(a, b) Fundus photographs demonstrating early stage findings of DUSN. There are crops evanescent, multifocal, gray-white lesions at the level of the outer retina in the superior fundus (arrow). The intraocular worm is seen in insert (b) as a motile, white worm
This chapter reviews the pathogenesis, clinical features, differential diagnoses, and management options for diffuse unilateral subacute neuroretinitis.
Etiology and Mode of Transmission
Various parasites and nematodes have been reported as the etiologic agent of DUSN; however, most of these reports did not provide conclusive evidence (Arevalo et al. 2013). The smaller nematodes measuring 400–700 μm in size include Toxocara canis and Ancylostoma caninum were seen more commonly than the larger ones ranging from 1000 to 2000 μm in length, corresponding to Baylisascaris procyonis (Gass 1987). Rarely, Thelazia, nematodes of 4500–17,000 μm in size, were implicated in DUSN (Gass and Scelfo 1978; Kunavisarut et al. 2014). The smaller nematodes are endemic to the southeastern United States, the Caribbean islands, and South America, whereas the larger nematodes are found in the Midwestern United States. Trematodes, flatworms, have also been reported in DUSN.
Identification of the causative nematode in DUSN has been challenging as few were surgically extracted from the eye, and fewer were recovered intact (Arevalo et al. 2013). Blumenkranz and Culbertton performed a retinal biopsy via a transcleral approach but could not identify the organism (Blumenkranz and Culbertton 1985). Gass extracted a subretinal nematode transclerally after applying cryotherapy, although he could not identify the organism due to poor histologic details (Gass 1987). Therefore, traditionally, identification of the organism has been based on a combination of examination of morphologic features, serologic testing, and epidemiologic studies. More recently, newer techniques allow for the identification of nematodes through molecular studies and phylogenetic analyses (Poppert et al. 2017; Liu 2012). Polymerase chain reaction amplification and sequencing analysis of ribosomal ribonucleic acid and internal transcribed spacer regions 1 and 2 are used as target regions to differentiate between various parasites (Liu 2012). In the future, perhaps these techniques can be applied to intraocular fluid samples to help the identification of nematodes.
Toxocara canis
Toxocara is an infection in canine hosts accounting for the most prevalent human helminthic infection in industrialized countries (Hotez and Wilkins 2009). Humans acquire the disease via contaminated water sources and ingestion of infected raw meat. Gass initially hypothesized that Toxocara was a cause of DUSN (Gass et al. 1978), however ruled out this possibility based on negative serology in many patients. Additionally, the small size of the larval stage of Toxocara made it difficult to be seen biomicroscopically (Gass and Braunstein 1983). It is poorly understood why the clinical picture is different from that associated with ocular toxocariasis. Goldberg et al. described cases with evidence that low or nondiagnostic serum titers can be found in cases of Toxocara ocular larva migrans and may represent a false-negative test result (Goldberg et al. 1993; Searl et al. 1981; Wilson and Schantz 1991). Oppenheim et al. reported a case of Toxocara DUSN in which the patient’s positive ELISA titer decreased fourfold over a 2-year period (Oppenheim et al. 1985). Therefore, a negative serologic test may be related to the timing of the serology in relation to the onset of the disease or the immune status of the patient.
Ancylostoma caninum
This worm is a parasitic infection of dogs in South America. Ancylostoma ceylanicum has been reported in dogs and cats in Southeast Asia, India, and Australia (Carroll and Grove 1986). A. caninum is a frequent cause of cutaneous larva migrans in the southeastern United States. Cutaneous larva migrans can be acquired through the fecal–oral route with dog feces contaminated with infectious eggs. Alternatively, larvae may enter through the skin, migrate through the blood stream to the lungs and trachea, and are then coughed up and swallowed into the gastrointestinal system. They attach themselves to the intestinal wall and begin to reproduce. Once eggs are shed into the environment through feces, the life cycle is complete (Arevalo et al. 2013).
In earlier reports, Gass and Braunstein suggested that the nematode less than 1000 μm in length was the dog hookworm, Ancylostoma caninum (Gass and Braunstein 1983). Later, de Souza et al. recovered an intact and motile organism via transvitreal approach (de Souza and Nakashima 1995). While parasitologists believed that morphologic features were consistent with a third-stage Toxocara larva, a photograph review by Bowman concluded that it was most likely A. caninum (Gass 1987). The association of cutaneous larva migrans months, several years, or immediately preceding the onset of DUSN in some patients suggests that Ancylostoma caninum may be the small nematode that causes the syndrome (Gass 1987; Gass and Olsen 2001). In addition, the infective third larval stage of A. caninum is capable of surviving in host tissue for years without changing size or shape (Gass and Olsen 2001). In one case reported by Poppert et al., although the worm was destroyed during surgical extraction, it was identified through DNA sequencing and phylogenetic analysis of intraoperative fluids as A. ceylanicum (Poppert et al. 2017).
