Infectious agents may be carried from elsewhere in the body and cause one or more foci of infection in the retina and less often in the choroid in one or both eyes. If treated early with specific antibiotics, the ocular damage may be minimized ( Figure 10.01 ). Infectious diseases can be caused by bacteria, fungi, viruses, and parasites. They can involve both the retina and the choroid. Certain agents can contiguously spread to the vitreous cavity causing endophthalmitis, while certain others are limited to the retina and choroid. In some instances when bacteria and fungi gain entrance into the vitreous, either endogenously or exogenously, vitritis with or without periphlebitis may be the earliest sign of an endophthalmitis.
Septic emboli containing bacteria derived from focal areas of infection such as diseased heart valves, or focal abscesses involving the teeth, skin, or other organs, may lodge in the retina and produce focal white areas of retinitis and overlying vitritis ( Figures 10.01 and 10.02 ). These may be accompanied by white-centered hemorrhages ( Figures 10.01 , B; 10.02 , E). Less frequently the septic emboli lodge in the choroid and may produce a subretinal abscess (see Figure 10.03 , A–C). Most patients with bacterial retinitis will have signs and symptoms of systemic illness, including fever, chills, elevated white blood cell counts, petechiae, splinter hemorrhages of the nail bed, and physical findings pointing to the primary site of the infection. Roth described white retinal lesions and separate hemorrhages in patients with sepsis. Litten described white-centered hemorrhages in patients with endocarditis and called them ‘Roth’s spots’. The white center may contain organisms, although most are sterile and are composed of white blood cells. In many instances the white center is composed of fibrin occurring at the site of extravasation of blood from the retinal blood vessels. Roth’s spots occur most frequently in patients with severe anemia from any cause, including leukemia and subacute bacterial endocarditis. If bacterial sepsis is suspected, prompt medical evaluation, including blood cultures, a search for the primary site of the infection, and institution of antibiotic therapy, may succeed in preservation of useful vision in some patients ( Figure 10.01 ). Overt endoph-thalmitis may require pars plana vitrectomy in addition to intravenous therapy if progression occurs. The majority of patients with metastatic bacterial retinitis are already hospitalized for their systemic illness, but a high index of suspicion is necessary to detect those who are ambulatory with evidence of disseminated sepsis in their eyes.
Focal Indolent Metastatic Bacterial Retinitis in Acquired Immune Deficiency Syndrome (AIDS)
Patients with AIDS may develop multifocal, discrete, yellow–white patches of bacterial retinitis that enlarge slowly over weeks, and accumulate large amounts of subretinal fluid and fibrinous exudate with minimal inflammatory cell reaction in the overlying vitreous ( Figure 10.01 , G–L). This form of indolent bacterial retinitis is caused by relatively nonpathogenic bacteria, such as Rhinococcus equi and Bartonella (see discussion of cat-scratch disease in the next section), that usually respond to oral doxycycline. In immunosuppressed patients the retinal lesions may be mistaken for the more frequently encountered retinal infections caused by Herpes viruses, Candida , Cryptococcus , and Toxoplasma organisms.
Nocardia asteroides is a gram-positive filamentous bacterium found in soil and decaying vegetable matter that shares some features with fungi. It is an opportunistic pathogen known to affect the retina and choroid in a small number of solid organ transplant recipients. N. asteroides accounts for 80–90% of human infections, followed by N. brasiliensis , N. farcinica , and N. nova . The infection is generally disseminated with abscesses involving the lung, brain, skin, eye, and other sites. It begins as a solitary subretinal or choroidal yellow lesion that grows in size with new satellite lesions appearing over days (Figure 10.03 D and I). Overlying retinal hemorrhages are seen ( Figure 10.03 , D–H). Diagnosis is based on demonstrating the organism by a transvitreal fine needle retinal biopsy, blood cultures, or biopsy of any other affected site. Ring lesions are quite characteristic of Nocarida on MRI (Figure 10.03 J). The organism is a gram-positive branching hypha. Treatment consists of reduction or discontinuation of immunosuppressives and institution of appropriate antibiotics/a such as trimethoprim–sulfamethoxazole, amoxicillin–clavulanate, imipenem–cilastatin, cefotaxime, clarithromycin, and ciprofloxacin.
Cat-scratch disease (CSD) classically is described as tender regional lymphadenopathy developing in association with a primary skin lesion received as a result of contact with cats, termed Parinaud’s oculoglandular fever. This may be accompanied by generalized ache, malaise, anorexia, and occasionally fever. Whereas a scratch is the common mode of transmission of CSD, it may be transmitted by cat bites, licking, or handling of objects associated with cats, particularly kittens. CSD is caused by a pleomorphic gram-negative bacillus, referred to previously as the English–Wear bacillus, the Rochalimaea bacillus, and recently Bartonella. It is a worldwide zoonotic disease; the cat flea Ctenocephalides felis is the transmission vector between cats. Twenty-one species of Bartonella have been identified either by culture or polymerase chain reaction (PCR), eight of which are known to cause human disease including CSD, trench fever, endocarditis, myocarditis, Oroya fever (Carrion’s disease), and retinitis. Bartonella henselae , B. quintana , B. elizabethae , and B. grahamii cause ocular lesions. The focal white retinal lesions may occur anywhere in the fundus but have some predilection to occur adjacent to and obstruct major retinal arteries and, less often, veins ( Figure 10.04 , A–H).
These retinal lesions, as well as similar lesions involving the optic nerve head, may be associated with an angiomatous proliferation of capillaries ( Figure 10.04 , I–L). The white lesions typically involve the inner half of the retina and may or may not be associated with overlying vitreous cells. They may simulate cotton-wool ischemic spots, but their distribution in the fundus is not necessarily associated with the distribution of a first-order arteriole as is the case with cotton-wool spots.
The focal white retinal and optic disc lesions, swelling of the optic disc, and macular star figure typically clear spontaneously within several weeks or months and the visual acuity usually returns to normal or near normal. Most of the retinal lesions resolve without causing retinal pigment epithelium (RPE) damage. In 1977 and 1987 the author noted the association of CSD in patients with Leber’s stellate neuroretinitis and multifocal retinitis, and this relationship has been documented by several subsequent reports ( Figure 10.05 , A–I). CSD is probably an important, but not the only, cause of the clinical syndrome of self-limited acute idiopathic multifocal retinitis and neuroretinitis ( Figure 10.05 , A–F) (see Leber’s idiopathic stellate neuroretinitis, Chapter 15, p. 000). Occasionally severe occlusive vasculitis with involvement of both arteries and veins can be seen. A case of unilateral elevated intraocular pressure associated with anterior synechiae secondary to possible involvement of the angle structures from CSD has been documented. Isolated optic disc neovascularization without evidence of retinal ischemia in one patient hypothesizes the predilection of the bacillus to multiply in vascular endothelium and result in inflammatory neovascularization.
The CSD bacillus may also cause acute encephalopathy and other neurologic and systemic manifestations in otherwise healthy patients and in patients with AIDS. Ocular and central nervous system (CNS) involvement typically occurs in children or young adults. Patients with CNS involvement may manifest convulsions and fever in approximately 50% of cases and neuroretinitis in 10–15% of cases. Spontaneous recovery of vision and neurologic deficits occurs in nearly all cases, usually within 3 months. Biopsy of enlarged lymph nodes may reveal evidence of the infection. The bacillus may be demonstrated by the Warthin–Starry stain or culture from skin or lymph node specimens. Detection of antibodies to the cat-scratch bacillus is helpful in the diagnosis. The indirect fluorescent antibody assay for Bartonella henselae and B. quintana , available through the Centers for Disease Control and Prevention (CDC) in Atlanta, is sensitive for the diagnosis of CSD. The favorable prognosis without treatment makes evaluation of treatment with doxycycline, ciprofloxacin, and prednisone difficult.
The tendency for some of the retinal and optic nerve inflammatory lesions to appear very vascular bio-microscopically and angiographically may be an important feature of cat-scratch infection ( Figure 10.04 , J–L). Angioma like masses referred to as epithelioid angiomatosis and caused by the cat-scratch bacillus have occurred on the skin and mucous membranes of patients with AIDS. In these patients the lesions may appear clinically similar to Kaposi’s sarcoma. In the eye the lesions may simulate capillary angiomas or astrocytic hamartomas of the retina ( Figure 10.04 , I–L). Treatment is indicated only for those with significant loss of vision or when associated with the immunocompromised state as in patients with AIDS. The organism is susceptible to several antibiotics including trimethoprim and sulfamethoxazole, rifampin (rifampicin), azithromycin, doxycycline, ciprofloxacin and others.
Lyme borreliosis is a tick-transmitted disorder caused by the spirochete Borrelia burgdorferi carried by the Ixodes tick. The clinical course is believed to occur in three stages: early, disseminated and chronic. This disorder usually begins with a characteristic expanding red maculopapular annular skin lesion. After several weeks the organism may spread systemically and be associated with secondary annular skin lesions, meningitis, cranial or peripheral neuritis, migratory musculoskeletal pain, and carditis. The early and disseminated stages are caused directly by the organisms. The patient often does not recall a tick bite. Months to years later, intermittent or chronic arthritis, or chronic neurologic or skin abnormalities may develop. The chronic stage is immunologically mediated with deposition of immune complexes.
A miscellaneous group of fundus pictures – including pars planitis, retinal vasculitis, bilateral diffuse choroiditis, acute posterior multifocal placoid pigment epitheliopathy, macular edema, papilledema, and Leber’s stellate neuropathy, cranial nerve palsies (specifically abducens nerve), and optic neuritis – have been reported in patients with systemic illness and serologic evidence of previous exposure to B. burgdorferi . Often the VI nerve palsy is secondary to raised intracranial pressure; however, isolated involvement without evidence of intracranial hypertension is seen occasionally. Keratitis, conjunctivitis, episcleritis, posterior scleritis, and anterior uveitis are other ocular manifestations. Only pars planitis associated with snow-bank exudates, and anterior uveitis, however, have occurred with sufficient frequency to suggest a significant relationship to Lyme disease ( Figure 10.06 , A–F). Ocular involvement in systemic borreliosis is not very common, the incidence being approximately 1–4%. Treatment is with oral doxycycline or intravenous ceftriaxone for 2–3 weeks in addition to corticosteroids.
Ocular leptospirosis can present in both the infective and immunologic stage of systemic leptospirosis. A majority of cases present as acute or subacute anterior nongranulomatous uveitis or panuveitis. The onset and severity are variable and do not correlate with systemic severity. The ocular features can appear several weeks after the systemic illness, hence the difficulty and delay in diagnosis. Unless one has a high index of suspicion it is often misdiagnosed as idiopathic uveitis. Panuveitis is usually severe, acute, and relapsing, and is characterized by membranous vitritis and vasculitis, mostly affecting the veins. Retinal vascular occlusion and neovascularization are rare. Vitreous inflammation is fibrinoid with clumps of vitreous cells often arranged in a string of pearls similar to Candida vitritis ( Figure 10.06 , G). It is often mistaken for endophthalmitis. Retinal and choroidal infiltrative involvement or exudative retinal detachment is not seen. Optic neuritis and neuroretinitis can be seen. Anterior uveitis can be insidious, unilateral, or bilateral, and may recur. Occasionally hypopyon is seen in the anterior chamber ( Figure 10.06 , H).
Systemic leptospirosis is a zoonotic systemic infectious disease caused by a spirochete Leptospira . It is a febrile illness associated with jaundice, hemorrhages, and renal failure. This clinical picture was first described in 1886 by Adolf Weil, hence the name Weil’s disease. Although rats are the common reservoir, mice, cattle, pigs, dogs, and other wild animals can also harbor the organism. The urine of the infected host transmits the bacteria. The organisms can live in alkaline soil and water for a few weeks. Leptospira enters the body through broken skin and mucous membrane. Multiplication and hematogenous spread results in the involvement of various organs. The severity of the disease is highly variable from mild to fatal disease. Jaundice due to hepatic involvement is seen in 10–15%; renal involvement with renal failure is the cause of death in most fatal cases. Intense headache, myalgia, muscle tenderness involving the calves and the lumbar region, icterus, meningeal irritation, delirium/psychosis, anuria or oliguria, multiorgan hemorrhages, and cardiac arrhythmia or failure can all be presenting signs. This clinical picture can mimic other infectious fevers seen in the tropics such as influenza, dengue, malaria, typhoid, viral hepatitis, rickettsial disease, meningitis, relapsing fever, and encephalitis.
