Dr. Altaweel is an Assistant Professor of Ophthalmology at the University of Wisconsin School of Medicine and Public Health and Co-Director of the University of Wisconsin Department of Ophthalmology Fundus Photograph Reading Center. His clinical specialties include diseases and surgery of the retina and vitreous, and fundus interpretation. His research interests include clinical trials of drug efficacy as well as the scientific grading of retinal photographs and fluorescein angiograms.
Combined minimally invasive conjunctival surgery with lens repositioning for traumatic bleb leak with dislocated intraocular lens
Trauma Case Rep. 2023 Sep 24;48:100936. doi: 10.1016/j.tcr.2023.100936. eCollection 2023 Dec.
PURPOSE: We report a case of traumatic bleb leak following trabeculectomy and dislocated intraocular lens treated with combined minimally invasive conjunctival surgery (MICS) and lens repositioning.
OBSERVATIONS: A 36-year-old woman with a history of phacomorphic glaucoma secondary to microspherophakia and status post trabeculectomy underwent combined MICS and lens repositioning for a late-onset bleb leak and dislocated intraocular lens following minor trauma. The patient's vision rapidly improved postoperatively with prompt resolution of hypotony.
CONCLUSION/IMPORTANCE: MICS is an effective treatment for traumatic bleb leak following trabeculectomy that can be a particularly useful approach for patients undergoing concurrent ophthalmic surgery.
Cataract Surgery in Patients With Uveitis Treated With Systemic Therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study: Risk Factors and Outcomes
Am J Ophthalmol. 2023 Oct;254:210-220. doi: 10.1016/j.ajo.2023.06.023. Epub 2023 Jul 3.
PURPOSE: To evaluate the rate of, risk factors for, and outcomes of cataract surgery in patients with intermediate, posterior, and panuveitides treated with systemic corticosteroids and immunosuppression.
DESIGN: Cohort study of participants from a randomized clinical trial.
METHODS: A multicenter clinical trial with extended follow-up comprised the study setting. From the cohort of participants assigned to systemic therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study, 125 phakic eyes of 74 patients with intermediate, posterior, or panuveitides treated with systemic therapy were included. The main outcome measures were cataract surgery and visual acuity after cataract surgery.
RESULTS: The cumulative incidence of cataract surgery was 43% at 7 years of follow-up, and the risk did not plateau. Risk factors for cataract surgery included age >50 years (hazard ratio [HR] 2.86, 95% CI 1.52, 5.42; P = .001), topical corticosteroid use (time-updated HR 3.13, 95% CI 1.42, 6.94; P = .005), glaucoma medication use (HR 2.75, 95% CI 1.38, 5.47; P = .004), and possibly history of anterior chamber inflammation (HR 1.90, 95% CI 0.95, 3.84; P = .07). Median gain in acuity and median best corrected visual acuity 1 year after cataract surgery were 4.8 lines and 20/25, respectively, among 42 eyes undergoing cataract surgery with 1-year follow-up data.
CONCLUSIONS: Among patients with intermediate, posterior, and panuveitides, treated with oral corticosteroids and immunosuppression, there is a substantial long-term risk of cataract surgery. Visual acuity outcomes after cataract surgery are generally good.
Coats' Disease in a Patient With Cornelia de Lange Syndrome: Management With Laser and Bevacizumab
J Pediatr Ophthalmol Strabismus. 2023 Jul-Aug;60(4):e45-e48. doi: 10.3928/01913913-20230619-03. Epub 2023 Jul 1.
Cornelia de Lange syndrome is a congenital disorder with multisystem abnormalities including multiple ocular findings. The authors report a case of Coats' disease in a patient with Cornelia de Lange syndrome who was successfully treated with laser and intravitreal bevacizumab. This case demonstrates the importance of fluorescein angiography in making the diagnosis and directing treatment and the efficacy of combined laser with intravitreal anti-vascular endothelial growth factor therapy for persistent vascular leakage associated with Coats' disease in Cornelia de Lange syndrome. [J Pediatr Ophthalmol Strabismus. 2023;60(4):e45-e48.].
Intravitreal Therapy for Uveitic Macular Edema-Ranibizumab versus Methotrexate versus the Dexamethasone Implant: The MERIT Trial Results
Ophthalmology. 2023 Sep;130(9):914-923. doi: 10.1016/j.ophtha.2023.04.011. Epub 2023 Jun 13.
PURPOSE: To evaluate the effectiveness of 3 different intravitreal treatments for persistent or recurrent uveitic macular edema (ME): dexamethasone implant, methotrexate, and ranibizumab.
DESIGN: Single-masked, randomized controlled clinical trial.
PARTICIPANTS: Patients with minimally active or inactive uveitis and persistent or recurrent uveitic ME in one or both eyes.
METHODS: Patients at 33 centers were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME received the same treatment in both eyes.
MAIN OUTCOME MEASURES: The primary outcome, measured at 12 weeks, was reduction in central subfield thickness (CST) expressed as a proportion of baseline (CST per CST at baseline) assessed with spectral-domain OCT by readers masked to treatment assignment. Secondary outcomes included improvement and resolution of ME, change in best-corrected visual acuity (BCVA), and elevations in intraocular pressure (IOP).
RESULTS: One hundred ninety-four participants (225 eligible eyes) were randomized to dexamethasone (n = 65 participants and 77 eyes), methotrexate (n = 65 participants and 79 eyes), or ranibizumab (n = 64 participants and 69 eyes). All received at least 1 injection of the assigned treatment. At the 12-week primary outcome point, each group showed significant reductions in CST relative to baseline: 35%, 11%, and 22% for dexamethasone, methotrexate, and ranibizumab, respectively. Reduction of ME was significantly greater in the dexamethasone group than for either methotrexate (P < 0.01) or ranibizumab (P = 0.018). Only the dexamethasone group showed a statistically significant improvement in BCVA during follow-up (4.86 letters; P < 0.001). Elevations of IOP by 10 mmHg, to 24 mmHg or more, or both were more common in the dexamethasone group; IOP spikes to 30 mmHg or more were uncommon overall and were not significantly different among groups. Reductions in BCVA of 15 letters or more were more common in the methotrexate group and typically were attributable to persistent ME.
CONCLUSIONS: At 12 weeks, in eyes with minimally active or inactive uveitis, dexamethasone was significantly better at treating persistent or recurrent ME than methotrexate or ranibizumab. Risk of IOP elevation was greater with dexamethasone, but elevations to levels of 30 mmHg or more were infrequent.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Central Retinal Thickness and Visual Acuity Outcomes After Vitrectomy for Epiretinal Membrane With and Without Internal Limiting Membrane Peel
J Vitreoretin Dis. 2021 May 6;6(2):122-125. doi: 10.1177/24741264211009505. eCollection 2022 Mar-Apr.
PURPOSE: This work compares best-corrected visual acuity (BCVA) and central retinal thickness (CRT) outcome measures following pars plana vitrectomy (PPV) with and without internal limiting membrane (ILM) peel for epiretinal membrane (ERM).
METHODS: A retrospective cohort study was conducted of 114 eyes of 114 patients with visually significant ERM undergoing PPV with membrane peel (PPV/MP) at a single institution. CRT measurements were collected from Heidelberg and Zeiss spectral-domain optical coherence tomography imaging units. Results compared preoperative and postoperative CRT and BCVA among patients with at least 60 days of follow-up.
