REVIEW URRENT C OPINION

An update on neuro-ophthalmology of multiple sclerosis: the visual system as a model to study multiple sclerosis Sara S. Qureshi a, Shin C. Beh a, Teresa C. Frohman a, and Elliot M. Frohman a,b

Purpose of review The purpose of this review is to familiarize the reader with the landscape of current neuro-ophthalmology research in the field of multiple sclerosis and to highlight important findings, directions of future research and advances in the clinical management of visual and ocular motor manifestations of multiple sclerosis. Recent findings Research pertaining to the visual system in multiple sclerosis has identified new biomarkers of disease and is contributing to a better understanding of disease mechanisms. Progress has been made in the symptomatic management of visual manifestations of multiple sclerosis and visual outcome measures are now being included in clinical trials, with important quality of life ramifications. Perhaps the most prominent contribution from neuro-ophthalmology research in multiple sclerosis has been the establishment of the visual system as a model to study disease pathogenesis, and for the systematic, objective, and longitudinal detection and monitoring of protective and restorative neurotherapeutic strategies. The emergence of these sophisticated capabilities has been in large part due to the application of high speed, high definition, and objective methods for the elucidation of both the structure and function of visual system networks. Summary Advances in neuro-ophthalmology research in multiple sclerosis have led to the establishment of the visual system as a model to objectively study disease pathogenesis, and for the identification of novel neurotherapeutic capabilities. With the prospects of myelin repair and neuroprotective agents increasingly becoming recognized as achievable goals, the validation and utility of new visual outcome measures quantifying changes in axonal integrity, myelin protection, and repair will likely prove invaluable. Keywords internuclear ophthalmoplegia, multiple sclerosis, ocular motor, optic neuritis, visual

INTRODUCTION ‘Shortly after the funeral I was obliged to have my letters read to me, and their answers written for me as my eyes were so attacked that when fixed upon minute objects indistinctness of vision was the consequence. . . .Soon after, I went to Ireland, and without anything having been done to my eyes, they completely recovered.’ Augustus d’Este (1822–1844). This early account, by the grandson of King George III, of a disorder we would recognize today as classic multiple sclerosis, conspicuously illustrates for us that visual symptoms are common and often the earliest manifestations of multiple sclerosis. It would be much later in 1868, when the French neurologist Jean-Martin Charcot would coin the term ‘scle´rose en plaques’ to describe this disease [1–3]. www.co-neurology.com

Multiple sclerosis, now known to be a leading cause of disability in young adults, affects about 300 000 people in the United States alone [4]. A broad spectrum of visual disturbances spanning both the visual sensory and ocular motor systems has been identified as a consequence of multiple sclerosis. We now know that acute optic neuritis (AON) affects at least half the patients with multiple sclerosis, and is the initial event in about 15–20% of a Department of Neurology and bDepartment of Ophthalmology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA

Correspondence to Dr Elliot M. Frohman, MD, 5323 Harry Hines Blvd, Dallas, TX 75390-8806, USA. Tel: +1 214 645 0555; e-mail: elliot. [email protected] Curr Opin Neurol 2014, 27:300–308 DOI:10.1097/WCO.0000000000000098 Volume 27  Number 3  June 2014

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Neuro-ophthalmology of multi ple sclerosis Qureshi et al.

KEY POINTS  Neuro-ophthalmology research in multiple sclerosis has established the visual system as a model to study disease pathogenesis and for the identification of novel therapeutic agents.  New biomarkers of disease pertaining to the visual system are being identified and visual outcome measures are now being included in clinical trials.  Advances are being made in the symptomatic management of visual and ocular motor manifestations of multiple sclerosis.

