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Toxoplasmic Coats' Retinitis*
T O X O P L A S M I C COATS' R E T I N I T I S * A
PARÁSITO LOGICALLY
RENATO FREZZOTTI, M . D , AND
ALVISE BERENGO, M . D , FABIO CAVALLINI, Siena,
CASE ROBERTO GUERRA,
M.D,
M.D.
Italy
In several instances Coats' disease has etiologically been referred to a Toxoplasma infection on the basis of positive serologic tests. " W e observed a serologically posi tive case with suspected retinal pseudocysts but animal inoculation was unsuccessful. In eight additional cases, with no indication for enucleation, the serologic diagnosis was accompanied by microscopic observation of Toxoplasmalike bodies in the cerebrospinal fluid sediment. * 1
PROVED
4
6
5
Recently, definite parasitologic demon stration of Toxoplasma in the globe has been obtained in a case of Coats' disease.
mg/100 ml. Coagulation and bleeding time were normal. Serologic tests were negative for syphilis. Antistreptolysin O titer: 166 units/ml. C-reactive protein one plus positive. Skull and chest films were negative. EEG and ecg were normal. The dye test was positive 1 / 1 0 , complement fixation test negative. A spinal puncture showed O.P. 400 mm H.O, F.P. 280 mm H.O. The cerebrospinal fluid was clear in appearance, cells 2.6/mm. Pandy and Nonne Apelt reactions negative; a few Toxo plasmalike bodies in the sediment were observed at the phase-contrast microscope (fig. 1 ) . The patient requested enucleation for cosmetic reasons. On April 4, the right eye was removed and a nylon implant performed. The postoperative course was uneventful. Eighteen days after enu cleation the dye test was positive 1 / 5 0 ; 33 days after it was positive 1 / 1 0 . PRESENT S T U D I E S
CASE REPORT
A 17-year-oid girl was admitted on March 13, 1963, to the University Eye Clinic. She had been complaining of blurred vision in the right eye since the age of four years, when a vertical squint also appeared. She was first seen in the out-patient clin ic at the age of 11 years. A t that time, vision of the right eye was reduced to counting fingers. Fun dus examination revealed areas of choroidal atro phy surrounding the optic disc. The left eye was normal. The patient was re-examined at the age of 16 years at which time a typical pattern of Coats' retinitis was found. During the last year, the eye had become repeatedly inflamed and painful and a cataract had developed. Physical examination was otherwise normal. The abnormal findings were limited to the right eye, in which vision was reduced to perception of light. The pupil was dilated and did not react to light; ectropion uveae was present. The aqueous was clear. A complete cataract prevented fundus examination; diascleral transillumination was not informative. Intraocular pressure was 8.0 mm Hg. Urinalysis was negative. Blood studies gave the following results: R B C 4.30 million, Hb g 13.3, W B C 7,800 with N.50, E.8, L.41, M.l. Sedimentation rate 5 mm hr. Fasting blood sugar 105 mg/100 ml. Urea nitrogen 34 *From the Istituto di Clínica Oculística (Drs. Frezzotti and Guerra) and the Istituto di Patolo gía Medica (Drs. Berengo and Cavallini), Univer sity of Siena Medical School.
Immediately after removal, the globe was opened along the sagittal plane under sterile conditions. A very fluid and yellowish vitre ous escaped. Inspection of the interior of the eyeball showed a complete detachment of the retina which was folded behind the lens. The half of the globe which contained the greatest part of the retina was immediately homogenized and inoculated into mice. The
1 (Frezzotti, Berengo, Guerra and Fig. Cavallini). Two Toxoplasmalike bodies in the cere brospinal fluid sediment. (Unstained, phase con trast, X 1 5 3 6 ) .