RESULTS: A total of 114 eyes with ERM met the inclusion criteria. Eighty-one eyes (71%) underwent PPV/MP with ILM peel and 33 eyes (29%) underwent PPV/MP without ILM peel. There was no statistically significant difference between preoperative CRT between the 2 study groups (P = .95). The mean follow-up time of eyes undergoing PPV/MP without ILM peel and with ILM peel was 391 days and 319 days, respectively. There was no statistical difference in the mean reduction of CRT between the 2 groups (P = .470). Both groups had improvement of BCVA following surgery and there was no statistical difference in final logMAR visual acuity when comparing the 2 groups (P = .738).
CONCLUSIONS: There was an overall improvement of CRT and BCVA among patients undergoing PPV/MP for ERM with or without ILM peel. There was no statistically significant difference in the final BCVA or CRT between the 2 groups.
Bilateral Globe Penetration From Electromyography Electrode Placement for Intraoperative Neurophysiologic Monitoring
J Vitreoretin Dis. 2019 Oct 16;4(2):136-138. doi: 10.1177/2474126419868888. eCollection 2020 Mar-Apr.
PURPOSE: This interventional case report discusses inadvertent bilateral temporal globe penetration during placement of intramuscular wire electrodes to the lateral rectus muscles for intraoperative neurophysiological monitoring (IONM) via electromyography.
METHODS: An 11-year-old girl underwent surgical resection of massive medulloblastoma within the fourth ventricle, requiring IONM. Placement of an electrode in each lateral rectus muscle resulted in bilateral globe penetration, with choroidal rupture, retinal tears, and hemorrhage.
RESULTS: Sterile needle perforation of the globe did not result in endophthalmitis. Encircling laser retinopexy was performed, and no retinal detachments occurred.
CONCLUSIONS: Insertion of needle electrodes without guidance imaging can potentially lead to globe penetration and incorrect electrode placement. Direct visualization with ultrasound, electromyography, or other advanced image-guided systems may offer a safe solution for electrode placement to avoid injury. Verbal patients should be made aware of postoperative warning signs of globe penetration. For nonverbal patients, a postoperative dilated exam is warranted.
The Conundrum of Clinical Trials for the Uveitides: Appropriate Outcome Measures for One Treatment Used in Several Diseases
Epidemiol Rev. 2022 Dec 21;44(1):2-16. doi: 10.1093/epirev/mxac001.
The uveitides consist of >30 diseases characterized by intraocular inflammation. Noninfectious intermediate, posterior, and panuveitides typically are treated with oral corticosteroids and immunosuppression, with a similar treatment approach for most diseases. Because these uveitides collectively are considered a rare disease, single-disease trials are difficult to impractical to recruit for, and most trials have included several different diseases for a given protocol treatment. However, measures of uveitis activity are disease specific, resulting in challenges for trial outcome measures. Several trials of investigational immunosuppressive drugs or biologic drugs have not demonstrated efficacy, but design problems with the outcome measures have limited the ability to interpret the results. Successful trials have included diseases for which a single uveitis activity measure suffices or a composite measure of uveitis activity is used. One potential solution to this problem is the use of a single, clinically relevant outcome, successful corticosteroid sparing, defined as inactive uveitis with a prednisone dose ≤7.5 mg/day coupled with disease-specific guidelines for determining inactive disease. The clinical relevance of this outcome is that active uveitis is associated with increased risks of visual impairment and blindness, and that prednisone doses ≤7.5 mg/day have a minimal risk of corticosteroid side effects. The consequence of this approach is that trial visits require a core set of measures for all participants and a disease-specific set of measures, both clinical and imaging, to assess uveitis activity. This approach is being used in the Adalimumab Versus Conventional Immunosuppression (ADVISE) Trial.
Management of Iris Retraction Syndrome with Heterochromia and Retinal Detachment
Case Rep Ophthalmol. 2021 Sep 23;12(3):809-815. doi: 10.1159/000519148. eCollection 2021 Sep-Dec.
Iris retraction syndrome (IRS) is an uncommon condition caused by retinal detachment that is characterized by back bowing of the peripheral iris, leading to a deep anterior chamber. It is commonly associated with ocular hypotony, ciliochoroidal detachment, and anterior proliferative vitreoretinopathy. We describe a case of a 66-year-old man presenting with 2 weeks of right eye pain, redness, and iris heterochromia. The patient was diagnosed with IRS secondary to a chronic retinal detachment. Initial management with topical steroids and mydriasis allowed resolution of the iris retraction and heterochromia, normalization of intraocular pressure, and improvement of choroidal detachment. Subsequent vitrectomy with endolaser and oil tamponade led to successful detachment repair. Initial pharmacologic management allows a more controlled approach to the repair of retinal detachment associated with IRS. The patient's presentation is consistent with the hydrodynamic hypothesis of IRS.
Outcomes of Rhegmatogenous Retinal Detachment Repair When Comparing Surgeon Continuity in a Team-Based Practice
Ophthalmic Surg Lasers Imaging Retina. 2021 Oct;52(10):560-566. doi: 10.3928/23258160-20210922-01. Epub 2021 Oct 1.
BACKGROUND AND OBJECTIVE: To facilitate timely surgery and efficient use of operating room time, our practice uses a team-based approach so patients may undergo primary rhegmatogenous retinal detachment (RRD) surgery with a different surgeon instead of the diagnosing surgeon.
PATIENTS AND METHODS: This was a retrospective cohort study of 331 eyes that underwent RRD surgery. Patients were divided into two groups: RRD surgery performed by the diagnosing surgon, and RRD surgery performed by a different surgeon.
RESULTS: Of 331 eyes, 200 eyes (60.4%) were repaired by the diagnosing surgeon and 131 eyes (39.6%) were repaired by a different surgeon. Primary anatomic success (PAS) rates at 3 months postoperatively were equivalent between the two groups (87.0% and 87.8% in the diagnosing surgeon and different surgeon groups, respectively [P = .83]). There was no significant difference in preoperative (P = .08) or final (P = .28) visual acuity between the groups. Time between diagnosis and RRD repair was shorter in the different surgeon group (median of 1.5 days [IQR: 1.0-3.6] in the surgeon group versus 2.2 days [IQR: 0.8-5.7] in the diagnosing surgeon group) (P = .03). Logistic regression analysis gave no evidence to suggest that PAS rates depended on day of week, time of day surgery was performed, group, or the interaction between those factors (P = .93).
CONCLUSIONS: Visual and anatomic success in RRD repair are equivalent when surgery is performed by either the diagnosing surgeon or a surgical colleague because time to surgery is reduced. Neither time of day nor day of the week had any influence on the outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:560-566.].
Management of Retinal Detachment Associated with Morning Glory Disc Syndrome
Case Rep Ophthalmol. 2021 May 25;12(2):457-463. doi: 10.1159/000516205. eCollection 2021 May-Aug.
