Ocular Manifestations of Ehlers-Danlos Syndrome

Ehlers-Danlos syndromes (EDS) are a group of hereditary connective tissue disorders with multisystem involvement, affecting the skin, ligaments, joints, blood vessels, internal organs, and ocular tissues.¹

Historically classified under the Villefranche classification system, Ehlers-Danlos syndromes are now recognized as 13 distinct subtypes.² Because ocular complications can occur across the spectrum of EDS, individuals with a confirmed or suspected diagnosis should undergo regular monitoring by an eyecare provider.

Ocular manifestations vary greatly between both EDS subtypes and individual patients. Any collagenous structure of the eye can be affected by EDS.¹

Reported findings include:¹

Eyelid and conjunctival abnormalities
Corneal thinning and ectasias
Dry eye disease
Pathological myopia
Angioid streaks
Abnormal retinal vasculature
Retinal detachments
Scleral atrophy
Globe perforation

Ehlers-Danlos subtypes and classification

Several subtypes of EDS are associated with ocular involvement.

These subtypes include:

Classic (cEDS)
Hypermobility (hEDS)
Vascular (vEDS)
Kyphoscoliotic (kEDS)
Brittle cornea syndrome (BCS)

It is also important to note that clinical findings often have overlapping characteristics between the EDS subtypes, which can complicate accurate diagnosis.

Classic EDS

Classic Ehlers-Danlos is clinically characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility.³ It is among the most common forms of EDS, and represents a spectrum of findings that have historically been recognized as type I and type II EDS.³

The genetic mutations in the majority of pathogenic variants of classic cases are linked to COL5A1 or COL5A2, which encode for type V collagen chains.³

Hypermobility EDS

Hypermobility Ehlers-Danlos, also known as EDS type III, is most often associated with the hallmark sign of joint hypermobility.³ Skin involvement can resemble the classic type of EDS; however, this subtype is particularly complicated by degenerative joint disease, chronic pain from joint dislocations, and arthritis.³

The underlying genetic link remains unclear, but the association with a single mutation in the COL3A1 gene has been suggested.³

Vascular EDS

Vascular Ehlers-Danlos, EDS type IV, represents one of the most severe subtypes.³ Clinical features include translucent skin, easy bruising, and certain craniofacial features.³

Life-threatening complications include the risk for arterial rupture, aneurysm formation, and vascular dissections.³ Similar to hypermobility EDS, there are mutations in the COL3A1 gene; however, instead of a single mutation, multiple occur.³

Kyphoscoliotic EDS

Kyphoscoliotic Ehlers-Danlos, EDS type VI, often presents with progressive spinal deformities and abnormal curvature of the spine.³ Additional features include joint laxity, muscle hypotonia, and ocular fragility with risk of globe rupture.³

Serious systemic complications may involve medium-sized arterial rupture and respiratory insufficiency.³

Brittle cornea syndrome

Brittle cornea syndrome is defined by extreme ocular fragility, with complications including spontaneous or trauma-induced corneal rupture, keratoconus, keratoglobus, and blue sclera.⁴

Systemic manifestations may involve skin hyperextensibility and joint hypermobility.⁴ This collagen vascular condition is frequently confused with kyphoscoliotic EDS due to both conditions carrying high risks of corneal or globe rupture after minor trauma.⁴

Ocular manifestations of Ehlers-Danlos syndromes

Ehlers-Danlos syndromes can present with a wide variety of ocular findings secondary to abnormal collagen synthesis affecting multiple collagen-rich structures of the eye, including the cornea, sclera, lens capsule, vitreous, and retina.²

Orbit and ocular adnexa

Findings may include epicanthal folds (Figure 1), excess skin of the eyelids from cutaneous hyperelasticity (Figure 2), and spontaneous periorbital ecchymosis.^1,2

Floppy eyelid syndrome, caused by an easily everted tarsal plate, may further complicate ocular surface disease.⁵ These adnexal findings often contribute to the distinct facial characteristics observed in EDS patients.¹

Figure 1: Epicanthal fold of the upper eyelid.

^{Figure 1: Courtesy of Devyn Moran Glover, OD.}

Figure 2: Anterior segment photo of excess skin of the eyelids and lid laxity.

