Management of submacular hemorrhage with intravitreal versus subretinal injection of recombinant tissue plasminogen activator

Aim  

To compare the efficacy of pars plana vitrectomy (ppV) with intravitreal injection of recombinant tissue plasminogen activator (rtPA) and gas versus ppV with subretinal injection of rtPA and intravitreal injection of gas.     

Induction of posterior vitreous detachment in rabbits by intravitreal injection of tissue plasminogen activator following cryopexy

The purpose of this study was to generate intravitreal plasmin after intravitreal injection of tissue plasminogen activator (TPA) and cryopexy, and to assess its proteolytic effect on the vitreoretinal border region.Twenty-four hr after a mild cryopexy, 25 microg recombinant tissue plasminogen activator (TPA) was injected into the vitreous cavity, the fellow eye received an intravitreal injection of the same volume of buffered salt solution. Light, scanning and transmission electron microscopy was performed in 24 eyes that underwent vitrectomy 1 week later. Plasmin was measured prior and 2 hr after intravitreal TPA injection (4 eyes). Hyaluronic acid (8 eyes) and vitronectin (4 eyes) were measured 1 week after TPA- or BSS-injection and compared to untreated controls.In all eyes treated with TPA, histopathologic examination by scanning and transmission electron microscopy demonstrated a complete detachment of the vitreous from the surface of the retina as well as from the posterior surface of the lens. After BSS-injection, vitreous cortex attachment to the retina was demonstrated in all eyes. Two hr after TPA-injection, plasmin increased to 9.75 mU ml(-1)(s.d.+/-2.3). Neither a decrease of hyaluronic acid nor an increase of transglutaminase, that might alter the vitreous structure leading to a collapse of the vitreous, were detected in treated eyes. There was no increase of vitronectin indicating proliferative activity.A temporary breakdown of the blood-retinal barrier by cryopexy combined with intravitreal injection of TPA is a sufficient technique to induce a posterior vitreous detachment enzymatically. The method may be useful prior to mechanical vitrectomy.     

Pars plana vitrectomy with peripheral retinotomy after injection of preoperative intravitreal tissue plasminogen activator: a modified procedure to drain massive subretinal haemorrhage

AIMS: To report outcome of a modified procedure for draining massive subretinal haemorrhages (SRHs). METHODS: The charts of eight consecutive eyes from eight patients with massive SRHs extending to the periphery and involving two or more quadrants with haemorrhagic and bullous retinal detachment were reviewed. Tissue plasminogen activator (tPA) was injected intravitreally 12-24 h preoperatively; vitrectomy was carried out with peripheral retinotomy, drainage of the SRH from the retinotomy using perfluorocarbon liquid and gas tamponade with prone positioning postoperatively. RESULTS: The preoperative visual acuities ranged from light perception to 20/200. Most of the subretinal haematomas moved postoperatively to the vitreous cavity through the peripheral retinotomy using perfluorocarbon liquid. Residual SRHs were drained from the anterior chamber at the bedside after prone positioning overnight. SRH recurred in one eye 14 months postoperatively and was successfully retreated. No other serious complications developed. The final visual acuity improved in seven eyes (range 20/1000-20/60). Polypoidal lesions in choroidal vasculatures were present in three of seven patients. CONCLUSIONS: The technique seems safe and effective for treating massive SRH. However, visual recovery is limited by the underlying macular pathology. Polypoidal choroidal vasculopathy, other than age-related macular degeneration, may be another cause of massive SRHs.     

Electrophysiological evaluation of the safety of injection of tissue plasminogen activator into optic nerve in rabbits

AIM: To investigate the safety of tissue plasminogen activator (tPA) intra optic nerve injection in rabbits. METHODS: Group 1 and 2 (6 eyes in each group) received injection of tPA 25μg and 12.5μg in 0.1mL balanced saline solution (BSS). Group 3 (6 eyes) received injection of 0.1mL BSS. Six eyes in Group 4 as a normal control received no injection. The eyes were examined with slit lamp biomicroscope, indirect ophthalmoscope, visual evoked potentials (VEP) and electroretinography (ERG) at 1, 3, 7, 14 and 28 days after injection. RESULTS: No evidence of optic nerve or retinal toxicity or physical damage were revealed by ophthalmoscopy, VEP, and ERGs after the injection of tPA into the optic nerve. The means of the latency of the first peak of the VEP were 24.6±1.5, 24.1±1.9, 24.0±2.0 and 24.6±1.3mS respectively for the above specified groups (P =0.4112). The means of the amplitude of the first peak of the VEPs were 124±42, 145±41, 132±48 and 117±29μV respectively (P =0.0649). The means of the latency of a-waves were 6.0±0.4, 5.9±0.4, 5.9±0.5 and 5.8±0.3mS respectively (P =0.6279). The means of the amplitude of a-waves were 110±14, 112±15, 110±16 and 108?1μV respectively (P =0.7248). The means of the amplitude of b-waves were 151±12, 148±14, 144±16 and 141?0μV respectively (P =0.0957). CONCLUSION: Injection of tPA upto 25μg in 0.1mL into optic nerve is well tolerated.     

