Pathogenesis, diagnosis, and clinical manifestations

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in AIDS. CMV retinitis has been reported to occur in 15–40% of AIDS patients with the rate declining since the arrival of HAART.^37,52,89,90 In contrast to the noninfectious lesions of AIDS, CMV retinitis demands aggressive treatment to prevent severe visual loss.^6,91,92 Patients with active CMV disease may have systemic symptoms of fever, arthralgia, and pneumonitis, or leukopenia, retinitis, or hepatitis; blood cultures and urine specimens may be positive for CMV. CMV retinitis often is the presenting sign of systemic CMV infection, and all patients should be thoroughly evaluated for systemic disease.

The clinical presentation of CMV retinitis in AIDS is similar in many respects to CMV retinitis found in iatrogenically immunosuppressed patients and infants with cytomegalic inclusion disease.^93,94 Correlation of the clinical and typical pathologic findings at autopsy has been demonstrated.⁹⁵ Specifically, it is known that CMV is a neurotropic virus with a tendency to infect neural tissues and the retina. Necrosis of the retina in AIDS-associated CMV retinitis is typical, with pathognomonic cytomegaly and minimal inflammatory cells present in the lesions. Choroidal involvement is rare, and whether vascular endothelium is involved is unclear. These lesions also may appear as noncontiguous patches rather than the more commonly seen contiguous spreading lesion. Antigens to CMV have been found by immunofluorescence, immunoperoxidase staining, and DNA hybridization techniques.^96,97 The most distinctive anterior segment finding is the presence of fine stellate keratic precipitates on the corneal endothelium.⁹⁸ Retinal vascular nonperfusion and retinal neovascularization resulting from CMV retinitis and choroiditis also have been reported.⁹⁹

CMV is a slowly progressive necrotizing retinitis that may affect the posterior pole, the periphery, or both, and may be unilateral or bilateral. Involved retinal areas appear as white intraretinal lesions, areas of infiltrate, and often necrosis along the vascular arcades in the posterior pole. In addition, prominent retinal hemorrhages often are present within the necrotic area or along its leading edge (Fig. 81.4). Peripherally, CMV retinitis occurs commonly; it tends to have a less intense white appearance, with areas of granular, white retinitis that may or may not demonstrate associated retinal hemorrhage (Fig. 81.5). As the retinitis progresses, an area of atrophic, avascular retina may remain with underlying retinal pigment epithelial atrophy or hyperplasia.^6,37,100 Peripheral CMV retinitis is common in AIDS patients who initially may report only floaters with or without a visual field deficit. Wide-angle fundus photography and fluorescein angiography may be of benefit if the diagnosis is uncertain. These techniques may be used to document progression of retinitis, and fluorescein leakage in areas of retinitis may be helpful in confirming the diagnosis (Fig. 81.6).

Fig. 81.4 CMV retinitis with hemorrhagic areas are seen superior to the fovea and a more dense area just below the fovea. Borders are opaque and associated with variable amounts of hemorrhage.

Fig. 81.5 (A) Peripheral CMV retinitis without retinal hemorrhage is characterized by white areas of retinal necrosis. (B) After healing, CMV retinitis leaves behind a glial scar without opacification (not same eye as in panel A). Often only minimal pigmentary changes are seen.

Fig. 81.6 Fluorescein angiogram of CMV retinitis lesion shows lack of perfusion and blockage, as well as staining and leakage of fluorescein from damaged retinal vessels.

Reactivation of CMV retinitis is characterized by reopacification of the border of the lesion followed by advancement. Smoldering retinitis (Fig. 81.7) and subtle reactivation may be difficult to recognize without prior fundus photographs. Several studies have shown that wide-angle fundus photographs are a more sensitive indicator of retinitis progression than is clinical examination by indirect ophthalmoscopy.^101,102

Fig. 81.7 Smoldering CMV retinitis is a low grade of retinitis border activity that is associated with slow progression of retinitis. It may be difficult to diagnose without fundus photographs. (A) Low grade CMV lesion. (B) Lesion has progressed slowly over 2 months.

Several investigators have shown that untreated CMV retinitis is inexorably progressive in AIDS patients.^{6,52,94,96,102,103} As in our experience, untreated CMV becomes bilateral in the vast majority of patients. In an observational study of 26 patients treated for CMV retinitis, vision scores decreased with greater abnormalities found on ophthalmologic examination. Visual symptoms were most strongly related to findings in the worse eye. Patients reported considerable impairment, including blurred vision (42%), difficulty reading (40%), difficulty driving (44%), treatment interference with social activities (40%), and substantial trouble with vision (50%).¹⁰⁴ Treatment of AIDS-related CMV retinitis minimizes loss of vision and may protect previously uninfected eyes, prolonging visual independence.¹⁰⁵

Recurrent CMV retinitis exhibiting a foveal-sparing pattern within 1500 mm of the foveola has been described and occurs primarily in patients with recurrent CMV retinitis resistant to treatment (“clinically resistant”), particularly that which has arisen temporally. Despite its foveolar proximity and ultimate significant loss of function, the pattern of progression allows for preservation of useful foveal vision for longer periods than would have been expected.¹⁰⁶

Other manifestations of CMV retinitis include retinal edema, attenuated vessels, perivascular sheathing, and exudative retinal detachment¹⁰⁷ (Fig. 81.8). In addition, vitritis and anterior uveitis are often seen, and optic atrophy may occur as a late manifestation resulting from widespread retinal destruction. CMV occasionally may be demonstrated in vitreous biopsy specimens in these patients.⁹⁵ The yield may be higher in the presence of marked vitritis because CMV is a cell-associated virus. Other causes of retinitis, including herpes simplex retinitis,^93,108 toxoplasmosis,⁶² candidal infection, Behçet disease, syphilis, acute retinal necrosis,^109,110 and subacute sclerosing panencephalitis, usually can be distinguished from CMV on clinical grounds, although this may not be the case in retinitis caused by other members of the herpesvirus family.¹⁰⁹ CMV has a very characteristic clinical appearance, but the lesions in CMV retinitis vary from patient to patient, and it is important to maintain a high index of suspicion for the above infections, especially in light of frequent superinfection of AIDS patients with multiple organisms.^6,82,83

Fig. 81.8 CMV affecting the perifoveal area or the optic nerve can result in an exudative retinal detachment often involving the macula. If there has not been actual involvement of a vital structure, treatment may result in improvement of central vision.

CMV retinitis is a reflection of underlying active systemic CMV infection. In almost all cases it is a blinding disease if not controlled. Thus, in the face of changing mental status, development of focal signs on neurologic examination, or other symptoms consistent with subacute encephalitis in AIDS patients, a comprehensive ophthalmologic examination is indicated, and an increased index of suspicion of CMV infection of the CNS and possible CMV retinitis is warranted. There is also evidence that patients with CMV retinitis, especially peripapillary disease, have a much higher incidence of CMV encephalitis. CMV infection of the brain, optic nerves, and retinas from 47 consecutive autopsies of patients with AIDS was examined.¹¹¹ Immunocytochemistry demonstrated CMV infection in 11 (23%) brains, 2 (2%) of 94 optic nerves, and 38 (40%) of 94 retinas. Ten (91%) of 11 patients with CMV encephalitis had concurrent retinitis. While 10 (42%) of 24 patients with CMV retinitis had CMV encephalitis, when the retinitis included the peripapillary region, 75% had encephalitis. The optic nerve parenchyma usually was not infected histologically despite extensive peripapillary retinitis. The strength of these associations suggests that CMV retinitis defines a group of patients with AIDS at risk for development of CMV encephalitis (relative risk, 9.5%), especially when the retinitis involves the peripapillary region (relative risk, 13%). Furthermore, in patients with AIDS without CMV retinitis, central nervous system symptoms are unlikely to be attributable to CMV encephalitis.¹¹¹ The pathologic correlation between ocular and cerebral lesions in patients with AIDS has been reviewed.¹¹²

CMV retinitis is less frequent in children with AIDS, with reported rates of approximately 5–6%, though rates of extraocular CMV are higher than in adults. CMV retinitis has been reported in young children with high absolute CD4 counts, though these counts are low relative to the child’s age. Older children tend to have low absolute CD4 counts similar to adults. There is a higher incidence of bilateral and posterior pole disease in children, however this is likely due in part to delays in diagnosis in children from lack of subjective vision complaints.^113–115

Screening techniques for retinal and systemic CMV infection

Screening for CMV retinitis is a difficult problem. Many patients who are CMV-viremic or -viruric may not have end-organ disease, and studies employing quantitative CMV polymerase chain reaction (PCR) in plasma or CMV antigenemia have not been able to definitively predict the development of CMV retinitis.¹¹⁶ Currently no laboratory marker exists that reliably predicts the occurrence of clinical CMV retinitis.

