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Abstract
Aim To evaluate short-term and long-term outcomes of subretinal coapplication of recombinant tissue plasminogen activator (rtPA) and bevacizumab followed by intravitreal injections of bevacizumab or ranibizumab for neovascular age-related macular degeneration with submacular haemorrhage (SMH).
Methods Retrospective, consecutive, interventional case series of 41 eyes of 40 patients. All patients underwent pars plana vitrectomy with subretinal coapplication of rtPA and bevacizumab and intravitreal gas tamponade. Postoperatively, repeated intravitreal injections of bevacizumab or ranibizumab were applied following a flexible, predominantly visual acuity-driven re-treatment regimen.
Results Mean diameter of SMH was 4.5 disc diameters (range 1.5–12). Complete displacement of SMH was achieved in 35 of 41 eyes. Large and prominent SMH extending beyond the vascular arcades were completely displaced in six of eight eyes. SMH recurred in eight eyes after a mean of 9.1 months (2–19). A mean of 4.5 (2–9) intravitreal anti-vascular endothelial growth factor injections were applied during 12 months postoperatively. Short-term (3 months, n=41), mean best corrected logMAR visual acuity (BCVA) improved significantly from the preoperative value 1.7 (3.0–0.5) to 0.8 (1.6–0.2). 12 eyes had reading ability (≤logMAR 0.4) and 29 eyes had gained ambulatory visual acuity (≤logMAR 1.6). Long-term (mean 17 months (12–32), n=26) BCVA was 0.9 (1.6–0.1). Compared with short-term, BCVA had decreased in 12 of 26 eyes.
Conclusion The operation effectively displaces small and large SMHs. In the long-term, a predominantly visual acuity-driven re-treatment regimen puts the initial functional improvement at risk. More sensitive re-treatment parameters may help to improve long-term functional outcome.
- Age-related macular degeneration
- recombinant tissue plasminogen activator
- bevacizumab
- submacular haemorrhage
- macula
- treatment surgery
- imaging
- physiology
- pathology
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- Age-related macular degeneration
- recombinant tissue plasminogen activator
- bevacizumab
- submacular haemorrhage
- macula
- treatment surgery
- imaging
- physiology
- pathology
Introduction
Submacular haemorrhage (SMH) is not an unusual cause of acute central visual loss, particularly in the elderly. The most common cause is neovascular age-related macular degeneration (AMD). Without treatment, the long-term prognosis is usually poor because the underlying choroidal neovascularisation (CNV) lesion progresses and the resolution of SMH is associated with the formation of a macular scar.1 Invasive subretinal operations involving the removal of clotted submacular blood with or without CNV extraction have been abandoned because of poor functional outcome.2 3 In the early 1990s, recombinant tissue plasminogen activator (rtPA) was introduced to facilitate clot liquefaction to alleviate the trauma of subretinal manipulation. Functional improvement was reported in up to 60–80% patients, but postoperative visual acuity was <20/200 in most cases.4 With the aim of avoiding surgical manipulation of the macular retina altogether, the displacement of SMH by intravitreal injection of rtPA and gas was proposed. According to several case series, using this approach SMH was successfully displaced in 60–100% of patients.5–7 However, because of the size of the molecule it is unclear whether or not intravitreally injected rtPA penetrates the retina to reach a subretinal clot.8–11 Delivery of rtPA to the subretinal space may be ensured by subretinal injection.12–15 In a case series of 11 patients reported by Haupert et al, pars plana vitrectomy (PPV) with subretinal injection of rtPA was shown to effectively clear SMH but the procedure was associated with a 27% risk of haemorrhage recurrence.12 Olivier et al reported complete displacement of SMH in 25 of 28 patients with PPV with subretinal injection of rtPA, significant vision improvement in 17 patients and minimal complications.13 In a previous study, we have retrospectively compared PPV with either intravitreal or subretinal injection of rtPA and fluid–gas exchange. We found that subretinal injection of rtPA was more effective in terms of complete displacement of SMH. Functional improvement in the majority of our patients suggested the absence of direct retinal toxicity of subretinally applied rtPA.14
In the past, visual acuity often improved after successful displacement of SMH by rtPA and gas but frequently deteriorated because of progression of the underlying CNV. Since the advent of anti-vascular endothelial growth factor (VEGF) pharmacotherapy, new aspects have been added to the management of neovascular AMD with SMH.16 Due to the intriguing clinical results, a combined intraocular application of bevacizumab and rtPA seems to be a promising treatment for AMD with SMH. While an early application of rtPA can help to prevent an early toxic effect of SMH by effective displacement,12–14 the equally early application of anti-VEGF agents could potentially prevent CNV progression or recurrence.