We report a case of morning glory disc anomaly in a young patient with tractional retinal detachment successfully repaired with complex pars plana vitrectomy, membrane peel, laser, and oil tamponade. A 19-year-old female with a history of right morning glory disc anomaly associated with PAX6 gene mutation presented with floaters, photopsia, central scotoma, and visual acuity (VA) of 1/200. A complex macula-involving tractional retinal detachment centered around the optic nerve with a morning glory disc anomaly. Retinal detachment was treated with 25-gauge pars plana vitrectomy with difficult separation of the posterior hyaloid. Fibrous preretinal membranes were peeled, a temporal relaxing retinotomy was required, subretinal fluid was drained through a superonasal retinotomy during air-fluid exchange, endolaser was applied, and tamponade was achieved with 1,000-centistoke silicone oil. The retina remained attached at 1-year follow-up, with VA count fingers throughout. Morning glory disc is a rare congenital anomaly associated with PAX6 gene mutation that most often occurs unilaterally. It is rarely associated with tractional retinal detachment. Optimization of visual outcome is imperative despite a poor visual prognosis.
Seven-Year Outcomes of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial and Follow-up Study Results
Ophthalmology. 2021 May;128(5):719-728. doi: 10.1016/j.ophtha.2020.08.035. Epub 2020 Sep 10.
PURPOSE: To evaluate the long-term outcomes of uveitic macular edema (ME).
DESIGN: Longitudinal follow-up of a cohort of participants in a randomized clinical trial.
PARTICIPANTS: A total of 248 eyes of 177 participants with uveitic ME enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study.
METHODS: OCT measurements, taken at baseline and annually, were graded by reading center graders masked to clinical data. Macular edema was defined as a center macular thickness (CMT) ≥240 μm on time-domain OCT or time-domain OCT equivalent. Resolution of ME was defined as normalization of macular thickness on OCT. Relapse of ME was defined as increase in macular thickness to ≥240 μm in an eye that previously had resolution. Visual acuity was measured at each visit with logarithmic visual acuity charts.
MAIN OUTCOME MEASURES: Resolution and relapse of ME. Visual acuity.
RESULTS: Among 227 eyes with ME followed ≥1 year, the cumulative percent of eyes with ME resolving at any point during 7 years was 94% (95% confidence interval [CI], 89-97). Epiretinal membranes on OCT were associated with a lower likelihood of ME resolution (hazard ratio [HR], 0.74; 95% CI, 0.55-1.01; P = 0.05). Among 177 eyes with resolved ME, the cumulative percent with relapse within 7 years was 43% (95% CI, 32-51). Eyes in which ME resolved gained a mean of 6.24 letters (95% CI, 4.40-8.09; P < 0.001) compared with eyes that remained free from ME during the 1-year follow-up intervals, whereas eyes in which ME did not resolve experienced no gain in vision (mean change -1.30 letters; 95% CI, -2.70 to 0.09; P = 0.065), and eyes that developed ME during the year (incident or relapsed) experienced a mean loss of -8.65 letters (95% CI, -11.5 to -5.84, P < 0.001).
CONCLUSIONS: Given sufficient time and treatment, nearly all uveitic ME resolves, but episodes of relapse were common. Visual acuity results were better among eyes with resolved ME, suggesting that control of inflammation and resolution of ME might be visually relevant treatment targets.
Alcohol Pads and Nonsterile Gloves in Preparation of Aflibercept
Ophthalmol Retina. 2020 Aug;4(8):853-854. doi: 10.1016/j.oret.2020.04.006.
Use of nonsterile gloves and an alcohol pad does not significantly impact the contamination of the rubber septum of the aflibercept vial. Other contamination points might instead be explored for endophthalmitis risk.
Incidence and Outcome of Uveitic Glaucoma in Eyes With Intermediate, Posterior, or Panuveitis Followed up to 10 Years After Randomization to Fluocinolone Acetonide Implant or Systemic Therapy
Am J Ophthalmol. 2020 Nov;219:303-316. doi: 10.1016/j.ajo.2020.06.038. Epub 2020 Jul 3.
PURPOSE: To evaluate long-term risk and outcomes of glaucoma in eyes with intermediate, posterior, and panuveitis managed with systemic or fluocinolone acetonide (0.59 mg, "implant") therapy.
DESIGN: Prospective Follow-up of the Multicenter Uveitis Steroid Treatment (MUST) Clinical Trial Cohort.
METHODS: Patients with intermediate, posterior, or panuveitis randomized to implant or systemic therapy (corticosteroid plus immunosuppression in >90%) were followed prospectively for glaucoma incidence and outcome.
RESULTS: Among 405 uveitic at-risk eyes of 232 patients (median follow-up = 6.9 years), 40% (79/196) of eyes assigned and treated with implant and 8% (17/209) of eyes assigned and treated with systemic therapy (censoring eyes receiving an implant on implantation) developed glaucoma (hazard ratio [HR] = 5.9, 95% confidence interval [CI] 3.2, 10.8; P < .001). Adjustment for intraocular pressure (IOP) elevation during follow-up only partially mitigated the association of implant treatment with glaucoma incidence: HR = 3.1 (95% CI 1.6, 6.0); P = .001. Among 112 eyes of 83 patients developing glaucoma, the 5-year cumulative incidence following diagnosis of sustained (2 or more consecutive visits) worsening of mean deviation by ≥6 dB was 20% (95% CI 12%, 33%); 5-year cumulative incidence of sustained worsening of cup-to-disc ratio by ≥0.2 was 26% (95% CI 17%, 39%).
CONCLUSIONS: The implant has substantially higher risk of glaucoma than systemic therapy, a difference not entirely explained by posttreatment IOP elevation. Management of IOP elevation was effective in preventing worsening of glaucoma for the large majority of cases, but even under expert clinical management, some glaucoma worsened. Uveitis cases should be monitored carefully for IOP elevation and glaucoma indefinitely.
Visual Acuity Outcome over Time in Non-Infectious Uveitis
Ocul Immunol Inflamm. 2021 Aug 18;29(6):1064-1071. doi: 10.1080/09273948.2019.1687733. Epub 2019 Dec 10.
Introduction: We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population.Methods: Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up.Results: Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels.Conclusion: Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.
Periocular Triamcinolone vs. Intravitreal Triamcinolone vs. Intravitreal Dexamethasone Implant for the Treatment of Uveitic Macular Edema: The PeriOcular vs. INTravitreal corticosteroids for uveitic macular edema (POINT) Trial
Ophthalmology. 2019 Feb;126(2):283-295. doi: 10.1016/j.ophtha.2018.08.021. Epub 2018 Sep 27.
PURPOSE: To evaluate the comparative effectiveness of 3 regional corticosteroid injections for uveitic macular edema (ME): periocular triamcinolone acetonide (PTA), intravitreal triamcinolone acetonide (ITA), and the intravitreal dexamethasone implant (IDI).
DESIGN: Multicenter, randomized clinical trial.
PARTICIPANTS: Patients with uveitic ME.
METHODS: Patients were randomized 1:1:1 to receive 1 of the 3 therapies. Patients with bilateral ME were assigned the same treatment for both eyes.
MAIN OUTCOME MEASURES: The primary outcome was the proportion of baseline (PropBL) central subfield thickness (CST) at 8 weeks (CST at 8 weeks/CST at baseline) assessed with OCT by masked readers. Secondary outcomes included ≥20% improvement and resolution of ME, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) events over 24 weeks.
