Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

634 CHAPTER 31 Diseases of the Retina

laser photocoagulation for 30 years. More studies with larger enrollments are needed to further clarify the role of IVTA in DME as a new treatment modality.

Retinal Vein Occlusions. CRVO, whether nonischemic or ischemic, is frequently accompanied by CME. IVTA has been used in single cases and in several small series of patients with both types of CRVO. Individuals with nonischemic CRVO frequently, but not universally, experienced both anatomic improvements in retinal thickness and marked improvements in acuity (often twofold or better). In patients with longer follow-up, the clinical gains were usually sustained at 6 months but not at 1 year. Individuals with ischemic CRVO tended to demonstrate anatomic improvement only, without a concurrent improvement in acuity. BRVOs are also accompanied by CME, and several studies demonstrated improvements in both retinal anatomy and vision, although the follow-up times were typically no longer than 6 months. Improvements in vision were found to be statistically significant, using the logarithm of the minimal angle of resolution. Because studies of both CRVOand BRVO-related CME have had follow-up no greater than 12 months at the most (with the majority having 6 months of follow-up), it becomes apparent that clinical trials with larger enrollment and longer duration are critically needed. The National Eye Institute has sponsored a multicenter, randomized, clinical trial (the Standard Care vs. Corticosteroid for Retinal Vein Occlusion study) evaluating the use of 1- and 4-mg IVTA versus the standard of care for the treatment of retinal vein occlusions. This 3-year study will evaluate 630 patients with BRVO and 630 patients with CRVO at 4-month intervals, with additional treatment as required. Patients will be randomized in a 1:1:1 ratio to one of three groups: intravitreal injection of 4 mg of triamcinolone acetonide, intravitreal injection of 1 mg of triamcinolone acetonide, or standard care (observation of macular edema with CRVO, immediate grid laser photocoagulation of macular edema in BRVO without a dense macular hemorrhage, or observation of macular edema in BRVO with subsequent grid laser if the dense macular hemorrhage clears sufficiently).

Chronic Uveitis. IVTA has been used in several small series of patients with chronic CME due to chronic uveitis. Despite the long duration of edema, most patients demonstrated improvement in acuity lasting for 3 to 6 months, but others experienced a decline between 6 and 12 months after the initial injection, returning to the pretreatment acuity level. Anatomic improvement, demonstrated as reduced retinal thickening by optical coherence tomography, was likewise achieved by patients with CME that had been persistent for up to 11 years. Few of these patients had subsequent injections, so the ability of IVTA to maintain the initial improvement in acuity is unknown. An intravitreal implant device (Retisert, Bausch & Lomb Incorporated, Tampa, FL, USA)

is able to provide an extended release of fluocinolone acetonide.This device was approved by the United States Food and Drug Administration in 2005 for chronic CME associated with noninfectious posterior uveitis. Almost 90% of treated patients experienced stabilized or improved vision, and the rate of disease recurrence was reduced eightfold.

Complications. Endophthalmitis is a well-known complication of intravitreal injections. A comprehensive evaluation of 14,866 injections in 4,382 eyes determined an estimated prevalence of endophthalmitis to be 1.4% per eye and 1.4% per injection. (These prevalences included suspected cases of “noninfectious” endophthalmitis, “sterile” endophthalmitis, and “pseudoendophthalmitis.”) When endophthalmitis was considered to be only infectious, prevalences were 0.6% per eye and 0.6% per injection, which is a small but not negligible risk. Infectious endophthalmitis presents with common clinical findings of iritis, vitreitis, hypopyon, pain, conjunctival injection, and decreased vision.The median time to presentation of infectious endophthalmitis was 7.5 days in one study. Sterile or noninfectious endophthalmitis is proposed to be caused by an inflammatory reaction to some constituent in the triamcinolone formulation. It has features in common with infectious endophthalmitis: blurred vision, hypopyon, severe anterior chamber inflammation, and vitreitis. However, the sterile form causes no pain, cause mild to moderate conjunctival hyperemia, and appears to occur earlier than the infectious form (with hypopyon occurring on the first day postinjection). Any suspected case of endophthalmitis requires immediate attention; infectious forms are managed with vitreous tap and injection of antibiotics (typically vancomycin plus ceftriaxone or ceftazidime for gram-positive microbes or third-generation cephalosporins for gram-negative microbes).

