Uveitis masquerade syndromes

Uveitis Masquerade Syndromes Aniki Rothova, MD, PhD, Francien Ooijman, MD, Frank Kerkhoff, MD, Allegonda Van der Lelij, MD, PhD, Henk M. Lokhorst, MD, PhD Background: Incorrect diagnosis of the uveitic masquerade syndromes (UMS) may have severe consequences. In this study, the frequency, clinical manifestations, and informative diagnostic tests for UMS are described. Design: Retrospective observational case series. Participants: Forty patients with UMS were identified in a cohort of 828 consecutive patients with uveitis. The mean follow-up was 4.5 years. Methods: A review of clinical, laboratory, photographic, and angiographic records was performed. Main Outcome Measures: Clinical features, associated systemic diseases, diagnostic procedures and their role in the diagnostic process, and systemic and visual outcomes. Results: Nineteen patients had intraocular malignancy (48% of all with UMS; 2.3% of all with uveitis), mainly intraocular lymphoma (n ⫽ 13) and leukemia (n ⫽ 3). The ophthalmologist was the first to recognize malignant disease in 11 of 19 patients (58%). Of 21 patients with nonmalignant UMS, 10 had an ocular vascular disease and 5 a hereditary ocular disorder. The patients with malignant UMS were older than those with nonmalignant UMS (average age, 50 vs 44 years, P ⬍ 0.05). During follow-up, 9 of 19 patients with malignant UMS died. The most informative diagnostic procedure for malignant UMS was intraocular fluid analysis; for nonmalignant UMS, fluorescein angiography. The cytologic analysis of intraocular fluids yielded the best results for diagnosing intraocular malignancies (7 of 11 patients, 64%); the association of negative cytologic results with the recent administration of systemic corticosteroids was noted. Immunophenotyping of the aqueous confirmed the diagnosis of hematologic malignancy for 3 of 5 patients examined. Panuveitis was the most frequent manifestation of malignant UMS. Intraocular lymphomas presented with isolated vitreitis (n ⫽ 6), chorioretinal lesions (n ⫽ 5) and iris infiltration (n ⫽ 2). Clinical presentation of nonmalignant UMS was diverse but consisted mainly of abnormalities of the retinal vasculature. Conclusions: UMS was diagnosed in 5% of the patients with uveitis at a tertiary center. Despite the variety of underlying disorders and different clinical presentations, a high frequency of malignant and vascular diseases was found. Awareness of the clinical manifestations of UMS and application of the correct diagnostic procedures should promote timely diagnosis and treatment, which are essential not only for visual acuity but also for the life of the patient. Ophthalmology 2001;108:386 –399 © 2001 by the American Academy of Ophthalmology. The uveitic masquerade syndromes (UMS) are a group of ocular disorders that present as intraocular inflammatory processes but are in fact noninflammatory diseases.1 In these patients, either intraocular inflammation is secondary to another initial disorder or the (supposedly inflammatory) intraocular cells and opacities are of noninflammatory origin (e.g., pigment, blood, or malignant cells). Many disorders may masquerade as uveitis, including hematologic malignancies, retinoblastoma, retinal detachment or degeneration, and intraocular trauma.2–12 Because the incorrect diagnosis may have very severe consequences, even for the patient’s life, the correct diagnosis and treatment of a masquerade syndrome is of extreme importance. In this report, the clinical features of 40 patients with a Originally received: December 7, 1999. Accepted August 28, 2000. Manuscript no. 99791. From F.C. Donders Institute of Ophthalmology, University Medical Center, Utrecht, The Netherlands. Reprint requests to Aniki Rothova, MD, PhD, F.C. Donders Institute of Ophthalmology and Department of Hematology, University Medical Center Utrecht, PO Box 85 500, 3508 GA Utrecht, The Netherlands. E-mail: [email protected]

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© 2001 by the American Academy of Ophthalmology Published by Elsevier Science Inc.

masquerade syndrome of 828 patients with uveitis in a tertiary ophthalmologic center are described, and the importance of various diagnostic procedures for the diagnosis of intraocular malignancies is evaluated.

Material and Methods The patients were selected from 828 consecutive patients with uveitis who visited the Ophthalmologic Department of the University Hospital in Utrecht between 1994 and 1998. Depending on the anatomic classification, all patients underwent the standard screening protocol for uveitis, which included erythrocyte sedimentation rate, red and white blood cell counts, HLA-B27 typing, determination of serum angiotensin-converting enzyme levels, serologic tests for syphilis, and chest radiography. Selected patients (depending on their medical history, clinical presentation, and activity of the ocular disease, as well as the outcomes of laboratory and radiographic screening procedures) underwent special tests and diagnostic procedures (“tailored approach”). Systemic diseases were diagnosed according to current diagnostic criteria. The entire uveitis series included 21 patients with acquired immune deficiency syndrome (AIDS), but human immunodeficiency virus (HIV) seropositivity was not routinely investigated, so the true number of asymptomatic HIV-positive individuals is not known. ISSN 0161-6420/00/$–see front matter PII S0161-6420(00)00499-1

Rothova et al 䡠 Uveitis Masquerade Syndromes Table 1. Masquerade Syndromes in Uveitis

No.

Average Age at Onset (years)

Male/Female Ratio

Time to Diagnosis (months)

Average no. of Diagnostic Examinations

Intraocular Fluid Examination

Predominant Anatomic Location

Uni/bilateral Involvement Ratio

Malignant masquerade syndromes Nonmalignant masquerade syndromes

19

50

1.3/1

11

4.2

15

Panuveitis (9/19)

0.9/1

21

44

1.1/1

7

4.5

12

Posterior (15/21)

1.3/1

Total

40

47

1.2/1

9

4.4

27

Posterior (21/40)

