Clinical efficacy

Deep-brain stimulation is an appropriate treatment for advanced PD patients suffering from levodopa-associated motor complications. Deep-brain stimulation combined with standard medical therapy is superior to medication alone to reduce the adverse effects of medication and improve patient quality of life [2, 7, 8]. The benefits of high-frequency electrical stimulation include significantly reduced levodopa-associated dyskinesias and motor fluctuations [9, 10], improved quality of life [2, 11] and reduced need for PD medication [7, 12, 13]. Thus, DBS is now the standard of care for appropriately selected advanced PD patients.

The success of DBS in advanced PD encourages discussions of whether therapeutic benefits could be extended or even enhanced if offered sooner in PD. A recently completed multinational study was the first appropriately powered, randomized, controlled clinical trial to investigate DBS effects in PD subjects with midstage PD [14]. Quality of life in the neurostimulation group improved by 26% 2 years after surgery, with no improvement in the medication group. Between-group scores for motor disability, ADLs, levodopa-associated motor complications, and time with good mobility and no dyskinesias all significantly favored the neurostimulation group. Medication was reduced by 39% in the DBS group but was increased by 21% in the medication-alone group. Overall, neurostimulation plus medical therapy was superior to medication alone in midstage PD patients after 2 years of treatment.

While this large midstage PD trial was well executed, notable limitations to this study should be considered. First, PD research historically suffers from a robust placebo effect, partially due to patients’ expected benefit inducing dopamine release [15]. Except for the motor subset of the Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, outcome measures for this study were not blinded, and it is possible that the superiority of the DBS group was influenced by the placebo effect. Secondly, subjects were randomized either to undergo DBS surgery or to continue standard medical treatment. This study design inherently established divergent treatment procedures between the two groups. Since the neurostimulation group experienced additional procedures associated with DBS, performance bias may have been introduced into the study and influenced its outcomes [16]. Thirdly, PD is a slowly progressing condition that causes increased disability for several decades after onset. This midstage PD study only reported outcomes after 2 years of treatment, and the results of long-term stimulation in midstage PD remain unknown. Finally, this study was conducted in a younger PD population (average age <53 years; Table 29.1) whose outcomes may not reflect the average midstage PD patient (average onset of PD is 60–65 years [18]). Therefore, these results should be interpreted carefully and verified by independent investigators before definitive conclusions are made about the efficacy of DBS in the general midstage PD population.

Surgical candidacy

Successful DBS therapy relies on careful patient selection [19]. The widespread use of DBS in advanced PD has led to well-defined selection criteria for patients who are predicted to respond favorably to neurostimulation. The best outcomes for DBS are with advanced PD patients who (i) respond well to levodopa; (ii) lack levodopa-resistant axial symptoms; (iii) are not significantly cognitively impaired; (iv) are without active psychiatric conditions; and (v) are younger in age [19]. The current US Food and Drug Administration (FDA)-approved indication for DBS is advanced PD when symptoms are not adequately controlled by medications. Midstage PD patients are often sufficiently treated with medications, a feature that distinguishes them from those currently offered DBS. Ideally, the midstage DBS selection criteria would expand candidacy to include individuals before experiencing comorbidities that might preclude them from receiving the therapy. More research is required to fully understand the optimal DBS selection criteria for patients effectively managed by PD medication.

The potential for misdiagnosis is increased in the initial stage or with younger-onset PD. Parkinson’s disease is challenging to diagnose because there is currently no biomarker available. Medical history, neurological examinations and response to dopaminergic medication are clinical measures cumulatively assessed by physicians in order to reach the diagnosis. This is often challenging, because not only is PD a heterogeneous condition but initial PD symptoms are mild and share features of other parkinsonian disorders. Despite symptom overlap, these atypical parkinsonism syndromes typically do not respond to DBS [20]. Therefore, offering stimulation before the disease is advanced might increase the rate of implanting patients who later prove to have a neurodegenerative condition other than PD [21]. A clear advantage to delaying DBS until PD symptoms are not adequately controlled with medications is reducing the chance of exposing patients who will not respond to stimulation to the risks, costs and expectations of DBS.

Deep-brain stimulation risks

Deep-brain stimulation is safe, and device surgery has very low complication rates. However, DBS remains an invasive procedure that involves intracranial implantation of stimulating electrodes and associated hardware. The potential benefits of DBS must be carefully weighed against the risks of surgery, the device and stimulation-associated side effects. These risks are often justified by the potential benefits of DBS for advanced PD patients who suffer from diminished quality of life without other viable treatment options. Noninvasive treatments are available for earlier-stage PD patients, and DBS in this population would expose patients to the risks before exhausting safer therapeutic options. Additionally, implanting sooner in PD would inherently mean that patients would live longer with any lasting adverse device effects compared with if they were offered DBS later in life. Without evidence supporting safe and effective longitudinal outcomes for DBS in earlier PD stages, there are ethical concerns with exposing patients to the risks of surgery while medication remains beneficial.

