Bilateral Intravitreal Injections Research Articles

Bedside bilateral sequential intravitreal anti-VEGF injections for retinopathy of prematurity.

To evaluate the outcome and ocular adverse events of bedside bilateral sequential intravitreal anti-vascular endothelial growth factor injections for retinopathy of prematurity (ROP) (BBSIR). This retrospective interventional study included infants who received BBSIR with a follow-up of at least 1 month. Clinical history, intravitreal injection details, indications, intraoperative and postoperative ocular adverse events, and outcomes were analyzed. The study cohort included 192 babies (384 eyes) spread over 9 years. The mean gestational age was 30.2 ± 2.6 weeks (28.8-34.1), and the birth weight was 1098.11 ± 271.65 g (650-2000). The indications for BBSIR were as follows: 73.4% (n = 141 infants) were too sick to transfer to an ophthalmic unit, 10.9% (n = 21 infants) due to the parents' inconvenience of traveling to the ophthalmic center, and 15. 6% (n = 30 infants) due to both reasons. The injections were given by an ROP specialist/ROP-trained ophthalmologist after due parental consent, considering each eye as a fresh eye with separate scrubbing and draping. Light from the head-worn indirect ophthalmoscope served as the source of illumination. The retinopathy was regressing/regressed in 92.4% of babies until the last follow-up. The major ocular complication was cataract in 2 eyes (0.5%). There was no incidence of endophthalmitis till last follow-up (median 5.7 months). As per this study, BBSIR was observed to be effective and safe if given by those fully trained in the management of ROP. Though the rate of complications like cataract is small, they can pose management challenges and impact vision in a growing child.

Different Retinopathy of Prematurity Severity, Onset Therapy and Outcomes in Triplet Babies: A Case Report

Introduction : Retinopathy of prematurity (ROP) is a vasoproliferative disease of the premature infants, characterized by abnormal vascularization at the junction of vascular and avascular retina. Intravitreal anti-VEGF injection is one of promising management of ROP. The aim is to present the therapy outcomes of triplet babies with different severity and onset therapy.
 Case Illustration : This case shows ROP in triplets born at 25-26 weeks gestational age. First baby, weighed 630 g with Bilateral Stage 2 Zone II Posterior with Plus Disease treated with intravitreal ranibizumab injection at 11 weeks (PMA 36-37 weeks). Second baby, weighed 620 g and get bilateral intravitreal ranibizumab injection a week after first baby, left eye got worse on first week, but getting better on the last follow up. Third Baby, weighed 750 g with bilateral Stage 3 Zone I with Plus Disease (worst eye condition), but because he had worst general condition, so the latest got screening, got no intervention. Two babies were treated with anti-VEGF therapy – bevacizumab. All babies has outcome regression, no recurrence of ROP in those short term end point, and no adverse reactions were observed until the last follow up at 27 weeks old (PMA 52-53 weeks) recorded for all babies.
 Discussion : 
 Conclusion : Primary prevention through well-managed screening programme for premature infants was the more effective way to manage the ROP. Intravitreal anti-VEGF treatment could be promising for management of ROP if it was given on the right time and early stadium.

Systemic adverse events and all-cause mortality following same-session bilateral intravitreal anti-VEGF injections: a systematic review.

To review the risk of systemic adverse events and all-cause mortality following same-day bilateral anti-VEGF injections. Twelve literature databases were searched for studies on same-session bilateral intravitreal anti-VEGF injections. Studies reporting on systemic adverse events and mortality were included. Data extraction was made independently by two authors and discussed afterwards until consensus was reached. Seven studies were included with a total of 13,406 intravitreal anti-VEGF injections (6703 bilateral injections sessions) given to 689 patients. Across all studies, mean age of patients ranged from 55.7 to 82.5years, and mean follow-up times ranged from 1.3 to 41months. Six studies reported on systemic adverse events: Two cases of non-fatal cardiac adverse events were reported after 12,964 injections (6482 bilateral injection sessions) in 626 patients. Four studies reported on death: 12 deaths were recorded after 6233 bilateral injection sessions in a total population of 554 subjects. We suggest that the risk of non-fatal systemic adverse events and death after same-session bilateral anti-VEGF injection is reasonably low, but larger studies with follow-ups of several years are needed to quantify the exact risk. Prospectively registered in PROSPERO, registration ID: CRD42023428254, registration date: 20/05/2023.

