The Utility of Optical Coherence

Tomography in Multiple Sclerosis

Raed Behbehani , MD FRCSC

What is OCT ?

• Ultrasound of the eye, but uses light instead.

• Gives reproducible cross-sectional images of the retinal layers.

• Four generations of OCT (3rd is time domain , 4th is spectral domain).

What is OCT ?

• Non-invasive imaging technique routinely used in ophthalmology (glaucoma ,retinal diseases)

• The retina contains axons and glia but no myelin , thus ideal to monitor neurodegeneration.

• Quantitative Measurement of retinal nerve fiber layer (RNFL) , macular thickness (MT).

• Qualitative assessment (Ultra-high resolution).

Why OCT ?• Axonal degeneration was recognized as an early

pathological manifestation of MS ( Trapp et al 1998)

• The role of inflammation, acute and chronic axonal loss, and neuro-degeneration is in the core of pathophysiology of MS.

• Noninvasive methods of monitoring and treating axonal pathologic changes in MS patients.

• “In-vivo” optical biopsy.

Axonal Loss in Asymptomatic MS

Patients

Fundoscopic Identification in Patients With and Without Visual Complaints

Lars Frisén, MD; William F. Hoyt, MD• 1974 . Arch Ophth

• Slit-like defects in RNFL in two visually asymptomatic patients ( spinal cord, brain stem syndrome).

Axonal Loss in MS

• Post-mortem analysis showed that most MS were found to have changes in the optic nerve and RNFL, regardless of whether they had optic neuritis (Ikuta and Zimmerman, 1976; Toussaint et al., 1983 , Green et al. 2010)

Retinal Anatomy

Time Domain Retinal Nerver Fiber Layer Scan

Variables Influencing OCT

• RNFL in OCT is affected by age , and eye refractive status (high myopia or hyperopia).

• Normal RNFL loss 0.3μm/year ( 7th decade- 89.5±7.5μ , 3rd decade- 104.4±7.6μm). (Harwerth et al 2007)

• Gender does not significantly affect OCT ( Ahn et al 2005).

Optic Neuritis

• 1st clinical manifestation of MS in approximately 20% of cases.

• In course of disease 30%-70% develop ON,

• Best studied CIS.

• Ideal for studying early axonal loss and neuro-degeneration in MS .

Optic Neuritis • Axonal loss following optic neuritis initially

reported by Parisi et al 1999 ( loss of Average RNFL in optic neuritis at 1 year compared to controls)

• Trip et al (2005) showed 33% reduction in RNFL thickness in the affected eyes in 25 optic neuritis vs 15 controls (3rd generation OCT)

• A 27% reduction when the affected and unaffected eyes of the same patient were compared (p<0.001) ( Trip et al 2005)

RNFL in Early Stage of Optic Neuritis

• Pro et al (2006) showed that thinning of RNFL can occur as early as 2-4 months following optic neuritis .

• If disc edema ( initially thickened RNFL then thinning) even in retrobulbar neuritis .

• Mild thickening occur even with no fundoscopic disc edema.

Optic Neuritis

RNFL in Optic Atrophy in a patient with SPMS

Follow Up RNFL After Optic Neuritis

• Costello et al (2006) followed 38 patients with optic neuritis using TD OCT.

• Most of RNFL loss occurred between 3-6 months (85%).

• Visual recovery is correlated with remaining RNFL at 6 months. (Henderson et al. 2010)

Follow Up RNFL in Optic Neuritis

• Follow up 78 patients for 1 year post-neuritis . (Costello et al. 2008)

• RNFL thinning starts at 2-3 months , progressed till 6 months and then stabilized up to 2 years (Costello et al. 2009)

• A meta-analysis (14 studies) showed that RNFL values are reduced from 5 to 40 μm (averaging 10 to 20 μm) in eyes with MS and ON. (Petzold et al. 2010)

RNFL Loss Following ON

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

RNFL of the Contralateral Eye in Optic Neuritis

• Many studies showed that RNFL loss occurs also in the asymptomatic affected eye in optic neuritis. (Fisher et al., 2006; Henderson et al., 2008; Jeanjean et al., 2008; Pueyo et al., 2009; Pueyo et al., 2008; Pulicken et al., 2007; Sepulcre et al., 2007).

