Fig. 11.1
Lax eyelid condition (LEC) in nonobese patient (Case 1) with sleep apnea (peak 70 s without breathing)
In discussing the nature of the ocular surface disease and its management with the patient, an important step is to address the patient’s expectations. The chronic nature of the disease must be made clear and that completely eliminating the symptoms may not be possible but that definite but small improvements in symptoms are what we look for. The goals of therapy are to improve not eliminate the symptoms, and the improvement might be definite but slight. No response must be carefully distinguished from small improvements since the incremental improvement is the very goal of the various approaches to therapy.
Using the treatments at the appropriate frequency and duration is also important. Questioning the patient if the treatment helps or does not help is important. If the treatment helps, then what is the least frequent dose/regimen to provide this help is key. The corollary of this approach is to stop treatments that do not help. The targeted therapy schedule should also be reviewed with the patient. For those treatments that the patient feels help, then the next step is to reduce the frequency of the treatment until they arrive at the least effective dose. Finally it is important to emphasize to patients that managing chronic ocular surface disease requires a prophylactic approach. They are used to prevent/reduce the symptoms. I use the sunscreen analogy. If you get sunburned and then run onto the house to put the sunscreen on and discover it not effective, that is not a problem with the sunscreen.
The ocular surface exam and diagnostic testing must also be equally sequence systematic and thorough [6]. This always includes an external exam, slit lamp exam, diagnostic testing, and immediate assessment of responses to drops (i.e., anesthetic). If patients deny improvement in symptoms following topical anesthetic, then other explanations for the symptoms need to be explored.
The external exam must include the skin type (Fitzpatrick scale ), presence of rosacea, eyelid position (retraction, ptosis, lagophthalmos, entropion, ectropion), presence and degree of laxity (graded as % tarsal conjunctiva visible with moderate upper lid skin elevation [7]), direction of the eyelashes (eyelash ptosis, trichiasis), and resting blink frequency. Pen light exam of the eyelids, conjunctiva on manual lid retraction and elevation can also provide useful information (conjunctival subepithelial fibrosis, fornix shortening, symblepharon, pinguecula, and papillary reaction (from the light reflex off the bulbar conjunctiva)).
Slit lamp exam should focus on the eyelid margins including keratinization, meibomian glands (volume, plugging, thickening, vascularization, dropout), presence of demodex mites, and any subtle blond eyelashes. Next should be the tear film including meniscus, quality of the film (oily), and breakup time (BUT). The conjunctival exam should identify conjunctivochalasis, temporal lid parallel conjunctival folds (LIPCOFs) [8], lymphangiectasis, vascular dilation (focal and diffuse), and lissamine green staining presence and distribution (van Bijsterveld Index) [9]. The corneal exam should focus on the limbal neovascularization, presence and distribution of punctate staining, filaments, anterior basement membrane dystrophy, and focal keratitis. The anterior chamber and lens exams should also be documented.
Diagnostic testing should first include the findings from the ocular surface disease index (OSDI) [1], Schirmer (without anesthetic, 3 min), vital dye staining (fluorescein, Rose Bengal, lissamine green) of the cornea and bulbar and tarsal conjunctiva, tear breakup time (TBUT) , and objective evaluation of the meibomian glands (plugging, volume, vascularization, thickening). Additional diagnostic testing options include the following: matrix metalloproteinase (MMP) testing (I nflammaDry®), tear osmolarity (TearLab), Meibography (e.g., Lipiview®) impression cytology , and OCT quantitation of tear meniscus height [6].
On physical exam, the patient was a well-nourished man with normal habitus and BMI. His vision was 20/20 and 20/25 with spectacle correction. Pupil and confrontation visual field exams were normal.
On external exam your patient demonstrated eyelash ptosis, peau d’orange periocular skin changes, as well as rosacea, grade 2–3 eyelid laxity with medial canthal laxity [ 7 ]. The eyelid position demonstrated mild ptosis of the right eye with good levator function in both eyes. There was slight lower lid ectropion but no entropion or misdirected lashes. The tarsal conjunctiva demonstrated 1−+ diffuse papillary conjunctivitis and the bulbar conjunctiva trace to 1+ injection.
