Zoonotic helminths affecting the human eye
© Otranto and Eberhard; licensee BioMed Central Ltd. 2011
Received: 31 January 2011
Accepted: 23 March 2011
Published: 23 March 2011
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© Otranto and Eberhard; licensee BioMed Central Ltd. 2011
Received: 31 January 2011
Accepted: 23 March 2011
Published: 23 March 2011
Nowaday, zoonoses are an important cause of human parasitic diseases worldwide and a major threat to the socio-economic development, mainly in developing countries. Importantly, zoonotic helminths that affect human eyes (HIE) may cause blindness with severe socio-economic consequences to human communities. These infections include nematodes, cestodes and trematodes, which may be transmitted by vectors (dirofilariasis, onchocerciasis, thelaziasis), food consumption (sparganosis, trichinellosis) and those acquired indirectly from the environment (ascariasis, echinococcosis, fascioliasis). Adult and/or larval stages of HIE may localize into human ocular tissues externally (i.e., lachrymal glands, eyelids, conjunctival sacs) or into the ocular globe (i.e., intravitreous retina, anterior and or posterior chamber) causing symptoms due to the parasitic localization in the eyes or to the immune reaction they elicit in the host. Unfortunately, data on HIE are scant and mostly limited to case reports from different countries. The biology and epidemiology of the most frequently reported HIE are discussed as well as clinical description of the diseases, diagnostic considerations and video clips on their presentation and surgical treatment.
Homines amplius oculis, quam auribus credunt
Seneca Ep 6,5
Men believe their eyes more than their ears
Blindness and ocular diseases represent one of the most traumatic events for human patients as they have the potential to severely impair both their quality of life and their psychological equilibrium. Although it is highly unusual, blindness has always been of great interest in human medicine. For example, the evaluation of the emotional and quality of life impacts in patients with some diseases causing blindness (e.g., macular degeneration) gave results similar to those found in diseases such as AIDS, chronic obstructive pulmonary disease, cardiac disorders and leukemia . In addition, blindness has profound human and socio-economic consequences with high costs for the individual, and society, linked to lost productivity and rehabilitation estimated at $42 USD billion per year in 2000, and predicted to reach as high as $110 USD billion per year in 2020 .
There are many causes of blindness and those induced by parasitic agents (i.e., Protozoa, Helminths and Diptera) are of major public health concern in developed and developing countries. For example, eye disease caused by river blindness (Onchocerca volvulus), affects more than 17.7 million people inducing visual impairment and blindness elicited by microfilariae that migrate to the eyes after being released by female adult worms in the subcutaneous tissues . Several parasites localize in human eyes as an effect of a specific neurotropism (e.g., Toxoplasma gondii in the foetuses), larval migration (e.g., ascarids, Dirofilaria spp., Trichinella spp.) and, in a few cases, as a primary localization being released directly into the eyes (e.g., Thelazia callipaeda eyeworm and some oestrid fly larvae causing myiasis) .
Classification (Order, Family and Species) of zoonotic helminths causing human blindness divided according their route of transmission (Vector borne zoonosis, VbZ, food consumption, FbZ, and those at direct transmission from the environment, EbZ), geographical distribution, localization in the eyes and zoonotic relevance.
