Neurol Sci (2009) 30:9–14 DOI 10.1007/s10072-008-0001-y
ORIGINAL ARTICLE
Neuropsychological assessment in myasthenia gravis Emilia J. Sitek Æ Małgorzata M. Bilin´ska Æ Dariusz Wieczorek Æ Walenty M. Nyka
Received: 22 February 2008 / Accepted: 10 October 2008 / Published online: 16 January 2009 Ó Springer-Verlag 2009
Abstract Neuropsychological studies in myasthenia gravis (MG) were undertaken to prove the central nervous involvement. However, they still produce contradictory results. In the present study, a battery of cognitive measures was administered to examine global cognitive functioning, verbal learning, attention, executive function and motor performance. Analysis of partial scores in verbal learning and response fluency trials did not reveal fatigue effect in MG patients. It was shown that in tasks requiring motor, and particularly oculomotor, involvement, the muscle fatigue could account for the deficits observed. Thus, impaired performance on some cognitive measures in MG should be interpreted as an effect of muscle fatigability rather than central nervous system involvement. Keywords Myasthenia gravis Cognitive Motor speed Fatigue Neuropsychological assessment
E. J. Sitek Department of Neurological and Psychiatric Nursing, Medical University of Gdan´sk, ul. Do Studzienki 38, 80-227 Gdan´sk, Poland E. J. Sitek (&) Department of Neurology, St Adalbert Hospital, Al. Jana Pawła II 50, 80-462 Gdan´sk, Poland e-mail:
[email protected] M. M. Bilin´ska W. M. Nyka Department of Neurology, Medical University of Gdan´sk, ul. Debinki 7, 80-952 Gdan´sk, Poland D. Wieczorek Department of Rehabilitation, Medical University of Gdan´sk, ul. Debinki 7, 80-952 Gdan´sk, Poland
Introduction Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission characterized by increased fatigability of voluntary muscles [1]. Central nervous system (CNS) involvement in MG has been suggested since the disease was described for the first time. At least some of the subsequent studies, such as reports of increased coexistence of MG and other neurological disorders such as multiple sclerosis [2], Meige syndrome [3], and epilepsy [4], as well as reports of higher frequency of left-handedness in MG [5] seemed to confirm these preliminary suggestions. As a result, further research [6] focused mainly on the detection of electroencephalographic and evoked response abnormalities [7, 8], rapid eye movement sleep disturbance [9] and the presence of specific muscle nicotinic acetylcholine receptor (AChR) antibodies in the cerebrospinal fluid (CSF) [10]. With those methods used, no clear evidence of CNS involvement has been found. Due to scarcity of biological data supporting the aforementioned hypothesis, some authors such as Tucker et al. [11], resorted to cognitive studies as an alternative— although indirect—way to prove the presence of central cholinergic deficits in MG patients. Since Mertens et al.’s [12] first neuropsychological study of MG, four alternative explanations of the possible neuropsychological deficits in MG have been formulated. Neuropsychological impairment has been interpreted as (1) a central cholinergic deficit manifestation [11, 13–19], (2) as a consequence of nocturnal respiratory problems [20], (3) as a possible effect of nonspecific immunological processes [21], and (4) as a result of increased mental fatigue [22]. The abundance of hypotheses generated or tested in those studies contrasted with their methodological
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shortcomings such as insufficient sample size, lack of common cognitive measures, lack of sample description in terms of the disease type and medication—reviewed in detail by Paul et al. [23] and Paul and Gilchrist [24]. The aim of the present study was to examine the cognitive function in MG patients through a detailed and multidimensional analysis of performance on measures frequently used to assess cognition in MG patients, such as verbal learning tests and response fluency trials. We hypothesized that there should be no impairment in global cognitive functioning, memory and executive function, but a possible fatigue-related decrement might appear in the second part of performed tasks (4th and 5th trial in verbal learning test, the second part of each verbal fluency trial). In some previous studies, motor fatigability could account for the observed deficient performance in cognitive testing that was misattributed to CNS involvement. This hypothesis was tested by means of comparing the results of Trail Making Test (TMT) and Digit Span tests. If both test results were deficient in MG group, it would indicate global attention or working memory deficit. However, if the difference was statistically significant only for TMT—which is dependent on near visual acuity and motor speed, it would clearly demonstrate that conclusions about CNS involvement in MG from previous studies relying on measures combining cognitive, visual and/or motor requirements were methodologically questionable. Amongst such measures are Benton Visual Retention Test [12] or Visual Reproduction from Wechsler Memory Scale [11], Symbol Digit Modalities Test (even in its oral version that still requires visual searching and can be prone to dysarthria [21, 22]). Control of motor speed, with such methods as Finger Tapping Test, could additionally clarify this interpretation. Instead of excluding patients with visual disturbance, as Paul et al. [23] recommended, we used methods that did not rely on visual function or those in which the oculomotor involvement could be eliminated through the result analysis.
