10 Deep Brain Stimulation for Dystonia—Clinical Review and Surgical Considerations

10.1 Introduction

Dystonia musculorum deformans, or simply “dystonia,” is a multifaceted movement disorder, coined as such by Dr. Hermann Oppenheim in 1911 and characterized as “a very peculiar [disorder] … pronounced tonic cramping states … in the neck, head, and the proximal extremities … [with a] ‘torqued gait’ … representing an inextricable mix of voluntary movements, tic movements, and choreiform movements.”1,2 A syndromic classification rather than an etiological one, dystonia is characterized by intermittent or sustained involuntary muscular contractions or postures of the limbs, often twisted, writhing, or tremulous. The resulting postures lead to difficulties in activities of daily living (ADLs), reduced independence, lost work hours, chronic pain, and an increased risk of eventual irreversible musculoskeletal comorbidities such as scoliosis, limb and axial bony deformities, and contractures. In this chapter, we review relevant clinical considerations of dystonia focusing on neurosurgical pre-, peri-, and postoperative considerations.

10.2 Classification and Examination of Dystonias

Historically an imprecise diagnosis, dystonia was reclassified by an international panel using two major axes: clinical (time of onset: childhood- vs. adult-onset, or anatomical distribution of regions: focal, segmental, hemibody, generalized, or multifocal) and etiological (i.e., primary vs. secondary).3,4,5,6 We briefly review each axis in semi-isolation. Clinical differentiation is particularly relevant to surgical preassessment and warrants some elaboration. However, it should be noted that despite recent advances in mapping pathophysiology, a consensus regarding phenomenology or globally unifying mechanistic explanation is lacking.^7,8 When more than one region is involved, dystonias may be segmental (contiguous regions), multifocal (noncontiguous), or hemidystonia (hemibody, usually secondary to acquired structural pathology). Dystonias may be “generalized” when involving the trunk and two other regions. These dystonias cause lifelong disability and often necessitate more aggressive intervention, such as deep brain stimulation (DBS).

10.2.1 Axis I—Clinical Considerations

The diagnosis of dystonia remains a bedside one requiring several phenomenological and provocative considerations. At a minimum, a dystonic contraction occurs with the simultaneous activity of muscle agonists and antagonists, such as with forearm flexors and extensors leading to the development of a sustained posture of the hand and fingers. The duration of contractions may vary considerably from brief moments (myoclonus-like durations9) to sustained spasms (which may be confused with contractures). Commonly, rhythmic or semirhythmic movements accompany the posture, appearing as a tremor and mistaken as “essential” or rubral tremor. The presence of temporal fluctuations and focal involvement further impede prompt diagnosis and represent an emerging research focus.⁸ Focal dystonias may be a forme fruste of a later, more generalized dystonia (e.g., lower limb predominance with DYT5 or rostral presentation with ADCY5¹⁰). When present, a dystonic tremor may briefly abate when the dystonia is fully unopposed (i.e., the complete uncompensated manifestation) in a “null point” which may be thought of as a new, default, “resting state” of the limb.

Dystonic movements may lead to abnormal twisting postures, hence the historical term “torsion dystonia” is also used. Particular attention is paid to the distribution of symptoms, whether involving an isolated region of the body (focal dystonia as with the most common manifestation spasmodic torticollis or cervical dystonia), multiple contiguous regions (segmental dystonia, formerly Meige’s syndrome or oromandibular dystonia), or generalized. The presence of comorbid movement phenomena, such as decrementing bradykinesia or resting tremor (Parkinsonism), myoclonus, or cerebellar pathology may implicate an identifiable etiology. Temporal variability is also notable, including diurnal fluctuations or the presence of periods of normality before paroxysmal “storms.”

