A 77-year-old woman with exudative macular degeneration underwent bilateral intravitreal injections of “stem cells” at a clinic in Georgia. One month and 3 months after injection, she developed retinal detachments in the left and right eyes, respectively. Increased awareness within the medical community of such poor outcomes is critical so that clinics offering untested practices that have been shown to be potentially harmful to patients can be identified and brought under U.S. Food and Drug Administration oversight.
Enthusiasm for stem cell treatment has given rise to numerous clinics in the United States offering unproven “stem cell” therapies without the oversight of the U.S. Food and Drug Administration (FDA). Though current FDA-regulated clinical trials are ongoing to evaluate the use of stem cell technology, unproven and unregulated “stem cell” therapies are already being offered to patients in hundreds of clinics in the United States. In June 2016, the American Academy of Ophthalmology published a clinical statement warning that unproven “stem cell” therapies “require further scientific evaluation to assure their safety and effectiveness to the public in well-conducted clinical trials under the aegis of the FDA.”1 Here, we describe a case of delayed retinal detachment with poor visual acuity and anatomical outcomes following bilateral intravitreal injection of autologous adipose tissue-derived “stem cell” therapy in a clinic in Georgia performed without FDA oversight.
Full Paper: Bilateral Retinal Detachments After Intravitreal Injection of Adipose-Derived ‘Stem Cells’ in a Patient With Exudative Macular Degeneration
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New and unique physiologic and pathologic systemic and neuro-ocular responses have been documented in astronauts during and after long-duration space flight. Although the precise cause remains unknown, space flight–associated neuro-ocular syndrome (SANS) has been adopted as an appropriate descriptive term. The Space Medicine Operations Division of the US National Aeronautics and Space Administration (NASA) has documented the variable ccurrence of SANS in astronauts returning from long-duration space flight on the International Space Station. These clinical findings have included unilateral and bilateral optic disc edema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and nerve fiber layer infarcts. The clinical findings of SANS have been correlated with structural changes on intraorbital and intracranial magnetic resonance imaging and in-flight and terrestrial ultrasonographic studies and ocular optical coherence tomography. Further study of SANS is ongoing for consideration of future manned missions to space, including a return trip to the moon or Mars.
Full Paper: Space Flight Associated Neuro-Ocular Syndrome
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Floaters become more prevalent with age because of degenerative vitreous changes that occur throughout life. In youth, hyaluronan keeps collagen fibrils separated in the vitreous cavity and thus maintains transparency of the vitreous. However, with time, hyaluronan dissociates from collagen, causing cross-linking and aggregation of collagen with fibrous structures that scatter light—a process known as vitreous liquefaction.1-3
Clinically, a posterior vitreous detachment (PVD) is often marked by a degree of fibroglial tissue known as a Weiss ring that is free floating over the optic nerve. A PVD allows the vitreous body to move when the head or eye moves, and thus, the Weiss ring and vitreous opacities cast shadows onto the retina that are perceived as floaters.
A PVD is present in approximately 65% of patients reaching the age of 65 years.4,5 Although most patients grow accustomed to the visual disturbance associated with Weiss rings and other floaters, many find them bothersome.6 Floaters can reduce contrast sensitivity and quality of life.7,8
Three management options exist for symptomatic floaters: patient education and observation, pars plana vitrectomywith a 1-incision Intrector (in which a 1-incision, limited core vitrectomy is performed while visualizing through an indirect ophthalmoscope; Insight Instruments) or a standard 3-port vitrector, and YAG vitreolysis.
Existing literature assessing the effect of YAG laser on the properties of rabbit vitreous has suggested that pathologic disruption may occur with laser application in the middle or posterior vitreous.9 There are limited published studies on the effect of YAG vitreolysis for treating symptomatic floaters in humans. Small, uncontrolled cases series6,10,11 assessing YAG vitreolyisis report some symptomatic success and suggest a good safety profile. No prospective, sham-controlled trials have been performed, to our knowledge. This is particularly important because of the subjective nature of floater related visual disturbance and the potential of placebo effect confounding the efficacy of treatment. Research by Karickhoff12 showed the most robust outcomes when treating Weiss rings. Therefore, the current study evaluated YAG vitreolysis in patients with symptomatic Weiss rings.
Full Paper: YAG Laser Vitreolysis vs Sham YAG Vitreolysis for Symptomatic Vitreous Floaters
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Recent practices at “stem cell clinics” in the United States have resulted in blinding complications for three patients who underwent bilateral intravitreal injection of adipose-derived stem cell injections for dry age-related macular degeneration, as recently published in the New England Journal of Medicine: patient’s vision went from 20/30 to no light perception and 20/200.
The “stem cell clinics” problem is that they provide unproven, unregulated, and costly ($50,000) treatment for a variety of disorders and raise high concern for patients.