Risk of endophthalmitis can be minimized by scrupulous preparation and control of the following areas of contamination: microbes from multiuse drug bottles, bacteria from conjunctiva, bacteria from eyelids, and the surgical site. Specific procedures include the following: preand posttreatment with topical broad-spectrum antibiotics, rigorous use of 5% povidone-iodine for control of eyelid and conjunctival flora, administration of eyedrops from single-use bottles, use of sterile eyelid specula, and maintenance of sterile operating conditions.

Increases in intraocular pressure and development of posterior subcapsular cataracts are familiar sequelae to corticosteroid therapy. Increased intraocular pressure after IVTA is considerably more common than endophthalmitis and has been established in different studies. Results are not readily comparable, because different amounts of triamcinolone were administered. However, it should be noted that approximately 30% or more of patients had an increase in intraocular pressure, regardless of the dose given, which is consistent with the finding that a significant number of patients are steroid

responders, with intraocular pressure increases secondary to steroid therapy. The intraocular pressure increase may be of longer duration with higher concentrations of steroids than with lower concentrations (about 7 to 9 months versus 3 to 5 months). It should also be noted that virtually all patients with intraocular pressure increases after IVTA were successfully managed with topical glaucoma medications. Posterior subcapsular cataracts became visually significant at 1 year in almost half of 93 eyes after treatment with IVTA for macular edema in a retrospective case series.

Age-Related Macular Degeneration

Etiology

Age-related macular degeneration (AMD) is the leading cause of legal blindness.AMD has classically been divided into “dry” and “wet” forms, separated between nonexudative pigmentary alteration for dry forms and exudative maculopathy due to choroidal neovascularization in the wet forms.The dry or nonexudative forms of this disease constitute about 85% of cases, and many cases of AMD do not result in legal blindness; of those individuals who were legally blind due to AMD in the Framingham study, 90% had neovascular maculopathy. Retinal aging changes, such as large or soft drusen or RPE alterations, are not uncommon in older patients. More individuals face the likelihood of AMD and potential loss of vision because they live longer.

In the late 1980s studies proposed that photooxidative stress underlies the pathogenesis of AMD, with most solar radiation–induced retinal damage resulting from photochemical mechanisms. Excess photon energy remaining unabsorbed by retinal elements produces a cascade of free radicals. These free radicals damage polyunsaturated free fatty acids of photoreceptor membranes, which in turn remain undigested by the RPE. They accumulate as lipofuscin, which subsequently alters normal metabolism to the extent that RPE cellular by-products are extruded as basal laminar deposits. Additional RPE compromise leads to drusen and debris within Bruch’s membrane, which further speeds degeneration of the overlying RPE. This process is followed by increasing damage to Bruch’s membrane with deposition of abnormal collagen, cellular debris, and development of multiple gaps and cracks (Figure 31-11).

Choroidal vessels invade Bruch’s membrane for reasons that are not yet clear, although the role of VEGF is becoming increasingly important, as new information establishes the responsiveness of VEGF to local hypoxia or ischemia, with resultant development of neovascularization. The risk of developing a CNVM is highest when the RPE is at an advanced degenerative stage, with thickened basal laminar deposits and soft drusen. New vessels penetrate the inner collagenous layer of Bruch’s membrane, with an increased risk of discrete leakage of blood and serous fluid that detaches both the RPE and

FIGURE 31-11 Age-related macular degeneration with multiple soft drusen of varying sizes. Corrected visual acuity is 20/20.

overlying retina (Figure 31-12). Hemorrhage under the retina or RPE stimulates proliferation of fibrous tissue, ultimately producing a disciform scar (Figure 31-13).