Next, provocative maneuvers or the effect of action should be assessed; many dystonias are now recognized to have exquisite task specificity or be induced by specific actions. Task-specific dystonias may develop in parts of the body that are involved in skilled or repetitive movements such as writing or playing a musical instrument, as in an embouchure dystonia.^11,12 Previously suspected to be mostly functional (i.e., psychogenic), action-induced dystonia may be difficult to clarify phenomenologically. Persons may subconsciously fight against postures by compensatory activation of adjacent or more proximal antagonists. Unfortunately, well-established diagnostic criteria for task-specific dystonias are lacking and remain the subject of study.⁸

Lastly, the presence of subtle exam findings of overflow, mirroring, or geste antagonistes can support a dystonia diagnosis. Overflow movements occur when muscles adjacent to those implicated in the dystonia are unconsciously activated either ipsilaterally or contralaterally, usually in concert with provocative maneuvers. In contrast, mirroring occurs when the use of less severely affected or unaffected limb (in the case of a unilateral dystonia) provokes dystonic movements ipsilaterally. These have high positive predictive value to confirm the presence of a task-specific dystonia, though sensitivity may be low.13

Special consideration is reserved for alleviating maneuvers (AMs),¹⁴ formerly known as sensory tricks or geste antagonistes, which implicate emerging sensorimotor circuit inhibition models of dystonia. Classically, a patient might report an improvement of a cervical torticollis by touching his or her cheek or chin,¹⁵ illustrating the most common tactile example of an AM. Prevalence reports vary in literature, but more than 70% of patients with dystonia have an AM of varying efficacy. However, emerging research suggests a broader possibility of sensory, nontactile stimuli^16,17 and interoceptive manifestations¹⁸ that may have an alleviating or exacerbating effect.¹⁹ These maneuvers relieve the dystonic posturing to different degrees both within an individual and among persons with dystonia in general. Converging lines of evidence from blink reflex prepulse inhibition and electromyography^20,21 studies suggest anomalous gating of sensorimotor integration between motoric efferent and sensory afferent systems.²² As a result, feedback signals, such as by touch (in the case of a tactile AM), briefly normalize a pathological imbalance between cortical facilitation and inhibition.²³

10.2.2 Axis II—Etiological Considerations

Etiologically, dystonias may be “primary” when they present early in life and cannot be attributed to an acquired cause. Primary (or genetic) dystonias may present in a generalized or focal fashion. The dopa-responsive dystonia (DRD) gene (Segawa Disease, DYT5a-GCH1) was sequenced in the early 1990s.24 Since then, more than 25 monogenic forms have been identified (as of this writing).²⁵ These may be subdivided as either “isolated” or “combined.” Broadly, combined dystonias are associated with myoclonus, Parkinsonism, or hyperkinetic movements. The majority have an autosomal dominant inheritance, albeit variable penetrance. For instance, early-onset generalized dystonias resulting from mutation of TOR1A (DYT1) or THAP1 (DYT6) have a penetrance of 30 to 60%, respectively, despite autosomal dominant inheritance.²⁶

In addition, dystonias may fluctuate with anxiety, circadian rhythms, exercise, or fasting. Action specificity implicates a reproducible and consistent relationship with an action and may cause severe disability in persons repeatedly engaging in complex or repetitive movements. Examples include writer’s cramp, musician’s dystonia, or runner’s dystonia.¹¹

While the majority of primary dystonias have autosomal dominant inheritance, notable exceptions include X-linked dystonia-parkinsonism (Lubag dystonia, DYT3-TAF1, Xq13.1), autosomal recessive variant DRD (DYT5b-TH, 11p15.5), or dystonias associated with matrilineal mitochondrial disorders such as Leigh syndrome. Accordingly, dystonia is a global disorder with a higher preponderance in more genetically homogenous populations, such as persons with Ashkenazi ancestry²⁷ or from the Faroe Islands.²⁸ Pooled analysis of multiple population-based studies with a substantial sample (n > 10 million) suggest a combined prevalence of primary dystonia as 16.4 per 1 million persons.²⁹ The predominant cases were focal dystonias (primarily dominant arm, as in writer’s cramp or primary writing tremor) and cervical dystonias, each with a pooled prevalence of 15.4 and 5.0 per 1 million, respectively. These are suspected to be underestimates due to referral bias of the tertiary medical centers driving data collection.