RNFL in CIS

• No RNFL thinning in CIS patients without optic neuritis compared to controls over 1 year, but tend towards temporal RNFL loss. ( Outteryck O et al, 2009)

Spectral Domain OCT

Spectral Domain OCT in Optic Neuritis

• Twenty patients with ON followed with SD OCT.( Garas et al., 2011)

• Thinning of the ganglion cell layer plus the inner plexiform layer, was evident in affected optic neuritis eyes starting at 3 months.

• This was not difference between CIS and MS.

Spectral Domain OCT in Optic Neuritis

• Ganglion cell layer thickness decreased after the baseline visit in affected acute optic neuritis eyes and was not influenced by the presence of initial disc or retinal nerve fibre layer oedema (Garas et al., 2011)

GCL loss in ON

GCL loss in Optic Neuritis

At 3 weeks post-optic neuritis

RNFL Correlation with Visual Functions

• Costello et al (2006,2008) showed that RNFL correlate linearly with mean deviation of Humphrey visual field below 70 microns , and linearly with visual acuity below 75 microns.

RNFL and Visual Field

75 microns is a threshold value for visual recovery

Predictive Value of OCT

• No significant differences in RNFL thickness in either ON eyes or non-ON eyes between patients who developed clinically definite MS (42%) and those who did not develop MS (58%) during the 2-year study period. (Costello et al. 2008)

• OCT does not predict conversion to MS at 6 months in CIS patients.

Correlation between MS and MRI

• No link between RNFL and (1) MRI evidence of CNS inflammation at baseline; (2) disseminated CNS inflammation according to the revised McDonald criteria; (3) gadolinium enhancement on initial MRI. (Outteryck O et al. 2009)

Ongoing Axonal Loss in MS

• MS and ON and non-ON eyes each year of follow-up was associated with an average 2-μm decrease in RNFL (P < .001) (Talman LS et al.2010)

• Progressive sub-clinical axonal loss in MS.

• Gives a case to early aggressive treatment to prevent axonal loss.

• Longitudinal studies with high-resolution SD-OCT to minimize repeat measurement variability are needed.

Macular Volume and MS

• Macula is 60% Ganglion cells.

• MV is a good index to assess neuro-degeneration.

• Not influenced by edema in acute stage of ON.

• Reductions of volume in the macula (approximately 34% neuronal cells by average thickness) accompany RNFL axonal loss.

• Peripapillary RNFL thinning and inner macular volume loss are more strongly linked in eyes of MS patients with a history of ON, which suggests an alternative mechanism for neurodegeneration. (Burkholder 2009).

RNFL Loss and MS Severity

• Baseline temporal RNFL atrophy was associated with the presence of new relapses and EDSS changes (P < .05) at 2 years, (Sepulcre et al. 2007, Spain et al 2009) and recent progression and disease activity (Toledo et al. 2008)

• PPMS had temporal RNFL loss while SPMS had overall mean, superior and temporal RNFL loss (Henderson et al 2008).

• Greater RNFL loss in PPMS or SPMS compared to RRMS (Pulicken et al., 2007).

• RNFL thickness (particularly the temporal quadrant) in the eye with no prior history of optic neuritis of MS patients may be helpful in differentiating MS subtypes.

OCT and Disability

Costello F, Hodge W, Pan YI, Eggenberger E, Freedman MS. Using retinal architecture to characterize multiple sclerosis patients. Can J Ophthalmol.2010;45:520–526

RNFL correlates with EDSS for mild-mod

neurological impairment

RNFL and Brain Atropht• RNFL may be a surrogate marker for brain atrophy in MS

(Fisher et al. 2006).

• RNFL thickness correlates with brain white and grey matter volumes measured on conventional MRI, but not with the volume of T1, T2 or gadolinium–enhanced lesions (Spulcre et al. 2007)

• Correlation between RNFL and brain volume is stronger if no history of ON. (Sieger et al 2008)

• RNFL thickness correlates with T1 or T2 lesion volume, grey matter atrophy, MTR, and diffusion tensor imaging measures (DTI). (Frohman et al. 2009)

Beyond RNFL

Beyond RNFL- Inner and Outer Nuclear Loss

• Subset of patients with predominantly macular thinning and near normal RNFL, had thinner inner and outer nuclear layers compared to other subsets and normal ganglion cell layer.

• Different mechanism from retrograde ganglion cell death due to axonal loss.

• Primary process in deeper retinal layers analogous to grey matter loss in MS (anterogrde degenration). (Saidha et al,2012)

Beyond RNFL - Inner and Outer Nuclear Loss

Saidha et al, Brain 2012

Beyond RNFL - Inner and Outer Nuclear Loss

• Patients with thin INL and ONL had more progressive disease.