1099
1100
R. FREZZOTTI, A. BERENGO, R. GUERRA A N D F. C A V A L L I N I
remaining half was fixed in 10-percent for malin and embedded in paraffin after ade quate dehydration in alcohol. Sections were stained with Weigert's hematoxylineosin, Giemsa, periodic acid-Schiff and Wilder's silver impregnation. At histologic examination it was found that only small areas of retina were included in the block. Moreover, the marked wrin kling of the scleral calotte and the shrinkage of the sections had severely altered the ar chitecture of the tissues. The small retinal specimens showed extensive thickening, dis organization and necrosis. The choroid and ciliary body appeared diffusely edematous and a moderate number of infiltrative cells were scattered throughout. The pigment epi thelium had proliferated and large exudates were seen in front of the choroid. In the sclera, there was no evidence of inflammation. A considerable number of cysts, round or ovoid in shape, were found in the inner layers of the choroid and ciliary body, each measuring 20-30 μ in diameter. They showed well-defined walls and con tained a granular material which stained poorly with hematoxylin-eosin, while it was darkly colored by Giemsa, by P A S and by silver impregnation. In two sections, a group of small Toxoplasmalike bodies could be observed (figs. 2 and 3 ) .
Fig. 2 (Frezzotti, Berengo, Guerra and Cavallini). Two cysts in the ciliary body. (Giemsa, X614.)
Fig. 3 (Frezzotti, Berengo, Guerra and Cavallini). A group of crescentic forms in the cili ary body. (Hematoxylin-eosin, X1S36.)
Intracerebral and intraperitoneal inocula tions were performed with repeated pas sages (fig. 4 ) in a Toxoplasma-free strain of mice raised in our laboratories. In these animals a Toxoplasma strain was isolated, whose virulence was at least sufficient to double the mortality rate of cortisone-treat ed (2.5 mg twice weekly subcutaneously) mice as compared with noninoculated con trols. Parasites were microscopically demon strated in smears from some of the dead an imals. No virulence could be observed in four-week-old mice untreated with cortisone, as well as in adult rabbits. Six litters were obtained from infected mice and toxoplasmosis was transmitted in four of them. In some animals, defects in development were observed. The general mortality rate in the infected baby mice was 16/24, the dye test being positive in 6/8 of those tested. In the adult mice the dye test was positive between 1/5 and 1/500 in 2 2 / 63 inoculated mice and in 0/100 controls. Nine challenges were performed by studying the survival time after inoculation of the R.H. strain of Toxoplasma into the animals inoculated with the eye suspension, as compared to adequate controls. The re sults were examined by analyzing variance with multiple classification (different chal lenges, inoculated vs. controls). A highly
TOXOPLASMIC COATS' RETINITIS
1101
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niLiraliij
iuí mtuu
killt! mint i]t tut mjalive moute iy ttit HU live mouii
Fig. 4 (Frezzotti, Berengo, Guerra and Cavallini). Summary of animal inoculation.
significant difference was observed in the survival time (with an average value of 18 hr) showing a partial immunity to the R.H. strain in the mice inoculated with the eye suspension ( F = 17.32**; 296 mice were in cluded in the comprehensive analysis). COMMENT
The results reported herein identify Tox oplasma gondii as the cause of our case of Coats' disease. The virulence of the present strain was low for rabbits as well as for adult mice not treated with cortisone but, in repeated challenges, it was sufficient to pro tect against the R.H. strain. Toxoplasma has previously been recovered from human
eyes in several instances, " but, as far as we know, in no case of Coats' disease. A slight variation in the dye test titer was re corded after enucleation in the present as well as in previous ocular cases. Toxoplasmalike bodies were observed in the cere brospinal fluid of our previous cases of Coats' disease and in the present case. This suggests a nervous origin of the disease but, at the time of this study, we had not inject ed cerebrospinal fluid into mice. 7
12
SUMMARY
A Toxoplasma strain was isolated in mice after inoculation with a retinal suspension from a patient with Coats' disease.
1102
Κ. F R E Z Z O T T I ,
Λ.
BERENGO,
R. G U K R R A
AND
F.
