Download Ocular Parasitic Diseases: A Review on Toxocariasis and Diffuse

Review Article
Ocular Parasitic Diseases: A Review on Toxocariasis
and Diffuse Unilateral Subacute Neuroretinitis
Rafael T. Cortez, MD; Gema Ramirez, MD; Lucienne Collet, MD; Gian Paolo Giuliari, MD
ABSTRACT
Parasitic infections may damage various ocular tissues,
thereby causing visual dysfunction. In 1950, Wilder described the first case in which larval forms of nematodal
intestinal roundworms (Ascaridoidea: Ascaris, Toxocara,
Ancylostoma, Necator, and Strongyloides) were implicated as a cause of intraocular disease. This review focuses on two disorders associated with parasitic infections: ocular toxocariasis and diffuse unilateral subacute
neuroretinitis. [J Pediatr Ophthalmol Strabismus
20XX;XX:XX-XX.]
INTRODUCTION
Parasitic infections may produce severe damage to various ocular tissues, thereby causing visual
dysfunction. In this review, we will focus on two of
these infections, ocular toxocariasis and diffuse unilateral subacute neuroretinitis (DUSN). Although
these diseases are not widely distributed worldwide,
we believe it is of great value to the general ophthalmologist to be familiar with their different presentations, due to the poor visual prognosis they carry.
OCULAR TOXOCARIASIS
Human infection by Toxocara, a common
roundworm that infects dogs and cats, may take one
of two forms: visceral larva migrans and ocular toxocariasis.1-5 The characteristics of the infection will
depend on the number of parasites, site of infection,
migratory behavior, and the host immunological response.6,7
Visceral larva migrans is characterized by generalized systemic involvement due to the migration
capabilities of the second stage larvae of Toxocara
canis. It typically presents in children from the ages
of 6 months to 5 years. The disease is usually selflimited and subclinical; however, fever, pulmonary
manifestations, hepatomegaly, eosinophilia, pallor,
irritability, anorexia, and malaise can occur.6,7
On the other hand, ocular toxocariasis appears
in older patients, with an average age of 7.5 to 8.6
years.7-9 Several studies have revealed Toxocara and
other visceral larvae migrans to be the cause of intraocular inflammation in 9.4% of pediatric uveitis.10,11
Rarely does a patient present with both visceral larva
migrans and ocular toxoplasmosis at the same time
or even at separate intervals.3,6,12
Epidemiology and Life Cycle of T. canis
The adult dog usually acquires the T. canis parasite
by ingesting the parasite’s eggs or second stage larvae
found in contaminated soil, infected meat, and feces.
The larvae form cysts and reactivation of the larvae
during gestation can infect the fetal puppies in the
uterus. Following birth, the larvae migrate to the puppies’ lungs and then travel up the respiratory tract to
the pharynx, where they are swallowed. They then mature to become egg-laying adult worms in the gastrointestinal tract. Approximately 4 weeks after their birth,
From Centro de Cirugía Oftalmológica (RTC, GR, LC), Caracas, Venezuela; and Princess Margaret Hospital (GPG), University of Toronto, Toronto,
Ontario, Canada.
Originally submitted January 4, 2010. Accepted for publication May 3, 2010.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Gian Paolo Giuliari, MD, 77 Elm Street, Apt. 903, Toronto, Ontario M5G H14, Canada. E-mail: [email protected]
doi: 10.3928/01913913-20100719-02
Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
Figure 1. Posterior pole Toxocara granuloma. Note a traction band
extending from the lesion to the optic disc and retinochoroidal
anastomosis.
worms begin laying eggs. Older dogs can harbor adult
worms that do not lay eggs.13 Toxocara eggs are found
in the soil throughout tropical and temperate climate
regions. In the United States and Western Europe, soil
from parks and public areas has been found to carry a
contamination rate of 10% to 30%.14 In Venezuela, a
33% contamination rate was found in a metropolitan
area.
