Ophthalmic Manifestations of HIV Infection

Digital Journal of Ophthalmology 2004

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Breno Rocha Lima, M.D. | University of Miami School of Medicine - William J. Harrington Medical Training Programs

ABSTRACT INTRODUCTION DISCUSSION ACKNOWLEDGEMENTS REFERENCES CLINICAL PICTURES

Abstract

ObjectiveThis review is intended to describe the most common ophthalmic manifestations of HIV infection. It is estimated that more than 70% of adult AIDS patients will experience an ocular complication at some point of the disease. Orbital and adnexal manifestations include tumors of the periocular tissues and external infections. Anterior segment findings consist of keratitis, keratoconjunctivitis sicca, iridocyclitis, and other complications. Posterior segment findings include a HIV associated retinopathy and a number of opportunistic infections of the retina and choroid. HIV has also been related to neuro-ophthalmic manifestations such as visual field defects and papilledema.

MethodsThe author performed a search of Medline, using PubMed. Search words included HIV, cytomegalovirus retinitis, retinal microvasculopathy, herpes zoster ophthalmicus, Kaposi`s sarcoma, immune recovery uveitis, orbital lymphoma, toxoplasmosis, herpes simplex virus, pneumocystis carinii, microsporidia, syphilis, molluscum contagiosum, ganciclovir and keratoconjunctivitis sicca. Articles were selected based on clinical importance. Additional references of key articles were also included. Articles were excluded if they had non-English abstracts.

KeywordsHIV, Cytomegalovirus (CMV) retinitis, Retinal microvasculopathy, Herpes Zoster Ophthalmicus, Kaposi`s Sarcoma, Immune Recovery Uveitis, Toxoplasmic Retinochoroiditis

topIntroduction

The human immunodeficiency virus (HIV) infection has spread worldwide, with various adverse health and economic implications, particularly in the developing world.(1) A global summary of the HIV/AIDS epidemic from December 2003 by the Joint United Nations Programee on HIV/AIDS (UNAIDS) and World Health Organization (WHO) estimates that there are 40 million people worldwide living with HIV/AIDS. Approximately 5 million people were infected with HIV and there were about 3 million AIDS deaths in 2003.(2) At present, around 90% of HIV-infected persons live in developing countries, particularly those in sub-Saharan Africa and Southeast Asia.(2, 3) Unless a cure is found or life prolonging therapy can be made more widely available, the majority of people will remain suffering the profound impacts the disease has on their quality of life.(4) Numerous ophthalmic manifestations of HIV infection may involve the anterior or posterior segment of the eye. Since the first report of the ocular manifestations of AIDS by Holland et al. in 1982,(5, 6) subsequent studies have described several AIDS related conditions in the eye and orbit. 7080% of adult AIDS patients will experience an ocular complication at some point of their illness.(5, 7) Orbital and adnexal findings include tumors of the periocular tissues and external infections. Anterior segment manifestations consist of keratitis, keratoconjunctivitis sicca, iridocyclitis, and other complications. Posterior segment findings include a HIV associated retinopathy and a number of opportunistic infections (OI) of the retina and choroid. HIV has also been related to neuro-ophthalmic manifestations, such as visual field defects, papilledema, and diplopia. The occurrence of ophthalmic complications associated with HIV infection is significantly lower in the pediatric age group. All patients with HIV disease should undergo routine ophthalmologic examinations, since proper diagnosis and treatment may help to maintain vision and prolong life. Some retinal OI may have a rapid and devastating course.CD4+ T Lymphocyte proved to be a reliable predictor of ocular complications of HIV infection.(7, 8) The use of highly active antiretroviral therapy (HAART), which consists of a combination of nucleoside reverse transcriptase inhibitors, HIV protease inhibitors and non nucleoside reverse transcriptase inhibitors, has decreased plasma levels of HIV RNA and increased CD4+ T lymphocytes counts, improving the immune function of patients with HIV infection.(9, 10, 11) The clinical presentation of HIV related diseases may be modified by HAART, which has dramatically improved the prognosis of HIV infection. Before the introduction of HAART, patients with cytomegalovirus retinitis commonly had CD4+ counts less than 50 cells/l with minimal ocular inflammation.(9) There are some reports of spontaneous resolution of cytomegalovirus retinitis in patients with increased CD4+ counts related to such therapy, although the recovery in T lymphocytes may take many months.(12, 13, 14) Nevertheless, substantial intraocular inflammation in patients with healed cytomegalovirus retinitis receiving HAART has been reported, which is known as immune recovery uveitis.(9,105)