视盘内注射组织凝血酶原激活剂安全性的电生理学评价(英文)

目的:探讨视盘内注射组织凝血酶原激活剂的电生理学安全性。方法:首先将记录VEP的电极植入兔颅骨内。经兔睫状体扁平部将25μg tPA,12.5μg tPA及BSS注入视神经内0.1mL,并与第四组正常眼作比较(n=6)。注入后1,3,7,14和24d行裂隙灯及间接眼底镜检查,记录VEP及ERG。结果:检查未发现视神经内注射tPA对视神经和视网膜有明显的毒性作用和其它损伤。各组VEP第1个波峰的潜伏期分别是24.6±1.5, 24.1±1.9, 24.0±2.0和24.6±1.3mS(P=0.4112);振幅分别是124±42, 145±41, 132±48和117±29μV(P=0.0649)。各组ERG的a波的潜伏期分别是6.0±0.4, 5.9±0.4, 5.9±0.5和5.8±0.3mS(P=0.6279);振幅分别是110±14, 112±15, 110±16和108±11μV(P=0.7248)。b波的振幅分别是151±12,148±14, 144±16和141±20μV(P=0.0957)。结论:经睫状体扁平部向兔视神经内注射tPA,安全可行。     

Treatment of subretinal hemorrhages with tissue plasminogen activator

Submacular hemorrhages pose a danger to visual acuity. Intervention may help prevent or mitigate severe visual loss. Pneumatic displacement and vitrectomy with direct evacuation are two methods of treating submacular hemorrhages. Tissue plasminogen activator may be an important adjunct to these techniques.     

Intravitreal and subretinal injection of tissue plasminogen activator (tPA) in the treatment of experimentally created retinal vein occlusion in rabbits

PURPOSE: To evaluate the effectiveness of intravitreal or subretinal injection of tPA in the treatment of experimentally created retinal vein occlusion (RVO) in rabbits. METHODS: Fifteen rabbits were included in this study. RVO was created in all using an argon green laser following intravenous injection of rose Bengal. Follow-up examinations included color fundus photography, fundus fluorescein angiography, and optical coherence tomography. Following examinations at day 2, animals were divided into three groups: six rabbits were kept as control, four rabbits received subretinal injection of tPA, and five rabbits received intravitreal tPA. RESULTS: Of 14 eyes that had capillary drop out at day 2 following creation of RVO, 12 remained the same at week 3. Only one eye in the control group and one eye in the subretinal group developed complete reperfusion of capillaries. Although there was more revascularization in all groups at week 3, there was not a significant difference in the amount of revascularization between the control group and those animals receiving subretinal or intravitreal tPA. CONCLUSION: Intravitreal or subretinal injection of tPA 2 days following vein occlusion did not improve reperfusion of retinal vessels in experimentally created RVO in rabbits when compared to control group.     

Efficacy and toxic effect associated with subretinal tissue plasminogen activator injection in treating submacular hemorrhage

AIM: To review the demographics, clinical manifestations, and surgical experiences of patients with congenital ocular counter-roll, whose treatments were performed exclusively by ophthalmologists. METHODS: A retrospective review was conducted consisting of patients who received strabismus surgery between 2017 to 2019. Patients with obvious ocular counter-roll were included. RESULTS: A total of 7008 patients who received strabismus surgery, 28 (12 males, 16 females) were diagnosed as congenital ocular counter-roll, accounting for 0.40%. All patients were initially misdiagnosed: 21 patients were misdiagnosed as superior oblique palsy (SOP), 3 as inferior oblique overaction, 2 as dissociated vertical deviation (DVD), 1 as superior oblique overaction with A-pattern exotropia, and 1 as medial rectus palsy. The mean±SD age was 12.4±9.4y (range 2.5-36y). The most common clinical findings included ocular counter-roll, vertical deviation or vertical deviation combined with outward deviation and head tilt. At follow-up, an excellent surgical result was achieved in 20 patients. Preoperative horizontal deviation of 26±24 PD and vertical deviation of 18±12 PD were reduced to 0±12 PD (P=0.0001) and 3±4 PD (P=0.001), respectively. CONCLUSION: Congenital ocular counter-roll is a rare supranuclear vertical strabismus caused by congenital abnormalities involving vestibule-ocular reflex pathways. In addition to ocular counter-roll, the most salient clinical features included, but were not limited to, hyperdeviation, outward deviation, overelevation in adduction and head tilt.     

Management of submacular hemorrhage with intravitreal injection of tissue plasminogen activator and expansile gas

PURPOSE: To evaluate the clinical outcome of intravitreal tissue plasminogen activator (tPA) and expansile gas injection as a minimally invasive treatment for submacular hemorrhage (SMH). METHODS: This study was a retrospective clinical case series examining 104 eyes that received an intravitreal injection of 30-100 mcg of tPA and expansile gas (SF6 or C3F8) for SMH. The main outcomes evaluated were visual acuities (VA), anatomic displacement of submacular blood, and surgical complications. RESULTS:: A total of 85, 77, and 81 eyes were available at 1 week, 3 months, and 12 months follow up, respectively. Postoperatively, > or = 2 Snellen lines improvement were achieved in 43/85 eyes (51%) at 1 week, 49/77 eyes (63%) at 3 months, and 52/81 eyes (64%) at 12 months. Postoperative VA improvement was significantly associated with preoperative VA, submacular blood displacement, and the underlying cause of SMH. Diagnostic postoperative angiogram and clinical examination were possible at 8.2 +/- 7.4 weeks and 9.5 +/- 7.4 weeks, respectively. The observed complications included breakthrough vitreous hemorrhage in 8 eyes (8%) and retinal detachment in 3 eyes (3%). CONCLUSIONS: In this retrospective series, intravitreal injection of tPA and expansile gas was shown to be a safe and effective technique that can improve VA in most eyes with SMH and assist in the diagnosis of the underlying cause.     

Results of intravitreal tissue plasminogen activator and expansile gas injection for submacular haemorrhage in Thais

PURPOSE: To study the results of intravitreal tissue plasminogen activator (tPA) and expansile gas injection for submacular haemorrhage in Thai patients. METHODS: The medical records of Thai patients who presented with submacular haemorrhage between January 1998 and December 2002 were reviewed. The inclusion criteria were acute onset of bleeding (<1 month), treatment with intravitreal injection of tPA solution (50-100 mug in 0.1 ml) and expansile gas (0.3-0.4 ml of 100% perfluoropropane or sulphur hexafluoride), and at least 6 months of follow-up. Our main outcome measures were best final postoperative visual acuity and surgical complications. RESULTS: A total of 19 eyes of 19 patients completed the inclusion criteria with a mean duration of 13.1 days. The causes of haemorrhage were age-related macular degeneration in 15 eyes (78.9%), idiopathic choroidal neovascularization in two eyes (10.5%), and traumatic, and valsalva retinopathy in one eye each (5.2%). After a mean follow-up of 13 months (range 6-39 months), postoperative visual acuity improved two lines or greater in 12 eyes (63.2%), stabilized in six eyes (31.6%) and worsened in one (5.2%). The final visual acuity measured 20/63 or better in 10 eyes (52.6%). The surgical complications were breakthrough vitreous haemorrhage (three eyes) and cataracts (three eyes), and two had retinal detachments. CONCLUSION: The treatment of submacular haemorrhage with intravitreal injection of tPA and expansile gas improved visual acuity in more than half of the patients. In all, 10 in 19 eyes demonstrated final visual acuity at a functional level.     

Intravitreal injection of tissue plasminogen activator and gas in subretinal hemorrhage caused by age-related macular degeneration

PURPOSE: To assess the efficacy and safety of intravitreal injection of recombinant tissue plasminogen activator and sulfur hexafluoride gas for displacement of subretinal hemorrhages in patients with age-related macular degeneration. METHODS: The authors injected 25 microg of recombinant tissue plasminogen activator and 0.5 mL sulfur hexafluoride gas intravitreally in 11 patients with subretinal hemorrhages of less than 3 weeks duration. Anatomic and functional results were evaluated. RESULTS: Displacement of subretinal blood was successful within the first week after surgery in 10 of 11 patients. This was accompanied by visual improvement in eight patients. After 1 year, visual acuity was better than before surgery in five patients. Diagnosis of a choroidal neovascularization by fluorescein angiography was possible in all patients, and was treated with laser photocoagulation in five. The authors observed no adverse effects of treatment. CONCLUSION: Recombinant tissue plasminogen activator and gas effectively displace subretinal blood in patients with age-related macular degeneration. Randomized studies are necessary to prove the benefit of this simple and safe method in patients with subretinal hemorrhage due to age-related macular degeneration.     

