European Dry Eye Society
The European Dry Eye Society (EuDES) was founded in 2020. Its goal is to support European researchers and clinicians to expand our knowledge in the area of Dry Eye and other ocular surface diseases. Close collaborations with the existing TFOS and Asian Dry Eye Society are desired. Sharing cutting-edge scientific knowledge and practical skills on dry eye disease (DED) with other European experts, as well as anyone interested in DED and optimizing ocular surface treatment for patients is important to EuDES. EuDES hopes to fill the gap between basic science research in the ivory towers and the practitioners in the trenches, attending to the needs of real people in disabling pain with very poor quality of life. The website of EuDES was just released and is accessible under https://www.dryeye-society.com . An educational program with life talks and other webinars as well as an annual congress (EuDEC) are planned. The authors of this chapter are closely involved in the foundation of this new society and are part of the current Executive Committee.
Definition of DED in Europe
The definition of the DEWS II report from 2017 is typically also used in Europe; however, there is some containment. The term “homeostasis” is perceived as very theoretical, the loss of visual symptoms in this definition is deeply regret, and the problem to analyze hyperosmolarity in dry eye patients in Europe—although being a definition criterion—is seen critical. Recently a group of dry eye researchers from Europe, Asia, and United States published a revised definition seemingly more relevant to the clinician: “Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.”
Classification of DED in Europe
Barabino et al. recently suggested an update of DED classification defining three types of disease to improve grading of severity : Type I is a transient and reversible form with subclinical inflammation, possible epithelial alterations, and occasional alterations in vision. Type II is a recurrent form characterized by a reduced ability to reequilibrate the ocular surface, frequent symptoms and alterations in vision with clinically evident inflammation, and clear evidence of epithelial alterations. Type III is a chronic form with inability to reequilibrate the ocular surface and accompanied by clinically evident and chronic inflammation, persistent epithelial alterations, and frequent alterations in quality of vision. They state that the vast majority of patients with DED can be easily classified into one of these three forms. Rolando and coworkers support this concept and propose in addition to include the frequency of symptoms (sporadic, intermittent, persistent, or permanent) into the classification of DED.
Epidemiology of DED in Europe
Epidemiological data are available for a number of European countries including United Kingdom, France, Spain, Italy, Germany, Norway, and Denmark. Dry Eye prevalences are reported between 10% and 34% depending on the age and sex of the examined population as well as the definition used. Asymptomatic Meibomian Gland Dysfunction (MGD) occurred in 21.9% and symptomatic MGD in 8.6% in a study from Spain. An Italian study on VDT users found a prevalence of definite DED in 23.4% and suspected DED in 44.4% of persons. The German Register for Glaucoma patients documented a high prevalence of DED in glaucoma patients (56.9% in females, 45.7% in males). Moreover, also in European DED patients, allergy, cataract surgery, rheumatoid arthritis, migraine and stroke, other pain syndromes, and depressive symptoms are confounding factors. The economic burden and reduction of quality of life due to DED is as high as in other areas of the world.
Dry Eye Diagnosis in Europe
In its Diagnostic Methodology Report, The Dry Eye Workshop II established a valuable diagnostic flow including triage questions, risk factor analysis, diagnostic tests including questionnaires for symptomology, and analysis of homeostasis markers such as noninvasive break-up time, osmolarity, and ocular surface staining followed by subtype classification with tear meniscus measurements to diagnose aqueous tear deficiency, and meibomian gland evaluation for the diagnosis of MGD. For the European clinician this diagnostic flow, however, seems to be complicated and recommended tests are not available to the general ophthalmologists. In specific dry eye clinics, the recommended diagnostic steps are typically followed with site- and country-specific alterations.
