Raja Narayanan, MD,
Baruch D. Kuppermann, MD, PhD
Contents
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Cystoid Macular Edema |
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Diabetic Macular Edema |
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Epiretinal Membrane |
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Retinal Vein Occlusion |
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Macular Hole |
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Macular Degeneration |
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Photic Injury |
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Conclusions |
Great advancements in the field of cataract surgery have been made over the past 2 decades, with fewer rates of complications and better surgical outcomes. However, for good visual outcome after cataract surgery, a fully functional, healthy macula is necessary. Every surgeon who has performed cataract surgery has encountered disappointing cases of poor visual outcome in spite of a successful cataract surgery, where the problem lies in the macula. Additionally, when complications during cataract surgery do occur, the outcomes can be adversely affected due to secondary macular issues.
In advanced cataracts with inadequate visualization of the macula, macular pathologies may be undetected until the postoperative period. Similarly, there are no investigative modalities that give a precise estimate of the macular function in such cases. A few of the macular disorders, such as cystoid macular edema (CME) and epiretinal membrane formation, occur postoperatively, both in cases associated with complications as well as in uncomplicated surgery. It is important for the anterior segment surgeon to remain alert to these conditions, and this chapter deals with a few important macular conditions causing poor postoperative visual acuity. Some of the important macular disorders associated with poor visual acuity are listed in Table 54-1.
Table 54-1 -- Common macular diseases causing poor postoperative vision after cataract surgery
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1. Cystoid macular edema |
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2. Epiretinal membrane |
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3. Diabetic macular edema |
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4. Vitreo-macular traction |
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5. Macular hole |
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6. Retinal vein occlusions |
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7. Age-related macular degeneration |
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8. Photic Injury |
Cystoid macular edema
Macular edema as a complication of cataract surgery causing a reduction in central vision was first recognized by Irvine in 1953.[1] Also known as Irvine–Gass syndrome, cystoid macular edema (CME) after cataract surgery is characterized by multiple cyst-like (cystoid) areas of fluid in the macula. The incidence of Irvine–Gass syndrome is variable depending on the type of surgical procedure performed and the clinical series reported. Overall, the incidence of angiographic CME is approximately 50% after intracapsular cataract extraction,[2]and 20% after extracapsular cataract extraction (ECCE),[3] and 19% after phacoemulsification,[4] but the overall incidence of clinically evident CME is much less. Various studies have reported that the occurrence of clinically significant CME varies between 1.5 and 2.3%.[5] Postoperative CME in one eye is associated with an increased risk of CME developing in the other eye. Fortunately, however, most patients recover their vision with treatment.
The condition may be divided into CME based on biomicroscopic examination and angiographic CME based on fluorescein angiography. Angiographic CME does not necessarily reduce the visual acuity.[6] Multiple remissions and exacerbations of macular edema or persistent macular edema may result in photoreceptor damage and foveal atrophy with permanent impairment of central vision.
Pathophysiology
Leaking perifoveal capillaries lead to accumulation of fluid in Muller cells, [7] or in the loosely arranged outer plexiform layer of Henle,[8] the fibers of which are arranged horizontally. This produces a petalloid pattern on fluorescein angiography. Breakdown of the inner blood retinal barrier leading to CME has many possible etiologies. The most popular theory implicates intraocular inflammation. Inflammatory mediators, such as prostaglandins and leukotrienes have been implicated in the pathogenesis. In the prostaglandin pathway, inflammation causes the enzyme phospholipase to release arachidonic acid from cell walls. Subsequently, cyclooxygenase converts the arachidonic acid to prostaglandins. Steroids inhibit the enzyme phospholipase, and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase pathway. Leukotrienes account for an alternate pathway where the enzyme lipoxygenase converts arachidonic acid to leukotrienes, which are chemotactic agents. However, the exact role of leukotrienes in CME remains unclear.
In Irvine–Gass syndrome, light toxicity originating from the operating microscope or postoperative inflammation may contribute to free radical release with subsequent prostaglandin synthesis. Vitreoretinal traction to the macula may also contribute to postoperative CME.[9] Vitreous incarcerated in the surgical wound and pulling on the retina at points of vitreo-retinal attachment have been found to be associated with an increased risk of CME. [10]
Symptoms
Although complicated surgery accounts for most cases of CME (Table 54-2), this condition may also occasionally occur after uneventful surgery. Vision ranges from 20/25 to 20/400 depending on the severity of the edema. Patients may also experience metamorphopsia. The natural history of CME is variable. Pseudophakic CME often resolves spontaneously, and 90% of eyes improve to 20/40 or better visual acuity in cases with a posterior-chamber (PC) intraocular lens (IOL). However, remissions and exacerbations of macular edema can result in photoreceptor damage with permanent impairment of central vision.
