Thursday, August 9, 2007

Study criticism: "A cure for dry eye" (and a little editorializing about letters to the editor)

Few things in life give me so much pleasure as truly masterful use of language.

I admire it most when used for a constructive purpose. After all, it's easy and almost commonplace to be amusingly eloquent as a critic. Furthermore, caustic wit is usually directed at people, which I do not like witnessing.

Once in awhile, though, a critique of an issue or performance is so badly needed that when someone steps up to the plate and swings, there is great pleasure to be had in seeing the ball not merely struck square on and flying out of the park but making heavenly music as it soars. (Particularly pleasureable when contrasted to the worn-out tired old sports metaphors I slip into when I'm on a no-coffee kick.)

Anyway, this morning I experienced a mouth-wateringly beautiful specimen of this type of writing. It comes from the unlikely pen of a pediatric ophthalmologist.

Sandra Brown is a master of the genre of the Letter to the Editor of a peer-reviewed medical journal. Now, when I say master, I mean The Real Thing. I am not talking about just effectively pointing out the flaws of a study. I am not talking about unusually skillful manipulation of fact and language to prove a truly important point. I'm not even talking about the exercise of genius in content, style, wit and timing in addition to all the above. I'm talking about a breathtakingly concise musical arrangement, an articulation of exclusively relevant facts wielding linguistic scalpels with such deftness and delicacy that the artistry of it makes you laugh for joy. Dr. Brown has taken this craft to a level of unequalled sophistication.

But the beautiful part is that it's not the people who are targeted. Even those who come in for some collateral damage may remain mercifully untouched by the humiliation since the average reader even of a medical journal probably does not have the insider insights to appreciate each and ever needle - and in any case, the absence of emotion in Dr. Brown's tone seems to take some of the personal sting out of even the deepest of her needle jabs.

No. Dr. Brown's target is, as always, Bad Science. That's Bad Science with a capital B and a capital S.

I'm referring, of course, to "A Cure for Dry Eye" (Ophthalmology, August 2007).

The context: A study published in January's Ophthalmology which claimed that "Topical cyclosporine treatment appears to be associated with a cure of symptoms and signs in a subgroup of chronic dry eye patients".

Dear Editor:

I read with interest the recent article by Wilson and Perry describing 8 patients with dry eye syndrome who were cured "of symptoms and signs" after treatment with topical cyclosporine 0.05% (Restasis, Allergan Inc., Irvine, CA). In their Tables 2 and 3, the authors report objective findings (tear breakup time, Schirmer testing, vital dye staining) before and after treatment; these data support their conclusion that examination findings of dry eye resolved.

Their Table 1 gives patient demographics, including specific pretreatment symptoms. We are not given primary data regarding posttreatment symptoms or lack thereof; the authors declare in narrative that all subjects were symptom-free. However, clinicians know that patients who are miserable will arrive with a symptom list in hand; patients who are much improved and are satisfied with their current treatment may report "all better", which means that they do not feel the need to complain about low-grade and infrequent symptoms.

In general, journal editors and reviewers should require better science in the measurement of dry eye symptoms, now that simple, efficient, validated patient questionnaires are available (e.g. the Ocular Surface Disease Index, developed by Allergan). Despite the authors' national recognition as experts in the field of dry eye, readers are under no obligation to take their word for it that these unusual patients were entirely without symptoms after cyclosporine treatment. Further, the greater the perceived potential for investigator bias, the more carefully authors must defend their neutrality through excellent methodology in data collection and analysis.

My high school English teacher railed against the phrase very unique, as an object or event is either unique or it is not. Similarly, a patient is either improved or cured, and mostly improved is not cured. Cure is a potent word, and I do not believe the authors have proved their statement that topical cyclosporine cures symptoms of dry eye syndrome in a subgroup of patients.

Sandra M. Brown, MD
Concord, North Carolina


Ophthalmology, August 2007, p. 1585-1586

Wednesday, August 8, 2007

Study: What works best... plugs or Restasis or both?

