Fatigue And Beyond How Vision Captures Disease in MS

Transcription

1 Fatigue And Beyond How Vision Captures Disease in MS Salim Chahin, MD Fellow Multiple Sclerosis University of Pennsylvania Outline Introduction. Visual function testing disease outcomes. Optical Coherence Tomography disease outcomes. Fatigue in Multiple Sclerosis. Vision and Fatigue the story. 1

2 Introduction Visual dysfunction is a common occurrence in Multiple Sclerosis (MS). Up to 50% of patients will develop optic neuritis (ON). Up to 80% of patients have subclinical visual system involvement. The visual pathway is now recognized as a system that can capture both structure and function in MS. Visual outcome measures are now routinely included in clinical trials. Sakai JNO 2011, Balcer NEJM 2006, Frohman neurology continuum 2010, Sisto Invest Ophthal 2005, Lycke J. Neurol 2001 Visual Function Testing 2

3 Visual Function Testing Visual function testing (VFT) traditionally performed using high contrast visual acuity (VA). Incorporated into the expanded disability status scale (EDSS). High contrast VA does not capture all aspects of visual dysfunction. Sakai JNO 2011, Balcer Multiple Sclerosis 2000, Balcer Neurology 2003 Visual Function Testing High Contrast VA 3

4 Visual Function Testing Visual function testing (VFT) traditionally performed using high contrast visual acuity (VA). Incorporated into the expanded disability status scale (EDSS). High contrast VA does not capture all aspects of visual dysfunction. Low contrast letter acuity (LCLA) uses gray letter on a white background. More sensitive to visual dysfunction. Predictive of real-world visual tasks such as reading, facial recognition and driving. Sakai JNO 2011, Balcer Multiple Sclerosis 2000, Balcer Neurology 2003 Visual Function Testing LCLA 4

5 Visual Function Testing Binocular vs. monocular VFT High contrast VA LCLA Early Treatment Diabetic Retinopathy Study (ETDRS) charts. 2.5% and 1.25% contrast levels using retro-illuminated lowcontrast Sloan letter charts (Precision Vision, LaSalle, IL). Clinically meaningful differences are 5-letters for VA and 7-letter for LCLA. Balcer Multiple Sclerosis 2000, Balcer Neurology 2007, Talman Ann Neurol 2010 VFT structure and function LCLA correlates with structural measures: Retinal nerve fiber layer (RNFL). MRI lesion burden. LCLA correlates with other visual functional measures: Visual evoked potentials. Talman 2010, Baier Neurology 2005, Wu Neurology 2007, Weinstock-Guttman Multiple Sclerosis

6 VFT Captures treatment effects Visual function testing, notably LCLA is a sensitive measure of visual dysfunction in MS. LCLA captured treatment effect on sustained visual loss and visual improvement in the natalizumab trial. Balcer Neurology 2007, Balcer J Neurol Sci 2012 VFT Treatment effect Balcer et al, Journal of the Neurological Sciences

7 VFT Captures treatment effects Visual function testing, notably LCLA is a sensitive measure of visual dysfunction in MS. LCLA captured treatment effect on sustained visual loss and visual improvement in the natalizumab trial. Treatment with Alemtuzumab also improved LCLA. Balcer Neurology 2007, Balcer J Neurol Sci 2012, Graves Multiple Sclerosis 2013 VFT Treatment effect Graves J et al. Mult Scler 2013;19:

8 VFT Treatment effect Graves J et al. Mult Scler 2013;19: VFT and neurologic impairment LCLA correlated with the expanded disability status scale (EDSS) and the MS functional composite (MSFC). Worsening of LCLA can occur independently from EDSS progression. Baier Neurology 2005, Chahin JNO 2014 in press 8

9 VFT - EDSS EDSS progressed (n=188) EDSS not progressed (n=754) Patients with worsening of vision by 7-letter criterion (%) % p= % 26.6% p= % 28.2% p= % HCVA LCVA (2.5%) LCVA (1.25%) VFT score Chahin JNO 2014 in press VFT and neurologic impairment LCLA correlated with the expanded disability status scale (EDSS) and the MS functional composite (MSFC). Worsening of LCLA can occur independently from EDSS progression. A composite measure of progression that included both LCLA and EDSS was more sensitive to treatment effect. Chahin JNO 2014 in press 9

10 VFT - EDSS Chahin JNO 2014 in press Optical Coherence Tomography 10

11 Optical Coherence Tomography (OCT) Optical Coherence Tomography (OCT) is a reliable, noninvasive and inexpensive tool that measures neuronal and axonal loss in the retina. LIGHT Galettta Neurotherapeutics 2011 Optical Coherence Tomography (OCT) Oberwahrenbrock T et al. Mult Scler 2013;19:

