**4. Protozoan eye infections**

#### **4.1. Toxoplasmosis**

Toxoplasmosis is caused by obligatory intracellular protozoan parasite known as *Toxoplasma gondii.* The mode of infection is either by the ingestion of oocysts shed in feces of the cats or other Felidae (definitive host) or by the consumption of tissue cyst present in the raw or uncooked meat. Life cycle of *Toxoplasma* includes three stages that are oocysts, tachyzoites and bradyzoites. It completes its life cycle in two phases, one as an intestinal phase in its homolo‐ gous host, such as cats and another as an extraintestinal phase in its heterologous host, such as mouse, man and other animals. When cats feed on mouse brain containing tissue cysts of *T. gondii*, a large number of oocysts are released in the infected cat's feces. After 1–5 days, oocysts get matured and become infective to man and other animals. After ingestion, oocysts liberate sporozoites, which penetrate intestinal mucosa and reach to distant organs such as brain, eyes, liver, spleen, lymph nodes, heart, skeletal muscles and placenta by blood and lymphatic stream. *Toxoplasma* tissue cysts also occur in the skeletal muscles of the intermediate host such as sheep and pigs (Figure 2) [54]. In addition, developing fetus can acquire the infection transplacentally from the mother during pregnancy. Rarely, infection may also result from consumption of drinking water contaminated with oocysts. The ocular infection can be either congenital or acquired.

Approximately, one-third of the world's population is thought to be infected by *T. gondii.* It is common in hot and humid climates such as Central America, Asia and the Caribbean region (Table 1, Figure 3). In Europe, toxoplasmosis is common and the highest prevalence rates have been reported in France. Various risk factors such as geographical region, meat consumption, personal habits, animal reservoir and climatic conditions play a significant role in the trans‐ mission of infection. In recent years, due to indoor keeping of livestock and improvement in hygiene standards, the risk of acquiring infection has decreased tremendously in the devel‐ oped nations. However, in the developing nations, risk has increased due to population growth, urbanization trends and increase in meat consumption. Drinking water, seawater and

**Figure 2.** Life cycle of *T. gondii* (Diagrammatic representation).

**Figure 3.** World map showing geographical areas endemic for ocular protozoal infections.

seafood contaminated with oocysts when consumed may account for many unreported cases. Therefore, exact prevalence would be much higher than reported in the literature [55–58].

Ocular toxoplasmosis usually manifests in immunocompromised *T. gondii-*infected individu‐ als and in neonates who acquire infection transplacentally [4]. The main target organs in congenital toxoplasmosis are the brain, eyes and placenta. *T. gondii* disseminates through the blood stream, lodges at particular site(s) and develops into tissue cysts. The dendritic cells and macrophages act as "Trojan horses" to guide the parasite through blood-brain barrier to reach at its target site in brain [59]. Inside the host cell, it protects itself from the toxic host molecules by hiding inside the parasitophorous vacuole (structure produced by apicomplexan parasites that allows the parasite to develop inside host cell and protects from phagolysosomes). There are three main clonal lineages of *T. gondii.* Type I strains being the highest virulent, whereas types II and III are moderately virulent. However, at present more than 130 "atypical" genotypes are known, but their exact role in pathogenesis is not well established. Host genetic factors such as polymorphism in Toll-like receptors (TLR) (TLR2, 5 and 9) are also known to play a role in the susceptibility to and severity of ocular toxoplasmosis [60, 61].

Congenital ocular toxoplasmosis usually involves both the eyes, whereas acquired ocular toxoplasmosis is usually unilateral [62, 63]. Chorioretinitis is caused by necrotizing inflam‐ mation due to the rupture of an older cyst. Intense form of choriretinitis may occur in newborns and patients infected with HIV. In addition, congenital toxoplasmosis patients may present with wide range of ocular symptoms such as strabismus, nystagmus and blindness. Acute, acquired infection may result in photophobia, scotoma and loss of central vision. Ptosis may occur due to oculomotor nerve involvement.

Diagnosis of ocular toxoplasmosis in children with congenital infection is established by recognizing distinctive clinical findings such as focal necrotizing retinitis, vitritis, anterior uveitis and cataract [64] However, in cases with atypical presentation or having severe fulminant disease, diagnosis is usually established by analyzing the intraocular fluid for the presence of specific antibodies or the presence of parasite DNA by molecular techniques such as PCR or real-time PCR [65, 66]. PCR is performed by targeting the *Toxoplasma* B1 gene or other multiple repeat sequences [67–69]. Though, in general, PCR with amniotic fluid is known to have significantly high sensitivity (64%) and specificity (100%) for the diagnosis of toxo‐ plasmosis [70], sensitivity of only 53 and 83% has been documented for the diagnosis of ocular toxoplasmosis [71]. PCR can be performed on either aqueous humor or vitreous fluid, but aqueous humor can be collected more easily. However, the DNA burden in aqueous humor is low, and in rare instances a confirmation would necessitate vitreous sampling [72].

