AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

More than 900,000 individuals are infected with HIV in the United States, and close to 40 million individuals carry the virus worldwide. Among the individuals infected with HIV, approximately 70-80% will be treated for an HIV-associated eye disorder during the course of the illness.

In general, CD4⁺ T-lymphocyte count has been used to predict the onset of certain ocular infections in patients who are HIV positive. CD4⁺ T-cell count less than 500 cells/mm³ is associated with Kaposi sarcoma, lymphoma, and tuberculosis; CD4⁺ T-cell count less than 250 cells/mm³ is associated with pneumocystosis and toxoplasmosis; and CD4⁺ T-cell count less than 100 cells/mm³ is associated with retinal or conjunctival microvasculopathy, cytomegalovirus (CMV) retinitis, varicella-zoster virus (VZV) retinitis, mycobacterium avium complex infection, cryptococcosis, microsporidiosis, HIV encephalopathy, and progressive multifocal leukoencephalopathy.

The predictive value of CD4⁺ T-cell count for ocular complications in HIV infection has been questioned by the recent reports of CMV retinitis in patients with CD4⁺ cell count more than 200 cells/mm³. These patients reportedly were taking highly active antiretroviral therapy. While such findings may argue against the protective effect of an increased CD4⁺ cell count, the possibility that the CMV retinitis preceded the recovery of CD4⁺ cell count was not ruled out. Thus, whether reconstituted T-cell count will serve as a better predictor of specific ocular infection is under active evaluation. Based on these uncertainties, use of CD4⁺ cell count has remained the predicting parameter for the occurrence of specific ocular infection in patients who are HIV positive, at least until antigen-specific tests of T-lymphocyte function become widely available.

Adnexal Manifestations

Background: The ocular adnexa consist of the eyelid, the conjunctiva, and the lacrimal drainage system. Common ocular adnexa lesions in patients who are HIV positive include herpes zoster ophthalmicus (HZO), Kaposi sarcoma, molluscum contagiosum, and conjunctival microvasculopathy.

Herpes Zoster Ophthalmicus

Background: HZO is a painful vesiculobullous dermatitis, which results mostly from the reactivation of previously established primary VZV infection. About 20% of adults with primary infection eventually show clinical symptoms. Clinical manifestation usually begins as pain over the involved dermatome, most commonly the first division of trigeminal nerve (V1), lasting for several days, followed by dermatitis in the form of vesicular rash. Herpes zoster can involve any dermatome, particularly T3 to L3 and cranial V1 (most common), V2, and V3. When the ophthalmic division is affected with or without ocular involvement, it is referred to as HZO.

Pathophysiology: HZO results from the reactivation of latent VZV from a previous primary infection that subsequently travels down the involved nerve; the most common nerve involved is the first division of cranial nerve V (trigeminal nerve). The loss of regulatory control of T-cells that occurs with aging and immunocompromised conditions may contribute to the reactivation of the virus.

Frequency: HZO affects about 5-15% of patients who are infected with HIV. Although, most persons developing clinical zoster are healthy, other predisposing factors include neoplasm, HIV infection, trauma, irradiation, immunosuppression, surgery, or debilitating system disease. The most common predisposing factor for herpes zoster infection is age. By age 80 years, as many as 50% of adults who are seropositive with VZV will develop zoster, of which HZO represents a small fraction.

Kaposi Sarcoma

Background: Kaposi sarcoma is a painless mesenchymal derived vascularized tumor often affecting the skin and mucous membranes.

Pathophysiology: This tumor is caused by human herpesvirus type 8. It is seen commonly in patients who are infected with HIV, where 3 histologic types of tumors have been described based on appearance of the vascular endothelium and the number of spindle cells.

Frequency: Kaposi sarcoma occurs in about 25% of patients who are HIV positive. About 20% of these patients have their eyelids or conjunctiva affected.

Molluscum Contagiosum

Background: Molluscum contagiosum is the most common ocular adnexal manifestation in patients who are HIV positive. It is a highly contagious dermatitis caused by DNA poxvirus, and it may affect skin or mucous membranes.

Pathophysiology: Molluscum contagiosum is caused by a DNA poxvirus, which spreads by direct contact with infected persons or by fomites. The small, painless, umbilicated lesions contain poxvirus particles that are released into tears with associated toxic keratoconjunctivitis.

Frequency: Molluscum contagiosum is more frequent and severe in patients who are HIV positive than in patients who are HIV negative. The eyelid is involved in 5% of HIV-positive patients.

Conjunctival Microvasculopathy

Background: Several conjunctival microvascular changes commonly are seen in HIV-positive patients during the course of the disease. These changes include segmental vascular dilation and narrowing, microaneurysm formation, and appearance of comma-shaped vascular fragments.

Pathophysiology: The specific etiology of the microvascular changes is not known; however, increased plasma viscosity and immune-complex deposition are believed to be involved. Direct infection of the conjunctival vascular endothelium by HIV has been suggested as a possible cause.

Frequency: These microvascular changes occur in as many as 70-80% of patients who are HIV positive.

Anterior Segment Manifestations

Background: The anterior segment is comprised of the cornea, the anterior chamber, and the iris. More than 50% of HIV-positive patients manifest anterior segment complications, including dry eyes (keratoconjunctivitis sicca), corneal infection (keratitis), and anterior chamber inflammation (iridocyclitis). Common symptoms include irritation, pain, photophobia, and decreased vision.

Keratoconjunctivitis Sicca

Background: Dry eyes (keratoconjunctivitis sicca) are seen in about 10-20% of patients who are HIV positive, usually during later stages of the disease.

Pathophysiology: The etiology is related to HIV-mediated inflammation and damage of the accessory and major lacrimal glands.

Frequency: It occurs in about 20% of HIV-positive patients, usually in the later stages of the illness.

Infectious Keratitis

Background: VZV and herpes simplex virus (HSV) most commonly cause infectious keratitis in HIV-positive patients. Keratitis due to VZV usually is associated with HZO, with or without the presence of dermatitis. VZV and HSV keratitis tend to reoccur more often, and they may be resistant to treatment in HIV patients. The frequency of bacterial and fungal keratitis is not more in HIV patients, but it tends to be more severe. The most common organism is candidal species, especially in intravenous drug users. Microsporidia also has been implicated. In general, Gram stain and cultures are used to guide treatment. Microsporidia is very difficult to culture, but it is seen readily within corneal or conjunctival epithelial cells with the use of Masson trichrome or Giemsa stain.

Varicella-Zoster Virus

Background: See HZO.

Pathophysiology: VZV is morphologically identical to HSV. Similar to HSV, VZV can establish latency after primary infection with subsequent reactivation of the disease when the host individual's immune system is compromised. Chickenpox is the primary human infection and occurs by direct contact of airborne droplets from cutaneous lesions or respiratory secretions. It is extremely contagious to susceptible individuals. VZV primary infection usually develops during childhood, and the disease tends to be mild and self-limited.

Frequency: VZV keratitis occurs in fewer than 5% of patients who are HIV positive, but it may cause permanent visual loss. Prevalence of VZV keratitis is higher in HIV-infected patients compared to the general US population.

Herpes Simplex Virus Keratitis

Background: HSV is a DNA virus that often infects humans. Two strains of HSV exist herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2).

Pathophysiology: In the United States, approximately 50-90% of adults have serum antibodies to HSV-1. HSV infection is spread by direct contact with infectious secretions from infected carriers. HSV-1 commonly is responsible for oral and ocular infections, while HSV-2 is responsible for genital infections. However, some cases of HSV-2 causing oral or ocular infections and HSV-1 causing genital infections have been reported.

Similar to VZV, HSV can establish latency after primary infection with subsequent reactivation of the disease when the host individual's immune system is compromised. Following primary infection, HSV may spread from the epithelial site of infection to sensory nerve endings in the infected tissue, where the virus is then transported down the nerve axon to the cell body located in a sensory ganglion. In the cell body, the viral genome enters the nucleus of a neuron, where it persists in a latent nonpathogenic state until reactivation in pathogenic or an immunocompromised state. Following reactivation, HSV is transported down the nerve axon to the epithelial cells on the ocular surface or cornea.