Diagnosis

Diagnosis of AMD is based on ophthalmoscopic findings of drusen of all sizes, RPE dropout and stippling, geographic atrophy, discrete hemorrhage and/or exudate (particularly in the absence of coexisting background diabetic retinopathy), and CNVMs. Visual acuity may be quite variable; often the funduscopic appearance correlates poorly with visual acuity, and many patients with drusen only have normal acuity. Results of Amsler grid testing often, but not consistently, show metamorphopsia

FIGURE 31-12 Wet age-related macular degeneration with disciform serous detachment, discrete hemorrhages, and exudates. Corrected visual acuity is 20/100.

CHAPTER 31 Diseases of the Retina

31-13 End-stage age-related macular degeneration with a disciform fibrovascular scar. Corrected acuity is worse than 20/400.

but may correlate poorly with the retinal appearance. Fluorescein angiography demonstrates hyperfluorescence from drusen of all sizes as well as from RPE dropout (“window defects”), allowing choroidal fluorescence to be easily seen. CNVMs may be visualized with fluorescein angiography if unobscured by bleeding or turbid serous fluid. In questionable cases ICGA can often better detect CNVM than fluorescein angiography.

Management

Nutritional. Because most cases of AMD are nonexudative, increasing emphasis has been placed on preventative strategies in patients at risk. Protection against oxidative stress using supplemental antioxidant compounds (vitamin C, vitamin E, beta-carotene, lutein, and zeaxanthin) has gained acceptance since the 1990s. Vitamin C is a water-soluble antioxidant capable of quenching superoxide, hydroxyl radicals, and singlet oxygen. Vitamin E is a lipid-soluble antioxidant found in cell membranes, able to quench singlet oxygen, superoxide, and the lipid peroxyl radicals. Beta-carotene is a lipid-soluble pigment produced by plants, capable of quenching singlet oxygen and free radicals. It is a proform of vitamin A and is an effective antioxidant, although vitamin A itself does not share this property. Lutein and zeaxanthin are carotenoids that are very efficient filters for blue light, acting in a passive antioxidant fashion by reducing oxidative stress on the retina.

One approach to preventing or managing AMD may involve enhancing the body’s free radical defenses. Because the body does not produce antioxidant vitamins or minerals internally, it must continuously receive them from either diet or supplements. Researchers studied nutritional supplementation in human subjects with AMD. Early research demonstrated less vision loss in patients taking oral zinc, but further studies using zinc have been contradictory. Several reports demonstrated protective aspects to AMD patients with increased levels

of vitamins A and E as well as of carotenoids, particularly lutein and zeaxanthin, which are primarily obtained from dark leafy green vegetables. Studies evaluating an “antioxidant index” or a mixture of vitamins, carotenoids, and other substances (including ascorbic acid and selenium) found benefits from supplements containing mixtures of antioxidants. Results are interesting but often contradictory, which raises the issue that AMD remains a disease of multifactorial causes, many of which are difficult to control or prevent (e.g., smoking).

Only large randomized clinical trials have the potential to provide definitive results regarding the impact of nutritional supplements on AMD. The National Eye Institute designed the Age-Related Eye Disease Study to evaluate the benefit of high-dose nutrients on progression of AMD. The nutrients used were vitamin C, 500 mg; vitamin E, 400 IU; beta-carotene, 15 mg; and zinc, 80 mg as zinc oxide with copper and 2 mg as cupric oxide. Patients were divided into four separate groups based on visible retinal changes of increasing severity. Category 1 subjects had a few small drusen only (smaller than 64 mcm in diameter).

A second AREDS trial (AREDS-2) will evaluate the benefits of lutein, zeaxanthin and omega-3 fatty acids (docosahexaenoic acid and eicosapentaenoic acid) in addition to the original high-dose mineral components of the first AREDS trial. AREDS-2 has enrolled 4,000 adults with either bilateral large drusen or large drusen in one eye and advanced AMD in the fellow eye (neovascular AMD or geographic atrophy).The trial will run seven years, similar to the initial AREDS trial. Definitive recommendations for these additional constituents are eagerly awaited, although they are already included (sometimes haphazardly) in many over-the-counter “ocular vitamins” at the present time.

