Dalfampridine Treatment in Nonarteritic Anterior Ischemic Optic Neuropathy

Letters to the Editor Dalfampridine Treatment in Nonarteritic Anterior Ischemic Optic Neuropathy W e read with interest the editorial by Kupersmith and Miller (1) regarding a clinical trial for the treatment of nonarteritic anterior ischemic optic neuropathy (NAION). We would like to share our experience with a pilot study we undertook also in the hopes of finding some form of treatment for this optic nerve disorder. Dalfampridine (4-aminopyridine) is a voltagedependent potassium channel blocker that enhances conduction in demyelinated neurons (2). Extendedrelease dalfampridine (Ampyra) has been shown to improve walking in some patients with multiple sclerosis (MS) and is FDA approved for this purpose (3). Early studies showed improvements in visual function in MS treated with dalfampridine (4,5), but recent clinical trials have conflicting results (6,7). In addition, a study of middle cerebral artery occlusion in rats showed improvement in sensorimotor function with dalfampridine compared with placebo (8). Based on these findings, we performed a pilot clinical trial to determine whether dalfampridine could improve vision in patients with NAION. After obtaining institutional review board approval, we recruited 20 subjects older than 40 years with stable visual deficits at least 6 months after an episode NAION. A double masked crossover design was used. At initial visit, patients had a neuro-ophthalmologic history and examination, completed the National Eye Institute Visual Functioning Questionnaire (VFQ) 25 questionnaire, and had measurement of highcontrast visual acuity (VA) (The Early Treatment Diabetic Retinopathy Study [ETDRS]) and automated Humphrey visual field (HVF) (Central 24-2, second test data were used). Multifocal electroretinogram (mfERG), pattern and flash visual evoked potential (VEP), and spectral domain optical coherence tomography (OCT) with the Spectralis device (Heidelberg, Franklin, MA) were performed. Patients were randomized to a 2-week course of either dalfampridine 10 mg twice a day orally or placebo followed by a 2-week washout period and then 2 weeks with the alternative treatment. Dalfampridine for NAION is an off-label use. Baseline subject characteristics were summarized overall and by randomization assignment using descriptive statistics. The primary analysis used data from the affected eye. In bilateral cases, the eye with longer duration of NAION was selected. Subjects were analyzed as randomized under the intention-to-treat principle. For each continuous outcome, mixed-effects linear regression was used to model change scores during each period (i.e., V2-V1 or V4-V3) adjusting for sequence effects and accounting for correlation among repeated measurements from the same subject using a random intercept term. Average changes for each treatment were calculated from 348 this model and compared. Positive average change means the measure increased or became more positive over the treatment period. Negative average change means the measure decreased or became more negative over the treatment period. The study was designed to have 80% power to detect a difference in randomization arms of 0.95 SDs using a 2-sided test of size 0.05. Categorical change in acuity (logarithm of the minimum angle of resolution [logMAR] improvement $0.1 and 0.3) was calculated for each subject for both treatment periods, and differences in treatment and placebo periods were evaluated using exact McNemar tests. P-values were not adjusted for multiple comparisons. Ten men and 10 women completed the study. Age range was 49-72 years (mean age: 63 years). The primary outcome of the study was VA. During treatment with drug, VA improved on average by 0.10 logMAR (Diff = 20.10 95% confidence interval [CI]: 20.22 to 0.01). By contrast, there was no evidence of change in logMAR under placebo (Diff = 0.01 95% CI: 20.10 to 0.13). There was no significant difference between treatments (Drug-Placebo: 20.12 (20.28, 0.04); P = 0.15). A supplemental analysis was performed to determine the rate of response in VA using improvement of 0.1 or greater in logMAR over the treatment period to define response. When considering first-diagnosed NAION eyes (1 eye per subject), 45% of eyes had improvement in VA of 0.1 logMAR or more during the drug period, whereas 25% had improvement during the placebo period (P = 0.34) (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A234). Similar results were found when considering all NAION eyes (ignoring clustering among eyes within the same subject [see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A235]). When defining response as improvement of 0.3 or greater in logMAR, in first-diagnosed NAION eyes, 25% of eyes had improvement in VA of 0.3 logMAR or more during the drug period, whereas 5% had improvement during the placebo period (P = 0.22) (see Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A236). Similar results were found when considering all NAION eyes (see Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A237). There were no significant differences between drug and placebo for VEP, OCT, mfERG, HVF, or