Ophthalmology Practice Controversies in neuro‑ophthalmology: Steroid therapy for traumatic optic neuropathy Rohit Saxena, Digvijay Singh, Vimla Menon Background: There is an increase in the incidence of traumatic optic neuropathy (TON) due to increasing urbanization and rapid spurt in the number of motor vehicles on the road. Despite early presentation and ease of diagnosis the visual outcomes in TON are still limited. There is also significant confusion about the timing, dose and efficacy of steroid treatment in its management. Purpose: To provide a clinical update of the pros and cons of steroid therapy for TON. Design: The paper is a retrospective review of the currently available literature in the English language indexed in PubMed. Methods: A PubMed search was conducted by the authors using the following terms: Traumatic optic neuropathy, megadose, steroids, methylprednisolone. Relevant original articles, review articles, and case reports related to the topic of discussion were evaluated and discussed in the paper. Results: There is no prospective randomized control trial evaluating the effect of steroids in TON. There are varying reports on the effect of steroid therapy from significant improvement to no difference compared to observation. Conclusion: The decision to give steroids to patients with TON has to be on an individual case to case basis and must involve informed consent from the patient. There are documented advantages and disadvantages of steroid therapy and a prospective, randomized, controlled trial is necessary comparing steroids, surgery and observation before definitive management can be evolved.

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Key words: Megadose, methylprednisolone, steroids, traumatic optic neuropathy

Traumatic optic neuropathy (TON) refers to an acute injury of the optic nerve secondary to trauma. In the presence of history of nonpenetrating trauma to the forehead or malar region, subconjunctival hemorrhage, a relative afferent pupillary defect in unilateral cases and a normal fundus in the early posttraumatic period, the diagnosis can be made with relative ease. There may be associated injury to the orbital/facial bones but severe signs of blunt trauma to the eye are uncommon often only sign of injury being subconjuctival hemorrhage.[1] It is most commonly seen in young adult males in the setting of a road traffic accident or an alleged assault.[2] However, it is the management that is controversial. In this manuscript, we examine the factors that make therapeutic decision making in TON so difficult and focus on the controversies regarding use of steroids for treatment.

Anatomy and Pathophysiology Currently two basic mechanisms for TON are understood. Direct mechanical injury to the optic nerve causing a tear or interruption of the nerve which has a worse prognosis. Indirect injury is a closed injury causing a reactionary edema in the nerve sheath which can compromises the vascular supply and neurotrophic supply of the ganglion cells by compressing the nerve in the tightly packed optic canal. In both these processes, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India Correspondence to: Dr. Vimla Menon, Room No. 485, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi ‑ 110 029, India. E‑mail: [email protected] Manuscript received: 07.07.14; Revision accepted: 10.10.14

there is retrograde degeneration of the ganglion cells which are irreversibly lost. The optic nerve is surrounded by pia, arachnoid, and dura mater which move along with the optic nerve during normal eye movements. At the entry to the optic canal, the optic nerve sheath fuses with the sphenoid periosteum and at the posterior foramen with an overlying falciform fold of dura. Therefore, the nerve and its sheath are tightly fixed to the bony canal within a confined space. In indirect TON cases, optic nerve injury results from shearing forces to the fibers or to the vessels supplying the nerve. Cadaveric skull studies have demonstrated that if a force is given at the frontal bone or malar eminences they are concentrated and transferred to the optic canal. As the dural sheath is tightly adhered to the periosteum inside the optic canal this force is transferred to the nerve. Such injury leads to ischemic injury to the retinal ganglion cells within the optic canal followed by optic nerve swelling. This increases the intraluminal pressure of the canal further exacerbating retinal ganglion cell degeneration and compromises the vascular blood supply.

Treatment Therapeutic options for TON revolve around minimizing the damage by stemming the above mechanisms.[3] The basic concept is to decompress the nerve by either decreasing the edema by steroid therapy or creating more space by surgical decompression. The controversy in therapy of TON primarily stems from two facts. Firstly, literature lacks a well‑executed randomized controlled clinical trial, due to both the relative difficulty in recruitment of adequate numbers and the highly heterogeneous presentation of such patients. The second reason is the unpredictable yet frequent incidence of spontaneous recovery.