The diagnosis can be confirmed by the microscopic agglutination test (MAT) for leptospirosis or by PCR of aqueous or vitreous fluid. Clinically the disease has to be differentiated from other causes of nongranulomatous anterior uveitis, endophthalmitis, Behçet’s disease, sarcoid, and candidiasis. Leptospirosis can be seen worldwide though it is more common in the tropics. Ocular involvement varies from 3% to 92% in the tropics, 10–44% in Europe, and 2% in the United States.
Treatment of the systemic illness in its acute stage involves the use of antibiotics such as penicillin, amoxicillin, doxycycline, or ceftriaxone. The uveitis is treated by topical, sub-Tenon, or oral steroids depending on the extent of involvement and cycloplegics.
Many different fundus lesions have been described in congenital and acquired syphilis ( Figures 10.07–10.11 ). Salt-and-pepper changes affecting primarily the peripheral retina are the most frequent alterations described with congenital syphilis. Severe involvement of the ocular fundus, however, may occur and produce a picture simulating retinitis pigmentosa ( Figure 10.11 , E and F). In acquired syphilis, particularly in patients with secondary syphilis, several acute fundoscopic pictures should suggest the possibility of syphilis. Secondary syphilis occurs 6 weeks to 6 months after the primary inoculation, which particularly in homosexuals may be overlooked. During the secondary stage of syphilis there is widespread dissemination of the spirochetes, and the patient often experiences malaise, fever, hair loss, papular macular rash, condyloma lata, mucous patches, and generalized lymphadenopathy ( Figures 10.07 , J–L; 10.11 , J and K). Approximately 5% of patients with secondary syphilis will show evidence of panuveitis. Probably the most common fundus change is that of vitreous cellular infiltration and either single or multiple, nonelevated (placoid), geographic, yellow–white, ill-defined, chorioretinal lesions that often are confluent in the posterior pole and mid periphery of the fundus ( Figures 10.07 , B and G; 10.10 , H; 10.11 , I and L). Both eyes are affected in half of all cases. In some patients the chorioretinal lesions may be largely confined to the area around the optic disc. They may be associated with superficial, flame-shaped hemorrhages. The fundus picture may simulate the early stages of the acute retinal necrosis syndrome. Secondary retinal detachment and choroidal detachment develop in some patients. The active yellow–gray placoid outer retinal and choroidal lesions fade centrally, and often there is clumping of the RPE in a leopard-spot configuration ( Figures 10.07 , D, H, and I; 10.10 ). These pigment clumps may become less apparent over a period of months. The clinical course is variable. In some cases the chorioretinitis resolves spontaneously, and the appearance of the fundus and retinal function may return to near normal. In others widespread areas of chorioretinal atrophy and loss of retinal function occur ( Figure 10.11 , A–C). Migration of RPE into the overlying retina in a bone-spicule pattern may occur many months later. Choroidal neovascularization developing at the edge of a chorioretinal scar may be a late complication ( Figure 10.11 , D).
Fluorescein angiography in the region of the active yellow–white chorioretinal lesions initially shows evidence of hypofluorescence, followed by late staining at the level of the RPE ( Figure 10.07 , D, E, H, and I). Fluorescein staining of the optic disc and major retinal veins is frequent. During the early stages of resolution of the active chorioretinal lesions, the leopard-spot change in the RPE may be more apparent angiographically than ophthalmoscopically.
The acute placoid chorioretinal lesions of secondary syphilis may be mistaken for those of acute placoid multifocal pigment epitheliopathy and serpiginous choroiditis. Eliciting a history and/or the detection of any of the nonocular manifestations of secondary syphilis, and institution of prompt treatment with penicillin, is important in making the correct diagnosis and in preventing permanent visual loss. Return of visual function may be dramatic. The patient should be evaluated for evidence of AIDS, which often accompanies secondary lues. Syphilis may be accelerated and neurosyphilis encountered earlier in patients with AIDS.
In the past 5 years there have been several cases of ocular syphilis with a specific clinical presentation that resembles acute retinal necrosis, most often seen in homosexual and heterosexual men who have sex with men (MSM). The findings include a characteristic ground glass appearance of multifocal whitish lesions present in the inner retina and at the preretinal level, associated with occlusive vasculitis of the vessels in their vicinity ( Figures 10.08 , B, D, and I; 10.09 , H–J). The inner retinal and preretinal collection, along with the perivascular infiltration, resolve with treatment ( Figures 10.08 , E–G and K; 10.09 , M and N). This presentation is now seen in nearly 35% of cases of ocular syphilis, with the placoid lesion making up another third, and the remaining third accounted for by nonspecific anterior uveitis, disc edema, vasculitis, and other lesions ( Figures 10.09 , O–X; 10.10 , A–G). Whether different serotypes of Treponema pallidum cause different clinical manifestations is the explanation of the diverse manifestations is not known.
In some patients with acquired syphilis the fundus picture is primarily that of retinal vasculitis with retinal hemorrhages, occlusive arterial disease, and retinitis proliferans (see Figure 10.11, G and H). Many different fundoscopic changes have been attributed to syphilis, including neuroretinitis, disciform scar, acute retinal necrosis, pseudo-retinitis pigmentosa, Kyrieleis’ plaques, and optic atrophy. Syphilis has been called the ‘great imitator’. Anterior segment involvement with a syphilitic gumma ( Figure 10.10 , G) presents with an iris mass. It is often difficult to determine the stage of syphilis based on the ocular findings, though most inflammatory presentations of syphilis occur in the secondary stage. Similar findings have been seen in patients with neurosyphilis, tertiary syphilis, and latent syphilis. The incidence of syphilis has been on the rise since 2000 with a 33.5% increase noted between 2000 and 2004. Several outbreaks have been reported from New York City, Miami-Dade County, Washington, Houston, San Francisco, and Southern California. A CDC analysis estimates that 64% of the early stage syphilis cases in 2004 were in MSM compared to 5% in 1999.
Since it is a common infection, however, care must be used in assigning it as the cause of an ocular disease solely on the basis of positive serologic tests for syphilis. These include the nonspecific reagin tests, such as VDRL, or more specific tests, including fluorescent treponemal antibody-absorption (FTA-Abs) and microhemagglutination assay- Treponema pallidum (MHA-TP). There is some controversy concerning the criteria for diagnosis of neurosyphilis and for the dosage and route of administration of penicillin in these patients. Because of the high incidence of positive reaction of the cerebrospinal fluid (CSF) to the serologic tests for syphilis during the secondary stages of the disease, CSF examination is usually not recommended for patients presenting with the ocular manifestations of secondary syphilis. Recommended treatment for patients with active chorioretinal disease caused by syphilis is aqueous crystalline penicillin G (18–24 million U IV daily) or procaine penicillin (2.4 million U IM daily) with oral probenecid (500 mg four times daily) for 10–14 days. If CSF pleocytosis has been noted, these patients should be monitored at 6-monthly intervals with CSF studies until the cell count normalizes. In patients allergic to penicillin, IV or IM ceftriaxone (2 g per day for 10–14 days) can be used. All patients with syphilis should be tested for HIV status and the treatment in HIV-positive patients lasts for 3 weeks. Those who are HIV-positive should be monitored for treatment failure at 6, 12, 18, and 24 months.
Even though pulmonary and extrapulmonary tuberculosis (TB) has been prevalent worldwide for hundreds of years, reports of ocular TB apart from Eales’ disease have been meager until the past 10 years. This is likely due to the inability to confirm the diagnosis accurately, lack of knowledge among the ophthalmic personnel in countries with a high prevalence of the disorder, and less access to specialized care in these countries. Several new manifestations of intraocular TB have been reported. With an increase in the number of HIV patients, ocular TB is on the rise. Extrapulmonary involvement is seen in 50% of patients with both TB and AIDS.
Tuberculosis is a systemic disease caused by Mycobacterium tuberculosis and is characterized by caseating granuloma formation in the affected tissues. Although pulmonary TB is the commonest manifestation, extrapulmonary involvement can include the gastrointestinal, genitourinary, cardiovascular, skin and central nervous system including the eyes. Pathogenesis of tuberculous infection evolves through five stages following implantation of inhaled mycobacteria in a respiratory bronchiole or alveolus.
Stage 1: The alveolar macrophage phagocytoses the bacteria and either destroys them or the bacteria grow and destroy the macrophage.
Stage 2: Circulating monocytes are recruited to this nidus and phagocytose the bacteria. The bacteria prevent the fusion of the lysosome to the phagosome, thus preventing their destruction.
Stage 3: A delayed type hypersensitivity reaction develops destroying the bacteria, resulting in caseous necrosis. This lesion contains central caseation surrounded by activated and nonactivated macrophages, T lymphocytes, and other immune cells. If the cell-mediated immunity is good, the highly activated macrophages destroy the bacteria, thus halting the progression of the lesion at this subclinical stage.
Stage 4: If the cell-mediated immunity is poor, the bacteria escape from the edge of the caseation and multiply within macrophages, causing more caseation and growth of the tubercle. A few bacteria-laden macrophages may enter the lymphatics or blood vessels and reach other parts of the lung and other organs including the eye.
Stage 5: The central caseous material liquefies and relentless multiplication of the bacteria ensues in spite of good cell-mediated immunity. The bacteria erode the bronchial wall and spread to other organs.
Acute and chronic granulomatous uveitis with mutton fat keratic precipitates, iris and angle nodules, and anterior chamber granulomas are features of tuberculous anterior uveitis (see Figure 10.15 , D). Sometimes a hypopyon may be seen and the iris nodules may become vascularized. Essential iris atrophy has also been reported. Tubercular anterior uveitis may also present as a mild or moderate recurrent iridocyclitis; granulomas are absent in these eyes but small translucent nodules may be seen at the pupillary margin (Koeppe nodules).
Patients present with low-grade smoldering chronic uveitis, vitritis, snowball opacities, snow banking, peripheral vascular sheathing, and peripheral retinochoroidal granulomas. Fluorescein gonioangiography shows early hyperfluorescence of small, discrete, whitish lesions in the ciliary body band near the iris root. Cystoid macular edema is often present.
Retinochoroiditis Caused by Mycobacterium Tuberculosis in Immunosuppressed Patients
The eye in the immunocompetent individual with pulmonary tuberculosis is infrequently affected. Patients with miliary tuberculosis may develop multifocal choroidal granulomas and, less often, endophthalmitis. Patients with AIDS and tuberculosis, however, may develop severe multifocal retinochoroiditis, caused by M. tuberculosis as well as by the ordinarily less pathogenic M. avium.
Posterior Uveitis and Panuveitis
Multifocal small choroidal tubercles is the commonest manifestation, being either unilateral or bilateral and sarcoid-like, suggesting hematogenous spread of the organism. They vary from one-fourth to one disc area in size, have a grayish-yellow color, and very occasionally may have adjacent retinal hemorrhages ( Figure 10.12 , A–D). This presentation is also a feature of miliary TB. Once treatment is instituted, the yellow–gray lesions turn whiter with sharp borders and eventually get pigmented ( Figure 10.12 , E).
The caseous material can liquefy secondary to rapid multiplication of the bacilli, resulting in necrosis and abscess formation. These may be seen in disseminated TB or in isolation without evidence of TB in other parts of the body. A high index of suspicion and prevalence in endemic countries should alert the physician to the diagnosis. Chorioretinal anastomosis or subretinal neovascularization can occur over healing lesions ( Figure 10.12 , G–K).
This is a solitary mass that is yellow–white, elevated, sometimes with overlying retinal folds and retinal hemorrhage. The mass can be located anywhere in the fundus and continues to grow both in height and diffuse spread.
The hallmark of this presentation is the relentless progression of the active edge, with the initial lesion being: (1) multifocal choroiditis that progresses to become confluent and has several advancing active edges ( Figure 10.13 , A–F); (2) an initial plaque-like lesion with ameboidal spread ( Figure 10.13 , G and H); and (3) inactive healed scars that show new activity at their edges and progress ( Figure 10.13 , I–K). When any of these serpiginous choroiditis-like presentations continue to progress despite oral steroids and other immunosuppressives, one should suspect tubercular choroiditis. Workup should include Mantoux skin test, chest X-ray and CT scan, and QuantiFERON-TB Gold (QFT-G) to establish the diagnosis of TB. In the event that all of these are negative, PCR of aqueous or vitreous fluid should be performed to establish the diagnosis.
