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Intraocular Toxocara
INTRAOCULAR TOXOCARA CHARLES P. W I L K I N S O N , M . D , AND ROBERT B. W E L C H , M.D.
Baltimore, Maryland In 1952, Beaver and associates described a syndrome of childhood secondary to Toxocara canis invasion and proposed the term "visceral larva migrans." This condition follows the ingestion of Toxocara ova which hatch in the small intestine. The larvae migrate into the blood and lymph vessels, reach the liver and the lungs, and then enter the arterial circulation and are distributed to peripheral organs where they migrate until they are consumed or encapsulated by an eosinophilic granulomatous response. The life cycle is never completed in man and ends at this point. 1
In the natural canine host, larvae from the upper respiratory tract reach the small intestine directly, and the worms mature and produce ova which are passed in the feces to be ingested by other animals, most importantly the human child. Historically, intraocular nematode infestations first gained significant attention in 1950, when Wilder found larvae in histologic sections of over half of a selected series of pseudogliomata at the Armed Forces Institute of Pathology. These lesions were originally considered to be secondary to hookworms, but Nichols later identified several of the organisms as Toxocara larvae. Since then, many similar cases of severe nematode endophthalmitis have been reported, " and the importance of Toxocara in the differential diagnosis of leukocoria has become well recognized. ' In 1960, Ashton reported four cases of isolated posterior pole lesions secondary to Toxocara and thereby established a distinct second form of the disease, markedly different from the more se2
3
4
7
8 9
10
From the Wilmer Ophthalmological Institute of the Johns Hopkins Hospital and University, Baltimore, Maryland. Reprint requests to Robert B. Welch, M . D , 14 West Mount Vernon Place, Baltimore, Maryland 21201. 921
verely involved cases previously reported. Soon thereafter, Duguid ' presented a larger series of cases and reemphasized that intraocular Toxocara infestation could result in either a solitary retinal "granuloma" or chronic endophthalmitis. He stated that the granulomatous form of the disease had never been recognized in the peripheral fundus or nasal to the optic disk. Reports of well-localized peripheral inflammatory masses secondary to Toxocara have infrequently appeared in the literature. ' Some of these have not resulted in severe disruption of the entire eye and represent a third and intermediate form of the disease which is becoming increasingly well recognized. '" The purpose of this paper is to review our experiences with presumed and proven cases of intraocular Toxocara at the Wilmer Institute. 8 7
11 12
13
MATERIALS AND METHODS
This group of patients is composed of those whose fundus lesions were considered to be diagnostic of Toxocara infestation or whose histologic pictures were indicative of this entity. Most cases were obtained by reviewing clinical records of the Johns Hopkins Hospital and histologic specimens of the Wilmer Eye Pathology Department. Others were seen in consultation by one of us ( R B W ) , and a very few were examined by other ophthalmologists at the Wilmer Institute. The ophthalmic evaluation consisted of a thorough history, a recording of the visual acuity, and detailed external, slit-lamp and fundus examinations. Retinal drawings of focal lesions were performed, and photographs were taken when possible. Only pathologic specimens judged to be diagnostic of intraocular Toxocara were included, but the presence of larval remnants was not considered necessary for a positive histologic diagnosis.
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AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 1 CLASSIFICATION OF INTRAOCULAR TOXOCARA INFESTATION
1. Diffuse nematode endophthalmitis 2. Posterior pole "granuloma" 3. Peripheral inflammatory mass in a quiet eye Total
No. Eyes
Pathologic Diagnosis
13 10
10 0
18
1
41
11
APRIL, 1971
scesses; larval remnants were discovered within three of these. The 11th patient has been followed for two years, and the eye remains asymptomatic and unchanged with bare light perception. The significance of this form of nematode endophthalmitis lies in its similarity to other causes of leukocoria, particularly retinoblastoma. Important factors concerning this frequently difficult differential diagnosis have been well described in the past. 8
15
The 10 patients in the second group were similar to those first described by Ashton. Their ages ranged from six to 14 years, and the average age was slightly greater than in the first group. Past histories were not significant. Chief complaints were diminished vision or strabismus. The eyes were uninflamed, and pertinent findings were limited to the posterior pole. Eight of the 10 granulomata were considered classic and were associated with no apparent active inflammation (Fig. 1 ) . One patient's lesions progressed from a stage of minimal inflammation to a severe endophthalmitis with total retinal detachment and dense leukocoria. The 10th patient's quiet focal lesion had caused sufficient traction on the surrounding 10
RESULTS
Forty-one eyes of 40 patients were included in this series. These were divided into three groups (Table 1 ) : Group 1 consisted of patients with diffuse nematode endophthalmitis, Group 2 included those with focal posterior-pole granulomata, Group 3 was made up of those with peripheral inflammatory masses in a relatively quiet eye. The latter group will be discussed in greatest detail, for this form of the disease has not received sufficient attention in the literature. The 13 patients in the first group were typical of those with extensive unilateral intraocular inflammation as previously described in excellent articles on Toxocara endophthalmitis. ' The patients were in the usual age group of two to nine years. They invariably presented with complaints of visual loss and leukocoria, often accompanied by strabismus. Histories were never contributory. Examination of the affected eye typically revealed markedly diminished vision and leukocoria secondary to marked vitreous inflammation, a cyclitic membrane, or a huge retinal detachment. Occasionally, a poorly visualized inflammatory mass was seen in the vitreous cavity, and in one case, two such foci were described. The eyes were usually asymptomatic, but since the differential diagnosis always included retinoblastoma, most of them were enucleated. Ten of the 11 positive pathologic specimens were obtained from this group (Table 1 ) . Microscopic examination revealed typical eosinophilic ab7 15
Fig. 1 (Wilkinson and Welch). Two posterior pole granulomata. Note clear media and traction upon surrounding retina.
