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Histopathological Features of Ocular Toxoplasmosis in the Fetus and Infant
Fiona Roberts, MD;
Marilyn B. Mets, MD;
David J. P. Ferguson, PhD;
Richard O'Grady, MD;
Carol O'Grady;
Philippe Thulliez, PhD;
Antoine P. Brézin, MD;
Rima McLeod, MD
Arch Ophthalmol. 2001;119:51-58.
ABSTRACT
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Background Ocular disease is a frequent manifestation of congenital Toxoplasma gondii infection. There are only limited data available
in the literature concerning early stages of this disease in fetuses and infants.
The purpose of our study was to characterize histopathological features in
the eyes of 10 fetuses and 2 infants with congenital toxoplasmosis.
Methods Fifteen eyes from 10 fetuses, 3 eyes from 2 premature infants, and both
eyes from a 2-year-old child with congenital toxoplasmosis were examined by
light microscopy. Immunohistochemical analysis to identify inflammatory cells
and T gondii antigens was performed. The findings
in infected eyes were compared with those of age-matched control eyes.
Results Retinitis (10/18 eyes), retinal necrosis (4/18 eyes), disruption of
the retinal pigment epithelium (12/18 eyes), and choroidal inflammation and
congestion (15/18 eyes) were characteristic findings. Optic neuritis was present
in 5 of 8 fetal eyes with associated optic nerve available for evaluation.
An eye obtained from a 32-week-old fetus showed retinal rosettes at the edge
of a scar. T cells predominated in retinal lesions and choroid. Parasites
were identified by immunohistochemical analysis in 10 of 18 eyes.
Conclusions Ocular toxoplasmosis causes irreversible damage to the retina in utero.
The fetus and infant mount inflammatory responses that may contribute to ocular
damage. These findings have important implications for serological screening
programs and in utero therapy.
INTRODUCTION
OCULAR toxoplasmosis is a major cause of visual impairment and accounts
for 30% to 50% of all cases of posterior uveitis.1
Humans can become infected with the protozoan parasite, Toxoplasma gondii, by ingesting tissue cysts in the meat of infected
animals or oocysts released in the feces of recently infected cats. If a woman
is infected for the first time during pregnancy, transplacental transmission
of T gondii may result in congenital toxoplasmosis
in her child. Congenital infection has been estimated to affect 3000 infants
born in the United States each year. It costs between $0.4 and $8.8 billion
annually for the medical care of these children and subsequent loss of productivity.2-4
Although congenital infection can affect any organ, ocular disease is
the most common manifestation.5-7
A prospective clinical study, as part of a US National Collaborative Treatment
Trial by the Chicago Toxoplasmosis Study Group, defined the ophthalmic manifestations
of congenital toxoplasmosis in individuals both treated and untreated during
the first year of life.8 Retinochoroidal scars
were the most common findings, present in 79% of patients. Twenty-nine percent
of patients had significant bilateral visual loss, and a further 28% had unilateral
visual loss.
Several reports have described the pathological features of ocular lesions
in adults, children, and infants.9-12
These include focal retinochoroidal scars in healed lesions and retinal necrosis
in active lesions. However, the early stages of ocular toxoplasmosis during
acute infection of the fetus have not been extensively studied. We found only
1 study of 4 fetuses between the ages of 22 and 27.5 weeks.13
In 2 of these cases the eyes were normal; however, the other 2 cases showed
retinal necrosis, neovascularization, and marked chorioretinal inflammation.
The purpose of our study was to document the ocular lesions in 10 fetuses,
2 infants, and a 2-year-old child with congenital toxoplasmosis, characterize
the associated inflammatory cells, and determine whether parasites were present.
The eyes were studied by routine light microscopy as well as with immunohistochemical
techniques to identify infiltrating inflammatory cells and T gondii antigens. The findings were compared with those already described
and correlated with the recognized clinical signs and symptoms.
