Version July 2025
INTRODUCTION —
The treatment of dystonia is primarily symptomatic, although some causes of dystonia are amenable to specific therapies. No curative therapies are available. Management options include oral medications, botulinum toxin (BoNT) injections, and deep brain stimulation (DBS).
This topic will review the treatment of dystonia. Other clinical aspects of dystonia are discussed separately. (See "Etiology, clinical features, and diagnostic evaluation of dystonia".)
Clinical features, diagnosis, and treatment of tardive dyskinesia, including tardive dystonia, are reviewed separately. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis" and "Tardive dyskinesia: Prevention, treatment, and prognosis".)
CHILDREN AND ADOLESCENTS —
Most dystonia presenting in childhood is genetic or idiopathic, either isolated or in combination with other movement disorders. In a small but important subset of patients, dystonia is exquisitely sensitive to levodopa. In the remaining patients, the therapeutic window of symptomatic medications is narrow, and side effects often limit clinical benefit (algorithm 1 and table 1). (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Early-onset isolated dystonia'.)
Levodopa trial — For children with isolated, idiopathic focal or generalized dystonia, an initial trial of carbidopa-levodopa is indicated to identify those with dopa-responsive dystonia (DRD). Although relatively rare, DRD represents a treatable dystonia syndrome, and levodopa is the treatment of choice. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Dopa-responsive dystonia'.)
Levodopa is always given in combination with a peripheral decarboxylase inhibitor (eg, carbidopa or benserazide). In the United States, the combination of carbidopa-levodopa is used; outside the United States, benserazide-levodopa may also be available. A treatment trial should be initiated with low doses of levodopa, such as carbidopa-levodopa 25/100 mg, one-half to one tablet daily, irrespective of age. Once started without side effects, the total daily levodopa dose can be increased as tolerated by 50 to 100 mg daily every week up to a full tablet of 25/100 mg three times daily, or more.
The usual practice is to titrate to the lowest levodopa dose that produces a useful clinical response. Children whose dystonia fails to improve by 600 mg daily seldom find relief at higher doses, and complete lack of improvement at 1000 mg daily should prompt discontinuation of this medication.
Patients with a clinically significant positive response (ie, those with DRD) should continue levodopa indefinitely. The dose can be adjusted over time to obtain the optimum response.
Carbidopa-levodopa is dramatically beneficial in patients with DRD. Often, small doses of levodopa (50 to 100 mg) one to three times daily can virtually eliminate the dystonic symptoms of DRD for an indefinite period of time without causing motor complications [1-3]. A sustained and complete response occurs with variable doses ranging from 100 to 750 mg daily [1,4]. One case series of 20 patients reported that the mean daily levodopa doses for clinical benefit in patients with and without associated dyskinesia were 343 and 189 mg, respectively [3]. Of note, although levodopa-induced dyskinesias are not typical in patients with DRD, unusual, long-lasting dyskinesias have been reported in Korean families with novel GTP cyclohydrolase 1 (GCH1) mutations [5]. The evaluation and genetic testing of patients with DRD is reviewed separately. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Dopa-responsive dystonia'.)
In other forms of dystonia, the response rate with carbidopa-levodopa is approximately 15 percent [6]. The degree of improvement among these patients is highly variable, and genetic testing can be pursued to exclude DRD whenever clinically relevant. Carbidopa-levodopa is mostly used as an adjunct in patients without DRD who find it beneficial [7]. It is often worth tapering off carbidopa-levodopa completely first to be sure that it is offering meaningful benefit before continuing it long term. This helps to avoid exposing patients to long-term side effects for marginal or no benefit.
Early-onset generalized isolated dystonia — For children and adolescents with isolated generalized dystonia that does not respond to a trial of levodopa, anticholinergic drug therapy is an appropriate first-line strategy in most patients (algorithm 1). High trihexyphenidyl doses may be necessary to achieve a clinically significant response in children. Second-line symptomatic therapies include baclofen and benzodiazepines.
Anticholinergic therapy — The mechanism of action of anticholinergic therapy in dystonia is not well understood. Trihexyphenidyl is a nonselective muscarinic receptor antagonist, which in animal models of DYT-TOR1A dystonia increases striatal dopamine release and efflux [8].
Although there is substantial clinical experience and agreement on the role of anticholinergic therapy in children with dystonia, supporting evidence is relatively limited [4,9-12]. In one of the few controlled trials, high-dose trihexyphenidyl (titrated in weekly increments of 5 mg daily up to 30 mg daily, in four divided doses) resulted in a clinically significant response in 71 percent of 31 children and young adults with mostly early-onset isolated dystonia [11].
