Best clinical judgment guides therapy in the absence of study data.

Acute submacular hemorrhage (SMH; subretinal hemorrhage greater than 1 disc diameter in the macular region) associated with neovascular age-related macular degeneration (nAMD) or polypoidal choroidal vasculopathy (PCV) often leads to significant, sudden vision loss in affected individuals. It has been reported to occur in up to 17% of patients with pigment epithelial detachments associated with nAMD;¹ PCV was associated with SMH in 20% of cases in one series.²

Macular photoreceptor cell loss occurs with thick SMH due to (1) low oxygen and nutrient availability to photoreceptors due to increased diffusion distance and decreased permeability between the choriocapillaris and photoreceptors, (2) iron toxicity to the photoreceptors, and (3) mechanical shearing of the photoreceptor elements by contracting fibrin.³

While thin SMH may resolve after treatment with serial intravitreal anti-VEGF agents without dramatic loss of vision in these patients, the natural history of thick (at least 500 microns) SMH in nAMD and PCV patients is not good (average VA stabilizes at 20/1250).⁴ In the Submacular Surgery Trial report 13 observation arm, only 11% of 140 eyes had VA better than 20/200 at 24 months, and 40% had vision worse than 20/800.⁵

Although irreversible photoreceptor loss has been noted within 24 hours and total macular photoreceptor atrophy has been noted within 1 week after experimental SMH in rabbits,⁶ vision improvement has been noted with intervention up to 21 days after thick SMH in humans.⁷

Historically, the Submacular Surgery Trial showed that surgical removal of the choroidal neovascular membrane complex in patients with SMH had an outcome no better than natural history,⁵ and macular translocation and RPE patching have had success in general limited to those (relatively few) practitioners highly experienced in those techniques.

Given the poor natural history of SMH and potential for vision improvement, more recent interventions have been attempted, such as various combinations of intravitreal gas (SF₆ and C₃F₈), intravitreal anti-VEGF, intravitreal tissue plasminogen activator (tPA), photodynamic therapy, and pars plana vitrectomy with subretinal tPA with or without subretinal anti-VEGF and subretinal filtered air. All have shown promise, but because no head-to-head series has been performed, preferred treatments may vary based on clinical scenario and practitioner preference.

Which treatments should we consider? Will tPA injection increase risk of rebleeding? How should our selection of intervention change based on clinical scenario? We are fortunate to hear from retina specialists Sunir J. Garg, MD, and Bradley T. Smith, MD, on this topic.

REFERENCES

1. Poliner LS, Olk RJ, Burgess D, et al. Natural history of retinal pigment epithelial detachments in age-related macular degeneration. Ophthalmology. 1986;93:543-551.
2. Papavasileiou E, Steel DH, Liazos E, et al. Intravitreal tissue plasminogen activator, perfluoropropane (c3f8), and ranibizumab or photodynamic therapy for submacular hemorrhage secondary to wet age-related macular degeneration. Retina. 2013;33:846-853.
3. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol. 1982;94(6):762-773.
4. Scupola A, Coscas G, Soubrane G, et al. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica. 1999;213:97-102.
5. Bressler NM, Bressler SB, Childs AL, et al. Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: Ophthalmic findings: SST Report Number 13. Ophthalmology. 2004;111:1993-2006.
6. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol. 1982;94:762-773.
7. Hattenbach LO, Klais C, Koch FH, et al. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology. 2001;108:1485-1492.

Vitrectomy With Subretinal tPA for Thick SMH

SUNIR J. GARG, MD

Mid Atlantic Retina and Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania

Although some patients with SMH are treatment naive, many times our established patients who have been receiving anti-VEGF injections for some time develop SMH, and it often seems like the better eye is the one that gets affected. There is no clear consensus on treatment and a number of different techniques have been tried.¹

There are 2 basic approaches. Pneumatic displacement involves an in-office injection of gas into the vitreous cavity followed by several days of face-forward positioning. Intravitreal tPA injection sometimes is performed along with the intravitreal gas injection, although some authors suggest that tPA does not enter the subretinal space, so is unnecessary.^2-4 The benefit of this technique is that it is simple to perform and avoids the expense and hassle of the operating room. However, for some of our older patients, it can be challenging for them to position the small gas bubble over the hemorrhage appropriately.

