Imaging Vitreous Cortex Hyalocyte Response to Paracentral Acute Middle Maculopathy (PAMM) Using En Face OCT

Abstract

Introduction:

Vitreous cortex hyalocytes (VCH) are resident macrophage cells that provide immunosurveillance, respond to tissue injury and inflammation, and help maintain the transparency of the media. In this case report we demonstrate the use of en face optical coherence tomography (OCT) to image VCH in vivo in a patient presenting with PAMM secondary to antiphospholipid syndrome.

Case description:

A 38-year-old female with no known medical history presented with complaints of visual disturbances in the right eye. OCT revealed hyperreflective bands in the IPL and INL nasal to the fovea. A diagnosis of PAMM was made. Work-up revealed elevated titers of antiphospholipid antibodies. En face OCT revealed a decline in the inflammatory activation over a seven-month period as evidenced by changes in VCH distribution and morphology.

Conclusions:

Our findings suggest that monitoring changes in the distribution and morphology of VCH could have a potential clinical utility for assessing disease severity, predicting recovery, and early recognition of treatment response in various inflammatory ocular pathologies such as PAMM.

Introduction

Paracentral acute middle maculopathy (PAMM) is characterized by the presence of characteristic hyperreflectivity within the inner nuclear layer (INL) and inner plexiform layer (IPL) on spectral-domain optical coherence tomography (OCT) in the acute stage followed by subsequent atrophy of these layers in the chronic stage.¹ PAMM has been reported in a variety of ocular diseases that involve microvascular ischemic injury, following ocular surgeries, or in the stings of certain systemic diseases.²

Recent advances in optical imaging techniques using clinical OCT and adaptive optics scanning light ophthalmoscopy (AOSLO) have enabled in vivo visualization of Vitreous Cortex Hyalocytes (VCH),^3-6 resident tissue macrophages that help maintain the transparency and avascularity of the vitreous body.⁷ These cells are believed to play pivotal roles inhibiting intraocular inflammation, changing their morphology and density in response to damage or external threats.⁷

In this case report, we describe the morphology, distribution, and activity of VCH in a patient with antiphospholipid syndrome presenting with PAMM as the initial clinical manifestation using en face OCT. This case was HIPAA compliant and adhered to the tenets of the Declaration of Helsinki. Written informed consent to publish these images was gathered from the patient.

Case description:

A 38-year-old Asian female with no known medical history presented with complaints of visual disturbances in the right eye of one-day duration. She denied any systemic symptoms such as blood clots or recurrent miscarriages. On initial presentation, her best-corrected visual acuity (BCVA) was 20/25 in the right eye and 20/20 in the left eye. Fundus examination of the left eye was within normal limits. Fundoscopy of the right eye revealed an edematous optic nerve with a “flame-shaped” hemorrhage in the superior quadrant, increased retinal vessel tortuosity, and a prominent gray-white lesion nasal to the fovea (Figure 1a). Spectral domain OCT (SD-OCT) across the fovea demonstrated abnormal hyperreflective bands in the IPL and INL nasal to the fovea (Figure 1b). A diagnosis of PAMM associated with non-ischemic Central Retinal Vein Occlusion (CRVO) was made.

Figure 1.

Colour fundus pictures (a, b) and SD-OCT scans across the fovea (c, d) in a PAMM patient at initial presentation and at seven months follow-up. (a) At initial presentation, fundoscopy revealed an edematous optic nerve with a “flame-shaped” hemorrhage in the superior quadrant, increased retinal vessel tortuosity, and a gray-white lesion nasal to the fovea. (b) SD-OCT showed hyperreflective bands in the IPL and INL compatible with ischemia (red arrowhead). (c) At seven months follow up, the edema of the optic nerve was markedly reduced, the retinal vessels were less pronounced, and the gray-white intraretinal lesion was less perceptible. (d) SD-OCT scan showed a resolution of the hyperreflective bands in the IPL and INL, however, note the thinning of the inner layers of the retina (red arrowhead).

Using the same method previously described by our laboratory, ten sequential 3x3mm OCT scans (Avanti RTVue-XR; Optovue) centered nasal to the fovea were acquired and averaged during this first encounter and at follow-up seven months later.³ VCH identification was performed on an en face OCT slab located 3μm above the inner limiting membrane (ILM) surface. Acutely, en face OC T revealed a significant area of ischemia in the intermediate layer (Figure 2a). OCT-A imaging of the deep vascular layer confirmed reduced capillarity in the ischemic region (Figure 2b). The morphology of the VCH were round with few projections, consistent with an “activated” phenotype (Figure 2c, 2d). Laboratory work-up revealed abnormal elevated titers of antiphospholipid antibodies (anticardiolipin antibodies (ACA) IgG > 80 GPL). The patient was referred to rheumatology who started 100 mg aspirin for primary thrombosis prophylaxis.

Figure 2.

