- Email: [email protected]
Acute response of non-motor symptoms to subthalamic deep brain stimulation in Parkinson's disease
Accepted Manuscript Acute response of non-motor symptoms to subthalamic deep brain stimulation in Parkinson's disease Margherita Fabbri, MD, Miguel Coelho, MD, PhD, Leonor Correia Guedes, MD, Mario M. Rosa, MD, PhD, Daisy Abreu, MsC, Nilza Gonçalves, MsC, Angelo Antonini, MD, PhD, Joaquim J. Ferreira, MD, PhD PII:
S1353-8020(17)30165-7
DOI:
10.1016/j.parkreldis.2017.05.003
Reference:
PRD 3295
To appear in:
Parkinsonism and Related Disorders
Received Date: 21 March 2017 Revised Date:
3 May 2017
Accepted Date: 6 May 2017
Please cite this article as: Fabbri M, Coelho M, Guedes LC, Rosa MM, Abreu D, Gonçalves N, Antonini A, Ferreira JJ, Acute response of non-motor symptoms to subthalamic deep brain stimulation in Parkinson's disease, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Acute response of non-motor symptoms to Subthalamic Deep Brain Stimulation in Parkinson’s disease
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Margherita Fabbri1,MD, Miguel Coelho1,2, MD, PhD, Leonor Correia Guedes1,2, MD, Mario M. Rosa1,2,3,MD, PhD, Daisy Abreu1, MsC, Nilza Gonçalves 1, MsC, Angelo
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Antonini4,5, MD, PhD, Joaquim J Ferreira1,2,3, MD, PhD
Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Portugal
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Neurology Service, Department of Neurosciences, Hospital Santa Maria, Lisbon,
Portugal 3
Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine,
Fondazione Ospedale San Camillo"-I.R.C.C.S., Parkinson and Movement Disorders
Unit, Venice, Italy
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Department of Neurosciences (DNS), Padova University, Padova
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University of Lisbon, Portugal 4
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*Corresponding author: Joaquim J Ferreira, MD, PhD, Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon Av. Prof. Egas Moniz
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ACCEPTED MANUSCRIPT 1649-028 Lisbon, Portugal Tel: + 351 21 7802120
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E-mail: [email protected]
Title character count: 85 References: 13
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Tables: 2
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Paper word count: 1979 Abstract word count: 241
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Fax: + 351 21 7802129
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Running Title: Acute response of non-motor symptoms to STN-DBS in Parkinson; Key words: Parkinson Disease, non-motor symptoms, STN-DBS, challenge test; Funding: The study had no specific funding.
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ACCEPTED MANUSCRIPT Abstract Background: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for the motor complications of Parkinson’s disease (PD) and may have beneficial effects on non-motor symptoms (NMS). However, the acute effect of STN
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stimulation on NMS has only been explored in small PD cohorts with short postsurgical follow-up.
Objective: To study NMS response to an acute stimulation challenge in an STN-DBS
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PD population with a medium/long-term post-surgical follow-up.
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Methods: 32 STN-DBS PD patients were tested twice (MED OFF/STIM OFF and MED OFF/STIM ON). MDS-UPDRS-III, blood pressure (BP) assessment, a visual analogue scale for pain and fatigue and State Trait Anxiety Scale score were evaluated during both stimulation conditions. NMS were assessed with MDS-UPDRS-I, Non-
scale.
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Motor Symptoms Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory
Results: Mean (SD) age was 62.5 (±13.3) years, mean disease duration 18.7 (±5.1)
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years, mean post-surgical follow-up 4.6 (±1.3) years, and the mean reduction of levodopa equivalent daily dose after surgery was 58.9% (±25.4%). Mean (SD) motor
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response to stimulation was 40% (15%). STN stimulation significantly improved anxiety (mean 18% ±19%, P<0.005) and fatigue (mean 25% ±51%; P<0.05), while pain, although improved did not reach statistical significance. With stimulation ON, BP significantly decreased during orthostatism (P<0.05) and there was a significant increase in asymptomatic orthostatic hypotension (P<0.05). Conclusions: Acute STN stimulation improves anxiety and fatigue but decreases orthostatic BP in PD, several years after surgery. These effects should be considered
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when assessing long-term effect of DBS.
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ACCEPTED MANUSCRIPT Introduction Subthalamic deep brain stimulation (STN-DBS) is an established treatment for levodopa-related motor complications (MCs) of patients with advanced Parkinson’s disease (PD) [1]. However, non-motor symptoms (NMS), which increase in prevalence
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and severity with disease progression, are often more troublesome and exert a greater
impact than motor symptoms on the health-related quality of life (QoL) of PD patients. Recent studies with variable post-surgical follow-up (usually 6-12 months, up to 8
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years) suggest a long-term benefit of STN-DBS on NMS of PD, more evidently for
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some NMS than others, i.e., pain, fatigue, sleep, hallucinations, and urinary symptoms [2, 3]. Less established is the acute effect of STN-DBS on NMS, where very few reports with small samples and shorter post-surgical follow-up suggest a slight benefit on anxiety, fatigue and mood [4, 5], while results on autonomic symptoms are conflicting
Objective
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Patients and methods
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[6].
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To study the NMS (blood pressure [BP], orthostatic hypotension [OH], pain, fatigue and anxiety) response to an acute stimulation challenge in an STN-DBS PD population with a medium/long-term post-surgical follow-up. Study protocol and patients recruitment A cross-sectional study of PD patients (UK Brain Bank criteria) submitted to STN-DBS at least three years previously at the Neuroscience Department of the Hospital Santa Maria, Lisbon, Portugal. Patients with PD dementia (PDD) were excluded (see below).
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ACCEPTED MANUSCRIPT The Local Ethical Committee approved the study and all patients provided informed consent. Assessment of patients
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Patients were assessed in the MED OFF/STIM OFF condition, i.e., condition A (at least 12 hours after the last L-dopa/aromatic amino acid decarboxylase inhibitor intake, and with the stimulator switched OFF for at least 60 minutes) and after the neurostimulator
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was switched ON for at least 60 minutes (MED OFF/STIM ON-condition B) setting the stimulation to previously effective parameters. In both conditions, BP (OH was defined
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as a decrease in systolic pressure ≥ 30 mmHg or in diastolic pressure ≥15 mmHg, within 3 minutes of standing, i.e. criteria I, or a decrease in systolic pressure ≥20 mmHg or in diastolic pressure ≥10 mmHg, within 3 minutes of standing, i.e. criteria II), pain (visual analogue scale for pain- VAS-p), fatigue (visual analogue scale for fatigue- VAS-f),
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anxiety (State Trait of Anxiety Inventory-STAI), and motor performance (MDSUPDRS-III) were assessed. STAI is a psychological inventory consisting of 40 selfreport items, 20 items to assess trait anxiety and 20 for state anxiety, each item is scored
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on a 4-point Likert-type response scale. For the purpose of our study only the 20 items for state anxiety were assessed.
