REVIEW ARTICLE

A New Perspective on Dry Eye Classification: Proposal by the Asia

Dry Eye Society
Kazuo Tsubota, M.D., Ph.D., Norihiko Yokoi, M.D., Ph.D., Hitoshi Watanabe, M.D., Ph.D., Murat Dogru, M.D., Ph.D.,
Takashi Kojima, M.D., Ph.D., Masakazu Yamada, M.D., Ph.D., Shigeru Kinoshita, M.D., Ph.D.,
Hyo-Myung Kim, M.D., Ph.D., Hung-Won Tchah, M.D., Ph.D., Joon Young Hyon, M.D., Ph.D.,
Kyung Chul Yoon, M.D., Ph.D., Kyoung Yul Seo, M.D., Ph.D., Xuguang Sun, M.D., Ph.D., Wei Chen, M.D., Ph.D.,
Lingyi Liang, M.D., Ph.D., Mingwu Li, M.D., Ph.D., Louis Tong, M.D., Ph.D., Fung-Rong Hu, M.D.,
Vilavun Puangsricharern, M.D., Ruben Lim-Bon-Siong, M.D., Then Kong Yong, M.D., Zuguo Liu, M.D., Ph.D., and
Jun Shimazaki, M.D., Ph.D., Members of The Asia Dry Eye Society

stemmed from the definition, and which is centered on provision of

Abstract: The 2017 consensus report of the Asia Dry Eye Society (ADES) insufficient components in each tear film layer and ocular surface epithe-
on the definition and diagnosis of dry eyes described dry eye disease as lium. The current ADES report proposes a simple classification of dry eyes
“Dry eye is a multifactorial disease characterized by unstable tear film based on the concept of tear film–oriented diagnosis and suggests that there
causing a variety of symptoms and/or visual impairment, potentially accom- are three types of dry eye: aqueous-deficient, decreased wettability, and
panied by ocular surface damage.” The report emphasized the instability of increased evaporation. It is suggested that these three types respectively
tear film and the importance of visual dysfunction in association with dry coincide with the problems of each layer: aqueous, membrane-associated
eyes, highlighting the importance of the evaluation of tear film stability. mucins, and lipid/secretory mucin. Although each component cannot be
This report also discussed the concept of tear film–oriented therapy, which quantitatively evaluated with the current technology, a practical diagnosis

From the Department of Ophthalmology (K.T., M.D., T.K.), Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology (N.Y., S.K.),
Kyoto Prefectural University of Medicine, Kyoto, Japan; Eye Division (H.W.), Kansai Rosai Hospital, Amagasaki, Japan; Japanese Red Cross Gifu Hospital
(T.K.), Gifu, Japan; Eye Center (M.Y.), Kyorin University School of Medicine, Tokyo, Japan; Department of Ophthalmology (H.-M.K.), Korea University Anam
Hospital, Seoul, Korea; Department of Ophthalmology (H.-W.T.), Ulsan University Asan Medical Center, Seoul, Korea; Department of Ophthalmology (J.Y.H.),
Seoul National University, Seoul National University Bundang Hospital, Seoul, Korea; Department of Ophthalmology (K.C.Y.), Chonnam National University
Hospital, Gwangju, Korea; Department of Ophthalmology (K.Y.S.), Yonsei University Severance Hospital, Seoul, Korea; Department of Ophthalmology (X.S.),
Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, Beijing, China; Cornea Service (W.C.), The Affiliated Eye Hospital of Wenzhou Medical
University, Menzhou, China; Zhongshan Ophthalmic Center Sun Yat-Sen University (L.L.), Guangzhou, China; Department of Ophthalmology (M.L.), Peking
University International Hospital, Beijing, China; Singapore National Eye Center (L.T.), Singapore; Department of Ophthalmology (F.-R.H.), National Taiwan
University Hospital, Taipei, Taiwan; Department of Ophthalmology (V.P.), Chulalongkorn University (V.P.), Bangkok, Thailand; Department of Ophthalmology
