Infective stage in man
Cats and dogs
Birds and rodents
Cyst, migrating larvae
Deer fly (Chrysops)
Dogs, cats, wild carnivores
Cyclops (first), fish, snakes, frog (second )
Mosquito – Aedes, Anopheles, Culex
Snails, prawns, crabs
Bancroftian and Brugian filariasis
Mosquito – Aedes, Anopheles, Culex Anopheles, Mansonia
Adult worm or microfilariae
18.2.3 Clinical Features
Toxocara larvae can be found in any organ in humans, and many cases are discovered accidentally. Clinically the disease occurs in two forms: systemic toxocariasis and ocular toxocariasis. Both the forms rarely coexist [2, 9].
It is also known as visceral larva migrans (VLM) and occurs in children aged between 2 and 3 years, who have history of pica. They develop symptoms of fever, anorexia, weakness, failure to gain weight, myalgia and arthralgia. These symptoms are due to host immune response to toxoplasma larvae. There can be allergic pulmonary symptoms and other symptoms of pneumonitis, pneumonia, hepatomegaly, splenomegaly, lymphadenopathy, eosinophilia, hypergammaglobulinaemia, elevated level of IgE, neurological involvement with seizures and myocarditis .
It is also known as ocular larva migrans (OLM). Ocular involvement usually occurs in children older than 3 years and in young adults. The symptoms occur due to weak host immune response. Children may present with strabismus, decreased vision and leukocoria which is an important differential diagnosis for retinoblastoma . Ocular involvement occurs in five ways. Anterior segment involvement is very rarely involved. Only few case reports are available in literature . In peripheral variant a fibrovascular band may be seen running from a whitish granuloma in the periphery to the optic nerve or posterior pole (Fig. 18.1). It can lead to tractional or rhegmatogenous retinal detachment [2, 9]. Sometimes a well-defined mass of variable size of ¼–4 disc diameter may be seen in the posterior pole associated with vitreous haze. It may masquerade as retinoblastoma. In the later stage, there may be either atrophy or hyperplasia of the retinal pigment epithelium in the macula [2, 11]. Optic nerve involvement is a rare entity, and when present it has the clinical features of optic neuritis/papillitis . The most common presentation of Toxocara is as endophthalmitis. Dense vitreous haemorrhage may be present, and a yellowish-whitish mass may be faintly visible through vitreous haze. Externally the eye may look quiet or may sometimes have a granulomatous reaction with mutton fat keratic precipitates. Hypopyon may be seen in very severe cases .
Fundus image showing peripheral form of toxocariasis
The various differential diagnosis of toxocariasis includes retinoblastoma, Coats’ disease, persistent hyperplastic primary vitreous (PHPV), familial exudative vitreoretinopathy (FEVR) and retinopathy of prematurity (ROP).
The clinical diagnosis of Toxocara is quite obvious, but still a confirmatory diagnosis is required in suspicious cases or for documentation. The larvae or its fragments may be directly visible under the microscope from tissue sections, but it’s extremely cumbersome and risky to collect samples from ocular tissues. In a Wilder’s classic study, only one larva was detected in 2300 cases examined . Eosinophilia is noted in the blood of patients with systemic toxocariasis; however, the eosinophil count can be normal in patients with ocular toxocariasis . The diagnosis of Toxocara can be clinched by indirect enzyme-linked immunosorbent assay (ELISA) which detects the immunogenic proteins known as Toxocara excretory-secretory (TES) antigens that are shed from the larvae . A titre of 1:8 or more of ELISA along with signs and symptoms of Toxocara is sufficient to aid the diagnosis of Toxocara [2, 14]. However, there are few case reports of negative ELISA in Toxocara . In literature the sensitivity for ELISA for Toxocara is variable with a range between as low as 33 % and as high as 92.2 % (depending upon the cutoff value of the titres) . Detecting rising titres of anti-TES-Ag immunoglobulin E (IgE) antibody indicates acute toxocariasis. The titres return to normal after treatment and help in monitoring treatment therapy . Increased IgG titres confirm a past or present infection without significant inflammation. Ultrasonography (USG) is important to differentiate it from retinoblastoma, where Toxocara appears as mass lesion and multiple vitreous membranes can be seen running from mass to disc, some of which are highly reflective. Intraocular calcification has been reported in some cases, and in that case other imaging modalities and serological test differentiate it from retinoblastoma . The role of ultrasound biomicroscopy (UBM) is synergetic with USG as demonstrated by Zhou et al., where they could identify 95 % of the peripheral subtypes of toxocariasis . Typical pseudocystic degeneration of the vitreous was picked up on UBM by Tran et al. .