Urine is culture-positive for CMV in more than 50% of homosexual men and the majority of AIDS patients; thus urine culture may not be of diagnostic value. Serology in AIDS patients is nonspecific, and documentation of rising CMV titers is unusual.^6,96 Studies of newly diagnosed CMV retinitis patients indicate that many are CMV culture-negative in the blood. Positive blood cultures for CMV, fever, and weight loss are associated with more extensive CMV retinitis at the time of diagnosis.¹¹⁷ The results of virologic blood assays for CMV also have been associated with clinical outcome in patients with CMV retinitis.¹¹⁸ Thus assays for the detection of CMV antigenemia may be a simple and rapid means of identifying those patients with unilateral retinitis at highest risk of developing CMV retinitis of the fellow eye or of visceral CMV disease if intravitreal injections or implants are used as the sole treatment for CMV retinitis.¹¹⁹

A positive PCR result supports the clinical diagnosis and may be useful for monitoring response to antiviral treatment. By prospective monitoring for increases in plasma CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.¹²⁰

It is also reasonable and practical to use the CD4 cell count as a threshold below which to screen patients, since the risk of CMV retinitis increases at CD4 cell counts below 50/mm³.⁷⁴ The incidence and prevalence of CMV retinitis in a cohort study of patients with CD4 cell counts below 0.10 × 10⁹/L (100/µl) revealed a 25% chance for the development of CMV retinitis by 4 years of follow-up. Among those subjects in whom CMV retinitis developed, about 19% had retinitis before a CD4 cell count of less than 0.05 × 10⁹/L (<50/µl) was observed, and 81% had CMV retinitis after the CD4 cell count reached this threshold.¹²¹ In the HAART era, some patients may develop CMV retinitis with CD4 counts above 100/ml, probably because of incomplete restoration of the immune repertoire against CMV.¹²²

A technique for screening for central CMV retinitis, entoptic perimetry, employs patient visualization of moving particles on a computer monitor, appears to have a very high sensitivity and specificity (over 90%) in detecting CMV retinitis within the central 30-degrees radius of fixation⁷⁹ (Fig. 81.9).

Fig. 81.9 Entoptic perimetry can allow detection of CMV retinitis lesions. (A) The patient is asked to view particle motion programmed on a monitor. (B) An overlay of the CMV lesion (dotted white border) and the patient’s own sketch of the scotoma seen (black line).

Techniques for detection of CMV DNA based on PCR are increasingly being applied to ocular fluids; however, the clinical significance of such findings can sometimes be unclear. The application of PCR-based methods to ocular fluids made a useful contribution to the treatment of the patients.¹²³

This appears to be a sensitive and specific diagnostic assay that could assist in the diagnosis of CMV retinitis.¹²⁴ PCR detection of CMV DNA has been reported to be a more sensitive method than analysis of locally produced antibodies by calculating a Goldman–Witmer coefficient to determine local ocular antibody production. There is also an immune predisposition to the development of CMV retinitis in patients with AIDS.^125,126

Treatment of CMV retinitis

The treatment of CMV retinitis has been reviewed.^127,128 Treatment may be systemic, local, or a combination of the two. There are currently five medications approved by the US Food and Drug Administration (FDA) for the treatment of CMV retinitis: ganciclovir, valganciclovir, cidofovir, foscarnet. Fomivirsen, the first antisense drug with a relatively long duration of action, is no longer available in the United States.

Systemic therapy of CMV retinitis

CMV retinitis may be treated systemically or intravitreally. However, systemic treatment is associated with less spread of CMV retinitis from one eye to the other.¹²⁸ In addition, local treatment including the sustained release ganciclovir implant has been shown to be associated with higher risk of the development of systemic CMV.^129,130

Systemic CMV may cause gastrointestinal disease, with colitis being the most common manifestation as well as esophagitis. Systemic CMV diagnosis may be difficult and usually requires histopathologic evidence of CMV infection. The cumulative incidence of systemic CMV disease that becomes clinically apparent is approximately 25%.¹³¹ Therefore, although systemic CMV disease may not be clinically apparent at the time of diagnosis of CMV retinitis, some experts believe that initial systemic therapy may be warranted despite the inconvenience, expense, and potential toxicities.

Intravenous ganciclovir

Ganciclovir is a nucleoside analog of 2-deoxyguanosine, similar to acyclovir.¹³² Despite its structural similarities with acyclovir, ganciclovir is much more active in vitro against CMV than acyclovir.¹³³ Ganciclovir inhibits all herpesviruses, including CMV, by preventing DNA elongation. CMV lacks the virally specified thymidine kinase (TK) that converts ganciclovir (or acyclovir) to its monophosphate form.¹³⁴ TK-altered strains resistant to acyclovir are as sensitive to ganciclovir as the unaltered parent strains. Thus ganciclovir is phosphorylated to its triphosphate form much more efficiently than acyclovir, which accounts for the greater activity of ganciclovir against CMV.¹³⁵

The majority of AIDS patients treated with ganciclovir respond within 2–4 weeks with decreased retinal opacification and stabilization of the retinitis⁸⁹ (Fig. 81.10). Ganciclovir is commercially available as an intravenous and oral formulation (and also is included in an intraocular device), and indefinite maintenance therapy is necessary as long as the patient remains in immune failure with a CD4 count below 50/µl. An intravenous loading dose of 5 mg/kg every 12 hours for 14–21 days should be followed by maintenance doses of 5 mg/kg/day. If the drug is discontinued, retinitis often recurs within 10–21 days, continuing its progression at the borders of healed areas.⁸⁹ Recurrences have been common, even during maintenance therapy, being reported 3 weeks to 5 months after institution of therapy and occurring in 30–40% of patients.⁸⁹ Many investigators have found that discontinuation or delay of ganciclovir therapy results in nearly 100% recurrence of retinitis, at which time reinstitution of the loading dose regimen often is necessary.^134,136,137 Multiple series in patients with AIDS and CMV retinitis have shown response rates of 80–100%, with 60–80% of patients achieving a remission with ganciclovir therapy.^37,137–141

Fig. 81.10 (A) Active peripheral CMV retinitis with secondary retinal vasculitis. (B) The area is healed after intravenous ganciclovir therapy. Note absence of border opacification. Also seen are pigmentary changes characteristic of healed CMV.

The treatment of CMV retinitis usually includes an induction phase followed by a maintenance phase to prevent relapse. Before the advent of HAART, relapse occurred almost universally, given a sufficiently long period after induction courses of ganciclovir. Therapy therefore continued for a lifetime. The median time to relapse in patients treated with just an induction dose is 3–4 weeks.¹³⁷

Most clinicians use a 14-day induction course of intravenous ganciclovir consisting of 5 mg/kg/day every 12 hours and indefinite maintenance of 5 mg/kg/day. Lower doses and every-other-day dosing schedules have been associated with high rates of early relapse. Since treatment may be lifelong if the patient’s CD4 count cannot be elevated with anti-HIV therapy, usually a permanent or semipermanent indwelling venous catheter is placed at the onset of therapy if intravenous therapy is chosen as maintenance therapy. Ganciclovir requires modification of dosing in the presence of renal insufficiency.

Side-effects of ganciclovir include granulocytopenia, neurologic dysfunction, abnormal liver function tests, and rarely, thrombocytopenia. The most serious toxicity is granulocytopenia, which may occur in up to one-third of patients when defined as less than 500 neutrophils per microliter.¹³⁷ Granulocytopenia is generally reversible, and this adverse effect is exacerbated when used with AZT.¹⁴² The use of colony-stimulating factors rGM-CSF (recombinant granulocyte–macrophage colony-stimulating factor) and rG-CSF (recombinant granulocyte colony-stimulating factor) for reversing or preventing neutropenia may be useful.

