Discussion
DON is an optic nerve dysfunction that is one of the most severe complications of TAO, characterised by thyroid-related impairment of visual function, leading to permanent sight loss.4 Multiple criteria grade the symptoms of TAO, including EUGOGO consensus, Bartley criteria and so on, however, no single protocol completely characterises DON.34 It might be especially difficult to detect whether DON has recently formed in newly presented patients, which implies that considerable efforts should be made to improve DON diagnosis and treatment.35 Several mechanisms including optic nerve inflammation, compression, stretch and ischaemia contributed to the development of DON.6–11 OCT and OCTA, novel non-invasive imaging modalities, can monitor changes in structure and microvascular network in the different retinal layers.36 37 It could be crucial in the clinical process of DON.
This systematic review and meta-analysis investigated the changes in OCT and OCTA parameters between healthy control, non-DON and DON. In terms of ophthalmic examination results, the CAS and exophthalmos of the DON group were higher than the non-DON group. During the progression of TAO, the patient’s VA decreased and IOP increased gradually. Besides, the DON group presented a larger VF loss than the non-DON group. These clinical manifestations might help ophthalmologists distinguish between DON and TAO without DON in the initial diagnosis.
Intriguingly, five articles24 25 27 28 30 reported that the PRNFL of the DON group decreased while Wu et al32 and Guo et al26 recorded an increasing tendency of PRNFL in the DON group than the healthy control group and non-DON group. Meta-analysis showed no difference in these three groups in terms of PRNFL overall or by region. In addition to the comparison of non-DON and DON, two articles26 28 recorded PRNFL based on the severity of TAO from moderate to severe. A decrease of PRNFL could be seen from mild TAO to moderate-to-severe TAO (online supplemental figures S73–S75). Several factors could explain this phenomenon. The EOMs and fatty connective tissue of the orbit induce volume expansion and compression of the optic nerve at the orbital apex, resulting in optic nerve ischaemia and inhibition of the axonal nerve flow, which is the significant cause of increased PRNFL thickness.26 34 The thinning of PRNFL can be attributed to demyelination and axonal injury that arise from compression over time.38 39 The optic disc may be edematous in the early stages of the disease with normal vision, and later on, optic nerve dysfunction can manifest with a normal, swollen or pale disc.4 Furthermore, the DON group witnessed a decrease in overall GCL+IPL in Wu et al33 and Guo et al’s26 articles through analysis. A previous study demonstrated that there was a significant correlation between visual functions and GCL/IPL thickness in chiasmal compression optic neuropathy.40 The thinning of GCL/IPL might be a strong suggestion for closer vision follow-up and earlier decompression surgery.26 In terms of MGCCL, five studies5 28 30 32 33 recording MGCCL changes presented a similar result that DON group had lower MGCCL compared with the non-DON group. Previous studies have proved that GCC loss is closely correlated with the VFs and could detect changes before the appearance of abnormal VF.41 42 It was of great significance to the diagnosis of DON at the initial stage. GCL+IPL and MGCCL have the potential to be an early indicator of optic neuropathy. There are a few articles recording them in the progression of TAO. More researches are needed in the future to prove the role of GCL+IPL and MGCCL in following up patients.
As for OCTA results of meta-analysis, seven studies5 13 24 28 30 32 33 reported the changes of ONH-VD, RPC-VD or RCL. We found that ONH-VD in the DON group were less than the other two groups. In addition, a similar trend could also be seen in the RPC-VD of the DON group. Except for inferior and inferior hemifield, RPC-VD saw a decrease in DON groups compared with the non-DON group. Two studies5 33 also collected data on RCL including M-SRCL and M-DRCL, results of the meta-analysis showed that the M-SRCL of the non-DON group and DON group was less than the healthy group. Both macroscopic and microscopic mechanisms could explain this phenomenon. Symptoms become severe when the disease involves the orbital apex, where the bony orbit narrows. The extraocular muscle encircles the optic nerve becoming the annulus of Zinn.43 The optic nerve and its vasculature are then compressed, including the ophthalmic veins, central retinal veins, central retinal arteries and posterior ciliary arteries, which are the main areas of ocular perfusion, which caused the reduced vessel density.6 Ocular endothelin-1 (ET-1) is an important peptide that modulates retinal blood flow and neuronal functions.44 It exerts vasoactive and neuroactive functions through its G-protein-coupled receptors, endothelin receptor A (ET-A) and endothelin receptor B (ET-B), respectively, which are abundantly present in many ocular tissues.45 It was higher than normal in thyroid hormone disorders caused by Graves’ disease, which might be another reason for the lower vessel density.46 Together, these results suggested that parameters of OCTA such as ONH-VD and RPC-VD gradually decreased with the progression of TAO from healthy condition to DON. Besides, the thickness of the retinal nerve fiber layer is paralleled to the ONH-VD and RPC-VD.47 48 OCT has better sensitivity in monitoring early visual compromise at present. OCTA can be used as a supplementary examination to OCT.
In addition to the literature we included, there were several studies reporting the OCT or OCTA parameters before and after orbital decompression in dealing with DON. A significant decrease in PRNFL thickness could be detected after orbital decompression surgery in patients with DON. Noteworthily, greater preoperative superior, inferior and nasal PRNFL thickness was associated with better visual outcomes.25 49 50 However, the reduction of RPC-VD could not be reversed immediately by medical and surgical decompression when vision and VF were improved.32 After decompression, eyes with DON had a much greater reduction in ONH-VD than eyes without DON. The mechanism of ONH-VD reduction after orbital decompression is still unclear, we speculated that the body protectively lowered vascular density to avoid damage to the retina caused by reperfusion after long-term ischaemia under the condition of rapid recovery of blood supply after orbital decompression. One patient had worsening of the DON eye despite orbital decompression, and in this case, the vessel density was noted to have increased rather than decreased. This suggested that a reduction in ONH-VD correlated with improvement in DON while worsening DON may manifest as an increase in vessel density in the same area.51 Because this conclusion was reached through only one case report. Therefore, the validity of this result needs to be verified by future comparative studies. We hypothesised that increasing vessel density meant more need of blood perfusion, combined with factors such as oedema of the vascular endothelium, which could lead to relatively lower blood perfusion after orbital decompression surgery, which affects prognosis. It proved that OCT and OCTA acted an essential part in diagnosing and treating DON. Ophthalmologists should undertake a comprehensive consideration of the retinal structure and microvasculature in estimating and treating patients with DON.
Despite the findings we achieved, the present meta-analysis had several limitations. First, heterogeneity in our meta-analysis may limit the generalisation of the pooled result and the source of heterogeneity could not be discerned by a subgroup analysis. Second, the number of studies in this meta-analysis is relatively small. Third, no single protocol completely characterises DON at present and diagnostic criteria were inconsistent across studies. Finally, all samples included in our analysis were all from Asia, and lack of coherence from other continents.
In conclusion, this systematic review and meta-analysis provided evidence on the associations of PRNFL, MGCCL and GCL+IPL in OCT and RPC-VD, ONH-VD, M-SRCL and M-DRCL in OCTA with DON. These results have important clinical implications since OCT and OCTA metrics may have the potential to be used as biomarkers of DON, which help ophthalmologists diagnose and treat patients with DON. Due to several limitations, future longitudinal studies with larger sample sizes and more potential confounders controlled are warranted to confirm our results.