Assessing functional and structural visual outcomes in human acute optic neuritis and murine experimental optic neuritis

Abstract

Optic neuritis (ON) is an acute inflammatory, demyelinating event affecting the optic nerve, and a common manifestation in multiple sclerosis (MS). It can affect MS patients throughout their disease course, and 20 % of patients present with acute ON as their initial symptom. ON primarily affects the optic nerve in its myelinated portion, but also triggers neurodegeneration in the entire afferent visual pathway (AVP) through retrograde and anterograde (trans-synaptic) degeneration. Visual outcomes are diverse, including severe persistent visual impairment. High-dose corticosteroids are the current mainstay in the therapy of acute autoimmune ON. However, despite clear acceleration of functional visual recovery in the short-term, any mid- to long-term impact on visual outcomes remains unproven. Apart from its high prevalence and clinical relevance, ON also offers a unique model to study neurodegeneration as well as the potential of neuroprotective and –regenerative therapies: a clinical episode of acute ON can be assigned in its occurrence to an approximate time window, and in its impact on tissue integrity to a discrete, anatomically isolated structure. The AVP is retinotopically organized, linking its structural integrity with clinical function. Almost the entire AVP can be probed using imaging tools of different modalities, including optical coherence tomography (OCT) and structural magnetic resonance imaging (MRI) techniques such as diffusion-tensor-imaging (DTI). Furthermore, the function of the AVP can be assessed by simple but sensitive measurements such as low-contrast visual acuity (LCVA). Therefore, ON provides an optimal paradigm to study the consequences of an MS-relapse on tissue integrity and function. In the first section of this thesis, we reviewed the growing relevance of monitoring the thicknesses of different retinal layers using OCT to reveal AVP damage in MS. We summarized that the thicknesses of the macular ganglion cell and inner plexiform layer (GCIP) and the peripapillary retinal nerve fiber layer (pRNFL) are informative with regard to early detection of neuronal degeneration and long-term axonal damage, respectively, of the retinal ganglion cells (RGCs) in MS. A significant body of literature demonstrates that OCT-derived measures are not only associated with visual function, but also with other clinically relevant parameters such as grey matter atrophy or the Expanded Disability Status Scale (EDSS) score − a standard measure of overall disability in MS. Additionally, based on current research in the field, the review paper also highlights the possible role of the macular inner nuclear layer (INL) in detecting inflammatory disease activity and response to treatment in MS. Taking into account that ON is the main driver of neuro-axonal retinal damage in MS, we highlighted the further importance of the application of OCT in patients with ON. Although a great number of cross-sectional OCT studies in ON have been published to date, longitudinal studies remain relatively rare but are indispensable in order to achieve better knowledge of the temporal dynamics and magnitude of retinal neuro-axonal and functional visual damage following ON. Therefore, in a retrospective longitudinal study, we attempted to describe the changes in retinal structure and visual function over one year following clinically first-ever unilateral ON in both affected and unaffected eyes, using OCT as well as high- contrast visual acuity (HCVA) and LCVA testing. We found that the GCIP and pRNFL had substantial thinning in ON eyes, with early GCIP thinning (74.5 % of the total reduction occurring within the first month), and slightly later thinning of pRNFL (87.8 % within the first three months following ON). Furthermore, we found that the INL thickness was significantly increased in ON eyes (by month 1), but also, and more surprisingly, in the contralateral non-ON (NON) eyes (by month 12) following clinically unilateral ON, which is a novel finding. It is possible that subclinical involvement of the fellow eye resulted in this INL increase, indicating bilateral retinal pathology, although further research is needed to confirm this hypothesis. Additionally, we observed severely impaired visual acuity in ON eyes at onset of symptoms. Even though we detected functional improvement over time, particularly in HCVA, LCVA remained clinically impaired up to the final study time point. Overall, this data can have an impact on future therapeutic strategies by highlighting the particular importance of early treatment of ON. Pathology of the optic nerve and retina has also been described in murine models of MS, including myelin oligodendrocyte glycoprotein (MOG) peptide-induced experimental autoimmune encephalomyelitis (EAE). Therefore, in a longitudinal EAE study, we aimed to further investigate the mechanisms involved in ON-induced pathology of the AVP using a multimodal imaging approach. Because the retina is void of myelin, an important contributor to chronic neuro-axonal damage following ON, namely demyelination, cannot be assessed using OCT. Therefore, we assessed the utility of DTI as a means to investigate AVP pathology following ON, allowing the assessment of the myelinated portion of the optic nerve and tract. Consistent with previous literature, we found a gradual decrease in fractional anisotropy values in the optic nerve and tract implying white matter tissue damage in EAE. In parallel, radial diffusivity (RD) significantly increased in EAE mice, likely reflecting ongoing demyelination. Hence, we concluded, that DTI is valuable in capturing demyelination of the optic nerve and tract in EAE. In order to avoid permanent neuro-axonal tissue loss and associated disability, the search for new strategies to either prevent demyelination or enhance remyelination is of increasing importance in the field of MS. Therefore, eligible outcome measures should be able to capture these target mechanisms, pointing out the valuable role of RD as a biomarker. Currently, there are no satisfactory neuroprotective therapies or visual rehabilitation programs available for patients with ON. As visual function has been rated as one of the most important bodily functions by MS patients, the high prevalence of visual impairment in MS following episodes of ON remains a major unsolved problem in the disease management. With the aim of finding new therapeutic options that specifically target long-term prevention of persistent visual disability, we performed an interdisciplinary literature review. We found a significant body of preclinical as well as clinical evidence showing that low-current electrical stimulation of the retina and optic nerve in optic neuropathies of different causes may have neuroprotective and - restorative effects on RGCs. Clinical research exploring the potential of this so-called repetitive transorbital alternating current stimulation (rtACS) in patients with autoimmune ON has not yet been performed. We discussed why we would expect a beneficial effect of rtACS on remyelination, on other repair-promoting mechanisms in RGCs, and also on visual outcomes in patients with a first-ever acute ON. Moreover, we presented an optimal study design to investigate the safety, tolerability and preliminary efficacy of rtACS in this specific patient cohort.