Frequency: About 0.15% of the population has a history of external ocular HSV infection. Approximately 67% of patients with HSV infections develop epithelial keratitis. Prevalence of HSV keratitis is higher in patients who are infected with HIV compared to the general US population.

Fungal Keratitis

Background: Candidal species are the most common fungal organisms causing keratitis in HIV-positive patients, especially in intravenous drug users. Other fungal organisms known to cause keratitis include Fusarium or Aspergillus species.

Pathophysiology: Immunosuppression predisposes HIV-positive patients to infection by fungus. The nonfilamentous fungi (candidal species) are very common in already compromised eyes, particularly with immunosuppression. The filamentous fungi (eg, Fusarium or Aspergillus species) are seen in association with trauma with vegetable matter.

Frequency: Fungal keratitis is a frequent cause of keratitis in immunocompromised patients when compared with immunocompetent patients. In some developing countries, fungal keratitis may be an indicator of HIV infection. One study compared the prevalence of HIV infection between patients with fungal keratitis and those with nonfungal keratitis. Twenty of 32 (81.2%) cases with fungal keratitis were found to be HIV positive; 60 of 180 (33%) of those with nonfungal keratitis were HIV positive (P value was <0.001). Fusarium solani was the most common organism, accounting for 75% of cases with fungal keratitis.

Microsporidia

Background: Microsporidia has emerged as an important opportunistic infectious protozoon in HIV-positive patients. Five species have been identified in patients who are HIV positive.

Pathophysiology: Immunosuppression predisposes patients who are HIV positive to infection by microsporidia, which are intracellular parasites capable of causing corneal and conjunctival infection.

Frequency: In general, microsporidia corneal or conjunctival infection is very rare.

Iridocyclitis

Background: Iridocyclitis in patients who are HIV positive tends to be mild and often is associated with retinitis due to CMV or VZV. When iridocyclitis is severe, it usually is seen in association with ocular toxoplasmosis, tuberculosis, syphilis, or bacterial or fungal retinitis (rare). Other causes of iridocyclitis in HIV-positive patients include medications (eg, rifabutin, cidofovir).

Pathophysiology: The etiology of iridocyclitis in HIV-positive patients includes sequelae of retinitis, retinochoroiditis, and drug toxicity. Iridocyclitis may manifest as part of generalized autoimmune and endogenous uveitis (eg, Reiter syndrome).

Frequency: Its occurrence is usually in association with HSV and VZV infections.

Posterior Segment Manifestations

Background: Posterior segment structures involved in HIV-positive patients include the retina, choroid, and optic nerve head. Disorders of at least one of these structures are seen in more than 50% of patients who are HIV positive. Common presenting complaints include floaters, flashing lights, visual field defect, and decreased visual acuity. Presence of an afferent pupillary defect strongly suggests significant retinal or optic nerve involvement. Diagnoses often are based on clinical evidence seen on funduscopic examinations.

HIV Retinopathy

Background: This is the most common retinal pathology in patients who are HIV positive, often manifesting as cotton-wool spots.

Pathophysiology: The cause of retinal microvasculopathy in patients who are infected with HIV is similar to those suggested for conjunctival vascular changes. The specific etiology of the microvascular changes has not been elucidated completely; however, increased plasma viscosity, immune-complex deposition, and a direct cytopathic effect of the virus on the retinal vascular endothelium are believed to be involved. It has been suggested that the HIV infection of the retinal vascular endothelium alone is not sufficient to account for the arteriolar occlusion responsible for cotton-wool spots. The arteriolar occlusion in HIV microvasculopathy leads to interruption of the axoplasmic flow, which manifests as cotton-wool spots.

Frequency: HIV retinal microvasculopathy occurs in as many as 50-70% of patients who are HIV positive. However, it is likely that the increased use of the newly available, highly active antiretroviral agents has lowered the prevalence of the retinal microvasculopathy seen in these patients.

HIV-Related Retinochoroiditis

Background: Viral retinitis and/or choroiditis is the most common cause of infectious retinitis and/or choroiditis. The herpesvirus family is implicated most commonly in infections of the retina and/or choroid in patients who are HIV positive. These viruses are obligate intracellular parasites that can damage the retina and/or choroid, either by direct invasion or by their ability to alter the host immune system.

CMV is the most common cause of necrotizing retinitis in patients who are HIV positive. VZV and HSV may cause acute retinal necrosis (ARN), with VZV as a more common cause of such necrotizing retinitis. This necrotizing retinitis may be unilateral or bilateral. Another form of necrotizing retinitis, progressive outer retinal necrosis (PORN), may occur in advanced HIV disease. To date, VZV is the only organism associated with PORN.

Among the bacterial, fungal, and parasitic organisms known to cause retinitis and/or choroiditis, not all have been reported to cause retinitis and/or choroiditis in patients who are HIV positive. Common bacterial causes of retinitis in patients who are HIV positive include Treponema pallidum (syphilis) and Mycobacterium tuberculosis. Fungal causes of retinitis and/or choroiditis include Pseudallescheria boydii, Cryptococcus neoformans, Histoplasma capsulatum, as well as Candida, Sporothrix, and Aspergillus species. Parasitic causes include Toxoplasma gondii and Pneumocystis carinii.

Cytomegalovirus Retinitis

Background: This is the most common cause of intraocular infection in patients with AIDS.

Pathophysiology: CMV is predominantly transmitted perinatally. In childhood, the major mode of transmission is by close contact, while in adolescence and adulthood, it is mostly transmitted through sexual contact or blood transfusion. Primary infection by CMV usually is asymptomatic. The reactivated CMV infection is responsible for the vision and life-threatening complications of this infection. Reactivation of the latent CMV commonly is seen in the setting of an immunocompromised host, especially HIV-infected patients with a CD4⁺ count less than 100 cells/mL, patients on chronic immunosuppressive agents, and patients with malignancies. The use of highly active antiretroviral agents has led to fewer patients with CD4⁺ T-cell count less than 100 cells/mm³; thus, putting fewer patients at risk of CMV retinitis.

Frequency: The seropositive prevalence of CMV is about 50% in adults and 95-100% in homosexual and AIDS patients. CMV retinitis occurs in as many as 40% of patients with advanced HIV infection. In the highly active antiretroviral therapy (HARRT) era, the incidence of CMV retinitis has declined and the survival after diagnosis has increased to over 1 year.

Acute Retinal Necrosis

Background: ARN is a fulminant retinal vaso-occlusive necrotizing retinitis that may complicate VZV, HSV, or, rarely, CMV infections. HIV-positive patients with ARN tend to have a CD4⁺ count greater than 60 cells/mL, usually with an associated history of VZV or HSV dermatitis.

Pathophysiology: The underlying pathophysiologic mechanisms for causing ARN rests on the virulence of these viruses following their reactivation, especially in the immunocompromised host. The severity of ARN depends on the degree of the patient's immunocompromise.

Frequency: Incidence of VZV-associated retinitis after HZO in patients who are HIV positive is 4-17%. For retinitis following HSV or CMV infections, the frequencies are much lower compared to the VZV-associated retinitis. Generally, VZV has been associated more frequently with ARN compared to HSV and CMV infections. ARN has been associated with either HSV-1 or HSV-2, with a similar course and severity of the infection as seen in VZV-induced ARN. A 2:1 male-to-female predilection with the occurrence of ARN exists.

Progressive Outer Retinal Necrosis

Background: PORN is a rapidly progressive, necrotizing retinitis that has been reported in patients with advanced AIDS. PORN is associated with a history of VZV infection in patients with AIDS.

Pathophysiology: While the exact pathophysiologic mechanism for PORN has not been elucidated completely, the general consensus is that severe immunocompromise along with a previous infection with at least VZV infection are necessary. PORN also has been described in patients with severe immunocompromise secondary to chemotherapy.

Frequency: Incidence of PORN is much lower than ARN.

Syphilis

Pathophysiology: Syphilis is believed to result from the proliferation and subsequent infiltration of T pallidum spirochetes into ocular structures. Histologic evaluation demonstrates mononuclear and polymorphonuclear cell infiltration of the involved ocular tissue, particularly cornea, iris, retina, and choroid. A modification of the host response to syphilis in HIV-infected patients may occur, which is partly responsible for the rapid course of CNS involvement in these patients.

