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.
Author Year Country Research Design PEDro Sample Size |
Methods | Outcomes |
Aminmansour et al. (2016)
Iran RCT PEDro= 9 Ninitial= 32, Nfinal= 32 |
Population: Progesterone + Vitamin D group: Mean age= 41.88±13.6yr; Gender: male= 56.2%, female= 43.8%; Level of injury: cervical, thoracic, lumbar; Severity of injury: Incomplete. Placebo group: Mean age= 45.2±13.7yr; Gender: male= 50%, female= 50%; Level of injury: cervical, thoracic, lumbar; Severity of injury: Incomplete.
Treatment: Patients were first administered methylprednisolone per standard protocol. Patients were then randomly assigned to receive progesterone (0.5 mg/kg) twice daily and vitamin D3 (5ug/kg) twice daily or placebo for up to 5 days. Outcome Measures: Assessed baseline, 6 days, 3 and 6 months post-injury. ASIA motor and sensory scores Chronicity: Individuals were studied within 8 hr of sustaining injury. |
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Costa et al. 2015
Italy RCT PEDro= 7 Ninitial= 19, Nfinal= 19 |
Population: Mean age= 27.67y Gender: male= 94.7%, female= 5.3%; Level of injury: cervical, thoracic; Severity of injury: AIS A or B
Treatment: Participants were randomized to receive either methylprednisolone or erythropoietin treatment groups for 48 hours. Outcome Measures: ASIA motor and sensory, MAS, Penn Score, VAS, SCIM. Evaluated at baseline, day 3, 7, 14, 30, 60, and 90. Chronicity: Screened and enrolled within 8 hours of sustaining injury. |
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Pointillart et al. (2000)
(English translation of Petitjean et al. (1998)) France RCT PEDro=6 N=106 |
Population: Age range=20-47 yr; Gender: male=90%, female=10%; Level of injury: not specified; Severity of injury: complete=45%, incomplete=55%.
Treatment: Patients were randomly assigned to one of four groups: methylprednisolone (MP), nimodipine, MP + nimodipine, or no treatment. The dosages of nimodipine were 0.15 mg/kg/h over 2 hr followed by 0.03 mg/kg/h for 7 days. The dosages of MP followed National Acute Spinal Cord Injury Study (NASCIS) II guidelines and were 30 mg/kg over 1 hr followed by 5.4 mg/kg/h for 23 hr. Outcome Measures: The following after 1 year: neurological function based on ASIA score (motor and sensory), adverse event outcomes. Chronicity: Individuals were hospitalized within 8 hr of sustaining injury. |
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Pettersson & Toolanen (1998)
Sweden RCT PEDro=8 N=40 |
Population: Mean age=35 yr; Gender: male=55%, female=45%; Level of injury: not specified; Severity of injury: complete=0%, incomplete=100%.
Treatment: Patients treated for whiplash injuries received either methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or placebo. Outcome Measures: The following after 6 months: degree of disabling symptoms, total number of sick days from work, sick-leave profile 6 months after injury. Chronicity: Individuals were administered treatment within 8 hr of sustaining injury. |
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Bracken et al. (1997)
USA RCT PEDro=7 N=499 |
Population: Mean age: not specified; Gender: male=85%, female=15%; Level of injury: not specified; Severity of injury: complete=50%, incomplete=50%;
Treatment: Patients were randomly assigned to receive either methylprednisolone (MP) for 24 hr (5.4 mg/kg), MP for 48 hr (5.4 mg/kg), or tirilazad mesylate for 48 hr (2.5 mg/kg). All treatment groups initially received a bolus of MP (30 mg/kg). All patients received the study drug within 8 hr of injury. The 24 hr MP group served as the reference; there was no placebo group. Outcome Measures: The following after 6 weeks and 6 months: motor function, sensory function (pinprick, light touch, deep pain), adverse event outcomes. The following after 6 months: Functional Independence Measure (FIM). Chronicity: Individuals received the study treatment within 8 hr of sustaining injury.
