Dystonia Treatment: Current Approach and Future Directions

Dystonia is characterized by sustained or intermittent involuntary co-contraction of agonist and antagonist muscles, leading to abnormal movements, postures, or both. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. The movements associated with dystonia are typically patterned or twisting and may be tremulous.¹

The treatment of dystonia has evolved over the years. This progress in therapeutic modalities is reflected in the wide variety of available treatments, including oral pharmacotherapy, botulinum toxin (BTX) injections, neuromodulation, and surgical lesioning. The treatment options are split into 2 categories: 1) etiologic and 2) symptomatic. Symptomatic treatments are more commonly used, but several conditions have specific treatments that can modify the course of the disease if identified and treated in time (see Table).

During assessment of the individual with dystonia, it is imperative to recognize the broader therapeutic goals beyond addressing abnormal movements. Symptomatic treatment should always include treating pain, spasms, functional capacity, and psychiatric comorbidities.^2,3 By considering the multifaceted nature of the disorder, clinicians can tailor interventions to enhance overall well-being. Clinicians need to pay special attention to the factors that cause individuals with dystonia to seek clinical care.

Another aspect of management that should not be overlooked is the treatment of other phenomenologic aspects of the dystonic syndrome. Several of the genetic forms of dystonia are associated with myoclonus, parkinsonism, or ataxia, and treatment of those features is important to improve functional status.^4,5

In this review, we focus on symptomatic treatment that can be used in the majority of individuals with dystonias. The Table includes a quick reference guide of some of the treatable etiologies, and the Figure serves as a general algorithm for dystonia treatment.

Some general rules to consider in the treatment of dystonia include the following:

• Younger individuals can tolerate higher doses of oral pharmacologic agents than can older individuals.⁶
• In cases in which 1 or 2 contiguous body parts are affected by dystonia (focal or segmental dystonia, respectively), BTX is commonly the most effective treatment and should be considered as the first approach to treatment.⁷
• Surgical treatment and neuromodulation are adjuvant therapies rather than replacements for pharmacologic treatment; most individuals still require oral medication or BTX injections to achieve optimal outcomes.⁸

Oral Pharmacologic Treatment

The principle to remember when using systemic drugs is to “start low and go slow.”⁹ All drugs should be started at the minimum dose and titrated in small increments until sufficient symptom control is achieved with the least bothersome side-effect profile. Dose increases can be made every 3 to 4 days in children and every 7 days in adults. With every titration step, 2 to 4 weeks may be needed to observe complete therapeutic effect. If patients experience intolerable side effects, downtitration of the dose is recommended.¹⁰ In case of inadequate benefit or unacceptable side effects, adding a different medication or another form of treatment is an option.¹¹ Efficacious oral pharmacologic agents typically target the dopaminergic, cholinergic, or GABAergic networks.

Levodopa and Dopamine Agonists

Any individual in the pediatric age group and any adult with focal dystonia should receive an initial treatment trial with levodopa. About 5% to 10% of dystonias that begin in childhood are dopamine-responsive dystonias (DRDs), and levodopa has a dramatic and sustained effect on symptoms.¹² DRD is an inherited syndrome caused by several genetic sequence variations that lead to decreased dopamine synthesis or impair its signaling pathways. The levodopa dose needed to achieve dramatic and sustained results is often very low compared with the doses used for treatment of Parkinson disease.¹³

Levodopa should be started at a small dose of 50 mg 3 times per day and gradually increase up to a dose of 600 to 1000 mg in adults and 20 mg/kg in children.¹⁰ The mean dose to obtain a good response in individuals with DRD is 375 mg daily.² The levodopa trial may be extended for 3 months. In the absence of a clear benefit with levodopa or dopamine agonist, investigation for an alternative etiology is indicated.⁶

In addition to DRD, levodopa may have a substantial effect on dystonia symptoms in individuals with dystonia-plus syndromes, such as spinocerebellar ataxia type 3¹⁴ or PRKN2 sequence variation.¹⁵ Individuals with PRKN2 sequence variation will eventually manifest levodopa-induced dyskinesia, which is less likely in individuals with true DRD.¹² Other forms of dystonia can have a mild to modest improvement with levodopa treatment, such as some cases of TOR1A sequence variation,¹⁶ PDH1 deficiency,¹⁷ or structural basal ganglia lesions.¹⁸

Anticholinergics

Anticholinergics are highly effective oral drugs for the treatment of dystonia and often are the first choice in individuals with idiopathic dystonia.¹⁹ Titration must be very slow, with small dose increases in 1-week intervals. The most studied drug in this class is trihexyphenidyl, which can be started with 1 mg at bedtime and then increased slowly to 6 to 8 mg/d divided in 3 or 4 doses, which is the lowest dose expected to be beneficial. After that, it can be slowly increased up to 100 mg total per day depending on the individual’s response and presence of side effects.¹⁰ Trihexyphenidyl is effective in about two-thirds of individuals with generalized dystonia at a mean dose of 30 mg/d.²⁰

The primary concern with anticholinergic drugs is the wide prevalence and severity of side effects, particularly in older individuals. Anticholinergic drugs can cause cognitive impairment, hallucinations, blurry vision, and urinary retention.¹² Children can tolerate titration to higher doses and greatly benefit from them.

GABAergic Drugs

Baclofen, a GABA-B receptor agonist, is less effective than anticholinergic drugs in general, but is helpful in individuals who have generalized dystonia or a focal dystonia other than cervical dystonia.²¹ Baclofen is usually taken orally, although some individuals with generalized dystonia who have some response to oral baclofen can be treated with an intrathecal baclofen pump. Baclofen is also effective for spasticity, making it an option for individuals with spasticity and dystonia or those who have truncal or lower extremity dystonia that does not respond well to other therapies.²²

Benzodiazepines are also commonly used to treat dystonia, clonazepam in particular, because of its long half-life. The most common side effect of drowsiness should be considered alongside any treatment benefit benzodiazepines may provide. Long-acting benzodiazepines are particularly effective in individuals with SGCE (formerly DYT11) myoclonus-dystonia syndrome.¹¹ The risk of substance abuse should be considered while prescribing benzodiazepines in patients with cervical dystonia. This risk is higher in younger males with a diagnosed psychiatric disease.²³

Botulinum Toxin

BTX acts at the neuromuscular junction by cleaving a vesicle-fusion protein, preventing the release of acetylcholine that would lead to muscle contraction. Different forms of BTX cleave different proteins within the same apparatus, effectively resulting in paralysis of the affected muscle fibers.²⁴ Three types of BTX type A are commonly used in the United States: onabotulinumtoxinA (Botox; Allergan/AbbVie, Chicago, IL), abobotulinumtoxinA (Dysport; Ipsen, Cambridge, MA), and incobotulinumtoxinA (Xeomin; Merz Pharmaceuticals, Raleigh, NC). The only form of BTX type B used in the United States is rimabotulinumtoxinB (Myobloc; Solstice Neurosciences, South San Francisco, CA).⁷

In dystonia, muscles undergo involuntary contractions as a result of disordered brain networks. As such, injecting the appropriate dose of BTX in the correct muscles can lead to considerable benefit without noticeable side effects. BTX is considered the most effective and well-tolerated treatment for dystonia overall, particularly for individuals with focal or segmental dystonias. The mechanism of action may also involve a central network modulation effect.^25,26

The specific muscles to inject depend on the individual’s presentation and our understanding of neuroanatomy. The use of EMG or ultrasound increases injection accuracy. The injection patterns are specific to the individual and often require trial and error. There are consensus guidelines on dosage and location that can be used as a starting point before being tailored to the individual’s primary complaint.⁷ In general, the first set of injections should start with a relatively low dose and a conservative choice of muscles. In subsequent injection sessions, the dose can be increased, and new muscles can be added to the regimen. In addition to benefit on motor severity, studies have demonstrated that BTX reduces pain and anxiety associated with dystonia.^27,28

BTX side effects may include reactions to the injections (eg, discomfort, infection, bleeding), excessive dose (eg, muscle weakness), or local spread of the toxin (eg, dysphagia when injecting the neck, dry eye when injecting close to the medial canthus).²⁹ Both the side effects and benefits of BTX are ephemeral. It takes about 5 to 7 days for the toxin to start showing benefit, with the best benefit around 4 to 6 weeks, and a duration of benefit of ~12 weeks.³⁰

Recently, daxibotulinumtoxinA (Daxxify; Revance Therapeutics, Nashville, TN), a new form of BTX type A, was tested in a phase III clinical trial in individuals with cervical dystonia, with an effect lasting from a mean of 20.3 to 24 weeks in 250- and 125–international unit groups, respectively.³¹ DaxibotulinumtoxinA was approved by the Food and Drug Administration (FDA) for the treatment of glabellar lines in 2022. In 2023, it received an expanded indication to treat cervical dystonia. An open-label trial analyzed the long-term effects after repeated injections of daxibotulinumtoxinA for a period of up to 88 weeks. Results demonstrated a median duration of benefit from 19.9 to 26 weeks (Long-Term Safety and Efficacy of Repeat Treatments of DaxibotulinumtoxinA for Injection in Adults With Isolated Cervical Dystonia [ASPEN-OLS], NCT03617367). The advantage of using a preparation that lasts longer is that injections are less frequent and it may be effective for patients who experience loss of benefit before the 3 month interval used for other forms of BTX. It is still unclear if the side effects of daxibotulinumtoxinA will last longer due to its extended benefit duration.