^{Figure 2: Courtesy of Devyn Moran Glover, OD.}

Ocular surface and cornea

The ocular surface is commonly affected, with many patients reporting dry eye symptoms, abnormal Ocular Surface Disease Index (OSDI) score, and decreased tear breakup time (TBUT).^1,2 These findings may reflect altered collagen makeup of the surface epithelial cells as well as abnormalities in the extracellular matrix of the lacrimal glands.^1,2

The cornea is frequently thin and steep, predisposing patients to irregular astigmatism.^1,2 In some subtypes of EDS, microcornea is also noted.⁵ Severe complications include keratoconus, keratoglobus, and corneal perforation after minor trauma, particularly in brittle cornea syndrome and kyphoscoliotic EDS subtypes.⁴

Conjunctiva and sclera

EDS patients may develop conjunctivochalasis, likely associated with hyperelasticity of the conjunctiva, which contributes to further ocular surface irritation.⁶ Recurring subconjunctival hemorrhages have also been reported.⁵

Atrophic scleral changes, known as “blue sclera,” can be present. The atrophic progression is usually a result of chronic, progressive thinning of scleral type I collagen.² This progressive thinning leads to a more visible underlying choroid, which has a blue appearance upon examination.

Lens and zonules

Findings involving the crystalline lens in EDS patients include opacifications that are early onset and can progress to be visually significant.⁵ Additionally, ectopia lentis, dislocation of the crystalline lens, has also been reported.⁵

The pathophysiology of this complication may be similar to that of the dislocation found in patients with Marfan syndrome, which is due to weak zonular fibers and structural lens capsule abnormalities.⁵

Posterior segment findings associated with EDS

Several posterior segment abnormalities have been documented. In vascular EDS, spontaneous vitreous hemorrhage may occur due to the compromised vascular wall fragility.⁵ Angioid streaks, or radial breaks in Bruch’s membrane, are especially a concern in the hypermobility EDS subtype.⁶ The compromise in Bruch’s membrane may predispose patients to the development of choroidal neovascularization.⁶

Abnormalities in scleral composition and alterations in the extracellular matrix of the vitreous contribute to increased axial length in EDS patients.² When axial length is longer than average (Figure 3), patients face a higher risk of degenerative myopia, retinal tears and detachments, and secondary choroidal neovascularization (Figure 4).^2,5

Figure 3: Increased axial length measurements of an eye with high myopia.

^{Figure 3: Courtesy of Devyn Moran Glover, OD.}

Figure 4: Fundus photography of macular scarring of a previous choroidal neovascular membrane in a patient with degenerative myopia.

Fundus photography of macular scarring of previous choroidal neovascular membrane in a patient with degenerative myopia.

^{Figure 4: Courtesy of Devyn Moran Glover, OD.}

Optic nerve and neuro-ophthalmic findings in EDS

Some patients with EDS present with bilateral small optic nerves and optic disc colobomas.⁷ Neuro-ophthalmic manifestations, often vascular in origin, can include carotid-cavernous fistulas, nystagmus, Horner syndrome, visual field defects, migraines, and intracranial hypertension (Figure 5).⁷

Figure 5: Fundus photograph of papilledema secondary to intracranial hypertension.

^{Figure 5: Courtesy of Devyn Moran Glover, OD.}

Refractive errors and strabismus

Structural abnormalities contribute to various refractive disorders, including high myopia, irregular astigmatism, and amblyopia.⁵ Certain subtypes are also associated with increased prevalence of keratoconus or keratoglobus. The resulting corneal changes often make spectacle and contact lens correction particularly challenging.

Strabismus is observed more frequently in patients with EDS. Its development is thought to be associated with craniofacial bone asymmetry and abnormal collagen deposition in the extraocular muscles.⁷

Diagnosis of Ehlers-Danlos syndromes

Establishing a diagnosis of Ehlers-Danlos syndrome can be challenging and often requires a multidisciplinary team. Because collagen tissue is widely distributed throughout the body, EDS often involves multiple organ systems. Furthermore, the wide variety of ocular manifestations can also mimic several other pathological conditions.

Ocular examination considerations for EDS patients

Once a diagnosis is confirmed, a comprehensive ocular examination is essential to screen for the wide spectrum of potential ocular manifestations. A thorough slit lamp examination, along with assessment of refractive and binocular status, can help identify structural abnormalities associated with collagen defects involving the eye and determine whether further testing is indicated to maximize visual function.

