Deep Brain Stimulation for Dystonia

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CHAPTER 82 Deep Brain Stimulation for Dystonia

Torsion dystonia is a neurological disorder characterized by twisting, repetitive movements that result in abnormal, often painful postures.¹ Different muscle groups may be involved to a variable extent and severity. Dystonia is not one disease; rather, it is a neurological manifestation of many pathologic conditions, most of which are poorly characterized. Prevalence estimates for primary dystonia in the general population range from 2 to 50 cases per million for early-onset dystonia and from 30 to 7320 cases per million for late-onset dystonia.² However, prevalence rates are significantly higher in some ethnic groups.²^,³

Because of the limitations of available medical therapies, a variety of surgical interventions that target both the peripheral and central nervous systems have been attempted for dystonia.⁴^,⁵ The dystonia literature is filled with case reports and small cohort studies, mostly relating mixed or conflicting outcomes. Long-term results in significant numbers of patients are virtually absent.

In the more recent past, the successful use of deep brain stimulation (DBS) for medically refractory Parkinson’s disease (PD) and essential tremor (ET) led to investigation of its utility in treating dystonia. In particular, the observation that pallidal interventions improve “off-state” dystonia in PD patients shifted attention from the thalamus to the globus pallidus interna (GPi) as the target of choice for treating primary dystonia.⁶ The result of these efforts has been development of the most effective treatment currently available for primary dystonia and one of the most successful applications of neuromodulation technology yet described. This chapter focuses on the current status of pallidal DBS for dystonia. Because of space constraints, discussion of alternative therapeutic targets for stimulation is limited.

Diagnosis and Classification of Dystonia

Dystonia may be classified in three ways: (1) by the anatomic distribution of the abnormal movements, (2) by the age at onset of symptoms (early versus late), and (3) by the absence or presence of a specific underlying cause (i.e., primary versus secondary).¹ Focal dystonias (e.g., writer’s cramp, spasmodic torticollis) are limited to a single body region, segmental dystonia affects contiguous body parts, and widespread involvement of the axial and limb musculature characterizes generalized dystonia. Patients with early symptom onset (i.e., age < 26 years) are more likely to have a heritable form of dystonia and more likely to suffer generalized symptoms.¹^,³

A dystonia is classified as primary or idiopathic when no structural brain abnormality or specific toxic, metabolic, traumatic, or infectious cause is identified. The heritable forms of dystonia are traditionally included in this group. At least 13 different mutations are now associated with dystonia, with each mutation occurring at a unique gene locus.⁷ The most common form of genetic dystonia results from a GAG deletion of the gene encoding the protein torsin A.⁷ This mutation, referred to as DYT1, is associated with a form of childhood-onset dystonia formerly known as dystonia musculorum deformans or Oppenheim’s disease. DYT1-associated dystonia is inherited in an autosomal dominant pattern but with a penetrance of just 30% to 40%, thus suggesting that additional genetic or environmental factors, or both, contribute to expression of the dystonic phenotype.⁷

When a structural brain abnormality or specific underlying cause is identified, a dystonia is classified as secondary or symptomatic.¹ Symptomatic dystonia is more prevalent than primary dystonia and may arise from a variety of causes, including static encephalopathy, stroke, traumatic brain injury, or any number of toxic, metabolic, or infectious disorders. Consequently, this is a heterogeneous patient population with varied pathophysiologies and responses to treatment.¹

Medical Therapy for Dystonia

In most cases, medical therapy for dystonia is limited to symptom control and is marginally effective.⁸ Anticholinergic medications (e.g., trihexyphenidyl) are the mainstay of medical therapy but often yield only modest improvements and, at the high doses used for dystonia, may cause significant side effects such as drowsiness, blurred vision, and poor memory. Additional medications for dystonia include baclofen, benzodiazepines, and tetrabenazine. A minority of patients with symptomatic generalized dystonia will benefit from specific therapy targeted at the underlying disorder. Children and adolescents with “clinically pure” dystonia of unknown etiology should be evaluated for Wilson’s disease and undergo a trial of levodopa therapy because a small subpopulation with dopa-responsive dystonia will experience a profound and sustained response to this medication.⁸

Targeted injections of botulinum toxin (Botox) can alleviate focal dystonias, but this intervention is impractical in patients with generalized symptoms.⁸^,⁹ Some patients will not respond to Botox initially, and in up to 10%, resistance may develop over time through the production of blocking antibodies.⁹