In contrast, the incidence of secondary, acquired dystonias is unknown in the setting of complex genotype–phenotype interactions and often occult environmental triggers. Neoplastic, hemorrhagic, or ischemic insults to the thalamus or basal ganglia may cause focal, segmental, or hemibody dystonias with or without comorbid hyperkinetic movement of chorea-ballism or myoclonus.^30,31 Even dystonia-associated perinatal hypoxicischemic damage may manifest well into young adulthood.^32,33 A variety of medications may induce a delayed tardive dystonia, including antipsychotics, antiemetics, antidepressants, and anticonvulsants.³⁴

10.2.3 Rating Scales

Given the heterogeneity of primary and secondary dystonias, both regarding phenotypic presentation and etiology, a rigorous systematic approach is necessary to facilitate categorization and further study. For this, several standardized rating scales have been developed and validated over the years relevant to both specific dystonia and the disorder as a whole. A number of different scales are available specific to blepharospasm,35 cervical dystonia,³⁶ and focal³⁷ and generalized dystonias.³⁸ While a comprehensive review is tangential to the goal of this manuscript, nonetheless, a few scales deemed “recommended” by the Movement Disorders Society Task Force on Rating Scales relevant to preoperative assessment merit further comment. These scales are as follows:

• Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)³⁶: This scale has been in use since 1994 for clinical assessments and is a validated outcome measure in clinical trials of botulinum toxin, pharmacotherapies, and DBS. It has three subscales that measure the clinician-assessed physical severity and response to alleviating maneuvers, as well as patient-informed sections on disability and pain. It is the most widely utilized scale for cervical dystonia with fair interrater reliability, though it may be considered too extensive for routine clinical use.

• Fahn–Marsden Dystonia Rating Scale (FMDRS)^39,40: The FMDRS is a widely used clinician rating scale assessing generalized dystonia by the regional motor manifestation and degree of disability. It has also been widely utilized to determine DBS outcomes in adults and children, though it was formulated to assess primary dystonia in adults.

10.3 Medical Management

Many patients with dystonia can have adequate control of their symptoms without surgery, though no current therapy can alter the natural history of the disease.41 Symptomatic management is complex and multifaceted and focuses on the most disabling symptom and mechanism by which dystonia restricts independence or ADLs. Broadly, medical management for dystonia can be divided into three categories: (1) nonpharmacological options, such as physical therapy and bracing, (2) pharmacological treatment, and (3) chemodenervation (botulinum toxin). A selected review of various treatment options follows.

10.3.1 Physical and Supportive Therapy

There are a multitude of nonpharmacological therapies for dystonia, such as biofeedback training, postural exercises, bracing, and behavioral therapies.41,42,43,44 The majority of investigations of these treatments have been case series, with few clinical trials.^41,42,43,44 Some evidence are promising, particularly recent studies of motor retraining and transcutaneous electrical nerve stimulation (TENS) in focal dystonia such as writer’s or musician’s cramp. Notably, TENS does not seem to provide a benefit in primary writing dystonia.^45,46,47 Due to the lack of high-quality evidence of the efficacy of physiotherapy in dystonia, these therapies should be adjuvant, not first-line, treatments.⁴³ Clinical evidence does support the use of physical rehabilitation programs in conjunction with other therapy, such as botulinum toxin injection.⁴⁸ Further evidence is needed to delineate what specific physical therapy interventions are useful for patients.

10.3.2 Pharmacological Considerations

A subset of dystonias may be exquisitely sensitive to dopamine, such as DRD (Segawa disease, DYT5a).49,50 Dopamine is often tried first in a person presenting with an unspecified dystonia to rapidly winnow differential diagnoses. Classically described DRDs are rapidly responsive to low-dose levodopa, though higher amounts may ultimately be necessary. A lack of meaningful response within 3 months suggests revisiting the suspected etiology.

