Retinal Pigment Epithelial Proliferation Secondary to Retinal Ischemia: A Case Report and Literature Review

Antiphospholipid syndrome is one of the most common causes of acquired hypercoagulable conditions. It most frequently manifests in women between the ages of 20 and 40 years and is linked to an increased risk of arterial, venous, and capillary thrombosis as well as pregnancy [1]. Notably, there is a definite correlation between antiphospholipid syndrome and the number of ischemic ocular disorders, including retinal ischemia, where clotting may occur in veins, arteries, or the microvasculature [2].

Proliferation of the retinal pigment epithelium (RPE) is a well-known phenomenon in association with multiple retinal or choroidal pathologies including advanced age-related macular degeneration, retinitis pigmentosa, following retinal laser procedures, and associated with retinal detachment [3‒6]. However, retinal ischemia is also considered a trigger for such an event, although it is very rarely reported [7]. Combined hamartoma of the RPE and retina can be considered as a differential diagnosis for cases of retinal hyperpigmentation, although it typically involves foveal dragging, gliosis, and often includes an epiretinal membrane, features which do not match the characteristics of the lesion in our case [8].

Herein, we report a case of a young female who developed unilateral retinal ischemia with associated RPE proliferation. This report focuses on the association between the ischemic trigger and the proliferation of the RPE and describes a possible pathophysiology that may help to better understand such an association.

A female in her thirties with no significant medical history, presented to our tertiary care center with painless vision loss in the left eye over a period of 2 months. She had no history of trauma, surgery, or medication use. However, she had a history of two abortions and a family history of sickle cell anemia. There was no personal or family history of any thromboembolic disease.

Upon examination, her best-corrected visual acuity was 20/20 in the right eye, but only hand motion in the left eye. The left eye also has an afferent pupillary defect, as well as an outward deviation. Fundus examination showed clear vitreous, a pale disc, and peripapillary atrophy with a pigmented lesion extending from the disc temporally, which was indicative of RPE hypertrophy. Additionally, there were multiple intraretinal hemorrhages in all quadrants, but no neovascularization or vascular sheathing was found (Fig. 1). The right eye had a normal ocular exam.

To further investigate the pigmented lesion, an ultrasound A-scan was performed, which yielded negative results. A fluorescein angiography (FA) of the left eye was also performed, showing an area of hypo-fluorescence surrounding the disc and extended temporally representing a blockage effect and matching the area of the RPE hypertrophy, and a delay in fluorescence in the choroidal, arterial, and venous filling. An indocyanine green angiography (ICGA) was performed, showing a blocking effect within the lesion area, accompanied by the observation of choroidal ischemia during both the early and late phases of the angiogram (Fig. 2). A macular optical coherence tomography (OCT) was performed on the same day, showing epiretinal proliferation, macular schisis with intraretinal fluid, hyper-reflectivity of the inner retinal layers, and nodular RPE elevations. An OCT angiography (OCTA) was done and showed a masking effect in the choroidal layer matching the same lesion (Fig. 3).

Results from immunology blood tests showed positive lupus antibodies and negative anti-nuclear antibodies, anti-cardiolipin, and anti-B2 glycoprotein. The patient was subsequently seen by a rheumatologist in her local hospital, where she was diagnosed with antiphospholipid syndrome.

Treatment with Enoxaparin and warfarin was initiated for antiphospholipid syndrome. Ocular management was performed at our tertiary care center where FA guided retinal photocoagulation was performed to prevent the development of neovascularization.

The patient responded well to enoxaparin treatment for antiphospholipid syndrome and currently has regular follow-up with her rheumatologist. Moreover, she also tolerated ocular laser photocoagulation and keeps a regular follow-up with our tertiary care center to monitor her condition and to manage neovascularization promptly if they develop.

Retinal ischemia, resulting from ocular and systemic factors, could have ocular causes such as CRVO which is a significant source of retinal ischemia, and rare systemic conditions like antiphospholipid syndrome [9]. Consequently, multiple studies have proposed the potential involvement of antiphospholipid antibodies in the pathogenesis of CRVO, contributing to the development of a hypercoagulable state [10]. In our case, the patient’s history of antiphospholipid syndrome likely predisposed her to the occurrence of CRVO which led to retinal ischemia.

RPE is a monolayer of highly differentiated pigmented cells located below the neurosensory retina [11]. It is vital for the integrity of retinal photoreceptors and retinal hemostasis. It is implicated in phagocytosis of the outer segment of the photoreceptors, maintaining the visual cycle, and preserving the outer blood-retinal barrier [12]. It also plays a major role to refine the immune responses by providing immunosuppressive signals to prevent infiltration of immune cells [12].

