Journal of Neuro-Ophthalmology, June 2009, Volume 29, Issue 2

Increased anti-saccade latency is an isolated lingering abnormality in Sydenham chorea.

ORIGINAL CONTRIBUTION Increased Anti-saccade Latency Is an Isolated Lingering Abnormality in Sydenham Chorea Sheree Cairney, PhD, Paul Maruff, PhD, Jon Currie, FRACP, and Bart J. Currie, FRACP Abstract: Sydenham chorea (SC) is an autoimmune response to group A b-hemolytic streptococcal infection whose clinical and imaging manifestations usually resolve within 6 months. We used ocular motor analysis and neuropsychologic assessment to investigate residual striatal dysfunction in two individuals with histories of childhood SC whose most recent episodes of chorea had occurred 5 and 17 years before testing. Compared with the performance of 33 age-matched control subjects, both SC subjects showed significantly increased anti-saccade latencies. These findings support recent theories that acute episodes of SC may cause long-term corticostriatal changes in some individuals. (J Neuro-Ophthalmol 2009;29:143-145) As an expression of rheumatic fever, Sydenham chorea (SC) is an autoimmune response to group A b-hemolytic streptococcal infection characterized by severe impairment in psychomotor function with involuntary movements, muscle weakness, and emotional lability (1). The manifestations of SC usually subside spontaneously within 2-6 months of an acute episode (1). A more persistent form of SC has been reported with manifestations continuing beyond 2 years (2), but complete recovery from chorea does occur eventually. Recurrent episodes of SC are most likely to occur within the 2 years after a previous Menzies School of Health Research (SC, BJC), Institute of Advanced Studies, Charles Darwin University, Casuarina, Northern Territory, Australia; Neuropsychology Laboratory (SC, PM), Mental Health Research Institute of Victoria, Parkville, Victoria, Australia; Department of Addiction Medicine (SC, JC), St. Vincent's Health, Melbourne, Australia; and Northern Territory Clinical School and Flinders University (BJC), Casuarina, Northern Territory, Australia. This research was supported by a grant and a training fellowship for the corresponding author, both funded by the National Health and Medical Research Council of Australia. Address correspondence to Dr. Sheree Cairney, PhD, Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811, Australia; E-mail: [e-mail] episode of SC, but in some individuals an increased sus-ceptibility to further episodes continues into adulthood (3). Striatal abnormalities are consistently implicated as the origin of SC on the basis of behavioral characteristics and neuroimaging (2). Whereas neuroimaging studies and behavioral observations generally affirm complete resolu-tion (2), there is evidence of permanent striatal dysfunction after an acute episode of SC. For example, some individuals with a history of SC maintain an increased susceptibility to dopaminergic agents and to recurrent episodes of chorea that may continue throughout their lives (3). The episodes have been stimulated by pregnancy (chorea gravidarum), oral contraceptive treatment, and senescence. For some individuals, an acute episode of SC may produce irre-versible changes in the basal ganglia and thereby a sub-sequent long-term susceptibility to recurrent episodes of chorea (3). To investigate residual neurologic dysfunction long after SC occurring in childhood and adolescence, we examined ocular motor indicators and neuropsychologic parameters in two individuals with a history of acute rheumatic fever and SC and compared their results to those of a matched healthy control group of 33 individuals. CASE STUDY Subjects For the two SC subjects, diagnosis was based on the 1992 updated Jones criteria (4) and confirmed from clinical notes and hospital admission data. Other causes of chorea were excluded. At the time of testing, these individuals showed no chorea and no neuropsychiatric symptoms. Their most recent episodes had been 5 and 17 years earlier. All subjects had been enrolled in a large study of substance abuse in remote Aboriginal communities in northern Australia (5,6), but neither the SC subjects nor the members of the healthy control group had histories of substance abuse or psychiatric illness. The study was approved by the relevant institutional ethics committees with input from an Aboriginal subcommittee. All subjects J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 143 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 Cairney et al gave written informed consent to participate before the assessment procedure. Procedure The ocular motor and neuropsychologic tests used here are identical to those used in our previous studies based on Aboriginal Australians living in remote commu-nities and have been described in detail in earlier publications (5,6). Ocular motor recordings were per-formed in a darkened room with the head stabilized, using a high-resolution infrared scleral reflectance technique (IRIS, Skalar; bandwidth DC to 100 Hz [ 2 3 dB]). Participants were seated 1 m from a horizontal display of light-emitting diode (LED) (16.9 cd/m2; rise time 3 ms) visual targets with computer-controlled illumination tim-ing. Eye and target position signals were digitized at 1 kHz and scored for off-line computer analysis. Eye position was differentiated using a computer-based algorithm to obtain eye velocity. Subjects were required to make visually guided reflexive eye movements (saccades) to fixate random targets moving with unpredictable direction, amplitude (615), and timing (range 1.5-2.5 s). For each subject, the initial saccade was scored as hypometric if it attained less than 85% of the target step and hypermetric if it attained more than 115% of the target step. Anticipatory saccades were defined as saccades made before or less than 70 ms after target appearance (7). Saccade latency was calculated as the duration from the onset of the target to the onset of the saccade, and