To determine the magnitudes of binocular summation for low- and high-contrast letter acuity in a multiple sclerosis (MS) cohort, and to characterize the roles that MS disease, age, interocular difference in acuity, and a history of optic neuritis have on binocular summation. The relation between binocular summation and monocular acuities and vision-specific quality of life (QoL) was also examined.
Cross-sectional observational study.
Low-contrast acuity (2.5% and 1.25% contrast) and high-contrast visual acuity (VA) were assessed binocularly and monocularly in patients and disease-free controls at 3 academic centers. Binocular summation was calculated as the difference between the binocular and better eye scores. QoL was measured using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and the 10-item neuro-ophthalmic supplement. The relation of the degree of binocular summation to monocular acuity, clinical history of acute optic neuritis, age, interocular acuity difference, and QoL was determined.
Binocular summation was demonstrated at all contrast levels, and was greatest at the lowest level (1.25%). Increasing age ( P < .0001), greater interocular differences in acuity ( P < .0001), and prior history of optic neuritis ( P = .015) were associated with lower magnitudes of binocular summation; binocular inhibition was seen in some of these patients. Higher magnitudes of summation for 2.5% low-contrast acuity were associated with better scores for the NEI VFQ-25 ( P = .02) and neuro-ophthalmic supplement ( P = .03).
Binocular summation of acuity occurs in MS but is reduced by optic neuritis, which may lead to binocular inhibition. Binocular summation and inhibition are important factors in the QoL and visual experience of MS patients, and may explain why some prefer to patch or close 1 eye in the absence of diplopia or ocular misalignment.
Visual function, particularly as measured by low-contrast letter acuity, has been identified as an important component in the profile of patients with multiple sclerosis (MS). Low-contrast acuity is an easily administered quantitative measure that correlates well with overall visual dysfunction, quality of life (QoL), magnetic resonance imaging (MRI) lesion burden, and response to treatment in MS. In assessing contrast sensitivity in healthy patient cohorts, investigators have noted the presence of “binocular summation,” or improved vision under binocular viewing conditions, when compared to scores for either eye individually. However, the magnitude of binocular summation is not as great in patients with cataracts, advanced age, and amblyopia. Furthermore, in patients with large interocular differences in contrast sensitivity, there appears to be “binocular inhibition,” by which the contrast sensitivity score with both eyes together is worse than that of the better eye alone. The phenomena of binocular summation and inhibition are not well understood, but appear to be related to neural interactions of input from both eyes within the post-geniculate visual pathway.
Binocular low-contrast acuity has been used frequently as a visual outcome in MS trials. At the same time, monocular measurements have been introduced into MS trials with the inclusion of optical coherence tomography (OCT) scanning as a structural correlate to vision in MS. Since binocular and monocular acuities are likely complementary, it will be critical to know how these 2 types of measurements relate to each other, and to determine whether patients with MS have the capacity for binocular summation. For understanding visual function following optic neuritis, it would also be useful to know whether those patients with unilaterally poor vision demonstrate the phenomenon of binocular inhibition. In a study of 15 patients with MS and a history of unilateral optic neuritis, the majority showed evidence of binocular summation.
The purpose of our study was to determine the magnitude of binocular summation of acuity in patients with MS compared to that of disease-free control subjects, and to determine the impact that age, interocular difference in acuity, and a history of acute optic neuritis have on the magnitude of binocular summation. We also sought to examine how the magnitude of binocular summation relates to vision-specific quality of life and to individual eye acuities in patients with MS.
Patients and disease-free control subjects were enrolled as part of an ongoing prospective study of visual outcome measures in MS at the University of Pennsylvania, Johns Hopkins University, and the University of Texas Southwestern Medical Center at Dallas. MS was diagnosed by standard clinical and neuroimaging criteria.
A history of 1 or more episodes of acute optic neuritis was determined for eyes of patients with MS by self-report and physician diagnosis, and confirmed by medical record review. The diagnosis of a prior history of clinical optic neuritis was usually made in the presence of clinical symptoms consistent with optic neuritis (acute change in visual acuity with pain on eye movements, loss of color vision, afferent pupillary defect, or decreased contrast sensitivity) with a normal ophthalmology examination, or optic nerve edema. An MRI scan demonstrating optic nerve enhancement was useful but not essential for confirming the diagnosis. Patients were excluded if they had any comorbid ocular conditions that impacted visual acuity (ascertained by a detailed history and examination), or if they had acute optic neuritis within the previous 1 to 3 months. Patients were excluded if their Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) equivalent on the ETDRS chart was worse than 20/200 in either eye, because such poor vision precludes testing of low-contrast acuity. Disease-free control participants were recruited from staff and family members of patients, and were required to have had no history of ocular or neurologic disease. Controls were excluded if their VA was worse than 20/20 in either eye.
