Contarino, M.F.

Hilten, J.J. van

Marinus, J.

Leiden University Scholary Publications

1  Does Deep Brain Stimulation of the subthalamic nucleus prolong survival in Parkinson’s disease?  M.F. Contarino, MD PhD1,2, J. Marinus1, PhD, J.J. van Hilten, MD PhD1 1. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands. 2. Department of Neurology, Haga Teaching Hospital, The Hague, The Netherlands.   Corresponding authors:  *M.F. Contarino, Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands (tel.: +31 71 526 3964; fax: +31 71 524 8253; e-mail: m.f.contarino@lumc.nl).  *J.J. van Hilten, Department of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands (tel.: +31 71 526 2134; fax: +31 71 524 8253; e-mail: j.j.van_hilten@lumc.nl).   Manuscript word count: 1393   Running title: Does DBS prolong survival in PD?  Keywords: Deep brain stimulation, survival, Parkinson’s disease  Financial disclosure / conflict of interest:  MFC: Advisory board: Medtronic, Boston Scientific. Independent consultant for Medtronic for research and educational issues. Speaking fees: Novartis Pharma BV (Jan 2017 – CME activity). Received a grant from the Stichting Parkinson Fonds. JM: None. JJvH: None. The DBS center of the Haga Teaching Hospital/LUMC received compensation for DBS training activities and an unrestricted educational grant from Medtronic. Funding sources: none.  2   Parkinson’s disease (PD) is associated with increased mortality, which has not changed much after the introduction of levodopa.1-3 According to a recent study, however, mortality rates in idiopathic PD are increased only moderately, with a reduction in life expectancy of about one year as compared to the general population (hazard ratio [HR] = 1.75; 95% CI: 1.39-2.21).4 Over the last decades, Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an effective treatment for drug-resistant resting tremor and disabling drug-induced motor complications in patients with PD. Growing data show an improvement of motor symptoms and quality of life in PD patients over a period of up to five years after DBS.5 The few available studies with longer follow-up periods (8-10 years), show a persistent effect on dopaminergic motor symptoms, although axial symptoms (gait, speech, postural stability) and non-motor symptoms (e.g. cognitive function) deteriorate. Data on quality of life in follow up above 5 years are scanty.6-11   It is hitherto still unclear whether STN DBS improves survival of patients with PD.  Several studies reported on survival of PD patients after DBS,10, 12, 13 but only three studies used a control group and are therefore potentially informative of a survival difference between patients who did or did not undergo STN DBS.14-16 One of these studies found no significant difference in survival in the DBS group in comparison with a PD control group derived from a population-based control series.14 Due to the study design and inclusion criteria used, biases in favour of the control group cannot be excluded. Indeed, patients were included if they were still alive after the inclusion period of four years and had completed two motor examinations, which led to the exclusion of 81 patients who had already died in the control group, as opposed to only two patients in the DBS group. In addition, important data such as disease duration at baseline or age at onset were not reported. Two other studies reported longer survival in the DBS-group.15, 16 In one study, the control group included patients who were deemed eligible for surgery but decided to continue medical treatment.15 The two patient groups did not show significant differences at baseline concerning age, gender, ethnicity, disease duration, amount of medication, or pre-existing diagnosis of depression. Even after adjusting for potential confounding factors, patients undergoing STN-DBS showed significantly longer survival (HR=0.29, 95% CI: 0.13-3  0.64, p=0.002) and were significantly less likely to be admitted to a residential care home (OR=0.1, 95% CI: 0.0-0.3, p<0.001) than those managed purely medically. Although this is a convincing study, some uncertainties remain because the control group was relatively small (41 patients), and the fact that patients in the control group refused surgery could theoretically by itself introduce some bias. In addition, relevant information on comorbidity, baseline UPDRS score and cognition was not available. The most recent study16 involved a large multicentre cohort study of 611 veterans with PD who received DBS and were retrospectively propensity-score matched to a cohort of 611 veterans with PD who were only medically managed. The results showed a survival advantage of approximately 7.6 months for patients with DBS (2291 vs 2063 days; HR=0.69, 95% CI: 0.56-0.85). It must be noted that, comparable to other methods aiming to resolve confounding problems in causal inference, the propensity score approach has its limitations.17 The justification of using a propensity score approach is evidently dependent on the availability of information on the individual and contextual confounders. Unfortunately, the authors had no information on age at onset, disease duration and disease stage at the index date. More importantly, they had also no information on the severity of motor (including postural instability, freezing, and speech) and non-motor symptoms (including cognitive function and psychiatric symptoms). Most of these symptoms that are often considered as exclusion criteria for DBS and negatively affect survival18, 19 will inevitably occur more frequently in the control group, thus favorably affecting survival in the DBS cohort. In addition, while, on the one hand, DBS may have been offered to patients in more advanced stages of the disease (with negative consequences for survival of the DBS cohort), on the other hand, surgery is usually withheld to patients who are too advanced in their disease to benefit from the procedure or have other comorbidities (with negative consequences for survival of the medically managed cohort). Despite the use of large cohorts and attempts to match groups properly, it is of note that the selection procedure for DBS involves some intrinsic biases that cannot be avoided, if not in a randomized controlled trial of sufficient sample size, in which patients are recruited from the same population, in the same time period, and where they are followed up sufficiently long. Such a trial in patients with advanced PD is probably unethical and not 4  feasible, given the demonstrated superiority of DBS in improving quality of life of selected patients as compared to best medical treatment, at least in the short to medium term. Nevertheless, although the evidence thus far is not fully conclusive, the data that are available seem to point to some increased survival in favour of DBS. This survival benefit may potentially be attributed to improved motor control in DBS patients, which may in turn positively influence general health, for example by restoration of weight loss, better swallowing and respiratory functions, and more efficient personal care. The results of one study indeed showed that a significantly lower proportion of DBS patients died of respiratory causes in comparison with medically managed patients,15 although this difference was not found in another study.16 Alternatively, increased survival after STN DBS might also point to a direct effect of stimulation on the disease course. The suggestion of neuroprotection has been proposed since the dawn of STN DBS therapy, based on the idea that the reduced glutamatergic cytotoxicity induced by STN neuromodulation, would favourably affect neurodegeneration.20 However, the experimental papers supporting this hypothesis were based on the use of artificial animal models that in many ways differs from the degenerative disease affecting patients with PD.20-22 So far, studies in PD patients have failed to convincingly demonstrate any neuroprotective effect of DBS. For example, a prospective study with serial functional neuroimaging (PET),23 showed annual progression rates in the caudate and putamen that were within the range of those reported in PD patients without DBS. Furthermore, neuropathology studies showed no differences in loss of pigmented neurons in the substantia nigra of patients with DBS as compared with PD patients without DBS.24 There could be several reasons for failure in demonstrating a neuroprotective effect, including the lack of appropriate biomarkers of disease progression and the fact that the few available studies were conducted in patients with advanced PD.  Indeed, DBS has traditionally been offered to PD patients at advanced stages of the disease, when it is possibly too late to halt neurodegeneration since the pathological processes are already too progressed.25 An important development is the recent trend towards operating at an earlier stage of the disease.26 It would be interesting to know whether survival would be more influenced by intervening earlier in the disease course. In this respect, the existing RCTs comparing the effect of surgery for patients at an earlier stage of the disease with the effect of “best 5  medical treatment”26 may provide important information after a sufficient follow-up. In this scenario, patients originally allocated to “best medical treatment” could still be offered DBS later in the disease course, allowing detecting a potential effect of a “delayed-onset” of neuromodulation and thus revealing important information on this issue.  In this context it is important to consider that DBS is a burdensome surgical treatment for the patients with potential serious, albeit rare, complications. More importantly, especially in the long term, DBS offers little or no benefit for non-dopaminergic motor and non-motor symptoms, affecting cognitive function, independent locomotion, and communication. Notably, these aspects have a predominant influence on quality of life. Against the background of the relatively small overall differences in life expectancy between PD patients and controls, any ‘true’ difference in survival between operated and non-operated patients, if existent at all, may be very hard to detect. Nevertheless, even if this issue is never fully resolved, it is important to realize that any potentially existent difference in survival is clearly outweighed by a considerable improvement in quality of life that operated patients experience over an extensive period of time.   Authors’ roles All authors have participated in the conception, writing, review and critique of the manuscript, and have approved the final version.  Financial disclosure last 12 months: MFC: Speaking fees: Novartis Pharma BV (Jan 2017 – CME activity). Received a grant from the Stichting Parkinson Fonds. J.Marinus and JJvH: none.  References:  1. Hely MA, Morris JG, Traficante R, Reid WG, O'Sullivan DJ, Williamson PM. The sydney multicentre study of Parkinson's disease: progression and mortality at 10 years. J Neurol Neurosurg Psychiatry 1999;67:300-307. 2. Posada IJ, Benito-Leon J, Louis ED, et al. Mortality from Parkinson's disease: a population-based prospective study (NEDICES). Mov Disord 2011;26:2522-2529. 3. Macleod AD, Taylor KS, Counsell CE. Mortality in Parkinson's disease: a systematic review and meta-analysis. Mov Disord 2014;29:1615-1622. 6  4. Savica R, Grossardt BR, Bower JH, et al. Survival and Causes of Death Among People With Clinically Diagnosed Synucleinopathies With Parkinsonism: A Population-Based Study. JAMA neurology 2017;74:839-846. 5. Lezcano E, Gomez-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. 6. Deuschl G, Agid Y. Subthalamic neurostimulation for Parkinson's disease with early fluctuations: balancing the risks and benefits. Lancet Neurol 2013;12:1025-1034. 7. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. Arch Neurol 2011;68:1550-1556. 8. Zibetti M, Merola A, Rizzi L, et al. Beyond nine years of continuous subthalamic nucleus deep brain stimulation in Parkinson's disease. Mov Disord 2011;26:2327-2334. 9. 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. 10. Bang Henriksen M, Johnsen EL, Sunde N, Vase A, Gjelstrup MC, Ostergaard K. Surviving 10 years with deep brain stimulation for Parkinson's disease--a follow-up of 79 patients. Eur J Neurol 2016;23:53-61. 11. Aviles-Olmos I, Kefalopoulou Z, Tripoliti E, et al. Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson's disease using an MRI-guided and MRI-verified approach. J Neurol Neurosurg Psychiatry 2014;85:1419-1425. 12. 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Propensity Score-Based Methods versus MTE-Based Methods in Causal Inference: Identification, Estimation, and Application. Sociological methods & research 2016;45:3-40. 18. de Lau LM, Verbaan D, Marinus J, van Hilten JJ. Survival in Parkinson's disease. Relation with motor and non-motor features. Parkinsonism Relat Disord 2014;20:613-616. 19. van Rooden SM, Verbaan D, Stijnen T, Marinus J, van Hilten JJ. The influence of age and approaching death on the course of nondopaminergic symptoms in Parkinson's disease. Parkinsonism Relat Disord 2015. 20. Rodriguez MC, Obeso JA, Olanow CW. Subthalamic nucleus-mediated excitotoxicity in Parkinson's disease: a target for neuroprotection. Ann Neurol 1998;44:S175-188. 21. Piallat B, Benazzouz A, Benabid AL. Subthalamic nucleus lesion in rats prevents dopaminergic nigral neuron degeneration after striatal 6-OHDA injection: behavioural and immunohistochemical studies. The European journal of neuroscience 1996;8:1408-1414. 22. 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Does Deep Brain Stimulation of the Subthalamic Nucleus Prolong Survival in Parkinson's Disease?

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Does Deep Brain Stimulation of the Subthalamic Nucleus Prolong Survival in Parkinson's Disease?

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