Subject Matter Experts: Istvan Takacs, M.D.; Gonzalo J. Revuelta, DO; and Nathan C. Rowland, M.D., Ph.D.
by Kimberly McGhee
Illustrations by Emma Vought
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For select patients with movement disorders, deep brain stimulation (DBS) can be life-changing. Though not a cure, DBS can alleviate some of the most debilitating symptoms of advanced Parkinson’s disease (PD),1-3 essential tremor (ET)4-6 and dystonia,7-8 often dramatically improving quality of life. Optimal DBS candidate selection can be facilitated with evaluation by a movement disorders specialist.
During lead implantation, the movement disorders neurologist and neurophysiologist work with the functional neurosurgeon to map the target region. A microelectrode targeting relevant basal ganglia structures is inserted through a burr hole in the skull. In traditional DBS, patients are placed in a stereotactic headframe and are awake for lead implantation; the team can get direct feedback on symptom control, monitor for possible side effects of stimulation and make necessary adjustments immediately. For patients who are intimidated by the headframe, smaller “frameless” platforms that are still bolted to the skull but do not surround it like the frame are available.
In a second operation, a pulse generator, a sort of pacemaker, is implanted below the collar bone to drive the system. Some weeks after implantation, allowing for wound healing, the DBS is activated and, over a series of follow-up visits, calibrated to best effect.
The cardinal symptoms of PD — bradykinesia, tremor, rigidity and postural instability — are associated with reduced striatal dopamine. Drug therapy is centered around dopamine replacement, in one of many formulations. Initially, levodopa (L-DOPA) helps patients maintain a predictable “on” period when most of their symptoms are well controlled. However, over time, the response to medication becomes less reliable. To address these fluctuations, the dosage is adjusted, and adjunctive dopaminergic therapies are added, raising the L-DOPA equivalent daily dose and subsequently raising the risk of L-DOPA-induced dyskinesias.
For PD patients experiencing motor fluctuations and dyskinesias, DBS can offer more predictable symptom relief. It can also be used to treat refractory tremor in patients with PD. The two primary DBS targets in PD are the subthalamic nucleus (STN) and the globus pallidus internus (GPi).
Multiple clinical trials have shown greater improvements in PDQ-39 scores (lower scores = improvement), a quality-of-life measure, with DBS than medical therapy alone. In a landmark trial by Deuschl et al in 156 patients with advanced PD younger than 75 (NCT00196911),1 the PDQ-39 score decreased by 10 points, a 25 percent improvement, six months after DBS, whereas almost no change was seen in the medical therapy group. In another randomized trial of 255 patients with advanced PD (NCT00056563) reported by Weaver et al in 2009,2 quality of life improved significantly more in the DBS arm than the medical therapy alone arm at six months, as evidenced by improved scores on the overall PDQ-39 and on seven of eight individual quality-of-life metrics. The multi-center PD SURG trial (Current Controlled Trials, number ISRCTN34111222),3 which enrolled 366 patients with advanced PD, showed a five-point improvement in the PDQ-39 summary score at one year in the DBS plus medical therapy group vs. 0.3 in the medical therapy group. The study is important as it shows lasting benefits for quality of life beyond the “honeymoon” period in the months just after surgery.
These trials also reported better control of motor symptoms, as well as greater gains in “on” time per day in the DBS plus medical therapy group. “On” time is defined as a period of good symptom control and mobility without dyskinesias. In the Deuschl trial, Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores improved by 41 percent in the DBS plus medical therapy group but remained virtually unchanged in the medical therapy alone group.1 In the Weaver trial, motor function improved meaningfully (i.e., by at least five points) in 71 percent of DBS patients but only 32 percent of best medical therapy patients.2 Gains of 4.5 hours and 4.6 hours of “on” time were reported by Deuschl and Weaver, respectively, in the DBS plus medical therapy group, with little or no change in the medical therapy group.
The Early STIM trial9 showed that DBS, initially considered a last- resort measure, can be effective earlier than once thought in patients with advanced PD. Most trials of DBS vs. medical therapy alone have enrolled patients with advanced PD who are 11.1 to 13.8 years from diagnosis. In contrast, the EARLY STIM trial, which evaluated quality of life at two years, enrolled patients who were on average 7.5 years from diagnosis and experiencing early motor complications. PDQ-39 scores improved by 7.8 points in the DBS group but decreased by 0.2 points in the medical therapy group. Motor disability, activities of daily living, motor complications and “on” time with no dyskinesia all were significantly better at two years in the DBS-treated group than in the medical therapy group.
As with any surgery, DBS has its risks, which include intracerebral hemorrhage (ICH), infection and device failure and migration that sometimes require reoperation. In both the Deuschl and Weaver trials, DBS was associated with a higher rate of serious adverse events than the medical therapy group; however, the medical therapy group had more adverse events overall. The most common serious adverse event reported in the Weaver trial was surgical site infection (9.9 percent): 12 DBS-treated patients had 16 infections that resulted in antibiotic therapy and removal of the leads, neurostimulator or both. The rate of infection is quite variable among studies, with some groups reporting infection rates as low as 1.5 percent in first observation.10 Although most serious adverse events in both trials resolved without permanent sequelae, there was a fatality due to ICH among the DBS-treated group in both the Deuschl and Weaver trials. Two other fatalities — one due to suicide and one to pneumonia — were reported in the Deuschl trial for the DBS-treated group, but not in any other large-scale trials. In EARLY STIM, almost 18 percent of DBS-treated patients experienced a surgery-related adverse event, such as infection or device failure. All but one of these resolved without permanent consequence, though reoperation was necessary in four patients.