By having studies listed on clinicaltrials.gov, “stem cell clinics” seemingly bolster their legitimacy to patients. clinicaltrials.gov website is simply a repository of clinical studies and does not judge the merits of the listed studies.
It is important to encourage patients to speak with a “trusted healthcare professional” prior to enrolling in a study. Exploring the difference between the positive stem cell research and the activities carried out at “stem cell clinics” is essential in preventing such catastrophic outcomes.
Further regulation of these “stem cell clinics” is also necessary to help prevent similar outcomes in the future.
“Implications of Stem Cell Clinics for Retina Patients and Clinical Trials” Retinal Physician, Volume 14, Issue: May 2017, page(s) 32,40: Ajay E. Kuriyan, MD, MS; Thomas Albini, MD; Harry W. Flynn, Jr., MD
“The Growing ‘Stem Cell Clinic’ Problem” American Journal of Ophthalmology, Volume 177, xix–xx: Ajay E. Kuriyan, MD, MS; Thomas Albini, MD; Harry W. Flynn, Jr., MD
Table 1. “Age-Related Macular Degeneration Clinical Trials With Oral Medications”
(Retinalphysician.com | April 2017)
Full Paper: Age-Related Macular Degeneration Clinical Trials With Oral Medications Table
Study: A Phase 2/3 Trial to Assess the Safety and Efficacy of Intravitreous Administration of Zimura (Anti-C5 Aptamer) in Subjects With Geographic Atrophy Secondary to Dry Age-Related Macular Degeneration
Purpose: To evaluate the safety and efficacy of intravitreous administration of Zimura when administered in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration
Design: Randomized, Safety/Efficacy, Parallel Assignment, Double Blind
Number of Patients: 300
Inclusion Criteria: Diagnosis of non-foveal GA secondary to dry AMD
Exclusion Criteria: Retinal atrophy involving the fovea; evidence of CNV; any prior treatment for AMD or any prior intravitreal treatment for any indication in either eye, except oral supplements of vitamins and minerals; any intraocular surgery or thermal laser within 3 months of trial entry; any prior thermal laser in the macular region, regardless of indication; any ocular or periocular infection in the 12 weeks prior to entry; previous therapeutic radiation in the region of the study eye; any sign of diabetic retinopathy in either eye
Full Paper: Retinal Physician Clinical Trial Update
Purpose: To characterize the first 10 years of intravitreal anti-vascular endothelial growth factor (VEGF) medication use for ophthalmic disease, including bevacizumab, ranibizumab, and aflibercept.
Design: A retrospective cohort study using administrative claims data from January 1, 2006 to December 31, 2015.
Subjects: Total of 124 835 patients 18 years of age or over in the United States.
Methods: OptumLabs Data Warehouse, which includes administrative claims data for over 100 million commercially insured and Medicare Advantage individuals, was used to identify patients receiving intravitreal anti-VEGF injections based on Current Procedural Terminology codes.
Main Outcome Measures: Total and annual numbers of intravitreal anti-VEGF injections, as well as injections per 1000 enrolled patients per general category of ophthalmic disease, overall and for each available medication.
Results: There were 959 945 anti-VEGF injections among 124 835 patients from 2006 to 2015. Among all injections, 64.6% were of bevacizumab, 22.0% ranibizumab, and 13.4% aflibercept; 62.7% were performed to treat age-related macular degeneration (AMD), 16.1% to treat diabetic retinal diseases (including 0.9% of all injections that were for proliferative diabetic retinopathy), 8.3% to treat retinal vein occlusions, and 12.9% for all other uses. Use of bevacizumab and ranibizumab for AMD plateaued as of 2011/2012 and decreased thereafter (in 2006, 58.8 and 35.3 injections/1000 AMD patients, respectively; in 2015, 294.4 and 100.7 injections/1000), whereas use of aflibercept increased (1.1 injections/1000 AMD patients in 2011 to 183.0 injections/1000 in 2015). Bevacizumab use increased each year for diabetic retinal disease (2.4 injections/1000 patients with diabetic retinal disease in 2009 to 13.6 per 1000 in 2015) while that of ranibizumab initially increased significantly and then declined after 2014 (0.1 in 2009 to 4.0 in 2015). Aflibercept use increased each year in patients with diabetic etinal diseases and retinal vein occlusions (both >0.1 per 1000 retinal vein occlusion patients in 2011, 5.6 and 140.2 in 2015).
