FP416 : A novel angio-OCT finding at the vitreoretinal interface in Mac Tel type 2

Dr.Apoorva A G,Dr.Shrinivas M Joshi,Dr.Guruprasad Ayachit

Abstract:

Objective:

To report anovel finding ofEpiRetinalNeovascularization(ERN in cases of macular telangiectasiatype 2 (Mac Tel) and describe it’s clinical and multimodal imaging features.

Design:

Retrospective chart review

Subjects/ participants:

Patients attending the retina clinic from January 2017 to April 2018. Those diagnosed as Mac Tel by clinical and imaging findings were included.

Methods:

Best corrected visual acuity in the logarithm of minimal angle of resolution(logMar), anterior segment examination, slit lamp biomicroscopy, fundus photography, spectral domain- optical coherence tomography (SD-OCT), autofluorescence (AF) imaging, fundus fluorescein angiography (FFA) and optical coherence tomography angiography (OCTA)were done in all patients of Mac Tel. Length of ellipsoid zone disruption (EZ), external limiting membrane (ELM) disruption, area of the ERNin square millimeter (sq. mm.)and central macular thickness (CMT) were noted.

Outcome measures- The finding of an epiretinal membrane on SD-OCTand a well-defined vascular complex on vitreoretinal interface on OCTA in patients of Mac Tel was considered as evidence of epiretinal neovascular membrane (ERNM).

Results- Sixty eight eyes of Mac Tel underwent multimodal imaging, out of which 7 eyes of 4 patients were identified to haveERN/ ERNM. Males: Females: 1:1(n=4); unilateral(n=1), bilateral(n = 3). Mean age was 56.75 ± 10.71 yrs. Mean BCVA 0.74±0.39 log Mar. Retinal pigment and dipping venule was present in 100% eyes.Diffuse thinning and collapse sign was seen in all eyes. OCTA revealed a vascularmembrane owing to the ERNMat the vitreoretinal interface. Mean area of the ERNMwas 0.44± 0.248 sq. mm. This vascular membranehad a demonstrable communication with the intraretinal abnormal vascular plexus in 6/7 eyes. None of the eyes had a choroidal neovascular membrane (CNVM).

Conclusions –ERNis a novel finding in Mac Tel type 2. Theseneovascular membranes are best visualized using OCT and OCTA. They are associated with retinal pigment and diffuse retinal thinning. Histopathological studies are needed to characterize these membranes further

Key words- Epiretinal neovascular membrane, epiretinal neovascularization, OCTA, , Mac Tel, epiretinal membrane

Introduction

Macular telangiectasia type 2 (MacTel) is a neurodegenerative disorder that primarily affects Muller cells. ¹ Clinical staging was first proposed by Gass and modified later by Yannuzzi.²Capillary abnormalities in deep capillary plexus, superficial capillary plexus and the outer retinal slabs have been described.³Staging systems based on spectral domain optical coherence tomography (SD- OCT), fundus autofluorescence (AF), confocal blue reflectance (CBR) and optical coherence tomography angiography (OCTA) have been proposed.⁴ OCTA imaging has provided insights into the pathogenesis and natural course of MacTel, due to its ability to resolve the deep capillary plexus in greater detail. We describe the clinical and multimodal imaging characteristics of EpiRetinalNeovascularization (ERN)/ Epiretinal neovascularMembrane (ERNM) at the vitreoretinal interface in MacTel.

Materials and methods

This was a retrospective chart review carried out in patients diagnosed as Mac Tel type 2 attending the retina clinic from January 2017 to April 2018 at a tertiary referral center in India.Institutional Review Board (IRB)/Ethics Committee approval was obtained. The study adhered to the tenets of declaration of Helsinki.Written informed consent was obtained from all participants.  Demographic data, associated systemic diseases and clinical examination findings were recorded. Best corrected visual acuity(BCVA) inlogarithm of minimal angle of resolution (Log Mar), intraocular pressure, slit lamp examination findings were noted.

Slit lamp biomicroscopy findings, supplemented by fundus photography findings of foveal and perifoveal graying, dipping venule and retinalpigment were noted.SD-OCT, fundus fluorescein angiography(FFA) and OCTA were done using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany). Selected patients underwent indocyanine green angiography (ICGA) in the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany).

Eyes with ERN/ERNMwere identified as a thin epiretinal membrane- like structure. SD- OCT was done with a scan angle of 20 degrees, in the infrared photography+ OCT mode with the Automatic real time (ART) mode switched on. Distance between B scans was 30 microns. Central macular thickness was noted at the foveal center as the distance from the internal limiting membrane (ILM) to the retinal pigment epithelium(RPE). Temporal, nasal and foveal loss of ellipsoid zone (EZ) was noted.Presence of empty spaces, intraretinal pigment with back shadowing were also noted. The horizontal length of ellipsoid zone disruption, external limiting membrane (ELM) disruption were measured manually using the caliper function inbuilt in the imaging system. OCTA scans were carried out (high speed protocol) with a scan angle of 10 degrees and pattern size of 2.9 mm *2.9 mm.

