Disease Overview

Pediatric dry eye (PeDED) is a neglected and not fully understood disease. Because of the lack of high-evidence epidemiological and normative data, the poor consensus on the diagnostic algorithm, the difficulties in symptom quantification and interpretation, together with attention focused on the hyposecretive form of the disease, PeDED has been considered a rare condition. It has previously mostly been associated with congenital disorders or autoimmune and inflammatory diseases. Recent evolution in dry eye disease understanding and reports on tear film and ocular surface changes in children are calling into question this view of PeDED, which has led to a growing awareness of the importance of this condition.

Definition

The Tear Film and Ocular Surface Dry Eye Workshop II (TFOS DEWS II) recently updated the dry eye disease definition, stating that “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”¹

This definition has shaped the approach to treating the disease in adults, and it may be helpful in understanding PeDED. This is a multifactorial disease involving the whole ocular surface morphofunctional unit, not just a condition or a disturbance involving the tear film. It is a symptomatic disease with significant impact on quality of life,^2,3 and specific efforts are needed to elucidate this aspect in children. Moreover, the updated definition suggests 5 potential etiologic mechanisms that need to be thoroughly investigated.

Epidemiology

Prevalence

PeDED is considered a rare condition⁴ but its diagnosis is often overlooked, affecting the accuracy of our epidemiological data.

The TFOS DEWS II Epidemiology Report⁵ recently showed that, after the fourth decade of life, the prevalence of dry eye linearly increases. Interestingly, the few data on children included in the analysis showed, in the age range of 15 to 18 years,^6,7 the lowest prevalence of clinically diagnosed dry eye (median value < 5%) but an anomalous high prevalence of dry eye symptoms (median value > 20%) and dry eye identified on the basis of the Women's Health Study criteria (median value > 20%).⁸ 

The population-based cross-sectional study performed by Uchino and colleagues⁶ on 3433 Japanese high school students provided major evidence of the discrepancy between clinically diagnosed dry eye (4.3% and 8% in boys and girls, respectively) and severe dry eye symptoms (21% and 24.4% in boys and girls, respectively).

Selected studies investigating PeDED epidemiology are reported in Table 1.

Table 1. Selection of studies investigating the epidemiology of PeDED

 N/A: not applicable

Risk Factors

Known risk factors for PeDED account for several congenital disorders, autoimmune diseases, ocular allergy, and environmental and iatrogenic factors.

Congenital disorders include familial dysautonomia, Allgrove syndrome, alacrima, ectodermal dysplasia syndromes, multiple endocrine deficiency, cystic fibrosis, and congenital corneal anesthesia.⁴ These rare conditions mainly affect lacrimal glands and corneal nerve function, leading to hyposecretive dry eye and/or potentially severe damage of ocular surface epithelia.

Autoimmune diseases causing dry eye include Sjögren syndrome (SS),¹⁵ graft-vs-host disease (GVHD),^16,17 and juvenile idiopathic arthritis (JIA).^18,19 As in adults, SS and GVHD induce a hyposecretive and inflammatory dry eye, ranging from mild-moderate to very severe forms requiring topical and systemic immunosuppression. JIA may be associated with milder forms of hyposecretive PeDED.

Although the potential association between ocular allergy and dry eye was hypothesized more than 20 years ago,²⁰ recent evidence sheds light on the pathogenic mechanisms underlying the correlation between the 2 conditions.²¹ Ocular allergies, mainly severe forms of keratoconjunctivitis (vernal and atopic), are able to decrease tear film stability, impairing both meibomian gland function²² and tear mucin secretion,^22,23 to induce ocular surface inflammation and damage,^24,25 and to affect corneal innervation.^26,27 In general, ocular allergy-related PeDED does not show decreased tear film volume and secretion; reduced tear film break-up time (TBUT) seems to be the hallmark of this condition, interestingly potentially persisting in the quiet phases of severe allergic disease.²⁸

With regard to environmental factors, the use of visual display terminals is the best-known risk factor for PeDED. The prolonged daily use of these devices, especially of smartphones, reduces the blink rate and induces hyperevaporation of the tear fluid.^10,11

Dietary vitamin A deficiency is associated with ocular surface squamous metaplasia and xerophthalmia. This condition is typically associated with malnutrition and it represents a major health issue in developing countries. Cases occurring in developed countries may be related to eating disorders,²⁹ vegetarian dietary regimen,³⁰ or various forms of malabsorption syndrome.

