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Optic Neuritis and OCT in Multiple Sclerosis
- 1. Optic Neuritis Raed Behbehani , MD FRCSC
- 2. 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)
- 3. Visual Field Defact • In ONTT : Central field > peripheral • Focal defect (42%) : Arcuate , Altitudinal , Nasal
- 4. International Consensus Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorders 2015
- 6. Neuro-imaging NMO Khanna et al: J Neuro-Ophthalmol 2012
- 7. Neuro-imaging in NMO Bennett: J Neuro-Ophthalmol 2016; 36: 238-245
- 8. Is NMO Screening Indicated in All Optic Neuritis Cases? • Sensitivity issues. • NMO-negative patients . • Anti-MOG antibodies .
- 9. Pediatric Optic Neuritis and Risk of MS Ann Neurology 2015
- 10. Pediatric Optic Neuritis and NMO • AQP4-IgG was associated with early recurrence and visual impairment. Absoud et al. 2015 • Negative AQP4-IgG associated with physical disability . Absoud et al. 2015 • Rituximab is the first choice. (Oliveri et al. 2016 , Chitnis et al. 2016)
- 11. Anti-MOG Optic Neuritis • Male • Monopahsic • Simultaneous/sequential optic neuritis and myelitis. • Better visual and motor (EDSS) recovery • Two recent RCT recurrent disease course with optic neuritis as the most frequent symptom, particularly in women. • Frequent attacks are often associated with accumulating damage and functional impairment
- 12. Anti-MOG and Pediatric Optic Neuritis • Favorable prognosis • 19/33 of ADEM were positive for anti-MOG . Baumenn at al. J Neurol Neurosurg Neuropsych 2015 • A phenotype of ADEM followed by recurrent optic neuritis (positive for anti-MOG) Miyauchi et al. 2014 • Anti-MOG positive Recurrent Optic Neuritis . Tsubaraya et al. 2015
- 13. 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)
- 14. 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.
- 15. Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)
- 18. 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
- 19. The Use of OCT in MS Raed Behbehani , MD FRCSC
- 20. 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).
- 22. How Can OCT Help in MS? • Diagnose sub-clinical optic neuritis • Differentiate NMOSD optic neuritis from demyelinating optic neuritis • Predict progression and disability in MS • Outcome measure for neuro-protection • Correlates with brain atrophy • Monitor side effects of DMD (Fingolimod) • Differentiate optic neuritis from other causes of loss of vision
- 23. Optic Atrophy in MS • Post-mortem analysis show that most MS have changes in the optic nerve and RNFL in 94%-99% (Ikuta and Zimmerman, 1976; Toussaint et al., 1983 , Green et al. 2010)
- 24. Diagnosis of Optic Neuritis • RNFL thinning starts at 2-3 months , progressed till 6 months and then stabilized up to 2 years (Costello et al. 2009) • PRNFL thinning of around 20.38 um in MS eyes with history of ON , and 7.08 u in MS eyes without history of ON.
- 25. GCL loss in ON
- 26. RNFL and Visual Field 75 microns is a threshold value for visual recovery
- 27. Differentiation of NMOSD from MS • RNFL thickness was significantly worse in NMO than in RRMS (Bichuetti et al, 2013) • RNFL 41 um thickness is 100% specific for NMO . (Bichuetti et al, 2013) • RNFL loss tends to be more diffuse in NMO , while in MS it’s more temporal.
- 28. OCT in NMO JL Benett et al . MSJ 2015
- 29. OCT Predicts Disability • PRNFL =< or equal to 87 μm (Cirrus) or 88 um (Spectralis) had double the risk of disability worsening at any time after the 1st and up to the 3rd years of follow-up • Risk was increased by nearly four times after the third and up to the 5th year.
- 31. Button et al. Neurology 2017 Outcome Measure For Neuro-protection
- 33. RNFL and Brain Atrophy • 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 (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)
- 34. Fingolimod-Associated Macular Edema (FAME) • 1.5% cumulative incidence • 68% develop within 4 months, 11% after 12 months • Seven times more common in diabetes • New selective S1P receptor modulator (ozanimod, siponomod) had no cases of ME after 24 months (phase 2 trial)
- 35. Alemtuzimab and Thyroid Disease • Anti-CD 52 monoclonal antibody. • Cum prevalence is 34% of thyroid dysfunction in phase 2 trial. • Anti-TSH receptor body > anti-TPO positive. • Few cases in Phase 2 and 3 trials reported ophthalmopathy (tears , steroids , surgery)
- 36. PML • Typical MRI is T2 hyperintense , T1 hypointense lesions of white matter. • Most common presentation is homonymous hemianopia. • Cortical blindess and higher cortical visual dysfunction.
