A review of the topic at this length cannot be exhaustive; the subject of immunodeficiency diseases is far too broad and complex. Instead, the reader is provided with a general overview of the topic, on which a rational approach to the evaluation and management of ophthalmic disorders in immunodeficient patients can be based.

Table 1. Primary Immunodeficiency Disorders

1. Combined immunodeficiencies
   1. Severe combined immunodeficiency
      
      1. T-lymphocyte-deficient variant
         
      2. T- and B-lymphocyte-deficient variant
         
   2. X-linked hyper-immunoglobulin M syndrome
      
   3. Purine nucleoside phosphorylase deficiency
      
   4. Major histocompatibility complex class II deficiency
      
   5. CD3 deficiency
      
   6. Zap-70 deficiency
      
   7. TAP-2 deficiency
      
   
   
2. Predominantly antibody deficiencies
   1. X-linked agammaglobulinemia
      
   2. Non-X-linked hyper-IgM syndrome
      
   3. Immunoglobulin heavy-chain deletions
      
   4. Autosomal recessive K-chain deficiency
      
   5. Selective immunoglobulin subclass deficiency
      
   6. Antibody deficiency with normal immunoglobulin
      
   7. Common variable immunodeficiency
      
   8. IgA deficiency
      
   9. Transient hypogammaglobulinemia of infancy
      
   10. Autosomal recessive agammaglobulinemia
       
   
   
3. Predominantly T-lymphocyte deficiencies
   1. CD4 deficiency
      
   2. CD7 deficiency
      
   3. Interleukin-2 deficiency
      
   4. Multiple cytokine defect
      
   5. Signal transduction defect
      
   6. Calcium flux defect
      
   
   
4. Other well-defined syndromes
   1. Wiskott-Aldrich syndrome
      
   2. Ataxia-telangiectasia
      
   3. DiGeorge's anomaly
      
   
   
5. Complement deficiencies*
   
6. Congenital defects of phagocytic number and/or function
   1. Severe congenital neutropenia
      
   2. Cyclic neutropenia
      
   3. Leukocyte adhesion defect
      
   4. Chédiak-Higashi syndrome
      
   5. Specific granule deficiency
      
   6. Schwamann's syndrome
      
   7. Chronic granulomatous disease
      
   8. Neutrophil G6PD deficiency
      
   9. Myeloperoxidase deficiency
      
   10. Interferon-γ deficiency
       
   
   

Our knowledge of the abnormal genes and altered biochemical pathways that result in primary immunodeficiency diseases has increased dramatically in the last decade. More than 60 genetic loci have been identified that are associated with specific defects in the immune system.¹⁰ Abnormalities in the production of cell surface receptor molecules, cytoskeletal proteins, enzymes involved in purine and oxidative metabolism, immunoglobulins, complement components, and cytokines have been described; in addition, defects in intracellular signaling pathways and T-lymphocyte cell receptors, as well as defective rearrangements of immunoglobulin genes, have been identified. Understanding the genetics and pathophysiology of these abnormal states has provided new insights into the functioning of the immune system in health and disease.

Distinct and disparate immunologic diseases such as X-linked agammaglobulinemia, C3 deficiency, and neutropenia can produce similar clinical features, even though they are caused by unrelated pathogenic mechanisms affecting different components of the immune system. With selective defects of immune function, other intact immune mechanisms may partially compensate for the deficiency and further blur any clinical distinction between disorders. A similar phenomenon has been found in gene knock-out mice, strains that lack very specific effectors of immune function; they reveal redundancies in the immune system that, although confusing in research models, can be critical for maintaining function. Some diseases, however, do have unique clinical features that aid in establishing a diagnosis.

It has been estimated that in the general population approximately 2500 persons per million (0.25%) have primary immunodeficiencies, most of whom are male.¹¹ Selective immunoglobulin A (IgA) deficiency is believed to be the most common primary immunodeficiency, with a reported prevalence of 1:700 in whites.² It is estimated that agammaglobulinemia occurs in 1 of 50,000 live births and severe combined immunodeficiency in 1 of 100,000 to 1 of 500,000 live births.³

LYMPHOCYTE DISORDERS

Predominantly Antibody Defects

Defects of humoral immunity may involve all or only selected types of antibodies. Antibody deficiency alters several protective immunologic mechanisms, thus increasing the frequency, chronicity, and severity of infections caused by various bacterial, viral, and protozoan pathogens. Lack of secretory antibodies, which usually accompanies a deficiency of serum antibodies, increases host susceptibility to attachment of bacteria, viruses, and parasites to mucosal surfaces.⁴ Gastrointestinal (GI) and respiratory tract infections therefore predominate, and the ocular surface may be at increased risk. Systemic seeding of pathogens and violation of the blood-brain barrier may occur more readily because levels of antibodies that function in neutralization, cytotoxicity, or antibody-dependent cellular cytotoxicity reactions are low. Failure to form antibody-antigen complexes limits the actions of the innate, nonspecific immune defense mechanisms normally called into play, such as activation of the complement system with subsequent chemotaxis of phagocytic cells.

Bacterial pathogens commonly associated with antibody deficiencies include many encapsulated organisms, such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Neisseria meningitidis. Common viral agents include enteroviruses and rotaviruses. Giardia lamblia and Cryptosporidium species are considered the most common protozoa that cause disease in these patients. Infections with Pneumocystis carinii, (previously classified as a protozoan parasite but now considered to be more closely related to the fungi¹²), as well as infections with cryptosporidium, occur in patients with X-linked hyper-IgM syndrome.^13,14

In addition to recurrent pneumonia and chronic diarrhea, infectious disorders associated with antibody deficiencies include sinusitis, otitis, viral hepatitis, paralytic poliomyelitis, arthritis related to Mycoplasma sp., cystitis, and urethritis. Meningitis and viral encephalitis are the most important complications. Ocular disorders usually involve the eyelid, conjunctiva, or cornea. In most cases, they are attributed to recurrent bacterial infection.

Sjögren's syndrome and other autoimmune diseases have been associated with immunoglobulin deficiencies,^15–17 most commonly with IgA deficiency and common variable immunodeficiency. Those with primary Sjögren's syndrome may be deficient in the IgG2 subclass as well.¹⁶ Infiltration of the salivary glands by lymphocytes is observed. It is possible that xerophthalmia will be more commonly recognized as experience with immunodeficient patients increases.

Described subsequently are several immunodeficiency disorders for which there have been specific references to associated ophthalmic disorders. There is no evidence, however, that there are unique ocular changes in any of the specific antibody deficiency syndromes.

X-LINKED AGAMMAGLOBULINEMIA.

X-linked agammaglobulinemia (Bruton's agammaglobulinemia) is associated with a deficiency of a tyrosine kinase that is required for B-lymphocyte maturation; the gene for this enzyme is found on the X-chromosome. Patients with X-linked agammaglobulinemia have repeated bouts of pyogenic infections. Keratoconjunctivitis has been reported in these patients,¹⁸ but in most cases, the eyes remain unaffected.^19,20 Eczema is common in this condition,²¹ and involvement of the eyelids might be expected.

SELECTIVE DEFICIENCY OF IMMUNOGLOBULIN ISOTYPES.

Some patients with IgG4 deficiency have multiple hordeola and chalazia, marginal corneal infiltrates, and vascularization of the limbus.²² Other cases, however, have no reported ocular findings.²³

Little information is available about ophthalmic involvement with other selective antibody disorders. Selective IgM deficiency results in severe eczema, verrucae vulgaris, and recurrent bacterial infections of the skin.²¹ Periorbital cellulitis has been reported with this condition.³ Patients who have immunodeficiency with hyper-IgM develop severe verrucae vulgaris,²¹ which could involve the eyelids.

SELECTIVE IGA DEFICIENCY.

IgA deficiency is found in 1:700 whites but in only 1:18,500 Japanese.² Ocular infection with IgA deficiency is believed to be rare.^9,24 Ocular disease is more common when other immunoglobulin classes are also grossly affected.¹⁸ In cases in which low serum levels of IgA do not reflect a deficit in secretory IgA, the ocular surface may be at no increased risk for infection. It may be dangerous to attempt IgA replacement; patients with IgA deficiency may have anaphylactic reactions to IgA-containing fluids.²⁵ Even if IgA replacement in blood were possible, it would not protect the ocular surface in most cases; IgA cannot be transported into tears without a secretory piece.

Hemorrhagic retinitis was associated with IgA deficiency in one patient, but it may actually have been the result of systemic lupus erythematosus in that situation.²⁶ Retinal vasculitis has been described in patients with common variable immunodeficiency, which may be a related syndrome, because it is associated with low levels of serum IgA in some people.²⁷ IgA levels in those patients were not reported, however.

An infant with an unusual phacomatosis that included findings of oculocutaneous pigmentation, neurologic abnormalities, and cutaneous vascular abnormalities also had an IgA deficiency.²⁸ He had unilateral glaucoma and abnormal intraocular vessels, described as being similar to those found in Sturge-Weber syndrome.

COMMON VARIABLE IMMUNODEFICIENCY.

Common variable immunodeficiency is associated with decreased levels of serum IgA and IgG (and in some cases IgM). Approximately 25%; of cases are familial. The genetic defect is not known. There is an equal gender distribution. There are two peaks of disease onset, at ages 1 to 5 years and 16 to 20 years. Patients may have been immunologically normal before onset of IgA deficiency. Patients with IgA deficiency may progress to common variable immunodeficiency. This disorder resembles X-linked hypogammaglobulinemia clinically; the spectrum of associated disorders is similar, although infections are usually less severe and have later onset.³ In some cases, medications (e.g., sulfasalazine, hydantoin, and carbamazepine) have been implicated as causes.²⁹

Franklin and associates¹⁸ reported on five patients, four of whom had conjunctivitis or keratoconjunctivitis. H. influenzae was isolated from three of these patients, one of whom also was found to be infected with S. aureus; Staphylococcus epidermidis was isolated from the fourth patient. Ocular findings are believed to be rare in this syndrome, however. Among approximately 500 cases in the United Kingdom, one patient was reported to have acute unilateral uveitis³⁰ and another acute annular detachment of the choroid and retina with panuveitis (William J. Dinning, unpublished data). These findings may have been incidental; they could not be attributed specifically to the immunodeficiency. A patient with common variable immunodeficiency has been reported with severe corneal thinning that was thought to be sterile in both eyes.³¹ The problem progressed to corneal perforation in his right eye and a secondary H. influenzae endophthalmitis developed, with loss of the eye. The fellow eye was treated with a lamellar corneal graft, and the patient had 20/25 vision in that eye until his death 2 years later.

Autoimmune diseases, including Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis have been associated with IgA deficiency and common variable immunodeficiency. Retinal vasculitis, presumed to be autoimmune in origin, has been reported in three patients with common variable immunodeficiency.²⁷ Associated findings included macular edema, vitreitis, optic disc edema, and retinal neovascularization. No evidence of infection was found. Therapy with periocular injections of corticosteroids, oral prednisone, and cyclosporine appeared to be responsible for maintaining 20/40 or better vision in two patients, but visual acuity dropped to 5/200 in both eyes of the third patient.

Combined Immunodeficiencies

SEVERE COMBINED IMMUNODEFICIENCY DISEASE (SCID).

The combined immunodeficiencies are a group of disorders in which both T- and B- lymphocyte function is abnormal. The abnormalities that have been found appear to be primarily in T lymphocytes, highlighting the importance of these cells for normal B-lymphocyte function, as well as in cell-mediated immunity. Defects in the common γ chain of several cytokine receptors, in intracellular signal transduction, in Class II major histocompatibility complex (MHC) expression, in enzymes involved in purine metabolism, and in T-lymphocyte receptor gene rearrangement have all been described in patients with combined T- and B-lymphocyte immunodeficiencies.¹⁰

SCID is a designation that refers to potentially fatal, profound defects in both cellular and humoral immunity. Cases may be X-linked, autosomal recessive, or autosomal dominant. Because of the severe lack of normal immune function, patients with these disorders are at risk for overwhelming infection by multiple types of pathogens: viruses, bacteria, fungi, and protozoa. Patients usually succumb to infection during the first year of life, although bone marrow transplantation (BMT) may result in reconstitution of the immune system in some cases. Patients are particularly susceptible to normally mild viral respiratory pathogens (parainfluenza, adenovirus, respiratory syncytitial virus).⁴ Reports of fatal, disseminated adenoviral infection in these children have not mentioned the cornea or conjunctiva among the sites of disease, however. Perhaps because of the rapidly fatal nature of SCID, morbidity from opportunistic infections of the eye has not been among the commonly reported features of these syndromes. Infection with herpes simplex virus (HSV), type 1, including ocular involvement, has been reported in an infant with SCID, but no details were given.³² Cytomegalovirus (CMV) retinitis has been reported in three children with SCID^33–35; two patients had been treated by BMT, however.^33,35 Severe, disseminated CMV infections occur frequently in patients undergoing this procedure; the relationship between the retinal infection and the immunologic defects of SCID in these patients is therefore uncertain. The third patient was a 5-month-old girl who presented with meningismus and lethargy and was found to have leukocoria.³⁴ SCID was diagnosed during the evaluation of the patient's systemic illness. White vitreous humor masses were found in both eyes, as well as retinal necrosis and retinal detachment. A fine needle biopsy of the mass in one eye revealed cells with cytoplasmic inclusion bodies consistent with CMV infection. Serologic test results were consistent with recent CMV infection in the patient and her mother. Despite treatment with intravenous (IV) ganciclovir, she died 1 month later from pneumonia; CMV and P. carinii were found in her lungs.

Nezelof's syndrome refers to the presence, in infants, of cell-mediated immune defects and an embryonic thymus, but normal circulating immunoglobulins; as such, it is a variant of SCID. There has been no consistency in the literature in the use of this term, and, therefore, it is difficult to compare reports of its manifestations. Among five patients with disorders labeled Nezelof's syndrome, Friedlander and associates³⁶ identified S. aureus blepharitis in one and Pseudomonas aeruginosa-related blepharoconjunctivitis in one. The other patients were without apparent ophthalmic disease. A patient with Nezelof's syndrome and tuberculous meningitis did have optic atrophy among her constellation of findings.³⁷

OTHER DISORDERS OF T AND B LYMPHOCYTES.

Bare lymphocyte syndrome consists of a group of defects that lead to defective expression of Class I or Class II MHC molecules. Candidal chorioretinitis has been reported in a patient with this disorder, but the patient had other, well-established risk factors for disseminated candidiasis, including indwelling catheters and systemic use of broad-spectrum antibiotics.³⁸ The infection cleared with appropriate antifungal therapy; therefore, the effect, if any, of the specific immune defect on the infection cannot be assessed.

Immunodeficiencies Associated With Other Major Defects

WISKOTT-ALDRICH SYNDROME.

Wiskott-Aldrich syndrome is a sex-linked congenital immunodeficiency disease with both humoral and cellular disorders. Patients are also thrombocytopenic at birth. The involved gene, designated WASP (for Wiskott-Aldrich syndrome protein), is expressed in hematopoietic cells and is associated with the cytoskeletal reorganization of activated platelets and lymphocytes. The syndrome is characterized by deficiencies in IgM and elevations in IgA and IgE. Patients develop eczema; thrombocytopenia; and recurrent infections, including laryngitis, bronchitis, gastroenteritis, pyoderma, sinusitis, and otitis media. Infection is caused most often by pyogenic bacteria, but patients with this syndrome are also susceptible to various fungi, viruses, and protozoa. Kaposi varicelliform eruption, a disseminated form of cutaneous HSV infection, may occur. Such infections become apparent by 6 months of age, and susceptibility to infection increases with age. Death often occurs in the first decade of life because of bleeding or infection.

