed that this technique might temporarily improve handwriting impaired by dystonic writer’s cramp (eight of 16 patients reported improvement that lasted longer than 3 h), presumably by increasing inhibition (and thus reducing excitability) of the underlying cortex. Finally, neck-muscle vibration of the contracting muscle could have therapeutic value in some patients with cervical dystonia. This notion was lent support by the finding of transient (minutes) improvement in head position in one patient treated for 15 min with muscle vibration.24 Transcutaneous electrical stimulation improved dystonic 865
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writer’s cramp for at least 3 weeks in a double-blind, placebo-controlled trial.25 This observation is consistent with the idea that proprioceptive sensory input affects cervical dystonia.
Medical therapy Dopaminergic drugs Although most patients with dystonia have limited or no improvement with levodopa, a small subset, possibly representing up to 5% of childhood dystonias, have substantial improvement and even complete resolution of dystonia with levodopa, hence the designation doparesponsive dystonia. This type of dystonia, characterised by childhood onset, parkinsonian features, gait and postural abnormalities, diurnal fluctuation, and autosomal dominant inheritance, is usually caused by mutations in the GTP cyclohydrolase 1 gene on chromosome 14q or abnormalities in tyrosine hydroxylase or sepiapterin reductase.26–28 GTP cyclohydrolase 1 indirectly regulates the production of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme in the synthesis of dopamine. Because the presentation of dopa-responsive dystonia is multifaceted and the disorder is wrongly attributed to cerebral palsy (eg, spastic diplegia) in many cases, levodopa should be considered in all patients with childhood-onset and young-onset dystonia. In my experience, most patients with dopa-responsive dystonia improve substantially, even with small doses of levodopa (100 mg of levodopa with 25 mg of decarboxylase inhibitor), but some patients might need doses of levodopa as high as 1000 mg per day (unpublished). By contrast with patients with juvenile Parkinson’s disease, most with dopa-responsive dystonia do not develop levodopa-induced fluctuations or dyskinesias. If no clinically evident improvement is noted after 1 month of treatment at adequate doses, the diagnosis of doparesponsive dystonia is unlikely. In addition to levodopa, patients with dopa-responsive dystonia also improve with dopamine agonists, anticholinergic drugs, and carbamazepine, but no controlled studies have been done. Modest improvements with levodopa have been reported in patients with other types of dystonia besides dopa-responsive dystonia.10
Antidopaminergic drugs Although used extensively in the past, most clinical trials have produced mixed results with dopamine-receptorblocking drugs. Because of the poor response and the possibility of undesirable side-effects, especially sedation, parkinsonism, and tardive dyskinesia, the use of these drugs in the treatment of dystonia should be discouraged. Clozapine, an atypical neuroleptic, has been reported in a small, open trial to be moderately effective in the treatment of segmental and generalised dystonia, but its usefulness was limited by potential side-effects.29 Although antidopaminergic drugs might be beneficial in 866
the treatment of dystonia, the potential clinical benefit is usually limited by the development of side-effects. Dopamine depleting drugs, however, such as tetrabenazine, have proven useful in some patients with dystonia, particularly in those with tardive dystonia.30 Tetrabenazine, an inhibitor of vesicular monoamine transporter 2, has the advantage over other antidopaminergic drugs in that it does not cause tardive dyskinesia, although it can cause transient acute dystonic reaction.31 The drug is not readily available in the USA, but it is dispensed by prescription under the trade name Nitoman or Xenazine 25 in other countries, including the UK and Canada.