CAVALLINI
REFERENCES
1. Straub, W . : Unsere Erfahrungen bei der Augentoxoplasmc.se Erwachsener. Klin. Monatsbl. Augenh, 118:483-499, 1951. 2. Marchesani, O , and Sautter, Η.: Atlas des Augenhintergrunde. München, Urban, 1954, v. 1, tab. 80-81. 3. Frangois, J , Rabaey, Μ , Evans, L , and De Vos, Ε.: Étude histopathologinue d'une rétinite de Coats probablement toxoplasmique. Ophthalmologica, 132:1-12, 1956. 4. Bauer, F.: Ueber einem Fall von Retinitis exudativa externa Coats. Graefes Arch. Ophth, 161:373380, 1959. 5. Berengo, A , and Frezzotti, R.: Active neuro-ophthalmic toxoplasmosis: A clinical study on 19 pa tients. Advanc. Ophth, 12:265-343, 1962. 6. Frezzotti, R , and Guerra, R.: Sur 1'atteinte oculaire dans la toxoplasmose neuro-ophtalmique active: Considerations cliniques et morphologiques. Ann. ocul, 196 :649-672, 1963. 7. Jacobs, L , Fair, J . R , and Bickerton, J . H.: Adult ocular toxoplasmosis: Report of a parasitologically proved case. Arch. Ophth, 52:63-71, 1954. 8. Habegger, H.: Toxoplasmose humaine: Mise en evidence des parasites dans les milieux intraoculaires humeur aqueuse, exsudate rétrorétinien). Arch. Ophtal, 14:470-488, 1954. 9. Pillat, A , and Thaihammer, O.: Herdförmige Iridocyclitis als (einzige) Manifestation einer erworbenen Toxoplasmose, ätiologisch gesichert durch Titerkurve und Tierversuch. Graefes Arch. Ophth, 158:403-415, 1957. 10. Hogan, Μ. Τ, Zweigart, P. A , and Lewis, Α . : Recovery of Toxoplasma from a human eye. Arch. Ophth, 60:548-554, 1958. 11. Matsubayashi, H , Koike, T , Uyemura, M , Sob, Y , and Hamann, Κ . : A case of ocular toxoplas mosis in an adult, the infection heing confirmed hv the isolation of the parasite from suhretinal fluid. Kein J . Med, 10:209-224, 1961. 12. Frenkel, J . K,: Pathogenesis of toxoplasmosis with a consideration of cvst rupture in Bcsnoitia infection. Surv. Ophth, 6:799-825, 1961.
CATARACT
EXTRACTION ABSOLUTE ULYSSES
M.
IN
FAR-ADVANCED
AND
GLAUCOMA* CARBAJAL,
Manila,
This paper is based on a seven-year stud}' and follow-up of cataract extractions per formed on 27 glaucomatous eyes (23 pa tients). Twenty-two of these eyes were in the absolute stage of glaucoma and the rest were in the far-advanced stage. Quimotrase was used in nine eyes. As shown in Table 1, the majority of these patients were past the age of 60 years. Of the 23 patients, 20 were Filipinos, one American, one Mexican and one Chinese. Absolute glaucoma may be defined as the end-stage of all types of glaucoma. In this condition, the eye is stone-hard, blind, often painful and, in most cases, congested. After absolute glaucoma has lasted a variable length of time, the eyeball is likely to degen erate. The cornea loses its clarity and fre* From the Manila Sanitarium and Hospital, and the Manila Central University Hospital.
M.D.
Philippines
quently is covered by fine vesicles. Bluishblack staphylomas appear between the lim bus and the equator, and the lens is prone to be cataractous. In this study (table 2 ) all the eyes had cataracts, mostly hypermature, so that it was difficult to see the fundus. In the two pa tients with immature cataracts, the nerveheads were seen to he cupped. With the use of a Schepen's scope the discs could be seen TABLE AGE
1
DISTRIBUTION
Age Groups (yr)
No. Patients
41-50 51-60 61-70 71-80 81-85
2 5 7 7 2
2 7 8 8 2
Total
23
27
No. Eyes
PARÁSITO LOGICALLY
RENATO FREZZOTTI, M . D , AND
ALVISE BERENGO, M . D , FABIO CAVALLINI, Siena,
CASE ROBERTO GUERRA,
M.D,
M.D.
