Map (Map-like lines)
Irregular gray-white linear structures: Due to abnormal folding or sheet-like proliferation of the basement membrane. Observed as map-like borders surrounded by clear zones.
Corneal Epithelial Basement Membrane Dystrophy
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is Epithelial Basement Membrane Dystrophy?
Section titled “1. What is Epithelial Basement Membrane Dystrophy?”Epithelial basement membrane dystrophy (EBMD) is an anterior corneal dystrophy in which the basement membrane of the corneal epithelium becomes abnormally thickened and deformed, impairing normal differentiation and migration of epithelial cells. It is also called map-dot-fingerprint dystrophy or Cogan microcystic dystrophy.
EBMD is the most common anterior corneal dystrophy, with a reported prevalence ranging from 2% to 43% depending on the study 2). In individuals over 50 years old, up to 75% may show some findings 3).
According to the latest IC3D classification (International Committee for Classification of Corneal Dystrophies), this disease is primarily considered an age-related corneal degeneration 2). However, some cases have a genetic background, and mutations in the TGFBI (transforming growth factor β-induced) gene (chromosome 5q31) have been identified in about 10% of EBMD patients 2). The mutation patterns are diverse, indicating genetic heterogeneity.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Many patients are asymptomatic and are discovered incidentally during routine examinations or preoperative evaluation for cataract surgery. However, up to 30% of patients experience episodes of recurrent corneal erosion (RCE) 2).
The main subjective symptoms are as follows:
- Sudden eye pain or foreign body sensation upon waking (epithelial detachment due to nocturnal corneal dehydration)
- Visual fluctuation and blurred vision (due to irregular astigmatism)
- Tearing and photophobia
Symptoms tend to worsen upon waking. This is because nocturnal corneal dehydration weakens the adhesion between the epithelium and the basement membrane.
Clinical Findings
Section titled “Clinical Findings”Slit-lamp microscopy reveals three characteristic patterns 2).
Dot (Dot-like opacities)
Cogan microcysts: Clusters of degenerated cells enclosed within the epithelium. Epithelial cells, whose normal migration to the surface is hindered by basement membrane abnormalities, undergo apoptosis in situ and form cysts.
Fingerprint (Fingerprint lines)
Concentric fine striae: Due to wavy elevations of the basement membrane. Easier to detect with retroillumination or under dilated pupils.
These patterns may appear alone or in combination. Central lesions cause irregular astigmatism and are detected as irregular ring patterns on corneal topography 3).
Anterior segment optical coherence tomography (AS-OCT) can reveal small hyperreflective areas beneath the epithelium and thickening of the basement membrane 2). In vivo confocal microscopy visualizes extracellular hyperreflective deposits at the basal cell layer, hyperreflective striae at the Bowman’s layer level, and hyporeflective structures corresponding to intraepithelial microcysts 2).
Q
How do EBMD symptoms affect daily life?
A
Many people are asymptomatic and have no problems in daily life. However, when recurrent corneal erosion occurs, it can cause sudden severe eye pain and tearing upon waking, which may interfere with work or driving for several days. In addition, if there is a central lesion, visual fluctuations that are difficult to correct with glasses or contact lenses may occur.
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”The causes of EBMD are broadly classified into two categories.
Age-related (degenerative): Most common. The main cause is degeneration and thickening of the basement membrane with aging, and it frequently occurs in people aged 50 and older3).
Hereditary: TGFBI gene mutations have been identified in about 10% of patients2). Young-onset cases are more likely to have a genetic background. Association with 22q11.2 deletion syndrome (DiGeorge syndrome) has also been reported, suggesting the involvement of unknown genetic pathways2).
Risk factors for the development of recurrent corneal erosion include a history of corneal trauma and the presence of corneal dystrophy. After trauma, the reconstruction of normal adhesion structures is impaired, and in dystrophy, abnormalities in constituent proteins destabilize epithelial adhesion.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”The diagnosis of EBMD is mainly based on observation of corneal epithelial patterns using a slit-lamp microscope.
| Examination Method | Purpose | Characteristic Findings |
|---|---|---|
| Slit-lamp microscope | Basic diagnosis | Map/dot/fingerprint |
| Negative fluorescein staining | Detection of epithelial irregularity | Reveals fine irregularities |
| Corneal topography | Assessment of irregular astigmatism | Irregular ring pattern |
Negative fluorescein staining is useful for detecting subtle EBMD and can clarify the extent of lesions that are not clearly visible macroscopically3).