Anticholinergic drugs Anticholinergic drugs, such as trihexyphenidyl, are useful in the treatment of generalised and segmental dystonia.6,32 When the dose is started low and increased very slowly, anticholinergic drugs can be well tolerated. We recommend starting trihexyphenidyl, 2 mg tablet, a half tablet at bedtime and advancing up to 12 mg per day over the next 4 weeks, eventually switching to a sustained release preparation. Some patients need up to 60–100 mg per day of trihexyphenidyl, but may experience doserelated drowsiness, confusion, memory difficulty, and hallucinations. Pyridostigmine, a peripherally acting anticholinesterase, and eye drops of pilocarpine (a muscarinic agonist) commonly improve at least some of the peripheral side-effects such as urinary retention and blurred vision. Pilocarpine 5 mg four times per day, cevimeline 30 mg three times a day, and synthetic saliva have proven effective in the treatment of dry mouth.
Other pharmacological treatments Many patients with dystonia need a combination of several drugs and treatments.10 Muscle relaxants, such as benzodiazepines (diazepam, lorazepam, or clonazepam), tizanidine, cyclobenzaprine, metaxalone, carisoprodol, methocarbamol, orphenadrine, and chlorzoxazone could provide additional benefit for patients whose response to anticholinergic drugs is unsatisfactory. Clonazepam might be especially useful in patients with blepharospasm and with myoclonic dystonia.33 Oral baclofen might occasionally be helpful, particularly in the treatment of oromandibular dystonia and in levodopa-related wearingoff dystonia. Narayan and colleagues34 first suggested that intrathecal baclofen infusion could be effective in the treatment of dystonia in 1991 in a report of an 18-year-old man with dystonic storm. Subsequent reports have provided support for this form of treatment, especially in patients with dystonia associated with spasticity (spastic dystonia).35,36 There are many other drugs used in the treatment of dystonia, but their benefits have not been assessed by well-designed controlled trials. For example, slow release morphine sulfate has been reported to improve not only pain but also dystonic movements in some patients with http://neurology.thelancet.com Vol 5 October 2006
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primary and tardive dystonia.37 Besides clonazepam, gamma-hydroxybutyrate, used in the treatment of alcohol abuse, is beneficial in the treatment of myoclonusdystonia syndrome.38 Although kinesigenic paroxysmal dystonia might be well controlled with anticonvulsants (eg, carbamazepine, phenytoin), the non-kinesigenic forms of paroxysmal dystonia are less responsive to pharmacological therapy, although clonazepam and acetazolamide might be beneficial.39 Peripheral deafferentation with anaesthetic was previously reported to improve tremor, but this approach could also be useful in the treatment of focal dystonia, such as writer’s cramp,40 or oromandibular dystonia41 unresponsive to other pharmacological treatment. An injection of 5–10 mL of 0·5% lidocaine into the target muscle improved focal dystonia for up to 24 h. This short effect can be extended for up to several weeks if ethanol is simultaneously injected. Mexiletine, an oral derivative of lidocaine, has been shown to be effective in the treatment of cervical dystonia at doses ranging from 450 mg a day to 1200 mg a day.42 Two-thirds of patients, however, experience adverse effects such as heartburn, drowsiness, ataxia, and tremor. On the basis of review and rating of videotapes by a “blind” rater, Lucetti and colleagues43 reported a significant improvement in six patients with cervical dystonia treated with mexiletine. The observation that blocking of muscle-spindle afferents reduces dystonia provides additional evidence that somatosensory input is important in the pathogenesis of dystonia.44 Local electromyography-guided injections of phenol have also been proposed as a potential treatment of cervical dystonia, but the results have not been very encouraging because of pain associated with the procedure and unpredictable response.45 Chemomyectomy with muscle necrotising drugs, such as doxorubicin, has been tried in some patients with blepharospasm and hemifacial spasm,46 but because of severe local irritation, this approach is unlikely to be adopted into clinical practice. In addition to conventional forms of treatment described above, many patients with dystonia seek complementary or alternative forms of therapy. In one survey of 180 members of the German Dystonia Group, 131 (73%) patients used some form of alternative treatment, such as acupuncture (56%), relaxation techniques (44%), homoeopathy (27%), and massage (26%).47 None of these alternative therapies, however, have been subjected to careful scrutiny by well designed, controlled trials.
