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Differentiation Between Presumed Ocular Histoplasmosis Syndrome and Multifocal Choroiditis With Panuveitis Based on Morphology of Photographed Fundus Lesions and Fluorescein Angiography
Jeffrey R. Parnell, MD;
Lee M. Jampol, MD;
Lawrence A. Yannuzzi, MD;
J. Donald M. Gass, MD;
Michael K. Tittl, MD
Arch Ophthalmol. 2001;119:208-212.
ABSTRACT
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Objective To evaluate whether inactive cases of presumed ocular histoplasmosis
syndrome (POHS) and multifocal choroiditis with panuveitis (MFC) can be differentiated
from each other by their appearance on fundus photography and fluorescein
angiography.
Methods Two masked observers classified 50 patients' photographs (27 with fluorescein
angiograms) as POHS, MFC, or "indeterminate." Twenty-five patients had known
POHS and 25 had known MFC. Statistical analysis was performed to assess agreement
and interrater reliability.
Results Observer A classified 33 patients and was indeterminate on 17. Of the
33, he was correct on 26 (79% crude accuracy;  = 0.560; 95% confidence
interval [CI], 0.286-0.834). Observer B classified 40 patients and was indeterminate
on 10. Of the 40, he was correct on 33 (82% crude accuracy; = 0.650;
95% CI, 0.422-0.878). Both observers ventured a diagnosis on 28 common patients.
Of these, they selected the same diagnosis on 26 (93% crude agreement). When
the 2 observers' diagnoses were compared and indeterminate patients were factored
in, the value was 0.408 (95% CI, 0.215-0.601). When the indeterminate
patients are excluded, the agreement increased to 0.825 (95% CI, 0.592-1).
When pictures only were available, observer A and observer B values
against the gold standard were 0.625 (95% CI, 0.270-0.980) and 0.588 (95%
CI, 0.235-0.940), respectively. The pictures-only values for observer
A vs observer B were 0.582 (95% CI, 0.316-0.848) with indeterminate patients
factored in and 1.0 (95% CI, 1.0-1.0) when indeterminate patients were excluded.
Pictures and fluorescein angiogram values were 0.493 (95% CI, 0.076-0.909)
for observer A and 0.706 (95% CI, 0.413-0.999) for observer B against the
gold standard. For observer A vs observer B, the value was 0.261 (95%
CI, -0.002 to 0.524) with indeterminate patients factored in and 0.567
(95% CI, 0.032-1) excluding indeterminate patients. Sensitivity for all cases
for observer A was 60% (±13%) for POHS and 94% (±6%) for MFC.
For observer B, the sensitivity for all cases was 70% (±10%) for POHS
and 95% (±5%) for MFC.
Conclusions Given adequate funduscopic information, the experienced observer can
often accurately distinguish between POHS and MFC without the need for ancillary
testing. Angiography in addition to fundus photography does not appear to
increase diagnostic ability. There appears to be a higher sensitivity for
MFC than for POHS.
INTRODUCTION
THE PRESUMED ocular histoplasmosis syndrome (POHS) and multifocal choroiditis
with panuveitis (MFC) share many common features that may make their distinction
difficult. Both conditions may show punched-out chorioretinal scars, peripapillary
scarring, and choroidal neovascularization.1
Certain features of MFC, such as the presence of anterior chamber and vitreous
inflammation, active yellow-gray choroidal lesions that leak on angiography,
and the development of photopsias and visual field defects during acute episodes,
help in making an accurate differentiation.1
Alternatively, patients with POHS by definition have no evidence of anterior
chamber reaction or vitritis and often have a positive reaction to Histoplasma capsulatum antigen skin testing.2
This fungal organism is endemic to the Mississippi and Ohio River valleys,
where there is a high incidence of POHS.3 Previous
infection by histoplasmosis can result in calcified hilar adenopathy on chest
x-ray examination and the characteristic eye findings. HLA test results are
often positive for the DR2 antigen in individuals with POHS and the B7 antigen
in individuals with POHS and choroidal neovascularization, whereas patients
with MFC do not have these haplotypes.4-6
In the absence of active inflammation, the chorioretinal scarring of
these diseases is similar, and the correct diagnosis is much less easily made.
It is important to make the correct diagnosis as this may influence the treatment
and prognosis. This study was undertaken to assess the ability of experienced
observers to reliably make a correct differentiation, using masked clinical
photographs and fluorescein angiograms, between inactive cases of POHS and
MFC.