RESULTS: All treatment groups demonstrated improved CST during follow-up. At 8 weeks, each group had clinically meaningful reductions in CST relative to baseline (PropBL: 0.77, 0.61, and 0.54, respectively, which translates to reductions of 23%, 39%, and 46% for PTA, ITA, and IDI, respectively). Intravitreal triamcinolone acetonide (PropBL ITA/PropBL PTA, hazard ratio [HR], 0.79; 99.87% confidence interval [CI], 0.65-0.96) and IDI (PropBL IDI/PropBL PTA, HR, 0.69; 99.87% CI, 0.56-0.86) had larger reductions in CST than PTA (P < 0.0001). Intravitreal dexamethasone implant was noninferior to ITA at 8 weeks (PropBL IDI/PropBL ITA, HR, 0.88; 99.87% CI, 0.71-1.08). Both ITA and IDI treatments also were superior to PTA treatment in improving and resolving uveitic ME. All treatment groups demonstrated BCVA improvement throughout follow-up. Both ITA and IDI groups had improvements in BCVA that was 5 letters greater than in the PTA group at 8 weeks (P < 0.004). The risk of having IOP ≥24 mmHg was higher in the intravitreal treatment groups compared with the periocular group (HR, 1.83; 95% CI, 0.91-3.65 and HR, 2.52; 95% CI, 1.29-4.91 for ITA and IDI, respectively); however, there was no significant difference between the 2 intravitreal treatment groups.
CONCLUSIONS: Intravitreal triamcinolone acetonide and the IDI were superior to PTA for treating uveitic ME with modest increases in the risk of IOP elevation. This risk did not differ significantly between intravitreal treatments.
Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial
JAMA Ophthalmol. 2018 Apr 1;136(4):337-345. doi: 10.1001/jamaophthalmol.2017.6843.
IMPORTANCE: Comparisons of monthly vs treat-and-extend anti-vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed.
OBJECTIVE: To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016.
MAIN OUTCOMES AND MEASURES: Change from month 6 to month 12 in best-corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study).
RESULTS: The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, -1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, -1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001).
CONCLUSIONS AND RELEVANCE: One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes.
TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT01969708.
Association Between Long-Lasting Intravitreous Fluocinolone Acetonide Implant vs Systemic Anti-inflammatory Therapy and Visual Acuity at 7 Years Among Patients With Intermediate, Posterior, or Panuveitis
JAMA. 2017 May 16;317(19):1993-2005. doi: 10.1001/jama.2017.5103.
IMPORTANCE: A randomized clinical trial comparing fluocinolone acetonide implant vs systemic corticosteroids and immunosuppression for treatment of severe noninfectious intermediate, posterior, and panuveitides did not result in a significant difference in visual acuity at 2 and 4.5 years; longer-term outcomes are not known.
OBJECTIVE: To compare the association between intravitreous fluocinolone acetonide implant vs systemic therapy and long-term visual and other outcomes in patients with uveitis.
DESIGN, SETTING, AND PARTICIPANTS: Nonprespecified 7-year observational follow-up of the Multicenter Uveitis Steroid Treatment (MUST) randomized clinical trial comparing the alternative treatments. Follow-up was conducted in tertiary uveitis subspecialty practices in the United States (21), the United Kingdom (1), and Australia (1). Of 255 patients 13 years or older with intermediate, posterior, or panuveitis (active within ≤60 days) enrolled in the MUST trial between December 6, 2005, and December 9, 2008, 215 consented to ongoing follow-up through at least 7 years postrandomization (last visit, February 10, 2016).
INTERVENTIONS: Participants had been randomized to receive a surgically placed intravitreous fluocinolone acetonide implant or systemic corticosteroids supplemented by immunosuppression. When both eyes required treatment, both eyes were treated.
MAIN OUTCOMES AND MEASURES: Primary outcome was change from baseline in best-corrected visual acuity in uveitic eyes (5 letters = 1 visual acuity chart line; potential range of change in letters read, -121 to +101; minimal clinically important difference, 7 letters), analyzed by treatment assignment accounting for nonindependence of eyes when patients had 2 uveitic eyes. Secondary outcomes included potential systemic toxicities of corticosteroid and immunosuppressive therapy and death.
RESULTS: Seven-year data were obtained for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy) (77% female; median age at enrollment, 48 [interquartile range, 36-56] years). Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1-12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).
CONCLUSIONS AND RELEVANCE: In 7-year extended follow-up of a randomized trial of patients with severe intermediate, posterior, or panuveitis, those randomized to receive systemic therapy had better visual acuity than those randomized to receive intravitreous fluocinolone acetonide implants. Study interpretation is limited by loss to follow-up.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00132691.
TWO CASES OF ACUTE RETINAL NECROSIS DUE TO VARICELLA ZOSTER DESPITE PRIOR SHINGLES VACCINATION
Retin Cases Brief Rep. 2019 Summer;13(3):241-243. doi: 10.1097/ICB.0000000000000567.
PURPOSE: To review two cases of acute retinal necrosis in adults due to varicella zoster virus despite prior shingles vaccination.
METHODS: Retrospective chart review.
PATIENTS: A 62-year-old man and a 64-year-old man with unilateral acute retinal necrosis who had shingles vaccinations 16 and 7 months before their ocular symptoms.
RESULTS: Polymerase chain reaction confirmation of varicella zoster virus in the anterior chambers of both patients. Both patients had good responses to oral antiviral therapy and topical and/or oral steroids.
DISCUSSION: These two cases demonstrate that singles vaccination is not an absolute protection against varicella zoster virus-related acute retinal necrosis. However, such vaccination may reduce the severity of the acute retinal necrosis.
VISCOELASTIC ASSISTED DRAINAGE OF SUPRACHOROIDAL HEMORRHAGE ASSOCIATED WITH SETON DEVICE IN GLAUCOMA FILTERING SURGERY
Retina. 2017 Feb;37(2):396-399. doi: 10.1097/IAE.0000000000001141.
PURPOSE: The purpose of this article is to describe a novel surgical technique for the management of large suprachoroidal hemorrhages associated with the insertion of glaucoma seton devices.
METHODS: In this interventional case series, the authors describe six eyes of six patients who had management of suprachoroidal hemorrhage with pars plana choroidal drainage along with simultaneous insertion of viscoelastic into the posterior segment. All patients had a median of 8-month postoperative follow-up.
RESULTS: Five of the 6 patients had useful final vision ranging from 20/40 to 20/200. In all cases, the postoperative intraocular pressures did not increase beyond 28 mmHg and responded to aqueous humor suppressants.
CONCLUSION: As suprachoroidal hemorrhage can be a devastating complication of glaucoma surgery, the authors report a relatively straightforward surgical technique that can restore ambulatory vision in a high proportion of patients.
Morphological assessment of the retina in uveitis
J Ophthalmic Inflamm Infect. 2016 Dec;6(1):33. doi: 10.1186/s12348-016-0103-2. Epub 2016 Sep 9.
BACKGROUND: The objective of this study is to describe a system for color photograph evaluation in uveitis and report baseline morphologic findings for the Multicenter Uveitis Steroid Treatment (MUST) Trial. Four-hundred seventy-nine eyes of 255 subjects with intermediate, posterior, and panuveitis had stereoscopic color fundus photographs obtained by certified photographers and evaluated by certified graders using standardized procedures to evaluate morphologic characteristics of uveitis. The posterior pole was evaluated for macular edema, vitreoretinal interface abnormalities, and macular pigment disturbance/atrophy; the optic disk was assessed for edema, pallor, or glaucomatous changes. The presence of neovascularization, vascular occlusion, vascular sheathing, and tractional retinal changes was determined. A random subset of 77 images was re-graded to determine the percentage agreement with the original grading on a categorical scale.
