Internal limiting membrane: The innermost retinal barrier

Internal limiting membrane: The innermost retinal barrier

Accepted Manuscript Internal limiting Membrane: The innermost retinal barrier Rohan Chawla, Koushik Tripathy, Shreyas Temkar, Vinod Kumar PII: DOI: Re...

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Accepted Manuscript Internal limiting Membrane: The innermost retinal barrier Rohan Chawla, Koushik Tripathy, Shreyas Temkar, Vinod Kumar PII: DOI: Reference:

S0306-9877(16)30666-1 http://dx.doi.org/10.1016/j.mehy.2016.11.017 YMEHY 8423

To appear in:

Medical Hypotheses

Received Date: Accepted Date:

6 October 2016 24 November 2016

Please cite this article as: R. Chawla, K. Tripathy, S. Temkar, V. Kumar, Internal limiting Membrane: The innermost retinal barrier, Medical Hypotheses (2016), doi: http://dx.doi.org/10.1016/j.mehy.2016.11.017

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Internal limiting Membrane: The innermost retinal barrier Rohan Chawla, FRCS (Glasg);1 Koushik Tripathy, MD;1 Shreyas Temkar, MD;1 Vinod Kumar, FRCS (Glasg);1 1

Department of Ophthalmology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India

Institute of Medical Sciences, Ansari Nagar, New Delhi, India- 110029 Corresponding author: Dr. Koushik Tripathy, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India- 110029 Phone- +911126593133, [email protected] The authors declare no financial or conflicts of interest. Acknowledgments: None The findings were not presented in any conference.

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Abstract Recently, peeling of internal limiting membrane (ILM) has become one of the most common and effective surgical procedures for macular disorders. The authors discuss the adverse effects of such procedures and explore the possible functions of the membrane. We also suggest a barrier function of this membrane in addition to its possible other physiological roles. Thus, apart from the well-known inner and outer retinal barriers, ILM might be the third and innermost retinal barrier. The possible evidences supporting this hypothesis are presented.

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Introduction The internal limiting membrane (ILM) is the basement membrane of the retinal Müller cells at the vitreoretinal interface. It contains various high molecular weight extracellular matrix proteins like collagen (type IV, XVIII), laminin, fibronectin, nidogen 1 and 2, agrin, and perlecan.1,2 It is a multilaminar structure and includes the fusing point of anchoring vitreous fibrils from the vitreous cortex, lamina densa, and lamina lucida. Being the innermost part of the retina, it has been linked to the pathogenesis of a number of pathophysiological conditions of the vitreoretinal interface. It has been implicated in the formation of macular hole, myopic traction maculopathy, and vitreomacular traction.[1] ILM acts as a scaffold for the proliferation of fibrocytes, myofibroblast, glial cells, and the retinal pigment epithelium and may aid formation of epiretinal membranes (ERM).[3,4] As ILM is thought to play a role in the pathogenesis of these macular disorders, ILM peeling is now considered an integral part of various vitreoretinal surgeries for macular hole, myopic traction maculopathy, resistant diabetic macular edema, and epiretinal membrane. ILM peeling improves anatomical outcomes by eliminating stiffness at the vitreoretinal interface and removing the scaffold for future membrane proliferation.[3] Though the exact role of the ILM has not been elucidated, it has been postulated to serve important anatomical and physiological functions. Müller cells, the foot processes of which are integral to the ILM, have been known to be involved in ionic balance, acid-base regulation and other important metabolic functions of the inner retina.[1,5] Anatomically the ILM provides a supportive function to the neurosensory retina by draping it internally.[5] The ILM plays a critical role in embryonic retinal histogenesis, the growth of optic nerve axons, and proper development of the ganglion cell layer.[3]

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Despite achieving good anatomical success following ILM peeling for various macular surgeries, it has been shown that ILM peeling can be associated with various adverse structural and functional outcomes.[6,7] Some of these might also possibly be related to the dyes used to stain the membrane, intraoperative phototoxicity, mechanical trauma during removal of ILM. Thus, whether these complications are directly related to ILM peeling alone is difficult to prove. Mechanical removal of the ILM can manifest as Dissociated Optic Nerve Fibre Layer (DONFL) 1-3 months after surgery.[8] DONFL appears as concentric arcuate dark lines along the retinal nerve fiber layer more evident on blue filtered imaging or OCT retinal surface imaging. This condition is seen in up to 43% of patients undergoing surgery for epiretinal membrane removal.[9] ILM peeling appears to be a prominent risk factor for the development of DONFL. The possible pathogenesis suggested are traction over the inner retina during the removal of ILM, damage to the Müller cells and exposure of the inner rough surface of the nerve fiber layer. The DONFL appearance is supposed to be the successor of the acute postoperative swelling of the arcuate retinal nerve fiber layer [SANFL] which is seen to disappear within 3 months after surgery.[10] Other reported ill-effects of ILM peeling are the development of macular hypotrophy along with visual deterioration in cases of chronic diabetic macular edema.[11] Foveal thickness in such cases reduces significantly following ILM peeling resulting in a ‘foveal subatrophy’ or ‘floor effect’.[11] It has also been suggested that cases of macular hole that underwent ILM peeling had reduced retinal sensitivity, and a higher incidence of microscotomas.[6] Paracentral retinal hole formation has also been reported following ILM peeling for various macular pathologies using various different dyes.[12] The probable cause appears to be retinal weakening due to damage to the Müller cells.[12]

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Hypothesis Two forms of the blood-retinal barrier are known to exist, the outer barrier being formed by the tight junctions of the retinal pigment epithelium. The inner retinal barrier is formed by the tight junctions between the non-fenestrated endothelium of the retinal capillaries. From experimental data and our observations on optical coherence tomography, we suggest a possible barrier function ('third barrier' or ‘innermost barrier’) of the ILM. Discussion We would like to support our postulate by the following observations – 1) In an experimental setting, ILM has been shown to act as a barrier to retinal transduction following intravitreal adeno-associated virus injection done for Gene therapy.12 This way it acts as a barrier preventing flow of molecules from the vitreous across the retinal layers towards the photoreceptors. 2) In cases of focal macular retinitis, OCT scans frequently show dehiscence with subsequent thinning and necrosis of the inner retinal layers. However, we have seen the ILM to be intact over the necrotic areas in such cases at an early stage of retinitis (Figure 1a). The infective elements do not seem to breach the integrity of this membrane, preventing the infection from spreading from the retina into the vitreous. We have seen this phenomenon in cases of both viral retinitis[13] and toxoplasma related retinitis. However, some organisms like Candida albicans can break through the ILM and invade the vitreous in untreated metastatic candida endophthalmitis.[14] Fungi are known to even penetrate an intact Descemet’s membrane as well in cases of fungal keratitis. 5

3) In cases of Valsalva retinopathy[15] or Terson syndrome (Figure 1b), blood is seen to accumulate under the ILM rather than the posterior hyaloid as conventionally believed. With time as the blood absorbs, a stretched separated ILM can be seen above a cavity formed by the pre-existing blood (Figure 1c). In this situation again the ILM restricts movement of molecules from the retina towards the vitreous. Some cases of Terson syndrome may go on to develop a vitreous hemorrhage. This occurs when the amount of blood is quite large and is able to generate a force enough to tear the ILM at some point and enter the subhyaloid space. A laser hyaloidotomy also works by puncturing the ILM rather than posterior hyaloid and is more appropriately termed as laser membranotomy. 4) In long standing cases of subhyaloid or vitreous hemorrhage, ILM is the barrier preventing blood from flowing across the retinal layers towards the photoreceptors. Surprisingly in most such cases we do not find the formation of epimacular membranes, even if the subhyaloid hemorrhage has persisted for a long time, despite there being so much of cellular elements and enzymes in the blood/plasma. There are only few case reports of epimacular membrane formation after long-standing vitreous hemorrhage.[16] An epiretinal membrane formation in such cases might be rarely occurring in those in which the ILM somehow got breached and the barrier function was lost. The ILM may not be a barrier for smaller molecules as some studies show that both the posterior vitreous cortex and ILM do not prevent diffusion of smaller molecules such as various ions, glucose, lactate, and ascorbate.[17] Yet the other experimental and clinical evidence presented above strongly point towards ILM having an important barrier function. Other than the retinal barriers formed by the tight junctions between the retinal capillary endothelial cells and the tight 6

junctions between the retinal pigment epithelial cells, the ILM may be the third and innermost barrier. Thus, it may be prudent to peel ILM in only those cases where the benefits of removal outweigh the risks of losing this natural barrier. Large studies are required to better characterize and explore this barrier function of the ILM.

