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  • 1. Introduction Anterior Segment Disease Kaposi Sarcoma Infections Herpes Zoster Ophthalmicus Herpes Simplex Keratitis Fungal Infections Uveitis Reactive Arthritis Syphilis Posterior Segment Disease Manifestations Not Associated with Opportunistic Infections Retina Optic Disk Manifestations Due to Opportunistic Infections Cytomegalovirus Retinitis Toxoplasma Retinochoroiditis Candida Endophthalmitis Bacterial Retinitis Cryptococcus Chorioretinitis Pneumocystis Choroiditis Acute Retinal Necrosis References Figures Figure 1. Cotton-wool spots Figure 2. CMV infection of the retina
  • 2. Figure 3. Frosted branch angiitis Figure 4. The ganciclovir implant Figure 5. Toxoplasmic retinochoroiditis Introduction Numerous ophthalmic manifestations of HIV infection may involve the anterior or posterior segment of the eye. Anterior segment findings include tumors of the periocular tissues and a variety of external infections. Posterior segment changes include an HIV-associated retinopathy and a number of opportunistic infections (OIs) of the retina and choroid. The increasing longevity of individuals with HIV disease may result in greater numbers of patients with OIs of the retina. Fortunately, many of these infections are now treatable with therapeutic agents. It is important to recognize these infections early so that appropriate therapy can be instituted. Partial immune system recovery following initiation of effective antiretroviral therapy (ART) may modify clinical presentation of ophthalmic OI and can affect response to treatment. In addition, in one eye, several infections may occur at the same time, rendering diagnosis and therapeutic intervention more difficult. Due to the potentially devastating and rapid course of retinal OI, all persons with HIV disease should undergo routine ophthalmologic evaluations. Any HIV-infected person who experiences ocular symptoms also should receive prompt and competent ophthalmologic care. In patients with early- stage HIV disease (CD4 count >300 cells/µL), ocular syndromes associated with immunosuppression are uncommon. Nonetheless, eye infections associated with sexually transmitted diseases (STDs) such as herpes simplex virus, gonorrhea, and chlamydia may be more frequent in HIV-infected persons;therefore,clinicians should screen for HIV in the presence of these infections. Anterior Segment Disease Kaposi Sarcoma Kaposi sarcoma (KS) is a highly vascular tumor that appears as multiple purple-to-red nodules on the skin and mucous membranes. In approximately 20% of individuals with HIV-associated KS, the tumor involves the eyelids, conjunctiva, and, in rare cases, the orbit.(1) The appearance of KS on the eyelids is similar to that of KS lesions elsewhere on the skin. In the conjunctiva, KS may appear as a persistent subconjunctival hemorrhage or as a raised, purplish-red mass.(2) KS does not invade the eye, and no treatment is necessary if it causes no symptoms and is
  • 3. cosmetically acceptable. However, KS may cause discomfort through a mass effect and secondary corneal changes, and also may be disfiguring. Under these circumstances, KS may be treated by cryotherapy, surgical excision, radiation, or chemotherapy. Infections Herpes Zoster Ophthalmicus Herpes zoster ophthalmicus (HZO) is characterized by a vesiculobullous rash over the ophthalmic branch of the trigeminal nerve and may be associated with keratitis, conjunctivitis, blepharitis, and uveitis.(3) Although HZO most commonly affects individuals in the sixth and seventh decades of life, it may be an initial manifestation of HIV infection in young persons.(4,5) In New York City, 61% of patients less than 45 years of age with HZO had HIV risk factors, and 91% had a reduction in the T- lymphocyte helper-suppressor ratio. None of the older patients had risk factors for HIV infection or unexplained depression of the helper-suppressor ratio.(6) In Africa, 100% of a consecutive series of patients with HZO who were younger than age 47 had HIV antibodies. HIV infection appeared to correlate with more severe corneal involvement and postherpetic neuralgia.(7) Although acyclovir may diminish ocular sequelae of HZO in immunocompetent patients, this treatment has not been evaluated systematically in HIV-infected patients.(8) Adults with an acute, moderate-to- severe skin rash may receive acyclovir orally and bacitracin in ointment form for skin lesions. In the presence of uveitis, topical prednisolone and a cycloplegic should be applied. In cases of retinitis, choroiditis, or cranial nerve involvement, intravenous acyclovir and oral prednisone are indicated. Herpes Simplex Keratitis Herpes simplex virus (HSV) can cause painful and often recurrent corneal ulcerations with a characteristic branching or dendritic pattern on slit lamp exam. HSV keratitis often is associated with corneal scarring and iritis, appears to require a prolonged course of treatment, and recurs frequently. Treatment consists of trifluorothymidine and cycloplegic drugs, with debridement of the ulcer using a cotton-tip applicator. Oral acyclovir (400 mg twice daily for 1 year) decreases the risk of recurrent HSV keratitis by 50%.(9) Fungal Infections Defects in cellular immunity also may play a role in susceptibility to corneal infections. Spontaneous fungal keratitis secondary to Candida parapsilosis and Candida albicans has been observed in persons with advanced HIV disease and a history of antecedent trauma.(10,11)
  • 4. Uveitis Uveitis occurs with, and may be the first sign of, several chronic infections seen frequently in patients with HIV disease, including tuberculosis, syphilis, histoplasmosis, coccidioidomycosis, and toxoplasmosis. Unexplained uveitis in an HIV-infected patient should prompt a search for an underlying infection. Clinical signs of anterior uveitis include cells in the anterior chamber, keratic precipitates, posterior synechiae, and hypopyon. Clinical signs of posterior uveitis include vitritis, chorioretinal infiltrates, vascular sheathing, and retinal hemorrhages. Reactive Arthritis Conjunctivitis and uveitis have occurred in HIV-infected patients in association with reactive arthritis, also known as Reiter syndrome.(12) This syndrome, consisting of asymmetric oligoarthropathy, urethritis, and conjunctivitis or uveitis, is of unknown etiology, but may represent an abnormal host response to an infectious agent.(13) Although the association of reactive arthritis and HIV disease may be no more than a chance occurrence, derangement of the cellular immune system may play a pathogenic role. Syphilis Syphilitic involvement of the posterior segment of the eye in patients with concurrent HIV infection has been well documented.