Dopamine antagonists and depleters

Dopamine antagonists, such as clozapine, have been used in the treatment of both acute tardive dystonias and idiopathic dystonias,^51,52,53 though efficacy is equivocal and the side effects (both immediate and long term) are notable. However, dopamine modulation via inhibition of vesicular monoamine transporter 2 (VMAT2; tetrabenazine, valbenazine, and deutetrabenazine) seems to have efficacy for tardive dystonia⁵⁴ and idiopathic dystonia.⁵⁵ Expensive and difficult to obtain agents in the United States, dopamine modulators are primarily used in conditions when dystonia is an ancillary manifestation along with choreoathetosis, myoclonus, or tics.^56,57,58

Anticholinergic

Before the Food and Drug Administration approval of botulinum toxin and the advent of surgical interventions, pharmacological treatment of dystonia relied upon anticholinergic agents that have long been observed to improve acute dystonic reactions from antipsychotics.^59,60,61 The earliest observations were largely empirical and anecdotal from the early 20th century. Fahn recognized that the anticholinergic trihexyphenidyl was better tolerated in children than adults, especially with regards to xerostomia, urinary retention, and constipation common to adults at high doses.⁶² Early clinical trial data supported this observation,⁶³ prompting improvements in clinician-rated measures of dystonia severity and disability indices. Similar observations were made with secondary forms of dystonia such as cerebral palsy.^64,65 However, botulinum toxin has consistently demonstrated superior efficacy and tolerability over anticholinergics,⁶⁶ consigning them to second- or third-line agents in management. The available evidence is primarily anecdotal in children with little systematic evidence in adults.⁶⁷

Anticonvulsants

Early interest in nootropics and possible disease-modifying treatments suggested the use of pyrrolidone derivatives, piracetam, and levetiracetam in animal models of paroxysmal dystonias.⁶⁸ Initially supported by case reports in focal and generalized dystonia,^69,70 a larger open-label prospective study refuted these findings.⁷¹

10.3.3 Botulinum Injections

Intramuscular injection of botulinum toxin is widely regarded as the first-line treatment for dystonia, with level 1A recommendations by several multidisciplinary societies42 and national organizations.^72,73,74 Evidence support the use of botulinum injections in primary cranial (excluding oromandibular) dystonia, cervical dystonia, and writer’s cramp.^75,76,77 Botulinum is safe in adults as well as pediatric patients.⁷⁸ The two serotypes of botulinum toxin available in the United States, onabotulinumtoxinA (type A) and rimabotulinumtoxinB (type B), differ in their pharmacological mechanism of action but both have been shown to be effective in the treatment of dystonia.^79,80

10.4 Surgical Treatment

Surgical neuromodulation for dystonia increased over the past century. Modern surgical approaches include variations on ablative pallidotomies and thalamotomies, performed since the 1940s to 1960s,81,82 and DBS.^83,84 Evidence have shown that DBS of the pallidum can provide excellent relief, though the outcomes vary on the basis of patient characteristics.^{85,86,87,88,89,90,91} Careful preoperative evaluation and counseling about expected results of surgery are critical to select patients who will have maximum benefit from surgery. Multiple approaches for DBS for dystonia exist. Here we will review both the classical stereotactic frame-based and intraoperative magnetic resonance imaging (MRI)-guided approaches to the internal globus pallidus (GPi).

10.4.1 Deep Brain Stimulation

Pallidal DBS is an accepted treatment for dystonia in many patients resistant to medical therapy and botulinum injections. Long-term follow-up with multiple randomized, controlled trials has shown significant benefit of DBS in primary generalized and cervical dystonia.85,86,87,88,89,90 There is also evidence that patients with specific secondary forms of dystonia may benefit from DBS.⁸⁵ Though DBS is beneficial in many subtypes of dystonia, the outcomes vary based on subtype. Moreover, many other patient factors can affect a patient’s response to DBS. Preoperative evaluation by an interdisciplinary team can ensure dystonia patients achieve maximum benefit from intervention. A multidisciplinary team is also helpful for subsequent perioperative care and postoperative optimization and management.

