2012 Journal highlights



New prosthetic retina a better mimic of real vision
Investigators have restored vision in blind mice by combining a prosthetic device and targeted genetic modification to ganglion cells to reproduce an image that appears more realistic than previous attempts at artificial vision. Unlike typical prosthetic retinas that stimulate the ganglion cells directly, this system uses the “code” that ganglion cells normally use when communicating with the brain. They then used gene therapy to transfer the protein channelrhodopsin into the ganglion cells of blind mice, in order to make them responsive to light. This prosthetic system stimulates tens of thousands of ganglion cells that express channelrhodopsin, compared to current prosthetics which use electrodes to stimulate only a handful of cells, which brings its capabilities into the realm of normal image representation. Proceedings of the National Academy of Sciences, Aug. 13, 2012
  Overnight Orthokeratology may be causing mechanical trauma
Researchers measured concentrations of several tear markers involved in corneal wound healing response in myopic patients 12 months after treatment with either corneal refractive therapy or continuous wear silicone-hydrogel contact lenses. They showed increased levels of inflammatory markers, matrix proteinase and EGF in the tears of subjects wearing Paragon corneal refractive therapy lenses compared with controls and continuous-wear contact lens wearers. The magnitude of this response was associated with the degree of myopia to be corrected and the presence of fluorescein corneal staining, suggesting the Paragon lens compressive effect and mechanical trauma as the main causes of the inflammatory upregulation. British Journal of Ophthalmology, August 2012
 DALK comparable to PK in treatment of keratoconus
This prospective study compared results of deep anterior lamellar keratoplasty (DALK) with the big-bubble technique and penetrating keratoplasty (PK) in 140 patients (174 eyes) with moderate to advanced keratoconus. Postoperative BSCVA, mean spherical equivalent, maximum keratometry, aberrometric parameters and photopic contrast sensitivity were comparable between the treatment groups. However, mesopic contrast sensitivity for three cycles/degree was significantly higher in the DALK group (P = 0.01).British Journal of Ophthalmology, August 2012
Link  Between Cataract and Cataract Extraction and AMD 
Beaver Dam Eye Study participants aged 43 to 86 years were involved in the baseline examination in 1988–1990 of the following longitudinal population-based study of age-related eye diseases to examine the associations of cataract and cataract surgery with early and late age-related macular degeneration (AMD) over a 20-year interval. 

Participants were followed up at five-year intervals after the baseline examination. Examinations consisted of ocular examination with lens and fundus photography, medical history, measurements of blood pressure, height, and weight. Values of risk variables were updated, and incidences of early and late AMD were calculated for each five-year interval. Additionally, odds ratios were computed using discrete linear logistic regression modeling with generalized estimating equation methods to account for correlation between the eyes and multiple intervals. AMD was the main outcome measure. 

After adjusting for age and sex, neither cataract nor cataract surgery was associated with increased odds for developing early AMD. Further adjusting for high-risk gene alleles (CFH and ARMS2) and other possible risk factors did not materially affect the odds ratio (OR). However, cataract surgery was associated with incidence of late AMD (OR 1.93; 95% confidence interval [CI], 1.28–2.90). This OR was not materially altered by further adjusting for high-risk alleles (CFH Y402HARMS2) or other risk factors. It was noted that the OR for late AMD was higher for cataract surgery performed five or more years prior compared with less than five years prior. 

These data strongly support the past findings of an association of cataract surgery with late AMD independent of other risk factors, including high-risk genetic status, and suggest the importance of considering these findings when counseling patients regarding cataract surgery. These findings should provide further impetus for the search for measures to prevent or delay the development of age-related cataract. 

SOURCE: Klein BE, Howard KP, Lee KE, et al. The relationship of cataract and cataract extraction to age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2012;119(8):1628–1633.
 Use of Enzymatic Vitreolysis with Ocriplasmin for Treatment of Vitreomacular Traction and Macular Holes 
Vitreomacular adhesion (VMA) can lead to pathologic traction and macular hole. The standard treatment for severe, symptomatic VMA is vitrectomy. Ocriplasmin is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. 

