Letters to the Editor
a small signal of some benefit. A study with a larger patient
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Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
REFERENCES
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 neuroophthalmol-
ogists 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
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, concentration-
controlled, 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 invali-
dated its conclusion. Pakravan et al (5) treated 30 patients
with high-dose intravenous corticosteroids, using a treat-
ment protocol basically similar to that used in optic neu-
ritis. 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 corticoste-
roid 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 unfortu-
nate that Kupersmith, Miller, and Levin apparently attach
more importance to those 2 highly flawed studies support-
ing 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
 Letters to the Editor
REFERENCES
1. Kupersmith MJ, Miller NR, Levin LA. New treatments in Neuro-
Ophthalmology: the role for evidence. J Neurophthalmol.
2017;37:1–2.
2. Hayreh SS, Zimmerman MB. Non-arteritic anterior ischemic
optic neuropathy: role of systemic corticosteroid therapy.
Graefes Arch Clin Exp Ophthalmol. 2008;246:1029–1046.
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3. Hayreh SS. Ischemic optic neuropathies—where are we now?
Graefes Arch Clin Exp Ophthalmol. 2013;251:1873–1884.
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4. Rebolleda G, Pérez-López M, Casas-Llera P, Contreras I, Muñoz-
Negrete FJ. Visual and anatomical outcomes of non-arteritic
Corticosteroid Therapy in Nonarteritic
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Anterior Ischemic Optic Neuropathy:
Response
W
e thank Dr. Hayreh for the opportunity to continue
the discussion on this most important topic—
namely, the need for Level I evidence in medicine to assess
potential therapies. We recognize and appreciate Dr. Hay-
reh's contributions to the understanding of nonarteritic
anterior ischemic optic neuropathy (NAION), and we
are sorry that he seems to have misinterpreted our com-
mentary as a personal attack. Our editorial is an unbiased
evaluation of the issue of steroid treatment of NAION and,
more importantly, a plea for well-designed, prospective
clinical trials that collect and analyze meaningful data
and come to an evidence-based conclusion regarding the
efficacy of a potential therapy. These trials must include
masking and randomization, for without them, the con-
clusions could be flawed. Even when unintended, bias from
study subjects and investigators are known contaminants.
Uncontrolled cases series, no matter how many patients are
included, are still simply large series, and physicians should
be cautious in interpreting the results of such studies, as the
studies do not follow the accepted principles for conduct-
Role of Nocturnal Arterial Hypotension in
Nonarteritic Anterior Ischemic Optic
Neuropathy
I
was interested to read the discussion of the role of
nocturnal arterial hypotension in nonarteritic anterior
ischemic optic neuropathy (NAION) (1). Since my studies
were the first to raise this issue (2–4), I believe that a num-
ber of comments are in order.
It was stated that my 24-hour ambulatory blood pressure
monitoring (ABPM) studies (2,3) in patients with NAION
had no control group and, therefore, the “data had significant
limitations.” I have discussed at length why it is impossible to
have a valid control group in such a study (2), given the fact
350
Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.
anterior ischemic optic neuropathy with high-dose systemic
corticosteroids. Graefes Arch Clin Exp Ophthalmol.
2013;251:255–260.
5. Pakravan M, Sanjari N, Esfandiari H, Pakravan P, Yaseri M. The
effect of high-dose steroids, and normobaric oxygen therapy, on
recent onset non-arteritic anterior ischemic optic neuropathy:
a randomized clinical trial. Graefes Arch Clin Exp Ophthalmol.
2016;254:2043–2048.
6. Hayreh SS. Treatment of non-arteritic anterior ischemia optic
neuropathy with high-dose systemic corticosteroid therapy.
Graefes Arch Clin Exp Ophthalmol. 2013;251:1029–1030.
ing clinical trials. Uncontrolled data are useful for generat-
ing hypotheses and exploring new concepts, but they
should be viewed only as pilot or preliminary information
on which to base controlled clinical trials. We recommend
that, given his expertise in this area, Dr. Hayreh attempt
once again to perform a prospective trial of steroid therapy
for NAION using the methodology that all trials of in-
vestigational agents require to properly test a hypothesis.
Mark J. Kupersmith, MD
Icahn School of Medicine at Mount Sinai and New York Eye
and Ear Infirmary,
New York, New York
Neil R. Miller, MD
Johns Hopkins School of Medicine and Wilmer Eye Institute,
Baltimore, Maryland
Leonard A. Levin, MD, PhD
McGill University Faculty of Medicine,
Montreal, Canada
University of Wisconsin,
Madison, Wisconsin
The authors report no conflicts of interest.
that NAION is a multifactorial disease with many systemic
and optic nerve head risk factors. Hence, a true control
population would have to be matched for systemic and optic
nerve head factors in addition to age and sex. My studies, in
fact, had an important built-in reliable control, because
patients with nocturnal hypotension, compared with those
without it, had a significant association with progression of
visual field deterioration in NAION.
The ABPM study in 24 patients with NAION by
Landau et al (5) has been cited as contradictory to my
findings regarding nocturnal arterial hypotension in
NAION. I have discussed at length the flaws in that study
which invalidate its conclusions (6).
Anthony Arnold, MD, raised a number of concerns
regarding the data from my studies. Following are my
responses.
Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 347-353