Pablo Villoslada

Department of Neurology

University of California, San Francisco (UCSF)

San Francisco, CA, USA

Declared receipt of grants and contracts from Roche, Biogen, Genzyme, ISCII, ECHoryzon2020, Fundation Marato TV3, GAEM. Declared receipt of honoraria or consultation fee from Roche, Novartis, Health Engineering, Araclon. He is takeholder in Bionure Inc, Spire Bioventures, MintLabs

1. Does visual evoked potential (VEP) still have a role in MS monitoring?

2. It has been recently proposed to incorporate optic nerve among sites of damage accounting for dissemination in space (DIS)

3. Some new tools have been proposed to study anatomical integrity of the optic nerve and retina, among these OCT is the newer and more promising

4. Review the data available about the role of OCT in quantifying optic nerve damage, facilitating differential diagnosis (NMO vs MS), monitoring disease progression, evaluating therapeutic efficacy, and detect novel pathology

Objectives

Martinez-Lapiscina et al Mult Scl, 2014

Visual Pathway as a model for studying CNS damage

• Clinical presentation

– Optic Neuritis: 1/4 relapses and CIS

– Vision impairment along disease course

• Subclinical ON

• Primary damage retina (normal appearing grey matter)

– Visual impairment in PMS: vision is impaired with progression but less than motor function

• Impact in quality of life

– Patients always rate vision in the top 5 priorities

– Validated QOL for vision: NEI-VFQ-25 with 10 neuro-ophthalmology items

– Loss of 7 letters (1.5 lines) on LCVA is meaningful from patient perspectives

Damage of the visual pathway in MS

Galetta et al. Neurol Neuroimmunol Neuroinflamm, 2015 Heesen et al. Mult Scler, 2008

• Visual Acuity

– High contrast visual acuity (Snellen) is NOT sensitive in ON/MS damage => STOP

– Low contrast (2.5%) is the most sensitive measurement (Sloan charts)

– Contrast sensitivity (Pelli Robertson)

• Color Vision

– Isihara is NOT sensitive => STOP

– Hardy Rand Rittler pseudoisochromatic plates (HRR)

– Comprehensive test: Farnsworth-Munsell 100 hue test, Lanthony

• Visual fields (perimetry)

• Electrophysiology

– Visual Evoke Potentials (VEP)

– Multifocal visual evoked potentials (mfVEP)

– Electroretinography (ERG)

• Imaging

– MRI: optic nerve, chiasm, optic tracts, Lateral Geniculate Nucleus (Thalamus), Optic Radiations, Visual Cortex

– OCT: spectral domain

– Retinography (Fundoscopy)

– Other: GDX, HRT

Assessment of visual function in MS

Galetta et al. Neurol Neuroimmunol Neuroinflamm, 2015

Sensitivity of vision scales in ON and MS 2.5% LCVA

Performance of clinical outcomes AON in Barcelona cohort HCVA

1.25% LCVA HRR

2.5% LCVA

Ceiling effect

Floor effect

• Thickness of central retina – pRNFL: peripapillar Retinal Nerve Fiber

Layer

– MV: Macular Volume

– mRNFL> Macular RNFL

– GCIP> Retinal Ganglion cell layer

– INL: Inner Nuclear Layer

– Outer layers

• Fast, not expensive, convenient for patients, suitable at Neurology outpatient

• High accuracy: 3 µm

• High reproducibility: eye tracking

• Limitations – Central retina

– Eye diseases (myopia, cataracts)

– Incidental findings

– Each device use different quantification system => no interchange

Spectral domain OCT

• LCVA is associated with reduced pRNFL:

– 1-line LCVA => RNFL 4 µm.

• pRNFL, mRNFL and GCL correlates with high and LCVA (2.5% and 1.25%)

• Decrease below 75 µm predict permanent visual impairment (time domain OCT)

• The change in the GCIP thickness from baseline to month 1 predicted visual impairment by month 6:

– a decrease >4.5 μm predicts poor LCVA (sensitivity of 91% and specificity of 88%)

– > 7 um predicted poor VF and CVA (sensitivity of 78% and 100% respectively and specificity of 71%)

OCT is a validated marker of ON severity

Baier et al. Neurology 2006; Walter et al. Opthalmol, 2012; Talman et al. Ann Neurol, 2010; Seigo et al. J Neurol, 2012;

Fisher et al. Ophthalmol, 2006; Henderson et al. Brain, 2007; Gabilondo et al Ann Neurol, 2015

Fellow-eye

AON-eye

AON vs Fellow eye

pRNFL Macular Thickness

Gabilondo et al. Ann Neurol, 2015

• Almost all damage is established in the first 3 months

• Atrophy: pRNFL, mRNFL, GCIP

• Swelling: Outer layers (pRNFL at baseline)

Dynamics of retina atrophy in ON

• IMSVISUAL consortium www.imsvisual.org

• Multicentric longitudinal evaluation of OCT as predictor disability worsening

• 879 MS: CIS=74, RRMS=664, PMS=141

• OCT (Spectralis or Cirrus) at baseline

• Disability worsening: 252 (29%) out of 879

• Median follow-up of 2·0 years (range 0·5–5 years).

• pRNFL < 87 -88 μm (Spectralis or Cirrus)

– x2 risk of disability worsening at any time 1-3 year follow-up

– x4 risk of disability worsening at any time 4-5 year follow-up

• MV < 8.7 mm3: x2 risk of disability worsening at any time 1-4 year follow-up

Martinez-Lapsicina et al. Lancet Neurol 2016a

Retina atrophy is a predictor of worsening disability in MS

Martinez-Lapsicina et al. Lancet Neurol 2016a

<87-88 µm

88-97 µm >97µm

Biomarker: pRNFL <88 => EDSS next 2-5 years

• Trans-synaptic degeneration is present in the visual pathway: correlation between RNFL thickness and lesion load Optic Radiations

• Domino effect?

