6 months after the acute event, however, analyses showed that red/green ... acuity loss, but the type of dyschromatopsia present (red/green versus blue/ ...... ally show me by example what a career can be like, and I thank Drs. Arthur.
THE DYSCHROMATOPSIA OF OPTIC NEURITIS: A DESCRIPTIVE ANALYSIS OF DATA FROM THE OPTIC NEURITIS TREATMENT TRIAL BY: Barrett Katz, MD ABSTRACT
Purpose: We sought to characterize the dyschromatopsia of optic neuritis, to determine the type and severity of color defect present and its relation to central vision and spatial acuity, to examine changes in this dyschromatopsia over time, and to determine the applicability of Kollner's rule to patients with optic neuritis.
Methods: We analyzed the raw data on color vision performance as assembled within the Optic Neuritis Treatment Trial (ONTT). The ONTT was designed to evaluate corticosteroids as a treatment for acute demyelinating optic neuritis and to allow long-term outcome and natural history analyses. Between July 1, 1988 and June 30, 1991, 488 patients were enrolled in this trial. All patients underwent extensive neurologic and ophthalmologic examinations including standardized testing ofvisual function that included testing of color vision. The ONTT population thus afforded a unique opportunity to characterize acquired dyschromatopsias in a large, homogenous, well-characterized cohort of patients with optic neuritis. We used quantitative analysis of FM-100 scores from this patient cohort to determine the severity of the dyschromatopsia, the selectivity of the dyschromatopsia (polarity of errors) and the type of dyschromatopsia (axis of confusion) by employing quadrant analysis of FM-100 scores.
Results: The results of high- and low-selectivity analyses of the FM-100 data showed that during the acute phase of optic neuritis, blue/yellow, red/ green, and non-selective color defects occurred; among patients with pure defects, blue/yellow defects were more frequent than red/green defects. At 6 months after the acute event, however, analyses showed that red/green defects were more common than blue/yellow defects. Among patients with selective color defects both acutely and at 6 months, the defect was as likely to change over time as remain the same. The likelihood of persistent dyschromatopsia at 6 months was related to the severity of initial central acuity loss, but the type of dyschromatopsia present (red/green versus blue/ yellow) was not.
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Conclusions: Our results suggest that at the time of the acute attack ofoptic neuritis, the majority of selective color defects were blue/yellow defects, whereas at 6 months, more of the selective defects were red/green defects, though both types of defects (as well as nonselective defects) were seen acutely and at 6 months. Despite the rigorous inclusion criteria ofthe ONTT, the large number of patients we studied, correlation of color vision with visual acuity, and longitudinal follow up, this study showed that no single type of color defect was consistently associated with optic neuritis. Demyelinating optic neuritis does not obey Kollner's rule. Moreover, the type of defect present changed in some patients over the course of recovery. Thus, the type of defect may not even be consistent in individual patients as they recover. The type of defect appeared to be related to spatial vision at the time of the test, but the type of defect present at 6 months was not related to the severity of the initial visual loss. Therefore, in evaluating color defects associated with optic neuritis, the level of central visual function must be considered. INTRODUCTION