Antibody detection in serum samples is widely used for establishing the diagnosis of toxo‐ plasmosis [73–76], while its role is limited in establishing the diagnosis of the ocular toxoplas‐ mosis. A rising titer of specific IgG over a period of 3 weeks helps in establishing the diagnosis [77]. The detection of specific antibodies in intraocular fluids by the enzyme-linked immuno‐ sorbent assay (ELISA) is the most commonly used test for the diagnosis of toxoplasmosis. The Goldmann-Witmer coefficient (GWC) calculation is a common method to estimate the local versus systemic *Toxoplasma*-specific IgG. This index helps in measuring the intraocular levels of specific antibodies against *Toxoplasma*. It is expressed as the level of *Toxoplasma*-specific IgG relative to the level of total IgG in the aqueous humor as a fraction of the level of *Toxoplasma*specific IgG relative to the level of the total IgG in the serum. A value of 2 or above is considered as an evidence of intraocular infection. Toxoplasma specific IgG antibodies are produced in

seafood contaminated with oocysts when consumed may account for many unreported cases. Therefore, exact prevalence would be much higher than reported in the literature [55–58].

Toxoplasmosis; A*ĐĂŶƚŚĂŵŽĞďĂ͘ŬĞƌĂƚŝƚŝƐ*; Chagas disease; Malaria; Leishmaniasis; Giardiasis.

**Figure 3.** World map showing geographical areas endemic for ocular protozoal infections.

**Figure 2.** Life cycle of *T. gondii* (Diagrammatic representation).

48 Advances in Common Eye Infections

response to the actively multiplying tachyzoites at local site of infection [72, 78] The presence of *T. gondii*-specific IgM is the hallmark of a recently acquired systemic or, possibly, ocular infection. However, high rate of false-positive results due to the persistence of antibodies, decreases its utility as a diagnostic marker for recent ocular toxoplasmosis. In patients with reactivated ocular toxoplasmosis, it is not useful as *T. gondii*-specific IgM antibodies are either absent or present in very low quantity [79]. Saliva samples have also been tested for the detection of specific antibodies for the diagnosis of toxoplasma encephalitis in immunocom‐ promised individuals, but it may play a limited role in ocular toxoplasmosis [74].

An algorithm for the laboratory confirmation of clinically suspected cases of ocular toxoplas‐ mosis has been reported [72]. Reactivated form of ocular toxoplasmosis is considered in patients with typical lesions of toxoplasmic retinochoroiditis, specific IgG seropositive, specific IgM seronegative and responding to anti-*Toxoplasma* treatment. However, if patients are specific IgM seropositive, then additional laboratory tests are required. If doubt persists about diagnosis, paired serum and aqueous samples are required to be tested in parallel. The clinical diagnosis along with laboratory evidence is documented in 60-85% of cases and thus, labora‐ tory evidence is lacking in 15-40% of clinically suspected patients. Analysis of aqueous humor is useful in patients presenting with atypical ocular lesions or not responding to specific treatment [72].

In immunocompetent individuals, toxoplasma retinochoroiditis usually resolves within 2–3 months [80]. Classic therapy or triple therapy with a combination of pyrimethamine, sulfa‐ diazine and systemic corticosteroids is recommended for lesions involving or near to fovea, an area critical for vision. Classic therapy is usually associated with significant side effects, therefore other drugs such as trimethoprim-sulfamethoxazole, clindamycin, atovaquone and azithromycin are being evaluated for the treatment of ocular toxoplasmosis [81].

Trimethoprim-sulfamethoxazole (Bactrim) appears to be a safe and effective substitute for sulfadiazine, pyrimethamine and folinic acid for the treatment of ocular toxoplasmosis.

Progressive and recurring necrotizing retinitis, with vision-threatening complications such as retinal detachment, choroidal neovascularization and glaucoma, may occur at any time during the clinical course if the infection is not treated on time. Congenital toxoplasmosis can lead to cataract. The aim of the treatment is to arrest parasite multiplication during the active period of retinochoroiditis and to minimize damage to the retina and optic disc [64].

Animal model(s) can be used to study various aspects of ocular toxoplasmosis [40].

#### **4.2.** *Acanthamoeba* **keratitis**

*Acanthamoeba* keratitis (AK) is caused by *Acanthamoeba* spp., a free-living protest parasite [82]. The word "acanth" in Greek means "spikes" and has been added as a prefix to "amoeba" to denote the spine-like structures present on its surface. The parasite is present ubiquitously in the environment and exists in two forms, trophozoite and cyst forms. In humans, it can enter through eye, nasal passage or ulcerated broken skin (Figure 4). Infection of the eye can cause blinding keratitis and life-threatening granulomatous encephalitis. Various risk factors contributing to the development of *AK* are (1) wearing of contact lenses for long time, (2) poor personal hygiene, (3) cleaning of lenses with contaminated water and (4) formation of biofilm on contact lenses [82].

