Association of peripheral multifocal choroiditis with sarcoidosis: A study of thirty-seven patients

Authors


Abstract

Objective

To assess the clinical spectrum of peripheral multifocal choroiditis (PMC) and its association with sarcoidosis.

Methods

Thirty-seven patients examined between November 1997 and November 2001 who met all diagnostic criteria for PMC were included in this retrospective study. Patients were assessed for the following signs of sarcoidosis: typical changes on chest radiography or computed tomography; predominantly CD4 lymphocytosis in bronchoalveolar lavage fluid; elevated serum angiotensin-converting enzyme levels; elevated gallium uptake; and noncaseating granuloma on biopsy.

Results

Most of the patients were female (30 of 37; 81%) and white (30 of 37; 81%). Mean ± SD age at onset was 57.5 ± 18.7 years. Seven (19%) of the 37 patients had biopsy-proven sarcoidosis and 18 patients (49%) with presumed sarcoidosis met at least 2 of the above-mentioned criteria for sarcoidosis but had normal biopsy results. Twelve patients (32%) had an indeterminate diagnosis. Patients with presumed sarcoidosis did not differ from those with proven sarcoidosis as regards the above-mentioned criteria, except for noncaseating granuloma, implying that more than two-thirds of patients (predominantly whites) had underlying sarcoidosis. Most patients with positive gallium scintigraphy had increased mediastinal uptake, as described in sarcoidosis. Patients with underlying sarcoidosis had more severe visual impairment due to cystoid macular edema (CME). Weekly methotrexate (0.3 mg/kg) seemed to control CME.

Conclusion

White patients with PMC should be considered to have sarcoidosis. The identification of sarcoidosis in patients with severe ocular disease can help with therapeutic choices.

INTRODUCTION

Sarcoidosis is a systemic disease characterized histologically by noncaseating granulomas with mononuclear cells and activated T lymphocytes at sites of inflammation. Because the etiology is unknown, sarcoidosis is still diagnosed on the basis of old criteria, such as multiorgan damage, alveolitis with increased numbers of lymphocytes (predominantly CD4+), elevated serum angiotensin-converting enzyme (ACE) levels, gallium uptake by activated macrophages, and no evidence of infections or other diagnoses. The diagnosis is usually established when clinical or radiographic findings are supported by histologic studies showing noncaseating epithelioid cell granuloma (1, 2).

Sarcoidosis mainly affects women (female:male ratio 1.36) between 25 and 35 years of age, but there is a second, smaller and broader peak between ages 45 and 65 years (3). Sarcoidosis commonly affects the lungs, lymph nodes, and skin. Uveitis can occur in the final stages of the disease, but is also the presenting sign in 10–20% of cases (4). Granulomatous lesions have been described in 80% of patients (5) and can be associated with peripheral choroiditis (6, 7).

Peripheral multifocal choroiditis (PMC) occurs mainly in women >55 years of age and is characterized by peripheral punched-out lesions associated with intraocular inflammation (Figure 1). Posterior uveitis may be sight-threatening when associated with inflammation of the posterior pole and with cystoid macular edema (CME). Elevated ACE levels accompanied by typical signs on chest radiographs are suggestive of sarcoidosis (8). In a recent study, chest computed tomography (CT) identified mediastinal and/or hilar lymphadenopathy and other abnormalities suggestive of sarcoidosis in ∼50% of patients with chronic uveitis (9).

Figure 1.

Fluorescein angiograms (intermediate phase) of peripheral multifocal choroiditis. Peripheral punched-out abnormalities appear as hyperfluorescent spots. a, Confluent abnormalities may be seen in dense areas of choroiditis. b, In other cases, peripheral abnormalities are more scarce.

Based on these data, previous investigators have postulated that PMC might be a feature of sarcoidosis (8, 9). In a retrospective study, we examined 37 patients with PMC for signs of sarcoidosis. We also investigated the ocular features and outcome of PMC in patients with underlying sarcoidosis.

PATIENTS AND METHODS

The patients were recruited in an academic referral center where their uveitis was managed. PMC was diagnosed on the basis of the 3 criteria defined by Lardenoye et al, namely multiple (>10), small, round, punched-out lesions in the peripheral retina; no central chorioretinal lesions; and intraocular inflammation (8). Consecutive patients seen between November 1997 and November 2001 were enrolled. The 37 patients meeting the criteria for PMC were included in this analysis.

The following data were recorded: sex, age, race, age at PMC onset, unilateral or bilateral involvement, time since onset of intraocular inflammation, best corrected visual acuity, clinical features at onset and during followup, initial and current treatments, and complications of PMC warranting corticosteroid or immunosuppressive treatment. All patients underwent a comprehensive eye examination.

