The goal of medical management of uveitis is to effectively control disease activity to eliminate or reduce the risk of vision loss from structural complications of uncontrolled inflammation. It is critical to determine whether the uveitis is related to a systemic or ocular infection, as anti-inflammatory therapy may severely exacerbate an untreated infection. Once infection is properly addressed, any residual inflammation may be cautiously treated with adjuvant anti-inflammatory therapy. Some diseases, such as multiple evanescent white dot syndrome or acute posterior multifocal placoid pigment epitheliopathy, are self-limited and resolve without treatment. Other diseases, such as Fuchs uveitis syndrome and mild pars planitis, are chronic but do not require treatment. However, most patients with chronic uveitis benefit from sustained suppression of the inflammation.
Corticosteroids are the best agents to control inflammation quickly. Route and dose are tailored to each patient, considering any systemic disease involvement and other factors, such as age, immune status, tolerance of adverse effects, local factors to the eye, and response to treatment. Systemic immunomodulatory therapy (IMT) is used widely in the treatment of noninfectious uveitis when a steroid-sparing effect is required. In the correct clinical scenario, cycloplegic agents, nonsteroidal anti-inflammatories (NSAIDs), and carbonic anhydrase inhibitors may be used as adjunctive therapy.
Corticosteroids are the mainstay of uveitis therapy. They are used to treat active inflammation in the anterior chamber, vitreous, retina, choroid, or optic nerve, and to treat complications such as macular edema. They may be administered locally (as topical eyedrops, or periocular or intraocular injections) or systemically (orally or intravenously or, less frequently, intramuscularly).
The dose and duration of corticosteroid therapy must be individualized. It is generally preferable to begin therapy with a high dose of corticosteroids (topical or systemic) and taper the dose as the inflammation subsides, rather than to begin with a low dose that may have to be progressively increased to control the inflammation. To reduce the complications of therapy, patients should be maintained on the minimum dosage needed to control the inflammation. Systemic corticosteroids must be tapered gradually (over days to weeks), and not stopped abruptly if utilized for longer than 2–3 weeks to prevent cortisol deficiency, resulting from hypothalamic-pituitary-adrenal (HPA) axis suppression. If surgical intervention to treat uveitis or its complications is required, the dosage may need to be increased to prevent postoperative exacerbation of the uveitis.
For uveitis that is not immediately vision-threatening and that is not known to be chronic, corticosteroids are slowly tapered, and the disease is closely monitored. The corticosteroid dosage at which disease recrudescence occurs determines whether additional treatments are required.
Given enough treatment time and dosage, any route of corticosteroid administration will have adverse effects, so the risk–benefit ratio of their use should be considered carefully and discussed with the patient. Corticosteroids in any form, but particularly local corticosteroids, can cause serious adverse effects in the eye, most notably posterior subcapsular cataract and ocular hypertension. The significant systemic risks of steroids are discussed later in this chapter. (See also BCSC Section 1, Update on General Medicine, and Section 2, Fundamentals and Principles of Ophthalmology.)
Topical steroid administration
Topical corticosteroid drops are effective primarily for anterior uveitis, although they may have beneficial effects on vitritis or macular edema with some patients. These drops are given at intervals ranging from once daily to hourly. The drugs can also be administered in ointment form for nighttime use. Difluprednate (0.05%), a fluorinated corticosteroid, is highly potent and has deeper tissue penetration than other topical preparations; dosing at 4 times daily is considered the equivalent of 8 or more total drops per day of prednisolone acetate (1%). Clinical studies suggest difluprednate has a similar adverse effect profile to prednisolone but is associated with potentially higher rises and rates of rise in intraocular pressure (IOP), especially in children. Of the topical preparations, loteprednol and fluorometholone produce a smaller ocular hypertensive effect than that of other medications; however, these drugs are not as effective as prednisolone in controlling more severe uveitis. Differences in physical properties of branded versus generic suspensions of prednisolone acetate can affect the bioavailability of the formulations, although some of this discrepancy can be overcome by vigorous agitation of the drug before instillation. (See also BCSC Section 2, Fundamentals and Principles of Ophthalmology.)
Slabaugh MA, Herlihy E, Ongchin S, Van Gelder RN. Efficacy and potential complications of difluprednate use for pediatric uveitis. Am J Ophthalmol. 2012;153(5):932–938.
