The fluocinolone implant, Retisert, is the first U.S. Food and Drug Administration (FDA) approved treatment for non-infectious intermediate, posterior, or panuveitis. The fluocinolone implant was designed to offer local therapy for non-infectious uveitis, obviating the risk of systemic side-effects. The implant is surgically implanted through the pars plana and releases steroids into the vitreous cavity for 2½ to 3 years. This article will summarize currently available data regarding the implant, describe how the implant is placed, and offer suggestions about which patients might benefit most from this new treatment.
Efficacy and Associated Risks
FDA approval of the Retisert implant in April, 2005, was based in part on data from Bausch and Lomb trial 415-001, a 3-year, multi-centered, randomized clinical trial of 2 steroid implant doses. The less involved fellow eye served as a control. Two hundred and seventy-eight patients with non-infectious intermediate, posterior or panuveitis of at least 1 year's duration were enrolled. If both eyes were involved, the more severely affected eye received the Retisert implant. Outcome measures included uveitis recurrence rate, visual acuity, requirement for adjunctive therapy, and safety.
The fluocinolone implant was shown to be very effective in decreasing inflammation. The recurrence rate at 2 years in the study was 11.2 % in implanted eyes compared with 59.6 % in the year preceding the study and 50% in the fellow eye compared with 25.4% in the year prior to the study (ARVO; May 3, 2005; Fort Lauderdale, FL). Requirements for adjunctive local and systemic therapy were also significantly reduced.
The advantage that the Retisert implant offers over other currently available local therapies is the possibility of long-term control of inflammation. Intravitreally injected triamcinolone, for example, lasts approximately 3 to 8 months (Am J Ophthalmol. 2004;138:158-160). This is appropriate for some diseases, but in other cases triamcinolone treatment may result in a cycle of repeated bouts of inflammation and a possibly permanent reduction in visual function. Other steroid delivery devices such as the Medidur injectable fluocinolone device (Alimera Sciences) and the Posurdex and Surodex biodegradable dexamethasone implants (Allergan) are currently being tested.
Although the Retisert implant carries no risk of systemic side effects, it does markedly increase the risk for cataract and glaucoma, necessitating additional intraocular surgery. These risks are related to the steroid itself rather than to the implantation procedure. Retinal detachment and infection are also possibilities. Two-year data from the Bausch and Lomb trial revealed an 89% incidence of cataract surgery in implanted eyes compared with 13% in the fellow eye and, more importantly, a 30% requirement for glaucoma surgery compared with less than 1% in the fellow eye (ARVO; May 3, 2005; Fort Lauderdale, FL).
Fortunately, fewer difficulties are associated with cataract surgery in eyes with the implant than in uveitis patients without the implant. This is because the eyes tend to be very quiet. Glaucoma surgery also tends to be more successful in eyes with implants than in uveitic eyes without Retisert. However, the intraocular pressure (IOP) elevation that is seen with the implant may be dramatic in terms of the rapidity of its development and its severity. IOP after implant placement may be normal for a year or more, before climbing fairly rapidly to 30-50 mmHg. This pressure, while very high, is not associated with pain. Careful follow-up and IOP monitoring is, therefore, essential, even in those patients who were not previously felt to be “steroid responders.” Failure to adequately monitor IOP may result in irreversible glaucomatous visual loss.
Specifications and Surgical Implantation
The Retisert implant itself is approximately 2 mm by 5 mm and consists of a plastic strut with a hole for the suture and a pellet of 0.59 mg of fluocinolone. The implant may be prepared prior to starting surgery. A double-armed 8-0 prolene suture on a TG-175 needle is passed through the hole on the implant strut, and a single knot is tied. Implantation is accomplished through a pars plana incision, and the device is usually placed inferonasally or inferotemporally; the location is modified to avoid areas of retinal traction, snow banking, detachment, or conjunctival abnormality. After conjunctival peritomy, the sclera is marked 3.5 mm to 4 mm posterior to the limbus.
An MVR blade is used to fashion a 3 mm to 3.5 mm scleral incision parallel to the limbus; the surgeon should ensure that the incision extends through the choroid as well as the sclera. The prolapsed vitreous is then excised with a vitrectomy cutter, and the implant is placed into the eye with the implant pellet facing anteriorly. The device is secured via an almost full thickness suture placed anteriorly with 1 needle and posteriorly with the other. Any further prolapsed vitreous is excised.