Surgical Therapy for Dystonia

Surgical intervention for dystonia should be considered when a patient’s symptoms are disabling and the response to medical therapy is either inadequate or limited by side effects. Historically, surgical interventions for dystonia have targeted both the peripheral and central nervous systems.⁴^,⁵ Peripheral denervation procedures for focal dystonias have largely been supplanted by chemical denervation with Botox.⁹ Chronic intrathecal baclofen infusions can alleviate dystonia of the lower extremities, but this intervention may not be appropriate for dystonias affecting the arms and neck, and positive responses may not result in significant functional gains.¹⁰

Advances in stereotactic technique, the success of DBS for PD and ET, and the observation that pallidotomy improves off-medication dystonia in PD patients ⁶ renewed interest in basal ganglia interventions for torsion dystonia in the 1990s. Stereotactic pallidotomy does improve symptoms of primary generalized dystonia (PGD)¹¹; however, unilateral pallidotomy may not sufficiently treat generalized symptoms, and bilateral pallidotomy entails significant risk, including cognitive dysfunction, dysarthria, dysphagia, and limb weakness.¹² Consequently, DBS, which is reversible and may be used bilaterally with relative safety, has emerged as a preferable alternative.

Deep Brain Stimulation Procedure

Consistently successful DBS surgery is dependent on three critical steps: (1) careful patient selection, (2) precise lead implantation, and (3) skillful device programming. Failure to perform any of these three steps properly may lead to suboptimal results.

Patient Selection

As discussed in the introduction, dystonia is a complex group of disorders, most of which are not responsive to DBS. Therefore, it is important to have all surgical candidates evaluated by a movement disorders neurologist before proceeding. The neurologist will ensure that the diagnosis of dystonia is correct and that all reasonable medical therapies have been tried. At our center the neurologist also programs the DBS devices after implantation, manages changes in medication, and monitors patient progress.

In the United States, Activa Dystonia Therapy (Medtronic, Inc., Minneapolis, MN) is approved under a Humanitarian Device Exemption exclusively for the treatment of primary dystonia. All other uses are considered to be “off-label.” Patients should not be offered surgery unless their symptoms are disabling and they have failed to respond to standard medical therapies. Recent magnetic resonance imaging (MRI) of the brain should have been performed to rule out structural lesions. Patients with childhood-onset generalized dystonia should be tested for Wilson’s disease and the DYT1 mutation and should receive an adequate trial of levodopa before proceeding with surgery.

Surgical Procedure

The implanted device is composed of four primary components (Fig. 82-1) that are implanted in two stages. During the first stage, the stimulating lead or leads are implanted into the GPi stereotactically and secured by means of an anchoring system that also covers the bur hole. The remaining two components (i.e., the extension cable or cables and pulse generator or generators) are implanted during the second procedure, which may be performed on the same day or shortly thereafter. It is acceptable to implant DBS leads bilaterally during the same procedure. Dystonia patients are typically much younger than patients with PD and ET and, in our experience, tolerate the bilateral frontal lobe penetrations without difficulty.

FIGURE 82-1 The deep brain stimulation (DBS) system. The DBS system (Activa, Medtronic, Inc., Minneapolis, MN) has three primary components: (1) the stimulating lead, which is implanted stereotactically into the desired target; (2) the programmable neurostimulator, which generates the electrical impulses; and (3) the extension cable, which is tunneled subcutaneously and connects the stimulator to the lead. A fourth component, the bur hole cap, which holds the lead in place and covers the bur hole, is not pictured.

The first stage of the DBS procedure is ideally performed with the patient fully awake, but this may not be possible for young children or patients with severely contorted postures. Anticholinergic medications, benzodiazepines, and baclofen are withheld on the morning of surgery because these medications may interfere with intraoperative microelectrode recording (MER). If painful muscular spasms or abnormal postures make awake surgery arduous, conscious sedation with propofol or dexmedetomidine can be used. Antibiotics are administered intravenously during application of the head frame so that serum levels are therapeutic during the implantation procedure.

Anatomic Targeting

Stereotactic head frames remain the “gold standard” for implanting DBS leads; however, “frameless” technologies are being used for DBS surgery with greater frequency.¹³ We use axial and coronal fast spin echo/inversion recovery (FSE/IR) MRI for anatomic targeting because the images are acquired rapidly (6 to 9 minutes per scan) and provide superior resolution of the commissures and deep nuclei (Fig. 82-2). The thickness of the axial slices (3 mm) required to generate these high-resolution images increases our initial targeting error along the z-axis (i.e., depth), but this is compensated for by MER, which delineates the depth of specific structures along the implantation trajectory with a resolution of approximately 0.1 mm. The scanning parameters for FSE/IR MRI are presented in Table 82-1. These images alone are sufficient for implanting the DBS system under microelectrode guidance; however, additional image sets such as gadolinium-enhanced three-dimensionally acquired T1-weighted MRI (e.g., spoiled gradient echo [SPGR]) or computed tomography (CT), or both, may also be used. We have found that the volume error of fiducial registration is enhanced with SPGR MRI (unpublished results). Moreover, contrast enhancement demonstrates the cortical veins so that they may be avoided when selecting an entry point. CT provides the most geometrically accurate images for fiducial registration and may also be performed rapidly on the morning of surgery.