saccade accuracy was calculated as the displacement of the final eye position with respect to the target position. The duration and peak velocity for visually guided saccades were plotted against saccade amplitude. The anti-saccade task involved making voluntary saccades to fixate a central green LED (16.9 cd/m2) target that was offset simultaneously with the appearance of a peripheral red target at either 6 1 0 or 615. Subjects were instructed to inhibit a reflexive saccade to the peripheral red target and instead to generate an anti-saccade to its mirror location and hold fixation until the green LED reappeared in the center. Displacement and timing (3.0-3.5 seconds after fixation) of the appearance of the peripheral red target was random. A correct anti-saccade response was an initial eye movement away from the midline to the side opposite to that of the peripheral red target. Any initial reflexive eye movement toward the target was scored as incorrect even if a subsequent correction to the opposite side was made. The latency for the onset of correct anti-saccades was recorded and a percent error rate was calculated. Neuropsychologic tests were drawn from the touch screen-based Cambridge Automated Neuropsychological Test Battery (CANTAB). The selected assessment battery included tasks of psychomotor speed, recognition memory, and paired-associate learning. More detail on these assessments and the experimental setup is available elsewhere (6,8). Data Analysis Demographic, ocular motor, and neuropsychologic data for patients with SC were compared against confidence intervals derived from control data based on 1.96 standard deviations from the group mean. Before analysis, the distributions of data for each performance measure were inspected for normality and heterogeneity of variance. Where data did not meet the assumptions for parametric statistics, the distributions of scores were transformed. Accuracy measures on the recognition memory task that were scored as percent correct formed negatively skewed distributions, and arcsine transformations were used to normalize these distributions. RESULTS All data for patients and control subjects are pre-sented in Table 1. In comparison with control data, both SC subjects showed no sign of dysmetria or anticipatory sac-cades and normal performance for saccadic duration, saccade peak velocity, anti-saccade errors, paired associate learning, and recognition memory. On the anti-saccade task, both patients with SC showed normal error rates but significantly elevated latencies to perform correct anti-saccades. DISCUSSION The two individuals who had had episodes of SC 5 and 17 years earlier showed significantly increased latencies in the initiation of anti-saccades, evidence of lingering corticostriatal dysfunction. They had no dysme-tria or saccadic disinhibition, as judged by the normal anti-saccade error rates and no deficits in recognition memory or paired-associate learning. Increased anti-saccade latency in combination with normal anti-saccade error rates have been observed in patients with lesions of the frontal eye fields (FEFs) and in individuals with Tourette syndrome, which affects the basal ganglia (9,10). Neuroimaging studies and neuronal studies in primates have further validated the importance of neural networks that involve cortical and basal ganglia brain regions for triggering voluntary saccades (9). Thus, the pattern of ocular motor performance observed here among individuals with a history of SC is observed typically when corticostriatal pathways are disrupted. These data therefore provide evidence of residual striatal dysfunction after SC. Our findings of ocular motor abnormalities many years after the manifestations of acute SC have subsided may reflect the benefit of specific functional investigation enabled through ocular motor analysis. However, these 144 © 2009 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Sydenham Chorea J Neuro-Ophthalmol, Vol. 29, No. 2, 2009 TABLE 1. Demographics and neuropsychologic and ocular motor performance Sydenham chorea and 33 healthy control subjects Measure Age (years) Sex No. episodes chorea Age first episode (years) Time since most recent episode (years) Rheumatic heart disease Psychomotor speed Recognition memory (arcsine % correct) Paired associate learning (total number of errors) No. hypometric saccades No. hypermetric saccades No. anticipatory saccades Reflexive saccades: Latency (ms) Accuracy (%) Peak velocity (coefficient of variation) Duration (amplitude gradient) Anti-saccades Error rate (%) Latency (ms) Control data are presented as group mean (SD). Control subjects (n = 33) 19.3 (5.4) M (n = 33) N/A N/A N/A N/A 734 (285) 0.99 (0.26) 24.5 (16.7) 18.6 (14.1) 10.2 (17.5) 9.6 (10.8) 170.0 (23.3) 98.8 (12.74) 146.8 (31.7) 2.16 (0.43) 16.3 (12.4) 260.9 (38.8) *Values fall outside confidence intervals based on control data (mean 6 1.96 SD). F, female; M, male; N/A, not applicable. SC, Sydenham chorea; SC1, first patient with measures for two subjects with SC1 19 F 2 8 5 Yes 896 0.91 2 2 5 5 173.5 (46.5) 100.9 (9.6) 201.0 2.20 0 372.9 (91.4)* SC; SC2, second patient with SC. a history of SC2 25 F 1 8 17 No 997 0.84 11 1 0 1 188.2 (37.1) 97.4 (6.8) 133.4 2.17 9 373.5 (76.2)* observations are based on only two individuals. Further investigation is therefore necessary to explore these hypotheses. They appear to support the recent theory that in some individuals, acute episodes of SC cause permanent damage in the basal ganglia that may not produce ongoing clinical manifestations, but perhaps a susceptibility to recurrent episodes, especially in response to additional striatal stressors such as pregnancy, aging, or brain dopamine fluctuations (2,3). Acknowledgments We gratefully acknowledge the Aboriginal health workers and clinic staff from the communities involved. REFERENCES 1. Moore DP. Neuropsychiatric aspects of Sydenham's chorea: a comprehensive review. 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