I prefer vitrectomy with subretinal tPA and a larger gas bubble to manage these eyes. This surgery is fairly straightforward. After completing the vitrectomy, I use a 41-gauge cannula to inject a 10 microliters/mL concentration of tPA into the subretinal space.^5,6 Usually I place the cannula into an area of thick hemorrhage outside of the fovea and infuse tPA until the fluid entirely separates the neurosensory retina from the underlying hemorrhage. When possible, I infuse subretinal fluid so that it creates a “pocket” inferior to the hemorrhage so the hemorrhage can more easily be displaced, although this is likely unnecessary. Sometimes I’ll inject 0.3 cc of air into the subretinal space although I have had a macular hole develop after doing this.⁷ The 41-gauge retinotomy self seals. An 80% air-fluid exchange usually gives an optimal size bubble. Although air works well, I often do an air-gas exchange with 20% SF₆. For 3 days afterwards, the patients maintain a face-forward (not head-down) position.

I administer preoperative anti-VEGF injection at the time of presentation. After displacement, continuing the anti-VEGF injections is important. A study from our group found that in eyes that had surgery without anti-VEGF injection, there was considerable loss of vision over time. In contrast, eyes that continued to receive anti-VEGF injections better maintained their postoperative gains.⁸

It is hard to predict which eyes will have significant VA improvement after surgery. If a patient has a significant sub-RPE hemorrhage this procedure does not work well and if I see this involving the fovea preoperatively, I do not recommend surgery. Similarly, if there was significant RPE atrophy or subretinal fibrosis prior to the hemorrhage, there may not be much healthy tissue to save; thus, surgery may not be worth pursuing.

There is no consensus in the literature on how long you can safely wait to between onset of hemorrhage and surgery. Ideally, the surgery would be performed within a couple of weeks; however, I have had success even with patients who have had thick SMH present for over a month.

Vitrectomy with subretinal tPA and pneumatic displacement can help many patients improve vision. It is important to tell patients that they will not likely ever regain the vision that they had before the hemorrhage and continuing anti-VEGF injections after surgery remains important to maintain VA gain.

REFERENCES

1. Vander JF, Federman JL, Greven C, Slusher MM, Gabel VP. Surgical removal of massive subretinal hemorrhage associated with age-related macular degeneration. Ophthalmology. 1991;98(1):23-27.
2. Heriot WJ. Intravitreal gas and TPA: an outpatient procedure for submacular hemorrhage. Paper presented at: AAO Annual Vitreoretinal Update, 1996; Chicago, Illinois.
3. Hassan AS, Johnson MW, Schneiderman TE, et al. Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology. 1999;106(10):1900-1906.
4. Lewis H. Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol. 1994;118:559-568.
5. Haupert CL, McCuen BW 2nd, Jaffe GJ, et al. Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. Am J Ophthalmol. 2001;131(2):208-215.
6. Olivier S, Chow DR, Packo KH, et al. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration. Ophthalmology. 2004;111(6):1201-1208.
7. Martel JN, Mahmoud TH. Subretinal pneumatic displacement of subretinal hemorrhage. JAMA Ophthalmol. 2013;131(12):1632-1635.
8. Chang W, Garg SJ, Maturi R, et al. Management of thick submacular hemorrhage with subretinal tissue plasminogen activator and pneumatic displacement for age-related macular degeneration. Am J Ophthalmol. 2014;157(6):1250-1257.

Surgery vs Anti-VEGF for SMH

BRADLEY T. SMITH, MD

The Retina Institute and the Washington University School of Medicine, Department of Ophthalmology and Visual Sciences, St. Louis, Missouri

The selection of intervention is currently based on best clinical judgment in the absence of a randomized clinical trial. Retina specialists must consider general health and visual expectation of patient; use of antiplatelets, anticoagulants, and status of INR; presence and level of control of systemic hypertension; visual potential of affected eye and status of fellow eye; timing of symptoms related to the hemorrhage; presence of hemorrhage beneath RPE; and thickness of hemorrhage and relationship to fovea.

