Review Article Current intravitreal therapy and ocular hypertension: A review Aditya Sudhalkar1,2,3, Alper Bilgic1, Shail Vasavada2, Laurent Kodjikian4,5, Thibaud Mathis4,5, Fransesc March de Ribot5, Thanos Papakostas6, Viraj Vasavada2, Vaishali Vasavada2, Samaresh Srivastava2, Deepak Bhojwani2, Pooja Ghia3, Anand Sudhalkar3 To determine the effect of commonly used intravitreal agents on immediate and long‑term IOP Access this article online elevations and their association, if any, with glaucoma. Literature searches in PubMed and the Cochrane Website: databased in January 2020 yielded 407 individual articles. Of these, 87 were selected for review based www.ijo.in on our inclusion criteria. Based on the evidence provided, 20 were assigned level I, 27 level II, and 22 DOI: level III. Eight articles were rejected because of poor quality, insufficient clarity, or irrelevance based 10.4103/ijo.IJO_1028_20 on standardized protocols set out by the American Academy of Ophthalmology. The studies that PMID: ***** reported on short‑term IOP elevation (i.e., between 0 and 60 min) showed that an immediate increase in IOP is seen in all patients who receive anti‑VEGF agents or triamcinolone acetonide when measured Quick Response Code: between 0 and 30 min of intravitreal injection and that the IOP elevation decreases over time. The data on long‑term IOP elevation were mixed; Pretreatment with glaucoma medications, anterior chamber tap, vitreous reflux, longer intervals between injections, and longer axial lengths were associated with lower IOP elevations after injection of anti‑VEGF agents, while the position of the implant vis‑à‑vis, the anterior chamber was important for steroid therapy. Data were mixed on the relationship between IOP increase and the type of intravitreal injection, number of intravitreal injections, preexisting glaucoma, and globe decompression before injection. There were no data on the onset or progression of glaucoma in the studies reviewed in this assessment. However, some studies demonstrated RNFL thinning in patients receiving chronic anti‑VEGF therapy. Most, if not all, intravitreal agents cause ocular hypertension, both in the short term and long term. The functional consequences of these observations are not very clear. Key words: Anti‑VEGF agent, drug volume, intraocular pressure, ranibizumab Intravitreal injection of therapeutic agents has in recent times Description of Evidence become the mainstay of therapy for a variety of macular diseases. The treatment options available to the physician Literature searches were conducted on January 1, 2020 in today are varied, as are their indications and applicability. the PubMed and Cochrane Library databases. A total of 287 An important consideration with any therapy is the attendant articles were found. The following search terms were used: adverse effect; the development of ocular hypertension being Intraocular pressure OR glaucoma OR ocular hypertension OR one of them. This adverse effect assumes importance in light IOP OR visual field analysis OR RNFL analysis OR antivascular of the fact that the development of ocular hypertension and endothelial growth factor OR anti‑VEGF OR angiogenesis subsequent glaucoma can offset the gains achieved courtesy inhibitors Avastin/bevacizumab OR Lucentis/Accentrix/ intravitreal therapy. It is important, therefore, to be aware ranibizumab OR Eylea/Aflibercept OR dexamethasone implant/ of the degree of risk associated with a particular therapeutic Ozurdex or ILUVIEN/fluocinolone acetonide OR intravitreal agent and the benefits that may accrue with continuation or insert or cohort studies OR randomized studies OR Case Series cessation thereof. This review has been proposed with the OR controlled trial. Filters used were Humans, English. Articles intention of reviewing current literature with reference to that did not assess intravitreal injections were excluded, and a ocular hypertension and the risk factors that may predispose total of 107 articles were found eligible for review. These articles one to its occurrence. were initially screened using their titles and abstracts, and 87 were selected for full‑text review. The following inclusion criteria were used: 1) the study reported on original research and 2) the population consisted of at least 20 adults (>18 years) 1 Alphavision Augenzentrum, Bremerhaven, Germany, 2Raghudeep This is an open access journal, and articles are distributed under the terms of Eye Hospital, Ahmedabad, India, 3MS Sudhalkar Medical Research the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, Foundation, Baroda, India, 4Croix Rousse University Hospital, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under Hospices Civils de Lyon, Université Lyon 1, Lyon, France, 5UMR-CNRS the identical terms. 