In addition to surgical risks such as stroke (0–2%), intracranial hemorrhage (0–10%), infection (0–15%) and death (0–4.4%) [19], there are also concerns with the DBS hardware. Device-related problems include infection, electrode migration, lead fracture or erosion, and battery failure [22]. Correcting for DBS hardware deficiencies requires more surgery, which correlates with increased risk and additional costs. Even optimally functioning stimulator batteries only last an average of 4–7 years, after which they must be surgically replaced [23]. Since PD patients implanted sooner with DBS would have a longer in vivo device time, this population could experience an increased frequency of hardware malfunction or device-related repairs.

Advocates contend that earlier DBS intervention may extend the benefits of stimulation (i.e. motor function, quality of life and ADLs) over a longer period of time. This argument is counterbalanced by the chance of prolonged exposure to adverse effects known to accompany DBS. Although stimulation does not cause neuropsychological decline [24], subthalamic nucleus (STN)-DBS surgery is consistently associated with reduced verbal fluency performance [25]. Deep-brain stimulation is also linked to neuropsychiatric issues and weight gain [26, 27]. A controversial neuropsychiatric concern tied to DBS surgery is an increased risk of suicide [28], although multiple factors independent of the surgery and stimulation could account for this perceived rise in suicidality. Physicians, patients and caregivers considering earlier intervention must fully understand the potential lifelong consequences of DBS.

Economic impact

The increased costs of DBS are attributed to the device, surgery, hospitalization and follow-up visits. These expenses are partially offset by the reduced need for medication after surgery, but studies evaluating the cost-effectiveness of DBS were conducted over relatively short time periods (i.e. less than 5 years after surgery) [12, 13, 29]. Implanting patients sooner in the course of PD would extend their time with the device, which may ultimately increase the number of device-related procedures (i.e. battery replacements) [23]. Additionally, DBS patients require visits with neurologists who are familiar with adjusting stimulation settings and medication regimens to provide optimal clinical benefit. This specialized care often involves travel to distinct centers, which can be more burdensome than visits to local neurologists. This travel may impact both patient and caregiver productivity by requiring more time off work. Additionally, long-term adverse effects of DBS could also force early retirement of the patient and/or the caregiver and negatively impact the economic value of neurostimulation. Therefore, it is not yet known whether or not DBS is cost-effective over longer periods of time.

Disease modification

Many therapies treat PD symptoms, but no intervention has been shown to slow, halt or reverse neurodegeneration, disease progression or increasing disability. Efforts to identify neuroprotective strategies are hindered by the lack of an objective biomarker to track disease progression. Dopaminergic imaging studies quantifying nigral neurons are difficult to interpret because of compensatory mechanisms likely arising both naturally in PD and from the therapeutic interventions used to treat PD symptoms (i.e. dopaminergic medications) [30]. Therefore, neuroprotection can only be inferred by clinical rating scales or patient questionnaires. These measures are highly subjective and are ultimately influenced by multiple variables. Until a validated biomarker for PD is identified, it will be challenging to conduct clinical trials to definitively address neuroprotection.

The FDA approved DBS as an adjunctive therapy for advanced PD in 1997. Despite the wealth of clinical research on DBS in PD, there is no conclusive evidence that stimulation modifies PD progression. Several randomized, controlled trials of DBS in advanced PD show progressive worsening of symptoms over time [9, 31, 32]. Furthermore, despite active and clinically beneficial stimulation, DBS-treated PD patients develop axial, levodopa-resistant symptoms as the disease progresses [33]. This clear advancement of PD in late-stage patients suggests that DBS only treats PD symptoms and does not impact the natural course of the disease.

One study addressed disease progression in PD using fluorodopa positron emission tomography (¹⁸F-DOPA PET) to quantify dopaminergic function [34]. Despite clinically efficacious DBS treatment (i.e. reduced PD medication and improved UPDRS scores), advanced PD patients showed a continuing decline in dopaminergic function over 16 months. This study was limited by its small sample size and the absence of a comparative medical therapy control group, but these results suggest that stimulation cannot protect dopaminergic neurons in advanced PD.

