0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Brief Report |

Landolt Ring–Shaped Epithelial Keratopathy A Novel Clinical Entity of the Cornea FREE

Tomoyuki Inoue, MD1; Naoyuki Maeda, MD2; Xiaodong Zheng, MD1; Takashi Suzuki, MD1; Daikichi Mitsuyama, MD3; Norio Okamoto, MD4; Tomoko Miura, MD5; Tomiya Mano, MD6; Yuichi Ohashi, MD1
[+] Author Affiliations
1Department of Ophthalmology, Ehime University School of Medicine, Ehime, Japan
2Department of Ophthalmology, Osaka University Medical School, Osaka, Japan
3Mitsuyama Eye Clinic, Kanagawa, Japan
4Okamoto Eye Clinic, Osaka, Japan
5Okubo Ophthalmological Clinic, Suzaka Branch Hospital, Nagano, Japan
6Tane Memorial Eye Hospital, Osaka, Japan
JAMA Ophthalmol. 2015;133(1):89-92. doi:10.1001/jamaophthalmol.2014.2381.
Text Size: A A A
Published online

Importance  Landolt ring–shaped epithelial keratopathy is a newly identified disease with vesicular changes of unknown origin in the epithelial cells.

Observations  Eleven Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium were assessed. The main symptoms of Landolt ring–shaped epithelial keratopathy are foreign-body sensation and photophobia. Slitlamp examination indicates that Landolt ring–shaped lesions located only in the corneal epithelium are randomly distributed and occur unilaterally, bilaterally, or asymmetrically. Small lesions are sometimes connected to each other to form a large Landolt ring in a fractal pattern. Confocal microscopy reveals that the Landolt ring lesions are vesicular changes in the epithelial cells from the basal cell layer to the superficial cell layer without inflammation. The lesions form for weeks to months with sporadic exacerbations and natural remissions with or without treatments. The outcomes do not include epithelial disorders in the affected corneas or visual disruptions.

Conclusions and Relevance  We describe a new disease entity of unknown origin referred to as Landolt ring–shaped epithelial keratopathy, which is usually bilateral and characterized by specific Landolt ring–shaped focal epithelial lesions with vesicular changes only in the epithelial cells. The disorder has an insidious onset and self-limiting nature despite treatment and should be included in the differential diagnosis of corneal epithelial disorders.

Figures in this Article

The Landolt ring, a characteristic standardized symbol used to measure visual acuity (VA) in the daily outpatient clinic, is a ring with a gap that resembles the letter C (Figure 1A).1 We describe 11 Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium (Figure 1B). The institutional review board of Ehime University approved this study. All patients provided oral informed consent.

Place holder to copy figure label and caption
Figure 1.
The Landolt Ring

A, Schematic figure of a Landolt ring used during visual acuity examinations. The Landolt ring is incomplete, with a gap resembling the letter C. B, Slitlamp photograph with fluorescein staining obtained from patient 10 shows representative Landolt ring–shaped epithelial lesions. Slitlamp photographs with fluorescein staining from patients 9 (C), 8 (D), 5 (E), and 7 (F).

Graphic Jump Location

Patient profiles are provided in eTable 1 in the Supplement. The patients were unrelated and not from the same hometown. The mean (SEM) patient age was 45.9 (5.3) years (age range, 17-73 years); 7 patients (64%) were in their 40s to early 50s. With bilateral disease (10 patients [91%]), the number of ring-shaped lesions differed between the eyes. The symptoms included a foreign-body sensation in 7 patients (64%), ocular pain in 5 patients (45%), or blurred vision in 4 patients (36%). Two patients (patients 2 and 3) had a history of dry eye, 2 (patients 5 and 9) had cataracts, 1 (patient 7) had allergic conjunctivitis, and 1 (patient 9) had glaucoma; 6 patients had no ocular complications before diagnosis. Regarding systemic disease, 2 patients (patients 4 and 5) had a history of cancer treatment, 1 (patient 1) had thyroid disease, and 1 (patient 6) had hepatitis and hypertension. No association was found with a systemic illness in any patients.

