Relationship between antisaccades and the clinical symptoms in Parkinson's disease Mayumi Kitagawa, Junko Fukushima and Kunio Tashiro Neurology 1994;44;2285
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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 © 1994 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
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Relationship between antisaccades and the clinical symptoms in Parkinson's disease Mayumi Kitagawa, MD; Junko Fukushima, MD; and Kunio Tashiro, MD
Article abstract-We studied voluntary control of saccadic eye movement in 32 parkinsonian patients using the antisaccade task (the subjects were instructed not to look at the target but to look in the opposite direction). Mean latencies and error rates in the antisaccade task were significantly increased in advanced parkinsonian patients. The latencies of the antisaccades correlated with the severity of bradykinesia as well as the results of the Wisconsin Card Sorting Test. Patients taking anticholinergics showed significantly higher error rates. These results suggest that disturbance in the initiation of voluntary saccades in advanced patients may be associated with frontal lobe dysfunction, while anticholinergics may affect the inhibitory control of reflexive saccades. NEUROLOGY 1994;44:2285-2289
eye movement, severity of disease, results of the The antisaccade task can study the voluntary control of saccades.'-l0In the antisaccade task,l0 at the WCST, and antiparkinsonian drugs. same time the central fixation light is turned off, a Methods. Subjects. A total of 32 patients (14 men, 18 target light is turned on. The subjects are required women) with idiopathic PD were studied. Idiopathic PD not to look at the target but to look in the opposite was diagnosed on the basis of clinical evaluation, the abdirection at an approximately equal distance from sence of signs accompanying any other parkinsonian synthe fixation point. When the subject makes sacdrome, and response to levodopa and dopamine agonists. cades toward the target, these inappropriate sacMotor disabilities were evaluated according to the Hoehn cades are judged as err0rs.l Significantly higher and Yahr clas~ification~~ and a modified Columbia scalez6 error rates in the antisaccade task have been ob(total scores = 92; subscores for gait = 4; posture = 4; postural stability = 4; speech = 4; facial appearance = 4; served in patients with frontal lobe or dis= 32; rigidity = 20; and tremor = 20; for each eases associated with frontal lobe d y s f u n c t i ~ n . ~ -bradykinesia ~ item, the score varied from normal = 0 to maximum = 4). Lueck et a19 examined 10 patients with Parkinson's None of the patients showed clinical evidence of dementia disease (PD) using the antisaccade task and rein the Mini-Mental State E x a m i n a t i ~ n The . ~ ~ age of the ported that there was no difference between the paparkinsonian patients ranged from 45 to 70 years (mean tients and the controls. In animal studies, the age, 57.5 i 7.8, SD). To study the effect of the seventy of frontal eye field, the supplementary eye field, and the disease, the patients were classified into two groups acthe prefrontal cortex are important in the voluncording to their neurologic states (group P1 = Hoehn and tary control of sa~cades.'l-'~ The other important Yahr I and 11; group P2 = Hoehn and Yahr 111). Twentyarea in the inhibitory control of reflexive saccades two of the 32 PD patients were classified into the P1 group, and the other 10 patients were assigned to P2. There was is the basal ganglia.14 There may be pathology of no significant difference in age or duration of illness bethe frontal cortex in PD,15-17and the Wisconsin tween patients in groups P1 and P2. The motor impairCard Sorting Test (WCST) has revealed frontal ment scores were as follows: for group P1, 6.6 & 2.6 for dysfunction in PD patients.18-z1 Thus, PD patients bradykinesia, 4.6 * 1.6 for rigidity, and 2.2 * 2.9 for tremor, might be expected to have disturbed voluntary sacand for group P2, 17.0 & 3.7 for bradykinesia, 8.8 * 1.7 for cades correlating with t h e severity of t h e rigidity, and 2.0 i 2.8 for tremor. Twenty-three patients disea~e.~~-~~ were on antiparkinsonian therapy (levodopa, levodopa and To examine which factors influence abnormalities carbidopa, anticholinergics, amantadine, and bromocripin voluntary saccades in PD, we studied the antitine) at the time of testing, and the other nine had never saccade task in mild- to advanced-stage PD patients been treated with antiparkinsonian drugs. Seven of the nine patients who were not treated were in P1, and the and looked at correlations among abnormalities of
From the Department of Neurology (Drs. Kitagawa and Tashiro), Hokkaido University School of Medicine, and College of Medical Technology (Dr. Fukushima), Hokkaido University, Sapporo, Japan. Received November 5, 1993. Accepted in final form June 14, 1994 Address correspondence and reprint requests to Dr. Mayumi Kitagawa, Department of Neurology, Hokkaido University School of Medicine, N14 W5, Kitaku, Sapporo 060, Japan.