Table 54-2 -- Surgical factors that may contribute to cystoid macular edema
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Posterior capsule rupture |
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Vitreous prolapse |
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Repeated iris prolapse |
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Prolonged surgery |
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Improper positioning of IOL causing iris tuck |
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Vitreous or iris incarceration in the wound |
History
Patients presenting with Irvine–Gass syndrome often have a history of prior intraocular surgery. Risk factors may be present in the affected eye. The patient presents with gradually decreasing vision, usually 1 to 3 months after cataract surgery.
Examination
Clinical examination of the anterior segment can provide important clues. Peaked pupil, poorly positioned IOL, anterior-chamber (AC) IOL, and anterior-chamber inflammation may be found in cases of CME. Biomicroscopic examination reveals the characteristic cystic spaces in the foveal region (Table 54-3). Subtle CME can be highlighted by the technique of light scattering. Retro-illumination by focusing the slit beam of illumination at the edge of the fovea delineates the cystic spaces. These cysts may coalesce into a macular cyst and which may then progress to form a hole. CME may also be associated with perifoveal hemorrhages.
Table 54-3 -- Clinical signs of cystoid macular edema
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Prominence of yellow xanthophyll pigment dot |
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Multiple cysts in the fovea |
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Perifoveal splinter hemorrhages |
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Macular thickening |
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Disc edema |
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Vitreous cells |
Imaging studies
Fluorescein angiography
In the early and mid phases of the fluorescein angiogram, parafoveal retinal capillary leakage occurs in most cases. In the late phases of the fluorescein angiogram, a petaloid pattern of leakage in the macula and leakage on or around the optic disc occurs.[11] However, visual acuity is not predicted by the amount of leakage.[12]
Optical coherence tomography
Optical coherence tomography (OCT) is an important modality in confirming the diagnosis and in monitoring the course of the disease. OCT demonstrates well-defined cystic spaces in the fovea and increased foveal thickness.[13]
Management
Pharmacologic treatment
Most cases of pseudophakic CME resolve spontaneously within several weeks to a few months. However, 20% of cases are evident angiographically for more than 5 years after onset. When other conditions cause CME, treatment often entails managing the underlying problem. Corticosteroids inhibit the enzyme phospholipase and have a primary role in the treatment of CME secondary to uveitis. Corticosteroids can be administered topically, orally, injected in the sub-Tenon space or intravitreally. Intravitreal triamcinolone has been shown to improve visual acuity that may be sustained for an extended period. [14] NSAIDs inhibit the enzyme cyclooxygenase and can be highly effective in the treatment of CME.[15–17] In a prospective, double-masked, multicenter study of ketorolac versus placebo in the treatment of patients with chronic aphakic or pseudophakic CME, statistically significant improvement in visual acuity occurred in patients that received ketorolac after 30, 60, and 90 days of therapy.[18] This remained significant 1 month after cessation of treatment. Preoperative use of ketorolac for 3 days has been shown to be effective in preventing postoperative CME.[19] The Italian Diclofenac Study Group reported a prospective, randomized, double-blind, multicenter study of diclofenac versus fluorometholone in the treatment of CME after ECCE with PC IOL placement.[20] At both 36 and 140 days postoperatively, angiographic CME was lower in patients treated with diclofenac compared with the control group. A newer non-steroidal agent, nepafenac, is being studied in clinical trials. Early reports suggest that it is more efficacious than the traditional non-steroidal agents that have been used until now.
Surgical treatment
In select cases, YAG laser may be a preferable option to cut adherent strands of vitreous and relieve traction.[21] When vitreous traction contributes to CME, surgical vitrectomy can lessen the CME and improve vision.[22] Vitrectomy is effective through the following mechanisms:
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Remove inflammatory mediators |
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Remove retained lens fragments |
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Reposition a dislocated or malpositioned IOL |
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A greater penetration of topical and oral corticosteroids into the posterior segment occurs after pars plana vitrectomy (PPV). |
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Diabetic macular edema
In the Wisconsin Epidemiologic Study, macular edema was present in 2–6% of patients with background, diabetic retinopathy; 20–63% in pre-proliferative diabetic retinopathy; and 70–74% in proliferative diabetic retinopathy. The prevalence of macular edema also increased with the duration of diabetes mellitus. Diabetic macular edema (DME), defined as retinal thickening within one disc diameter of the macula, is often aggravated by cataract surgery. In a recent study, the incidence of preoperative macular edema as determined by OCT in diabetics undergoing cataract surgery was 22%. Eyes with no pre-existing diabetic retinopathy did not develop any significant increase in central foveal thickness, whereas patients with moderate-to-severe diabetic retinopathy had an increase of 145μm in the central foveal thickness 1 month after cataract surgery. This was associated with a less than two line improvement in visual acuity after cataract surgery.[23] Rupture of the posterior capsule often increases the macular edema. Over the previous few decades, there have been a few large-scale trials that have influenced the management of diabetic complications in the eye. The Early Treatment Diabetic Retinopathy Study (ETDRS) identified macular edema as a study objective. To date, the ETDRS has presented the most comprehensive and detailed directives in the management of diabetic macular edema.[24] More recently, the Diabetic Retinopathy Clinical Research network (DRCR.net) has initiated a series of trials assessing laser, surgical, and pharmacological treatments of DME.
