¡¡¡¡NEOPLASM

¡¡¡¡Cancer in individuals living with HIV/AIDS is a common source of morbidity and mortality. Although ocular malignancies are rare, they occur in the late stage of AIDS. The etiologies, primary sites, and treatments of three common ocular tumors in HIV/AIDS patients were summarized in Table 4.
Ocular Surface Squamous Neoplasia  Squamous cell carcinoma which is characterized as a lowª²grade malignancy is the third most common AIDSª²related neoplasm[48]. When the eyes are involved in the disease, the most common sites are the anterior parts, especially the conjunctiva and the eyelids. The pathogenesis of ocular surface squamous neoplasi (OSSN) is not well understood. However, exposure to ultraviolet radiation, genetic susceptibility and infection by HIV and HPV are the recognized factors that contribute to the high risk of developing OSSN[49]. Squamous cell conjunctival carcinoma is much more commonly seen in tropical, subtropical and poorer areas than in developed countries such as Europe and the United States[50]. It is reported that HIV positive patients have as high as 13ª²fold increased risk of developing OSSN than the normal group[51] and the occurrence rate of OSSN reach 7.8% in AIDS patients[52]. HIV patients from subª²Saharan Africa seem to be at increased risk of OSSN. OSSN is more aggressive in HIV patients. In some cases, OSSN can be the initial clinical manifestation of HIV infection[53]. Although the DNA of HPV, predominantly type 16, has been found in ocular surface squamous neoplasias, the roles of HPV in the pathogenesis of OSSN have been controversial[50]. Diagnosis of OSSN can easily be mistaken with conjunctivitis and Pterygium[54] and the common treatment is the surgical excision of the lesion. As a result of the high recurrence after the surgery, cryotherapy, radiation and chemotherapy are also suggested and periodic followª²up examination is needed[55]. When the disease progresses and intraocular invasion occurs, such as perineural invasion, the disease may lead to death[56].

¡¡¡¡Kaposi¬ðs Sarcoma  Kaposi¬ðs sarcoma (KS) is one of the most common and important AIDSª²related neoplasms and can be considered as an AIDSª²defining illness[57]. Since human herpes virusª²8 (HHVª²8) has been identified in all four clinicalª²epidemiological forms of KS and since the viral load is correlated to the risk and severity of KS, HHVª²8 is considered to be the etiology of KS. However, only some HHVª²8ª²positive populations develop KS. Therefore, HHVª²8 is necessary, but not sufficient, for the development of KS[58,59]. Other pathogens, such as CMV, HHVª²6, HHVª²7 and human papilloma viruses (HPV), may also be associated with the development of KS. Prior to the AIDS epidemic, KS was extremely rare. Now, however, KS is commonly seen, especially in AIDS patients. The incidence of KS in AIDS patients is about 20000 times higher than that found in the general population. The pathogenesis of AIDSª²KS may represent a series of events involving interaction of immunosuppression, altered expression and response to cytokines, and the coª²transactivation between HIV and HHVª²8[60,61]. HIVª²1 Tat protein has been shown to be a potent mitogen for human KSª²derived cell lines and facilitates the development of KS by protecting KS cells from apoptosis[62]. Before the era of HAART, approximately 20% of HIVª²positive patients suffer asymptomatic KS of the eyelids or conjunctiva[63]. Ocular involvement accounts for 10ª²20% of AIDSª²related KS cases even in the era of highly active antiretroviral therapy (HAART)[64ª²66], mostly the anterior parts, such as eyelids, the bulbar, tarsal, and forniceal conjunctiva, the plica semilunaris, the caruncle, the lacrimal sac, and rarely the orbit and lacrimal gland[67,68]. Eyelid and conjunctiva are the most commonly affected sites, and HHVª²8 has been detected in KS of the eyelid and conjunctiva in an AIDS patient[69]. Ocular KS usually presents as a red mass and can easily be mistaken for hemorrhage[65]. No specific therapy is available for ocular KS, although HAART may be used for treatment of AIDSª²associated KS. If the lesion is painful or causes functional disruption, cryotherapy, surgical excision, radiation and/or chemotherapy are suggested[66,70].
Lymphoma  Nonª²Hodgkin¬ðs lymphoma (NHL), a kind of malignancy of Bª²cell origin associated with Epsteinª²Barr virus (EBV) infection[71], is the second most common malignant disorder associated with AIDS[72]. Ocular NHL may arise from the central nervous system (CNS) and/or retina, termed as primary CNS lymphoma, or may appear as intraocular metastasis from systemic lymphomas via blood circulation to the uvea, which is termed primary intraocular lymphoma. NHL can present in posterior and anterior parts, but are mostly confined to the conjunctiva and eyelid. Coª²existence of intraocular and orbital nonª²Hodgkin¬ðs lymphoma has been reported in AIDS patients. Massive necrosis involving the retina, choroid, and optic nerve, as well as several solid retinal pigment epithelial detachments and retinal vasculitis, could be observed[73]. The pathogenesis of AIDSª²related lymphoma is unknown. Some studies, however, have found that HIVª²1 Vpu and Tat protein can support the expansion of malignant B cells[74]. HIV has no direct oncogenic effect since HIV sequences have never been detected within the neoplastic lymphoid cells[75]. Lack of immunoª²surveillance and viral infection, other than HIV, may be key factors contributing to lymphomagenesis[76]. No specific treatment, but only the traditional radiation and chemotherapy are recommended.