Methods Sample A sample of 33 individuals with MG and 30 healthy controls volunteered to participate in the study. All participants gave informed consent. The subjects who reported a history of alcohol or drug abuse, or who had evidence of CNS lesions (confirmed by MRI or CT scans) were excluded from the sample. All of the patients were recruited from Myasthenia Gravis Outpatient Clinic. Diagnosis was confirmed by means of electromyography results, the presence of antinicotinic antibodies in serum and a positive Tensilon Test.
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Patients averaged 47 years of age (SD 12; range 20–68), 12 years of education (SD 3; range 7–22), 8 years (SD 7; range 0–29) since MG onset. According to Myasthenia Gravis Foundation of America (MGFA) Clinical Classification, 4 patients were classified as Class 1, 17 patients as Class II (IIA-15, IIB-2), 7 patients as Class III (IIIA-6, IIIB1), 5 patients as IVB [25]. Nineteen patients were treated with anticholinesterase inhibitors, 11 with both anticholinesterase inhibitors and glucocorticosteroids, two also took immunosuppressive medication (apart from aforementioned therapy) and 1 received no pharmacological treatment. A total of 22 patients (67%) were thymectomized. Control group averaged 49 years of age (SD 12; range 24–76), 13 years (SD 3; range 8–21) of education. Both groups were matched in terms of age (t = 0.7; P = 0.48), sex (v2 = 0.65; P = 0.44) and years of education (t = 0.97; P = 0.34), and presumed premorbid cognitive abilities (WAIS-R Similarities; Table 1). Procedure A neurological examination and a demographic interview preceded the cognitive testing. The order of test administration was the same for all patients: Mini Mental State Examination (MMSE), Auditory Verbal Learning Test (AVLT), Digit Span and Similarities from Wechsler Adult Intelligence Scale Revised (WAIS-R), Trail Making Test, verbal fluency trials, Finger Tapping Test (FTT), Beck Depression Inventory (BDI) and MG Disability Scale. Measures Global cognitive functioning was assessed by MMSE [26]. Similarities were used to control for premorbid cognitive function [27]. Verbal learning was tested with a modification of AVLT [28] with five learning trials of a list of 15 words, and a delayed recognition trial, administered 30 min after the last learning trial. In this trial, 30 words were presented and the total score was computed by subtracting false positive recognitions from the correctly recognized words. Taking into account a higher depression level in MG patients, and the fact that spontaneous recall trials can be slightly impaired in depression probably due to motivational problems [29, 30], delayed recall was replaced in our study with delayed recognition, which is supposed to be less prone to mood effect. Digit Span Test served as a measure of attention span [31]. TMT Parts A and B [32] were used as a measure of attention dependent on psychomotor speed and visual function. Scaled score difference in TMT (B-A), that refers to normative data, removes the speed and oculomotor factor from the test result and constitute an additional indicator of working memory—more reliable than raw score.