We have previously reported the principal feasibility of PPV with subretinal coapplication of rtPA and bevacizumab followed by intravitreal fluid–gas exchange. The analysis included short-term outcome of 12 patients.15
As an extension of the original case series,15 the purpose of the present investigation was to evaluate efficacy and safety of PPV with subretinal coapplication of rtPA and bevacizumab with intravitreal fluid–gas exchange followed by repeated postoperative intravitreal injections of bevacizumab or ranibizumab in a greater number of patients with long-term follow-up compared with the original case series.
Patients and methods
In this retrospective, consecutive, interventional case series we reviewed the medical records of all patients with neovascular AMD complicated by SMH treated at the Department of Ophthalmology of the University Medical Center Schleswig-Holstein, Kiel, Germany, between January 2008 and January 2011. Inclusion criteria were neovascular AMD complicated by SMH involving the fovea, a maximum history of symptoms of 2 weeks and a minimum age of 18 years. Exclusion criteria were other aetiologies of SMH, massive SMH extending beyond the equator and pre-existing macular scar.
Preoperative evaluation included standard ophthalmologic examination, best corrected Snellen visual acuity (BCVA) and fundus colour photograph. Visual acuity of ‘counting fingers’ in 60 cm was equal to logMAR 2.0 and ‘hand motion’ to logMAR 3.0. Surgery was performed within 24–36 h from diagnosis. The fovea was defined as the circular area with a diameter of 1.5 mm or approximately one disc diameter in the centre of the macula.
Main outcome measures were: (1) complete displacement of SMH from the fovea, (2) change of BCVA short-term (3 months) and long-term (≥12 months) and (3) recurrence of SMH during follow-up. In all patients, the type of surgery and alternative options were explained in detail. Informed consent was obtained before surgery from all patients. Ethics committee approval was obtained.
Surgical technique
All patients underwent standard three-port PPV with induction of posterior hyaloid detachment if not already present, subretinal injection of 10–20 μg rtPA (Actilyse, Boehringer Ingelheim, Germany) dissolved in 0.05–0.1 ml balanced salt solution (BSS) followed by subretinal injection of 1.25 mg bevacizumab (Avastin, Roche, Basel, Switzerland) dissolved in 0.05 ml BSS through a 41-gauge subretinal flexible cannula (D.O.R.C., Zuidland, The Netherlands) and fluid–gas exchange with 20%-SF6 gas to a complete intravitreal fill. Phakic patients underwent concomitant standard small incision cataract surgery. Patients were instructed to keep a prone position for at least 1 day postoperatively. All patients were operated by the same surgeon (JH).
