Deep brain stimulation

Abstract

Levodopa therapy represents a major breakthrough in the treatment of Parkinson’s disease (PD). As time and disease severity progresses, however, the shortcomings and adverse effects of this neurotransmitter replacement strategy become apparent and patients develop disabilities despite best medical therapy. The heightened awareness of these difficulties has given birth to a re-examination of functional neurosurgery for advanced PD. In the 20 years since the renewed interest in deep brain stimulation (DBS), approximately 60,000 patients with PD have undergone this surgery, with an annual accrual of 8000–10,000 new patients per year worldwide. Clinical studies have confirmed the beneficial effects of DBS surgery for the treatment of the cardinal motor features of PD. The likelihood of improvement, however, varies from symptom to symptom and from patient to patient. Surgery is very effective in reducing the motor fluctuations and dyskinesias—the primary reasons for patients’ intolerance to medical therapy. Other problems are less or non-responsive. Further, despite the widespread use of this technology, the mechanism through which DBS alleviates symptoms is not fully understood. This review will discuss the patient population most likely to benefit from surgery, what aspects of the disease are most responsive, the current limitations of DBS, and new therapeutic targets that are being examined to address these limitations.

Introduction

Surgery for Parkinson’s disease (PD) initially focused on treating tremor. Early treatments were ablative, producing lesions in the brain using open or stereotactic techniques in the subcortical structures, the basal ganglia, and the thalamus. Since the 1950s, neurosurgeons have performed temporary and reversible focal inactivations or modulations of the intrinsic neural elements prior to making lesions. These tests used a variety of strategies, including injections of local anesthetics, cooling, or electrical stimulation, to both predict efficacy and warn of potential adverse effects with permanent lesions. It is in the course of these tests that the therapeutic effects of electrical stimulation were characterized. Benabid expanded and pursued the observation that tremor was reliably arrested during high-frequency stimulation in the thalamus (Benabid et al., 1987, Benabid et al., 1989). He applied the same principle to another structure, the subthalamic nucleus (STN), and showed improvement of tremor, rigidity, and bradykinesia, as well as a reduction in the required levadopa dose (Benabid et al., 1994). Others targeted additional structures, including sites in the basal ganglia, thalamus, and cortex, and their input and output pathways.

The use of deep brain stimulation (DBS) became widespread in the late 1990s, and several large studies have subsequently confirmed the efficacy and safety profile of the procedure (Burchiel et al., 1999, Deuschl et al., 2006, Hariz et al., 2008, Krack et al., 2003, Rodriguez-Oroz et al., 2005). Recently, a multicenter randomized controlled trial of DBS versus medical therapy concluded that, at 6 months, the surgery was more effective in improving motor function, quality of life, and reducing dyskinesias (Weaver et al., 2009).

DBS has become an established tool in the management of patients with advanced PD. This review highlights the benefits and limitations of DBS in various brain targets and discusses some of the understanding of the mechanism of action.