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Medical Forum / General / Vision / March 2006I could use some brainstorming - when dry eye isn't
As many of you know, I was using cycloplegia daily for about 6yrs to control ciliary spasm. Toward the end, I was using Atropine BID. In 8/04, Dr. Melvin Rubin ("The Fine Art of Prescribing Glasses") advised me that the preservative, Benzalkonium Chloride, was cytotoxic to corneas and that I should cease using cycloplegics. I did. Unable to keep the spasm at bay, I was declared disabled from work. I've been trying to pursue life at a distance, limiting my near work and maximizing my running, biking, hiking, travel, etc. But the dry eye is worse than ever. During the six years of cycloplegic use, I watched my eyes go from subclinical dry eye (or not at all) to lower punctal plugs to upper punctal plugs to full cautery. The situation got precipitously worse. As I began to look into the BAK thing, it became abundantly clear that BAK can, indeed, INDUCE dry eye, dramatically reducing T-BUT I've been seen by a few dry eye specialists, including one yesterday at Southern California College of Optometry, Dr. Jerry Paugh. Dr. Paugh sees all of the telltale signs of dry eye (corneal and conjunctival staining via rose bengal and fluorescein), but got reasonable Schirmer's numbers and /reasonable/ tear meniscus numbers. He sees fairly normal meibomian gland function with minimal frothing/foaming (?). T-BUT, however, was ~3s. I go back next week--off the drops, ointments, supplements, contact lenses, etc. for another go. He is at a loss as to the etiology, but thinks that the meticulous care that I'm taking (drops, cautery, supplements, ointments, Lacriserts, wraparound glasses, avoidance, etc.) may be the only thing that's keeping infection, SPK, and the like at bay. Doesn't see markers of inflammation that would lead him to prescribe steroids or Restasis. I have to believe it's the BAK. Everything fits (see below). But....any other possibilities to consider?? TIA, Neil -------- CITES (in case anecdotal evidence isn't automatically persuasive): -------- EFFECTS OF BAK ON CORNEAS 1. Toxic endothelial cell destruction from intraocular benzalkonium chloride a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 1709246&dopt=Abstract 2. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro a. http://www.ingentaconnect.com/content/bsc/ceo/2004/00000032/00000002/art00013 3. Evaluation of the Corneal Effects of Topical Ophthalmic Fluoroquinolones Using In Vivo Confocal Microscopy a. http://snipurl.com/kkut 4. Influence of cyclosporin A, dexamethasone, and benzalkonium chloride (BAK) on corneal epithelial wound healing in the rabbit and guinea pig eye a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3 843318&dopt=Citation 5. Comparison of the Short-Term Effects on the Human Corneal Surface of Topical Timolol Maleate With and Without Benzalkonium Chloride a. http://snipurl.com/km0n 6. Confocal microscopic studies of living rabbit cornea treated with benzalkonium chloride a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 587129&dopt=Abstract 7. Clinical tolerance of antiglaucoma eyedrops with and without a preservative a. http://snipurl.com/kn4m 8. Preservative cytotoxicity to cultured corneal epithelial cells a. http://snipurl.com/kn4o 9. Cytotoxicity of ophthalmic preservatives on human corneal epithelium a. http://snipurl.com/kn4s 10. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro a. http://snipurl.com/kqyy 11. The effects of ophthalmic drugs, vehicles, and preservatives on corneal epithelium: a scanning electron microscope study a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 262158&dopt=Abstract 12. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1 630776&dopt=Citation 13. Effect of timolol with and without preservative on the basal tear turnover in glaucoma a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=7742279&query_hl=20&itool=pubmed_docsum 14. Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=8034210&query_hl=20&itool=pubmed_docsum 15. Iatrogenic dry eye: late effect of topical steroid formulations a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=1460313&query_hl=20&itool=pubmed_docsum 16. Quantitative evaluation of the corneal epithelial barrier: effect of artificial tears and preservatives a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=1914501&query_hl=20&itool=pubmed_docsum 17. Influence of artificial tears on corneal epithelium in dry-eye syndrome a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=2721982&query_hl=20&itool=pubmed_docsum 18. The effects of topical drugs and preservatives on the tears and corneal epithelium in dry eye a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=3898475&query_hl=20&itool=pubmed_docsum 19. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=10067965&query_hl=4&itool=pubmed_docsum 20. Pre-clinical investigation of the efficacy of an artificial tear solution containing hydroxypropyl-guar as a gelling agent a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15512952&query_hl=9&itool=pubmed_docsum 21. Relationship between in vitro toxicity of benzalkonium chloride (BAC) and preservative-induced dry eye a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=12613979&query_hl=9&itool=pubmed_docsum 22. Cytoprotective effects of hyaluronic acid and Carbomer 934P in ocular surface epithelial cells a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=12407150&query_hl=9&itool=pubmed_docsum 23. Air pollutants and tear film stability--a method for experimental evaluation a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=11380526&query_hl=9&itool=pubmed_docsum 24. Prolonged adverse effects of benzalkonium chloride and sodium dodecyl sulfate in a primary culture system of rabbit corneal epithelial cells a. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8 812229&dopt=Abstract b.  SignatureLive simply so that others may simply live You do not have to show the signs of in inflammatory process to benefit from Restasis. As a matter of fact, the literature from Allergan from their clinical investigations show that they simply don't know what the "true" mechanism of action of cytosporine. You should run a 30 day trial of Restasis twice daily and wait for your body's subjective response. Damn, I can't spell on the fly. That was cyclosporine. >Damn, I can't spell on the fly. That was cyclosporine. I gotcha. I'll talk with the doc about it next week. I've been through two restasis trials in the past, though--six months each time--with no clear improvement. Maybe things are different this time. Thanks again.... SignatureLive simply so that others may simply live > >Damn, I can't spell on the fly. That was cyclosporine. > [quoted text clipped - 5 lines] > > Thanks again.... Were you off the BAK at the time of the Restasis trial? If so, then 6 months of Restasis pretty much addresses the issue of whether or not that is an appropriate treatment, eh? Did your research indicate permanent lacrimal system affects from BAK? Permanent cornea nerve de-innervation? (How is your cornea sensitivity? If the nerves don't connect to signal dryness, then the lacrimal system wont repond.) If not, then an attempt at anti-inflamatory/cyclosporin trial is reasonable. One protocol many find effective is: one week of high potency steroid, then second through tapering off by 6th week of low potency/ dose steroid, Restasis beginning second week. The thinking is of rapid anti-inflammatory response while waiting for the Restasis to kick in. Meanwhile, have a written report of your situation and hypothisis in hand next time you're at the SCCO clinic and ask that the case be presented to one of the profs there. There are two or three who are pretty up on cornea/anterior segment disorders. Hey, maybe you'll make the "Some Favorite Cases" segment in the continuing ed program next weekend! I may even be there! Best, (but I actually mean it) LB, O.D. Great post, as usual,Doc. I have read that Restasis is the first of 4 meds that are going through the FDA approval process for thw treatment of dry eyes. When these meds hit the market I hope more of our colleagues treat dry eye as a true pathology (which it is) and not just a nuisance side effect of aging and allergy. Dr. B- I responded via e-mail last night, thinking I'd have left for a weekend vacation by now ;-) Thanks much. Good to have you dropping in again/still. SignatureLive simply so that others may simply live Neil, I hate to say this, but I have to reject your hypothesis. BAK is present in most topical eye medications, including drugs that are used on a chronic basis for many years, such as glaucoma medications. BAK cytotoxicity is dose-dependent. You were using the atropine q.d. for a number of years, and never more than twice daily, which is the same dosing as topical glaucoma medications. Yet, most patients with glaucoma tolerate their medications fairly well. BAK got a really bad rap with contact lens solutions because the chemical became concentrated on the lens surface, exposing the cornea over a much longer period. It also got a really bad rap when used as a preservative in viscoelastic solutions used in cataract surgery due to toxicity to the endothelial cells. Unlike the epithelium, endothelial cells are not replaced. It is possible that the cause of your dry eye is totally independent of the BAK, and due to permanent anticholinergic effects. Long-term use of atropine has been known to cause accommodative paralysis. It may be the case that molecules of atropine are still sitting on the receptor sites of some of the accessory tear glands. DrG http://www.coppellfamilyeyecare.com >Neil, I hate to say this, but I have to reject your hypothesis. I'm equally eager to have it (rejected or) replaced as I am to have it confirmed.... >BAK is present in most topical eye medications, including drugs that >are used on a chronic basis for many years, such as glaucoma [quoted text clipped - 8 lines] >toxicity to the endothelial cells. Unlike the epithelium, endothelial >cells are not replaced. (trying to run out of here, but...) I found another few cites last evening that are intriguing: 1) The cationic detergent and quaternary ammonium compound benzalkonium chloride (BAK) is especially damaging to the ocular epithelium. BAK emulsifies the cell membrane lipids and breaks down their intercellular junctions (Calonge). The use of preserved artificial tears in patients with closed puncta causes increased damage to the ocular surface due to the longer contact time (decreased tear clearance) and undiluted preservative build-up. [1] [during the vast majority of the time that I used BAK, I had either full plugs or full cautery] 2) The most widely used preservative, benzalkonium chloride (BAC), is retained within epithelial cell membranes for several days. High concentrations of this cationic detergent lead to cell necrosis, whereas concentrations as low as 0.0001% induce growth arrest and apoptotic cell death. [2] If the qd use of cycloplegics was /always/ last thing before bedtime (because of the pain on instillation and how debilitated I was when cycloplegia set in), then the drops--coupled with cautery--had no place to go.... As my primary care ophthalmologist continually reminds me, "Your eyes break all the rules." >It is possible that the cause of your dry eye is totally independent of >the BAK, and due to permanent anticholinergic effects. Long-term use >of atropine has been known to cause accommodative paralysis. It may be >the case that molecules of atropine are still sitting on the receptor >sites of some of the accessory tear glands. I'd welcome accommodative paralysis with open arms. In fact, my docs continue to consider a monofocal IOL procedure /if/ we can control the dry eye. I'm trying to get in to see Dr. Pflugfelder. My concern at the moment is some reasonably definitive diagnosis that will inform a narrowly focused course of treatment. Throwing the kitchen sink at my eyes may not have always helped me. Thanks, as always, Dr. G. [1] http://www.clsa.info/ContinuingEducation/pdf/ew_2q_02_article1.pdf [2] http://www.iovs.org/cgi/content/full/42/5/948 SignatureLive simply so that others may simply live > 1) The cationic detergent and quaternary ammonium compound > benzalkonium chloride (BAK) is especially damaging to the ocular [quoted text clipped - 6 lines] > [during the vast majority of the time that I used BAK, I had either > full plugs or full cautery] More evidence, then, to reject the BAK hypothesis, since the effects apparently were not cumulative. > 2) The most widely used preservative, benzalkonium chloride (BAC), is > retained within epithelial cell membranes for several days. High > concentrations of this cationic detergent lead to cell necrosis, > whereas concentrations as low as 0.0001% induce growth arrest and > apoptotic cell death. [2] Epithelial cells are rapidly replaced. Besides, you apparently don't have one of the hallmarks of BAK toxicity, which is SPK. > I'd welcome accommodative paralysis with open arms. In fact, my docs > continue to consider a monofocal IOL procedure /if/ we can control the > dry eye. The fact that you don't have accommodative paralysis does not mitigate against atropine toxicity on a different level. > I'm trying to get in to see Dr. Pflugfelder. My concern at the moment > is some reasonably definitive diagnosis that will inform a narrowly > focused course of treatment. Throwing the kitchen sink at my eyes may > not have always helped me. Shouldn't have hurt, either. DrG [snip] Very valid points, all, of course. Wednesday was the f/u app't. One week sans cl's, no drops, no fish/flax seed/cod liver supp's, no nightly ointments, etc. Cold turkey. Won $ at Vegas, but it was a pyrrhic victory.... Doc sees virtually identical corneal and conjunctival staining, good Schirmer's, 3s t-buts, despite rainy morning and absolutely -0- air moving in the exam room. Assumes tbut must drop down to -0- with wind, dry air, pollution, dust, etc. Interferometry looks good. Meibography looks good. MGs seem to work just fine. He's still stumped re: serious instability of tear film. Doesn't see a reason to try steroids or Restasis. Recommends I stay the course on the palliative treatments and check back in six months. Hmm. Still thinking about this. I'll surf around to see what Atropine toxicity looks like. I'm also trying to understand more about BAK toxicity. I've certainly found citations that explain what the superficial damage from BAK looks like, but: 1) I've never seen anything that studies LONG-term use. Perhaps the superficial problems DO self-repair. I'm curious whether there's potential--over years--to decimate the healing mechanism; 2) Most of the studies use steroid or lubricant drops which likely have a mild buffering effect; 3) The literature points to more frequent, more severe problems in existing dry eye Pts, which, perhaps, I was; Question: When you evaluate DES Pts over time, do you see differing levels of staining, and in different parts of the cornea/conjunctiva? In other words, is the staining static or variable? My staining--at least in these first two visits--seems not to have changed at all; I also talked with the doc about Hyaluronic Acid--a recommendation from my ophthalmologist. I'm trying to score some in 3-4% concentration. Not easy. Anybody have any experience with this alleged ambrosia?? TIA, Neil |
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