Fig. 1.11 Progressive outer retinal necrosis with retinal vein occlusion of inferotemporal branch in a patient with AIDS. (a and b) Right eye (RE) and left (LE), with a typical

onset in the posterior pole in the RE and atypical uninvolvement of the posterior pole in the LE. (c and d) The evolution with involvement of the entire retina and vein occlusion

epiretinal membrane (ERM), vitreous hemorrhage, retinal neovascularization, vitreomacular traction syndrome (VMTS), and PVR. Both the extent of past CMV retinitis and prior use of cidofovir appear to be risk factors for the development of IRU [63]. IRU should be treated with topical, periocular, and/or intraocular corticosteroids, as indicated [64].

Recently, there has been a report of a new clinical entity, CMV retinitis occurring in HIVpositive or HIV-negative patients after intravitreal triamcinolone injection. This likely occurs because of the immunosuppressed ocular environment after such injections. One must be aware that viral retinitis, though rare, may also occur after intravitreal triamcinolone [65].

To minimize the opportunity for IRU in patients not on HAART at the time of diagnosis, HAART should be started following the induction phase of anti-CMV treatment, and the CMV retinitis should be treated aggressively through the period of immune recovery [66].

Necrotizing Herpetic Retinitis (by Varicella Zoster)

Clinically, varicella zoster virus (VZV) may cause different diseases. Other than the classic picture of herpes zoster ophthalmicus, it has two other clinical forms: acute retinal necrosis (ARN) syndrome, a necrotizing retinitis that responds well to antiherpetic medication and can occur at any CD4+ T-lymphocyte counts, and progressive outer retinal necrosis syndrome which is associated with low CD4+ T-lymphocyte counts [1].

Retinitis caused by VZV in patients with AIDS is a clinical entity characterized initially by a multifocal outer retinitis that typically affects the posterior pole followed by a progressive outer retinal necrosis (PORN) with or without vitritis or with limited vasculitis (Fig. 1.11) [65–69]. Retinal whitening is occasionally accompanied by retinal hemorrhages. The visual prognosis is extremely poor; most of the cases reported so far have a final visual acuity of hand motions or worse. Although the reported incidence is only

4% of all retinal infections associated with AIDS, VZV retinitis is the second (in frequency) retinal infection in this patient group. The prevalence of PORN has dropped by nearly 90% in recent studies [15]. A concurrent or recent herpes zoster dermatitis provides added circumstantial support for the diagnosis [66–72], and 4–17% of HIV/AIDS patients with herpes zoster ophthalmicus go on to develop necrotizing herpetic retinopathy [73, 74]. The visual effects in the infected eyes are the most severe of all eye infections associated with HIV. In addition, contralateral eye involvement (initially not involved) even under antiviral therapy is over 70%, and the retinal detachments are common (>75% of cases) [65–71]. The risk of RD is greater than that observed with CMV retinitis. Herpes simplex virus is a rare cause of retinitis in HIV-infected patients [75, 76]. Like VZV retinitis, onset of symptoms and disease progression are rapid. Clinical appearance may mimic VZV retinitis.

VZV retinitis in AIDS patients currently consists of the following characteristics: (1) frequent previous episodes of cutaneous zoster in the 18 months preceding retinitis, (2) an account of CD4 + lymphocyte less than 50 cells/mL, (3) multifocal outer retinitis with initial predilection for the posterior pole, (4) relative absence of intraocular inflammation, (5) poor visual prognosis despite aggressive and prolonged intravenous therapy, and (6) increased risk of VZV encephalitis. These features distinguish it from acute retinal necrosis syndrome that typically occurs in immunocompetent patients but may also occur in HIV-positive patients with relatively higher CD4+ cell counts [71]. This may explain the features that differentiate ARN from PORN, including more prominent vitritis, more apparent involvement of the inner retina, retinal vasculitis, and involvement of the anterior segment.