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NMS characteristics were evaluated using the MDS-UPDRS part I, Non-Motor Symptoms assessment scale for PD (NMSS), and the Neuropsychiatric Inventory test 12-items. Diagnosis of PDD was made according to the recommendation of the MDS Task Force. Depression was diagnosed if a patient had a Geriatric Depression Scale (GDS) score ≥ 11 (mild depression if between 11 and 20; severe if between 21 and 30). Psychosis was considered if patients had an MDS-UPDRS 1.2 ≥1. Levodopa-induced MCs were stratified as follows: presence of motor fluctuations (MDS-UPDRS 4.3 ≥1);
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ACCEPTED MANUSCRIPT troublesome motor fluctuations (MDS-UPDRS 4.4 >2); presence of dyskinesias (MDSUPDRS 4.1 ≥1), and troublesome dyskinesias (MDS-UPDRS 4.2 >2). L-dopa equivalent daily dose (LEDD) was calculated according to recognized standard conversions [7].
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Statistical analysis
Descriptive statistics of demographic, clinical, and therapeutic data were provided for
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continuous [mean and standard deviation (SD)] and categorical (count and percentage) variables.
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The acute effect of stimulation was calculated by comparing the median values of BP, VAS-p, VAS-f, STAIS and MDS-UPDRS-III and the occurrence of OH between Condition A versus Condition B, using T test or Chi-square test, as appropriate. Pearson’s rank correlation coefficient was used to assess the correlation between the
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magnitude of motor (∆ MDS-UPDRS-III) and NMS response to stimulation (∆ BP, ∆STAI, ∆ VAS-f and ∆VAS-p) and between motor severity (MDS-UPDRS-III during condition A) and NMS severity (MDS-UPDRS-I, NMSS and NPI-12 items, and GDS).
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used.
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P value <0.05 considered significant. The software SPSS 22.0 (SPSS, Chicago, IL) was
Results
Thirty-two patients were included (Table 1). Mean (SD) age was 62.5 (± 13.3) years and mean (SD) disease duration 18.7 (±5.1) years. After surgery, the mean (SD) reduction of LEDD was 59.8% (±53%), mean improvement of MCs 60% (SD ±53) (UPDRS part IV total score), mean improvement of dyskinesia duration 48.8% (SD
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ACCEPTED MANUSCRIPT ±52) and disability 46% (SD ±61) (UPDRS part IV items 32 and 33, respectively), and mean improvement of OFF duration 72% (SD ±56) (UPDRS part IV item 39). Mean (SD) post-surgical follow-up was 4.6 (±1.3) years. We found fatigue in 28 (of whom 22, i.e., 78%, had an MDS-UPDRS 1.13 score ≥2), and anxiety in 22 patients (of
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whom 16, i.e., 72% had an MDS-UPDRS 1.4 ≥2), as assessed by the MDS-UPDRS-I; painful off-dystonia in 15% (MDS-UPDRS-IV), and troublesome general pain (MDSUPDRS 1.9 ≥ 2) was reported by almost half (56%). Symptoms probably related to OH
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(MDS-UPDRS-I) were present among 54% of the patients and were bothersome (MDS-
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UPDRS 1.12 ≥ 2) for 21% of them.
Acute response of NMS to stimulation
The motor response (MDS-UPDRS-III score) to stimulation was statistically significant
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with a mean (SD) improvement of 40% (±15; P<0.005) (Table 2). STN-DBS acute effect significantly improved anxiety (improvement: 18%±19; P<0.005) and fatigue (improvement: 25% ± 51; P<0.05), while pain, although improved, did not reach
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significance (Table 2). There was a statistically significant decrease in the mean values
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of BP during orthostatism with the stimulator ON. The number of patients developing OH after switching ON the stimulation was statistically significant in agreement with criteria II (Table 2). One patient had an episode of acute depressive dysphoria when the stimulator was switched OFF, this completely reversed with the stimulation ON. No other adverse effects (AEs) were reported. A weak, non-significant correlation was found between the ∆MDS-UPDRS-III score and the ∆ diastolic/systolic BP during orthostatism (R= -0.28/-0.33, respectively), ∆VAS-f, ∆STAI and MDS-UPDRS-I (respectively R=0.268; R= 0.276 and R= -0.277). 8
ACCEPTED MANUSCRIPT The correlation between the ∆MDS-UPDRS-III score and the ∆VAS-f was moderate (R= 0,438; p=0.045) when analysing only patients (n=22) with an MDS-UPDRS 1.13 ≥2 . A strong correlation was found between the ∆MDS-UPDRS-III score and the ∆STAI when analysing only patients (n=16) with an MDS-UPDRS 1.4 ≥2 (R=0.66;
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p=0.006). No correlation was found between the ∆MDS-UPDRS-III score and the ∆VAS-p. A weak correlation was found between MDS-UPDRS-III during MED
OFF/STIM OFF and NPI-total score (R=0.301) while no correlation was found between
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MDS-UPDRS-III during MED OFF/STIM OFF and NMSS total score, GDS or MDS-
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UPDRS-I.
Discussion
We report the effect of acute response of NMS to STN-DBS in a PD population with a
and fatigue.
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mean post-surgical follow-up of 4.6 years and found a benefit particularly on anxiety
The acute motor benefit after switching ON the stimulation was similar to the motor
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benefit of these same patients after a suprathreshold dose of levodopa (data not shown),
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which indicates good lead location and suggests that the lack of acute benefit of the stimulation on pain is not due to poorly implanted leads. The magnitude of benefit on anxiety and fatigue was greater in patients showing greater motor improvement in the acute stimulation test. The beneficial effect of STN-DBS on anxiety and fatigue could be due to two principal factors: a) the amphetamine-like psychotropic effects of stimulation, possibly related to the stimulation of the medial STN, linked with the limbic part of the pallidum and the striatum, the prefrontal and cingulate cortices, mimicking the levodopa psychotropic effect [8]; and b) the appropriate well-being
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ACCEPTED MANUSCRIPT related to motor improvement. Our results are in agreement with two previous studies with a post-surgical follow-up of 12 months exploring the acute effect of stimulation on anxiety, fatigue and other cognitive/affective symptoms among patients with a mean disease duration of 10 years [5, 8]. Our study contributes by demonstrating that such a
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benefit are presents even after 5 years of surgery and in PD with much longer duration. STN-DBS has a chronic well known beneficial effect on pain, usually more evident on dystonic pain, followed by central pain [9]. It has been suggested that pain improvement
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after STN-DBS can be associated to a central modulation of pain, through an increase in
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pain tolerance and pain perception [10]. Indeed, STN-DBS could modulate the sensorydiscriminative component of pain via the connection of the STN with the descending pain inhibitory control system and the modulation of the activity of the nucleus accumbens, which is involved in the modulation of emotional and motivationalaffective status [10]. Nevertheless, after long-term follow-up many DBS patients may
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develop pain, especially of the musculoskeletal type [3]. In our study, the limited improvement of pain was probably due to few patients having painful off dystonia, suggesting that our cohort was more affected by other types of pain that usually respond
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less well to stimulation [3, 11]. Moreover, we found no correlation between the change
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in pain and the motor response to STN-DBS, further confirming that the slight response of pain to stimulation in our patients does not share the same mechanism of motor symptoms.