Overall, the data provide strong evidence that DBS can greatly improve quality of life and provide significant relief from some of the most debilitating symptoms of PD, but they also show that DBS is not without risk and that careful patient selection is crucial for best outcomes.
Deep brain stimulation is most effective for PD patients with motor fluctuations, dyskinesias and/or refractory tremor. For more complicated symptoms such as gait problems, DBS is often very effective at treating them if they are L-DOPA-responsive symptoms.
Contraindications for DBS include dementia and serious comorbidities. Age and psychiatric conditions need to be considered but are not contraindications. Most large clinical trials showing improved quality of life and motor control have involved patients under 70 or 75, and increased surgical complications would be expected in older patients. However, a retrospective cohort study of 1757 patients who had undergone DBS showed that patients older than 75 had the same complication rate at 90 days as younger patients. This suggests that age alone should not exclude patients from treatment.11
Essential tremor, one of the most common movement disorders, especially among the elderly, often goes undiagnosed.6 Referral of patients with tremor to a movement disorders specialist will ensure appropriate management. For medication-refractory ET, DBS to the nucleus ventrointermedius (Vim) of the thalamus effectively controls tremor long-term4-6 — out to 13 years in one study.12 Complications are fewer than with traditional thalamotomy. Focused ultrasound, a noninvasive form of thalamotomy that concentrates multiple intersecting beams on targeted brain tissue, was recently approved by the FDA for ET (and is under trial for PD). It offers the advantage over DBS of not requiring permanent implantation of a device. However, unlike DBS, which enables adjustment of stimulation parameters to achieve best outcomes, the effects of focused ultrasound, a type of lesional surgery, are irreversible and can only be performed unilaterally.
In dystonia, muscles with opposing function contract simultaneously to cause tense abnormal posture and movement. Strong clinical trial evidence suggests that bilateral neurostimulation to the GPi can improve motor symptoms more than sham stimulation in patients with generalized primary dystonia,7-8 with the Burke-Fahn-Marsden Dystonia Scale improving by 14.6 points from baseline at three months7 and by 25.3 points at one year.8 Successful DBS in primary dystonia has led patients with secondary dystonia to seek DBS, but results have been variable.13 For tardive dystonia, GPi DBS can also be very effective, with some symptoms resolving immediately and others, such as neck and trunk dystonia, improving over time.14 Subjective improvements have been reported in patients with dystonia secondary to cerebral palsy13; however, more research is needed to establish the efficacy of DBS in patients with cerebral palsy, especially children.
Traditional DBS leads stimulate circumferentially. Newer-generation electrodes are directional, enabling the electrical stimulation to be “steered” toward the intended targets and limiting spread of current to surrounding tissue. The Infinity™ System (St. Jude Medical/Abbott, St. Paul, MN), which has directional leads, was approved in 2016, and the Vercise™ System (Boston Scientific, Marlborough, MA), which enables independent control of the current in each contact, was approved in 2017.
Current DBS systems are open-looped — they deliver constant electrical stimulus. Closed-loop systems, such as the RNS® System (NeuroPace, Mountain View, CA) for epilepsy, deliver electrical stimulus only when they sense a seizure about to occur. Research is progressing on closed-loop DBS for PD. One of the closed-loop systems in development relies on changes in the cortical regions of the brain to signal the DBS system to fire. Closed-loop systems remain investigational but are promising and could represent the future of DBS.
1. Deuschl G, et al. N Engl J Med. 2006 Aug 31;355(9):896-908.
2. Weaver FM, et al; for the CSP 468 Study Group. JAMA 2009 Jan 7;301(1):63-73.
3. Williams A, et al; Lancet Neurol. 2010 Jun;9(6):581-591.
4. Koller WC, et al. Mov Disord 2001;16: 464-468.
5. Pahwa R, et al. J Neurosurg 2006; 104: 506-512.
6. Deuschl G, et al. Lancet Neurol. 2011; 10: 148–161.
7. Kupsch A, et al; for the Deep-Brain Stimulation for Dystonia Study Group. N Engl J Med 2006;355:1978-1990.
8. Vidailhet M, et al. N Engl J Med. 2005 Feb 3;352(5):459-467.
9. Schuepbach WM, et al; for the EARLYSTIM Study Group. N Engl J Med. 2013 Feb 14;368(7):610-622.
10. Voges J, et al. J Neurol Neurosurg Psychiatry. 2006 Jul;77(7):868-872.
11. Delong M, et al. JAMA Neurol. 2014;71(10):1290-1295.
12. Baizabal-Carvallo JF, et al. J Neurol Neurosurg Psychiatry 2014;85:567–572.
13. Koy A, Timmermann L. Eur J Paediatr Neurol. 2017 Jan;21(1):118-121.
14. Shaikh AG, et al. Parkinsonism Relat Disord. 2015 Feb;21(2):116-119.
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