Ocular Safety and Toxicokinetics of Bevacizumab-bvzr (Zirabev), a Bevacizumab Biosimilar, Administered to Cynomolgus Monkeys by Intravitreal Injection.

Purpose: Bevacizumab-bvzr (Zirabev®), a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor and a biosimilar to bevacizumab, is approved for intravenous administration for various indications worldwide. The objectives of this study were to evaluate the ocular toxicity, systemic tolerability, and toxicokinetics (TKs) of bevacizumab-bvzr following repeat intravitreal (IVT) injection to cynomolgus monkeys. Methods: Male monkeys were administered saline, vehicle, or bevacizumab-bvzr at 1.25 mg/eye/dose once every 2 weeks (3 doses total) for 1 month by bilateral IVT injection, followed by a 4-week recovery phase to evaluate the reversibility of any findings. Local and systemic safety was assessed. Ocular safety assessments included in-life ophthalmic examinations, tonometry (intraocular pressure, IOP), electroretinograms (ERGs), and histopathology. In addition, concentrations of bevacizumab-bvzr were measured in serum and in ocular tissues (vitreous humor, retina, and choroid/retinal pigment epithelium) and ocular concentration-time profiles and serum TKs were evaluated. Results: Bevacizumab-bvzr was tolerated locally and systemically, with an ocular safety profile comparable to the saline or vehicle control group. Bevacizumab-bvzr was observed in both serum and in the evaluated ocular tissues. There were no bevacizumab-bvzr-related microscopic changes or effects on IOP or ERGs. Bevacizumab-bvzr-related trace pigment or cells in vitreous humor (in 4 of 12 animals; commonly associated with IVT injection) and transient, nonadverse, mild ocular inflammation (in 1 of 12 animals) were noted upon ophthalmic examination and fully reversed during the recovery phase. Conclusions: Bevacizumab-bvzr was well tolerated via biweekly IVT administration in healthy monkeys, with an ocular safety profile comparable to saline or its vehicle control.

Current and Emerging Therapies for Leber Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA disorder, presenting typically as a sequential, painless, subacute, optic neuropathy in young males. Despite the very limited therapeutic options in LHON, recent developments involving novel pharmacological agents and emerging gene therapy interventions have shown promising results for improved visual outcomes. A synthetic analogue of coenzyme Q (idebenone) is the most common medical treatment in LHON. In a multicentre, double-blind randomized, placebo-controlled clinical trial (Rescue of Hereditary Optic Disease Outpatient Study [RHODOS]), a dose of 900 mg/day of idebenone for 24 weeks was found to be well tolerated and safe. In a follow-up study (RHODOS-OFU), the visual acuity of 70% of patients enrolled in RHODOS was reassessed 30 months after discontinuation of idebenone. Results from this study suggested that visual acuity continued to improve even after discontinuation of the drug. Gene therapy has recently emerged as a potential treatment for LHON. RESCUE and REVERSE were two phase III clinical trials of viral-mediated gene therapy using lenadogene nolparvovec intravitreal injections in patients with early-stage LHON. Results in these trials have shown long-term safety and bilateral visual acuity improvement after unilateral intravitreal injections at 96 weeks, and sustained visual improvement after 3 years of treatment. The most recent phase III clinical trial in LHON (REFLECT) has shown significant improvement of vision after bilateral intravitreal injections of lenadogene nolparvovec compared with unilateral injections. These promising results suggest that, in the near future, LHON might become the first mitochondrial disorder to benefit from gene therapy.

