Necrotizing herpetic retinopathy:
Necrotizing herpetic retinopathy (NHR) is a continuous spectrum of posterior segment inflammation induced by herpes viruses, most commonly varicella zoster virus (VZV). Its two most recognizable clinical patterns are ARN and PORN.[18] Usually, the former occurs in healthy persons and AIDS patients with only mild immune dysfunction and elevated CD4+ counts, whereas the latter usually develops in those who are severely immunosuppressed. In addition to varicella zoster virus, herpes simplex virus and CMV have been isolated in patients with ARN, and herpes simplex in eyes with PORN.[11] The differential features between ARN, PORN and CMV retinitis are given in Table 2.
Table 2: Differentiating features of Viral retinitis in AIDS patients
|
ARN | PORN |
CMV Retinitis |
| Immune status | Immunocompetent |
Immunosuppressed | Immunosuppressed |
| Laterality | Unilater/Bilateral |
Bilateral |
Unilateral/Bilateral |
Visual loss |
Usually gross |
Early loss of vision |
Variable |
Anterior Segment |
Mild-moderate Ant. Uveitis |
Non Granulomatous Uveitis |
Usually normal |
Vitreous reaction |
Significant vitritis |
Minimum/No Vitritis |
Minimum/No Vitritis |
Retinal involvement |
Full thickness |
Deep retinal involvement |
Full thickness with Granular border |
Pattern of involvement |
Multifocal, predominantly peripheral |
Multifocal , early macular involvement |
Usually Unifocal , starts peripherally |
Vasculitis |
Common |
Uncommon |
Seen |
Retinal hmges |
common |
Uncommon |
Common |
Retinal detachment |
Common |
Common |
Less common |
Optic nerve involvement |
Common |
Uncommon |
Uncommon |
Progression |
Rapid |
Rapid | Slow |
Toxoplasmosis:
In the majority of AIDS cases, toxoplasmosis is a primary infection rather than a reactivation. Ocular toxoplasmosis in AIDS, in contrast to toxoplasmosis in immunocompetent individuals, can be bilateral, multifocal, and not associated with chorioretinal scars. It may cause a variety of ocular abnormalities including iritis, vitritis, choroiditis, multifocal or diffuse necrotizing retinitis, papillitis or retrobulbar neuritis, or outer retinal toxoplasmosis.[19] Toxoplasma retinitis may resemble CMV retinitis; however, intraocular inflammation is usually more severe and hemorrhages are fewer. Treatment with standard antiparasitic drugs (pyrimethamine, clindamycin, sulfonamides) is successful in controlling ocular toxoplasmosis in most cases.
Choroiditis:
Pneumocystis:
Ocular manifestations of P. carinii include conjunctivitis, orbital mass, optic neuropathy, and choroiditis.[20] It is seen as classically bilateral and multifocal yellowish, well-demarcated, choroidal lesions located in the posterior pole not associated with vitritis, iritis, or vasculitis.[21] Ocular lesions respond in most cases to induction and subsequent maintenance treatment with systemic pentamidine, trimethoprim and sulfamethoxazole, or dapsone.
Mycobacterial disease:
Tuberculosis (TB) implies the presence of active disease from infection with the acid-fast bacillus.[22] Mycobacterium tuberculosis is the commonest systemic opportunistic infection associated with AIDS even though ocular TB is not as common.[23] It is important to consider it as a differential diagnosis, especially in developing countries like India.
Clinical manifestations include ulcers, tubercles, granular masses or pedunculated polypoid tumours. Patients may present with localized nodule in the eyelid simulating chalazion. Orbital and lacrimal gland involvement by M. tuberculosis leads to localized granuloma though unusually they can present as a conjunctival mass. Infection of the iris can present either with or without iris nodules. TB is also a known cause of uveitis, although it is uncommon, even among those with systemic TB.[24] TB may cause interstitial keratitis with stromal infiltration. Interstitial keratitis secondary to TB may be associated with uveitis. It may occur as an isolated finding or in association with scleritis. Sclerokeratitis can be seen with peripheral stromal inflammation in a triangular fashion associated with localized scleritis. Localized lesions are focal elevated nodules of the sclera that may undergo necrosis leading to scleromalacia and scleral perforation if untreated. Diffuse scleritis is less common than localized nodular scleritis. M. tuberculosis infection of the conjunctiva may involve the palpebral, bulbar, or forniceal conjunctiva. Tuberculous conjunctivitis is a very rare condition in the developed world. In recalcitrant cases of chronic red eye,[25] a definitive diagnosis requires the identification of Mycobacterium tuberculosis organisms in conjunctival biopsy specimens, either through microscopic detection of acid-fast bacilli or through more sensitive culture techniques. Keratoconjunctivitis may occur in association with cutaneous TB.[26] While intraocular disease is mostly a secondary infection, cutaneous TB is almost always primary.[27] Commonest posterior segment manifestations include discrete choroidal tubercles or solitary mass-like lesions of the posterior pole. Rarely, endogenous endophthalmitis also occurs.
