- Email: [email protected]
Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions
Intravitreous Injection of Tissue Plasminogen Activator and Gas in the Treatment of Submacular Hemorrhage Under Various Conditions Lars-Olof Hattenbach, MD, Christina Klais, MD, Frank H. J. Koch, MD, Hermann O. C. Gu¨mbel, MD Objective: To investigate the efficacy and safety of treating submacular hemorrhages secondary to agerelated macular degeneration (ARMD) with intravitreous recombinant tissue plasminogen activator (rt-PA) and gas under various conditions. Design: Prospective, noncomparative case series. Participants: Forty-three consecutive eyes of 42 patients with recent (range, 2–28 days) subfoveal hemorrhage secondary to ARMD were included in this study. The size of subretinal hemorrhage ranged from 0.25 to 30 disc areas. Methods: All patients were treated with intravitreous injections of rt-PA (50 g) and sulfur hexafluoride (0.5 ml). Postoperative prone positioning was maintained for 24 to 72 hours. Patient follow-up ranged from 4 to 18 months (mean, 6 months). Main Outcome Measures: Best and final postoperative visual acuity in relation to size and onset of hemorrhage, displacement of subretinal blood, and surgical complications. Results: Best postoperative visual acuity compared with preoperative visual acuity was improved two or more Snellen lines in 19 eyes (44%) and stable in 24 eyes (56%). Final visual acuity was improved two or more lines in 13 eyes (30%), stable in 26 (61%), and two or more lines worse in 4 eyes (9%). Duration of hemorrhage ⱕ14 days was associated with a better gain of lines of vision (P ⫽ 0.0058). Best postoperative acuity was maintained for an average of 4.2 months (range, 0.5–12 months). Overall, complete displacement of blood from under the fovea was achieved in 35 eyes (81%). Nine eyes (21%) developed recurrent hemorrhage, which required repeat treatment. In three patients (7%), a mild breakthrough vitreous hemorrhage was observed. Conclusions: Our findings suggest that intravitreous injections of rt-PA and gas are of value for an improved and accelerated visual recovery in ARMD patients with submacular hemorrhage, although final visual outcome is often limited by the progression of the underlying ARMD. Patients with retinal hemorrhages of recent onset (ⱕ14 days) seem to have the most favorable results. A rapid displacement of submacular blood may reveal discrete choroidal neovascular membranes amenable to further treatment. The complication rate of this minimally invasive technique seems to be low. Ophthalmology 2001;108:1485–1492 © 2001 by the American Academy of Ophthalmology. Submacular hemorrhage secondary to choroidal neovascularization (CNV) can cause sudden visual loss in patients with age-related macular degeneration (ARMD). Although such patients occasionally may have spontaneous improvement in visual acuity,1 several studies suggest that the overall prognosis of untreated submacular hemorrhage is poor.1–5 Experimental studies have demonstrated that irreversible retinal damage occurs as early as 24 hours after the onset of hemorrhage.6 Originally received: August 31, 2000. Accepted: March 20, 2001. Manuscript no. 200664. Department of Ophthalmology, Johann Wolfgang Goethe University Hospital, Frankfurt am Main, Germany. Reprint requests to Lars-Olof Hattenbach, MD, Klinik fu¨r Augenheilkunde, Klinikum der Johann Wolfgang Goethe-Universita¨t, 60590 Frankfurt am Main, Germany. © 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.
Recognition of the damaging effects of subretinal blood has stimulated interest in strategies to improve patients’ visual recovery. In previous attempts to treat massive submacular hemorrhage associated with ARMD, vitreoretinal surgery to remove the subretinal blood clot has been performed.7–10 The results of these operations, however, have been disappointing. Interestingly, several recent studies have indicated that the preoperative or intraoperative use of the fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) may have a beneficial effect, but the true value of this therapeutic approach remains to be investigated.11–13 From the current data, surgical intervention may be recommended in selected cases. However, in view of a high rate of intraoperative and postoperative complications, concern about a surgical approach is particularly pertinent for patients with small areas of subretinal blood. As an alternative to surgical drainage, Heriot (Heriot ISSN 0161-6420/01/$–see front matter PII S0161-6420(01)00648-0
1485
Ophthalmology Volume 108, Number 8, August 2001 WJ. Intravitreal gas and tPA: an outpatient procedure for submacular hemorrhage. Vail Vitrectomy Meeting, March 1996; Vail, CO) recently reported on the management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. His encouraging initial experience has been further substantiated by the findings of other investigators.14,15 In a retrospective study, Hassan et al14 demonstrated that intravitreous injection of rt-PA and gas is effective in displacing thick submacular blood and facilitating visual improvement, although final visual outcomes seem to be limited by the progression of the underlying macular disease in many patients. However, thus far, there is no consensus about indication criteria, the optimal dose of rt-PA, or the ideal timing after the onset of subretinal hemorrhage. Moreover, because intravitreous rt-PA and gas have been used mainly for the treatment of thick or large subretinal blood clots, there is a need to determine the usefulness of this approach in the management of small subfoveal hemorrhages. In the current prospective study, 43 consecutive eyes with recent submacular hemorrhage secondary to ARMD received intravitreous injections of rt-PA and expansile gas. The objective of our investigation was to determine the efficacy and safety of this minimally invasive procedure. In particular, we investigated whether the presence or absence of various clinical baseline characteristics had an effect on visual outcome.
Patients and Methods The study was carried out with the agreement of our institutional review board. All participants gave written informed consent. Eligible subjects were investigated for possible contraindications. Individuals with bleeding disorders, anticoagulant therapy, or a history of inflammatory eye disease were excluded from the study. From October 1998 to December 1999, 42 consecutive patients (43 eyes) who were seen at our institution with acute (ⱕ28 days) submacular hemorrhage secondary to ARMD were enrolled. All patients had subretinal hemorrhages centered in or close to the fovea and reading vision in the affected eye before the onset of hemorrhage. Patients were excluded whenever vitreous hemorrhage was present at the initial examination. Clinical data were recorded prospectively by the authors with standardized forms. In all patients, complete bilateral ocular examinations including bestcorrected visual acuity, slit-lamp biomicroscopy, applanation tonometry, and indirect ophthalmoscopy were conducted at the initial examination, 1 to 5 days after treatment, and at 2- to 6-week intervals. In all cases, follow-up data were obtained over a minimum period of 4 months (mean, 6 months; range, 4 –18 months). Patients or their ophthalmologists were contacted regularly to optimize participants’ compliance and maintain a constant followup. Whenever possible, additional examinations were performed over an extended period of time. All visual acuities were measured using a linear Snellen chart. The size of the subfoveal hemorrhage was measured in standardized Macular Photocoagulation Study (MPS) disc areas.16 The presence of a submacular neovascular lesion was confirmed by both clinical examination with a 90-diopter lens and by fluorescein angiography. All patients had at least some classic or occult neovascularization, unless the lesion was obscured by subretinal hemorrhage. Subjects with mature disciform scars were excluded
1486
from the study. Color fundus photography was performed in all patients, at least at the initial examination and after total or partial displacement or dissolution of the subretinal hemorrhage. The injection procedure was performed with the patient under retrobulbar anesthesia with 2% lidocaine. Betadine was applied to the lids and periorbita, and the eye was irrigated with sterile saline, followed by neomycin sulfate drops. Fifty micrograms of commercial rt-PA solution (Actilyse, Boehringer, Ingelheim, Germany) in a volume of 50 l, was drawn in a tuberculin syringe and injected slowly into the midvitreous cavity through a 30-gauge needle. After an aqueous tap to reduce intraocular pressure, 0.5 ml of 100% sulfur hexafluoride gas was injected into the vitreous cavity. Both injections were administered via the pars plana in the superotemporal quadrant, 3 mm posterior to the limbus in pseudophakic patients and 3.5 mm posterior to the limbus in phakic patients. Patients were then instructed to maintain prone positioning for 72 hours. Whenever blood displacement from under the fovea was not complete, prone positioning was continued for an additional 24 to 48 hours. Primary outcome measures were best and final postoperative visual acuity and degree of blood displacement. Changes in visual acuity were defined as improvement (increase of 2 or more Snellen visual acuity lines), stable (within ⬍2 lines from baseline visual acuity), and worse (loss of 2 or more Snellen visual acuity lines). The degree of blood displacement was measured ophthalmoscopically after completion of prone positioning and graded as complete (ⱖ1 disc area from the center of the fovea), partial, or no displacement. In addition, presenting characteristics were examined to determine their importance in predicting visual outcome. Age, gender, initial visual acuity, duration of subretinal hemorrhage before treatment and initial size of hemorrhage (disc diameters) were used to subdivide patients and to investigate their prognostic value. Secondary outcome measures included intraoperative or postoperative complications. Testing for any relationship between preoperative characteristics and visual outcome was performed with Fisher’s exact test. All tests were two-tailed, and acceptable significance was recorded when P values were ⬍0.05. All analyses were performed with the SAS statistical software package (SAS Institute, Inc., Cary, NC).
