Sindrom Mata Kering

Mohammad-Ali Javadi , MD dan Sepehr Feizi , MD

Penulis informasi catatan Pasal Hak Cipta dan Lisensi informasi
Artikel ini telah dikutip oleh artikel lainnya di PMC.
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Abstrak
Pemahaman kita tentang keratoconjunctivitis sicca (KCS), juga dikenal sebagai sindrom mata
kering, telah berubah selama beberapa tahun terakhir. Sampai akhir-akhir ini, kondisi itu
dianggap hanya karena insufisiensi air mata berair. Hari ini, dipahami bahwa KCS adalah
gangguan multifaktorial karena peradangan pada permukaan mata dan kelenjar lakrimal,
defisiensi neurotropik dan disfungsi kelenjar meibom. Perubahan paradigma telah menyebabkan
pengembangan obat baru dan lebih efektif.
Kata kunci: Dry Eye Syndrome, Xerophtalmia
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PENDAHULUAN
Mata kering adalah gangguan dari film air mata yang terjadi karena kekurangan merobek atau
robek penguapan yang berlebihan; hal itu menyebabkan kerusakan pada permukaan mata
interpalpebral dan berhubungan dengan berbagai gejala yang mencerminkan ketidaknyamanan
okular. 1 Sindrom mata kering, juga dikenal sebagai Xerophtalmia (KCS), adalah kondisi umum
yang dilaporkan oleh pasien yang mencari perawatan oftalmologi dan ditandai oleh peradangan
dari permukaan dan lakrimal okular kelenjar.
Gejala mata kering dapat merupakan manifestasi dari penyakit sistemik, oleh karena itu deteksi
tepat waktu dapat mengakibatkan pengakuan dari kondisi yang mengancam jiwa. Selain itu,
pasien dengan mata kering cenderung berpotensi membutakan infeksi, seperti bakteri keratitis 2
dan juga pada peningkatan risiko komplikasi setelah prosedur umum seperti operasi laser bias.
Pengetahuan tentang patofisiologi mata kering baru ini telah ditingkatkan dan kondisi sekarang
dipahami sebagai penyakit multifaktorial, yang ditandai dengan peradangan pada permukaan
mata dan penurunan produksi air mata. 3 Kesadaran ini telah menyebabkan pengembangan terapi
yang sangat efektif.
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EPIDEMIOLOGI
Sekitar 1 dari 7 orang berusia 65-84 tahun melaporkan gejala mata kering sering atau sepanjang
waktu. 4 Moss et al 5 melaporkan prevalensi mata kering menjadi 14,4% pada 3722 subjek

berusia 48-91 tahun dan mencatat bahwa prevalensi kondisi dua kali lipat setelah usia 59. Schein
et al 4 , sebaliknya, menemukan korelasi antara mata kering dan usia atau jenis kelamin,
sementara peneliti lain telah melaporkan asosiasi seperti ada. Sebuah studi pada 926 subyek yang
berusia 40 tahun dan lebih tua, menemukan prevalensi lebih tinggi dari mata kering pada wanita
yang juga lebih mungkin untuk memiliki diagnosis-mata terkait kering atau prosedur. 6 Menurut
penelitian lain, perempuan mengalami peningkatan tajam dalam prevalensi mata kering lebih
awal dari laki-laki, sekitar usia 45, kira-kira pada awal menopause. 7
Studi epidemiologis pada sindrom mata kering menunjukkan perbedaan besar dalam prevalensi.
Kesulitan dalam menentukan luasnya penyakit sebagian berasal dari pemahaman terbatas
patofisiologi mata kering. Dengan demikian, definisi sindrom mata kering berbeda dari satu
penelitian ke penelitian lainnya, membuat hasil sulit untuk membandingkan. 8 ini lebih rumit
oleh kurangnya protokol uji klinis standar untuk mendiagnosa kondisi.
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JENIS KLINIS
Film air mata prekornea merupakan komponen penting dari permukaan mata dan dapat dibagi
lagi menjadi lapisan lipid anterior, lapisan berair menengah dan lapisan musin terdalam. Lapisan
tersebut diproduksi oleh kelenjar meibom, kelenjar lakrimal dan sel goblet konjungtiva, masingmasing. 2 Film air mata melumasi mata, mempertahankan nutrisi dan oksigenasi struktur okular,
bertindak sebagai komponen bias dan membantu menghilangkan kotoran dari permukaan
okular . Dalam hal produksi air mata, mata kering dapat dibagi menjadi air mata jenis
kekurangan dan menguapkan. 3 defisiensi air mata mata kering selanjutnya dapat dibagi lagi
menjadi sindrom non-Sjogren dan sindrom Sjogren, yang merupakan penyakit autoimun yang
terkait dengan lakrimal dan ludah infiltrasi limfosit kelenjar. Mata kering evaporasi dapat dibagi
menjadi penyakit kelenjar meibom (MGD) dan mata kering paparan terkait. 4 , 5 Dalam kelompok
lain pasien, musin kekurangan karena sindrom Stevens-Johnson atau pemfigoid sikatrisial okular
adalah mekanisme yang mendasari mata kering. 8
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ETIOLOGI
Sindrom mata kering dikaitkan dengan daftar panjang penyebab yang dapat dibagi menjadi
primer dan sekunder. Mata kering dapat mengembangkan sekunder untuk penyakit radang
(misalnya pembuluh darah, alergi), kondisi lingkungan (misalnya alergen, asap rokok, iklim
kering), ketidakseimbangan hormon (misalnya wanita perimenopause dan pasien di bawah terapi
penggantian hormon), dan memakai lensa kontak. Gangguan sistemik, seperti diabetes mellitus,
penyakit tiroid, rheumatoid arthritis dan lupus eritematosus sistemik juga dapat menyebabkan
mata kering. Selain itu, kekurangan neurotropik, operasi mata sebelumnya (seperti transplantasi
kornea, prosedur katarak ekstrakapsular dan bedah refraktif), atau penggunaan jangka panjang
dari obat yang membuat hipersensitivitas atau toksisitas pada mata dapat menyebabkan rentan
terhadap kering mata. Banyak obat sistemik, seperti diuretik, antihistamin, antidepresan,

