Neurosurgical and pharmacological management of dystonia

Abstract

Dystonia characterizes a group of neurological movement disorders characterized by abnormal muscle movements, often with repetitive or sustained contraction resulting in abnormal posturing. Different types of dystonia present based on the affected body regions and play a prominent role in determining the potential efficacy of a given intervention. For most patients afflicted with these disorders, an exact cause is rarely identified, so treatment mainly focuses on symptomatic alleviation. Pharmacological agents, such as oral anticholinergic administration and botulinum toxin injection, play a major role in the initial treatment of patients. In more severe and/or refractory cases, focal areas for neurosurgical intervention are identified and targeted to improve quality of life. Deep brain stimulation (DBS) targets these anatomical locations to minimize dystonia symptoms. Surgical ablation procedures and peripheral denervation surgeries also offer potential treatment to patients who do not respond to DBS. These management options grant providers and patients the ability to weigh the benefits and risks for each individual patient profile. This review article explores these pharmacological and neurosurgical management modalities for dystonia, providing a comprehensive assessment of each of their benefits and shortcomings.

Key Words: Botulinum toxin, Magnetic resonance imaging-guided focused ultrasound, Surgical ablation, Deep brain stimulation, Peripheral denervation surgery, Antipsychotics

Core Tip: Dystonia is a neurological movement disorder affecting different regions of the body with variable responses to current interventions. Pharmacological agents, such as oral anticholinergic and botulinum toxin injection, play a major role in the initial treatment of patients. However severe and/or refractory cases require the identification and targeting of focal areas for neurosurgical intervention. Deep brain stimulation (DBS) targets these anatomical locations to manage symptoms. Surgical ablation procedures and peripheral denervation surgeries also offer potential treatment to patients who do not respond to DBS.

INTRODUCTION

Dystonia is the third most common movement related disorder, behind Parkinson’s and essential tremor[1]. Dystonia is defined by numerous characteristics including age of onset, region of body where symptoms occur, and pattern of occurrence[2]. Clinical manifestations of dystonia vary widely but are often characterized by contracted and slowed movements with associated jerky or rapid movements intermittently occurring[3]. It is estimated that 16.7% of patients will also have an observable tremor[4]. They can occur anywhere in the body and once they occur, they usually do not regress[3].

The incidence of dystonia is commonly debated but has been estimated to affect 16.43 per 100000[5]. The incidence rates rise as the subjects age, with a study showing that there were 743 cases per 100000 in patients over the age of 50[6,7]. Pairing this rate with the additional information that only 33% of the subjects being previously diagnosed suggests that the true prevalence of dystonia is higher than officially reported[6,8]. Dystonia is more commonly reported in patients that regularly partake in skillful, precise movements such as painting or playing golf[9]. Dystonia is also more likely to occur in females[10]. Dystonia is highly linked with sensory dysfunction as well and can present as decreased sensation to light touch and proprioception[11,12]. In certain instances of focal hand dystonia, vibration of the affected arm can actually induce dystonia.

Despite the symptoms being well described, the origin of dystonia disorders is not[13,14]. With that being said, there is mounting evidence that suggests there are specific genes that could potentially play a role in the development of dystonia, which vary with the location and subclassification of dystonia[13,15]. The most common cause of early onset dystonia is a deletion at position 302/303 of TorsinA, although the function of the gene itself is still largely unknown[16]. Additional non-genetic factors, including cigarette smoking and head/neck trauma, play a role in the pathogenesis [17,18]. Thirty percent of Parkinson’s patients have dystonia, suggesting there is genetic overlap with the two conditions which are often mistaken for each other[19].

With variable presentation and treatment response based on the affected region of the body, understanding management approaches and their efficacy is crucial in providing patients with dystonia the most suitable treatment options. This review will discuss pharmacological and neurosurgical management options for dystonia, highlighting the benefits and drawbacks of each management approach.