- 37. 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
- You all know the classic presentation of ON . This is the typical profile of an optic neuritis patient..
- The most common is the central defect. Visual field is important because many times visual acuity is NORMAL.
- You are all familiar with the new revised classification of NMOSD , which has allowed us now to diagnose more cases of NMOSD than before. It’s critical since the treatment is drastically different than MS. So now you can it can be AQP4 positive + core clinical characteristic (of which ON is one) Patients with NMOSD who do not have detectable AQP4-IgG must have a minimum of 2 core clinical presentations, and 1 presentation must be ON, TM, or an area postrema syndrome.
- There are some neuro-radiologic features that can give a clue that this is NMOSD 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
- In fact some have reported that posterior optic nerve and chaismal involvement occurred ONLY in 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 differential dagnoses based on this neurorad picture : Sarcoid , TB , Infiltrative disorders (IgG4)
- If you image you will see other things along the spectrum of neuroradiological picture in NMOSD. Magnetic resonance imaging in neuromyelitis optica spectrum disorders. LETM And E --- central spinal cord lesions. C. Optic nerve . D. Chiasmal involvement . E. Area postrema , which is a core clinical feature . F. lesions in the mid-pons. G. periependymal lesions around the fourth ventricle. H. hypothalamic inflammation. I, J and thalamic lesions
- 1) 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. 2) Cell-based serum assays using microscopy-based or flow cytometry–based detection are recommended for AQP4-IgG serologic testing. Enzyme-linked immunosorbent assay (ELISA) and indirect immunofl uorescence (IIF) of tissue sections are typically less sensitive 3) 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). And I must add that you (personal communication with experts) you are never positive for two ; either AQP4 or MOG
- Abnormal MRI and the presence of bands predicted the progression to MS , while sex and laterality had no influence. Patients with combined abnormal MRI and positive oligoclonal band had 27 the risk for conversion to MS compared to those without neither.
- Again what applies to NMO in adults seem to apply to children
- MOG + patients tended to have monophasic course and more favorable prognosis (less relapses and lower EDSS) Brain lesions look like MS lesions (supra-tentorial and periventricular) Approximately 20% of AQP4-IgG–seronegative patients are seropositive for MOG-IgG. 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 The test is still not commercially available though and must be sent to a special lab (Rostásy K et al, Mult Scler 2013)
- There have been various reports of the MOG in kids with ADEM . In fact there is one phenotype with ADEM followed by recurrent optic neuritis that is often is diagnosed as MS but if you test for MOG you may see it’s postive and this becomes another entity altogather .
- 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.
- 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.
- 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. Now we have EDI and Swept source OCT which provide even greater detail and depth of imaging .
- 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.
- RNFL loss starts at 2-3 months and stabilzes by 6 months. This is a mataanalysis by Petzold and they showed that even eyes with no prior ON , you will have loss of RNFL of 7 u and this is outside the range of variability. I underlined WITHOUT history of ON is because I get to see many patuents who have symptoms but no objective findings in exam. Did these patients have subclinical optic neuritis ? So in a patient who you think has MS a difference of 6 microns in the RNFL between the two eyes can indicate prior unilteral ON.
- 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.
- Because these are two different diseases and have different treatments and traditional MS therapy can make NMO worse , it’s important to differentiate the two .
- 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).
- Multicenter study of 879 published in Lancet Neurol 2016 patients with CIS, RRMS and PMS followed after baseline OCT. Patients with optic neuritis excluded. This study showed that basline OCT can predict the risk of disability worsening and has a role in monitoring MS patients. So OCT can help you in knowing who will likely to progress and then perhaps adjust your therapy.
- We have published a paper recently in JNS that showed good correlation between neurological disability and EDSS in mild disability MS without ON.
- Retrospective review of 402 patient on DMD. At least follow up of 1 year with aderence to DMD. Aggressive therapy with NAT slows the rate of GCIP, ONL, INL, and AMT thinning relative to more conventional MS treatments such as GA and the IFNs (particularly IFNSC). This support the role of OCT in monitoring the neuroprotective effects of DMD.
- This is from the recent anti-LOINGO trial , which showed that remyelination did not diff significantly between the opicinumab and placebo groups in the ITT population at week 24. However , it did show that ganglion cell loss occurs as early as 2-4 weeks following ON and this is the probably the window of opportunity for treatment. You can extrapolate from this to other DMD in MS.
- Visual complaints occur in patients with PML and are often the presenting sign. Patients with PML can present with homonymous hemianopsia . Remember , HH is extremely uncommon in MS patients it just does not happen when you see it always suspect PML.
- 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.