Humans are primarily infected through the ingestion of soil and food contaminated with Toxocara
larvae. After the eggs are ingested, they develop into
second stage larvae in the small intestine. They then
enter the portal circulation, following hematogenous and lymphatic routes to form cysts in tissue
structures.15 The parasites reach the eye through the
retinal, ciliary, and choroidal circulation. Humans
are not natural hosts of Toxocara, and the parasite
cannot mature into an adult worm in the intestine.13
Clinical Presentation
Ocular toxocariasis is typically unilateral. Patients present with unilateral decrease in visual acuity, strabismus, or leukocoria.14,16 Cases with bilateral
involvement are extremely rare.17 Younger children
generally do not report visual changes, even if visual
acuity is profoundly decreased, and it is common
that parents may seek medical attention only when
the signs become striking. As such, diminished visual acuity is frequently detected in routine examination.14,16 Impairment of visual acuity and leukocoria
are the most common presenting manifestations.
Figure 2. Fundus photograph montage showing Toxocara’s peripheral granuloma with retinal fold extending from the optic
nerve to the retinal periphery.
Several ocular presentations have been recognized,
the most common of which is granulomatous inflammation in the posterior pole or periphery.14,18-20 Some
patients may present with a more marked chronic inflammation in the retina and the vitreous known as
nematode endophthalmitis.5,14
Posterior Pole Granuloma. In the acute stage,
retinochoroiditis appears clinically as a hazy, ill-defined white lesion with overlaying inflammatory cells
in the vitreous. As the acute inflammatory reaction
subsides, the lesion appears as a well-defined elevated
mass ranging from one-half to four disc diameters in
size.14,21 In some cases, traction bands may extend
from the lesion to the optic disc or to the macular
area. In the case of chronic granulomatous inflammation, large retinal vessels may infiltrate the mass
and disappear into its substance, probably representing retinochoroidal anastomosis (Fig. 1).
Peripheral Granuloma. Ocular toxocariasis
can occur as an acute inflammatory process in the
peripheral retina and ciliary body. This may either
be preceded by mild acute inflammation in the anterior or posterior segment or the eye may be quiet.
The peripheral granuloma appears as a hazy, white,
elevated mass in the peripheral fundus. It can be associated with retinal folds that may extend from the
peripheral mass to the optic nerve head or to other
areas of the fundus. In some cases, the traction may
lead to heterotopia of the macula, resulting in severe vision loss. It is likely that many cases of “congenital” retinal folds are acquired peripheral retinal
granulomas due to T. canis (Fig. 2).
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Figure 3. Anterior segment photograph showing leukocoria in a
patient with a cicatricial peripheral inflammatory mass and a cyclitic membrane in a child with ocular toxocariasis.
Chronic Endophthalmitis. Another common
manifestation of ocular toxocariasis is chronic endophthalmitis (Fig. 3). This is usually associated
with cyclitic membrane, retinal detachment, low
grade anterior uveitis, and posterior synechiae. The
cyclitic membrane begins to form in the peripheral
quadrant of the fundus where the most severe inflammation lies and progresses across the posterior
surface of the lens. Severe vitritis may also manifest
as leukokoria (Fig. 4).1-5 A yellow–white mass, usually in the peripheral retina, which may resemble an
endophytic retinoblastoma, can be seen through a
hazy vitreous. Toxocara endophthalmitis does not
produce much pain or photophobia and external
ocular examination reveals only minimal signs of inflammation, usually with no ciliary flush. Hypopyon may develop in severe cases.16 A cicatricial stage
is characterized by tractional bands that may pull
on the retina and ciliary body. Patients with endophthalmitis are usually younger than patients with
posterior pole granuloma.
Atypical Presentation. Optic nerve granuloma,
papillitis, inflammatory iridial mass, intracorneal
larvae, motile larvae in the vitreous and retina, and
scleritis may occur.2,19,22,23 We evaluated two cases
that presented with vitreous hemorrhage; after the
hemorrhage cleared up, the typical fundus changes
of a posterior pole granuloma were detected.
