New Approaches in Managing Corneal Disease

Rebamipide promising for dry eye

A 52-week study has found that 2 per cent rebamipide is effective in improving both the objective signs and subjective symptoms in patients with dry eye. The study found the ophthalmic suspension was well tolerated and there were no particular safety concerns.

In patients with dry eye (estimated to make up 35 per cent of the population), components of the ocular surface are disrupted, resulting in tear film instability. According to the authors, “the tear film can be destabilised by decreased tear production, delayed clearance or altered tear composition, ultimately leading to inflammation and exacerbating tear film instability”.

The authors studied rebamipide because it is a mucosal protective agent with mucin secretagogue activity, marketed in Japan as an oral drug to treat gastric mucosal disorders and gastritis. Mucins play an important role in lubricating and maintaining the health of the ocular surface.

2 per cent rebamipide is effective in improving both the objective signs and subjective symptoms…

“Reduced amounts of mucins and changes in their distribution and glycosylation have been reported in patients with dry eye, indicating that agents with the ability to increase mucin levels present a therapeutic option for treating the disease,” they wrote.

The study was particularly significant because it assessed both subjective symptoms and objective signs in patients with dry eye, acknowledging the weak association between self-reported symptoms and objective measures of dry eye. “Improvements in subjective symptoms, as well as objective signs, are needed for an effective treatment of dry eye,” they proposed.

Objective signs measured were fluorescein corneal staining score, lissamine green conjunctival staining score, and tear film break-up time. Subjective symptoms were dry eye–related ocular symptoms (foreign body sensation, dryness, photophobia, eye pain, and blurred vision).

Results from the multi-centre open-label, single-arm study, which involved 154 patients, (127 of whom completed the study) found that for all objective signs and subjective symptoms, the scores rapidly improved at week two compared with baseline (P<.001, paired t test). Scores continued to improve at almost every visit up to 52 weeks, findings which the authors reported supported previous double masked placebo controlled phase II study.

Furthermore the study found that five patients with Stevens-Johnson Syndrome – where severe dry eye is often seen – showed

an improvement in both their objective signs and subjective symptoms of dry eye up to 52 weeks. “These findings suggested that 2 per cent rebamipide could be an effective agent for treating severe dry eye caused by Stevens-Johnson Syndrome” they wrote.

There were no significant safety concerns with the treatment, the most common drug-related adverse event being dysgeusia, which the authors said could possibly be attributed to the bitter taste associated with the active ingredient. Nasopharyngitis, was also common, possibly reflecting “the year-long duration of the study which encompassed the annual cold and flu seasons”.

Comment
Rebamipide, a derivative of quinolone-class antibiotics, is a mucin secretagogue. Rebamipide was initially developed and approved for use in treating gastric ulcers. Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. In nonclinical studies, it was found that rebamipide increased corneal and conjunctival mucin, and also increased the conjunctival goblet cells in rabbits. The rebamipide ophthalmic suspension was launched in January 2012 in Japan. It has been approved in Japan for protection of gastric mucosa and for treatment of dry eye. Rebapamide has been shown to enhance secretion of mucin to support tear film adhesion and slow tear film break-up time in human and animal studies. Another important feature of rebamipide ophthalmic suspension is that it does not contain preservatives. Benzalkonium chloride is one of the most commonly used preservatives in ocular products. It is known to disrupt the tear film as well as decrease the density of goblet cells. Rebapamide is preservative-free and therefore may be an ideal choice in patients with chronic dry eye syndrome.

In the present study, topical rebapamide 2 per cent solution was found to be effective in alleviating dry eye symptoms subjectively as well as objectively in a multi-centre, open label trial that included 154 patients with dry eyes. The main strengths of this study include a long-term follow-up of 52 weeks and a multi-cenre trial design. In addition, the authors have used a very robust study design that includes evaluation of efficacy through fluorescein staining score and tear break up time. Safety of the drug was evaluated by ocular symptom scores for foreign body sensation, dryness, photophobia, eye pain, and blurred vision. Drug-related adverse events included dysgeusia (13.6 per cent), blurred vision (3.2 per cent), and ocular irritation (2.6 per cent). Although the present study is a single arm study.

