Chapter 119 Surgical Management of Choroidal Neovascularization and Subretinal Hemorrhage
Choroidal neovascular membranes
Introduction
The growth of choroidal neovascular membranes (CNV) beneath the macula usually causes significant disturbance of central visual function. Prior to the advent of photodynamic therapy and anti-vascular endothelial growth factor (anti-VEGF) agents, the only therapy of proven benefit compared with observation was thermal photocoagulation of the CNV.1 During that era, surgical removal of subfoveal CNV of various etiologies was an alternative method of eradicating the CNV and improved visual function was achieved in a variety of etiologic settings. Even with current anti-VEGF agents, on occasion extensive subretinal hemorrhage occurs and surgical intervention is appropriate. Infrequently, surgical removal of CNV without hemorrhage is indicated. This chapter presents current concepts regarding the use of vitreoretinal surgical techniques as treatment of CNV with or without extensive hemorrhage.
Surgical technique
De Juan and Machemer first reported vitrectomy for the removal of macular CNV through large temporal retinal incisions.2 Thomas and Kaplan subsequently modified the technique to utilize an eccentric, small retinotomy. Fluid was injected through the retinotomy, and manipulation and extraction of the CNV were achieved.3,4 Face down positioning overnight proved adequate to close the small retinotomies without laser photocoagulation.5 Complications with this technique were minimal.
Early results
These surgical techniques were applied to macular CNV and favorable visual outcomes were reported for CNV of a variety of etiologies.6–17 It was soon recognized that although some eyes regained excellent central visual function following removal of subfoveal CNV, others did not. Gass hypothesized that some CNV proliferate within Bruch’s membrane and beneath the retinal pigment epithelium (RPE), as well as beneath the neurosensory retina (Type I CNV – typical of AMD). Removal of such CNV would be expected to leave defects in RPE and result in poor vision. In other eyes, he postulated that CNV grow through relatively discrete defects in Bruch’s membrane and proliferate anterior to native RPE in the subneurosensory retinal space (Type II CNV – typical of histoplasmosis).18 Eyes with CNV associated with the ocular histoplasmosis syndrome, other chorioretinal inflammatory conditions, and idiopathic CNV indeed often demonstrated preserved central RPE and good foveal function after vitrectomy. Eccentricity of the choroidal ingrowth site was found to be an important prognostic factor for good vision in these cases with focal ingrowth sites.19 Recurrent CNV proved to be a major obstacle to good vision following surgery, as is the case with essentially all other therapies for choroidal neovascularization.20
Submacular surgery trials
The Submacular Surgery Trials (SST) were four NIH-sponsored, multicenter, randomized, prospective trials conducted to compare outcomes of submacular surgery versus then-current standard therapy.21 The SST Pilot Trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration enrolled 70 patients with 34 receiving surgery and 36 laser. At 2-year follow-up, 65% of surgery eyes versus 50% of lasered eyes had vision more than one line worse than at baseline. The data offered no reason to prefer surgery over photocoagulation.22
The SST Group N enrolled 454 patients with new subfoveal choroidal neovascularization secondary to AMD and randomly assigned patients to surgery or observation. Both groups declined in visual acuity from 20/100 at baseline to 20/400 by month 24, and the investigators concluded that surgery should not be recommended for these patients.23
At all time points, median visual acuity was better in the surgery group than in the observation group, but the difference did not reach statistical significance. At 24 months, median visual acuity was 20/250 for observation eyes and 20/160 for surgery eyes. Only those eyes with acuity worse than 20/100 at baseline achieved a significantly better outcome with surgery than observation at 24 months (76% versus 50%, respectively, for vision better or at most one line worse than initially measured). Of surgery eyes, 4% suffered retinal detachment and 58% of surgery eyes experienced recurrent neovascularization by month 24. The study concluded that submacular surgery may be considered in similar eyes with poor vision (worse than 20/100).24
Current indications for surgical removal of CNV
In the era of anti-VEGF therapy, surgical removal of CNV is rarely appropriate. Possible indications would include large peripapillary CNV unresponsive to anti-VEGF agents and/or photodynamic therapy and too large for thermal laser photocoagulation.25 In such extrafoveal lesions, the CNV can be removed to produce a small, quiet, atrophic scar around the nerve. If the fovea is involved in the neovascular process, then surgical extraction will likely lead to loss of foveal RPE in AMD and likely limited vision. However, in histoplasmosis, central RPE and reasonable visual acuity may be preserved.26–31
Submacular hemorrhage
Etiology
Subretinal hemorrhage involving the macula is most often caused by CNV. Any macular condition that causes growth of CNV can therefore lead to submacular hemorrhage. In a series of 47 consecutive cases of submacular hemorrhage reported by Ibanez et al., over 80% were due to AMD with retinal arterial macroaneurysm and CNV due to histoplasmosis, angioid streaks, and idiopathic submacular hemorrhage being less common.32 Pathologic myopia and idiopathic polypoidal choroidal vasculopathy have also been reported as causes of submacular hemorrhage.33,34 Trauma is another possible cause of submacular hemorrhage. This may occur either at the time of trauma due to localized choroidal rupture, or remotely due to the development of CNV at the edge of the rupture site.35 Other sources of subretinal hemorrhage in the macula are rare.
Natural history
The natural history of untreated submacular hemorrhage has been described by several authors. Bennet et al.35 described 29 eyes with submacular hemorrhage and found that the etiology was the most important factor in predicting the final visual outcome. In this series, of the 12 patients with AMD as the cause of the hemorrhage, 67% of the patients had unimproved or worsened visual acuity at the end of the follow-up period. The final mean visual acuity was 20/1700. Another study by Scupola et al.36 examined 60 eyes with subretinal hemorrhage due to AMD, and confirmed this poor prognosis, with 80% of the eyes having a worse mean visual acuity of 20/1250. In contrast to this, in Bennet’s series, the five patients with traumatic choroidal rupture with subretinal hemorrhage fared much better. All five eyes improved, with mean visual acuity of 20/35.35 Likewise, in a case series of 11 patients with subretinal hemorrhage due to Best disease, 10 of the 11 patients had improved, with a final mean visual acuity of 20/50.37
The largest natural history study of AMD-associated subretinal hemorrhage to date is the observation arm of the Submacular Surgery Trials Group B in which 168 eyes with subfoveal choroidal neovascular lesions composed of at least 50% blood involving the foveal center and with initial visual acuity between 20/100 and light perception were followed for 2–3 years. Only 19% of eyes gained two or more lines of vision during follow-up, while loss of two or more lines occurred in 59% and 36% experienced severe vision loss of 6 lines or more. At 2 years, only 10% of eyes had visual acuity of 20/200 or better.38
Management options
Surgical removal of blood and CNV
Small retrospective reviews of surgical extraction of clots and associated CNV appeared encouraging compared to the poor natural history outlined above.32 The SST Group B was a randomized, prospective, multi-center trial comparing surgical extraction of the clot and CNV to observation for patients with hemorrhagic lesions (AMD-associated lesions >3.5 MPS disc areas in size in which blood comprised >50% of the lesion). Surgery entailed vitrectomy, optional use of subretinal tissue plasminogen activator, and manual extraction of the clot and any apparent CNV beneath the foveal center through a single retinotomy. Of 168 eyes randomized to surgery, only 18% had visual acuity of 20/200 or better after 2 years and there was no statistically significant difference between the surgery and observation arms in terms of stabilization of vision at any point during 24–36 months follow-up. However, at 2 years, fewer surgery eyes (21%) compared with observation eyes (36%) had experienced severe vision loss of 6 lines or more (P = 0.004). This benefit of surgery was most evident in eyes with relatively better vision at presentation (20/100 to 20/160). A high rate of retinal detachment was seen in the surgical arm (16% of all eyes) and these were more common in eyes with very poor vision and very large hemorrhagic lesions on presentation. In the better vision group (20/100 to 20/160), 10% of surgery eyes experienced retinal detachment. Progression of cataract was the most common complication of surgery; of eyes that were initially phakic, 44% of surgery eyes and only 6% of observation eyes underwent cataract extraction by the 24-month examination. The study concluded that surgical removal of hemorrhagic AMD lesions was generally not beneficial, although the data would support considering the procedure for lesions that were neither very large, nor had very poor vision.38
Vitrectomy, injection of subretinal tissue plasminogen activator, and aspiration of liquefied blood
The disappointing results obtained with direct surgical extraction of clot led investigators to study possible adjuvants to assist in the removal of subretinal blood. Experimental models of subretinal hemorrhage in animals suggested that the subretinal injection of tissue plasminogen activator (tPA) was safe in doses up to 50 µg/mL. Proponents of subretinal tPA injection hypothesized that it could decrease the thickness of hemorrhage,39 improve the rate of clearance,40 and potentially reduce outer retinal damage during surgical removal of subretinal clots.41
In 1991, Peyman et al. first reported their experience with five patients treated for submacular hemorrhage using a standard pars plana vitrectomy, followed by tPA (12.5 µg/mL) injected into the subretinal space. After dissolution of the clot, the subretinal hemorrhage could then be removed with presumed minimal trauma via gentle irrigation of balanced salt solution.42 Despite this approach, visual acuity results in cases of AMD were disappointing. In 1994, Lewis43 published a pilot study involving 24 consecutive eyes with recent submacular hemorrhage secondary to AMD-treated with tPA followed by surgical drainage. This study showed an improved final visual outcome when causative CNV is eccentric to the fovea. Additionally, the study showed a statically significant relationship between duration of subretinal hemorrhage (>7days) and poor visual outcome. In 1995, Lim et al.44 reported 18 patients retrospectively, with similar surgical technique, but the results were less impressive.
Intravitreal tissue plasminogen activator with pneumatic displacement
In 1997, Heriot initially described a novel method for the management of submacular hemorrhage using intravitreal tPA injection and pneumatic displacement of blood.45 The potential benefits of this treatment modality are that it is minimally invasive and can be performed in the office.
Hesse et al. reported their experience with this technique in 11 eyes with submacular hemorrhage due to AMD.46 The method described by these investigators involved intravitreal injection of 50 µg or 100 µg of tPA and injection of a long-acting gas bubble (C3F8 or SF6), either immediately or 24 h after the tPA injection, followed by 24 h face-down positioning. A typical clinical outcome with this technique was partial but not total displacement of submacular hemorrhage, leading to asymptomatic exudative inferior retinal detachment. Complications included breakthrough vitreous hemorrhage, which occurred in all four eyes treated with 100 µg of tPA and only one of the seven eyes (14.3%) treated with the 50 µg dose.46 Hassan et al. reported similar results in their case series of 15 patients, with 10 of 15 patients having improved final visual acuity. Vitreous hemorrhage was the common complication, and there was one case of postoperative endophthalmitis in this group.47
The rationale behind using intravitreal tPA is controversial. Some experimental models have shown clinical evidence of subretinal clot lysis after intravitreal tPA injection.48,49 However, fluorescently labeled tPA injected intravitreally was undetectable in the subretinal space in a rabbit experimental model reported by Kamei et al.50 Based on these findings, Ohji et al.51 have modified this in-office technique of pneumatic displacement. They reported a series in which five patients with submacular hemorrhage were treated with pneumatic displacement without intravitreal tPA. In this small series, anatomic and visual improvement was noted in all five eyes. Because subretinal hemorrhage will undergo some degree of gradual spontaneous liquefaction 7–10 days after onset, maximum displacement of submacular hemorrhage using this technique may be achieved with the use of long-acting gas bubble such as C3F8 and repeated overnight sessions of prone positioning for 7–10 days for as long as the gas is sizeable.
Subretinal injection of tissue plasminogen activator with pneumatic displacement
More recently, Haupert et al. reported their preliminary results using pars plana vitrectomy followed by subretinal injection of tPA (25–50 µg/mL) using a bent 36-gauge needle. Care was taken to minimize manipulation of the clot. Complete air–fluid exchange and injection of 20% SF6 followed the subretinal injection. Postoperatively, the patients were instructed to maintain prone positioning. In their series of 11 patients with thick submacular hemorrhage related to AMD, anatomic inferior displacement of the clot was achieved in all eyes, while final postoperative visual acuity was improved in eight (73%) cases, unchanged in one case and worse in two cases.52
This technique has been slightly modified by Olivier et al. and others. tPA is injected into the subretinal space using a straight 39- or 40-gauge cannula. The infusion of fluid “balloons up” the retina, creating a neurosensory retinal detachment in the macula. The subretinal blood collects in this potential space and is pushed inferiorly by an air bubble inserted at the end of the vitrectomy surgery. Following postoperative prone positioning, the macula is generally cleared of subretinal hemorrhage, permitting fluorescein angiography and possible treatment of the underlying CNV. In the series of 29 eyes in 28 patients reported, total submacular blood displacement was achieved in 25 eyes (86%), with subtotal displacement in the others.53
The advantages of this technique are maximal chemical lysis of the clot via subretinal injection of tPA, which minimizes the risk of mechanical trauma to the retina and RPE from manual clot extraction. The considerable complication rate associated with manual clot extraction should also be significantly reduced. In addition, vitrectomy surgery allows for a larger gas bubble to be placed in the vitreous cavity compared to in-office gas injection, allowing for more complete displacement of blood from the submacular space. Sandhu et al. reported that vitrectomy with subretinal tPA and air–fluid exchange displaced subretinal hemorrhage in three of four patients who failed expansile gas injected in the office.54 Also, Hillenkamp et al. compared vitrectomy with intravitreal tPA injection versus subretinal tPA injection with both groups receiving nonexpansile SF6. They found the hemorrhage was displaced completely in 22% of the intravitreal tPA group and 55% of the subretinal tPA group.55
Anti-VEGF agents
Anti-VEGF agents alone have been shown to be effective in treating submacular hemorrhage in patients with AMD.56–58 Other studies have shown success with anti-VEGF agents with expansile gas displacement.59–60 One retrospective study compared patients with combination anti-VEGF and expansile gas versus only anti-VEGF treatment and found that vision improved in 80% of patients with both agents compared to 60% with the anti-VEGF agent alone. This study was retrospective and the duration of hemorrhage was not well matched between the groups.61 Three studies have evaluated anti-VEGF agents used after vitrectomy with subretinal tPA. These small studies documented modest improvement in vision.54,62,63 To date, there are no prospective data to guide the clinician in the use of anti-VEGF agents alone or in combination with expansile gas displacement or with vitrectomy and tPA injection.
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