Results Of the 42 patients (43 eyes) enrolled in the current study, 15 were men and 27 were women, with a mean age of 74.6 years (range, 50 –91 years). The size of the subretinal hemorrhage ranged from 0.25 to 30 Macular Photocoagulation Study disc areas; the mean duration of subretinal hemorrhage was 15.4 days (range, 2–28 days) (Table 1). Best postoperative visual acuity compared with preoperative visual acuity was improved 2 or more lines in 19 of 43 eyes (44%) and stable (within less than 2 lines from baseline) in 24 eyes (56%). Final visual acuity, when compared with preoperative visual acuity, was improved 2 or more lines in 13 of 43 eyes (30%), stable in 26 (61%), and decreased 2 or more lines in 4 eyes (9%). Scatter plots of initial versus best and final visual acuity are provided in Figure 1. An overview of clinical baseline characteristics including initial and postoperative visual acuities is given in Table 1. Preoperative visual acuities ranged from hand motions to 20/50. Best and final acuities achieved after intravitreous rt-PA and gas ranged from counting fingers to 20/30. Twenty-one eyes (49%) achieved a best visual acuity better than 20/200, and 15 eyes (35%) maintained this level at the final visit. Of these, four eyes (9%) attained a final visual acuity of 20/50 or better (Table 1). Best postoperative visual acuity was maintained for an average of 4.2 months (range, 0.5–12 months). Of the 13 patients with a fol-
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage Table 1. Clinical Profile of 42 Consecutive Patients (43 Eyes) with Submacular Hemorrhage Secondary to Age-related Macular Degeneration Patient No./Gender/ Age (yrs)/Eye 1/M/88/OS 2/F/74/OD 3/M/85/OD 4/F/50/OS 5/F/60/OD 6/F/82/OS 7/M/85/OD 8/M/76/OD 9/M/81/OS 10/F/72/OD 11/F/86/OS 12/F/67/OD 13/M/83/OS 14/M/75/OD 15/M/63/OD 16/M/74/OD 17/F/71/OS 18/M/79/OS 19/F/50/OS 20/F/81/OD 21/F/74/OD 22/M/72/OS 23/F/73/OS 24/F/82/OS 25/F/91/OS 26/F/80/OS 27/F/73/OD 28/F/85/OD 29/F/81/OD 30/F/81/OS* 31/F/72/OS 32/F/91/OS 33/M/80/OS 34/F/65/OS 35/M/71/OD 36/F/73/OD 37/M/63/OS 38/F/60/OD 39/F/75/OS 40/F/78/OD 41/M/78/OD 42/F/51/OD 43/F/78/OS
Visual Acuity
Duration (Days)
Hemorrhage Size Disc Areas
Initial
Best
Final
Follow-Up (Months)
28 7 12 15 14 14 21 18 20 17 10 21 5 3 18 21 21 28 13 21 21 2 7 14 3 21 7 21 10 7 28 7 21 28 14 5 21 21 28 12 11 7 21
4 10 1 1⁄2 4 21⁄2 11⁄2 2 10 1⁄2 25 5 11⁄2 30 1⁄2 5 1⁄2 11⁄2 12 1 1⁄2 1 1⁄2 1 14 21⁄2 20 2 1⁄4 1⁄4 1 12 1 3 20 4 1⁄4 1 1⁄4 10 2 2 1⁄2
20/600 20/400 20/200 20/500 20/400 20/200 20/200 20/400 CF 20/50 HM 20/60 20/400 20/400 20/100 20/50 20/600 20/200 20/200 20/200 20/600 20/100 20/600 20/200 HM 20/200 20/200 CF 20/200 20/100 20/200 20/600 20/200 20/100 CF CF 20/60 20/600 20/100 20/400 20/200 20/60 20/200
20/400 20/60 20/60 20/200 20/100 20/200 20/100 20/400 20/600 20/30 20/400 20/60 20/80 20/400 20/50 20/30 20/600 20/200 20/60 20/400 20/500 20/100 20/400 20/60 20/600 20/200 20/200 20/100 20/60 20/50 20/200 20/200 20/200 20/100 20/300 20/800 20/40 20/500 20/100 20/60 20/60 20/30 20/200
20/600 20/600 20/60 20/300 20/100 HM 20/400 20/400 20/600 20/30 20/400 20/600 20/300 20/400 20/600 20/30 20/600 20/200 20/60 20/500 20/500 20/100 20/400 20/100 20/600 20/200 20/200 20/100 20/60 20/60 20/200 20/200 20/200 20/100 CF 20/800 20/40 20/500 20/100 20/60 CF 20/30 20/300
4 5 8 17 4 4 18 12 5 10 4 5 12 4 12 8 4 4 4 6 5 4 5 4 4 5 4 7 6 6 5 5 4 4 4 4 5 4 4 4 5 6 4
* The same patient with bilateral submacular hemorrhage. CF ⫽ counting fingers; HM ⫽ hand motion; OD ⫽ right eye; OS ⫽ left eye.
low-up time of at least 6 months (range, 6 –18 months), 7 (54%) maintained a visual improvement of at least 2 lines and 5 (38%) remained stable. With respect to best postoperative visual acuity, a better outcome (i.e., gain of lines of vision) was associated with duration of hemorrhage. In a subgroup of 21 eyes with duration of hemorrhage ⱕ14 days, 14 (67%) improved 2 or more Snellen visual acuity lines, whereas only 5 of 22 eyes (29%) with duration of hemorrhage ⬎14 days showed a comparable outcome (P ⫽ 0.0058). In contrast, there was no statistically significant relationship between size of hemorrhage alone and better postoperative visual recovery. However, of the nine eyes with duration of hemorrhage ⱕ14 days and hemorrhage size ⱕ2 disc areas, seven (78%) gained 2 or more lines of vision (P ⫽ 0.03). Moreover, subgroup analysis for only those 25 eyes with hemorrhage size ⱕ2 disc areas confirmed that duration of hemorrhage ⱕ14 days was associated with a better
visual outcome (P ⫽ 0.017); only 4 of 16 eyes (25%) with hemorrhage size ⱕ2 disc areas and duration of hemorrhage ⬎14 days improved 2 or more Snellen visual acuity lines. The preoperative factor found to have an effect on absolute final acuity was preoperative visual acuity. Of the 15 eyes with final visual acuity equal to or better than 20/100, 8 (53%) had an initial visual acuity ⱖ20/100, whereas only 2 of 28 eyes (7%) with final acuity less than 20/100 had ⱖ20/100 initial vision (P ⫽ 0.0013). However, better preoperative visual acuity (ⱖ20/100) was not associated with a gain of lines (ⱖ2 Snellen lines) of vision (P ⫽ 0.14, not significant). Factors that had no significant effect on final visual outcome included patient age, gender, and size of hemorrhage (data not shown). There was a tendency for the 21 eyes with duration of hemorrhage ⱕ14 days to have better final visual recovery. By the end of the follow-up period, nine (43%) of these eyes had gained 2 or more Snellen lines, whereas only four
1487
Ophthalmology Volume 108, Number 8, August 2001
Figure 1. A, Initial visual acuity versus best visual acuity. Triangles indicate eyes that required repeat treatment for recurrent submacular hemorrhage. B, Initial visual acuity versus final visual acuity after single (squares) or repeat (triangles) treatment.
