Ocular manifestations of HIV

Ocular involvement in HIV could be caused by opportunistic infections, vascular abnormalities, neoplasms, neuro-ophthalmic conditions, and adverse effects of medications.
Ocular involvement in HIV infection occurs most commonly due to opportunistic infections and neoplasms. But also can be due to drug related and direct infections.
Opportunistic infections like CMV retinitis occur with a significantly reduced CD4 T-cell count and are one of the common causes of blindness in HIV patients.
Unlike other diseases, ocular infection in these immunosuppressed patients is associated with minimal inflammatory signs.
HIV has been isolated from tears, cornea, vitreous, and chorioretinal tissue in affected persons.
The ocular structures affected by HIV include the adnexa, anterior segment, posterior segment, and orbit.
Neuro ophthalmological manifestations also may be seen.
The institution of highly active antiretroviral therapy (HAART) has caused a dramatic improvement in the immune status of HIV-infected individuals and a change in the clinical presentation and course of opportunistic infections.

1. Ocular manifestation of HIV Getachew . K December, 2019 17/12/2019 1

2. Introduction Human Immunodeficiency Virus (HIV) is a retrovirus which causes a multisystemic disease called Acquired Immune Deficiency Syndrome (AIDS). The first reported case of HIV was in Los Angeles in 1981. Ocular manifestations commonly are seen in HIV patients, and the first description of the same was made by Maclean more than 20 years ago. Ocular involvement in HIV could be caused by opportunistic infections, vascular abnormalities, neoplasms, neuro-ophthalmic conditions, and adverse effects of medications. 17/12/2019 2

3. History The identification in 1981 of a cluster of gay men with unusual clinical manifestations later ascribed to infection with human immunodeficiency virus-I (HIV-I) was followed within a year by publication of typical ocular manifestations: cotton wool spots, cytomegalovirus, periphlebitis , and conjunctival Kaposi sarcoma. The acquired cellular immunodeficiency syndrome, rapidly became the world-wide focus of numerous surveys of eye disease, randomized clinical trials, and case series detailing optimal management of the ocular complications of AIDS. After 1996 ocular manifestations were modified by the improved immune status achieved by many patients who were treated with highly active anti-retroviral therapy (HAART ) The earliest retrospectively described case of AIDS is believed to have been in Norway beginning in 1966 . In the beginning, the CDC did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example,  lymphadenopathy , the disease after which the discoverers of HIV originally named the virus.  They also used  Kaposi's Sarcoma and Opportunistic Infections , the name by which a task force had been set up in 1981 .  In the general press, the term  GRID , which stood for  gay-related immune deficiency , had been coined .  The CDC, in search of a name, and looking at the infected communities coined "the 4H disease", as it seemed to single out homosexuals, heroin users,  hemophiliacs , and  Haitians .  However, after determining that AIDS was not isolated to the  gay community ,  it was realized that the term GRID was misleading and  AIDS  was introduced at a meeting in July 1982.By September 1982 the CDC started using the name AIDS.(Wikipedia) 17/12/2019 3

4. Etiology HIV is a retrovirus which replicates in CD4 T lymphocytes. Transmission occurs by exposure to blood and other body fluids. The natural history of an untreated HIV-infected person can be divided into three stages, namely, stages of primary infection, clinical latency, and, finally, opportunistic infections called AIDS. The Centers for Disease Control and Prevention (CDC) defines AIDS as being present when there is an AIDS-defining disease or a CD4 T-cell count less than 200 microliters. Some studies suggest that an HIV test should be requested if there is atypical, bilateral, treatment-unresponsive ocular toxoplasmosis or suspicion of cytomegalovirus (CMV) retinitis. 17/12/2019 4