Several ophthalmic disorders are associated with Wiskott-Aldrich syndrome.^39,40 Patients may develop ocular surface and adnexal disease, including eczema on the eyelids; blepharoconjunctivitis and pannus formation associated with molluscum contagiosum virus (MCV) lesions; and recurrent, sometimes bilateral, HSV keratitis. Recurrent periocular HSV infections have been reported.⁴¹ In many reported cases, the specific pathogens responsible for conjunctivitis are not mentioned. Marginal infiltrates and episcleritis also have been reported; these findings have been attributed to an altered immune response to infectious agents. Papilledema and oculomotor disorders have been attributed to intracranial lesions. Hemorrhage, both intraocularly and on the ocular surface, may occur. In a review of reported cases, Podos and associates³⁹ found that ophthalmic disease (excluding eczema of the eyelids) had been mentioned in 18 of 80 cases. Fifteen patients had infections and five had bleeding of the conjunctiva, periorbital tissues, retina, or into the vitreous humor. Excision of MCV lesions by expression and curettage should be performed with caution in these patients because of the increased risk of hemorrhage.

ATAXIA-TELANGIECTASIA.

Ataxia-telangiectasia is a rare, autosomal recessive disorder characterized by neurologic abnormalities, including cerebellar ataxia, vascular changes of the conjunctiva and skin, recurrent respiratory infections, and malignancies, especially lymphomas. The gene responsible for ataxia-telangiectasia, termed ataxia-telangiectasia muted (ATM), has been mapped to chromosome 11 (11q). Its gene product is a protein kinase involved in cell cycle regulation and deoxyribonucleic acid (DNA) repair.⁴² Defects in DNA repair, cell cycle regulation, and chromosomal instability may play a role in the observed increase in lymphoid malignancies, as well as in abnormal development of the thymus.

Patients have alterations in both cellular and humoral immune functions; markedly decreased IgA and IgE levels are often present. The disease is progressive, with gradual loss of immunologic and neurologic function. Patients may become mentally retarded. They usually die as a result of this disease before 20 years of age.

Conjunctival vascular changes and eye movement disorders constitute the ophthalmic manifestations of this syndrome.^43–45 Dilated venules and irregular vascular segments in the horizontal exposure area give the eye an injected appearance. These findings appear in most people with ataxia-telangiectasia between the ages of 2 and 7 years. These vascular changes have no functional importance. Similar vascular changes occur on the nose, ears, and extremities.

The disorder is associated with various eye movement disorders involving systems that stabilize images on the retina.⁴⁶ Abnormalities include difficulties in fixation, pursuit, and convergence; nystagmus; an increased delay time for initiation of voluntary horizontal and vertical saccades; hypometria of voluntary saccades (an abnormality in the initiation of the fast component of involuntary saccades induced by optokinetic or vestibular stimuli, with deviation of the eyes in the direction of the slow component, rather than in the direction of the fast component, as in normal study subjects); and decreased slow component velocity of optokinetic nystagmus.^44,46 Those affected may have head thrusts when making horizontal refixations, in an attempt to redirect the eyes for fixation on objects of interest; such thrusts are identical to those seen in people with congenital oculomotor apraxia. Visual acuity, pupillary reaction, and fundi are normal.

Other Lymphocyte Disorders

There are many other incompletely characterized disease states that include immunodeficiency among their findings. Those diseases with defects in cell-mediated immunity make the host susceptible to a broad array of infectious diseases caused by bacteria, viruses, fungi, and protozoa. They include opportunistic infections with organisms that generally are commensal to nonimmunocompromised hosts, such as P. carinii and Candida albicans. Devastating, disseminated viral infections by members of the herpesvirus family, adenovirus, rotavirus, enteroviruses, parainfluenza virus, and respiratory syncytial virus can occur. Atypical mycobacterial infections are common and may be widely disseminated.

CHRONIC MUCOCUTANEOUS CANDIDIASIS.

Persons with chronic mucocutaneous candidiasis may have subtle defects both in cell-mediated immunity and in specific antibody responses to Candida sp.^47,48 These individuals have severe skin and mucous membrane infections, which can include ulcerative candidal blepharitis and candidal keratoconjunctivitis.⁴⁹ Photophobia from keratopathy may be the first symptom of disease, occurring at an early age. Findings may include fine punctate erosions of the upper cornea, superficial pannus, and superficial stromal infiltration with scarring. Easty⁹ believes that these findings are due to bacterial, rather than fungal, infections, but organisms are rarely identified.

These immunologic defects rarely result in candidemia or systemic candidiasis, however. Although people with this disorder have not been reported to develop endogenous candidal chorioretinitis or endophthalmitis in the absence of other predisposing factors, deep tissue infection, including central nervous system (CNS) involvement, has been reported.^50–52

Chronic mucocutaneous candidiasis may occur as an isolated disorder, or it may be one of multiple disorders in several different syndromes. Endocrine disorders are common, being seen in perhaps half of patients.⁵³ In 1962, Gass⁵⁴ reported that keratoconjunctivitis was a frequent initial finding in young children with multiple endocrine deficiency, autoimmune disease, and candidiasis syndrome, a disorder characterized by idiopathic hypoparathyroidism and adrenal insufficiency. Organisms were isolated from the conjunctiva in only one of these cases; it was suggested that the conjunctival disease was an immunologic reaction to fungal antigen. Wagman and associates⁵⁵ reported a series of 16 patients with the syndrome, 4 of whom had keratitis, anterior stromal vascularization, and scarring. A report of two siblings with this disorder mentioned the additional findings of eyelash and eyebrow loss in both, and small diffuse keratic precipitates in one.⁵⁶ Wong and Kirkpatrick⁵⁷ reported clinical improvement in one patient with this syndrome, who was treated with allogeneic lymphocytes and administration of transfer factor and amphotericin B.

Chronic mucocutaneous candidiasis is also part of a syndrome that includes keratitis, ichthyosis, and deafness.⁵⁸ The precise immunologic defect has not been identified, and evidence of chronic candidiasis has been found in only approximately 20% of cases. Corneal vascularization apparently occurs in most patients with this syndrome, and loss of eyelashes and eyebrows is common. Cowan and associates⁵⁹ described a family in which three siblings had defects in lymphocyte function and antibody production that they attributed to a defect in biotin metabolism. Clinical disorders included CNS dysfunction and severe mucocutaneous candidiasis, with blepharoconjunctivitis and corneal ulceration. Although candidal infections usually are associated with defects in cellular immunity, antibody defects, such as occurred in these patients, may play a role in their development as well.⁴⁹

PRIMARY PHAGOCYTIC DYSFUNCTION

Neutrophils, monocytes, and eosinophils comprise the nonspecific phagocyte system, providing immunologic defense against pyogenic bacteria, such as S. aureus, and fungi, such as Aspergillus sp. To accomplish this role, phagocytes are capable of many sequential functions, including response to chemotaxis, adhesion, opsonization, ingestion, and intracellular microbial lysis. Defects in one or more of these functions can result in chronic or recurrent infections that are refractory to antibiotic therapy. Targets of infection include skin, mucous membranes, lung, bone, lymph node, and components of the reticuloendothelial system.

Disorders of phagocytic function can occur in combination with other immune defects. Wheeland and associates⁶⁰ described a father and son with chronic purulent blepharitis and secondary corneal ulceration who had abnormal neutrophil function and cellular immunodeficiency. Their disease did not fit other well-established syndromes.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is an inherited disorder characterized biochemically by an inability of phagocytes to use molecular oxygen for generation of important microbicidal byproducts, such as hydrogen peroxide, hydroxyl radicals, and superoxide anions, thus making those affected people susceptible to recurrent life-threatening infections. X-linked recessive and autosomal recessive inheritances are seen. The genetic heterogeneity of the disease primarily reflects different mutations in the genes for the four subunits of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The diagnosis can be pursued by in vitro testing of phagocyte function, including measurements of the respiratory burst by chemiluminescence or by measuring the ability of an individual's phagocytes to kill catalase-positive bacteria in vitro.

CGD is characterized by recurrent and often chronic infections involving the lungs, lymph nodes, skin and soft tissues, liver, GI tract, bone, and brain. The pathogens involved most often in the disease are S. aureus, Aspergillus sp., Chromobacterium violaceum, Pseudomonas cepacia, and Nocardia sp. Most of the pathogens are catalase-positive microorganisms. Catalase-positive microbes destroy the hydrogen peroxide they generate. CGD phagocytes are defective in hydrogen peroxide generation and are deprived of an alternative source of hydrogen peroxide by which their antimicrobial function could be maintained. Infections with catalase-negative microbes, such as S. pneumoniae, are rare in people with CGD.

The ocular signs of CGD fall into two groups: recurrent blepharokeratoconjunctivitis and chorioretinal lesions^61–64 (Fig. 1). Focal, pigmented chorioretinal lesions appear to be a common finding of CGD. Goldblatt and associates⁶⁴ examined 38 patients with CGD and 36 of their family members. They found that nine of 38 affected children had chorioretinal lesions, as did three asymptomatic carriers of the gene.⁶⁴ The lesions are usually perivascular or peripapillary in distribution and can progress to large areas of chorioretinal atrophy.^62–64 They are most often described as punched-out chorioretinal scars. Goldblatt and associates⁶⁴ described small white foveal lesions similar to drusen in some patients, but the typical chorioretinal lesions have not involved the central macula. Visual field defects may occur, corresponding to the location of chorioretinal scars.⁶³ Histopathologic studies of the chorioretinal lesions show foci of granulomatous inflammation of the choroid and sclera.⁶⁵ The granulomatous inflammation has been seen to extend through Bruch's membrane,⁶⁵ and areas of Bruch's membrane may be absent.⁶⁶ Pigment-filled macrophages in the retina and choroid are similar to those found elsewhere in the body.⁶⁶ Chorioretinal scars with glial proliferation and areas of retinal pigment epithelium (RPE) hypertrophy and hyperplasia surrounded by atrophy of the RPE and the overlying retina are also found.⁶⁶ Special stains and cultures of the reported ocular pathology and vitrectomy specimens have not revealed any infectious agents.^65–67

In an isolated case report,⁶⁵ a 3-year-old child with CGD, who had been documented to have chorioretinal scars previously, was found to have chorioretinal lesions that appeared to be actively inflamed with an associated mild vitreitis. The lesions remained stable for several months, but after 7 months, his left eye developed a severe anterior uveitis, vitreitis, and exudative retinal detachment. A lensectomy and vitrectomy was performed. Cultures and stains of vitreous humor were negative. The presumed endophthalmitis did not respond to IV ceftazidime, nafcillin, and amphotericin B administered for 4 weeks. The eye was ultimately enucleated; cultures and stains of the enucleated eye did not reveal any infectious agents. It is not clear, however, whether there might have been an abnormal response to an infectious agent that had been eliminated by the therapy he received. Most people with CGD do not have any evidence of active inflammation or infection, however.

Chronic blepharoconjunctivitis and marginal or punctate keratitis have been reported in patients with CGD, often accompanied by both pannus formation and perilimbal infiltrates.⁶³ These findings are believed to represent an immune reaction to staphylococcal antigens or toxins, rather than a direct invasion of the cornea by organisms. Because it is caused by a catalase-positive bacterium, staphylococcal blepharitis is often a chronic condition in patients with CGD. Regular eyelid hygiene and the selective use of topical antibiotics and corticosteroids has been used to prevent corneal neovascularization and scarring.⁶³

Aggressive and prompt medical and surgical therapy of infections has been important for improving the prognosis of patients with CGD. Granulomata do respond to corticosteroids. The neutrophils of some patients with CGD do respond to interferon (IFN)-γ with a respiratory burst, which may depend on the production of nitric oxide rather than superoxide anions.⁶⁸ Treatment of CGD with IFN-γ is associated with augmented production of nitric oxide by neutrophils.⁶⁸ IFN-γ has also been used as a prophylactic agent.⁶⁹ Although there are reports of cures with BMT, there have been problems with failures to engraft.⁷⁰

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder, usually occurring in the children of consanguineous parents. It is characterized by partial oculocutaneous albinism, increased susceptibility to both viral and bacterial infections (with both catalase-positive and catalase-negative organisms), anemia, leukopenia, thrombocytopenia, cutaneous ulcers, and peripheral and central neurologic changes, including cerebral atrophy.⁷¹ CHS often leads to death in early childhood from infections or, less commonly, from hemorrhage.

Neutrophil abnormalities associated with CHS include neutropenia, reduced bone marrow neutrophil reserves, and reduced neutrophil chemotaxis. Abnormal granules in neutrophils and eosinophils can be seen on routine peripheral blood smears and also are present in other granule-containing cells, such as hepatocytes, renal tubular cells, melanocytes, Schwann's cells, and thyroid cells.⁷² Ingestion of particulate organisms occurs normally, but the rate of bacterial killing by neutrophils following ingestion is abnormal because of slow release of the abnormally large peroxidase-positive granules, leading to the delayed appearance of myeloperoxidase within phagocytic vacuoles. In addition to the deficient microbicidal activity of lysosomal degradation, natural killer cell activity also has been demonstrated to be abnormal in some cases.⁷³ Heterozygous carriers of CHS have been identified by studies of degranulation in leukocytes.⁷²

Children surviving past early childhood may be afflicted later with a so-called accelerated phase of the disease, characterized by lymphohistiocytic infiltration of the liver, spleen, nerves, and other tissues. Neoplastic transformation of these cells may occur. In addition to antimicrobial chemotherapy for infections, antineoplastic drugs and corticosteroids have been used to treat this accelerated phase.

Oculocutaneous albinism may be a prominent feature of CHS; an ultrastructural defect of melanosomes distinguishes this condition from true forms of albinism. Giant abnormal melanosomes, believed to be result from fusion of smaller abnormal organelles, have been reported. Hair color ranges from blonde to light brown, but most often has been reported as silver or gray.^71,74 The iris is translucent with variable color. The amount of pigment in the uveal tract is variable and may be within normal limits. Histologic examination of the eyes also has revealed decreased pigmentation of the RPE, ciliary body, and choroid. These abnormal granules have been observed in monocytes and neutrophils present in the corneal limbus, iris, and choroid.^71,75–79 Ultrastructural study of a conjunctival biopsy specimen from a patient with CHS revealed giant intracytoplasmic lysosomal granules in stromal fibroblasts, which are considered to be pathognomonic for CHS; thus, such a biopsy has been suggested as an ancillary diagnostic test in suspected cases of this syndrome.⁷¹

Nystagmus and photophobia generally are present, although not in all cases. During the accelerated phase of this disorder, infiltration of the optic disc and central retinal artery has been noted, and papilledema has been reported clinically.^71,75–79

COMPLEMENT DEFICIENCIES

The complement system consists of approximately 20 serum proteins that are critical mediators of antigen-antibody reactions. Sequential activation of the complement proteins (complement cascade) is caused by either antibody-antigen interaction, through the so-called classic pathway, or by various stimulants, such as lipopolysaccharide, aggregated immunoglobulin, cobra venom, thrombin, or proteases through the so-called alternate pathway. Specific complement components and complexes of more than one complement protein serve different functions. C3b, for example, promotes immune adherence, phagocytosis, lymphokine production, and antibody-dependent cell-mediated cytotoxicity. C1,4 and C1,4,2,3 complexes aid in neutralization of viruses to which antibodies have attached. The completed complement cascade leads to lysis of viruses, mycoplasma, protozoa, and spirochetes by creating holes in membranes, capsules, or envelopes.

