August 2011
Volume 52, Issue 9
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Cornea  |   August 2011
The Application of In Vivo Confocal Scanning Laser Microscopy in the Diagnosis and Evaluation of Treatment Responses in Mooren's Ulcer
Author Affiliations & Notes
  • Shin Hatou
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
  • Murat Dogru
    Johnson & Johnson Ocular Surface and Visual Optics Department, Keio University School of Medicine, Tokyo, Japan.
  • Osama M. A. Ibrahim
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
    Johnson & Johnson Ocular Surface and Visual Optics Department, Keio University School of Medicine, Tokyo, Japan.
  • Tais Wakamatsu
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
    Johnson & Johnson Ocular Surface and Visual Optics Department, Keio University School of Medicine, Tokyo, Japan.
  • Enrique Adan Sato
    Johnson & Johnson Ocular Surface and Visual Optics Department, Keio University School of Medicine, Tokyo, Japan.
  • Shigeto Shimmura
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
  • Kazuno Negishi
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
  • Kazuo Tsubota
    From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; and
  • Corresponding author: Shin Hatou, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; tr97469@zc4.so-net.ne.jp
Investigative Ophthalmology & Visual Science August 2011, Vol.52, 6680-6689. doi:10.1167/iovs.10-5906
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      Shin Hatou, Murat Dogru, Osama M. A. Ibrahim, Tais Wakamatsu, Enrique Adan Sato, Shigeto Shimmura, Kazuno Negishi, Kazuo Tsubota; The Application of In Vivo Confocal Scanning Laser Microscopy in the Diagnosis and Evaluation of Treatment Responses in Mooren's Ulcer. Invest. Ophthalmol. Vis. Sci. 2011;52(9):6680-6689. doi: 10.1167/iovs.10-5906.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To evaluate the extent of corneal inflammation and the response to treatment in patients with Mooren's ulcer, by in vivo confocal microscopy (IVCM).

Methods.: Twenty-two eyes of 15 patients with Mooren's ulcer were enrolled in this prospective study. All subjects underwent routine ophthalmic examinations, IVCM, and conjunctival histopathologic examination of specimens in patients undergoing conjunctival excision. Eyes with active ulcer were treated with topical corticosteroids and additional therapy, depending on the signs and symptoms. Eyes in remission continued to receive the previous treatment protocols. The relation between the severity of ulcer and inflammation status as assessed by IVCM was also studied. The endpoints were inflammatory cell density (ICD), counted by IVCM, and the extent of the limbal arc involved with ulcers.

Results.: Ten eyes had active corneal ulcers, and 12 eyes had been in remission for the past year. The mean ICD of eyes with active ulcers before treatment was 2092.7 ± 1538.6 cells/mm2 (range, 835.3–7832.7; 95% CI, 3232.5–952.9). Nine of the eyes improved at 8 weeks, with a decrease in ICD to 249.1 ± 109.0 cells/mm2 (range, 100.3–595.3; 95% CI, 329.8–168.3). One eye had corneal perforation, and ICD immediately before perforation was 1677.6 ± 247.6 cells/mm2. The mean ICD of 12 eyes in remission was 357.5 ± 266.8 cells/mm2 (range, 12.7–1127.0; 95% CI, 555.2–159.8). The correlation of the ICD and the extent of limbal involvement with ulcers was strong (R 2 = 0.8119).

Conclusions.: ICD evaluated by IVCM is a useful and promising parameter for evaluation of the degree of inflammation in eyes with Mooren's ulcer and for assessment of response to treatment.