Finally, our results showed that STN-DBS acutely decreases BP, especially while standing, although no patient was symptomatic for OH, possibly mimicking the effect of levodopa in PD. However, there is some evidence that STN-DBS has no direct effect on autonomic cardiac innervation or muscle vasoconstrictor neurons, although it can slightly enhance cutaneous sympathetic vasoconstriction [12]. Moreover, one small 10
ACCEPTED MANUSCRIPT report showed acute improvement of OH with simulation among 14 PD STN-DBS patients 7 months post-surgery [13]. These conflicting findings encourage further studies to specifically address this condition. Additionally, the few studies available investigating the effect of STN-DBS on BP, have variable wash-out periods of
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stimulation, different medication conditions and usually short post-surgical follow-up
(up to17 months), making it difficult to compare results. Our study has the advantage of including only PD patients with homogeneous age range, long disease duration and
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follow-up. This is particularly important as it is well established that autonomic
dysfunction in PD increases with disease duration and patient’s age. Accordingly, our
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results may suggest that STN-DBS does not maintain its effect on sympathetic vasoconstriction in older PD patients with longer disease duration. Study limitations
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The findings of this analysis are limited due to its cross-sectional nature, the lack of blinding and the lack of a control group.
We did not adopt a baseline threshold score for anxiety, pain and fatigue as an inclusion
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criterion for patients, thus limiting the interpretation of STN-DBS effect on these NMS. However, anxiety, fatigue and pain were present in the majority of the sample.
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Moreover, pre-surgical NMS characteristics were not collected in order to determine pre-surgical predictive features for a better stimulation response. Secondly, we should have better characterized pain types in affected patients, to understand which responds better to acute stimulation. Finally, lead contacts position was not specifically explored, limiting the interpretation of stimulation effect on NMS. Nevertheless, this is the first study to explore the acute effect of STN-DBS on NMS in a representative sample of PD patients with long-term post-surgical follow-up. These preliminary results may guide future research and possibly help the clinical management of DBS PD patients. 11
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Conclusion
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In conclusion, anxiety and fatigue improve with the acute stimulation of the STN even after 5 years of DBS, in PD patients with long disease duration who still have an
optimal motor response to stimulation. This improvement is best in patients showing
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greater motor response to stimulation. The improvement in pain probably depends on
the type of pain most affecting patients, and this must be better addressed in the future.
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STN-DBS may have an acute effect on BP similar to levodopa, although minimal and probably asymptomatic. The acute autonomic effect of STN-DBS also deserves further research, adopting specific autonomic tests.
Neurologists should be aware of the possible acute effect of STN stimulation on some
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NMS during routine adjustments of parameters in clinical practice, which can couple or
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not the motor benefit and influence the outcome of patient management.
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ACCEPTED MANUSCRIPT Acknowledgments: The authors thank Anne-Marie Williams for editorial assistance (English language editing and referencing).
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Authors’ Roles 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical
A. Writing of the first draft, B. Review and Critique.
Dr. Miguel Coelho: 1A, 1B, 2C, 3B; Dr. Leonor C Guedes: 1B, 3B;
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Dr. Mario M. Rosa: 1B, 3B;
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Dr. Margherita Fabbri: 1A, 1C, 2A, 3A;
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Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation:
Daisy Abreu: 1B, 2A, 2B; Nilza Costa: 2A, 2B, 2C;
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Prof. Angelo Antonini: 1A, 3B;
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Prof. Joaquim J Ferreira: 1A, 1B, 3B;
Full Financial Disclosures of all Authors Dr. Margherita Fabbri, Dr. Miguel Coelho, Dr. Leonor Guedes, Dr. Mario Miguel Rosa, Daisy Abreu and Nilza Gonçalves: no conflict of interest to report. Prof. Angelo Antonini: no conflict of interest to report. Stock Ownership in medicallyrelated fields: none; Consultancies: UCB, Boston Scientific, AbbVie, Zambon. 13
ACCEPTED MANUSCRIPT Advisory Boards: Boston Scientific, AbbVie, Zambon. Honoraria to speak: AbbVie, Zambon, Lundbeck. Grants: Mundipharma, Neureca Foundation, the Italian Ministry Research Grant N RF-2009-1530177 and Horizon 2020 Program Grant N: 643706;
expert testimony on legal cases for pathological gambling;
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Intellectual Property Rights: none; Expert Testimony: Served as Boehringer Ingelheim
Prof. Joaquim J. Ferreira: no conflict of interest to report. Stock Ownership in
medically-related fields: none; Consultancies: Ipsen, GlaxoSmithKline, Novartis, Teva,
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Lundbeck, Solvay, Abbott, BIAL, Merck-Serono and Merz; Advisory Boards: none;
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Partnership: none; Honoraria to speak: none; Grants: GlaxoSmithKline, Grunenthal, Teva and Fundação MSD; Intellectual Property Rights: none; Expert Testimony: none;
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Employment: Laboratory of Clinical Pharmacology and Therapeutics of Lisbon.
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ACCEPTED MANUSCRIPT References