1.1/1

The diagnosis of UMS was established in 40 patients who were initially diagnosed as having uveitis and were referred to our center for further diagnosis or management. Excluded were all patients with a secondary inflammatory reaction resulting from other causes subsequently recognized and diagnosed (e.g., uveitis secondary to retinal detachment, trauma). In addition, all cases of bacterial or fungal endophthalmitis, even those with a doubtful initial diagnosis, were not included. Diabetes mellitus–associated anterior uveitis was diagnosed in six cases; because there is no definitive proof of this (exclusion) diagnosis, these patients were excluded from our series.13 Patients with diabetic retinopathy masquerading as posterior uveitis (e.g., acute retinal necrosis) were, however, included. The patients with UMS included seven immunocompromised patients, all receiving immunosuppressive medication, and one HIV-positive patient who, before his UMS, did not have AIDS. We retrospectively reviewed the clinical records of the 40 patients with UMS to assess the specific clinical characteristics and the nature of the underlying disorders. Special emphasis was directed toward the various diagnostic procedures and the visual and systemic outcomes. The following data were recorded: gender and age at the onset of disease, anatomic site of uveitis, the definitive diagnosis, interval between the onset of symptoms and the moment of final diagnosis, the number of diagnostic procedures and their role in the diagnostic process, the presence and outcome of systemic diseases, and maximum visual acuity at the end of follow-up. Average follow-up from the onset of ocular symptoms was 54 months; follow-up after the definitive diagnosis was 45 months. Legal blindness was defined as a best-corrected visual acuity worse than 20/200. This corresponds to the standard World Health Organization definitions of severe visual impairment (equal to or better than 20/400 but worse than 20/200) and blindness (from no light perception to 20/400).14,15 The criterion for visual impairment was a best-corrected visual acuity equal to or worse than 20/60. The visual loss was defined by the final visual acuity, not the worst visual acuity at any visit. Diagnostic vitrectomy was performed in 17 cases. In all cases, an undiluted vitreous fluid sample collected during an initial stage of standard three-port pars plana vitrectomy was subdivided into several samples and examined by standard microbiologic and cytologic methods and by previously described serologic and polymerase chain reaction (PCR) analyses for Toxoplasma gondii, herpes simplex virus, varicella zoster virus, and cytomegalovirus.16 Cytologic examination of all specimens was performed for the 17 patients who underwent diagnostic vitrectomy (nine with malignant and eight with nonmalignant UMS). Because of the limited volume of the samples, anterior chamber fluid was examined predominantly by serologic and PCR methods; cytologic examination of aqueous was performed in four cases (three with malignant and one with nonmalignant UMS). Three-color fluorescence-activated cell sorter analysis (Becton Dickinson Immunocytometry System; Becton Dickinson, San

Jose, California) and/or immunofluorescence microscopy of 13 intraocular fluid samples was performed (11 patients, five aqueous and eight vitreous samples). The intraocular fluid samples were collected in 10% fetal calf serum (Gibco, Paisley, Scotland). After centrifugation, cells were resuspended in RPMI-1640 containing 20% fetal calf serum and immunostained for CD4⫹ and CD8⫹ T cells (CD3-Cy5; Beckman Coulter, Mijdrecht, The Netherlands), CD4-FITC and CD8-PE (Becton Dickinson Immunocytometry System), and B cells expressing kappa and lambda light chains on their surface, (CD19-Cy5, Beckman Coulter), anti– kappa-FITC, anti–lambda-PE, (Becton Dickinson Immunocytometry System). If no pellet was visible after the first wash, all cells were directly cytocentrifuged and analyzed for the presence of B lineage cells expressing cytoplasmic light chains by means of double cytoplasmic staining with FITC- and TRITC-labeled goat antihuman kappa and lambda antibodies, respectively. After rinsing in phosphate buffered saline, slides were examined in a fluorescence microscope. Monoclonality was defined as a kappa:lambda shift greater than 90:10 within the CD19 population (fluorescence-activated cell sorter analysis) or within the heavy chain population (cytocentrifuged cells).17 Chi-square and Fisher’s exact tests were used for statistical analysis, and P less than 0.05 was considered significant.

Results Among the 828 patients with uveitis, we identified 40 patients (5%) with the masquerade syndrome (18 females and 22 males, average age 47 years). The general data are presented in Table 1. Nineteen patients had an intraocular malignancy (19 of 40, 48% of the masquerading syndromes; 19 of 828, 2.3% of all cases of uveitis). The intraocular malignancies consisted mainly of intraocular lymphoma (13 of 19, 68% of the malignant UMS; 13 of 40, 33% of all masquerading syndromes; 13 of 828, 1.6% of all cases of uveitis; Table 2). The remaining patients with an intraocular malignancy had leukemia (n ⫽ 3), melanoma of the iris (n ⫽ 1), retinoblastoma (n ⫽ 1), or metastasis of lung carcinoma (n ⫽ 1). Of the 21 patients with nonmalignant masquerading conditions, 10 had a retinal vascular disease (including vascular occlusion, ocular ischemic syndrome, systemic hypertension, and diabetic retinopathy), 5 a hereditary disorder (one in combination with an intraocular foreign body), 2 a degenerative vitreous opacity, 2 retinal detachment, 1 Coats’ disease, and 1 iris retraction syndrome (Table 3). The average age at onset of those with intraocular malignancy was 50 years; in nonmalignant UMS, it was 44 years (P ⬍ 0.05). The unilateral to bilateral ocular involvement ratio was 9:10 for malignant and 12:9 for nonmalignant UMS. An anterior location of UMS was found for 5 patients, posterior for 21, and panuveitis for 14 patients. In malignant UMS, the majority of patients had either posterior segment or dual segment involvement (n ⫽ 15, Table 2); in nonmalignant UMS, the posterior location was the most frequent site (Table 3). Patients with vitreitis only

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Ophthalmology Volume 108, Number 2, February 2001 Table 2. Malignant Masquerade Syndromes in Uveitis NumGen- Immunober Age der suppression

Definitive Diagnosis

Time to Decisive Diagnosis Diagnostic (months) Procedure

1

59

F

No

CNS-NHL

12

2

74

M

No

CNS-NHL

1

3

57

F

Yes

CNS-NHL

36

4

45

M

Yes*

CNS-NHL

3

5

54

M

No

CNS-NHL

48

6

63

F

No

CNS-NHL

10

7

49

M

No

CNS-NHL

24

8

72

F

Yes

CNS-NHL

1

9

46

M

No

CNS-NHL

4

10

61

F

No

Large B cell NHL

8

11

72

M

Yes

1

12

35

M

No

Transformed peripheral T-cell lymphoma MALT lymphoma

13

57

M

No

14

50

F

Yes

15

60

M

No

16

6

M

Yes

17

46

F

No

18

44

M

No

Lung carcinoma metastasis

4

19

6

F

No

Retinoblastoma

1

Lymphoplasmacytoid lymphoma Chronic lymphocytic leukemia Prolymphocytic leukemia Acute lymphoblastic leukemia Melanoma

Visual Acuity at Onset

Sarcoidassociated uveitis, UMS Aspecific uveitis, UMS Aspecific uveitis

20/30

20/30

20/50

20/25

†

20/25

20/200

†

20/60

20/60

†

20/20

20/20

20/50

Unknown

†

20/30

20/30

†

20/50

20/40

†

20/25

Hand movement

2

3

Yes

Intraocular fluid analysis

Vitreitis

Vitreitis

No No

Cerebrospinal Vitreitis fluid analysis MRI

Posterior

Vitreitis, serous retinal detachment Papillitis

Intraocular fluid analysis Intraocular fluid analysis Intraocular fluid analysis MRI