Trihexyphenidyl — Trihexyphenidyl is the most commonly used anticholinergic drug for dystonia. In children and young adults, a typical starting dose is 2 mg twice daily. The dose is titrated gradually upwards in weekly increments of 2 to 5 mg per day as needed to achieve benefit; the rate of titration should be slowed if side effects occur. The maximum dose of trihexyphenidyl may be as high as 100 mg daily given in three to four divided doses [11]. Benefit may be delayed for several weeks. However, children and adolescents who do not experience response at 20 to 30 mg/day rarely exhibit meaningful symptomatic improvements at higher doses.
Discontinuation of anticholinergic agents should be gradual, as withdrawal effects may occur.
Anticholinergic side effects include dry mouth, blurred vision, constipation, urinary hesitancy or retention, tachycardia, pupil dilatation, and increased intraocular pressure. Dry mouth may increase the occurrence of dental caries.
Additional side effects of trihexyphenidyl include dizziness, confusion, memory impairment, nausea, vomiting, and anxiety. The central side effects, including memory loss and sedation, are dose limiting and can interfere with school and other activities. Cognitive side effects may become more apparent as the child ages into adulthood and the high doses are no longer tolerated.
Other anticholinergic drugs — Other anticholinergic agents, including benztropine, and those with both anticholinergic and antihistaminergic effects (eg, procyclidine, diphenhydramine) have also been used anecdotally for dystonia. For each of these agents, a similar slow titration to benefit or side effects is recommended.
Second-line medications — For patients who do not respond to or tolerate anticholinergic therapy, options include high-dose baclofen and benzodiazepines (algorithm 1). Whereas benzodiazepines may provide a more robust antidystonic effect than baclofen, sedation and the potential for tolerance and abuse are considerations when prescribing a benzodiazepine.
Baclofen and benzodiazepines may have a specific role for pediatric patients with dystonia in the context of other neurologic conditions, including epilepsy and cerebral palsy [13].
High-dose baclofen — One review found retrospective evidence that high-dose oral baclofen (40 to 180 mg daily) was associated with improvement in approximately 30 percent of children and adolescents (n = 31) with idiopathic generalized dystonia [14]. Side effects of oral baclofen, including nausea and sedation, may be intolerable. The sudden withdrawal of baclofen can cause serious side effects, including seizures.
Due to poor tolerance of high doses of oral baclofen, there is growing experience with the use of intrathecal and intraventricular baclofen for the treatment of dystonia and spasticity in pediatric patients with dystonic cerebral palsy. (See "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues".)
Benzodiazepines — Clonazepam is a frequently used benzodiazepine in the pediatric dystonia population. A typical starting dose in older children is half of a 0.5 mg tablet at bedtime. The drug can be titrated slowly (every fourth day, or longer) as tolerated, until the desired response occurs. The usual maintenance dose of clonazepam is 1 to 3 mg daily given in three divided doses. For children under 10 years of age, a starting dose of 0.01 mg/kg per day is recommended. The usual maintenance dose is 0.1 to 0.2 mg/kg daily given in three divided doses [7].
Rapid discontinuation may lead to withdrawal symptoms. Therefore, if treatment is not effective or side effects arise, the dose should be slowly tapered.
Refractory disease — Children with generalized dystonia that is refractory to oral medications or who have a particularly problematic area may benefit from botulinum toxin (BoNT). However, it is not reasonable to use widespread BoNT injection treatment for all symptoms of generalized dystonia because of dose limitations. (See 'Botulinum toxin injections' below.)
For some genetic forms of childhood-onset dystonia, specific therapy may be helpful. In ADCY5-related dyskinesia, for example, theophylline or caffeine may be useful [15,16]. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'ADCY5-related dyskinesia'.)
Children with debilitating, early-onset isolated generalized dystonia who do not respond to or tolerate oral medications or BoNT may be candidates for deep brain stimulation (DBS). (See 'Deep brain stimulation' below.)
Pediatric dystonic storm — Dystonic storm (also known as status dystonicus) is an infrequent medical emergency that requires early recognition and aggressive, multimodal treatment to minimize morbidity and mortality [17]. The mortality of dystonic storm has been reported to exceed 10 percent in some series [18]. The frequency of dystonic storm has increased since the advent of DBS for dystonia. Malfunction of the DBS can elicit dystonic storm without the usual triggers of infection or rapid discontinuation of oral medications [19].
