Internal limiting membrane detachment in acute central retinal artery occlusion: a novel prognostic sign seen on OCT

Background To present a series of acute central retinal artery occlusion (CRAO) cases showing internal limiting membrane detachment (ILMD) on optical coherence tomography (OCT) and to describe the possible etiopathogenesis and outcomes associated with it. Methods Demographic and OCT features of patients with acute CRAO were analysed retrospectively. OCT parameters noted were posterior vitreous opacities, ILMD, inner retinal layer stratification, hyperreflectivity and thickening, cystoid macular edema, neurosensory detachment. Eyes were grouped into Group (1) CRAO with ILMD; Group (2) CRAO with no ILMD. Results A total of 28 eyes of acute CRAO who had undergone OCT scans at the time of the acute episode were identified. Out of these, ILMD was noted in 5 eyes. The study findings suggested that cases of acute CRAO with ILMD are associated with poor presenting visual acuity and have more severe signs of retinal hypoperfusion on OCT, like inner retinal thickening, inner retinal hyperreflectivity and loss of inner retinal layer stratification. Patients with ILMD have poor final visual acuity and thinning and atrophy or necrosis of the inner retinal layers. Conclusion ILMD can occur in acute CRAO due to total retinal artery occlusion and severe retinal hypoperfusion. The presence of ILMD on OCT can be considered a sign of poor prognosis in cases of acute CRAO. Trial registration: Not applicable.


Background
Central retinal artery occlusion (CRAO) was first described by von Graefes in 1859 [1]. It is a disastrous ophthalmic emergency which presents with acute painless vision loss and carries a poor prognosis. Acute CRAO classically presents with retinal whitening, a cherry red spot and retinal vessel attenuation [2]. According to Hayreh, CRAO mainly affects the inner retinal layers [3]. In addition, different inner and outer retinal features of CRAO on optical coherence tomography (OCT) have also been described in literature [4]. The typical findings seen on the OCT include presence of inner retinal layer thickening, hyperreflectivity and loss of inner retinal layer stratification (which are directly related to the severity of occlusion) and retinal hypoperfusion [4]. No  occlusion of the central retinal artery. The intraretinal hyperreflectivity of the acute phase gradually disappears leaving behind a thinner retina with atrophic inner layers [5]. On histopathology, there is inner ischemic retinal thinning of the nerve fibre layer, ganglion cell layer, inner plexiform layer and inner nuclear layer after occlusion of retinal circulation [6]. Considering the ischemic changes to the inner retinal layers, there is no affection of the ILM following CRAO. In this study, the authors present a series of acute CRAO cases showing a peculiar finding on OCT, which is described as the internal limiting membrane detachment (ILMD) and further venture to describe the possible etiopathogenesis and outcomes associated with the presence of ILMD in acute CRAO cases.

Methods
This work was approved by our Institutional Review Board and Ethics Committee and respected the tenets of the Declaration of Helsinki. In this retrospective non-interventional study, analysis of optical coherence tomography (OCT) images in patients with acute CRAO identified through the institute's internal database from April 2017 to March 2020 was included. The study was carried out at the Narayana Nethralaya eye hospital, India. An acute obstruction of central retinal artery was defined as recent history of sudden, painless loss of vision with presence of retinal thickening and whitening, retinal vessel attenuation and a cherry red spot at the macula. The medical records of all acute CRAO cases were reviewed and the following data were collected: age, gender, involved eye, corrected distance visual acuity at presentation and final visit, clinical features on retinal examination and follow-up duration. Patients with a history of ocular trauma, macular disease, vitreomacular interface disorders, severe non-proliferative or proliferative diabetic retinopathy, ocular surgery other than cataract surgery or high myopia were identified and excluded from the study. Such patients may have previous OCT findings that could include or lead to ILM detachment. A high-resolution spectral-domain OCT scan was obtained using the Spectralis HRA OCT system (Heidelberg Engineering, Heidelberg, Germany) with 25-line horizontal volume scans covering the area centered on the fovea. The descriptive features which were noted on SD-OCT included the presence of posterior vitreous opacities, ILMD, inner retinal thickening, hyperreflectivity and loss retinal layer stratification, presence of cystoid macular edema and subretinal fluid during the acute phase and thinning and atrophy of the retinal layers during the chronic phase of the disease.

Results
A total of 28 eyes of acute CRAO who had undergone OCT scans at the time of the acute episode were identified. Out of these, ILMD was noted in 5 eyes and no ILMD cases were 23. Their clinical and OCT findings have been documented in detail in Table 1; Figs. 1, 2, 3 and 4. A comparison of the OCT findings between eyes with ILMD and eyes without ILMD in cases of acute CRAO are described in Table 2. The mean duration of symptoms in the ILMD group was 3.8 (1-7) days and in the non-ILMD group was 3.78 (1-10) days respectively. All the cases in the ILMD group presented with a visual acuity of ≤ 3/60. 16 (70%) eyes in the non-ILMD group presented with a visual acuity of ≤ 3/60. Two patients each were lost to follow-up in the ILM detachment group and non-ILM detachment group respectively. At the final visit, all the patients in the ILMD group had a poor visual acuity (range: perception of light (PL) present to PL absent) while only 44% (10 eyes) of the cases in the non-ILMD group had a final visual acuity of ≤ 3/60. In the ILMD group, restoration of the ILMD was noted in one eye while thinning and atrophy of the inner retinal layers was noted in 3 eyes. Retinal thinning and atrophy were noted in 21 eyes in the non-ILMD group at the final visit.