October 2014

Saxena, et al.: Steroid therapy in traumatic optic neuropathy

Steroid therapy in TON has been examined in multiple case series, mostly nonrandomized, unblended and without controls.[4,5] The doses used in these trials can be categorized as follows: Moderate dose (60–100 mg of oral prednisolone), high dose (1 g of intravenous [IV] methylprednisolone/day), or megadose (30 mg/kg loading dose of IV methylprednisone, followed by 5.4 mg/kg/h for 24 h). The expected role of steroids has been in reducing inflammation and edema in the closed confines of the optic canal thereby preventing secondary compressive damage and providing neuroprotection by virtue of preventing free radical induced lipid peroxidation. The initial concept of the role of steroids was derived from the National Acute Spinal Cord Injury Study 2.[6] This was a multicenter clinical trial evaluating the role of steroids in patients with acute brain and spinal cord injury. The study evaluated the role of placebo, methylprednisolone, or naloxone in the outcome of these cases. The results showed that methylprednisolone (30 mg/kg loading dose, followed by 5.4 mg/kg/h for 24 h) started within 8 h of injury resulted in a significant improvement in neurological outcome compared with placebo. This fuelled an increasing role of IV steroids in the treatment of TON. Several studies though mostly retrospective have shown that patients with both conventional or megadose steroids have a greater likelihood of improvement in vision compared to natural recovery.[7,8] Subsequently the Corticosteroid Randomization After Significant Head injury trial was a large randomized placebo controlled study evaluating used the role of megadose of steroids in traumatic brain injury compared to placebo.[9] This study had to be stopped early due to the significantly increased risk of death in patients that received megadose steroids compared with the placebo group. The important difference with the previous study was the presence of significant head injury in these patients. Due to the widely differing results of these two major studies and the histological differences between the spinal cord and optic nerve there are concerns about extrapolating data from spinal cord injury studies to TON. The International Optic Nerve Trauma study was a comparative nonrandomized interventional study with concurrent treatment groups involving 133 enrolled patients. [10] The study included patients who had an initial visual assessment within 3 days of injury and were willing for at least 1 month of follow‑up. On the basis of treatment received within 7 days of injury, patients with unilateral injuries were categorized as being in one of three treatment groups: Untreated (n = 9), corticosteroid (n = 85), or optic canal decompression surgery (n = 33). The study found no difference between steroid therapy as against surgical or no intervention with 52% who received steroids showing visual improvement of three or more lines versus 57% in the observation group. The medical treatment included five levels of therapy ranging from low dose (5400 mg/day). The study concluded that neither the dosage nor the timing of steroid therapy had an effect on visual recovery. Several other authors have concurred with these results.[11,12] While no animal study has demonstrated any beneficial effect of


steroid treatment, a dose dependent decrease in axons with increasing dose of steroids indicating negative impact of high doses of steroids on the injured optic nerve axon has been demonstrated.[13,14] Moreover, megadose IV steroids are not without side effects including steroid psychosis, immunosuppression and impaired glucose metabolism.

Conclusion There has been no large prospective placebo controlled trial evaluating the role of steroids for the treatment of TON and studies done till date show no convincing data that steroids provide additional benefit. While there is a relatively high rate of spontaneous visual recovery reported, anecdotal reports and case series have shown good outcomes with various doses of steroids. Current evidence definitely indicates that cases with concomitant brain injury may have poorer neurological outcomes with megadose steroids. Also in the presence of optic nerve transection or avulsion there is no advantage of treatment. Rationale of the use of lower doses of steroids for their anti‑inflammatory effect is though unsubstantiated can be considered safe in cases with isolated TON. In these cases, presenting with significant visual loss, having a definite lucid interval, that is, time between injury and loss of vision and those presenting within 8 h of the injury, high dose steroids may be offered. Each case therefore needs to be assessed on an individual basis and proper informed consent is essential before initiating IV steroids in TON.

References 1. Lessell S. Indirect optic nerve trauma. Arch Ophthalmol 1989;107:382‑6. 2. Pirouzmand F. Epidemiological trends of traumatic optic nerve injuries in the largest Canadian adult trauma center. J Craniofac Surg 2012;23:516‑20. 3. Spoor TC, Hartel WC, Lensink DB, Wilkinson MJ. Treatment of traumatic optic neuropathy with corticosteroids. Am J Ophthalmol 1990;110:665‑9. 4. Bendel RE, McHenry JG, Ramocki JM, Spoor TC. Traumatic optic neuropathy and intravenous megadose corticosteroids. Invest Ophthalmol Vis Sci 1993;34 Suppl: 1215. 5. Mauriello JA, DeLuca J, Krieger A, Schulder M, Frohman L. Management of traumatic optic neuropathy – A study of 23 patients. Br J Ophthalmol 1992;76:349‑52. 6. Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal‑cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405‑11. 7. Seiff  SR. High dose corticosteroids for treatment of vision loss due to indirect injury to the optic nerve. Ophthalmic Surg 1990;21:389‑95. 8. Spoor TC, McHenry JG. Management of traumatic optic neuropathy. J Craniomaxillofac Trauma 1996;2:14‑26. 9. Edwards P, Arango M, Balica L, Cottingham R, El‑Sayed H, Farrell B, et al. Final results of MRC CRASH, a randomised placebo‑controlled trial of intravenous corticosteroid in adults with head injury‑outcomes at 6 months. Lancet 2005;365:1957‑9. 10. Levin LA, Beck RW, Joseph MP, Seiff S, Kraker R. The treatment of traumatic optic neuropathy: The International Optic Nerve Trauma Study. Ophthalmology 1999;106:1268‑77. 11. Yu‑Wai‑Man P, Griffiths PG. Steroids for traumatic optic


Indian Journal of Ophthalmology

neuropathy. Cochrane Database Syst Rev 2011;CD006032. 12. Entezari M, Rajavi Z, Sedighi N, Daftarian N, Sanagoo M. High‑dose intravenous methylprednisolone in recent traumatic optic neuropathy; A randomized double‑masked placebo‑controlled clinical trial. Graefes Arch Clin Exp Ophthalmol 2007;245:1267‑71. 13. Steinsapir KD. Treatment of traumatic optic neuropathy with high‑dose corticosteroid. J Neuroophthalmol 2006;26:65‑7. 14. S t e i n s a p i r   K D , G o l d b e r g   R A , S i n h a   S , H o v d a   D A .


