Local delivery of corticosteroids in clinical ophthalmology: a review.

Abstract Locally administered steroids have a long history in ophthalmology for the treatment of inflammatory conditions. Anterior segment conditions tend to be treated with topical steroids whilst posterior segment conditions generally require periocular, intravitreal or systemic administration for penetration. Over recent decades, the clinical applications of periocular steroid delivery have expanded to a wide range of conditions including macular oedema from retino‐vascular conditions. Formulations have been developed with the aim to provide practical, targeted, longer‐term and more efficacious therapy whilst minimizing side effects. Herein, we provide a comprehensive overview of the types of periocular steroid delivery, their clinical applications in ophthalmology and their side effects.

types of periocular steroid delivery, their clinical applications in ophthalmology and their side effects.

K E Y W O R D S
corticosteroid, dexamethasone, Fluocinolone acetonide, prednisolone acetate, triamcinolone acetonide

| INTRODUCTION
The first use of corticosteroids in ophthalmology by Gordon and McLean 1 in the 1950s was a landmark event that revolutionized the management of inflammatory eye disease. The following decades led to further research into the mechanisms and immunological pathways within the eye, as well as the development of various forms of steroid that are locally administered in clinical practice today. Variations in ocular steroid delivery sites, dosages and preparations have all improved efficacy and durability whilst minimizing side effects. Despite development of systemic immunomodulatory (steroid-sparing) agents and intravitreal monoclonal antibodies, locally administered steroids continue to retain a fundamental role in the management of many ophthalmic diseases. This paper reviews the mechanism of action, preparations, indications and side effects of locally administered steroids.

| STEROID SUBTYPES AND MECHANISM OF ACTION
Steroids are organic compounds with 17 core carbon atoms bonded in three fused cyclohexane and one fused cyclopentane ring. The main two groups are corticosteroids (glucocorticoids and mineralocorticoids) and sex steroids (progestogens, androgens and estrogens; Figure 1). 2 Most steroids used in ophthalmology are glucocorticoids, which have anti-inflammatory and immunosuppressive activity. The synthetic steroid prednisolone has both glucocorticoid and mineralocorticoid receptor activity, whilst the other three main ocular steroids (triamcinolone acetonide [TA], dexamethasone acetonide [DA] and fluocinolone acetonide [FA]) are predominantly active against glucocorticoid receptors (Table 1). 2 The therapeutic effect of glucocorticoids are mediated via the glucocorticoid receptor in the cytosol which upon activation, undergoes conformational changes and translocate toward the cell nucleus. This activated glucocorticoid receptor signals the transactivation or trans-repression of gene transcription factors which cause both therapeutic and side effects. There are over 40 distinct isoforms of the glucocorticoid receptor which have varying distribution within the tissues of the eye, each with different downstream signalling effects allowing for diverse cell-specific actions. 4 The anti-inflammatory effect of steroids is caused by inhibiting the transcription of inflammatory and immune genes. These actions block the release of arachidonic acid and its subsequent eicosanoids (prostaglandins, thromboxanes, prostacyclins and leukotrienes). 5 This affects the F I G U R E 1 Classification of steroids and actions blood-retinal barrier with a reduction in fibroblast proliferation, collagen and scar formation, retinal oedema, fibrin deposition, capillary leakage, intraretinal migration of inflammatory cells and levels of vascular endothelial growth factor (VEGF).

| STEROID PREPARATIONS AND METHODS OF LOCAL ADMINISTRATION TO TREAT OPHTHALMIC DISEASE
Glucocorticoids may be locally administered in the following ways: topical, sub-conjunctival, periocular (sub-Tenon, orbital floor, peribulbar) and intravitreal ( Figure 2). Regional administration allows for high levels of ocular delivery (intravitreal steroid bypasses the blood-retinal barrier) whilst minimizing systemic side effects. An overview of steroid preparations and their local delivery methods are presented in Table 2.

| Topical
Topical steroids are used to treat inflammation of the conjunctiva, cornea and the anterior segment. In certain circumstances they can also be useful in treating uveitic or postoperative macular oedema. Penetration into the aqueous humour occurs by diffusion across the cornea. 6 Dexamethasone is approximately 25 to 30 times intrinsically more potent than hydrocortisone. 7 However, the efficacy of each preparation depends not only on the  drug's intrinsic potency, but its penetration and durability. Acetate preparations are more lipophilic than those with phosphate preparations, and hence have greater corneal penetration. 8 Although prednisolone acetate is six times less potent on a molar basis than dexamethasone or betamethasone, due to the acetate preparation, topical prednisolone acetate 1% provides greater antiinflammatory effect than either dexamethasone or betamethasone phosphate 0.1%. 9 Solutions with preservatives also have greater penetrance than those without, as the preservative disrupts tight junctions between corneal epithelial cells. The frequency of application also increases the anti-inflammatory effect. A study on corneal inflammation demonstrated greater antiinflammatory effects when topical prednisolone acetate is applied every 15 minutes (or five doses at 1 minute intervals each hour) versus hourly. 10 It is important that suspensions are shaken immediately prior to use, otherwise the administered dosage will vary.

| Sub-conjunctival
Sub-conjunctival steroids are frequently administered at the conclusion of intraocular surgery. The most common preparation used is dexamethasone, although methylprednisolone may also be given. 11 Dexamethasone has been shown to achieve good ocular penetration following subconjunctival injection, with higher levels of concentration in the aqueous and vitreous than when it is administered as a peribulbar injection or orally. 12 Sub-conjunctival TA has been shown to be efficacious and safe for anterior uveitis and non-necrotising, non-infectious anterior scleritis. 13,14

| Periocular
Sub-Tenon, orbital floor and peribulbar steroids are frequently used to treat ocular inflammatory conditions, particularly when there is associated macular oedema and in whom systemic side effects are less desirable. After 30 days following a single sub-Tenon injection of 40 mg of TA, corticosteroid levels can be found in all ocular tissues, with highest levels within the choroid and retinal pigment epithelium, whilst systemic levels remain low. 15 The drug of choice is usually TA, formulations of which include Kenacort and Triesence.
Posterior juxtascleral depot injection of anecortave acetate was previously used to treat choroidal neovascularisation. Anecortave acetate (Retaane) is a synthetic angiostatic steroid that was formulated to be devoid of glucocorticoid receptor-mediated activity. It was delivered as a posterior juxtascleral depot every 6 months. Although its efficacy in neovascular agerelated macular degeneration (AMD) was shown against placebo, 16 it did not strongly demonstrate significant benefit against photodynamic therapy with verteporforin. 17 The role of anecortave acetate was soon superceded by the emergence of intravitreal anti-VEGF.

| Intravitreal
Steroids are most potent against retinal disease when delivered intravitreally. Intravitreal steroids are used for macular oedema, uveitis and to stain the vitreous during intraocular surgery for improved visualization. As the procedure involves globe penetration, it must be done under aseptic conditions. It may be given as an intravitreal injection (Kenacort, Triesence), or as a slowrelease intravitreal implant (OZURDEX, Iluvien, Retisert).

