However, as the disease progresses, disabling medication-related side effects, particularly motor fluctuations and dyskinesia, often occur and can become resistant to medication adjustments.
Due to the limitations of pharmacological treatments and advances in surgical and targeting techniques, deep brain stimulation (DBS) has been increasingly used as a treatment for advanced PD. Multiple studies have reported the safety and efficacy of DBS for the treatment of motor symptoms and medication-related motor complications in PD.2 There are currently three targets for DBS in PD: the subthalamic nucleus (STN), globus pallidus interna (GPi), and ventral intermediate (Vim) nucleus of the thalamus.
Candidates for STN or GPi DBS should have idiopathic levodopa responsive PD with medication-resistant motor fluctuations or dyskinesia. Several studies have demonstrated that the strongest predictor of outcome after STN DBS is pre-operative levodopa responsiveness.3,4 PD patients older than 75 years are generally not considered candidates for DBS as they may have difficulty tolerating the procedure. Furthermore, younger age in addition to levodopa responsiveness has been reported to be a predictor of STN DBS outcome.5,6
Candidates should be seen by a neurologist specializing in movement disorders and should have been tried on multiple antiparkinsonian medications before being recommended for surgery. Neuropsychological assessment should be completed to rule out dementia and any significant cognitive, psychiatric, or behavioral abnormalities as these can worsen after surgery. There should be no significant abnormalities on neuroimaging and no other medical conditions that might increase surgical risk. Finally, the patient should have an adequate support network and be able to attend multiple follow-up visits to the surgical site.
DBS of the Vim nucleus of the thalamus is rarely used as a treatment for PD. Several studies demonstrated significant long-term tremor control with this procedure; however, there was minimal if any effect on bradykinesia, rigidity, and motor complications, which led to significant disability as the disease progressed.7,8 This procedure is therefore recommended only in patients with medication-resistant tremor dominant PD and minimal to no disability related to bradykinesia or rigidity. DBS Hardware
The DBS System Components
The DBS electrode is implanted into the targeted brain structure.The intracranial end of the electrode has four platinum-iridium contacts. There are two electrodes, one with contacts separated by 1.5mm and one with contacts that are separated by 0.5mm.
Implantable Pulse Generator
The Implantable pulse generator (IPG) is the power source for the system. There are two IPGs currently available: the Soletra®,which requires a separate IPG for each side of the brain, and the Kinetra®,which requires only one IPG to control the electrodes for both sides of the brain.The IPGs can be programmed for monopolar or bipolar stimulation. Adjustable parameters include pulse width, amplitude, frequency, and the choice of active contacts. The typical stimulation parameters are frequency of 135–185Hz, pulse width of 60–120 microseconds, and amplitude of 1–3 volts. The IPG generally needs replacement every three to five years, depending upon usage. The patient can turn the stimulator on or off using a hand-held magnet or an Access Review Therapy Controller®.
The extension wire connects the electrode to the IPG. It is tunneled under the skin down the neck to the IPG, which is generally placed in the infraclavicular area.
DBS versus Best Medical Therapy
Recently, the results of a study comparing 133 PD patients randomized to best medical therapy and 120 to DBS were reported.9 The DBS group had significantly greater improvements compared to the best medical therapy group at six months compared to baseline on patient diaries (5.2 hours versus 0.1 hours increase in daily on time), Unified Parkinson’s Disease Rating Scale (UPDRS) motor score off medication (35.2% versus 4.6% improvement) and quality of life. Similarly, Deuschl et al. reported 156 PD patients in which 78 were randomized to best medical therapy and 78 to STN DBS.10
At the six month follow-up visit, the DBS group had significantly greater improvements compared to the best medical therapy group on patient diaries (4.4 hours versus -0.5 hours increase in daily on time), UPDRS motor score off medication (41% versus 1.7% improvement) and quality of life. Based on these studies, it can be concluded that DBS provides significant benefits over best medical therapy alone in advanced PD patients.
