Deep Brain Stimulation for Dystonia

Acknowledgments

R.L. Alterman wishes to thank Donald Weisz, PhD, for his assistance with the production of Figure 112.3 , for his friendship, and for his passionate commitment to patient care.

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, often elicited by specific actions, causing twisting, repetitive movements that result in abnormal, often painful postures.
Deep brain stimulation (DBS) at the internal globus pallidus is currently the treatment of choice for medically refractory primary dystonia.
Younger patients with shorter disease duration and without joint contractures, and those patients who are DYT1 positive, generally exhibit the best response to DBS therapy.
The response to stimulation is gradual, and the full benefit of surgery may not be realized for a year or more.
Patients with secondary dystonia respond to DBS therapy more modestly and inconsistently than do primary dystonia patients.
Brain lead implantation techniques, including stereotactic delivery systems, microelectrode recording, and optimized preoperative and/or intraoperative brain imaging, are critical to achieving accurate, safe, and efficacious DBS surgery.
Standard stimulation parameters for treating dystonia typically include frequencies of 130 Hz or more and pulse widths of 90 to 450 μs.

Dystonia is a neurological movement disorder characterized by sustained or intermittent muscle contractions, often elicited by specific actions, causing twisting, repetitive movements that result in abnormal, often painful postures. ^, Different muscle groups may be engaged to a varying extent and severity, commonly involving agonist-antagonist co-contraction and overflow of movement to neighboring muscle groups. Dystonia is not one disease; rather, it is a neurological manifestation of many pathologic conditions, most of which are poorly characterized. The 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. However, prevalence rates are significantly higher in some ethnic groups. ^,

Because of the limitations of available medical therapies, a variety of surgical interventions targeting both the peripheral and central nervous systems have been attempted for dystonia. 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 have only recently been published. Moreover, many techniques were highly invasive and/or associated with a high incidence of denervation-related complications, leading them to fall out of favor.

In more recent decades, the successful use of deep brain stimulation (DBS) for medically refractory Parkinson disease (PD) and essential tremor (ET) led to investigations of its utility for treating dystonia. In particular, the observation that pallidal interventions improve “off”-state dystonia in PD patients shifted attention from the thalamus to the internal globus pallidus (GPi) as the target of choice for treating primary dystonia. The result of these efforts has been the development of the most effective treatment presently 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 several ways, with the most recent consensus statement emphasizing two distinct axes: clinical features and etiology. ^, Several features describe the clinical characteristics of a given patient: (1) the anatomic distribution of the abnormal movements, (2) the age at symptom onset (early versus late), (3) the temporal pattern of symptoms, and (4) the coexistence of other movement disorders or neurological manifestations. Focal dystonias (e.g., writers’ cramp, spasmodic torticollis) are limited to a single body region, segmental dystonia affects more than one contiguous body part (e.g., craniocervical dystonia), multifocal dystonia involves noncontiguous body regions, hemidystonia denotes multiple noncontiguous body regions restricted to one side of the body, and generalized dystonia involves widespread axial and limb musculature. Patients with early symptom onset (i.e., age < 26 years) are more likely to have a heritable form of dystonia and are more likely to suffer generalized symptoms. ^, The temporal course can be static or progressive, with superimposed persistent, action-specific, diurnal, and paroxysmal patterns of manifestation. Dystonia may be combined with other movement disorder phenotypes (e.g., myoclonus, parkinsonism), systemic features (e.g., solid organ involvement, hematologic abnormalities), or neurological symptoms (e.g., ophthalmologic abnormalities, cognitive impairment).

Dystonia is etiologically classified as primary versus secondary based on the absence or presence, respectively, of a specific underlying cause. Primary or idiopathic dystonia implies no identified structural brain abnormality or specific toxic, metabolic, traumatic, or infectious etiology. The heritable forms of dystonia are traditionally included in this group; however, they have been separated into their own category in the newest classification system. A growing list of more than 20 primarily single-gene mutations are associated with primary dystonia, with dystonia being the sole or most prominent symptom. The first discovered and most common form of monogenetic dystonia results from a GAG deletion of the gene encoding the protein torsin-A. This mutation, referred to as DYT1, is associated with a form of childhood-onset dystonia formerly known as dystonia musculorum deformans or Oppenheim disease. DYT1 -associated dystonia is inherited in an autosomal dominant pattern but with a penetrance of just 30% to 40%, suggesting that additional genetic and/or environmental factors contribute to the expression of the dystonic phenotype.

When a structural brain abnormality or specific underlying etiology is identified, dystonia is classified as secondary or symptomatic. Secondary 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. Often included here is a large group of genetic syndromes that, unlike their mainly monogenic DYT counterparts, often express dystonia as a component of a complex phenotype. Consequently, this is a heterogeneous patient population with varied pathophysiologies and responses to treatment.

Pathophysiology

Dystonia is primarily conceived of as a circuit disorder in which various patterns of nodal or connectivity dysfunction within motor control networks give rise to disease phenotypes. To this end, the basal ganglia network has received the most attention, and therefore medical therapies have focused on its modulation (generally targeting cholinergic and dopaminergic neurotransmission). Although increasing data point to involvement of the cerebellum and associated motor circuits in some forms of dystonia, this has yet to translate into new-targeted treatments. Research efforts examining different forms of monogenetic dystonia continue to better characterize changes at the gene and protein levels; however, mechanistic understanding at the motor network level remains poorly elucidated.