Fluorescein angiography or optical coherence tomography was used to confirm the diagnosis of CME or papillitis. Visual acuity data were measured on a decimal scale, and analyzed by conversion to a log minimum angle of resolution (MAR) scale as previously reported (10). Legal blindness was defined as decimal visual acuity ≤0.1 in the better eye (log MAR visual acuity ≥ 1) (11). Mean best corrected visual acuity in the better and worse eyes was compared between patient subgroups. Relapses of CME were only considered relevant when systemic corticosteroid therapy or immunosuppressive treatment failed to control inflammation.

All patients underwent a standard screening protocol that included a medical history-taking and laboratory tests for syphilis and Borrelia burgdorferi (and human T lymphotropic virus type I [HTLV-I] serology in patients with risk factors for this infection). Patients with ophthalmic features compatible with birdshot retinochoroidopathy were excluded if they carried the HLA–A29 allele.

The diagnostic battery for sarcoidosis included a purified protein derivative (PPD) skin test (by comparison to any previous results), standard chest radiographic examination, and ACE serum assay. A history of contacts with Mycobacterium tuberculosis and of pulmonary disease was sought. Most patients, and particularly candidates for systemic steroid treatment, underwent other investigations including high-resolution CT of the chest, bronchoalveolar lavage (BAL), and bronchial and/or salivary gland biopsy. Two patients also underwent conjunctival biopsy. Gallium-67 scintigraphy was used when sarcoidosis was strongly suspected but when CT and other tests were inconclusive. Based on chest radiographic findings, the patients were divided into 5 subgroups according to the American Thoracic Society chest staging system (0, I, II, III, IV) (1).

Thirty-two patients underwent both conventional and high-resolution CT (CT Twin; Elscint, Haifa, Israel). High-resolution CT was performed at 200 mA and 120 kV. Sections 1-mm thick were acquired from the apex to the base of the lung, at 10-mm intervals. A high-spatial-frequency reconstruction algorithm was used for both conventional 5-mm and thin-section images. CT scans were viewed at windows appropriate for pulmonary parenchyma and mediastinum. CT images were reviewed blindly by a pulmonary radiologist. Findings were considered consistent with pulmonary sarcoidosis if they showed parenchymal abnormalities, hilar adenopathies, or mediastinal adenopathies typical of sarcoidosis. Typical signs of lung involvement were thickened bronchovascular bundles; spherical, mass-like opacities; linear opacities; multiple small discrete nodules; thickening of the pleural surface; ground-glass opacities; and hilar or mediastinal adenopathies >10 mm (12).

Twenty-seven patients underwent bronchial endoscopy, 25 underwent biopsy of the main branches using alligator forceps, and 22 underwent BAL (right middle lobe, 0.9% saline). Cells were stained with May-Grunwald-Giemsa and cell populations were counted per 500 cells. The CD4:CD8 T-cell ratio in BAL fluid was determined by using fluorescent monoclonal antibodies and flow cytometry (Coulter Beckman SA, Paris Nord II, France). A patient treated with systemic corticosteroids was excluded from this analysis. BAL was considered consistent with pulmonary sarcoidosis if lymphocytes represented >15% of total cells and were predominantly CD4+, and if the CD4:CD8 cell ratio was >3.5 (13, 14).

Sixteen patients underwent gallium scintigraphy. Planar images (head, neck, thorax, abdomen, and pelvis) were followed by thoracic single-photon–emission computed tomography imaging. Scans were acquired with a double-head gamma camera (SOPHA, DST-XL, Buc, France) and medium-energy collimators, 48 hours after injection of 111 MBq of gallium-67 citrate (Schering, Gif Sur Yvette, France). Images were reviewed blindly by 3 nuclear physicians: gallium uptake was assessed in the lacrimal and salivary glands, thorax, and viscera (liver, spleen, etc.). Uptake intensity was determined by comparison with the liver background; it was recorded as grade 1 if less intense than the liver; grade 2 if equal to the liver; and grade 3 if more intense than the liver. Gallium scans were considered highly suggestive of sarcoidosis if lacrimal or salivary gland uptake or mediastinal, hilar, or pulmonary uptake was grade 2 or 3; the probability of sarcoidosis was considered low if lacrimal or salivary gland uptake or mediastinal, hilar, or pulmonary uptake was grade 1.

