P. Andrew Pearson

Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial

PURPOSE We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). DESIGN Prospective, evaluator-masked, controlled, multicenter clinical trial. PARTICIPANTS We included 196 eyes with refractory DME. METHODS Patients were randomized 2:1 to receive 0.59-mg FA implant (n = 127) or standard of care (SOC additional laser or observation; n = 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. MAIN OUTCOME MEASURES The primary efficacy outcome was ≥15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). RESULTS Overall, VA improved ≥3 lines in 16.8% of implanted eyes at 6 months (P=0.0012; SOC, 1.4%); in 16.4% at 1 year (P=0.1191; SOC, 8.1%); in 31.8% at 2 years (P=0.0016; SOC, 9.3%); and in 31.1% at 3 years (P=0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P<0.0001), 1 year (P<0.0001; 72% vs 22%), 2 years (P=0.016), and 3 years (P=0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P=0.0006), 1 year (P=0.0016), 2 years (P=0.012), and 3 years (P=0.0207). Intraocular pressure (IOP) ≥30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. CONCLUSIONS The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Microangiopathy of the brain, retina and cochlea (Susac syndrome). A Report of five cases and a review of the literature

OBJECTIVE This study reports five new cases of microangiopathy of the brain, retina, and cochlea (Susac syndrome) and reviews the worlds literature. DESIGN Five cases were systematically studied by the authors. The cases in the literature were identified through Medline searches for Susac syndrome; microangiopathy of the brain, retina, or ear; and cross-referencing the indexes of each retrieved article. PARTICIPANTS The number of new patients studied in this report was five. An additional 41 patients were culled from the literature. INTERVENTION Patients were treated with corticosteroids, antineoplastic agents, and other methods in a noncontrolled, nonrandomized fashion. MAIN OUTCOME MEASURES With respect to therapeutic intervention, the main clinical outcome measures were return of vision, improvement of neurologic and psychiatric manifestations, and recovery of auditory function. Alterations of abnormalities observed by cranial magnetic resonance imaging also were monitored. RESULTS Of 46 identified patients, 39 were women. The mean age of the patients was 30 years. Forty-one patients (89%) had arterial occlusions, which were bilateral in 60%. Thirty-one patients (67%) reported hearing loss. Twenty patients (44%) had a global encephalopathy, but other neurologic manifestations were common. The mean duration of the illness was 46.7 months. CONCLUSION This rare syndrome is more common than previously thought, has a strong female preponderance, and often can be identified at an early stage with a careful history and physical examination. Magnetic resonance imaging of the brain often shows lesions suggestive of multiple sclerosis. Fluorescein angiography may show arteriolar wall hyperfluorescence. Early treatment with corticosteroids often is, although not invariably, associated with a good prognosis. The disease appears to be self-limited in most patients.

Vitreous loss rates in extracapsular cataract surgery by residents

Vitreous loss is a serious complication of cataract surgery. It has been suggested that high rates of vitreous loss may be an inevitable consequence when residents are learning extracapsular cataract extraction (ECCE). The authors retrospectively analyzed all (n = 936) cataract operations done by second- and third-year residents in a single Veterans Administration hospital from 1982 through 1988. Between 1982 and 1985, the incidence of vitreous loss was 10.3%. In 1985, a new program of resident surgical education was introduced, and the incidence from 1985 through 1988 declined to 3.2% (P less than 0.001). Statistical analysis confirms that this decrease cannot be attributed to any individual surgeon, class of residents, or year of surgery. The authors believe that an educational program including practice surgery, graded responsibility, and experienced assistance may be responsible in part for dramatically reducing the rate of this serious complication during surgery done by the beginning resident.

Airbags and bilateral eye injury: five case reports and a review of the literature.

We report five cases of bilateral eye injuries from airbag deployment in motor vehicle crashes and review the worlds literature on ocular injuries associated with airbags. The cases in the literature were identified by cross-referencing Medline searches from airbags and ocular injuries. Additional cases were identified after review of references from each article in the search. An additional 89 cases from the literature were identified and are included for discussion. Patients were treated individually in a noncontrolled, nonrandomized fashion according to the nature of each injury with regular follow-up examinations in clinic. Of the 94 cases studied, 24 (27%) were bilateral eye injuries, and 15 (16%) patients were wearing spectacles at the time of the accident. The most common injuries included corneal abrasions, eyelid trauma, and hyphemas. Outcomes ranged from complete resolution of symptoms and return of normal visual acuity to primary enucleation. This report describes the wide spectrum of eye injuries that may occur after airbag deployment. We suggest a management plan for the evaluation and treatment of the ocular complications of airbag-related trauma.