Given its nature as a fully differentiated (post-mitotic) structure, its ability to divide is limited or non-existent entirely [13]. This can be noticeable in the setting of normal aging in which physiologic decline of number of RPE cells being compensated by multi-nucleation cells and increase in the size of the remaining viable RPE in order to cover the defected areas [14]. The repair mechanism of RPE in normal physiologic aging is not different at all when compared to pathologic conditions [15].

Expansion, proliferation, and even migration of RPE cells was documented in age-related macular degeneration, retinal detachment, after exposure to laser, and as a sequela of ocular ischemia [3‒7]. RPE injury in the form of apoptosis or necrosis seems to be the responsible factor for the chain reaction that leads to proliferation [4]. This sequence can be explained in which RPE injury motivates the activation of an immune response, infiltration of immune cells, and upregulation of inflammatory receptors overlying the adjacent RPE cells, leading finally to reactive hypertrophy of the RPE [4]. This sequence of immune reactivity can be attributed certainly to the initial damage of RPE, a structure responsible for immunosuppression and keeping the immune responses controlled and balanced [4].

On the other hand, congenital proliferation of RPE in the form of either hypertrophy or hyperplasia should be always suspected in the context of retinal pigmentation as in our case, but given that our patient did not have any ocular or visual complaints before presentation, the absence of retinal screening during early childhood, and the presence of concomitant retinal ischemia are all factors in favor of the acquired form of RPE proliferation rather than congenital etiology. One of the main congenital proliferative lesions includes combined hamartoma of the RPE and retina, although it typically involves foveal dragging, gliosis, and often includes an epiretinal membrane [8].

Tumour necrosis factor alpha (TNF-α) is one of the most investigated inflammatory cytokines, being confirmed to have a deleterious effect in certain pathological conditions affecting the RPE [15‒17]. Chronic exposure to this pro-inflammatory factor has been proven by histopathological reports to alter normal RPE morphology and depletion in the number of RPE cells, which was compensated by multinucleated and abnormally enlarged RPE cells [15]. In age-related macular degeneration, it was found that oxidative stress leading to necrotic RPE cell death can induce an inflammatory response and the upregulation of inflammatory gene expression of TNF-α in the adjacent RPE cells [17].

Regarding retinal ischemia, TNF-α receptors has been observed to be upregulated from the inner retinal layers in induced retinal ischemia [18], but no study yet has investigated the upregulation of this factor in healthy RPE to promote the reactive hypertrophy as the reports in macular degeneration [15‒17]. Putting together the knowledge of retinal ischemia producing overexpression of TNF-α, and this factor stimulating RPE differentiation, we believe it would be interesting to evaluate and validate that immunohistochemically in induced retinal ischemia as has been demonstrated in age-related macular degeneration reports.

In this case, we demonstrate the importance and accuracy of the OCT in assessment of the RPE. Hughes reported that RPE hyperplasia in a histopathological study induced by retinal ischemia in rats [7]. In our patient, Cross-sectional imaging of the OCT significantly matched the histopathological report. In this paper, we elected to use the term (RPE proliferation) instead of RPE hyperplasia or hypertrophy since these are histopathological terms, and our study is based only on imaging modalities. This brief report is the first that, to our knowledge, has thoroughly examined the behavior of RPE growth through imaging, in the context of retinal ischemia.

Post-retinal ischemia, RPE proliferation is a well-known occurrence. To better comprehend inflammatory cascade and match results with age-related macular degeneration, a well-structured histopathological study using immunohistochemistry staining is required. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540771).

• RPE is a post-mitotic structure with theoretically limited if not absent proliferation potential.

• However, following retinal ischemia, laser photocoagulation or degenerative disease, retinal pigment epithelial proliferation is a common occurrence.

• RPE injury motivates the activation of an immune response, infiltration of immune cells, and upregulation of inflammatory receptors overlying the adjacent RPE cells, inducing reactive hypertrophy of the RPE.

• This case report confirms with imaging modalities previously reported histological studies of RPE proliferation.

The Institutional Review Board at king Khaled eye specialist hospital approved conducting and publishing this case repot reference number is RD/26001/IRB/0260-23. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

The authors acknowledge no conflict of interest.

The authors declare no funding received for this study.

Conception and data preparation: Wael A. Alsakran; writing: Abdullah F. Alnaim and Hammam A. Alotaibi; editing: Hammam A. Alotaibi; and final draft approval: Wael A. Alsakran, Abdullah F. Alnaim, and Hammam A. Alotaibi.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.