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Assessing Cognitive and Psychomotor Performance in Patients with Fibromyalgia Syndrome

Introduction Patients with fibromyalgia syndrome (FMS) generally present with chronic widespread pain, accompanied by a range of additional and non-specific symptoms, such as fatigue, disturbed sleep, and cognitive dysfunction, which tend to increase with overall severity. Previous studies have shown moderate cognitive impairment in patients with FMS, but there are few valid data explicitly assessing the relevance of these findings to everyday functions, such as driving ability. Therefore, we studied patients with FMS to assess the impact of FMS on tests that predict driving ability. Methods Female patients with FMS were prospectively compared to a historical control group of healthy volunteers. The test battery comprised assessments of visual orientation, concentration, attention, vigilance, motor coordination, performance under stress, and reaction time. Results A total of 43 patients were matched to 129 controls. The results indicated that the patients’ psychomotor and cognitive performances were significantly non-inferior when compared to healthy controls (with 0.05% alcohol), with the exception of motor coordination. Patients and healthy controls showed an age-related decline in test performance. Correlations were smaller in patients and reversed for vigilance which was linked to a greater FMS symptom load in younger patients. Conclusion The results of the present study demonstrate that, in general, the driving ability of patients with FMS was not inferior to that of healthy volunteers based on a standardized computer-based test battery. However, variables, such as younger age, depression, anxiety, fatigue, pain, and poor motor coordination, likely contribute to the subjective perception of cognitive dysfunction in FMS. Electronic supplementary material The online version of this article (doi:10.1007/s40122-014-0028-0) contains supplementary material, which is available to authorized users.


INTRODUCTION
Patients with fibromyalgia syndrome (FMS), a chronic widespread pain syndrome of unknown pathophysiology, generally show diffuse and generalized musculoskeletal pain accompanied by reduced pain thresholds (i.e., the presence of tender points) which may represent evidence of central sensitization. Other typical clinical features include sleep disturbance, fatigue, and morning stiffness [1]. Although the traditional classification criteria (American College of Rheumatology 2010) remain controversial [2], in agreement with other countries, 3-4% of the German population is affected with FMS [3].
Several studies have replicated these subjective reports using more objective and standard tests and have identified subtle cognitive impairments in patients with FMS [7][8][9][10]. No study data have explicitly assessed the clinical relevance of these findings, although significant impairments in the functions of daily living have been convincingly demonstrated for patients with FMS [11]. In addition, these patients are often treated in clinical practice with centrally acting analgesics and coanalgesics [12,13], despite overall mixed evidence for their long-term effectiveness [14].
Thus, the cognitive functions of these patients may be impaired by both the syndrome and by its pharmacological treatment.
Safely driving a motor vehicle requires a complex interaction of operational, physical, cognitive, perceptual, and psychological skills. Because driving ability depends on complex psychomotor and cognitive skills, national and international recommendations indicate that tests should examine concentration, attention, reaction time, and an individual's performance and orientation while under stress. These skills may be assessed by computerized neuropsychological test batteries, such as the Vienna test system [15], by driving simulators [16], or by road tests [17].
Because driving ability is considered an important aspect of self-determination and social participation, previous studies in the pain field using this methodology have focused on the effect of opioids on the complex psychomotor and cognitive functions of non-cancer patients under long-term opioid therapy and in drug addicts in opioid substitution programs [15,[18][19][20][21][22][23]. Only a few studies have examined the impact of chronic pain on complex psychomotor and cognitive tasks. According to a systematic review of the quality and generalizability of studies on the effects of opioids on driving and cognitive/ psychomotor performance [24], high levels of pain may also affect aspects of these complex tasks. Moreover, it is important to note that cognitive impairment may occur in patients only when pain intensity levels exceed a certain threshold, which has been located between 64 and 71 of 100 [25]. However, even low-level pain may interfere with complex tasks, resulting in less accuracy and reduced performance speed [26]. Furthermore, any pain-related disruptions of attention seem to be worsened through such factors such as pain catastrophizing [27].
Driving ability can be compromised if one or more of the aspects involved in cognitive and psychomotor functions, such as attention, reaction time, visual orientation, perception, vigilance, and motor coordination, are impaired [15,19,20,22]. To assess all of these factors, a battery of tests and statistical analyses complying with international recommendations, as well as with German legislation, were applied [28][29][30][31][32][33].
We included only patients with FMS currently off medication to assess the impact of FMS itself on tests that predict driving ability.

METHODS
This was a prospective comparison of patients with FMS and a historical group of healthy volunteers. Subjects and controls were matched for age and sex, with three controls selected for every patient with FMS. The controls were not matched for educational level and social status, as the corresponding data for the control group (CG) were not available.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the well as summary scores for both physical and mental health and a single health utility index [36]. The Brief Pain Inventory (BPI) is a comprehensive instrument for pain assessment and has been validated in the German language [38]. The BPI measures both the intensity of pain (average, worst, and recurrent pain) and the interference of pain in the patient's life (reactive dimension) [39].
The Brief Fatigue Inventory (BFI) was constructed to assess the severity and impairment from fatigue and has been validated in the German language [40] [41].

Test Battery
The test battery followed the German national recommendations for tests used to determine driving ability [42], which require the assessment of (1) performance under pressure, score was calculated as the sum of the MRT and the square root of the product of the MRT and the wrong answers [44].

