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

624 CHAPTER 31 Diseases of the Retina

is 900 mg twice a day followed by maintenance therapy of 900 mg daily. The single study of valganciclovir induction therapy for CMV retinitis suggested that valganciclovir was not inferior to intravenous ganciclovir. The most common adverse events related to valganciclovir in a trial of maintenance therapy were diarrhea, nausea, fever, anemia, and neutropenia. Because of convenience and efficacy, valganciclovir appears to be a reasonable first choice for systemic therapy of CMV retinitis, unless there are problems with drug absorption.

Present State of CMV Retinitis. Replication of HIV can be reduced through judicious combination of one or two HIV protease inhibitors or a single nonnucleoside reverse transcriptase inhibitor with two nucleoside inhibitors of HIV reverse transcriptase. Combination therapy (HAART) results in striking reductions in HIV viral load and significant increases in CD4+ cell counts over pretreatment levels. Additionally, after initiation of HAART patients have experienced dramatically reduced risks of opportunistic infections, which are associated with qualitative improvements in host immune responses. It is assumed that restoration of pathogen-specific immune defenses is responsible for the reduced risk of opportunistic infections, including CMV retinitis. Some patients experiencing CD4+ increases can stop maintenance anti-CMV therapy without progression of retinitis. Restoration of partial immunity takes 3 to 4 months after initiation of combination antiretroviral therapy, and authorities advocate discontinuing CMV therapy only in patients who demonstrate a sustained elevation of CD4+ cell counts over 3 to 6 months (over 100 to 150 cells/mm3) with healed retinitis that is stable for greater than 4 months.

Some patients have developed “immune recovery uveitis” in eyes with inactive CMV retinitis after immune restoration from HAART. This was presumably due to some degree of heightened immune response to residual CMV antigens. Immune recovery uveitis ranges widely in incidence (11% to 83%), depending on definitions of the syndrome. Common findings are immediate inflammation (vitreitis) and the subsequent complications of inflammation, including CME and epiretinal membranes. Eyes with the smallest area of retinal involvement or those with optimal control of retinitis appear to be at lower risk of immune recovery uveitis than eyes with larger areas of retinitis or suboptimal control (typically with intravenous therapies). Management of immune recovery uveitis consists of topical and periocular corticosteroids, or intravitreal triamcinolone injections.

Not all patients experiencing immune reconstitution may discontinue CMV retinitis therapy due to a lack of restored CMV-specific T lymphocyte defenses, despite increases in the overall CD4+ cell count. Additionally, patients who have experienced CD4+ cell increases but later discontinue HAART run the risk of experiencing recurrence of CMV retinitis, if the CD4+ count drops

below 50 cells/mm3. Regular follow-up at 6- to 12-week intervals is critical in these cases.

Because of widespread use of HAART, there has been a reduction of about 75% to 85% in the number of new cases of CMV retinitis.A number of individuals have been able to discontinue maintenance CMV therapy indefinitely. There are also individuals with CMV retinitis who have not experienced the striking immune reconstitution seen in many AIDS patients but demonstrate lower rates of retinitis progression than were seen in patients with comparable immunologic function in the era before combination antiretroviral therapy.This suggests possible indirect benefits from anti-HIV therapy, despite the patient remaining severely immunodeficient. Finally, CMV retinitis, although less frequently encountered, has not been eradicated and remains a condition with potential for serious visual loss in certain groups, including AIDS patients unresponsive to or noncompliant with HAART, and iatrogenically immunosuppressed individuals (cytotoxic therapy for cancer, transplant recipients).

Progressive Outer Retinal Necrosis or Rapidly Progressive Herpetic Retinal Necrosis

Etiology

A third necrotizing retinal syndrome was first described in the early 1980s and initially named progressive outer retinal necrosis (PORN). Although originally described as a visually devastating condition involving the outer retinal layers, an alternative name, rapidly progressive herpetic retinal necrosis, was proposed to reflect the consistent presence of herpesvirus, rapid disease progression, and involvement of all retinal layers.This latter name, despite its greater descriptiveness and accuracy, has not superseded the unfortunate older acronym of PORN, which remains in use to this day. Most patients with PORN are in the late stages of AIDS, with a CD4+ count less of than 50 per mm3. Like ARN, PORN is frequently preceded by episodes of cutaneous varicella-zoster, which suggests that the syndrome may be a localized varicella-zoster virus recurrence with ocular and neural dissemination. Cutaneous infections with herpes simplex types 1 and 2 have been implicated less frequently.

PORN is relatively uncommon in AIDS, compared with the much higher frequency of CMV retinitis. PORN was considered potentially to be the second most common cause of infectious retinitis in AIDS patients, with reported incidences of 2% to 4%. With the widespread benefit of combination antiretroviral therapy, it is very likely that new cases of PORN will be even less frequently encountered than before, similar to the decline in cases of CMV retinitis. It should be noted that PORN has presented in patients without AIDS but with iatrogenic immunosuppression and that this condition should be considered a rare but possible disease among this patient group.

FIGURE 31-5 Rapidly progressive herpetic retinal necrosis syndrome, with multiple discrete and confluent foci of necrosis. (Reprinted with permission from Holland GN, Tufail A, Jordan MC. Cytomegalovirus diseases. In: Pepose JS, Holland GN,Wilhelmus KR, eds. Ocular infection and immunity. St. Louis, MO: Mosby, 1996.)