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References [1] Semeraro F, Morescalchi F, Duse S, Gambicorti E, Russo A, Costagliola C. Current Trends about Inner Limiting Membrane Peeling in Surgery for Epiretinal Membranes. J Ophthalmol 2015;2015:1–13. doi:10.1155/2015/671905. [2] Halfter W, Dong S, Dong A, Eller AW, Nischt R. Origin and turnover of ECM proteins from the inner limiting membrane and vitreous body. Eye 2008;22:1207–13. doi:10.1038/eye.2008.19. [3] Gelman R, Stevenson W, Prospero Ponce C, Agarwal D, Christoforidis JB. Retinal Damage Induced by Internal Limiting Membrane Removal. J Ophthalmol 2015;2015:1–10. doi:10.1155/2015/939748. [4] Almony A, Nudleman E, Shah GK, Blinder KJ, Eliott DB, Mittra RA, et al. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina Phila Pa 2012;32:877–91. doi:10.1097/IAE.0b013e318227ab39. [5] Guidry C. The role of Müller cells in fibrocontractive retinal disorders. Prog Retin Eye Res 2005;24:75–86. doi:10.1016/j.preteyeres.2004.07.001. [6] Tadayoni R, Svorenova I, Erginay A, Gaudric A, Massin P. Decreased retinal sensitivity after internal limiting membrane peeling for macular hole surgery. Br J Ophthalmol 2012;96:1513–6. doi:10.1136/bjophthalmol-2012-302035. [7] Haritoglou C, Ehrt O, Gass CA, Kristin N, Kampik A. Paracentral scotomata: a new finding after vitrectomy for idiopathic macular hole. Br J Ophthalmol 2001;85:231–3. [8] Ito Y, Terasaki H, Takahashi A, Yamakoshi T, Kondo M, Nakamura M. Dissociated optic nerve fiber layer appearance after internal limiting membrane peeling for idiopathic macular holes. Ophthalmology 2005;112:1415–20. doi:10.1016/j.ophtha.2005.02.023. [9] Tadayoni R. Dissociated optic nerve fiber layer appearance of the fundus after idiopathic epiretinal membrane removal. Ophthalmology 2001;108:2279–83. doi:10.1016/S01616420(01)00856-9. [10] Pichi F, Lembo A, Morara M, Veronese C, Alkabes M, Nucci P, et al. Early and late inner retinal changes after inner limiting membrane peeling. Int Ophthalmol 2014;34:437–46. doi:10.1007/s10792-013-9831-6. [11] Romano MR, Romano V, Vallejo-Garcia JL, Vinciguerra R, Romano M, Cereda M, et al. Macular hypotrophy after internal limiting membrane removal for diabetic macular edema. Retina 2014;34:1182–9. doi:10.1097/IAE.0000000000000076. [12] Steven P. Secondary paracentral retinal holes following internal limiting membrane removal. Br J Ophthalmol 2006;90:293–5. doi:10.1136/bjo.2005.078188. [13] Chawla R, Tripathy K, Gogia V, Venkatesh P. Progressive outer retinal necrosis-like retinitis in immunocompetent hosts. BMJ Case Rep 2016;2016. doi:10.1136/bcr-2016216581. [14] Griffin JR, Pettit TH, Fishman LS, Foos RY. Blood-borne Candida endophthalmitis. A clinical and pathologic study of 21 cases. Arch Ophthalmol Chic Ill 1960 1973;89:450–6. [15] Tripathy K, Chawla R. Valsalva retinopathy. Natl Med J India 2015;28:310. [16] Spraul CW, Grossniklaus HE. Vitreous Hemorrhage. Surv Ophthalmol 1997;42:3–39. [17] Lund-Andersen H, Sander B. The Vitreous. Adlers Physiol. Eye. 11th ed, Edinburgh: Elsevier Health Sciences; 2011, p. 164–81. 8

Legends Figure 1a: Spectral-domain Optical coherence tomography image of a case of focal retinitis showing a stretched intact Internal limiting membrane over an area of inner retinal tissue loss. The corresponding fundus image is shown below the OCT. Figure 1b: An Intraoperative Optical coherence tomography image of a case of Terson syndrome showing the scanned area of the fundus on the left and a separated Internal limiting membrane (with some blood attached to its inner surface) forming a cavity above the retina on the right. Figure 1c: A Swept source Optical coherence tomography image of a case of Valsalva retinopathy with nearly resolved sub-ILM bleed showing a separated Internal limiting membrane (with some blood attached to its inner surface) forming a cavity above the retina. The corresponding fundus image is shown below the OCT.

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