patients [5,6]. There is increasing evidence, mainly from visual evoked potential (VEP) studies traditionally, and more recently from optical coherence tomography (OCT) studies, to support the presence of sub-clinical or chronically dynamic forms of optic neuropathy in multiple sclerosis patients. Distinction of acute from chronic forms of optic neuropathy in multiple sclerosis is important; confirmation of breakthrough disease activity in the former circumstance may provoke transition to a new disease-modifying therapy [7]. The most commonly recognized efferent, ocular motor manifestations of multiple sclerosis include internuclear ophthalmoparesis (INO), nystagmus, and saccadic dysmetria. Not all visual symptoms in multiple sclerosis patients are manifestations of AON. Intermediate uvietis (pars planitis), an immune-mediated disorder that can resemble AON, occurs more frequently in multiple sclerosis patients, and may precede or follow the diagnosis of multiple sclerosis [8]. Also seen are age-related visual system changes: cataract formation, advancing myopia, presbyopia, astigmatism, and anisometropia. Alternately, medications can result in visual symptoms that are reminiscent of multiple sclerosis. For instance, fingolimod can cause a reversible macular edema in 0.5–1% of patients, most commonly occurring around 3 months after initiating therapy, and often characterized by metamorphopsias. Chronic use of steroids may predispose to cataracts and glaucoma. Amantadine, utilized for the management of fatigue, may rarely cause blurred vision. Never to be overlooked is the possibility that progressive multifocal leukoencehalopathy, a potentially fatal complication of natalizumab therapy in multiple sclerosis, can present with visual disturbances, most typically in a pattern that implicates the retrochiasmal visual pathways [4,7,9 ,10]. The purpose of this review is to familiarize the reader with the landscape of current neuroophthalmology research in the field of multiple &

sclerosis, and to highlight important findings and directions of future research. Research pertaining to the visual system in multiple sclerosis has identified new biomarkers of disease and is contributing to a better understanding of disease mechanisms. Progress has been made in the symptomatic management of visual manifestations of multiple sclerosis and visual outcome measures are now being included in clinical trials, with important quality of life ramifications. Perhaps the most prominent contribution from neuro-ophthalmology research in the field of multiple sclerosis has been the establishment of the visual system as a model to study disease pathogenesis, and for the systematic, objective, and longitudinal detection and monitoring of protective and even restorative neurotherapeutic strategies. The emergence of these sophisticated capabilities has been in large part due to the application of high speed, high definition, and objective methods for the elucidation of both the structure and function of visual system networks.

THE VISUAL SYSTEM AS A MODEL TO STUDY MULTIPLE SCLEROSIS: STRUCTURE FUNCTION CORRELATION The visual system, an accessible and frequently affected part of the central nervous system (CNS) in multiple sclerosis, is amenable to non-invasive structure and function testing; these features make it an ideal model for studying disease pathogenesis and novel therapeutics.

UPDATES ON FUNCTIONAL ANALYSIS OF THE VISUAL SYSTEM Traditional measures of function of the afferent visual system include high-contrast visual acuity, Humphrey visual fields, zVEPs [11] and electroretinography (ERG). More recently, multifocal VEP (mfVEP) [12,13] and multifocal ERG (mfERG) have been introduced as more sensitive measures of visual function, expanding global summed responses of the entire field in the former, and of the entire retina in the latter, to an impressive array of localized responses that facilitate the detection of parochial physiologic derangements, which would not have been identified upon traditional assessments. The application of a low contrast, patternreversal method to conventional VEP promised to be a refinement in cortical response sensitivity and specificity [14]. Further, a recent study [15 ] established that mfVEP response timing and magnitude are also influenced by variable contrast stimulation (Fig. 1). This study confirmed the hypothesis that multiple sclerosis patients with inter-eye asymmetry

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(a)

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FIGURE 1. (a–c) Multifocal visual evoked potential (mfVEP) responses in the right (red) and left (blue) eyes from a normal subject at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast, pattern-reversal stimulation. The waveforms derived from the two eyes are superimposed with near-complete coregistration. (d–f) mfVEP cortical responses from a patient with a history of left optic neuritis. With low-contrast stimulation, there is a corresponding prolongation in the timing responses of the visual cortical responses in the left eye (blue), most prominently illustrated by the central field clusters within the green boxes. Further, at very low-contrast stimulation (f), both timing response prolongation and amplitude attenuation are observed. These findings are in keeping with the established pathophysiologic principles of multiple sclerosis-related demyelination. Reproduced from [15 ]. &

on low contrast visual acuity (LCVA) and retinal nerve fiber layer (RNFL) thickness exhibit predicted side-to-side differences on variable-contrast, patternreversal mfVEP. Furthermore, unmasking of occult abnormalities in a significant number of ‘apparently unaffected eyes’ was observed, indicating that mfVEP with variable contrast stimulation is an extremely sensitive measure of visual function, as well as a means by which to identify localized pathophysiologic signatures associated with disease related tissue injury. If confirmed by larger studies, this could establish mfVEP with variable-contrast stimulation as an exquisitely sensitive and specific measure of visual function, and a promising outcome measure in trials of neuroprotective and remyelinating agents [15 ]. Another study [16 ] showed that that the mfERGderived optic nerve head component (ONHC) waveform was found to be abnormal in multiple sclerosis patients, particularly in eyes previously affected by AON (Fig. 2). Although almost all patients recover highcontrast visual acuity following AON, many have deficits in LCVA [17,18]. LCVA has been shown to significantly correlate with OCT-measured RNFL &