(14-17) The findings are variable and include chorioretinitis, retinal perivasculitis, intraretinal hemorrhage, papillitis, and panuveitis. Ocular involvement may be unilateral or bilateral and is associated with evidence of central nervous system (CNS) infection in up to 85% of patients.(14,15,17,18) In addition, one third of patients with both ocular and CNS infection manifest symptomatic neurosyphilis.(17) This high correlation between neurosyphilis and ocular involvement supports the current recommendation of lumbar puncture and cerebrospinal fluid (CSF) evaluation in patients with ocular syphilis who are seropositive for HIV.(14,17) The most reliable laboratory studies for diagnosing ocular syphilis are the serum fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutination assay (MHA-TP), both of which provide evidence of past luetic infection and remain positive for years.(14,15) Nontreponemal test results (rapid plasma reagent [RPR] and Venereal Disease Research Laboratory [VDRL]) are positive in 99% of patients with secondary syphilis,(14,15) but the sensitivities of the tests are lower for tertiary disease. A negative nontreponemal test result was found in 1 HIV-positive patient with secondary syphilis (16) and 1 HIV-positive patient with syphilitic neuroretinitis. The nontreponemal test usually is confirmed with treponemal tests (either the FTA-ABS or MHA-TP) to avoid false positives.(15) CSF evaluations with determinations of protein and glucose levels, a leukocyte count, and a VDRL have a high degree of accuracy in the diagnosis of neurosyphilis.(14,15)
  • 5. Syphilis can run a more rapid and aggressive course in HIV-infected patients than in immunocompetent individuals.(15,17,18) One comparison of patients with ocular syphilis who were either HIV infected or immunocompetent demonstrated that the HIV-infected group had more extensive ocular disease.(15) Antibiotic regimens recommended by the CDC for the treatment of syphilis in immunocompetent patients may not be appropriate for patients with HIV disease.(14,15,17) Several HIV-infected patients developed recurrent syphilitic infection after treatment of primary or secondary lues with 2.4 million units of intramuscular penicillin benzathine.(15,17) Administration of intravenous penicillin for longer periods resulted in improvement of vision in HIV-positive patients with ocular syphilis. Some authors have recommended that all HIV-positive patients with ocular syphilis be treated with the antibiotic regimen for neurosyphilis (12-24 million units of aqueous penicillin G given intravenously for a minimum of 10 days).(17) One HIV-infected patient, however, was treated with intravenous penicillin (24 million units daily) for 10 days and still presented 14 months later with recurrent syphilis.(15) Posterior Segment Disease Infection with HIV predisposes the retina, choroid, and optic nerve to a variety of disorders that may be divided broadly into 2 categories: those associated with noninfectious causes and those associated with a variety of infectious disorders. Manifestations Not Associated with Opportunistic Infections Retina HIV retinopathy is a noninfectious microvascular disorder characterized by cotton-wool spots, microaneurysms, retinal hemorrhages, telangiectatic vascular changes, and areas of capillary nonperfusion. These microvascular changes are the most common retinal manifestation of HIV disease and are clinically apparent in about 70% of persons with advanced HIV disease.(19) They also are seen in approximately 40% of patients with symptomatic intermediate-stage HIV disease and in approximately 1% of those with asymptomatic HIV infection.(20) Cotton-wool spots occur in approximately 50-60% of patients with advanced HIV disease and are the earliest and most consistent finding in HIV retinopathy (Figure 1).(21-24) They represent infarcts of the nerve fiber layer and are no different from cotton-wool spots seen with other systemic disorders such as diabetes mellitus and systemic hypertension. They are not vision threatening, although we have seen several patients with advanced HIV disease who presented with small visual field defects
  • 6. corresponding to the cotton-wool spots. Although they can be confused with early cytomegalovirus (CMV) retinitis lesions, cotton-wool spots usually can be distinguished by their smaller size, superficial location, lack of progression, and tendency to resolve over weeks to months. Hemorrhages are seen less commonly than cotton-wool spots and are estimated to occur in about 20% of patients with advanced HIV disease (25-27) and in approximately 3% of patients with mildly symptomatic HIV disease.(20) They may involve both the nerve fiber layer and the deeper retina and may appear as flame-shaped, dot, or blot hemorrhages. Telangiectatic vascular changes may be seen in patients with HIV disease and are often associated with microaneurysms.(26) Areas of capillary nonperfusion may accompany these changes. We saw two nondiabetic patients with advanced HIV disease who developed small tufts of disk neovascularization confirmed by fluorescein angiography. Neither patient developed vitreous hemorrhages or required treatment for those findings. Retinal vein and artery occlusions also have been observed in patients with HIV disease.(28,29) Therefore, individuals with unexplained vascular occlusions should be considered for HIV testing. Optic Disk Noninfectious optic nerve involvement in patients with HIV disease includes papilledema, anterior ischemic optic neuropathy, and optic atrophy.(2,27,30) Papilledema usually occurs in patients with advanced HIV disease and CNS malignancies. KS also occasionally may result in metastatic CNS involvement.(31) In addition, anterior ischemic optic neuropathy has been reported as an early manifestation of advanced HIV disease.(30) Also noteworthy is the number of patients with advanced HIV disease who present with slightly swollen, "full-appearing" disks with small or absent cups. Evaluation of this finding did not reveal any neurologic abnormalities or evidence of other infectious processes, such as syphilis, and the etiology of this condition is not clear. Among the most prevalent conditions causing increased intracranial pressure in persons with HIV disease are non-Hodgkin's lymphoma, toxoplasma encephalitis, and cryptococcal meningitis.(31-33) Manifestations Due to Opportunistic Infections A number of infections of the retina and choroid have been reported to affect individuals with advanced HIV disease.(34,35) The more commonly encountered or more debilitating infections are included in this review. Although a number of these infections also can be seen in immunocompetent individuals, HIV-infected patients may present with less accompanying inflammation, take longer to respond to therapy, and be more likely to experience recurrence after therapy. Multiple foci of infection, bilateral infection, and multiple infections in the same eye also are more likely to occur in HIV-infected patients.