Vitreitis

Vitreitis

No

Vitreitis

Vitreitis

No

Posterior

Vitreitis

No

Vitreitis

Vitreitis

Retinal biopsy Panuveitis Chorioretinal lesions, serous retinal detachment Iris biopsy Anterior Infiltration of iris, anterior segment cells Intraocular Anterior Infiltration of fluid analysis iris, anterior segment cells

Intraocular fluid analysis

23

Presumed Initial Diagnosis

Vitreitis

24

1

High Intraocular Pressure

Vitreitis

Lymph node biopsy

1

Ocular Features

MRI

3

8

Location UMS

Posterior

Chorioretinal lesions

Panuveitis Panuveitis, serous retinal detachment Intraocular Posterior Chorioretinal fluid analysis lesion, vitreitis Cerebrospinal Posterior Papillitis, fluid analysis chorioretinal lesions Intraocular Anterior Infiltration of fluid analysis iris, anterior segment cells Iris biopsy Anterior Infiltration of iris, anterior segment cells Lymph node Posterior Vireitis, serous biopsy retinal detachment, CME Intraocular Panuveitis Infiltration of fluid analysis iris, hypopyon, vitreal infiltrates

No

No No

Infectious papillitis Aspecific uveitis Aspecific uveitis Aspecific uveitis Aspecific uveitis, pars planitis Toxoplasmosis

Final Visual Survival Acuity (years) 4

(2) (2) (3) 1 (4) (1) (2)

Yes

Aspecific uveitis

20/25

Unknown

Yes

Aspecific uveitis, UMS

20/25

20/40

No

20/20

20/20

4

Yes

Sarcoidassociated uveitis Sclerouveitis

20/60

20/25

8

No

Toxoplasmosis 20/20

20/40

†

No

Infectious retinitis

20/25

20/50

†

Yes

Aspecific uveitis, UMS Aspecific uveitis

20/30

20/25

1

20/20

0

8

No

Aspecific uveitis

20/50

20/200

1

Yes

Toxocariasis, Hand UMS movement

0

5

Yes

†

(1)

(2) (1)

CME ⫽ cystoid macular edema; CNS-NHL ⫽ primary ocular and central nervous system non-Hodgkin’s lymphoma; MALT ⫽ mucosal associated lymphoid tissue; MRI ⫽ magnetic resonance imaging of brain; UMS ⫽ uveitic masquerade syndrome. * HIV infected patient. † Patient died.

were classified as panuveitis (n ⫽ 8), 6 of whom had central nervous system non-Hodgkin’s lymphoma (CNS-NHL).

388

For all cases of UMS, the mean interval between the first ophthalmologic consultation and definitive diagnosis was 9

Table 3. Nonmalignant Masquerade Syndromes in Uveitis ImmunoNumGen- suppresber Age der sion

Definitive Diagnosis

Time to Decisive Diagnosis Diagnostic Location (months) Procedure UMS

1

77

F

No

Retinal detachment

1

2

41

M

No

Retinal detachment

1

3

1

M

No

Coats’ disease

1

4

65

M

No

3

5

72

M

No

6

19

F

No

7

22

F

No

Vitreous degeneration Vitreous degeneration Dominant cystoid macular degeneration Hyperhomocystinemia

8

41

M

No

Hereditary Lebers’ optic atrophy

24

9

33

F

No

Tapetoretinal degeneration

1

Electroretinography

Posterior

10

53

M

No

Clinical features

Posterior

11

67

M

No

Fundus 36 flavimaculatus and intraocular foreign body Iris 13 retraction syndrome

12

29

M

No

Radiation retinopathy

13

26

F

Yes

14

25

F

No

15

81

F

No

Retinal vessel occlusion* Branch retinal occlusion vein Diabetic retinopathy

16

39

M

No

17

82

F

18

68

19

1 8

12

Ocular Features

Ultrasono- Panuveitis Anterior graphy segment cells, vitreous infiltrates Clinical Panuveitis Anterior features segment cells, vitreous infiltrates Fluorescein Posterior Vitreous angiography infiltrates Clinical Vitreitis Vitreitis features Clinical Vitreitis Vitreitis features Fluorescein Posterior Cystoid angiography macular edema, vitreous cells Methionine Posterior Papillitis, tolerance vasculitis, curve Roth’s spots DNA Posterior Optic neuritis analysis

24

Fluorescein Posterior angiography

Retinal vasculitis, retinal pigmentary changes Panuveitis, retinal pigmentary changes Anterior segment cells, retinal detachment Retinal vasculitis

1

Clinical Posterior features Fluorescein Posterior angiography

Chorioretinal lesion Chorioretinal lesion

1

Fluorescein Posterior angiography

Diabetic retinopathy

2

Fluorescein Posterior angiography

Peripheral retinal lesions and necrosis Chorioretinal lesions

No

Ocular ischemic syndrome

1

Duplex ultrasonography

M

No

6

33

F

No

Ocular ischemic syndrome Hypertension

20

21

F

No

Hypertension

1

Duplex ultrasonography Blood pressure Blood pressure

21

28

M

Yes

Hypertension

6

1

1

High Intraocular Pressure

Ultrasono- Anterior graphy

Panuveitis Anterior segment cells, vitreous infiltrates Posterior Retinal vasculitis Posterior Posterior

Fluorescein Posterior angiography

Chorioretinal lesions Retinal vasculitis, chorioretinal lesions Retinal vasculitis

UMS ⫽ uveitic masquerade syndrome. * Probably combined retinal branch artery and vein occlusion. † Patient died.

Presumed Initial Diagnosis

Visual Acuity at Onset

Final Visual Survival Acuity (years)

No

Aspecific uveitis

No

Aspecific uveitis

No

Aspecific uveitis, Light Light UMS perception perception Sarcoid20/40 20/30 associated uveitis Aspecific 20/100 20/200 uveitis Pars planitis 20/200 20/200

No No No

No No

No

Hand Light movement perception 20/80

Finger counting

Infectious Hand 20/40 emboli, aspecific movement vasculitis Neuritis retroFinger Finger bulbaris, counting counting multiple sclerosis Infectious 20/60 20/60 uveitis

2

2 2 5 5

4 7

6

Infectious uveitis

Yes

Aspecific uveitis

Hand Hand movement movement

4

No

Aspecific retinal vasculitis Infectious uveitis Infectious uveitis

Hand movement

20/60

4

20/30

20/100

1

20/20

20/20

5

20/200

20/50

1

No

20/30

(5)

No

No

20/25

†

No

Acute retinal necrosis

No

Acute retinal 1/2 Light necrosis, infectious perception endophthalmitis Aspecific Light 0 uveitis perception

Yes

Yes

Aspecific retinal vasculitis

No

8

5 5

Finger counting

0

3

Toxoplasmosis

20/25

20/25

5

No

Toxoplasmosis

20/60

Unknown

3

No

Aspecific retinal vasculitis

20/30

20/30

6

Ophthalmology Volume 108, Number 2, February 2001 Table 4. Intraocular Fluid Examination in Malignant Uveitis Masquerade Syndromes