Baylisascaris procyonis
Baylisascaris procyonis is a nematode causing a parasitic infection of raccoons. In humans, it causes severe neurologic and ocular diseases, including visceral larva migrans, ocular larva migrans, and eosinophilic meningoencephalitis (Fox et al. 1985; Mets et al. 2003). B. procyonis can be detected in the serum and cerebrospinal fluid using indirect immunofluorescence assays. Goldberg reported ocular larva migrans and DUSN occurring without systemic evidence of infection (Goldberg et al. 1993).
In 1984, Kazacos suggested that the larger worm in patients with DUSN living in more northern climates was Baylisascaris procyonis (Kazacos et al. 1984). He proposed that B. procyonis larvae produce ocular larva migrans with a clinical picture that is similar to that of early DUSN in subhuman primates and other experimental animals after oral infection (Kazacos et al. 1985). Additionally, the B. procyonis larvae may grow while in the eye and can account for the range of lengths of larvae seen (400–2000 μm), matching the larger nematode variant of DUSN (Kuchle et al. 1993). Although most patients have no history of raccoon exposure, most patients with large nematode DUSN are from the areas of the United States with raccoons commonly infected with B. procyonis (de Souza et al. 1999; Kazacos and Boyce 1989). Furthermore, large nematode DUSN occurred in the same regions where animal and human diseases due to B. procyonis have been recorded (midwestern and northeastern regions of the United States). Environmental contamination with raccoon fecal materials is common around suburban homes and barns. Accidental hand-to-mouth transfer of infective B. procyonis eggs may cause infection in humans (Goldberg et al. 1993).
Trematodes
Four cases of intraocular trematodes have been reported in the literature in association with DUSN (McDonald et al. 1994; Shea et al. 1973; Schweitzer et al. 2008). All of them were identified based on shape, size, and movement. McDonald et al. encountered two cases of human intraocular infection with Alaria mesocercariae in which the probable source of infection was ingestion of undercooked frog legs containing the trematode (McDonald et al. 1994). The worm in the first case was analyzed from fundus photographs, whereas in the second case, it was removed surgically from the vitreous cavity.
Clinical Features and Pathogenesis
Clinical characteristics can be classified into early and late stages. DUSN is most frequently seen in healthy children or young adults with no significant past ocular history. In the largest series of patients with DUSN described by de Amorim Garcia Filho et al., 69.4% of 121 patients were younger than 20 years of age (de Amorim Garcia Filho et al. 2012). Most patients presented in the late stage (92.6%) compared to 7.4% of patients presenting in the early stage. DUSN manifests as an intraocular inflammatory process characterized by multifocal chorioretinal lesions. The most common clinical features were subretinal tracks (91.7%), focal alterations of the RPE (89.3%), small white spots (80.2%), and optic nerve atrophy (76.9%). The pathogenesis of DUSN is believed to be a result of a local toxic effect on the outer retina caused by the worm, as well as a diffuse reaction in the inner and outer retina due to a toxin (Gass and Braunstein 1983; Arevalo et al. 2013b). Early and late stage findings outlined below correspond to an inflammatory reaction to the worm and its secreted toxins.
Early Stage
Late Stage
Diagnostic Testing
The diagnosis of DUSN is clinical and depends on the ability to identify a worm in the retina (Arevalo et al. 2013). These cases are defined as confirmed DUSN. Eyes with early and late stage clinical features consistent with DUSN, but without identification of the worm, should be classified as presumed DUSN (de Amorim Garcia Filho et al. 2012). The diagnostic tests described below are nonspecific for the diagnosis of DUSN. The advent of phylogenetic analysis of ocular fluids may become useful in the future as a diagnostic tool in identifying the parasite.
Serology
Serologic testing, stool examinations, and peripheral blood smears are of little value in making the diagnosis of DUSN (Gass et al. 1978). Moreover, no serologic test exists for Ancylostoma (Gass and Olsen 2001). When a worm is identified in the eye of an otherwise healthy person, unless a peripheral eosinophilia is present, no further evaluation seems warranted to make the diagnosis.