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thinning, MRI lesion burden and atrophy, and VEP abnormalities [19–23]. It has been established as a reliable outcome measure in several multiple sclerosis trials including the AFFIRM trial of natalizumab [24 ] and more recently alemtuzumab [25 ]. &

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UPDATES ON STRUCTURAL ANALYSIS OF THE VISUAL SYSTEM Improved OCT technology (high-speed, high-definition, spectral-domain OCT) with automated segmentation, and scanning laser polarimetry (SLP) with variable corneal compensation allow validated, reproducible, and high-resolution analysis of retinal architecture, providing new biomarkers of disease such as RNFL, macular, and ganglion cell/inner plexiform (GCIP) layer thickness [26–30] (Fig. 3). OCT and SLP reveal different aspects of RNFL changes associated with optic nerve head swelling. OCT reveals thickening due to edema (using interference patterns of backscattered near-infrared light), whereas SLP reveals a decrease in retardance or birefringence (a property dependent on integrity of axon microtubules and neurofilaments) in eyes with axonal injury associated with visual field loss, Volume 27  Number 3  June 2014

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Retinal layers Retinal nerve fiber layer

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Stimulated retinal patch Retinal component Optic nerve head component Disrupted optic nerve head component

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Oligodendrocyte Membrane conduction along demyelinated axonal segment Demyelinated axons Myelin sheath Node of ranvier

Myelin sheath Oligodendrocyte Axon Saltatory axonal conduction Node of ranvier Retinal component Waveform Optic nerve head component waveform

Unmyelinated retinal nerve fibers Lamina cribrosa Myelinated axons of the optic nerve Central retinal artery

Retinal component waveform Absent optic nerve head component waveform

FIGURE 2. By using two interleaved global flashes in the multifocal electroretinography stimulation protocol, two induced waveforms are evoked – the retinal component and the optic nerve head component (ONHC). The waveform is believed to be derived from the activity of various cells at the retinal patch being stimulated. However, the ONHC is hypothesized to be generated at the region of the optic nerve head as the action potential travels from the stimulated retinal region to the optic nerve head, and transforms from membrane to saltatory conduction, as retinal ganglion cell axons traverse the lamina cribrosa and acquire myelin. Any disorder that affects the integrity of the retinal ganglion cells, their axons, or the acquisition of myelin in the retrolaminar region may result in ONHC abnormalities. If validated, by larger studies, as a measure of visual function, and perhaps a ‘signature of myelination’, the ONHC response may provide important insights into disease mechanisms and form an invaluable outcome measure in the evaluation of myelin repair or neuroprotective therapies. Reproduced from [16 ]. &

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which is unlikely to recover [31 ]. SLP reveals the status of axon integrity and visual prognosis, whereas OCT is relatively insensitive for revealing acute axon damage at the time of presentation or even 1 month later. This is because any RNFL thinning resulting from axonal loss takes time to develop and even if present may be confounded by edema [32]. Vision loss at 1 month after AON correlates with visual deficits at 6 months. A recent study by Kupersmith et al. [33 ] confirmed that RFNL thinning at 1 month, as measured by OCT and SLP, predicts RNFL loss at 6 months in patients with acute anterior ischemic optic neuropathy. This established the importance of the 1-month &

time point for predicting the outcome of an AON attack [33 ]. It will be interesting to see whether future longitudinal studies of AON will confirm SLP to be superior to OCT in predicting visual prognosis. &

RETINA: A MODEL TO STUDY NEURODEGENERATION The retina, as opposed to the optic nerve and medial longitudinal fasciculus, is a unique part of the CNS in that it contains axons and glia, while being devoid of myelin. This makes the retina an ideal system from which to dissect the mechanisms of axonal degeneration, as opposed to demyelination

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Patient: Patient ID:

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FIGURE 3. Optical coherence tomography scan from patient at University of Texas Southwestern with unilateral optic neuritis affecting the left eye. (a) Images of the optic disc centered on the scan target, (b) corresponding images of the retinal layers with automated segmentation of RNFL, (c) the distribution of RNFL thickness circumferentially around the retina compared with normative database (note the characteristic increased thickness of the superior and inferior quadrants), (d) RNFL thickness by quadrants and (e) RNFL thickness by sectors, both compared to normative database. G, global average; I, inferior; N, nasal; OCT, optical coherence tomography; OD, right eye; OS, left eye; RNFL, retinal nerve fiber layer; S, superior; T, temporal.