A disease similar to MFC but without the vitritis seen in the active
phase is called punctate inner choroidopathy (PIC).7
For purposes of this article, MFC and PIC are considered the same disease.
MATERIALS AND METHODS
A set of 50 patients' photographs serving as a gold standard for the
study was selected from a file archive of one of the authors (L.A.Y.). Informed
consent was obtained. Twenty-five patients had known POHS and 25 had known
MFC. To make these diagnoses, the patients previously had undergone detailed
clinical ophthalmic and medical examination and histoplasmin skin testing,
HLA-DR2 testing, and chest x-ray examination. All cases of MFC had demonstrated
evidence of vitreous inflammation at some point. By definition, this excluded
most cases of PIC, which do not show vitritis, even during the active phase.
Conversely, the POHS cases could never have had any evidence of vitritis.
For purposes of this study, the concept of a gold standard is imperfect since
there is no definitive test that will correctly identify cases of POHS or
MFC with 100% sensitivity and specificity. Some patients with POHS have negative
skin test results, and some patients who live in endemic areas for Histoplasma can have a positive skin test result but true MFC. We acknowledge
that some patients, especially those with few or nondescript fundus changes
and those with resolved vitritis, could have their conditions misdiagnosed
in the reference file. For this reason, a constellation of findings and tests
was used to best determine the most likely diagnosis in creating the gold
standard photofile. Attempts were made to exclude patients with other retinal
diseases to avoid confounding information.
To be eligible for inclusion as 1 of the 50 cases, the photographs had
to contain posterior pole and midperipheral images of the chorioretinal scarring.
No photographs that had evidence of obvious media haze were allowed to avoid
this sign as bias for MFC.
Twenty-seven patients had fluorescein angiograms included with the color
photographs to evaluate the value of fluorescein angiography in distinguishing
between the 2 disorders. Fourteen of the 27 had known POHS and 13 had MFC.
The photograph sets were duplicated, coded, masked, and randomized for
distribution to the observers, designated A (L.M.J.) and B (J.D.M.G.). The
observers were instructed to independently evaluate each case as MFC, POHS,
or "indeterminate." The indeterminate category was added for cases in which
the observer deemed there was inadequate representation of lesions, poor photographic
coverage, or confounding abnormalities. All patients' photographs were nonstereoscopic.
The diagnostic sheets of each observer were then sent back to the originating
center for comparison against the master list of the gold standard.
Both observers formulated their own criteria in selecting their diagnosis
(Table 1). For observer A, a diagnosis
of MFC was facilitated by clusters of lesions, growth of lesions, bridging
subretinal scars, myopic disc changes, hyperplastic retinal pigment epithelium
(RPE), RPE changes between scars, sheathing of vessels, and subretinal fibrous
hyperplasia around the disc.
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Table 1. Observer Criteria for Multifocal Choroiditis With Panuveitis
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Observer B used the following characteristics for MFC: multiple small
white or yellow chorioretinal lesions, often clustered in the macula, some
appearing atrophic (punched out), and others appearing more solid; multiple
foci of tightly clustered atrophic and/or solid small chorioretinal lesions
in the peripheral fundus; RPE changes between focal scars; subretinal fibrous
metaplasia of the RPE; intraretinal migration of RPE; and narrowing of retinal
vessels in the zones of RPE changes.
The sizes of the lesions and the presence of disciform scars, choroidal
neovascular membranes, and Schlaegel lines8
were deemed not helpful.
Activity was not relevant to the patients in this study because active
cases were excluded. For both observers, MFC could be diagnosed in the face
of obvious inflammation: active white lesions, vitritis, and disc blurring
with leakage and cystoid macular edema.
Statistical analysis that incorporated chance-expected agreement into
the assessment of interrater reliability was performed to measure agreement.
When comparing the observer vs the gold standard, values were generated
excluding indeterminate patients. However, the values were calculated
with and without the indeterminate patients factored in when the observers'
responses were compared with each other. Additional analysis was performed
to evaluate the agreement when a fluorescein angiogram was included with the
photographs vs cases that had color photographs only. A value greater
than 0.75 denotes excellent agreement, a of 0.4 to 0.75 denotes good
agreement, a of 0 to 0.4 denotes marginal agreement, and less
than 0 indicates that observed agreement is less than chance agreement.