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retina to produce a large posterior retinal tear and detachment (Fig. 2 ) . All of these patients were seen after the publication of Ashton's 1960 article, and none of these eyes was enucleated. Only three of the classic cases have been closely followed, and these have not changed in any way. The differential diagnosis of these lesions includes dense macular scars, other types of focal inflammation of the posterior pole, and tumors. Eighteen of the 41 eyes presented with a peripheral inflammatory mass lesion unassociated with profound inflammation in the vitreous, and it is this third group that will be discussed in detail. Most of the patients fell into the age distribution of the second group, but three were over 20 years of age when first examined. A history strongly suggestive of visceral larva migrans was never obtained, and those who were evaluated did not have significant eosinophilia. Several of the patients had been exposed to puppies, as have most children, but a significant history of pica was obtained in only two. One of these children had a history of passing large amounts of hair of his pet collie in his own feces over a four-month period between the ages of five and nine months. All patients
Fig. 2 (Wilkinson and Welch). Fundus drawing of a retinal tear and detachment secondary to traction secondary to a posterior pole granuloma.
TABLE 2 V I S I O N I N E Y E S W I T H P E R I P H E R A L LESIONS
Vision 20/20-20/40 20/50-20/100 20/200-20/400 20/400-LP Unknown (illiterate)
No. Eyes 3 2 5 5 3
were full-term babies with normal birth weights, and no histories of significant oxygen exposure were obtained. None of the patients had sustained significant trauma about the involved eye. None of the group were physically or mentally retarded, and all were without systemic anomalies. Ocular examination revealed visual acuities that ranged from 20/20 to bare light perception, but vision was usually significantly reduced in the affected eye (Table 2 ) . Right and left eyes were involved with equal frequency, and the affected eye usually deviated from the orthotropic position. No eyes appeared significantly injected on external examination. Minimally active inflammatory signs were occasionally present in the anterior chamber, but these were never active enough to be graded as one-plus on a scale of one to four. One patient had a few small old posterior synechiae. Minimal lens changes were often present in the posterior subcapsular area, but significant lens opacities were present in only two instances. One of these patients, a 40-year-old woman, presented with a mature cataract, which was subsequently removed without problems. Tensions in this group were always within normal limits. Vitreous cells and strands were invariably noted, but the reaction was moderately severe in only four cases and never significant enough to prevent a thorough examination of the entire retina. In the periphery of the fundus, each of these eyes exhibited a dense white elevated inflammatory mass; these masses demonstrated various degrees of activity, were located at different depths in retinal or uveal structures, and were pro-
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dated with these vitreous bands and often extended from the mass to the disk. The focal lesions were usually several disk diameters in size and generally occurred with their centers near the ora ; in only three eyes were the masses located completely posterior to this boundary (Table 3 ) . In two eyes, definite multiple sites of involvement were ob-
Fig. 3 (Wilkinson and Welch). Typical appearance of a peripherally located, dense, white, inflammatory mass. Note the clear medial and normal surrounding retina
Fig. 5 (Wilkinson and Welch). Fundus drawing of a classic peripheral inflammatory mass associated with a large retinal fold and multiple vitreous bands attached to surrounding retina.
Fig. 4 (Wilkinson and Welch). Peripheral inflammatory mass with characteristic vitreous bands running to surrounding retina.
jecting toward the center of the vitreous cavity. The masses were always associated with dense connective-tissue strands in the vitreous cavity (Figs. 3, 4 ) . Many of these were directed posteriorly and were attached to either the disk or to surrounding retina in a "sucker foot" configuration (Figs. 5, 6 ) . Elevated folds of retina were frequently asso-
Fig. 6 (Wilkinson and Welch). Fundus drawing of a superiorly located inflammatory lesion.
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served (Figs. 7, 8 ) . A single patient presented with bilateral involvement (Fig. 9 ) ; interestingly, this child was the patient with the amazingly positive history of pica described earlier; he was a normal full-term infant of normal birth weight who required no oxygen therapy. Associated fundus lesions other than those described above were rare. The optic nerve heads, per se, were always normal, and remnants of hyaloid vessels were not encountered. The retinal vessels were without structural or inflammatory anomalies and appeared normal. Cystoid macular edema was TABLE
3
LOCATION OF INFLAMMATORY MASSES
Center of Inflammation: Completely posterior to ora More anterior Quadrants: Temporal Inferior Nasal Superior Multiple
Fig. 8 (Wilkinson and Welch). Fundus drawing of three distinct peripheral lesions ; a fourth site of involvement lies over the nerve head and appeared similar to one of the lesions in Figure 1.
3 15 4 6 3 3 2
Fig. 9 (Wilkinson and Welch). Fundus drawing of a child with bilateral involvement. The small lesion at three o'clock was much denser than the more peripheral inflammatory reaction and possibly represented the location of the parasite. The right eye was a mirror image of the left with the exception of this dense minute focus.
Fig. 7 (Wilkinson and Welch). Fundus drawing of two distinct inflammatory masses with a vitreous band running between them and attached to the disk.
present in only one eye, and there were no exudative retinal detachments. Occasional areas of mild scarring and pigment proliferation surrounding the masses were seen, but more classic forms of chorioretinal scarring
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Fig. 10 (Wilkinson and Welch). Fundus drawing from a patient with diplopia, 20/25 vision in the involved right eye, a pseudohypotropia of the right eye of approximately five diopters, a true hypertropia of the right eye of 20 diopters, and a heterotopia of the macula secondary to an interiorly located peripheral inflammatory lesion.
occurring in other types of uveitis were never encountered. Lipid deposits were never noted, and calcification was not clinically visible. Heterotopia of the macula (Figs. 10, 11) secondary to traction occurred in three eyes markedly similar to cases previously reported in the literature. ' In a single patient, traction resulted in peripheral retinal hole formation and a large retinal detachment.
APRIL, 1971
flammation. The first received a course of thiobendazole, and activity of the lesion very slowly and minimally diminished over the next 30 months, with a slight decrease in the size of the mass. The second improved minimally on a short course of systemic steroids, but this therapy was stopped because it did not prove successful. In summary, all eyes which were adequately followed changed very little, regardless of the activity of the lesions or the therapy used. Undoubtedly, these statistics are of little help in discussing the natural course of this disease or in assessing therapy, and we have not had the opportunity to follow a case of Toxocara endophthalmitis from its onset to the stage represented by these relatively quiet peripheral lesions. Of interest in the regard is a recent article describing a 13year-old patient who presented with only a few floating vitreous opacities and a peripheral subretinal nodule in an otherwise normal eye. Over the next six months, the child's vision deteriorated markedly, as the lower half of the retina became detached. However, over the following six months, this detachment slowly disappeared, leaving what was described as a "typical retinal 18
16 17
Only one of the eyes in this group was enucleated. The lesion was very typical clinically (Figs. 5, 12), and histologic sections revealed a characteristic eosinophilic granuloma containing remnants of Toxocara larva in the posterior ciliary body (Fig. 13). Of the 17 remaining eyes, nine were seen on only one occasion and there were insufficient referral or follow-up notes to allow an assessment of the course of the disease. Eight eyes have been followed from 18 months to five years. Six of these had insignificant intraocular inflammation when first seen, and activity did not increase; the two remaining patients had moderately severe in-
Fig. 11 (Wilkinson and Welch). Fundus photograph from the patient with an inferiorly displaced macula described in Figure 11.