Discussion
The findings in this study suggest that ILMD (5/28 eyes) in cases of acute CRAO are associated with poor presenting visual acuity and more severe signs of retinal hypoperfusion on OCT like inner retinal thickening, inner retinal hyperreflectivity and loss of inner retinal layer stratification. Patients with ILMD have poor final visual acuity and thinning and atrophy or necrosis of the inner retinal layers.
Retinal artery occlusions such as an ophthalmic artery occlusion, central retinal artery occlusion, or, less commonly, a branch retinal artery occlusion can be associated with life-threatening conditions (e.g., carotid occlusive or cardiac valve disease). In patients > 50 years of age, one must additionally suspect giant cell arteritis and if diagnosed should be treated with urgent systemic corticosteroid therapy [7]. Majority of CRAOs occur due to obstruction caused by platelet-fibrin thrombi and emboli as a result of atherosclerotic disease leading    of their reports [4,11]. Some authors attribute it to the presence of macular edema and inner retinal fluid [4,11]. While others believe that there is involvement of the outer retinal layers which could be responsible for this peculiar finding [4,11,12]. No clear explanation exists.
In this paper, we propose the sequence of events responsible for the occurrence of ILMD in CRAO cases. The explanation is as follows: All tissues or organs can withstand variably short periods of ischemia without producing detectable functional deficits or evidence of injury. Once a critical duration of ischemia is exceeded, which varies by cell type and organ, cell injury and/or death ensues. The extent of cell dysfunction, injury, and/or death is influenced by both the magnitude and the duration of ischemia. During prolonged ischemia, there are several intracellular biochemical and metabolic changes which occur, leading to cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms [13]. Although prompt reperfusion restores the delivery of oxygen and substrates, reperfusion itself appears to have detrimental consequences due to a surge in the generation of reactive oxygen species and proinflammatory neutrophilic infiltration of the ischemic tissues. This concept is termed as reperfusion injury [14,15]. Thus, following acute CRAO, retinal cell injury and/ or death can occur due to severe retinal ischemia and reperfusion injury. The ILM is the basal lamina of the inner retina that is formed by the footplates of Müller cells [16]. Muller cells are the principal glial cell of the retina. They form architectural support structures stretching radially across the thickness of the retina and are the limits of the retina at the outer and inner limiting membrane, respectively [17]. Müller cell surround blood vessels at the surface of the retina as well as vessels in deeper retinal layers. Following CRAO, there is injury and/or death to the cells of the inner retina depending upon the magnitude of ischemia. With further progression of the tissue injury due to ischemia and reperfusion, there is necrosis and apoptosis of the retinal tissue leading to intraretinal degeneration, permanent necrosis and atrophy. This leaves the ILM unsupported, leading to an ILMD. The hyper reflective dots and material noted in the sub ILM space and in the posterior cortical vitreous could be the proinflammatory neutrophilic infiltrates seen as a response to the reperfusion induced tissue injury. The extensive permanent retinal damage due to atrophy and necrosis is responsible for the poor visual prognosis in these patients. In some cases of CRAO, the ILM detachment was not seen. This could be due to the prompt restoration of retinal reperfusion, thereby allowing the retinal cells to recover immediately without further progression of retinal injury due to ischemia or reperfusion. In 2 cases (case 1 and case 5), where there was reattachment of the ILM to the retinal layers, there was only thinning and atrophy of the inner retinal layers noted without any features of retinal necrosis. The ILMD did not restore in one case where there was necrosis and thinning of the inner retinal tissue.
The major drawbacks of this study are the small number of cases with this peculiar finding and lack of OCTangiography. The OCT-angiography features in these eyes could have added some valuable information for the development of this finding. Also, further subgroup analysis with statistical tests between the cases of CRAO showing ILMD and those not showing ILMD could have been considered. Unfortunately, the number of eyes with CRAO and ILMD were small. Nonetheless, the results of this study provide newer insights onto the pathomechanism of ILMD in CRAO.

Conclusion
From the current series of cases, we can conclude that ILMD can occur in acute CRAO due to total retinal artery occlusion and severe retinal ischemia. The presence of ILMD on OCT could be associated with poor visual prognosis. Further work comparing the SD-OCT findings (including ILMD and others) and their relation with OCT-angiography and other multimodal imaging findings needs to be considered in future.