Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial.

STUDY DESIGN: Randomized controlled trial with single-blinded primary outcome assessment. OBJECTIVES: To determine the efficacy and safety of autologous incubated macrophage treatment for improving neurological outcome in patients with acute, complete spinal cord injury (SCI). SETTING: Six SCI treatment centers in the United States and Israel. METHODS: Participants with traumatic complete SCI between C5 motor and T11 neurological levels who could receive macrophage therapy within 14 days of injury were randomly assigned in a 2:1 ratio to the treatment (autologous incubated macrophages) or control (standard of care) groups. Treatment group participants underwent macrophage injection into the caudal boundary of the SCI. The primary outcome measure was American Spinal Injury Association (ASIA) Impairment Scale (AIS) A-B or better at ≥6 months. Safety was assessed by analysis of adverse events (AEs). RESULTS: Of 43 participants (26 treatment, 17 control) having sufficient data for efficacy analysis, AIS A to B or better conversion was experienced by 7 treatment and 10 control participants; AIS A to C conversion was experienced by 2 treatment and 2 control participants. The primary outcome analysis for subjects with at least 6 months follow-up showed a trend favoring the control group that did not achieve statistical significance (P=0.053). The mean number of AEs reported per participant was not significantly different between the groups (P=0.942). CONCLUSION: The analysis failed to show a significant difference in primary outcome between the two groups. The study results do not support treatment of acute complete SCI with autologous incubated macrophage therapy as specified in this protocol.

A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics.

STUDY DESIGN: Post hoc analysis from a randomized controlled cellular therapy trial in acute, complete spinal cord injury (SCI). OBJECTIVES: Description and quantitative review of study logistics, referral patterns, current practice patterns and subject demographics. SETTING: Subjects were recruited to one of six international study centers. METHODS: Data are presented from 1816 patients pre-screened, 75 participants screened and 50 randomized. RESULTS: Of the 1816 patients pre-screened, 53.7% did not meet initial study criteria, primarily due to an injury outside the time window (14 days) or failure to meet neurological criteria (complete SCI between C5 motor/C4 sensory and T11). MRIs were obtained on 339 patients; 51.0% were ineligible based on imaging criteria. Of the 75 participants enrolled, 25 failed screening (SF), leaving 50 randomized. The primary reason for SF was based on the neurological exam (51.9%), followed by failure to meet MRI criteria (22.2%). Of the 50 randomized subjects, there were no significant differences in demographics in the active versus control arms. In those participants for whom data was available, 93.8% (45 of 48) of randomized participants received steroids before study entry, whereas 94.0% (47 of 50) had spine surgery before study enrollment. CONCLUSION: The 'funnel effect' (large numbers of potentially eligible participants with a small number enrolled) impacts all trials, but was particularly challenging in this trial due to eligibility criteria and logistics. Data collected may provide information on current practice patterns and the issues encountered and addressed may facilitate design of future trials.

Intramuscular fat and glucose tolerance after spinal cord injury--a cross-sectional study.

STUDY DESIGN: Survey. OBJECTIVE: Determine intramuscular fat (IMF) in affected skeletal muscle after complete spinal cord injury using a novel analysis method and determine the correlation of IMF to plasma glucose or plasma insulin during an oral glucose tolerance test. SETTING: General community of Athens, GA, USA. METHODS: A total of 12 nonexercise-trained complete spinal cord injured (SCI) persons (10 males and two females 40+/-12 years old (mean+/-SD), range 26-71 years, and 8+/-5 years post SCI) and nine nonexercise-trained nondisabled (ND) controls 29+/-9 years old, range 23-51 years, matched for height, weight, and BMI, had T(1) magnetic resonance images of their thighs taken and underwent an oral glucose tolerance test (OGTT) after giving consent. RESULTS: Average skeletal muscle cross-sectional area (CSA) (mean+/-SD) was 58.6+/-21.6 cm(2) in spinal cord subjects and 94.1+/-32.5 cm(2) in ND subjects. Average IMF CSA was 14.5+/-6.0 cm(2) in spinal cord subjects and 4.7+/-2.5 cm(2) in nondisabled subjects, resulting in an almost four-fold difference in IMF percentage of 17.3+/-4.4% in spinal cord subjects and 4.6+/-2.6% in nondisabled subjects. The 60, 90 and 120 min plasma glucose or plasma insulin were higher in the SCI group. IMF (absolute and %) was related to the 90 or 120 min plasma glucose or plasma insulin (r(2)=0.71-0.40). CONCLUSIONS: IMF is a good predictor of plasma glucose during an OGTT and may be a contributing factor to the onset of impaired glucose tolerance and type II diabetes, especially in SCI. In addition, reports of skeletal muscle CSA should be corrected for IMF.