RESULTS
The demographic information regarding the study patients is presented
in Table 2. There were a total
of 50 patients, 25 in each group. The average ± SD age was 31.1 ±
9.1 years for the MFC group and 35.1 ± 10.5 years for the POHS group.
Women constituted 23 (92%) of the 25 patients in the MFC group, but only 10
(40%) of the 25 patients in the POHS group. The MFC group was more myopic,
with an average spherical equivalent of -3.1 ± 3.8 diopters (D)
vs -1.9 ± 2.7 D for POHS patients. Twenty-one patients in the
POHS group had a histoplasmin skin test performed, and 18 (86%) had a positive
reaction. Twenty-two patients in the MFC group had histoplasmin skin testing,
and none had a positive reaction. Chest x-ray films were obtained for 20 POHS
patients, and 9 had evidence of granulomatous hilar adenopathy and/or calcifications.
Only 6 patients with MFC had chest x-ray films obtained, with none showing
abnormalites. All cases of MFC had previous documentation of vitritis. Conversely,
no cases of POHS by definition had vitritis.
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Table 2. Patient Demographics
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Observer A classified 33 patients as having POHS or MFC and 17 as indeterminate.
Of the 33, he was correct on 26 (79% crude accuracy; = 0.560; 95%
confidence interval [CI], 0.286-0.834). Observer B classified 40 patients
as having POHS or MFC and 10 as indeterminate. Of the 40, he was correct on
33 (82% crude accuracy; = 0.650; 95% CI, 0.422-0.878).
Each observer was asked to judge the quality of the indeterminate photographs
and/or make comments on the reasons for rating them indeterminate. Observer
A qualified 14 of 17 indeterminate photographs as good quality, 2 of 17 as
adequate, and 1 of 17 as inadequate. In 8 of 17, he specifically stated that
there were too few lesions to judge. Observer B judged 1 of 10 of his indeterminate
patients as good quality, 4 of 10 as adequate, and 5 of 10 as inadequate.
In 2 of 10 cases, he thought there were too few lesions and in another 2 of
10 the fundus appearance was confounded by myopic changes. Of the total indeterminate
patients between both observers (22 cases), there were 5 common patients.
For observer A, 16 (48%) of 33 rated patients had color photographs
only. He was correct on 13 (81%) of 16 ( = 0.625; 95% CI, 0.270-0.980).
Seventeen (52%) of 33 cases had photographs and fluorescein angiography. He
made a correct selection in 13 (76%) of the 17 ( = 0.493; 95% CI, 0.076-0.909).
For observer B, 20 (50%) of 40 rated patients had color photographs, and he
was correct on 16 (80%) of 20 ( = 0.588; 95% CI, 0.235-0.940). The
other 20 had color photographs and fluorescein. He selected correctly on 17
(85%) of 20 ( = 0.706; 95% CI, 0.413-0.999).
In terms of concordance, both observers ventured a diagnosis for 28
common patients. Of these, they selected the same diagnosis for 26 (93% crude
agreement) and, therefore, only differed on 2 patients. When the 2 observers'
responses were compared and indeterminate patients were factored in, the
value was 0.408 (95% CI, 0.215-0.601). If the indeterminate patients are excluded,
the agreement was 0.825 (95% CI, 0.592-1). Fifteen of 28 common patients
had color photographs only. Of these, the observers were correct on 12 (80%).
The 3 patients for whom they selected the incorrect diagnosis were the same
for both observers. The values for observer A vs observer B (color
photograph only patients), therefore, were 0.582 (95% CI, 0.316-0.848) with
indeterminate patients factored in and 1.0 (95% CI, 1.0-1.0) when indeterminate
patients were excluded. Thirteen of 28 had an angiogram in addition to color
photographs. Observer A was correct on 9 (69%) of 13 and observer B was correct
on 11 (85%) of 13. The values for observer A vs observer B (color
photographs and angiogram) were 0.261 (95% CI, -0.002 to 0.524) with
indeterminate patients factored in and 0.567 (95% CI, 0.032-1) excluding indeterminate
patients. Observer A was correct on 24 (86%) and observer B was correct on
26 (93%) of the 28 common patients whose conditions they attempted to diagnosis.
Observer A classified 17 as indeterminate and made a diagnosis for 33.
Seven (41%) of the indeterminate cases had MFC and 10 (59%) had histoplasmosis.
