Thursday, January 17, 2013

Top dry eye publishers

According to Citation analysis of the dry eye literature recently published in The Ocular Surface, the winners are...

KAZUO TSUBOTA (Keio University, Tokyo) has published the most studies on dry eye. We owe him a great deal - among other things for being instrumental in making autologous serum the treatment it is today.

HARVARD has been the home base of the most studies published on dry eye. And while I haven't actually tried to run the numbers myself, I would guess it's safe to assume a large proportion of that is David Sullivan's doing. Thank you!

INVESTIGATIVE OPHTHALMOLOGY AND VISUAL SCIENCE is the peer-reviewed journal that has published the most on dry eye. I knew I liked them for a reason - though it's the quality not the quantity that I've always admired.

Ocul Surf. 2013 Jan;11(1):35-46. doi: 10.1016/j.jtos.2012.08.004. Epub 2012 Aug 11. Nichols JJ.

Abstract: The plug hunt goes on...

Potential plug-ees take note.... 

To investigate the retention rate and complications of 2 different types of silicon lacrimal punctal plugs with the focus on the relationship to punctum size.

Don't forget there are umpteen on the market. 

A prospective, nonrandomized, interventional, comparative study.
Forty-four patients with dry eye syndrome received lacrimal punctal plug insertion with the Punctal Plug F (FCI Ophthalmics) and 30 patients received plug insertion with the Super Flex plug (Eagle Vision; Softplug-Oasis Medical Inc). In total, 110 plug insertion regions were performed using the Punctal Plug F (group A) and 110 insertion regions were carried out using Super Flex plug (group B). The gauging system of Eagle Vision was used before the lacrimal punctal plug insertion in all subjects. Plug conditions (retention rates, spontaneous plug loss, and removal) and complications related to lacrimal punctal sizes were compared between the 2 groups.
Retention rates were 70.4% in group A and 30.1% in group B at 6 months. Spontaneous plug loss occurrence was significant with the larger lacrimal punctum size in group A (P < .05), whereas no significant differences were observed between lacrimal punctum sizes and spontaneous loss in group B. Spontaneous plug loss occurrence was significant in elderly patients in group B (P < .05). Granuloma and injector troubles were observed in 1 and 2 cases in group A, respectively.

Those retention rates stink. BOTH of them. 

Don't be distracted by the 30% which is obviously ridiculous. If an entire group of patients averaged 70% retention, well geez, almost every second person lost a plug. And these things are casually referred to as "permanent".

Make sure your doctor knows how to size people for plugs and has more than two brands to choose from, that's all I can say. And definitely ask who pays to replace them if they fall out.
The Punctal Plug F seems to be more applicable for insertion into the smaller punctal sizes. Punctum size and age seem to be important factors in determining the appropriate types of lacrimal punctal plugs.
J Ophthalmol. 2013 Jan 11. pii: S0002-9394(12)00769-6. doi: 10.1016/j.ajo.2012.10.024. [Epub ahead of print]
Lacrimal Punctal Plugs in the Treatment of Dry Eye Disease.
Kaido M, Ishida R, Dogru M, Tsubota K.
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; Wada Eye Clinic, Chiba, Japan. Electronic address:

Abstract: Blood vessels & nerves at cross purposes?

Fascinating study from my favorite journal, IOVS.

It's a mouse study, and the protein acronym babble is always way over my head, but the basic concept I've never come across before. And...
RESULTS: No nerves were detected in the areas subject to corneal neovascularization,
is plain enough English and it sounds like things ricocheted downhill from there. I will definitely follow up on this one if/when I get ahold of a copy of the full study. I want to know what happened to the mice where they messed with the trigeminal nerve.