Phenotypic adaptations in human muscle fibers 6 and 24 wk after spinal cord injury.

The effects of spinal cord injury (SCI) on the profile of sarco(endo) plasmic reticulum calcium-ATPase (SERCA) and myosin heavy chain (MHC) isoforms in individual vastus lateralis (VL) muscle fibers were determined. Biopsies from the VL were obtained from SCI subjects 6 and 24 wk postinjury (n = 6). Biopsies from nondisabled (ND) subjects were obtained at two time points 18 wk apart (n = 4). In ND subjects, the proportions of VL fibers containing MHC I, MHC IIa, and MHC IIx were 46 +/- 3, 53 +/- 3, and 1 +/- 1%, respectively. Most MHC I fibers contained SERCA2. Most MHC IIa fibers contained SERCA1. All MHC IIx fibers contained SERCA1 exclusively. SCI resulted in significant increases in fibers with MHC IIx (14 +/- 4% at 6 wk and 16 +/- 2% at 24 wk). In addition, SCI resulted in high proportions of MHC I and MHC IIa fibers with both SERCA isoforms (29% at 6 wk and 54% at 24 wk for MHC I fibers and 16% at 6 wk and 38% at 24 wk for MHC IIa fibers). Thus high proportions of VL fibers were mismatched for SERCA and MHC isoforms after SCI (19 +/- 3% at 6 wk and 36 +/- 9% at 24 wk) compared with only ~5% in ND subjects. These data suggest that, in the early time period following SCI, fast fiber isoforms of both SERCA and MHC are elevated disproportionately, resulting in fibers that are mismatched for SERCA and MHC isoforms. Thus the adaptations in SERCA and MHC isoforms appear to occur independently.

Muscle fiber type-specific myofibrillar Ca(2+) ATPase activity after spinal cord injury.

Biopsies of the vastus lateralis muscle were analyzed to determine if increased energy demand of contraction, as indirectly reflected by myofibrillar Ca(2+) adenosine triphosphate activity (qATPase), contributes to greater fatigue in affected muscle of spinal cord injured (SCI) patients. The qATPase activity showed a fiber-type effect, IIax + IIx > IIa > I. Average fiber qATPase and fiber specific qATPase activities were not different between SCI and able-bodied controls, nor did they change over time. We suggest greater fatigue in SCI subjects early after injury does not reflect increased energy demand of contraction.

Influence of complete spinal cord injury on skeletal muscle mechanics within the first 6 months of injury.

In this study we examined the influence of complete spinal cord injury (SCI) on the mechanical characteristics of skeletal muscle in vivo within 6 months of the injury. Surface electrical stimulation (ES) was applied to the left m. quadriceps femoris of patients at 6, 11 and 24 weeks after injury. Surface ES was also applied to seven able-bodied controls (AB) at two time points 18 weeks apart. ES consisted of 2 bouts of 20, 1-s isometric contractions with 2 s and 2 min of rest between contractions and bouts, respectively. The time from 20-80% of peak torque (rise time) and the half relaxation time (1/2 RT) were determined for the first and for the last few contractions. Force loss over repeat contractions was greater in SCI than AB (27% vs 95%; P = 0.0001), and did not change over the 18-week period. Rise time did not change over repeat contractions, was not different between groups, and nor did it change over the 18-week period (range: 150-172 ms). 1/2 RT showed several group differences. Overall, 1/2 RT was longer at the beginning of ES in SCI than AB [mean (SE) 133 (15) ms vs 90 (6) ms, P = 0.037]. Slowing of relaxation time with force loss over repeat contractions was found in SCI at 24 weeks after injury [167 (18) ms, P = 0.016], but not at 6 [128 (14) ms] or 11 [145 (12) ms] weeks after injury. AB, in contrast, showed prolonged relaxation times, with force loss at both time points [115 (10) ms and 113 (11) ms; P = 0.0001]. The results indicate that SCI alters the relaxation but not contractile properties of mixed skeletal muscle within the first 24 weeks of injury. Altered calcium handling and contraction-induced fiber injury are suggested to explain the slower relaxation time per se, and the prolonged relaxation with force loss observed after SCI.

Medical complications during acute rehabilitation following spinal cord injury--current experience of the Model Systems.