PHARMACOLOGICAL MANAGEMENT

Pharmacological management of dystonia traditionally consists of the use of anticholinergic drugs, baclofen, clonazepam, and other dopamine-related medications[20,21]. This review will also discuss the use of antipsychotics and botulinum toxin (BT) injections.

Anticholinergics

The most common anticholinergic drug used to treat dystonia is trihexyphenidyl[22]. It is a selective muscarinic acetylcholine receptor agonist that blocks cholinergic activity. It can also increase the availability of dopamine which plays a role in the initiation and control of muscle movements. The onset of action is about an hour after when administered orally, with a peak after 2-3 h, while the duration of action is between 6 h to 12 h[23]. Dosage begins at 1 mg per day and is raised until either a dose of 30 mg is achieved or adverse drug responses present[22]. A study on Dyt1 knocking mice (mice with the ΔE-TorsinA mutation which causes DYT1 dystonia) found that trihexyphenidyl can correct dopamine release in the mice indirectly through the use of a nicotinic receptor-dependent pathway[24]. Another study found that 20% of patients reported a favorable response when treated with the drug[25]. Despite the common use of trihexyphenidyl, there is literature that has shown that it may be ineffective in treating certain types of dystonia like cerebral palsy, although it did show promising results in the treatment of others like Costello syndrome[23,26]. Other anticholinergics have also been used such as benztropine, ethopropazine, procyclidine, and biperiden but did not show the same effectiveness as trihexyphenidyl[27].

Baclofen

Baclofen is a GABA-B agonist that binds to the pre-synaptic GABA-B receptors, leading to the hyperpolarization of the motor horn cells and reduction in the reflexes that lead to muscle spasms. Due to its inability to cross the blood-brain barrier, high doses of oral baclofen are required to reach therapeutic effects resulting in a greater possibility of adverse drug reactions such as muscle weakness, nausea, and dizziness. In contrast, intrathecal baclofen can bypass the blood-brain barrier, allowing for its administration at a lower dose. However, it is reserved for patients who experience intolerable adverse effects or fail to respond to the maximum recommended dose of oral baclofen[28]. It was found that the same proportion of patients reported a similar favorable response to baclofen as trihexyphenidyl[25]. It is administered 3 to 4 times per day. Dosage is started at 5 mg and increased by 5 mg per day for 3 d to 5 d until either a favorable effect is achieved or adverse drug reactions present[22].

Clonazepam

Clonazepam is the most commonly used benzodiazepine in the treatment of dystonia[22]. Clonazepam directly impacts the benzodiazepine receptors by impacting the GABAergic transmission in the brain. Administration begins at 0.5 mg and is increased to 1.0 mg to 4.0 mg, divided three times a day. Forty percent of patients reported a favorable response to Clonazepam[25]. Adverse effects include confusion, impaired coordination, depression, and dependence[22].

Dopamine-related medications

Some dystonia, such as dopamine-responsive dystonia, can be responsive to treatment with dopamine-related medications such as levodopa[22]. Levodopa is a precursor to dopamine[29]. Upon oral administration, much of the dose is decarboxylated to dopamine so only a small amount reaches the central nervous system. As a result, it is often prescribed with a dopa-decarboxylase inhibitor, like carbidopa, to reduce its conversion in peripheral tissue and reduce side effects. Administration is usually 100 mg tablets with a 100 mg increase every day up to 1200 mg daily to reach therapeutic effects[22]. There have also been instances in which treatment with levodopa has induced dystonia, specifically in patients with atypicalparkinsonism[30-32]. Slightly over 10% of patients reported favorable responses with levodopa[25].

Clozapine

There have also been several different studies that have utilized clozapine to treat dystonia and associated disorders[33-36]. Clozapine is an antipsychotic that will occupy dopamine D2 receptors and will be displaced after a rise in synaptic dopamine[37]. In one study, Clozapine was administered at 12.5 mg per day and was increased by 25.0 mg per day up to a total of 900.0 mg per day unless adverse drug reactions such as persistent symptomatic orthostatic hypotension or tachycardia presented. Of the five participants in the study, all had reached significant improvement in dystonia presentation by the third week, but only two continued to use the medication following the completion of the study[34]. The use of clozapine is limited due to its side effects and need for additional monitoring.

