Inside This Issue 

CLINICAL PEARLS

ANSWER TO "YOU MAKE THE DIAGNOSIS"

Multifocal Choroiditis and Panuveitis (MCP)

This photo represents a patient with multifocal choroiditis and panuveitis (MCP) Multifocal Choroiditis and Panuveitis is a relatively common disease that is characterized by multifocal chorioretinal lesions with anterior and posterior segment inflammation.

In the United States, the incidence of MCP is 52.4/100,000 people/years. It occurs predominantly in myopic females, with a mean age of onset of 33 years. Patients usually present with an acute onset of blurred vision, photopsias, and scotomata. Bilateral involvement is present in the majority of patients.

The active fundus lesions can progress into punched-out atrophic scars that develop pigmentation over time, resembling POHS.³ The optic disc is usually normal, although, in some cases, it may be edematous. Peripapillary scarring and prominent linear chorioretinal streaks also may be present. Choroidal neovascularization (CNV) can develop. Almost all patients have vitreous cells, and many have anterior chamber inflammation. Patients with MCP also may present with cystoid macular edema (CME), secondary to chronic inflammation leading to breach of the blood-retinal barrier.

The diagnosis of MCP is based on clinical examination, and can be confirmed by angiography. Fluorescein angiography demonstrates that active lesions show early hypofluorescence and late hyperfluorescence. The main differential diagnosis of MCP is Presumed Ocular Histoplasmosis Syndrome (POHS). POHS may present with multiple atrophic fundus spots, CNV, and peripapillary atrophy. The lesions in POHS are less numerous and smaller than in MCP. The key distinguishing feature is that POHS does not present with anterior and posterior segment inflammation.

The pathogenesis of MCP is unknown. Controversy exists regarding the statistical significance of an association with the Epstein-Barr virus. It is likely that MCP is related to a past exposure to an infectious organism with the phenotypic presentation being related to the patient's immune predisposition.

The main initial treatment of MCP consists of corticosteroids. Systemic or periocular steroids are helpful in eyes with active posterior segment inflammation or in eyes with CME. Topical corticosteroids are beneficial if there is significant anterior segment inflammation. To reduce the dose of corticosteroids, long-term systemic immunomodulation may be required. Use of immunosuppressive drug therapy can reduce the risk of posterior pole complications and poor vision prognosis. Common drugs for this purpose include methotrexate and mycophenolate.

The most common complication of MCP is CNV, which develops in 30% of patients. Laser photocoagulation may be indicated in these patients. Concurrent CNV has been treated successfully with Photodynamic Therapy (PDT), but collateral damage may occur in patients with active inflammation. The treatment of CNV due to MCP is shifting over to anti-VEGF agents because of their apparent efficacy and better preservation of tissue. Treatment with anti-VEGF agents alone is usually not applicable because patients with MCP almost always have concurrent inflammation.

Patients with MCP require long-term follow-up care. Visual prognosis is variable, with final visual acuity of 20/40 or better in 66% of eyes. With each bout of inflammation, patients with MCP develop more active lesions, which later become atrophic with significant scarring. Visual loss may result from inflammatory scars in the macula, CME, CNV, and iatrogenic induced by long-term corticosteroid use.

Joe Pizzimenti, O.D., F.A.A.O., ORS fellow

FDA Declines To Approve Iluvien For Diabetic Macular Edema

The U.S. Food and Drug Administration has issued a complete response letter to Alimera Sciences for its investigational sustained drug delivery system Iluvien, effectively denying approval at this time, according to a press release.

The letter notes that Alimera's application did not offer sufficient data supporting the safety and efficacy of Iluvien (sustained-release fluocinolone acetonide) for treatment of diabetic macular edema, the press release said. The FAME study demonstrated that risks of adverse reactions from Iluvien were significant and were not offset by Iluvien's benefits, according to the letter.

The FDA's Center for Drug Evaluation and Research issues a complete response letter when it finishes its review of a new drug application but has further questions that must be answered before it can approve the drug The FDA is calling for two more clinical trials to answer its concerns, the press release said.

"We are surprised and disappointed with the FDA's decision on our application to market Iluvien in the U.S. to patients with this devastating disease," Dan Myers, president and CEO of Alimera, said in the release. "Based on extensive research with U.S. retinal physicians, we have learned that Iluvien's long-term sustained delivery treatment benefit is desired and that Iluvien has a manageable risk-to-benefit ratio. We continue to believe in Iluvien as a long-term effective treatment option for DME. We are committed to, and have the funds for, pursuing approval in Europe and for evaluating our options in the U.S."

Alimera expects notification in 2012 on whether Iluvien will be approved in Europe, the release said.

Implant For End-Stage AMD Used For First Time In U.S.