Mooren's ulcer begins as a crescent-shaped gray-white infiltrate in the peripheral cornea, which usually progresses to epithelial breakdown and stromal melting, eventually developing into a chronic, usually painful, peripheral corneal ulcer. 1 The leading edges of the ulcer are undermined, infiltrated, and deepithelialized, and the adjacent conjunctiva and sclera are usually inflamed and hyperemic. 1 Histopathology of resected conjunctiva from subjects with Mooren's ulcer has been reported to show a large number of plasma cells, lymphocytes, and histiocytes. 2  
Currently, a stepladder approach to therapy is recommended. 3 Initially, patients with Mooren's ulcer are aggressively treated with topical corticosteroids. 3 If there is no improvement in the signs and symptoms, conjunctival excision is performed. Systemic immunosuppressive agents (prednisolone, cyclosporine, cyclophosphamide, methotrexate, or azathioprine) can be used. 3 6 If such management steps fail or there is a corneal perforation or descemetocele, surgical approaches such as amniotic membrane transplants, keratoepithelioplasty, or lamellar or penetrating keratoplasty can be performed. 6 10  
The response to therapy is generally judged subjectively by degree of pain and the conventional slit lamp microscopic examination, such as resolution of conjunctival hyperemia, ciliary injection, and corneal reepithelization judged by fluorescein staining. 3 It is important to quantify the degree of inflammation and the changes in response to treatment in patients with Mooren's ulcer. In vivo laser scanning confocal microscopy is a new emerging less-invasive technology, which is useful as a supplementary diagnostic tool for in vivo assessment of the histopathology of many ocular surface diseases and anterior segment disorders. 11 18 In this study, we used in vivo laser scanning confocal microscopy (the Rostock Corneal Software Version 1.2 of the Heidelberg Retina Tomograph II: RCM/HRT II; Heidelberg Engineering, Dossenheim, Germany) to evaluate the degree of inflammation in the cornea and conjunctiva of patients with Mooren's ulcer and also to study the changes in response to anti-inflammatory treatment. To the best of our knowledge, this is the first report to describe the confocal laser microscopy findings in Mooren's ulcer. 
Materials and Methods
Fifteen adult patients (seven men, eight women; mean age, 59.9 ± 19.4 years) with a diagnosis of Mooren's ulcer who were willing to comply with the protocol and who provided informed consent were enrolled in the study. Examination procedures were board reviewed. The study complied with the principles of the Declaration of Helsinki for research involving human subjects. Ten eyes of seven patients who had active peripheral corneal ulcers in the peripheral cornea, with pain and the adjacent inflamed and hyperemic conjunctiva and sclera, were diagnosed as patients with active Mooren's ulcer. Twelve eyes of nine patients with a history of Mooren's ulcer, whose corneal ulcers had not relapsed for the past 12 months, were diagnosed as Mooren's ulcers in remission. One patient had bilateral Mooren's ulcers, whose right eye was in remission and whose left eye was active. Patients who had rheumatoid arthritis or other collagen vascular diseases, staphylococcal marginal keratitis accompanied by blepharitis, infectious ulcers, giant cell arteritis, local infectious causes, including herpes simplex and herpes zoster, Terrien's degeneration, pellucid marginal degeneration, senile furrow degeneration, ocular rosacea, or leukemia, were excluded. 6 To exclude rheumatoid arthritis and other collagen diseases, blood tests of RA factor, antinuclear antibody, anti-Ro/SSA antibody, anti-La/SSB antibody, CRP, and CBC were performed. To exclude staphylococcal marginal keratitis or other infectious diseases, we performed bacterial cultures from conjunctival sac swabs, eye discharge, or margin of ulcers. To exclude herpes simplex and herpes zoster infections, we requested SRL Laboratory (Tokyo, Japan) to perform herpes antigen test by the fluorescein antibody (FA) method using scratch samples from the ulcer beds. Other diseases meeting the exclusion criteria were checked by clinical record and anamnesis. 
Patients with active Mooren's ulcers underwent in vivo laser confocal microscopy and a complete ophthalmic examination, including measurement of visual acuity and intraocular pressure, slit lamp microscopic examination, and dilated fundus examination at the enrollment visit, day 0. At the study follow-up visits (scheduled on weeks 1, 4, and 8 after enrollment), in vivo laser confocal microscopy and ophthalmic examination were performed, consisting of visual acuity testing, intraocular pressure, and slit lamp microscopic examination. At the enrollment visit, patients with Mooren's ulcers in remission underwent in vivo laser confocal microscopy and ophthalmic examination, including slit lamp microscopic examination. 
All patients at day 0 had anterior segment photographs and slit lamp microscopic examination, including fluorescein staining of the ocular surface. The extent of limbal involvement with ulcers and adjacent gray-white infiltration was expressed in degrees (0–360°). To measure it, the corneal circumference of a slit lamp photograph was divided in 24 sections of 15° each. The count of sections of limbal involvement along with ulcers was then recalculated in degrees. The extent of limbal involvement in eyes with Mooren's ulcer in remission was regarded as 0°, according to the protocol of the study. 
In vivo laser confocal scanning laser microscopy (CSLM) was performed on all subjects with a new-generation confocal microscope (the Rostock Corneal Software, ver. 1.2, Heidelberg Retina Tomograph II [RCM/HRT II]; Heidelberg Engineering GmbH). After the administration of topical anesthesia with 0.4% oxybuprocaine, the subject's chin was placed in the chin rest. The objective of the microscope was an immersion lens (magnification 63×; Carl Zeiss, Oberkochen, Germany) covered by a polymethylmethacrylate (PMMA) cap (Tomo-cap; Heidelberg Engineering GmbH). Comfort gel (Bausch & Lomb, GmbH, Berlin, Germany) was used as a coupling agent between the applanating lens cap and the conjunctiva. By adjusting the controller, the center of the cap was applanated onto the cornea, and in vivo digital images of the cornea were visualized directly on the computer screen. When the first superficial cells were seen, the digital micrometer gauge was set at 0; then, when the operator pressed on the foot pedal, sequence images were recorded by a charge-coupled device (CCD) color camera (maximum 30 frames/s) while the focal plane was gradually moved forward into the corneal stroma. Corneal and adjacent limbal conjunctival lesions were scanned while the applanating lens was moved through the entire length of the ulcer with minute vertical or horizontal movements. Four nonoverlapping areas with images of inflammatory cells were selected from all vertical scan areas, and inflammatory cell density (ICD) was counted at the basal cell layer level of the corneal epithelium in each 400 × 400-μm frame, with the help of the accompanying software. To avoid overlap, the scans were performed along the entire length of the ulcers on the limbal side, central corneal side, and superior/inferior edges, at all four sites with minute movements of the PMMA cap, and three nonoverlapping scans per site with best resolution quality were selected and underwent ICD calculations. The depth chosen for ICD calculations in the ulcers corresponded to the level of the healthy basal epithelium along the edge of the ulcer. White round cells of 5- to 15-μm diameter were chosen for counting ICD, and images with many dendritic cells were not used, because it is hard to count dendritic cells accurately. The mean ICD of each (limbal side, central side, superior edge, and inferior edge) site and the mean of ICDs of the four sites was calculated. Confocal microscopy scans were performed by one examiner who was masked to the diagnosis of the subjects. Analysis of the scans was performed by three different investigators who were also masked to the diagnosis in each case. For intraobserver variability testing, the same investigator performed the same ICD analysis on three occasions. For evaluating intraobserver variability, these investigators carried out ICD calculations, and the differences between the investigator calculations were sought. 
The laser source used in the Retina Tomograph II/Rostock Corneal Module (Heidelberg Engineering) is a diode laser with a wavelength of 670 nm. Two-dimensional images consisted of 384 × 384 picture elements, covering an area of 400 × 400-μm field of the view (FOV). The transverse field of view was captured with the 400 FOV lens. Digital resolution was quoted as 1 μm/pixel transversely and 2 μm/pixel longitudinally by the manufacturer. 
Eyes with active Mooren's ulcer were treated with topical corticosteroids and additional therapy, including systemic corticosteroids, topical cyclosporine, systemic cyclosporine, conjunctival excision, and/or keratoepithelioplasty in a severity-based stepladder approach. 1 Eyes with Mooren's ulcer in remission continued to receive the previous treatment protocols. 
Statistical Analysis
Data are presented as the mean ± SD and were compared by Student's t-test or Kruskal-Wallis test. Correlations were analyzed by Pearson's correlation analysis (Excel 2007 software; Microsoft, Redmond, WA). P <0.05 denoted statistical significance. 
Results
Patient Characteristics
Ten eyes had active ulcers, and 12 eyes were in remission. The patients' characteristics, extent of limbal involvement with ulcers in degrees of arc (deg arc), and the mean ICDs calculated from in vivo confocal microscopic images are shown in Table 1. The intraobserver variability of the ICD measurement was 14.3 ± 17.3 (maximum, 54.7; minimum, 0) cells/mm2 and interobserver variability was 58.0 ± 62.9 (maximum, 146.7; minimum, 2.7) cells/mm2. The left eye of patient 1 could not be examined by in vivo confocal microscopy at day 0, due to refusal by the patient. The mean ICD in the nine eyes with active ulcers before treatment was 2092.7 ± 1538.6 cells/mm2 (range, 835.3–7832.7; 95% CI, 3232.5–952.9). The mean ICD in the 12 eyes in remission was 357.5 ± 266.8 cells/mm2 (range, 12.7–1127.0; 95% CI, 555.2–159.8). To demonstrate that there was an adequate number of eyes for a more than 80% power, one-sided analysis was performed with the following calculation:   where n is the number, σ is the standard deviation, Zα is the percentage of the 0.05 significance level = 1.64; Zγ is the percentage of the 0.20 significance level = 0.84; μ is the expected (i.e., mean value) ICD in the eyes with active ulcers, and μ0 is the expected ICD in the eyes in remission. 
Table 1.
 
Patients' Characteristics and Examination Findings
Table 1.
 