Total number of patients Total number of samples Number of aqueous samples Number of vitreous samples

Microbiologic Examination (Number of Positives)

Serologic and PCR Analysis* (Number of Positives)

Cytologic Examination† (Number of Positives)

Immunophenotyping Examination† (Number of Positives)

9 (0) 10 (0) 1 (0) 9 (0)

11 (0) 15 (0) 7 (0) 9 (0)

11 (7) 12 (7) 3 (2) 9 (5)

9 (5) 10 (6) 5 (3) 5 (3)

* For Toxoplasma gondii, herpes simplex virus, varicella zoster virus, and cytomegalovirus. †

In six patients both examinations were performed; positive result in cytology three of six, in phenotyping four of six.

months: 11 months for malignant UMS compared with 7 months for those with the nonmalignant masquerade syndromes (P ⫽ 0.3). The number of diagnostic procedures performed per patient was 4.3; 4.2 for malignant and 4.5 for nonmalignant UMS. In the whole series, the most informative diagnostic procedures were intraocular fluid analysis (positive result of cytologic and/or immunophenotyping examinations in 9 of 14 malignant cases, Table 4), fluorescein angiography (n ⫽ 7), and tissue biopsy (n ⫽ 5). In malignant UMS, definitive diagnosis was obtained in 9 cases by intraocular fluid analysis (4 anterior chamber and 5 vitreous fluid samples) and in 5 cases by tissue biopsy (Tables 2 and 4). The presumed diagnosis of nonmalignant UMS was supported by the absence of malignant cells in the vitreous biopsy in 4 additional cases (intraocular glass fiber in one eye with fundus flavimaculatus, intraocular vascular process in one eye with vitreous hemorrhage, and aspecific degeneration in 2 patients with degenerative vitreous opacities). The results of intraocular fluid analysis for patients with malignant UMS are presented in Table 4. Combined methods of cytologic examination and immunophenotyping confirmed malignancy in 9 of 14 cases (64%) of malignant UMS (Table 4). Cytologic examination was performed in 11 cases (3 aqueous and 9 vitreous fluid samples) and was positive for 7 of 11 patients (64%; 7/12, 58% samples). Of the vitreous fluid samples, 5 of 9 patients were positive on cytologic examinations (55%, all with NHL), although one had been negative at a previously performed diagnostic vitrectomy. Of the aqueous fluid samples, 2 of 3 were positive (Table 2, numbers 16 and 19, retinoblastoma and leukemia) and 1 was negative (Table 2, number 7, NHL). Immunophenotyping was performed for 9 patients with malignant UMS (5 aqueous and 5 vitreous samples) and confirmed malignancy in 5 of 9 cases (55%; 6 of 10, 60% samples). Of the five cases of immunophenotyping of the aqueous humor, 3 were positive (Table 2, numbers 11, 13, and 14; 1 with leukemia and 2 with NHL). Two of the 5 patients with malignant UMS and negative intraocular fluid analysis used systemic corticosteroids within 3 months of the sampling in contrast to none of the 9 patients with positive results. For 5 patients with malignant UMS whose intraocular fluids were not examined and 5 patients with a negative intraocular fluid analysis (3 with NHL, 1 with leukemia, and 1 with metastatic adenocarcinoma), the diagnosis of a malignant process was established by other methods (Table 2). Of 13 patients with intraocular lymphoma, 9 had primary intraocular CNS-NHL lymphoma, 1 had large B-cell NHL with iris and meningeal involvement (this patient was classified separately and was not included in the group of patients with primary ocular and CNS-NHL lymphoma), 1 had mucosal-associated lymphoid tissue lymphoma, 1 lymphoplasmacytoid lymphoma (immunocytoma, Waldenstro¨m’s disease), and 1 had transformed peripheral T-cell NHL (Table 2). Six were known to have NHL before the

390

onset of their ocular complaints. During follow-up, 9 of 19 patients with malignant UMS died (2 with leukemia, 1 with transformed T-cell NHL, and 6 with primary CNS-NHL lymphoma), all from their malignant disease. A diagnostic delay of more than 12 months occurred in 5 cases of NHL lymphoma and 1 of melanoma of the iris. The diagnostic delay for patients with malignant UMS who died during follow-up was not different from that for survivors (P ⫽ 0.9). In 11 of 19 cases (58%), malignant UMS was the first manifestation of malignant disease. In nonmalignant UMS, the most informative diagnostic procedure was fluorescein angiography (Table 3). Clinical development of the disease and negative results of diverse diagnostic procedures (e.g., vitreous analysis) led to the final diagnosis in 5 cases. A diagnostic delay of more than 12 months occurred in 5 cases (3 patients with hereditary eye disease, 1 with the iris retraction syndrome, and 1 with radiation retinopathy). One of 21 patients with nonmalignant UMS (retinal detachment) died from a cerebrovascular accident. For 5 patients UMS was the first manifestation of systemic disease (2 with carotid occlusive disease and 3 with systemic hypertension). In 5 cases the ophthalmologic diagnosis led to subsequent systemic treatment. For 5 patients, the diagnosis of ocular disease led to the diagnosis of an unsuspected hereditary disorder. The clinical presentations of malignant UMS were not identical (Table 2; Figs 1 to 8). Initial presumed diagnoses consisted mainly of aspecific uveitis; for patients with chorioretinal lesions, infectious processes (especially toxoplasmosis) were considered (Table 2, Fig 8). The group of patients with intraocular lymphomas presented with isolated vitreitis (n ⫽ 6), chorioretinal lesions (n ⫽ 5; Figs 5, 6, and 7) and iris infiltration (n ⫽ 2; Fig 2). Of 9 patients with primary CNS-NHL, 8 exhibited bilateral involvement at presentation. Of 3 patients with leukemia, 2 adults had chorioretinal infiltrates (Fig 8) and 1 child presented with bilateral iris involvement. Iris infiltration of malignant cells was documented in 5 cases (large B-cell NHL, T-cell NHL, leukemia, melanoma, retinoblastoma; Figs 1 to 3). Seven patients with malignant UMS had a high intraocular pressure (unilateral in 5 cases); in 1 case, trabeculectomy was performed before diagnosis of the malignant UMS was established. Serous, nonrhegmatogenous detachment was seen in 4 patients, 1 with metastasis and 3 with NHL. The clinical presentations of nonmalignant UMS were diverse but consisted mainly of abnormalities of the retinal vasculature (Table 3, Figs 9 to 15). The most common initial diagnosis was nonspecific retinal vasculitis (Table 3). For patients with chorioretinal lesions, an infectious cause was considered; 2 patients were suspected of having acute retinal necrosis, because large whitish lesions with hemorrhages were seen in the periphery of the retina (Fig 15). In both cases, the serologic analysis for syphilis and toxoplasmosis was performed as well as an analysis of intraocular fluids, and neither of them contained evidence of an