Deficiencies have been reported for each of the proteins that comprise the complement system. Complement deficiencies can result in increased susceptibilities to infections, connective tissue disorders (systemic lupus erythematosus and other autoimmune diseases), or angioedema, depending on which components are involved. For example, C2-deficient patients generally do not have problems with recurrent infections, unless other components, acting later in the cascade, are deficient as well. In contrast, deficiency of C3, which plays an integral role in both the classic and alternate pathways, results in repeated infections. Deficiencies of the later acting components (C5, C6, C7, or C8) have been linked with serious and sometimes fatal infections with N. meningitidis and Neisseria gonorrhoeae. The association between complement deficiency and autoimmune diseases, such as systemic lupus erythematosus, may relate to the host's inability to clear circulating immune complexes.

Although complement has been found in tears,⁸⁰ cornea,⁸¹ aqueous humor,⁸² and sclera,⁸³ ocular infections have not been reported to be prominent features of complement disorders.⁹ One should assume, however, that patients will be at risk for ocular infections with the same pathogens seen in nonocular sites. Experimental evidence in animal models shows that the complement system may play a role in protecting the eye against corneal infection⁸⁴ and endophthalmitis⁸⁵ caused by P. aeruginosa, an organism whose endotoxins activate the alternate pathway. Complement levels are increased in the vitreous humor of inflamed eyes.⁸⁶ Patients with complement deficiencies who develop intraocular infections for some other reason may, therefore, have more severe disease than their immunocompetent counterparts.

In many acquired immunodeficiency states, immune dysfunction does not contribute substantially to clinical manifestations. Reviewed here are several disorders in which altered host defenses lead to prominent clinical problems.

ACQUIRED IMMUNODEFICIENCY SYNDROME

AIDS was first reported in the early 1980s, and its ocular complications were described soon thereafter.^87–89 It is the most severe in a spectrum of immunodeficiency states caused by infection with the human immunodeficiency virus (HIV).

Infection with HIV is characterized predominantly by T-lymphocyte deficiency. The initial step in HIV infection is binding of the envelope protein of HIV to the receptor on the host CD4+ T lymphocyte; chemokine receptors, such as CCR5 or CXCR4, act as coreceptors and are also necessary for binding. After fusion with the host cell membrane has occurred, the RNA of the virus undergoes reverse transcription, forming DNA, which enters the host cell nucleus and is integrated into the genetic material of the cell. This HIV-encoded DNA is transcribed into messenger RNA, which is then translated into viral proteins, including HIV protease, that are required for processing other HIV-encoded proteins into their functional forms. The newly assembled virus then buds from the cell surface, and new cellular infections occur. Host CD4+ T lymphocytes are depleted through a combination of increased destruction and impaired thymic production.⁹⁰

The mechanisms of HIV-related disease are far too complicated to be reviewed here, but they ultimately result from dysregulation of the immune system, especially cell-mediated immunity, that occurs because of continuous CD4+ T-lymphocyte destruction and depletion. Impaired cellular immunity facilitates diseases associated with infectious agents, including both productive infections in various end organs and neoplasms that result from malignant transformation of infected cells; examples of the latter include Kaposi's sarcoma (KS), caused by human herpes virus type 8, and squamous cell carcinoma, caused by human papillomavirus. Many opportunistic infections result from reactivation of previously acquired agents of low virulence that are usually controlled by normal host immune defenses; examples include CMV, P. carinii, varicella-zoster virus, and Toxoplasma gondii. People infected with HIV seem to be predisposed to specific infectious agents (including those already noted, as well as Candida sp. and MCV) with involvement of specific organs (e.g., CMV retinitis or P. carinii pneumonia). Humoral immunity is also affected. Although HIV infection is associated with a polyclonal gammopathy, the B-lymphocyte response to new antigens is markedly impaired. In addition, production of cytokines, such as IFN-γ (which activates macrophages to kill intracellular pathogens) and interleukin-2 (which allows T-lymphocyte proliferation), is impaired.

Most patients are infected with HIV-type 1 (HIV-1). A retrovirus with lymphotropic properties similar to HIV-1 was isolated from two people in West Africa in 1986 and is called human immunodeficiency virus, type 2 (HIV-2).⁹¹ Although HIV-2 also causes AIDS, it appears to be less pathogenic than HIV-1, with a longer latency period of infection, less severe manifestations of disease, and longer survival after diagnosis of AIDS. The seroprevalence of HIV-2 is greatest in West Africa. Ocular complications of HIV-2 infection appear to be uncommon.⁹² For this reason, the term HIV in this chapter refers to HIV-1, unless specifically indicated otherwise.

The severity of immune dysfunction varies considerably between HIV-infected people but tends to become progressively worse over time, if untreated. Those infected with HIV can be asymptomatic; they can have nonspecific manifestations of HIV infection itself, such as lymphadenopathy; or they can have the overt manifestations of HIV-associated opportunistic infection and neoplasms. The AIDS is defined as a CD4+ T-lymphocyte count less than 200/μl (or percentage of CD4+ T-lymphocytes less than 14% of total lymphocytes) or the occurrence of one or more of a specific group of opportunistic infections and neoplasms predictive of severe immunodeficiency.⁹³

HIV can be transmitted by one of three routes: (1) sexual intercourse; (2) percutaneous inoculation (sharing of needles by injection drug users, transfusion of contaminated blood products, accidental needle-stick injuries in health care workers); and (3) maternal-infant (vertical) transmission (in utero, during birth, or by breast-feeding). In the first two decades of the AIDS epidemic, the demographics of the disease in the United States have changed from largely a disorder of homosexual white men to one affecting a mix of homosexuals, heterosexuals, and injecting drug-users, disproportionately involving African Americans and the poor.

In the United States, over 400,000 people had died of AIDS by the year 2000, and there were over 700,000 people living with HIV infection. By 2000, over 60% of new HIV infections in 13- to 19-year-old people were occurring in women. Worldwide, over 16 million people had died, and over 33 million were infected, with over 95% of the 5.6 million adults and children who were newly infected in 1999 living in sub-Saharan Africa and other developing countries.

Currently available drugs that act against HIV include reverse transcriptase inhibitors (both nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors) and protease inhibitors.⁹⁴ AIDS was initially uniformly fatal, but it can now be controlled in many patients with these medications, which are known collectively as highly active antiretroviral therapy (HAART) or potent antiretroviral therapy. These drugs, by interrupting the infection cycle of HIV, allow a partial restoration of immune function and have thereby resulted in a substantial decline in opportunistic infections. At the same time, the widespread use of potent antiretroviral therapy has resulted in new presentations of clinical disease and clinically important side effects. The cost of these drugs precludes their use in all but the wealthiest of countries. Even in the United States, the combination of intolerable side effects, drug resistance, and lack of adequate compliance with complicated treatment regimens has resulted in a long-term success rate for potent antiretroviral therapy of only 40% in some geographic areas.⁹⁵

Ophthalmic disorders are among the most common manifestations of AIDS (Table 2). These manifestations include (1) noninfectious vasculopathies, (2) opportunistic infections, (3) neoplasms, (4) neuro-ophthalmic abnormalities attributable to intracranial and orbital disorders, and (5) drug-induced ocular side effects. Recognition and treatment of ocular disease are important not only because of the morbidity associated with vision loss but because ophthalmic manifestations of HIV infection often indicate progressive dysfunction of the immune system and can be the first manifestation of multisystemic diseases. Discussion of these disorders in later sections deal primarily with the manifestations of HIV infection in those people with severe immune dysfunction. The use of potent antiretroviral therapy has reduced the frequency of many HIV-related ophthalmic disorders and in some cases has altered their clinical features, course, and response to treatment.

Table 2. Ophthalmic Disorders Associated with HIV Infection

1. Non-infectious vasculopathy
   1. Microvasculopathy
      1. Retina
         1. “HIV retinopathy” (characterized clinically by presence of cotton-wool spots, retinal hemorrhages)
            
         
         
      2. Conjunctiva
         
      3. Optic nerve
         
      
      
   2. Macrovasculopathy
      1. Retina
         1. Venous occlusions
            
         2. Arterial occlusions
            
         
         
      
      
   
   
2. Infections
   1. Ocular surface and adnexal
      1. Herpes zoster ophthalmicus
         
      2. Herpes simplex virus keratitis
         
      3. Molluscum contagiosum virus dermatitis, blepharitis
         
      4. Microsporidial keratoconjunctivitis
         
      5. Crack cocaine-associated keratopathy
         
      6. Other
         
      
      
   2. Retinal and choroidal
      1. Cytomegalovirus retinitis
         1. Immune recovery uveitis
            
         
         
      2. Varicella zoster virus retinitis
         
      3. Herpes simplex virus retinitis
         
      4. Syphilitic uveitis/retinitis
         
      5. Toxoplasma gondii retinochoroiditis
         
      6. Pneumocystis carinii choroidopathy
         
      7. Mycobacterium tuberculosis choroiditis
         
      8. Other
         
      
      
   3. Orbital infections
      
   
   
3. Neoplasms
   1. Eyelid/ocular surface
      1. Kaposi's sarcoma
         
      2. Lymphoma
         
      3. Squamous cell carcinoma
         
      
      
   2. Intraocular
      1. Lymphoma
         
      
      
   3. Orbit
      1. Lymphoma
         
      2. Kaposi's sarcoma (rare)
         
      
      
   
   
4. Neuro-ophthalmologic abnormaities associated with intracranial or orbital diseases
   1. Infections
      1. Cryptococcal meningitis
         
      2. Intracranial toxoplasmosis
         
      3. Progressive multifocal leukoencephalopathy
         
      4. Varicella-zoster virus infection
         
      5. Syphilitic meningitis
         
      6. Other
         
      
      
   2. Neoplasms
      1. Intracranial lymphoma
         
      
      
   
   
5. Adverse effects of systemic drugs
   1. Uveitis
      1. Cidofovir
         
      2. Fomivirsen
         
      3. Rifabutin
         
      
      
   2. Optic neuropathy
      1. Ethambutol
         
      
      
   3. Retinopathy
      1. Didanosine
         
      
      
   
   

Noninfectious Microvasculopathy

Noninfectious retinal lesions associated with microvascular abnormalities (cotton-wool spots, retinal hemorrhages; known as HIV retinopathy) are the most common ocular findings reported in people with HIV infection (Fig. 2). The extent and severity of these retinal findings are greater in patients with AIDS than in iatrogenically immunosuppressed people who occasionally have similar lesions.⁹⁶ The presence of HIV retinopathy is related to overall immune status; asymptomatic HIV-infected patients rarely have clinically apparent lesions, but nearly all patients with advanced AIDS have some degree of HIV retinopathy.^97,98 In addition to cotton-wool spots and retinal hemorrhages, clinical manifestations include retinal capillary microaneurysms, white-centered hemorrhages, telangiectasias, and capillary nonperfusion.^{87–89,97,99,100} Cotton-wool spots occur in the posterior pole and are seen as superficial white patches with feathery edges that sometimes obscure underlying retinal blood vessels. They are caused by stasis of axoplasmic flow within the retinal nerve fiber layer, as a result of ischemia, either because of precapillary arteriolar occlusion or reduced blood flow.¹⁰¹ Cotton-wool spots tend to resolve over 4 to 6 weeks. Affected patients are rarely symptomatic. Microaneurysms are found clinically in only about 20% of patients but are detected in eyes of nearly all patients with AIDS when studied by fluorescein angiography or by trypsin digestion of retinal tissue at autopsy.^96,100,102 Ischemic maculopathy has been reported rarely.¹⁰⁰ Noninfectious microvasculopathy is also the most common ocular manifestation of HIV-2 infection, and affected people have a shorter survival that HIV-2-infected people without microvasculopathy.⁹²

The underlying abnormality of HIV retinopathy is disease of the retinal vasculature. Trypsin digest preparations and ultrastructural studies reveal selective loss of pericytes, microaneurysm formation, swollen endothelial cells, occluded vascular lumina, and thickened basal lamina,^96,100 similar to findings in diabetic retinopathy. Fluorescent microsphere infusion studies have identified breaches in microaneurysms of 200 nm or more, even in the absence of visible hemorrhage; these defects might play a role in the passage of CMV into the retina with development of CMV retinitis.¹⁰³

The cause of noninfectious microvasculopathy is unknown and likely multifactorial. HIV has been identified within retinal endothelial cells but not in amounts sufficient to account for the widespread changes seen.¹⁰⁴ Other proposed mechanisms include deposition of circulating immune complexes,¹⁰⁰ release of cytotoxic substances such as monokines or proteolytic enzymes¹⁰⁴ and abnormal blood flow.¹⁰¹ Slowing of blood flow probably further contributes to the focal ischemia that results in periodic development of cotton-wool spots.¹⁰¹ The presence of both cotton-wool spots and conjunctival microvasculopathy, consisting of dilated capillaries, vessels of irregular caliber, and sludging of blood flow, has been related to elevated fibrinogen levels and red blood cell aggregation but not with levels of circulating immune complexes or immunoglobulin.¹⁰¹ People infected with HIV have increased neutrophil rigidity, which may also slow blood flow and contribute to microvascular damage.¹⁰⁵ Souza Ramalho and associates¹⁰⁶ reported a patient with HIV-2 infection and noninfectious retinal vasculitis who had elevated plasma viscosity and red blood cell filterability, both indices of abnormal blood flow. The patient's clinical and hemorheologic status improved following treatment with prednisone and chlorambucil.

Less commonly, occlusion of larger retinal blood vessels (macrovasculopathy) can occur. Both retinal artery and vein occlusions have been reported, with a prevalence greater than would be expected for age-matched controls.^99,107 Hypertension and thrombotic disease are found in a high proportion of affected patients.

Other causes of noninfectious microvasculopathy, such as diabetes mellitus or hypertension, should always be considered. Patients with both diabetes mellitus and HIV disease may have particularly severe noninfectious retinopathy. Reports of hyperlipidemia, glucose intolerance, and accelerated vascular disease among patients treated with protease inhibitors¹⁰⁸ have raised concerns that retinal vascular disease may become more frequent in HIV-infected patients. For example, lipemia retinalis has been found in a patient treated with protease inhibitors who had hyperlipidemia.¹⁰⁹

Ocular Opportunistic Infections

CMV RETINITIS.

CMV retinitis is by far the most common intraocular infection in people with AIDS.^99,110 CMV retinitis is rarely the first manifestation of AIDS^111,112; most affected patients have CD4+ T-lymphocyte counts of less than 50 cells/μl at diagnosis.^111,113 One study found that 85% of people with extraocular CMV infection developed CMV retinitis after a mean follow-up period of 6.4 months.¹¹⁴ Other risk factors for the development of CMV retinitis include high HIV levels in the blood, a previous AIDS-defining illness, homosexual activity as the route of HIV infection, lack of protease inhibitor therapy in antiretroviral regimens, high CMV levels in the blood, and CMV seropositivity.¹¹⁵ Up to 40% of patients with advanced HIV disease developed CMV retinitis in the era before potent antiretroviral therapy.^{110,111,115,116} Since the introduction of these drugs, the rate is much lower,¹¹⁷ probably on the order of 5% or less. The decline in frequency may reflect not only the widespread use of potent antiretroviral therapy but also the changing demographics of AIDS; heterosexual men are less likely than homosexual men to develop CMV retinitis,perhaps because homosexuals have a higher rate of pre-existing CMV infection.¹¹⁵ Nevertheless, CMV retinitis remains a major cause of morbidity in HIV-infected people. It is especially important to diagnose the infection early, because currently available therapy is usually effective for controlling retinal lesions and because treatment of systemic CMV infection may favorably affect concurrent HIV replication.

