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Ocular Toxoplasmosis
A 50th Anniversary Tribute to the Contributions of Helenor Campbell Wilder Foerster
Gary N. Holland, MD;
Kevan G. Lewis, MS;
G. Richard O'Connor, MD
Arch Ophthalmol. 2002;120:1081-1084.
ABSTRACT
In 1952, Helenor Campbell Wilder (later Helenor Campbell Wilder Foerster)
confirmed the growing suspicion that Toxoplasma gondii
was a cause of uveitis in otherwise healthy adults by identifying the presence
of parasites in eyes enucleated because of severe intraocular inflammation.
Ocular toxoplasmosis was previously known to occur only in newborns with congenital T gondii infection. Her report ushered in a new era in
the field of uveitis in which toxoplasmosis, rather than tuberculosis, was
confirmed to be the most common cause of retinochoroiditis. Fifty years later,
issues raised in her landmark publication are still being investigated.
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It has been said that the contributions of Helenor Campbell Wilder Foerster
(1895-1998) advanced the field of ophthalmic pathology 50 years.1
Among her most important accomplishments was the confirmation of the presence
of Toxoplasma gondii in retinal tissue of adult eyes
with posterior uveitis.2-3 Her
observations were described in the article "Toxoplasma Chorioretinitis in
Adults,"3 which was published 50 years ago
this month in the ARCHIVES. It is appropriate on this anniversary to revisit
that landmark publication and to reflect on the profound impact that it has
had on the field of uveitis.
Wilder2-3 was the first
to recognize T gondii histopathologically in necrotic
retinochoroidal lesions of adults. She performed her work in an era when tuberculosis
was assumed to be the most common cause of granulomatous uveitis.4-5 In 1941, for example, Guyton and Woods5 attributed almost 50% of uveitis cases to tuberculosis.
Ironically, many of the specimens in which Wilder visualized T gondii had actually been photographed for inclusion in a teaching
manual as examples of ocular tuberculosis. The implication of her observations
was that a substantial proportion of cases diagnosed previously as ocular
tuberculosis were, in fact, toxoplasmosis and that T gondii should be considered an important cause of uveitis in adults. Within
a decade, it was recognized that ocular tuberculosis was in fact rare, while
ocular toxoplasmosis became accepted as the most common cause of posterior
uveitis.
At the time of her discovery, Wilder was Head of the Ophthalmic Pathology
Section of the Armed Forces Institute of Pathology (Washington, DC). In her
article3 (and in an earlier preliminary communication2), she presented histologic data from 53 eyes that
had been enucleated because of pain and blindness. Patient ages ranged from
14 to 83 years. Retinochoroidal lesions were present in all eyes, but the
globes had been enucleated from a diverse group of patients. There had been
a history of direct injury to the eye, at various intervals before enucleation,
for 13 patients, but in only 3 was the eye penetrated. One patient had diabetes
mellitus; 2 had rheumatoid arthritis; 1 had a history of severe tonsil and
tooth infections; 1 had a history of gallbladder attacks and heart failure;
and 1 had had a sore throat when retinochoroiditis was first noted. A variety
of clinical diagnoses had been considered, including neoplasia. Among the
53 cases, 37 were submitted with a prior clinical diagnosis of uveitis; 9
of the 37 were thought to be tuberculosis. Although 3of the 53 patients were
known to have positive Sabin-Feldman dye tests for anti–T gondii antibodies, with titers of 1:64 or 1:256, diagnoses of ocular
toxoplasmosis were apparently not considered.
In many cases, a histopathologic diagnosis had not been made before
submission to the Armed Forces Institute of Pathology; 20 were simply identified
as having granulomatous retinochoroiditis of undetermined cause. Syphilis
was diagnosed in 3 eyes, and the remaining 30 came with a prior histopathologic
diagnosis of tuberculosis or possible tuberculosis.
On examination, Wilder found all 53 specimens to have lesions that were
granulomatous with central necrosis. Disease was observed in the retina, choroid,
and sclera. Within the necrotic areas of retina, she observed organisms, 3
to 5.3 µm in length, with morphologic characteristics consistent with T gondii. These crescentic forms of the parasite (trophozoites)
were found in pairs or rosettes (Figure 1) and were characteristically rounded on one end and pointed on
the other, with large nuclei displaced toward the blunt end. Spherical forms
(bradyzoites within tissue cysts) were also found in what Wilder called "pseudocysts."
