Ocular manifestations in Ehlers-Danlos syndrome

This exploratory study used the TriNetX platform to examine the demographics of EDS and prevalence of ocular conditions in patients with recorded diagnoses of EDS, distributed across the age cohorts 0–30, 31–60, and 61 + . We found an EDS diagnosis was most prevalent in white females across all age groups, and the age of first ICD-10 encounter diagnosis was heavily skewed towards the 0–30 age cohort with a prevalence of 259.6 per 100,000. This data shows that EDS is frequently diagnosed in the early decades of life. As many included ocular ICD-10 diagnoses increase with age, the prevalence and risk in EDS patients may be underestimated compared to age-matched comparators.

Yet, many of the included ocular diagnoses were more prevalent in EDS records, especially among patients 0–60 years old. Overall, patients diagnosed with EDS had the highest prevalence of ICD-10 diagnoses for myopia (prevalence in EDS per 100,000: 5227.0), dry eye syndrome (4211.6), IIH (1995.4), and glaucoma (1532.8). Patients diagnosed with EDS had the highest PORs for diagnoses of angioid streaks (POR 18.72, CI 10.32, 33.94, p value 0) and IIH (POR 18.43, CI 17.51, 19.39, p value 0), while having decreased odds for diagnoses of T2 DR, AMD, and hypertensive retinopathy. Across every EDS age group, IIH consistently demonstrated the highest increased odds, and carotid cavernous fistula emerged as one of the most significant conditions in patients aged 0–30 (POR 17.21, CI 14.18, 20.88, p value 0).

Our data suggests that an EDS diagnosis has significant implications on ocular health. The altered mechanisms of procollagen formation, extracellular matrix (ECM) bridging molecules, and glycosaminoglycan synthesis contribute to the complex pathogenesis of EDS and its subtypes [27]. Collagenous structures of the eye include the cornea, sclera, vitreous body, lens capsule, retina, and choroid [28, 29]. Thus, these widespread ocular pathologies with demonstrated increased odds in EDS records confirm that EDS collagen malformations extend systemically and a referral to ophthalmology should not be undermined.

Confirming smaller studies on ocular manifestations of EDS, we found increased odds of ICD-10 diagnoses for IIH (overall POR 18.43), myopia (4.40), degenerative myopia (3.48), carotid cavernous fistula (3.99), and dry eye (3.89) in both our overall and age-stratified patient groups (Fig. 1a–d). Although angioid streaks had a markedly elevated POR (18.72) in the overall group, there were only 11 EDS records with angioid streaks. Additionally, there exist controversial associations between angioid streaks and EDS in the literature which can introduce sources of misdiagnosis and an inadvertent inflation of its true prevalence rate in this population [30,31,32]. Combined with the rarity of this diagnosis, the POR for angioid streaks may be inadvertently skewed, making this association an area for future study.

Myopia and degenerative myopia are two of the most commonly reported ocular findings in EDS, yet the literature remains inconclusive with contradictory findings [1, 18, 33]. Our findings show that patients diagnosed with EDS have a higher POR of myopia compared to the general population. Myopia is typically diagnosed in childhood, and adult-onset myopia progression can be observed up to the 5^th decade of life [34]. Given that the mean age of EDS records was higher than its general comparator in the 0–30 age cohort, when a myopia diagnosis is most common, the impact of our findings is particularly pronounced. The proposed pathogenesis involves EDS mediated changes to the vitreous ECM secondary to decreased bridging molecule integrity and altered scleral composition secondary to abnormal collagen formation. Both ECM and scleral structure regulate the axial length of the eye, and therefore EDS impacts on both of these components can lead to myopia and its progressively degenerative subtypes [18, 35]. Additionally, animal studies examining EDS mouse models have shown abnormal collagen structure in the cornea, causing changes to the biomechanical properties of the cornea [36, 37]. Others have also found that classic EDS patients have both thinner and steeper corneas [19, 38,39,40]. Such corneal changes may also explain the pathophysiology of increased myopia seen in EDS.

