Analysis of the molecular biologic milieu of the vitreous in proliferative vitreoretinopathy.

PURPOSE: Previous investigations have explored molecular differences between proliferative vitreoretinopathy and primary retinal detachment. An exploration of a greater number of molecules might provide novel insight into the biology of this disorder and identify potential therapeutic targets. METHODS: Vitreous specimens were obtained from patients with epiretinal membranes or macular puckers (n = 15), patients with a primary retinal detachment without proliferative vitreoretinopathy (n = 15), and patients with retinal detachments and proliferative vitreoretinopathy (n = 15). A multiplex assay was performed to calculate the concentrations of 48 different cytokines and chemokines, and statistical analyses were performed to identify differences between the groups. RESULTS: Of the 48 molecules that were studied, we identified 10 that were statistically significantly different in cases of proliferative vitreoretinopathy, including interleukins 4, 5, 6, and 15; granulocyte-macrophage colony-stimulating factors; stem cell factor; stem cell growth factor; macrophage inflammatory protein 1α; and interferon γ-induced protein 10. CONCLUSION: Proliferative vitreoretinopathy represents a highly ordered molecular process that involves discrete changes in the concentrations of specific cytokines and chemokines. These molecules may represent novel therapeutic targets.

Adverse events after intravitreal infliximab (Remicade).

PURPOSE: To determine the tolerability of intravitreal infliximab (Remicade) in patients with refractory diabetic macular edema or choroidal neovascularization secondary to age-related macular degeneration. METHODS: This is a prospective, interventional, noncomparative, open-label, 12-week pilot study of intravitreal infliximab in four patients who failed conventional therapies. Two had diabetic macular edema and two had choroidal neovascularization secondary to age-related macular degeneration. All patients received 0.5 mg/0.05 mL intravitreal infliximab and were eligible for a second injection at 6 weeks if reinjection criteria were met. Outcome measures were best-corrected visual acuity using standard Early Treatment Diabetic Retinopathy Study refraction, central retinal thickness on optical coherence tomography, fluorescein angiography, standard electroretinography, and microperimetry. Patients were evaluated at Days 0 and 1 and Weeks 2, 6, and 12. Six months after study completion, all patients were tested for human antimouse and human antichimeric antibodies. RESULTS: At Week 12, visual acuity scores had declined in three patients. All patients had persistence of cystoid macular edema on optical coherence tomography, although two had a decrease in central retinal thickness. Three patients had an overall worsened appearance on angiography. On the final electroretinography, all patients had a decrease in maximal combined responses, from 7% to 24% from baseline, which may have been within expected variability of electroretinography data. To photopic flicker stimulus, three patients had slower latency of response, and all had decreased amplitudes. All patients declined on microperimetry. The first patient entered in the study met the criteria for a second injection because of improved standard electroretinography and microperimetry at Week 6. However, 2 weeks after the second injection, he developed panuveitis. Two other patients, after one injection only, had evidence of inflammation (vitritis or panuveitis) on examination at Week 6. Three patients developed systemic antibodies against infliximab (human antichimeric antibodies). CONCLUSION: Low-dose intravitreal infliximab was not well tolerated in this small group of patients and was both immunogenic and probably retinotoxic.

Infliximab stability after reconstitution, dilution, and storage under refrigeration.

PURPOSE: The purpose of this study was to investigate the stability of reconstituted infliximab solutions and determine whether infliximab is suitable for compounding for potential intravitreal use. METHODS: Infliximab was reconstituted, and the solution was aliquoted and stored refrigerated. On each day of testing, an aliquot was serially diluted to concentrations ranging from 50,000 pg/mL to 69 pg/mL. Each dilution was assayed by microsphere immunoassay daily for 5 days and weekly for a total of 6 weeks. The outcome measure was median fluorescence intensity measured by dual laser flow analysis of fluorochrome-labeled secondary antibodies to infliximab bound to tumor necrosis factor-alpha-coated microspheres. RESULTS: There was an increasing median fluorescence intensity for increasing infliximab concentration in a sigmoidal dose-response curve with a variable slope that was equivalent for each time point. Each respective concentration of infliximab showed nearly equivalent median fluorescence intensity for every time point over the 6-week period. CONCLUSION: The authors found that the immunoreactivity of 2 different concentrations of infliximab stored at 4 degrees C over a 6-week period remained stable. Infliximab is suitable for compounding and could be a cost-effective intravitreal medication for use in clinical practice if further study supports its safety and efficacy.

