Changes in tear film metrics and ocular signs induced by different types of refractive correction in an aging population

Ocular surface integrity, in other words, its ability to respond adequately to environmental challenges, depends on a proper information intake at the ocular surface, the transmission of the created signal to the brain and the generation of a response, that will modulate secretory function and local immunity. It is easily understandable that any disturbance of one of the three steps of this closed loop could trigger an inappropriate response and further unbalance the compensatory mechanisms taking place at the ocular surface. The LFU can be defined as a set of anatomical structures whose harmonious functioning maintains tear osmolarity within narrow limits. It is composed of the cornea and the conjunctiva, both protected by the upper and lower lids. All of the structures named above share the same main afferent innervation path represented by the fifth craneal nerve (i.e. trigeminal nerve) and its terminal branches, which allow the cornea and the conjunctiva to take information related to environmental changes and transmit it to the brainstem. Corneal nerves provide a range of afferent inputs modalities such as pain (nociceptor), mechanoreception and temperature (thermoreceptor). Lacrymal glands and blink response are the effectory part of this LFU. LGs are stimulated in response to ocular surface afferent inputs and allow appropriate tear secretion and proper osmolarity values in physiological conditions. This efferent loop is driven by a parasympathetic, secretory innervation which transmits the response signal to the LGs (main, palpebral and accessory), the conjunctival goblet cells, the MGs and adapts tear secretion and composition to environmental challenges. Proper drainage of tears is also involved in this reflex loop as tear secretion is in part evaporated at the ocular surface but also needs to be evacuated since lacrimal secretion is a continuous process. According to TFOS DEWS II, “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles”. The term multifactorial is appropriate since numerous factors have been identified as triggers: age, gender, hormones, environment, ocular surgery and more particularly cataract surgery, auto immune diseases, CL wear, systemic medications, preservatives in eyedrops between others, all of the former potentially conducting to one or both subtypes of the disease. Tear hyperosmolarity, next to a loss of tear film stability, are keystone of the inflammation cascade, both leading to cellular stress and the inflammatory processes, as acute as chronic, inducing auto alimentation and promoting the vicious circle of dry eye disease. As the disease progresses, ocular surface is gradually jeopardized and is characterized by cellular loss. Other key findings are the neurosensory abnormalities; indeed, impaired afferent pathways involving mechanisms that will be explain in further details, prevent a normal information intake at the ocular surface further fostering the auto-promotion of the disease. A wide range of pathologies and disorders, age-related changes, environmental conditions and surgical interventions can trigger inflammatory cascades leading to dryness or worsen ongoing inflammatory processes at the ocular surface. Despite this multitude of entry doors, all of the etiologies of dry eye share a common inflammatory pathway leading to ocular surface damage: cellular death, increased epithelial cells shedding and turnover and above all, impaired afferent pathways leading to self-perpetuation of the vicious circle of the disease. The scientific significance of epidemiological studies relies on a precise definition and classification of the disease, which, until recently, represented the main challenge for DED as no consensus was adopted regarding dry eye objective and subjective diagnostic criteria. Furthermore, the absence of gold standard tests to diagnose the pathology, which goes hand to hand with an acknowledged heterogeneity between signs and symptoms, make the interpretation and comparison of different epidemiological studies more difficult to assess. However, even if DED is considered a symptoms-driven disease, epidemiological studies focusing only on clinical signs are source of a considerable variation in prevalence values. Standardization of diagnostic criteria and clinical tests are the great goal to achieve. The actual situation could explain the difficulties searchers are facing when it comes to diagnosis criteria; dry eye clinical tests evaluating the same parameter don’t have the same sensibility and specificity in diagnosing the disease, tests used often only assess one aspect of the pathology, no gold standard or combination of tests have been chosen to evaluate clinical features; adding to the previous statements a great extent of DED signs, all of them with