In a retrospective, hospital-based study of 23 children hospitalized with dystonic storm, patients required multiple oral medications (including anticholinergics, benzodiazepines, levodopa, and tetrabenazine, among others), intravenous midazolam infusion, and, in some cases, mechanical ventilation, to achieve symptom control [20]. The successful use of emergency deep brain stimulation has been reported in the most refractory cases. Consensus recommendations for the initial management of acutely worsening dystonia (including pre-status dystonicus and status dystonicus), as well as refractory status dystonicus in children, are available [17]. Management is reviewed in more detail separately. (See "Hyperkinetic movement disorders in children", section on 'Status dystonicus'.)
Focal dystonia in children — For children with isolated cervical dystonia, which is rare in childhood, or other types of isolated focal dystonia, BoNT injections are considered first-line therapy, as in adults (algorithm 1). (See 'Botulinum toxin injections' below.)
If BoNT injections are not tolerated or injections are not feasible, oral medications can be tried. We typically use an anticholinergic drug such as trihexyphenidyl or benztropine first. For those who do not respond to or tolerate anticholinergic therapy, benzodiazepines or baclofen can also be tried. Often, larger doses of these medications are required for improvement, and they are mostly well tolerated in the pediatric population. (See 'Anticholinergic therapy' above and 'Second-line medications' above.)
We suggest bilateral DBS of the internal globus pallidus (GPi) for children with debilitating isolated cervical dystonia or other types of isolated focal dystonia who do not respond to or tolerate BoNT treatment or oral pharmacologic therapy, including levodopa. (See 'Surgical therapy' below.)
ADULTS —
Most dystonia presenting in adulthood is isolated and either focal or segmental. Cervical dystonia is the most common isolated dystonia in adults seen in clinical practice, and botulinum toxin (BoNT) injections are the preferred approach (algorithm 2). Oral medications and deep brain stimulation (DBS) play a secondary role for refractory disease and for adults with generalized dystonia.
Role of levodopa trial — A levodopa trial is suggested for certain adults with isolated, idiopathic focal or generalized dystonia, since adult onset, although atypical, is part of the phenotype of dopa-responsive dystonia (DRD), and some adults may respond favorably. In particular, a levodopa trial is appropriate in patients with a family history of DRD or parkinsonism and for those in whom the dystonia may have been present since childhood or adolescence. Dosing is reviewed above. (See 'Levodopa trial' above.)
DRD is discussed in greater detail separately. (See "Etiology, clinical features, and diagnostic evaluation of dystonia", section on 'Dopa-responsive dystonia'.)
Focal dystonia — BoNT injection therapy is the treatment of choice for adults with cervical dystonia as well as other forms of focal dystonia (algorithm 2).
Treatment of cervical dystonia is reviewed separately. (See "Cervical dystonia: Treatment and prognosis".)
Botulinum toxin injections — BoNT is a potent neurotoxin produced by Clostridium botulinum that causes regional muscle weakness through its action as a zinc endopeptidase that cleaves specific proteins involved in vesicular fusion. Disruption of these fusion proteins interferes with the release of acetylcholine at the neuromuscular junction, resulting in localized muscle weakness.
Dosing and side effects — In the United States, four different forms of BoNT type A (BoNT-A) are marketed, which are designated abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), onabotulinumtoxinA (Botox), and daxibotulinumtoxinA-lanm (Daxxify) [21,22]. Type B BoNT (BoNT-B) is designated rimabotulinumtoxinB (Myobloc). Each of these products is a unique drug with regard to formulation, potency, and dosing [23].
There is no unique dose ratio to permit switching among the available BoNT products [24]. However, clinical trial experience suggests that treatment can be switched between onabotulinumtoxinA and incobotulinumtoxinA using a 1:1 conversion ratio [25]. Similarly, onabotulinumtoxinA may be converted to daxibotulinumtoxinA using a 1:1 ratio, although guidelines are not available, and clinicians should use their best judgment when attempting conversions. Dosing equivalency between rimabotulinumtoxinB and various BoNT-A formulations has not been well established. There is little evidence to support the use of one brand over another, and rotating brands or serotypes is not recommended except for reasons of insurance coverage or patient preference.
There is no consensus regarding standard practices for BoNT injections, including dilution ratios for the different BoNT products, the dose per injection, the total dose per muscle, the number of injections at each site, or the methods of targeting injections (eg, whether guided by vision and palpation, electromyography, electrical stimulation, or ultrasound) [23]. All of these parameters vary among practitioners and centers.
