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Show ORIGINAL CONTRIBUTION Stereoacuity Testing Discloses Abnormalities in Multiple Sclerosis Without Optic Neuritis Gu ¨ ngo ¨ r Sobaci, MD, Seref Demirkaya, MD, Fatih C. Gundogan, MD, and Fatih M. Mutlu, MD Background: We aimed to determine the value of stereoacuity testing in detecting subclinical disease activity in patients with multiple sclerosis ( MS) without a history or clinical evidence of optic neuritis. Methods: We enrolled 23 patients with MS and 23 age- matched and sex- matched healthy control sub-jects with Snellen acuities of 20/ 20 in both eyes. We recorded monocular pattern visual evoked potentials ( PVEPs) to 60- minute and 15- minute check sizes and tested stereoacuity by the Randot stereoacuity ( RSA) test. Results: The MS group showed delayed PVEP latencies to 60- minute and 15- minute patterns ( P < 0.001 and 0.002). Stereoacuity by the RSA test was significantly worse in patients with MS than in control subjects ( P < 0.001). In the MS group, the PVEP P100 latency and the RSA values showed sig-nificant positive correlations. There was no signifi-cant correlation between the time from MS diagnosis and the RSA and PVEP values. Conclusions: Based on this study, patients with MS without optic neuritis have considerable abnormali-ties in stereopsis. RSA testing may be a useful marker of subclinical disease activity in this condition. ( J Neuro- Ophthalmol 2009; 29: 197- 202) M ultiple sclerosis ( MS) is an autoimmune- mediated neurodegenerative disease with characteristic in-flammatory demyelination in the central nervous system ( 1,2). Most patients present with a relapsing- remitting pattern of acute neurologic dysfunction and have variable periods of remission punctuated by exacerbations. MS is often associated with involvement of the visual pathway ( 3). Psychophysical and visual evoked potential ( VEP) studies are often used in the evaluation of visual dysfunction in patients with MS without a history of optic neuritis ( ON) ( 4,5). The pattern visual evoked potential ( PVEP) test has been shown to be more sensitive than contrast sensitivity at detecting hidden visual loss in patients with MS with 20/ 20 visual acuity and without a history of ON ( 5). We have found that PVEP is more valuable than optical coherence tomography ( OCT) in detection of subclinical optic nerve involvement in patients with MS without a history of ON ( 6). Patients with MS report blurred vision even if visual acuity is normal ( 7). The Pulfrich stereophenomenon, an altered perception of the vector of a moving target, is awell-recognized finding in patients with MS ( 8). Deficient binocular depth perception has been suggested to contrib-ute to a higher incidence of postural instability and falling in these patients ( 9). However, there is a paucity of data on binocular function in patients with MS ( 10- 13). Therefore, we aimed to determine whether MS is associated with stereoacuity abnormalities and whether there is a correlation between stereoacuity and PVEP in the detection of subclinical disease activity in patients with 20/ 20 visual acuity and without a history of ON. METHODS Participants Twenty- three patients with a definite diagnosis of MS ( 10) who had a best- corrected Snellen visual acuity of at least 20/ 20 in both eyes, no ocular history of optic nerve involvement, and a minimum follow- up of 1 year were enrolled in this study. They were under the care of a neurologist ( SD) and had been in remission for at least 6 months before enrollment. An Expanded Disability Status Scale ( EDSS) score was recorded during each visit to determine the extent of neurologic disability. Patients with reversible disability of less than 6 months' duration and those who had any visual complaint in the past and during the follow- up period were excluded. At the initial exami-nation and during the follow- up examinations, they were asked about vision blur, visual loss, diplopia, periocular pain, and color vision disturbances ( change in seeing traffic Departments of Ophthalmology ( GS, FCG, FMM) and Neurology ( SD), Gulhane Military Medical Academy, Ankara, Turkey. Address correspondence to Prof. Dr. Gu ¨ ngo ¨ r Sobaci, Gulhane Askeri