CMV retinitis may begin with infection of retinal vascular endothelial cells, with subsequent spread to adjacent glial and neuronal cells as well as to RPE,¹¹⁸ although early autopsy studies failed to identify infected endothelium in all cases.¹⁰⁰ It is also possible that infection results from diapedesis of CMV-infected leukocytes in some cases.¹¹⁹

The diagnosis of CMV retinitis is based on clinical signs and symptoms.^{87,88,99,119,120} Vision is usually good at the time of diagnosis,¹¹³ and there is no pain or redness. People with early CMV retinitis usually have floaters and may also complain of photopsias or visual field defects, but between 10% and 75% of patients may be unaware of any symptoms,^121,122 especially if the disease is unilateral.⁹⁸ One study found that over half of new cases of CMV retinitis were diagnosed during routine screening eye clinic visits and that over 75% of affected patients were asymptomatic at the time of diagnosis.¹²² Routine dilated indirect ophthalmologic examination of patients at highest risk of CMV retinitis, based on a CD4+ T-lymphocyte count of less than between 50 and 100/μl, has been recommended.^98,123

Only about 10% of people with AIDS-related CMV retinitis have clinically apparent extraocular CMV disease, although about half have a positive blood or urine cultures for CMV.¹¹³ The characteristic retinal lesion has a dry-appearing, granular border surrounding an area of retinal edema and full-thickness retinal necrosis. Findings are similar to those of CMV retinitis described in patients with iatrogenic immunosuppression before the AIDS epidemic began.¹²⁴ There is a spectrum of lesion appearances; the fulminant or edematous type has prominent necrosis and hemorrhage, often along blood vessels in the posterior pole (Fig. 3). The indolent or granular type is more often found in the retinal periphery and has less dense retinal opacification and little or no hemorrhage. Many cases of CMV retinitis have features of both types. Patients who have an incomplete response to potent antiretroviral therapy may develop CMV retinitis that is less hemorrhagic and less densely opaque. Perivascular sheathing, which may be widespread, occurring in areas of the retina away from the site of necrosis, is found in between 35% and 50% of cases. Bilateral involvement occurs in 30% to 40% of cases at diagnosis.^113,122,125 There are usually mild anterior chamber and vitreous inflammatory reactions, and fine keratic precipitates are often seen. Untreated lesions enlarge slowly; spread toward the fovea occurs at a median rate of only 24 μm/day and is somewhat faster toward the ora serrata.¹²⁶

Vision loss may result from primary or secondary optic nerve involvement,^127,128 retinal necrosis involving the central macula, rhegmatogenous retinal detachment, retinal vein or artery occlusion, or serous macular exudation.¹²⁹ Electrophysiologic and psychologic testing suggests that there is a diffuse dysfunction of the retina even when only localized, peripheral lesions are seen clinically.¹³⁰

Peripapillary CMV retinitis is associated with an increased risk of CMV encephalitis.¹³¹ Early detection and treatment may reverse some of these complications and result in improved vision,¹³² but in most patients the goal of therapy is to prevent further vision loss in affected eyes and to reduce the risk of involvement in uninfected eyes of unilateral cases.¹³³

CMV retinitis occurs less frequently in children with AIDS than in adults,^134–136 but it is more likely to be associated with symptomatic extraocular CMV disease.¹³⁷ Perhaps because children are less likely to complain of visual symptoms and are, therefore, less likely to undergo ocular examination than adults, CMV retinitis in children also more commonly presents with bilateral and posterior pole involvement.^134,137 Very young children with CMV retinitis may also have high absolute CD4+ T-lymphocyte counts, because the normal CD4+ T-lymphocyte count in the first few years of life is substantially higher than in adults; however, affected children still have counts that are much lower than normal, when adjusted for age.¹³⁷ Older children with CMV retinitis usually have CD4+ T-lymphocyte counts that are less than 20/μl.¹³⁴

The differential diagnosis of CMV retinitis includes other necrotizing herpetic retinopathies, as described later, toxoplasmic retinochoroidopathy, candidal chorioretinitis, aspergillic retinitis, ocular cryptococcosis, endogenous bacterial endophthalmitis, syphilitic retinitis, intraocular lymphoma, and Bartonella henselae retinitis (cat-scratch disease).¹³⁸ Although the distinction between these diseases is usually made clinically and additional workup is unnecessary, there are patients in whom vitrectomy or endoretinal biopsy may be useful diagnostically.^139–144 In addition, concurrent ocular opportunistic infections with more than one pathogen have been reported in many people with AIDS.

There were four drugs approved by the U.S. Food and Drug Administration (FDA) as of the year 2000 for treatment of CMV retinitis: ganciclovir, foscarnet, cidofovir, and fomivirsen. The first three are available in IV forms; ganciclovir is also available in an oral preparation and as a sustained-release intraocular implant. The first three drugs act by inhibiting CMV DNA polymerase. Fomivirsen is an antisense oligonucleotide that acts by preventing the elaboration of a protein needed for infectivity of the virus; it is delivered by intravitreous injection. All these drugs are virostatic, not virucidal; discontinuation of therapy in persistently immunosuppressed patients, therefore, invariably leads to recurrence of CMV retinitis.

Ganciclovir is a nucleoside analogue. The recommended IV dose is 5 mg/kg every 12 hours for 2 to 3 weeks (induction), followed by 5 to 10 mg/kg once daily (maintenance therapy). Ganciclovir is a bone marrow suppressant; anemia, leukopenia, and thrombocytopenia are common findings associated with its therapy. Foscarnet is a pyrophosphate analogue. The recommended IV dosage is 90 mg/kg every 12 hours for 2 weeks (induction therapy), followed by 90 to 120 mg/kg once daily (maintenance therapy). Foscarnet is nephrotoxic and must be carefully dose adjusted for patients with renal insufficiency. Randomized, controlled studies have shown no therapeutic difference between ganciclovir and foscarnet; both control retinitis initially in about 90% of cases, but reactivation of retinal infection despite prolonged therapy is common, with a median time to progression of retinitis of less than 3 months. Because both IV foscarnet and ganciclovir must be given daily, a permanent indwelling catheter is placed for long-term therapy. Catheter-related infections are a major reason why other options have been developed.

Oral ganciclovir has limited bioavailability but may be effective as maintenance therapy following a course of IV induction therapy for limited periods of time.¹⁴⁵ Commonly used doses range from 1 to 1.5 g three times daily. Side effects include GI disturbances and bone marrow suppression. Although use of oral ganciclovir as primary prophylaxis may reduce the risk of CMV infection, including retinitis,¹⁴⁶ its use is not routinely recommended because of the cost and associated toxicity.¹⁴⁷ An oral prodrug of ganciclovir (valganciclovir) holds the promise of providing serum drug levels comparable with those achieved with IV ganciclovir, while avoiding catheter-related complications; approval by the FDA is anticipated in 2001.

The ganciclovir implant is a sustained-release form of ganciclovir in which a 4.5-mg pellet of the drug, attached to a strut made of ethyl vinyl acetate, is placed surgically into the vitreous cavity through the pars plana and sutured to the sclera. Steady state levels of ganciclovir are reached within approximately 24 hours of placement, and intraocular drug levels are roughly four times greater than those achieved with IV ganciclovir therapy.^148,149 Randomized, controlled studies have shown that the ganciclovir implant is more effective for maintaining inactivity of CMV retinitis than IV ganciclovir, with a median time to reactivation of approximately 220 days.^149,150 The ganciclovir implant provides no benefit to the fellow eye; there is a substantial risk of second-eye involvement if concurrent systemic therapy is not given.¹⁵⁰ Oral ganciclovir, as an adjunct to the placement of a ganciclovir implant in a patient with unilateral CMV retinitis, reduces the risk of second-eye involvement and extraocular disease¹⁴⁹ and is, therefore, recommended, if there are no medical contraindications to its use.¹⁵¹ The long-term risk of retinal detachment is not increased in patients treated with ganciclovir implants compared with those patients treated with IV ganciclovir,^149,152 although detachments may occur earlier. Surgical complications of the procedure range from temporary astigmatism and foreign body sensation to severe vision loss from hypotony, endophthalmitis, and vitreous hemorrhage.^149,153 In addition, the ganciclovir implant must be replaced every 6 to 12 months in patients who remain immunosuppressed. The risk of serious surgical complications appears to be greater in patients undergoing multiple implant procedures.^153,154

IV cidofovir has been proven to be effective for treatment of CMV retinitis¹⁵⁵ but has not been compared with other anti-CMV therapies; thus, its relative efficacy has not been determined. Cidofovir is a nucleotide analogue with a long intracellular half-life, obviating the need for daily infusion or placement of a permanent, indwelling catheter for long-term therapy. The drug is given IV at a dose of 5 mg/kg once weekly for 2 weeks, followed by 5 mg/kg every 2 weeks. Cidofovir is nephrotoxic, and strict adherence to treatment guidelines is necessary. The use of oral probenecid and large amounts of IV saline for hydration at the time cidofovir is administered is mandatory.

Cidofovir does not require phosphorylation by a protein kinase produced by CMV to be taken into infected cells. Consequently, patients with low-level resistance to ganciclovir (UL 97 gene mutations) may respond to cidofovir, but high-grade ganciclovir resistance is often associated with cidofovir resistance as well, because of mutations at the level of CMV DNA polymerase.¹⁵⁶ Resistance to anti-CMV drugs is rare before initial exposure to the drug,¹⁵⁷ but it becomes more common with prolonged treatment.¹⁵⁸ Resistance is associated with a worse clinical outcome, including progression of retinitis and second-eye involvement.¹⁵⁸

Fomivirsen is an phosphorothioate antisense oligonucleotide that impairs production of an early gene product essential for CMV replication.¹⁵⁹ The drug is given as an intravitreous injection consisting of 0.05 ml (330 μg) every 2 weeks for 2 doses, then every 4 weeks thereafter. Fomivirsen has not been compared directly with other anti-CMV therapy, but some evidence suggests that CMV retinitis resistant to other anti-CMV therapy may respond to fomivirsen. As with the ganciclovir implant, fomivirsen provides local control of retinitis only, with an associated risk of second-eye and extraocular CMV infection. Side effects of the injection include a small risk of vitreous hemorrhage or endophthalmitis, as well as uveitis, glaucoma, and cystoid macular edema. No systemic side effects have been reported.

Reactivation (relapse) of CMV retinitis with enlargement of lesions (progression) in patients who remain immunosuppressed is almost inevitable, even with continued maintenance therapy.^99,133 With reactivation, there is recurrent whitening of the borders of inactive CMV retinitis scars, with centripetal spread into previously healthy retina. New lesions may also develop. Changes in lesion size may be subtle. Studies have shown that careful comparison of serial retinal photographs is a more sensitive means of detecting lesion enlargement than clinical observation only.^160,161 The primary reason that reactivation occurs appears to be the limited intraocular drug delivery across the blood-retina barrier.¹⁴⁸ Ironically, healing of CMV retinitis lesions may result in less intraocular penetration of anti-CMV therapy as the blood-retina barrier is reformed. Other causes of retinitis reactivation include development of drug resistance,^162–164 noncompliance with therapy, and further waning of host immunity as HIV disease advances. Risk factors for development of new lesions in previously uninvolved eyes include positive blood and urine cultures for CMV and lower CD8+ T-lymphocyte counts.¹⁶⁵

In the era before introduction of potent antiretroviral therapy, the time to progression (defined for study purposes as advancement of previously inactive lesion borders by 750 μm or more, as determined by a masked observer evaluating serial retinal photographs, or development of new foci of retinal infection) was on the order of 3 months or less. Retreatment with antiviral therapy at induction doses for 2 weeks, followed by higher maintenance therapy doses, was often effective at reestablishing control of the disease, but an accelerating rate of subsequent reactivations was observed.¹³³ The use of combination antiviral therapy, such as IV foscarnet and ganciclovir, may also prolong the time to subsequent reactivation.¹⁶⁶ Quality of life suffers when combination IV therapy is given, however.

Antiviral resistance is more likely to occur in patients who have suffered multiple reactivations. In such cases, changing from ganciclovir to foscarnet or cidofovir may be effective.¹⁶² Although data suggest that CMV DNA levels in the aqueous humor or vitreous humor¹⁶⁷ or blood^168,169 in treated patients may predict reactivation and that phenotypic or genotypic resistance may be determined by polymerase chain reaction (PCR) techniques using blood or vitreous humor isolates,¹⁵⁸ such tests have not become as widely used in clinical practice as measurement of HIV levels in the blood and determination of antiretroviral drug resistance.^170,171 Limited data suggest that patients who fail to respond to repeated induction regimens with ganciclovir or foscarnet may respond to intravitreous injections of fomivirsen.¹⁵⁹

Before introduction of potent antiretroviral therapy, median survival following a diagnosis of CMV retinitis was 7.8 months⁹⁹ to 12.4 months,¹⁷² and a reasonable goal of therapy for CMV retinitis was merely to delay advancement of lesions into the macular region, thereby preserving central vision before death. In the era of potent antiretroviral therapy, survival after the diagnosis of CMV retinitis may go on for many years,¹⁷³ and more sustained control of CMV retinitis is necessary, if visual function is to be preserved.

Progression of CMV retinitis is less likely in patients being treated with anti-CMV drugs, if they are also receiving potent antiretroviral therapy, even if they do not show elevated CD4+ T-lymphocyte counts. The choice of anti-CMV therapy should, therefore, be based on a number of factors, including the location of lesions, the likelihood of the patient remaining on potent antiretroviral therapy, the response to antiretroviral agents, the presence or absence of extraocular CMV disease, the patient's overall medical condition, and patient preference.¹²³ For example, a patient with perifoveal CMV retinitis who cannot be treated with potent antiretroviral therapy, would be a good candidate for a ganciclovir implant and oral ganciclovir therapy, whereas a patient with peripheral CMV retinitis who is expected to respond to potent antiretroviral therapy and is adherent to his or her medical regimen might safely and effectively be treated with systemic ganciclovir, avoiding the surgical risks of a ganciclovir implant.¹⁵¹

Rhegmatogenous retinal detachment is an important cause of vision loss in people with CMV retinitis. About 3% have detachments at the time of retinitis diagnosis, and the risk increases over time, affecting about one third of eyes with CMV retinitis per year, or approximately 50% per person-year.^174–176 The risk of retinal detachment increases with active lesions, larger lesion size,^174,175 and involvement of the anterior retina near the vitreous base.¹⁷⁵ Older people and those with lower Karnofsky scores and lower CD4+ T-lymphocyte counts are also more likely to develop retinal detachments. Use of the ganciclovir implant does not increase the long-term risk of retinal detachment compared with systemic therapy only.^151,152

Although large holes, horseshoe tears, and giant tears can be seen in patients with CMV retinitis and retinal detachments, most retinal detachments result from multiple, small, ill-defined holes within necrotic retina or at the junction of necrotic and normal retina. The difficulty in visualizing these small holes and the relative lack of inflammation in patients with CMV retinitis, which probably contributes to poor adhesions between the neurosensory retina and the RPE, help to account for the low success rate with conventional retinal detachment surgical techniques, such as scleral buckling alone. Despite studies indicating that laser retinopexy alone or vitrectomy with gas tamponade, laser, and scleral buckling may be effective in some cases,¹⁷⁷ pars plana vitrectomy with long-term silicone oil tamponade and endolaser retinopexy has been considered the definitive technique for repair of retinal detachments associated with CMV retinitis, with macular reattachment rates exceeding 90%.^177,178 Adjunctive scleral buckling does not appear to improve the success rate further.¹⁷⁸ The risk of severe proliferative vitreoretinopathy was less than 4% of eyes in one study.¹⁷⁷ Final vision often is decreased as a result of recurrent retinal detachment beneath the oil, corneal endothelial toxicity, epiretinal membrane formation, or cataract. In many cases, decreased central visual acuity occurs after retinal detachment repair, but an obvious reason cannot be identified on clinical examination.