Local steroid administration
Sustained-release steroid may be delivered directly into the vitreous cavity or into the periocular space of an eye with noninfectious uveitis when a more posterior effect is needed, or when a patient is nonadherent or only partially responsive to topical or systemic administration. Intermediate- and short-acting local steroid injections may be used intermittently to treat breakthrough inflammation in otherwise well-controlled or mild uveitis. Long-acting intravitreal steroids can be used as alternatives to long-term IMT in certain clinical settings. A limitation of regional therapies is the variable duration of effect, with relapse being the only sign of waning steroid efficacy. Each relapse before reinjection or reimplantation can result in cumulative damage, creating a phenomenon called a “saw-tooth decline.” In chronic uveitis, scheduled replacement or reinjection of steroid before the effect wears off may improve long-term prognosis.
Periocular steroid administration
Periocular corticosteroids are generally given as depot injections into the sub-Tenon space or orbital floor. Although systemic absorption is minimal, periocular corticosteroids can cause systemic adverse effects similar to those of oral corticosteroids. Triamcinolone acetonide (40 mg) and methylprednisolone acetate (40–80 mg) are the most commonly used drugs. Short-acting nondepot steroids, such as dexamethasone or betamethasone, may be injected subconjunctivally for a limited duration of effect.
Periocular injections can be performed using either a transseptal or a sub-Tenon (Nozik technique) approach (Fig 6-1). The technique for a sub-Tenon injection given in the superotemporal quadrant is as follows:
The upper eyelid is retracted, and the patient is instructed to look down and nasally.
After anesthesia is applied with a cotton swab soaked in proparacaine or tetracaine, a 25- or 27-gauge, ⅝-inch needle on a 3-mL syringe is placed bevel-down against the sclera and advanced through the conjunctiva and Tenon capsule using a gentle side-to-side movement, which allows the physician to determine whether the needle has entered the sclera. If the globe does not torque with the side-to-side movement of the needle, the physician can be reasonably sure that the needle has not penetrated the sclera.
Once the needle has been advanced to the hub, the corticosteroid is injected into the sub-Tenon space.
Figure 6-1 Posterior sub-Tenon injection of triamcinolone acetonide demonstrating correct position of the clinician’s hands and the needle. The needle is advanced to the hub with a gentle side-to-side motion to detect any scleral engagement and directed caudad and nasally prior to injection of the corticosteroid. The positioning of the tip of the needle in its ideal location is between the Tenon capsule and the sclera.
(Courtesy of Ramana S. Moorthy, MD.)
Complications of the superotemporal approach include upper eyelid ptosis, periorbital hemorrhage, and globe perforation.
An inferotemporal sub-Tenon injection can also be performed with the Nozik technique, but a transseptal, orbital floor approach (Fig 6-2) using a short 27-gauge needle may be preferred:
The index finger is used to push the temporal lower eyelid posteriorly and to locate the equator of the globe.
The needle is inserted inferior to the globe through the skin of the eyelid and directed straight back through the orbital septum into the orbital fat to the hub of the needle.
The needle is aspirated, and if there is no blood reflux, the corticosteroid is injected.
Complications of the inferior approach can include periorbital and retrobulbar hemorrhage, lower eyelid retractor ptosis, orbital fat prolapse with periorbital festoon formation, orbital fat atrophy, and skin discoloration.
Periocular injections should be avoided in infectious uveitis; their use in necrotizing scleritis should also be avoided due to rare cases of scleral thinning and perforation (see Chapter 7). The physician should be aware that periocular corticosteroid injections have the potential to raise the IOP precipitously or for an extended period, particularly with the longer-acting depot drugs. If this effect occurs, the periocular steroid may be removed surgically if it is located anterior to the septum or in a subconjunctival space.
Leder HA, Jabs DA, Galor A, Dunn JP, Thorne JE. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Am J Ophthalmol. 2011;152(3):441–448.
Figure 6-2 Inferior transseptal (orbital floor) injection of triamcinolone acetonide in the right eye. A 27-gauge, ½-inch needle on a 3-mL syringe is inserted through the skin of the lower eyelid and the inferior orbital septum. By using the index finger of the opposite hand, the physician can determine the location of the equator of the globe to prevent perforation and to place the depot corticosteroid as posteriorly as possible.
(Courtesy of Ramana S. Moorthy, MD.)