Researchers conducted two multicenter, randomized, double-blind, Phase III clinical trials to compare a single intravitreal injection of ocriplasmin (125 µg) with a placebo injection in patients with symptomatic VMA. The primary end point was resolution of VMA at day 28. Secondary end points were total posterior vitreous detachment and nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy, and change in best-corrected visual acuity (BCVA). 

Overall, the researchers treated 652 eyes: 464 with ocriplasmin and 188 with placebo. They reported that VMA resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (p<0.001). They also found that total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, p<0.001). The study researchers achieved nonsurgical closure of macular holes in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (p<0.001). They noted that the BCVA was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Furthermore, ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain—all self-reported—or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (p<0.001), and the incidence of serious ocular adverse events was similar in the two groups (p=0.26). 
In conclusion, intravitreal injection of the vitreolytic agent ocriplasmin resolved vitreomacular traction and closed macular holes in significantly more patients than did injection of placebo and was associated with a higher incidence of ocular adverse events, which were mainly transient. 

SOURCE: Stalmans P, Benz MS, Gandorfer A, et al; for the MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Eng J Med. 2012;Aug 16. [Epub ahead of print].
Safety, Tolerability, and Reproducibility of Continuous 24-Hour IOP Pattern Monitoring in Glaucoma Patients 

To examine the safety, tolerability, and reproducibility of intraocular pressure (IOP) patterns during repeated continuous 24-hour IOP monitoring with a contact lens sensor, the authors of this study investigated 40 patients suspected of having glaucoma (n=21) or with established glaucoma (n=19). 

Patients participated in two 24-hour IOP monitoring sessions (S1 and S2) at a one-week interval. Patients pursued daily activities, and sleep behavior was not controlled. The authors assessed reproducibility of signal patterns using Pearson correlations as well as the incidence of adverse events and tolerability (visual analog scale score). 

They reported that the mean (SD) age of the patients was 55.5 (15.7) years, and 60% were male. Main adverse events were blurred vision (82%), conjunctival hyperemia (80%), and superficial punctate keratitis (15%). The mean (SD) visual analog scale score was 27.2 (18.5) mm in S1 and 23.8 (18.7) mm in S2 (p=.22). Overall correlation between the 2 sessions was 0.59 (0.51 for no glaucoma medication and 0.63 for glaucoma medication) (p=.12). Moreover, the study authors detected mean (SD) positive linear slopes of the sensor signal from wake to two hours into sleep in both sessions for the no glaucoma medication group (S1: 0.40 [0.34], p<.001; S2: 0.33 [0.30], p<.01) but not for the glaucoma medication group (S1: 0.24 [0.60], p=.06; S2: 0.40 [0.40], p<.001). 

To conclude, repeated use of the contact lens sensor demonstrated good safety and tolerability. The recorded IOP patterns showed fair to good reproducibility, suggesting that data from continuous 24-hour IOP monitoring may be useful in the management of patients with glaucoma. 