Botulinum toxin The introduction of botulinum toxin into clinical practice in the 1980s clearly revolutionised the treatment of dystonia. As the most potent biological toxin, botulinum toxin has become a powerful therapeutic tool in the treatment of a variety of neurological, ophthalmic, and http://neurology.thelancet.com Vol 5 October 2006
other disorders manifested by abnormal, excessive, or inappropriate muscle contractions.48 In December, 1989, after extensive laboratory and clinical testing, the US Food and Drug Administration (FDA) approved botulinum toxin A (formulation BOTOX) as a therapeutic agent in patients with strabismus, blepharospasm, and other facial nerve disorders, including hemifacial spasm. In December, 2000, the FDA approved Botox and botulinum toxin B (Myobloc) as treatments for cervical dystonia. In addition to improving blepharospasm, hemifacial spasm, and cervical dystonia, botulinum toxin provides meaningful relief in other focal dystonias, including oromandibular dystonia, such as involuntary jaw-opening and trismus with bruxism,49–51 dystonic writer’s cramp, and other task-specific dystonias, such as musician’s dystonia.52 Although its widest application is still in the treatment of disorders manifested by abnormal, excessive, or inappropriate muscle contractions, the use of botulinum toxin is rapidly expanding to include treatment of various ophthalmological, gastrointestinal, urological, orthopaedic, dermatological, secretory, painful, and cosmetic disorders.48 The therapeutic benefit of botulinum toxin is mainly due to its primary mechanism of action of blocking the release of acetylcholine into the neuromuscular junction causing local temporary chemodenervation and muscle paralysis. There are seven immunologically distinct toxins that share structurally homologous subunits. Synthesised as single-chain polypetides (molecular weight of 150 kD), these toxin molecules have relatively little potency, until they are cleaved by trypsin or bacterial enzymes into a heavy chain (100 kD) and a light chain (50 kD). Botulinum toxin A enters neurons by binding to the synaptic vesicle protein SV2 (isoform C), which acts as the botulinum toxin A receptor.53,54 The neural membrane proteins synaptotagmin I and II act as receptors for botulinum toxins B and G.54 Although the heavy chain of the toxin binds to the presynaptic cholinergic terminal, the light chain acts as a zincdependent protease that selectively cleaves proteins that are critical for fusion of the presynaptic vesicle with the presynaptic membrane. Thus, the light chains of botulinum toxins A and E cleave SNAP-25 (synaptosome associated protein), a protein needed for synaptic vesicle targeting and fusion with the presynaptic membrane. The light chains of botulinum toxins B, D, and F prevent the quantal release of acetylcholine by proteolytically cleaving synaptobrevin-2, also known as VAMP (vesicle associated membrane protein), an integral protein of the synaptic vesicle membrane. Botulinum toxin C cleaves syntaxin, another plasma membrane associated protein. Botox and Myobloc (Neurobloc in Europe) are the only types of botulinum toxin currently approved for clinical use in the USA, but other formulations of botulinum toxin A, such as Dysport55 and Xeomin (NT 201),56 are available in other countries. These other formulations have similar efficacy and adverse effect profiles to Botox. 867
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Figure 1: Effects of botulinum toxin in a patient with cervical dystonia There is substantial improvement of head and neck position from before treatment (left) to 4 weeks after injection (right).