Pathophysiology
DME is the result of retinal microvascular changes that occur in patients with diabetes.[25–27] Thickening of the basement membrane and reduction in the number of pericytes is believed to lead to increased permeability and incompetence of retinal vasculature.[28] This compromise of blood–retinal barrier leads to the leakage of plasma constituents in the surrounding retina, resulting in retinal edema. Focal retinal thickening is almost always caused by leaking microaneurysms. Diffuse retinal thickening is usually caused by a generalized breakdown of the inner and outer blood–retinal barriers. Macular ischemia may sometimes be the cause of significant visual loss.
History
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Diabetic history: Specific inquiry should be made into risk factors for the development of diabetic retinopathy. |
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Type of diabetes: After 20 years of disease, nearly all patients with type I and 60% of patients with type II have some degree of retinopathy. |
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Duration of the diabetes: Increased risk of diabetic retinopathy |
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Diabetic control: The Diabetes Control and Complication Trail (DCCT) has clearly demonstrated that tighter control of blood sugar is associated with reduced incidence of diabetic retinopathy.[29] |
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Renal disease: Proteinuria is a good marker for the development of diabetic retinopathy; thus, patients with diabetic nephropathy should be observed more closely. |
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Systemic hypertension: Increased risk of retinopathy (diabetic retinopathy with superimposed hypertensive retinopathy). |
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Triglycerides and lipids: Normalization of lipid levels reduces retinal leakage and exudate deposition. |
Examination
Fundus evaluation under stereopsis and high magnification should be performed on every patient with diabetes, to assess DME and diabetic retinopathy. DME is defined as retinal thickening within two disc diameters of the center of the macula. Focal edema is associated with hard exudate rings resulting from leakage from microaneurysms. Diffuse edema results from breakdown of blood–retinal barrier with leakage from microaneurysms, retinal capillaries, and arterioles.
Clinically significant macular edema (CSME), as defined by the ETDRS (Table 54-4), exists when any of the following conditions exist:
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Retinal thickening within 500µm of the center of the fovea |
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2. |
Hard, yellow exudates within 500µm of the center of the fovea with adjacent retinal thickening |
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3. |
At least one disc area of retinal thickening, any part of which is within one disc diameter of the center of the fovea. |
Table 54-4 -- Clinically significant macular edema
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Definition |
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1. Retinal thickening at or within 500μm of the center of macula |
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2. Hard exudates at or within 500μm from the center of the macula with associated thickening of the adjacent retina |
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3. Retinal thickening at least 1 disc diameter in size, any part of which lies within 1 disc diameter of the center of the macula |
Visual acuity is an important parameter in following the progression of CSME, although it does not aid in the diagnosis of CSME because patients may have a visual acuity of 20/20 with co-existing CSME. The status of the posterior hyaloid, if detached, taut, thickened should also be noted.
Management
The goal of treatment is to decrease retinal edema which may result in visual gain in some patients. It is important to treat any pre-existing CSME prior to cataract surgery, as cataract surgery may aggravate the macular edema. Cataract surgery can be performed after the macular edema resolves. However, if there is significant cataract which precludes adequate examination or treatment with focal photocoagulation of macular edema, it may still be possible to obtain a pre-operative OCT to determine if central macular edema is present. If so, off-label pharmacotherapy with intravitreal triamcinolone or bevacizumab as per below can be initiated prior to cataract surgery. Pre- and postoperative management options for CSME are listed below and can be used simultaneously.
Systemic treatment
Hypertension, renal failure, congestive heart failure may worsen DME. Control of blood pressure and diuresis may decrease retinal capillary perfusion pressure with reduction of macular edema.
Photocoagulation
Macular photocoagulation is indicated for clinically significant macular edema and despite recent off-label use of pharmacotherapy remains the gold standard. Photocoagulation is performed for macular thickening, and not fluorescein angiographic leakage, which can often be seen without clinical evidence of thickening.