topDiscussion

II Orbital Manifestations

Orbital manifestations of HIV infection are not seen very often. However, some cases of orbital cellulitis and orbital lymphoma have been reported. The cases of orbital cellulitis were related to Aspergillus infection most times, being treated with systemic antimicrobial drugs. Other organisms reported in the literature that caused orbital infections in patients with HIV include Rhizopus arrhizus, Toxoplasma gondii, and Pneumocystis carinii. Children may present with recurrent episodes of orbital/peri-orbital cellulitis.(15, 16) Primary non-Hodgkin`s lymphoma (NHL) of the orbit and ocular adnexa is a rare disease. It accounts for only 1% of all NHL. In general, the risk of developing NHL is higher in HIV infected patients. The reported cases of lymphoma responded well to radiotherapy. However, high doses may be correlated to late ocular complications.(17, 18)

III Adnexal Manifestations

The most common adnexal manifestations in patients who have HIV infection are Kaposi`s sarcoma, herpes zoster ophthalmicus, moluscum contagiosum and conjunctival microvasculopathy.(19) Conjunctival squamous-cell carcinoma is a rare finding.

Kaposi`s Sarcoma

Kaposi`s sarcoma was a rare tumor. After the spread of HIV, the incidence markedly increased. It is a highly vascularized, painless mesenchymal tumor that affects the skin and mucous membranes and occurs in up to 25% of HIV infected patients. Around 20% of these patients have asymptomatic Kaposi`s sarcoma of the eyelids, conjunctiva and rarely the orbit.(7, 20)However, a study by Biswas et al., who followed 100 HIV positive individuals in India, did not observe a single case of Kaposi`s sarcoma of the eye. The low prevalence of this tumor in India may be attributed to the lower proportion of cases associated with homosexual behavior in that country. DNA sequences of human herpes virus 8 have been detected in patients with Kaposi`s sarcoma either with or without HIV infection. The low incidence of human herpes virus 8 in India may also contribute to the low occurrence of this tumor in that country.(3, 21)Kaposi`s sarcoma may present as purple papules in the eyelids, which may be either flat or slightly raised. Sometimes, these lesions are part of a multifocal presentation, which may include visceral involvement.(5, 22)Conjunctival Kaposi`s sarcoma may occur in up to 1% of patients with HIV infection. The classic presentation is a reddish plaque that may mimic a subconjunctival hemorrhage or chalazion. This lesion is often located in the cul de sac. Even small lesions can cause important cosmetic and functional discomfort, which may be related to mass effect or secondary corneal changes.(5, 23)Kaposi`s sarcoma does not invade the eye. Most lesions are slowly progressive and respond to systemic drug therapy (106). Radiation therapy may be effective when functional discomfort is reported. Nevertheless, it is expensive and can cause skin irritation and conjunctivitis. Doses of 20 Gy may be sufficient to produce shrinkage of the tumor. Excision and intralesional chemotherapy with vinblastine are other treatment options. If there is systemic involvement, systemic chemotherapy may be indicated.(7, 23)There are some reports of regression in patients treated with HAART containing a protease-inhibitor. Saquinavir, indinavir, ritonavir and nelfinavir may affect angiogenesis, cell survival, tumor growth and invasion.(24)

Herpes Zoster Ophthalmicus

Reactivation of latent varicella zoster virus in the ophthalmic division of the trigeminal nerve causes herpes zoster ophthalmicus. The ophthalmic division branches into the lacrimal, nasociliary and frontal nerves. Involvement of the frontal nerve is common. When the nasociliary nerve is affected, the patients may present with vesicles at the tip of the nose, known as Hutchinson`s sign. Studies have shown ophthalmic involvement in 99% of patients with this sign.(25) Herpes zoster occurs in patients with HIV infection as well as other patients with depressed cellular immunity such as lymphoma patients and patients receiving immunosuppressive therapy. Characteristic prodromal symptoms include headache, generalized malaise and fever.(26)In younger individuals, it may be the initial manifestation of HIV infection.(27) Any patient younger than 50 years of age who presents with herpes zoster ophthalmicus is suspect of having HIV infection or any other immunosuppressive condition.(5, 28) A study by Hodge et al. showed a relative incidence risk ratio of 6.6/1 in HIV positive patients compared to HIV negative patients.(29) Reports suggest that it affects 515% of HIV positive patients and may have a high rate of painful and sight threatening complications.(7, 27) Forty one percent of the patients studied by Lewallen in Malawi developed corneal perforation and seventeen percent of the patients studied by Sellitti et al. in Miami developed necrotizing retinitis. Ocular complications result from inflammation, nerve damage and tissue scarring.(30, 31) Herpes zoster ophthalmicus presents as vesicobullous rash and may be associated with keratitis, scleritis, uveitis, retinitis or encephalitis.(27) The severity of the skin rash is an important prognostic parameter of subsequent ocular involvement.(32)Significant entropion or trichiasis may result from herpes zoster, because the virus can cause permanent contraction scars of the deep dermal tissues of the eyelids.(25)Patients should be treated with intravenous acyclovir (10 mg per kilogram of body weight three times a day for seven days) followed by an oral maintenance regimen (800 mg 35 times a day). Other options are famciclovir, which requires long term maintenance therapy, and valaciclovir.(7, 25)