On corneal topography, distortion of the Placido image within the central 6 mm suggests EBMD3). In preoperative cataract evaluation, if keratometry values are inconsistent between devices, the presence of EBMD should be suspected3).
AS-OCT can visualize subepithelial hyperreflective areas and thickening of the basement membrane, and in vivo confocal microscopy can visualize morphological changes at the cellular level, aiding in definitive diagnosis in cases where slit-lamp examination is inconclusive2).
Q
Can EBMD be mistaken for other corneal diseases?
A
Yes. Findings of EBMD can resemble other corneal basement membrane abnormalities, and differentiation from early Fuchs endothelial corneal dystrophy or Reis-Bücklers dystrophy may be necessary. In vivo confocal microscopy is useful for this differentiation. Additionally, asymptomatic EBMD is often overlooked and may be first discovered during preoperative cataract testing.
5. Standard Treatment
Section titled “5. Standard Treatment”Treatment is performed stepwise according to the presence and severity of RCE.
Conservative Treatment
Section titled “Conservative Treatment”This is the first choice for mild cases or for preventing RCE.
- Artificial tears: 0.1% sodium hyaluronate eye drops (Hyalein) used frequently during the day
- Hypertonic saline eye drops/ointment: 5% NaCl eye drops or ointment to reduce corneal edema
- Nighttime ointment: Prevents epithelial drying at night and reduces detachment upon waking
- Therapeutic soft contact lens: Acts as a bandage lens for mechanical protection of the epithelium
Surgical Treatment
Section titled “Surgical Treatment”Indicated when recurrence occurs despite conservative treatment.
Epithelial debridement: Mechanical removal of irregular epithelium to promote regeneration of healthy epithelium. For preoperative management of cataract surgery, extensive debridement of the central epithelium is performed 3). The standard method involves placing a bandage contact lens after debridement, and re-epithelialization takes an average of 6.8±0.6 days 3). Using cryopreserved amniotic membrane after debridement slightly accelerates re-epithelialization to 4.6±0.8 days, but there is no significant difference in long-term recurrence rate or IOL calculation stability 3).
Anterior stromal puncture (ASP): A method using a 27G needle to puncture the epithelium into the superficial stroma, inducing firm scar adhesion. Performed when the epithelium has regenerated to some extent.
Diamond burr polishing: Polishing the Bowman layer surface with a diamond burr to remove irregular basement membrane.
PTK (phototherapeutic keratectomy): Excision of abnormal epithelium and basement membrane using an excimer laser 2). This offers the most reliable prevention of recurrence, but may cause hyperopic shift and is not covered by insurance.
Preoperative Management for Cataract Surgery
Section titled “Preoperative Management for Cataract Surgery”EBMD reduces the accuracy of corneal topography and biometry. One month after debridement, the IOL calculation changes by an average of 1.56 D, and treatment can keep postoperative refractive error within ±0.5 D 3).
Q
Is EBMD treatment necessary if I am planning cataract surgery?
A
Yes. If EBMD is present in the central cornea, errors in corneal curvature measurement and IOL power calculation can occur, leading to unexpected refractive errors after surgery. Particularly for those desiring multifocal or toric IOLs, it is important to treat EBMD preoperatively to stabilize the corneal surface. Re-examination should be performed at least one month after treatment, and surgical planning should be based on stable measurements.
6. Pathophysiology and Detailed Mechanism
Section titled “6. Pathophysiology and Detailed Mechanism”The essence of EBMD is abnormal thickening and deformation of the corneal epithelial basement membrane.
In a normal cornea, basal cells adhere to the basement membrane on Bowman’s layer via hemidesmosomes, then differentiate and migrate toward the surface. In EBMD, the basement membrane abnormally protrudes and invades from Bowman’s layer into the corneal epithelium 2). This thickened basement membrane acts as a barrier, inhibiting normal superficial migration of epithelial cells.
Inhibited epithelial cells attempt to differentiate into superficial cells in place and eventually undergo apoptosis. This process leads to encapsulation by surrounding cells (microcyst formation) 1). Microcysts form through a passive process where adjacent cells surround dead cells, not by phagocytosis 1).