  • 7. Cytomegalovirus Retinitis (See also HIV InSite Knowledge Base chapter Cytomegalovirus.) CMV retinitis is the most common retinal infection in patients with HIV disease, occurring in 15-40% of patients with advanced HIV disease.(20,36-39) It is bilateral in 30-50% of patients,(40) although that rate may be lower in the setting of treatment, as the disease often presents unilaterally and the administration of anti-CMV medication almost always prevents the onset of retinitis in the fellow eye.(36) It is uncommon to find CMV retinitis in HIV-infected patients with a CD4 count >40 cells/µL, and a CD4 count >50-100 cells/µL in an individual with retinitis should prompt a reconsideration of the diagnosis of CMV retinal infection. CMV is a DNA virus classified in the herpes group of viruses. Serologic studies indicate a past CMV infection in approximately 50% of the adult population in urban areas of the United States and Europe (41) and close to 100% in the male homosexual population. CMV disease affecting the eye, however, tends to occur only in developing fetuses and in immunocompromised patients. CMV infection of the retina leads to viral invasion of retinal cells with resultant retinal necrosis. Clinically, lesions appear within the retina as multiple granular white dots with varying amounts of hemorrhage (Figure 2). Although they can be confused with cotton-wool spots (which may be present in the same eye), CMV lesions differ by their tendency to enlarge and coalesce over time. As areas of retinitis enlarge, they appear to follow the vascular arcades, resulting in an arcuate or triangular zone of infection. Areas of active infection also may appear to be linear, seemingly following the retinal vessels or nerve fiber layer into the periphery. Frosted branch angiitis may be seen in conjunction with CMV retinitis (Figure 3). After several weeks, atrophic tissue that has lost the capacity to support viral replication replaces actively infected regions of retinal tissue.(42,43) The underlying retinal pigment epithelium demonstrates pigment loss and migration, resulting in increased visualization of the underlying choroidal vasculature. Other findings associated with CMV retinitis include perivasculitis, vascular attenuation, and vessel closure,(20,44) as well as vitritis, anterior uveitis, and papillitis.(45-47) Although CMV retinitis usually responds to initial therapy, the prompt recognition of recurrent CMV retinitis is of particular importance. The presentation of recurrence may be so subtle that active disease may remain undetected for extended periods of time. Early recurrences appear as subtle white or gray zones of retinitis with little, if any, accompanying retinal hemorrhage. Recurrence usually begins at the margins of previously active infection and tends to "smolder" rather than actively progress. Nevertheless, it will continue to spread, slowly but inexorably, if the treatment regimen is not altered. The reintroduction of induction doses of medication for a period of 2-3 weeks often will inhibit progression of these recurrent lesions. Retinitis progression may recur, however, eventually necessitating alternative treatments. Patients with recurrent infection that is quite "active" in
  • 8. appearance and accompanied by the presence of significant retinal whitening and hemorrhage while they are on appropriate levels of maintenance therapy have an especially poor prognosis for preservation of sight, even with the use of increased doses of medication. With the introduction of effective ART, the incidence of CMV retinitis has been noted to decrease by about 75%.(48) However, the incidence of OI, especially new or recurrent CMV retinitis, remains high during the first few months of ART, consistent with the delay in immune recovery following initiation of ART.(49) Prior to the availability of effective ART, the median time to progression of treated CMV was 3-9 months, and the lack of CMV progression in patients on ART is most likely due to improved CMV- specific immunity.(50) In patients with a history of CMV disease who subsequently receive ART, immune reconstitution may result in inflammatory retinal lesions, vitritis, or uveitis. (See chapter Immune Reconstitution.) Systemic Anti-CMV Therapy For oral and intravenous treatment of CMV infection, see HIV InSite Knowledge Base chapter Cytomegalovirus. Ganciclovir Intraocular Implant In the early years of the HIV epidemic, patients unable to tolerate systemic CMV therapy sometimes benefited from intravitreal injection of ganciclovir (51,52,53-56) or foscarnet.(57) In 1996, the FDA approved intraocular implants for the treatment of CMV retinitis. Direct intraocular administration of ganciclovir has the benefit of achieving therapeutic levels by bypassing the blood-retinal barrier. Furthermore, systemic absorption is minimal. Therefore, systemic complications are avoided, but protection of other CMV-susceptible sites, including the contralateral eye, is not achieved. Therefore, oral prophylaxis with ganciclovir or valganciclovir often is used in combination with the intraocular device.(58) The ganciclovir intraocular device (GIOD) consists of a 6-mg pellet of ganciclovir that is 2.5 mm in diameter and coated with 10% polyvinyl alcohol, which is impermeable to ganciclovir. A suturing strut is attached to one edge of the pellet and the pellet is then sealed on 3 sides by ethyl-vinyl acetate. The resultant sustained linear drug release provides 3 or 6 months (depending on pellet construction) of anti-CMV activity. The surgical technique involves a conjunctival peritomy (a 360º incision of the conjunctiva at the limbus) in the inferotemporal quadrant followed by a 5.5-mm pars plana incision located 4.0 mm posterior to the limbus. A limited vitrectomy without infusion is performed through the incision and at the wound site to remove prolapsed vitreous. The suturing strut of the implant is trimmed to approximately 1 mm in length and a double-armed 9-O Mersilene suture is passed and locked through both edges of the strut. The implant is placed carefully into the vitreous cavity and the preplaced 9-O Mersilene is sutured to the sclera and tied. The sclerotomy is then closed with a continuous 8-O nylon suture (Figure 4).