Photodynamic therapy for choroidal neovascularization associated with submacular hemorrhage in age-related macular degeneration.

BACKGROUND AND OBJECTIVE: To describe visual acuity results after photodynamic therapy (PDT) with verteporfin for choroidal neovascularization in age-related macular degeneration (AMD) associated with large submacular hemorrhage (SMH). PATIENTS AND METHODS: Eyes that had AMD, at least 12 months' follow-up, and SMH of at least 2.5 mm2, and had received no other treatment modality in conjunction with PDT, were divided into two groups: eyes with spontaneous SMH that was treated with PDT and eyes with SMH that occurred following PDT treatment. The presence of SMH did not preclude the patients from undergoing further PDT. RESULTS: Mean acuity of the spontaneous SMH group was 20/294 initially and 20/252 after 12 months. Mean acuity of the post-PDT SMH group was 20/336 initially and 20/406 after 12 months. Initial and 12-month acuities in both groups were not statistically different. Mean size of the hemorrhage was 11.5 mm2 in the spontaneous SMH group and 17.8 mm2 in the post-PDT SMH group. Subgroup analysis showed no statistically significant difference between initial and final visual acuities, regardless of the presence of blood under the fovea. Analysis by size of the SMH showed only the spontaneous SMH group with hemorrhages over 10 mm2 to have a statistically significant difference in visual acuity at 12 months (P= .0001; initial acuity, 20/230; 12-month acuity, 20/456). CONCLUSION: Eyes treated with PDT for choroidal neovascularization associated with submacular hemorrhage and AMD maintained stable vision over 12 months.

Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide injection.

BACKGROUND AND OBJECTIVE: To report acute postoperative, presumed sterile endophthalmitis following intravitreal injection of triamcinolone acetonide (IVTA). PATIENTS AND METHODS: Retrospective, interventional, multicenter study of patients with acute sterile endophthalmitis following IVTA injection. RESULTS: A total of 922 IVTA injections were performed. Eight eyes of 8 patients with presumed sterile endophthalmitis were identified. The incidence of endophthalmitis was 0.87% (95% confidence interval, 0.38% to 1.70%). Median time to presentation was 1.5 days (range, 1 to 7 days). Median presenting visual acuity was 20/563 (range, 20/80 to light perception). Initial treatment included vitreous tap and injection of antibiotics (n = 4), pars plana vitrectomy and injection of intravitreal antibiotics (n = 2), or systemic treatment alone with oral levofloxacin (n = 2). Six of 6 intraocular cultures were sterile. Median follow-up was 5.9 months (range, 4 to 9 months) with a median visual acuity at last follow-up of 20/75 (range, 20/40 to counting fingers). CONCLUSIONS: Acute presumed sterile endophthalmitis following IVTA injection presents early in the postoperative period. Visual outcomes are generally good.

Flat Electroretinography and Acute Visual Loss After Ocriplasmin Injection for Vitreomacular Adhesion Complicating Macular Schisis.

A 53-year-old woman with macular and diffuse retinoschisis complicated by presumed vitreomacular traction underwent unilateral intravitreal ocriplasmin injection. Within hours after injection, she noted a loss of vision and the perception of "negative" images in the treated eye. Electrophysiologic testing revealed flat waveforms, and optical coherence tomography (OCT) showed initial decreased central macular thickness at day 1, followed by massive increased macular thickness with subfoveal neurosensory retinal detachment at 1 week. Her central macular thickness on OCT slowly returned to baseline during a period of 1 month until development of a macula-off rhegmatogenous retinal detachment at 6 months after injection. The authors believe this unique case of vitreomacular adhesion and macular schisis complicated by post-injection visual loss and electroretinography changes may offer further insight into this unusual complication.