| Triamcinolone acetonide
TA is a minimally water-soluble suspension. After intravitreal injection, triamcinolone crystals slowly dissolve into the vitreous. This creates a diffusional gradient from the vitreous to the macula with minimal systemic exposure. While a portion of the drug targets the macula, another portion either clears through the retina or diffuses to the anterior segment where it can cause cataract or elevation of intraocular pressures (IOPs).
Kenacort was formulated for intra-articular and intramuscular injection and thus its application in ophthalmology is off-label. In contrast, Triesence is a preservative-free preparation of TA. The pharmacokinetics and pharmacodynamics of different TA preparations have been shown to differ in animal studies. 18,19 Since only dissolved free triamcinolone has a therapeutic effect, durability depends on multiple factors such as pH, particle size (smaller and more uniform for Triesence compared with Kenacort), crystallinity, solubility and dissolution kinetics in the vitreous. 19 The duration of effect of intravitreal TA (IVTA) lasts between 3 20 and 6 21 months in non-vitrectomised eyes, but is up to six times shorter in vitrectomised eyes. 20 Kenacort comes in two dosages: Kenacort-A 10 (10 mg/ml) and Kenacort-A 40 (40 mg/ml). As its use in ophthalmology is off-label, no specific dosage is recommended however most studies for diabetic macular oedema (DMO) have injected 4 mg in 0.1 mL. The SCORE studies for macular oedema secondary to retinal vein occlusion showed no significant differences between the 1 mg/0.1 mL and 4 mg/0.1 mL preservative-free IVTA (Trivaris Allergan, Inc., Irvine, California) arms. 22,23 The manufacturer of Triesence (Alcon) recommends an initial dosage of 4 mg/0.1 ml for therapeutic purposes, and 1 to 4 mg for visualization during vitrectomy. 24

| Dexamethasone intravitreal implant
OZURDEX is a biodegradable intravitreal implant that contains 0.7 mg dexamethasone in a NOVADUR solid rod-shaped polymer drug delivery system. It is designed to release drug over 3 to 6 months in a biphasic fashion with higher doses in the initial 6 weeks followed by lower doses for up to 6 months. It is injected using a single-use intravitreal applicator with a stepped technique. It is used to treat DMO, macular oedema due to branch or central retinal vein occlusion (BRVO, CRVO) and non-infectious posterior uveitis.
OZURDEX is contraindicated if there is active ocular infection, hypersensitivity to the drug, advanced glaucoma or posterior lens capsule rupture. 25 In vitrectomised eyes, there may be an advantage in using the dexamethasone intravitreal implant (DII) over other bolus intravitreal therapies which have a reduced half-life. 20 Rabbit-studies have shown no difference in clearance rates of DII in vitrectomised and non-vitrectomised eyes. 26 The efficacy of DII has also been shown to be similar in vitrectomised and non-vitrectomised eyes when used to treat macular oedema secondary to CRVO. 27

| FA implant
Fluocinolone acetonide implants are synthetic corticosteroid with low solubility in aqueous allowing extended drug release.
Iluvien is an injectable intravitreal 0.19 mg implant within a rod-shaped (3.5 × 0.37 mm) non-biodegradable reservoir that has a duration of action of 18 to 36 months. The FAMOUS study demonstrated a sustained release by measuring aqueous concentrations, with levels of slightly more than 2 ng/mL for the first 3 months followed by maintained concentrations of 0.5 to 1.0 ng/mL from 6 to 36 months. 28 Retisert is a non-biodegradable disc-shaped intravitreal implant containing 0.59 mg of FA within a silicone elastomer. It is surgically inserted through a pars plana incision and removed by a second surgical procedure. It has a duration of 18 to 30 months with an initial active drug release of 0.6 μg/day to an eventual steadystate release of 0.3 to 0.4 μg/day for 30 months. 29 Yutiq is a recently developed intravitreal implant containing 0.18 mg of FA which is designed to deliver sustained release for up to 36 months. Fluocinolone is contained in the core of a polyamide polymeric cylinder (3.5 × 0.37 mm) with a permeable polyvinyl alcohol membrane. It is injected by a pre-loaded sterile applicator with a 25-gauge needle. The drug delivers an approximate initial rate of 0.2 μg daily followed by 0.1 μg daily over 36 months. 30

| USES OF LOCALLY ADMINISTERED STEROIDS
An outline of studies on the local delivery of corticosteroids in clinical ophthalmology is presented in Table 3.

| Ocular adnexae-eyelids, lacrimal gland and orbit
Oculoplastic uses of topical or intra-lesional steroids is limited to a few conditions.

| Thyroid eye disease
Peribulbar and intra-orbital steroids have been used in management of active thyroid eye disease (TED). Two randomized studies, with small patient numbers, showed reduction in clinical activity score and extraocular muscle size. 31,32 Both studies required multiple peribulbar injections of TA 20 mg. There were few reported side effectsonly two cases developed raised IOP. Although they can have an adjunctive role in active TED, they are not firstline therapy.
Peribulbar and sub-conjunctival steroids have also been used for upper eyelid retraction in TED. [33][34][35][36] Studies show that repeat injections of 20 mg of TA are required (one to four injections at monthly intervals) and the response rate is better in patients with recent onset of upper lid retraction or active disease. Xu et al 37 noted an improvement in 83.3% of patients with symptom duration less than 6 months, compared to 36.4% who responded if symptoms were greater than 6 months. Joos et al 36 showed that a superior orbital peri-levator injection technique improved lid retraction and demonstrated reduction in size of the levator/superior rectus complex on MRI imaging after repeat injections.

| Histiocytic orbital lesions
Histiocytic lesions are divided into Langerhans cell histiocytosis (LCH) and non-LCH lesions, of which Juvenile Xanthogranuloma (JXG) is the most common. Langerhans cell histiocytosis can be monofocal (often seen in the frontal bone of the orbit), or systemic. It often presents in children, but can occur in all age groups. It results in bone destruction and secondary soft tissue expansion. 38 The treatment of choice for orbital LCH is incisional biopsy with curettage of the lesion and intralesional steroids (triamcinolone 40 mg/mL or methylprednisone). 39,40 JXG often presents with cutaneous involvement. Eyelid and orbital lesions are rare and can be managed with a combination of intra-lesional steroids with or without surgical debulking. 41

| Periorbital capillary haemangiomas
The treatment of choice for periorbital infantile haemangiomas has traditionally been intra-lesional and systemic steroids. In 2008 Léaute-Labrèze et al 42 published a series of 11 cases of infantile haemangioma cases managed with propranolol which has revolutionized treatment. Two systematic reviews show both intralesional steroids and propranolol are effective, though less side effects occur with propranolol. 37,43 Propranolol is now the mainstay of treatment for periorbital infantile haemangioma and intra-lesional steroids are used as an adjunct in resistant cases.

| Nasolacrimal disease
Topical steroid drops and steroid nasal spray have been used in management of nasolacrimal duct obstruction (NLDO), with little evidence for their use. In functional NLDO with associated symptoms of rhinitis, topical steroid nasal spray (eg, mometasone and budesonide) may improve epiphora. 44 The anecdotal improvement of epiphora and mucus discharge in complete NLDO with topical steroid drops is likely secondary to the antiinflammatory effect and reduced mucus in the lacrimal sac. Mansur et al 45 recently assessed the lacrimal complications associated with systemic chemotherapy agents and suggested minor canalicular blockages may be effectively treated with probing and topical steroid drops. If there is a more significant blockage or likely long-term chemotherapy, then lacrimal surgery is advised. 45

| Chalazia
Traditionally non-resolving or large chalazia of the eyelids are treated by surgical incision. However, studies show equally effective results with 0.2 to 0.4 mL of 10 mg/mL intra-lesional triamcinolone. 46,47 A metaanalysis of randomized studies showed incision and curettage was more effective than steroid injection as a single procedure, but with repeat procedures similar outcomes were shown. 48 Intra-lesional steroid for chalazia is an acceptable treatment for primary and recurrent chalazia.

