Nada S. Jabbur
Sharon D. Solomon*
*In previous editions, Andrew Schachat, MD, contributed to this chapter.
Refractive Errors and Corrective Surgery
Anatomy and Types of Refractive Errors
Refractive errors of the eye include myopia, hyperopia and astigmatism. A myopic eye is nearsighted and needs diverging (minus) corrective lenses to be able to see at distance. A hyperopic eye is weaker for near vision and can see better at distance when uncorrected; it requires converging (plus) lenses to improve vision. Both myopia and hyperopia may be congenital; the curvature of the cornea and anteroposterior length of the eyeball often explain the amount and type of refractive error (e.g., a longer than average eye will be more myopic). Acquired myopia may be due to progression of a cataract or elongation of the eye after retinal detachment repair. Acquired hyperopia may be due to latent hyperopia that becomes manifest later in adulthood, or may be related to swelling in the retina. Astigmatism is generally caused by irregularities of the cornea or crystalline lens and causes distortion of vision and difficulty with night vision when uncorrected. It is rarely an isolated condition and is generally associated with myopia or hyperopia. Presbyopia is an age-related condition that affects everyone, in which the crystalline lens progressively loses its elasticity or ability to accommodate. Individuals approaching the age of 40 may begin to depend on magnifying glasses to improve their near vision activities, including reading. Those individuals who are hyperopic will notice their presbyopia before the age of 40, while those who are nearsighted can use their myopia to read without glasses.
The cornea is the transparent avascular anterior portion of the eye, typically 540 microns thick centrally and closer to 1,000 microns in the periphery. The cornea contributes 43.25 diopters or 74% of the focusing power of the eye; in addition it is usually responsible for most astigmatism in the eye. The remaining focusing power of the eye is provided by the lens. When patients undergo cataract surgery, refractive surgery is being performed and the power of the monofocal intraocular lens can be chosen to improve distance and/or near vision. When there is no abnormality of the lens, and in most young patients, refractive surgery may performed on the cornea to improve vision, if a
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patient is found to be a good candidate for such an elective surgery.
Refractive Surgery Techniques
Radial Keratotomy
In the 1980s, radial keratotomy (RK) was a popular incisional surgery. This involved making peripheral pupil sparing radial corneal incisions (typically 4 to 8) to flatten the central curvature of the cornea, thereby reducing myopia. This was often associated with smaller peripheral arcuate corneal incisions to treat any associated astigmatism. This type of surgery was often successful initially, but a long-term followup study revealed that the stability of the surgery was lacking and that there was a tendency for a hyperopic shift because of a continued long term flattening effect, especially in those who were initially more myopic (1). In addition, some patients had night vision disturbances because of the proximity of the incisions to the physiologically dilated pupil in dim light conditions. Finally, patients who have undergone RK are prone to traumatic rupture of the globe through the incisions when subject to trauma to the face and eye.
Excimer Laser and Wavefront Technology
RK was superseded by excimer laser vision correction when the U.S. Food and Drug Administration (FDA) approved the first such laser to reshape the cornea and treat myopia in 1995. Since then, excimer lasers have been developed with newer software and features and are now employed in the treatment of moderate farsightedness, nearsightedness, and mixed astigmatism (2,3). Excimer lasers work in the ultraviolet range and ablate corneal tissue, under topical anesthesia (numbing drops), by breaking molecular bonds of the corneal molecules that they are focused on. Myopic ablations thin the cornea centrally and hyperopic revisions are midperipheral ablations that flatten the cornea in a ring fashion, thereby steepening the central cornea. Conventional excimer lasers correct the spherical as well as the astigmatic component of a refraction; these are known as lower order aberrations. With the advent of wavefront technology, adapted from astronomy, higher order aberrations or irregularities of the eye can be treated to improve the quality of vision, especially under low light conditions. This is especially beneficial in persons with larger pupils, in dim light, or low contrast conditions. An image of the eye, measuring both higher and lower order aberrations, is taken and entered digitally into the computer of the laser. Customized algorithms direct the laser surgery, but require a deeper corneal ablation and may not be an option in patients with thinner central corneas.