Observer B classified 10 as indeterminate and attempted a diagnosis on 40.
Five (50%) of his indeterminate cases had MFC and 5 (50%) had histoplasmosis.
Twenty-three (70%) of 33 of observer A's diagnosed cases had MFC and
10 (30%) of the 33 had histoplasmosis. Observer A was correct on 17 (74%)
of 23 cases with MFC and 9 (90%) of 10 cases with histoplasmosis. Twenty-five
(62%) of 40 of observer B's diagnosed cases had MFC and 15 (38%) of 40 had
histoplasmosis. He was correct for 19 (76%) of 25 patients with MFC and 14
(93%) of 15 patients with histoplasmosis.
Analysis of the incorrect selections revealed that observers A and B
were incorrect for 7 (21%) of 33 and 7 (18%) of 40, respectively. Five (71%)
of 7 incorrect selections were common patients for observers A and B. Three
had pictures only and 2 had pictures and an angiogram. All 5 of the common
patients whose conditions were incorrectly diagnosed had known POHS but were
thought to have MFC by the observers. For each observer, 6 (86%) of the 7
incorrect selections had known POHS but were called MFC. Thus, only 1 of 7
for each observer had known MFC but was misdiagnosed as POHS. The observers
were much more likely to misdiagnose cases with POHS as MFC than the reverse
scenario.
Each observer's sensitivity for a particular diagnosis was as follows.
The sensitivity of observer A for all cases was 60% (±13%) for POHS
and 94% (±6%) for MFC. When he had pictures only, sensitivity was 63%
(±17%) for POHS and 100% for MFC. With pictures and fluorescein angiography,
sensitivity for POHS was 57% (±19%) and 90% (±9%) for MFC. The
sensitivity of observer B for all cases was 70% (±10%) for POHS and
95% (±5%) for MFC, 67% (±6%) for POHS and 91% (±9%) for
MFC with pictures only, and 73% (±13%) for POHS and 100% for MFC with
pictures and fluorescein angiography.
COMMENT
This study shows that experienced observers can usually distinguish
correctly between inactive cases of POHS and MFC by noting differences in
fundus appearance between these 2 disorders.
These entities do resemble each other.9
Differentiating features between these 2 conditions are the presence or absence
of inflammation and progressive vision loss due to the waxing and waning nature
of MFC. Patients with MFC are usually female. At the time of presentation
with acute lesions or thereafter when inactive, they may have an enlarged
blind spot or, less frequently, other visual field defects not explained by
fundus changes. The same is true for photopsia.1, 10
In contrast, patients with POHS by definition do not have evidence of anterior
or posterior segment inflammation.11 They tend
to be asymptomatic unless they develop macular or peripapillary choroidal
neovascularization. Current theory states that patients with POHS have previously
been infected with the fungus H capsulatum.12 Although this fungus has never been cultured from
peripheral chorioretinal scars or disciform macular scars, it has been reported
histopathologically in these same scars.13
Furthermore, this disorder is seen much more commonly in endemic areas in
the Ohio and Mississippi River valleys3; 95%
of patients with the characteristic eye findings in these endemic areas will
have a positive histoplasmin skin test result.2
There may be a genetic susceptibility to POHS in that affected patients who
develop choroidal neovascularization exhibit a higher prevalence of the HLA-B7
antigen than MFC patients and the general population at large.4
Furthermore, a high prevalence of HLA-DR2 antigen has been reported in POHS
patients,5 with a total absence in MFC patients.6
When both POHS and MFC conditions are quiescent and there is no previous
examination or documentation of the patient's fundus appearance, differentiation
can be difficult. Inactive lesions can look identical. Furthermore, patients
in both categories can be asymptomatic, and there may be no evidence of current
or previous anterior or posterior inflammation. Nevertheless, it is very important
to attempt to differentiate the disorders because the course, prognosis, and
treatment can be very different. Because of the chronic relapsing nature of
MFC, patients may need to be followed up more closely. There is also a possible
beneficial role for periocular or systemic corticosteroids in the treatment
of the choroiditis and perhaps choroidal neovascularization for MFC.1 On the other hand, there are well-established studies
that describe a known benefit of laser treatment for extrafoveal and juxtafoveal
choroidal neovascular membranes in POHS.14-15
For POHS cases where the choroidal neovascular membrane is too close to the
fovea to apply laser treatment, there may be a benefit from corticosteroids
or even submacular surgical excision, but this remains unproved.