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[9 ]. Loss of GCIP and of RNFL thickness, validated biomarkers of disease activity in multiple sclerosis, are being used as outcome measures in clinical trials and are providing insights into disease mechanisms. Although the pathogenesis of multiple sclerosis is thought to involve histopathological facets of both inflammation and degeneration, the degree to which neurodegeneration is a consequence of inflammation remains unknown. Current multiple sclerosis therapies appear to provide some degree of secondary neuroprotection by reducing the incidence and severity of new lesions and clinical exacerbations. However, the effect of these agents on the mechanisms that principally determine axonal and neuronal degeneration in the absence of active inflammation remains enigmatic. Even with the most effective therapies utilized in patients exhibiting no evidence of clinical exacerbations or MRI activity, some degree of brain atrophy and neurodegeneration continues. This supports the existence of alternate neurodegenerative mechanisms, making it crucial to identify outcome measures for studies evaluating potential primary neuroprotective agents [34 ]. Ratchford et al. [35 ] published a large, prospective, longitudinal study analyzing the effect of clinical and radiologic disease activity on the rate of thinning of GCIP and RNFL, as measured by OCT. Non-ocular disease activity was hypothesized to be associated with neuroaxonal damage, translating into more rapid thinning of the RNFL and GCIP layers. These investigations confirmed that patients with clinical or radiologic nonocular disease activity, particularly early in the disease course, exhibited accelerated GCIP thinning. Hence, retinal changes in multiple sclerosis reflect global CNS processes and OCT-derived GCIP thickness may have utility as an outcome measure for assessing neuroprotective agents within the eye, the local effects of which may be more broadly generalized to the CNS. Traditional clinical and radiologic outcome measures will be of limited use in clinical trials evaluating primary neuroprotective therapies. Clinical disability measures and measures of neuronal degeneration (RNFL and GCIP layer thickness) will likely be used [34 ,35 ,36]. Indeed, in an ongoing phase IV trial of neuroprotection with adrenocorticotropic hormone (ACTH) in AON, outcome measures include OCT-derived RNFL and GCIP layer thickness. (www.clinicaltrials.gov; NCT01838174). Saidha et al. [37 ] recently showed that increased inner nuclear layer (INL) thickness as measured by OCT is associated with disease severity in multiple sclerosis. If this finding is confirmed, INL thickness &

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with or without accompanying microcystic macular edema may be established as a useful predictor of disease progression in multiple sclerosis [37 ]. &

INTERNUCLEAR OPHTHALMOPARESIS AND OPTIC NEURITIS: STRUCTURE FUNCTION CORRELATION MODELS OCT and mfVEPs in optic neuritis and highprecision oculography along with sensitive MRI techniques to interrogate the medial longitudinal fasciculus in INO makes accurate structure and function analysis possible. Optic neuritis and INO are unique models of myelinated systems within the CNS that facilitate the study of disease mechanisms and evaluation of potential agents for symptom management, myelin repair, and neuroprotection [9 ]. &

STRUCTURE AND FUNCTION CORRELATION IN THE VISUAL SYSTEM: A MODEL TO EVALUATE NEUROTHERAPEUTICS Employing the visual system as a model to evaluate neurotherapeutics has important implications now that potential remyelinating and neuroprotective agents may be just over the horizon.

