Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature

The Spine Journal 6 (2006) 335 343 Review Article Methylprednisolone treatment in acute spinal cord injury: the myth challenged through a structured analysis of published literature Faisal T. Sayer, MD, MSc*, Erik Kronvall, MD, Ola G. Nilsson, MD, PhD Department of Neurosurgery, Lund University Hospital, Lund 221 85, Sweden Received 27 May 2005; accepted 12 November 2005 Abstract Keywords: BACKGROUND CONTEXT: Methylprednisolone has evolved during the 1990s, through the results obtained from the National Acute Spinal Cord Injury Studies NASCIS II and III, as a standard treatment in acute spinal injury. PURPOSE: To evaluate the scientific basic for the use of methylprednisolone in acute spinal cord injury. STUDY DESING: Systematic review of the accumulated literature. METHODS: Critical evaluation of the data obtained in the NASCIS II and III studies plus other accumulated literature. RESULTS: Analyses have been made on subgroups of the study populations, and the results were based on statistical artefacts. Furthermore, improved functional recovery shown by these studies was not clinically significant. CONCLUSION: There is insufficient evidence to support the use of methylprednisolone as a standard treatment in acute spinal cord injury. Ó 2006 Elsevier Inc. All rights reserved. Methylprednisolone; Spinal cord injury; Spine trauma; Secondary injury; National Acute Spinal Cord Injury Study; NASCIS Introduction Spinal cord injury (SCI) is a catastrophic event that imposes an enormous medical, psychological, social, and economic impact on individuals, families and society [1]. During the First World War, the immediate mortality of SCI was 50-65% [2]. Today, life expectancy after SCI in the industrialized world is only slightly reduced [3,4]. In one study, the mean life expectancy of spinal cord injured people compared with that of the whole population was estimated to approach 70% for individuals with complete tetraplegia, 84% for complete paraplegia, and 92% for patients with an incomplete lesion (spared motor functional capabilities) [4]. Because there is a lack of effective treatment for restoring neurological function below the level of the injury, positive symptoms (such as spasticity and FDA device/drug status: not applicable. Nothing of value received from a commercial entity related to this manuscript. * Corresponding author. Department of Neurosurgery, Lund University Hospital, 221 85 Lund, Sweden. Tel.: 46-46-177439; fax: 46-46-189287. E-mail address: Faisal.Sayer@neurokir.lu.se (F.T. Sayer) hyperreflexia) that interfere with the remaining function, and increased long-term survival [5], the majority of SCI victims face many years of lost independence and continued medical expenses. In most cases, traumatic SCI is characterized by severe contusion rather that transection of the spinal cord, even when there are massive bony injuries [6]. However, the primary lesion is gradually enlarged by delayed secondary damaging processes [7 9], leading to necrotic changes and cavity formation of the injured spinal cord tissue [9 11]. The exact pathogenesis of secondary spinal cord damage has not been fully elucidated, but there is considerable evidence that it occurs within minutes and continues for days or weeks, resulting in further neurological deterioration [12]. Furthermore, secondary spinal cord damage has the propensity to worsen during the first few hours after injury, and thus treatment during this window of time has the potential to prevent or reduce the resulting neurological deficit. Unfortunately, there is incomplete knowledge of the exact time course of many secondary mechanisms, and therefore the exact therapeutic window in which to treat many of these processes is unknown [13]. 1529-9430/06/$ see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.spinee.2005.11.001

336 F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 Treatment of spinal cord injury Surgical intervention following spinal trauma aims at preventing further mechanical damage to the spinal cord through reestablishing the stability of the vertebral column. However, it has not been shown to prevent the posttraumatic neurological deterioration, which starts immediately after injury and can progress over the following months to years [14]. The results of recent clinical studies of neuroprotective pharmacotherapy have shown only modest improvement in neurological recovery and functional capability, such as motor and sensory function, in patients with SCI [15 17]. For monosialotetrahexosylganglioside (GM-1) gangliosides [18 20], tirilazad mesylate [21,22], naloxone [16], and nimodipine [23], more substantial evidence regarding their clinical efficacy is needed. Other current recovery of function treatments such as walkinginduced learning of the cord and 4-aminopyridine (4-AP) are under evaluation; however, their efficacy remains to be confirmed [24 26]. Methylprednisolone (MP) is currently in widespread use for the treatment of acute SCI and is widely considered the gold standard treatment. Methylprednisolone