More than a year after gaining approval from the U.S. Food and Drug Administration, the Implantable Miniature Telescope from VisionCare Ophthalmic Technologies has successfully been implanted in a patient in the United States, according to a press release.

The device, created by Isaac Lipshitz, MD, is designed to be implanted into one eye of patients 75 years or older with severe to profound visual impairment associated with end-stage age-related macular degeneration, the release said.

The procedure allows for enlarged central vision images over much of the retina, improving central vision, while leaving the other eye to provide peripheral vision for mobility and orientation.

"Patients with end-stage AMD have been underserved, and they have had limited options until now. Our patients who have exhausted all wet AMD treatment options, or who have the untreatable, advanced form of dry AMD, now have a potential for improved vision and quality of life," Henry L. Hudson, MD, retina specialist for the patient, said in the release.

Kristin Carter, MD, anterior segment surgeon in the CentraSight provider team, implanted the device.

First Retinal Prosthesis Implanted In Blind Patient With Retinitis Pigmentosa

A blind patient with advanced retinitis pigmentosa became the first recipient of a commercial implant intended to restore some vision, according to a press release.

The patient received the Argus II Retinal Prosthesis System, made by Second Sight, on Oct. 29 in Pisa, Italy, the release said. The device received marketing clearance in Europe this year.

The prosthesis uses a miniature camera in the patient's glasses to capture video images, which are then converted into electric impulses that are transmitted wirelessly to an array of electrodes on the surface of the retina, according to the release. The impulses stimulate the retina's remaining cells, allowing the recipient to perceive and interpret patterns of light, regaining some vision. The patient is recovering, the release said. Testing and customization will begin shortly, with the patient potentially using the prosthesis at home by the end of November.

Topical Bromfenac May Aid Reduction Of Retinal Thickness In AMD Patients

Topical bromfenac may help to further reduce retinal thickness when used in combination with ranibizumab to treat neovascular age-related macular degeneration, a small pilot study published in Retina found.

Xibrom (bromfenac ophthalmic solution 0.09%, Ista Pharmaceuticals) is a nonsteroidal anti-inflammatory agent that blocks the production of prostaglandins. It is currently approved for inflammation after cataract surgery and is also being investigated as a treatment for macular edema after cataract surgery.

In the single-site, prospective, open-label, interventional, phase 2 trial, 30 eyes with new or recurrent exudative AMD were randomized at a ratio of 2:1 to combination therapy with Lucentis (ranibizumab, Genentech) and bromfenac or ranibizumab alone. Patients received ranibizumab on a monthly basis for 4 months and then as needed; bromfenac was self-administered as one drop twice daily for 12 months.

No differences in best corrected visual acuity or number of injections were observed. However, mean decrease in central macular thickness in the combination group was 81.56 µm compared to 42.50 µm in the ranibizumab group (P = .03). Additionally, the proportion of eyes experiencing a reduction of 50 µm or more was significantly higher in the combination group (P = .046).

Mild burning or stinging sensation was reported more frequently in the combination therapy group, but the difference was not statistically significant and no safety concerns were raised.

Anti-VEGF Results Maintained At 1 Year In COPERNICUS Study

Less frequent dosing was needed and efficacy was maintained to week 52 in eyes treated with VEGF Trap-Eye, a speaker at the American Academy of Ophthalmology meeting, reporting the 1-year results of the phase 3 COPERNICUS study.

The COPERNICUS study is a randomized, double-masked controlled phase 3 trial in which one arm of patients with central retinal vein occlusion was treated with a 2-mg dose of VEGF Trap-Eye (aflibercept ophthalmic solution, Regeneron Pharmaceuticals, Bayer HealthCare) every 4 weeks for 24 weeks before being switched to an as-needed regimen. A second arm of patients was treated with sham therapy and then switched to as-needed dosing of aflibercept.

One-year results were similar to results reported at 24 weeks, in that mean change in best corrected visual acuity at week 52 in the aflibercept group was within one letter of outcomes reported for the same group at week 24.

Improved Visual Acuity Results Similar In Two Arms Of The Read-3 Study

At month 6, improvement in visual acuity and reduction in retinal thickness were similar between two arms of the Read-3 study, according to a presenter at Retina Subspecialty Day that preceded the American Academy of Ophthalmology annual meeting.

In the Read-3 study, patients with diabetic macular edema (DME) were randomized 1:1 to receive either 0.5 mg or 2 mg ranibizumab (Lucentis, Genentech). The primary endpoint at 6 months was mean change in BCVA, Dr. Quan Dong Nguyen said.

At month 12, an interim analysis showed no statistically significant difference in visual gain between the two groups, and there was a trend toward fewer injections in the 2-mg group, he said.

Regarding safety, there were more hospitalizations in the 2-mg group, although "the majority were not associated with anti-VEGF therapy," Dr. Nguyen said. Furthermore, "there were no cases of endophthalmitis," he said.