| Periocular scarring
Hypertrophic scarring following surgery or trauma has traditionally been managed with a mixture of topical or intra-lesional steroids or surgery. Recently, combination therapy of intra-lesional triamcinolone and 5-FU has shown great promise in improving periocular scarring post-surgery. 49

| Anterior segment
Steroids are used frequently in anterior segment diseases, 4 however there is a considerable lack of randomized control trials (RCTs) to guide treatment.

| Corneal transplants
Corticosteroids are the principle medication in the management of corneal transplantation. They are readily absorbed through the cornea and achieve a high concentration in the anterior chamber through topical application. Prednisolone and dexamethasone are the most commonly used forms. 50 Multiple treatment regimes exist, but as a guide prednisolone 1% or dexamethasone 0.1% drops are used every 2 hours initially, tapered over a period of 6 to 12 months, and a mild steroid used daily for maintenance treatment in endothelial keratoplasties.
Some have advocated for the use of steroids prior to high-risk transplantation [50][51][52][53] but this has been variably adopted. A survey of the Bowman's Club (The UK Society of corneal surgeons) found that topical dexamethasone was used in 33%, oral prednisolone by 22% and single dose IV methylprednisolone (IVMP) by 14%. 54 During corneal allograft rejection, topical, subconjunctival, periocular and/or systemic corticosteroid use is the treatment of choice, with the majority of corneal specialists favouring topical formulations (with a preference for prednisolone acetate 1%). 55,56 In severe cases of allograft rejection oral or IVMP is often added, and one prospective study suggested that a single dose of 500 mg of IVMP is more effective and better tolerated than daily oral prednisolone. 57 Unfortunately there are no RCTs to add weight to this study.

| Bacterial keratitis
The greatest evidence for the use of steroids in bacterial keratitis come from the Steroids for Corneal Ulcers Trials (SCUT). [58][59][60] A cochrane review of steroid use in bacterial keratitis 61 found four RCTs that met inclusion criteria, but only the SCUT trial was of sufficient power to determine the effect of steroids in bacterial keratitis.
This SCUT trial examined the outcomes of 500 cases of culture-positive bacterial keratitis where fungal, acanthamoeba, HSV, impending perforation and previous corneal transplant patients were all excluded. All cases received moxifloxacin q1h for 48 hours prior to randomization; at randomization, half the patients received prednisolone 1% for a total of 3 weeks only (QID for 1 week, BD for 1 week and daily for 1 week) compared to placebo. In both 3 and 12 months reports, there were no difference between groups in any parameters measured (best-subjective corrected visual acuity [BSCVA], scar size, rate of re-epithelialization, rate of perforation). This report added to the weight of evidence that steroids do not cause corneal perforation in bacterial keratitis. The IOP was lower in the steroid group at 3 months as inflammation was better controlled (p = .04).
However, subsequent subgroup analysis demonstrated a benefit for the use of steroids. In the 3-month report, those with baseline BSCVA of CF or worse and those with an infiltrate covering the central 4 mm of the cornea performed better with early introduction of steroids compared to placebo (a two-line difference in vision, p < .05) indicating that there is a benefit of steroids in severe, central infections in the early stage of recovery. At 12 months, when Nocardia infections were removed from the cohort, those who had steroids after 48 hours of antibiotic treatment had a one-line improvement in BSCVA compared to those who did not have steroids.

| Herpes simplex keratitis
Steroid use in herpes simples keratitis (HSK) is mainly for stromal and endothelial keratitis. Much of the evidence for the use of steroids in HSK comes from the double blind, placebo-controlled RCT known as the Herpetic Eye Disease Study (HEDS). 62 The HEDS demonstrated a clear benefit of the use of topical prednisolone in the treatment of stromal keratitis. 62 Those on trifluridine plus prednisolone had a treatment failure rate of 26% compared to 73% on trifluridine plus placebo (p < .001). The study also demonstrated that a 10-week tapering course of steroids was too brief as 50% developed a recurrence within 6 weeks. Thus, for non-necrotising stromal keratitis without an epithelial defect, antiviral treatment in conjunction with topical steroids for at least 10 weeks is recommended.
Endothelial disease typically presents independently of other forms of HSV keratitis and only few studies are available to guide treatment. [63][64][65] These compare topical betamethasone with topical acyclovir against topical acyclovir alone (all five times a day) and found that the addition of steroid resulted in a faster response and fewer treatment failures than antiviral alone. Thus, the recommendation for HSV endothelial disease is the combination of antiviral treatments with topical steroids, tapered according to patient signs and symptoms.

| Allergic eye diseases
Allergic eye diseases cover a spectrum from seasonal allergic disease through to vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis. Corticosteroids play an important role in controlling acute exacerbations; however, they should not be used as long-term maintenance due to their side effects. 66 In children with severe VKC, intraocular pressure rises have been reported in up to 28.3% of patients, with 5.5% progressing to glaucoma. 67 Various regimes of topical steroids can be employed depending on severity of disease with early introduction of a steroid-sparing agent when the patient is expected to require long-term disease control.
Supratarsal injection of steroid is effective in refractory, severe and challenging cases of allergic eye diseases. 68 Two prospective, randomized, double-masked, case-control trials showed no difference between dexamethasone sodium (2 mg) phosphate, TA (10-20 mg) and hydrocortisone sodium succinate (50 mg) in improving severe refractory VKC with resolution of many symptoms by 3 weeks. 69,70 However, symptoms recurred about 12 weeks post-treatment without anti-allergy medication. 69

| Corneal neovascularization
Topical steroids are the mainstay of treatment for the suppression of early proliferating corneal vessels. [71][72][73][74][75] They act primarily due to suppression of inflammation associated with new vessels and are not necessarily angio-regressive. 76 As such, steroids are most effective when applied before, or immediately after corneal injury. 71

| Keratoconjunctivitis sicca
Topical steroids have a role for treating keratoconjunctivitis sicca (KCS), as outlined in the Tear Film and Ocular Surface Society Dry Eye Workshop II (TFOS DEWS II) report. 77 This report summarizes the currently available evidence on managing dry eye disease, including results from several RCTs, [78][79][80][81][82][83][84][85][86][87] and concluded that short courses of corticosteroid are effective in improving symptoms of KCS. However, this is not an effective long-term strategy due to potential side effects. Typically, low strength steroids such as FML were used QID.