Although botulinum toxin has been used in several focal dystonias, including blepharospasm, oromandibular dystonia, dystonic writer’s cramp, and other occupational dystonia,48 its therapeutic application has been most studied in cervical dystonia. Botulinum toxin A and botulinum toxin B were directly compared in 139 patients with cervical dystonia in a randomised, double-blind, parallel-group study.57 The patients were assessed at baseline, 4 weeks, 8 weeks, and at 2 week intervals thereafter until a loss of 80% of clinical effect or completion of 20 weeks of observation. The severity of cervical dystonia was measured with the TWSTRS and adverse events were assessed by structured interview. Whereas improvement in TWSTRS score at 4 weeks after injection did not differ between the two serotypes, dysphagia and dry mouth were less common with botulinum toxin A than with botulinum toxin B (dysphagia 19% vs 48%, p=0·0005; dry mouth 41% vs 80%, p<0·0001). In clinical responders, botulinum toxin A had a modestly longer duration of benefit than did botulinum toxin B (14 weeks vs 12·1 weeks, p=0·033). The effects on drooling may be even more robust with botulinum toxin B than with botulinum toxin A. To compare autonomic effects of botulinum toxin we randomly assigned patients with cervical dystonia to receive either botulinum toxin A or botulinum toxin B in a double-blind manner.58 Efficacy and physiological questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with botulinum toxin B had significantly less saliva production (p<0·01) and greater severity of constipation (p=0·037) than did those treated with botulinum toxin A, but did not differ with respect to 868
other tests of autonomic function, including changes in blood pressure, heart rate, and ocular function. These and other studies have provided evidence that botulinum toxin is the treatment of choice for patients with cervical dystonia (figure 1). Many clinical studies have provided evidence that botulinum toxin is not only safe and effective, but also leads to meaningful improvements in quality of life,59,60 and the benefits are long-lasting.61 Although antigenicity and development of immunoresistance due to blocking antibodies with consequent loss of response to botulinum toxin was a concern with the original formulation of Botox that contained 25 ng of neurotoxin protein per 100 units, occurrence of blocking antibodies is quite rare with the current formulation, which contains only 5 ng of neurotoxin protein per 100 units.62 Of 119 patients enrolled in a multicentre study of patients treated with botulinum toxin B for cervical dystonia, 13 (26%) patients with history of exposure to botulinum toxin B had evidence of blocking antibodies to botulinum toxin B, whereas 15 (21%) of those exposed to botulinum toxin A had blocking antibodies to botulinum toxin A.63 Furthermore, 30 (32%) patients who were negative for botulinum toxin B antibodies at baseline became positive for botulinum toxin B antibodies at last visit. These studies suggest that although botulinum toxin B offers a useful alternative to patients with immunoresistance to botulinum toxin A, long-term efficacy might be limited by the development of autonomic adverse effects and blocking antibodies, probably as a result of cross-reactivity between the two serotypes. Low antigenicity has been predicted with NT 201 because it is presumably free of complexing proteins, but no long-term data exist. If http://neurology.thelancet.com Vol 5 October 2006
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detected by a reliable method, such as the mouse protection assay, the presence of blocking antibodies indicates immunoresistance; therefore, the response to subsequent injections will be substantially diminished or non-existent. Although the mouse protection assay is regarded to be the most reliable method for detecting blocking antibodies,48,62 this assay is not readily available and, therefore, a simple clinical test, known as unilateral brow injection, can ascertain whether poor or lack of response is due to immunoresistance. In this test, botulinum toxin (eg, 20 U of botulinum toxin A or 1000 U of botulinum toxin B) is injected unilaterally into one corrugator-procerus muscle complex and if, 1 week later, the patient frowns asymmetrically because of weakness of the injected muscles, this indicates absence of neutralising antibodies.
