Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

[1]  Laura J. Balcer,et al.  Ocular motor assessment in concussion: Current status and future directions , 2016, Journal of the Neurological Sciences.

[2]  Mengling Liu,et al.  The King-Devick test of rapid number naming for concussion detection: meta-analysis and systematic review of the literature , 2015, Concussion.

[3]  M. Puell,et al.  Repeatability of mesopic visual acuity measurements using high- and low-contrast ETDRS letter charts , 2015, Graefe's Archive for Clinical and Experimental Ophthalmology.

[4]  P. Calabresi,et al.  20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought? , 2016, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[5]  Deborah M. Miller,et al.  Vision in a Phase 3 Trial of Natalizumab for Multiple Sclerosis: Relation to Disability and Quality of Life , 2015, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[6]  Darrel Conger,et al.  Retinal damage and vision loss in African American multiple sclerosis patients , 2015, Annals of neurology.

[7]  Jerry L Prince,et al.  Relationships between quantitative spinal cord MRI and retinal layers in multiple sclerosis , 2015, Neurology.

[8]  David H. Miller,et al.  Vision and vision-related outcome measures in multiple sclerosis , 2014, Brain : a journal of neurology.

[9]  C. McCulloch,et al.  Magnetic resonance imaging correlates of clinical outcomes in early multiple sclerosis. , 2014, Multiple sclerosis and related disorders.

[10]  L. Balcer.  Clinical Trials to Clinical Use: Using Vision as a Model for Multiple Sclerosis and Beyond , 2014, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[11]  S. Galetta,et al.  The King–Devick (K–D) test of rapid eye movements: A bedside correlate of disability and quality of life in MS , 2014, Journal of the Neurological Sciences.

[12]  Shin C. Beh,et al.  Retinal architecture and mfERG , 2014, Neurology.

[13]  P. Calabresi,et al.  Monocular and binocular low-contrast visual acuity and optical coherence tomography in pediatric multiple sclerosis. , 2014, Multiple sclerosis and related disorders.

[14]  F. Paul,et al.  Relations of low contrast visual acuity, quality of life and multiple sclerosis functional composite: a cross-sectional analysis , 2014, BMC Neurology.

[15]  Fiona Costello,et al.  The Afferent Visual Pathway: Designing a Structural-Functional Paradigm of Multiple Sclerosis , 2013, ISRN neurology.

[16]  D. Arnold,et al.  Alemtuzumab improves visual outcomes in treatment-naïve patients with relapsing–/INS;remitting multiple sclerosis (RRMS): Analysis from the phase 3 CARE-MS I study , 2013, Journal of the Neurological Sciences.

[17]  Elena Garcia-Martin,et al.  Neuro-ophthalmologic evaluation, quality of life, and functional disability in patients with MS , 2013, Neurology.

[18]  Jesse Richman,et al.  Contrast sensitivity basics and a critique of currently available tests. , 2013, Journal of cataract and refractive surgery.

[19]  A. Conger,et al.  Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy , 2013, Neurology.

[20]  S. Galetta,et al.  Alemtuzumab improves contrast sensitivity in patients with relapsing–remitting multiple sclerosis , 2013, Multiple sclerosis.

[21]  P. Martinková,et al.  Assessment set for evaluation of clinical outcomes in multiple sclerosis: psychometric properties , 2012, Patient related outcome measures.

[22]  Shiv Saidha,et al.  Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. , 2012, JAMA neurology.

[23]  M. Crossland,et al.  Text Accessibility by People with Reduced Contrast Sensitivity , 2012, Optometry and vision science : official publication of the American Academy of Optometry.

[24]  Shin C. Beh,et al.  Multifocal visual evoked potentials are influenced by variable contrast stimulation in MS , 2012, Neurology.

[25]  F. Paul,et al.  Retinal Damage in Multiple Sclerosis Disease Subtypes Measured by High-Resolution Optical Coherence Tomography , 2012, Multiple sclerosis international.

[26]  C. Polman,et al.  Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS , 2012, Journal of the Neurological Sciences.