Despite lacking overt clinical evidence supporting stimulation-related modification of PD progression, advocates of DBS earlier in the course of PD are motivated by preclinical findings suggesting that active stimulation is neuroprotective [35–39]. Several studies show stimulation applied after dopaminergic lesioning protects nigral neurons [38, 39]. While animal models of PD have been useful tools to understand certain aspects of the disease (such as identifying treatments for dopamine deficiency), they do not fully recapitulate the age-dependent, progressive nature of PD [40]. So far, neuroprotective therapies that show promise in laboratory models have failed to translate into successful interventions in clinical trials. The DBS-induced neuroprotection observed in animal studies could be an artifact that fails to reflect accurately how stimulation influences the basal ganglia in PD.

Clinical efficacy

Randomized controlled trials have demonstrated that DBS effectively relieves medication-induced motor complications in advanced PD patients [2, 7]. Long-term analyses confirm that these benefits are retained for up to 10 years after surgery [33, 41, 42]. Recently, a longitudinal study showed that DBS-mediated improvements in motor function and quality of life translated to enhanced survival and a reduced need for residential nursing care compared with standard medical therapy [43]. Results from this 10-year trial support the idea that the established symptomatic benefits of DBS also have lasting effects for patients via enhanced survival and functional independence. The long-term success of DBS therapy for advanced PD patients raises the intriguing question of whether there could be additional value from stimulation if offered earlier in the disease.

This hypothesis was tested recently in a population of midstage PD patients who still responded to PD medications but who also experienced motor complications [14]. This 2-year, randomized, multinational, parallel-group clinical trial compared STN-DBS plus medical therapy with medication alone in midstage PD patients experiencing levodopa-associated motor complications for 3 years or less (Hoehn and Yahr scale score <3 on medication; Table 29.1). Quality of life was significantly improved in the neurostimulation group over a 2-year period compared with the medication group. Subjects treated with DBS also improved considerably in motor disability, ADLs, levodopa-induced motor complications, and time with good mobility without dyskinesias. Although this was an open-label study, the validity of their findings was supported by blind assessments of the motor subset of the UPDRS. Furthermore, medications were appropriately managed according to current guidelines, as determined by an independent expert panel. This study was the first randomized controlled DBS trial in PD subjects who were still effectively managed by dopaminergic medication. Additional investigations in midstage PD are strongly encouraged to verify the results of this landmark study.

Surgical candidacy

Although DBS is an effective PD treatment, it is currently restricted to use in late-stage patients (disease duration 10–15 years, Table 29.1) [19]. Deep-brain stimulation is only considered in PD patients whose symptoms are no longer adequately controlled with medication (i.e. individuals with severe levodopa-associated side effects) and in those without significant cognitive and psychiatric symptoms. Unrelated to DBS, neuropsychiatric symptoms arise as part of PD and are relentlessly progressive when they occur [44]. Advancing age is also associated with the development of comorbidities, such as cardiac disease, dementia, diabetes and hypertension. Withholding DBS treatment until the late disease stage often excludes PD patients who would otherwise benefit from the therapy.

Because stimulation improves levodopa-dependent PD features, DBS success correlates strongly with patients who are highly responsive to levodopa without significant axial symptoms [45]. By the time patients reach the advanced stages of PD, symptoms develop that are resistant to medication and subsequently also refractory to stimulation [9, 46]. Therefore, DBS intervention sooner in PD, when dopaminergic symptoms predominate, should be considered to maximize the therapeutic benefit of stimulation.

In order to be considered for DBS surgery, advanced PD patients must have exhausted all other medical treatment options. Withholding DBS until this advanced stage can leave patients desperately searching for a viable treatment, and expectations of patients and families often exceed what is therapeutically possible. A difficult issue arises with late-stage DBS that stems from patient and family disappointment after surgery [22]. Unrealistic expectations combined with the stimulation-resistant symptoms that develop in late PD could contribute to the diminished psychosocial outcomes for some DBS patients [47]. Because patients with midstage PD are more responsive to levodopa therapy and experience fewer medication-resistant symptoms, this population is innately poised to achieve a better response to stimulation. Since medication still effectively treats symptoms, midstage PD patients are also less likely to adopt a last-resort mentality reported in some DBS patients with advanced PD [48]. Thus, midstage patients might have more realistic expectations of DBS outcomes compared with advanced PD patients.