Category 2 subjects had multiple small drusen, single or nonextensive intermediate drusen (64–124 in diameter), pigment abnormalities, or any combination of these features. Category 3 subjects could not have advanced AMD in either eye but required that at least one eye have at least one large drusen (125 or greater in diameter), extensive intermediate drusen, or geographic atrophy that did not involve the center of the macula. Category 4 subjects had advanced AMD in one eye, with the fellow eye meeting criteria for categories 1, 2, or 3. Advanced AMD was defined as choroidal neovascularization, other exudative maculopathy, or geographic atrophy involving the center of the macula. Groups 1 and 2 were at low risk of progression, whereas groups 3 and 4 were at the highest risk of progression. Risk reductions for progression to advanced AMD were 17%, 21%, and 25% for subjects taking antioxidants alone, zinc alone, and antioxidants plus zinc, respectively. Benefits were seen for groups 3 and 4 only; there were too few advanced AMD events in category 2 participants to determine whether treatment could slow the progression to this stage of disease in individuals with milder drusen and RPE abnormalities.

Recommendations for over-the-counter vitamin or mineral supplements should be made only after discussion with the patient and informed consent. Based on the results of Age-Related Eye Disease Study, it seems reasonable to defer nutritional supplementation until patients present with higher risks of progression, because no benefit was seen in individuals in either category 1 or 2, and additional analysis did not determine efficacy in slowing the progression of AMD from category 2 to either category 3 or 4. Additionally, patients with a prior or present history of smoking should not take beta-carotene because of a greater risk of lung cancer.There is no information yet about benefits of dietary intervention as a “preemptive strike” in patients with normal vision but with a family history of vision loss from AMD. A prudent approach would be for patients to take only those products suggested for possible prevention of macular degeneration, to take only specific “smoker’s formula” products if there is a prior or present history of smoking, and to avoid haphazard ingestion of antioxidants and vitamins. Both practitioners and patients should be aware that few products meet the exact doses advocated by the AgeRelated Eye Disease Study and that a normal diet plus routinely used multivitamins do not meet those requirements. The only major concerns regarding overdosing relate to zinc and copper. Patients who should not take these minerals without prior consultation with a physician are individuals with ischemic heart disease (zinc may exacerbate cardiovascular disease) or Wilson’s disease (excess copper may cause hepatic, neurologic, or psychiatric disease). Additional attention should be paid to potential drug–drug reactions between the patient’s habitual medications (whether prescription or over the counter) and zinc.

In the past management of AMD due to choroidal neovascularization depended on laser photocoagulation of the CNVM. The Macular Photocoagulation Study demonstrated that photocoagulation effectively prevented large decreases in visual acuity compared with observation without laser intervention. However, no more than 26% of patients with exudative ARMD had well-demar- cated “classic”CNVM eligible for laser treatment according to Macular Photocoagulation Study criteria. Individuals with poorly demarcated or “occult” membranes make up most patients with AMD and were ineligible for laser therapy in the Macular Photocoagulation Study.

Photodynamic Therapy. A newer approved treatment for exudative AMD is photodynamic therapy (PDT). This technique derives its benefit from cancer therapy, in which a tissue-targeted photosensitizing agent causes localized damage to tumor tissues. PDT for AMD uses an intravascular compound that causes vascular occlusion after stimulation by a specific wavelength of light at sufficiently low intensity to spare the irradiated tissues from thermal damage. Verteporfin (Visudyne, Novartis AG, Basel, Switzerland) is liposome encapsulated to enhance delivery

to vascular tissue via low-density lipoprotein receptors on proliferating vascular endothelium. Very low laser energies release the dye from the liposomes and stimulate formation of reactive free radical species, which then cause photooxidative damage to the targeted tissue, occlusion of vessels, and damage to neovascular endothelium, whereas retinal areas overlying the occluded CNVM maintained normal function.

Multiple studies of PDT have been undertaken to evaluate its benefit in patients with CNVM. Evaluation of the type of CNVM was a critical part of patient selection for these trials, using the definitions of “classic” and “occult” CNVM from the Macular Photocoagulation Study. Classic CNVM has well-demarcated areas of hyperfluorescence visible in the early phase of the angiogram, whereas occult CNVM has leakage at the level of the RPE in the late phase of the angiogram without visible well-demarcated early hyperfluorescence. The Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) investigation evaluated patients with evidence of some classic CNVM. The AMD arm of the Verteporfin in Photodynamic Therapy evaluated patients with occult with no classic CNVM with recent disease progression or with presumed early onset of classic CNVM with good visual acuity. Both trials demonstrated a reduction in risk of losing three or more lines of visual acuity or losing six or more lines of visual acuity compared with no treatment. When compared with patients with predominantly classic lesions, individuals with occult CNVM with no classic lesions and minimally classic lesions had a greater reduction in risk of vision loss with lesions of smaller size.

Selection of patients for PDT depends on fluorescein angiography to establish the presence of CNVM, plus evaluation of lesion composition (classic or occult), size, visual acuity, recent disease progression, and location. PDT is recommended for patients with predominantly classic CNVM (in which the area of the classic CNVM occupies 50% or more of the area of the entire lesion at baseline). PDT should be considered for patients with minimally classic lesions no greater than four disc areas in size (in which the area of classic CNVM occupies less than 50% but more than 0% of the area of the entire lesion). PDT is recommended for patients with subfoveal occult CNVM with no classic lesions and recent disease progression, defined as presence of blood from the CNVM and either at least a 10% increase in the greatest linear dimension or deterioration of visual acuity (at least five letters or one line) within the last 12 weeks. Further analysis indicated greater benefit for patients with smaller lesions (no greater than four disc areas) or lower levels of acuity (approximately 20/50 or less). Subfoveal lesions or juxtafoveal lesions that are so close to the fovea that conventional laser photocoagulation would involve the central fovea are appropriate for PDT. Patients are followed at 3-month intervals after the initial PDT session. Treatments are repeated if there is any fluorescein leakage

638 CHAPTER 31 Diseases of the Retina

but are deferred if leakage is absent. Due to verteporfin’s potential for photosensitization, patients should scrupulously avoid skin exposure to direct sunlight or bright indoor light for 48 hours after treatment.

PDT is not an inexpensive therapy, and it is hopeful to note, from the TAP Report No. 5, that the frequency of repeat verteporfin treatments decreased over 3 years: 3.6 treatments during the first year of follow-up, to 2.4 during the second year of follow-up, and then to 1.3 during the third year of follow-up. The frequency of retreatment sessions in the first year may be reduced in number by the combination of PDT with intravitreal triamcinolone injections, in which the immediate effect of verteporfin can be combined with the longer lasting and possibly synergistic effects of triamcinolone, but randomized largescale clinical trials are needed to establish guidelines for combined use of PDT and IVTA.

Antiangiogenesis Therapy. It has been clearly demonstrated that PDT is most beneficial in patients with predominantly classic CNVM or in those with occult CNVM with recent progression. Some patients do not fit into either of these groupings.The newest treatments for exudative maculopathy use agents targeting the physiologic processes of angiogenesis, several of which are specific for VEGF, the protein that promotes new vascular proliferation. Theoretically, these agents should work for all types of neovascularization, because it should respond to the blockage of VEGF. These anti-VEGF agents include pegaptanib, a pegylated oligonucleotide aptamer that binds VEGF; bevacizumab, a recombinant humanized monoclonal antibody that binds VEGF; and ranibizumab, a second recombinant humanized monoclonal antibody, derived from bevacizumab, which likewise binds VEGF. Anecortave, an antiangiogenic cortisol derivative without glucorticoid activity, acts at a variety of sites during the process of angiogenesis.