(R.L.-B.-S.), University of the Philippines, Manila, Philippines; International Specialist Eye Centre/National University Hospital (T.K.Y.), Kuala Lumpur,
Malaysia; and Eye Institute of Xiamen University (Z.L.), Xiamen, China; and Department of Ophthalmology (J.S.), Tokyo Dental College, Ichikawa, Japan.
Outside the submitted work, these authors report COI as follows: K. Tsubota reports research funding and consultancies from Santen Pharmaceutical Co, Ltd and Otsuka
Pharmaceutical Co, Ltd, and holds the patent right for the method and apparatus used for the functional visual acuity measurement system (US patent no: 7470026 by
Kowa Company); and is a consultant for Shire. N. Yokoi reports personal fees from Santen Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, and consultancies
from Rhoto Co, Ltd, Alcon Japan Co, Ltd, and patents for ophthalmologic apparatus with Kowa Co, Ltd. H. Watanabe reports personal fees from Santen Pharmaceutical
Co Ltd, Otsuka Pharmaceutical Co, Ltd, Senju Pharmaceutical, Alcon and Pfizer Inc. M. Dogru reports personal fees from Echo Electricity, Santen Pharmaceutical, and
Otsuka Pharmaceutical Co, Ltd. T. Kojima reports personal fees from Staar Surgical, Santen Pharmaceutical, Otsuka Pharmaceutical, Johnson & Johnson, and Alcon. M.
Yamada reports research funding from Santen Pharmaceutical Co, Ltd, and personal fees from Santen Pharmaceutical Co, Ltd, Otsuka Pharmaceutical Co, Ltd, Johnson &
Johnson Vision Care Co, and Alcon Co. S. Kinoshita reports research funding and consultancies from Santen Pharmaceutical Co, Ltd Otsuka Pharmaceutical Co, Ltd,
Senju Pharmaceutical Co, Ltd, and KOWA Co, Ltd, research funding from Oncolys Biopharma Inc, HOYA Corporation, and Lion Corporation, personal fees from Alcon
Japan and AMO Inc. J. Y. Hyon reports researching funding and consultancy with Santen Pharmaceutical Co, Ltd. K. C. Yoon reports research funding and consultancies
from Santen Pharmaceutical Co, Ltd and Pfizer. K. Y. Seo reports personal fees from Santen Pharmaceutical Co, Ltd and Lumenis Korea Ltd. L. Tong reports funding for
research, advisory boards and conference related travels from Alcon-Novartis, Allergan, Bausch and Lomb, and Santen Pharmaceutical Co, Ltd. V. Puangsricharern reports
honorarium as a speaker for Santen, Alcon and Allergan. R. Lim-Bon-Siong is a member of the Santen Advisory Board and receives educational and research grants from
Santen Pharmaceutical Co, Ltd. T. K. Yong received travel grants from Santen and Allergan. Z. Liu reports research funding or consultancies or travel grants from: Alcon,
Allergen, Novartis Johnson & Johnson Vision, Santen, Senju, Yuejia, Xingqi, Zhuhaiyisheng, Reilin, Dakai. J. Shimazaki reports research funding and consultancies from
Santen Pharmaceutical Co, Ltd and Otsuka Pharmaceutical Co, Ltd. The remaining authors have no conflicts of interest to disclose.
The Asia Dry Eye Society is partially supported by Santen Pharmaceutical Co, Ltd.
Address correspondence to Kazuo Tsubota, M.D., Ph.D., Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi,
Shinjuku-ku, Tokyo, 160-8582 Japan; e-mail: [email protected]
Accepted July 1, 2019.
Copyright Ó 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Contact Lens Association of Opthalmologists. This is an
open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it
is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without
permission from the journal.
DOI: 10.1097/ICL.0000000000000643