MATERIALS AND METHODS
EYES
Fifteen eyes were collected post mortem from 10 fetuses with congenital
toxoplasmosis. These eyes came from France, where routine serological screening
for T gondii infection has been carried out since
1978. Maternal infections were confirmed by seroconversion in both the Sabin-Feldman
dye test and the IgM-immunosorbent agglutination assay. The fetuses were aborted
between 19 and 32 weeks' gestation following a positive diagnosis of toxoplasmosis
by polymerase chain reaction that demonstrated the presence of the T gondii B1 gene in amniotic fluid.14
Prior to termination of pregnancy, additional evidence of severe T gondii infection, as demonstrated by intracerebral ventricular dilatation
on ultrasound, was obtained in 5 cases. In 6 cases the mother received spiramycin
therapy in an attempt to prevent transplacental transmission of the parasite.
Spiramycin cannot cross the placenta and does not treat the infection in the
fetus. The mother of the 26-week-old fetus had received pyrimethamine and
sulfadiazine therapy for 3 weeks prior to termination of pregnancy. In most
cases, necropsy and/or subinoculation of placental tissue, amniotic fluid,
or brain into mice was carried out to confirm the diagnosis. One second-trimester
fetus was also infected with cytomegalovirus.
The infants and the child in this study had died of complications of
congenital toxoplasmosis. Three infant eyes were available from 2 cases. Both
infants were born prematurely, one at 34 weeks' gestation, the other unrecorded.
The infants survived 7 days and 5 days, respectively. For each of these cases
there was either serological confirmation of the infection during life, autopsy
documentation, or positive subinoculation of tissues into mice. The histopathological
findings of one infant were previously described in a case report by Frenkel
and Friedlander.15 The 2-year-old child had
well-documented changes of severe ocular and cerebral toxoplasmosis, which
had been partially treated. This case was included in the study for comparison
with the earlier stages of the disease in the fetus and infant.
Eyes from normal, uninfected, age-matched fetuses, infants, and a 2-year-old
child were used as controls. Institutional review board approval was obtained
for this study.
HISTOPATHOLOGICAL ANALYSIS
Specimens retrieved from archives were already embedded in paraffin.
The remainder of the eyes were received in 10% buffered formalin. These were
opened horizontally, processed, and embedded in paraffin. Sections (6 µm)
were cut and stained with hematoxylin-eosin and periodic acid–Schiff
for light microscopy.
IMMUNOHISTOCHEMICAL ANALYSIS
Inflammatory Cells
Following antigen retrieval, immunohistochemical analyses for pan–B
cell (anti-CD20; 1:200), pan–T cell (anti-CD3; 1:10), CD4+ T cells (anti-CD4;
1:25), CD8+ T cells (anti-CD8; 1:50), and macrophages (anti-CD68; 1:100) (all
supplied by DAKO, Santa Barbara, Calif) were performed using a standard ABC
technique. The slides were visualised with 3-3'-diaminobenzidine and
counterstained with hematoxylin.
T gondii Antigens
Similarly, for T gondii immunohistochemical
analysis, slides were incubated with a monoclonal antibody (L43; donated by
E. Petersen, PhD, Copenhagen, Denmark), which recognizes both bradyzoite and
tachyzoite life cycle stages. Immunohistochemical staining was performed using
an indirect alkaline phosphatase, anti–alkaline phosphatase (APAAP)
technique. The slides were visualized using APAAP substrate solution containing
napthol-AS-BI-phosphate (substrate) and new fuschin (chromagen) (Sigma-Aldrich
Chemical Corp, St Louis, Mo). This gives a red reaction product that allows
distinction of extracellular organisms from the brown melanin granules of
the disrupted retinal pigment epithelium (RPE).
RESULTS
CONTROL EYES
The uninfected, age-matched, control eyes showed no lesions or inflammation.
The histopathological findings are summarized in Table 1 and illustrated in Figure
1.