Surgical treatment Although surgery has been used for a long time in the treatment of dystonia, there has been a recent resurgence in this approach, largely because of improved understanding of the functional anatomy of the basal ganglia and of physiological mechanisms underlying dystonia, coupled with refinements in imaging and surgical techniques.64–70 Intraoperative recordings in patients with dystonia have shown not only abnormal discharge rates but also, more importantly, abnormal patterns of discharge in the various portions of the basal ganglia, particularly in the external and internal portions of the globus pallidus (GPe and GPi).71 On the basis of various physiological and functional imaging studies, a model of basal ganglia circuitry has been proposed suggesting an overactivity of both direct (striatum–GPi) and indirect (striatum–GPe–GPi) pathways. Therefore, ablative surgery (pallidotomy) and high-frequency stimulation of the main basal ganglia outflow nucleus, GPi, seem to be rational strategies in patients with dystonia, perhaps because they disrupt the abnormal discharge pattern in the GPi and thus reduce cortical overactivation, a characteristic of dystonia. Deep-brain stimulation of the GPi is now the preferred surgical treatment for dystonia because it has a lower risk of complications than does pallidotomy, and the stimulation parameters can be customised for each individual patient. Primary generalised dystonia seems to respond better than secondary dystonia to GPi deep-brain stimulation, although uncontrolled evidence also suggests that patients with cervical dystonia,72 pantothenate kinaseassociated neurodegeneration,65,67,70 and tardive dystonia73 also substantially improve. In a prospective, multicentre study of 22 patients with generalised dystonia, seven of whom had mutations in DYT1, the mean BFMS score improved after bilateral GPi deep-brain stimulation from 46·3 (SD 21·3) to 21·0 (14·1) at 12 months (p<0·001).70 A “blinded” review of the videos at 3 months showed improvement with stimulation in mean BFMS from 34·63 (12·3) to 24·6 (17·7; p<0·001). The improvement http://neurology.thelancet.com Vol 5 October 2006
in mean dystonia motor scores was 51% and a third of the patients improved more than 75% compared with preoperative scores. Additionally, there was a significant improvement in health-related quality of life as measured by the SF-36, but there was no change in cognition or mood. The sample was rather small and the authors were not able to find any predictors of response, such as DYT1 gene status, anatomic distribution of the dystonia, or exact location of the electrodes. Patients with phasic form of dystonia improved more than those with tonic contractions and posturing. The maximum benefit was not achieved in some patients until 3–6 months after surgery. These findings are consistent with those in our study of patients undergoing bilateral GPi deep-brain stimulation.66 We showed significant improvements (p≤0·05) in mean total UDRS score, especially in the subscores for neck, trunk, arm, and leg, and a 23·6% (p=0·008) improvement in walking. The mean voltage was 3·5 V (SD 0·9), the frequency was 150·8 Hz (29·9), and the pulse width was 151·5 μsec (98) at the most recent follow-up. Most studies of deep-brain stimulation in dystonia have reported very low frequency of complications and no serious adverse effects on cognitive and neuropsychiatric functions.69 However, in one series of 16 patients treated for dystonia with GPi deep brain stimulation, two patients committed suicide, although a clear association with deep brain simulation could not be established.68 In addition to stereotactic procedures targeting thalamus and basal ganglia, peripheral denervation procedures have been used extensively before the advent of botulinum toxin, especially for focal and segmental dystonias. Three procedures have been used in the treatment of cervical dystonia: extradural selective sectioning of posterior (dorsal) rami (posterior ramisectomy) with or without myotomy; intradural sectioning of anterior cervical roots (anterior cervical rhizotomy); and microvascular decompression of the spinal accessory nerve. Although the first procedure, championed by Bertrand and MolinaNegro,74 is regarded by many clinicians to be the procedure of choice, no study has compared the different surgical approaches. Bertrand and Molina-Negro74 reported that 97 of 111 (87%) patients had “excellent” or “very good” results. We reported the effects of 70 intradural or extradural approaches in 46 patients with severe cervical dystonia.75 During a mean duration of follow-up of 6·5 years, 21 patients (46%) reported excellent or marked improvement on a global outcome scale. There was no difference when patients who still responded to botulinum toxin were compared with the botulinum toxin nonresponders. By use of the modified TWSTRS scale, we found significant improvements not only in the severity of dystonia, but also in occupational and domestic work, as well as in various activities of daily living. Our results were comparable to those of Ford and colleagues76 who reported an open-label, retrospective study of a selective denervation for severe cervical dystonia in 16 patients 869
