Journal of Neuro-Ophthalmology, March 2006, Volume 26, Issue 1

Treatment of Traumatic Optic Neuropathy with High-Dose Corticosteroid

Based on the favorable clinical results in acute spinal cord injury, high-dose methylprednisolone at an intravenous loading dose of 30 mg/kg followed by a continuous infusion of 5.4 mg/kg/h for 24 or 48 hours has been adopted for the treatment of acute traumatic optic neuropathy (TON). Although there is anecdotal evidence of the efficacy of high-dose corticosteroid in this condition, there are no prospective, randomized trials to attest to its benefit. On the other hand, the largest retrospective study showed no benefit of high-dose corticosteroid treatment of TON. Moreover, subsequent study of such treatment of acute spinal cord injury has disclosed that the clinical benefit is modest and that treatment is actually harmful if administered more than eight hours after injury. A recently reported placebo-controlled randomized clinical trial of high-dose corticosteroids in head injury was stopped prematurely because of a significantly greater mortality in the corticosteroid-treated patients. Recent experimental studies suggest that methylprednisolone may be harmful to the optic nerve. Considering this clinical and experimental evidence, there is no basis for treating TON with high-dose corticosteroid.

VIEWPOINT Treatment of Traumatic Optic Neuropathy with High- Dose Corticosteroid Kenneth D. Steinsapir, MD Abstract: Based on the favorable clinical results in acute spinal cord injury, high- dose methylprednisolone at an intravenous loading dose of 30 mg/ kg followed by a con­tinuous infusion of 5.4 mg/ kg/ h for 24 or 48 hours has been adopted for the treatment of acute traumatic optic neuro­pathy ( TON). Although there is anecdotal evidence of the efficacy of high- dose corticosteroid in this condition, there are no prospective, randomized trials to attest to its benefit. On the other hand, the largest retrospective study showed no benefit of high- dose corticosteroid treatment of TON. Moreover, subsequent study of such treatment of acute spinal cord injury has disclosed that the clinical benefit is modest and that treatment is actually harmful if adminis­tered more than eight hours after injury. A recently reported placebo- controlled randomized clinical trial of high- dose corticosteroids in head injury was stopped prematurely be­cause of a significantly greater mortality in the corticosteroid-treated patients. Recent experimental studies suggest that methylprednisolone may be harmful to the optic nerve. Considering this clinical and experimental evidence, there is no basis for treating TON with high- dose corticosteroid. ( J Neuro- Ophthalmol 2006; 26: 65- 67) A s a recent Point Counter Point article in this journal demonstrated, high- dose methylprednisolone is fre­quently used in the treatment of traumatic optic neuropathy ( TON) ( 1). When colleagues are queried, they typically reply that in the absence of clear information, the treatment rationale is based more on the plaintiff's bar than evidence-based medicine. The authors of the International Optic Nerve Trauma Study, published in 1999, stated that there is " sufficient evidence to conclude that neither corticosteroids nor optic canal surgery should be considered the standard of care for patients with traumatic optic neuropathy" ( 2). But without Orbital and Ophthalmic Plastic Surgery Division, Jules Stein Eye Institute, The David Geffen School of Medicine at UCLA, Los Angeles, California. Address correspondence to Kenneth D. Steinsapir, MD, 11645 Wilshire Boulevard, Suite 750, Los Angeles, CA 90025; E- mail: kenstein@ ix. netcom. com evidence that the treatment is harmful, there has been a natu­ral reluctance to withhold high- dose corticosteroid for TON in the hope that it may be beneficial. Several new lines of evidence now support a firmer conclusion, namely that high-dose corticosteroid in treatment of TON may be harmful. WHAT IS HIGH- DOSE CORTICOSTEROID AND WHY HAS IT BEEN USED FOR TRAUMATIC OPTIC NEUROPATHY? High- dose corticosteroid refers to an intravenous loading dose of methylprednisolone at 30 mg/ kg followed by a continuous infusion of 5.4 mg/ kg/ h for 24 or 48 hours. This protocol was used to treat spinal cord injury in the second and third National Acute Spinal Cord Injury Studies ( NASCIS II and NASCIS III) ( 3,4). It was widely adopted for treatment of TON after the NASCIS II reported in 1990 that patients with spinal cord injury, if started on this pro­tocol within eight hours of injury, had a better clinical out­come than did placebo- treated patients ( 5). The scientific rationale for the use of this protocol was based on research into the mechanisms of action of cor­ticosteroids conducted by Demopoulos ( 6), Flamm ( 7), and Seligman ( 8) at New \ brk University; Hall and Braughler ( 9) at the Upjohn Company; and Anderson et al ( 10) at the University of Cincinnati. Their work led to the hypothesis that pathologic free radical reactions are initiated following major central nervous system trauma and that very high doses of corticosteroid functioned as antioxidants to inhibit free radical damage. Doses of methylprednisolone in the 15- 30 mg/ kg range were found to improve microcirculation, energy metabolism, post- injury histology, and functional outcomes in animal models of spinal cord injury ( 7,11,12). The NASCIS II was a multi- center, randomized, double-masked, and placebo- controlled study of acute spinal cord injury ( 3). Patients were randomized to one of three treat­ment arms within 12 hours of injury: placebo, naloxone, or methylprednisolone. Patients treated with high- dose meth­ylprednisolone within eight hours of injury had a small but measurable improvement in motor and sensory function compared with placebo- treated patients. But those treated with either medication more than eight hours after injury did not demonstrate an improvement in neurologic scores J Neuro- Ophthalmol Vol. 26, No. 1, 2006 65 