Remyelination Anti-LINGO-1, a human monoclonal antibody, currently in phase II trials, is a potential remyelinating agent targeting LINGO-1, a CNS protein that serves to developmentally arrest oligodendrocyte progenitors (www.clinicaltrials.gov; NCT01244139). Deshmukh et al. [38 ] showed through various in-vitro and in-vivo animal studies that benztropine, a well established treatment for Parkinson’s disease, promotes oligodendrocyte differentiation in vitro, and remyelination in vivo in animal models of multiple sclerosis. &

Neuroprotection A phase IV trial of neuroprotection with ACTH in AON is currently ongoing, to evaluate potential melanocortin-mediated anti-inflammatory effects of ACTH, that may reduce axonal loss. Effects of ACTH and intravenous methylprednisolone therapy on axonal injury following AON will be compared. The primary outcome measure is average RNFL thickness at 6 months, while the secondary outcome measure is RNFL swelling at 1 and 3 months. Tertiary outcomes include changes in mfVEP, ONHC responses, and pupillary response metrics.

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A predefined exploratory outcome is GCIP thickness at 6 months (www.clinicaltrials.gov; NCT01838174). Future research of myelin repair and neuroprotective agents will undoubtedly involve the application of the INO and optic neuritis models. Elucidating cases with ‘axon preservation’ (which may benefit from myelin repair) from those with ‘axon involvement’ (requiring reconstitution of axon circuitry before myelin repair) may become relevant.

probes) and improves with cooling. Further, 4aminopyridine (4-AP), a potassium channel blocker, prolongs action potential duration and enhances the fidelity of conduction in segmentally demyelinated axons [39] (Fig. 4) [40]. Using this model of Uhthoff’s phenomenon, pilot studies are currently underway to determine whether the combination of active body cooling and 4-AP is superior to either treatment strategy alone in mitigating the visual manifestations of multiple sclerosis that worsen with a rise in body temperature [41,42,43 ]. &

MODELING UHTHOFF’S PHENOMENON TO STUDY POTENTIAL THERAPEUTIC AGENTS Research shows that adduction velocity slowing in multiple sclerosis-related INO worsens with increases in core body temperature (utilizing tubelined water infusion suits and ingestible temperature

ADVANCES IN SYMPTOMATIC MANAGEMENT OF VISUAL DISTURBANCES Although the search for new disease-modifying agents continues, it is equally important to focus

Uhthoff’s phenomenon: pathophysiologic ion channel mechanisms Core temperature > 98°f–99°f Na+ channel failure

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FIGURE 4. Underlying mechanisms and potential treatment interventions for Uhthoff’s phenomenon. (a) Elevation in core body temperature with underlying axonal demyelination results in pore closure of voltage-gated sodium channels, compromising action potential depolarization. Furthermore, segmental demyelination unmasks an increased density of potassium channels with a high predilection for current leak via potassium efflux. (b) Active cooling and 4-aminopyridine (4-AP), a broad spectrum potassium channel blocker which reduces potassium efflux, improve action potential fidelity and duration respectively. Studies are underway to establish if a combination of active cooling and 4-AP is superior to either treatment strategy alone in mitigating the effects of Uhthoff’s phenomenon. Reproduced from [40].

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on better symptom management strategies. Down beat nystagmus (DBN), the most frequent form of acquired persisting nystagmus, can be seen in multiple sclerosis [9 ] and has previously been shown to be mitigated by the use of the potassium channel antagonists [44,45]. Chlorzoxazone (CHZ), a non-selective activator of calcium-activated potassium channels, is already approved as a centrally acting agent for muscle spasms [46,47]. A recent proof-of-concept study provided Class IV evidence that CHZ may improve eye movements and visual fixation in patients with DBN [48 ]. A randomized, double-blinded trial of 4-AP for DBN confirmed reduction in slow-phase eye velocity, along with improved near acuity, in addition to some locomotor parameters. Older patients, in particular, benefit from the effects of 4-AP on nystagmus and postural stability [49 ]. Following an episode of AON, LCVA may remain impaired, producing difficulty with edge detection, night vision, stereopsis, and motion detection. This is further compromised with Uhthoff’s phenomena [41,42]. A randomized, placebo-controlled study analyzed the effect of 4-AP on vision in patients with multiple sclerosis-related optic neuropathy. It provided Class IV evidence supporting the use of 4-AP in certain patients (with RNFL thickness between 60 and 80 nm) to improve visual parameters. Future clinical trials should employ RNFL thickness measures as part of inclusion/exclusion criteria [43 ].