Conventional phacoemulsification and posterior chamber intraocular lens implantation can be performed for silicone oil-associated cataracts, but adjustments in the intraocular lens power must be made to account for the hyperopia induced by silicone oil, depending on the style of implant used.¹⁷⁹ Visual outcomes after cataract extraction have generally been disappointing,¹⁷⁹ even in some cases in which no macular abnormalities were evident, raising the possibility of retinal toxicity from prolonged contact with silicone oil. Removal of silicone oil is associated with improvement in vision in some cases, suggesting that some visual symptoms in oil-filled eyes are optical and not due to toxicity.¹⁸⁰

Immune reconstitution associated with potent antiretroviral therapy has had an enormous impact on the rate of CMV retinitis. Initiation of potent antiretroviral therapy in those at high risk for CMV disease results in significantly lower rates of CMV retinitis.^{117,173,181,182} Increasing CMV DNA levels in the blood are associated with an increased risk of CMV retinitis¹⁶⁹; immune reconstitution induces a progressive decline in CMV viremia in the absence of specific anti-CMV therapy.^183,184

There are differences in the presentation and clinical course of CMV retinitis in patients who are already taking antiretroviral agents. They may present with inactive CMV retinitis, indicating regression of the CMV disease as a result of immune reconstitution alone. Others may present with CMV retinitis and CD4+ T-lymphocyte counts that have risen above 200 cells/μl¹⁸⁵ after recently beginning antiretroviral therapy; presumably the retinal infection developed before the counts rose. Patients may also have pronounced intraocular inflammation and cystoid macular edema;¹⁸⁶ these findings were rare in patients with CMV retinitis before the introduction of potent antiretroviral therapy.

In a study of 14 consecutive patients with CMV retinitis diagnosed in 1997 or 1998, Jacobson and associates¹⁸¹ found that four of five patients who never received potent antiretroviral therapy either before or after the diagnosis of retinitis either died within 2 months or had active retinitis after 6 weeks of systemic anti-CMV therapy. In contrast, all five patients who responded well to potent antiretroviral therapy after the diagnosis of retinitis, as evidenced by a nondetectable plasma HIV level or a CD4+ T-lymphocyte count above 50/μl, also responded well to anti-CMV therapy and had no reactivation of retinitis over a median 15.5 months of ophthalmologic monitoring. In the remaining patients, who had received suboptimal antiretroviral therapy before diagnosis of CMV retinitis and who were changed to an effective antiretroviral regimen, two patients died within 1 month and two patients had persistent CMV retinitis despite 2 to 4 months of systemic anti-CMV therapy. Although the number of patients in this study was small, the results suggested that long-term ophthalmic outcomes for patients with CMV retinitis are dependent on the response to potent antiretroviral therapy.

Kempen and associates¹⁵² have shown that the use of potent antiretroviral therapy is associated with a 60% reduction in the rate of retinal detachment in eyes with CMV retinitis, with the greatest benefit observed among patients who developed an immunologic response. The use of potent antiretroviral therapy had a greater effect on the risk of retinal detachment than other well-established factors such as lesion size and anterior location of retinitis. It has been suggested that immune recovery results in a stronger adherence at the retina/RPE interface.¹⁸⁷ Because potent antiretroviral therapy also reduces other risk factors for retinal detachment, such as active retinitis and increased lesion size, it may be that some retinal detachments in patients treated with potent antiretroviral therapy may be surgically corrected without the need for silicone oil.¹⁸⁰

Numerous studies have shown that maintenance therapy can be discontinued without reactivation of retinitis in patients with CMV retinitis who are then successfully treated with potent antiretroviral therapy.^188–190 CMV-specific CD4+ T-lymphocyte responses in patients with CMV disease may be restored by potent antiretroviral therapy,¹⁹¹ but it can take 3 to 6 months after the rise in absolute CD+ T-lymphocyte counts for the repertoire of cells with specific activity against CMV to be restored.¹⁹² Most investigators therefore recommend that the CD4+ T-lymphocyte count show a sustained elevation for at least 3 months and that the CMV retinitis be inactive before maintenance therapy is discontinued.¹⁹³ It must be kept in mind, however, that the failure rate of potent antiretroviral therapy in unselected patients in clinical practice may be substantially greater than the failure rate in patients closely monitored in clinical trials.⁹⁵ Failure of potent antiretroviral therapy may result from noncompliance with therapy, inability to take the medications because of intolerable side effects, or antiretroviral resistance.^95,194 There is a risk of reactivation of CMV retinitis in patients who initially respond to, but who eventually fail, potent antiretroviral therapy, with a fall in CD4+ T-lymphocyte count to less than 50 cells/μl.¹⁶⁸ The roles of HIV RNA and CMV DNA blood levels or specific tests of CMV immunity in determining which patients are at greatest risk for reactivation of CMV retinitis remain unclear. Furthermore, increases in CD4+ T-lymphocyte count alone do not completely reflect the immunologic status, and reactivation of CMV retinitis has occurred even in patients with persistently elevated counts.¹⁹⁵ Patients who are taken off maintenance anti-CMV therapy therefore must understand the importance of strict adherence to the potent antiretroviral therapy regimens and of regular ophthalmic follow-up.

Immune recovery uveitis is a condition characterized by increased intraocular inflammation in eyes of patients with CMV retinitis, attributable to immune reconstitution.^196–198 The CMV retinitis is usually, although not always, inactive.¹⁹⁸ Although there is no universally accepted clinical definition of immune recovery uveitis, the most characteristic findings include prominent anterior chamber and vitreous humor cellular reactions. Patients with immune recovery uveitis may have optic disc edema,¹⁹⁹ epiretinal membrane formation,¹⁹⁹ cystoid macular edema,¹⁸⁶ vitreomacular traction,²⁰⁰ and retinal neovascularization.^199,201 Posterior synechiae²⁰¹ and optic disc neovascularization²⁰² have been reported less commonly. Immune recovery uveitis, which may be either acute, recurrent, or chronic, is now the leading cause of severe, new vision loss in people with AIDS and CMV retinitis.²⁰³ The macular edema may not be clinically evident; therefore, patients with CMV retinitis and unexplained vision loss should undergo fluorescein angiography.

Disease mechanisms associated with immune recovery uveitis remain poorly understood. The disease occurs only in patients receiving potent antiretroviral therapy and whose CD4+ T-lymphocyte counts have increased, usually to the range of 75/μl or higher. Immune recovery uveitis does not occur in patients with CMV retinitis who are not treated with potent antiretroviral therapy or who fail to respond to antiretroviral agents and does not occur in the uninvolved eye of patients with unilateral CMV retinitis.¹⁸⁷ Currently available anti-CMV therapy is virostatic, not virucidal, and continued production of viral proteins can occur in CMV lesions that are clinically inactive.^204,205 Immune recovery uveitis is presumably a response against these retained viral proteins. Immune recovery uveitis can also occur in patients with active CMV retinitis who have recently started potent antiretroviral therapy.^185,198 In fact, some authors have suggested that a more prominent inflammatory reaction is actually a good prognostic sign for control of infection.²⁰⁶

A syndrome similar to immune recovery uveitis has been described in patients with CMV retinitis following organ transplantation, when doses of immunosuppressive drugs are reduced and immune function improves.²⁰⁷ Nussenblatt and Lane¹⁹² suggested that the development of immune recovery uveitis occurs along a spectrum of immune function. With profound immunodeficiency, people with CMV retinitis produce very little inflammation against the virus, explaining the relatively quiet appearance of eyes with active disease. As immune function improves, a much greater inflammatory reaction against viral proteins occurs, and immune recovery uveitis develops. At still greater levels of immune function, production of antigen ceases, and the inflammatory reaction resolves. Similarly heightened inflammatory reactions occur in some patients with other AIDS-related infections and neoplasms, such as tuberculosis, Mycobacterium avium complex (MAC) infection, hepatitis B and C, progressive multifocal leukoencephalopathy (PML), lymphoma, and KS, after initiation of potent antiretroviral therapy.²⁰⁸ Current theories do not explain why only a few patients develop immune recovery uveitis.

The reported frequency of immune recovery uveitis ranges from 0.109 per person-year¹⁹⁷ to as much as 0.83 per person-year.¹⁸⁷ Although this range might reflect subjective differences in interpretation of inflammatory reactions, other factors are likely involved. Cidofovir has been associated with the development of uveitis,²⁰⁹ and patients treated with cidofovir may be at higher risk for immune recovery uveitis than those patients treated with other drugs.¹⁹⁷ In addition, the type of therapy used to control CMV retinitis initially and the duration of anti-CMV therapy after initiating potent antiretroviral therapy may affect the rate of immune recovery uveitis.²¹⁰ It has been shown that some patients with immune recovery uveitis have detectable amounts of CMV in the blood after the start of potent antiretroviral therapy, despite clinically inactive CMV retinitis.¹⁹⁰ The use of ganciclovir implants, which is more effective than systemic therapy at reducing intraocular virus activity,¹⁴⁹ may reduce the subclinical production of virus or viral proteins that stimulate inflammatory reactions. Furthermore, immune recovery uveitis has been reported to occur less frequently among patients who are treated with anti-CMV drugs for long durations after initiation of potent antiretroviral therapy.^187,197

Treatment of immune recovery uveitis with oral corticosteroids or periocular corticosteroid injections has been successful for reducing macular edema^187,211 and optic disc neovascularization in some patients.²⁰² In one series, nine patients with immune recovery uveitis had persistent cystoid macular edema when treated with oral acetazolamide and topical corticosteroids, but three of these patients improved following periocular corticosteroid injections.¹⁸⁶ Spontaneous improvement in inflammation and vision within 6 weeks has also been reported¹⁹⁸; all these patients were receiving anti-CMV therapy when they developed inflammation. A combination of continued, aggressive anti-CMV therapy and either local or systemic corticosteroid therapy should therefore be considered in patients for whom there is no medical contraindication to use of these drugs and for whom there is no spontaneous improvement in inflammation. However, even aggressive therapy may not be effective, and late complications of persistent immune recovery uveitis, such as posterior synechiae, proliferative vitreoretinopathy, and posterior subcapsular cataracts, may result in severe vision loss.^199,201 Although corticosteroids and chronic inflammation are well-recognized causes of posterior subcapsular cataracts, the mechanisms of other sequelae of immune recovery uveitis remain poorly understood.

OTHER POSTERIOR SEGMENT OPPORTUNISTIC INFECTIONS.

Acute retinal necrosis (ARN) syndrome is a necrotizing retinitis that is also characterized by prominent anterior uveitis, retinal and choroidal occlusive vasculitis, vitreitis, and papillitis.²¹² Varicella-zoster virus is the most frequently identified cause of ARN syndrome, but HSV can cause it as well. ARN syndrome can also occur in immunosuppressed people, although it was initially reported in immunocompetent patients.²¹³ Patients with AIDS and ARN syndrome usually have a CD4+ T-lymphocyte counts higher than 60 cells/μl and a history of dermatomal herpes zoster or HSV dermatitis.²¹⁴ It has occurred in up to 17% of HIV-infected patients following the development of herpes zoster ophthalmicus.²¹⁵ A mild unilateral case of ARN syndrome was reported in an 11-year-old girl with AIDS (CD4+ T-lymphocyte count of 115/μl) after she developed chickenpox.²¹⁶

Diagnosis of ARN syndrome is usually made clinically. Diagnostic criteria for ARN syndrome have been established by the American Uveitis Society.²¹⁷ These criteria are based on the clinical features of the disease and course of infection and do not depend on the patient's immunologic status. The umbrella term necrotizing herpetic retinopathy is recommended when the characteristics of the retinitis do not fit those of a well-defined clinical syndrome. The presence of optic neuritis, scleritis, or pain helps support, but does not establish, a diagnosis of ARN syndrome. In some cases, it may be difficult to distinguish ARN syndrome from CMV retinitis, in which case PCR techniques can be used to test vitreous humor specimens¹³⁹ or endoretinal biopsy specimens obtained at the time of retinal detachment repair¹⁴¹ to determine the causal agent.

Because data regarding treatment are limited in patients with both AIDS and ARN syndrome and because affected patients are usually not profoundly immunosuppressed, therapy is usually based on experience in immunocompetent patients with ARN syndrome. IV acyclovir (500 mg/m² or 10 mg/kg every 8 hours) is usually effective; IV foscarnet may be necessary in acyclovir-resistant cases. IV therapy should be continued until the lesion borders are inactive, after which time oral antiviral therapy (acyclovir 800 mg five times daily, famciclovir 500 mg three times daily, or valacyclovir 1000 mg three times daily) should be used for at least 6 months. Consideration should be given to prophylactic laser retinopexy to reduce the risk of retinal detachment, which can occur in up to two thirds of patients. The benefit of aspirin to treat vasoocclusive and ischemic manifestations of ARN syndrome remains unproved. Although prednisone may reduce the associated vitreous humor inflammation in immunocompetent patients with ARN syndrome,²¹⁴ oral corticosteroids are usually contraindicated in HIV-infected patients who are severely immunosuppressed, to prevent further immunosuppression.

Cunningham and associates¹³⁹ reported two patients with AIDS and HSV retinitis, confirmed by PCR assay. Both patients had rapidly progressive bilateral retinal necrosis associated with intraretinal hemorrhages and diffuse vasculitis. One patient had HSV-1-associated retinitis, characterized primarily by retinal arteriolar involvement, with marked capillary dropout and occlusion of larger arcade vessels. The other patient had HSV-2-associated retinitis, characterized by greater involvement of the retinal veins and an exudative retinal detachment. It remains unclear whether these different findings are related to the two types of HSV or were simply variations in disease presentation related to host or other factors.

Progressive outer retinal necrosis (PORN) syndrome is another variant of necrotizing herpetic retinopathy that occurs in patients with advanced HIV disease. It is nearly always caused by varicella-zoster virus^218,219; although a patient with PORN syndrome caused by HSV-1 has recently been documented.¹⁴² In contrast to ARN syndrome, PORN syndrome is characterized by multifocal lesions, initial involvement of the outer retina, absence of vascular inflammation, minimal or no vitreous inflammation, and extremely rapid progression.²¹⁸ A “cracked mud” perivascular pattern is characteristic, caused by early removal of necrotic debris or edema from retinal tissue adjacent to blood vessels. Lesions may begin peripherally or in the macula. Optic neuropathy may occur early in the disease course and may even precede the retinitis.²²⁰ Early vitreous hemorrhage can occur. As with other ocular opportunistic infections, the frequency of PORN syndrome has declined markedly in patients treated with potent antiretroviral therapy.²²¹

PORN syndrome, like ARN syndrome, is usually diagnosed clinically. Various treatment regimens have been reportedly successful in anecdotal series, including combination IV acyclovir and foscarnet, combination IV ganciclovir and foscarnet, IV foscarnet with placement of a ganciclovir implant, and intravitreous injections of ganciclovir.²²¹ In severely immunosuppressed patients, chronic antiviral therapy is necessary to prevent reactivation of disease^218,222; oral acyclovir is inadequate for this purpose.