Molluscum Contagiosum

Molluscum contagiosum is caused by a DNA poxvirus and affects the skin and mucous membranes as translucent papules with a central umbilication. In HIV patients it occurs commonly and lesions may become quite large and are often more numerous and more rapidly growing. Involvement of the eyelids may occur in up to 5% of HIV infected patients. They are usually multiple, bilateral, confluent, and tend to recur within 6 to 8 weeks after removal.(3) Treatment options are cryotherapy, incision, curettage and excision. The use of podophyllotoxin cream as an adjunct to cryotherapy may be helpful. Lesions may recur particularly when CD4+ counts decrease.(33, 34)

Conjunctival Microvasculopathy

Patients with HIV infection may present with asymptomatic microvascular changes, which is correlated with retinal microvasculopathy. The severity of the microvasculopathy has been correlated to increased zeta sedimentation ratios and fibrinogen levels.(35) Usually, no treatment is necessary. Those patients may have microaneurysms and segmental vascular dilatations and narrowings.(7) The cause of these vascular changes is not clear yet, but it is probably associated with the deposition of immune complexes related to HIV or the direct infection of HIV in the conjunctival vascular endothelium.(36)

Conjunctival Squamous-Cell Carcinoma

A study by Agaba in Uganda showed a correlation between an increase in cases of conjunctival squamous-cell carcinoma and HIV infection. These tumors have also been related to exposure to ultraviolet light and conjunctival papillomavirus infection and usually arise in the limbus of the eye.(37)

IV-Anterior Segment Disease

The anterior segment of the eyes (cornea, anterior chamber and iris) may also suffer changes related to HIV infection. Reports indicate that more than 50% of HIV infected patients have anterior segment manifestations.(38) Keratitis, keratoconjunctivitis sicca and iridocyclitis are among the most common complications in the anterior segment of the eyes. However, studies have shown no difference in the ocular flora between HIV-negative patients and patients with AIDS.(39)

Herpes Simplex Keratitis

Herpes simplex keratitis has been reported in AIDS patients, but whether there is an increase risk of this disease is still unknown. The infection has a predilection for the peripheral cornea and may cause corneal ulcerations, being usually painful. In general, the course of the disease is longer in AIDS patients and the rate of recurrences is also higher. It is associated with corneal scarring and iritis. The treatment of choice for epithelial keratitis consists of topical trifluridine six to eight times a day during the first several days. Orally administered acyclovir is also effective.(22, 40)

Varicella-Zoster Virus Keratitis

As mentioned before, the varicella zoster virus may be associated with keratitis in AIDS patients. The patients may present with elevated intraocular pressure. Commonly, the patients have herpes zoster ophthalmicus as well, although the dermatitis may be mild. As in herpes simplex keratitis, the course of the disease tends to be longer in AIDS patients. The treatment is similar to that of zoster ophthalmicus. (25, 28, 31)

Bacterial and Fungal Corneal Infections

Bacterial and fungal infections are generally more severe in HIV infected patients. Spontaneous fungal keratitis secondary to Candida albicans has been reported in patients with advanced HIV disease.(41) Candida species are particularly common in intravenous drugs users. Although uncommon, Microsporidia is associated with a bilateral diffuse punctate epithelial keratopathy and conjunctivitis. The treatment consists of oral itraconazole, oral albendazole or topical fumagillin.(42, 43, 44)