  • 9. Surgical Management of Retinal Detachment Retinal detachments secondary to CMV retinitis occur in 17-34% of patients,(59-63) usually in areas of peripheral retinitis where there are retinal breaks either within the zone of necrotic retina or at the interface between necrotic and uninvolved tissue. These detachments may occur during periods of active infection or after antiviral therapy has stabilized the retinitis. Retinal breaks in this setting may be extremely difficult to visualize due to the presence of marked retinal thinning in areas of necrosis.(60) Furthermore, control of any concomitant zones of active retinitis is critical for a lasting, anatomically successful surgical outcome. Surgery should be considered in all patients with bilateral CMV retinitis because the eye with the retinal detachment ultimately may be the better-seeing eye. Vitrectomy with an intraocular silicone oil tamponade is the preferred operation in these patients. Surgery for retinal detachments secondary to unilateral CMV retinitis also should be considered, although the prognosis for useful vision and the patient's life expectancy should be taken into consideration. Vitrectomy is an intraocular procedure in which the vitreous gel is surgically removed, retinal defects repaired, and the retina repositioned. The pars plana vitrectomy procedure with silicone oil as a permanent intraocular tamponade results in the highest reattachment rate (70-100%).(62-64) Silicone oil's permanent tamponade of the retina is fundamental to the high rate of success of this procedure for retinal detachments secondary to CMV retinitis; it effectively tamponades multiple retinal holes in the areas of retinal necrosis, which are otherwise difficult to completely identify and treat. Vitrectomy that employs gas as the temporary intraocular tamponade is associated with a higher rate of recurrent detachment, in part because the multiple retinal defects may reopen as the gas resorbs in the weeks following surgery. Because silicone oil is lighter than physiologic intraocular fluid and because it is impossible to completely fill the vitreous cavity with silicone oil, recurrent retinal detachments occur inferiorly and eventually may involve the fovea. Intraocular silicone oil also causes significant cataract formation in up to 20% of patients after 6 months.(65) These can be managed by a standard cataract operation with the oil remaining in situ. Other common silicone oil complications such as late-onset glaucoma and corneal dysfunction also may merit consideration, given dramatically improved survival on ART. Scleral buckling is a different surgical technique in which a silicone sponge or band is affixed to the equator of the globe to support and keep the retina in position. For this procedure to be successful, the area of CMV retinitis responsible for the detachment should be small enough to be supported entirely on the scleral buckle. Pneumatic retinopexy is an office or outpatient procedure that involves the injection of a gas bubble into the globe, with subsequent positioning of the patient so that the bubble's natural upward force
  • 10. pushes the retina back into position. This procedure is successful in only a limited number of patients with retinal detachment secondary to CMV retinitis. Furthermore, this procedure generally is thought to be appropriate only when the defects responsible for the detachment are located in the superior retina. Retinal laser or cryopexy may be used to "surround" and tack down the retina around a small peripheral retinal detachment in patients who are unable or unwilling to undergo surgical intervention. The use of retinal laser to create a prophylactic "barrier" around areas of healed CMV retinitis may reduce the subsequent risk of retinal detachment.(66) Toxoplasma Retinochoroiditis Toxoplasma gondii is a protozoan parasite, the life cycle of which includes encysted and active forms. In contrast to its presentations in immunocompetent individuals, toxoplasmosis in HIV-infected patients is more likely to cause multifocal sites of retinochoroidal infection with less accompanying vitritis.(67) Bilateral eye involvement also may be seen in patients with HIV disease,(68) and proliferative vitreoretinopathy may accompany later stages of the disorder. In contrast to the situation with immunocompetent individuals in whom this infection almost always represents recurrence of a congenital lesion, patients with HIV disease usually have no evidence of a preexisting retinochoroidal scar, suggesting that these represent recently acquired infections.(69,70) Toxoplasma retinochoroiditis may be confused with other forms of retinitis, but it usually can be differentiated by the presence of intense, almost fluffy, areas of retinal whitening with accompanying vitritis (Figure 5). The degree of accompanying retinal hemorrhage is usually less than that seen in individuals with untreated CMV retinitis. Fluorescein angiography may demonstrate more leakage with active toxoplasmosis than with CMV infection. Of note is the fact that toxoplasmosis commonly involves the central nervous system in patients with advanced HIV disease and results in neurologic manifestations in 10-40% of affected individuals.(71-73) Serologic studies have been relatively unreliable for the diagnosis of toxoplasmosis in HIV-infected patients.(67) IgG anti-Toxoplasma antibody titers in patients with toxoplasmosis are sometimes low in the presence of disease; when high, they do not distinguish old from active toxoplasmosis. In addition, HIV-infected patients with CNS toxoplasmosis may not have detectable, increasing levels of serum anti-Toxoplasma antibody titers.(67,74) However, toxoplasmosis is unlikely in a patient with a negative IgG anti-Toxoplasma antibody. Patients with a confusing clinical presentation and a vision-threatening lesion (as determined by decreased acuity and the lesion's proximity to the optic disk or macula) may warrant a therapeutic trial using antitoxoplasmosis medications. Treatment consists of pyrimethamine and either sulfadiazine or clindamycin in standard dosages.(72,73) Adjunctive steroid therapy has been reported