Treatment of Toxocara depends upon the severity of disease. Oral steroids in a dose of 0.5–1 mg/kg body weight or periocular steroids may be required in cases of posterior uveitis along with topical steroids and cycloplegics for associated anterior uveitis . The role of anthelmintic drugs (diethylcarbamazine, thiabendazole, mebendazole, albendazole) is controversial due unavailability of ocular pharmacodynamics and pharmacokinetics of these drugs. However, Barisani AT et al.  have treated seven eyes of five patients with oral albendazole along with steroids and have shown promising results. Ahn SJ et al. demonstrated that albendazole with steroids could reduce the recurrence to 17.4 % as compared to 54.5 % in patients who were administered only steroids by the end of 6 months, though the vision and inflammation improvement was the same in both the groups . In majority of cases at the time of presentation, the parasite is dead and can be treated with steroids alone due to the inflammation caused by the dead parasite; however, in cases of live parasite, systemic albendazole can be tried/recommended (adult dose 800 mg BID, children 400 mg BID for 7–14 days) . Surgical intervention is required for associated tractional or rhegmatogenous retinal detachment or endophthalmitis .
Gnathostomiasis is a food-borne disease caused by infection with larvae of Gnathostoma species. Intraocular infection by Gnathostoma species is quite rare but can be devastating .
Around 12 species of Gnathostoma are known till now; however, only four species (Gnathostoma spinigerum, Gnathostomiasis hispidum, Gnathostoma doloresi, Gnathostoma nipponicum) have been reported to be zoonotic. Among these Gnathostoma spinigerum is a well-studied species and was discovered in Thailand in 1889. The cases of infection with G. spinigerum are mostly reported from Thailand, Japan, Malaysia, China, India, Java, Israel, Vietnam and the Philippines [22–24]. The total 74 cases of gnathostomiasis were reported worldwide, and about 83.5 % of the cases have been reported from Asian countries or among people travelling from these endemic countries .
18.3.2 Parasitology/Life Cycle (Table 18.1)
Dogs/cats are the definitive host parasitizing the adult worms in their stomach; the eggs are released from the animal’s stools. Cyclops are the first intermediate host, and freshwater fish, eel, frog or snake are the second intermediate host. Pigs, ducks and chicken are the paratenic hosts. Humans acquire infection by eating the second intermediate host or the paratenic hosts. The third-stage larvae migrate in the internal organs, eyes and subcutaneous tissues; however, they do not mature into adult in humans. In humans a third larval stage, immature worms and adult worms can be found .
18.3.3 Clinical Features
Skin and mucous membrane involvement is known as Gnathostoma externa. The classical cutaneous lesions are migratory where the larvae can travel a centimetre or more within an hour under the skin producing local oedema and haemorrhage. The patient will have painless, non-pitting oedema with associated erythema and pruritus . Internal organ involvement is also known as Gnathostoma interna . The patient presents with nausea, vomiting, pruritus, urticaria and abdominal pain. High mortality in gnathostomiasis is due to invasion of parasite to the brainstem and medulla oblongata or due to subarachnoid haemorrhage. Initially, the patient may present with symptoms of meningitis or meningoencephalitis [27–29].
It occurs due to third larval stage of the parasite. The ocular involvement is due to migration of worm from the brain to the eye via optic nerve or directly through the scleral invasion. Two most striking forms of ocular involvement are of eyelid and the intraocular migration of the parasite (Fig. 18.2). The cornea and conjunctiva can also be involved. The patient may present with corneal ulceration, orbital cellulites like picture, hyphema, vitreous haemorrhage, central retinal artery occlusion, secondary glaucoma, traumatic retinal hole (due to larva migration) and retinal detachment [25, 30–34].
