Dr. Parul Priyambada, Dr.Sumita Mohapatra, Dr. Saumendu Mohanty,
Dr.Harshavardhan V K
Co-authors- Prof (Dr) Sumita Mohapatra, Harshavardhan V K, Saumendu Mohanty
Introduction
Superior limbic keratoconjunctivitis is an uncommon chronic inflammation of the superior limbus and superior bulbar and tarsal conjunctiva. It affects one or both eyes and is most commonly seen in middle aged women. The etiology is largely unknown. However a large number, that is over 50 % of patients of SLK have abnormal thyroid function (mostly hyperthyroidism). 3% of patients with thyroid disease have SLK. Keratoconjunctivitis sicca is seen in 25 % of patients with SLK. Other associations of SLK are contact lens wear, host vs graft reactions. This condition occurs when there is tear film insufficiency and an excess or lax conjunctival tissue which leads to friction between the eye lid and conjunctiva leading to blink related micro trauma. This induces an inflammatory response which in turn leads to conjunctival edema and redundancy, and hence a self- perpetuating cycle is created.
Histopathologically, SLK is characterized by keratinization of epithelial cells with dyskeratosis, acanthosis and nuclear balloon degeneration. Stromal infiltration by polymorphonucear leukocytes, plasma cells, mastocytes and lymphocytes is seen. Decreased level of mucin like glycoprotein is seen which is responsible for interaction of epithelium and mucin of conjunctiva.
The symptoms consist of foreign body sensation, burning, mild photophobia, mucoid discharge, frequent blinking, and are often intermittent. Signs in the conjunctiva are papillary hypertrophy of the superior tarsal plate, hyperemia of superior bulbar conjunctiva, limbal papillary hypertrophy. In cornea superior punctate corneal erosions and superior filamentary keratitis can be seen.
Treatment of SLK consists of lubricants that reduce friction, acetylcysteine 5% or 10% to break down filaments, mast cell stabilizers and steroids to reduce inflammation, cyclosporin. Soft contact lens and supratarsal steroid injection can also be used. Surgically, temporary superior and/or inferior punctual occlusion , resection of superior limbic conjunctiva and conjunctival ablation by silver nitrate can be done. One of the new modalities of treatment which has shown promising results is topical rebamipide.
Rebamipide , is a mucosal protective agent with mucin secretagogue activity and is approved in Japan as an oral drug for the treatment of gastric mucosal disorders and gastritis. It has been reported that rebamipide increases production of mucin like substance in the cornea and conjunctiva of a rabbit model in which ocular mucin was decreased by N-acetylcysteine. Rebamipide increased MUC1 and MUC4 gene expression in human corneal epithelial cells, promoting glycoconjugate production, an indicator of mucin like glycoprotein. It has been found in various studies that rebamipide is effective in improving objective signs( fluorescein corneal staining score, lissamine green conjunctival staining score, and tear film break up time) and subjective signs ( foreign body sensation, dryness, photophobia, pain, and blurred vision) in patients of dry eye. It has been shown that rebamipide increases conjunctival goblet cell number, protects corneal and conjunctival microvilli, increase mucin like glycoprotein production, upregulates memberane associated mucins, prevents ocular surface inflammation and antagonizes effects of TNF alpha on barrier functions and cytokine expression. In a retrospective study in japan, it was shown that rebamipide had definite role in improving symptoms and signs of SLK in thyroid eye disease.
Aim of study-
The objective of this study is to evaluate the efficacy of2% rebamipide eye drops, instilled QID for 4 weeks in patients of SLK.
Methods and materials
It is a prospective observational study including 26 patients, male 16 (61.53%), female 10 (38.46%), in the age group of 15- 75, attending Regional Institute of Ophthalmology during July 2015- May 2016. After a thorough history was taken, the signs and symptoms were evaluated and the patients meeting inclusion criteria were started on 2% rebamipide ophthalmic suspension QID in the affected eye for four weeks. A total of 32 eyes from these 26 patients were studied. The patients were evaluated at a weekly interval. The signs evaluated were fluorescein corneal staining, tear film break up time, schirmers test and conjunctival impression cytology. The symptoms were evaluated on basis of the Ocular surface disease index ( OSDI ) score where the patients were asked a series of 12 questions, according to the answers the score was obtained on a scale of 0-100 and patients were accordingly graded into normal, mild ,moderate and severe dry eye disease.