Posterior Intracorneal Infiltrates

Posterior intracorneal infiltrates have been reported in HIV infected hosts with concomitant cytomegalovirus retinitis and in children who have been treated with prophylactic rifabutin. Those infiltrates tend to be distributed primarily in the inferior cornea. The cause of those corneal infiltrates is still under investigation. They may be caused by direct deposition of immune complexes or viral particles, toxicity of medication or even the direct effect of opportunistic infections.(45)

Keratoconjuctivitis Sicca

More than 20% of patients with HIV infection may have keratoconjunctivitis sicca, also called dry eye syndrome, which results from deficiency of any of the tear film layers. Apparently, it is not related to CD4+ counts or associated with the severity of HIV.(46) Symptoms may include foreign body sensations, photophobia and decreased visual acuity. It is likely caused by both the destruction of primary and secondary lacrimal glands and inflammation mediated by the HIV virus. The treatment is based on the administration of artificial tears, often six to eight times a day, and lubricating ointments.(47)

Iridocyclitis

An HIV infected patient complaining of photophobia and red eye may have iridocyclitis. This presentation requires a thorough ocular examination in order to rule out anterior or posterior segment infection.(5) It may be associated with retinal or choroidal infection with multiple opportunistic organisms, such as cytomegalovirus, herpes simples virus, varicella zoster virus, Candida species, Cryptococcus species, Toxoplasma gondii, Treponema pallidum and Mycobacterium species.(48) In the differential diagnosis of acute iridocyclitis in a patient with AIDS, infection with syphilis or toxoplasmosis should always be considered. Immunocompromised hosts may have T. gondii infection bilaterally and have multiple infectious foci. Encysted T. gondii organisms have been found in an iris biopsy specimen from an AIDS patient presenting with iridocyclitis.(49)PCR of the aqueous humor or vitreous of those patients may be used for identification of those organisms. Vitreous samples have a higher sensitivity.(49,107,108)Some medications, such as rifabutin and cidofovir, have also been associated with iridocyclitis.(50, 51). Rifabutin is also related to ocular hypotony, and cidofovir may cause an endophthalmitis-like manifestation.Iridocyclitis may also be associated with Reiter`s syndrome, which is defined by the classic triad of arthritis, urethritis, and conjunctivitis. This syndrome appears to be more common in patients with HIV infection.The treatment of iridocyclitis depends on the specific infectious agent. In the cases associated with medications, the dose should be tapered or the drug should be discontinued. Topical corticosteroids are usually indicated, but must be used carefully whenever a infectious cause is suspected.(7)

V Posterior Segment Disease

The posterior segment of the eye (retina, choroid and optic nerve head) is affected in more than 50% of AIDS patients. Those disorders may be either associated with infectious causes or non infectious causes. Decreased visual acuity, visual field defects and photopsias are among the most common symptoms.(97)

Retinal Microvasculopathy

The microvascular changes in the retina are the most common retinal manifestations of HIV infection. Nevertheless, they are generally asymptomatic and transient. These changes may occur in up to 70% of AIDS patients at some point of the disease. The patients presenting with HIV retinopathy may have cotton-wool spots (CWS) in the retina, intraretinal hemorrhages, and retinal microaneurysms, especially when CD4+ T lymphocyte count is below 100 cells/mm3. Forty five percent of the patients with HIV related retinopathy have CD+ cell counts below 50 cells/mm3. (5, 52) The CWS result from occlusion of precapillary arterioles, normally do no affect visual acuity and do not require treatment. They appear as small, white, superficial retinal opacities and are mainly localized on the posterior pole. Pathologically, the CWS are nerve fiber layer infarcts, related to accumulations of axoplasmic debris, subsequent to obstruction of axoplasmic flow.(53) They may represent an increased risk for cytomegalovirus (CMV) retinitis. The appearance of CWS is sometimes similar to CMV retinitis. CWS, however, tend to be smaller, do not progress, are not characteristically associated with retinal hemorrhage and resolve over weeks to months. AIDS patients with CWS should have close follow up.(52)Intraretinal hemorrhages, including Roth`s spots, may be present in AIDS patients. They are commonly innocuous in the setting of HIV retinopathy and may occur within different layers of the retina.(5)The pathogenesis of retinal microvasculopathy is probably similar to that of conjunctival microvasculopathy.(36) Hypothesis including hemorheologic abnormalities, like increased plasma viscosity and fibrinogen levels; circulating immune complexes and infectious damage of the retinal vasculature have been postulated. Schmetterer and colleagues studied the ocular blood flow in patients infected with HIV. They detected a decreased macular leukocyte density in HIV infected persons. The study also suggested that abnormal retinal hemodynamics in this group may be involved in the pathogenesis of HIV-related microvasculopathy. No correlation between antiretroviral treatment and ocular blood flow parameters was found.(53)Branch retinal artery and retinal vein obstructions have been seen in HIV infected patients. (54, 55) There are some reports of ischemic maculopathy associated with HIV infection, which can be severe, however the condition is apparently uncommon. The presence of opacification of the superficial retina, resulting in a cherry red spot, or intraretinal hemorrhages near the fovea may suggest the diagnosis, although some patients may not present with these findings. Bilateral involvement of the eyes, with an abrupt onset often occurs. Fluorescein angiography should be done on HIV infected patients with unexplained vision loss.(52) A study by Cunningham and associates suggested the possibility that occult herpetic infection may be a contributing factor to ischemic maculopathy, as well as alterations in blood flow in the setting of microvascular abnormalities.(52)