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Dystonia
Oral drugs
Levodopa
Chemodenervation
Botulinum toxin A
Botulinum toxin B
Anticholinergics
Surgical therapies
Peripheral surgery
Selective peripheral denervation
Other treatments
Central surgery
Myectomy
Deep brain stimulation (globus pallidus)
Physical and occupational therapy
Immobilisation, constraint-induced therapy
Pallidotomy
Baclofen
Benzodiazepines
Tizanidine, tetrabenazine, etc
Figure 2: Algorithm for the treatment of dystonia
refractory to injections with botulinum toxin A. By use of functional capacity scales, they concluded that six patients (38%) had “a moderate or complete return of normal neck function”. Despite some improvement in 12 of 14 (86%) patients on the TWSTRS dystonia rating scale applied to “blinded” ratings of videotaped examinations, the surgery did not return patients to their occupations. These and other studies suggest that surgical treatment tailored to the specific pattern of dystonic activity in the individual patient is an effective alternative in the long-term management of cervical dystonia. Surgical treatments, such as facial nerve lysis and orbicularis oculi myectomy, once used extensively in the treatment of blepharospasm, have been essentially abandoned because botulinum-toxin treatment is very effective in most cases and without frequent postoperative complications such as ectropion, exposure keratitis, facial droop, and postoperative swelling and scarring.77 Likewise, recurrent laryngeal nerve section, once used in the treatment of spasmodic dysphonia,78 is rarely used currently and only when botulinum toxin fails to provide a satisfactory relief. Another once popular procedure, namely spinal-cord stimulation for cervical dystonia, was ineffective in a controlled trial.79
Experimental therapeutics Inhibition of expression of mutant torsin A could be a powerful therapeutic strategy in DYT1 dystonia. Gonzalez-Alegre and colleagues80 successfully suppressed expression of this abnormal protein in transfected cells, which was allele-specific, with small interfering RNA. This strategy is being tested in animal models of the 870
disease.81 As new dystonia-causing genes are being discovered and the understanding of mechanisms of dystonia is improving, there is hope that more pathogenesis-targeted, rather than merely symptomatic treatments, will become available in the future.
Treatment guidelines Any form of treatment should be preceded by a thorough assessment designed to rule out secondary causes of dystonia. Before considering pharmacological treatment for dystonia, comorbities such as depression and secondary orthopaedic problems should be addressed and physical and occupational therapies should be considered (figure 2). Besides abnormal movement, posture, pain, depression, anxiety, and other psychological comorbidities could have important effects on the quality of life of patients with dystonia and must be appropriately treated.13 Patients with segmental or generalised dystonia beginning in childhood or adolescence should be initially tried with levodopa up to 1000 mg per day. If this treatment is successful, it should be maintained at the lowest possible dose. If ineffective after 1 month, highdose anticholinergic treatment (eg, trihexyphenidyl, diphenhydramine) may be considered. In most patients with adult-onset dystonia, the distribution is focal and, therefore, botulinum-toxin injections are the treatment of choice. Botulinum toxin might also be helpful in controlling the most disabling symptoms of segmental or generalised dystonia. Peripheral denervation for cervical dystonia or myectomy for blepharospasm are seldom needed as these forms of focal dystonia usually respond well to botulinum toxin. Surgical treatment with http://neurology.thelancet.com Vol 5 October 2006
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Search strategy and selection criteria References for this review were identified by searches of PubMed from 1980 to June 2006, with the terms “dystonia”, “blepharospasm”, “torticollis”, “levodopa”, “anticholinergics”, “BTX”, and “deep brain stimulation”. Articles were also identified through searches of the author’s own files. Only papers published in English were reviewed. Books on dystonia and other movement disorders published during the same period, personal experience and judgment, and comments from the reviewers were also used in preparation of this review.
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GPi deep brain stimulation should be reserved only for patients whose symptoms continue to be disabling despite optimum medical treatment.
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Conflicts of interest I have no conflicts of interest.
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