Safety of Lenadogene Nolparvovec Gene Therapy Over 5 Years in 189 Patients With Leber Hereditary Optic Neuropathy

To evaluate the safety profile of lenadogene nolparvovec (Lumevoq) in patients with Leber hereditary optic neuropathy. Pooled analysis of safety data from 5 clinical studies. A total of 189 patients received single unilateral or bilateral intravitreal injections of a recombinant adeno-associated virus 2 (rAAV2/2) vector encoding the human wild-type ND4 gene. Adverse events (AEs) were collected throughout the studies, up to 5 years. Intraocular inflammation and increased intraocular pressure (IOP) were ocular AEs of special interest. Other assessments included ocular examinations, vector bio-dissemination, and systemic immune responses against rAAV2/2. Almost all patients (95.2%) received 9×1010 viral genomes and 87.8% had at least 2 years of follow-up. Most patients (75.1%) experienced at least one systemic AE, but systemic treatment-related AEs occurred in 3 patients; none were serious. Intraocular inflammation was reported in 75.6% of lenadogene nolparvovec-treated eyes. Almost all intraocular inflammations occurred in the anterior chamber (58.8%) or in the vitreous (40.3%), and were of mild (90.3%) or moderate (8.8%) intensity; most resolved with topical corticosteroids alone. All IOP increases were mild to moderate in intensity. No AE led to study discontinuation. Bio-dissemination of lenadogene nolparvovec and systemic immune response were limited. The safety profile was comparable for patients treated bilaterally and unilaterally. Lenadogene nolparvovec had a good overall safety profile with excellent systemic tolerability, consistent with limited bio-dissemination. The product was well tolerated, with mostly mild ocular side effects responsive to conventional ophthalmologic treatments.

Randomized trial of bilateral gene therapy injection for m.11778G > A MT-ND4 Leber optic neuropathy.

Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G > A mutation in the MT-ND4 gene being the most common disease-causing mitochondrial DNA (mtDNA) variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G > A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary endpoint was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary endpoint). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (p < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (p < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G > A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.

Study design and baseline characteristics for the reflect gene therapy trial ofm.11778g>A/ND4-LHON

ObjectiveREFLECT is the first randomised, double-masked, placebo-controlled multicentre phase 3 clinical trial that evaluated the efficacy and safety of bilateral intravitreal (IVT) injection of lenadogene nolparvovec in subjects with Leber...

Safety of simultaneous bilateral intravitreal versus unilateral anti-vasculo-endothelial growth factors injection in an operating room setting.

Chorioretinal diseases requiring the use of anti-vascular endothelial growth (anti-VEGF) injections often occur in both eyes simultaneously. This can necessitate injecting both eyes together rather than one eye at a time. The purpose of the study was to determine whether simultaneous bilateral intravitreal injections of anti-VEGF agents are safe when administered in an operation theatre setting. Retrospective review of data was conducted. Single center study conducted in a tertiary care hospital in Karachi Pakistan. Approximately 30,000 eyes that received anti-VEGF injection during a 10-year study period were included (March 2008-February 2018). Patients who were lost to follow up prior to completion of treatment were excluded. Consecutive sampling technique was employed. The patients who received bilateral anti-VEGF injections were analysed separately from the ones who received unilateral injections. All injections were administered in operating theatre setting. The rate of endophthalmitis was measured in each group. A total of 30,258 injections were administered of which 15,338 were bilateral injections. Four cases (4/30,258, 0.013%) of endophthalmitis occurred during the study period. Only one case (1/15,338, 0.0065%) of endophthalmitis occurred after the administration of simultaneous bilateral anti-VEGF injections. Administration of simultaneous bilateral anti-VEGF injections was safe in our population.

Leber hereditary optic neuropathy: new and emerging therapies.