Chronic Multifocal Retinal Infiltrates

Levinson and associates described a distinct syndrome in HIV infected subjects that was characterized by the presence of stable or slowly progressive multifocal peripheral infiltrates, often in association with inflammatory reactions in the vitreous humor and anterior chamber and lack of retinal necrosis. Those infiltrates do not seem to be related to drug toxicity or to opportunistic infections. Generally, they were round or irregular in shape, and typically less than 200 m in the greatest dimension. Floaters were the most frequent complaint among the patients studied, followed by blurred vision. An auto immune phenomenon associated with immune response to the presence of HIV in the ocular tissue has been suspected to cause these inflammatory reactions. The long term effect of this syndrome on visual function remains unknown.(56)

Infectious Retinitis

Retinal infections in HIV infected patients may result from different pathogens, which may affect the retina at the same time.(57) Syphilis, candida, varicella-zoster, toxoplasmosis, herpes simplex and cytomegalovirus retinitis are among the most common ones. Although these infectious may also occur in immunocompetent hosts, the course tends to be longer in AIDS patients, and the rate of recurrences is also higher.

Varicella Zoster Virus and Herpes Simplex Retinitis

Varicella zoster virus has been associated with acute retinal necrosis, which affects 14% of HIV infected patients. It is characterized by peripheral retinal whitening, often accompanied by intraretinal hemorrhages associated with rapidly progressing necrosis over several days. Multifocal lesions are commonly seen. Retinal detachment with proliferative vitreoretinopathy as well as the involvement of the other eye may also occur.(58, 59) Central retinal vein occlusion as the initial presentation of herpes zoster ophthalmicus has also been reported.(60)Although not frequently seen, herpes simplex virus has also been related to retinitis in HIV-positive patients. It has been associated with a rapid progressing visual loss.The treatment for these two pathogens is normally long. Intravenous acyclovir and intraocular ganciclovir or foscarnet are commonly required.(59, 61), and long-term treatment with acyclovir prevents recurrences and is important in prophylaxis of the fellow eye (102,103)

