1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Assessing Visual Changes in Multiple Sclerosis: How Vision Captures Disease Salim Chahin, MD, MSCE University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania A REPORT FROM THE 28 TH ANNUAL MEETING OF THE CONSORTIUM OF MULTIPLE SCLEROSIS CENTERS AND THE 19 TH ANNUAL MEETING OF THE AMERICAS COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Assessment of Visual Complaints in MS The source of visual complaints in patients with multiple sclerosis (MS) may be related to the visual pathway (optic nerve) or the occulomotor system. The first step in the evaluation of MS patients with visual complaints is to correct for refractive errors. The use of a diagnostic algorithm can help facilitate the workup of visual complaints.

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Assessment of Visual Complaints in MS

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 Diplopia Diplopia is the experience of seeing two images of the same object. Diplopia in MS is binocular. Most common causes of diplopia in MS: » Intranuclear ophthalmoplegia (INO) » 6 th nerve palsy » 3 rd nerve palsy » 4 th nerve palsy » Skew deviation INO, present in up to 40% of patients, is the most common cause of diplopia in MS. Chen L, Gordon LK. Curr Opin Ophthalmol. 2005;16:315

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 Intranuclear Ophthalmoplegia (INO) INO in MS can be unilateral or bilateral. INO is caused by lesions to the ipsilateral medial longitudinal fasciculus (MLF). » The affected eye demonstrates adduction slowing or limitation. » When an attempt is made to gaze contralaterally, the affected eyes adducts minimally or not at all. » The contralateral eye abducts, often with nystagmus. Chen L, Gordon LK. Curr Opin Ophthalmol. 2005;16:315; Tsuda H et al. Rinsho Shinkeigaku. 2004;44:513; Bolanos I et al. Acta Neurol Scand. 2004;110:161

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Nystagmus Nystagmus, an involuntary, often jerking, movement of the eyes, is a frequent ocular motor deficit in MS. Nystagmus can occur independently or in conjunction with diplopia. Nystagmus can be: » Horizontal » Vertical » Pendular » Gaze-evoked Chen L, Gordon LK. Curr Opin Ophthalmol. 2005;16:315

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Optic Neuritis Optic neuritis, one of the most common presentations of MS, results from inflammation of the optic nerve. It often presents as a subacute, painful loss of vision. Symptoms of optic neuritis can include: » Blurred vision (“looking through frosted glass”) » Reduced color perception » Loss of visual fields (most commonly, central scotomas). Severe, complete monocular vision loss can occur. In almost all cases, symptoms are accompanied by pain that is worsened with eye movements Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074; Lycke J et al. J Neurol. 2001;248:1079; Sisto D et al. Invest Ophthalmol Vis Sci. 2005;46:1264

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 Assessment of Optic Neuritis Visual acuity » High-contrast visual acuity commonly assessed in clinic. » May not capture all elements of visual dysfunction. » Low-contrast visual acuity is a more sensitive tool. Visual fields » Commonly done by confrontation at bedside. » Not sensitive to small scotomas. » Can be confirmed by automated neuro-ophthalmic tools. Fundoscopic examination » Evaluate for optic disk pallor Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074; Balcer LJ et al. Mult Scler. 2000;6:163; Balcer LJ et al. Neurology. 2003;61:1367

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Assessment of Optic Neuritis Pupillary light reflex » A relative afferent pupillary defect (APD) is a sensitive measure of optic nerve dysfunction. » Damage to the optic nerve will result in less light perception and less pupillary constriction when the light is shone onto the affected eye. Visual evoked potentials » Useful tool to detect subclinical or remote optic nerve involvement Magnetic resonance imaging (MRI) » Can show T2 signal changes, swelling, and contrast enhancement of the optic nerve Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 New Measures of Visual Pathway Structure and Function Low-Contrast Visual Acuity (LCVA) Both high- and low-contrast visual acuity (LCVA) can be monocular or binocular. Despite recovery of high-contrast visual acuity to 20/40 or better following optic neuritis, patients continue to complain of visual symptoms. LCVA testing can distinguish patients with MS from healthy controls. LCVA is more reflective of real-world tasks. LCVA is sensitive to treatment effect. Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074; Balcer LJ et al. Mult Scler. 2000;6:163; Balcer LJ et al. Neurology. 2003;61:1367

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 New Measures of Visual Pathway Structure and Function Optical Coherence Tomography (OCT) OCT is a reliable, noninvasive imaging method that uses near-infrared light to produce high-resolution images of the retina. Images of peripapillary and macular regions are segmented. Thickness of individual layers is obtained: » Retinal nerve fiber layer (RNFL) = white matter = axons » Ganglion cell layer (GCL) = gray matter = neurons » Total macular volume (TMV) = surrogate for gray matter volume when segmentation is not done Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074; Galetta KM et al. Neurotherapeutics. 2011;8:117