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Fig. 12 (Wilkinson and Welch). Gross specimen of the eye drawn in Figure S demonstrating the large dense inflammatory mass and elevated retinal fold which runs posteriorly to the disk.
fold" connecting the nerve head with the peripheral nodule. The authors did not list possible etiologies, but the report is certainly compatible with the peripheral lesions we have been discussing. COMMENT
In most reported cases of proved Toxocara endophthalmitis the responsible larvae are located in the posterior eye, but in this series, anteriorly situated centers of inflammation were much more common. Of the 13 15
eyes with diffuse nematode endophthalmitis, 10 came to enucleation. In five of these, the primary inflammatory focus was in the retrolental area of the vitreous, and in four others it was in the anterior retina or ciliary body. In only one did the larva appear to emerge from the posterior retina. The positions of the presumed Toxocara larvae in the second and third groups of eyes are obvious. Perkins stated that anteriorly situated lesions secondary to Toxocara might be more common than posterior forms, and he 15
Fig. 13 (Wilkinson and Welch). Microscopic section through an eosinophillic abscess containing characteristic larval remnants and located in the peripheral mass shown in Figures 5 and 13 (hematoxylin and eosin, X250).
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therapy. Retrolentalfibroplasia(RLF) is almost invariably bilateral, and an examination revealing signs of inflammation in the involved eye and a typically normal fellow Congenital and developmental anomalies eye is evidence against a diagnosis of RLF. Retrolental fibroplasia Congenital retinal folds with classical septi Congenital retinal folds Anomalies of the hyaloid and primary vitreous beginning at the disk and radiating into a Uveitis largefibrousextension in the periphery may Pars planitis mimic both peripheral Toxocara lesions and Toxoplasmosis Focal endophthalmitis RLF. However, congenital folds are nearly Coats' disease always associated with some persistence of Trauma the hyaloid system, and they typically extend Tumor Retinoblastoma into only the lower temporal quadrant. Other There are usually no signs of active inflammation. More severe cases of retinal dysplaequated the migration of the worm peripher- sia are associated with severe systemic ally with a more intense vitreous reaction anomalies. Disorders of the primary vitreand an increased tendency to form cyclitic ous and hyaloid system may simulate diffuse membranes or retinal detachments. Duguid Toxocara endophthalmitis but do not cause stated that the quieter granulomatous form problems in distinguishing the more focal of the disease had never been recognized in forms of the disease. the periphery. We believe that the initial site Several forms of uveitis occurring in of the larva is determined solely by chance. childhood deserve mention in the differential The activity of the worm and the various diagnosis of the peripheral lesions secondary host defenses determine the extent of the in- to Toxocara. The pars planitis and chronic flammation. If this reaction remains localcyclitis syndromes have been reported secized, the lesion probably slowly subsides and ondary to proven toxocariasis, and the disresults in a dense gliotic mass. However, if tinction between the two entities can indeed the inflammation progresses unabated, more be quite difficult. However, the par planitis significant and irreversible changes occur, syndrome is bilateral in 80% of cases, and with the development of leukocoria and a the inflammation is classically distributed in generally useless eye. The location of the ini- a "snowbank" pattern which is typically lotial inflammatory focus, per se, does not de- cated inferiorly and anterior to the retina ; it termine the ultimate outcome of the eye. usually appears much less solid and localized The differential diagnosis of the periph- than the reaction of the inflammatory masses eral inflammatory masses includes many en- due to Toxocara. In addition, perivasculitis, macular edema, and papillitis occur more tities, as listed in Table 4. Toxocara endophthalmitis typically occurs frequently in pars planitis, and the general in childhood, and congenital and develop- course of this disease is probably more unremental anomalies therefore form an impor- lenting. The retinitis of the presumed toxotant class of lesions to be differentiated from plasmosis syndrome may cause enough vitrethe peripheral masses. The Grade III cicatri- ous inflammation to make its recognition cial stage of retrolentalfibroplasiaappears quite difficult, but if the characteristic scars similar to a temporally-situated Toxocara in- and daughter lesions are visible, the differentiation of this entity from peripheral toxoflammatory mass with a fold of retina extending posteriorly. However, in our series, cara is usually not at all difficult. Focal inhistories were negative for diminished birth- flammatory lesions secondary to other orgaweight, prematurity, and significant oxygen nisms may present a variety of pictures, as TABLE 4
19
DIFFERENTIAL DIAGNOSES IN PERIPHERAL TOXOCARA LESIONS
20
21
7
22
23
12
recently discussed by Perkins. Although it is obviously impossible to completely rule out other causes of some of the peripheral lesions we have described, we believe that the evidence to date indicates that the intraocular picture which we have been describing is very characteristic of Toxocara. 15
The peripheral vascular anomalies and lipid seen in mild cases of Coats' disease are not seen in cases of peripheral toxocariasis, although severe cases of the former are frequently confused with diffuse Toxocara endophthalmitis. Ocular trauma can result in localized proliferative changes and inflammatory signs which simulate those caused by Toxocara. However, the history and associated lesions secondary to the injury greatly aid in differentiating the two conditions. Neoplasms must be included in the differential diagnosis of all intraocular mass lesions, especially in childhood. Retinoblastomas generally occur in a younger age group and are often bilateral. Evidences of growth and vitreous seeding will often appear on follow-up examinations. Inflammation from the tumors is variable, but the tendency to form characteristic vitreous bands is not present. Finally, the tumors are much more likely to calcify than Toxocara lesions. Nevertheless, one must always be aware that small peripheral retinoblastomas can mimic inflammatory foci, although we have not seen this in patients who presented the typical picture described above. Benign neoplasms such as those associated with the phakomatoses are usually recognized by associated systemic lesions and the relative absence of inflammation, and they rarely simulate Toxocara. 8