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Table 1. Summary of Histopathological Findings in the Eyes of Fetuses,
Infants, and a Child With Congenital Toxoplasmosis*
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Figure 1. Ocular histopathology in congenital
toxoplasmosis. A, top, A well-demarcated area of retinal necrosis (n) at the
posterior pole in the eye of a 22-week-gestation fetus (hematoxylin-eosin,
original magnification x250). A, bottom, The edge of a large retinochoroidal
scar from the eye of the 2-year-old child. The scar is well demarcated with
tubuloacinar proliferation of the retinal pigment epithelium (rpe) at the
edge of the scar. The center of the scar is devoid of retina (hematoxylin-eosin,
original magnification x250). B, top, Eye from the 32-week-gestation
fetus showing a large hyperpigmented scar, with a white rim, in the superotemporal
region of the eye (arrow). B, bottom, The retina from the edge of the scar
shows disorganization with formation of Flexner-Wintersteiner rosettes (arrows)
(hematoxylin-eosin, original magnification x400). C, left, Retina from
the 5-day-old infant eye showing retinal detachment with an exudate (e) between
the retina and choroid. The inner retinal layer is edematous and inflamed
(hematoxylin-eosin, original magnification x100). C, right, Retina from
the eye of a 22-week-gestation fetus showing gliosis (g) of the inner retinal
layers (hematoxylin-eosin, original magnification x250). D, Eye from
a 23-week-gestation fetus showing a moderate inflammatory infiltrate (i) within
the primary vitreous and surrounding the hyaloid artery (ha) (hematoxylin-eosin,
original magnification x20). E, Optic nerve from the eye of a 24-week-gestation
uninfected fetus showing normal nerve architecture (hematoxylin-eosin, original
magnification x100). F, Optic nerve from the eye of a 23-week-gestation
fetus with congenital toxoplasmosis. The nerve architecture is disrupted with
an inflammatory cell infiltrate (hematoxylin-eosin, original magnification
x100).
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FETAL EYES
Two eyes, from a 21- and 26-week-old fetus, respectively, were normal.
In all other cases the anterior segment showed mild chronic inflammation within
the iris and ciliary body. In the posterior segment, focal retinal lesions
were identified in 8 of the 15 eyes. Some lesions consisted of frank retinal
necrosis with disruption of the underlying RPE (Figure 1A). Free pigment granules were scattered throughout the
necrotic areas. Other lesions were devoid of retina and consisted of disruption
and proliferation of the RPE. The choroid underlying the lesion was congested
with chronic inflammation. There was diffuse choroiditis. Lesions varied in
size, from less than 1 mm to more than 7 mm in a 22-week-old fetus. Of 4 cases
in which both eyes were available, lesions were bilateral in only 1 case.
The most frequent location of lesions was the posterior pole, which was involved
in 5 eyes. In 3 of these cases the lesions were confined to the peripapillary
area. The remaining eyes had lesions in the peripheral retina. In 2 cases,
both peripapillary and peripheral retina were involved. The lesion in the
peripheral retina of the 32-week-old fetus was unusual compared with other
retinal lesions. Unlike other cases that showed evidence of continuing inflammation,
this lesion was almost devoid of inflammatory cells. At the edge of this lesion
the retina showed abnormal maturation with loss of distinction of nuclear
layers and formation of Flexner-Wintersteiner rosettes (Figure 1B, bottom). Distant from this lesion the retina had appropriate
maturation for gestational age. These appearances were interpreted as a form
of focal retinal dysplasia. In addition to focal retinal lesions, there was
retinal gliosis and neovascularization in 5 eyes (Figure 1C, right). In 3 eyes in which no focal retinal lesions were
identified, the retina was normal in 2 eyes but showed widespread gliosis
and neovascularization in 1 eye.
Inflammation extended into the vitreous in 7 eyes with condensation
bands, scattered inflammatory cells, and necrotic debris. Remnants of the
tunica vasculosa lentis were identified in 9 eyes. The hyaloid artery and
primary vitreous were present in 2 eyes, and were surrounded by inflammatory
cells (Figure 1D).
The optic nerve was present in sections from 8 eyes and was normal in
only 3 eyes. In 5 eyes there was a leptomeningitis associated with optic neuritis
(Figure 1E and 1F). In 3 of these
eyes, the nerve architecture was disrupted. In 2 of the eyes with optic neuritis
there was a peripapillary lesion.
INFANT EYES
Both eyes from the 7-day-old infant had a large retinal detachment with
atrophy of the photoreceptors and a subretinal serous exudate (Figure 1C, left). There was bilateral extensive retinal necrosis
with lesions extending from the pars plana to the posterior pole. Within the
areas of retinal necrosis there were scattered pigment granules and focal
calcification. The adjacent RPE was disrupted, showing tubuloacinar proliferation.
There was diffuse choroiditis. Elsewhere the RPE was intact; however, the
retina showed edema, gliosis, and mononuclear cell infiltration. There was
an organizing vitritis with continuing inflammation. The optic nerve was not
present in sections examined.
