**5. Nematode infections**

#### **5.1. Onchocerciasis**

orable in the small intestine, encystment occurs and cysts are released along with feces. After ingestion, within 30 minutes, cyst hatches out trophozoites that further multiply in the small intestine. It is found both in developing and developed nations (Table 1, Figure 3). Although it mainly causes diarrhea and malabsorption, in one-third of the patients, it can also result in

Barraquer was the first to report the ocular manifestation (iridiocyclitis, choroiditis and retinal hemorrhages) in patients who were suffering from diarrhea due to *G. duodenalis.* Retinal changes in the form of "salt and pepper" degeneration have been reported in children suffering from giardiasis. Corsi et al. [146] reported salt and pepper retinal changes in 19.9% of the patients with giardiasis. This occurs due to the damage of the retinal cells and subsequent release of pigment granules in retina giving an appearance of blackish dots on a background of light yellow pink retina. The exact mechanism(s) by which giardiasis leads to ocular manifestations is still unknown, although possibility of direct invasion by the parasite is excluded (137). Further studies are desired to exactly pinpoint the mechanism by which retinal manifestations follow the occurrence of intestinal giardiasis. Alterations in the retinal pigment layer are most common but do not cause functional changes in retina, and these lesions do not

long-term extra intestinal manifestations [145].

60 Advances in Common Eye Infections

**Figure 9.** Life cycle of *Giardia lamblia* (Diagrammatic representation).

progress or regress with time [146].

Onchocerciasis, also known as "river blindness", is caused by *Onchocerca volvulus*, the filarial nematode. It is transmitted from person-to-person by the repeated bites of infected blackflies (*Simulium* species). These blackflies are mostly found near the flowing rivers and streams and transmit the infection to the people residing in nearby remote villages [148]. The life cycle of the parasite passes between black flies and humans as shown in Figure 10. While taking a blood meal, stage 3 larvae present in infected blackfly are transmitted onto human skin and penetrate into bite wound. In subcutaneous tissue, these larvae develop into adult filariae. Adult worm produces hundreds of thousands of embryonic larvae (microfilariae) that may persist for 3-5 years in the human host. These embryonic larvae migrate to the skin, eyes and other organs. The microfilariae are ingested by the female blackfly when it bites infected humans and develop further in the blackfly. During subsequent bites, it transmits infection to new human host [148, 149].

Onchocerciasis mainly occurs in tropical countries and majority of the cases (99%) have been reported from sub-Saharan Africa. It is also found in some countries of the Middle East and Latin America such as Brazil, Guatemala, Mexico and Venezuela (Table 1, Figure 11). Ap‐ proximately, 25 million people are known to be affected by onchocerciasis worldwide, and it is known to cause visual impairment and blindness in approximately 800,000 and 300,000 people, respectively [148, 150]. The inflammatory response initiated against dying microfilar‐ iae causes gradual and progressive loss of vision due to sclerosal keratitis [149, 151]. Apart from causing keratitis, clinical features may also manifest as iridiocyclitis, chorioretinitis and optic atrophy. Autoimmune mechanisms have also been postulated to cause inflammation in the posterior eye. Accumulation of retinal and retinoic acids, strong eosinophilic response and immune reaction against *Wolbachia* antigens [152] released by dying microfilariae also contributes to the ocular pathogenesis [153].

The filarial parasites of major medical importance in humans contain the symbiotic bacterium *Wolbachia,* and reports have revealed that targeting of these bacteria with antibiotics results in a reduction in worm viability, development, embryogenesis and survival. *Wolbachia* is present as an intracellular bacteria symbiont in all the developmental stages of *Onchocerca volvulus.* Clearance of the endosymbionts by antibiotic treatment causes inhibition of worm develop‐ ment. *Wolbachia* contributes directly to the metabolic activity of the nematode. Various

**Figure 10.** Life cycle of *Onchocerca volvulus* (Diagrammatic representation).

biochemical pathways such as heme, nucleotide and enzyme co-factor biosynthesis are intact in *Wolbachia* but absent or incomplete in nematode [154].