Photocoagulation is beneficial for both diffuse and focal retinal thickening, though the benefit appears greater for focal retinal thickening. The Early Treatment Diabetic Retinopathy Study group showed that macular photocoagulation is beneficial in treating macular edema and stabilizing the vision.[30] Photocoagulation decreases the risk of significant visual loss, defined as doubling of the visual angle, by about 50% at the end of 3 years. This benefit was seen regardless of the baseline vision or angiographic characteristics. However, these reports stress that laser treatment does not necessarily improve vision. Patients should be reviewed 2–3 months after macular photocoagulation to assess the need for additional macular laser if macular edema persists.
Pharmacologic treatment
Various steroids and anti-vascular endothelial growth factors (VEGF) are in clinical trials for use in DME. The anti-VEGF agents pegaptanib (Macugen) and ranibizumab (Lucentis), which are USFDA approved for the treatment of age-related macular degeneration, are under evaluation for the treatment of DME.[31,][32] Triamcinolone acetonide has been found to be useful in reducing macular edema, but the need for repeated injections and the risks of cataract and glaucoma have been concerning factors. However, the success of intravitreal triamcinolone acetonide as well as bevacizumab in reducing macular edema has been such that, despite the lack of data from randomized controlled clinical trials, off-label pharmacotherapy has been adopted by many retina specialists as a key element in the management of CSME. The Diabetic Retinopathy Clinical Research network has completed enrollment in a study that compares triamcinolone acetonide to laser photocoagulation for the treatment of CSME but as of this date no results are available. Other steroids that are being evaluated in clinical trials are delivered in drug-delivery implants in the hopes of providing more durable control. They include Posurdex, a dexamethasone based injectable biodegradable drug delivery system (Allergan Pharmaceuticals),[33] Medidur, a fluocinolone acetonide injectable non-biodegradable implant (Alimera Sciences),[34] and I-vation, a triamcinolone acetonide helical coil implant (Surmodics),[35] all of which are in phase 3 clinical trial testing for CSME.
Surgical management
Occasionally, the cause of CSME may be due to vitreomacular traction or taut posterior hyaloid. Evaluation with OCT is beneficial in this setting. When either condition is encountered, and is felt to be the main cause of vision loss, pars plana vitrectomy with removal of vitreo-retinal attachments and the posterior hyaloid is indicated.[36]
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Epiretinal membrane
In early stages, epiretinal membrane (ERM) may be asymptomatic, or it may create only a minor reduction in acuity. Its progression may cause metamorphopsia and lead to severe visual impairment. The incidence of mild ERM may almost double within 1 year of cataract surgery, although this may not cause significant visual impairment.[37]
Pathophysiology
ERM formation occurs as a result of retinal glial cell proliferation along the surface of the internal limiting membrane (ILM). Small, focal defects in the ILM allow these cells to “break through” to the retinal–vitreous interface and reproduce, creating a thin veil of tissue. ERMs have been found in association with retinal vascular diseases, retinal breaks and detachments, ocular trauma, uveitis, and following retinal cryopexy, laser photocoagulation, and intraocular surgery.[38] Often, the membranes occur idiopathically in patients over 50 years of age.[39]
Examination
The ophthalmoscopic picture of ERM varies from a fine, glistening membrane overlying the macula (cellophane maculopathy), to a thick opaque scar that obscures the underlying vasculature.
As the ERM progresses, traction at the macula creates a puckering effect that may be seen as retinal folds radiating outward from the macula. Vision in eyes with ERM may be reduced through various causes that may include full-thickness retinal folds, foveal ectopia, macular edema or a dense opaque membrane. Early identification of ERM requires careful inspection with a slit-lamp fundus lens (78diopter (D), 90D or Goldmann lens). Both OCT and fluorescein angiography are useful for confirming the presence of ERMs. Typical fluorescein patterns in ERM show “corkscrew” distortion and dragging of the retinal vessels at the posterior pole, with a characteristic diminishing of the foveal avascular zone. OCT findings including macular edema, ERM with macular pucker, vitreomacular traction, and cystic changes are readily visible on the OCT scans.
Management
Most patients suffer only a minimal reduction of acuity or slight metamorphopsia. Reassurance as to the nature of the disorder and follow-up periodically, using an Amsler grid for home monitoring of progression, is all that may be required. In severe cases, vision may drop to 20/50 or worse, and this may indicate the need for vitrectomy and surgical peeling of the membrane.