Cytomegalovirus Retinitis

Human cytomegalovirus (HCMV) is part of the beta subgroup of herpes viruses (Herpes viridae) and has strong species specificity. Although the infection with CMV is usually subclinical in immunocompetent hosts, there may be a life long persistence in 5090% of the population. In immunocompromised hosts, such as patients infected with HIV, CMV may lead to several complications.(62, 63)Cytomegalovirus (CMV) retinitis is the most common intraocular infection related to HIV infection, affecting around 25% of patients according to reports of the past decade and may cause progressive loss of vision and blindness.(5) The prevalence of visual impairment at the time of CMV retinitis diagnosis is high and is related to demographic characteristics.(64)A study performed by Doan et al. showed a decrease in the incidence and prevalence of CMV retinitis after the advent of HAART. The relapses of CMV retinitis were less frequent (36% before HAART vs. 17% after HAART) and newly diagnosed CMV retinitis also decreased (6.1% before HAART to 1.2% after HAART). Remission durations from recurrent CMV retinitis have increased in patients receiving HAART, which is associated with decreased progression of retinal necrosis, and to lower risk of retinal detachment. Nevertheless, it does not restore the retina where such damage has already occurred.(65, 101) Kempen et al. followed up 589 patients to evaluate the relationship of anti-CMV treatment and immune reconstitution in response to HAART on the mortality risk of patients with AIDS and CMV retinitis. The use of HAART reduced the risk of mortality by 81%; it was 96% lower for those who developed immune recovery and 49% lower for those who did not.(66)Vision related quality of life (QOL) may still be compromised by CMV retinitis even when general health related QOL has improved in response to HAART. Therefore, prevention of CMV with anti-CMV medications may be warranted in high risk subjects.(67) The study by Doan et al. also suggested that a CD4+ cell count above 50 cells/mm3 or a low viral load does not fully protect from CMV disease. Immune response reconstitution may be only partial after HAART, because lack of pathogen specific CD4+ T cell response may persist even in the presence of a significant rise in the absolute CD4+ T cell counts. Therefore, HIV-infected patients still require close ocular follow up even if they are being treated with HAART. Moreover, virologic resistance to HAART is becoming more frequent.(63, 65, 68) Occasionally, HAART may cause vision loss via the mechanism of immune recovery uveitis.(67) It may be characterized by vitritis and optic disc and macular edema. Ocular neovascularization at the optic disc and the retinal periphery may also occur. Clinically important complications of immune-recovery uveitis may include cataract, epiretinal membrane formation, and cystoid macular edema. The mechanism of this condition remains unclear. Generally, substantial inflammation does not occur in eyes without prior CMV retinitis. Therefore, immune recovery uveitis may be caused by an immune response related to the persistence of CMV antigen in the eye. There are some reports showing that protease inhibitors may be associated with increased cytomegalovirus-specific lymphocyte proliferation and production of inflammatory cytokines.(9, 69) Song et al. showed that the risk of immune recovery uveitis was strongly correlated with prior use of cidofovir. It was not clear whether continuing noncidofovir anti-CMV therapy after immune recovery would reduce the risk of immune recovery uveitis.(70) Recent reports show that CMV retinitis progression does not necessarily correlate with viral CMV loads, which is different from other CMV diseases, such as colitis and pneumonitis.(63)Generally, CMV retinitis is characterized by hemorrhagic necrosis that may extend along the vascular arcade, as well as retinal whitening. (Figure 1b) The lesion tends to enlarge over time. The patients may also present with mild vitreal inflammation, anterior uveitis, and up to 5% of them may have involvement of the optic disc. Visual field loss, blurred vision and photopsias are common complaints by the patients.(7, 65)The administration of systemic anti-CMV medication may prevent the occurrence of retinitis in the fellow eye.The choice of a drug for the treatment of CMV retinitis should be based on the response to previous treatments, side effects as well as extension and severity of the disease.In patients on chronic suppressive, maintenance therapy, CMV resistant to the treatment being used may develop. The identification of resistant virus in the blood or urine may have an association with adverse clinical outcomes of the CMV retinitis. There may be an increased risk of retinitis progression, as well as an increase in the amount of retinal area affected by CMV. Patients treated with ganciclovir implant alone probably have a higher rate of contralateral ocular or visceral disease than the ones receiving concomitant oral ganciclovir. The detection of CMV viral load in the blood or direct sequencing of blood specimens for CMV UL97 gene mutations may be important in the clinical setting, in order to determine the patients with resistant virus.(71)Intravenous ganciclovir may be indicated when there is bilateral retinitis or when systemic treatment is required.(72) However, it may cause myelosuppression. Intravitreal ganciclovir injection is another option, though frequent injections are required and the fellow eye and distant organs are not protected. Standard doses range from 200 g to 400 g administered twice a week, for up to 3 weeks, followed by weekly maintenance injections. A report presented by Velez et al. suggested that higher doses of ganciclovir may be tolerated by the eye, and when associated with intravitreous foscarnet, they may be effective in controlling CMV retinitis in patients who do not respond to conventional treatment.(73, 74, 75) A controlled trial of valganciclovir by Martin et al. showed that it appears to be as effective as intravenous ganciclovir for induction treatment and is effective for long-term management of CMV retinitis.(76)A ganciclovir intravitreal implant has been developed as a local treatment option that does not involve intravitreal injections and avoids systemic side-effects.(77) It is a non-erodable drug delivery device, which can provide therapeutic levels of ganciclovir to the posterior segment of the eye. The implants are designed to release ganciclovir over a period of months. Factors in the decision to use the ganciclovir implant include the location and severity of CMV retinitis, the patient's potential for immunologic improvement, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy. Endophthalmitis is an uncommon complication of ganciclovir implant surgery.(78)Intravenous foscarnet is another treatment option; nevertheless, it is associated with renal insufficiency.(72)Combined intravenous ganciclovir and foscarnet offers the maximal protection of other eye and distant organs disease, though long daily infusions are required and the side effects are combined.(79)In resistant cases, cidofovir therapy may be used. However, it has been associated with iritis and hypotonia and has the potential for nephrotoxicity, particularly in patients with history of kidney disease.(72, 79)Other treatment alternatives are formivirsen injected into the vitreous or oral valganciclovir.(72)