Slit lamp exam demonstrated no keratinization of the lid margin or ocular surface, 2+ meibomian gland dysfunction with plugging, thickening, and mild gland dropout. No demodex mites were observed. There were no lid parallel conjunctival folds and no conjunctival lissamine staining, but a mild decreased BUT. The cornea demonstrated trace-1+ inferior fluorescein staining and minimal limbal vascularization. The rest of the slit lamp exam, anterior chamber, and lens were normal.
Fundus exam dem onstrated a c/d ratio of .4 OU, with a normal posterior pole.
Diagnostic testing included a Schirmer 1 test result of 18 mm/20 mm without anesthetic at 3 min, a positive InflammaDry ® testing for matrix metalloproteinase (MMP), and a tear osmolarity reading of 305 and 308.
At This Point, What Do You Conclude from the History and Exam?
In creating a differential diagnosis, it is also important to be systematic. We use the D4Vitamins mnemonic (Diet, Developmental, Drug, Degenerative, Vascular, Infectious, Traumatic/Toxic, Anoxic/Autoimmune, Metabolic, Endocrine, Neoplastic, Special) to run through the possibilities. This reduces the likelihood of overlooking a possible diagnosis by quickly jumping to conclusions from a few of the patient’s complaints and some of the physical findings.
At this point, the patient has mild ocular surface disease with associated findings of rosacea and lax eyelids. There were no dietary restrictions in the history, and there were no findings to support vascular, infectious, metabolic, endocrine, neoplastic, and traumatic etiologies. He was not taking long-term preserved topical agents suggesting that a toxic etiology less likely. A Schirmer result of 18/20 rules out aqueous tear deficiency. A grade 2 mild laxity finding with a positive history of snoring suggests lax eyelid syndrome with possible sleep apnea even though the patient was not overweight. This is also supported by a positive family history of snoring. A sleep study was recommended.
Additional review of systems uncovers that the patient had a sleep study after his wife noticed that he would stop breathing at night and she would have to shake him to wake him up and get him to start breathing. Following the sleep study, he reported a peak apneic episode of 70 s (see video attached).
Floppy Eyelid Syndrome and Sleep Apnea
Floppy eyelid syndrome (FES) was first reported by Culbertson in 1981 and later by Parunovic and characterized by overweight young men with distensible eyelids and chronic conjunctivitis [3, 4]. Netland (1994) reported the histological findings of a reduction in elastin in the eyelid of FES patients [10]. Schlotzer (2005) further characterized the involvement of MMP in FES in addition to elastin reduction [11]. Series (2004) reported elastin disorganization in the soft palate of patients with snoring that underwent uvulopalatopharyngectomy [12]. Although it was unclear if the elastin changes were the cause or result of the snoring trauma, this finding suggests a possible systemic elastin dysfunction in these patients.
Woog first reported the association of sleep apnea and the lax eyelids in 1990 [13]. Multiple papers have reported this relationship, and Chambe in 2012 reported a 35% incidence of OSA in patients with FES [14]. Others have reported 90–100% of patients with FES have OSAS [15–19]. There might be a genetic association in OSA [20] (Fig. 11.2).
Fig. 11.2
Nonobese patient with glaucoma, lax eye syndrome (LES), and OSAS (Case 2)
Van den Bosch (1994) introduced the condition of “lax eyelid syndrome” (LES) with similar findings in nonobese individuals of any sex [2]. Finally, Fowler and Dutton (2010) broadened the finding of eyelid laxity and associated findings and divided the laxity into three categories: lax eyelid condition (LEC), lax eyelids of any age without associated eye findings; lax eyelid syndrome (LES), adding ocular surface changes conjunctivitis to the LEC; and finally floppy eyelid syndrome, FES in overweight men [5]. The association of eye lid laxity with ocular surface disease is well documented [21–26] (Figs. 11.3, 11.4 and 11.5).
Fig. 11.3
Lax eyelid syndrome (LES), undiagnosed
Fig. 11.4
Laxometer device for quantitating lid laxity
Fig. 11.5
Lax eyelid condition (LEC) (any age)
What Is the Association Between Ocular Surface Disease, Sleep Apnea And Floppy (Lax) Eyelid Syndrome?