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Retinal vein occlusion
Signs and symptoms
The patient will usually be elderly, often with a history of systemic diseases such as diabetes and hypertension. The patient may be asymptomatic, but often will complain of sudden painless unilateral loss of vision and/or visual field, and may complain of a sudden onset of floating spots or flashing lights. Acuity may range anywhere from 20/20 to finger counting. If vision loss is severe, there may be a relative afferent pupillary defect.
Ophthalmoscopically, in central retinal vein occlusion (CRVO), there will be retinal edema, intraretinal hemorrhages in all four quadrants, disc swelling, cotton wool spots, and tortuous and dilated retinal veins. A hemi-central retinal vein occlusion will involve only the superior or inferior half of the retina. A branch retinal vein occlusion will present with findings in only one quadrant, usually supero-temporal, with the apex of the hemorrhages at an arteriovenous crossing.
The hemorrhaging may be so severe that all features of the underlying retina are obscured. Multiple cotton wool spots indicate retinal ischemia and capillary non-perfusion. Anterior and posterior segment neovascularization may occur later in the disease.
Pathophysiology
The etiology of central and hemi-central retinal vein occlusion is an obstruction of the central retinal vein, or one of the vein's two trunks, as it constricts through the lamina cribrosa.[40]The cause is obscure, but may involve abnormal blood flow or blood constituents, atherosclerosis, vessel anomalies or a combination of these factors.
The etiology of a branch retinal vein occlusion is an arteriolosclerotic arteriole crossing and constricting the underlying venule.[41] This will result in leakage from the capillary beds draining into these vessels. The capillary beds may be irreversibly damaged by this leakage, resulting in perpetual non-perfusion of the retinal tissue. If a significant area of capillary non-perfusion is present, then the occlusion is considered ischemic. Loss of retinal capillary beds with subsequent retinal non-perfusion will lead to retinal hypoxia and the subsequent release of vasoproliferative substance. Vasoproliferative factors will then stimulate the proliferation of neovascularization from nearby viable capillary beds.
In branch and hemi-central occlusions, neovascularization will most often form on the optic disc or adjacent retina and can lead to vitreous hemorrhage and tractional retinal detachment. In central retinal vein occlusions, the closest viable capillary network from which neovascularization will form is typically the posterior iris. This can lead to rubeosis irides and neovascular glaucoma. In all cases of venous occlusion, the main cause of vision impairment is macular edema, which is caused by the increased venous pressure. However, if retinal capillary non-perfusion involves the perifoveal region, then vision is dramatically and irreversibly lost.
Management
Fluorescein angiography, which was long held to be the gold standard in assessing retinal vascular disease, is not indicated initially, as the fresh hemorrhage will block transmission and reveal no useful information. Later in the course of the disease, it can provide useful information about retinal capillary perfusion and whether or not the occlusion is ischemic, and also about any areas of retinal neovascularization. OCT is useful in quantitating and monitoring the course of macular edema. Ischemic central retinal vein occlusions do not benefit from prophylactic panretinal photocoagulation and it is best to withhold this procedure until the patient develops frank neovascularization of the iris, disc or retina. These patients also do not benefit from grid photocoagulation for macular edema.[42] Intravitreal triamcinolone and anti-VEGF agents may be useful in treating the macular edema and improving the vision, although evidence from large prospective randomized studies is not available.
Patients need to be monitored monthly with serial ophthalmoscopy, fundus photography and gonioscopy until the neovascularization resolves. If the patient has a hemi-central or branch retinal vein occlusion and vision is below 20/40 due to macular edema, the patient may benefit from focal laser photocoagulation anywhere between three and 18 months after the occlusion's onset.[43] Since vein occlusions have an association with systemic disease, it is essential to have an internist evaluate the patient. Tests to be ordered include blood pressure, fasting blood glucose, lipid and cholesterol studies.
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Macular hole
Signs and symptoms
Idiopathic or senile macular holes are typically encountered in patients older than 60, and occur slightly more often in women than in men. Presenting symptoms include decreased central acuity, a central scotoma and/or metamorphopsia. The various stages of macular hole include: foveal detachments (stage I), partial-thickness holes (stage II), and full-thickness holes (stage III). A stage IV macular hole is an advanced full-thickness hole, with vitreous separation from the optic disc and macula.[44] Depending on the stage, vision may range from 20/20 to <20/400, although in full-thickness macular holes, the visual acuity is generally 20/80 to 20/200. Patients usually report blurring of central vision or metamorphopsia in one eye when they cover the other eye.