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[1] J.J. Ferreira, R. Katzenschlager, B.R. Bloem, U. Bonuccelli, D. Burn, G. Deuschl, E. Dietrichs, G. Fabbrini, A. Friedman, P. Kanovsky, V. Kostic, A. Nieuwboer, P. Odin, W. Poewe, O. Rascol, C. Sampaio, M. Schupbach, E. Tolosa, C. Trenkwalder, A. Schapira, A. Berardelli, W.H. Oertel, Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease, European journal of neurology : the official journal of the European Federation of Neurological Societies 20(1) (2013) 5-15. [2] H.S. Dafsari, P. Reddy, C. Herchenbach, S. Wawro, J.N. Petry-Schmelzer, V. VisserVandewalle, A. Rizos, M. Silverdale, K. Ashkan, M. Samuel, J. Evans, C.A. Huber, G.R. Fink, A. Antonini, K.R. Chaudhuri, P. Martinez-Martin, L. Timmermann, Beneficial Effects of Bilateral Subthalamic Stimulation on Non-Motor Symptoms in Parkinson's Disease, Brain stimulation 9(1) (2016) 78-85. [3] Y.J. Jung, H.J. Kim, B.S. Jeon, H. Park, W.W. Lee, S.H. Paek, An 8-Year Follow-up on the Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease, JAMA neurology 72(5) (2015) 504-10. [4] A. Berney, M. Panisset, A.F. Sadikot, A. Ptito, A. Dagher, M. Fraraccio, G. Savard, M. Pell, C. Benkelfat, Mood stability during acute stimulator challenge in Parkinson's disease patients under long-term treatment with subthalamic deep brain stimulation, Movement disorders : official journal of the Movement Disorder Society 22(8) (2007) 1093-6. [5] A. Funkiewiez, C. Ardouin, R. Cools, P. Krack, V. Fraix, A. Batir, S. Chabardes, A.L. Benabid, T.W. Robbins, P. Pollak, Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 21(10) (2006) 1656-62. [6] H.J. Kim, B.S. Jeon, S.H. Paek, Nonmotor Symptoms and Subthalamic Deep Brain Stimulation in Parkinson's Disease, Journal of movement disorders 8(2) (2015) 83-91. [7] C.L. Tomlinson, R. Stowe, S. Patel, C. Rick, R. Gray, C.E. Clarke, Systematic review of levodopa dose equivalency reporting in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 25(15) (2010) 2649-53. [8] A. Funkiewiez, C. Ardouin, P. Krack, V. Fraix, N. Van Blercom, J. Xie, E. Moro, A.L. Benabid, P. Pollak, Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 18(5) (2003) 524-30. [9] H.J. Kim, B.S. Jeon, S.H. Paek, Effect of deep brain stimulation on pain in Parkinson disease, Journal of the neurological sciences 310(1-2) (2011) 251-5. [10] A. Marques, O. Chassin, D. Morand, B. Pereira, B. Debilly, P. Derost, M. Ulla, J.J. Lemaire, F. Durif, Central pain modulation after subthalamic nucleus stimulation: A crossover randomized trial, Neurology 81(7) (2013) 633-40. [11] R.G. Cury, R. Galhardoni, E.T. Fonoff, M.G. Dos Santos Ghilardi, F. Fonoff, D. Arnaut, M.L. Myczkowski, M.A. Marcolin, E. Bor-Seng-Shu, E.R. Barbosa, M.J. Teixeira, D. Ciampi de Andrade, Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease, Neurology 83(16) (2014) 1403-9. [12] J. Ludwig, P. Remien, C. Guballa, A. Binder, S. Binder, J. Schattschneider, J. Herzog, J. Volkmann, G. Deuschl, G. Wasner, R. Baron, Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease, Journal of neurology, neurosurgery, and psychiatry 78(7) (2007) 742-5. [13] B. Stemper, A. Beric, G. Welsch, T. Haendl, D. Sterio, M.J. Hilz, Deep brain stimulation improves orthostatic regulation of patients with Parkinson disease, Neurology 67(10) (2006) 1781-5. 15
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ACCEPTED MANUSCRIPT STN-DBS (n= 32)
Age (yrs), mean (SD)
62.5 (± 13.3)
Women (n/total (%))
13/32 (40%)
Age at disease onset (yrs), mean (SD)
45.6 (± 9.1)
Disease duration (yrs) , mean (SD)
18.7 (± 5.1)
Age at DBS (yrs), mean (SD)
58.1 (± 12.6)
Months after DBS, mean (SD)
56.6 (± 16.1)
Stimulation Voltage, mean (SD) R_STN/L_STN* LEDD before surgery (mg), mean (SD) LEDD after surgery (mg), mean (SD)
3.0 (± 0.4) /3.0 (± 0.3) 1178.8 (±553.9) 484.4 (±249.1)
S&E _ MED ON/STIM ON, mean (SD)
81.2 (17.1)
HY stage _ MED ON/STIM ON (n (%))
1=2 (6%) 2= 29 (91%) 3=1 (3%)
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10 (31%) 13 (± 7.5) 17(53%) 10 (31%) 7 (22%)
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GDS, mean (SD) Depression (n (%)) Light Severe
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18 (56%) 8 (25%) 6 (19%)
Akinetic-Rigid Tremor dominant Mixed Psychosis (n (%))
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Clinical phenotype (n (%))
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Patients’ data
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MDS-UPDRS-I Mean (SD) and percentage of patients scoring ≥ 1(%) Total score
16.4 (± 6.7)
Cognition Hallucinations & psychosis Depressed mood Anxious mood Apathy DDS Sleep problems Daytime sleepiness Pain Urinary problems Constipation problems Light headedness Fatigue
1 (±0.9) - 65% 0.4 (±0.8) - 31% 1.8 (1.1) - 84% 1.4 (±1.2) - 68% 1.5 (±1.0) - 84% 0.4 (±0.6) - 34% 1.1 (±0.9) - 72% 1.3 (±0.9) - 78% 1.5 (±1.2) - 71% 1.5 (±1.0) - 81% 1.5 (±1.3) - 69% 0.8 (±0.9) - 56% 1.8 (±1.1) - 87%
MDS-UPDRS-II, mean (SD)
16.4 (±7.2)
MDS-UPDRS-IV, mean (SD)
3.7 (±3.9)
L-dopa induced Motor complications (n (%))
24 (75%)
Motor fluctuations (n (%)) Troublesome motor fluctuations (n (%)) Dyskinesias (n (%)) Troublesome Dyskinesias (n (%)) Painful off-dystonia (n (%))
14 (44%) 3 (9%) 19 (60%) 2 (6%) 5 (15%)
NPI-12 items
n=26
Mean (SD) and percentage of patients scoring ≥ 1(%)
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11.2 (±8.5)
NMSS
0.03 (±0.1) – 3% 0.7 (±2.4) – 27% 0.4 (±1.0) – 18% 3.1 (±3) – 70% 1.8 (±2.2) – 62% 0 1.9 (±2.4) - 56% 0 0.5 (±1.2) – 22% 0 1.9 (±1.9) – 65% 0.5 (±0.9) - 37%
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Delirium/Delusion Hallucinations Agitation/Aggression Depression Anxiety Elation/Euphoria Apathy/indifference Disinhibition Irritability/Lability Motor aberrant behaviour Sleep and Night-time Behaviour Disorders Appetite and Eating Disorders
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total score
total score
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Mean (SD) and percentage of patients scoring ≥ 1(%)
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Cardiovascular Sleep/Fatigue Mood/Cognition Hallucination/perception Memory Gastrointestinal tract Urinary Sexual function Miscellaneous
61.4 (±31.3) 1.6 (±2.5) - 56% 7.1 (±6.5) - 90% 12.1 (±10.2) - 96% 1.6 (±5.1) - 34% 5.3 (±5.1) - 78% 6.3 (±5.4) - 96% 5.7 (±6.9) - 84% 12.5 (±8.3) - 100% 8.6 (±5.3) - 100%
Table 1. Demographic, clinical and NMS characteristics of DBS patients. LEDD: levodopa equivalent daily dose; S&E: Schwab and England Scale; YH: Hoehn Yahr. GDS: Geriatric depression scale. PDD: Parkinson’s disease with dementia. NMSS: Non-motor symptom assessment scale; NPI-12 items: Neuropsychiatric Inventory test 12-items; *Monopolar stimulation with 130 Hz and 60 µS except: 3 patients with bipolar stimulation, 3 patients with interleaving program and 1 patients with 90 µS;
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VAS-p VAS-f BP_supine BP_ortho
31.7 (13.6)
48.6 (10.3)
39.6 (11.2)
1.7 (2.6)
1.1 (2.5)
4 (3.3)
2.7 (2.7)
153/91 (23/13) 147/94 (26/15) 2 (6 %)
2-OH (n (%))
6 (18%)
HY
2.2 (0.7)
9 (9.6)
<0.005
<0.005 0.079
1.1 (2.7)
<0.05
152/87 (23/13)
2/4 (18/10)
0.6/0.043
138/88 (23/15)
9/5 (19/13)
<0.05
4 (12%)
2
0.4
11 (34%)
5
0.034
/
/
2.1 (0.6)
1 patient with acute depressive dysphoria
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Occurrence of AEs
21 (8.8)
p -value
0.9 (1.7)
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1-OH (n (%))
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52.7(14.7)
Effect size (∆)
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STAI
MED OFF/STIM ON
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MDS-UPDRS-III
MED OFF/STIM OFF
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Table 2. NMS response to stimulation challenge test. Values are presented as mean (SD). STAI: State Trait of Anxiety Inventory (only the 20 items of state anxiety have been applied); VAS-p: visual analogue scale for pain; VAS-f: visual analogue scale for fatigue; BP_supine: blood pressure in supine position: BP_orto: blood pressure after 3 minutes of standing; OT: orthostatic hypotension; p*: MED OFF/STIM OFF versus MEN OOFF/STIM ON; 1-OH: defined as a decrease in systolic pressure ≥ 30 mmHg and in diastolic pressure ≥ 15 mmHg, within 3 minutes of standing; 2-OH: defined as a decrease in systolic pressure ≥ 20 mmHg and in diastolic pressure ≥ 10 mmHg, within 3 minutes of standing.