Nevertheless, in an earlier study by the same group of researchers, 308 patients were randomised to receive placebo or topical 1 per cent or 2 per cent rebamipide administered in each eye four times daily for four weeks. The results of this double-masked, multi-centre, placebo-controlled phase two clinical study showed response in fluorescein corneal staining, lissamine green conjunctival staining and tear film breakup time scores with rebamipide.

Topical rebamipide was reported to be effective for other ocular surface disorders with or without dry eye, such as superficial limbic keratopathy, lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosions. However, rebapamide may not be the solution for all types for dry eyes. Although mucin secretagogues have a theoretical advantage over artificial tears, they may not benefit patients with inflammatory dry eye. For example, rebapamide may not be able to substitute topical cyclosporine eye drops in patients with inflammatory dry eye. Another important point to consider is that all the studies done so far are from Japan due to the availability of the drug in that region. Further trials and results from other regions of the world would be awaited before the drug can acquire a definitive status for dry eye treatment. Nevertheless, it certainly is a promising alternative in the armamentarium of ophthalmologists dealing with dry eye in their clinics every day.

Reference:

Shigeru Kinoshita; Sakiawamura; Norihiro Nakamichi; Hiroyuki Suzuki; Kazuhide Oshiden and Norihiko Yokoi on behalf of the Rebamipide Ophthalmic Suspension Long-term Study Group. A Multicenter, Open-Label, 52-Week Study of 2 per cent Rebamipide (OPC-12759) Ophthalmic Suspension in Patients with Dry Eye. American Journal of Ophthalmology, March 2014.

DALK Results Improved with AS-OCT

A study conducted at the Singapore National Eye Centre has found that good-quality images of the cornea using Intraoperative high-definition AS-OCT during deep anterior lamellar keratoplasty (DALK) were useful in helping surgeons decide on a number of steps during more complicated surgery. The prospective study assessed whether AS-OCT during DALK surgery could help reduce the risk for perforation and for uneven residual stroma as well as guide the surgeon intraoperatively.

Recent studies have found that DALK is superior to penetrating keratoplasty for the treatment of corneal stromal diseases and has also been shown to be a more cost-effective procedure.

The Singapore National Eye Centre performed sequential intraoperative AS-OCT scans using iVue 100-2 (Optovue, Fremont, CA, USA) during the various DALK techniques.

The researchers noted that an optimal big bubble cannot always be achieved during DALK and visualisation can make it difficult for the surgeon to decide which way to proceed. “Although reasonably good outcomes are achieved even if residual stroma is left in place, better contrast sensitivity and visual acuity are obtained if the Descemet membrane is exposed,” they reported.

The researchers analysed seven eyes of seven Asian patients, each of whom had a different condition; a nine-year-old male with corneal scarring secondary to neurotropic keratopathy; a 57-year-old male with lattice dystrophy; a 38-year-old male with macular dystrophy; a 41-year-old male who suffered bilateral corneal scarring and irregular thinning after corneal infections following epipolis laser in situ keratomileusis (epi-LASIK) surgery; a 30-year-old male with keratoconus and no previous history of hydrops, a 22-year-old female with a previous failed DALK and a 30-year-old male who suffered bilateral alkaline injury resulting in diffuse, severe corneal scarring the decreased visualisation of the underlying stroma both with the operating microscope and with the AS-OCT. In the latter case, during the initial manual dissection, the intraoperative AS-OCT revealed an intrastromal pocket of fluid that had not been clinically evident under the operating microscope and helped locate the intact Descemet membrane.

The surgeons found intraoperative AS-OCT, which “allows for rapid, non-contact, high resolution imaging of the interior segment”, was useful in several steps of each of these cases. They reported that it was useful in guiding manual dissection in cases of a failed big bubble, ensuring a thin and even residual stromal bed in order to improve visual outcomes. In cases with irregular scarring and thinning, they reported that the AS-OCT helped determine the initial trephination depth and in doing so helped surgeons to avoid perforation and reach an adequate depth to achieve a big bubble.

They said “the AS-OCT was especially useful in cases of decreased visualisation under the operating microscope where the image obtained with the OCT provided invaluable information to the surgeon”.