Rothova et al 䡠 Uveitis Masquerade Syndromes infectious or malignant process. On fluorescein angiography, however, it became apparent that the lesions were caused by severe diabetic retinopathy. One patient reacted well to laser treatment; the second patient developed a vitreous hemorrhage in the course of laser treatment and an additional pars plana vitrectomy was required. Three young adult patients had had previously undiagnosed systemic hypertension; two presented with acute visual loss and focal chorioretinal lesions, which were similar to lesions of ocular toxoplasmosis but were caused by a chorioretinal infarction (Fig 9). The remaining hypertensive patient presented with sudden onset of visual impairment and retinal abnormalities resembling the features of vasculitis. One of the two immunosuppressed patients with nonmalignant UMS also had a focal chorioretinal lesion suggestive of cytomegalovirus retinitis; ultimately, it was found to be a retinal infarction, probably resulting from a combined macular branch vein and artery occlusion (Fig 12).

Case Histories Case 1 A 57-year-old male patient (Table 2, number 13) was referred to our uveitis clinic for analysis of his unilateral uveitis with intermittent high intraocular pressure, which had become manifest 6 months earlier and was treated symptomatically with topical steroids. On presentation, the visual acuity of his affected eye was 20/60; the eye was clear except for some vitreous opacities. On fundoscopy, peripheral demarcation lines of old retinal detachment and chorioretinal scars were visible. Fluorescein angiography showed the old pigmented lines, but pathologic leakage from the retinal vessels was not apparent (Fig 7). The presumed diagnosis was sclerouveitis with a previous secondary retinal detachment. The patient underwent screening for uveitis and scleritis, which revealed an erythrocyte sedimentation rate of 80 mm/hour but no further abnormalities, specifically no indications of rheumatoid arthritis or Wegener’s disease. The chest x-ray was normal. The patient was referred to the internist for further evaluation. Within 4 weeks, the patient complained of a further decrease in visual acuity and pain. On examination, conjunctival and scleral redness was noted, and visual acuity was 20/200. Small keratic precipitates were seen on the corneal endothelium, and there were cells in the anterior chamber and the vitreous; the iris was normal. Intraocular pressure was 30 mmHg. On fundoscopy, serous retinal detachment was seen. Ultrasongraphy showed subretinal fluid and an intumescent choroid. Further examination revealed enlarged axillary and abdominal lymph nodes. The differential diagnosis was sarcoidosis and lymphoma. Aqueous fluid immunophenotyping revealed a monoclonal population of kappa-positive lymphocytes. Subsequent bone marrow and lymph node biopsies as well as further analyses confirmed the diagnosis of lymphoplasmacytoid lymphoma, stage IV.

Case 2 A 6-year-old girl (Table 2, number 19) was referred to our institution because of panuveitis of unknown origin. Medical and family histories were not significant. Present history revealed a period of fever and general malaise 2 months ago, followed by repeated episodes of redness of the right eye. On examination, visual acuity was hand movements for the right eye, the anterior chamber contained cells with atypical hypopyon (Fig 1), the iris was hyperemic, the lens was clear, and the vitreous contained infiltrates. On fundoscopy, only a red light reflex in the temporal and superior regions could be seen. Ultrasonography showed an

immobile prominence in the vitreous without calcifications. The left eye exhibited no abnormalities and had full visual acuity. The presumed diagnosis was toxocariasis or masquerade syndrome, and the patient was admitted to the hospital. General examination by a pediatrician revealed no abnormalities; general blood examination, chest x-ray, and computed tomographic scan of the abdomen were normal. A bone marrow biopsy and cerebrospinal and aqueous taps were obtained. Bone marrow and cerebrospinal fluid were normal, but cytologic examination of the aqueous fluid revealed retinoblastoma cells. Subsequent magnetic resonance imaging examination and enucleation followed.

Case 3 A 48-year-old female (Table 2, number 17) was referred to our uveitis clinic for analysis of her chronic unilateral uveitis and elevated intraocular pressure, both of 2 years’ duration. In the past, trabeculectomy of the left eye had been performed because of persistent high pressure and increasing visual field defects. Her medical history included no abnormalities, except for migraine. On examination, the right eye was normal with a visual acuity of 20/20. Visual acuity of the left eye was 20/30 with a small filtering bleb; the anterior chamber contained sporadic cells, and a grossly pathologic iris exhibited local areas with a velvety appearance together with intumescent areas (Fig 3). The differential diagnosis included masquerade syndrome and granulomatous iritis. The results of screening for uveitis and chest radiography were within normal limits. B-scan ultrasonography was normal. A biopsy of the iris contained melanoma cells. Ultrasonography of the anterior segment of the left eye showed multiple intumescent areas in the iris suggestive of diffuse melanoma. On enucleation, an epithelioid type of melanoma of the ciliary body was found.

Case 4 A 68-year-old male (Table 3, number 18) was referred to our uveitis clinic for analysis of his unilateral posterior uveitis of 3 months’ duration. Medical and family histories were not significant; the patient was healthy and took no medications. On presentation, the right eye had full vision and was without abnormalities. Visual acuity of the left eye was finger counting. The anterior chamber was clear, and there was rubeosis iridis. Fundoscopy showed no abnormalities except for a small peripapillary hemorrhage, but peripheral dot-blot hemorrhages were not present. Intraocular pressure was normal. On fluorescein angiography, diffuse staining of the main retinal vessels without associated characteristics of retinal ischemia was noted (Fig 11). The diagnosis of UMS, specifically ocular ischemic syndrome, was suspected. The patient was referred to a neurologist, and subsequent examinations revealed occlusion of the internal carotid artery. Retinal photocoagulation was initiated, and vascular surgery was discussed.

Case 5 A 33-year-old female (Table 3, number 19) consulted our department because of acute onset of black spots in her only functioning eye. Eleven years ago, she had had a perforating injury to her other eye, complicated by retinal detachment, which required repeated surgery and ultimately led to permanent visual loss. The patient had no health complaints, was never seriously ill, and took no medications. The anterior segment was normal, the vitreous was clear, and fundoscopy revealed an old pigmented lesion in the retina next to a white lesion with fuzzy margins. Toxoplasmic retinitis was suspected, and an aqueous tap was performed for subsequent analysis. The patient was started on antitoxoplasmic

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Figure 1. Pseudohypopyon in retinoblastoma (Table 2, number 19). Pseudohypopyon was an unusual first sign of retinoblastoma in a 6-year-old girl without a positive family history. Diagnosis was made by cytologic examination of aqueous aspirate. Figure 2. Infiltration of transformed peripheral T-cell lymphoma into the iris (Table 2, number 11). Multiple pink elevated lesions with rich vascularization are visible on the iris, especially in the lower peripupillary area. Biomicroscopic examination revealed flare and intraocular cells with posterior synechiae. The posterior segment was without abnormalities, and intraocular pressure was 38 mmHg. Diagnosis was established by immunophenotyping of an aqueous sample. After radiotherapy, the lesions on the iris gradually disappeared and the intraocular pressure normalized.