**Figure 4.** Life cycle of *Acanthamoeba* (Diagrammatic representation).

response to the actively multiplying tachyzoites at local site of infection [72, 78] The presence of *T. gondii*-specific IgM is the hallmark of a recently acquired systemic or, possibly, ocular infection. However, high rate of false-positive results due to the persistence of antibodies, decreases its utility as a diagnostic marker for recent ocular toxoplasmosis. In patients with reactivated ocular toxoplasmosis, it is not useful as *T. gondii*-specific IgM antibodies are either absent or present in very low quantity [79]. Saliva samples have also been tested for the detection of specific antibodies for the diagnosis of toxoplasma encephalitis in immunocom‐

An algorithm for the laboratory confirmation of clinically suspected cases of ocular toxoplas‐ mosis has been reported [72]. Reactivated form of ocular toxoplasmosis is considered in patients with typical lesions of toxoplasmic retinochoroiditis, specific IgG seropositive, specific IgM seronegative and responding to anti-*Toxoplasma* treatment. However, if patients are specific IgM seropositive, then additional laboratory tests are required. If doubt persists about diagnosis, paired serum and aqueous samples are required to be tested in parallel. The clinical diagnosis along with laboratory evidence is documented in 60-85% of cases and thus, labora‐ tory evidence is lacking in 15-40% of clinically suspected patients. Analysis of aqueous humor is useful in patients presenting with atypical ocular lesions or not responding to specific

In immunocompetent individuals, toxoplasma retinochoroiditis usually resolves within 2–3 months [80]. Classic therapy or triple therapy with a combination of pyrimethamine, sulfa‐ diazine and systemic corticosteroids is recommended for lesions involving or near to fovea, an area critical for vision. Classic therapy is usually associated with significant side effects, therefore other drugs such as trimethoprim-sulfamethoxazole, clindamycin, atovaquone and

Trimethoprim-sulfamethoxazole (Bactrim) appears to be a safe and effective substitute for sulfadiazine, pyrimethamine and folinic acid for the treatment of ocular toxoplasmosis.

Progressive and recurring necrotizing retinitis, with vision-threatening complications such as retinal detachment, choroidal neovascularization and glaucoma, may occur at any time during the clinical course if the infection is not treated on time. Congenital toxoplasmosis can lead to cataract. The aim of the treatment is to arrest parasite multiplication during the active period

*Acanthamoeba* keratitis (AK) is caused by *Acanthamoeba* spp., a free-living protest parasite [82]. The word "acanth" in Greek means "spikes" and has been added as a prefix to "amoeba" to denote the spine-like structures present on its surface. The parasite is present ubiquitously in the environment and exists in two forms, trophozoite and cyst forms. In humans, it can enter through eye, nasal passage or ulcerated broken skin (Figure 4). Infection of the eye can cause blinding keratitis and life-threatening granulomatous encephalitis. Various risk factors contributing to the development of *AK* are (1) wearing of contact lenses for long time, (2) poor

azithromycin are being evaluated for the treatment of ocular toxoplasmosis [81].

of retinochoroiditis and to minimize damage to the retina and optic disc [64].

Animal model(s) can be used to study various aspects of ocular toxoplasmosis [40].

promised individuals, but it may play a limited role in ocular toxoplasmosis [74].

treatment [72].

50 Advances in Common Eye Infections

**4.2.** *Acanthamoeba* **keratitis**

*Acanthamoeba* keratitis is common among the contact lens users, and its geographic distribution is depicted in Table 1 and Figure 3. However, in India the infection is reported even in noncontact lens users [7]. The incidence of *Acanthamoeba* keratitis in developed nations varies from 1 to 33 cases per million contact lens wearers. In developing nations where contact lens users are limited, the other suggested risk factors are trauma, exposure to contaminated water, use of traditional eye medicine, low socioeconomic background, splashing contaminated water into the eye following dust fall and corneal injury with mud [7, 22, 83]. The pathogenesis of *Acanthamoeba* involves following sequential events, i.e., breach in the epithelial barrier, invasion of stroma by amoeba, depletion of keratocytes, induction of inflammatory response, photophobia and finally necrosis of stroma leading to blindness [82].