Patients' Characteristics and Examination Findings
A. Active Ulcers
Patient Eye No. Age Sex Eye R/L Extent of Limbal Involvement with Ulcers (deg arc) Confocal Microscopy
ICD (cells/mm2) Limbal Subconjunctival Cysts Harboring Polymorphs
Day 0 1 Week 4 Weeks 8 Weeks
Patient 1 1 36 M R 360 Limbal 7832.7 ± 548.3 1069.3 ± 158.1 844.3 ± 424.1 595.3 ± 514.3
Central 2975.7 ± 1114.8 647.0 ± 468.8 766.7 ± 523.4 380.0 ± 53.4
Superior 4721.3 ± 2850.8 846.7 ± 476.1 857.0 ± 351.9 506.3 ± 369.4 (+)
Inferior 3490.0 ± 1521.9 751.3 ± 600.2 421.7 ± 247.2 449.0 ± 105.7
Mean 5524.4 ± 2526.0 828.6 ± 421.6 722.4 ± 387.7 482.7 ± 286.8
2 L 360 Not examined Not examined Not examined Not examined
Patient 2 3 51 F L 150 Limbal 2319.7 ± 948.5 1428.3 ± 535.6 380.3 ± 353.1 233.0 ± 102.7
Central 1575.7 ± 478.8 791.7 ± 582.7 35.3 ± 37.8 260.0 ± 84.3
Superior 1601.0 ± 539.4 1156.7 ± 750.7 180.0 ± 176.0 126.0 ± 6.0 (+)
Inferior 1429.0 ± 289.3 1015.3 ± 431.0 178.3 ± 217.2 164.3 ± 57.7
Mean 1731.3 ± 635.5 1098.0 ± 555.2 193.5 ± 231.5 195.8 ± 83.2
Patient 3 4 92 F L 90 Limbal 1935.0 ± 224.2 440.3 ± 203.8 406.3 ± 226.6 394.0 ± 291.5
Central 1329.3 ± 765.5 169.0 ± 173.9 287.0 ± 65.0 234.0 ± 240.8
Superior 1971.7 ± 258.5 322.7 ± 224.4 281.7 ± 136.7 273.3 ± 313.7 (+)
Inferior 1256.3 ± 351.6 245.7 ± 211.9 260.0 ± 153.0 141.7 ± 79.6
Mean 1623.1 ± 519.8 294.4 ± 203.3 308.8 ± 146.1 260.8 ± 232.4
Patient 4 5 62 F L 120 Limbal 1839.7 ± 180.5 1846.0 ± 315.5 938.3 ± 181.4 131.7 ± 85.2
Central 1505.3 ± 417.1 1569.3 ± 158.9 448.0 ± 286.0 271.3 ± 134.2
Superior 1667.7 ± 553.3 1556.0 ± 100.3 765.0 ± 294.5 107.7 ± 26.8 (+), (fluid-filled cyst(+) before perforation)
Inferior 1551.3 ± 463.1 1739.0 ± 338.2 506.3 ± 421.6 100.3 ± 45.3
Mean 1641.0 ± 387.8 1677.6 ± 247.6 664.4 ± 334.3 152.8 ± 101.8
Patient 5 6 69 F L 60 Limbal 2114.7 ± 158.1 1810.3 ± 550.5 675.3 ± 402.9 255.3 ± 169.8
Central 1627.3 ± 327.8 1470.7 ± 368.5 771.0 ± 202.7 303.7 ± 171.9
Superior 1839.7 ± 828.3 1308.0 ± 500.7 926.3 ± 498.5 176.3 ± 73.5 (+)
Inferior 1793.7 ± 460.2 1358.0 ± 440.6 445.7 ± 266.6 208.0 ± 124.2
Mean 1843.8 ± 469.9 1486.8 ± 450.0 704.6 ± 358.1 235.8 ± 130.1
Patient 6 7 30 F R 30 Limbal 1301.3 ± 243.5 1078.3 ± 347.0 676.7 ± 181.6 145.0 ± 37.3
Central 835.3 ± 182.8 453.7 ± 348.5 386.0 ± 76.3 132.3 ± 61.7
Superior 1082.0 ± 566.0 753.3 ± 285.5 315.7 ± 39.6 218.7 ± 265.6 (−)
Inferior 1143.0 ± 492.5 352.3 ± 223.8 234.3 ± 100.7 250.7 ± 248.8
Mean 1090.4 ± 387.1 659.4 ± 394.3 403.2 ± 198.8 186.7 ± 166.4
8 30 F L 45 Limbal 1455.3 ± 48.6 1099.0 ± 336.0 558.3 ± 762.2 322.0 ± 185.5
Central 1150.7 ± 486.0 635.3 ± 309.9 118.0 ± 16.5 157.3 ± 110.4
Superior 987.7 ± 79.0 654.3 ± 357.0 145.7 ± 75.4 202.3 ± 117.7 (−)
Inferior 1185.7 ± 194.6 302.7 ± 198.2 139.3 ± 114.5 234.3 ± 128.5
Mean 1194.8 ± 286.6 672.8 ± 394.6 240.3 ± 382.1 229.0 ± 134.0
Patient 7 9 34 M R 360 Limbal 4564.7 ± 1127.5
Central 2950.7 ± 1017.1
Superior 2603.7 ± 1757.2 Not examined Not examined Not examined (+)
Inferior 3446.3 ± 1391.5
Mean 3391.3 ± 1389.7
10 M L 360 Limbal 2621.7 ± 1321.6
Central 2775.0 ± 1759.1
Superior 2489.7 ± 1083.4 Not examined Not examined Not examined (+)
Inferior 2549.0 ± 578.7
Mean 2608.8 ± 1080.2
Overall mean ± SD (1–8)* 2092.7 ± 1538.6 959.7 ± 490.7 462.5 ± 229.4 249.1 ± 109.0
(95% CI) (3232.5–952.9) (1323.1–596.2) (632.4–292.5) (329.8, 168.3)
B. Ulcers In Remission
Patient Eye No. Age Sex Eye (R/L) Extent of Limbal Involvement with Ulcers (deg arc) Confocal Microscopy
ICD (cells/Mm2) Limbal Subconjunctival Cysts Harboring Polymorphs
Patient 2 11 51 F L 0 Limbal 12.7 ± 2.5
Central 25.0 ± 5.6
Superior 41.3 ± 6.5 (−)
Inferior 25.3 ± 9.0
Mean 26.1 ± 11.9
12 R 0 Limbal 173.0 ± 70.2
Central 121.0 ± 107.0
Superior 725.3 ± 74.5 (−)
Inferior 337.7 ± 92.0
Mean 339.3 ± 258.3
Patient 8 13 71 M L 0 Limbal 118.7 ± 59.0
Central 450.7 ± 88.5
Superior 123.7 ± 25.0 (−)
Inferior 221.0 ± 57.1
Mean 228.5 ± 150.1
Patient 9 14 77 M L 0 Limbal 890.0 ± 76.2
Central 669.7 ± 203.9
Superior 673.0 ± 51.7 (−)
Inferior 575.7 ± 125.2
Mean 702.1 ± 162.7
Patient 10 15 54 M R 0 Limbal 133.0 ± 33.0
Central 172.0 ± 22.6
Superior 191.3 ± 54.3 (−)
Inferior 167.7 ± 72.4
Mean 166.0 ± 47.6
16 L 0 Limbal 735.3 ± 351.7
Central 638.3 ± 157.9
Superior 666.0 ± 221.6 (−)
Inferior 671.7 ± 198.4
Mean 677.8 ± 210.9
Patient 11 17 57 F R 0 Limbal 773.7 ± 195.0 (−)
Central 1127.0 ± 218.8
Superior 778.3 ± 78.4
Inferior 641.7 ± 313.3
Mean 830.2 ± 264.4
18 R 0 Limbal 226.3 ± 112.2
Central 86.0 ± 32.1
Superior 69.7 ± 30.9 (−)
Inferior 106.3 ± 41.5
Mean 122.1 ± 84.3
Patient 12 19 88 M L 0 Limbal 48.0 ± 13.0
Central 195.3 ± 29.6
Superior 146.3 ± 12.5 (−)
Inferior 160.3 ± 45.2
Mean 137.5 ± 62.1
Patient 13 20 41 M L 0 Limbal 586.7 ± 149.5
Central 151.7 ± 24.0
Superior 235.7 ± 105.9 (−)
Inferior 199.7 ± 65.9
Mean 293.4 ± 198.1
Patient 14 21 59 F R 0 Limbal 186.7 ± 92.8
Central 343.3 ± 46.5
Superior 130.7 ± 7.0 (−)
Inferior 148.0 ± 49.9
Mean 202.2 ± 100.6
Patient 15 22 78 F R 0 Limbal 483.0 ± 219.2
Central 649.0 ± 367.2
Superior 645.7 ± 89.2 (−)
Inferior 481.7 ± 168.5
Mean 564.8 ± 217.5
Overall Mean ± SD 357.5 ± 266.8
(95% CI) (555.2–159.8)
An adequate number was more than 4.87, and the number of recruited eyes with active ulcer exceeded the adequate number. 
The treatment outcome and ICD decrease/week in 10 eyes with active ulcers are shown in Table 2A. All 10 eyes with active ulcers were treated initially with hourly topical betamethasone eyedrops. In addition, 9 of 10 subjects received topical cyclosporine three times a day. Five of these 10 subjects received additional systemic corticosteroids; 3 of the 10 received systemic cyclosporine. Seven of the eyes responded to subsequent treatment at 8 weeks with improvement in conjunctival injection and corneal re-epithelization. Eyes 9 and 10 of patient 7 were lost to follow-up. The mean ICD decrease per week in the seven eyes with active ulcers was 1109.2 ± 1644.7 cells/mm2/wk. ICD decrease per week of treatment was observed to be less in the patient with corneal perforation and the patient who did not respond to treatment and underwent conjunctival excision. The treatment and periods in remission of the eyes in remission are shown in Table 2B. Eleven of the 12 eyes in remission were treated with topical betamethasone three to six times a day, and one eye received no therapy. Pearson's correlation analysis revealed that the correlation between ICD and periods of remission was not significant (P = 0.086; R 2 = 0.2663). 
Table 2.
 