Species (common name)
Route of transmission
Angiostrongylus cantonensis (rat lungworm)
Ingestion of snails, slugs, shellfish and crustacean (FbZ)
Asia, Australia, Africa, USA, Pacific Islands, Caribbean Islands, and South America
Anterior chamber, vitreous
Toxocara canis (dog roundworm)
Dog faeces (EbZ)
Eyebrows and eyelds, aqueous humor and vitreous
Toxocara cati (feline roundworm)
Cat faeces (EbZ)
Aqueous humor and vitreous
Baylisascaris procyonis (raccoon roundworm)
Raccoon faeces (EbZ)
North America, Europe, Japan
Spirurida Suborder Spirurina
Gnathostoma spinigerum, G. hispidum,
Ingestion of crustacean (cyclops),
Anterior chamber, eye lid
Dog, cat, wild carnivores,
G. doloresi and G. nipponicum
infected fish, frogs (FbZ)
Aedes, Anopheles, Culex (VbZ)
Europe, Asia, Africa
Aedes, Anopheles, Culex (VbZ)
Aedes, Anopheles, (VbZ)
Aedes, Taeniorhynchus (VbZ)
Canada, Oregon, USA
Fleas, louses (VbZ)
Simulium spp. (VbZ)
Culicoides spp. (VbZ)
Culicoides spp. (VbZ)
Culicoides spp. (VbZ)
Europe, Asia, Africa
O. dewittei japonica
Simulium spp. (VbZ)
Simulium spp. (VbZ)
Aedes, Anopheles, Culex
P. (Loaina) scapiceps
Thelazia callipaeda T. californiensis
Phortica spp. (VbZ)
China, Southeastern Asia, Europe, USA
Dogs, cats, rabbits and wild carnivores
Ingestion of raw meat (FbZ)
Orbit, Ocular muscles
Numerous, domestic and wild animals
Spirometra erinaceieuropaei (Sparganosis)
Ingestion of crustacean, frogs, birds, snakes (FbZ)
Middle East, Australia
Spargana (other species)
Ingestion of crustacean, frogs, birds, snakes (FbZ)
South America, Asia
Food contaminated by dog faeces (EbZ)
USA and Europe
Food contaminated by dog faeces (EbZ)
Food contaminated by wild carnivores dog faeces (EbZ)
Wolf, jackal, coyote
Food contaminated by wild carnivores dog faeces (EbZ)
South and Central America
Coenurus cerebralis (Multiceps multiceps)
dog faeces (EbZ)
water plants (FbZ)
Domestic and wild ruminants, horse
Alaria mesocercaria, A. americana
Asia, USA, Canada
Contaminated food or direct contact with the eye mucosa (EbZ)
Europe, Asia, and America
Helminths at the adult and/or larval stages may infect human ocular tissues externally (i.e., eyelids, conjunctiva sacs, subconjunctiva, and lachrymal glands) or the ocular globe (i.e., optical nerve, intravitreous retina, anterior and posterior chamber). Several parasitic helminths adapted a tropism for animal eyes and related tissues when migrating throughout the host body mainly during their immature stages. This is the case of ascarids and strongylids, causing ocular larva migrans, filarioid species, and larvae of Trichinella, as well of trematode and cestode parasites. Nonetheless, human ocular infestations by zoonotic helminths may also be caused by the parasitic adult stages as in the case of thelaziids (eye worm infestation) and filarioid species including those belonging to the genera Dirofilaria and Onchocerca[8–10]. Thus, ocular localization of helminths is mainly caused by aberrant migration in host tissues and, only in one case (i.e., T. callipaeda), by direct inoculation into the eyes. What is equally unclear is the route that most follow to gain entry into the eye. It is supposed that some migrate along and follow the optic nerve but others may enter the bloodstream and be carried to the eye in that manner; however, it is not known if these are the preferred or aberrant routes, or even which is the most common route that helminths follow to reach the eye. Once in the eye, larvae likely find it to be a more protected site from host immune responses, but it is not clear that a directed migration into the eye had occurred.
Ocular tissue affected
Eyebrows and eyelids
Eye lid edema
Taenia solium (cysticercus), Spirometra, Ancyclostoma, A. Americana Gnathostoma, Toxocara, Trichinella, Dirofilaria
Lacrimal duts and glands
Echinococcus, coenurus, Taenia solium (cysticercus), spargana, Trichinella, Dirofilaria, Gnathostoma
Trichinella, Angiostrongylus, Ancyclostoma, spargana,
Taenia, Dirofilaria, Acanthocheilonema, Habronema, Mansonella, spargana, Philophthalmus
Chemosis and conjunctivitis
Thelazia, Trichinella, Onchocerca
Onchocerca, Toxocara, Ancylostoma
Parasites in the anterior Chamber
Onchocerca, Schistosoma, Taenia, spargana, Angiostrongylus, Gnathostoma, Toxocara, Dirofilaria, Thelazia, Acanthocheilonema
Cysts in the anterior chamber
Taenia, Gnathostoma, Toxocara
Taenia, Echinococcus, Angiostrongylus, Dirofilaria, Onchocerca spp., Gnathostoma, Toxocara
Distortion of the pupil
Iritis and iridocyclitis
Taenia, Angiostrongylus, Ancyclostoma, Trichinella Toxocara, Onchocerca, Pelecitus
Trichinella, cysticercus, Gnathostoma
Cysticercus, Echinococcus, coenurus
Parasites in the vitreous Cyclitis
spargana, Acanthocheilonema, Dirofilaria, Onchocerca Gnathostoma, Onchocerca, Toxocara, Trichinella
Papilledema, papillitis, and optic atrophy
Taenia, Ancylostyoma, Toxocyara, Trichinella, Onchocerca
Retina and chorioidea
Ancylostoma, Gnathostoma, Toxocara, Trichinella
Retinitis and choroiditis
Baylisascaris, Taenia, Toxocara, Trichinella, Onchocerca
There are many nematode parasites that can be found in the orbit or within the eye proper (Table 1). Although most nematode infections of the eye are rare, some are more frequently reported than others. In this section, we will discuss those zoonotic nematodes that are most likely to be encountered and reported, by examining their aetiology, case reports and epidemiology.
