The treatment of nonarteritic anterior optic neuropathy (NAION) remains very limited and disappointing. Recent publications have suggested that oral steroids as well as intravitreal injections of steroids might be helpful to accelerate resolution of disc edema and improve visual outcome. However, the use of steroids to treat acute NAION remains largely debated.
PRO-Steroids should be offered to patients with nonarteritic anterior ischemic optic neuropathy: Andrew G. Lee, MD
It remains an inconvenient truth that to date, there is no proven effective therapy for nonarteritic anterior ischemic optic neuropathy (NAION). This situation is frustrating for both the patient and the clinician. Although clinicians make recommendations for improving the general health of the patient and treating any vasculopathic risk factors (e.g., blood glucose, cholesterol, blood pressure, diet, exercise, tobacco cessation, and sleep apnea), the lack of an effective therapy for NAION remains a major issue for neuro-ophthalmologists. A number of older and more recent reports (1-5) have suggested that systemic corticosteroids might be useful in NAION. Much speculation in the past and more recently has surrounded the potential mechanisms for steroids in NAION, including reduction of vascular permeability, cell membrane stabilization, reduction of edema, and even neuroprotection. Indeed, many physicians are currently offering steroids to patients as a treatment option for NAION (6).
The pro-con debate in this issue of the Journal of Neuro-ophthalmology is not designed to answer the question or provide a standard of care. Instead, it is meant to be thought provoking and promote dialogue among neuro-ophthalmologists on an important subject. Valerie Biousse, MD, and I will debate this issue in a Point-Counter-Point format and will review and summarize the relevant literature.
Over the past 4 decades, a variexty of reports have documented various routes of administration for steroid therapy for NAION. These include intravenous (6), peribulbar (7), retrobulbar (2,7), and, most recently, intravitreal (8-10). However, these studies are all anecdotal and yielded only limited and unconvincing data.
Sohan Hayreh, MD, an acknowledged expert in the field, has devoted a great deal of time and effort in his career to the study of NAION. Two prior studies had looked at the use of systemic steroids for NAION using very small numbers of patients. Foulds (1) reported improvement in visual acuity in 11 of 13 patients (85%) treated with systemic corticosteroids (60 mg prednisone daily), compared to 5 of 11 patients (45%) not treated with systemic corticosteroids. Hayreh (3) noted improvement in visual acuity in 6 of 8 patients (75%) treated with steroids (40-60 mg prednisone daily combined with initial dose of 40 units ACTH) compared to 2 (25%) in which vision either stabilized or deteriorated.
A prospective, randomized, controlled study with masked outcome assessment (Class 1 evidence) would be the best means to answer the question of efficacy of steroids in NAION. However, prior attempts by Hayreh and others have been unsuccessful in securing funding for such a study.
In 2007, Hayreh (4) reported on 591 consecutive patients (749 eyes) with NAION. From clinical data available, 237 eyes with NAION were started on steroid therapy within 2 weeks of onset and 343 eyes did not receive treatment. The protocol for steroid therapy called for an initial dosage of 80 mg of prednisone daily. After 2 weeks, tapering down of therapy was started in steps of 5 days each to 70 mg, 60 mg, and then cutting down by 5 mg every 5 days to 40 mg until the optic disc edema was no longer present. The prednisone was then rapidly tapered and discontinued. Most patients were on treatment for approximately 2 months. Results of this study demonstrated that when steroid therapy was begun within 2 weeks of onset of NAION, the median time for optic disc edema resolution was 6.8 weeks, compared to 8.2 weeks in untreated cases (P < 0.0001).