December 1994 NEUROLOGY 44 2285
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A Visually guided saccade task
3 -6 sec
on
Off
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Center l i g h t 1 Target light
500 msec
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1 500 mseC
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C. Examples of antisaccades and errors in the antlsaccade task
2
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other two patients were in P2. They were all treated aRer the examination of eye movement, and responded well to levodopa. No patients showed the "on-off phenomenon. Twenty age-matched normal volunteers (mean age, 57.3 9.2) were examined as t h e control group for the eye movement task. Of these, 16 normal volunteers (mean age, 54.6 7.0) were tested with the WCST. None of them showed any abnormalities under neurologic examination. Eye movement recording and target paradigms. The procedures for recording eye movements, the presentation of the targets, and the data analysis were generally similar to the previous studies to which reference should be Subjects were seated on a chair in the dark, facing a tangent screen placed 100 cm away from their eyes. The visual targets were a series of seven red light-emitting diodes (LEDs). One of them was used as a central fixation light, and the other six were positioned at 8, 12, and 24" to the right and leR of the central LED. When the LED was not turned on, its position could not be seen by the subjects. In the visually guided saccade task (figure, A), subjects were asked to stare at the central fixation light while it was turned on for 3 to 6 seconds (the duration was random). At the same time as the fixation light was turned off, the target LED was turned on for 500 msec (both the direction and the position were random), and the instruction was given to look at the target LED as quickly as possible. A total of 60 runs were tested for each subject. In the antisac-
*
Figure. Paradigms of the visually guided saccade task (A)and the antisaccade task (B)and an example of errors in the antisaccade task (0. (A)Center light was used as a fixation point and turned on for 3 to 6 seconds. At the same time the center light was turned off; one of the six LEDs was turned on. The subject was told to look at the target as quickly as possible. (B)At the same time the central light was turned off; either the right or left target was turned on. The subject was told not to look at the target but to look in the opposite direction at an approximately equal distance from the target. (01 = A n example in which the subject performed antisaccades correctly. When the right target was turned on, the subject looked to the left. 2 =An example of a n error i n the antisaccade task. The subject looked at the target and then made a saccade i n the opposite direction. EOG = electrooculograph, L = left, R = right, E = eye position, E = computed velocities, CL = center light, LL = left light, RL = right light.