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Five years after surgery, acute STN-DBS improves anxiety and fatigue;
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STN-DBS may decrease orthostatic blood pressure probably mimicking levodopa effect; These effects should be considered when assessing long-term effect of
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DBS.
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S1353-8020(17)30165-7
DOI:
10.1016/j.parkreldis.2017.05.003
Reference:
PRD 3295
To appear in:
Parkinsonism and Related Disorders
Received Date: 21 March 2017 Revised Date:
3 May 2017
Accepted Date: 6 May 2017
Please cite this article as: Fabbri M, Coelho M, Guedes LC, Rosa MM, Abreu D, Gonçalves N, Antonini A, Ferreira JJ, Acute response of non-motor symptoms to subthalamic deep brain stimulation in Parkinson's disease, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Acute response of non-motor symptoms to Subthalamic Deep Brain Stimulation in Parkinson’s disease
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Margherita Fabbri1,MD, Miguel Coelho1,2, MD, PhD, Leonor Correia Guedes1,2, MD, Mario M. Rosa1,2,3,MD, PhD, Daisy Abreu1, MsC, Nilza Gonçalves 1, MsC, Angelo
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Antonini4,5, MD, PhD, Joaquim J Ferreira1,2,3, MD, PhD
Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Portugal
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Neurology Service, Department of Neurosciences, Hospital Santa Maria, Lisbon,
Portugal 3
Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine,
Fondazione Ospedale San Camillo"-I.R.C.C.S., Parkinson and Movement Disorders
Unit, Venice, Italy
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Department of Neurosciences (DNS), Padova University, Padova
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University of Lisbon, Portugal 4
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*Corresponding author: Joaquim J Ferreira, MD, PhD, Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon Av. Prof. Egas Moniz
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E-mail: [email protected]
Title character count: 85 References: 13
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Paper word count: 1979 Abstract word count: 241
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Fax: + 351 21 7802129
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Running Title: Acute response of non-motor symptoms to STN-DBS in Parkinson; Key words: Parkinson Disease, non-motor symptoms, STN-DBS, challenge test; Funding: The study had no specific funding.
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ACCEPTED MANUSCRIPT Abstract Background: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for the motor complications of Parkinson’s disease (PD) and may have beneficial effects on non-motor symptoms (NMS). However, the acute effect of STN
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stimulation on NMS has only been explored in small PD cohorts with short postsurgical follow-up.
Objective: To study NMS response to an acute stimulation challenge in an STN-DBS
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PD population with a medium/long-term post-surgical follow-up.
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Methods: 32 STN-DBS PD patients were tested twice (MED OFF/STIM OFF and MED OFF/STIM ON). MDS-UPDRS-III, blood pressure (BP) assessment, a visual analogue scale for pain and fatigue and State Trait Anxiety Scale score were evaluated during both stimulation conditions. NMS were assessed with MDS-UPDRS-I, Non-
scale.
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Motor Symptoms Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory
Results: Mean (SD) age was 62.5 (±13.3) years, mean disease duration 18.7 (±5.1)
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years, mean post-surgical follow-up 4.6 (±1.3) years, and the mean reduction of levodopa equivalent daily dose after surgery was 58.9% (±25.4%). Mean (SD) motor
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response to stimulation was 40% (15%). STN stimulation significantly improved anxiety (mean 18% ±19%, P<0.005) and fatigue (mean 25% ±51%; P<0.05), while pain, although improved did not reach statistical significance. With stimulation ON, BP significantly decreased during orthostatism (P<0.05) and there was a significant increase in asymptomatic orthostatic hypotension (P<0.05). Conclusions: Acute STN stimulation improves anxiety and fatigue but decreases orthostatic BP in PD, several years after surgery. These effects should be considered
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when assessing long-term effect of DBS.
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ACCEPTED MANUSCRIPT Introduction Subthalamic deep brain stimulation (STN-DBS) is an established treatment for levodopa-related motor complications (MCs) of patients with advanced Parkinson’s disease (PD) [1]. However, non-motor symptoms (NMS), which increase in prevalence
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and severity with disease progression, are often more troublesome and exert a greater
impact than motor symptoms on the health-related quality of life (QoL) of PD patients. Recent studies with variable post-surgical follow-up (usually 6-12 months, up to 8
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years) suggest a long-term benefit of STN-DBS on NMS of PD, more evidently for
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some NMS than others, i.e., pain, fatigue, sleep, hallucinations, and urinary symptoms [2, 3]. Less established is the acute effect of STN-DBS on NMS, where very few reports with small samples and shorter post-surgical follow-up suggest a slight benefit on anxiety, fatigue and mood [4, 5], while results on autonomic symptoms are conflicting
Objective
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Patients and methods
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[6].
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To study the NMS (blood pressure [BP], orthostatic hypotension [OH], pain, fatigue and anxiety) response to an acute stimulation challenge in an STN-DBS PD population with a medium/long-term post-surgical follow-up. Study protocol and patients recruitment A cross-sectional study of PD patients (UK Brain Bank criteria) submitted to STN-DBS at least three years previously at the Neuroscience Department of the Hospital Santa Maria, Lisbon, Portugal. Patients with PD dementia (PDD) were excluded (see below).
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ACCEPTED MANUSCRIPT The Local Ethical Committee approved the study and all patients provided informed consent. Assessment of patients
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Patients were assessed in the MED OFF/STIM OFF condition, i.e., condition A (at least 12 hours after the last L-dopa/aromatic amino acid decarboxylase inhibitor intake, and with the stimulator switched OFF for at least 60 minutes) and after the neurostimulator
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was switched ON for at least 60 minutes (MED OFF/STIM ON-condition B) setting the stimulation to previously effective parameters. In both conditions, BP (OH was defined
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as a decrease in systolic pressure ≥ 30 mmHg or in diastolic pressure ≥15 mmHg, within 3 minutes of standing, i.e. criteria I, or a decrease in systolic pressure ≥20 mmHg or in diastolic pressure ≥10 mmHg, within 3 minutes of standing, i.e. criteria II), pain (visual analogue scale for pain- VAS-p), fatigue (visual analogue scale for fatigue- VAS-f),
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anxiety (State Trait of Anxiety Inventory-STAI), and motor performance (MDSUPDRS-III) were assessed. STAI is a psychological inventory consisting of 40 selfreport items, 20 items to assess trait anxiety and 20 for state anxiety, each item is scored
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on a 4-point Likert-type response scale. For the purpose of our study only the 20 items for state anxiety were assessed.
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NMS characteristics were evaluated using the MDS-UPDRS part I, Non-Motor Symptoms assessment scale for PD (NMSS), and the Neuropsychiatric Inventory test 12-items. Diagnosis of PDD was made according to the recommendation of the MDS Task Force. Depression was diagnosed if a patient had a Geriatric Depression Scale (GDS) score ≥ 11 (mild depression if between 11 and 20; severe if between 21 and 30). Psychosis was considered if patients had an MDS-UPDRS 1.2 ≥1. Levodopa-induced MCs were stratified as follows: presence of motor fluctuations (MDS-UPDRS 4.3 ≥1);
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ACCEPTED MANUSCRIPT troublesome motor fluctuations (MDS-UPDRS 4.4 >2); presence of dyskinesias (MDSUPDRS 4.1 ≥1), and troublesome dyskinesias (MDS-UPDRS 4.2 >2). L-dopa equivalent daily dose (LEDD) was calculated according to recognized standard conversions [7].