Diagnosis

Classic features of PORN include multifocal retinal necrosis, occurring as discrete foci in early stages, followed by rapid confluence (Figure 31-5). Necrosis occurs in the periphery, mid-periphery, or posterior pole and may spread anteriorly or posteriorly, with peripheral involvement being most common. Presumably due to profound immunosuppression, PORN is characterized by relative infrequency of other inflammatory processes, including iritis, vitreous cells, and vasculopathy (vessel sheathing or occlusion). Patients report a sudden change in visual status, usually a painless loss of either central or peripheral vision.

Features distinguishing PORN from CMV retinitis are its multifocal nature, lack of granular borders, lack of

Table 31-1

Differential Diagnosis of Necrotizing Herpetic Retinitis

extensive hemorrhage, and very rapid spread. Visual dysfunction is widespread in PORN, compared with CMV retinitis, in which vision loss is linked to the size and location of retinitis lesions. Features distinguishing ARN from PORN are primary involvement of the peripheral retina in ARN, with marked anterior chamber and vitreous inflammation, and marked vasculitis. PORN is more often bilateral than ARN; up to 71% of PORN cases in a series involved both eyes. PORN is painless, in contrast to ARN, in which visual changes are usually associated with red eyes and pain from iridocyclitis (Table 31-1).

Sequelae of PORN include vision loss and retinal detachment. In early reports vision reduction was typically profound, with up to two-thirds of patients progressing to no light perception within 1 month after diagnosis. Retinal detachment results from full-thickness retinal necrosis and retinal holes, occurring in up to 70% of patients, often within 1 month of disease onset.

Management

The earliest cases of PORN were treated with intravenous acyclovir for a median of 2 weeks, followed by maintenance oral acyclovir. Most outcomes were dismal despite aggressive treatment, with only 18% of cases responding to therapy in a series. Maintenance oral acyclovir, with relatively low oral bioavailability, was often unable to prevent recurrence of PORN.

Intravenous foscarnet and ganciclovir, routinely used for CMV retinitis, resulted in significantly better preservation of vision when used either in combination or individually, combined with intravenous acyclovir. Many patients retained 20/100 or better vision and retinal detachment was less frequent, although outcomes were not uniformly successful and all patients did not retain functional vision. The regimen most often used was 5 mg/kg ganciclovir twice a day plus 60 mg/kg foscarnet three times a day, followed by maintenance therapy of 5 mg/kg ganciclovir daily plus 120 mg/kg foscarnet daily. Intravitreal ganciclovir

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and foscarnet have been used in PORN patients with good results. Some authors consider intravitreal plus systemic intravenous therapy to be the most efficacious treatment modality for PORN. Similar to AIDS patients, individuals with iatrogenic immunosuppression presenting with PORN were treated with intravenous two-drug regimens (ganciclovir plus foscarnet) plus intravitreal ganciclovir and foscarnet with good results.

PARASITIC RETINAL INFECTIONS

Toxoplasmosis

Etiology

Toxoplasma gondii is a single-celled, obligate, intracellular parasite existing in varying forms, with a serologic prevalence in the United States ranging from 3% to 70% of healthy adults. Oocysts, products of sexual reproduction, can survive in soil for more than 1 year and are ingested with unwashed produce or inhaled from dust or soil. Tissue cysts persist for the life of the host, most commonly in the central nervous system and skeletal or cardiac muscle; ingestion of tissue cysts in undercooked meat is the most common mode of transmission of toxoplasmosis. Tachyzoites are the obligate intracellular form and can be transmitted transplacentally or through ingestion of contaminated milk.

Transplacental transmission of T. gondii occurs most frequently when infection is acquired by women during pregnancy, with a prevalence of 0.2% to 1.0% in the United States. Seventy percent to 80% of women of childbearing age are at risk for primary or newly acquired infection, and 30% to 50% of infants develop congenital infection if born to mothers with serologic evidence of new infection acquired during pregnancy. The rate of fetal infection relates to the stage of pregnancy during which the mother becomes infected and is highest during the third trimester. Severity of infection is highest during the first trimester, however, and often results in spontaneous abortion. In individuals with congenital toxoplasmosis, toxoplasmic retinochoroiditis is the most common manifestation, with a frequency of 70% to 90%.

T. gondii reaches the eye by hematogenous spread, penetrates host cells, and is surrounded by a vacuole resistant to both microbicides and normal digestion. The host’s major defense against toxoplasmic infections is cellular immunity. For reasons not clearly understood, retinal toxoplasmosis results from rupture of tissue cysts containing live organisms, with subsequent retinal invasion by actively multiplying T. gondii. Retinal tissue destruction is accompanied by inflammatory events involving retinal vessels, choroid, vitreous, iris, and trabecular meshwork.

Ocular toxoplasmosis is a frequent cause of posterior segment infection, probably accounting for at least 25% of cases in the United States. Most cases of ocular toxoplasmosis were earlier believed to result from recurrence of

congenital infections, although acquired toxoplasmosis is now believed to be considerably more frequent, with one study suggesting that at least two-thirds of patients acquired the infection postnatally rather than prenatally. Recurrences of retinal toxoplasmosis are common, occurring with either congenitally or postnatally acquired infections, reaching prevalence as high as 79% in patients followed for more than 5 years.

Toxoplasmosis occurs frequently in immunosuppressed patients. Retinal toxoplasmosis was seen commonly at the height of the AIDS epidemic, but was less frequent than CMV retinitis; it occurred more often as a newly acquired infection rather than as reactivation of a congenital infection.