The best way to examine the macula is with a contact fundus lens. For suspected macular holes that appear equivocal, the Watzke-Allen test can be useful. A vertical beam of light is projected at the fovea, using a slit-lamp beam with a fundus lens or a direct ophthalmoscope. The patient is asked if the line is uniform or broken in the center. Patients with full-thickness macular hole will report a broken line. A full-thickness macular hole clinically appears as a round, brick-colored lesion in the center of the macula, usually one-third to two-thirds of a disc diameter. The surrounding retinal tissue appears gray and elevated, and often there are small yellow deposits within the hole (Klein's tags), reminiscent of drusen. Foveal detachments and partial-thickness holes do not appear red, but rather present as a loss of the foveolar depression with the development of a central yellow spot or ring. Stage II holes are accompanied by a red, crescent-shaped retinal break at the lesion's edge. OCT is the confirmatory test to be performed in patients with suspected macular hole. Fluorescein angiography reveals an RPE “window defect” with early-stage hyperfluorescence.
Pathophysiology
Controversy surrounds the etiology of idiopathic macular holes. Diverse mechanisms have been proposed, including systemic vascular disease, hormonal variations, cystic retinal degeneration, anterior vitreoretinal traction, and tangential vitreoretinal tractional forces.[45] Currently, the most widely held theory proposes that pre-foveal vitreal shrinkage induces tangential traction on the fovea, eventually promoting hole formation. As contraction ensues, the tangential tugging at the fovea induces a separation of the sensory retina from the underlying RPE. Ultimately, the sensory retina atrophies, forming a break and progressing to a full-thickness hole. Macular holes may also result from chronic macular edema, solar retinopathy and blunt ocular trauma.
Management
Untreated 50% of stage I holes will progress to stage II, and 70% of stage II holes will progress to stage III. Pars plana vitrectomy, excision of the attached cortical vitreous with or without peeling of the internal limiting membrane and fluid–gas exchange with perfluropropane is the standard of care. Candidates for surgical intervention usually have 20/50 visual acuity or worse. OCT is a useful guide to determine the dimensions of a full-thickness hole which can help guide in surgical decision making.
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Macular degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over the age of 50 years in developed countries.[46–48] Early manifestations of AMD include focal drusen associated with minor visual complaints, but the later stages of the disease result in severe vision loss. The nonexudative or dry form of AMD is approximately 10 times more prevalent than the exudative form, but the latter is the leading cause of blindness from AMD.
Examination of the other eye may give a very important clue if the fundus of the eye to be operated can not be visualized preoperatively.
Prevalence
The prevalence of exudative AMD in the Framingham Eye Study was 1.5%, while the dry type of AMD accounted for 90% of all cases.[49] The Beaver Dam Eye Study defined early age-related maculopathy (ARM) as the presence of any drusen (except for hard, distinct drusen) with degeneration of the retinal pigment epithelium (RPE) or increased pigment in the macular area. It defined late ARM or AMD as the presence of geographic atrophy or exudative disease or both. The prevalence of late ARM was 1.6% in the Beaver Dam eye study,[50] and exudative maculopathy in at least one eye was present in 1.2% of the population. The prevalence of late ARM was 7.1% in subjects older than 75 years.
Risk factors
Demographic factors
All studies indicate that both the prevalence and the incidence of all forms of AMD increase with age. The Framingham Study found a 17-fold increased risk of AMD when comparing the oldest to the youngest age group.[49] Several studies indicate a genetic factor in the pathogenesis of the disease.[51] Those examining the concordance of AMD in monozygotic and dizygotic twins strongly support the role of genetics in the pathogenesis of AMD.[52]
Lifestyle factors
Most of the epidemiological evidence indicates a strong positive association between dry and wet AMD with smoking.[53] Supplementation with zinc and vitamins A, C, and E helped prevent wet AMD as well as advance atrophic AMD in the Age-Related Eye Diseases Study (AREDS).[54]
Excessive exposure to light can damage the retina. In the Beaver Dam Eye Study, participants exposed to the summer sun for more than 5h a day during their teens, in their 30s, and at the baseline examination were at a higher risk of developing increased retinal pigmentation and early ARM by 10 years than those exposed less than 2h per day during the same periods.[55] The shorter wavelengths of light pose the greatest hazard to the retinal photoreceptors, because they contain more energy. Exposure to these wavelengths has been called the blue-light hazard, because they appear blue to the human eye. It has also been suggested that the removal of the natural lens, as in cataract surgery, should be followed by replacement with a tinted IOL to restore the eye's natural barrier to light radiation.[56] (See Chapter 41 for a full discussion of spectral factors and vision)
Cardiovascular factors
High cholesterol, especially HDL cholesterol[57,][58] and oxidized LDL,[59] as well as hypertension,[60,][61] have been associated with a higher incidence of AMD. In the Macular Photocoagulation Study, there was an increased risk of exudative AMD associated with hypertension in the second eye of individuals with exudative AMD in one eye at baseline.