In another illustration, she showed tissue cysts, which she described as "cystoid
structures, possibly pseudocysts with dead organisms" (Figure 2). We now know, of course, that these tissue cysts contain
living bradyzoites. Histologic examination of a lymph node biopsy specimen
from one patient also showed lesions morphologically similar to the ocular
lesions.
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Figure 1. Two side-by-side trophozoites
("crescentic forms") within a focus of necrotizing retinochoroiditis are seen
in the center of this field (hematoxylin-eosin, original magnification x1260).
These crescentic forms can be overlooked easily by unskilled observers. This
illustration appeared as Figure 9C in Wilder's 1952 article.3
Reproduced from the original negative.
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Figure 2. A large, spherical tissue cyst
containing bradyzoites is present in a focus of necrotizing retinochoroiditis
(hematoxylin-eosin, original magnification x1260). This illustration
appeared as Figure 5B in Wilder's 1952 article.3
Reproduced from the original negative.
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In her article, Wilder stated that the method of preparation, using
celloidin (rather than paraffin) for embedment of specimens, and oil-immersion
light microscopy, were reasons that she was able to observe the organisms,
while others had overlooked them for so many years.3
Pseudocysts could be seen in paraffin-embedded sections, but crescentic forms
were observed only by oil-immersion examination of celloidin-embedded sections.
At that time, the Armed Forces Institute of Pathology was routinely embedding
all specimens in celloidin.
Robert Y. Foos, MD, Emeritus Professor of Pathology at UCLA (Los Angeles,
Calif), agrees that oil immersion facilitates the identification of parasites
(oral communication, September 2001). As a young ophthalmic pathologist attending
the Western Pathology Club (precursor to the Michael Hogan Society) in San
Francisco during the early 1960s, he commented that he could not see parasites
in a tissue specimen containing T gondii that meeting
attendees were examining. An older, distinguished woman sitting next to him
suggested that he look through her microscope. That woman was Helenor Campbell
Wilder, and through her microscope, which was set up for oil immersion, parasites
were clearly visible. Foos also agrees that celloidin embedment is a particularly
good technique for identifying T gondii in tissue.
This technique offers the advantage of a thicker section (16 µm); the
greater amount of tissue allows the observer to focus up and down through
a section, providing a better sense of its 3-dimensional aspects than the
thinner sections (8 µm) that are cut after paraffin embedment. With
thinner sections, unless they are fortuitously sectioned through their long
axes, trophozoites will appear as small round or oval figures that may not
be recognized as parasites. Nevertheless, many subsequent investigations have
shown that celloidin embedment is not necessary for demonstration of T gondii in tissue. As one example, Holland et al6 later clearly demonstrated both trophozoites and tissue
cysts by light microscopy in paraffin-embedded tissue from the eyes of patients
with acquired immunodeficiency syndrome (AIDS). Celloidin is not routinely
used now because of the excessive time required (up to 6 weeks) for it to
harden sufficiently for sections to be cut.
One cannot attribute Wilder's success to laboratory methodology alone.
The reason that she could find T gondii in so many
specimens, while others before her could not, has been a subject of discussion
for many years. She once told one of us (G.R.O.) that she had been daydreaming
about Christmas shopping and other subjects when she recognized the presence
of the parasites, but she was being characteristically modest. Everyone who
knew her was familiar with the diligence and care with which she evaluated
histologic preparations. Wilder later attributed her discovery to curiosity
over the morphologic characteristics of retinochoroidal lesions.7
According to William H. Spencer, MD, an ophthalmic pathologist who worked
closely with Wilder during many years, she also attributed her observations
to "curiosity and persistence" (oral communication, September 22, 2001). Her
observation was clearly not serendipitous.
Wilder's description has been considered a watershed event in the study
of ocular toxoplasmosis, and her contribution is best understood in context.
Although the profundity of her observation is indisputable, Wilder was not
working in a vacuum. During the late 1940s and early 1950s, there was a growing
interest among investigators in the potential role of T
gondii in the pathogenesis of ocular disease in otherwise healthy adults.