In the early part ofthis century, Kollnerl reviewed an already extensive body of knowledge on acquired dyschromatopsia. Most patients with retinal disease (especially macular disease), he found, had defects in blue/yellow discrimination, whereas most patients with optic neuropathies had defects in red/green discrimination. "Kollner's rule," as this generalization came to be known, holds fairly well2 but is not inviolate.3-5 Exceptions to Kollner's rule include macular disease associated with red/green defects, optic neuropathies with blue/yellow defects, and acquired dyschromatopsias with equal impairment in blue/yellow and red/green discrimination. Moreover, acquired dyschromatopsias may change over time; the defect may be blue/yellow initially and become red/green as disease progresses.'6'17 Optic neuritis, the most prevalent optic neuropathy in otherwise healthy young adults, causes alterations in visual acuity, pupillary symmetry, and visual field, as well as dyschromatopsia. As an optic neuropathy, optic neuritis has been expected to be characterized by red/green confusion; recent evaluation suggests that this characterization may not be valid.18-20 Most studies that have sought to characterize the dyschromatopsia of optic neuritis have been limited by small sample sizes, non-homogeneous patient populations, incomplete clinical data, variations in the time of testing (ie, acute versus recovery phase), and the lack of correlation with central vision and spatial acuity. Most prior analyses of color vision in optic neuritis have failed to recognize that blue/yellow defects are often observed in conditions in which central vision is preserved (consistent with the concentration of blue cones away from the central fovea and the relative lack of involvement of
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blue cones in spatial vision tasks). As well, previous studies have incompletely assessed the type of dyschromatopsia and changes over time. Moreover, the results of the most commonly used test of color vision, the Farnsworth-Munsell 100-hue test (FM-100), are conventionally scored to evaluate congenital dyschromatopsias. In patients with acquired dyschromatopsias, the results of the FM-100 are difficult to interpret when the conventional scoring method is used. The Optic Neuritis Treatment Trial (ONTT), a multicenter collaborative study funded by the National Institutes of Health, was designed to evaluate corticosteroids as a treatment for acute demyelinating optic neuritis21 and to allow long-term outcome and natural history analyses.22-25 Between July 1, 1988, and June 30, 1991, 488 patients who met all of the entry criteria (Table I) were enrolled in the trial. All patients underwent neurologic and ophthalmologic examinations, including extensive standardized testing of visual function, both initially and at 6 months. Although it was designed primarily as a clinical trial, the ONTT also afforded a unique opportunity to characterize acquired dyschromatopsias in a large, homogeneous, well-characterized cohort of patients with optic neuritis (Table II). Patients enrolled in the ONTT were assigned randomly to one of three groups: (1) intravenous methylprednisolone followed by oral prednisone, (2) oral prednisone alone for 14 days, and (3) oral placebo. All subgroups were remarkably similar in clinical characteristics, including sex, age, presence of pain, occurrence of a preceding viral syndrome, initial appearance of the optic nerve head, severity of visual loss, pattern of field defect, presence of abnormality in the fellow eye, antinuclear antibody determination, presence of multiple sclerosis, and magnetic resonance imaging findings. Abnormal MRI head scans were associated with the presence of definite multiple sclerosis26 and with acuity worse than 20/200. Otherwise, there were negligible differences between groups. The analysis described in this thesis was an ancillary study ofthe ONTT; the ONTT data were analyzed to characterize acquired dyschromatopsia in patients with optic neuritis. New techniques were used to score and analyze the FM-100 to make it more applicable for patients with acquired dyschromatopsia. The goals of this thesis were to determine the type and severity of color defects in optic neuritis, their relation to central vision and spatial acuity, changes in color vision over time, and the applicability of Kollner's rule to patients with optic neuritis. METHODS
VISUAL FUNCTION TESTS
All patients underwent visual function testing within 8 days after onset of visual symptoms, and again at 6 months. All tests were performed before
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TABLE I: MAJOR ELIGIBILITY AND EXCLUSION CRITERIA FOR THE OPFTIC NEURITIS TREATMENT TRIAL ELIGIBILITY