The study authors noted two drawbacks, one being interruptions to surgery because the operating microscope had to be moved so that the AS-OCT could be positioned over the eye every time an image was required. Additionally they wrote that metallic instruments obstructed the image so that deeper structures of the cornea were obscured. This meant the depth of the needle could only be obtained by assessing the tunnel created once the needle was removed.

Comment
Deep anterior lamellar keratoplasty (DALK) is the preferred technique of corneal transplantation in patients with corneal stromal pathologies and a normal corneal endothelium. It is believed that the visual acuity results of DALK are better if a bare Descemet membrane is achieved or if there is minimal residual stroma. However, it is not always easy to achieve the desired corneal dissection depth during lamellar corneal transplantation.

Anterior segment optical coherence tomography allows for rapid, noncontact, high-resolution imaging of the anterior segment. Intraoperative OCT imaging has been shown to be useful during Descemet stripping automated endothelial keratoplasty to detect the presence of interface fluid and assess the effect of the procedure and air tamponade on graft thickness.

De Benito-Llopis et al have utilised an optical coherence tomography (OCT) to visualise the depth of corneal dissection during deep lamellar keratoplasty. OCT is a quick and noncontact method that employs low-coherence interferometry to obtain cross-sectional images and pachymetric mapping of the cornea. The authors have used spectral-domain optical coherence tomography (SDOCT) in this study, which allows improved spatial resolution and minimises the effect of ocular movement during data acquisition. SDOCT has also been shown to have excellent repeatability for corneal thickness measurements. The current study by De Benito-Llopis et al demonstrates the ease and usefulness of an intraoperative SDOCT machine to monitor corneal thickness during DALK. The authors assessed whether the use of intraoperative OCT during DALK surgery could help reduce the risk for perforation during air injection and lamellar corneal dissection and, if OCT would be useful in cases with uneven residual stroma where the surgery is more complicated. The study found that the use of intraoperative OCT proved useful in various cases of DALK to help the surgeon decide various surgical steps. The OCT was useful in guiding manual dissection in cases of failed big bubble, ensuring a thin and even residual stromal bed in order to improve visual outcomes. It was also useful in cases of decreased visualisation under the operating microscope, where the image obtained with the OCT provided vital information to the surgeon.

The surgeons also reported shortcomings with the current model of the OCT machine. The surgery had to be interrupted in order to capture an image because the operating microscope had to be moved away to allow for the AS-OCT device to be placed over the eye. This caused a delay in the overall duration of the surgery.

The present study is an excellent
endeavour to utilise high-resolution corneal imaging intraoperatively. Further modifications in the design of the machine would hopefully allow a real-time capture of the ocular structures through an OCT attached to the operating microscope.
This would be tremendously useful in difficult cases requiring otherwise laborious corneal dissection.

Reference

Laura De Benito-Llopis; Jodhbirs S. Metha; Romesh I. Angunawela; Marcus Ang and Donald T.H. Tan. Intraoperative Anterior Segment Optical Coherence Tomography: A Novel Assessment Tool during Deep
Anterior Lamellar Keratoplasty; American Journal of Ophthalmology February 2014.

Long Term Looks Good for Implantable Collamer Lenses

An eight-year study has found that implantable collamer lens implantation for patients with moderate to high myopia is a viable surgical option.

This is believed to be the first study which takes into account patient outcomes over an eight year period (other studies have observed patients three, four and five years after surgery). The authors noted the long-term clinical study was “essential” because of the prevalence of this surgical procedure.

In patients treated for both high myopia and low to moderate myopia, posterior chamber phakic IOL using collamer lenses has been found to induce significantly fewer ocular higher order aberrations than wavefront-guided laser in situ keratomileusis (LASIK) and to significantly increase contrast sensitivity. Importantly, and unlike LASIK, implantations are largely reversible and lenses can be replaced in the case of unexpected refractive changes post-surgery.

The retrospective observational study analysed 41 eyes of consecutive patients who underwent implantation of the posterior phakic ICL (STAAR Surgical) to treat moderate to high myopia. Only one eye per subject was randomly selected using the envelope technique.