Differential Diagnosis
Toxocara endophthalmitis may closely resemble
an endophytic retinoblastoma. Shields et al. found
Figure 4. Chronic Toxocara endophthalmitis with partial retinal
detachment.
that 42% of patients with presumed retinoblastoma
had pseudoretinoblastoma, and 16% of these had
ocular toxocariasis.24,25 The clinical features that
may help differentiate both entities are: (1) the
mean age at presentation for retinoblastoma is 22
to 23 months, whereas for ocular toxocariasis it is
7.5 to 8.9 years10; (2) retinoblastoma shows tumor
growth; (3) there is a family history; and (4) there is
lack of inflammation in retinoblastoma.14
Vitreoretinal traction, signs of inflammation,
and posterior subcapsular cataracts may be seen in
ocular toxocariasis. However, these signs are uncommon in patients with retinoblastoma. Computed
tomography and B-scan ultrasonography may show
the typical tumor pattern in patients with retinoblastoma, with evidence of calcification within the
mass.26 On the other hand, endophthalmitis secondary to toxocariasis does not commonly demonstrate a tumor pattern.14
Additionally, ocular toxocariasis may present
with eosinophils in the vitreous or aqueous humor
without evidence of malignant cells on histopathologic examination. This may be observed in the
presence of normal levels of lactate dehydrogenase
and phosphoglucose isomerase. Other entities to be
excluded are toxoplasmic retinochoroiditis, pars planitis, retinopathy of prematurity, familial exudative
vitreoretinopathy, persistent fetal vasculature, Coats’
disease, and organized vitreous hemorrhage.14
Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
Diagnosis
The current gold standard to test for systemic or
ocular infection with T. canis is the enzyme-linked
immunosorbent assay (ELISA), which carries both
a sensitivity and specificity rate of approximately
90%.14 Although the Centers for Disease Control
and Prevention considers serum ELISA titers of less
than 1:32 to be insignificant for the diagnosis of
systemic toxocariasis, other institutions have stated
that a serum titer of 1:8, or even lower, is sufficient
to support the diagnosis if the patient has signs and
symptoms compatible with the disease.14,18,27 However, a positive serum titer cannot be used to definitively confirm the diagnosis of ocular toxocariasis,
although the absence of serologic evidence of Toxocara presence could reduce the odds of this organism being the cause of ocular disease.14,18 Authors
have found that 31.8% of affected children without
signs of ocular toxocariasis exhibited a serum titer
of 1:16 or greater.14,18 ELISA testing of intraocular
fluids has been demonstrated to be of great value in
diagnosing ocular toxocariasis.10,14,18,19,28
Treatment
The treatment of ocular toxocariasis depends primarily on the extent of inflammation at presentation
and the secondary structural changes in the vitreous
and retina that are associated with the disease.14 In
most cases of severe nematode endophthalmitis, numerous complications ensue that frequently result in
total blindness in the involved eye. Therefore, prompt
treatment is justified in such cases.14
Medical Treatment. With ocular toxocariasis,
the objective of treatment is to reduce inflammation to prevent the formation of membranes that
can consequently affect intraocular structures.
Periocular and systemic steroids (0.5 to 1 mg/kg
prednisone daily) are the mainstays of therapy for
eyes with active vitritis. Cycloplegic agents should
be employed when signs of anterior segment involvement are present.14 There have been reports of
clinical improvements of ocular toxocariasis treated
with antihelmintic agents thiabendazole (25 mg/kg
twice daily for 5 days with a maximum of 3 g per
day), albendazole (800 mg twice daily for 6 days),
or mebendazole (100 to 200 mg twice daily for 5
days).14,29 Although it has been proposed that antihelmintic treatment may initiate an intraocular
inflammation due to a hypersensitivity response to
dead larvae, clinical and experimental evidence in
dicate that this is not the case.20,30-32 The ultimate
utility of antihelmintic therapy remains equivocal.