Diagnosis is difficult to establish in light infections. Skin snips can be subjected to microscopy for visualizing the larvae, but it yields very low sensitivity. Infections of the eye can be diagnosed with direct demonstration of the parasite by slit-lamp examination or by demon‐ strating the parasite in sclerocorneal punch biopsy. Newer techniques such as skin-snip PCR can establish the diagnosis if larvae are not visualized [155]. Antibodies can be detected by ELISA or EIA, but these tests cannot distinguish between past and current infections [156, 157]. Skin-snip PCR has 84–91% sensitivity and 100% specificity [149]. The sensitivity and specificity of serum antibody detection has been reported to be 78–99% and 95–100%, respec‐ tively [149]. A promising antigen detection by dipstick assay was recently developed, but its specificity was found to be low in high endemic areas due to cross reaction with urine filarial antigen [158, 159]. Xenodiagnosis (exposing possible infected tissue to a vector and then examining the vector for the presence of microorganism) has also provided clue in some cases.

If the infection is not treated on time, it can progress toward blindness [160]. Drug of choice for the treatment is ivermectin, given 150 to 200 µg /kg body weight, every 6 months to prevent the skin damage and blindness. Treatment with ivermectin has been shown to decrease visual field loss and severity of keratitis. Ivermectin only kills the larvae but not the adult worms. Doxycycline can be used to kill the adult worm. The mechanism of action is that it kills the

Echinococcosis;

**Figure 11.** World map showing geographical areas endemic for ocular nematode and cestode infections.

*Wolbachia* bacteria residing in the worm, on which the adult worm depends for its survival. Treatment with a 6-week course of doxycycline has been shown to kill more than 60% of adult female worms and to sterilize 80–90% of females 20 months after treatment. Thus, treatment with ivermectin is advised one week prior to treatment with doxycycline to provide relief to patient [148, 161].

The best method to get the protection from insect bite is the use of insect repellent. Communitydirected treatment with ivermectin (CDTI) along with vector control measures is the main approach to control onchocerciasis. Ivermectin kills microfilariae and also prevents adult worms from producing more microfilariae for few months following treatment, so reduces transmission [148].

#### **5.2. Loiasis**

biochemical pathways such as heme, nucleotide and enzyme co-factor biosynthesis are intact

Diagnosis is difficult to establish in light infections. Skin snips can be subjected to microscopy for visualizing the larvae, but it yields very low sensitivity. Infections of the eye can be diagnosed with direct demonstration of the parasite by slit-lamp examination or by demon‐ strating the parasite in sclerocorneal punch biopsy. Newer techniques such as skin-snip PCR can establish the diagnosis if larvae are not visualized [155]. Antibodies can be detected by ELISA or EIA, but these tests cannot distinguish between past and current infections [156, 157]. Skin-snip PCR has 84–91% sensitivity and 100% specificity [149]. The sensitivity and specificity of serum antibody detection has been reported to be 78–99% and 95–100%, respec‐ tively [149]. A promising antigen detection by dipstick assay was recently developed, but its specificity was found to be low in high endemic areas due to cross reaction with urine filarial antigen [158, 159]. Xenodiagnosis (exposing possible infected tissue to a vector and then examining the vector for the presence of microorganism) has also provided clue in some cases.

If the infection is not treated on time, it can progress toward blindness [160]. Drug of choice for the treatment is ivermectin, given 150 to 200 µg /kg body weight, every 6 months to prevent the skin damage and blindness. Treatment with ivermectin has been shown to decrease visual field loss and severity of keratitis. Ivermectin only kills the larvae but not the adult worms. Doxycycline can be used to kill the adult worm. The mechanism of action is that it kills the

in *Wolbachia* but absent or incomplete in nematode [154].

**Figure 10.** Life cycle of *Onchocerca volvulus* (Diagrammatic representation).

62 Advances in Common Eye Infections

Loiasis is caused by *Loa loa*, the African eyeworm. It is transmitted by the bite of tabanid flies, belonging to the genus *Chrysops.* It affects approximately 3 million people, residing in certain rain forests of Central and West Africa (Table 1, Figure 11) [162, 163]. The tabanid flies most commonly bite during day time and are more common during rainy season. The smoke of wood fires and movement of people attract them. These flies are more commonly found near rubber plantations and are attracted by the well-lit homes. The larvae are passed from flies to humans when humans are bitten by these flies [162]. The larvae develop into adults in the human host over one year and migrate through cutaneous and subcutaneous tissue (Figure 12). Migration of the adult worm is painless, but it is associated with mild tingling sensation. It may involve the nasal area, bulbar conjunctiva and eyelids [164].

