Fading of Deep Brain Stimulation Efficacy Versus Disease Progression: Untangling a Gordian Knot Alfonso Fasano, MD, PhD1,2,3,4

and Marcelo Merello, MD, PhD5,6,7,*

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 longterm 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.


Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada; 2Division of Neurology, University of Toronto, Toronto, Ontario, Canada; 3Krembil Brain Institute, Toronto, Ontario, Canada; 4Center for Advancing Neurotechnological Innovation to Application, Toronto, Ontario, Canada; 5Edmond J. Safra Program in Parkinson’s Disease, Movement Disorders Unit, Neuroscience Department, Raul Carrea Institute of Neurological Research, FLENI, Buenos Aires, Argentina; 6Pontifical Catholic University of Argentina, Buenos Aires, Argentina; 7 National Scientific and Technological Research Council, Buenos Aires, Argentina *Correspondence to: Dr. Marcelo Merello; E-mail: [email protected] Relevant disclosures and conflicts of interest are listed at the end of this article. Received 7 July 2020; accepted 15 July 2020. Published online 21 September 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.13041

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 747–749. doi: 10.1002/mdc3.13041 © 2020 International Parkinson and Movement Disorder Society




FIG. 1. A possible framework to understand the natural history of PD after STN DBS. Besides the obvious selection bias at the time of surgery (eg, patients with good cognition, no comorbidities, and so on are offered DBS), other long-term effects are indirectly or directly related to DBS. Tremor reduction is the only proven direct effect of DBS on disease progression so far. DBS, deep brain stimulation; PD, Parkinson’s disease; STN, subthalamic nucleus.

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 748

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 levodopaequivalent 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.■

Author Roles (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

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 747–749. doi: 10.1002/mdc3.13041



Disclosures Ethical Compliance Statement: 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. Funding Sources and Conflicts of Interest: 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. Financial Disclosures for the Previous 12 Months: 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.

5. Constantinescu R, Eriksson B, Jansson Y, et al. Key clinical milestones 15 years and onwards after DBS-STN surgery-a retrospective analysis of patients that underwent surgery between 1993 and 2001. Clin Neurol Neurosurg 2017;154:43–48. 6. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008;23:837–844. 7. Tagliati M, Martin C, Alterman R. Lack of motor symptoms progression in Parkinson’s disease patients with long-term bilateral subthalamic deep brain stimulation. Int J Neurosci 2010;120:717–723. 8. Hilker R, Portman AT, Voges J, et al. Disease progression continues in patients with advanced Parkinson’s disease and effective subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry 2005;76:1217–1221. 9. Kempster PA, Williams DR, Selikhova M, Holton J, Revesz T, Lees AJ. Patterns of levodopa response in Parkinson’s disease: a clinicopathological study. Brain 2007;130:2123–2128. 10. Ngoga D, Mitchell R, Kausar J, Hodson J, Harries A, Pall H. Deep brain stimulation improves survival in severe Parkinson’s disease. J Neurol Neurosurg Psychiatry 2013;85:17–22. 11. Lilleeng B, Brønnick K, Toft M, Dietrichs E, Larsen JP. Progression and survival in Parkinson’s disease with subthalamic nucleus stimulation. Acta Neurol Scand 2014;130:292–298. 12. Lezcano E, Gómez-Esteban JC, Tijero B, et al. Long-term impact on quality of life of subthalamic nucleus stimulation in Parkinson’s disease. J Neurol 2016;263:895–905. 13. Weaver FM, Stroupe KT, Smith B, et al. Survival in patients with Parkinson’s disease after deep brain stimulation or medical management. Mov Disord 2017;32:1756–1763. 14. Contarino MF, Marinus J, van Hilten JJ. Does deep brain stimulation of the subthalamic nucleus prolong survival in Parkinson’s disease? Mov Disord 2018;33:947–949. 15. Lau B, Meier N, Serra G, et al. Axial symptoms predict mortality in patients with Parkinson disease and subthalamic stimulation. Neurology 2019;92:e2559–e2570. 16. Deuschl G, Schuepbach MWM, Schade-Brittinger C, Tonder L, Krack P. Author response: quality of life predicts outcome of deep brain stimulation in early Parkinson disease. Neurology 2020;94:413–413.

References 1. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003;349:1925–1934. 2. Fasano A, Romito LM, Daniele A, et al. Motor and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic implants. Brain 2010;133:2664–2676.

17. Thomsen BLC, Jensen SR, Clausen A, Karlsborg M, Jespersen B, Løkkegaard A. Deep brain stimulation in Parkinson’s disease: still effective after more than eight years. Mov Disord Clin Pract 2020; https://doi. org/10.1002/mdc3.13040. 18. Mahlknecht P, Peball M, Mair K, et al. Has deep brain stimulation changed the very long-term outcome of Parkinson’s disease? A controlled longitudinal study. Mov Disord Clin Pract 2020; https://doi.org/10.1002/ mdc3.13039.

3. Rizzone MG, Fasano A, Daniele A, et al. Long-term outcome of subthalamic nucleus DBS in Parkinson’s disease: from the advanced phase towards the late stage of the disease? Parkinsonism Relat Disord 2014;20: 376–381.

19. Moro E, Poon YY, Lozano AM, Saint-Cyr JA, Lang AE. Subthalamic nucleus stimulation: improvements in outcome with reprogramming. Arch Neurol 2006;63:1266–1272.

4. Fasano A, Aquino CC, Krauss JK, Honey CR, Bloem BR. Axial disability and deep brain stimulation in patients with Parkinson disease. Nat Rev Neurol 2015;11:98–110.

20. Hacker ML, Turchan M, Heusinkveld LE, et al. Deep brain stimulation in early-stage Parkinson’s disease: five year outcomes. Neurology 2020;95: e393–e401.

MOVEMENT DISORDERS CLINICAL PRACTICE 2020; 7(7): 747–749. doi: 10.1002/mdc3.13041


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EDITORIAL COMMENTARY CLINICAL PRACTICE Fading of Deep Brain Stimulation Efficacy Versus Disease Progression: Untangling a Gordian Knot Alfonso Fasano...
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