SOURCE: Mansouri K, Medeiros FA, Tafreshi A, Weinreb RN. Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma. Arch Ophthalmol. 2012; Aug 13. [Epub ahead of print].
 LUCENTIS APPROVED FOR TREATMENT OF DME. Genentech recently announced that Lucentis (ranibizumab injection) 0.3 mg once monthly was approved by the FDA for the treatment of diabetic macular edema (DME) and physicians can now place orders for the drug. Lucentis 0.5 mg once monthly was first approved by the FDA to treat wet age-related macular degeneration (AMD) in 2006 and for macular edema following retinal vein occlusion in 2010. The approval of Lucentis in DME was based on Genentech's Phase III trials, RIDE and RISE, two identically designed, parallel, double-masked, three-year clinical trials, which were sham-treatment controlled for 24 months. Lucentis demonstrated improved clinical outcomes including substantial visual gain for many DME patients.
 Study supports long-term Bevacizumab for persistent DME
This randomized, controlled, single-center trial included 80 patients with center-involving macular edema treated with either intravitreous bevacizumab or macular laser therapy. Improvements in BCVA and central macular thickness seen with bevacizumab at one year were maintained at year two with a mean of four injections. At two years, the bevacizumab group achieved a higher mean BCVA (20/50 vs. 20/80), higher mean letter gain (8.6 vs. a loss of 0.5 letters) and a greater reduction in central macular thickness (146 μm vs. 118 μm). During the 2-year study, the median number of treatments was 13 for bevacizumab and four for laser. Archives of Ophthalmology, August 2012


 Safety and Efficacy of Immediately Sequential Versus Delayed Sequential Bilateral Cataract Surgery 
At multiple clinics on the Canary Islands in Spain, researchers performed a multi-center, randomized clinical trial to assess the safety and effectiveness of immediately sequential bilateral cataract surgery (ISBCS) versus delayed sequential bilateral cataract surgery (DSBCS). 
They randomized patients with cataracts requiring bilateral surgery to ISBCS or DSBCS. Outcome measures were the incidence of intraoperative and postoperative surgical complications, corrected and uncorrected visual acuities and self-perceived visual function (VF-14 questionnaire). The researchers measured all outcomes 30 days postoperatively and assessed self-perceived visual function after one year. They analyzed data with repeated measures to assess temporal effects on surgical complications, visual acuity and function and also estimated effect size for self-perceived visual function. 

The researchers found no differences in intraoperative or postoperative surgical complications, visual acuity 30 days postoperatively or self-perceived visual function after one year between the two techniques. They noted that effect size for visual function 30 days postoperatively was moderate in the ISBCS group (n=834) and small in the DSBCS group (n=780). This difference disappeared at one-year follow-up after second-eye surgery in the delayed group. 

There were no relevant surgical complications in 1,614 operated eyes and no significant difference in surgical complications, visual acuity or long-term, self-perceived visual function between ISBCS and DSBCS, the researchers reported. They related these safety and effectiveness outcomes to careful patient selection, surgical expertise and the systematic use of standardized surgical guidelines to ensure aseptic and independent surgery in each eye. 

SOURCE: Serrano-Aguilar P, Ramallo-Fariña Y, Cabrera-Hernández JM, et al. Immediately sequential versus delayed sequential bilateral cataract surgery: safety and effectiveness. J Cataract Refract Surgy. 2012;Aug 10. [Epub ahead of print].
 “Radiation-First” Combination Treatment for Neovascular AMD 

To describe “radiation-first” combination treatment with a non-invasive, low-voltage x-ray irradiation system followed by as needed ranibizuamb for neovascular age-related macular degeneration (AMD), investigators conducted this Phase I study of non-invasive, low-voltage 16 Gy x-ray irradiation delivered in three beams via the inferior pars plana in patients with active neovascular AMD. 

They administered ranibizumab as needed per protocol and followed patients monthly for safety and efficacy over 12 months. 

The investigators enrolled 13 patients and completed 12 months of follow-up. They found that safety was good with no serious ocular/non-ocular adverse events or radiation-related ocular complications. They also noted that 11 patients lost <15 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters, seven gained ≥0 ETDRS letters and 0 gained ≥15 ETDRS letters. Patients received a total of 31 subsequent ranibizumab injections (of possible 156) over the 12 months following x-ray irradiation. Mean time to first injection was 3.9 months. The investigators reported that one patient received no ranibizumab injections, three received one injection, four received two injections and five received three or more injections. 

To conclude, after 12 months, noninvasive, low-voltage x-ray irradiation with as needed ranibizumab rescue therapy demonstrated good safety with a visual acuity stabilizing effect and reduction in retinal thickness in patients with neovascular AMD. 