RESULTS: At baseline, 437/479 eyes had images available to grade. Fifty-three eyes were completely ungradable due to media opacity. Common features of intermediate and posterior/panuveitis were epiretinal membrane (134 eyes, 35 %), and chorioretinal lesions (140 eyes, 36 %). Macular edema was seen in 16 %. Optic nerve head and vascular abnormalities were rare. Reproducibility evaluation found exact agreement for the presence of chorioretinal lesions was 78 %, the presence and location of macular edema was 71 %, and the presence of epiretinal membrane was 71 %. Vertical cup-to-disk ratio measurement had intra-class correlation of 0.75.
CONCLUSIONS: The MUST system for evaluating stereoscopic color fundus photographs describes the morphology of uveitis and its sequelae, in a standardized manner, is highly reproducible, and allows monitoring of treatment effect and safety evaluation regarding these outcomes in clinical trials.
Cataract Surgery Outcomes in Uveitis: The Multicenter Uveitis Steroid Treatment Trial
Ophthalmology. 2016 Jan;123(1):183-90. doi: 10.1016/j.ophtha.2015.09.022. Epub 2015 Oct 20.
PURPOSE: To assess the visual outcomes of cataract surgery in eyes that received fluocinolone acetonide implant or systemic therapy with oral corticosteroids and immunosuppression during the Multicenter Uveitis Steroid Treatment (MUST) Trial.
DESIGN: Nested prospective cohort study of patients enrolled in a randomized clinical trial.
PARTICIPANTS: Patients that underwent cataract surgery during the first 2 years of follow-up in the MUST Trial.
METHODS: Visual outcomes of cataract surgery were evaluated 3, 6, and 9 months after surgery using logarithmic visual acuity charts. Change in visual acuity over time was assessed using a mixed-effects model.
MAIN OUTCOME MEASURES: Best-corrected visual acuity.
RESULTS: After excluding eyes that underwent cataract surgery simultaneously with implant surgery, among the 479 eyes in the MUST Trial, 117 eyes (28 eyes in the systemic, 89 in the implant group) in 82 patients underwent cataract surgery during the first 2 years of follow-up. Overall, visual acuity increased by 23 letters from the preoperative visit to the 3-month visit (95% confidence interval [CI], 17-29 letters; P < 0.001) and was stable through 9 months of follow-up. Eyes presumed to have a more severe cataract, as measured by inability to grade vitreous haze, gained an additional 42 letters (95% CI, 34-56 letters; P < 0.001) beyond the 13-letter gain in eyes that had gradable vitreous haze before surgery (95% CI, 9-18 letters; P < 0.001) 3 months after surgery, making up for an initial difference of -45 letters at the preoperative visit (95% CI, -56 to -34 letters; P < 0.001). Black race, longer time from uveitis onset, and hypotony were associated with worse preoperative visual acuity (P < 0.05), but did not affect postsurgical recovery (P > 0.05, test of interaction). After adjusting for other risk factors, there was no significant difference in the improvement in visual acuity between the 2 treatment groups (implant vs. systemic therapy, 2 letters; 95% CI, -10 to 15 letters; P = 0.70).
CONCLUSIONS: Cataract surgery resulted in substantial, sustained, and similar visual acuity improvement in the eyes of patients with uveitis treated with the fluocinolone acetonide implant or standard systemic therapy.
Bevacizumab Versus Ranibizumab in the Treatment of Macular Edema Due to Retinal Vein Occlusion: 6-Month Results of the CRAVE Study
Ophthalmic Surg Lasers Imaging Retina. 2015 Sep;46(8):844-50. doi: 10.3928/23258160-20150909-09.
BACKGROUND AND OBJECTIVE: To compare efficacy of monthly treatment with bevacizumab or ranibizumab for macular edema due to retinal vein occlusion.
PATIENTS AND METHODS: Randomized, multicenter, comparative trial (ClinicalTrials.gov identifier: NCT01428388). Participants were randomized 1:1 to receive monthly treatment with bevacizumab or ranibizumab. The primary outcome was change in central foveal thickness at 6 months compared to baseline.
RESULTS: The trial randomized 98 patients to treatment with bevacizumab or ranibizumab. At 6 months, there were no differences in change in central foveal thickness between groups (bevacizumab: mean reduction of 212.6 µm, 95% confidence interval [CI], -288.3 to -137.0; ranibizumab: mean reduction of 243.8 µm, 95% CI, -309.6 to -178.0; P=.72, analysis of variance [ANOVA]). Both groups showed similar functional outcomes (bevacizumab: 0.33 logMAR gain, 95% CI, -0.47 to -0.18; ranibizumab: 0.34 logMAR gain, 95% CI, -0.45 to -0.23; P=.38, ANOVA).
CONCLUSION: In the treatment of retinal vein occlusion, bevacizumab and ranibizumab have similar effects on reducing macular thickness and improving visual acuity.
Factors Predicting Visual Acuity Outcome in Intermediate, Posterior, and Panuveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial
Am J Ophthalmol. 2015 Dec;160(6):1133-1141.e9. doi: 10.1016/j.ajo.2015.09.017. Epub 2015 Sep 18.
PURPOSE: To identify factors associated with best-corrected visual acuity (BCVA) presentation and 2-year outcome in 479 intermediate, posterior, and panuveitic eyes.
DESIGN: Cohort study using randomized controlled trial data.
METHODS: Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and at 2 years follow-up used gold-standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and 2-year change in BCVA.
RESULTS: Baseline factors significantly associated with reduced BCVA included age ≥50 vs <50 years; posterior vs intermediate uveitis; uveitis duration >10 vs <6 years; anterior chamber (AC) flare >grade 0; cataract; macular thickening; and exudative retinal detachment. Over 2 years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter (P = .52) and 10 letters (P < .001), respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, resolution of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6-10 or >10 vs <6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening.
CONCLUSIONS: Intermediate, posterior, and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.
Benefits of Systemic Anti-inflammatory Therapy versus Fluocinolone Acetonide Intraocular Implant for Intermediate Uveitis, Posterior Uveitis, and Panuveitis: Fifty-four-Month Results of the Multicenter Uveitis Steroid Treatment (MUST)…
Ophthalmology. 2015 Oct;122(10):1967-75. doi: 10.1016/j.ophtha.2015.06.042. Epub 2015 Aug 20.
PURPOSE: To compare the benefits of fluocinolone acetonide implant therapy versus systemic corticosteroid therapy supplemented (when indicated) with immunosuppression for intermediate uveitis, posterior uveitis, and panuveitis.
DESIGN: Additional follow-up of a randomized comparative effectiveness trial cohort.
PARTICIPANTS: Two hundred fifty-five patients with intermediate uveitis, posterior uveitis, or panuveitis randomized to implant or systemic therapy.
MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), visual field mean deviation (MD), activity of uveitis, and presence of macular edema (per reading center grading) ascertained prospectively.
METHODS: Trial participants were followed-up for 54 months from original randomization.