The prevalence of CMV resistance to ganciclovir is unknown, but ever-increasing induction regimens may be necessary to control CMV retinitis. Strains of CMV that develop resistance to ganciclovir may remain susceptible to foscarnet. Because of the question of ganciclovir resistance, a trial of combined vs alternating foscarnet–ganciclovir maintenance therapy has been reported to be effective.¹⁴³

Visual acuity depends on the location of the involved retina, and involvement of the fovea or optic nerve may result in decreased visual acuity even if there has been a response to therapy. Ganciclovir has been shown to be effective in preserving visual acuity. For example, 73% of eyes maintained a visual acuity of 20/40 or better when treated with ganciclovir.¹⁴⁴

Summary of initial systemic CMV retinitis treatment

The initial treatment of CMV retinitis is usually oral valganciclovir 900 mg twice a day for induction therapy of approximately 3 weeks followed by 900 mg daily for maintenance therapy. Intravenous ganciclovir can be used if a patient has a contraindication to oral treatment such as malabsorption. The dose for intravenous ganciclovir is 5 mg/kg twice a day for induction therapy for 2–3 weeks followed by maintenance therapy at 5 mg/kg daily or 6 mg/kg 5 days/week. Induction therapy with intravenous foscarnet is dosed at 90 mg/kg twice a day for approximately 2 weeks followed by maintenance therapy at 120 mg/kg daily. Intravenous cidofovir for induction therapy is dosed at 5 mg/kg weekly for approximately 3 weeks followed by maintenance therapy dosed at 3–5 mg/kg every 2 weeks.

Intraocular therapy of viral retinitis

Ganciclovir intraocular device

An intraocular sustained-release ganciclovir delivery implant that releases drug into the vitreous is commercially available.¹⁹⁸ These surgically implanted, time-release implants have been shown to be more effective than intravenous ganciclovir alone in delaying the progression of CMV retinitis.^129,199,200

Insertion of the device requires a pars plana incision and a partial vitrectomy. The implant is sewn into the pars plana behind the lens.¹⁹⁸ Insertion of the ganciclovir intraocular device (GIOD) requires trimming the strut of the device so that it is nearly flush with the drug pellet. A 5.5 mm incision can be made 4 mm posterior to the limbus with a microvitreoretinal blade or similar instrument (Fig. 81.11). A unimanual bipolar intraocular cautery can be used to coagulate bleeding choroid. It is important to ensure that the incision is full-thickness, since the device can be inserted inadvertently under the pars plana. A suture is placed through the preplaced hole (the surgeon must make the hole) in the strut of the device; 8–0 Prolene can be used. The device is anchored in the middle of the wound, and running or interrupted sutures can be used to close the wound. Astigmatism can result from overzealous wound closure; this is usually transient. This procedure can be performed in an outpatient setting under local anesthesia.

Fig. 81.11 (A) Insertion of ganciclovir intraocular device. (B) The device can be seen inferotemporally through a dilated pupil.

Despite the relative ease of insertion, it has become clear that the risk of retinal detachment in the first 2 months after insertion is substantially higher than if other methods are used to control retinitis, though in the long term there is no statistical difference in retinal detachment rate.^{198,201–203} In addition, the risk of postoperative endophthalmitis appears to be a real one, with incidences on the order of 1% or sometimes higher.²⁰⁴ The intravitreal levels attained by this drug are over twice those after intravenous administration, and this appears to be associated with a lower incidence of resistance and progression of retinitis. This is particularly true in newly diagnosed cases, but failure can occur in up to 25% of such cases within the first 2 months. In a study of 91 implants in 70 eyes, GIOD was effective as an adjunct to continued systemic therapy in those patients with recurrent CMV retinitis.²⁰⁰ Intraocular sustained-release implants have been used to treat acute CMV disease and to prevent recurrence. Pathology studies of eyes having undergone implantation with the GIOD have shown no evidence of intraocular toxicity.¹³⁶ It is not certain whether implants should be exchanged at the 7-month time period or whether retinitis should be allowed to reactivate before replacing the implant.

Intravitreal cidofovir

Another form of intraocular therapy is intravitreal cidofovir (HPMPC), which is injected every 6 weeks. This work was initiated after discovery of long-acting properties of the drug in the eye. The safety and efficacy of intravitreal cidofovir for CMV retinitis in humans were reported in a phase I/II unmasked, consecutive case series in a single-center institutional referral practice. Eligible patients with AIDS had active CMV retinitis in at least one eye, despite adequate intravenous therapy with ganciclovir or foscarnet, were intolerant to intravenous therapy, were noncompliant with intravenous therapy, or refused intravenous therapy. In a preliminary safety study (group 1), 10 eyes of nine patients received 14 injections of cidofovir while being treated concurrently with intravenous ganciclovir. In a dose-escalating efficacy study (group 2), eight eyes of seven patients received 11 injections of cidofovir as sole treatment for CMV retinitis. The primary outcome was time to retinitis progression. In group 1 eyes receiving 20 µg of cidofovir, the median time to retinitis progression was between 49 and 92 days (mean, 78 days). In group 2 eyes treated with 20 µg of cidofovir with probenecid, the median time to retinitis progression was 64 days (mean 63 days). Hypotony occurred in the two eyes treated with a 100 µg dose of cidofovir and in one of three eyes receiving a 40 µg dose. No adverse effects resulted from the remaining 20 µg cidofovir injections. Cidofovir was found to be safe and effective for the local treatment of CMV retinitis, providing a long duration of antiviral effect (Fig. 81.12).²⁰⁵

Fig. 81.12 (A) Active CMV retinitis with no systemic treatment. The eye was injected with a single injection of cidofovir 20 µg via the pars plana. (B) The retinitis remains healed 53 days later, with no other therapy.

It was then shown that injections of 20 µg of intravitreal HPMPC resulted in complete suppression of CMV replication with no advancement of retinitis borders when given every 6 weeks.^{170,205–209} This medication must be given with oral probenecid. Probenecid 2 g is given orally 2 hours before, and 1 g 2 hours and 8 hours after injection.

Two types of adverse events may occur after intravitreal cidofovir injection: iritis and hypotony. The incidence of these is not dissimilar to what is seen after intravenous administration. The incidence of iritis can be reduced from 70% to 18% if oral probenecid is used, and it is now recommended universally. Iritis can be managed with topical steroids and cycloplegia; however, it may lead to cataract and synechiae in the long term. A mild, asymptomatic 20% reduction in intraocular pressure (IOP) is seen almost universally after cidofovir injection, and this appears to be of no concern. The mechanism of this has been defined by ultrasound biomicroscopy, which has disclosed that severe hypotony after cidofovir injections is associated with ciliary body atrophy.²⁰⁶ Reduction in aqueous flow has been demonstrated by aqueous fluorophotometry. This effect on secretory epithelia also is probably responsible for the nephrotoxicity of the drug when given intravenously. Indeed, probenecid also is given before and after each intravenous infusion to prevent uptake by the proximal tubule of the kidney and associated nephrotoxicity. Profound hypotony with vision loss occurs in approximately 1% of injections.

A retrospective, cohort study described iritis and hypotony after treatment with intravenous cidofovir for CMV retinitis in association with intraocular inflammation.¹⁶⁸ Eleven cases of iritis (26%) occurred among 43 patients. In six cases the iritis was bilateral. Patients who experienced iritis were more likely to have been previously treated for CMV retinitis (P = 0.03), to be diabetic (P = 0.05), or to be receiving protease inhibitors (P = 0.001). The onset of iritis occurred at a mean (±SD) of 4.9 ± 1.8 days after a cidofovir dose and after a mean (±SD) of 4.2 ± 1.6 doses of cidofovir. Six eyes of four patients had hypotony. Five eyes of five patients had a persistent decrease in visual acuity of at least 2 Snellen lines. Acute intraocular inflammation may occur with or without hypotony after intravenous cidofovir therapy, similar to the reactions seen after intravitreous administration. Cidofovir therapy can be continued in some patients if medical necessity warrants, but inflammation may recur or permanent hypotony develop.