psikotropika, agen penurun kolesterol, beta-blocker dan kontrasepsi oral juga dapat dikaitkan
dengan mata kering. 9 , 10
Wanita pasca menopause mungkin terbesar di kelompok risiko; hal ini disebabkan penurunan
kadar hormon menyebabkan hilangnya perlindungan anti-inflamasi dan penurunan sekresi
lakrimal. 9
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PATOGENESIS
Studi dilakukan pada profil proteomik dari permukaan okular membandingkan kering dengan
mata yang normal menggunakan enzim-linked Immunosorbent Assay (ELISA) telah
mengungkapkan penurunan laktoferin dan pertumbuhan epidermal faktor dalam mata kering.
Sebuah protein yang ditemukan dalam sel-sel asinar kelenjar lakrimal, AQP-5, terbukti
ditingkatkan dalam jenis Sjogren sindrom mata kering, yang menunjukkan kemungkinan
kebocoran protein tersebut dalam film air mata karena infiltrasi limfosit dari kelenjar lakrimal. 9
Solomon et al 10 menemukan peningkatan sitokin inflamasi interleukin 1 (IL-1) alpha dan IL-1
beta di kedua MGD dan Sjogren sindrom, menunjukkan peningkatan aktivitas protease pada
permukaan okular, terutama di epitel konjungtiva. Terlepas dari IL-1, IL-6 juga meningkat pada
sindrom Sjogren, 11 menunjukkan proses inflamasi dalam subkelompok ini mata kering. Studi
lain menyelidiki asam sialat, komponen musin menangis, menemukan tingkat yang lebih rendah
pada pasien mata kering dibandingkan dengan kontrol, menunjukkan perubahan kuantitas dan
kualitas glikoprotein film air mata pada penyakit mata kering. 12 Perubahan profil protein air
mata dalam kering sindrom mata, terutama pada penyakit Sjogren, telah menjelaskan mekanisme
mata kering.
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GEJALA KLINIS
Gejala yang berhubungan dengan mata kering mungkin termasuk pembakaran okular, sensasi
benda asing, sensasi menyengat, nyeri, fotofobia dan penglihatan kabur. 9 - 12
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Hasil pemeriksaan
Sebagai sindrom mata kering dapat dikaitkan dengan berbagai penyebab, penting untuk
melakukan evaluasi menyeluruh sebelum melanjutkan pengobatan. Anamnesis yang cermat
harus diperoleh dengan perhatian khusus pada diabetes, penyakit tiroid, gangguan jaringan ikat
dan memakai lensa kontak. Prosedur okular sebelumnya, seperti bedah refraktif laser juga
penting dalam menentukan penyebab sindrom mata kering. Banyak obat dapat mempengaruhi
sekresi air mata dan penting untuk meninjau sejarah obat pasien. Pemeriksaan klinis yang cermat
harus mencakup celah lampu biomicroscopy untuk menentukan status permukaan mata dan

mendiagnosa terkait disfungsi kelenjar meibom, blepharitis atau seborrhoea meibom.