BT therapy

BT is commonly used for blepharospasm, adult spasticity, headache, and cervical dystonia treatment[38,39]. It is the treatment of choice for those with focal dystonia[40,41]. BT inhibits acetylcholine release in the α-motor neuron[42]. It is injected into muscles and produces a localized peripheral paresis[43]. Therapeutic effects usually manifest within 2 wk and will last for about 3 to 4 months[22]. Adverse effects include dry mouth, neck weakness, dysphagia, and voice changes/hoarseness. Most adverse effects were considered to be mild[41].

Certain types of dystonia had a more favorable response to BT injections. For instance, BT injection benefits lasted significantly longer in patients who used treatment for focal handdystonia[44]. There is also some evidence that BT type A could be affected by changes in the cerebral cortex[45]. In order to administer the toxin, ultrasound can be used. This allows the injector to clearly identify and inject the correct muscle rather than relying on blind injections. It also allows for the accurate administration of the drug to deeper muscles[46]. Unfortunately, there is a possibility of developing antibodies for BT, resulting in the need for more frequent injections[47].

NEUROSURGICAL MANAGEMENT

Neurosurgical management of dystonia is considered in cases that impact quality of life and activities of daily living, typically following a lack of response to pharmacological interventions[48]. Deep brain stimulation (DBS) is the mainstay of treatment, replacing previously common ablative procedures[49-52]. Along with DBS, other surgical procedures include pallidotomy, thalamotomy, and peripheral denervation[48].

DBS

The use of DBS for treatment of dystonia has been validated by several cohort studies, demonstrating significant improvements of symptoms from 3 months to up to 7 years[50,51,53,54]. Several target sites have been investigated for DBS treatment of dystonia, including the ventral intermediate nucleus of the thalamus, the subthalamic nucleus, and the globus pallidus pars interna (Figure 1)[55-59], with the primary target site being the globus pallidus pars interna[60-63]. Electrodes are implanted at sites relevant to muscle contractility such as the subthalamic nucleus and globus pallidus pars interna, exhibiting stimulatory effects on axon terminals, in turn, inducing neurotransmitter release[64]. This external source of activation stimulates the malfunctioning regions to produce their normal functions. The frequency of stimulation has the potential to alter both the rate and pattern of firing of the neurons in the area surrounding the electrode[65]. Adverse effects of treatment may include incoordination, postural instability, rigidity, dysphonia, dysarthria, paresthesia, perioral tingling, and micrographia. These effects are mediated by way of inadvertent targeting of neighboring structures around the globus pallidus pars interna, including the optic tract ventrally, internal capsule medially, and hypothalamus superiorly[66,67]. Other hardware related adverse events include infection of the skin or implant, malfunction related to internal pulse generator erosion of failure, and electrode or extension wire damage[68]. Battery life is an additional challenge of DBS, presenting with the most difficulty in pediatric cases where many battery changes are required over the course of their life and thus a higher risk of surgical complications is apparent[69,70]. The advent of rechargeable devices has somewhat alleviated this problem in both pediatric and adult populations, demonstrating lower complication rates and higher patient satisfaction[71,72]. DBS of the subthalamic nucleus and globus pallidus pars interna has also demonstrated favorable outcomes in patients who previously underwent pallidotomy but continued to present with progressive symptoms[73,74].