5. Pathophysiology Ocular involvement in HIV infection occurs most commonly due to opportunistic infections and neoplasms. But also can be due to drug related and direct infections. Opportunistic infections like CMV retinitis occur with a significantly reduced CD4 T-cell count and are one of the common causes of blindness in HIV patients . Unlike other diseases, ocular infection in these immunosuppressed patients is associated with minimal inflammatory signs. HIV has been isolated from tears, cornea, vitreous, and chorioretinal tissue in affected persons. The ocular structures affected by HIV include the adnexa, anterior segment, posterior segment, and orbit. Neuro ophthalmological manifestations also may be seen. The institution of highly active antiretroviral therapy (HAART) has caused a dramatic improvement in the immune status of HIV-infected individuals and a change in the clinical presentation and course of opportunistic infections. 17/12/2019 5

6. Ocular manifestation of HIV Adnexal involvement in HIV-infected persons may include herpes zoster ophthalmicus (HZO), Kaposi sarcoma, molluscum contagiosum , and conjunctival microvasculopathy . Anterior segment involvement in HIV includes keratoconjunctivitis sicca , keratitis, and iridocyclitis . Posterior segment involvement in HIV is quite common and can cause visual loss. They include Retinal microangiopathy , CMV retinitis, VZV retinitis, toxoplasma retinchoroiditis , and bacterial and fungal retinitis. 17/12/2019 6

7. Manifestations of HIV Infection in the Ocular Adnexa include: Herpes zoster ophthalmicus Kaposi's sarcoma Molluscum contagiosum Squamous cell carcinoma/intraepithelial neoplasia of conjunctiva Cutaneous lymphoma Trichomegaly / Hypertrichosis Conjunctival microvasculopathy Preseptal cellulitis 17/12/2019 7

8. HZO Also Called varicella Zoster or shingles. Caused by human herpes virus 3 the same virus that causes varicella (chicken pox) in children. It is seen in 5% to 15% of HIV patients and may be associated with a simultaneous occurrence of keratitis, scleritis , uveitis, retinitis, or encephalitis. Reactivation of latent infection in the sensory trigeminal ganglia causes vesiculo -bullous dermatitis involving the ophthalmic distribution of the trigeminal nerve. Ophthalmic divisions of trigeminal nerve is affected >20x more than other divisions of the 5 th CN. 17/12/2019 8

9. Cont … HZO OHZ in someone younger than 50 years of age is uncommon, and should raise the suspicion of systemic immunosuppression due to malignancy, pharmacologic immunosuppression, or HIV infection. OHZ typically occurs at CD4+ T-lymphocyte counts of less than 200 cells/ μL , and is considered disseminated if it involves multiple dermatomes or unrelated organ systems. It manifests with a maculo - papulo -vesicular rash which often is preceded by pain. Usually involves a single dermatome and does not cross the midline 17/12/2019 9

10. HZO Involvement of the lateral nasal wall skin up to the tip of the nose in the HZO dermatitis indicates that the nasociliary branch of ophthalmic division of trigeminal nerve is affected. Papules/Vesicles seen at the tip of the nose in OHZ involving nasociliary nerve is called “Hutchinson's” sign This nerve gives sensory innervation to the intraocular structures (cornea, iris.) Because of this, OHZ involving nasociliary branch can have associated intraocular inflammation and vision loss. In these patients keratitis, scleritis , uveitis, retinitis, or central nervous system involvement may develop. 17/12/2019 10

11. Treatment Acyclovir 800mg po 5x/day for 7-10 days. If Acyclovir is given with in 72 hours of the onset of dermatitis, it can reduce pain and prevent the onset of severe ocular complications. Alternative drug is Famicyclovir 500mg po 5x/day for 7-10 days Topical steroids are useful in the management of sclerokeratitis , keratouveitis , interstitial keratitis, anterior corneal stromal infiltrates, and disciform keratitis. Topical cycloplegic drugs (Atropine or cyclopentolate ) prevent ciliary spasm associated with OHZ inflammation. Herpes zoster retinitis, optic neuritis, chorioreti-nitis …are best treated with a combination of systemic steroids and acyclovir i.v. 17/12/2019 11