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based on the patterns of fluorescein breakup is recommended. The Asia Dry BACKGROUND OF ASIAN COUNTRIES FOR A
Eye Society classification report suggests that for a practical use of the
REGIONAL CONSENSUS
definition, diagnostic criteria and classification system should be integrated
and be simple to use. The classification system proposed by ADES is First, in Asia, optometrists are not involved in clinics of dry eye
a straightforward tool and simple to use, only through use of fluorescein, disease, but only ophthalmologists. The base membership of
which is available even to non-dry eye specialists, and which is believed to ADES believed that there was a need for simple and effective
contribute to an effective diagnosis and treatment of dry eyes. examination methods that could appeal to ophthalmologists and be
used as a guide in Asian countries. Second, in Asian countries, in
Key Words: Asia Dry Eye Society—Classification—Dry eye—Tear
contrast to North America and continental Europe, it has become
film–oriented therapy—Tear film stability.
possible to prescribe secretagogue eye drops that can treat dry eye
(Eye & Contact Lens 2020;46: S2–S13) disease. Another important point is that Japan and most Asian
countries have access to diagnostic tools and imaging technology
that help to view and assess the lipid and the aqueous layers. These
led to the evolution of the concept of tear film–oriented therapy
T he Asia Dry Eye Society (ADES) was founded in 2012 in
Tokyo by Korean, Chinese, and Japanese dry eye specialists
(http://asia-dry-eye.biz). The aim of the society was to facilitate
(TFOT), that is, evaluation and treatment tailored to the problems
in each layer. Third, epidemiological studies have shown that dry
collaborative research, encourage mutual communication, and gen- eye prevalence in Asia is higher than in Europe and the United
erate agreements on the essential fields such as the definition of dry States. Moreover, their epidemiological studies showed that short
eye, diagnostic criteria, and classification. The first agreement on BUT type of dry eyes are prevalent in Japan and in other Asian
the definition was achieved in October 2014 in Tokyo after which countries, compared with other types of dry eye disease.36,37 With
the new definition and diagnostic criteria proposal were published such a background, ADES was launched in 2014, and Asian dry
in the January 2017 issue of The Ocular Surface.1 This consensus eye clinicians met together, and the current definition of dry eye
was made through extensive discussion over the years with ADES and diagnostic criteria were reported.1 After that, discussions
member countries. The definition emphasized the importance of an continued further in ADES, leading to the present classification.
unstable tear film as the most important mechanism for the devel-
opment of dry eye. Because the normal corneal sensation is asso-
ciated with a stable and healthy tear film, an unstable tear film
induces discomfort and pain via a possible increase of tear osmo-
HISTORY OF THE CLASSIFICATION OF DRY EYE
lality. An unstable tear film is also known to affect vision, because The first comprehensive classification of dry eye was published
an irregular tear film over the visual axis has been reported in in 1995 on the basis of consensus from the NEI/Industry working
studies using the tear film stability assessment system, ocular aberr- group on Clinical Trials in Dry Eye.38 In the 1995 report, dry eye
ometers, and functional visual acuity systems.2–4 was divided into 2 primary categories; tear-deficient and evapora-
With the emergence of new aqueous tears and/or mucin secreta- tive. These two subgroups were further subclassified according to
gogue eye drops containing diquafosol sodium (Diquas) or rebamipide a range of intrinsic and extrinsic etiological factors. It is of note that
(Mucosta) and based on the accumulating evidence in relation to their in this report, dry eye was defined as “a disorder of the tear film due
favorable effects on the tear film and ocular surface epithelium,5–31 we to tear deficiency or excessive tear evaporation” suggesting that dry
took further steps to emphasize the importance of a stable tear film of eye caused either by tear deficiency or excessive evaporation were
dry eye patients in Asia. These two eye drops work to increase tear exclusively considered to be the main categories of dry eye. Since
breakup time by increasing aqueous and or mucin components to the then, this classification scheme has had a great impact on dry eye
ocular surface.5,32 Many earlier reports have pointed out the impor- research and clinical practice. The scheme was basically retained in
tance of a stable tear film in ocular surface health.33–35 the DEWS report published in 2007 (Fig. 1).39 Aqueous deficient
In this consensus paper, we would like to introduce our new dry eye (coined as “tear-deficient” in the NEI report) was further
classification system for dry eye based on the ADES definition.1 classified into Sjogren and non-Sjogren categories. Evaporative dry
For the daily practice of dry eyes, a simple and practical definition eye was sub classified into intrinsic and extrinsic categories, and
and evidence-based diagnostic criteria are mandatory. Because they were further classified according to etiological factors.
there are two types of dry eye that includes aqueous deficient The classification system also took its place in the recent TFOS
and evaporative dry eye, the latter for which meibomian gland DEWS II report with some modification.40 The newly proposed
dysfunction (MGD) is responsible as the major cause, the clinicians classification scheme considers the cases where patients exhibit dry
need a straightforward classification, which may be useful for eye symptoms without evidence of obvious signs, or present with
determining the most useful treatment. Thus, discussion on classi- marked signs, but lack of dry eye symptoms. The former includes
fication was initiated in ADES to fulfill this need. cases with neuropathic pain where the somatosensory system is
Along with the definition consensus meetings, the classification affected, and the latter is related to the reduced corneal sensitivity
discussion also began concurrently with preliminary discussion in (neurotrophic condition) (Fig. 2). Eyes with both signs and symp-
November 2014. After completion of the definition consensus, we toms were classified into either aqueous deficient or evaporative
continued the discussion of classification. However, because TFOS dry eyes. Although this part of classification is basically the same
DEWS II started in April 2015, we decided to postpone the as the previous classifications, there is a slight modification to
classification discussion until TFOS DEWS II was published to clarify that there are a significant number of eyes that have both
avoid the possible conflict of interest. The final meeting was held in aqueous deficient and evaporative components, and that these two
Osaka on October 20, 2017. subcategories were not exclusive.