Showing Gnathostoma worm in the anterior chamber
The diagnosis of gnathostomiasis can be reached by this classical triad of patients travelling from endemic countries, history of consuming raw fish and peripheral eosinophilia, though reports in literature have shown that patients may present without eosinophilia and eosinophils are increased only during the migratory phase of the parasite . Eosinophil count can also be used as a marker for treatment response . Microscopic identification of the parasite is the only way of making the definitive diagnosis, though it’s challenging due to the migratory nature of the parasite. ELISA test is a more recent and reliable methodology for diagnosis . However, ELISA test for both Gnathostoma and Angiostrongylus species should be performed together as both of them show cross sensitivity for each other [25, 31, 32]. Elevated levels of immunoglobulin E (IgE) antibodies are noted in acute infections. Ultrasonography (USG) and ultrasound biomicroscopy (UBM) have been reported to be a useful entity for the diagnosis of nematode, where the parasite is not clinically visible. Bhende et al.  have shown the nematode to move from the iris root to the posterior segment through zonules over 6-min time span on UBM .
Surgical removal of the parasite from the skin, anterior chamber and vitreous cavity of the eye is preferred because if the parasite migrates to the brain, the outcomes are fatal [30, 33, 34]. The role of anthelmintic medicine is controversial, though in literature there are case reports of successful treatment of Gnathostoma with oral albendazole 400 mg/day for 21 days [22, 24, 25].
Onchocerciasis is an infection of humans caused by filarial nematode Onchocerca species, transmitted to human beings by the bite of infected black fly of the genus Simulium . Of lately there has been increasing reports of zoonotic Onchocerca, and many reports have been with infections in and around the eye . It may also manifest as dermatitis, subcutaneous nodules and sclerosing lymphadenitis [35–37].
About 37 million people are infected with onchocerciasis worldwide, and most of the cases (99 %) of onchocerciasis have been reported from Africa . It has also been reported from Eastern Mediterranean, the United States, Hungary, Turkey and India [41–43]. The ‘Onchocerca Control Programme’ started by WHO in 1974 in Africa has been successful in interrupting the transmission of onchocerciasis to near zero level [44, 45].
18.4.2 Parasitology/Life Cycle (Table 18.1)
The species reported to cause ocular infection are O. volvulus, O. gutturosa or O. cervicalis, O. reticulata and O. lupi [1, 8]. Adult worm is present in the skin of the host (man); it may produce half to one million microfilariae, which migrate to the skin or eyes of the host. When a black fly bites these infected humans (only female fly can bite), they suck blood with microfilariae and are then released to the skin of other hosts when it bites .
18.4.3 Clinical Features
The clinical features include dermatitis, subcutaneous nodules, sclerosing lymphadenitis and ocular lesions. There is intense pruritus and depigmentation of the skin along the track of the worm. ‘Onchocercomas’ are painless fibrous nodules that are predominantly seen on the head and face and on the body involving the skin, periosteum or bone [35, 36]. These are due to female worms and microfilaria encapsulated in fibrous coat. The lymph nodes draining the affected area show granulomatous inflammation .
18.104.22.168 Ocular Features
The ocular features are mainly due to dead microfilaria. The corneal involvement is in the form of punctate keratitis (dead microfilaria) and sclerosing keratitis (live microfilaria). The peripheral cornea is most commonly involved with snowflake-like opacities which gradually progress towards the centre of the cornea leading to blindness. Microfilaria can also be seen in the iris stroma or anterior chamber causing granulomatous or non-granulomatous uveitis leading to iris atrophy, synechia and occlusio pupillae. There is involvement of the retina, or choroid is in the form of bilateral and symmetrical focal areas of atrophy and eventually progresses to large areas of atrophy. This chorioretinitis progresses to involve the optic disc leading to optic neuritis and secondary optic atrophy leading to blindness [35, 38, 42, 43, 45–49].
Microfilaria can be demonstrated in the dermis or epidermis on skin biopsy . Mazzotti test is an allergic reaction to oral administration of diethylcarbamazine (DEC), which causes intense pruritus, fever, swollen and tender lymph nodes and can be life threatening. This allergic reaction occurs due to death of the microfilaria. ELISA test and polymerase chain reaction (PCR) are the other tests for detection of microfilaria.
The most effective drug against Onchocerca is ivermectin; it is administered orally as a single dose of 150 mg/kg/day and repeated every 6–12 months. It is microfilaricidal and is not effective against the adult worm [43, 45, 48]. Diethylcarbamazine (DEC), in a dose of 25 mg/day for 3 days, 50 mg/day for 5 days, 100 mg/day for 3 days and 150 mg/day for 12 days, is given. However, this regimen does not kill all the microfilaria; besides it is also associated with high recurrence of onchocerciasis. An allergic reaction (Mazzotti reaction) is also common with it . Doxycycline is a microfilaricidal and well-tolerated drug. It has also been tried effectively for treatment of O. volvulus in co-infection with Loa loa . Surgical removal of the onchocercomas can be done, but it’s challenging in deep-seated nodules.