The ocular surface changes are definitely associated with floppy eyelids. Acar et al. reported on 280 patients with OSAHS with OHS severity determined by AHI Index [27]. They all underwent a complete eye exam with Schirmer, TBUT, and ocular surface staining . Each patient also completed the OSDI questionnaire. FES was present in 23% of the non OHSH group, 41.7% in the mild OSHS group, 66.7% in the moderate, and 74.6% in the severe OSAS group. The OSDI questionnaire, Schirmer test, TBUT, and corneal staining all demonstrated a significant correlation with the severity of the OSAS.
What Are the Next Steps in the Management of This Patient?
The chronic low-grade inflammation associated with the chronic papillary conjunctivitis associated with lax eyelid syndrome may be due in part to elevation in MMP in the tear film. The inflammatory mediators associated with the rosacea blepharoconjunctivitis probably also contribute to the process. OSDI, TBUT, and ocular surface staining need to be carefully evaluated in patients with FES and OSAH [22]. Treatment needs to be directed toward reducing inflammation and repair the eyelid to globe apposition. This can be accomplished through lateral canthal ligament tightening and or full thickness wedge resection. Management of the meibomian gland dysfunction with topical azithromycin 1% (AzaSite ® ), compresses, and tetracyclines may also help [28, 29].
What Were the Outcomes of the Management?
The diagnosis of lax eyelid syndrome (LES) was made, and the patient had an upper lid wedge resection and lateral canthal tightening [30, 31]. There was better apposition of the lid against the globe. The signs and symptoms improved over 2–3-week period. The punctate keratitis and discharge resolved. The lateral lower lid ectropion improved as well. The lash ptosis also improved slightly. Histological specimens demonstrated moderate subconjunctival chronic inflammatory infiltrate especially around the accessory lacrimal tissue with bacterial colonies on the conjunctival surface [10, 11]. The tarsal plate demonstrated lipomatous atrophy, and the dermis showed severe elastic degeneration. Demodex brevis was present in the meibomian glands.
Summary and Conclusions
- 1.
Evaluation of all patients with complaints of chronic irritation should include a careful evaluation of the eyelid laxity including distraction test of both the upper and lower lids as well as tarsal conjunctival inflammation.
- 2.
Patients with complaints of chronic irritation with a normal Schirmer and who are unresponsive to frequent topical preservative-free tear drops should suggest a diagnosis other than aqueous tear deficiency (lax eyelids, allergic conjunctivitis, conjunctival chalasis, etc.).
- 3.
Identification of lax eyelids should prompt an evaluation of sleep apnea and the many associated ocular (and systemic) neurovascular diseases associated with sleep apnea (glaucoma, ischemic optic neuropathy, papilledema, retinal vein occlusion).
Case 2
A 66-year-old Caucasian woman was referred for a glaucoma management. Her past medical history is significant for diabetes, hypertension, hypercholesterolemia, and atrial fibrillation. She denies a family history of glaucoma. Her ocular medications included brimonidine/timolol drops (Combigan ® ), latanoprost (Xalatan ® ), and preservative-free artificial tears. Her systemic medications included amiodarone, atorvastatin, and enalapril (Vasotec).
On external exam she had mild rosacea and bilateral slight lash ptosis. She had moderate lid laxity (grade 2), with mild papillary conjunctivitis .
Slit lamp exam demonstrated mild papillary conjunctivitis, mild arcus, and mild nuclear sclerotic cataract. There was no punctate staining and the Schirmer was 18 both eyes.
Fundus exam demonstrated an optic nerve cup to disk ratio of 0.7 in both eyes. The remainder of her fundus exam demonstrated mild vascular attenuation and a normal macula. Her applanation pressures were 14 and 15. Humphrey visual field testing demonstrated bilateral superior arcuate scotomas. OCT testing demonstrated moderate NFL loss bilaterally.
Remembering the Mechanical and Ischemic Causes of Glaucoma, What Other Tests Might Be Helpful to Explain the Progressive Visual Loss with Pressures in the Mid to Low Teens?