Trichinellosis (Trichuroidea, Trichinellidae) has a cosmopolitan distribution, but is generally less important as an infection of humans in the tropics than in more temperate regions of the world. Once thought to be a single species (Trichinella spiralis), there are now at least eight distinct species recognized. Each of these species has a slightly different geographical distribution and host range, and only Trichinella zimbabwensis of crocodiles in Tanzania, has not been reported from humans to date. The most striking feature of this group of parasites is their obligatory transmission by ingestion of infected meat containing larvae, either in typical cysts or unencapsulated in the case of several species . The clinical course is characterized by two phases, the enteric/enteral phase, when adult worms are present in the intestinal mucosa, and the parenteral phase, when the released larvae invade the host muscles . During the parenteral phase, which follows the enteral, a typical syndrome of fever, myalgia, periorbital edema and eosinophilia occur. In addition to periorbital and facial edema, conjunctivitis is also frequent. The cause of the orbital and facial edema is not well known. but probably includes some component of an allergic response. Periorbital edema often appears early in the parenteral phase, and typically begins to wane after several weeks. Larvae also affect the macula and retina, causing hemorrhage and other damage as they migrate through and into these ocular tissues . The diagnosis can be suggested from clinical history of ingesting raw or inadequately cooked meat, and the ophthalmologist is often the first contact because of the swollen eyelids and conjunctivitis. Demonstration of larvae in muscle biopsies of patients or in frozen sample of the ingested meat, if available, is still standard procedure to confirm infection. Good serological tests exist and are also very useful in confirming infection, especially in cases with low-level infection where symptoms may be minimal and the number of larvae in muscle may be low. Some areas of the world, such as the United States and Europe, have effectively controlled the infection in humans by removing the parasite from the domestic pig cycle through heightened food safety regulations regarding inspection and feeding practices. In other areas of the world, the domestic pig cycle continues to be responsible for human infection, and in all areas, human infection continues to occur when infected wild game meat is ingested without proper cooking. Because of the wide range of animals that can harbour infection with Trichinella larvae, proper handling and cooking of all meats is recommended.
Ascarids (Ascaridida, Ascaridiidae) occur worldwide infecting various mammals, including humans [16, 17]. Many of these nematodes are causative agents of zoonoses transmitted to humans via contaminated soil. Within the ascarids, Toxocara canis, Toxocara cati and Baylisascaris procyonis are zoonotic parasites of dogs, cats and raccoons, respectively, and they are among the most widespread causes of neural and ocular larva migrans. Indeed, larvae of T. canis are probably the most common nematode infection of the human eye, also known as ocular larva migrans (OLM), and infection in humans occurs worldwide . Infection occurs through the ingestion of infective eggs, most often from soil or other environmental surfaces that have been contaminated with faeces from infected animals. Examination of soil or sand from parks and playgrounds often demonstrates infective Toxocara eggs, which might remain infectious for long periods of time (even years) in the environment . When ingested, the eggs hatch and larvae migrate in the tissues, most often to the liver, but on occasion to other sites such as the eye and central nervous system (CNS). The wandering larvae cause a syndrome, called visceral larva migrans (VLM), of marked eosinophilia, hepatomegaly, fever, cough, and pulmonary infiltrates. The severity of symptoms is often related to the number of larvae acquired, and can range from asymptomatic to acute, with a fatal outcome. The ability of Toxocara larvae to cause OLM was recognized about 60 years ago [19, 20]. OLM occurs most typically in older children (mean 8 yr versus 2 yr for VLM), generally have no other evidence of organ involvement, and hypereosinophilia, hepatomegaly, and pulmonary symptoms are absent, there is no history of pica, and evidence suggests that OLM is caused by a single larva entering the eye. Antibodies to Toxocara tend to be lower in cases of OLM, possibly as a result of fewer infective larvae, and there is experimental evidence that somewhat different immune responses occur between OLM and VLM . Hundreds of cases have been reported and described and untold thousands of cases have probably occurred, even in developed countries, as evidenced by seropositivity in population-based surveys [22, 23]. Worldwide, cases continue to be reported in the literature, including descriptions of lesions, effective treatments, and new/modified methods to observe the infection in the eye [24–37]. Visual observation of motile larvae in the eye is possible, although accurate diagnosis is difficult; serodiagnosis continues to be very useful in detecting and confirming cases [38, 39]. Toxocara larvae are approximately 400 by 20 μm and a larva of this size in the eye is highly suggestive. In this presentation, destruction of the larva by photocoagulation is recommended, and prognosis is favourable when recognized early and prompt treatment is provided . After an undefined period of wandering in the tissues, but probably for several weeks or longer, larvae become encapsulated, including those in the eye. These cases, typically present with unilateral visual deficits, with or without ocular pain, and a raised white retinal mass that presents difficulty in distinguishing from retinoblastoma. Unfortunately, in these situations, loss of visual acuity, blindness, and even enucleation of the eye may result. Toxocara larva seen in biopsy specimens or surgically resected tissues are rather easily identified based on size and morphological features. Generally the larva will be enclosed in a granuloma, coiled, and one or more sections of the larva evident. In tissue sections, larvae measure 15-21 μm in diameter and are characterized by a single prominent lateral ala, non- patent gut, and large excretory columns . The prevention of toxocariasis, including OLM, is based on good personal hygiene, including washing hands, and the proper disposal of pet waste, including and specifically not letting pets and stray animals defecate in public places where children and others play and could come in contact with infective eggs. Rubinsky-Elefant and colleagues  recently reviewed the subject.