Diagnosis

Active lesions of toxoplasmic retinochoroiditis are white, thick, and focal, with overlying vitreous haze often obscuring the retina (“headlight in the fog”) and possibly an intense iridocyclitis (Figure 31-6). Active lesions have the same clinical characteristics whether resulting from congenital or acquired disease. Recurrent lesions tend to occur at the borders of quiet chorioretinal scars, implying loss of immune control, but immunosuppression alone does not seem to precipitate recurrence of retinal lesions in patients with inactive scars. Individuals with recurrent disease experience more episodes in previously affected eyes (with old retinal scars) than in the healthy fellow eyes. Although bilateral macular lesions are considered the hallmark of congenital infection, whereas acquired lesions are more often unilateral, congenital toxoplasmosis does not seem to be associated with any unique ocular characteristics.

FIGURE 31-6 Recurrent toxoplasmosis. Active satellite lesion at inferior border of a retinochoroidal scar, with significant vitritis. (Reprinted with permission from Holland GN, O’Connor GR, Belfort R Jr,, et al.Toxoplasmosis. In: Pepose JS, Holland GN,Wilhelmus KR, eds. Ocular infection and immunity. St. Louis, MO: Mosby, 1996.)

FIGURE 31-7 Inactive retinochoroidal scar from toxoplasmosis.

In most cases toxoplasmic retinochoroiditis is selflimited, brought under control by both cellular and humoral immunity. Untreated lesions begin to heal after 1 to 2 months, although larger lesions may take longer to resolve. Healing lesions become gray-white and less ill-defined with time; the borders become more discrete and often hyperpigmented (Figure 31-7).

The diagnosis of active toxoplasmic retinochoroiditis in immunocompetent patients is straightforward, with a recurrent lesion appearing adjacent to a retinochoroidal scar. Immunocompetent patients have only one focus of active disease, even if there are multiple retinal scars. Differential diagnosis of toxoplasmic retinochoroiditis in immunosuppressed patients can be difficult. Vitreitis varies from almost nil to moderately severe, and retinal lesions may be single or multifocal or encompass broad areas of necrotic retina. Toxoplasmic lesions may resemble CMV retinitis or the necrotizing herpetic retinal necrosis syndromes but are opaque and thick with smooth borders (compared with dry granular borders in CMV retinitis); vitreous and anterior chamber reactions are more severe than in CMV retinitis or PORN. In most cases of toxoplasmosis retinochoroiditis in AIDS patients, no preexisting scars were noted.

Ocular toxoplasmosis is an important cause of posterior segment infection in older patients, with reports of disease presentation describing many atypical findings, including diffuse disease, multifocal lesions, and areas of involvement greater than three disc diameters in size. These individuals were not immunocompromised, but the disease severity was attributed to the decline in immune function that naturally occurs with aging.

In toxoplasmic retinochoroiditis, serologic tests are used to confirm past exposure to T. gondii by demonstration of specific antibodies, although they cannot confirm a diagnosis, because antibodies can persist for years after acute infection. Enzyme-liked immunosorbent assays

detect antibodies against T. gondii, but they vary widely in sensitivity and specificity.Toxoplasmic retinochoroiditis is a clinical diagnosis, although confusing presentations may be clarified by serologic testing, analysis of aqueous humor antibodies, or Toxoplasma DNA analysis by polymerase chain reaction.

Management

The primary goal of therapy is to prevent damage to both retina and optic nerve and to reduce complications due to inflammation. Caveats to treatment of toxoplasmic retinochoroiditis are that the condition is self-limiting, medications are frequently toxic, and virtually no drug eliminates tissue cysts and therefore cannot prevent further recurrences.A general rule is that lesions that are peripheral and do not threaten the macula or papillomacular bundle do not warrant treatment. Most uveitis specialists surveyed in 1991 believed that lesions could be observed without treatment if acuity remained 20/20 in the affected eye and lesions were located in the far retinal periphery. Medical therapy was warranted, however, when the following situations occurred: decreased visual acuity, macular or peripapillary lesions, moderate to severe vitreitis, lesions larger than one disc diameter in size, persistence of disease for more than 1 month, or lesions associated with recently acquired disease. A 2002 survey of the same group (the American Uveitis Society) indicated that the factors most likely to influence treatment decisions were the location of the lesion and the presence of vitreal inflammation; virtually all respondents were likely to initiate therapy if lesions were in macular or peripapillary locations or if the vitreous inflammatory reaction was severe. Additional factors favoring treatment were poor vision in the fellow eye, proximity of lesions near major retinal vessels, prominent retinal vasculitis, serous retinal detachment, and good response to treatment during past episodes of disease.

It should be noted that a recent, evidence-based, systematic review of published randomized clinical trials of therapy for toxoplasmic retinochoroiditis found only three studies that met the authors’ criteria for inclusion, two of which were carried out more than 35 years ago. Based on this evaluation the authors concluded that there was a lack of evidence to support routine antibiotic treatment for ocular toxoplasmosis, finding no evidence for a beneficial effect on the duration and severity of signs of the disease process. However, the preponderance of evidence supports the concept that appropriate antibiotic therapy is a community standard of care, which is bolstered by guidelines for treatment in many published sources, plus the responses of those practitioners recently surveyed about their preferred patterns of management of the condition.