Pemeriksaan tarsus dan forniks untuk bekas luka dan symblepharon penting untuk
mengecualikan sindrom Stevens-Johnson yang sudah ada sebelumnya, penyakit radang
permukaan mata atau infeksi sebelumnya. Sebuah hati-hati melihat konjungtiva dan kornea akan
membantu untuk menilai keparahan mata kering; peningkatan pewarnaan diamati dalam kasus
yang lebih berat. Kadang, filamen kornea dan edema dapat diamati pada mata sangat kering. Hal
ini penting untuk menjadi menyeluruh dalam pemeriksaan untuk menemukan daerah-daerah lain
keterlibatan. Penyebab sistemik tertentu mata kering, seperti rheumatoid arthritis dan lupus
eritematosus sistemik tidak hanya melibatkan permukaan mata tetapi juga menyebabkan
peradangan pada episklera atau sklera, dan kadang-kadang segmen posterior.
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KRITERIA DIAGNOSTIK
Ohashi et al 9 menyatakan bahwa kombinasi dari (1) gejala mata kering, (2) temuan sugestif dari
Schirmer (<5 mm pembasahan setelah 5 menit) dan tes izin fluorescein, dan (3) fluorescein dan
Rose Bengal pewarnaan (> 3 + ) akan memverifikasi mata kering klinis. Penulis lain telah
menyusun kriteria diagnostik yang berbeda dan tidak ada konsensus dalam hal ini. 13 - 15 Untuk
lebih memperumit masalah, gejala dan tanda-tanda tidak selalu berkorelasi dengan baik dengan
satu sama lain dalam banyak pasien. 14
Untuk mengkonfirmasi diagnosis mata kering, tes tertentu yang diperlukan dalam pengaturan
klinis. Stabilitas air mata film dapat dinilai dengan uji waktu break-up air mata fluorescein
(TBUT). Ini mengukur interval dalam detik antara berkedip lengkap dan penampilan pertama
dari tempat kering atau diskontinuitas dalam film prekornea. Pasien dengan TBUT kurang dari 3
detik diklasifikasikan dengan mata kering klinis. Jika ada kekurangan air, meniskus air mata
akan tampak kurang dari 1 mm tipis,. Metode lain klinis untuk menilai keparahan mata kering
adalah mata dye permukaan pewarnaan. Fluorescein dan Rose Bengal noda dapat digunakan
sebagai pewarna diagnostik. Pewarnaan fluorescein terjadi ketika penghalang epitel terganggu
dan berfungsi sebagai tes yang baik untuk evaluasi mata kering. Rose Bengal noda sel epitel
devitalized pada konjungtiva dan melayani tujuan yang sama. Namun, Rose Bengal
menyebabkan iritasi sementara setelah berangsur-angsur dan mungkin kurang nyaman. Pasien
dengan sindrom mata kering dapat menunjukkan tanda-tanda belang-belang epitheliopathy dan
bahkan lecet kornea.
Tes klinis yang penting lainnya adalah tes Schirmer yang mengukur produksi air mata berair. Tes
ini mudah dilakukan dalam pengaturan klinis tetapi mungkin akan dikenakan kesalahan. Strip
kertas filter, yang disebut Schirmer strip, ditempatkan pada tutup lebih rendah dalam konjungtiva
tarsal. Pasien diperbolehkan untuk berkedip normal dan strip air mata skor sesuai dengan itu
membasahi gelar dalam 5 menit. Ada dua cara untuk melakukan tes ini: (a) tanpa anestesi topikal
(Schirmer tes I) yang mengevaluasi kemampuan permukaan okular untuk menanggapi
rangsangan permukaan; dan (b) di bawah anestesi topikal (Schirmer tes II) yang mengevaluasi
sekresi air mata basal. Pasien dengan air mata membasahi kurang dari 10 mm dianggap memiliki
mata kering klinis dan mata dengan kurang dari 5 mm pembasahan didiagnosis sebagai sangat

kering. Namun, penting untuk dicatat bahwa tes Schirmer tunduk pada perubahan lingkungan
dan fisiologis dengan hasil yang bervariasi dari waktu ke waktu.
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MANAJEMEN
Pengelolaan mata kering tergantung pada penyebab dan keparahan kondisi. Air mata buatan yang
digunakan untuk mengisi lapisan berair kekurangan dari film air mata dan untuk mencairkan
sitokin inflamasi. Air mata buatan yang tersedia dalam viskositas yang berbeda dan diawetkan
atau non-diawetkan persiapan. Jika kekurangan air mata parah, agen lebih kental seperti gel atau
salep dapat digunakan untuk mempertahankan perlindungan lebih lama. Sejak KCS, termasuk
sindrom Sjogren, terkait dengan peradangan, penggunaan steroid topikal atau obat anti-inflamasi
non-steroid kadang-kadang membantu. Antibiotik topikal mungkin diperlukan jika sindrom mata
kering dikaitkan dengan komplikasi kornea. Meibomian kelenjar waran penyakit resep
kebersihan kelopak mata dan tutup hangat kompres, bersama-sama dengan antibiotik topikal atau
bahkan sistemik seperti doxycycline. 13 , 14
Untuk penyakit yang lebih berat, agen imunomodulasi topikal, seperti tetes siklosporin-A,
mungkin menjadi perlu. Studi telah menunjukkan peningkatan tanda-tanda dan gejala mata
kering, bersama dengan penurunan konjungtiva infiltrasi sel-T dan tingkat sitokin air mata
setelah penggunaan siklosporin-A tetes. 15 , 16
Dalam kasus yang sangat parah, sering pelumas topikal mungkin tidak cukup. Penelitian telah
melihat ke dalam penggunaan serum autologus mata topikal tetes mata sangat kering dengan
perbaikan dilaporkan setelah rejimen pengobatan jangka panjang mulai dari 4 sampai 6 minggu.
Faktor pertumbuhan yang disediakan oleh serum autologus penting untuk penyembuhan epitel.
Serum autologus dapat dibuat dengan pemusingan darah vena dan mencampurnya dengan
larutan garam seimbang untuk 20%. 17
Lensa kontak perban kadang-kadang berguna dalam mata kering untuk meminimalkan tingkat
keratopati eksposur. Penyakit mata kering yang parah dengan komplikasi kornea dapat menjamin
intervensi bedah seperti oklusi punctal. Puncta lakrimal dapat dipasang sementara dengan
colokan kolagen diserap atau untuk jangka waktu yang lebih lama dengan colokan nonabsorbable yang perlu dihapus jika muncul masalah. Tetap oklusi punctal juga dapat dilakukan
untuk mencegah air mata dari pengeringan melalui sistem drainase. Untuk pasien dengan mata
kering sekunder akibat penyakit jaringan ikat, penting untuk berkolaborasi dengan internis dan
mengoptimalkan pengobatan untuk gangguan sistemik. Dalam mata kering sangat parah
sekunder terhadap penyakit permukaan mata (seperti cedera kimia, sindrom Stevens-Johnson,
atau pemfigoid sikatrisial okular), transplantasi membran amnion, tarsorrhaphy, keratoplasty,
transplantasi sel induk limbal, atau bahkan prostesis okular, seperti kontak scleral kaku lensa,
mungkin menjadi perlu untuk pemulihan penglihatan. 18