instead of TPE for steroid-refractory optic neuritis [52 ]. &

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MANAGEMENT OF ACUTE OPTIC NEURITIS: AN UPDATE The optic neuritis treatment trial showed that highdose intravenous methylprednisolone followed by prednisone taper hastens the recovery of vision and delays the onset of clinically definite multiple sclerosis [50 ]. ACTH is approved for AON in patients who are unable to tolerate methylprednisolone [51]. As mentioned previously, a phase IV trial of neuroprotection with ACTH in AON is currently underway (www.clinicaltrials.gov; NCT01838174). Treatment options for steroid-refractory demyelinating optic neuritis include a second round of high-dose steroids, therapeutic plasma exchange (TPE), or intravenous immunoglobulin (IVIG) [50 ]. Studies analyzing the efficacy of IVIG have shown mixed results [52 ]. A case series of TPE for steroid-refractory optic neuritis provided evidence that TPE can be associated with good outcomes [53,54 ]. A recent prospective study of eleven patients suggested that immunoadsorption, which is associated with fewer allergic reactions, may be used &

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CONCLUSION Advances in neuro-ophthalmology research in the field of multiple sclerosis have led to the establishment of the visual system as a model to study disease pathogenesis and evaluate novel therapeutics. With myelin repair and neuroprotective strategies potentially over the horizon, visual outcome measures quantifying changes in axon integrity and myelin repair will likely prove invaluable for clinical trials. Acknowledgements None. Conflicts of interest There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Charcot J. Histologie de la scle´rose en plaques. Gazette des hopitaux. Paris 1868; 41:554–555. 2. Landtblom AM, Fazio P, Fredrikson S, et al. The first case history of multiple sclerosis: Augustus d’Este´ (1794–1848). Neurol Sci 2010; 31:29–33. 3. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci 2009; 1:277. 4. Graves J, Balcer LJ. Eye disorders in patients with multiple sclerosis: natural history and management. Clin Ophthalmol 2010; 4:1409–1422. 5. Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol 2005; 139:1101–1108. 6. McDonald WI, Barnes D. The ocular manifestations of multiple sclerosis I: abnormalities of the afferent visual system. J Neurol Neurosurg Psychiatr 1992; 55:747–752. 7. Zein G, Berta A, Foster CS. Mutiple sclerosis-associated uveitis. Ocul Immunol Inflamm 2004; 12:137–142. 8. Frohman EM, Frohman TC, Zee DS, et al. Neuroophthalmology of multiple sclerosis. Lancet Neurol 2005; 4:111–121. 9. Bermel RA, Balcer LJ. Optic neuritis and the evaluation of visual impairment & in multiple sclerosis. Continuum (Minneap Minn) 2013; 19 (4 multiple sclerosis):1074–1086. This is a recent article in Continuum reviewing neuro-ophthalmologic manifestations of multiple sclerosis. 10. Frohman TC, Graves J, Balcer LJ, et al. The neuro-ophthalmology of multiple sclerosis. Continuum (Minneap Minn) 2010; 16:122–146. 11. Gronseth GS, Ashman EJ. Practice parameter: the usefulness of evoked potentials in identifying clinically silent lesions in patients with suspected multiple sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000; 54:1720–1725. 12. Klistorner A, Arvind H, Nguyen T, et al. Multifocal VEP and OCT in optic neuritis: a topographical study of the structure-function relationship. Doc Ophthalmol 2009; 118:129–137. 13. Klistorner A, Arvind H, Garrick R, et al. Interrelationship of optical coherence tomography and multifocal visual-evoked potentials after optic neuritis. Invest Ophthalmol Vis Sci 2010; 51:2770–2777. 14. Thurtell MJ, Bala E, Yaniglos SS, et al. Evaluation of optic neuropathy in multiple sclerosis using low-contrast visual evoked potentials. Neurology 2009; 73:1849–1857. 15. Frohman AR, Schnurman Z, Conger A, et al. Multifocal visual evoked & potentials are influenced by variable contrast stimulation in MS. Neurology 2012; 79:797–801. This is a study showing variable contrast multifocal evoked potentials are sensitive measures of visual function and a promising outcome measure in trials of neuroprotective and remyelinating agents.