cade task (figure, B), subjects were told not to look at the target LED but to look immediately in the opposite direction at an approximately equal distance from the fixation point. In this task, the direction of the target LED was random, but the target LED was positioned 12" horizontally from the central LED during the first 20 runs. Then, 20 runs of 8" and 20 runs of 24" were tested. The experiments were performed with the head held motionless. All the performances and saccade trajectories were carefully checked by t h e examiners, a n d saccades associated with head movement were eliminated from the analysis. Horizontal eye movement was recorded electro-oculographically. Direct-current recording with a high frequency cutoff of 100 Hz was used. The data were stored on magnetic tape and played back later on a digital memory scope (Nihon Denki San-Ei 7T17). Eye velocities were derived by electronic differentiation of eye position records and were displayed on the screen of a computer (sampling clock, 10 msec). The latencies, amplitudes, and peak velocities of the visually guided saccades and antisaccades were analyzed. In the antisaccade task, we judged it a s an antisaccade error when the initial saccade (primary saccade) was not toward the opposite direction but toward the target (figure, C2). Antisaccade errors were all eliminated from the analysis of the latencies, amplitudes, and peak velocities. The accuracy of the primary saccade was calculated from the saccade gain (primary saccade amplituddtarget amplitude) of
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each visually guided saccade. The accuracy of the antisaccades was not taken into consideration, and we included any successful antisaccades away from the target light whether their amplitude was equal or not to the amplitude of the target light. The peak velocities of all the saccades and antisaccades were plotted against the amplitudes for each subject. Bahill e t alz8 expressed t h e velocityamplitude relationship with a logarithm curve; we also did so, calculating the peak velocities for 8, 12, and 24" saccades from the best-fit logarithm curve. The Wisconsin Card Sorting Test WCST). The WCST modified by Nelson29was performed on 27 of the 32 patients to whom we had given the eye movement task. The results were compared with those of the 16 normal controls. Assessment of the overall proficiency on the WCST was judged by the number of categories achieved (maximum, 6) and the total number of errors. The number of perseverative errors29 and the number of trials taken to reach the first correct category were also counted. Statistical analysis. Comparisons of the results of the saccades and the antisaccades between the PD group and the control group were studied using the Mann-Whitney U test. We used the Spearman's rank correlation coefficient test to examine the correlation between abnormalities in saccadic eye movement and the clinical factors (eg, age, parkinsonian motor disabilities, and results of the WCST). The effects of the antiparkinsonian drugs and the severity of the disease (P1 and P2) on abnormalities in saccades were studied using a two-way ANOVA.
Results. Visually guided saccade task. The mean latencies, accuracies, and peak velocities of the PD patients were not significantly different from those of the normal controls (table 1).However, the patients in the P2 group showed a tendency towards prolongation in the mean latency (291.3 [mean] * 60.0 [SDI msec) compared to the control group (254.1 * 37.4 msec, p = 0.06) and P1 group (239.8 * 33.4 msec, p < 0.01). Antisaccade task. There was a significant difference in the error rates in the antisaccade task between the control group (15.7 +- 10.7%)and the total PD group (28.1 f 19.0%)( p < 0.05).Patients in the P1 group did not show a significant difference in their error rates in antisaccades (24.4 A 18.5%)compared to the control group. The mean error rate of the P2 group (36.2 f 18.4%)was significantly higher than that of the control group ( p < 0.01). There was no significant difference in the mean error rate between the P1 group and the P2 group. The mean latency of the antisaccades of the total PD group (358.6 f 71.1 msec) was not significantly longer than that of the controls (327.4 41.8 msec). Patients in the P2 group showed significantly longer latencies (410.3 f 80.1 msec) than the control group (327.4 * 41.8 msec, p < 0.01) and the P1 group (335.0 * 53.4 msec, p < 0.05). There was a significant correlation between the latency of the saccades and that of the antisaccades in each subject ( p < 0.01).No significant difference was observed in the peak velocities of the antisaccades between the PD patients and the controls (table 1). Clinical correlation. There was a significant correlation between the mean latency of the antisaccades
Table 1. Results of saccadic eve movements Parkinsonian patients Total P1 P2 Mean (SD) Mean (SD) Mean (SD)
Controls Mean (SD)
No. of subjects 20 Age 57.3 (9.2) Visually guided saccade Mean latency 254.1 (37.4) (msec) Accuracy 8 deg 1.08 (0.11) 12 deg 1.00 (0.10) 0.92 (0.09) 24 deg Mean peak velocity (deglsec) 8 deg 255.8 (42.4) 12 deg 318.6 (45.7) 423.3 (56.4) 24 deg Antisaccade Error 15.7 (10.7) Mean latency 327.4 (41.8) (msec) Mean peak velocity (deg/sec) 8 deg 248.2 (37.5) 303.1 (43.9) 12 deg 24 deg 394.6 (62.8)
32 57.5 (7.8)
22 56.9 (7.3)
255.9 (48.9)
239.8 (33.4)
291.3 C60.0)$
1.04 (0.10) 0.98 (0.09) 0.88 (0.11)
1.02 (0.11) 0.97 (0.10) 0.83(0.10)
1.09 (0.09) 0.99 (0.06)
247.3 (31.5) 310.6 (30.3) 416.3 (39.9)
247.1 (35.0) 310.2 (32.7) 415.5 (39.7)
247.7 (23.6) 311.6 (25.6) 418.1 (42.3)
10 58.8 (9.0)
0.86 (0.13)
28.1 (19.0)* 24.4 (18.5) 358.6 (71.1) 335.0 (53.4)
36.2 (18.4)** 410.3 (80 l)**t
239.9 (47.1) 293.1 (43.0) 381.7 (45.8)
225.6 (53.3) 278.0 (47 8) 365.3 (45.7)
246.4 (43.8) 299.9 (39.9) 389.1 (44.9)
Mean accuracy calculated as the saccade amplituddtarget amplitude in each subject and the mean (SD). Mean latencies (msec), peak velocities (deglsec) of saccades (both visually guided saccades and antisaccades), which were calculated from the best-fit logarithm curve The error rates of antisaccades.