**Figure 12.** Life cycle of *Loa loa* (Diagrammatic representation).

Ocular manifestations may occur due to the presence of both microfilariae and adult worms. The adult worms may survive up to 15 years and have been found in the conjunctiva, vitreous, eyelid and anterior chamber. Calabar swellings [165] may occur as a result of localized angioedema due to intense atopic reaction. Retinal hemorrhages may occur due to aneurysmal dilatation of the retinal vessels due to the invasion of the retinal and choroid vessels by the microfilariae present in blood stream. Perivascular inflammation can also be present, and ocular examination under slit lamp examination is useful in establishing the diagnosis.

The diagnosis is usually confirmed by the direct demonstration of the microfilariae in the blood by visualizing Giemsa-stained slides under the microscope. However, many of the individuals having visible worm in the eye may test as amicrofilaraemic [166]. Blood should be drawn during the midday as this time coincides with the periodicity of the microfilariae in the blood. The microfilariae can also be demonstrated in unstained blood smear. Adult worm extraction establishes the diagnosis in patients having conjunctival involvement [167]. Antibody detec‐ tion [168] may aid in establishing the diagnosis, but its presence cannot differentiate between recent and past infection. Eosinophilia and high IgE also indicate active infection [169].

Eye worm if not treated causes very little damage to eye as it lasts less than one week (often just hours). Surgical removal relieves eye symptoms, in addition medical treatment is required

**Figure 13.** Life cycle of *Dirofilaria repens* (Diagrammatic representation).

for treating loiasis [170]. Therapy involves manual removal of adult worms and administration of diethylcarbamazine (DEC), which kills both adult worms and microfilariae.

#### **5.3. Dirofilariasis**

**Figure 12.** Life cycle of *Loa loa* (Diagrammatic representation).

64 Advances in Common Eye Infections

Ocular manifestations may occur due to the presence of both microfilariae and adult worms. The adult worms may survive up to 15 years and have been found in the conjunctiva, vitreous, eyelid and anterior chamber. Calabar swellings [165] may occur as a result of localized angioedema due to intense atopic reaction. Retinal hemorrhages may occur due to aneurysmal dilatation of the retinal vessels due to the invasion of the retinal and choroid vessels by the microfilariae present in blood stream. Perivascular inflammation can also be present, and ocular examination under slit lamp examination is useful in establishing the diagnosis.

The diagnosis is usually confirmed by the direct demonstration of the microfilariae in the blood by visualizing Giemsa-stained slides under the microscope. However, many of the individuals having visible worm in the eye may test as amicrofilaraemic [166]. Blood should be drawn during the midday as this time coincides with the periodicity of the microfilariae in the blood. The microfilariae can also be demonstrated in unstained blood smear. Adult worm extraction establishes the diagnosis in patients having conjunctival involvement [167]. Antibody detec‐ tion [168] may aid in establishing the diagnosis, but its presence cannot differentiate between recent and past infection. Eosinophilia and high IgE also indicate active infection [169].

Eye worm if not treated causes very little damage to eye as it lasts less than one week (often just hours). Surgical removal relieves eye symptoms, in addition medical treatment is required Dirofilariasis is caused by nematodes belonging to the genus *Dirofilaria.* The various species of *Dirofilaria* that are natural parasites of domestic and wild animals are *D. immitis*, *D. repens*, *D. tenuis* and *D. ursi* [37]. It is prevalent worldwide and is an important zoonotic infection. It is being reported in increasing numbers from Mediterranean countries such as Italy and have also been reported from France, Greece, Spain, Croatia, India, Serbia, Denmark, Russia and Tunisia (Table 1, Figure 11). The parasite passes its life cycle in canids as definitive host as shown in Figure 13. Mosquitoes act as intermediate host and vector for the transmission of infection from animals to human host. Mosquitoes take up microfilariae along with blood meal from the infected host, develop inside the mosquitoes and are subsequently transmitted to other hosts while taking a fresh blood meal. Larvae migrate from the subcutaneous tissue to the right side of the heart and/or to other parts of the body where maturation takes place. Depending on the site of lodgment, it can cause pulmonary, cardiovascular, subcutaneous or ocular infection [28].