Surface Ablations: Prk, Lasik, Lasek
Excimer lasers reshape the cornea superficially in a procedure known as surface ablation. In surface ablations, the epithelial layer of the cornea is removed so that the superficial stroma can be exposed and ablated to achieve the desired refraction. When the epithelium is discarded prior to the stromal ablation, the procedure is known as photorefractive keratectomy (PRK), and the patient will require a bandage contact lens for the first week while healing occurs. When there is an attempt to preserve the epithelium, this is known as a lamellar surgery, in which a superficial corneal flap is created. In LASIK (laser-assisted in situ keratomileusis), the flap is composed of epithelium and a thin layer of the underlying stroma. LASEK, or e-LASIK, is a modification of this technique in which the flap consists only of epithelium. Surface ablations are typically chosen when patients have thinner corneas, or have problems with the corneal epithelium. Whether to use PRK or LASIK techniques is determined by the ophthalmologist.
LASIK is currently the most common refractive procedure performed. It has the dual advantage of a shorter recovery period and reduced perioperative discomfort. The energy of the excimer laser is typically applied to the superficial area of the stroma after creating a 100- to 160-micron-deep anterior corneal flap (this typically includes approximately 50 microns of epithelium and the remainder is superficial stromal tissue). The corneal flaps are created using a microkeratome, a mechanical device which cuts the cornea using a blade, or by using an infrared femtosecond laser, which gives a more precise thickness of flap and has a reduced chance of complications such as an incomplete or very thin flap (4).
Correction of Presbyopia
There is no corneal procedure available in the United States that can improve reading vision without affecting distance acuity in the same eye. Monovision is an approach in which the dominant eye is corrected for distance vision and the non-dominant eye is corrected for improved near vision. This technique may be tried first with contact lenses and when successful, can be adapted surgically. Conductive keratoplasty (CK) is a surgical technique that can improve presbyopia temporarily. It uses radiofrequency energy applied to the periphery of the cornea, where consequent shrinking of the corneal tissue leads to steepening of the central cornea. Patients may need multiple enhancements of the surgery as the effect regresses, and some patients have induced astigmatism (5). Multi-focal intraocular lenses at the time of cataract surgery are being introduced to improve distance, intermediate, and near vision (presbyopia). These lenses are not yet the standard of care for intraocular lens implantation, and 5%
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of patients may experience severe halos at night. In the future, multifocal corneal ablations may allow simultaneous bilateral improvement of distance vision and presbyopia.
Patient Selection and Evaluation
In spite of multiple advances in technology, some patients are not candidates for excimer laser vision correction. Contraindications to laser vision correction may be elicited upon a review of systems and a thorough ophthalmologic exam. Patients in whom refractive surgery is not indicated include those with unstable vision, dry eyes, thin corneas, corneal scars, and autoimmune diseases, as well as patients taking amiodarone or isotretinoin (Accutane) or who are pregnant or nursing. Keratoconus, a progressive condition which causes steepening of the cornea is another contraindication to refractive surgery; early forms are diagnosed by mapping of the corneal surface, a procedure known as corneal topography. Patients with extreme degrees of myopia and hyperopia also are not good candidates for laser surgery. Some highly myopic patients may be candidates for an intraocular procedure in which an intraocular lens is inserted in addition to the normal crystalline lens of the eye (phakic intraocular lens [IOL]).
Patients interested in being evaluated for refractive surgery should not wear contact lenses for at least 2 to 3 weeks prior to the evaluation and surgery. Contact lens wear can cause a reversible change in the cornea, known as corneal warpage, that needs to be differentiated from an early form of keratoconus.
Patient Experience and Outcomes
Corneal refractive surgery is performed under topical anesthesia. Some patients require an anxiolytic agent since patient cooperation for laser centration is essential. Patients will experience mild discomfort 30 minutes after the numbing effect wears off and are advised to refrain from work the rest of the day and avoid activities that increase the risk of flap dislocation (e.g., contact sports) or infection (e.g., no swimming for a month). Topical medications including an antibiotic and an anti-inflammatory agent are given for a short period of time. Patients who undergo lamellar surgeries such as LASIK tend to have a quicker recovery, and more than 80% of patients find that they may drive the following day without distance glasses. Other patients who undergo surface ablations may take 1 to 2 weeks to recover. Most patients will experience mildly dry eyes in the first month postoperatively. Patients with a larger refractive error to be corrected may experience more fluctuations in comfort and vision postoperatively; this is discussed on an individual basis with the ophthalmologist. Patients in the presbyopic age group are warned about needing near vision aids.