High-dose MP, as recommended on the basis of the National Acute Spinal Cord Injury Studies (NASCIS-2 and NASCIS-3), is the only effective neuroprotective agent tested in controlled multicenter clinical trials [22,27 29]. The recommendation obtained, based on these two studies, was that MP should be given as a bolus dose of 30 mg/kg over 15 minutes, and followed by a continuous infusion of 5.4 mg/ kg/hour. If treatment is initiated within 3 hours after sustaining SCI, the infusion would be for 23 hours (total treatment time of 24 hours). However, if treatment is initiated within 3 8 hours then the infusion should be continued for 47 hours (total treatment time of 48 hours). No MP should be given if the patient arrives 8 hours or more after SCI. MP was tested as an inhibitor of lipid peroxidation and hypothesized to reduce the posttraumatic degenerative changes in the injured spinal cord. However, conflicting experimental reports [30 33] combined with the relatively small neurological improvements in humans [29,34] have prompted some researchers and physicians to question the efficacy of MP for the treatment of acute traumatic SCI [34,35]. The Section on Disorders of the Spine and Peripheral Nerves of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons published in the spring of 2002 the guidelines for the treatment of SCI, and MP was considered most controversial [36]. In May 1999, a survey of every trauma facility medical director in the state of Colorado showed that 98% of the health-care facilities administer steroids to SCI patients. However, approximately half of the medical directors were either uncertain or did not believe that the data regarding the corticosteroid treatment for SCI supported its use [37]. It is probable that many centers still use MP, despite lack of clear evidence of its efficacy, to avoid legal repercussions [38]. In this article, we will review the literature regarding MP as a treatment for SCI. The National Acute Spinal Cord Injury Studies The NASCIS were conducted under the leadership of Michael Bracken at the department of epidemiology and public health at Yale University. All of the three studies were multicenter, randomized, double-blinded clinical trials. NASCIS I In the first study, NASCIS I (1979), a standard dose of MP (100 mg) was compared with a megadose (1,000 mg) given intravenously once daily for 10 days. A total of 330 patients were included in this study and were evaluated with sensory and motor assessment at 6 weeks, 6 months, and 1 year after spinal cord injury. There was no difference between the two groups with respect to either modality at all time points [40]. NASCIS II Later animal experiments have suggested that only much higher doses of MP (compared with NASCIS I) have a neuroprotective effect after SCI. When NASCIS II was conducted in 1985, the effect of placebo was compared with a megadose of MP (30 mg/kg bolus followed by 5.4 mg/ kg/hour infusion over 23 hours). Another group received naloxone, an opiate antagonist, which had shown promise in previous animal experiments [39]. The NASCIS II Study included 487 patients who arrived to the hospital within 12 hours and were randomized to one of the treatment groups. Exclusion criteria included patients with isolated peripheral nerve injury (nerve root or cauda equina symptom), patients with other serious diseases, and pregnant women. A standard neurological examination was conducted on admission, after 6 weeks, 6 months, and 1 year. Motor function was evaluated in 14 muscle groups, and power was graded from 0 to 5. This means that the total score would be between 0 and 70 points. Sensory function was also evaluated through pinprick and tactile sensation in 29 dermatomes (C2 to S5). The response was graded between 1 3, which means that the total score would range between 29 and 87 points. The patients were divided before statistical analysis into those in whom treatment was initiated within 8 hours and those who received treatment after 8 hours. Patients were then subdivided into those with complete SCI (no motor or sensory function below level of injury) and incomplete SCI (some spared function). The results were published as change in total score from the starting point (when the patient first presented to the hospital). Regarding the sensory function, patients who received MP had better outcome at 6 months as compared with the control group. However, this effect disappeared at 1 year. Improvement