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Demyelinating diseases 16. Frohman TC, Beh S, Saidha S, et al. Optic nerve head component responses of the multifocal electroretinogram in MS. Neurology 2013; 81:545–551. If validated, by larger studies, as a measure of visual function, and perhaps a ‘signature of myelination’, the optic nerve head component response may provide important insights into disease mechanisms and form an invaluable outcome measure in the evaluation of myelin repair or neuroprotective therapies. 17. Cleary PA, Beck RW, Bourque LB, et al. Visual symptoms after optic neuritis. Results from the Optic Neuritis Treatment Trial. J Neuroophthalmol 1997; 17:18–23. 18. Baier ML, Cutter GR, Rudick RA, et al. Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis. Neurology 2005; 64:992–995. 19. Fisher JB, Jacobs DA, Markowitz CE, et al. Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis. Ophthalmology 2006; 113:324–332. 20. Talman LS, Bisker ER, Sackel DJ, et al. Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis. Ann Neurol 2010; 67:749– 760. 21. Burkholder BM, Osborne B, Loguidice MJ, et al. Macular volume by optical coherence tomography as a measure of neuronal loss in multiple sclerosis. Arch Neurol 2009; 66:1366–1372. 22. Wu GF, Schwartz ED, Lei T, et al. Relation of vision to global and regional brain MRI in multiple sclerosis. Neurology 2007; 69:2128–2135. 23. Weinstock-Guttman B, Baier M, Stockton R, et al. Pattern reversal visual evoked potentials as a measure of visual pathway pathology in multiple sclerosis. Mult Scler 2003; 9:529–534. 24. Balcer LJ, Galetta SL, Polman CH, et al. Low-contrast acuity measures visual & improvement in phase 3 trial of natalizumab in relapsing MS. J Neurol Sci 2012; 318:119–124. This article discusses the establishment of low contrast visual acuity as a reliable outcome measure in multiple sclerosis trials, the AFFIRM trial of natalizumab. 25. Graves J, Galetta SL, Palmer J, et al. Alemtuzumab improves contrast & sensitivity in patients with relapsing–remitting multiple sclerosis. Mult Scler 2013; 19:1302–1309. This article discusses the establishment of low contrast visual acuity as a reliable outcome measure in multiple sclerosis trials. 26. Seigo MA, Sotirchos ES, Newsome S, et al. In vivo assessment of retinal neuronal layers in multiple sclerosis with manual and automated optical coherence tomography segmentation techniques. J Neurol 2012; 259: 2119–2130. 27. Syc SB, Saidha S, Newsome SD, et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain 2012; 135:521–533. 28. Walter SD, Ishikawa H, Galetta KM, et al. Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 2012; 119:1250–1257. 29. Ratchford JN, Saidha S, Sotirchos ES, et al. Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning. Neurology 2013; 80:47–54. 30. Saidha S, Sotirchos ES, Oh J, et al. Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. JAMA Neurol 2013; 70:34–43. 31. Kupersmith MJ, Kardon R, Durbin M, et al. Scanning laser polarimetry reveals & status of RNFL integrity in eyes with optic nerve head swelling by OCT. Invest Ophthalmol Vis Sci 2012; 53:1962–1970. This article discusses how scanning laser polarimetry as opposed to OCT reveals a decrease in birefringence in eyes with axonal injury associated with visual field loss, which is unlikely to recover; this may have implications for selecting subjects in study of neuroprotective agents. 32. Zaveri MS, Conger A, Salter A, et al. Retinal imaging by laser polarimetry and optical coherence tomography evidence of axonal degeneration in multiple sclerosis. Arch Neurol 2008; 65:924–928. 33. Kupersmith MJ, Anderson S, Kardon R. Predictive value of 1 month retinal & nerve fiber layer thinning for deficits at 6 months after acute optic neuritis. Mult Scler 2013; 19:1743–1748. This study established the importance of the 1-month time point for predicting the outcome of an AON attack. 34. Bermel RA, Inglese M. Neurodegeneration and inflammation in MS: the eye & teaches us about the storm. Neurology 2013; 80:19–20. This reviews the importance of identifying primary neuroprotective agents as the pathogenesis of multiple sclerosis is thought to involve histopathological facets of both inflammation and degeneration. 35. Ratchford JN, Saidha S, et al. Active MS is associated with accelerated retinal & ganglion cell/inner plexiform layer thinning. Neurology 2013; 80:47–54. This recent study suggests that retinal changes in multiple sclerosis reflect global CNS processes and OCT measures may have utility as an outcome measure for assessing neuroprotective agents within the eye, the local effects of which may be more broadly generalized to the CNS. &

