Chapter 173 – Posterior Parasitic Uveitis
JONATHAN D. WALKER
• Ocular inflammation as a result of infection with a helminthic parasite. The three most common are Toxocara canis, Cysticercus cellulosae, and microfilariae of Onchocerca volvulus.
• A result of ingesting eggs of Toxocara.
• Intraocular granuloma formation in the posterior pole or periphery.
• A result of ingestion of tapeworm eggs.
• Ocular cysticercosis may occur anywhere in and around the eye.
• The appearance of cysticercosis is characteristic. It has a spherical, translucent cyst cavity associated with a protoscolex that may evaginate or invaginate in response to examination lights.
• The presence of the microfilaria, alive or dead, in the ocular structures.
• Manifestations include sclerosing keratitis, iridocyclitis, glaucoma, and chorioretinitis.
• Ocular manifestations occur in systemically asymptomatic older children.
• Traction develops on the macula or optic disk or both.
• Death of the organism causes marked intraocular inflammation.
• Central nervous system cysticercosis may occur.
• Onchocerciasis causes punctate keratitis.
• Secondary glaucoma.
• Optic atrophy occurs.
EPIDEMIOLOGY AND PATHOGENESIS
The adult dog usually acquires Toxocara canis infection by eating eggs or second-stage larvae found in contaminated soil or infected meat or feces. The larvae encyst, and if the animal becomes pregnant some of the larvae may reactivate, at which time they can infect the fetal puppies in the uterus. Following birth the larvae then migrate to the puppy’s lungs, are coughed up and swallowed, and finally grow to become egg-producing adult worms in the gastrointestinal tract. The eggs begin to be excreted about 4 weeks after birth. Puppies are extremely important in the development and spread of this organism; ascertaining exposure to puppies may be a key part of the clinical history. However, T. canis is ubiquitous and soil samples show a rate of contamination in the range 10–92%.  As a result, human infection can occur fairly easily, especially in people who are exposed to puppies or who have a history of ingesting contaminated soil. Studies on populations demonstrate serological evidence of T. canis infection in the range 2–10%, but this may be as high as 80% in endemic areas. 
Following ingestion of the eggs a systemic Toxocara infection, known as visceral larva migrans, develops. This generally occurs in patients who are around 2 years old, which is younger than the average age of patients who have ocular disease. The actual clinical picture of patients who have visceral larva migrans may vary, depending on the number of eggs ingested, distribution, and host immune factors. The eggs hatch in the intestines, and the larvae enter the bloodstream and migrate until the narrowing of the vascular lumen blocks progress. At this point the larvae enter the tissue and encyst; they often are found in the brain, liver, and lungs. Patients may have irritability, fever, and pulmonary and dermatological findings. Most cases probably go unrecognized because of few or no symptoms. Typical laboratory findings include a very elevated white blood cell count with a very high percentage of eosinophiIs. Because the larva is incapable of completing its life cycle in humans, there is no point in checking stool for ova and parasites. It is uncommon for patients who have ocular toxocariasis to report a history suggestive of visceral larva migrans.
The ocular disease may appear in a number of ways, the most common being in the form of a dense white granuloma in the posterior pole or retinal periphery where the larva has encysted. The inflammatory mass then contracts and draws the retina and vitreous toward the lesion ( Fig. 173-1 ). A common finding with peripheral granulomas is a radial fold in the retina that extends from the optic nerve to the mass ( Fig. 173-2 ). Vision may decrease markedly if the granuloma affects the optic nerve or posterior pole, or if significant dragging of the posterior pole occurs toward a more peripheral lesion. Late development of a rhegmatogenous retinal detachment may develop if holes occur in the atrophic retina that is being elevated by the traction. The granuloma itself often is white and globular, with a size of about one disc diameter. The eye usually is quiet, but low-to-moderate levels of smoldering inflammation may occur, even with what appears to be an old quiescent granuloma.
Patients may have a more marked inflammation that may simulate endophthalmitis, probably due to massive antigen release by dying organisms. Usually a significant vitreous reaction
Figure 173-1 Typical toxocara granuloma located over the optic nerve. Note how the surrounding retina is drawn toward the lesion.
occurs with a variable anterior chamber response. The eye may have surprisingly little injection or discomfort. As the inflammation subsides, it may be possible to identify a typical granuloma. Some eyes, however, may develop severe complications that can lead to phthisis. Another clinical picture consists of living, mobile larvae identified within the eye,    although this simply may be other nematodes in a patient who also happens to have identifiable Toxocara titers. Other more unusual manifestations include optic neuritis, neuroretinitis, and late choroidal neovascularization.     Also, this disease entity can be acquired in later ages and should be considered in older patients who have new onset of a localized inflammatory granuloma. 