Copyright Ó 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the CLAO S3
K. Tsubota et al. Eye & Contact Lens
Volume 46, Supplement 1, January 2020

FIG. 1. Major etiological cause of dry eye in TFOS

DEWS report in 2007. Reprinted from the ocular
surface, Vol 5(2), the definition and classification of
dry eye disease: Report of the definition and classifi-
cation subcommittee of the International Dry Eye
Workshop (2007), pages No. 75–92, copyright
2007, with permission from Elsevier.

There are other groups which have proposed various classifica- ture of tear film and tear dynamics. Dry eye was divided into five
tion systems. In Asia, Chinese scholars proposed their dry eye types, including lipid deficient dry eye (evaporative dry eye), aque-
classification in 2004.41 It proposed a method based on the struc- ous deficient dry eye, mucin deficient dry eye, abnormal tear

FIG. 2. Classification of dry eye disease in TFOS DEWS II. Reprinted from the ocular surface, Vol 15(3),
Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II definition and classification report, pages 276–283,
copyright 2017, with permission from Elsevier.

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dynamics dry eye, and mixed dry eye. The Chinese dry eye con- An unstable tear film can be caused by several mechanisms. Any
sensus subsequently adopted this classification.42 The classification ocular surface components comprising those of tear film and surface
based on the structure and tear film dynamics is very helpful for the epithelium can affect the tear film stability, including lipids, aqueous/
treatment of different types of dry eye. In 2005, Murube et al.43 secretory mucins, and membrane-associated mucins. An abnormality
published an article entitled “The triple classification of dry eye for in the lipid components is thought to accelerate tear evaporation,
practical use”. His classification consisted of the three following resulting in an unstable tear film, despite big discussions as to the
aspects: etiopathogenesis, affected glands/tissues, and grade of suppression of the tear film lipid layer on the evaporation of aqueous
severity. In relation to etiopathogenesis, dry eye was classified into tears from aqueous layer.46–52 Aqueous tear deficiency is the classical
the following 10 subcategories; age-related, hormonal, pharmaco- type of dry eye, including Sjogren syndrome, which of course is
logic, immunopathic, hyponutritional, dysgenetic, adenitic, trau- associated with an unstable tear film due to aqueous tear deficiency.
matic, neurologic, and tantalic. In a classification according to Decrease of secretory mucins may be involved in the unstable tear
the affected glands/tissues, there were the following five subcate- film.53–56 Deficiency of membrane-associated mucin decreases the
gories; aqueous deficient, lipid deficient, mucin-deficient, epithe- wettability of the cornea and conjunctiva, and may contribute to the
liopathic, and nonocular exocrine-deficient. Murube’s classification stability of tear film and their deficiency may shorten the tear film
systems emphasized more of the physiological or pathological breakup time. Asia Dry Eye Society discussions led to a dry eye
abnormalities in dry eye compared with those proposed by those classification based on the components of two-layered tear film and
in NEI/DEWS/TFOS DEWS II. of the surface epithelium (Fig. 4). However, a mixed type of dry eye
There is also a classification system, the Delphi approach, may exist. It should be noted that TFOS DEWS II classification has
proposed by dry eye specialists in the United States and Europe.44
shown that it is difficult to strictly distinguish between the aqueous
In their report, dry eye is viewed in relation to the presence or
deficient type dry eye and the increased evaporative type, and a hybrid
absence of lid margin disease, and tear distribution abnormalities
form has been proposed. Asia Dry Eye Society classification scheme
(Fig. 3). The Delphi classification was based on the treatment
is valuable for the concept of TFOT (Fig. 5). Because this classifica-
algorithm for dry eye patients, and different treatment methods
tion is principally based on the abnormalities of the components of
were described in each subcategory.
each tear film layer and the ocular surface epithelium, the diagnosis
itself automatically leads us to TFOT. When the lipid layer is abnor-
mal, such as due to MGD, then treatment for MGD becomes the
NEW DRY EYE CLASSIFICATION BASED ON obvious approach for dry eye. When the aqueous tear secretion is
THE TEAR FILM–ORIENTED deficient such as in Sjogren or non-Sjogren aqueous tear-deficient type
DIAGNOSIS CONCEPT of dry eyes, aqueous components should be provided by artificial
Dry eye was reported as Sjogren syndrome related dry eye in tears, hyaluronic acid, or tear secretagogues such as diquafosol
1933. This is a typical form of decreased aqueous secretion and sodium, or using punctal plugs in combination with eye drops. When
was considered the classic type of dry eye. However, according the secretory mucin and membrane-associated mucin is abnormal, the
to the recent epidemiological study targeting office workers, mucin components should be provided to the ocular surface such as by
most dry eye showed tear film instability and ocular surface mucin secretagogues such as diquafosol sodium or rebamipide. Our
abnormalities without reduction in tear secretion, and this short classification scheme automatically finds the way to an appropriate
BUT type is now more dominant than the so-called classic treatment modality (Fig. 6). Although we categorized dry eye disease
type.45 into three types according to the tear film abnormality or epithelial

FIG. 3. Dry eye disease classification in

Delphi approach (2006). Reprinted from
cornea, Vol 25, Behrens A, Doyle JJ,
Stern L, et al. Dysfunctional tear syn-
drome: A Delphi approach to treatment
recommendations, pages 900–7, copy-
right 2006, with permission from Wol-
ters Kluwer.

Copyright Ó 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the CLAO S5
K. Tsubota et al. Eye & Contact Lens
Volume 46, Supplement 1, January 2020

FIG. 4. New dry eye disease classifica-

tion by the Asia Dry Eye Society.

surface abnormality, not all patients are diagnosed with only one of vision which is related to dry eye, because tear film instability
these categories and a mixed type diagnosis can exist. In the TFOS disturbs the light entering the eyes, by increasing the scattering and
DEWS II report, patients may have aqueous tear deficiency and MGD optical aberrations. It is well known that dry eye decreases the
together, or they may have MGD and a decrease of membrane-type quality of vision in daily life from driving to reading. An unstable
mucin abnormalities together. Therefore, it may be necessary to go tear film can explain such deterioration in visual experiences. Many
through several steps in treatment as well. studies on functional visual acuity in dry eye conditions and
Tear film–oriented diagnosis (TFOD) concept is important not increased aberrations as assessed by aberrometers support this
only from the aspect of discomfort, but also from the impairment of hypothesis.57–61

FIG. 5. The concept of tear film-ori-

ented therapy. *Diquafosol sodium may
increase the function of the tear film
lipid layer by promoting spreading of
the lipid layer through lipid and tear
fluid secretion. **Rebamipide may sup-
press the inflammation of the ocular
surface in dry eye by its anti-inflamma-
tory action. Figure provided by Dry Eye
Society Japan.