Though the GPi is the most common target for stimulation, other targets have been explored, including cortical and thalamic targets.^92,93,94 More commonly, when significant tremor accompanies dystonia, the thalamic ventralis intermedius nucleus (Vim) DBS may improve both dystonia and tremor features when performed unilaterally,^95,96 bilaterally,⁹⁷ or in association with GPi DBS.^94,98,99,100 DBS targeting the posterior region of the ventrolateral nucleus of the thalamus has also been shown in some case series to improve dystonic features.¹⁰¹

Clinical observations of subthalamic DBS for Parkinson’s disease improving secondary dystonia have prompted an inquiry into subthalamic nucleus (STN) and STN-adjacent targets for dystonia.^93,102 Subsequently, other groups have postulated that nearby regions such as the caudal zona incerta (cZi)¹⁰³ or posterior subthalamic area may be a more relevant node to target.^104,105,106 Thus far, the available literature does not strongly support the superiority of one target above another for all patients with dystonia, highlighting the need for head-to-head randomized trials in the future.

Surgical procedure, frame-based DBS

Preoperative workup and counseling, including general medical clearance and evaluation by an interdisciplinary movement disorders team, is performed. In most centers, frame-based targeting requires patients to be awake during the procedure with intravenous sedation administered during the opening. Preoperative counseling to ensure patients will be able to tolerate the awake method is critical. Before surgery, an MRI is obtained to assist with target planning that includes gadolinium-enhanced volumetric T1 imaging as well as T2 volumetric imaging with fast spin-echo, 3D gradient echo, and axial inversion recovery images. The patient is placed in a stereotactic frame set parallel to the Frankfort plane. Computed tomography (CT) is performed using the fiducial localizer box and fused to a preoperative MRI on a computerized planning station. A combination of atlas-based targeting using anterior commissure-posterior commissure (AC-PC) distance and other midline structures (indirect targeting) and MRI-guided targeting (direct targeting) may be performed, using a computerized stereotactic planning station. The trajectory is planned, and the X, Y, Z and arc and ring angle coordinates are obtained. In the operating room, the stereotactic frame is fixed to the operating table to minimize head movement during surgery. The skin incision is made and a burr hole is drilled at each entry point. A DBS electrode fixation device used to anchor the lead at the end of the case is seated securely around each burr hole. An introducer cannula is placed along the intended trajectory using intraoperative X-ray or CT to guide placement. The microelectrode is passed along the trajectory through the cannula and microelectrode recording (MER) proceeds utilizing an arrangement of microelectrodes, for example, two electrodes descending in parallel central and more medial trajectories to assess for tetanic responses. MER techniques may vary among different DBS centers due to differences in electrodes used and the number simultaneously passed simultaneously passed. For a long time, most North American and European DBS centers have been using some form of MER. However, intraoperative image guidance (discussed subsequently) is challenging this paradigm.

To perform MER, a high-impedance platinum-iridium microelectrode is threaded into the cannula which is attached to a micro-drive on a head stage above the burr hole. The microelectrode is advanced to within 15 mm of the target, subsequently advanced in step-wise fashion while a physiologist, neurologist, or neurosurgeon monitors the audio and digitized field recording. Relevant grey matter nuclei or sensorimotor regions are confirmed by characteristic firing pattern observed and the presence of a kinesthetic response to passive movement. Regions may be delineated based on patterns of high- or low-frequency activity, the absence thereof (suggesting a white matter bundle), tonic or phasic discharge patterns, and background ambient noise. MER may be followed by macrostimulation at the base of the track and then ascending often using a guard ring electrode mounted above the microelectrode tip. High-frequency stimulation ranging between 0.5 and 5 mA in current may be utilized to test for induced side effects. Patients may be screened for changes in dystonia, though improvements are not commonly seen intraoperatively. More importantly, intraoperative stimulation facilitates earlier detection of visual and somatosensory symptoms, buttressing image-based localization relative to the optic tract, internal capsule, and medial lemniscus.

The initially planned trajectory may be modified based on information gleaned by MER, resulting in the ultimate track in which the DBS electrode will be implanted. Stimulation may be attempted again in bipolar fashion, as opposed to the monopolar stimulation previously performed for side effects or symptomatic benefit using the microelectrode assembly. The DBS lead localization and depth may be confirmed with intraoperative fluoroscopy or CT, which is the final stage at which revisions to lead position are feasible. Leads are then secured with the cranial fixation system and the lead cabling is tunneled under the scalp in preparation for the implantable pulse generator (IPG) placement, which is commonly performed in a second stage procedure at a later date. A final fluoroscopic image is obtained to confirm that the leads have not migrated during tunneling and the incision is closed. Postoperative or intraoperative head CT imaging may also be obtained to compare the actual trajectory against the planned trajectory on the planning station. At a later date, the patient returns for the second stage of the procedure, i.e., implantation of the DBS system pulse generator. The right side is preferred to avoid interfering with any potential future need for a cardiac pacemaker.