Deep-brain stimulation risks

Overall perioperative adverse event rates are 18–23%, but the majority of these events are transient and resolve without sequelae [2–4]. Furthermore, DBS is an adjustable therapy – stimulation settings can be fine-tuned to maximize the clinical benefit and also minimize the occurrence and magnitude of stimulation-associated side effects. Unlike other surgical treatments, DBS is reversible, such that the device can be turned off or even removed if necessary. The surgical procedure for DBS has improved since the technique was introduced in the 1980s. Since DBS has emerged as an effective therapy for late-stage PD, the device technology and experience of surgical teams has also continually progressed. These advances account for reduced complication rates, especially with regard to intracerebral hemorrhage (<2%) and incidence of lead fracture or migration [19]. There are few reports of perioperative adverse event rates for DBS in earlier PD stages, but similar implanting procedures and target brain regions suggest that surgical complications would be comparable to later stages. A midstage PD study reported surgical complication rates similar to those accepted for advanced-stage PD [14]. This midstage PD data suggests there is no increased surgical risk associated with implanting the device sooner in PD.

Although DBS improves motor symptoms and complications of PD, cognitive domains are also impacted by surgery and/or neurostimulation. These post-surgery cognitive changes often resolve over the long term, but one cognitive dysfunction that is commonly reported is reduced verbal fluency scores after STN-DBS. This cognitive decline is believed to be due to effects of microlesions from the surgical procedure and is not a result of neurostimulation [8]. Reduced verbal fluency after DBS surgery is often relatively mild, and in some cases, patients and families are unable to detect the declines that are reported by neuropsychological tests [49]. Preexisting cognitive impairment is a predictor of poorer cognitive performance after surgery [24, 50]. The contradictory reports on cognitive assessments after DBS are further confounded by underlying PD progression, which likely accounts for the reported cognitive decline [46]. For most patients, the dramatic benefits in quality of life and motor symptoms far exceed the risks of mildly reduced verbal fluency.

An increased risk of postoperative suicide in STN-DBS patients has been suggested [28], but recent analysis of data from a prospective, randomized, controlled study found no increase in suicidal behavior after STN-DBS surgery [51]. Instead, the authors pointed to the increasing evidence supporting the hypothesis that risk factors such as rapid and significant decreases in dopaminergic medication as well as substantial medical and psychiatric comorbidities may contribute to suicidal behaviors in the PD population. If this model is true, midstage PD patients would be expected to have reduced risk for suicidal ideation because they require less medication (Table 29.1) and have less comorbidity than in advanced PD. Alternatively, others suggest that PD patients who choose to undergo surgery have a higher risk for suicidal behavior than patients who opt against surgery [14]. This hypothesis is supported by studies in mid- and advanced-stage PD that report similar suicidal risk between treatment groups, which was higher than the risk in the general PD population [4, 14]. Investigators in the midstage PD study developed a suicidal risk monitoring procedure to offer surveillance and immediate intervention in order to address suicidal ideation [14]. Based on the currently available reports, there is no evidence confirming that STN-DBS increases suicidal risk. Thus, this speculative risk does not justify withholding DBS from patients sooner in PD

Economic impact

Parkinson’s disease causes a significant economic burden on the individual patient due to its progressive nature over many years. Direct costs of PD (i.e. medication and patient care) significantly increase over time as PD progressively advances. Although DBS is initially an expensive procedure, it may prove to be a cost-effective alternative to standard medical therapy. The use of STN-DBS considerably reduces the requirement for PD medication [12, 13], which results in savings after 2 years that are projected to extend long term [12, 52]. It is reasonable to hypothesize that implanting sooner may extend and improve this economic benefit, due to more years with reduced medication costs.

There are also indirect measures of the economic impact of PD therapies to consider. The average onset age of PD is 60–65 years [17], which affects a population transitioning into retirement. Parkinson’s disease patients experience decreasing productivity and uniformly become disabled from gainful employment. Improving quality of life and reducing symptoms may extend workable years and delay the retirement that PD often forces prematurely. Deep-brain stimulation improves patient quality of life and ADLs for late-stage PD patients [29], and these measures are also improved by stimulation in midstage PD [14]. The enhanced quality of life provided by DBS could also potentially provide patients with more-active and enjoyable retirement years if implanted sooner, rather than waiting until more-severe disability develops. A longitudinal study recently showed that DBS significantly reduced the need for residential nursing care and enhanced the survival of advanced PD patients [43]. Additionally, patient access to programming is becoming more obtainable, as increasing numbers of community-based general neurologists are adopting DBS therapy. Caregiver burden is also not increased as a result of DBS therapy [53]. Extending patient and caregiver vocational productivity (i.e. during midstage PD) and reducing the cost of nursing care (i.e. during advanced PD) may offer significant economic benefit for PD patients considering DBS.