Villani et al. and Gharbiya et al. hypothesize over the role of EDS in dry eye syndrome, which we also found to be increased in patients diagnosed with EDS. Increased ocular surface disease index scores and tear film instability in EDS patients suggests a role in the altered collagen of the ocular surface epithelial cells [19, 41]. Alternatively, altered ECM of the lacrimal glands may explain the association between EDS and dry eyes [18].

The increased odds of an IIH diagnosis in EDS may be due to altered dynamics of cerebrospinal fluid secondary to Chiari malformation comorbid with hypermobile EDS [22, 42, 43]. Inferior displacement of the cerebellar tonsils creates an elongated and obstructed system for cerebrospinal fluid outflow which promotes a hypertensive state in the subarachnoid space, directly affecting the optic nerve and causing IIH findings such as papilledema [44, 45]. Another hypothesis is related to the increased odds of finding carotid-cavernous fistula formation in vascular EDS patients [46, 47]. Pollack et al., reports that structural deficits in type III collagen have been associated with ophthalmic arterial wall abnormalities and concurrent fistula formation with the cavernous sinus [48]. Resulting changes to cavernous sinus pressure may act as a nidus for turbulent flow and increased pressure around the optic nerve [49].

Conversely, T2 DR, AMD, and hypertensive retinopathy were among those diagnoses with the most significantly decreased odds in overall patients diagnosed with EDS. This may be the combination of the shortened life expectancy of people with EDS (median life span of 48 years), younger mean ages of the EDS cohort in the dataset, and the delayed presentation of T2 DR, AMD, and hypertensive retinopathy leading to diagnoses at later stages of life [50,51,52]. This is further corroborated by the dramatically lower numbers of EDS diagnoses in the 61+ cohort and lack of significant PORs for the ocular conditions in this cohort (Fig. 1d). Future study pursuits could aim to include age-matching and explore the prevalence of the disease, such as diabetes, that underlies the related ocular comorbidity in EDS patients.

Another notable finding in this study was that a diagnosis of ROP had significantly decreased odds in EDS records. ROP is most often a consequence of preterm birth and pregnancies, and an EDS foetus has a higher rate of preterm birth [53,54,55]. The opposite finding in our study raises further questions about the pathogenesis of ROP with EDS that would benefit from study from a molecular perspective.

Limitations inherent to the use of the platform include lack of visibility into patient cases if the query results in patient counts between 1–10 patients. Thus, rare conditions, especially when broken into 30-year-age cohorts, could not be included in the study to preserve the accuracy of the analysis. Additionally, because the platform depends on accurate diagnoses and reliable ICD coding, the study data is likely an underestimation of true clinical cases. The platform’s general population carries an inherent bias towards those utilizing the healthcare system, as it captures anyone who has a visit recorded in the EHR. Thus, although it is not a true measure of the US population, the platform has been found to have comparable percentages of patients to the US Census with the exception of Hispanic patients [56]. Similarly, because socioeconomic factors cannot be coded for, uncontrollable confounding variables may have been introduced into the study. A limitation inherent to the study was the inability to gather nor analyse data on EDS subtypes because the platform did not contain this granularity. A final study limitation involves bypassing Bonferroni correction through the statistical analysis of multiple comparisons on the dataset. This was attempted to be addressed through the inclusion of the p values in the figures.

In conclusion, this study demonstrated that an EDS diagnosis was most prevalent in white females aged 0–30 years old. Additionally, it showed that patients aged 0–60 years old who are diagnosed with EDS are at increased odds for many ocular conditions that involve collagenous structures of the eye, compared to counterparts of the same age. Specifically, diagnoses of IIH, myopia, dry eye syndrome, and carotid cavernous fistulas were among the highest odds in EDS records. Although angioid streaks demonstrated markedly increased odds in EDS records, this condition was ultimately too rare to be studied in this platform and may be better suited for targeted retrospective study. However, the frequency of ocular findings in EDS patients suggests that an ophthalmological referral may be a beneficial addition to the initial care of a newly diagnosed EDS patient. Inclusion of screenings for these conditions can also guide patient-provider conversations on the potential impacts of an EDS diagnosis on the patient’s ocular health. Future studies should examine the effects of these findings after propensity matching by potential confounders such as age, further clarify the pathogenesis of EDS ocular manifestations, or explore the associations between ocular conditions and causes of EDS morbidity, such as cardiovascular events.