Additional studies are needed to assess safety parameters, and longer monitoring of the index group is needed to determine the utility of higher-dose ranibizumab in patients with DME, Dr. Nguyen said.

The Read-3 study will follow and treat patients through at least month 24.

Surgeon Asks For Silence While Delivering Intravitreal Injections

Endophthalmitis following intravitreal injection of anti-angiogenic agents is rare, with reports ranging from one in 1,200 to one in 5,233, but the consequences are devastating, a speaker told colleagues at Retina Subspecialty Day preceding the American Academy of Ophthalmology meeting.

One way for retina specialists to prevent transmission of oral streptococcal pathogens while delivering intravitreal injections is to not speak during drug delivery, Colin A. McCannel, MD, said.

There are considerable differences in colonization on culture plates between persons speaking with and without a face mask and between persons speaking with a face mask and those who are silent, Dr. McCannel said. Current published consensus recommendations include use of povidone-iodine and a lid speculum during intravitreal injections.

"However, there is no recommendation for a face mask," Dr. McCannel said. "I propose...that retina specialists should consider not talking or, if talking, to wear a face mask during injection."

Furthermore, Dr. McCannel suggested that patients be asked not to speak as well.

FDA Issues Alert After Repackaged Bevacizumab Causes Endophthalmitis Infections In Florida

The U.S. Food and Drug Administration has warned physicians that repackaged intravitreal injections of Avastin have caused a cluster of sight-threatening endophthalmitis infections in the Miami area, according to an FDA news release.

The Florida Department of Health reported a cluster of Streptococcus endophthalmitis infections at three clinics. The contaminated injections were traced to one pharmacy in Hollywood, Fla., that repackaged Avastin (bevacizumab, Genentech) from sterile injectable 100 mg/4 mL single-use, preservative-free vials into individual 1 mL single-use syringes, the release said.

The pharmacy distributed the bevacizumab to several eye clinics. At least 12 patients treated at the clinics sustained eye infections. Some reportedly lost remaining vision because of endophthalmitis, the release said. "The agency and Florida health officials continue to investigate the cause of the infection," the release said. "While the investigation is not yet complete, the common link for the infections is the pharmacy that repackaged the Avastin and the single lot of Avastin used in the repackaging."

The FDA advised health care professionals to be aware that repackaging sterile drugs without taking aseptic measures may diminish drug sterility and increase patients' risk of infection.

"Health care professionals should ensure that drug products are obtained from appropriate, reliable sources and property administered," the release said.

Aspirin Use May Be Associated With Increased Risk Of AMD

Frequent aspirin use may be associated with an increased risk of early or wet late age-related macular degeneration, with an odds ratio that increases upon frequency of consumption, a study in Ophthalmology found.

Researchers from the European Eye Study, a population-based, cross-sectional analysis including 4,691 subjects 65 years or older at seven centers from northern and southern Europe, used logistic regression to assess odds ratios for AMD in aspirin users.

Early and late AMD occurred in 36.4% and 3.3% of subjects, respectively; 41.2% of subjects reported monthly aspirin use, 7% reported at least once weekly use, and 17.3% reported daily use.

For participants who used daily, the odds ratios steadily increased with increasing severity of AMD grades: 1.26 for grade 1, 1.42 for grade 2 and 2.22 for wet late AMD.

The study was limited by the unknown amount of aspirin taken, as well as the possibility that participants may have taken aspirin after experiencing visual problems.

Sustained Benefits Seen In 12-Month CRUISE Outcomes

Outcomes from months 6 through 11 of the CRUISE study suggest that as-needed ranibizumab may maintain benefits achieved by six monthly injections in patients with macular edema after central retinal vein occlusion, according to a recent study in Ophthalmology.

"This [study] indicates that after a period of aggressive treatment with ranibizumab, visual benefits can be maintained by close follow-up and treatment if there is evidence of persistent or recurrent disease. What is not answered by this trial is whether even better visual outcomes would have resulted by continuing monthly injections during the second 6 months of the study," the study authors said.

In the prospective, double-masked, multicenter trial, 392 patients were randomized to receive sham therapy or monthly injections of 0.3 mg or 0.5 mg ranibizumab. After 6 months, patients with a best corrected visual acuity of less than or equal to 20/40 or a central subfield thickness of at least 250 µm received ranibizumab.

At 12 months, mean change in BCVA from baseline was 13.9 letters in the 0.3 mg and 0.5 mg treatment groups and 7.3 letters in the sham group. The percentages of patients who gained at least 15 letters from baseline were 47.0% and 50.8% in the 0.3- and 0.5-mg, respectively, and 33.1% in the sham group.

Notably, as-needed treatment with ranibizumab in the sham group resulted in an unequal improvement in BCVA and rapid reduction of central foveal thickness similar to that of the previously treated groups.