The treatment of nematode endophthalmitis remains controversial. The efficacy of antinematode agents such as thiobendazole has not been sufficiently established to date. Corticosteroids have proved helpful in severe cases of visceral larva migrans, and they appear to have been of value in a few ocular cases. * Certainly, they are indicated 25
25
2
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in Toxocara in actively inflamed, salvageable eyes, as they are in most types of posterior uveitis. Nematode endophthalmitis is an entity with a very distinct histologic picture but a variable clinical presentation. In cases of leukocoria, surely the mere possibility of toxocariasis cannot prohibit enucleation, for in severely involved eyes, the distinction between nematode endophthalmitis and retinoblastoma can be impossible. However, visible focal masses occurring in association with vitreous inflammation and the characteristic vitreous bands and retinal folds described above should be suggestive of Toxocara and this presumption or suspicion should not require immediate overaggressive histologic documentation. All intraocular masses should be followed very closely ; progression indicative of a neoplastic process should prompt enucleation, whereas a picture more consistent with active endophthalmitis should invite medical therapy. As a significant disease of known etiology, Toxocara endophthalmitis in all its forms needs to be studied in greater detail; better answers to the questions posed by this entity would undoubtedly improve our knowledge of other types of intraocular inflammation. SUMMARY
Of 40 patients with presumed or proven intraocular Toxocara, 17 patients (one with bilateral involvement) presented with peripheral inflammatory masses. Typically, these eyes were quiet, without anterior segment inflammation, and significant changes were located posteriorly, where large retinal or subretinal inflammatory masses of variable activity were observed in association with mild vitreous inflammation and characteristic vitreous bands running from the mass to surrounding retina and often to the optic nerve. These bands were frequently associated with retinal folds. The differential diagnosis of these peripheral lesions includes congenital and developmental anomalies, other forms of uveitis, Coats' disease,
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AMERICAN JOURNAL OF OPHTHALMOLOGY
trauma, and tumors. It is suggested that in intraocular Toxocara, the site of the infestation is determined by chance, and the differences observed in the clinical forms of this disease are secondary to variations in nematode activity and host response. REFERENCES
1. Beaver, P. C , Snyder, C. H , Correrá, G. M , Dent, J. H , and Lafferty, J. W. : Chronic eosinophilia due to visceral larva migrans. Report of three cases. Pediatrics. 9:7, 1952. 2. Wilder, H. C. : Nematode endophthalmitis. Tr. Am. Acad. Ophth. Otolarng. 55:99, 1950. 3. Nichols, R. L. : The etiology of visceral larva migrans. I. Diagnostic morphology of infective second-stage Toxocara larvae. J. Parisit. 42:349, 1956. 4. Benedict, W. H. : Nematode endophthalmitis. J. Tenn. Med. Assoc. 51:328, 1958. 5. Bourke, G. M , and Yeates, F. M. : Blindness due to household pets (Toxocara canis infestation). Med. J. Australia 48:12, 1961. 6. Duguid, I. M. : Chromic endophthalmitis due to Toxocara. Brit. J. Ophth. 45:705, 1961. 7. Duguid, I. M. : Features of ocular infestation by Toxocara. Brit. J. Ophth. 45:789, 1961. 8. Howard, G. M , and Ellsworth, R. M. : Differential diagnosis of retinoblastoma (Parts I and I I ) . Am. J. Ophth. 60:610, 1965. 9. Kogan, L , and Boniuk, M. : Causes of enucleation in childhood with special reference to pseudogliomas and unsuspected retinoblastomas. Int. Ophth. Clin. 2:507, 1962. 10. Ashton, N. : Larval granulomatosis of the retina due to Toxocara. Brit. J. Ophth. 44:129, 1960. 11. Irvine, W. C , and Irvine, A. R , Jr. : Nematode endophthalmitis: Toxocara canis. Am. J. Ophth. 47:185, 1959.
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12. Hogan, M. J, Kimura, S. J, and Spencer, W . H. : Visceral larva migrans and peripheral retinitis. J.A.M.A. 194:1345, 1965. 13. Maumenee, A. E. : An approach to the study of uveitis. In Aronson, S. B , Gable, C. N , Goodner, E. K , and O'Connor, G. R. (eds.) : Clinical Methods in Uveitis. St. Louis, Mosby, 1968, p. 21. 14. Perkins, E. S.: Pattern of uveitis in children. Brit. J. Ophth. 50:169,1966. 15. Perkins, E. S. : The differential diagnosis of uveitis in children. In Proceedings of the 20th International Congress of Ophthalmology. Amsterdam, Excerpta Medica Foundation, 1967, p. 363. 16. Foulds, W. S. : Post-inflammatory ectopia of the macula resulting in apparent hypertropia. Brit. J. Ophth. 40:571, 1956. 17. Willetts, G. S. : Heterotopia of the macula. Brit. J. Ophth. 50:595,1966. 18. Vrabec, F.: Leukocoria-pseudoglioma. EENT Monthly 48:78, 1969. 19. Duke-Elder, W. S, and Dobree, J. H. : System of Ophthalmology. St. Louis, Mosby, 1967, vol. I, p. 189. 20. Duke-Elder, W. S. : System of Ophthalmology. St. Louis, Mosby. 1964, vol. 3, part 2, p. 636 21. Reese, A. B , and Straatsma, B. R. : Retinal dysplasia. Am. J. Ophth. 45:199, 1958. 22. Welch, R. B , Maumenee, A. E., and Wahlen, H. E. : Peripheral posterior segment inflammation, vitreous opacities, and edema of the posterior pole : Pars planitis. Arch. Ophth. 64:540, 1960. 23. Hogan, M. J, Kimura, S. J, and O'Connor, G. R. : Peripheral retinitis and chronic cyclitis in children. Tr. Ophth. Soc. U.K. 85 :39, 1965. 24. Nolan, J. : Chronic toxocaral endophthalmitis: Successful treatment of a case with subconjunctival depot corticosteroids. Brit. J. Ophth. 52: 276, 1968. 25. Zinkham, W. H. : Visceral larva migrans due to Toxocara as a cause of eosinophilia. Johns Hopkins Med. J. 123:41,1968.