Syphilis Retinitis

Syphilis may affect the retina in HIV positive patients. As Treponema pallidum and HIV may be both transmitted sexually, it is not uncommon to detect both pathogens in the same patient. The retinitis is characterized by a deep yellow lesion. Retinal vasculitis and intraocular inflammation may be present. The diagnosis can be confirmed by the serum fluorescent treponema antibody absorption test (FTA ABS) and microhemagglutination assay (MHA-TP). When the diagnosis is confirmed, vigorous treatment should be started with 12-24 million units of intravenous penicillin G for 7-10 days.(80) Tetracycline, erythromycin and chloramphenicol are options for patients allergic to penicillin. Some authors believe that HIV positive patients may require maintenance therapy, because ocular symptoms may recur.(81, 82) Frequently, there may be atypical presentations of ocular syphilis in these patients, such as vitritis.(82)

Candidal Endophthalmitis

Candidal endophthalmitis generally presents as a focal white infiltrate in the choroid, and may break through the retina into the vitreous. Usually, an overlying vitritis is present. Vitreous abscesses may also be seen. Once the diagnosis is confirmed, the patients should receive intravenous amphotericin.(5)

Toxoplasmic Retinochoroiditis

Around 12% of HIV infected patients may present with toxoplasmic retinochoroiditis. The prevalence of T. gondii infection varies between geographic regions and between population groups. Toxoplasmic retinochoroiditis still has a high prevalence in regions such as southern Brazil, where it may be as high as 8% (104). Ocular lesions may first develop many years after T. gondii infection. It is usually bilateral and presents multifocal sites of infection, which is not common in immunocompetent persons. Retinochoroidal scars and retinal hemorrhage may be absent. The appearance of the lesions varies with intensity of inflammation and duration of active retinal infection. Patients usually complain of seeing floaters, pain and decrease in visual acuity. Serologic studies should be performed; however they may be negative even in the presence of disease. PCR of the ocular fluid may be helpful in distinguishing between toxoplasmic retinochoroiditis and other ocular diseases.The treatment consists of oral sulfadiazine, combined with pyrimethamine or clindamycin, or both. Trimethoprim-sulfamethoxazole may also be effective. Atovaquone may be used in immunocompromised patients who are at increased risk of bone marrow toxicity from sulfonamides. The patients may have fewer relapses when receiving maintenance sulfadiazine or trimethoprim-sulfamethoxazole. Recent studies have shown that a half-dosage regimen is also effective in preventing recurrences, which are believed to be caused either by the release of parasites from tissue cysts in the retina or dissemination of parasites from non-ocular sites. (83-86, 104)

Infectious Choroiditis

Mycobacterium tuberculosis, Candida species, Cryptococcus species, Pneumocystis carinii and Treponema pallidum are among the most common entities related to infectious choroiditis, which is seen in less than 1% of HIV positive patients. Multiple, bilateral, round or ovoid, yellow-white lesions characterizes Pneumocystis carinii choroiditis. These lesions are usually slowly progressive and are not associated with iritis, vitritis, or vasculitis. The treatment is the same for Pneumocystis carinii pneumonia.(87-89, 98)