Classic triple therapy for retinal toxoplasmosis consists of pyrimethamine plus sulfadiazine, with steroids to reduce inflammation. Pyrimethamine and the sulfonamides act synergistically on T. gondii. Pyrimethamine is

628 CHAPTER 31 Diseases of the Retina

typically administered as a 75to 100-mg loading dose on the first day, followed by 25 to 50 mg daily for 4 to 6 weeks depending on clinical response. Sulfadiazine is administered as a 2- to 4-g loading dose, followed by 1 g four times daily for 4 to 6 weeks. Because pyrimethamine can cause both leukopenia and thrombocytopenia, some authorities urge that patients be monitored regularly during therapy. Folinic acid is usually added to pyrimethamine therapy; it is given as a 5-mg tablet two to three times per week more often than as a 3-mg intravenous preparation. In place of sulfadiazine clinicians use trimethoprim/ sulfamethoxazole more often; clinical efficacy appears to be similar to pyrimethamine/sulfadiazine. A recent study suggested that trimethoprim/sulfamethoxazole (160 mg/800 mg) twice daily with corticosteroids seems to be an acceptable alternative to classic therapy. The coformulation is readily available, less expensive, and does not require either folinic acid supplementation or hematologic monitoring, unless the patient has renal failure or is elderly. Clindamycin is an effective alternative in cases of sulfonamide allergy. It is also combined with sulfadiazine, pyrimethamine, and a corticosteroid as quadruple therapy for use when lesions threaten the macula or optic nerve or acuity is no better than 20/70 due to vitreous opacification. Clindamycin 300 mg is administered orally four times a day for 4 weeks; side effects include colitis and diarrhea.

Two other agents show promise in treatment of ocular toxoplasmosis. Atovaquone, primarily used for mild to moderate episodes of Pneumocystis carinii pneumonia, has been effective in small series of patients with toxoplasmosis. It appears to have activity against both tachyzoites and tissue cysts. More recent studies on atovaquone in toxoplasmosis are limited to murine models, and no further reports on this drug therapy in humans have been published. Azithromycin, a macrolide antibiotic, is efficacious against T. gondii and can also kill tissue cysts. A randomized study of 46 patients compared the combinations of azithromycin plus pyrimethamine versus pyrimethamine plus sulfadiazine in treatment of ocular toxoplasmosis; efficacy was similar, but the azithromycin/ pyrimethamine regimen caused less adverse effects.

The anti-inflammatory effects of corticosteroids reduce CME, vitreous inflammation, and retinal vasculitis. Use of corticosteroids is especially important if the macular area is threatened. Because they are immunosuppressive, they should never be used without concurrent antimicrobial agents. Oral prednisone 40 to 60 mg is given daily for 2 to 6 weeks depending on clinical response. Topical corticosteroids are used for the secondary anterior chamber reaction but have no impact on retinal inflammation, and periocular injections should be used cautiously,if at all,because of their intense anti-inflammatory activity.

Most clinicians use a combination of oral antimicrobial agents and corticosteroids until there are definite signs of disease resolution. Decreasing inflammation with healing

of retinal lesions typically occurs within 4 to 6 weeks. At that time corticosteroids are tapered, but antimicrobial agents are continued until corticosteroids are stopped completely, and then they are discontinued as well. Drug therapy can be discontinued before all signs of inflammation have resolved. Management of ocular toxoplasmosis is sometimes modified in certain patient groups, including pregnant women, patients anticipating cataract extraction, individuals with HIV/AIDS, and the elderly.

Pregnant Women. Suspected acquired ocular toxoplasmosis in a pregnant woman that is severe and sightthreatening should be treated to prevent vision loss. Antimicrobial agents are both toxic and potentially teratogenic, particularly pyrimethamine. Spiramycin, with the lowest risk of toxicity for the fetus, has been advocated for therapy; although not licensed in the United States, it can be obtained from the U.S. Food and Drug Administration on a compassionate basis. Many providers refer pregnant women with ocular toxoplasmosis to either an infectious disease specialist or their obstetrician/gynecologist for treatment.

Patients Anticipating Cataract Extraction. A recent study identified an increased risk of reactivation of retinal toxoplasmosis after cataract extraction in 36% of patients, which was significantly higher than the incidence of recurrences in ageand sex-matched control subjects, raising the possibility that the mechanical trauma, psychological stress of surgery, or postoperative use of corticosteroids may have contributed to the development of recurrent disease. The study suggested that antibiotic prophylaxis might be justified during and after surgery in patients with old lesions in the proximity of retinal areas that are crucial for visual function.

Individuals With HIV/AIDS. Most clinicians treat all cases of toxoplasmic retinochoroiditis in AIDS patients regardless of visual acuity or retinal location, because untreated disease is continuously progressive. With treatment, retinitis typically heals within 4 to 6 weeks. The antimicrobial agents used for immunocompetent patients are similarly used for AIDS patients, although pyrimethamine can be problematic because of its potential for exacerbating the bone marrow suppression caused by many drugs used for HIV infection or opportunistic infections. Corticosteroids are generally not combined with antimicrobial agents, because they may further impair host defenses.

The Elderly. Older patients may be considered to have a degree of immunosuppression due to the waning of immune defenses associated with aging; choices of antibiotic agents are no different from those of younger patients with typical lesions, but corticosteroid therapy may be reduced or eliminated out of consideration for altered host defenses.

Because recurrences of ocular toxoplasmosis are frequent, providers have questioned whether a preventative strategy is worthwhile, particularly in reducing the risk of vision loss resulting from reactivation of infection from scars adjacent to critical retinal areas.An open-label randomized trial evaluated the benefits of intervention with trimethoprim (160 mg)/sulfamethoxazole (800 mg) every 3 days in patients with histories of recurrent toxoplasmic retinochoroiditis. A significant reduction in recurrences was demonstrated with the therapy intervention (6.6% in treated patients versus 23.8% in control patients), suggesting that this strategy may be beneficial for patients with recurrent toxoplasmic retinochoroiditis, particularly with those at risk of further vision loss.