Presence of acute unilateral optic neuritis of unknown or demyelinative origin Visual symptoms for < 8 days Age between 18 and 46 yrs Presence of relative afferent pupillary defect in affected eye Presence of visual field defect in affected eye (either mean deviation, pattern standard deviation, or corrected pattern standard deviation below age-specific 95% confidence limits, or, eight of 76 test points with sensitivity values on total deviation below 95th percentfle confidence limits for age-specific normative data) EXCLUSION
Treatment for optic neuritis already instituted Previous diagnosis of optic neuritis for which patient received corticosteroids or corticotropin Diagnosis or evidence of any systemic condition other than multiple sclerosis that might cause optic neuritis, or for which corticosteroids would be contraindicated History consistent with previous optic neuritis or evidence of optic disc pallor in currently affected eye Ocular findings suggestive of nondemyelinating cause for optic neuritis (such as macular exudates, vitreous cells more than trace, or iritis) Pre-existing ocular abnormalities that might affect assessment of visual function Reliability indexes (fixation losses, false positives, or false negatives) on Humphrey field analyzer not exceeded in eye with better vision (almost always fellow eye) Painless visual loss associated with disc swelling and either (1) disc or peripapillary hemorrhage or (2) altitudinal (or other nerve fiber bundle) type visual field defect Myopia measuring > 6 D (spherical equivalent) or hyperopia or astigmatism measuring 3 D in affected eye Narrow-angle glaucoma induced by pupillary dilation Intraocular pressure >30 mm Hg in affected eye currently or in past, with or without treatment Patient receiving medication that may produce retinal or optic nerve toxitiy (eg,
ethambutol, plaquenil, phenothiazines) Patient received systemic corticosteroid treatment or corticotropin for any condition for any duration within past 3 mo or for >7 days within past 6 mo Blood pressure >180 mm Hg systolic or 110 mm Hg diastolic; heart rate > 120/min or presence of pathologic arrhythmia Blood glucose level > 11.1 mmol/L in patient who is not receiving medical treatment for diabetes (which would exclude patient)
D, diopter.
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TABLE II: DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF 448 PATIENTS AT ENTRY INTO STUDY
CHARACTERISTIC
% OF PATIENTS
DEMOGRAPHICS
Women
77.2
White
85.0 31.8 ±6.7
Meanage± SDinyrs CHANGE IN VISION BETWEEN ONSET AND EXAMINATION
No change Progression Improvement
26.1 69.0 4.9
OCULAR PAIN, IF PRESENT
Mild Moderate Severe
50.1 37.5 12.3
ACUITY IN AFFECTED EYES
20/20 or better 20/25-20/40 20/50-20/190 20/200-20/800 Finger counting Hand motion Light perception No light perception
10.5 24.8 28.8 20.3 3.6 5.6 3.3 3.1
FUNDUS FINDINGS
Optic disc Normal Swollen Disc or peripapillary hemorrhages Retinal exudates Vitreous cells (trace)
64.7 35.3 5.6 1.8 3.3
BRAIN MRI FINDIN(;S
(DEMYELINATION)
Grade 0 (normal, without plaques) Grade I (1 lesion < 3mm) Grade II (1 ovoid lesion > 3mm) Grade III (2 ovoid lesions . 3mm) Grade IV (. 3 ovoid lesions . 3mm) MULTIPLE SCLEROSIS
40.3 11.0 9.3 6.8 32.5
STATUS*
No Possible
Probable Definite
66.9 19.9 7.6 5.6
ANA TITER
0 450), and their patterns could not be characterized. At presentation, 2 patients had a blue/yellow defect, 11 had nonspecific defects, and 2 had normal color vision; no patient had a red/green defect. At 6 weeks, 2 patients had red/green defects, and at 6 months, 3 different patients had red/green defects. No patient had a blue/yellow dyschromatopsia at recovery. At 6 months, 14 patients had normal color vision and 16 had persistent defects, which were considered permanent. These findings are similar to ours. Few patients had a recognizable pattern of color defect at any of the 3 examinations, and the investigators concluded that there was no consistent pattern of color defects at recovery. However, analysis of pooled data showed a type III tritan color axis during presentation, consistent with our observations. OTHER PATTERNS OF COLOR DEFECT