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Rothova et al 䡠 Uveitis Masquerade Syndromes Figure 3. Infiltration of malignant melanoma into the iris (Table 2, number 17). Grossly pathologic iris with atrophic and intumescent parts. Biomicroscopic examination revealed keratic precipitates, occasional intraocular cells, and posterior synechiae. Optic disc had a cup–to-disc ratio of 0.9; further posterior segment findings were normal. Intraocular pressure was 30 mmHg despite the previous trabeculectomy and recent antiglaucomatous treatment. Diagnosis was established by cytologic examination of a biopsy of the iris. Figure 4. Optic disc edema in human immunodeficiency virus-positive patient (Table 2, number 4) masquerading as infectious papillitis. Patient presented with bilateral loss of vision and bilateral, but asymmetric, papillary edema with associated hemorrhages and mid-dilated nonreactive pupils. A, Optic disc swelling with flame-shaped hemorrhages and secondary edema of peripapillary retina with cotton wool and hard exudates. B, Fluorescein angiography documents leakage from peripapillary capillaries. Differential diagnosis included infectious papillitis and optic disc edema resulting from elevated intracranial pressure. The analysis of intraocular fluid disclosed no evidence of an infectious process. Subsequently, the patient was diagnosed with obstructive hydrocephalus and cerebral lymphoma. Figure 5. Chorioretinal infiltration of primary ocular and CNS large B-cell NHL masquerading as multifocal chorioretinitis. (Table 2, number 7). Note the multiple small fundus lesions, which resemble the lesions of multifocal chorioretinitis. The diagnosis was based on a vitreous biopsy. Patient had had neurologic symptoms in the past, and although the magnetic resonance imaging examination of the brain at that time was indicative of lymphoma, the cerebrospinal fluid and brain biopsy were negative. Figure 6. Chorioretinal lesions in mucosal-associated lymphoid tissue lymphoma masquerading as choroiditis in sarcoidosis (Table 2, number 12). Multiple small yellow lesions are present in the peripapillary area. Angiography showed late staining of the lesions. Because of the concurrent lacrimal gland involvement, this patient was initially misdiagnosed as presumed ocular sarcoidosis. Š

therapy. Three days after the onset of complaints, two hemorrhages appeared in the proximity of the retinal lesions. Her blood pressure was 180/140 mmHg. Antihypertensive treatment was added to the antitoxoplasmic therapy. On the fourth day the results of both serum and aqueous examinations were negative for antibodies against T. gondii (serology for undiluted serum was also negative in two reference laboratories, and aqueous sample was negative for PCR and antibodies against T. gondii, herpes simplex virus, and varicella zoster virus). The antiparasitic treatment was withdrawn, and a diagnosis of choroidal infarction based on systemic hypertension was established. The lesion slowly became pigmented (Fig 9A). The patient had no further ocular complaints during the 5-year follow-up.

Discussion In this study, the frequency of UMS among the patients with uveitis in a tertiary ophthalmologic center was 5%. Despite the variety of underlying disorders and the different clinical presentations, this study reveals a high frequency of malignant disease (n ⫽ 19, 48%; especially intraocular lymphoma, n ⫽ 13, 33%) and vascular disease (n ⫽ 10, 25%) among the patients with UMS. The diagnosis of UMS was troublesome, as illustrated by long intervals between the first ophthalmologic consultation and establishment of the definitive diagnosis. The long diagnostic delays were found predominantly for patients with ocular hereditary diseases and intraocular lymphoma (average 16 and 14 months, respectively). The absence of uniform clinical features, unusual clinical presentations, and initially negative vitrectomy results for six patients with malignant UMS undoubtedly contributed to the diagnostic delay. Other published series report similar diagnostic delays for intraocular lymphoma, for example, the mean time from onset of symptoms to diagnosis was 21 months in the series described by Whitcup et al.18 The frequency of 5% found for UMS among patients with uveitis might even be too low. Not all patients with uveitis of unknown origin underwent detailed evaluations, including intraocular fluid analysis. The decision to perform more aggressive examinations was dictated by the clinical features and the age of the patients, their medical histories, and associated systemic

diseases,1,2 so that the possibility of missing an occasional patient with UMS cannot be excluded entirely. For patients with suspected malignant UMS, cytologic analysis of intraocular fluids with quick and careful handling of the specimens was repeatedly reported to be an essential diagnostic procedure.1,2,19 Although the cytologic analysis of intraocular fluids yielded the most positive results for diagnosis of intraocular malignancies (7 of 11 patients, 64%), we support the previous report of frequent negative findings of intraocular fluid examinations for patients with hematologic malignancies as well as the negative influence of systemic corticosteroids.20,21 The use of flow cytometry to study vitreous specimens for diagnosis of intraocular lymphoma has been reported to be promising. Davis et al22 detected 7 of 10 patients with intraocular lymphoma by flow cytometry compared with only 3 diagnosed by cytology. However, not all authors obtained such promising results.21 Moreover, immunophenotyping performed by fluorescence-activated cell sorter analysis needs a sufficient number of cells (⬎1,000) to be able to analyze B- and T-cell subsets. Immunophenotyping of B cells on cytocentrifuged cells, as used in our study, can be performed with an even smaller number of cells (⬎100) and can therefore also be used for evaluation of aqueous fluid samples. Immunophenotyping of aqueous and vitreous fluids by hematopoetic cell-surface markers in the present series resulted in positive findings for 6 of 10 samples, whereas cytologic examination was positive for 7 of 12 samples. The additive value of immunophenotyping for diagnosis of intraocular hematologic malignancy and the eventual differences between aqueous and vitreous examinations cannot be evaluated in the present series because of the different inclusion criteria for specific examinations and the very limited number of samples. The cytologic examination was performed in an earlier stage of the study, and immunophenotyping was not carried out until the last 2 years for those with suspected hematologic malignancies. In our study, 6 patients with malignant UMS (5 with a definitive diagnosis of hematologic malignancy) were examined by means of both methods. The cytologic examination was positive in 3, and immunophenotyping in 4 cases. The diagnosis of intraocular hematologic malignancy by immu-

