Original Article
Recovery of Motor Function after Spinal-Cord Injury — A Randomized, Placebo-Controlled Trial with GM-1 Ganglioside
N Engl J Med 1991; 324:1829-1838June 27, 1991
- Abstract
- Abstract
Background.
Spinal-cord injury is devastating; until recently, there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons.
Methods.
A prospective, randomized, placebo-controlled, double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study, 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses, with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100, derived from strength tests of 20 specific muscles, each scored from 0 to 5).
Results.
There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0, 1, 2, and 3 grades in 13, 4, 1, and 0 patients, respectively, in the placebo group and 8, 1, 6, and 1 patients, respectively, in the GM-1 group; P = 0.034 by the Cochran—MantelHaenszel chi-square test). The GM-1—treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles.
Conclusions.
This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted, however, before GM-1 is considered efficacious and safe in treating spinal-cord injury. (N Engl J Med 1991; 324:1829–38.)
Media in This Article
Figure 1
Distribution of Frankel Grades at Entry and One-Year Follow-up, According to Treatment Group.Figure 2
Histogram of the Number of Patients with Neurologic Recovery, as Shown by Improvement in ASIA Motor Scores from Entry to the One-Year Follow-up.Article Activity
- Article
THE modern treatment of patients with spinal-cord injuries began during World War II in England, and its success led to the development of centers treating such injuries in the United States.1 2 3 The emergency medical systems developed concurrently provided prompt triage of patients with spinal-cord injuries to these centers. The protocols used in these centers decreased morbidity and mortality by preventing and treating associated medical sequelae, increased the patients' ultimate functional ability through intensive rehabilitation services to optimize the remaining neurologic function, and provided an environment to prevent further injury to the spinal cord and facilitate any possible spontaneous recovery of neurologic function.4 , 5 Despite these important advances, it has remained disappointing that although most patients recover some function, only a minority have major neurologic recovery, and that recovery, when it does occur, is almost never complete.6 No acute treatment or rehabilitation therapy in humans other than that recently reported by the Second National Acute Spinal Cord Injury Study (NASCIS 2)7 , 8 has demonstrated enhanced recovery from, or reversal of, the neurologic injury received in the initial insult. Although spinal-cord injury is relatively uncommon (10,000 cases per year in the United States,9 10 11 as compared with 150,000 fatal injuries12), it is a prominent disease entity, because it produces permanent disability that is particularly devastating in the typical trauma patient, a young person just starting adult life.
Several studies have reported enhanced neurologic recovery with different drug treatments, including gangliosides, after spinal-cord injuries in laboratory animals.13 These results are difficult to extrapolate to therapy in humans, however, because there is controversy about which animal model best simulates injury in humans, about whether all the models are reproducible, and about why there is a dissimilarity between animals and humans in the pathophysiologic features of the response to the drug.14 , 15 Drug trials in humans that have used steroids and naloxone to examine neurologic recovery after spinal-cord injury have failed to demonstrate any improvement in outcome with drug treatment, except in the NASCIS 2 treatment group receiving high-dose methylprednisolone (a bolus of 30 mg per kilogram of body weight, followed by an infusion of 5.4 mg per kilogram per hour for 23 hours) within 8 hours of the injury 7 , 8 , 15 16 17 18 The NASCIS 2 study was performed at the same time as this study. Several reviews of the pathophysiologic features of spinal-cord injury indicate possible therapeutic strategies to improve ultimate neurologic function by decreasing cell mortality and enhancing the regeneration or recovery of the remaining cells.15 , 19 20 21 22 23
Gangliosides, complex acidic glycolipids present in high concentrations in central nervous system cells, form a major component of the cell membrane and are located predominantly in the outer leaflet of the cell membrane's bilayer.24 Although the functions of the neuronal gangliosides remain unknown, there is experimental evidence that they augment neurite outgrowth in vitro, induce regeneration and sprouting of neurons, and restore neuronal function after injury in vivo. In many recent studies in animals,13 , 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 45 gangliosides have stimulated the growth of nerve cells and the regeneration of damaged nervous tissues. These encouraging experimental results have led to clinical trials in stroke and animal trials in diabetic neuropathy that suggest a positive effect of gangliosides on neurologic recovery.46 47 48
The current study examined the recovery of neurologic function after spinal-cord injury in humans. The model of spinal-cord injury was chosen to examine neurologic recovery in central nervous system tissue because small changes in the size of parenchymal lesions cause large, quantifiable, clinical changes in motor and sensory function distal to the injury. This study was designed as a pilot study to test whether the neurologic recovery in humans after a spinal-cord injury could be altered by adding monosialotetrahexosylganglioside (GM-1) ganglioside to the protocol of medical and surgical care with which these trauma patients are initially treated.
