Effect of subthalamic nucleus deep brain stimulation on driving in Parkinson disease
Carsten Buhmann, MD Lea Maintz Jonas Hierling Eik Vettorazzi Christian K.E. Moll, MD Andreas K. Engel, MD Christian Gerloff, MD Wolfgang Hamel, MD Wolfgang H. Zangemeister, MD
Correspondence to Priv.-Doz. Dr. Buhmann: [email protected]
ABSTRACT
Objective: To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD).
Methods: Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: “stimulation on” (STIM) (equated to daily treatment), “stimulation off” (OFF), and “stimulation off/levodopa” (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed. Results: Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition. Conclusion: DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general.
Classification of evidence: This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations. Neurology® 2014;82:32–40 GLOSSARY DBS 5 deep brain stimulation; H&Y 5 Hoehn and Yahr; LD 5 levodopa; LED 5 levodopa equivalency dose; PANDA 5 Parkinson Neuropsychometric Dementia Assessment; PD 5 Parkinson disease; STN 5 subthalamic nucleus; UPDRS 5 Unified Parkinson’s Disease Rating Scale.
Patients with Parkinson disease (PD) drive less safely1,2 and cease driving more often than controls.3 However, a standard clinical battery to predict driving performance does not exist, and driving ability in PD should be evaluated individually on the basis of cognitive, visual, and motor measures.4 It is unknown whether deep brain simulation (DBS) of the subthalamic nucleus (STN) affects driving. On the one hand, DBS might enhance driving ability with improvement of motor performance and quality of life.5 On the other hand, STN-DBS might hamper driving because it potentially induces a decline of executive functions6,7 and possibly alters impulse control.8 The first objective of this study was to compare the driving simulator performance of patients with PD with STN-DBS surgery (DBS patients), patients with PD who have not had surgery (no-DBS patients), and controls. In a second step, the treatment effect of stimulation (STIM) vs Supplemental data at www.neurology.org From the Departments of Neurology (C.B., L.M., J.H., C.G., W.H.Z.), Medical Biometry and Epidemiology (E.V.), Neurophysiology and Pathophysiology (C.K.E.M., A.K.E.), and Neurosurgery (W.H.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 32
© 2013 American Academy of Neurology
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levodopa (LD) on driving ability was evaluated in the group of DBS patients. Furthermore, we investigated the influence of the characteristics age, cognition, driving experience, disease severity, disease duration, LD equivalency dose (LED), and duration of stimulation on driving ability in the patients with PD. We hypothesized no negative but a potentially beneficial effect of DBS on driving in patients with PD. METHODS Subjects. Subject groups (23 DBS patients, 21 no-DBS patients, and 21 controls) were matched for age, sex, cognition, and driving experience (table 1). All subjects held a valid driving license and were classified as experienced drivers if they had driven a car at least once a week for more than 30 minutes within the last 3 years. In all subjects, visual field was unimpaired, visual acuity was $0.9, and Mini-Mental State Examination9 score was $26 of 30. Disease severity was classified according to Hoehn and Yahr (H&Y) staging. In the DBS group, additionally the Parkinson Neuropsychometric Dementia Assessment (PANDA)10 score had to be $15 of 30 and disease severity was also classified according to the Unified Parkinson’s Disease Rating Scale (UPDRS), parts III and IV.11 Patients were recruited from our outpatient clinic.
Standard protocol approvals, registrations, and patient consents. Written informed consent was obtained from all
Table 1
subjects, and the study was approved by the local ethics committee of the Medical Council Hamburg (trial number PV3557).
Primary research questions and level of evidence. First, we investigated the influence of patient characteristics on driving performance for all of the patients with PD (ALL) and separately for the DBS group. Second, we compared the driving ability among the DBS patients, no-DBS patients, and controls. Both PD patient groups were examined in the morning during motor “on” condition and with their normal “everyday” treatment, which was medication and stimulation in the DBS group and medication in the no-DBS group. Third, we examined the effect of STIM vs LD on the driving ability of the DBS patients (Class IV). Driving simulator. The driver cockpit mimicked an average automatic car. Different driving situations were simulated via a color beamer display (figure e-1 on the Neurology® Web site at www. neurology.org). Simulator hardware and software (SimuTech, Bremen, Germany) fulfill criteria of European Union guideline 2003/59/EG for driver qualification law training. The faceLAB GazeTracker system (version 4.54, 2009) was used to present and record data (steering, indicator, and accelerator/brake signals). Parameters were analyzed with the software tool INTERACT and DataView (version V2.4, 2010; Mangold International GmbH, Arnstorf, Germany). Paradigm and experimental setup. After verbal instruction, patients practiced for 5 minutes driving in a virtual carpark. Controls and no-DBS patients underwent one regular test run, DBS patients were monitored in 3 fixed sequenced test runs under
Subject characteristics of controls and the no-DBS and DBS patient groups Controls (n 5 21)
No-DBS (n 5 21)
DBS (n 5 23)
p Values
Age, y
61.4 6 5.2
63.6 6 10.0
62.2 6 8.0
0.67a
Male, n (%)
17 (81)
17 (81)
19 (82)
0.93b
Experienced drivers, n (%)
15 (71)
14 (67)
16 (70)
1.0b
Disease duration, y
NA
6.0 6 5.0
14.0 6 5.1
,0.001a
Duration of stimulation, mo
NA
NA
18.2 6 18.0
NA
LED, mg
NA
647 6 412
778 6 400
Levodopa, %
NA
57.1
91.3
,0.01c
Dopamine agonists, %
NA
76.2
65.2
0.43c
MAO-B inhibitors, %
NA
42.9
13.0
0.03c
COMT inhibitors, %
NA
23.8
52.2
0.054c
Amantadine, %
NA
33.3
9.0
0.04c
Anticholinergics, %
NA
10.0
9.0
0.92c
H&Y score
NA
1.9 6 0.5
3.0 6 0.8
,0.001d
Total UPDRS (I–IV) score
NA
NA
32.5 6 14.2
NA
UPDRS III score
NA
NA
15.4 6 1.8
NA
PANDA score
NA
NA
20.9 6 4.0
NA
MMSE score
28.9 6 0.8
28.7 6 1.2
28.1 6 1.3
0.29a
0.12a
Abbreviations: COMT 5 catechol-O-methyltransferase; DBS 5 deep brain stimulation; H&Y 5 Hoehn and Yahr; LED 5 levodopa equivalency dose; MAO-B 5 monoamine oxidase B; MMSE 5 Mini-Mental State Examination; NA 5 not applicable; PANDA 5 Parkinson Neuropsychometric Dementia Assessment; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Values are mean 6 SD unless otherwise indicated. Between-group differences are given with p values. a Analysis of variance. b Fisher exact test. c 2 x test. d Median test. Neurology 82
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Table 2
Comparison of driving performance of controls and the no-DBS and DBS patient groups p Values (ANCOVA)
Controls (n 5 21)
No-DBS (n 5 21)
DBS (n 5 23)
p Values (ANOVA)
158.8 6 42.3
199.0 6 77.6
252.3 6 64.5
,0.001, F2,62 5 12.14
0.02
46.7 6 41.6
86.0 6 71.8
64.8 6 47.7
,0.076, F2,62 5 2.69
0.19
4.5 6 2.7
6.5 6 4.7
2.7 6 1.4
,0.001, F2,62 5 7.98
0.001
11.3 6 6.0
18.0 6 8.5
10.7 6 5.1
,0.001, F2,62 5 7.73
0.002
7.5 6 3.8
11.4 6 5.0
3.8 6 1.7
,0.001, F2,62 5 23.04
3.0 6 2.9
4.4 6 4.4
5.0 6 3.8
,0.20, F2,62 5 1.63
0.70
1.0 6 1.4
2.1 6 2.0
1.9 6 2.1
,0.11, F2,62 5 2.29
0.90
0
0
0.04 6 0.2
,0.41, F2,62 5 0.91
0.37
16.3 6 13.8
25.6 6 13.8
19.5 6 11.2
,0.040, F2,62 5 3.39
0.17
Driving times, s Total p 5 0.043a p 5 0.007b p < 0.001c Inaccurate a
p 5 0.043 NSb NSc Errors
Rate (per min) p 5 0.043a p < 0.001b NS (p 5 0.06)c No. a
p 5 0.002
p < 0.001b NSc Slight
,0.001
a
p 5 0.001
p < 0.001b p 5 0.043c Moderate a
NS
NSb NSc Severe p 5 0.046a NSb NSc Very severe a
NS
NSb NSc Sum score (errors) a
p 5 0.044 NSb NSc
Abbreviations: ANCOVA 5 analysis of covariance; ANOVA 5 analysis of variance; DBS 5 deep brain stimulation; NS 5 not significant. ANOVA with post hoc analysis (least significant difference) was applied. Driving performance measures are expressed as means 6 SD. The p values are adjusted for disease duration and severity according to Hoehn and Yahr staging for comparison between both Parkinson disease patient groups (ANCOVA). a Comparison of controls and no-DBS patients. b Comparison of no-DBS patients and DBS patients. c Comparison of controls and DBS patients.