Surgical Treatment. Surgery is reserved for
post-inflammatory complications such as persistent vitreous opacification, retinal detachment, and
epiretinal membrane formation with vitreomacular
or optic nerve traction (Fig. 5).The most common
indication for surgical intervention in ocular toxocariasis is retinal detachment.27,30,31,33 Retinal reattachment has been performed in 71% to 88% of
ocular toxocariasis cases, with visual improvement
in most patients.27,30,31,33
DIFFUSE UNILATERAL SUBACUTE
NEURORETINITIS
DUSN was first described by Gass et al.34 and
Gass and Scelfo35 in 1978. They described 29 patients
between the ages of 5 and 22 years with severe visual
loss in one eye, vitritis, mild papillitis, and recurrent
crops of evanescent, gray–white lesions affecting the
outer retina and pigment epithelium. These lesions
are usually followed by progressive loss of visual field,
optic atrophy, narrowing of the major retinal vessels,
diffuse and focal depigmentation of retinal pigment
epithelium throughout the fundus, and a moderate to
marked reduction of the b-wave amplitude on multifocal electroretinogram. Previously, this condition
was termed “unilateral wipe-out syndrome.”34,35
DUSN is most prevalent in the southeastern
United States and the Caribbean, although some
cases have been reported in many sections of the
United States, Canada, the northern part of South
America, Europe, and China.36-41
In the United States, DUSN is probably caused
by at least two different nematodes. The smaller
one, Ancylostoma caninum, measures between 400
and 1,000 µm in length and has a diameter of approximately one-twentieth of its length.36-39 It is
mainly found in the southeastern United States, the
Caribbean, and the northern part of South America.36-39 A larger nematode, Baylisascaris procyonis,
1,500 to 2,000 µm long, is responsible for DUSN in
the northern-midwestern United States and in some
parts of Brazil.34,38,42,43
Clinical Manifestations
Ocular findings in DUSN have been well described by Gass et al.34-39 Most patients are young
and healthy, with ages ranging from 11 to 65 years
(the mean age being 24 years) at the time of the iniCopyright © SLACK Incorporated
Figure 5. (A) Toxocara peripheral granuloma with traction fibrotic band extending to the optic nerve. (B) Fundus photograph of the same
patient 6 weeks after pars plana vitrectomy.
Figure 6. Early stage of diffuse unilateral subacute neuroretinitis.
Note the vitritis, optic disc swelling, and crops of multifocal gray–
white lesions.
tial presentation.39 For the most part, it is a unilateral condition; although uncommon, bilateral cases
have been described.37,39,40
Many patients, particularly children, may be
asymptomatic and visual loss is usually discovered
on routine eye examination. Other patients may
present with acute onset of multiple, and rapidly
changing, central or paracentral scotomata, photopsias, or unilateral vision loss.34,35,44-46 In the
early stages, inflammation in the anterior segment
is uncommon, although keratic precipitates and
hypopyon were observed and reported in one patient.34,35 Visual acuity may be reduced moderately
if the condition is detected early, but it is usually
markedly decreased at the time of presentation.
The fundus changes, which are the most prominent feature of this syndrome, have been divided
into early and late.34,35
The onset of DUSN is subtle and progressive.34,35 Patients in the early stages of the disease
may present with low vision in the affected eye, mild
to moderate vitritis, optic disc swelling, and recurrent crops of evanescent, multifocal, gray–white lesions at the level of the outer retina (Fig. 6). The
lesions are typically clustered in one segment of the
fundus, and successive crops of these lesions may recur in close proximity to previously affected areas.
The nematode, which often assumes an S-shape
or coiled position, should be sought out in the vicinity of the active lesions. In the absence of these white
lesions, no other markers exist for the location of the
worm. Nematodes propel themselves by a series of
slow coiling and uncoiling movements, or by slithering, snake-like movements. The examining light
seems to stimulate movement in the nematode and
causes it to move deeper into the subretinal space
Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
was 20/400 or worse in 69 patients (84.1%). Additionally, a subretinal nematode was identified in
33 eyes (40.2%). All of the nematodes were small,
measuring approximately 400 µm in length.
Diagnosis
Figure 7. Late stage of diffuse unilateral subacute neuroretinitis.
Diffuse and focal changes of the retinal pigment epithelium. Narrowing of the retinal arterioles and mild pallor of the optic nerve.