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 26, No. 1, 2006 Steinsapir compared with placebo- treated patients. In fact, a post- hoc analysis of this study found that methylprednisolone treat­ment started more than eight hours after injury was actually detrimental to outcome ( 13). STUDIES OF TREATMENT OF TRAUMATIC OPTIC NEUROPATHY Since 1990, 16 major studies have reported the treat­ment of 715 patients with TON, 500 of whom received corticosteroid. None of these studies had appropriate con­trols and many had other substantial design flaws ( 5). Even the International Optic Nerve Trauma Study was a non­randomized, uncontrolled study with a lack of uniformity regarding corticosteroid dose, timing of treatment, and in­dications for optic canal decompression ( 2). A casual exam­ination suggests that treated patients in recent studies have better visual outcomes than do untreated patients from older studies. However, recent treatment studies tend to identify optic nerve trauma patients closer in time to the initial injury, making improvement more likely irrespective of whether they are treated ( 5). EXPERIMENTAL STUDIES Since the International Optic Nerve Trauma Study, three studies have been published examining the effects of high- dose methylprednisolone on experimental optic nerve injury and one on its effects on experimental optic neuritis. Two experimental TON studies ( 14- 16) involved ten- second optic nerve crush injuries that produced nearly complete disruption of all optic nerve axons. In the first study, by Ohlsson et al ( 14,15), high- dose methylprednisolone had no discernible effects, which is consistent with such a severe injury. In the second experimental TON study, Sheng et al ( 16) were able to show that high- dose methylprednisolone reduced the number of retinal ganglion cells that showed evidence of apoptosis. This effect may become clinically important if techniques are developed to regenerate injured optic nerves, in which case methods of preserving retinal ganglion cells will be critical. My experimental TON study ( 17) involved a five-second optic nerve crush injury in rodents that leaves intact approximately 25% of optic nerve axons. Thirty minutes after injury, animals received one of five intravenous treat­ments: saline, methylprednisolone 30 mg/ kg, 60 mg/ kg, 90 mg/ kg, or 120 mg/ kg, repeated at six- hour intervals for three additional treatments. Following a six- week recovery, the remaining axons in the injured nerves were counted. Saline- treated animals retained the greatest number of axons and there was a dose- dependent decline in axons with increasing doses of methylprednisolone. Methylpredniso­lone exacerbated axonal loss ( P < 0.02) ( 17). The study left unexplored whether a lower dose of methylprednisolone would be helpful. Diem et al ( 18) examined the effect of high- dose methylprednisolone on experimental autoimmune optic neuritis. In their study, methylprednisolone significantly increased apoptotic retinal ganglion cell loss. Methylpred­nisolone in a dose of 20 mg/ kg was administered once the animal developed optic neuritis to simulate pulse treatment. It was found that, compared with controls, animals with optic neuritis treated with methylprednisolone possessed fewer surviving retinal ganglion cells. This decline cor­responded to functional visual deterioration based on visual evoked potential testing. CONCERNS ABOUT CORTICOSTEROID TREATMENT OF ACUTE SPINAL CORD INJURY Several investigators have raised questions regarding the perceived efficacy of methylprednisolone for acute spi­nal cord injury and its inherent safety ( 19- 21). NASCIS II appeared to be a vindication of 30 years of basic science research on spinal cord injury that had suggested that meth­ylprednisolone was neuroprotective. However, clinical im­provement was modest. This limited benefit has to be weighed against the increased risk of sepsis and pneumonia found among patients treated with corticosteroids for 48 hours in the NASCIS III ( 4). Some critics have suggested that without stratifying patients between those treated within eight hours and after eight hours of spinal cord injury, the NASCIS II would not have shown a beneficial effect for methylprednisolone ( 19). These critics suggest that the time frame of eight hours was based on post- hoc analysis rather than a planned analysis point. The distinction is important because post- hoc stratification permits bias in the pre­sentation of data. Defenders of the study answer that a time stratification of the data was always intended ( 22). THE CORTICOSTEROID RANDOMIZATION AFTER SIGNIFICANT HEAD INJURY TRIAL RESULTS The results of the Corticosteroid Randomization After Significant Head Injury ( CRASH) trial ( 23) raise further concerns about corticosteroid treatment of head trauma. CRASH was a multi- center, randomized, and placebo-controlled study that investigated the value of methylpred­nisolone in the treatment of head trauma. Patients were randomized within eight hours of injury to placebo or high-dose methylprednisolone for 48 hours. The goal of recruit­ing 20,000 patients into the study was never reached because the study was stopped at 10,008 patients when safety moni­toring data revealed a higher risk of death from all causes at two weeks after trauma in the methylprednisolone- treated 66 © 2006 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Traumatic Optic Neuropathy J Neuro- Ophthalmol, Vol. 26, No. 1, 2006 patients ( 21%) than in the placebo- treated patients ( 18%, P = 0.0001). The CRASH study results are relevant because TON is associated with loss of consciousness in 40% - 72% of cases ( 5). These clinical findings, together with the newer ex­perimental data, provide a very cogent rationale for with­holding high- dose methylprednisolone in TON. REFERENCES 1. Levin LA, Baker RS. Management of traumatic optic neuropathy. JNeuroophthalmol 2003; 23: 72- 5. 2. Levin LA, Beck RW, Joseph MP, et al. 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