Tip Akademisi Goz Hastaliklari A. D., 06018 Etlik- Ankara, Turkey; E- mail: gsobaci@ hotmail. com J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 197 lights or in the brightness of colors in one or both eyes) throughout their life. All patients had undergone a thorough ophthalmologic examination, including tests for ocular misalignment by one of the study investigators ( FMM). Slit- lamp and ophthalmoscopic findings were always normal. There was no abnormality in the neuro- ophthalmic examination, including testing of color vision by Ishihara plates and testing for a relative afferent pupillary defect ( RAPD). The results of stereoacuity and PVEP examina-tions obtained at the last patient visit were used for statistical evaluation. Twenty- three age- matched and sex-matched healthy subjects without any known ophthalmic and systemic disease ( including diabetes and systemic hypertension) comprised the control group. PVEP Recordings The recordings were performed using the RETI- scan system ( Roland Consult, Wiesbaden, Germany) on the basis of International Society for Clinical Electrophysiol-ogy of Vision ( ISCEV) standards. In accordance with the ISCEV clinical protocol, monocular PVEP responses for both eyes were recorded with gold disc surface electrodes. However, only the results for the right eye were included, so as not to violate independence in statistical analysis. Active electrodes were placed on the scalp over the visual cortex at Oz with the reference electrode at Fz. The ground electrode was placed on the forehead. Refractive errors of the subjects were corrected with trial lenses before recordings were made. Each subject sat in a moderately lighted room at 1 m from a 20 cm 3 30 cm black- and- white video display monitor. The checkerboard stimulus subtended a visual angle of 5.7 vertically and 8.5 horizontally on either side of fixation. Luminance was < 1 cd/ m 2 for the black hexagons and 115 cd/ m 2 for the white hexagons ( contrast: 99%). The responses to a large ( 60- minute arc) and a small check ( 15- minute arc) were recorded. Background light was dimmed ( 20 cd/ m 2 ). The reversal rate was 1/ s. The responses to 100 stimuli were averaged. Subjects were instructed to fixate on a red marker at the center of the screen. If the cooperation of the subject was poor, the PVEP recording was repeated. Fixation stability, eye movements, and prolonged closing of the eye were monitored closely by an experienced electrophysiology technician throughout the entire testing period. Randot Stereoacuity ( RSA) Testing Stereoacuity was measured at 40 cm using the Randot stereoacuity test ( RSA, Stereo Optical Co., Chicago, IL) with the accompanying polarizing filters. The same examiner ( FCG) performed all tests. Refractive errors of the subjects were corrected with trial lenses before RSA testing. The illumination level ( 100 lux) during stereoacuity testing was the same for all participants. Subjects who used spectacle correction wore the polarized glasses over their spectacles. The last component of the RSA- the 10 circular disparate areas- was used. The disparities of the circular areas range from 400 to 20 seconds of arc. Higher scores indicate lower stereoacuity. Statistical Analysis The data are reported as mean values 6 1 SD. The differences between control subjects and patients with MS were statistically evaluated with the Mann- Whitney U test. The x2 or Fisher exact test was used where appropriate. The Spearman correlation coefficient was adopted to assess whether a correlation existed between the variables. The statistical analyses were performed with the Statistical Package for the Social Sciences ( SPSS) software ( version 10.0; SPSS, Chicago, IL). A P value of < 0.05 difference was considered statistically significant. RESULTS Characteristics of Study Subjects The mean age was 34.9 6 8.2 years ( range, 21- 53 years) and 35.2 6 8.1 years ( range, 20- 52 years) in the TABLE 1. Pattern evoked visual potential P100 amplitude and latency results in multiple sclerosis and control groups 60- Minute Arc Check Size 15- Minute Arc Check Size P100 Latency ( ms) P100 Amplitude ( mV) P100 Latency ( ms) P100 Amplitude ( mV) Multiple sclerosis ( 95% CI) 119.3 6 19.8 ( 92.6- 158.8) 12.3 6 4.1 ( 5.0- 22.4) 129.5 6 23.7 ( 98.4- 176.6) 12.6 6 6.5 ( 4.0- 25.4) Control group ( 95% CI) 101.1 6 4.8 ( 94.0- 112.0) 14.5 6 4.3 ( 5.9- 19.8) 108.4 6 7.1 ( 97.2- 119.8) 15.4 6 7.3 ( 6.9- 35.5) P* < 0.001 0.053 0.002 0.150 Data are mean 6 SD ( minimum- maximum). * Mann- Whitney U test. CI, confidence interval. 