Well, I'm glad we're seeing more comparative studies and I hope they continue. I also hope we see something soon with longer-term follow-up. I will put a new subscription to Cornea on my Christmas wishlist so I can learn more about the methods and drop-out rates used in studies like this.

I've probably missed some along the way but this is the first thing I recall seeing that specifically supports the use of plugs plus Restasis.

Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye.
Cornea. 2007 Aug;26(7):805-9
Roberts CW, Carniglia PE, Brazzo BG

In brief...

They both help, individually.
Together, they do better than either treatment individually.


ABSTRACT - from which I had to leave some parts out because this stupid blog software thinks that the >'s are HTML rather than "greater than" signs, grrr. If anybody knows how to get the blog to ignore it please let me know.

PURPOSE:: To compare the efficacy of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. METHODS:: Patients with dry eye (N = 30) seen in a university-affiliated private practice were randomized to 1 of 3 treatments: cyclosporine 0.05% ophthalmic emulsion (RESTASIS) twice daily, lower-lid punctal plugs (PARASOL), or a plugs-cyclosporine combination. Tear volume, ocular surface staining, and artificial tear use were assessed at baseline and 1, 3, and 6 months. RESULTS:: All treatments improved Schirmer scores by 6 months..., with plug-containing regimens favored at 1 and 3 months (P < 0.001 vs. cyclosporine alone). Cyclosporine-containing regimens, but not plugs alone, improved rose bengal staining at 3 and 6 months.... Artificial tear use decreased with plug-containing regimens at 1 month and with all treatments at 3 and 6 months.... Combination therapy produced the greatest overall improvements and was superior to plugs alone in decreasing artificial tear use at 6 months.... CONCLUSIONS:: All 3 regimens effectively treated dry eye. Plug-containing regimens increased wetness initially; cyclosporine appeared to promote long-term ocular surface health. The effects may be additive. Patients with punctal occlusion may benefit from adjunctive cyclosporine.

Study: Variation on the autologous serum theme...

An interesting possibility for graft-vs-host-disease patients who cannot use regular serum drops:

Allogeneic serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease.
Chiang CC, Lin JM, Chen WL, Tsai YY.
Cornea. 2007 Aug;26(7):861-3.

Abstract (my highlight):

PURPOSE:: To describe the use of allogeneic serum eye drops to treat 2 patients with chronic graft-versus-host disease (GVHD)-induced severe ocular surface disease. METHODS:: Small case series. RESULTS:: Conventional therapy failed to control the ocular symptoms of 2 patients with GVHD who presented with severe dry eye syndrome. Because autologous serum was unavailable in these cases, we used allogeneic serum eye drops as an alternate option for treating their ocular surface disease. Both donors had serologic tests performed before donation. Use of the allogeneic serum eye drops had a beneficial clinical effect, with marked attenuation of the patients' symptoms. This therapy proved to be safe during 10 months of treatment. CONCLUSIONS:: Allogeneic serum eye drops may be a good alternative treatment for patients with severe dry eyes caused by GVHD.

Study: Carbamazepine and dry eye

A case study was reported of an instance of squamous metaplasia blamed on oral carbamazepine, which also goes under the names Carbitrol, Epitol and Tegretol.

It's an anticonvulsant and is used in treating many mental illnesses including bi-polar; seizure disorders; neuralgia; and alcohol withdrawal. People considering or already using this drug may want to take note especially if they already have risk factors for dry eye or are already suffering from dry eye.