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Statistical analysis
Descriptive statistics of demographic, clinical, and therapeutic data were provided for
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continuous [mean and standard deviation (SD)] and categorical (count and percentage) variables.
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The acute effect of stimulation was calculated by comparing the median values of BP, VAS-p, VAS-f, STAIS and MDS-UPDRS-III and the occurrence of OH between Condition A versus Condition B, using T test or Chi-square test, as appropriate. Pearson’s rank correlation coefficient was used to assess the correlation between the
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magnitude of motor (∆ MDS-UPDRS-III) and NMS response to stimulation (∆ BP, ∆STAI, ∆ VAS-f and ∆VAS-p) and between motor severity (MDS-UPDRS-III during condition A) and NMS severity (MDS-UPDRS-I, NMSS and NPI-12 items, and GDS).
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used.
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P value <0.05 considered significant. The software SPSS 22.0 (SPSS, Chicago, IL) was
Results
Thirty-two patients were included (Table 1). Mean (SD) age was 62.5 (± 13.3) years and mean (SD) disease duration 18.7 (±5.1) years. After surgery, the mean (SD) reduction of LEDD was 59.8% (±53%), mean improvement of MCs 60% (SD ±53) (UPDRS part IV total score), mean improvement of dyskinesia duration 48.8% (SD
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ACCEPTED MANUSCRIPT ±52) and disability 46% (SD ±61) (UPDRS part IV items 32 and 33, respectively), and mean improvement of OFF duration 72% (SD ±56) (UPDRS part IV item 39). Mean (SD) post-surgical follow-up was 4.6 (±1.3) years. We found fatigue in 28 (of whom 22, i.e., 78%, had an MDS-UPDRS 1.13 score ≥2), and anxiety in 22 patients (of
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whom 16, i.e., 72% had an MDS-UPDRS 1.4 ≥2), as assessed by the MDS-UPDRS-I; painful off-dystonia in 15% (MDS-UPDRS-IV), and troublesome general pain (MDSUPDRS 1.9 ≥ 2) was reported by almost half (56%). Symptoms probably related to OH
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(MDS-UPDRS-I) were present among 54% of the patients and were bothersome (MDS-
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UPDRS 1.12 ≥ 2) for 21% of them.
Acute response of NMS to stimulation
The motor response (MDS-UPDRS-III score) to stimulation was statistically significant
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with a mean (SD) improvement of 40% (±15; P<0.005) (Table 2). STN-DBS acute effect significantly improved anxiety (improvement: 18%±19; P<0.005) and fatigue (improvement: 25% ± 51; P<0.05), while pain, although improved, did not reach
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significance (Table 2). There was a statistically significant decrease in the mean values
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of BP during orthostatism with the stimulator ON. The number of patients developing OH after switching ON the stimulation was statistically significant in agreement with criteria II (Table 2). One patient had an episode of acute depressive dysphoria when the stimulator was switched OFF, this completely reversed with the stimulation ON. No other adverse effects (AEs) were reported. A weak, non-significant correlation was found between the ∆MDS-UPDRS-III score and the ∆ diastolic/systolic BP during orthostatism (R= -0.28/-0.33, respectively), ∆VAS-f, ∆STAI and MDS-UPDRS-I (respectively R=0.268; R= 0.276 and R= -0.277). 8
ACCEPTED MANUSCRIPT The correlation between the ∆MDS-UPDRS-III score and the ∆VAS-f was moderate (R= 0,438; p=0.045) when analysing only patients (n=22) with an MDS-UPDRS 1.13 ≥2 . A strong correlation was found between the ∆MDS-UPDRS-III score and the ∆STAI when analysing only patients (n=16) with an MDS-UPDRS 1.4 ≥2 (R=0.66;
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p=0.006). No correlation was found between the ∆MDS-UPDRS-III score and the ∆VAS-p. A weak correlation was found between MDS-UPDRS-III during MED
OFF/STIM OFF and NPI-total score (R=0.301) while no correlation was found between
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MDS-UPDRS-III during MED OFF/STIM OFF and NMSS total score, GDS or MDS-
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UPDRS-I.
Discussion
We report the effect of acute response of NMS to STN-DBS in a PD population with a
and fatigue.
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mean post-surgical follow-up of 4.6 years and found a benefit particularly on anxiety
The acute motor benefit after switching ON the stimulation was similar to the motor
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benefit of these same patients after a suprathreshold dose of levodopa (data not shown),
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which indicates good lead location and suggests that the lack of acute benefit of the stimulation on pain is not due to poorly implanted leads. The magnitude of benefit on anxiety and fatigue was greater in patients showing greater motor improvement in the acute stimulation test. The beneficial effect of STN-DBS on anxiety and fatigue could be due to two principal factors: a) the amphetamine-like psychotropic effects of stimulation, possibly related to the stimulation of the medial STN, linked with the limbic part of the pallidum and the striatum, the prefrontal and cingulate cortices, mimicking the levodopa psychotropic effect [8]; and b) the appropriate well-being
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ACCEPTED MANUSCRIPT related to motor improvement. Our results are in agreement with two previous studies with a post-surgical follow-up of 12 months exploring the acute effect of stimulation on anxiety, fatigue and other cognitive/affective symptoms among patients with a mean disease duration of 10 years [5, 8]. Our study contributes by demonstrating that such a
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benefit are presents even after 5 years of surgery and in PD with much longer duration. STN-DBS has a chronic well known beneficial effect on pain, usually more evident on dystonic pain, followed by central pain [9]. It has been suggested that pain improvement
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after STN-DBS can be associated to a central modulation of pain, through an increase in
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pain tolerance and pain perception [10]. Indeed, STN-DBS could modulate the sensorydiscriminative component of pain via the connection of the STN with the descending pain inhibitory control system and the modulation of the activity of the nucleus accumbens, which is involved in the modulation of emotional and motivationalaffective status [10]. Nevertheless, after long-term follow-up many DBS patients may
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develop pain, especially of the musculoskeletal type [3]. In our study, the limited improvement of pain was probably due to few patients having painful off dystonia, suggesting that our cohort was more affected by other types of pain that usually respond
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less well to stimulation [3, 11]. Moreover, we found no correlation between the change
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in pain and the motor response to STN-DBS, further confirming that the slight response of pain to stimulation in our patients does not share the same mechanism of motor symptoms.
Finally, our results showed that STN-DBS acutely decreases BP, especially while standing, although no patient was symptomatic for OH, possibly mimicking the effect of levodopa in PD. However, there is some evidence that STN-DBS has no direct effect on autonomic cardiac innervation or muscle vasoconstrictor neurons, although it can slightly enhance cutaneous sympathetic vasoconstriction [12]. Moreover, one small 10
ACCEPTED MANUSCRIPT report showed acute improvement of OH with simulation among 14 PD STN-DBS patients 7 months post-surgery [13]. These conflicting findings encourage further studies to specifically address this condition. Additionally, the few studies available investigating the effect of STN-DBS on BP, have variable wash-out periods of
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stimulation, different medication conditions and usually short post-surgical follow-up
(up to17 months), making it difficult to compare results. Our study has the advantage of including only PD patients with homogeneous age range, long disease duration and
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follow-up. This is particularly important as it is well established that autonomic
dysfunction in PD increases with disease duration and patient’s age. Accordingly, our
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results may suggest that STN-DBS does not maintain its effect on sympathetic vasoconstriction in older PD patients with longer disease duration. Study limitations
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The findings of this analysis are limited due to its cross-sectional nature, the lack of blinding and the lack of a control group.