Methods
We conducted a prospective, randomized, placebo-controlled, double-blind drug trial of GM-1 ganglioside in patients with spinal-cord injuries, with a follow-up period of one year after the injury to assess recovery.6 This study was approved by the Human Volunteers Research Committee of the University of Maryland at Baltimore.
Patient Population and Study Design
All 351 patients who were admitted to the Shock Trauma Center of the Maryland Institute for Emergency Medical Services Systems with spinal-cord injuries over the 17-month recruitment period (January 1986 through May 1987) were considered for entry into the study. The criteria for entry were written informed consent, the absence of contraindications to the use of GM-1, sterility or postmenopausal status in the case of female patients, an age of 18 years or older, and the presence of a spinal-cord injury with a major motor deficit in the hands or legs. The criteria for exclusion from the study were the presence of a major medical illness, a high likelihood of becoming lost to follow-up, involvement in other experimental drug protocols, the presence of substantial damage to the cauda equina, or inability to receive the first dose of the study drug within 72 hours after the injury.
At entry into the study, each patient was assigned the next sequential prerandomized drug-study number, underwent a neurologic evaluation, and was given the first dose of the study drug. There was no crossover of patients between groups, and no patient requested to be dropped from the study. The study's double-blind status was maintained for the patients, the study investigators, the statisticians, and all clinical personnel until the entire study group had completed the year of follow-up, the data entry had been double-checked, and the data had been verified by an independent medical consulting firm. No changes with respect to exclusion of patients or data were allowed after the code was broken.
The complete composition of the GM-1 ganglioside used in the study (Sygen, Fidia, Abano Terme, Italy) is 100 mg of GM-1 sodium salt, 12.7 mM; 1.25 mg of sodium dihydrogen phosphate dihydrate, 1.6 mM; 15.0 mg of disodium hydrogen phosphate dodecahydrate, 8.4 mM; 40.0 mg of sodium chloride, 137.9 mM; and a quantity of water sufficient to yield an isotonic solution with a total volume of 5 ml for injection. The placebo vials were identical in appearance and composition, except that the GM-1 was absent. The 100-mg daily dose was the highest dose marketed in Europe and approved for human trials by the Food and Drug Administration. Most of the test drug was administered by injection through an intravenous heparin lock. Some of the first few injections were given by an intravenous catheter, and occasionally, when the heparin lock was nonfunctional, a single direct-puncture intravenous injection was used.
During the trial, there was no time-coincident or delayed physiologic response to the injection of the study drug that would have violated the double-blind status of the study for either the patient or the clinical personnel. Specifically, no discomfort or rash was noted at the injection site, and no systemic response was observed clinically or noted by the patients.
Table 1Table 1
Patients Who Were Excluded from the Study on the Basis of the Entry Criteria. shows the reasons why 314 patients admitted to the Shock Trauma Center with spinal injuries during the recruitment period were excluded from entry into the study; most had either no neurologic deficits (123 patients) or only minor ones (87 patients). Only three patients refused to participate in the study. All the exclusions were based on an initial evaluation of the patient and were made before randomization.During the recruitment period, 37 patients met the entry criteria. Three of the patients were excluded from the study after entry: one man after 8 doses, when the box containing his remaining study doses was lost during a room transfer and presumably discarded; one woman after 7 doses, when her potential fertility status was clarified; and one man after 17 doses, when his pulmonary status deteriorated, requiring medical paralyzation for treatment and thus preventing the required neurologic evaluations. He ultimately died of acute respiratory distress syndrome precipitated by aspiration during a surfing accident. For these three patients, the study drug was discontinued for technical rather than therapeutic reasons. The follow-up neurologic examinations were stopped for these patients after they were excluded from the study, and the patients were not included in the analysis of efficacy. They were, however, included in the analysis of adverse events. When the treatment-group code was eventually broken, the three patients were found to have been in the placebo group, the placebo group, and the GM-1 group.