ACE levels were determined with a spectrometric method (Sigma-Aldrich chimie SARL, Isle d'Abeau, France), as previously described (15), and were considered elevated if >52 IU/liter (mean ± 2 SD; SD = 11 IU/liter). Results were unavailable in 1 case, and 5 patients treated with systemic corticosteroids or ACE inhibitors were excluded from this analysis.

Patients with active pulmonary tuberculosis were excluded when Mycobacterium tuberculosis was detected in bronchoalveolar fluid or sputum by direct examination and culture. Patients were also excluded when they had had untreated tuberculosis. Sarcoidosis was considered proven when histologic examination of bronchial, salivary gland, or conjunctival biopsy material showed a noncaseating granuloma. For the purposes of this study, presumed sarcoidosis was diagnosed when patients met at least 2 of the 4 above-mentioned criteria (CT, BAL, gallium scintigraphy, and ACE) but biopsy results were normal or unavailable. The diagnostic work-up for sarcoidosis was considered indeterminate when patients had only 1 diagnostic criterion.

The Kruskal-Wallis and Fisher exact tests were used to analyze quantitative (mean ± SD) and qualitative variables, respectively. The presumed and indeterminate sarcoidosis groups were compared with the biopsy-proven sarcoidosis group in terms of epidemiologic characteristics and each diagnostic criterion for sarcoidosis. Ocular features were compared among the 3 groups. All analyses were 2-sided and P values < 0.05 were considered significant. Calculations were performed using the SAS software package version 8.01 (SAS Institute, Cary, NC).

RESULTS

General features

The individual characteristics of the 37 patients with PMC are listed in Table 1 and analyzed in Tables 2 and 3, according to the sarcoidosis diagnostic category (proven, presumed, or indeterminate). None of the patients tested positive for Treponema or Borrelia infection. HTLV-I infection was ruled out in patients with risk factors for this infection. Seven patients (19%) had been in close contact with a person with active tuberculosis, and 13 patients (35%) had had either skin-test conversion or had been treated for pulmonary disease, but active pulmonary tuberculosis was ruled out by Mycobacterium tuberculosis culture negativity of alveolar fluid or sputum. None of the patients had a strongly positive PPD reaction (>15 mm) or a papulonecrotic tuberculid following the PPD skin test.

Table 1. Extraophthalmologic characteristics of each patient with PMC*
Patient numberAge at diagnosis, yearsRaceSexMT contactsChest radiographChest CT scan HA/MA/PIBALGallium uptake L/S/ITPPD skin test, mmACE 8 < N < 52 (IU/L)BiopsyBiopsy site B/SG/C
Cells/mm3Lymph, %CD4/CD8
  • *

    PMC = peripheral multifocal choroiditis; MT = Mycobacterium tuberculosis; CT = computed tomography; HA = hilar adenopathy >10 mm; MA = mediastinal adenopathy >10 mm; PI = parenchymal involvement (thickened bronchovascular bundles, spherical opacities, linear opacities, parenchymal nodules, thickening of the pleural surface, ground glass opacities); BAL = bronchoalveolar lavage; Lymph = lymphocytes; L = lacrimal; S = salivary; IT = intrathoracic uptake; PPD = purified protein derivative; ACE = angiotensin-converting enzyme; B = bronchial biopsy; SG = salivary gland biopsy; C = conjunctival biopsy; W = white; NA = not available; II = bilateral hilar lymphadenopathy plus pulmonary infiltrations; PT = pulmonary tuberculosis; A = anergy; BCG = BCG vaccine; I = bilateral hilar lymphadenopathy; O = normal chest radiograph findings; G3 = grade 3 intrathoracic uptake; N = normal; CC = close contact; NAfr = North African; Conv = conversion from a negative to a positive tuberculin skin test; Bl = black; III = pulmonary infiltrations without bilateral hilar lymphadenopathy; G2 = grade 2 intrathoracic uptake; IV = pulmonary fibrosis; G1 = grade 1 intrathoracic uptake; Car = Caribbean.

  • Patient receiving systemic corticosteroids.

  • Patient receiving ACE inhibitors.