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Tear film breakup occurs because of various reasons including

increased evaporation, decreased aqueous tear volume, and
decreased wettability of corneal surface, which resulted in different
patterns of fluorescein breakup (Fig. 7). The detailed pattern of
each classification is described later, but the fundamental point is
very simple. If dry eye occurs because of aqueous deficiency, line
or area breakup patterns are dominant. When the dry eye occurs
because of a lipid deficiency, the breakup pattern is the random
type. Decreased wettability type results in showing spot or dimple
breakup patterns as representative breakup patterns.
To obtain a reproducible breakup pattern, it is necessary to put
a small amount of fluorescein into the eye. Specifically, after
wetting the fluorescein test paper, it is shaken to remove excess
dye, and the test paper is placed on the edge of the lower eyelid.
Also, by having the patient open their eyes quickly, it is possible to
detect any hidden abnormality in the tear film.
FIG. 6. Tear film-oriented therapy based on dry eye disease classi- The dry eye diagnosis in ADES concept is also tear film-
fication by ADES. ADES, Asia Dry Eye Society. oriented, because diagnosis of aqueous deficiency, decreased
corneal wettability, or increased evaporation is done from the
breakup pattern of the tear film. The TFOS DEWS II report
Asia Dry Eye Society also discussed the dynamic aspects of dry
suggests that the Schirmer test is an invasive test. In contrast, the
eye disease in relation to the etiology or classification. A decreased
current consensus acknowledges that aqueous deficiency can be
blink rate in visual display terminal (VDT) workers may increase
detected by Schirmer test without anesthesia, meniscometry, and
tear evaporation,1,62,63 thus this type can be categorized as evapo-
strip meniscometry. In dry eye clinical routine, Schirmer test
rative dry eye. Lagophthalmos is a condition in which the eye
without anesthesia should be done at least once to evaluate the
remains open all the time, thus too much evaporation occurs and
possibility of aqueous deficiency. Moreover, for the diagnosis of
consequently damages the ocular surface epithelium and thus it can
lipid deficiency, lipid layer interferometry is to be used to evaluate
be categorized as evaporative dry eye. So, whatever the reason for
decreased lipid thickness in patients with dry eye, but it is not
the particular classification, we can still classify dry eye based on
widely used. In a practical way, presence of MGD and poor
the abnormalities in two-layer components of tear film and in
Meibomian gland expressibility determined by manual pressure to
ocular surface epithelium. A more detailed discussion is provided
the eyelid can be used to diagnose lipid deficiency. The current
in each section of the three classifications (Fig. 4).
challenge for the TFOD is the decreased wettability dry eye,
Subjective symptoms and objective findings-oriented severity scales
namely the deficiency of membrane-associated mucin.
have been considered in the diagnosis and treatment of dry eyes. In the
Although several studies have provided evidence that the short
2007 DEWS report, there is a table showing the severity of objective
BUT type of dry eye, which includes evaporative and decreased
findings and severity of subjective symptoms.39 In the TFOS DEWS
wettability dry eye is related to decreased mucin components in the
II report, the severity matrix table was eliminated. Because the signs
tear film layer and the surface epithelium,45,68,69 there is no easy
and symptoms do not always match in dry eye disease,64–66 this table
method to evaluate the mucin layer. This area should be investigated
was not regarded as practical by ADES, although there are definitely
further in the near future, but for the time being, tear film breakup
mild, moderate, and severe dry eyes based on the symptoms. Accord-
ing to the ADES agreement in the previous consensus paper, the dry patterns can provide a clue not only to the diagnosis of evaporative
eye disease severity was not thought to be related to the ocular surface and decreased wettability dry eye (Fig. 7). Moreover, repeatability of
tear film breakup pattern should be studied in future studies.
condition. As we will cover in the final section of this paper, the
severity is more related to the neuropathic pain components. Thus,
it was decided not to include severity as a classification component. Aqueous Deficient Dry Eye
This classic type of dry eye was first described in association
The subjective severity is rather the “target” for the treatment whether
the selected treatment is effective or not. with Sjogren syndrome in 1933 and later with non-Sjogren
In ADES classification, dry eye is classified into three subtypes: aqueous deficiency type. Because aqueous components decrease,
the tear film layer becomes incompletely established with very
aqueous deficient type, decreased wettability type, and increased
unstable tear film. When tears are almost nonexistent as in Sjogren
evaporation type. It should be noted that TFOS DEWS II
classification has shown that it is difficult to strictly distinguish syndrome, the tear film layer is not established after a blink. In this
situation, “area break” can be observed (Figs. 4 and 7). The aque-
between the aqueous deficient type and the increased evaporative
ous deficient dry eye with limited or no reflex tear secretion is also
type, and a hybrid form has been proposed.
associated with severe dry eyes such as seen in patients with
chronic graft-versus-host disease (cGVHD), ocular cicatricial pem-
phigoid, or Stevens-Johnson syndrome. According to the compen-
TEAR FILM BREAKUP PATTERNS AND THE sation theory of the tear film, this type of dry eye may have a very
CLASSIFICATION OF DRY EYE thick lipid layer compensating for the aqueous tear components,
A major breakthrough reported by Yokoi et al.67 for the classi- occasionally accompanied by increased mucin production resulting
fication of dry eye was based on the fluorescein breakup patterns. in the too much discharge.70 Aqueous tear deficiency is known to

Copyright Ó 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the CLAO S7
K. Tsubota et al. Eye & Contact Lens
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FIG. 7. Classification of fluorescein

breakup patterns.