Side effects with BoNT treatment are frequent but typically mild and transient. Systemic side effects such as clinical botulism are infrequent at typically prescribed doses. In the systematic reviews of BoNT for cervical dystonia, adverse events that were significantly more frequent with BoNT-A compared with placebo injections were diffuse weakness/tiredness and dysphagia; other adverse events included neck weakness, dry mouth/sore throat, and voice changes/hoarseness [26]. Adverse events associated with BoNT-B treatment included dysphagia and dry mouth [27]. These side effects are clearly related to the mechanism of action of BoNT. They are attributable to excessive weakness in injected muscles or to diffusion of toxin into nearby structures. In order to effectively use BoNT for any form of dystonia, it is crucial that the injector has knowledge of the functional anatomy of the area involved in order to inject the appropriate muscle, and to avoid nearby structures, such as the apex of the lung, carotid artery, or brachial plexus in the case of cervical dystonia.
Efficacy — Both BoNT-A and BoNT-B are more effective than placebo or oral anticholinergic therapy for the treatment of cervical dystonia [26-29]. (See "Cervical dystonia: Treatment and prognosis", section on 'Efficacy'.)
BoNT-A is the preferred first-line therapy for other types of focal dystonia, including blepharospasm, focal upper limb dystonia (eg, writer's cramp), and adductor laryngeal dystonia (ie, adductor spasmodic dysphonia) [30-32]. Abductor spasmodic dysphonia (ie, abductor laryngeal dystonia) responds less predictably [32]. RimabotulinumtoxinB is typically reserved for patients who develop clinical resistance to BoNT-A, as the higher acidity of this formulation may cause increased pain during the injection.
●Blepharospasm – A systematic review by the American Academy of Ophthalmology identified two placebo-controlled randomized trials (n = 194) and four blinded comparative trials (n = 719) of different types of BoNT-A for blepharospasm in adults [33]. The review concluded that periocular BoNT-A injections are more effective than placebo for reducing blepharospasm severity based on standardized rating scales and that the three types of BoNT-A (onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA) have similar efficacy. In the largest placebo-controlled trial, patients treated with incobotulinumtoxinA improved by 0.8 points on a 4-point severity scale from a baseline score of 3.1 (adjusted mean difference compared with placebo 1.0 points, 95% CI 0.5-1.4) [34]. The most common adverse effects of injections were eyelid ptosis (19 versus 6 percent in placebo group), dry eye (19 versus 12 percent), and dry mouth (15 versus 3 percent). Lower-quality data suggest that pretarsal injections are associated with higher response rates than preseptal injections (figure 1), and that efficacy can be maintained with repeated injections for at least 10 years [33].
●Focal upper limb dystonia – A trial randomly assigned 40 patients with writer's cramp to treatment with either BoNT-A or placebo injections [35]. At 12 weeks, the proportion of patients who reported a beneficial effect and chose to continue treatment (the primary outcome measure) was significantly greater in the BoNT-A group than the placebo group (70 versus 32 percent). In addition, improvement on most, but not all, of the clinical rating scales favored BoNT-A treatment. Transient hand weakness, generally mild, was a side effect of BoNT-A in 75 percent. BoNT has also been used to treat dystonic tremor associated with upper limb dystonia [36].
●Spasmodic dysphonia – In a double-blind trial involving 13 patients with adductor-type laryngeal dystonia, seven patients were treated with BoNT-A and six received saline [37]. There was significant benefit for several outcomes in the BoNT-A group, including quantitative measures of voice function and subjective patient ratings. Likewise, a meta-analysis published in 2019 suggests BoNT injections improved voice-related quality of life in patients with adductor spasmodic dysphonia [38]. Most patients with spasmodic dysphonia may require smaller BoNT doses over time [39].
In a trial of 15 patients with abductor spasmodic dysphonia that compared different injection techniques of BoNT-A into the posterior cricoarytenoid muscle, improvement with BoNT-A injections was reported by 11 patients [40]. However, blinded assessment by speech pathologists found no statistically significant objective benefit with either BoNT-A injection technique. In addition, there were no differences between techniques.
Loss of clinical response — Most patients with dystonia continue to respond to long-term treatment with BoNT [41]. However, the absence or loss of treatment response to BoNT can occur for a variety of reasons, including inadequate dose, inappropriate muscle selection, concurrent drug therapy, or a change in disease state [42].
Several observational studies of the long-term effect of BoNT demonstrate continued efficacy over at least 1 year and up to 10 years [43-45]. However, for those patients who experience suboptimal benefits from BoNT therapy, limited data suggest that physical therapy can be considered as adjunct treatment [46,47].
Neutralizing antibodies — Antibodies against BoNT (referred to as "neutralizing antibodies") can be detected in a proportion of patients treated with BoNT. However, the clinical significance of such antibodies is not clear, and data on the correlation between antibodies and clinical response are mixed [42,48-50]. Therefore, we do not routinely measure antibodies. A clinical test, such as a unilateral brow injection, is a better test of unresponsiveness and may be used to determine the clinical significance of antibodies, if necessary.