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Overall Analyses:
Analyses of Time to Loading Dose (within 3-8 hr vs >8 hr):
Analyses of Severity of the Injury (complete vs. incomplete):
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Bracken et al. (1998)
(One year follow up to Bracken et al. (1997)) N=431 |
Outcome Measures: The following after 1 year: motor function, sensory function (pinprick and light touch), Functional Independence Measure (FIM). | Initial Analysis:
Analyses of patients treated within 3 hr compared to patients treated between 3-8 hr:
Analyses of Severity of the Injury (complete vs. incomplete):
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Bracken et al. (1990)
USA RCT PEDro=10 N=487 |
Population: Mean age: not specified; Gender: not specified; Level of injury: not specified; Severity of injury: complete=60%, incomplete=40%.
Treatment: Patients were randomly allocated to receive either methylprednisolone (MP; 62.5 mg/mL), naloxone (25 mg/mL) or placebo. Both drugs were administered as a 15 minute loading dose followed by a 23 hr maintenance dose. Chronicity: Individuals were randomized to study groups within 12 hr of sustaining injury.
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Overall Analysis:
Analyses of Time to Loading Dose (≤8 h vs >8 h):
Analyses by Injury Severity:
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Bracken et al. (1992)
(One year follow up to Bracken et al. (1990)) N=427 |
Outcome Measures: The following after 1 year: motor function, and sensory function (response to pinprick and touch sensation) |
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Wu et al. (2011)
Taiwan Case Control N=32 |
Population: Mean age=41.7 yr; Gender: male=84%, female=16%; Level of injury: cervical-lumbar; Severity of injury: complete=9%, incomplete=91%.
Treatment: Patients either received methylprednisolone (MP) within 8 hr post injury or delayed MP treatment (≥8 hr of sustaining injury). Outcome Measures: The following after questionnaire follow up (time span 3-69 months post injury): severity of pain and presence of neuropathic pain. Chronicity: The time period since injury ranged from 3-69 months. |
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Ito et al. (2009)
Japan Case control N=79 |
Population: Mean age: not specified; Gender: male=80%, female=20%; Level of injury: cervical; Severity of injury: complete=27%, incomplete=73%, AIS A-D.
Treatment: Patients were either given methylprednisolone sodium succinate (MPSS) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines (2003-July 2005) or no MPSS (August 2005-2007). Outcome Measures: The following after 3 months: neurological recovery using the ASIA motor score and ASIA impairment score at 3 months post injury, and complications. Chronicity: Individuals received treatment within 8 hr of sustaining injury. |
Overall Analyses
Analyses of Severity of Injury and Type of Injury:
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Zhuang et al. (2008)
China Pre-Post Test N=43 |
Population: Mean age=43.4 yr; Gender: male=77%, female=23%; Level of injury: cervical-lumbar; Severity of injury: complete=28%, incomplete=72%.
Treatment: All patients received methylprednisolone (MP) 30 mg/kg for 15 minutes and 5.4 mg/kg/h for 23 hr after a 45 minute interval, according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines. Outcome Measures: The following after MP treatment compared to before MP treatment (time period not specified): sensory function (acupuncture sense and light touch) and motor function. Chronicity: Individuals received treatment within 8 hr of sustaining injury. |
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Suberviola et al. (2008)
Spain Case Control N=82 |
Population: Mean age: not specified; Gender: male=84%, female=16%; Level of injury: cervical and non-cervical; Severity of injury: complete=54%, incomplete=46%.
Treatment: Patients either received methylprednisolone (MP) 30 mg/kg for 15 minutes and 5.4 mg/kg/h for 23 hr after a 45 minute interval, according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or no MP. Outcome Measures: The following after intensive care unit discharge: mortality, neurological function using the Frankel scale, adverse event outcomes. Chronicity: Individuals were hospitalized within 8 hr of sustaining injury. |
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Leypold et al. (2007)
USA Case Control N=82 |
Population: Mean age: not specified; Gender: male=80%, female=20%; Level of injury: cervical; Severity of injury: complete=100%, incomplete=0%, AIS A.
Treatment: Patients were treated with methylprednisolone (MP) bolus 30 mg/kg plus 5.4 mg/kg/h for 24 hr, according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines (1987-1993), or were given no MP (1998-2002; historical controls). Outcome Measures: The following within 3 days of injury using MRI: presence/absence of intramedullary hemorrhage, length of intramedullary hemorrhage, length of spinal cord edema. Chronicity: Individuals received treatment within 8 hr of sustaining injury. |
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Lee et al. (2007)
China Case Control N=138 |
Population: Mean age=48.5 yr; Gender: male=68%, female=32%; Level of injury: C2-C7; Severity of injury: complete=69%, incomplete=31%.