The diagnosis of AK is difficult as it is usually confused with symptoms of bacterial, fungal or viral keratitis. However, history of contact lens use together with a history of excruciating pain is a strong indication toward the diagnosis of AK. For establishing the clinical diagnosis with high sensitivity, in vivo confocal microscopy can be used, which is a non-invasive procedure. The *Acanthamoeba* cysts appear as hyper-reflective, spherical structures that are well defined because of their double wall. However, trophozoites are difficult to distinguish from leuko‐ cytes and keratocyte nuclei [84, 85]. Laboratory confirmation is established by direct demon‐


**Table 1.** Ocular parasitic infections and geographical distribution

stration of parasite by immunofluorescence microscopy or by isolating the parasite in culture. Although culture remains the gold standard, it is tedious and time consuming. Multiplex realtime PCR assays (multiplex assays targets more than one region and simultaneously can detect two or more target regions) have also been developed for the detection of different pathogenic free-living amoeba and/or different genotypes of *Acanthamoeba*. Although molecular techni‐ ques have high sensitivity and specificity, these are only available at apex laboratories and also require a well-established molecular laboratory [86]. Newer techniques such as Matrix-Assisted Laser Desorption Ionization Time-Of-Flight (MALDI-TOF) and 1 H-NMR spectrosco‐ py [87] are also being tested for the rapid identification of *Acanthamoeba* in the clinical specimens [88].

Chances of recovery are good if the pathogen is restricted to cornea epithelium but can lead to vision loss, if it invades stroma leading to necrosis and intense inflammation. Medical treatment, if started early, can lead to a significant improvement within 2–3 weeks [89].

Preventive measures include thorough and adequate disinfection of contact lenses. It is recommended to remove contact lenses before any activity involving contact with water, including showering, using a hot tub, or swimming. Hands should be washed with soap and water and dried before handling contact lenses. Contact lenses should not be rinsed with tap water and should be cleaned and stored as per manufacturer's guidelines. It is suggested that the increased awareness about the other predisposing factors (corneal injury, fall of foreign body in eye) among the general public may enable early and frequent recognition and proper management of AK in patients other than contact lens wearers [7].

#### **4.3. Chagas disease**

stration of parasite by immunofluorescence microscopy or by isolating the parasite in culture. Although culture remains the gold standard, it is tedious and time consuming. Multiplex real-

Myiasis Worldwide with greater abundance in poor socioeconomic regions of tropical

of America (USA)

Tick infestation Case reports from Ireland, Turkey and USA

**Ocular protozoal infections Geographical distribution**

Chagas disease Central and South America

Loiasis Central and West Africa Dirofilariasis Asia, Africa and Europe

Microsporidiosis Worldwide

**Ocular nematode infections**

52 Advances in Common Eye Infections

**Ocular cestode infections**

**Ocular trematode infections**

*Clinostomum* lacramalitis Thailand Fascioliasis Iran

**Ocular infections by ectoparasites**

Phthiriasis palpebrum

*Alaria* mesocercariasis San Francisco, California

**Table 1.** Ocular parasitic infections and geographical distribution

Toxoplasmosis Worldwide particularly in Central America, Asia, Caribbean region, Europe

Acanthamoeba keratitis Worldwide significantly in Chicago, San Francisco, Boston, Philadelphia,

Leishmaniasis Africa, Mediterranean region, Middle East, Central and South America, parts

Gnathostomiasis South East Asia particularly Thailand, China, Japan and India, Central and

Thelaziasis Asia Pacific region - China, India, Thailand, Indonesia, Japan and Korea Toxocariasis Worldwide particularly in Asia, Japan, Korea, Ireland, Alabama

Cysticercosis Indian subcontinent, Central and South America, Africa and Far East Echinococcosis South America, Middle East, Mediterranean countries, India and Australia

Fascioliasis France, Spain, Italy, Austria, Belgium, United Kingdom, Algeria, Tunisia, Iran,

America (i.e., Mexico, and the United States)

Philopthalmosis Europe (Yugoslavia), Israel, Asia (Thailand, India, Sri Lanka, Japan) and

Sweden, Portland, New Zealand, United Kingdom, India, Africa

South America particularly in Mexico, Guatemala, Peru and Ecuador

Uzbekistan, Korea, China, Argentina, Chile, Peru, Brazil, Guatemala

and subtropical countries, Mediterranean basin and Middle East

Case reports from Tunisia, Taiwan, India, Pakistan, China, Korea, Lebanon, Israel, Brazil, Turkey, United Kingdom, Belgium, Italy, Cyprus, United States