Methylprednisolone exacerbates axonal loss following optic nerve trauma in rats. Restor Neurol Neurosci 2000;17:157‑63.

Cite this article as: Saxena R, Singh D, Menon V. Controversies in neuroophthalmology: Steroid therapy for traumatic optic neuropathy. Indian J Ophthalmol 2014;62:1028-30. Source of Support: Nil. Conflict of Interest: None declared.

some cited by Saxena et  al., have radically changed what is appropriate for high‑dose corticosteroids.

Kenneth D Steinsapir Authors Saxena, Singh, and Menon (Saxena et al.) undertake the difficult task of analyzing the traumatic optic neuropathy (TON) literature. They correctly note that treatment has been controversial with a confusing array of small case series. Recent clinical series tend to indentify patients closer in time to injury compared to older series. Identifying TON patients close to the time of injury increases the opportunity to observe spontaneous visual recovery. The improved outcome is often incorrectly attributed to the use of high dose steroids or surgery rather than ascertainment bias.[1] Saxena et al. leave the reader with the conclusion that high dose steroid treatment should be used to treat TON presenting with significant visual loss, cases diagnosed within 8 h of injury, and in cases where there has been visual deterioration after the injury (i.e. a lucid period). I disagree with the authors: High‑dose steroids should not be given for TON under any circumstances.[1] The International Optic Nerve Trauma Study (IONTS) published in 1999, concluded that there was no clear evidence that corticosteroids or optic canal decompression were better than no treatment for TON.[2] The IONTS authors opined that clinicians had to make individualized choices based on this limited data. In the context of the IONTS, the guidelines presented by Saxena et  al. would have been reasonable. Since the publication of the IONTS, several lines of evidence, Access this article online Quick Response Code:

Vol. 62 No. 10

Website: www.ijo.in DOI: 10.4103/0301-4738.146022 PMID: ***

Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Correspondence to: Dr. Kenneth D. Steinsapir, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. E‑mail: [email protected] Manuscript received: 07.07.14; Revision accepted: 10.10.14

The first of these studies is the Corticosteroid Randomization After Significant Head Injury (CRASH) trial published in 2004.[3] This was a randomized, placebo‑controlled study of high‑dose methylprednisolone for head trauma. Patients were assigned within 8 h of trauma to treatment with placebo or high‑dose methylprednisolone (30 mg/kg loading followed by an infusion of 5.4 mg/kg/h) for 48 h. The study was designed to include 20,000 patients, but recruitment was halted at 10,008 patients for patient safety reasons. Data revealed a higher risk of death from all causes 2 weeks after trauma in the corticosteroid‑treated patients (21% vs. 18% mortality, P = 0.0001). This is one excess death for every 31 patients treated. TON commonly occurs in the setting of concomitant head trauma, so this study has immediate relevance.[1] No study of TON had used death as a study end point. We now understand that treatment of TON with high‑dose steroids will cause treatment‑associated mortality. What evidence exists that demonstrates the efficacy of high‑dose corticosteroids for TON that might balance the potential risks? In the intervening years since the IONTS, no new studies have established such a benefit. The authors cite one animal study that suggests high‑dose corticosteroids are toxic to traumatically injured optic nerve.[4] Two other animal studies also support this conclusion.[1,5] There are no well‑designed clinical studies that support the use of high‑dose corticosteroids for TON. The CRASH study proves this treatment causes loss of life in the setting of head trauma. Taken together, these lines of evidence suggest that TON patients treated with high dose corticosteroids are improving despite this treatment. As pointed out by Saxena et al., limited data suggests that corticosteroids treatment equivalent to methylprednisolone 1 mg/kg every 6 h may not be harmful to traumatically injured optic nerve. This means that patients with TON who might benefit from standard doses of corticosteroids for other conditions can continue to receive them. It does not imply in anyway that these corticosteroids are useful for treating TON. Unless new experimental data defines a role for high dose steroids, their use in the treatment of TON should be abandoned.

References 1. Steinsapir KD, Goldberg RA. Traumatic optic neuropathy: An evolving understanding. Am J Ophthalmol 2011;151:928‑33.e2. 2. Levin LA, Beck RW, Joseph MP, Seiff S, Kraker R. The treatment of traumatic optic neuropathy: The International Optic Nerve Trauma Study. Ophthalmology 1999;106:1268‑77.

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Controversies in neuro-ophthalmology: steroid therapy for traumatic optic neuropathy.

There is an increase in the incidence of traumatic optic neuropathy (TON) due to increasing urbanization and rapid spurt in the number of motor vehicl...
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