To review recent therapeutic advances in Leber hereditary optic neuropathy (LHON). Idebenone, a synthetic analog of ubiquinone (Coenzyme Q10) is an antioxidant and component of the mitochondrial electron transport chain. Since the initial approval of the drug in 2015 in Europe, recent trials have evaluated its role as prolonged treatment in LHON. Gene therapy has recently emerged as a promising alternative for the treatment of LHON. Among several investigations, RESCUE and REVERSE are two phase 3 clinical trials of gene therapy in patients with LHON in early stages. Results in these trials have shown a bilateral visual acuity improvement with unilateral intravitreal injections at 96 weeks and sustained visual improvement after 3 years of treatment. The most recent REFLECT phase 3 clinical trial in LHON has shown significant improvement of vision after bilateral intravitreal injections compared with the group that received unilateral injections. Historically, LHON has been considered an untreatable disease, but recent developments show that new pharmacological and gene therapy approaches may lead to visual recovery. Further studies are needed to support these data.

A Rare Case of Bilateral Post Intravitreal Avastin Endophthalmitis with Bilateral Good Visual Outcome – A Case Report

This is a case report of post intravitreal injection endophthalmitis encountered at the University Teaching Hospitals–Eye Hospital in Lusaka, Zambia. Endophthalmitis is a clinical diagnosis made when intraocular inflammation involving both the anterior and posterior chambers is attributable to bacterial or fungal infection. Post injection endophthalmitis is a dreaded complication that occurs following intraocular surgery or procedures such as intravitreal administration of anti-vascular endothelial growth factors or corticosteroids. We attended to a rare case of bilateral post intravitreal injection endophthalmitis in a 51- year- old female patient who presented with bilateral severe pain and acute visual loss in both eyes following intravitreal injection of Avastin (bevacizumab) the previous day. On examination, there was severely decreased visual acuity from 6/36 right eye and 6/60 left eye to hand movement in both eyes. There was also corneal haziness, fibrin in the anterior chambers, hypopyon and vitreous cells in both eyes. A clinical diagnosis of bilateral post-injection endophthalmitis was made. There was immediate administration of intravitreal antibiotics of Vancomycin 1.0mg/0.1mL and Ceftazidime 2.25mg/0.1mL with intravitreal Dexamethasone 0.4mg/0.1ml stat dose and systemic ciprofloxacin 750mg 12 hourly for 7 days. Due to prompt diagnosis and treatment vision recovery was excellent in both eyes and both eyes were preserved.

Hesperidin Exherts Antiglaucoma Effects by Activating Overexpression of BMP4 Signaling and Management of Retinal Ganglionic Cells Degeneration

We investigated the effect of hesperidin on bone morphogenetic protein 4 signaling, which is involved in preventing retinal ganglion cell degeneration in rats with glaucoma. We investigated the therapeutic efficacy of hesperidin as an enhancer of the bone morphogenetic protein 4 signaling pathway at three dose levels (50, 100, and 200 mg/kg) using a rat glaucoma model produced by injecting conjunctival fibroblasts intracamerally into the eyes of the animals. Bone morphogenetic protein 4 was stimulated with bilateral intravitreal injections of 2 mL adeno-associated virus vectors cloned with bone morphogenetic protein 4 primers into the right eye. The intraocular pressure, expression of bone morphogenetic protein 4 and Smad 4, and the distribution of the retinal ganglion cells count were performed a week following the onset of glaucoma. When compared to the model group, the retinal ganglion cells survival rate was increased proportionately in the hesperidin group (P &lt; 0.01). A significant increase in bone morphogenetic protein 4 messenger ribonucleic acid expression was observed in the hesperidin group (P &lt; 0.01) compared to the model group. The hesperidin group showed similar positive results (P &lt; 0.01) with intraocular pressure, Western blot analysis, retinal explant culture, and histological analysis. Further, the model group showed a decline in retinal ganglion cells survival rate (P &lt; 0.01) compared to the control group, and similar trends were noticed in intraocular pressure, Western blot analyses, retinal explant culture, and histological analysis. According to our findings, hesperidin increases the activity of the bone morphogenetic protein 4 pathway, which in turn increases the survival of retinal ganglion cells and the function of the eyes in an experimental glaucoma model.

Intravitreal ranibizumab for postlaser anterior segment ischemia in retinopathy of prematurity

This case report documents the successful management of anterior segment ischemia, a very rare complication following laser in retinopathy of prematurity (ROP), by intravitreal injection of Ranibizumab, an anti-vascular endothelial growth factor agent. This is the first report as per MEDLINE search on the use and efficacy of bilateral intravitreal injection of Ranibizumab in anterior segment ischemia postlaser in ROP.

Bilateral acute retinal necrosis during treatment with alemtuzumab for multiple sclerosis

Alemtuzumab is a humanized monoclonal antibody used as a treatment of multiple sclerosis (MS) and chronic lymphocytic leukemia. It decreases T cell count leading to significant immunosuppression, with increased risk of systemic and ocular infections. Herein, we report a unique case of bilateral acute retinal necrosis (ARN) caused by varicella-zoster virus (VZV) in a patient affected by MS under treatment with alemtuzumab. A 36-year-old man with a relapsing-remitting MS under treatment with alemtuzumab developed bilateral visual loss. Anterior segment examination displayed granulomatous keratic precipitates and 3+ cells in the anterior chamber, while fundoscopy showed bilateral 1+ vitritis and peripheral retinal necrosis, complicated by retinal detachment in the left eye. The high viral load for VZV in aqueous humor samples had a univocal interpretation for viral reactivation. In addition to systemic therapy with acyclovir, the patient was treated with bilateral intravitreal injections of foscarnet and underwent pars-plana vitrectomy and silicone oil tamponade for retinal detachment in the left eye. This report shows a unique case of bilateral ARN caused by VZV associated with alemtuzumab. Any visual loss in MS patients under biologic therapy should not be underestimated, performing an accurate differential diagnosis with optic neuritis.

Safety Evaluation of Bilateral Same-day Intravitreal Injections of Bevacizumab

ëª©ì  양안 동시 ìœ ë¦¬ì²´ê°•ë‚´ ë² ë°”ì‹œì£¼ë§™ì£¼ìž ìˆ ì˜ 단기간 ì•ˆê³¼ì  부작용 빈도를 확인하여 ì•ˆì •ì„±ì„ í‰ê°€í•˜ê³ ìž 하였다. 대상과 방법 í›„í–¥ì ìœ¼ë¡œ 차트 리뷰를 통하여 2015ë „ 1월부터 2019ë „ 6월까지 양안 동시 ìœ ë¦¬ì²´ê°•ë‚´ ë² ë°”ì‹œì£¼ë§™ì£¼ìž ìˆ ì„ 시행한 환자들을 모두 분석하였다. 환자들은 주사 후 1일 뒤, 1주일 뒤, 1달 뒤 내원하였다. ê²°ê³¼ 총 281ëª , 562안, 950회의 양안 동시 ìœ ë¦¬ì²´ê°•ë‚´ ë² ë°”ì‹œì£¼ë§™ì£¼ìž ìˆ ì´ 시행되었다. 이들의 í‰ê· ì—°ë ¹ì€ 58.87 ± 13.44세였으며 남성 153ëª , 여성 128ëª ì´ì—ˆë‹¤. 주사 치료의 원인 질환으로 가장 많았던 것은 당뇨망막병증에 의한 합병증이며(66.3%), ë‚˜ì´ê´€ë ¨í™©ë°˜ë³€ì„±ì´ 22.2%, ë§ë§‰ì •ë§¥íì‡„ê°€ 5.1%, 중심성장액성맥락망막병증이 2.1%를 차지하였다. 총 950회의 ì£¼ìž ìˆ ì´í›„ 발생한 안내염은 없었으며, 결막하출혈이 발생한 경우는 13안, ì¼ì‹œì ìœ¼ë¡œ 안압이 상승한 환자는 17ëª ì´ 있었다. 11안에서 급성 안내염증 소견이 나타났으나 주사 후 최대 2주 이내 ëª¨ë“ í™˜ìžë“¤ì´ ì™„ì „í•œ í˜¸ì „ 소견을 보였다. 주사 ì „ê³¼ 1달 뒤 비교 시 ì‹œë ¥ì€ í˜¸ì „ë˜ëŠ” 양상을 보였다(p<0.001). ê²°ë¡ ë‹¨ê¸°ê°„ì˜ ì•ˆê³¼ì  부작용 빈도를 평가하였을 때, 양안 동시 ìœ ë¦¬ì²´ê°•ë‚´ ë² ë°”ì‹œì£¼ë§™ì£¼ìž ìˆ ì€ 높지 않은 부작용 빈도를 보였으며, 시행하여도 ì•ˆì „í• ê²ƒìœ¼ë¡œ 생각된다. Keywords: Acute intraocular inflammation, Bevacizumab, Endophthalmitis, Safety