Surgical procedure, MRI-guided DBS^107,108

Intraoperative imaging-guided DBS for dystonia may utilize MRI or CT for real-time verification of lead placement, i.e., iMRI or iCT, respectively. Due to higher resolution of cortical and subcortical anatomy, iMRI guidance may have superior favorability to CT guidance. Due to the author’s familiarity with iMRI, we review it here as an illustration of intraoperative imaging in dystonia. For additional consideration of iCT in DBS, the interested reader should refer: Servello et al109 and Bot et al.¹¹⁰

Preoperative evaluation for MRI-guided DBS is similar to considerations for general anesthesia. The patient is brought into the operating room suite for induction for endotracheal general anesthesia, then placed into an MRI-compatible head fixation system ( Fig. 10.1 and Fig. 10.2) and fiducial grids are placed at the estimated scalp entry point for GPi targeting after standard prepping and draping ( Fig. 10.3). A standard whole-head 3D T1 volumetric acquisition MRI scan with gadolinium is obtained to formulate an initial entry point. Skin incisions and burr holes are made at each entry point, followed by fixation of alignment bases ( Fig. 10.4). Repeat whole-head 3D T1 volumetric scan (without contrast) and high-resolution thin-slice slabs are performed to visualize the relevant anatomical target. These scans are used to align the introducer cannula to achieve less than 1 mm radial error in targeting. Ceramic guidance stylets are inserted through the cannula into the target positions. A 3D T1-weighted volumetric acquisition scan is obtained to confirm good positioning within the GPi and quantify placement error ( Fig. 10.5). The stylets are then removed and replaced with two DBS leads after removal from the MRI bore. The DBS leads are secured with the burr hole fixation system and tunneled under the scalp in preparation for the IPG placement. The incision is closed, and the patient returns for implantation of the DBS system pulse generator at a later date.

Fig. 10.1 Photograph of intraoperative magnetic resonance imaging coil, with head fixation system.

10.4.2 Postoperative Complications

Though DBS for dystonia is regarded to be safe and effective, the procedure is associated with the same types of complications as DBS for other movement disorders.111,112,113,114,115,116, 117,118,119,120,121,122,123,124,125 Complications due to DBS can be procedure related, hardware related, or stimulation related.

Procedure-related complications

These complications include hemorrhage, postoperative delirium/psychosis, and seizures.^{111,112,113,114,115,116,117,118,119,120,121,122,123,124} Many procedure-related complications from DBS, such as postoperative delirium, seizure, vasovagal response, and headache, are self-limited and do not cause permanent deficits.^{111,112,113,114,115,116,117,118,119,120,121,122,123,124} However, DBS carries a risk of intracranial hemorrhage that can lead to significant neurological deficits and death.^{114,116,118,121,123,126} Fortunately, the rate of hemorrhage after DBS is quite low, ranging from 0.78 to 5%, with approximately half of patients showing symptoms.^{114,116,118,121,123,126} Large series of patients undergoing DBS have shown that dystonia does not appear to be associated with higher rates of hemorrhage compared to other diagnoses treated with DBS. Other patient factors, such as older age and hypertension, are correlated with hemorrhage.¹²³ Some studies found a higher rate of hemorrhage in the GPi DBS than in the STN DBS, but further analysis has not shown an association between anatomic target and risk of hemorrhage.^125,127,128 One particular consideration in dystonia patients is status dystonicus, a rare acute exacerbation of dystonic symptoms triggered by changes in therapy, infection, or dehydration. Resulting autonomic instability, respiratory compromise, rhabdomyolysis, or acute renal failure may be life-threatening.^129,130 Management of status dystonicus requires careful observation in a critical care unit with intravenous hydration and other supportive medical therapy such as benzodiazepines and antipyretics.^129,130

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