Approximately 90% of patients obtain vision in the 20/25 to 20/20 range and more than 95% of patients obtain 20/40 or good driving vision. The ophthalmologist should discuss these likely outcomes with every patient, as well as the influence of important variables such as the age of the patient and any impairments to wound healing, the amount and type of refractive error, and the proposed surgical technique and the surgeon's experience. In the cases where the desired outcome is not obtained and if there are no contraindications, the surgeon may recommend an enhancement procedure. This is typically not done within 3 months from the initial surgery, since stability of vision is important for a good outcome. Patients who are good candidates for laser vision correction may retain their corrected vision for life (if there are no other ocular changes as they age, e.g., cataract).
Complications of Refractive Surgery
Complications are reduced when patients are screened carefully for corrective surgery, but may still occur in 5% or less. Complications of initial or enhancement surgery include fluctuations of vision and corneal ectasia, dry eyes, inflammation under the flap created in LASIK, infection, flap folds or striae, epithelial downgrowth (cells growing under the flap), flap dislocation after trauma, and permanent qualitative or quantitative changes in vision.
Cataracts
A cataract is an opacification of the lens of the eye. Approximately 95% of people older than 60 years of age have some opacification of the lens, but most often these opacities are of no visual importance. A significant cataract results in interference with visual acuity and daily activities. According to the World Health Organization (WHO), cataracts are the leading cause of blindness and visual impairment in the world. The incidence of diminished visual acuity from cataracts increases steadily after 50 years, reaching almost 50% in people older than 75 years of age. Cataracts are usually bilateral, and the progression is slow and may vary between eyes. The rate of progression is not individually predictable, and there is no treatment that retards the progression. When the cataract is diagnosed, prescribing new glasses may help improve the vision and when it is advanced, the only therapy is surgery.
Anatomy and Physiology
The lens is located immediately posterior to the iris and is suspended there by radially attached zonular fibers from the ciliary body. It is a biconvex, transparent structure with an elastic capsule whose shape is altered by ciliary body contraction, permitting images to be brought into sharp
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focus on the retina. The lens is acellular and avascular and lacks innervation. Nourishment is provided from the surrounding aqueous and vitreous humor, and metabolic byproducts are removed by diffusion into the aqueous humor. The continued transparency of the lens requires the active metabolism of the elastic capsular epithelium, so any insult to the epithelium may result in lenticular opacities. New lenticular fibers are produced throughout life, and, because none are lost, increasing density of the fibers of the lens develops with age, which also contributes to cataract formation.
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TABLE 107.1 Causes of Cataracts |
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Causes
There are many causes of cataracts (Table 107.1). Although senescent cataracts—the result of the aging process just described—account for the vast majority of cataracts, the generalist occasionally sees patients with congenital or traumatic lens opacities. The mechanism of opacification in all of these instances is thought to be direct trauma or interference with metabolic activity of the capsular epithelium and with continued fiber production.
Many types of cataracts have a distinctive appearance. The ophthalmologist may therefore suggest the possibility of an underlying disorder such as myotonic dystrophy (iridescent spots) or Wilson disease (sunflower cataract). Steroid therapy, diabetes mellitus and radiation treatment are typically associated with posterior subcapsular cataracts, although these may also be idiopathic or related to numerous other conditions. Age-related cataract is significantly associated with dermatologic abnormalities and their treatment (e.g., steroid use).
Symptoms and Examination
The primary symptom of cataract is impaired vision; usually patients describe a constant fog over the eye. They may also see rings or halos around lights and objects. Objects appear more blue and yellow in color. With immature cataract formation, distant vision often is impaired to a greater extent than is near vision.
The location of the cataract within the lens determines the extent of the visual loss. Central opacities cause noticeable loss of vision and a distinct glare when the patient is in bright light. They also cause a myopic shift in the lens, thus worsening distance vision and sometimes improving near vision. Bright light constricts the pupil so that the dense portion of the lens occludes and diffuses light. Therefore the patient who has central opacities finds that vision is better in low light, when the pupil is widely dilated. In selected cases, use of dilating drops (mydriatics) is helpful and delays the need for surgery. Because there may be contraindications to the use of mydriatics (e.g., narrow-angle glaucoma attacks may be precipitated), it is best to rely on an ophthalmologist to prescribe them. Peripheral opacities cause noticeable loss of vision only late in the development of the cataract.