Anomalous optical coherence tomography findings in Wyburn-Mason syndrome and isolated retinal arteriovenous malformation.

We report 2 cases of unilateral retinal arteriovenous malformation (AVM) with previously unreported anomalies of the inner retinal layers detected on spectral domain optical coherence tomography (SD-OCT): a 5-year-old girl with a large unilateral retinal AVM, ipsilateral visual acuity of 20/200, and ipsilateral intracranial AVM; and a 10-year-old boy with a large unilateral retinal AVM, ipsilateral visual acuity of 20/20, ipsilateral temporal visual field defects, and no intracranial AVM. Both macular SD-OCT findings showed multiple large inner retinal vessels that created a prominent shadowing artifact, retinal thickening, and speckling and heterogeneity of inner retinal layers.

Acute endophthalmitis following intravitreal triamcinolone acetonide injection.

PURPOSE: To report the clinical features, causative organisms, management, and visual acuity outcomes of eight eyes of eight patients who developed acute postoperative endophthalmitis following intravitreal injection of triamcinolone acetonide (IVTA). DESIGN: Retrospective, multicenter, interventional, case series. METHODS: A retrospective, interventional, case series of all patients with acute postoperative endophthalmitis following IVTA at seven academic clinical centers between March 2001 and July 2002. RESULTS: A total of 922 IVTAs were performed. Eight eyes of eight patients with acute postoperative endophthalmitis were identified in the 6 weeks following IVTA for an incidence of 0.87% (95% confidence interval of 0.38% to 1.70%). The median time to presentation was 7.5 days (range, 1-15 days) after IVTA. The most common clinical findings were iritis (n = 8), vitritis (n = 8), hypopyon (n = 8), pain (n = 7), red eye (n = 6), and decreased vision (n = 5). The median presenting visual acuity was 20/1127 (range, 20/60 to light perception). Initial treatment consisted of vitreous tap and injection of antibiotics (n = 6) or pars plana vitrectomy and injection of intravitreal antibiotics (n = 2). Intraocular cultures yielded identification in seven patients. One demonstrated intracellular gram-positive cocci in chains with numerous polymorphonuclear cells on gram stain. The median postinfection vision was 20/400 (range, 20/40 to no light perception). Three patients ended up with no light perception visual acuity, including enucleation (n = 1) and phthisis (n = 1). CONCLUSIONS: Acute postoperative endophthalmitis following IVTA occurs rapidly and can result in severe loss of vision.

The effect of intravitreal triamcinolone acetonide on intraocular pressure.

BACKGROUND AND OBJECTIVE: To ascertain whether a single 4-mg intravitreal triamcinolone acetonide injection is associated with elevated intraocular pressure (IOP). PATIENTS AND METHODS: Retrospective noncomparative interventional case series. Forty-three consecutive eyes of 38 patients who had 12 weeks of follow-up were included. The IOPs before and after triamcinolone acetonide treatment were recorded by Goldmann applanation at each patient visit. RESULTS: Within 12 weeks after intravitreal triamcinolone acetonide injection, 21 of 43 eyes (48.8%) demonstrated an increase in IOP of 5 mm Hg or greater, and 12 of 43 eyes (27.9%) had an increase in IOP of 10 mm Hg or greater. The mean time for an increase in IOP of 5 mm Hg or greater to occur was 4.1 weeks (standard deviation = 4.8 weeks), and the mean time to reach maximum IOP was 6.6 weeks (standard deviation = 5.1). The difference between the mean pre-injection IOP (15.12 mm Hg, n = 43) and the maximum post-injection IOP (20.74 mm Hg, n = 43) was statistically significant (P < .0001). CONCLUSION: A single 4-mg intravitreal triamcinolone acetonide injection is associated with an increase in IOP of 10 mm Hg or greater in 27.9% of eyes after the first injection. All eyes responded to topical glaucoma medication.

Photodynamic therapy with verteporfin for classic choroidal neovascularization secondary to focal laser photocoagulation for radiation retinopathy.