| Graft vs host disease
Ocular involvement of Graft Versus Host Disease (GVHD) may cause an acute or chronic immunologically mediated inflammatory disease of the ocular surface. Whilst systemic corticosteroids are the mainstay of controlling the acute exacerbations of chronic GVHD, adjunctive topical steroids is often used to allow tapering and cessation of systemic immunosuppression. Small series have retrospectively demonstrated efficacy of topical steroid treatment in controlling acute conjunctival inflammation and reducing scarring, however signs of KCS remained. 88 Long-term topical steroids are not recommended after the acute inflammatory phase, when other antiinflammatory agents, such as cyclosporin A and tacrolimus may be employed. This is supported by a recent RCT of 42 patients that assessed dry eye disease in chronic GVHD. Topical loteprednol etabonate 0.5% was found to have a minimal effect in ocular surface disease index (OSDI) and corneal fluorescein staining compared to topical lubricants. 89

| Cicatrising conjunctival disorders
Chemical and thermal injury The goal of therapy following chemical and thermal anterior segment injuries is to restore the ocular surface and maintain long-term corneal clarity by preventing cicatrisation and limbal stem-cell deficiency. Along with other important aspects of treatment, topical steroids may be used to limit the profound associated inflammation and promote healing. However, there has been controversy regarding the use and timing of topical corticosteroids.
Corticosteroids may have beneficial effects on inflammatory cell suppression and collagenase inhibition, however they may also suppress keratocyte migration and collagen production and thus cause corneal thinning. 90 Generally, their anti-inflammatory effect is maximal in the first week after which they should be tapered due to the risk of corneal thinning. Their use alone has been cautioned as it has been shown to cause further corneoscleral melt. 91 Monitoring for infection or prophylactically adding topical antibiotics prior to epithelialisation is also recommended. One study found a risk of corneoscleral melting if topical steroids were used after 10 days of the chemical injury. The timing coincides where suppression of keratocyte collagen production by corticosteroids may outweigh the advantages of inflammatory cells suppression and collagenase inhibition to promote corneal ulceration. 90 Davis et al and Brodovsky et al, found in their retrospective series that the prolonged use of topical prednisolone 0.5% used concurrently with topical ascorbate 10% was not associated with corneoscleral melt. 92,93 Ocular cicatricial pemphigoid/mucous membrane pemphigoid Mucous membrane pemphigoid is a systemic disease primarily affecting mucous membranes. When localized to the conjunctiva, the condition is known as ocular cicatricial pemphigoid. It manifests as a chronically progressive conjunctival inflammation causing bilateral blindness. Systemic immunosuppression is required to halt the progressive inflammation and achieve adequate long-term remission. 94 Topical and sub-conjunctival corticosteroids are used adjunctively with systemic therapy. They may offer short-term relief of symptoms but are not effective in halting progression of the systemic autoimmune disease. 95 Due to the infrequency and nature of the condition, there have been no studies assessing their role. Other topical agents shown to give variable results include: calcineurin inhibitors, cyclosporine A, tacrolimus and mitomycin C. 94

| Anterior uveitis
Topical corticosteroids are the mainstay of treating uncomplicated anterior uveitis as it has fewer local and systemic side effects compared to periocular or systemic administration. The interval of drop instillation is tailored to each patient; however, it is generally initiated on frequent intervals then slowly tapered according to the clinical response to prevent rebound inflammation. Where anterior uveitis has not adequately responded to topical corticosteroids, periocular steroids such as subconjunctival dexamethasone may provide greater therapeutic effect with a short duration of action of 1 to 2 days. 96 Similarly, sub-conjunctival triamcinolone or betamethasone has also been shown to be safe and effective in severe cases of anterior uveitis. 14 4.2.10 | Non-necrotising, non-infectious anterior scleritis Sub-conjunctival TA may be given for the treatment of non-necrotising, non-infectious anterior scleritis. 13,97

| Glaucoma surgery
The use of corticosteroids in modulating conjunctival wound healing is essential in glaucoma surgery. Topical corticosteroids are routinely used postoperatively and their frequency is often titrated according to the desired effect on wound healing. Sub-conjunctival corticosteroids are also often injected at the end of surgery, though not usually at the surgical filtration site.

| Glaucoma filtration surgery
Glaucoma filtration surgery is aimed at creating a filtering bleb which allows aqueous drainage and thus lowers the IOP. The long-term success of surgery is dependent on modulating wound healing at the site of filtration, namely the scleral flap and overlying conjunctiva and Tenon's capsule.
Topical postoperative corticosteroids after trabeculectomy have been widely used since the apparent effect on filtering blebs was first described in 1965. 98 The beneficial effects of steroids after trabeculectomy were first demonstrated in a prospective study in 1985, before the revolutionary widespread use of adjunctive local antimetabolites. 99 Forty-six eyes of 35 patients with a diagnosis of primary open-angle glaucoma or primary angle-closure glaucoma underwent trabeculectomy were randomized into three groups. Group 1 received no additional steroids, group 2 received topical 1% prednisolone acetate initially every 3 hours then tapered over 20 days, group 3 received the same treatment as in group 2 with additional of oral prednisone (80 mg daily) with a progressive taper over 16 days. The results were followed after 1.5 years, and long-term data were later published at 5 and 10 years on 58 and 46 eyes, respectively. At 10 years, patients in group 1 (who did not have steroids) had a significantly higher rate (66.7%) of additional glaucoma procedures compared to those in group 2 (11.1%) and group 3 (38.5%). Furthermore, patients in group 1 had higher IOPs, were treated with more glaucoma drops and had lower rate of stabilized glaucoma (based on optic disc photography and visual fields). 100 Perioperative injection of sub-conjunctival corticosteroids at the filtering site have been demonstrated to give favourable bleb formation and IOP control in a small pilot series, 101 In contrast, the only prospective randomized study comparing postoperative topical steroids to postoperative topical steroids in addition to steroid depot injection of TA found no significant differences in outcomes. 102 Nevertheless, since the introduction of locally administered antimetabolites such as 5-fluorouracil and mitomycin C were found to be more potent in impairing wound healing and thus increase long-term success rates of trabeculectomy, the potential role of perioperative subconjunctival steroid administration had become less significant. 103 Currently, locally administered antimetabolite therapy is routinely used in conjunction with topical postoperative corticosteroids to modulate conjunctival wound healing in glaucoma filtration surgery. Corticosteroids predominantly modulate wound healing by reducing the release of acute inflammatory mediators and fibroblast recruitment. They also have a lesser effect in the proliferative phase of wound healing by limiting fibroblast activity. In contrast, antimetabolites modulate wound healing by inhibiting proliferation of fibroblasts and their profibrotic mechanisms. 104,105 Modulating both the inflammatory and proliferative phases of the wound healing response with these agents increases the likelihood of long-term filtration and lower postoperative IOPs. 106

| Aqueous shunt surgery
Modulation of wound healing is important in the process of bleb encapsulation in aqueous shunt surgery. The use of corticosteroids to control postoperative inflammation is thought to influence the hypertensive phase after glaucoma drainage implantation. The hypertensive phase is characterized by a rise in IOP due to bleb encapsulation or capsular fibrosis that occurs at approximately 1 to 3 months postoperatively. 107 It is particularly observed after implantation of non-valved glaucoma drainage devices such as the Ahmed glaucoma device where it may occur in 56% to 82%. 108 It has been reported that in 72% of these cases, the elevated IOP does not resolve indicating early surgical failure. 109 Turalba and Pasquale 110 retrospectively compared patients who received intraoperative sub-Tenon during Ahmed device implantation with those who did not. The hypertensive phase was found to be 26% in those who received triamcinolone compared to those without (52%). There was no difference in final IOP outcomes and the authors warned of a higher rate of early complications including tube erosion and endophthalmitis. Yadnazi et al 111 demonstrated in a prospective randomized trial of 90 eyes that adjunctive sub-Tenon TA during Ahmed valve implantation had significantly lower IOPs at 1 month and lower peak IOPs, however had no difference in the rates of success or incidence of a hypertensive phase.

| Posterior segment
Ocular steroids are used to treat macular oedema of varied aetiology (diabetic, retinal vein occlusion, postoperative and inflammatory), intraocular inflammation including uveitis and scleritis and to assist visualization of the vitreous during vitrectomy.