(18%) eyes with duration of hemorrhage ⬎14 days showed a comparable improvement. However, this difference did not reach statistical significance (P ⫽ 0.104, not significant). Moreover, a duration of hemorrhage ⬎21 days was found to have an effect on final outcome. Of the five eyes with a symptom to treatment interval ⬎21 days, none had a change from initial to final postoperative visual acuity (0 lines gained or lost). By the time of the initial examination, visual acuities in the fellow eyes ranged from hand motions to 20/20. Of the 42 patients enrolled in this study, 32 (76%) had visual acuities ⬍20/50 in the partner eye, including 19 (45%) eyes with ⱕ20/200 vision. Only one patient, a 50-year-old woman, had normal visual acuity (20/20) in the fellow eye. Overall, intravitreous injection of rt-PA and gas resulted in complete displacement of blood from under the fovea in 35 of 43 eyes (81%). A partial displacement of blood was found in eight eyes (19%). Typically, we observed a shift of subretinal blood inferotemporal to the macula, regardless of the size of the hemorrhage. The fundus photographs of a patient with large (30 disc areas) subfoveal hemorrhage before injection of rt-PA and gas and after therapy are shown in Figure 2. Figure 3 demonstrates a complete displacement of blood in a patient with small (ⱕ2 disc areas) subretinal hemorrhage. In eight patients (eight eyes, 19%), displacement of subretinal blood revealed a classic choroidal neovascular membrane (CNVM), with or without occult choroidal neovascularization. Of these, three underwent thermal photocoagulation for juxtafoveal CNVM. When this study was conducted, photodynamic therapy was not an available treatment option. Retrospective analysis of the fluorescein angiograms revealed that, after successful treatment with rt-PA and gas, five (12%) eyes would have met the photodynamic therapy eligibility criteria.17 Figure 4 shows the preoperative fundus photograph and the postoperative fluorescein angiogram of an eye with a subfoveal CNVM. During the course of the follow-up, nine (21%) of the eyes examined in our study had recurrent subretinal hemorrhage develop, which required repeat treatment with intravitreous rt-PA and gas. In four of these patients, visual acuity had improved by the end of the follow-up period, and in two patients a further decline in visual acuity (2 or more Snellen lines) was noted (Fig 1). This was attributed to the progression of their underlying macular disease. We observed no major intraoperative or postoperative complications. In particular, we found no evidence of retinal toxicity associated with rt-PA such as exudative retinal detachment or pigment epithelium changes. However, in three patients (7%), a mild breakthrough vitreous hemorrhage occurred within 1 day after treatment. One of these patients had received a repeat injection of rt-PA and gas. Moreover, in two eyes, an elevated intraocular pressure (22 and 24 mmHg) was observed on the first postoperative day. None of these patients, however, required treatment with antiglaucomatous medications.
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3
Figure 2. A, Fundus photograph of a 75-year-old man with massive subretinal hemorrhage secondary to age-related macular degeneration. B, Fundus photograph 2 weeks after treatment, demonstrating a complete displacement from the center of the fovea. Note the gas-bubble–shaped shift of subretinal blood in the perimacular region. Figure 3. A, Preoperative fundus photograph of a 78-year-old man with submacular hemorrhage involving the fovea and onset of symptoms 11 days before treatment. B, Fundus photograph of the same eye 72 hours after intravitreous injection of rt-PA and gas, demonstrating a typical displacement of blood inferotemporal to the macula. By this time, visual acuity had improved from 20/200 to 20/60. Figure 4. A, Preoperative fundus photograph of an 79-year-old male patient, showing a small subretinal hemorrhage involving the fovea. B, Fluorescein angiography 2 weeks after treatment, revealing a subfoveal choroidal neovascular lesion.
1488
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage
1489
Ophthalmology Volume 108, Number 8, August 2001
Discussion There are multiple clinical consequences of submacular hemorrhage associated with ARMD. First, most patients experience a sudden loss of vision with the onset of hemorrhage. This is particularly devastating in subjects with bilateral ARMD and reduced vision in the partner eye at the time of presentation. Therefore, strategies to hasten patients’ visual recovery or delay the progression of visual loss may lead to improvements in quality of life. Second, even small hemorrhages may obscure subretinal neovascularization amenable to further treatment. Thus, appropriate therapy such as thermal photocoagulation of juxtafoveal CNVM or photodynamic therapy in patients with classic subfoveal neovascularization may be delayed. Third, there is much evidence that subretinal hemorrhage, by itself, causes severe retinal damage. Clot retraction, iron toxicity, and blockage of nutrient diffusion are among the mechanisms that have been proposed to explain the visual loss in eyes with subretinal blood.6 –21 In our study, best visual acuity compared with preoperative visual acuity was improved 2 or more lines in 44% of cases and maintained for an average of 4.2 months, with a range of 0.5 to 12 months. After a mean follow-up time of 6 months, visual acuity was improved 2 or more lines in approximately one third of patients (30%). Our findings parallel those reported by other investigators, who found a beneficial effect of intravitreous rt-PA and pneumatic displacement in submacular hemorrhage.14,15 In a retrospective case series, Hassan et al14 investigated the efficacy of rt-PA in the treatment of thick submacular hemorrhage, which ranged in extent from 2 to 13 disc areas. They observed a complete displacement of submacular blood in 100% of eyes. By the end of a follow-up period of 4 to 19 months, final visual acuity had improved two or more lines in 67%. However, because of the small sample size and relative homogeneity of this case series, they were not able to investigate whether preoperative variables such as hemorrhage size or duration may serve as predictors of visual outcome after therapy. In a recent study by Hesse and coworkers,15 intravitreous injections of 50 to 100 g of rt-PA and gas were performed in 11 eyes with submacular hemorrhage secondary to ARMD. In their case series, visual acuity improved by 2 lines in 45.5% of eyes. By contrast to other investigators, we included subjects with small submacular hemorrhages (ⱕ2 disc areas). Although it may be suspected that such eyes have a generally better prognosis, there was no direct relationship between hemorrhage size and better postoperative visual recovery. However, among eyes with duration of hemorrhage equal to or less than 14 days and hemorrhage size ⱕ2 disc areas, 78% were observed to improve 2 or more lines of vision after treatment. Because subgroup analysis for only those cases with small hemorrhage size (ⱕ2 DA) revealed that a short time (ⱕ14 days) from onset of hemorrhage to treatment was associated with a better gain of lines of vision, we believe that this improvement is at least partially the result of an early therapeutic intervention with rt-PA and gas. Overall, eyes with a shorter symptom to treatment interval tended to have more favorable results. Among eyes with
1490
duration of hemorrhage ⱕ14 days, two thirds (67%) improved two or more Snellen lines to their best postoperative acuity compared with one third (29%) of eyes with duration of hemorrhage ⬎14 days. By the end of the follow-up period, 43% of the eyes with duration of hemorrhage ⱕ14 days had gained 2 or more Snellen lines, whereas only 18% of eyes with clots of longer duration showed a comparable outcome. Moreover, it is noteworthy that none of the eyes with a symptom to treatment interval ⬎21 days showed an improvement from initial to final postoperative visual acuity. In conclusion, it may be suggested that duration of hemorrhage has potential as a predictor of visual recovery after treatment with rt-PA and gas in subretinal hemorrhage. The better visual results in eyes with a shorter duration of hemorrhage may be explained by the time course of damaging effects associated with the formation of subretinal blood clots. In an experimental study, Glatt and Machemer6 produced subretinal hemorrhage by injecting autologous blood under the rabbit retina. They found that photoreceptors degenerated in less than 24 hours with pyknosis of the outer nuclear layer. Other investigators found evidence for clot retraction as a major cause of damage in an animal model of subretinal hemorrhage. In their studies, severe outer retinal degeneration occurred within 3 to 7 days in the rabbit retina18 and within 7 to 14 days in the cat retina.19,20 These findings highlight the potential for improved retinal survival and visual recovery if submacular blood clots can be eliminated or displaced soon after formation. The major complication seen in this series was mild breakthrough vitreous hemorrhage, which occurred in 7% of patients. Interestingly, repeat treatment with rt-PA and gas was not associated with a higher risk of hemorrhage. Moreover, we found no evidence of retinal or other intraocular toxic reactions to rt-PA in the dose used in our study (50 g). This is consistent with the findings of other investigators, who observed no definite signs of retinal toxicity in eyes injected with rt-PA.14,22,23 However, from the available data, intravitreous injections of rt-PA in high concentrations are potentially unsafe. Hesse et al15 reported exudative retinal detachment, retinal pigment epithelium hyperpigmentation, and a marked reduction in the electroretinogram postoperatively in eyes that received intravitreous rt-PA injections of 100 g but not in eyes treated with 50 g. By contrast, Hassan and colleagues14 found no evidence of retinal or other intraocular toxic reactions to rt-PA in the doses used in their study (25–100 g). Additional evidence that retinal toxicity from intravitreous commercial rt-PA is a dose-dependent problem has been provided by several experimental studies. Johnson et al24 found no toxic reactions in rabbit eyes after injections of rt-PA in a dose of 25 g. In their study, one of four eyes injected with 50 g showed localized loss of photoreceptor cells, whereas severe retinal damage was seen at higher concentrations. The toxic effect was attributed to the L-arginine vehicle of the commercially available rt-PA solution. On the assumption that the larger vitreous volume, greater vitreous liquefaction, and vascularized retina in human eyes might raise the threshold for toxicity, higher concentrations of rt-PA have been used in several clinical studies. However, just recently, Hrach and coworkers25 observed fundus pig-