Cataracts are easily identified by illuminating the lens with a slit lamp, but most general physicians find that they can see a cataract easily through a moderately plus lens (such as a +2 or +3 lens on the dial) of the direct ophthalmoscope. Visual acuity should be tested in both eyes if cataracts are suspected. If the patient describes any impairment in visual acuity, the patient should be referred to an ophthalmologist. In adults, screening for cataracts is best done by a visual acuity examination with use of a Snellen chart. Additionally, other testing such as a brightness acuity test (BAT) evaluates a patient's vision with bright lights simulating situations such as night driving.
Cataract Surgery
Indications
Before surgery is indicated, new glasses for the progressive myopia associated with many nuclear cataracts may improve the vision of patients with cataracts. Also, visual aids, such as magnifying lenses and large-print materials, may be helpful. The decision to remove a cataract is determined by the visual needs of the patient, the degree of the cataract, and the presence of any other ocular abnormalities (e.g., the need to follow closely retinal pathology especially if laser treatment is required). The ophthalmologist performs a complete ocular assessment before advising the patient about surgery.
Each patient must determine his or her own visual needs based on daily activities. The ability to read, drive, cross streets safely, and perform daily routines is clearly of prime importance. For example, a patient usually requires visual acuity of at least 20/40 in the better eye to operate a motor vehicle safely or to continue moderately active daily life. Blurred vision has an important impact on
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a patient's functioning and well-being. Because the impact of blurred vision is so significant and the success rate for cataract surgery so high, it is not surprising how often the procedure is performed.
Surgery
Cataract surgery should be performed after thoughtful deliberation, keeping in mind that complications occur occasionally. For patients with other health problems, the generalist and the ophthalmologist should plan cataract surgery together. Cataract extraction is an elective procedure, and the patient should be in the best possible condition at the time of operation.
Approximately 2 million cataract extractions are performed yearly on Medicare beneficiaries, and cataract surgery is the most common major surgical procedure performed in the elderly in this country. Surgery involves removal of the opacified lens from the eye. Prior to 1990, the overwhelming majority of cataract surgeries were extracapsular (i.e., the posterior capsule of the lens was left intact) and used microsurgical techniques. Since then, small wound cataract surgery or phacoemulsification have greatly improved the immediate outcome of surgery and have significantly shortened the period of disability. In the small wound technique, a phacoemulsification instrument tip (2- to 3-mm wide) is introduced into the eye and emulsifies the cataract using a small vibrating piezo electrode. Cold fluid irrigates the eye to prevent any thermal injury and helps to aspirate the tiny pieces out of the eye.
Both eyes usually require an operation, but normally only one lens is extracted at a time, so that the patient has vision on the nonoperated side when the eye that has been operated on is covered by a patch for a few days after surgery. Some surgeons attempt to avoid the use of a patch, and so-called no-stitch surgery with very small incisions is popular. There is no definitive evidence that any particular extracapsular surgical approach is better than any other. For patients with bilateral cataracts, the second procedure is usually performed as early as a week after the first; once the visual result is known in the first eye.
Preoperative Evaluation
The current standard of care is a careful history and physical examination, but few if any laboratory investigations are required. A randomized trial showed that routine preoperative testing before cataract surgery did not reduce the incidence of perioperative medical complications (6). The testing evaluated in this study included electrocardiogram (ECG), complete blood count (CBC), and levels of electrolytes, urea, nitrogen, creatinine, and glucose
The history should elicit clues about bleeding tendencies. Patients who take anticoagulants, such as aspirin or aspirin-containing products or oral warfarin, should inform their ophthalmologists about these medications. If possible, aspirin should be discontinued for 7 to 14 days before the surgery, although some surgeons do not stop aspirin, given the low risk of bleeding with small-incision surgery. When anticoagulants cannot be discontinued, the surgeon will elect a clear corneal avascular incision. In adult patients, the surgery is often performed using topical and intraocular preservative-free lidocaine, supplemented in many patients with a periocular anesthetic.
The ability of the patient to lie flat should be assessed. If a patient cannot lie flat, the neck can be hyperextended and a temporal approach to the eye may be more helpful, especially if the patient has a prominent supraorbital rim. Additional support can be placed under the head and a mild Trendelenburg position can help patients with stiff necks (e.g., ankylosing spondylitis or rheumatoid arthritis). Diabetes mellitus and hypertension, if present, should be controlled. A recent myocardial infarction (within 6 months) should delay surgery.
