Infectious Diseases of the Pediatric Retina

With few exceptions, infectious agents causing posterior uveitis in children are the same as those causing disease in adult patients. The mode of transmission, clinical presentation, and the implications of infection in children, however, may vary significantly compared to the same disease in an adult. Clinical features also vary depending on the age of the child, route of transmission, and developmental status.

This chapter is organized into six sections, based upon the etiologic agents responsible for infection: protozoa, viruses, parasites, bacteria, fungi, and rickettsia. The focus is primarily on the posterior segment manifestations of the infectious process. Other ocular manifestations and systemic manifestations are included where knowledge of these features may prove useful in facilitating diagnosis.

The bulk of the literature on infectious posterior segment disease involves disease in adults, reflecting the fact that such diseases are more common in older individuals. Information about specific disease manifestations in childhood is provided when available, though some information must be extrapolated from the adult literature.

M. Hussein

UT Southwestern Medical center, Dallas, TX, USA

D.K. Coats (*)

Baylor College of Medicine, Texas Children’s Hospital, 6621 Fannin, CCC 640, Houston, TX 77030, USA e-mail: dcoats@bcm.tmc.edu

Protozoa are the simplest and most common animals within nature. Their name (proto: first; zoon: animals) underscores their position in the evolutionary sequence as these unicellular animals are thought to have preceded multicellular species. They do not form differentiated tissues but are capable of organization. A number of protozoal agents are capable of causing ocular disease in children. Toxoplasma gondii is the commonest protozoal infection involving the eye and is thought to be among the most common causes of posterior uveitis [1, 2]. Trypanosoma cruzi, trypanosoma bruci, giardia lamblia, plasmodium falciparum, and entamoeba histolytica are other protozoal agents that can involve the eye, though posterior uveitis caused by protozoal infections other than toxoplasma is uncommon.

16.2.1  Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite. Members of the cat family are its only definitive host, but hundreds of other species including mammals, birds, and reptiles may serve as an intermediate host. T. Gondii exists in three forms. Oocysts are products of sexual production and are shed in the feces of cats. Ingestion of sporulated oocysts can cause infection in both the definitive and intermediate host. Tachyzoites are the obligate intercellular form of the parasite. They are capable of invading nearly all host tissues. Tissue cysts begin to form 6–8 days after the initial infection and may persist in a viable state within tissues for life of the host. The term bradyzoites is used to describe organisms within these tissue cysts.

16.2.1.1  Life Cycle and Transmission

Cats are the definitive hosts of the parasite T. gondii. Cats are infected with T. gondii through ingestion of the tissue cysts in the flesh of infected birds and rodents or through ingestion of sporulated cysts. During an enteroepithelial cycle that takes place within the villi of the feline ileum, the organism develops into the sexual form, known as gametocytes. This process results in the shedding of a resistant form of the organism known as oocysts [3]. Large numbers of oocysts are shed in the feces following even a shortlived infection, and they may remain viable for as long as 13–18 months depending on the climatic conditions [4]. As a result of fecal contamination of food and water, the oocysts may be either reingested by cats or ingested by intermediate hosts, including humans. Humans can be infected in a variety of other ways. Ingestion of undercooked meat of intermediate hosts containing bradyzoits, transmission through blood products and organ transplantation ([5, 6], and inhalation of sporulated oocysts [7] are known routes of transmission to humans. Ingestion of materials contaminated with cat feces is the most important route of transmission to children.

After ingestion, rapidly replicating parasites (tachyzoites) are released and pass through the intestinal wall. They probably enter leucocytes from which they become widely disseminated throughout the body [8]. In an immunocompetent patient, an acute acquired infection is usually asymptomatic or presents with lymphadenopathy.

16.2.1.2  Epidemiology

Kean [1] estimated the number of infected persons around the world to be around 500 millions. In the United States, serological evidence of T. gondii infection ranges from 3 to 70% of the healthy adult population [2, 9]. A recent decline in the incidence of the disease may be related, in part, to widespread public awareness of the dangers of exposure of pregnant women to cats [10]. Freezing of commercial meats may play a role in reducing the incidence of the disease spread through undercooked meat [10]. Environmental conditions greatly influence the presence of antitoxoplasma antibodies in certain areas. Their presence is higher in tropical areas and is lower in cooler areas [11].

Understandably, they are more common in areas where consumption of raw meat is common and in areas with poor sanitation.

In the United States, about 70–80% of women at childbearing age are at risk of developing a primary infection by exposure to the organism [12]. The prevalence of acquired toxoplasmosis during pregnancy has been estimated to range from 0.2 to 1% [13]. The risk of fetal infection is highest (approximately 60%) when infection is acquired during the third trimester and lowest (approximately 30%) when acquired in early pregnancy ([13]. The severity of fetal damage is less with infection acquired in the later stages of pregnancy ([14].

Maternal immunity protects against fetal infection and thus mothers infected before pregnancy have only a remote chance of giving birth to an infected child. Mothers with one infected child are likewise less likely to have a second infected child [12, 15, 16]. Estimates on the incidence of congenital infection are highly variable ranging from 1 in 300 to 1 in 8,000 births [12, 13, 15].

16.2.1.3  Congenital Infection

Infants may have congenital infection without clinical evidence of disease. Guerina and associates [17] used routine serological screening to detect toxoplasmosis specific IgM antibody. Through routine serology of 635,000 infants, congenital infection was confirmed in 52 infants, 50 of whom were identified through ­screening but not through clinical examination. Many infected infants will develop retinal disease or neurological abnormalities later in life, despite apparent disease inactivity at birth. Examination of apparently normal infants may reveal chorioretinal scars, intracranial calcifications, or other manifestations of infection. Because congenital toxoplasma infection may not produce obvious signs of infection at birth, there is growing interest for more sophisticated investigations and well-planned serological testing for those newborns suspected of having the disease [17]. Early detection of an “inactive” disease may allow prophylactic treatment.

Active disease at birth is characterized by encephalitis, lymphadenopathy, hepatosplenomegaly, pneumonitis, jaundice, rash, thrombocytopenia with petechiae, gastrointestinal symptoms, and a range of neurological

manifestations including hydrocephaly, microcephaly, and seizures [18]. The classic triad of convulsions, calcifications, and chorioretinitis are no longer necessary for the diagnosis of congenital infection, which can now be established on the basis of serology and the presence of CNS manifestations. Markedly elevated CSF protein is the hallmark of active congenital toxoplasmosis [18, 19]. Active disease at birth is almost uniformly fatal with few infants surviving past the first few months of life.

16.2.1.4  Ocular Disease

Toxoplasma is the most common pathogen to infect the retina in otherwise healthy individuals [2]. Chorioretinal scars are the most common ocular manifestation of inactive congenital toxoplasmosis. Characteristically, retinochoroidal lesions in congenital toxoplasmosis are bilateral and have a predilection for the posterior pole. A high incidence of macular scars and severe visual impairment is common [11, 14, 20] (Fig. 16.1). In active congenital Toxoplasmosis (Fig. 16.2), severe vision loss from retinal disease or cortical blindness is common [21].

Toxoplasmic retinochoroiditis have similar features whether due to congenital or acquired infections. The retinal lesions may be localized or diffuse, single or multiple. They are often unilateral in acquired infection. The lesions are typically reasonably circumscribed with overlying vitreous haze, which may be mild or severe (Fig. 16.3). Intense iridocyclitis with cellular reaction in the aqueous or in the cornea can be seen in some cases. When the lesions heal, they leave atrophic scar with

Fig. 16.1  Inactive toxoplasmosis with multilple pigmented and non-pigmented scars involving both the central and midperipheral retina

Fig. 16.2  Congenital toxoplasmosis

Fig. 16.3  Active toxoplasmosis with vitreous haze overlying a circumscribed lesion of chorioretinitis

pigmented borders [22] (Fig. 16.1). A high incidence of posterior pole involvement was found in a study conducted by Friedman and Knox [23]. Hogan and associates, on the other hand (1964) [22], could not confirm this predilection for posterior pole involvement.

Three distinct types of retinochoroidal lesions have been described [23]. They are (1) large destructive lesions more than one disc diameter in size and associated with high incidence of visual loss, (2) inner punctate lesions that are smaller and associated with less vitreous reaction, and (3) deep punctate lesions that typically have a more central location. Retinal edema is more common with deep lesions, but less vitreous reaction is noted.