There are a number of different filarioids that have been reported infecting the eye or the conjunctiva, and those reports date back several hundred years, making them one of the oldest groups of parasites known to occur in or on the eye. Indeed, besides the well-known (but not zoonotic) Wuchereria bancrofti, Brugia malayi and Loa loa, some filarioids from domestic and wild mammals (e.g., Dirofilaria spp., Onchocerca spp., Acanthocheilonema (Dipetalonema) spp., Brugia spp., and Loaina spp.) have a zoonotic origin and may infect human eyes [8, 62, 63]. In addition, a number of yet incompletely identified filarioids have been described in human eyes in the Amazon forest regions [64, 65]. For many of them, the life cycle and animal reservoir hosts are poorly known. Animal filarioids occur globally, in many different forms, and all filarioid infections are transmitted by various bloodsucking arthropods; the majority of them, including zoonotic infections, by mosquitoes, although blackflies, culicoids, and others may be involved. Most persons worldwide are at some risk, and those who are more likely to be exposed to the vectors may be at increased risk, but given the worldwide occurrence of animal filaria, there are probably other undefined risk factors.
Additional File 1: Surgical removal of Dirofilaria repens from patient's conjunctiva. This video shows the surgical removal of Dirofilaria repens from the patient's conjunctiva, after topical anaesthesia. The palpebral fissure was maintained open by using the blefarostat, the nematode was extracted after incision of the conjunctiva membranes and it was collected. A shortened version of a video in Otranto D, Brianti E, Gaglio G, Dantas-Torres F, Azzaro S, Giannetto S. Human ocular infestation by Dirofilaria repens (Ralliet and Henry, 1911) in a canine dirofilariosis-endemic area. Am Jour Trop Med Hyg 2011 (in press). (MP4 3 MB)
Additional File 2: Surgical removal of a Dirofilaria immitis -like nematode. This video shows the surgical removal of a Dirofilaria immitis -like female nematode from the anterior eye chamber of a patient from Parà, Brasil. Eye was clipped and the cornea incised with a crescent Beaver corneal knife. The nematode was extracted alive with forceps and Fukasacu hook. The patient recovered without complications after the surgery. A shortened version of a video in Otranto D, Diniz DG, Dantas-Torres F, Casiraghi M, de Almeida INF, de Almeida LNF, Nascimento dos Santos J, Penha Furtado A, de Almeida Sobrinho AF, Bain O Human intraocular filariasis caused by Dirofilaria sp., Brazil. Emerg Infect Dis 2011 (in press). (MP4 4 MB)
Additional File 3: Surgical removal of Pelecitus sp. from the iris fibers of a patient. This video shows the surgical removal of a Pelecitus sp. male nematode (approximately 4 mm in length) from the iris fibers of a patient from the Amazon region, Brasil. After peribulbar anesthesia and corneal incision of 2 mm. The nematode was extracted by aspiration and the surgery had no complication. A shortened version of a video in Bain O, Otranto D, Diniz DG, Nascimento dos Santos J, Pinto de Oliveira N, Negrão Frota de Almeida I, Negrão Frota de Almeida R, Negrão Frota de Almeida L, Dantas-Torres F, Frota de Almeida, Sobrinho E: Human intraocular filariasis caused by Pelecitus sp., Brazil. Emerg Infect Dis 2011 (in press). (MP4 3 MB)
Analogously, adult Spirometra cestodes live in the small intestine of carnivores where they release eggs which reach the environment with the host faeces. Larvae of Spirometra spp. tapeworms infect domestic animals and humans. Humans are dead-end hosts given that they become infected mostly by drinking polluted water (via ingesting the immature procercoid), or eating inected intermediate hosts (i.e., frogs, birds, snakes, that, along with rats and mice are infected with the larval stages) and assuming the plerocercoid larvae. Once ingested, the larvae ("spargana") may invade muscles, subcutaneous tissue, urogenital and abdominal viscera, and, sometimes, the central nervous system and the eyes . Human ocular sparganosis has been reported from South America , Central Europe  and Asia [102–105]. Spargana usually infect subconjunctival and conjunctival tissues causing symptoms varying from simple itching due to local granulomata to more serious signs represented by local pain, epiphora, chemosis, and ptosis [105, 106]. Conjunctival infection may also be characterized by irritation, continued foreign body sensation, redness  and mimic signs and symptoms of orbital cellulitis, with exophthalmia and corneal ulcers. When the immature cestode invades the orbit it may cause acute anterior uveitis and iridocyclitis  and severe inflammation with blindness . Unfortunately, surgery is the only effective treatment [104, 105].