Note the intraretinal parasite superior to the fovea.
where the clinician may lose the opportunity to
identify it. In such cases, the light stimulus should
be discontinued for the organism to reemerge from
the deeper structures.34-36,43,47
Occasionally, perivenous retinal exudation and
sheathing may be observed. In addition, cystoid
macular edema, intraretinal and subretinal hemorrhages, retinal exudation, and neovascularization
may present during the early stages of the disease.34
Over a period of weeks to months, late manifestations begin to appear.36 Diffuse and focal depigmentation of the retinal pigment epithelium is seen. This
is usually less prominent in the central area. Gradual
narrowing of the retinal vessels and an increase in
pallor of the optic disc will frequently result in an
afferent pupillary defect (Fig. 7). In general, the degree of optic disc pallor and retinal vessel narrowing parallel that of central visual loss, but striking
exceptions do occur.34,35 Fluorescein angiography
will reveal hypofluorescent lesions that turn hyperfluorescent in the late stages of the test. Dye leakage occurs at the optic nerve level; active lesions and
petaloid hyperfluorescence are observed in cases of
cystoid macular edema. In more advanced stages of
the disease, fluorescein angiography may reveal multiple hyperfluorescent lesions due to window defects
secondary to retinal pigment epithelium alterations
together with a delay in retinal circulation time.35
The clinical evaluation of 78 patients in Venezuela39 showed the typical funduscopic late changes described by Gass et al.36 The mean age of these
patients was 16.7 years; the presenting visual acuity
As mentioned, patients with DUSN suffer progressive vision loss and seek medical attention in the
late stages of the disease. Consequently, the clinician
should focus on the early recognition of this syndrome because treatment may prevent further deterioration of visual function and may even result in
visual improvement.34,35 In patients with suspected
DUSN, we first suggest an evaluation using indirect
ophthalmoscopy with a 20-diopter lens (or in some
cases a 14-diopter lens) to locate the crops of evanescent white lesions and to attempt to locate the nematode around these areas. Subsequent biomicroscopy
in that area with a 78-diopter lens allows the examiner to definitely identify the nematode.34,36 In the
absence of white lesions, a careful biomicroscopic
search of the entire fundus is necessary to find the
worm, and multiple patient visits may be required.
It is also possible to identify the parasite by careful
examination of fundus photographs that include the
suspicious areas.
Fluorescein angiography is not helpful in locating the nematode.36 Scanning laser ophthalmoscopy
using a blue light can help locate the worm due to
the provided advantage of enhancing contrast, improving visualization, and recording a videography
of the worms’ movements.48
Multifocal electroretinogram is subnormal in
the affected eye during all stages of the disease, with
b-wave being more affected than a-wave.36 Serologic
studies, stool examination, and peripheral blood
smears are of little value in diagnosing DUSN.10,37
Toxocara and B. procyonis antibody titers have been
proposed as diagnostic tools to try to identify the
disease.49 No serologic test is currently available for
Ancylostoma caninum. Because of the possibility of
commonly shared antigens by different nematodes
or seropositivity unrelated to the actual infecting
nematode, interpretation of serologic testing may be
subject to error.48
Etiology and Pathogenesis
There is no consensus regarding the identification of the subretinal nematode frequently found in
DUSN. Reports suggest B. procyonis, A. caninum,
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Figure 8. (A) Late stage of diffuse unilateral subacute neuroretinitis. Note the parasite around the retinal vessel (arrow). (B) Fundus photograph of the same patient after retinal photocoagulation of the parasite.
Dirofilaria, and a larval form of T. canis as possible
infectious agents involved in DUSN.50 However,
the larval form of T. canis is smaller than the worm
that causes DUSN and there is a lack of serologic
evidence to support the mentioned reports. In addition, funduscopic manifestations are different than
those associated with other forms of ocular toxocariasis and the high prevalence of T. canis does not
correlate with the scant number of DUSN cases reported.36
A. caninum, which is a common nematode parasite that infects dogs, is suspected of causing DUSN
because it frequently results in cutaneous larval migrans that may later manifest signs of DUSN. The
worm can survive for months and even years without changing form and its infective larva measures
approximately 650 µm. This better corresponds to
the entity described in DUSN.34,35 Scanning electron microscopy of a nematode excised from a case
of DUSN by means of an eye wall biopsy was compatible with, but not diagnostic for, A. caninum.
B. procyonis is an intestinal nematode that infects raccoons and skunks. The larva measures between 300 and 2,000 µm, and it has been proposed
as the larger nematode responsible for DUSN.49,50
Nevertheless, infrequent exposure to raccoons or
skunks and the absence of central nervous system
involvement make B. procyonis a highly unlikely
pathogen in DUSN.