Follow-up and postoperative anti-VEGF re-injection scheme
Short-term follow-up (4 weeks and 3 months postoperative) and long-term follow-up (≥12 months postoperative) included BCVA, fundus colour photograph and fluorescein angiography. Bevacizumab (1.25 mg) was administered for 4 weeks intravitreally and for 8 weeks postoperatively. Thereafter, repeated intravitreal injections of either bevacizumab or 0.5 mg ranibizumab (Lucentis, Novartis, Nürnberg, Germany) were applied following a previously described flexible, predominantly visual acuity-driven re-treatment regimen commonly applied in clinical practice in Germany. This included a decrease of BCVA and/or increase in retinal thickness on optical coherence tomography (OCT) (central retinal thickness >100 μm) and/or if new leakage on fluorescein angiography and/or if new retinal haemorrhages developed.17
Statistical methods
In the statistical analysis of the outcome measures, type I error (α) was set at 0.05. Statistical significance of differences before and after surgery was calculated using the Wilcoxon test. The results were analysed using SPSS V.15.0 software (SPSS Inc.) and Statistica V.7 software (StatSoft Inc.).
Results
Table 1 summarises the relevant patient data. Between January 2008 and January 2011, we operated a total number of 51 eyes of 50 patients. Four patients were excluded from the data analysis because of pre-existing macular scar, one patient was excluded because SMH was caused by retinal macroaneurysm and five patients were lost to follow-up. Forty-one eyes of 40 patients (25 female, 15 male) were included in the data analysis. Short-term follow-up was completed for 41 eyes and long-term follow-up was completed for 26 eyes. Six patients did not keep follow-up appointments. Mean age was 77 years (SD=7, range 64–90). The mean history of symptoms was 4.0 days (SD=3.2, range 1–14) and the mean maximal diameter of SMH was 4.5 disc diameters (SD=2.5, range 1.5–12). Eighteen patients were treated with systemic anticoagulation and two patients had thrombocytopenia. One patient presented with vitreous haemorrhage and one 74-year-old patient presented with drusen and high myopia. Eleven patients had received one to six intravitreal injections of bevacizumab or ranibizumab several weeks to months prior to the occurrence of SMH. All the other patients did not receive any treatment for AMD prior to the occurrence of SMH. At presentation, the degree of lens opacity was described as mild in all phakic patients and one patient refused concomitant cataract surgery. Intraoperatively, we observed minimal or no reflux of the subretinally injected solutions through the small retinotomy created by the 41-gauge cannula. The subretinally injected volume produced a dome-shaped retinal elevation which remained unchanged intraoperatively after fluid–air exchange.
Patients' data
Displacement of SMH
Complete displacement of SMH from the fovea was achieved in 35 of 41 eyes. Large and prominent SMH extending beyond the vascular arcades were completely displaced in six of eight cases (figure 1, table 1).
Representative fundus photographs preoperative and 4 weeks postoperative demonstrating complete displacement of large submacular haemorrhage extending beyond the vascular arcades. Early and late phase fluorescein angiography revealed occult choroidal neovascularisation. Patient 1 (A–D): best corrected logMAR visual acuity (BCVA) preoperative=‘hand motion’, 3 months postoperative=0.7 logMAR. Patient 2 (E–H): BCVA preoperative=1.3 logMAR, 3 months postoperative=0.4 logMAR. Patient 3 (I–L): BCVA preoperative=1.0 logMAR, 3 months postoperative=0.8 logMAR.
BCVA
Short-term (n=41): BCVA improved significantly from preoperative logMAR 1.7 (range 3.0–0.5) to logMAR 1.0 (range 2.0–0.3) at 1 month postoperative (p=0.0005) and to logMAR 0.8 (range 1.6–0.2) at 3 months postoperative (p=0.0001). At 3 months postoperative, 12 eyes had gained reading ability (≤logMAR 0.4) and 29 eyes had gained ambulatory visual acuity (≤logMAR 1.6). As compared with the preoperative situation, BCVA had improved in 33 eyes, remained unchanged in 4 eyes and worsened in 4 eyes (table 2, figure 2A).
Visual acuity (VA) preoperatively and during short-term and long-term follow-up
Scatterplots comparing preoperative and postoperative best corrected logMAR visual acuity (BCVA) at 3 months follow-up (A), 12 months follow-up (B), final follow-up (mean 17 months, range 12–32) (C) and comparing BCVA at 3 months postoperative with final follow-up (D).