This process stops in RGC and may not extend to bipolar cells or visual cortex: role of multiple afferences / synapsis?

• Unknown how long time takes to be produced

• Role in progressive MS?

• Other types of neuronal degeneration

– Anterograde (Wallerian) axonal degeneration

– Retrograde axonal degeneration

– Dendrites (synapses) pruning

– Soma shrinking

Trans-synaptic degeneration: a model of progressive MS?

Gabilondo et al. Ann Neurol 2013; Keller et al. PloSONE 2014; Klistoner et al. Neurology 2014. Balk et al JNNP 2014, Jindara et al Brain 2012; Tur et al Brain 2016

Galetta et al. Neurol Neuroimmunol Neuroinflamm, 2015; Klistoner Ann Neurol, 2014; Frohman Neurology, 2016

• Latencies are sensitive to demyelination (>120 ms)

• Standardization of VEP for RCT

• Latencies VEP the most sensitive for diagnosing ON (than OCT)

• mfVEP more objective than perimetry and sensitive to sectorial damage

• ERG (pattern, mf) very sensitive for minor retina damage, including RGC damage

• VEP and mfVEP under testing in RCT with remyelinating drugs (e.g. anti-Lingo, Clemastine, etc)

Electrophysiology for MS monitoring

Ortiz-Perez et al Neurology 2013; Sepulcre et al. Neurology 2007; Rio et al. Neurologia 1993

• Perivenular vasculitis in the peripheral retina

• Prevalence has decreased in the last decades (20% 90s => 10% 2000s => <1% now) => effect of immunotherapies?

• Associated with presence of gad+ lesions => same pathogenesis that brain inflammatory infiltrates in the absence of myelin?

• Easy to monitor with wide-field retinography

Retinal Periphlebitis in MS

✔ ✔

Bennet et al. Mult Scl, 2015

• More severe visual impairment and RNFL and GCIP thinning and more frequent development of microcystic macular edema than in MS

• Preferences for superior and inferior quadrant (MS: temporal)

• Subclinical damage seems to be rare in NMO

• Useful but not patognomomic for the differential diagnosis for different causes of ON

Damaged visual pathway in NMO

• Indication

– ON

• Model of MS relapses

• Acute, orphan, easy to recognize

– MS

• Always damaged in almost all patients

• Visual disability: significant unmet need

Drug mechanism of action

Neuroprotection: OCT + mfERG

Remyelination: mfVEP (e.g. anti-Lingo trial)

Regeneration: OCT + AO + mfERG + fMRI

Specific molecular target: molecular imaging

• Good prediction from surrogate to clinical end-points

– 4 µm decrease GCIP => 7 letters in 2.5%LCVA

– 7µm decrease GCIP => color vision and visual fields (mean deviation)

– 7 letters change in 2.5% LCVA => quality of vision

The visual pathway as a platform for clinical trials

• Indication: ON defined using the ONTT definition

• Trial duration: 3 month

• Sample sizes calculation

– OCT: > 25 ON patients per arm

– LCVA: > 35 ON patients per arm

• Disease duration is critical: <10 days?

• Idiopathic CIS and MS first relapse (to avoid heterogeneity in baseline measurements)

• Primary clinical end-point

– 2.5% LCVA> change from baseline fellow-eye to 3-6 month in ON-eye

Design of clinical trials in ON (OK FDA)

• Surrogate end-points • Primary (for a phase 2 trial):

thickness GCIP by OCT • Secondary

• OCT: pRNFL • VEP: latencies • clinical: BCVA, LCVA, clor

vision, perimetry, QOL • Meaningful clinical improvement

• 7 letters improvement translate to quality of vision

• FDA retina diseases: 15 letters

Gabilondo et al. Ann Neurol, 2015 Martinez-Lapsicina et al. Lancet Neurol, 2016a Martinez-Lapsicina et al. Lancet Neurol, 2016b

2.5% LCVA as primary end-point in ON trials

1. VEP in MS monitoring?

2. Optic nerve for DIS

3. OCT for monitoring integrity of

CNS/retina

4. OCT for diagnosis, monitoring and

clinical trials

2.5% LCVA as primary end-point in ON trials

✔

✔

✔

✔

1. Damage of the visual pathway reflects overall CNS damage in MS

2. ON must be considered an emergency

3. Always use low contrast vision and color vision (perimetry and quality of vision) for monitoring visual disability

4. OCT and VEP are validated markers of severity of ON and should be used for monitoring and performing therapeutic decisions

5. OCT has been demonstrated as a marker of disability progression in MS and can be used for monitoring and performing therapeutic decisions

1. Performing OCT once per year

2. Identifying patients reaching cut-offs and use it for decision making process

6. New technologies coming for clinical use

– Electrophysiology: mfVEP, ERG

– Laser based imaging: Retina spectroscopy, Doppler OCT, Adaptive Optics, wide field retinography, pupilography

What’s relevant for your clinical practice?

Monitoring vision and damage of the visual pathway is useful for monitoring the course of MS and help in the decision making process.

Take home message

Monitoring vision and damage of the visual pathway is useful for monitoring the course of MS and help in the decision making process.

Take home message

Monitoring vision and damage of the visual pathway is useful for monitoring the course of MS and help in the decision making process.

Take home message