Echinococcus granulosus, Echinococcus multilocularis and Echinococcus oligarthrus are tapeworms that occur worldwide. Adult stages of E. granulosus and E. multilocularis infect mainly dogs or wild canids (e.g., wolves, jackals, coyotes and foxes) while E. oligarthrus adults infect wild felines [108–111]. Along with several other animal species, human may act as (accidental) intermediate hosts of these cestodes by ingesting food contaminated by their eggs [110, 111]. When a human being inadvertently ingests eggs, the larvae hatch and disseminate via the bloodstream into different organs and viscera (mostly liver or lungs but also heart), where they produce a typical hydatid cyst (E. granulosus, E. oligarthrus) or many alveolar small cysts (E. multilocularis) causing a major zoonotic disease [108–111].
Although not very common, ocular infection by larval Echinococcus spp. may thus occur as a consequence of bloodborne dissemination of the oncospheres. Ocular localization by the larval form of E. granulosus accounts for 1 to 2% of all reports. Intra-orbital hydatid cysts by E. granulosus may cause severe exophthalmia  pain and blindness as the hydatids have the ability to fill the vitreous cavity  or severe inflammation of orbital structures and acute eyesight loss due to the rupture of intraorbital hydatids . Ocular alveolar hydatidosis caused by E. multilocularis may occur after spreading of the larval cestodes to other sites. For instance a choroidal eye mass has been reported in a patient with history of visceral alveolar hydatid disease with cerebral metastasis . Human infection by E. oligarthrus is very rare with only a few cases published in the international literature, two of which involve the eye . Nonetheless, the ocular localization of E. oligarthrus has a relevant clinical impact since it causes the presence of a single orbital, retro-ocular cyst in the orbit  or the occurrence of a retroocular cystic tumor-like mass inducing exophthalmia, chemosis, palpebral ptosis, and blindness .
Fascioliasis, also known as liver fluke, is caused by Fasciola hepatica and Fasciola gigantica, trematodes which localize in the biliary ducts of the definitive hosts, grass-grazing domestic and wild ruminants (i.e., cattle, sheep, goats, buffaloes) and also horses and rabbits. This parasite develops through various larval stages in water snails of the genus Limnaea which release cercariae that encyst as metacercariae on aquatic vegetation. Infection occurs when animals ingest freshwater plants or water containing encysted metacercariae . Within the last decade, reports of human cases of fascioliasis have increased . Although migrating immature F. hepatica flukes in humans have been mainly reported in blood vessels, lung, subcutaneous tissue, and ventricles of the brain , they have also been recovered from the anterior chamber of a patient in Iran .
The trematode Philophthalmus lacrimosus (Philophthalmidae), as adults, parasitize the eyes of birds (definitive host). Eggs containing miracidia hatch in the water, miracidia penetrate snails (intermediate hosts) and develop into redia and cercariae. When the metacercariae encyst on surfaces of food for birds the infection of a new definitive host can take place by entering the eye or by oral intake . Human cases of philophthalmosis have been reported in Europe (Yugoslavia), Israel, Asia (Thailand, Sri Lanka, Japan) and America (i.e., Mexico, and the United States) .