In the first half of the century, ocular toxoplasmosis was known only as a
disease of newborns with congenital infection.8
With the introduction of the Sabin-Feldman dye test in 1948,9
however, it became apparent that T gondii infection
was widespread among otherwise healthy adults, a fact that stimulated great
interest in the possibility of T gondii–associated
ocular disease. For example, Vail et al10 described
a series of patients with chorioretinal lesions who had positive anti–T gondii antibody tests. Likewise, Frenkel11
and Rieger12 both reported high rates of T gondii antibodies or positive skin tests, or both, in
adults with chorioretinal lesions. These associations did not confirm causation,
of course, but did add to the growing suspicion that T gondii plays a role in adult disease. In a 1951 German-language publication,
Rieger12 suggested that T gondii infection might be responsible for ocular disease. Although
he had no histologic confirmation of this hypothesis, the article includes
a drawing of a fundus lesion that is suggestive of what we now consider to
be a typical toxoplasmic retinochoroiditis lesion. Despite these earlier publications,
it is appropriate to credit Wilder with finally confirming the link between T gondii and ocular disease through her meticulous studies.
In an era of scientific questioning, it was Wilder's observations that confirmed
the clinical suspicions and anecdotal data of her contemporaries, illustrating
the maxim that "Discovery favors the well-prepared mind."
The actual conclusions of Wilder's article were fairly limited in scope.
In the summary of her article, she said "Organisms having the morphologic
characteristics of Toxoplasma have been found in
the necrotic retina in granulomatous chorioretinal lesions in 53 eyes of adults."
Also, she went on to say that "the lesions were strikingly uniform and their
appearance had in many instances led to a pathologic diagnosis of tuberculosis."
Nevertheless, her contribution dramatically advanced our understanding of
ocular toxoplasmosis. In stark contrast to the earlier work by Guyton and
Woods5 cited already, Woods and his colleagues13 attributed 29% of their uveitis cases to toxoplasmosis
just 2 years after Wilder's report. In a 1960 publication, Woods14
stated, "The discovery of the parasite by Wilder in the chorioretinal lesions
of adults stimulated a great flood of clinical, serologic, histologic, and
experimental investigations."
Wilder also continued her own studies of ocular toxoplasmosis. In 1954,
she and her colleagues went on to characterize the original cohort further
with serologic testing on additional patients.15
All patients had positive Sabin-Feldman dye tests, and in 87.5% of cases,
titers were 1:16 or greater. These additional data strongly supported the
hypothesis that the ocular disease found in these patients was caused by T gondii infection. By their estimate, the random chance
that a cohort of patients with retinochoroiditis would all be seropositive
for T gondii infection was less than 1 in 1000.
Despite her profound discovery, Wilder's study was limited in the information
it could provide about ocular toxoplasmosis. As Wilder herself admitted, her
observations were consistent with, but did not prove, the presence of T gondii.3 She lacked the
confirmatory tests, such as immunofluorescent staining or polymerase chain
reaction identification of parasitic DNA, that would be required of a more
modern study. She provided an initial understanding of the histologic characteristics
of ocular toxoplasmosis in adult patients, but we have to remember that the
cohort she studied was a selected population, consisting exclusively of eyes
that had been enucleated because of severe disease, and thus would not be
representative of the general population, nor could it define the full spectrum
of disease. In addition, her article lacked clinicopathologic correlations
that would aid ophthalmologists in diagnosing the disease.
In retrospect, we can look at Wilder's article and realize that it foreshadowed
many of the issues we are studying today, including the role played by postnatally
acquired T gondii infections in otherwise healthy
adults with ocular disease, ocular toxoplasmosis in the immunocompromised
host, and ocular disease in the elderly. During the several decades after
Wilder's publication, it came to be assumed generally that ocular toxoplasmosis
in adults represents a late recurrence of congenital disease in nearly all
cases.16 A subject that has generated substantial
discussion, primarily in the past decade, has been the frequency with which
ocular toxoplasmosis can be related to acquired infection.17-18
We know that the prevalence of acquired ocular toxoplasmosis is much higher
in certain geographic areas, such as southern Brazil, and in some recent epidemics
than traditional teachings would lead us to predict.8
In addition, serologic evidence using new techniques confirms that recurrent
ocular toxoplasmic retinochoroiditis is more frequently a manifestation of
postnatal infection than heretofore believed.19
Wilder3 had suggested that at least some of
her subjects might have been the victims of acquired toxoplasmosis in adult
life. She gave credit for the concept of postnatally acquired T gondii to Rieger.12 In Wilder's article,
clinical information can be found that supports this contention; at least
2 patients had signs and symptoms of acquired infection. For example, they
had associated lymphadenopathy and pharyngitis, which are hallmarks of acquired,
systemic toxoplasmosis.