In patients with severe immune compromise, VZV retinitis occurs with less iridocyclitis, vitritis, and vasculitis than typically seen in ARN. Furthermore, there is a trend of initial lesions to appear at the posterior pole rather than at the periphery and to be multifocal rather than confluent. The progression is fulminant with dramatic changes taking place in a week even

under therapy. Another interesting feature is that perivascular involvement occurs early and then progresses into the area between the vessels. This pattern leaves a perivascular area of retinal atrophy that appears to be relatively respected or unaffected, when in reality it is a completely atrophic area. It is not uncommon the progression to total retinal atrophy and retinal detachment in a few weeks despite antiviral treatment.

There are HIV-positive cases (with a lower degree of immunosuppression) with clinical characteristics identical to those of ARN in immunocompetent patients [71]. Is likely to be of the same illness (necrotizing herpetic retinitis) and with a progressive immunosuppression, depending on the degree of this, the clinical features of infection may change from ARN to PORN with fulminant course and extremely poor visual prognosis in most cases.

Treatment involves the use of intravenous, oral, and intravitreal antivirals. PORN has been suggested to be less responsive than ARN to therapy with intravenous (IV) acyclovir, or intravitreal ganciclovir or foscarnet [66, 77]. Despite the availability of at least three effective antivirals (acyclovir, ganciclovir, and foscarnet) with high activity in vitro against herpes virus family, the results are still unsatisfactory, and proper management of these patients is still unclear. Because most patients have been in contact with acyclovir in a chronic form (for the treatment of skin lesions), many have drug resistance. Therefore, a combined therapy of intravenous ganciclovir and foscarnet should be instituted immediately, and this should be continued indefinitely. In addition, one must consider the possibility of injecting foscarnet (2,400 mg) or high-dose ganciclovir (5,000 mg) into the vitreous cavity immediately to minimize the time that antiviral therapy will take to reach the affected tissue in an attempt to improve the prognosis of this devastating eye infection.

Toxoplasmic Retinochoroiditis

While ocular toxoplasmosis affects less than 1% of HIV-infected patients in the United States [78–84], there are areas with a higher seroprevalence of Toxoplasma gondii. The prevalence of toxoplasmosis varies according to dietary habits

and, therefore, from country to country. In Latin America, the rate is as high as 65% in some populations. As an example, in a native Yucpa community in Venezuela, the overall prevalence of infection was 63%. Fifty-nine subjects had total antibodies and 14 had IgM antibodies [85]. In addition, ocular toxoplasmosis affects up to 8.5% of patients with AIDS in Brazil [1].

Unlike ocular toxoplasmosis in immunocompetent individuals, the retinal lesions in toxoplasmic retinitis in patients with AIDS include multifocal or diffuse yellow-white areas of necrotizing retinitis with edematous aspect, blurred edges, and a relative lack of retinal hemorrhage (Fig. 1.12). The lesions are more edematous in appearance than those associated with CMV. Occasionally, vascular sheathing (usually periarterial) may be seen in these cases [78, 81]. Also, there may be a moderate-to-severe anterior chamber and vitreous inflammation (but in a much lesser degree than that observed in immunocompetent individuals) in one or both eyes which can cause visual impairment if left untreated. In contrast to infection in immunocompetent patients, the disease does not appear to originate from previous scars and probably results from a recently acquired infection or the spread of organisms from extraocular foci of disease.

Between 30% and 50% of patients with ocular toxoplasmosis will have involvement of the central nervous system, and all patients with HIV/AIDS thought to have toxoplasmic retinochoroiditis should undergo magnetic resonance imaging (MRI) scanning of the brain [80, 81]. The infection can be generalized, involving the

brain, eyes, lungs, heart, gastrointestinal tract, lymph nodes, liver, spleen, and bone marrow. Cerebral toxoplasmosis is the most common cerebral infection in AIDS and requires urgent treatment because it can be rapidly fatal [71].

Testing should include serological assays for IgG and IgM antibodies against toxoplasmosis, although the results may be negative in profoundly immunosuppressed patients [16]. The analysis of polymerase chain reaction (PCR) from samples of aqueous and vitreous humor has been reported, and this test is becoming more widespread and available.