Clinical findings of the Landolt ring–shaped epithelial keratopathy are provided in eTable 2 in the Supplement. Eight patients initially had a VA of 20/20 or better; patients 5, 6, and 9 had VA in the worse affected eye below 20/20. The bilateral VA decrease in patients 5 and 9 resulted from cataracts. Only patient 6 had no ocular complications that led to decreased VA before disease onset. The intraocular pressure was not elevated in any patients. Slitlamp examination revealed the Landolt ring–shaped lesions in the corneal epithelium, which can be observed more easily with fluorescein staining (Figure 1). The Landolt ring–shaped lesions, which were randomly distributed on the cornea, were single or multiple in the diseased corneas and different sizes; the gap in the C shape was randomly located. The Landolt ring–shaped lesions appeared and disappeared over time with or without treatment. The lesions were unilateral, bilateral, or asymmetric. Although, in some cases, the Landolt lesions were independent of each other, several small lesions were connected to form a large Landolt ring (Figure 2A) in a fractal pattern, with a statistical similarity in form over a range of magnifications of many natural shapes, objects, and phenomena.24Figure 2 shows representative fractal lesions of Landolt ring–shaped epithelial keratopathy in patients 4 and 6.

Place holder to copy figure label and caption
Figure 2.
Fractal Patterns of Landolt Ring–Shaped Lesions

A, Schematic figure of a fractal pattern of the Landolt ring. Several small lesions are connected to each other to form a large Landolt ring. Large lesions with a fractal pattern form a large letter C seen by retroillumination (B) and fluorescein staining (C) in patient 4. Large lesions with a fractal pattern on a slitlamp photograph with fluorescein staining in patient 6 form large circular lesions in the right (D) and left (E) eyes when small Landolt rings became connected.

Graphic Jump Location

The keratopathy was restricted to the epithelium in all patients, with no corneal infiltration, edema, or endothelial changes. No anterior chamber inflammation or keratic precipitates were observed. No conjunctivitis was observed except in patient 7. The corneal sensitivity was measured using Cochet-Bonnet esthesiometry in patients 1, 2, 3, 4, 7, and 11; no decreased corneal sensitivities (60 mm) were observed. No funduscopy findings were apparent in any patients. Polymerase chain reaction was performed to detect human herpesvirus 1 to 8 DNA57 on scraped corneal specimens and/or in tear samples from 6 patients (patients 1, 2, 3, 5, 7, and 11), of which results were negative for all patients.

The clinical course of the Landolt ring–shaped epithelial keratopathy is provided in eTable 3 in the Supplement. The Landolt ring–shaped lesions developed at clinical diagnosis in December in 5 patients (45%), March in 4 patients (36%), November in 1 patient (9%), and February in 1 patient (9%). The disease onset and resolution were within the first year after diagnosis. The periods of recurrence after the second year or later after the initial diagnosis were January to March of year 2 after diagnosis in patient 2; December to April of year 2 in patient 5; and December of year 2, November to May of year 3, and October to March of year 4 in patient 3. The months at onset of all 11 patients were October to March, and the periods during which the Landolt lesions were observed were October to June. The Landolt ring lesions tended to form in winter, especially with seasonal change. After development, the lesions gradually resolved (mean [SEM] time to resolution, 3.0 [0.6] months). The numbers and sizes of the Landolt ring lesions often repeatedly decreased and increased, and the severities varied during the disease course.

The slitlamp findings revealed that after lesion development, no epithelial disorders occurred in the affected corneas of any patients (Figure 3). No patients reported a visual disturbance, foreign-body sensation, or eye pain at the final examination. Landolt ring–shaped lesions recurred in 3 patients (27%) during the follow-up period. The mean (SEM) follow-up period from detection of this epithelial keratopathy was 11.0 (5.3) months (range, 2 weeks to 54 months). Topical treatments included a corticosteroid agent for 5 patients (45%), an immunosuppressive agent for 1 patient (9%), an antiallergic agent for 3 patients (27%), an antimicrobial agent for 5 patients (45%), artificial tears for 2 patients (18%), and an antiherpetic agent for 1 patient (9%). Two patients (18%) were untreated.