Questions surrounding the role of immune function in adult patients
with ocular toxoplasmosis were also planted during this time. Rieger,12 for example, had postulated that recurrences of ocular
toxoplasmosis might be related to some kind of compromise of the patient's
immunologic defense system, a rather precocious concept for the early 1950s.
The relevance of this concept would not become fully apparent until the era
of the AIDS epidemic. In recent years there have been many reports of severe,
atypical ocular toxoplasmosis among immunocompromised patients, including
those with AIDS6 and those taking immunosuppressive
drugs. The description of disease in Wilder's cases is much more reminiscent
of findings in these immunocompromised patients than it is of typical recurrent
ocular toxoplasmosis in the general population. For example, Wilder3 described infection extending to the sclera; a more
recent report described similar findings in a patient with AIDS and toxoplasmic
panophthalmitis.20 In Wilder's article,3 several patients had debilitating diseases, including
diabetes mellitus and rheumatoid arthritis, that may have compromised host
defenses. It is ironic that our understanding of "typical" ocular toxoplasmosis
arose out of a relatively atypical series, including populations that would
not be studied in detail for decades to come.
In recent years, several groups21-22
have emphasized that severe, prolonged ocular toxoplasmosis can occur in elderly
patients as well, and is more common than heretofore believed, in contrast
to the concept that evolved after Wilder's report that ocular toxoplasmosis
(at least recurrent disease) has its peak in the second and third decades
of life.23 It is interesting to note that in
Wilder's article,3 8 of the cases involved
patients whose disease might have occurred after the seventh decade of life.
The impact of Wilder's discovery demonstrates the potential of a single
observation to advance science and the understanding of disease substantially.
For its tremendous impact on the field of uveitis, we remember Wilder's seminal
article3 on this 50th anniversary of its original
publication. In doing so, we also pay tribute to the perspicacious Helenor
Campbell Wilder Foerster and her unique talents. Duke-Elder24
expressed a sentiment that was likely shared by many of her contemporaries.
Referring to an opportunity to interact with Mrs Foerster, he wrote, "To visit
her, always enthusiastically looking for something new in her uniquely rich
material, was indeed a joy."
AUTHOR INFORMATION
Submitted for publication November 15, 2001; final revision received
February 12, 2002; accepted March 27, 2002.
This study was supported in part by Research to Prevent Blindness Inc,
New York, NY (Dr Holland); the Skirball Foundation, Los Angeles, Calif (Dr
Holland); and the David May II Endowed Professorship, UCLA Department of Ophthalmology
(Dr Holland). Dr Holland is a recipient of a Research to Prevent Blindness–Lew
R. Wasserman Merit Award.
We thank Robert Y. Foos, MD, William H. Spencer, MD, and Lorenz E. Zimmerman,
MD, 3 ophthalmic pathologists who contributed to our understanding of Mrs
Wilder's contributions by sharing with us memories of their interactions with
her. Additional appreciation is extended to Dr Zimmerman, who located the
original negatives from Mrs Wilder's 1952 publication in the files of the
Armed Forces Institute of Pathology and provided them to us for reproduction
herein.
Corresponding author and reprints: Gary N. Holland, MD, Jules Stein
Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7003 (e-mail: uveitis{at}jsei.ucla.edu).
From the Ocular Inflammatory Disease Center, Jules Stein Eye Institute,
and Department of Ophthalmology, University of California, Los Angeles, UCLA
School of Medicine, Los Angeles, Calif (Dr Holland and Mr Lewis); and the
Francis I. Proctor Foundation for Research in Ophthalmology and Department
of Ophthalmology, University of California, San Francisco, School of Medicine,
San Francisco (Dr O'Connor).
REFERENCES
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