Neuromodulation

Deep Brain Stimulation

Deep brain stimulation (DBS) was approved by the FDA in 2003 for the treatment of dystonia under Humanitarian Device Exemption. DBS is useful to treat individuals with different forms of dystonia who have inadequate benefit or intolerable side effects from less invasive treatment.³

The globus pallidus pars interna (GPi) and the subthalamic nucleus are both common targets for treating dystonia with DBS. Although the GPi has been used as a target for a longer time, studies suggest comparable long-term efficacy in treating dystonia with DBS that targets the GPi or the subthalamic nucleus.³² The side effect profile, experience of the treating team, and well-informed patient preference may dictate the target. Individuals with predominantly dystonic tremor may benefit from targeting the ventral intermedius nucleus of the thalamus.³³ DBS may take weeks to months to demonstrate benefit with dystonia in contrast to the nearly instant changes observed with DBS treatment for essential tremor and Parkinson disease.³⁴ This might reflect long-term changes in network connections and plasticity-dependent effects rather than immediate correction of cortical physiology.³⁵

There is some benefit to requesting genetic testing before DBS for dystonia of unknown etiology.³⁶ Certain genetic forms of dystonia are known to respond better to DBS than others: for example, sequence variation of TOR1A (formerly DYT1), SCGE (myoclonus-dystonia syndrome), or TAF1 (X-linked dystonia parkinsonism). Other genetic sequence variations have less response to DBS, such as sequence variations of THAP1 (formerly DYT6) and ATP1A3 (rapid-onset dystonia parkinsonism).³⁷ Other factors that predict the effect of DBS are shorter duration of disease, younger age at onset, absence of severe psychiatric comorbidities, and greater baseline range of motion.³⁸ Among secondary dystonias, DBS has been shown to demonstrate benefit in individuals with medically refractory tardive dystonia.³⁹ The field of preoperative imaging to optimize sites and networks for maximum benefit is rapidly advancing.^40,41 More widespread use of advanced structural (7T MRI) and functional imaging (functional MRI, tractography) to improve surgical targeting and programming is anticipated in the future.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) consists of using a magnetic coil over the scalp to target the structure of interest based on anatomic landmarks. This modality has been used successfully to treat depression.⁴² TMS has been used in small studies to treat individuals with focal hand dystonia and cervical dystonia with results indicating some degree of transient improvement in symptoms. Some of these studies also showed changes in cortical excitability after the TMS sessions, which may reflect functional network changes.⁴³ Challenges associated with TMS include modeling the stimulated areas, defining the appropriate target, and developing an adequate outcome measure to gauge its effect.⁴⁴

Lesion Surgery

Pallidotomies and thalamotomies were some of the most effective treatments for dystonia, Parkinson disease, and tremor from the 1950s to the 1980s.⁴⁵ Pallidotomies have fallen in popularity since DBS became available, in part because the side effects of lesions are permanent, whereas DBS stimulation-related effects are reversible. The most common permanent side effects after bilateral pallidotomies are speech problems, facial weakness, and, rarely, limb paresis.⁴⁶ Pallidotomies remain an important tool in the treatment of status dystonicus, a life-threatening exacerbation of dystonia.⁴⁷ Long-term efficacy is often sustained, but several cases of re-emergence of symptoms that required DBS as a rescue measure have been reported.⁴⁸ Whether this represents true loss of benefit or underlying disease progression is not known. Although not approved by the FDA, the use of focused ultrasound to lesion the GPi has demonstrated some benefit with focal hand dystonia.⁴⁹

Complementary Treatment Modalities

Physical therapy and stretching exercises can improve range of motion in individuals with dystonia. When used in conjunction with BTX, physical therapy can improve pain, disability, and quality of life.^5,50 In addition, motor retraining has led to improvement of focal dystonia.⁵¹

Most people with dystonia try some form of complementary treatment, such as massage therapy, chiropractic treatment, biofeedback, or acupuncture.⁵² These therapies have low risk and potential benefit and can be attempted safely, although there is no scientific evidence that proves their benefit.

Individuals with dystonia have an increased risk of depression, anxiety, and fatigue. There are no known targeted treatments for these issues in people with dystonia, although treatment with BTX improves anxiety to some degree.²⁷ Individuals should be screened and treated using the same strategies used for people without dystonia, including cognitive behavioral therapy, selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors.⁵³

Summary

The management of dystonia calls for a multifaceted approach aimed at alleviating symptoms, improving functional capacity, and enhancing overall well-being. Symptomatic treatments, including systemic pharmacologic interventions, BTX injections, neuromodulation techniques, and physical therapy, play pivotal roles in addressing the diverse manifestations of dystonia. In addition to the search for efficacious pharmacotherapy, including better formulations of BTX, progress in brain stimulation procedures and modalities is anticipated to enable better care of individuals with dystonia.