Italy
In several instances Coats' disease has etiologically been referred to a Toxoplasma infection on the basis of positive serologic tests. " W e observed a serologically posi tive case with suspected retinal pseudocysts but animal inoculation was unsuccessful. In eight additional cases, with no indication for enucleation, the serologic diagnosis was accompanied by microscopic observation of Toxoplasmalike bodies in the cerebrospinal fluid sediment. * 1
PROVED
4
6
5
Recently, definite parasitologic demon stration of Toxoplasma in the globe has been obtained in a case of Coats' disease.
mg/100 ml. Coagulation and bleeding time were normal. Serologic tests were negative for syphilis. Antistreptolysin O titer: 166 units/ml. C-reactive protein one plus positive. Skull and chest films were negative. EEG and ecg were normal. The dye test was positive 1 / 1 0 , complement fixation test negative. A spinal puncture showed O.P. 400 mm H.O, F.P. 280 mm H.O. The cerebrospinal fluid was clear in appearance, cells 2.6/mm. Pandy and Nonne Apelt reactions negative; a few Toxo plasmalike bodies in the sediment were observed at the phase-contrast microscope (fig. 1 ) . The patient requested enucleation for cosmetic reasons. On April 4, the right eye was removed and a nylon implant performed. The postoperative course was uneventful. Eighteen days after enu cleation the dye test was positive 1 / 5 0 ; 33 days after it was positive 1 / 1 0 . PRESENT S T U D I E S
CASE REPORT
A 17-year-oid girl was admitted on March 13, 1963, to the University Eye Clinic. She had been complaining of blurred vision in the right eye since the age of four years, when a vertical squint also appeared. She was first seen in the out-patient clin ic at the age of 11 years. A t that time, vision of the right eye was reduced to counting fingers. Fun dus examination revealed areas of choroidal atro phy surrounding the optic disc. The left eye was normal. The patient was re-examined at the age of 16 years at which time a typical pattern of Coats' retinitis was found. During the last year, the eye had become repeatedly inflamed and painful and a cataract had developed. Physical examination was otherwise normal. The abnormal findings were limited to the right eye, in which vision was reduced to perception of light. The pupil was dilated and did not react to light; ectropion uveae was present. The aqueous was clear. A complete cataract prevented fundus examination; diascleral transillumination was not informative. Intraocular pressure was 8.0 mm Hg. Urinalysis was negative. Blood studies gave the following results: R B C 4.30 million, Hb g 13.3, W B C 7,800 with N.50, E.8, L.41, M.l. Sedimentation rate 5 mm hr. Fasting blood sugar 105 mg/100 ml. Urea nitrogen 34 *From the Istituto di Clínica Oculística (Drs. Frezzotti and Guerra) and the Istituto di Patolo gía Medica (Drs. Berengo and Cavallini), Univer sity of Siena Medical School.
Immediately after removal, the globe was opened along the sagittal plane under sterile conditions. A very fluid and yellowish vitre ous escaped. Inspection of the interior of the eyeball showed a complete detachment of the retina which was folded behind the lens. The half of the globe which contained the greatest part of the retina was immediately homogenized and inoculated into mice. The
1 (Frezzotti, Berengo, Guerra and Fig. Cavallini). Two Toxoplasmalike bodies in the cere brospinal fluid sediment. (Unstained, phase con trast, X 1 5 3 6 ) .
1099
1100
R. FREZZOTTI, A. BERENGO, R. GUERRA A N D F. C A V A L L I N I
remaining half was fixed in 10-percent for malin and embedded in paraffin after ade quate dehydration in alcohol. Sections were stained with Weigert's hematoxylineosin, Giemsa, periodic acid-Schiff and Wilder's silver impregnation. At histologic examination it was found that only small areas of retina were included in the block. Moreover, the marked wrin kling of the scleral calotte and the shrinkage of the sections had severely altered the ar chitecture of the tissues. The small retinal specimens showed extensive thickening, dis organization and necrosis. The choroid and ciliary body appeared diffusely edematous and a moderate number of infiltrative cells were scattered throughout. The pigment epi thelium had proliferated and large exudates were seen in front of the choroid. In the sclera, there was no evidence of inflammation. A considerable number of cysts, round or ovoid in shape, were found in the inner layers of the choroid and ciliary body, each measuring 20-30 μ in diameter. They showed well-defined walls and con tained a granular material which stained poorly with hematoxylin-eosin, while it was darkly colored by Giemsa, by P A S and by silver impregnation. In two sections, a group of small Toxoplasmalike bodies could be observed (figs. 2 and 3 ) .
