optic neuritis and oct in multiple sclerosis
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Optic Neuritis Raed Behbehani , MD FRCSC
Eye involvement in MS
• Afferent : Optic neuritis , Intermediate Uveitis , Visual Pathway Lesions
• Efferent : INO , nystagmus , Cranial nerve palsy
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)
Visual Field Defact
• In ONTT : Central field > peripheral
• Focal defect (42%) : Arcuate , Altitudinal , Nasal
ONTT 15 years
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.
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)
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.
Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION)
Neuro-retinitis
http://medstat.med.utah.edu/NOVEL
Leber Mitochondrial Optic Neuropathy
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
International Consensus Diagnostic Criteriafor Neuromyelitis Optica Spectrum
Disorders 2015
Neuro-imaging NMO
Neuro-imaging NMO
Khanna et al: J Neuro-Ophthalmol 2012
Is NMO Screening Indicated in All Optic
Neuritis Cases?
• Sensitivity issues.
• NMO-negative patients .
• Anti-MOG antibodies .
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
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
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
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.
The Use of OCT in MS
Raed Behbehani , MD FRCSC
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).
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.
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)
Spectral Domain OCT
Optic Neuritis
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
• 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).
GCL loss in Optic Neuritis
At 3 weeks post-optic neuritis
GCL loss in ON
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)
RNFL and Visual Field
75 microns is a threshold value for visual recovery
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
OCT vs VEPOCT 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 ONDi Maggio G et al. MSJ 2014
Sensitivity of VEP and OCT
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)
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 )
OCT in NMO
JL Benett et al . MSJ 2015
Beyond RNFL
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.
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).
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.
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.