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Table 1 Performance on cognitive and mood measures in patients and controls Measure
Control group mean (SD)
MG patients mean (SD)
t/U
P
Global cognitive functioning Similarities
15.87 (5.40)
15.79 (5.54)
0.06
0.95 (ns)
MMSE
28.67 (1.45)
28.18 (1.40)
1.35
0.18 (ns)
47.83 (7.59)
46.97 (9.35)
2.60 (2.74)
3.30 (3.08)
13.70 (1.58)
Tapping, dominant hand Tapping, non-dominant hand
Verbal learning and retention AVLT—five trials (max. = 75)
0.40
0.69 (ns)
-0.95
0.34 (ns)
13.61 (2.46)
0.18
0.86 (ns)
46.13 (8.37)
37.72 (13.82)
2.94
\0.01
41.33 (6.46)
34.88 (12.01)
2.63
0.01
35.00 (10.07)
42.64 (15.92)
-2.25
0.03
73.07 (25.93)
101.38 (59.83)
-2.44
0.02
1.77 (6.94)
1.64 (9.59)
-0.61
0.95 (ns)
Digits forward
5.27 (1.05)
5.18 (0.88)
0.35
0.73 (ns)
Digits backward
4.03 (1.27)
3.85 (0.91)
0.67
0.51 (ns)
Letter fluency, total
14.70 (4.10)
13.82 (4.30)
0.83
0.41 (ns)
Semantic fluency, total
22.40 (5.86)
20.61 (4.78)
1.34
0.19 (ns)
6.30 (5.95)
11.10 (6.29)
-3.06
0.003
AVLT—confabulations AVLT-delayed recognition Motor performance
Psychomotor speed TMT A (s) Working memory with a motor component TMT B (s)
Working memory without motor component TMT B–A (T score) Attention span
Executive function
Mood BDI
FTT served as a measure of motor performance [32]. Executive function was assessed by means of verbal fluency. Two trials were administered, one for letter (K) fluency and another one for semantic (animal) fluency. Participants had 60 s to generate words according to the given criteria. BDI [33] was used to assess mood. Finally, the translation of MG disability Scale [34] was used as a subjective measure of daily function impairment in the patient group. The scale contains six items assessing superior and inferior limb fatigability, swallowing, voice, eyesight and breathing. The global score ranges from 0 to 18, where 18 indicates maximum severity. Time since MG onset was a period of time since the first MG symptoms were noticed by patients, but not the time since MG diagnosis. We included this measure, apart from time since MG diagnosis, as the period between the appearance of symptoms and the MG diagnosis, averaging 2 years (SD 3), ranged from 0 to 18 years in our sample. Statistical analysis Group comparisons were performed with the use of Student two-tailed t test. Tau-B Kendall correlation coefficient was used to assess the strength of a relationship between ordinal
variables, whilst r-Pearson was used for normally distributed data.
Results In the MG disability scale individuals with MG averaged 4.70 ± 3.12 (range 0–12). As shown in Table 1, MG patients performed significantly poorer than the control subjects in FTT and TMT (parts A and B, respectively). Other differences observed in cognitive performance were not statistically significant. MG patients exhibited an elevated depression score in relation to control subjects. However, the mean score on BDI for the patient group did not significantly exceed the cut-off score for depression. We did not find it possible in our sample to include the medication dosage in the regression analysis as recommended by Paul et al. [23] as the patients were treated with different kinds of agents and the dose was not stable, but depended on the fluctuation of symptoms. Therefore, we compared the cognitive performance of patients with (n = 19) and without steroid treatment (n = 14), using t test. No significant differences were
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found on the same measures as those enumerated in Table 1. As shown in Table 2, no fatigue effect was observed in either AVLT learning trials or fluency tasks, as the final trials did not reveal decrements in MG group in comparison with the control group. Correlation analysis for BDI score, time since MG onset, time since MG diagnosis, age, MGFA Clinical Classification score and MG disability score was performed exclusively for the MG group. No statistically significant correlations were detected. Subsequently, correlations of TMT with Digit Span and FTT scores for MG patients were computed. TMT A raw score correlated with FTT dominant hand score (r = -0.37, P = 0.03). Similar correlation was revealed for TMT B raw score (r = -0.41, P = 0.02), but not for TMT B–A scaled score difference. TMT A raw score correlated with Digit Span backward (r = -0.54, P = 0.001), as did TMT B score (r = -0.63, P \ 0.001). TMT B–A scaled score difference did not correlate with FTT.