Evaluation of Optic Nerve Sheath Fenestration in Pseudotumor Cerebri Using Automated Perimetry

Evaluation of the efficacy of optic nerve sheath fenestration in pseudotumor cerebri has been hindered by a lack of quantitative indicators of visual function before and after treatment. Nine patients (14 eyes) were treated who had pseudotumor with optic nerve sheath fenestration, in whom automated perimetry was used as a major parameter in the decision to undertake surgery and in evaluating the results. Visual field results demonstrated significant improvement in this group of patients. Seven of 8 eyes with total loss less than 1500 dB had improvement or no further deterioration. Using results of the last preoperative examination as baseline, it was found that six of the eight had improvement over 150 dB. In one patient, a slight deterioration occurred postoperatively. Those eyes with total loss above 1500 dB demonstrated stabilization of fields postoperatively. Statistical analysis of total loss preoperatively and postoperatively for this group of patients demonstrated significant improvement for five of the six comparisons investigated. Average preoperative total loss and average postoperative total loss were not significantly different. Comparisons of results of the last preoperative examination to those of the first postoperative and most recent follow-up examinations, and evaluation of average total loss postoperatively showed significant improvement had occurred. Results of the first postoperative examination and those of the most recent follow-up examination showed significant improvement from the average preoperative total loss.

Characterization of Intraocular Pressure Increases and Management Strategies Following Treatment With Fluocinolone Acetonide Intravitreal Implants in the FAME Trials

BACKGROUND AND OBJECTIVE To compare elevated intraocular pressure (IOP) management and outcomes among patients with diabetic macular edema who received fluocinolone acetonide (FAc) implants versus sham-control treatment and explore the prior ocular steroid exposure impact on IOP outcomes. PATIENTS AND METHODS Best-corrected visual acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study charts or electronic VA testers. Goldmann applanation tonometry was used to measure IOP. RESULTS Elevated IOP was more common in FAc-versus sham control-treated patients. Medication, and less often trabeculoplasty or surgery, was used to lower IOP without affecting VA outcomes. No patient treated with 0.2 µg/day FAc who received prior ocular steroid required IOP-lowering surgery. CONCLUSION Elevated IOP may occur following FAc implant receipt; however, in the present study, it was manageable and did not impact vision outcomes. Patients previously treated with ocular steroid did not require IOP-lowering surgery following 0.2 µg/day FAc implant administration. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:426-435.].

Triamcinolone crystal size.