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Rothova et al 䡠 Uveitis Masquerade Syndromes Figure 7. Chorioretinal lesions in lymphoplasmacytoid lymphoma masquerading as posterior scleritis with secondary exudative retinal detachment (Table 2, number 13). Fluorescein angiography, late phases. A, Serous retinal detachment and old hyperpigmented demarcation lines. B, In the temporal periphery, a chorioretinal lesion with hypofluorescent central area was surrounded by hyperfluorescence and by a reticular pattern of clumping of retinal pigment epithelium (lesion corresponds with whitish infiltrate on fundoscopy). Figure 8. Leukemic infiltration of the retina masquerading as infectious chorioretinitis (Table 2, number 14). A 50-year-old female had a 5-year history of chronic lymphocytic leukemia, when she developed sepsis and chorioretinal lesion in her left eye. Note grayish-white focal lesion suggesting the diagnosis of infectious retinitis, for example, toxoplasmosis. Before (A) and after (B) local radiotherapy for relapsed chronic lymphocytic leukemia. Diagnosis was performed by analysis of vitreous aspirate. Figure 9. Chorioretinal lesions in systemic hypertension masquerading as infectious retinitis. A, 33-year-old female hospital nurse (Table 3, number 19) noted loss of vision. At that time, a focal whitish area adjacent to atrophic area with hyperpigmented borders simulated the appearance of a toxoplasmic scar. Toxoplasma antibodies were negative in serum and aqueous humor; however, blood pressure was 210/140 mmHg. B, 21-year-old female (Table 3, number 20) with acute loss of vision. Note focal atrophic lesions with irregular hyperpigmentations mimicking the lesions of ocular toxoplasmosis. The lesions were probably caused by choroidal infarctions. In the acute stage, whitish necrotic lesions surrounded by a cellular infiltrate were visible. Patient was unaware of her systemic hypertension (blood pressure was 180/130 mmHg). Figure 10. Radiation retinopathy in a 29-year-old male patient 3 years after radiotherapy for recurred astrocytoma (Table 3, number 12). Note leakage from the disc and absence of both evident ischemic areas and associated hemorrhages. The diagnosis was based on more characteristic lesions seen on angiography in a later stage of the disease. The evaluation for systemic vascular diseases and uveitis remained negative. Figure 11. Ocular ischemic syndrome masquerading as retinal vasculitis (Table 3, number 18). Fluorescein angiography. Note the collateral vessel loop located on the optic nerve head, small peripapillary hemorrhage, and diffuse staining of the large vessels. Š

nophenotyping of cells from aqueous samples was possible in 3 cases. Ideally, the combination of immunophenotyping and cytologic examination ought to be employed for all patients suspected of having malignant UMS, because this would cover not only the morphologic differentiation but also evaluation of monoclonality in possible hematologic malignancies. So far, combination of the two examinations is possible only for vitreous specimens, because the volume of the aqueous samples (sometimes with only occasional cells present) is not sufficient for both examinations. For patients with a hematologic malignancy of known phenotype, we recommend primarily the immunophenotyping of an aqueous sample. The collection of aqueous fluid is a safe and nonaggressive procedure with fewer complications than an intraocular biopsy,23 and immunophenotyping allows quick comparison of the phenotypes of intraocular cells with a malignant cell clone. The positive results with aqueous make a more aggressive vitrectomy unnecessary. For patients with a negative aqueous finding, the subsequent diagnostic vitrectomy should be performed, preferably after a period of 2 to 3 months without systemic corticosteroid administration.18,20 With the larger vitreous fluid sample, diverse combinations of examinations may be performed. For patients with UMS, determination of the hematologic malignancy at the molecular level, such as the detection of immunoglobulin IgH gene rearrangement by PCR amplification for B-cell malignancies in vitreous as reported by Shen et al,24 might become a useful additive tool for diagnosis of CNS-NHL in a small-cell population. The characteristic clinical manifestations of intraocular lymphoma include bilateral painless visual loss resulting from tumor infiltration of the vitreous, retina, and subretinal space, predominantly manifest in elderly patients.1,2 Several distinct forms of lymphoma may masquerade as uveitis. The most frequent is primary large B-cell malignant intraocular CNS-NHL, which may become manifest primarily in the eye, usually in the vitreous or the choroid (n ⫽ 9 in our series).2,18,25,26 Less frequently, systemic non-Hodgkin’s lymphoma, which may metastasize into the eye, usually in the uveal tract, may be encountered (n ⫽ 3 in our series).27

In our series, the mean age for malignant UMS was 50 years (age at onset less than 30 years in 2 of 19), for intraocular lymphoma 57 years (age at onset less than 30 years in none) in contrast to 44 years for those with nonmalignant UMS (age at onset less than 30 years in 8 of 21). The incidence of primary intraocular CNS-NHL in immunocompetent individuals has increased in the past years for reasons that are yet unknown.28 This malignancy is associated with poor survival, as illustrated by this series in which 7 of 9 patients with primary intraocular CNS-NHL died within less than 4 years of follow-up. The bilateral and multifocal presentation in the majority of patients of our study had already been noted previously.1,2,20 The most frequent clinical features, vitreitis and chorioretinal lesions, are consistent with the literature.20,29 Anterior segment involvement in lymphoma has been described as unusual30,31 but was noted in 3 of 13 patients of our population. In all cases, it was associated with elevated intraocular pressure. One patient with primary large B-cell CNS-NHL exhibited primarily iris involvement (Fig 3) with normal posterior segment findings; evaluation for other evidence of lymphoma was negative. One year after the diagnosis of ocular lymphoma was established, meningeal localization without concurrent intracerebral involvement developed. The characteristics of the involvement of this patient differ from the usual manifestations of primary ocular and CNS NHL. The association of peripheral T-cell lymphoma with anterior segment UMS, found in one patient, has already been described.30,37 Retinal involvement in systemic nonHodgkin’s lymphoma has been reported to be exceptionally rare32,33 but was noted in 1 patient in our series (lymphoplasmacytoid lymphoma, Fig 7). In lymphoplasmacytoid lymphoma with hyperviscosity (Waldenstro¨m’s macroglobulinemia), retinopathy resulting from vascular abnormalities is seen regularly, but recently an occurrence of vitreitis was also described.8 Our patient with lymphoplasmacytoid lymphoma (Fig 7) presented with retinal infiltrates with associated serous detachment and elevated intraocular pressure. Noteworthy is a patient with extensive mucosal-associated lymphoid tissue lymphoma and ocular manifestations con-