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36. Syc SB, Saidha S, Newsome SD, et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain 2011; 135:521–533. 37. Saidha S, Sotirchos ES, Ibrahim MA, et al. Microcystic macular oedema, & thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study. Lancet Neurol 2012; 11:963– 972. This study showed that increased INL thickness as measured by OCT is associated with disease severity in multiple sclerosis and may be established as a useful predictor of disease progression in multiple sclerosis. 38. Deshmukh V, Tardif V, Lyssiotis V, et al. A regenerative approach to the & treatment of multiple sclerosis. Nature 2013; 502:327–332. This recent study showed previously unknown myelin repair properties of benztropine, an agent previously used for tremor in Parkinson’s disease patients. Clinical trials will likely involve the use of the visual system model to study myelin repair in human subjects. 39. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 2009; 373:732–738. 40. Frohman TC, Davis SL, Beh S, et al. Uhthoff’s phenomena in MS: clinical features and pathophysiology. Nat Rev Neurol 2013; 9:535– 540. 41. Davis SL, Wilson TE, White AT, et al. Thermoregulation in multiple sclerosis. J Appl Physiol 2010; 109:1531–1537. 42. Frohman TC, Davis SL, Frohman EM. Modeling the mechanisms of Uhthoff’s phenomenon in multiple sclerosis patients with internuclear ophthalmoparesis. Ann NY Acad Sci 2011; 1233:313–319. 43. Horton L, Conger A, Conger D, et al. Effect of 4-aminopyridine on vision in & multiple sclerosis patients with optic neuropathy. Neurology 2013; 80:1862– 1866. This recent study provided evidence supporting the use of 4-AP in certain patients (with RNFL thickness between 60 and 80 nm) to improve visual parameters. Future clinical trials should employ RNFL thickness measures as part of inclusion/ exclusion criteria 44. Strupp M, Schuler O, Krafczyk S, et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology 2004; 61:165–170. 45. Kalla R, Glasauer S, Schautzer F, et al. 4-Aminopyridine improves downbeat nystagmus, smooth pursuit, and VOR gain. Neurology 2004; 62:1228– 1229. 46. Cao Y, Dreixler JC, Roizen JD, et al. Modulation of recombinant smallconductance Ca(2þ)-activated K(þ) channels by the muscle relaxant chlorzoxazone and structurally related compounds. J Pharmacol Exp Ther 2001; 296:683–689. 47. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage 2004; 28:140–175. 48. Feil K, Claaßen J, Bardins S, et al. Effect of chlorzoxazone in patients & with downbeat nystagmus: a pilot trial. Neurology 2013; 81:1152– 1158. This study showed benefit of using chlorzoxazone in patients with downbeat nystagmus. 49. Claassen J, Spiegel R, Kalla R, et al. A randomised double-blind, cross-over & trial of 4-aminopyridine for downbeat nystagmus–effects on slowphase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry 2013; 84:1392–1399. This trial showed the benefits of using 4-AP in patients with downbeat nystagmus. 50. Pula JH, MacDonald JC. Current options for the treatment of optic neuritis. & Clin Ophthalmol 2012; 6:1211–1223. This article reviews the current treatment options for optic neuritis. 51. Catania A, Gatti S, Colombo G, et al. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol Rev 2004; 56: 1–29. 52. Koziolek MJ, Tampe D, Bahr M, et al. Immunoadsorption therapy in patients & with multiple sclerosis with steroid-refractory optical neuritis. J Neuroinflammation 2012; 9:80. This article discusses the benefits of using immunoadsorption therapy in multiple sclerosis patients with steroid refractory optic neuritis. 53. Trebst C, Reising A, Kielstein JT, et al. Plasma exchange therapy in steroidunresponsive relapses in patients with multiple sclerosis. Blood Purif 2009; 28:108–115. 54. Roesner S, Appel R, Gbadamosi J, et al. Treatment of steroid-unresponsive & optic neuritis with plasma exchange. Acta Neurol Scand 2012; 126:103– 108. This article discusses the use of plasma exchange in multiple sclerosis patients with steroid refractory optic neuritis.

Volume 27  Number 3  June 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

An update on neuro-ophthalmology of multiple sclerosis: the visual system as a model to study multiple sclerosis.

The purpose of this review is to familiarize the reader with the landscape of current neuro-ophthalmology research in the field of multiple sclerosis ...
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