Treatment and Course of Patients
Table 2.
 
Treatment and Course of Patients
A. Active Ulcers
Patient Eye No. Treatment Course ICD Decrease (cells/mm2/wk)
Patient 1 1 Topical betamethasone/topical cyclosporine/systemic Improved 4695.8
2 Methylprednisolone/systemic cyclosporine Improved
Patient 2 3 Topical betamethasone/topical cyclosporine Improved 633.3
Patient 3 4 Topical betamethasone Improved 1328.7
Patient 4 5 Topical betamethasone/topical cyclosporine after the corneal perforation conjunctival excision and keratoepithelioplasty/systemic-cyclosporine/systemic prednisolone Corneal perforation, 8 days after initiation of treatment −36.6
Patient 5 6 Topical betamethasone/topical cyclosporine/conjunctival excision Improved 357.1
Patient 6 7 Topical betamethasone/topical cyclosporine Improved 431.0
8 Topical betamethasone/topical cyclosporine Improved 522.0
Patient 7 9 Topical betamethasone/topical cyclosporine/systemic prednisolone Lost to follow-up
10
Mean ± SD 1447.6 ± 1985.7
B. Ulcers In Remission
Patient Eye No. Treatment Periods in Remission
Patient 2 11 Free of therapy 2 Years and 2 months
Patient 8 12 Topical betamethasone 1 Year 1 month
13 Topical betamethasone 1 Year 1 month
Patient 9 14 Topical betamethasone 3 Years 4 months
Patient 10 15 Topical betamethasone 3 Years
16 Topical betamethasone 3 Years
Patient 11 17 Topical betamethasone 10 Years
Patient 12 18 Topical betamethasone 2 Years and 3 months
19 Topical betamethasone 2 Years 3 months
Patient 13 20 Topical betamethasone 1 Year
Patient 14 21 Topical betamethasone 1 Year 1 month
Patient 15 22 Topical betamethasone 1 Year
The anterior segment photographs, fluorescein staining of the ocular surface, and in vivo laser confocal microscopy findings of the left eye of patient 2 are shown in Figure 1. The patient had already relapsed several times, and vessels as well as conjunctival invasion were seen in the superior corneal limbus (Fig. 1A). The corneal ulcer relapsed at the head of the conjunctival invasion (Figs. 1A, 1B). In vivo confocal microscopy scans of four sites (limbal side, central side, superior edge, and inferior edge) disclosed marked infiltration with dendritic cells as well as polymorphs (Figs. 1C-1–1C-4,). Dark cysts harboring numerous polymorphs were also seen in limbal subconjunctival regions (Fig. 1D, 1E). Such cysts were seen in six of seven patients with active ulcers, but were exclusively nonobservable in all eyes in remission (Table 1). Although the corneal ulcers of patient 2 extended up to 150°, the ulcer was shallow and responded to the treatment very well (Figs. 1F, 1G), and the ICD of each site immediately decreased with subsequent treatment (Figs. 1H-1–1H-4). 
Figure 1.
 
Slit lamp microscopy examination, fluorescein staining of the ocular surface, and in vivo laser confocal microscopy findings in the left eye of patient 2. (A, B) Slit lamp photograph and fluorescein staining at the enrollment day. (C) In vivo confocal microscopy scan showing marked infiltration with polymorphs, which were counted to determine the ICD (C-1; limbal side, C-2; central side, C-3; superior edge, C-4; inferior edge). (D) Dendritic cells (yellow arrows) were also seen. (E) Dark cysts harboring polymorphs in the limbal subconjunctival region (red arrows). (F, G) In response the treatment, epithelization improved and the corneal ulcers regressed in 1 week. (H) In vivo confocal microscopy scans of limbal side (H-1), central side (H-2), superior edge (H-3), and inferior edge (H-4) in 1 week. Note that the infiltration decreased substantially.
Figure 1.
 