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Rothova et al 䡠 Uveitis Masquerade Syndromes Figure 12. Occlusion of a retinal vessel in an immunosuppressed 26-year-old female patient (Table 3, number 13) after renal transplantation simulating an infectious process such as cytomegalovirus retinitis. The aqueous and serum analyses were negative for Toxoplasma gondii, herpes simplex virus, varicella zoster virus, and cytomegalovirus. A, On fundoscopy, the lesion was characterized by multiple hemorrhages, cotton wool spots, and hard exudates along the course of the macular branch vein, suggesting the diagnosis of branch retinal vein occlusion. B, Fluorescein angiography exhibited retinal hemorrhage (possibly masking the eventual obstruction site) and staining of the macular branch vein. The patient also developed pulmonary emboli and subsequently received anticoagulation therapy. The possibility of a branch retinal artery (or combined artery and vein) occlusion resulting from retinal embolism is also possible. However, the signs typical for the acute stage of an artery occlusion were not seen. C, Within several weeks, the hemorrhage disappeared and the secondary changes of pigment epithelium along the upper macular artery became visible. Increased retinal circulation time in the area of occluded segment was not present. Figure 13. Macular lesion in retinal pattern dystrophy masquerading as infectious retinitis (Table 3, number 9). The patient was a 33-year-old Hungarian woman who came to our hospital for treatment of her long-standing subnormal visual acuity in both eyes. The bilateral atrophic lesions in the macula simulated infectious lesions. A, Central atrophic lesion resembles scar from previous infectious retinitis. B, Peripheral pigmentary changes were apparent on fluorescein angiography. Note the normal aspect of the optic disc and vessels. Electroretinogram (ERG) revealed normal photopic and scotopic responses; electrooculogram (EOG) was grossly abnormal and peripheral visual fields were full. There was a long-standing history of poor vision in the dark. Figure 14. Retinal lesions in hyperhomocystinemia masquerading as occlusive vasculitis (Table 3, number 7). A 22-year-old woman noted severe visual loss 1 day after giving birth to her first child. At that time, she also had thrombophlebitis of her arm. There was no associated toxemia resulting from pregnancy or hypertension. Examination for infectious and autoimmune diseases as well as blood studies revealed no abnormalities except for an erythrocyte sedimentation rate of 48 mm/hour. A, Multiple pericentral hemorrhages and exudates resulting from multiple occlusions of a branch of the retinal artery probably combined with a central retinal vein occlusion. Note swollen optic disc with flame-shaped hemorrhage and attenuated arteries. Obstructed arteries are visible on the surfaces of the hemorrhages. Retinal veins are dilated and tortuous. B, Fluorescein angiography demonstrates multifocal filling defects in the retinal arteries and the choroid. Note the retrograde filling of retinal veins and their pathologic staining. Visual acuity was hand movements, and there were cells in the anterior chamber and vitreous. The ischemic retinopathy was treated with laser coagulation. A similar course of events occurred 1 year later in her other eye; at that time, the diagnosis of hyperhomocystenemia was confirmed. Figure 15. Diabetic retinopathy masquerading as infectious retinitis (Table 3, number 15). Note the confluent yellow-white lesions with associated hemorrhages and the sparing of the macular area. Similar lesions were also present in the nasal mid-periphery. The patient presented with sudden decrease of vision 3 months after cataract surgery in the affected eye. Š

sisting of a lacrimal gland tumor, dry eyes, and episcleritis associated with choroidal white lesions, which together closely resemble the recently reported masquerade syndrome of scleritis and choroidal white dots in mucosalassociated lymphoid tissue (Fig 6).34 The typical ocular manifestations of leukemia are leukemic retinopathy and orbital infiltration.35,36 The ocular relapse in acute lymphoblastic leukemia is known to indicate a poor prognosis and is commonly associated with bone marrow (but not necessarily with CNS) relapse.35,37– 41 In contrast, CNS involvement was associated with posterior segment relapse. The course of the disease in our three patients was in accordance with the literature. Two patients had leukemic chorioretinal infiltrates, which suggested infectious retinitis (Fig 8) and were associated with bone marrow relapse; one child with acute lymphoblastic leukemia developed bilateral anterior segment UMS with elevated intraocular pressure as a first sign of CNS relapse. The nonhematologic malignancies in UMS included retinoblastoma, melanoma, and metastasis of a lung cancer. None of these patients had a history of cancer, and in all cases the ophthalmologist was the first to diagnose malignancy. Approximately one third of all patients with uveal metastases did not have a history of primary cancer.42 Breast and lung cancers represented more than two thirds of the primary tumor sites.42 Just as retinoblastoma should be included in the differential diagnosis of ocular inflammation in childhood,12 uveal melanomas should be considered for adults. In a series of 450 enucleations for uveal melanoma, 22 (4.9%) initially presented with ocular inflammation.9 So far, nonmalignant UMS has not been described systematically. The nonmalignant UMS syndromes should, however, be recognized, because in our patient population they revealed previously unknown systemic or ocular dis-

orders in 10 of 21 patients (systemic hypertension in 3, carotid occlusive disease in 2, hereditary ocular disorder in 5). The majority of ocular manifestations of systemic vascular disease mimicked posterior uveitis (Figs 9, 11, and 12). The clinical features of focal chorioretinal lesions caused by choroidal infarction were accompanied by a cellular reaction suggesting a combination of old scars and new active focal lesions. This combination of features can be typical for ocular toxoplasmosis (Fig 9). Unrecognized retinal vascular lesions in immunosuppressed patients might suggest infectious processes (Fig 12). This study indicates that unexplained chorioretinal lesions, especially in elderly and/or immunosuppressed patients, require evaluation for cardiovascular disease. Multiple and/or rare pathologies (such as unnoticed perforating trauma in hereditary ocular disease) may disguise the correct diagnosis, which may therefore remain elusive for a long time. Iris retraction syndrome had already been noticed as a cause of UMS.7 Iris retraction syndrome might become manifest after an unrepaired retinal detachment, but it may also occur after intraocular surgery, masquerading as persistent postoperative uveitis. Despite an extensive search for the causes of intraocular inflammatory disease, approximately 40% of all uveitis cases remain idiopathic.43 Therefore, ophthalmologists encounter patients with idiopathic uveitis regularly and treat them symptomatically. The identification of those with UMS is, however, necessary because of the high frequency of underlying malignant and nonmalignant systemic conditions. Patients aged 40 years and older with unexplained vitreitis and chorioretinal lesions, especially those with an incomplete therapeutic response, should undergo evaluation for UMS. The diagnosis of UMS should also be considered when evaluating patients with unexplained unilateral uveitis

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Ophthalmology Volume 108, Number 2, February 2001 and elevated intraocular pressure.44 In a significant number of cases (approximately 50% in the present UMS series), the ophthalmologist may be the first to recognize systemic malignancy or accurately identify the nonmalignant systemic disease so that treatment to preserve the quality of life and vision may be instituted. Our study covers causes, clinical presentations, and informative diagnostic tests for noninflammatory disorders that present clinically as uveitis (masquerade syndromes). Awareness of the clinical manifestations of UMS and application of the correct diagnostic procedures should shorten the diagnostic delay and improve the differentiation of UMS from genuine inflammations. Timely diagnosis and treatment of UMS, especially the malignant type, are essential not only for the visual acuity but also for the life of the patient.

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