  • 11. to be unnecessary.(69,70) Maintenance therapy with pyrimethamine and either sulfadiazine or clindamycin results in fewer relapses of infection than does pyrimethamine alone,(72) and may need to be continued indefinitely while CD4 counts remain low. Candida Endophthalmitis Typical candidal fungal lesions appear as fluffy white "mounds," which are frequently bilateral and superficially located, and often extend into the vitreous. There usually is an overlying vitritis, and vitreous abscesses also may be seen.(75) Candida retinitis is not commonly seen in HIV-infected patients, but may be more likely in the setting of intravenous sources of infection (including indwelling catheters). Bacterial Retinitis Several cases of endogenous bacterial retinitis have been documented in patients with advanced HIV disease.(31,76) It may present as a vitritis or a slowly progressive retinitis with multifocal, yellow- white retinal lesions, subretinal fluid, and exudate.(76) Bacterial chorioretinitis, although infrequently seen, should be considered in patients with advanced HIV disease who present with posterior segment infection unresponsive to treatment for suspected viral, fungal, or protozoan causes. Cryptococcus Chorioretinitis Cryptococcus neoformans is a yeast that causes OI in immunosuppressed individuals.(75) CNS involvement with Cryptococcus in HIV-infected patients is relatively common and often results in meningitis with secondary ocular findings.(31) Choroiditis and chorioretinitis from cryptococcal infection also have been observed in HIV-infected patients.(26,31,77) Typical cryptococcal lesions are located in the choroid and retina and appear as multiple, discrete yellowish spots varying in size from 500 to 3,000 µm in diameter.(78,79) Papilledema may be present due to increased intracranial pressure from meningitis. Visual loss may occur and has been attributed to cryptococcal involvement of afferent tissues including the optic nerve, chiasm, and tract.(80) Pneumocystis Choroiditis Pneumocystis jiroveci is an unusual fungus that exhibits some protozoan characteristics.(5) It is the cause of P jiroveci pneumonia (PCP), the most common systemic infection in patients with HIV disease.(81) Pneumocystis ocular involvement in advanced HIV disease was first suspected in 1982 when a patient with advanced HIV disease and PCP had evidence of the organism in the ganglion and plexiform layers of the retina on histopathologic study.(82) In 1987, postmortem histopathologic examination of eyes obtained from a patient with HIV disease and disseminated PCP revealed areas of choroidal thickening and exudate which harbored the characteristic cysts of P jiroveci.(83) Clinical
  • 12. reports of Pneumocystis choroiditis first appeared in late 1988 and early 1989.(84,85) Multiple pale yellow-white choroidal lesions, usually in both eyes, clinically characterize Pneumocystis choroiditis.(5,84,85) The lesions generally are round or ovoid and of variable size, and may coalesce to form large regions of confluent involvement with resultant choroidal necrosis.(5,84) If this process involves the foveal area, loss of central vision may occur.(84) Fluorescein angiography of the choroidal lesions reveals early hypofluorescence and late staining with minimal evidence of dye leakage. Of note is the almost total lack of an associated inflammatory response in the retina, vitreous, and anterior segment. A similar choroidal lesion occurs in early cryptococcal chorioretinitis, but typically is accompanied by vitritis.(84) Treatment is the same as that for PCP. Acute Retinal Necrosis Acute retinal necrosis (ARN) is a rapidly progressive viral uveitis that was first reported as a new clinical syndrome in immunocompetent patients in 1971.(85) The first case report of this disorder in an HIV-infected patient appeared in 1985.(37) Peripheral retinal whitening that progresses to necrosis over several days characterizes ARN. Bilateral involvement may occur, and retinal detachments with proliferative vitreoretinopathy commonly occur.(20,86) Several viral pathogens have been associated with ARN. Varicella-zoster has been the most frequently implicated virus.(31) HSV and CMV also have been associated with this disorder.(86,87-90) Whereas ARN responds to treatment with intravenous acyclovir in immunocompetent individuals, it is much more recalcitrant to treatment in HIV-infected patients. The currently recommended treatment involves standard induction dosages of ganciclovir or foscarnet, with adjunctive high-dose intravenous acyclovir (15 mg per kilogram every 8 hours). Citing Articles (34) The human immunodeficiency virus (HIV) has infected nearly 900,000 persons in North America and more than 30 million worldwide.1,2 Since the initial description of eye abnormalities in HIV-positive patients more than 15 years ago,3 numerous reports have described the spectrum and natural history of HIV-associated eye disorders, which affect 70 to 80 percent of all patients at some point during their illness.4 We present here the key clinical features of the most commonly encountered ocular manifestations of HIV infection, as well as the main issues in their management. CD4+ T-Lymphocyte Count as a Predictor of Risk
  • 13. For years, the CD4+ T-lymphocyte count proved a reliable predictor of the risk of ocular complications of HIV infection (Table 1Table 1 CD4+ T-Lymphocyte Counts in Patients Presenting with Common HIV-Associated Disorders Involving the Eyes.).5 Recently, however, the use of highly active antiretroviral therapy6 has allowed substantial and sustained, albeit incomplete, repopulation of T lymphocytes to occur in many patients.7 Such observations have raised the question of whether reconstituted T-lymphocyte populations are in fact functional and, more specifically, whether the current or the lowest CD4+ T-lymphocyte count is a better predictor of the risk of HIV-associated disorders.8 One would hope that increases in circulating CD4+ T lymphocytes induced by highly active anti-retroviral therapy would be protective, and reports of spontaneous resolution of cytomegalovirus retinitis in patients with increased CD4+ counts as a result of such therapy are now beginning to appear.9,10 However, the recovery of CD4+ T lymphocytes takes months to years,7 and patients have permanent or long-lasting depletion of T-lymphocyte repertoires.11 A recent report12 on cytomegalovirus retinitis in patients who were receiving highly active antiretroviral therapy and whose CD4+ counts were higher than 200 cells per cubic millimeter suggests that reconstituted CD4+ cells may fail to provide protective immunity, although the possibility that the onset of cytomegalovirus retinitis preceded the recovery of CD4+ T lymphocytes was not ruled out.8 Given