In the eye from the 5-day-old infant there was also a large retinal
detachment with subretinal exudate and atrophy of photoreceptors (Figure 1C, left). However, there were only
small foci of retinal necrosis and the RPE was intact. The retina showed changes
similar to those described above, but in addition there were collections of
intracellular organisms. The optic nerve showed leptomeningitis. Condensation
bands were present in the vitreous with necrotic debris and mononuclear cells.
In both cases the anterior segment was normal.
CHILD EYES
Both eyes showed features of end-stage disease. The right eye contained
2 retinochoroidal scars situated in the posterior pole and superior region
of the peripheral retina (Figure 1A,
bottom). Overlying these lesions there was organization of the vitreous. The
left eye was firm, partially collapsed, and smaller than the right eye. On
opening, the anterior chamber was shallow with a cataractous lens displaced
into the posterior chamber. Within the posterior chamber there was massive
retinal gliosis.
INFLAMMATORY CELLS
Findings were similar for both fetal and infant eyes and are summarized
in Table 2 and illustrated in Figure 2. The inflammatory cells present
in the lesions consisted of lymphocytes, plasma cells, and macrophages. Immunohistochemical
staining showed both B and T lymphocytes. Overall, T lymphocytes predominated
although scattered B lymphocytes were present, confined mainly to the choroid.
There were focal collections of T lymphocytes in the choroid underlying lesions
and in the retina adjacent to lesions (Figure
2B). These were of both CD4+ and CD8+ subtypes although CD4+ cells
predominated (Figure 2C). In addition,
in the cases with optic neuritis, the nerve contained B cells as well as T
cells of both CD4+ and CD8+ subtypes. Similar to the inflammatory infiltrate
in the retina and choroid, CD4+ T cells predominated in the optic nerves.
The eye from the 32-week-old fetus and both eyes from the 2-year-old child
contained only rare lymphocytes. In 2 fetal eyes numerous macrophages were
identified in the choroid underlying retinal lesions (Figure 2D). In all other eyes only occasional macrophages were identified
within the choroid.
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Table 2. Immunohistochemical Staining for Inflammatory Cells and Toxoplasma gondii Antigens in Congenital Toxoplasmosis*
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Figure 2. Inflammatory cells and Toxoplasma gondii organisms present in ocular toxoplasmosis. A through D represent
the same discrete ocular lesion from a 21-week-gestation fetus with a peripapillary
lesion. A, Disruption of the retinal pigment epithelium (RPE) with choroidal
congestion and inflammation (hematoxylin-eosin, original magnification x400).
Immunohistochemical staining for T cells, CD3 (B) and T-cell subset. CD4 (C),
shows numerous positive lymphocytes within the choroid (arrows). D, In this
case CD68-positive macrophages are numerous within the choroid underlying
the area of RPE disruption (arrows). No staining was identified in the negative
control or in sections stained with anti-CD8 (not shown). E and F demonstrate
staining for T gondii. E, left, Retina from the 5-day-old infant
showing a collection of intracellular T gondii within the retina
(arrow) (hematoxylin-eosin, original magnification x100). Note the small
blood vessel (v). The inset shows a high-power view of these organisms (hematoxylin-eosin,
original magnification x400). Right, Retina from the 5-day-old infant
eye showing immunohistochemical staining for T gondii antigen.
Note the same small blood vessel (v) also identified in E, left. Many extracellular
T gondii organisms are identified (arrows). In addition, the
inset shows the presence of organisms in a perivascular location (L43 stain,
original magnification x100 and x250). F, left, Gliotic retina
in an eye from a 22-week-gestation fetus showing extracellular organisms scattered
throughout the retinal layers (arrows) (polyclonal antibody, original magnification
x250). Right, Disrupted retina and necrotic debris in an eye from a
23-week-gestation fetus. Numerous extracellular T gondii organisms
(arrows) are present within the necrotic debris (L43 stain, original magnification
x400). The red staining product allows distinction from melanin pigment
granules (pg) of disrupted RPE.