5510 Matéis, Villeurbane, France, Universitat de Autonoma, Barcelona, Spain, 6Weill Cornell Medicine, New York, United States of America For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com Correspondence to: Dr. Aditya Sudhalkar, 22 Pratapgunj, Baroda ‑ 390 002, Gujarat, India. E‑mail: adityasudhalkar@yahoo.com Cite this article as: Sudhalkar A, Bilgic A, Vasavada S, Kodjikian L, Mathis T, Received: 20-Apr-2020 Revision: 16-Jun-2020 de Ribot FM, et al. Current intravitreal therapy and ocular hypertension: A review. Indian J Ophthalmol 2021;69:236-43. Accepted: 14-Jul-2020 Published: 18-Jan-2021 © 2021 Indian Journal of Ophthalmology | Published by Wolters Kluwer - Medknow February 2021 Sudhalkar, et al.: Intravitreal therapy and intraocular pressure rise 237 treated with one or more of the aforementioned intravitreal Short‑term IOP fluctuations consequent to increased therapeutic agents. Articles evaluating neovascular glaucoma intraocular volume upon injection can also adversely affect were excluded. Since this was a review of published articles, RNFL thickness. Conversely, pretreatment with topical IOP ethics committee approval was not required. lowering medication has shown to maintain IOP immediately after injection within the normal range (i.e., 21 mm Hg or less). The panel assigned a rating to each article based on the level The functional significance of these RNFL thickness changes of evidence therein using standardized protocols.[1] Based on are not immediately clear; studies do demonstrate perimetric the level of evidence, 20 articles were assigned level, 27 level II, defects,[32] especially superior rim thinning in eyes that require and 22 level III. A total of eight articles were excluded, either on continued intravitreal therapy. However, this risk must be the grounds of poor study design or irrelevance. Metaanalyses viewed in tandem with the threat to vision upon cessation of and reviews were not rated separately. intravitreal anti‑VEGF therapy. Another point to be taken into consideration is the role of anterior chamber paracentesis[17] Questions for Assessment during the procedure; a simple test is confirmation of light The assessment attempts to address the following questions: (1) perception on table. Absence of light perception is a definite What is the effect of various medications in current use for indication for anterior chamber paracentesis on table. This is intravitreal therapy on short‑ and long‑term IOP and does readily achieved with the use of a 30 gauge needle and can be it predispose patients to glaucoma? (2) What are the risk done safely in phakic eyes as well. It is important to fix the globe factors for development of ocular hypertension with various well before needle insertion, especially in phakic eyes, to avoid intravitreal medications. inadvertent lens touch and subsequent cataract formation. This is also a useful manoeuvre in patients who have already This review article focuses exclusively on current therapy manifest an IOP rise, and the aim is to avoid a surge in IOP and does not include analyses on therapeutic agents now intraoperatively. considered obsolete or intravitreal agents that are not in practical use as of today. Additionally, most studies that do report IOP rise are ones that follow patients over a mean of 84 weeks. We demonstrate Intravitreal Anti‑VEGF Therapy an association between sustained IOP rise and the following: older age, male sex, South Asian ethnicity, narrow angles, Sustained intraocular pressure (IOP) rise following intravitreal preexisting glaucoma, >6 injections, AMD and RVO, use of anti‑VEGF injections is a known phenomenon with several ranibizumab, concentration of ranibizumab injected, and publications addressing this issue in part or whole.[1‑5] There switch to ranibizumab or bevacizumab. Patients manifesting is a certain measure of discrepancy in reporting insofar as a short‑term IOP rise were not necessarily predisposed to the potential risk factors as well as definitions of IOP rise are develop sustained IOP rise. Patients who had sustained IOP concerned.