RESULTS: The visual function trajectory in uveitic eyes demonstrated a similar (P = 0.73) degree of modest (not statistically significant) improvement from baseline to 54 months in both groups (mean improvement in BCVA at 54 months, 2.4 and 3.1 letters in the implant and systemic groups, respectively). Many had excellent initial visual acuity, limiting the potential for improvement. The mean automated perimetry MD score remained similar to baseline throughout 48 months of follow-up in both groups. Overall control of inflammation was superior in the implant group at every time point assessed (P < 0.016), although most eyes in the systemic therapy arm also showed substantial improvement, achieving complete control or low levels of inflammation. Although macular edema improved significantly more often with implant treatment within the first 6 months, the systemic group gradually improved over time such that the proportions with macular edema converged in the 2 groups by 36 months and overlapped thereafter (P = 0.41 at 48 months).
CONCLUSIONS: Visual outcomes of fluocinolone acetonide implant and systemic treatment for intermediate uveitis, posterior uveitis, and panuveitis were similarly favorable through 54 months. The implant maintained a clear advantage in controlling inflammation through 54 months. Nevertheless, with systemic therapy, most patients also experienced greatly improved inflammatory status. Macular edema improved equally with longer follow-up. Based on cost effectiveness and side-effect considerations, systemic therapy may be indicated as the initial treatment for many bilateral uveitis cases. However, implant therapy is a reasonable alternative, especially for unilateral cases and when systemic therapy is not feasible or is not successful.
Shaggy photoreceptors with subfoveal fluid associated with a distant choroidal melanoma
Case Rep Ophthalmol Med. 2015;2015:187542. doi: 10.1155/2015/187542. Epub 2015 Feb 2.
Purpose. To describe the enhanced depth imaging optical coherence tomography (EDI-OCT) findings in a patient with an extra macula choroidal melanoma before and after treatment. Methods. Observational case report. Results. A 45 year-old Caucasian male patient was referred to retina clinic for management of choroidal melanoma. Examination revealed a nasal choroidal melanoma while EDI-OCT illustrated subfoveal fluid pocket with elongated shaggy photoreceptors distant and separate from the tumor. The patient was treated with plaque brachytherapy and intravitreal bevacizumab. One week after plaque removal, there was a dramatic reduction in the shaggy photoreceptors. Conclusion. Choroidal melanomas have effects that are not localized to the area of the tumor. This loculated pocket of subretinal fluid and coinciding changes to photoreceptor morphology may be related to global changes in choroidal function or release of tumor related cytokines.
Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)
Ophthalmology. 2015 Feb;122(2):391-398.e5. doi: 10.1016/j.ophtha.2014.08.020. Epub 2014 Oct 11.
OBJECTIVE: To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
DESIGN: Prospective cohort study within a multicenter randomized clinical trial.
PARTICIPANTS: CATT patients with neovascular age-related macular degeneration (AMD).
METHODS: Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA.
MAIN OUTCOME MEASURES: Morphologic features and VA at 1 and 2 years.
RESULTS: The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years.
CONCLUSIONS: In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood.
Response to aflibercept in patients with persistent exudation despite prior treatment with bevacizumab or ranibizumab for age-related macular degeneration
Ophthalmic Surg Lasers Imaging Retina. 2014 Sep-Oct;45(5):394-7. doi: 10.3928/23258160-20140909-03.
BACKGROUND AND OBJECTIVE: This study examines the clinical response of patients transitioned to aflibercept, the newest anti-VEGF medication, due to persistent evidence of exudation on optical coherence tomography (OCT) despite regular treatment with bevacizumab and/or ranibizumab.
PATIENTS AND METHODS: Aflibercept was administered to 111 patients considered for study inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with at least three injections of ranibizumab or bevacizumab. Retrospective data were collected from medical records.
RESULTS: Complete resolution of exudation was seen in 34% of eyes at final follow-up. Clear improvement in exudation amount or severity without complete resolution was seen in 25%. No improvement was seen in 34%, and 6% demonstrated worsening of exudation. Snellen visual acuity at the time of transition versus final follow-up after aflibercept injection did not appreciably change (logMAR 0.494 to 0.505, Snellen equivalent 20/62 to 20/64; P = .84). The mean center point neurosensory retina thickness decreased from 228.6 to 176.9 µm (P = .001).
CONCLUSION: Aflibercept may decrease the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity.
Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis
Ophthalmology. 2014 Oct;121(10):1855-62. doi: 10.1016/j.ophtha.2014.04.022. Epub 2014 Jun 5.
OBJECTIVE: To evaluate the 3-year incremental cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for the treatment of noninfectious intermediate, posterior, and panuveitis.
DESIGN: Randomized, controlled, clinical trial.
PARTICIPANTS: Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment Trial.
METHODS: Data on cost and health utility during 3 years after randomization were evaluated at 6-month intervals. Analyses were stratified by disease laterality at randomization (31 unilateral vs 224 bilateral) because of the large upfront cost of the implant.
MAIN OUTCOME MEASURES: The primary outcome was the incremental cost-effectiveness ratio (ICER) over 3 years: the ratio of the difference in cost (in United States dollars) to the difference in quality-adjusted life-years (QALYs). Costs of medications, surgeries, hospitalizations, and regular procedures (e.g., laboratory monitoring for systemic therapy) were included. We computed QALYs as a weighted average of EQ-5D scores over 3 years of follow-up.
RESULTS: The ICER at 3 years was $297,800/QALY for bilateral disease, driven by the high cost of implant therapy (difference implant - systemic [Δ]: $16,900; P < 0.001) and the modest gains in QALYs (Δ = 0.057; P = 0.22). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.003 and 0.04, respectively. The ICER for unilateral disease was more favorable, namely, $41,200/QALY at 3 years, because of a smaller difference in cost between the 2 therapies (Δ = $5300; P = 0.44) and a larger benefit in QALYs with the implant (Δ = 0.130; P = 0.12). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.53 and 0.74, respectively.
CONCLUSIONS: Fluocinolone acetonide implant therapy was reasonably cost-effective compared with systemic therapy for individuals with unilateral intermediate, posterior, or panuveitis but not for those with bilateral disease. These results do not apply to the use of implant therapy when systemic therapy has failed or is contraindicated. Should the duration of implant effect prove to be substantially >3 years or should large changes in therapy pricing occur, the cost-effectiveness of implant versus systemic therapy would need to be reevaluated.
Fluorescein angiography versus optical coherence tomography for diagnosis of uveitic macular edema
Ophthalmology. 2013 Sep;120(9):1852-9. doi: 10.1016/j.ophtha.2013.01.069. Epub 2013 May 21.
OBJECTIVE: To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis.
DESIGN: Multicenter cross-sectional study.
PARTICIPANTS: Four hundred seventy-nine eyes with uveitis from 255 patients.
METHODS: The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used.
MAIN OUTCOME MEASURES: Macular thickening (MT; center point thickness, ≥ 240 μm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema.
RESULTS: Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent.
CONCLUSIONS: Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Optical coherence tomography evaluation in the Multicenter Uveitis Steroid Treatment (MUST) trial
Ocul Immunol Inflamm. 2012 Dec;20(6):443-7. doi: 10.3109/09273948.2012.719258. Epub 2012 Nov 19.
PURPOSE: To describe the evaluation of optical coherence tomography (OCT) scans in the Muliticenter Uveitis Steroid Treatment (MUST) trial and report baseline OCT features of enrolled participants.
METHODS: Time-domain OCTs acquired by certified photographers using a standardized scan protocol were evaluated at a reading center. Accuracy of retinal thickness data was confirmed with quality evaluation, and caliper measurement of centerpoint thickness (CPT) was performed when retinal thickness data were unreliable. Morphological evaluation included cysts, subretinal fluid, epiretinal membranes (ERMs), and vitreomacular traction.