There are several cases that document ocular involvement due to dirofilariasis [37, 171–173]. Ocular symptoms depend on the site of infection. Eyelid involvement [174] leads to edema, pain, pruritus and congestion of conjunctiva, whereas intraocular [175] involvement leads to foreign body sensation, diplopia, photophobia and floaters.

Diagnosis can be established by the direct demonstration and identification of the adult worm. Intraocular presence of the parasite can be confirmed by ophthalmoscopy. Serological techniques are not useful in establishing the diagnosis due to the cross reaction with other parasitic helminths, particularly *Toxocara canis*. Recombinant proteins proved to exhibit 100% sensitivity and 90% specificity by ELISA for the diagnosis of pulmonary dirofilariasis [176].

Without treatment, worm remains in eye causing symptoms due to its presence [177]. Surgical excision is the treatment of choice; however use of diethylcarbamazine (DEC) has also been reported with some success [37, 178].

#### **5.4. Gnathostomiasis**

Gnathostomiasis is a food-borne zoonotic parasitic infection, caused by ingestion of raw or undercooked freshwater fish, pork, chicken, frog and snake [179, 180] contaminated with the third-stage larvae of *Gnathostoma* species. The life cycle of the parasite passes in pigs, cats and wild animals as definitive host, whereas small crustaceans act as first intermediate host and fish, frog or snake act as second intermediate host as depicted in Figure 14. In the infected person, larvae migrate through viscera and reach internal organs and subcutaneous tissues. Depending on the location of lodgment, it can cause cutaneous, visceral, ocular or cerebral gnathostomiasis. Majority of the cases have been reported from East Asia (Thailand, China, Japan and India) and Central and South America (Mexico, Guatemala, Peru and Ecuador) (Table 1, Figure 11). However, sporadic cases have been reported worldwide [181]. *Gnathos‐ toma spinigerum* is the most common species causing infection in humans.

Ocular manifestations occur due to the migration of the parasite and its metabolites, leading to inflammatory response. Conjunctiva and corneal infection may lead to congestion of the conjunctiva and corneal ulceration, respectively. Intraocular involvement may lead to glau‐ coma, uveitis, retinitis and vitreous hemorrhage [182, 183]. In severe cases, retinal detachment has also been reported due to the fibrinous scarring along the migratory path.

Diagnosis is difficult to establish and high index of suspicion is required. Patients may present with marked eosinophilia [184] and elevated IgE levels [185]. ELISA for specific antibody detection and histopathological examination of the biopsy samples may assist in establishing the diagnosis [186–188]. ELISA for antibody detection reported to have low sensitivity, ranging from 59 to 87%, with a specificity of 79–96% [189, 190]. If parasite is not removed, it leads to persistence of visual disturbances such as floaters. Surgical treatment is curative and only modality available [191].

#### **5.5. Thelaziasis**

Thelaziasis is caused by nematode *Thelazia callipaeda*, transmitted to humans by drosophilid flies [192]. It is also known as oriental eyeworm due to its geographical distribution in Asia Pacific region (China, India, Thailand, Indonesia, Japan and Korea) and Russia [12, 193] (Table

**Figure 14.** Life cycle of *Gnathostoma* (Diagrammatic representation).

pain, pruritus and congestion of conjunctiva, whereas intraocular [175] involvement leads to

Diagnosis can be established by the direct demonstration and identification of the adult worm. Intraocular presence of the parasite can be confirmed by ophthalmoscopy. Serological techniques are not useful in establishing the diagnosis due to the cross reaction with other parasitic helminths, particularly *Toxocara canis*. Recombinant proteins proved to exhibit 100% sensitivity and 90% specificity by ELISA for the diagnosis of pulmonary dirofilariasis [176]. Without treatment, worm remains in eye causing symptoms due to its presence [177]. Surgical excision is the treatment of choice; however use of diethylcarbamazine (DEC) has also been

