I was interested to read the comments by Drs Lee and Biousse (1) in “Point Counter-Point,” dealing with steroid therapy in nonarteritic anterior ischemic optic neuropathy (NA-AION). The impetus for this discussion came from my prospective “patient randomized” study on the subject (2). That report showed that when patients with NA-AION were treated, according to the steroid therapy protocol in the study, 69.8% (95% confidence interval [CI], 57.3%-79.9%) of eyes with initial visual acuity of 20/70 or worse, seen within 2 weeks of onset, experienced visual acuity improvement compared to 40.5% (95% CI, 29.2%-52.9%) in the untreated group (odds ratio of improvement: 3.39; 95% CI, 1.62-7.11; P = 0.001). Among those seen within 2 weeks of NA-AION onset, with moderate-to-severe initial visual field defect, there was improvement in 40.1% (95% CI, 33.1%-47.5%) of the treated group and 24.5% (95% CI, 17.7%-32.9%) of the untreated group (odds ratio: 2.06; 95% CI, 1.24-3.40; P = 0.005).
Neuro-ophthalmologists, however, are of the opinion that steroid therapy has no role in the treatment of NA-AION, as I have learned from multiple e-mails, letters, and telephone calls from patients with NA-AION who have been told by neuro-ophthalmologists that steroid therapy will not benefit them and that there is no known treatment available. I feel impeled to defend my study's findings and conclusions, respond to criticism, and place the role of steroid therapy in NA-AION in proper perspective. This is vital because there has not previously been any effective treatment for NA-AION, and this study provides hope to these patients.
1. Scientific rationale for visual improvement with steroid therapy in NA-AION.Primary and secondary changes in the optic nerve head (ONH) produce optic disc edema in NA-AION (2). The primary change is ischemic axoplasmic flow stasis; vascular changes and fluid leakage (as shown by fluorescein angiography initially in NA-AION) occur secondarily. There is good evidence that steroid therapy reduces capillary permeability. A large study showed that systemic steroid therapy given within 2 weeks after the onset of NA-AION resulted in significantly (P = 0.0006) faster resolution of optic disc edema in treated than in untreated cases (3).The most likely scenario to explain the beneficial effect of steroid therapy on visual outcome in NA-AION, as discussed in detail in my article (2), seems to be as follows: The faster resolution of optic disc edema with steroid therapy compared to the untreated patients → Progressive decrease of compression of the capillaries in the ONH → Improved circulation in the ONH → Improved function of the surviving hypoxic axons. There is a possibility that the steroids may also have additional beneficial effects such as inhibition of damage by free radicals. Therefore, in NA-AION, steroid therapy does have a scientifically valid rationale.
2. There was no conventional randomization in this study.Lacking extramural funding, I decided on a prospective “patient choice” controlled study instead of the “conventional randomized study”-the next best choice. Every patient with NA-AION seen in my clinic was given a free and informed “patient choice.” The crucial criterion for any “conventional randomization” is to have treated and untreated groups at baseline comparable in demographic and clinical characteristics. In my study, that was the case.
1. In the study, 51% voluntarily opted for systemic steroid therapy and 49% opted for no treatment. Thus, the numbers of patients in the treated and untreated groups were similar.
2. There was no significant difference between the 2 groups in visual acuity, visual fields, and systemic diseases, except that patients who opted for treatment were slightly younger (59.2 vs 62.0 years) and had a lower prevalence of arterial hypertension (34% vs 43%).To determine if those factors influenced the visual outcome, they were accounted for in the statistical analysis by including them as covariates in the logistic regression model-they made no difference in visual outcome (age, P = 0.8; hypertension, P = 0.6). Contrary to the assertion in Point Counter-Point, there was no difference in the frequency of diabetes or other vascular risk factors between the 2 groups. The assertion by Biousse et al (4) that the statistical analysis given above does not rule out a higher prevalence of systemic diseases in the untreated group compared with the treated group, contradicts standard scientific practice.
