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Optic Neuritis and OCT in Multiple Sclerosis
- 1. Optic Neuritis Raed Behbehani , MD FRCSC
- 2. Eye involvement in MS • Afferent : Optic neuritis , Intermediate Uveitis , Visual Pathway Lesions • Efferent : INO , nystagmus , Cranial nerve palsy
- 3. Optic Neuritis • Young, female • Pain ( dull-aching , peri-ocular headache , worse with EOM) • Visual acuity can be normal. • RAPD • Visual field defect • Fundus : 60%-70% Normal (retrobulbar neuritis)
- 4. Visual Field Defact • In ONTT : Central field > peripheral • Focal defect (42%) : Arcuate , Altitudinal , Nasal
- 6. Course of optic neuritis • Vision recovery starts within 2 weeks. • ONTT : at 3 months, visual acuity was >=20/40 in 93 %. • 35 % recurrence in the affected or fellow eye ( 10 year ONTT) • Recurrence twice more common in MS patients than non-MS patients.
- 7. Atypical optic neuritis “Red Flags” • Age <12 years or >50 years • Severe loss of vision (NLP) , Bilateral onset in an adult, no improvement after 6 weeks , progressive course. • No pain. • Ocular findings : severe disc edema , marked hemorrhages, uveitis, exudate, retinitis, phelbitis • Recurrences within a short interval or during steroid taper. • Pre-existing systemic diagnosis ( Cancer, CT disease, Vasculitis, immunosuppression)
- 8. Mimickers of Typical Optic Neuritis • Ischemic (AION, PION). • Neuromyelitis Optica (NMO) • Compressive. • Infectious/ para-infectious. • Inflammatory and infiltrative. • Leber’s optic neuropathy. • Auto-immune. • Paraneoplastic.
- 9. Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)
- 12. Neuromyelitis OpticaWingerchuk et al, Neurology, 2006 • Median age : 35-44 years ; children : 4.4 years • Less common than demyelinating (Asia , African , West Indies 50% of demyelination) Diagnostic Criteria 1) Optic neuritis 2) Transverse Myelitis 3) At least 2 of 3 • LETM ( 3 contiguous veterbal segments) • NMO IgG (70% sensitive , 100% specific) • Brain lesions not compatible with MS
- 13. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders 2015
- 15. Neuro-imaging NMO Khanna et al: J Neuro-Ophthalmol 2012
- 16. Is NMO Screening Indicated in All Optic Neuritis Cases? • Sensitivity issues. • NMO-negative patients . • Anti-MOG antibodies .
- 17. Anti-MOG Optic Neuritis • Younger or even pediatric onset (25%) • MS-like Brain lesions or ADEM , positive OCB • Antibody level show fluctuating course (need to re-test to follow up) • Monophasic usually. • Simultaneous/sequential optic neuritis and myelitis. • Better visual and motor (EDSS) recovery
- 18. Neuromyelitis Optica Spectrum Disorders With Aquaporin-4 and Myelin-Oligodendrocyte Glycoprotein Antibodies: A Comparative Study JAMA Neurol. 2014;71(3):276-283. doi:10.1001/jamaneurol.2013.5857 MRI In MOG + vs AQP4 + ON
- 19. Suggested Blood Work up for Atypical Optic Neuritis Test Disease CBC with Differntial, ESR, CRP Infections, Inflammatory Serum CSF-VDRL, FTA-Abs Syphilis ACE Sarcoid ANA, Anti-DNA SLE NMO IgG (Anti-AQP4, Anti-MOG) NMO C-ACNA, anti-pretinase 3 PPD TB Bartoenlla Hensellae Serology Cat Scratch LHON genetic testing LHON
- 20. Additional Work up • Tissue biopsy of lesions of conjunctiva , ocular adnexa , sinus mucosa and sometimes optic nerve sheath. • Radiologic studies : must include MRI of the brain and orbit with fat-suppression and gadolinium enhancement of the optic nerve sheath. • PET/CT imaging, galluim scan.
- 21. The Use of OCT in MS Raed Behbehani , MD FRCSC
- 22. Optical Coherence Tomography • 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), Ganglion cell layer (GCL). • Qualitative assessment (Ultra-high resolution).
- 23. Why OCT ? • Axonal degeneration was recognized as an early pathological manifestation of MS . • 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.
- 24. Optic Atrophy 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) • Post-mortem analysis show that most MS have changes in the optic nerve and RNFL. (Ikuta and Zimmerman, 1976; Toussaint et al., 1983 , Green et al. 2010)
- 26. Optic Neuritis
- 27. 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)
- 28. Follow Up RNFL in Optic Neuritis • 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)
- 29. 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
- 30. 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).