particularly in France

Malaria Africa, Central & South America, Middle East and Asia

of Asia

Giardiasis Southeast Asia, South Africa, Europe and USA

Onchocerciasis Africa, South America, Arabian peninsula

Schistosomiasis Sub-Saharan Africa, China, South Asia

Chagas disease or American trypanosomiasis is caused by *Trypanosoma cruzi* [90]. It is a chronic systemic disease, included in the WHO's list of most neglected tropical diseases. Approxi‐ mately, 8 million people are known to be affected in Latin America (Table 1, Figure 3) [8]. The life cycle of the parasite is passed in two stages involving trypomastigotes and amastigotes forms as depicted briefly in Figure 5. *T. cruzi* passes its life cycle in two hosts: one in man or the reservoir host and other in the transmitting insect. The infection is transmitted by the bloodsucking triatomine bugs when infective metacyclic trypomastigotes in bug's feces are released onto the skin of humans. These infective trypomastigotes enter the human host when bite wound is either scratched or rubbed, or through permissive mucosal or conjunctival surfaces. Parasites circulate in the human body affecting various tissues and organs. If the initial bite of the triatomine bug is near the orbit, it may lead to severe palpebral and periorbital edema (Romana's sign) [91]. It causes a painless edema and constitutional symptoms of fever, malaise and anorexia are common. Ocular involvement (posterior uveitis) in congenital Chagas disease is recently reported. Although ocular fundus examination has been unobtrusive, small parafoveolar retinal pigment epithelium defects have been reported in 7.6% of chagasic patients [92].

The diagnosis of acute Chagas disease is established by the direct demonstration of trypo‐ mastigotes in the blood/buffy coat preparation. Parasites can also be isolated by direct culturing of blood on NNN medium (Novy, MacNeal, Nicolle's medium). It may take 7 to 10 days for culture to become positive. Diagnosis may also be established by xenodiagnosis. During acute phase, the role of serology is limited in the diagnosis as antibodies take time to

**Figure 5.** Life cycle of *Trypanosoma cruzi* (Diagrammatic representation).

develop and false positive results have also been known to be associated with serological tests due to cross-reaction of antibodies to non-pathogenic *Trypanosoma rangeli* [8, 91]. Furthermore, detailed examination by the ophthalmologist may aid in establishing the diagnosis. However, accumulation of retinal pigment epithelium defects have been shown in patients with intra‐ ocular involvement of intermediate and chronic Chagas disease in Paraguay/South America, but overall fundus examination has shown to be unobtrusive [92, 93].

Acute cases of Chagas disease are treated by nifurtimox and benznidazole. Benznidazole is given as 5–7.5 mg/kg per day orally in two divided doses for 60 days. Nifurtimox is given as 8–10 mg/kg per day orally in three or four divided doses for 90 days [91, 94].

Within few weeks, symptoms of acute Chagas disease such as Romana's sign fade away, but infection persists. The average life-time risk of developing complications of chronic phase is around 30%. It may take more than 20 years to develop chronic complications. However, trypanocidal therapy did not significantly reduce cardiac clinical deterioration through 5 years of follow-up as documented by randomized trial of benznidazole for chronic Chagas' cardio‐ myopathy [95, 96].

#### **4.4. Leishmaniasis**

Leishmaniasis is caused by protozoan parasite that belongs to genus *Leishmania.* Humans get infection by the bite of phlebotomine sand flies. There are different clinical forms of leishma‐ niasis, such as visceral leishmaniasis (VL), cutaneous, diffuse cutaneous and mucocutaneous caused by different species of *Leishmania*. Worldwide, approximately 1.3 million new cases occur every year with a mortality of 20,000 to 30,000 persons per annum [97]. While taking the blood meal, infected sandfly injects promastigotes into humans. Further in the human body, the promastigotes are transformed into amastigote forms, and these are engulfed by tissue macrophages. Amastigote forms replicate inside the cells and further spread either systemi‐ cally or through cutaneous route, depending on the species of the parasite (Figure 6). Ocular involvement due to leishmaniasis has been reported from various countries such as India, Sudan, Italy, Norway, Turkey and Iran (Table 1, Figure 3) [98–103]. Anterior uveitis is the most common ocular manifestation in VL, which can occur during the course of infection and can further progress to glaucoma [104, 105]. Focal retinal whitening, cotton wool spots, hemor‐ rhages and increased vessel tortuosity have also been reported on fundus examination [106– 110]. In severe cases, flame-shaped lesions also appear, which denote hemorrhage from the anterior capillaries of the nerve fiber layer. These findings have also been correlated with anemia and thrombocytopenia as these hemorrhages usually get resolved with treatment, leading to improvement in anemia/thrombocytopenia. Optic neuropathy has been reported due to mucosal leishmaniasis. Eyelid involvement has been documented in cutaneous and mucocutaneous leishmaniasis [111, 112]. Severe involvement can progress to ptosis and ectropion secondary to cutaneous leishmaniasis leading to keratopathy and altered vision [112]. However, eyelid is rarely involved by leishmaniasis and is reported in approximately only 2.5% of cases with cutaneous leishmaniasis [113]. The most common aspect of eyelid leishmaniasis is chalazion-like lesions, but other forms such as ulcerous, phagedenic, cancerlike forms and unilateral chronic granulomatous blepharitis may be observed. Chronic dacryocystitis has been reported in patients suffering from mucocutaneous leishmaniasis, which can effect formation of tear film, leading to dryness of eyes [114]. Endo-ocular lesions have been observed in patients having disseminated cutaneous leishmaniasis. A report from Brazil documented the presence of *Leishmania* in the aqueous humor along with iridiocyclitis [115]. Although ocular manifestations are not very common, it is suggested that a person with ocular manifestation from endemic country should undergo fundus examination for early diagnosis [116].