3. The data were not collected in a masked fashion.
The following are proofs of the collected data that had no bias:
1. Visual acuity: Our results exactly mirrored those of the Ischemic Optic Neuropathy Decompression Trial, a randomized and masked study (5). In that study, in the untreated eyes seen within 2 weeks after the onset of NA-AION with visual acuity of 20/70 or worse, the visual acuity improved in 43% of the untreated eyes. In my study, in an exactly identical group of patients with NA-AION, in the untreated group, the visual acuity improved in 41% of the untreated eyes. In both studies, the visual acuity improved up to 6 months. This is the most convincing proof that the visual acuity data in my study were unbiased.
2. Visual fields: These were plotted by perimetrists who were unaware of the diagnosis. The fields were graded by 3 neuro-ophthalmologists, independently, in a masked fashion, without any knowledge of the patients' diagnosis.
Three additional factors have played an important role in the controversy of using steroids in the treatment of NA-AION:
1. As stated in Point Counter-Point: “A number of well-designed studies in the neurologic literature have shown that steroid do not improve outcome of patients with acute arterial or venous cerebral ischemia.” There is a fundamental problem with this argument. Cerebral stroke is a thromboembolic disorder. Steroid therapy has no role in such a situation. In contrast, we have scientifically valid evidence that NA-AION is primarily a hypotensive disorder in the majority of cases, with much less severe ischemic damage (6-8), and not a thromboembolic disorder. Thus, the 2 diseases are totally unrelated pathogenetically and in their management (7). To equate NA-AION and stroke is a fundamental mistake.
2. It seems that 1 major reason for the controversy on NA-AION management is the lack of in-depth understanding of its pathogenesis. I have discussed the pathogenesis of NA-AION elsewhere at length (7,8) and concluded that available evidence shows that “the pathogenesis of NA-AION is complex but not, as often stated, unknown.”
3. Many physicians are uncomfortable treating patients, particularly the elderly, with high-dose steroid therapy. For more than 45 years, I have treated several thousand patients with high-dose steroid therapy for a variety of ophthalmic diseases. Based on my clinical practice, I find that steroids can be used safely, provided patients are followed closely and meticulously.
I realize that my findings challenge conventional wisdom in the management of NA-AION. I urge my colleagues to look at this study with unbiased and open minds, in the interest of helping these desperate patients. Given the visual devastation of NA-AION, our patients deserve nothing less!
Sohan Singh Hayreh, MD, MS, PhD, DSc, FRCS, FRCOphth(Hon)
Department of Ophthalmology & Visual Sciences, College of Medicine University of Iowa, Iowa City, IA firstname.lastname@example.org
1. Lee AG,
Biousse V. Should steroid be offered to patients with nonarteritic anterior ischemic optic neuropathy? J Neuroophthalmol. 2010;30:193-198.
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.
3. Hayreh SS,
Zimmerman MB. Optic disc edema in non-arteritic anterior ischemic optic neuropathy. Graefes Arch Clin Exp Ophthalmol. 2007;245:1107-1121.
4. Biousse V,
Bruce BB, Newman NJ. Non-arteritic anterior ischemic optic neuropathy: role of systemic corticosteroid therapy. Surv Ophthalmol. 2010;55:400-401.
5. Ischemic Optic Neuropathy Decompression Trial Research Group.
Optic nerve decompression surgery for nonarteritic anterior ischemic optic neuropathy (NAION) is not effective and may be harmful. JAMA. 1995;273:625-632.
6. Hayreh SS,
Podhajsky PA, Zimmerman B. Non-arteritic anterior ischemic optic neuropathy-time of onset of visual loss. Am J Ophthalmol. 1997;124:641-647.
7. Hayreh SS.
Ischemic optic neuropathy. Prog Retin Eye Res. 2009;28:34-62.
8. Hayreh SS.
Acute ischemic disorders of the optic nerve: pathogenesis, clinical manifestations and management. Ophthalmol Clin North Am. 1996;9:407-442.