Air pollution might be an additional environmental risk factor for dry eye disease. At present, preliminary and conflicting evidence on this issue is mainly focused on adults.^31-33 A recent study showing a significant association between air pollution and the rate of pediatric conjunctivitis of unknown origin (not clearly due to infections, allergy, or blepharoconjunctivitis) suggests that the relationship between air pollution and pediatric ocular surface disease needs to be better investigated.³⁴

Iatrogenic risk factors for PeDED mainly include medications and contact lenses. Several drugs can induce or exacerbate dry eye disease, the most relevant in the pediatric population being systemic and topical retinoids for acne vulgaris, systemic and topical anti-allergic drugs, and benzalkonium chloride-preserved eyedrops.^4,35

Contact lens use was reported as a risk factor for dry eye in several epidemiological studies on dry eye.³⁵ About PeDED, a few conflicting data are present in literature, with the prevalence of ocular surface symptoms in children wearing contact lens ranging from 7% to 37%.^6,36

Clinical and Diagnostic Examination

The current and most widely accepted diagnostic algorithm for dry eye disease requires the presence of symptoms plus at least 1 of 3 objective homeostasis markers (reduced tear film break-up time, increased osmolarity, and ocular surface staining). Given the diagnosis, additional examinations may be aimed to assess tear film volume and meibomian gland (MG) function.³⁷

This diagnostic approach has been developed to be applied to adults. However, its peculiarities, including the secondary role assigned to tear film volume and secretion, seem to make it suitable for PeDED. Major challenges are due to the lack of pediatric normative data, of validated diagnostic cut-offs, and of tests specifically developed for children.

Figure 1 proposes and elaborates on a diagnostic approach, planned to minimize the impact of each test on the following one.

Assessment of symptoms

The assessment and quantification of systems may be a major issue in pediatric ophthalmology.

In preverbal children, information provided by parents can be useful, but their interpretation may be challenging because of disagreement between parents and health professionals and the influence of socioeconomic status.^38,39

In children of verbal age, major issues include the need for validated tools for assessment and quantification of symptoms, as well as interpretation of their features and severity. If standardized questionnaires are complex and tailored to adults, visual analogue scales that explore a few key items might be the best approach to pediatric patients. Moreover, interestingly, mild-moderate and chronic DED symptoms might be underreported by children.⁴⁰

Objective diagnostic tests (assessment of signs)

As mentioned earlier, tear film break-up time, osmolarity, and ocular surface staining are 3 key objective homeostasis markers for DED diagnosis.³⁷

Tear film break-up time is the most frequently employed test of tear film stability and it may be assessed by instilling sodium fluorescein (F-BUT), or noninvasively, without dye (NI-BUT).

F-BUT is low-tech and low-cost, it is supported by a large body of evidence in literature, and it can be performed in a standardized manner in order to limit the variability related to fluorescein instillation and to subjective assessment by the observer.³⁷ However, in children, eyedrop instillation may induce an overreaction, including hyperlacrimation, abnormal and forced blinking, and poor cooperation.

NI-BUT, mainly based on the observation of the specular reflection of an illuminated grid pattern from the tear film, may be automatically assessed with specific software.⁴¹ This approach, not requiring eyedrop instillation, may be suitable for tear film stability evaluation in children. The challenges of using this system in children relate to availability of instruments, cooperation (patients have to maintain stable fixation without blinking for up to 15-20 seconds), and lack of normative data in pediatric patients.

Tear film osmolarity, frequently reported as the single best metric to diagnose and classify DED,³⁷  can be measured using a lab-on-a-chip system (TearLab Corp, San Diego, CA). At present, there is scarcity of evidence about this test in children and no data suggesting whether specific diagnostic thresholds in pediatric DED should be adopted. Moreover, recent studies reported conflicting data on the association between osmolarity values and ocular surface health in children.^42,43

Ocular surface staining, performed with sodium fluorescein (and lissamine green), is a low-tech and low-cost clinical examination that can provide useful information on epithelial damage. This procedure requires very limited cooperation and it may be helpful in grading the disease severity. Thanks to lessons learned from severe ocular allergies,^44,45 quantification and pattern of corneal epitheliopathy can provide indirect information on ocular surface inflammation and visual disturbance.

DED subclassification, aimed to investigate the hyposecretive and the hyperevaporative components of the disease,³⁷ is mainly based on the assessment of tear film secretion/volume and of the morphology and function of the meibomian glands.

The Schirmer test without anesthesia is a very common and well-standardized test to investigate tear film secretion but, because of its relative invasiveness, is not ideal for use in children. Good alternatives might be the phenol red thread test,⁴⁶ which can be performed in 15 seconds using a thin cotton thread, and tear meniscometry⁴⁷ performed through optical coherence tomography or other infrared instruments. However, at present, both approaches are limited by the lack of a normative dataset validated in pediatric subjects.

