Fading of Deep Brain Stimulation Efficacy Versus Disease Progression: Untangling a Gordian Knot

Parkinson's disease (PD) is a relentlessly progressive neurodegenerative disorder leading to increasingly motor and nonmotor disabling symptoms with a substantial risk of functional decline and reduced life expectancy. Since its approval for treating PD, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has gained a place as an effective treatment for the cardinal signs of the disease and—more important—for PD-related motor complications, that is, motor fluctuations and levodopa-induced dyskinesias. Several articles have shown significant improvement of motor symptoms and quality of life up to 5 years after DBS.1 Few others with follow-up periods ranging from 8 to 11 years have confirmed a persistent effect on motor complications and appendicular levodopa-responsive motor signs.2, 3 The patients of these long-term prospective series had, however, declined in terms of axial motor signs (speech, postural stability, and gait) as well as nonmotor symptoms, cognition in particular, thus presenting the typical features of the “long-term DBS syndrome.”4 Subsequent cohorts with follow-up up to 15 years after surgery have instead focused on disease milestones, such as psychosis, urinary incontinence, and death rate,5 confirming overall what was seen in non-DBS patients of the Sydney cohort.6 Because retrospective studies have shown that the motor scores off medication (usually for 12 hours) and OFF stimulation (usually for only 30 minutes) are not different than the preoperative scores,7 it has been argued that STN DBS might have a disease-modifying effect. There are a handful of experimental papers suggesting that DBS exerts disease-modifying effects mostly based on animal models and the appealing theory that a supposed excitotoxic effect of STN (the only glutamatergic nucleus of the basal ganglia) is mitigated by DBS. However, although large, randomized, and prospective trials are lacking—and probably not even ethical—studies using nuclear tracers of dopaminergic function have shown that STN DBS does not halt the underlying neurodegenerative processes.8 Clinical evolution of PD can be subdivided into early, moderate, and advanced phases, the latter characterized by the development of clinical milestones such as visual hallucinations, cognitive deterioration, recurrent falls, and admission in a long-term care facility. After the development of those milestones, independently from age or disease duration, all patients share a similar survival time, with cognitive disability milestone as the main survival predictor.9 Whether STN DBS is able to delay the development of these milestones and therefore survival have not been definitively answered. There are only a few uncontrolled long-term studies reporting frequencies of key disability milestones in DBS patients and a handful of controlled studies yielding conflicting findings.3, 10-16 In this issue of Movement Disorders Clinical Practice, 2 elegant papers addressed whether STN DBS effects wear off and whether DBS patients acquire disability milestones earlier than non-DBS patients. Although driven by different objectives, these studies are complementary and challenged by the unavoidable confounder of evaluating the long-term outcome of a surgical technique adopted in a highly variable and progressive disorder. Thomsen and colleagues17 compared the total intake of dopaminergic medication to baseline and found it to be significantly reduced by 44% at the long-term follow-up (8.5–15 years after surgery), in line with the findings by Mahlknecht and colleagues18 in patients on STN DBS for 15 years. These latter authors found that DBS patients carry a lower risk of experiencing recurrent falls and psychosis compared with control patients extracted from a registry study (EuroPa), supposedly through an improved motor status and dopaminergic therapy reduction. In keeping with studies with a shorter follow-up,2, 19 the study by Thomsen and colleagues showed that reprogramming DBS settings is beneficial also in the long term, as 83% of cognitively unaffected patients who consented to be reprogrammed improved after settings were changed. Interestingly, reprogramming strategy led to an increase of volume of tissue activated, thus supporting the view that either a tolerance to DBS or underdosed stimulation contributed to a decay of therapeutic efficacy, which could be mistaken instead as medication/stimulation resistance. The key question is whether STN DBS changed the natural history of these patients with PD. Mahlknecht and colleagues compared the incidence of recurrent falls, psychosis, dementia, and institutionalization in patients with PD with and without DBS during an observational period of 14 years.18 They found that only falls and psychosis milestones were less common in the DBS group, whereas no significant difference was observed for dementia, institutionalization, or death. Moreover, disease progression as assessed by the means of Hoehn and Yahr scores was not slower in DBS-treated patients. These results contrast with a recent study suggesting that STN DBS patients with PD survive longer as long as axial symptoms are under control.15 Despite the use of large cohorts and attempts to match groups properly, any long-term DBS study adopting a historical control cohort of non-DBS patients is heavily biased because of patient selection at baseline. For example, the development of dementia is paradoxically low in DBS cohorts perhaps as a result of strict cognitive screening to determine surgical eligibility.2 Overall, because of these intrinsic limitations, none of these studies can reach firm conclusions. The only available study able to answer these questions is the prospective, single-blind clinical pilot trial that randomized 30 subjects with early-stage PD to receive bilateral STN DBS plus optimal drug therapy versus optimal drug therapy alone (DEG050016, NCT0282152, IRB040797). Such a study has been ethically possible as enrolled patients on PD medications for 6 months to 4 years who did not need DBS, a paradox. Recently, the 5-year outcomes of 28 patients have been published, overall concluding that early STN DBS + optimal drug therapy subjects were on lower levodopa-equivalent daily doses and less polypharmacy and had reduced rest tremor off medication and OFF stimulation.20 Although the medication-related outcomes are expected and in keeping with the long-term observations published in this issue of Movement Disorders Clinical Practice,17, 18 the conclusion that the study “provides Class II evidence that DBS implanted in early-stage Parkinson's disease decreases the risk of disease progression” is challenged by the lack of significant effects on quality of life.20 In conclusion, disentangling how the fading of DBS efficacy and disease progression lead to the end of a second honeymoon of patients with PD is a complex issue needing future studies (Fig. 1). The evidence published in this issue of Movement Disorders Clinical Practice17, 18 suggest that the clinical milestones or survival of patients with PD are neither positively nor negatively influenced by DBS. Therefore, until further overwhelming evidence is published, we are obliged to still consider DBS a symptomatic elective procedure for patients with PD. Nevertheless, the overall safety and high efficacy of STN DBS is so well established that it should be readily proposed to patients with bothersome motor complications regardless of claims on disease progression. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A.F.: 1A, 1B, 1C, 2A, 2B M.M.: 1A, 1B, 1C, 2A, 2B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed patient consent as well as institutional review board approval were not necessary for this work. This work did not receive funding. A.F. received honoraria and/or research support from Abbott, Boston Scientific, Brainlab, Ceregate, and Medtronic. M.M. received honoraria and/or research support from Abbott. A.F. reports the following: consultancies with Abbvie, Abbott, Medtronic, Boston Scientific, Ceregate, Sunovion, Ipsen; advisory boards of Abbott, Abbvie, Boston Scientific, Ceregate, and Ipsen; honoraria from Abbott, Abbvie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, and Ipsen; and grants from University of Toronto, Weston Foundation, Abbvie, Medtronic, Boston Scientific, and Brainlab. M.M. reports the following: consultancies with St Jude and Abbott; advisory board of Abbott; honoraria from Abbott and Wiley/International Parkinson and Movement Disorders Society (IPMDS); royalties from Random House; and grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FLENI, Allergan, Mertz, and Sanofi Genzyme.

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