[6‑8] With numerous publications on the subject, it rise with anti‑VEGF therapy were not predisposed to develop is only natural that contrasting outcomes are noted in studies IOP rise with the dexamethasone implant. conducted across the globe[1‑8]; the most disputed among risk factors for IOP rise being the number of injections administered Pretreatment [10,11,17] with IOP lowering medications or and the treatment interval[2] between consecutive injections. ocular massage has been suggested for short term IOP rise; the When one factors in the indication, the anti‑VEGF agent used, long‑term effect of this measure is unknown. Typically, IOP the phakic status, the anterior chamber angle status, family can increase up to 50 mm Hg in the first 5 min after injection history of glaucoma, and other characteristics,[1,2] it is evident and returns to baseline 45 min post‑injection. RNFL thinning[18] that the condition (IOP rise) and analysis thereof is a complex has been suggested as a short‑term consequence of acute IOP phenomenon. fluctuations. Also, vitreous reflux[19] is said to play a role in reducing immediate rise in IOP. Most studies that advise Despite a plethora of literature[5‑36] on the subject, a recently preemptive lowering of IOP did not look at the long‑term published review[1] highlights the lack of a comprehensive consequences of these measures on sustained IOP rise or their overview and hazards analysis of risk factors and IOP rise. role in preventing visual field defects.[1] This suggests that the Sustained IOP rise with aflibercept and ranibizumab use cause for RNFL thinning as described by Martinez de la Casa for AMD has been documented and studied[16]; studies have and associates is probably short‑term IOP rise. thrown up conflicting reports as regards the risk factors A short treatment interval appears to influence IOP rise as studied for IOP rise. Indeed, some studies do not report of any per the study by Mathalone et al. They reported an incidence of sustained IOP rise following anti‑VEGF injections.[1,2,6,8] The sustained IOP rise of 11% (comparable to our study). Overall, most studied and documented risk factors are the number of 22 patients in their series were noted to have IOP rise. Other injections and the treatment interval, followed by lens status, studies, including our own analysis,[33] do not seem to suggest presence of vein occlusion,[2] preexisting glaucomatous disease, that the treatment interval can influence IOP rise. and angle chamber depth. Literature[31] suggests the following mechanisms for the development of ocular hypertension after The anti‑VEGF agent used has generated considerable intravitreal therapy: trabecular alterations over repeated peaks interest, with reasonably consistent findings reported of IOP with multiple injections, trabecular congestion due from various studies. Bevacizumab[1,2,15,20] has been noted to antibodies, silicone micro‑droplets, protein aggregation by most authors to lead to sustained IOP rise followed by with bevacizumab, and a chronic trabeculitis or a trabecular ranibizumab.[1,2] Our data corroborate with past literature in autoimmune reaction. These factors along with several that ranibizumab has a higher probability of causing sustained probable mechanisms that we describe subsequently may have IOP rise when compared with aflibercept [1,2,20]; only one had a collaborative effect. study (with insufficient numbers) reports that ranibizumab is 238 Indian Journal of Ophthalmology Volume 69 Issue 2 not associated with IOP rise.[8] We also determine in our study that alteration of trabecular outflow facility with steroid use through multivariate analysis that switching to ranibizumab or may influence sustained IOP rise after anti‑VEGF injections bevacizumab increases the chances of the patient developing probably needs further evaluation. sustained IOP rise, whereas switching to aflibercept does not.[7] The extreme variations in reports on long‑term IOP rise along This agrees well with past reports and may have something to with the risk factors responsible for it as reported in literature do with the structure of ranibizumab. Also, per our analysis, are testimony to the complexity of this disease process.[1,2,19‑26] switching to the dexamethasone implant after primary therapy with anti‑VEGF agents does not increase the probability of IOP Studies vary in their structure, number, indications, inclusion, rise, regardless of the agent used (ranibizumab or aflibercept). and exclusion of certain groups of patients (glaucomatous This finding is somewhat in conflict with the discussion by eyes, for instance) and their definitions of IOP rise.[1,2] RNFL Dedania and associates[2] wherein they discuss past literature. thickness has not shown to vary significantly in literature published earlier.[28] Unlike most reports on dexamethasone The outcome of research on the number of injections and its implant‑induced transient ocular hypertension,[29,30] the rise influence on long‑term IOP rise is mixed; some studies suggest in IOP with anti‑VEGF agents seems to be chronic, sustained, that this is a consideration,[23] while other authors reject this thereby suggesting a higher chance of progression to theory.