Inclusion criteria
- Patients having symptoms and signs which are confirmtory to the diagnosis of Superior limbic keratoconjunctivitis.
- Patients in the age group of 15- 75.
Exclusion criteria
- One eyed patients
- Contact lens wearers
- Patients having other active inflammatory conditions or anterior ocular disorders like blepharitis or blepharospasm.
- Patients having known allergy to any of the components of the eye drop.
- Operation to ocular surface within 12 months or intaocular surgery within 3 months.
- Patients with continued use of eye drops.
- Patients having a punctal plug or had it removed within 3 months.
Statistical analysis and Results
Demographic profile-
Sex distribution Age distribution
Efficacy evaluation–
Signs-
- Fluorescein corneal staining-
| No of patients Fl stain positive | Percentage of total with residual staining. | Percentage of total with no residual staining. | |
| At baseline | 32 | 100% | 0 |
| Week 1 | 24 | 75% | 25% |
| Week 2 | 16 | 50% | 50% |
| Week 3 | 9 | 28.12% | 71.88% |
| Week 4 | 5 | 15.62% | 84.38% |
At the end of 4 weeks, only 5 patients (15.62%) showed residual fluorescein staining, and 27 patients ( 84.38% ) showed no residual fluorescein staining.
2.Tear film break – up time-
| No of patients showing improvement in TBUT | Percentage of patients showing improvement in TBUT | |
| Week 1 | 11 | 34.38% |
| Week 2 | 17 | 53.12% |
| Week 3 | 21 | 65.62% |
| Week 4 | 25 | 78.12% |
78.12% of patients showed improvement in TBUT at the end of 4 weeks.
Mean TBUT
| Mean TBUT | |
| Baseline | 4.34 |
| Weak 1 | 4.90 |
| Weak 2 | 5.19 |
| Weak 3 | 5.96 |
| Weak 4 | 6.63 |
The mean TBUT improved from 4.34 seconds at baseline to 6.63 seconds at 4 weeks.
- Schirmer test evaluation
| No of patients showing improvement in schirmer test results | Percentage of patients showing improvement in schirmer test results | |
| Week 1 | 8 | 25% |
| Week 2 | 15 | 46.88% |
| Week 3 | 19 | 59.37% |
| Week 4 | 22 | 68.75% |
Mean schirmer test reading-
| Mean schirmer test reading in mm at 5 minutes | |
| Baseline | 3.84 |
| Week 1 | 4.50 |
| Week 2 | 4.84 |
| Week 3 | 5.28 |
| Week 4 | 5.53 |
The mean schirmet test value at 5 minutes improves from 3.84 mm to 5.53 mm at the end of 4 weeks.
3.Conjunctival goblet cell count-
The conjunctival goblet cell count was done at baseline and at the end of 4 weeks, by impression cytology.23 patients (71.8 %) patients showed improvement in conjunctival goblet cell count.
Symptoms
1.According to the OSDI scores patients are divide as having normal, mild, moderate and severe dry eye disease. No of eyes
| normal | Mild | moderate | Severe | |
| Baseline | 8 | 4 | 9 | 11 |
| Week 1 | 8 | 6 | 10 | 8 |
| Week 2 | 10 | 5 | 9 | 8 |
| Week 3 | 17 | 3 | 6 | 6 |
| Week 4 | 25 | 2 | 3 | 2 |
Total of 24 eyes (75 % ) shows some improvement in the grade of OSDI scores. The number of eyes having severe OSDI score decreased from 11 (34.37%) to 2 (6.25%).The above table shows a definite improvement in the OSDI scores.
Side effects- No side effects were recorded in all 26 patients studied.
