In this study, we mainly demonstrated differences of retinal microstructure and vasculature between MOGAD-ON and AQP4-ON. MOGAD-ON eyes presented with severe thinning of RNFL, the extent and quadrant of which were comparable to eyes with AQP4-ON. The vessel densities of DRCP in macular area of MOGAD-ON eyes were significantly lower than that of AQP4-ON eyes. Furthermore, the reduced microvascular densities were positively correlated with the deterioration of the visual acuity in MOGAD-ON.
MOGAD has gradually been a separate disease entity from NMOSD as the distinct pathologies mediated by MOG-Abs. In previous studies, changes of the retinal structure in MOGAD eyes and NMOSD eyes have been separately described[22, 23]. Consistent with the previous observations of pRNFL thinning and ganglion cell loss in MOGAD, we also described that the average thickness of RNFL in MOGAD-ON eyes was significantly lower than that in normal eyes. It is indicated that the apoptosis of retina ganglion cells and the retrograde degeneration of its axons existed in MOGAD-ON eyes.
However, OCT findings regarding the comparison of retinal microstructure changes between MOGAD-ON and AQP4-ON eyes have been inconclusive. Some studies have shown that compared with AQP4-Ab-positive NMOSD, MOGAD-ON leaded to less severe retinal damages[24, 25], but others including us found comparable thinning of the RNFL and GCIPL between these two groups[16, 22]. AQP4-Abs could directly attack AQP4 proteins highly expressed on the surface of Müller cells (mainly located in the INL) and astrocytes (mainly located in the RNFL) . Müller cells are involved in various homeostatic functions of the retina. The loss of AQP4 reduces the capability of Müller cells to maintain osmotic pressure and induces retinal inflammation, leading to irreversible damages to the retina. Unlike AQP4, MOG is a myelin protein specifically expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes, and the autoimmune response to MOG cause demyelination. The retinal ganglion cells are myelinated by oligodendrocytes when the bundle passes through the lamina cribrosa. Consequently, retinal changes observed in MOGAD are expected to be a retrograde degenerative process.
The OCTA data regarding MOG-Ab associated retinal vessels degeneration are scarce. In conformity with previous study, the microvascular densities of SRCP and DRCP in MOGAD eyes were significantly lower than that of normal eyes. We further found out that retinal microvascular densities, especially in the DRCP, were significantly lower in MOGAD than in AQP4-Abs-ON. Similar to previous studies, the whole deep retinal vessel densities were also significantly positively correlated with the thickness of outer retina layer. The retinal microcirculation are high oxygen extraction systems whose flow is related with local neuronal activity. The density of the capillary plexus used for oxygen diffusion in retina is more compressed in the deep layer than surface layer, thus any insult to it could lead to vascular retinal abnormalities. The retinal blood vessels share similar anatomic, physiological, and embryological characteristics to the cerebral vessels. It seems to indicate that the presence of MOG-Ab may be related to more severe vascular damages. A case of MOGAD presented with primary CNS vasculitis with perivascular inflammatory cell infiltration. And another study confirmed that all vessels in MOG-Abs related demyelinating lesions were accompanied by macrophages during the acute phase, which was clearly different from AQP4-Abs-positive NMOSD. Therefore, we speculate that MOG-Abs might cause the retinal destruction and degeneration by leading the peri-microvascular inflammation, rather than directly damaging retinal ganglion cells and their axons.
MOGAD-ON relatively preserved visual acuity compared with AQP4-ON, even if the severity of retinal damages was similar. Unlike AQP4-IgG seropositivity ON, poor visual accuracy was related to changes of retinal structure and function, the deterioration visual accuracy in MOGAD patients was related with the reduction of microvascular density of SRCP after adjusting the correlation. The visual stimulation can increase neural activity and cerebral blood flow under normal physiological conditions. Therefore, we speculate that when the retinal microvascular structure was damaged by inflammatory or any other pathologies, retinal perfusion becomes insufficient and affects the activity of retinal ganglion cells and causes photoreceptor damages in MOGAD-ON.
The limitations of our study mainly included that the sample size was relatively small, which is expected given the rarity of these conditions. Whether the vascular changes precede the changes of retinal structure or secondary to retinopathy cannot be proved. In addition, we didn’t include eyes that were positive for MOG-Ab and AQP4-Ab because "double positive" cases were extremely rare.
In conclusion, the retinal neuro-axonal damages in MOGAD-ON were comparable to AQP4-Abs-positive ON. Compared to AQP4-Abs, the MOG-Abs might be related to more severe vascular damages. And the reduced microvascular densities were positively correlated with the deterioration of the visual acuity in patients with MOGAD-ON. Here, we stressed the different pathophysiology between MOGAD-ON and AQP4-ON, but mechanisms by which MOG-Abs destroys the retinal structure and function is still unclear.
List of abbreviation
Antibodies against myelin-oligodendrocyte-glycoprotein, MOG-Abs; Antibodies against myelin-oligodendrocyte-glycoprotein associated disorders, MOGAD; Aquaporin-4 antibody, AQP4-Ab; Best-Corrected Distance Visual Acuity, BCVA; Central nerve systems, CNS; Cell-based assay, CBA; Deep retinal capillary plexus, DRCP; Early Treatment Diabetic Retinopathy Study, ETDRS; Ganglion cell layer, GCL; Ganglion cell complex, GCC; Health controls, HCs; Inner nuclear layer, INL; inner segment layer, ISL; Inner plexiform layer, IPL; Inferonasal, IN; Inferotemporal, IT; Inferior section, INF; Magnetic resonance imaging, MRI; Neuromyelitis optica spectrum disease, NMOSD; Nasal section, NAS; Nasal inferior, NI; Nasal superior, NS; Optic neuritis, ON; Optical coherence tomography, OCT; Optical coherence tomography angiography, OCTA; Optic nerve head, ONH; Outer plexiform layer, OPL; Outer nuclear layer, ONL; Outer segment layer, OSL; Peripapillary retinal nerve fiber layer, pRNFL; Retina capillary plexus, RCP; Retinal pigment epithelium, RPE; Retinal nerve fiber layer, RNFL; Radial peripapillary capillaries, RPC; Superotemporal, ST; Superonasal, SN; Superior section, SUP; Superficial retinal capillary plexus, SRCP; Three-dimension, 3D; Temporal inferior, TI; Temporal superior, TS; Temporal section, TEM; Visual field, VF.