[24,25] Even the average number of injections to IOP rise glaucomatous changes, the lower incidence overall of ocular fluctuate between 6[26] and 24.[22,23] hypertension with anti‑VEGF therapy notwithstanding. The concentration of the injected drug, a consideration only Repeat intravitreal injections affect Bruch’s Membrane with ranibizumab in the South Asian region in our study (given opening, cup size, and other optic disc changes typically that aflibercept is only used in a dose of 0.5 mg), seems to considered to be clinical signs of glaucomatous optic correlative positively and independently with sustained IOP neuropathy.[34] The discussion thus far is applicable to a rise. A literature search using the key words “anti‑VEGF large extent to the new molecule on the horizon as well: agent, IOP, ranibizumab, drug volume, 0.3 mg, 0.5 mg ml, Brolucizumab. Preliminary studies[35] report an incidence age‑related macular degeneration, macular edema, sustained of ocular hypertension around 5.6%. Logically, the same IOP rise, long‑term IOP rise” on PubMed, Scopus, and the precautions and prophylaxis should work as containment Cochrane Database on September 11, 2019 failed to reveal any of sustained IOP rise with brolicizumab although detailed study that looks at the concentration of injected ranibizumab analyses will follow once physicians around the world and IOP rise. This has probably something to do with greater publish their real‑life experience. The role of gender and probability of trabecular meshwork obstruction with higher ethnicity in trabecular meshwork function along with the drug concentrations. proposed hypothesis needs further study. At present, the Whereas a narrow anterior chamber angle predisposed inference that we may draw from this analysis is that all the patient to sustained IOP rise in our study, the axial length patients on chronic intravitreal anti‑VEGF therapy, regardless seemingly did not. Short term IOP rise has been associated of indication, choice of drug or the presence or absence of with short eyes and narrow chambers,[27] but its influence on glaucoma should be carefully monitored for IOP rise, and long‑term IOP rise does not seem to have been adequately therapy instituted at the earliest. In patients with established addressed. ocular hypertension/glaucoma, it might be prudent to consider pretreatment (prophylaxis) with IOP lowering medications Preexisting glaucoma and sustained IOP rise seem to have at the time of injection and to continue IOP lowering therapy a controversial association,[1,2] with some studies reporting a during the course of anti‑VEGF treatment and thereafter. Our strong correlation and another reporting none. Studies that recent publication deals with these issues in some detail.[33] report no influence of preexisting glaucoma on long‑term IOP rise generally have small numbers.[1] A family history Steroids and Ocular Hypertension of glaucoma was reported to be a risk factor by Hoang and Ocular hypertension is a known consequence of steroid associates[24]; Dedania et al.[2] suggest that their exclusion of administration irrespective of the molecule or route of three patients with glaucoma might have confounded the administration used,[33,36-38] albeit with varying degrees of IOP results. Whereas one study reports the average time to IOP elevation. The mechanisms involved therewith are complex, rise to be 39 weeks in glaucoma patients,[27] we noted the but the most accepted theory is the modification or blockage time to be 25 weeks on an average in our analysis. Whereas of the ultrastructure of the trabecular meshwork that impedes preexisting glaucoma appeared to be a risk factor for sustained aqueous outflow by inhibition of proteases and phagocytosis IOP rise in our study, a family history of glaucoma did not of trabecular meshwork making the extracellular matrix of the seem to predispose a patient to long‑term IOP rise. Unlike the trabecular meshwork less permeable. findings of Kim and associates,[5] a low baseline IOP did not seem to predispose the patient to sustained IOP rise. AMD and The Intravitreal Dexamethasone Implant RVO, however, were strongly associated with sustained IOP rise. Patients with AMD in our study tended to receive on an Pivotal studies[39‑42] that established the role of the dexamethasone average a greater number of injections probably leading to a implant (Ozurdex, Allergan, Irvine, CA) in uveitis, diabetic greater buildup of