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PRESENCE OF T gondii
Immunohistochemical staining for T gondii was
negative in control eyes. The findings are summarized in Table 2 and illustrated in Figure
2 E and 2F. Tissue cysts were not seen by light microscopy in any
of the eyes, although, as previously mentioned, collections of intracellular
organisms were identified in the eye from the 5-day-old infant.15
Immunohistochemical analysis for T gondii antigens
demonstrated extracellular organisms and amorphous antigens in 10 eyes (7
fetal, 3 infant, and 0 child) and 9 eyes (6 fetal, 3 infant, and 0 child),
respectively. In the fetal eyes the parasites were most numerous within the
retina immediately adjacent to areas of necrosis. In the 5-day-old infant's
eye, in addition to the groups of intracellular parasites seen by light microscopy,
numerous extracellular parasites were apparent in the abnormal retina with
immunohistochemical staining. In one area parasites were identified surrounding
an inner retinal vessel. In the 7-day-old infant's eye, very few parasites
were identified despite the presence of extensive necrosis.
Parasites were not identified within the choroid despite the presence
of numerous inflammatory cells. In 1 fetal eye with optic neuritis, a few
extracellular parasites were identified in the perivascular space around the
central retinal vessels. However, parasites were not identified within the
substance of the optic nerve.
COMMENT
Retinitis, retinal necrosis, and disruption of the RPE with marked choroidal
inflammation and congestion are the characteristic findings in the eyes of
fetuses with congenital toxoplasmosis. These lesions represent irreversible
in utero damage to the retina. They frequently affect extensive areas including
the peripapillary area, posterior pole, and peripheral retina. The 2 infants
in this study had severe ocular disease with retinal necrosis, retinal detachment,
and large subretinal exudates. Within the surviving retina there was neovascularization
and gliosis. Much of this damage must have occurred in utero since postnatal
survival was only a few days.
It is not possible to document the kinetics of T gondii infection in human fetuses in utero. In this study, the time from
maternal seroconversion to fetal diagnosis and subsequent termination of pregnancy
estimated the maximum length of fetal infection to be on average 11.5 weeks.
However, in reality, it is probably much shorter than this because there is
a delay between maternal and fetal infection.16
The length of this delay varies but can be longer than 16 weeks. In addition,
delay between fetal infection and ocular involvement may occur. Furthermore,
unlike an animal model, in human infections, it is rarely feasible to document
the clonal derivation of the parasite (ie, clonal type I, II, or III),17 parasite life cycle stage, or the size of the inoculum
with which the mother has been infected. Despite these differing parameters,
the findings in the fetal eyes are remarkably similar and seem to represent
a continuum of the same process. Specifically, retinal necrosis occurs in
the acute lesions of ocular toxoplasmosis. As these lesions heal they leave
an early scar devoid of normal retina but with proliferation of the RPE. The
end stage of this process is formation of a retinochoroidal scar. End-stage
scars such as these were seen in the eyes from the 2-year-old child.
Acute retinitis with necrosis may also be seen in children and adults
following reactivation of ocular toxoplasmosis.10
This is rarely as extensive as that seen in the fetus except in the immunocompromised
host.18
Clinically established retinochoroidal scars have been identified at
birth in some infants,8, 19 implying
that ocular damage, healing, and repair can all occur in utero. Indeed a retinochoroidal
scar, almost devoid of inflammatory cells, was the main abnormality detected
in the eye of the 32-week-old fetus. Adjacent to this scar, the retinal disorganization
and rosettes, which we consider to represent a form of retinal dysplasia,
was an unusual finding. Retinal dysplasia occurs most frequently with multiple
congenital anomalies associated with chromosomal aberrations.20-21
At necropsy, this fetus (case 10) was not dysmorphic and showed no evidence
of any malformations other than those associated with congenital toxoplasmosis.
In addition, the retinal dysplasia was confined to the area immediately adjacent
to the scar.