Ocular risk factors
The Macular Photocoagulation Study group described the risk factors for a patient's developing choroidal neovascularization (CNV) in his fellow eye when his opposite eye already has CNV. They include five or more drusen, focal hyperpigmentation, one or more large drusen (>63µm), and systemic hypertension.[62] Based on the follow-up of patients with juxtafoveal CNV, the 5-year incidence rate for the development of CNV was 87% if all four risk factors were present. Lanchoney et al reported that the 10-year risk of developing CNV in patients with bilateral soft drusen ranged from 8.6% to 15.9%.[63] Hyperopia has a higher association with AMD, whereas darker irides may be protective against AMD.[64,][65]
Protective mechanisms in the retina and crystalline lens
Carotenoids, including the xanthophyllic yellow pigments lutein and zeaxanthin, protect the macula from damaging blue light because of their maximum absorption spectrum at the lower wavelengths. When molecules within the retinal pigment epithelium (RPE) absorb blue light, however, the formation of free radicals ensues, leading to cellular injury.[66] The crystalline lens is the major protective barrier to near-UV radiation (between 300 and 400nm). Yellowing of the natural crystalline lens results in a greater absorbance of light of lower wavelengths such as blue light.[67]
Data from the Framingham Eye Study showed that nuclear cataracts were associated with a slightly reduced incidence of mild-to-severe macular changes compared with cortical cataracts.[68] Recent analysis of data from the AREDS showed no correlation between cataract surgery and the development of advanced neovascular AMD, although there was a possible risk of advancing geographic atrophy.[69] In a subset analysis of patients in the AREDS who underwent cataract surgery, the risk for developing exudative (neovascular) AMD after cataract surgery was only 1% greater when compared with subjects who did not undergo cataract surgery, but the risk for developing advanced geographic atrophy was 47% greater in patients who underwent cataract surgery. Recently, Alcon Laboratories, Inc. (Fort Worth, TX), began marketing the Acrysof Natural lens, an IOL that blocks both UV radiation and blue light.[70] Researchers have demonstrated that yellow-tinted IOLs reduce the death of RPE laden with the lipofuscin fluorophore A2E.[71] Moreover, the incidence of CNV in patients with bilateral drusen and pigmentary changes was much higher in eyes that received untinted IOLs than in phakic fellow eyes.[72] However, the use of blue-blocking IOLs has been controversial. Blue-blocking IOLs may affect color and scotopic vision especially in the elderly,[73] but no studies to date have been conducted to prove this hypothesis.
Photodynamic therapy
In photodynamic therapy (PDT), tissues treated with photosensitizers (verteporfin) are exposed to low-intensity light exposure to produce a photochemical effect. It causes selective destruction of CNV with preservation of the overlying neurosensory retina (Table 54.5).
Table 54-5 -- Treatment options for choroidal neovascular membrane (CNVM) in exudative age-related macular degeneration
|
Lesion |
Treatment |
|
Extrafoveal |
Thermal laser |
|
Juxtafoveal |
Thermal laser, ranibizumab or bevacizumab, pegaptanib, or PDT (with or without steroid adjuvant |
|
Subfoveal, predominantly classic |
Ranibizumab, bevacizumab, PDT (with steroid), pegaptanib |
|
Subfoveal, minimally classic, less than 4 MPS disc area |
Ranibizumab, bevacizumab, PDT (with steroid), pegaptanib |
|
Subfoveal, minimally classic, greater than four MPS disc area |
Ranibizumab, bevacizumab, pegaptanib |
|
Subfoveal, occult only with no classic |
Ranibizumab, bevacizumab, PDT (with steroid), pegaptanib |
|
PDT: Photodynamic therapy; MPS: macular photocoagulation study |
The efficacy and safety of Verteporfin therapy were studied in the treatment of AMD with photodynamic therapy (TAP) investigation. In the total population, the treatment benefit was sustained at month 24, with fewer verteporfin-treated patients (47%) having moderate vision loss compared with patients given placebo (62%).[74]
The Verteporfin in Photodynamic Therapy (VIP) trial, another large-scale, double-masked, placebo-controlled, randomized clinical trial, investigated the efficacy of verteporfin therapy in a different group of patients from those in the TAP Investigation. The study mainly included patients with occult with no classic CNV with presumed recent disease progression, and patients with AMD who had classic CNV and visual acuity better than an approximate Snellen equivalent of 20/40.[75] At 24 months, the risk of moderate and severe vision loss was significantly reduced in verteporfin-treated patients compared with patients given placebo. The treatment benefit of verteporfin therapy was greater for patients with occult with no classic CNV who presented with either smaller lesions (=4 MPS disc areas), or lower levels of visual acuity (≤20/50−1 approximate Snellen equivalent). PDT helps prevent severe visual loss, but improvement of visual acuity is rare.