Medical Therapy for Dystonia

In most cases, medical therapy for dystonia is limited to symptom control and is variably effective. ^, Physical therapy and orthotic devices can sometimes help maintain range of motion and prevent contractures in affected body parts. Anticholinergic medications (e.g., trihexyphenidyl) are the mainstay of medical therapy for generalized dystonias but often yield only modest improvements and, at the high doses employed for dystonia, may cause significant side effects such as drowsiness, blurred vision, and poor memory. Additional medications for dystonia include baclofen, benzodiazepines, zolpidem, 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 disease and should undergo a trial of levodopa therapy, because a small subpopulation with levodopa-responsive dystonia will experience a profound and sustained response to this medication.

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

Surgical Therapy for Dystonia

Surgical intervention for dystonia is generally considered when a patient’s symptoms are disabling and the response to medical therapy is either inadequate or limited by side effects. A possible exception to this paradigm is the use of DBS at a relatively early treatment stage for highly responsive monogenetic dystonias, as is outlined in detail. Historically, surgical interventions for dystonia have targeted both the peripheral and central nervous systems. ^, Peripheral denervation procedures for focal dystonias have largely been supplanted by chemical denervation with Botox. ^, Chronic intrathecal baclofen infusions can alleviate dystonia, though existing case series have reported mixed motor and functional results with significant hardware-related complication rates. Intrathecal baclofen infusion is more commonly considered for secondary dystonia with comorbid spasticity, most commonly seen in cerebral palsy.

Advances in stereotactic techniques, the success of DBS in PD and ET, and the observation that pallidotomy improves “off”-medication dystonia in PD patients renewed interest in basal ganglia interventions as a means for modulation of the malfunctioning motor circuit thought to be responsible for generating dystonia in the 1990s. Stereotactic pallidotomy does improve symptoms of primary generalized dystonia (PGD) ; however, unilateral pallidotomy may not sufficiently treat generalized symptoms and bilateral pallidotomy entails significant risk, including cognitive dysfunction, dysarthria, dysphagia, and limb weakness. DBS, which is reversible, is titratable, and may be employed bilaterally with relative safety, has emerged as a preferable alternative.

The Deep Brain Stimulation Procedure

Consistently successful DBS surgery involves three critical steps: (1) careful patient selection, (2) precise lead implantation, and (3) skillful device programming. Failure to perform any one 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. He or she will ensure that the diagnosis of dystonia is correct, and that all reasonable medical therapies have been tried. At many centers, the neurologist also programs the DBS devices after implantation, manages medication changes, and monitors patient progress.

In the United States, the Activa DBS System (Medtronic) is approved for unilateral or bilateral stimulation of the GPi or subthalamic nucleus under a Humanitarian Device Exemption exclusively for the treatment of primary dystonia in patients 7 years of age or older. All other uses are considered to be off-label. Patients should not be offered surgery unless their symptoms are disabling and have failed to respond to standard medical therapies. A notable caveat to this may be select children with primary generalized dystonia. Here, GPi-DBS is increasingly considered a first-line treatment with the goal of reducing loss of mobility and joint deformity prior to the development of contractures, and to minimize the impact of centrally acting medications on cognitive and social development. A magnetic resonance imaging (MRI) study of the brain should be obtained to rule out structural lesions. Patients with childhood-onset generalized dystonia should be tested for Wilson disease and the DYT1 mutation, and should receive an adequate trial of levodopa before proceeding with surgery. Moreover, an argument can be made for more extensive genetic testing panels in certain cases, given that existing and emerging small series suggest that DBS has efficacy in some less common forms of genetic dystonia.

Surgical Procedure

The implanted device is composed of four primary components ( Fig. 112.1 ) that are implanted in two phases, as either a single or a staged operation. During the first phase, the stimulating lead(s) are implanted into the GPi stereotactically and secured by means of an anchoring system that also covers the bur hole. The remaining two components—the extension cable(s) and pulse generator(s)—are implanted during the second phase of the procedure, which may be performed at the same setting or during a second stage 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 112.1, The deep brain stimulation (DBS) system.

Stereotactic Technique

Stereotactic head frames remain the primary means for performing DBS lead implants; however, newer methods, including robotic-assisted and frameless techniques, are being employed with greater frequency. These systems employ either a custom-built or adjustable targeting platform in concert with skull-mounted fiducials or an MRI-compatible implantation platform that allows real-time MRI guidance of the lead and target during implantation. Good outcomes are reported using each of these methods, with accuracies rivaling those achieved with conventional head frames. No reports directly compare these techniques to suggest the superiority of one technique over another. Potential advantages of newer systems include enhanced patient comfort, workflow efficiency, adjustment for brain shift, and anatomic accuracy. In contrast, stereotactic frames may provide greater head stability during surgery, compatibility with microelectrode recording (MER) platforms, entry point and trajectory flexibility, and lower procedure cost, and they enjoy the greatest published experience. The choice of technique should be driven primarily by the ability to safely, reliably, and accurately implant leads and achieve expected clinical outcomes, because even small deviations from optimal placement can negatively impact treatment response.

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