Gnathostomiasis is a food-borne zoonotic parasitic infection, caused by ingestion of raw or undercooked freshwater fish, pork, chicken, frog and snake [179, 180] contaminated with the third-stage larvae of *Gnathostoma* species. The life cycle of the parasite passes in pigs, cats and wild animals as definitive host, whereas small crustaceans act as first intermediate host and fish, frog or snake act as second intermediate host as depicted in Figure 14. In the infected person, larvae migrate through viscera and reach internal organs and subcutaneous tissues. Depending on the location of lodgment, it can cause cutaneous, visceral, ocular or cerebral gnathostomiasis. Majority of the cases have been reported from East Asia (Thailand, China, Japan and India) and Central and South America (Mexico, Guatemala, Peru and Ecuador) (Table 1, Figure 11). However, sporadic cases have been reported worldwide [181]. *Gnathos‐*

Ocular manifestations occur due to the migration of the parasite and its metabolites, leading to inflammatory response. Conjunctiva and corneal infection may lead to congestion of the conjunctiva and corneal ulceration, respectively. Intraocular involvement may lead to glau‐ coma, uveitis, retinitis and vitreous hemorrhage [182, 183]. In severe cases, retinal detachment

Diagnosis is difficult to establish and high index of suspicion is required. Patients may present with marked eosinophilia [184] and elevated IgE levels [185]. ELISA for specific antibody detection and histopathological examination of the biopsy samples may assist in establishing the diagnosis [186–188]. ELISA for antibody detection reported to have low sensitivity, ranging from 59 to 87%, with a specificity of 79–96% [189, 190]. If parasite is not removed, it leads to persistence of visual disturbances such as floaters. Surgical treatment is curative and only

Thelaziasis is caused by nematode *Thelazia callipaeda*, transmitted to humans by drosophilid flies [192]. It is also known as oriental eyeworm due to its geographical distribution in Asia Pacific region (China, India, Thailand, Indonesia, Japan and Korea) and Russia [12, 193] (Table

*toma spinigerum* is the most common species causing infection in humans.

has also been reported due to the fibrinous scarring along the migratory path.

foreign body sensation, diplopia, photophobia and floaters.

reported with some success [37, 178].

**5.4. Gnathostomiasis**

66 Advances in Common Eye Infections

modality available [191].

**5.5. Thelaziasis**

1, Figure 11). The life cycle passes in dogs and other canids, cattle and horses as definitive host and flies act as intermediate host as shown in Figure 15. First-stage larvae are present in the lacrimal secretions of infected humans/animals. The arthropod vectors while feeding on infected lacrimal secretions ingest these larvae, which further develop into infective third-stage larvae. The vector transmits accidentally third-stage larvae when it feeds on lacrimal secretion of other persons/animals. Within 5–6 weeks, these larvae further develop into adult form in the eye of an infected person. These parasites mainly cause infection of the anterior segment of the eye, but intraocular infections involving vitreous and retina have also been reported. It is a disease associated with poor personal hygiene.

Without treatment, worm remains in eye causing symptoms due to its presence [194]. Treat‐ ment is surgical removal of worms along with the topical application of thiabendazole. Preventive measures include use of bed nets at night, maintenance of personal hygiene and keeping surroundings clean to control the vector population responsible for the transmission of infection [8].