| Diabetic macular oedema
Diabetic macular oedema is the most common cause of vision loss in people with diabetes. 112 The pathogenesis of DMO is multifactorial, with not only VEGF but other pro-inflammatory factors involved in breaking down the blood-retinal barrier and increasing vascular permeability. 113 Although intravitreal anti-VEGF therapy remains first-line treatment for centre-involving DMO in phakic patients, ocular steroids may be considered for pseudophakic patients, those with planned cataract surgery, or in patients with suboptimal response or contraindication to intravitreal anti-VEGF therapy. 114 A suboptimal response to intravitreal anti-VEGF therapy is not uncommon. In the RISE/RIDE registration trials, BCVA was worse than 6/12 in 42.8% of patients and central foveal thickness greater than 250 μm in 24.8% of patients despite 2 years of monthly intravitreal ranibizumab (0.3 mg) injections. 25 Intravitreal TA for diabetic macular oedema Intravitreal TA (Kenacort-A 40, Bristol-Myers Squibb Pharmaceuticals, Noble Park, Australia) was first shown to be superior to sham treatment for BCVA in patients with centre-involving DMO in a prospective, doublemasked, placebo-controlled randomized controlled trial. 115 Compared with those receiving placebo, eyes receiving TA had a 5.7 Logarithm of Minimum Angle of Resolution (LogMAR) letter better improvement at 2 years.
The Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol I study was a multi-centre RCT comparing sham injection + prompt laser, 0.5 mg ranibizumab + prompt laser, 0.5 mg ranibizumab + deferred laser and 4 mg TA + prompt laser for centreinvolving DMO. 116 The main outcome measure was improvement in BCVA at 1 year, and 854 study eyes of 691 patients were enrolled. The ranibizumab arms showed greater improvement in BCVA compared with laser alone. Although overall the TA + prompt laser arm did not do as well as the ranibizumab arms, TA was shown to be as effective as ranibizumab when only pseudophakic patients were analysed. However, at 5-year follow-up the TA arm was inferior to ranibizumab arms, even when only analysing pseudophakic patients and allowing for the addition of "very deferred ranibizumab" after 74 weeks from baseline. 117 DII for diabetic macular oedema The MEAD study included two 3-year, multi-centre, masked, randomized controlled phase III clinical trials that compared a minimum of 6-monthly dosing with DII 0.7 mg, 0.35 mg and sham procedure. Patients had centre-involving DMO, visual acuities between 6/15 and 6/60 and central retinal thickness ≥300 μm on optical coherence tomography scans. 118 The main outcome measures were proportion of patients achieving ≥15 LogMAR letters of improvement in BCVA and safety profile. At baseline there were 1048 patients enrolled, and 57.9% completed the 3-year study. Both DII doses had a significantly greater proportion of patients achieving ≥15-letters of improvement in BCVA (22.2% for 0.7 mg, 18.4% for 0.35 mg and 12.0% for sham).
The BEVORDEX study was a prospective, multi-centre, randomized single-masked clinical trial comparing 4-weekly bevacizumab and DII 0.7 mg (OZURDEX) that could be given more frequently (4-monthly) in 88 eyes of 61 patients with centre-involving DMO. 119 The main outcome measure was the proportion of patients achieving an improvement in vision of 10 LogMAR letters. Each arm had similar proportion of patients reaching the main outcome measure at 12 and 24 120 months (40% with bevacizumab and 41% with DII at 12 months). The group receiving DII had fewer mean injections (2.7) compared to the bevacizumab arm (8.6) over the first 12 months with a greater reduction in central macular thickness at 12 but not 24 months. However, more patients in the DII arm lost vision, mainly because of cataract progression.

FA intravitreal implant for diabetic macular oedema
Iluvien is a sustained delivery FA injectable implant that has been shown to treat patients with DMO. The FAME A and B studies were identically designed parallel-group, phase 3 double-masked, randomized controlled phase III clinical trials that compared two doses (0.2 and 0.5 μg/ day) of FA over a 3-year period. The primary end point was a gain of ≥15 letters at 24 months with follow-up to 36 months.
A pre-planned subgroup analysis examined visual outcomes as a function of duration of DMO at randomization revealed that the treatment effect resided primarily in patients with chronic DMO (duration ≥3 years). At month 36, a significantly higher proportion of FA treated patients from both studies showed an improvement of ≥15 letters from baseline compared to the sham group (FAME A: 31.8% for 0.2 μg/day, 13.5% for sham; FAME B: 36.4% for 0.2 μg/day, 13.2% for sham). In patients with non-chronic DMO (duration <3 years), the proportion of patients gaining ≥15 letters were similar between the FA and sham groups in both studies. 121 In Europe and in the United Kingdom, it has been approved for the treatment of persistent DMO that has not sufficiently responded to available therapies. In the USA, it is approved for the treatment of DMO in patients who have been previously treated with corticosteroids without a clinically significant rise in IOP.
Intravitreal TA for retinal vein occlusion Ocular steroids may be considered in pseudophakic eyes in which anti-VEGF is contraindicated or failing to provide an adequate result. 135 Ocular steroids not only inhibit VEGF, but their anti-inflammatory and neuroprotective effects may also benefit eyes with RVO. 22,123 The Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) studies were multi-centre randomized clinical trials evaluating the benefit of IVTA for the treatment of macular oedema secondary to retinal vein occlusion. 22,23 In the SCORE-CRVO Study (Report 5), 271 patients were randomized to observation (the standard of care at that time), 1 or 4 mg preservative-free IVTA (Trivaris). 22 The main outcome measure was the proportion of patients with ≥15 letter improvement from baseline to month 12. This was achieved in significantly more patients on 1 or 4 mg triamcinolone (27 and 26%, respectively) than those who were observed (7%). For the SCORE-BRVO Study (Report 6) the observation arm was replaced with grid photocoagulation because grid laser was the standard of care at that time for treating macular oedema secondary to BRVO according to the Branch Vein Occlusion Study. 136,137 Unlike SCORE-CRVO, there was no significant difference between the arms in the proportion of patients achieving a ≥15 letter improvement from baseline to month 12.

Intravitreal dexamethasone implant for retinal vein occlusion
The Global Evaluation of Implantable Dexamethasone in Retinal Vein Occlusion with Macular Edema (GENEVA) study included two identical multi-centre, masked, 6-month, sham-controlled RCTs assessing the efficacy of DII implant for vision loss due to macular oedema from both CRVO and BRVO. 123 A total of 1267 patients were randomized to receive a single treatment of DII 0.7, 0.35 mg, or sham procedure. Both DII groups performed significantly better than the sham arm in the time to reach a ≥15 letter improvement in BCVA, proportion of patients achieving a ≥15 letter improvement in BCVA, mean BCVA and proportion of patients losing ≥15 letters.