In one study, two of six patients with PORN syndrome had simultaneous varicella-zoster virus encephalitis,²²³ emphasizing the importance of systemic therapy in the treatment of the disease. Unfortunately, the prognosis is usually poor even in eyes treated promptly, with two thirds of patients progressing to no light perception vision within 1 month of diagnosis.²¹⁸ Blindness can result from optic nerve disease, macular infection, or retinal detachment. Prophylactic laser retinopexy has been less successful for preventing retinal detachment in patients with PORN syndrome than in patients with ARN syndrome.²¹⁸ Retinal detachment occurs in 70% of patients²¹⁸ and requires vitrectomy and silicon oil tamponade for anatomic repair. Even if the retinitis is initially controlled, recurrence of disease while on maintenance therapy (manifesting as increased border opacification and spread of old lesions or development of new lesions) and development of disease in a previously uninfected eye is common.²²² As with other ocular viral opportunistic infections, the most effective therapy may be recovery of immune function with potent antiretroviral therapy.

Ocular toxoplasmosis has been reported to occur in as many as 3% of people with AIDS in France.²²⁴ The current prevalence of ocular toxoplasmosis among HIV-infected people in the United States is much lower because of potent antiretroviral therapy and widespread use of trimethoprim-sulfamethoxazole for primary prophylaxis of intracranial toxoplasmosis. Holland and associates²²⁵ noted that ocular toxoplasmosis in HIV-infected patients may have different clinical features than in HIV-negative people. Bilateral involvement, absence of preexisting chorioretinal scars, and evidence of systemic toxoplasmosis may be found, suggesting that acquired disease rather than reactivation of congenital infections is relatively more common in HIV-infected people. Atypical presentations of ocular toxoplasmosis, such as miliary disease,²²⁶ optic neuritis,²²⁷ panophthalmitis,²²⁸ and acute unilateral toxoplasmic iridocyclitis in the absence of retinal lesions,²²⁹ have been reported. In one study, 20% of patients with ocular toxoplasmosis developed CMV retinitis during follow-up,²²⁴ and toxoplasmic retinitis can mimic CMV retinitis.¹⁴⁰ The two infections can also occur simultaneously. Prominent vitreous and anterior chamber inflammation; relative absence of retinal hemorrhage; and the presence of a thick, densely opaque lesion with a smooth, nongranular border suggests toxoplasmosis. Serologic tests are usually not helpful for diagnosis, because many HIV-infected people test seropositive for both T. gondii and CMV. False-negative serologic test results for T. gondii infection can occur.^226,228 Endoretinal biopsy¹⁴⁰ or PCR techniques^226,229 may be necessary in some cases to make a definitive diagnosis.

Treatment of ocular toxoplasmosis is similar to that used for toxoplasmosis in immunocompetent patients, except that indefinite maintenance therapy may be necessary to prevent recurrences in persistently immunosuppressed patients and oral corticosteroids are generally contraindicated in persistently immunosuppressed patients.^225,226,228 Pyrimethamine and sulfadiazine are the preferred treatment, with clindamycin used in patients with allergies to sulfonamides. A delay in the initiation of appropriate therapy may result in progressive disease and blindness.^226–228

Various infectious choroidopathies have been reported, albeit infrequently, in HIV-infected patients. The frequency is greater in autopsy than in clinical studies.¹⁴³ Choroidal lesions tend to be localized in the choriocapillaris and are usually multifocal and bilateral. P. carinii pneumonia (PCP) was once the most common opportunistic infection in patients with AIDS. P. carinii choroidopathy has been associated with the use of aerosolized pentamidine as primary prophylaxis against PCP, presumably because it suppresses lung disease locally, but does not prevent dissemination of organisms to other organs.^99,230 Affected people may have evidence of disseminated disease, such as fever, weight loss, and malaise without pulmonary symptoms. Ocular disease is characterized by bilateral multifocal choroidal lesions that do not involve the retina.^230,231 Active lesions are slightly thickened, oval, or lobulated; appear yellow-orange; and range in size from several hundred to several thousand microns in diameter. Vision is not usually affected. No vitreous humor or anterior chamber cells are seen. Treatment with IV trimethoprim-sulfamethoxazole or pentamidine is usually effective. Treated lesions become flat and may regress completely but often leave well-demarcated, nonpigmented, orange scars behind. P. carinii choroidopathy has become rare with the widespread use of trimethoprim-sulfamethoxazole, dapsone, or other systemic agents as primary prophylaxis against PCP.

Cryptococcus neoformans is an uncommon cause of choroidopathy in HIV-infected people.²³² There may be concurrent optic nerve involvement. Carney and associates²³³ suggested that ocular involvement in disseminated cryptococcosis occurs in stages, beginning with choroiditis and/or optic nerve disease and progressing to uveitis, retinitis, and endophthalmitis. IV amphotericin B is the treatment of choice.

Although the risk of tuberculosis is dramatically increased in people with AIDS, and extrapulmonary tuberculosis is more common in HIV-infected people, tuberculous choroidopathy has been reported only rarely.²³⁴ The lesions are usually small, yellow-white infiltrates that may coalesce, and there may be an associated vitreitis. Conversely, some patients present with anterior uveitis or vitreitis, but with apparently healed choroidal lesions, as a result of previous antituberculosis therapy.

Other reported causes of infectious retinopathy or choroidopathy include metastatic bacteria, MAC, B. henselae, Histoplasma capsulatum, Candida sp., and Aspergillus fumigatus. Morinelli and associates^143,232 found that the organism causing infectious choroidopathy was thought to be the cause of death in most of their patients and reported mean survival of only 25 days after identification of choroidal lesions. The ophthalmologist can, therefore, play an important role in helping to diagnose disseminated infection, thereby allowing appropriate therapy to begin as soon as possible.

Although not usually considered an opportunistic infection, syphilis does occur more frequently in HIV-infected people. In one large urban study, approximately 1% of HIV-infected subjects had ocular syphilis.²³⁵ The exchange of drugs for sex and unprotected sexual activity are the major risk factors for the spread of the disease. People with HIV infection are more likely to have contracted syphilis at a less advanced stage of immunosuppression than many other secondary infections,⁹⁹ presumably because of the decline in sexual activity among people with advanced AIDS.

The possibility of syphilis should always be considered in patients presenting with ocular inflammatory disease. As in the pre-AIDS era, iridocyclitis is the most common presentation,^99,235 but retinitis, neuroretinitis, optic neuritis,²³⁶ and scleritis have also been reported.²³⁷ Syphilitic uveitis in HIV-infected people is often associated with neurosyphilis. Treatment with intramuscular penicillin has been associated with persistent infection and relapse of disease²³⁷; IV therapy, similar to that used to treat neurosyphilis, is therefore recommended.^235,237 False-negative serum Venereal Disease Research Laboratories (VDRL) or rapid plasma reagin (RPR) titers have been found in some people who were coinfected with HIV and Treponema pallidum.²³⁷ Thus, results from more specific diagnostic tests (e.g., fluorescent treponemal antibody, absorbed) should also be obtained for diagnosis.

Intraocular inflammation, without identifiable opportunistic infections, and possibly related directly to HIV has been reported. Rosberger and associates²³⁸ reported six patients with anterior uveitis, of whom four patients also had vitreitis. The CD4+ T-lymphocyte counts in the affected patients ranged from 21 to 2118 cells/μl. None of the patients improved with topical corticosteroids, but all responded to zidovudine within 1 month, suggesting that the uveitis might be caused by HIV. Chronic multifocal retinal infiltrates have also been associated with HIV infection in the absence of other opportunistic infections.²³⁹ The CD4+ T-lymphocyte counts have ranged from 7 to 2118 cells/μl in patients with this disorder. The infiltrates have been described as clusters of white lesions smaller than 200 μm, located in the midperipheral and anterior retina; there was vitreitis in 94% and vasculitis in 21% of eyes in the reported series.²³⁹ Bilateral disease was noted in 81% of patients. Nine of the 26 reported patients improved with zidovudine alone, again suggesting a primary HIV-induced inflammation. These two studies were retrospective and the pathogenesis of the findings remains unclear. Clinicians should not attribute uveitis or retinal lesions to HIV infection alone unless other, more common, causes have been ruled out.

ADNEXAL AND OCULAR SURFACE INFECTIONS.

Adnexal and ocular surface infections are uncommon in HIV-infected patients.^97,240 Various viral, bacterial, and fungal pathogens have been reported. The clinician should be aware of the clinical presentation of these infections, which may differ in frequency, appearance, course, and response to treatment from the same infections when they occur in immunocompetent patients.

MCV is a DNA poxvirus that can cause a self-limited follicular conjunctivitis in immunocompetent people. In HIV-infected people, MCV lesions tend to be multiple and more widespread on the body. Lesions may be the classic avascular, waxy, 2 to 3 mm in diameter, umbilicated papules noted in immunocompetent people, but they may also become coalescent or ulcerated. HIV-infected patients with MCV infection usually do not develop irritation, conjunctival injection, or follicles, although lesions near the eyelid margin may cause a mild keratoconjunctivitis.²⁴¹ The differential diagnosis includes bacillary angiomatosis, papilloma, basal cell carcinoma, and disseminated fungal infection. Biopsy will reveal classic eosinophilic cytoplasmic inclusion bodies. Treatment includes surgical excision, chemical cautery, or cryotherapy, but recurrence in 6 to 8 weeks is frequent. Improvement in patients treated with IV cidofovir has been reported.²⁴² Lesions may regress completely in patients with a good response to potent antiretroviral therapy.

C. neoformans may cause eyelid,²⁴³ conjunctiva,^244,245 or iris nodules. Conjunctival cryptococcosis may mimic squamous cell carcinoma clinically but is easily distinguished by biopsy.²⁴⁵ Conjunctival disease may occur simultaneously with choroidal cryptococcosis.²⁴⁴

Corneal microsporidiosis is a rare parasitic disease caused by the genera Encephalitozoon or Septata. It results in chronically red, irritated eyes; decreased vision; and photophobia that results from diffuse, fine corneal epithelial infiltrates. The corneal stroma is spared. Most cases are bilateral. The diagnosis is made by conjunctival scraping or corneal biopsy; examination reveals characteristic gram-positive ovoid organisms within the cytoplasm of epithelial cells but few inflammatory cells. Topical fumagillin appears to be the most effective treatment but must be continued indefinitely.²⁴⁶

HSV keratitis does not appear to be more common in HIV-infected people, although it may be more prolonged and recurrences may be more frequent.²⁴⁷ One study suggested that herpetic dendrites occur more often in the peripheral cornea and that stromal keratitis is less likely in patients with AIDS.²⁴⁸ Treatment with débridement followed by topical trifluridine 1% nine times a day for 10 to 14 days is usually effective. Patients with recurrences may benefit from chronic oral acyclovir (400 mg twice daily) as secondary prophylaxis.

Herpes zoster ophthalmicus may have cutaneous, corneal, and intraocular complications. Corneal manifestations range from punctate epithelial keratitis and stromal or subepithelial infiltrates to severe peripheral ulcerative keratitis and neovascularization.²⁴⁹ Concurrent uveitis and cutaneous lesions are common, and PORN syndrome may develop. In some HIV-infected people, varicella-zoster virus infection of the corneal epithelium can persist for many weeks,²⁵⁰ in contrast to findings in immunocompetent patients with herpes zoster ophthalmicus. The corneal infection responds to topical and systemic antiviral agents.

Patients younger than 45 years who develop herpes zoster ophthalmicus should be considered for HIV testing, particularly in geographic areas with a high prevalence of HIV infection or in patients with known risk factors for HIV infection. In one study from Miami, over half of patients with herpes zoster ophthalmicus younger than 45 years had HIV infection.²¹⁵ When HIV infection is present, there is a higher rate of corneal involvement and postherpetic neuralgia.²⁵¹ Vision loss can result from corneal scarring, exposure keratopathy, or secondary infectious keratitis. In addition, Sellitti and associates²¹⁵ found that 17% of patients with herpes zoster ophthalmicus and HIV infection developed retinitis, most of which was bilateral. Treatment of herpes zoster ophthalmicus in HIV-infected patients should be more aggressive than in immunocompetent patients; IV acyclovir (10 mg/kg every 8 hours) is recommended until the lesions are crusted, followed by prolonged oral antiviral therapy. Anterior uveitis usually responds well to topical corticosteroids. Periodic funduscopic examinations should be performed to detect any herpetic retinopathy and patients should be made aware of symptoms of retinitis.

Fungal and bacterial keratitis has been reported in HIV-infected patients but appears to be uncommon. Atypical pathogens such as C. albicans and Bacillus sp. appear to be disproportionately involved, and multiple organisms may be present.^252,253 Conventional risk factors for infectious keratitis (e.g., contact lens wear, trichiasis, use of topical corticosteroids, and trauma) should be considered, but they may be absent in HIV-infected patients. Keratoconjunctivitis sicca is more common in HIV-infected patients²⁵⁴ and may predispose patients to corneal infection. The use of crack cocaine may cause punctate epithelial keratopathy, sterile corneal epithelial defects, and microbial keratitis (“crack eye syndrome”)²⁵⁵; epithelial defects may be caused by neurotrophic keratitis, direct thermal or chemical toxicity of the alkaline smoke, or eye rubbing.

Treatment of infectious keratitis should be based on results of appropriate cultures and stains, keeping in mind that multiple pathogens may be present. Treatment is often difficult because of poor adherence to treatment recommendation and inconsistent follow-up.

HIV may uncommonly result in diffuse superficial keratitis, herpes-like ulcerations, and interstitial keratitis.²⁵¹ As with posterior segment disease attributed to HIV infection, other causes of keratitis should be ruled out. CMV may cause conjunctivitis. CMV retinitis is often associated with fine, diffuse, pigmented endothelial deposits; the presence of such keratic precipitates, especially in the presence of a mild iritis, is strongly suggestive of posterior segment disease and mandates a dilated funduscopic examination.

NEOPLASMS

KS is the most common ocular tumor in HIV-infected people, but ocular involvement is much less common than extraocular disease. In a study of 200 patients with AIDS seen between 1983 and 1988, only 5 patients had ocular KS.⁹⁷ Up to 20% of patients with KS have ocular involvement, and ocular involvement may be the first manifestation of the disease.²⁵⁶ About 70% of lesions occur on the eyelids, with the conjunctiva affected less frequently.²⁵⁶ Orbital involvement is exceptionally rare. Homosexual men constitute the overwhelming majority of patients with KS. The rate of KS has been declining, which may reflect that homosexual men constitute a smaller portion of cases of AIDS or it may be related to the widespread use of potent antiretroviral therapy.²⁵⁷

Conjunctival lesions can occur on the palpebral or bulbar conjunctiva, but are most common in the inferior fornix (Fig. 4). Bilateral disease is frequent. The tumor spreads slowly and does not involve the cornea or intraocular structures. Lesions are bright to deep red or violaceous and may be mistaken initially for subconjunctival hemorrhages. The differential diagnosis also includes atypical hordeolum, pyogenic granuloma, cavernous hemangioma, and bacillary angiomatosis. Patients are usually asymptomatic or have only mild irritation, although larger lesions and those involving the eyelid margin may cause blurred vision, entropion, or trichiasis.