12. Kaposi sarcoma highly-vascularized, mesenchymal tumor and may present as painless, violaceous lesions on the eyelid skin or conjunctivamicroangiopathy . Occurs in up to 25% of HIV-infected patients, and it is often the presenting sign of disease. A member of the herpes virus family, human herpes virus-8 (HHV-8), is associated in the pathogenesis of Kaposi's sarcoma. Kaposi's sarcoma involving the ocular adnexa will develop in approximately 5% of patients infected with HIV. 17/12/2019 12

13. Kaposi's sarcoma Both the eyelids and the conjunctiva may be involved . Conjunctival lesions are most commonly found in the inferior fornix, but may occur on any aspect of the palpebral or bulbar conjunctiva. Conjunctival Kaposi's sarcoma is often mistaken for benign subconjunctival hemorrhage. 17/12/2019 13

14. Treatment of Kaposi's sarcoma Radiation therapy is effective in treating eyelid and conjunctival Kaposi's sarcoma, but it can be associated with loss of lashes, skin irritation, and a mild conjunctivitis. Alternatively , lesions of the eyelid may be treated by cryotherapy or intralesional chemotherapy. 17/12/2019 14

15. Molluscum contagiosum A highly contagious papulonodular dermatitis caused by a poxvirus. Both the skin and mucous membranes may be affected, typically with multiple, small, umbilicated lesions. characterized by multiple, small (1-3 mm in size ) with a central depression, painless umbilicated lesions on the eyelid skin. . The lesions are more likely to be numerous and bilateral in HIV infection but patients may be asymptomatic unless the eyelid margin is involved. Crusted , painful vesicles suggest herpetic infection. Seventy percent to 80% of HIV patients may present with conjunctival microvasculopathy , characterized by segmental dilatation and narrowing of blood vessels, comma-shaped vascular segments, and sludging of blood column. The cause is thought to be either immune complex deposition, increased plasma viscosity or invasion of vascular endothelium by HIV and is found to correlate with retinal. Treatment options include cryotherapy, incision and curettage or excision. 17/12/2019 15

16. Trichomegally Acquired trichomegaly , or hypertrichosis of the eyelashes, typically occurs in the late stages of HIV infection. The cause is unknown, although elevated viral titers, drug toxicity, and poor nutrition have been implicated as contributing factors. Excessively long lashes may be trimmed, as needed, if they interfere with the use of eyeglasses or if the patient finds them cosmetically unacceptable. 17/12/2019 16

17. CONJUNCTIVAL MICROVASCULOPATHY Most HIV-infected patients will eventually develop conjunctival microvascular changes which includes: Segmental vascular dilatation and narrowing, Microaneurysm formation, The appearance of comma-shaped vascular fragments, and a visible granularity to the flowing blood-column, termed “ sludging .” 17/12/2019 17

18. CONJUNCTIVAL MICROVASCULOPATHY These changes are usually most evident near the limbus inferiorly, and are highly correlated with the occurrence of retinal microvasculopathy . The reason is unknown but suggested theories included: HIV-induced increase in plasma viscosity, HIV-related immune complex deposition, And direct infection of the conjunctival vascular endothelium by HIV . No treatment is indicated. 17/12/2019 18

19. Manifestations of HIV Infection in the Anterior Segment of the eye include:   Keratoconjunctivitis sicca Infectious keratitis Viral keratitis—herpes zoster virus, herpes simplex virus Bacterial and fungal keratitis Microsporidial keratitis    17/12/2019 19

20. Keratoconjunctivitis sicca , or dry eyes, are seen in approximately 20% of HIV patients and are thought to be an HIV-mediated inflammatory destruction of lacrimal glands. Keratitis in HIV is rare, seen in less than 5% of cases, but can lead to loss of vision. Herpes simplex virus and varicella-zoster virus are the most common causes. They may be recurrent and resistant to treatment. Microsporidia are protozoa which can cause a punctuate epithelial keratopathy. Bacterial and fungal keratitis also may be seen. Iridocyclitis is fairly common in HIV; mild iridocyclitis may be seen in association with VZV or CMV retinitis and severe iridocyclitis in association with toxoplasmosis, syphilis, tuberculosis, and bacterial or fungal retinitis. Medications , like Rifabutin and Cidofovir , prescribed for HIV patients also may cause iridocyclitis . Clinical examination in cases of iridocyclitis may reveal KPs, cells in AC,  patches of iris necrosis, posterior synechiae , and hypopyon . 17/12/2019 20