Test for Motor Coordination (2-Hand)
The subjects had to keep a signal on a track by simultaneously turning two steering wheels: one controlling horizontal movements and the other controlling vertical movements. The track consisted of three different sections (circle, Vshape, and L-shape) and had to be negotiated 19 times. The mean time taken to negotiate the track (T, in seconds) and the mean percentage of the total time during which the signal was off the track (Off %) were recorded. The score was

Vigilance Test (VIG)
Subjects were presented with a circle consisting of separate small white spots on a dark monitor.
A bright spot moved stepwise around this circle, similar to the hand of a watch. At long but irregular intervals, the spot sometimes missed one of the positions (i.e., jumped over one of the marker spots). When this occurred, the subjects had to press a button as quickly as possible. The number of mistakes (incorrect responses or undetected jumps) and the MRT were recorded. The score was calculated as the sum of the MRT and the square root of the product of the MRT and the sum of the missed and wrong answers [46].

Non-Inferiority
The study was designed as a non-inferiority trial; i.e., the objective was to demonstrate that patients with FMS do not perform significantly worse in the tests than controls. This means, that their performance was not inferior when compared to the control group.
In such non-inferiority trials, a clinically significant difference (delta, d) from the standard outcome or performance must be defined. Typically, cognitive performance under the influence of defined levels of alcohol has been used as a standard to assess the degree of impairment induced by several drugs [47]. A blood alcohol level of C0.05% has been shown to cause a marked impairment in driving ability and is the threshold for being unfit to drive under German law [48][49][50]. In a previous study, the effect of different antidepressants on cognitive and psychomotor functions was compared using a computerized test battery similar to our study. During this study, patients received alcohol orally with a targeted blood concentration of 0.05%. The strongest impairment was observed in the testing of vigilance [49]; from the data in this previous study, an effect size of d = 0.57 for the alcohol-related impairment of vigilance was calculated. Using this effect size, the raw values of the control group in our study were transformed to obtain virtual values that would be equivalent to test performance under the influence of a 0.05% blood alcohol level.
Using this assumption, non-inferiority in the test battery results of the fibromyalgia patients compared to controls could be interpreted as a performance significantly better than that of the CG with a blood alcohol concentration of 0.05%, which likely reflects sufficient fitness to drive. In accordance with prior studies from our group with patients on acute and chronic opioid therapy [15,19,20,22,51], we used 1:3 randomizations to increase the power of the study. With 43 patients and 129 controls, the power of this study was calculated to be close to 1 (one-sided t test, a = 0.05).
Each of the five tests used involved the recording of several parameters. To reduce the problem of multiple testing, one 'relevant score' for each test was defined prior to the analysis of the study data.

Passed Tests
Another method for evaluating driving ability using the various cognitive tests previously described is to assume unimpaired driving ability only if all test results are above the 16th percentile of the age-independent reference range [33]. Accordingly, for both subjects with FMS and healthy controls, the passing of the 16th percentile was recorded using the original raw data and not the transformed data reflecting the influence of alcohol.

Secondary Analysis
In the secondary analysis, the effects of age on the test results of the two groups were explored, as well as the rates of correct versus incorrect responses.

Statistical Testing
The Mann-Whitney U test was used because a normal distribution of the data could not be ascertained for all parameters. Because the direction of the expected change in a non-inferiority trial is defined, a one-sided  Table 2). The low number of wrong answers likely explains the non-inferiority in the overall score, as it compensated for the slowest reaction times.

2-Hand
The

VIG
The difference in the number of ''correct answers'', ''wrong answers'', ''omitted answers'', the MRT and the scores for the FMS group proved to be significantly non-inferior compared to the CG ? d (P\0.01; Table 2).

Passed Tests
The percentages of patients who passed the single tests, that is, those whose relevant test scores were above the 16th percentile compared to an age-independent reference group (RG), are displayed in Fig. 1

Secondary Analysis
To assess the potentially different effects of age on the results of the cognitive testing, age was correlated with all four primary scores in patients with FMS and in the CG ? d      53-55, 57, 59]. Computerized test batteries can be designed to measure different aspects related to driving ability (e.g., reaction time, vigilance, psychomotor coordination), and their high capacity for standardization helps to minimize observer biases. On the other hand, the most of the neuropsychological tests, especially when using single tests, are not sufficient for the effective prediction of potential outcome measures like, for example, fatalities while driving a car [60]. However, as proposed by Lincoln et al. [61] a combination of cognitive tests might overcome this limitation. In our study, a combination of different tests, as proposed by the German legislation, has been used to assess fitness of driving. To our knowledge, there has only been one other study using a computerized neuropsychological test battery in patients with FMS, and it did not demonstrate significant differences between FMS patients and controls [57].
A small yet interesting finding of this study relates to the poorer results in the 2-Hand test. A recent study [62] [4,[7][8][9][53][54][55]. Patients with FMS have been shown to have poorer cognitive performance than carefully matched adults of similar age and to perform more like to people 20 years older [63].
Interestingly, in our study age had an overall negative effect in both groups but correlation coefficients tended to be smaller in FMS patients compared to healthy controls for most parameters. Vigilance even demonstrated a different pattern with greater relative impairment in younger FMS patients and more pronounced symptoms that may indirectly affect memory function, which was not tested in our study. This interpretation of a possible differential effect of age is supported by findings that older patients show lower reductions of health-related quality of life than younger and middle-aged patients, especially on physical and social dimensions [64].
The results of previous studies on attention are not uniform [65]. In our study, the FMS