Many studies have suggested that nonspecific defects occur in patients with optic neuritis. 15,18,40-44Travis and Thompson45 found mixed defects in 18 patients with multiple sclerosis who were presumed to have optic neuritis. The Pickford-Nicolson anomaloscope was used to test color vision, and Rayleigh and Engelking-Trendelenburg equations were used to determine red/green and blue/green deficits. Two control groups were assessed, one for each equation. Fifteen patients had a color defect; 2 of these patients had both red/green and blue/yellow defects. Six patients (9 eyes) had a red/ green defect, but 11 patients (19 eyes) had blue/yellow defects. The age of their patients (some were in their 60s), the incompleteness of the clinical information, and unconfirmed diagnoses of optic neuritis make it impossible to draw appropriate conclusions from their findings. Other studies have shown that hue discrimination can be normal or without specific color axis in patients with optic neuritis. Burde and Gallin46 tested 9 patients after recovery with the FM-100 and the Farnsworth D-15 panel. Scoring methods on the FM-100 were not specified. Two patients had a green deficiency, 1 had a red/green deficit, and 6 had normal color vision. Thus, there was no consistent hue discrimination in these patients after resolution of their optic neuritis. Wildberger and van Lithl5 used the FM-100 and the Farnsworth D-15 panel to test 17 patients (22 eyes) with optic neuritis. The FM-100 was analyzed as described by Krill and Fishman.9 During the acute and early recovery period (within 3 months after onset), 11 patients (12 eyes) had abnormal scores on both tests. Six eyes had a red/green defect, 2 had a blue/yellow
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defect, and 4 were unclassified. Sixteen patients (20 eyes) were tested during late recovery (4 to 24 months after pnset). Six eyes had abnormal FM100 scores; both tritan and deutan deficits were seen. Mullen and Plantl reported optic neuritis patients (not otherwise characterized) with residual visual deficits. All patients had recently recovered from optic neuritis and had marked interocular differences in visual parameters. Color vision was tested with chromatic red/green and blue/yellow gratings that had a spatial frequency of 1 cycle per degree and with Ishihara plates and the FM-100. Red/green and blue/yellow defects were equally common, and the investigators concluded that no firm conclusions could be drawn about the selectiveness ofthe color deficit in patients with optic neuritis. OTHER MEASURES OF COLOR VISION
Several studies have employed more unusual measures of color vision. Using chromatic gratings, Russell and associates47 analyzed spectral sensitivity at 1 Hz and at 25 Hz in 32 patients with multiple sclerosis or optic neuritis. In 38 eyes (28 patients) with symptoms of optic neuritis, wavelength depressions occurred over the entire spectrum evaluated, indicating that there was no color-system specific loss. The investigators concluded that the damage associated with optic neuritis is not wavelength-specific; however, their testing was confounded by concomitant measure ofluminance mechanisms. Studies with Gunkel's chromograph have suggested the existence ofcolor defects in optic neuritis not even mentioned by Kollner. Using this method, Chu and associates48 studied a large, heterogeneous group of patients with acquired diseases, including optic neuritis. Nine of 51 eyes from patients with multiple sclerosis showed sector defects in the orange area (ie, difficulty distinguishing orange from white). One eye had a sector defect in cyan, and 2 eyes had defects in turquoise. Thus, in this disparate group ofpatients with optic neuritis, the investigators concluded that there was an overall weakness in color discrimination; sector defects appeared in the yellow, orange, red, blue, cyan and turquoise regions. APPLICABILITY OF KOLLNER'S RULE IN PATIENTS WITH OPTIC NEURITIS
The results of our analysis of the ONTT data set and our review of the literature demonstrate that Kollner's rule is far from reliable in patients with optic neuritis; indeed, as suggested in a recent editorial,20 it ought not be applied to patients with optic neuritis. Our findings suggest that the type of dyschromatopsia identified in patients with optic neuritis depends on when, in the course of the disease, color vision is tested; moreover, the type of defect appears to be related to spatial vision at the time of the test, which suggests that some of the inconsistencies among earlier studies may stem from differences in visual acuity at the time of testing.