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Figure 1
Comparison of driving performance among patients with Parkinson disease with and without DBS and controls
speed. All-day traffic situations including driving key conditions13 were simulated. Driving errors were defined according to an official driving instructor handbook14 and reviewed by a professional driving instructor. The number of driving errors was counted, and error severity was categorized from slight to very severe (table e-1). We analyzed total and inaccurate driving time, error number, error rate (number per time), error severity, and sum score of errors (reflecting quality and quantity of errors by considering error number and severity, with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error).
Statistical procedures. The influence of patient characteristics on driving parameters was estimated by Spearman rank correlation or x2 test. Between-group comparisons of subject characteristics were performed with analysis of variance, median test, x2 test, or Fisher exact test (table 1). Between-group differences in driving times and errors were calculated by analysis of covariance with post hoc analysis and adjustment for disease severity and duration. Within the DBS group, a mixed-model analysis was used to investigate the influence of the treatment condition (STIM, OFF, or LD) on driving parameters. In this model, we allowed unequal variances within the different conditions. UPDRS III score was included as covariate into the mixed model to adjust for potential confounding due to individual motor score differences between conditions. The model was furthermore adjusted for the treatment condition–related factor tremor and for treatment-unrelated patient characteristics proven to influence driving ability (age, PANDA score). Because our study was exploratory, no correction of statistical significance for multiple testing was performed to avoid inflating type II errors and thus missing real differences.15–18
RESULTS Baseline characteristics. Baseline characteristics are detailed in table 1. DBS patients had longer disease duration and were more severely affected according to H&Y stage than no-DBS patients. Daily mean LED was comparable in both PD patient groups.
Driving performance was compared among patients with Parkinson disease with deep brain stimulation (PD-DBS), patients without DBS (PD–no DBS), and controls (CON). (A) Values (mean 6 SD) for total and inaccurate driving time in seconds. (B) Values (mean 6 SD) of total number of errors; error rate (errors/min); number of slight, moderate, and severe errors; and sum score of errors. The latter parameter includes quality and quantity of errors with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error. ns 5 not significant.
3 different treatment conditions: 1) “STIM,” with chronic stimulation switched on, 2) “OFF,” with stimulation switched off, and 3) “LD,” with stimulation switched off and after administration of soluble LD (Madopar LT; Roche Products Ltd., Hertfordshire, UK). LD was given in a 1.5-fold dosage of individual normal LED12 (mean 165 6 49 mg) to compensate for off-stimulation and to reach clinical motor “on” status comparable to condition STIM. In each condition, a realistic and demanding urban test course of 1.7 km was presented with a randomized sequence of the sceneries. Stimulation was switched off immediately after test run 1; 30 minutes later, test run 2 started. After test run 2, Madopar LT was given and test run 3 started another 30 minutes later. Before test run 1, UPDRS parts I to IV were evaluated. Directly before test runs 2 and 3, UPDRS III and presence of dyskinesia (yes/no) were rated. To reach a balanced speed-accuracy trade-off, patients were instructed to complete the given test course as fast as they could without sacrificing accuracy. Accuracy was favored over
Influence of PD patient characteristics on driving performance. Investigation was done for all patients
with PD (ALL) and separately for patients undergoing DBS (see table e-2 for detailed statistics). Age influenced driving performance negatively with an increase of inaccurate driving time, error number, moderate errors, and error sum score in both, ALL and DBS patients, an increase of error rate in the DBS patient group, and an increase of severe errors in ALL patients. Regression analysis yielded an estimated increase of 0.3 (p , 0.05) in error number and 0.7 (p , 0.05) in error sum score per year of participant’s life in the DBS patient group. Higher Mini-Mental State Examination scores correlated with shorter inaccurate driving time (ALL patients: rs 5 20.32, p 5 0.033) and higher PANDA scores correlated with fewer slight errors (DBS patients: rs 5 20.41, p 5 0.050). Experienced DBS drivers drove faster (driving time 231.6 vs 299.4 seconds, p 5 0.02) but apart from that, driving experience had no significant influence on any other driving parameter in ALL or DBS patients. Higher disease severity according to H&Y stage was significantly associated with a longer total Neurology 82
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Table 3
Differential effects of treatment conditions STIM, OFF, and LD on driving performance within the DBS patient group p Values, mixed models
Condition
UPDRS III, points
1 STIM
2 OFF
3 LD
1 vs 2
2 vs 3
1 vs 3
15.39 6 1.80
24.52 6 1.32
15.57 6 1.06
,0.001
,0.001
0.92
15.33 6 2.36
24.47 6 1.75
15.50 6 1.88
,0.001
,0.001
0.92
250.79 6 14.92
276.39 6 11.83
258.09 6 12.49
0.13
0.21
0.64
241.67 6 19.30
267.77 6 14.49
248.93 6 16.82
0.14
0.20
0.65
Driving times, s Total
63.15 6 10.40
80.77 6 11.01
75.05 6 11.09
0.11
0.62
0.21
55.80 6 13.06
73.85 6 11.42
67.67 6 13.38
0.11
0.59
0.23
Rate, per min
2.82 6 0.33
3.12 6 0.41
3.10 6 0.33
0.38
0.93
0.17
2.49 6 0.49
2.89 6 0.48
2.78 6 0.49
0.27
0.73
0.19
No.