198 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Sobaci et al study and control groups, respectively. The female- to- male ratio was 1.87 in both groups. Seventeen patients ( 73.9%) had relapsing- remitting ( RR) MS, 5 patients ( 21.7%) had secondary progressive ( SP) MS, and 1 patient ( 4.3%) had relapsing- progressive ( RP) MS. Disease duration was 4.1 6 4.4 years ( range, 1- 21 years) and EDSS score was 2.21 6 2.53 ( range, 0- 7) in the MS group. VEPs The P100 latency was delayed significantly in patients with MS for the 60- minute arc and 15- minute arc checks ( Table 1). The PVEP results showed subclinical optic nerve involvement in some patients with MS although there were no symptoms of ON in those patients. We divided the patients with MS into two subgroups according to their PVEP latency values to the 60- minute arc check size ( Table 2). The 95% CI value of the P100 latency of the control group for the 60- minute arc check was selected ( 109 ms) for categorization ( normal or delayed) ( Table 2). Patients with MS with a lower P100 latency than that value were determined as MS- P100 normal and those with a longer P100 latency were determined as MS- P100 delay. There were 9 MS- P100 normal ( 39.1%) and 14 MS- P100 delay ( 60.9%) patients. The age and gender differences between the MS-P100 normal and MS- P100 delay patients were not significant ( Table 2). RSA The RSA score was severely reduced in patients with MS ( MS, 80.7 6 87.8 arc seconds; control, 22.3 6 3.6 arc seconds; P < 0.001). The 95% confidence interval ( CI) level of the RSA in control group was 30 seconds of arc. Among the MS group, 17 ( 73.9%) of 23 patients had a reduced RSA with respect to that value. The RSA- reduced (> 30- minute arc seconds) MS patients had similar age and sex distribution compared with RSA- normal MS patients ( Table 3). There was a positive correlation between the P100 latency and the RSA values, especially for the 15- minute check size in patients with MS ( increased RSA values represent lower stereoacuity). However, correlations were negative and were not significant between P100 amplitude and RSA values ( Figs. 1 and 2). PVEP variables and RSAvalues showed insignificant correlations to the time from diagnosis ( Fig. 3). We also investigated the significance of distribution differences of the patients according to their PVEP and RSA results. Among the patients with MS, 12 ( 52%) of 23 had reduced RSA and delayed PVEP values ( P = 0.16) ( Table 4). DISCUSSION In this study of MS patients without evidence of previous ON, we found a high prevalence of stereoacuity dysfunction as measured by the RSA test. These results correlated with PVEP abnormalities. Halliday et al ( 14) first described delayed PVEPs in carefully examined MS patients without ON. In our study, 14 of 23 ( 60.8%) patients with MS had a P100 latency delay with respect to a 95% CI value of the control subjects. These statistical differences were found to be unrelated to age and gender differences in our study groups. Similar findings have been reported previously ( 7,15,16). In recent studies with OCT, axonal loss was detected not only in MS eyes with previous acute ON, but also in MS eyes with TABLE 2. Characteristics of the patients with multiple sclerosis based on the pattern visual evoked potential P100 latency results P100 Latency ( 60- minute arc check) Test Results Age ( years) Gender ( Female/ Male) Stereoacuity Normal ( n = 9) 36 ( 23- 40) 7/ 2 40 ( 20- 50) Delayed ( n = 14) 36 ( 21- 52) 8/ 6 70 ( 20- 400) P 0.570* 0.400† 0.007* Data are median ( minimum- maximum). * Mann- Whitney U test. † Fisher exact test. TABLE 3. Characteristics of the patients with multiple sclerosis based on the Randot stereoacuity scores Randot Stereoacuity Test Score Age ( years) ( mean 6 SD) Gender ( Male/ Female) Normal ( n = 10) 32.1 6 6.0 5/ 1 Reduced ( n = 22) 35.8 6 8.8 10/ 7 P 0.44* 