Treatment consists of sulfadiazine (2 g initial dose and then 1 g orally every 6 h) and pyrimethamine (two doses of 50 mg every 12 h and then 25 mg orally every 12 h) or clindamycin (300 mg by mouth every 6 h for 4 to 6 weeks), either alone or in combination. Trimethoprim/ sulfamethoxazole (800/160) is given as one tablet by mouth twice daily. Atovaquone has been used successfully [1, 81] but is expensive and has yet to be shown superior to standard therapy [1]. Atovaquone is given as 750 mg by mouth four times daily for 3 months. Steroids are uncommonly used in HIV-positive patients with ocular toxoplasmosis unless there is a very severe vitreous reaction. Chronic or repeated therapy is often necessary, because reactivation and progression of retinochoroiditis occur frequently, particularly in patients with persistent severe immune deficiency. Silveira et al. have reported some evidence that long-term intermittent treatment with trimethoprim/sulfamethoxazole can reduce the rate of recurrent toxoplasmosis retinochoroiditis [86].

Fig. 1.13 (a) Luetic vitritis in a patient with AIDS. (b) Neurosyphilitic retinitis in a patient with AIDS

Syphilitic Uveitis, Papillitis, and Retinitis

Ocular syphilis is the most common intraocular bacterial infection in HIV-positive patients, historically affecting up to 2% of patients. The prevalence may be on the rise, with current estimates on the order of 6–9% [87], presumably due to resurgence in syphilis infections. The ocular manifestations of syphilis in patients with HIV are varied (syphilis is the “great imitator”) and include chorioretinitis, iridocyclitis, papillitis, vitritis (Fig. 1.13), intraretinal hemorrhages, and perivasculitis [88]. Intraocular inflammation may result in epiretinal membrane formation and tractional retinal detachment. The clinical appearance can vary; however, over 80% of HIV-positive patients with ocular syphilis have clinical or serological evidence of infection of the central nervous system (CNS) by Treponema pallidum. Therefore, we recommend conducting serological testing for confirmation of clinical diagnosis (FTA-ABS, VDRL, RPR); the tests are useful in

most cases (but may be negative in some cases of HIV-positive patients with evidence of secondary or tertiary syphilis).

The high correlation between neurosyphilis and ocular manifestations supports the current recommendation to perform a lumbar puncture and analysis of cerebrospinal fluid (CSF) in all HIV-positive patients with ocular syphilis. The treatment of ocular syphilis in this population should be the same as that used in cases of neurosyphilis: high doses of aqueous penicillin G at doses of 12–24 million units daily intravenously for 10–14 days. Most recommend IV therapy, but a second-line therapy includes 2.4 million units of intramuscular procaine penicillin daily plus 500 mg of oral probenecid four times daily for 10–14 days [89]. Recurrences may occur even after adequate treatment, and it is important to monitor serum and CSF reagin titers monthly for 3 months following the cessation of treatment, and every 6 months thereafter until the CSFVDRL becomes nonreactive and the CSF white cell count normalizes.

Candida Vitritis and Retinitis

Immunosuppression is a risk factor for the development of systemic candidemia with endogenous ocular affection, especially in patients who have been or remain with a central line catheter for a long time. AIDS patients fall naturally within this category, and Candida ocular involvement occurs frequently in HIV-positive patients.

Candida typical lesions have the appearance of white spots, not well-defined edges, often bilateral and located on the inner surface of the retina with frequent extension into the vitreous (Fig. 1.14). The vitreous usually shows inflammatory activity (vitreous abscesses have been reported in immunocompetent patients). If left untreated, these focuses of Candida will increase in size, resulting in extensive involvement with diffuse vitritis and potential severe vision loss (endogenous endophthalmitis).

Amphotericin B remains the drug of choice. This drug can be administered intravenously but has potentially severe side effects; therefore, each case must be individualized. The resolution of retinitis has been reported with a single intravitreal injection of amphotericin B (dose of