Visual Function Testing
After a distance refraction was performed, low-contrast acuity was tested with Sloan letter charts at 1.25% and 2.5% contrast levels positioned at 2 meters on a retroilluminated cabinet (Precision Vision, LaSalle, Illinois, USA) using the appropriate refractive correction. Sloan charts have a format similar to the ETDRS VA charts (5 letters per line), and each Sloan chart corresponds to a different contrast level. The low-contrast acuity score is the number of letters identified correctly, with a maximum score of 70 (14 lines). High-contrast visual acuity (VA) was tested using the ETDRS charts at 3.2 meters (Lighthouse Low-Vision Products, Long Island City, New York, USA) with the appropriate refractive correction. The VA score is also the number of letters identified correctly, with a maximum score of 70 (Snellen equivalent of 20/12.5). Each of the 3 acuity measures (2.5%, 1.25%, VA) were tested with both eyes together (binocular testing), and then for each eye individually (monocular testing). All testing was performed by trained technicians experienced in examination of patients for research studies. Technicians adhered to detailed standard protocols, including written scripts and instructions for testing.
For each participant and each contrast level, the difference between the binocular letter score and the monocular score for the better eye was calculated. This value was called the “magnitude of binocular summation” ( Table 1 ). If this value was less than 0, then this was defined as binocular inhibition .
|Acuity Score Term||Definition and Calculation|
|Monocular acuity score||Number of letters identified correctly using either eye separately|
|Better eye||Eye with greater score for high-contrast visual acuity (VA) based on number of letters identified correctly|
|Binocular acuity score||Number of letters identified correctly using both eyes together|
|Magnitude of binocular summation||Extent to which binocular acuity score is greater than monocular acuity score for better eye = binocular acuity score minus better eye acuity score|
|Binocular inhibition||Binocular acuity score is less than monocular acuity score for better eye|
The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was self-administered in all participants to assess self-reported, vision-specific QoL. The NEI VFQ-25, the standard QoL measure for ophthalmology clinical trials, consists of 12 sub-scales (general health, general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision); the composite score is generated as the unweighted average of all items, excluding the single item for general health. A 10-item neuro-ophthalmic supplement to the NEI VFQ-25 was also administered.
All data analyses were performed using Stata statistical software (version 11.0; StataCorp, College Station, Texas, USA). Groups were compared with respect to mean values for acuity scores and magnitudes of binocular summation using 2-sample t tests. To determine whether the magnitudes of binocular summation were significantly different from zero (and thus likely to represent true improvements of vision for binocular compared to monocular scores), a t test was also used comparing each group mean to the null value of 0; a 2-sided test was used as some patients showed binocular inhibition (magnitude of binocular summation <0). A type I error level α = 0.05 was used for statistical significance.
Evaluation of factors associated with the magnitude of binocular summation
Linear regression analyses were performed to assess the relation between the magnitude of binocular summation and MS vs control status (or optic neuritis vs non-optic neuritis history within the MS cohort), accounting for age. Similar models were constructed to account for interocular acuity differences and to determine their effects on magnitude of binocular summation.
Relation of binocular low-contrast acuity scores and magnitude of summation to monocular acuities
Also using linear regression models, we examined the relation of binocular low-contrast acuity scores and magnitude of summation to 1) better eye low-contrast acuity scores, 2) worse eye low-contrast acuity scores, and 3) average of low-contrast acuity scores for the 2 eyes.
Impact of interocular difference on binocular summation and inhibition
The proportions of patients demonstrating binocular summation and binocular inhibition were calculated for each patient subgroup. Test-retest variability for low-contrast acuity, defined as 2 standard deviations of the published inter-rater difference, is approximately 7 letters for MS and control subjects. For purposes of these analyses of proportions, the 7-letter cutoff was used to categorize patients as having binocular inhibition (magnitude of binocular summation ≤−7) or binocular summation (magnitude of summation ≥7). Subjects whose magnitudes of summation were >−7 and <7 were categorized as having neither binocular summation nor binocular inhibition. Proportions of patients demonstrating binocular summation or inhibition within patient groups were compared using the χ 2 test.
Relation of binocular acuity scores and magnitude of summation to quality of life
Linear regression analysis was used to determine whether greater magnitudes of binocular summation are associated with better composite and sub-scale scores for the NEI VFQ-25, accounting for age, interocular acuity difference, and high-contrast VA.
Among 1007 patients with MS and 324 disease-free control participants, the mean age of the 2 groups was similar (43 ± 11 years for MS and 40 ± 11 years for controls, P = .19). Within the MS group, 46% of patients had a prior history of acute optic neuritis.