UPDRS=Unified Parkinson’s Disease Rating Scale; ADL=activities of daily living; a = % improvement from baseline medication off state to medication off/stimulation on at follow-up; b = % reduction
DBS of the Subthalamic Nucleus
STN DBS is currently the most commonly performed surgical procedure for the treatment of PD. Multiple reports have confirmed the short- and long-term benefits of STN DBS in improving PD motor symptoms and reducing dyskinesia, off time, and antiparkinsonian medications. A meta-analysis of 20 STN DBS studies reported an average improvement in UPDRS activities of daily living (ADL) scores of 49.9% and an average improvement of 52% in UPDRS motor scores. Levodopa equivalence dose was reduced by an average of 55.9%, dyskinesia by 69.1%, and daily off time by 68.2%.11 Table 1 depicts the results of several STN DBS long-term studies.3,12-16 In the two studies with a follow-up of five years, continued benefits of STN DBS compared to baseline were demonstrated at the longest follow-up; however, some deterioration was reported over time, which appeared to be related to the natural progression of the disease.15,16
DBS of the Globus Pallidus Interna
Several studies have reported the efficacy of GPi DBS in controlling bradykinesia, rigidity, tremor, and dyskinesia in PD patients (see Table 2);however, most of these studies have a small number of patients or a relatively short follow-up period.14,17-19 Results have been inconsistent regarding the long-term benefits of GPi DBS.Volkmann et al. reported a significant improvement in bradykinesia, rigidity, tremor, and postural instability/gait at 12 months compared to baseline; however, at 36 months there were significant improvements only in bradykinesia and postural instability/gait, and by 60 months only rigidity was significantly improved.19 In contrast,Rodriguez-Oroz et al. reported sustained and significant benefits in tremor, rigidity, and bradykinesia at the 3–4 year follow-up visit.14 There is, however, consensus regarding a significant and sustained reduction in dyskinesia despite minimal if any reductions in anti-parkinsonian medications.
UPDRS=Unified Parkinson’s Disease Rating Scale; ADL=activities of daily living; a = % improvement from baseline medication off state to medication off/stimulation on at follow-up; b = % reduction in dyskinesia
DBS of the Subthalamic Nucleus or the Globus Pallidus Interna
Several small retrospective studies comparing STN and GPi DBS have suggested that overall benefit is greater with STN DBS.20,21 In a blinded, randomized trial of GPi versus STN DBS, Anderson et al. compared 10 patients with bilateral STN DBS to 10 patients with bilateral GPi DBS 12 months after surgery.18 UPDRS scores were significantly improved for both groups and there were no significant differences between groups. Although not significantly different, STN DBS improvement was consistently greater than that of GPi DBS on most measures including UPDRS motor scores (48% versus 39%); UPDRS ADL scores (28% versus 18%); bradykinesia (44% versus 33%); and tremor (89% versus 79%). Rigidity was improved 48% with STN DBS and 47% with GPi DBS, and axial symptoms were improved 44% with STN DBS and 40% for GPi DBS. Finally, dyskinesia was reduced by 62% with STN DBS and 89% with GPi DBS in spite of a levodopa reduction of 38% with STN DBS and only 3% with GPi DBS. The results of larger, randomized, blinded studies are necessary before the two targets can be adequately compared.
Complications of DBS
Complications of DBS can be categorized as those resulting from the surgical procedure, DBS hardware, or stimulation. Complication rates are related to the technique and experience of the neurosurgeon, accurate placement of the DBS electrodes, appropriate patient selection, and post-surgical management. Complication rates reported below are based on the combined results of four large series focusing on complications of DBS for a total of 360 patients (288 PD).22-25
These are complications that occur during or within 30 days of surgery. In these series, the surgical complications included death (0.6%—pulmonary embolism and aspiration pneumonia each in one patient); permanent neurologic deficits (2.8%); infection (5.8%); hemorrhage (3.1%); confusion/disorientation (2.8%); seizures (1.1%); CSF leak and peripheral nerve injury (0.6%); and venous infarction (0.3%).