Intravitreal fluocinolone implant for retinal vein occlusion
There is a lack of studies on intravitreal FA implants for the treatment of CMO from retinal vein occlusions. The Fluocinolone Acetonide Intravitreal Inserts for Vein Occlusion in Retina (FAVOUR) study started recruiting patients however the study was terminated early. Currently, Iluvien has not been approved for macular oedema from retinal vein occlusions in the USA, UK or Europe and any use for this indication is off-label.
Retisert has been used for CMO in retinal vein occlusions within a small pilot series by Ramachandran et al 138 which demonstrated 69% of eyes showing visual acuity improvement, 15% were stable and 15% lost two lines from baseline at 12 months. Cataract formation occurred in almost all patients and 39% eyes required glaucoma filtration surgery by 12 months. A follow-up study recruited 10 further patients and indicated sustained benefit up to 30 months. 139

| Posterior non-infectious uveitis
For patients with posterior segment inflammation and macular oedema, topical steroid therapy is often inadequate. These patients have the option of periocular (sub-Tenon, orbital floor, peribulbar), intravitreal (IVTA, OZURDEX) and systemic steroids. In an attempt to minimize the systemic side effects (such as Cushingoid state, osteoporosis and elevated blood glucose), local steroid is often considered, especially for unilateral inflammation. In the retrospective cohort of the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) study, over half of 1192 eyes in 914 patients with uveitis demonstrated improved visual acuity at some point within 6 months of receiving periocular steroid. 140 Intravitreal steroids are particularly useful in two groups of patients: those with severe vitritis or cystoid macular oedema (CMO) that is unlikely to respond rapidly to periocular corticosteroids, and those with inflammation that are refractory to other treatment. In patients with persistent disease, these options may also be combined effectively with systemic steroids and steroidsparing agents (eg, methotrexate, mycophenolate and cyclosporin) for acute unilateral relapses or persistent disease activity to reduce the dosages and side effects of the systemic treatment.
It should also be noted that although ongoing repeated depot steroid injections could be considered as a treatment option for chronic persistent intermediate, posterior or panuveitis, such a management approach must be considered with caution given the recent 7-year follow-up findings from the NIH sponsored MUST (Multi-centre Uveitis Steroid Treatment) trial. This study was also a prospective RCT that compared the FA containing Retisert implant with standard systemic immunosuppression in 479 eyes. Although the implant group initially had a faster gain in BCVA, the systemic treatment group had a more gradual gain in BCVA such that there was no significant difference at 2 and 5 years. 141 However, at 7 years, the systemic group overtook the implant group in terms of BCVA outcomes, 142 with the implication being that the uveitis relapses occurring once the depot steroid "wears off" are more severe and more likely to result in more (irreversible) damage than lower grade relapses seen with systemic treatment when oral prednisolone/immunosuppression is being gradually weaned.
A prospective 3-year randomized, sham-controlled study is comparing Yutiq with placebo. Yutiq is designed to release FA for up to 36 months and the 12-month data has shown it was effective in lowering the rate of recurrence of posterior uveitis. At 36-months, the effect of reducing recurrence rate was still significantly lower with Yutiq (56.3%) compared to sham-treated eyes (92.9%). 30

| Uveitic macular oedema
Cystoid macular oedema is a common cause of vision loss in uveitis. 24 Intravitreal TA has been shown to effectively reduce uveitic CMO. 143 Visual acuity improvements are more significant if the CMO is present for 12 months or less and for patients aged 60 years or younger. It is useful in improving visual acuity in patients with CMO, even when their non-infectious uveitis has been quiescent. 144 As a single IVTA injection lasts approximately 3 to 6 months, repeated injections may be required. 145 Alternatives to IVTA for treating uveitis include DII or FA implants. The HURON trial demonstrated efficacy of a single OZURDEX injection in non-infectious intermediate, posterior or panuveitis in comparison to placebo, with a reduction of inflammation and CMO in 47%, and ≥15 letter gain in up to 43%. 146 Most recently, the National Institute of Health (NIH) funded POINT trial compared all three of the above depot steroid options (periocular TA, IVTA and OZURDEX) for the treatment of CMO secondary to uveitis in a prospective, multi-centre RCT. 147 In this trial, 235 eyes were randomized 1:1:1 to either periocular TA (40mg/1ml), unpreserved IVTA (4mg/0.1ml) or OZURDEX (0.7mg dexamethasone). The primary outcome was central subfield macular thickness (CMT) at 8 weeks, with secondary outcomes including visual acuity and rate of adverse events over 24 weeks of follow-up. Overall, the CMT in all three groups improved, however IVTA and OZURDEX were found to be superior to periocular TA, with rates of improvement of 39% and 46%, respectively, vs 23% for periocular TA (p < .0001). However, no statistically significant difference was demonstrated between IVTA and OZURDEX. Similarly, BCVA also improved in all three groups, with greater gains (four to seven letters to more greater gains) seen with intravitreal treatments, with again no clinical or statistically significant differences seen between IVTA or OZURDEX. Interestingly, despite the findings in other studies, the duration of effect of OZURDEX on CMT was found to decrease after 8 weeks (rather than 12-16 weeks) in this cohort of patients. This may indicate that patients with uveitic CMO may require intravitreal injections more frequently than for other indications. It should be noted that the POINT study design did allow the IVTA arm to have retreatments at 8 weeks, but only at 12 weeks for the OZURDEX arm.

| Bacterial endophthalmitis
Intravitreal steroids have been described for the management of acute bacterial endophthalmitis in conjunction with intravitreal antibiotics, although their use remains controversial. 148,149 They may tamper the inflammatory response that causes damage to the retina, but, conversely, they may interfere with infection control, lower the concentration of intravitreal antibiotics and the additional volume may elevate the IOP. 149 If they are used, intravitreal dexamethasone is preferred due to its rapid elimination from the eye. 149 A dosage of 0.4 mg/0.1 mL is usually prescribed, as higher doses have been shown to cause Müller cell damage in animal studies. 150 Evidence for intravitreal dexamethasone in acute endophthalmitis is limited to retrospective case series which gave mixed results, and four prospective RCTs 151-154 which failed to show statistically significant improvements in final visual outcomes. 149 Although traditional teaching is to avoid intraocular steroids for fungal endophthalmitis, this fear may be exaggerated in patients treated with vitrectomy and intravitreal anti-fungal therapy. 155

| Postoperative macular oedema
Macular oedema is a well-known complication of cataract surgery. Topical non-steroidal and steroidal therapy are usually first-line treatment. 156 Topical and oral carbonic anhydrase inhibitors and intravitreal anti-VEGF agents have also been described, but strong evidence for these are lacking. In recalcitrant cases, local steroid injections may be considered. IVTA has been shown to reduce retinal thickness and improve vision in cases of persistent pseudophakic macular oedema [157][158][159][160] with an effect that may be sustained for more than 6 months. 158

| Other indications for intravitreal TA and dexamethasone implant
Intravitreal steroids have been used with variable results for a variety of other causes of macular oedema including: neovascular AMD, 161 retinal angiomatous proliferation, 162 macular telangiectasia, 163,164 Coat's disease, 165 vasoproliferative tumour, 166 radiation retinopathy, 167,168 retinitis pigmentosa, 169,170 proliferative vitreoretinopathy, 171-173 following scleral buckling 174 or vitrectomy surgery 175 and from idiopathic CMO. 160,176 Intravitreal TA can be used intraoperatively to visualize the vitreous. This is particularly useful for iatrogenic induction of a posterior vitreous detachment, peeling internal limiting membrane and when vitreous needs to be highlighted for clearance in complicated cataract surgery. 177

| COMPLICATIONS OF OCULAR AND PERIOCULAR STEROID DELIVERY
Complications arising from use of ocular steroids may be related to the procedure itself, or the pharmacological effects of the steroids.