Tubercular Retinal Vasculitis
Active exudation around the veins and sometimes arteries, associated with retinal hemorrhages, lipid leakage, and occasionally with focal chorioretinitis, should alert one to the diagnosis of tubercular vasculitis ( Figure 10.14 ). This should be differentiated from sarcoid vasculitis and Behçet’s disease, which are more arterial than venular. With time, retinal nonperfusion and neovascularization of the retina may occur. Whether the vasculitis is infective per se or represents a hypersensitivity response to M. tuberculosis antigens remains speculative. These patients should also undergo various diagnostic tests to confirm TB and rule out sarcoid and Behçet’s disease. They require anti-TB therapy and monitoring for future neovascularization that warrants laser ablation of the ischemic retina. Hypersensitivity reaction to TB antigens is likely in a subgroup of patients with Eales’ disease (see Chapter 6).
All patients suspected of ocular TB should undergo Mantoux testing, chest X-ray, chest CT if needed, and QuantiFERON-TB Gold test initially. PCR of tissue fluid can help establish the diagnosis when the other tests are inconclusive. Patients begun on corticosteroids alone when all these tests are negative should be monitored closely for persistence or progression of the lesions, in which case invasive testing with a fine needle biopsy should be performed to demonstrate presence of the organism. All patients with ocular TB should be started on four drugs for the first 2 months and continued on two drugs for a total of 18 months. Both 9- and 12-month treatments are inadequate and the lesions are likely to recur after completion of treatment. The bacilli divide very slowly in solid organs, unlike in the lung, hence the need for the longer duration of treatment. Oral steroids at a dose of 0.5–1 mg/kg are also started along with the anti-TB regimen, and tapered slowly over 9–12 months depending on the response.
A paradoxical reaction similar in mechanism to Jarisch–Herxheimer may be seen after initiation of anti-TB therapy that requires an increase in the dose of steroids for a few weeks until the lesions begin to involute.
Nearly 2 billion people are infected with M. tuberculosis worldwide, though only 10% develop active disease in their lifetime. Twenty-two countries have been identified that harbor 80% of the world’s TB population: India, China, Indonesia, Bangladesh, Pakistan, Nigeria, the Philippines, South Africa, the Russian Federation, Ethiopia, Vietnam, the Democratic Republic of the Congo, Brazil, Tanzania, Kenya, Thailand, Myanmar, Afghanistan, Uganda, Peru, Zimbabwe, and Cambodia.
When it occurs focally in the choroid, it produces a nonspecific choroidal inflammatory mass similar to that seen in cryptococcosis, nocardiosis, or other inflammatory diseases of the choroid including sarcoidosis ( Figure 10.15 , A–C). A large choroidal tuberculoma mass may simulate a melanoma and may fail to respond to anti-TB therapy. Barondes et al. described a healthy patient with a negative tuberculin skin test and a focal choroidal lesion which on trans pars plana biopsy contained acid-fast bacilli. In some apparently healthy patients the disease may progress rapidly to produce a picture of panophthalmitis. Mycobacterium avium-intracellulare , in addition to M. tuberculosis , may cause multifocal choroiditis as well as retinitis in patients with AIDS.
A small subgroup of Eales’ disease patients who present with recurrent vitreous hemorrhages, peripheral venous sheathing, and retinal neovascularization may have a hypersensitivity response to tuberculous antigen (see Chapter 6).
Phlyctenular conjunctivitis is an allergic response to various microbial proteins including tuberculous protein ( Figure 10.15 , E).
Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae . Depending on the immunologic status of the patient the disease presents in three forms: lepromatous with poor cell-mediated immunity, tuberculoid with good cellular immunity, and borderline (tuberculoid or lepromatous). Polar lepromatous leprosy is the anergic form of the disease with marked lack of cell-mediated immunity. These patients have a high bacterial index; the bacilli grow and multiply within foamy macrophages and are transported to all parts of the body. The bacteria are known not to tolerate warm temperatures and are found in the cooler parts of the body – skin, peripheral nerves, cornea and iris in the eye. Hence there are no firmly documented cases of leprosy affecting the retina and choroid. A case with fundus involvement in the form of heaped-up, highly reflective, white material reported in the literature by Choyce and another fundus lesion by Chatterjee in 1964 have never been further substantiated, though a couple of enucleated eyes have shown the presence of M. leprae within macrophages in the retina and choroid. This is very unusual and extremely rare.
Ocular involvement is mostly limited to madarosis, lack of corneal sensation, beaded corneal nerves, keratitis, granulomatous anterior uveitis with iris atrophy, keratic precipitates, lepra pearls in the iris, and involvement of the skin, lacrimal sac, and lid muscles resulting in lagophthalmos ( Figure 10.15 , F). Glaucoma occurs secondary to iris changes and uveitis. Low intraocular pressure has also been found due to infiltration of the ciliary body and decreased aqueous production.
Histology of enucleated blind eyes has found bacteria and foamy macrophages laden with M. leprae in the cornea, iris, anterior uveal tissue, and anterior choroid due to its affinity to cooler areas. The retina was found to be free of the bacilli.
This acid-fast bacillus cannot be grown in vitro and has only been cultured in the foot pads of the nine-banded armadillo. Recent use of reverse transcriptase-polymerase chain reaction (RT-PCR) has enabled confirmation of the diagnosis in several cases. The disease is endemic in India, Nepal, Brazil, and the tropics of Asia and Africa, with 70% of affected individuals residing here.
Certain fungi either involve primarily the retina or extend rapidly from the choroid into the retina where they produce white intraretinal fungal abscesses ( Aspergillus fumi-gatus , Candida albicans , Trichosporon beigelii , Scedosporium apiospermum , and Sporothrix schenckii ). Others produce primarily yellow–white multifocal choroidal infiltrates that may cause serous and hemorrhagic retinal detachment ( Histoplasma capsulatum , Blastomyces dermatitidis , Coccidioides immitis , and Cryptococcus neoformans ). These latter diseases may be associated with disciform retinal detachment. Mucormycosis invades blood vessels and presents with vascular obstruction such as central or branch retinal artery or ophthalmic artery obstruction, due to the rather large size of the hyphae.
Hospitalized patients, particularly those with postoperative complications of abdominal surgery receiving prolonged intensive antibiotic treatment by an intravenous catheter, are prone to develop candidemia and focal white retinal abscesses ( Figure 10.16 , A–F). The focal white retinal lesions are typically superficially located in the retina and are frequently associated with small cottony balls in the vitreous overlying the primary lesion ( Figure 10.16 , D). Other predisposing factors for development of retinal candidiasis include IV drug abuse, chemotherapy, corticosteroid administration, malignancy, bone marrow transplantation, diabetes, severe burns, endocrine hypofunction, other debilitating diseases, contaminated intravenously administered medications, and maternal birth canal infection. The author has seen two diabetic patients developing Candida retinitis following ureteral stent placement whose urine culture grew Candida albicans .
The appearance of the fundus lesion is strongly suggestive of the diagnosis. The diagnosis may be confirmed by cultures of the site of IV administration, blood cultures, or vitreous aspiration. Multiple white-centered superficial retinal hemorrhages may also occur. The white centers may be caused by microabscesses containing the fungi, or by sterile fibrin–platelet aggregates (see previous discussion of pyogenic bacterial infection). The disease may respond to systemically administered amphotericin B or 5-fluorocytosine, or both. Intravitreal injection of amphotericin B has been used successfully as a primary form of treatment and as an adjunct to systemic treatment ( Figure 10.16 , C–F). More recently, fluconazole, voriconazole, and caspofungin have been successful in treating Candida retinitis in addition to, or with no response to, amphotericin. Spontaneous resolution of Candida retinal abscesses may occur. For this reason patients with mild retinal involvement and no evidence of other organ involvement may be followed for evidence of progression. The development of retinal striae around a focal retinal monilial abscess is a sign suggesting early resolution of the lesion. If the retinal lesion(s) progresses, or if evidence of more advanced disease is present, the administration of fluconazole, itraconazole, voriconazole, posaconazole, or caspofungin may be effective. To avoid renal toxicity associated with treatment with systemic amphotericin B, some patients with ocular involvement in the absence of evidence of other organ involvement with monilial infection may be managed successfully with pars plana vitrectomy and intravitreal injection of amphotericin B.
Candida retinitis is more common in patients post gastrointestinal surgery, hyperalimentation, toxic megacolon, and in diabetics, whereas Aspergillus infections are more commonly seen post organ transplant or cardiac surgery. In an outpatient setting, Candida is seen in IV drug abusers and often can be mistaken for Toxoplasma retinitis. Presence of a ‘string of pearls’ and absence of Kyrieleis’ arteriolitis and old scars adjacent to active retinitis should raise the suspicion of Candida ; efforts should be made to confirm a history of IV drug abuse since the treatment for the two conditions is vastly different.
The development of epiretinal membranes may be the cause of visual loss in some patients otherwise successfully treated for chorioretinal monilial infection. Surgical removal of these membranes may result in partial restoration of visual function.
Intravenous drug abuse is the primary cause of intraocular infection with Aspergillus. In these patients it ranks only behind Candida as the cause of endogenous fungus endophthalmitis. It is also acquired in an organ transplant immunosuppressed state, whereas Candida is seen in patients after gastrointestinal surgery and hyperalimentation. Ocular involvement is typically the first manifestation of the infection except when it occurs in immune incompetent individuals. The patients present with subacute visual loss, mild pain, and redness of the eye that may be associated with a varying degree of anterior chamber reaction. Chorioretinitis and endophthalmitis caused by Aspergillus have characteristic clinical features. Deep retinal or chorioretinitis with progressive horizontal enlargement of the lesion is characteristic of Aspergillus as compared to Candida that has a small retinal focus and grows progressively into the vitreous. Preretinal or subretinal exudation may be accompanied by a hypopyon as a result of layering of inflammatory cells ( Figure 10.16 , G and H). A hemorrhagic retinal vasculitis may be present. Isolated retinal hemorrhages and preretinal fluffy vitreous opacities may obscure fundus details. In some cases only a mild vitritis may be present initially. A variety of species of Aspergillus may be responsible for human infection. Pars plana vitrectomy and systemic azoles such as fluconazole, voriconazole, and posaconazole are the first choice in treatment of Aspergillus infection of the inner eye. Intravitreal injection of voriconazole can be used as an adjunct to systemic therapy.
Rao and Hidayat found Aspergillus to grow preferentially in the sub-RPE and subretinal space and to invade choroidal and retinal blood vessels, whereas Candida grew preferentially into the vitreous cavity in eyes enucleated for fungal endophthalmitis.
Retinochoroiditis Caused by Other Fungi
Other fungal diseases, such as trichosporonosis and sporotrichosis, Scedosporium apiospermum , and Fusarium , may cause chorioretinal lesions and endophthalmitis similar to that produced by Candida.
Primary infection with the fungus Coccidioides immitis , like that with Histoplasma capsulatum , is a common cause of an acute, benign, self-limiting pulmonary disease. It is most prevalent in the interior valleys of California. It is unknown whether it is a common cause of subclinical chorioretinal scars and late visual complications similar to those found in areas where histoplasmosis is endemic ( Figure 10.18 , A–C). As part of the primary infection, this fungus does occasionally cause loss of vision secondary to focal infectious granulomatous choroiditis, retinitis, and endophthalmitis ( Figures 10.17 , A–C and J; 10.18 , D and E). Patients inhale the anthrospores causing pneumonia, which secondarily may spread via the bloodstream, most often to the CNS and bones. Flu-like symptoms, cough, erythema nodosum, and arthralgias are often the presenting symptoms. Hydrocephalus and meningitis have been reported ( Figure 10.17 , A–F).
Cryptococcosis is a chronic or subacute pulmonary systemic or meningitic infection caused by Cryptococcus neoformans. Patients with the meningitic form of the disease may develop papilledema, papillitis, optic atrophy, and extraocular muscle palsies ( Figure 10.18 , G–I). Spread to the juxtapapillary choroid and retina may occur directly or via the bloodstream. Multifocal irregular yellow–white choroidal lesions, focal subretinal masses, and vitreoretinal abscesses have been described, usually in debilitated or immunosuppressed patients ( Figure 10.18 , F). Simultaneous chorioretinal infection with Cryptococcus and cytomegalovirus has occurred. Cryptococcal chorioretinitis may occasionally occur in apparently healthy patients prior to their developing evidence of meningitis. When confined to the choroid and outer retina, the lesion may simulate a variety of diseases, including a melanoma, focal granuloma, or a disciform exudative process ( Figure 10.18 , F). It is important to consider the possibility of cryptococcosis before placing a patient on corticosteroid treatment, which may cause a fulminant and fatal spread of the infection. The diagnosis may be confirmed by examination of the CSF and vitreous. Treatment with the newer azole antifungal agents will cause resolution of the infection. Spontaneous resolution of intraocular lesions occasionally occurs.