VI-Neuro-Ophthalmic Manifestations of HIV Infection

Optic neuropathies in HIV positive patients may be related to compression, infiltration, infection, vaso occlusion or inflammation. Cryptococcal meningitis and intracerebral toxoplasma cysts, which are intracranial manifestations associated with HIV, can affect the eyes, causing nerve palsies. Neuro ophthalmic complications of HIV have also been reported in the absence of associated opportunistic infections. Optic neuritis associated with a multiple sclerosis like illness in the presence of HIV has also been described.(90) Other neuro ophthalmic complications are visual field defects, papilledema, secondary to elevated intracranial pressure and ocular motility disorders, occurring in up to 15% of HIV-infected patients.(5, 91) HIV may also cause diplopia due to palsies of cranial verves III, IV, and VI. Neurosyphilis, progressive multifocal leukoencephalopathy (PML), which is caused by JC polyomavirus, meningeal and parenchymal lymphoma, and intracerebral infection with herpes virus have also been related to neuro-ophthalmic manifestations. The diagnosis of PML should be considered in immunocompromised patients with neuro-opthalmic findings, especially in those presenting with homonymous hemianopia and nystagmus.(92) Herpes virus may present with papilledema and extraocular muscle palsies.Microvascular oculomotor nerve palsies may occur in association with HIV. Premature atherosclerosis is commonly seen in HIV-infected patients due to an unknown mechanism.(93)Lumbar puncture and magnetic resonance imaging are usually required in order to determine the pathogen causing the neuro ophthalmic symptoms, and to start the proper treatment. Generally, intracranial lymphoma is treated with radiation and chemotherapy. The infections are treated with specific antimicrobial drugs.(7)The optic nerve may be affected by HIV due to direct infection. Another explanation is related to HIV viral proteins. Tat and gp 120, which are viral proteins, may have direct and indirect toxic effects on neurons. Moreover, HIV may induce the production of TNF alpha, IL I and arachidonic acid metabolites, which may cause neurotoxicity. Some studies suggest that non-nucleoside and nucleoside reverse transcriptase inhibitors (NRTIs) may impair mithocondrial function.(90)HIV infected persons differ in measures of the retinal nerve thickness, cross sectional area and cup shape. Most defects are found in patients with associated CMV retinitis. A study by Plummer et al. demonstrated that HIV positive patients without CMV retinitis still have statistically significantly abnormal measures in retinal fiber layer thickness, rim volume, retinal fiber layer area and disk area, indicating that there may be destruction of the retina as a complication of HIV infection, with or without CMV retinitis.(94, 95)

VII Ocular Manifestations in the Pediatric Group

The first reports of HIV infection in children are from 1982, after the description of the disease in intravenous drug abusers and homosexual men.(96) A global summary of HIV/AIDS epidemic dating from December 2003 from UNAIDS/WHO estimates that there are 2.5 million children under 15 years worldwide living with HIV/AIDS, and 700,000 were newly infected with HIV in 2003. Approximately 500,000 children died from the disease in 2003.(2) The most frequent mode of transmission of HIV in the pediatric group is mother to child transmission. The incubation period tends to be shorter in children. Some bacterial infections are more common in this age group than in adults, whereas cryptococcosis and toxoplasmosis are less frequent. Therefore, HIV infection may be different in children in several ways. The occurrence of ophthalmic complications associated with HIV infection is significantly lower in the pediatric group. The first reports of eye complications in children related to HIV infection are from 1982. Kaposi`s sarcoma, as well as CMV retinitis are not as common as in the adult population. The reason for this fact is still unclear, but may be related to an altered immune response to HIV in children. The most frequent manifestation in the pediatric group is dry eye syndrome, which occurs in approximately 20% of patients. Some authors described perivasculitis of the peripheral fundus vessels as a common finding in children with AIDS.(96, 99)A report by Kestelyn et al., who followed 162 HIV infected children in Africa, showed a high incidence (38%) of perivasculitis and/or sheathing of the peripheral retinal vessels. Bilateral involvement was very common and the severity tended to be symmetrical. Veins were affected more often than arteries. The lesions frequently originated in the periphery, sometimes extending towards the posterior pole without invading it. The authors also described a possible link between lymphocitic interstitial pneumonia, parotitis, lacrimal gland involvement, and perivasculitis of the retinal vessels as the expression of the same immunopathological process in different sites. CMV retinitis and cotton-wool spots, the most frequent ocular finding in adult HIV infection, as well as external lesions, such as herpes zoster ophthalmicus and Kaposi`s sarcoma of the eyelids were rare in the African pediatric group.(96) Purdy et al. reported three cases of bilateral progressive outer retinal necrosis due to varicella-zoster virus in children with HIV infection. All three lost vision in both eyes.(100)

topAcknowledgements

The author wishes to thank the National Eye Institute, National Institutes of Health for providing the clinical pictures and the anonymous reviewers for their constructive comments.

topReferences

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topClinical Pictures

Figure 1a. Normal fundusFigure 1b. Fundoscopic changes seen in CMV retinitis

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Figure 1aNormal fundus

Figure 1bFundoscopic changes seen in CMV retinitis