distinct severity, sensitivity to pain specific to each individual, age-related/ongoing ocular surface pathologies and systemic conditions with ocular impact or age-related changes taking place in the LFU, make a proper diagnosis based on both signs and symptoms challenging. The first TFOS report stated that hyperosmolarity and tear film instability are the key drivers of DED. From that statement, two subtypes of the disease could be defined: ADDE where tear hyperosmolarity is due to a decrease of the aqueous content available on ocular surface (secondary to reduced tear secretion) in presence of a normal tear evaporation rate. EDE is the other subtype of the disease, and in this case, hyperosmolarity follows an excessive tear evaporation rate in the presence of normal lacrimal function. According to the TFOS Epidemiology Report, prevalence of the disease based on symptoms and on clinical signs both show a gradual shift from aged 50. It seems very likely that important age-related changes take place in the LFU at this period of life (that could be due to a combination of aging eye and systemic changes), unbalancing the complex homeostasis mechanisms and leading to onset or excacerbation of signs and symptoms of dryness. Indeed, when it comes to risk factors for the disease, increased age, again depending on diagnostic criteria and variability of the definition of DED, appears to be the most consistent factor associated with dry eye. Every part of the human body is subject to aging and LFU is no exception: LG, the eyelid area, MGs and conjunctiva are affected in their structure and function over the life span. Various histopathologic age-related changes occur in LGs. In the first place, a low grade of dacryoadenitis occurs along with acinar atrophy, periacinar fibrosis and paraductal blood vessel loss tend to appear in young adults but increases with age. Interestingly, the secretory ducts following the acini dilate over the life span and show an increased tortuosity suggesting the presence of an obstruction of the ducts. LG lymphocytic infiltration is directly related to aging as its incidence was found to be higher in subject aged 40 and older. It is mainly concentrated around the secretory ducts and acini leading to their gradual destruction. Besides, it is believed that LG aging comes with fatty infiltration and decrease in LG mass, the former eventually leading to LG dysfunction, reduced reflex tear secretion and breakup time. However, it is thought that the reported decrease in reflex Schirmer values over the life span could be due to a variety of factors such as reduced availability of secretory neurotransmitters, loss of functionality of the gland itself as explained earlier and more important, loss of sensory drive originating from ocular surface. Indeed, terminal afferent corneal pathways taking information relative to mechanical and chemical stimuli at ocular surface, loose sensitivity with age, which is expected to reduce sensory drive to the lacrimal gland. Over and above to the age-related changes aforementioned taking place in the LFU, two additional, visual impairing processes take place within the eye and more precisely within the crystalline lens leading to presbyopia and cataractogenesis respectively, highlighting the need for an optical correction. The present manuscript will describe these two age-related changes and the potential impact of existing refractive approaches to correct them on the onset/ worsening of dry eye signs and symptoms. Accommodation is the process by which the eye, more precisely the crystalline lens, changes its shape in order to focus on near objects. This optical phenomenon relies on the contraction of the ciliary muscle, which in turn loosens the ciliary fibers attached to the crystalline lens. It allows the lens to take a more curved shape, which increases its refractive power and reduces the focal length to the target of interest. With age, the lens progressively looses its ability to change shape, it is called presbyopia. Presbyopia refers to the age-related progressive loss of accommodation of the crystalline lens that result in an inability to focus on near objects. It is one of the most common refractive defects as everyone eventually develops presbyopia, increased age being the major risk factor even if other elements may influence its onset and progression (disease, medications, trauma). Presbyopia directly affects quality of life over all in high-income countries where the main near distance activities involve writing and reading. According to the WHO, cataract is the leading cause of blindness and the loss of useful vision is expected to affect 16 million people worldwide. Cataractogenesis is multifactorial, and can develop from a wide variety of causes ; UV radiation ( in particular UV B) are involved in cortical cataract changes, genetic factors systemic drugs, infectious diseases, but aging is by far the major risk factor for its onset. It induces a broad spectrum of changes regarding biochemical processes taking place in the lens leading to alteration in water balance, proteins, vitamins and enzymes, being responsible for progressive loss of lens transparency. Age-related cataract seems to be the result of a prolonged and gradual process of crystalline proteins denaturation, which can occur principally in three different ways: repeated environmental insults (mainly UV radiation), reduction in intrinsic stability of crystalline proteins, or decline of lens cell homeostasis. DED has become a public health issue worldwide as its impact on healthcare systems is growing steadily. In addition to the economic cost, the social impact of the disease gained a foothold and showed reduced quality of life due to the major impact of the disease on patient’s visual function with more frequent visits to the physician, higher frequency of depression and reduced workplace productivity between other impairments. Numerous studies have looked into the influence of aging on dry eye signs and symptoms and according to them, age is a significant risk factor for the disease as people over 50 years old present a prevalence of dry eye increasing significantly with women being more affected. The burden to become for the society is thus undeniable. Various refractive means exist to correct presbyopia, from spectacles (including simple reading glasses, bifocal, trifocals and multifocal), to CLs with different geometries (monovision, bifocals, simultaneous vision). However, CLs, once upon eye, sit in the TF, disturbing its normal structure and interact with the ocular surface possibly worsening an already unbalanced environment. Refractive surgery is another option available (cataract surgery with implantation of different geometry IOLs (monofocal, bifocal, trifocal), corneal refractive surgery) but its invasiveness, even if great steps forwards have been made, could as well disturb the ocular surface and worsen or induce signs and symptoms of dryness. The aim of this project is to evaluate changes in tear film metrics and ocular signs induced by different types of refractive correction (refractive surgery, IOL implantation and CL) focusing on the older population, since the prevalence of DED increases with age and due to presbyopia most people over 40 need refractive correction for distance, intermediate or near vision, or all three. In Chapter 1, a general introduction is made, exposing various aspects related to the pathophysiology of dry eye syndrome, the clinical manifestations of aging on the eye describing anterior segment changes as well as presbyopia and cataract onset, and therapeutic and optical treatment options for these conditions. In Chapter 2, the importance of studying the impact of optical aids to correct presbyopia on the signs and symptoms of ocular dryness is justified describing the actual situation using epidemiological data. The hypothesis and objectives of the Doctoral Thesis are presented. In Chapter 3, the general methodology and designs choosed in the clinical studies that compose this Doctoral Thesis are described. This chapter presents the characteristics of the parameters evaluated as well as the devices used to obtain the results of the studies presented in subsequent chapters. In Chapter 4, the purpose was to assess the performance of a new daily disposable CL material on the ocular surface of a presbyopic population. A water gradient daily CL material (delefilcon A) was fitted in a presbyopic population and evaluated over their first day of CL wear. To achieve that goal, TF and ocular surface parameters were investigated across a 8 hours’ time of CL wear. Tear film metrics were evaluated at baseline, twenty minutes after CL insertion and then at 8 hours of CL wear. Measurements were taken from the less to the most invasive test as follow: visual acuity, monocular and binocular refraction, anterior segment slit lamp biomicroscopy, osmolarity, measurement of the inferior TMA, topographic examination and TBUT assessment using fluorescein. Participants were recluted among the employees of the University of Valencia and did not present any anterior segment pathology or previous corneal surgery. The average age of the participants was 50.0±4.4 years, ranging between 41 and 60 years old. Mean spherical equivalent refractive error was +1.11±0.35 D and ranged from -4.25 to +2.50 D. From the 40 eyes included, 18 were myopic (mean spherical equivalent error -2.80±0.72D) and 22 hypermetropic (+0.90±0.24D). Significant changes in osmolarity values were found between baseline (306.93±2.32 mOsm/L) and 20 minutes (312.43±2.42 mOsm/L) (p < 0.05). TMA values diminished across the day (from 0.020±0.003 mm2 to 0.017±0.03 mm2) (P=0.061), but were not statistically significant. Ocular surface higher order RMS aberrations showed a statistically significant increase between baseline (0.38±0.21 µm) and 20 minutes (0.61±0.44 µm) (P≤0.001) and between baseline and 8 hours (0.64±0.41 µm) (P≤0.001). TBUT worsened by the end of the day from 10.4±0.4 seconds at baseline to 9.0±0.3 seconds after 8 hours of CL wear (P<0.05). No statistically significant differences were found between the measurements at baseline, and after 8 hours of CL wear regarding fluorescein corneal (P=0.727) and conjunctival staining (P=0.092). According to our results, no significant changes were found regarding corneal or conjunctival staining by the end of the day, which means that even if osmolarity was above cut-off values, it was not clinically significant since there was no significant cellular damage. Osmolarity values did not change over the time of wear, which may imply that CL surface properties remain rather stable during the 8 hours of CL wear and provide enough oxygen transmission and lubrication to the ocular surface in order not to induce any additional staining. However, if the osmolarity changes occured in a similar pattern over longer-term wear, corneal integrity could well be compromised. Besides, we speculated that increases in osmolarity at 20 minutes might also be partly due to both an ocular surface response to CL insertion, and an individual tear interaction with the CL material. DED, according to its severity, is also known to induce a significant rise in aberrations, which implies that in the case of CL wear, pre-lens tear film surface quality would be impacted. The fact that ocular surface high order RMS remained rather stable during the wearing period may imply that the pre-lens TFSQ and dynamics were minimally impacted over the course of the day. We conclude that CL insertion induces an initial decrease in TF stability observed by osmolarity values rising after 20 minutes of wear, but it did not impact tear meniscus metrics and seemed to be transitory, as a decrease, without reaching baseline values, occurred by the end of the wearing period. Ocular surface aberrations remained largely stable from CL insertion, demonstrating an even repartition of TF over the CL material surface. In Chapter 5, the purpose was to assess the effect of lens wearing modality on the ocular surface physiology across a month in a presbyopic population. A total of forty eyes of 40 subjects, employees of the University of Valencia, no previous CL wearers, aged between 41 and 60 years old, were included in this study. Two different wearing Schedule CL material were used: a daily disposable CL (delefilcon A) and a monthly CL (lotrafilcon B). The following parameters were evaluated across the month of wear for each CL material: OSDI questionnaire, CLDEQ-8 questionnaire, visual acuity and refraction, SL biomicroscopy, topographic examination, CCT measurements using OCT and a swept-source biometer, osmolarity measurements, TBUT and TMA. Previously described parameters were measured at: baseline (t0), 20 min margin (t1) and 8 hours margin after insertion (t2), in morning hours (t3) and in the afternoon (t4) of the 30th day excepted for OSDI/CLDEQ-8 that were assessed at the end of the wearing period for each CL material. CL wear was discontinued for four days between each period of one month of wear in order for the eyes to fully recover. OSDI scores obtained at (t0) an (t4) for the daily and EW lenses were 8.5, 13.2 and 24.4 points respectively and showed significant differences over time only regarding the EW lens (p=0.042). CLDEQ-8 scores obtained at (t0) and (t4) for the daily and extended wear EW material were 6.2 ± 3.8 points (t0), 10.6 ± 8.5 points (t4) and 18.1 ± 9.8 points (t4) respectively and showed significant differences lotrafilcon B giving the higher scores (P=0.012). For both lenses, TMA decreased with time (p<0.001) and (p<0.002) respectively (Figure 2). The post-hoc analysis revealed only significant differences for the daily lens between the measurements taken at baseline (t0)/(t2), (t0)/(t3), (t0)/(t4), as well as between (t1)/(t2) and (t1)/(t4) (p<0.05). For the EW lens, significant differences were found between (t0)/(t1) (p=0.016), (t0)/(t3) (p=0.009), (t0)/(t4) (p=0.001) and (t1)/(t4) (p=0.017). No statistical significant differences in osmolarity were found across the day and at the end of the month for each lens (Figure 3). When comparing both lenses, significant differences exist at (t1)(p=0.006) and at (t2) (p=0.002) values being greater for Delefilcon A . For both lenses, higher order aberrations showed significant differences with time whereas Wilcoxon test found significant differences between (t0)/(t1), (t0)/(t2), (t0)/(t3) and (t0)/(t4) (p<0.001) for each lens respectively. No differences were found between lenses across the month of lens wear. Regarding overall central thickness, when comparing both lenses, significant differences were found between all paired comparisons (p