Figure 1 Tracts associated with optimal outcome for patients with cervical (left) and generalized (right) dystonia[85]. A: On a broader scale (slightly lower threshold), modulation of corticofugal tracts from the somatomotor head and neck region was associated with optimal outcomes in cervical dystonia, while tracts from the whole somatotopical domain were associated with generalized dystonia; B: On a localized level (slightly higher threshold), in cervical dystonia, striatopallidofugal tracts of the posterior comb system were associated with optimal outcomes. In contrast, fibers from the fasciculus lenticularis were negatively associated. In generalized dystonia, both pallidothalamic bundles (ansa and fasciculus lenticularis) were associated with optimal outcomes, as was a more anterior portion of the comb system; C: Across the cervical and generalized cohorts, the degree of how fittingly the identified networks were modulated by each patient’s E-field correlated with clinical improvements. While these correlation analyses are of circular nature, a permutation statistic (bottom) showed superior model fits for unpermuted vs permuted improvement values. Citation: Horn A, Reich MM, Ewert S, Li N, Al-Fatly B, Lange F, Roothans J, Oxenford S, Horn I, Paschen S, Runge J, Wodarg F, Witt K, Nickl RC, Wittstock M, Schneider GH, Mahlknecht P, Poewe W, Eisner W, Helmers AK, Matthies C, Krauss JK, Deuschl G, Volkmann J, Kühn AA. Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia. Proc Natl Acad Sci U S A 2022; 119: e2114985119. Copyright© The Authors 2022. Published by National Academy of Sciences of the United States (Supplementary material).

In pediatric patients, benefits following DBS have been reported 5 or more years following implantation[69]. The anatomical changes depending on the age of the child also pose difficulties as the anatomical structure is growing rapidly and altering the surgical target site. Intraoperative visualization of brain anatomy and site targeting require significantly increased precision to successfully localize DBS electrodes[75,76]. Furthermore, children may lack the appropriate endurance and communication abilities needed to determine the therapeutic window during the postoperative stimulation sessions[77]. Therefore, reaching stable stimulation settings may pose a greater limitation in the pediatric population. Pre- and post-operative measures of dystonic qualities must also be considered when assessing the validity of DBS. The Burke-Fahn-Marsden Dystonia Rating Scale, a universally applied scale for dystonia used for both adult and pediatric patients, may not properly delineate the difference between dystonic movements and movements of healthy, developing children[78,79]. For the pediatric patient specifically, multidimensional assessment of disability prior to and after neurosurgical intervention is necessary beyond the level of mere impairment-focused quantitative measures[80]. Long-term adverse effects of DBS should also be examined, as the duration of implantation increases with decreasing age. An additional consideration in the pediatric patient is requiring more battery changes for non-rechargeable devices over their lifetime, potentially increasing the complication rates[70]. In a 6-month pediatric follow-up study, 10.3% of implant participants experienced surgical site infections, most of them necessitating total removal of the device[81]. Another study with a longer 4.6-year average follow-up duration yielded similar results, with 9.7% of the cohort undergoing postoperative surgical intervention for wound infections[82]. More comprehensive reviews targeting the pediatric population should be implemented to assist physicians and caregivers in making informed decisions on utilizing DBS.

Electrode types for DBS are platinum-iridium wires and connectors made of nickel alloy encased in a sheath of polyurethane[83]. Electrode configurations vary based on contact number, shape, and spacing. Precise stimulation control is achieved with small contact spacing whereas a greater range of neural targets can be achieved with increased contact spacing. Stimulation types include unipolar, bipolar, interleaving, multiple level, and directional. Unipolar stimulation describes current movement directed either from the battery to the contact or from the contact to the battery. Bipolar stimulation describes current movement between at least one cathode and one anode contact. Interleaving stimulation describes a system of interchanging settings and multiple level stimulation allows for stimulation of several neuronal targets along the electrodes trajectory. Directional stimulation allows for current shaping. Directional stimulation has specifically demonstrated treatment efficacy and reduced adverse effects[84]. Because of the use of radially segmented contacts, directional stimulation enables horizontal plane movement of the stimulation field. In the context of directional stimulation, increasing contact numbers and current amplitudes must be weighed against their impact on treatment feasibility in the context of programming and hindrances on stimulation field shaping.