Corneal assessment may include topography (Figure 6), keratometry, and pachymetry to evaluate the severity of thinning and steepening of the corneal curvature.

Dry eye testing is also valuable in addressing ocular surface disease; Schirmer’s testing, utilizing an OSDI questionnaire, tear osmolarity, and TBUT measurements are tools that help with navigating the dry eye management plan for EDS patients.

Figure 6: Corneal topography of a patient with keratoconus.

^{Figure 6: Courtesy of Devyn Moran Glover, OD.}

Which imaging modalities are best for monitoring ocular manifestations of EDS?

Imaging modalities play an important role in the long-term management of these patients. Anterior segment and fundus photography provide documentation for tracking structural changes found in various ocular structures.

Optical coherence tomography (OCT) is particularly useful in detecting early retinal and optic nerve complications that can arise in these patients (Figure 7). Additionally, testing such as optical biometry or A-scan ultrasound imaging can assist in evaluating the axial length of the eye.

Figure 7: Five-line raster OCT imaging of choroidal neovascular membrane secondary to degenerative myopia.

5 Line Raster OCT imaging of choroidal neovascular membrane secondary to degenerative myopia.

^{Figure 7: Courtesy of Devyn Moran Glover, OD.}
Furthermore, the various structural changes associated with EDS often predispose patients to a variety of refractive errors and binocular vision dysfunction. Regular refractions and binocular assessments are critical for preserving functional vision.

In some cases, specialized interventions such as prism correction for strabismus-related diplopia or specialty contact lens fittings may be necessary.

Management within a multi-specialty model

Given the multisystem nature of Ehlers-Danlos syndromes, ocular management is most effective within a multi-specialty care model utilizing the expertise of multiple providers from various subspecialties. Patients should be educated to notify their eyecare provider promptly if any changes in vision, ocular pain, diplopia, or symptoms suggestive of retinal complications arise.

The eyecare provider plays a crucial role in EDS care; however, it is highly individualized. Providers must utilize the various imaging modalities and specialized testing previously mentioned to assess and manage ocular pathology secondary to the systemic condition.

The frequency and scope of follow-up care are highly dependent on disease severity and specific ocular structures involved in each individual. The targeted services that eyecare physicians provide highlight the importance of individualized care to maintain visual quality, promptly address complications, and reduce the progression of functional impairment.

Co-management of EDS patients and referrals

Because of the systemic and ocular complexity of Ehlers-Danlos syndromes, co-management with multiple specialists is often necessary. Collaboration ensures both systemic conditions and ocular manifestations are addressed in a comprehensive manner. The management of ocular health alone may require the collaboration of both optometrists and ophthalmologists within various subspecialties.

Refractive error management by the optometrist often involves the use of protective eyewear, as well as the fitting of specialty contact lenses in order to provide the patient with the best possible visual correction.

For anterior segment disease, referral to a corneal specialist may be required. Severe thinning, steepening, and risk of corneal perforation can necessitate advanced interventions such as corneal cross-linking and transplantation. In cases of lens subluxation or dislocation, highly skilled cataract surgeons are essential to minimize surgical risks and optimize outcomes.

Posterior segment involvement often warrants collaboration with a retina specialist. While many patients can be monitored primarily by their eyecare provider with serial OCT imaging and fundus photography, timely referrals are critical when structural complications arise.

Conditions such as degenerative myopic changes or secondary choroidal neovascularization may require prompt intervention to preserve vision.

5 key takeaways

As with any systemic condition, eyecare providers play a critical role in educating patients and setting realistic expectations for maintaining ocular health.

Key principles for effectively managing patients with Ehlers-Danlos syndromes include:

Prioritize routine care: Annual comprehensive eye examinations with dilation are essential for preserving ocular health and detecting comorbidities early.
Order targeted testing: Utilize tools such as OCT, corneal topography, anterior and posterior segment imaging when indicated to monitor for structural and functional complications dependent on the individual patient's assessment.
Educate proactively: Inform and educate patients about potential ocular complications specific to their EDS subtype and provide clear guidance on when to seek immediate care.
Utilize specialty services: Incorporate interventions such as complex contact lens fittings or prism correction to optimize visual function.
Refer appropriately: Recognize when referral to subspecialists is warranted for advanced management and intervention.