¡¡¡¡NEUROª²OPHTHALMIC ABNORMALITIES

¡¡¡¡Histological studies have shown that up to 75%ª²90% of HIV/AIDS patients have brain damage, including the optic nerve. Sixty percent of HIV patients with neurological symptoms have some form of neuroª²ophthalmological deficit. Many factors, such as CNS infection by HIV alone or with other coª²infecting pathogens, neoplasms, inflammatory processes etc. may contribute to the neuroª²ocular manifestation in HIV/AIDS patients[77]. Optic neuropathy, papilledema, and cranial nerve palsies are the most commonly found cases. Optic neuropathies can be caused by viral, bacterial or fungal infections, commonly found are CMV and Cryptococcus neoformans invasion. Cryptococcal meningitis can also be the cause of papilledema. Along with the HIV ongoing replication, neurotoxins are produced to cause apoptosis in specific neural tissues that lead to axonal loss, neuronal damage, and finally, neuroª²ophthalmologic abnormalities.

¡¡¡¡CAUTIONS OF HAART

¡¡¡¡Drug resistance, adverse side effects and drugª²drug interaction have been universal problems with the application of HAART for HIV infected patients. Clinicians should be particularly aware of the side effects of HAART related to the eyes. For instance, the toxicity of nucleoside reverse transcriptase inhibitor therapy in terms of the potential inhibition of host mitochrondrial DNA polymerase is well known. There are reports that longª²term use of zidovudine may account for the late complication of Leber¬ðs hereditary optic neuropathy, which is caused by an induced mutation in the mitochondrial DNA[78,79]. So, HIVª²infected patients with a family history of Leber¬ðs hereditary optic neuropathy should be warned of this ocular disorder. Zidovudine and protease inhibitors (PIs) used alone can induce endothelial cell proliferation, causing a dysregulation of angiogenesis, which makes HIVª²positive patients more prone to hemangiomas such as KS[41,80]. The continued use of PIs may also increase the incidence of herpes zoster in AIDS patients. Application of nevirapine can lead to Stevensª²Johnson syndromeª²induced dry eye[81].
¡¡¡¡Surprisingly, combination of HAART and antiª²tuberculosis therapy in AIDS patients may actually weaken ocular condition[82]. On the other hand, the discontinuation of HAART can lead to ocular opportunistic infections, such as cryptococcal meningitis, which may result in choroiditis[27]. Immune recovery uveitis may occur in HIV/AIDS patients with CMV retinitis who have experienced immune recovery due to HAART[5]. Therefore, individualized treatment and regular monitoring should always be undertaken in HIV/AIDS patients.
OPHTHALMIC FINDINGS IN PEDIATRIC HIV INFECTIONS
The introduction of HAART seems to have a more significant impact on the nature of ocular manifestation in pediatric HIV infection in developed countries than that in the poor countries. A study in Milan, Italy, showed that there was 7.7% cases of ocular complication in the preª²HAART era while no case was found since the introduction of HAART in HIVª²infected children[83]. However, similar incidence rate of ocular complication was found in African HIVª²infected children regardless of HAART(Table 5).

¡¡¡¡CMV retinitis occur far less frequently in HIVª²positive children than in adults and it is diagnosed predominantly in patients with CD4 cells counts below 20cell/¦ÌL, owing to the immature immune status and less frequent exposure to CMV in pediatric HIVª²infected patients. The most significant ocular finding is the high incidence of perivasculitis and/or sheathing of retinal vessels in Africa and anterior uveitis in India. Nutritional status is probably the most important factor that contributes to the high prevalence of ocular involvement in HIVª²positive children in developing countries.

¡¡¡¡CONCLUSION

¡¡¡¡HIV/AIDSª²related ophthalmologic problems will remain an important issue for the coming decades. Nowadays, the study of ocular complications in HIV/AIDS patients mainly focuses on the clinical features and prevalence, but seldom the potential mechanism of the pathogenesis, perhaps due to the lack of proper animal system models. In any case, it is only when we clearly understand what happens during the ocular/HIV pathogenic process that we can find successful therapeutic strategies. This will require the longª²term commitment of both virologists and ophthalmologists.

¡¾²Î¿¼ÎÄÏס¿
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