Surgical ablation

Ablation approaches include radiofrequency ablation, stereotactic radiosurgery, and magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS)[48,85-88]. The main concern for these procedures is the irreversible nature and potential damage of neighboring structures near the site of ablation. With the main target site being the thalamus, the surgical depth required carries an increased risk for damaging surrounding structures such as those of the optic tract, internal capsule, and hypothalamus[89]. Despite these concerns, recent studies emphasize the non-invasive nature of MRgFUS, highlighting the precision allowing for ablation of target tissue without damage to surrounding structures[90-93]. MRgFUS uses focused ultrasound waves to generate heat at the target area, resulting in coagulative necrosis which non-invasively destroys the targeted tissue. This is guided with high-resolution MRI imaging to allow clinicians to precisely visualize the target tissue and surrounding structures. The continuous monitoring and adjustment during the procedure maximizes safety and accuracy. Additionally, the development of dysarthria is an important, potentially irreversible side effect that may occur with bilateral ablation, most likely attributable to ventrolateral thalamic damage[52,94,95]. With the advent of DBS, surgical ablation may still be indicated in cases where patients are not eligible for DBS, such as limited access to postoperative programming, previous hardware complications, or previous infections[48]. In such cases, evaluation of the benefits and drawbacks of different surgical ablation techniques is required.

MRgFUS is a common option for surgical ablation, allowing for preoperative region mapping, non-invasive administration, and attenuation of damage to neighboring structures[96,97]. However, gait disturbances, paresthesias, and limb dysmetria are considerable side effects associated with this procedure, often due to the primary lesion itself or to perilesional edema[98-100]. MRgFUS may be the preferred technique for surgical ablation as more transient and less severe adverse effects have been reported compared with radiofrequency ablation[86,101,102]. For radiofrequency ablation, electrode placement requires craniotomy or a small burr hole[103,104]. However, recent trials have demonstrated safe bilateral lesioning with this technique[104]. Additionally, the capacity for region mapping prior to the procedure gives radiofrequency ablation an upper hand over stereotactic radiosurgery in preoperative surgical preparation. Although stereotactic radiosurgery provides a non-invasive alternative, radiation induced neurotoxicity is an additional accompanying drawback of the procedure[105-107]. MRgFUS coalesces both the region mapping abilities of radiofrequency ablations and decreased adverse effect profile of the stereotactic technique, placing it at the forefront of therapeutic options for patients with dystonia[108]. A pilot study investigated the efficacy of MRgFUS thalamotomy of the ventro-oral nucleus of the thalamus in 10 patients with focal hand dystonia (Figure 2). They reported significantly improved symptoms and only one serious adverse event (suicide attempt) related to previously concealed attempts and depression, in addition to mild dysarthria in one patient at 12 months (Figure 3). The study sample included professional musicians, writers, and dart-related dystonia. Researchers utilized three scales for quantifying patient clinical improvement: Writer’s Cramp Rating Scale, Tubiana Musician’s Dystonia Scale, and Arm Dystonia Disability Scale. All three scales demonstrated statistically significant improvement 12 months after treatment. These findings are critical in suggesting the potential benefits of MRgFUS utilization in patients with dystonia, underpinning its clinical efficacy and safety profile.

Figure 2 Representative magnetic resonance images obtained before and after treatment[86]. A and B: The lesion unexpectedly encroached on the posterior limb of the internal capsule (case 4: A; case 7: B); C: The precise lesion on the intended target. Citation: Horisawa S, Yamaguchi T, Abe K, Hori H, Fukui A, Iijima M, Sumi M, Hodotsuka K, Konishi Y, Kawamata T, Taira T. Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Focal Hand Dystonia: A Pilot Study. Mov Disord 2021; 36: 1955-1959. Copyright© The Authors 2021. Published by Movement Disorders published by John Wiley & Sons, Inc. (Supplementary material).