The study group comprised 34 patients (23 with cervical injuries and 11 with thoracic injuries) who were randomly assigned to a treatment group and who followed the test-drug protocol and completed the one-year follow-up period. Sixteen patients were included in the GM-1 group, and 18 were in the placebo group. Table 2Table 2
Characteristics of the Two Study Groups.* shows the demographics and study characteristics of these 34 patients according to treatment group. There were no noteworthy differences between the two groups in age, weight, height, sex, race, time from injury to the emergency room, time from injury to entry into the study, or days of study-drug administration. The notably short median injury-to-emergency-room time of just over two hours for both treatment groups allowed spinal-cord decompression and resuscitation to begin promptly, to maximize the recovery potential of the injured spinal cord. The variability in the total number of doses administered to each patient was determined by both the choice and the timing of transfer to a rehabilitation hospital. Although some of the final doses of the study drug were administered at one local rehabilitation hospital, the study drug was usually discontinued when the patient was transferred to one of several rehabilitation hospitals serving our population of patients.The spinal-cord injury occurred in the cervical area in 12 patients assigned to GM-1 and 11 patients assigned to placebo, and in the thoracic area in 4 patients assigned to GM-1 and 7 patients assigned to placebo. The most rostral traumatic lesion occurred at C3–4, and the most caudal lesion at T12. The causes of the spinal-cord injuries (13 motor vehicle accidents, 9 falls, 6 gunshot wounds, 4 diving or surfing accidents, and 2 assaults) were evenly distributed between the two groups. In the GM-1 and the placebo groups, 14 of the 16 and 13 of the 18 patients, respectively, underwent surgery soon after hospitalization. Surgery was performed within 72 hours (median, 13.5) after the injury in nine patients assigned to GM-1 and nine patients assigned to placebo to alleviate continued neural compression or provide prompt internal stabilization to prevent reinjury to the spinal cord.49 Five patients receiving GM-1 and four patients receiving placebo had deferred spinal surgery (more than 72 hours after the injury; median, 16 days after the injury) to relieve chronic compression of the cervical spinal cord after their neurologic status reached a plateau. There were no noteworthy differences between groups in the number of operations or in their timing (early vs. deferred). Furthermore, the literature does not support the expectation of any benefit from earlier surgery for decompression or stabilization.50 51 52 53 54 55
Standard Protocol of Medical Management
The protocol used at the Shock Trauma Center for the initial evaluation and medical care of patients with spinal-cord injuries has been described elsewhere.56 , 57 The acute management consisted of six phases of care: (1) initial assessment and spinal immobilization, (2) medical treatment to correct neurogenic shock and optimize tissue perfusion and oxygenation, (3) prompt anatomical alignment of the spinal bony elements, (4) radiologic diagnostic examination, (5) prompt surgical decompression of neural elements if the closed spinal alignment failed to relieve the compression, and (6) stabilization of any bony instability. Most patients required continuous treatment with intravenous dopamine hydrochloride, beginning at admission and continuing for several days, to reverse the neurogenic shock and maintain a normal-to-high-normal systolic blood pressure.58 , 59 The protocol of medical management during this study included 250 mg of methylprednisolone sodium succinate given intravenously on admission followed by 125 mg given intravenously every 6 hours for 72 hours. This regimen of methylprednisolone was chosen after consideration of the medical information available at the time the study began. The results of the NASCIS 2 study (using much larger doses of methylprednisolone) were not known to us until after the first draft of this paper was submitted.
All the patients in this study were treated according to this protocol. Specifically, a patient who entered the study with a complete spinal-cord deficit (no clinically detectable motor or sensory function caudal to the level of the spinal-cord injury) was treated according to the same protocol as one who initially had a partial spinal-cord deficit (paretic muscles or abnormal sensation caudal to the level of spinal-cord injury). Patients with injuries of the cervical central spinal cord without fracture or dislocation were treated with cervical traction for approximately one week and then placed in hard cervical collars to minimize cervical motion.49 , 60
Adverse Events
During the drug trial, 131 adverse events were noted in 35 of the 37 patients. Table 3Table 3
Adverse Events during the Drug Trial, According to Treatment Group.* summarizes the events, subdivided according to study group. There were no substantial differences between groups in the distribution of adverse experiences, nor did the number of adverse experiences per patient in each group appear to differ. The type and frequency of such events were typical for patients with acute spinal-cord injuries6 and were not obviously altered by the administration of the study drug. The most frequent adverse experience was urinary tract infection, which occurred in 10 of the 17 GM-1—treated patients and in 16 of the 20 patients assigned to placebo. This study provides evidence that GM-1 is safe to administer in patients with acute spinal-cord injuries, because there was no noteworthy difference between the two groups in the rate of medical complications.Neurologic Assessment
The severity of spinal-cord injury and its subsequent recovery were quantified by serial measurement with both the Frankel scale61 and the American Spinal Injury Association (ASIA) motor score.62 Each measurement was made at the time of the first contact in the emergency room, at entry into the study, then twice per week for the first 4 weeks and after 2, 3, 6, and 12 months. The delay of about 50 hours from the initial presentation in the emergency room to entry into the study was created intentionally to provide a more reliable neurologic examination.50 The examinations performed at study entry were done after the immediate psychological reaction to the traumatic injury and disability had stabilized and after the initial assessment of the total body in the emergency room and any emergency surgery had been completed.