10.96 6 1.16
14.23 6 1.58
12.90 6 1.36
0.02a
0.37
0.03a
9.27 6 1.82
13.02 6 1.79
11.22 6 1.94
0.01a
0.23
0.045a
3.77 6 0.39
5.62 6 0.45
4.69 6 0.40
0.002a
0.10
0.046a
3.57 6 0.69
5.46 6 0.63
4.48 6 0.70
0.002a
0.11
0.048a
5.04 6 0.83
6.80 6 1.01
5.56 6 0.90
0.09
0.24
0.49
Inaccurate
Errors
Slight
Moderate
Severe
Very severe
Sum score of errors
a
3.41 6 1.09
5.57 6 0.97
3.92 6 1.13
0.02
0.10
0.53
1.83 6 0.45
2.33 6 0.57
2.23 6 0.61
0.32
0.87
0.41
2.03 6 0.72
2.40 6 0.72
2.42 6 0.83
0.49
0.98
0.41 a
0.16
0.04 6 0.04
0
0.17 6 0.81
0.33
0.04
0.04 6 0.04
0
0.17 6 0.81
0.33
0.04a
0.16
20.16 6 2.52
24.98 6 3.50
23.69 6 2.99
0.09
0.68
0.044a
17.52 6 4.05
22.91 6 4.04
21.05 6 4.28
0.07
0.55
0.049a
Abbreviations: DBS 5 deep brain stimulation; LD 5 levodopa; OFF 5 stimulation off; SE 5 standard error; STIM 5 stimulation on; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Values are expressed as estimated means 6 SE. For each characteristic, results in the first row of entries are adjusted for UPDRS III score; results in the second row of entries are additionally adjusted for tremor, age, and cognition (Parkinson Neuropsychometric Dementia Assessment [PANDA] score). Although age and PANDA score are treatment condition–unrelated parameters, they influence driving and therefore are included in this second analysis. This adjusted analysis also shows a significant difference for moderate errors between conditions STIM and OFF. a Significant differences.
driving time but lower error rate, error number, and slight errors in ALL patients. H&Y and UPDRS III did not correlate with any driving parameter in DBS patients. Longer disease duration was associated with a lower error rate and lower error number due to fewer slight errors in ALL patients. Total LED (ALL and DBS patients) and duration of stimulation (DBS patients) were not associated with any driving parameter. Between-group comparison (controls, no-DBS patients, DBS patients). Driving performance. Detailed parameters
are given in table 2 and figure 1. Driving time. Total driving time was significantly longer in both PD patient groups than in controls and significantly longer in DBS than in no-DBS patients. Mean (SD) speed (km/h) was 41.2 6 11.1 36
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in controls, 32.5 6 11.4 in no-DBS patients, and 25.8 6 6.8 in DBS patients. Inaccurate driving time was significantly worse in no-DBS but not in DBS patients compared with controls. Driving errors. Compared with controls, no-DBS patients performed significantly worse in all error categories except “moderate errors.” In contrast, DBS patients did not perform significantly worse than controls in any category, but even significantly better in slight errors and by trend (p 5 0.06) regarding error rate. Compared with no-DBS patients, DBS patients showed a lower rate and number of driving errors, which was highly significant for slight errors. Focused on the error sum score, noDBS patients but not DBS patients performed significantly worse than controls. However, the absolute sum score was also inferior in DBS patients compared with controls, which was related to an insignificant higher rate
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Figure 2
Comparison of treatment effects (STIM, OFF, LD) on driving performance in patients with Parkinson disease with DBS
condition (estimates of fixed effects in the mixed model). Results were heterogeneous with an increase of 1 point on the UPDRS III scale leading to insignificant increases of error rate and number, moderate errors, and error sum score. However, UPDRS III increase led to insignificant decreases of total and inaccurate driving times and slight and severe errors. Tremor and dyskinesias. Although tremor is part of the UPDRS III scale, we investigated its influence on driving as a separate parameter (present yes/no). We included tremor as an adjusted covariate in the mixed model, because it usually immediately reappears when switching off stimulation, often above-average because of a rebound effect. This might dominate and bias short-time changes of the UPDRS III score. Tremor occurred in 3 patients in condition OFF, and dyskinesias in 6 patients in condition LD, without significant influence on any driving parameters. In these 6 patients, the levodopa dose in condition LD did not influence the incidence of dyskinesias (logistic regression, p 5 0.294). Driving performance. The effect of treatment conditions (STIM, OFF, LD) on driving performance is detailed in table 3 and figure 2. We found no differential effect of age and cognition (PANDA) on driving parameters between conditions. Driving time. Total and inaccurate driving times were shortest in STIM and longest in OFF. Duration of total and inaccurate driving time in LD was in between STIM and OFF. No significant difference was found.
Treatment-condition effects (stimulation on [STIM], stimulation off [OFF], and levodopa [LD]) on driving performance were compared in patients with Parkinson disease with deep brain stimulation (DBS). (A) Values (mean 6 standard error [SE]) for total and inaccurate driving time in seconds. (B) Values (mean 6 SE) of total number of errors; error rate (errors/min); number of slight, moderate, and severe errors; and sum score of errors. The latter parameter includes quality and quantity of errors with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error. ns 5 not significant.
of moderate and severe driving errors. Superior sumscore values in DBS patients compared with no-DBS patients did not reach statistical significance. All conclusions remain identical after adjustment for patient group differences in disease duration and H&Y stage (analysis of covariance). Within-group comparison of treatment condition effects (STIM, OFF, LD) in DBS patients. Motor performance.