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage mentary alterations and a loss of photoreceptor elements in cat eyes receiving commercial rt-PA solution in doses greater than or equal to 50 g. Because cat eyes, in contrast to those of the rabbit, have a vascularized inner retina and a vitreous volume similar to that of human eyes, they recommended avoiding intravitreal injections of rt-PA in concentrations greater than 25 g. In light of the potential damaging effects of intravitreous rt-PA, several investigators have suggested that the intravitreous injection of gas alone may be effective in displacing subretinal blood. Ohji and coworkers26 documented the beneficial effects of pneumatic displacement without rt-PA on the vision of patients with subfoveal hemorrhage. However, in their study, intravitreous gas without rt-PA failed to produce displacement in two of five cases. Moreover, four of these patients had a symptom to treatment interval of 4 to 6 days, indicating that this therapeutic approach may only be useful in eyes with recent onset of hemorrhage. There is much evidence that intravitreously injected rt-PA can migrate across the retina, thereby facilitating the dissolution of subretinal blood clots.18,19,21,24,27,28 Coll and coworkers28 found that, after intravitreous injections of rt-PA in the rabbit, subretinal blood clots disappeared within 24 hours, whereas there was no change in control eyes injected with saline solution. Experimentally, albumin, a protein with a molecular weight similar to that of rt-PA, is detectable in the subretinal space within 1 hour, suggesting that rt-PA might not be exempt from traversing the retina.29 Other investigators observed a significant enlargement of subretinal hemorrhages in a gravity-dependent manner in ARMD patients 24 hours after intravitreous injection of rt-PA.30 On the basis of their results, they postulated a causal relationship between change of hemorrhage size and subretinal clot lysis induced by rt-PA. Moreover, they concluded that the diffusion of rt-PA across the retina may be explained by retinal microlesions secondary to subretinal blood clots. A number of studies suggest that the natural course of submacular hemorrhage is associated with a poor prognosis.1–5 Avery and coworkers2 described the clinical course of eyes with subfoveal hemorrhage secondary to ARMD. After a follow-up period of 6 months, a loss of 3 or more lines of visual acuity from the baseline level was observed in 48% of eyes. In a retrospective case series, Bennett et al3 reviewed the clinical course of untreated eyes with submacular hemorrhages under the foveal avascular zone. They found that patients with subretinal hemorrhage caused by ARMD had a considerable decrease in visual acuity over time, with an average visual acuity of 20/1700 at the final follow-up visit, whereas patients with subretinal hemorrhage secondary to choroidal rupture showed a far better outcome. However, Berrocal and associates1 demonstrated that eyes with submacular hemorrhage secondary to ARMD may have spontaneous visual improvement. Interestingly, they observed no association between visual outcome and thickness or size of the hemorrhage. Overall, our data show that intravitreous rt-PA and gas have the potential to improve vision or delay the progression of visual loss for an extended period of time. During the course of our study, 91% of eyes either lost little or no
visual acuity (61%) or gained visual acuity (30%) from the baseline level. Because follow-up times varied considerably in some patients, our long-term data must be interpreted with caution. However, the fact that the proportion of patients who gained 2 or more visual acuity lines decreased from 44% to 30% within an average follow-up period of 6 months indicates that final visual outcome is limited by the progression of the underlying macular disease. Another interesting finding of our study is the observation that intravitreous rt-PA and gas may constitute a useful treatment strategy in patients with thick contiguous subretinal blood that obscures the boundaries of neovascular membranes amenable to further treatment. In particular, the ability to determine the proportion of the lesion that is classic CNV is important in photodynamic therapy or thermal photocoagulation. After successful displacement of subretinal blood, we identified eight eyes (19%) with predominantly classic CNV. Of these, three underwent photocoagulation for juxtafoveal CNVM and five had subfoveal CNV. Moreover, we identified several characteristics that may significantly affect outcome. The information presented indicates that early intravitreous rt-PA and gas injection provide a better chance for prompt recovery of useful vision in patients with recent onset of subretinal hemorrhage. This advantage seems to be clearly present in eyes with small subfoveal hemorrhages. By contrast, eyes with a longer duration of hemorrhage may have less to gain from this treatment strategy. A major limitation of this study is the lack of a control group. More research and controlled randomized trials are needed to definitively determine the benefit of this therapeutic approach. However, because no treatment exists that consistently results in improved vision in patients with submacular hemorrhage secondary to ARMD, intravitreous injection of rt-PA and gas may be recommended as a minimally invasive alternative to observation or surgical drainage.
References 1. Berrocal MH, Lewis ML, Flynn HW Jr. Variations in the clinical course of submacular hemorrhage. Am J Ophthalmol 1996;122:486 –93. 2. Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina 1996;16:183–9. 3. Bennett SR, Folk JC, Blodi CF, Klugman M. Factors prognostic of visual outcome in patients with subretinal hemorrhage. Am J Ophthalmol 1990;109:33–7. 4. Scupola A, Coscas G, Soubrane G, Balestrazzi E. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102. 5. Wood WJ, Smith TR. Senile disciform macular degeneration complicated by massive hemorrhagic retinal detachment and angle closure glaucoma. Retina 1983;3:296 –303. 6. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol 1982;94:762–73. 7. de Juan E Jr, Machemer R. Vitreous surgery for hemorrhagic and fibrous complications of age-related macular degeneration [case report]. Am J Ophthalmol 1988;105:25–9.
1491
Ophthalmology Volume 108, Number 8, August 2001 8. Vander JF, Federman JL, Greven C, et al. Surgical removal of massive subretinal hemorrhage associated with age-related macular degeneration. Ophthalmology 1991;98:23–7. 9. Ibanez HE, Williams DF, Thomas MA, et al. Surgical management of submacular hemorrhage. A series of 47 consecutive cases. Arch Ophthalmol 1995;113:62–9. 10. Lim JI, Drews-Botsch C, Sternberg P Jr, et al. Submacular hemorrhage removal. Ophthalmology 1995;102:1393–99. 11. Lewis H. Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol 1994;118:559 – 68. 12. Kamei M, Tano Y, Maeno T, et al. Surgical removal of submacular hemorrhage using tissue plasminogen activator and perfluorocarbon liquid. Am J Ophthalmol 1996;121:267–75. 13. Chaudhry NA, Mieler WF, Han DP, et al. Preoperative use of tissue plasminogen activator for large submacular hemorrhage. Ophthalmic Surg Lasers 1999;30:176 – 80. 14. Hassan AS, Johnson MW, Schneiderman TE, et al. Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology 1999;106:1900 – 6; discussion 1906 –7. 15. Hesse L, Schmidt J, Kroll P. Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 1999;237:273–7. 16. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1991;109:1220 –31. 17. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials. TAP report 1. Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329 – 45. 18. Lewis H, Resnick SC, Flannery JG, Straatsma BR. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Am J Ophthalmol 1991;111:197–204. 19. Toth CA, Morse LS, Hjelmeland LM, Landers MB III. Fibrin
1492
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
directs early retinal damage after experimental subretinal hemorrhage. Arch Ophthalmol 1991;109:723–9. Benner JD, Hay A, Landers MB III, et al. Fibrinolytic-assisted removal of experimental subretinal hemorrhage within seven days reduces outer retinal degeneration. Ophthalmology 1994; 101:672– 81. Morse LS, Benner JD, Hjelmeland LM, Landers MB III. Fibrinolysis of experimental subretinal haemorrhage without removal using tissue plasminogen activator. Br J Ophthalmol 1996;80:658 – 62. Jaffe GJ, Abrams GW, Williams GA, Han DP. Tissue plasminogen activator for postvitrectomy fibrin formation. Ophthalmology 1990;97:184 –9. Jaffe GJ, Green GDJ, McKay BS, et al. Intravitreal clearance of tissue plasminogen activator in the rabbit. Arch Ophthalmol 1988;106:969 –72. Johnson MW, Olsen KR, Hernandez E. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Retina 1991;11:250 – 8. Hrach CJ, Johnson MW, Hassan AS, et al. Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes. Arch Ophthalmol 2000; 118:659 – 63. Ohji M, Saito Y, Hayashi A, et al. Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. Arch Ophthalmol 1998;116:1326 –32. Boone DE, Boldt HC, Ross RD, et al. The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model. Retina 1996;16:518 – 24. Coll GE, Sparrow JR, Marinovic A, Chang S. Effect of intravitreal tissue plasminogen activator on experimental subretinal hemorrhage. Retina 1995;15:319 –26. Takeuchi A, Kricorian G, Yao XY, et al. The rate and source of albumin entry into saline-filled experimental retinal detachments. Invest Ophthalmol Vis Sci 1994;35:3792– 8. Hesse L, Schroeder B, Heller G, Kroll P. Quantitative effect of intravitreally injected tissue plasminogen activator and gas on subretinal hemorrhage. Retina 2000; 20:500 –5.