Though rare, mucormycosis is a severe, often fatal fungal infection unless diagnosed early, caused by fungi of the Zygomycetes class. Its classic presentation is in an immunocompromised host, often with severe diabetes and ketoacidosis, cancers, cirrhosis, or renal failure, and in patients on immunosuppressives and steroids. The route of entry is mostly through inhalation of fungal spores, though percutaneous entry can occur. Ocular involvement is usually due to contiguous spread from rhinocerebral mucormycosis, and patients present with ophthalmoplegia, rapid decrease in vision due to central retinal artery or ophthalmic artery occlusion, multiple large nerve fiber infarcts, and hypotony. Intravenous entry can result in endogenous endophthalmitis ( Figure 10.19, A–I). 253 Early diagnosis is by clinical examination of the oral and nasal cavity and confi rmation by obtaining scrapings or biopsy from the dark eschar in these areas. The hyphae, which are large, nonseptate, and highly invasive, spread rapidly into soft tissue and blood vessels ( Figure 10.19 , B, C). They exert their effect by occluding ocular and orbital vessels and the vasa nervorum, resulting in proptosis, phthalmoplegia, and choroidal and retinal infarcts. Treatment consists of early extensive debridement, local and IV amphotericin, and newer antifungals such as posaconazole.
Endogenous infection with Blastomyces dermatitidis following inhalation of conidia into the lungs may cause multifocal choroiditis ( Figure 10.18 , J and K), endophthalmitis, and panophthalmitis. Whereas pulmonary and cutaneous granulomas are the most frequent manifestations of systemic blastomycosis, ocular involvement occasionally occurs and may affect otherwise apparently healthy patients. Biopsy of skin lesions, if present, is helpful in establishing the diagnosis. The ocular as well as the systemic infection may respond favorably to ketoconazole, amphotericin, and newer azole therapy.
Histoplasmosis Retinitis and Choroiditis in Immune Incompetent Patients
Histoplasma capsulatum may cause multifocal, active, white, retinal, subretinal, and choroidal lesions in one or both eyes of patients with AIDS ( Figure 10.16 , J–L) or other immune incompetent states (see Figure 3.43, A–C). In immune incompetent individuals histoplasmosis may cause focal choroiditis that typically results in multiple focal atrophic chorioretinal scars without producing ocular symptoms. These scars later in life may be the site of development of subretinal neovascularization and visual loss (see presumed ocular histoplasmosis syndrome in Chapter 3).
Though rare, mucormycosis is a severe, often fatal fungal infection unless diagnosed early, caused by fungi of the Zygomycetes class. Its classic presentation is in an immunocompromised host, often with severe diabetes and ketoacidosis, cancers, cirrhosis, or renal failure, and in patients on immunosuppressives and steroids. The route of entry is mostly through inhalation of fungal spores, though percutaneous entry can occur. Ocular involvement is usually due to contiguous spread from rhinocerebral mucor-mycosis, and patients present with ophthalmoplegia, rapid decrease in vision due to central retinal artery or ophthalmic artery occlusion, multiple large nerve fiber infarcts, and hypotony. Intravenous entry can result in endogenous endophthalmitis ( Figure 10.19 , A–I).
Early diagnosis is by clinical examination of the oral and nasal cavity and confirmation by obtaining scrapings or biopsy from the dark eschar in these areas. The hyphae, which are large, nonseptate, and highly invasive, spread rapidly into soft tissue and blood vessels ( Figure 10.19 , B, C). They exert their effect by occluding ocular and orbital vessels and the vasa nervorum, resulting in proptosis, ophthalmoplegia, and choroidal and retinal infarcts.
Treatment consists of early extensive debridement, local and IV amphotericin, and newer antifungals such as posaconazole.
Toxoplasmosis is the most frequent cause of focal necrotizing retinitis in otherwise healthy human individuals ( Figures 10.21 – 10.23 ). The protozoan Toxoplasma gondii is either transmitted to the fetus in utero when the mother acquires the infection during pregnancy or, less commonly, it infects the retina following ingestion of the organism. There is a predilection for infection of the CNS and the retina. In congenital toxoplasmosis the retinal lesion may occur as part of a generalized severe infection (encephalomyelitis, convulsions, fever, jaundice, cerebral calcification, hydrocephalus, and paralyses of various types) or more frequently as part of a mild subclinical infection. Large, atrophic, often excavated, chorioretinal scars centered in or near the macular area or elsewhere in the fundus in children and adults are probably caused in many cases by congenital toxoplasmosis ( Figure 10.20 , B, C, H, J, and K). When they are symmetric, however, these macular lesions must be differentiated from similar-appearing inherited dystrophic lesions.
Whether acquired in utero or postnatally, the Toxoplasma organisms may lie dormant in the encysted form in the apparently normal retina, either adjacent to or remote from chorioretinal scars. When the organisms become unencysted, one or more acute, white, necrotizing lesions may occur in a previously normal-looking retina or at the margin of an old chorioretinal scar ( Figure 10.21 ). The lesions usually involve the full thickness of the retina but in some cases may be confined to either the inner or, less frequently, the outer half of the retina. In the former they are associated with overlying vitreous inflammatory cell infiltration. When the retinitis involves primarily the outer retina, serous detachment of the underlying retina is frequently present ( Figure 10.21 , A–I). When the acute lesion includes a major retinal vessel, it may cause either a branch retinal arterial occlusion ( Figure 10.22 , A–C) or a venous occlusion ( Figure 10.22 , D and E).
Most patients with acute retinitis are seen initially because of a history of floaters and less often because of loss of central vision caused by foveal involvement by focal retinitis ( Figure 10.21 ), cystoid macular edema, or detachment associated with paracentral focal retinitis. Focal periarterial exudates and arterial atheromatous plaques (Kyrieleis’ arteriolitis) simulating arterial emboli may occur either in the immediate vicinity of the acute retinitis or remote from it ( Figure 10.22 , F–I). Fluorescein angiography shows no permeability alterations or evidence of artery obstruction in the area of the arterial plaques but demonstrates marked fluorescein staining in the area of the retinitis ( Figures 10.21 , B, C, E, H, and I; 10.22 , C). The periarterial plaques may fade or may persist following resolution of the retinitis. Occasionally acute multifocal arterial wall opacification is widespread throughout the fundus and may be accompanied by similar multifocal gelatinous-appearing opacities scattered along the major retinal veins. Ophthalmoscopic and angiographic evidence of diffuse perivenous exudation may occasionally occur in areas remote from the acute retinitis. The presence in those patients with retinal vasculitis of reduced levels of antibody affinity to retinal S-antigen with normal levels of circulating immune complexes suggests a defective regulation of antiretinal autoimmunity. Swelling of the optic disc and angiographic evidence of staining of the disc may accompany focal areas of retinitis or, in some cases, may be the presenting manifestation of toxoplasmosis ( Figure 10.22 , J–L). Multiple, small, gray deposits (presumably inflammatory cells) may develop along the inner retinal surface in the vicinity of the acute retinitis, and it may be difficult to distinguish these from small foci of active retinitis. If the vitreous separates from the retina near the acute lesion, these gray deposits usually remain attached to the posterior surface of the vitreous.
The active focus of retinitis usually enlarges for a period of 1–2 weeks before gradually fading over a period of several months, usually leaving in its wake a pigmented atrophic chorioretinal scar. Segmental optic disc pallor may develop in the zone of nerve fiber atrophy caused by the retinitis.
In some patients the onset of the disease is characterized by the development of multifocal small foci of retinitis, largely confined to the outer retinal layers ( Figure 10.23 , A). After resolution, some of these small lesions may leave no chorioretinal scarring. There may be a series of remissions and exacerbations before development of the larger, more typical, full-thickness focus of acute retinitis ( Figure 10.23 , A–D). Another atypical presentation is that of an acute papillitis before the development of a focal area of retinitis ( Figure 10.22 , J–L). Findings that suggest that disc swelling may be caused by toxoplasmosis are severe vitreous inflammation, fluffy white peripapillary lesions, nerve fiber bundle defect, and often good visual acuity.
The clinical diagnosis of ocular toxoplasmosis is always a presumptive one. Most patients will demonstrate skin test and serologic evidence of previous contact with the organism with positive IgG titers. The diagnosis of acute toxoplasmosis is very likely in otherwise healthy patients with a focus of acute retinitis in an eye with one or more chorioretinal scars. Even in the absence of another scar, a solitary focus of acute retinitis in a healthy patient occurs most often in patients with serologic evidence of the infection with positive IgM antibodies; a few do not, and the titers may be low in many patients. In addition to the enzyme-linked immunosorbent assay (ELISA) test, the immunofluorescent antibody test, and the Sabin–Feldman dye test (rarely done anymore), detection of evidence of toxoplasmosis in the aqueous humor may be accomplished using PCR. Cytologic diagnosis of toxoplasmosis may occasionally be made from vitreous biopsy.
Most chorioretinal scars caused by toxoplasmosis are atrophic, partly pigmented, and associated with postinflammatory changes in the overlying vitreous and a nerve fiber bundle visual field defect. Hypertrophic disciform scars, however, develop in some patients ( Figure 10.23 , E and F). In rare cases reactive proliferation of the RPE in these scars may be mistaken for a melanoma. Remodeling of the retinal circulation caused by previous occlusion of vessels passing through the area of retinitis is often present ( Figure 10.22 , D and E). Evidence of retinochoroidal anastomosis may develop due to full-thickness retinal involvement and subsequent atrophy, thus bringing the retinal vessels in close proximity to the choroidal vessels ( Figure 10.22 , D). Development of subretinal neovascularization, usually type 2, at the edge of an inactive scar may cause loss of central vision ( Figure 10.21 , L). The large macular chorioretinal scars seen in children and attributed to congenital toxoplasmosis usually do not show evidence of postinflammatory changes in the vitreous. Unusual and unexplained associations with toxoplasmosis retinitis are the development of Fuchs’ heterochromic cyclitis and either unilateral or bilateral zones of retinitis pigmentosa-like fundus changes. Gary Holland has categorized the location of Toxoplasma retinitis into three zones: zone 1 (3000 microns from the fovea center or 1500 microns from the optic disc margin), zone 2 (from zone 1 to the anterior borders of the vortex veins), and zone 3 (from the anterior border of zone 2 to the ora serrata).
Familial involvement with ocular toxoplasmosis is rare. In southern Brazil (Alto Uruguai region), however, familial ocular toxoplasmosis is endemic. The prevalence of ocular toxoplasmosis there is 30 times higher than elsewhere, with 85% of the population being infected and 18% of them have evidence of Toxoplasma retinochoroiditis. The frequent ingestion of raw or undercooked pork has been suggested as a possible explanation for this. In the United States, the prevalence of T. gondii infection is 22.5%, although the prevalence of ocular involvement in these is only 2%.
This difference in the prevalence rates in different parts of the world is likely related to the prevalence of the different genotypes. Three genotypes have been isolated in humans and animals: types I, II, and III. Type II is the mildest genotype and is seen in the United States and Europe. South America, especially southern Brazil, has the more virulent type I and atypical genotypes. Sexual recombinants (atypical genotypes) also have increased virulence.
Even though toxoplasmosis is considered an endemic disease, there have been a few outbreaks around the world and a recent epidemic in Coimbatore, a city in southern India. These outbreaks and clustering of cases have been linked to a source – either contaminated municipal water or infected kittens and a feral cat harboring the more virulent genotype. The largest epidemic has been reported from one center in southern India where 248 patients (254 eyes) with retinochoroiditis were seen between August 2004 and July 2005. Of the 230 eyes (90.5%) with unifocal retinitis, 67% were located in zone 1, 25% in zone 2, and the remainder in zone 3.
Although recurrence is a hallmark of Toxoplasma retinochoroiditis, no definite factor(s) has been found to trigger recurrences. The risk of recurrence decreases as the disease-free interval increases; however, once a reactivation occurs, the risk of further recurrences increases (clusters). This is likely from some of the oocysts degenerating over time and hence the smaller load of dormant cysts, but with a recurrence the number of organisms increases, thus increasing the chance of another recurrence. Patients greater than 40 years of age had a higher chance of recurrence, likely from altered immunologic state. The longer the duration of infection, the greater the chance of recurrence, again implying organism load.
Histopathologic examination of an acute toxoplasmosis lesion in eyes of immunocompetent patients reveals a focal necrotizing retinitis associated with an underlying acute and chronic granulomatous choroiditis and scleritis ( Figures 10.23 , G and H; 10.24 , A and B). The inflammatory reaction surrounding the necrotizing retinitis is markedly reduced in immunosuppressed patients ( Figure 10.23 , I). In spite of the presence of scleritis that may be evident ultrasonographically beneath the focal retinitis in immunocompetent patients, only occasionally do they complain of pain. The encysted and free forms of Toxoplasma organisms are found in the relatively normal retina surrounding the necrotic retina ( Figure 10.23 , J and K). They are occasionally found in the choroid in immunosuppressed patients.
The value of pyrimethamine (Daraprim), sulfadiazine, clindamycin, minocycline, trimethoprim–sulfamethoxazole, and corticosteroids in the treatment of active lesions in immunocompetent humans is uncertain. Treatment probably has no value in preventing recurrences. These drugs have been demonstrated to be effective in experimental infections with Toxoplasma in animals. There is only minimal evidence, however, that they are of value in the treatment of toxoplasmosis in immunocompetent humans. Most authors agree that treatment is unnecessary and inadvisable in lesions outside the macular area. In cases where the center of the macula is threatened, use of one or more of the antibiotics in combination with systemic corticosteroids is advisable. Intravitreal clindamycin at a dose of 1 mg is a rapid means of treating Toxoplasma retinitis, and can be used in fovea-threatening cases, in severely immunosuppressed patients for a quick onset, and in pregnant women. Topical corticosteroids and mydriatics are indicated in the presence of accompanying iridocyclitis. Those children born to mothers who acquired Toxoplasma during pregnancy should be on anti- Toxoplasma treatment up to their first birthday.
In patients with AIDS or who are immunocompromised for other reasons, toxoplasmosis may cause a fulminant and widespread necrotizing retinitis as well as encephalitis. Features of toxoplasmosis retinitis in patients with AIDS that differ from those in immunocompetent patients are multiple active lesions, infrequency of acute lesions arising adjacent to inactive scars, frequent involvement of both eyes, and frequent evidence of CNS involvement. Some of these patients present with multifocal, small, widely scattered lesions that may rapidly become confluent and produce a clinical picture identical to acute retinal necrosis. Vitritis is usually present but may be less than that seen in immuno-competent patients with similar size retinal lesions. Clinically, the retinal lesions may simulate those caused by cytomegalic inclusion disease, although typically retinal hemorrhages are less prominent and vitritis more evident in lesions caused by toxoplasmosis. Toxoplasmosis encephalitis is a leading cause of death in patients with AIDS. Approximately 10–20% of patients with intracranial toxoplasmosis develop retinal lesions. Involvement of the brain often occurs in the absence of ocular involvement. Toxoplasmosis may cause either a diffuse necrotizing encephalitis or discrete space-occupying intracranial lesions. In the former, computed tomography may be normal; in the latter, it may show focal lesions with ring-shaped enhancement after contrast infusion. Coinfections of the retina and choroid may occur. The retinal and the brain lesions caused by Toxoplasma respond favorably to pyrimethamine and sulfadiazine, but recurrence of the infection is common after cessation of treatment. Corticosteroid treatment may be necessary to reduce cerebral edema but probably is unnecessary in the treatment of retinitis since the intensity of the inflammation is less than in normal patients. The results of serologic tests in patients with AIDS are unreliable. The presence of elevated IgM in as many as 12% of these patients suggests a high incidence of acquired infection.
Solitary active toxoplasmosis retinitis may be simulated by other infections ( Candida , pyogenic bacteria, bacteria of low pathogenicity in patients with AIDS, cat-scratch disease bacillus), ischemic retinopathy, and neoplasia (large-cell lymphoma, metastatic carcinoma to the retina). Retinal artery occlusion caused by a focal area of toxoplasmosis may appear similar to that occurring in patients with acute multifocal retinitis associated with cat-scratch disease or of unknown cause (see Figure 10.04 ), and patients with bilateral idiopathic recurrent branch retinal artery occlusion (see Figures 6.10 and 6.11). Multifocal outer toxoplasmosis may simulate punctate inner choroiditis (pseudo-presumed ocular histoplasmosis) (see Figure 11.21-11.23), and diffuse unilateral subacute neuroretinitis (see Figures 10.28 and 10.29 ).
Plasmodium vivax , P. falciparum , P. ovale , P. malariae , and P. knowlesi are the parasites causing malaria characterized by intermittent fevers – chills that recur on a regular basis every 24–48 h depending on the parasite subtype. Each year up to 3 million deaths and 5 billion episodes of clinical illness are reported, with 90% of them occurring in Africa.
Cerebral involvement with Plasmodium falciparum malaria major is an important cause of mortality, particularly in children in tropical regions. Those manifesting papilledema and outer retinal edema outside the major retinal vascular arcades are more likely to die or survive with neurologic sequelae. Other fundus findings include retinal hemorrhages (orange color hemorrhages due to the associated anemia), cotton-wool spots, intraretinal edema, narrowed and obstructed arteries and small capillaries in the macula, and venous distension and tortuosity. The erythrocytes that have engulfed the parasites are less pliable and block small vessels causing the small retinal infarcts and hemorrhages ( Figure 10.24 , A–C). The retinal whitening resolves over time, as do the lipid exudates ( Figure 10.24 , D–F).
Pneumocystis Jiroveci Choroiditis
Pneumocystis jiroveci (pronounced ‘‘yee-row-vetsee’’, previously known as P. carinii ) is an opportunistic pathogen in patients with various humoral and cell-mediated immunologic abnormalities and is the most common infection in patients with AIDS (over 80%). It was previously classified as a protozoan, but reclassified in 1998 as a yeast-like fungus based on nucleic acid and biochemical analysis. Its name was changed in 2001 to Pneumocystis jiroveci , a species specific to humans. It is a normal commensal of the pulmonary system and becomes pathogenic in immunocompromised states. Pneumocystis jiroveci infection is the initial manifestation of AIDS in over 50% of patients. Those with T- and B-cell abnormalities appear more susceptible than patients with B-cell deficiency alone. Infection with Pneumocystis may be life threatening. In humans infection is primarily limited to lungs, lymph nodes, spleen, and less often liver, bone marrow, small and large intestine, pericardium, myocardium, hard palate, periureteral soft tissue, and choroid. Pneumocystis jiroveci choroiditis often occurs in patients receiving long-term aerosolized pentamidine therapy. Clinically the multifocal choroidal lesions are placoid or slightly elevated, yellow–white, round or oval, multilobulated, and variably sized, with finely granular RPE that may simulate lesions seen in large cell lymphoma, metastatic carcinoma, atypical mycobacterial infection, sarcoidosis, or Dalen–Fuchs nodules ( Figure 10.25 , A–F). The choroidal lesions progress slowly and are associated with minimal vitreous reaction and visual loss. Although both eyes are usually affected, unifocal unilateral lesions may occur. Angiographically these focal lesions are hypofluorescent early, and stain late ( Figure 10.25 , B and C).
Pneumocystis is a unicellular organism with many morphologic features but it is considered to be a fungus ( Figure 10.25 , H and I). It exists exclusively in extracellular spaces. It is not readily cultured. There is no reliable serologic test for identification; most recently PCR for its DNA is being used. Diagnosis depends upon demonstration of organisms with special stains – methenamine silver, toluidine blue, or Giemsa. Silver stains primarily the mature cysts ( Figure 10.25 , I). Choroidal infiltrates are acellular, eosinophilic, vacuolated, and frothy, and involve the full-thickness choroid including choriocapillaris ( Figure 10.25 , G and H). Foci of hemorrhage and calcification may be present. Silver stains show Histoplasma -like organisms ( Figure 10.25 , I). Electron microscopy (EM) provides a definitive diagnosis and shows trophozoites and thick-walled cystic organisms ( Figure 10.25 , J). The over-lying RPE is usually minimally affected.
Treatment consists of IV or oral therapy with tri-methoprim–sulfamethoxazole, dapsone, pentamidine, or co-trimoxazole. Potential side effects include neutropenia, thrombocytopenia, skin rash, fever, nephrotoxicity, hepatotoxicity, and others. Early ophthalmoscopic detection of choroiditis may save sight as well as prevent a fatal outcome. Failure of the choroidal lesions to respond to treatment should suggest the possibility of a coexisting infection of the choroid, e.g., Mycobacterium avium-intracellulare , Cryptococcus neoformans , Mycobacterium tuberculosis , and Histoplasma capsulatum .
Ocular as well as other sites of infection with Pneumocystis probably occur at the time of spread from pneumonitis. These lesions become inactivated but not sterilized and may reactivate at a later time. Patients receiving prophylactic aerosolized pentamidine therapy are not protected against extrapulmonary disease, hence immuno-compromised patients are on prophylaxis with tri-methoprim–sulfamethoxazole or co-trimoxazole. Presumed P. jiroveci choroiditis served as a marker for disseminated infection before oral prophylaxis. The number of HIV cases developing P. jirovecii choroiditis has since dropped dramatically. Only two case reports have been seen in the past decade, one an HIV patient on a low dose of co-trimoxazole and another a post transplant leukemic patient.
Patients, typically healthy children or young adults, may experience unilateral loss of vision secondary to invasion of the eye by a single second-stage larval form of the Toxocara canis ascarid ( Figure 10.26 ). The eggs of the dog ascarid are deposited in the soil, where they undergo a change required before they become infectious to humans, who contract the disease primarily by ingestion of contaminated soil and not by direct contact with dogs. Following hatching of the eggs in the gastrointestinal tract, the second-stage larvae invade the blood vessels of the gastrointestinal tract and enter the eye, probably via the uveal tract. Bilateral ocular invasion probably occurs rarely. The patients manifest a variety of clinical pictures, including: (1) localized disciform macular detachment ( Figure 10.26 , A–C); (2) multifocal granulomas with interconnecting tracks, so-called meandering toxocariasis ( Figure 10.26 , F–I); (3) peripheral disciform retinal detachment; (4) papillitis; (5) optic nerve head tumor ( Figure 10.26 , D and E); (6) peripheral retinal or pars plana mass with vitritis (unilateral pars planitis; Figure 10.26 , I–K); (7) retinal detachment; (8) endophthalmitis; and (9) cataract. These patients typically have externally quiet eyes in spite of having endophthalmitis. The organism, which measures approximately 300–400 μm in length, is at the subbiomicroscopic level in size. It presumably enters the subretinal space by way of the choriocapillaris, where it may incite an eosinophilic granulomatous reaction and cause a serous and hemorrhagic disciform detachment of the retina ( Figure 10.26 , A). The reaction may destroy the overlying retina and extend into the vitreous ( Figure 10.26 , C). On healing, a gray or white umbilicated disciform scar, often with retinochoroidal vascular anastomosis, may result ( Figure 10.26 , B and C).
The diagnosis of a subretinal granuloma caused by Toxocara canis is presumptive. Eosinophilia can be demonstrated in some patients. The ocular disease rarely occurs in children with other clinical evidence of visceral larva migrans (coughing, wheezing, pulmonary infiltration, hepatomegaly, leukocytosis, persistent eosinophilia, elevation of isohemagglutinins, and elevated serum immunoglobulin levels). Visceral larva migrans occurs presumably with ingestion of a large number of eggs. Toxocara catis is rarely if ever the cause of ocular toxocariasis. The ELISA test may detect serum IgG antibodies in as high as 90% of patients with clinically suspected ocular disease. The ELISA test titer of aqueous humor and vitreous is usually higher than that demonstrated in the serum and in some cases may be positive when the serum shows no evidence of antibodies. This is likely due to intraocular antibody production. Monoclonal antibodies to larval excretory–secretory antigens that bind with species specificity to the cuticular surface of infective larvae may prove to be of value in the laboratory diagnosis of toxocariasis.