Toxocariasis

Etiology

Toxocara canis, the common roundworm of dogs, can cause systemic infection in humans as visceral larva migrans (VLM). Ocular manifestations are less common, presenting as a solitary posterior pole retinal granuloma, peripheral granuloma, or chronic endophthalmitis. T. canis is a common parasite in puppies (higher than 80% frequency in puppies between 2 and 6 months) but is less frequent in adult animals (20% or less). Dogs, the definitive mammalian host, are infected by ingestion of infective eggs or larvae, by transplacental infection, via transmammary passage in milk to nursing pups, or by ingestion of organisms in vomit or feces of infected pups. Larvae invade multiple organs and lie dormant for many years. Infected puppies shed the eggs in feces, and eggs remain viable for months in humid soil. Transmission to humans occurs by ingestion of eggs in soil or from contaminated hands or other objects. T. canis seropositivity in U.S. children is 7% or less, with higher rates of seropositivity occurring in children of lower socioeconomic standing, those living in rural areas, boys, and older children.

When ingested by humans, eggs hatch in the proximal small intestine, enter the systemic circulation, and are impeded when their diameter is larger than that of the surrounding blood vessel. They then bore through the vessel wall and migrate aimlessly in the surrounding tissue,leaving necrosis and immune-mediated inflammatory processes in their wake.

Diagnosis

VLM is diagnosed in children between 1 and 4 years of age with a history of pica (eating nonnutritive substances) and typical clinical signs, including cough, wheeze, pallor, malaise, irritability, hepatomegaly, and weight loss. Pulmonary involvement is typically mild, presenting as acute bronchitis, asthma, or pneumonitis. Clinical findings result from the human host’s immune response to the migrating worm.

Ocular larva migrans, the other form of this disease, is most often seen in children at an average age of 7.5 years.

Varying retinal manifestations of ocular larva migrans depend on the site of lodgment of the larva, severity of the individual reaction, and the stage at which the eye is examined. Ocular presentations are typically unilateral, with symptoms ranging from none to profound vision loss. It should be noted that ocular larva migrans rarely coexists with VLM.

Localized retinal involvement begins as an acute fluffy lesion with overlying vitreitis, which is later replaced by a focal elevated granuloma as inflammation abates. Granulomas may occur more often in the posterior pole than periphery, but data on location frequencies are contradictory. Posterior pole granulomas, which are white, round, and the size of the optic disc or larger, may have fibrous bands extending into the vitreous and pars plana. A dark gray area within the whitish mass may represent the dead larva. Peripheral granulomas have dense connective tissue strands in the vitreous that may connect to the optic disc or macula (Figure 31-8). Cicatrization of fibrous bands produces traction on various retinal structures.

Chronic endophthalmitis presents with severe retinal vessel leakage, frequently causing exudative retinal detachment, and inflammatory vitreal debris, which may organize and cover the posterior lens surface. Complications include posterior subcapsular cataract, secondary glaucoma, leukocoria, and phthisis bulbi. Interestingly, patients with nematode endophthalmitis are usually quite comfortable, although they may have an intense anterior chamber reaction. Endophthalmitis is considerably less frequent than toxocaral granulomas occurring in either the posterior pole or retinal periphery.

Hypereosinophilia is common in VLM, but eosinophilia is usually absent in ocular toxocariasis. Laboratory testing with the enzyme-liked immunosorbent assay is currently the most valuable diagnostic test.Titers of 1:32 or greater are generally considered positive for VLM, but titers of 1:8 are considered positive for ocular toxocariasis. If the

FIGURE 31-8 Peripheral granuloma in ocular toxocariasis.

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enzyme-liked immunosorbent assay on serum is not definitive, the test can be performed on aqueous samples. Definitive diagnosis, however, results only from histologic demonstration of larvae in ocular tissue.

Differential diagnosis of ocular toxocariasis includes retinoblastoma (frequently confused with toxocariasis), Coats’ disease, persistent hyperplastic primary vitreous, retinopathy of prematurity, familial exudative vitreoretinopathy, intermediate uveitis, toxoplasmosis, and idiopathic subretinal neovascular membranes. Because toxocariasis frequently mimics retinoblastoma, differential diagnosis is critical, because their treatments are radically different.

Management

Most authors agree that treatment of ongoing nematode endophthalmitis is necessary to prevent vision loss. If inflammation is mild and primarily located at the pars plana, topical corticosteroids may be sufficient, although more diffuse inflammation requires subconjunctival or sub-Tenon’s injections of longer-acting corticosteroids. With severe or vision-threatening forms of endophthalmitis, systemic steroids are mandatory. Because many patients are younger than 10 years of age, they must be observed for adverse effects on the pubertal growth process. Steroid therapy typically requires weeks to months, so very careful tapering is necessary. Use of steroids may also prevent exacerbation of inflammation resulting from the death of the worm.

The anthelmintic agents thiabendazole, albendazole, mebendazole, and diethylcarbamazine have been used with varying degrees of success. Albendazole resulted in more clinical cures when compared with thiabendazole, although no more than one-third of either treatment group achieved a clinical cure. No report of anthelmintic therapy provided conclusive proof that larvae were killed. It is likewise difficult to evaluate the efficacy of these drugs, because they are frequently used with corticosteroids. Most authors believe that anthelmintic drugs may result in clinical improvement and reduction of antibody levels, although observed changes may represent no more than the natural course of the disease.

A stepwise approach to therapy was proposed for cases of ocular toxocariasis. For eye disease alone, local and periocular or systemic steroids should be used, with surgery (vitrectomy, membrane peel) when appropriate. For eye disease unresponsive to steroids, a specific anthelmintic agent is added and systemic steroids are continued (e.g., thiabendazole 50 mg/kg per day for 7 days plus prednisolone 0.5 to 1.0 mg/kg per day). For eye disease with systemic symptoms (VLM) or high antibody levels, local steroids and mydriatics are used, in addition to oral thiabendazole and oral steroids from the outset.