Subjective Symptoms of DED
A multitude of subjective symptoms is reported in dry eye, and the spontaneous terms to express symptoms vary between European countries. Whereas “itchiness,” for example, is reported in 38% of the Spanish DED population, it is only prevalent in 16% of French DED patients. “Burning” on the other hand is common in France, Germany, and Italy with over 30%, but not in Spain with only 3% of the reported symptoms. Moreover, DED is perceived differently in various European countries. Whereas it is felt to be a “discomfort” in 77% of patients in United Kingdom (compared 56% of patients in Spain), it is thought to be a “disease” in 34% of DED patients in Spain (compared to 8% in United Kingdom) and a “handicap” in 21% of French DED patients (compared to 2% in Italy). Dry eye symptoms are typically judged as being useful by European Ophthalmologists in the diagnosis of DED; however, symptom questionnaires are rarely used in daily general practice. Questionnaires are usually reserved for specific dry eye clinics. The OSDI questionnaire is well known and commonly used. The standard patient evaluation of eye dryness (SPEED) questionnaire with less questions and an easy interpretation has recently been reported to be suitable for the detection of DED, especially MGD, and replaces the OSDI questionnaire in some countries in Europe as the standard questionnaire.
Clinical Signs of DED in Europe
The analysis of homeostasis markers is recommended by the DEWS II. However, there are problems in European Ophthalmology practices to follow this diagnostic algorithm. Noninvasive tear film break-up time is only available in some specific dry eye clinics. Tear film break-up testing is mainly performed invasively with fluorescein. Tear film osmolarity has been shown to be helpful in the diagnosis of moderate to severe DED in German cohorts , ; however, it was not able to diagnose DED in a large Norwegian cohort regardless of cut-off value and intereye difference analysis. Independent of this, tear film osmolarity is rarely measured in Europe due to reimbursement issues. Ocular surface staining is relevant for European Ophthalmologists to grade severity of DED. Baudouin et al. published a clear and practical algorithm of diagnosing severe dry eye with a combination of symptoms (OSDI >33) and fluorescein ocular surface staining using the Oxford Scale of ≥3
Lissamine green is rarely used outside of studies to evaluate ocular surface staining. The recommendation of DEWS II to measure tear film quantity by OCT is typically not followed in Europe as anterior segment OCTs are not available in every practice and the calculation of the tear meniscus is still cumbersome. Many clinicians only judge fluorescein tear meniscus at the slit-lamp. Schirmer testing is still in vogue in Europe to diagnose aqueous deficient DED, , , although not recommended in the DEWS II workflow. Schirmer testing together with fluorescein BUT were the tests mainly performed by Spanish practitioners and UK ophthalmologists. Schirmer testing was only rarely performed by UK optometrists. Also, in the Netherlands, the use of diagnostic tests between optometrists and ophthalmologists was significantly different Matrix-Metalloproteinase-9-Testing was not recommended by DEWS II; however, it seems to be helpful to diagnose relevant ocular surface inflammation in DED, and institute antiinflammatory treatment. MMP-9 testing is performed rarely by general ophthalmologists but becomes increasingly important for specific dry eye clinics. It is not reimbursed by health insurances.
In addition, the evaluation of lid-parallel conjunctival folds is commonly used by general ophthalmologists in Europe to support the diagnosis of DED.
Treatment of DED in Europe
General Treatment Principles
Treatment of DED in Europe is not uniform. Treatment algorithms are similar but differ in detail between countries. Treatment options may vary profoundly due to the different availability of drugs. In addition, the reimbursement of specific therapies in one country and not in the other influences DED management. Evaporative DED is often overlooked by the general ophthalmologist and may go untreated.
For mild DED, patients usually first see their general practitioner (GP) or their pharmacist. GPs typically are hardly aware of the symptoms and signs of DED and typically diagnose either bacterial conjunctivitis or allergy. Accordingly, in most cases either antibiotics or antiallergics are prescribed by GPs. Also, in pharmacies, DED diagnosis is often missed. This was demonstrated elegantly by a study in the United Kingdom where a mystery shopper with simulated dry eye visited 50 pharmacies in major towns. All pharmacy staff gave a diagnosis with only 42% correctly identifying dry eye. Eight percent of the pharmacists referred directly to a GP or optometrist. Dry eye treatment recommended included topical ocular lubrication and lipid sprays with administration and/or dosage advice in only 10%. Patients with moderate to severe DED are usually seen by ophthalmologists or optometrists (mainly UK) where the diagnosis of DED is established, and treatment for DED is instituted.