Baltimore, Maryland In 1952, Beaver and associates described a syndrome of childhood secondary to Toxocara canis invasion and proposed the term "visceral larva migrans." This condition follows the ingestion of Toxocara ova which hatch in the small intestine. The larvae migrate into the blood and lymph vessels, reach the liver and the lungs, and then enter the arterial circulation and are distributed to peripheral organs where they migrate until they are consumed or encapsulated by an eosinophilic granulomatous response. The life cycle is never completed in man and ends at this point. 1
In the natural canine host, larvae from the upper respiratory tract reach the small intestine directly, and the worms mature and produce ova which are passed in the feces to be ingested by other animals, most importantly the human child. Historically, intraocular nematode infestations first gained significant attention in 1950, when Wilder found larvae in histologic sections of over half of a selected series of pseudogliomata at the Armed Forces Institute of Pathology. These lesions were originally considered to be secondary to hookworms, but Nichols later identified several of the organisms as Toxocara larvae. Since then, many similar cases of severe nematode endophthalmitis have been reported, " and the importance of Toxocara in the differential diagnosis of leukocoria has become well recognized. ' In 1960, Ashton reported four cases of isolated posterior pole lesions secondary to Toxocara and thereby established a distinct second form of the disease, markedly different from the more se2
3
4
7
8 9
10
From the Wilmer Ophthalmological Institute of the Johns Hopkins Hospital and University, Baltimore, Maryland. Reprint requests to Robert B. Welch, M . D , 14 West Mount Vernon Place, Baltimore, Maryland 21201. 921
verely involved cases previously reported. Soon thereafter, Duguid ' presented a larger series of cases and reemphasized that intraocular Toxocara infestation could result in either a solitary retinal "granuloma" or chronic endophthalmitis. He stated that the granulomatous form of the disease had never been recognized in the peripheral fundus or nasal to the optic disk. Reports of well-localized peripheral inflammatory masses secondary to Toxocara have infrequently appeared in the literature. ' Some of these have not resulted in severe disruption of the entire eye and represent a third and intermediate form of the disease which is becoming increasingly well recognized. '" The purpose of this paper is to review our experiences with presumed and proven cases of intraocular Toxocara at the Wilmer Institute. 8 7
11 12
13
MATERIALS AND METHODS
This group of patients is composed of those whose fundus lesions were considered to be diagnostic of Toxocara infestation or whose histologic pictures were indicative of this entity. Most cases were obtained by reviewing clinical records of the Johns Hopkins Hospital and histologic specimens of the Wilmer Eye Pathology Department. Others were seen in consultation by one of us ( R B W ) , and a very few were examined by other ophthalmologists at the Wilmer Institute. The ophthalmic evaluation consisted of a thorough history, a recording of the visual acuity, and detailed external, slit-lamp and fundus examinations. Retinal drawings of focal lesions were performed, and photographs were taken when possible. Only pathologic specimens judged to be diagnostic of intraocular Toxocara were included, but the presence of larval remnants was not considered necessary for a positive histologic diagnosis.
922
AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 1 CLASSIFICATION OF INTRAOCULAR TOXOCARA INFESTATION
1. Diffuse nematode endophthalmitis 2. Posterior pole "granuloma" 3. Peripheral inflammatory mass in a quiet eye Total
No. Eyes
Pathologic Diagnosis
13 10
10 0
18
1
41
11
APRIL, 1971
scesses; larval remnants were discovered within three of these. The 11th patient has been followed for two years, and the eye remains asymptomatic and unchanged with bare light perception. The significance of this form of nematode endophthalmitis lies in its similarity to other causes of leukocoria, particularly retinoblastoma. Important factors concerning this frequently difficult differential diagnosis have been well described in the past. 8
15
The 10 patients in the second group were similar to those first described by Ashton. Their ages ranged from six to 14 years, and the average age was slightly greater than in the first group. Past histories were not significant. Chief complaints were diminished vision or strabismus. The eyes were uninflamed, and pertinent findings were limited to the posterior pole. Eight of the 10 granulomata were considered classic and were associated with no apparent active inflammation (Fig. 1 ) . One patient's lesions progressed from a stage of minimal inflammation to a severe endophthalmitis with total retinal detachment and dense leukocoria. The 10th patient's quiet focal lesion had caused sufficient traction on the surrounding 10
RESULTS
Forty-one eyes of 40 patients were included in this series. These were divided into three groups (Table 1 ) : Group 1 consisted of patients with diffuse nematode endophthalmitis, Group 2 included those with focal posterior-pole granulomata, Group 3 was made up of those with peripheral inflammatory masses in a relatively quiet eye. The latter group will be discussed in greatest detail, for this form of the disease has not received sufficient attention in the literature. The 13 patients in the first group were typical of those with extensive unilateral intraocular inflammation as previously described in excellent articles on Toxocara endophthalmitis. ' The patients were in the usual age group of two to nine years. They invariably presented with complaints of visual loss and leukocoria, often accompanied by strabismus. Histories were never contributory. Examination of the affected eye typically revealed markedly diminished vision and leukocoria secondary to marked vitreous inflammation, a cyclitic membrane, or a huge retinal detachment. Occasionally, a poorly visualized inflammatory mass was seen in the vitreous cavity, and in one case, two such foci were described. The eyes were usually asymptomatic, but since the differential diagnosis always included retinoblastoma, most of them were enucleated. Ten of the 11 positive pathologic specimens were obtained from this group (Table 1 ) . Microscopic examination revealed typical eosinophilic ab7 15
Fig. 1 (Wilkinson and Welch). Two posterior pole granulomata. Note clear media and traction upon surrounding retina.