Distance between B cans was 11 microns. In case of macular thinning and/ or loss of retinal architecture, manual segmentation was carried out in 5- 7 scans and semi- automated scans were procured and analyzed. ERNwas diagnosed on the basis of the presence of a vascular membraneatthe vitreoretinal interface which was distinct from the vascular alterations present in the superficial vascular complex (SVC),deep vascular complex (DVC) and avascular complex. Location of abnormal capillaries were sub-classified as that present temporally (stage 1), nasally (stage 2) or circumferentially (stage 3)(Toto staging). Stage 4 on OCTA is the presence of choroidal neovascular membrane(CNVM) in addition to the findings in stage 1, 2 and 3.⁴A connection was noted to be present if there was a visible communication from the ERNMto the intraretinal abnormal capillary network (seen as a hyperreflective structure) corresponding to a flow signal on OCTA. The areaof the ERN on OCTAwas measured manually using ‘’draw region’’ tool. All patients underwent FFA using 3 ml of 20% dye.Thirty degree,55degree and 102 degree scans were carried out. Patterns of leakage and staining were noted along with FFA findings of diabetic retinopathy if present.Leakage from the ERNwas also noted when present.FFA findings were also sub-classified into hyperfluorescence temporally, nasally or circumferentially (stage 1,2 and 3 respectively) by the Toto staging.⁴ ICGA was done to rule out the presence of a CNVM in 2 patients.

Results

Sixty eight eyes of Mac Tel underwent multimodal imaging, of which 7 eyes of 4 patients were identified to have anERNM. There were 2 females and 2 males (F: M: 1:1). Mean age was 56.75 ± 10.71 years. One female patient was diabetic and had moderate non proliferativediabetic retinopathy. (Figure 1) Mean BCVA was 0.74 ±0.39logMar. All patients had Mac Tel in both eyes. ERN was present in both eyes in 3patients whereas one patient had unilateral involvement (right eye).

Clinically, ERNMwas not apparent in any of the eyes. Pigment and dipping venule was present in all eyes. Perifovealgreying was also present in all the eyes. On OCT a beaded epiretinal membrane was present in all 7 eyes that was diagnosed as ERNM. Temporal, subfoveal and nasal thinning was seen in 6/7 (85.71%) eyes. A collapse of the inner retinal layers was seen in all eyes. Barring one eye, none of the eyes had intraretinal empty spaces or neurosensory detachments (n=6). ILM drape sign was also not seen.On FFA theERN was seen in early frames but was later obscured by the hyperfluorescence of the perifoveal capillary leakage. OCTA showed a distinctive vascular structureat the vitreoretinal interface apart from the typical dilated ectatic capillaries in the superficial and deep vascular plexustypical of Mac Tel.ThisERNhad a demonstrable communication with the intraretinal abnormal vascular plexus in six out of seven eyes.None of the eyes had CNVM.

CMT was 150.28 ± 40.81 micrometers (µ). Mean ELM disruption ranged from 1433.44 µ to 2983.12 µ (Mean± SD- 2208.28±837.80). Mean EZ disruption was 2369.29± 773.49 µ (Mean± SD).Mean areaof the ERNwas 0.44 ±0.248 squaremillimetres.All eyes were categorized as stage 3 on OCT and OCTA. FFA also showed circumferential hyperfluorescence categorizing them as stage 3.  All eyes had patchy areas of hypo and hyperautofluorescence and hence wereclassified as stage 3.

Discussion

Macular telangiectasia is a vision threatening disease because of its course of neuronal and vascular degeneration leading on to CNVM formation and further visual morbidity. OCT findings of intraretinal empty spaces with ILM drape sign and subretinal hyporeflective spaces have also been described.^5,6 Our series is notable for the absence of these spaces in all but one eye. All cases had temporal and nasal parafoveal with foveal thinning.Abnormal capillaries in Mac Tel are described as irregular, ectatic and dilated. The temporal foveal region is affected first, nasal affected next and progressively circumferential involvement is seen. In the late stages, there is formation of a subretinal neovascular network

That can cause intraretinal and subretinal fluid transudation that would necessitate treatment with anti- vascular endothelial growth factor (VEGF) therapy.⁷Toto et al has proposed an OCTA based staging for Mactel based on this progression, stage 1 being- involvement of temporal fovea, stage 2- involving nasal fovea, stage 3- showing circumferential involvement and stage 4- CNVM.⁴OCT- angiography in cases of MacTel have shown that the deep capillary plexus is involved first, followed by superficial capillary plexus and the outer retinal layers.

