The internal limiting membrane (ILM), the basement membrane of the Müller cells, serves as the interface between the vitreous body and the retinal nerve fiber layer. It has a fundamental role in the development, structure, and function of the retina, although it also is a pathologic component in the various vitreoretinal disorders, most notably in macular holes. It was not until understanding of the evolution of idiopathic macular holes and the advent of idiopathic macular hole surgery that the idea of adjuvant ILM peeling in the treatment of tractional maculopathies was explored. Today intentional ILM peeling is a commonly applied surgical technique among vitreoretinal surgeons as it has been found to increase the rate of successful macular hole closure and improve surgical outcomes in other vitreoretinal diseases. Though ILM peeling has refined surgery for tractional maculopathies, like all surgical procedures it is not immune to perioperative risk. The essential role of the ILM to the integrity of the retina and risk of trauma to retinal tissue spurs suspicion with regard to its routine removal. Several authors have investigated the retinal damage induced by ILM peeling and these complications have been manifested across many different diagnostic studies.
The internal limiting membrane (ILM) is the basal lamina of the inner retina that is formed by the footplates of Müller cells. It is the structural interface between the retina and the vitreous and is composed of collagen fibers, glycosaminoglycans, laminin, and fibronectin. The ILM is 1.5
ILM peeling is now a widely recognized technique used routinely for traction maculopathies, but what are the possible complications of this intervention? It is a technique that requires additional intraoperative agents, instruments, and surgical time. No studies or reports to date have shown adverse visual outcomes in patients status after an ILM peel, but there has yet to be a large enough randomized control trial assessing side effects of ILM removal, and therefore the question remains: Does the ILM have a function vital to the integrity of the retina that would render it damage upon ILM removal? If so, what type of retinal damage can this surgical technique induce?
ILM peeling is a surgical technique commonly used today to treat various vitreoretinal disorders including macular holes, macular puckers, epiretinal membranes, diabetic macular edema, retinal detachment, retinal vein occlusions, vitreomacular traction, optic pit maculopathy, and Terson syndrome [
ILM peeling begins with pars plana vitrectomy and posterior hyaloid removal. Following these steps, adjuvant dyes are used to stain the translucent ILM to improve visualization and ensure complete removal in a technique called chromovitrectomy. The most commonly used dyes are indocyanine green (ICG), infracyanine green (IfCG), trypan blue, brilliant blue, and triamcinolone acetonide. Following dye injection, the ILM is grasped directly with forceps or a flap of the ILM is created and vitreoretinal forceps are used to grasp the flap (Figure
ILM peeling after staining with brilliant blue dye [
Macular holes are full thickness defects through the fovea centralis causing loss of central visual acuity, central scotoma, and metamorphopsia in affected eyes. Most of these holes are idiopathic, though trauma, inflammation, and high myopia are less common causes.
As Gass eloquently classified the progression of macular holes and, later, demonstrated with optical coherence tomography (OCT), idiopathic macular holes begin with the development of tangential traction of the prefoveal vitreous cortex [
(a) Schematic and OCT representation of macular hole formation [
In a large prospective study focusing on the long-term outcomes of ILM peeling for macular holes after at least 12 months, Haritoglou et al. described promising results. The authors reported anatomic closure in 87% after 1 surgery, closure in 96% of reoperated eyes, and a median best-corrected visual acuity improvement from a median of 20/100 preoperatively to 20/40 postoperatively in 94% [
As several sources have displayed favorable anatomic and functional outcomes with ILM peeling, this technique has become part of the standard of practice for vitreoretinal surgeons repairing full thickness macular holes.
Diabetic macular edema (DME), caused by intraretinal fluid accumulation in the macula, is the most common cause of visual impairment in diabetic patients and a major cause of legal blindness in the United States. The pathogenesis is multifactorial and includes breakdown of the blood-retinal barrier (BRB) secondary to weakened capillary intercellular tight junctions, loss of pericytes, and leukostasis in the retinal vessels and vasoactive factors such as vascular endothelial growth factor-A (VEGF-A), various growth factors, and matrix metalloproteinases. Abnormalities at the vitreoretinal interface (the posterior vitreous cortex and ILM) have also been found to promote DME. Specifically, the hyaloid becomes taut and thickened with induced cellular proliferation and production of cytokines. The fovea and the vitreous base, where the ILM is thinnest, are the points at which the posterior vitreous cortex and the ILM have the strongest attachment. Advanced Glycation End-Products (AGEs), accumulated in the posterior vitreous cortex, increase cross-linking of collagen fibrils and induce structural changes in the posterior hyaloid that strengthen vitreomacular adhesions between the posterior hyaloid and ILM. This is further aggravated by AGE receptors (RAGEs), which are attached to the footplates of the Müller cells and extend to the external limiting membrane (ELM). RAGE activation by the binding of AGEs stimulates VEGF upregulation and retinal vessel permeability, further exacerbating DME [
Laser photocoagulation is the standard treatment for clinically significant macular edema (CSME) as established by the Early Treatment Diabetic Retinopathy Study (ETDRS), but not uncommonly DME persists despite laser treatment [
Epiretinal membrane (ERM) is a disease of the vitreomacular interface characterized by cellular proliferation on the inner retinal surface. It is classified as either idiopathic in nature or secondary to an independent ocular pathology such as inflammation, trauma, retinal vascular disease, and surgery. Regardless of the underlying etiology, it is the contractile properties of ERM elements that have the potential to create vitreomacular traction, distort foveal morphology, and promote retinal thickening, producing symptoms of decreased visual acuity or metamorphopsia. Though ERM is relatively common among older persons, most are asymptomatic and can be managed conservatively with observation; however, development of visual disturbances or deterioration of vision warrants surgical intervention [
The standard surgical technique for treating ERM has been established since the 1970s and entails pars plana vitrectomy with ERM removal. In general, this approach has proven to have good outcomes with the potential for few associated complications. ERM recurrence is one such complication and though uncommon, reported by Grewing and Mester to occur in approximately 12% of cases, reoperation may be indicated in cases of symptom exacerbation [
Additional ILM peeling in surgery for ERM removal does not eliminate the potential for future ERM development, but, according to a retrospective study of 440 eyes, the recurring membrane is thin and asymptomatic. ERM does not recur often, and the need for reoperation is rare, but as of yet ILM peeling is the only measure proven to be preventative; therefore, though not a necessary component of every operation for ERM, in select cases ILM removal is invaluable in maximizing postoperative visual potential [
Macular retinoschisis is a traction-induced maculopathy common among highly myopic eyes with posterior staphyloma, with manifestations including retinal thickening, formation of cystoid spaces, foveal detachment (termed myopic foveoschisis), and lamellar or full thickness macular hole. With the advent of OCT, such retinal anomalies, previously difficult to diagnose, were better characterized and discovered to be present in up to one-third of highly myopic eyes with staphylomata [
Vitreous traction is pivotal in the pathogenesis of macular retinoschisis in highly myopic eyes, but the source of this traction is variable with etiologies including ERM, remnant cortical vitreous plaques following posterior vitreous detachment (PVD), perifoveal PVD, and a taut ILM [
Retinal toxicity can occur secondary to the specific dye used during chromovitrectomy. Indocyanine green (ICG), introduced in 2000, is a chromophore that stains the ILM secondary to its affinity for laminin and collagen type IV. Several authors have reported side effects observed with ICG use, the most common being visual field defects, reduced retinal nerve fiber layer thickness on OCT, and RPE or ganglion cell changes that manifest as abnormalities on multifocal electroretinography (mfERG), light and transmission electron microscopies, and reduced enzymatic activity [
Trypan blue (TB) is a dye that stains damaged cell membranes often used in epiretinal membrane removal in addition to ILM peeling. The formulations used in vitreoretinal surgery are low concentrations, but experimental studies have shown TB induces neurotoxic effects on retinal ganglion cells in a dose- and time-dependent manner [
Triamcinolone acetonide (TA) is used to identify the posterior vitreous cortex, epiretinal membranes, and the ILM during vitrectomy. Conflicting evidence makes it difficult to definitively say if TA is toxic to the retina, though there are published reports of its use producing similar adverse effects to ICG. Crystal deposition secondary to TA, which aids in ILM removal, has been proposed to delay the healing process and affect macular hole closure [