Place holder to copy figure label and caption
Figure 3.
Slitlamp Photograph From Patient 1 Obtained by Various Forms of Illumination

A, Diffuser illumination; B, broad slit illumination; C, fluorescein staining; D, thin slit illumination; E, retroillumination; F, broad slit illumination with fluorescein staining; and G, fluorescein staining. H, Schematic figure of the corneal epithelium and the Bowman membrane. I, Confocal image at the depth of the blue line (line 1) for superficial epithelial level scanning shows cellular ballooning and hyporeflective cytoplasmic changes (arrows). J, Confocal image at the depth of the blue line (line 2) for wing cell layer level scanning shows hyperreflective nuclear (arrow) and cell membranes. K, Confocal image at the depth of the blue line (line 3) for basal cell layer scanning shows ridge formation into the Landolt shape. L, Confocal image at the depth of the blue line (line 4) for the bottom level of the basal cell layer shows abnormal hyperreflective precipitates. M, Confocal image at the depth of the blue line (line 5) for the subbasal nerve plexus shows normal morphologic features.

Graphic Jump Location

To obtain more detailed lesion characterization at the cellular level, in vivo confocal microscopy using the Heidelberg Retinal Tomograph II Rostock Cornea Module (Heidelberg Engineering)8,9 was performed. Figure 3I-M shows representative images of the Landolt ring–shaped lesions in patient 1. Superficial epithelial layer scanning revealed cellular ballooning and hyporeflective cytoplasmic changes (Figure 3I). Wing cell level scanning revealed hyperreflective nuclear and cell membranes (Figure 3J). Basal cell layer level scanning revealed ridge formation into the Landolt ring (Figure 3K). The bottom level of the basal cells had abnormal hyperreflective precipitates (Figure 3L). At the Bowman layer, the subbasal nerve plexus had normal morphologic features (Figure 3M). The long nerve fibers ran parallel to the Bowman layer.10 These findings indicate that the Landolt ring–shaped lesions formed as a result of morphologic changes; vesicular cellular ballooning in the basal cells was continuous with the superficial cellular layer only within the epithelial layer. Fluorescein staining of the Landolt ring–shaped lesions did not reveal epithelial erosion but revealed disruption of the epithelial junction from swelling of the epithelial cellular surface caused by serial cellular ballooning from the basal cell layer. The corneal stromal layer was normal without activated keratinocytes with highly reflective cellular bodies; the endothelial layer was normal. No Langerhans cells were seen around the lesions.

We propose a new disease entity called Landolt ring–shaped epithelial keratopathy. Our 11 patients had interesting disease characteristics. This disease of unknown origin was usually chronic, bilateral, and characterized by a specific focal epithelial lesion that resembled the letter C and was composed of vesicular changes in the epithelial cell layer without apparent inflammation. The lesions often continued to appear for weeks to months with sporadic exacerbation and natural remission. Landolt ring disease differed from other previously described corneal epithelial disorders.1115 Although the current study described 11 Japanese patients with Landolt ring–shaped epithelial keratopathy, it is unclear whether this is relevant only to a Japanese population or worldwide. To our knowledge, no other patients currently have this condition. If this report draws worldwide attention to this disease, more information about its distribution may later be revealed. Genetic studies may be useful to clarify the features. The origin of Landolt ring–shaped corneal epitheliopathy is unknown, and further investigation is needed.

Submitted for Publication: December 8, 2014; final revision received April 7, 2014; accepted April 8, 2014.

Corresponding Author: Tomoyuki Inoue, MD, Department of Ophthalmology, Ehime University School of Medicine, Shitsukawa, Toon-City, Ehime, 791-0295, Japan (tomonoue@m.ehime-u.ac.jp).

Published Online: October 9, 2014. doi:10.1001/jamaophthalmol.2014.2381.

Author Contributions: Dr Inoue had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Inoue, Ohashi.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Inoue, Zheng, Suzuki, Mitsuyama, Okamoto, Miura, Mano.

Critical revision of the manuscript for important intellectual content: Maeda, Ohashi.

Administrative, technical, or material support: Inoue, Maeda, Suzuki, Mitsuyama, Okamoto, Miura, Mano.