A 50-year-old patient developed extrafoveal predominantly classic choroidal neovascularization in the right eye 2 months after undergoing focal laser photocoagulation for macular edema with hard exudates secondary to radiation retinopathy, with vision dropping from 20/20 to 20/100. The choroidal neovascularization responded to three verteporfin photodynamic therapy treatments with angiographic closure, which persisted for more than 15 months after the last treatment. At last follow-up 15 months after the third treatment, visual acuity improved by 8 lines to 20/20. Photodynamic therapy with verteporfin may be useful for treating patients with choroidal neovascularization secondary to argon laser photocoagulation.

Intravitreal triamcinolone injection for diabetic macular edema: a clinical and fluorescein angiographic case series.

BACKGROUND: A significant number of eyes with diabetic macular edema remain refractory to treatment despite numerous attempts at photocoagulation. Triamcinolone acetonide, a minimally water soluble steroid injected in suspension form, has been reported to be a well-tolerated agent for intravitreal injection, prompting a decrease in diabetic macular edema on optical coherence tomography. We report our experience with this treatment in 19 eyes with persistent diabetic macular edema. METHODS: We reviewed the charts of 16 patients (19 eyes) from a clinical practice with diabetic macular edema persistent after focal or grid laser photocoagulation. All eyes had received 4 mg of triamcinolone, injected into the vitreous cavity 3.5 mm posterior to the limbus. Fluorescein angiography was performed before and about 2 weeks after the injection. Snellen visual acuity and intraocular pressure (as determined with Goldmann applanation tonometry) were also measured before and after the injection. RESULTS: Fluorescein angiography showed marked improvement of macular edema in 4 eyes (21.0%), mild improvement in 10 eyes (52.6%) and no change in 5 eyes (26.3%); no patient had worsening of macular edema. Visual acuity improved by at least 1 line in 13 eyes (68.4%), by 2 or more lines in 5 eyes (26.3%), by 3 or more lines in 2 eyes (10.5%) and by 4 lines in 1 eye (5.3%); visual acuity remained unchanged in 5 eyes (26.3%) and deteriorated by 1 line in 1 eye (5.3%). Intraocular pressure elevation of 10 mm Hg or greater occurred in two eyes (10.5%) and was successfully treated with topical administration of 0.15% brimonidine.The triamcinolone was well tolerated, and there were no other ocular complications. INTERPRETATION: Intravitreal injection of triamcinolone has potential in the treatment of diabetic macular edema and warrants investigation in a randomized prospective clinical trial.

Intraocular bevacizumab levels 24 hours after intravitreal injection in a normal eye.

BACKGROUND: To determine intraocular levels of bevacizumab in a normal eye 24 hours after the injection of bevacizumab into the vitreous cavity. METHODS: Fluid and tissue samples were analyzed for unbound bevacizumab levels using microsphere immunoassays. RESULTS: After a loading dose of 2.5 mg (0.1 mL) of bevacizumab, levels of unbound drug could be detected in all tissue extracts 24 hours after its injection. At least 60.2% of the injected bevacizumab could be accounted for in this study. Levels of 0.06 mg (2.4%) of bevacizumab were recorded in the choroid. CONCLUSION: At 24 hours, unbound bevacizumab levels can be detected at the level of the choroid. Therefore, bevacizumab can reach the site where choroidal neovascularization develops. This explains its reported therapeutic effect.

Effect of adjunctive diclofenac with verteporfin therapy to treat choroidal neovascularization due to age-related macular degeneration: phase II study.