Treatment: Patients either received methylprednisolone (MP; according to National Acute Spinal Cord Injury Study (NASCIS) II and III guidelines) or received no MP. Some patients also received surgery. Outcome Measures: The following at follow-up examination (unspecified date): neurological function using the Frankel scale, adverse event outcomes. Chronicity: The mean interval between injury and transfer and injury and transport was 6.9 hr and 23 minutes, respectively. |
*Patients not stratified by those receiving MP only vs. MP plus surgery, or those receiving MP according to NASCIS II vs. NASCIS III (for those who did not receive MP). |
Tsutsumi et al. (2006)
Japan Case Control N=70 |
Population: Age range=13-86 yr; Gender: male=86%, female=14%; Level of injury: cervical; Severity of injury: complete=61%, incomplete=39%, AIS A-D.
Treatment: Patients received methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or no MP. Outcome Measures: The following after 6 weeks and 6 months: neurological recovery using the ASIA motor scale, improvement in myotomal level. The following within 6 weeks: adverse event outcomes. Chronicity: Individuals were admitted to hospital within 7 days after sustaining injury. |
Overall Analyses:
Analyses of Severity of the Injury (complete vs. incomplete):
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Rasool et al. 2004
India Prospective Controlled Trial N=48 |
Population: Mean age: not specified; Gender: male=80%, female=20%; Level of injury: cervical; Severity of injury: complete=20%, incomplete=80%.
Treatment: Patients received methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or no MP (control group). Outcome Measures: The following after 6 weeks and 6 months: neurological function using the ASIA scale (both motor and sensory function). Chronicity: Individuals who presented to hospital within 8 hr of sustaining injury received treatment. Those who presented later than 8 hr post injury were placed in the control group. |
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Pollard & Apple (2003)
USA Case Control N=412 |
Population: Mean age: not specified; Gender: not specified; Level of injury: cervical; Severity of injury: complete=0%, incomplete=100%.
Treatment: Patients received methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or did not receive MP. Outcome Measures: The following after discharge from rehabilitation: neurological function using the ASIA scale. Chronicity: Individuals were admitted to hospital within 90 days of injury. |
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Poynton et al. (1997)
Ireland Case Control Ninitial=71, Nfinal=63 |
Population: Age range=17-76 yr; Gender: not specified; Level of injury: not specified; Severity of injury: complete=58%, incomplete=42%.
Treatment: Patients admitted before 8 hr of injury received methylprednisolone (MP) 30 mg/kg for 15 minutes and 5.4 mg/kg/h for 23 hr after a 45 minute interval according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines; patients admitted after 8 hr of injury received no MP. Outcome Measures: The following at a follow-up examination (mean=29.6 months): neurological function using ASIA motor and sensory scores. Chronicity: Individuals who presented to hospital within 8 hr of sustaining injury received treatment. Those who presented later than 8 hr post injury did not receive treatment. |
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Heary et al. (1997)
USA Case Control N=254 |
Population: Mean age=26 yr; Gender: male=91%, female=9%; Level of injury: cervical-lumbar; Severity of injury: complete=75%, incomplete=25%.
Treatment: Patients with gunshot wounds to the spine either received methylprednisolone (MP; according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines), dexamethasone (initial dose of 10-100 mg), or no steroids. Outcome Measures: The following at follow-up examination (unspecified date): Frankel score, AIS score, adverse event outcomes. Chronicity: Thirty-one patients received MP within 8 hr of injury. Of patients initially treated at an outside hospital (n=119), 95% were transferred to the study hospital within 48 hr of injury. |
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Merry et al. (1996)
USA Case Control Ninitial=19, Nfinal=15 |
Population: Mean age=50 yr; Gender: male=53%, female=47%; Level of injury: cervical-lumbar; Severity of injury: complete=0%, incomplete=100%.
Treatment: Patients with incomplete SCI received steroids (either methylprednisolone (MP), dexamethasone or both) or no steroids. Treatments differed with regards to duration, combination, and protocol among patients. Outcome Measures: The following at hospital discharge: neurological function using Frankel scale, adverse event outcomes. The following at last clinic visit (mean=14.4 months): neurological function using Frankel scale. Chronicity: Four of 6 patients treated before May 1990 were administered steroid treatment on average 7 hr post injury. Eight of 13 patients treated after May 1990 received steroid treatment on average 4 hr post injury. One patient received treatment 41 hr post injury. |
*No statistical analyses were performed. |
Levy et al. (1996)
USA Case Control N=236 |
Population: Mean age=25.6 yr; Gender: male=94%, female=6%; Level of injury: cervical-lumbar; Severity of injury: complete=55%, incomplete=45%.
Treatment: Patients with penetrating gunshot wounds either received methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II within 8 hr of admission or did not receive MP. Outcome Measures: The following at discharge from rehabilitation compared to admission to rehabilitation: neurological function based on the Frankel scale, autonomy after injury, ability to ambulate. The following during hospital stay: adverse event outcomes. Chronicity: Individuals received steroid treatment within 8 hr of sustaining injury. |
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Gerhart et al. (1995)
USA Case Control N1990-1991=151, N1993=127 |
Population: Mean age: not specified; Gender: not specified; Level of injury: cervical-sacral; Severity of injury: Frankel A-D.
Treatment: Patients either received methylprednisolone (MP) according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines or did not receive MP. Two observation periods were analyzed: 1990-1991 and 1993. Outcome Measures: The following at hospital discharge: neurological function based on the Frankel Scale. Chronicity: Not specified. |
Analyses During 1990-1991:
Analyses During 1993:
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George et al. (1995)
USA Case Control Ninitial=145, Nfinal=130 |
Population: Mean age=34 yr; Gender: male=77%, female=23%; Level of injury: cervical, dorsal spine region, lumbar; Severity of injury: complete=64%, incomplete=36%.
Treatment: Patients were analyzed from a 1989-1992 registry. Those from the first half of this time span were given no methylprednisolone (MP) and patients from the second half of this time span were given MP according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines. Outcome Measures: The following at hospital discharge: mortality, patient mobility, adverse event outcomes. The following at rehabilitation discharge (when available): Functional Independence Measure (FIM). Chronicity: Mean time from injury to treatment administration was 152 minutes. |
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Prendergast et al. (1994)
USA Case Control N=54 |
Population: Mean age=35.8 yr; Gender: male=80%, female=20%; Level of injury: not specified; Severity of injury: complete=46%, incomplete=54%.
Treatment: Patients were given no methylprednisolone (MP; before 1990) or were given MP according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines (after 1990). Outcome Measures: The following after 4 days, 1 week, 2 weeks, 1 month, and two months: motor function, sensory function (pinprick and light touch). Chronicity: Not specified. |
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Kiwerski (1993)
Poland Case Control N=620 |
Population: Mean age: not specified; Gender: not specified; Level of injury: cervical; Severity of injury: complete=60%, incomplete=40%.
Treatment: Patients received one of three treatments during 1976-1991: low doses dexamethasone (<24 mg), high doses dexamethasone (>24 mg), or no dexamethasone. The dosages and duration of delivery varied from patient to patient. Outcome Measures: The following during hospital stay: neurological recovery (outcome measure not specified). Recovery is considered ‘marked’ if patient advanced 2 degrees on the scale or if paresis disappeared. Chronicity: Individuals were admitted to hospital within 24 hr post injury. |
No statistical analyses were reported. |
Galandiuk et al. (1993)
USA Case Control N=32 |
Population: Mean age: not specified; Gender: not specified; Level of injury: cervical-thoracic; Severity of injury: complete=69%, incomplete=31.
Treatment: Patients received either methylprednisolone (MP; from 1990-1993) 30 mg/kg followed by 5.4 mg/kg/h for 23 hr, according to National Acute Spinal Cord Injury Study (NASCIS) II guidelines, or no MP (from 1987-1993). Outcome Measures: The following during hospital stay: length of hospital stay, adverse event outcomes and length of hospital stay, the immunosuppressive effects of steroids. The following after 6 months: motor function, sensory function. Chronicity: Not specified. |
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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.