to evaluate the regulatory cross talk of the vascular and neural networks in the cornea.
b-FGF micropellets (80ng) were implanted in the temporal side of the cornea of healthy C57Bl/6 mice. On day seven, blood vessels (hemangiogenesis) and nerves were observed by immunofluorescence staining of corneal flat mounts. The next group of mice underwent either trigeminal stereotactic electrolysis (TSE), or sham operation, to ablate the ophthalmic branch of the trigeminal nerve. Blood vessel growth was detected by immunohistochemistry for PECAM-1 (CD31) following surgery. In another set of mice following TSE or sham operation corneas were harvested for ELISA (VEGFR3 and Pigment Epithelium Derived Factor: PEDF) and for quantitative RT-PCR (VEGFR3, PEDF and CD45). PEDF, VEGFR3, beta 3-tubulin, CD45, CD11b and F4/80 expression in the cornea were evaluated using immunostaining.
 RESULTS: No nerves were detected in the areas subject to corneal neovascularization, while they persisted in the areas that were neovessel-free. Conversely, seven days after denervation, significant angiogenesis was detected in the cornea, and this was associated with a significant decrease in VEGFR3 (57.5% reduction, P = 0.001) and PEDF protein expression (64% reduction, P < 0.001). Immunostaining also showed reduced expression of VEGFR3 and PEDF expression in the normal corneal epithelial layer. Finally, an inflammatory cell infiltrate including macrophages was observed.
 Conclusion: Our data suggest that sensory nerves and neovessels inhibit each other in the cornea. When vessel growth is stimulated, nerves disappear and, conversely, denervation induces angiogenesis. This phenomenon, here described in the eye, may have far reaching implications in understanding angiogenesis.

Invest Ophthalmol Vis Sci. 2013 Jan 10. pii: iovs.11-8379v1. doi: 10.1167/iovs.11-8379. [Epub ahead of print] Ferrari G, Hajrasouliha AR, Sadrai ZP, Ueno H, Chauhan SK, Dana R.
Ophthalmology - Cornea and Ocular Surface Unit - Eye Repair, San Raffaele Scientific Institute, Via Olgettina, 60, Milan, Italy.

Abstract: Restasis and SJS (shudder)


But I like how simply it's all put in the abstract. To dumb it down even further....

The ones it was helping (about half) stuck with it for the whole six months. (We don't know if they continued after that.)

The ones it was hurting (about a quarter) dropped out. So did others for reasons we don't know.

Conclusion: It "might" help.

She loves me, she loves me not....

To evaluate the efficacy of cyclosporine 0.05% (CsA) eye drops in patients with Stevens Johnson syndrome (SJS) who had chronic dry eye.
Prospective noncomparative interventional case series.
Thirty cases of SJS patients who developed dry eye defined by symptoms and signs, including the Schirmer I test, the fluorescein clearance test (FCT), and corneal staining (fluorescein and Rose Bengal staining) were treated with CsA 0.05% eye drops twice daily for 6 months. Dry eye symptoms, eye injection, tear break up time (TBUT), and corneal staining were evaluated before and after the treatment at 0, 2, 4, and 6 months. The Shirmer I test and FCT were evaluated at 0 and 6 months.
Seventeen patients (56.67%) completed the study. Eight patients (26.67%) withdrew from the study as a result of intolerable side effects of CsA, which included pain, redness, and eyelid swelling. Five cases were lost in follow up. All 17 cases demonstrated significant improvement in dry eye symptoms, conjunctival injection, corneal staining, Schirmer I test, and FCT (P<0 .05=".05" o:p="o:p"> 
Conclusions: CsA 0.05% eye drops might be beneficial in the treatment of chronic dry eye associated with SJS.

J Ocul Pharmacol Ther. 2013 Jan 5. [Epub ahead of print]
Prabhasawat P, Tesavibul N, Karnchanachetanee C, Kasemson S.
Department of Ophthalmology, Faculty of Medicine, Siriraj Hospital, Mahidol University , Bangkok, Thailand .

Abstract: Moist cool air device

That's right, lead us to water but don't let us... mist our eyes.

C'mon, can't somebody please cough up the name of this "new device"?

It's actually quite nice to see any non medical devices studies. But why doesn't anybody ever study moisture chamber glasses. Because no optical manufacturers will cough up the dough to sponsor it? Say it isn't so (where's that mildly sarcastic emoticon when I need it).

