Steroids

To date, there have been two steroids used for neuroprotection in acute SCI: dexamethasone and methylprednisolone (MP). These pharmaceutical agents are both glucocorticoid steroids, which are known for their strong anti-inflammatory properties (Barnes 2006). Limited information on the role of dexamethasone for acute SCI exists, but the mechanism of action for MP is beginning to be better understood. MP has long been used to treat brain edema, although the dose administered for SCI is much higher (Heary et al. 1997). It has been reported that, in addition to its anti-inflammatory properties, the main role for this drug at high doses is to act as an antioxidant to scavenge reactive oxygen species (Hall 1992; Lee et al. 2005). Furthermore, MP is thought to inhibit lipid peroxidation (Hall 2003) and reduce cell apoptosis (Vaquero et al. 2006). The high doses administered very early after injury are necessary because the absorption into the spinal tissues rapidly decreases over time. Determining the appropriate MP dosage is complex due to its biphasic dose response curve whereby potential benefits at low doses transition to toxic effects at higher doses (Hall & Springer 2004).

Before testing for the efficacy of pharmacological treatments in acute SCI existed, dexamethasone was occasionally prescribed (Heary et al. 1997). Promise in animal models for MP resulted in the first randomized controlled trial (RCT) of any pharmacological agent for treating acute SCI (Bracken et al. 1984). The National Acute Spinal Cord Injury Study (NASCIS) conducted a trial comparing high and low dose MP. The results of this study suggested that patients who received high dose MP had no neurological improvement but significant increases in medical complications compared to those who received low dose MP. Following the release of this study, further RCTs and retrospective studies were launched to further understand the neuroprotective effectiveness of steroids during acute SCI.

Discussion

MP has been the main pharmacological treatment of acute SCI since the 1980s (Bracken et al. 1984), but its effectiveness still remains unclear. The first large-scale RCT to report significant neurological recovery due to do this pharmaceutical agent (NASCIS II, Bracken et al. 1990), and its follow up study (NASCIS III, Bracken et al. 1997) initiated the mandatory protocol that MP be the standard of care for all acute SCI patients. These studies have since received several criticisms for their statistical analyses, randomization methods and interpretations (Coleman et al. 2000; Hurlbert 2000; Nesathurai 1998; Short et al. 2000). For example, the initial overall findings reported no improvement between the group receiving MP and the groups that did not. Significant results were only obtained from subsequent post hoc analyses of a subset of individuals, and these results showed only minor improvements.

Following these concerns, several studies were launched to specifically address the efficacy of MP. As a result of the initial broad acceptance of MP as a required therapy, a randomized placebo comparison study was not feasible in North America due to ethical considerations. Researchers instead conducted retrospective studies comparing individuals injured before and after MP administration was mandated. Many of these studies found no effect of MP on neurological recovery (e.g., Ito et al. 2009; Pointillart et al. 2000; Pollard & Apple 2003; Poynton et al. 1997; Suberviola et al. 2008), with a few exceptions (e.g., Rasool et al. 2004; Tsutsumi et al. 2006). Overall improvements in motor and sensory function (due to MP or other methods) tend to be more likely in younger patients (Burns et al. 1997; Pollard & Apple 2003) and in patients with incomplete injuries more so than complete injuries (Tsutsumi et al. 2006; Zhuang et al. 2008).

One of the main concerns with administering MP unnecessarily is that it is known to have many side effects. The final NASCIS study reported MP to be significantly associated with urinary tract infections (Bracken et al. 1997). Studies have since confirmed that patients receiving MP experience significantly more total infections (Suberviola et al. 2008), pneumonia (Gerndt et al. 1997; Ito et al. 2009), pancreatitis (Heary et al. 1997) and gastrointestinal complications (Chikuda et al. 2014; Matsumoto et al. 2001) compared to patients who do not receive the drug. Higher rates of hyperglycemia (Pointillart et al. 2000), myopathy (Qian et al. 2005) and wound infection (Bracken et al. 1984; Ito et al. 2009) have also been attributed to MP. Because of rising concerns that this drug may only incur moderate benefits at the cost of high risk side effects, MP is now only a therapeutic option, and no longer the mandate, for treating acute SCI.

There have been no RCTs published investigating the effects of dexamethasone. One retrospective study examining the effect of this steroid also found no effect on neurological improvement, and this drug was associated with significantly more gastrointestinal complications than the control group (Heary et al. 1997).

One study prospectively assessed the effectiveness of progesterone and vitamin D in improving neurological recovery post acute SCI in a randomized clinical trial (Aminmansour et al. 2016) reported a neurological benefit (motor and sensory scores) for the experimental, but not placebo, group at 6 months. However, there were no improvements in ASIA scores.

Conclusion

There is level 1a evidence (from four RCTs, one pre-post test, one prospective controlled trial, and nine case control studies: Pointillart et al. 2000; Bracken et al. 1997; Bracken et al. 1998; Bracken et al. 1990; Zhuang et al. 2008; Rasool et al. 2004; Ito et al. 2009; Suberviola et al. 2008; Pollard and Apple 2003; Poynton et al. 1997; Heary et al. 1997; Levy et al. 1996; Gerhart et al. 1995; George et al. 1995; Prendergast et al. 1994) that methylprednisolone is not effective in promoting neurological recovery in acute SCI individuals.

There is level 1a evidence (from two RCTs and three case control studies: Pointillart et al. 2000; Bracken et al. 1997; Ito et al. 2009; Suberviola et al. 2008; Heary et al. 1997) that methylprednisolone is associated with the development of medical complications when used in acute SCI individuals; However, there is level 3 evidence (from three case control studies: TsuTsumi et al. 2006; Levy et al. 1996; Galandiuk et al. 1993) that methylprednisolone is not associated with the development of medical complications in acute SCI individuals.

There is level 3 evidence (from two case control studies: Heary et al. 1997; Kiwerski 1993) that dexamethasone is not effective in promoting neurological recovery in acute SCI individuals.

There is level 3 evidence (from two case control studies: Heary et al. 1997; Merry et al. 1996) that dexamethasone may be associated with the development of medical complications when used to treat acute SCI individuals.

There is level 1b evidence (from one RCT: Aminmansour et al. 2016) that progesterone and vitamin D is not effective in promoting neurological recovery in acute SCI individuals.