be associated with thicker lipid layer and accumulated mucus. This In treatment, aqueous deficiency type of dry eye requires
accompaniment is supported by the compensation theory,70 where replacement of necessary aqueous components. Eye drops such
decreased production of aqueous is compensated by the increased as the artificial tear substitutes also supply the lacking components
production of lipids from meibomian glands and increased mucins of the tear film. Hyaluronic acid and carboxymethylcellulose are
from goblet cells. However, this may be explained by the delayed eye drops that supplement the aqueous layer, and these negatively-
aqueous tear clearance.71,72 charged and high molecular weight polymers can retain water in
Typical aqueous tear-deficient dry eye shows a “line break” as the aqueous layer. Artificial tears or hyaluronic acid eye drops are
the breakup patterns (Fig. 7). The “line break” can be observed usually preferred as the initial line of therapy, but their residence
during the upward movement of fluorescein-stained aqueous tear time for the ocular surface are temporary, say 3 or 5 min.73 Tear
after the eye is opened at the inferior part of the cornea. Aqueous secretagogues such as diquafosol sodium are currently the first
tear-deficient dry eye is often accompanied by the superficial punc- choice of treatment (Fig. 6). Studies have shown that the staining
tate keratopathy and this should be the result of the repeated score decreased compared with baseline from 2 weeks of diquafo-
breakup. The aqueous deficient dry eye is diagnosed by Schirmer sol treatment,90,91 and efficacy increased with longer use of diqua-
test without anesthesia. According to the ADES consensus, fosol sodium.91 When a quicker therapeutic efficacy is necessary,
Schirmer test without anesthesia of less than or equal to 5 mm in punctal plug becomes the choice of treatment. There are proven
5 min is considered to be aqueous tear-deficient. When it is more evidences which showed the efficacy of punctal plug treatment for
than 5 mm, but less than or equal to 10 mm, it is considered to be aqueous deficient type dry eye disease.73,92,93 Punctal occlusion
moderate aqueous tear deficiency, because a normal value is more improves not only the aqueous components, but the lipid and
than 10 mm. Video interferometry is also a useful methodology in mucin components as well, because it sustains all the three tear
this diagnosis. Video interferometer mainly observes the lipid film layer components because of the delayed aqueous tear clear-
layer, but it can predict the aqueous condition because the lipid ance as stated above. A combination of punctal plug with diqua-
layer spreads by each blink when the proper aqueous components fosol sodium may provide immediate and long-term relief, and is
exist. If the aqueous components are absent, we can see that the also a viable treatment approach.
upwardly spreading lipid layer is undetectable by interferometry.73 Anti-inflammatory treatment is also important, and it is believed
Tear meniscus observation also provides a clue for tear that instability of the tear film increases the friction between the
deficiency via meniscometry (or strip meniscometry).73–75 When eyelids and the eye, which will result in ocular inflammation due to
the strip meniscometry is less than 4 mm in 5 sec, a diagnosis of
epithelial damage. T cells play an important role in dry eye onset.
aqueous tear deficiency can be made.76
Cyclosporin A reduces T-cell activation via IL-2. Several studies
The tear-deficient type of dry eye includes Sjogren syndrome,
have reported improvement in symptoms, improvement in tear
ocular cicatricial pemphigoid, Stevens-Johnson syndrome,
cGVHD, and non-Sjogren type dry eye, such as seen in long- stability, and improvement in tear secretion. Also, recently, 5%
term VDT users.77–89 The mechanism of non-Sjogren type aqueous lifitegrast has been FDA approved. This drug mimics the ICAM-1
deficiency is unknown, but there is a hypothesis that long-term use cell adhesion molecule and blocks the interaction between ICAM-1
of VDT induces a lacrimal gland hypo-function resulting in accu- and lymphocyte function-related antigen (LFA-1), which influen-
mulation of excess secretary vesicles in the acinar cells which ces T-cell migration and activation. Phase 3 clinical trials reported
cannot be secreted with normal stimulation (Fig. 8).77,79 improvement in dry eye symptoms and vital staining scores.94

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shampoo.106–112 Small amounts of lipid or lipid-containing eye

drops are reported to be effective.108 Recently, washing with an
ointment is reported to be effective in keeping the meibomian
orifices open.113
Warming of the lids by heated towels is also a simple and long-
standing treatment. Eye warming devices such as infrared LED
devices or disposable eye warming masks are gaining in popularity
in Asia.114–116 Since the problem of the lipid deficiency resulting in
excessive evaporation, suppression of evaporation by increased
ambient humidity is another strategy. Not only increasing the room
humidity, but the local environment around the eye is an important
target. Goggles, moisture glasses and moisture devices are the
choices of treatment for lipid deficiency type of dry eye.