Neutralizing antibodies have been reported in association with nearly all BoNT formulations, with a prevalence of approximately 10 to 15 percent among patients treated chronically with abobotulinumtoxinA [51,52] and as high as 42 percent among patients treated with BoNT-B [49]. IncobotulinumtoxinA and onabotulinumtoxinA have been associated with the lowest rates of neutralizing antibody formation (<1 percent) [52,53]. The immunogenicity of daxibotulinumtoxinA is not yet determined [50].
At least one study has suggested that neutralizing antibodies can be clinically relevant in patients with cervical dystonia [54]. The antibodies were correlated with worse head position and pain, and the need for higher doses of BoNT-A when compared with patients without the antibodies.
Second-line therapies — Most patients with focal dystonia continue to respond to long-term treatment with BoNT [41]. For those who fail to respond or who do not tolerate injection therapy, oral medications can be tried, although the therapeutic window is narrow, and side effects are often dose limiting.
We generally use clonazepam as a first-line therapy in most adults and consider anticholinergic drugs, vesicular monoamine transporter type 2 (VMAT2) inhibitors, and baclofen to be second-line options (algorithm 2). Dosing and administration in adults are reviewed below. (See 'Oral medications' below.)
Adults with debilitating isolated cervical dystonia who do not respond to or tolerate BoNT or oral medications should be referred to a multidisciplinary movement disorder clinic for discussion of surgical options such as bilateral DBS of the internal globus pallidus (GPi). (See 'Surgical therapy' below.)
Generalized dystonia in adults — Symptomatic oral medication trials play a role in adults with generalized dystonia and those with focal dystonias who do not have access to BoNT therapy. For medication-refractory generalized dystonia, surgical therapy is beneficial in appropriate candidates.
Oral medications — We generally use clonazepam as a first-line oral medication for dystonia in adults, since trihexyphenidyl and other anticholinergic drugs tend not to be as well tolerated in adults compared with children (algorithm 2). Low doses of trihexyphenidyl or baclofen are reasonable to try as an alternative second-line therapy. A VMAT2 inhibitor such as tetrabenazine may be beneficial for adults with debilitating generalized isolated dystonia, although careful monitoring for side effects, including depression, is necessary.
●Clonazepam – Clonazepam may be particularly beneficial for patients who note worsening of dystonia with stress and anxiety, although this has not been studied formally. In uncontrolled studies, clonazepam improves symptoms of dystonia in approximately 20 percent of patients at doses ranging from 1.5 to 12 mg per day [6]. In a review of 206 patients with dystonia receiving oral treatment, clonazepam was associated with the most favorable response rate (40 percent), followed by baclofen (20 percent) and trihexyphenidyl (20 percent) [55].
A reasonable starting dose of clonazepam for dystonia in most adults is 0.5 mg once a day, given before bedtime. The dose may be slowly increased in 0.5 mg increments every week, with daytime dosing added once it is clear that the evening dose is tolerated. Daily doses above 0.5 to 1 mg are typically divided twice or three times daily. Adverse effects from clonazepam include sedation, depression, confusion, and dependence.
Clonazepam should not be stopped abruptly due to risk of withdrawal symptoms. When possible, the dose should be tapered slowly over the course of weeks to months.
●Anticholinergic drugs – For adults, the typical starting dose of trihexyphenidyl is 1 mg twice daily. The dose can be gradually increased in 2 mg increments at intervals of three to seven days until sufficient improvement or unacceptable side effects occur. Full benefit from gradual dose escalation may be delayed for several weeks or months [11].
The drug label suggests a maximum total daily dose (given in three or four divided doses) of 15 mg daily for adults and 6 to 10 mg daily for older adults. However, some patients with dystonia may tolerate a higher dose if needed to control symptoms.
Narrow-angle glaucoma, confusion, and dementia are contraindications to the use of trihexyphenidyl in adults. Trihexyphenidyl should be used with caution in people over 60 years of age and in patients with benign prostatic hypertrophy or obstructive gastrointestinal disorders. Other side effects are reviewed above. (See 'Trihexyphenidyl' above.)
Supporting evidence for trihexyphenidyl in adults with dystonia is scant [4,56]. A trial of nine adult patients with cranial dystonia found no benefit for trihexyphenidyl or a peripheral anticholinergic agent compared with placebo [12]. A separate open-label study reported that anticholinergic treatment for dystonia was effective in a greater proportion of children than adults, probably because children were able to tolerate higher doses [10].
