AA

Summary

Despite promising results from preclinical and early phase clinical trials, the neuroprotective properties of pharmacotherapeutic candidates have been difficult to demonstrate when scaled to later phase clinical trials. This could be attributable to several factors. First, there is high variability in the potential for patient recovery, as individuals with cervical injuries tend to recover more neurological function than those with thoracic injuries (Casha et al. 2012; Fehlings et al. 2011). Likewise, patients with incomplete injuries tend to recover more so than those with complete injuries (Bracken et al. 1997; Pitts et al. 1995; Tsutsumi et al. 2006). Recovery also varies depending on age (Burns et al. 1997; Leypold et al. 2007; Pollard & Apple, 2003) and whether or not the SCI is penetrating as opposed to non-penetrating (Heary et al. 1997; Levy et al. 1996). Accommodating for these differences through sub-group analysis is hindered with statistical robustness of smaller sample sizes. Second, there has currently been no consensus regarding a method for selecting agents suitable for translation to humans based on preclinical performance. Tator et al. (2012) suggested that preclinical data should be assessed based on 1) the animal/injury model(s) used; 2) timing of therapy; 3) evidence of beneficial effects of therapy; 4) reproducibility/replication and publication of results; 5) safety/toxicity of the agent; and 6) other factors such as preclinical lab environments. That human injuries are variable in their etiology and are often accompanied by other injuries makes them less straight-forward to treat compared to SCI in well controlled animal models (Sharif-Alhoseini, 2014). Lastly, the efficacy of the drug also depends on the time when it was administered. Although timing of therapy is reported in the preclinical literature, it does not currently reflect feasible timing for treatment in humans ((Tator et al. 2012; Wilson & Fehlings, 2014).

Along with the 6 criteria proposed by Tator et al. (2012), only one other publication by Kwon et al. (2009) addressing preclinical grading criteria to determine translatability to human trials proposes an objective scoring system to select the most promising candidates for translation. Continued development and validation of a preclinical scoring system involving worldwide experts in preclinical and clinical SCI is the next step towards selecting the next most promising pharmacotherapy for translation to humans (Tator et al. 2012).

In the interim, there is currently no pharmaceutical therapy recognized as the standard of care for neuroprotection during acute SCI. To date, EPO, G-CSF, TRH, and riluzole must be considered carefully due to the small study sample sizes used to investigate these pharmaceutical agents. Alternative study design methods might also be considered to mitigate for the large sample sizes required in a relatively small and heterogenous patient population to reach statistical significance ((Tanadini et al. 2014) for a potential pharmacotherapeutic agent to be proven effective as a neuroprotectant in acute SCI.

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; Bracken et al. 1990) that naloxone is not effective for the promotion of neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Bracken et al. 1997) that tirilazad mesylate is no more effective than methylprednisolone in promoting neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Pointillart et al. 2000) that nimodipine is not effective in promoting neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT and one prospective controlled trial; Alibai et al. 2014; Xiong et al. 2011) that erythropoietin is effective in promoting neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Geisler et al. 2001a, 2001b, 2001c) that GM-1 ganglioside is not effective in promoting neurological recovery in acute SCI individuals; However, there is level 1b evidence (from one RCT; Geisler et al. 1991, 1992) that GM-1 ganglioside may be effective in promoting neurological recovery in acute SCI individuals.

There is level 2 evidence (from one cohort study and one prospective controlled trial;Kamiya et al. 2014; Takahashi et al. 2012) that a moderate dose (10 µg/kg/day) of granulocyte-colony stimulating factor may be effective in promoting motor and sensory recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Pitts et al. 1995) that thyrotropin-releasing hormone may be effective in promoting neurological recovery in individuals with incomplete acute SCI.

There is level 2 evidence (from one RCT; Tadie et al. 2003) that gacyclidine is not effective in promoting neurological recovery in acute SCI individuals.

There is level 2 evidence (from one prospective controlled trial; Fehlings et al. 2011) that Cethrin® is a safe and tolerable drug, and may promote neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Casha et al. 2012) that minocycline is not effective in promoting motor or sensory recovery in acute SCI individuals.

There is level 2 evidence (from one cohort study; Grossman et al.  2014) that riluzole may be effective in promoting long term motor or sensory recovery in acute SCI individuals.