develop and false positive results have also been known to be associated with serological tests due to cross-reaction of antibodies to non-pathogenic *Trypanosoma rangeli* [8, 91]. Furthermore, detailed examination by the ophthalmologist may aid in establishing the diagnosis. However, accumulation of retinal pigment epithelium defects have been shown in patients with intra‐ ocular involvement of intermediate and chronic Chagas disease in Paraguay/South America,

Acute cases of Chagas disease are treated by nifurtimox and benznidazole. Benznidazole is given as 5–7.5 mg/kg per day orally in two divided doses for 60 days. Nifurtimox is given as

Within few weeks, symptoms of acute Chagas disease such as Romana's sign fade away, but infection persists. The average life-time risk of developing complications of chronic phase is around 30%. It may take more than 20 years to develop chronic complications. However, trypanocidal therapy did not significantly reduce cardiac clinical deterioration through 5 years of follow-up as documented by randomized trial of benznidazole for chronic Chagas' cardio‐

Leishmaniasis is caused by protozoan parasite that belongs to genus *Leishmania.* Humans get infection by the bite of phlebotomine sand flies. There are different clinical forms of leishma‐ niasis, such as visceral leishmaniasis (VL), cutaneous, diffuse cutaneous and mucocutaneous caused by different species of *Leishmania*. Worldwide, approximately 1.3 million new cases

but overall fundus examination has shown to be unobtrusive [92, 93].

**Figure 5.** Life cycle of *Trypanosoma cruzi* (Diagrammatic representation).

myopathy [95, 96].

54 Advances in Common Eye Infections

**4.4. Leishmaniasis**

8–10 mg/kg per day orally in three or four divided doses for 90 days [91, 94].

Diagnosis of leishmaniasis can be achieved by the direct demonstration of parasites in the tissue smears and/or biopsy samples, culture technique(s), antigen and/or antibody detection and molecular technique(s). However, each technique has its own merits and demerits. Amastigotes can be easily identified in the cutaneous and mucocutaneous lesions but are not easily identified in cases with ocular disease [103, 117, 118]. Molecular techniques such as PCR/ real-time PCR can identify the genome of parasite with greater sensitivity (100%) and specif‐ icity (100%) [119, 120]. The treatment of leishmaniasis depends on several factors such as clinical form of the disease. The antileishmanial drugs include pentavalent antimony, sodium stibogluconate, liposomal Amphotericin B, miltefosine and paromomycin [118, 121].

Ocular lesions do not heal without treatment and could lead to vision loss if conjunctiva is involved due to severe ulceration. Healing occurs without visual impairment if treatment is initiated early during the course of infection and vigorous treatment is required to prevent blindness [121, 122].

**Figure 6.** Life cycle of *Leishmania* (Diagrammatic representation).

#### **4.5. Malaria**

Malaria is caused by the parasites of Genus *Plasmodium* and is transmitted by the bite of female anopheles mosquitoes. The malarial parasite passes its life cycle in humans and mosquitoes. Inside human host, *Plasmodium* undergoes exoerythrocytic and erythrocytic schizogony as shown briefly in Figure 7. Malarial parasite multiplies by asexual method (schizogony) while residing inside liver cell and the red blood cells. After the parasites have undergone erythro‐ cytic schizogony for a certain period, some of the merozoites give rise to gametocytes, which are taken up by mosquitoes during their blood meal. The gametocytes further develop into sporozoites that are infective to man. Sporozoites when introduced into humans are not directly infective for red blood cells, but undergo development initially in hepatic cells (exoerythrocytic schizogony) and later on invade red blood cells to complete erythrocytic schizogony. As per World Malaria Report 2014 [123], an estimated 3.3 billion people are at risk of developing malaria (Table 1, Figure 3). Complications of severe malaria due to *P. falcipa‐ rum* mainly occur due to the sequestration of malarial parasite in the microvasculature leading to occlusion and hypoxia. Most of the ocular manifestations occurring in malaria are a result of the same mechanism. Sequestration is further amplified by auto agglutination and resetting [124, 125].