Artificial Tears
The mainstay in the treatment for all forms and all severities of DED are artificial tears. They come with many different ingredients and additives. Different options are available in various European countries. However, hyaluronic acid (HA) with different chain lengths, concentrations, qualities, and preparations is the most often used artificial tear in Europe. Artificial tears are typically prescribed with a fixed treatment plan. Patients are instructed to use their artificial tears before symptoms reappear. Applications can range from twice a day to every half hour. Patients may use artificial tears with different mode of actions concomitantly. Patients are informed that special visual tasks such as PC work, reading, or driving may afford increased artificial tear application. For the treatment of MGD, a number of artificial tears with variable lipid components is available. Gels and ointments are added in more severe disease or complaints especially at nighttime. In Europe, artificial tears without preservatives, especially without epitheliotoxic benzalkonium chloride are preferred. Patients are very much aware of the toxicity of benzalkonium chloride and ask for preservative-free or at least benzalkonium-free preparations. Artificial tears with “better preservatives” with less or no toxicity such as polyquad, sodium perborate, and oxychloro-complex are available. An increasing number of artificial tears without preservatives, however, is now on the European market either as unidoses or as preservative-free multidose containers.
Only view studies with appropriate evidence level document the efficacy of artificial tears in the management of DED.
Hyaluronic Acids
HA is a glycosaminoglycan component of the extracellular matrix.
The principal receptor for HA belongs to a family of cell membrane glycoproteins termed CD44 and is involved in a wide range of biological functions including cell adhesion, cell motility, extracellular matrix binding, and lymphocyte homing. CD44 receptors are present in the corneal epithelium and might be responsible for long-lasting adhesion of HA eye drops to the ocular surface. HAs are available in eye drops, gels, and ointments in Europe. Concentration in drops ranges from 0.18% to 0.4%. HA drops alone are often used as basic treatment for aqueous deficient dry eye. Together with lipid-containing artificial tears either as HA–lipid–preparations or together with lipid-containing artificial tears they are used in MGD. Baeyens et al. recently documented the efficacy of 0.18% hypotonic sodium hyaluronate ophthalmic solution in the treatment of symptoms and signs of DED. It was as efficient as 0.3% carbomer with less blur of vision. In a prospective, multicenter, randomized, single-masked phase IIIb, noninferiority study of nonpreserved HA 0.2% versus nonpreserved HA 0.18% both treatments reduced ocular surface staining, tear film BUT, and ocular comfort index values. On treatment day 35 0.2% HA achieved a 47% reduction in staining scores which further increased to 64% on day 84. A preservative-free combination of carboxymethylcellulose (CMC) with HA was compared to CMC alone in a multicenter study in mild to moderate DED. The combined CMC + HA formulation achieved a significant better reduction of overall ocular pain and discomfort compared to CMC alone. HA is also available in combination with Trehalose, a natural bioprotectant in Europe. In a phase III, randomized, active-controlled, investigator masked multicenter study comparing HA alone with HA plus trehalose, both treatments reduced ocular surface staining significantly. HA plus trehalose was able to significantly alleviate symptoms such as stinging, itching, and blurred vision compared to HA alone, and its global performance was judged superior by investigators and patients.
Carboxymethylcellulose
CMC is a component in many lubricants used in the treatment of DED in Europe. It is used in combination or as substitute for HA. CMC has been shown to bind to human corneal epithelial cells (HCECs) probably through interaction of its glucopyranose subunits with glucose transporters. In cell culture studies, CMC binding to matrix proteins stimulated HCEC attachment, migration, and reepithelialization of corneal wounds. In a randomized, controlled, multicenter study comparing CMC alone to CMC with HA, CMC alone was able to significantly reduce subjective symptoms, tear film BUT, and ocular surface staining. CMC is also available together with osmoprotective levocarnithine and erythritol. Moreover, a CMC-lipid preparation with castor oil is frequently used in the care of MGD.