Pegaptanib (Macugen, Eyetech Pharmaceuticals, Inc., New York, NY, USA) is an aptamer that potently inhibits the binding of VEGF to its receptors, thus inhibiting neovascularization in cancer cells. A phase IA trial of this drug evaluated a small number of patients with subfoveal CNVM, determining that 80% of subjects showed stable or improved vision 3 months after treatment. A subsequent phase II trial in 21 patients revealed similar stabilization of vision 3 months after treatment. The largest, randomized, double-blind trial of pegaptanib (VEGF Inhibition Study on Ocular Neovascularization; V.I.S.I.O.N.) enrolled 1,186 patients with all types of angiographic subtypes of CNVM. It determined that 70% of patients lost fewer than 15 letters of visual acuity, compared with 55% of control patients (“sham injection” or usual care) at 54 weeks. Pegaptanib was beneficial for all lesion subtypes. A reduced risk of loss of visual acuity was noted as early as 6 weeks after treatment was begun, with intraocular injections administered at

6-week intervals. Study investigators performed an exploratory analysis of the V.I.S.I.O.N. trial and determined that early detection and treatment may result in better visual outcomes than delayed treatment in patients with early disease. These small subgroups met the following criteria for early disease: lesion size less than 2 disc areas, baseline acuity greater than or equal to 54 ETDRS letters, no prior PDT or laser in the study eye, and no scarring or atrophy within the lesion (group 1); or occult with no classic CNVM, absence of lipid, and better acuity at baseline in the fellow eye.The latest evaluation of subjects in the V.I.S.I.O.N. trial at 102 weeks suggests that the benefit of pegaptanib therapy in stabilizing vision continues into the second year, and this benefit may be greater after 2 years of treatment than after only 1 year, although just 10% of patients experienced a gain in visual acuity (three or more lines). Bevacizumab and ranibizumab are both humanized monoclonal antibodies, resulting from the engineering of genes of the murine (mouse) antibody system to express human antibodies. Both drugs bind directly to VEGF and suppress angiogenesis. Bevacizumab is a fully sized antibody, whereas ranibizumab is the antigen-binding portion of that parent molecule. Bevacizumab (Avastin, Genentech Pharmaceuticals, Inc., South San Francisco, CA, USA) has become established as a preferred therapy for advanced colorectal cancer when used in combination with fluorouracil.

Ranibizumab (Lucentis, Genentech Pharmaceuticals, Inc.) has been evaluated in monkey models of choroidal neovascularization and was noted to cause a greater reduction in angiographic leakage than PDT. A doseranging study in human subjects found the maximal tolerated single dose to be 500 mcg. Follow-up of patients in the phase I/II study for over 1 year revealed that ranibizumab treatment stabilized both visual acuity and lesion characteristics. The initial dosing frequency of every 4 weeks was relaxed to deferring a dose if acuity and lesion characteristics were stable on two consecutive visits, and the median rate of intravitreal injections decreased to 0.22 every 4 weeks. The most common adverse event noted in the phase I/II trial was a transient, painless, reversible inflammatory response that was most severe on the day after injection, usually resolving without treatment within 14 days.

Ranibizumab was subsequently evaluated in two large clinical trials. The MARINA trial (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration) evaluated monthly injections of either 0.3 or 0.5 mg in patients with minimally classic or occult CNVM. Ninty four percent of patients lost fewer than 15 letters of acuity at one year; 24.8% (0.3-mg group) and 33% (0.5-mg group) had gains of 15 or more letters. Those benefits were maintained at two years.The ANCHOR trial (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovasculatization in Age-Related

Macular Degeneration) compared monthly ranibizumab (0.3 0r 0.5 mg) to PDT in patients with predominantly classic CNVM. At one year, approximately 95% of ranibizumab-treated patients had lost less than 15 letters, compared to 64% of those in the PDT group. Vision improved by 15 or more letters in 37.5% (0.3-mg group) and 40.3% (0.5-mg group) of ranibizumab-treated patients.