The diagnosis usually is straightforward, with the classic features of a whitish granuloma and surrounding vitreoretinal traction. Confirmation usually is by enzyme-linked immunosorbent assay (ELISA) titers. In general, a titer of 1:8 or greater supports a diagnosis of ocular toxocariasis. In the appropriate clinical situation even lower titers may be useful, and there is at least one case of histologically confirmed infection with negative ELISA testing results. The possible seropositivity of a given population to this test must be considered, and any positive results should be viewed only in terms of the overall clinical picture. Other diagnostic approaches include ELISA titers on aqueous or vitreous specimens, or the demonstration of a preponderance of eosinophils on cytological examination of the aspirate.  Ultrasonography may show characteristic findings, which include a highly reflective peripheral mass, and vitreous bands or retinal folds that extend from the mass. Ultrasonographic biomicroscopy may demonstrate a very unusual pseudocystic appearance in the vitreous base.
The differential diagnosis of ocular toxocariasis varies depending on the clinical picture. In the past, perhaps the most common difficult diagnosis was between toxocariasis and retinoblastoma. Retinoblastoma usually is diagnosed earlier in life, and a positive family history often is present. Exophytic retinoblastoma usually has an overlying retinal detachment with clear vitreous, whereas endophytic retinoblastoma may have a hazy vitreous but no evidence of the vitreoretinal traction that occurs around Toxocara lesions. Patients who have retinoblastoma also are less likely to develop a cataract. Computed tomography may be useful, especially in demonstrating areas of calcification in retinoblastoma. Although small amounts of calcium have been
Figure 173-2 Falciform fold. It extends from the optic nerve (top) to a peripheral toxocara granuloma (bottom).
described echographically in Toxocara lesions, this is more likely to be seen in older patients who have quiet eyes in whom the differentiation of a Toxocara granuloma from retinoblastoma is much less problematic.
Other conditions may be confused with toxocariasis. Coats’ disease can be differentiated by the lack of discrete granuloma formation, the presence of an exudative detachment, and the abnormal retinal vasculature associated with prominent subretinal fluid. Persistent hyperplastic primary vitreous generally is recognized earlier in life; the characteristic findings include a smaller eye and a retrolental fibrovascular membrane. More posterior persistent hyperplastic primary vitreous usually has an obvious hyaloid artery that extends from the nerve, with no peripheral granuloma. Retinopathy of prematurity, familial exudative vitreoretinopathy, and peripheral trauma may be seen with peripheral traction that superficially may resemble a Toxocara lesion. These entities usually are differentiated on the basis of history and clinical appearance. Toxocariasis should also be considered in the differential diagnosis of patients who appear to have a purely unilateral pars planitis.
It may be difficult to distinguish between the endophthalmitic manifestation of toxocariasis and other causes of acute endophthalmitis. Toxocara endophthalmitis has a tendency to be gradual and indolent; however, it may be fulminant and if the diagnosis is not clear, a vitrectomy with culture and injection of intraocular antibiotics may be necessary.
The pathology of toxocariasis consists of granuloma formation with a predominance of eosinophils ( Fig. 173-3 ). The eosinophilic infiltrate may be so severe as to create an abscess, which is surrounded by a more typical granulomatous response of epithelioid cells, lymphocytes, and plasma cells. The actual identification of a larva may require multiple sections of the tissue; the simple presence of a marked eosinophilic response is essentially diagnostic for toxocariasis.
Eyes that have active inflammation generally require treatment with systemic or periocular corticosteroids. Patients who have a mild inflammatory component to their toxocariasis may have disease that smolders for some time; therapy should be designed to both control inflammation and minimize systemic side effects. No clear guidelines exist about the use of antihelminthic therapy. If the eye disease is not responsive to corticosteroids, or if it is associated with systemic symptoms or a very high antibody
Figure 173-3 Histopathology of a toxocara lesion. Inflammatory infiltrate surrounds the organism.
titer, it may be more reasonable to treat with an anhelmintic agent such as thiabendazole  or albendazole.[21A] Vitrectomy may be required for anatomical abnormalities such as retinal detachment, epiretinal membranes, or macular distortion. The granuloma itself usually is invested in retinal tissue and not removed easily without a retinectomy. Small et al. reported a series in which it was shown that improvement in visual function generally occurred only with reasonably good preoperative levels of vision. A poor outcome is associated with a large fold in the macular region, and there is a fairly high risk of late redetachments.  For cases in which a mobile larva can be identified, photocoagulation has been recommended.   It is important to destroy the larva completely to avoid a significant inflammatory response; a marked increase in inflammation should be anticipated and the patient treated as needed with corticosteroids.