To our knowledge this is the first report of retinal dysplasia associated
with T gondii infection. There have been several
reports of infectious agents other than T gondii
causing retinal dysplasia in animals. For example, retinal dysplasia develops
in 2-day-old hamsters but not 25-day-old hamsters following intracerebral
injection of measles virus.22 Similarly, retinal
dysplasia was the most common finding following intraocular injection of feline
leukemia virus into fetal kittens.23 Finally,
canine herpesvirus infection in puppies produces severe ocular inflammation
with subsequent retinal dysplasia.24 The mechanism(s)
whereby these infectious agents cause abnormal retinal development remains
to be determined. However, it has been postulated that progressive disorganization
of the retina and necrosis are followed by differential repair of the retinal
layers.23-25 Furthermore,
the RPE seems to be important in normal retinal development.20-21
Therefore, disruption of the RPE also may contribute to retinal dysplasia
and rosette formation, perhaps owing to loss of polarity of retinal cells
or lack of specific growth or maturation factors produced by the RPE.26-27 Both retinal necrosis and RPE disruption
occur in ocular toxoplasmosis. This form of retinal dysplasia might therefore
represent a rare complication of early T gondii infection
where the insult occurs prior to organization of the retinal layers.
The location of lesions is important because patients are at risk for
visual loss if tissues such as the macula or optic nerve are involved. In
clinical studies there seems to be a definite predilection for the macular
region in patients with congenital toxoplasmosis. In the Chicago study, peripheral
scars were present in 64% of patients whereas macular scars were present in
58%.8 Considering the much smaller area of
the macula, these results support a predilection for the macular region.
The development of the macular region is markedly retarded relative
to that of the rest of the retina and differentiation in this region continues
for at least the first 4 years of life.28 In
view of this lack of specialization and small size we were unable to identify
the macular region in the fetal or infant eyes. However, where lesions were
extensive and involved the posterior pole, it seems likely that the cells
that form the macula were involved.
In congenital infection, T gondii probably
reaches the eye by a hematogenous route. The identification of parasites around
an inner retinal vessel in one of our cases supports a hematogenous route.
Therefore, this predilection for the posterior pole may reflect the fact that
it is vascularized earlier in development than other portions of the retina.
In addition, although the macula is avascular, it obtains its blood supply
from end arterioles, which form a capillary plexus around it. Lodging of parasites
in these capillaries could facilitate establishment of infection in this delicate
region of the eye.
The optic nerve was present in sections from only 8 fetal eyes; however,
optic neuritis was present in 5 of these with distortion of the normal nerve
architecture in 3 cases. Distortion of the nerve architecture may represent
another instance in which inflammation of a structure early in gestation results
in its abnormal development. Because of a lack of appropriate neural connections,
optic atrophy may be the clinical outcome in surviving patients. In the Chicago
study, optic atrophy was present in 20% of patients with congenital toxoplasmosis.8 However, fetuses in our study were known to have intracranial
disease with ventricular dilatation and optic neuritis may simply reflect
the severity of encephalitis. Papillitis, papilledema, and optic atrophy are
recognized clinical manifestations of toxoplasmic encephalitis.8, 29
True optic neuritis is a rare complication of disease reactivation,
although T gondii may involve the optic disc or retina
immediately adjacent to the optic disc, resulting in a papillitis sometimes
referred to as Jensen juxtapapillary retinitis.30 This may represent a clinical correlate for the 2
cases of optic neuritis associated with a peripapillary lesion. Optic neuritis
with necrosis and numerous parasites has been described in a patient with
human immunodeficiency virus–associated ocular toxoplasmosis31 and a patient with fulminant congenital infection.32 This has led to the suggestion that congenital infections
may be transmitted to the eye from the brain via the optic nerve. Alternatively,
parasites infecting the eye anlage may accompany it to the developing eye.
However, in our cases although there was inflammation and distortion of the
normal nerve architecture, there was no necrosis or parasites. It is possible
that the inflammatory response had killed parasites within the optic nerve.
However, it seems unlikely that the optic nerve is the usual means of T gondii spread to the eye. Indeed the presence of parasites
in the optic nerve may simply reflect hematogenous spread via the ocular branches
of the ophthalmic artery. This is supported by the finding of a few parasites
surrounding the central retinal artery in 1 fetal eye.
Immunity to T gondii requires a cell-mediated
immune response that involves macrophages, natural killer cells, and their
monokine and cytokine products.33 In particular
interferon  (IFN-) seems to be a critical cytokine for effective
immunity.34 The fetus and neonate are unduly
susceptible to infections with intracellular pathogens such as T gondii. Nonetheless, the presence of inflammatory cells in the eyes
of infected fetuses suggests that the fetus is capable of mounting, albeit
a less-effective, immune response to T gondii infection.