Recognition of the damaging effects of subretinal blood has stimulated interest in strategies to improve patients’ visual recovery. In previous attempts to treat massive submacular hemorrhage associated with ARMD, vitreoretinal surgery to remove the subretinal blood clot has been performed.7–10 The results of these operations, however, have been disappointing. Interestingly, several recent studies have indicated that the preoperative or intraoperative use of the fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) may have a beneficial effect, but the true value of this therapeutic approach remains to be investigated.11–13 From the current data, surgical intervention may be recommended in selected cases. However, in view of a high rate of intraoperative and postoperative complications, concern about a surgical approach is particularly pertinent for patients with small areas of subretinal blood. As an alternative to surgical drainage, Heriot (Heriot ISSN 0161-6420/01/$–see front matter PII S0161-6420(01)00648-0
1485
Ophthalmology Volume 108, Number 8, August 2001 WJ. Intravitreal gas and tPA: an outpatient procedure for submacular hemorrhage. Vail Vitrectomy Meeting, March 1996; Vail, CO) recently reported on the management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. His encouraging initial experience has been further substantiated by the findings of other investigators.14,15 In a retrospective study, Hassan et al14 demonstrated that intravitreous injection of rt-PA and gas is effective in displacing thick submacular blood and facilitating visual improvement, although final visual outcomes seem to be limited by the progression of the underlying macular disease in many patients. However, thus far, there is no consensus about indication criteria, the optimal dose of rt-PA, or the ideal timing after the onset of subretinal hemorrhage. Moreover, because intravitreous rt-PA and gas have been used mainly for the treatment of thick or large subretinal blood clots, there is a need to determine the usefulness of this approach in the management of small subfoveal hemorrhages. In the current prospective study, 43 consecutive eyes with recent submacular hemorrhage secondary to ARMD received intravitreous injections of rt-PA and expansile gas. The objective of our investigation was to determine the efficacy and safety of this minimally invasive procedure. In particular, we investigated whether the presence or absence of various clinical baseline characteristics had an effect on visual outcome.
Patients and Methods The study was carried out with the agreement of our institutional review board. All participants gave written informed consent. Eligible subjects were investigated for possible contraindications. Individuals with bleeding disorders, anticoagulant therapy, or a history of inflammatory eye disease were excluded from the study. From October 1998 to December 1999, 42 consecutive patients (43 eyes) who were seen at our institution with acute (ⱕ28 days) submacular hemorrhage secondary to ARMD were enrolled. All patients had subretinal hemorrhages centered in or close to the fovea and reading vision in the affected eye before the onset of hemorrhage. Patients were excluded whenever vitreous hemorrhage was present at the initial examination. Clinical data were recorded prospectively by the authors with standardized forms. In all patients, complete bilateral ocular examinations including bestcorrected visual acuity, slit-lamp biomicroscopy, applanation tonometry, and indirect ophthalmoscopy were conducted at the initial examination, 1 to 5 days after treatment, and at 2- to 6-week intervals. In all cases, follow-up data were obtained over a minimum period of 4 months (mean, 6 months; range, 4 –18 months). Patients or their ophthalmologists were contacted regularly to optimize participants’ compliance and maintain a constant followup. Whenever possible, additional examinations were performed over an extended period of time. All visual acuities were measured using a linear Snellen chart. The size of the subfoveal hemorrhage was measured in standardized Macular Photocoagulation Study (MPS) disc areas.16 The presence of a submacular neovascular lesion was confirmed by both clinical examination with a 90-diopter lens and by fluorescein angiography. All patients had at least some classic or occult neovascularization, unless the lesion was obscured by subretinal hemorrhage. Subjects with mature disciform scars were excluded
1486
from the study. Color fundus photography was performed in all patients, at least at the initial examination and after total or partial displacement or dissolution of the subretinal hemorrhage. The injection procedure was performed with the patient under retrobulbar anesthesia with 2% lidocaine. Betadine was applied to the lids and periorbita, and the eye was irrigated with sterile saline, followed by neomycin sulfate drops. Fifty micrograms of commercial rt-PA solution (Actilyse, Boehringer, Ingelheim, Germany) in a volume of 50 l, was drawn in a tuberculin syringe and injected slowly into the midvitreous cavity through a 30-gauge needle. After an aqueous tap to reduce intraocular pressure, 0.5 ml of 100% sulfur hexafluoride gas was injected into the vitreous cavity. Both injections were administered via the pars plana in the superotemporal quadrant, 3 mm posterior to the limbus in pseudophakic patients and 3.5 mm posterior to the limbus in phakic patients. Patients were then instructed to maintain prone positioning for 72 hours. Whenever blood displacement from under the fovea was not complete, prone positioning was continued for an additional 24 to 48 hours. Primary outcome measures were best and final postoperative visual acuity and degree of blood displacement. Changes in visual acuity were defined as improvement (increase of 2 or more Snellen visual acuity lines), stable (within ⬍2 lines from baseline visual acuity), and worse (loss of 2 or more Snellen visual acuity lines). The degree of blood displacement was measured ophthalmoscopically after completion of prone positioning and graded as complete (ⱖ1 disc area from the center of the fovea), partial, or no displacement. In addition, presenting characteristics were examined to determine their importance in predicting visual outcome. Age, gender, initial visual acuity, duration of subretinal hemorrhage before treatment and initial size of hemorrhage (disc diameters) were used to subdivide patients and to investigate their prognostic value. Secondary outcome measures included intraoperative or postoperative complications. Testing for any relationship between preoperative characteristics and visual outcome was performed with Fisher’s exact test. All tests were two-tailed, and acceptable significance was recorded when P values were ⬍0.05. All analyses were performed with the SAS statistical software package (SAS Institute, Inc., Cary, NC).
Results Of the 42 patients (43 eyes) enrolled in the current study, 15 were men and 27 were women, with a mean age of 74.6 years (range, 50 –91 years). The size of the subretinal hemorrhage ranged from 0.25 to 30 Macular Photocoagulation Study disc areas; the mean duration of subretinal hemorrhage was 15.4 days (range, 2–28 days) (Table 1). Best postoperative visual acuity compared with preoperative visual acuity was improved 2 or more lines in 19 of 43 eyes (44%) and stable (within less than 2 lines from baseline) in 24 eyes (56%). Final visual acuity, when compared with preoperative visual acuity, was improved 2 or more lines in 13 of 43 eyes (30%), stable in 26 (61%), and decreased 2 or more lines in 4 eyes (9%). Scatter plots of initial versus best and final visual acuity are provided in Figure 1. An overview of clinical baseline characteristics including initial and postoperative visual acuities is given in Table 1. Preoperative visual acuities ranged from hand motions to 20/50. Best and final acuities achieved after intravitreous rt-PA and gas ranged from counting fingers to 20/30. Twenty-one eyes (49%) achieved a best visual acuity better than 20/200, and 15 eyes (35%) maintained this level at the final visit. Of these, four eyes (9%) attained a final visual acuity of 20/50 or better (Table 1). Best postoperative visual acuity was maintained for an average of 4.2 months (range, 0.5–12 months). Of the 13 patients with a fol-
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage Table 1. Clinical Profile of 42 Consecutive Patients (43 Eyes) with Submacular Hemorrhage Secondary to Age-related Macular Degeneration Patient No./Gender/ Age (yrs)/Eye 1/M/88/OS 2/F/74/OD 3/M/85/OD 4/F/50/OS 5/F/60/OD 6/F/82/OS 7/M/85/OD 8/M/76/OD 9/M/81/OS 10/F/72/OD 11/F/86/OS 12/F/67/OD 13/M/83/OS 14/M/75/OD 15/M/63/OD 16/M/74/OD 17/F/71/OS 18/M/79/OS 19/F/50/OS 20/F/81/OD 21/F/74/OD 22/M/72/OS 23/F/73/OS 24/F/82/OS 25/F/91/OS 26/F/80/OS 27/F/73/OD 28/F/85/OD 29/F/81/OD 30/F/81/OS* 31/F/72/OS 32/F/91/OS 33/M/80/OS 34/F/65/OS 35/M/71/OD 36/F/73/OD 37/M/63/OS 38/F/60/OD 39/F/75/OS 40/F/78/OD 41/M/78/OD 42/F/51/OD 43/F/78/OS
Visual Acuity
Duration (Days)
Hemorrhage Size Disc Areas
Initial
Best
Final
Follow-Up (Months)
28 7 12 15 14 14 21 18 20 17 10 21 5 3 18 21 21 28 13 21 21 2 7 14 3 21 7 21 10 7 28 7 21 28 14 5 21 21 28 12 11 7 21
4 10 1 1⁄2 4 21⁄2 11⁄2 2 10 1⁄2 25 5 11⁄2 30 1⁄2 5 1⁄2 11⁄2 12 1 1⁄2 1 1⁄2 1 14 21⁄2 20 2 1⁄4 1⁄4 1 12 1 3 20 4 1⁄4 1 1⁄4 10 2 2 1⁄2
20/600 20/400 20/200 20/500 20/400 20/200 20/200 20/400 CF 20/50 HM 20/60 20/400 20/400 20/100 20/50 20/600 20/200 20/200 20/200 20/600 20/100 20/600 20/200 HM 20/200 20/200 CF 20/200 20/100 20/200 20/600 20/200 20/100 CF CF 20/60 20/600 20/100 20/400 20/200 20/60 20/200
20/400 20/60 20/60 20/200 20/100 20/200 20/100 20/400 20/600 20/30 20/400 20/60 20/80 20/400 20/50 20/30 20/600 20/200 20/60 20/400 20/500 20/100 20/400 20/60 20/600 20/200 20/200 20/100 20/60 20/50 20/200 20/200 20/200 20/100 20/300 20/800 20/40 20/500 20/100 20/60 20/60 20/30 20/200
20/600 20/600 20/60 20/300 20/100 HM 20/400 20/400 20/600 20/30 20/400 20/600 20/300 20/400 20/600 20/30 20/600 20/200 20/60 20/500 20/500 20/100 20/400 20/100 20/600 20/200 20/200 20/100 20/60 20/60 20/200 20/200 20/200 20/100 CF 20/800 20/40 20/500 20/100 20/60 CF 20/30 20/300
4 5 8 17 4 4 18 12 5 10 4 5 12 4 12 8 4 4 4 6 5 4 5 4 4 5 4 7 6 6 5 5 4 4 4 4 5 4 4 4 5 6 4
* The same patient with bilateral submacular hemorrhage. CF ⫽ counting fingers; HM ⫽ hand motion; OD ⫽ right eye; OS ⫽ left eye.
low-up time of at least 6 months (range, 6 –18 months), 7 (54%) maintained a visual improvement of at least 2 lines and 5 (38%) remained stable. With respect to best postoperative visual acuity, a better outcome (i.e., gain of lines of vision) was associated with duration of hemorrhage. In a subgroup of 21 eyes with duration of hemorrhage ⱕ14 days, 14 (67%) improved 2 or more Snellen visual acuity lines, whereas only 5 of 22 eyes (29%) with duration of hemorrhage ⬎14 days showed a comparable outcome (P ⫽ 0.0058). In contrast, there was no statistically significant relationship between size of hemorrhage alone and better postoperative visual recovery. However, of the nine eyes with duration of hemorrhage ⱕ14 days and hemorrhage size ⱕ2 disc areas, seven (78%) gained 2 or more lines of vision (P ⫽ 0.03). Moreover, subgroup analysis for only those 25 eyes with hemorrhage size ⱕ2 disc areas confirmed that duration of hemorrhage ⱕ14 days was associated with a better
visual outcome (P ⫽ 0.017); only 4 of 16 eyes (25%) with hemorrhage size ⱕ2 disc areas and duration of hemorrhage ⬎14 days improved 2 or more Snellen visual acuity lines. The preoperative factor found to have an effect on absolute final acuity was preoperative visual acuity. Of the 15 eyes with final visual acuity equal to or better than 20/100, 8 (53%) had an initial visual acuity ⱖ20/100, whereas only 2 of 28 eyes (7%) with final acuity less than 20/100 had ⱖ20/100 initial vision (P ⫽ 0.0013). However, better preoperative visual acuity (ⱖ20/100) was not associated with a gain of lines (ⱖ2 Snellen lines) of vision (P ⫽ 0.14, not significant). Factors that had no significant effect on final visual outcome included patient age, gender, and size of hemorrhage (data not shown). There was a tendency for the 21 eyes with duration of hemorrhage ⱕ14 days to have better final visual recovery. By the end of the follow-up period, nine (43%) of these eyes had gained 2 or more Snellen lines, whereas only four
1487
Ophthalmology Volume 108, Number 8, August 2001
Figure 1. A, Initial visual acuity versus best visual acuity. Triangles indicate eyes that required repeat treatment for recurrent submacular hemorrhage. B, Initial visual acuity versus final visual acuity after single (squares) or repeat (triangles) treatment.
(18%) eyes with duration of hemorrhage ⬎14 days showed a comparable improvement. However, this difference did not reach statistical significance (P ⫽ 0.104, not significant). Moreover, a duration of hemorrhage ⬎21 days was found to have an effect on final outcome. Of the five eyes with a symptom to treatment interval ⬎21 days, none had a change from initial to final postoperative visual acuity (0 lines gained or lost). By the time of the initial examination, visual acuities in the fellow eyes ranged from hand motions to 20/20. Of the 42 patients enrolled in this study, 32 (76%) had visual acuities ⬍20/50 in the partner eye, including 19 (45%) eyes with ⱕ20/200 vision. Only one patient, a 50-year-old woman, had normal visual acuity (20/20) in the fellow eye. Overall, intravitreous injection of rt-PA and gas resulted in complete displacement of blood from under the fovea in 35 of 43 eyes (81%). A partial displacement of blood was found in eight eyes (19%). Typically, we observed a shift of subretinal blood inferotemporal to the macula, regardless of the size of the hemorrhage. The fundus photographs of a patient with large (30 disc areas) subfoveal hemorrhage before injection of rt-PA and gas and after therapy are shown in Figure 2. Figure 3 demonstrates a complete displacement of blood in a patient with small (ⱕ2 disc areas) subretinal hemorrhage. In eight patients (eight eyes, 19%), displacement of subretinal blood revealed a classic choroidal neovascular membrane (CNVM), with or without occult choroidal neovascularization. Of these, three underwent thermal photocoagulation for juxtafoveal CNVM. When this study was conducted, photodynamic therapy was not an available treatment option. Retrospective analysis of the fluorescein angiograms revealed that, after successful treatment with rt-PA and gas, five (12%) eyes would have met the photodynamic therapy eligibility criteria.17 Figure 4 shows the preoperative fundus photograph and the postoperative fluorescein angiogram of an eye with a subfoveal CNVM. During the course of the follow-up, nine (21%) of the eyes examined in our study had recurrent subretinal hemorrhage develop, which required repeat treatment with intravitreous rt-PA and gas. In four of these patients, visual acuity had improved by the end of the follow-up period, and in two patients a further decline in visual acuity (2 or more Snellen lines) was noted (Fig 1). This was attributed to the progression of their underlying macular disease. We observed no major intraoperative or postoperative complications. In particular, we found no evidence of retinal toxicity associated with rt-PA such as exudative retinal detachment or pigment epithelium changes. However, in three patients (7%), a mild breakthrough vitreous hemorrhage occurred within 1 day after treatment. One of these patients had received a repeat injection of rt-PA and gas. Moreover, in two eyes, an elevated intraocular pressure (22 and 24 mmHg) was observed on the first postoperative day. None of these patients, however, required treatment with antiglaucomatous medications.
