Optic Neuritis and OCT in Multiple Sclerosis

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.