Optic Nerve Head Evaluation Through Multimodal Blood Flow Analysis: a Prospective Observational, Multi-center Study

BACKGROUND AND RATIONALE The vascular component of the ONH, like that of the retina, is an essential part for the ONH homeostasis, but is considered difficult to be precisely analyzed, especially in optic nerve pathologies. Little is known about the vascular component and its role in both acute and chronic ONH diseases, particularly in conditions that cause swelling, where it is mandatory to differentiate edema from pseudo-edema.

Today, the gold standard for the vascular imaging of the retina is angiography, using either fluorescein or indocyanine green. However, conventional angiography has the disadvantage that the invasive administration of dye into the venous system is required, leading to low but potentially life-threatening side effects as allergic reactions; furthermore, data obtained are not standardizable or exploitable for a quantitative analysis. However, new technologies such as OCT-A can provide standardizable and quantifiable data on vascular structures that can be used in a statistical analysis. Additionally, eco-colordoppler ultrasound provides direct measurements of ONH blood-flow.

OBJECTIVES AND ENDPOINTS Objectives Endpoints: The aim of the study is to assess ONH vascular and structural components optic neuropathies with and without ONH edema or pseudo-edema through OCT-A (OCT-angiography) and ocular blood-flow through eco-colordoppler.

Primary Objective: to identify parameters correlated to the development and progression (prognostic biomarkers) of the diseases.

Primary Endpoint: Analysis of data collected in symptomatic and asymptomatic eyes, obtained through OCT-A in order to evaluate the relationship between functional and structural parameters in order to identify parameters correlated to the development and progression of the diseases.

Timepoint: 24 months from the enrollment.

Secondary Objectives: To assess and compare different ONH vascular components through OCT-A and eco-colordoppler in order to identify parameters correlated to the diseases.

Secondary Endpoints: To detect OCT-A parameters (vessel density, perfusion density), and eco-colordoppler parameters of central retina artery (CRA) and short posterior ciliary artery (SPCA) (systolic and diastolic flow and resistance). in order to evaluate their relationship in each optic neuropathy.

Timepoint: 24 months from the enrollment.

STUDY DESIGN OCT-A and eco-colordoppler are technologies which enable optic nerve head (ONH) blood perfusion detection. The aim of the study is to assess ONH vascular and structural components in patients affected by ONH edema or pseudo-edema with OCT-A and, in a subset of 35 patients, analyze the ONH vascular blood flow through eco-colordoppler analysis.

This is a national, prospective observational, multicentre study:

\- in the cohort study (70 patients) will be included patients with chronic optic neuropathies with or without ONH pseudo-edema (NTG, ODD, DOA, WS) and contralateral eye (not affected) for each optic neuropathy and patients with acute optic neuropathies with ONH edema and pseudo-edema (NAION, LHON, papilledema, anterior neuritis). The study includes an observational period of 24 months, from baseline (date of signing of informed consent) to 24 months (4 follow-up visits 6 months apart, as in clinical practice).

Moreover, a normative database will be created in order to compare data for different ages.

Only variables obtained according to routine clinical practice, available in the hospital charts or patient's clinical records, and collected according to the study objectives can and should be documented in this study.

All patients enrolled will undergo at the same procedures reported in Figure 1, according to routine clinical practice.

In details, for every patient belonging to each disease group, a complete neuro-ophthalmologic evaluation and the data of the methodic, at baseline and in every time-point, will be collected from all the recruiting centers. Finally, the data obtained will be statistically analyzed, with the primary objective of finding a possible diagnostic and prognostic biomarker for every disease group.

The data obtained using the Orion OCT analysis Software, Voxeleron, will be analyzed by IRCCS San Raffaele.

Eco-colordoppler will be performed and analyzed at IRCCS San Raffaele, O.U. of Ophthalmology in a subset of 35 non-consecutive patients for the secondary endpoint.

Study duration Duration of enrollment: 12 months Duration of treatment: 24 months Duration of total follow-up: 24 months Duration of total study period: 36 months

STUDY POPULATION Study Participants The study will include 70 subjects, regardless of age, gender, comorbidities or drugs taken.

Inclusion Criteria

1. Participant (or parents/legal representative/tutor for minors) is willing and able to give informed consent for participation in the study; 2. patients affected by acute ONH edema (NAION, papilledema, optic neuritis); 3. patients affected by acute pseudoedema (LHON); 4. patients affected by chronic pseudoedema (LHON, ODD); 5. patients affected by chronic ONH neuropathies (NTG, DOA, WS) non-affected eyes in each optic neuropathy patient; 6. The medical product is the standard of care for the patient or the participant is taking the medicinal product according to clinical practice.

