Perhaps we’re imagining things, but there seems to be a correlation between the information overload of our increasingly wired world and the burgeoning popularity of complementary and alternative medicines, or CAM. Like it or not, filtering through the case reports, testimonials and even controlled studies on non-traditional therapies has become a necessary part of ophthalmology. Even if we never prescribe a single herbal extract, patients are employing them at an ever-increasing rate so, at a minimum, we need to beaware of the adverse effects and potential interactions between these CAM treatments and conventional therapies.
The subject of alternative pharmacotherapy elicits strong emotions and opinions from both its proponents and its skeptics. While much of the literature supporting use of alternative medicines doesn’t meet the standard of evidence-based medicine we have come to expect, these treatments cannot simply be ignored as modern equivalents of snake oil. In this month’s column, we’ll consider examples of the alternative treatments recommended for ocular disorders. In many cases we fi nd good scientifi c rationale (if not proof of efficacy) behind their indication. In addition, we’ll look at examples of alternative therapies with ocular side effects. While the data is incomplete or inconclusive in many cases, we hope to show that traditional therapeutic principles can be applied equally to both atropine sulfate and Atropa belladonna.
The Natural Pharmacopeia
The NIH classifi cation of CAM includes mind-body interventions, energy therapies and biological-based treatments.http://nccam.nih.gov/health/providers/digest/safety-science. htm Accessed 28 April 2013. This last group includes herbs, vitamins, minerals and nutrition- based approaches. All of these therapies are regulated under the Dietary Supplement and Health Education Act of 1994. The most signifi cant effect of this law is the requirement of natural products to state, “This product and its claims have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease. Consult a health-care professional before using this or any product if you are pregnant or have a serious medical condition.” While this statement represents the primary oversight of the production and sale of CAM therapies, there is an increasing pressure for more rigorous, controlled clinical testing of herbalbased and nutriceutical medicines.
Vitamins and dietary supplements therapies. The AREDS study refl ects a naturopathic approach to AMD, and has established that either a combination of antioxidants, zinc supplements or both can reduce age-related macular degeneration progression by 17 to 25 percent.Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age- Related Eye Disease Study Report Number 3. Age-Related Eye Disease Study Research Group. Ophthalmology 2000;107:2224- 32. Several other studies examined other dietary approaches, including β-carotene, vitamin E, or α-tocopherol, but none of these treatments showed a signifi – cant effect against AMD progression. Antioxidants, multivitamins and individual vitamins A, C and E have all been screened in large cohort, observational studies such as the Beaver Dam Eye Study, the Women’s Health Initiative and the Blue Mountains Eye Study.West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and herbal medicines in common eye diseases. Am J Ophthalmol 2006;141:157–166.Some of these studies reported modest effects of these various treatments on AMD progression, cataract formation or progression of diabetic retinopathy, but there was no clear consensus. There is evidence, however, from several cohort studies showing a protective effect of the B vitamins (niacin, ribofl avin) in reducing cataract progression.Cumming RG, Mitchell P, Smith W. Diet and cataract: The blue mountains eye study. Ophthalmology 2000;107:450-456.
One of the most-often recommended herbal treatments for ocular disease is Ginkgo biloba; extracts of this plant are suggested as therapies for degenerative retinal diseases including AMD and glaucoma.Quaranta L, Bettelli S, Uva MG, Semeraro F, Turano R, Gandolfo E. Effect of Ginkgo biloba extract on preexisting visual fi eld damage in normal tension glaucoma. Ophthalmology 2003;110:2:359-62. The extracts have been shown to inhibit platelet activation and enhance blood flow, and several small studies have suggested that Ginkgo extract treatments may have protective effects on visual fi eld changes in normal tension glaucoma. Other examples of herbal remedies suggested for glaucoma include the Chinese wolfberry (Lycium barbarum), Coleus forskohlii and bilberry. Lycium is known as an “anti- aging” herb in Chinese medicine, and studies demonstrating its neuroprotective properties have recently been published;Chan HC, Chang RC, Koon-Ching Ip A, Chiu K, Yuen WH, Zee SY, So KF. Neuroprotective effects of Lycium barbarum on protecting retinal ganglion cells in an ocular hypertension model of glaucoma. Exp Neurol 2007;203:1:269-73. whether these can be translated to an effective treatment for retinal degeneration is unknown. Coleus species are the source of the diterpene forskolin, a compound used experimentally as an activator of adenylate cyclases. This action would be comparable to that of a non-selective beta-adrenergic agonist, and so would have mixed effects on ocular hypertension. It has been reported that the extracts of this plant elicit a mild, transient decrease in ocular pressure.Head KA. Natural therapies for ocular disorders, part two: Cataracts and glaucoma. Altern Med Rev 2001;6:141-66. Also, stories traced to British pilots during World War II have given the bilberry (as well as the carrot) a claim to enhanced visual function, especially night vision. Although both plants have well-established antioxidant constituents, there are no clinical studies that support these assertions.