degradation microparticles and causing a macular edema, or macular edema secondary to vein occlusion rise in IOP. Additionally, we hypothesize that the development report that up to a third of patients receiving intravitreal of AMD reflects an overall degenerative process affecting the therapy may develop ocular hypertension at some point in eye and that this affects trabecular meshwork outflow as well, time during therapy and follow up. The peak in IOP typically causing a buildup of microdegradation products and leading occurs a mean of 60 days after the injection. Patients with to the development of ocular hypertension. The hypothesis preexisting ocular hypertension or glaucoma tend to respond February 2021 Sudhalkar, et al.: Intravitreal therapy and intraocular pressure rise 239 early and more to implant injection, with 50–100% of patients upon by most authors). Finally, there appears to be some ethnic demonstrating some measure of IOP spike, especially those on predisposition to the development of ocular hypertension per dual or triple therapy with IOP lowering medications. the GEODEX‑IOP study,[45] wherein it was demonstrated that south Asians and Latinos have a greater propensity to develop A third of patients on monotherapy for preexisting IOP ocular hypertension, especially when an IOP >25 mm Hg is an elevations tend to develop a rise in IOP.[43] Typically, patients inclusion criterion. There is no particular racial predisposition who demonstrate a rise in IOP post injection tend to do so after if one considers and IOP >20 mm Hg. A genetic predisposition the first or second injection, and of these, nearly 87% manifest to develop ocular hypertension secondary to steroid a spike of 6 mm Hg or more. Past analyses show that there is administration is known.[44] The dexamethasone implant and its little or no cumulative risk of IOP rise with the dexamethasone association with ocular hypertension have been well studied in implant, i.e., if the patient does not manifest an IOP spike with patients with glaucoma and in patients who are known steroid the first or second injection, there is little risk of development of responders as well[46,47]; the results are largely encouraging in ocular hypertension with future injections. “Late” responders, i.e., people generally have one of the predisposing risk factors that most patients who did demonstrate an IOP rise responded discussed subsequently. An overwhelming majority of the well to medical management and incisional surgery was seldom cases can be managed with topical therapy; only a handful required. Steroid induced ocular hypertension in uveitis[46-49] require systemic therapy or some form of incisional surgery needs to be looked at with a different perspective; presences for IOP control. of peripheral anterior synechiae may adversely influence the frequency and severity of IOP spikes, necessitating surgical Risk factors[29,43] for development of ocular hypertension intervention. In our series discussed earlier,[29] the solitary secondary to the dexamethasone implant include younger age patient who received trabeculectomy for IOP control was a (<60 years), male gender, presence of type 1 diabetes mellitus, case of pan‑uveitis with peripheral anterior synechiae affecting vein occlusion or uveitis, and patients already on dual or triple trabecular outflow. therapy for ocular hypertension/glaucoma. Type II diabetics on the other hand are not necessarily predisposed to IOP rise. Triamcinolone Acetonide Additionally, our analysis of IOP rise and the dexamethasone Preservative‑free triamcinonolone acetonide has been implant[29] demonstrates that the position of the dexamethasone used for a variety of retinal conditions and has been used implant in‑situ is an important determinant of and independent intravitreally, subconjunctivally, and in the subtenon space. risk factor for IOP rise; the closer the implant lies to the ciliary Several studies[50‑61] have documented its cataractogenesis and body, the greater the chance of developing ocular hypertension. IOP spikes. Intravitreal triamcinolone acetonide injections can This finding is in line with the theory that the entry of the steroid cause both short‑term IOP fluctuations and persistent ocular molecule in the anterior chamber is an essential component of hypertension, the former being related in part to the volume the development of ocular hypertension. Further evidence for of the injected drug and the latter a “pharmacopathological” this is provided by the rates of incisional surgery in patients response. Younger age, preexisting glaucoma, narrow angles, who receive the RETISERT versus those who receive the and a history of diabetes mellitus are clinically evident risk fluocinolone acetonide intravitreal insert (ILUVIEN); a lower factors[52,60,61] associated with IOP rise in patients. dose and a more posterior placement of the depot preparation reduces the rate for incisional surgery for uncontrolled ocular The short‑term rise in IOP[50] immediately postoperatively hypertension from 33% for patients who receive the RETISERT logically follows an increase in intraocular volume and implant to approximately 5.6% for patients who received the is absent/low in eyes that demonstrate vitreous reflux ILUVIEN implant.[44] Additionally, eyes with the implant immediately after injection. In a series of 38 eyes who had positioned closed to the ciliary body may manifest IOP spikes received intravitreal triamcinolone, Benz and associates as early as 3 days post injection.[29] Vitrectomized eyes probably measured IOP with Goldmann applanation tonometry show increased clearance of drug from the intravitreal cavity preoperatively and then immediately postoperatively as well and the presence or absence of vitreous does not influence as 2, 5, 10, 20, and 30 min after injection. They concluded IOP rise.[33,36] that eyes that do not demonstrate vitreous reflux at the site of injection tend to show, on average, a spike of around 20 An important limitation of all retrospective analyses must mm Hg or more from baseline immediately after injection and be taken into account; it is possible that missed follow‑ups that it tends to normalize over 30 min. This is not unlike what explain the lower incidence of ocular hypertension when we have elaborated upon for short‑term IOP rise consequent compared with validation or pivotal studies such as the to intravitreal anti‑VEGF injections.[33] Additionally, there are MEAD study; the SAFODEX study documented an incidence reports[51] of a “Postop day 4 IOP rise” in a few patients who of around 17%; we noted an incidence of approximately 20%. were part of the triamcinolone arm in the Diabetic Retinopathy The MEAD study, for instance, noted that almost a third of Clinical Research Network study groups. This appears to be patients demonstrated ocular hypertension at some point in transitory, and the authors do not suggest more stringent time during the course of follow‑up. The MEAD study was a follow‑up protocols or therapy for the same. prospective study with strict follow‑up regimes and therefore recorded an incidence of ocular hypertension that is probably Long‑term development of ocular hypertension with closer to the real incidence. Conversely, real‑life studies depict a triamcinolone acetonide follows closely the pattern noted with scenario that is more prevalent, and therefore more relevant; not other intravitreal steroid injections, such as the dexamethasone every spike in IOP is clinically significant and a more relaxed implant. This typically happens between weeks 2 and 5 post follow‑up schedule should be able to pick up in timely manner injection. In a retrospective analysis[61] involving 929 eyes of clinically significant elevations of IOP (>25 mm Hg, as agreed 841 patients, the cumulative incidence of IOP rise >21 mm Hg 240 Indian Journal of Ophthalmology Volume 69 Issue 2 in patients receiving multiple injections rose from 28.8% at Ocular hypertension is one of the most common adverse 6 months to 44.6% at 24 months. Preexisting glaucoma would events associated with the use of intraocular steroids, and the naturally translate into a higher probability of IOP spikes, ILUVIEN insert is no exception.[44,64‑74] Up to 13% of patients and the severity of the spikes are also greater. Conversely, might have an IOP of >30 mmHg[70] (range of occurrence, approximately 28% eyes had IOP elevation >25 mm Hg at 7‑50%).[64,74,75] 2 years after initiation of therapy. Finally, a quarter of these No ocular hypertension was present in the fellow eyes required IOP lowering medications at 2 years. This does untreated eye when specifically assessed.[71] In the FAME not necessarily imply a cumulative rise in IOP secondary study, IOP increased in 37.1% of patients who received the to multiple injections; it is more reflective of a diminishing 0.2‑µg/day FA implant (n = 375) and in 11.9% of those who sample size. Only three eyes ever required incisional surgery received placebo (n = 185). A >30‑mmHg rise in IOP was for uncontrolled IOP rise. IOP rise does not preclude further more frequent in patients who received the 0.2‑µg/day FA injection as long as the IOP rise can be satisfactorily controlled implant (P < 0.001) than in those who received placebo in medically; for patients who have received incisional surgery to the overall population and in those without prior ocular counter IOP rise, the need and permissibility for further steroid corticosteroid exposure.