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 How Vision Captures Disease in Patients with MS Visual Dysfunction and MS Visual dysfunction is common in MS. Up to 50% of MS patients will develop optic neuritis. Up to 80% of MS patients have subclinical visual system involvement. The eye is now being evaluated as a potential window to the brain. Visual dysfunction and evaluation of the visual system may serve as surrogates for overall disease dysfunction in MS. Bermel RA, Balcer LJ. Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):1074; Lycke J et al. J Neurol. 2001;248:1079

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 How Vision Captures Disease in Patients with MS Visual Function Testing Structure/function correlations within the visual system: » LCVA correlates with structural measures: Retinal nerve fiber layer (RNFL) thickness MRI lesion burden » LCVA correlates with other visual functional measures: Visual evoked potentials LCVA captures treatment effect: » LCVA captured treatment effect on sustained visual loss and visual improvement in the natalizumab trial. » Treatment with alemtuzumab also improved LCVA. Talman LS et al. Ann Neurol. 2010;67:749; Baier ML et al. Neurology. 2005;64:992; Wu GF et al. Neurology. 2007;69:2128; Balcer LJ et al, Neurology. 2007;68:1299; Balcer LJ et al. J Neurol Sci. 2012;318:119; Graves J et al Mult Scler. 2013;19:1302

14. © 2014 Direct One Communications, Inc. All rights reserved. 14 How Vision Captures Disease in Patients with MS LCVA and Neurologic Impairment LCVA correlates with scores on the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). Worsening of LCVA can occur independently of EDSS progression. A composite measure of progression that includes both LCVA and EDSS scores is more sensitive to treatment effect than either alone. Baier ML et al. Neurology. 2005;64:992; Chahin S et al. J Neuroophthalmol. 2014 [ms submitted for review]

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 How Vision Captures Disease in Patients with MS Natural History RNFL and GCL thickness decreases over time in the eyes of patients with MS—even without a history of optic neuritis. Talman LS et al. Ann Neurol. 2010;67:749; Sakai RE et al. J Neuroophthalmol. 2011;31:362

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 How Vision Captures Disease in Patients with MS OCT and Disease Course Retinal pathology occurs early in the disease course, as can be seen in clinically isolated syndrome. RNFL and GCL atrophy is most pronounced in patients with secondary progressive MS. Patients with benign MS experience thinning of their retinal structures, when compared with healthy controls, but the loss in RNFL and GCL is less severe than in patients with relapsing-remitting MS. The loss of RNFL in patients with benign MS is similar to that in patients with more typical MS. Oberwahrenbrock T et al. Mult Scler. 2013;19:1887; Balk L et al. Mult Scler. 2014;20:1198; Lange AP et al Mult Scler. 2013;19:1275; Galetta KM et al. J Neuroophthalmol 2012;32:116

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 How Vision Captures Disease in Patients with MS RNFL/GCL Loss and MRI Findings A growing body of evidence supports an association between retinal neuronal and axonal loss and measures of global pathology on MRI. RNFL and GCL thickness in the eyes of patients with MS is associated with cortical gray matter and caudate volume. A decrease in RNFL thickness in patients with MS correlates with an increase in the bicaudate ratio, a measure of brain atrophy. Saidha S et al. JAMA Neurol. 2013;70:34; Abalo-Lojo JM et al. J Neuroophthalmol. 2014;34:23

18. © 2014 Direct One Communications, Inc. All rights reserved. 18 How Vision Captures Disease in Patients with MS OCT Findings and Neurologic Impairment RNFL thinning in patients with MS is associated with executive and attention deficits. EDSS scores strongly correlate with RNFL and GCL thickness. MS patients with progressive RNFL loss have lower physical quality-of-life scores. MS patients with reduced total macular volume demonstrate an overall reduction in ambulatory performance, as measured by the Timed 25-Foot Walk test and the 6-minute walk test. Abalo-Lojo JM et al. J Neuroophthalmol. 2014;34:23; Toledo J et al. Mult Scler. 2008;14:906; Tugcu B et al. J Neurol Sci. 2013;355:182; Garcia-Martin E et al. Ophthalmology. 2014;121:573; Balantrapu S et al Mult Scler Int. 2013;2013:481035

19. © 2014 Direct One Communications, Inc. All rights reserved. 19 How Vision Captures Disease in Patients with MS Summary Visual function testing is a sensitive and reliable test that captures neurologic impairment beyond the visual system in patients with MS. Retinal neuronal and axonal loss continues to show associations with global structural and functional outcomes. Can we use the visual system to better understand fatigue in MS?