Mean UPDRS III in conditions STIM and LD was almost identical and significantly lower than in condition OFF (table 3). This indicates a comparable motor function in test runs STIM and LD. To estimate the influence of motor performance on driving, we calculated the effect of changes in UPDRS III score on driving parameters independently of the
Driving errors. Error rate, error number, slight and moderate errors, and sum score of errors were lowest in STIM and highest in OFF with all parameters in LD found to be in between STIM and OFF. Severe driving errors were made once in one patient in STIM, not at all in OFF, and once by 4 patients in LD, without statistical difference. Condition (STIM, OFF, LD) showed a significant influence on error number, slight errors, and error sum score. In detail, in STIM vs OFF, driving performance was significantly better regarding error number and slight errors and by trend for moderate errors (p 5 0.09) and sum score (p 5 0.09). Furthermore, in STIM vs LD, patients performed significantly superior regarding error number, slight errors, and sum score. No differences were found in driving errors between LD and OFF. Patients in STIM not only drove less inaccurately but also more homogeneously compared with OFF and (less distinctive) LD. For error sum score, the estimated variance of residual covariance parameters was 2.4 for STIM, 122.5 for OFF, and 58.7 for LD. The high group performance inhomogeneity in OFF explains the marginally missed significance for error sum-score difference in STIM vs OFF in Neurology 82
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contrast to STIM vs LD, despite a higher mean sumscore error in OFF vs the LD condition. DISCUSSION Our data support the hypothesis that DBS has no negative but rather a beneficial effect on driving in patients with PD. Driving not only was superior in even more clinically affected DBS compared with no-DBS patients but also DBS patients drove better with stimulation than with levodopa. This might reflect favorable driving-relevant nonmotor effects due to STN-DBS. The driving simulator setting allows faithful replication of the experimental road condition across participants, in contrast to on-road settings.13 We presented key safety traffic situations13 such as “turning at street crossings,” “holding lane line,” “passing a roundabout,” “following give way sign,” or “attending to traffic lights.” Performance reflects real-life driving ability19 and is suitable to monitor on-road driving impairments in patients with PD.2 Driving time (speed) in the free-flowing traffic and driving errors are approved safety-related parameters in traffic simulation models.20 The sum score weights for the quality of driving errors and accounts for highfrequency/low-severity and low-frequency/high-severity errors. This is meaningful for determining crash risk in PD, because especially the latter errors lead to car crashes.13 Our data are consistent with prior investigations describing impaired simulator driving in medicated patients with PD compared with controls1,21 and investigations reporting that age and lower cognition scores have a negative impact on driving in PD.1,22–24 Slower but more accurate driving in patients with higher H&Y stages is in line with prior findings of inconsistent influence of motor impairment on driving in PD.22,24,25 In contrast to others,2 we found that patients with a longer disease history drive more accurately, potentially as a result of more careful driving. Unlike driving speed, driving safety was not higher in experienced drivers, which is in accordance with the findings of a previous study.24 Following others, and using the total annual mileage,26 or a minimum annual mileage of 3,000 km as parameter for driving experience, did not change the results. As expected, controls had a higher annual mileage than patients with PD (details in table e-3). Unexpectedly, DBS patients and controls drove comparably well. The driving course was demanding but short and patients reported lower annual mileage. Driving of longer distances might be worse in patients because of problems with sustained attention. Therefore, the present results might be limited to shorter driving distances, such as inner-city or neighborhood driving. Further studies should address long-distance driving. 38
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Sleep attacks as a potential cause of unsafe driving in PD27 were excluded by analyzing faceLAB GazeTracker data. LED and percentage of dopamine agonist use as risk factors for daytime sleepiness28,29 were comparable in both patient groups. Disease duration as further risk factor was even higher in the betterperforming DBS patient group. To compare stimulation and levodopa effects on driving, levodopa had to compensate for the lost clinical effect after switching off stimulation, on the basis of identical underlying medication. We did not intend to reach “worst-off” stimulation or “best-on” levodopa condition. However, mean UPDRS III score was significantly worse 30 minutes after switching off stimulation because the main clinical effect is usually lost fast, within 200 seconds, and in comparably diseased patients, the half-life of following slow stimulation washout phase is approximately 6 to 7 minutes for bradykinesia.30 Furthermore, mean UPDRS III score was significantly better 30 minutes after levodopa intake and, as intended, comparable to the initial UPDRS score under stimulation. This seems plausible, because tmax plasma levels have been found 60.0 6 45.6 minutes after Madopar LT intake in patients with PD, comparable to ours.31 However, in our study, tmax likely was reached earlier because we used a 1.65-fold higher mean Madopar LT dosage and excluded a preceding albuminous meal. To avoid learning effects favoring levodopa, sequences of otherwise identical sceneries within the test runs were randomized. Running of tests on different days was avoided to eliminate unreliable comparison of treatment effects (STIM, OFF, LD) due to intraindividual and unpredictable daily variability of symptoms. To prevent exhaustion penalizing levodopa, the investigation time was kept as short as possible considering the stimulation washout and levodopa absorption times discussed above. Total driving times on average were less than 5 minutes and exceeded 6 minutes only once (423 seconds in condition LD). Worse driving with LD compared with STIM might be partly explained by the inverted U-shape relationship between dopamine and cognition and related to a dopamine overdosage in corticostriatal circuits beyond motor loops with negative effects on learning.32 Also, inferior driving caused by LDinduced impulsivity33 is conceivable. Compatibly, we found a severe driving error once in 4 patients in condition LD but only once in one patient in condition STIM and none in condition OFF. DBS might positively influence driving-relevant nonmotor skills. Impairments of sequence and implicit procedural learning,34 planning and sequencing,35 and information updating36 probably reduce driving ability in patients with PD. STN-DBS selectively improves implicit procedural learning, possibly by altering basal
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ganglia output to the frontal cortex.37 Concordant with our results, sequence learning has been described to be superior with STN stimulation “on” compared with stimulation “off” and compared with sequence learning after levodopa infusion titrated to motor response equivalent to stimulation.38 Furthermore, STN stimulation improves goal-directed action selection39 and decision learning,40 both of which are cognitive skills crucial in driving a car. In conclusion, regaining a better driving ability in PD might be one aspect of improved quality of life with DBS in comparison to medical treatment alone. Based on our data, we suggest handling driving permission for DBS-treated patients with PD not more restrictively than permissions for patients with PD in general.
6.
7.
8.
9.
10.
11. AUTHOR CONTRIBUTIONS Drafting/revising the manuscript for content, including medical writing for content: C.B., E.V., C.K.E.M., A.K.E., C.G., W.H. Study concept or design: C.B., W.H.Z. Analysis or interpretation of data: C.B., E.V., L.M., J.H., W.H.Z. Acquisition of data: C.B., L.M., J.H., W.H. Statistical analysis: C.B., E.V. Study supervision or coordination: C.B., W.H.Z. Obtaining funding: C.B., W.H.Z.
12.
ACKNOWLEDGMENT The authors thank Thomas Wriedt for rating driving errors and configurating the driving simulator device.
13.
STUDY FUNDING
14.
Supported by the Georg & Jürgen Rickertsen Stiftung Hamburg.
DISCLOSURE C. Buhmann received study research support from the Georg & Jürgen Rickertsen Stiftung Hamburg. PD Dr. C. Buhmann served on the scientific advisory board for GSK and UCB Pharma and received honoraria for lectures from GSK, Medtronic, Orion Pharma, and UCB. L. Maintz, J. Hierling, E. Vettorazzi, and C.K.E. Moll report no disclosures. A.K. Engel acknowledges support of the German Research Foundation (DFG SFB 936) and the European Union (EU) (FP7-ICT-270212, ERC-2010-AdG269716). C. Gerloff is supported by the German Research Foundation (DFG Ge 844/4-1, SFB 936) and the EU (FP7-HEALTH-2011278276). W. Hamel reports no disclosures. W.H. Zangemeister received study research support from the Georg & Jürgen Rickertsen Stiftung Hamburg. Go to Neurology.org for full disclosures.
15. 16. 17. 18. 19. 20.
Received April 17, 2013. Accepted in final form September 23, 2013.
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Effect of subthalamic nucleus deep brain stimulation on driving in Parkinson disease Carsten Buhmann, Lea Maintz, Jonas Hierling, et al. Neurology 2014;82;32-40 Published Online before print December 18, 2013 DOI 10.1212/01.wnl.0000438223.17976.fb This information is current as of December 18, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/1/32.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2013/12/18/01.wnl.000043822 3.17976.fb.DC1.html
References
This article cites 38 articles, 15 of which you can access for free at: http://www.neurology.org/content/82/1/32.full.html##ref-list-1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Parkinson's disease/Parkinsonism http://www.neurology.org//cgi/collection/parkinsons_disease_parkinso nism Surgery/Stimulation http://www.neurology.org//cgi/collection/surgery-stimulation
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2013 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Carsten Buhmann, MD Lea Maintz Jonas Hierling Eik Vettorazzi Christian K.E. Moll, MD Andreas K. Engel, MD Christian Gerloff, MD Wolfgang Hamel, MD Wolfgang H. Zangemeister, MD
Correspondence to Priv.-Doz. Dr. Buhmann: [email protected]
ABSTRACT
Objective: To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD).