In 2008, Hayreh and Zimmerman (5) reported a patient choice study that included 613 consecutive patients (696 eyes) with NAION. Of the patient cohort, 312 patients (364 eyes) voluntarily opted for systemic corticosteroid therapy and 301 (332 eyes) chose no treatment. Of the 312 patients who opted for steroid therapy, 236 received treatment within 2 weeks of onset. At the initial visit, all study patients underwent detailed ophthalmic evaluation. Snellen visual acuity and Goldmann perimetry were performed on all patients, and improvement in visual function was the primary outcome measure. The treatment group received 80 mg oral prednisone daily for 2 weeks followed by a tapering dose (70 mg for 5 days, 60 mg for 5 days, and 5 mg reductions thereafter every 5 days). The median follow-up was 3.8 years. At 6 months from the onset of the NAION, eyes with an initial visual acuity of 20/70 or worse and seen within 2 weeks of onset in the treated group had a visual acuity improvement in 69.8% (95% confidence interval (CI): 57.3%-79.9%). This was in contrast to the control group of untreated patients who had a 40.5% (95% CI: 29.2%-52.9%) visual improvement. The odds ratio of improvement was 3.39 (95% CI: 1.62-7.11; P = 0.001). Likewise, for visual field improvement at 6 months from onset of NAION, in the treated group for those seen within 2 weeks of onset with moderate to severe initial visual field defect, there was improvement in 40.1% (95% CI: 33.1%-47.5%) compared with 24.5% (95% CI: 17.7%-32.9%) in the untreated group. The odds ratio for visual field improvement was 2.06% (95% CI: 1.24-3.40; P = 0.005). Hayreh concluded that NAION treated during the acute phase with systemic corticosteroids resulted in a significantly higher probability of improvement in visual acuity (P = 0.001) and visual field (P = 0.005) than in the untreated group.
I believe that this evidence cannot be completely ignored and that patients deserve the opportunity to hear about the results of this study in an objective manner from a trusted source. In my own practice, I explain to patients the results of the Hayreh studies and the controversial components. We review the difference between a patient choice methodology (such as Dr. Hayreh's work) and a randomized, prospective, controlled clinical trial. I believe that the published reports by Hayreh are useful for generating a hypothesis, but I acknowledge that for hypothesis testing, a randomized clinical trial is necessary. One of the worst things that can happen to a patient with an untreatable disease like NAION is for the physician to say, “Nothing can be done.” Admittedly, I am operating in a less than optimal and, in some cases, data free zone for many of my current therapeutic recommendations, but much of medicine remains outside the realm of Class I evidence. In addition, I acknowledge that corticosteroids have significant systemic side effects in elderly and patients with vasculopathy for whom steroids might worsen many systemic disorders including hypertension and diabetes.
I tend to steer patients away from steroids if they have minimal or mild visual loss from their NAION, severe or brittle diabetes or hypertension, active infections, or significant peptic ulcer disease history. On the other hand, for patients with 20/70 or worse visual acuity who I see within 2 weeks of onset of NAION and who do not have significant risk for steroid-related side effects, I do offer them the opportunity to choose or decline steroid treatment. Inevitably, patients who are told that nothing can be done will find the long list of purported therapies for NAION including the steroid literature. I would much prefer them to ask me questions and receive an informed opinion rather than getting all of their information from the Internet. I do not offer steroids to patients with 20/70 or better vision, who have risks for steroid use, or who are greater than 2 weeks out from the event. I am also more likely to offer steroid treatment in 3 clinical settings: patients with optic disc edema from NAION in whom no visual loss has occurred (incipient NAION), patients with monocular vision, or the uncommon patient with bilateral simultaneous NAION.
Finally, we might be dismissive of steroid therapy for NAION since this form of treatment has not been efficacious in ischemic events of the central nervous systems such as stroke. However, it is still unproven that ischemia due to arterial insufficiency is the cause of NAION. Inflammatory, mechanical, and venous etiologies have all been postulated for NAION and, with any of these mechanisms, steroids may play a beneficial role.
In summary, I believe until a randomized clinical trial is performed, the decision for steroids in NAION should be an individual one that is made by the patient and not by the doctor. In my opinion, the role of the physician is to treat vasculopathic risk factors of the patient, provide information for an informed decision, and act as a trusted source of therapeutic decision making in a controversial area.