| Periocular injections
Periocular injections can be performed using different techniques: into the sub-conjunctival space, into the sub-Tenon space, into the orbital floor alongside the globe, (usually inferiorly, via a transcutaneous or transconjunctival injection), or into the peribulbar or retrobulbar space. Complications of these injections include: orbital swelling, chemosis, proptosis, subconjunctival haemorrhage, retrobulbar haemorrhage, globe ischaemia, posterior ischaemic optic neuropathy, optic atrophy, globe perforation, orbital cellulitis, fat atrophy, fat herniation, damage to the rectus muscles resulting in diplopia, ptosis, dural puncture and an oculocardiac reflex. [178][179][180][181] The likelihood of complications differs depending on the site of the injection. Posterior injection reduces the chances of unsightly sub-conjunctival plaques resulting from anterior seepage of depot, conjunctival or corneoscleral melting, depigmentation and granuloma related to the methylcellulose vehicle of the depot injection. Injection into the orbital floor is easily performed with a 25 mm 25-gauge needle. It is well tolerated and carries only a very small risk of globe perforation if the needle is directed away from the globe at all times. It is frequently difficult to access the sub-Tenon's space of patients who have had previous surgery (notably scleral buckling), these eyes may be more suited to an orbital floor injection. Peribulbar and retrobulbar injection are more likely to lead to globe perforation or inadvertent intravascular injection with vascular occlusion from embolization. Additional caution is required in myopic patients as they have a thinner sclera and larger globes which are at an increased risk of perforation.

| Intravitreal injections
Intravitreal injections may be associated with endophthalmitis, ocular inflammation, vitreous haemorrhage, retinal tears, rhegmatogenous retinal detachment, IOP elevation, cataract and lens subluxation. 182 Although rare (with a reported incidence of 0.09%-0.87%), 183 acute bacterial endophthalmitis is the most serious of these complications and requires immediate treatment with intravitreal antibiotics. Rates of vitreous haemorrhage, 118 wound leak hypotony and retinal tears and detachment 123 may be higher with DII, as the needle is larger (23-gauge) and the force of injection greater than for standard 30-gauge needle intravitreal injections. DII is contraindicated in aphakic and pseudophakic patients with posterior capsular rupture, as the implant may migrate into the anterior chamber. 184 If this occurs, early removal is recommended to avoid chronic corneal oedema. 184

| Pharmacologic related complications
The two most important pharmacologic related complications of ocular steroids are raised IOP and development of cataract, which are more frequent with intravitreal injections compared to periocular injections.

| Raised IOP
Raised IOP with subsequent development of glaucomatous optic neuropathy is one of the most significant complications of locally administered corticosteroids. If other therapeutic options are available, ocular steroids are best avoided in patients with pre-existing glaucoma. The pathogenesis is not well understood but may involve downregulation of trabecular meshwork matrix metalloproteinase activity, increased myocilin production and/or decreased trabecular meshwork phagocytic activity that increases aqueous outflow resisance. 185 The susceptibility to pressure response may be due to genetic differences and variations in corticosteroid receptors whilst the degree of effect on IOP appears to be dosedependent.
Raised IOP with TA In the SCORE Study Report 15, the proportion of patients being treated for BRVO or CRVO with a cumulative incidence of IOP elevation ≥10 mm Hg from baseline to 36 months was 2% (no IVTA), 9% (1 mg IVTA) and 45% (4 mg IVTA). Consideration of a lower dose (1 or 2 mg) of IVTA to treat RVO may be appropriate in patients at risk of an IOP-related event, particularly as little difference has been reported in efficacy between the 1 and 4 mg doses. 22,23,185 Other risk factors for an IOP-related event include higher baseline IOP and younger age. A cumulative incidence of 32% of patients in the SCORE study reached an IOP ≥25mm Hg at 12 months. The incidence of IOP elevation in other reports is comparable. [186][187][188] Although most cases of IOP elevation occur in the first 1 to 2 months of initiating therapy, in some cases it may take several months to develop (in SCORE Study Report 15 this ranged up to 598 days), so long-term vigilance is required even if no IOP rise is seen after the first few injections. 185 Raised IOP with DII IOP elevation can also occur with DII, although possibly at lower rates than for IVTA. In the MEAD study for DMO, the incidence of IOP elevation ≥10 mm Hg from baseline to 36 months at any visit for those receiving DII 0.7 mg was 27.7%. 118 The cumulative incidence of at least one visit with IOP ≥25 mm Hg or ≥35 mm Hg was 32% and 6.6%. The large majority of these patients with IOP elevation could be managed with medical therapy. Only one patient required incisional glaucoma surgery, and no patients required removal of the implant. Mean IOP returned to baseline by month 6 after each injection, and there did not appear to be a cumulative effect on IOP elevation with repeated injections. Similar findings were found in a 12-month trial by the OZURDEX PLACID Study Group 189 and a recent large retrospective analysis of 2736 eyes of 1441 patients treated with a total of 6015 DII in which 26.5% of eyes had an IOP rise >25 mm Hg but only 0.91% required glaucoma filtration surgery. 190 Raised IOP with FA intravitreal implant In the FAME trials, an IOP of ≥30 mm Hg developed in 16.3% of FA injectable implant treatment groups at month 23 and 18.4% by month 36. Elevated IOP that required incisional surgery by 36 months was 4.8% in the low-dose group, 8.1% in the high-dose group and 0.5% in the sham group. 191 Raised IOP with periocular steroid IOP elevation can also occur with periocular steroid. In a study by Sen et al 140 of patients being treated with periocularly administered corticosteroid (predominantly TA 40mg) for uveitis, the cumulative incidence of at least 1 visit with IOP ≥24 mm Hg or ≥30 mm Hg at 12 months was 34% and 15%.

Raised IOP in uveitic patients
Corticosteroid-induced raised IOP is much more common in the uveitic population than for other indications, and even higher in paediatric patients. [192][193][194] In the POINT trial 20%, 30% and 41% recorded an IOP of ≥24 mm Hg by 24 weeks in the periocular, IVTA and OZURDEX groups, respectively, with 9%, 18% and 39%, respectively, developing an IOP rise of ≥10 mm Hg from baseline. 147 Interestingly, only 4% to 6% overall developed an IOP of ≥30 mm Hg. Although both intravitreal treatments had a significantly higher rate of raised IOP when compared with periocular steroid, there was no significant difference seen between IVTA and OZURDEX in a direct comparison.

Raised IOP in children
Children are more likely than adults to have an IOP response to steroids. 195 Compared to adult patients, the IOP rise can be more severe and resulting glaucoma may progress more rapidly and has even been reported within hours of starting treatment. 196 The effect can result from topical, periocular, intravitreal, oral and intravitreal dosing regimes.
Dexamethasone is more likely to cause a steroid response than FML in children. A study by Kwok et al 195 included 19 Chinese children undergoing bilateral strabismus surgery, with one eye randomized to receive topical dexamethasone 0.1% and the other to receive FML 0.1% six times per day for 4 weeks postoperatively. The mean increase in IOP in eyes receiving dexamethasone (15.48 ± 8.71 mm Hg) was almost double that of eyes receiving FML (5.83 ± 4.96 mm Hg; P = .001). 195 FML also causes ocular hypertension, in a dosedependent manner in children. In a study by Fan et al, 197 31 children undergoing bilateral strabismus surgery had one eye randomized to receive topical FML six times per day and the other eye to receive topical FML three times per day, each for 4 weeks postoperatively. The IOP increased significantly from baseline in both groups, but the peak IOP was higher (19.0 ± 5.06 mm Hg vs 17.13 ± 3.32 mm Hg, P < .001) and the net increase was also greater (4.37 ± 4.79 vs 2.57 ± 3.32 mm Hg, P = .005) in the group with more frequent dosing. More frequent dosing was correlated with reaching peak IOP sooner (6 days vs 13 days; P = .033), but there was no difference in postoperative inflammation between the groups. 197