Proven sarcoidosis
 174WF-IINA19515NANANA112+B
 275WFPTIIMA/HA/PI260754NAA359+SG
 332WMBCGIMA/HA/PI690267NA> 590+/−B/SG
 480WMPTOMANANANA−/−/G3AN+/−B/SG
 580WF-OMA/PI138226NA< 562+/−/−C/SG/B
 660WFCCOMA2701710NAAN+/−/−B/SG
 730NAfrMBCGOPI40082−/−/−>5N+/−B/SG
Presumed sarcoidosis
 856WFBCGO-420665−/−/−> 587B
 965WFPTIMA/HA274204NAA81−/−SG/B
 1081WFPTIHA/PINANANANA> 573NANA
 1168WFCCO-280356−/−/G3< 5NB
 1250NAfrMBCGO-100254NA> 588−/−SG
 1371WFConvO-6502515−/−/G3AN−/−SG/B
 1473WF-OMA/PI270265.5NA< 5118−/−B
 1550WFPTIMA/HA/PI280625−/−/G3NAN−/−SG/B
 1663WMCCIHA/MA349264−/−/G3< 5115−/−SG/B
 1739BlMConvO-140629−/−/−> 569−/−SG/B
 1850WFBCGIHA/MA140394NA< 5N−/−SG/B
 1986WFCCOMA/PINANANANA< 5N−/−SG/C
 2048WFBCGOMA/PI89173NA< 554−/−SG/B
 2160WFCCIIIHA/PI258163−/−/G3< 587−/−SG/B
 2257WFConvOHA/MANANANA−/G2/G3A61−/−SG/B
 2371WFCCIHA/MA/PI12O229−/G2/G3AN−/−SG/B
 2443WFPTIIIPI260665−/−/−> 5NSG/B
 2582WFCCIHA/MA/PINANANA−/−/G3< 5N−/−SG/B
Indeterminate sarcoidosis
 2652NAfrF-ONA8625NANA< 5N−/−SG/B
 2773WFConvIVFibrosisNANANA−/−/G1> 553NANA
 2868WF-IIIPINANANANA< 5NB
 2935WFBCGONANANANANANA98SG
 3035WFBCGOPINANANANANANSG
 3140CarMBCGOPI170351.5NANAN−/−SG/B
 3281WFConvONANANANANAANANANA
 3362WFPTONANANANANANANNANA
 3420WFBCGO-NANANA−/−/G1NANNANA
 3523NAfrFConvO-NANANANA> 5N−/−SG/B
 3670WF-O-NANANANA< 5NSG
 3726NAfrFBCGO-NANANA−/−/−< 5NSG
Table 2. Extraophthalmologic characteristics of patients with PMC*
 SarcoidosisPTotal n = 37
Proven n = 7Presumed n = 18PIndeterminate n = 12
  • *

    PMC = peripheral multifocal choroiditis; Stage I = bilateral hilar lymphadenopathy (BHL); Stage II = BHL plus pulmonary infiltrations; Stage III = Pulmonary infiltrations without BHL; Stage IV = pulmonary fibrosis; CT = computed tomography; BAL = bronchoalveolar lavage; ACE = angiotensin-converting enzyme; PPD = purified protein derivative.

  • Comparison between proven and presumed sarcoidosis groups.

  • Comparison between proven sarcoidosis group and indeterminate uveitis group.

  • §

    Patients receiving systemic corticosteroids were excluded.

  • Patients receiving ACE inhibitors were excluded.

Women/men4/315/30.411/10.330/7
Race, no./n (%)  0.46 0.6 
 White6/7 (85.5)16/18 (89) 8/12 (66.5) 30/37 (81)
 Other categories1/7 (14.5)2/18 (11) 4/12 (33.5) 7/37 (19)
Age at onset, mean ± SD years61.6 ± 21.9461.8 ± 13.820.7548.75 ± 21.530.257.5 ± 18.7
Chest X-radiograph, no./n (%)  0.99 0.03 
 Normal4/7 (57)9/18 (50) 10/12 (83.5) 23/37 (62)
 Stages I, II3/7 (43)7/18 (39) 0/12 (0) 10/37 (27)
 Stages III, IV0/7 (0)2/18 (11) 2/12 (16.5) 4/37 (11)
CT scan, no./n (%)  0.32 0.01 
 Normal0/6 (0)5/18 (28) 4/8 (50) 9/32 (28)
 Adenopathy (A)2/6 (33)4/18 (22) 0/8 (0) 7/32 (22)
 Parcnchymal involvment (PI) or fibrosis1/6 (16.5)1/18 (5.5) 4/8 (50) 6/32 (19)
 Both (A and PI)3/6 (50)8/18 (44.5) 0/8 (0) 10/32 (31)
Lymphocytosis >15% and CD4/CD8 ratio ≥3.5 in BAL, no./n (%)4/5 (80)§12/14 (85.5)0.990/2 (0)0.1416/21 (76)
Positive G67 scintigraphy, no./n (%)1/2 (50)8/11 (73)0.990/3 (0)0.49/16 (56)
ACE >52 IU/liter, no./n (%)4/6 (66)§10/15 (66)0.992/10 (20)0.1016/31 (51.5)
PPD skin test, no./n (%)  0.42 0.35 
 >5 mm2/6 (33)5/17 (29) 2/7 (29) 9/30 (30)
 <5 mm1/6 (17)8/17 (47) 4/7 (57) 13/30 (43)
 Anergy3/6 (50)4/17 (24) 1/7 (14) 8/30 (27)
Table 3. Histologic findings on biopsy specimen from patients with PMC*
 Sarcoidosis
Proven n = 7Presumed n = 18Indeterminate n = 12Total n = 37
  • *

    PMC = peripheral multifocal choroiditis.