20. © 2014 Direct One Communications, Inc. All rights reserved. 20 Fatigue and the Visual System Fatigue in Patients with MS Fatigue is associated with axonal loss. No consistent relationship has been shown between fatigue and lesion load or location. No consistent relationship has been shown between fatigue and specific regions. Fatigue predicts brain atrophy. Fatigue can herald MS and can worsen during a relapse. Kos D et al. Neurorehabil Neural Repair. 2008;22:91; Krupp LB et al. Expert Rev Neurother. 2010;10:1437

21. © 2014 Direct One Communications, Inc. All rights reserved. 21 Fatigue and the Visual System Visual Function Testing and Fatigue Worse binocular high-contrast and low-contrast visual acuity (LCVA) scores are associated with increased levels of both cognitive and physical patient-reported fatigue, as measured by the Modified Fatigue Impact Scale. The association between LCVA and fatigue is stronger for physical fatigue (r = –0.26; P = 0.0003) than for cognitive fatigue (r = –0.19; P = 0.02). Patients with MS categorized as fatigued have worse overall LCVA scores than nonfatigued patients. Chahin S et al. ECTRIMS 2012, Abstract 118; Chahin S et al. AAN 2014, Poster P06.018

22. © 2014 Direct One Communications, Inc. All rights reserved. 22 Fatigue and the Visual System Visual Function Testing and Fatigue Comparison of average LCVA scores between fatigued and nonfatigued patients and healthy controls Chahin S et al. AAN 2014, Poster P06.018

23. © 2014 Direct One Communications, Inc. All rights reserved. 23 Fatigue and the Visual System OCT Findings and Fatigue Loss of gray matter in the retina is associated with an increase in the level of fatigue. The effect of optic neuritis on GCL thinning differs between patients with and without fatigue: » In nonfatigued patients, optic neuritis caused a 1-µm loss in GCL thickness (P = 0.426). » In fatigued patients, optic neuritis caused a 6-µm loss in GCL thickness (P < 0.001). » The difference in effect of optic neuritis on GCL between fatigued and nonfatigued patients was 4.5 µm (P = 0.026). Chahin S et al. AAN 2014, Abstract S39.008

24. © 2014 Direct One Communications, Inc. All rights reserved. 24 Fatigue and the Visual System OCT Findings and Fatigue Effect of optic neuritis on GCL thickness in fatigued and nonfatigued patients with MS Chahin S et al. AAN 2014, Abstract S39.008

25. © 2014 Direct One Communications, Inc. All rights reserved. 25 Fatigue and the Visual System OCT Findings and Fatigue The effect of optic neuritis on RNFL thinning differed between patients with and without fatigue. » In nonfatigued patients, optic neuritis caused a 5-µm loss in RNFL thickness (P = 0.006). » In fatigued patients, optic neuritis caused a 10-µm loss in RNFL thickness (P < 0.001). » The difference in effect of optic neuritis on GCL between fatigued and nonfatigued patients was 5 µm. Compared with patients who were neither fatigued nor had optic neuritis, patients with both fatigue and optic neuritis had a 7.4-µm loss in GCL and a 11.2- µm micron loss in RNFL (P < 0.001 for both). Chahin S et al. AAN 2014, Abstract S39.008

26. © 2014 Direct One Communications, Inc. All rights reserved. 26 Fatigue and the Visual System OCT Findings and Fatigue Effect of optic neuritis on RNFL thickness in fatigued and nonfatigued patients with MS Chahin S et al. AAN 2014, Abstract S39.008

27. © 2014 Direct One Communications, Inc. All rights reserved. 27 Fatigue and the Visual System Summary Impaired vision in patients with MS is highly associated with fatigue. The association between visual function testing and fatigue is stronger for physical fatigue than for cognitive fatigue. Physical fatigue may need to be evaluated and treated separately from cognitive fatigue. There is significantly more neuronal loss due to optic neuritis in the context of fatigue. The combination of fatigue and optic neuritis results in the most neuronal and axonal loss in the retina.

28. © 2014 Direct One Communications, Inc. All rights reserved. 28 Fatigue and the Visual System Summary The presence of fatigue may reflect disease susceptibility and overall gray matter injury in MS. Visual dysfunction may contribute to, and partially explain, fatigue in patients with MS. Evidence continues to build demonstrating the validity of the anterior visual pathway as a sensitive measure of structure and function in MS. Changes in LCVA, easily obtained at bedside, may reflect impairment beyond the visual system. Retinal neuronal and axonal thinning may also be reliably measured and used to capture global neuronal atrophy and neurologic impairment.