these uncertainties, we have decided to monitor otherwise asymptomatic HIV-positive patients on the basis of the lowest CD4+ T- lymphocyte count,8 at least until antigen-specific tests of T-lymphocyte function become more widely available.13 Adnexal Manifestations The ocular adnexa include the eyelids, conjunctiva, and lacrimal drainage system. The most common complications affecting these structures are herpes zoster ophthalmicus, Kaposi's sarcoma, molluscum contagiosum, and conjunctival microvasculopathy.14 Herpes Zoster Ophthalmicus Herpes zoster ophthalmicus is a vesiculobullous dermatitis caused by varicella–zoster virus. The infection involves the ophthalmic distribution of the trigeminal nerve (Figure 1AFigure 1 HIV- Associated Eye Disorders.),15 and pain may be severe. The occurrence of varicella–zoster virus dermatitis in a person less than 50 years old is uncommon and should suggest the possibility of an immunosuppressive condition.15 Herpes zoster ophthalmicus affects 5 to 15 percent of HIV-positive patients.4 Concurrent or delayed keratitis, scleritis, uveitis, retinitis, or encephalitis may also
  • 14. occur.15Treatment consists of intravenous acyclovir (10 mg per kilogram of body weight three times a day for seven days) followed by an oral maintenance regimen (800 mg three to five times a day), which reduces the frequency of recurrences. Famciclovir (500 mg three times a day) offers the advantage of fewer daily doses, but for long-term maintenance therapy, its efficacy as compared with that of acyclovir is still under study. For patients with poor responses to acyclovir or famciclovir, a trial of intravenous foscarnet should be considered. Kaposi's Sarcoma Kaposi's sarcoma is a highly vascularized, painless mesenchymal tumor affecting the skin and mucous membranes in up to 25 percent of HIV-positive patients.16 Approximately 20 percent of such patients have asymptomatic Kaposi's sarcoma of the eyelids or conjunctiva (Figure 1B),17 which may mimic a chalazion or subconjunctival hemorrhage, respectively. Radiation therapy is effective for eyelid and conjunctival Kaposi's sarcoma, but it is expensive and may cause loss of lashes, skin irritation, and conjunctivitis.18 Excision of conjunctival lesions can be performed with little difficulty, whereas surgical removal of eyelid lesions is often complicated by substantial bleeding. Alternative therapies for both eyelid and conjunctival lesions include local cryotherapy and intralesional chemotherapy with vinblastine. Ocular lesions accompanied by systemic Kaposi's sarcoma are often best treated with systemic chemotherapy. Molluscum Contagiosum Molluscum contagiosum is a highly contagious dermatitis caused by a poxvirus. Both the skin and the mucous membranes may be affected, with multiple, small, painless, umbilicated lesions. Molluscum contagiosum is more common and tends to be more severe in HIV-positive persons than in HIV-negative persons, with larger, more numerous, and more rapidly growing lesions.16 Involvement of the eyelids (Figure 1C) occurs in up to 5 percent of HIV-infected patients.19 Associated follicular conjunctivitis and superficial keratitis have been reported in immunocompetent patients but are uncommon in HIV- infected persons. Treatment options include cryotherapy, curettage, incision, and excision. Conjunctival Microvasculopathy Seventy to 80 percent of HIV-positive patients eventually have asymptomatic conjunctival microvascular changes, including segmental vascular dilatation and narrowing, microaneurysm formation, the appearance of comma-shaped vascular fragments, and “sludging” of the blood column.20,21 These changes, which are best seen with a slit-lamp biomicroscope near the limbus (Figure 1D), are correlated with the occurrence of retinal microvasculopathy. The cause of conjunctival microvascular changes is unknown, although increased plasma viscosity, HIV-related immune-complex deposition, and direct infection of the conjunctival vascular endothelium by HIV have been proposed as possible causes.21 No treatment is indicated. Anterior-Segment Manifestations
  • 15. The anterior segment includes the cornea, anterior chamber, and iris. More than half of HIV-positive patients have anterior-segment complications.14 The most common visually important complications include dry eyes (keratoconjunctivitis sicca), corneal infection (keratitis), and anterior-chamber inflammation (iridocyclitis). Although best seen with a slit lamp, anterior-segment complications are often detectable with a penlight. Common symptoms include irritation, pain, sensitivity to light, and decreased visual acuity. Keratoconjunctivitis Sicca Keratoconjunctivitis sicca occurs in 10 to 20 percent of patients with HIV infection, typically at later stages of illness.22 Abnormal results on Schirmer's testing and interpalpebral rose-bengal staining help establish the diagnosis. The cause is probably related to HIV-mediated inflammation and destruction of the primary and secondary lacrimal glands. If encephalopathy is also present, incomplete lid closure (lagophthalmos), a decreased blink rate, or both may exacerbate the condition. Treatment with artificial tears and long-acting lubricating ointments usually provides symptomatic relief. Infectious Keratitis Although corneal infections occur in less than 5 percent of HIV-infected patients, they may result in permanent loss of vision.14 Varicella–zoster virus (Figure 1E) and herpes simplex virus are the most common causes of keratitis. Decreased corneal sensation and elevated intraocular pressure provide clues to the diagnosis. Keratitis related to varicella–zoster virus infection is often characterized by the presence of herpes zoster ophthalmicus, although the dermatitis may be mild or even absent.15,23 Both varicella–zoster virus keratitis and herpes simplex virus keratitis may recur more frequently and in some cases be more resistant to treatment in HIV-positive patients than in other patients.24,25 Treatment of varicella–zoster virus keratitis is similar to that of herpes zoster ophthalmicus, whereas herpes simplex virus keratitis usually responds to lower doses of oral acyclovir (400 mg five times a day) or famciclovir (125 to 500 mg three times a day). Long-term therapy may be necessary for both varicella–zoster virus keratitis and herpes simplex virus keratitis. Bacterial and fungal corneal infections do not appear to be more common in HIV-positive persons than in others but do tend to be more severe.14 Numerous causative organisms have been reported, although candida species are particularly common in intravenous drug users.26 Gram's staining and cultures should be performed to help guide therapy. Microsporidia are obligate intracellular parasites known to cause gastroenteritis, sinusitis, and pneumonitis in HIV-positive patients.27 Ocular microsporidiosis is uncommon but can produce a punctate superficial keratopathy (Figure 1F), often with a mild papillary conjunctivitis.28 The organism is extremely difficult to culture but can be readily seen within corneal or conjunctival epithelial cells with the use of either Masson trichrome or Giemsa staining. Treatment options include oral itraconazole, topical fumagillin, and oral albendazole. Iridocyclitis