Terapi Anti-inflamasi

Sebelum penemuan terbaru dibingkai kembali pemahaman kita tentang mata kering, pengobatan
terbatas pada penggunaan air mata buatan, salep, dan terapi non-farmakologis, seperti oklusi
punctal, pengendalian lingkungan, kelembaban-penahan kacamata, dan operasi. Masing-masing
telah kemanjuran terbatas dan sedikit menghasilkan tahan lama peningkatan kualitas hidup
pasien. Hari ini, mata kering dapat diobati dengan sukses dengan agen anti-inflamasi, yang
paling menguntungkan dari yang cyclosporine topikal. Bukti klinis menunjukkan bahwa terapi
anti-inflamasi menghambat produksi mediator inflamasi dan mengurangi tanda-tanda dan gejala
KCS.
Kortikosteroid
Kortikosteroid adalah agen anti-inflamasi yang kuat secara rutin digunakan untuk mengendalikan
peradangan di berbagai organ. Kortikosteroid memiliki beberapa mekanisme aksi. Mereka
bekerja melalui reseptor glukokortikoid jalur mediasi tradisional yang secara langsung mengatur
ekspresi gen dan juga dengan jalur non-reseptor yang mengganggu regulator transkripsi gen proinflamasi. Di antara beberapa aktivitas biologisnya, kortikosteroid menghambat produksi sitokin
inflamasi dan kemokin, mengurangi sintesis matriks metaloproteinase dan mediator lipid
inflamasi (misalnya prostaglandin), mengurangi ekspresi molekul-molekul adhesi sel (misalnya
antar molekul adhesi 1), dan merangsang limfosit apoptosis. 19 - 21 Steroid telah dilaporkan untuk
mengurangi produksi sejumlah sitokin inflamasi, termasuk IL-1, IL-6, IL-8, tumor necrosis
factor-alpha (TNF-), dan granulosit macrophage colony-merangsang . Faktor (GM-CSF), dan
matriks metalloproteinase 9 (MMP-9) oleh epitel kornea 22 Kortikosteroid telah berhasil
digunakan untuk pengobatan penyakit epitel kornea karena mata kering dalam beberapa
penelitian klinis. 23 - 25
Cyclosporine
Cyclosporine A (CSA) adalah undecapeptide siklik lipofilik diisolasi dari jamur Hypocladium
inflatum Gams. 26 Ini pertama kali diperkenalkan untuk penggunaan klinis sebagai obat
kekebalan-penekan untuk pencegahan penolakan transplantasi organ pada tahun 1983. Efek
modulatory immuno agen ini telah terbukti bermanfaat untuk pengobatan berbagai penyakit
seperti psoriasis, rheumatoid arthritis dan kolitis ulserativa yang memiliki basis inflamasi yang
mendasari. Salah satu mekanisme kerjanya adalah penghambatan kalsineurin, sebuah fosfatase
serin / treonin, dengan pengurangan berikutnya dalam ekspresi gen tertentu yang terlibat dalam
aktivasi sel-T seperti IL-2, IL-4, IL-12.
Potensi CSA untuk mengobati penyakit mata kering telah ditunjukkan dalam beberapa acak uji
klinis double-bertopeng. 27 - 29
Tetrasiklin dan Derivatif mereka
Tetrasiklin memiliki anti-inflamasi, serta antibakteri, sifat yang dapat membuat mereka berguna
untuk manajemen penyakit peradangan kronis. Agen-agen ini menurunkan aktivitas kolagenase,
fosfolipase A 2, dan beberapa metaloproteinase matriks. Mereka juga menurunkan produksi IL-1
dan TNF- dalam berbagai jaringan, termasuk epitel kornea. 30 - 32 Pada konsentrasi tinggi,
tetrasiklin menghambat sitokin eksotoksin yang disebabkan stafilokokus dan kemokin. 33 , 34

Tetrasiklin juga diketahui menghambat ekspresi matriks metaloproteinase, menunjukkan alasan