A lower cidofovir dose (10 µg) has been used to investigate methods of reducing the toxicity of intravitreal cidofovir. This dose is effective in healing retinitis in 75% of patients, but the response in 25% is inadequate. The 10 µg dose, however, is not associated with a significant incidence of iritis or IOP lowering. Cidofovir should be diluted in a sterile manner by a pharmacist. It can be diluted in normal saline and frozen for extended periods in single-dose vials.

The efficacy and safety of multiple intravitreal cidofovir (HPMPC) injections given every 5–6 weeks for the maintenance treatment of CMV retinitis with 20 µg intravitreally injected was shown to be highly effective, with only rare episodes of reactivation and progression.¹⁷⁰

A correlation between IOP and CD4 T-lymphocyte counts in patients with HIV with and without CMV retinitis has been described.²¹⁰ IOP was measured with calibrated Goldmann applanation tonometers in two groups of patients. Group A included 84 HIV patients (120 eyes) with CMV retinitis, and group B included 110 HIV patients (183 eyes) without CMV retinitis; 33 patients without HIV (66 eyes) were included as a control group. Step-wise regression analysis of IOP included correlation with CMV retinitis (presence, extent, and activity), CD4 T-lymphocyte count, age, and gender. The mean IOP was 9.8 mmHg in group A, 12.6 mmHg in group B, and 16.1 mmHg in the control group. All three groups were statistically different from each other when intraocular pressure was compared (P < 0.0001). Step-wise regression showed that low CD4 T-lymphocyte count and extent of CMV retinitis both correlated to low IOP. These results demonstrate that IOP is lower than normal in patients with HIV and that decreased CD4 T-lymphocyte count is the major factor associated with low IOP, accounting for 20% of the effect. The extent of CMV retinitis accounts for 8% of the effect.

Investigational agents for CMV retinitis

Rhegmatogenous retinal detachment in CMV retinitis

Retinal detachment is a common cause of vision loss in patients with CMV retinitis. In the pre-HAART era, the incidence rate of retinal detachment in patients with CMV retinitis was approximately 33% per eye per year.^{137,144,203,222–224} The incidence of retinal detachment in immunosuppressed patients with CMV retinitis was believed to be higher in patients treated with anti-CMV therapies, specifically ganciclovir.^225–227 These retinal detachments were characterized by multiple peripheral breaks in areas of healed atrophic retinitis; and in some patients severe proliferative vitreoretinopathy resulted (Fig. 81.13).²²⁸ Detachment occurred from weeks to months after institution of intravenous ganciclovir therapy and was frequently bilateral. Retinal detachment may also complicate the course of CMV retinitis.

Fig. 81.13 Retinal breaks are seen just peripheral to the area of border opacification; the retina is detached.

However, it now appears that rhegmatogenous retinal detachment is associated with healed or active CMV retinitis due to breaks in the necrotic retina.²²⁹ Results of a multicenter, prospective, randomized, controlled clinical trial analyzing incidence and risk factors for rhegmatogenous retinal detachment in a population of patients with newly diagnosed CMV retinitis treated with foscarnet vs ganciclovir revealed that retinal detachment in patients with CMV retinitis is unrelated to the type of intravenous therapy used or to refractive error. The median time to retinal detachment in an involved eye with CMV retinitis and free of retinal detachment at baseline was 18.2 months.²²³

Studies have confirmed that the risk factors for retinal detachment in eyes with CMV retinitis include the extent of peripheral CMV disease, as well as retinitis activity and involvement of the anterior retina near the vitreous base.^203,223,230 This is logical, considering that in most cases the causative retinal breaks are within or at the border of healed CMV retinitis lesions. In addition, any intervention that violates the vitreous (e.g. vitreous biopsy or insertion of the ganciclovir implant) would be expected to accelerate the development of vitreous detachment or liquefaction, which would increase the risk of retinal detachment.^199,201,203

With the advent of HAART therapy the incidence of CMV retinitis-related retinal detachment has decreased by 60%. The success of HAART in the reduction of retinal detachment risk may be related to the improved immune control over CMV replication, thus protecting against progression of disease to larger lesion sizes. The altered pattern of inflammation with HAART-mediated immune improvement may also change the course of vitreous detachment, a key step in the development of CMV-related detachments, thus altering the retinal detachment risk.^199,203,231

Patients with AIDS and CMV retinitis are surviving longer as a result of the use of HAART and improved treatment of opportunistic infections. As a result, though the incidence rate of retinal detachment is lower, the overall prevalence of retinal detachment may become an increasingly common cause of visual morbidity in these patients. In the pre-HAART era, the incidence and outcome of retinal detachment complicating CMV retinitis were studied at two London AIDS centers. Patients with CMV retinitis were identified prospectively and underwent standard treatment. Retinal detachments were diagnosed during regular follow-up. If retinal reattachment surgery was performed, a standard procedure of vitrectomy and internal tamponade with silicone oil was employed. Of 147 patients with CMV retinitis, 41 (28%) developed retinal detachments (47 eyes); 43 detachments were rhegmatogenous and four were exudative. At the last clinic visit, eight eyes (53%) maintained a visual acuity of 6/60 or better. The visual results of surgery are good in selected patients, bearing in mind the progressive nature of the underlying disease and poor life expectancy.²³²

Vitrectomy with silicone oil tamponade also was studied in eyes with retinal detachments related to CMV retinitis or acute retinal necrosis.²³³ Anatomic reattachment was achieved in all eyes, and preservation of ambulatory vision was achieved in most eyes. Visual acuity was limited by concomitant optic nerve disease in some eyes. The authors noted that surgical repair employing silicone oil produces excellent results and that prognosis for vision is strongly related to preoperative visual acuity.

Treatment of retinal detachment consists of vitrectomy, posterior hyaloid removal, and intraocular tamponade with silicone oil or long-acting gas.²³⁴ Retinal reattachment surgery in 29 eyes of 24 patients with AIDS and retinal detachment associated with CMV retinitis was described by Freeman et al.²²⁹ In this study the total retinal reattachment rate was 76%, and the macular attachment rate was 90% after one operation. The mean postoperative visual acuity (best corrected) was 20/60, but in some patients visual acuity decreased because of progressive CMV retinitis. Prophylactic laser photocoagulation of fellow eyes did not appear to prevent retinal detachment (Fig. 81.14).

Fig. 81.14 (A) Preoperatively the macula has been shallowly detached, associated with a rhegmatogenous CMV-related retinal detachment. (B) Postoperatively the retina is reattached; silicone oil is in place, and the visual acuity is 20/40. Good visual recovery may be possible even with macula-off detachments because the detachment may be shallow as the vitreous is well formed; the retina may not be completely detached from the macula, and the macular detachments may be shallow.

The repair of retinal detachment in eyes with viral retinitis is complex and is performed using a combination of pars plana vitrectomy, internal tamponade (usually with silicone oil or a long-acting gas such as perfluoropropane), and endolaser often combined with scleral buckling.²²⁹ Pneumatic retinopexy can cause retinal traction and seldom is useful in these eyes. The most common causes of rhegmatogenous retinal detachment in AIDS patients with viral retinitis are acute retinal necrosis syndrome and previously treated CMV retinitis. In these eyes proliferative vitreoretinopathy occasionally is established at the time of detachment or has the potential to occur as a result of multiple retinal breaks and necrosis combined with intraocular inflammation. Scleral buckling alone often is unsuccessful in these cases because of the numerous areas of retinal necrosis and break formation. Retinal breaks are often not apparent until the time of vitrectomy, and the configurations of the retinal detachments are atypical because of peripheral retinal scarring and adhesion to the pigment epithelium and choroid. Thus in these eyes rhegmatogenous retinal detachments may not extend to the ora serrata. In eyes with CMV retinitis, we have favored an approach using complete delamination of the posterior hyaloid combined with endodrainage and permanent tamponade with silicone oil, although we have had good success with intraocular long-acting gases in cases of more limited retinitis and retinal detachment. We have had a very high surgical success rate with this approach. Patients with AIDS and CMV retinitis appear to be surviving longer, and survival after retinal reattachment surgery has been increased to between 6 months and 2 years.²²⁹