Symptomatic patients or those who are bothered cosmetically by the lesions usually respond well to various treatments, including chemotherapy (often a combination of doxorubicin, bleomycin, and vincristine); single-dose²⁵⁸ or fractionated radiation therapy²⁵⁹; intralesional IFN-α2a; cryotherapy; or surgical excision.^256,259,260 Local therapy of ocular lesions is necessary only if patients cannot tolerate systemic therapy, have failed to respond to systemic therapy, or have bulky or ocular lesions that need immediate resolution. In some cases, improvement of immune function with potent antiretroviral therapy alone may be sufficient to stabilize KS, without the need for potentially toxic chemotherapy.²⁶⁰ Human herpes virus 8 has recently been identified as the cause of KS.²⁶¹ This finding helps explain why the use of oral ganciclovir as adjunctive therapy to the ganciclovir implant in patients with CMV retinitis reduces the risk of KS compared with findings in patients treated with the ganciclovir implant alone.¹⁴⁹

Squamous cell carcinoma of the conjunctiva, sclera, or eyelid is increasingly common, especially in Africa,²⁶² and ophthalmologists who detect squamous cell carcinoma in a young patient should consider the possibility of HIV infection. In contrast to squamous cell carcinoma in older immunocompetent people, HIV-associated squamous cell carcinoma is usually faster growing and more likely to infiltrate the cornea, sclera, and substantia propria.^262–264 Human papillomavirus may play a permissive role in the development of squamous cell carcinoma in HIV-infected people.²⁶² Fogla and associates²⁶⁵ reported conjunctival squamous cell carcinoma as the presenting sign of HIV-2 infection in one patient.

Treatment of limbal or conjunctival squamous cell carcinoma should involve total excision of the tumor with clear margins and cryotherapy to the underlying sclera. In cases of intraocular extension, exenteration should be performed.^262,265

Lymphoma in HIV-infected patients is an important cause of orbital disease (see later discussion). CNS lymphoma may also be associated with intraocular disease,²⁶⁶ causing bilateral hypopyon²⁶⁷ or retinitis with vitreitis.²⁶⁸

NEURO-OPHTHALMIC DISORDERS

Neuro-ophthalmic disorders in people with AIDS include cranial nerve palsies, abnormal eye movements, visual field defects, papilledema, pupillary abnormalities, cortical blindness, and optic atrophy. The most common causes include cryptococcal meningitis, PML, intracranial toxoplasmosis,²⁶⁹ viral (HIV, CMV, varicella-zoster virus, HSV) encephalopathy, neurosyphilis, and orbital infections or tumors. Magnetic resonance imaging studies, cerebrospinal fluid analysis, and empiric therapy (e.g., for toxoplasmosis) are usually sufficient to distinguish these diseases, but in some cases a definitive diagnosis may be impossible without brain or orbital biopsy.²⁷⁰ Complicating the diagnostic task is the fact that up to one third of those with neurologic abnormalities have more than one coexisting intracranial disease.²⁷¹ Although the published frequency of neuro-ophthalmologic complications based on series from eye clinics is less than 10%,^97,99 underreporting because of dementia or coma that limits complete evaluation is likely. Autopsy studies have shown that 70% to 8% of HIV-infected people have neuropathologic changes. A case of HIV-2-associated uveomeningoencephalitis causing diplopia, decreased vision, and nystagmus has been reported.²⁷²

Papilledema is most commonly caused by cryptococcal meningitis or cerebral toxoplasmosis^97,271 and is often associated with headache. Sixth cranial nerve palsy, causing horizontal diplopia, can occur. Evaluation should include contrast-enhanced computed tomography or magnetic resonance imaging. If scans are normal, lumbar puncture should be performed with appropriate studies to rule out other causes of meningitis, including syphilis, carcinoma, or lymphoma.

Cryptococcal meningitis is the most common cause of neuro-ophthalmic lesions in people with AIDS. Jabs and associates⁹⁷ found that one third of their patients with AIDS and cryptococcal meningitis had neuro-ophthalmic lesions. Vision loss attributable to cryptococcosis can result from direct fungal infiltration of tissues with necrosis, adhesive arachnoiditis, or papilledema. Lipson and associates²⁷³ reported a patient with sudden, severe, bilateral vision loss without papilledema as a result of meningeal infiltration near the optic canals. Kestelyn and associates²⁷⁴ described a series of 80 Africans with AIDS and cryptococcal infection. Papilledema was observed in 26 (32.5%) of the cases, whereas seven people had vision loss and sixth cranial nerve palsy, and only two had optic atrophy. Four also had CMV-related retinitis. Optic neuropathy is caused by extension of cryptococcal infection from the intracranial sites of disease, whereas intraocular infection (most commonly chorioretinitis) is much less common and results from hematogenous spread of the organism.²⁷⁴

PML is an insidious, demyelinating disorder of the CNS caused by infection with a papovavirus designated the JC virus. Up to 4% of people with AIDS are affected. Hemiplegia or hemiparesis and disturbances in speech, gait, and cognitive functions are the most common neurologic signs. Neuro-ophthalmic manifestations occur in the most of those affected; these include progressive retrochiasmal visual field defects, supranuclear and nuclear cranial nerve palsies, occipital blindness, nystagmus, and ataxia.^275,276 Diagnosis is based on characteristic clinical features in the presence of hyperintense white-matter lesions without mass effect on T2-weighted magnetic resonance imaging studies. A PCR test to detect JC virus in the blood and cerebrospinal fluid is now available. Although PML was a preterminal event in the era before potent antiretroviral therapy, with survival of only a few months in most cases, patients may now show stabilization or even improvement of neurologic symptoms, with increased survival, when treated with potent antiretroviral therapy.²⁷⁷

Winward and associates²⁷⁸ have divided HIV-associated optic neuropathies into four categories: (1) optic perineuritis, (2) papillitis, (3) retrobulbar neuritis, and (4) papilledema associated with intracranial hypertension. Perineuritis is characterized by optic disc edema in the presence of normal vision, pupils, and intracranial pressure and is most commonly associated with syphilis. Papillitis is characterized by reduced visual acuity, central scotoma, and an afferent pupillary defect. CMV is the most common cause,¹²⁷ but other infections such as syphilis²³⁶ and necrotizing herpetic retinopathy²¹³ should be considered. Optic neuropathy may be caused by varicella-zoster virus and may precede the development of necrotizing retinopathy.²²⁰ Retrobulbar neuritis may also be caused by syphilis, CMV infection, or cryptococcosis.²⁷⁹ Papilledema may be caused by several infectious or neoplastic processes increase intracranial pressure, the most common being cryptococcal meningitis.

Syphilitic optic neuropathy may take the form of optic neuritis,^236,280 retrobulbar neuritis, neuroretinitis, or optic nerve gumma.²⁸¹ Papilledema caused by concurrent meningitis and increased intracranial pressure may be found. Vision loss may be mild to severe. Treatment with IV penicillin is usually effective.

Optic neuropathy attributed directly to HIV infection has been reported but should be considered a diagnosis of exclusion. Decreased color vision and contrast sensitivity have been noted in HIV-infected patients with normal visual acuity,²⁸² and a pattern of visual field loss consistent with optic nerve disease has also been identified in such patients.²⁸³ It remains unclear whether optic neuropathy in HIV-infected patients is caused by direct HIV infection or by microvascular changes in the optic nerve similar to those affecting the retina or is unrelated to the underlying HIV infection. If infectious, neoplastic, and drug-induced causes of optic neuropathy have been ruled out, systemic corticosteroids may be helpful in some patients.²⁸⁴

Orbital lesions in people with AIDS may cause optic neuropathy, proptosis, or cranial nerve palsies with diplopia. In suspected cases, the clinician should first rule out lymphoma and infections, such as invasive aspergillosis^285,286 arising from the sinuses, which are the two most common causes of orbital lesions. Contrast-enhanced imaging studies and biopsy may be necessary. Malignant non-Hodgkin's lymphoma associated with AIDS tends to be high grade and aggressive.²⁸⁷ Both small, noncleaved (Burkitt's lymphoma) and large cell immunoblastic types of lymphoma have been identified. Orbital involvement is rare.^240,288 Affected patients may have slow onset of mild, unilateral proptosis or a more rapid onset of proptosis and marked eyelid swelling. Computed tomography studies may demonstrate bony erosion and displacement of the globe, which are features not found in cases of orbital non-Hodgkin's lymphoma without HIV infection. Concurrent paranasal sinus, CNS, or intraocular involvement with hypopyon formation²⁶⁷ has been reported. Immunohistochemical staining of biopsy specimens is diagnostic. The development of high-grade non-Hodgkin lymphoma in HIV-infected patients meets the revised U.S. Centers for Disease Control and Prevention criteria for the diagnosis of AIDS.⁹³ The prognosis for people with AIDS-related non-Hodgkin's lymphoma is poor, with a 90% mortality rate at 2 years.

Orbital infections are uncommon and usually result from contiguous sinus involvement in those with advanced HIV disease.²⁸⁵ Clinical findings may be atypical, without impairment of ocular motility or visual acuity.²⁸⁶ Orbital infections may be life threatening. A high index of suspicion should be maintained and prompt diagnostic biopsy undertaken. Orbital cellulitis resulting from extrascleral extension of toxoplasmic panophthalmitis has been reported, although T. gondii organisms were not identified in orbital tissue.²²⁸

OCULAR DRUG TOXICITY

Ocular toxicity from medications used to treat ocular or systemic diseases in patients with HIV infection is uncommon but can threaten vision. IV cidofovir has been associated with the development of a nongranulomatous anterior uveitis in a substantial proportion of patients.²⁰⁹ Cochereau and associates²⁸⁹ examined 16 eyes in 10 patients with cidofovir-associated uveitis. All eyes had inactive CMV retinitis, and all patients were taking protease inhibitors. Those authors found anterior uveitis in all eyes, low intraocular pressure in 94% of eyes, posterior synechiae in 75% of eyes, and vitreitis in 50% of eyes. The finding of posterior synechiae is more common in cidofovir-associated uveitis than in immune recovery uveitis. Hypotony is a poor prognostic sign, and irreversible vision loss can occur in affected patients if cidofovir is continued; however, most patients respond well to treatment with topical corticosteroids and cycloplegic agents, with temporary discontinuation or reduction in the dose of cidofovir. Profound hypotony with ciliary body detachment has been managed with vitrectomy and silicon oil tamponade.²⁹⁰

Rifabutin, a semisynthetic drug related to rifamycin that is used to prevent or treat MAC infections, can cause a fulminant uveitis with hypopyon²⁹¹ that can mimic metastatic bacterial endophthalmitis or human leukocyte antigen HLA-B27-associated anterior uveitis. One or both eyes may be affected. Vitreous humor involvement is usually only mild, and posterior uveitis and chorioretinitis are usually absent. The cause of rifabutin-associated uveitis is unknown, but the concurrent use of fluconazole or clarithromycin, which elevate serum rifabutin levels, appears to be a risk factor. Diagnosis is based on the history, clinical findings, and a negative workup for other causes, including infections. The uveitis usually responds quickly to cessation of the drug and the use of intensive topical corticosteroid therapy and cycloplegic agents. Because other drugs are also effective for preventing or treating MAC infections, rifabutin is no longer commonly used.

Intravitreous injections of fomivirsen can cause uveitis, glaucoma, and RPE damage, with nyctalopia and permanent visual field loss.²⁹² Vision-limiting complications are uncommon at currently used doses.

Other drug-induced ocular complications include ethambutol-induced optic neuropathy⁹⁷ and peripheral pigmented lesions of the retina caused by didanosine.²⁹³ Possible drug-induced phospholipidosis of the cornea, resembling microsporidial keratoconjunctivitis, has been reported in patients being treated for AIDS-related opportunistic infections.²⁹⁴ Findings resolved with reduction in dosage of acyclovir and ganciclovir, but the role of these drugs in the pathogenesis of the keratopathy could not be confirmed. These patients were seen before the introduction of potent antiretroviral therapies.

IATROGENIC IMMUNOSUPPRESSION

Patients who receive radiation therapy or immunosuppressive drug treatment for neoplasia or prevention of allograft rejection are at risk for development of many of the infections that occur in patients with AIDS.

ORGAN TRANSPLANTATION AND OCULAR COMPLICATIONS

Before the AIDS epidemic, renal transplant recipients were the most common group to develop CMV retinitis.^124,295 The prevalence of this infection is much lower in allograft recipients, however, than among people with AIDS; the reported rate has been between 0.6%; and 3.4% in renal, liver, and heart transplant recipients.^296–298 Infection is most common among those with prolonged CMV viremia.²⁹⁹ In these people, the most effective treatment for CMV infection is to stop or reduce the dose of immunosuppressive drugs that are being administered. The current frequency of opportunistic infections in transplant patients may be lower than previously reported because more selective immunosuppressive therapy is now used to prevent allograft rejections. There has been an overall drop in the rate of CMV infections in cardiac transplant recipients during the 2 months after surgery from 15% in patients receiving azathioprine and prednisone to 3% in patients receiving cyclosporine.³⁰⁰

Other disseminated infections with ocular involvement after organ transplantation have been reported more rarely. Ocular infections after organ transplantation have included HSV retinitis³⁰¹; H. capsulatum infection of the choroid³⁰²; Aspergillus sp. endophthalmitis^297,303,304; cryptococcal choroiditis^305,306; Pseudallescheria boydii endophthalmitis³⁰⁷; severe, necrotizing T. gondii retinochoroiditis³⁰⁸; candidal chorioretinitis; HSV keratitis; and varicella-zoster virus panophthalmitis.²⁹⁷

People who have undergone organ transplantation may have other ocular complications. Diabetic retinopathy and vascular occlusions are seen but are related to the underlying disease rather than immunosuppression.³⁰⁹ Cataract formation probably relates to corticosteroid use,^296,309 although some investigators have considered that corticosteroids alone are not responsible.³¹⁰

Posttransplantation lymphoproliferative disorder (PTLD) is found in 2% to 3% of patients who have undergone solid organ transplantation and it may have ocular manifestations. PTLD is thought to be caused by the host's inability to regulate abnormal proliferation of lymphoid tissue, stimulated by Epstein-Barr virus infection. Manifestations can range from mild polyclonal proliferation of lymphocytes to malignant lymphoma. Cho and associates³¹¹ reviewed the ophthalmic manifestations of several children with PTLD who developed ocular lesions. They included iris nodules; chronic, low-grade anterior chamber cellular reactions; and subretinal mass lesions. PTLD can respond to reduction of immunosuppressive drug therapy and possibly to acyclovir or other antiviral agents, in some cases.

OPPORTUNISTIC INFECTIONS IN HEMATOLOGIC MALIGNANCIES

CMV retinitis has been associated with both Hodgkin's disease and non-Hodgkin's lymphoma and may be difficult to discriminate from intraocular lymphoma in some cases.^312,313 CMV retinitis has been confirmed by PCR techniques in patients with both Hodgkin's disease³¹³ and non-Hodgkin's lymphoma.³¹⁴ Although the retinal findings may be typical for CMV retinitis, as seen in other diseases,³¹⁵ an atypical presentation suggestive of bilateral ARN syndrome may occur.³¹⁴ Initial treatment for CMV retinitis is identical to that described for other immunosuppressed patients. If, however, patients respond successfully to chemotherapy for the hematologic malignancy and it can be discontinued, maintenance therapy may not be necessary, and the retinitis may remain inactive without further antiretroviral therapy after immune function improves.³¹⁵

Necrotizing herpetic retinopathy has been reported in a patient with Richter's syndrome undergoing chemotherapy.³¹⁶ Richter's syndrome is an aggressive malignant lymphomatous transformation in a patient with chronic lymphocytic leukemia (Fig. 5). DNA from HSV, varicella-zoster virus, and CMV was identified in vitreous humor by PCR techniques. It is possible that the viral DNA was present in leukocytes associated with the inflammatory response, and that the immunodeficient state allowed increased viral replication without all three viruses necessarily being involved in the retinal necrosis. The retinopathy responded to IV ganciclovir.