Patient Experience
Cataract surgery is performed on an outpatient basis. After discharge from the surgical unit a patient must restrict his or her activities for several weeks to minimize the frequency of complications, although with small incisions and the newest microsurgical techniques the rehabilitation period is shorter. There are no permanent restrictions; however, caution with steps or when walking and working with machinery may be necessary if perception is seriously altered by an imbalance between the two eyes, especially while waiting to have the other eye surgery performed. Postoperative appointments with the ophthalmologist are typically on the first day after surgery, and 1 week and 4 to 6 weeks postoperatively. The primary care clinician should be aware of the following postoperative problems.
Complications
Complications may occur intraoperatively or in the early or late postoperative period. The overall rate of any complication is approximately 5% of cataract operations, and is also related to the surgeon's experience and to the patient's preexisting eye condition; in only 1 in every 5,000 eyes operated is eyesight lost because of complications.
Inflammation and Infection
All postoperative patients have some degree of traumatic intraocular inflammation. This is usually controlled effectively with topical corticosteroids. Bacterial intraocular infection, endophthalmitis, is a dangerous postoperative inflammation that must be recognized early before it devastates the eye. If a patient complains of decreased vision, pain, discharge, and redness, endophthalmitis may be present and the patient should be seen immediately by
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an ophthalmologist. Most infections occur within a few days after surgery; however, an operated eye is predisposed to involvement from systemic infection, so a patient with an acute red eye occurring at any time after eye surgery should be seen urgently by an ophthalmologist. Low-grade chronic inflammation is common after cataract surgery, and resultant macular edema is one of the most common causes of postoperative visual loss.
Hemorrhage
The sudden occurrence of hemorrhage in the uveal tract (the iris, the ciliary body, and the choroid) can adversely influence the final visual outcome. Although this complication is usually seen intraoperatively, it may rarely occur postoperatively. It is recognized usually by painless but precipitous change in visual acuity. Postoperative hemorrhage from the iris or an inadequately closed corneoscleral wound is more common than is vitreous hemorrhage. In all instances of hemorrhage, urgent referral to an ophthalmologist is indicated. Although anticoagulation is not an absolute contraindication to cataract extraction, it probably does increase the risk of hemorrhage. For this reason, anticoagulants and antiplatelet agents such as aspirin are stopped, if possible, before and for 1 to 2 weeks after surgery.
Retinal Detachment
The incidence of retinal detachment after cataract surgery is approximately 1% to 3%. Retinal detachment may present as suddenly decreased visual acuity, flashes of light, and the development of floaters, veils, or curtains in the visual field. Patients with symptoms of retinal detachment should be seen immediately by an ophthalmologist so that surgical reattachment of the retina may be accomplished.
Glaucoma
A rise in intraocular pressure may occur in the first few days after surgery and may present as blurred vision, a painful red eye and often nausea and vomiting. This may be due to increased inflammation or retained viscoelastic material used during surgery. Glaucoma may also appear as late as 1 to 2 years after surgery in 0.6% to 5% of patients, depending on the type of surgery. This may also result in decreased visual acuity caused by corneal edema.
Delayed Opacification of the Posterior Capsule
Approximately 20% to 50% of patients experience a gradual decrease in vision in the first few years after cataract surgery because of opacification of the posterior lens capsule. This complication can be treated effectively by a special laser instrument (yttrium-aluminum-garnet [YAG]) that opens the posterior capsule without the need for intraocular surgery. The procedure is painless and is performed in the office. However, it is performed only when the potential for visual improvement outweighs the risks, because retinal detachment and perhaps macular edema become somewhat more common (7).
Optical Correction after Cataract Extraction
The removal of a cataract improves light transmission to the retina, but vision remains blurred without corrective lenses. Three types of lenses are used: aphakic spectacles, contact lenses, and intraocular lenses. The last option is now the norm. Aphakic spectacles are discussed mainly for historical reasons. Contact lenses are used more than aphakic spectacles, but almost all patients, even children, are now candidates for intraocular lenses.
Aphakic spectacles are rarely used today. With aphakic spectacles there is a narrower field of vision, as well as considerable distortion of images, which appear rounded and three to five times larger than when the lens is present in the eye. Peripheral ring scotomata and loss of some depth perception also occur. The use of contact lenses after cataract extraction provides considerable improvement over spectacles. There is substantial distortion reduction and expansion of the field of vision. However, the patient must be motivated to use contact lenses and most patients as they get older become contact lens–intolerant due to dry eyes.