We recently reviewed our patient outcomes with large SMH and compared 2 groups.¹ The first group underwent surgical displacement using subretinal tPA and the second group was treated only with anti-VEGF. There were significant differences in baseline characteristics that revealed some preferences of our surgeons at The Retina Institute. Bigger hemorrhages of shorter duration and worse vision were selected for surgery rather than anti-VEGF alone. Those who were selected for surgery were more likely to have hypertension, take more than one anticoagulant, and have already received anti-VEGF. We found that patients who underwent surgical clearance reached their best VA faster than those receiving anti-VEGF alone. Both groups had significant improvement in vision. The patients selected for surgery had the largest improvement in vision although they may have experienced a “floor effect” on vision change given their much poorer vision at baseline. Ideally patients would be randomly selected for surgery vs management with anti-VEGF alone with volumetric measurements of the hemorrhage to ensure baseline characteristics were more similar.

The myriad presentations and treatment approaches complicate the design of a prospective, randomized controlled trial. Best clinical judgement will have to do for now, because we lack a definitive guideline on when to displace SMH. Thin hemorrhages can be managed with anti-VEGF alone. Thick hemorrhages resulting in substantial displacement of the photoreceptors from the RPE should probably be displaced unless a significantly greater amount of the hemorrhage is superior to the fovea at presentation. Patient expectations in this setting should be discussed thoroughly as well as the risks with either therapy.

Another option for displacement of submacular hemorrhages utilizes an intravitreal injection of tPA and an expanding gas bubble.² This procedure can be done in the office setting and is an appropriate compromise for the patient unwilling or who is unsafe to go to the operating room. However, the anatomic result appears to be inferior to that of surgical displacement using vitrectomy and a subretinal injection of tPA.³

The patient with SMH should be displaced soon after its onset as those less than 7 days old have a better prognosis.⁴ The presence of hemorrhage beneath the RPE should not be considered a contraindication to surgical displacement. Following a thorough vitrectomy tPA is injected into the subretinal space. A bleb is created that expands well beyond the borders of the hemorrhage. I prefer to direct the subretinal cannula so that most of the detached retina is inferior to the macula. During the exchange to air the surgeon must be careful not to cause a retinal fold. This is a risk when the air-fluid exchange is completed down to the optic nerve head. Leaving some posterior fluid just below the apex of the detached retina should prevent a significant fold from occurring. Depending on the amount of fluid drained from the vitreous cavity the concentration of gas can be adjusted while keeping in mind that pure perfluoropropane (C3F8) gas will quadruple in size and a nonexpansile concentration ranges from 12% to 14%. The concentration can be increased depending on how much fluid is left behind. C₃F₈ is a good choice for these cases because of the slower rate of expansion compared with SF₆. The patient is told to remain supine for a few hours after the surgery so that the hemorrhage can be fully saturated with tPA to achieve a more complete fibrinolysis. The patient should then remain upright so the lysed blood moves inferior to fixation as the gas bubble rises and expands. On the first postoperative visit the hemorrhage is usually found underneath the inferior peripheral retina.

The patient should remain upright for a few days to a week depending on the size of the detachment to give adequate time for any remaining hemorrhage to layer inferiorly. It is not necessary to laser the site where the tPA is injected. Keeping the patient upright provides adequate tamponade to the retinotomy. Vision may be limited by atrophic changes or fibrosis from the regressing CNVM, but substantial displacement can be achieved using this method. Patients should be warned of these limitations as well as the fact that intravitreal injections of anti-VEGF should be continued if the CNVM remains clinically active following displacement of the SMH. It is not uncommon to have breakthrough hemorrhage into the vitreous cavity. However, this will usually clear over a few weeks in the post-vitrectomized eye. RP

REFERENCES

1. Liu EM, Rajagopal R, Smith BT, Grand MG. Management of large submacular hemorrhages due to exudative AMD utilizing pars plana vitrectomy, subretinal tissue plasminogen activator, and gas insertion compared with antivascular endothelial growth factor alone. J Vitreoretin Dis. 2017;1(1):34-40.
2. Sacu S, Stifter E, Vecsei-Marlovits PV, et al. Management of extensive subfoveal haemorrhage secondary to neovascular age-related macular degeneration. Eye (Lond). 2009;23(6):1404-1410.
3. Hillenkamp J, Surguch V, Framme C, Gabel VP, Sachs HG. Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator. Graefes Arch Clin Exp Ophthalmol. 2010;248(1):5-11.
4. Lewis H. Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol. 1994;118(5):559-568.