Fig. 2 (Frezzotti, Berengo, Guerra and Cavallini). Two cysts in the ciliary body. (Giemsa, X614.)
Fig. 3 (Frezzotti, Berengo, Guerra and Cavallini). A group of crescentic forms in the cili ary body. (Hematoxylin-eosin, X1S36.)
Intracerebral and intraperitoneal inocula tions were performed with repeated pas sages (fig. 4 ) in a Toxoplasma-free strain of mice raised in our laboratories. In these animals a Toxoplasma strain was isolated, whose virulence was at least sufficient to double the mortality rate of cortisone-treat ed (2.5 mg twice weekly subcutaneously) mice as compared with noninoculated con trols. Parasites were microscopically demon strated in smears from some of the dead an imals. No virulence could be observed in four-week-old mice untreated with cortisone, as well as in adult rabbits. Six litters were obtained from infected mice and toxoplasmosis was transmitted in four of them. In some animals, defects in development were observed. The general mortality rate in the infected baby mice was 16/24, the dye test being positive in 6/8 of those tested. In the adult mice the dye test was positive between 1/5 and 1/500 in 2 2 / 63 inoculated mice and in 0/100 controls. Nine challenges were performed by studying the survival time after inoculation of the R.H. strain of Toxoplasma into the animals inoculated with the eye suspension, as compared to adequate controls. The re sults were examined by analyzing variance with multiple classification (different chal lenges, inoculated vs. controls). A highly
TOXOPLASMIC COATS' RETINITIS
1101
HOMOQCNATE •
ι
• ··· ·
+ + + +
ooo
ι
πτ-ι-τ—1
, —
9
o
+ + + +
+ + + O O
c
·
+ ++
ι ι ι ι ι ι 0 0 + + + +
SALINE
+
+
+
9
+ O O O
O O + + + +
OO+ + + + OO+O+I
® O Φ Φ Φ
O ·
οο·9 + · ·,",+ o
+
o
+
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9
9
9
9
+
Γ-+
+ + ±_+JL__f_o 0 0 +
o o o
^
o •
o
o
+
·
+
t
·
o oooo
+
+ + + o
é
+ ++o o
·
+ +o o o
o
1 o
+
·
o
o
o
o
O OΌ OO I
ifltrf»triL«i
c
•trairiWil
c
»Ue Mitil'i litt.»
+
Φ
O 9
niLiraliij
iuí mtuu
killt! mint i]t tut mjalive moute iy ttit HU live mouii
Fig. 4 (Frezzotti, Berengo, Guerra and Cavallini). Summary of animal inoculation.
significant difference was observed in the survival time (with an average value of 18 hr) showing a partial immunity to the R.H. strain in the mice inoculated with the eye suspension ( F = 17.32**; 296 mice were in cluded in the comprehensive analysis). COMMENT
The results reported herein identify Tox oplasma gondii as the cause of our case of Coats' disease. The virulence of the present strain was low for rabbits as well as for adult mice not treated with cortisone but, in repeated challenges, it was sufficient to pro tect against the R.H. strain. Toxoplasma has previously been recovered from human
eyes in several instances, " but, as far as we know, in no case of Coats' disease. A slight variation in the dye test titer was re corded after enucleation in the present as well as in previous ocular cases. Toxoplasmalike bodies were observed in the cere brospinal fluid of our previous cases of Coats' disease and in the present case. This suggests a nervous origin of the disease but, at the time of this study, we had not inject ed cerebrospinal fluid into mice. 7
12
SUMMARY
A Toxoplasma strain was isolated in mice after inoculation with a retinal suspension from a patient with Coats' disease.
1102
Κ. F R E Z Z O T T I ,
Λ.
BERENGO,
R. G U K R R A
AND
F.