Because of the visual handicap experienced after cataract extraction, plastic intraocular lenses are inserted at the time of surgery in 95% or more of patients undergoing cataract extraction. Long-term survival of these inert prostheses is very good. The insertion of intraocular implants adds a few minutes to the operative time beyond that required for lens extraction. If the eye is otherwise healthy, more than 90% of patients undergoing this technique experience an improvement in vision to 20/40 or better. New multifocal lenses and accommodative intraocular lenses (to replace bifocals) have been approved by the FDA. Patients who drive at night frequently, who have one functional eye, or who have severe astigmatism are not good candidates for these lenses.
Age-Related Macular Degeneration
The macula is the anatomic center of the retina, defined by its unique cellular configuration, pigment content, and ability to provide fine visual acuity for reading. Normal aging results in numerous changes in the macula, many of which are clinically undetectable. However, as degeneration of the outer retinal layers continues to progress, central vision loss may occur. This condition is known as age-related macular degeneration (AMD).
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Epidemiology
AMD is the leading cause of severe loss of central visual acuity in people older than 65 years of age in the United States. The prevalence is strongly correlated with age, with 30% of adults age 75 years or older already affected with early AMD, and another 28% predicted to develop it over the next 5 years (8). While the occurrence of AMD increase with advancing age, a number of other risk factors are associated with this disorder. AMD is much more prevalent in populations of European descent, particularly in those with fair skin and light-colored irides (9). Studies of monozygotic twins have shown markedly similar incidences of AMD prevalence and progression, suggestive of a genetic component (10). Tobacco use has been associated with an increased risk for the development of AMD in many population-based studies, with susceptible individuals developing the disease 5 to 10 years earlier than their nonsmoking counterparts (11). Systemic hypertension has also been strongly correlated with the development of AMD (12). Although excessive exposure to light can damage the retina through the formation of reactive oxygen intermediates, clinical assessment of this potentially important factor is limited by the difficulty of quantifying light exposure over a lifetime. Thus, there are conflicting studies on the association of ultraviolet light and the development of AMD in susceptible individuals.
Clinical Features
The clinical hallmark of AMD is the presence of drusen, which are discrete, dull yellow deposits located in the outer retina and typically confined to the macula. Many people older than the age of 50 have some drusen. Because drusen do not always affect the function of overlying photoreceptors, not all patients with drusen develop visual symptoms. For this reason, a classification system for AMD has been developed, from population-based studies, that characterizes the number, size, and quality of drusen and their associated features. These features are predictive of an individual's risk for advanced disease and severe vision loss.
Drusen are classified morphologically as either hard (discrete, well-demarcated boundaries) or soft (amorphous, poorly demarcated boundaries). Small drusen are difficult to see with the direct ophthalmoscope, but larger or soft drusen should be apparent. Hard drusen (Fig. 107.1, see Color Plate section) are typically less than 63 µm in diameter. Patients with small numbers of hard drusen are considered to be at low-risk for the progression of AMD. Numerous hard drusen, soft drusen, especially when confluent, and intermediate size (≥63 µm) and large size drusen (≥125 µm) are independent risk factors for vision loss from AMD (Fig. 107.2, see Color Plate section).
Non-neovascular AMD (referred to commonly as dry AMD), the more common form of the disease, is less likely to account for severe vision loss in those affected. It is characterized by the presence of drusen with varying degrees of pigmentary changes and atrophy of the outer retina. The presence of drusen may lead to attenuation or atrophy of the outer layer of the retina known as the retinal pigment epithelium (RPE). Geographic atrophy of the RPE occurs when this attenuation covers a contiguous area and is associated with overlying photoreceptor loss. Consequently, geographic atrophy in AMD may be associated with severe visual loss depending on its extent and location relative to the fovea, the anatomic center of the macula (Fig. 107.3, see Color Plate section). As atrophy develops, other abnormalities of the RPE may occur. Pigment may migrate from the RPE layer to the inner photoreceptor layer, resulting in focal clumps of hyperpigmentation. Pigmentary alteration, in association with intermediate and large-sized drusen, is a risk factor for progression of the nonneovascular form of AMD.
Neovascular AMD (referred to commonly as wet AMD) is characterized by the growth of new blood vessels from the choroid through disturbances in Bruch membrane into the subretinal or sub-RPE space. These abnormal subretinal blood vessels form a fibrovascular network, known as choroidal neovascularization (CNV), that leaks, disturbing the integrity and function of the regional photoreceptors. The patient may present with clinically evident macular subretinal fluid, subretinal hemorrhage, and/or subretinal lipid (Fig. 107.4, see Color Plate section), signifying deterioration from the previous, often visually stable, non-neovascular state and heralding the onset of severe vision loss.
