Introduction
Macular telangiectasia type 2 (MacTel) is a slowly progressive macular disease. It had previously been considered a vascular disease, but recent evidence suggests a neurodegenerative etiology, with primary involvement of Muller cells. Retinal pigment epithelium (RPE) hyperplasia and subretinal neovascularization (SNV) are responsible for most vision loss in advanced cases.
This review will discuss the pathophysiology, clinical features, important diagnostic imaging studies, and treatment options available for MacTel.
Demographics
MacTel is a bilateral asymmetric condition1 that affects patients older than 40 years,1,2 with a predilection for women.1,3 The Beaver Dam Eye Study reported a prevalence of 0.1% in 4,790 individuals aged 43 to 86 years, 4 but the Melbourne Collaborative Cohort estimated a considerably lower prevalence of 0.0045% in 22,415 participants.2 MacTel is equally prevalent worldwide with no racial predilection.5
Pathogenesis
Vascular theory
Gass and Oyakawa proposed that stasis within the retinal veins due to the impact of arterial crossing has an etiological role.1 They believed that the chronic exudation of telangiectasia led to external atrophy of the retina and RPE metaplasia.
Several inconsistencies affected the widespread acceptance of the vascular theory. MacTel usually begins in the temporal parafovea although the reason for this predilection is unclear. Anastomoses between the superior and inferior temporal arcade vessels could be associated with vascular decompensation, although the reason for this mechanism had not been elucidated.6 Retinal thickness is substantially reduced (not increased) despite leakage of dye in fluorescein angiography (FA) and loss of due vision. Photoreceptor atrophy occurs without any evidence of cystoid macular edema.7 Optical coherence tomography (OCT) shows abnormalities inconsistent with vascular leakage and leakage in the AF often precedes the development of telangiectasias.
Neurodegenerative theory
Muller cells are important in maintaining the retinal blood barrier and providing trophic factors to surrounding neurons. Muller cell dysfunction is central to MacTel’s neurodegenerative theory.8
Muller cells surround the neurons and provide them with nutrition. Muller cell processes are in close contact with retinal blood vessels in the external plexus.8–10 Nutritional deprivation may be an important factor leading to the commonly observed loss of retinal transparency. in MacTel.7 Muller cell dysfunction is associated with atrophy and disorganization. of the outer retina, resulting in hyporeflective spaces in the outer layers of the retina seen on OCT.10 OCT and ERG changes in the form of inner lamellar holes and reduced cone responses manifested before the development of typical vascular changes. 10 Xanthophyll, which is mainly stored. in Muller cells, it decreases in early MacTel.
Vascular proliferative changes
Neurodegeneration leads to retinal thinning. As the disease progresses, the associated capillary endothelial cell degeneration leads to hypoxia.11,12 The combination of VEGF secretion and Muller cell dysfunction leads to intraretinal edema, that when it occurs with neuroretinal thinning it can be associated with a normal thickness of the retina in the early stages.13 -15
It has been suggested that SNV probably originates from retinal blood vessels, and indocyanine green angiography (ICGA) has shown an intraretinal anastomosis.11,16,17.
genetics
Reports of affected monozygotic twin and family groups suggest that MacTel has a genetic component, although no inheritance pattern has yet been established.18–20 The MacTel Project group suggested an autosomal dominant pattern of inheritance with variable penetrance .21 Twin studies with asymmetric findings between twins. suggest that epigenetics may be the cause of discordance between monozygotic twins.22 Secondary factors, such as smoking, diabetes mellitus (DM), coronary artery disease, or hypertension, may increase the risk of disease clinic.4,5.
Genome-wide linkage analysis has identified a unique peak on chromosome 1 at 1q41-42 that may lead to the development of MacTel.21 Serine biosynthesis and lipid recycling in the retina occur primarily in retinal cells. Muller’s cells and the RPE. Defects in metabolism with accumulation of deoxysphingolipids result in a loss of photoreceptors in MacTel.23,24 Eade et al have found a nonsense mutation in the PHGDH gene involved in the serine synthesis pathway in ~3.2% of affected individuals.25 PHGDH mutation decreased serine. biosynthesis with accumulation of deoxysphingolipids in RPE cells.26 Table 1 provides details of known MacTel-associated genes.
Table 1 Genes associated with Mactel
Ocular and systemic associations
Up to 45% of patients with MacTel have a systemic disorder most commonly DM, obesity, hypertension, and cardiovascular disease.5,29 Although Gass and Blodi recognized that DM could predispose patients to develop MacTel, they found that the incidence of diabetic retinopathy was significantly lower in diabetic patients with MacTel.11,12 MacTel has also been found to be associated with celiac sprue,30 polycythemia vera, Alport disease, CREST syndrome31 and pseudoxanthoma elasticum.32 MacTel also s ‘has been associated with ocular conditions such as soft confluent drusen,33 microhemangiomas of the pupillary margin,34 full-thickness macular holes (FTMH)35 and epiretinal membranes.7
Clinical characteristics
Gass and Blodi classified MacTel based on the severity of the disease into five stages: Stage 1: slight loss of retinal transparency, usually in the temporal juxtafoveal area. Stage 2: A loss of transparency may be seen around the fovea with surface crystals. Stage 3 – right angle venules; stage 4: hyperplastic EPR within the retina; and stage 5: retinal neovascularization or SNV exudation.11 Yannuzzi revised the classification into nonproliferative and proliferative disease.12 MacTel nonproliferative refers to exudative telangiectasia and foveal atrophy and proliferative disease refers to proliferative changes with SNV and fibrosis. The modified Mactel classification described in 2013 divides MacTel into 5 stages.36 The first stage is non-proliferative deep capillary involvement characterized by thickening of the inner retina and a few cysts. The superficial capillary of the second stage shows loss of transparency and few telangiectatic vessels temporarily. Stage 3 is involvement of the subinternal limiting membrane and foveal area with distortion and constriction of FAZ. Stage 4 is the proliferative stage showing the presence of telangiectatic vessels in the deep and superficial capillary plexus, with proliferation to sub ILM and subretinal spaces. Stage 5 fibrovascular proliferation shows a subretinal vascular complex perfused by descending arterioles and venules. Venkatesh et al proposed a preproliferative stage of MacTel that could help identify patients at risk of proliferative disease.37
Retinal aging usually begins temporally and then expands in an oval fashion, with the horizontal linear dimension greater than the vertical dimension, usually within one disc diameter from the central fovea. The earliest clinical feature is a slight grayish discoloration of the temporal retina due to loss of retinal transparency (Figure 1). 11,38 Vascular changes are absent or rarely evident early in the disease and AF is often required to identify them.39 Ironically, fluorescein leakage in AF is not associated with retinal cystoid changes, and there lack of lipid exudation or bleeding. .39
Figure 1 Fundus photograph (A) and early (B) and late (C) fluorescein angiography, OCT (D) and OCTA (E and F) in a patient with MacTel. There is loss of temporal retinal transparency in the fovea with angiographic leakage. (B and C) OCT (D) shows parafoveal retinal thinning with hyporeflective cavities in the outer retina. OCTA (E and F) demonstrates dilatation and telangiectasia of the deep temporal capillary plexus in the fovea.
Blunt and slightly dilated venules are seen in the later stages of the disease with pigmentary hyperplasia (Figure 2). The venules do not narrow as they approach the foveola and appear to dip at right angles into the deeper retinal layers. Right-angle venules originate in the deep capillary plexus and form a radiating stellate pattern due to tissue contraction in the temporal macula.40 They may appear dilated due to increased blood flow through of the telangiectatic capillaries.23
Figure 2 Fundus photograph (A) showing blunted retinal venule and early pigmentation. The corresponding fluorescein angiogram (B) shows a mild late-phase leak with hypofluorescence in the pigmented areas. OCTA (C) shows dilatation and telangiectasia of the temporal deep capillary plexus in the fovea, and OCT (D) shows foveal thinning with loss of the ellipsoid zone.
Eyes with MacTel have multiple tiny yellow crystalline deposits on the inner surface of the retina adjacent to the telangiectases (Figure 3). Almost half of patients have crystalline deposits (60% bilateral), but they do not correlate with disease severity.41,42 The origin of crystalline deposits remains unknown, although research has suggested that they are due to degeneration of Muller cells or lipofuscin-containing pigmented cells.11,43 Brown pigment-containing cells surrounding abnormal blood vessels may represent RPE hyperplasia.12
Figure 3 Fundus photograph (A) showing pronounced crystalline deposits, blunt retinal venules, and pigment proliferation. OCT images (horizontal and vertical cross-sections depicted as (B and C) respectively) show loss of outer retinal layers with hyporeflective inner and outer retinal cavities. The aftershadow under a hyperreflective region corresponds to pigmentary changes in the background photo.
Yellow foveal lesions occur in up to 5% of MacTel cases. Foveal atrophy can create a…