Granuloma on biopsy, no./n (%)7/13 (54)0/30 (0)0/11 (0)7/54 (13)
 Bronchial5/6 (83)0/15 (0)0/4 (0)5/25 (20)
 Salivary glands1/6 (17)0/14 (0)0/7 (0)1/27 (4)
 Conjunctival1/1 (100)0/1 (0)0/0 (0)1/2 (50)

Respectively, 7 (19%) and 18 (49%) patients were diagnosed with proven and presumed sarcoidosis, whereas 12 (32%) patients had indeterminate findings. PMC usually affected female patients (30 of 37; 81%) of white origin (30 of 37; 81%). Mean ± SD age at presentation was 55 ± 18.7 years. None of the patients had a preexisting diagnosis of sarcoidosis or reported systemic symptoms. Sarcoid granulomas were found in 7 (13%) of 54 biopsy samples from 32 patients, and were most frequent on bronchial biopsy (5 of 25; 20%). Only 14 (38%) of the 37 patients with PMC had signs of granulomatous lung disease on standard posteroanterior and lateral chest radiographs. Patients with proven sarcoidosis differed significantly from those with indeterminate sarcoidosis with regards to findings consistent with sarcoidosis on chest radiographs (P = 0.03). In particular, patients with proven sarcoidosis were more likely to have pulmonary infiltration (stage II) or bilateral hilar lymphadenopathy (stage I) than patients with indeterminate disease (43% versus 0%). In contrast, the proven sarcoidosis group did not differ significantly from the presumed sarcoidosis group in this respect (43% versus 39%). Chest CT showed parenchymal abnormalities and mediastinal or hilar adenopathies in 23 (72%) of the 32 patients concerned (Figure 2).

Figure 2.

Typical findings of sarcoidosis based on high-resolution computed tomography (CT) in patient number 3 with peripheral multifocal choroiditis. a, Parenchymal involvement shows up as multiple, small nodules (arrow). b, Contrast-enhanced CT shows bilateral hilar lymphadenopathies and a subcarinal lymphadenopathy (arrows). R = right; L = left.

Patients with proven sarcoidosis also differed significantly from patients with indeterminate sarcoidosis regarding chest CT findings consistent with sarcoidosis (P = 0.01). In particular, patients with proven sarcoidosis had more mediastinal or hilar adenopathies (83.5% versus 0%) but they did not differ significantly in this respect from patients with presumed sarcoidosis (83.5% versus 66.5%). BAL lymphocytosis >15% with an elevated CD4:CD8 cell ratio (>3.5) was found in 16 (76%) of the 21 patients concerned. The proportion of patients with lymphocytosis and an elevated CD4:CD8 cell ratio in BAL tended to be larger in the proven sarcoidosis group than in the indeterminate sarcoidosis group (80% versus 0%; P = 0.1), whereas patients with proven sarcoidosis did not differ from patients with presumed sarcoidosis in this respect (80% versus 85%).

Nine (56%) of the 16 patients who underwent gallium scintigraphy had positive results. Abnormal gallium uptake was most frequently intrathoracic (Figure 3). Nine patients had grade 2 or 3 mediastinal or hilar uptake. Only 2 patients (numbers 22 and 23) had significant salivary gland uptake (grade 2). The other 7 patients had no significant gallium uptake. All patients with adenopathies on CT had increased mediastinal gallium uptake. Even though CT findings were found to be normal on review in patients 11 and 13, mediastinal gallium uptake was significant.

Figure 3.

The particular pattern of gallium uptake in peripheral multifocal choroiditis with underlying sarcoidosis (patient number 22): Note the multiple foci of gallium hyperfixation in the thorax, corresponding to mediastinal and hilar uptake with a lambda pattern; low symmetric lacrimal gland gallium uptake; and no significant salivary gland uptake. ANT = anterior; POST = posterior.