**Figure 7.** Life cycle of *Plasmodium* (Diagrammatic representation).

**4.5. Malaria**

56 Advances in Common Eye Infections

**Figure 6.** Life cycle of *Leishmania* (Diagrammatic representation).

[124, 125].

Malaria is caused by the parasites of Genus *Plasmodium* and is transmitted by the bite of female anopheles mosquitoes. The malarial parasite passes its life cycle in humans and mosquitoes. Inside human host, *Plasmodium* undergoes exoerythrocytic and erythrocytic schizogony as shown briefly in Figure 7. Malarial parasite multiplies by asexual method (schizogony) while residing inside liver cell and the red blood cells. After the parasites have undergone erythro‐ cytic schizogony for a certain period, some of the merozoites give rise to gametocytes, which are taken up by mosquitoes during their blood meal. The gametocytes further develop into sporozoites that are infective to man. Sporozoites when introduced into humans are not directly infective for red blood cells, but undergo development initially in hepatic cells (exoerythrocytic schizogony) and later on invade red blood cells to complete erythrocytic schizogony. As per World Malaria Report 2014 [123], an estimated 3.3 billion people are at risk of developing malaria (Table 1, Figure 3). Complications of severe malaria due to *P. falcipa‐ rum* mainly occur due to the sequestration of malarial parasite in the microvasculature leading to occlusion and hypoxia. Most of the ocular manifestations occurring in malaria are a result of the same mechanism. Sequestration is further amplified by auto agglutination and resetting

Wide range of ocular symptoms has been reported in patients suffering from malaria. Un‐ complicated malaria is usually not associated with significant ocular findings but rarely may be associated with edema and hyperemia of the eyelids, chemosis of conjunctiva, conjunctival hemorrhage and anterior uveitis [126]. On the other hand, severe ocular manifestations may occur in cerebral malaria due to *P. falciparum* leading to visual field defects, cortical blindness, optic neuritis, papilledema and optic atrophy [127]. Ocular motor disturbances have also been reported. Occasionally, infarcts in brainstem may cause changes in pupillary reaction and disorders of eye movements. Patients with cerebellar syndromes may present as nystagmus [128, 129]. Characteristics features such as retinal whitening consisting of irregular patchy areas may be localized or diffused in all segments of retina [130]. Blood vessel changes manifest as discoloration (white or orange) occurring mainly in the peripheral fundus, whereas whitecentered retinal hemorrhages may manifest as malaria retinopathy. Discoloration of retinal vessels occurs due to the absence of hemoglobin in parasitized erythrocytes, sequestered within retinal vasculature and thus cannot reflect normal red color. Retinal changes in cerebral malaria are considered as poor prognostic markers [131]. The prevalence of any retinopathy, papilledema, hemorrhages, vessel changes, macular whitening and peripheral whitening has been reported in 61, 15, 46, 32, 46 and 44%, respectively, among children with cerebral malaria in Malawi [132].

Diagnosis of malaria is established by light microscopy or by rapid antigen detection kits. Light microscopic examination of Giemsa-stained peripheral blood smear is considered as gold standard for the diagnosis of malaria with a threshold of about 50–100 parasites/µL [133]. However, in addition, ocular examination may provide clue to the diagnosis as specific retinal changes can be seen directly [129, 134, 135].

Treatment depends on the species of *Plasmodium* causing infection. Artemisinin combination therapy is recommended for malaria due to *P. falciparum.* Artemisinin combination therapy includes short-acting artemisinin derivative and long-acting antimalarial (sulphadoxinepyrimethamine, lumefantrine). Chloroquine along with primaquine is recommended for malaria due to *P. vivax.* Ocular toxicity [136] is very well documented with chloroquine therapy. This includes corneal changes (cornea verticillata) and corneal deposits. Toxic maculopathy and scotoma has also been reported. Quinine overdose has also been known to cause decreased vision, retinal and macular degeneration, mild scotomas and color vision defects [136].

If not treated, malarial retinopathy is associated with serious consequences as reports indicate that the severity of retinopathy is related to prolonged death and coma. After antimalarial treatment and resolution of coma in severe malaria, malarial retinopathy resolves after some time [132, 137].

#### **4.6. Microsporidiosis**

Microsporidiosis is the term used to denote the infection caused by microsporidia belonging to phylum Microspora [23]. Microsporidia were once thought to be protists but are now known to be fungi. Although it is classified as a protozoal disease in ICD-10, their phylogenetic placement has been resolved to be within the fungi [138]. Microsporidiosis is considered as an opportunistic infection in AIDS/HIV-infected individuals and is prevalent worldwide (Table 1) [1]. Microsporidia are small, unicellular, spore forming, obligate intracellular pathogens. Important genera responsible for ocular manifestations are Encephalitozoon and Nosema. Another species, Septata, has also been reported to cause keratoconjunctivitis [139]. The prevalence of microsporidiosis ranges from 2 to 50% among severely immunocompromised, HIV-infected patients found in North America, western Europe and Australia. The prevalence data for microsporidiosis is limited among non-HIV-infected persons [9].


**Figure 8.** Life cycle of *Microsporidia* (Diagrammatic representation).

Ocular manifestations caused by *Microsporidia* are mainly limited to conjunctiva and cornea. Corneal involvement may lead to punctate epithelial keratitis, hyphema, necrotizing keratitis and corneal ulcer. Symptoms include foreign body sensation, photophobia and decrease in visual acuity [23].

Diagnosis is established by direct demonstration of the spores by microscopy or electron microscopy of the corneal scrapping or biopsy specimens. Isolation of the parasites in culture has also been attempted [140]. There are no reports on use of serological tests to detect antibodies in serum or tears in ocular microsporidiosis [9]. Lesions usually heal after 1–2 weeks as it is self-limiting. Treatment of microsporidial keratoconjunctivitis with polyhexamethylene biguanide does not offer any significant advantage but treatment with topical fumagillin showed significant improvement [141–143].

#### **4.7. Giardiasis**

been reported in 61, 15, 46, 32, 46 and 44%, respectively, among children with cerebral malaria

Diagnosis of malaria is established by light microscopy or by rapid antigen detection kits. Light microscopic examination of Giemsa-stained peripheral blood smear is considered as gold standard for the diagnosis of malaria with a threshold of about 50–100 parasites/µL [133]. However, in addition, ocular examination may provide clue to the diagnosis as specific retinal

Treatment depends on the species of *Plasmodium* causing infection. Artemisinin combination therapy is recommended for malaria due to *P. falciparum.* Artemisinin combination therapy includes short-acting artemisinin derivative and long-acting antimalarial (sulphadoxinepyrimethamine, lumefantrine). Chloroquine along with primaquine is recommended for malaria due to *P. vivax.* Ocular toxicity [136] is very well documented with chloroquine therapy. This includes corneal changes (cornea verticillata) and corneal deposits. Toxic maculopathy and scotoma has also been reported. Quinine overdose has also been known to cause decreased vision, retinal and macular degeneration, mild scotomas and color vision

If not treated, malarial retinopathy is associated with serious consequences as reports indicate that the severity of retinopathy is related to prolonged death and coma. After antimalarial treatment and resolution of coma in severe malaria, malarial retinopathy resolves after some

Microsporidiosis is the term used to denote the infection caused by microsporidia belonging to phylum Microspora [23]. Microsporidia were once thought to be protists but are now known to be fungi. Although it is classified as a protozoal disease in ICD-10, their phylogenetic placement has been resolved to be within the fungi [138]. Microsporidiosis is considered as an opportunistic infection in AIDS/HIV-infected individuals and is prevalent worldwide (Table 1) [1]. Microsporidia are small, unicellular, spore forming, obligate intracellular pathogens. Important genera responsible for ocular manifestations are Encephalitozoon and Nosema. Another species, Septata, has also been reported to cause keratoconjunctivitis [139]. The prevalence of microsporidiosis ranges from 2 to 50% among severely immunocompromised, HIV-infected patients found in North America, western Europe and Australia. The prevalence

**3.** The spore injects the infective sporoplasm into the host cell. Inside the host cell, sporo‐ plasm undergoes multiplication either in the cell cytoplasm or inside parasitophorous vacuole. Microsporidia develop to mature spores by sporogony that are released by

disruption of cell membrane. The free mature spores are the infective forms.

data for microsporidiosis is limited among non-HIV-infected persons [9].

**1.** The life cycle of parasite involves three stages (Figure 8):

**2.** The resistant spore (infective form)

in Malawi [132].

58 Advances in Common Eye Infections

defects [136].

time [132, 137].

**4.6. Microsporidiosis**

changes can be seen directly [129, 134, 135].

Giardiasis is caused by *Giardia duodenalis* (syn. *G. lamblia* or *G. intestinalis*) [144]. The infection is transmitted by ingestion of contaminated water/food or directly by feco-oral route. The parasite exists in trophozoite and cyst forms as shown in Figure 9. In the trophozoite stage the parasite multiplies in the intestine of man by binary fission. When conditions become unfav‐ 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 long-term extra intestinal manifestations [145].

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

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 progress or regress with time [146].

The diagnosis is established by direct demonstration of the parasite in the fecal samples by microscopy. Concentration techniques of the samples yield higher sensitivity. Nitroimidazole group of drugs are highly effective against *G. duodenalis*. Most commonly used drugs are metronidazole for 5–7 days or ornidazole/tinidazole in single dose [147]. Treatment of intestinal infection is recommended if present, but no specific treatment is required for ocular manifestations related to retina [146].
