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 Table of Contents  
Year : 2021  |  Volume : 33  |  Issue : 2  |  Page : 226-229

Journal Review

Department of Ophthalmology, Government Medical College, Thrissur, Kerala, India

Date of Submission29-May-2021
Date of Acceptance02-Jun-2021
Date of Web Publication21-Aug-2021

Correspondence Address:
T U Laly
Department of Ophthalmology, Government Medical College, Thrissur, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kjo.kjo_129_21

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How to cite this article:
Laly T U. Journal Review. Kerala J Ophthalmol 2021;33:226-9

How to cite this URL:
Laly T U. Journal Review. Kerala J Ophthalmol [serial online] 2021 [cited 2021 Nov 30];33:226-9. Available from: http://www.kjophthal.com/text.asp?2021/33/2/226/324212

  Five-Year Follow-up of First eleven Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure Top

Numa K, Imai K, Ueno M, Kitazawa K, Tanaka H, Bush JD, et al. Five-year follow-up of first 11 patients undergoing injection of cultured corneal endothelial cells for corneal endothelial failure. Ophthalmology 2021;128:504-14.

Penetrating keratoplasty, descemet stripping automated endothelial keratoplasty (DSAEK) and descemet membrane endothelial keratoplasty (DMEK) are the current surgical treatments for corneal endothelial failure. They require donor cornea, are invasive, and can result in early surge of endothelial cell loss, graft detachment, or dislocation. The corneal shape may not be well restored. Ideal is a surgical procedure that reproduces normal shape with high corneal endothelial cell density (ECD) with no structural irregularity with good postoperative visual acuity and proper corneal function for all types of corneal endothelial failure.

A novel surgical procedure of injection of cultured human corneal endothelial cells (hCECs) with Rho-associated protein kinase inhibitor to promote corneal endothelial cell (CEC) engraftment for the treatment of endothelial failure conditions was published earlier. The objective of the present study is to report the safety and efficacy of this novel cell injection therapy, a 5-year postoperative clinical data from a first-in-humans clinical trial group.

This was a prospective observational study involving 11 eyes of 11 patients with pseudophakic endothelial failure conditions with total corneal edema who underwent hCEC injection therapy between December 2013 and December 2014. That is, fuchs endothelial corneal dystrophy (FECD) (7 eyes), argon laser iridotomy induced (2 eyes), pseudoexfoliation syndrome keratopathy (1 eye), and intraocular surgery-related corneal edema with intraocular lens suturing (1 eye), and all with posterior chamber intraocular lens.

Three hundred milliliter of unique fluid-based cell suspension in modified Opti- MEM I Reduced-Serum Medium supplemented with Rho-associated protein kinase inhibitor was aspirated into a dead space-free syringe and then injected into the anterior chamber, with patients placed in a face-down position for 3 h to enhance the adhesion and engraftment of the injected cells. Systemic and topical steroids were given after the procedure.

All patients were examined at 1, 4, 12, 24 weeks and 1, 2, 3, 4, 5 years after hCEC therapy. Results showed ECD more than 500 cells/mm2 in 10 of 11 eyes. Eight eyes had ECD more than 1000 cells/mm2 and 2 had ECD more than 2000 cells/mm2. The mean standard deviation of ECD at 3, 4, and 5 years was 1384 ± 451, 1268 ± 472, and 1257 ± 467 cells/mm2, respectively. Coefficient of variation improved from 0.46 ± 0.076 to 0.37 ± 0.088 and percentage of hexagonality improved from 47 ± 8.7% to 54 ± 6.2% indicating that CECs stabilized over 5-year postoperative period. Guttae in FECD eyes had not changed or decreased in size and area as compared to at 6 months and 2 years. Corneal thickness at center was within the normal range (<630 μm) with a rapid decrease within 4 weeks, followed by a gradual decrease that was maintained up to 5 years and corneal epithelial and stromal edema completely disappeared in 10 eyes. Best-corrected visual acuity (BCVA) improved in 10 eyes (91%) and mean BCVA improved to 0.046 from 0.876 logarithm of the minimum angle of resolution before surgery. Surgery done for 1 eye with raised intraocular pressure (IOP) due to steroid-induced glaucoma at 8 months, followed by normal IOP in all eyes up to 5 years. There is no anterior uveitis or allogeneic immune reaction.

At 5 years, this novel therapy is thus equivalent in clinical outcomes to DSAEK and DMEK. Corneal transplantation requires one donor cornea to treat one diseased eye, while this allows for enough hCECs to treat at least 300 diseased eyes to be cultured from just 1 donor cornea. Limitations of the study are small number of eyes enrolled.

  Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group Top

Spaide RF, Jaffe GJ, Sarraf D, Freund KB, Sadda SR, Staurenghi G, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data consensus on neovascular age-related macular degeneration nomenclature study group. Ophthalmology 2020;127:616-36.

Age-related macular degeneration (AMD) is a disease complex beyond 50 years of age, in which the structure and function of the macula deteriorates. A salient characteristic is the accumulation of extracellular deposits including subretinal drusenoid deposits, basal linear, and basal laminar deposits. In the early phases of AMD, only minimal visual changes. With time, vitelliform deposit accumulate, pigments migrate into retina, drusen size increase, and hypopigmentation and hyperpigmentation of the retinal pigment epithelial (RPE) develop. Late phases show atrophy of the outer retina, thinning and loss of the RPE, and macular neovascularization (MNV). MNV can lead to leakage, bleeding, and scarring as well as severe vision loss. The terminology used in most of the literature is based on fluorescein angiography (FFA). With better AMD knowledge by recent advances in imaging technology such as optical coherence tomography (OCT) and OCT angiography (OCTA), nomenclature system needs revision. To evaluate and standardize nomenclature for reporting AMD data, a consensus meeting of an international panel of retina specialists, imaging and image reading center experts, and ocular pathologists was organized under the auspices of the Macula Society, an international study group referred to as the Consensus on Neovascular AMD Nomenclature group. They discussed and codified a set nomenclature framework for classifying the subtypes of neovascular AMD and associated lesion components.

Type 1 MNV represents areas of neovascular complexes arising from the choriocapillaris into the sub-RPE space. OCT shows as an elevation of the RPE by material with heterogeneous reflectivity; vascular elements may be seen. OCTA shows vessels below the level of the RPE. Occult choroidal neovascularization (CNV) old term shows stippled hyperfluorescence over an area of elevated RPE, which expands to coalesce in the later phases of FFA. Indocyanine green angiography (ICGA) shows just late staining of the lesion, referred to as plaque. Polypoidal choroidal vasculopathy is defined by a branching vascular network and nodular vascular agglomerations. OCT findings similar to Type 1 MNV. Dilated vascular elements at the outer border of the lesion are apparent in OCT. Because of the slow perfusion dynamics, polyps remain undetected by OCTA. The pattern of the RPE elevation may suggest nodules in FFA. ICGA shows a branching vascular network with aneurysmal dilations. Late staining of tissue around the dilatations occurs. In Asian persons, the typical presentation comprises isolated macular involvement, unilateral, and male preponderance.

In Type 2 MNV, proliferation of new vessels arises from the choroid into the subretinal space above the level of RPE. Although these vessels traverse the sub-RPE space, the disease process is dominated by the subretinal portion. It is associated with exudation directly into the sub retinal space. OCTA demonstrates vascular elements above the level of RPE. FFA shows early, typically well-defined hyperfluorescence with late leakage. Type 2 MNV also seen in angioid streaks, lacquer cracks, and chorioretinitis.

Type 3 MNV refers to a downgrowth of vessels from the retinal circulation toward the outer retina. Thus, the term CNV is not accurate for Type 3 and shows extension of hyperreflectivity from the middle retina toward to level of the RPE associated with intraretinal edema, hemorrhage, and telangiectasis. ICGA shows a small hyperfluorescent lesion and represents descending vessels viewed axially. OCT shows varying amounts of intraretinal edema, subretinal fluid (SRF) and exudation, pigment epithelial detachment (PED). OCTA shows the downgrowth of new vessels toward or even penetrating the level of the RPE and also known as retinal angiomatous proliferation and shows focal hyperfluorescence associated with intraretinal staining.

Retinal-choroidal anastomosis is an aberrant connection between the retinal and the choroidal circulation. Course of vessel can be seen with OCT or OCTA. Although visible on FFA, ICGA is better. If prominent neovascularization is present in subretinal and sub-RPE compartments, the term mixed Type 1 and Type 2 neovascularization used. An eye with Type 3 disease that has penetrated the RPE monolayer without making an anastomosis with the choroidal circulation is said to have extension of Type 3 disease into the sub-RPE space. Some eyes show Type 3 neovascularization and a separate unconnected region of Type 1 neovascularization. This situation may be summarized as Type 3/1 neovascularization, in which the “/” is interpreted as meaning “and” in an independent sense.

Exudation is a common feature of MNV and can manifest in 4 basic forms: Leakage, SRF, lipid, and subretinal hyperreflective exudative material (SHRM). Leakage is the release of excess fluid and serum components as the result of the breakdown of the blood-retinal barrier.Detected with FFA, in which hyperfluorescence outside of vascular confines is seen to expand in area over the course of the angiographic sequence. The dye may accumulate in tissue, a process called staining, or into fluid-filled spaces, termed pooling. Intraretinal fluid may accumulate from retinal vasculature leakage or intraretinal neovascularization or diffusion of fluid through the outer retina related to abnormalities of the external limiting membrane (ELM) and associated structures. SRF is separation of the neurosensory retina from the RPE by fluid. Readily detected using OCT.

