Deep Brain Stimulation for Parkinson's Disease: Where Do We Stand?

Deep brain stimulation (DBS) is an established treatment for Parkinson’s disease (PD) patients who present with disabling motor complications, such as fluctuations and dyskinesias unmanageable by medical treatment alone (The Deep-Brain Stimulation for Parkinson’s Disease Study Group, 2001). In recent years, two main targets have emerged: the subthalamic nucleus (STN) and the globus pallidum internum (GPi). These brain nuclei differ significantly for anatomical connections, size, and functional role within the basal ganglia. The available clinical experience, arising either from mono-center or multi-center studies, is more detailed for STN compared to GPi DBS. First, short-term data have shown that, compared to best medical treatment, STN stimulation is more efficacious for controlling dyskinesias, motor function, and quality of life, but is associated with a higher risk of serious adverse events (Deuschl et al., 2006). Furthermore, long-term sustained motor efficacy of STN implants has been demonstrated for up to 8 years now (Fasano et al., 2010), compared to 5.5 years of GPi (Moro et al., 2010b). Medicationand stimulation-resistant symptoms, mainly axial signs (such as gait and postural impairment) become evident after 5 years after STN implants. These features are likely due to disease progression, which also require either the increase of dopaminergic medication dosage or of the total electrical energy delivered to the STN (Fasano et al., 2010). Three recent studies (two randomized and one uncontrolled) have compared the effects of STN and GPi stimulation in complicated PD patients (Table 1). Taken together, they indicate that STN and GPi stimulations have similarities and differences. They both improve motor signs of PD and reduce dyskinesias; however, STN stimulation generates more pronounced motor improvement allowing to reduce dopaminergic medication to a higher degree. The trade-off is a higher incidence of treatment-related adverse events, in particular speech disturbances and postoperative confusion, in patients receiving STN implants. These trials have intrinsic methodological limitations that curb their external validity, particularly due to the multi-center design with heterogeneity of targeting techniques, equipment, selection criteria, and post-operative procedures. Currently, most centers in Europe and in North America perform implants in the STN rather than in the GPi; in most instances, this preference is based on the team experience. Recent data indicate, however, that target selection could be tailored to the patient’s clinical and personal profile: GPi DBS may suit better patients with dose-limiting dyskinesias or behavioral and cognitive issues, whereas STN DBS may be more indicated for younger patients with prominent akinesia and tremor or with behavioral disorders related to dopaminergic medication. Non-motor features may provide predictive information on long-term STN DBS efficacy. A recent prospective study showed that the occurrence of REM sleep behavior disorder in PD patients undergoing STN DBS may be per se associated with a less favorable outcome and a more prominent development of axial symptoms over time (Zibetti et al., 2010); by contrast, cardiovascular dysautonomia is compatible with satisfactory motor outcome, as reported 1 year after STN DBS (Holmberg et al., 2005). The observation of a decay of motor outcome 8 year after STN implants (Fasano et al., 2010) raises the issue whether surgery should be considered an earlier therapeutic option, being also performed on patients with uncomplicated PD. The rationale would be to maximize motor benefit and spare dopaminergic medication before disability accumulates and the quality of personal and social life decays. Most implanting centers apply patients selection criteria stated by the CAPSIT-PD