F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 337 in the motor function was statistically significant at 6 months and even after 1 year in the MP group compared with the control group (17.2 and 12.0 points improvement, respectively, p5.030). Naloxone showed similar effect to placebo for all modalities at all time points. Results were published in 1992, and the conclusion was to recommend MP within 8 hours after spinal cord injury [27]. NASCIS III The third study, NASCIS III, was conducted in 1991. In this study, only patients with SCI who presented within 8 hours were included. As in the previous study, pregnant women and patients with serious illness were excluded. A total of 499 patients were included and randomized to 30 mg/kg bolus followed by 5.4 mg/kg/hour infusion over 23 hours (24MP), a group that received MP bolus and infusion for 47 hours infusion (48MP) or MP bolus followed by tirilazad infusion. Tirilazad has the same lipid peroxidation effect as MP but lacks the glucocorticoid effect, which was hypothesized to be the biological effect of MP that would be helpful in acute SCI. A standard neurological examination was conducted on admission, after 6 weeks, 6 months, and 1 year. In addition to the motor and sensory score, the patient s functional recovery was measured by using the Functional Independence Measure (FIM) developed by the American Spinal Injury Association. This scale included self-care, sphincter control, mobility, locomotion, communication and social cognition. As in previous studies, analysis was carried out as change in total score. Follow-up after 6 months revealed no significant difference between the groups with regard to any modality. At that point, patients were divided into those who received treatment within 3 hours and those in whom treatment was initiated after 3 hours but less than 8 hours after SCI. After this statistical maneuver, there was a statistically significant difference in motor score in patients who received MP bolus and infusion for 47 hours infusion (48MP) compared with 24MP, in the groups treated between 3 and 8 hours after injury. This statistically significant difference was observed at 6 weeks and 6 months, but was less apparent at 1 year (p5.053). No similar recovery was observed for the sensory function in any group. No statistically significant difference was observed for FIM between the groups at 1 year [29]. The tirilazad group was similar to the 24-hour MP; however, no solid conclusion was drawn because in both groups the treatment was initiated with a bolus dose of MP. A scientific basis for reconsidering the role of MP in SCI follows: Critical evaluation of the NASCIS II NASCIS II has received intensive criticism on several important methodological, scientific, and statistical issues: 1) It was always hypothesized that the effect of MP would depend on the rapidity of its administration after SCI. The initial study plan was to include patients up to 12 hours after injury. However, during the study period this was changed to 8 hours without any logical explanation. It is clear that the authors have tested the effect at different time points and found that the best effect was at the 8-hour time point. Changing the time points after analyzing the data compromises their scientific value [38,41]. 2) Only right-sided motor scores were reported in NASCIS II, but bilateral sensory scores were reported. Lack of evidence describing left-sided motor scores and total body motor scores in NASCIS II is confusing [28,42 44]. 3) The data were presented as obtained from the whole study population; however, the fact is that in the groups that presented within 8 hours, only 62 patients of the placebo group and 65 of the MP group were analyzed. This means that statistical analysis was done on only 30% of the study population (487 patients) and the other 70% were excluded. 4) Results comparing complete and incomplete lesions were published in 1993 [28]. There was no statistically significant difference between the treatment and control groups in patients with complete SCI. The beneficial effect of MP was only observed in patients with incomplete SCI who presented and were treated within 8 hours. However, only 17 patients received MP and 22 had placebo in that group of patients with incomplete SCI. 5) There have been strange results indicating that all of these conclusions were based on statistical artifacts. For example, patients with incomplete SCI who received placebo within 8 hours had worse outcome not only as compared with patients with incomplete SCI who presented and received MP within 8 hours but also when compared with patients with incomplete SCI who presented after 8 hours and received placebo. Furthermore, the placebo group of patients with incomplete SCI who presented after 8 hours had almost identical outcome to patients treated with MP within 8 hours after injury. So MP had the same effect as placebo! The previously described difference between MP and placebo groups could be a result of problems with the control group [35,41]. 6) The study did not offer a standardized medical and surgical treatment regimen for patients in NASCIS II study. The medical management of study patients including monitoring, blood pressure augmentation, respiratory care, deep venous thrombosis prophylaxis, nutritional support, and initiation of rehabilitation activities was neither consistent within centers nor consistent from center to center. The timing and type of surgical intervention for individual patients was not documented. There was no consideration given to the independent effect that either aggressive medical management or surgery had, or may have had, on outcome [17,35,38,41,45].

338 F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 7) Lack of a minimum motor impairment for inclusion (hence, patients with normal motor function were admitted to the study) and no vertebral level of injury cutoff [35,38,41]. 8) The failure to measure patient s functional recovery using the FIM to determine whether the modest improvement reported in neurological examination (change in motor scores) in the MP-treated patients had meaningful clinical significance to the injured patients [34,35,38,46,47]. Critical evaluation of The NASCIS III NASCIS III has been prone for criticism on three major issues: determination of optimum timing of therapy, method of motor assessment of SCI patients, and insignificant differences in motor recovery scores and functional outcome measures among study patients [17,35,38,41,45]. 1) More patients with normal motor score were randomized into the 24-hour MP group [35]. 2) There was some difference in the score of motor function in certain muscle groups, but the FIM was similar in all groups. These final recommendations seem to be based on motor recovery score improvement alone. 3) For optimum timing of therapy, time-to-treatment data were not offered or explained. Like the 8-hour time for treatment cutoff result that came from the NASCIS II study, the within 3 hours of injury versus the 3 to 8 hours after injury timeframes reported in NASCIS III seem arbitrary [35,38,41]. Itis not clear when it was decided to have the 3-hour time point as a cutoff point [35,38]. 4) Motor scores were reported as change in motor scores for the right side of the body. Left-side motor scores and total body motor scores were not provided. The failure to provide this scientific data suggests that changes on the right side were the only findings that approach significance at 1 year (p 5.053) and argue against the meaningful nature of the data as interpreted and provided by the authors [35,38,41]. 5) Finally, the clinical relevance of the changes in motor scores between groups, in light of the nonsignificant differences in patient function as determined by FIM scores, is not evident. 6) Lack of standardized medical and surgical treatment. 7) Lack of a minimum motor impairment for inclusion (hence, patients with normal motor function were admitted to the study) and no vertebral level of injury cutoff [35,38,41]. Other clinical studies of MP treatment in SCI Others could not reproduce results obtained in the NASCIS II and III. Here we will review the most relevant clinical studies. Several other double-blind studies, comparing MP with placebo, were not published mostly because of the great publicity that MP received that made comparing it with placebo unethical. In 1993, Galandiuk et al. [48] studied 32 patients with cervical or upper thoracic SCI managed in an urban trauma center from January 1987 to February 1993. Fourteen patients who received NASCIS II doses of MP within 8 hours of injury were compared with 18 patients with similar injuries managed without corticosteroids. There was no difference in neurological outcome between the MP and control groups. However, the MP-treated patients had immune response alterations, a higher rate of pneumonia, and longer hospital stays as compared with the control group. The scientific value of this study was compromised by the mix of historical patients with contemporary patients, the lack of a prospective design, and the haphazard assignment and assessment of patients. Gerhart et al., in 1995 [49], reported a population-based, concurrent cohort comparison study of 363 SCI survivors treated in Colorado (218 SCI survivors injured between May 1, 1990 and December 31, 1991, and 145 persons spinal cord injured 2 years later, during 1993). There were no significant differences in outcome as assessed by the Frankel scale at the time of hospital discharge when 188 patients who received protocol MP were compared with those (n590) who did not receive any MP during treatment. This was a retrospective study, and the number of patients in each group was small enough to compromise the statistical power of this study. In 1995, George et al. [50] compared the outcome of 145 acute SCI patients: 80 treated with MP and 65 with no MP. There was no statistically significant difference in mortality or neurological outcome between patients treated with MP and those who were not. It is unclear from the study why most patients did not receive corticosteroid therapy, and this is the weakness of a nonrandomized study in which patient assignment to treatment may introduce bias. Gerndt et al., in 1997 [51] reported a retrospective review of 140 patients with SCI admitted within 8 hours of injury: 93 patients who received MP according to the NASCIS II protocol and 47 patients who received no corticosteroid. MP therapy was associated with a 2.6-fold increase in the incidence of pneumonia and an increase in ventilated and intensive care days. However, it was associated with a decrease in duration of rehabilitation and had no significant impact on other outcome parameters, including mortality. In 1997, Poynton et al. [52] reviewed 71 consecutive SCI patients managed at the National Spinal Trauma Unit in Dublin, Ireland. The objective was to determine the factors influencing neurological recovery. A total of 63 patients were available for follow-up at a mean of 29.6 months. The American Spinal Injury Association scoring system was used on admission and at follow-up to determine change in neurological status. They found no difference in neurological outcome between patients treated with MP and those who were not.