●VMAT2 inhibitors – Tetrabenazine is a VMAT2 inhibitor and combines monoaminergic depletion and dopamine antagonist effects. Evidence from small trials and case series suggests that tetrabenazine is beneficial in a variety of hyperkinetic movement disorders, including dystonia [55,57-60]. However, it is seldom used for the treatment of dystonia because of the adverse effect profile.
When used, tetrabenazine is initiated with 12.5 mg daily for one week and increased by 12.5 mg increments every week, according to clinical response and as tolerated, to a level of 75 to 150 mg daily.
Side effects of tetrabenazine are frequent and include sedation, parkinsonism, depression, akathisia, nervousness, orthostatic hypotension, and insomnia. Patients should be warned specifically that severe depression can occur and that they should notify their clinician if signs or symptoms of depression or suicidality develop.
Tardive dyskinesia has not been associated with tetrabenazine, probably because its site of action is the presynaptic nerve terminal. It has no dopamine receptor blocking properties.
The safety, tolerability, and efficacy of the newer VMAT2 inhibitor deutetrabenazine has been evaluated for its use in isolated, non-dopa-responsive dystonia [61]. Valbenazine may have a role in the management of cranial dystonias including cervical dystonia. (See "Cervical dystonia: Treatment and prognosis", section on 'Second-tier oral medications'.)
●Baclofen – Patients who are unable to tolerate the sedative effect of clonazepam, or who have coexisting spasticity, can consider a trial of baclofen. In adults, baclofen is usually started at 10 mg at night and increased by 5 to 10 mg daily every three to four days as tolerated up to a usual maximum total daily dose of 80 mg/day, divided in three doses.
Baclofen appears to be less effective in adults compared with children. In a review that included 60 adults with focal cranial dystonia, sustained benefit was observed in 18 percent [14].
●Others – Several other medications are under investigation for dystonia but are not routinely used.
•Zolpidem has been reported to improve dystonia in patients with blepharospasm, Meige syndrome, myoclonus dystonia, DYT6, musician's dystonia, and X-linked dystonia-parkinsonism in small series and single cases [62-67]. A 2019 literature review highlighted the need for randomized trials and long-term follow-up to define the role of this agent in the treatment of dystonia [68].
•Sodium oxybate treatment was associated with improved voice symptoms in a small open-label study of patients with spasmodic dysphonia [69] and in a follow-up placebo-controlled randomized trial in 106 patients [70]. Sodium oxybate may act upon abnormal neural activity within the dystonic network (in particular, it may attenuate hyperfunctional activity of cerebellar, thalamic, and primary/secondary sensorimotor cortical regions) [71]. It remains to be demonstrated whether other dystonic disorders that are responsive to ethanol (like myoclonus dystonia) would respond to sodium oxybate as well [72], but there is emerging evidence to suggest this [73]. Sodium oxybate is a controlled substance, and the side effect profile can be limiting. (See "Treatment of narcolepsy in adults", section on 'Oxybates'.)
•Dopamine receptor blockers such as clozapine can be beneficial in some patients with dystonia [74,75]. However, this class of medications is not recommended for the treatment of dystonia because of the associated risk of tardive dyskinesia, a disorder that may be disabling and irreversible. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis".)
Refractory disease — In patients with generalized dystonia, BoNT injections of selected areas that are the most troublesome may be beneficial [76]. However, it is not reasonable to use widespread BoNT injection treatment for all symptoms of generalized dystonia because of dose limitations. (See 'Botulinum toxin injections' above.)
We suggest bilateral DBS of the GPi for adults with debilitating generalized isolated dystonia who do not respond to or tolerate pharmacologic therapy or BoNT, and who are appropriate candidates for the procedure. (See 'Deep brain stimulation' below.)
SURGICAL THERAPY —
Surgical treatment is reserved for patients with dystonia who fail treatment with pharmacologic agents and botulinum toxin (BoNT) injections. The mainstay of surgical treatment is microelectrode deep brain stimulation (DBS) of the internal segment of the globus pallidus.
Intrathecal baclofen is sometimes used in patients with dystonia and elements of spasticity, although not often in adults. (See "Cerebral palsy: Treatment of spasticity, dystonia, and associated orthopedic issues", section on 'Intrathecal baclofen'.)
Deep brain stimulation — Among surgical therapies, DBS of the internal globus pallidus (GPi) has emerged as the treatment of choice for children and adults with disabling isolated generalized or cervical dystonia who do not respond to pharmacologic therapy or chemodenervation with BoNT [77-86]. Although it is technically possible to implant younger children, most centers in the United States will consider DBS for children aged five years and above.
