Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

Diagnostic Support

Meticulous examination using a Goldmann contact lens on a patient with clear media is enough to diagnose clinical CME with an incidence of 1%-2%(11); however, if there is no evidence and visual loss cannot be explained, fluorescein angiography is recommended.

Angiographic CME has a reported incidence of 3% to 70%; 30% of patients following ECCE.(9,11) Fluorescein angiography shows hyperfluorescence from different focuses during the early phases. This means that contrast material is leaking from perifoveal capillaries. The leakage increases in late phases, filling the cystoid spaces in the Henle fiber layer and manifesting the classic “petalloid” shape(12) (Figure 4). The optic disk can also

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be hyperfluorescent due to leakage from the nerve head capillaries because of inflammatory changes.

OCT provides noninvasive, noncontact, transpupillary cross-sectional detailed imaging of retinal structures with 8-10 μm axial resolution allowing quantification of macular thickness and mapping of retinal damage. OCT is useful to determine lesion depth as well as the alterations in the retinal anatomy showing that both the outer plexiform layer (OPL) and internal nuclear layer (INL) are preferred sites for retinal swelling or cystic spaces.(13) This image technique helps in the diagnosis and follow-up for CME with or without treatment, especially in patients whom angiography is contraindicated for any medical reason (Figure 5).

Other supportive test for these patients ares used less often: fluorophotometry, which detects an increase in vascular permeability(12); laser tomography, which supplies a threedimensional quantitative analysis, allowing us to evaluate information regarding visual prognosis and macular cyst pathogenesis, together with fluorescein angiography.(14)

Medical Treatment

A large number of drugs have been investigated both for prophylaxis and treatment of an established CME. As we have already mentioned, the theory implicating prostaglandins as inductors of CME hystopathologic changes was a guideline for using certain drugs which act on prostaglandin synthesis, helping to accomplish an average lower CME incidence from 10.1% in the control group to 4.9% the group receiving prophylactic treatment,(15) as well as chronic CME resolution.

Indomethacin and ketorolac, non-steroidal antiinflammatory drugs (NSAIDs), belong to a group of useful drugs that act through nonselective inhibition of both isoforms of cyclooxygenase (COX-1, COX-2) who have distinct tissue expression patterns and transcriptional regulation mechanisms.(16,17) COX is a catalytic enzyme that transforms arachidonic acid into prostaglandin. Oral indomethacin has been used in patients with CME, although a high daily dosage (100mg) is required to properly control the condition. Then undesirable side effects of the gastrointestinal tract and central nervous system changes may occur with subsequent cessation of treatment, especially

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in elderly patients.(8) Therefore, topical indomethacin has yielded better results.(8,10)

Ketorolac, another non-steroidal anti-in- flammatory drug, improved visual acuity by two or more lines in 67% of treated patients, with CME resolving within a shorter period of time, an average of 2.3 months. It is reported to improve contrast sensitivity in 55% of treated patients, and to cause disappearance of angiographic changes in 55% of patients who have had CME for more than 24 months. These improvements, however, would probably require long-term application of the drug.(8,10) In combination with one steroid, ketorolac was shown to improve visual acuity by two or more lines in 89% of treated patients, within 2 months after initiation; with 89% contrast sensibility improvement and 77% improvement of angiographic changes, which proves its potential effect on CME.(16)

Expression of COX-2 is highly regulated and is markedly increased by inflammatory factors subsequent to tissue injury, producing rises in prostaglandins that are themselves mediators of inflammation.(17) Valdecoxib, celecoxib, rofecoxib are COX-2 inhibitors that allow effective treatment ofinflammation while reducing side effects of NSAIDs. Increased cardiovascular risk and increased rate of skin reactions were observed when the application period lasted at least 12 months, reason why U.S. FDA removed it from the market as an chronic anti-inflammatory treatment. A prospective clinical trial showed that 10 mg of the COX-2 inhibitor valdecoxib once daily for 3 weeks is effective and well tolerated in treating CME without any side effects.(18)

Nepafenac, a pro-drug of arylacetic acid NSAID introduced in 2005, has greater permeability that results in less active drug exposure to the cornea and greater drug concentration at the site of action. Due to its pro-drug property, a reservoir of parent drug that is later converted to amfenac may be created in the anterior chamber of the eye, prolonging the duration of the anti-inflam- matory action. It has shown a reduction in visually significant CME in patients treated with nepafenac and prednisolone compared with patients treated with prednisolone alone (0% and 2%, respectively; P.0354).(19)

Acetazolamide may reduce CME as an inhibitorofcarbonicanhydrase;themechanism of action involves alteration of the polarity of the ionic transport systems in the retinal pigment epithelium cells, Müller cells, cone internal segments, and endothelial cells, where carbonic anhydrase is found. Encouraging results have been obtained with oral dosages of 500mg/12 or 24 hours.(20,21)