[27]  Hiroshi Ishikawa,et al.  Ganglion cell loss in relation to visual disability in multiple sclerosis. , 2012, Ophthalmology.

[28]  P. Calabresi,et al.  Visual Pathway Axonal Loss in Benign Multiple Sclerosis: A Longitudinal Study , 2012, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[29]  Jeffrey A Cohen,et al.  Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects , 2012, The Lancet Neurology.

[30]  Shiv Saidha,et al.  In vivo assessment of retinal neuronal layers in multiple sclerosis with manual and automated optical coherence tomography segmentation techniques , 2012, Journal of Neurology.

[31]  Laura J. Balcer,et al.  Vision in Multiple Sclerosis: The Story, Structure-Function Correlations, and Models for Neuroprotection , 2011, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[32]  P C M van Zijl,et al.  Diffusion Tensor Imaging of the Optic Nerve in Multiple Sclerosis: Association with Retinal Damage and Visual Disability , 2011, American Journal of Neuroradiology.

[33]  P. Calabresi,et al.  Retinal Ganglion Cell Layer Volumetric Assessment by Spectral-Domain Optical Coherence Tomography in Multiple Sclerosis: Application of a High-Precision Manual Estimation Technique , 2011, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[34]  S. A. Meyer,et al.  Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness , 2011, Multiple sclerosis.

[35]  Maureen G Maguire,et al.  One eye or two: a comparison of binocular and monocular low-contrast acuity testing in multiple sclerosis. , 2011, American journal of ophthalmology.

[36]  Gunter Loffler,et al.  The effects of visual degradation on face discrimination , 2011, Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians.

[37]  Jared M. Bruce,et al.  Visual Acuity Is Associated with Performance on Visual and Non-Visual Neuropsychological Tests in Multiple Sclerosis , 2011, The Clinical neuropsychologist.

[38]  S. Saidha,et al.  Cup to disc ratio by optical coherence tomography is abnormal in multiple sclerosis , 2011, Journal of the Neurological Sciences.

[39]  C. Pfueller,et al.  Impairment of contrast visual acuity as a functional correlate of retinal nerve fibre layer thinning and total macular volume reduction in multiple sclerosis , 2011, British Journal of Ophthalmology.

[40]  M. Freedman,et al.  Using retinal architecture to help characterize multiple sclerosis patients. , 2010, Canadian journal of ophthalmology. Journal canadien d'ophtalmologie.

[41]  Javad Heravian Shandiz,et al.  Contrast Sensitivity versus Visual Evoked Potentials in Multiple Sclerosis , 2010, Journal of ophthalmic & vision research.

[42]  G. Ying,et al.  Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis , 2010, Annals of neurology.

[43]  Bin Zhang,et al.  Assessing visual pathway function in multiple sclerosis patients with multifocal visual evoked potentials , 2009, Multiple sclerosis.

[44]  P. Calabresi,et al.  Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. , 2009, Archives of neurology.

[45]  Eliza M. Gordon-Lipkin,et al.  Damage to the optic radiation in multiple sclerosis is associated with retinal injury and visual disability. , 2009, Archives of neurology.

[46]  Amy Conger,et al.  Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: A pilot study , 2009, Journal of the Neurological Sciences.

[47]  M. Freedman,et al.  Differences in retinal nerve fiber layer atrophy between multiple sclerosis subtypes , 2009, Journal of the Neurological Sciences.

[48]  P. Calabresi,et al.  Retinal architecture predicts pupillary reflex metrics in MS , 2009, Multiple sclerosis.

[49]  A. J. Thompson,et al.  Assessing structure and function of the afferent visual pathway in multiple sclerosis and associated optic neuritis , 2009, Journal of Neurology.

[50]  M. Maguire,et al.  Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity , 2009, Journal of Neurology, Neurosurgery, and Psychiatry.

[51]  Amy Conger,et al.  Retinal imaging by laser polarimetry and optical coherence tomography evidence of axonal degeneration in multiple sclerosis. , 2008, Archives of neurology.