CAVALLINI
REFERENCES
1. Straub, W . : Unsere Erfahrungen bei der Augentoxoplasmc.se Erwachsener. Klin. Monatsbl. Augenh, 118:483-499, 1951. 2. Marchesani, O , and Sautter, Η.: Atlas des Augenhintergrunde. München, Urban, 1954, v. 1, tab. 80-81. 3. Frangois, J , Rabaey, Μ , Evans, L , and De Vos, Ε.: Étude histopathologinue d'une rétinite de Coats probablement toxoplasmique. Ophthalmologica, 132:1-12, 1956. 4. Bauer, F.: Ueber einem Fall von Retinitis exudativa externa Coats. Graefes Arch. Ophth, 161:373380, 1959. 5. Berengo, A , and Frezzotti, R.: Active neuro-ophthalmic toxoplasmosis: A clinical study on 19 pa tients. Advanc. Ophth, 12:265-343, 1962. 6. Frezzotti, R , and Guerra, R.: Sur 1'atteinte oculaire dans la toxoplasmose neuro-ophtalmique active: Considerations cliniques et morphologiques. Ann. ocul, 196 :649-672, 1963. 7. Jacobs, L , Fair, J . R , and Bickerton, J . H.: Adult ocular toxoplasmosis: Report of a parasitologically proved case. Arch. Ophth, 52:63-71, 1954. 8. Habegger, H.: Toxoplasmose humaine: Mise en evidence des parasites dans les milieux intraoculaires humeur aqueuse, exsudate rétrorétinien). Arch. Ophtal, 14:470-488, 1954. 9. Pillat, A , and Thaihammer, O.: Herdförmige Iridocyclitis als (einzige) Manifestation einer erworbenen Toxoplasmose, ätiologisch gesichert durch Titerkurve und Tierversuch. Graefes Arch. Ophth, 158:403-415, 1957. 10. Hogan, Μ. Τ, Zweigart, P. A , and Lewis, Α . : Recovery of Toxoplasma from a human eye. Arch. Ophth, 60:548-554, 1958. 11. Matsubayashi, H , Koike, T , Uyemura, M , Sob, Y , and Hamann, Κ . : A case of ocular toxoplas mosis in an adult, the infection heing confirmed hv the isolation of the parasite from suhretinal fluid. Kein J . Med, 10:209-224, 1961. 12. Frenkel, J . K,: Pathogenesis of toxoplasmosis with a consideration of cvst rupture in Bcsnoitia infection. Surv. Ophth, 6:799-825, 1961.
CATARACT
EXTRACTION ABSOLUTE ULYSSES
M.
IN
FAR-ADVANCED
AND
GLAUCOMA* CARBAJAL,
Manila,
This paper is based on a seven-year stud}' and follow-up of cataract extractions per formed on 27 glaucomatous eyes (23 pa tients). Twenty-two of these eyes were in the absolute stage of glaucoma and the rest were in the far-advanced stage. Quimotrase was used in nine eyes. As shown in Table 1, the majority of these patients were past the age of 60 years. Of the 23 patients, 20 were Filipinos, one American, one Mexican and one Chinese. Absolute glaucoma may be defined as the end-stage of all types of glaucoma. In this condition, the eye is stone-hard, blind, often painful and, in most cases, congested. After absolute glaucoma has lasted a variable length of time, the eyeball is likely to degen erate. The cornea loses its clarity and fre* From the Manila Sanitarium and Hospital, and the Manila Central University Hospital.
M.D.
Philippines
quently is covered by fine vesicles. Bluishblack staphylomas appear between the lim bus and the equator, and the lens is prone to be cataractous. In this study (table 2 ) all the eyes had cataracts, mostly hypermature, so that it was difficult to see the fundus. In the two pa tients with immature cataracts, the nerveheads were seen to he cupped. With the use of a Schepen's scope the discs could be seen TABLE AGE
1
DISTRIBUTION
Age Groups (yr)
No. Patients
41-50 51-60 61-70 71-80 81-85
2 5 7 7 2
2 7 8 8 2
Total
23
27
No. Eyes