Macular telangiectasia type 2

Abstract

Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment-outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure-function correlation may help to develop surrogate outcome measures for future clinical trials. In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

Fig. 1

Clinical findings and corresponding early (respective upper frame) and late (respective lower frame) fluorescein angiography in patients with MacTel type 2. All findings are most pronounced temporal to the foveola, but may encompass a central oval area. Staging is used according to the Gass & Blodi classification. A,B) Stage 1 with only mild angiographic leakage and no typical funduscopic findings. C,D) Stage 2 with loss of retinal transparency (“retinal graying”) C) only temporal to the foveola or D) within the entire paracentral area. E) Foveal yellow spot in a stage 2 eye with pronounced crystalline deposits. F) Stage 3 with a blunted retinal venule. G–J) Stage 4 with various manifestations of pigment proliferation. G) Early pigmentations; note also the pseudo-lamellar hole, the graying and the crystalline deposits. H) Pigment proliferation without obvious other findings characteristic for MacTel type 2. I,J) Retinal pigment proliferations with different degrees of surrounding RPE-atrophy. Some graying and crystalline deposits are seen in I).

Fig. 2

Neovascular complexes originating from the retinal vasculature may occur at any disease stage. A) Fluorescein (A1) and indocyanine green (A2) angiography of a large neovascular complex (left: early angiographic frames; middle: late frames). There is some fibrotic appearance (A3) and relatively little intraretinal exudation (A4). The arrow (A2) marks the arterial feeding vessel and the arrow heads mark draining venules of a neovascular complex. B–D) Active neovascular membrane with foveal hemorrhage (B), early (C) and late (D) phases of a fibrotic stage with pigmentation. There is remarkably little exudation and no cystoid edema or subretinal fluid. The arrows (D) mark corresponding positions.

Fig. 3

Phenotypic findings on spectral domain OCT imaging in patients with MacTel type 2. The optic nerve head is always to the left side in each of these horizontal scans through the foveal center. A) Normal retina. B) An asymmetric foveal contour may occur very early in the disease. C) Hyperreflectivity within the inner retinal layers due to capillary leakage may also be an early finding. D–F) Hyporeflective cavities within the inner foveal layers may remain without marked functional loss. There is some discontinuity of the highly reflective line above the retinal pigment epithelium and thinning of the outer nuclear layer mainly centrally and temporal to the foveal center. G) Hyporeflective cavities within the outer retina. H) Collapse of such outer retinal cavities. E–J) Atrophic outer retina with hyperreflective pigment plaques. J–K) The inner retinal layers appear to detach from the inner limiting membrane. L) A lamellar macular hole may develop after disruption of the inner limiting membrane. M–N) Localized complete atrophy of the outer retina with reactive pigment epithelial proliferation (N).

Fig. 4

“En Face”-view of OCT volume-scans. The left image shows the correspondent fundus autofluorescence, the black box indicating the position of the volume scan. The dotted line indicates the position of the B-scan shown in the middle and right image. The asterisk marks the foveal center. The arrow marks the position of the en-face image. The middle images are aligned parallel to the inner limiting membrane to show the inner retinal layers. There is a round hole centered on the foveola. The right images are aligned along the RPE band and show the topographic distribution of the disruption of the line representing the inner segmenteouter segment border of the photoreceptors. In patient A, the area of altered reflectivity within the inner segment–outer segment border corresponds to the entire retinal area affected by disease, whereas in patient B, this area is more confined to an area centered temporal to the foveola.

Fig. 5

Retinal thickness maps in an age-matched normal control (A) and patients with MacTel type 2 (B–F), representing the phenotypic variability. The B-scan underneath each thickness map was recorded through the foveal center (marked by an asterisk). Overall, there is an asymmetry of the foveal depression, a loss of retinal contour, and a general thinning of the macular area. In later disease stages, there is pronounced retinal thinning due to outer retinal atrophy.

Fig. 6

Confocal blue reflectance imaging (left) shows a highly reflective oval areas that correspond to loss of blue light-absorbing lutein and zeaxanthin on macular pigment maps (middle). Fluorescein angiography reveals leakage within a smaller area than that of macular pigment loss. The white line delineates the area of increased blue reflectance. Examples of three individual patients are shown (A–C). A representative normal confocal blue reflectance image can be found in Charbel Issa et al., 2008a, Fig. 1A. A representative normal macular pigment distribution is shown in Fig. 7B.

Fig. 7

Macular pigment distribution in a normal eye (B) and at various stages in eyes with MacTel type 2 –(C–G). Macular pigment loss may be very subtle only affecting a wedge-shaped area temporal to the foveal center (C,D), may encompass a larger area with some degree of central/nasal sparing, or may encompass an oval area centered on the fovea. The post-mortem photographs show the normal macular pigment distribution with the highest peak centrally in an unaffected eye (A) and the ring like distribution with central loss of macular pigment in an eye with MacTel type 2 (H). The post-mortem photographs (A,H) were kindly provided by Dr. Gregory Hageman.

Fig. 8

Fundus autofluorescence (AF; excitation at 488 nm) imaging in MacTel type 2. AF imaging may reveal increased signals (B–G) compared to normal (A) for various reasons. B,C) Where macular pigment (lower images) is decreased, there is usually a lack of the normal foveal masking of the AF signal (upper image) by macular pigment, which absorbs the blue excitation light. D) Another reason for an increased AF signal in MacTel type 2 may be the loss of photoreceptors and therefore less absorption of the excitation light by photopigment. Unbleached photopigment in the surrounding area absorbs blue light and therefore decreases the AF signal (left). OCT confirms atrophy of the photoreceptor layer (marked by vertical bars). After bleaching the photopigment with the excitation light for 1 min, the contrast between areas of preserved and those with lost photopigment decreases; compare the upper (before bleaching) and lower (after bleaching) images of the middle panel. In this case, bleaching of the surrounding photopigment reduces the contrast between the area of preserved photoreceptors and the area of photoreceptor loss. Note the different area of macular pigment loss (right) in the same eye. E) The same recordings as in D), but in an eye where the increased signal is not due to loss of macular pigment or photoreceptors, but rather appears to originate from additional subfoveal fluorophores. F) A similar phenomenon as in E), but more pronounced (same patient as in Fig. 1E with strong fluorescence of the yellow spot). G) Increased AF due to a full thickness macular hole. H) A decreased fundus AF signal due to blockage by pigment plaques (same patient as in Fig. 1H).

Fig. 9

Microperimetry in 3 different patients (rows A–C) with MacTel type 2 over a 4-year-follow up. Absolute scotoma temporal to the fovea (deep red color) progresses considerably, whereas visual acuity (VA) remains largely stable.

Fig. 10

Effects of intravitreal bevacizumab therapy in neovascular MacTel type 2. A) Findings at baseline visit: Foveal hemorrhage in funduscopy (left, cf. Fig. 2B), due to neovascular membrane with leakage in fluorescein angiography (top, early phase; bottom, late phase). In microperimetry, there is a large absolute scotoma which encompasses the foveal center. Four months after one single treatment with intravitreal bevacizumab (B), the hemorrhage had been resorbed and leakage was reduced. The foveal center after treatment shows only a relative defect and visual acuity has improved from 20/80 to 20/50.