The clinical finding of a localized subretinal exudative lesion in the macula or a localized disciform scar, usually associated with retinochoroidal anastomosis of one eye of a child with no other evidence of ocular disease, should suggest the diagnosis of Toxocara canis. It must be remembered, however, that occasionally focal areas of retinitis associated with toxoplasmosis may also produce a proliferative subretinal scar that resembles in every way that produced by Toxoplasma (see Figure 10.23 , F). Bilateral disciform detachments occurring in children are unlikely to be caused by Toxocara canis. In such a case, other family members should be studied for evidence of a macular dystrophy. Serous and hemorrhagic disciform detachments in children may occur occasionally as a complication of Best’s vitelliform disease (see Chapter 5), other hereditary dystrophies (see chapter 5), rubella retinitis (see pp. 000, 000), and diffuse unilateral subacute neuroretinitis (see p. 000), and in patients with idiopathic panuveitis, vitritis, and multifocal chorioretinitis (see chapter 11).
Histopathologically, material left in the wake of the migrating larvae may cause a strongly eosinophilic granulomatous reaction along its path. The organism is usually identified in the center of an eosinophilic abscess ( Figure 10.26 , E and J). Ocular toxocariasis has been produced experimentally.
There is no satisfactory medical treatment for ocular Toxocara canis. Photocoagulation may be of some value in the treatment of subretinal granulomas in the paracentral region causing macular detachment. Vitrectomy procedures have been used successfully in the treatment of retinal detachment associated with vitreous traction caused by intravitreal or more peripherally located subretinal granulomas.
Cysticercosis is caused by human ingestion of the eggs of Taenia solium (pork tapeworm). The eggs disintegrate in the gastrointestinal tract, the embryos invade the intestinal wall and are carried throughout the body, where they undergo metamorphosis to become Cysticercus cellulosae ( Figure 10.27 , A). Most patients have several larvae in the body though only one may be seen in the eye. Often larvae are seen in the brain and subcutaneous tissue. Some of the integumental and brain cysts can calcify and can be detected by plain X-ray of the abdomen, forearms, and skull. Seizures and headache may be the presenting signs of CNS cysticercus. These larvae may enter the eye (more frequently the left) by way of either the central retinal artery or the ciliary arteries. They may gain entrance to the subretinal space ( Figure 10.27 , B and C), the vitreous cavity ( Figure 10.27 , G), or the anterior chamber ( Figure 10.27 , H). Over a period of many months they grow into a large cystic structure. When they are located beneath the retina, they may be mistakenly diagnosed as a serous detachment of the RPE or retina, as a choroidal tumor ( Figure 10.27 , B, C, and I), or a retinoblastoma.
Recognition of the white head or scolex that is often invaginated and moving within the cystic body permits accurate clinical diagnosis ( Figure 10.27 , A–C). The scolex reacts and moves to light shone into the eye. Echography may be helpful in localization and differential diagnosis in some cases associated with retinal detachment and vitreous opacification. Multiple organisms may occasionally be found in one or both eyes. During its early growth the organism may incite minimal reaction. Eventually, however, secondary inflammation, usually caused by the death of the organism, may destroy the eye, or leakage of cyst fluid through the wall may cause inflammatory debris. Extraocular locations often seen are in the subconjunctiva, along the rectus muscles, eyelids, and in the orbit. In endemic areas ocular involvement is encountered most frequently during the early decades of life, though other studies have found them predominantly in the third and fourth decades. There is a male predilection of 2:1, suggesting that working men are more exposed to unhygienic food and water. Almost 30% of affected individuals are vegetarians; hence contaminated water and uncooked vegetables may carry the eggs in addition to poorly cooked pork. Approximately one half of patients will show evidence of antibodies to cysticercus. The infestation is common in Mexico, India, Pakistan, and other developing countries.
Because of the predilection for inflammation after death of the organism, surgical excision of the living organism is the ideal treatment. When located in the far periphery of the eye, the larvae may be removed transsclerally ( Figure 10.27 , B–E). Transscleral removal of larvae located in the posterior pole is difficult. Photocoagulation of small larvae that do not exceed two disc diameters in size has been reported by Barsante. Even when small, however, photocoagulation treatment results in considerable inflammation and scar tissue reaction. When in the vitreous the organism may be removed by vitrectomy. Even though it is best to remove the organism intact, meticulous washout following accidental rupture during vitrectomy has resulted in preservation of the eye and visual recovery. All patients should be evaluated for additional extraocular cysticerci. Praziquantel is an anthelmintic used in treating intracranial cysticerci along with systemic steroids to quell the inflammatory response to the death of the organisms.
Diffuse Unilateral Subacute Neuroretinitis
Diffuse unilateral subacute neuroretinitis (DUSN) is a clinical syndrome characterized early by visual loss, vitritis, papillitis, retinal vasculitis, and recurrent crops of evanescent gray–white outer retinal lesions and later by progressive visual loss, optic atrophy, retinal vessel narrowing, and diffuse RPE degeneration occurring in one eye of otherwise healthy patients ( Figures 10.28–10.31 ). DUSN is caused by at least two as yet unidentified species of nematodes: a smaller one believed to be the third-stage larva of the dog hookworm and a larger worm, the larva of a raccoon roundworm, that may wander in the subretinal space for 4 years or longer and cause progressive ocular damage.
Patients may be seen initially during the early or subacute stage of the disease because of persistent vitritis and/or acute visual loss in one eye. Vitreous cells are invariably present but in some patients may be few in number. There may be mild to moderate swelling of the optic disc in the affected eye. There may or may not be any other visible changes in the fundus at that time. Visual acuity may be mildly or severely affected. A Marcus Gunn pupil reaction is usually present. A few patients may demonstrate a mild ciliary flush, anterior chamber cells, flare, and keratic precipitates. An occasional patient may have a hypopyon. Usually within several days or weeks, careful observation of these patients will disclose focal, gray–white or yellow–white lesions (with the smaller worm) and more gray–brown (with the larger worm) with fuzzy borders that involve the external layers of the retina and RPE ( Figures 10.28 , A and D; 10.29 , A, B, D, F, G, and J; 10.30 , A–C).
The lesions are typically confined to a single zone, frequently in the macular or juxtamacular areas. They typically fade from view, usually within several days, leaving minimal or mild ophthalmoscopic evidence of change in the underlying RPE. Successive crops of these lesions may occur from week to week in the same or adjacent areas of the fundus ( Figure 10.29 ) and in some cases these may completely resolve only to recur again. Focal retinal hemorrhages, perivenous exudation similar to that seen in sarcoidosis ( Figure 10.28 , J), and occasionally localized serous detachment of the retina may occur. In some patients during the early course of the disease the visual acuity may be normal or minimally affected. Over a period of weeks (larger worm) or months (smaller worm), diffuse as well as focal depigmentation of the RPE occurs ( Figure 10.28 , G–I). These changes are usually least prominent in the central macular area. The multifocal areas of depigmentation, which are most numerous in the mid peripheral fundus, may simulate those seen in the presumed ocular histoplasmosis syndrome.
Accompanying these progressive changes in the RPE is a gradual narrowing of the retinal arterioles and increasing pallor of the optic disc ( Figure 10.28 , D–I). Pigment migration into the overlying retina is uncommon. In many cases, particularly in young children, the disease is not detected until the defective vision is found on a school vision examination. Choroidal neovascularization and disciform lesions may occur in some patients. One young boy in Florida was found to have large macular subretinal fibrosis. In general, the degree of optic disc pallor and retinal vessel narrowing parallels that of central visual loss, but striking exceptions occur.
The disease is caused by a motile, white, often glistening nematode that is gently tapered at both ends and varies in length from 400 to 2000 μm, with its largest diameter being approximately one-twentieth of its length ( Figures 10.28 , A–D; 10.29 , B, C, F, and G; 10.30 , A–D, and G–L; 10.31 ). It propels itself by a series of slow coiling and uncoiling movements and less often by slithering, snake-like movements in the subretinal space. It may be found during any stage of the disease and should be looked for even in patients with advanced optic atrophy, narrowing of the retinal vessels, and degenerative changes in the RPE. The second eye is rarely affected; only one such incidence has been reported. There are at least two endemic areas in the United States for this disease. In the southeastern United States, the Caribbean islands, and Latin America the nematode varies in length from approximately 400 to 700 μm. In the other endemic area, the north midwestern United States, and in other parts of the United States, it measures approximately 1500–2000 μm in length ( Figures 10.30 , A–F; 10.31 ). Individual cases have been reported from Germany, Venezuela, India, Bangladesh, Europe, and Ghana. A careful search with a fundus contact lens, a 70 or 90 diopter lens, is required to locate the smaller worm. The larger worm is relatively easy to detect using indirect ophthalmoscopy and a fundus contact lens. The worm is most likely to be found somewhere in the vicinity of active deep retinal white lesions that probably are caused by a toxic inflammatory reaction to material left in the wake of the wandering nematode. These lesions and the worm are more frequently located in the extramacular areas. The magnification and wide field of view provided by a fundus contact lens and the fundus camera are ideal for locating these worms.
Fluorescein angiography in the early stages of the disease usually demonstrates leakage of dye from the capillaries on the optic nerve head. The gray–white areas of active retinitis are nonfluorescent early but stain during the later phases of angiography ( Figures 10.28 , E and F; 10.29 , E). Prominent perivenous leakage of dye may occur in some patients in the earliest stage of the disease ( Figure 10.28 , K), and there may be minimal or no angiographic evidence of damage to the RPE. As the disease progresses, greater evidence of loss of pigment from the RPE is manifested angiographically as an irregular increase in the background choroidal fluorescence ( Figure 10.28 , I).
The electroretinogram in the affected eye is usually reduced in all stages of the disease and often is moderately or severely reduced, with the b-wave being affected more than the a-wave in the later stages of the disease. Rarely the electroretinogram may be extinguished.
The identification of the worm is unknown. Serologic tests for Toxocara canis are typically negative. The stools are free of ova and parasites. Eosinophilia is infrequently detected. These patients do not manifest evidence of systemic disease. A small nematode was excised by means of eye-wall biopsy in one patient ( Figure 10.30 , G–I). Although there were some features that suggested the possibility of Ancylostoma caninum , its precise identification could not be made. Cunha de Souza et al. extracted a subretinal nematode through a retinotomy after pars plana vitrectomy ( Figure 10.30 , L). Unfortunately, because of poor fixation, definite identification of the worm was not possible. Grossly it showed similar features to the worm removed in Miami, and to a 380 μm long subretinal worm successfully aspirated from the eye of a patient by Professor Kuhnt in 1886 ( Figure 10.30 , K). Dr Dwight D. Bowman recently reviewed the pictures of the worm removed by Cunha de Souza ( Figure 10.30 , L) and concluded that it is most likely Ancylostoma caninum. It is of interest that three of the last 10 patients with a subretinal worm identified at the Bascom Palmer Eye Institute had cutaneous larval migrans months or several years before the onset of ocular symptoms. Ancylostoma caninum , a hookworm of dogs, is a common cause of cutaneous larval migrans in the southeastern United States. The infective third-stage larva of A. caninum is approximately 650 μm in length and is capable of surviving in host tissue, including that of humans, many months and probably years without changing size or shape. The second-stage larvae of Baylisascaris procyonis (larger worm), a nematode found in the intestinal tract of raccoons, has been suggested as a possible cause for DUSN. Although this nematode, whose larval stage measures 1000–1500 μm in length, is a common cause for meningoencephalitis in other animals, it has been rarely incriminated in similar disease in humans except a few cases in children. The infrequent history of exposure to raccoons and the absence of CNS involvement in over 100 patients with DUSN seen at the Bascom Palmer Eye Institute make Baylisascaris highly unlikely as a cause for DUSN in the southeastern United States, the Caribbean, and Latin America. In DUSN the size of the nematodes, the geographic distribution of reported cases, the clinical picture, and the infrequency of serologic evidence of infection with Toxocara canis make it unlikely that T. canis is the cause of DUSN.
The pathogenesis of DUSN appears to involve a local toxic tissue effect on the outer retina caused by worm byproducts left in its wake, as well as a more diffuse toxic reaction affecting both the inner and outer retinal tissues. This latter reaction is manifest initially by rapid loss of visual function and alteration of the electroretinogram, and later by evidence of loss of the ganglion cells (optic atrophy) and narrowing of the retinal vessels. Optical coherence tomography has shown disruption of the photoreceptor layer within weeks of onset of visual loss both at the site of the lesions and in the fovea ( Figure 10.31 , E, N, and O). Subsequently the inner retinal layers thin out ( Figure 10.31 , N). The variability of the inflammatory signs and tissue damage seen in these patients suggests great differences in host immune response to the organism.
There are differences in the color of the lesions, the motility speed, and the rate of progression of the disease between the smaller Ancylostoma caninum hookworm larva and the larger Baylisascaris procyonis ascarid larva. The lesions caused by Ancylostoma are gray–white ( Figures 10.28 A, D, and J; 10.29 , A, B, G, H, and K) and hence more visible than the lesions secondary to Baylisascaris where the lesions are gray–brown and more difficult to discern ( Figure 10.31 , C, I, and J). The larger worm travels much faster than the smaller worm. In the author’s experience, those patients who harbor the Baylisascaris worm show a more rapid rate of progression of the disease (the vision dropped to the 20/80–20/100 level within a month and to count fingers by 2 months) while in the patients with the smaller worm, the visual loss was slower and took approximately 4 or more months to drop to the 20/80–20/100 level. A possible explanation for this phenomenon is likely from the more rapid movement of the larger worm resulting in widespread release of toxic products.
Childhood infection with Baylisascaris procyonis can be associated with neural larva migrans featured by severe neurologic degeneration. Four cases have been described with ocular and neural larva migrans. The neural degeneration is progressive and widespread, with developmental delay and cerebellar and cerebral degeneration resulting in being confined to a wheelchair, incontinent, and fed by gastrostomy tubes.
Only one eye believed to be affected by DUSN has been studied histopathologically. The eye was enucleated 15 months after the onset of the disease, which was clinically suggestive of the early acute and subacute phases of DUSN. This occurred at a time before recognition of the cause of this syndrome, and it is probable that the subretinal worm was lost during sectioning of the eye during gross examination. Histopathologically the eye showed evidence of a nongranulomatous vitritis, retinitis, and retinal and optic nerve perivasculitis with extensive degeneration of the peripheral retina, mild degeneration of the posterior retina, mild optic atrophy, mild degenerative changes in the RPE, and a low-grade, patchy, nongranulomatous choroiditis. No evidence of eosinophilia or a worm was present. Failure to find sufficient structural retinal and optic nerve damage to account for the patient’s light perception-only vision at the time of enucleation suggested that the loss of visual function was partly explained on a pathophysiologic rather than an anatomic basis.
Photocoagulation, the treatment of choice, is effective in destroying the worm without causing significant intraocular inflammation ( Figures 10.29 , H; 10.30 , E; 10.31 , J and K). Locating the worm, which is always found in the vicinity of the white outer retinal lesions when they are present, may require prolonged and repeated examinations. The destruction of the Ancylostoma worm is very quick and complete with laser due to its smaller size and slower mobility. However, the larger Baylisascaris worm is far more motile and will run when laser touches it, hence it is wise to wait until it moves to an area some distance from the fovea and use fairly intense white burns to stun it and then complete the laser photocoagulation. Obtaining photographs of the laser site post treatment is important in ensuring the worm is completely dead; it often survives and can move to a new area ( Figure 10.31 , J and K). When migrating in the subretinal space, the worm is relatively isolated from the effect of orally administered thiabendazole or diethylcarbamazine, except in those patients with moderate to severe vitreous inflammation. In these latter patients, thiabendazole has been successful in causing death of the worm ( Figure 10.29 , J–L). The presence of a focal area of intense retinitis and fading of the other white lesions 7–10 days after oral administration of thiabendazole is evidence of success of the treatment, and is followed by rapid and permanent resolution of the disease. Another strategy for treatment that has proved successful in one patient, after numerous unsuccessful attempts to locate the worm in an eye with minimal inflammation, was the application of scatter laser applications surrounding and within the zone of outer retinal white lesions to disrupt the blood–retinal barrier before administration of thiabendazole ( Figure 10.32 , A and B).
Diffuse unilateral subacute neuroretinitis is a great imitator. In the acute and subacute stages, it may simulate diseases associated with unilateral papillitis, papilledema, retrobulbar neuritis, and vitritis. When associated with perivasculitis, it may simulate retinal sarcoidosis ( Figure 10.28 , J–L). When associated with active outer retinal white lesions, it may mimic acute multifocal posterior placoid pigment epitheliopathy ( Figure 10.28 , D), serpiginous choroiditis, evanescent white dot syndrome, Behçet’s disease, multifocal outer toxoplasmosis, and the pseudo-presumed ocular histoplasmosis syndrome ( Figure 10.29 , A and B). In the later stages it may be misdiagnosed as unilateral optic atrophy caused by retrobulbar or intracranial lesions, the presumed ocular histoplasmosis syndrome, unilateral retinitis pigmentosa, posttraumatic chorioretinopathy, and chorioretinal atrophy after ophthalmic artery occlusion ( Figure 10.28 , H and I). It is important to consider the diagnosis in patients with the early findings of the disease because photocoagulation of the worm will prevent further loss of visual function and occasionally will be followed by visual improvement.
It is imperative to suspect the diagnosis in those eyes that do not seem to fit the profile of multiple evanescent white dot syndrome (MEWDS), which is most often the misdiagnosis, since both diseases are unilateral and ‘photopsia’ is a common symptom in both. The fluorescein angiogram shows mild hyperfluorescence early and gets more intense in the late phase. One has to think of DUSN in any patient diagnosed as MEWDS who does not improve within 3 weeks, and if fluorescein changes persist or new lesions appear after 3 weeks ( Figure 10.31 , A, B, and H). Questions about outdoor activity, cutaneous larva migrans, travel to South and Central America, Florida, etc. should be explored. Unless one has a high index of suspicion, the diagnosis is missed until irreversible visual loss has occurred.
Also known as river blindness, onchocerciasis is caused by a nematode filarial worm called Onchocerca volvulus . It causes blindness and debilitating skin lesions infecting more than 18 million people, 99% of whom live in Africa, especially in Central and East Africa. More than 300 000 are blind and double that number are visually impaired. The remaining patients are in Latin America: Mexico, Guatemala, Brazil, Colombia, Venezuela, and Ecuador. The parasite is transmitted by small blackflies of the genus Simulium , which breed in fast-flowing streams and rivers. The microfilaria is deposited by the fly during a bloody meal and it grows into an adult worm in about a year. They live in the subcutaneous tissues over bony prominences. The adult female has a lifespan of 12–15 years and produces millions of microfilariae when fertilized by an adult male. The microfilariae swarm into the dermal layers throughout the body, have a lifespan of about 2 years themselves, and are taken by blackflies during a bloody meal.
Symptomatically and ophthalmoscopically this syndrome closely simulates some of the tapetoretinal dystrophies and begins 1–3 years after infection. The patient’s primary complaints are loss of peripheral vision and night blindness. The primary fundoscopic findings consist of varying degrees of atrophy of the RPE, choroid, and retina, with the most prominent involvement being initially in the posterior fundus, particularly in the juxtapapillary area and often in rather discretely outlined zones temporal to the macular area ( Figure 10.32 ). The chorioretinal changes are secondary to the inflammation produced by the thousands of microfilariae in the choroid, and it is only rarely that a worm is seen in the retina or vitreous. It is uncertain whether autoimmune mechanisms play a role in the pathogenesis of onchocercal chorioretinitis. These changes are usually associated with progressive pallor of the optic disc and occasional optic disc swelling and focal areas of slight swelling of the choroid. Longitudinal studies of lesions of the posterior segment in patients with untreated onchocerciasis have demonstrated progressive changes that include live microfilariae, intraretinal hemorrhages, cotton-wool patches, intraretinal pigment, white and shiny intraretinal deposits, RPE window defects, and progressive depigmentation at the edge of chorioretinal scarring at rates up to 200 μm/year. Ivermectin and mebendazole therapy did not appear to alter the progression of depigmentation of the scars.
These observations suggest that onchocercal chorioretinitis is associated with early changes in the retina and RPE, and that the retinal disease may progress rapidly. Angiographically, both the optic disc and the area of choroidal swelling show evidence of fluorescein staining. Varying degrees of RPE hyperplasia and subretinal fibrosis occur. Disciform detachment of the macula is not part of the picture. Peripheral visual field loss is often out of proportion to the atrophy of the choroid and retina, and much of the visual loss is believed to be caused by optic nerve damage. Microfilariae 100–200 μm in length have been observed biomicroscopically within or beneath the retina in patients with normal fundi and visual function. The fact that organisms occur in the choroid of these patients who have filariae throughout the body does not necessarily prove that they are the cause of the fundus changes. The observations of acute transient multifocal areas of staining at the level of the RPE and progressive changes in the optic nerve in these patients following treatment with diethylcarbamazine citrate, however, lend some support to the concept that Onchocerca volvulus is responsible for the fundus changes occurring chronically in these patients. There is some evidence to suggest that these fundus changes may be more prominent in patients who have received treatment over a prolonged period of time, compared to those who have not. Thus, it appears that onchocerciasis, either alone or in concert with some other organisms or genetic factors, is responsible for a night-blinding disease and, in at least some endemic areas, is responsible for severe disabling posterior ocular disease. The pathogenesis of this disease may prove to share some features with that of the pseudo-retinitis pigmentosa sine pigmenti that occurs in patients with diffuse unilateral subacute neuroretinitis (see p. 000).
Unlike diethylcarbamazine, which quickly eliminates microfilaria from the eye and is associated with reactive and occasionally functional ocular changes, ivermectin eliminates microfilariae slowly from the anterior chamber of the eye over a period of 6 months and causes minimal ocular inflammatory reaction or functional deficit. This slow action of ivermectin may be attributed in part to its inability to cross the blood–aqueous barrier and/or the mode of action of ivermectin, which may inactivate (paralyze) rather than kill the microfilaria. A single dose of ivermectin, 150 μg/kg, repeated once a year leads to a marked reduction in skin microfilaria counts and ocular involvement. It has no long-term effect on adult worms. There is no significant exacerbation of either anterior or posterior segment eye disease. Treatment leads to a marked and prolonged improvement in ocular status. Safety and effectiveness permit its use on a massive scale and it promises to revolutionize treatment of this disease.
The bacterium Wolbachia has been known to infest the parasite in a symbiotic relationship. Recent findings of depleting the bacterium Wolbachia by use of doxycycline has made the adult worm sterile and affected worm development.
Loa loa is a human filaria endemic in central and western Africa. The adult worm resides in the subcutaneous tissue rather than in the lymphatics. It sheds microfilariae into the bloodstream and is transmitted by the bite of a blood-sucking fly Chrysops . The microfilariae mature in the fly and move into its brain and proboscis, and are deposited in a human by the bite of the fly. They are commonly found under the skin causing ‘Calabar swelling’, that is, painful nodules. The adult worm may be seen under the conjunctiva and over the sclera. It is not known to migrate intraocularly. Those patients that are coinfected with Onchocerca and Loa loa react with significant inflammation when treated with ivermectin, resulting in severe neurologic symptoms including coma, encephalitis, retinal hemorrhages, and membranous glomerulonephritis. This is believed to be from the rapid death of a large number of microfilariae. Systemic steroids and supportive care are required in this situation.
There are over 40 species of Dirofilaria in wild (foxes) and domestic animals such as dogs and cats worldwide. All four species found in the subcutaneous tissues of humans are accidental zoonotic infections: D. immitis (dog heart worm), D. repens , D. tenuis (raccoons), and D. ursi (bears). Cases have been reported mostly in the Mediterranean region, Southern Europe, the Russian Federation, Sri Lanka, India, and the Middle East. Though subconjunctival and orbital locations are the common sites, D. repens and D. immitis have been removed from the vitreous of the human eye.
In its natural host the adult female lives in the subcutaneous tissues or the heart, and sheds microfilariae into the bloodstream. The infective third-stage larva (microfilaria) is transmitted into human subcutaneous tissue by the bite of an adult Culex or Aedes mosquito. Subcutaneous, subconjunctival, and orbital granulomatous reaction is the most common human manifestation. Sometimes, the larva grows into a small adult and has been recovered from the vitreous ( Figure 10.33 , A and B), subconjunctival space ( Figure 10.33 , G) and anterior chamber of the eye. The worm can be in the subretinal space and the vitreous cavity. Chorioretinal scars are seen diffusely all over the fundus; these do not typically look like tracks that are seen with the maggots of the botfly ( Figure 10.33 , C–F). It is possible that the dirofilarial larva moves around haphazardly in the vitreous cavity and subretinal space causing the diffuse chorioretinal changes. The visual loss appears to be moderate compared to DUSN worms, which are very toxic to the retina, and the ophthalmomyiasis from botfly larvae where patients are often asymptomatic even though the maggot has traversed the length and breadth of the subretinal space ( Figures 10.35 , G and H; 10.36 , A–I). The adult D. immitis varies in length from a few centimeters to 35 cm. Surgical removal of the subconjunctival or intravitreal worm is the treatment of choice. It is possible that the large intraocular nematode illustrated in Figure 10.34 (J–L) may have been a dirofilarial worm.
Brugia Malayi and Wuchereria Bancrofti
These are human filarial worms endemic in Asia, Latin America, and Africa. The adult worm lives in the lymphatics of humans and can block lymph flow causing elephantiasis. The adult periodically sheds microfilariae into the bloodstream. Very rarely the microfilariae can gain entrance intraocularly, likely via the choroidal circulation, and has been found in the vitreous cavity and anterior chamber, or the subcutaneous tissue of the eye and orbit. A case of placoid pigment epitheliopathy and retinal vasculitis causing neovascularization of the retina was seen by the author in a patient with W. bancrofti microfilariae in his peripheral blood. The chorioretinopathy did not respond to systemic steroids alone, but did respond to oral diethylcarbamazine citrate and the subsequent retinal neovascularization to panretinal photocoagulation.
Gnathostoma spinigerum is the most common species known to cause human gnathostomiasis. Others causing human infestation are G. hispidum , G. nipponicum , G. doloresi , and recently G. binucleatum and G. malaysiae. The worm is primarily found in Asia and Central and South America. The definitive hosts are cats and dogs. It has been reported in mammals in North America. Its life cycle involves three larval stages that develop in fresh water. In the first stage, as a free-living form, it is ingested by copepods and matures to the second larval stage. The copepods are ingested by fish, snakes, and other animals that drink contaminated water. The worm completes its third larval stage in them. At this stage humans may become facultative hosts by eating the raw infected intermediate host. Second-stage larvae can also be ingested from eating or handling raw fish. Outbreaks of visceral and cutaneous migrans have been reported due to consumption of raw fish in certain areas. It is at the third stage that the larvae may migrate for many years in humans, causing inflammation in multiple organ systems, including the skin, lungs, CNS, and eye ( Figure 10.34 , A–E).
Nineteen cases of intraocular gnathostomiasis have been reported and the worm has involved the posterior ocular segment in six instances. The commonest symptom is the sudden onset of a moving vertical or curved floater in the eye following an episode of significant eye ache. The ache in the eye subsides with the onset of the floater. Visual acuity is usually normal or only mildly affected, suggesting that the worm does not liberate any toxins early on. The parasite likely enters the eye through the retinal artery at the optic nerve head or elsewhere. The head is the broader end with a mouthpart consisting of two broad lips with two papillae on each. There are four rows of 40–48 hooklets soon after the lips. The rest of the body has transverse rows of cuticles with minute spines. The worm attaches its mouth to the retina and feeds off the blood vessels; one can see a blood column through its translucent body. The larva is alive most of the time and has been successfully removed by vitrectomy ( Figure 10.34 , A–E), with recovery of vision in most instances. At vitrectomy, efforts to suck the parasite into a soft tip cannula may be met with resistance by its tenacious attachment to the retina. Bleeding from the site(s) of its attachment is also common. A report of several retinal holes resulting in a retinal detachment by Bathrick et al. alludes to this feature. Once the worm is removed, no specific anthelmintic is necessary.
Other Nematode Infections of the Eye
Goodart and associates have reported the successful removal of a 9 mm nematode, either Porrocaceum or Hexametra , from the subretinal space of a young man with uveitis and total retinal detachment ( Figure 10.34 , F–I). The adult stages of these large ascarid larvae are found in the stomach and intestine of carnivorous reptiles, birds, or mammals. The larvae ordinarily develop within the tissues of small mammals before becoming infective for the final host. This patient probably ingested the eggs from soil or water contaminated with the feces of an owl, hawk, snake, or other carnivorous final host.
Angiostrongylus cantonensis is very rarely seen in the eye, and can be found in the anterior chamber, vitreous cavity or subretinally. The patients may be asymptomatic, mildly symptomatic, or present with significant decline in vision, pain, and redness. These patients can have uveitis, subretinal tracks, necrotizing retinitis, disc swelling, papillitis, macular and retinal edema, retinal pigment alteration, and retinal detachment. The severe pigmentary alteration is probably from inflammation of the choroid and retina due to subretinal migration of the worm prior to access into the vitreous cavity. The intermediate host is Pila sp. snail and other aquatic animals, and infection is acquired by eating raw snails, shrimp, and monitor lizards. The incubation period is between 2 weeks and 2 months.
Eosinophilic meningitis and encephalitis are other disorders caused by this nematode; the latter is fatal. It is prevalent in tropical countries, mainly Thailand, Vietnam, Japan, Taiwan, and Papua New Guinea, although ocular infestation has been seen occasionally in India and Sri Lanka. Headache, associated CSF eosinophilia, and serologic evidence of antibodies, along with a history of ingesting raw snails, help in making the diagnosis. Most reports are from Thailand. Persistent headache for more than 7 days and elderly age differentiate meningitis from encephalitis. The A . cantonensis larvae are in the meninges and subarachnoid space and cause inflammatory damage. Treatment involves albendazole and systemic steroids. The worms in the eye have all been removed surgically given the size of the worm.
In the summer of 2009, three cases of a new larva that measured approximately 2000 microns in length with a characteristic central black line through its middle ( Figure 10.33 , H, K–M) were seen in Western Pennsylvania (two in Pittsburgh and one in Williamsburg). All patients were asymptomatic or had mild symptoms. The larva leaves a track that is partly pigmented ( Figure 10.33 , K–M) and seems to move slower than the botfly larva that leaves several crisscross tracks (see Figures 10.35 , A–C, G, and H; 10.36 , A–I). There was mild inflammation at the site of entry into the subretinal space with a decrease in vision to the 20/50 level ( Figure 10.33 , I and J). Vision recovered following one injection of intravitreal bevacizumab and has remained at 20/20. The two other patients also had a similar larva and were mostly asymptomatic since the track was away from the fovea in both cases.
In order to establish the identity of the worm, exclusive search of the literature (both human and veterinary) and the Internet resulted in the larva being identified as possibly Calliphoridae, a blowfly larva ( Figure 10.33 , N).
The term ‘myiasis’ describes the invasion of the living vertebrate organism by the larval form (maggot) of certain flies in the order Diptera. The larvae responsible for intraocular invasion (ophthalmomyiasis interna) belong mostly to those genera that are obligatory tissue parasites, that is, those that exclusively require living host tissue for the completion of their larval development. These include the cattle, sheep, horse, deer, reindeer, rodent, squirrel, chipmunk, rabbit, and human botflies. Flies identified as causes of ophthalmomyiasis interna include Hypoderma bovis , Hypoderma tarandi , Cuterebra sp., Gasterophilus intestinalis , H. lineatum , Oedemagena tarandi , Oestrus ovis , Cochliomyia hominivorax , Rhinoestrus purpureus , and Gedoelstia cristata. The rodent botfly maggot Cuterebra ( Figure 10.35 , J and K) and Hypoderma are probably responsible for most cases of ophthalmomyiasis interna in the United States. The eggs or larvae may be transported to the human corneal or conjunctival surface by the adult fly, by a secondary vector such as a tick or mosquito, or by the patient’s hands. Most patients give no history of being struck in the eye by a fly. The maggots may either remain in the periocular tissues (ophthalmomyiasis externa), or bore their way through the ocular coats and come to lie in the anterior chamber, posterior chamber, or subretinal space ( Figures 10.35 and 10.36 ).
The reaction of the eye to the larval invasion varies. Signs of inflammation usually develop only after the death of the maggot. In some cases the maggot gains entrance into the subretinal space and over a period of months makes many excursions back and forth across the breadth of the fundus, creating an unusual pattern of crosshatching or ‘railroad’ tracks in the RPE ( Figures 10.35 and 10.36 ). During its entrance through the sclera and choroid and its course beneath the retina it may cause one or more small subretinal hemorrhages (see Figure 7.16, D–F). In some cases it exits from the eye without causing any symptoms, despite widespread damage to the RPE in the macular area ( Figures 10.35 , A–C; 10.36 , A and B). In one case a Cuterebra maggot was found in the conjunctiva of a boy who presented with a subconjunctival and a subretinal hemorrhage and tracks. In some cases the maggot may die in the subretinal space and cause a localized toxic reaction and a scar. In other cases it may enter the vitreous cavity, where usually it dies soon afterward, probably from lack of nutrition. The inflammatory reaction that follows varies from a minimal vitritis to an intense endophthalmitis. The caliber of the retinal vessels and the color of the optic nerve head are usually unaffected; however, optic atrophy and visual loss may occur in a few cases ( Figure 10.35 , G). Invasion of the cornea has occurred. Only rarely are both eyes affected, and this occurred in a patient from Guam (see discussion of Lytico-Bodig after this section).
Linear and arcuate tracks in the ocular fundus should always suggest the possibility of ophthalmomyiasis. The tracks are less numerous and more easily recognized in the peripheral fundus. In the posterior pole the tracks may be so numerous that their confluence may be mistaken for a variety of diffuse inflammatory, traumatic, or degenerative diseases affecting the RPE ( Figures 10.35 , A; 10.36 , A and B). In such cases fluorescein angiography is especially valuable in silhouetting the tracks ( Figure 10.35 , B and C). Although other organisms such as Toxocara canis (the nematodes responsible for diffuse unilateral subacute neuro-retinitis) and trematodes may migrate into the subretinal space, they do not produce the widespread pattern of broad RPE tracks that are believed to be pathognomonic for myiasis. The transverse rings that are present on its body leave a characteristic track with crosshatchings The curvilinear depigmented bands or bead-like arrangement of atrophic chorioretinal scars that may occur, usually at the equator in the presumed ocular histoplasmosis syndrome (POHS) and pseudo-POHS, may be mistaken for the tracks in myiasis. The author has seen two patients with an extensive network of subretinal fibrous strands and demarcation lines following spontaneous reattachment of a chronic rhegmatogenous retinal detachment incorrectly diagnosed as myiasis. A positive clinical diagnosis of ophthalmo-myiasis can be made only with visualization of the white or semitranslucent segmented maggot, tapered slightly at both ends ( Figures 10.35 , D–F; 10.36 , A and D–I).
In the presence of significant intraocular inflammation, the initial treatment of intraocular myiasis should be directed toward the reduction of inflammation with the use of corticosteroids. If inflammation cannot be controlled, surgical removal of the maggot is indicated. If the maggot is alive and the eye is free of inflammation, the clinician may elect to observe the patient carefully for spontaneous exit of the maggot from the eye. If treatment of a subretinal maggot is elected, photocoagulation is probably preferable to removal of the organism by sclerotomy ( Figure 10.36 , F). The maggot should be watched until it moves beyond the macular and juxtapapillary area before photocoagulation treatment is begun. In three patients treated with photocoagulation, no unusual inflammatory reaction occurred.
A pigmentary retinopathy simulating ophthalmo-myiasis interna is endemic in the native Chamorro Indians ( Figures 10.36 , J and K; 10.37 , A–C). This retinopathy is particularly prevalent in patients who also have Lytico-Bodig (also known as amyotrophic lateral sclerosis–Parkinsonism–dementia complex of Guam). No maggot has been observed in any of these patients. Histopathologic examination of eyes with the tracks has revealed focal attenuation of the RPE but no evidence of inflammation or a larva ( Figures 10.36 , L; 10.37 , A–C). Population surveys in Guam suggest that all of the patients with the subretinal track-like lesions are 50 years of age or older. Other than the frequent association of retinopathy in patients with Lytico-Bodig, there is no other evidence that the retina and CNS share a common etiology. The pathogenesis of both disorders is unknown. The remarkable similarity of the retinopathy to that in myiasis suggests that it may have been caused by a fly that was prevalent in Guam before the Japanese occupation in World War II. Unlike the tracks in patients with ophthalmo-myiasis, these tracks do not have the crosshatchings. The decimation of livestock and other wildlife hosts during the occupation, in addition to the widespread use of insecticides at the end of the War, may have eradicated all of the botflies, which are no longer found in Guam. These tracks are strikingly similar to tracks observed most recently in patients from Central Namibia and other regions of South Africa, suspected to be caused by the botfly Gedoelstia cristata (see next section and Figure 10.37 , G).