OCT is a non-invasive technology used in ophthalmology to assess retinal diseases and glaucoma. In recent years , OCT has been used to assess axonal loss and neurodegeneration in MS. This presentation will highlight the main uses of the OCT in MS and review of the literature.

1. The Utility of Optical
Coherence Tomography
in Multiple Sclerosis
Raed Behbehani , MD FRCSC

2. 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).

3. 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).

4. 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.

5. 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).

6. 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)

7. Retinal Anatomy

9. Time Domain Retinal Nerver Fiber Layer Scan

10. 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).

11. 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 .

12. 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)

13. 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.

14. Optic Neuritis

15. RNFL in Optic Atrophy in a patient with SPMS

16. 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)

17. 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)

18. 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

19. 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).

20. 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)

21. Spectral Domain OCT

22. 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.

23. 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)

24. GCL loss in ON

25. GCL loss in Optic Neuritis
At 3 weeks post-optic neuritis

26. 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.

27. RNFL and Visual Field
75 microns is a threshold value for visual recovery

28. 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.

29. 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)

30. 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.

31. 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).

32. 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.

33. OCT and Disability
RNFL correlates with
EDSS for mild-mod
neurological impairment
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

34. 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)

35. Beyond RNFL

36. 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)

37. Beyond RNFL - Inner and
Outer Nuclear Loss
Saidha et al, Brain 2012

38. 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.

39. 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.

40. 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

41. Microcystic Macular Edema
Gelfand et al , Brain 2012

42. 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)

43. 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)

44. 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)

45. 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).

46. 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.

47. Spectral Domain OCT

48. 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

49. 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.

50. 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)

51. 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.