Brilliant blue G (BBG) selectively binds to and stains ILM similarly to ICG and IfCG, optimizing ILM peeling. Historically found to have good clinical outcomes without evidence of toxicity on mfERG, it has widely been accepted as a good alternative dye, though its safety profile is still a matter of controversy [
Given the close proximity of the ILM to the inner retina and its interdigitation with Müller cell footplates, it is not surprising to find retinal tissue and Müller cell debris on removed ILM specimens (Figure
Light micrographs (LM) and transmission electron micrographs (TEM) of the ILM (asterisks) removed from eyes with diabetic macular edema ((a) and (b)) and stage IV idiopathic macular hole ((c) and (d)). The ILM is characterized by an undulated retinal side and a smooth vitreal side. ((a), (b)) Cell membrane fragments (arrow) on the retinal side of the ILM. The vitreal side of the ILM (arrowhead) is devoid of cells and collagen. ((c), (d)) LM shows a cell (arrow) with nucleus on the retinal side of the ILM. EM shows one large cell fragment (arrow) in contact with ILM and a single cell on the vitreal side of the ILM (arrowhead), which is likely a fibrous astrocyte [
(a) Focal macular ERGs before and 6 weeks and 6 months after IMH surgery without ILM removal and the fellow eye. The b-wave amplitudes increase 6 weeks and even further 6 months after surgery. (b) Focal macular ERGs before and 6 weeks and 6 months after IMH surgery with ILM removal and the fellow eye. The b-wave amplitudes are significantly decreased 6 weeks after surgery but recover 6 months after surgery to the same level as that prior to surgery [
In a case series from 2006, Steven et al. reported the formation of paracentral retinal holes following seemingly atraumatic ILM removal, observed with ICG, TB, and TA and when no adjuvant dye was used. They suggested that this postoperative finding might be a consequence of Müller cell damage causing weakening of the glial structures of the retina and ultimately hole formation. Specifically, as Müller cells remove metabolic waste products from retinal neurons, their removal in the process of ILM peeling may induce glial apoptosis and resultant retinal dysfunction. As these secondary paracentral holes always developed in the area of ILM removal, the authors discuss possibly limiting the area of retina that is peeled [
Scanning laser ophthalmoscope microperimetry after idiopathic macular hole surgery. (a) One month after surgery without ILM peeling showing normal retinal sensitivity and no deep microscotomas in the central 9 degrees of the visual field. (b) Two months after surgery with ILM peeling showing decreased mean retinal sensitivity and deep absolute and relative microscotomas in the central 9 degrees of the visual field [
A dissociated optic nerve fiber layer (DONFL) appearance is described as arcuate retinal striae along the optic nerve fibers in the macular region, slightly darker than the surrounding retina. A retrospective case series of 91 eyes with closed idiopathic macular holes, 67 ILM-peeled and 24 non-ILM-peeled, detected a DONFL on color fundus photography in 54% (36 of 67 eyes) of ILM-peeled eyes and 0% of nonpeeled eyes. OCT was performed on 20 of the 36 eyes and all of the nonpeeled eyes and demonstrated focal dehiscence of the optic nerve fiber layer only in the 20 eyes that demonstrated DONFL. Despite these findings and previous reports of DONFL associated with ILM peeling, no functional outcomes were observed; that is, visual acuity, visual field testing, and SLO microperimetry did not show abnormalities. The authors suggest DONFL appearance may be secondary to mere shifting of optic nerve fibers, rather than deterioration, resulting from loss of Müller cell support or postoperative regenerative processes of Müller cells or astrocytes [
Phototoxic damage to the retina can occur because of photothermal, photomechanical, or photochemical mechanisms. Photothermal damage results from prolonged exposure of the retina to a light source. Photomechanical retinal damage is a possibility if there is physical contact between the light probe and the retina. Photochemical damage results when the visible light excites endogenous or exogenous chromophores. The endogenous chromophores excitable by visible light wavelengths are the photoreceptor pigments, as well as the melanin and lipofuscin of the RPE. ICG is an example of an exogenous chromophore excitable by visible light. Chromophore excitation produces reactive oxygen species, which cause lipid peroxidation and ultimately destroy cell membranes [
Though the ILM is integral to the histogenesis, structure, metabolism, and function of the retina, its detrimental role in inducing or exacerbating traction in various vitreoretinal diseases has made its removal in the treatment of traction-induced maculopathies logical and absolutely necessary, so much so that its indications have extended from the idiopathic full thickness macular hole from which it was born to include several other conditions that have an element of prefoveal traction. ILM peeling has revolutionized and become a vital component in vitreoretinal surgery as it has repeatedly been shown to be safe and effective in improving anatomic and functional outcomes across a range of retinal diseases, but the technique is not resistant to causing perioperative retinal damage and several authors in the literature have reported objective abnormal findings postoperatively. Despite its widespread acceptance and high safety profile, it is of paramount importance to always be aware of the possible deleterious consequences ILM peeling can impose, because as routine as the technique has become for the field and for the surgeon, it indeed is not routine for the patient.
The authors declare that there is no competing/conflict of interests related to any topic in this paper.