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DYSCHROMATOPSIA OF OPTIC NEURITIS: POSSIBLE EXPLANATIONS
How does one explain the dyschromatopsias of optic neuritis? Why do selective blue/yellow defects predominate during the acute phase and red/ green defects predominate after recovery? Marre'0 has suggested that all such defects in patients with optic nerve disease represent multiple stages of a single color-vision deficiency. Of three color defects - red, green, and blue - blue deficiency occurs earliest and is most pronounced. In the first stage, which is short-lived, there is an isolated deficiency of blue color vision; red/green vision is more normal, but there may be an overall loss of hue discrimination. In the second stage, which is considered a transitional one, both blue and green color vision mechanisms are disturbed. In the third stage, blue, green, and red color vision mechanisms are all disturbed, blue most severely, and hue discrimination is more drastically impaired. In the last stage, the most typical of optic neuropathies, reds and greens are preferentially affected. In support of the notion that color vision changes from the acute to the recovery phase in patients with optic neuritis, Wildberger,49 in his study of a heterogeneous group of 59 eyes with optic neuritis, found a tritan defect during the first week and a red/green defect during recovery. These results are similar to ours.
Spatial Organization The spatial organization of the visual defect may be the primary determinant ofwhether blue/yellow or red/green color defects occur in optic neuritis.10,50-52 Sensitivity to red/green light is constant throughout the central 20 of the visual field, whereas sensitivity to blue light is markedly reduced at the central fovea and increases in perifoveal regions.53 54 Physiologic observations in primate eyes support the concept that the density of blue cones in humans varies across the visual field.55 Thus, selective impairment of afferent channels serving the foveal region would likely prevent transmission of signals primarily from red/green cones, whereas impairment of the perifoveal region would disproportionately affect signals from blue cones.m This topographic disparity may explain why optic neuritis, which frequently impairs foveal function and reduces central visual acuity, has commonly been associated with red/green rather than blue/yellow defects. However, the region most affected by demyelination (and inflammation) in optic neuritis is variable and unpredictable; it could include or exclude the fovea and papillomacular bundle. Thus, it should not be surprising to find blue/yellow defects associated with acute optic neuritis. The results of high-selectivity quadrant analysis are consistent with this theory relating type of defect present to central acuity. The observation of more blue/yellow than red/ green defects acutely, when foveal function is most severely disturbed, remains unexplained. Thus the spatial organzation of the visual defect cannot be the sole determinant of the type of dyschromatopsia in patients with optic neuritis.
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Additional support linking the dyschromatopsia of optic neuritis to preferential spatial dysfunction comes from a study specifically designed to determine if color defects paralleled central field involvement. In a heterogeneous group of 28 patients (29 eyes) who had recovered from optic neuritis, Silverman and associates,52 used the FM-100 and automated threshold static perimetry to ascertain whether foveal involvement results in red/green color defects and perifoveal involvement results in blue-yellow defects. The FM100, analyzed as described by Smith and associates,33 showed red/green defects in 15 eyes and blue/yellow defects in 14. Twenty-two of the 29 eyes (76%) showed relative foveal impairment, and 7 (24%) showed relative foveal sparing. All 7 eyes with foveal sparing had blue/yellow defects, and eyes with foveal impairment generally had red/green defects. Statistical analysis using Pearson's correlation coefficient and Fisher's exact t test demonstrated a strong correlation between the spatial distribution of the visual field defect (foveal versus perifoveal) and the resulting dyschromatopsia (red/green versus blue/yellow).52 Large Versus Small Axons Another theory concerning color vision in patients with optic neuritis derives from the function and distribution oflarge and small axons in the optic nerve. 56 In primate optic nerve, small axons transmit color information, whereas large axons do not. Therefore, selective impairment of small axons would be expected to impair chromatic sensitivity; optic neuropathies that preferentially involve small axons would cause more severe dyschromatopsia than neuropathies that spare small axons.57 Smaller axons are concentrated at the fovea; larger axons are located extrafoveally.58 A loss of small axons would yield different color effects than loss of larger axons.57 Selective destruction of small and large axons versus destruction of foveal and perifoveal axons might also affect the type of color defect.57 A loss of foveal axons relative to perifoveal axons would not have much effect on blue/yellow color vision because the fovea is primarily tritanopic.53-55 However, a loss ofsmall axons relative to larger axons would be expected to decrease blue/yellow discrimination, because small axons have been reported to convey blue/yellow information.-5 To test a potential selective loss between small and large axons, Dain and associates,57 used color-mixture thresholds, contrast-sensitivity functions, and flicker modulation sensitivity to study a heterogeneous group of 10 subjects (15 eyes) who had recovered from optic neuritis. The sensitivity losses were nonselective in various ways: sensitivity loss was independent of spatial and temporal frequencies, chromatic (red/green and blue/yellow) and achromatic thresholds were elevated equally, and all losses proved to be similar in all tests administered. Dain and colleagues57 concluded that, generally, small and large axons are affected equally, as are foveal and perifoveal axons, in patients with optic neuritis.