untuk mereka gunakan dalam rosacea okular. 35 Mereka juga dapat menghambat angiogenesis,
yang dapat berkembang pada rosacea.
Doxycycline ditemukan pada awal 1960-an. Ini adalah turunan tetrasiklin long-acting
semisintetik yang menghambat ribosom bakteri dalam berbagai macam mikro-organisme. Dalam
dosis subantimicrobial itu juga efektif sebagai pengobatan utama untuk rosacea dan steril ulserasi
kornea. 36 , 37 studi sebelumnya yang menggunakan model mata kering eksperimental
menunjukkan bahwa doksisiklin adalah berkhasiat dalam menurunkan aktivitas gelatinolitik di
epitel permukaan mata, serta menurunnya kadar MMP- 9 transkrip mRNA, dan mencegah
kenaikan mata-diinduksi kering eksperimental di IL-1 dan TNF-. 38 Doxycycline juga
meningkatkan kornea keteraturan permukaan dan fungsi penghalang. 39
Asam Lemak Esensial
Asam lemak esensial yang diperlukan untuk kesehatan. Mereka tidak dapat disintesis oleh
vertebrata dan harus diperoleh dari sumber makanan. Di antara asam lemak esensial adalah asam
omega-6 dan omega-3 asam lemak 18 karbon. Dalam diet Barat yang khas, asam omega-6 lemak
yang dikonsumsi 20 sampai 25 kali lebih banyak daripada asam lemak omega-3. Asam lemak
omega-6 merupakan prekursor asam arakidonat dan mediator lipid pro-inflamasi tertentu seperti
prostaglandin E 2 dan leukotrien B 4. Sebaliknya, omega-3 asam lemak tertentu, seperti asam
eicosapentaenoic ditemukan dalam minyak ikan, menghambat sintesis mediator lipid dan juga
memblokir produksi IL-1 dan TNF-. 40 , 41 A efek klinis yang menguntungkan dari ikan omega
minyak -3 asam lemak pada rheumatoid arthritis telah diamati pada beberapa uji klinis terkontrol
plasebo double-bertopeng. 42 , 43 Dalam percobaan prospektif terkontrol plasebo klinis, asam
linoleat dan gamma-asam linoleat diberikan secara oral dua kali sehari menyebabkan
peningkatan yang signifikan dalam gejala iritasi mata, dan pengurangan mata lissamine
permukaan pewarnaan hijau konjungtiva HLA-DR reaktivitas. 44 Dalam model hewan diinduksi
mata kering, pengobatan topikal dengan asam alpha-linolenic signifikan menurun kornea
pewarnaan fluorescein dibandingkan dengan kendaraan dan kontrol tidak diobati, menurun
CD11b (+) sel dan mengurangi ekspresi kornea IL-1 dan TNF-, dan konjungtiva TNF-. 45
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KESIMPULAN
Sindrom mata kering terdiri dari spektrum yang luas dari gangguan dengan penyebab yang
berbeda. Dokter harus menyadari sejauh mana gejala mata kering. Sejarah menyeluruh dan
penyelidikan sangat diperlukan untuk mengidentifikasi penyebab mata kering. Uji klinis yang
berguna untuk menilai keparahan kondisi ini termasuk Schirmer, pewarna fluorescein, dan putus
air mata tes waktu. Manajemen tergantung pada diagnosis yang akurat dan keparahan kondisi.
Perawatan yang mengisi air mata kekurangan meliputi air mata buatan, gel dan salep di penyakit
ringan sampai sedang. Terapi lainnya seperti steroid topikal, obat imunomodulasi, antibiotik,
lensa kontak perban, serum autologus dan transplantasi membran amnion dapat digunakan dalam
kasus yang lebih berat. Di mata sangat kering, intervensi bedah seperti oklusi punctal dapat

digunakan untuk meminimalkan drainase air mata. Konjungtiva dan tutup operasi tertentu juga
dapat dilakukan untuk mengobati penyebab yang spesifik.

J Ophthalmic Vis Res. Jul 2011; 6(3): 192198.

PMCID: PMC3306104

Dry Eye Syndrome

Mohammad-Ali Javadi, MD and Sepehr Feizi, MD
Author information Article notes Copyright and License information
This article has been cited by other articles in PMC.
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Abstract
Our understanding of keratoconjunctivitis sicca (KCS), also known as dry eye syndrome, has
been changed over recent years. Until lately, the condition was thought to be merely due to
aqueous tear insufficiency. Today, it is understood that KCS is a multifactorial disorder due to
inflammation of the ocular surface and lacrimal gland, neurotrophic deficiency and meibomian
gland dysfunction. This change in paradigm has led to the development of new and more
effective medications.
Keywords: Dry Eye Syndromes, Keratoconjunctivitis Sicca
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INTRODUCTION
Dry eye is a disorder of the tear film which occurs due to tear deficiency or excessive tear
evaporation; it causes damage to the interpalpebral ocular surface and is associated with a variety
of symptoms reflecting ocular discomfort.1 Dry eye syndrome, also known as
keratoconjunctivitis sicca (KCS), is a common condition reported by patients who seek
ophthalmologic care and is characterized by inflammation of the ocular surface and lacrimal
glands.
Dry eye symptoms may be a manifestation of a systemic disease, therefore timely detection may
lead to recognition of a lifethreatening condition. Additionally, patients with dry eye are prone
to potentially blinding infections, such as bacterial keratitis2 and also at an increased risk of
complications following common procedures such as laser refractive surgery.
Knowledge of the pathophysiology of dry eye has recently been improved and the condition is
now understood to be a multifactorial disease, characterized by inflammation of the ocular
surface and reduction in tear production.3 This awareness has led to the development of highly
effective therapies.