F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 339 Table 1 Experimental studies where MP was shown to be neuroprotective Author Journal Species Experimental design Route of administration Evaluation parameters Fu and Saporta J Neurosurg Anesthesiol. Rat Aneurysm clip, saline Subcutaneous Biochemical interleukin levals 2005 Apr as control Lee et al. J Korean Med Sci. 2005 Feb Rat Spinal clamps, saline control Intravenous Behavioral electrophysiological (evoked potentials) Jiang et al. Int J Immunopathol Pharmacol. 2004 Sep Dec Rat Compression Intraperitoneal Behavioral histology (tissue loss and astrogliosis) Nakashima et al. 2004 Neuroreprot. 2004 Oct Rat Weight-drop, saline control Intravenous Immunohistochemical (GDNF gene expression) Cayli et al. Eur Spine J. 2004 Dec Rat Weight-drop, vehicle Intraperitoneal Behavioral (ethanol) control Yan et al. Exp Neurol. 2003 Oct Rat Weight-drop Intravenous Immunohistochemical (TNF-alpha-receptor expression) Fukaya et al. 2003 J Neurosurg. 2003 Jan Cat Vascular clip Intravenous Electrophysiological (evoked potentials) Nash et al. 2002 J Neurosci. 2002 Aug Rat Transection Intravenous Histology Benton et al. Brain Res. 2001 Mar Rat Transection Intravenous Biochemical, Taurine levels Perez-Espejo et al. Surg Neurol. 1996 Oct Rat Compression Intraperitoneal Electrophysiological, (evoked potentials) Chen et al. Exp Neurol. 1996 Mar Rat Transection Not available Histology Farooque et al. J Neurosurg. 1996 Mar Rat Compression Intravenous Biochemcial (microdialysis, aminoacids) Baffour et al. J Neurosurg. 1995 Jul Rat Compression Intravenous Histology, behavioral Koc et al. Res Exp Med (Berl). 1995 Rat Compression N/A Biochemical (MDA levels) Behrmann et al. Exp Neurol. 1994 Mar Rat Compression Intravenous Behavioral, Histology Farooque et al. Acta Neurol Scand. 1994 Jan Rat Compression Intravenous Behavioral Body water content Constantini and J Neurosurg. 1994 Jan Rat Compression Intravenous Histology (lesion volume) Young Ross et al. Surg Neurol. 1993 Dec Rat Compression Intravenous Behavioral, Electrophysiologic, and Anatomic De Ley and Leybaert J Neurotrauma. 1993 Spring Cat Compression Intravenous Electrophysiologic, SCBF and interstitial Ca 12 and K 1 activity Rosenberg-Schaffer Brain Res. 1993 Mar In vitro In vitro In vitro Neuron survival and Lucas Akdemir et al. Res Exp Med (Berl). 1993 Rat Compression Intravenous Evoked potentials, Tissue Na 1,K 1 Holtz et al. Acta Neurol Scand. 1990 Jul Rat Compression Intravenous Behavioral, Autoradiography (SCBF) Braughler et al. J Neurosurg. 1987 Jul Cats Compression Intravenous Behavioral, Histology Iizuka et al. J Neurosurg. 1986 Jul Rat Compression Intravenous Histology Anderson et al. Cent Nerv Syst Trauma. 1985 Cat Compression N/A Histology Laschinger et al. Ann Thorac Surg. 1984 Nov N/A Aorta clamp Intravenous SCBF, SEPs Braughler and Hall J Neurosurg. 1984 Aug Cat Weight-drop Intravenous Histology, Biochemical Hall et al. J Neurosurg. 1984 Jul Cat Weight-drop Intravenous Histology, Biochemical Braughler and Hall J Neurosurg. 1983 Aug Cat Weight-drop Intravenous Biochemical (Lactate and pyruvate metabolism) Young and Flamm J Neurosurg. 1982 Nov Cat Weight-drop Intravenous SCBF Naftchi Peptides. 1982 May Jun Cat Weight-drop N/A (SEPs), carotid arterial BP, abdominal aorta BF Anderson et al. J Neurosurg. 1982 Jan Cat Weight-drop Intravenous Microvascular perfusion, Biochemical Means et al. J. Neurosurg. 1981 Aug Cats Compression Intravenous Behavioral, Histology BF5blood flow; BP5blood pressure; GDNF5glial derived neurotrophic factor; MDA5malondialdehyde; MP5methylprednisolone; N/A5not available; SCBF5spinal cord blood flow; SEPs5somatosensory evoked potentials; TNF5tumor necrosis factor. Pointillart et al., in 2000 [46], conducted a prospective clinical study in which 106 SCI patients were randomized into four groups: MP (according to the NASCIS II protocol), nimodipine, both agents, and neither medication. Neurological assessment (American Spinal Injury Association score) before treatment and at 1-year follow-up showed no statistically significant difference between groups. Short et al. [34] conducted an evidence-based review of the medical literature on the use of MP for SCI (animal and human experimental studies, including randomized human

340 F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 Table 2 Experimental studies where MP was not shown to be neuroprotective Author Journal Species Experimental design Route of administration Evaluation parameters Carlson et al. J Bone Joint Surg Am. 2003 Jan Dog Compression Intravenous SCBF, SEPs Takami et al. J Neurotrauma. 2002 May Rat Weight-drop Intravenous Behavioral, Histology Rabchevsky et al. J Neurosci Res. 2002 Apr Rat Weight-drop Intravenous Behavioral, Histology Merola et al. J Orthop Trauma. 2002 Mar Rat Weight-drop Intravenous Histology Haghighi et al. Spinal Cord. 1998 Jan Rat Compression N/A Behavioral Koyanagi and Tator Neurol Res 1997 Jun;19(3):289 99. Rat Compression Intravenous SCBF, SEPs, Histology Review. Hal et al. J Neurosurgery. 1995 Jun Cat Compression Intravenous Enzyme immunoassay Coates et al. Vet Surg. 1995 Mar Apr Dog Weight-drop Intravenous Behavioral, Histology Ross and Tator Neurosurgery. 1993 Sep Rat Compression Intravenous SCBF, Electrophysiological Xu et al. J Neurotrauma. 1992 Fall Rat Weight-drop Intravenous Histology Benzel et al. J Spinal Discord. 1990 Dec Rat Compression N/A Behavioral Hall J Neurosurg. 1988 Mar Cat Weight-drop N/A SCBF Faden et al. J Neurosurg. 1984 Apr Cat Weight-drop Intramuscular Behavioral, Histology Green et al. Surg Neurol. 1980 Feb Rhesus monkeys Weight-drop Intravenous Behavioral MP5methylprednisolone; N/A5not available; SCBF5spinal cord blood flow; SEP5somatosensory evoked potentials. clinical trials). The evidence obtained from three clinical trials and six cohort study publications indicated that the high-dose MP should be excluded from consideration as an intervention for acute SCI. Furthermore, the validity and the functional significance of results obtained from 12 larger animal publications were of concern for many. They concluded that the available evidence does not support the use of MP in the treatment of SCI. Complications associated with MP treatment Besides the narrow trauma-to-treatment time window of 8 hours [49,50,53 55], the use of MP is associated with increased risk for infections [22,27,50]. In the NASCIS II, although not statistically significant, patients who received MP had a 2.6-fold higher incidence of pneumonia, required longer periods of assisted ventilation and more ICU time [51]. The NASCIS III patients who received 48MP treatment had a twofold higher incidence of severe pneumonia, a fourfold higher incidence of severe sepsis, and a sixfold higher incidence of death due to respiratory complications than patients in the 24MP treatment group [28,38]. These differences, although not statistically significant, raise questions about the safety of the 48-hour treatment strategy. A randomized, prospective, double-blind study showed that the difference in all complications Table 3 Clinical trials where MP was not shown to improve neurological outcome following spinal core injury Author Method Participants Results Limitations Bracken et al. 1984, RCT 330 total No significant difference in 100 mg vs. 1000 mg daily for 10 days 1985 (NASCIS I) neurological recovery Prendergast et al. 1994 Historical controls 29 MP No differences motor and sensory Design, penetrating injuries, small sample 25 no MP scores George et al. 1995 Retrospective 80 MP 65 no MP Poorer discharge mobility in the MP group Design, FIM data on 45 MP and 25 no MP only Gerhardt et al. 1995 Retrospective 363 No difference between MP protocol Design and not (Frankel scale) Levy et al. 1996 Retrospective 55 MP 181 no MP Did not improve functional outcome (Frankel scale) Design, penetrating injuries Pointillart et al. 2002 RCT 27 MP1 nimodipine 27 MP 27 nimodipine 27 no medication No difference between groups (ASIA motor, sensory, pain scores) Pollard and Apple 2003 Retrospective 412 total No correlation between motor recovery and compliance with NASCIS protocol Wang et al. 2004 Retrospective 8 MP 22 no MP No statistical association between MP and neurological recovery Small sample Design Design, pediatric, small size ASIA5American Spinal Injury Association; FIM5Functional Independence Measure; MP5methylprednisolone; NASCIS5National Acute Spinal Cord Injury Study; RCT5randomized clinical trial.

F.T. Sayer et al. / The Spine Journal 6 (2006) 335 343 341 between the MP and placebo groups was not statistically significant (p5.139). However, there was a higher incidence of pulmonary (p5.009) and gastrointestinal complications (p5.036) in the MP group as compared with the control group [56]. Moreover, its potential effect on the long-term prospects of neuronal regeneration is not well established [57,58]. Wing et al. [59] examined the effect of MP administered according to the NASCIS II protocol on avascular necrosis of the femoral heads of 91 SCI patients; 59 of these patients received the corticosteroid, and 32 did not. The authors estimated the relative risk of avascular necrosis with high-dose 24-hour MP therapy to be less than 5%. Discussion The literature search was conducted using the National Library of Medicine s search service (PubMed). Key words used for the search were Methylprednisolone, Spinal cord injury, Spine trauma, Secondary injury, The National Acute Spinal Cord Injury Study, NASCIS. The search period was 1980 2005. Only articles published in peer group reviewed journals were included. For the clinical part, only clinical trials were included and a total of 15 publications were found to satisfy the review criteria. Review articles, metaanalysis, and commentaries were excluded. For the basic science studies, only experimental work testing the effect of MP on the injured spinal cord histology, physiology, or functional outcome in treated animals after experimental SCI was included. A total of 47 publications were found to satisfy the review criteria. Although there is an abundance of evidence from experimental work supporting the use of MP (33 pro and 14 con MP) (Tables 1 and 2), the interpretation of these results is not easy where different animal species, experimental models, route of administration, dose of MP, and evaluation parameters were used. Furthermore, these results were not substantiated by clinical trials (3 pro and 8 con MP) (Tables 3 and 4). Despite the great variation in approach to elucidate the role of MP in SCI, no single publication has shown a clear superiority of MP over other agents or vehicle. An interesting observation was that, with a few exceptions, none of the researchers who have shown that MP has a neuroprotective effect revisited the issue. For example, if a study showed through behavioral or histopathological evaluation a positive effect of MP, then the logical continuation would be to investigate the issue at the molecular level. This would aim mainly to find a possible explanation for the observed positive effect, which could be used to exploit this therapeutic approach further. The clinical papers advocating the use of MP were all, except for three, published by the same group of authors. Although the results obtained from the NASCIS studies were statistically significant, there was no corresponding clinically obvious effect. This can be seen by the large number of review articles, meta-analyses, and commentaries written by experienced neurosurgeons and neurologists indicating their skepticism regarding the efficacy of MP in SCI. One of the major strengths of the NASCIS studies was the ability to recruit several hundred patients into the study. This has only been possible, until now, in the United States because of its large population size, incidence of SCI, and interest in this kind of research. Other clinical trials from other parts of the world included only a small number of patients, and this limited their comparability to the NASCIS studies. This might explain the large number of meta-analysis and review articles by those who do not believe in MP as a treatment in SCI. The problem for a physician responsible for the care of patients with SCI is that not using MP in the light of current evidence might lead to medico-legal problems. A possible way to solve this dilemma is to have multinational studies (eg, European Union level) or another study in the United States to be conducted by another group of researchers. The Food and Drug Administration and National Institutes of Health are possible candidates to play a leading role in this effort. Conclusion Based on the background of the enormous criticism that the NASCIS II and III have attained in the last few years, there have been many neurosurgical departments that have stopped using MP as a standard routine in acute SCI [36,60]. It is also important to note that MP is not recommended for use in acute SCI according to the Food and Drug Administration [35]. Table 4 Clinical trials where MP was shown to improve neurological outcome after spinal cord injury Author Method Participants Results Limitations Bracken et al. 1990, 1991, 1992 (NASCIS II) RCT 162 MP (154 naloxone) 171 placebo Increased recovery of neurological function (motor scores) MP!8 hr Only 62 MP/65 placebo in final analysis Bracken et al. 1997, 1998 RCT 166 24-hr MP 167 48-hr Improved neurological recovery Only motor scores, not FIM (NASCIS III) MP (166 tirilazade) 48-hr MP compared with 24-hr if 3 8 hr Aito et al. 2005 Retrospective 65 total MP seemed to influence neurological outcome positively Design, small sample FIM5Functional Independence Measure; MP5methylprednisolone; NASCIS5National Acute Spinal Cord Injury Study.

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