CON-Steroids should not be offered to patients with nonarteritic anterior ischemic optic neuropathy: Valérie Biousse, MD
Although numerous practitioners recommend steroids to treat nonarteritic anterior ischemic optic neuropathy (NAION) (7), this practice is not based on any Class I evidence and is potentially dangerous (6). Not being able to offer treatment to patients with potentially blinding disorders is very difficult and frustrating, and it takes much longer to make a patient with NAION understand why no treatment is a reasonable option than to write a prescription for steroids. This might explain why approximately 10% of physicians reported treating NAION with oral steroids and 19% of neurologists chose high-dose intravenous steroids in a recent survey (6). Since this survey was conducted, a large case series proposing oral steroids within 2 weeks of onset of NAION was published (5), followed by a few case reports suggesting that intravitreal injections of steroids might also be used to treat NAION (8-10). These reports leave room for debate as to whether patients with NAION should receive steroids or not.
Because the pathophysiology of NAION remains elusive, it is difficult to propose informed hypotheses regarding treatment of NAION (7,11). Small vessel circulatory insufficiency of the optic nerve head is the most widely accepted pathophysiology of NAION, but the mechanism of ischemia remains uncertain (11-15). The optic nerve head is supplied by an anastomotic arterial circle (derived from the short posterior ciliary arteries) with distinct upper and lower halves, consistent with the altitudinal defects often seen in NAION (16). Fluorescein angiography studies provide the most compelling indirect evidence that circulatory insufficiency in the paraoptic branches of the short posterior ciliary arteries is the primary cause of NAION; however, no adequate systematic histopathologic studies of these vessels have been performed, and it is not known whether there is associated atherosclerotic change or thrombosis (12). Levin and Danesh-Meyer (15) even recently proposed that NAION may primarily be a venous disease; however, this theory remains speculative.
A number of well-designed studies in the neurologic literature have shown that steroids do not improve the outcome of patients with acute arterial or venous cerebral ischemia (17,18). Indeed, it has even been suggested that steroids can be detrimental to patients with acute cerebral ischemia and should not be prescribed (17,18). The same concerns may apply to NAION, which is a presumed vascular disorder, most often occurring in older patients who have vascular risk factors (19-21).
Initially widely used in acute cerebral injuries to reduce cerebral edema, steroids are currently limited to treating cerebral edema associated with brain tumors and bacterial meningitis. Over the past decade, studies have shown that the efficacy of steroids in acute spinal cord injury is limited and that steroids should not be prescribed to patients with acute traumatic brain injury or traumatic optic neuropathies (22). Although steroids are commonly used in numerous ocular disorders, including selected ocular vascular disorders, it is important to emphasize that the main purpose of the steroids in various ocular vascular disorders is to reduce retinal edema, a major cause of visual loss in diabetic retinopathy and retinal vein occlusion (23). Although a recent study utilizing optical coherence tomography (OCT) demonstrated that 8 of 76 patients with NAION examined within 4 weeks of visual loss had subfoveal fluid, likely responsible for some of the reversible visual loss (24), and the primary cause of irreversible visual loss in NAION is direct damage to the optic nerve (11). Administration of steroids to reduce macular edema does not seem necessary in most cases of NAION.
Patients with a small cup to disc ratio are predisposed to NAION and are said to have a disc at risk (4,25,26). It has been suggested that swelling within the confines of a tight disc may produce a compartment syndrome (4). The crowded axons swell in the restricted space, and capillaries and other small vessels among the nerve fibers are compressed, resulting in cytotoxic and vasogenic edema that worsens infarction and tissue loss. A number of medical and surgical interventions have been proposed to shorten the duration of disc edema, presumably to stop this vicious circle and treat the compartment syndrome (7,11).
Optic disc edema is by definition present in NAION and characteristically persists a few weeks (4,11). A recent study showed that the median time (25th-75th percentile) to spontaneous resolution of optic disc edema from onset of visual loss was 7.9 (5.8-11.4) weeks (4). Resolution time was longer in patients with diabetes than in patients without diabetes (P = 0.003), and multifactor analysis showed that worse initial visual field defects (P < 0.0001) and acuity (P = 0.04) were associated with faster resolution (4). There is, however, no evidence that decreasing the duration of disc edema improves visual outcome.