Decreased Wettability Dry Eye

FIG. 8. Lacrimal gland hypofunction in visual display terminal
(VDT) users and animal model. Upper Figures: Rat VDT user model
This type of dry eye may be increasing with the increase in VDT
causes alterations in lacrimal gland morphology. Electron micro- users.45 The characteristic phenotype is the so-called short BUT
scopic analysis of acinar cells of normal and VDT rat model. Images type dry eye in which BUT is short but the tear production is
showing expanded acinar cells accompanied by accumulated normal and staining is none or slight. Toda et al.33 originally
enlarged secretory vesicle in the cytoplasm, decreased endoplasmic reported short BUT dry eye in 1995 which mainly included this
reticulum. Scale bar ¼ 10 micrometers. Lower Figures: Electron
microscopic findings of the lacrimal gland acinus in human normal type of dry eye and increased evaporation dry eye.
and VDT user. Homogeneous secretory vesicles in normal controls. Because the membrane-associated mucin is deficient or abnor-
Scale bar ¼ 5 micrometers. High magnification view of secretory mal, the wettability of the surface of the cornea becomes impaired.
vesicles in the VDT user. Red arrows, arrowheads and asterisk show According to the DEWS or TFOS DEWS II consensus reports of
nuclei, secretory vesicles and ductal lumen, respectively. Figures
from77,79 Nakamura et al. and Kamoi et al., respectively. These are
dry eye, this type is categorized as “evaporative” with lipid defi-
open access articles distributed under the terms of the Creative ciency type, but the fundamental mechanism of the disease is com-
Commons Attribution License. pletely different. The representative patterns of tear breakup in this
category are “spot break” or “dimple break.” These types of
Patients with Sjogren syndrome, cGVHD, ocular cicatricial breakup pattern appear respectively during the phase of deposition
pemphigoid, or Stevens-Johnson syndrome may require special of aqueous tears on the cornea immediately after eye opening or
attention because of the severity and immune-orientated disease. during the phase of upward movement of aqueous tears before the
For those patients, control of autoimmune reaction by steroids or establishment of precorneal tear film. Especially for the “spot
immunosuppressants such as cyclosporine may become neces- break” (Fig. 7), BUT is very short corresponding to 0 sec. In this
sary.88,95–99 For the severe aqueous tear-deficient dry eye, autolo- breakup pattern, breakup occurs during eye opening, which means
gous serum eye drops are sometimes necessary to provide the breakup already exists when eye opening was completed. In the
essential tear components to the ocular surface epithelium.96,100,101 recent reports, rapid expansion of the breakup is proposed as a mod-
In addition, consultation with an internal medicine specialist for the ification of some breakup patterns that are possibly associated with
systemic evaluation is recommendable. a decreased corneal wettability mechanism and are often seen in
the short BUT type dry eye.117,118 The patient’s complaint of
Increased Evaporation Dry Eye decreased wettability dry eye is relatively obvious and was usu-
This type of dry eye may be caused by the lack of lipid or ally difficult to treat except by punctal plug. Recently, it has been
abnormal quality of lipid resulting in an unstable tear film. The reported that the amount of ocular surface glycocalyx signifi-
most frequent representative condition is thought to be cantly correlated with tear film breakup time (Fig. 9).119 From
MGD.102–105 This type provides the “random break” as a breakup this result, eyes with “spot break” as the breakup patterns should
pattern (Figs. 4 and 7), because pure lipid deficiency type has have a localized membrane-type mucin deficiency at the cornea.
normal aqueous and mucins. According to the compensation After the introduction of rebamipide and diquafosol sodium, the
hypothesis, pure MGD patients have an increased aqueous tear mucin layer deficiency can now be treated adequately120 and thus
volume to compensate the lipid layer deficiency to try to stabilize the unstable tear film due to the mucin deficiency has now
the tear film.70 In addition to the pattern of “random break,” lipid become treatable.
layer interferometry is the supplementary equipment to observe the
lipid deficiency type of dry eye. The lipid layer is measured as Tear Dynamics and Dry Eye Development
more than 40 mm in this system, but it is less than 40 mm when In addition to the three-layer classification that includes the two-
lipid deficiency occurs. Video interferometer is also a useful tool layered tear film and the surface epithelial layer, the ADES report
for the observation of lipid deficiency in addition to the “random emphasized the role of tear dynamics such as decreased blink, lid
break” pattern observed during BUT testing. deformity, low environmental humidity, lagophthalmos, conjunctivo-
For the treatment, the primary target is thought to be the chalasis, and the other ocular surface diseases with decreased tear
meibomian gland, although meibomian lipids may have limited clearance. Those factors may affect the tear film stability and thus can
action to suppress aqueous evaporation from the tear film.46 Lid constitute to an independent classification. However, the treatment for
hygiene is the first choice of treatment using lid scrubs or eye decreased blinking or excessive evaporation eventually falls into one

Copyright Ó 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the CLAO S9
K. Tsubota et al. Eye & Contact Lens
Volume 46, Supplement 1, January 2020

a marker for the therapeutic efficacy, but not for the purpose of
classification. In other words, we classified dry eyes according
to the two tear film layers and the surface epithelium, increased
evaporation, aqueous-deficient and decreased wettability types
for various treatment options, but the therapeutic efficacy
should be evaluated by the symptoms such as dry eye–related
pain, discomfort, or visual disturbances.

