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Subthalamic Stimulation Improves Motor Function But Not Home and Neighborhood Mobility Jean-Franc¸ois Daneault, PhD(c),1,2 Christian Duval, PhD,2,3 !bastien Barbat-Artigas, PhD(c),3 Se Myle`ne Aubertin-Leheudre, PhD,3,4 Nicolas Jodoin, MD, FRCP(c),5 Michel Panisset, MD, FRCP(c)5 and Abbas F. Sadikot, MD, PhD, FRCS(c)1* 1

Cone Laboratory for Research in Neurosurgery, Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada 2Centre de !riatrie de Montre !al, MonRecherche de l’Institut Universitaire de Ge !partement des Sciences Biologiques, Uni!al, Que !bec, Canada 3De tre ! du Que !bec a " Montre !al, Montre !al, Que !bec, Canada versite 4 !partement de Kinanthropologie, Universite ! du Que !bec a " MonDe !al, Montre !al, Que !bec, Canada 5Unite ! des troubles du mouvement tre !-Barbeau, Centre Hospitalier de l’Universite ! de Montre !al, MonAndre !al, Que !bec, Canada tre

ABSTRACT Objective: Subthalamic (STN) deep brain stimulation (DBS) is a recognized therapy for alleviating motor symptoms of Parkinson’s disease (PD). However, little is known about its impact on mobility, an important component of quality of life (QoL). To address this issue, we assessed the impact of STN DBS on lifespace mobility and QoL. Methods: Twenty surgical patients with PD were assessed using mobility and QoL scales and the United Parkinson’s disease rating scale, and results were compared before surgery and 6 to 9 months postoperatively. Results: STN DBS significantly improved motor dysfunction but had a limited impact on measures of lifespace mobility and QoL. Interpretation: STN DBS improves motor function and some components of QoL. However, motor recovery does not translate into improved life-space in the intermediate term. In addition to a focus on motor function, multidisciplinary attention to increasing mobility may further improve C 2014 InternaQoL in the intermediate and long-term. V tional Parkinson and Movement Disorder Society Key Words: Parkinson’s disease, movement disorder, STN, DBS, quality of life, life-space

REPORTS

symptoms in Parkinson’s disease (PD).1 The subthalamic nucleus (STN) is a validated target with welldemonstrated motor efficacy.2-4 At present, optimization of the stimulation parameters is mainly based on the control of cardinal motor symptoms, with avoidance of acute side effects.5 How improvements in motor symptoms after parameter optimization translate into changes in everyday mobility is currently unknown. One way to quantify mobility is to evaluate patients’ “life-space.” Life-space is defined as the size of the area a person purposely moves through in daily life, frequency of travel within that space,6,7 and the person’s dependency in getting to specific locations within that space.8 Life-space captures home and community mobility; hence the desire for movement and participation in the larger social environment. Increased lifespace is highly related to quality of life (QoL) and reduced life-space is associated with mortality.6 In PD, loss of mobility leads to reduced participation in social activities, which impairs QoL.9,10 This phenomenon is exacerbated by disease progression and complications related to treatments.11,12 Studies demonstrate a significant but variable improvement in overall QoL after STN DBS, ranging from 14% to 58%.2,3,13 Improvement for subsections of QoL showed just as much variability.14-16 For example, the mobility subscore in the PDQ-39 shows improvement ranging from 26% to 60% after STN DBS. Since QoL questionnaires are not designed specifically to assess home and community mobility (e.g., life-space), they may lack specificity, which may explain the wide range of observed

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*Correspondence to: Abbas F. Sadikot MD, PhD, FRCSC, Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, 3801 University Street, Room: 688, Montreal, H3A 2B4 Canada, E-mail: [email protected] Funding agencies: This study was supported by Parkinson Society Canada Graduate Student Award (Daneault) and a Canadian Institute of Health Research (CIHR) Doctoral scholarship (Barbat-Artigas). Drs. Duval and Aubertin-Leheudre are supported by a Fonds de la Recherche du !bec-Sante ! salary grant. This work is also supported by operating Que grants to Drs. Sadikot and Duval from the CIHR and the Parkinson’s Society of Canada Relevant conflicts of interest/financial disclosures: Drs. Daneault, Barbat-Artigas, Aubertin-Leheudre, Duval, and Sadikot declare that they have no competing interests. Dr. Jodoin received research grants from AbbVie and travel grants from Teva Canada Innovation. Dr. Panisset received research grants from Teva Neuroscience, Novartis, and Allergan. He was a lecturer for Allergan, Merz, Novartis and Teva. He participated in advisory boards for Merck, EMD Serono, Allergan, Merz, Novartis, and Teva.Author roles may be found in the online version of this article. Author roles may be found in the online version of this article.