Interestingly, the rationale for the use of steroids in NAION comes from a study from the late 1960s that postulated that steroids would decrease capillary permeability, thereby inducing faster resolution of disc edema (1). This, in turn, would reduce compression of capillaries in the optic nerve head and improve blood flow, restoring the function of surviving but nonfunctioning ischemic axons. In that study (1), improvement in visual acuity occurred in 11 of 13 patients (85%) treated with systemic steroids (60 mg prednisone daily), compared to 5 of 11 patients (45%) not treated with systemic steroids. In 1974, Hayreh (3) reported improvement in visual acuity in 75% of 8 treated NAION eyes, compared to 17% of 6 untreated eyes. Neither study was randomized, and it is difficult to draw conclusions from so few subjects. There have been no studies using high-dose intravenous steroids in NAION and no randomized controlled studies investigating the role of oral or intravitreal corticosteroid therapy (7). The current controversy was triggered by a recent report by Hayreh and Zimmerman (5) supporting the use of oral steroids to treat acute NAION and a few anecdotal reports of patients with NAION treated with intravitreal injections of triamcinolone (8-10,27-29).
The recent large study by Hayreh and Zimmerman (5) suggested that oral prednisone might improve the visual fields and visual acuity of patients with NAION. In this nonrandomized study, patients self-selected their treatment and the examiner was not blinded to treatment. Despite the large number of patients, these 2 major causes of bias severely limit the validity of the study. In those patients treated with steroid therapy within 2 weeks, the median time to optic disc edema resolution was 6.8 weeks, compared to 8.2 weeks in untreated cases (P < 0.0001). However, the untreated group had more vascular risk factors (especially diabetes), making it impossible to objectively interpret the results. Indeed, the earlier resolution of disc edema seen in the treated group is particularly subject to selection bias, since patients with severe diabetes were much less likely to be treated, and the authors' own data have previously demonstrated that disc edema persists longer in patients with diabetes (4).
The rationale for intravitreal steroids is presumably the same as for systemic steroids. The advantages of intravitreal over systemic administration of steroids are obvious and include a potential greater effect on the retina (and optic nerve head) and reduced systemic complications. To date, 3 reports (8-10) have included 9 eyes with NAION treated with 4 mg of intravitreal triamcinolone acetonide (similar to what is routinely used in macular edema (23)) within 4-22 days of onset. The first report included 4 patients with NAION with severe visual loss (20/200 or worse) within 22 days of onset (8). The visual outcome was compared to 6 consecutive patients with NAION who received no treatment. All patients completed at least 9 months of follow-up. In the treated group, the mean improvement in visual acuity was 6.2 Snellen lines at the final visit. Optic disc swelling markedly decreased by the first postinjection week and had disappeared by 3 weeks in all eyes. In the nontreated group, the mean improvement in visual acuity was 1.3 lines at the final visit and optic disc swelling resolved between 4-12 weeks. The authors concluded that 4 mg of intravitreal triamcinolone acetonide provided better recovery of visual acuity and more rapid resolution of optic disc swelling, but no visual field improvement was seen in this small sample. This report was criticized by Hayreh (27) who emphasized that changes in fixation strategy may explain why the visual acuity improved, while the visual fields did not. He also emphasized that although intravitreal triamcinolone has the advantage of fewer systemic side effects, it may result in persistent increased intraocular pressure that may worsen optic nerve damage. Since this first report, 5 others reported that patients with NAION (4 from Turkey (9) and 1 from Korea (10)) have received 4 mg intravitreal triamcinolone acetonide, 4-10 days after visual loss. All patients experienced some visual improvement and the authors suggested that triamcinolone improved disc edema (9,10). However, a previous report from Germany (28) described 3 patients treated with a much higher dose (20 mg) of intravitreal triamcinolone within 1 week of visual loss. One eye developed triamcinolone-induced ocular hypertension, and visual acuity did not improve in these patients.