• Unique visual symptoms (photophobia , glare, poor night vision)

• Retina may serve as model to understand the heterogeneity of the inflammatory and demyelinating mechanisms of MS.

Inner and Outer Nuclear Layer

• RRMS patients INL thickness were not different from controls and they did not have predominantly macular thinning.

• Inner and Outer Nuclear Layer loss does not exclude a primary process in retina.

Beyond RNFL - Microcystic Macular

Edema• Microcystic Edema of the inner nuclear layer in a subset of patients with MS. (Gelfand et al, Brain 2012).

• Subset had higher EDSS and MSSS (Gelfand 2012, Saidha et al 2012) .

• Predicted the development of contrast- enhancing lesions (p=0·007), new T2 lesions (p=0·015), EDSS progression (p=0·034), and relapses ( Saidha et al 2012)

• More common in patients with prior optic neuritis (50 versus 27%).

• Mechanism : ? Patients did use Fingolimod or ? had uveitis.

• Breakdown of the retinal-blood barrier

Microcystic Macular Edema

Gelfand et al , Brain 2012

Microcystic Maculr Edema

• MME Has been found in other optic neuropathies (NMO) and non-MS optic neuritis. (Balk et al , 2012 , Abegg et al, 2013, Sotirchos ES , 2013)

• Nine patients who did not have MS nor NMO. (Abegg et al, 2013)

• Retrograde degeneration of the inner retinal layers (Muller cells) resulting in impaired fluid absorption (Retrograde Maculopathy) (Abegg et al, 2013)

• Doubtful prognostic significance independent of the severity of optic neuropathy. (Abegg et al, 2013)

NMO• NMO is a distinct disease from MS

(Pathophysiology and Treatment)

• Need more ways to distinguish NMO from MS.

• Visual acuity and RNFL thickness were significantly worse in NMO and CRION eyes than in RRMS (Bichuetti et al, 2013)

• RNFL 41 um thickness is 100% specific for NMO and CRION. (Bichuetti et al, 2013)

OCT in NMO• Ganglion cell layer plus inner plexiform layer, RNFL and average

macular thickness were all reduced compared with MS optic neuritis eyes and non-optic neuritis multiple sclerosis eyes ( B Syc et al, 2012).

• NMO non-ON has reduced GCL+IPL compared to controls (?ongoing disease activity even in NMO)

Use of RNFL in Clinical Trials

• Can detect axonal loss before MRI (high resolution)

• The “clinical radiological paradox”

• Retina has no myelin and not affected by myelin disorders.

• Retina has glial elements as well not only axon.

• OCT is cheap and easy to use , but interpretation requires understanding of ophthalmic disease.

• OCT correlates with other visual functions (contrast, colour , visual fields , VEP etc).

Spectral Domain OCT in Clinical Trials

• Ganglion cell layer layer measurements may be robust for clinical trials for neuro-protection. ( B Syc et al, 2012).

• Not affected by swelling of optic disc like RNFL.

Spectral Domain OCT

Neuroprotection With Riluzole Patients With Early Multiple

Sclerosis• Neuroprotection With Riluzole Patients With Early Multiple

Sclerosis (completed) : RCT oral riluzole or placebo following CIS before starting Avonex

Neuroprotection Trials Using OCT as Outcome

Meaure• Tysabri Effects on Cognition and Neurodegeneration

in Multiple Sclerosis (recruiting) : Tysabri in preventing neurological degeneration, end points include MRI and OCT.

• Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) (recruiting) : Safety/efficacy study in which RNFL measures at 12 and 52 weeks post-infusion autologous adult mesenchymal stem cells.

Neuroprotection Trials Using OCT

• Neuroprotection With Phenytoin in Optic Neuritis.

• Treatment of Optic Neuritis With Erythropoietin (TONE)

• A Phase IV Trial of Neuroprotection With ACTH in Acute Optic Neuritis (ACTHAR)

• Amiloride Clinical Trial In Optic Neuritis (ACTION)

Summary • OCT is an excellent method to follow the effects of

various neurological diseases by assessing neural tissue .

• Our understanding of the mechanisms of diseases is evolving thanks to new ultra-high resolution OCT.

• RNFL has long been known to be a marker of optic nerve involvement but attention seem to shifting towards to deeper retinal layers .

• The non-invasiveness and the reporducibility of OCT makes it ideal to assess neuroprotective effects of drugs in trials.