Deep brain stimulation (DBS) is an invaluable tool for the management of medically intractable motor

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Movement Disorders, Vol. 29, No. 14, 2014

Received: 20 January 2014; Revised: 3 April 2014; Accepted: 8 April 2014 Published online 22 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25911

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FIG. 1. Impact of STN DBS on motor function as measured by the UPDRS-III. (A) Mean UPDRS-III scores were significantly improved after surgery (ON medication-ON stimulation, 12.9 6 8 [6SD]), compared with UPDRS-III scores before surgery (ON medication, 18.5 6 11). (B) Patients also showed significant improvement of UPDRS-III scores OFF medication after surgery (OFF medication-ON stimulation, 16.4 6 9) compared with UPDRS-III scores before surgery (OFF medication, 33.6 6 11). Asterisks (*) indicate significance levels at P < 0.05* and P < 0.001***. STN, subthalamic; DBS, deep brain stimulation; UPDRS-III, Section III of the Unified Parkinson’s Disease Rating Scale.

outcomes. How treatment affects life-space in PD is currently unclear. The goal of the present prospective study was to assess whether significant improvements in motor symptoms observed in advanced PD patients with STN DBS translate to a significant increase in lifespace and QoL.

Subjects and Methods Subjects

Twenty patients (13 men; 57.2 6 7.7 years old; 11.3 6 3.7 years since diagnosis) with idiopathic PD were recruited through the neurosurgical clinic of the Montreal Neurological Institute. Patients were first evaluated while going through the selection process for STN DBS. Patients were followed prospectively and were reevaluated 6 to 9 months after STN DBS surgery (18 bilateral). Levodopa equivalent daily dose (LEDD)17 was computed to be 1,456 6 682 mg preoperatively and was significantly reduced to 782 6 538mg postoperatively. None of the patients

FIG. 2. Top: This graph illustrates the mean subscore results of the LifeSpace Assessment (LSA) questionnaire for PD patients before and after surgery (N 5 20). Note that sphere 1 relates to mobility inside the home; sphere 2 relates to mobility outside the home, but on the patient’s property; sphere 3 relates to mobility in the patient’s neighborhood; sphere 4 relates to mobility in the patient’s town of residence but outside of his neighborhood; sphere 5 relates to mobility outside of the patient’s town of residence; the composite score is an addition of all previous scores; and the maximum score is the maximum obtained regardless of the sphere. Asterisks (*) indicate a significant difference in mean score for a given subsection (e.g., sphere 1) before and after surgery (P < 0.05). Bottom: This graph illustrates the mean subscore results of the SF-36 quality of life questionnaire for PD patients before and after surgery (N 5 20). Asterisks (*) indicate a significant difference in mean score for a given subsection (e.g., pain) before and after surgery (P < 0.05). PD, Parkinson’s disease.

had known comorbidities that could significantly affect mobility. This research was approved by the institutional research ethics review board.

Evaluation Patients were asked to fill-out the Short Form Health Survey (SF-36), and the Life-Space Assessment


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(LSA)18 questionnaires. Patients completed the questionnaires 1 to 3 weeks before surgery and again 6 to 9 months postoperatively when their condition was deemed stable by their treating physician. The outcome of the SF-36 consists of eight scores related to physical functioning, role limitations because of physical health, role limitations because of emotional health, energy/fatigue, emotional wellbeing, social functioning, pain, and general health. The outcome of the LSA consists of five scores related to the subject’s movements within his or her environment, ranging from within his home to outside of his town of residence, and two composite scores of total and maximal life-space. Section III of the Unified Parkinson’s Disease Rating Scale (UPDRS)19 was used to assess the motor function of patients preoperatively and postoperatively.

Surgery A two-stage frame-based DBS insertion was performed under local anesthesia. All PD-related medications were withheld beginning on midnight of the day of surgery. Intraoperative microelectrode recordings (MicroGuide pro, Alpha-Omega Engineering, Israel) were performed for the verification of DBS lead placement (Medtronic 3387). Both electrophysiological monitoring and stimulation were performed under local anesthesia. The 7482A extension, and Soletra, Kinetra or Activa (PC or SC) pulse generators (Minneapolis, MN, USA) were implanted under general anesthesia. Activation of the electrodes was performed 5 days postoperatively, and stimulation parameters were subsequently adjusted to optimize patient response.