Treatment:
Systemic anti-tuberculous therapy (ATT) with drugs such as isoniazid, rifampin, pyrazinamide and ethambutol is important as pulmonary or other foci of disease may coexist. Modified DOTS regimen (Directly Observed Treatment Short course) is the recommended regime in India. Specific ocular treatment should be instituted along with ATT. There have been reports of scleral TB responding favorably to additional topical (every 2 h) and subconjunctival (every three days) streptomycin sulfate along with ATT with healing of the lesion. In individuals with HIV infection, therapy may require longer duration and additional drugs. Newer drugs have also been incorporated in the ATT group of drugs, especially in the newer setting of multidrug-resistant TB, particularly in case of HIV-infected individuals. These include quinolones, newer rifamycins like rifabutin and macrolides antibiotics.
Fungal infections:
In the general population, fungal corneal ulcers are rare in the absence of preceding trauma, ocular surface disease or corticosteroid therapy while HIV/AIDS patients can develop spontaneous fungal infections. Candida causes anterior segment keratitis. Cryptococci commonly triggers posterior segment pathology although they can sometimes cause conjunctivitis, limbal infection and iris granulomas.[28] Cryptococcus albidus causing scleral ulceration has been reported.[29] Histoplasma and Pneumocystis are more likely to result in bilateral disease with corneal perforation.[30] Hence, culture or biopsy of lesions is important for HIV-infected patients with ocular surface infections, to differentiate between bacterial and fungal etiology.
Cryptococcus:
Cryptococcus meningitis is the most common cause of AIDS-related neuro-ophthalmolgic lesions. Cryptococcal choroiditis may be multifocal, solitary, or confluent and may be associated with eyelid nodule, conjunctival mass, granulomatous iritis, iris mass, vitritis, necrotizing retinitis, endophthalmitis, and optic neuritis.[28] Fluconazole maintenance therapy 200 mg/day is currently recommended in all patients even in the era of HAART.
Spirochaetal infections:
Treponema pallidum:
Ocular syphilis caused by Treponema pallidum tends to present with more aggressive, severe and relapsing manifestations in HIV-positive hosts as compared with immunocompetent hosts.[32,33,34] All patients with syphilis should be evaluated for HIV and vice versa. Anterior segment manifestations of syphilis include chancres of the conjunctiva (primary syphilis), conjunctivitis (secondary syphilis) and gummata (late syphilis).[32] Conjunctivitis can be granulomatous and histologically similar to sarcoidosis. The diagnosis of syphilis is done by serologic screening and confirmatory tests such as the rapid plasma reagin or fluorescent treponemal antibody absorbent tests, respectively. Direct examination using darkfield microscopy or biopsy of suspicious lesions can be performed if results are uncertain. Isolated episcleritis and scleritis are uncommon during any stage of the disease, but when present, are usually features of secondary or late syphilis.
Treatment of ocular syphilis is similar to that of neurosyphilis. The most effective treatment involves high-dose IV penicillin G 12 to 24 million units/d for 14 days.[34,35] Because of the high rate of relapse, HIV-positive patients are recommended to have extensive follow-up subsequently at least for two years.[36]
Bacterial keratitis:
The risk of infection with this ''normal'' flora may be greater for severely immunosuppressed individuals.[37] Staphylococcus aureus , Staphylococcus epidermidis and Pseudomonas aeruginosa are most frequently implicated.[37] Some cases of recalcitrant infection may require keratoplasty and even evisceration of the globe.[38,39,40] Other risk factors predisposing to epithelial defects include the use of crack cocaine by HIV-infected individuals.[41]
The clinical presentation of bacterial keratitis in HIV-infected individuals differs from that in the general population. In immunosuppressed individuals, they are usually bilateral, involve multiple pathogens and carry a higher risk of perforation. There have been reports of eyes having to be eventually enucleated despite having been treated with intensive antibiotic therapy, based on in vitro sensitivities, for more than two weeks. Paucity of inflammation in immunosuppressed patients also contributes to delay in diagnosis and treatment. Gram staining and culture helps in the identification of the etiological agent. Systemic treatment with ceftriaxone or other appropriate antibiotics must be used to treat gonococcal conjunctivitis. Topical therapy alone will be ineffective.