Discussion-
32 eyes from 26 patients ( 16 male,10 female) were evaluated for symptoms and signs of SLK at the initiation of treatment with 2% rebamipide ophthalmic suspension instilled at a dose one drop four times daily in the affected eye. Follow up was done at the end of week 1,2 ,3 and 4. Definite, improvement was seen for both signs and symptoms of SLK. The fluorescein corneal staining improved for 27 eyes (84.38%) and only 5 eyes (15.62%) showed residual fluorescein staining at 4 weeks. The TBUT improved in 25 eyes (78.12%) at the end of 4 weeks and the mean TBUT improved to 6.63 seconds at 4 weeks from 4.34 seconds at baseline. The schirmer test value improved in 22 eyes (68.75%) at the end of 4 weeks and mean schirmer test value improved from 3.84 mm at baseline to 5.53 mm at the end of 4 weeks. The conjunctival goblet cell count increased in 23 eyes ( 71.8%) at the end of 4 weeks. 24 eyes (75 % ) showed some improvement in the OSDI score grading with the number of eyes having severe dry eye disease decreasing from 11 ( 34.37%) to 2 (6.25%).
Conclusion-
2% rebamipide ophthalmic suspension is effective and safe in improving both signs and symptoms of SLK and can be considered in the management of SLK.
References–
A multicenter, open- label , 52 week study of 2% rebamipide ophthalmic suspension in patients with dry eye.( shigeru kinoshita, saki awamura, norihiro nakamichi, hiroyuki Suzuki, kazuhide oshiden and norihiko yokoi on behalf of rebamipide ophthalmic suspension long term study group) , ajo 2013.
A Randomized, Multicenter Phase 3 Study Comparing 2% Rebamipide (OPC-12759) with 0.1% Sodium Hyaluronate in the Treatment of Dry Eye .Presented in part at: Association for Research in Vision and Ophthalmology Annual Meeting,May 2011, Fort Lauderdale, Florida.Shigeru Kinoshita, MD, PhD , , Kazuhide Oshiden, MS, Saki Awamura, BS, Hiroyuki Suzuki, Bs,Norihiro Nakamichi, MS, Norihiko Yokoi, MD, PhD, Rebamipide Ophthalmic Suspension Phase 3 Study Group⁎, aao 2013
Usefulness of a New Therapy Using Rebamipide Eyedrops in Patients with VKC/AKC Refractory to Conventional Anti-Allergic Treatments. Mayumi Ueta, , mueta@koto.kpu-m.ac.jp, Chie Sotozono , Ayaka Koga , Norihiko Yokoi , Shigeru Kinoshita , allergology international volume 63, 2014.
4. Effect of Rebamipide Ophthalmic Suspension on Signs and Symptoms of Keratoconjunctivitis Sicca in Sjogren Syndrome Patients With or Without Punctal Occlusions. Arimoto, Atsushi MD; Kitagawa, Kazuko MD, PhD; Mita, Norihiro MS; Takahashi, Yoriko MD; Shibuya, Eri; Sasaki, Hiroshi MD, PhD.cornea 2014 aug.
5. Effect of Rebamipide Ophthalmic Suspension on Intraocular Light Scattering for Dry Eye After Corneal Refractive Surgery Igarashi, Akihito MD, PhD; Kamiya, Kazutaka MD, PhD; Kobashi, Hidenaga MD, PhD; Shimizu, Kimiya MD, PhD, cornea 2015 may.
6. Rebamipide Increases the Amount of Mucin-like Substances on the Conjunctiva and Cornea in the N-Acetylcysteine-Treated In Vivo Model Urashima, Hiroki MS; Okamoto, Takashi MS; Takeji, Yasuhiro MS; Shinohara, Hisashi MS; Fujisawa, Shigeki MS, cornea 2004.
7.Rebamipide increases barrier function and attenuates TNFα-induced barrier disruption and cytokine expression in human corneal epithelial cells Hiroshi Tanaka, Ken Fukuda, Waka Ishida, Yosuke Harada, Tamaki Sumi, Atsuki Fukushima. British journal of ophthalmology
8..Topical rebamipide treatment for superior limbic keratoconjunctivitis in patients with thyroid eye disease. Takahashi Y1, Ichinose A2, Kakizaki H, ajo 2014 april.
9.Kanski’s clinical ophthalmology, 8th edition pg 158- 160