Carotid ultrasounds, CT, and MRI imaging were normal. Diurnal and nocturnal IOP measurements were all less than 17. A 24-h electrocardiogram demonstrated intermittent atrial fibrillation. She was started on amiodarone with resolution of the atrial fibrillation. Over several years her HVF continued to worsen in spite of pressures less than 15 mmHg.
Upon further questioning, the patient reported a history of daytime fatigue, difficulty concentrating, and some morning headache. She admits to snoring occasionally, and her spouse confirms that the snoring occurs more regularly.
What Are the Next Steps in the Diagnosis and/or Management of This Patient?
The history of snoring and daytime fatigue as well as her lax eyelids should prompt a suspicion of sleep apnea [32–35]. The patient was sent for a polysomnography (PSG) , and she was diagnosed with obstructive sleep apnea syndrome (OSAS). Upper airway obstruction can be classified into three categories: (1) OSAS, the most severe associated with complete cessation of airflow associated with daytime sleepiness, (2) sleep hypopnea, and (3) upper airway resistance syndrome which is snoring without a significant decrease in airflow. Not all patients with OSA have daytime sleepiness and are described as having OSA. Most patients do not remember waking at night during the apneic episode, which makes the diagnosis more difficult. OSAS is defined as > 5 apnea/hypopnea events (AHI)/hour, and severity is graded as mild, moderate, and severe. The respiratory disturbance index (RDI) measures the number of events/hour. Symptoms of OSAS include daytime sleepiness, daytime headaches, difficulty concentrating, and memory problems (Faridi et al.). In sleep apnea, the patient does not remember awakening. The Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure identify OSAS as a treatable secondary cause of hypertension [36]. OSAS is also associated with pulmonary hypertension, myocardial infarction, cardiac arrhythmia, congestive heart failure, stroke, cardiac related mortality, and all-cause mortality [37, 38]. The Sleep Heart Health Study (SHHS) concluded that there was a definite relationship between RDI in patients with OSAS and stroke, heart failure, and vascular disease [39].
Glaucoma is a progressive optic neuropathy, an ocular neurodegenerative disorder that is characterized by optic nerve changes and characteristic visual field changes. Vascular risk factors include a variety of diseases associated with reduced blood flow and ischemia. Several of these disease including migraine , Raynaud’s phenomenon , atrial fibrillation, and reduced nocturnal blood pressure can lead to decreased ocular perfusion pressure. These are just risk factors and not necessarily causes of the optic neuropathy. Although lowering IOP is the only established modifiable risk factor, it is well known that deterioration in the visual field can occur despite good IOP control stimulation a search into other modifiable factors. Faridi et al. published an excellent review of the role of sleep apnea and glaucoma [40].
In 1982, Walsh and Montplaisir first reported the association between glaucoma and OSAS [41]. During sleep, local and systemic vascular alterations also occur in that are balanced by local autoregulation in order to maintain homeostasis. However, in OSA, the normal physiological balance is upset. OSA is a potentially modifiable risk factor, which has been increasingly associated with glaucoma independent of intraocular pressure. OSAS is a common but often unrecognized disorder [42]. Because of the chronic intermittent hypoxia , OSAS has been increasingly associated with increasing risk of neurovascular disease (diabetes) including pulmonary, cardiovascular (atherosclerosis, heart disease, peripheral neuropathy), and cerebrovascular disease (stroke, cognitive decline, depression, headache, and nonarteritic ischemic optic neuropathy NION) [43–46]. The relationship between OSAS and glaucoma risk is controversial. Many studies support that the OSAS has also been known to be associated with glaucomatous optic neuropathy with 5.7–27% of glaucoma patients having OSAS [47–57]. Several studies have failed to demonstrate a relationship between OSAS and glaucoma [58–62]. Associations between RDI and VF indices have been reported. Shi et al. performed a meta-analysis of papers reporting the association of OSAS and glaucoma [63]. They reviewed 16 cross-sectional (six case control and nine cohorts) clinical studies with 2,278,832 participants. Pooled odd ratios were calculated for the association of OSAS and glaucoma. They found an adjusted hazard ratio of glaucoma in this OSAS population of 1.67 (95% CI = 1.30–2.17). Muniesa et al. found that FES was a risk factor for glaucoma in the OSA population [64].