En face OCT-reflectance (OCT-R) and OCT-angiography (OCT-A) of a PAMM patient at initial presentation and at seven months follow-up. (a) At initial presentation, OCT-R imaging of the intermediate layer revealed a significant hyperreflective area of ischemia. (b) OCT-A deep vascular layer showed a decreased perfusion in the ischemic area. (c) Vitreous Cortex Hyalocytes (VCH) appeared round, clustering around the ischemic area. (d) Magnified panel shows a better visualization of the VCH in an “activated” state. (e) At seven months follow-up, OCT-R imaging of the intermediate layer showed a decrease in the hyperreflectivity of the ischemic area. (f) OCT-A deep vascular layer showed increased perfusion in the ischemic area. (g) VCH appeared in a spindle-like configuration, with a more uniform distribution across the retinal surface. (h) Magnified panel shows a better visualization of the VCH in a “quiescent” state.

At seven months follow-up, her BCVA in the right eye improved to 20/20; however, she noted a persistent paracentral scotoma. Fundoscopy of the right eye revealed resolution of the optic nerve edema, reduced tortuosity of the retinal vessels, and fading of the gray-white lesion nasal to the fovea (Figure 1c). The SD-OCT demonstrated thinning of the inner retinal layers (Figure 1d). The area of ischemia appeared markedly reduced (Figure 2e). The deep vascular layer was marked by increased capillary filling in the previously ischemic region (Figure 2f). The VCH appeared to be more uniformly distributed with a ramified morphology, consistent with a “quiescent” state of activity (Figure 2g, 2h).

Conclusions:

Hyalocytes are the primary resident immune cells of the eye and act as the first responders to neuronal injury, playing an integral role in maintaining homeostasis in the retinal microenvironment.^8,9 Under physiological conditions, these cells are primarily found in two locations, anteriorly adjacent to the ciliary body and posteriorly above the vitreoretinal interface. Vitreous cortex hyalocytes (VCH) are considered to be resident macrophages and have been identified on histopathology to localized within the 50μm region above the inner limiting membrane (ILM), entangled with the collagen fibrils that compose the formed component of the vitreous cortex.^7,10

Until recently, studies investigating VCH were predominantly performed ex vivo or in animal models using confocal imaging modalities or immunohistochemistry. Advances in retinal imaging have enabled in vivo visualization of VCH,^3-6 showing phenotypic variation of these cells in response to changes in their environment. Under healthy conditions, these cells are characterized by spindle cell bodies and ramified filopodia-like processes that constantly probe the local environment, releasing anti-inflammatory and neurotrophic factors in a “quiescent” or “neuroprotective” state.⁷ In retinopathic eyes, the cells transmorph in an “activated” or “neurotoxic” phenotype in which cell bodies change into an amoeboid state with plumper cell bodies, as they proliferate and migrate to the site of injury or disease, releasing inflammatory factors and becoming highly phagocytic.⁷ This new clinical ability to monitor cellular behavior in physiological and pathological conditions may prove useful as biomarkers of early disease activity or response to therapy.

Antiphospholipid syndrome is a form of autoimmunity characterized by the presence of antiphospholipid antibodies which have been implicated in venous or arterial thrombosis, often observed in the eye as retinal vein occlusions or deep capillary plexus ischemia.¹¹ As it presented in this patient, ocular involvement may be the initial clinical manifestation of the disease. In our patient, OCT-A revealed reduced parafoveal perfusion in the deep capillary plexus during the acute stage. These findings are consistent with the hypothesis that the acute release of proinflammatory and proangiogenic cytokines and chemokines in ischemic conditions subsequently activate VCH in an attempt to restore the immunity and homeostasis of the retinal microenvironment. In the acute stage, VCH proliferated and appeared round, clustering around the ischemic area, in an “activated” or “neurotoxic” state.

At follow-up seven months later, OCT confirmed improvement in the patient’s overall ocular health. SD-OCT scan revealed a resolution of the hyperreflective bands in the IPL and INL with thinning of the inner retinal layers, as is typical with the resolution of PAMM.¹ En face OCT of the intermediate layer also appeared less hyperreflective in the ischemic area. Perfusion of the deep capillary plexus appeared partially restored, and the VCH density decreased, with a return of their morphology to a more slender and ramified appearance, consistent with the “quiescent” or “neuroprotective” state.

In conclusion, clinical OCT is capable of imaging VCH in PAMM and revealing the activity status of these tissue resident macrophages in response to injury. Our findings suggest that higher density and an “activated” morphology of these cells could potentially reveal an active inflammatory state of the retina. After management, resolution of the initial inflammatory trigger and/or appropriate treatment would be suggested if VCH density decreases and their morphology changes to a "quiescent" state. Therefore, this new clinical ability to monitor cellular behavior in physiological and pathological conditions could have a potential clinical utility for assessing disease severity, predicting recovery, and early recognition of treatment response in various inflammatory ocular pathologies such as PAMM.