0.37† Data are mean SD. * Mann- Whitney U test. † Fisher exact test. 199 Stereoacuity in MS J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 no known ON attack ( 17,18). PVEP amplitude reflects axonal/ neuronal loss, whereas increased latency reflects demyelination. The fact that PVEP amplitudes are lower but not significantly different in the MS eyes may be due to the relatively short disease duration and lack of a history of ON in this study group. In a recent controlled clinical study, we demonstrated that the PVEP test is more valuable than OCT in detecting subclinical optic nerve involvement ( 6). These two studies together may indicate that demyelination precedes or predominates over axonal loss in the optic neuropathy in MS and emphasize the importance of routine PVEP recordings in patients with MS to diagnose subclinical optic nerve involvement. In this study, we included only the patients who did not report any visual complaints and had a visual acuity of 20/ 20 during follow- up visits. Our PVEP recording protocol applying ISCEV standards with the RETI- port system ( Roland Consult) has been validated in a previous study ( 6). We used the Randot circles stereotest, which has been shown to be a reliable test of stereoscopic vision ( 19). The P100 latency but not the amplitude values had significant correlations to the stereoacuity scores ( Fig. 1). This correlation seems to be related to the subclinical demyelinating process in MS, which essentially affects latency values. It is noteworthy that 73.9% of our patients had low stereoacuity levels compared with 60.8% of patients with a PVEP abnormality. Impairment of the clinically unaffected optic nerve in patients with MS with optic neuritis has been noted ( 20). As shown in an earlier study ( 21), interocular PVEP recordings FIG. 2. Sixty- minute check size visual evoked potential P100 latency/ amplitude correlations to Randot stereoacuity in patients with multiple sclerosis but without optic neuritis. FIG. 1. Fifteen- minute check size visual evoked potential P100 latency/ amplitude correlations to Randot stereoacuity in patients with multiple sclerosis but without optic neuritis. 200 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Sobaci et al FIG. 3. Correlations between test results and time from diagnosis of multiple sclerosis. 201 Stereoacuity in MS J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 in the control group may vary 16% and 20% for 60- minute and 15- minute check sizes, respectively. Abnormalities in the unstudied left eyes may be responsible for some inconsistencies between PVEP and RSA results in this study. Various disease processes including decreased vision are known to affect stereoacuity. In this study, we included only patients with MS who had 20/ 20 vision to disclose the impairment of stereoacuity with the disease process. The high rate of RSA impairment ( 73.9%) in this study is an unexpected finding, given the previously reported close correlation between stereoacuity and visual acuity ( 22). We suggest that alterations in interactions between higher- order neurons, known to be affected in patients with MS, may be responsible for this finding ( 23,24). Although our study suggests a link between RSA abnormality and subclinical disease activity in MS, its design cannot identify a cause-and- effect relationship. Further clinical studies on larger patient populations are needed to clarify the value of RSA testing in detection of subclinical optic nerve involvement and the pathophysiologic mechanisms in this form of visual processing in patients with MS. REFERENCES 1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. Multiple sclerosis. N Engl J Med 2000; 343: 938- 52. 2. Constantinescu CS, Hilliard B, Fujioka T, et al. Pathogenesis of neuroimmunologic diseases. Experimental models. 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Distribution of patients according to P100 latency and Randot stereoacuity scores P100 Latency in Patients with Multiple Sclerosis Randot Stereoacuity Score Total P* Normal Reduced Normal 4 5 9 0.162 Delayed 2 12 14 Total 6 17 23 * Fisher exact test. 202 q 2009 Lippincott Williams & Wilkins J Neuro- Ophthalmol, Vol. 29, No. 3, 2009 Sobaci et al |