  • 16. Mild iridocyclitis is common in HIV-positive patients and is usually observed in association with retinitis caused by cytomegalovirus29 or varicella–zoster virus.30 Severe inflammation of the anterior chamber is uncommon but can occur in association with toxoplasmic retinochoroiditis,31 syphilitic retinochoroiditis,32 or rarer forms of bacterial or fungal retinitis.4 Medications used to treat opportunistic infections in HIV-positive patients, such as rifabutin33 and cidofovir,34 may also cause iridocyclitis. Lastly, iridocyclitis may be part of a more generalized autoimmune and endogenous uveitis, such as Reiter's syndrome, which may be more common in patients with HIV infection than in those without it.35 Identification of iridocyclitis requires high-power slit-lamp examination. Treatment should be directed at a specific infectious cause. If toxicity is suspected, the dose should be tapered or the offending drug withdrawn. Topical corticosteroid drops are often indicated but should be used with extreme caution and only with appropriate antimicrobial treatment when infection is suspected. Posterior-Segment Manifestations The posterior segment includes the retina, choroid, and optic-nerve head. More than half of HIV-positive patients have disorders involving these structures. Typical symptoms include floaters, flashing lights (photopsias), visual-field defects, and decreased visual acuity. An afferent pupillary defect constitutes strong evidence of extensive retinal or optic-nerve involvement, and every patient with visual loss should be tested for such a defect. Diagnoses are usually based on characteristic clinical findings observed on dilated-fundus examination with the use of either a direct or an indirect ophthalmoscope. Retinal Microvasculopathy Retinal microvasculopathy, also termed acquired immunodeficiency syndrome (AIDS) or HIV retinopathy, occurs in 50 to 70 percent of HIV-infected persons. The most commonly observed manifestations include cotton-wool spots, intraretinal hemorrhages, and retinal microaneurysms (Figure 1G).36,37 These findings increase in frequency when the CD4+ T-lymphocyte count falls below 100 cells per cubic millimeter.4,36,37 Hypotheses about the pathogenesis of retinal microvasculopathy parallel those suggested for conjunctival vascular changes.21 HIV-associated retinal microvasculopathy is typically asymptomatic and transient but may play a part in progressive optic-nerve atrophy, with loss of color vision, contrast sensitivity, and visual-field defects.38 The role of retinal microvasculopathy in the development of cytomegalovirus retinitis remains unclear.36,39,40 Infectious Retinitis Cytomegalovirus Retinitis Cytomegalovirus retinitis affects 30 to 40 percent of HIV-positive patients in developed countries,4,29 typically occurring when the CD4+ T-lymphocyte count has fallen below 100 cells per cubic millimeter. Affected patients usually report floaters, photopsias, visual-field loss, or blurred vision. Classically, anterior-chamber and vitreous examinations reveal little inflammation, and fundus examination shows full-thickness retinal whitening, often associated with intraretinal hemorrhages (Figure 1H). The optic nerve is involved in up to 5 percent of patients.
  • 17. The use of highly active antiretroviral therapy has changed the natural history of HIV-associated cytomegalovirus retinitis in two important ways. First, since fewer patients have CD4+ T-lymphocyte counts below 100 cells per cubic millimeter, fewer patients are at risk for the development of cytomegalovirus retinitis. As a consequence, the incidence of cytomegalovirus retinitis in countries where highly active antiretroviral therapy is available has decreased dramatically.8 Second, patients receiving such therapy who have early or partial reconstitution of CD4+ cell populations may have otherwise uncommon features of cytomegalovirus infection, including moderate-to-severe anterior- chamber or vitreous inflammation41 and spontaneous healing in the absence of specific anticytomegalovirus therapy.9,10 The treatment of cytomegalovirus retinitis is a rapidly evolving field that has been thoroughly covered in several recent reviews (Table 2Table 2 Treatments for Cytomegalovirus Retinitis.).29,42,43 The choice of an appropriate antiviral agent and the route of delivery should be based on the location and extent of disease, potential drug-related side effects, and the effectiveness of prior treatments. Varicella–Zoster Virus Retinitis Varicella–zoster virus is the second most common cause of necrotizing retinitis in HIV-positive persons, affecting 1 to 4 percent of patients.21 Like cytomegalovirus, varicella–zoster virus produces retinal whitening, often accompanied by intraretinal hemorrhages (Figure 1I). However, varicella–zoster virus retinitis is usually distinguished by rapid progression, multifocal lesions, and the initial involvement of deep retinal layers. A concurrent or recent herpes zoster dermatitis provides additional support for the diagnosis. The risks of retinal detachment and involvement of the other eye are high.44 Although rare, herpes simplex virus retinitis can also cause rapid and profound visual loss in HIV-positive patients.45 Control of retinitis caused by varicella–zoster virus or herpes simplex virus is difficult and often requires combination therapy with intravenous acyclovir and intravenous as well as intraocular ganciclovir or foscarnet.45 Long-term therapy is often necessary. Toxoplasmic Retinochoroiditis Ocular toxoplasmosis affects 1 to 2 percent of HIV-positive patients.4 Although the presentation may be atypical, toxoplasmic chorioretinitis is often distinguished by the occurrence of a moderate-to-severe anterior-chamber and vitreous inflammation, a relative absence of retinal hemorrhage, and pigmented chorioretinal scars (Figure 1J).31 In contrast to immunocompetent persons with ocular toxoplasmosis, HIV-infected patients tend to have multifocal or bilateral disease. Testing should include serologic assays for IgG and IgM antibodies against toxoplasmosis, although the results may be negative in profoundly immunosuppressed patients. From 30 to 50 percent of patients with ocular toxoplasmosis have central nervous system involvement. Treatment consists of pyrimethamine in combination with a sulfonamide
