The upper eyelid is a composite structure supported by a stiff tarsal plate, which under normal conditions is a dense rigid fibrous structure composed mainly of collagen types I and III and thus provides a strong structural framework for the upper eyelid.¹,³,⁵

The etiology of the condition is unknown, but there are three competing theories to explain the loss of this intrinsic rigidity in FES: the mechanical theory, the ischemia-reperfusion theory, and the leptin resistance theory, which is related to obesity.²,³,⁶,⁷ The mechanical theory implies that the eyelids become vulnerable to repeated mechanical stress because of recurrent pathologic cyclic eyelid loading resulting from repeated pillow to eyelid interaction during sleep. The tarsus consequently suffers dramatic biomechanical changes becoming pliant and overly flexible. This allows easy eversion of the upper eyelid and chronic exposure of the ocular surface. A positive cycle of morbid events is thus initiated.⁵ This cyclic tissue stress results in the inability of the tarsus to maintain tensional homeostasis between external mechanical stimuli and internal (cytoskeletal) tension with a definite alteration in the mechanical properties of the affected tarsus.⁸ Recent evidence is more in favor of the mechanical theory, where there is an upregulation of elastic matrix metalloproteinase activity, especially matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9). This results in a subsequent reduction or depletion in mature elastic fiber abundance within the tarsus; a paradoxical increase in the contractility of tarsal fibroblasts, which is probably an adaptive response; and surprisingly, upregulation of V-CAM1 and PPP1R3C genes in tarsal fibroblasts.³,⁵,⁹,¹⁰,¹¹

The ischemia-reperfusion theory is supported by the association with of FES obstructive sleep apnea (OSA).³ According to this theory, sleeping on one side leads to pressure-induced ischemia of the tarsal plate. But when the patient suddenly awakes, the immediate reperfusion of the tarsal plate causes free radical release that damages the tarsal stroma and quite possibly induces corneal ectatic changes as well.³,¹² This theory is supported by the significant association with obstructive sleep apnea and the laterality of FES with the sleeping side.²,¹² It is also supported by an increase in inflammatory markers in the blood as well as the tear film (MMP-9), possibly induced by local tarsal ischemia.¹² Some authors maintain that the hypoperfusion theory is a less likely alternative to the mechanical stress theory because the upper eyelids are richly perfused with blood and,
more importantly, because a reciprocal association between both FES and OSA is currently disputed.¹²,¹³ Of note is that hyperpeptinemia is associated with up-regulation of MMP-9 and is also closely associated with OSA.²,³,⁶,⁷ Therefore, it is interesting to speculate that the etiology of FES may be multifactorial and that all three theories may contribute to a final common pathway at the molecular level resulting in tarsal elastin depletion, which eventually leads to the development of FES.²,⁷

Two and half decades ago, Van der Bosch and Lemij introduced another term for a broader or a closely related condition called the lax eyelid syndrome, which is characterized by similar symptomatology irrespective of age, sex, or basal metabolic index of the patient. By definition, these patients, who may be young and healthy, may also suffer from ptosis, canthal tendon laxity, laxity of the upper and lower eyelids, as well as ectropion or even entropion.¹³,¹⁴,¹⁵ Furthermore, because there is an additional subset of individuals with lid hyperlaxity, which may also occur at any age but without any symptomatology or conjunctival reaction, Fowler and Dutton coined an all-encompassing term lax eyelid condition as a catchall term to describe all the aforementioned conditions.² According to the authors, it is important to differentiate between a (1) lax eyelid condition, which is any condition of eyelid laxity caused by cutaneous or systemic disease and without papillary conjunctivitis or dry eye symptoms; (2) lax eyelid syndrome, which is a subset of lax eyelid condition but is associated with papillary conjunctivitis or dry eye symptoms, which may occur at any age and may affect either sex; and (3) floppy eyelid syndrome, which they consider as a specific subset of lax eyelid syndrome. The term (FES) is therefore reserved for patients with obesity and obstructive sleep apnea with a strong male predominance.² Of note is that the terms lax eyelid syndrome and lax eyelid condition have not yet achieved broad recognition, and the term FES is still widely used in the literature.