The pathogenesis of DUSN appears to involve
a mechanical, inflammatory, and toxic assault on the
outer retina. A local toxic effect in the outer retina
is caused by products left in the worm’s wake, and a
more diffuse toxic reaction affecting both the inner
and outer retinal tissues ensues.36 Histopathologic
study of an eye believed to be affected by DUSN
revealed nongranulomatous vitritis and retinitis. It
also showed retinal and optic nerve perivasculitis,
extensive degeneration of the posterior retina, mild
optic atrophy, mild degenerative changes in the retinal pigment epithelium, and a low-grade, patchy,
non-granulomatous choroiditis.34,35
Differential Diagnosis
The condition most likely to be mistaken for
DUSN is multiple evanescent white-dot syndrome
(MEWDS), although in the early stages DUSN
may resemble toxoplasmosis, cytomegalovirus, and
bacterial abscesses. MEWDS can be distinguished
from DUSN by an accompanying history of flu-like
symptoms, photophobia, wreath-like hyperfluorescent dots on fluorescein angiography, blind spot
enlargement, multiple gray or whitish outer retinal
lesions, and decreased electroretinogram recordings.51,52 Visual acuity may even return to normal
levels in some cases after several weeks or months.
On fluorescein angiography, the white lesions in
DUSN block the fluorescence in the early phase,
whereas in MEWDS the lesions are hyperfluorescent in the early stages of the angiogram. Rarely, one
can mistake DUSN for sarcoidosis, presumed ocular
histoplasmosis syndrome, and multifocal choroiditis due to the appearance of focal chorioretinal scars
scattered throughout the fundus.53 The absence of
Journal of Pediatric Ophthalmology & Strabismus • Vol. xx, No. x, 20XX
optic atrophy, vitritis, vessel attenuation, and the
presence of normal-looking retinal pigment epithelium between punched out lesions is more likely to
be encountered in DUSN. Eyes with central retinal
artery occlusion may show some characteristics that
look like DUSN. Also, the late stages of DUSN may
be confused with retinitis pigmentosa, secondary
bone-spicules migration, and posterior subcapsular
opacification, but unilaterality is characteristically
a feature of DUSN.34,35 Trauma may exhibit some
DUSN characteristics such as retinal pigment epithelial changes and optic atrophy.34,35
Treatment
Photocoagulation of the parasite when visible,
using 200 to 500 µm, 0.2 to 0.5 second of thermal
laser application, is the treatment of choice36,43,47
(Fig. 8), although visual acuity does not significantly
improve unless the worm is killed soon after onset
of visual loss.54,55 Photocoagulation does not cause
exacerbation of inflammation and results in prompt
and permanent inactivation of the disease; however,
the search for the nematode can become a time-consuming and frustrating task.36,43,47
Several oral antihelmintic medications, such
as thiabendazole and dietylcarbavazine, have been
used in an effort to treat this disease.36,56,57 However,
most of the studies reported that only the subretinal
worms were killed, probably due to inadequate ocular penetration of the drugs. Hence, it has been suggested that if the worm cannot be found in a patient
with a high suspicion of DUSN, a scatter pattern of
laser burns in the vicinity of the multifocal active
lesions can be performed to alter the blood–retinal
barrier prior to administration of the oral medication.29,47
Recently, several studies have demonstrated albendazole as a safe and beneficial treatment modality for these patients.39,58 Our group published the
results of the use of oral albendazole in 6 patients
with DUSN, following a 10-day regimen at 200
mg orally 3 times daily.39 The nematode was killed
and was slowly reabsorbed in three cases. Adverse
effects of short-term albendazole treatment were
rare.
Findings such as bilateral DUSN and the presence of a nematode in a patient who had undergone
successful photocoagulation have been described.37
In light of such reports, we recommend a course of
systemic therapy for all patients with DUSN.39
CONCLUSION
Ocular toxocariasis and DUSN may produce severe damage to the intraocular structures, causing significant visual impairment. Although these diseases
are not well distributed worldwide due to their poor
visual prognosis, it is of great importance that physicians be aware of the variety of clinical forms in an
effort to achieve an early diagnosis and treatment.
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