Evaluation of the Safety of Bilateral Same-Day Intravitreal Injections of Anti-Vascular Endothelial Growth Factor Agents: Experience of a Large Korean Retina Center.

PurposeTo evaluate the short-term ophthalmic side effects of bilateral same-day intravitreal anti-vascular endothelial growth factor (VEGF) injections.Patients and MethodsWe retrospectively analyzed patients who received intravitreal bevacizumab, ranibizumab, and aflibercept injections in both eyes on the same day between January 2014 and June 2019. The patients were followed up for 1 day, 1 week, and 1 month after the injections.ResultsA total of 323 patients (646 eyes) received 1418 bilateral same-day intravitreal anti-VEGF injections. The patients’ mean age was 62.47 ± 13.97 years. The most common cause of bilateral injection was age-related macular degeneration (54.80%), followed by complications due to diabetic retinopathy (35.33%), retinal vein occlusion (2.40%), and central serious chorioretinopathy (1.27%). There were 22 cases of subconjunctival hemorrhage, 17 cases of temporary elevation of intraocular pressure, and no case of endophthalmitis. Twenty-one patients showed acute intraocular inflammation after the bilateral injection. All patients showed complete improvement within 2 weeks after the injection.ConclusionBilateral same-day intravitreal anti-VEGF injection is a well-tolerated procedure on short-term follow-up. It is one of the more convenient approaches for both the patient and ophthalmologist.

Ranibizumab Population Pharmacokinetics and Free VEGF Pharmacodynamics in Preterm Infants With Retinopathy of Prematurity in the RAINBOW Trial.

PurposeTo develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD).MethodsThe RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations.ResultsElimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship.ConclusionsIn preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing.Translational RelevanceOur population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Primate model of chronic retinal neovascularization and vascular leakage

The purpose of this study was to characterize and develop a primate model of chronic retinal neovascularization and vascular leakage that can be employed to assess efficacy of experimental therapeutics targeting retinal ischemic and neovascular diseases. African green monkeys received bilateral intravitreal (IVT) injection of DL-alpha-aminoadipic acid (DLAAA; 5 mg) following ophthalmic examination, color fundus photography, fluorescein angiography (FA) and optical coherence tomography (OCT). Imaging was repeated to evaluate progression and subsequent stabilization of retinal vascular pathology elicited by DLAAA. Aflibercept (Eylea) was administered IVT (1.4 mg) to assess effects on vascular leakage. Ocular tissue was collected for histopathology and glial fibrillary acidic protein (GFAP), von Willebrand Factor (vWF), CD105/endoglin, VEGF and CD68 immunohistochemistry to study retinal degeneration and vascular remodeling. IVT DLAAA administration resulted in telangiectatic vessel formation as early as two-weeks post-injection, followed by retinal vascular leakage and inner retinal edema. Neovascular lesion progression was evident up to 8–10 weeks post-injection before stabilizing into a vascular leakage state that persisted beyond 90 weeks. Histopathology and immunostaining revealed retinal degeneration and neovascularization, increased expression of vWF, CD105/endoglin, VEGF and CD68 immunoreactivities in addition to Müller cell loss. Aflibercept significantly attenuated vascular leakage for 2–4 weeks before progressive return of leakage from weeks 4–8. Lesions remained responsive to anti-VEGF administration at 90 weeks after DLAAA injection. Findings support application of the primate DLAAA-induced retinal vascular leakage model for efficacy evaluations of candidate therapeutics and sustained release strategies targeting exudative AMD, diabetic retinopathy, macular telangiectasia and other retinal ischemic and neovascular diseases. Findings confirm relevance of the DLAAA primate phenotype to understanding shared retinal vascular disease mechanisms and macular susceptibility to vascular and metabolic insults.