BACKGROUND: To determine short-term effects of topical diclofenac administered in conjunction with verteporfin therapy for predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS: Randomized, multicenter (14), prospective, placebo-controlled, double-masked clinical trial. Patients (n=61) were randomly assigned to treatment with diclofenac sodium ophthalmic solution 0.1% or placebo and followed for 12 weeks. Patients instilled diclofenac or placebo two drops four times daily, 2-4 days before verteporfin treatment until 2 weeks after treatment, then two drops twice daily for 10 weeks. This exploratory study was not powered to detect differences between treatment groups. Statistical analyses were conducted solely to aid interpretation of results. RESULTS: In diclofenac-treated eyes, mean changes in visual acuity letter score from baseline in the diclofenac and placebo groups were +1.8 letters and -1.0 at week 1 (P=0.505 between groups). Mean visual acuity letter scores decreased in both groups at all subsequent visits, with a mean change at 12 weeks of -7.4 with diclofenac and -2.6 with placebo (P=0.213). Percentages of eyes with stable or improved vision (change or=5 letters) were similar in the diclofenac and placebo groups at all study visits. No significant between-group differences in changes from baseline in lesion area, greatest linear dimension (GLD), fluorescein leakage, or retinal thickness were detected. CONCLUSION: In patients with predominantly classic subfoveal CNV due to AMD, administration of topical diclofenac with verteporfin therapy was associated with similar vision outcomes to placebo plus verteporfin therapy.

Role of intravitreal triamcinolone acetonide in the treatment of postoperative endophthalmitis.

PURPOSE: To report the use of commercially available triamcinolone acetonide as adjunct treatment for acute-onset endophthalmitis after intraocular procedures. METHODS: Charts of 14 patients who received intravitreal triamcinolone in combination with intravitreal antibiotics for treatment of acute endophthalmitis were reviewed. Patients were included if they presented with pain, vision loss, and severe anterior chamber reaction or hypopyon. Visual acuities, intraocular pressures, anterior chamber reaction, and view of fundus details were recorded at baseline, 1 day, 1 week, 1 month, and 3 months to 5 months. RESULTS: Culture-positive results were found for 57% (8/14) of patients. Isolated species included Staphylococcus epidermidis, viridans streptococcus, group D Streptococcus (nonenterococcus), Propionibacterium acnes, and diphtheroid bacilli. Visual acuities improved an average of 7.5 Snellen lines. Preendophthalmitis level visual acuities were recovered in 78.6% patients (11/14), with 64% (9/14) of patients achieving visual acuity of 20/40 or better regardless of presenting vision. Resolution of anterior chamber reaction and view of fundus details were consistent with visual acuities. CONCLUSIONS: Intravitreal triamcinolone combined with intravitreal antibiotics appears to have a safety profile similar to current modalities with a favorable effect on visual recovery and function in the setting of acute postoperative endophthalmitis.

Vitreous penetration of topical moxifloxacin and gatifloxacin in humans.

PURPOSE: To determine the vitreous penetration of the new fourth-generation topical fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3%. METHODS: A prospective randomized clinical trial comprising 12 eyes of 12 patients scheduled for pars plana vitrectomy between August 2003 and September 2003 was performed in a clinical practice. The patients were randomly assigned to receive topical moxifloxacin 0.5% (n = 6) or gatifloxacin 0.3% (n = 6). One half the patients in each antibiotic group received 1 drop every 15 minutes for a total of 3 doses starting 1 hour before surgery, and the other one half self-administered the antibiotic drop 4 times daily for 3 days before surgery and at 7 am on the day of surgery. Undiluted vitreous samples were obtained and analyzed using high-performance liquid chromatography. RESULTS: Either moxifloxacin 0.5% or gatifloxacin 0.3% was detected in the vitreous in all 12 patients in the study. There was no significant difference between the mean vitreous concentration of moxifloxacin 0.5% given over 1 hour preoperatively (0.012 +/- 0.011 microg/mL) and that given in the 3-day regimen (0.011 +/- 0.008 microg/mL) (P = 0.93). There was also no significant difference between the mean vitreous concentration of gatifloxacin 0.3% given over 1 hour preoperatively (0.001 +/- 0.0003 microg/mL) and that given over 3 days (0.008 +/- 0.006 microg/mL) (P = 0.11). Vitreous concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% in each eye were all lower than the 90% minimum inhibitory concentration for the commonest bacterial isolates causing endophthalmitis. With both dosing regimens, the mean vitreous concentration of moxifloxacin 0.5% was higher than that of gatifloxacin 0.3% administered at the same regimen, but this was not statistically significant. CONCLUSION: Both topical moxifloxacin 0.5% and gatifloxacin 0.3% penetrated the vitreous in the uninflamed eye, but the vitreous concentrations attained were all lower than the 90% minimum inhibitory concentration for the commonest bacterial pathogens causing acute postoperative endophthalmitis.

Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients.

BACKGROUND: Vitreous levels of unbound bevacizumab (Avastin) and unbound vascular endothelial growth factor (VEGF) were determined in two patients. Patient 1 underwent repair of an 8-day-old rhegmatogenous retinal detachment 4 weeks after a single intravitreal bevacizumab injection, and Patient 2 underwent vitreous biopsy for endophthalmitis 48 hours after a combined bevacizumab and triamcinolone injection. METHODS: The samples of vitreous fluid were analyzed for unbound bevacizumab and unbound VEGF levels using microsphere immunoassays targeted for bevacizumab and VEGF. RESULTS: In Patient 1, the unbound bevacizumab level was 0.16% of the loading dose (or 500,000 pg/mL) and the unbound VEGF concentration was <41 pg/mL 4 weeks after the bevacizumab injection. In Patient 2, the unbound bevacizumab level was 53% of the loading dose (or 166,000,000 pg/mL) at 48 hours, with an unbound VEGF level of <41 pg/mL. CONCLUSION: A single dose of intravitreal bevacizumab is likely to provide complete intravitreal VEGF blockade for a minimum of 4 weeks, with an intravitreal bevacizumab half-life of approximately 3 days.

Vitreoretinal surgery for optic pit associated serous macular detachment: a discussion of two cases.

PURPOSE: To report the successful surgical outcome of two patients with a serous macular detachment and cystoid macular edema associated with a congenital optic nerve pit. METHOD: Case reports. Two patients with a serous macular detachment associated with a congenital optic nerve pit were treated with 360 degrees peripapillary endophotocoagulation during vitrectomy, attempted internal subretinal fluid drainage, and fluid-gas exchange. RESULTS: In both cases, the retina remained attached during a follow-up period of 6 months, and the patient's vision improved dramatically. One patient improved from the counting finger level to 20/70, and the other improved from 20/200 to 20/70. CONCLUSION: The use of 360 degrees peripapillary endophotocoagulation after pars plana vitrectomy for the treatment of optic nerve pit associated retinal detachment resulted in excellent visual acuity and anatomic reattachment. Attempted internal subretinal fluid drainage was unsuccessful and did not contribute to the success of the case.

Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection.

PURPOSE: To describe the pharmacokinetics occurring after the direct injection of triamcinolone acetonide into the vitreous humor of humans. DESIGN: Interventional case series. PARTICIPANTS: Five patients who received a single 4-mg intravitreal injection of triamcinolone acetonide. METHODS: An aqueous humor sample was obtained from 5 eyes via an anterior chamber paracentesis at days 1, 3, 10, 17, and 31 after injection. At each visit, visual acuity and intraocular pressure were measured and indirect ophthalmoscopy was performed. A fluorescein angiogram was carried out at day 10. Concentrations were determined using high performance liquid chromatography; pharmacokinetic analysis was carried out using PK Analyst, an iterative, nonlinear, weighted, least-squares regression program. MAIN OUTCOME MEASURES: Intraocular concentrations of triamcinolone were measured and population pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic data followed a two-compartment model. Peak aqueous humor concentrations ranged from 2151 to 7202 ng/ml, half-lives from 76 to 635 hours, and the integral of the area under the concentration-time curve (AUC(0-t)) from 231 to 1911 ng/h per milliliter. After a single intravitreal injection of triamcinolone, the mean elimination half-life was 18.6 days in nonvitrectomized patients. The half-life in a patient who had undergone a vitrectomy was shorter at 3.2 days. CONCLUSIONS: There was considerable intrasubject variation among peak concentration, AUC(0-t) values, and elimination half-lives. After intravitreal injection, measurable concentrations of triamcinolone would be expected to last for approximately 3 months (93 +/- 28 days) in the absence of a vitrectomy. Because triamcinolone pharmacokinetics were characterized only in elderly patients with macular edema, the results cannot be extrapolated to other patient populations.