[44,64‑71] A posthoc analysis showed injections can be decided on a case‑to‑case basis. that glaucomatous optic nerve changes were not dissimilar Triamcinolone crystals have been observed to remain in the between the patients in the two arms of the trial.[73] A recent vitreous cavity for a period of 12 weeks post injections and even multicentre study from three European countries (United longer in some cases, as noted clinically and pharmacologically Kingdom, Germany, and Portugal) published by the IRISS by Sophie and Beer. [57] It follows that patients must be group confirmed the results of the FAME study: about 23% of monitored for the said time period.[56‑58] The persistence of patients required IOP‑lowering medication without clinically triamcinolone crystals does not correlate with pharmacologic significant changes in the cup‑to‑disc ratio (CDR).[67] However, activity. In patients with persistent IOP elevations refractory a small percentage of patients in IRISS (5.2%) had a baseline to medical or surgical therapy, vitrectomy and evacuation of IOP of >21 mmHg, which was an exclusion criterion in the the triamcinolone crystals may be considered as the last option FAME trials. (ultima ratio). The subtenon route[59] might be associated with The need for glaucoma drops varied from 0 to 15%, with a lower incidence of ocular hypertension. The efficacy and some larger series having an even higher rate.[44,64‑77] These safety of the subtenon route depends upon the exact plane of higher rates are more in accordance with the FAME study, injection; inadvertent subconjunctival injection may actually in which 26% of patients required glaucoma drops. A need raise the IOP to a greater extent than the subtenon space itself. for glaucoma surgery despite appropriate topical treatment Vitrectomized eyes show increased uptake and excretion of was seen in up to 14.3% of cases.[44] Careful patient selection triamcinolone acetonide and may correspondingly demonstrate remains critical to avoid complications related to ocular a lower and ill‑sustianed rise in IOP.[62] hypertension. Intravitreal triamcinolone continues to be used regularly Intraocular hypertension in vitrectomized eyes was in developing countries with poor/absent health insurance assessed by Meireles et al.[77] in a retrospective study of 26 systems because it is cheap and readily available. A reasonable eyes with a mean follow‑up of 255 days. A mean IOP change alternative is posterior subtenon injection of the said drug, of 1.4 mmHg was found between baseline and the last visit which, as discussed earlier, can lessen or delay the occurrence (range, −9.0 to +8.0 mmHg), with eight eyes (30.7%) initiating of ocular hypertension but is said to be less effective than or continuing antiglaucoma drops. Pessoa et al.[70] performed the intravitreal route. In countries with universal healthcare a retrospective study of 43 eyes (24 vitrectomised and 19 systems,[12] triamcinolone acetonide has largely been replaced nonvitrectomized eyes) with a mean follow‑up of 8.5 months with the safer dexamethasone implant. However, it continues and reported no significant difference in the IOP changes to be an important alternative for therapy of uveitis, diabetic between the two groups; however, vitrectomized eyes exhibited macular edema, and retinal vein occlusion in developing a higher mean IOP elevation (1.6 vs. 0.8 mmHg). countries with little or no insurance support. Currently, we can infer that 0.05 ml (2 mg) or 0.1 ml are the two most commonly Use of the FA implant is contraindicated in the presence of used doses and that a higher dose correlates with a higher risk preexisting glaucoma, and it is not approved for use in steroid of IOP rise. Close follow‑ups, especially in younger patients and responders in the United States. Safety could be improved by those with DME and uveitis, are recommended. Vitrectomy as introducing a steroid provocation test. While such a test could a probable treatment option should be thought of whenever not absolutely predict the absence of ocular hypertension, it IOP control with medical therapy is no longer possible. The would highlight patients who may require surgical intervention possibility of triamcinolone crystals[63] entering and obstructing so that they could be excluded from the treatment. In the FAME the trabecular meshwork must also be kept in mind, and the study, 6.1% of steroid‑naïve patients required IOP‑lowering infero‑temporal site of injection is the most preferred. surgery (n = 18), highlighting the importance of knowing whether patients have a strong IOP response to corticosteroid ILUVIEN therapy.