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EPIDEMIOLOGY
Approximately 1 out of 7 individuals aged 65 to 84 years reports symptoms of dry eye often or
all of the time.4 Moss et al5 reported the prevalence of dry eye to be 14.4% in 3,722 subjects aged
48 to 91 years and noted that the prevalence of the condition doubled after the age of 59. Schein
et al4, in contrast, found no correlation between dry eye and age or sex, while other researchers
have reported such associations to exist. A study on 926 subjects aged 40 years and older, found
a higher prevalence of dry eye in women who were also more likely to have a dry eye-related
diagnosis or procedure.6 According to another study, women experienced a sharp increase in the
prevalence of dry eye earlier than men, around the age of 45, roughly at the onset of menopause.7
Epidemiological studies on dry eye syndrome suggest vast differences in prevalence. The
difficulty in determining the extent of the disease stemmed in part from limited understanding of
the pathophysiology of dry eye. As such, definitions of dry eye syndrome differed from one
study to another, making results difficult to compare.8 This is further complicated by the lack of a
standardized clinical testing protocol to diagnose the condition.
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CLINICAL TYPES
The precorneal tear film is an essential component of the ocular surface and can be subdivided
into an anterior lipid layer, a middle aqueous layer and an innermost mucin layer. These layers
are produced by the meibomian glands, the lacrimal gland and goblet cells of the conjunctiva,
respectively.2 The tear film lubricates the eye, maintains nutrition and oxygenation of ocular
structures, acts as a refractive component and helps remove debris from the ocular surface. In
terms of tear production, dry eye can be divided into tear deficient and evaporative types.3 Tear
deficiency dry eye can further be subdivided into non-Sjogren syndrome and Sjogren syndrome,
which is an autoimmune disease associated with lacrimal and salivary gland lymphocytic
infiltration. Evaporative dry eye can be divided into meibomian gland disease (MGD) and
exposure-related dry eye.4,5 In yet another group of patients, mucin deficiency due to StevensJohnson syndrome or ocular cicatricial pemphigoid is the underlying mechanism of dry eye.8
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ETIOLOGY
Dry eye syndrome is associated with a long list of causes which can be divided into primary and
secondary. Dry eye may develop secondary to inflammatory disease (e.g. vascular, allergic),
environmental conditions (e.g. allergens, cigarette smoke, dry climate), hormonal imbalance (e.g.
perimenopausal women and patients under hormone replacement therapy), and contact lens wear.
Systemic disorders, such as diabetes mellitus, thyroid disease, rheumatoid arthritis and systemic
lupus erythematosus can also lead to dry eye. In addition, neurotrophic deficiency, previous eye

surgery (such as corneal transplantation, extracapsular cataract procedures and refractive

surgery), or long-term use of medications which create hypersensitivity or toxicity in the eye can
predispose to dry eye. Many systemic medications, such as diuretics, antihistamines,
antidepressants, psychotropics, cholesterol lowering agents, beta-blockers and oral
contraceptives may also be associated with dry eye.9,10
Postmenopausal women may be the largest at risk group; this is due to a decrease in hormonal
levels leading to loss of anti-inflammatory protection and decreased lacrimal secretion.9
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PATHOGENESIS
Studies performed on the proteomic profile of the ocular surface comparing dry with normal eyes
using enzyme-linked immunosorbent assay (ELISA) has revealed a decrease in lactoferrin and
epidermal growth factor in dry eyes. A protein found in acinar cells of the lacrimal gland, AQP-5,
was shown to be increased in the Sjogren type of dry eye syndrome, indicating possible leakage
of such proteins into the tear film due to lymphocytic infiltration of the lacrimal gland.9 Solomon
et al10 found an increase in inflammatory cytokines interleukin 1 (IL-1) alpha and IL-1 beta in
both MGD and Sjogren syndrome, indicating increased protease activity on the ocular surface,
mainly in the conjunctival epithelium. Apart from IL-1, IL-6 was also increased in Sjogren
syndrome,11 indicating an inflammatory process in this subgroup of dry eye. Another study
investigating sialic acid, a component of mucin in tears, found a lower level in dry eye patients
compared to controls, indicating a change in quantity and quality of tear film glycoproteins in
dry eye disease.12 The change in tear protein profile in dry eye syndrome, especially in Sjogren
disease, has shed light on mechanisms of dry eye.
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CLINICAL SYMPTOMS
Symptoms associated with dry eye may include ocular burning, foreign body sensation, stinging
sensation, pain, photophobia and blurred vision.912
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WORKUP
As dry eye syndrome may be associated with a variety of causes, it is important to perform a
comprehensive evaluation before proceeding to treatment. A careful history should be obtained
with particular attention to diabetes, thyroid disease, connective tissue disorders and contact lens
wear. Previous ocular procedures, such as laser refractive surgery are also important in
determining the cause of dry eye syndrome. Many medications can affect tear secretion and it is
important to review the patients drug history. A careful clinical examination should include slit
lamp biomicroscopy to determine ocular surface status and diagnose associated meibomian gland