Hyperbaric oxygen therapy is another option for treating CME, using highly concentrated oxygen to produce some changes in oxygenation and ocular blood flow. Even though favorable results have been obtained, these studies have included a follow-up period of no longer than 3 months.(7)

Corticosteroids inhibit synthesis of the enzyme phospholipase A2, thus both the cyclooxienase and lipoxigenase pathways, lessening the production of substances such as arachidonic acid, which is a prostaglandin precursor and leukotrienes. These drugs thereby diminish the inflammatory process;(1)

they also have anti-angiogenic, anti-edematous and anti-proliferative effects. Stern et al have used corticosteroids orally with a satisfactory response in 40 of 49 studied patients.(16) Oral steroids, unfortunately, can cause a spectrum of systemic side effects, including osteoporosis, cushingoid state, adrenal suppression and exacerbation of diabetes.(22,23) However, almost all steroids produce undesirable side effects, which subsequently cause some patients to abandon treatment.

Topical ocular steroids are associated with certain risks, such as glaucoma, posterior subcapsularcataracts,opportunisticinfections,and delayed wound healing. Steroids have been injected into the sub-Tenońs space or have been used topically (prednisolone acetate)(10) in an attempt to control the systemic side effects, with favorable results. After cessation of treatment, however, CME may recur. This can also happen with oral administration of corticosteroids. Increased intraocular pressure is a well-known possibility in patients with a significant response and a faster CME resolution. We do not yet have an explanation for this phenomenon.(22)

Intravitrealuseofcorticosteroidshasproved useful as a result of the anti-inflammatory effects and stabilization of the blood-retinal barrier (BRB). Intravitreal delivery allows the steroid to bypass the BRB, leading to a more concentrated dose of steroid for a prolonged period of time, although the duration of the action is typically short-term.(22,23) The most common delivery is via direct injection through the pars plana, other methods include through a sustained-release or biodegradable implants, or injection of conjugate compounds.

Intraocular steroid sustained-delivery device that can help release a consistent amount of drug in a longer period of time are in development since most of the intravitreous drugs have a relative short intraocular halflife.(23) The DDS (Dexamethasone Posterior Segment Drug Delivery System, Allergan Inc.) is an implant of a biodegradable copolymer of lactic acid and glycolic acid that provides gradual release of 350 or 700 μg of dexamethasone after inserted through a small pars plana incision or puncture (Figure 6).

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The intraocular half-life of dexamethasone has increased from approximately 3 hours up to 6 months after insertion. The polymer slowly biodegrades until it dissolves completely.(24) Another implant containing 0.59 mg fluocinolone acetonide demonstrated efficacy in clinical trials. Eventually this technology can provide a better and longer intravitreal drug treatment without the hazard of multiple reinjections.

Intravitreal injection of triamcinolone acetonide (TA) has proved long-term safety and efficacy. A 4-mg dose, in a non-vitrectomized eye, maintains measurable concentrations for approximately 3 months.(23) CME treated with 8-mg of intravitreal TA a month after injection

noted a decrease in macular thickness from a mean 502 to 233μm and a mean improvement in visual acuity of 3.7 Snellen lines; however the edema recurred in some cases two to 4 months after injection(25) (Figure 7).

The main vehicle for TA is benzyl alcohol, which at higher concentrations, can damage the outer-segments and photoreceptors, reason why some support the idea to pour off the main vehicle. The possible complications after an intravitreal triamcinolone injection include endophthalmitis (0.5%), increased IOP (42%), retinal detachment, non-infectious endophthalmitis (1.6%), and cataract forma- tion (24%).(22,23,25)

Antiangiogenics (Bevacizumab, Ranibizumab), until recently, have been used offlabel to treat a variety of ocular diseases as they inhibit the effects of vascular endothelial growth factor (VEGF) that has been implicated as a major angiogenic stimulus responsible for neovascularization and is also a potent permeability factor causing a breakdown of the BRB and increasing the permeability of the perifoveal capillary net with resultant fluid accumulation in the perifoveal retina.(26,27) CME is related to the disruption of the BRB and blood-aqueous barrier and the inflammation induced by prostaglandins or other inflammatory mediators (cytokines, endotoxin and immune complex) resulting from an increased expression of VEGF.(27)

Bevacizumab is a complete full-length humanized antibody that binds to all subtypes of VEGF. An open-label uncontrolled clinical study of 4303 injections in human eyes with 1.25 mg or 2.50 mg intravitreal bevacizumab, found systemic adverse events in 18 patients (1.5%) being the most frequent acute elevation of systemic blood pressure (7 cases 0.59%)