The most commonly affected demographic age group is obese males with a high body mass index from the 5th till the 8th decade, with or without a history of sleep problems.²,³ However, it has been reported in children,¹⁶ as well as in females.⁶

Patients usually present with symptoms of ocular discomfort, bilateral ocular redness, ropy discharge, and chronic eye rubbing that are more severe upon awakening in the morning.¹ These symptoms are usually nonspecific, which explains why in some patients the condition may linger undiagnosed or can be mislabeled as chronic infective conjunctivitis for up to 10 years unless the clinician directly looks for eyelid laxity.¹,³,¹⁷ Therefore, in any obese patient with chronic recalcitrant conjunctivitis, family members should specifically be asked if the patient wakes up frequently during sleep, whether they sleep with their eyelids everted against the pillow, or whether the ocular surface is exposed during sleep.

In the resting awake state, the eyelids may look entirely normal, although an astute observer can notice there is usually some skin redundancy (dermatochalasis) that is out of proportion to the age of the patient, along with a significant amount of whitish mucous discharge around the corners of the eye.¹,³,¹⁷ But more importantly, the upper eyelids are very elastic, and with very slight effort and a bare minimum of superotemporal traction, the upper eyelids become grossly distorted and everted, easily exposing the conjunctiva and the globe (Figure 34.1).¹,³ The tarsal plates are rubbery and pliant with a loss of intrinsic rigidity, which allows them to be folded with ease. Symptoms and signs are bilateral; however, because the pivotal event in FES is upper eyelid nocturnal eversion, the condition is usually asymmetrical with the more severely affected side corresponding to the side on which the patient preferentially sleeps. Both sides may be affected equally if the patient frequently reverses their position during sleep.³

The lower eyelids may be affected as well, although this is less frequently identified as a part of FES (Figure 34.2A).¹³ Other associated palpebral findings include blepharitis, blepharoptosis (Figure 34.2B), entropion, or ectropion.¹³ An additional important yet subtle finding is the presence of eyelash ptosis and possibly loss of eyelash alignment (Figure 34.2C). In more severe cases, the upper eyelid is so lax that it overhangs the lower eyelid during sleep causing significant ocular irritation. This condition is termed eyelid imbrication (Figure 34.2D).¹⁴,¹⁸

Few studies in the literature have attempted quantification of the eyelid laxity in patients with FES, or a systematic grading of the eyelid abnormalities.¹³ A vertical upper eyelid distraction of 15 to 25 mm or a horizontal lid distraction of ≥5 mm is strongly suggestive of FES.¹³ The vertical eyelid pull is calculated by measuring the difference between the resting position of the upper eyelid and its position with a maximum pull.¹³ On the other hand, Ricardo Salinas and associates reviewed and summarized the different grading systems for FES. Several grading systems are available, but they are all limited by the subjective identification of hyperlaxity. One of the more commonly applied grading systems that has been used among several clinical studies is a crude screening test that assesses the degree of exposure of the tarsal conjunctiva upon lifting the upper eyelid skin with the examiner’s thumb while the patient is looking downward. Grade 0 patients do not have FES (the tarsal conjunctiva is not visible upon lifting the eyelids). Patients are classified as grade 1 (mild FES) if less than one-third of the upper conjunctiva is visible and grade 2 (moderate FES) if one-third to half of the upper tarsal conjunctiva is exposed, whereas in grade 3 patients (severe FES), more than half of the tarsal conjunctiva is visible (Figure 34.1).¹³

Ocular surface abnormalities include moderate to severe papillary conjunctivitis, which is almost a universal finding; meibomianitis; blepharitis; and tear film instability.³,¹⁵ Patients with FES may have associated corneal abnormalities, observed in almost 70% of patients,⁶,⁷ including widespread punctate keratopathy, filamentary keratitis, recurrent corneal erosions, corneal vascularization, severe exposure keratopathy, corneal scarring, thinning, and very rarely ulcerative microbial keratitis and even corneal perforation.⁴,¹⁷ Therefore, FES is a potentially blinding condition and patients may indeed experience a drop in visual acuity.¹,²,³ Another enigmatic association between FES and
the cornea is an increased incidence of overt keratoconus seen in roughly 10% to 20% of patients.⁶,⁷,¹⁹ All the aforementioned corneal problems are related to nocturnal eversion, whereas keratoconus is attributed to eye rubbing.³,²⁰ Other postulated ocular associations include normal-tension glaucoma and nonarteritic anterior ischemic optic neuropathy. To the best of our knowledge, a causal association between FES and either condition (glaucoma and ischemic optic neuropathy) is not clear and it may be indirectly attributable to the association of FES with sleep apnea because a relation with both conditions has statistically been shown with obstructive sleep apnea and not with FES.¹³,²¹ Irrespective of the exact cause, it has been suggested that, when a patient is diagnosed with FES, they should be screened for glaucoma.¹³