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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 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)

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)

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.

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)

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)

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 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.

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)

(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 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).

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 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 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 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.

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).

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 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 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 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 (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).