Pharmacologic intervention
The recent approval of ranibizumab (Lucentis, Genentech) as well as the off-label use of bevacizumab (Avastin, Genentech) has for the first time provided an effective treatment for choroidal neovascularization associated with AMD that results in improvement in vision in a significant number of patients. Pharmacotherapy not only avoids laser-induced damage to the overlying retina, but also may serve as either an adjunct or sole treatment of poorly defined lesions, occult lesions, and may prevent recurrences. At present the therapies are based on either inhibition of vascular endothelial growth factor (VEGF) or use of various formulations of steroids to control the inflammatory response associated with CNV.
Rosenfeld and colleagues published a case report in July 2005 describing encouraging results with off-label use of intravitreal bevacizumab (the monoclonal antibody to vascular endothelial growth factor, VEGF) for exudative AMD.[76] The suggestion of the potential clinical efficacy of intravitreal bevacizumab, coupled with the impressive results from two phase 3 clinical trials of intravitreal ranibizumab (the Fab fragment to the VEGF monoclonal antibody) in patients with choroidal neovascularization due to AMD had led to the widespread use of intravitreal bevacizumab for AMD.
Bevacizumab (Avastin™) is an anti-VEGF antibody approved by FDA in USA and Europe for use in treatment of metastatic colorectal cancers and is reported to bind to all known isoforms of VEGF. Spaide and colleagues reported a retrospective study of 266 patients treated with bevacizumab for ARMD and observed improvement in visual acuity, macular thickness.[77] No significant ocular or systemic side effects were observed.
Ranibizumab (Lucentis™) is a monoclonal antibody fragment against VEGF-A that has been affinity matured to provide stronger binding. In the MARINA study at 12 months, 94.6% of those given ranibizumab 0.5mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections.[78] Visual acuity improved by 15 or more letters in 33.8% of the 0.5mg group, as compared with 5.0% of the sham-injection group. Mean increases in visual acuity was 7.2 letters in the 0.5mg group, as compared with a decrease of 10.4 letters in the sham-injection group. The benefit in visual acuity was maintained at 24 months.
Pegaptanib sodium (Macugenä, anti-VEGF165 aptamer) is an FDA approved anti-VEGF agent. Aptamers are oligonucleotides that are designed to bind to specific molecular targets. This agent is a polyethylene glycol (PEG)-conjugated oligonucleotide that binds specifically to the VEGF165 isoform.[79] Pegaptanib is administered intravitreally every 6 weeks. The 2-year efficacy results of the VEGF inhibition study in ocular neovascularization (V.I.S.I.O.N.) trial have been published recently,[80] and has shown that patients who continued to receive pegaptanib injections were less likely to lose = 15 letters than those who discontinued treatment at 1 year (P<0.05). The number of patients who gained more than three lines of visual acuity at 54 weeks was not impressive.
It has been demonstrated that intravitreal triamcinolone acetonide could re-establish the blood–retinal barrier and down-regulate the inflammatory markers.[81] However, Triamcinolone Acetonide seems to be ineffective as monotherapy in the treatment of CNV.[82] It may be potentially effective as an adjunct to PDT,[83,][84] but it is associated to numerous side effects, such as elevated intraocular pressure (25–30%), cataract formation or progression (25–75%), infectious (0.87% range 0–2.3%) or presumed noninfectious endophthalmitis.[85,][86]
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Photic injury
Photic injury of the macula is an uncommon condition and the exact incidence is not known. Clinical features include blurring of vision, paracentral scotoma and a round to oval hypopigmented lesion at the macula due to RPE atrophy. Although there is no known treatment, it can be prevented by using the minimum possible intensity of illumination during surgery, especially after placing the IOL, and using a filter to block the central light from the microscope whenever possible.
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Conclusions
Various macular disorders may affect complete recovery of vision after cataract surgery. All patients planned for cataract surgery should have preoperative evaluation of the fundus. This will not only help in prognosticating as well as adequate management of the condition prior to cataract surgery when possible, but also give the patient a realistic expectation of postoperative recovery of vision. All patients with poor postoperative vision should have a retinal evaluation to rule out any macular causes of poor postoperative vision. Many of the macular diseases can be treated and may help in the visual rehabilitation of the patient.
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