[73] The ILUVIEN insert (an intravitreal insert of fluocinolone No increase in the CDR was detected with a 0.2‑µg/day acetonide) has had a limited release worldwide and has dose after 36 months, whereas the CDR increased by 0.1 in the primarily been studied for two major indications: Uveitis 0.5‑µg/day group[73] Therefore, a 0.2‑µg/day dose is the implant and DME. The use of the insert has reduced the number of used worldwide, but careful long‑term follow‑up focusing on interventions required to manage uveitis and DME.[64] IOP is required. February 2021 Sudhalkar, et al.: Intravitreal therapy and intraocular pressure rise 241 Retisert Implant (0.59 mg) 7. Rusu IM, Deobhakta A, Yoon D, Lee M, Slakter JS, Klancnik JM, et al. Intraocular pressure in patients with neovascular age‑related One of the first fluocinolone acetonide implants[78,79] available; macular degeneration switched to aflibercept injection after it finds limited applicability today. There are better and previous anti‑vascular endothelial growth factor treatments. Retina perhaps safer alternatives available today as is evidenced by 2014;34:2161‑6. the preceding discussion. Notwithstanding, for the sake of 8. Wehrli SJ, Tawse K, Levin MH, Zaidi A, Pistilli M, Brucker AJ. completion, we discuss in brief the Retisert implant and its A lack of delayed intraocular pressure elevation in patients treated association with ocular hypertension. with intravitreal injection of bevacizumab and ranibizumab. Retina 2012;32:1295‑301. Of note here is the position of the implant vis‑à‑vis the 9. Hussain N, Ghanekar Y, Kaur I. The future implications and anterior chamber and the higher dose of fluocinolone delivered indications of anti‑vascular endothelial growth factor therapy in to the posterior segment of the eye when compared to the ophthalmic practice. Indian J Ophthalmol 2007;55:445‑50. ILUVIEN implant. The anterior positioning of the implant, 10. Theoulakis PE, Lepidas J, Petropoulos IK, Livieratou A, sutured as it is in the pars plana region, facilitates entry of the Brinkmann CK, Katsimpris JM. Effect of brimonidine/timolol fixed steroid molecule in the anterior chamber to a greater extent combination on preventing the short‑term intraocular pressure than what would be expected in cases with a more posteriorly increase after intravitreal injection of ranibizumab. Klin Monbl Augenheilkd 2010;227:280‑4. positioned implant.[42,44] The incidence of ocular hypertension is correspondingly higher with nearly 61% of patients 11. Gregori NZ, Weiss MJ, Goldhardt R, Schiffman JC, Vega E, Mattis CA, et al. Ocular decompression with cotton swabs demonstrating IOP rise, whereas a significant proportion of lowers intraocular pressure elevation after intravitreal injection. these patients required incisional surgery for glaucoma. The J Glaucoma 2014;23:508‑12. implant is effective, but the overall availability is restricted, 12. Stellungnahme DOG. Available from: https://www.dog. as is its use. org/?cat=199. [Last accessed on 2019 Jun 01]. Conclusion 13. Al‑Abdullah AA, Nowilaty SR, Asghar N, Al‑Kharashi AS, Ghazi NG. Intraocular pressure trends after intravitreal injections To conclude, intravitreal therapy, regardless of the agent or of anti‑vascular endothelial growth factor agents for diabetic indication, does predispose the patient to the development macular edema. Retina 2015;35:440‑8. of ocular hypertension. The risk varies with the age, gender, 14. Palimkar A, Khandekar R, Venkataraman V. Prevalence and ethnicity, drug used, the indication, and the frequency of distribution of glaucoma in central India (Glaucoma Survey 2001). treatments, among other things. Barring a few exceptions, the Indian J Ophthalmol 2008;56:57‑62. onset is insidious and the threat of glaucomatous damage real. 15. Dandona L, Dandona R, Srinivas M, Mandal P, John RK, The common thread running through this entire discussion McCarty CA, et al. Open‑angle glaucoma in an urban population is careful follow‑up, early intervention, and an appropriate in southern India: The Andhra Pradesh eye disease study. Ophthalmology 2000;107:1702‑9. patient counselling. 16. Freund KB, Hoang QV, Saroj N, Thompson D. Intraocular pressure Financial support and sponsorship in patients with neovascular age‑related macular degeneration Nil. receiving intravitreal aflibercept or ranibizumab. Ophthalmology 2015;122:1802‑10. Conflicts of interest 17. 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