Frequency: Incidence of syphilis has been on the rise since 1985, with 25% of the new cases reported from 1986-1987. This rise in the number of new cases of syphilis was correlated to a shift from heterosexual to homosexual and bisexual males who constitute approximately 30-40% of all the new cases. Usually a 5% rate of ocular involvement in untreated cases occurs with rare ocular involvement within 6 months of primary infection.

Tuberculosis

Background: The increasing number of HIV-infected population has, in part, contributed to the resurgence of reactivation of latent tubercle bacilli in previously infected individuals. Tuberculosis still represents a significant cause of granulomatous uveitis in patients who are HIV positive.

Pathophysiology: Reactivation of quiescent tubercle bacilli as a result of the immunocompromised condition of the host has been demonstrated to account for close to 90% of new cases of ocular tuberculosis. The caseating tubercle contains the inactive organism until reactivation. Inflammation of tuberculosis usually manifests as areas of necrosis surrounded by mononuclear and giant cells.

Frequency: Annual incidence of tuberculosis is close to 20,000 cases, with as many as 10 million infected individuals. Approximately 90% of the new cases result from the reactivation of the latent tubercle bacilli in previously infected individuals. The group at high risk for acquiring primary and/or secondary tuberculosis infection includes persons with HIV infection; close contacts of tuberculosis patients; low-income populations, including persons of African, Hispanic, and Native American descent; alcoholics and intravenous drug users; and nursing home residents.

Pneumocystis carinii Choroidopathy

Background: Infectious choroiditis is diagnosed in fewer than 1% of ocular disorders in HIV-positive patients, with P carinii as the most common identified organism.

Pathophysiology: P carinii choroidopathy tends to occur in immunocompromised hosts, particularly HIV patients with disseminated infection. An increased association with use of aerosolized pentamidine prophylaxis has occurred.

Frequency: P carinii choroidopathy represents fewer than 1% of ocular disorders in patients who are HIV positive.

Toxoplasma Retinochoroiditis

Background: Toxoplasmosis is the most common cause of retinochoroiditis. Infection with T gondii may be congenital, but most of the infection is acquired. Ocular manifestation usually follows systemic disease.

Pathophysiology: T gondii is an intestinal parasite in cats. The organism usually forms cysts that contain many organisms. The cysts may exist in 1 of 3 forms: (1) oocysts, in cat feces; (2) tachyzoites, proliferative form; and (3) bradyzoites, encysted form. Infection in humans may occur either by inhalation or by ingestion of oocysts by consuming poorly cooked meat or unpasteurized milk that has been infested with the organism. In general, toxoplasma infection is well tolerated in most tissues of the body, except the eyes. T gondii may remain as bradyzoites within an inactive chorioretinal scar until reactivated as a result of immunosuppression. The exact mechanism of reactivation has not been elucidated completely. However, it is the transformation of the bradyzoites into tachyzoites that allows for new infection of the retina and choroid, leading to recurrent retinochoroiditis.

Frequency: Toxoplasmosis is the most common cause of retinochoroiditis, accounting for about 30-50% of all posterior uveitis.

Histoplasma Chorioretinitis

Background: H capsulatum is a small, gram-positive, mycelial dimorphic fungus, approximately 3-5 micrometers in diameter. The organism is endemic in the central and eastern United States, particularly the Mississippi-Ohio River Valley, as well as Central America, Asia, Turkey, Israel, and Australia. The organism enters the body via the respiratory tract by inhalation of spores.

Pathophysiology: Acute histoplasmosis tends to be benign and self-limiting, mostly affecting the pulmonary system. This also may take a subclinical route. Disseminated histoplasmosis is uncommon. The organism often is spread hematogenously producing lesions throughout the body, especially in the reticuloendothelial system of the liver, spleen, lymph nodes, and bone marrow. Risk factors contributing to the dissemination of infection include a defective immune system, such as seen in AIDS or malignancies, immature immune system in infants, or iatrogenic immunosuppression. Disseminated histoplasmosis has a high mortality in AIDS patients. This disease tends to have a fulminant course, usually complicated by disseminated intravascular coagulation. It is uncommon to see disseminated histoplasmosis infection in healthy adults without any immunologic defects.

Frequency: A high frequency of histoplasmosis in the eastern and central United States exists. Other endemic areas of the world include Central America, Asia, Turkey, Israel, and Australia. Disseminated infection frequently is seen in the setting of immunosuppression. The patients affected usually are aged 20-50 years.

Cryptococcal Chorioretinitis

Background: C neoformans is a budding, spore-forming, yeastlike fungus, with a diameter of 5-10 µm. A clear mucinous capsule usually surrounds this organism. This capsule can be detected easily by India ink and mucicarmine preparations. The distribution of the organism is worldwide. Infection from C neoformans most frequently is acquired from pigeon or other bird droppings. This organism has been isolated from soil, fruit, and milk.

Pathophysiology: Cryptococcal infection occurs by inhalation of airborne spores. Organisms initially remain in the lungs; then, they hematogenously spread to other parts of the body. This organism has predilection for the brain and meninges. Intraocular infection may occur either via direct extension from the CNS or through the bloodstream from a localized or disseminated cryptococcal infection. Most intraocular cryptococcal infections have been seen in association with cryptococcal septicemia with severe meningeal infection. This often occurs in immunocompromised individuals or debilitated patients (eg, HIV-positive patients, or patients with malignant lymphoma, Hodgkin disease, or systemic lupus erythematosus).

Frequency: While no report of the exact frequency of cryptococcal infection exists, most of the infection is seen in immunocompromised individuals.

Neuro-ophthalmologic manifestations

Pathophysiology: The common causes of neuro-ophthalmologic complications include cryptococcal meningitis, meningeal and parenchymal lymphoma, neurosyphilis, and toxoplasmosis. More diffuse encephalopathy may be due to either direct effects of the virus (HIV retinopathy) or to superimposed infection from Polyomavirus causing progressive multifocal leukoencephalopathy (PML).

Frequency: Neuro-ophthalmologic complications are seen in approximately 10-15% of patients who are infected with HIV.

Orbital Manifestations

Background: It is uncommon to observe orbital complications in HIV-positive patients. The most common complications include orbital lymphoma and orbital cellulitis due to Aspergillus infection. Lymphomas are treated with radiation and chemotherapy, whereas orbital cellulitis is amenable to systemic antibiotics.

Ocular Manifestations in Children

Background: Children with HIV infection are less likely to have ocular manifestations, including CMV retinitis. The reason for this difference is uncertain, but it may be related to an altered immune response to HIV or lower prevalence of CMV seropositivity in children.

Ocular Manifestations in Developing Countries

Background: Most HIV-infected individuals are in developing countries, particularly, sub-Saharan Africa and Southeast Asia. Prevalence of CMV retinitis among these HIV-infected persons in these developing countries is lower compared to those in the developed countries. However, ocular complications of toxoplasmosis and tuberculosis, HZO, and papillomavirus-associated conjunctival squamous cell tumor are more prevalent in HIV-infected persons in developing countries. The reason for this difference is believed to be related to the frequencies of the causative agents and the poor control of HIV infection in these countries.

Ocular Toxicity in HIV-Infected Patients

Background: As many as 33% of HIV-infected patients on high-dose rifabutin experience intraocular inflammation, especially when an antifungal azole is used concurrently. Cidofovir causes uveitis in about 25-30% of patients and may lower intraocular pressure in as many as 10% of patients. While mild uveitis may be treatable with topical corticosteroids, severe uveitis and hypotony can cause permanent visual loss; therefore, medication should be discontinued.

High-dose didanosine has been associated with retinal pigment epithelial abnormalities. Corneal epithelial inclusions have been associated with intravenous ganciclovir and acyclovir, while atovaquone is associated with corneal subepithelial deposits. These adverse effects are dose related and resolve following discontinuation of the drug, with the exception of the abnormal retinal pigment epithelial changes.

Mortality/Morbidity

• Adnexal Manifestations

  The consequence of HZO may be 1 of 3 categories, as follows: (1) those that are secondary to infectious/noninfectious inflammatory processes, (2) those resulting from nerve damage, or (3) those due to tissue scarring. Infectious and inflammatory changes can affect almost all adnexal, ocular, and orbital tissues. The infectious/noninfectious inflammatory process may manifest as a keratitis or vasculitis, iritis, ischemic papillitis or retrobulbar optic neuritis, and orbital vasculitis. Other complications may include retinitis or encephalitis.

  Nerve damage may be associated with neurotrophic keratitis. Cranial nerve palsies have been reported in as many as 33% of cases of HZO; the third cranial nerve being the most frequently affected. The cranial nerve involvement may take place within the orbit or the cavernous sinus. Tissue scarring may result in eyelid deformities causing marginal notching, loss of cilia, trichiasis, and cicatricial entropion. Scarring and occlusion of the lacrimal puncta or canaliculi may occur.

  Kaposi sarcoma: Some of the complications of ocular Kaposi sarcoma include trichiasis and entropion formation. Untreated ocular Kaposi sarcoma may lead to obstructive disruption of the visual axis.

  Molluscum contagiosum: Chronic follicular conjunctivitis frequently is present with occasional associated punctate epithelial erosions and/or superficial vascular pannus on the cornea. Severe keratitis due to molluscum contagiosum tends to mimic chlamydial keratoconjunctivitis. It is uncommon to find conjunctivitis and superficial keratitis in HIV-positive patients.

  Conjunctival microvasculopathy: There is no reported mortality and morbidity.

• Anterior Segment Manifestations

  Keratoconjunctivitis sicca: The concurrent presence of encephalopathy in these patients may cause incomplete eyelid closure and decreased blink rate, leading to a worsened dry eyes condition.

  Varicella-zoster virus keratitis: Complications of VZV include subepithelial infiltrates, stromal keratitis, disciform keratitis, uveitis, and increased intraocular pressure. Varicella keratitis is a self-limited disease. Corneal scarring may occur, but it is rare.

  Herpes simplex virus keratitis: Stromal keratitis and uveitis occur in fewer than 10% of the patients with primary HSV infection. Blepharoconjunctivitis may occur in patients with recurrent ocular HSV infection. It may or may not be associated with epithelial keratitis. Other complications of HSV infection include dendritic and geographic epithelial keratitis, nonnecrotizing stromal keratitis, and iridocyclitis.

  Fungal keratitis: Fungal keratitis may be complicated by uveitis, endophthalmitis, and/or retinitis. These complications may cause vitreous abscesses, retinal hemorrhages with or without Roth spots. In severe cases, retinal detachment may develop.

  Microsporidia: Superficial keratoconjunctivitis is the most common complication seen in HIV-positive patients infected with Microsporidia.

  Iridocyclitis: Its occurrence usually is in association with HSV and VZV infections.

• Posterior Segment Manifestations

  Cytomegalovirus retinitis: Complications of CMV retinitis include papillitis, seen in about 5% of these patients, and it can lead to significant visual loss. If untreated or inadequately treated, CMV retinitis progresses (usually less rapid than HSV or HZV retinitis) to involve a larger area of the retina including the macular and/or foveal. Cystoid macular edema, retinal vein or artery occlusion, rhegmatogenous retinal detachment (RRD), or blindness may result from inadequately treated CMV retinitis in these patients. Incidence of RRDs tends to increase with time in patients with CMV retinitis, with a cumulative probability of 26-61% in different studies. Immune recovery uveitis (IRU) is the HAART dependent inflammatory response that may occur in up to 63% of patients with regressed CMV retinitis and elevated CD4 counts and is associated with vision loss from epiretinal membrane, cataract, and cystoid macular edema.

  Acute retinal necrosis: ARN frequently is complicated by anterior uveitis, retinal and choroidal vasculitis, vitritis, and papillitis. Episcleritis, scleritis, or optic neuropathy also may be present. During the initial phase of the infection, the severity of the retinitis could lead to exudative retinal detachment. However, following the resolution of the retinitis, traction between the vitreous and the resulting gliotic scar of the necrotic retina may occur and can cause retinal breaks at the interface between the normal and necrotic retina. Subsequently, this may result in RRD. As many as 75% of eyes affected by ARN may be complicated by RRD after 2-3 months of onset.

  Progressive outer retinal necrosis: Complications of PORN may include macular retinitis, optic nerve disease, acute vitreous hemorrhage, and/or retinal detachment. Up to 66% of patients diagnosed with PORN eventually become blind within 6 weeks of diagnosis despite aggressive treatment.

  Syphilis: Syphilitic anterior uveitis may be complicated by cataract and glaucoma formation. Posterior segment complications may include posterior placoid chorioretinitis, neuroretinitis, vitritis, pigmentary chorioretinopathy, choroiditis, papillitis, choroidal neovascular membranes, and retinal vasculitis.

  Tuberculosis: Complications include conjunctivitis, oculoglandular syndrome, interstitial keratitis, phlyctenular keratitis, anterior uveitis (most common), endophthalmitis, scleritis, chorioretinitis, disseminated choroiditis, choroidal neovascularization, and optic atrophy. These ocular manifestations tend to occur in patients with other extrapulmonary disease.

  Pneumocystis carinii choroidopathy: Usually, minimal vitreous inflammation occurs. The major morbidity and/or mortality results from the debilitating pneumonia caused by this organism.

  Toxoplasma retinochoroiditis: Complications of T gondii infection depend on the mode of infection. Infection with T gondii may be congenital or acquired. In general, these include abortion, infantile retinochoroiditis, encephalitis, hydrocephalus, mental retardation, leukocoria, and anterior and posterior uveitis.

  Histoplasma chorioretinitis: Disseminated histoplasmosis has a high mortality rate in AIDS patients. This disease tends to have a fulminant course, usually complicated by disseminated intravascular coagulation. Ocular complications of disseminated histoplasmosis include retinitis, choroiditis, optic neuritis, or uveitis. Secondary choroidal neovascularization also may develop.

  Cryptococcal chorioretinitis: The most frequent intraocular sequela of cryptococcal infection is chorioretinitis. In the absence of treatment, or poor management, endophthalmitis may result. Other reported ocular complications of cryptococcal infection include papilledema, optic atrophy, and ophthalmoplegia.

  Neuro-ophthalmologic manifestations: The most common complications include papilledema due to increased intracranial pressure, cranial nerve palsies, ocular motility disorders, and visual field defects.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Physical

• Herpes zoster ophthalmicus: Clinical manifestation of HZO may be acute, chronic, or a relapsing course. The acute lesions usually develop within 3 weeks of the rash. These lesions may resolve rapidly and completely, or they may pursue a chronic course for months to years. Recurrence is a characteristic feature of the disease, and relapse may occur as late as 10 years after the primary infection. Vesicular rash in the distribution of all or one of the divisions of the trigeminal nerve is one of the early clinical manifestations. Fever, malaise, and headache also may be part of the presenting complaint. Crusts usually develop after the sixth day. Involvement of the nasociliary nerve often is associated with ocular involvement; although severe ocular complications can occur with vesicular rash anywhere on the forehead. Some of the acute complications and neurologic complications include the following:

  Acute tissue changes

  • Eyelids: Ptosis, edema, hemorrhagic necrosis
  • Disciform keratitis: Appears after 3 weeks of onset of symptom; causes severe visual loss; steroid sensitive
  • Corneal edema: Appears after 3 weeks; steroid sensitive
  • Sclerokeratitis: Appears after 3 weeks; steroid sensitive
  • Neuropathic keratitis: May occur after 5 days; with ulceration, immediate management is necessary
  • Iritis: May be seen after 5 days, usually steroid sensitive
  • Glaucoma: Usually steroid sensitive, and may need antiglaucomatous therapy
  • Retinitis: Systemic antivirals