There is scant literature on epiretinal membranes in association with MacTel. Gomes et al described a case of ERM with MacTel in 2014.⁸ In our opinion, SD- OCT in their case, did not show typical features of MacTel but the FFA did show some semblance of abnormal perifovealcapillaries with late hyperfluorescence. Our series demonstrates an epiretinal membrane which was noted to be vascular on OCTA. These vascular epiretinal membranes had a communication with an intraretinal hyperreflective structure suggesting that either (i) extreme retinal thinning led to the ‘’baring’’ of the abnormal capillaries in the superficial capillary plexuson the retinal surfaceOR (ii) Like CNVM, ERN is a distinct end- point of Mac Tel associated neovascularizationNotably all our cases had intraretinal pigment that was abutting the ILM..We hypothesize that like CNVM, that occurs after the stage of intraretinal pigment deposition in Mac Tel eyes; the location of the pigment just abutting the ILM may incite the development of epiretinal instead of subretinal neovascularization in some eyes.

Foveal neovascularization has been described in the setting of diabetic retinopathy.⁹In our series, one patient did have moderate diabetic retinopathy however, in both eyes of this patient; there was a communication of the epiretinal vascular network with the intraretinal vascular plexus through a clearlyvisualised breach in the ILM. In addition, we have clearly demonstrated this finding in non-diabetic patients in this case series.  Anti- VEGFs have shown benefit in the proliferative stage of Mac Tel. ¹⁰Whether ERN is part of the proliferative stage of Mac Tel and needs treatment with anti VEGF agents needs to be studied.  It would be interesting to note the effect of anti-VEGF agents on the ERN morphology in terms of vascularity and size.The natural history of ERN also needs to be studied over months and years to look for vision loss, micro-morphometric changes on SD- OCT and development of CNVM. Sequential monitoring of the effect of anti VEGF agents can be effectively achieved non-invasively by OCTA.

Interestingly epiretinal membranes have been described in the setting of adult- onset Coats disease.¹¹ Coats disease is typically associated with aneurysms and telangiectasia and MacTel type 1 is described as a variant of Coats. Thus, although epimacular membranes have been described in aneurysmal conditions like MacTel and Coats disease, a beaded vascular membrane with communication to the intraretinal plexus has never been described.Further studies are needed to study the histopathology of these lesions since they seem to differ from regular epiretinal membranes because of the absence of ILM wrinkling and macular pucker.  OCTA was very useful in our case, to demonstrate that the beaded membrane was in fact, a well- defined vascular net at the vitreoretinal interface. Considering the association of lamellar holes with Mac Tel,¹² the other close differential for ERNM is lamellar hole epiretinal proliferation (LHEP).¹³ The absence of lamellar hole in our cases helps us differentiate ERNM from LHEP. We carried out OCTA in cases of LHEP and found no vascularity or flow signal at the vitreoretinal interface. (Unpublished data).

Dipping retinal venules have been described and visualized on OCTA which communicate from the epiretinal surface to the deep capillary plexus.¹⁴ In our case however, there is a well- defined vascular net on the retinal surface, with an associated dipping venule.In extreme retinal thinning as seen in Mac Tel, segmentation errors are frequently encountered on OCTA. (Figure 4B, 4C) Since ERN is at the vitreoretinal surface, projection artifacts are not a concern in their interpretation.¹⁵ However, the presence of an ERN may cause confusion in the interpretation of the abnormal capillaries seen in the superficial and deep vascular complexes because of the projection artifact cast by the ERN on the deeper slabs. (Figure 2 e2).

Conclusion

Our series demonstrates a hitherto undescribed finding of epiretinal neovascularization in Mac Tel. The small sample size is a limitation of our paper. All epimacular membranes in MacTel should be multi-modally imaged and characterized. There is a striking association of epiretinal neovascularization with retinal thinning, presence of retinal pigment and absence of degenerative intraretinal spaces. ERN may represent a hitherto unknown form of a proliferative form of Mac Tel developing in the late stages in eyes who have progressed to intraretinal pigment formation and severe retinal thinning.

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Legends

Figure 1 – (A) Right eye of patient 1 showing retinal pigment and dipping venule. Moderate NPDR features are also seen. (B) Line scan through the pigment showing a beaded ERNM overlying the pigment that is corresponding to a vascular network seen on enface image and OCTA on D1 and D2 respectively. D3 and D4 show segmentation line passing through the vitreoretinal interface. (C) White arrow showing a defect in the ILM and a communication of the ERNM with an intraretinal hyperreflective complex. The connection is seen as a hyperreflective signal on E2 with a yellow flow signal (white arrow) in E4. (F) and (G) show early and late FFA frames. (G) Shows predominantly temporal and mild nasal hyperfluorescence. Early and late ICGA frames in (H) and (I) showing no CNVM.

Figure 2- Patient 2- (a) Blue arrow showing an ERNM. Outer retinal thinning, collapse of OPL seen along with intraretinal pigment with back shadowing (b) FFA showing circumferential hyperfluorescence. (c) ICGA showing hypofluorescence due to pigment, No CNVM seen. (d1) Dark slab on enface imaging at vitreoretinal surface. (d2) showing the vascular ERN complex. (d3) and (d4) showing the red segmentation line passing through the vitreoretinal surface. (d4) showing the ERNM with yellow flow signal.(e2) showing the projection artifact of the ERNM at the SVC slab. (e3) and (e4) showing the red segmentation lines passing through ILM and IPL.