Treatment of experimental intravitreal fibrin with tissue plasminogen activator

We produced experimental intravitreal fibrin clots in rabbits that had previous gas compression of the vitreous or intact vitreous. Twenty-four hours after production of fibrin, the eyes were injected with 25 micrograms of tissue plasminogen activator or physiologic irrigation solution. In the gas compression group (n = 11), all tissue plasminogen activator-treated eyes cleared within six hours of injection; complete clearing was not seen until six days in the physiologic irrigation solution-treated eyes (n = 9). A similar response was seen in the intact vitreous group. No evidence of toxicity was observed as measured by slit-lamp biomicroscopy, intraocular pressure, corneal thickness, electroretinography, or histopathologic examination.     

Resolution of experimental intravitreal fibrin by tissue plasminogen activator

Intravitreal fibrin clots were produced by intravitreal injection of 0.2 ml of autologous plasma in 62 rabbit eyes. The intravitreal injection of 0.25 micrograms or more of tissue plasminogen activator(tPA) resulted in a total clearing of intravitreal fibrin within one day in all treated eyes. This was significantly faster than in the control eyes, in which complete clearing was not seen until 8 days later. This represents the plateau on the dose-response curve in doses ranging from 0.25 to 200 micrograms. With light microscopy and transmission electron microscopy, retinal toxicity was demonstrated in eyes enucleated seven days after injection of 25 micrograms or more of tPA. This study demonstrates that tPA was effective and safe at 12.5 micrograms or less in clearing intravitreal fibrin in an experimental model. These results suggest that low dosages of tPA, probably of 3 micrograms or less, may be useful in the treatment of severe postvitrectomy fibrin formation seen clinically.     

视盘内注射组织凝血酶元激活剂安全性的电生理学评价

目的探讨视盘内注射组织凝血酶元激活剂（tPA）的安全性和可行性。方法经兔睫状体扁平部将0．1mL tPA或者BSS注入视神经内研究其安全性和可行性。白色家兔共24只,分为4组,每组6只兔（6只眼）。视觉诱发电位（VEP）的记录电极植入兔颅骨内。每组分别注入25μg tPA、12．5μg tPA及BSS,6只正常眼不做任何处理。分别在注药后的第1天、3天,1、2和4周行裂隙灯及间接检眼镜检查,记录闪光视觉诱发电位（F-VEP）及闪光视网膜电图（F-ERG）结果。结果经裂隙灯、间接检眼镜、F-VEP、F—ERG检查视神经内注射tPA后未发现视神经和视网膜有明显的毒性作用和其他损伤。各组VEP P1的隐含时分别为（24．60±1．54）、（24．09±1．92）、（24．01±1．96）、（24．57±1．25）ms,差异无统计学意义（P=0．411）;各组VEPP,振幅分别为（123．91±41．77）、（145．16±41．22）、（132．36±48．22）、（116．78±29．44）μV,差异无统计学意义（P=0．065）。各组ERGa波的隐含时分别为（5．95±0．42）、（5．86±0.41）、（5．87±0．46）、（5．81±0．33）ms,差异无统计学意义（P=0．627）;a波的振幅分别为（110．28±13．91）、（111．97±15．28）、（109．73±15．90）、（107．74±10．87）μV,差异无统计学意义（P=0．725）;b波的隐含时分别为（41．58±6．46）、（40．87±5．88）、（40．52±6．24）、（41．60±6．67）ms,差异无统计学意义（P=0．257）;b波的振幅分别为（150．80±11．86）、（147．59±13．60）、（144．52±16．54）、（141．00±20．46）μV,差异无统计学意义（P=0．096）。结论经睫状体扁平部向兔视神经内注射tPA操作简单、安全可行,有望成为局部药物治疗视网膜中央静脉阻塞的新方法。     

Intravitreal injection of tissue plasminogen activator and gas bubble for treatment of subretinal hemorrhage in ARMD.

BACKGROUND: Subretinal hemorrhage (SRH) can arise from any number of underlying etiologies and can stem from either the choroidal and/or retinal circulation. It is most commonly associated with age-related macular degeneration (ARMD), in which a choroidal neovascular membrane is the usual source of bleeding. Vision loss resulting from SRH can be secondary to toxic, tractional, and barrier effects from persistent blood. To minimize long-term visual loss from SRH, several treatment modalities have evolved over the past few years. The most-recent therapeutic techniques involve treatment with the thrombolytic agent tissue plasminogen activator The value of surgical removal of subretinal hemorrhage to improve visual outcome remains unsubstantiated, as definitive studies have not been completed. CASE REPORT: A 73-year-old man manifested a 1-day history of decreased vision in his right eye. A large submacular hemorrhage had developed as a result of exudative age-related macular degeneration. Treatment included intravitreal injection of tissue plasminogen activator, followed by intravitreal injection of SF6 gas, which displaced the subretinal hemorrhage away from the fovea and resulted in clearance of the submacular blood. This case describes a new treatment for submacular hemorrhage secondary to ARMD. CONCLUSIONS: Subretinal hemorrhage secondary to ARMD can cause significant permanent visual loss. A thorough understanding of the pathogenesis of vision loss and the treatment options available are essential in successful management of these patients. Intravitreal injection of tissue plasminogen activator and gas bubble may provide an effective treatment for subretinal hemorrhage in age-related macular degeneration.     

Combined treatment of acute subretinal haemorrhages with intravitreal recombined tissue plasminogen activator,expansile gas and bevacizumab: a retrospective pilot study

Purpose: To assess the effectiveness of consecutive intravitreal injections of recombined tissue plasminogen activator (rtPA), expansile gas and bevacizumab in eyes with acute subretinal haemorrhage (SRH). Methods: A retrospective, non‐randomized consecutive case series included 19 eyes in 19 patients with SRH related to exudative age‐related macular degeneration (AMD). The initial size of the subfoveal SRH was 1–3 disc diameters. Each patient received a triple procedure using 0.05 ml rtPA (50 μg), 0.3 ml of sulphur hexafluoride (SF6) gas and 0.05 ml bevacizumab (1.25 mg). Lesion size, location of the SRH and early treatment in diabetic retinopathy study (ETDRS) visual acuity were evaluated pretreatment as well as 1 and 3 months after the procedure. Results: At the initial presentation, the patients’ mean age was 77 years (range 63–88 years) and the mean duration of symptoms was 9.3 days (range 4–12 days). The mean visual acuity pretreatment (20/133) improved significantly to 20/86 at 1 month and to 20/74 at 3 months. The mean ETDRS visual acuity improved from baseline by 2.1 lines at 1 month (Wilcoxon ranks test; P < 0.005) and 3.7 lines at 3 months after treatment (Wilcoxon ranks test; P < 0.005). None of our patients had reading visual acuity prior to treatment, with visual acuity below 0.3. One month after the triple procedure, 25% of our patients had reading visual acuity (≥ 0.4); at 3 months, the figure was 35%. A successful inferior displacement of the SRH was achieved in 17/19 eyes. Eyes with elevated intraocular pressure were treated immediately by a corneal paracentesis. Conclusion: The intravitreal application of rtPA, gas and bevacizumab appears to be beneficial and well tolerated in the treatment of SRH in the short term. The triple approach seems a logical alternative to the current combined dual approach in limiting the progression of the underlying disease and achieving better visual outcome. Further randomized evaluations are warranted.     

Effects of indocyanine green injection on the retinal surface and into the subretinal space in rabbits

PURPOSE: To evaluate the effects of indocyanine green (ICG) injection on the retinal surface and into the subretinal space of rabbit eyes. METHODS: Twenty-two Dutch-belted rabbits underwent two-port vitrectomy followed by injection of ICG (5 mg/mL) on the retinal surface and into the subretinal space. Balanced salt solution (BSS) was also injected subretinally. The locations where ICG was delivered (both epiretinal and subretinal) were exposed to light from an endoilluminator for 7 minutes. The animals were examined at 1, 7, and 14 days after surgery. The eyes were studied by fluorescein angiography as well as light and electron microscopy. RESULTS: No damage was observed after epiretinal ICG injection, but subretinal ICG injection resulted in damage to the outer nuclear layer, photoreceptor inner and outer segments, and retinal pigment epithelium. This damage was more severe with longer follow-up. Control experiments without ICG, in which balanced salt solution was injected into the subretinal space or light was delivered on the epiretinal surface, demonstrated only damage to the photoreceptor outer segments. CONCLUSION: Subretinal delivery of ICG (5 mg/mL) in rabbits induces retinal pigment epithelium, photoreceptor inner and outer segment, and outer nuclear layer damage. These mechanisms of damage may explain the retinal pigment epithelium changes that are sometimes seen after ICG-assisted internal limiting membrane peeling in humans.