™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™3
Figure 2. A, Fundus photograph of a 75-year-old man with massive subretinal hemorrhage secondary to age-related macular degeneration. B, Fundus photograph 2 weeks after treatment, demonstrating a complete displacement from the center of the fovea. Note the gas-bubble–shaped shift of subretinal blood in the perimacular region. Figure 3. A, Preoperative fundus photograph of a 78-year-old man with submacular hemorrhage involving the fovea and onset of symptoms 11 days before treatment. B, Fundus photograph of the same eye 72 hours after intravitreous injection of rt-PA and gas, demonstrating a typical displacement of blood inferotemporal to the macula. By this time, visual acuity had improved from 20/200 to 20/60. Figure 4. A, Preoperative fundus photograph of an 79-year-old male patient, showing a small subretinal hemorrhage involving the fovea. B, Fluorescein angiography 2 weeks after treatment, revealing a subfoveal choroidal neovascular lesion.
1488
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage
1489
Ophthalmology Volume 108, Number 8, August 2001
Discussion There are multiple clinical consequences of submacular hemorrhage associated with ARMD. First, most patients experience a sudden loss of vision with the onset of hemorrhage. This is particularly devastating in subjects with bilateral ARMD and reduced vision in the partner eye at the time of presentation. Therefore, strategies to hasten patients’ visual recovery or delay the progression of visual loss may lead to improvements in quality of life. Second, even small hemorrhages may obscure subretinal neovascularization amenable to further treatment. Thus, appropriate therapy such as thermal photocoagulation of juxtafoveal CNVM or photodynamic therapy in patients with classic subfoveal neovascularization may be delayed. Third, there is much evidence that subretinal hemorrhage, by itself, causes severe retinal damage. Clot retraction, iron toxicity, and blockage of nutrient diffusion are among the mechanisms that have been proposed to explain the visual loss in eyes with subretinal blood.6 –21 In our study, best visual acuity compared with preoperative visual acuity was improved 2 or more lines in 44% of cases and maintained for an average of 4.2 months, with a range of 0.5 to 12 months. After a mean follow-up time of 6 months, visual acuity was improved 2 or more lines in approximately one third of patients (30%). Our findings parallel those reported by other investigators, who found a beneficial effect of intravitreous rt-PA and pneumatic displacement in submacular hemorrhage.14,15 In a retrospective case series, Hassan et al14 investigated the efficacy of rt-PA in the treatment of thick submacular hemorrhage, which ranged in extent from 2 to 13 disc areas. They observed a complete displacement of submacular blood in 100% of eyes. By the end of a follow-up period of 4 to 19 months, final visual acuity had improved two or more lines in 67%. However, because of the small sample size and relative homogeneity of this case series, they were not able to investigate whether preoperative variables such as hemorrhage size or duration may serve as predictors of visual outcome after therapy. In a recent study by Hesse and coworkers,15 intravitreous injections of 50 to 100 g of rt-PA and gas were performed in 11 eyes with submacular hemorrhage secondary to ARMD. In their case series, visual acuity improved by 2 lines in 45.5% of eyes. By contrast to other investigators, we included subjects with small submacular hemorrhages (ⱕ2 disc areas). Although it may be suspected that such eyes have a generally better prognosis, there was no direct relationship between hemorrhage size and better postoperative visual recovery. However, among eyes with duration of hemorrhage equal to or less than 14 days and hemorrhage size ⱕ2 disc areas, 78% were observed to improve 2 or more lines of vision after treatment. Because subgroup analysis for only those cases with small hemorrhage size (ⱕ2 DA) revealed that a short time (ⱕ14 days) from onset of hemorrhage to treatment was associated with a better gain of lines of vision, we believe that this improvement is at least partially the result of an early therapeutic intervention with rt-PA and gas. Overall, eyes with a shorter symptom to treatment interval tended to have more favorable results. Among eyes with
1490
duration of hemorrhage ⱕ14 days, two thirds (67%) improved two or more Snellen lines to their best postoperative acuity compared with one third (29%) of eyes with duration of hemorrhage ⬎14 days. By the end of the follow-up period, 43% of the eyes with duration of hemorrhage ⱕ14 days had gained 2 or more Snellen lines, whereas only 18% of eyes with clots of longer duration showed a comparable outcome. Moreover, it is noteworthy that none of the eyes with a symptom to treatment interval ⬎21 days showed an improvement from initial to final postoperative visual acuity. In conclusion, it may be suggested that duration of hemorrhage has potential as a predictor of visual recovery after treatment with rt-PA and gas in subretinal hemorrhage. The better visual results in eyes with a shorter duration of hemorrhage may be explained by the time course of damaging effects associated with the formation of subretinal blood clots. In an experimental study, Glatt and Machemer6 produced subretinal hemorrhage by injecting autologous blood under the rabbit retina. They found that photoreceptors degenerated in less than 24 hours with pyknosis of the outer nuclear layer. Other investigators found evidence for clot retraction as a major cause of damage in an animal model of subretinal hemorrhage. In their studies, severe outer retinal degeneration occurred within 3 to 7 days in the rabbit retina18 and within 7 to 14 days in the cat retina.19,20 These findings highlight the potential for improved retinal survival and visual recovery if submacular blood clots can be eliminated or displaced soon after formation. The major complication seen in this series was mild breakthrough vitreous hemorrhage, which occurred in 7% of patients. Interestingly, repeat treatment with rt-PA and gas was not associated with a higher risk of hemorrhage. Moreover, we found no evidence of retinal or other intraocular toxic reactions to rt-PA in the dose used in our study (50 g). This is consistent with the findings of other investigators, who observed no definite signs of retinal toxicity in eyes injected with rt-PA.14,22,23 However, from the available data, intravitreous injections of rt-PA in high concentrations are potentially unsafe. Hesse et al15 reported exudative retinal detachment, retinal pigment epithelium hyperpigmentation, and a marked reduction in the electroretinogram postoperatively in eyes that received intravitreous rt-PA injections of 100 g but not in eyes treated with 50 g. By contrast, Hassan and colleagues14 found no evidence of retinal or other intraocular toxic reactions to rt-PA in the doses used in their study (25–100 g). Additional evidence that retinal toxicity from intravitreous commercial rt-PA is a dose-dependent problem has been provided by several experimental studies. Johnson et al24 found no toxic reactions in rabbit eyes after injections of rt-PA in a dose of 25 g. In their study, one of four eyes injected with 50 g showed localized loss of photoreceptor cells, whereas severe retinal damage was seen at higher concentrations. The toxic effect was attributed to the L-arginine vehicle of the commercially available rt-PA solution. On the assumption that the larger vitreous volume, greater vitreous liquefaction, and vascularized retina in human eyes might raise the threshold for toxicity, higher concentrations of rt-PA have been used in several clinical studies. However, just recently, Hrach and coworkers25 observed fundus pig-