To determine if scleral buckling is of any benefit in surgical repair of CMV-associated retinal detachment if combined with vitrectomy, silicone oil, and inferior midperipheral endolaser, 22 consecutive eyes with CMV-associated retinal detachments were repaired with vitrectomy and endolaser to all breaks and to the inferior midperipheral retina using silicone oil without scleral buckling. Results were compared with another series of 56 consecutive eyes undergoing vitrectomy, silicone oil injection, endolaser to all breaks, and 360 degrees encircling scleral buckling. Total retinal reattachment rates were 84% for group 1 and 86% for group 2. Rates of macular reattachment were 91% for group 1 and 91% for group 2. Mean best postoperative refracted visual acuity was 20/66 for group 1 and 20/67 for group 2. Median best postoperative refracted visual acuity was 20/74 for group 1 and 20/80 for group 2. These differences between the two groups were not statistically significant. Patients who underwent surgery with the macula attached had a better postoperative visual outcome. Thus, scleral buckling may not be necessary in CMV-related retinal detachment if repaired with vitrectomy, silicone oil, and inferior midperipheral endolaser.²³⁵ Elimination of scleral buckling may reduce intraoperative time, patient morbidity, and the risk of an accidental needle-stick. Patients with macula-on-retinal detachments also should be considered for surgery before macular detachment occurs.²³⁶

The long-term visual results of CMV retinal detachment surgery are still in question, however, and visual acuity may be limited by factors such as refractive problems resulting from silicone oil and cataract^{228,237–241} (Fig. 81.15). In addition, posterior capsule fibrosis is very common if subsequent cataract surgery is performed in the presence of silicone oil. Methods to reduce visual acuity loss from cataract include judicious use of gas tamponade with scleral buckling instead of silicone oil, and removal of silicone oil prior to or at the time of cataract surgery. Posterior capsule fibrosis can be treated with Nd : YAG capsulotomy, though success is higher if the silicone oil has been previously removed.²³⁸

Fig. 81.15 Postoperatively, inferior retinal redetachment posterior to scleral buckle with use of silicone oil. The detachment has been walled off by laser that was applied intraoperatively. Inferior laser photocoagulation may obviate the need for encircling scleral buckling in CMV-related retinal detachments.

The general operative approach to these eyes is by pars plana vitrectomy, and the surgeon should leave the lens intact whenever possible. After the vitreous gel is removed, all epiretinal membranes are segmented and traction is removed, allowing the retina to become mobile. In some cases the peripheral vitreous gel is adherent to the necrotic peripheral retina and cannot be removed without causing further retinal damage. The use of a soft-tipped extrusion needle may allow the surgeon to remove the posterior hyaloid over broad areas of the retina. A posterior retinotomy is made, and, if an endoretinal biopsy is to be performed, it is done at the location of the posterior retinotomy that will be used for internal drainage.^229,234 A pneumohydraulic exchange is made through the retinotomy site, attaching the retina and filling the eye with air using a constant-pressure, sterile, air-delivery pump. Retinopexy is placed around all breaks in eyes to be treated with a long-acting gas. The peripheral retina may be encircled with either a small buckle or a band to relieve vitreous base traction, which may become a problem later in these inflamed eyes. In eyes with widespread retinal necrosis, most surgeons use silicone oil because it permanently tamponades all retinal breaks, including future sites of retinal necrosis and break formation.

In the HAART era, PVR may be seen in CMV detachment. This may be due to immune recovery uveitis causing a propensity to intraocular inflammation.²⁴² The management of CMV-related rhegmatogenous retinal detachments has been reviewed.²⁴³ Certainly, it may be useful in acute retinal necrosis (ARN) because rhegmatogenous retinal detachment develops in a large number of patients with ARN. Similar considerations apply in bilateral healed CMV retinitis. The difficulty in both diseases is that all areas of retinal involvement must be surrounded with three rows of argon laser treatment. It is often impossible to carry out treatment to the ora serrata, however, and fluid may leak anteriorly and cause retinal detachment despite treatment. The widespread availability of the indirect laser ophthalmoscopic delivery system should solve this problem. In addition, subretinal fluid may break through a wall of laser treatment if the mass of detached retina and subretinal fluid is relatively large. For this reason most surgeons advocate placement of a panretinal type of pattern within the area of healing retinitis as well.^244–247

HIV disease/CMV retinitis in the HAART era

Since the advent of HAART many patient have had dramatic restoration of immune system function. This also may be associated with a sustained drop in the plasma HIV viral load to low or undetectable levels. This suppression of plasma viremia may be prolonged; however, the HIV genome may still be found.^37,248 As mentioned earlier, with the prevalent use of HAART, the incidence of CMV retinitis has decreased approximately 75%.^249–252 For patients with CMV retinitis on HAART the risk of vision loss is lower,²⁴⁹ the risk of retinal detachment is approximately 60% less, and long term survival is much higher.^203,249

In fact, for patients who have healed CMV retinitis and respond to HAART, discontinuation of maintenance therapy for CMV disease has been shown to be safe in a subset of patients.^{249,253–257} We have found that some of these patients may discontinue anti-CMV therapy without reactivation of retinitis (Fig. 81.16). These data suggest that HAART therapy also is permitting at least partial immune reconstitution in some patients. Thus a trial of withdrawal of CMV therapy may be indicated in some patients with good response to HAART therapy and well-healed CMV retinitis. Patients should have a sustained CD4 count elevation of over 100 cells/mm³ for at least 3–6 months before discontinuing anti-CMV treatment and should be carefully monitored for reactivation. Reactivation of CMV retinitis may occur after successful HAART therapy when the CD4 count diminishes.²⁵⁸ In addition, some patients may develop CMV retinitis on HAART with CD4 counts above 100/µl, probably because of incomplete restoration of the immune repertoire against CMV.¹²²

Fig. 81.16 (A) Active CMV retinitis required treatment with systemic ganciclovir. (B) The patient was subsequently treated with highly active antiretroviral therapy, with increase in CD4+ cell count to over 100 cells/ml. The retinitis had remained healed. (C) The patient’s systemic anti-CMV therapy was withdrawn, and the retinitis has remained healed for over 6 months. The CD4+ cell count remains over 100.

The effects of HAART on the natural history of other AIDS-related opportunistic disorders have been summarized^259,260 and reflect the improvement or resolution of changes in the natural history of these disorders with inflammatory syndromes. The development of CMV retinitis relatively soon after initiation of HAART has been described.²⁶¹

Immune recovery uveitis

In conjunction with the dramatic improvements in the immune system reported in some patients on HAART therapy, inflammation at sites of OIs is common, and related to recovery of immunity with effective antiretroviral therapy.²⁶² The syndrome has been described in the eye as “immune recovery vitritis” or “immune recovery uveitis” (IRU).^263–269

Immune recovery uveitis appears to occur in eyes with healed CMV lesions in patients with immune reconstitution on HAART. The incidence rate of this phenomenon has varied, with reports from 0.11 to 0.83 per person-year in HAART responders with CMV retinitis.^268,269 Jabs et al. reported the frequency of IRU at 15.5% of 200 prevalent cases of CMV retinitis.²⁷⁰ Arevalo et al. reported IRU in 37.5% of 32 patients.²⁷¹ Eyes in which CMV retinitis lesions involve large surface areas of retina seem to be at higher risk for the development of IRU.²⁷² Previous treatment with cidofovir may also be a risk factor.²⁷³ Patients with IRU exhibit signs of inflammation such as iritis, vitritis, macular edema, and epiretinal membrane formation (Fig. 81.17).^274–277 Cataract, vitreomacular traction, proliferative vitreoretinopathy, optic disc and retinal neovascularization, panuveitis with hypopyon, and uveitic angle closure glaucoma with posterior synechia have also been reported in IRU.^278–284 Vision loss from these inflammatory sequelae may range from mild to moderate and is usually associated with macular edema and associated macular surface changes or cataract in most cases.

Fig. 81.17 Macular edema in a patient with immune recovery uveitis.