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retina to produce a large posterior retinal tear and detachment (Fig. 2 ) . All of these patients were seen after the publication of Ashton's 1960 article, and none of these eyes was enucleated. Only three of the classic cases have been closely followed, and these have not changed in any way. The differential diagnosis of these lesions includes dense macular scars, other types of focal inflammation of the posterior pole, and tumors. Eighteen of the 41 eyes presented with a peripheral inflammatory mass lesion unassociated with profound inflammation in the vitreous, and it is this third group that will be discussed in detail. Most of the patients fell into the age distribution of the second group, but three were over 20 years of age when first examined. A history strongly suggestive of visceral larva migrans was never obtained, and those who were evaluated did not have significant eosinophilia. Several of the patients had been exposed to puppies, as have most children, but a significant history of pica was obtained in only two. One of these children had a history of passing large amounts of hair of his pet collie in his own feces over a four-month period between the ages of five and nine months. All patients
Fig. 2 (Wilkinson and Welch). Fundus drawing of a retinal tear and detachment secondary to traction secondary to a posterior pole granuloma.
TABLE 2 V I S I O N I N E Y E S W I T H P E R I P H E R A L LESIONS
Vision 20/20-20/40 20/50-20/100 20/200-20/400 20/400-LP Unknown (illiterate)
No. Eyes 3 2 5 5 3
were full-term babies with normal birth weights, and no histories of significant oxygen exposure were obtained. None of the patients had sustained significant trauma about the involved eye. None of the group were physically or mentally retarded, and all were without systemic anomalies. Ocular examination revealed visual acuities that ranged from 20/20 to bare light perception, but vision was usually significantly reduced in the affected eye (Table 2 ) . Right and left eyes were involved with equal frequency, and the affected eye usually deviated from the orthotropic position. No eyes appeared significantly injected on external examination. Minimally active inflammatory signs were occasionally present in the anterior chamber, but these were never active enough to be graded as one-plus on a scale of one to four. One patient had a few small old posterior synechiae. Minimal lens changes were often present in the posterior subcapsular area, but significant lens opacities were present in only two instances. One of these patients, a 40-year-old woman, presented with a mature cataract, which was subsequently removed without problems. Tensions in this group were always within normal limits. Vitreous cells and strands were invariably noted, but the reaction was moderately severe in only four cases and never significant enough to prevent a thorough examination of the entire retina. In the periphery of the fundus, each of these eyes exhibited a dense white elevated inflammatory mass; these masses demonstrated various degrees of activity, were located at different depths in retinal or uveal structures, and were pro-
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dated with these vitreous bands and often extended from the mass to the disk. The focal lesions were usually several disk diameters in size and generally occurred with their centers near the ora ; in only three eyes were the masses located completely posterior to this boundary (Table 3 ) . In two eyes, definite multiple sites of involvement were ob-
Fig. 3 (Wilkinson and Welch). Typical appearance of a peripherally located, dense, white, inflammatory mass. Note the clear medial and normal surrounding retina
Fig. 5 (Wilkinson and Welch). Fundus drawing of a classic peripheral inflammatory mass associated with a large retinal fold and multiple vitreous bands attached to surrounding retina.
Fig. 4 (Wilkinson and Welch). Peripheral inflammatory mass with characteristic vitreous bands running to surrounding retina.
jecting toward the center of the vitreous cavity. The masses were always associated with dense connective-tissue strands in the vitreous cavity (Figs. 3, 4 ) . Many of these were directed posteriorly and were attached to either the disk or to surrounding retina in a "sucker foot" configuration (Figs. 5, 6 ) . Elevated folds of retina were frequently asso-
Fig. 6 (Wilkinson and Welch). Fundus drawing of a superiorly located inflammatory lesion.
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served (Figs. 7, 8 ) . A single patient presented with bilateral involvement (Fig. 9 ) ; interestingly, this child was the patient with the amazingly positive history of pica described earlier; he was a normal full-term infant of normal birth weight who required no oxygen therapy. Associated fundus lesions other than those described above were rare. The optic nerve heads, per se, were always normal, and remnants of hyaloid vessels were not encountered. The retinal vessels were without structural or inflammatory anomalies and appeared normal. Cystoid macular edema was TABLE
3
LOCATION OF INFLAMMATORY MASSES
Center of Inflammation: Completely posterior to ora More anterior Quadrants: Temporal Inferior Nasal Superior Multiple
Fig. 8 (Wilkinson and Welch). Fundus drawing of three distinct peripheral lesions ; a fourth site of involvement lies over the nerve head and appeared similar to one of the lesions in Figure 1.
3 15 4 6 3 3 2
Fig. 9 (Wilkinson and Welch). Fundus drawing of a child with bilateral involvement. The small lesion at three o'clock was much denser than the more peripheral inflammatory reaction and possibly represented the location of the parasite. The right eye was a mirror image of the left with the exception of this dense minute focus.
Fig. 7 (Wilkinson and Welch). Fundus drawing of two distinct inflammatory masses with a vitreous band running between them and attached to the disk.
present in only one eye, and there were no exudative retinal detachments. Occasional areas of mild scarring and pigment proliferation surrounding the masses were seen, but more classic forms of chorioretinal scarring
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Fig. 10 (Wilkinson and Welch). Fundus drawing from a patient with diplopia, 20/25 vision in the involved right eye, a pseudohypotropia of the right eye of approximately five diopters, a true hypertropia of the right eye of 20 diopters, and a heterotopia of the macula secondary to an interiorly located peripheral inflammatory lesion.
occurring in other types of uveitis were never encountered. Lipid deposits were never noted, and calcification was not clinically visible. Heterotopia of the macula (Figs. 10, 11) secondary to traction occurred in three eyes markedly similar to cases previously reported in the literature. ' In a single patient, traction resulted in peripheral retinal hole formation and a large retinal detachment.
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flammation. The first received a course of thiobendazole, and activity of the lesion very slowly and minimally diminished over the next 30 months, with a slight decrease in the size of the mass. The second improved minimally on a short course of systemic steroids, but this therapy was stopped because it did not prove successful. In summary, all eyes which were adequately followed changed very little, regardless of the activity of the lesions or the therapy used. Undoubtedly, these statistics are of little help in discussing the natural course of this disease or in assessing therapy, and we have not had the opportunity to follow a case of Toxocara endophthalmitis from its onset to the stage represented by these relatively quiet peripheral lesions. Of interest in the regard is a recent article describing a 13year-old patient who presented with only a few floating vitreous opacities and a peripheral subretinal nodule in an otherwise normal eye. Over the next six months, the child's vision deteriorated markedly, as the lower half of the retina became detached. However, over the following six months, this detachment slowly disappeared, leaving what was described as a "typical retinal 18
16 17
Only one of the eyes in this group was enucleated. The lesion was very typical clinically (Figs. 5, 12), and histologic sections revealed a characteristic eosinophilic granuloma containing remnants of Toxocara larva in the posterior ciliary body (Fig. 13). Of the 17 remaining eyes, nine were seen on only one occasion and there were insufficient referral or follow-up notes to allow an assessment of the course of the disease. Eight eyes have been followed from 18 months to five years. Six of these had insignificant intraocular inflammation when first seen, and activity did not increase; the two remaining patients had moderately severe in-
Fig. 11 (Wilkinson and Welch). Fundus photograph from the patient with an inferiorly displaced macula described in Figure 11.