  Neurologic complications of herpes zoster ophthalmicus

  • Optic neuritis: Usually rare, and can cause severe visual loss; vasculitis
  • Encephalitis: Rare, and can cause profound visual loss as a result of acute viral damage, and often in immunocompromised patients
  • Hemiplegia: Rare, contralateral; due to the associated vasculitis.
  • External ocular muscle palsies: Usually ipsilateral, recovery good
  • Acute neuralgia: Due to stimulation of pain afferents by inflammation, resolves in most of the cases
  • Postherpetic neuralgia: Usually starts after the rash resolves; tends to be worse with advancing age; neuralgia may be peripheral or central; also may arise from larger nerve fiber loss in central pathways
• Kaposi sarcoma: Kaposi sarcoma usually presents on the eyelid as a painless, violet-brown papule. It may involve the orbit with associated eyelid and conjunctival edema. Kaposi sarcoma of the conjunctiva usually appears as reddish-blue, vascularized, subconjunctival lesions most frequently seen in the inferior fornix as nodular or diffuse lesion. Eyelid and conjunctival Kaposi sarcoma tend to mimic chalazion and localized subconjunctival hemorrhage, respectively.
• Molluscum contagiosum: Molluscum contagiosum is characterized by multiple, small, painless, umbilicated lesions. The lesions of molluscum contagiosum tend to be larger, more numerous, and rapidly growing in HIV-positive patients than in HIV-negative patients. Compared to keratoacanthoma, molluscum contagiosum is smaller and associated with less inflammation. It may give rise to elevated, pearly, umbilicated nodules on the eyelids. The lesions are seen easily on the eyelids, but they sometimes may be missed with casual examination. Diagnosis is based on clinical findings of the characteristic skin lesions. Molluscum contagiosum is a self-limiting disease with spontaneous resolution taking months to years.
• Conjunctival microvasculopathy: The microvascular changes in conjunctival microvasculopathy are best seen with slit lamp examination near the limbus and correlate with the presence of retinal microvasculopathy.
• Keratoconjunctivitis sicca: Diagnosis of keratoconjunctivitis sicca usually is made with the aid of an abnormal Schirmer test and rose bengal stain.
• Varicella-zoster virus keratitis
  • VZV infection usually manifests with fever, malaise, and cutaneous rash, which typically lasts 7-10 days. The cutaneous manifestations usually start as macules and progress to papules, vesicles, and, ultimately, pustules, which dry and crust. The vesicles may be on the eyelid margins or bulbar conjunctiva. Associated papillary conjunctivitis with membrane formation may be present.
  • Other signs include decreased corneal sensation and increased intraocular pressure.
  • Unlike HSV, some unique clinical features of VZV include complete dermatomal distribution, increased pain, smaller dendrites without central ulceration or terminal bulbs, frequent scarring of skin, frequent postherpetic neuralgia, sectoral iris atrophy, no bilateral involvement, no recurrent lytic epithelial keratitis, and frequent corneal hypoesthesia.
• Herpes simplex virus keratitis
  • Primary ocular HSV infection often presents as unilateral blepharoconjunctivitis. The conjunctival inflammatory response is frequently follicular with associated preauricular lymphadenopathy. Cutaneous vesicles on the eyelid skin or margin appear in most of the cases.
  • Follicular conjunctivitis caused by HSV sometimes may be difficult to distinguish from that caused by adenovirus. Helpful distinguishing features include the characteristic dendritic morphology of HSV keratitis, presence of cutaneous vesicles, absence of an associated epidemic, and the predominant unilaterality (approximately 10% of HSV keratitis cases are bilateral, whereas most of the adenovirus keratoconjunctivitis cases are bilateral).
  • Patients with dendritic epithelial keratitis may have no obvious symptom, or they may complain of mild foreign body sensation, photophobia, redness, and blurred vision. Recurrent HSV epithelial keratitis usually manifests as characteristic dendritic branching. The lesions may start as distinct punctate epithelial keratitis, which then coalesce into dendritic-shaped lesions composed of swollen opaque epithelial cells within days. The dendritic terminals have a peculiar bulblike morphology. A narrow ulcer often develops in the center of the dendrite within days of onset, usually as a result of lysis of virus-infected cells. The opaque cells around the central ulcer stain well with rose bengal and fairly well with fluorescein. The predisposing factors for developing geographic ulcers include the strain of involved HSV virus, topical or systemic immunosuppressive therapy, and HIV infection.
  • Unlike VZV keratitis, some unique clinical features of HSV infection include incomplete dermatomal distribution; less pain; larger dendrites with central ulceration and terminal bulbs, rare skin scarring; rare postherpetic neuralgia; patchy, no sectoral iris atrophy; rare bilateral involvement; frequent recurrent lytic epithelial keratitis; and sectoral or diffuse corneal hypoesthesia depending on the number of recurrences.
  • Other conditions that may produce dendritic epithelial lesions include the following: VZV, healing epithelial defects, and soft contact lens wear.
  • Diagnosis of HSV predominantly is based on clinical features and staining pattern with rose bengal and/or fluorescein. In the absence of such classic clinical features, tissue culture, and/or antigen detection techniques may be helpful.
• Fungal keratitis: Patients with fungal keratitis usually present with eye pain, photophobia, discharge, foreign body sensation, or history of ocular trauma with vegetable material. Slit lamp examination usually reveals corneal stromal infiltrate with feathery border. Associated small focal lesions around the primary corneal infiltrate often are present, along with conjunctival injection, anterior chamber reaction, and hypopyon.
• Microsporidia keratoconjunctivitis: Superficial keratoconjunctivitis is more common in HIV-positive patients with Microsporidia infection, while focal stromal keratitis tends to occur more commonly in healthy individuals infected with Microsporidia.
• HIV-associated retinal microvasculopathy: HIV-associated retinal microvasculopathy often is asymptomatic and transient, but it may contribute to the optic nerve atrophy seen in many of the patients. Common findings may include cotton-wool spots, intraretinal hemorrhages, Roth spots (white-centered hemorrhages), and retinal microaneurysms.
• CMV retinitis: Patients with CMV retinitis typically complain of floaters, photopsias, or visual loss, without associated eye pain or injection. Patients tend to have good vision at diagnosis of CMV retinitis. Often minimal anterior chamber reaction in CMV retinitis is present. The characteristic lesion tends to be a single or multiple white lesion(s) with a granular irregular feathery border associated with retinal edema and necrosis. Associated intraretinal hemorrhage may or may not be present initially. Over time, the lesions of CMV retinitis may coalesce with a full-thickness retinal whitening often associated with intraretinal hemorrhage.
• Acute retinal necrosis: Patients with ARN usually present with eye pain associated with decreased visual acuity, floaters, and history of recent HSV or HZV infection. In early disease, funduscopic examination often reveals small, necrotic yellowish lesions in the periphery, which rapidly spread into a larger confluent white area, most often involving the entire peripheral retina, and then progress toward the posterior pole. In about 36% of cases, the second eye is involved. Associated anterior uveitis, retinal vasculitis, episcleritis, scleritis, or retinal detachment may be present.
• Progressive outer retinal necrosis: Patients with PORN usually present with minimal anterior chamber inflammation, with no vitritis or retinal vasculitis. In general, the lesions in PORN usually are multifocal, deep to the retina, opaque, and patchy, with a tendency to start from the posterior pole and spread with extreme rapidity to involve the entire retina.
• Syphilis: The presentation of the patient depends on the stage of the disease. The ocular findings in syphilis can mimic any ocular inflammatory disorder, including conjunctivitis, interstitial keratitis, episcleritis, scleritis, choroiditis, vascular occlusion, Argyll-Robertson pupil, Raeder syndrome, cranial nerve palsies, optic neuritis, and optic atrophy. Most of the ocular findings are seen in stage 2 (secondary) and stage 3 (tertiary). Initial presentation of ocular syphilis is unilateral with subsequent contralateral eye involvement in 50% of cases.
  • Primary - Eyelid or conjunctival chancre
  • Secondary or tertiary - Iridocyclitis or more diffuse intraocular inflammation is present. Other manifestations of secondary and/or tertiary syphilis include optic neuritis, active chorioretinitis, retinitis, retinal vasculitis, conjunctivitis, episcleritis dacryoadenitis, dacryocystitis, scleritis, and monocular interstitial keratitis. Dissemination of the disease in secondary syphilis may be accompanied by arthralgia, headache, low-grade fever, and maculopapular rash. Three distinct patterns of iris findings may be seen prior or during the active stage of the disease, as follows: (1) iris roseata in which reddish spots or engorged vascular tufts that resolve with treatment are present, (2) iris papulosa in which the roseata spots increase in size to resemble a papule, and (3) iris nodosa in which the area of iris lesion forms a large yellow-red nodule.
  • Tertiary - Inadequately treated syphilis or untreated disease sets the stage for tertiary syphilis, which includes the development of an obliterative endarteritis in about one third of the patients. Optic atrophy, old chorioretinitis, chronic iritis, and Argyll-Robertson pupil also are seen in this stage.
• Tuberculosis: Clinical presentation of ocular tuberculosis can take a variety of forms. This usually is accompanied by constitutional symptoms, such as malaise, night sweats, and other pulmonary complaints, including shortness of breath and dyspnea. The most common ocular manifestation is anterior uveitis and disseminated choroiditis. The anterior segment inflammation may be granulomatous or nongranulomatous, with varied severity. Usually, granulomatous keratitic precipitates and posterior synechiae are present. It is possible to have anterior uveitis without clinically active tuberculosis. Untreated chronic uveitis from tuberculosis can gradually result in panophthalmitis. Choroidal tubercle invasion in miliary tuberculosis may cause unifocal or multifocal yellowish, grayish, or whitish choroiditis, mostly in the posterior pole. These lesions tend to show delayed hyperfluorescence that increase in size on fluorescein angiogram. With time, these lesions heal with residual scars that may or maynot
  have pigmentation. Sequela of subretinal neovascularization arising from the area of scars may be present.
• Pneumocystis choroidopathy: P carinii choroidopathy can cause mild visual loss, but most patients are asymptomatic. Funduscopic examination usually reveals multifocal, round, creamy, yellow, deep choroidal lesions mostly in the posterior pole. These choroidal lesions may measure 0.5-2 disc diameters in size. Usually, minimal vitritis with no retinal vascular changes is present. Fluorescein angiography shows early hypofluorescence with late staining of the choroidal lesions.
• Toxoplasma retinochoroiditis
  • Transplacental infection of toxoplasma retinochoroiditis to the fetus has been shown to occur in only 20% of pregnancies with active maternal infection. Moreover, the severity of the fetal infection depends on time in pregnancy. In the first trimester, toxoplasmosis can result in abortion or in an infant with retinochoroiditis, encephalitis with associated intracerebral calcification, hydrocephalus, and mental retardation.
  • Ocular manifestation often consists of bilateral retinochoroiditis in the posterior pole particularly in the macula region. Ocular manifestation may become evident during or shortly after a systemic infection, or months to years later. The usual ocular lesion of toxoplasmosis is a focal necrotizing retinitis, with white infiltration and surrounding retinal edema. Anterior segment uveitis, with keratic precipitates and anterior chamber cells and flare, is common. The areas of retinitis may be single or multiple, small or large, and frequently are adjacent to inactive chorioretinal scars. Vitreous cellular reactions over the areas of retinitis often are present.
  • Vitreous precipitates on the posterior surface of the detached vitreous may be present. In addition, vitreous debris, optic disc swelling, neuroretinitis, mild granulomatous iritis, localized vasculitis, and retinal artery or vein occlusion in the area of the inflammation may be present. Occasionally, a chorioretinal scar may be seen in the uninvolved eye.
• Histoplasma chorioretinitis
  • The typical triad of ocular histoplasmosis syndrome are yellowish-white, punched-out circular lesions, histo spots, which are scattered in the fundus; a macular choroidal neovascular membrane (CNVM) seen as a grayish-green patch underneath the retina; and area(s) of atrophy or scarring adjacent to the optic disc.
  • A rim of pigmented area separating the disc from the area of atrophy or scarring may be present. The formed macular CNVM may be associated with retinal neurosensory detachment, subretinal blood or exudate, or a pigmented ring evolving into a disciform scar.
  • In children, disseminated histoplasmosis often manifests with symptoms and/or signs of fever, hepatosplenomegaly, nausea, vomiting, diarrhea, and weight loss. Interstitial pneumonia is expected to develop within a few weeks and may be fatal if not treated aggressively.
  • Adults with disseminated histoplasmosis often present with fever and acute pneumonia. The central nervous system, kidneys, and GI tract often are involved secondarily.
  • Ocular involvement of disseminated histoplasmosis may include retinitis, choroiditis, optic neuritis, or uveitis. The retinitis often appears as discrete multiple, yellowish-white intraretinal and subretinal infiltrates, approximately one fourth to one sixth disc diameter. The granulomatous choroiditis of histoplasmosis may appear as small white drusenoid bodies. The disease rarely is diagnosed acutely but most commonly is recognized by the clinical appearance of the lesion. Patients often are diagnosed to have ocular histoplasmosis following the development of choroidal neovascularization leading to significant loss of central vision.
  • During acute illness from disseminated histoplasmosis, diagnosis can be made from positive blood cultures and cultures of urine, mouth ulcers, and/or tissue biopsies. Liver biopsies have been reported to be positive for H capsulatum in as many as 80% of patients. A high fixation titer for histoplasmin complement substantiates the diagnosis. Immunodefective patients may show negative histoplasmin skin test. The vitreous aspirates obtained during pars plana vitrectomy may be used to isolate the organisms.
• Cryptococcal chorioretinitis: The most common intraocular manifestation of cryptococcal infection is chorioretinitis. This usually starts as multiple, yellowish-white, minimally elevated chorioretinal lesions. The size of these lesions is from one-fifth to one disc diameter. Usually, minimal or no associated vitritis is present. In the absence of proper treatment, these lesions may progress to endophthalmitis. This usually results in the development of vitritis with haze, debris, and vitreous exudates, which may extend throughout the entire vitreous.