Other opportunistic infections have been reported rarely in patients being treated with chemotherapy or radiation therapy for hematologic malignancies. A Nocardia sp. choroidal abscess was reported in one patient with chronic lymphocytic leukemia³¹⁷ and candidal keratitis leading to endophthalmitis in another.³¹⁸ A patient undergoingchemotherapy for acute myeloid leukemia developed an A. fumigatus endophthalmitis.³¹⁹

TOXOPLASMOSIS AND IMMUNOSUPPRESSION

Patients receiving immunosuppressive therapy have developed severe multifocal or diffuse forms of ocular toxoplasmosis in rare cases. Nicholson and Wolchok³²⁰ reported a woman with a lymphoproliferative disorder of unknown type who developed widespread bilateral retinal necrosis while receiving prolonged systemic corticosteroid therapy. Early lesions were primarily perivascular in location, suggesting that organisms reached the eye through the bloodstream. Hoerni and associates³²¹ reported two patients with Hodgkin's disease who developed focal inflammatory chorioretinal lesions consistent with T. gondii infection after being treated with chemotherapeutic agents. Yeo and associates³²² reported a patient with lymphoma treated by irradiation and chemotherapy who developed a focal retinochoroidal lesion in one eye that spread to involve the entire posterior pole. As in many people with AIDS who develop ocular toxoplasmosis, none of these people had pre-existing retinochoroidal scars. They probably had new ocular infections, in contrast to most patients with active ocular toxoplasmosis who are believed to have reactivation of encysted organisms that remain in retinochoroidal scars.

It is well-known that treatment of recurrent ocular toxoplasmosis with corticosteroid therapy alone may increase the severity of the infection. There is little evidence, however, that immunosuppression will cause reactivation of disease in a patient with retinochoroidal scars.³²³ Studies in a nonhuman primate model suggest that cellular immunodeficiency alone cannot reactivate encysted organisms in the eye.³²⁴ If organisms are acquired; newly disseminated to the eye; or reactivated by other, as yet undetermined, factors, immunosuppression may then allow proliferation of trophozoites with development of severe disease.

GRAFT-VERSUS-HOST DISEASE

BMT from an allogeneic (or syngeneic monozygotic twin) donor is an accepted therapy for aplastic anemia, for many lymphohematopoietic neoplasms (e.g., acute myelogenous leukemia and acute lymphocytic leukemia), and for some primary immunodeficiencies. Despite the fact that most patients receive bone marrow grafts from donors matched at the major histocompatibility loci, many develop graft-versus-host disease (GVHD), a serious and sometimes fatal complication that occurs when immunocompetent cells derived from the bone marrow donor attack the new host's skin, GI tract, liver, and other tissues that can include the ocular surface.^325,326 Ocular problems often resolve with improvement or resolution of GVHD. GVHD also can occur in patients with combined immunodeficiency who receive blood transfusions, unless the blood is irradiated before infusion. Patients with GVHD have profound defects in immune function.

Acute GVHD occurs in the early weeks following BMT. It is characterized by a maculopapular skin rash, hepatic cholestasis, and diarrhea. Chronic GVHD generally occurs 100 days or more after BMT and can occur either de novo or following a protracted period of acute GVHD. Manifestations include sclerodermatoid or lichenoid skin involvement; myositis and fasciitis resulting in contractures; oral disease (inflammatory mucositis or fibrosing sialoadenitis resembling Sjögren's syndrome); and liver disease with elevated levels of alkaline phosphatase, transaminases, and bilirubin.

Ocular disorders associated with GVHD include conjunctival GVHD, dry eyes, opportunistic infections, cataracts, microvasculopathy, retinal hemorrhages, and drug toxicity. The ocular involvement that occurs with acute GVHD can be classified according to the nature and severity of conjunctival and corneal changes³²⁷ (Table 3). Stage 1 disease may resolve without sequelae. Stage 2 or higher is seen in 12% of patients with acute GVHD and is associated with more severe systemic disease and a poor prognosis.

Table 3. Classification System for Ocular Involvement in Graft-Versus-Host Disease

  Stage 1. Conjunctival hyperemia only.
  Stage 2. Chemosis or serosanguinous exudation.
  Stage 3. Peudomembranous conjunctivits.
  Stage 4. Corneal epithelial sloughing.

Ocular involvement occurred in 11% of patients with chronic GVHD in one series.³²⁷ The ocular disorders associated with GVHD include opportunistic infections, but not all disorders can be attributed to infection. Both prospective and retrospective studies of ocular complications after BMT have revealed the most common ocular finding to be keratoconjunctivitis sicca.^328,329 A prospective study of 45 patients who underwent BMT revealed that profound dry eye syndrome and associated keratinization of the ocular surface was related to acute GVHD.³²⁹ It has been postulated that lacrimal gland stasis is the cause of dry eyes in acute GVHD³³⁰ (Fig. 6), whereas an inflammatory infiltrate may be seen in chronic disease.³³¹ Most cases of sicca syndrome respond well to topical lubricants, punctal occlusion, or tarsorrhaphy.

Course epitheliopathies, persistent epithelial defects, and sloughing of the corneal epithelium are sometimes erroneously assumed to be manifestations of dry eyes in patients with GVHD. These changes can occur even in the absence of dryness and are thought to be a direct result of GVHD (Fig. 7). Patients with sloughing of the corneal epithelium may respond to soft contact lens wear, conjunctival flaps, or conjunctival homografts. Topical cyclosporine³³² was thought to be useful in five patients, and topical retinoic acid³³³ in one patient with ocular manifestations of GVHD, but there have been no controlled studies to confirm these effects.

Ocular infections with bacteria after BMT are uncommon, perhaps in part because of routine, intensive antibiotic use when there is any evidence of infection after the procedure. Fungal endophthalmitis was found after BMT in only 1.5% of patients in one report; viral (CMV or varicella-zoster virus) or toxoplasmic retinochoroiditis was even less common.³³⁴ Fungal infections tend to occur in the first 4 months after BMT, whereas viral and parasitic infections occur later.³³⁴ Intraocular infections may have atypical features, and vitreous or endoretinal biopsy may be necessary to make a definitive diagnosis.³³⁴ Early relapse of leukemia may simulate fungal endophthalmitis.³³⁴

Cataracts develop in 10% to 23% of patients after BMT.^335–338 Even though GVHD alone may be a risk factor for cataract formation, the medications used in conjunction with BMT, in particular corticosteroids, as well as total body irradiation, are probably more important factors.^336–338 The use of fractionated total body irradiation has markedly reduced the frequency of cataracts after BMT.³³⁷

An occlusive retinal microvasculopathy has been described in 4% to 10% of patients after BMT.^326,334,339 It appears to be more common in patients treated for leukemia, and there have been suggestions that it may be related to the use of total body irradiation, cyclosporine, or cytarabine hydrochloride; in one series, however, it was related most strongly with GVHD.^334,339,340 Optic disc edema may be seen after BMT and has been thought to be an idiosyncratic reaction to cyclosporine use in some cases.³⁴¹ Other causes of optic disc edema, such as meningitis, intracerebral hemorrhage, and relapse of leukemia in the CNS should be considered in the differential diagnosis.

Other ocular findings of GVHD include cicatricial lagophthalmos, ectropion following lichenification of the skin of the eyelids, pseudomembranous conjunctivitis (see Fig. 7), corneal ulcers, iritis, and histologic evidence of choroiditis.^328,329,342 Subconjunctival, retinal, and vitreous hemorrhage may occur early in the posttransplant period, as a result of induced bone marrow aplasia, but the risk of vision loss is low.³³⁴

Ocular problems do not usually develop in patients who survive BMT without developing severe GVHD, but patients with chronic GVHD and dry eye have a low probability of recovery of normal tear function.³²⁹ Continued treatment of dry eye is therefore usually necessary.

Ophthalmic disorders in patients with immunodeficiency diseases, like other manifestations of these syndromes, fall into five categories: (1) opportunistic infections, (2) neoplasms, (3) disorders related to the primary disease but not a result of the immunodeficient state per se, (4) autoimmune disease, and (5) complications (usually infections) arising from treatment of the primary disorder. Opportunistic infections are the most serious complications. Some are specific for a given immunodeficiency disease, but, in most cases, opportunistic infections are common to several syndromes. The common predisposing immune functional defect in these syndromes usually is not known. It is hoped that advances in the study of immunogenetics may provide a better understanding of these defects.

The eyelids and ocular surface are the most common sites for development of ophthalmic infections. In a mixed group of patients with various immunodeficiency diseases, Friedlaender and associates³⁶ found that the rate of ocular surface infection was increased when compared with findings in a control population but that the flora did not differ between groups. The most common pathogen was S. aureus. Blepharitis was more common among patients with predominantly B-lymphocyte disorders than in patients with predominantly T-lymphocyte disorders. Many patients had positive cultures but no evidence of disease, indicating the importance of natural, nonspecific defenses, such as an intact epithelium, for prevention of ocular infections. With the eye's unique anatomic and physiologic features, ocular infections will not necessarily parallel their nonocular counterparts in spectrum or frequency.

There is a definite association between certain ocular infections and immunosuppression; CMV retinitis, for example, is not seen in immunocompetent hosts. It is often stated that certain other infections, such as C. albicans chorioretinitis and HSV retinitis, are also causally associated with immunosuppression, but there has been little substantiation for these claims. It has not been well established that these infections occur at higher rates in immunodeficient patients than in immunocompetent patients in the absence of other risk factors. Host defenses against Candida sp. infections involve a complex interaction between cellular and humoral immune mechanisms, but the influence of immunosuppression on the development of candidal chorioretinitis remains poorly understood. Neutrophils from patients receiving immunosuppressive drugs for malignancy or after organ transplantation have impaired candidacidal activity.⁴⁹ In vitro studies show that hydrocortisone does not alter neutrophilic fungicidal activity.⁴⁹ Immunodeficiency or previous use of immunosuppressive drugs, however, have not been among the prominent predisposing factors for intraocular candidal infections in most reported series. Among 38 patients with candidemia studied by Parke and associates,³⁴³ none who developed candidal endophthalmitis had received immunosuppressive drugs and only one had received systemic corticosteroids. Conversely, of those who did not develop eye disease, 29% had received systemic corticosteroids and 18% had received immunosuppressive drugs. Only one of six patients with candidal chorioretinitis observed by Griffin and associates³⁴⁴ had received systemic corticosteroids. In the review of 76 cases of candidal chorioretinitis by Edwards and coworkers,³⁴⁵ only 8%; were known to have received immunosuppressive drugs; only 54%; were known to have received corticosteroids, and in many cases their use followed the development of infection. In contrast, Donahue and associates³⁴⁶ performed a prospective study of 118 patients with candidemia, in which 9.3% had chorioretinitis. Immunosuppression, defined as neutropenia, history of organ transplantation, use of corticosteroids, or use of cancer chemotherapy, was present in 10 (91%) of 11 patients with chorioretinitis but was present in only 40 (48%) of 83 patients without chorioretinitis, which was a statistically significant difference. Neutropenia and diabetes mellitus were not risk factors for the development of candidal chorioretinitis. The patients were not further stratified by immunosuppressive and other risk factors, however. It is likely that candidal chorioretinitis develops only in patients predisposed to candidemia by GI surgery, prolonged broad-spectrum antibiotic use, seeding of the bloodstream by IV drug use or indwelling IV catheters, or other factors that broach natural defenses and allow fungi access to vascular spaces. If fungi reach the eye in these cases, immunosuppression may facilitate the development of severe infection. Immunosuppression alone, however, probably does not increase substantially the risk of fungi reaching the eye through the bloodstream, even if there is extensive mucocutaneous disease. Thus, as the use of immunosuppressive drugs becomes more widespread, and as prophylactic antifungal treatment of patients with candidemia becomes more common, immunosuppressed patients may constitute an increasing proportion of patients with candidal chorioretinitis, as in the series reported by Donahue and associates,³⁴⁶ even though immunosuppression was not the factor precipitating infection.

Severe localized and disseminated HSV infections occur in patients with certain primary (Wiskott-Aldrich syndrome, atopic eczema) and acquired (burns, malnutrition, measles, immunosuppressive drugs) immunodeficiency states.^347–349 The immunologic defect common to these various disorders is not known. Herpetic keratitis in patients with Wiskott-Aldrich syndrome and atopic eczema may be severe and prolonged.⁶ HSV keratitis also has been reported in patients on immunosuppressive drug therapy after renal transplantation,⁶ but whether its frequency in this group is higher than in the general population is not known. Conversely, although ARN syndrome caused by HSV has occurred in patients receiving immunosuppressive drug therapy,³⁰¹ it has more often been reported in patients without well-established immunodeficiency syndromes. Inapparent alterations in immune function cannot be ruled out as an underlying factor common to all patients, but it is possible that host resistance and susceptibility to herpetic retinal infection may exist at the cellular level, unrelated to the immune response.³⁵⁰ When infections do become established, by whatever predisposing factors may be present, it can be anticipated that they will be more severe and more difficult to treat in an immunodeficient patient.

Neoplasms, especially lymphoproliferative disorders, are common in immunodeficient patients. There is an unusually high proportion of B-cell lymphomas among lymphoreticular malignancies in patients with primary immunodeficiencies, as opposed to unselected populations. There have been several proposed mechanisms for this association. It may be attributable to chromosomal instability, related to the underlying genetic defect in primary immunodeficiency diseases. Other possibilities include defective immunologic surveillance, defective immune response to oncogenic viruses (such as Epstein-Barr virus), or chronic overstimulation and proliferation of responsive cells to antigens. As previously mentioned, recent evidence suggests that KS is caused by human herpes virus, type 8.

Some ophthalmic disorders that occur in association with immunodeficiency states appear to be independent effects of the same common cause, although the mechanisms by which the ophthalmic disorders develop are obscure. Examples include the vascular changes and neuro-ophthalmic abnormalities of ataxia-telangiectasia, the oculocutaneous albinism of Chédiak-Higashi syndrome, and possibly the fundus lesions of CGD. Although these findings are not the result of opportunistic infections, they help to identify and categorize the patient's immunologic disorder. Careful examination of the eye, even in the absence of symptoms, is therefore warranted to assist in diagnosis.

Autoimmune disorders including Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and possibly retinal vasculitis have been associated with immunodeficiency syndromes but are not specific for any one disease. Not only are these autoimmune disorders important clinically but they may also give clues to the nature of autoimmune disease and immunoregulation.

Many of the published associations between ocular disorders and immunodeficiency diseases have been anecdotal. The presence of eye lesions in isolated cases does not prove causation; they may be related as much to treatment of the primary disease (unique exposures to pathogens by indwelling catheters, invasive procedures, or broad-spectrum antibiotics) as they are to the immunodeficient state itself. Other rare associations may simply be incidental.

There are several principles to be considered in the ophthalmic care of patients with immunodeficiency diseases. Infections should be identified early, because they will be difficult to manage in the absence of normal host defenses. Care must be taken to avoid factors that might increase the risk of infection, such as damage to the corneal epithelial barrier by trichiasis or dry eyes or by contaminated IV catheters that give rise to fungemia.

Infections should be treated early and aggressively with narrow-spectrum antibiotics based on sensitivity testing to avoid selection of resistant organisms or fungal pathogens.⁹ For the same reason, prophylactic antibiotic use is not warranted in most cases.

Patients may require prolonged therapy for control of infection. If therapy is stopped or interrupted, patients should be observed closely for signs indicating reactivation of infection. Chronic suppressive therapy may be needed for established infections.

The AIDS epidemic has provided a unique opportunity to study the relationship between ocular disease and immune function. The ophthalmic manifestations of other rare immunodeficiency disorders will be more difficult to establish. It is apparent, however, that the eye is at increased risk in patients with altered immune function and should be given special attention.

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