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Our results suggest that at the time of the acute attack of optic neuritis, the majority of selective defects were blue/yellow defects, whereas at 6 months, more of the selective defects were red/green defects. Both types of defects, as well as nonselective defects, were seen acutely and at 6 months. Thus, despite the rigorous inclusion criteria of the ONTT, the large number of patients, correlation of color vision with visual acuity, and longitudinal follow-up, this study showed that no single type ofcolor defect was consistently associated with optic neuritis. Demyelinating optic neuritis does not obey Kollner's rule. Moreover, the type of defect changed in some patients over the course of recovery and thus may not even be consistent in individual patients as they recover. The type of defect appeared to the related to spatial vision at the time of the test, but the type of defect present at 6 months was not related to the severity of the initial visual loss. Therefore, in evaluating color defects associated with optic neuritis, the level of central vision function must be considered. Finally, we conclude that our understanding of optic neuritis and its clinical characteristics is, at best, rudimentary, worthy of both continuing investigation and periodic reevaluation.20 ACKNOWLEDGEMENTS
I wish to acknowledge the invaluable collaboration of Dr. Marilyn Schneck, whose enthusiastic efforts brought this work to fruition, as well as all the principal investigators and clinical centers of the Optic Neuritis Treatment Trial, who shared their raw data. I also wish to express my gratitude to Drs. Robert L. Stamper, William H. Spencer, and William F. Hoyt who continually show me by example what a career can be like, and I thank Drs. Arthur Jampolsky and Alan B. Scott for adopting me into their Smith-Kettlewell family, where much of this work was done. REFERENCES 1. Kollner H: Die Storungen des Farbensinnes: Ihre klinische Bedeutung and ihre Diag-
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8. Grutzner P: Acquired color vision defects secondary to retinal drug toxicity.
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color vision with Gunkel's chromagraph. Arch Ophthalmol 1983; 101:1232-1235. 49. Wildberger H: Neuropathies of the optic nerve and visual evoked potentials with special reference to color vision and differential light threshold measured with the computer perimeter OCTOPUS. Doc Ophthalmol 1984; 58 (2):147-227. 50. Hart WM, Burde RM: Color contrast perimetry: The spatial distribution of color defects in optic nerve and retinal diseases. Ophthalmology 1985; 92:768-776. 51. Hart WM: Acquired dyschromatopsias. Surv Ophthalmol 1987; 32:10-31. 52. Silverman SE, Hart WM Jr., Gordon MO, et al: The dyschromatopsia of optic neuritis as determined in part by the foveal/perifoveal distribution of visual field damage. Invest Ophthalmol Vis Sci 1991; 31:1895-1902. 53. Williams DR, MacLeod DI, Hayhoe MM: Foveal tritanopia. Vision Res 1981; 21:13411356. 54. Williams DR, MacLeod DI, Hayhoe MM: Punctate sensitivity ofthe blue-sensitive mecha-
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