21. KERATOCONJUNCTIVITIS SICCA Keratoconjunctivitis sicca , or dry eye, occurs in 10% to 20% of HIV-infected patients, typically at late stages of their illness. Patients complain of irritation and burning uncomfortable red eyes Abnormal Schirmer's testing and interpalpebral rose bengal staining are invariably present. It is most probably related to combined effects of HIV-mediated inflammation and destruction of the lacrimal and salivary glands and direct HIV infection of the conjunctiva. Concurrent exposure due to lagophthalmos and decreased blink rate can worsen the keratopathy. Treatment consists of artificial tear supplement and long-acting lubricating ointments, which are applied at bedtime. 17/12/2019 21

22. VIRAL KERATITIS Herpes zoster ophthalmicus is often associated with either a dendritic epithelial or disciform stromal keratitis in HIV-infected patients. H owever , also occur with transient or no skin lesions, a condition termed herpes zoster sine herpete and reported to occur rarely in HIV-positive persons. Decreased corneal sensation and elevated intraocular pressure are clues to the diagnosis. Treatment is similar to that for herpes zoster ophthalmicus , as discussed earlier. 17/12/2019 22

23. BACTERIAL AND FUNGAL KERATITIS Bacterial keratitis and fungal keratitis do not appear to be more common in HIV-positive persons, but when they do occur, they tend to be more severe and have a higher tendency toward perforation. Various reported organisms have included α- hemolytic streptococci, Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa , Treatment should be aggressive, with intensive use of fortified topical antibiotics. 17/12/2019 23

24. Fungal and bacterial keratitis respectively 17/12/2019 24

25. MICROSPORIDIAL KERATITIS Microsporidia are obligate intracellular parasites known to cause gastroenteritis, sinusitis, pneumonitis, and urogenital infections in HIV-infected patients. In these patients, ocular infection with microsporidia is uncommon, but when present typically produces a punctate epithelial keratopathy with a mild papillary conjunctivitis. 17/12/2019 25

26. MICROSPORIDIAL KERATITIS Microsporidia are extremely difficult to culture, but can be readily seen within Geimsa -stained corneal or conjunctival epithelial cells. Treatment options include oral itraconazole , topical propamidine , topical fumagillin , and oral albendazole . 17/12/2019 26

27. Posterior segment manifestations of HIV Infection Retinal microvasculopathy HIV retinopathy Cytomegalovirus retinitis Varicella-zoster virus retinitis Toxoplasmosis retinochoroiditis Bacterial and fungal retinitis Other Infectious Retino-choroiditis (syphilis, TBC…) Intraocular lymphoma Patients may complain of floaters, flashes of light, decreased visual acuity or visual field defects.    17/12/2019 27

28. RETINAL MICROVASCULOPATHY Retinal microvasculopathy occurs in Retinal microangiopathy is the most common ophthalmic manifestation of HIV (more than 50% of HIV-infected patients.) Associated with low CD4 T-cell counts. It is characterized by the presence of cotton wool spots, retinal hemorrhages, and microaneurysms . The pathogenesis is thought to be similar to that of conjunctival microvasculopathy . All forms of retinal microvasculopathy increase in frequency in more advanced stages of HIV infection . They can be distinguished from infectious retinitis by a size less than 500 microns, a feathered edge, and transience, with fading over 6 to 8 weeks 17/12/2019 28