Methods: Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: “stimulation on” (STIM) (equated to daily treatment), “stimulation off” (OFF), and “stimulation off/levodopa” (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed. Results: Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition. Conclusion: DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general.
Classification of evidence: This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations. Neurology® 2014;82:32–40 GLOSSARY DBS 5 deep brain stimulation; H&Y 5 Hoehn and Yahr; LD 5 levodopa; LED 5 levodopa equivalency dose; PANDA 5 Parkinson Neuropsychometric Dementia Assessment; PD 5 Parkinson disease; STN 5 subthalamic nucleus; UPDRS 5 Unified Parkinson’s Disease Rating Scale.
Patients with Parkinson disease (PD) drive less safely1,2 and cease driving more often than controls.3 However, a standard clinical battery to predict driving performance does not exist, and driving ability in PD should be evaluated individually on the basis of cognitive, visual, and motor measures.4 It is unknown whether deep brain simulation (DBS) of the subthalamic nucleus (STN) affects driving. On the one hand, DBS might enhance driving ability with improvement of motor performance and quality of life.5 On the other hand, STN-DBS might hamper driving because it potentially induces a decline of executive functions6,7 and possibly alters impulse control.8 The first objective of this study was to compare the driving simulator performance of patients with PD with STN-DBS surgery (DBS patients), patients with PD who have not had surgery (no-DBS patients), and controls. In a second step, the treatment effect of stimulation (STIM) vs Supplemental data at www.neurology.org From the Departments of Neurology (C.B., L.M., J.H., C.G., W.H.Z.), Medical Biometry and Epidemiology (E.V.), Neurophysiology and Pathophysiology (C.K.E.M., A.K.E.), and Neurosurgery (W.H.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 32
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levodopa (LD) on driving ability was evaluated in the group of DBS patients. Furthermore, we investigated the influence of the characteristics age, cognition, driving experience, disease severity, disease duration, LD equivalency dose (LED), and duration of stimulation on driving ability in the patients with PD. We hypothesized no negative but a potentially beneficial effect of DBS on driving in patients with PD. METHODS Subjects. Subject groups (23 DBS patients, 21 no-DBS patients, and 21 controls) were matched for age, sex, cognition, and driving experience (table 1). All subjects held a valid driving license and were classified as experienced drivers if they had driven a car at least once a week for more than 30 minutes within the last 3 years. In all subjects, visual field was unimpaired, visual acuity was $0.9, and Mini-Mental State Examination9 score was $26 of 30. Disease severity was classified according to Hoehn and Yahr (H&Y) staging. In the DBS group, additionally the Parkinson Neuropsychometric Dementia Assessment (PANDA)10 score had to be $15 of 30 and disease severity was also classified according to the Unified Parkinson’s Disease Rating Scale (UPDRS), parts III and IV.11 Patients were recruited from our outpatient clinic.
Standard protocol approvals, registrations, and patient consents. Written informed consent was obtained from all
Table 1
subjects, and the study was approved by the local ethics committee of the Medical Council Hamburg (trial number PV3557).
Primary research questions and level of evidence. First, we investigated the influence of patient characteristics on driving performance for all of the patients with PD (ALL) and separately for the DBS group. Second, we compared the driving ability among the DBS patients, no-DBS patients, and controls. Both PD patient groups were examined in the morning during motor “on” condition and with their normal “everyday” treatment, which was medication and stimulation in the DBS group and medication in the no-DBS group. Third, we examined the effect of STIM vs LD on the driving ability of the DBS patients (Class IV). Driving simulator. The driver cockpit mimicked an average automatic car. Different driving situations were simulated via a color beamer display (figure e-1 on the Neurology® Web site at www. neurology.org). Simulator hardware and software (SimuTech, Bremen, Germany) fulfill criteria of European Union guideline 2003/59/EG for driver qualification law training. The faceLAB GazeTracker system (version 4.54, 2009) was used to present and record data (steering, indicator, and accelerator/brake signals). Parameters were analyzed with the software tool INTERACT and DataView (version V2.4, 2010; Mangold International GmbH, Arnstorf, Germany). Paradigm and experimental setup. After verbal instruction, patients practiced for 5 minutes driving in a virtual carpark. Controls and no-DBS patients underwent one regular test run, DBS patients were monitored in 3 fixed sequenced test runs under
Subject characteristics of controls and the no-DBS and DBS patient groups Controls (n 5 21)
No-DBS (n 5 21)
DBS (n 5 23)
p Values
Age, y
61.4 6 5.2
63.6 6 10.0
62.2 6 8.0
0.67a
Male, n (%)
17 (81)
17 (81)
19 (82)
0.93b
Experienced drivers, n (%)
15 (71)
14 (67)
16 (70)
1.0b
Disease duration, y
NA
6.0 6 5.0
14.0 6 5.1
,0.001a
Duration of stimulation, mo
NA
NA
18.2 6 18.0
NA
LED, mg
NA
647 6 412
778 6 400
Levodopa, %
NA
57.1
91.3
,0.01c
Dopamine agonists, %
NA
76.2
65.2
0.43c
MAO-B inhibitors, %
NA
42.9
13.0
0.03c
COMT inhibitors, %
NA
23.8
52.2
0.054c
Amantadine, %
NA
33.3
9.0
0.04c
Anticholinergics, %
NA
10.0
9.0
0.92c
H&Y score
NA
1.9 6 0.5
3.0 6 0.8
,0.001d
Total UPDRS (I–IV) score
NA
NA
32.5 6 14.2
NA
UPDRS III score
NA
NA
15.4 6 1.8
NA
PANDA score
NA
NA
20.9 6 4.0
NA
MMSE score
28.9 6 0.8
28.7 6 1.2
28.1 6 1.3
0.29a
0.12a
Abbreviations: COMT 5 catechol-O-methyltransferase; DBS 5 deep brain stimulation; H&Y 5 Hoehn and Yahr; LED 5 levodopa equivalency dose; MAO-B 5 monoamine oxidase B; MMSE 5 Mini-Mental State Examination; NA 5 not applicable; PANDA 5 Parkinson Neuropsychometric Dementia Assessment; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Values are mean 6 SD unless otherwise indicated. Between-group differences are given with p values. a Analysis of variance. b Fisher exact test. c 2 x test. d Median test. Neurology 82
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Table 2
Comparison of driving performance of controls and the no-DBS and DBS patient groups p Values (ANCOVA)
Controls (n 5 21)
No-DBS (n 5 21)
DBS (n 5 23)
p Values (ANOVA)
158.8 6 42.3
199.0 6 77.6
252.3 6 64.5
,0.001, F2,62 5 12.14
0.02
46.7 6 41.6
86.0 6 71.8
64.8 6 47.7
,0.076, F2,62 5 2.69
0.19
4.5 6 2.7
6.5 6 4.7
2.7 6 1.4
,0.001, F2,62 5 7.98
0.001
11.3 6 6.0
18.0 6 8.5
10.7 6 5.1
,0.001, F2,62 5 7.73
0.002
7.5 6 3.8
11.4 6 5.0
3.8 6 1.7
,0.001, F2,62 5 23.04
3.0 6 2.9
4.4 6 4.4
5.0 6 3.8
,0.20, F2,62 5 1.63
0.70
1.0 6 1.4
2.1 6 2.0
1.9 6 2.1
,0.11, F2,62 5 2.29
0.90
0
0
0.04 6 0.2
,0.41, F2,62 5 0.91
0.37
16.3 6 13.8
25.6 6 13.8
19.5 6 11.2
,0.040, F2,62 5 3.39
0.17
Driving times, s Total p 5 0.043a p 5 0.007b p < 0.001c Inaccurate a
p 5 0.043 NSb NSc Errors
Rate (per min) p 5 0.043a p < 0.001b NS (p 5 0.06)c No. a
p 5 0.002
p < 0.001b NSc Slight
,0.001
a
p 5 0.001
p < 0.001b p 5 0.043c Moderate a
NS
NSb NSc Severe p 5 0.046a NSb NSc Very severe a
NS
NSb NSc Sum score (errors) a
p 5 0.044 NSb NSc
Abbreviations: ANCOVA 5 analysis of covariance; ANOVA 5 analysis of variance; DBS 5 deep brain stimulation; NS 5 not significant. ANOVA with post hoc analysis (least significant difference) was applied. Driving performance measures are expressed as means 6 SD. The p values are adjusted for disease duration and severity according to Hoehn and Yahr staging for comparison between both Parkinson disease patient groups (ANCOVA). a Comparison of controls and no-DBS patients. b Comparison of no-DBS patients and DBS patients. c Comparison of controls and DBS patients.
