Ocular Complications of Epidermolysis Bullosa

Key Points at a Glance

Summary of This Disease

• It is a hereditary blistering disease caused by structural protein abnormalities at the dermal-epidermal junction.
• There are 4 major types (simplex, junctional, dystrophic, and Kindler) with 34 subtypes.
• Typical ocular complications include corneal erosion, ectropion, and symblepharon, which can lead to visual impairment.
• The mainstay of treatment is ocular surface protection with preservative-free lubricants.
• Research on novel therapies such as gene therapy and stem cell transplantation is ongoing.

1. What is Epidermolysis Bullosa?

Epidermolysis bullosa (EB) is a group of hereditary skin diseases characterized by dysfunction of the dermal-epidermal junction. Due to abnormalities in structural proteins of the cutaneous basement membrane zone, blisters form even with minor mechanical trauma.

There are 34 subtypes, classified into 4 major groups.

Epidermolysis Bullosa Simplex (EBS)

Number of subtypes: 14

Inheritance: Autosomal dominant

Lesion site: Intraepidermal (basal cell layer)

Junctional EB (JEB)

Number of subtypes: 9

Inheritance: Autosomal recessive

Lesion site: Lamina lucida

Dystrophic EB (DEB)

Number of subtypes: 11

Inheritance: Both autosomal dominant and recessive

Lesion site: Sublamina densa (deficiency or reduction of anchoring fibrils)

Kindler EB

Reported cases: Approximately 250 worldwide

Inheritance: Autosomal recessive

Lesion site: Involves multiple layers

Epidermolysis bullosa acquisita (EBA) is an autoimmune disease that differs from the above, typically developing in the 30s to 40s. It is caused by autoantibodies against type VII collagen.

More than 16 causative genes have been identified, and mutations lead to abnormalities in structural proteins of the epidermis, basement membrane, and upper dermis. Severity depends on the type and location of the gene mutation.

2. Main Symptoms and Clinical Findings

Epidermolysis Bullosa image

Brendon W H Lee, Jeremy C K Tan, Melissa Radjenovic, Minas T Coroneo, et al. A review of scoring systems for ocular involvement in chronic cutaneous bullous diseases 2018 May 22 Orphanet J Rare Dis. 2018 May 22; 13:83 Figure 1. PMCID: PMC5964694. License: CC BY.

Slit-lamp photograph showing symblepharon, adhesion between the palpebral and bulbar conjunctiva. Chronic scarring has shortened the conjunctival fornix, indicating ocular surface changes.

Ocular involvement can occur in all subtypes but is more frequent and severe in recessive dystrophic, junctional, Kindler, and severe simplex types. Onset can be as early as 1 month of age.

Subjective Symptoms

• Eye pain: Persistent irritation due to corneal erosion or trichiasis
• Tearing: Reflex tearing due to corneal epithelial damage or ectropion
• Photophobia: Light sensitivity due to corneal epithelial defects
• Foreign body sensation: Discomfort from trichiasis or conjunctival lesions
• Vision loss: Progression of corneal scarring, irregular astigmatism, and amblyopia

Clinical Findings (Findings Confirmed by Physician Examination)

Various lesions occur in the cornea, eyelids, conjunctiva, and lacrimal ducts.

Site	Main Findings
Cornea	Erosion, scarring, neovascularization
Eyelid	Ectropion, entropion, blister formation
Conjunctiva	Symblepharon, cicatricial changes

Corneal lesions are the most frequent. Recurrent corneal erosion and abrasions occur repeatedly, progressing to corneal scarring and neovascularization. Ultimately, it may lead to limbal stem cell deficiency or refractory epithelial defects.

Eyelid ectropion results from blister formation and cicatricial contracture around the eyelids. When combined with entropion, it causes trichiasis and worsens corneal epithelial damage.

Symblepharon forms when epithelial defects of the bulbar and palpebral conjunctiva persist, accompanied by inflammatory reactions. Progression leads to restricted eye movement and incomplete eyelid closure.

In the dystrophic type, the following complications have also been reported:

• Meibomian gland cysts, blepharitis
• Iris cysts, retinal detachment
• Madarosis, lagophthalmos
• Lacrimal duct stenosis

Ocular complications can also cause refractive errors, strabismus, and amblyopia.

Q What is the most common ocular complication in epidermolysis bullosa?

A

Corneal abnormalities (recurrent corneal erosion, abrasion, scarring, neovascularization) are the most common, followed by ectropion and eyelid blister formation. These can occur in all subtypes, but are particularly severe in recessive dystrophic and junctional types.

3. Causes and Risk Factors

Genetic Background

Epidermolysis bullosa is caused by mutations in genes encoding structural proteins of the cutaneous basement membrane zone.

• Simplex type: Abnormalities of intraepidermal proteins such as keratin 5/14
• Junctional type: Abnormalities of lamina lucida proteins such as laminin 332 and type XVII collagen
• Dystrophic type: Abnormalities of type VII collagen (main component of anchoring fibrils)
• Kindler type: Abnormalities of kindlin-1 (affecting multiple layers)

Risk Factors for Ocular Complications

• Recessive inheritance: Tends to be more severe than dominant types
• Dystrophic and junctional types: Higher frequency and severity of ocular complications
• Childhood onset: Cumulative tissue damage progresses with chronic course
• Inappropriate periorbital care: Minor friction can induce corneal injury

Things to be careful about in daily life

• Minimize friction around the eyes.
• Avoid eyelid scrubs (eyelid washing) as they can induce blisters.
• Wearing glasses may also cause blisters at contact sites. Choose frames carefully.
• Use preservative-free artificial tears daily to prevent dryness.

4. Diagnosis and Examination Methods

Ophthalmic Screening

All patients with epidermolysis bullosa should be referred to an ophthalmologist for baseline examination. Thereafter, regular follow-up should be performed according to disease severity.

• Slit-lamp microscopy: Evaluation of corneal erosion, scarring, neovascularization, and epithelial defects.
• Fluorescein staining: Confirmation of the extent and depth of corneal epithelial damage.
• Eyelid assessment: Presence and degree of ectropion, entropion, blisters, and scarring.
• Conjunctival assessment: Presence of symblepharon and conjunctival sac shortening.

Multidisciplinary Collaboration

Management of epidermolysis bullosa requires multidisciplinary collaboration including dermatology, pediatrics, ophthalmology, and plastic surgery. Since ocular complications can appear from infancy, prompt detection and treatment of vision-threatening lesions are important.

5. Standard Treatment

Ocular Surface Protection (Basic Treatment)

Preservative-free lubricants (artificial tears, eye ointments) to maintain ocular surface moisture are the mainstay of treatment. This is the most important intervention for preventing corneal and mucosal erosions.

For recurrent corneal erosions, antibiotic eye drops are used to prevent infection and hyaluronic acid eye drops to promote epithelial repair. The use of therapeutic soft contact lenses and application of eye ointment before bedtime are also effective.

Surgical Treatment

When corneal lesions or symblepharon progress, the following surgical interventions are considered.

• Lamellar keratectomy: Vision restoration for corneal scarring and opacities
• Symblepharon lysis: Release of adhesions and reconstruction of the conjunctival fornix
• Amniotic membrane transplantation: Promotion of epithelial repair and suppression of scarring
• Autologous keratinocyte transplantation: To promote blister healing before ectropion repair in Herlitz junctional EB

Management of Eyelid Complications

For entropion and ectropion, surgical intervention is the main treatment¹⁾.

For ectropion, the following surgical techniques are selected according to severity.

• Full-thickness wedge resection of the eyelid
• Kuhnt-Szymanowski procedure (orbicularis muscle shortening + excess skin excision)
• Lateral tarsal strip procedure

For trichiasis associated with entropion, symptomatic treatment by epilation is performed, but if recurrence is frequent, electrolysis or eyelash relocation (Machek procedure, Spencer-Watson procedure) is considered.

For symblepharon, consider Z-plasty of the adhesive tissue or conjunctival sac reconstruction using conjunctival or amniotic membrane transplantation. However, if tear secretion is severely impaired, mucosal transplantation is often ineffective.