29. HIV retinopathy 50-70 % of HIV patients. Arteriolar occlusion in HIV retinal micro vascularity leads to interruption of the axoplasmic flow and the subsequent accumulation of axoplasmic debris, which manifests as cotton wool spots Increased plasma viscosity, immune –complex deposition, and a direct cytopathic effect of the virus on the retinal vascular endothelium are believed to be involved. Asymptomatic and transient but it may contribute to the optic nerve atrophy seen in many of patients. common findings include cotton wool spots, intraretinal haemorrhages , roth spots(white centred haemorrhages ,retinal micro aneurysms No treatment is indicated, but only observation. 17/12/2019 29

30. CMV retinitis A ffects nearly 30% to 40% of HIV-infected individuals and is usually seen with CD4 counts less than 100/microliters . Fundus examination reveals full thickness intraretinal opacification associated with retinal hemorrhages. There is minimal AC reaction, and the vitreous is generally clear. Loss of vision can occur due to the direct involvement of macula or optic nerve, retinal detachment, and immune recovery uveitis. Widespread use of HAART has caused a change in the natural history of CMV retinitis, leading to marked reduction in the incidence of this condition and clinical findings not seen in classical CMV retinitis like AC and vitreous inflammation.  Before the era of HAAR, CMV retinitis affected up to 40% of HIV-infected patients. CMV retinitis typically occurs at CD4 + T-lymphocyte counts of less than 50 cells/mm 3 , and almost always at counts less than 100 cells/mm 3 . 17/12/2019 30

31. Toxoplasmosis Retinochoroiditis Ocular toxoplasmosis affects less than 1% of HIV-infected patients. Toxoplasmosis retinochoroiditis in HIV-positive patients is usually distinguished by The occurrence of a moderate to severe anterior chamber and vitreous inflammation, A relative lack of retinal hemorrhage, and The presence of a smooth rather than granular leading edge 17/12/2019 31

32. Toxoplasma retinochoroiditis usually bilateral and multifocal and may be associated with central nervous system (CNS) involvement . Pyrimethamine and Sulfadiazine combination plus folinic acid Cotrimoxazole , Clindamycin alternative drugs as effective as pyrimethamine /sulfadiazine for lesions outside fovea. At least 6 weeks treatment needed 17/12/2019 32

33. Toxoplasma retinochoroiditis Recurrence over an old scar Old scar (pigmented) Active recurrent lesion(white) 17/12/2019 33

34. Orbital and Neuro-Ophthalmic Manifestations of HIV infection Orbital Neuro -ophthalmic Orbital lymphoma Papilledema Orbital cellulitis Optic neuritis Orbital Kaposi's sarcoma Optic atrophy   Cranial nerve palsies   Ocular Motility disorders   Visual field defects 17/12/2019 34

35. The Impact of HAART on Ophthalmic manifestations HAART has changed the face of HIV /AIDS by leading to dramatic decreases in HIV-related morbidity and mortality . Since the introduction of HAART, the incidence of ocular opportunistic infections causing retinitis such as cytomegalovirus (CMV), varicella zoster virus (VZV), tuberculosis, and toxoplasmosis , has dramatically decreased . 17/12/2019 35

36. Ocular toxicities may develop in patients receiving medications for HIV or opportunistic infections. These include uveitis with Cidofovir and Rifabutin , retinal pigment epithelial abnormalities with high dose Didanosine , corneal epithelial inclusions with intravenous Cidofovir or Acyclovir , and corneal subepithelial deposits with Atovaquone . Patients with CMV retinitis on HAART may suffer from a condition called immune recovery uveitis which causes diminution of vision and is characterized by cataract, vitritis , macular edema , optic disc edema , and epiretinal membrane. 17/12/2019 36

37. Immune Recovery Uveitis/IRU/ Since the advent of HAART, immune recovery uveitis (IRU) has become an ocular manifestation described in patients with inactive CMV retinitis from prior lesion. It has become a major visually-threatening condition and occurs in 10% of patients with inactive CMV retinitis and on HAART . It is believed to be a result of the restored immune system to mount an exuberant inflammatory response. Immune reconstitution syndrome can cause posterior segment inflammation in a patient with prior inactive CMV retinitis and can lead to visual morbidity in patients with AIDs. 17/12/2019 37

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