Submacular Hemorrhage in AMD: How Should We Manage it? Techniques and Decisions
A review of the literature with clinical pointers.
At the 2019 ARDS meeting, David H.W. Steel, MBBS, FRCOphth, delivered a presentation titled “Submacular Hemorrhage in AMD: How Should We Manage It? Techniques and Decisions.” Dr. Steel reviewed some of the literature and shared his experience managing submacular hemorrhages (SMH) in patients with age-related macular degeneration. This article presents a summary of portions of his presentation.
Untreated subfoveal hemorrhage can cause vision loss through several mechanisms, including shear stress from fibrin contraction, oxidative stress from iron toxicity, and recruitment of macrophages and fibrotic factors. Bopp et al found that about 12% of patients with age-related macular degeneration experience some degree of SMH,1 although UK population studies have found the rate to be 5 to 20 per 1 million.2,3
Risk factors for hemorrhage include use of warfarin and antiplatelet agents; hypertension and smoking have not been shown to be risk factors. There have been no associations with neovascular lesion type, although high retinal pigment epithelium (RPE) detachments are a risk factor in some series. In 9% to 22% of cases, RPE rips may be observed after resolution of SMH.
Most of the pivotal clinical trials of anti-VEGF agents excluded patients with large SMH, and therefore long-term prospective studies in this patient population are not available. Furthermore, some of the literature on SMH may include patients with polypoidal choroidal vasculopathy, which has a different and generally more favorable course. These factors should be taken into account when interpreting the literature.
Aside from observation, treatments for submacular hemorrhage can include intravitreal anti-VEGF injections alone, anti-VEGF injections combined with expansile gas displacement with or without intravitreal tissue plasminogen activator (tPA), or pars plana vitrectomy (PPV) with subretinal tPA and gas displacement.
EYETUBE MEETING COVERAGE: ARDS
Dr. Steel stated that it is best to administer treatment within 14 days of subretinal hemorrhage (SRH) diagnosis. If the SRH is changing to a yellow hue, this suggests chronicity, and it may be resistant to breakdown. He also noted the importance of distinguishing between SRH and sub-RPE hemorrhage, which has a darker red-brown tinge and can be readily seen on OCT. The presence of a sub-RPE hemorrhage typically does not change visual prognosis much, however.4
Dr. Steel showed a time-lapse set of photographs of an individual who was treated with anti-VEGF therapy alone, illustrating clinical improvement and resolution with time.
Many studies have shown benefit to patients of treatment with anti-VEGF therapy alone. One study using anti-VEGF monotherapy in 13 patients found that 60% of patients exhibited improved VA and 40% maintained stable VA; no patient worsened.5 A study by Shin et al in Asia, using specific cutoff criteria for treating patients with anti-VEGF therapy only (central macular thickness < 550 µm and SRH < 300 µm), suggests that this may be a reasonable approach for smaller SRH.6
Does the removal or displacement of subfoveal blood make a difference to visual outcomes? If so, approaches such as pneumatic displacement with expansile gas and intravitreal tPA may be preferable. Dr. Steel said his approach includes injecting 0.3 cc of C3F8 and 50 µg of tPA in 0.05 cc, plus an anti-VEGF agent; he typically performs a 0.4 cc anterior chamber tap with globe compression immediately beforehand. This technique can work well, but it requires a patient who can maintain positioning, although complete prone positioning may not be necessary.
PPV with air or gas with subretinal tPA injection is another very effective management option. De Jong et al found no difference in amount of displacement between PPV displacement techniques and pneumatic displacement.7 However, that study included only patients with relatively small hemorrhages, and high-contrast central vision was used to gauge success, which may have missed subtle effects from paracentrally nondisplaced hemorrhage.
Is subretinal tPA necessary? Intravitreal tPA may not penetrate into the subretinal space in normal eyes, but it seems to do so in eyes with SMH. One study found that subretinal tPA achieved better displacement than intravitreal tPA combined with PPV.8
The benefits of PPV and subretinal tPA include allowing a greater air or gas fill, requiring less need for posturing, and causing less shear stress due to immediate clot lysis and displacement.9 Dr. Steel said his approach includes PPV, subretinal tPA injection (12.5 µg/0.01 cc, up to 0.3 cc for larger heme) mixed with subretinal bevacizumab (Avastin, Genentech) or ranibizumab (Lucentis, Genentech), and complete air-fluid exchange. He advised against using aflibercept (Eylea, Regeneron), as he said it is broken down by tPA.10 Instruments for subretinal injection include several manufactured by Dutch Ophthalmic and MedOne Surgical.
Dr. Steel advised injecting slowly and as far from the fovea as possible.11 Other pearls include making a bleb that surrounds the clot and avoiding areas of pigment epithelial detachment. A complete air-fluid exchange immediately follows this step. A drainage retinotomy is rarely necessary.
Displacement of SRH using this technique occurs within hours. Air is typically gone in a week with a full air fill, whereas displacement with expansile C3F8 may last for several weeks.12,13 Martel and Mahmoud described a technique in which subretinal air is injected after tPA, requiring about a 50% air fill in the vitreous cavity.14 The additional effectivity added by this technique is uncertain.
Although displacement of the hemorrhage occurs with pneumatic therapy, the displaced hemorrhage may cause a scotoma. VA results are difficult to compare directly among these treatments because patients who undergo vitrectomy typically have larger SRH than those who undergo pneumatic displacement. Rebleeding afterward is common (in 20%–30% of eyes), and close follow-up and vigilant treatment with anti-VEGF therapy are recommended to reduce the risk of rebleeding.
Dr. Steel ended his talk by noting that we do not yet know which patients will benefit from displacement surgery compared with anti-VEGF therapy alone. A randomized controlled trial is needed. He is involved in a pilot trial in the United Kingdom investigating four modalities of treatment for SMH (TAPAS) that recently finished recruiting, as well as a large pan-European trial funded by Euretina comparing anti-VEGF therapy alone to vitrectomy with subretinal tPA (TIGER) that will start soon.
Dr. Steel closed his talk by sharing his current algorithm for managing SRH (Table).