The pathophysiology of IRU is not well understood. One hypothesis is that once the CMV retinitis is healed and the immune system is reconstituted, the patient can mount an inflammatory response to residual CMV antigens in retinal glial cells in or adjacent to the necrotic CMV lesion. Another hypothesis is that control of CMV retinitis is incomplete in certain individuals with continued subclinical virus or viral protein production that stimulates the immune system. It has been reported that CMV antigens persist in cells of all retinal layers at the borders of clinically healed CMV lesions and in CMV infected retinal glial cells after treatment with ganciclovir.^283–285

Periocular steroids may be used successfully to treat this disorder, but ophthalmologists should be aware of CD4 cell counts. It appears that if the CD4 cell count is elevated above 60/mm³, treatment of immune recovery vitritis can be carried out without reactivation of retinitis (Fig. 81.13).^262,278 Recently, one case of reactivated CMV retinitis has been reported after treatment of IRU with periocular steroids.²⁸⁶ Intravitreal triamcinolone is also effective in reducing macular edema, however, caution is needed not to reactivate retinitis.^287,288

Other complications of CMV retinitis

Central visual loss in AIDS patients with CMV retinitis occurs in two forms: direct macular tissue destruction and secondary involvement as part of rhegmatogenous retinal detachment. We treated 32 patients (35 eyes) with macular exudation that caused reversible visual loss and initially manifested as neurosensory retinal detachment and lipid exudates. Of 35 eyes, 25 showed papillary or peripapillary active retinitis and 10 showed retinitis 1500–3000 µm from the fovea. Of 23 eyes with reduced vision that were followed up until healing of the retinitis and resolution of subretinal fluid and lipid exudates, 22 (96%) showed visual improvement with anti-CMV treatment. Our findings suggest that macular exudation is a reversible cause of visual loss in patients with CMV retinitis.¹⁰⁷

Cystoid macular edema can occur in the setting of resolving CMV retinitis in patients with immunodeficiency other than AIDS. This entity is distinct from serous macular exudation, which can occur in patients with AIDS with active CMV retinitis involving the posterior pole.²⁸⁹

Acute retinal necrosis in HIV patients

Acute retinal necrosis (ARN) has been reported in AIDS patients.²⁹⁰ It is a devastating disease characterized by the acute onset of a fulminant panuveitis with confluent, well-demarcated areas of retinitis, plus prominent anterior uveitis, occlusive retinal and choroidal vasculitis, vitritis, and papillitis.^{54,109,291,292} In most cases the cause of the clinical syndrome of ARN is varicella zoster but HSV can also cause ARN. The retinitis is characterized by deep retinal whitening, minimal hemorrhage, and a rapid progression. In some cases, ARN in AIDS patients may be preceded by VZV optic neuropathy.²⁹³ A history of preceding cutaneous zoster infection may be helpful in making the diagnosis in such cases.^294,295 In addition, the CD4 count is usually above 60/ml.²⁹² The diagnosis of ARN is clinical based on criteria established by the American Uveitis Society that do not include immune status of the patient.²⁹⁶

No evidence of retinal vascular abnormalities may be present either clinically or angiographically early in the course of ARN. Retinal detachment is a common sequela, with multiple retinal breaks evident within areas of retinal necrosis. Retinal atrophy, often accompanied by proliferative vitreoretinopathy, is a common endstage finding, and there may be associated anterior uveitis, scleritis, and ocular hypotension.¹⁰⁹

Large numbers of herpesvirus particles in retinal tissue affected with ARN have been demonstrated by electron microscopy using endoretinal biopsy techniques. Virus may be detectable only during the acute phase of the disease.¹⁰⁹ Necrotic retinal tissue or retina reduced to thin glial remnants may not demonstrate virus. The difficulty in growing virus from these specimens is consistent with the hypothesis of VZV as the causative agent, since VZV is difficult to isolate and grow in vitro. CMV initially was believed to be the presumed infectious agent of ARN, but subsequent studies have not confirmed this.²⁹⁷

Studies employing endoretinal biopsy and PCR techniques have enabled definitive identification and culture of the causative virus, which has important diagnostic and therapeutic implications. Recent studies have suggested that combination antiviral therapy given intravenously (usually acyclovir or ganciclovir in combination with foscarnet), if given promptly, can arrest the disease and salvage vision.¹⁸⁹ Retinal detachment in VZV retinitis is common (up to two-thirds of patients) and may be associated with PVR or retinal shortening. Repair with vitrectomy and silicone oil after relief of traction with membrane segmentation and sometimes retinotomy may result in useful vision.^189,298 Prophylactic barrier laser around lesions should be considered to lower the risk of retinal detachment in ARN.

Ganciclovir has good efficacy against all herpesviruses but has a lower therapeutic index and must be given indefinitely because it acts as a virostatic agent. Determination of a specific viral cause early in the course of the disease when large numbers of viral particles are present is therefore imperative. Both HSV and VZV may be sensitive to acyclovir. However, VZV requires higher serum concentrations than HSV. Treatment for ARN in AIDS patients is usually based on established treatment for non-HIV-infected patients. Acyclovir IV 500 mg/m² or 10 mg/kg every 8 hours is effective followed by oral famciclovir 500 mg TID, acyclovir 800 mg five times a day or valacyclovir 1000 mg TID for maintenance therapy.⁸⁵ Duration of maintenance therapy is controversial, with reports of contralateral ARN infection decades later.²⁹⁹ This may support lifetime maintenance therapy, especially in immunosuppressed AIDS patients. Valacyclovir 1000 mg TID has been reported effective for initial treatment of ARN in a small series of immunocompetent individuals.³⁰⁰ Intravenous foscarnet may be used in acyclovir resistant cases.^301,302 Corticosteroids have been used to decrease vitritis in immunocompetent patients with ARN, but steroids are usually contraindicated in HIV patients with advanced immunosuppression.^85,294

Progressive outer retinal necrosis

Progressive outer retinal necrosis (PORN) is another variant of herpetic retinitis in AIDS patients and is nearly always caused by VZV. The incidence of PORN has decreased during the HAART era.³⁰³ It has been described in association with VZV as the onset of retinitis either succeeded by or coincident with an eruption of dermatomal zoster.³⁰⁴ Most patients with this syndrome have had low CD4 cell counts (i.e., below 50/ml). PORN syndrome is an extremely rapid progressive necrotizing retinitis characterized by early patchy multifocal deep outer retinal lesions (Fig. 81.18) with late diffuse thickening of the retina, absence of vascular inflammation and minimal to no vitreous inflammation.³⁰⁵ Severe vision loss develops as a result of a widespread retinal necrosis and from retinal detachment, the latter reported in up to 70% of patients in early studies.^305–312 Perivascular clearing of the retinal opacification is characteristic of PORN syndrome (Fig. 81.19).³⁰⁵

Fig. 81.18 Deep, round retinal lesions seen superior to the optic disc are characteristic of varicella zoster retinitis in AIDS patients, also termed progressive outer retinal necrosis (PORN) syndrome.

Fig. 81.19 Varicella zoster retinitis in an HIV patient shows retinal opacification and perivascular “clearing.” The perivascular edema and necrosis is cleared first; the tissue is not spared.

Therapy of PORN often requires immediate high-dose anti-zoster or -HSV therapy. The earliest reports of treatment of PORN with single intravenous antivirals, primarily acyclovir, showed poor visual results. Engstrom et al. reported final vision of no light perception (NLP) in 67% of 63 eyes within 4 weeks.³⁰⁵ Poor outcomes with IV acyclovir were possibly due to development of HSV or VZV resistance to acyclovir in patients who developed PORN while on prophylactic anti-HSV therapy with acyclovir. Recent studies have shown improved visual outcomes employing combination intravenous and intravitreal antiviral treatment. Scott et al. reported final vision of 20/80 or better in 5 of 11 eyes (45%) with only two of 11 eyes (18%) progressing to NLP vision utilizing a regimen of intravitreal ganciclovir and foscarnet plus IV foscarnet and IV ganciclovir or oral valganciclovir. In addition, the authors’ data suggested that laser demarcation may be beneficial to decrease the rate of retinal detachment.³⁰⁶ Combination of antiviral drugs and HAART preserved vision in a report by Kim et al.³¹²

Pneumocystis carinii choroidopathy

In 1987 Macher and associates³¹⁴ described a patient with AIDS with disseminated pneumocystosis, and choroidal P. carinii was found at autopsy; no clinical correlation was reported. In 1989 Rao and colleagues⁵⁸ reported the histopathologic findings in an autopsy series of three patients with AIDS who clinically demonstrated yellow choroidal infiltrates while receiving aerosolized pentamidine for P. carinii pneumonia (PCP) prophylaxis. In two cases a presumptive diagnosis of disseminated pneumocystosis was made by ophthalmologic examination. Histopathologically, the choroidal infiltrates were eosinophilic, acellular, vacuolated, and frothy, with the infiltrates within the choroidal vessels and choriocapillaris. Both Gomori’s methenamine-silver stain and electron microscopy demonstrated organisms.