The present study demonstrates a good diagnostic ability when the individual
observers believed they had enough information to venture a selection. Moreover,
there was a high degree of agreement between the 2 observers. Although the
observers were allowed to decline making a diagnosis on cases with too little
information to classify, the predictive value was high with or without the
indeterminate patients factored into the statistical analysis. It should be
noted that a subset of MFC patients had PIC.7
This variant of MFC does not typically have inflammatory signs or cells, and
there tends to be a clustering of lesions in the macula without the peripheral
scarring seen in MFC. By excluding potential cases of MFC because of the absence
of a history of vitreous cells (eg, PIC), some of the more difficult cases
to distinguish from POHS may not be included in this study. Furthermore, because
there is no true gold standard test to distinguish these 2 disorders, it is
possible that the reference photofile could contain some incorrect diagnoses.
There was no specific bias toward POHS or MFC in the indeterminates
for observer A or B. Most indeterminate patients' photographs either had too
few lesions and not enough information to classify or had inadequate photographic
quality.
Interestingly, almost 75% of the incorrect selections were common for
observers A and B. All of these patients were misdiagnosed as having MFC when
they actually had POHS. In fact, both observers had a tendency to miscall
cases that had POHS as having MFC. For each observer, only 1 patient with
MFC was diagnosed as having POHS. This concordance may be due to the similarity
of clinical clues and criteria that the observers applied to arrive at their
diagnoses. Thus, because there are enough distinct clinical characteristics
in patients with MFC, these patients were very rarely misdiagnosed as having
POHS. The converse does not seem to be true.
There was little or no benefit in improving the accuracy of diagnosis
when fluorescein angiography was available. This was true in regard to the
observers' ability to arrive at the correct diagnosis and their tendency to
be more likely to attempt a diagnosis. Almost half of all the indeterminate
patients had a fluorescein angiogram and color photographs. Curiously, observer
A was slightly less accurate when he had both color pictures and an angiogram.
CONCLUSIONS
This series demonstrates that experienced observers can often accurately
differentiate MFC from POHS by fundus appearance alone, without the need of
clinical history, histoplasmin skin testing, chest x-ray examination, or HLA
testing. Each observer formulated diagnostic criteria, which were similar.
The concordance between the observers is not surprising given their similar
criteria. Because these cases were derived from a nonstandardized photofile,
there were a large number of patients who the observers believed did not have
enough or adequate funduscopic information to venture a diagnosis. Nevertheless,
because only inactive cases without inflammatory signs were included in this
study, the observers were forced to make their decisions based on the appearance
and characteristics of the fundus lesions alone. Perhaps it is not surprising
that the additional information provided by the fluorescein angiography was
not helpful because these cases were inactive and therefore would be less
likely to demonstrate vascular staining, disc leakage, or leakage from active
lesions. The observers' criteria seem to have a higher sensitivity for MFC
cases, because almost all the incorrect selections had POHS but were misdiagnosed
as having MFC.
This study has emphasized the fundus photographic clues to differentiate
POHS from MFC. In the examining room, the clinician has available other clues
that will increase his or her accuracy in diagnosis. Clues that suggest MFC
include a history of photopsias, floaters (particularly during the early stage
of the disease), and a temporal blind spot. On physical examination, visual
field defects (particularly an enlarged blind spot) not explained by fundus
findings, postinflammatory changes in the vitreous, including cells, vitreous
strands, and a Weiss ring also point to MFC.
AUTHOR INFORMATION
Accepted for publication August 5, 2000.
This study was supported in part by an unrestricted grant from Research
to Prevent Blindness, Inc, New York, NY (Northwestern University Medical School),
and The Macula Foundation, Inc, New York.
Statistical consultation was provided by Alfred W. Rademaker, PhD, Department
of Preventive Medicine, Northwestern University Medical School, Chicago, Ill.
Corresponding author and reprints: Lee M. Jampol, MD, 645 N Michigan
Ave, Suite 440, Chicago, IL 60611.
From the Department of Ophthalmology, Northwestern University Medical
School, Chicago, Ill (Drs Parnell and Jampol); LuEsther T. Mertz Retinal Research
Center of Cornell University, New York, NY (Drs Yannuzzi and Tittl); and Department
of Ophthalmology, Vanderbilt University, Nashville, Tenn (Dr Gass).
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