Meibomian gland morphology and function should be assessed combining direct clinical examination, in vivo imaging, and indirect analysis aimed to study the tear film lipid layer.³⁷ Recent advances in meibography have made this the most interesting and promising approach to examining meibomian gland function in children. Infrared systems (including both noncontact and mobile, handheld, and pen-shaped instruments) do not require transillumination, do not dazzle the patient, induce no-to-low discomfort, and allow quick capture and recording of images and videos.^48-50 Open issues are related to the availability and validation of software for automated quantitative image analysis and to the clinical interpretation of findings such as meibomian gland atrophy, drop-out, and tortuosity.

Figure 1. Proposed diagnostic approach for PeDED. Light blue: medical history and symptoms; Blue: key signs for the diagnosis; Gold: volume/secretion assessment for sub-classification; Green: meibomian gland (MG) assessment for subclassification.

BUT= breakup time; IR=infrared; NI-BUT=noninvasive breakup time; OCT=optical coherence tomography; VAS=visual analog scale.

Management and Therapy

The first-line treatment of DED, both in adults and children, includes modification of local environment, education regarding potential dietary modifications, lid hygiene, and warm compresses, and ocular lubricants of various types.^4,51 If literature and clinical experience seem to suggest an important role for the complexities of these management options, the individual measures are often poorly supported by Level 1 studies. Several molecules have been studied as potential additional agents for first-line treatment of DED. One of the most promising is N-acetylcysteine, given its antioxidant and mucolytic activity,⁵² and preliminary studies reported its efficacy (on symptoms more than on objective signs) both in murine models and in patients.^{53, 54}

In 2014, a formulation of chitosan-N-acetylcysteine, a new biopolymer aimed to form a protective glycocalyx-like layer on the ocular surface, was approved in Europe as a class III medical device, and 2 recent retrospective uncontrolled studies reported its efficacy on both signs and symptoms of DED.^{55, 56}

In children, particular attention should be paid to minimize the impact of annoying procedures and of frequent daily eyedrop instillation on everyday activities and quality of life.

Second-line treatments include tea tree oil for Demodex, punctal occlusion, in-office device-assisted therapies (eg, physical heating and expression of the meibomian glands, intense pulsed light), and prescription drugs (mainly intended to control inflammation).⁵¹

At present, we have no evidence supporting the efficacy of in-office device-assisted therapies in children. However, if future data supports their use (or the use of modified, less uncomfortable, devices) in PeDED, they might be a precious weapon, potentially able to limit the need for frequent eyedrop instillation.

Prescription drugs for DED include topical corticosteroids, topical secretagogues (not available in US and Europe), topical cyclosporine (limited availability in some countries), topical LFA-1 antagonist (not available outside US), and oral or topical tetracycline/doxycycline or macrolide antibiotics.

Several adults studies have demonstrated the efficacy of topical steroids, used with pulsed or tapered regimens, and clinical experience confirmed their efficacy in PeDED.^51,57 However, in treating pediatric patients, even if using topical steroids such as fluorometholone, loteprednol, or hydrocortisone, which have a lower likelihood of having an intraocular effect, special attention should be paid to the risk of inducing ocular hypertension and cataracts.^57,58

Use of steroid-sparing drugs in PeDED, indirectly supported by data on children with severe allergic diseases, may be complicated by cost, limited availability, poor tolerability, and lack of specific regimens validated in children.

Oral or topical tetracycline, doxycycline, or macrolide antibiotics are able to decrease bacteria-producing lipolytic exoenzymes, to inhibit lipase production, to decrease the activity of collagenase, phospholipase A2, and several MMPs, and to decrease the production of inflammatory mediators.⁵¹ Evidence seems to mostly support the use of oral tetracycline or analogues. However, the use of these drugs should be avoided in prepuberal patients, because it interferes with tooth and bone development.⁴ Topical antibiotics and oral macrolides are useful alternatives, although supported by less evidence. Topical azithromycin has been shown to improve lipid architecture, TBUT, and patient comfort in a number of studies in adults, and it may also be useful in PeDED.^{59, 60}

Most severe cases of PeDED may require additional therapies including biological tear substitutes (homologous serum from a parent or sibling can be used if venipuncture or blood is impossible or impractical), soft or scleral therapeutic contact lenses, and amniotic membrane grafts.

Summary

PeDED is not yet well known, and is often overlooked. Recent advances of our knowledge of pathophysiology and clinical manifestations of DED in adults might be of crucial importance to begin to better understand, assess, and manage PeDED.

The pediatric tear film and ocular surface have peculiar physiology and pathology, which need to be better understood. Major open issues on PeDED clinical management include the need of specific diagnostic tests to assess both symptoms and signs, the need for normative data, the need for validated diagnostic thresholds, and for a specific therapeutic algorithm that takes into account the specificity of efficacy, safety, and impact on quality of life of treatments in children.

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