Purpose:To evaluate the efficacy and safety of new moist cool air device (MCAD) for ocular symptoms, tear film stability and ocular surface status in office workers with dry eye disease (DED).
 Methods:In this prospective single-centre clinical trial, 40 eyes of 20 patients with DED were recruited and randomly divided into two groups (group with MCAD exposure and group without MCAD). All subjects are visual display terminals (VDTs) workers spending at least 4h/day in front of VDTs. Patients using MCAD underwent moist air applications for 4h/day for a total of five working weekdays during VDT works at their offices. The other group of patients performed their VDT work without moist cool air device exposure. The change in symptoms of ocular surface (OS) dryness, fatigue and discomfort was evaluated using visual analogue scale (VAS) scores. Changes in visual function, tear functions and ocular surface status were evaluated using best-corrected visual acuity (BCVA), the functional visual acuity (FVA) test, blink rate, BUT measurements, strip meniscometry (SM), tear evaporation rate, fluorescein staining and rose bengal staining scores. Tear film lipid layer interferometry was also performed to assess the status of the lipid layer over the tear film. In addition, adverse events were recorded.
 Results:In group with MCAD, symptoms of OS dryness during VDTs work, and FVA and BUT were significantly improved. SM and tear evaporation rate were significantly improved. There were no statistically significant differences on lipid layer stability and corneal staining scores in both groups. Blink rate was significantly increased in group without MCAD. No adverse events were reported during this trial.
Moist cool air device use provided symptomatic relief of ocular dryness and improvement on tear stability in office workers with DED. This new device seems to be a safe and promising alternative in the treatment of DED.

Hirayama M, Murat D, Liu Y, Kojima T, Kawakita T, Tsubota K.
Acta Ophthalmol. 2012 Dec 24. doi: 10.1111/j.1755-3768.2012.02485.x. [Epub ahead of print]
Department of Ophthalmology, School of Medicine, Keio University, Tokyo, Japan Minami-Aoyama Eye Clinic, Tokyo, Japan.

Abstract: Signs vs symptoms... let's put this one to bed already!

Ooooh lovely. See complete abstract below for condensed version documentation of the age-old sign vs symptom discrepancy, from some of my favorite drs/researchers.

Jumping ahead to the conclusion, for those like me who are too lazy to read:
Conclusions:No consistent relationship was found between common signs and symptoms of DED. 

How can we argue with that... supported, as it is, by everything from common sense to years of research and published studies (because let's be honest, for every study that purports to infallibly associate thus-and-such sign with any one or all symptoms, there's another that contradicts it).

Yet there are SO many things that OUGHT to be altered by accepting this as established fact or as good as. 

For example... How can the FDA insist on improving both signs and symptoms to the extent they do, thus barring so many therapies that could help people with severe disease? 

Or... How can general ophthalmologists dole out Restasis prescriptions like candy to anybody who walks in the door complaining of gritty eyes? Can somebody please educate these guys?

Or... Why must we continue treating people with few-to-no clinical signs but with severe pain or other symptoms as though they really did have severe dry eye when they don't, allowing or encouraging them to try every drug, device or surgery available, postponing the inevitable conclusion that there's nerve pain issues involved and re-directing their pursuits to palliative treatments till better able to diagnose & treat the real pathology?

And the list goes on. We know now and we always have known that signs and symptoms don't correlate. What are we going to DO about it, is what I want to know!

Purpose:To evaluate the relationship between signs and symptoms of dry eye disease (DED) in a clinic-based population.
 Methods:In a retrospective analysis, clinical signs and symptoms were evaluated for 344 subjects (n=82, normal; n=263, dry eye), across 11 sites from the EU and United States. Pearson correlations between signs and symptoms (r(2) ) and an independent components analysis (ICA) mixing matrix were derived from the data set. Similar analysis was performed on an independent data set from 200 subjects in a previous study in Munich, Germany.
 Results:No correlations above r(2) =0.17 were found between any signs and symptoms, except for corneal and conjunctival staining, which reported an r(2) =0.36. In the multisite study, the average r(2) for osmolarity (0.07), tear breakup time (0.12), Schirmer test (0.09), corneal (0.16) and conjunctival staining (0.17), meibomian grading (0.11) and Ocular Surface Disease Index(®) (0.11) were consistently low. Among patients who showed evidence of DED by consensus of clinical signs, only 57% reported symptoms consistent with a diagnosis of DED. Similar results were observed in the Munich-based study data set. Each component of the ICA mixing matrix exhibited minimal residual information.
 Conclusions:No consistent relationship was found between common signs and symptoms of DED. Each type of measurement provides distinct information about the condition of the ocular surface. These results also demonstrate that symptoms alone are insufficient for the diagnosis and management of DED and argue for a consensus of clinical signs that better reflect all aspects of the disease.
Acta Ophthalmol. 2012 Dec 28. doi: 10.1111/aos.12012. [Epub ahead of print]
Sullivan BD, Crews LA, Messmer EM, Foulks GN, Nichols KK, Baenninger P, Geerling G, Figueiredo F, Lemp MA.
TearLab Corporation, San Diego, California, USA Department of Ophthalmology, Ludwig Maximilian University, Munich, Germany Kentucky Lions Eye Center, University of Louisville, Louisville, Kentucky, USA College of Optometry, University of Houston, Houston, Texas, USA Royal Victoria Infirmary & Newcastle University, Newcastle Upon Tyne, England Department of Ophthalmology, University of Dusseldorf, Germany Department of Ophthalmology, Georgetown University, Washington, District of Columbia, USA Department of Ophthalmology, George Washington University, Washington, District of Columbia, USA.