After observation of beneficial responses from ranibizumab in phase I/II trials, investigators proposed that bevacizumab, the parent molecule of ranibizumab, be used off-label as an anti-VEGF drug for neovascular AMD. It was initially used in a salvage trial, the Systemic Avastin for Neovascular AMD Study, administered intravenously to nine patients with CNVM over a period of 12 weeks, with infusions given at 2-week intervals. At 12 weeks the median and mean visual acuity letter scores had increased by 8 and 12 letters, respectively, and optical coherence tomography measurements detected significant improvement in retinal thickness. After two or three treatments, no retreatment was needed through 3 months of follow-up, and only one of the four patients followed to 6 months needed retreatment. Based on the results of intravenous bevacizumab therapy, investigators questioned if intravitreal administration would provide similar benefit, while avoiding the risk of adverse events with systemic therapy. Bevacizumab was administered intravitreally to a patient who was responding poorly to pegaptanib therapy, with improvement in retinal anatomy and stabilized visual acuity at 4 weeks. This initial report suggested that this agent, used off-label, may have potential for management of CNVM. Subsequent intravitreal administration of bevacizumab to a nonrandomized series of 79 patients with neovascular AMD determined that therapy was associated in the short term (1 to 8 weeks) with improved acuity, decreased retinal thickness, and reduction in angiographic leakage. Another series of 266 eyes (in 266 consecutive patients) treated with intravitreal bevacizumab reported significant decreases in macular thickness, and more than 30% of patients experienced visual acuity improvement (defined as a halving of the visual acuity angle).

Off-label use of bevacizumab has become increasingly popular for treatment of hemorrhagic AMD. The gains in vision are similar to those occurring with ranibizumab and there is a pronounced difference in cost between the two drugs: average costs are approximately $50 for a bevacizumab injection versus $2,000 for a ranibizumab injection. Comparison of clinical results is complicated by several factors: studies of bevacizumab injections are not randomized or placebo-controlled but are retrospective; many individuals treated with bevacizumab had failed other AMD treatments, including PDT and pegaptanib injections; and none of the becizumab-treated patients has been followed for two years. A head-to-head comparison trial of these drugs is sorely needed, to detect overall differences between the drugs, evaluate the potential for

reduced frequency of dosing, and to evaluate the degree of increased risk of hypertension and thromboembolic events associated with the nonspecific inhibition of VEGF. The National Eye Institute is funding a multicenter clinical trial comparing ranibizumab and bevacizumab intravitreal injections in patients with AMD.

Anecortave (Retaane, Alcon Laboratories, Inc.) is one of a class of angiostatic steroids that inhibit angiogenesis by interference with proteinases that promote vascular endothelial cell migration and proliferation.This group of steroids has minimal glucorticoid (anti-inflammatory) or mineralocorticoid (salt-retaining) activity. Anecortave is administered through a posterior juxtascleral depot delivery system (periocular injection), which requires surgical implantation of a specially designed 56-degree blunt-tipped cannula in the superotemporal quadrant of the orbit between superior and lateral rectus muscle insertions. The cannula tip, after being fully inserted, is positioned near the macula.The drug was studied in 128 patients with subfoveal CNVM, 80% of whom presented with classic lesions at baseline. At 12 months, with administrations of anecortave at 6-month intervals, the drug was found to be effective for both stabilization of vision and for inhibition of lesion growth. Efficacy results at 2 years demonstrated that this treatment was superior to placebo for the parameters described above. Anecortave is being evaluated in a number of clinical trials, two of which warrant specific mention. A clinical study with verteporfin in over 500 patients with CNVM eligible for PDT therapy failed to demonstrate the noninferiority of anecortave to PDT, determining no statistically significant difference at 12 months between treatment groups. Clinical study C-01-99 compared anecortave to PDT with verteporfin in over 500 patients with CNVM eligible for PDT therapy; this noninferiority study found no statistically significant difference at 12 months between treatment groups. Clinical study C-02-60 will evaluate the effect of anecortave in reducing the risk of progression from dry AMD to exudative AMD in patients with multiple intermediate/large drusen in the study eye and exudative maculopathy or AMD in the nonstudy eye.

There has been a significant change in the available treatments for exudative AMD. More direct comparison trials of these different modalities are critically needed, particularly of the VEGF inhibitors, plus guidelines to establish which patients benefit most from treatment, similar to those established by the TAP and Verteporfin in Photodynamic Therapy studies. Whether these new agents are used alone, in combination with established therapies, or with newly developing modalities, they represent a new era in treatment, with patients being the beneficiaries of these treatments, which have the potential to stabilize vision loss and improve quality of life and independence for many patients.