The Frankel classification system separates neurologic disability into five ordinal grades, according to the type and completeness of neurologic function remaining below the level of the spinal-cord injury, as follows: grade A, complete neurologic injury (no motor or sensory function clinically detectable below the level of the injury); grade B, only sensation preserved (no motor function clinically detectable below the level of the injury, but some sensory function preserved below that level, excluding subjective phantom sensations); grade C, nonfunctional motor ability preserved (voluntary motor function preserved below the level of injury that serves no useful purpose; sensory function may or may not be preserved); grade D, functional motor ability preserved (voluntary motor function preserved that is useful functionally); and grade E, normal motor function (complete return of all motor and sensory function; abnormal reflexes may remain). The letters designating each grade were used by Frankel in his original description of this scale.61 Improvement on the scale (i.e., movement to a grade with a higher letter) results from the recovery, repair, and regeneration of spinal-cord function through the injury site. The main limitation of the Frankel scale derives from its categorization of spinal-cord injury into five discrete groups, whereas in fact the injury and the recovery are on a continuum.50
The second clinical scale used to assess spinal-cord injury and its recovery was the ASIA motor score. This scale has a range of 0 (complete quadriplegia) to 100 (normal motor function).62 Five key muscles in each extremity (the biceps, wrist extensors, triceps, flexor profundus, and hand intrinsics in the upper extremity, and the iliopsoas, quadriceps, tibialis anterior, extensor hallucis longus, and gastrocnemius in the lower extremity) are assessed on a scale for strength from 0 to 5 points in which 0 (absent) denotes total paralysis, 1 (trace) palpable or visible penetration, 2 (poor) active movement through a range of motion in which gravity is not involved, 3 (fair) active movement through a range of motion against gravity, 4 (good) active movement through a range of motion against resistance, and 5 normal. The ASIA motor score is the sum of the scores for muscle strength in these 20 motor groups. Improvement on this scale (the attainment of a higher score) can be due to the recovery, repair, or regeneration of spinal-cord tissue passing through the injury site, the recovery of function of a small amount of tissue at the most caudal level of function in a complete injury, or a generalized increase in the motor strength of initially paretic muscles, as occurs in a central cord injury.60 Thus, although this scale largely overcomes the discrete nature of the Frankel scale, it does not identify a unique anatomical site for the improvement. Hence, these two clinical scales examine recovery from spinal-cord injury in somewhat different ways.
These tools for spinal-cord assessment were selected on the basis of clinical experience in assessing and following neurologic status. A gain in the Frankel grade or the ASIA motor score indicates an increase in functional ability. When there is an increase in either score, the physicians, the patient, and the family members all agree that the patient has more ability to function. Our experience with these tools for assessing spinal-cord injury is that a number of observers obtain very similar or identical values when a standardized method of examination is used. Uniformity in the neurologic examination in this study was maximized by having the principal investigator perform all initial examinations and many subsequent ones, with the remaining examinations performed by physical therapists blinded to treatment assignment, using the Frankel scale and the ASIA motor score according to a standardized protocol.
The primary variables chosen to assess neurologic recovery in the study design were the changes in the Frankel scale and ASIA motor scores from the values obtained at study entry to those obtained after the one-year follow-up. The analysis of subgroups according to anatomical region (performed in patients with cervical injuries only), along with the analysis of the initially paralyzed groups, was devised after the initial analysis to determine which subgroup of patients or motor groups were improving and to provide a basis for correlating the study observations with the pathophysiologic features of spinal-cord injury.
Results
The distribution of Frankel grades at entry and follow-up according to region of injury and treatment group is shown in Figure 1Figure 1
Distribution of Frankel Grades at Entry and One-Year Follow-up, According to Treatment Group.. The grades obtained at entry revealed no bias according to either group or anatomical region of injury. The improvements in these grades after one year revealed three features, however. First, the overall number of patients whose scores improved by two or more Frankel grades was larger than historical data would have predicted (23.5 percent, or 8 of 34 patients, in this study as compared with 4.4 percent in historical data6). Second, the majority of the patients (seven of eight) who had this considerable neurologic recovery were in the GM-1 group. Third, in the placebo group, the recovery observed was similar to that predicted on the basis of historical data (1 of 18 patients, or 5.6 percent). Overall, the GM-1—treated patients improved more than the placebo-treated patients with respect to Frankel grade (P = 0.034 by the Cochran—MantelHaenszel chi-square test). Furthermore, among 28 patients who had room to improve by two or more Frankel grades, 7 of 14 of the GM-1—treated patients improved as compared with 1 of 14 of the placebo-treated patients (50 percent vs. 7.1 percent, P = 0.033 by Fisher's exact test, two-tailed). Although the study sample was large enough to show a difference in improvement between the GM-1 group and the placebo group, it was not large enough to permit a simultaneous analysis of the timing of intervention, the level or severity of injury, management-related variables, or other categories of patients.Table 4Table 4
Clinical Features of Eight Patients Who Recovered by Two or Three Frankel Grades.* summarizes the clinical features of the eight patients who improved by two or three Frankel grades. The ages, sites of injury, and types of surgical intervention in these patients represented a typical cross-section of patients with spinal-cord injuries at the time of admission to the emergency room; nothing unusual was noted except the greater-than-expected recovery of function. The two patients who had Frankel grade A injuries both in the emergency room and at entry into the study had priapism in the emergency room. Both these patients regained some sensory function distal to the injury by week 4 after the injury and motor recovery was noted at weeks 8 and 12. Another patient whose injury was classified as grade A in the emergency room had some return of sensation before entry into the study. He started to regain motor function four weeks after the injury. Four patients with injuries classified as grade B in the emergency room and at entry into the study had a return of motor function between 3 and 12 weeks after the injury. One patient whose injury was classified as grade B in the emergency room started to regain motor function before entry into the study and went on to recover completely.The distribution of improvement in ASIA motor scores from study entry to the end of the one-year follow-up is shown in Figure 2Figure 2
Histogram of the Number of Patients with Neurologic Recovery, as Shown by Improvement in ASIA Motor Scores from Entry to the One-Year Follow-up. for each treatment group. There was a natural break in the distribution between scores of 15 and 25 points, with 16 patients below and 18 patients above this break. There were more patients with motor recoveries of more than 20 points in the GM-1 group (11 of 16, or 68.8 percent) than in the placebo group (7 of 18, or 38.9 percent). Also, three GM-1—treated patients had a greater degree of recovery than any patient assigned to placebo, and there were more patients with no recovery in the placebo group (six patients) than in the GM-1 group (one patient).Table 5Table 5
Mean ASIA Motor Scores at Study Entry and Follow-up, with Improvements in Scores, for All Patients and the Subgroup of Cervical Patients, According to Treatment Group. shows the ASIA motor scores at entry, those after the one-year follow-up, and the improvement in mean scores during this period, according to treatment group, for all patients completing the study and for the subgroup of patients with cervical injuries; it also presents the mean, standard deviation, and 95 percent Student's t confidence intervals. There was an imbalance in the mean ASIA motor scores at study entry despite randomization, with greater motor deficit in the GM-1 group. The mean ASIA motor score at entry was 25.9 (95 percent confidence interval, 14.3 to 37.5) for the GM-1 group and 39.8 (95 percent confidence interval, 29.5 to 50.1) for the placebo group.The mean ASIA motor score and mean improvement from the score obtained at entry are shown plotted against time in Figure 3Figure 3
Improvement in Mean ASIA Motor Scores from Entry to Follow-up for All 34 Patients Completing the Study, According to Treatment Group. for the two treatment groups, including all 34 patients who completed the study. Inspection of the two upper curves, those for the mean ASIA motor score, reveals an imbalance at base line between the two groups with respect to severity of injury and essentially equivalent scores at the one-year follow-up. The two lower curves show the mean improvement in the motor score from the score obtained at entry, to normalize the initial imbalance between groups. These two graphs disclose a consistent separation between the GM-1 and the placebo groups (one that favors the drug effect) with regard to the magnitude of neurologic recovery. For each treatment group, half the total ASIA motor score recovered over the one-year period was completed a mean of 67 days after the injury. In the GM-1 group, no improvement in recovery was associated with the interval between the time of the injury and the start of administration of the study drug.Table 5 also shows the ASIA motor score subdivided according to the respective contributions of the upper and lower extremities among the 23 patients with cervical injuries. This subdivision shows that the improvement in the scores of the patients in the GM-1 group resulted from greater improvement in their scores for the lower extremities, since the improvements in the scores for the upper extremities were similar in the two treatment groups.
The GM-1—treated patients had a mean motor recovery of 36.9 points (95 percent confidence interval, 21.9 to 51.9) from their ASIA motor score at entry to the score after one year, whereas for the placebo-treated patients the mean recovery was 21.6 points (95 percent confidence interval, 10.2 to 33.1). The oneyear improvement in the ASIA motor score for the placebo-treated group was comparable to the improvement of 15.7 (adjusted for differences in the motor groups evaluated) reported in the literature.16 Also shown in Table 5 are the difference between treatment groups in improvement in ASIA motor score (mean, 15.3; 95 percent confidence interval, —2.6 to 32.2) and the difference in improvement as calculated after adjustment for the difference in base-line values by an analysis of covariance in which the base-line score was used as a covariate (mean, 11.5; 95 percent confidence interval, 0.2 to 22.9). The adjusted difference in the improvement of motor recovery between the two groups was significant for drug effect (P = 0.043 by analysis of covariance with the base-line ASIA motor score as the covariate).
Only 4 muscle groups of a total of 680 (representing 34 patients, each with 20 muscle groups studied) were in worse condition at follow-up than at entry into the study. These four muscle groups were all initially evaluated as grade 3, and all were in one limb of a patient in the GM-1 group who had severe heterotopic ossification in that limb. To aid in clarifying which muscles were improving, the 20 individual muscle groups in each patient were subdivided into three categories at entry: those initially paralyzed (a motor score of 0), those initially paretic (a motor score of 1 through 4), and those functioning normally (a motor score of 5). The muscle groups with motor scores of 1 through 4 at entry appeared to improve by an approximately equal amount in both treatment groups. Scores of 5 are normal and hence, by definition, cannot improve. However, an imbalance was noted in the pattern of recovery between treatment groups when the proportion of muscle groups paralyzed at entry (those with a motor score of 0) that regained useful-to-normal function (a motor score of 3 to 5) after one year was compared with the proportion that remained paralyzed. In the GM-1 group, 30.9 percent of the paralyzed muscle groups (64 of 207) remained paralyzed, and 51.7 percent (107 of 207) recovered to regain useful-to-normal motor function; in the placebo group, 65.5 percent (127 of 194) remained paralyzed, and 25.3 percent (49 of 194) regained useful-to-normal motor function. Similar proportions were obtained in the analysis of patients with cervical-spine injuries only.
Recoveries of the 20 muscle groups in an individual patient are correlated, because typically, when improvement occurs, several muscle groups improve. Thus, the muscles tabulated above do not recover independently, and consequently the proportions listed above cannot be used as independent variables in statistical tests. A post hoc analysis was developed, however, to address muscle-group improvement on a per-patient basis that conformed with the requirement for independence of statistical tests. The number of patients in each treatment group who had at least one paralyzed muscle group at entry that improved to a motor score of 3 or more at the one-year follow-up was compared with the number of patients who had no muscle group paralyzed at entry for which there was that degree of improvement. This analysis revealed a significant drug effect when all patients completing the study were included (13 of 16, or 81.3 percent, in the GM-1 group and 8 of 18, or 44.4 percent, in the placebo group; P = 0.039 by Fisher's exact test, two-tailed) and a positive trend in the subgroup of patients with cervical injuries only (11 of 12, or 91.7 percent, in the GM-1 group and 7 of 11, or 63.6 percent, in the placebo group; P = 0.155 by Fisher's exact test). This analysis demonstrates that the improvement between the two treatment groups, the drug effect, is due to the regaining of useful function by paralyzed muscles rather than to paretic muscles improving strength.
Discussion
The observed difference in improvement between the two treatment groups, when correlated with the pathophysiologic features of the spinal cord, can be used to infer the anatomical site of action of GM-1 in enhancing motor recovery.15 , 22 , 23 , 58 , 63 Trauma alone rarely causes the anatomical transection of the spinal cord, even when there is complete loss of clinical neurologic function caudal to the level of the injury. Instead, the neurologic deficit is caused by the microscopic physical disruption of axons traversing the injury site, by ischemia or hypoxia that results in a local infarction, or by microhemorrhages or edema within the spinal cord at the injury site that prevents the transmission of neuronal impulses. The injury causes the maximal physical damage to occur in the center of the spinal cord, at the location of the gray matter, with lesser damage to the surrounding white matter. This initial central contusion is believed to evolve and cause secondary damage 24 to 72 hours after the injury that may potentially be altered by treatment. The force of the injury determines the size and density of the central microhemorrhages. If the injury is sufficiently great, the central area affected can be as large as the diameter of the spinal cord and cause a complete clinical transverse myelopathy. The gray matter in the center of the spinal cord is inherently more susceptible to trauma because it has a higher metabolic activity, requiring more blood flow for survival; it contains the bodies of the alpha motoneurons, making recovery more difficult because the biomolecular machinery for repair is also damaged; and the gray matter is irreversibly damaged in the first hour. The recovery of function of spinal-cord gray matter after its traumatic destruction may require regeneration or transplantation to replace the lost alpha motoneurons or nearby interneurons. Strategies for limiting or controlling gray-matter dysfunction will probably need to be initiated in the first few minutes or hours after the injury. In contrast, the circumferential white-matter tracts at the site of the injury are conceptually easier to consider as a locus for enhancing recovery because they are tissues with a lower metabolic rate, they have cell bodies with biomolecular machinery for DNA and protein synthesis that is distant from the injury site, and they are known in some cases to survive the initial injury. The initial neurologic deficit in these tracts can be repaired up to 72 hours after the injury or later.64 , 65
Experiments in animals support the concept that motor function can recover to normal levels after a spinal-cord injury if as few as 4 to 6 percent of the cortical motor neurons regain physiologic connection through the injured spinal-cord segment to the caudal spinal cord. In addition, these experiments support a threshold effect in the return of motor function after the recovery of the surviving neurons in these tracts. An increase in axonal survival at the injury site of from less than 3 percent to more than 6 percent allows neurologic function to return through the site and converts paralyzed muscles to muscles with normal movement caudal to the injury.15 Thus, the model of spinal-cord injury is a sensitive clinical tool for determining the recovery, preservation, or potency of a minority of the axons in the white-matter tracts passing through the injury site. The considerable neurologic recovery observed in some patients in this study and the conclusion that useful motor function was regained in initially paralyzed muscles are consistent with these data.
The beneficial effect of GM-1 observed in this study can be interpreted as a GM-1—related increase in the proportion of patients who have surviving or effective neurons above this threshold of axonal survival. The treatment groups had similar motor recovery over time in the upper extremities (Fig. 4Figure 4
Improvement in ASIA Motor Scores for the Upper and Lower Extremities over the One-Year Study Period in the 23 Patients with Cervical Injuries Who Completed the Study, According to Treatment Group.), implying that in both groups dysfunctional gray matter at the injury site had a similar recovery. However, motor recovery over time was enhanced in the lower extremities in the GM-1 group as compared with the placebo group (Fig. 4). Enhanced recovery or effectiveness in initiating the motor response of the circumferential white-matter tracts in the GM-1 group (positive GM-1 effect) but similar gray-matter recovery at the injury site in both groups (no GM-1 effect) would account for the observed difference in improvement with respect to neurologic recovery between treatment groups in the upper and lower extremities in the patients with cervical injuries. Possible biochemical mechanisms by which GM-1 ganglioside may enhance neuronal survival in the white-matter tracts or increase the response of the distal spinal cord to the attenuated signal in the damaged white-matter tracts after a spinal-cord injury and other central nervous system insults have been covered in recent review articles.13 14 15 , 39 , 66 67 68 69 70 71 Although this study and the recent NASCIS 2 study7 , 8 on spinal-cord injury initially appear to be closely related, allowing direct comparison, they differed substantially with respect to (1) timing and duration of drug therapy (methylprednisolone was effective when therapy began within 8 hours of the injury and continued for 24 hours; GM-1 was begun a mean of 48 hours after the injury and administered for a mean of 26 days); (2) follow-up period (six months for the NASCIS 2 study; one year for this study); (3) assessment scales (14 muscle groups on each side with the right side only reported, sensory-function assessment, and no functional scale in the NASCIS 2 study; 10 motor groups on each side with both sides reported, the Frankel scale as a functional index, and no sensory assessment in GM-1 study); (4) criteria for entry (mildto-severe spinal-cord injury in the NASCIS 2 study; major motor deficit in the GM-1 study); (5) protocols for initial resuscitation72 , 73 and medical and surgical management (varied in NASCIS 2, with each center having its own protocol and the details not being reported; uniform, aggressive early intervention in the GM-1 study); (6) reporting of the analysis of individual muscle groups to determine the region of drugeffect improvement (not done in the NASCIS 2 study, but analyzed in the GM-1 study); and (7) base-line assessment with which all subsequent neurologic assessments were compared (performed on initial contact in the emergency room in the NASCIS 2 study; at an average of 50 hours in the GM-1 study after correction of the shock, mechanical decompression of the spinal cord, and early resolution of any mild head injury or initial hysteria). If one ignores potential bias from these effects and any nonlinearity between the two motor scales but does make a linear adjustment for the differences in ranges (0 to 70 in the NASCIS 2 study and 0 to 100 in this study), then the improvements in the placebo and methylprednisolone groups treated within eight hours of injury in the NASCIS 2 study are equivalent to 16.0 and 22.9 ASIA motor points, respectively (a 6.9 ASIA-point drug effect of methylprednisolone). These values can be compared with the improvement in the placebo and GM-1 groups in this trial of 21.6 and 36.9 ASIA motor points, respectively (a drug effect of GM-1 of 15.3 ASIA points, unadjusted, and 11.5 points after adjustment for base-line differences). Although any of the differences noted above between study designs could affect the comparison of motor scores, it appears that the magnitude of the drug effect was similar in both studies.
In the GM-1 study, motor recovery from the spinal-cord injury as measured by the ASIA motor score continued throughout the one-year follow-up period in both treatment groups (Fig. 3), and the maximal improvement in the rate of recovery in both groups occurred between one and three months after the injury and favored the drug effect of GM-1. Since GM-1 was administered only for the first month after the injury and the maximal drug effect occurred one to three months after the injury, the drug effect must involve a delay either in the clinical expression of an earlier salvage of neurons or in the mechanism of drug action. Furthermore, because the first injection of GM-1 occurred a mean of 48 hours after the injury, the drug effect is presumably by a different mechanism than has been proposed with other drug-administration protocols (such as several steroid or steroid-related compounds, thyroid-releasing hormone, naloxone, some gangliosides, and most notably methylprednisolone administered less than 8 hours after the injury7 , 8) that are designed for maximal benefit in the hyperacute phase of injury. The increase in neurologic recovery from the combination of GM-1 administered according to this study protocol and methylprednisolone given in the hyperacute phase would be purely speculative, but the combination has the potential of being more than additive if methylprednisolone treatment allowed the initial survival of injured neurons and then GM-1 enhanced recovery in this larger pool of surviving neurons. There is also the potential that GM-1 administered in the hyperacute phase could have additional benefits beyond those observed in this study, because its neuroprotective effects have been reported in the hyperacute phase after trauma.13 14 15 , 39 , 66 , 67
No untoward neurologic events related to GM-1 administration were observed in this trial; however, a case of Guillain—Barré syndrome has been observed in a GM-1—treated patient in a stroke trial (data on file with Fidia Pharmaceutical). Currently, there is no evidence that Guillain—Barré syndrome occurs in GM-1—treated patients at a rate greater than that in the general population.
Although some neurologic recovery is expected after a spinal-cord injury at the one-year follow-up, the magnitude of improvement and the presence of a beneficial drug effect separate this study and NASCIS 2 from previous clinical trials of spinal-cord injuries in humans. The improvement of patients by two or three Frankel grades in this study represents a dramatic increase in neurologic function, with the majority of these patients changing from paralyzed to ambulatory status. The marked improvement in the recovery of paralyzed motor groups, along with the similar recovery of the paretic muscles in the two treatment groups, indicates that the observed effect of GM-1 occurs by the conversion of motor groups initially paralyzed into those with useful motor function after one year. The patients in this study had uniform, aggressive initial treatment of their neurologic spinal-cord injuries, both partial and complete. This treatment and the prompt arrival of the patients from the accident scene are major features of this study. Adherence to these procedures may be necessary to obtain the drug effect reported here. Although this small study suggests that GM-1 is safe to administer in spinal-cord injury and enhances the recovery of neurologic function after one year, a larger study must be conducted to confirm its clinical benefit and safety.
Supported in part by a grant to the University of Maryland Research Foundation from the Fidia Pharmaceutical Corporation.
Presented in part at the Joint Section on Disorders of the Spine and Peripheral Nerve, American Association of Neurological Surgeons and Congress of Neurological Surgeons, Cancun, Mexico, February 11 to 15, 1989; the Society of Critical Care Medicine, New Orleans, June 5 to 9, 1989; and the Satellite Symposium of the 31st International Congress of Physiological Sciences, Recovery from Brain Damage: Behavioral and Neurochemical Approaches, Warsaw, Poland, July 4 to 7, 1989.
We are indebted to the patients who participated in this trial; to the physicians, nurses, and physical therapists assisting in their care and follow-up at the Shock Trauma Center of the Maryland Institute for Emergency Medical Services Systems and at several rehabilitation hospitals; to Thomas Ducker, M.D., for the initial concept of the study and for continuing encouragement; to Daniela Kantor and Richelle Kennedy for their help in data collection; to Elaine Rice for assistance in the preparation of the manuscript; and to Danilo Massari and the personnel of the Fidia Pharmaceutical Corporation for assistance in design and analysis.
Source Information
From the Shock Trauma Center of the Maryland Institute for Emergency Medical Services Systems, Baltimore (F.H.G., W.P.C.); the Department of Surgery, Division of Neurosurgery, University of Maryland, Baltimore (F.H.G.); the Department of Neurosurgery, Patuxent Medical Group, Columbia, Md. (F.H.G.); the Department of Biometrics, Fidia Pharmaceutical Corporation, Washington, D.C. (F.C.D.); and the Department of Mathematics and Statistics, University of Maryland Baltimore County, Baltimore (W.P.C.). Address reprint requests to Dr. Geisler at 7106 Long View Rd., Columbia, MD 21044.
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