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. any other ONH disease or neurological /retinal diseases impairing the evaluation of the ONH; 2. evidence of media opacities affecting the quality of the vascular assessment; 3. patients affected Alzheimer/Parkinson disease will be considered separately.

Screening Failures Screen failures are defined as participants who consent to participate in the clinical study but do not meet the criteria for participation in the study. A minimal set of screen failure information is required to ensure transparent reporting of screen failure participants. Minimal information includes demography, screening failure details, eligibility criteria.

No re-screening procedure is foreseen.

STUDY OBJECTIVES The aim of the study is to asses ONH vascular and structural components optic neuropathies with and without ONH edema or pseudo-edema with OCT-A and analyze the ONH vascular blood-flow with eco-colordoppler ultrasound.

The primary objective is to assess ONH vascular and structural components in optic neuropathies with and without ONH edema or pseudo-edema, through OCT-A (OCT-angiography) in order to identify parameters correlated to the diseases and obtain diagnostic and prognostic biomarkers.

The secondary objective is to evaluate ONH vascular supply using two different devices, OCT-A and eco-colordoppler, which specifically evaluate the ONH ocular and retro-ocular vessels in order to identify different disease patterns. The eco-colordoppler measurements will be collected on 35 patients enrolled only.

In accordance to the inclusion/exclusion criteria, patients to be enrolled will be those with Acute optic neuropathies with ONH edema and pseudo-edema (NAION, LHON, papilledema, anterior neuritis) and chronic optic neuropathies with or without ONH pseudo-edema (NTG, ODD, DOA, WS) and contralateral eye (not affected) for each optic neuropathy.

In the prospective observational part of the study, data will be collected from patient chart review, as is the case for clinical practice, from ICF collection up to 24 months.

For OCT-A, the following devices are allowed:

1. DRI OCT Triton, 3D Optical Coherence Tomography (Topcon Healthcare, Tokyo, Japan); OCT-A is a non-invasive imaging technique based on optical coherence tomography (OCT) developed to image and visualize vascular networks in the human retina; 2. Cirrus OCT-A (Carl Zeiss Meditech Inc., Dublin, CA, USA): OCT-A is a non-invasive imaging technique based on OCT developed to image and visualize vascular networks in the human retina; 3. Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany): OCT-A is a non-invasive imaging technique based on optical coherence tomography (OCT) developed to image and visualize vascular networks in the human retina;

The medical devices are CE marked and are used according to the indications of use of the marketing authorization released by the national Regulatory Authority (CE marking documents that the medical device complies with applicable EU legislation are required) and already used in OSR and in the other Clinical Units as part of normal clinical practice.

Furthermore, only variables obtained according to routine clinical practice, available in the hospital charts or patient's clinical records, and collected according to the study objectives can and should be documented in this study.

During the observational period, assessments are routinely performed in accordance with current guidelines and local standard of care. The decision of any treatment (or interruption) related to the disease under study and to concomitant diseases, is the responsibility of the treating physician and is not regulated by this protocol.

The additional examination, eco-color doppler, in a subset of 35 patients will be performed. Eco-colordoppler is a non-invasive method developed to visualize blood flow in color and the main blood vessels. Venous blood is shown in blue, while oxygen-rich arterial blood, is displayed in red. The device used is Digital Color Doppler Ultrasound System (Sonoscape Medical Corporation), a medical device with CE mark and used according to the indications of use of the marketing authorization released by the national Regulatory Authority. The exam will be performed in every follow-up visit (6 months) at San Raffaele Hospital; the duration of the exam is about 5 minutes for each eye.

Study object description OCT and OCT-A: structural and vascular analysis of the optic nerve head employing a coherent light to assess the morphology and vascular supply of the area (DRI OCT Triton, 3D Optical Coherence Tomography (Topcon Healthcare, Tokyo, Japan; Cirrus OCT-A (Carl Zeiss Meditech Inc., Dublin, CA, USA; Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). All the devices are equivalent in terms of results for this study. The OCT/OCT-A scans take approximately 5-10 minutes to be performed and it is not invasive.

Ecocolordoppler: vascular assessment of the retrobulbar vessels which supply the optic nerve employing ecosonography (Digital Color Doppler Ultrasound System (Sonoscape Medical Corporation)). The exam takes 10-15 minutes and it is not invasive.

• To assess and compare different ONH vascular components through OCT-A and eco-colordoppler in order to identify parameters correlated to the diseases. [Срок оценки: 24 Months]