In 1989 Freeman et al. described a woman with AIDS with multifocal, slowly enlarging, round-to-oval lesions in the choroid.³¹⁵ Fluorescein angiography revealed early hypofluorescence with late staining of the lesions, which appeared deep to the retinal circulation, without evidence of retinal involvement or inflammation (Fig. 81.20). A transscleral choroidal biopsy revealed, by electron microscopy, cystic structures characteristic of P. carinii within necrotic choroid.

Fig. 81.20 (A) Pneumocystis choroiditis. The round lesions are associated with minimal inflammation. Overlying the lesions in the superior portion of the macula is a typical CMV retinitis lesion. (B) Electron micrograph of Pneumocystis carinii organisms seen after choroidal biopsy.

A multicenter study of pneumocystis choroidopathy in 1991 reported 21 patients with AIDS and presumed P. carinii choroidopathy.³¹⁶ The lesions were characteristically yellow to pale yellow, appeared in the choroid, and were found in the posterior pole. They enlarged slowly before systemic anti-pneumocystis therapy and eventually resolved. Of 21 patients, 18 were receiving topical therapy with aerosolized pentamidine. There was little evidence of retinal destruction by visual acuity and visual field testing. The choroidal infiltrates were not associated with vitreous inflammation unless another infectious retinitis was present. Resolution of choroiditis took from 6 weeks to 4 months after systemic therapy. Survival after the diagnosis ranged from 2 to 36 weeks.

The CDC recommends double strength trimethoprim-sulfamethoxazole (TMP-SMX) daily or three times weekly for primary prophylaxis of PCP when CD4 counts are below 200/ml, with alternatives including dapsone, dapsone plus pyrimethamine and leucovorin, aerosolized pentamidine administered by the Respirgard II nebulizer, and atovaquone.³¹³ PCP is the most common AIDS-defining opportunistic infection. Choroidal P. carinii infection appears to have been more common when the prophylactic use of nonsystemically absorbed aerosolized pentamidine for PCP was widespread. The choroidal lesions of P. carinii appear as pale, cream- or orange-colored, space-occupying lesions from several hundred to several thousand microns in size and they rarely are symptomatic or lead to a decrease in visual acuity. The lesions may be unilateral or bilateral.^{58,315,317–319} P. carinii choroidopathy appears to be a marker for disseminated pneumocystosis and should be treated systemically. The need for maintenance systemic therapy for choroidopathy has not been established.

Although the diagnosis of disseminated pneumocystosis may be suggested by the characteristic appearance of P. carinii choroidopathy, isolated retinal disease may rarely be the earliest clinical manifestation of disseminated pneumocystosis. The incidence of P. carinii choroiditis has decreased, probably because of more widespread use of systemic PCP prophylaxis such as trimethoprim–sulfamethoxazole, immune restoration from HAART, and decreased use of aerosolized pentamidine for prophylaxis and therapy.³²⁰

Ocular toxoplasmosis

Toxoplasmosis is a common CNS opportunistic infection in patients with AIDS. Ocular toxoplasmosis is much less common,^62,321,322 with reported incidence of 3% in HIV-infected patients in France.³²³ US incidence is decreased in the HAART era by immune restoration and primary toxoplasmosis prophylaxis with TMP-SMX for those with CD4 counts less than 200/ml.⁸⁵ Eight patients with presumed ocular toxoplasmic retinochoroiditis were described in 1988 by Holland et al.⁶² In two cases the diagnosis was confirmed histologically. Lesions were usually bilateral (5/8) and multifocal, with vitreous inflammation noted clinically. Therapy resulted in remission, but reactivation and disease progression followed in two of three patients when therapy was stopped. Three patients had retinal tears or detachment as a result of severe retinal necrosis. The ocular lesions were the first manifestation of toxoplasmosis in four of five patients with disseminated disease, although all patients had pre-existing HIV infection, and in four the diagnosis of AIDS had not been made. In four of five patients with no evidence of nonocular infection, evidence of Toxoplasma was demonstrated in the CNS (encephalitis or brain abscess). No patient had evidence of pre-existing chorioretinal scars, and all had IgG antibodies to T. gondii at the time of diagnosis. Ocular disease was believed to be secondary to reactivation of Toxoplasma or to newly acquired or newly disseminated disease to the eye from nonocular sites of disease (Fig. 81.21).

Fig. 81.21 (A) Toxoplasmosis retinitis in an HIV patient who was healed after antitoxoplasmosis therapy with clindamycin. (B) Systemic treatment for toxoplasmosis was withdrawn 6 months later, and the retinitis reactivated.

Retinal toxoplasmosis in HIV infection may present as a focal necrotizing nonhemorrhagic retinitis that does not heal spontaneously and may simulate ARN, CMV, or luetic retinitis.^85,324 Prominent vitreous and anterior chamber reaction, relative absence of retinal hemorrhage, and thick, densely opaque yellow-white lesions with smooth nongranular borders suggest toxoplasmosis. Endoretinal biopsy or PCR techniques may be useful if diagnosis is difficult.^85,325,326

Ocular toxoplasmosis often presents differently in AIDS compared to immunocompetent individuals, spreading as a contiguous or multifocal retinitis. AIDS patients more often have extensive areas of retinal necrosis plus multiple areas of active infection.^327,328 Histopathologic studies show absent to scant inflammatory cells in the infected retina of immunocompromised patients. AIDS patients can develop ocular toxoplasmosis in the absence of preexisting chorioretinal scars. This pattern combined with frequent systemic toxoplasmosis at diagnosis suggests that acquired disease is more common than reactivation of congenital disease.^85,329 For immunocompetent individuals, current evidence also suggests that most patients with ocular toxoplasmosis were infected postnatally, even though the risk of ocular toxoplasmosis is higher from congenital infection³³⁰ (Fig. 81.21). Ocular toxoplasmosis in AIDS patients has also been reported to cause miliary disease, optic neuritis, panophthalmitis, and acute unilateral iridocyclitis without retinal lesions.^331,332 Ocular toxoplasmosis is diagnosed clinically and using PCR from a vitreous fluid sample.

Ocular, as well as disseminated, toxoplasmosis in patients with AIDS is treated with standard antitoxoplasma regimens used in immunocompetent patients such as sulfadiazine (4–6 g/day) or clindamycin in sulfa allergic patients plus pyrimethamine/leucovorin, with apparent response rates of 80%.³³³ TMP-SMX was reported in a small (77 patients) randomized trial to be effective and better tolerated than pyrimethamine–sulfadiazine.³³⁴ Other treatments for patients unable to tolerate sulfa drugs such as azithromycin or atovaquone have been primarily studied for CNS toxoplasmosis in AIDS patients and ocular toxoplasmosis in immunocompetent patients.^335–337 Atovaquone was originally synthesized as an antimalarial and has been shown to have activity against both P. carinii and T. gondii. Ocular toxoplasmosis in patients with AIDS frequently recurs when medical therapy is terminated so maintenance therapy generally is given. Corticosteroids may be given as adjunctive therapy for intracranial toxoplasmosis to reduce cerebral edema, although this is unproved; systemic corticosteroids are sometimes given to reduce inflammation in ocular disease, although these should be administered cautiously in HIV-infected patients. In addition, resolution of ocular toxoplasmosis in AIDS patients has been seen without corticosteroid therapy.⁶²

Toxoplasma retinitis is decreasing because of more widespread use of HAART and of prophylaxis, such as TMP-SMX.³²⁰ Currently the CDC recommends consideration of discontinuing maintenance therapy (sulfadiazine plus pyrimethamine/leucovorin with clindamycin used in sulfa-allergic patients) for toxoplasma encephalitis if a patient maintains a CD4 count above 200/ml for greater than 6 months.