There is definite evidence that recurrent retinal disease is caused by reactivation of bradyzoites located at the border of retinochoroidal scars [24, 25]. Lesions remote from the site of old scars, however, are not uncommon. The presence of retinal cysts without

previous disruption of the retinal architecture is one proposed explanation for this phenomenon [26]. Traditional teaching assumed that active ocular disease usually resulted from reactivation of a congenital infection. Wilson et al. [27] reported ocular lesions in congenitally infected individuals to be as high as 85%. In contrast, only 3.6% of individuals infected in an epidemic of acquired toxoplasmosis developed ocular lesions after 4 years of follow-up [7, 28]. Another argument that favors reactivated congenital infection as the usual cause of ocular disease is the fact that the prevalence of ocular disease does not increase with age, whereas the prevalence of T. gondii infection does [29].

The mechanism by which the acute inflammatory ocular disease is triggered is not fully understood. Toxoplasma cysts remain within intact host cells in the retina and only when host cells die are the parasites released [30]. One hypothesis is that the bradyzoites rupture initiating an acute inflammatory episode resulting in a hypersensitivity reaction to the toxoplasma antigen and causing a characteristic granulomatous inflammatory response [3]. It is clear that T. cell lymphocytes working together with macrophages are responsible for killing or halting the reproduction of the toxoplasma parasite in tissues [31]. Release of acid hydrolase and other enzymes produced by phagocytosis in the killing of the organism is thought to be responsible for the destruction of the adjacent normal cells. Necrotizing retinitis due to toxoplasmosis may occur without an inflammatory response in immunosuppressed patients with impaired T cell function [32].

The factors that cause recurrence with reactivation of the organism are not fully understood. Senescent changes of the bradyzoites and perhaps spontaneous rupture of the cyst wall may be to blame [33]. Mechanical rupture of the cyst with parasite multiplication, reinfection with other strains, or a hypersensitivity reaction to toxoplasmic antigens has been proposed [34, 35].

Hormonal factors may also be important based on the increased frequency of reactivation during pregnancy [36, 37]. Trauma was suspected as a cause of recurrence in some cases [37, 38]. Reports are conflicting regarding the role of immunosuppression in triggering disease reactivation. While disease reactivation was achieved by immunosuppression in a rabbit by injection of antilymphocyte serum [38], immunosuppression induced by total irradiation in cynomolgus monkeys failed to reactivate the disease [39].

Recurrent toxoplasmic retinochoroiditis is not usually associated with symptoms but can be associated

with floaters from vitreous haze and diminution of vision caused by macular involvement with retinitis or edema. An associated anterior uveitis may present with red and painful eye. Other less common ocular manifestations can occur. The optic nerve can be involved in a variety of ways, including toxoplasmosis induced papillitis and juxtapapillary retinitis. Optic disc edema may also develop secondary to macular lesions [40]. Neuroretinitis with optic disc swelling, splinter-shaped hemorrhages, and star-shaped hard exudates involving the macula has also been reported [41, 42]. Periarteritis and periphlebitis with sheathing of the retinal vessels have been seen, and panuveitis with extensive retinal necrosis resulting in phthisis bulbi may rarely occur [22, 43].

Isolated cases of microphthalmos and microcornea [44, 45] in association with congenital infection have been reported. Nystagmus and strabismus may be present in congenital toxoplasmosis, due to cortical cranial nerve palsy, or extensive macular involvement with sensory deprivation [46, 47]. Strabismus and ocular motility problems can also occur with acquired ocular infections and in toxoplasmic encephalitis [27]. Finally, macular edema [48], retinal and subretinal neovascularization [48–50], rhegmatogenous, and tractional retinal detachment [39] are possible.

Fluorescein angiography of the main reactivating focus is characterized by early hypofluorescence rapidly replaced by progressive hyperfluorescence of the lesion [51] (Fig. 16.4). It is of little use in diagnosis and management of the disease. Indocyanine green angiography produces hypofluorescence in the main lesion at all phases of the angiogram in most patients. The most important feature, however, is the presence of multiple hypofluorescent satellite dark spots, which are not seen clinically, and which disappear in most cases following therapy [51].

Fig. 16.4 Fluorescein angiography showing hyperfuorescence of an active toxoplasma chorioretinal lesion