One of the larger controlled trials of DBS randomly assigned 40 patients (18 to 75 years old) with segmental or generalized isolated dystonia to either GPi stimulation or sham stimulation [87]. Two investigators, who were blind to both group assignment and to chronologic order of the examinations, assessed the severity of dystonia by reviewing videotaped sessions of patients made at baseline and after treatment. The primary endpoint was the change from baseline in the movement subscore on the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The following observations were reported:
●At three months, improvement in the severity of symptoms on the BFMDRS movement subscore was significantly greater in the GPi stimulation group than in the sham stimulation group (-15.8 versus -1.4 points). DBS was significantly more effective than sham stimulation for reduction in disability and improvement in the physical aspects of quality of life.
●In the GPi stimulation group, a positive response to treatment (ie, a >25 percent reduction in the BFMDRS movement subscore) at three months was observed in 15 patients (75 percent).
●During a six-month open-label extension period, patients originally assigned to sham stimulation had a similar benefit when switched to active treatment. In addition, improvement was sustained among patients originally assigned to GPi stimulation. During the extension phase, dysarthria (n = 5) and infection at the stimulator site (n = 4) were the most frequent adverse events. There was one lead dislodgement.
●A longer open-label extension study included 38 patients from the parent trial, all on active stimulation, and reported significant improvement in dystonia at three to five years compared with baseline [88]. There were 21 serious adverse events, mostly related to the device, and one attempted suicide. In 10-year follow-up data on 31 patients, benefits were sustained in many patients, although one-third of patients had discontinued DBS due to side effects [89].
Other long-term data regarding the utility of DBS for dystonia are limited [81,89-93].
Genetic forms of dystonia have been reported to respond differently to DBS [94]. Whereas DYT-TOR1A and DYT-SGCE tend to have excellent, sustained responses, DYT-TAF1 and DYT-THAP1 can have variable responses, and DBS is contraindicated in patients with DYT-ATP1A3 [95]. Positive responses to DBS have also been reported in patients with DYT-GNAL, an adult-onset cranial-cervical dystonia [96].
Accurate placement of stimulating electrodes in the area of the intercommissural plane provides for optimal outcome in generalized dystonia [97]. Specific locations in the GPi should be targeted for dystonia in specific body regions, reflecting the somatotopic organization of that structure [98].
Although not mentioned in the larger prospective trials, several smaller reports have observed the development of bradykinetic movement disorders including micrographia, parkinsonism, and hypokinetic gait in patients with dystonia who were treated with DBS of the GPi [99-103]. In one of the larger studies that retrospectively analyzed 71 such patients who had no gait disorder due to dystonia before treatment, a new gait disorder developed after bilateral DBS in six patients (8 percent) [102]. The gait disorder was reported at three to six months after DBS surgery and was characterized by shuffling steps and difficulty with gait initiation and turning. Freezing of gait developed at higher voltages but resolved within minutes of stopping stimulation. In all cases, electrode misplacement was ruled out as a cause for the gait disorder. Because all six patients otherwise showed benefit, the DBS settings were adjusted to achieve an optimal balance between controlling dystonia and eliciting freezing of gait.
Although less well studied than the GPi, the subthalamic nucleus (STN) is a promising alternative target for DBS in patients with isolated dystonia [104-107]. The long-term benefit from bilateral STN-DBS in adults with either cervical or generalized dystonia may be similar in magnitude and safety to that of GPi-DBS [108-111]. Whether targets like the globus pallidus externa (GPe) or the ventral oralis (VO) nucleus of the thalamus will have a role in the treatment of dystonia remains to be established [112].
DBS has not been consistently effective for the treatment of acquired dystonia, although small case series and case reports indicate improvement in some patients with various types of acquired dystonia [86,113-118]. One series of six patients with pantothenate kinase-associated neurodegeneration reported that GPi stimulation was associated with major improvement in all six [116].
Other approaches — Bilateral thalamotomy was used in the 1960s and 1970s for generalized dystonia. However, permanent and serious complications from the procedure (hemiparesis, spasticity, ataxia, dysphagia, and dysarthria) were prohibitive. Since the advent of DBS, stereotactic thalamotomy, pallidotomy, and cervical rhizotomy are only occasionally used to treat refractory dystonia.
Pallidotomies performed under magnetic resonance imaging (MRI) guidance using high-intensity focused ultrasound (FUS) are under study for the treatment of dystonia [119,120]. FUS thalamotomy has been reported for the treatment of musician's dystonia [121], focal hand dystonia [122], and cervical dystonia. (See "Cervical dystonia: Treatment and prognosis", section on 'Others'.)