* p < 0.05 and ** p < 0.01, for patients versus controls (Mann-WhitneyU test). ip < 0.05 and $ p < 0.01, for patients in P1 versus patients in P2 (Mann-Whitney U test).
and bradykinesia ( p < 0.05) but not between the errors and bradykinesia. No significant correlation was found between age and the abnormalities of antisaccades. Neither rigidity nor tremor correlated with the abnormalities of antisaccades. WCST. PD patients as a whole showed poor performances on the WCST. Total errors on the WCST were significantly correlated with bradykinesia ( p < 0.05) and the mean latency of visually guided saccades ( p < 0.05) and antisaccades ( p < 0.05). The number of perseverative errors was also significantly correlated with bradykinesia ( p < 0.05) and the mean latency of visually guided saccades (p < 0.01) and antisaccades (p < 0.05). Effect of antiparkinsonian drugs. We studied the effect of antiparkinsonian drugs (levodopa and anticholinergics) on saccadic eye movement and neurologic signs (bradykinesia, rigidity, tremor). In the patients on levodopa treatment, bradykinesia and rigidity were severer and the mean latency of antisaccades was longer than in the patients without levodopa (table 2). The patients on anticholinergics made significantly more antisaccade errors (35.6 17.6%) than the patients without anticholinergics (15.7 +14.6%)(p < 0.01), although there was no significant difference in the severity of motor impairment (table 2). Anticholinergics showed a significant effect on antisaccade errors using the two-way ANOVA (F = 6.57, p < 0.05). However, there was no significant group effect related to the seventy of the disease (P1 and P2), and also no interaction between the anticholinergics and the seventy of the disease.
*
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Table 2. Effects of antiparkinsonian drugs (levodopa and anticholinergics) Levodopa (-1 Mean (SD)
No of subjects Age Bradykinesia Rigidity Tremor Latency of visually guided saccades (msec) Latency of antisaccades (rnsec) Antisaccade errors ( %
Levodopa
Anticholinergics
(+)
(-)
(c)
Mean (SD)
Mean (SD)
Mean (SD)
15 56.7 (8.51
20 55.3 (8.21 9.9 (5.81 6.3 (2.31 2.8 (3.1) 263.6 (53.1)
376.3 (77.11
17 58.2 (7.31 7.6 (4.6) 4.8 12.41 1 6 12.7) 241.7 139.7)
12.3 (6.017.2 12.0lt 2.7 12.9) 272.0 154.41
12 61.3 I5 4)‘ 9.8 15.91 5.3 (2.81 1 . 1 (2.11 243.1 (39.71
333.1 (56.71
387.4 (76.31*
328.9 (49.41
26.8 (19.51
Anticholinergics
29.6 119.01
15.7 (14.6)
35.6 ( 17.61~
The p a t i e n t s on levodopa th erap y [levodopa (+]I showed higher scures in bradykinesia, rigidity, and increased mean latencies of antisaccades than the patients not taking levodopa [levodopa (-11. The patients taking anticholinergics [anticholinergic I + ) ] were younger than those not taking anticholinergics [anticholinergics 1-11 and made more antisaccade errors.