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and ocular complications included 7 cases (0.16%) of bacterial endophthalmitis, 7 cases (0.16%) of tractional retinal detachment, 4 cases (0.09%) of uveitis, and a case (0.02%) each of rhegmatogenous retinal detachment and vitreous hemorrhage.(28)

An interventional, retrospective multicenter study reviewed 25 consecutive patients (28 eyes) with pseudophakic CME treated with at least 1 intravitreal injection of 1.25 mg (16 eyes 57.1%) or 2.50 mg (12 eyes 42.9%) of Avastin 13 months (mean time) after surgery. A mean follow-up of 32 weeks revealed 28 eyes (71.4%) had improved best corrected visual acuity (BCVA) (≥2 ETDRS lines). The mean baseline BCVA was 20/160 (logMAR 0.92) and the mean final BCVA 20/63 (logMAR 0.50); the difference was statistically significant (P<.0001). The mean central macular thickness at baseline (466.3 mm; range 208 to 784 mm) decreased significantly (264.5 mm; range 176 to 513 mm) by the end of follow-up (P<.0001) (Figure 8 A-B). No statistically significant differences in duration, anatomical, or functional effectiveness between the 2 doses. Eight eyes (28.6%) required a second injection and 4 eyes (14.3%) a third injection on either group. No ocular or systemic effects were reported at 6 months.(29)

This may be an excellent and safe treatment modality for patients with CME unresponsive to topical medications or patients who are steroid responders or hesitant to have corticosteroid treatment.

Surgical Treatment

Studies provide evidence to recommend vitrectomy as a therapeutic measure in patients with chronic CME presenting papillary distortion secondary to vitreous adherent to the corneo scleral wound in addition to anterior segment inflammatory signs (classic Irving-Gass syndrome) and with some posi-

tive response to medical therapy. Favorable results have been documented in aphakic and pseudophakic patients, with a postoperative improvement in visual acuity. The operation is recommended when visual acuity has remained stable for 2 or 3 months (since visual acuity fluctuation is well known in CME early phases), and also when visual acuity is 20/80 or worse within 2 years of the onset of the

CME.(30,31,32)

A significant finding in the above mentioned studies is that the majority of patients had posterior vitreous detachment. Only 3% of aphakic patients and no pseudophakic patients presented vitreous traction strands on the macula. Therefore, the mechanism of action in vitrectomy might involve removing a series of substances that are inflammatory mediators. This would reduce the CME but not lessen traction on the macular area, as one might suppose it would.(30)

Recently with the advantage of highresolution images obtained with OCT, new insights into the pathogenesis and progression of cystoid macular edema have been proposed. Similar to macular hole, tangential vitreomacular traction involving the internal limiting membrane (ILM) seems to play an important factor acting as an scaffold for proliferation of cellular components. ILM represents the structural boundary between the retina and the vitreous measuring an average of 2.5μm in thickness.(33,34,35) Pars plana vitrectomy allows the complete removal of vitreous and posterior hyaloid as well as of any vitreous traction strands that can affect the macula, and by ILM peeling, it is possible to relief any residual tangential traction and ensure complete removal of epiretinal tissues. Also ILM peeling can potentiate the effect of topically administered medications by removing a diffusion barrier.(33) ILM peeling can be achieved by using a blunt retinal pick, a bent MVR blade, a diamond dusted ILM scrapper or a vitreoretinal forceps; also staining of the ILM either with indocyanine green (ICG), trypan blue, TA and most recently brilliant blue G has made the removal easier

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and safer, reducing the operating time and mechanical trauma to the retina.(34) Although the combined procedure is more challenging, with the possibility of severe complications like retinal tears, hemorrhages, RPE changes, macular phototoxicity and opening macular cysts, resulting in important damage to the fovea and a poor visual outcome.(34,35)

Patients who present vitreous adherent to the surgical wound as a complication of cataract extraction may have anterior segment inflammatorychanges,leadingtothemigration of substances towards the posterior pole and the onset of CME. YAG laser vitreolysis has been investigated as a treatment. It allows bisection of vitreous strands adherent to the cataract wound, thus resolving this pathology. Access is difficult, however, because of the location of the vitreous strands. Reports of this technique show its benefits, but the studies have several limitations: no control groups are mentioned, treatment has been given to patients with short-term CME evolution, and concurrent corticosteroid therapy was administered as well.

Conclusion

New techniques and better equipment have contributed to a dramatic decrease in the incidence of cystoid macular edema, especially secondary to cataract extraction surgery. However, CME still represents pathology that can cause a significant change in the visual prognosis of patients who presented no alterations before surgery. This is a surprisingly serious concern for the surgeon. The etiology

of this disease has not yet been totally elucidated; therefore, the types of treatment we know today are not completely effective. If properly prescribed and used, however, the available series of pharmaceutical drugs and available procedures will help reduce the irreversible damage caused by cystoid macular edema.

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