We did not adopt a baseline threshold score for anxiety, pain and fatigue as an inclusion
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criterion for patients, thus limiting the interpretation of STN-DBS effect on these NMS. However, anxiety, fatigue and pain were present in the majority of the sample.
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Moreover, pre-surgical NMS characteristics were not collected in order to determine pre-surgical predictive features for a better stimulation response. Secondly, we should have better characterized pain types in affected patients, to understand which responds better to acute stimulation. Finally, lead contacts position was not specifically explored, limiting the interpretation of stimulation effect on NMS. Nevertheless, this is the first study to explore the acute effect of STN-DBS on NMS in a representative sample of PD patients with long-term post-surgical follow-up. These preliminary results may guide future research and possibly help the clinical management of DBS PD patients. 11
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Conclusion
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In conclusion, anxiety and fatigue improve with the acute stimulation of the STN even after 5 years of DBS, in PD patients with long disease duration who still have an
optimal motor response to stimulation. This improvement is best in patients showing
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greater motor response to stimulation. The improvement in pain probably depends on
the type of pain most affecting patients, and this must be better addressed in the future.
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STN-DBS may have an acute effect on BP similar to levodopa, although minimal and probably asymptomatic. The acute autonomic effect of STN-DBS also deserves further research, adopting specific autonomic tests.
Neurologists should be aware of the possible acute effect of STN stimulation on some
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NMS during routine adjustments of parameters in clinical practice, which can couple or
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not the motor benefit and influence the outcome of patient management.
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ACCEPTED MANUSCRIPT Acknowledgments: The authors thank Anne-Marie Williams for editorial assistance (English language editing and referencing).
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Authors’ Roles 1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical
A. Writing of the first draft, B. Review and Critique.
Dr. Miguel Coelho: 1A, 1B, 2C, 3B; Dr. Leonor C Guedes: 1B, 3B;
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Dr. Mario M. Rosa: 1B, 3B;
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Dr. Margherita Fabbri: 1A, 1C, 2A, 3A;
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Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation:
Daisy Abreu: 1B, 2A, 2B; Nilza Costa: 2A, 2B, 2C;
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Prof. Angelo Antonini: 1A, 3B;
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Prof. Joaquim J Ferreira: 1A, 1B, 3B;
Full Financial Disclosures of all Authors Dr. Margherita Fabbri, Dr. Miguel Coelho, Dr. Leonor Guedes, Dr. Mario Miguel Rosa, Daisy Abreu and Nilza Gonçalves: no conflict of interest to report. Prof. Angelo Antonini: no conflict of interest to report. Stock Ownership in medicallyrelated fields: none; Consultancies: UCB, Boston Scientific, AbbVie, Zambon. 13
ACCEPTED MANUSCRIPT Advisory Boards: Boston Scientific, AbbVie, Zambon. Honoraria to speak: AbbVie, Zambon, Lundbeck. Grants: Mundipharma, Neureca Foundation, the Italian Ministry Research Grant N RF-2009-1530177 and Horizon 2020 Program Grant N: 643706;
expert testimony on legal cases for pathological gambling;
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Intellectual Property Rights: none; Expert Testimony: Served as Boehringer Ingelheim
Prof. Joaquim J. Ferreira: no conflict of interest to report. Stock Ownership in
medically-related fields: none; Consultancies: Ipsen, GlaxoSmithKline, Novartis, Teva,
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Lundbeck, Solvay, Abbott, BIAL, Merck-Serono and Merz; Advisory Boards: none;
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Partnership: none; Honoraria to speak: none; Grants: GlaxoSmithKline, Grunenthal, Teva and Fundação MSD; Intellectual Property Rights: none; Expert Testimony: none;
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Employment: Laboratory of Clinical Pharmacology and Therapeutics of Lisbon.
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ACCEPTED MANUSCRIPT References
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[1] J.J. Ferreira, R. Katzenschlager, B.R. Bloem, U. Bonuccelli, D. Burn, G. Deuschl, E. Dietrichs, G. Fabbrini, A. Friedman, P. Kanovsky, V. Kostic, A. Nieuwboer, P. Odin, W. Poewe, O. Rascol, C. Sampaio, M. Schupbach, E. Tolosa, C. Trenkwalder, A. Schapira, A. Berardelli, W.H. Oertel, Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease, European journal of neurology : the official journal of the European Federation of Neurological Societies 20(1) (2013) 5-15. [2] H.S. Dafsari, P. Reddy, C. Herchenbach, S. Wawro, J.N. Petry-Schmelzer, V. VisserVandewalle, A. Rizos, M. Silverdale, K. Ashkan, M. Samuel, J. Evans, C.A. Huber, G.R. Fink, A. Antonini, K.R. Chaudhuri, P. Martinez-Martin, L. Timmermann, Beneficial Effects of Bilateral Subthalamic Stimulation on Non-Motor Symptoms in Parkinson's Disease, Brain stimulation 9(1) (2016) 78-85. [3] Y.J. Jung, H.J. Kim, B.S. Jeon, H. Park, W.W. Lee, S.H. Paek, An 8-Year Follow-up on the Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease, JAMA neurology 72(5) (2015) 504-10. [4] A. Berney, M. Panisset, A.F. Sadikot, A. Ptito, A. Dagher, M. Fraraccio, G. Savard, M. Pell, C. Benkelfat, Mood stability during acute stimulator challenge in Parkinson's disease patients under long-term treatment with subthalamic deep brain stimulation, Movement disorders : official journal of the Movement Disorder Society 22(8) (2007) 1093-6. [5] A. Funkiewiez, C. Ardouin, R. Cools, P. Krack, V. Fraix, A. Batir, S. Chabardes, A.L. Benabid, T.W. Robbins, P. Pollak, Effects of levodopa and subthalamic nucleus stimulation on cognitive and affective functioning in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 21(10) (2006) 1656-62. [6] H.J. Kim, B.S. Jeon, S.H. Paek, Nonmotor Symptoms and Subthalamic Deep Brain Stimulation in Parkinson's Disease, Journal of movement disorders 8(2) (2015) 83-91. [7] C.L. Tomlinson, R. Stowe, S. Patel, C. Rick, R. Gray, C.E. Clarke, Systematic