EPIDEMIOLOGY AND PATHOGENESIS
Cysticercosis is caused by the Cysticercus cellulosa larvae of the adult tapeworms Taenia solium and T. saginata. Although the larvae may be present in many tissues, clinical disease usually is identified only in patients who have cerebral or ocular problems. The term cysticercosis implies infestation with the larval stage of the organism and should not be confused with taeniasis, which describes the presence of the adult tapeworm in the intestines.
Humans are the definitive host of T. solium. The adult worm lives in the small intestine, where it releases proglottids, which ultimately disintegrate to release eggs. Pigs are the intermediate hosts. They become infected by ingestion of soil contaminated with eggs. The eggs hatch and the organisms spread through the animal and encyst. Human beings are then infected by eating incompletely cooked pork that contains the cysts. The cysts then go on to develop into adult tapeworms in the intestines to complete the cycle. Cysticercosis occurs when human beings ingest the actual eggs; this may occur through fecal-oral contamination or autoinfection from reverse peristalsis. These eggs then hatch and penetrate the gut wall to disseminate throughout the body forming cysts, as normally occurs in the intermediate host. 
Any part of the visual system can be affected, from the visual cortex to subconjunctival involvement. Posterior segment involvement
Figure 173-4 Cysticercus in the eye. The large cavity of the cysticercus is visible, as well as the denser white area of the protoscolex.
appears to be most common.  Ocular symptoms may vary depending on the location of the infection. They include loss of vision and orbital or even neuro-ophthalmic symptoms. The appearance of the organism is very characteristic; it has a spherical, translucent cyst cavity associated with a protoscolex that may evaginate or invaginate in response to examination lights ( Fig. 173-4 ).
The diagnosis usually is made by identification of the organism in the eye. Extraocular involvement may require radiological imaging of the orbit and central nervous system. In patients who have opaque media, the ultrasonographic appearance is very characteristic. It shows the spherical area of the cyst associated with the localized solid region of the protoscolex.
The clinical manifestations of cysticercosis depend on the location, size, and number of organisms present in the body. Central nervous system symptoms occur in a high percentage of cases, including seizures, focal neurological deficits, hydrocephalus, and mental status changes, and also symptoms of meningitis. 
A living cysticercus usually induces no significant immune response. There is only mild fibrosis around the cyst. When the cysticercus dies, however, the inflammation becomes much more marked, with an acute granulomatous inflammatory infiltration. Secondary pathological findings then are related to the amount of inflammatory damage, which may include disruption or scarring in the retina, retinal pigment epithelium, or choroid. Glaucoma or cataract also may occur if anterior segment structures are involved.
Localized ocular or adnexal cysticercosis generally is treated by surgical removal, because death of the organism results in marked inflammation and severe damage to the eye.    Vitrectomy usually is required for posterior segment involvement. The organism itself can be removed either by aspiration through the vitrectomy handpiece or by extraction through a pars plana sclerotomy. If the cyst is ruptured, care should be taken to remove all of the residual debris to prevent severe postoperative inflammation. Orbital involvement may respond to
medical therapy alone, but patients may need to be treated with steroids to avoid inflammatory damage around dying cysts. The treatment of neurocysticercosis generally involves observation or use of oral albendazole or praziquantel and supportive measures for neurological problems.
COURSE AND OUTCOME
Reviews of treated cases suggest that early removal of the organism is associated with preservation of visual function.    If possible, ocular cysts should be removed before systemic treatment is undertaken to prevent damage from death of the intraocular organisms.
EPIDEMIOLOGY AND PATHOGENESIS
The parasite Onchocerca volvulus is transmitted by the blackfly. The geographical distribution of the disease is characterized by local areas where the blackfly breeds most effectively. Onchocerciasis is endemic across equatorial Africa, Yemen, Mexico, and areas of Central America and northern South America.
An infected blackfly deposits several larvae with each bite. Over a year the larvae develop into mature adult worms. The worms remain encapsulated in characteristic nodules from which they release large numbers of microfilariae. These microfilariae then migrate throughout the body and may be taken up by another blackfly when the host is bitten. The result is that people who live in endemic areas are reinfected continually. As long as adult worms are present in the nodules, a constant stream of microfilariae is produced and all susceptible tissues are invaded. The microfilariae themselves may live up to 2 years. Upon their deaths they may stimulate a localized immune reaction in the involved tissues.