WORKUP

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Herpes zoster ophthalmicus
• • Diagnosis of HZO is primarily by history and examination. However, baseline complete blood count, electrolytes, glucose, blood urea nitrogen, and creatine may be necessary prior to starting antiviral drugs.
  • When a clear diagnosis cannot be made, a noncontrast CT scan should be considered to evaluate for other causes of new-onset headache.
• Fungal keratitis
• • Diagnosis of fungal keratitis includes a detailed history and complete ophthalmologic examination. History should include contact lenses use, lens-care regimen, previous corneal disease, and topical or systemic steroid use.
  • A thorough slit lamp examination is important. Deep corneal scrapings or even corneal biopsy for Giemsa, periodic acid-Schiff, or Gomori methenamine-silver staining with culture and sensitivity to define treatment, particularly with persistent ulcer may be indicated.
• Microsporidia
• • History and detailed ophthalmic examination should be performed to diagnose Microsporidia.
  • Spores, sporoblasts, meronts, and sporonts can be identified in conjunctival or corneal scrapings from affected patients. The spores are Gram-positive and acid-fast by staining.
  • In general, Gram stain and cultures are used to guide treatment. Microsporidia is very difficult to culture, but it is seen readily within corneal or conjunctival epithelial cells with the use of Masson trichrome or Giemsa staining.
• HIV retinopathy
• • History and complete ophthalmologic examination with dilated funduscopic examination should be performed to diagnose HIV retinopathy.
  • Significant retinal nerve fiber layer occurs in HIV patients without CMV retinitis with low CD4 counts. Third-generation OCT may be useful in establishing a diagnosis of early subclinical HIV-associated visual functional loss.
• CMV retinitis
• • History and complete ophthalmologic examination with dilated funduscopic examination should be performed for diagnosis of CMV retinitis.
  • Consultation to primary care physician should be obtained for systemic CMV infection workup, checking for urine and serum CMV titers.
• Acute retinal necrosis
• • Perform a detailed history and a complete ophthalmologic examination with dilated funduscopic examination for diagnosis of ARN.
  • Check for HSV-1, HSV-2, and CMV IgG and IgM titers.
• Progressive outer retinal necrosis
• • Workup of PORN is similar to ARN, except that the serology focuses on HZV IgG and IgM titers.
  • See ARN for details.
• Syphilis
• • The VDRL becomes positive 1-3 weeks after the appearance of the chancre.
  • Fluorescent treponemal antibody absorption (FTA-ABS) test or microhemagglutination Treponema pallidum (MHA-TP) is highly sensitive and specific in all stages of syphilis. Once reactive, these tests do not reverse to normal, and they are not helpful in assessing the patient's response to treatment.
  • Lumbar puncture (LP) may be performed if the FTA-ABS test is positive combined with neurologic or neuro-ophthalmologic signs, papillitis, active chorioretinitis, or uveitis.
  • Diagnoses of ocular syphilis should include obtaining a specific treponemal-antibody assay (FTA-ABS or MHA-TP) and nonspecific treponemal-antibody assay (Venereal Disease Research Laboratory [VDRL] test or rapid plasma reagin [RPR]). VDRL or RPR correlates with disease activity, and it is useful in monitoring response to treatment. It also is used for screening, but it may show a false-negative result in early primary, latent, or late syphilis. It is not as specific as FTA-ABS or MHA-TP.
• Tuberculosis
• • Perform a detailed history and physical examination, attempting to rule out other causes of granulomatous disease, such as sarcoidosis, syphilis, leprosy, and brucellosis.
  • Chest radiograph
  • Perform a purified protein derivative (PPD) skin test; a reaction induration of more than 5 mm is considered positive in persons in close contact to patients with infectious tuberculosis, HIV-positive patients, and persons with positive chest x-ray of fibrotic lesions. A PPD reaction induration of more than 10 mm is considered positive for persons with medical risk factors for reactivation of latent tuberculosis; foreign-born individuals from areas with high tuberculosis prevalence, low-income populations, including blacks, Hispanics, and Native Americans; intravenous drug users; and nursing home residents. A PPD reaction induration of more than 15 mm is considered positive in individuals with no particular risk factor for tuberculosis.
  • Culture for positive growth of M tuberculosis is needed to confirm the diagnosis of tuberculosis.
• Pneumocystic carinii
• • Perform a detailed history for P carinii pneumonia and use of aerosolized pentamidine.
  • Obtain induced sputum or bronchoalveolar lavage (BAL) for histopathologic evaluation.
  • Complete an ophthalmologic examination.
  • Request a medical consultation.
• Toxoplasma retinochoroiditis
• • In the workup, consider syphilis, tuberculosis, and toxocariasis as differential diagnoses.
  • Perform a detailed history and ophthalmologic examination. Serologic detection of antibodies to T gondii is important. Current available testing assays include the indirect hemagglutination assay (IHA) and the immunofluorescent antibody (IFA) test. This test measures both the IgG and IgM antibodies to T gondii. Request that the laboratory perform a 1:1 dilution, as only a positive result is required. Some less commonly used tests include the Sabin-Feldman dye and the enzyme-linked immunosorbent assay (ELISA) tests. Polymerase chain reaction (PCR) and cytologic demonstration of the organism in vitreous samples could be useful in some cases. Diagnosis of ocular toxoplasmosis requires the demonstration of a characteristic retinochoroiditic lesion and a positive serology at any titer.
  • Fluorescein angiogram may be helpful when a choroidal neovascular membrane is suspected.
• Histoplasma chorioretinitis
• • In the workup, consider the following differential diagnoses: toxoplasmosis and multifocal choroiditis with panuveitis.
  • Perform a detailed history and complete ophthalmologic examination, including dilated funduscopic examination. Inquiring about possible time spent in the Ohio-Mississippi River Valley area is important. Also possible exposure to fowl should be inquired.
  • Amsler grid should be used to assess central visual field for each eye.
  • Fluorescein angiography may be used to detect a CNVM.
• Perform a detailed history and ophthalmologic examination for diagnosis of cryptococcal chorioretinitis. Diagnosis of cryptococcal chorioretinitis mostly is based on the clinical findings. A diagnostic vitreous tap may be performed, and the samples are examined by direct smear using India ink and cultured on Sabouraud agar at 37°C. Organism growth often takes place within 24-48 hours, producing mucoid, cream, or pink colonies.
• Evaluation of neuro-ophthalmologic manifestations in HIV typically includes MRI followed by a LP to determine cerebrospinal cell count, cytologic studies, culture, and antibody and antigen testing.

Imaging Studies

• Computer tomography of the head may be useful for patients with toxoplasmosis and cryptococcus.

TREATMENT

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Herpes zoster ophthalmicus
• • Intravenous acyclovir 10 mg/kg 3 times per day for 7 days, followed by oral acyclovir 800 mg to 1 g 3-5 times per day for an additional 7 days. This regimen is most effective when started within 72 hours of onset of the vesicular lesions. This treatment reduces the frequency of recurrences. Oral acyclovir used in the treatment of HZO has been demonstrated in a randomized clinical trial to reduce the shedding of the virus from the vesicles, decrease systemic spreading of the virus, and reduce the severity and duration of HZO complications (eg, dendritic keratitis, stromal keratitis, uveitis). However, oral acyclovir does not affect the incidence, severity, or duration of postherpetic neuralgia.
  • Famciclovir 500 mg 3 times per day for 7 days. This has an advantage of causing less adverse effects. If unresponsive to acyclovir or famciclovir, intravenous foscarnet should be tried.
  • Topical antiviral agents have not been shown to be effective for the management of HZO.
  • If intraocular inflammation is present, topical cycloplegic agent (ie, scopolamine 0.25% tid) and a topical steroid (ie, prednisolone acetate 1% q1-2h) should be started.
  • Generally, it is recommended that oral steroids be avoided because of the risk of further immunosuppression of the patient and exacerbation of the infection. However, oral steroids have been used by dermatology for the treatment of HZO to reduce the incidence of postherpetic neuralgia in patients older than 60 years.
  • Alternatively, topical capsaicin 0.25% ointment applied to the involved skin twice daily, or amitriptyline 25 mg by mouth 3 times daily may be useful in reducing the symptoms of postherpetic neuralgia.
  • In case of persistent punctate keratopathy, copious, nonpreserved ocular lubricant ointments, bandage contact lenses, or tarsorrhaphy may be needed.
• Kaposi sarcoma
• • Radiation therapy is effective for eyelid and conjunctival Kaposi sarcoma. Adverse effects of radiation therapy include loss of lashes, skin irritation, and conjunctivitis.
  • Local cryotherapy of eyelid and conjunctival lesions may be performed.
  • Intralesional chemotherapy with vinblastine, alpha interferon, and liposomal daunorubicin may be administered.
  • Surgical excision of the tumor may be performed in some patients with severe symptoms.
• Conjunctival microvasculopathy - Observation
• Keratoconjunctivitis sicca - Artificial tears and long-acting lubricating ointments used in association with punctal plugs for symptomatic relief.
• Varicella-zoster virus keratitis
  • Oral acyclovir 800 mg 5 times per day or famciclovir 125-500 mg by mouth 3-5 times per day. Chronic treatment may be required for VZV keratitis. This usually minimizes symptoms and shortens the duration of viral shedding.
  • Severe disciform stromal keratitis that causes significant reduction in visual acuity may be treated with topical corticosteroids.
• Herpes simplex virus keratitis
  • Most cases of HSV epithelial keratitis resolve spontaneously within several weeks. The rationale for treatment is to decrease corneal damage due to lytic viral infection and virus-incited immunologic response. Debridement of HSV epithelial keratitis with a dry cotton-tipped applicator or a cellulose sponge can hasten resolution and decrease the load of infectious virus and viral antigens.
  • Medical treatment includes the use of vidarabine ophthalmic 3% ointment 5 times daily for 14 days and/or trifluridine ophthalmic 1% solution every 3 hours for 14 days; or acyclovir topical 3% ointment 5 times daily for 14 days or oral dosage form 400 mg 5 times daily for 7 days; or famciclovir 500 mg by mouth 3 times daily for 7 days.
• Fungal keratitis - Initially, corneal infiltrates and ulcers usually are treated as bacterial infections until the results of cultures and/or staining are obtained. If cultures indicate fungal keratitis, then the following action is recommended:
  • Patient should be admitted, unless very reliable, and start natamycin 5% (50 mg/mL) drops every 1-2 hours while awake and every 2 hours during the night hours.
  • Use a cycloplegic agent (eg, homatropine 5% tid, scopolamine 0.25% tid).
  • Avoid topical steroids.
  • Avoid eye patching.
  • For deep stromal infection, combination medication is recommended; topical amphotericin B, topical fumagillin, miconazole or clotrimazole and/or oral fluconazole, itraconazole, or albendazole.
• Microsporidia - Topical fumagillin has been used successfully to treat keratoconjunctivitis secondary to Microsporidia.
• Iridocyclitis - Topical corticosteroid drops are used frequently but with extreme caution and with proper antimicrobial coverage when infection is suspected. If toxicity from the medication is suspected, the dose should be tapered or the causative agent should be discontinued.
• HIV retinopathy - No treatment is required.