Dear Editor: In the past few years, compounding pharmacies and pharmaceutical manufacturers have commercialized ready-to-use preservative-free triamcinolone acetonide (PFTA). PFTA marketing is fueled by the potential safety issues with the off-label intravitreous (IV) injection of Kenalog (TA; Bristol-Myers Squibb, Princeton, NJ), which is not specifically formulated for the eye and contains benzalkonium chloride (BAK), a toxic preservative associated with sterile endophthalmitis.1 Compounded PFTA (C-PFTA) was reported as a safe and effective replacement for TA,2 yet it can be prepared by many techniques, each with variable results on yield, concentration, and stability.3,4 Prior to the availability of pharmaceutical-manufactured PFTA products (P-PFTA, e.g. Triesence; Alcon, Fort Worth, TX), we purchased several C-PFTA vials from a regional compounding pharmacy. During the utilization of a particular lot of C-PFTA, we observed a dramatic increase in acute and severe elevations in intraocular pressure (IOP) after IV injection. In 1 month, 28 eyes with severe retinal disease were treated with IV C-PFTA (vials derived from single lot). None of the patients had a history of glaucoma or uveitis. We were surprised that 10 patients (35.7%) had significantly elevated IOP (≥29 mmHg) at 7 days with an average increase of 29.1±3.1 mmHg from baseline (P<0.001, Mann-Whitney U) (Fig. 1, available at http://aaojournal.org). An acute rise (within 72 hours) was evident in 5 patients, and 2 required filtering surgery. No pseudo-hypopyon or angle deposition of particulate matter was observed. Figure 1 Ten of 28 eyes from patients with various retinal diseases (diabetic macular edema, cystoid macular edema, age-related macular degeneration, branch vein occlusion, and non-AMD related choroidal neovascularization, CNV) were treated with a single injection ... In response to this case series, we initiated an investigation of the affected C-PFTA lot. Firstly, its usage was immediately halted, and we contacted the regional compounding pharmacy to report the events. The manufacturer re-tested the lot both in-house and at an independent laboratory with confirmation that there were no abnormal levels of contaminants or endotoxin. Given that C-PFTA preparation methods have been hampered by wide variability, we conducted particle characterization analyses to determine C-PFTA crystal size distributions compared with TA controls. TA control samples examined with phase-contrast microscopy revealed an average particle diameter of 11.8±1.2 μm and the formation of large (100-200 μm) aggregates. Using a more advanced laser diffraction technique (Beckman Coulter [Brea, CA], LS100Q), we observed unimodal (26.1 μm) crystal size distributions in TA samples with 80% of particle diameters measuring between 10 μm and 45 μm without aggregates. In contrast, microscopic studies of the affected C-PFTA samples and stock powder showed large aggregates and significantly decreased average particle diameters of 4.6±0.7 μm and 5.3±0.7 μm, respectively (P<0.001). Laser diffraction analyses of C-PFTA demonstrated smaller crystal size distributions (mode 12.4 μm) with 80% of particles between 4.2 μm and 55.0 μm and <10% of total particle population forming aggregates between 50-120 μm (Fig. 2, available at http://aaojournal.org). Raw stock powder showed slightly decreased differences (mode 21.7 μm). Figure 2 Crystal size analyses of TA (Kenalog) and C-PFTA samples were conducted using techniques in phase-contrast microscopy (left) and high-accuracy laser diffraction (right). With microscopy, TA crystals appeared uniform in aggregates (A) in comparison to ... We then purchased 3 additional samples from 2 different major compounding pharmacies, as well as P-PFTA (Triesence) for analysis. For comparison, crystal size distributions for TA both in vehicle and washed in balanced salt solution (BSS) were evaluated. Strikingly, reduced crystal sizes and highly variable aggregation were observed in all C-PFTA samples tested (Fig. 3, available at http://aaojournal.org). Two of these samples exhibited submicron crystal populations ranging from 0.5 to 4 μm, but these had been previously administered by us without such adverse effects. Our finding of increased particle aggregates in PFTA samples supports a recently published article,5 but we observed these aggregates in all of the C-PFTA samples tested suggesting that they may not be the issue. Instead, we hypothesized that the modal distribution of particles (~12 μm) in the affected lot may physically obstruct the trabecular meshwork resulting in acute and severe IOP spikes. In our final studies, we found that P-PFTA and TA washed and resuspended in BSS also showed reduced particle diameters compared with TA in vehicle (P<0.01) but with improved retention of unimodal distributions and minimal aggregate formation (Fig. 4, available at http://aaojournal.org). Figure 3 Further laser diffraction studies conducted on other commercial sources of C-PFTA demonstrated wide variability with regards to crystal size distributions and aggregate formation; however, a trend of decreased individual crystal size was identified in ... Figure 4 Laser diffraction particle analyses of P-PFTA (Triesence) (A) and on-site pre-procedural filtered TA (B) revealed improved retention of unimodal distributions and crystal size parameters compared to the C-PFTA samples. C-PFTA = compounded PFTA; PFTA = ... The question arose as to why these particle size variations in PFTA preparations had not been previously reported. In a follow-up study using a Hiac-Royco Particulate Analyzer (Pacific Scientific, Silver Spring, MD), a gold-standard in the pharmaceutical industry, no significant crystal size variations were detected between our C-PFTA samples. While there are fundamental differences in the detectors used by the 2 machines (light scatter versus obscuration), we suggest that in order to reliably assess deviations in PFTA crystal size populations and standardize uniformity, post-purification quality controls will need to be conducted with more highly sensitive particle sizing instruments.

CLEARANCE OF ANTITRANSFERRIN RECEPTOR IMMUNOTOXIN FROM THE RABBIT EYE

PURPOSE Antitransferrin receptor immunotoxin has potent antiproliferative effects on proliferating human ocular cells in vitro, and shows promise in the treatment of ocular proliferative diseases, such as proliferative vitreoretinopathy, bleb scarring after trabeculectomy, or corneal epithelial downgrowth syndrome. Before treating patients, the pharmacokinetics of immunotoxin must be known. The purpose of this study was to determine the clearance of antitransferrin receptor immunotoxin from the rabbit eye after ocular injection. METHODS Immunotoxin (1,000 ng/0.1 ml PBS) was injected into the vitreous cavity of gas vitrectomized rabbit eyes. Immunotoxin in aqueous, vitreous, and plasma was measured by ELISA at various times after injection. Similar measurements were obtained after immunotoxin was injected into the anterior chamber or subconjunctival space of eyes which had not received vitrectomy. Cultured human retinal pigment epithelial cells were exposed to vitreous fluid obtained after intravitreal injection, and counted after four days, to determine the bioactivity of immunotoxin recovered from vitreous samples. RESULTS Immunotoxin was cleared rapidly from the vitreous cavity over the first 24 hr (t1/2 = 8.0 hr), and thereafter was slow. Drug recovered from the vitreous cavity retained significant antiproliferative activity at 96 hr. Immunotoxin was cleared within 6 hr from the aqueous after anterior chamber injection, and was not present inside the eye after subconjunctival injection. The plasma did not contain immunotoxin after any of these injections. CONCLUSIONS The favorable pharmacokinetics of antitransferrin receptor immunotoxin in the rabbit eye suggests that it could be useful in the treatment of ocular proliferative disorders.