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Figure 1
Comparison of driving performance among patients with Parkinson disease with and without DBS and controls
speed. All-day traffic situations including driving key conditions13 were simulated. Driving errors were defined according to an official driving instructor handbook14 and reviewed by a professional driving instructor. The number of driving errors was counted, and error severity was categorized from slight to very severe (table e-1). We analyzed total and inaccurate driving time, error number, error rate (number per time), error severity, and sum score of errors (reflecting quality and quantity of errors by considering error number and severity, with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error).
Statistical procedures. The influence of patient characteristics on driving parameters was estimated by Spearman rank correlation or x2 test. Between-group comparisons of subject characteristics were performed with analysis of variance, median test, x2 test, or Fisher exact test (table 1). Between-group differences in driving times and errors were calculated by analysis of covariance with post hoc analysis and adjustment for disease severity and duration. Within the DBS group, a mixed-model analysis was used to investigate the influence of the treatment condition (STIM, OFF, or LD) on driving parameters. In this model, we allowed unequal variances within the different conditions. UPDRS III score was included as covariate into the mixed model to adjust for potential confounding due to individual motor score differences between conditions. The model was furthermore adjusted for the treatment condition–related factor tremor and for treatment-unrelated patient characteristics proven to influence driving ability (age, PANDA score). Because our study was exploratory, no correction of statistical significance for multiple testing was performed to avoid inflating type II errors and thus missing real differences.15–18
RESULTS Baseline characteristics. Baseline characteristics are detailed in table 1. DBS patients had longer disease duration and were more severely affected according to H&Y stage than no-DBS patients. Daily mean LED was comparable in both PD patient groups.
Driving performance was compared among patients with Parkinson disease with deep brain stimulation (PD-DBS), patients without DBS (PD–no DBS), and controls (CON). (A) Values (mean 6 SD) for total and inaccurate driving time in seconds. (B) Values (mean 6 SD) of total number of errors; error rate (errors/min); number of slight, moderate, and severe errors; and sum score of errors. The latter parameter includes quality and quantity of errors with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error. ns 5 not significant.
3 different treatment conditions: 1) “STIM,” with chronic stimulation switched on, 2) “OFF,” with stimulation switched off, and 3) “LD,” with stimulation switched off and after administration of soluble LD (Madopar LT; Roche Products Ltd., Hertfordshire, UK). LD was given in a 1.5-fold dosage of individual normal LED12 (mean 165 6 49 mg) to compensate for off-stimulation and to reach clinical motor “on” status comparable to condition STIM. In each condition, a realistic and demanding urban test course of 1.7 km was presented with a randomized sequence of the sceneries. Stimulation was switched off immediately after test run 1; 30 minutes later, test run 2 started. After test run 2, Madopar LT was given and test run 3 started another 30 minutes later. Before test run 1, UPDRS parts I to IV were evaluated. Directly before test runs 2 and 3, UPDRS III and presence of dyskinesia (yes/no) were rated. To reach a balanced speed-accuracy trade-off, patients were instructed to complete the given test course as fast as they could without sacrificing accuracy. Accuracy was favored over
Influence of PD patient characteristics on driving performance. Investigation was done for all patients
with PD (ALL) and separately for patients undergoing DBS (see table e-2 for detailed statistics). Age influenced driving performance negatively with an increase of inaccurate driving time, error number, moderate errors, and error sum score in both, ALL and DBS patients, an increase of error rate in the DBS patient group, and an increase of severe errors in ALL patients. Regression analysis yielded an estimated increase of 0.3 (p , 0.05) in error number and 0.7 (p , 0.05) in error sum score per year of participant’s life in the DBS patient group. Higher Mini-Mental State Examination scores correlated with shorter inaccurate driving time (ALL patients: rs 5 20.32, p 5 0.033) and higher PANDA scores correlated with fewer slight errors (DBS patients: rs 5 20.41, p 5 0.050). Experienced DBS drivers drove faster (driving time 231.6 vs 299.4 seconds, p 5 0.02) but apart from that, driving experience had no significant influence on any other driving parameter in ALL or DBS patients. Higher disease severity according to H&Y stage was significantly associated with a longer total Neurology 82
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Table 3
Differential effects of treatment conditions STIM, OFF, and LD on driving performance within the DBS patient group p Values, mixed models
Condition
UPDRS III, points
1 STIM
2 OFF
3 LD
1 vs 2
2 vs 3
1 vs 3
15.39 6 1.80
24.52 6 1.32
15.57 6 1.06
,0.001
,0.001
0.92
15.33 6 2.36
24.47 6 1.75
15.50 6 1.88
,0.001
,0.001
0.92
250.79 6 14.92
276.39 6 11.83
258.09 6 12.49
0.13
0.21
0.64
241.67 6 19.30
267.77 6 14.49
248.93 6 16.82
0.14
0.20
0.65
Driving times, s Total
63.15 6 10.40
80.77 6 11.01
75.05 6 11.09
0.11
0.62
0.21
55.80 6 13.06
73.85 6 11.42
67.67 6 13.38
0.11
0.59
0.23
Rate, per min
2.82 6 0.33
3.12 6 0.41
3.10 6 0.33
0.38
0.93
0.17
2.49 6 0.49
2.89 6 0.48
2.78 6 0.49
0.27
0.73
0.19
No.