The mean VA and low-contrast acuity scores for each patient group are summarized in Table 2 . All groups demonstrated evidence of binocular summation for each measure of visual function. Magnitudes of binocular summation were significantly different from zero for all groups ( P < .001, 1-sample t tests). The mean magnitude of binocular summation was greater at lower levels of contrast than at high contrast (4-7 letters vs 1 letter) in all groups.
|Visual Function Test||MS (n = 1007)||Disease-Free Controls (n = 324)||MS With No History of ON (n = 544)||MS With History of ON (n = 463)|
|Visual acuity (high-contrast)|
|Worse eye score||55 ± 14||61 ± 7||57 ± 11||52 ± 17|
|Better eye score||61 ± 9||64 ± 6||61 ± 8||60 ± 10|
|Binocular score||62 ± 8||66 ± 5||63 ± 7||61 ± 10|
|Magnitude of binocular summation a||1 ± 3||1 ± 2||1 ± 3||1 ± 3|
|P value b||<.001||<.001||<.001||<.001|
|Low-contrast acuity 2.5%|
|Worse eye score||24 ± 13||34 ± 8||27 ± 11||20 ± 14|
|Better eye score||32 ± 10||37 ± 7||33 ± 9||30 ± 12|
|Binocular score||36 ± 10||43 ± 6||38 ± 9||35 ± 11|
|Magnitude of binocular summation a||5 ± 4||5 ± 4||5 ± 4||4 ± 4|
|P value b||<.001||<.001||<.001||<.001|
|Low-contrast acuity 1.25%|
|Worse eye score||11 ± 11||23 ± 10||14 ± 11||9 ± 10|
|Better eye score||18 ± 11||27 ± 9||19 ± 11||17 ± 11|
|Binocular score||24 ± 11||34 ± 8||26 ± 11||22 ± 12|
|Magnitude of binocular summation a||6 ± 6||7 ± 5||7 ± 6||5 ± 6|
|P value b||<.001||<.001||<.001||<.001|
Magnitudes of Binocular Summation
Magnitudes of binocular summation for each patient group are summarized in the Figure . For VA and 2.5% low-contrast acuity, there were no significant differences between the MS cohort and controls. Within the MS cohort, there was no difference between patients with a history of optic neuritis and those with no history of optic neuritis, except at the lowest contrast level. Patients with optic neuritis summated less well than those without optic neuritis for the 1.25% contrast charts (difference of 5.3 ± 6 letters vs 7.0 ± 6 letters, P = .0001, 2-sample t tests).
Proportions of Patients With Binocular Summation and Inhibition Beyond Test-Retest Variability (Magnitude of Summation ≥7 Or ≤−7 Letters)
Less than 2% (14/1331 total study subjects for VA, 2/1331 total study subjects for 2.5% low contrast acuity, and 6/1331 total study subjects for 1.25% low contrast acuity) of patients had binocular inhibition ( Table 3 ). Most of the patients with binocular inhibition had interocular differences between 6 and 20 letters for VA and between 6 and 25 letters for low-contrast acuity. None of the 150 patients who had interocular acuity differences of >25 letters demonstrated binocular inhibition. The percentages of patients with binocular summation (binocular summation score ≥7) for high-contrast VA were less than 5% in all groups ( Table 3 ). The proportions with binocular summation were much higher for 2.5% low-contrast acuity (28%-31%) and 1.25% low-contrast acuity (29%-52%) compared to high-contrast testing. Within MS patients, those with a history of optic neuritis had a lower percentage with binocular summation on 1.25% low-contrast acuity than those without a history of optic neuritis ( P < .001).
|All MS (n = 1007)||Controls (n = 324)||MS Without a History of ON (n = 544)||MS With a History of ON (n = 463)|
|% binocular summation a||3.6% (2.5, 4.9)||3.0% (1.4, 5.6)||3.1% (1.8, 4.9)||4.2% (2.4, 6.3)|
|% binocular inhibition b||1.3% (0.7, 2.2)||0.4% (0.01, 1.7)||1.2% (0.5, 2.6)||1.4% (0.5, 2.8)|
|% binocular summation a||31% (28, 34)||31% (26, 36)||33% (29, 37)||28% (24, 32)|
|% binocular inhibition b||0.2% (0.02, 0.7)||0 (0, 1.1)||0.3% (0.04, 1.3)||0 (0, 8.0)|
|% binocular summation a||44% (41, 47)||49% (44, 55)||52% (48, 56)||29% (25, 33)|
|% binocular inhibition b||0.5% (0.16, 1.1)||0.4% (0.01, 1.7)||0.2% (0.004, 1.0)||0.9% (0.2, 2.0)|