• Cytomegalovirus retinitis
  • The drug of choice for the treatment of CMV retinitis depends on the extent and location of the disease, possible drug-related side effects, and effectiveness of prior treatments.
  • Specific agents and modalities for the treatment of CMV retinitis include the following: oral, intravenous, and intravitreal ganciclovir; intravenous and intravitreal foscarnet or combined intravenous ganciclovir and foscarnet; or intravenous cidofovir. These agents, ganciclovir, foscarnet, and cidofovir, act by inhibiting CMV DNA polymerase.
  • Ganciclovir - Start induction with 5 mg/kg IV q12h for 14 days, then change to a maintenance IV dose of 5 mg/kg/d for 7 days. Adjust dose accordingly with renal insufficiency. The significant adverse effect with ganciclovir is myelosuppression. Monitor CBC with differential 2-3 times a week during induction phase, and weekly thereafter. If absolute neutrophil count drops less than 500 or platelet count drops less than 10,000, discontinue ganciclovir treatment.
  • During the treatment of CMV retinitis with ganciclovir, the dose of zidovudine may need to be reduced, unless hematopoietic growth factors (eg, regramostim, filgrastim) are used concurrently. This prevents exacerbation of myelosuppression.
  • Alternatively, intravitreal ganciclovir may be implanted to ensure adequate and prolonged intravitreal concentration of the drug. However, this does not preclude the use of oral ganciclovir to control the systemic infection.
  • Foscarnet - Start induction with 60 mg/kg IV q8h for 14 days, then change to a maintenance IV dose of 90-120 mg/kg/d. Hydration with 1000 mL of isotonic sodium chloride solution is recommended due to renal toxicity of foscarnet. Therefore, it is recommended that electrolyte status, particularly calcium and magnesium, serum creatine, and hemoglobin be monitored 2-3 times per week for 2 weeks, and weekly thereafter. Dosage adjustment is recommended if renal insufficiency is present, and the drug should be discontinued if serum creatine is greater than 2.8 mg/dL.
  • Cidofovir - Start induction with 5 mg/kg IV over 1 hour once weekly for 2 weeks, then change to maintenance dose of 5 mg/kg over 1 hour once every other week. This drug is nephrotoxic. Concurrent use of probenecid with cidofovir and hydration with 1-2 liters of normal saline reduces the risk of renal toxicity. Other adverse effects of cidofovir include iritis and ocular hypotony.
• Acute retinal necrosis
  • Start acyclovir 5-10 mg/kg/d IV in 3 divided doses for 1 week, then change to oral acyclovir 800 mg 5 times daily for the following 1-2 months. Monitor blood urea nitrogen and creatine levels because of the nephrotoxic effect of acyclovir.
  • Start a slow tapering dosage of prednisone 60-100 mg PO daily 24 hours after starting acyclovir, continue for about 1-2 months. Be sure to obtain a chest x-ray and PPD before starting the oral steroid.
  • A topical steroid, such as prednisolone acetate 1%, instilled q2-6h, and a cycloplegic agent, such as homatropine 5% instilled 2-3 times daily.
  • Add Zantac 150 mg PO twice daily for steroid-induced gastritis.
  • In fulminate cases, particularly in HIV-positive patients, IV or intravitreal ganciclovir and/or foscarnet, or intravenous cidofovir may be considered (see CMV for dosage).
  • Use of retinal laser photocoagulation to surround the necrotic lesion is still controversial.
  • For retinal detachment, vitrectomy, membranectomy, endolaser, and silicone oil infusion usually is required.
• Progressive outer retinal necrosis - See ARN for the treatment of VZV-associated retinitis in HIV patients.
• Syphilis
  • All HIV-positive patients with syphilitic eye findings are considered to have tertiary syphilis and are treated accordingly.
  • Treatment of syphilis is with intravenous penicillin G (24 million U/d for 7-10 d). Relapse may occur in spite of adequate treatment. For penicillin-allergic patients, tetracycline 500 mg 4 times per day or doxycycline 200 mg twice a day by mouth for 30 days or a third-generation cephalosporin (ceftriaxone).
  • Cycloplegia with either cyclopentolate 2% or homatropine 5% 3 tid and prednisolone acetate 1% qid is recommended if anterior segment inflammation is present.
• Tuberculosis
  • Patients should be given isoniazid (INH) 300 mg PO daily, rifampin 600 mg PO daily, and pyrazinamide 25-35 mg/kg PO daily for 2 months; then, continue with INH and rifampin for an additional 7 months. Drug resistance is most common with streptomycin and INH; however, this may be minimized by the use of multiple bacteriocidal antituberculous drugs.
  • Pyridoxine 25 mg PO daily usually is added to the regimen to prevent peripheral neuritis.
• P carinii is treated with intravenous Bactrim (trimethoprim/sulfamethoxazole) or intravenous pentamidine.
• Toxoplasma retinochoroiditis
  • For small peripheral retinochoroiditis (not affecting or threatening the macula) - Treat anterior chamber inflammation with a topical cycloplegic with or without topical steroid (eg, prednisolone acetate 1% qid). The topical steroid should be tapered gradually as the anterior chamber inflammation resolves.
  • For active retinochoroiditis within 2-3 mm of the disc or fovea, which threatens vision, or peripheral lesion associated with severe vitritis - Start first-line therapy for 3-6 weeks, as follows: (1) pyrimethamine 75 mg PO load, 25 mg PO bid, plus, (2) folinic acid 3-5 mg PO twice weekly (to reduce the adverse effect of bone marrow toxicity of pyrimethamine), and (3) sulfadiazine 2 g PO load, then 1 g PO qid.
  • Clindamycin 300 mg PO qid may be used with sulfadiazine as alternative treatment. Patients on clindamycin should be monitored for the possible adverse effect of pseudomembranous colitis. Other alternative therapeutic regimens include the following: trimethoprim/sulfamethoxazole (160 mg/800 mg) 1 tablet PO bid, with or without clindamycin.
  • Platelet count and CBC should be monitored once to twice weekly for patients on pyrimethamine. If the platelet count falls below 100,000, then a reduction in the dose along with an increase in the dose of folinic acid should be initiated. It is important that patients on pyrimethamine avoid taking vitamins containing folic acid.
  • Retinal laser photocoagulation, cryotherapy, and vitrectomy have been used as adjunct therapy in the treatment of ocular toxoplasmosis.
• Histoplasma chorioretinitis
  • Following diagnosis of disseminated histoplasmosis, amphotericin, or ketoconazole is the recommended pharmacologic treatment of choice. Patients with AIDS usually receive a higher dose of amphotericin B (1-2.5 g), followed by daily ketoconazole (lifelong), or weekly maintenance amphotericin B treatment.
  • Laser retinal photocoagulation may be used to treat CNVM in the macula.
  • Treatment is recommended within 72 hours of the diagnosis of CNVM with positive fluorescein angiography.
  • Amsler grid use daily is recommended to assess central vision, and patients are advised to report any sudden change in vision as soon as possible.
• Cryptococcal chorioretinitis
  • Early diagnosis and treatment of cryptococcal chorioretinitis is important. Combination treatment with flucytosine and intravenous amphotericin B is considered the treatment of choice for disseminated or meningeal cryptococcal infection. However, there have been cases of cryptococcal chorioretinitis successfully treated with intravenous amphotericin B alone.
  • Fluconazole and itraconazole have been reported to be effective in the treatment of cryptococcal chorioretinitis.
  • Early vitrectomy is recommended with persistent vitritis despite treatment.
• Options for neuro-ophthalmologic manifestations in HIV include radiation for lymphoma and specific antibiotics for infectious causes. No treatment is available for progressive multifocal leukoencephalopathy (PML).

Consultations

Consultation with an internist for proper monitoring and treatment of the HIV infection is recommended.

MEDICATION

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antivirals

Reduce frequency of recurrence. In HZO, oral acyclovir has been reported to reduce shedding of virus from vesicles, decrease systemic spreading of virus, and reduce severity and duration of HZO complications (eg, dendritic keratitis, stromal keratitis, uveitis). However, oral acyclovir does not affect incidence, severity, or duration of postherpetic neuralgia. Topical antiviral agents have not been shown to be effective for the management of HZO.