Often, the CNV itself is not directly visible on examination and must be diagnosed by a technique known as fluorescein angiography. During this procedure, fluorescein dye is injected intravenously in the antecubital fossa. Within 10 to 20 seconds, the dye can be photographed traversing the normal retinal vessels and accumulating and then leaking from the abnormal choroidal neovascularization (Fig. 107.5).
The fluorescein angiographic leakage patterns of CNV are classified as either classic or occult. Hyperfluorescence from classic CNV tends to occur early in the course of the fluorescein study, typically by 50 seconds, and is usually well-defined with progressive leakage that increases in intensity and extent (Fig. 107.6). Occult CNV is characterized angiographically by poorly-defined stippled hyperfluorescence that develops late in the course of the study (Fig. 107.7). Characterizing the type of CNV that is the source of subretinal leakage is important in determining patient prognosis. Occult choroidal neovascularization tends to be more indolent and less often associated with rapid, severe vision loss compared to its classic CNV counterpart. Approximately 30% of patients with occult leakage may maintain vision and remain relatively clinically stable for a period of months without treatment. However, occult CNV
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may deteriorate and even decompensate into classic CNV, which is typically much more aggressive, resulting in a more precipitous clinical and visual decline.
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FIGURE 107.5. Fluorescein angiogram of the same eye as in Fig. 107.4. The black arrow points to an area of hyperfluorescence that represents CNV, confirming the diagnosis of neovascular AMD. The adjacent blocked fluorescence is from the subretinal hemorrhage seen in the previous photograph. |
Natural History and Prevention
The probability of progression of AMD depends on the clinical morphology at baseline. The Age-Related Eye Disease Study (AREDS) followed over 3,600 participants with various stages of AMD for more than 6 years. It was observed that participants with extensive small drusen, pigmentary abnormalities, or at least one intermediate size druse in the macula had only a 1.3% probability of progression to advanced AMD by 5 years. The 5-year estimated proba-bility of progression to advanced AMD was 18% in an eye with extensive intermediate drusen, large drusen, or noncentral geographic atrophy that was not beneath the foveal center. Participants in AREDS who already had advanced AMD in one eye or vision loss due to nonadvanced AMD in one eye had a 43% probability of progression to advanced AMD in the fellow eye at 5 years (13). In addition to characterizing the natural history of AMD, AREDS was a landmark controlled, clinical trial that demonstrated that micronutrient therapy, in the form of antioxidants plus zinc, may delay progression to advanced AMD and concomitant vision loss. Patients in AREDS with high-risk non-neovascular features, including extensive intermediate drusen, large drusen, noncentral geographic atrophy, or already advanced AMD in one eye who were randomized to oral antioxidants plus zinc, had as much as a 25% relative risk reduction in progression to advanced AMD in the fellow eye. Absolute benefits were modest; the estimated probability of significant visual loss at 5 years was 29% with placebo and 20% with antioxidants and zinc (14). The antioxidants (vitamin C 500 mg, vitamin E 400 international units, and β-carotene 15 mg) plus zinc (80 mg) are available in several commercially produced over-the-counter (OTC) supplements. Copper (2 mg) is added to the supplement to reduce the theoretical risk of zinc-induced copper deficiency anemia. Other potential adverse effects may include increased risk of urinary tract infection and prostatic hyperplasia in men and stress incontinence in women. Since previous studies have shown that β-carotene may increase lung cancer incidence and
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mortality in smokers, it may be advisable for smokers to avoid this combination of supplements.
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FIGURE 107.6. This fluorescein frame at 28.1 seconds shows early hyperfluorescence that is well-defined, indicative of classic CNV. The white arrow points to filling of the CNV itself with the fluorescein dye. The black arrow shows surrounding blocked fluorescence that could represent hemorrhage. |
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FIGURE 107.7. This fluorescein frame at 315.7 seconds shows intense hyperfluorescence in the inferior macula (white arrow) that may represent classic CNV that is actively leaking. The more superior speckled hyperfluorescence (black arrows) represents poorly defined late leakage consistent with occult CNV. |
A more recent epidemiologic study in a large cohort of persons age 55 or older in the Netherlands also showed that a high dietary intake of β-carotene, vitamins C and E, and zinc was associated with a 35% reduction in the incidence of AMD (15). Ophthalmologists generally counsel their patients to discuss micronutrient therapy with their primary care provider. Patients with no clinical features suggestive of AMD or with only small drusen in the macula have a low risk of progression to advanced disease and vision loss and have not been shown to derive increased benefit from micronutrient supplementation.