dysfunction, blepharitis or meibomian seborrhoea. Examination of the tarsus and fornices for
scars and symblepharon is important to exclude pre-existing Stevens-Johnson syndrome, other
ocular surface inflammatory disease or previous infections. A careful look at the conjunctiva and
cornea would be helpful to assess the severity of dry eye; an increase in staining is observed in
more severe cases. Occasionally, corneal filaments and edema may be observed in extremely dry
eyes. It is important to be thorough in the examination to find other areas of involvement. Certain
systemic causes of dry eye, such as rheumatoid arthritis and systemic lupus erythematosus not
only involve the ocular surface but also cause inflammation of the episclera or sclera, and
occasionally the posterior segment.
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DIAGNOSTIC CRITERIA
Ohashi et al9 suggested that a combination of (1) dry eye symptoms, (2) suggestive findings on
Schirmer (< 5 mm wetting after 5 minutes) and fluorescein clearance tests, and (3) fluorescein
and Rose Bengal staining (> 3+) would verify clinical dry eye. Other authors have devised
different diagnostic criteria and there is no consensus in this regard.1315 To further complicate the
issue, symptoms and signs do not always correlate well with each other in many patients.14
To confirm a diagnosis of dry eye, certain tests are required in the clinical setting. Tear film
stability can be assessed with the fluorescein tear break-up time test (TBUT). This measures the
interval in seconds between a complete blink and the first appearance of a dry spot or
discontinuity in the precorneal film. Patients with TBUT less than 3 seconds are classified with
clinical dry eye. If there is aqueous deficiency, the tear meniscus will appear to be thin, less than
1 mm in height. Another clinical method for assessing the severity of dry eye is ocular surface
dye staining. Fluorescein and Rose Bengal stains can be used as diagnostic dyes. Fluorescein
staining occurs when the epithelial barrier is disrupted and serves as a good test for evaluation of
dry eye. Rose Bengal stains devitalized epithelial cells on the conjunctiva and serves a similar
purpose. However, Rose Bengal causes transient irritation after instillation and may be less
comfortable. Patients with dry eye syndrome can show signs of punctate epitheliopathy and even
corneal abrasions.
Another important clinical test is the Schirmer test which measures aqueous tear production. This
test is easy to perform in clinical settings but may be subject to errors. Strips of filter paper,
called Schirmer strips, are placed on the lower lid inside the tarsal conjunctiva. The patient is
allowed to blink normally and the tear strip is scored according to the degree it wets in 5
minutes. There are two ways to perform this test: (a) without topical anesthesia (Schirmer test I)
which evaluates the ability of the ocular surface to respond to surface stimulation; and (b) under
topical anesthesia (Schirmer test II) which evaluates basal tear secretion. Patients with tear
soaking less than 10 mm are considered to have clinical dry eye and eyes with less than 5 mm
wetting are diagnosed as severely dry. However, it is important to note that Schirmer tests are
subject to environmental and physiologic changes with varying results over time.
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MANAGEMENT
Management of dry eye depends on the cause and severity of the condition. Artificial tears are
used to replenish the deficient aqueous layer of the tear film and to dilute inflammatory
cytokines. Artificial tears are available in different viscosities and preserved or non-preserved
preparations. If the tear deficiency is severe, more viscous agents such as gels or ointments can
be used to maintain longer protection. Since KCS, including Sjogren syndrome, is associated
with inflammation, the use of topical steroids or non-steroidal anti-inflammatory medications is
sometimes helpful. Topical antibiotics may be necessary if the dry eye syndrome is associated
with corneal complications. Meibomian gland disease warrants prescription of eyelid hygiene
and warm lid compresses, together with topical or even systemic antibiotics such as
doxycycline.13,14
For more severe disease, topical immunomodulating agents, such as cyclosporine-A drops, may
become necessary. Studies have demonstrated an improvement in signs and symptoms of dry
eye, together with reduction in conjunctival T-cell infiltration and tear cytokine levels following
the use of cyclosporine-A drops.15,16
In very severe cases, frequent topical lubricants may not suffice. Studies have looked into the use
of autologous serum as topical eye drops for severely dry eyes with improvement reported after
prolonged treatment regimens ranging from 4 to 6 weeks. Growth factors provided by autologous
serum are important for epithelial healing. Autologous serum can be prepared by centrifuging
venous blood and diluting it with balanced salt solution to 20%.17
Bandage contact lenses are sometimes useful in dry eyes to minimize the extent of exposure
keratopathy. Severe dry eye disease with corneal complications may warrant surgical
intervention such as punctal occlusion. Lacrimal puncta can be plugged temporarily with
absorbable collagen plugs or for a longer period of time with non-absorbable plugs which need
to be removed if problems arise. Permanent punctal occlusion can also be performed to prevent
tears from draining through the drainage system. For patients with dry eye secondary to
connective tissue disease, it is important to collaborate with internists and optimize treatment for
the systemic disorders. In very severe dry eye secondary to ocular surface disease (such as
chemical injury, Stevens-Johnson syndrome, or ocular cicatricial pemphigoid), amniotic
membrane transplantation, tarsorrhaphy, keratoplasty, limbal stem cell transplantation, or even
ocular prostheses, such as rigid scleral contact lenses, may become necessary for restoration of
vision.18

Anti-Inflammatory Therapy
Before recent findings reframed our understanding of dry eye, treatment was limited to the use of
artificial tears, ointments, and non-pharmacologic therapies, such as punctal occlusion,
environmental control, moisture-retaining eyewear, and surgery. Each had limited efficacy and
few resulted in long-lasting improvement in patients quality of life. Today, dry eye can be
treated successfully with anti-inflammatory agents, the most beneficial of which is topical
cyclosporine. Clinical evidence indicates that anti-inflammatory therapy inhibits the production
of inflammatory mediators and reduces the signs and symptoms of KCS.