Lipid (or hard exudates) is lipoprotein precipitates related to chronic vascular leakage. Concentration of lipoprotein molecules may exceed their solubility, resulting in tissue deposition. SRHM is the exudation into or under the retina of material (include an admixture of serum, fibrin, and inflammatory cells) excluding red blood cells, detected by color fundus photography. OCT appears as regions of featureless accumulations of relatively uniform increased reflectivity. SHRM is not hyperautofluorescent, as opposed to vitelliform material which is hyperautofluorescent. SHRM can resolve but fibrosis can occur in its wake. Presence of SHRM is associated with poorer visual outcomes. Clues to Type 2 MNV with SHRM include a classic pattern on FFA, disruption of the ELM, and intraretinal fluid. Reappearance of SHRM is a sign of recurrent exudative activity resulting from neovascularization.

Retinal PED is a clinically evident separation of the RPE monolayer from the underlying Bruch's membrane. This can occur from drusenoid material, serous fluid, neovascular infiltration, or blood. Collections of drusen material of more than 350 mm in diameter are called drusenoid PEDs. Serous PEDs are collections of fluid, but in AMD, serous PEDs typically are associated with neighboring MNV. Neovascular infiltration usually is associated with some element of fibrotic tissue and is called fibrovascular PEDs. Elevations with blood are called hemorrhagic PEDs. The RPE may be elevated by fluid released from the neovascularization, and this may occur eccentric to the neovascular tissue, producing a notched PED where the neovascularization is in the notch. OCT and OCTA can detect the internal anatomic structure of the PED, and OCTA particularly effective if the PED is shallow. PEDs can occur in the context of Type 1 or Type 3 MNV but not Type 2. The association with Type 1 may be related to the sub-RPE location of the vessels and potential exudation. Types 2 and 3 cause unknown.

Hemorrhage is an extravasation of blood from the neovascular complex and can be located in the sub-RPE, subretinal, intraretinal, and occasionally preretinal compartments. Fresh blood is red and hypoautofluorescent. As blood ages, it becomes yellow, does not stain during FFA and is hyperautofluorescent. Fibrosis refers to the apparent build-up of tissue (collagen) in any layers of the retina, including the subretinal space, RPE monolayer, or sub-RPE space. The fibrotic region typically stains on FFA and is not hyperautofluorescent. Rip (or tear) of the RPE is caused by a tractional dehiscence of the RPE monolayer following contracture of the sub-RPE fibrovascular tissue. It retracts producing a heaped-up region adjacent to a zone of absent RPE tissue. The retracted RPE monolayer causes decreased transmission to the deeper layer causing decreased fluorescence during FFA and choroidal hypotransmission with OCT. It is hyperautofluorescent because of the increased light path through fluorophores. Area of denuded RPE shows hyperfluorescence in FFA and ICGA and hypertransmission to the choroid on OCT. With the absence of the RPE, and likely atrophy of the choriocapillaris, flow signal can be obtained from deeper choroidal vessels in OCTA.

Outer retinal atrophy (ORA) is loss of the ellipsoid zone (EZ) and interdigitation zone (IZ) usually with corresponding loss of thickness of the outer nuclear layer (ONL) and occurs after prolonged SRF accumulation, regression of subretinal drusenoid deposit, or over large collections of drusen material. In complete ORA, the EZ and the IZ are not visible, the ELM may not be discernible, and ONL becomes thinner. In incomplete ORA, a discontinuous loss of the EZ has occurred, and the IZ is not visible. RPE and ORA refer to the absence of a clinically normal RPE monolayer, usually by cell death. In OCT imaging, RPE atrophy is characterized by a loss of the RPE band with associated choroidal hypertransmission. The loss of RPE cells usually is accompanied by concomitant loss of the outer retina. If the zone of abnormalities is more than 250 mm in diameter, it is termed complete RPE and ORA (cRPE and ORA). If the zone of abnormalities is <250 mm, or if the hypertransmission is fragmentary, it is termed incomplete RPE and ORA.

On substituting modern terms, late AMD would be cRPE and ORA that correspond roughly to geographic atrophy or MNV. Criticisms of this approach are that cRPE and ORA and MNV are different conditions with dissimilar pathophysiology, and therefore, they should not be lumped together. In conclusion, establishing a uniform set of definitions will facilitate comparison of diverse patient groups and different studies. The study group suggests that the consensus standards outlined in this article should be used in future reported studies of neovascular AMD and clinical practice.

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