OBJECTIVES: To examine the frequency of common secondary medical complications during acute rehabilitation in persons with new spinal cord injury (SCI). DESIGN: Survey and analysis of data in the National SCI Statistical Center (NSCISC) database. SETTING: Eighteen Model System SCI Centers located in urban, public medical centers around the United States. SUBJECTS: A total of 1,649 persons with new SCI entered into the NSCISC database between 1996 and mid-1998. RESULTS: Since 1992, the number of days from injury to admission to rehabilitation has steadily decreased, resulting in the increased potential to develop common secondary medical complications during rehabilitation hospitalization. Pressure ulcers occur with high frequency and were found to have developed in 23.7% of patients during rehabilitation. In addition, autonomic dysreflexia and atelectasis/pneumonia also occur with relative frequency during rehabilitation. Conversely, deep vein thrombosis and pulmonary embolism have decreased, most likely because of greater awareness of their potential to develop, as well as improved methods of prophylaxis. Cardiopulmonary arrest and gastrointestinal hemorrhage occur with relatively small frequency. The frequency of renal complications is difficult to gauge because of the decreasing number of patients who have any renal testing performed during rehabilitation hospitalization. CONCLUSION: The continued declining lengths of acute care hospitalization after SCI have resulted in the occurrence in the rehabilitation setting of medical complications that were previously seen in acute care. Greater awareness and attention to these conditions are necessary to reduce their occurrence, so that obstacles to recovery and functional improvement after SCI are minimized.

Economics of managed care in spinal cord injury.

OBJECTIVE: To determine and describe trends in economic variables related to the care of individuals with spinal cord injury (SCI) and significant changes in these trends coincident with major developments in medical care cost control. DATA SOURCES: Data from the National Spinal Cord Injury Statistical Center (NSCISC) database were used to review the economic trends in SCI management from 1973 to 1998 and their relation to managed care and other health care cost-containment measures. A panel of SCI health care specialists was interviewed to determine the appropriate data variables to be reviewed. The Shepherd Center Care Health Management Program, Atlanta, GA, is presented as an example of a fiscally successful managed care program for patients with SCI. DATA EXTRACTION: Data from the NSCISC database for the years studied were extracted and converted to a form suitable for analysis by means of the statistical software SAS. DATA SYNTHESIS: Statistical techniques included multiple regression analysis, logistic regression analysis, and model selection methods. CONCLUSIONS: Trends in economic variables, in the care of individuals with SCI show changes coincident with the introduction of Diagnostic Related Groups (DRGs) and managed care as models for provider reimbursement. Significant changes occurred in acute care charges, rehabilitation charges, length of stay, rehospitalization 1 year postinjury, time from injury to admission to a Model System, and discharges to a nursing home.

Influence of complete spinal cord injury on skeletal muscle cross-sectional area within the first 6 months of injury.

In this study we examined the influence of complete spinal cord injury (SCI) on affected skeletal muscle morphology within 6 months of SCI. Magnetic resonance (MR) images of the leg and thigh were taken as soon as patients were clinically stable, on average 6 weeks post injury, and 11 and 24 weeks after SCI to assess average muscle cross-sectional area (CSA). MR images were also taken from nine able-bodied controls at two time points separated from one another by 18 weeks. The controls showed no change in any variable over time. The patients showed differential atrophy (P = 0.0001) of the ankle plantar or dorsi flexor muscles. The average CSA of m. gastrocnemius and m. soleus decreased by 24% and 12%, respectively (P = 0.0001). The m. tibialis anterior CSA showed no change (P = 0.3644). As a result of this muscle-specific atrophy, the ratio of average CSA of m. gastrocnemius to m. soleus, m. gastrocnemius to m. tibialis anterior and m. soleus to m. tibialis anterior declined (P = 0.0001). The average CSA of m, quadriceps femoris, the hamstring muscle group and the adductor muscle group decreased by 16%, 14% and 16%, respectively (P< or =0.0045). No differential atrophy was observed among these thigh muscle groups, thus the ratio of their CSAs did not change (P = 0.6210). The average CSA of atrophied skeletal muscle in the patients was 45-80% of that of age- and weight-matched able-bodied controls 24 weeks after injury. In conclusion, the results of this study suggest that there is marked loss of contractile protein early after SCI which differs among affected skeletal muscles. While the mechanism(s) responsible for loss of muscle size are not clear, it is suggested that the development of muscular imbalance as well as diminution of muscle mass would compromise force potential early after SCI.

A simple means of increasing muscle size after spinal cord injury: a pilot study.