There are fewer herbal treatments described for ocular surface diseases. Several Chinese herbs or herb mixtures have been suggested as treatments for dry eye,Chang YH, Lin HJ, Li WC. Clinical evaluation of the traditional chinese prescription Chi-Ju-Di-Huang-Wan for dry eye. Phytother Res 2005;19:349-54. and a recent study described properties of Atropa acuminata extracts as treatments for several conditions including ocular infl ammation.Nisar A, Malik AH, Zargar MA. Atropa acuminata royle ex lindl blunts production of pro-infl ammatory mediators eicosanoids, leukotrienes, cytokines in vitro and in vivo models of acute infl ammatory responses. J Ethnopharmacol 2013;147:584-94. Clinical studies of omega-3 and omega-6 fats, including those found in sea buckthorn extracts,Järvinen RL, Larmo PS, Setälä NL, Yang B, Engblom JR, Viitanen MH, Kallio HP. Effects of oral sea buckthorn oil on tear fi lm fatty acids in individuals with dry eye. Cornea 2011;30:1013- 1019. support a therapeutic benefi t of herbs containing these ingredients for individuals with dry eye.
Beyond the use of herbal extracts, many CAM advocates also encourage the use of various elemental salts and colloidal preparations. Such treatments date to the historical use of mercurous chloride solutions (Calomel), both topically and in elixirs, for the treatment of diverse conditions, including infections. Obviously, mercury salts are no longer used, but other elemental preparations including chromium, selenium and silver are commonly employed. Chromium is CAM therapy for diabetes,Hua Y, Clark S, Ren J, Sreejayan N. Molecular mechanisms of chromium in alleviating insulin resistance. J Nutr Biochem 2012;23:4:313-9. selenium is a treatment for hypothyroidism (but has also been associated with cataract formation)Olson OE. Selenium toxicity in animals with emphasis on man. Int J of Toxicol 1986;5:45-70. and silver solutions, including silver nitrate or Argyrol, are still considered appropriate therapy for ophthalmia neonatorum, even though they’ve been replaced, at least in the United States, by erythromycin for this indication.U.S. Preventive Services Task Force. Ocular prophylaxis for gonococcal ophthalmia neonatorum: Reaffi rmation recommendation statement. Am Fam Physician 2012;85:2:195- 196.
When Herbs Go Bad
Many advocates of CAM therapies seem to make the a priori assumption that herbal therapies have no side effects— only drugs have side effects, right? In fact many herbs and other natural products can evoke signifi cant adverse effects, and many of these impact visual function directly or indirectly.Fraunfelder FW. Ocular side effects from herbal medicines and nutritional supplements Am J Ophthalmol 2004;138:639–647. Patients with this erroneous preconception are left with a false sense of security that can lead to overdosing or delays in responding to harmful reactions.
Examples of adverse ocular effects include those seen with topical use of Echinacea and Chamomile, plants commonly used for systemic treatments of conditions including colds, fevers, burns and infl ammation. Operating with the idea of “no adverse effects,” patients have used extracts of both plants topically to treat ocular infl ammation, which has resulted in a severe conjunctivitis characterized by hyperemia, itching and excessive watering.
The therapeutic effect of Ginkgo, the inhibition of platelet function, also leads to dose-dependent adverse effects such as subarachnoid and retinal hemorrhage. It’s clearly important to be aware of a patient’s use of Ginkgo, especially if he is also using other platelet inhibitors such as Coumadin or aspirin.
A second compound with significant ocular side effects is niacin. High doses of this vitamin have been recommended by naturopaths as a treatment for diabetes, atherosclerosis and hypertension, but there is also clear evidence of risk of cystoid macular edema in patients taking greater than 1.5 g niacin per day.
While most therapies espoused by supporters of alternative medicine are studies leaves open the questions of effi cacy and safety. In such an informational vacuum, it’s possible that misinterpretation of the few available studies can lead to adoption of unsubstantiated speculation as fact. The reported connection between silver and glaucoma is just such a case.
The Strange Silver Saga
Silver salts have been used at deliveries as both ocular antiseptics and to chemically cauterize the newborn umbilicus. Silver sulfadiazine is a useful topical antibacterial, especially for burn infection. The traditional antiseptic Argyrol was an essential part of any physician’s black bag before the advent of modern antibiotics, and today silver still has important application in dental reconstructions, implants, catheters and some contact lens storage devices. These devices take advantage of the bacteriostatic characteristics silver imparts to their exposed surfaces.Monteiro DR, Gorup LF, Takamiya AS, Ruvollo-Filho AC, de Camargo ER, Barbosa DB. The growing importance of materials that prevent microbial adhesion: Antimicrobial effect of medical devices containing silver. Int J Antimicrob Agents 2009;34:103- 110.
In contrast to its mainstream topical use, the systemic use of silver colloidal suspensions has become a mainstay of many naturopathic practitioners, and is purported to treat conditions including arthritis, cancer and infectious diseases including HIV. According to the National Institute for Complementary and Alternative Medicines, “Scientifi c evidence does not support the use of colloidal silver to treat any disease, and serious, irreversible side effects can result from its use.”http://nccam.nih.gov/health/silver. Accessed 6 May 2013.
The side effect referred to in relation to colloidal silver is argyria, a permanent bluing of the skin that results from silver deposition in the dermis. The ocular version of this condition, argyrosis, was common in silversmiths and others who routinely worked with silver in industrial settings. What is surprising, however, is that beyond this discoloration there is no evidence that systemic silver has any other signifi cant toxicities.
Several isolated reports have linked silver to glaucoma, in part because of the deposition of silver in ocular tissues that accompanies argyrosis. The most recent study suggested a potential relationship between glaucoma and argyrosis.Sanchez-Pulgarin, M, Matilla M, Martinez-de-la-Casa JM, Jerez M, Benitez-del-Castillo JM. Confocal microscopy in ocular argyrosis. Cornea 2010;29:5:580-582. With precise instrumentation, the authors analyzed in vivo silver deposition in a single patient exhibiting ocular hypertension and corneal opacity. This patient also suffered asthma secondary to 30 years of exposure to silver salts in his work as a jeweler. Confocal microscopy examination confi rmed silver deposits throughout the stroma, in Descemet’s membrane and in Bowman’s membrane, and showed pigmentation of the trabecular meshwork. The authors referenced earlier workSpencer WH, Garron LK, Contreras F, Hayes TL, Lai C. Endogenous and exogenous ocular and systemic silver deposition. Trans Ophthalmol Soc U K 1980;100:Pt 1:171-178. and stated, “A possible link between argyrosis and glaucoma has also been attributed to thickening of the trabecular endothelial basement membrane, obstruction of the trabecular meshwork by small silver granules and by unknown factors.” Surprisingly, the cited reference makes no such link, but simply provides an analysis of how different types of silver exposure (occupational, topical or ingested) can affect the location and extent of silver accumulation in ocular tissues. In addition, the researchers explicitly state that no silver deposition was observed in the trabecular meshwork. Despite this, other publications have cited the study when suggesting a link between argyrosis and glaucoma, when neither this report nor any other study provides evidence for such a link.Sanchez-Huerta V, De Wit-Carter G, Hernandez-Quintela E, Naranjo-Tackman R. Occupational corneal argyrosis in art silver solderers. Cornea 2003;22:7:604-611.,Friedman DS, Terebuh A. Argyrosis in a patient with glaucoma. Ophthalmic Surg 1995;26:3:274-275.
This case of this non-existent link between silver toxicity and glaucoma reminds us of the importance of fully vetting the peer-reviewed literature, particularly when we are making treatment decisions based upon it. This holds equally for both drugs developed by the pharmaceutical industry and for CAM therapeutics. Even with a mountain of medical literature at our fingertips, establishing valid therapeutic guidelines still comes down to blending our experience with a thoughtful consideration of individual trials and reports.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Dr. McLaughlin is a medical writer at Ora Inc.