Corticosteroids
Corticosteroids are potent anti-inflammatory agents routinely used to control inflammation in
various organs. Corticosteroids have multiple mechanisms of action. They work through
traditional glucocorticoid receptor mediated pathways which directly regulate gene expression
and also by non-receptor pathways that interfere with transcriptional regulators of proinflammatory genes. Among their multiple biological activities, corticosteroids inhibit the
production of inflammatory cytokines and chemokines, decrease the synthesis of matrix
metalloproteinases and lipid mediators of inflammation (e.g. prostaglandins), reduce the
expression of cell adhesion molecules (e.g. intercellular adhesion molecule 1), and stimulate
lymphocyte apoptosis.1921 Steroids have been reported to decrease the production of a number of
inflammatory cytokines, including IL-1, IL-6, IL-8, tumor necrosis factor-alpha (TNF-), and
granulocyte macrophage colony-stimulating factor (GM-CSF), and matrix metalloproteinase 9
(MMP-9) by the corneal epithelium.22 Corticosteroids have been successfully used for treatment
of corneal epithelial disease due to dry eye in several clinical studies.2325
Cyclosporine
Cyclosporine A (CsA) is a lipophilic cyclic undecapeptide isolated from the fungus Hypocladium
inflatum gams.26 It was first introduced for clinical use as an immune-suppressant drug for
prevention of organ transplant rejection in 1983. The immuno modulatory effect of this agent has
been proven to be beneficial for treatment of a broad range of disorders such as psoriasis,
rheumatoid arthritis and ulcerative colitis which have an underlying inflammatory basis. One of
its mechanisms of action is inhibition of calcineurin, a serine/threonine phosphatase, with
subsequent reduction in the expression of certain genes involved in T-cell activation such as IL2, IL-4, IL-12.
The potential of CsA for treating dry eye disease has been demonstrated in several randomized
double-masked clinical trials.2729
Tetracyclines and their Derivatives
The tetracyclines have anti-inflammatory, as well as antibacterial, properties that may make them
useful for management of chronic inflammatory diseases. These agents decrease the activity of
collagenase, phospholipase A2, and several matrix metalloproteinases. They also decrease the
production of IL-1 and TNF- in a wide range of tissues, including the corneal epithelium. 3032
At high concentrations, tetracyclines inhibit staphylococcal exotoxin-induced cytokines and
chemokines.33,34 Tetracyclines are also known to inhibit matrix metalloproteinase expression,
suggesting a rationale for their use in ocular rosacea.35 They can also inhibit angiogenesis, which
may develop in rosacea.
Doxycycline was discovered in the early 1960s. It is a semisynthetic long-acting tetracycline
derivative which inhibits bacterial ribosomes in a wide variety of micro-organisms. In
subantimicrobial doses it is also effective as primary treatment for rosacea and sterile corneal
ulceration.36,37 Previous studies using experimental dry eye models demonstrated that
doxycycline was efficacious in decreasing gelatinolytic activity in the ocular surface epithelia, as

well as decreasing levels of MMP-9 mRNA transcripts, and preventing experimental dry eyeinduced increase in IL-1 and TNF-.38 Doxycycline also improves corneal surface regularity and
barrier function.39
Essential Fatty Acids
Essential fatty acids are necessary for health. They cannot be synthesized by vertebrates and
must be obtained from dietary sources. Among the essential fatty acids are the 18 carbon omega6 and omega-3 fatty acids. In a typical western diet, omega-6 fatty acids are consumed 20 to 25
times more than omega-3 fatty acids. Omega-6 fatty acids are precursors of arachidonic acid and
certain pro-inflammatory lipid mediators such as prostaglandin E2 and leukotriene B4. In
contrast, certain omega-3 fatty acids, such as eicosapentaenoic acid found in fish oil, inhibit
synthesis of these lipid mediators and also block the production of IL-1 and TNF-.40,41 A
beneficial clinical effect from fish oil omega-3 fatty acids on rheumatoid arthritis has been
observed in several double-masked placebo-controlled clinical trials.42,43 In a prospective
placebo-controlled clinical trial, linoleic acid and gamma-linoleic acid administered orally twice
a day led to significant improvement in ocular irritation symptoms, and a reduction in ocular
surface lissamine green staining conjunctival HLA-DR reactivity.44 In an animal model of
induced dry eye, topical treatment with alpha-linolenic acid significantly decreased corneal
fluorescein staining as compared to both vehicle and untreated controls, decreased CD11b(+)
cells and reduced the expression of corneal IL-1 and TNF-, and conjunctival TNF-.45
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CONCLUSIONS
Dry eye syndrome consists of a wide spectrum of disorders with different causes. Clinicians
should be aware of the extent of dry eye symptoms. A thorough history and investigation is
necessary to identify the cause of dry eye. Useful clinical tests for assessing the severity of the
condition include Schirmer, fluorescein dye, and tear break up time tests. Management depends
on an accurate diagnosis and the severity of the condition. Treatments that replenish deficient
tears include artificial tears, gels and ointments in mild to moderate disease. Other treatment
modalities such as topical steroids, immunomodulating drugs, antibiotics, bandage contact
lenses, autologous serum and amniotic membrane transplantation may be used in more severe
cases. In severely dry eyes, surgical intervention such as punctal occlusion can be employed to
minimize tear drainage. Certain conjunctival and lid operations can also be performed to treat
specific causes.
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Footnotes
Conflicts of Interest
None.

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