This study tested that hypothesis that skeletal muscle within a year of spinal cord injury (SCI) would respond to intermittent high force loading by showing an increase in size. Three males about 46 weeks post clinically complete SCI underwent surface electrical stimulation of their left or right m. quadriceps femoris 2 days per week for 8 weeks to evoke 4 sets of ten isometric or dynamic actions each session. Conditioning increased average cross-sectional area of m. quadriceps femoris, assessed by magnetic resonance imaging, by 20+/-1% (p = 0.0103). This reversed 48 weeks of atrophy such that m. quadriceps femoris 54 weeks after SCI was the same size as when the patients were first studied 6 weeks after injury. The results suggest that skeletal muscle is remarkably responsive to intermittent, high force loading after almost one year of little if any contractile activity.

Influence of complete spinal cord injury on skeletal muscle within 6 mo of injury.

This study examined the influence of spinal cord injury (SCI) on affected skeletal muscle. The right vastus lateralis muscle was biopsied in 12 patients as soon as they were clinically stable (average 6 wk after SCI), and 11 and 24 wk after injury. Samples were also taken from nine able-bodied controls at two time points 18 wk apart. Surface electrical stimulation (ES) was applied to the left quadriceps femoris muscle to assess fatigue at these same time intervals. Biopsies were analyzed for fiber type percent and cross-sectional area (CSA), fiber type-specific succinic dehydrogenase (SDH) and alpha-glycerophosphate dehydrogenase (GPDH) activities, and myosin heavy chain percent. Controls showed no change in any variable over time. Patients showed 27-56% atrophy (P = 0.000) of type I, IIa, and IIax+IIx fibers from 6 to 24 wk after injury, resulting in fiber CSA approximately one-third that of controls. Their fiber type specific SDH and GPDH activities increased (P

Spinal cord injury occurring in patients with ankylosing spondylitis: a multicenter study.

Treatment of spinal fractures causing paralysis in patients with ankylosing spondylitis is difficult. A multicenter concurrent study evaluated 59 patients--22 managed operatively and 37 nonoperatively. The two groups were compared for neurologic outcome, complications, mortality, and length of stay. The results indicated that patients in the nonoperative group had a significantly shorter length of stay and, therefore, a significantly lower cost of care. No other differences between operative and nonoperative groups were identified in regard to other outcome variables. Results of descriptive analyses of patient characteristics and treatment choices have significant implications for practitioners.

Spinal cord injury in youth.

To identify special characteristics of the pediatric spinal cord-injured (SCI) population, we analyzed a database of 1,770 traumatic SCI patients; 88 (5%) fell into the two pediatric subgroups: 0-12 years (n = 26) and 13-15 years (n = 62) at time of injury. Differences between age groups were identified with regard to demographics, neurologic characteristics, associated injuries and complications, and management. Mode level of bony injury was C2 in preteens, C4 in teens, and C4-C5 in adults. Scoliosis developed far more frequently in children, particularly preteens (23%), than in adults (5%). Violent etiologies, predominantly gunshots, accounted for a disproportionate share of injuries to preteens (19%) and African-Americans (28%), as compared with adults (12%) and Caucasians (7%). This last finding underscores the urgent need to mount a response to the nationwide proliferation of gunshot-related SCI in children and minorities.

Hysterical spinal paralysis.

Seventeen patients were diagnosed as having hysterical paralysis. Although a variety of patterns of motor and sensory loss were seen, 15 out of 17 patients had normal reflexes, and all the patients had bowel and bladder control, an important diagnostic point. All but 1 were improved after an average 3.8 days hospital stay with 13 being fully recovered. When a patient is encountered with paralysis, normal reflexes and bowel and bladder control, the only initial diagnostic study indicated is routine X-rays.

MRI of the athletic knee. Findings in asymptomatic professional basketball and collegiate football players.

For the dedicated athlete in whom minor injuries are frequent and major injuries relatively common, a noninvasive knee assessment could either obviate the need for arthroscopy or focus its direction. The opportunity to study asymptomatic athletes was not feasible before the advent of magnetic resonance imaging (MRI). In this preliminary work, we examined 40 knees in 20 asymptomatic volunteer athletes, including five professional basketball players and 15 collegiate football players. Images were obtained at 0.5 T or 1.5 T. Spin echo sequences were used to obtain 5.0 mm thick coronal and sagittal sections. Fifty percent of asymptomatic athletes (10/20) had significant baseline MRI abnormalities that could have adversely affected scan interpretation in the context of an acute injury. Half of these athletes with MRI abnormalities, or 25% of the total (5/20), had no previous surgery and were unaware of significant injury.