Study supervision: Maeda, Ohashi.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Duke-Elder  S, ed. System of Ophthalmology.Vol V. London, England: Henry Kimptom; 1970:426-427.
Mandelbrot  B.  How long is the coast of Britain? statistical self-similarity and fractional dimension. Science. 1967;156(3775):636-638.
PubMed   |  Link to Article
Montague  PR, Friedlander  MJ.  Expression of an intrinsic growth strategy by mammalian retinal neurons. Proc Natl Acad Sci U S A. 1989;86(18):7223-7227.
PubMed   |  Link to Article
Landini  G, Mission  GP, Murray  PI.  Fractal properties of herpes simplex dendritic keratitis. Cornea. 1992;11(6):510-514.
PubMed   |  Link to Article
Inoue  T, Kandori  M, Takamatsu  F, Hori  Y, Maeda  N.  Corneal endotheliitis with quantitative polymerase chain reaction positive for human herpesvirus 7. Arch Ophthalmol. 2010;128(4):502-503.
PubMed   |  Link to Article
Inoue  T, Takamatsu  F, Kubota  A, Hori  Y, Maeda  N, Nishida  K.  Human herpesvirus 8 in corneal endotheliitis resulting in graft failure after penetrating keratoplasty refractory to allograft rejection therapy. Arch Ophthalmol. 2011;129(12):1629-1630.
PubMed   |  Link to Article
Inoue  T, Kawashima  R, Suzuki  T, Ohashi  Y.  Real-time polymerase chain reaction for diagnosing acyclovir-resistant herpetic keratitis based on changes in viral DNA copy number before and after treatment. Arch Ophthalmol. 2012;130(11):1462-1464.
PubMed   |  Link to Article
Patel  DV, McGhee  CN.  In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review. Br J Ophthalmol. 2009;93(7):853-860.
PubMed   |  Link to Article
Guthoff  RF, Zhivov  A, Stachs  O.  In vivo confocal microscopy, an inner vision of the cornea: a major review. Clin Experiment Ophthalmol. 2009;37(1):100-117.
PubMed   |  Link to Article
Zheng  X, Shiraishi  A, Okuma  S,  et al.  In vivo confocal microscopic evidence of keratopathy in patients with pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2011;52(3):1755-1761.
PubMed   |  Link to Article
Burstein  NL.  Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv Ophthalmol. 1980;25(1):15-30.
PubMed   |  Link to Article
Stocker  FW, Holt  LB.  Rare form of hereditary epithelial dystrophy of the cornea: genetic, clinical, and pathologic study. AMA Arch Ophthalmol. 1954;53(4):536-541.
PubMed   |  Link to Article
Kenyon  KR.  Recurrent corneal erosion: pathogenesis and therapy. Int Ophthalmol Clin. 1979;19(2):169-195.
PubMed   |  Link to Article
Cook  SD.  Herpes simplex virus in the eye. Br J Ophthalmol. 1992;76(6):365-366.
PubMed   |  Link to Article
Tabbara  KF, Ostler  HB, Dawson  C, Oh  J.  Thygeson’s superficial punctate keratitis. Ophthalmology. 1981;88(1):75-77.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
The Landolt Ring

A, Schematic figure of a Landolt ring used during visual acuity examinations. The Landolt ring is incomplete, with a gap resembling the letter C. B, Slitlamp photograph with fluorescein staining obtained from patient 10 shows representative Landolt ring–shaped epithelial lesions. Slitlamp photographs with fluorescein staining from patients 9 (C), 8 (D), 5 (E), and 7 (F).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Fractal Patterns of Landolt Ring–Shaped Lesions

A, Schematic figure of a fractal pattern of the Landolt ring. Several small lesions are connected to each other to form a large Landolt ring. Large lesions with a fractal pattern form a large letter C seen by retroillumination (B) and fluorescein staining (C) in patient 4. Large lesions with a fractal pattern on a slitlamp photograph with fluorescein staining in patient 6 form large circular lesions in the right (D) and left (E) eyes when small Landolt rings became connected.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Slitlamp Photograph From Patient 1 Obtained by Various Forms of Illumination