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Fig. 12 (Wilkinson and Welch). Gross specimen of the eye drawn in Figure S demonstrating the large dense inflammatory mass and elevated retinal fold which runs posteriorly to the disk.
fold" connecting the nerve head with the peripheral nodule. The authors did not list possible etiologies, but the report is certainly compatible with the peripheral lesions we have been discussing. COMMENT
In most reported cases of proved Toxocara endophthalmitis the responsible larvae are located in the posterior eye, but in this series, anteriorly situated centers of inflammation were much more common. Of the 13 15
eyes with diffuse nematode endophthalmitis, 10 came to enucleation. In five of these, the primary inflammatory focus was in the retrolental area of the vitreous, and in four others it was in the anterior retina or ciliary body. In only one did the larva appear to emerge from the posterior retina. The positions of the presumed Toxocara larvae in the second and third groups of eyes are obvious. Perkins stated that anteriorly situated lesions secondary to Toxocara might be more common than posterior forms, and he 15
Fig. 13 (Wilkinson and Welch). Microscopic section through an eosinophillic abscess containing characteristic larval remnants and located in the peripheral mass shown in Figures 5 and 13 (hematoxylin and eosin, X250).
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therapy. Retrolentalfibroplasia(RLF) is almost invariably bilateral, and an examination revealing signs of inflammation in the involved eye and a typically normal fellow Congenital and developmental anomalies eye is evidence against a diagnosis of RLF. Retrolental fibroplasia Congenital retinal folds with classical septi Congenital retinal folds Anomalies of the hyaloid and primary vitreous beginning at the disk and radiating into a Uveitis largefibrousextension in the periphery may Pars planitis mimic both peripheral Toxocara lesions and Toxoplasmosis Focal endophthalmitis RLF. However, congenital folds are nearly Coats' disease always associated with some persistence of Trauma the hyaloid system, and they typically extend Tumor Retinoblastoma into only the lower temporal quadrant. Other There are usually no signs of active inflammation. More severe cases of retinal dysplaequated the migration of the worm peripher- sia are associated with severe systemic ally with a more intense vitreous reaction anomalies. Disorders of the primary vitreand an increased tendency to form cyclitic ous and hyaloid system may simulate diffuse membranes or retinal detachments. Duguid Toxocara endophthalmitis but do not cause stated that the quieter granulomatous form problems in distinguishing the more focal of the disease had never been recognized in forms of the disease. the periphery. We believe that the initial site Several forms of uveitis occurring in of the larva is determined solely by chance. childhood deserve mention in the differential The activity of the worm and the various diagnosis of the peripheral lesions secondary host defenses determine the extent of the in- to Toxocara. The pars planitis and chronic flammation. If this reaction remains localcyclitis syndromes have been reported secized, the lesion probably slowly subsides and ondary to proven toxocariasis, and the disresults in a dense gliotic mass. However, if tinction between the two entities can indeed the inflammation progresses unabated, more be quite difficult. However, the par planitis significant and irreversible changes occur, syndrome is bilateral in 80% of cases, and with the development of leukocoria and a the inflammation is classically distributed in generally useless eye. The location of the ini- a "snowbank" pattern which is typically lotial inflammatory focus, per se, does not de- cated inferiorly and anterior to the retina ; it termine the ultimate outcome of the eye. usually appears much less solid and localized The differential diagnosis of the periph- than the reaction of the inflammatory masses eral inflammatory masses includes many en- due to Toxocara. In addition, perivasculitis, macular edema, and papillitis occur more tities, as listed in Table 4. Toxocara endophthalmitis typically occurs frequently in pars planitis, and the general in childhood, and congenital and develop- course of this disease is probably more unremental anomalies therefore form an impor- lenting. The retinitis of the presumed toxotant class of lesions to be differentiated from plasmosis syndrome may cause enough vitrethe peripheral masses. The Grade III cicatri- ous inflammation to make its recognition cial stage of retrolentalfibroplasiaappears quite difficult, but if the characteristic scars similar to a temporally-situated Toxocara in- and daughter lesions are visible, the differentiation of this entity from peripheral toxoflammatory mass with a fold of retina extending posteriorly. However, in our series, cara is usually not at all difficult. Focal inhistories were negative for diminished birth- flammatory lesions secondary to other orgaweight, prematurity, and significant oxygen nisms may present a variety of pictures, as TABLE 4
19
DIFFERENTIAL DIAGNOSES IN PERIPHERAL TOXOCARA LESIONS
20
21
7
22
23
12
recently discussed by Perkins. Although it is obviously impossible to completely rule out other causes of some of the peripheral lesions we have described, we believe that the evidence to date indicates that the intraocular picture which we have been describing is very characteristic of Toxocara. 15
The peripheral vascular anomalies and lipid seen in mild cases of Coats' disease are not seen in cases of peripheral toxocariasis, although severe cases of the former are frequently confused with diffuse Toxocara endophthalmitis. Ocular trauma can result in localized proliferative changes and inflammatory signs which simulate those caused by Toxocara. However, the history and associated lesions secondary to the injury greatly aid in differentiating the two conditions. Neoplasms must be included in the differential diagnosis of all intraocular mass lesions, especially in childhood. Retinoblastomas generally occur in a younger age group and are often bilateral. Evidences of growth and vitreous seeding will often appear on follow-up examinations. Inflammation from the tumors is variable, but the tendency to form characteristic vitreous bands is not present. Finally, the tumors are much more likely to calcify than Toxocara lesions. Nevertheless, one must always be aware that small peripheral retinoblastomas can mimic inflammatory foci, although we have not seen this in patients who presented the typical picture described above. Benign neoplasms such as those associated with the phakomatoses are usually recognized by associated systemic lesions and the relative absence of inflammation, and they rarely simulate Toxocara. 8