  • 18. or clindamycin, or both. Long-term or repeated therapy is often necessary. Atovaquone has been used successfully46 but is expensive and has yet to be shown to be superior to standard therapy. Bacterial and Fungal Retinitis Ocular syphilis is the most common intraocular bacterial infection in HIV-positive persons, affecting 1 to 2 percent of patients.4,32 Patients may present with either an iridocyclitis or more diffuse intraocular inflammation. Laboratory testing should include a specific treponemal-antibody assay. In rare cases, tests are negative despite the presence of active disease. Intravenous penicillin G (24 million units per day for 7 to 10 days) is the indicated treatment. Recurrences may occur despite adequate therapy. Other bacterial and fungal causes of retinitis or endophthalmitis are uncommon in patients with HIV infection but should be considered in intravenous drug users and patients with systemic bacterial or fungal infection.4 Infectious Choroiditis Infectious choroiditis accounts for less than 1 percent of ocular disorders in most series of HIV-positive patients.4,47 The infectious agent is usually Pneumocystis carinii (Figure 1K), although other organisms have been identified. Most of the reported cases have been identified at autopsy, reflecting the often serious nature of the underlying systemic infections.47 Orbital Manifestations Orbital complications of HIV infection are uncommon. Orbital lymphoma48 and orbital cellulitis, usually due to aspergillus infection,49 have been reported most frequently. Lymphoma responds well to radiation and chemotherapy, whereas orbital cellulitis is treated with systemic antimicrobial agents. Neuro-Ophthalmic Manifestations Neuro-ophthalmic complications occur in 10 to 15 percent of HIV-infected patients.50-52The most frequent findings include papilledema from elevated intracranial pressure, cranial-nerve palsies, ocular- motility disorders, and visual-field defects (Table 1). Virtually any infectious or neoplastic process can produce these changes, but cryptococcal meningitis (Figure 1L), meningeal and parenchymal lymphoma, neurosyphilis, and toxoplasmosis are the most frequent causes. Patients with more diffuse encephalopathies related either to the direct effects of HIV infection (HIV encephalopathy) or to secondary infection with the JC polyomavirus, which causes progressive multifocal leukoencephalopathy,53 may have similar complications. Evaluation usually includes magnetic resonance imaging followed by a lumbar puncture to obtain cerebrospinal fluid for a cell count, cytologic studies, culture, and antibody and antigen testing. Treatment includes radiation and chemotherapy, in the case of lymphoma, and specific antimicrobial therapy, in the case of identified infections. There is currently no treatment for HIV encephalopathy or progressive multifocal leukoencephalopathy. Ocular Manifestations in Children
  • 19. Children are less likely than adults to have ocular manifestations of HIV infection, and the prevalence of cytomegalovirus retinitis is especially low in children (estimated at 5 percent in one study54). The reason for this difference is unknown but may be related to an altered immune response to HIV or to a lower prevalence of cytomegalovirus seropositivity in children. HIV-infected children are, however, at increased risk for neurodevelopmental delay,55 a condition often associated with neuro-ophthalmic disorders. A fetal AIDS-associated embryopathy with downward obliquity of the eyes, prominent palpebral fissures, hypertelorism, and blue sclerae has also been described.56 Ocular Manifestations in Developing Countries Ninety percent of HIV-infected persons live in developing countries, particularly those in sub-Saharan Africa and Southeast Asia.1,2 The few studies of ocular complications of HIV infection in these parts of the world suggest that cytomegalovirus retinitis occurs less frequently than in developed countries and that ocular complications of toxoplasmosis and tuberculosis, herpes zoster ophthalmicus, and papillomavirus-associated conjunctival squamous-cell tumors are more prevalent.57 The reasons for such an altered spectrum of ocular disease in patients in developing countries are almost assuredly related to higher frequencies of exposure to causative infectious agents and higher rates of death early in the course of HIV infection.5 Ocular Toxicity in HIV-Infected Patients Intraocular inflammation, or uveitis, occurs in up to one third of patients treated with high-dose rifabutin, particularly when an antifungal azole is used concurrently.33 Cidofovir34 causes uveitis in 25 to 30 percent of patients and may also cause low intraocular pressure, or hypotony, in up to 10 percent of patients. Mild uveitis is usually manageable with topical corticosteroid drops, but more severe uveitis and hypotony can cause permanent visual loss and should therefore prompt a change in medication. There have also been isolated reports of patients with abnormalities of retinal pigment epithelium associated with high-dose didanosine,58 corneal epithelial inclusions associated with intravenous ganciclovir and acyclovir,59 and corneal subepithelial deposits associated with atovaquone.60 Each of these effects appears to be dose-related and, with the exception of abnormalities of retinal pigment epithelium, tends to resolve once the drug has been discontinued. Supported by a grant from Research to Prevent Blindness. Dr. Margolis is the recipient of a Lew Wasserman Merit Award from Research to Prevent Blindness. Source Information From the Francis I. Proctor Foundation and the Department of Ophthalmology, University of California, San Francisco, Medical Center, San Francisco. Address reprint requests to Dr. Cunningham at the Francis I. Proctor Foundation, UCSF Medical Center, San Francisco, CA 94143-0944.