10.96 6 1.16
14.23 6 1.58
12.90 6 1.36
0.02a
0.37
0.03a
9.27 6 1.82
13.02 6 1.79
11.22 6 1.94
0.01a
0.23
0.045a
3.77 6 0.39
5.62 6 0.45
4.69 6 0.40
0.002a
0.10
0.046a
3.57 6 0.69
5.46 6 0.63
4.48 6 0.70
0.002a
0.11
0.048a
5.04 6 0.83
6.80 6 1.01
5.56 6 0.90
0.09
0.24
0.49
Inaccurate
Errors
Slight
Moderate
Severe
Very severe
Sum score of errors
a
3.41 6 1.09
5.57 6 0.97
3.92 6 1.13
0.02
0.10
0.53
1.83 6 0.45
2.33 6 0.57
2.23 6 0.61
0.32
0.87
0.41
2.03 6 0.72
2.40 6 0.72
2.42 6 0.83
0.49
0.98
0.41 a
0.16
0.04 6 0.04
0
0.17 6 0.81
0.33
0.04
0.04 6 0.04
0
0.17 6 0.81
0.33
0.04a
0.16
20.16 6 2.52
24.98 6 3.50
23.69 6 2.99
0.09
0.68
0.044a
17.52 6 4.05
22.91 6 4.04
21.05 6 4.28
0.07
0.55
0.049a
Abbreviations: DBS 5 deep brain stimulation; LD 5 levodopa; OFF 5 stimulation off; SE 5 standard error; STIM 5 stimulation on; UPDRS 5 Unified Parkinson’s Disease Rating Scale. Values are expressed as estimated means 6 SE. For each characteristic, results in the first row of entries are adjusted for UPDRS III score; results in the second row of entries are additionally adjusted for tremor, age, and cognition (Parkinson Neuropsychometric Dementia Assessment [PANDA] score). Although age and PANDA score are treatment condition–unrelated parameters, they influence driving and therefore are included in this second analysis. This adjusted analysis also shows a significant difference for moderate errors between conditions STIM and OFF. a Significant differences.
driving time but lower error rate, error number, and slight errors in ALL patients. H&Y and UPDRS III did not correlate with any driving parameter in DBS patients. Longer disease duration was associated with a lower error rate and lower error number due to fewer slight errors in ALL patients. Total LED (ALL and DBS patients) and duration of stimulation (DBS patients) were not associated with any driving parameter. Between-group comparison (controls, no-DBS patients, DBS patients). Driving performance. Detailed parameters
are given in table 2 and figure 1. Driving time. Total driving time was significantly longer in both PD patient groups than in controls and significantly longer in DBS than in no-DBS patients. Mean (SD) speed (km/h) was 41.2 6 11.1 36
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in controls, 32.5 6 11.4 in no-DBS patients, and 25.8 6 6.8 in DBS patients. Inaccurate driving time was significantly worse in no-DBS but not in DBS patients compared with controls. Driving errors. Compared with controls, no-DBS patients performed significantly worse in all error categories except “moderate errors.” In contrast, DBS patients did not perform significantly worse than controls in any category, but even significantly better in slight errors and by trend (p 5 0.06) regarding error rate. Compared with no-DBS patients, DBS patients showed a lower rate and number of driving errors, which was highly significant for slight errors. Focused on the error sum score, noDBS patients but not DBS patients performed significantly worse than controls. However, the absolute sum score was also inferior in DBS patients compared with controls, which was related to an insignificant higher rate
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Figure 2
Comparison of treatment effects (STIM, OFF, LD) on driving performance in patients with Parkinson disease with DBS
condition (estimates of fixed effects in the mixed model). Results were heterogeneous with an increase of 1 point on the UPDRS III scale leading to insignificant increases of error rate and number, moderate errors, and error sum score. However, UPDRS III increase led to insignificant decreases of total and inaccurate driving times and slight and severe errors. Tremor and dyskinesias. Although tremor is part of the UPDRS III scale, we investigated its influence on driving as a separate parameter (present yes/no). We included tremor as an adjusted covariate in the mixed model, because it usually immediately reappears when switching off stimulation, often above-average because of a rebound effect. This might dominate and bias short-time changes of the UPDRS III score. Tremor occurred in 3 patients in condition OFF, and dyskinesias in 6 patients in condition LD, without significant influence on any driving parameters. In these 6 patients, the levodopa dose in condition LD did not influence the incidence of dyskinesias (logistic regression, p 5 0.294). Driving performance. The effect of treatment conditions (STIM, OFF, LD) on driving performance is detailed in table 3 and figure 2. We found no differential effect of age and cognition (PANDA) on driving parameters between conditions. Driving time. Total and inaccurate driving times were shortest in STIM and longest in OFF. Duration of total and inaccurate driving time in LD was in between STIM and OFF. No significant difference was found.
Treatment-condition effects (stimulation on [STIM], stimulation off [OFF], and levodopa [LD]) on driving performance were compared in patients with Parkinson disease with deep brain stimulation (DBS). (A) Values (mean 6 standard error [SE]) for total and inaccurate driving time in seconds. (B) Values (mean 6 SE) of total number of errors; error rate (errors/min); number of slight, moderate, and severe errors; and sum score of errors. The latter parameter includes quality and quantity of errors with 1 point for a slight, 2 points for a moderate, 3 points for a severe, and 4 points for a very severe driving error. ns 5 not significant.
of moderate and severe driving errors. Superior sumscore values in DBS patients compared with no-DBS patients did not reach statistical significance. All conclusions remain identical after adjustment for patient group differences in disease duration and H&Y stage (analysis of covariance). Within-group comparison of treatment condition effects (STIM, OFF, LD) in DBS patients. Motor performance.