Hydroxypropyl Guar
The mucomimetic agent hydroxypropyl guar (HPG) with tensioactive, gelificaton, and lubrication properties is formulated in eye drops with polyethylene glycol (PEG) and propylene glycol (PG), borate and sorbitol, which compete in the eye drop bottle to reduce borate-mediated cross-linking of HPG. When the low-viscosity formulation is applied to the ocular surface, the sorbitol is diluted by tears, allowing the borate and divalent ions present in the tear film to interact with HPG. This promotes HPG cross-linking to create a structured polymeric network with bioadhesive properties on the ocular surface that prolongs retention of PEG and PG to increase tear film stability, provide sustained lubrication, and protect the ocular surface. In a randomized, double-masked crossover study of patients with dry eye, HPG/PEG/PG maintained visual acuity for a longer duration between blinks 90 min after instillation compared with a CMC-based eye drop. In a multicenter, randomized, observer-masked parallel-group study, ocular surface staining and symptoms were reduced significantly by both HPG/PEG/PG and an osmoprotective CMC product. An improvement in conjunctival impression cytologies in patients with severe DED has been documented in a study from Romania.
Artificial Tears with Specific Additives
In Europe, a number of artificial tears with very useful additives are on the market and regularly used in the management of DED patients. These additives include trehalose (anhydrobiotic, osmoprotective, and antiinflammatory), erythritol and l -carnitine (antioxidative), dexpanthenol (supports wound healing), Coenzyme Q 10 (antiapoptotic, antioxidative), and topical Omega fatty acids .
Artificial Tears with Lipids
Lipid-containing artificial tears are typically used in the care of MGD patients. Often, they are recommended to be used with either HA, CMC, or HPG in combination. Combination products are also on the European market. Lipid-containing artificial tears support the tear film lipid layer and increase TF-BUT. Lipids used in European preparations include castor oil, paraffin oil, triglycerides, phospholipids, and perfluorohexyloctane. Semifluorinated alkane eye drops, for example, have been shown to increase tear film thickness and lipid layer thickness over time thus stabilizing the tear film and reducing evaporation. Semifluorinated alkane eye drops have also resulted in improved signs and symptoms in MGD patients and improved symptoms of patients with severe ocular graft-versus-host disease
Lid Hygiene
Lid hygiene is recommended as a basic treatment in patients with MGD. There are many different ways to perform lid hygiene, and this has to be adjusted to the patient’s possibilities and needs. In general, hot compresses are recommended for approximately 5 min followed by lid massage toward the lid margin with either the clean finger tip or a cotton tip. Many options exist to improve eye lid warming including warming masks, electric eye lid warming devices, and red light. A little plastic massage tool is available for the patient to improve massaging. Multiple lid cleaners either as solution, wipes, or gels are available to support cleaning of the lid margin. The patients are instructed to use these cleaners after lid warming and lid massage, not instead.
In patients presenting with collarettes and broken eye lashes, a hyperinfestation with demodex mites is suspected, and tea tree oil either as wipes or foam recommended to be applied 2×/day after lid hygiene.
In specific dry eye clinics, microblepharoexfoliation is offered to reduce lid margin biofilm, debris, and meibomian gland capping. Dry eye specialists typically perform lid warming and meibomian gland expression with, e.g., the Tearse forceps. In patients not willing or not able to perform lid hygiene, automated thermodynamic therapy is provided again only in specific dry eye clinics. All these additional treatments for MGD are commonly not reimbursed by health insurance companies.
Intense Pulsed Light Treatment
Intense pulsed light (IPL) treatment is a relatively new and approved therapeutic option for MGD. It is typically offered when basic treatment with lipid-containing artificial tears and lid hygiene are not sufficient. The treatment consists of two to four sessions where light impulses are applied to the lower lid and temporal lid margin. The IPL technique is a safe form of treatment when the required safety precautions are followed. Current studies document an improvement of patients’ subjective symptoms and objectively measured clinical parameters. In Europe several different IPL devices are on the market equipped with or without additional Low Level Light Therapy. IPL treatment is only offered in specific dry eye centers and is usually not paid by the patient’s health insurance.