RESULTS: Of the 453 OCTs evaluated, automated retinal thickness was accurate in 69.5% of scans, caliper measurement was performed in 26%, and 4% were ungradable. Intraclass correlation was.98 for reproducibility of caliper measurement. Macular edema (centerpoint thickness ≥ 240 μm) was present in 36%. Cysts were present in 36.6% of scans and ERMs in 27.8%, predominantly central. Intergrader agreement ranged from 78 to 82% for morphological features.
CONCLUSION: Retinal thickness data can be retrieved in a majority of OCT scans in clinical trial submissions for uveitis studies. Small cysts and ERMs involving the center are common in intermediate and posterior/panuveitis requiring systemic corticosteroid therapy.
The impact of macular edema on visual function in intermediate, posterior, and panuveitis
Ocul Immunol Inflamm. 2012 Jun;20(3):171-81. doi: 10.3109/09273948.2012.658467. Epub 2012 Apr 24.
PURPOSE: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis.
DESIGN: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis.
PATIENTS & METHODS: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing.
RESULTS: Macular edema was associated with impaired visual acuity (p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (-5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (-13 letters) and with both cysts and thickening (-19 letters). Uveitis sufficient to satisfy the study's inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity (p < 0.01).
CONCLUSIONS: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24-2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma.
Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma
Ophthalmology. 2012 Aug;119(8):1596-603. doi: 10.1016/j.ophtha.2012.02.017. Epub 2012 Apr 21.
PURPOSE: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk).
DESIGN: Prospective, multicenter study.
PARTICIPANTS: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers.
TESTING: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status.
MAIN OUTCOME MEASURES: Patients were managed for their primary tumor and monitored for metastasis.
RESULTS: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status.
CONCLUSIONS: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.
Challenges in the design and implementation of the Multicenter Uveitis Steroid Treatment (MUST) Trial--lessons for comparative effectiveness trials
Clin Trials. 2011 Dec;8(6):736-43. doi: 10.1177/1740774511423682. Epub 2011 Oct 12.
BACKGROUND: Randomized clinical trials (RCTs) are an important component of comparative effectiveness (CE) research because they are the optimal design for head-to-head comparisons of different treatment options.
PURPOSE: To describe decisions made in the design of the Multicenter Uveitis Steroid Treatment (MUST) Trial to ensure that the results would be widely generalizable.
METHODS: Review of design and implementation decisions and their rationale for the trial.
RESULTS: The MUST Trial is a multicenter randomized controlled CE trial evaluating a novel local therapy (intraocular fluocinolone acetonide implant) versus the systemic therapy standard of care for noninfectious uveitis. Decisions made in protocol design in order to broaden enrollment included allowing patients with very poor vision and media opacity to enroll and including clinical sites outside the United States. The treatment protocol was designed to follow standard care. The primary outcome, visual acuity, is important to patients and can be evaluated in all eyes with uveitis. Other outcomes include patient-reported visual function, quality of life, and disease and treatment related complications.
LIMITATIONS: The trial population is too small for subgroup analyses that are of interest and the trial is being conducted at tertiary medical centers.
CONCLUSION: CE trials require greater emphasis on generalizability than many RCTs but otherwise face similar challenges for design choices as any RCT. The increase in heterogeneity in patients and treatment required to ensure generalizability can be balanced with a rigorous approach to implementation, outcome assessment, and statistical design. This approach requires significant resources that may limit implementation in many RCTs, especially in clinical practice settings.
Identifying a clinically meaningful threshold for change in uveitic macular edema evaluated by optical coherence tomography
Am J Ophthalmol. 2011 Dec;152(6):1044-1052.e5. doi: 10.1016/j.ajo.2011.05.028. Epub 2011 Sep 8.
PURPOSE: To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in visual acuity.
DESIGN: Cross-sectional and longitudinal study.
METHODS: One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more.
RESULTS: A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a -0.4-letter change (95% confidence interval, -4.1 to 3.3) in visual acuity for those without a 20% reduction (P < .01).
CONCLUSIONS: In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.
Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial
Ophthalmology. 2011 Oct;118(10):1916-26. doi: 10.1016/j.ophtha.2011.07.027. Epub 2011 Aug 15.
OBJECTIVE: To compare the relative effectiveness of systemic corticosteroids plus immunosuppression when indicated (systemic therapy) versus fluocinolone acetonide implant (implant therapy) for noninfectious intermediate, posterior, or panuveitis (uveitis).
DESIGN: Randomized controlled parallel superiority trial.
PARTICIPANTS: Patients with active or recently active uveitis.
METHODS: Participants were randomized (allocation ratio 1:1) to systemic or implant therapy at 23 centers (3 countries). Implant-assigned participants with bilateral uveitis were assigned to have each eye that warranted study treatment implanted. Treatment-outcome associations were analyzed by assigned treatment for all eyes with uveitis.
MAIN OUTCOME MEASURES: Masked examiners measured the primary outcome: change in best-corrected visual acuity from baseline. Secondary outcomes included patient-reported quality of life, ophthalmologist-graded uveitis activity, and local and systemic complications of uveitis or therapy. Reading Center graders and glaucoma specialists assessing ocular complications were masked. Participants, ophthalmologists, and coordinators were unmasked.
RESULTS: On evaluation of changes from baseline to 24 months among 255 patients randomized to implant and systemic therapy (479 eyes with uveitis), the implant and systemic therapy groups had an improvement in visual acuity of +6.0 and +3.2 letters (P = 0.16, 95% confidence interval on difference in improvement between groups, -1.2 to +6.7 letters, positive values favoring implant), an improvement in vision-related quality of life of +11.4 and +6.8 units (P = 0.043), a change in EuroQol-EQ5D health utility of +0.02 and -0.02 (P = 0.060), and residual active uveitis in 12% and 29% (P=0.001), respectively. Over the 24 month period, implant-assigned eyes had a higher risk of cataract surgery (80%, hazard ratio [HR] = 3.3, P < 0.0001), treatment for elevated intraocular pressure (61%, HR=4.2, P < 0.0001), and glaucoma (17%, HR=4.2, P = 0.0008). Patients assigned to systemic therapy had more prescription-requiring infections than patients assigned to implant therapy (0.60 vs 0.36/person-year, P=0.034), without notable long-term consequences; systemic adverse outcomes otherwise were unusual in both groups, with minimal differences between groups.
CONCLUSIONS: In each treatment group, mean visual acuity improved over 24 months, with neither approach superior to a degree detectable with the study's power. Therefore, the specific advantages and disadvantages identified should dictate selection between the alternative treatments in consideration of individual patients' particular circumstances. Systemic therapy with aggressive use of corticosteroid-sparing immunosuppression was well tolerated, suggesting that this approach is reasonably safe for local and systemic inflammatory disorders.
FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
Morphologic assessment for glaucoma in the Multicenter Uveitis Steroid Treatment (MUST) trial
Ocul Immunol Inflamm. 2011 Aug;19(4):267-74. doi: 10.3109/09273948.2011.583376.
PURPOSE: To compare Reading Center (RC) cup-to-disc ratio (CDR) assessment from stereoscopic photographs with clinician estimation in a uveitis clinical trial.