SOURCE: Moshfeghi AA, Morales-Canton V, Quiroz-Mercado H, et al. 16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a ‘radiation-first’ strategy. Br J Ophthalmol. 2012; Aug 15. [Epub ahead of print].
("Source: Eye World")
 Highlights from ARVO 2011              
This year's conference boasted more than 5,000 presentations and posters
The annual Association for Research in Vision and Ophthalmology meeting was highlighted this year by an in-depth discussion of the recent Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) 1-year results. Study co-chair Daniel F. Martin, M.D., Cole Eye Institute, Cleveland, stressed that although the study was fully funded by the National Eye Institute, drug costs were not considered. 
"When we submitted the protocol, Lucentis (ranibizumab, Genentech, South San Francisco, Calif.) had not even been approved, so we could not know what the pricing strategy was going to be," he said to a standing-room only crowd of more than 1,500.
Because a loss or gain of a single letter was not deemed clinically relevant, the CATT group eventually settled on five letter gains/losses as being statistically and clinically significant (one line gain/loss), said co-chair Maureen Maguire, Ph.D., Scheie Eye Institute, Philadelphia. Given monthly, Avastin (bevacizumab, Genentech) used off-label helped patients gain 8.0 letters, while Lucentis helped them gain 8.5 letters. When dosed on a PRN schedule, Avastin showed a 5.9 letter gain and Lucentis a 6.8 letter gain. Avastin dosed monthly was equivalent to Lucentis dosed PRN, Lucentis dosed monthly was equivalent to Lucentis dosed PRN, Dr. Martin said, but neither Avastin nor Lucentis dosed monthly were equivalent to Avastin dosed PRN. 
"Those latter results did not show non-inferiority," Dr. Martin said. "What we can say is that the findings are inconclusive at this time." As-needed dosing resulted in about four fewer injections during the first year than in the monthly group, but he added vigilance by study centers to ensure subject compliance may not be as easy to accomplish in real-world settings where patients have to pay for treatment. 
The CATT study enrolled 1,208 patients across 44 centers; 23 patients and one center were excluded from study results because of protocol breach, Dr. Maguire said.
Phase III data showed once-daily tafluprost as comparable to twice-daily timolol in 643 patients with open-angle glaucoma or ocular hypertension. Baseline IOPs ranged from 23.8-26.1 mm Hg in patients treated with tafluprost and 23.5-26.0 mm Hg in those treated with timolol. At the 12-week end of the study visit, IOPs ranged from 17.4-18.6 mm Hg in the tafluprost group and 17.9-18.5 mm Hg in the timolol group. Treatment effects were seen as early as week 2. 
A literature review compared the newer diagnostic imaging tools (optical coherence tomography [OCT, Carl Zeiss Meditec, Dublin, Calif.], Heidelberg Retina Tomograph [HRT, Heidelberg Engineering, Carlsbad, Calif.], and glaucoma diagnosis [GDx, Carl Zeiss Meditec)] to white-on-white perimetry in their ability to detect glaucoma. Presenters with the Ivey Eye Institute, London, Ontario, said the data "favors GDx and OCT over HRT for diagnostic accuracy in glaucoma compared to a gold standard of white-on-white visual field." The greatest accuracy, however, was with blue-on-yellow perimetry, said Francie F. Si, M.D. 
Clear lens extraction is more effective than laser peripheral iridotomy (LPI) as a first-line treatment for angle-closure glaucoma, according to Qi N. Cui, Ph.D., University of Rochester, N.Y., and colleagues. Provided the probability of a trabeculectomy following LPI exceeds approximately 6.4%, clear lens extraction yields fewer severe adverse outcomes (i.e., endophthalmitis) over 5 years. The incremental cost effectiveness ratio of LPI as opposed to lens extraction suggests an incremental cost effectiveness ratio of over $5 million per additional quality-adjusted life years saved, she said.
Ocular surface and cornea