[52]  E. D. Schwartz,et al.  Relation of vision to global and regional brain MRI in multiple sclerosis , 2007, Neurology.

[53]  Eliza M. Gordon-Lipkin,et al.  Optical coherence tomography and disease subtype in multiple sclerosis , 2007, Neurology.

[54]  N. Bressler,et al.  Visual acuity as an outcome measure in clinical trials of retinal diseases. , 2007, Ophthalmology.

[55]  N. Miller,et al.  Peripapillary Nerve Fiber Layer Thickness Measured by Optical Coherence Tomography in Patients With No Light Perception From Long-Standing Nonglaucomatous Optic Neuropathies , 2007, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[56]  L. Kappos,et al.  Natalizumab reduces visual loss in patients with relapsing multiple sclerosis , 2007, Neurology.

[57]  E. Bass,et al.  Evaluation of Minimum Clinically Meaningful Changes in Scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST Report Number 19 , 2007, Ophthalmic epidemiology.

[58]  M. Maguire,et al.  Validation and test characteristics of a 10-item neuro-ophthalmic supplement to the NEI-VFQ-25. , 2006, American journal of ophthalmology.

[59]  Fiona Costello,et al.  Quantifying axonal loss after optic neuritis with optical coherence tomography. , 2006, Annals of neurology.

[60]  C. Westall,et al.  Utility of the National Eye Institute VFQ-25 questionnaire in a heterogeneous group of multiple sclerosis patients. , 2006, American journal of ophthalmology.

[61]  Beatriz Muñoz,et al.  Measures of visual function and their association with driving modification in older adults. , 2006, Investigative ophthalmology & visual science.

[62]  Gary R Cutter,et al.  Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. , 2006, Ophthalmology.

[63]  Stephen J. Jones,et al.  Retinal nerve fiber layer axonal loss and visual dysfunction in optic neuritis , 2005, Annals of neurology.

[64]  R. Rudick,et al.  Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis , 2005, Neurology.

[65]  M. Maguire,et al.  Contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite , 2003, Neurology.

[66]  R. Rudick,et al.  Pattern reversal visual evoked potentials as a measure of visual pathway pathology in multiple sclerosis , 2003, Multiple sclerosis.

[67]  Fred W Fitzke,et al.  How sensitive to clinical change are ETDRS logMAR visual acuity measurements? , 2003, Investigative ophthalmology & visual science.

[68]  M. Maguire,et al.  Self-reported visual dysfunction in multiple sclerosis: new data from the VFQ-25 and development of an MS-specific vision questionnaire. , 2002, American journal of ophthalmology.

[69]  A. Antal,et al.  The paracentral visual field in multiple sclerosis: evidence for a deficit in interneuronal spatial summation? , 2001, Vision Research.

[70]  Jan E. Lovie-Kitchin,et al.  Repeatability and Intercorrelations of Standard Vision Tests as a Function of Age , 2000, Optometry and vision science : official publication of the American Academy of Optometry.

[71]  M. Maguire,et al.  New low-contrast vision charts: reliability and test characteristics in patients with multiple sclerosis , 2000, Multiple sclerosis.

[72]  P. Cavanagh,et al.  Stair Negotiation in Older People: A Review , 2000, Journal of the American Geriatrics Society.

[73]  S. Cole,et al.  The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Optic Neuritis Treatment Trial. , 2000, Investigative ophthalmology & visual science.

[74]  F Pierelli,et al.  Correlation between morphological and functional retinal impairment in multiple sclerosis patients. , 1999, Investigative ophthalmology & visual science.

[75]  S. Reingold,et al.  The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment , 1999, Multiple sclerosis.

[76]  S J Leat,et al.  What is low vision? A re-evaluation of definitions. , 1999, Optometry and vision science : official publication of the American Academy of Optometry.

[77]  K. Landau.  Visual symptoms after optic neuritis: results from the Optic Neuritis Treatment Trial. , 1998, Survey of ophthalmology.