NAION remains frustrating for clinicians and often devastating for patients. The pathophysiology remains unclear, and it is uncertain whether any treatment will be effective for NAION (7). The role of steroids remains controversial, and although steroids (particularly intravitreal steroids) might accelerate resolution of disc edema, there is currently no evidence that a shorter duration of disc edema is associated with improved visual outcome (29); additionally, the benefits of steroids on possible associated macular edema are probably very limited clinically. Results of recent studies need to be interpreted carefully, and controversy should be seen as stimulus to expand our research on the pathophysiology and treatment of NAION rather than as proof that steroids are an effective treatment for acute NAION (29).
I do not currently recommend the use of steroids (intravenous, oral, or intravitreal) to treat NAION, and I limit their use to those cases with arteritic anterior ischemic optic neuropathy.
Rebuttal: Andrew Lee, MD
Dr. Biousse nicely outlines the con side of the controversy. I have no problem with the facts that she elucidated, namely, that there is no Class 1 evidence (i.e., randomized controlled clinical trial) for the use of steroids in NAION. The absence of proof of efficacy however is not the same as proof of the absence of efficacy. I readily acknowledge that there is a junk yard in medicine littered with treatments, touted as effective anecdotally for multiple conditions, which are only later found to be ineffective or even harmful. Nevertheless, many treatments that have been proven to be effective in a large randomized clinical trial had their humble start in anecdotal case reports, case series, or observational cohorts.
The idea that reduction of macular edema might be one mechanism for the improvement in NAION after steroids is intriguing, and high-resolution OCT might show that subretinal fluid is a more common cause of visual loss in NAION than we think. After all, to paraphrase Goethe, “we only look for what we know and we only find that which we look for.” Finally, and perhaps most compelling, I do not believe that it is the role of the physician to decide what treatments should or should not be offered to or withheld from the patient. Today's patients are more informed, more savvy of new technology, and more engaged in their care than in generations past. My patients in Houston want to know about all the available treatments including the proven, the unproven, and, yes, the controversial. I believe that it is my role to inform, to advise, and in some cases, to recommend one or more options, but I do not think that it is my role to decide what they should do. The litmus test in my opinion is “What would you do if it was your eye?”
Rebuttal: Valérie Biousse, MD
Dr. Lee acknowledges being in a “data free zone” when treating patients with NAION. The history of medicine is filled with examples of treatments administered to thousands of patients without strong evidence, that later turned out not only to be ineffective, but also harmful. Optic nerve sheath decompression for NAION (30), corticosteroids for traumatic optic neuropathy and traumatic brain injury (22), oral steroids for acute optic neuritis (31), systematic anticoagulation for cerebral ischemia (17), and indiscriminatory carotid endarterectomy (17) are only a handful of these examples. I never tell a patient that “there is nothing to do” and I carefully weigh treatment options. However I do not prescribe a treatment based on a patient's request. Indeed, one of the roles of physicians is to decide what treatments should or should not be offered to patients, most of whom do not have the experience or training to make such decisions. It is because we as physicians have such an enormous responsibility, that we need to be as rigorous as possible in our recommendations. Modern medicine is about evidence, which remains weak in NAION.
Summary: Lanning B. Kline, MD
This Point Counter-Point highlights 2 issues that have proven very frustrating for clinicians in dealing with patients with NAION: 1) the underlying pathophysiology of NAION remains unknown, and 2) we have less than optimal data dealing with the treatment of this optic neuropathy.
Drs. Lee and Biousse have clearly addressed the pro and con sides of the use of corticosteroids in patients with NAION. They have outlined the 2 conundrums listed above yet realize that the practice of medicine is often imperfect. Much to his credit, Sohan Hayreh, MD, has gathered, in a meticulous fashion, a tremendous amount of clinical data on the natural course of NAION in both patients untreated and those given systemic steroids. Lacking a prospective, randomized, double-masked clinical trail, the results of Hayreh's studies provide the best data we have. As physicians, we do not want to deprive our patients of any treatments that may lead to improved visual function, yet at the same time, we strive to practice evidence-based medicine and use caution in prescribing corticosteroids, a treatment with significant potential side effects.
I hope you enjoyed reading this new format of Point Counter-Point. I look forward to filling the pages of Letters to the Editor with your comments. Please join in the discussion of this important yet controversial topic!
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