Conclusions: Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased. Ophthalmology 2017;124:352-358 ª 2016 by the American Academy of Ophthalmology
Full Paper: Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients
Since Kelly and Wendel introduced the victrectomy technique to reattach the macular hole (MH),1 considerable advances in surgical treatment have been achieved. As a consequence, MH has now become a surgically treatable disease with standardized techniques incorporating vitrectomy, induction of posterior vitreous detachment, internal limiting membrane (ILM) peeling, and gas tamponade.2 Although there was a debate on ILM peeling in the past, ILM peeling has been established to improve surgical success rates.3–6 In addition, retinal ILM peeling has been facilitated by staining dye such as indocyanine green.7,8
The rationale for ILM peeling is that MH can occur and enlarge owing to contraction of perifoveal vitreous and cellular constituents with myofibroblastic differentiation on the surface of the ILM.2,9 Although ILM has no inherent contractile properties, it does act as a scaffold for contractile tissue to exert tangential traction on fovea. Several studies using optical coherence tomography (OCT) have reported the dynamic sealing process after MH surgery.10–13 Foveal tissue elongation and macular migration have been noted following ILM peeling after surgery for MH and diabetic macular edema.14–17 In addition, there is a significant correlation between these morphologic changes and visual function such as metamorphopsia.14
Although ILM peeling has become a widely accepted surgical technique since the introduction of MH surgery, the optimal extent of ILM peeling is not known and the anatomic and functional outcomes according to peeling extent have not been investigated. The purpose of this study was to investigate the influence of the extent of ILM peeling on anatomic and functional outcomes of MH surgery.
Full Paper: Extent of Internal Limiting Membrane Peeling and its Impact on Macular Hole Surgery Outcomes: A Randomized Trial
Arecent Diabetic Retinopathy Clinical Research Network (DRCR.net) comparative effectiveness trial found that for patients with diabetic macular edema (DME) and approximate Snellen equivalent baseline visual acuity (VA) of 20/50 or worse aflibercept produced greater mean VA gains at 1 year than bevacizumab or ranibizumab. In contrast, no difference in mean VA improvement was identified for patients with baseline VAs of 20/32 to 20/40.1
These agents also vary substantially in cost. O nthe basis of 2015 wholesale acquisition costs, aflibercept (2.0 mg) costs $1850,2 ranibizumab (0.3mg) costs $1170,2 and bevacizumab repackaged at compounding pharmacies into syringes for ophthalmologic use containing 1.25mg of bevacizumab costs approximately $6 0per dose.3 Considering that these medicines may be given 9 to 11 times in the first year of treatment1 and, on average, 17 times during 5 years,4 total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of anti–vascular endothelial growth factor (VEGF)therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget.3 In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.5 Given these costs, the DRCR.net investigators believed it was important to analyze the relative cost-effectiveness of treating DME using each agent.
Full Paper: Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment
Age-Related Macular Degeneration (AMD) is one of the leading causes of visual impairment in individuals over the age of 55 years in developed countries.1 The neovascular form of AMD, with vascular endothelial growth factor (VEGF) as one of the key factors, causes severe and irreversible vision loss, frequently resulting in legal blindness.2,3 In recent years, VEGF inhibition by anti-VEGF antibodies has significantly improved visual outcomes in patients with neovascular AMD. However, in many patients with neovascular AMD anti-VEGF needs to be continuously administered over many years to persistently suppress disease activity and maintain visual function.
The need for long-term treatment with anti-VEGF agents has also become evident in the extension studies, where long-term outcomes 7-8 years after initiation of intensive ranibizumab therapy suggest that many patients require long-term treatment with anti-VEGF agents.4 However, despite the beneficial effect of anti-VEGF therapy, long-term side effects are not clarified yet and are a matter of ongoing controversy. There is evidence that repeated long-term anti-VEGF treatment may accelerate atrophy of different ocular tissues. Retinal pigment epithelium atrophy,5 as well as scleral thinning, has been reported.6 In the last years, several studies have investigated the effect of intravitreal anti-VEGF injections on the peripapillary retinal nerve fiber layer (RNFL). There exists some controversy regarding the effect of anti-VEGF agents on retinal ganglion cells (RGCs). In mice, some reports suggest severe damage to RGCs after local treatment with VEGF binding agents,7 while another report did not find any changes within the retinal ganglion cell layer (RGCL) after VEGF receptor blockade in mice.8 Because most studies have analyzed peripapillary optical coherence tomography (OCT) scans, these reports have focused on RNFL change after antiVEGF treatment. However, several studies focusing on glaucoma patients have shown that RGCL thickness changes may be a more sensitive marker for global and regional visual field sensitivities.9,10
In the present study, we investigated RNFL and RGCL changes in the macular area in eyes receiving long-term intravitreal anti-VEGF treatment for neovascular AMD using spectral-domain optical coherence tomography (Spectralis SDOCT; Heidelberg Engineering, Heidelberg, Germany) and automated segmentation of macular scans.
Full Paper: Retinal Ganglion Cell Layer Change in Patients Treated With Anti–Vascular Endothelial Growth Factor for Neovascular Age-related Macular Degeneration