Prevention should occur through two strategies: worm control in puppies and lactating bitches, and reduction of soil contamination. Additionally, children and

adults should avoid contact with puppy feces. Animal deworming is possible with various agents, including piperazine, thiabendazole, and ivermectin. Avoidance of direct contact with puppies is only partially effective, because ova are found in soil in most communities. Children exhibiting either pica (eating nonnutritive substances) or geophagia (eating dirt) should be removed as much as possible from potentially contaminated environments.

SARCOIDOSIS

Etiology

Sarcoidosis is a granulomatous multisystem disease of unknown etiology, affecting virtually every organ system, with lungs, thoracic lymph nodes, skin, and eyes most frequently involved. A helper/inducer T-cell response results in accumulation of large numbers of activated T cells in affected organs, which distort architecture of the affected tissue and cause organ dysfunction. The secondary phenomenon of granuloma formation results from mononuclear phagocytes, with granulomas simply taking up space without causing local dysfunction.

In the United States most patients are between 20 and 40 years of age when sarcoidosis is diagnosed. Black patients outnumber white patients by approximately 15 to 1, with annual adjusted incidences of 8 per 100,000 for whites and 82 per 100,000 for blacks. Outside the United States the incidence peaks bimodally at ages 20 to 30 and 50 to 60. In Europe most affected patients are white, and the disorder is most common in the United Kingdom (20 per 100,000) and Sweden (64 per 100,000).

Systemic sarcoidosis may present either acutely or chronically. Acute or subacute sarcoidosis develops abruptly over several weeks and represents up to 40% of all cases. Patients usually have constitutional symptoms such as fever, malaise, and weight loss. In the United States 40% to 70% of patients develop insidious disease and have respiratory complaints without constitutional symptoms. Up to 50% of patients, however, are asymptomatic at the time of diagnosis, with the disease detected only during a routine examination.

Although sarcoidosis is a systemic disease, it is important clinically because of pulmonary abnormalities and, to a lesser extent, eye, lymph node, and skin involvement. Thoracic manifestations are the hallmark of sarcoidosis, with bilateral hilar adenopathy being the most common finding. Respiratory symptoms typically consist of dyspnea, dry cough, and chest pain. Peripheral lymphadenopathy is also common, involving the cervical, axillary, epitrochlear, and inguinal nodes. Skin involvement is primarily characterized by erythema nodosum (red tender nodules mainly on the anterior surfaces of the legs) or lupus pernio, consisting of blue and purple skin lesions, primarily on the face. Neurologic involvement is uncommon and typically involves cranial nerves, particularly the trigeminal and optic nerves.

Diagnosis

The primary vision-threatening manifestations of sarcoidosis are uveitis, glaucoma, and optic nerve involvement; dry eye (keratoconjunctivitis sicca) is common but of lower risk. Anterior segment findings (including conjunctival granulomas, iris nodules, iridocyclitis, and keratoconjunctivitis sicca) occur in up to 70% of patients. In contrast, posterior uveitis occurs in up to 30% of patients. If only vasculitis, periphlebitis, or retinal neovascularization is considered, the frequency ranges from 4% to 17% of cases. Optic nerve involvement presents in up to 7% of patients.

Posterior segment involvement may be the only ocular manifestation in some individuals. A recent demographic analysis, evaluating posterior segment involvement in ocular sarcoidosis, found vitreitis to be the most common manifestation (69%), followed by choroidal “punchedout” lesions (56%), “snowball” lesions (46%), CME (31%), and periphlebitis (29%). Retinal hemorrhages and edema may occur with periphlebitis as well as the less common yellow perivenous exudates (taches de bougie or “candlewax drippings”), consisting of perivascular granular tissue with exudation (Figure 31-9). Retinal neovascularization develops as a complication of capillary nonperfusion. Granulomas may be preretinal, intraretinal, or sub-RPE, whereas choroidal granulomas may cause overlying sensory retinal detachments or mimic the appearance of metastatic choroidal carcinoma. Optic nerve involvement in ocular sarcoidosis manifests as edema, swelling, or, less commonly, granulomata, neovascularization, or optociliary shunts.

Definitive diagnosis of sarcoidosis requires both a consistent clinical or radiologic appearance and biopsyproven granulomata without bacterial or fungal involvement. The classic pathologic finding in sarcoidosis is the epithelioid granuloma. An abnormal chest film is

FIGURE 31-9 Retinal periphlebitis in ocular sarcoidosis. (Photo courtesy David P. Sendrowski, O.D.)

common in patients with sarcoidosis and facilitates staging of the patient’s disease, whereas computed tomography, magnetic resonance imaging, and positron emission tomography are also helpful with diagnosis of sarcoidosis in optic nerves, lungs, and other organs.

Gallium-67 citrate localizes to areas of active inflammation after injection and is increased in lymphoma, carcinoma, tuberculosis, silicosis, and other conditions besides sarcoidosis.Although not specific for sarcoidosis, gallium scanning can identify increased metabolic activity in lacrimal glands. Gallium uptake in lacrimal and parotid glands (“panda sign”) together with pulmonary and mediastinal uptake (“lambda sign”) is very suggestive of sarcoidosis. Diagnostic specificity of a positive gallium scan is improved with elevated levels of serum angiotensin-converting enzyme (ACE).