p.s. THANK YOU to whoever typed and edited that abstract for putting spaces after the equal signs. Helps to not give my dinosaur blog display the verbal diarrhea these symbols tend to trigger.

Abstract: Mucin deficiency

Mucous... the element we're always ignoring because there's so little we know about what to do about it.

MUC5AC is the most abundant gel-forming mucin in the ocular system. However, the specific function is unknown. In the present study, a Muc5ac knockout (KO) mouse model was subject to various physiological measurements as compared to its wide-type (WT) control. Interestingly, when KO mice were compared to WT mice, the mean tear break up time (TBUT) values were significantly lower and corneal fluorescein staining scores were significantly higher. But the tear volume was not changed. Despite the lack of Muc5ac expression in the conjunctiva of KO mice, Muc5b expression was significantly increased in these mice. Corneal opacification, varying in location and severity, was found in a few KO mice but not in WT mice. The present results suggest a significant difference in the quality, but not the quantity, of tear fluid in the KO mice compared to WT mice. Dry eye disease is multifactorial and therefore further evaluation of the varying components of the tear film, lacrimal unit and corneal structure of these KO mice may help elucidate the role of mucins in dry eye disease. Because Muc5ac knockout mice have clinical features of dry eye, this mouse model will be extremely useful for further studies regarding the pathophysiology of the ocular surface in dry eye in humans.

Floyd AM, Zhou X, Evans C, Rompala OJ, Zhu L, Wang M, Chen Y.
PLoS One. 2012;7(12):e50704. doi: 10.1371/journal.pone.0050704. Epub 2012 Dec 18.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, United States of America ; Department of Ophthalmology and Vision Science, College of Medicine, University of Arizona, Tucson, Arizona, United States of America.

Abstract: LPRR4, another potential DES biomarker

Dry eye syndrome (DES) is a complex, multifactorial, immune-associated disorder of the tear and ocular surface. DES with a high prevalence world over needs identification of potential biomarkers so as to understand not only the disease mechanism but also to identify drug targets. In this study we looked for differentially expressed proteins in tear samples of DES to arrive at characteristic biomarkers. As part of a prospective case-control study, tear specimen were collected using Schirmer strips from 129 dry eye cases and 73 age matched controls. 2D electrophoresis (2DE) and Differential gel electrophoresis (DIGE) was done to identify differentially expressed proteins. One of the differentially expressed protein in DES is lacrimal proline rich 4 protein (LPRR4). LPRR4 protein expression was quantified by enzyme immune sorbent assay (ELISA). LPRR4 was down regulated significantly in all types of dry eye cases, correlating with the disease severity as measured by clinical investigations. Further characterization of the protein is required to assess its therapeutic potential in DES.

PLoS One. 2012;7(12):e51979. doi: 10.1371/journal.pone.0051979. Epub 2012 Dec 18.
Aluru SV, Agarwal S, Srinivasan B, Iyer GK, Rajappa SM, Tatu U, Padmanabhan P, Subramanian N, Narayanasamy A.
Biochemistry and Cell Biology Department, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamilnadu, India.