Detachment and loss of orientation of basal cells from the basement membrane cause abnormal reformation of the basement membrane. This secondarily leads to the formation of fingerprint lines and map lines 4).
Mucous Membrane Pemphigoid Involvement Hypothesis
Section titled “Mucous Membrane Pemphigoid Involvement Hypothesis”In recent years, the involvement of matrix metalloproteinases (MMPs) in the pathogenesis of EBMD has attracted attention 1).
In the corneal epithelium of EBMD patients, the concentrations of MMP-2 and MMP-3 are significantly elevated compared to healthy individuals, and tend to be higher in EBMD patients than in patients with traumatic RCE. 1)
Based on these findings, the following “vicious cycle mechanism” has been proposed 1).
- MMPs accumulated in the basal layer degrade basement membrane components (type IV collagen, laminin, fibronectin, etc.)
- Degradation products form a barrier (midepithelial lamina) in the middle epithelial layer
- Superficial migration of epithelial cells is inhibited, and IL-1α is released from entrapped apoptotic cells.
- IL-1α stimulates keratinocytes to further induce the production of mucous membrane pemphigoid.
- The vicious cycle persists, leading to progressive destruction of the basement membrane structure.
The fine striae characteristic of EBMD are multilayered structures containing abnormal type IV collagen (a component of the basement membrane and a substrate for mucous membrane pemphigoid) and are thought to reflect the accumulation of degradation products from mucous membrane pemphigoid1).
On the other hand, the balance between mucous membrane pemphigoid activity and its inhibitors (TIMPs) has not yet been fully elucidated, and evaluation of TIMP concentrations and elucidation of the role of MMP inducers such as EMMPRIN remain future challenges1).
7. Latest Research and Future Perspectives
Section titled “7. Latest Research and Future Perspectives”TGFBI Mutations and Genetic Diversity
Section titled “TGFBI Mutations and Genetic Diversity”TGFBI gene mutations are found in approximately 10% of EBMD patients, but the identified mutation patterns vary between studies, indicating genetic heterogeneity2). The types of mutations differ between the reports by Boutboul et al. and Evans et al., supporting the diversity of the genetic basis of EBMD2).
Reports of New Disease Associations
Section titled “Reports of New Disease Associations”The association of EBMD has been reported for the first time in a young patient with 22q11.2 deletion syndrome (DiGeorge syndrome)2). Although deletion of the 22q11.2 region is unlikely to be a direct cause of EBMD, an indirect link through effects on systemic developmental pathways has been suggested2).
Research on the MMP-TIMP System
Section titled “Research on the MMP-TIMP System”Elevations of MMP-2 and MMP-3 in the corneal epithelium of EBMD have been demonstrated, but their association with TIMP (tissue inhibitor of metalloproteinases) levels has not yet been fully analyzed1). Elucidation of the MMP-TIMP balance may lead to the development of future therapeutic strategies using MMP inhibitors1).
Advances in Ocular Surface Treatment
Section titled “Advances in Ocular Surface Treatment”In the management of EBMD before cataract surgery, the use of preserved amniotic membrane after debridement may promote epithelial healing, but a clear advantage over existing bandage contact lenses has not been confirmed3). The development of new treatments utilizing amniotic membrane-derived growth factors and MMP inhibitors is expected in the future3).
8. References
Section titled “8. References”- Jadczyk-Sorek K, Garczorz W, Bubala-Stachowicz B, Francuz T, Mrukwa-Kominek E. Matrix Metalloproteinases and the Pathogenesis of Recurrent Corneal Erosions and Epithelial Basement Membrane Dystrophy. Biology. 2023;12(9):1263.
- Armentano M, Alisi L, Giovannetti F, Iannucci V, Lucchino L, Bruscolini A, Lambiase A. The Co-Occurrence of 22q11.2 Deletion Syndrome and Epithelial Basement Membrane Dystrophy: A Case Report and Review of the Literature. Life. 2024;14(8):1006.
- Yeu E, Hashem O, Sheha H. Treatment of Epithelial Basement Membrane Dystrophy to Optimize the Ocular Surface Prior to Cataract Surgery. Clin Ophthalmol. 2022;16:785-795.
- Adamis AP, Filatov V, Tripathi BJ, Tripathi RC. Fuchs’ endothelial dystrophy of the cornea. Surv Ophthalmol. 1993;38(2):149-168.