年龄相关性黄斑变性黄斑下出血的处理
【摘要】 年龄相关性黄斑变性引起的黄斑下出血是一个棘手的视力保护问题。文献报道对黄斑下出血可采用多种手术方法进行处理。本文对年龄相关性黄斑变性黄斑下出血的有关问题进行综述，包括出血的危险因素、继发损害、自然病程、特别是手术处理的技术方法、效果和并发症等。
【关键词】 黄斑下 出血 黄斑变性 手术
INTRODUCTION
Submacular Hemorrhage (SMH) is a common ocular disorder which leads to significant vision loss. Causes of SMH are more related to Bruchs membrane damages that usually occurred in agerelated macular degeneration (AMD), presumed ocular histoplasmosis, angioid streaks, polypoid choroidal vasculopathy and choroidal rupture. Other causes include ocular trauma, macroaneurysm and tumor.
Submacular Hemorrhage in AMD may come from the choroidal neovascularization (CNV), or tear in the area of pigment epithelium detachment (PED), or even with retinal pigment epithelial (RPE) atrophy［1］.
RISK FACTORS OF SMH
It has been shown that anticoagulant warfarin sodium may increase the risk of massive intraocular hemorrhage in AMD［2］. Patients with occult CNV who are receiving warfarin therapy and undergoing repetitive PDT appear to be at risk of SMH, which occurs within 12 weeks after the treatment［3］. Iguchi et al[4] suggested that SMH may be also related to systemic hypertension.
DAMAGES OF SMH
Sequential damage of SMH is related to the extent and duration of the hemorrhage. It has been shown in experimental studies that damages to photoreceptors may occur within 24 hours in rabbits［5］, and degeneration of the outer retina within 7 days in cats［6］. Large SMH may cause severe visual loss and obstructs expected treatment. In general, the SMH will resolve within 68 months in average, resulting in scar, atrophic change or RPE tears. The mechanism of damage caused by SMH includes iron toxicity from the blood, mechanical barrier of the clot, clot retraction and shearing of photoreceptors (PR), as well as the damage to RPE cells［6］.
NATURAL COURSE OF SMH
The natural course of SMH varies in different reports. Data from retrospective studies are reviewed herein. One study showed that no visual acuity (VA) improved in 12 eyes with large size of SMH in 23 years of followup［7］. Another study found that VA in 3 of 41 eyes decreased 3.5 lines in average within 3 years, and decreased more than 6 lines in 44% of the affected eyes［8］. Scupola et al[1] reported that SMH was absorbed within 228 months, but VA decreased in 80% of, and SMH recurred in 38% of the 60 eyes after 2 years followup. Berrocal et al[9] observed that VA improved in 40%, unchanged in 30% and decreased in 30% of the 20 eyes. Most SMH was absorbed in 2 years, resulting in scars［9］. In China, it was reported that repetitive SMH occurred in 23 of 25 eyes with SMH［10］.
Prognostic factors for the SMH are still controversial. Since RPE and PR are more severely damaged in AMD, SMH will result a worse visual outcome in majority of these eyes［7］. It was suggested that size and thickness of the SMH might be related to the visual outcome［1］, while others found that visual outcome was only related to the CNV membrane in these patients［9］.
MANAGEMENT OF SMH
Patients with SMH in AMD could be managed with one or more of the following choices: observation, systemic medical treatment, treatment on CNV, and surgery. Surgeries of SMH may be divided into vitrectomy vs nonvitrectomy, and either of them may be adjuvant with or without the use of tissue plasminogen activator (tPA), which could be used intravitreally or subretinally.
Reported surgical techniques include: 1) vitrectomy and removal of subretinal CNV membrane and the clot［11］, 2) subretinal injection of tPA and drainage of the liquefied hemorrhage［12, 13］, 3) subretinal injection of tPA with perfluorocarbon liquids (PFCL) steamrolling［14］, 4) subretinal injection of tPA with gas tamponade［15, 16］, 5) pneumatic displacement with tPA［1720］, and 6) pneumatic displacement without tPA［21, 22］.
Vitrectomy and Subretinal Clot Removal Surgical methods include a retinotomy at the site of SMH, subretinal lavage/drainage, clot/membrane removal with forceps, and fluidgas exchange. Early reports on the surgical outcome were not encouraging. Many eyes had postoperative complications, especially retinal detachment［23］. Postoperative rebleeding may occur, with no VA improvement［24, 25］. In contrast to these poor visual outcomes, VA improvement was reported in China in 12 of the 14 eyes (85.7%) after surgery［26］.
Vitrectomy with Subretinal tPA and Hemorrhage Removal Surgical methods include subretinal injection of tPA 650μg，waiting for 4045 minutes, enlarging the incision and drainage of liquefied hemorrhage. Lewis[13] reported a good result with this technique; VA improved in 83% of the eyes, and he suggested that better effect came with earlier (within 14 days) intervention. However, others reported unfavorable results later on. Postoperative VA declined continuously in majority of the patients with longer followup［27］. There was even no difference in final VA regardless of using or not using tPA［28］. Submacular Surgery Trials (SST) Research Group reported that no significant difference was found between groups of observation and complete removal of SMH with CNV after 2 years followup［29］. Complications include superchoroidal hemorrhage, retinal tear and retinal detachment［28］.
Vitrectomy and Subretinal tPA with PFCL Steamrolling Surgical methods include subretinal tPA injection and PFCL steamrolling instead of subretinal lavage, which may cause less damage to RPE and PR［27］. With this method, Kamei et al［14］ reported VA improvement in 82% of the treated eyes.
Vitrectomy and Subretinal tPA with Gas Tamponade Surgical methods include subretinal injection of tPA with 39G or thinner needle followed by fluidgas exchange. SMH may be displaced with less retinal damage in this way. Chaudhry et al[30] and Kimura et al[31] suggested that tPA might be used 24 hours prior to the surgery for eyes with larger and thicker SMH. Olivier et al［15］ reported that 25 of the 29 eyes were successful in complete displacement of the SMH without use of longacting gas, and 8 of these eyes received following treatment. Recurrence of SMH was reported in 27% of eyes［16］.
Pneumatic Displacement Pneumatic displacement (PD) describes the technique of intraocular gas injection with/without tPA. Advantages of PD include simplicity, less invasive, fewer intraocular complications, and nondirect damage to PR and RPE. Indications for PD are SMH within 3 weeks, better preoperative VA, smaller SMH in size and thicker SMH. Mechanism of PD involves a combined effect of buoyancy of the gas bubble and gravity on the SMH. To achieve better efficiency, it was suggested that the displacement plane should be best kept parallel to gravity force direction, so that face down position may not be appreciated［32］.
Intraocular gas and tPA injection This technique was first report by Heriot and was termed pneumatic displacement. The method includes intravitreal injection of 0.1mL tPA (2550μg) and longacting gas［33］. It was reported that SMH might be displaced within 15 days postoperatively［33］, and complete displacement was achieved in 71% of the 14 eyes［18］. A report from Thailand showed that 63% of the Asian patients gained VA improvement after 6 months［34］. An uncontrolled study suggested the result would be better if eyes were treated within 14 days of bleeding, although recurrence of hemorrhage occurred in 21% of eyes［35］. The relation between duration of SMH and visual outcome has not been found［17］. Complications include vitreous hemorrhage (15.7%) and retinal detachment［34］.
Intraocular gas without tPA injection Pure C3F8 injection has been recommended if tPA is not used simultaneously. It was reported that this technique was less effective for small SMH［22］, and that it was suitable for nonAMD patients comparing to AMD ones［36］. Johnson suggested that tPA could be injected 2448 hours after gas injection in nonresponded cases［33, 37］.
ISSUES OF tPA USAGE
As a biological agent, tPA should be kept in deep low temperature storage with asepsis and be diluted 4 hours prior to injection. Safe dosage for intraocular injection is between 1850g. Maximal effect of intraocular tPA occurs at 424 hours postinjection. A waiting time of 2030 minutes before gas injection is suggested, as well as avoidance of using tPA for SMH within 3 days.
Safety of intraocular tPA is another concern about its use in SMH surgery. Vitreous hemorrhage was reported after tPA injection［38］.
Disagreement still exists among doctors on the safety dosage of tPA, and dosage≤25ug is considered safe by the majority. There were reports concerning retinal toxicity of tPA. Chen et al[39] reported posterior pigment and ERG changes after two successive injections of 50ug tPA. Hesse et al［20］ reported exudative retinal detachment after 100μg tPA intravitreal injection. It was also concerned that injection of frozen prepared tPA may increase the risk of endophthalmitis. There was report of two cases of posttPA injection endophthalmitis with S. mitis culture positive［40］.
COMPARISON OF DIFFERENT MANAGEMENTS
In a retrospective study of 42 eyes with SMH ≥12 disc size, two techniques were compared. One was subretinal removal of clot and membrane, the other was subretinal tPA with gas tamponade. The results of one year followup showed that 48% of eyes in the first group and 13% of eyes in the second group gained VA improvement >3 lines, which suggests that the former technique is better［41］. SST (19982001) studied 336 eyes with SMH +/CNV. The inclusion criteria were patients with SMH+/CNV ≥3.5 disc size and SMH≥50% of the lesion size. Patients were divided into surgical group and observation group. After 24 months followup, no VA stabilization or improvement was found in both groups. Surgery was only of benefit in decreasing severe visual loss comparing to observation (21% vs 36%), but with increasing risk of retinal detachment (16%vs 2%). The study also suggested that large SMH and poor preoperative VA predisposed a high risk of retinal detachment. Postoperative subretinal or subRPE hemorrhage existed in 93% of the operated eyes［29］.
COMPLICATIONS OF SMH SURGERY
The reported incidence of surgical complications includes vitreous hemorrhage (8%20%)［15, 20, 33, 35, 38］, retinal detachment (3%25%)［14, 20, 28, 38］, endophthalmitis (7%)［33］, and epiretinal membrane (9%)［14］. In SST report, 16% of the operated eyes developed rhegmatogenous retinal detachment during the 12month followup, while only 2% in the observation group had rhegmatogenous retinal detachment within 36month followup［29］.
Many factors may contribute to the poor outcome of patients with SMH, which include irreversible photoreceptor damage, RPE atrophy, CNV and scar. Other related factors affecting the outcome of SMH include preoperative VA, duration and extent of SMH, severity of AMD, and followup period. Efficiency of intraocular tPA is still of considerable diversity. VA improvement ranges from 21% to 93% of the tPAcases reported. There was study showing that tPA can not penetrate through retina［42］.
The relation between SMH and CNV is uncertain. It has been reported that CNV presented in 18%68% of the cases with SMH, and CNV was found in 1/3 of the eyes with recurrence of SMH［43］.
In view of the riskbenefit ratio and the outcome of SMH, it seems that surgical management of SMH is not strongly emphasized. In current clinical practice, surgery for SMH is usually not the first choice. Doctors should not solely rely on surgical intervention in the management of SMH[44].
Evidencebased study is needed in future to validate the effect of intravitreal tPA and its theoretical basis. New therapeutic methods and their roles, such as antiVEGF therapy and microinvasive surgery also warrant further studies[45].
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