Serum ACE levels were elevated in 16 (51.5%) of the 31 patients for whom results were available. Patients 21 and 22 had elevated ACE levels and gallium scintigraphic signs consistent with sarcoidosis, but normal or equivocal chest radiographs. The proportion of patients with ACE elevation tended to be higher in the proven sarcoidosis group than in the indeterminate sarcoidosis group (66% versus 20%; P = 0.1), whereas patients with proven sarcoidosis did not differ from patients with presumed sarcoidosis in this respect (66% versus 66%).

Ophthalmologic features

Ocular findings at presentation are shown in Table 4. PMC involved both eyes in most cases (29 of 37; 78%). At the initial examination, PMC was associated with granulomatous anterior uveitis in 11 (30%) of the 37 patients and was complicated by vitreitis, papillitis, and CME in 27 (73%), 17 (46%), and 17 (46%) patients, respectively. Mean ± SD visual acuity (log MAR) at presentation was 0.31 ± 0.29 in the better eye and 0.54 ± 0.43 in the worse eye. None of patients with PMC was legally blind, but 1 patient in the presumed sarcoidosis group only perceived hand movements with the right eye. Mean best corrected visual acuity (log MAR) in the worse eye was significantly lower in patients with proven or presumed sarcoidosis than in those with indeterminate sarcoidosis (0.61 ± 0.2 and 0.69 ± 0.53, respectively, versus 0.29 ± 0.25; P = 0.03). Patients with proven or presumed sarcoidosis were slightly more likely than patients with indeterminate sarcoidosis to have CME (57% and 61% versus 17%; P = 0.08).

Table 4. Ophthalmologic features at presentation
 SarcoidosisP*Total n = 37
Proven n = 7Presumed n = 18Indeterminate n = 12
  • *

    Ocular features were compared among the 3 groups.

  • MAR = minimum angle of resolution.

Bilateral ocular involvement, no./n (%)6/7 (86)13/18 (72)10/12 (83)0.6629/37 (78)
Best corrected visual acuity, mean ± SD log MAR
 The better eye0.41 ± 0.360.36 ± 0.310.19 ± 0.180.180.31 ± 0.29
 The worse eye0.61 ± 0.20.69 ± 0.530.29 ± 0.250.030.54 ± 0.43
Granulomas, no./n (%)1/7 (14)7/18 (39)3/12 (25)0.4511/37 (30)
Vitritis, no./n (%)3/7 (43)7/18 (39)11/12 (92)0.2227/37 (73)
Papillitis, no./n (%)5/7 (71)9/18 (50)3/12 (25)0.1517/37 (46)
Macular edema, no./n (%)4/7 (57)11/18 (61)2/12 (17)0.0817/37 (46)

Treatments and outcomes are listed in Table 5. The mean ± SD duration of followup was 27 ± 22 months, and 25 (68%) of the 37 patients were followed for at least 6 months. Treatment of ocular inflammation included corticosteroid eye drops in all cases (37 patients) and periocular corticosteroid injections, systemic corticosteroids, alone or combined with methotrexate (MTX), in 12 (32%), 16 (43%), and 7 (19%) patients, respectively. None of the 12 patients with indeterminate sarcoidosis received MTX; only 3 (25%) received systemic corticosteroids, compared with 4 (57%) of 7 and 9 (50%) of 18 patients with proven and presumed sarcoidosis, respectively. The proportion of patients with CME relapses after a mean treatment period of >6 months tended to be lower among patients receiving MTX than among those receiving only systemic corticosteroids (20% versus 75%; P = 0.1). Whatever the initial treatment or underlying disease, punched-out lesions failed to improve, and all the patients developed sequelae.

Table 5. Outcome of patients with PMC*
 SarcoidosisTotal n = 37
Proven n = 7Presumed n = 18Indeterminate n = 12
  • *

    PMC = peripheral multifocal choroiditis; MTX = methotrexate.

  • P = 0.01 (MTX + systemic corticosteroids compared with corticosteroids alone).

Followup, mean ± SD months20.3 ± 5.228.5 ± 19.428.8 ± 28.227 ± 22
Followup ≥ 6 months, no./n (%)6/7 (85.5)12/18 (66.5)7/12 (58.5)25/37 (68)
Treatment, no./n (%)    
 Corticosteroid drops7/7 (100)18/18 (100)12/12 (100)37/37 (100)
 Periocular corticosteroid injections4/7 (57)5/18 (28)3/12 (25)12/37 (32)
 Systemic corticosteroids4/7 (57)9/18 (50)3/12 (25)16/37 (43)
 Systemic corticosteroids + MTX2/7 (29)5/18 (28)0/12 (0)7/37 (19)
Macular edema relapses, no./n (% of patients treated for at least 6 months)    
  With MTX + systemic corticosteroids1/2 (50)0/3 (0)1/5 (20)
  With systemic corticosteroids2/2 (100)3/5 (60)1/1 (100)6/8 (75)
PMC sequella, no./n (%)6/6 (100)12/12 (100)7/7 (100)25/25 (100)