review of levodopa dose equivalency reporting in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 25(15) (2010) 2649-53. [8] A. Funkiewiez, C. Ardouin, P. Krack, V. Fraix, N. Van Blercom, J. Xie, E. Moro, A.L. Benabid, P. Pollak, Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease, Movement disorders : official journal of the Movement Disorder Society 18(5) (2003) 524-30. [9] H.J. Kim, B.S. Jeon, S.H. Paek, Effect of deep brain stimulation on pain in Parkinson disease, Journal of the neurological sciences 310(1-2) (2011) 251-5. [10] A. Marques, O. Chassin, D. Morand, B. Pereira, B. Debilly, P. Derost, M. Ulla, J.J. Lemaire, F. Durif, Central pain modulation after subthalamic nucleus stimulation: A crossover randomized trial, Neurology 81(7) (2013) 633-40. [11] R.G. Cury, R. Galhardoni, E.T. Fonoff, M.G. Dos Santos Ghilardi, F. Fonoff, D. Arnaut, M.L. Myczkowski, M.A. Marcolin, E. Bor-Seng-Shu, E.R. Barbosa, M.J. Teixeira, D. Ciampi de Andrade, Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease, Neurology 83(16) (2014) 1403-9. [12] J. Ludwig, P. Remien, C. Guballa, A. Binder, S. Binder, J. Schattschneider, J. Herzog, J. Volkmann, G. Deuschl, G. Wasner, R. Baron, Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease, Journal of neurology, neurosurgery, and psychiatry 78(7) (2007) 742-5. [13] B. Stemper, A. Beric, G. Welsch, T. Haendl, D. Sterio, M.J. Hilz, Deep brain stimulation improves orthostatic regulation of patients with Parkinson disease, Neurology 67(10) (2006) 1781-5. 15
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ACCEPTED MANUSCRIPT STN-DBS (n= 32)
Age (yrs), mean (SD)
62.5 (± 13.3)
Women (n/total (%))
13/32 (40%)
Age at disease onset (yrs), mean (SD)
45.6 (± 9.1)
Disease duration (yrs) , mean (SD)
18.7 (± 5.1)
Age at DBS (yrs), mean (SD)
58.1 (± 12.6)
Months after DBS, mean (SD)
56.6 (± 16.1)
Stimulation Voltage, mean (SD) R_STN/L_STN* LEDD before surgery (mg), mean (SD) LEDD after surgery (mg), mean (SD)
3.0 (± 0.4) /3.0 (± 0.3) 1178.8 (±553.9) 484.4 (±249.1)
S&E _ MED ON/STIM ON, mean (SD)
81.2 (17.1)
HY stage _ MED ON/STIM ON (n (%))
1=2 (6%) 2= 29 (91%) 3=1 (3%)
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10 (31%) 13 (± 7.5) 17(53%) 10 (31%) 7 (22%)
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GDS, mean (SD) Depression (n (%)) Light Severe
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18 (56%) 8 (25%) 6 (19%)
Akinetic-Rigid Tremor dominant Mixed Psychosis (n (%))
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Clinical phenotype (n (%))
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Patients’ data
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MDS-UPDRS-I Mean (SD) and percentage of patients scoring ≥ 1(%) Total score
16.4 (± 6.7)
Cognition Hallucinations & psychosis Depressed mood Anxious mood Apathy DDS Sleep problems Daytime sleepiness Pain Urinary problems Constipation problems Light headedness Fatigue
1 (±0.9) - 65% 0.4 (±0.8) - 31% 1.8 (1.1) - 84% 1.4 (±1.2) - 68% 1.5 (±1.0) - 84% 0.4 (±0.6) - 34% 1.1 (±0.9) - 72% 1.3 (±0.9) - 78% 1.5 (±1.2) - 71% 1.5 (±1.0) - 81% 1.5 (±1.3) - 69% 0.8 (±0.9) - 56% 1.8 (±1.1) - 87%
MDS-UPDRS-II, mean (SD)
16.4 (±7.2)
MDS-UPDRS-IV, mean (SD)
3.7 (±3.9)
L-dopa induced Motor complications (n (%))
24 (75%)
Motor fluctuations (n (%)) Troublesome motor fluctuations (n (%)) Dyskinesias (n (%)) Troublesome Dyskinesias (n (%)) Painful off-dystonia (n (%))
14 (44%) 3 (9%) 19 (60%) 2 (6%) 5 (15%)
NPI-12 items
n=26
Mean (SD) and percentage of patients scoring ≥ 1(%)
RI PT
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11.2 (±8.5)
NMSS
0.03 (±0.1) – 3% 0.7 (±2.4) – 27% 0.4 (±1.0) – 18% 3.1 (±3) – 70% 1.8 (±2.2) – 62% 0 1.9 (±2.4) - 56% 0 0.5 (±1.2) – 22% 0 1.9 (±1.9) – 65% 0.5 (±0.9) - 37%
M AN U
Delirium/Delusion Hallucinations Agitation/Aggression Depression Anxiety Elation/Euphoria Apathy/indifference Disinhibition Irritability/Lability Motor aberrant behaviour Sleep and Night-time Behaviour Disorders Appetite and Eating Disorders
SC
total score
total score
TE D
Mean (SD) and percentage of patients scoring ≥ 1(%)
AC C
EP
Cardiovascular Sleep/Fatigue Mood/Cognition Hallucination/perception Memory Gastrointestinal tract Urinary Sexual function Miscellaneous
61.4 (±31.3) 1.6 (±2.5) - 56% 7.1 (±6.5) - 90% 12.1 (±10.2) - 96% 1.6 (±5.1) - 34% 5.3 (±5.1) - 78% 6.3 (±5.4) - 96% 5.7 (±6.9) - 84% 12.5 (±8.3) - 100% 8.6 (±5.3) - 100%
Table 1. Demographic, clinical and NMS characteristics of DBS patients. LEDD: levodopa equivalent daily dose; S&E: Schwab and England Scale; YH: Hoehn Yahr. GDS: Geriatric depression scale. PDD: Parkinson’s disease with dementia. NMSS: Non-motor symptom assessment scale; NPI-12 items: Neuropsychiatric Inventory test 12-items; *Monopolar stimulation with 130 Hz and 60 µS except: 3 patients with bipolar stimulation, 3 patients with interleaving program and 1 patients with 90 µS;
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VAS-p VAS-f BP_supine BP_ortho
31.7 (13.6)
48.6 (10.3)
39.6 (11.2)
1.7 (2.6)
1.1 (2.5)
4 (3.3)
2.7 (2.7)
153/91 (23/13) 147/94 (26/15) 2 (6 %)
2-OH (n (%))
6 (18%)
HY
2.2 (0.7)
9 (9.6)
<0.005
<0.005 0.079
1.1 (2.7)
<0.05
152/87 (23/13)
2/4 (18/10)
0.6/0.043
138/88 (23/15)
9/5 (19/13)
<0.05
4 (12%)
2
0.4
11 (34%)
5
0.034
/
/
2.1 (0.6)
1 patient with acute depressive dysphoria
EP
Occurrence of AEs
21 (8.8)
p -value
0.9 (1.7)
TE D
1-OH (n (%))
RI PT
52.7(14.7)
Effect size (∆)
SC
STAI
MED OFF/STIM ON
M AN U
MDS-UPDRS-III
MED OFF/STIM OFF
AC C
Table 2. NMS response to stimulation challenge test. Values are presented as mean (SD). STAI: State Trait of Anxiety Inventory (only the 20 items of state anxiety have been applied); VAS-p: visual analogue scale for pain; VAS-f: visual analogue scale for fatigue; BP_supine: blood pressure in supine position: BP_orto: blood pressure after 3 minutes of standing; OT: orthostatic hypotension; p*: MED OFF/STIM OFF versus MEN OOFF/STIM ON; 1-OH: defined as a decrease in systolic pressure ≥ 30 mmHg and in diastolic pressure ≥ 15 mmHg, within 3 minutes of standing; 2-OH: defined as a decrease in systolic pressure ≥ 20 mmHg and in diastolic pressure ≥ 10 mmHg, within 3 minutes of standing.
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•
Five years after surgery, acute STN-DBS improves anxiety and fatigue;
•
STN-DBS may decrease orthostatic blood pressure probably mimicking levodopa effect; These effects should be considered when assessing long-term effect of
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•
AC C
EP
TE D
M AN U
SC
DBS.
AC C
EP
TE D
M AN U
SC
RI PT
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AC C
EP
TE D
M AN U
SC
RI PT
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