12 Optical Coherence Tomography (OCT) Optical Coherence Tomography (OCT): Measures thickness of certain retinal structures. Non-invasive, easy to use. Reliable and valid results. Spectral domain (SD-OCT) = higher resolution. RNFL = Retinal nerve fiber layer = axons. GCL = Ganglion cell layer = neurons. TMV = Total macular volume (34% GCL). Galetta Neurotherapeutics 2011 Optical Coherence Tomography (OCT) RNFL and GCL thickness is reduced over time in eyes of patients with MS. Even without a history of optic neuritis. Talman Ann Neurol 2010, Narayanan Multiple Sclerosis

13 Thickness of retinal structures over time Narayanan D et al. Mult Scler 2014; Optical Coherence Tomography (OCT) RNFL and GCL thickness is reduced over time in eyes of patients with MS. Even without a history of optic neuritis. RNFL and GCL thickness is associated with measures of global pathology on MRI: Cortical gray matter volume Caudate volume. Bicaudate ratio. Spinal cord measures. Saidha JAMA neurol 2013, Abalo-Lojo JNO

14 Saidha et al. JAMA Neurol. 2013;70(1): OCT and disease course Retinal pathology occurs early in the disease course can be seen in Clinically isolated syndrome. Oberwahrenbrock. Mult Scler

15 OCT and CIS Oberwahrenbrock T et al. Mult Scler 2013;19: OCT and disease course Retinal pathology occurs early in the disease course can be seen in Clinically isolated syndrome. RNFL and GCL atrophy is most pronounced in patients with secondary progressive MS. Patients with benign MS have thinning of their retinal structures compared to controls but less severe than patients with relapsing remitting MS. Oberwahrenbrock. Mult Scler 2013, Balk Multiple Sclerosis 2014, 15

16 OCT and Benign MS Balk L et al. Mult Scler 2014 OCT and disease course Retinal pathology occurs early in the disease course can be seen in Clinically isolated syndrome. RNFL and GCL atrophy is most pronounced in patients with secondary progressive MS. Patients with benign MS have thinning of their retinal structures compared to controls but less severe than patients with relapsing remitting MS. RNFL thickness lower in benign MS. Oberwahrenbrock. Mult Scler 2013, Balk Multiple Sclerosis 2014, Lange Multiple Sclerosis

17 OCT and Benign MS Lange A P et al. Mult Scler 2013 OCT and disease course Retinal pathology occurs early in the disease course can be seen in Clinically isolated syndrome. RNFL and GCL atrophy is most pronounced in patients with secondary progressive MS. Patients with benign MS have thinning of their retinal structures compared to controls but less severe than patients with relapsing remitting MS. RNFL thickness lower in benign MS. Benign MS patients have RNFL loss that is similar to patients with more typical MS. Oberwahrenbrock. Mult Scler 2013, Balk Multiple Sclerosis 2014, Lange Multiple Sclerosis 2013, Galetta JNO

18 OCT and Benign MS Galetta et al, JNO OCT and cognition RNFL thinning is associated with executive and attention deficits. Toledo Multiple Sclerosis

19 OCT and Physical disability RNFL atrophy is associated with physical disability as measured by EDSS. Toledo Multiple Sclerosis 2008, Abalo-Lojo JNO 2014 Toledo Multiple Sclerosis

20 OCT and Physical disability Abalo-Lojo JNO OCT and Physical disability RNFL atrophy is associated with physical disability as measured by EDSS. EDSS strongly correlated with RNFL and GCL. Toledo Multiple Sclerosis 2008, Abalo-Lojo JNO 2014, Tugcu J Neuro Sciences

21 OCT and Physical disability Tugcu J Neuro Sciences 2013 OCT and Physical disability RNFL atrophy is associated with physical disability as measured by EDSS. EDSS strongly correlated with RNFL and GCL. Patients with progressive RNFL loss had lower physical Quality of life scores. Toledo Multiple Sclerosis 2008, Abalo-Lojo JNO 2014, Tugcu J Neuro Sciences 2013, Garcia-Martin Neurology

22 OCT and Physical QOL Garcia-Martin E et al. Neurology 2013;81:76-83 OCT and Physical disability RNFL atrophy is associated with physical disability as measured by EDSS. EDSS strongly correlated with RNFL and GCL. Patients with progressive RNFL loss had lower physical Quality of life scores. Patients with reduced total macular volume had overall reduced ambulatory performance on several, objective tests. Toledo Multiple Sclerosis 2008, Abalo-Lojo JNO 2014, Tugcu J Neuro Sciences 2013, Garcia-Martin Neurology 2013 Balantrapu Multiple Sclerosis International