Early in gestation the numbers of T cells and their repertoire for recognition
of antigens are limited compared with the latter half of gestation.35 Indeed, infants with congenital toxoplasmosis have
absent or diminished lymphocyte blastogenic responses to T gondii antigen and production of interleukin 2 and IFN- is
reduced.36 Their lymphocytes are, however,
capable of responding normally to other stimuli. This anergy to T gondii may reflect differences in route of acquisition, cytokine
environment, or costimulatory molecules present during gestation. Murine models
have shown that the cytokines IFN-, tumor necrosis factor  ,
and CD4+ and CD8+ lymphocytes are important in acquired ocular toxoplasmosis.37 Since T lymphocytes are clearly present in the fetal
eye at the time of infection, a decreased production of IFN- or other
cytokines by these lymphocytes may contribute to tissue destruction through
uncontrolled parasite proliferation. In our future studies we will examine
local cytokine production and distribution of costimulatory molecules in these
fetal eyes using immunohistochemical techniques.
Tissue cysts were not identified in the eyes of any of the fetuses or
infants by light microscopy, although they were identified in the brains of
5 of 7 fetuses and in 1 infant. In the immunocompetent adult, tissue cysts
may be found at the edge of retinochoroidal scars or within apparently normal
retina at some distance from previous lesions.38
Encystment usually occurs with the onset of effective immunity and studies
have shown a role for immune mediators, such as IFN-, in tachyzoite
to bradyzoite conversion and thus cyst formation.39
Extracellular organisms were present in lesions, particularly in areas of
necrosis, and numerous intracellular parasites were present in 1 infant case.
This may reflect the early acute nature of this disease in the eye as well
as a lack of effective immunity.
Our work demonstrates that significant irreversible ocular disease can
occur in utero. This finding has substantial implications for fetal and infant
treatment. In countries such as France that have prenatal screening programs,
studies suggest that antimicrobial treatment in utero may reduce ophthalmic
disease caused by this parasite.40-41
Similarly, early postnatal treatment of toxoplasmosis is associated with prompt
resolution of active retinochoroiditis.8 Documentation
of the early stages of this disease in unsuccessful pregnancies is therefore
important to allow clinical comparisons and assess effectiveness of therapies.
Further studies to examine the ocular immune response may help us understand
the complex interactions between the immature host and T gondii in the eye. A nontoxic, nonteratogenic medicine that crosses
the placenta and that kills tachyzoites and bradyzoites and that can be used
early in gestation as soon as infection is diagnosed is needed.
AUTHOR INFORMATION
Accepted for publication June 23, 2000.
This work was supported by grant AI 27530 from the National Institutes
of Health, Bethesda, Md; Research to Prevent Blindness Inc, New York, NY;
and the Toxoplasmosis Research Institute, Chicago, Ill. Dr Roberts received
a traveling fellowship from the Pathological Society of Great Britain and
Northern Ireland, London. Dr McLeod is the Jules and Doris Stein Research
to Prevent Blindness Professor at the University of Chicago.
We thank Jack Frenkel, MD, PhD, for providing tissue, helpful discussions,
and advice. We also thank Vicki Aitchison and Ellen Holfels for their excellent
assistance in preparation of the manuscript.
Corresponding author and reprints: Rima McLeod, MD, Department of
Ophthalmology/Visual Sciences, University of Chicago, 939 E 57th St, Chicago,
IL 60637 (e-mail: rmcleod{at}midway.uchicago.edu).
From the Department of Medicine, Michael Reese Hospital, Chicago, Ill,
and the Department of Pathology, Victoria Infirmary, Glasgow, Scotland (Dr
Roberts); Department of Ophthalmology, Children's Memorial Hospital, Northwestern
University, Chicago (Dr Mets); Nuffield Department of Pathology, John Radcliffe
Hospital, Oxford University, Oxford, England (Dr Ferguson); Department of
Ophthalmology, Northwestern University Medical School, Chicago (Dr R. O'Grady
and Ms C. O'Grady); Toxoplasmosis Laboratory, Institute of Puericulture of
Paris, Paris, France (Dr Thulliez); Department of Ophthalmology, Hopital Cochin,
Paris (Dr Brézin); and the Departments of Ophthalmology, Medicine,
and Pathology and Committees on Immunology and Genetics, The University of
Chicago (Dr McLeod).
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