Slit lamp microscopy examination, fluorescein staining of the ocular surface, and in vivo laser confocal microscopy findings in the left eye of patient 2. (A, B) Slit lamp photograph and fluorescein staining at the enrollment day. (C) In vivo confocal microscopy scan showing marked infiltration with polymorphs, which were counted to determine the ICD (C-1; limbal side, C-2; central side, C-3; superior edge, C-4; inferior edge). (D) Dendritic cells (yellow arrows) were also seen. (E) Dark cysts harboring polymorphs in the limbal subconjunctival region (red arrows). (F, G) In response the treatment, epithelization improved and the corneal ulcers regressed in 1 week. (H) In vivo confocal microscopy scans of limbal side (H-1), central side (H-2), superior edge (H-3), and inferior edge (H-4) in 1 week. Note that the infiltration decreased substantially.
The left eye of patient 4 had a corneal perforation 8 days after initiation of treatment (Fig. 2A). In vivo confocal microscopy scans disclosed marked infiltration by inflammatory cells (Figs. 2B-1–2B-4), with a mean ICD immediately before perforation of 1677.6 ± 247.6 cells/mm2. The scan also revealed marked infiltration with inflammatory cells in the corneal epithelial basal cell area, as well as cysts filled with inflammatory infiltrates and fluid-filled cysts in the limbal subconjunctival region (Figs. 2C, 2D). Conjunctival excision and keratoepithelioplasty were performed, and, after the operation, the ulcer healed and the patient was free of relapses. The corresponding area in histopathology specimens and ex vivo confocal microscopy examinations showed similar anatomic details and findings including polymorphs, and subconjunctival cysts (Figs. 2E, 2F). These findings reflected polymorphs and cysts seen in Figures 2C and 2D. 
Figure 2.
 
Slit lamp microscopy examination, in vivo laser scanning confocal microscopy, and histologic findings in the left eye of patient 4 (eye 5). (A) Corneal ulcer with 120° of limbal involvement. (B) Corneal findings by in vivo laser scanning confocal microscopy 1 day before corneal perforation (B-1, limbal side; B-2, central side; B-3, superior edge; B-4, inferior edge). (C) Dark cysts filled with inflammatory infiltrates (yellow arrows) in limbal subconjunctiva. (D) Fluid-filled cysts (red arrows) appeared, as well as dark cysts harboring polymorphs (yellow arrows). (E) Histologic findings in conjunctiva obtained by conjunctival excision (hematoxylin and eosin staining). (F) In vivo confocal microscopy finding in the same specimen shown in (E). Note that confocal microscopy effectively discerned features such as cysts (red arrows) and inflammatory cells (yellow arrows). Magnification: (E) ×100.
Figure 2.
 
Slit lamp microscopy examination, in vivo laser scanning confocal microscopy, and histologic findings in the left eye of patient 4 (eye 5). (A) Corneal ulcer with 120° of limbal involvement. (B) Corneal findings by in vivo laser scanning confocal microscopy 1 day before corneal perforation (B-1, limbal side; B-2, central side; B-3, superior edge; B-4, inferior edge). (C) Dark cysts filled with inflammatory infiltrates (yellow arrows) in limbal subconjunctiva. (D) Fluid-filled cysts (red arrows) appeared, as well as dark cysts harboring polymorphs (yellow arrows). (E) Histologic findings in conjunctiva obtained by conjunctival excision (hematoxylin and eosin staining). (F) In vivo confocal microscopy finding in the same specimen shown in (E). Note that confocal microscopy effectively discerned features such as cysts (red arrows) and inflammatory cells (yellow arrows). Magnification: (E) ×100.
Correlation between ICD and the Extent of Mooren's Ulcer
Pearson's correlation analysis revealed that the correlation of the mean ICD or ICD in each site at the enrollment visit was very strong and the limbal involvement with ulcers measured by slit lamp microscopic examination was extensive (limbal side: R 2=0.7618, P = 1.8726 × 10−7; central side, R 2=0.8775, P = 1.213 × 10−8; superior edge; R 2=0.7798, P = 1.150 × 10−6, inferior edge; R 2=0.8832, P = 2.747 × 10−8, mean of four sites; R 2 = 0.8199, P = 2.256 × 10−8; Fig. 3). 
Figure 3.
 
The correlation of the ICD of patients' eyes at day 0, and the extent of limbal involvement with ulcers measured by slit lamp microscopy examination. Pearson's correlation analysis revealed that the correlation was very strong.
Figure 3.
 
The correlation of the ICD of patients' eyes at day 0, and the extent of limbal involvement with ulcers measured by slit lamp microscopy examination. Pearson's correlation analysis revealed that the correlation was very strong.
ICD Alterations with Treatment
The change of mean ICD in eyes with active Mooren's ulcers in response to treatment is shown in Figure 4. Eyes 9 and 10 of patient 7 were excluded in this figure because the patient was lost to follow-up. At enrollment day, the mean ICD of the limbal side was the highest (2685.5 ± 2297.1) and the mean ICD of the central side was lowest (1571.3 ± 677.8) among the four sites. The Kruskal-Wallis test revealed no significant difference between the ICDs of these four sites. The ICD of each site in eyes with active Mooren's ulcers gradually decreased to the same level as that of eyes in remission with response to subsequent treatment. There was a significant decrease in the mean ICD at 1 month (462.5 ± 229.4 cells/mm2; range, 35.3–938.3; 95% CI, 632.4–292.5) and 2 months (249.1 ± 109.0 cells/mm2; range, 100.3–595.3; 95% CI, 329.8–168.3) of treatment, compared with the baseline (day 0) values. The mean ICD in patients with active Mooren's ulcers was also significantly higher than that in eyes of patients with Mooren's ulcers in remission (357.5 ± 266.8 cells/mm2; range, 12.7–1127.0; 95% CI, 555.2–159.8). 
Figure 4.
 
The course of ICD change in eyes with active ulcer in response to treatments, compared with the ICD in eyes in remission. Eyes 9 and 10 of patient 7 are excluded this figure, because he was lost to follow-up. The ICD of limbal side, central side, superior edge, inferior edge, and mean of these four sites, of eyes with active ulcer gradually decreased to the same level of ICD of eyes in remission with the treatment. Data are the mean ± SD of ICD values. *Statistically significant compared with the ICD at enrollment day (P < 0.05, Student's t-test).
Figure 4.
 