Figure 3 Changes in primary and secondary clinical endpoints during the study period[86]. Primary clinical endpoints were the scores of the Writer’s Cramp Rating Scale (WCRS; ranging from 0 to 30, with higher scores indicating greater severity) and Tubiana Musician’s Dystonia Scale (TMDS; ranging from 1 to 5, with lower scores indicating greater severity), which evaluate dystonia severity. Secondary clinical endpoint was the score of the Arm Dystonia Disability Scale (ADDS; ranging from 0% to 100%, with lower scores indicating greater disability) to evaluate dystonia disability. Significant improvements were observed in the WCRS, TMDS, and ADDS scores throughout the study period in group data (upper row). Individual data are shown in the lower row. Citation: Horisawa S, Yamaguchi T, Abe K, Hori H, Fukui A, Iijima M, Sumi M, Hodotsuka K, Konishi Y, Kawamata T, Taira T. Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Focal Hand Dystonia: A Pilot Study. Mov Disord 2021; 36: 1955-1959. Copyright© The Authors 2021. Published by Movement Disorders published by John Wiley & Sons, Inc. (Supplementary material).

Thalamotomy constitutes the main surgical ablation procedure for dystonia and has been evaluated in many controlled studies[109]. Small lesions of the thalamus appear reliable and even provide less risk of infection in comparison to DBS, the primary treatment for focal dystonia. Thalamotomy also provides permanent effects and is a more financially achievable technique than DBS. Pallidotomy has not been evaluated in any controlled studies for dystonia but has demonstrated efficacy in a number of case series[52,88,94]. Irreversible side effects remain a potential complication for any type of ablation procedure[109]. Because ablations for dystonia involve the severing of efferent nerve tracts including the pallidothalamic tract and ventral intermediate nucleus, absolute precision is required to mitigate the risk of dysphagia, dysesthesia, and local muscle atrophy can be a result of the procedure[110]. Besides the ventro-oral nucleus, other common sites of thalamotomy include the ventral intermediate nucleus and the globus pallidus pars interna.

Peripheral denervation surgery

The use of peripheral denervation surgery has demonstrated efficacy for treating cervical dystonia in several case series[111-114]. Peripheral denervation is a selective surgery that resects and avulses the specific nerves innervating the muscles responsible for dystonia. Short electrical stimulations are then used to identify other small nerve branches that could be supplementing dystonia symptoms. This is all done with respect to the accessory nerve to avoid post-operative shoulder weakness[111]. Targeted muscles are based on the dominant subtype contributing to symptoms and include muscles of the posterior neck and the sternocleidomastoid muscle[115-117]. Since it is an invasive option, it is typically implemented after conservative measures of treatment have proven ineffective or inappropriate. Additionally, the practice of peripheral denervation has been available for longer than other surgical management options but clinical preference remains unestablished, with one review of 18 studies including both DBS and peripheral denervation use suggesting a current lack of identification of patient subpopulations benefiting more from either approach[118]. Adverse effects of peripheral denervation include dysphagia and return of symptoms following denervation[112].

CONCLUSION

The current management options for patients with dystonia aim to optimally minimize the motor effects of dystonia on afflicted patients. While the exact etiology is unclear in most cases, potential interventions lie in surgical and pharmacological symptom alleviation. Advancements in precise neurosurgical procedures such as DBS have allowed for better long-term patient outcomes. For different types of dystonia, specific brain regions, such as the output efferent fibers of the globus pallidus pars interna and subthalamic nucleus, have been identified for optimal targeting. Previously used ablative surgeries have also improved through the advent of radiofrequency, stereotaxis, and ultrasound. Even with the use of state-of-the-art technologies, adverse effects remain a significant consideration when weighing these interventions. As a result, the use of pharmacological agents to modulate the aversive effects of dystonia on patient life is prevalent. Careful analysis of the etiology, associated symptoms, and potential side effects should be undertaken before beginning any individual medication. Continued research in the hopes of further symptom alleviation and cause identification is needed to better control the clinical presentation of dystonia and provide patients with more diverse, robust options to consider in their treatment.