- 31. GCL loss in Optic Neuritis At 3 weeks post-optic neuritis
- 32. GCL loss in ON
- 33. Changes in Outer Retinal Layers in ON • Decrease GC layer in first 4 months. • Concomitant thickening of the ONL+PS,and less markedly the INL+OPL. (Al-Louzi et al. Multi Scler 2015)
- 34. RNFL and Visual Field 75 microns is a threshold value for visual recovery
- 35. 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
- 36. OCT vs VEP OCT VEP p-value OCT + VEP Prior ON 68% 86% 0.12 98% No ON 19% 40% 0.01 44% OCT is more likely to be abnormal in eyes with history of ON Di Maggio G et al. MSJ 2014 Sensitivity of VEP and OCT
- 37. OCT in NMO • RNFL thickness was significantly worse in NMO and CRION than in RRMS (Bichuetti et al, 2013) • RNFL 41 um thickness is 100% specific for NMO and CRION. (Bichuetti et al, 2013) • Another study found no difference in amount of pRNFL loss if adjusted for optic neuritis episodes (Outteryck et al , Multi Scler 2015)
- 38. OCT in NMO • RNFL is generally not reduced in NMOSD non-ON eyes . (RNFL Loss is attack-related). (Lange AP et al. JNO 2013). • significant macular atrophy and lower average pRNFL thickness2 have already been reported in NMOSD-NON eyes. (Sortichos et al. Neurology 2013) • NMO non-ON has reduced GCL+IPL compared to controls (?ongoing disease activity even in NMO) • Delayed VEP P100 latency in NMOSD . (Ringelstein et al. Muti Scler )
- 39. OCT in NMO JL Benett et al . MSJ 2015
- 40. Beyond RNFL
- 41. Beyond RNFL- Inner and Outer Nuclear Loss • Predominantly macular thinning and near normal RNFL, had thinner inner and outer nuclear layers compared to other subsets and normal ganglion cell layer.
- 42. Use of OCT in Clinical Trials • Retina ( Glial cells and no myelin) • Can detect axonal loss before MRI • The “clinical radiological paradox” • OCT correlates with other visual functions (contrast, colour , visual fields , VEP etc).
- 43. OCT in Neuroprotection Raftopoulos R et al Lancet Neurology 2016 • Randomised, placebo-controlled, double-blind phase 2 trial. • Oral phenytoin (4-6 mg/kd/day) for 3 months vs Placebo • 42 assigned to phenytoin and 44 to placebo. • 30% reduction in the extent of RNFL loss with phenytoin vs placebo (81 u vs 74 u ) at 6 months. • There is a role for Neuroprotection with phenytoin in patients with acute optic neuritis at concentrations.
- 44. Summary • Typical demyelinating Optic neuritis is a clinical diagnosis . • NMO Optic neuritis should suspected in cases of ON with poor recovery and some neuro-radiologic and OCT findings . • Our understanding of the mechanisms of diseases is evolving thanks to new ultra-high resolution OCT. • The non-invasiveness and the reporducibility of OCT makes it ideal to assess neuroprotective effects of drugs in trials.
Editor's Notes
- The eye can be involved in several ways in MS and we as ophthalmologist often are in the front line and now especially with the Mcdonald criteria I often I have to break the news to the patients that he has MS and also talk about therapy ! It was a lot easier when we only had IFN but now I cannot keep up with the ever-growing list of medications and I let Raed do the talking :)
- You all know the classic presentation of ON . Many neurologists asks how come the patient has ON and normal VA ? Well it’s the VF —>
- The most common is the central defect.
- This is just to show that even if you find one Brain MRI lesion with ON in the setting of CIS , the risk of MS is really high unto 60% over 15 years. As we said now with the McDonald Criteria we can often make the diagnosis of MS with optic neuritis .
- These are some of the features that should alert you that you are not dealing with a typical ON.
- As you can see that there are hemorrhages and severe disc edema. Even the ONTT showed that if you are a male with severe disc edema and homorrhages , the chances of developing MS is really low <5%.
- Disc edema and star-shaped exudate . This clinical picture is very atypical for MSON. Cat-scratch Dx , Sarcoid , TB , Toxoplasmosis , Viral (CMV , HSV)
- Leber’s often causes bilateral sequential NAION and often misdiagnosed as ON. Key to diagnosis include history maternal cousin or uncles . Definitive diagnosis of course is by genetic testing for Mitochondrial DNA.
- Another entity now that is increasingly being recognized is NMO. The criteria of this disease is being revised and the spectrum keeps expanding . These were the 2006 Criteria for NMO.
- The classification has been revised now to NMOSD in order to include ever growing clinical presentation and characteristics of NMO. So now you can it can be AQP4 positive + core clinical characteristic (of which ON is one) or can even be AQP4 - 2 clinical relapses and additional MRI findings .
- So what are the typical MRI features of ON in NMO which are required to diagnose NMOSD with negative anti-AQP4 ? Unilateral or bilateral increased T2 signal or T1 gadolinium enhancement within optic nerve or optic chiasm; relatively long lesions (e.g., those extending more than half the distance from orbit to chiasm) and those involving the posterior aspects of the optic nerves or the chiasm are associated with NMO
- Posterior optic nerve involvement in the NMO group, with chiasmatic enhancement exclusively seen in NMO-related ON (3 patients, P = 0.0179). Chiasmal enhancement/enlargement and bilateral enhancement of the optic nerves was exclusively present in the NMO group. Other things that can cause chisamitis : Sarcoid , TB , Infiltrative disorders (IgG4)
- Now the question always arises should we test ALL ON for NMO ? Some people certainly do that and their arguments is that it’s becoming increasingly apparent that you cannot distinguish between the 2 clinically. I would certainly do it in atypical cases especially with severe vision loss and severe loss of RNFL on OCT and with negative MRI for MS or if the MRI shows findings I just described. However , must emphasize that NMO antibodies include anti-AQP4 , anti-MOG : * 10% to 50% can be AQP4-negative In a recent study , 20/61 AQP4-IgG seronegative patients tested MOG-IgG seropositive (33%) (Eur J Neurol from Netherlands).
- MOG + patients tended to have monophasic course and more favorable prognosis (less relapses and lower EDSS) Some studies showed positive MOG in pediatric MS and acute disseminated encephalomyelitis (ADEM) Brain lesions look like MS lesions (supra-tentorial and periventricular) , unlike NMO AQP4 positive patients who have lesion clustering around the brain stem . This is interesting since even long time we knew that there are two types of NMO (monophasic and recurrent) — perhaps monophonic = MOG +ve Therefore , it is probably worthwhile testing may be useful in NMO AQP4 - patients for MOG since it has better prognosis and patients may not need long-term immunosuppression (Rostásy K et al, Mult Scler 2013)
- MOG-Ab–positive patients were often acute ADEM–like with involvement of deep gray nuclei (A-C). A and B thalamic lesions C, T2 hyperintensity in the left basal ganglia + multiple fluffy T2 juxtacortical hyperintensities. Brain abnormalities in AQP4-Ab–positive patients tended to be small well-demarcated subcortical and deep white matter lesions and periventricular lesions (D and E). F, Pontine lesion at the floor of the fourth ventricle, considered characteristic of AQP4-Ab disease. However, lesions adjacent to the fourth ventricle were also seen in patients with MOG-Abs.
- Occasionally all the serological testing may not be helpful and we need to establish the diagnosis by histopathology in many inflammatory and neoplastic conditions. MRI of the brain and orbits with fat suppression is critical . I and Dr Raed have recently seen a patient who has been carrying the diagnosis of ON for many years only when she thin section orbital MRI with fat suppression it turns out that she had OSNM. PET/CT is very useful in ruling inflammatory and lympho-proliferative disorders.
- What is unique about the retina is that there is NO myelin and therefore you are looking in vivo at axons and studying the effects of many neurological diseases . MS now is now only one of several conditions that is being evaluated by MS but other neuro-denegerative diseases (Parkinson’s , Alzheimer’s , ALS) are being studies by OCT.
- We know that MS is no longer considered a demyelination diseases only and neurodegeneration is hallmark of our most recent understanding of the disease . OCT allows to monitor the disease from a neurodegeneration.
- This can be the typical appearance of a patient with MS who is completely asymptomatic and has no prior history of ON. It is known that there is ongoing axonal loss in MS whether patient had or did not have history of ON. This concurs with many post-mortem studies in which changes were found in the optic nerve and RNFL.
- Spectral domain thanks to its higher resolution and fast scan time has allowed us to look into greater details. We know no that almost all of these retinal layers are is either directly or indirectly involved in MS.
- This the typical RNFL of OCT anything in the green is within 2 standard deviations of age and sex matched healthy.
- So what happens to the RNFL after optic neuritis you will see thinning of the RNFL for a period of 3-6 months and then it remains stable. It shows that the contrast of what we see clinically when we say patient recovered , as in the vast majority of optic neuritis , while what's happening in Vivo is axonal loss (neurodegeneration)!
- This is another study also by Costello for 2 years follow up of optic neuritis and it sons that RNFL stays stable after 6 months .
- This diagram shows the rate of loss and you will see that it is highest between 5-6 months with little change After that ..
- RNFL loss occurs in the contralateral eye in ON patients . ? Bilateral onset from start ? Trans-synaptic degeneration from visual pathway lesions
- Recent OCT segmentation allowed us to look at the ganglion cells . This is useful since the early edema of axons we see with ON may confound the picture and prevents us to see the early the neurodegeneration .
- So the change following ON is not limited the inner retinal layers (RNFL,GCL) This study showed changes in the deeper retinal layers : At 4 months : thickening of ONL+PS 4 to 12 months : ONL+PS thickness declined and, at 12 months, was no longer significantly different from baseline (mean change: 0.5%; p = 0.37). Now why does this happen is open to speculation ? 1) Thickening in Neuronal swelling, glial hypertrophy, or extracellular fluid accumulation or deeper retinal inflammation. However, this is consistent with many post-mortem studies did show inflammation and neuronal loss in the outer retinal layers in MS.
- And you can see that well in this diagram as the visual filed mean deviation goes down precipitously below 70 microns and as result this value was used threshold for visual recovery, meaning if you have less than 70 microns RNFL . Clinically it means that you need to be careful suffers another relapse as he would likely not recover much visual function post- optic neuritis.
- This graph shows nicely the relationship between EDSS and RNFL and as we go higher EDSS we see corresponding reduction in RNFL . We have published a paper recently in JNS that showed good correlation between neurological disability and EDSS in mild disability MS without ON.
- There are controversies over the role of VEP. VEP measures function , while OCT measures structure. Most studies found that OCT is more sensitive in detecting lesions because VEP can detect lesions of the posterior visual pathway . OCT is more useful for follow up and has better reproducibility . Therefore OCT may be more useful as screening while OCT is better for follow up .
- Although previous studies found more RNFL loss in NMOSD than MS , they did not adjust for number of optic neuritis episodes (more frequent in NMO). Therefore , global RNFL atrophy may not be a good marker to distinguish MSON from NMSDON. It may be better to look at normal eye and look at temporal RNFL loss (more frequent in MS).
- Earlier studies using time domain OCT and subsequent studies have shown that axonal loss occurs even in NON in NOMSD. This is supported by VEP studies showing delayed latency even in NON NMOSD ( involvement of the posterior pathways, with a retrograde trans-synaptic degeneration process.
- The NMO-ON patient shows more severe thinning both in the RNFL and GCL. Notice that RNFL loss in MSON occurs usually in temporal quadrant (preferential involvement of small diameter axons in maculopapular bundle. However , in NMODS ON the RNFL loss is more diffuse ( more profound injury in arcuate and nasal fibres in NMOSD than in MS). Therefore , more temporal retinal nerve fibre involvement in MS and a more diffuse retinal nerve fibre involvement in NMOSD
- The newer machines of spectral domain OCT and their higher resolution we have now segmentation algorithms that allows us to examine the layers individually and inspect them closely.
- Saidha et al. have described a type of MS OCT patter characterized by relatively preserved inner retinal layers (GCL and RNFL) and thinner outer retinal layers (Inner and outer nuclear). This has been been associated with rapid disability progression and aggressive disease. The pathophysiology is thought to be ? retrograde GCL death or ?primary inflammatory process in deeper retinal layers .
- The retina is like a small brain (glial cells and no myelin only axons). Thus it is ideal for studying the effects of neuroprotective drug trials. Because of its high resolution it can detect axonal loss before the brain. Brain lesions often do not correlate clinically with functions , while OCT does correlated with visual function (VEP , visual fields , contrast , visual acuity etc)
- This study from the UK showed where patients were randomized to oral phenytoin started witihin 2 weeks of onset of ON. Other similar trials are being conducted on erythropietin and amiloride. Almost any theprapeutic trial now inlclude OCT as a secondary outcome measure.
- Atypical ON : Suspect (bilateral, painless, uveitis, no improvement after 6/52, severe disc edema and hemorrhages). It should be investigated more intensively (serology, LP, biopsy). NMO : poor visual recovery , posterior visual pathway (chiasmal involvement) OCT is an excellent method to follow the effects of various neurological diseases by assessing neural tissue . Not only that it is allowing us to study the effects and pathophysiology of disease. And finally the invasive and the reproducibility of OCT makes it idea to use as an outcome measure in therapeutic trial.