The treatment of nematode endophthalmitis remains controversial. The efficacy of antinematode agents such as thiobendazole has not been sufficiently established to date. Corticosteroids have proved helpful in severe cases of visceral larva migrans, and they appear to have been of value in a few ocular cases. * Certainly, they are indicated 25
25
2
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in Toxocara in actively inflamed, salvageable eyes, as they are in most types of posterior uveitis. Nematode endophthalmitis is an entity with a very distinct histologic picture but a variable clinical presentation. In cases of leukocoria, surely the mere possibility of toxocariasis cannot prohibit enucleation, for in severely involved eyes, the distinction between nematode endophthalmitis and retinoblastoma can be impossible. However, visible focal masses occurring in association with vitreous inflammation and the characteristic vitreous bands and retinal folds described above should be suggestive of Toxocara and this presumption or suspicion should not require immediate overaggressive histologic documentation. All intraocular masses should be followed very closely ; progression indicative of a neoplastic process should prompt enucleation, whereas a picture more consistent with active endophthalmitis should invite medical therapy. As a significant disease of known etiology, Toxocara endophthalmitis in all its forms needs to be studied in greater detail; better answers to the questions posed by this entity would undoubtedly improve our knowledge of other types of intraocular inflammation. SUMMARY
Of 40 patients with presumed or proven intraocular Toxocara, 17 patients (one with bilateral involvement) presented with peripheral inflammatory masses. Typically, these eyes were quiet, without anterior segment inflammation, and significant changes were located posteriorly, where large retinal or subretinal inflammatory masses of variable activity were observed in association with mild vitreous inflammation and characteristic vitreous bands running from the mass to surrounding retina and often to the optic nerve. These bands were frequently associated with retinal folds. The differential diagnosis of these peripheral lesions includes congenital and developmental anomalies, other forms of uveitis, Coats' disease,
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trauma, and tumors. It is suggested that in intraocular Toxocara, the site of the infestation is determined by chance, and the differences observed in the clinical forms of this disease are secondary to variations in nematode activity and host response. REFERENCES
1. Beaver, P. C , Snyder, C. H , Correrá, G. M , Dent, J. H , and Lafferty, J. W. : Chronic eosinophilia due to visceral larva migrans. Report of three cases. Pediatrics. 9:7, 1952. 2. Wilder, H. C. : Nematode endophthalmitis. Tr. Am. Acad. Ophth. Otolarng. 55:99, 1950. 3. Nichols, R. L. : The etiology of visceral larva migrans. I. Diagnostic morphology of infective second-stage Toxocara larvae. J. Parisit. 42:349, 1956. 4. Benedict, W. H. : Nematode endophthalmitis. J. Tenn. Med. Assoc. 51:328, 1958. 5. Bourke, G. M , and Yeates, F. M. : Blindness due to household pets (Toxocara canis infestation). Med. J. Australia 48:12, 1961. 6. Duguid, I. M. : Chromic endophthalmitis due to Toxocara. Brit. J. Ophth. 45:705, 1961. 7. Duguid, I. M. : Features of ocular infestation by Toxocara. Brit. J. Ophth. 45:789, 1961. 8. Howard, G. M , and Ellsworth, R. M. : Differential diagnosis of retinoblastoma (Parts I and I I ) . Am. J. Ophth. 60:610, 1965. 9. Kogan, L , and Boniuk, M. : Causes of enucleation in childhood with special reference to pseudogliomas and unsuspected retinoblastomas. Int. Ophth. Clin. 2:507, 1962. 10. Ashton, N. : Larval granulomatosis of the retina due to Toxocara. Brit. J. Ophth. 44:129, 1960. 11. Irvine, W. C , and Irvine, A. R , Jr. : Nematode endophthalmitis: Toxocara canis. Am. J. Ophth. 47:185, 1959.
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12. Hogan, M. J, Kimura, S. J, and Spencer, W . H. : Visceral larva migrans and peripheral retinitis. J.A.M.A. 194:1345, 1965. 13. Maumenee, A. E. : An approach to the study of uveitis. In Aronson, S. B , Gable, C. N , Goodner, E. K , and O'Connor, G. R. (eds.) : Clinical Methods in Uveitis. St. Louis, Mosby, 1968, p. 21. 14. Perkins, E. S.: Pattern of uveitis in children. Brit. J. Ophth. 50:169,1966. 15. Perkins, E. S. : The differential diagnosis of uveitis in children. In Proceedings of the 20th International Congress of Ophthalmology. Amsterdam, Excerpta Medica Foundation, 1967, p. 363. 16. Foulds, W. S. : Post-inflammatory ectopia of the macula resulting in apparent hypertropia. Brit. J. Ophth. 40:571, 1956. 17. Willetts, G. S. : Heterotopia of the macula. Brit. J. Ophth. 50:595,1966. 18. Vrabec, F.: Leukocoria-pseudoglioma. EENT Monthly 48:78, 1969. 19. Duke-Elder, W. S, and Dobree, J. H. : System of Ophthalmology. St. Louis, Mosby, 1967, vol. I, p. 189. 20. Duke-Elder, W. S. : System of Ophthalmology. St. Louis, Mosby. 1964, vol. 3, part 2, p. 636 21. Reese, A. B , and Straatsma, B. R. : Retinal dysplasia. Am. J. Ophth. 45:199, 1958. 22. Welch, R. B , Maumenee, A. E., and Wahlen, H. E. : Peripheral posterior segment inflammation, vitreous opacities, and edema of the posterior pole : Pars planitis. Arch. Ophth. 64:540, 1960. 23. Hogan, M. J, Kimura, S. J, and O'Connor, G. R. : Peripheral retinitis and chronic cyclitis in children. Tr. Ophth. Soc. U.K. 85 :39, 1965. 24. Nolan, J. : Chronic toxocaral endophthalmitis: Successful treatment of a case with subconjunctival depot corticosteroids. Brit. J. Ophth. 52: 276, 1968. 25. Zinkham, W. H. : Visceral larva migrans due to Toxocara as a cause of eosinophilia. Johns Hopkins Med. J. 123:41,1968.