Discussion In this study MG patients’ performance was comparable to controls’ on measures of global cognitive functioning, which contradicts Iwasaki et al.’s results [16, 35]. Individuals with MG exhibited significant difficulties only in tasks requiring motor speed and oculomotor accuracy, but eliminating the motor speed component showed working memory to be unimpaired, which confirms Bartel and Lotz’s results [18]. Furthermore, attention span was found to be intact, as in the previous studies [17, 21, 22]. Analysis of the relationships between a visually and motor dependent working memory measure (TMT) with a motor performance measure (FTT) and a working memory measure without motor component (Digit Span backward) Table 2 Analysis of fatigability effect in AVLT and verbal fluency trials
Measure
indicates that TMT is loaded by motor and attention factors. However, amongst measures related to TMT—Digit Span backward and FTT—only the latter, that is motor dependent differentiated between the groups as TMT did. The results pattern supports the claim about intact attention and working memory in MG. Paul et al. [20, 21] suggested that information processing speed was slowed as evidenced by MG group impairment on SDMT and measures requiring visual processing that were time constrained, such as Visual Reproductions, but not on Rey Complex Figure Test that is untimed. It could be argued that the observed impairment may be dependent on increased visual demands (due to ophthalmoparesis or more subtle visual searching problems) and is not a result of higher cognitive demands. The unimpaired verbal learning found in our study is in contradiction with the previous results [20, 21], where the differences were noted only for immediate recall trials. The comparison of the groups of patients tested in our study and the aforementioned ones in terms of mean disease severity and time since onset did not reveal large differences that could account for the discrepancies in cognitive performance. Two explanations are possible. First, the order of test administration may have influenced the results. In our study, AVLT was administered always at the beginning of the testing session, after MMSE, which may have limited the fatigue impact and resulted in unimpaired patients’ performance. Paul et al. [20, 21] administered the test battery in the counterbalanced order, which may indicate that a verbal learning test in a considerable number of patients was administered later in a test session than in our study. Second, the previous studies tested either significantly smaller samples of patients [11] (N = 12) or controls [20, 21] (N = 18) than in our study. Delayed retention and recognition were deficient in comparison to controls only in Tucker et al.’s study [11]. However, our MG sample size is three times as big as
Control group mean (SD)
MG patients mean (SD)
5.27 (1.57)
5.39 (1.62)
t
P
-0.32
0.75 (ns)
Verbal learning and retention AVLT, trial 1 AVLT, trial 2
8.67 (1.92)
8.61 (2.50)
0.11
0.92 (ns)
AVLT, trial 3
10.43 (2.01)
10.21 (2.42)
0.39
0.70 (ns)
AVLT, trial 4
11.23 (2.01)
11.21 (2.46)
0.04
0.97 (ns)
AVLT, trial 5
12.23 (1.79)
11.55 (2.94)
1.11
0.27 (ns)
9.50 (2.43)
9.00 (2.68)
0.77
0.44 (ns)
Executive function Letter fluency 0–30 s Letter fluency 30–60 s Semantic fluency 0–30 s Semantic fluency 30–60 s
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5.20 (2.52)
4.82 (2.46)
0.61
0.55 (ns)
14.10 (3.04) 8.23 (3.55)
13.45 (3.56) 7.15 (2.83)
0.77 1.34
0.44 (ns) 0.18 (ns)
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Tucker et al’s one. Like in Paul et al.’s studies [21, 22] we have not found memory impairment on delayed measures. Lack of fatigue-related decrement in the last trials of verbal learning task and the second part of each verbal fluency trial in our study contradicts Paul et al.’s [21] interpretation of the mental fatigue sensitivity in MG. However, when comparing our data with Paul et al.’s [20, 21], especially taking into account the order of test administration, it may be hypothesized that such an effect would emerge if an additional learning trial was used. To test the fatigue effect, we suggest that a verbal learning test should be administered twice, the standard version at the beginning of the test session and the alternative version at the end of it. Then, the greater decrement in patients than in the control subjects would prove the elevated sensitivity to mental fatigue in MG patients. Although we provided a larger sample than those previously reported in literature, our study has certain limitations. It could not fully address the effect of medication or mood on cognitive performance. The latter shortcoming is due to unavailability of a depression measure with separate scores for mood and vegetative components adapted for Polish conditions, such as Chicago Multiscale Depression Inventory. Inclusion of patients with visual impairment made it impossible to test visuospatial functioning. Furthermore, the severity of symptoms was assessed only by MGFA Clinical Classification score and a subjective measure. We did not find it possible to balance the patients’ number within each MG subgroup. However, it can be argued that overrepresentation of patients classified as Class II corresponds well to the clinical reality. Our results did not confirm CNS deficit in MG. MG patients’ cognitive performance seems to be unimpaired in tasks independent of motor or visual function. Acknowledgments We wish to thank Prof. Krzysztof Jodzio from University of Gdan´sk, Institute of Psychology for his help in preparing the testing procedure and supervising the research.
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