VFQ 25. There were no significant adverse events attributed to the drug. This study failed to find a statistically significant benefit of dalfampridine in NAION. However, 7 patients had improvement in VA of 0.1 logMAR or more better on drug and not placebo, and 5 patients showed an improvement of VA of 0.3 logMar or more better on drug and not placebo. This suggests a possible subgroup of "responders" similar to the findings of dalfampridine in MS. Although our pilot study was not powered to show definite evidence of improvement, there was Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor a small signal of some benefit. A study with a larger patient cohort might detect a subgroup responsive to dalfampridine. Mark L. Moster, MD Robert C. Sergott, MD Department of Neuro-Ophthalmology, Wills Eye Hospital, Departments of Ophthalmology and Neurology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania Benjamin E. Leiby, PhD Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania Supported by Acorda Therapeutics. The authors report no other conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Corticosteroid Therapy in Nonarteritic Anterior Ischemic Optic Neuropathy K upersmith et al (1) in their recent article stated that the conclusions of my study (2), showing beneficial effects of systemic corticosteroids in nonarteritic anterior ischemic optic neuropathy (NAION), was "inaccurate," and they listed several reasons for that. But if these authors had carefully read, with an unbiased mind, my detailed published rebuttals to those criticisms (3), they would have found that my conclusions were based on definite scientific evidence. This shows that their criticisms about my study are not valid. For more than 4 decades, I have found a built-in bias, without any scientific rationale, among neuroophthalmologists against the use of corticosteroid therapy in NAION, as is evident from the above and the following examples. In early 1970s, when I applied to the National Institutes of Health to run a multicenter clinical trial about the use of corticosteroids therapy in patients with NAION, the project was rejected on the grounds that there was "no scientific rationale for corticosteroid therapy in NAION." I have discussed that scientific rationale fully elsewhere (2,3). In justification of their comments, Kupersmith, Miller, and Levin cited 2 studies (4,5) showing no beneficial effects of corticosteroid therapy in NAION. But, as I have Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353 REFERENCES 1. Kupersmith MJ, Miller NR. A nonarteritic anterior ischemic optic neuropathy clinical trial: an industry and NORDIC collaboration. J Neuroophthalmol. 2016;36:231-234. 2. Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin. 2011;27:1415-1423. 3. Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, Marinucci LN, Blight AR. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol. 2010;68:494-502. 4. Jones RE, Heron JR, Foster DH, Snelgar RS, Mason RJ. Effects of 4-aminopyridine in patients with multiple sclerosis. J Neurol Sci. 1983;60:353-362. 5. Bever CT Jr, Young D, Anderson PA, Krumholz A, Conway K, Leslie J, Eddington N, Plaisance KI, Panitch HS, Dhib-Jalbut S, Fossler MJ, Devane J, Johnson KP. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentrationcontrolled, crossover trial. Neurology. 1994;44:1054-1059. 6. Horton L, Conger A, Conger D, Remington G, Frohman T, Frohman E, Greenberg B. Effect of 4-aminopyridine on vision in multiple sclerosis patients with optic neuropathy. Neurology. 2013;80:1862-1866. 7. Naismith RT, Tutlam NT, Trinkaus K, Lancia S. Phase II trial of dalfampridine to improve visual function in chronic optic neuritis due to MS. Ann Neurol. 2015;78(suppl 19):S66. 8. Iaci JF, Parry TJ, Huang Z, Finklestein SP, Ren J, Barrile DK, Davenport MD, Wu R, Blight AR, Caggiano AO. Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion. Stroke. 2013;44:1942-1950. pointed out (6), the study by Rebolleda et al (4), based on only 10 treated patients, was highly flawed, which invalidated its conclusion. Pakravan et al (5) treated 30 patients with high-dose intravenous corticosteroids, using a treatment protocol basically similar to that used in optic neuritis. But it is well established that etiologically NAION and optic neuritis are different diseases, and that simple fact and the study design used in this study invalidates their conclusion. In contrast, in my study, oral corticosteroid therapy (in 312 treated and 301 untreated patients) was used until optic disc edema resolved, that is, for about 8 weeks. Thus, comparing study designs and the numbers of patients in the 2 cited studies with those of my large study is like comparing apples and oranges. It is unfortunate that Kupersmith, Miller, and Levin apparently attach more importance to those 2 highly flawed studies supporting their bias than to my large, systematic, comprehensive study. Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth Department of Ophthalmology and Visual Science, College of Medicine, University of Iowa, Iowa City, IA The author reports no conflicts of interest. 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.