* p c 0.05 and t p < 0.01, for patients versus controls (Mann-Whitney U test1
Discussion. In the visually guided saccade task, the mean latencies, accuracies, and peak velocities were normal in PD patients. However, the advanced patients (P2) showed a tendency towards more prolonged mean latencies than either the normal controls or the mildly affected patients (Pl). Together with the previous report^,^*-^^ our results suggest that the initiation of visually guided saccades may be impaired in severe cases of PD but relatively wellpreserved in the early stage. In the antisaccade task, the mean latencies and the error rates were significantly increased in the P2 patients. These results suggest that the severity of the disease affects the results of visually guided saccades and antisaccades. The inconsistencies between our results and those of Lueck et a19 may be due to differences in the seventy of the patients examined. Abnormally increased error rates in antisaccades in PD patients indicate impairment of inhibition of reflexive saccades in PD. Several authors have observed a positive correlation between bradykinesia and saccade latencies.24.30 In the present study, only the mean latency of antisaccades significantly correlated with bradykinesia, while the other results of saccades did not. These results suggest that this disturbance in the initiation of voluntary saccades may be related to that of limb movements in PD. Aging could affect eye movements in normal subj e c t ~ However, .~~ in the PD patients in the present study, age did not correlate with the results of saccades o r motor impairments. This result suggests that the seventy of the disease and not aging is responsible for abnormalities in the voluntary control of saccades. The results of the WCST did not correlate with the
error rate in the antisaccades, but did correlate with the degree of bradykinesia and the mean latency of saccades (both the visually guided saccades and antisaccades). These results suggest that the mechanism causing the abnormalities in the WCST may be different from the mechanism that caused the antisaccade errors, and that the cognitive dysfunction associated with the WCST may be related to both bradykinesia and the initiation of voluntary saccades. The patients on levodopa showed significantly longer antisaccade latencies. Since both rigidity and bradykinesia in the patients on levodopa were significantly worse than in those patients not taking levodopa, it was impossible to distinguish whether the prolonged latencies of antisaccades in those patients were the result of the seventy of the illness or the effects of levodopa. On the other hand, the error rates of the antisaccades were significantly increased in the patients with anticholinergics.
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A reduction in serum glucocorticoids provokes experimental allergic encephalomyelitis: Implications for treatment of inflammatory brain disease Anthony T. Reder, MD; Manjula Thapar, MS; and Mark A. Jensen, BS
Article abstract-Glucocorticoid (GCC) therapy usually inhibits inflammatory diseases, but certain regimens can trigger relapses. Clinical use of steroids is not uniform and in some instances may be dangerous. In the present study, GCCs modified the course of experimental allergic encephalomyelitis (Em)in Lewis rats, a model of inflammatory CNS disease. Continuous treatment with dexamethasone (DEX) completely blocked E M . RU 486, a GCC antagonist, counteracted the effects of endogenous GCCs and worsened EAE. Sudden withdrawal of DEX also caused severe clinical and histologic exacerbations at a time when paired saline-treated animals had completely recovered. In rats that had complete clinical recovery from EAE, and would not have relapsed without this acute steroid deficit, a short pulse of DEX was followed by severe exacerbations. In contrast, a slow steroid taper prevented exacerbations. Abrupt discontinuation of GCCs provokes inflammatory brain disease. NEUROLOGY 1994;44:2289-2294
Glucocorticoids (GCCs) and ACTH are widely used to treat inflammatory neurologic disorders such as ternporal arteritis, myasthenia gravis, acute optic neuritis, and exacerbations of multiple sclerosis (MS). IM ACTH for 14 days,’ or IV methylprednisolone (rVMP) for 3 days followed by a 3-month taper of oral predn i s ~ n e , *ameliorates