The average endothelial cell loss following Descemet's stripping automated endothelial keratoplasty in patients with Fuchs' endothelial dystrophy "remains relatively stable up to 2 years post-operatively," according to a poster from Jennifer Y. Li, M.D., Devers Eye Institute, Portland, Ore. After the second year, there is a "gradual decline" in endothelial cell loss through year 4. 
In a Phase II dry eye trial, subjects receiving SAR 1118 (SARCode, Brisbane, Calif.) demonstrated a reduction in corneal staining, increased tear production, and improved visual-related function as compared to placebo, according to the company. SAR 1118 is a first-in-class, topically administered small molecule integrin antagonist that inhibits T-cell mediated inflammation. In the randomized, placebo-controlled, multicenter trial, which included 230 subjects with dry eye, SAR 1118 demonstrated dose-dependent significant improvements (P<.05) in inferior corneal staining over 12 weeks.
Refractive and cataract
 The occurrence of rhegmatogenous retinal detachment (RRD) after LASIK surgery for the correction of myopia is infrequent (0.19%), according to J. Fernando Arevalo, Clinica Oftal Centro Caracas, Venezuela, and colleagues. They retrospectively analyzed charts of 22,296 myopic eyes post-LASIK. Only 22 eyes (19 patients) developed retinal detachment, between 1 month and 13 years after LASIK. Those with RRD had baseline myopia from –1.5 D to –9.75 D. 
Zinc found in the lenses of patients with Alzheimer's and Down syndrome supports the theory that Alzheimer's is a systemic disorder. Accumulation of amyloid-? in the brain is a principal feature of Alzheimer's disease and Down  syndrome. In this study, Lee E. 
Goldstein, M.D., Boston University, and colleagues analyzed human Alzheimer's and Down syndrome lenses and identified co-localized zinc and amyloid-? in the same cytosolic compartments of lens fiber cells. The researchers said these data are the first to establish an Alzheimer's-linked amyloid pathology outside the brain and may  ultimately "pave the way for development of novel ophthalmic technology for early Alzheimer's detection and diagnosis." 
A total of 6,734 individuals undergoing anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD) were compared with the same number of individuals with neovascular AMD who did not undergo anti-VEGF treatment. The anti-VEGF group had an 87.9% higher risk of severe ocular complications overall and 2.6% increased risk per injection, said Shelley Day, M.D., Duke University, Durham, N.C. There were 38 cases of endophthalmitis in the anti-VEGF group compared with six in the control group; similarly, twice as many people in the anti-VEGF group had a vitreous hemorrhage (1.8%) compared to the control group (0.94%).
"Individuals with anti-VEGF injections had twice the risk of serious ocular complications, and a 
diagnosis of proliferative diabetic retinopathy doubled the risk of complications," she said. "A previous history of glaucoma surgery increased the risk by 70%." The group defined glaucoma surgery as uncomplicated trabeculectomy or tube implants.
Population-based studies
 The duration of diabetes and poor glycemic and blood pressure control are strongly associated with a higher prevalence in diabetic retinopathy, proliferative diabetic retinopathy, diabetic macular edema, and vision-threatening diabetic retinopathy, highlighting the "substantial public health impact of diabetes." The results are based on a population-based study of pooled data from general and diabetic populations in the United States, Australia, Europe, and Asia. 
A longitudinal study funded by the National Institutes of Health (NIH) suggested the ability to read, recognize faces, or find a street sign will deteriorate significantly over time for adults with age-related geographic atrophy of the macula (GA). A questionnaire was completed at baseline and annually by subjects enrolled in the NIH-funded prospective natural history study of geographic atrophy from AMD from 1992-2000. The reports showed that subjects' difficulty in reading, haziness, face recognition, and finding signs worsened with worse visual acuity and with larger GA area at baseline. Longitudinally, reading and face recognition deteriorated significantly.  
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