Finally, the suture is tied, and the ends are left long and secured under the sutures used to close the remaining scleral incision. Balanced salt solution may be injected to restore IOP. Indirect ophthalmoscopy is performed to verify that the implant is located within the vitreous cavity rather than suprachoroidally. The conjunctiva is then closed with sutures. If the patient has had a previous vitrectomy, placement of an infusion cannula will facilitate the procedure.
Patient Selection and Considerations
It may be difficult to decide which patient is a good candidate for a steroid implant. There are no hard and fast rules, but below are some general guidelines that may be helpful:
||The implant is approved only for intermediate, posterior, and pan-uveitis.|
||The ideal candidate should have a purely ocular disease that responds favorably to steroids, but which cannot be controlled at a drug dosage level that is deemed safe. Other good candidates are those with both ocular and systemic disease, but whose systemic disease is well controlled; that is, those patients in whom ocular disease drives therapeutic decisions. (Patients with birdshot retinochoroidopathy, for example, may be ideal candidates, because the disease is chronic, tends to respond well to corticosteroids, and is a purely ocular disease. Additionally, because disease progression may not be obvious, birdshot patients may lose visual field and electroretinogram (ERG) function with little discernable change in the clinical picture. Placement of an implant in these patients may prevent periods of unrecognized disease progression.)|
||Patients with controlled uveitis and associated active systemic disease requiring immunosuppression are not the best candidates, as placement of the implant may not allow for reduction in systemic medication.|
||The implant should only be considered for patients with disease expected to last at least 2 or 3 years. Any disease that is expected to be of shorter duration does not merit placement of an implant.|
||Infectious etiology for inflammation must be excluded before placement of a steroid implant. Herpetic infection such as acute retinal necrosis (ARN) and progressive outer retinal necrosis (PORN) will be dramatically worsened with intraocular steroid therapy. Any patient in whom these diagnoses cannot be excluded must be followed long enough to ensure a non-infectious etiology and a favorable response to corticosteroids.|
||Patients selected for implantation must also be able to be followed for development of glaucoma. Any patient unable or unwilling to be followed for IOP measurement should not receive a steroid implant.|
Other good candidates for the Retisert include those whose uveitis is associated with chronic cystoid macular edema (CME), as this complication may respond better to intraocular steroids than other treatment options (Ophthalmology. 2005;112:1916). Unfortunately, the implant appears unable to salvage hypotonous, pre-phthisical eyes.
Looking Down the Road
Intermediate, posterior, and panuveitis have been traditionally treated with systemic steroids such as prednisone as well as off-label “steroid-sparing” agents like methotrexate, cyclosporine and mycophenolate, and immunosuppressive drugs such as the alkylating agents cyclophosphamide and chlorambucil. Newer therapies that are used off-label for the treatment of uveitis are the so-called biologic agents, including the IL-2 inhibitor daclizumab (Zenapax) and the tumor necrosis factor (TNF) inhibitors etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). All of the systemically administered agents carry the risk of systemic side effects, ranging from weight gain to increased risk of cancer.
This is not the case with the fluocinolone implant, Retisert, which may be a very useful new addition to the traditional armamentarium for the treatment of chronic, non-infectious, intermediate, posterior, and pan-uveitis. The Multicenter Uveitis Steroid Treatment (MUST) trial, a randomized, controlled, 5-year study sponsored by the National Eye Institute (NEI), is currently underway to compare the Retisert implant with standard systemic therapy in the treatment of non-infectious intermediate, posterior, and pan-uveitis.
||Jaffe GK, Martin D, Callanan D, Levy B, Fluocinolone Acetonide Implant Uveitis Study Group. Fluocinolone acetonide intravitreal implant to treat posterior uveitis: 2-year results of a multi-center clinical trial. Paper presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 3, 2005; Fort Lauderdale, FL.
||Jonas JB, Degenring RF, Kamppeter BA, Kreissig I, Akkoyun I. Duration of the effect of intravitreal triamcinolone acetonide as treatment for diffuse diabetic macular edema. Am J Ophthalmol. 2004;138(1):158-160.|
||Kok H, Lau C, Maycock N, McCluskey P, Lightman S. Outcome of intravitreal triamcinolone in uveitis. Ophthalmology. 2005;112(11):1916.|
The author discloses an interest as a member of the speakers bureau for Bausch and Lomb pharmaceuticals and as a participant in Bausch and Lomb trial 415-001.