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Sarcoidosis

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Age-Related Macular Degeneration

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642 CHAPTER 31 Diseases of the Retina

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Historically, Graves’ disease has been used to describe any orbital disease related to abnormalities of the thyroid gland. Other synonymous terms are Graves’ orbitopathy, dysthyroid ophthalmopathy, thyroid eye disease, thyroidrelated immune orbitopathy, thyroid-related ophthalmopathy, and thyroid-related orbitopathy. Although approximately 80% of patients with Graves’ disease have some degree of ocular involvement, only 15% of those patients ever develop serious functional impairment of vision. Nevertheless, the diagnosis and management of thyroid-related eye disease are often significant challenges to the eye care practitioner and endocrinologist.

CLINICAL PRESENTATION OF THYROID-RELATED ORBITOPATHY

In most cases the diagnosis of Graves’ disease can be made on the basis of a careful clinical history and physical examination. In one report a diagnosis of thyroidrelated orbitopathy based on the clinical findings alone was made in 42 of 52 patients with laboratory-proven thyrotoxicosis. Patients often present with complaints of dry eye, such as epiphora, foreign body sensation, photophobia, and blurred vision. Family members may even have noticed proptosis or eyelid retraction (photographs can give evidence of the date of onset). More significant complaints can include orbital pain, double vision, decreased vision, and decreased color perception.

Clinically, the practitioner may observe conjunctival chemosis and erythema, abnormal eyelid position (lid retraction), lid lag, and proptosis. Conjunctival injection is most marked over the involved rectus muscles. Nervousness, palpitations, weight loss, hyperhidrosis, and heat intolerance are systemic symptoms occurring in more than 80% of hyperthyroid patients. Other signs, such as tremor, hyperreflexia, tachycardia, skin changes, stare, and eyelid lag, are observed in more than 60%. Additionally, goiter is present in more than 95% of Graves’ disease patients. In most cases, however, the laboratory confirmation of thyrotoxicosis is helpful to corroborate the diagnosis.

A small percentage of patients maintain a euthyroid state with ophthalmopathy consistent with Graves’ disease. The clinical diagnosis of Graves’ ophthalmopathy can frequently be made on the basis of eye findings alone. Indeed, 5% of patients present with the classic signs of Graves’ ophthalmopathy but are found to be chemically and clinically euthyroid. In the patient who has either a present experience or a history of hyperthyroidism, the diagnosis is usually immediate. However, in those patients without such history, evidence of eyelid retraction and eyelid lag is virtually pathognomonic. Important officebased tests include the following:

•Best corrected visual acuities

•Pupillary testing (rule out afferent papillary defect)

•Exophthalmometry (baseline readings)

•Monocular color testing (rules out optic nerve involvement)

•Motility testing (evaluates diplopia on up-gaze/possible forced duction on inferior rectus muscle)

•Lid position/assessment (rules out upper lid retraction)

•Bell’s phenomenon (intact/absent)

•Retropulsion of the globe (rules out orbital tumor)

•Biomicroscopy (evaluates corneal integrity/tear film/ superior limbic keratoconjunctivitis)

•Extended ophthalmoscopy (optic nerves)

•Automated perimetry (central threshold testing).

The measurement of proptosis, using an exophthalmometer to measure from the lateral orbital rim to the anterior corneal surface, is important in tracking disease progression. Vertical diplopia is common, secondary to fibrosis of the inferior rectus, and accounts for the majority of sudden-onset diplopia in middle-aged women. Therefore a thorough evaluation of the ocular motility is essential. Fibrosis of the inferior rectus muscle can also be associated with an increased intraocular pressure elevation of more than 10 mm Hg when, on attempted up-gaze, the superior rectus pulls against a tight inferior rectus, compressing the globe. Demonstrating this variation of intraocular pressure from the primary position and on attempting up-gaze strongly supports inferior rectus contracture.