Preservation of Tear Film
Punctum Plugs
Punctum plugs are a good therapeutic option for patients with low Schirmer test (<5 mm in 5 min) and ocular surface damage. However, ocular surface inflammation has to be controlled concomitantly with topical antiinflammatory medication. Punctum plugs are typically installed into the lower punctum. Their effect may be tested with resorbable collagen plugs; however, silicone plugs or intracanalicular plugs are superior for long-term treatment. Extrusion and loss is the main problem. Very rarely pyogenic granuloma develops around the plug in the punctual area and requires removal of the punctum plug.
Moisture Goggles
Moisture goggles help to preserve the available tear fluid at the ocular surface and prevent evaporation. They are often recommended by the treating physician, but are rarely used by patients due to their unfavorable looks.
Antiinflammatory Treatment in DED in Europe
Topical Corticosteroids
Inflammation is an important pathogenetic factor in DED. This knowledge is slowly spreading throughout the ophthalmology community in Europe, however, still is not uniformly present. Nonpreserved topical corticosteroids as a short-term tapering treatment for 2–4 weeks are prescribed when basic treatment with artificial tears and lid hygiene does not improve signs and symptoms of DED. They may be used as a proof of concept whether a longstanding antiinflammatory treatment is reasonable. So called “soft corticosteroids” are preferred. A topical low dose 0.335% preservative-free hydrocortisone is available on the European market and is used quite frequently in DED management. In a recent study, hydrocortisone 0.3% for 28 days in a tapering dosing scheme has been shown to reduce ocular surface inflammation and decrease subjective symptoms of DED without changes in IOP. In some European countries HA is available in combination with hydrocortisone 0.001%, where the antiinflammatory properties are minor. This product is mainly used as artificial tear promoting homeostasis of the tear film.
Topical Cyclosporine A
Until 2015, pharmacy-formulated cyclosporine A (CSA) in concentrations from 0.5% to 2.0% were used in the care of DED, as anionic CSA 0.05% was never released in Europe. Thereafter, a nonpreserved cationic oil-in-water emulsion of CSA 0.1 was approved for the European market for the treatment of DED. However, the indication is limited to “Treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.” This indication is based on the so-called SANSIKA study, a multicenter, randomized, double-masked, 2-parallel arms, 6 months phase III study with a 6-month open label treatment safety follow-up of CSA 0.1% vs. Vehicle. This study included patients with severe DED with corneal fluorescein staining grade 4 on the modified Oxford scale. In this study, CSA 0.1% significantly improved corneal fluorescein staining, reduced the ocular surface inflammatory marker HLA-DR, and improved tear film osmolarity compared to vehicle.
Discussions in the ophthalmology community concern the term “severe keratitis” in the indication of the drug. Many treating physicians would start treatment with CSA 0.1% in DED with obvious corneal staining of ≥2 in the Oxford Grading Scheme and would not wait for grade 4 staining as done in the study. If corneal staining was already reduced by topical corticosteroids with good effect, CSA 0.1% is also instituted with even lower ocular surface staining scores.
The recommended dose of CSA 0.1% is one drop at bedtime. Patients are instructed to continue their artificial tears. They are also informed that it may take 6–8 weeks until CSA drops take effect and that a typical side effect is burning/stinging on instillation which will improve with time.
Very often, topical corticosteroids are used before or in the first 4 weeks concomitantly with CSA to improve tolerability and to accelerate treatment success. In our own CSA 0.1% patients (E.M.), topical corticosteroids as bridging therapy reduced symptoms significantly earlier as seen in the Sansika study. Patients are typically followed up every 3 months. Treatment with CSA 0.1% should at least be continued for 6 months. The Sansika extension data, however, suggest that CSA 0.1% therapy for 1 year might be superior with less recurrences back to severe ocular surface damage. Although CSA 0.1% is approved for the treatment of DED with ocular surface damage, a number of European countries are still using compounded formulations due to cost and reimbursement issues. Also in countries where CSA 0.1% is approved and reimbursed, general ophthalmologists are sometimes reluctant to prescribe it due to missing knowledge on its properties, fear of side effects, and budget issues.