Mean UPDRS III in conditions STIM and LD was almost identical and significantly lower than in condition OFF (table 3). This indicates a comparable motor function in test runs STIM and LD. To estimate the influence of motor performance on driving, we calculated the effect of changes in UPDRS III score on driving parameters independently of the
Driving errors. Error rate, error number, slight and moderate errors, and sum score of errors were lowest in STIM and highest in OFF with all parameters in LD found to be in between STIM and OFF. Severe driving errors were made once in one patient in STIM, not at all in OFF, and once by 4 patients in LD, without statistical difference. Condition (STIM, OFF, LD) showed a significant influence on error number, slight errors, and error sum score. In detail, in STIM vs OFF, driving performance was significantly better regarding error number and slight errors and by trend for moderate errors (p 5 0.09) and sum score (p 5 0.09). Furthermore, in STIM vs LD, patients performed significantly superior regarding error number, slight errors, and sum score. No differences were found in driving errors between LD and OFF. Patients in STIM not only drove less inaccurately but also more homogeneously compared with OFF and (less distinctive) LD. For error sum score, the estimated variance of residual covariance parameters was 2.4 for STIM, 122.5 for OFF, and 58.7 for LD. The high group performance inhomogeneity in OFF explains the marginally missed significance for error sum-score difference in STIM vs OFF in Neurology 82
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contrast to STIM vs LD, despite a higher mean sumscore error in OFF vs the LD condition. DISCUSSION Our data support the hypothesis that DBS has no negative but rather a beneficial effect on driving in patients with PD. Driving not only was superior in even more clinically affected DBS compared with no-DBS patients but also DBS patients drove better with stimulation than with levodopa. This might reflect favorable driving-relevant nonmotor effects due to STN-DBS. The driving simulator setting allows faithful replication of the experimental road condition across participants, in contrast to on-road settings.13 We presented key safety traffic situations13 such as “turning at street crossings,” “holding lane line,” “passing a roundabout,” “following give way sign,” or “attending to traffic lights.” Performance reflects real-life driving ability19 and is suitable to monitor on-road driving impairments in patients with PD.2 Driving time (speed) in the free-flowing traffic and driving errors are approved safety-related parameters in traffic simulation models.20 The sum score weights for the quality of driving errors and accounts for highfrequency/low-severity and low-frequency/high-severity errors. This is meaningful for determining crash risk in PD, because especially the latter errors lead to car crashes.13 Our data are consistent with prior investigations describing impaired simulator driving in medicated patients with PD compared with controls1,21 and investigations reporting that age and lower cognition scores have a negative impact on driving in PD.1,22–24 Slower but more accurate driving in patients with higher H&Y stages is in line with prior findings of inconsistent influence of motor impairment on driving in PD.22,24,25 In contrast to others,2 we found that patients with a longer disease history drive more accurately, potentially as a result of more careful driving. Unlike driving speed, driving safety was not higher in experienced drivers, which is in accordance with the findings of a previous study.24 Following others, and using the total annual mileage,26 or a minimum annual mileage of 3,000 km as parameter for driving experience, did not change the results. As expected, controls had a higher annual mileage than patients with PD (details in table e-3). Unexpectedly, DBS patients and controls drove comparably well. The driving course was demanding but short and patients reported lower annual mileage. Driving of longer distances might be worse in patients because of problems with sustained attention. Therefore, the present results might be limited to shorter driving distances, such as inner-city or neighborhood driving. Further studies should address long-distance driving. 38
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Sleep attacks as a potential cause of unsafe driving in PD27 were excluded by analyzing faceLAB GazeTracker data. LED and percentage of dopamine agonist use as risk factors for daytime sleepiness28,29 were comparable in both patient groups. Disease duration as further risk factor was even higher in the betterperforming DBS patient group. To compare stimulation and levodopa effects on driving, levodopa had to compensate for the lost clinical effect after switching off stimulation, on the basis of identical underlying medication. We did not intend to reach “worst-off” stimulation or “best-on” levodopa condition. However, mean UPDRS III score was significantly worse 30 minutes after switching off stimulation because the main clinical effect is usually lost fast, within 200 seconds, and in comparably diseased patients, the half-life of following slow stimulation washout phase is approximately 6 to 7 minutes for bradykinesia.30 Furthermore, mean UPDRS III score was significantly better 30 minutes after levodopa intake and, as intended, comparable to the initial UPDRS score under stimulation. This seems plausible, because tmax plasma levels have been found 60.0 6 45.6 minutes after Madopar LT intake in patients with PD, comparable to ours.31 However, in our study, tmax likely was reached earlier because we used a 1.65-fold higher mean Madopar LT dosage and excluded a preceding albuminous meal. To avoid learning effects favoring levodopa, sequences of otherwise identical sceneries within the test runs were randomized. Running of tests on different days was avoided to eliminate unreliable comparison of treatment effects (STIM, OFF, LD) due to intraindividual and unpredictable daily variability of symptoms. To prevent exhaustion penalizing levodopa, the investigation time was kept as short as possible considering the stimulation washout and levodopa absorption times discussed above. Total driving times on average were less than 5 minutes and exceeded 6 minutes only once (423 seconds in condition LD). Worse driving with LD compared with STIM might be partly explained by the inverted U-shape relationship between dopamine and cognition and related to a dopamine overdosage in corticostriatal circuits beyond motor loops with negative effects on learning.32 Also, inferior driving caused by LDinduced impulsivity33 is conceivable. Compatibly, we found a severe driving error once in 4 patients in condition LD but only once in one patient in condition STIM and none in condition OFF. DBS might positively influence driving-relevant nonmotor skills. Impairments of sequence and implicit procedural learning,34 planning and sequencing,35 and information updating36 probably reduce driving ability in patients with PD. STN-DBS selectively improves implicit procedural learning, possibly by altering basal
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ganglia output to the frontal cortex.37 Concordant with our results, sequence learning has been described to be superior with STN stimulation “on” compared with stimulation “off” and compared with sequence learning after levodopa infusion titrated to motor response equivalent to stimulation.38 Furthermore, STN stimulation improves goal-directed action selection39 and decision learning,40 both of which are cognitive skills crucial in driving a car. In conclusion, regaining a better driving ability in PD might be one aspect of improved quality of life with DBS in comparison to medical treatment alone. Based on our data, we suggest handling driving permission for DBS-treated patients with PD not more restrictively than permissions for patients with PD in general.
6.
7.
8.
9.
10.
11. AUTHOR CONTRIBUTIONS Drafting/revising the manuscript for content, including medical writing for content: C.B., E.V., C.K.E.M., A.K.E., C.G., W.H. Study concept or design: C.B., W.H.Z. Analysis or interpretation of data: C.B., E.V., L.M., J.H., W.H.Z. Acquisition of data: C.B., L.M., J.H., W.H. Statistical analysis: C.B., E.V. Study supervision or coordination: C.B., W.H.Z. Obtaining funding: C.B., W.H.Z.
12.
ACKNOWLEDGMENT The authors thank Thomas Wriedt for rating driving errors and configurating the driving simulator device.
13.
STUDY FUNDING
14.
Supported by the Georg & Jürgen Rickertsen Stiftung Hamburg.
DISCLOSURE C. Buhmann received study research support from the Georg & Jürgen Rickertsen Stiftung Hamburg. PD Dr. C. Buhmann served on the scientific advisory board for GSK and UCB Pharma and received honoraria for lectures from GSK, Medtronic, Orion Pharma, and UCB. L. Maintz, J. Hierling, E. Vettorazzi, and C.K.E. Moll report no disclosures. A.K. Engel acknowledges support of the German Research Foundation (DFG SFB 936) and the European Union (EU) (FP7-ICT-270212, ERC-2010-AdG269716). C. Gerloff is supported by the German Research Foundation (DFG Ge 844/4-1, SFB 936) and the EU (FP7-HEALTH-2011278276). W. Hamel reports no disclosures. W.H. Zangemeister received study research support from the Georg & Jürgen Rickertsen Stiftung Hamburg. Go to Neurology.org for full disclosures.
15. 16. 17. 18. 19. 20.
Received April 17, 2013. Accepted in final form September 23, 2013.
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Effect of subthalamic nucleus deep brain stimulation on driving in Parkinson disease Carsten Buhmann, Lea Maintz, Jonas Hierling, et al. Neurology 2014;82;32-40 Published Online before print December 18, 2013 DOI 10.1212/01.wnl.0000438223.17976.fb This information is current as of December 18, 2013 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/1/32.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2013/12/18/01.wnl.000043822 3.17976.fb.DC1.html
References
This article cites 38 articles, 15 of which you can access for free at: http://www.neurology.org/content/82/1/32.full.html##ref-list-1
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2013 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