Long-term (n= 26): At 12 months postoperative mean BCVA was logMAR 0.8 (range 1.6–0.1). Ten eyes had reading ability (≤logMAR 0.4) and 16 eyes ambulatory visual acuity (≤logMAR 1.6). As compared with the preoperative situation, BCVA had improved in 22 eyes, remained stable in 2 eyes and worsened in 2 eyes. As compared with 3 months postoperative, BCVA had improved in 7 eyes, remained stable in 8 eyes and decreased in 11 eyes.
At final follow-up (mean 17 months, range 12–32), mean BCVA was logMAR 0.9 (range 1.6–0.1). Eight eyes had reading ability (≤logMAR 0.4) and 18 eyes ambulatory visual acuity (≤logMAR 1.6). As compared with the preoperative situation, BCVA had increased in 21 eyes, remained stable in 3 eyes and decreased in 2 eyes. As compared with 3 months postoperative, BCVA had improved in 8 eyes, remained stable in 6 eyes and decreased in 12 eyes (table 2, figure 2B–D).
Recurrence of SMH
SMH recurred in eight eyes after a mean of 9.1 months (range 3–19). In seven of these eyes the patients were either treated with systemic anticoagulation (n=5) or had thrombocytopenia (n=2). Recurrent SMH led to a decrease of BCVA from mean logMAR 0.5 (range 0.1–0.7) to 1.4 (range 1–1.6). Six of eight affected eyes were re-treated with the initial operation while two patients refused the re-operation. In five of six re-operated eyes SMH was successfully displaced from the fovea while BCVA improved in three of six eyes. Mean BCVA of eyes with recurrent SMH before re-operation was 1.4 (range 1–1.6) and 1.1 (range 0.3–1.6) after the re-operation.
Postoperative anti-VEGF injections
At 12 months postoperative, 25 of 26 eyes had received a mean of 4.5 (2–9) postoperative intravitreal injections of bevacizumab or ranibizumab.
Complications
In one eye, a circumscribed semi-circle shaped rip of the retinal pigment epithelium (RPE) was caused by the inadvertent injection of the rtPA and bevacizumab solution into the sub-RPE space. It seems likely that the SMH was located at least partially under the RPE as a haemorrhagic RPE detachment. In another eye, a secondary macular hole developed at the fovea during subretinal injection, apparently caused by the mechanical stress applied to the retinal tissue by the volume of the solution. Rhegmatogenous retinal detachment occurred in one eye.
Discussion
The main findings of this study are: (1) successful complete displacement of small and large SMH from the fovea in 35 of 41 patients, (2) significant mean functional improvement after three applications of bevacizumab at 3 months follow-up and (3) loss of initial functional improvement in approximately 50% of patients with a predominantly visual acuity-driven anti-VEGF re-treatment regimen long-term after surgery.
In 24 of 25 phakic eyes, improvement of BCVA may have been caused to some degree by concomitant cataract surgery. Systematic preoperative cataract grading was not performed; however, the contribution of cataract surgery to the overall change of BCVA was probably small because the degree of lens opacity was described as mild in all phakic patients.
In neovascular AMD with SMH the functional outcome largely depends on the extent of the underlying CNV which could be a reason for the scatter of BCVA in this study (figure 2) as well as in other studies.6 12–15 18 19 Successful displacement of SMH in neovascular AMD and significant functional improvement have been reported after intravitreal injection of gas without rtPA,18 after intravitreal injection of rtPA and gas,5–7 after PPV with subretinal injection of rtPA and fluid–gas exchange,12–14 and after intravitreal injection of rtPA, bevacizumab and gas.18 To date, there is no consensus regarding an optimal treatment for SMH or the key factors determining the outcome. Since studies evaluating different treatments of SMH have been either retrospective, uncontrolled case series with a limited number of patients2 4–7 12 13 15 18 19 or non-randomised, retrospective comparative case series14 with a weak level of evidence, the results cannot be directly compared with the present case series.
