Titolo progetto: PRIN2022 - ON-COLOUR - Investigating vascular predictors of poor visual outcome in the multidisciplinary management of immune-mediated optic neuritis 

Programma di finanziamento: PRIN 2022

Responsabile scientifico: prof. Luca Quartuccio

Ruolo del DAME: partner

Descrizione generale:

It is clear that too simplistically the term ‘optic neuritis’ is associated to an inflammatory optic neuropathy, and in relation to MS and NMOSD. Immune-mediated ON is indeed a much more complex condition, of partially unraveled nature and with only suboptimal management.

ON-COLOUR attempts to tackle the following main gaps of knowledge about ON and to provide clues to optimize its management:

1. the lack of consistent ON classification;
2. an inconsistently performed diagnostic pathway;
3. the overlooking of potentially relevant yet neglected prognostic factors; and, consequently
4. the lack of a multidisciplinary care pathway in the management of ON.

1. Lack of consistent ON classification. There is little consensus about a systematic nosology for ON and different studies adopt different classification systems, leading to confusion in interpreting their findings. ON is traditionally divided into ‘typical’ and ‘atypical’ forms based on clinical factors, wherein the ‘typical’ ON is generally associated with MS or regarded as a demyelinating clinically isolated syndrome at risk of conversion to MS. Alternatively, ON is classified by etiology: the immune-mediated ON can be subclassified into several types including ON associated to MS, to NMOSD, with systemic disorders (such as connective tissue disease, granulomatous disease, infective conditions), and other idiopathic ON without systemic disease (recurrent isolated ON, chronic relapsing inflammatory optic neuropathy, solitary isolated ON).

2. Inconsistently performed diagnostic pathway. Based on clinical specific manifestations at onset and in the attempt at framing the ON within known disorders of the CNS such as MS, NMOSD, or within other systemic disorders in differential diagnosis, ON patients are initially referred to either the ophthalmologist or to the neurologist. Depending on the setting of care, patients undergo different – ultimately incomplete - diagnostic pathways.

3. Overlooking of potentially relevant yet neglected prognostic factors. Cerebral hypoperfusion of the normal appearing white matter (NAWM) at perfusion-weighted MRI studies has been detected in patients with both relapsing-remitting and progressive MS and even at an early stage of the disease [Adhya et al, 2006]. By promoting mitochondrial dysfunction, oxidative stress, and axonal loss, hypoperfusion is directly associated with degeneration and atrophy in MS as compared to a control population [Marshall et al, 2014]. Cerebral hypoperfusion in MS has been hypothesized to be mediated by elevated levels of endothelin-1 (ET-1), a potent vasoconstrictive peptide released in the cerebral circulation from reactive astrocytes in MS focal lesions and actively implicated in modulating activities of neurons and glia [D'Haeseleer et al, 2013]. As acute MS-ON may feature peripapillary vascular hypoperfusion and disc swelling [Chen et al, 2017], leading to poor visual recovery in MS-ON by means of axonal loss. Vascular hypoperfusion in acute ON is therefore a potentially new neurovascular model for CNS demyelination [Chen et al, 2017]. ET-1 levels in the CSF are directly associated with clinically aggressive MS-ON with failure in the visual recovery [Castellazzi et al, 2019]. Not only ET-1 can be a detectable potential prognostic marker of immune-mediated ON, but its detection may allow to identify strata of patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan) [D'Haeseleer et al, 2013] rather than with high dose iv corticosteroids commonly used instead to treat acute visual exacerbation in MS.

4. Lack of a multidisciplinary care pathway in the management of ON. The overall management of ON (ie., diagnosis, treatment and clinical follow up) has so far been mostly performed in neurological and/or ophthalmological clinical settings, but its complexity should deserve a multidisciplinary approach, including rheumatology, neuroradiology/imaging, neurosonology of the optic nerve and orbit, CSF studies.

Partner del progetto:                                                                                

• Università degli Studi di Ferrara
• Università degli Studi di Napoli
• Università degli Studi di Udine
• Università degli Studi di Sassari

Date inizio e fine progetto: 18.10.2023 – 17.10.2025

Budget totale del progetto: 55.467,00€

Sito web: https://prin.mur.gov.it/ 

Finanziato dall’Unione europea – Next Generation EU