FIGURE 82-2 Fast spin echo inversion recovery (FSE/IR) magnetic resonance imaging. We use both axial (A) and coronal (B) FSE/IR images for targeting the globus pallidus interna (GPi). The anterior (A,) and posterior (A, AC/PC) commissures are readily visible on the axial image, as is the posteroventral GPi (A, black arrow). The target is the posteroventral GPi, 20 to 21 mm lateral to the midline (B, black arrow) and 2 to 3 mm superior and lateral to the optic tract (OT) (B, white arrow).

TABLE 82-1 Scanning Parameters for Axial Fast Spin Echo Inversion Recovery Images

Excitation time (Te)	120 msec
Relaxation time (Tr)	10,000 msec
Inversion time (Ti)	2200 msec
Bandwidth	20.83 KHz
Field of view	24 cm
Slice thickness	3 mm
Slice spacing	0 mm
Frequency	192 Hz
Phase	160
Number of excitations	1
Frequency direction	Anteroposterior
Autocontrol frequency	Water
Flow compensation direction	Slice direction

The target coordinates may be calculated directly by using the scanner’s software, or the imaging data sets may be transferred to an independent workstation that is equipped with advanced stereotactic targeting software. These advanced software packages provide at least five distinct advantages: (1) the target coordinates are calculated automatically, thereby eliminating human math errors; (2) a variety of image sets (e.g., CT and MRI) may be merged to allow one to exploit the advantages of different types of imaging; (3) the entire trajectory may be visualized in all three anatomic planes and orthogonal to the trajectory (so-called probe’s eye view), thereby allowing one to plan safer approaches to the target; (4) the image data sets are reformatted orthogonal to the intercommissural plane to control for variations in head frame placement; and (5) digitized versions of stereotactic atlases may be overlaid and digitally “fit” to the patient’s anatomy to help identify the desired target. A significant drawback with these systems is that they assume the patient’s brain to be symmetrical, which is not always the case. Congenital anomalies such as plagiocephaly can shift target structures, and it is the surgeon’s responsibility to account for these shifts during the targeting process.

We target the internal pallidal site first described by Leksell, which lies 19 to 22 mm lateral, 2 to 3 mm anterior, and 4 to 5 mm inferior to the midcommissural point (MCP).¹⁴ The coordinates for the MCP are determined by calculating the arithmetic mean of the coordinates for the anterior and posterior commissures, which may be determined directly. The calculated target point should be visualized on both axial and coronal images and should lie 2 to 3 mm superior and lateral to the optic tract (Fig. 82-2B). Our preferred trajectory rises at a 60- to 65-degree angle anterior and superior to the intercommissural plane and 0 to 10 degrees lateral to the vertical axis. This trajectory allows one to avoid the ipsilateral lateral ventricle and still use nearly parasagittal trajectories, which facilitates the process of mapping the intraoperative MER data to human stereotactic atlases (see later).

Microelectrode Recording

We use single-cell MER to refine our anatomic targeting. The finer details of our MER technique are beyond the scope of this report but are provided elsewhere.¹⁵ The need for MER is hotly debated; however, we find that MER provides important information that other neurophysiologic localization techniques simply do not. First, MER delineates the borders and expanses of the globus pallidus externa (GPe) and GPi along a given trajectory with a spatial resolution of approximately 100 µm. These data may be mapped onto scaled sagittal sections of human stereotactic atlases to determine the anatomic location of the recording trajectory. Acceptable trajectories for implantation include a 3- to 4-mm span of the GPe and at least 7 mm of the GPi. Such a trajectory must pass through the heart of the GPi and will allow three to four contacts to be positioned comfortably within the nucleus, depending on the lead used (Fig. 82-3).¹⁶ Second, the detection of kinesthetic cells confirms that the trajectory is traversing the sensorimotor subregion of the GPi, the physiologically defined target for the procedure. Third, delineating the inferior border of the GPi refines the depth of implantation. Fourth, identifying the optic tract 2 to 3 mm inferior to the GPi exit point confirms that the trajectory is exiting the nucleus inferiorly, not posteriorly into the internal capsule. Identification of the optic tract provides an additional level of confidence that the lead will be well positioned, but this should not be viewed as an absolute requirement for implantation because the optic tract may not be identified in many cases.