ILMP is challenged because it may injure the Retinal Fiber and the Retinal Ganglion cells layers. And indeed ILMP tears Muller Cells (MC) endfeet, and eventually retinal astrocytes, and endothelial cells. However numerous studies as well as routine clinical practice have long shown that well-conducted Vitrectomy-ILMP can reabsorb macular edema and improve visual acuity in the majority of cases. It is acknowledged today that EGFR (Epidermal Growth Factor Receptor) pathways are activated by retinal injury and drive ubiquitous adult reactive retinal astrogliosis (ARRA) and its hallmark, Glial Fibrillary Acidic Protein (GFAP) adult up-reactivation. ARRA has long been interpreted as detrimental in the experimental literature. To attempt to elucidate this intricate context, we have studied the relationship between ARRA reactional to trauma of mechanical nature and retinal edema (RE) in the entire eye in vivo. Light microscopy study and immunohistochemistry (IHC) EGFR and GFAP (Glial Fibrillary Acidic Protein) staining were performed 1) in ten entire human eyes presenting a retinal injury of mechanical nature (retinal detachment (RD) secondary to melanomas (two eyes), biochemical nature (venous occlusion, endophthalmitis) (three eyes) , and mixed nature (five eyes) 2) in two entire porcine eyes enucleated at Day 15 and 35 after creation of a RD mimicking the natural history in the human eye in vivo by vitrectomy and retinal browsing. Simultaneously, an extensive review of the literature in the field of brain and retinal gliosis, as well as in the field of wound healing, was undertaken.

Results:

1) In the human eyes in vivo : Retinal Edema is not present when GFAP is up-regulated according to a spanning pattern; GFAP and EGFR expressions vary according to the nature of the triggering factor and to the macroglial cell type involved. In the three eyes with biochemical injury alone, RE is present, restricted to the external retinal layers; horizontal retinal astrocytes (RAC) GFAP up-regulation is co-observed in the perivascular internal layers; Muller Cells (MC) gliosis is not observed. In the two eyes with RD only, there is neither RE nor macular edema (ME); a dramatic MC vertical gliosis spanning from the ILM to the outer limiting membrane (OLM) is obviated; there is no RAC gliosis. In the five cases with both triggering factors, both gliosis are observed without significant RE/ME. EGFR is co-expressed when RD is present. EGFR including HER2 is not expressed in case of biochemical injury alone.

2) In the porcine eyes in vivo: Retinal Edema is cured by GFAP up-regulation according to a spanning pattern under the control of EGFR activation. At Day 15, a RE is observed, prevailing in the external layers; a dramatic MC GFAP up-regulation, with a pattern spanning from the ILM to the external plexiform layer is co-observed; EGFR activation is dramatic in neuron and MC membranes, spanning from the ILM to the OLM. At Day 35, RE is no longer present; MC GFAP activation is spanning down to the OLM; EGFR activation is still present, but fainted.

3) Recent neuro-sciences research data confirm that ARRA is mechano-protective and neuro-regenerative through EGFR pathways which drive: a) anti-apoptotic, repair, proliferation and migration downstream transduction cascades b) macroglial cytoskeleton interfilament proliferation which reinforces the extracellular matrix adhesion, the blood retinal barrier and the glio-neural couplings c) the return of a quiescent MC contingent to the stem-like developmental condition of Radial Glia which generates new neurons and new glial cells. Altogether with boosting of glio-neuronal, glio-vascular, glio-glial couplings and microglial interactions, ME gets reabsorbed, and new neurons replace the necrotic tissues. Recent revision of the interpretation of ARRA suggest that it is graded along with time and intensity. Recent research data in wound healing suggest that tearing of MC endfeet basal membranes might induce their regeneration with an “hybrid” Mesenchymal to Epithelial Transformation (MET) as a result of the modification of their surface contact -from a tissue of mesenchymatous nature to a fluidic cavity- which in turn increases EGFR affinity and boosts their osmotic capacities.

Conclusion:

It is precisely because V-ILMP is traumatic that it works. ILMP is a retinal trauma of mechanical nature effected in the entire human globe in vivo on a chronically diseased macula with overwhelmed homeodynamic capacities. As so as, it triggers ARRA controlled by EGFR pathways. Sequential spatial and temporal MC spanning GFAP activation, and regenerated MC endfeet modified-type basal membranes, induce resorption of RE. Due to its mild intensity, ARRA remains limited to its early homeodynamic beneficial phase and to minor collateral damage. ILMP is a (non pharmaceutical) therapeutical manipulation of EGFR and ARRA.

Contact Details:

Email: cboscher@wanadoo.fr
Cell Phone: +33680637752

Claude Boscher