METHODS: Clinical estimation of CDR was performed by ophthalmologists via dilated biomicroscopy. Photographic evaluation was performed at an independent RC by masked, certified evaluators. Quality control was performed by repeat grading of 77 randomly selected images.
RESULTS: Among 479 eyes with uveitis, 353 eyes had clinical and photographic grades for CDR. Agreement between clinical and RC grading was fair, with exact agreement of 29%. Agreement within 0.1 and 0.2 CDR was 70 and 93%, respectively (weighted κ = .34). Intergrader reproducibility at the RC was better (weighted κ = .59, ICC 0.74).
CONCLUSION: Morphologic assessment of cup to disc ratio is an important outcome and safety measure for determining glaucomatous damage in clinical trials. Masked RC measurements are more likely to be accurate than biomicroscopic grading in identifying meaningful anatomical change associated with glaucoma.
Validation of a photographic vitreous haze grading technique for clinical trials in uveitis
Am J Ophthalmol. 2011 Aug;152(2):170-176.e1. doi: 10.1016/j.ajo.2011.01.058. Epub 2011 Jun 8.
PURPOSE: To validate a photographic vitreous haze grading technique using a 9-step logarithmic scale in patients enrolled in a randomized, controlled clinical trial in uveitis.
DESIGN: Retrospective study of clinical trials methodology.
SETTING: University-based department of ophthalmology.
STUDY POPULATION: Baseline fundus photographs of patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial.
OBSERVATIONAL PROCEDURE: Grading of vitreous haze using a previously described photographic scale. Regrading of a subset of photographs to assess intraobserver agreement.
MAIN OUTCOME MEASURES: Interobserver and intraobserver intraclass correlation for photographic haze grading, and correlation between photographic and clinical vitreous haze scores, assessment of the clinical findings that significantly affect the photographic haze score.
RESULTS: Vitreous haze was graded in 271 eyes (142 patients) by 3 postgraduate ophthalmologists. The interobserver and intraobserver intraclass correlations were excellent, with correlation coefficients between 0.84 and 0.93. There was moderately strong correlation between the photographic and clinical vitreous haze scores (r=0.51; P<.001), with significant differences among the mean and median photographic haze scores for the 3 lowest clinical grades of haze, 0, 1+, and 2+. Other parameters that correlated with photographic vitreous haze score included visual acuity of 20/50 or worse (P=.003), degrees of posterior synechiae (P<.001), lens abnormality (P=.023) or posterior capsule obscuration (P=.001), and amount of anterior vitreous cell (P=.002).
CONCLUSIONS: Photographic grading of vitreous haze with a 9-step logarithmic scale is a highly reproducible methodology that may be adaptable to use in future clinical trials.
Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study system for evaluation of stereoscopic color fundus photographs and fluorescein angiograms: SCORE Study Report 9
Arch Ophthalmol. 2010 Sep;128(9):1140-5. doi: 10.1001/archophthalmol.2010.193.
OBJECTIVE: To describe the procedures and reproducibility for grading stereoscopic color fundus photographs and fluorescein angiograms of participants in the SCORE Study.
METHODS: Standardized stereoscopic fundus photographs and fluorescein angiograms taken at 84 clinical centers were evaluated by graders at a central reading center. Type of retinal vein occlusion (RVO), area of retinal thickening, and area of retinal hemorrhage are evaluated from fundus photographs; area of fluorescein leakage and area of capillary nonperfusion are measured on fluorescein angiography. Temporal reproducibility consisted of annual regrading of a randomly selected dedicated subset of fundus photographs (60 subjects) and fluorescein angiograms (40 subjects) for 3 successive years. Contemporaneous reproducibility involved monthly regrading of a 5% random selection of recently evaluated fundus photographs (n = 73).
RESULTS: The intergrader agreement for RVO type and presence of retinal thickening was greater than 90% in the 3 annual regrades. The intraclass correlation (ICC) for area of retinal thickening in the 3 years ranged from 0.39 to 0.64 and for area of retinal hemorrhage, 0.87 to 0.96. The ICC for area of fluorescein leakage ranged from 0.66 to 0.75 and for capillary nonperfusion, 0.94 to 0.97. The contemporaneous reproducibility results were similar to those of temporal reproducibility for all variables except area of retinal thickening (ICC, 0.84).
CONCLUSIONS: The fundus photography and fluorescein angiography grading procedures for the SCORE Study are reproducible and can be used for multicenter longitudinal studies of RVO. A systematic temporal drift occurred in evaluating area of retinal thickening.
Association of fluorescein angiographic features with visual acuity and with optical coherence tomographic and stereoscopic color fundus photographic features of diabetic macular edema in a randomized clinical trial
Retina. 2010 Nov-Dec;30(10):1627-37. doi: 10.1097/IAE.0b013e3181dde5f5.
BACKGROUND: Fluorescein angiography (FA) has been performed as part of the management of diabetic macular edema for many years. Its current role relative to the role of optical coherence tomography (OCT) is not well defined.
PURPOSE: To evaluate the associations of FA features with visual acuity (VA) and with OCT and fundus photographic characteristics in eyes with diabetic macular edema.
METHODS: In a clinical trial, conducted by the Diabetic Retinopathy Clinical Research Network to compare two methods of laser photocoagulation to treat diabetic macular edema, FA (film and digital), color photographs, OCT, and VA measurements were obtained at baseline and at 1 year. Grading of morphologic features was performed at a reading center. Reproducibility of FAs was assessed, and the correlations of FA features with VA, OCT, and color photograph features were computed.
RESULTS: From 79 clinical sites, data of 323 study eyes and 203 fellow nonstudy eyes were analyzed. Fluorescein leakage area at baseline was associated with reduced VA, increased OCT measures of retinal thickness and volume, and color photographic measurements of retinal thickening (r = 0.33-0.58). No important associations were found with changes from baseline to 12 months in these parameters or with any of the other variables analyzed.
CONCLUSION: Fluorescein leakage is associated with VA and some OCT and color photographic variables. We did not identify any unique FA variables that had a stronger association with VA than OCT measures of retinal thickness. These data may be useful to investigators planning future diabetic macular edema clinical trials.
The multicenter uveitis steroid treatment trial: rationale, design, and baseline characteristics
Am J Ophthalmol. 2010 Apr;149(4):550-561.e10. doi: 10.1016/j.ajo.2009.11.019. Epub 2010 Jan 25.
PURPOSE: To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) trial and the baseline characteristics of enrolled patients.
DESIGN: Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) with fluocinolone acetonide implant placement.
METHODS: Eligible patients had active or recently active noninfectious intermediate uveitis, posterior uveitis, or panuveitis. The study design had 90% power (2-sided type I error rate, 0.05) to detect a 7.5-letter (1.5-line) difference between groups in the mean visual acuity change between baseline and 2 years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photographs, optical coherence tomography images, and fluorescein angiograms.
RESULTS: Over 3 years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200). Lens opacities (39% of gradeable phakic eyes), macular edema (36%), and epiretinal membrane (48%) were common. Mean health utility was 74.1.
CONCLUSIONS: The MUST trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate uveitis, posterior uveitis, and panuveitis. Patients with intermediate uveitis, posterior uveitis, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema, and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.
Ocular and systemic safety evaluation of calcium formate as a dietary supplement
Journal of ocular pharmacology and therapeutics, 25(3), pp.223-230