**Figure 15.** Life cycle of *Thelazia* (Diagrammatic representation).

#### **5.6. Toxocariasis**

Toxocariasis is caused by *Toxocara* species. *Toxocara canis* and *T. cati* are the most common species causing toxocariasis in humans worldwide, particularly in Asia, Japan, Korea, Ireland and Alabama [195–199] (Table 1, Figure 11). The life cycle of *Toxocara* involves dogs (*T. canis*)/ cats (*T. cati*) as definitive host (dog/cat). Infection is transmitted by consumption of eggs of *Toxocara* parasites, passed in the feces of definitive host (dog/cat) as shown in Figure 16. After the ingestion of eggs, larvae hatch out from the eggs in the small intestine and penetrate mucosa to migrate to different organs such as liver, lung and trachea, leading to visceral larva migrans (VLM). Sometimes, target larvae may migrate to eyes causing ocular larva migrans (OLM) [200, 201]. Host immune response is weaker in ocular larva migrans than visceral larva migrans. Various ocular clinical manifestations such as keratitis, hypopyon, iritis, uveitis, posterior pole granuloma, vitreous abscess and retinal detachment, strabismus, vision loss are attributed due to vitritis, cystoid macular edema and tractional retinal detachment [11, 202– 204]. Based on clinical and physical examination, ocular toxocariasis is classified as chronic endophthalmitis, posterior granuloma and peripheral granuloma [205]. Approximately 25– 50% of ocular toxocariasis patients present as posterior pole granuloma, due to lodging of the parasite in small perifoveal end-arteries, and approximately in 50% of ocular toxocariasis patients peripheral granuloma is present. Acute lesion appears as hazy, white mass in the peripheral fundus that may mimic the appearance of snowbank seen in patients with pars planitis.

**Figure 16.** Life cycle of *Toxocara* (Diagrammatic representation).

**5.6. Toxocariasis**

68 Advances in Common Eye Infections

**Figure 15.** Life cycle of *Thelazia* (Diagrammatic representation).

Toxocariasis is caused by *Toxocara* species. *Toxocara canis* and *T. cati* are the most common species causing toxocariasis in humans worldwide, particularly in Asia, Japan, Korea, Ireland and Alabama [195–199] (Table 1, Figure 11). The life cycle of *Toxocara* involves dogs (*T. canis*)/ cats (*T. cati*) as definitive host (dog/cat). Infection is transmitted by consumption of eggs of *Toxocara* parasites, passed in the feces of definitive host (dog/cat) as shown in Figure 16. After the ingestion of eggs, larvae hatch out from the eggs in the small intestine and penetrate mucosa to migrate to different organs such as liver, lung and trachea, leading to visceral larva migrans (VLM). Sometimes, target larvae may migrate to eyes causing ocular larva migrans (OLM) [200, 201]. Host immune response is weaker in ocular larva migrans than visceral larva migrans. Various ocular clinical manifestations such as keratitis, hypopyon, iritis, uveitis, posterior pole granuloma, vitreous abscess and retinal detachment, strabismus, vision loss are attributed due to vitritis, cystoid macular edema and tractional retinal detachment [11, 202– 204]. Based on clinical and physical examination, ocular toxocariasis is classified as chronic endophthalmitis, posterior granuloma and peripheral granuloma [205]. Approximately 25– 50% of ocular toxocariasis patients present as posterior pole granuloma, due to lodging of the parasite in small perifoveal end-arteries, and approximately in 50% of ocular toxocariasis patients peripheral granuloma is present. Acute lesion appears as hazy, white mass in the High index of suspicion is required for establishing the diagnosis of OLM during ocular examination [205]. Marked eosinophilia along with positive serology by ELISA [206] helps in confirming the diagnosis [207]. Detection of specific antibodies in the vitreous fluid also helps in differentiating it from retinoblastoma [208]. ELISA based on the excretory-secretory antigens of *T. canis* reported to have a sensitivity of 78% [209]. ELISA developed by Seoul National University, using crude antigen of *Toxocara* larvae, showed a sensitivity of 92.2% and specificity of 86.6% [210]. PCR available in research laboratories [211] may help in the diagnosis of ocular toxocariasis. Nucleotide homology of 97–99% has been reported between Vietnamese *Toxocara canis* and other *Toxocara* geographical strains by comparing the nucleotide sequence of internal transcribed spacer 2 (ITS2) of ribosomal DNA of *T. canis* [212]. Although PCR has been shown to be the best diagnostic modality in animal models of ocular toxocariasis, molecular techni‐ ques are not available in hospitals of resource limiting countries [213]. Vision loss, eye inflammation or damage to the retina occurs if not treated. Prognosis is good with medical and surgical treatment [200].

Albendazole and mebendazole are the drugs of choices for the treatment of VLM [214, 215]. However, there is a limited role of antiparasitic drugs in the treatment of OLM. Photocoagu‐ lation along with steroids has been recommended for the treatment of OLM.

**Figure 17.** Life cycle of *Taenia solium* (Diagrammatic representation).