Impression cytology of a case of conjunctival metaplasia associated with oral carbamazepine use?
Cont Lens Anterior Eye, Aug 2007
Doughty MJ, McIntosh M, McFadden S, Button NF


PURPOSE: To report a case of conjunctival squamous metaplasia associated with oral carbamazepine use. METHODS: Following completion of an ocular comfort questionnaire, biomicroscopy and a phenol red thread test, impression cytology from the inter-palpebral zone (nasal) of the bulbar conjunctival surface was undertaken using a Millcell((R))-CM filter after topical anaesthesia with oxybuprocaine 0.4%. The filter was stained with Giemsa and colour images taken at 400x magnification by light microscopy. The images were graded and also a 35mm was prepared. From the projected image, an overlay method was used to outline the borders such that the cell and nucleus area, and the longest and shortest dimensions could be measured by planimetry. RESULTS: A male subject, added 22 years, presented with slight conjunctival injection but no substantial symptoms and only slight surface staining with fluorescein. The subject reported use of oral carbamazepine (200mg, b.d.s.). Impression cytology showed large sheets of squamous cells (grade 2-3) with few goblet cells. The average cell area was 1509mum(2), the long:short dimension ration averaged 1.42 and the average nucleus/cytoplasm (N/C) value was just 0.092 (or 1:11.5 as a ratio). CONCLUSIONS: Since the drug has been reported to be excreted in the tear film, and with no other risk factors (such as contact lens wear, smoking or dry eye disease), the squamous metaplasia is attributed to the use of carbamazepine.

Study: Ocular manifestations of lupus

Ocular manifestations of systemic lupus erythematosus.
Rheumatology (Oxford), Aug 2007, Sivaraj RR, Durrani OM, Denniston AK, Murray PI, Gordon C.

I like seeing this highlighted in the professional literature for rheumatology. Lupus patients with dry eye might not be impressed with the suggestion that their dry eyes can be managed with topical drops, however.

Abstract (highlighting mine)

Ocular manifestations of lupus are fairly common, may be the presenting feature of the disease and can be sight-threatening. Almost any part of the eye and visual pathway can be affected by inflammatory or thrombotic processes. Ocular pain and visual impairment require urgent assessment by an ophthalmologist. Infection should be excluded. Optic neuritis and ischaemic optic neuropathy may be difficult to distinguish. Scleritis and severe retinopathy require systemic immunosuppression but episcleritis, anterior uveitis and dry eyes can usually be managed with local eye drops. Vaso-occlusive disease, particularly in the presence of antiphospholipid antibodies, requires treatment with anticoagulation and proliferative retinopathy is treated with laser therapy. Hydroxychloroquine rarely causes ocular toxicity at doses under 6.5mg/kg/day. When this has occurred, it has been associated with more than 5 years of drug exposure.

Tuesday, August 7, 2007

Newsclip: Kids and computer vision syndrome

Given the sharp rise in dry eye complaints among children and young adults I was very pleased to see this press release by the American Optometric Association in anticipation of the new school year starting:

Computer Vision Syndrome Threatens Returning Students
August 7 - St. Louis

The American Optometric Association (AOA) today warned that children heading back to school are at risk for developing Computer Vision Syndrome, which leaves them vulnerable to problems like dry eye, eyestrain and fatigue. According to VSP Vision Care, nearly half of U.S. children spend four hours a day or more using computers or other portable electronic devices....


The AOA identified several specific risks to children (in addition to the obvious like the very high number of hours per day the average kid spends glued to a screen of some kind) - including an interesting one about how children often have to look up at a computer screen rather than - as is best - slightly downwards.

Monday, August 6, 2007

Corporate news: AMO withdraws offer for B&L

Yikes, not sure how I missed this last week. So, I guess Soothe will be a B&L drop at least for a while!

August 1, 2007 - Wall Street Journal

Advanced Medical Withdraws Bausch Bid

The withdrawal came after Bausch said yesterday that its board decided not to grant Advanced Medical time beyond a Friday deadline to persuade its shareholders to support its $4.3 billion takeover bid. Some of Advanced Medical's largest shareholders have opposed the offer, spurring Bausch's board to express concern that Advanced Medical wouldn't be able to muster support from its holders.