Hind et al. report on their real-world experience at a Scottish university teaching hospital regarding the tolerability and persistence with topical CSA 0.1% treatment in patients with DED. Mean duration of treatment was 11 months (median 8.5; range 2–30). Sixty three percent of patients (33/52) were also treated with a tapering dose of topical steroids for the first month during the initiation phase of CSA 0.1% use. All patients remained on long-term topical lubrication treatment at least 4 times per day. At last case note CSA 0.1% was well tolerated and treatment persisted successfully in 88% (46/52) of patients. Only six patients discontinued CSA 0.1% due to intolerance in the time period identified, although two were able to restart and persist (intolerant of treatment 4/52; 7.7%). The reason stated for lack of persistence was local irritation, burning, or stinging.
Antibiotic Treatment in DED
Topical and systemic antibiotics with antiinflammatory properties are used in the management of MGD. Although these treatment options have been in the recommended treatment schedules for quite some time, general ophthalmologists are still reluctant to prescribe oral doxycycline or topical azithromycine in the care of patients with MGD. One reason being the fact that MGD is often not diagnosed in the general ophthalmology practice at all, and treatment for MGD is preferentially initiated in specific dry eye clinics.
Oral Doxycycline
Oral doxycycline treatment is an established therapy in patients with MGD due to rosacea due to its beneficial effect on skin and eye lids. In these cases, a dose of 40–100 mg/day is typically used. However, also in patients with MGD not associated with rosacea, oral doxycycline therapy at a dose of 100 mg/day is instituted as soon as lipid-containing artificial tears and lid hygiene are not sufficient. A 6-week to 3-month course is typically recommended but can be extended for longer duration.
Topical Azithromycine
Topical azithromycine is available as an oily 1.5% formulation in Europe. Different application protocols exist but seem to be similarly effective. Whereas some physicians apply the typical “Foulks” protocol with azithromycine 2×/day × 2 days followed by 1×/day × 4 weeks, others recommend to apply the oily drop in the conjunctival sac or to the lid margin 2×/day × 1 week for three cycles with 1 week of break in between the cycles. A randomized study in patients with MGD has just demonstrated the equal efficacy of oral doxycycline and topical azithromycine 1.5% in a 4-week study. However, side effects occurred in a much higher rate in the topical azithromycine group (56.3%; eye irritation, blurred vision) compared to the oral doxycycline group (21.1%, gastrointestinal problems). The number of patients discontinuing the treatment due to the side effect was however equal and low with around 5%. Thus, azithromycine is a good option for patients with gastrointestinal disease or pregnant patients. It may also be instituted together with oral doxycycline.
Autologous Serum
Autologous serum eye drops appear to be the perfect tear substitute containing a number of epitheliotropic factors to support epithelial healing. They are produced at concentrations of 20%–100%. The protocols to prepare and use autologous serum eye drops vary considerably in studies and in Europe. In Germany, the use of autologous serum eye drops has been hampered by regulatory issues. Only institutions with a license to produce blood-derived products are allowed to make and distribute autologous serum eye drops. This massively reduced the number of ophthalmological institutions being able to use and prescribe these drops. , In Spain, Plasma Rich in Growth factors is preferred.
Albumin eye drops or allogeneic serum eye drops may be an alternative for the treatment of ocular surface disease but have not been established in daily practice. The use of finger prick autologous blood has been advocated but does not appeal to be a good treatment option for most patients.
Taken together, DED treatment in Europe in general follows TFOS DEWS II recommendations. However, diagnostic and treatment options vary between different European countries due to availabilities and reimbursement issues. Pharmacists, optometrists (mainly UK), GPs, general ophthalmologists, and dry eye specialists are involved in the care of DED patients. Aqueous deficient DED and evaporative DED are often not discriminated by the general ophthalmologist; MGD is frequently overlooked. Specific Dry Eye Clinics are increasingly founded and welcome by DED patients to establish a correct diagnosis and initiate an appropriate treatment in DED.
References
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