Candida albicans

Since HIV can be a consequence of intravenous drug use, which is also associated with candidemia, it is surprising that candida endophthalmitis is not seen more frequently in HIV patients. Focal retinal and chorioretinal lesions and endophthalmitis from Candida spp. have been described in patients with AIDS.^55,338 Traditional therapy for candida endophthalmitis has been systemic amphotericin B. However, limited vitreous penetration has resulted in treatment failures, plus adverse effects including nephrotoxicity discourage its use.³³⁹ Trials comparing oral fluconazole to IV amphotericin B for systemic candidemia in immunocompetent patients suggested equivalent efficacy with fluconazole being the less toxic.³⁴⁰ Vitrectomy and intravitreal amphotericin B can be helpful in cases failing systemic therapy.

Cryptococcus neoformans

Cryptococcal infections may occur in 5–10% of patients with AIDS³⁴¹ and are associated with both direct and indirect ocular complications. Cryptococcal infection is a common occurrence in AIDS, resulting in meningitis and secondary ocular involvement. Chorioretinitis, endophthalmitis, or both, caused by direct intraocular invasion of the organism, have been described in immunosuppressed patients.^342,343 Visual loss caused by cryptococcal infection has been demonstrated to result from invasion of the visual pathways, including the optic nerve, tract, and chiasm.

The treatment of cryptococcal disease in patients with AIDS usually consists of an “induction” phase of about 2 weeks followed by a “consolidation” phase of about 8 weeks. Amphotericin B (>7 mg/kg/day) is most commonly used for induction, if possible combined with 5-flucytosine 100 mg/kg daily in four divided doses. If necessary because of toxicity, amphotericin can be replaced by fluconazole (800–1200 mg/day ); a third phase of prolonged maintenance therapy with oral fluconazole (200 mg/day) is continued unless CD4 counts are above 200/ml. Ophthalmologic complications of cryptococcal meningitis were seen infrequently before the description of AIDS .

Histoplasmosis

Histoplasmosis was initially reported in patients with AIDS in 1982, and in the next eight years more than 100 systemic cases were reported,³⁴⁴ mostly disseminated disease that presents as fevers without localized symptoms. The treatment of histoplasmosis in patients with AIDS usually consists of an induction phase with amphotericin B followed by a lifelong maintenance phase with either amphotericin B or itraconazole.³⁴⁵

Gonzales et al. reported bilateral endogenous endophthalmitis in an HIV-positive patient presenting with severe subretinal exudation, choroidal granulomas, and intraretinal hemorrhage leading to bilateral exudative retinal detachments. Vitreous cultures grew H. capsulatum var. capsulatum. Treatment involved systemic and bilateral intravitreal amphotericin B plus vitrectomy/scleral buckle in one eye.³⁴⁶ Ala-Kauhaluoma et al. reported a case of panuveitis in disseminated histoplasmosis in an HIV patient treated with liposomal amphotericin B, HAART, and topical steroids that ended up with anterior segment scarring.³⁴⁷

Aspergillosis

Endogenous endophthalmitis caused by Aspergillus fumigatus rarely has been described in AIDS and can arrive in the eye hematogenously or through extension to the orbit from adjacent sinuses. One case of disseminated, invasive aspergillosis with ocular involvement noted at autopsy was described in 13 patients with pulmonary aspergillosis; no clinical correlation of ocular findings was reported.³⁴⁸ Whereas four cases of orbital aspergillosis in HIV were reported, ocular aspergillosis is very rare in the HIV population.³⁴⁹

Coccidioidomycosis

To our knowledge, no cases of ocular coccidioidomycosis have been described in patients with AIDS. In a retrospective review of 77 patients with HIV infection and coccidioidomycosis, no case of endogenous endophthalmitis secondary to coccidioidomycosis was described, although disseminated disease (including meningitis) was described in a majority of patients.³⁵⁰ Other unusual mycotic infections causing endophthalmitis, some in association with chorioretinitis, but not necessarily HIV-seropositive patients, are reviewed by McDonnell and Green.³⁵¹

Paracoccidioidomycosis

Severe CNS plus ocular infection with Paracoccidioides brasiliensis that simulated CNS and ocular toxoplasmosis has been reported in a pregnant HIV-positive patient. The infection caused severe iridocyclitis, vitritis, plus a granulomatous chorioretinal lesion also involving the optic nerve that ultimately progressed to retinal detachment, NLP vision, and enucleation despite treatment.³⁵²

Advances in antifungal therapy

Fungal endophthalmitis traditionally has been treated with intravenous amphotericin B. Limitation of vitreous penetration plus systemic toxicity limit its effectiveness.³⁵³ Flucytosine and fluconazole have higher vitreous penetration but are limited by lack of broad coverage against many of the organisms typically seen in fungal endophthalmitis. As a result, vitrectomy and intravitreal amphotericin B is usually recommended in serious fungal endophthalmitis or cases unresponsive to systemic therapy.³⁵⁴

The triazole antifungal medications fluconazole, itraconazole, voriconazole, posaconazole, and ravuconazole are orally available and are less toxic drugs that can treat a variety of fungal organisms.³⁵⁵

Older drugs such fluconazole, which treats candida, and cryptococci and itraconazole, which treat histoplamosis and aspergillus, remain valuable. Voriconazole has been shown to have mean aqueous and vitreous minimum inhibitory concentrations for 90% of isolates (MIC90) for a wide spectrum of yeast and molds, including Candida and Aspergillus spp. after oral administration. Voriconazole and posaconazole have also been reported to successfully treat fungal endophthalmitis that was unresponsive to traditional antifungal agents.^356,357 Voriconazole and posaconazole have been shown to have efficacy against Candida albicans isolates from HIV patients.³⁵⁸

Syphilis

Concurrent ocular syphilis appears to be more common in HIV-infected than in uninfected persons.³⁵⁹ Ophthalmic manifestations of syphilis usually occur during or shortly after the secondary stage. Syphilitic uveitis and chorioretinitis in HIV-infected patients have been described. Nine patients with ocular syphilis and concurrent HIV infection were described by McLeish and colleagues in 1990.³⁶⁰ They found iridocyclitis in three of 15 eyes, vitritis in one eye, retinitis or neuroretinitis in five eyes, papillitis in two eyes, optic perineuritis in two eyes, and retrobulbar neuritis in two eyes. The three of nine patients with AIDS had the worst initial visual acuities. Six of nine had concomitant neurosyphilis. Benzathine benzylpenicillin, the only treatment in three of the patients, led to relapses in all three. Seven of nine patients treated with high-dose intravenous penicillin responded dramatically to therapy with no evidence of relapse.³⁶⁰

Concurrent ocular syphilis and neurosyphilis reported in two patients with HIV infection, in addition to a review of 13 other HIV-infected patients with ocular syphilis, revealed that 11 of the 13 HIV-infected patients with ocular syphilis had neurosyphilis.³⁶¹ The authors stress that neuro-ophthalmic syphilis may be the presenting feature of HIV infection and that ocular syphilis is strongly associated with concurrent neurosyphilis in patients that are HIV-seropositive (Fig. 81.22).

Fig. 81.22 Papillitis and vitritis from syphilis in an HIV-positive patient. Intravenous penicillin resolved the findings.

Necrotizing retinitis has been reported in a patient with HIV and syphilis. In some cases the appearance of luetic retinitis as a focal expanding white lesion may simulate CMV retinitis, ARN, or toxoplasmic retinitis. Marked inflammation of the vitreous and anterior chamber usually accompanies syphilitic retinal disease with posterior synechiae and keratic precipitates.^82,362

Standard treatment of primary and secondary syphilis with 2.4 MU of intramuscular benzathine penicillin in patients with and without HIV infection produce similar excellent clinical responses. Serolological responses to therapy (reducing nontreponemal antibody to unreactive levels), the primary method for ascertaining adequate treatment, are less certain in HIV patients.³⁶³

For retinitis, treatment for neurosyphilis with intravenous penicillin should be used and ceftriaxone may be used when penicillin is contraindicated. With regard to diagnosis, false-negative serum rapid plasma reagin (RPR) and Venereal Disease Research Laboratories (VDRL) may occur uncommonly with HIV-infection. Thus additional, more specific tests are recommended in this population (i.e. fluorescent treponemal antibody, absorbed [FTA-ABS]).³⁶³