A, Diffuser illumination; B, broad slit illumination; C, fluorescein staining; D, thin slit illumination; E, retroillumination; F, broad slit illumination with fluorescein staining; and G, fluorescein staining. H, Schematic figure of the corneal epithelium and the Bowman membrane. I, Confocal image at the depth of the blue line (line 1) for superficial epithelial level scanning shows cellular ballooning and hyporeflective cytoplasmic changes (arrows). J, Confocal image at the depth of the blue line (line 2) for wing cell layer level scanning shows hyperreflective nuclear (arrow) and cell membranes. K, Confocal image at the depth of the blue line (line 3) for basal cell layer scanning shows ridge formation into the Landolt shape. L, Confocal image at the depth of the blue line (line 4) for the bottom level of the basal cell layer shows abnormal hyperreflective precipitates. M, Confocal image at the depth of the blue line (line 5) for the subbasal nerve plexus shows normal morphologic features.

Graphic Jump Location

Tables

References

Duke-Elder  S, ed. System of Ophthalmology.Vol V. London, England: Henry Kimptom; 1970:426-427.
Mandelbrot  B.  How long is the coast of Britain? statistical self-similarity and fractional dimension. Science. 1967;156(3775):636-638.
PubMed   |  Link to Article
Montague  PR, Friedlander  MJ.  Expression of an intrinsic growth strategy by mammalian retinal neurons. Proc Natl Acad Sci U S A. 1989;86(18):7223-7227.
PubMed   |  Link to Article
Landini  G, Mission  GP, Murray  PI.  Fractal properties of herpes simplex dendritic keratitis. Cornea. 1992;11(6):510-514.
PubMed   |  Link to Article
Inoue  T, Kandori  M, Takamatsu  F, Hori  Y, Maeda  N.  Corneal endotheliitis with quantitative polymerase chain reaction positive for human herpesvirus 7. Arch Ophthalmol. 2010;128(4):502-503.
PubMed   |  Link to Article
Inoue  T, Takamatsu  F, Kubota  A, Hori  Y, Maeda  N, Nishida  K.  Human herpesvirus 8 in corneal endotheliitis resulting in graft failure after penetrating keratoplasty refractory to allograft rejection therapy. Arch Ophthalmol. 2011;129(12):1629-1630.
PubMed   |  Link to Article
Inoue  T, Kawashima  R, Suzuki  T, Ohashi  Y.  Real-time polymerase chain reaction for diagnosing acyclovir-resistant herpetic keratitis based on changes in viral DNA copy number before and after treatment. Arch Ophthalmol. 2012;130(11):1462-1464.
PubMed   |  Link to Article
Patel  DV, McGhee  CN.  In vivo confocal microscopy of human corneal nerves in health, in ocular and systemic disease, and following corneal surgery: a review. Br J Ophthalmol. 2009;93(7):853-860.
PubMed   |  Link to Article
Guthoff  RF, Zhivov  A, Stachs  O.  In vivo confocal microscopy, an inner vision of the cornea: a major review. Clin Experiment Ophthalmol. 2009;37(1):100-117.
PubMed   |  Link to Article
Zheng  X, Shiraishi  A, Okuma  S,  et al.  In vivo confocal microscopic evidence of keratopathy in patients with pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2011;52(3):1755-1761.
PubMed   |  Link to Article
Burstein  NL.  Corneal cytotoxicity of topically applied drugs, vehicles and preservatives. Surv Ophthalmol. 1980;25(1):15-30.
PubMed   |  Link to Article
Stocker  FW, Holt  LB.  Rare form of hereditary epithelial dystrophy of the cornea: genetic, clinical, and pathologic study. AMA Arch Ophthalmol. 1954;53(4):536-541.
PubMed   |  Link to Article
Kenyon  KR.  Recurrent corneal erosion: pathogenesis and therapy. Int Ophthalmol Clin. 1979;19(2):169-195.
PubMed   |  Link to Article
Cook  SD.  Herpes simplex virus in the eye. Br J Ophthalmol. 1992;76(6):365-366.
PubMed   |  Link to Article
Tabbara  KF, Ostler  HB, Dawson  C, Oh  J.  Thygeson’s superficial punctate keratitis. Ophthalmology. 1981;88(1):75-77.
PubMed   |  Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Supplement.

eTable 1. Patient Profiles

eTable 2. Clinical Findings of the 11 Cases

eTable 3. Clinical Course of the 11 Cases

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

726 Views
0 Citations
×

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs