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New Treatments in Neuro-Ophthalmology: The Role for Evidence

Kupersmith, Mark J. MD; Miller, Neil R. MD; Levin, Leonard A. MD, PhD

Journal of Neuro-Ophthalmology: March 2017 - Volume 37 - Issue 1 - p 1–2
doi: 10.1097/WNO.0000000000000482

Icahn School of Medicine at Mount Sinai and New York Eye and Ear Infirmary (MKJ), New York, New York

Wilmer Eye Institute, Johns Hopkin School of Medicine (NRM), Baltimore, Maryland

McGill University Faculty of Medicine (LAL), Montreal, Quebec, and University of Wisconsin, Madison, Wisconsin.

Address correspondence to Mark J. Kupersmith, MD, Icahn School of Medicine at Mount Sinai and New York Eye and Ear Infirmary, New York, NY 10019; E-mail:

M. J. Kupersmith and N. R. Miller receive compensation from Quark Pharmaceuticals for the conduct of the QP1007 NAION treatment trial. L. A. Levin has served as a consultant on neuroprotection to Aerie, GSK, Inotek, Quark, and Regenera. The authors report no other conflicts of interest.

Neuro-ophthalmic diseases affect relatively small numbers of patients. Thus, there are only a few good-quality clinical trials for their treatments (1–3). Given these facts, neuro-ophthalmologists faced with an ailing patient believe that they have to “do something.” They often choose therapies based on evidence gathered from underpowered or poorly conducted clinical trials, anecdotal case reports, and even data from animal models or cell culture. We recently wrote an editorial in the Journal of Neuro-Ophthalmology describing a carefully designed, ongoing trial using an antiapoptotic agent in the treatment of patients with nonarteritic anterior ischemic optic neuropathy (NAION) (4). Concern has been raised about withholding systemic corticosteroids in these patients. Here, we address the ethical question of whether a physician must offer an unproven therapy to a patient with an otherwise untreatable disease.

NAION is a disorder with no proven treatment at present. As such, there is no standard of care based on scientific evidence, nor is one considered as being generally accepted. Before the Ischemic Optic Neuropathy Decompression Trial (IONDT), there were several reports stating that optic nerve sheath decompression was an effective treatment, and it was commonly used for both progressive and nonprogressive NAION. However, the masked, randomized controlled trial reported by the IONDT Research Group demonstrated that sheath decompression was ineffective for nonprogressive NAION and was not likely to be effective for progressive NAION, leading to it being discontinued as a treatment (2).

In 2008, the use of systemic corticosteroids was suggested as a therapy for patients with NAION by Hayreh and Zimmerman (5). Although this was published in a peer-reviewed journal, the patients were not randomized; they were self-selected with respect to whether or not they wanted corticosteroids. In addition, patients did not undergo retesting of visual acuity and visual fields at study entry. Finally, the examiner was not masked as to which patients were or were not treated with prednisone. These methodological flaws are likely to have introduced significant bias and led to inaccurate conclusions, similar to what occurred with optic nerve sheath decompression for progressive NAION before the IONDT. Indeed, 2 randomized, prospective trials of steroid treatment for NAION revealed no difference in visual outcome or structural measures as assessed by optical coherence tomography between treated and untreated subjects (6,7). The arguments for and against steroid treatment have been detailed in other articles, including one in the Journal of Neuro-Ophthalmology by Lee and Biousse (8). In the meantime, until efficacy is demonstrated in a clinical trial that is conducted with proper methodology, the use of systemic steroids to treat NAION is neither mandatory nor supported by Level 1 evidence.

Other examples of treatments that are unsupported by Level 1 evidence include those for Leber hereditary optic neuropathy, traumatic optic neuropathy, and radiation optic neuropathy. Various treatments such as free radical scavengers, high-dose corticosteroids, hyperbaris oxygen, and bone marrow-derived stem cells have been proposed. In all of these cases, the quality of the evidence is absent or low, that is, not derived from efficacy demonstrated in properly performed prospective, randomized, controlled trials, yet the treatments are commonly used.

Given that a therapy is unproven for a disease for which there are no alternatives, what is the role of the physician in managing the patient? We cannot fault the physician who offers a treatment (assuming it is safe and the physician has no financial interest in the product) even if it has not been proven to be efficacious. In this setting, the presumption is that the physician's interpretation of the evidence, albeit inadequate, is convincing. At the same time, we strongly believe that a physician cannot be required to offer such a treatment, for 3 reasons. First, in the absence of evidence for efficacy but a risk of adverse effects, offering a treatment places the patient at greater risk than if nothing were done. Second, even if the treatment were to be without risk, there are so many potential unproven therapies that it would be practically impossible to offer all such therapies. Third, and most importantly, requiring the physician to offer an unproven therapy implies that physicians must practice medicine below the standard of care in their specialty. For these reasons, mandatory disclosure of unproven therapies to patients should not be obligatory. In the future, we hope that properly conducted clinical trials will yield efficacious therapies for the many untreatable neuro-ophthalmic diseases.

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© 2017 by North American Neuro-Ophthalmology Society