In disease states serum levels of ACE reflect the total body mass of ACE-producing granulomata. Serum ACE is elevated in most patients with active sarcoidosis. However, ACE is also elevated in other diseases, including tuberculosis, leprosy, asbestosis, silicosis, Gaucher’s disease, hyperthyroidism, and cirrhosis. Elevated ACE in patients with uveitis is largely limited to sarcoidosis, leprosy, histoplasmosis, and tuberculosis and is generally a useful diagnostic test for ocular sarcoidosis. With the increasing use of ACE inhibitors for management of hypertension, there is the potential for interference in testing serum ACE levels. Patients should be questioned about their use of ACE inhibitors before having serum ACE levels tested. A switch to an alternative modality for hypertension treatment for at least 1 month before testing serum ACE should be considered.

Management

Systemic corticosteroids are the mainstay of treatment for sarcoidosis and are mandatory for manifestations that are life-threatening or cause permanent structural damage. Either moderate doses (0.5 mg/kg per day) or high doses (1 mg/kg per day) of oral prednisone are used in organthreatening disease. Regimens are continued for 2 to 4 weeks until a clinical response is achieved and then are tapered very carefully and slowly, often over months, until the lowest maintenance dosage that controls the disease is reached. Relapses are common and typically require that the dosage be increased. Oral steroid therapy has multiple side effects,including peptic ulcer disease,systemic hypertension, endocrine irregularities, and impaired wound healing.

Posterior segment disease is unaffected by topical therapy and minimally requires periorbital administration of corticosteroids; systemic therapy is needed if the condition is bilateral or sight threatening. Indications for posterior segment treatment include significant vision loss from macular edema or severe vitreitis, choroidal granulomas, optic nerve involvement, or retinal neovascularization. Conversely, if vision remains at 20/40 or better and there are no complicating factors, systemic

632 CHAPTER 31 Diseases of the Retina

treatment may not be needed. Active retinal vasculitis and chorioretinitis generally respond to oral prednisone or periocular injections of methylprednisolone or triamcinolone. Laser photocoagulation is useful for retinal neovascularization.

Alternative medications are used to avoid iatrogenic effects of corticosteroids.These include cytotoxic agents (methotrexate, azathioprine), noncytotoxic agents (chloroquine, hydroxychloroquine), and agents that suppress tumor necrosis factor-α release (pentoxifylline, thalidomide, and infliximab). All steroid-sparing treatments have been used only in small numbers of patients, without randomized controlled clinical trials. Methotrexate has emerged as the preferred second-line drug for sarcoidosis treatment and has been effective in management of sarcoid-associated uveitis and panuveitis. Infliximab has been successful in treating cases of chronic sarcoid eye disease refractory to other immunosuppressive treatments but has been associated with cases of tuberculosis in patients taking the drug for treatment of rheumatoid arthritis and Crohn’s disease. Increased understanding of the molecular mechanisms of sarcoidosis may allow for development of new drugs that specifically affect macrophage function, including the release of tumor necrosis factor-α; these drugs may have ocular applications as well.

ACQUIRED MACULAR DISEASE

Cystoid Macular Edema

Etiology

CME results from many ocular conditions but is not an independent disease entity. Retinal cell processes in Henle’s layer run parallel to the surface of the internal limiting membrane, and the laxity of this layer forms a potential reservoir for extravascular fluid resulting from breakdown of the blood–retinal barrier, which forms extracellular cystoid spaces in the perifoveal area. CME accompanies several retinal vascular diseases, including diabetic maculopathy, central retinal venous occlusion, and branch venous occlusion. It may follow surgical procedures, most often cataract extraction and retinal detachment repair, or posterior inflammatory conditions, including pars planitis, chronic uveitis, and miscellaneous conditions such as retinitis pigmentosa.

CME after cataract extraction is classified as angiographic, in which most patients have good vision and undergo spontaneous recovery, or clinical, with both angiographic findings and reduced acuity, usually within the first 3 months after surgery. Current practices, in which extracapsular cataract extraction is followed by intraocular lens replacement, result in very low incidences of clinical CME, typically 0.2% to 0.4%, in striking contrast to older techniques of intracapsular procedures, with clinical CME occurring with an 8% incidence. Intraoperative complications, such as posterior capsular

rupture and vitreous loss, result in higher incidences of CME, and diabetic patients face a higher risk of CME after cataract extraction, particularly when diabetic retinopathy is present before surgery. CME after cataract surgery is presumably due to prostaglandin release from the iris with diffusion to the retina, altered capillary permeability, and fluid accumulation. Other factors theoretically related to postoperative CME include vitreoretinal traction on the macula and increased vitreal disruption or loss.

Retinal venous occlusive disease is frequently accompanied by CME. In eyes with ischemic central retinal vein occlusion (CRVO) edema is chronic and acuity is quite poor, with 90% of patients having acuity of 20/400 or worse. Branch retinal venous occlusion (BRVO) may also cause varying degrees of CME, with vision reduction correlating with the degree of compromised macular venous drainage. The course of CME complicating a supe- rior–temporal BRVO varies widely: 25% of cases have spontaneous resolution of edema and achieve acuity of 20/20 to 20/40, but 65% of cases have a poorer prognosis, with 90% declining to acuity of 20/50 or worse.

Diabetic macular edema (DME) is either focal or diffuse.As the severity of overall retinopathy increases, so does the proportion of eyes with macular edema. In a review, 3% of eyes with mild nonproliferative retinopathy had DME, 38% of eyes with moderate to severe non-prolif- erative retinopathy had DME, and 71% of eyes with proliferative changes had DME. In patients with diabetic retinopathy, CME usually occurs after long-standing DME.