| Cataract
Cataract is the other common complication of ocular and periocular delivered steroids. There are few studies that directly compare rates of cataract progression with different types of intravitreal steroids. However, the rates from various studies may suggest higher rates of cataract progression with IVTA and FA than DII. A head to head comparison between intravitreal FA and DII in uveitis patients showed a significantly higher incidence of cataract (and raised IOP) with FA. 198 In the SCORE Study Report 5 (CRVO), the estimate through month-12 of phakic patients developing newonset lens opacity or progression of existing opacity was 18%, 26% and 33%, respectively, in the observation, 1 mg IVTA and 4 mg IVTA groups. The percentage of patients requiring cataract surgery by 24 months in these respective groups were 0%, 0% and 33%. 22 In the SCORE Study Report 6 (BRVO) this was 13%, 25% and 35%, respectively, in the laser, 1 mg IVTA and 4 mg IVTA groups. 23 In the MEAD study for DMO, DII 0.7 mg was associated with cataract-related adverse events in 67.9% of patients over the course of the 3-year study, with 59.2% requiring cataract surgery during the study. 118 A recent large retrospective analysis of over 6000 DII injections found a statistically significant increase in cataract progression in eyes receiving injections (P = .004) although with a small co-relation co-efficient (r = .057). 190 In the FAME trials, the development of cataract and the proportion of patients requiring cataract surgery were significantly higher in both the low-and high-dose FA treatment arms than in the sham-control group. At 36 months, the percentage of patients developing cataracts were 81.7%, 88.7% and 50.7% in the low-dose, highdose and control group, respectively. 199 Uveitis patients may develop cataract from both intraocular inflammation and corticosteroid treatment. In the SITE cohort, 1192 eyes of 914 patients received periocular injections (sub-Tenon's or orbital floor) for uveitis. Cataract development attributing to an incident reduction in visual acuity of worse than 6/12 occurred in 20.2%, whilst cataract surgery was performed within 12 months in 13.8% of initially phakic eyes. 140 Periocular injection of corticosteroid used in the management of paediatric uveitis is associated with a high rate of cataract formation, [4 of 19 (21%) eyes] 200 and IVTA used to manage uveitic macular oedema in children has been found to induce cataract in 6 of 11 eyes (55%). 145

| Non-infectious endophthalmitis and pseudoendophthalmitis
Although acute bacterial endophthalmitis is the most serious complication of intraocularly administered steroids, acute non-infectious endophthalmitis following IVTA injection is more common, with most studies reporting an incidence of 0.5% to 2.0%. 201,202 Noninfectious endophthalmitis refers to a transient, inflammatory reaction, typically with hypopyon that presents within a day or two post injection of IVTA. 201 There is usually no or minimal inflammation of the sclera and conjunctiva, minimal anterior chamber fibrin and pain is rare, as might be expected since steroids are anti-inflammatory. 201 The condition is usually self-limiting and resolves in 1 to 2 weeks but may cause persistent vitreous opacification in a minority of cases.
Some authors have attributed non-infectious endophthalmitis following IVTA injection to the preservative vehicle 0.99% benzyl alcohol found in Kenacort. 202 In one study, the incidence of severe sterile endophthalmitis fell from 13.0% to 4.3% after switching from preserved to preservative-free TA. 203 However another study found no difference in the incidence of non-infectious endophthalmitis after removing benzyl  alcohol 204 and cases of non-infectious endophthalmitis have been reported with benzyl-alcohol free Triesence. 205,206 In fact, one study found a higher rate of non-infectious endophthalmitis following administration of Triescence compared with Kenalog-40 and preservative-free TA. 207 The authors attributed this result to the smaller particle size and higher particle load of Triesence. The pathogenesis for this phenomenon is likely to be multifactorial. A non-infectious, non-inflammatory pseudoendopthalmitis can also occur when TA particles migrate and settle in the anterior chamber, resembling a hypopyon. 201 Whenever there is uncertainty regarding whether an endophthalmitis is infectious or non-infectious, it should be managed with the standard treatment for infectious endophthalmitis.

| Activation of ocular or periocular infection
Corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. This can prolong the course and/or exacerbate the severity of viral (eg, herpes simplex epithelial keratitis), bacterial and fungal infections of the eye. In acute purulent infections of the eye, steroids may mask infection or exacerbate existing infection. Since corticosteroids are known to reduce resistance to infections, simultaneous bilateral intraocular injections of steroids should, if possible, be avoided to limit the potential for bilateral postoperative infection. 208 Infectious scleritis is a rare complication of sub-Tenon TA with a reported incidence of 0.04%. 209 A recent review found nine reported cases in which four were caused by fungal organisms. 210 Use of intraocular or periocular administered corticosteroids may reactivate HSK and concurrent antiviral prophylaxis for those with a history of HSK is advised. 211,212 Viral retinitis has been reported following local administration of corticosteroids. A recent review found 30 cases with causative viruses identified as cytomegalovirus in 76.7%, HSV in 16.7%, with one case of varicella zoster virus and another unspecified. Steroids were administered by IVTA (33.3%), intravitreal FA acetonide implant Retisert (33.3%), posterior sub-Tenon TA (6.6%) and anterior sub-Tenon TA (3.3%). 208 Unmasking or activation of dormant ocular syphilitic infection following IVTA have been reported in five cases. All cases manifested with small round yellow retinal lesions, retinovasculitis and optic disc involvement. 213 syphilitic posterior placoid chorioretinitis and all had devastating visual outcomes. 213,214 In contrast, a small series of seven patients demonstrated safety of DII in treating CMO in patients with infectious uveitis where other treatments for CMO had failed. All patients were concurrently treated on the appropriate antimicrobial agent and had resolution of CMO without reactivation of the infectious ocular disease. 216

| Steroid induced central serous chorioretinopathy
It is well established that any exogenous use of corticosteroids may precipitate or exacerbate central serous chorioretinopathy (CSC). 217 Despite topical, periocular and intravitreal steroids being common ophthalmic treatments, CSR is rarely reported in association with administration of ophthalmic steroids. 218 A recent literature review found only one case of IVTA causing new-onset CSC, 219 and another case of worsening pre-existing CSC. 220 Interestingly, a reported case of intravitreal Ozurdex implantation for refractory Irvine-Gass syndrome was found to precipitate CSC in the fellow eye. 221 One case presenting with bilateral multifocal serous retinal detachments initially diagnosed as Vogt-Koyanagi-Harada syndrome received high-dose oral steroids and IVTA. The treatment ultimately worsened the condition later diagnosed as CSC. 222 In contrast, IVTA experimentally used to treat chronic CSC and CMO secondary to CSC, did not improve or worsen the CSC. 223,224 Surprisingly, a recent literature review found only one report of CSC associated with periocular steroid use, 225 and no cases of CSC related to topical steroid eye drops. 218

| CONCLUSION
For over 70 years, ocular steroids have proven to be a major weapon in the treatment of ocular inflammation. An increasing variety of preparations and delivery sites have maximized their efficacy whilst attempting to minimize their major side effects-raised IOP and cataract. Multiple RCTs have improved our understanding of the utility and limitations of this versatile medication. ORCID Adrian T. Fung https://orcid.org/0000-0002-1117-3893 Tuan Tran https://orcid.org/0000-0002-0853-2226