Role of Vascular System in Glaucoma in Patients with OSAS
Perfusion Pressure (Blood Pressure: IOP)
The role of blood flow and ischemia in the pathophysiology of glaucoma is not well known. Drance reported in 1972 a series of NTG patients with about a third with a history of hemodynamic shock [65]. Progressive VF loss in the setting of normal or low IOP also suggests other factors than IOP. Low nocturnal perfusion pressure as a risk factor for glaucoma has support from several large studies [66]. The EMGT reported a decrease in risk of glaucoma with an elevation in systolic blood pressure [66]. The role of perfusion pressure in OSAS is also unclear. With a decrease in sympathetic tone at night, the normal blood pressure decreases by 10–20% or 15 mm. This is balanced by increase in ocular blood pressure from the supine position. There are conflicting reports regarding the role of lower systemic blood pressure in the pathophysiology of NTG due to local autoregulatory mechanisms. OSAS can alter the blood flow to the optic nerve and thus affect perfusion pressure. Mojon reported that the severity of the OSAS correlated with the severity of the glaucomatous nerve damage. OSAS associated with increased sympathetic tone can lead to vascular endothelial dysregulation from hypoxia mediated changes and can also affect optic nerve head blood flow.
Patients with a greater decrease in nocturnal blood pressure can be associated with progressive field loss [67].
The mechanical and vascular theories supporting the pathophysiology of glaucoma have support from OSAS. From the vascular theory, upper airway collapse leads to the hypoxia that stimulates sympathetic activation resulting in many effects including renin-angiotensin system activation and elevation in blood pressure.
Factors which can effect ocular perfusion and possibly glaucoma progression include: low blood pressure, IOP fluctuation, low intracranial pressure, and OSAS. CPAP can actually normalize the IOP as well as restore normal blood pressure [68]. The apnea-hypopnea index (AHI) was 60 and her respiratory disturbance index (RDI) with a peak apnea of 70 s and an oxygen saturation of 64%.
Hypopnea leads to hypoxia, which in combination with hypertension can lead to endothelial damage, decreasing responsiveness to nitric oxide. This results in autonomic dysfunction/altered blood flow from a vasodilation and vasoconstriction imbalance.
Hypoxia and subsequent reperfusion lead to oxidative stress, an inflammation with increased inflammatory markers and reactive oxygen species.
Autonomic Dysfunction
The increase in sympathetic tone in OSAS associated with intermittent hypoxic episodes is thought to result in endothelial damage [69]. Elevated levels of plasma and urine levels of catecholamines are found in OSAS. OSAS affects the vascular endothelium through oxidative stress, inflammation, atherosclerosis, and a decrease in nitric oxide [70, 71]. The vasoconstrictor endothelin-1 has been shown to upregulate in OSAS and in NTG [72]. OSAS then has a role in vascular regulation.
Ischemia
Although atherosclerosis and carotid vessel disease are not associated with glaucoma, silent cerebrovascular infarcts are elevated in patients with NTG [73]. Intermittent hypoxia, associated with vasospastic-induced ischemia such as migraine, has also been associated with LTG as reported by the Collaborative Normal Tension Glaucoma (CNTG) study . Hypoxia-induced platelet activation present in OSAS patients can be reduced with CPAP therapy [74].
Inflammation and Oxidative Stress
Intermittent hypoxia and reperfusion injury found in OSAS patients both systemically and in the eyelids result in inflammatory changes predisposing to glaucomatous damage.
Hypercapnia
Apnea results in peripheral vasoconstriction and then regional vasodilation of the cerebral and myocardial circulation. The post-apneic hyperventilation leads to hypocapnia and peripheral vasodilation. The lack of subsequent vasodilation in the ophthalmic vessels in glaucomatous eyes could then lead to a cerebrovascular “steal” from the blood flow to the optic nerve head. The hypercapnia also increases intracranial pressure as well as cause metabolic stress and acidosis.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