The course of ICD change in eyes with active ulcer in response to treatments, compared with the ICD in eyes in remission. Eyes 9 and 10 of patient 7 are excluded this figure, because he was lost to follow-up. The ICD of limbal side, central side, superior edge, inferior edge, and mean of these four sites, of eyes with active ulcer gradually decreased to the same level of ICD of eyes in remission with the treatment. Data are the mean ± SD of ICD values. *Statistically significant compared with the ICD at enrollment day (P < 0.05, Student's t-test).
Discussion
Mooren's ulcer is an autoimmune corneal disease of unknown etiology. 1 The diagnosis of Mooren's ulcer is a diagnosis of exclusion requiring an extensive search for a wide variety of diseases causing peripheral ulcerative keratitis, including rheumatoid arthritis and other collagen vascular diseases, staphylococcal marginal keratitis accompanied by blepharitis, giant cell arteritis, local infectious causes including herpes simplex and herpes zoster, Terrien's degeneration, pellucid marginal degeneration, senile furrow degeneration, ocular rosacea, and leukemia. 6 Pathologically, resected conjunctiva and limbal cornea specimens from subjects with Mooren's ulcer show a large number of plasma cells, lymphocytes, histiocytes, plasma cells, and macrophages. 2,19,20 Schaap et al. 21 reported that circulating autoantibodies in the IgG immunoglobulin class in human corneal epithelium were seen in the serum of patients with Mooren's ulcer. Brown et al. 22 demonstrated the presence of circulating antibodies in both the conjunctival and corneal epithelium in the sera of patients with Mooren's ulcer. Once the diagnosis is established, the only means of following up the course of the disease and/or the treatment responses is by a careful slit lamp examination and detection of circulating antibodies. Histopathologic specimens in patients undergoing conjunctival excision added to our understanding of the disease pathogenesis in Mooren's ulcers (Fig. 2). 
The ICD of eyes at the enrollment visit, day 0, showed a strong correlation with the extent of limbal involvement with ulcers measured at the slit lamp microscopic examination (R 2 = 0.8199). Although conjunctival histopathologic alterations have been reported extensively, PubMed and MedLine searches using the key words “in vivo confocal microscopy” and “Mooren's ulcer” revealed no studies in the literature. 
In vivo confocal microscopy examination in all patients with Mooren's ulcer showed variable degrees of keratoconjunctival inflammation, with a greater extent of inflammatory cell infiltrates in patients with active ulcers. As we mentioned, we counted only white round cells of 5- to 15-μm diameter. At the basal cell layer level, epithelial cell nuclei are not highly reflective, and so we believe that inflammatory cells could be differentiated from epithelial cell nuclei in that location. The inflammatory cell infiltrates consist of dendritic cells and polymorphs. Since dendritic cells may be mistaken for melanocytes, 16 we chose not to include them in the total count of inflammatory cells, which represents total polymorph densities. It should also be noted that since confocal microscopy diagnosis of an inflammatory cell is based mainly on size, we found it to be logical to refrain from specifying the type of inflammatory cells and thus collectively refer to them as polymorphs. Inflammatory cells in excision specimens from patients with Mooren's ulcers have been reported to consist of neutrophils, lymphocytes, natural killer cells, and monocytes. 20 Further confocal microscopy studies comparing inflammatory cell size and density scan information with size and density of differential inflammatory cell counts in excision specimens would provide invaluable information. 
Dark cysts harboring polymorphs were seen in six of seven patients with active ulcers. Such cysts were not observed in the patients in remission. ICD showed a time-wise decrease with treatment in all patients. The extent of decrease was less in patients 4 and 5, who eventually underwent conjunctival excision. It was noteworthy in the in vivo confocal microscopy observation performed on the day before perforation in patient 4 that the limbal conjunctiva contained two types of subconjunctival cysts: dark cysts, harboring numerous polymorphs that had presented from day 0, and fluid-filled cysts, harboring polymorphs that appeared 1 day before perforation. It is our belief that the fluid in the cysts before perforation might have been aqueous humor oozing through melting corneal tissue or serous fluid from the necrotic tissues. Observation of numerous cysts, especially the fluid-filled variety, may very well suggest imminent perforation and appears to be an important confocal microscopy finding. Since perforation in Mooren's ulcer is rare and since building up more evidence on this important finding is a challenge, observation in this perforated case, we believe, should serve as an open call to all corneal specialists who have access to in vivo confocal microscopy to pay close attention to the changes in the nature of the cysts and their relation to imminent perforation in patients with Mooren's ulcers. Ex vivo confocal microscopy examination of conjunctival histopathologic specimens showed the same architecture in the corresponding areas and revealed the intraepithelial and inflammatory cell infiltrates. ICD in confocal microscopy has been shown to correlate with the severity of ocular surface findings in Sjögren syndrome, atopic keratoconjunctivitis, and meibomian gland dysfunction. 16 18  
In the present study, eyes with active Mooren's ulcer were managed with aggressive treatment including hourly topical corticosteroids, topical cyclosporine, systemic corticosteroids and cyclosporine, conjunctival excision, and/or keratoepithelioplasty. It took 4 weeks for the ICD to decrease significantly compared with day 0, and it took 8 weeks to achieve the same level of the ICD in eyes in remission. 
ICD assessment adds to our armamentarium of currently existing subjective and objective diagnostic skills in judging the responsiveness of Mooren's ulcer to treatment, including evaluation of the changes in pain symptoms and slit lamp evidence of healing. 
In summary, we report the first in vivo confocal scanning laser microscopy study to elucidate the keratoconjunctival alterations in Mooren's ulcer. The study provided evidence that ICD was a useful procedure in evaluating the severity of ulcers and responses to treatment. Observation of numerous limbal cysts, especially fluid-filled cysts may imply imminent perforation, which necessitates a careful follow-up of such patients. 
Footnotes
 Supported by a grant from the Japanese Ministry of Health, Labor, and Welfare. The funding organization had no role in the design or conduct of the research.
Footnotes
 Disclosure: S. Hatou, None; M. Dogru, None; O.M.A. Ibrahim, None; T. Wakamatsu, None; E.A. Sato, None; S. Shimmura, None; K. Negishi, None; K. Tsubota, None
References
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Figure 1.
 
Slit lamp microscopy examination, fluorescein staining of the ocular surface, and in vivo laser confocal microscopy findings in the left eye of patient 2. (A, B) Slit lamp photograph and fluorescein staining at the enrollment day. (C) In vivo confocal microscopy scan showing marked infiltration with polymorphs, which were counted to determine the ICD (C-1; limbal side, C-2; central side, C-3; superior edge, C-4; inferior edge). (D) Dendritic cells (yellow arrows) were also seen. (E) Dark cysts harboring polymorphs in the limbal subconjunctival region (red arrows). (F, G) In response the treatment, epithelization improved and the corneal ulcers regressed in 1 week. (H) In vivo confocal microscopy scans of limbal side (H-1), central side (H-2), superior edge (H-3), and inferior edge (H-4) in 1 week. Note that the infiltration decreased substantially.
Figure 1.
 
Slit lamp microscopy examination, fluorescein staining of the ocular surface, and in vivo laser confocal microscopy findings in the left eye of patient 2. (A, B) Slit lamp photograph and fluorescein staining at the enrollment day. (C) In vivo confocal microscopy scan showing marked infiltration with polymorphs, which were counted to determine the ICD (C-1; limbal side, C-2; central side, C-3; superior edge, C-4; inferior edge). (D) Dendritic cells (yellow arrows) were also seen. (E) Dark cysts harboring polymorphs in the limbal subconjunctival region (red arrows). (F, G) In response the treatment, epithelization improved and the corneal ulcers regressed in 1 week. (H) In vivo confocal microscopy scans of limbal side (H-1), central side (H-2), superior edge (H-3), and inferior edge (H-4) in 1 week. Note that the infiltration decreased substantially.
Figure 2.
 
Slit lamp microscopy examination, in vivo laser scanning confocal microscopy, and histologic findings in the left eye of patient 4 (eye 5). (A) Corneal ulcer with 120° of limbal involvement. (B) Corneal findings by in vivo laser scanning confocal microscopy 1 day before corneal perforation (B-1, limbal side; B-2, central side; B-3, superior edge; B-4, inferior edge). (C) Dark cysts filled with inflammatory infiltrates (yellow arrows) in limbal subconjunctiva. (D) Fluid-filled cysts (red arrows) appeared, as well as dark cysts harboring polymorphs (yellow arrows). (E) Histologic findings in conjunctiva obtained by conjunctival excision (hematoxylin and eosin staining). (F) In vivo confocal microscopy finding in the same specimen shown in (E). Note that confocal microscopy effectively discerned features such as cysts (red arrows) and inflammatory cells (yellow arrows). Magnification: (E) ×100.
Figure 2.
 
Slit lamp microscopy examination, in vivo laser scanning confocal microscopy, and histologic findings in the left eye of patient 4 (eye 5). (A) Corneal ulcer with 120° of limbal involvement. (B) Corneal findings by in vivo laser scanning confocal microscopy 1 day before corneal perforation (B-1, limbal side; B-2, central side; B-3, superior edge; B-4, inferior edge). (C) Dark cysts filled with inflammatory infiltrates (yellow arrows) in limbal subconjunctiva. (D) Fluid-filled cysts (red arrows) appeared, as well as dark cysts harboring polymorphs (yellow arrows). (E) Histologic findings in conjunctiva obtained by conjunctival excision (hematoxylin and eosin staining). (F) In vivo confocal microscopy finding in the same specimen shown in (E). Note that confocal microscopy effectively discerned features such as cysts (red arrows) and inflammatory cells (yellow arrows). Magnification: (E) ×100.
Figure 3.
 
The correlation of the ICD of patients' eyes at day 0, and the extent of limbal involvement with ulcers measured by slit lamp microscopy examination. Pearson's correlation analysis revealed that the correlation was very strong.
Figure 3.
 
The correlation of the ICD of patients' eyes at day 0, and the extent of limbal involvement with ulcers measured by slit lamp microscopy examination. Pearson's correlation analysis revealed that the correlation was very strong.
Figure 4.
 
The course of ICD change in eyes with active ulcer in response to treatments, compared with the ICD in eyes in remission. Eyes 9 and 10 of patient 7 are excluded this figure, because he was lost to follow-up. The ICD of limbal side, central side, superior edge, inferior edge, and mean of these four sites, of eyes with active ulcer gradually decreased to the same level of ICD of eyes in remission with the treatment. Data are the mean ± SD of ICD values. *Statistically significant compared with the ICD at enrollment day (P < 0.05, Student's t-test).
Figure 4.
 
The course of ICD change in eyes with active ulcer in response to treatments, compared with the ICD in eyes in remission. Eyes 9 and 10 of patient 7 are excluded this figure, because he was lost to follow-up. The ICD of limbal side, central side, superior edge, inferior edge, and mean of these four sites, of eyes with active ulcer gradually decreased to the same level of ICD of eyes in remission with the treatment. Data are the mean ± SD of ICD values. *Statistically significant compared with the ICD at enrollment day (P < 0.05, Student's t-test).
Table 1.
 
Patients' Characteristics and Examination Findings
Table 1.
 
Patients' Characteristics and Examination Findings
A. Active Ulcers
Patient Eye No. Age Sex Eye R/L Extent of Limbal Involvement with Ulcers (deg arc) Confocal Microscopy
ICD (cells/mm2) Limbal Subconjunctival Cysts Harboring Polymorphs
Day 0 1 Week 4 Weeks 8 Weeks
Patient 1 1 36 M R 360 Limbal 7832.7 ± 548.3 1069.3 ± 158.1 844.3 ± 424.1 595.3 ± 514.3
Central 2975.7 ± 1114.8 647.0 ± 468.8 766.7 ± 523.4 380.0 ± 53.4
Superior 4721.3 ± 2850.8 846.7 ± 476.1 857.0 ± 351.9 506.3 ± 369.4 (+)
Inferior 3490.0 ± 1521.9 751.3 ± 600.2 421.7 ± 247.2 449.0 ± 105.7
Mean 5524.4 ± 2526.0 828.6 ± 421.6 722.4 ± 387.7 482.7 ± 286.8
2 L 360 Not examined Not examined Not examined Not examined
Patient 2 3 51 F L 150 Limbal 2319.7 ± 948.5 1428.3 ± 535.6 380.3 ± 353.1 233.0 ± 102.7
Central 1575.7 ± 478.8 791.7 ± 582.7 35.3 ± 37.8 260.0 ± 84.3
Superior 1601.0 ± 539.4 1156.7 ± 750.7 180.0 ± 176.0 126.0 ± 6.0 (+)
Inferior 1429.0 ± 289.3 1015.3 ± 431.0 178.3 ± 217.2 164.3 ± 57.7
Mean 1731.3 ± 635.5 1098.0 ± 555.2 193.5 ± 231.5 195.8 ± 83.2
Patient 3 4 92 F L 90 Limbal 1935.0 ± 224.2 440.3 ± 203.8 406.3 ± 226.6 394.0 ± 291.5
Central 1329.3 ± 765.5 169.0 ± 173.9 287.0 ± 65.0 234.0 ± 240.8
Superior 1971.7 ± 258.5 322.7 ± 224.4 281.7 ± 136.7 273.3 ± 313.7 (+)
Inferior 1256.3 ± 351.6 245.7 ± 211.9 260.0 ± 153.0 141.7 ± 79.6
Mean 1623.1 ± 519.8 294.4 ± 203.3 308.8 ± 146.1 260.8 ± 232.4
Patient 4 5 62 F L 120 Limbal 1839.7 ± 180.5 1846.0 ± 315.5 938.3 ± 181.4 131.7 ± 85.2
Central 1505.3 ± 417.1 1569.3 ± 158.9 448.0 ± 286.0 271.3 ± 134.2
Superior 1667.7 ± 553.3 1556.0 ± 100.3 765.0 ± 294.5 107.7 ± 26.8 (+), (fluid-filled cyst(+) before perforation)
Inferior 1551.3 ± 463.1 1739.0 ± 338.2 506.3 ± 421.6 100.3 ± 45.3
Mean 1641.0 ± 387.8 1677.6 ± 247.6 664.4 ± 334.3 152.8 ± 101.8
Patient 5 6 69 F L 60 Limbal 2114.7 ± 158.1 1810.3 ± 550.5 675.3 ± 402.9 255.3 ± 169.8
Central 1627.3 ± 327.8 1470.7 ± 368.5 771.0 ± 202.7 303.7 ± 171.9
Superior 1839.7 ± 828.3 1308.0 ± 500.7 926.3 ± 498.5 176.3 ± 73.5 (+)
Inferior 1793.7 ± 460.2 1358.0 ± 440.6 445.7 ± 266.6 208.0 ± 124.2
Mean 1843.8 ± 469.9 1486.8 ± 450.0 704.6 ± 358.1 235.8 ± 130.1
Patient 6 7 30 F R 30 Limbal 1301.3 ± 243.5 1078.3 ± 347.0 676.7 ± 181.6 145.0 ± 37.3
Central 835.3 ± 182.8 453.7 ± 348.5 386.0 ± 76.3 132.3 ± 61.7
Superior 1082.0 ± 566.0 753.3 ± 285.5 315.7 ± 39.6 218.7 ± 265.6 (−)
Inferior 1143.0 ± 492.5 352.3 ± 223.8 234.3 ± 100.7 250.7 ± 248.8
Mean 1090.4 ± 387.1 659.4 ± 394.3 403.2 ± 198.8 186.7 ± 166.4
8 30 F L 45 Limbal 1455.3 ± 48.6 1099.0 ± 336.0 558.3 ± 762.2 322.0 ± 185.5
Central 1150.7 ± 486.0 635.3 ± 309.9 118.0 ± 16.5 157.3 ± 110.4
Superior 987.7 ± 79.0 654.3 ± 357.0 145.7 ± 75.4 202.3 ± 117.7 (−)
Inferior 1185.7 ± 194.6 302.7 ± 198.2 139.3 ± 114.5 234.3 ± 128.5
Mean 1194.8 ± 286.6 672.8 ± 394.6 240.3 ± 382.1 229.0 ± 134.0
Patient 7 9 34 M R 360 Limbal 4564.7 ± 1127.5
Central 2950.7 ± 1017.1
Superior 2603.7 ± 1757.2 Not examined Not examined Not examined (+)
Inferior 3446.3 ± 1391.5
Mean 3391.3 ± 1389.7
10 M L 360 Limbal 2621.7 ± 1321.6
Central 2775.0 ± 1759.1
Superior 2489.7 ± 1083.4 Not examined Not examined Not examined (+)
Inferior 2549.0 ± 578.7
Mean 2608.8 ± 1080.2
Overall mean ± SD (1–8)* 2092.7 ± 1538.6 959.7 ± 490.7 462.5 ± 229.4 249.1 ± 109.0
(95% CI) (3232.5–952.9) (1323.1–596.2) (632.4–292.5) (329.8, 168.3)
B. Ulcers In Remission
Patient Eye No. Age Sex Eye (R/L) Extent of Limbal Involvement with Ulcers (deg arc) Confocal Microscopy
ICD (cells/Mm2) Limbal Subconjunctival Cysts Harboring Polymorphs
Patient 2 11 51 F L 0 Limbal 12.7 ± 2.5
Central 25.0 ± 5.6
Superior 41.3 ± 6.5 (−)
Inferior 25.3 ± 9.0
Mean 26.1 ± 11.9
12 R 0 Limbal 173.0 ± 70.2
Central 121.0 ± 107.0
Superior 725.3 ± 74.5 (−)
Inferior 337.7 ± 92.0
Mean 339.3 ± 258.3
Patient 8 13 71 M L 0 Limbal 118.7 ± 59.0
Central 450.7 ± 88.5
Superior 123.7 ± 25.0 (−)
Inferior 221.0 ± 57.1
Mean 228.5 ± 150.1
Patient 9 14 77 M L 0 Limbal 890.0 ± 76.2
Central 669.7 ± 203.9
Superior 673.0 ± 51.7 (−)
Inferior 575.7 ± 125.2
Mean 702.1 ± 162.7
Patient 10 15 54 M R 0 Limbal 133.0 ± 33.0
Central 172.0 ± 22.6
Superior 191.3 ± 54.3 (−)
Inferior 167.7 ± 72.4
Mean 166.0 ± 47.6
16 L 0 Limbal 735.3 ± 351.7
Central 638.3 ± 157.9
Superior 666.0 ± 221.6 (−)
Inferior 671.7 ± 198.4
Mean 677.8 ± 210.9
Patient 11 17 57 F R 0 Limbal 773.7 ± 195.0 (−)
Central 1127.0 ± 218.8
Superior 778.3 ± 78.4
Inferior 641.7 ± 313.3
Mean 830.2 ± 264.4
18 R 0 Limbal 226.3 ± 112.2
Central 86.0 ± 32.1
Superior 69.7 ± 30.9 (−)
Inferior 106.3 ± 41.5
Mean 122.1 ± 84.3
Patient 12 19 88 M L 0 Limbal 48.0 ± 13.0
Central 195.3 ± 29.6
Superior 146.3 ± 12.5 (−)
Inferior 160.3 ± 45.2
Mean 137.5 ± 62.1
Patient 13 20 41 M L 0 Limbal 586.7 ± 149.5
Central 151.7 ± 24.0
Superior 235.7 ± 105.9 (−)
Inferior 199.7 ± 65.9
Mean 293.4 ± 198.1
Patient 14 21 59 F R 0 Limbal 186.7 ± 92.8
Central 343.3 ± 46.5
Superior 130.7 ± 7.0 (−)
Inferior 148.0 ± 49.9
Mean 202.2 ± 100.6
Patient 15 22 78 F R 0 Limbal 483.0 ± 219.2
Central 649.0 ± 367.2
Superior 645.7 ± 89.2 (−)
Inferior 481.7 ± 168.5
Mean 564.8 ± 217.5
Overall Mean ± SD 357.5 ± 266.8
(95% CI) (555.2–159.8)
Table 2.
 
Treatment and Course of Patients
Table 2.
 
Treatment and Course of Patients
A. Active Ulcers
Patient Eye No. Treatment Course ICD Decrease (cells/mm2/wk)
Patient 1 1 Topical betamethasone/topical cyclosporine/systemic Improved 4695.8
2 Methylprednisolone/systemic cyclosporine Improved
Patient 2 3 Topical betamethasone/topical cyclosporine Improved 633.3
Patient 3 4 Topical betamethasone Improved 1328.7
Patient 4 5 Topical betamethasone/topical cyclosporine after the corneal perforation conjunctival excision and keratoepithelioplasty/systemic-cyclosporine/systemic prednisolone Corneal perforation, 8 days after initiation of treatment −36.6
Patient 5 6 Topical betamethasone/topical cyclosporine/conjunctival excision Improved 357.1
Patient 6 7 Topical betamethasone/topical cyclosporine Improved 431.0
8 Topical betamethasone/topical cyclosporine Improved 522.0
Patient 7 9 Topical betamethasone/topical cyclosporine/systemic prednisolone Lost to follow-up
10
Mean ± SD 1447.6 ± 1985.7
B. Ulcers In Remission
Patient Eye No. Treatment Periods in Remission
Patient 2 11 Free of therapy 2 Years and 2 months
Patient 8 12 Topical betamethasone 1 Year 1 month
13 Topical betamethasone 1 Year 1 month
Patient 9 14 Topical betamethasone 3 Years 4 months
Patient 10 15 Topical betamethasone 3 Years
16 Topical betamethasone 3 Years
Patient 11 17 Topical betamethasone 10 Years
Patient 12 18 Topical betamethasone 2 Years and 3 months
19 Topical betamethasone 2 Years 3 months
Patient 13 20 Topical betamethasone 1 Year
Patient 14 21 Topical betamethasone 1 Year 1 month
Patient 15 22 Topical betamethasone 1 Year
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