Over the last decade, parasitological knowledge has been considerably refined and enhanced by the use of sophisticated technologies and molecular tools, and by the interdisciplinary approach in many fields of the human and veterinary medical sciences. Increasing awareness of physicians on previously poorly known diseases likely is an important part of this process. Reports of several of these infections of the eye have been increasing, but whether this is due to a higher awareness or increasing rates of infection is unclear. Possible reasons for the highest number of reports may include changing epidemiological patterns in the natural definitive hosts, leading to increased exposure of humans, and new geographic range because of spreading into new areas. Three key examples, namely infections by Angiostrongylus cantonensis, Thelazia callipaeda and Onchocerca spp., are discussed below.
Metastrongylids encompass a large group of nematodes (Strongylida, Metastrongyloidae) infecting organs and tissues of different vertebrates . A. cantonensis, also known as rat lungworm, is a well recognized zoonotic infection and, as such, is the primary cause of eosinophilic meningitis in Southeast Asia. The infection has spread widely to many other areas of the world, including the Caribbean and Americas [126–130]. The parasite also enters the eye with some frequency. In a review of 484 cases of eosinophilic meningitis, Punyagupta and colleagues  noted that 47 (16%) of the cases had reported ocular involvement, and in 7 cases an actively motile worm (most probably A. cantonensis) was visualized and removed from the anterior chamber of vitreous of the eye [132, 133]. Human ocular infections by larval rat lungworm have been reported in several countries in Southeast Asia [134–143] and, they likely will continue to be reported wherever the parasite occurs, including in new geographical areas such as the Caribbean . Ocular lesions by A. cantonensis may either occur alone or may accompany other symptoms such as meningitis [142, 145]. Often these long and slender worms reach considerable size in the eye, and are up to a centimeter or more in length . The female worm has a distinctive helical pattern of dark intestine intertwined with light coloured reproductive tubes; male worms have a copulatory bursa and very long (> 1 mm) spicules. These features make it fairly simple to recognize and identify a large worm removed from the eye as A. cantonensis.
Additional File 4: Thelazia callipaeda infecting the eye of a dog in Basilicata region (southern Italy). This video shows Thelazia callipaeda nematodes floating in the eye of an infected dog in an endemic area of Italy. Conjunctivitis and lacrymation were the main symptoms observed. In the second part, numerous T. callipaeda specimens have been collected by an ocular swab. (MP4 1 MB)
Additional File 5: Onchocerca sp. infecting the anterior eye chamber of a human patient. This video shows the occurrence of Onchocerca sp. in the anterior chamber of a patient from Colorado, United States. The nematode was surgically removed, extracted alive and identified as Onchocerca. The patient recovered without complications after the surgery. A video from the case presented in Burr WE, Brown MF, Eberhard ML: Zoonotic Onchocerca (Nematoda: Filarioidea) in the cornea of a Colorado resident. Ophthalmology 105:1494-1497, 1998. Video courtesy of Dr. W.E. Burr. (MP4 483 KB)
≤ 400 μm × 15-21 μm
Smallest of the nematode larvae encountered in the eye
1-2 mm × 50-60 μm
Relatively small but easily recognized as being larger than Toxocara larvae
1-5 mm × 200-600 μm
Much more robust than other nematode larva; presence of cuticular spines and head bulb distinctive
≤1-2 cm × 200-300 μm
One of the larger, more robust worms found in intraocular location
5-20 mm × 250-800 μm
Distinct morphologic features; free in orbit
2-3 mm × 600-800 μm
Ovoid to oblong, flat, solid body
Intraocular or eyelid
5-20 mm × 1-2 mm
Long, flat solid body with pseudosegmentation
< 1 cm
Fluid filled cyst ovoid in shape and of variable size
Dirofilaria tenuis/Dirofilaria repens
2-15 cm × 150-400 μm
Males smaller than females; most often closely associated with conjunctiva; worms in the eye are appreciably smaller than those on conjunctiva
1-1.65 cm × 160-400 μm
Not a common location for this worm and very few confirmed cases exist
10 cm × 300 μm
3-5 cm × 80-100 μm
total length unknown but several cm or more × 150-250 μm
1.6 - 2.1 cm × <100 μm
Accurate identification to species has been
3.2 cm × <150 μm
On the other hand, when HIE are enclosed in a granuloma or within the subconjunctiva, the identification is more difficult. Furthermore, in certain situations, removal may increase the risk to the patient, as in the case of the cystic forms of Echinococcus spp. which could induce anaphylactic immunoreactions when disturbed. Indeed, although rare, the localization of Echinococcus spp. cysts in the eye are always cause of severe disease, thus the careful surgical removal of the cysts is the only option.
Where appropriate tests exist, serological diagnosis can often contribute to a definitive diagnosis of infection, such as in the case of some ascarids for which serological testing using a sensitive, specific enzyme immunoassay (EIA or ELISA) is available. Serological testing is available for baylisascariasis and can be very helpful in identifying and confirming infection, and, like for toxocariasis, in conducting serosurveys to document the degree of exposure in different populations. Unfortunately, individuals may not mount a measurable immune response during the early phases of acute infection and serologic testing will not provide conclusive evidence to help guide treatment, hence the need for aggressive presumptive treatment in cases with solid exposure history . Serologic assays can be very helpful to confirm infections caused by Gnathostoma, especially in cases where no larva or tissue is available to examine. Conversely, seropositivity to spargana in IFAT or ELISA tests always needs to be confirmed by histological examination [104, 105].
Unfortunately, surgery is often the only effective treatment for many HIE (e.g., ocular sparganosis, A. cantonensis) and this is one of the reasons why these infections represent a traumatic event for the patients and treatment is not a particularly cost-effective manner in which to manage the infection. In some cases, such as the typical zoonotic filarial infection, only a single worm is present and the surgical removal is both therapeutic and curative. In other instances, most notably OLM or larval tapeworms, there is some likelihood that additional larval stages may exist and chemotherapy may be indicated with corticosteroids in the case of inflammatory conditions such as retinitis or optic neuritis .
It should be noted that the use of photocoaggulation and laser ablation continue to prove useful in a number of cases infection with HIE, e.g., ascarid larvae, Alaria mesocercaria, and often result in improved visual outcome while at the same time destroying the invading helminth in situ.
Ophthalmologists and physicians often lack an in- depth knowledge of parasites, rendering it difficult for them to correctly address the etiological identification, treatments and control strategies for many HIE. In addition, the scientific information on HIE available in the international literature is scarce and limited to single case reports in which a clear comparative differentiation among helminth infections is not considered. The main limitation for correctly identifying the etiological agent is that often helminths are not removed, or they are seriously damaged during the surgical procedures thus rendering an accurate morphological identification difficult, if not impossible. The microscopic identification of helminths at the species level often relies on the examination of key morphological characters, not all of which are present on any given specimen or not recognized by the person making the examination, sometimes resulting in an incorrect diagnosis. Accurate identification is crucial to understanding both the source of infection and environmental risks, as well as prescribing correct treatment options.
There are several cases in the literature in which helminths were erroneously identified; for example, cases of Trichinella sp. in the vitreous of a woman and Toxocara sp. in the retina of a man both from Germany, and a case Angiostrongylus sp. recovered from the anterior chamber of a man from Sri Lanka were all incorrectly identified as filaria (reviewed in ). Twenty-eight cases of human dirofilariasis from the Old World were erroneously attributed to D. immitis, subsequently reviewed and correctly attributed to D. repens. Recently, the helminth causing a case of human intraocular infestation in Japan was erroneously identified as T. callipaeda although the picture published in the article portrayed a filarioid . In the same article, the authors stated that the life cycle of T. callipaeda remains unclear and discussed the possibility of human infection through the skin or by drinking untreated water. This somewhat implausible hypothesis was already dispelled in the late 1990s . The scant attention of medical researchers towards human thelaziasis may also be attributable to the difficulties in its clinical diagnosis and differentiation from allergic conjunctivitis, particularly when small numbers of adult or larval stages are present in affected patients. More recently, the advent of molecular biological techniques has largely supplemented and enhanced knowledge of parasitologists in areas such as systematics (taxonomy and phylogeny), population genetics and molecular identification, diagnosis and control of some HIE . Indeed, the advent of PCR made it possible to study damaged and incomplete specimens, or fragments of specimens encysted in tissues which otherwise would not be morphologically identifiable . The importance of molecular identification and barcoding approach (by the specific PCR-amplification of the cox 1 and 12S genes) for the rapid identification of specimens has been emphasized, including for either recognized or yet unknown species. Recently, an integrated DNA barcoding of cox 1 and 12S markers and morphology approaches was shown to be a powerful tool for the taxonomical identification of many filarioid species even if small nematode fragments were available . In addition, the delineation of Molecular Operational Taxonomical Units (MOUTS) was useful to infer potential new species .