Intravitreal steroid administration
Intravitreal therapy achieves a higher, more predictable concentration of steroids in the posterior segment than periocular injection. Intravitreal steroid administration for uveitis currently takes several forms in the United States (US):
triamcinolone acetonide (4 mg/0.1 mL), preservative free, via pars plana injection with a 30-gauge needle
fluocinolone acetonide implant (0.59 mg), surgically implantable, via pars plana incision
fluocinolone acetonide intravitreal insert (0.18 mg), via pars plan injection with integrated 25-gauge injector
dexamethasone pellet (700 μg), biodegradable, via pars plana injection with an integrated 22-gauge injector
Intravitreal injections of triamcinolone acetonide through the pars plana have been shown to produce sustained visual acuity improvements for 3–6 months in nonvitrectomized eyes; the technique is the same as for standard intravitreal injection (see BCSC Section 12, Retina and Vitreous). Published literature on intravitreal triamcinolone administration suggests a definite treatment benefit, although of limited duration, for recalcitrant uveitic macular edema. Intraocular pressure elevation may occur transiently in more than one-half of patients. Up to 25% of patients may require topical medications to control IOP, and 1%–2% may require filtering surgery. Infectious endophthalmitis and rhegmatogenous retinal detachment may occur, but these complications are rare when proper technique is used. This method of treatment is not curative of chronic uveitic conditions and should be used judiciously, as its effects are relatively short lived.
A surgically implantable, sustained-release 0.59-mg fluocinolone acetonide implant is available in the US and is approved by the US Food and Drug Administration (FDA) for the treatment of chronic noninfectious uveitis affecting the posterior segment. The implant is inserted through a small pars plana incision and sutured to the sclera.
Multicenter, controlled clinical studies have shown that the 0.59-mg implant is effective for a median of 30 months, with a mean time of 38 months to first recurrence. At 34 weeks after implantation, inflammation was well controlled in nearly all eyes, and recurrence rates decreased by 90%, with 77% of patients able to discontinue systemic therapy and 96% able to discontinue local corticosteroid injections. However, nearly all phakic eyes developed cataract within 2 years after implantation. Elevated IOP necessitating topical therapy developed in nearly 75% of patients after 3 years, and 37% required filtering surgery.
Postoperative complications (eg, endophthalmitis, wound leaks, hypotony, vitreous hemorrhage, and retinal detachments) have been reported. Reimplantation or exchange may be performed.
The 0.59-mg fluocinolone implant was compared with standard systemic therapy in the Multicenter Uveitis Steroid Treatment (MUST) Trial, which enrolled 255 patients over 3 years. Best-corrected visual acuity was not significantly different between the 2 treatment groups at the 2- and 4.5-year primary endpoints; however, 7-year data published in 2017 showed that the change in vision from baseline favored systemic therapy by 7.1 letters, with the risk of blindness decreasing by 1% in the systemic group but increasing by 8% in the implant group. This difference appeared to be due to retinal damage from relapse of the uveitis before reimplantation (see Table 6-1).
A sustained-release 0.18-mg fluocinolone acetonide injectable intravitreal insert is approved by the US FDA for the treatment of noninfectious posterior uveitis. The non-bioerodible device is injected via a nonshelved wound through the pars plana into the vitreous cavity, where it releases the drug over 36 months. A prospective randomized placebo-controlled clinical trial demonstrated statistically significantly lower uveitis recurrence rates in the implant group compared to sham at 6 months (28% vs 91%) and 12 months (38% vs 98%). Cataract formation was greater in the treatment group, but no significant differences were found in IOP-lowering treatment.
A biodegradable injectable pellet containing 700 μg of dexamethasone is approved by the US FDA and in Europe for the treatment of noninfectious uveitis affecting the posterior segment of the eye and retinal vein occlusion. This implant is injected through the pars plana into the vitreous cavity by creating a shelved wound using the injector (Video 6-1). A prospective randomized controlled clinical trial demonstrated that, at 8 weeks, 47% of eyes treated with a dexamethasone implant had improved vitreous haze, compared to 12% of eyes in the sham group. Statistically significant improvements in visual acuity and macula thickness were reported, and fewer eyes required rescue medication. Intraocular pressure elevation and cataracts were the most commonly reported treatment-related ocular adverse effects in this study.
Injection of dexamethasone implant.
Courtesy of Thomas Albini, MD.
Access the video at www.aao.org/bcscvideo_section09.
Several longer-term, multicenter retrospective studies have reported relatively positive results on the safety and efficacy of repeated dexamethasone intravitreal implants in uveitic patients with refractory macular edema, with an average time to reinjection of 6 months. Relative contraindications to the dexamethasone implant are aphakia, prior vitrectomy, and absence of lens capsule because of the risk of implant migration into the anterior chamber (see Table 6.1).
Table 6-1 Selected List of Major Treatment Studies in Uveitis
Androudi S, Letko E, Meniconi M, Papadaki T, Ahmed M, Foster CS. Safety and efficacy of intravitreal triamcinolone acetonide for uveitic macular edema. Ocul Immunol Inflamm. 2005;13(2–3):205–212.
Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol. 2007; 125(11):1478–1485.
Jaffe GJ. Reimplantation of a fluocinolone acetonide sustained drug delivery implant for chronic uveitis. Am J Ophthalmol. 2008;145(4):667–675.
Jaffe GJ, Foster S, Pavesio C, Paggiarinno D, Riedel GE. Effect of an injectable fluocinolone acetonide insert on recurrence rates in noninfectious uveitis affecting the posterior segment: 12-month results. Ophthalmology. 2018 Oct 24. pii: S0161-6420(18)31715-9.
Khurana RN, Appa SN, McCannel CA, et al. Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies. Ophthalmology. 2014;121(1):67–71.
Lowder C, Belfort R Jr, Lightman S, et al; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011;129(5):545–553.
Tomkins-Netzer O, Taylor SR, Bar A, et al. Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. Ophthalmology. 2014;212(8):1649–1654.
Writing Committee for the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study Research Group; Kempen JH, Altaweel MM, Holbrook JT, et al.
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;317(19):1993–2005.
Zarranz-Ventura J, Carreno E, Johnston RL, et al. Multicenter study of intravitreal dexamethasone implant in noninfectious uveitis: indications, outcomes and reinjection frequency. Am J Ophthalmol. 2014;158(6):1136–1145.
Systemic steroid administration
Systemic corticosteroids are used for vision-threatening chronic uveitis when local corticosteroids are insufficient or contraindicated or when systemic disease also requires therapy. Of the many oral corticosteroid formulations that are available, prednisone is the most commonly used. The readily available blister packages of methylprednisolone, which contain predetermined taper schedules, have no role in the treatment of uveitis. Most patients require 1–1.5 mg/kg/day of oral prednisone (usually no higher than 60–80 mg/day), which is gradually tapered every 1–2 weeks. Doses >60 mg/day are associated with an increased risk of ischemic necrosis of bone and should be avoided if possible. The lowest possible dose that will effectively quiet the ocular inflammation and minimize adverse effects is desired. If corticosteroid therapy at a dose of more than 7.5 mg/day is required for longer than 3 months, IMT is indicated. Long-term use at 7.5 mg or less per day shows no increased risk of steroid adverse effects over months to years, although there are data to suggest increased cardiovascular risks with large cumulative doses of prednisone (eg, 5 mg/day over 20 years).
In cases of an explosive onset or severe noninfectious uveitis, therapy with intravenous, high-dose, pulse methylprednisolone (1 g/day infused over 1 hour) may be administered for 3 days, followed by a gradual taper of oral prednisone starting at 1–1.5 mg/kg/day. Although this mode of therapy may control intraocular inflammation, it should only be administered by a physician experienced with this approach, as there are multiple adverse effects, some of which can be life-threatening.
The many adverse effects of both short- and long-term use of systemic corticosteroids must be discussed with patients, whose general health must be closely monitored, often with the assistance of an internist. Short-term risks include ocular hypertension, hyperglycemia, systemic hypertension, gastric reflux, insomnia, emotional lability, weight gain, fluid retention, and others. Intermediate-term risks include cataract, osteoporosis, avascular necrosis of joints, diabetes mellitus, and others. If possible, corticosteroids should be avoided in patients at high risk for corticosteroid-induced exacerbations of existing conditions (eg, diabetes mellitus, hypertension, peptic ulcer or gastroesophageal reflux disease, psychiatric conditions, or a history of immune compromise).
Patients taking systemic corticosteroids and NSAIDs concomitantly have a higher risk of gastric ulcers; therefore, this combination is best avoided. If necessary, these and other at-risk patients should receive a histamine-H2 receptor antagonist or proton-pump inhibitor. Patients receiving long-term systemic corticosteroid maintenance therapy should supplement their diets with calcium and vitamin D to lessen the risk of osteoporosis.
The following tests can be used to evaluate patients at risk for corticosteroid-induced bone loss:
serial height measurements
serum calcium and phosphorus levels
serum 25-hydroxycholecalciferol levels (if vitamin D stores are uncertain)
follicle-stimulating hormone and testosterone levels (if gonadal status is uncertain)
bone-mineral-density screening (for anyone receiving corticosteroid therapy for more than 3 months)
The USFDA has approved several drugs for the prevention and treatment of corticosteroid-induced osteoporosis in men and women. These medications may be administered to at-risk patients receiving prednisone.
The systemic adverse effects and potency of commonly used corticosteroids are discussed in BCSC Section 1, Update on General Medicine. See also BCSC Section 2, Fundamentals and Principles of Ophthalmology.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.