The study found all implantations were uneventful with no intraoperative complications. The authors wrote that the ICL implantations delivered “generally good outcomes in all measures of safety, efficacy, predictability and stability for the correction of moderate to high myopia throughout the long-term follow-up period”.

They noted a slight decrease in efficacy and predictability at eight years postoperatively with some eyes showing mild myopic regression. They reported “eight eyes showed axial elongations of more than 0.5 mm in eyes whose axial length was more than 27.5 mm” but concluded that “the longer preoperative axial length may result in a further increase in axial length, and thus can be one of the possible risk factors for long term myopic regression after this surgical technique”.

Only two of the 41 eyes examined developed clinically significant symptomatic cataracts eight years postoperatively, with these patients losing two or more lines in the CDVA. Both eyes successfully received simultaneous lens extraction and phacoemulsification with IOL implantation. The authors noted that the incidence of cataract formation was higher than in previous studies, possibly because of the longer observational period.

Endothelial cell loss was 6.2 per cent eight-years postoperatively, which they reported to be considerably lower than previous studies. “The differences in follow-up time, sample size, surgeon’s skill, or other patient background factors such as age, as well as the reproducibility obtained with a noncontact specular microscope may play roles in this discrepancy,” they wrote.

Comment
Laser in situ keratomileusis (LASIK) is the most commonly performed refractive surgery worldwide, although successful, alternatives to LASIK are constantly being sought in patients who are not suitable for this surgery. Phakic intraocular lenses (IOL) have been reported to be effective for the correction of moderate to high ametropia. The phakic IOLs induce significantly fewer ocular higher order aberrations than does wavefront-guided LASIK and significantly increases contrast sensitivity especially in the treatment of high myopia. There are few reports of long-term outcomes of phakic IOL implantation. In this article Igarashi et al report long-term (8-year) clinical outcomes of posterior phakic Implantable Collamer Lens (ICL) for the correction of moderate to high myopia in 41 eyes. In their study, the safety and efficacy indices were 1.13 ± 0.27 and 0.83 ± 0.36. At eight years, 68.3 per cent and 85.4 per cent of the eyes were within 0.5 and 1.0 D, respectively, of the targeted correction. Manifest refraction changes of – 0.32 ± 0.73 D occurred between one month and eight years. The mean endothelial cell loss from preoperative levels was 6.2 per cent at eight years. 9.8 per cent of the eyes developed asymptomatic anterior subcapsular cataracts, 9.8 per cent developed asymptomatic nuclear cataracts, of which half showed a drop and required cataract surgery.

The same group has published another study recently to evaluate the factors associated with regression after ICL implantation. The study found that with older age, a longer axial length, or both, the myopic regression of the initial surgical effect became significantly greater after ICL implantation. This may be related to an ongoing elongation of the axial length in high myopes. This may also be attributed to the formation of nuclear cataract which is associated with high myopia and/or with ICL surgery itself, especially in older patients.

Overall, the results of this study are encouraging in terms of visual outcomes. The main limitations are a retrospective design of the study and a small sample size. There is a lack of well-designed, long-term prospective trials in order to better understand the phenomenon of regression and complications associated with phakic IOL implantation. Clearly, the occurrence of cataract in the postoperative period is a concern. Further studies may be able to comment whether the current IOL designs can be modified to reduce the chances of cataract formation. The existing literature also does not report long-term data on use of toric phakic IOLs. However, the data is clinically useful for ophthalmologists to plan prospective clinical trials.

Reference

Akihito Igarashi, Kimiya Shimizu and Kazutaka Kamiya. Eight-Year Follow-up of Posterior Chamber Phakic. Intraocular Lens Implantation for Moderate to
High Myopia; American Journal of Ophthalmology
March 2014.

Attribution

Professor Rasik B Vajpayee received his Medical degree from the Gandhi medical College, Bhopal, India in 1981 where he also undertook his training in ophthalmology. He completed clinical fellowships in cornea and refractive surgery at the Royal Victorian Eye and Ear Hospital, Melbourne and the Massachusetts Eye and Ear Infirmary, Boston, USA.

Prof Vajpayee was Head of Cornea and Cataract Surgery at the University of Melbourne from 2006-2011 and recently acted as the Head of Corneal and Refractive Surgery Services at the RP Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi.