Secondary Logo

Journal Logo

The Role of GM-1 Ganglioside in Acute Spinal Cord Injury: Results of the Sygen® Multicenter Trial

The Sygen® Multicenter Acute Spinal Cord Injury Study

Geisler, Fred H. MD, PhD*; Coleman, William P. PhD; Grieco, Giacinto MD; Poonian, Devinder the Sygen Study Group

Author Information
  • Free


Sygen® (monosialotetrahexosylganglioside GM1 sodium salt) is a naturally occurring compound in cell membranes of mammals and is especially abundant in the membranes of the central nervous system. Acute neuroprotective and longer-term regenerative effects in multiple experimental models of ischemia and injury have been reported. 3,8,24,29,33,50–53,58–61,63,65–68,79–81,84,85,87–91,93,97,100,104,105,107,108 The proposed mechanisms of action of GM1 include anti-excitotoxic activity, apoptosis prevention, and potentiation of neuritic sprouting and the effects of nerve growth factors. 4,23,28,35–38,62,64,70,74,82,86,92,98,101,102,106,109 Beneficial effects have been reported in clinical trials in stroke 2,5,6,22,69,76,83 and Parkinson’s dis-ease. 34,54,94–96

A single-center trial 43–45,47 in acute spinal cord injury (SCI) randomized 37 patients to either placebo or 100 mg of Sygen® intravenous, once per day for a planned 30-day treatment period. Analysis showed that the severity at baseline grade greatly determines the degree of recovery. A significant drug effect was found (P = 0.034) in the proportion of patients able to improve by two grades on the Frankel Scale (1 of 14 on placebo, 7 of 14 on Sygen®).

That trial provided the rationale for this multicenter study of Sygen® in acute SCI after standard treatment with methylprednisolone (MPSS). The present article is the third of a series reporting the results, and it discusses the efficacy of the study medication. The first article 48 discussed recruitment and early treatment, and the second article 49 discussed measurement scales and recovery.

Eight prospective clinical trials, studying various compounds, have been completed in acute SCI. Four trials studied MPSS, 10–20,75 with one also studying naloxone and one tirilazad, 19,20 two trials (including the present one) studied Sygen® ganglioside, 41,43–47 and there were two pilot studies, with thyrotropin-releasing hormone 78 and with nimodipine. 77 Human SCI studies have been summarized by several authors. 9,39,40,42,103 Notably, four peer-reviewed critiques of the NASCIS studies have criticized the statistical methodology, published results, and nonavailability of the data for review. 26,57,73,99


Recruitment and Eligibility.

This was a prospective, double-blind, randomized, stratified, multicenter trial. The goal was to randomize approximately 800 patients so as to have at least 720 completed and evaluable in each of three initial treatment groups: placebo, low-dose Sygen®, and high-dose Sygen®. The patients were stratified into six groups, according to three degrees of injury severity (AIS grades A, B, and C + D, with definitions as in the previous article 49 in this series) and two levels of anatomic injury (cervical and thoracic).

The trial was sequential with preplanned interim analyses as each group of 720/4 = 180 patients reached their 26-week examination and became evaluable.

Recruitment and eligibility criteria are discussed at length in the first article 48 in this series. Patients were required to have at least one lower extremity with a substantial motor deficit. Patients with spinal cord transection or penetration were excluded, as were patients with a significant cauda equina, brachial or lumbosacral plexus, or peripheral nerve injury. Gunshot injuries that did not penetrate the cord were allowed. Multiple trauma was allowed as long as it was not so severe as to prevent neurologic measurement evaluation or interpretation.

Minor deviations from eligibility and protocol (technical ineligibility) were allowed, but gross violations (true ineligibility) were excluded. A blind Adjudication Committee (consisting of a neurosurgeon [F.H.G.], a statistician [W.P.C.], and the chief study monitor [D.P.]) reviewed all clinical data records as the study proceeded and made decisions on data integrity, based on general, written criteria. They classified patients into three groups: eligible, technically ineligible, and truly ineligible. The technically ineligible patients were those with minor to moderate deviations from the study entrance criteria, and they were included in the analysis in accordance with the principle of intent to treat. The truly ineligible patients were those few with major selection criteria violations and they were excluded. The Adjudication Committee used similar principles to decide on questionable data values. Before breaking the study blind, the Committee re-reviewed all of its rules and decisions for consistency and plausibility.

An Extramural Monitoring Committee (EMC) provided independent supervision of the conduct of the study with respect to patient safety and data integrity.

In the first planned interim analysis the EMC recommended early discontinuation of the high-dose Sygen® group while maintaining the blinding of investigators as to which group was being dropped. Their stated reason at that time was an apparent lack of efficacy in the dropped arm, although the prospectively specified guidelines for dropping a study arm had not been reached. After the conclusion of the trial it became known that a second reason had been an apparently higher death rate in the dropped arm. However, although no new patients were enrolled in that arm, as more of the existing patients reached follow-up, by the end of the trial the marked recovery rates (see below) in the two Sygen® arms became similar, the death rates were almost numerically identical, and were similar to that in the placebo arm (see below).

At that time the EMC also observed an age imbalance among the treatment groups. They recommended adding an additional stratification by age (younger ≤29 years vs. older >29 years) to correct it. Age-related SCI recovery patterns had been noted independently by Burns et al. 21

The EMC recommended skipping the second and third interim analyses and waiting until the end of the study before analyzing again.

Study Treatment.

All patients were to receive the NASCIS II dose regimen of MPSS starting within 8 hours after the SCI. To avoid any possible untoward interaction between MPSS and Sygen®, 27 the study medication was not started until after completion of MPSS administration.

The placebo group had a loading dose of placebo and then 56 days of placebo. The low-dose Sygen® group had a 300-mg loading dose followed by 100 mg/day for 56 days. The high-dose Sygen® group had a 600-mg loading dose followed by 200 mg/day for 56 days.

Assessment and Statistical Analysis.

The second article 49 in this series discusses measurement procedures in detail. The baseline neurologic assessment included both the AIS and detailed American Spinal Injury Association (ASIA) motor and sensory examinations. 1,25,30,31,71 The problem associated with motor measurement in these patients was also discussed. 7,32,55,56,72

The Modified Benzel Classification and the ASIA motor and sensory examinations were performed at 4, 8, 16, 26, and 52 weeks after injury. The Modified Benzel Classification was used for post-baseline measurement because it rates walking ability and, in effect, subdivides the broad D category of the AIS. Because most patients have an unstable spinal fracture at baseline, it is not possible to assess walking ability at that time; hence the use of different baseline and follow-up scales. Marked recovery was defined as at least a two-grade equivalent improvement in the Modified Benzel Classification from the baseline AIS.

The primary efficacy assessment was the proportion of patients with marked recovery at week 26. The secondary efficacy assessments included the time course of marked recovery and other established measures of spinal cord function (the ASIA motor and sensory scores, relative and absolute sensory levels of impairment, and assessments of bladder and bowel function).

The primary efficacy analysis was by a generalization of Fisher’s exact test, the linear logistic model, when covariates are used, as were the analyses of other binary outcomes. The motor and sensory scores and sensory levels were assessed by analyses of covariance with the baseline value as a continuous covariate, and with levels for the randomization strata of AIS (A, B, C + D), injury level (cervical vs. thoracic), and age (≤29 years vs. >29 years) in addition to center, treatment, and the AIS × treatment interaction. Similar logistic models were applied to categorical outcomes.

To maintain a trial-wise α of 0.05, the α for the principal efficacy analysis of placebo versus low-dose Sygen® (D1) was 0.0375 because of α “spent” on the interim analysis and subsequent dropping of the high-dose Sygen® arm. All other P values presented should be considered as relative measures of effect sizes. All data presented in this article compare placebo versus low-dose (D1) and high-dose (D2) Sygen® combined to probe the question: “Does either dose of Sygen® cause a different recovery pattern than placebo?” Analyses were performed in JMP, SPSS, SAS, StatXact, and LogXact.


Patient Population

Patients were randomized in a 5-year recruitment period at 28 neurotrauma centers in North America. Figure 1 shows the flow of patients into the stratified groups in the Sygen® SCI study. Of 797 patients recruited, the Adjudication Committee found 760 to be either eligible or technically ineligible and included them in the analysis. Of the other 37 patients, two received no study medication and 35 were adjudicated truly ineligible for the reasons shown in Table 1. The number of patients lost to follow-up did not differ between treatment arms (Figure 2).

Figure 1:
Flow of patients in trial.
Table 1:
Number of Truly Ineligible (Randomized in Error) Patients by Reasons for Ineligibility and Treatment Group
Figure 2:
Percent of patients lost to follow-up at each follow-up time.

Table 2 shows patients reporting a history of medically significant abnormalities by body system and treatment group in the 760 eligible patients.

Table 2:
Patients Reporting a History of Medically Significant Abnormalities by Body System and Treatment Group in the 760 Eligible Patients

In both the cervical and thoracic strata the majority of patients are in the most impaired severity Group A. Also, there were proportionally fewer Bs and C + Ds in the thoracic stratum compared with the cervical stratum. The treatment groups were well balanced with respect to all demographic parameters (except race), mechanism of injury, medical history, characteristics of the injury, level of injury, timing variables, hemodynamic parameters, other body system injuries, MPSS therapy, and study drug administration.

As shown in Table 3, well over half of the patients started receiving study medication between 48 and 72 hours from injury. The median time was 54.9 hours.

Table 3:
Time From Injury to Study Medication in the 760 Eligible Patients by Treatment Group


A total of 43 patients died that were entered into the study. Figure 3 shows survival by treatment group. The placebo group had 18 deaths of 330 patients (5.5%), and the combined Sygen® arms had 25 deaths of 430 patients (5.8%). The differences between treatment groups were not significant and there was a slightly higher death rate in the high-dose Sygen® group, perhaps because of its smaller sample size and greater frequency of high bony injuries.

Figure 3:
Fraction of patients surviving, by treatment.

As shown in the second article 49 in this series, analysis of the mortality disclosed a higher mortality in the highest bony levels and in the patients with no or very little motor function below the injury.

Marked Recovery in Sygen® and Placebo Treatment Groups

Figure 4 shows the fraction of patients exhibiting a marked recovery at each follow-up visit. The Sygen® group did not have a significantly higher proportion of patients with marked recovery at week 26, and the unique, prospectively chosen primary efficacy analysis for the Sygen® multicenter trial was negative.

Figure 4:
Fraction with marked recovery over time by treatment.

The time course of recovery suggests earlier attainment of marked recovery in the Sygen®-treated patients, regardless of their baseline severity. In particular, it suggests that the Sygen® group had greater recovery in the primary efficacy variable at the end of the study treatment period (8 weeks). Although end of treatment is a common drug study endpoint, this was not the point prospectively picked for the primary analysis.

The recovery patterns are shown in Figure 5 for the two treatment arms. Few patients in severity Group A had marked recovery versus three fourths of Group C + D. The marked recovery rate in Group B was intermediate.

Figure 5:
Fraction with marked recovery over time by treatment and severity. Death and lost to follow-up were counted as not marked recovery.

For patients in the baseline severity A group, there was a slight trend toward separation between treatments at weeks 8 and 16, favoring Sygen®. However, among all randomized Group A patients, the week 26 marked recovery rate was only 12%.

In the severity B patients there appeared to be an earlier and persisting difference in recovery. At week 26 the Sygen® group had a 47% rate of marked recovery. This is a more than 25% relative increase over the placebo group at the same time.

At weeks 4, 8 (P = 0.0072), and 16, the baseline C + D patients in the Sygen® group had a greater percentage of marked recovery than those in the placebo group. However, by week 26 the recovery rate was 85% and the placebo group appeared to have caught up, and they were again nearly equal at about 90% at week 52, suggesting a ceiling effect in both groups.

Table 4 presents these data as the visit at which marked recovery was first obtained. The recovery time course was significantly different between the placebo and low-dose Sygen® groups (P = 0.0275, 2 × 5 Fisher Freeman-Halton Exact Test). Significance was also apparent between the placebo and the combined Sygen® high- and low-dose groups (P = 0.0128, 2 × 5 Fisher Freeman-Halton Exact Test). This difference favors quicker recovery in the Sygen®-treated patients. In all the other prespecified groups, the pattern of earlier recovery among Sygen®-treated patients was evident.

Table 4:
Visit When Marked Recovery First Occurred in the Placebo, Sygen® 100 mg and Sygen® 200 mg Groups

An apparent benefit of Sygen® was observed in the patients who did not require spinal surgery (top graph in Figure 6). These patients are suspected to have a spinal contusion without significant external compression. A somewhat high potential for recovery may be expected because the spinal cord was not under continued pressure for a prolonged time. In these nonoperated patients there was a large difference between treatments throughout the follow-up time period, with accelerated recovery and a higher percentage attaining marked recovery.

Figure 6:
Marked recovery for placebo and Sygen® in less severe injury groups.

Patients with suspected central cord injuries and those without radiographic fracture dislocations appeared to show (Figure 6) an early benefit of Sygen®, perhaps followed by a ceiling effect later where the placebo group appeared to catch up.

Motor and Sensory Scores

Figure 7 shows the progression in difference from baseline in ASIA light touch, pinprick, and motor scores by treatment and baseline severity. The scores rise from baseline faster in the Sygen® groups than in the corresponding placebo groups. Sygen® maintains its apparent lead to week 52 in the two sensory scores in the AIS B and AIS CD strata and in motor score in the AIS B stratum. The Sygen® group reaches what may be a ceiling of 70% difference in motor score in the AIS CD stratum, and the placebo group catches up to it. There may also be a ceiling, much lower, in the AIS A stratum for all three measurements.

Figure 7:
Light touch, pinprick, and ASIA motor scores by treatment and spinal level.

Figures 8 and 9 show the progression of mean values for pinprick and light touch after adjustment by ANCOVA using a model that accounts for center, spinal level, baseline severity, age, treatment, baseline level, and treatment by severity interaction. It emphasizes the apparent superiority of Sygen® after taking these factors into account.

Figure 8:
Pinprick, least squares mean comparing the placebo and D1D2 study groups.
Figure 9:
Light touch least squares mean comparing the placebo and D1D2 study groups.

Figures 10 and 11 show Sygen® with a slight increase over placebo in light touch score and motor score difference from baseline for most, but not all, baseline values.

Figure 10:
Light touch score by treatment arm.
Figure 11:
AISA motor score by treatment arm.

Similar results were observed in the corresponding rostral and caudal levels of all three of these measures. Figure 12 shows the results for the rostral light touch level.

Figure 12:
Rostral abnormal light touch level by treatment and baseline severity.

Bowel and Bladder Function

Figure 13 presents the fraction of patients with normal bladder and bowel by study visit and treatment group. It is noteworthy that these percentages are higher for the Sygen® D1D2 group than for placebo at each of the scheduled visits after baseline. However, none of the differences generated a P value <0.05 (the bladder reaches a P = 0.0584, LogXact at 26 weeks).

Figure 13:
(Left) Fraction of patients with normal bladder function. (Right) Fraction of patients with normal bowel function.

Also noteworthy are the differences in recovery patterns by baseline AIS severity. Almost no severity Group A patients recover normal bowel or bladder function. Among severity Group B patients, roughly twice the percentage of Sygen®-treated patients as placebo patients have normal bladder function at week 8 and at week 52. The time courses of both bowel and bladder function recovery show earlier recovery within both the high- and low-dose Sygen® groups than in the placebo group. Similar results were obtained in sacral sensation and anal contraction.


The reported adverse events were typical for the acute SCI population, and there were no noteworthy differences among treatment groups in frequency or severity of events. An anticipated dose-associated pattern of modest elevations in cholesterol and triglycerides in the Sygen® groups during the treatment phase was noted. This change has been observed in other studies with Sygen® and is not clinically relevant.


This study had a single, prospectively specified primary outcome variable. The primary variable was percentage of patients with marked recovery. This would be analyzed using the linear logistic model, with the study strata, namely, anatomic level, AIS severity at baseline, and age, as the covariates. The time period was specified to be 26 weeks after injury.

This primary analysis was not positive, a fact whose importance should not be minimized. Although other choices could have been made, announcing ahead of time a single test is the normally accepted cornerstone of good statistics. Without this requirement one cannot define a P value for the study because the chance of error increases with the number of tests performed.

There were two Sygen® arms, one of which was terminated early by the EMC. In this report we have presented analyses comparing placebo with the pooled Sygen® arms to use the data from all evaluable patients, in the spirit of intent to treat. Analyses of placebo versus the lower-dose Sygen® arm have been preformed and presented to the Food and Drug Administration. The picture they present was not substantially different.

What evidence does this study provide for (or against) some effect of Sygen® in SCI?

  • There is a significant effect in all patients in the primary outcome variable (the percentage of marked recovery) at week 8, which is the end of the dosing period.
  • There is a significant effect in all patients in the time at which marked recovery is first achieved.
  • If the primary efficacy analysis is restricted to severity Group B, it has a large trend but does not reach statistical significance because of the small sample size in that group.
  • There is a large, consistent, and sometimes significant effect in the primary outcome variable in the nonoperated patients through week 26.
  • The ASIA motor, light touch, and pinprick scores have a consistent trend in favor of Sygen®, as also do bowel function, bladder function, sacral sensation, and voluntary anal contraction. Every graph in Figures 4–13 shows Sygen® better than placebo at almost every time point. These differences are statistically significant in several, although not most, cases.
  • This positive evidence of a beneficial drug effect was in the partial and mild injury groups. There was little if any effect in the complete injury group.
  • Any evidence in our data against a possible effect of Sygen® is minimal and scattered.

It is difficult not to conclude, from our possibly partisan viewpoint, that Sygen® is “active” in SCI, somehow: in some respect, using some regimen, and in some group of patients. We were limited in the kinds of patients we studied, in our recruitment in specific subgroups, and in the time point we chose for the primary variable. (It has previously been observed in stroke trials that the apparent effect of Sygen® compared with placebo declines after drug treatment stops.) We were also limited in the starting time, dose, and duration of the drug administration as only one of each was used in this study.

The controlled trial data for Sygen® in acute SCI now consist of one positive study (Maryland trial) and one study with consistent significant results in several secondary analyses but not in the primary efficacy analysis (the present multicenter trial).

The result for the primary endpoint in the current study was disappointing compared with the previous trial and positive findings in other indications. 2,5,6,23,45,47,50,51,67,75,81,84,90–93 Although one often hears the assertion that the Maryland study may be untrustworthy because of its small numbers, this is a misunderstanding of statistical principles: the formulas for the P value in all tests take the sample size into account and the results have the same meaning for any sample. If anything, the interpretation of the Maryland study is the opposite: the fact that significance was reached despite the small sample indicates either an exceptional, freakish sample or that the underlying effect of Sygen® (as given in that trial) is large.

This multicenter trial did not duplicate the procedures in the Maryland study as well as would have been desirable to take advantage of the hard data of the earlier study for planning purposes. In this study patients could not begin receiving study medication until approximately 24–32 hours after injury (depending on when MPSS administration was completed), but before 72 hours postinjury. Thus, the potential acute neuroprotective benefits of Sygen® were reduced, and partial recovery may have already occurred after arrival in the hospital but before the delayed start of study treatment. The MPSS dose was larger in the current trial than in the previous one by an order of magnitude. It should be noted that the apparent Sygen® effect reported in this study is in addition to any enhancement from MPSS because all patients received NASCIS II MPSS protocol and there is the possibility that MPSS and Sygen® may be antagonistic, which would diminish the apparent size of the Sygen® drug effect.

The planning of this study did not anticipate the changes in the state of neurotrauma care that seem to have increased chances for recovery after SCI, as documented in the first article 48 in this series. If it were known that the overall recovery in the placebo group would be so high, care would have been taken that the recruitment in the severity Group B should be higher in comparison with the severity Group A, and also in comparison with the severity Group C + D, which reached a nearly unbeatable ceiling with 90% of patients recovering by 52 weeks.

The marked recovery variable still seems in many ways a good indicator of outcome. It is free from statistical assumptions, it reflects a large change whose value to the patient is evident, and it accounts for all patients randomized including those that died. However, the detailed comparisons in these articles suggest that more delicate sensitivity may be possible with analysis using measurements such as light touch.

One of the benefits of good science is that it asks more questions than it answers.

Patients with SCI recovered in the 1990s at a rate that some thought impossible in the 1980s. In the same period there were advances in the speed, accuracy, and apparent appropriateness with which care was delivered.

Still, although many more patients improve, the majority do not and are left with a devastating injury that hurts them, their families, and society. Although the sum total of the changes in the system’s delivery of care has been beneficial, there is not uniformity and agreement in practice at the various centers, and there is a lack of data and analyses to support specific components of those changes as being the ones responsible or to suggest means for further advance. Protocol-driven tertiary neurotrauma systems with specialized spinal injury care units undoubtedly make a difference.

Further clinical trials in SCI will enhance understanding of the initial pathophysiology, recovery patterns, appropriate statistical analysis, and drug effects to dose, timing, and combined therapy. As for Sygen®, there have been two randomized controlled trials in acute SCI, the first of which was positive in its primary efficacy analysis, and the current study, which has numerous positive secondary analyses supporting it and no significant evidence against it.

Key Points

  • This study was a randomized, controlled trial of Sygen® in acute SCI in 760 patients at 28 centers in North America.
  • The prospectively planned primary efficacy analysis at the prespecified endpoint time for all patients was negative. When the primary efficacy analysis is restricted to the end of the dosing period, it is significant in favor of Sygen®, and the drug group has significantly earlier recovery.
  • The primary efficacy analysis has a trend in favor of Sygen® in the smaller-sample AIS B group and in the patients with milder injuries. The ASIA motor, light touch, and pinprick scores showed a consistent trend in favor of Sygen®, as also did bowel function, bladder function, sacral sensation, and anal contraction.
  • The evidence of beneficial drug effect was in the partial and mild injury groups, rather than the complete injury group. Evidence against an effect of Sygen® was minimal and scattered.
  • There have now been two randomized controlled trials of Sygen® in acute SCI, the first of which was positive in its primary efficacy analysis, and the current study, which has numerous positive secondary analyses.


Frank Dorsey, Francesca Patarnello, and Simonetta Piva provided statistical analysis support, and William Taylor provided SAS software support for the data analysis.


1. American Spinal Injury Association, International Medical Society of Paraplegia. International Standards for Neurologic and Functional Classification of Spinal Cord Injury. Chicago, IL: ASIA/IMSOP, 1992.
2. Ganglioside GM1 in acute ischemic stroke: the SASS trial. Stroke 1994; 25: 1141–8.
3. Agnati L, Fuxe K, Calza L, et al. Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting. Acta Physiol Scand 1983; 119: 347–63.
4. Agnati LF, Fuxe K, Calza L, et al. Gangliosides increase the survival of lesioned nigral dopamine neurons and favour the recovery of dopaminergic synaptic function in striatum of rats by collateral sprouting. Acta Physiol Scand 1983; 119: 347–63.
5. Alter M. GM1 ganglioside for acute ischemic stroke: trial design issues. Ann NY Acad Sci 1998; 845: 391–401.
6. Argentino C, Sacchetti ML, Toni D, et al. GM1 ganglioside therapy in acute ischemic stroke: Italian Acute Stroke Study—Hemodilution + Drug [see comments]. Stroke 1989; 20: 1143–9.
7. Blaustein DM, Zafonte R, Thomas D, et al. Predicting recovery of motor complete quadriplegic patients: 24 hour v 72 hour motor index scores. Am J Phys Med Rehabil 1993; 72: 306–11.
8. Bose B, Osterholm J, Kalia M. Ganglioside-induced regeneration and reestablishment of axonal continuity in spinal cord-transected rats. Neurosci Lett 1986; 63: 165–9.
9. Bracken M. Pharmacological interventions for acute spinal cord injury [The Cochrane Library, Cochrane Reviews Internet], 1999. Accessed 8/17/99, 1999.
10. Bracken MB. Methylprednisolone in the management of acute spinal cord injuries [Letter, comment]. Med J Aust 1990; 153: 368.
11. Bracken MB. Pharmacological treatment of acute spinal cord injury: current status and future projects. Paraplegia 1992; 30: 102–7.
12. Bracken MB. Steroids after spinal cord injury. Lancet 1990; 336: 279–80.
13. Bracken MB. Treatment of acute spinal cord injury with methylprednisolone: results of a multicenter, randomized clinical trial. J Neurotrauma 1991; 8 (suppl 1): 47–50; discussion 1–2.
14. Bracken MB, Collins WF, Freeman DF, et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984; 251: 45–52.
15. Bracken MB, Holford TR. Effects of timing of methylprednisolone or naloxone administration on recovery of segmental and long-tract neurological function in NASCIS 2 [see comments]. J Neurosurg 1993; 79: 500–7.
16. Bracken MB, Shepard MJ, Collins WF, 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 [see comments]. N Engl J Med 1990; 322: 1405–11.
17. Bracken MB, Shepard MJ, Collins WF Jr, et al. Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study [see comments]. J Neurosurg 1992; 76: 23–31.
18. Bracken MB, Shepard MJ, Hellenbrand KG, et al. Methylprednisolone and neurological function 1 year after spinal cord injury: results of the National Acute Spinal Cord Injury Study. J Neurosurg 1985; 63: 704–13.
19. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277: 1597–604.
20. Bracken MB, Shepard MJ, Holford TR, et al. Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial. J Neurosurg 1998; 89: 699–706.
21. Burns SP, Golding DG, Rolle WA Jr, et al. Recovery of ambulation in motor-incomplete tetraplegia. Arch Phys Med Rehabil 1997; 78: 1169–72.
22. Candelise L, Ciccone A. Gangliosides for acute ischaemic stroke. Cochrane Database Syst Rev, 2000:CD000094.
23. Carolei A, Fieschi C, Bruno R, et al. Monosialoganglioside GM1 in cerebral ischemia. Cerebrovasc Brain Metab Rev 1991; 3: 134–57.
24. Ceccareli B, Aporti F, Finesso M. Effects of Brain Gangliosides in Functional Recovery in Experimental Regeneration and Reinnervation. New York, NY: Plenum Press, 1976.
25. Cohen ME, Ditunno JF Jr, Donovan WH, et al. A test of the 1992 International Standards for Neurological and Functional Classification of Spinal Cord Injury. Spinal Cord 1998; 36: 554–60.
26. Coleman W, Benzel E, Cahill D, et al. A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury. J Spinal Disord 1999; 13: 185–99.
27. Constantini S, Young W. The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats. J Neurosurg 1994; 80: 97–111.
28. Cunha GM, Moraes RA, Moraes GA, et al. Nerve growth factor, ganglioside and vitamin E reverse glutamate cytotoxicity in hippocampal cells. Eur J Pharmacol 1999; 367: 107–12.
29. DiGregorio F, Ferrari G, Marini P, et al. The influence of gangliosides on neurite growth and regeneration. Neuropediatrics 1984; 15: 93–6.
30. Ditunno JF Jr, Graziani V, Tessler A. Neurological assessment in spinal cord injury. Adv Neurol 1997; 72: 325–33.
31. Ditunno JF Jr, Young W, Donovan WH, et al. The international standards booklet for neurological and functional classification of spinal cord injury: American Spinal Injury Association. Paraplegia 1994; 32: 70–80.
32. Dvir Z. Grade 4 in manual muscle testing: the problem with submaximal strength assessment. Clin Rehabil 1997; 11: 36–41.
33. Fass B, Ramirez J. Effects of ganglioside treatments on lesion-induced behavioral impairments and sprouting in the CNS. J Neurosci Res 1984; 12: 445–58.
34. Fazzini E, Durso R, Davoudi H, et al. GM1 gangliosides alter acute MPTP-induced behavioral and neurochemical toxicity in mice. J Neurol Sci 1990; 99: 59–68.
35. Ferrari G, Anderson BL, Stephens RM, et al. Prevention of apoptotic neuronal death by GM1 ganglioside: involvement of Trk neurotrophin receptors. J Biol Chem 1995; 270: 3074–80.
36. Ferrari G, Batistatou A, Greene LA. Gangliosides rescue neuronal cells from death after trophic factor deprivation. J Neurosci 1993; 13: 1879–87.
37. Ferrari G, Greene LA. Prevention of neuronal apoptotic death by neurotrophic agents and ganglioside GM1: insights and speculations regarding a common mechanism. Perspect Dev Neurobiol 1996; 3: 93–100.
38. Ferrari G, Greene LA. Promotion of neuronal survival by GM1 ganglioside: phenomenology and mechanism of action. Ann NY Acad Sci 1998; 845: 263–73.
39. Geisler F. Neuroprotection and regeneration of the spinal cord. In: Menezes A, Sonntag W, Benzel E, et al, eds. Principles of Spinal Surgery. New York, NY: McGraw-Hill, 1996:769–83.
40. Geisler F. Past and current human spinal cord injury drug trials. In: Tator C, Benzel E, eds. Contemporary Management of Spinal Cord Injury: From Impact to Rehabilitation. Rolling Meadows: American Association of Neurological Surgeons, 2000: 317–33.
41. Geisler F, Dorsey F, Patarnello F, et al. SYGEN acute spinal cord injury study [Abstract]. Neurotrauma 1998; 15: 868.
42. Geisler FH. Clinical trials of pharmacotherapy for spinal cord injury. Ann NY Acad Sci 1998; 845: 374–81.
43. Geisler FH. GM-1 ganglioside and motor recovery following human spinal cord injury. J Emerg Med 1993; 11 (suppl 1): 49–55.
44. Geisler FH, Dorsey FC, Coleman WP. Correction: recovery of motor function after spinal-cord injury—a randomized, placebo-controlled trial with GM-1 ganglioside [Letter]. N Engl J Med 1991; 325: 1659–60.
45. Geisler FH, Dorsey FC, Coleman WP. GM-1 ganglioside in human spinal cord injury. J Neurotrauma 1992; 9 (suppl 1): 407–16.
46. Geisler FH, Dorsey FC, Coleman WP. Past and current clinical studies with GM-1 ganglioside in acute spinal cord injury. Ann Emerg Med 1993; 22: 1041–7.
47. Geisler FH, Dorsey FC, Coleman WP. Recovery of motor function after spinal-cord injury: a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 1991; 324: 1829–38.
48. Geisler FH, Coleman WP, Grieco G, et al. Recruitment and early treatment in a multicenter study of acute spinal cord injury. Spine 2001; 26 (suppl 1): S58–67.
49. Geisler FH, Coleman WP, Grieco G, et al. Measurement and recovery patterns in a multicenter study of acute spinal cord injury. Spine 2001; 26 (suppl 1): S68–86.
50. Gorio A. Ganglioside enhancement of neuronal differentiation, plasticity, and repair. CRC Crit Rev Clin Neurobiol 1986; 2: 241–96.
51. Gorio A. Gangliosides as a possible treatment affecting neuronal repair processes. Adv Neurol 1988; 47: 523–30.
52. Gorio A, Carmignoto G, Facci L, et al. Motor nerve sprouting induced by ganglioside treatment: possible implications for gangliosides on neuronal growth. Brain Res 1980; 197: 236–41.
53. Gorio A, Ferrari G, Fusco M, et al. Gangliosides and their effects on rearranging peripheral and central neural pathways. Cent Nerv Syst Trauma 1984; 1: 29–37.
54. Gupta M, Schwarz J, Chen XL, et al. Gangliosides prevent MPTP toxicity in mice: an immunocytochemical study. Brain Res 1990; 527: 330–4.
55. Herbison GJ, Isaac Z, Cohen ME, et al. Strength post-spinal cord injury: myometer vs manual muscle test. Spinal Cord 1996; 34: 543–8.
56. Herbison GJ, Zerby SA, Cohen ME, et al. Motor power differences within the first two weeks post-SCI in cervical spinal cord-injured quadriplegic subjects. J Neurotrauma 1992; 9: 373–80.
57. Hurlbert RJ. Methylprednisolone for acute spinal cord injury: an inappropriate standard of care [see comments]. J Neurosurg 2000; 93: 1–7.
58. Itoh M, Fukumoto S, Baba N, et al. Enhancement of rat hypoglossal nerve regeneration by chitin sheet plus gangliosides. Br J Plast Surg 2000; 53: 607–11.
59. Itoh M, Fukumoto S, Baba N, et al. Prevention of the death of the rat axotomized hypoglossal nerve and promotion of its regeneration by bovine brain gangliosides. Glycobiology 1999; 9: 1247–52.
60. Itoh M, Fukumoto S, Iwamoto T, et al. Specificity of carbohydrate structures of gangliosides in the activity to regenerate the rat axotomized hypoglossal nerve. Glycobiology 2001; 11: 125–30.
61. Karpiak S. Ganglioside treatment improves recovery of alternation behavior after unilateral entorhinal cortex lesion. Exp Neurol 1983; 81: 330–9.
62. Karpiak S, Li Y, Mahadik S. Acute ganglioside effects limit CNS injury. In: Stein DG, Sabel BA, eds. Pharmacological Approaches to the Treatment of Brain and Spinal Cord Injury. New York, NY: Plenum Press, 1988.
63. Karpiak S, Li Y, Mahadik S. Ganglioside treatment: reduction of CNS injury and facilitation of functional recovery. Brain Inj 1987; 1: 161–70.
64. Karpiak S, Mahadik S. Reduction of cerebral edema with GM1 ganglioside. J Neurosci Res 1984; 12: 485–92.
65. Kojima H, Gorio A, Janigro D, et al. GM1 ganglioside enhances regrowth of noradrenaline nerve terminals in rat cerebral cortex lesioned by the neurotoxin 6-hydroxydopamine. Neuroscience 1984; 13: 1011–22.
66. Lainetti RD, Pereira FC, Da-Silva CF. Ganglioside GM1 potentiates the stimulatory effect of nerve growth factor on peripheral nerve regeneration in vivo. Ann NY Acad Sci 1998; 845: 415–6.
67. Ledeen R. Biology of gangliosides: neuritogenic and neuronotrophic properties. J Neurosci Res 1984; 12: 147–59.
68. Ledeen R. Ganglioside structures and distribution: are they localized at the nerve ending? J Supramol Struct 1978; 8: 1–17.
69. Lenzi GL, Grigoletto F, Gent M, et al. Early treatment of stroke with monosialoganglioside GM-1: efficacy and safety results of the Early Stroke Trial. Stroke 1994; 25: 1552–8.
70. Manev H, Favaron M, Vicini S, et al. Ganglioside-mediated protection from glutamate-induced neuronal death. Acta Neurobiol Exp (Warsz) 1990; 50: 475–88.
71. Maynard FM Jr, Bracken MB, Creasey G, et al. International standards for neurological and functional classification of spinal cord injury: American Spinal Injury Association. Spinal Cord 1997; 35: 266–74.
72. Medical Research Council of the U.K. Aids to the Examination of the Peripheral Nervous System [Memorandum No. 45]. London: Her Britannic Majesty’s Stationery Office, 1976.
73. Nesathurai S. Steroids and spinal cord injury: revisiting the NASCIS 2 and NASCIS 3 trials. J Trauma 1998; 45: 1088–93.
74. Nicoletti F, Cavallaro S, Bruno V, et al. Gangliosides attenuate NMDA receptor-mediated excitatory amino acid release in cultured cerebellar neurons. Neuropharmacology 1989; 28: 1283–6.
75. Otani K, Abe H, Kadoya S, et al. Beneficial effect of methylprednisolone sodium succinate in the treatment of acute spinal cord injury. Sekitsui Sekizui J 1994; 7: 633–47.
76. Papo I, Benedetti A, Carteri A, et al. Monosialoganglioside in subarachnoid hemorrhage [published erratum appears in Stroke 1991;22: 957]. Stroke 1991; 22: 22–6.
77. Petitjean ME, Pointillart V, Dixmerias F, et al. Medical treatment of spinal cord injury in the acute stage [in French]. Ann Fr Anesth Reanim 1998; 17: 114–22.
78. Pitts LH, Ross A, Chase GA, et al. Treatment with thyrotropin-releasing hormone (TRH) in patients with traumatic spinal cord injuries. J Neurotrauma 1995; 12: 235–43.
79. Pope-Coleman A, Tinker JP, Schneider JS. Effects of GM1 ganglioside treatment on pre- and postsynaptic dopaminergic markers in the striatum of parkinsonian monkeys. Synapse 2000; 36: 120–8.
80. Ramirez J, Fass B, Karpiak S, et al. Ganglioside treatments reduce locomotor hyperactivity after bilateral lesions of the entorhinal cortex. Neurosci Lett 1987; 75: 283–7.
81. Ramirez J, Fass B, Kilfoil T, et al. Ganglioside-induced enhancement of behavioral recovery after bilateral lesions of the entorhinal cortex. Brain Res 1987; 414: 85–90.
82. Ramirez J, Fass-Holmes B, Karpiak S, et al. Enhanced recovery of learned alternation in ganglioside-treated rats after unilateral entorhinal lesions. Behav Brain Res 1991; 43: 99–101.
83. Rocca WA, Dorsey FC, Grigoletto F, et al. Design and baseline results of the monosialoganglioside early stroke trial: the EST Study Group. Stroke 1992; 23: 519–26.
84. Roisen F, Bartfeld H, Nagele R, et al. Ganglioside stimulation of axonal sprouting in vitro. Science 1981; 241: 577–8.
85. Rybak S, Ginzburg I, Yavin E. Gangliosides stimulate neurite outgrowth and induce tubulin mRNA accumulation in neural cells. Biochem Biophys Res Commun 1983; 116: 974–80.
86. Ryu BR, Choi DW, Hartley DM, et al. Attenuation of cortical neuronal apoptosis by gangliosides. J Pharmacol Exp Ther 1999; 290: 811–6.
87. Sabel B. Anatomic Mechanisms Whereby Gangliosides Induce Brain Repair: What Do We R Know? New York, NY: Plenum Press, 1988.
88. Sabel B, DelMastro R, Dunbar G, et al. Reduction of anterograde degeneration in brain damaged rats by GM1-gangliosides. Neurosci Lett 1987; 77: 360–6.
89. Sabel B, Dunbar G, Stein D. Gangliosides minimize behavioral deficits and enhance structural repair after brain injury. J Neurosci Res 1984; 12: 429–43.
90. Sabel B, Slavin S, Stein D. GM1 ganglioside treatment facilitates behavioral recovery from bilateral brain damage. Science 1984; 225: 340–2.
91. Sabel B, Stein D. Pharmacological treatment of central nervous system injury [news]. Nature 1986; 323: 493.
92. Saito M, Berg MJ, Guidotti A, et al. Gangliosides attenuate ethanol-induced apoptosis in rat cerebellar granule neurons. Neurochem Res 1999; 24: 1107–15.
93. Sautter J, Hoglinger GU, Oertel WH, et al. Systemic treatment with GM1 ganglioside improves survival and function of cryopreserved embryonic midbrain grafted to the 6-hydroxydopamine-lesioned rat striatum. Exp Neurol 2000; 164: 121–9.
94. Schneider JS. GM1 ganglioside in the treatment of Parkinson’s disease. Ann NY Acad Sci 1998; 845: 363–73.
95. Schneider JS, Roeltgen DP, Mancall EL, et al. Parkinson’s disease: improved function with GM1 ganglioside treatment in a randomized placebo-controlled study. Neurology 1998; 50: 1630–6.
96. Schneider JS, Roeltgen DP, Rothblat DS, et al. GM1 ganglioside treatment of Parkinson’s disease: an open pilot study of safety and efficacy. Neurology 1995; 45: 1149–54.
97. Schneider JS, Schroeder JA, Rothblat DS. Differential recovery of sensorimotor function in GM1 ganglioside-treated vs. spontaneously recovered MPTP-treated cats: partial striatal dopaminergic reinnervation vs. neurochemical compensation. Brain Res 1998; 813: 82–7.
98. Shigemori M, Okamoto Y, Watanabe T, et al. Effect of monosialoganglioside (GM1) on transected monoaminergic pathways. J Neurotrauma 1990; 7: 89–97.
99. Short DJ, El Masry WS, Jones PW. High dose methylprednisolone in the management of acute spinal cord injury: a systematic review from a clinical perspective. Spinal Cord 2000; 38: 273–86.
100. Skaper S, Leon A. Monosialogangliosides, neuroprotection, and neuronal repair processes. J Neurotrauma 1992; 9 (suppl): 507–16.
101. Skaper SD, Leon A, Facci L. Ganglioside GM1 prevents death induced by excessive excitatory neurotransmission in cultured hippocampal pyramidal neurons. Neurosci Lett 1991; 126: 98–101.
102. Tan WK, Williams CE, Mallard CE, et al. Monosialoganglioside GM1 treatment after a hypoxic-ischemic episode reduces the vulnerability of the fetal sheep brain to subsequent injuries. Am J Obstet Gynecol 1994; 170: 663–9.
103. Tator C, Fehlings M. Review of clinical trials of neuroprotection in acute spinal cord injury [American Association of Neurological Surgeons Internet], 1999. Accessed 8/17/99, 1999.
104. Toffano G, Savoini G, Aldinio C, et al. Effects of gangliosides on the functional recovery of damaged brain. Adv Exp Med Biol 1984; 174: 475–88.
105. Toffano G, Savoini G, Moroni F, et al. GM1 ganglioside stimulates the regeneration of dopaminergic neurons in the central nervous system. Brain Res 1983; 261: 163–6.
106. Tseng EE, Brock MV, Lange MS, et al. Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest. Surgery 1998; 124: 298–306.
107. Walker M. Acute spinal-cord injury [editorial; comment]. N Engl J Med 1991; 324: 1885–7.
108. Wang MS, Chen ZW, Zhang GJ, et al. Topical GM1 ganglioside to promote crushed rat sciatic nerve regeneration. Microsurgery 1995; 16: 542–6.
109. Weber M, Mohand-Said S, Hicks D, et al. Monosialoganglioside GM1 reduces ischemia–reperfusion-induced injury in the rat retina. Invest Ophthalmol Vis Sci 1996; 37: 267–73.

acute spinal cord injury; GM-1 ganglioside; Sygen®; recovery]Spine 2001;26:S87–S98

© 2001 Lippincott Williams & Wilkins, Inc.