Precautions during ophthalmic surgery

When cicatricial keratoconjunctival lesions of epidermolysis bullosa are present, surgical treatments such as cataract surgery or entropion surgery may trigger ocular surface inflammation and rapidly worsen scarring. Adequate preoperative anti-inflammatory treatment and careful perioperative management are essential.

Systemic therapy

Symptomatic treatment is the mainstay of disease management, with avoidance of trauma, appropriate wound care, and disinfection as the basics.

The following systemic drug therapies have shown some efficacy in small-scale studies.

• Mycophenolate mofetil
• Cyclosporine
• G-CSF preparations
• Apremilast

Q Can eyelid scrubs be performed on patients with epidermolysis bullosa?

A

Eyelid scrubs (cleaning/washing of the eyelids) should not be used in patients with epidermolysis bullosa because they can cause blisters on the eyelids. Eyelid hygiene should be maintained using more gentle methods.

Q Can patients with epidermolysis bullosa wear glasses?

A

Wearing glasses is possible, but blisters may occur at the contact points of the frame. It is necessary to choose lightweight frames with a wide contact surface and minimal pressure, and to use cushioning materials for the nose pads.

6. Pathophysiology and detailed pathogenesis

Structure of the cutaneous basement membrane zone and lesions in each type

The cutaneous basement membrane zone is a structure that firmly adheres the epidermis and dermis, and is composed of the following layers.

• Basal cell layer: Keratin intermediate filaments connect to hemidesmosomes
• Lamina lucida: Between the basal cell membrane and the lamina densa
• Lamina densa: Basal lamina mainly composed of type IV collagen
• Sublamina densa: Anchoring fibrils composed of type VII collagen connect to the dermis

In simplex EB, keratin filaments within basal epidermal cells are fragile, leading to blister formation at the most superficial layer. In junctional EB, deficiency or reduction of laminin 332 or type XVII collagen causes tissue separation in the lamina lucida. In dystrophic EB, abnormalities in type VII collagen lead to deficiency or reduction of anchoring fibrils, forming clefts below the lamina densa. Kindler syndrome presents with lesions spanning multiple layers.

Effects on the ocular surface

The periorbital area and ocular surface are subject to the same shear forces and blister formation as the skin. Because the conjunctival and corneal epithelium also have a basement membrane structure, epithelial detachment, erosion, and blistering occur through the same mechanism as skin lesions.

Repeated damage to the corneal epithelium leads to chronic poor adhesion of the corneal epithelial basement membrane, forming the pathology of recurrent corneal epithelial erosion. In the eyelids, repeated blister formation and scar contracture progress to ectropion, entropion, and trichiasis. Persistent conjunctival epithelial defects lead to symblepharon, resulting in conjunctival sac shortening and impaired eye movement.

7. Latest research and future perspectives

Gene therapy

Gene therapy aimed at fundamentally modifying the disease activity of epidermolysis bullosa is the most promising area of research. The goal is to restore normal production of structural proteins by correcting or supplementing the abnormal gene.

Cell therapy

• Bone marrow transplantation: High mortality associated with immunosuppression remains a challenge
• Intravenous mesenchymal stem cell transplantation: Some successful cases have been reported, but long-term effects are limited.

New Developments in Drug Therapy

Losartan (ARB) has been reported as a potential first-line drug to delay fibrotic changes in recessive dystrophic epidermolysis bullosa. It is expected to have anti-fibrotic effects through inhibition of TGF-β signaling.

Disclaimer

This article is intended for informational purposes only and is not a substitute for diagnosis or treatment. If ocular complications of epidermolysis bullosa are suspected, please consult an ophthalmologist promptly. Optimal treatment for individual cases should be determined in consultation with the attending physician.

8. References

1. TFOS DEWS III: Management and Therapy of Dry Eye Disease. Am J Ophthalmol. 2025.

2. Hon KL, Chu S, Leung AKC. Epidermolysis Bullosa: Pediatric Perspectives. Curr Pediatr Rev. 2022;18(3):182-190. PMID: 34036913.
3. Bardhan A, Bruckner-Tuderman L, Chapple ILC, Fine JD, Harper N, Has C, et al. Epidermolysis bullosa. Nat Rev Dis Primers. 2020;6(1):78. PMID: 32973163.