Long‐term observation of the treatment of laser photocoagulation versus intravitreal bevacizumab in identical twins with aggressive posterior retinopathy of prematurity

AbstractPurposeIn recent years, a number of studies have been reported comparing the results of the treatment with intravitreal bevacizumab injection. We report a case of comparing effects of laser photocoagulation versus intravitreal bevacizumab injection in identical twins with AP‐ROP.MethodsGA 28 + 2 weeks, identical twins were born with 0.97 and 1.02 kg. Twins were diagnosed as bilateral AP‐ROP and they were refered to different hospital due to the lack of hospital neonatal room, and they received different treatments. At the PMA 32 + 6 weeks, the older sister underwent bilateral intravitreal bevacizumab injection, younger sister underwent laser photocoagulation. Younger sister underwent bilateral laser photocoagulation at the PMA 34 + 4 weeks and received additional bilateral intravitreal bevacizumab injection after 1week. Older sister underwent second intravitreal bevacizumab injection at the PMA 42 + 2 weeks.ResultsAfter 9 years, older sister’s BCVA was checked 0.8 in the right eye, 0.25 in the left eye. Both eyes showed good angiogenesis to the periphery of the retina and fovea showed normal development on the OCT. And younger sister’s BCVA was checked 0.5 in the right eye, FC 50cm in the left eye. Laser was well applied at the periphery, but the retinal vessels didn’t grow even in the zone 1 main arcade, and the fovea on the OCT was irregular and undeveloped.ConclusionsIn this case, the intravitreal bevacizumab injection in the same twin with all the same conditions supports the efficacy of bevacizumab injections because of better long‐term outcome of anatomical and functional retinal vessel development. There is no reported case of different initial treatment in Identical twin, so it can be a meaningful case to compare long term results of two treatments.

An audit of retinal lymphoma treatment at the University of California San Francisco.

To evaluate retinal lymphoma treatment at the University of California San Francisco. Prospective observational audit. Patients were treated systemically, usually with: methotrexate, temozolomide, and rituximab induction; etoposide consolidation; and maintenance with lenalidomide or another immunomodulatory agent. Persistent disease was treated initially by ocular radiotherapy or intravitreal melphalan and latterly by vitrectomy. The cohort comprised eight females and two males. The median age was 58 years (range, 38-73). Ocular manifestations were initially unilateral in four patients. Vitreous and subretinal infiltrates were initially present in 16 and 12 eyes, respectively, with three eyes having vision of 20/200 or worse. Four patients had a history of central nervous system (CNS) lymphoma. The median ophthalmic follow-up was 37 months (range, 8-56). Diagnostic and therapeutic vitrectomy were performed in 10 and 2 eyes, respectively. All patients had systemic chemotherapy and eight received maintenance immunotherapy. Four patients underwent ocular radiotherapy, bilaterally in two. One patient received bilateral intravitreal melphalan injections. Two eyes of four patients developed lymphoma during the study and two patients developed CNS disease. At study close, subretinal deposits were subtle in nine eyes and more prominent in two, whereas vitreous infiltrates were minimal in nine eyes, mild in one and moderate in one. The latest visual acuity was significantly worse than at presentation in two eyes and better in two. All patients were alive with no active CNS disease. Subretinal lymphomatous infiltrates respond to systemic chemotherapy with immunomodulatory maintenance, but dense vitreous infiltrates require therapeutic vitrectomy.