Loiasis is caused by ‘eye worm’ Loa loa and is transmitted by an insect vector deer fly of genus Chrysops. It has predilection for ocular tissue .
It is endemic in Africa and its prevalence is reported to be 50 % . There has been spread of loiasis to other countries like Spain. There are few case reports of loiasis from Italy and London [51–53]. Choi SU et al. studied 320 cases of parasitic infections from 2004 to 2011 and reported the incidence of Loa loa to 0.3 % .
18.5.2 Parasitology/Life Cycle (Table 18.1)
It is the adult worm that affects the eye as against the Onchocerca volvulus which is caused by microfilaria. Chrysops fly when it bites human beings (hosts) sucks the blood with microfilaria. This fly then inoculates the larvae into another host it bites. In host these microfilariae mature into adults in the subcutaneous area. The adult worm migrates to the eyes of the host. The adult worms live for 12–15 years .
18.5.3 Clinical Features
The patient has intense pruritus of the limbs, chest, back and face. There is oedema of the limbs and face . Later on in the disease, there can be involvement of the heart, kidney and CNS leading to death ultimately.
The most interesting manifestation is seeing the worm move across the conjunctiva: it is pathognomonic for loiasis . The patient may present with decreased vision, conjunctival injection and pain on ocular movement. There are numerous case reports of microfilaria migrating in the eyelids, anterior chamber, vitreous and retina (Loa-induced retinopathy) . Obstruction of the retinal and choroidal vessels leads to aneurysmal dilation and haemorrhages in superficial layers of the retina .
Diagnosis is mostly clinical in patients, who have travelled to endemic areas and are exhibiting symptoms suggestive of loiasis. Confirmatory diagnosis is made by seeing the worm under the microscope. The worm can be removed from subconjuctival space or subcutaneous space; however, the larvae may still be present in the blood after its removal . Afternoon and midnight blood films help in the detection and quantification of microfilaraemia.
Diethylcarbamazine is the mainstay of treatment. It is lethal to both adult worm and microfilaria. The standard regimen is Day 1, 50 mg; Day 2, 50 mg three times daily; Day 3, 100 mg three times daily; and from Day 4 to Day 21, constant dose of 3 mg/kg three times per day. Pretreatment with oral steroids should be considered before initiation of DEC therapy as it will take care of the severe immune reaction and encephalopathy caused by the death of microfilaria. Alternate treatment with ivermectin and albendazole can be considered [53, 57–59].
18.6 DUSN (Diffuse Unilateral Subacute Neuroretinitis)
Diffuse unilateral subacute neuroretinitis (DUSN) is a rare entity caused by a glistening white, motile nematode seen wandering in the subretinal space. It was initially known as ‘unilateral wipe-out syndrome’ . The term DUSN was coined by Gass in 1978 .
18.6.2 Parasitology/Life Cycle (Table 18.1)
18.6.3 Clinical Features
DUSN usually occurs in children and young adults. The patients may present with features of cutaneous larva migrans, which may precede the visual symptoms and the other devastating form of neural larva migrans .
Gass demonstrated a non-granulomatous reaction. In early stages it manifests as vitritis, multifocal choroiditis and papillitis. Early diagnosis can aid in laser photocoagulation of the worm along the vicinity of grey white retinal lesions. In late stage it leads to secondary optic nerve atrophy (due to destructions of retinal layers), retinal vessel narrowing, diffuse changes in retinal pigment epithelium, peripheral RPE hypopigmentation and formation of various RPE tracks which are visible clinically (Fig. 18.3). These changes are caused due to toxic effect of the worm products on the outer retina . DUSN though causes damage to all the layers of the retina, and it predominantly destroys the inner retina (nerve fibre layer) and retinal pigment epithelium [65, 66].
Showing tracks of DUSN worm
Seeing a motile worm on biomicroscopy is the gold standard for diagnosis . Berbel et al. have demonstrated that in cases where DUSN is suspected, optical coherence tomography (OCT) helps in the assessment of nerve fibre layer and areas of oedema . This non-invasive test helps to differentiate it from other mimicking conditions like toxoplasmosis where the retinal nerve fibre layer is spared. Intraretinal worm can be picked up on enhanced depth imaging OCT, where it appears as a hyperreflective object of irregular shape, affecting all the layers of the retina .