DISCUSSION

We studied a homogeneous group of patients strictly meeting the diagnostic criteria for peripheral multifocal choroiditis (8). Differential diagnoses such as active tuberculosis, syphilis, Lyme disease, and birdshot chorioretinopathy were ruled out (16–18). In addition, none of our patients had a strongly positive PPD reaction (>15 mm), ruling out underlying inactive untreated tuberculosis, as recently reported in a patient with a 30-mm PPD skin wheal (19).

Our patients were comparable to those described by Lardenoye et al in terms of mean age (58 and 55 years, respectively), the sex ratio, and ethnic origin (predominance of white women). None of the patients in either study reported systemic symptoms (8). Lardenoye et al identified a subgroup of patients with noncaseating granuloma, whereas others were diagnosed with suspected sarcoid choroiditis on the sole basis of hilar adenopathies on chest radiographs or elevated serum ACE levels (8, 17, 20). Because of the poor sensitivity and specificity of these 2 diagnostic criteria (9, 21), we only diagnosed presumed sarcoidosis when 2 of the 4 major criteria were present (elevated ACE levels, CT findings typical of sarcoidosis, predominantly CD4 lymphocytosis, and gallium uptake).

Chest radiographic or CT findings differed significantly between patients with proven sarcoidosis and those with an indeterminate diagnosis of sarcoidosis. Elevated ACE levels and significant BAL lymphocytosis seemed to be more frequent in the proven sarcoidosis group than in the small indeterminate group, whereas patients with proven sarcoidosis did not differ significantly from patients with presumed sarcoidosis in this respect.

Relative to one of the largest series of PMC (8), a similar proportion of patients had biopsy-proven sarcoidosis in our study (20% and 19%, respectively), whereas patients with a diagnosis of presumed sarcoidosis were more numerous in our study (5% versus 49%), partly owing to the high sensitivity (72%) of CT for mediastinal abnormalities. Kaiser et al reported that 65% of elderly patients with chronic panuveitis who had negative chest radiograph findings had positive chest CT findings, and that 93% of patients with histopathologic evidence of sarcoidosis had positive chest CT findings (9). In addition, Takahashi et al recently showed that patients with suspected ocular sarcoidosis, with mediastinal lymphadenopathy and parenchymal involvement (type II) on CT scan, had a 95% chance of having sarcoid granulomas on bronchial biopsy (or CT-oriented parenchymal biopsy) (22). In our study, a large proportion of patients (numbers 10, 14, 15, 19, 20, 21, 23, and 25) with presumed sarcoidosis (8 of 18) met type II CT criteria and none had granuloma, albeit solely on the basis of nonguided bronchial biopsy.

BAL also contributed to the diagnosis of presumed sarcoidosis in 5 patients (numbers 8, 11, 12, 13, and 17) in whom CT was negative. Significant lymphocytosis (>15% of total cells, and CD4:CD8 ratio >3.5) was also found in 3 patients (numbers 9, 16, and 18) who had type I CT criteria (bilateral hilar or mediastinal lymphadenopathy, without lung field involvement). In 82% of patients with presumed sarcoidosis and type 0 or I CT criteria, Takahashi et al also found significant BAL lymphocytosis, as in all patients with type II criteria. These authors considered that patients with type 0 or I CT criteria had sarcoidosis, even though most of them had no granuloma on biopsy (22), arguing that these findings were consistent with the concept that lymphocytosis occurs prior to granuloma formation in sarcoidosis (22–24). On this basis, 16 of 18 our patients with presumed sarcoidosis could be considered as having sarcoidosis.

In our series, scintigraphy showed significant abnormal gallium uptake in 9 of 13 patients with proven or presumed sarcoidosis, especially in the thorax. The distribution of gallium uptake was remarkably similar to each other in our patients. Gallium scanning usually discloses abnormal symmetric uptake by the salivary glands and symmetric uptake by the lacrimal glands (panda pattern), but the relevant publications offer no details on the type of ocular disease, and particularly PMC (25, 26). None of our patients had received corticosteroid therapy, which could have decreased gallium uptake in the salivary or lacrimal glands (27), and ACE inhibitors have not been shown to affect gallium uptake. However, Sulavik et al found a panda pattern in 79% of patients with sarcoidosis, whereas intrathoracic uptake (lambda pattern) was found in 72% of sarcoidosis patients but in none of 540 patients with other diagnoses (27, 28). Mediastinal gallium uptake was significant in 2 of our patients (numbers 11 and 13), although CT findings were normal at review. Gallium scintigraphy thus detected active intrathoracic lesions that were missed by CT. Gallium uptake consistent with sarcoidosis, and an elevated ACE level, were found in patient number 22, who had presumed sarcoidosis (BAL unavailable) without typical findings on standard chest radiography. According to Power et al, this combination of criteria is diagnostic of sarcoidosis (26). Taken together, our results and previously published data lead us to consider that 25 (68%) of our 37 patients with PMC had underlying sarcoidosis. Moreover, the frequency of sarcoidosis was probably underestimated because some of our patients with PMC of indeterminate origin had one diagnostic criterion for sarcoidosis but did not undergo BAL.

These results apply only to PMC as defined by Lardenoye et al. Multifocal choroiditis, consisting of multiple round retinal lesions at the posterior pole and macular neovascularization, was not taken into account in this study. However, our results especially might apply to whites with PMC. Twenty-two (73%) of 30 patients with underlying sarcoidosis were white. Geographic areas in which histoplasmosis or coccidioidomycosis are endemic would include more patients with PMC who definitely do not have sarcoid (29, 30).

PMC was usually bilateral, and was associated with granulomatous anterior uveitis in only 30% of patients. Granulomatous anterior uveitis was less sensitive than PMC for the diagnosis of ocular sarcoidosis, and also occurs in nonspecific inflammatory diseases, such as multiple sclerosis (31). Contrary to granulomatous anterior uveitis, histologic signs consistent with a granulomatous process have been found in choroidal infiltrates (7). Because of the risk of retinal damage, choroidal biopsy is not routinely performed in patients with suspected ocular sarcoidosis. Hershey et al considered conjunctival biopsy as an accurate and safer diagnostic tool for granulomatous abnormalities (20). However, the granulomatous process can involve organs other than the eye, as shown by positive bronchial or salivary gland biopsy specimens in some of our patients who had no systemic manifestation. This suggests that choroidal granulomas were more readily detected because of their symptomatic impact on visual acuity.

Patients with proven or presumed sarcoidosis had significantly poorer best corrected visual acuity in the worse eye than patients with indeterminate sarcoidosis. Moreover, best corrected visual acuity in the better eye was poor in the patients with proven or presumed sarcoidosis, suggesting that PMC with underlying sarcoidosis entails more severe visual disability. However, it must be noted that none of the patients with indeterminate sarcoidosis could be said definitively to not have sarcoid. Most of them did not undergo invasive investigations (bronchial biopsies or BAL), indicating that the extent of investigations depended on the severity of PMC.

CME was probably the main factor impairing visual acuity. Lardenoye et al reported that PMC carried a poor prognosis, mainly owing to CME, and that systemic corticosteroids were required in more than one-third of patients (8). In our series, 43% of patients required this treatment, particularly those with underlying sarcoidosis. Given the adverse effects of prolonged corticosteroid therapy, and the frequent relapses after treatment cessation, our patients with severe PMC received once-weekly MTX injections (0.3 mg/kg). This treatment was found in a noncomparative case series to improve visual acuity in patients with chronic sarcoid-associated panuveitis (4, 32). Baughman et al, in a double-blind, randomized trial, demonstrated the steroid-sparing properties of methotrexate in patients with symptomatic sarcoidosis (33). In our study, in which CME relapses were assessed after at least 6 months of treatment, MTX seemed to control macular inflammation much better than corticosteroids alone in patients with underlying sarcoidosis, although punched-out abnormalities did not improve. It must also be kept in mind that PMC usually occurs in elderly patients who are already at risk of bone demineralization, which may be compounded by steroid therapy.

Our data confirm the frequent association between presumed or proven sarcoidosis and PMC in white patients. Chest CT, BAL, and biopsies of bronchial tissue or salivary glands were useful for the diagnosis of sarcoidosis. Gallium scintigraphy appears to be as accurate as CT in this setting. However, in a subset of patients, no underlying systemic disease was diagnosed. Whether or not severe PMC is associated with extraocular findings, aggressive treatment may be warranted. Diagnosis of sarcoidosis in patients with PMC can help with therapeutic choices.

ACKNOWLEDGMENTS

We thank Martine Picard, MD, and Micheline Tulliez, MD, for technical assistance; Jacques Lacronique, MD, for editorial assistance; and Martine Grevet and Evelyne Cohen-Solal for administrative and secretarial help.

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