Because of the size of the rtPA molecule, it is unclear whether or not intravitreally injected rtPA penetrates the retina to reach a subretinal clot.8–11 The rtPA molecule exceeds the experimentally determined molecular exclusion limit of human retina.10 Indeed, in the experiments of Kamei et al, rtPA injected into the vitreous of rabbits failed to pass through the intact retina.8 On the other hand, molecules with similar molecular weight (eg, albumin) have been shown to penetrate the diseased retina.9 Heiduschka et al demonstrated that bevacizumab, which also exceeds the molecular exclusion limit of the retina, passed through the intact retina of cynomolgus monkeys.11 However, although bevacizumab traverses the retina it probably does so only at a slow rate because of its size. While intravitreal application of bevacizumab may suffice to produce a therapeutic response, subretinal application ensures the delivery of the drug directly at the site of the CNV and may enhance its effect. Furthermore, we chose subretinal instead of intravitreal application because the pharmacokinetics of bevacizumab in a vitrectomised, gas-filled eye is unknown and because retinal damage from SMH may alter permeability.
We injected 1.25 mg bevacizumab dissolved in a total volume of 0.1 ml BSS subretinally into the SMH. Taking the varying volume of SMHs into account this leads to a concentration of bevacizumab of several milligram/millilitre in the subretinal space. This concentration is far greater than that following intravitreal injection and probably in excess of what is needed to inhibit VEGF. On the other hand, the pharmacokinetics of subretinally injected bevacizmab is unknown and we do not know the optimal concentration. However, the observed absence of geographic atrophy or signs of retinal degeneration and, most importantly, functional improvement in most patients in the present study point towards a tolerance of highly concentrated bevacizumab in the subretinal space.
Intraoperative complications occurred rarely and mainly in the early phase during our learning curve. We recommend preoperative OCT imaging to localise RPE detachment in order to avoid inadvertent puncture of the RPE with subsequent RPE rip. Subretinal injection should be performed slowly with a maximal total volume of 0.1 ml in order to avoid rupture of retinal tissue at the fovea, the point of least mechanical resistance.
In accordance with reports of anti-VEGF injection schemes for neovascular AMD without SMH17 20 our results suggest that a predominantly function-driven postoperative anti-VEGF retreatment concept puts the initial functional improvement at severe risk. It appears that in neovascular AMD, following initiation of anti-VEGF treatment, morphological changes precede functional changes as indicators of recurrence.21 Because recurrent functional loss is less than fully reversible, an improved strict re-treatment regimen which prioritises OCT-based morphological criteria over functional criteria with early re-treatment when any subretinal or intraretinal oedema persists may lead to better long-term functional results.21 22
Eighteen patients in this study were on anticoagulation treatment and two patients had a coagulation disorder. Our results suggest that anticoagulation is probably a risk factor for development and recurrence of SMH. Seven of eight SMH recurrences occurred in patients either with systemic anticoagulation or with thrombocytopenia. The risk of recurrence may be reduced by early CNV regression induced by the simultaneous application of bevacizumab. Principally, the initial operation can be repeated in case of SMH recurrence. In the present study, recurrent SMH was successfully displaced in five of six eyes; however, functional improvement was limited. Since recurrences occurred during an extended period after surgery we recommend a strict postoperative anti-VEGF re-treatment regimen and, if possible, discontinuation of systemic anticoagulation, especially in only-eye situations.
In conclusion, PPV with subretinal coapplication of rtPA and bevacizumab followed by fluid–gas exchange for neovascular AMD complicated by SMH is a safe and effective treatment. More sensitive OCT-based morphological anti-VEGF re-treatment parameters may help to improve long-term functional outcome. Weaknesses of the present study include its retrospective character and the absence of a control group.
References
Footnotes
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None.
Ethics approval Ethics Committee of the University Medical Center Schleswig-Holstein, Campus Kiel.
Provenance and peer review Not commissioned; externally peer reviewed.