CME occurs in other somewhat uncommon posterior segment disease states. Pars planitis is associated with CME at a frequency of 28% of cases, and CME is the primary cause of vision loss in chronic severe uveitis.

Diagnosis

Visual acuity in clinical CME ranges from 20/25 to 20/400, with metamorphopsia and increased photostress test results. Direct ophthalmoscopy may demonstrate a foveal area appearing more yellow than usual with an absent foveal reflex, but only in the most severe cases are discrete foveal cysts ophthalmoscopically visible. With dilated fundus biomicroscopy, cystic spaces show a ground-glass or honeycomb appearance with retroillumination as the observer looks adjacent to the illuminating beam. Larger cysts may be surrounded by progressively smaller cysts extending away from the fovea.

CME is best diagnosed with fluorescein angiography. During the early phase of angiography there is slight leakage from the perifoveal capillaries, resulting in an irregular circular pattern, followed by the collection of fluorescein in cystic spaces centrally within the pattern and peripheral to it. A central stellate figure appears against the contrast of the surrounding fluorescein of the cystic spaces, and photographs taken later (5 to 15 minutes) reveal the classic petaloid pattern (Figure 31-10).

FIGURE 31-10 Cystoid macular edema, late phase of fluorescein angiogram. (Photo courtesy Sheila F. Anderson, O.D.)

Management

Management of CME depends on the underlying disease. CME after cataract surgery is usually managed with topical nonsteroidal anti-inflammatory drugs (NSAIDs), often in combination with topical corticosteroids. In contrast, pharmacologic management of CME resulting from venous occlusive disease, diabetes, or uveitis was previously disappointing but has been significantly impacted by the rapid increase in use of intravitreal triamcinolone acetonide (IVTA).

Cataract Surgery. Success in treating established CME after cataract surgery depends on the use of topical ophthalmic NSAID solutions. Studies have demonstrated the efficacy of topical 1% indomethacin, 0.5% ketorolac tromethamine, and 0.1% diclofenac in improving visual acuity in most patients with pseudophakic (or aphakic) CME. A meta-analysis reviewed randomized clinical trials using topical NSAIDs to treat CME and found a benefit of improved final visual acuity of two or more Snellen lines. Clinical judgment dictates the use of a topical NSAID four times a day for 8 to 12 weeks for treatment of pseudophakic CME. Neither of the newest topical NSAIDs, bromfenac 0.09% solution (Xibrom, ISTA Pharmaceuticals, Irvine, CA, USA) or nepafenac 0.1% suspension (Nevanac, Alcon Laboratories, Fort Worth, TX, USA), has yet been evaluated for treatment of CME. Because of less frequent dosing (bromfenac) and increased potency (nepafenac), these drugs may have the potential to be used off label as topical agents for CME after cataract surgery, but clinical data from patient trials are needed.The role of simultaneous therapy with NSAIDs and 1% prednisolone acetate is not clearly established, although many practitioners empirically combine the corticosteroid with a topical NSAID.There is potential for synergy between the NSAID and the corticosteroid, but it is difficult to conclude

whether the resolution of edema is related to the NSAID alone or that true synergy has resulted in clinical benefit, and studies are contradictory about the added therapeutic benefit of 1% prednisolone acetate.

IVTA has been used in several small series of patients with pseudophakic CME refractory to all therapies. The studies all noted initial benefit in both retinal thickness (monitored by optical coherence tomography) and in visual acuity, but differing amounts of triamcinolone were used (4, 8, and 25 mg) and outcomes varied, with most patients demonstrating recurrence of edema after 3 to 4 months. The most stable duration of benefit was seen with the highest dose (25 mg).

Many studies evaluated the use of topical NSAIDs in preventing CME after cataract extraction. Studies found consistent benefits in prevention of CME with administration of 0.5% ketorolac tromethamine, 0.03% flurbiprofen, and 0.1% diclofenac. A meta-analysis of 16 randomized clinical trials evaluating topical NSAIDs for prevention of CME found that NSAID use was beneficial in reducing the incidence of both angiographically evident and clinically relevant CME.

Diabetic Macular Edema. IVTA was initially proposed in 1999 as a potential therapy for diffuse DME in an attempt to control the increase in capillary permeability mediated by vascular endothelial growth factor (VEGF) presumed to cause DME. Diffuse macular edema in diabetic retinopathy responds poorly to laser therapy, in contrast to clinically significant macular edema, for which focal macular laser is the treatment of choice. In eyes with DME, laser therapy cannot be focused on localized leakage spots because the entire macula is involved. Several small clinical series have evaluated the use of IVTA in diffuse DME. Most researchers used injections of 4 mg triamcinolone, noting improvements in retinal thickness (per optical coherence tomography results) and modest improvements in acuity in the short term. However, these benefits had eroded at 6 months, suggesting that clinical improvement lasted as long as triamcinolone deposits were visible in the vitreous cavity. Others used 25 mg in similar types of patients and found that improvements in acuity, usually two Snellen lines, held at 6 months but would erode thereafter. Eyes with larger areas of macular ischemia tended to show less improvement after IVTA. Attempting to avoid complications of intravitreal injections, posterior sub-Tenon’s injections of triamcinolone acetonide were evaluated for refractory DME. This technique provided improvements in both retinal anatomy and acuity similar to those seen with IVTA. Clinical benefits were of longer duration with posterior sub-Tenon’s injections (about 12 months), but a direct comparison of IVTA and posterior sub-Tenon’s injections demonstrated a greater clinical benefit with IVTA. Triamcinolone acetonide therapy for DME has expanded significantly, and this trend is clearly beneficial for both patients and practitioners, who have only been able to depend on