Adult patients older than the age of 55 years should have a dilated examination by an ophthalmologist to ascertain their risk of developing advanced AMD. Those with high-risk non-neovascular features should consider micronutrient supplementation as recommended by their retina specialist and approved by their internist. Patients should also be instructed how to monitor their vision so that they can alert their ophthalmologist immediately should they develop a central decrease in vision or central distortion of vision in one eye.
Treatment
Interventional therapies are available for patients with neovascular AMD. The Macular Photocoagulation Study (MPS) compared the benefit of thermal laser photocoagulation with that of no treatment for patients with well-defined choroidal neovascularization that was extrafoveal or outside the foveal center. After 3.5 years of followup, 62% of untreated patients had a loss of six or more lines of vision, as measured on a Snellen visual acuity chart, compared with 47% of treated patients (16). Subsequent investigations extended the treatment recommendations to include neovascular lesions closer to the foveal center, or juxtafoveal lesions, as well as subfoveal lesions. Even with this new treatment approach, only 10% of patients with neovascular AMD met the strict morphologic criteria that predicted treatment benefit. Since the thermal laser destroys not only the choroidal neovascular vessels that cause central vision loss but also the overlying healthy retina, it leaves a resultant blank spot in the area of treatment, which itself often results in decreased vision. While thermal laser photocoagulation is still the preferred treatment for well-defined extrafoveal and juxtafoveal CNV lesions, newer options for the treatment of subfoveal neovascular AMD have been developed.
Photodynamic therapy (PDT) with verteporfin (Visudyne) is a two-step process that offers a chance for clinical and visual stabilization in patients with subfoveal CNV. First, a photosensitizing drug, verteporfin, is administered intravenously and allowed to circulate in the retinal and choroidal circulation, binding preferentially to neovascular endothelial cells. In the second step, a low-power laser is used to activate the verteporfin. Toxic intermediates are produced as the cold laser shines on the macula of the affected eye, damaging the choroidal neovascular vessels while leaving the normal retinal vasculature intact. Although the abnormal vessels tend to recur after treatment, with 90% of patients showing angiographic evidence of leakage three months after their first treatment, following a series of five to six treatments over 2 years the leakage gradually stops and a small fibrovascular or disciform scar forms in the macular center. The disciform scar that forms following treatment is typically less expansive than that forming in the eye with subfoveal CNV that remains untreated, thus preserving greater central vision.
In a randomized, placebo-controlled trial involving 600 patients with subfoveal CNV lesions caused by AMD, among those with classic CNV lesions, 59% of the verteporfin-treated patients compared to 31% of placebo-treated patients lost fewer than three lines of vision at the month 24 examination (17). Another trial showed that treatment with PDT with verteporfin reduced the risk of moderate and severe vision loss compared to placebo in patients with occult CNV and evidence of recent disease progression (18).
Verteporfin has a relatively short half-life and is cleared in 48 hours. Patients must therefore remain indoors and out of sunlight for the 48 hours following treatment to avoid photosensitivity reactions, such as mild sunburn. Severe vision loss as a result of treatment occurs in approximately 2% to 4% of patients. The annual cost for photodynamic therapy with verteporfin was estimated to be at least $5,000 for three or four treatments (19).
Therapies targeting the angiogenic processes underlying CNV formation have also been developed. Vascular endothelial growth factor (VEGF) has been shown to be necessary for the development of retinal neovascularization in experimental models (20). Pegaptanib (Macugen), a peptide that binds and blocks the activity of VEGF, has been approved for the treatment of all subtypes of neovascular AMD. In a randomized controlled trial, intravitreous injections of pegaptanib or placebo were administered every 6 weeks into one eye of patients with neovascular AMD. Over a period of 54 weeks, 70% of the patients receiving intravitreous pegaptanib lost fewer than 15 letters of visual acuity compared with 55% among the controls. The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22% in the sham-injection group to 10% in the treatment group (21).
Among serious adverse events observed were endophthalmitis (1.3%), a serious intraocular infection, traumatic injury to the lens (0.6%), and retinal detachment (0.7%). The cost of a single injection of pegaptanib is approximately $1,000 and is reimbursed by Medicare; a series of nine treatments at 6-week intervals is recom-mended (19).
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Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.