Hattenbach et al 䡠 rt-PA and Gas in Submacular Hemorrhage mentary alterations and a loss of photoreceptor elements in cat eyes receiving commercial rt-PA solution in doses greater than or equal to 50 g. Because cat eyes, in contrast to those of the rabbit, have a vascularized inner retina and a vitreous volume similar to that of human eyes, they recommended avoiding intravitreal injections of rt-PA in concentrations greater than 25 g. In light of the potential damaging effects of intravitreous rt-PA, several investigators have suggested that the intravitreous injection of gas alone may be effective in displacing subretinal blood. Ohji and coworkers26 documented the beneficial effects of pneumatic displacement without rt-PA on the vision of patients with subfoveal hemorrhage. However, in their study, intravitreous gas without rt-PA failed to produce displacement in two of five cases. Moreover, four of these patients had a symptom to treatment interval of 4 to 6 days, indicating that this therapeutic approach may only be useful in eyes with recent onset of hemorrhage. There is much evidence that intravitreously injected rt-PA can migrate across the retina, thereby facilitating the dissolution of subretinal blood clots.18,19,21,24,27,28 Coll and coworkers28 found that, after intravitreous injections of rt-PA in the rabbit, subretinal blood clots disappeared within 24 hours, whereas there was no change in control eyes injected with saline solution. Experimentally, albumin, a protein with a molecular weight similar to that of rt-PA, is detectable in the subretinal space within 1 hour, suggesting that rt-PA might not be exempt from traversing the retina.29 Other investigators observed a significant enlargement of subretinal hemorrhages in a gravity-dependent manner in ARMD patients 24 hours after intravitreous injection of rt-PA.30 On the basis of their results, they postulated a causal relationship between change of hemorrhage size and subretinal clot lysis induced by rt-PA. Moreover, they concluded that the diffusion of rt-PA across the retina may be explained by retinal microlesions secondary to subretinal blood clots. A number of studies suggest that the natural course of submacular hemorrhage is associated with a poor prognosis.1–5 Avery and coworkers2 described the clinical course of eyes with subfoveal hemorrhage secondary to ARMD. After a follow-up period of 6 months, a loss of 3 or more lines of visual acuity from the baseline level was observed in 48% of eyes. In a retrospective case series, Bennett et al3 reviewed the clinical course of untreated eyes with submacular hemorrhages under the foveal avascular zone. They found that patients with subretinal hemorrhage caused by ARMD had a considerable decrease in visual acuity over time, with an average visual acuity of 20/1700 at the final follow-up visit, whereas patients with subretinal hemorrhage secondary to choroidal rupture showed a far better outcome. However, Berrocal and associates1 demonstrated that eyes with submacular hemorrhage secondary to ARMD may have spontaneous visual improvement. Interestingly, they observed no association between visual outcome and thickness or size of the hemorrhage. Overall, our data show that intravitreous rt-PA and gas have the potential to improve vision or delay the progression of visual loss for an extended period of time. During the course of our study, 91% of eyes either lost little or no
visual acuity (61%) or gained visual acuity (30%) from the baseline level. Because follow-up times varied considerably in some patients, our long-term data must be interpreted with caution. However, the fact that the proportion of patients who gained 2 or more visual acuity lines decreased from 44% to 30% within an average follow-up period of 6 months indicates that final visual outcome is limited by the progression of the underlying macular disease. Another interesting finding of our study is the observation that intravitreous rt-PA and gas may constitute a useful treatment strategy in patients with thick contiguous subretinal blood that obscures the boundaries of neovascular membranes amenable to further treatment. In particular, the ability to determine the proportion of the lesion that is classic CNV is important in photodynamic therapy or thermal photocoagulation. After successful displacement of subretinal blood, we identified eight eyes (19%) with predominantly classic CNV. Of these, three underwent photocoagulation for juxtafoveal CNVM and five had subfoveal CNV. Moreover, we identified several characteristics that may significantly affect outcome. The information presented indicates that early intravitreous rt-PA and gas injection provide a better chance for prompt recovery of useful vision in patients with recent onset of subretinal hemorrhage. This advantage seems to be clearly present in eyes with small subfoveal hemorrhages. By contrast, eyes with a longer duration of hemorrhage may have less to gain from this treatment strategy. A major limitation of this study is the lack of a control group. More research and controlled randomized trials are needed to definitively determine the benefit of this therapeutic approach. However, because no treatment exists that consistently results in improved vision in patients with submacular hemorrhage secondary to ARMD, intravitreous injection of rt-PA and gas may be recommended as a minimally invasive alternative to observation or surgical drainage.
References 1. Berrocal MH, Lewis ML, Flynn HW Jr. Variations in the clinical course of submacular hemorrhage. Am J Ophthalmol 1996;122:486 –93. 2. Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina 1996;16:183–9. 3. Bennett SR, Folk JC, Blodi CF, Klugman M. Factors prognostic of visual outcome in patients with subretinal hemorrhage. Am J Ophthalmol 1990;109:33–7. 4. Scupola A, Coscas G, Soubrane G, Balestrazzi E. Natural history of macular subretinal hemorrhage in age-related macular degeneration. Ophthalmologica 1999;213:97–102. 5. Wood WJ, Smith TR. Senile disciform macular degeneration complicated by massive hemorrhagic retinal detachment and angle closure glaucoma. Retina 1983;3:296 –303. 6. Glatt H, Machemer R. Experimental subretinal hemorrhage in rabbits. Am J Ophthalmol 1982;94:762–73. 7. de Juan E Jr, Machemer R. Vitreous surgery for hemorrhagic and fibrous complications of age-related macular degeneration [case report]. Am J Ophthalmol 1988;105:25–9.
1491
Ophthalmology Volume 108, Number 8, August 2001 8. Vander JF, Federman JL, Greven C, et al. Surgical removal of massive subretinal hemorrhage associated with age-related macular degeneration. Ophthalmology 1991;98:23–7. 9. Ibanez HE, Williams DF, Thomas MA, et al. Surgical management of submacular hemorrhage. A series of 47 consecutive cases. Arch Ophthalmol 1995;113:62–9. 10. Lim JI, Drews-Botsch C, Sternberg P Jr, et al. Submacular hemorrhage removal. Ophthalmology 1995;102:1393–99. 11. Lewis H. Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol 1994;118:559 – 68. 12. Kamei M, Tano Y, Maeno T, et al. Surgical removal of submacular hemorrhage using tissue plasminogen activator and perfluorocarbon liquid. Am J Ophthalmol 1996;121:267–75. 13. Chaudhry NA, Mieler WF, Han DP, et al. Preoperative use of tissue plasminogen activator for large submacular hemorrhage. Ophthalmic Surg Lasers 1999;30:176 – 80. 14. Hassan AS, Johnson MW, Schneiderman TE, et al. Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology 1999;106:1900 – 6; discussion 1906 –7. 15. Hesse L, Schmidt J, Kroll P. Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefes Arch Clin Exp Ophthalmol 1999;237:273–7. 16. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol 1991;109:1220 –31. 17. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials. TAP report 1. Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) Study Group [published erratum appears in Arch Ophthalmol 2000;118:488]. Arch Ophthalmol 1999;117:1329 – 45. 18. Lewis H, Resnick SC, Flannery JG, Straatsma BR. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Am J Ophthalmol 1991;111:197–204. 19. Toth CA, Morse LS, Hjelmeland LM, Landers MB III. Fibrin
1492
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
directs early retinal damage after experimental subretinal hemorrhage. Arch Ophthalmol 1991;109:723–9. Benner JD, Hay A, Landers MB III, et al. Fibrinolytic-assisted removal of experimental subretinal hemorrhage within seven days reduces outer retinal degeneration. Ophthalmology 1994; 101:672– 81. Morse LS, Benner JD, Hjelmeland LM, Landers MB III. Fibrinolysis of experimental subretinal haemorrhage without removal using tissue plasminogen activator. Br J Ophthalmol 1996;80:658 – 62. Jaffe GJ, Abrams GW, Williams GA, Han DP. Tissue plasminogen activator for postvitrectomy fibrin formation. Ophthalmology 1990;97:184 –9. Jaffe GJ, Green GDJ, McKay BS, et al. Intravitreal clearance of tissue plasminogen activator in the rabbit. Arch Ophthalmol 1988;106:969 –72. Johnson MW, Olsen KR, Hernandez E. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Retina 1991;11:250 – 8. Hrach CJ, Johnson MW, Hassan AS, et al. Retinal toxicity of commercial intravitreal tissue plasminogen activator solution in cat eyes. Arch Ophthalmol 2000; 118:659 – 63. Ohji M, Saito Y, Hayashi A, et al. Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. Arch Ophthalmol 1998;116:1326 –32. Boone DE, Boldt HC, Ross RD, et al. The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model. Retina 1996;16:518 – 24. Coll GE, Sparrow JR, Marinovic A, Chang S. Effect of intravitreal tissue plasminogen activator on experimental subretinal hemorrhage. Retina 1995;15:319 –26. Takeuchi A, Kricorian G, Yao XY, et al. The rate and source of albumin entry into saline-filled experimental retinal detachments. Invest Ophthalmol Vis Sci 1994;35:3792– 8. Hesse L, Schroeder B, Heller G, Kroll P. Quantitative effect of intravitreally injected tissue plasminogen activator and gas on subretinal hemorrhage. Retina 2000; 20:500 –5.