INVESTIGATIONAL THERAPIES —
Novel approaches to the treatment of dystonia include gene therapy and transcranial magnetic stimulation.
●Gene therapy – In patients with DYT-TOR1A dystonia, gene editing using CRISPR-Cas9 aims to selectively disrupt the mutant TOR1A allele, which could, in turn, allow the remaining wildtype torsinA to exert its normal function in vivo [123]. The technique of ribonucleic acid interference (RNAi) is another promising avenue of therapy [124]. Using this method, it is possible to inhibit gene expression by inhibiting or degrading the targeted messenger RNA.
Gene silencing mediated by RNAi is particularly relevant to treatment of DYT-TOR1A dystonia, which arises from a single gene mutation and is primarily a disorder of neuronal function rather than neuronal degeneration. In one study, investigators successfully developed viral mediated RNAi and effectively silenced the expression of mutated torsinA [124]. This technique has not yet been applied to humans.
●Transcranial magnetic stimulation – Repetitive, low-frequency transcranial magnetic stimulation can enhance intracortical inhibition and has been evaluated for focal hand dystonia [125,126] and cervical dystonia [127] in small controlled trials, but additional investigations are needed [128].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dystonia in children and adults".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Dystonia (The Basics)")
SUMMARY AND RECOMMENDATIONS
Children and adolescents
●Levodopa trial – For children with idiopathic focal or generalized dystonia, we recommend a trial of levodopa to confirm or exclude the diagnosis of dopa-responsive dystonia (DRD). (See 'Levodopa trial' above.)
●Symptomatic therapy – Children with multifocal or generalized isolated dystonia who do not respond to levodopa can be treated with other oral medications (table 1), botulinum toxin (BoNT) injections, or deep brain stimulation (DBS) in refractory cases (algorithm 1):
•Oral medications – For most children and adolescents with debilitating generalized isolated dystonia that does not respond to a trial of levodopa, we suggest initial treatment with an anticholinergic drug such as trihexyphenidyl (Grade 2C). Second-line oral therapies include baclofen and benzodiazepines. (See 'Anticholinergic therapy' above.)
•Role of BoNT injections – For children and adolescents who have debilitating multifocal or generalized isolated dystonia that does not respond to pharmacologic treatment, and for those with focal dystonia, we suggest BoNT injections of selected muscles that are most troublesome (Grade 2C). However, widespread injections are not a reasonable option for multifocal or generalized dystonia. (See 'Refractory disease' above and 'Focal dystonia in children' above.)
•Surgical options – For children with debilitating isolated dystonia who do not respond to pharmacologic therapy or BoNT injections, we suggest referral to a multidisciplinary movement disorders clinic for consideration of bilateral DBS of the internal globus pallidus (GPi). Bilateral DBS of the subthalamic nucleus (STN) is a reasonable alternative in selected cases. (See 'Deep brain stimulation' above.)
Adults
●Role of levodopa trial – Although adult onset of DRD is atypical, we suggest a levodopa trial for most adults with idiopathic focal or generalized dystonia. However, there is no consensus regarding a trial of levodopa for adults in this setting. (See 'Role of levodopa trial' above.)
●Cervical dystonia – BoNT injections are the mainstay of therapy for cervical dystonia. Oral medications are used in patients who cannot receive injections and for those with an inadequate response to first-line therapy. (See "Cervical dystonia: Treatment and prognosis", section on 'Goals and approach'.)
●Other focal dystonias – For adults with blepharospasm, focal upper limb dystonia (including writer's cramp), and adductor spasmodic dysphonia (adductor laryngeal dystonia), we recommend BoNT injection therapy (Grade 1B). (See 'Focal dystonia' above.)
●Role of oral medications – Symptomatic medication trials play a role in adults with generalized dystonia and those with focal dystonias who do not have access to BoNT therapy (algorithm 2). (See 'Generalized dystonia in adults' above.)
•For most adults with refractory generalized dystonia, we suggest first-line therapy with a benzodiazepine such as clonazepam (Grade 2C). Low doses of trihexyphenidyl or baclofen are alternative second-line therapies. (See 'Oral medications' above.)
•A vesicular monoamine transporter type 2 (VMAT2) inhibitor such as tetrabenazine may be beneficial for adults with debilitating generalized isolated dystonia, although careful monitoring for side effects, including depression, is necessary.
●Refractory dystonia – For adults with debilitating generalized dystonia or other types of focal/segmental isolated dystonia who do not respond to oral pharmacologic therapy or BoNT injections, we suggest referral to a multidisciplinary movement disorders clinic for consideration of bilateral DBS of the GPi. (See 'Deep brain stimulation' above.)