[78]  Christian Confavreux,et al.  Recommendations from the national multiple sclerosis society clinical outcomes assessment task force , 1997, Annals of neurology.

[79]  Christian Confavreux,et al.  Clinical outcomes assessment in multiple sclerosis , 1996, Annals of neurology.

[80]  J D Trobe,et al.  Contrast sensitivity and other vision tests in the optic neuritis treatment trial. , 1996, American journal of ophthalmology.

[81]  S. Whittaker,et al.  Visual Requirements for Reading , 1993, Optometry and vision science : official publication of the American Academy of Optometry.

[82]  G. Legge,et al.  Psychophysics of reading. VI—The role of contrast in low vision , 1989, Vision Research.

[83]  C. Owsley,et al.  Contrast sensitivity, acuity, and the perception of 'real-world' targets. , 1987, The British journal of ophthalmology.

[84]  D Regan,et al.  Low-contrast letter charts in early diabetic retinopathy, ocular hypertension, glaucoma, and Parkinson's disease. , 1984, The British journal of ophthalmology.

[85]  J. Nelson,et al.  Contrast sensitivity loss in multiple sclerosis. Selectivity by eye, orientation, and spatial frequency measured with the evoked potential. , 1984, Investigative ophthalmology & visual science.

[86]  J. Kurtzke.  Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[87]  F. Ferris,et al.  New visual acuity charts for clinical research. , 1982, American journal of ophthalmology.

[88]  I. Bailey,et al.  Visual Factors and Orientation‐Mobility Performance , 1982, American journal of optometry and physiological optics.

[89]  R. Sekuler,et al.  Aging and low-contrast vision: face perception. , 1981, Investigative ophthalmology & visual science.

[90]  I. Bodis-Wollner,et al.  Detection of Visual Defects Using the Contrast Sensitivity Function , 1980, International ophthalmology clinics.

[91]  I. Bodis-Wollner,et al.  The measurement of spatial contrast sensitivity in cases of blurred vision associated with cerebral lesions. , 1976, Brain : a journal of neurology.

[92]  I L Bailey,et al.  New Design Principles for Visual Acuity Letter Charts* , 1976, American journal of optometry and physiological optics.

[93]  C. Adler,et al.  Abnormal visual contrast acuity in Parkinson's disease. , 2015, Journal of Parkinson's disease.

[94]  L. Balcer,et al.  Optical Coherence Tomography in Neurologic Diseases: Optical coherence tomography and low-contrast acuity , 2015 .

[95]  P. Calabresi,et al.  Optical coherence tomography in neurological diseases , 2015 .

[96]  R. Sergott.  Early Factors Associated with Axonal Loss after Optic Neuritis , 2012 .

[97]  R. Marrie,et al.  Validation of the NARCOMS Registry: Tremor and Coordination Scale. , 2011, International journal of MS care.

[98]  R. Sergott,et al.  Visual function 15 years after optic neuritis: a final follow-up report from the Optic Neuritis Treatment Trial. , 2008, Ophthalmology.

[99]  M. Brodsky,et al.  Visual function more than 10 years after optic neuritis: experience of the optic neuritis treatment trial. , 2004, American journal of ophthalmology.

[100]  J. Szlyk,et al.  Perceived and actual performance of daily tasks: relationship to visual function tests in individuals with retinitis pigmentosa. , 2001, Ophthalmology.

[101]  Susan J Leat,et al.  The validity of current clinical tests of contrast sensitivity and their ability to predict reading speed in low vision , 1997, Eye.

[102]  David B Elliott,et al.  Comparing clinical tests of visual function in cataract with the patient's perceived visual disability , 1990, Eye.

[103]  Denis G. Pelli,et al.  THE DESIGN OF A NEW LETTER CHART FOR MEASURING CONTRAST SENSITIVITY , 1988 .

[104]  D Regan,et al.  Visual acuity and contrast sensitivity in multiple sclerosis--hidden visual loss: an auxiliary diagnostic test. , 1977, Brain : a journal of neurology.