Statistical Analysis To assess the impact of STN DBS on motor symptoms, a paired t test was performed on the UPDRS scores. To evaluate the impact of STN DBS on QoL and life-space, multiple paired t tests were performed. Threshold for statistical significance was set to P < 0.05. Bonferroni adjustments for multiple comparisons were performed.

Results Motor function improved significantly 6 to 9 months after STN DBS surgery both on and off medication, indicating motor impairment was successfully managed by DBS, as detailed in Figure 1. Figure 2 illustrates the impact of STN DBS on QoL and life-space of PD patients preoperatively and postoperatively. Results for QoL are in the bottom pane. Paired t tests demonstrated that STN DBS significantly improved subscores of the SF-36 pertaining to physical functioning, role limitation attributable to functional health, and emotional well-being (P < 0.05). No signifi-

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cant improvements were observed in the other subscores (P > 0.05), indicating that 6 to 9 months after surgery, only certain aspects of QoL are improved by STN DBS. Results for life-space are in the top pane of Figure 2. Paired t tests showed that only sphere 5 of the lifespace assessment is significantly improved after STN DBS (P < 0.05). All other subsections of the life-space assessment showed no significant improvements after STN DBS (P > 0.05), indicating that STN DBS does not significantly improve PD patients’ life-space.

Discussion The current study demonstrates that STN DBS significantly improves motor symptoms and some aspects of QoL in advanced PD patients. However, life-space did not improve in the intermediate term with STN DBS. Although we cannot reject the possibility that STN DBS prevented a further decline in life-space, reasons for lack of improvement 6 to 9 months after surgery warrant attention. Our findings cannot be explained by a lack of DBS parameter optimization, because the improvements in motor symptoms observed in the current study are significant and similar to results of other studies.3,20,21 This indicates that improved motor function alone does not translate systematically to improvement in all measures of QoL or life-space in advanced PD patients with many years of disability. Besides motor impairment, nonmotor factors may also constrict life-space and QoL in PD. The current study evaluated mobility through the LSA, a measure encompassing the desire for movement and participation in the larger social environment.6-8 The lack of improvement in life-space may stem from a decreased desire for movement and participation in the social environment, or lack of social or economic support. Studies have shown that psychiatric factors such as apathy may decrease activities of daily living in advanced PD.22 Mild increases in apathy and lack of motivation have been reported after STN DBS.23 Indeed, STN DBS can induce transient apathy that appears to peak at around 6 months but can still be present 12 months after surgery.24,25 The causes of this possible increase in apathy after STN DBS are unclear. As DBS parameters are optimized, dopaminergic medication is often reduced, either because DBS now manages levodopa-responsive motor impairments or because the dyskinesia threshold is reduced with stimulation. Some authors suggest that reduction of dopaminergic medications after STN DBS may be an important factor in apathy.23,24,26 In the current study, LEDD was reduced by almost 50%. Dopamine agonists were tapered in the months before surgery, and few patients remained on agonists after surgery. Although we did not specifically measure apathy, the lack of motivation may have hindered life-space improvement. Although apathy is a relatively minor

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contributing factor to life-space in normal aging,7 potential mild and transient increases in apathy observed in a subgroup of patients after STN DBS could contribute to restricted life-space. Then, preoperative and postoperative measures of apathy may allow for targeted interventions to improve QoL27 and life-space in this subgroup. However, life-space constriction in advanced PD may also be dependent on the psychosocial environment, including assistance by caregivers, community support, and personal economic burdens of chronic disease.28 Finally, the present results may also support recent evidence indicating a role for DBS early in the course of PD.29 Surgery may fail to enhance life-space because multiple factors related to chronic disease contribute to an ingrained sedentary lifestyle. Modifying this behavior may be more difficult than improving motor symptoms. Indeed, advanced PD patients have a constricted life-space when compared with age- and sex-matched healthy controls.30 Performing the intervention earlier in the course of the disease may allow for more effective modification of life-space, because mobility behavior is not as impaired. Taken together, the current results indicate a need for further research aimed at identifying the causes of lifespace constriction in PD, and how patients can be allowed to take advantage of salutary motor effects after surgical interventions. In the meantime, treating physicians may wish to further promote complementary interventions, including physical and occupational therapy, addressing ingrained patterns of decreased home and community mobility. Attention to emotional health and psychosocial environment before and after surgery is also warranted. This multidisciplinary approach may potentiate the newly found motor improvements by increasing social participation, and further improve QoL. Acknowledgment: We thank the participants who volunteered their time for this study. We also thank Dr. Fahd Al-Subaie for help with the clinical assessment of patients.

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