23 OCT and Ambulatory performance Balantrapu Multiple Sclerosis International 2013 Summary Visual function testing is a sensitive and reliable test in MS that captures impairment beyond the visual system. 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? 23

24 Fatigue in Multiple Sclerosis Fatigue in Multiple Sclerosis Fatigue is a common and often disabling symptom experienced by patients with MS. MS related fatigue is complex. Primary or secondary. Several dimension. Overlapping etiologies. Kos Neurorehab 2008, Krupp Expert reviews neurology

25 Fatigue in Multiple Sclerosis Primary fatigue (related to disease process): Brain dysfunction. Increased inflammation. Secondary fatigue Sleep problems. Medication side effects. Depression. Kos Neurorehab 2008, Krupp Expert reviews neurology 2010 Fatigue Subtypes Physical fatigue performance fatigability. Cognitive fatigue impaired attention and concentration. Lassitude the subjective feeling of fatigue and exhaustion. Kos Neurorehab 2008, Krupp Expert reviews neurology 2010, Schwid J Rehabil Res Dev

26 Fatigue and the CNS - MRI Associated with axonal loss. No consistent relationship with lesion load and location. No consistent relationship with specific region. Fatigue predicts brain atrophy. Fatigue can herald MS and can worsen during a relapse. Kos Neurorehab 2008, Krupp Expert reviews neurology 2010, Tedeschi J Neurol Sci 2007, Marrie J Neurol Sci 2005, Tartaglia Arch Neurol 2004, Bakshi Neurology 1999, Van der Werf, J Neurol Sci 1998, Berger Multiple Sclerosis 2013, Flachenercker Multiple Sclerosis 2008 Fatigue in Multiple Sclerosis Mechanisms of MS related fatigue are complex and remain poorly understood. Treatment is difficult, non-specific and often unsuccessful. Fatigue is a multidimensional process with variable manifestations and different, overlapping contributing etiologies. Kos Neurorehab 2008, Krupp Expert reviews neurology 2010, Chahin 2014 in press 26

27 Fatigue in Multiple Sclerosis Cognitive Cognitive Cognitive Physical Cognitive Physical Physical Fisk J Neurol Sci 1994 Vision and Fatigue 27

28 Vision and fatigue How is fatigue, and its components associated with visual function testing. How is fatigue associated with neuronal and axonal loss in the retina. Explore differences between fatigued/non-fatigued patients in: Visual function testing. Vision-related quality of life (QOL). Neuronal and axonal loss VFT and fatigue Worse binocular LCLA and VA scores were associated with increased levels of patientreported fatigue by the MFIS. This included both cognitive and physical aspects of fatigue. 28

29 VFT and fatigue VFT and fatigue 29

30 VFT and fatigue Fatigue and vision QOL 30

31 Fatigue and vision QOL Fatigue and GCL 31

32 Fatigue and GCL No Fatigue 84.4 μm Fatigue 81.5 μm No ON 84.7 μm ON 83.4 μm No ON 83 μm 1.3 μm p= μm p<0.001 ON 77.3 μm 4.5 μm p= μm p<0.001 Fatigue and RNFL No Fatigue 85.2 μm Fatigue 82.4 μm No ON 86.5 μm ON 81.7 μm No ON 85.1 μm 4.8 μm p= μm p<0.001 ON 75.3 μm 5 μm p= μm p<

33 Fatigue and the visual system Reduced vision in MS is highly associated with fatigue. There were stronger associations for physical, rather than cognitive, fatigue with visual function testing. Physical fatigue may need to be evaluate and treated separately from cognitive fatigue. Fatigue and the visual system There was significantly more neuronal loss due to ON in the context of fatigue. The combination of fatigue and ON resulted in the most neuronal and axonal loss in the retina. Presence of fatigue may reflect disease susceptibility and overall gray matter injury in MS. Visual dysfunction may contribute to, and partially explain, fatigue in MS. 33

34 Conclusions Evidence continues to show the validity of the anterior visual pathway as a sensitive measure of structure and function in Multiple Sclerosis. Changes in low contrast vision, a test that can easily be obtained at bedside, may reflect impairment beyond the visual system. Retinal neuronal and axonal thinning can also be reliably measured and used to capture global neuronal atrophy and neurologic impairment. Thank you 34