The most significant morbidity associated with onchocerciasis occurs as a result of ocular involvement. The microfilariae can invade all the ocular structures, but the earliest sign of involvement is the presence of microfilariae in the anterior chamber, best demonstrated after the patient has been in a face-down position for several minutes before the examination. Live microfilariae are difficult to identify in the cornea, but a characteristic inflammatory infiltrate and punctate keratitis can surround dead microfilariae. The chronic inflammation brought on by the presence of large numbers of microfilariae in the cornea results in the development of sclerosing keratitis ( Fig. 173-5 ). This initially begins in the peripheral cornea in the intrapalpebral areas and gradually spreads across the entire cornea. A variable amount of anterior uveitis also may occur and patients may develop granulomatous changes, synechiae (leading to angle-closure glaucoma), and irregular iris depigmentation. Chronic, blinding chorioretinitis is another feature of this entity. Patients develop areas of depigmentation that proceed to coalesce and become large areas of geographical atrophy ( Fig. 173-6 ). Patients may develop optic atrophy in excess of the chorioretinal damage either as a function of a microfilaria in the optic nerve or as an inflammatory response caused by death of microfilaria. Occasional patients may have evidence of intraretinal inflammation, such as cotton-wool spots, hemorrhages, or vasculitis. Intraretinal microfilariae also may be identified with careful contact lens examination.
The diagnosis usually can be made by identification of the microfilariae in tissues. Skin snips can be used to look for the emergence
Figure 173-5 Sclerosing keratitis as a result of onchocerciasis. (Courtesy of Professor HR Taylor.)
Figure 173-6 Extensive chorioretinitis as a result of onchocerciasis.
of microfilariae from the sample. Skin nodules may be sampled for biopsy to determine the presence of adult worms as well. In endemic areas, a tentative diagnosis can be made based simply on the presence of typical skin nodules and ocular features.  Present research is directed at using polymerase chain reaction probes to identify small numbers of organisms to determine whether patients are truly free of disease or simply have a very low organism load.
Clinical features are a function of both degree of infection and of immune response. The bite of the blackfly usually resolves in a few days, followed by a latent interval of 6–24 months during which the larvae develop into mature worms, which release microfilariae that migrate and begin to die in tissues. The most common early manifestation is pruritus caused by inflammation around dead microfilariae in the skin. With time, the constant irritation in the skin results in pigment changes, lichenification, and loss of dermal collagen (the last results in the skin hanging loosely, especially around the groin and face). Nodules that contain adult worms (onchocercomas) usually are found around the pelvis or in the head and shoulder region.
Figure 173-7 Microfilariae. A, Histological section of a conjunctival biopsy shows a chronic nongranulomatous inflammation and a tiny segment of worm in the deep substantia propria. B, Shown under higher magnification. N, Human fibrocyte nucleus. (Case reported in Scheie HG et al. Ann Opthalmol. 1971;3:697.)
Microscopically the iridocyclitis is characterized by mild, chronic nongranulomatous inflammation. Microfilariae ( Fig. 173-7 ) can be found in the stroma; similar lesions have been observed in the choroid.
The treatment of onchocerciasis has been revolutionized by the development of ivermectin, and tremendous strides have been made because the company that makes the drug has offered it free of charge as long as necessary.
The drug is given at a dosage of 150?µg/kg PO and is repeated every 3 months. It is very effective at killing microfilariae, although it is ineffective against the adult worm. As a result, continuous treatment is required to decrease the load of microfilariae in infected individuals. Perhaps the most important treatment approach is to prevent infection. This involves vector control through treatment of areas infested with blackflies, as well as measures against fly bites, such as avoidance of areas known to be infected and the use of protective clothing and insect repellents. However, socioeconomic constraints in infested areas make preventive measures very difficult to implement.
COURSE AND OUTCOME
Blindness is the major disability caused by onchocerciasis and has profound effects on villages in endemic areas. This disease carries a significant toll, because it affects otherwise healthy adults who have the greatest responsibility for supporting families. If individuals are affected to the point of blindness, they have a high risk of death within 10 years.  Treatment with ivermectin can markedly reverse the anterior segment manifestations of onchocerciasis. Chorioretinitis responds less predictably and may be the result of a combination of infectious damage and possibly autoimmune mechanisms. The overall effect of treatment programs, however, has been a significant decrease in morbidity from the disease and prevention of the devastating socioeconomic consequences of this infection.
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