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Radiation Maculopathy

Alexandre Matet, MD; Aude Ambresin, MD; Gilda Cennamo, MD; and Leonidas Zografos, MD

Radiation maculopathy is a devastating cause of visual loss occurring in eyes receiving radiotherapy for ocular or orbital malignancies. It develops in approximately 50% to 60% of eyes treated by plaque brachytherapy or proton beam therapy for intraocular tumors,¹ the most frequent indication being uveal melanoma, and it results in variable degrees of visual alteration. Tumors located inside or close to the macular area are at higher risk to develop this complication.² The tumoricidal effect of radiation relies on 2 mechanisms: The “direct” action produces DNA damage that impairs cell division, and the “indirect” action generates free radicals from water and other molecules, which in turn induce DNA alterations.³ Radiation injury of the retinal vasculature generates endothelial cell loss and capillary closure, leading to microangiopathy. In the macular area, this microangiopathy also leads to cystoid macular edema.⁴ The diagnosis of radiation maculopathy relies on the presence of possible lipid exudates and hemorrhages on fundus examination, cystoid macular edema on optical coherence tomography (OCT), and exudative telangiectasia in the macular area on fluorescein angiography (FA). FA reveals the morphology of the perifoveal capillary network during early phases and indicates the presence of vascular wall lesions by showing progressive dye diffusion. Conventional B-scan OCT identifies the magnitude of cystoid macular edema, and evaluates the integrity of the outer retina, an important predictor of visual prognosis. En face OCT shows the geographical extension of cystoid cavities in cases presenting with macular edema.

Since optical coherence tomography angiography (OCTA) provides a representation of the macular microvasculature via flow detection, it may overcome limitations of FA due to dye diffusion. It also provides a more accurate visualization of the parafoveal and perifoveal capillary network.^5,6 Moreover, the segmentation of volumes acquired by OCTA allows us to display separately the superficial and the deep retinal capillary plexuses, where specific lesions may be identified.

Alterations of the retinal microvasculature have also been reported after I-125 plaque brachytherapy.^7,8 Furthermore, the recent adjunction of quantitative tools has expanded the ability of OCTA to investigate in detail abnormalities of the retinal microvasculature such as vessel density or nonflow areas.^6,9 All pictures presented in this chapter were obtained using the AngioVue OCTA system (Optovue Inc).

LOCALIZATION OF IRRADIATION-INDUCED DAMAGES IN THE SUPERFICIAL AND DEEP CAPILLARY PLEXUS

OCTA identifies progressive degrees of capillary network disruption in eyes affected by radiation maculopathy, as reported by Veverka et al.⁸ By displaying separately the superficial and deep capillary plexuses, it confirms that both plexuses are affected by irradiation-induced changes, a finding consistent with the aggression by an external physical process affecting all retinal layers. Consistently, Shields et al7 have also identified focal loss of choriocapil laris within tumor margins, although this finding could result from tumor growth beneath the choriocapillaris and not only from irradiation.

Figure 31-1 illustrates 3 degrees of irradiation-induced changes in the superficial capillary plexus:

1. Minimal changes: exacerbated capillary loops and discrete capillary loss at the border of the foveal avascular zone
   
2. Interrupted capillary network: more pronounced capillary tortuosity and several foci of absent capillaries
   
3. Disorganized capillary network: large areas of capillary loss leaving extended avascular zones between macular arterioles and venules, and complete loss of the foveal avascular zone morphology

Similarly, Figure 31-2 illustrates changes observed in the deep capillary plexus, which can also be categorized into 3 progressive degrees:

1. Minimal changes: absent to discrete capillary loss at the border of the foveal avascular zone
   
2. Interrupted capillary network: more pronounced capillary loss predominating at the border of the foveal avascular zone
   
3. Disorganized capillary network: complete loss of the normal microvasculature morphology of the deep capillary plexus with numerous foci of total capillary depletion

Interestingly, images of the superficial plexus show that for all stages, changes are more pronounced at the foveal avascular zone border, suggesting that these capillaries are more sensitive to irradiation. Moreover, the image quality of both plexuses decreases with more advanced stage, a finding consistent with altered fixation in severely affected cases, due to the limits of the motion correction algorithm of the AngioVue OCTA device.

FOVEAL AVASCULAR ZONE CHANGES

As observed in Figures 31-1 and 31-2, the capillaries surrounding the borders of the foveal avascular zone seem to be among the most fragile microvascular structures in the macula with respect to irradiation-induced damage. In a series of 65 cases undergoing plaque brachytherapy, Shields et al⁷ have reported that the foveal avascular zone area was significantly higher in treated vs contralateral untreated eyes, and this difference was observed in both the superficial and deep plexuses. Consistently, foveal avascular zone enlargement has been evidenced by OCTA in several macular microangiopathies, including diabetic retinopathy,¹⁰ retinal vein occlusion,^11,12 and sickle-cell retinopathy.¹³

The composite picture of the superficial capillary plexus shown in Figure 31-3 illustrates the complete loss of the parafoveal capillary ring and subsequent widening of the foveal avascular zone. After regression of the capillary bed, the residual arterioles and venules give a more linear and right-angled pattern to this altered perifoveal network. The fragility of capillary vessels forming the most inner ring of the macular microvasculature around the fovea also results in an increased susceptibility to form saccular microaneurysms described as telangiectasia, also visible in Figure 31-3. These changes are not systematically observed, as illustrated by a case of uveal melanoma treated by plaque brachytherapy (Figure 31-4).

NONPERFUSION AND QUANTITATIVE VESSEL DENSITY

Figure 31-3 also displays several foci of severe, localized capillary depletion extending in the whole parafoveal area. These areas are surrounded by exaggerated, anastomotic capillary loops that may result from the excessive production of pro-angiogenic factors by these nonperfused areas. Focal or diffuse capillary loss in eyes with irradiation-induced maculopathy results in a decrease in vessel density. Using the built-in vessel density analyzer provided with OCTA systems, vessel density can be automatically evaluated and displayed with density heat maps. In Figure 31-5, a vessel density map is provided for 3 incremental degrees of capillary alterations (as described previously). The grid-based mean vessel density indicates values for each 1 of 9 square sectors. It reflects the progressive capillary depletion at the edges of the foveal avascular zone, with decrease of the central square density, that extends to surrounding sectors of the parafoveal area. Arbitrarily, capillary bed depletion may be categorized according to the vessel density as:

• Normal vessel density (mean density ≥ 45%)
  
• Mild decrease (mean density between 37% and 45%)
  
• Severe decrease (mean density < 37%)

These 3 categories are illustrated in Figure 31-5.

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