CONCLUSION
The ADES proposes a simple classification of dry eyes
based on the concept of TFOD according to the definition
report proposed previously. 1 There are basically three types of
dry eye: increased evaporation, aqueous-deficient, and
decreased wettability. These three types coincide with the
problems of each layer: lipid, aqueous/secretory mucin, and
membrane-associated mucin. Although each component can-
not be quantitatively evaluated with exact precision with the
current technology, we can make a practical diagnosis using
FIG. 9. Correlation between tear film breakup time and amount of the patterns of tear film breakup simply using fluorescein. The
glycocalyx at corneal surface. Glycocalyx at corneal surface was “random break” corresponds to the increased evaporation dry
evaluated using a fluorescein-labeled wheat germ agglutinin (F- eye (evaporative dry eye), and “line break” and “area break”
WGA) as a marker. Reprinted from current eye research, Vol 41,
Fukui M, Yamada M, Akune Y, et al. Fluorophotometric analysis of correspond to the aqueous deficient dry eye respectively of
the ocular surface glycocalyx in Soft Contact Lens Wearers, pages mild-to-moderate and severe in their severity. Decreased wet-
9–14, copyright 2015, with permission from Elsevier. tability dry eye is related to “spot break” and “dimple break”
as representative patterns. These three simple classifications
or two layers of tear film including lipid layer and aqueous layer. If lead us to select the choices of treatment to target the impor-
excessive tear evaporation occurs because of less blink or lagoph- tant layer of tear film and the surface epithelium, each of which
thalmos, the basic treatment is the same, in addition to targeting each maintains tear film stability.
specific treatment such as lid closure or ointment application during For a practical use of the diagnostic criteria system, definition,
sleep for lagophthalmos. Visual display terminal users with decreased diagnostic criteria, and classification should be integrated and be
blink may need education on the importance of blinks. simple to use. The classification system proposed by ADES is
a straightforward tool and practical, because it only uses fluores-
Special Subtypes of Dry Eye cein, even for non-dry eye specialists, which can contribute to an
As we have described earlier, special subtypes of dry eye exist effective diagnosis and treatment of dry eyes.
such as Sjogren syndrome, GVHD, ocular cicatricial pemphigoid, Because the fluorescein breakup pattern is one of the tear film-
and Stevens-Johnson syndrome for which special attention should oriented diagnostic methods derived from physical theory and
be paid. In addition, there are certain types of conditions that affect clinical findings, the relationship with the ocular surface mucins
the stability of the tear film. These are conjunctivochalasis, contact and the tear film lipid layer needs be clarified in future studies. We
lens wear, superior limbic keratoconjunctivitis, and nocturnal are convinced that the suggestions of this paper may be used as
lagophthalmos. a guide, and serve as a basis for further discussions for the future
dry eye workshop meetings.

NEUROPATHIC PAIN COMPONENT AND ACKNOWLEDGMENTS

Members of Asia Dry Eye Society: China: Z. Liu, X. Sun, W.
SUBJECTIVE SEVERITY Chen, Yingping Deng, Jing Hong, Ying Jie, M. Li, Wei Li, Ying
The Asia Dry Eye Society discussed about a possible Li, L. Liang, Fan Lu, Hong Qi, Hua Wang, Xiaoming Yan, Wenz-
classification for the severity of the dry eye disease with hao Yang, Yufeng Ye, Jin Yuan, Hong Zhang, Hui Zhan, Min-
subcategories such as mild, moderate, and severe dry eyes. gchang Zhang, Shaozhen Zhao. Korea: H.-M. Kim, H.-W. Tchah,
For therapeutic purposes, the severity does not give us enough Chul Young Choi, Si Hwan Choi, Eui-Sang Chung, So-Hyang
information, because the symptoms do not directly correlate Chung, Tae Young Chung, Young keun Han, J. Y. Hyon, Hong
with the severity of the sign(s). An original report of the short- Kyun Kim, Hyung Joon Kim, Jae Yong Kim, Jin Hyoung Kim,
BUT-type of dry eye in 1995 clearly showed that the symptoms Mee Kum Kim, Myoung Joon Kim, Tae-Im Kim, Do-Hyung Lee,
Hyung-Keun Lee, Jong Soo Lee, Sang-Bumm Lee, Woo Chan
of a patient can be almost as severe as that in a patient with
Park, K. Y. Seo, Jong Suk Song, K.-C. Yoon, In Cheon You.
Sjogren syndrome, except that there was no observable ocular Japan: K. Tsubota, N. Yokoi, Shiro Amano, Reiko Arita, M. Dog-
surface damage.33 Now it is speculated that neuropathic com- ru, Masatoshi Hirayama, Yuichi Hori, Osama Ibrahim, Minako
ponents exist even in the ordinary type of dry eye, where the Kaido, Tetsuya Kawakita, Motoko Kawashima, Shizuka Koh, T.
neuropathic components determine the severity of symptoms. Kojima, Aoi Komuro, Naoyuki Morishige, Kohji Nishida, Yoko
Thus, we concluded that subjective severity could be used as Ogawa, J. Shimazaki, Chika Shigeyasu, Miki Uchino, Yuichi

S10 Eye & Contact Lens
Volume 46, Supplement 1, January 2020
Eye & Contact Lens
Volume 46, Supplement 1, January 2020 Dry Eye Classification by ADES

Uchino, H. Watanabe, M. Yamada, Masahiko Yamaguchi. Singa- 20. Igarashi T, Fujita M, Yamada Y, et al. Improvements in signs and symp-
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Caparas, Irwin Yang Cua, Ivo John Dualan, Reynaldo Santos, R. 2015;82:229–236.
21. Shigeyasu C, Hirano S, Akune Y, et al. Diquafosol tetrasodium increases
Lim Bon Siong. Thailand: Pinnita Tanthuvanit, V. Puangsrichar-
the concentration of mucin-like substances in tears of healthy human sub-
ern, Ngamjit Kasetsuwan, Olan Suwan-apichon, Wimolwan jects. Curr Eye Res 2015;40:878–883.
Tangpagasit. Malaysia: Shamala Ratnasabapathy, Chandrama- 22. Ueda K, Matsumiya W, Otsuka K, et al. Effectiveness and relevant factors
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Eye & Contact Lens
Volume 46, Supplement 1, January 2020 Dry Eye Classification by ADES

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