Basic parasitological research in this field is often fragmentary due to the fact that experimental human infections are rarely done, and the retrieval of helminths from the patients' eyes may be an infrequent occurrence during the ophthalmologic examination. For a number of these helminths, poor experimental models exist, or, if good models exist, the infections generally do not affect the eye in the same way that occurs in aberrant human infections. Thus, scientific knowledge in this field, as well the information on helminth migration patterns is limited, and often has been gained from studies of the same parasites in other animal models. All the above concerns need to be addressed through basic and applied research. For example, many nematode species have not yet been described and even those that are known are often poorly studied such that there is a lack of basic information on the helminth fauna of wild animals (e.g., O. lupi). This is particularly true, but not restricted to, regions of the world, such as the Brazilian Amazon forest, where there is wide biodiversity and a large amount of animal and plant species yet to be described . Consequently, species identification of some groups of HIE, such as filarial nematodes, can be difficult if not impossible. Another example of insufficient information is represented by the unknown risk of zoonotic infection, such as other species of Baylisascaris (in addition to B. procyonis), that may be considered as potential zoonotic agents . For example Baylisascaris transfuga, infecting bears worldwide [45, 187] has been reported to produce visceral, neural, or OLM syndromes in mice [188–190], gerbils [45, 191], and guinea pigs . In addition, cases of fatal neurological diseases have been reported in a colony of Japanese macaques (Macaca fuscata fuscata) housed with American black bears in a safari-zoo in Japan . However, the zoonotic role of this parasite for humans has never been demonstrated. Since bears are frequently kept in zoos and game parks and often have high prevalence of the infection in the population (up to 50-100% of bears harbour this parasite) studies on the zoonotic capacity of this parasitic species would be pivotal for a better understanding of the public health risk . Overall, a better understanding of the biology of a number of HIE is crucial for addressing their prevention.
Better awareness among physicians (including ophthalmologists) in the field of parasitology and more active collaboration with parasitologists would be very helpful in proper diagnosis, control and prevention of HIE. This would also allow a better knowledge of the potential risks for being infected by an HIE agent in a given area as well as exposure when travelling in endemic areas. Physicians and ophthalmologists need increased awareness about the existence of a range of zoonotic helminths other than those natural parasites of humans that might be expected to be found in patients' eyes.
Unfortunately, there is a lack of knowledge about many parasites in the local fauna and limited basic research studies are carried out. Monitoring and periodic surveillance for the infections of both domestic and wild animals is important to provide a better understanding of what potential pathogens exist locally, and to prevent the HIE. This is the case with B. procyonis which is an emerging infection in raccoons in the southeastern United States, an area traditionally considered to be at low risk [195, 196]. An increasing appreciation of onchocerciasis in domestic and wild animals in Europe and the United States is needed to accurately understand what species exist, what the natural definitive host is and, ultimately, what the risks for human infection are. Veterinarians, physicians, and public health officials all share the need to be alert to the possibility of zoonotic infections inside and outside of traditional high-risk areas. Lastly, we need a better understanding of why some parasites migrate to and occasionally enter the eye, especially given that none of these helminths typically resides in or around the eye.
Despite scientific advances and new methods for treating helminth infections in the human eye, therapies available to patients are somewhat limited and can only be applied in specific cases. This will lead to improvements in the clinical outcome in some cases, but for the foreseeable future, a number of these HIE have complex clinical presentations that still hold potential for serious outcome, including blindness or death, such as in the case of B. procyonis infections, where, despite treatment, neurological outcome is dismal in the overwhelming majority of documented cases . However, many cases of these zoonotic helminth infections are preventable by relatively simple measures of improved health and sanitation conditions and awareness on the part of both public and health care providers. Risks for toxocariasis and baylisascariasis could be significantly reduced through better hygiene and reduction of the amount of animal waste in areas where people, especially children, might come in contact with it. For the foodborne zoonoses, such as angiostrongyliasis, gnathostomiasis and others, proper handling and preparation of foods would minimize the risk of infection. For the vector-borne zoonotic infections, control and prevention is likely going to be much harder, as it involves not only the control of the infection in the definitive animal host, but a concerted control of vectors, which is often outside the control of any individual but almost always done at the community or regional level.
The authors are grateful to Alessio Giannelli (University of Bari, Italy) and Donato Traversa (University of Teramo, Italy), for their support during the preparation of the manuscript. We are grateful to Emanuele Brianti (University of Messina, Italy) and Riccardo Paolo Lia (University of Bari, Italy) for their assistance with the video editing and figure preparation. The authors thank Susan Montgomery, CDC, and of two anonymous reviewers for their helpful suggestions. DO and MLE would like to thank their wives Irene Canfora and Sandra Eberhard for their continuous support and assistance during the preparation of this article.
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