Microsporidial keratitis:
Microsporidia are spore-forming, obligate intracellular, protozoan parasites. They occur when the CD4 + counts drop to about 100cells/cu.mm. 39 to 44% of HIV-infected individuals with diarrhoea are infected with microsporidia, in comparison to only 2.3% of HIV-infected individuals without diarrhoea. [42] AIDS-associated microsporidial keratoconjunctivitis is characterized by bilateral superficial punctate epithelial keratitis, white intraepithelial infiltrates, mild anterior chamber reactions, and conjunctivitis in the form of mild conjunctival follicular hypertrophy.[42,43] Patients may complain of photophobia and grittiness. Vision loss is secondary to keratitis. Diagnosis is by Gram or Giemsa stain and spores from conjunctival scrapings or corneal biopsies can be easily seen with Masson trichrome or Giemsa stain. Immunofluorescence and electron microscopy can help confirm the diagnosis.
Treatment:
Fumagillin 70 mg/mL eye drops are used indefinitely in HIV-positive individuals. [44] Albendazole 400 mg twice daily orally should be used as an adjunct for the management of systemic infection.
Cytomegalovirus keratitis:[45]
CMV which can be transmitted by blood, saliva, breast milk, and mucous membrane contact is usually asymptomatic in immunocompetent individuals, but can sometimes produce transient conjunctivitis. CMV rarely involves the anterior segment tissues. CMV infection of the iris has been reported in a patient with CMV retinitis.[45] CMV has been reported to be associated with both epithelial and/or stromal keratitis, although both conditions are probably uncommon.[46] Corneal endothelial deposits have been described in about 80% of eyes with CMV retinitis. These asymptomatic lesions, seen in up to 81% of cases of HIV/AIDS-related CMV retinitis appear as linear or stellate lesions and form a reticular pattern. Best visualized in retroillumination, they are commonly found in the inferior cornea. These deposits are known to be composed of fibrin and macrophages, with no active CMV infection. CMV has been proven, with the help of aqueous humour analysis to be the causative agent of endothelitis and anterior uveitis in immunocompetent patients.
Herpes zoster ophthalmicus:
Herpes zoster ophthalmicus (HZO) is caused by varicella zoster virus (VZV) which causes varicella (chicken pox) and herpes zoster (shingles). Over 90% of the population develops clinical or serologic evidence of infection with VZV by adolescence, and the prevalence is almost 100% by age 60 years.[46] The virus usually remains latent in sensory neurons. Herpes zoster eventually occurs in 10–20% of all individuals and reactivation in the ophthalmic division of the trigeminal nerve gives rise to HZO. Incidence of HZO is greater in HIV-infected individuals than in non-infected, age-adjusted populations. Approximately 5–15% of HIV-positive patients are co-infected with herpes zoster, but only half of these individuals are at risk of ocular involvement.[47] It can even be an initial manifestation of HIV. In immunosuppressed individuals, herpes zoster is more likely to be severe, prolonged, and can lead to viremia, which may result in visceral or neurologic infection, leading to increased morbidity and mortality. It is characterized by vesiculobullous rash over the distribution of the ophthalmic branch of the trigeminal nerve and may be associated with dendritiform and stromal keratitis, conjunctivitis, blepharitis, uveitis (with secondary glaucoma), hemorrhagic hypopyon,[48] scleritis, retinitis[49] or encephalitis. Herpes zoster presenting in any apparently healthy young individual (<45 years) with these characteristics and without any obvious cause of immunosuppression should be investigated for HIV. Tissue damage can be mediated through a necrotizing vasculitis. Diagnosis of HZO is mainly clinical. To confirm a clinical diagnosis, however, various tests are available, including virus cultures, Tzanck smears, polymerase chain reaction (PCR) techniques for VZV DNA, fluorescent antibody testing, and antigen detection by direct immunofluoresence.
Treatment of HZO in individuals with HIV disease requires aggressive initial treatment, with intravenous acyclovir, followed by a prolonged course of oral antivirals as ''maintenance therapy,'' to prevent recurrence. The regime is intravenous acyclovir (10 mg/kg of body weight eight-hourly for seven days followed by an oral maintenance regimen of 800 mg five times a day for at least three to six weeks). [11] Recently, oral Valganciclovir has shown equal efficacy as intravenous acyclovir. Early initiation of systemic anti-viral therapy can reduce the duration of skin lesions and ocular complications by about 50%.
