Challenges for defining minimal clinically important difference (MCID) after spinal cord injury.

STUDY DESIGN: This is a review article. OBJECTIVES: This study discusses the following: (1) concepts and constraints for the determination of minimal clinically important difference (MCID), (2) the contrasts between MCID and minimal detectable difference (MDD), (3) MCID within the different domains of International Classification of Functioning, disability and health, (4) the roles of clinical investigators and clinical participants in defining MCID and (5) the implementation of MCID in acute versus chronic spinal cord injury (SCI) studies. METHODS: The methods include narrative reviews of SCI outcomes, a 2-day meeting of the authors and statistical methods of analysis representing MDD. RESULTS: The data from SCI study outcomes are dependent on many elements, including the following: the level and severity of SCI, the heterogeneity within each study cohort, the therapeutic target, the nature of the therapy, any confounding influences or comorbidities, the assessment times relative to the date of injury, the outcome measurement instrument and the clinical end-point threshold used to determine a treatment effect. Even if statistically significant differences can be established, this finding does not guarantee that the experimental therapeutic provides a person living with SCI an improved capacity for functional independence and/or an increased quality of life. The MDD statistical concept describes the smallest real change in the specified outcome, beyond measurement error, and it should not be confused with the minimum threshold for demonstrating a clinical benefit or MCID. Unfortunately, MCID and MDD are not uncomplicated estimations; nevertheless, any MCID should exceed the expected MDD plus any probable spontaneous recovery. CONCLUSION: Estimation of an MCID for SCI remains elusive. In the interim, if the target of a therapeutic is the injured spinal cord, it is most desirable that any improvement in neurological status be correlated with a functional (meaningful) benefit.

Two phase 3, multicenter, randomized, placebo-controlled clinical trials of fampridine-SR for treatment of spasticity in chronic spinal cord injury.

STUDY DESIGN: Two randomized, double-blind, placebo-controlled trials. OBJECTIVE: To evaluate the efficacy and safety of fampridine sustained-release tablets (fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients with incomplete chronic SCI were randomized to twice daily fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician's Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women). RESULTS: The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were -0.15 (placebo) and -0.19 (fampridine-SR) in the first study, and -0.16 (placebo) and -0.28 (fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments. CONCLUSION: Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI.

Clinical trials in spinal cord injury: lessons learned on the path to translation. The 2011 International Spinal Cord Society Sir Ludwig Guttmann Lecture.

After three decades of clinical research on interventions to improve neurological outcomes in persons with spinal cord injury (SCI), the promise of preclinical discovery has yet to be translated into a consensus standard of care treatment. Nonetheless, SCI researchers remain hopeful that advances in preclinical discovery coupled with improved clinical trial performance will yield effective restorative treatment. This historical review of key studies in SCI over the past 30 years illustrates the progress that has been achieved in establishing a high standard in the conduct of clinical research while providing important lessons for improving trial design, conduct and reporting. Through application of these lessons, the performance of SCI trials can be improved, thereby shortening the pathway to successful translation and the development of effective therapies.

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.

Characterization of neurological recovery following traumatic sensorimotor complete thoracic spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of sensory, motor and functional outcomes from individuals with thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI). OBJECTIVES: To characterize neurological changes over the first year after traumatic thoracic sensorimotor complete SCI. METHODS: A dataset of 399 thoracic complete SCI subjects from the European Multi-center study about SCI (EMSCI) was examined for neurological level, sensory levels and sensory scores (pin-prick and light touch), lower extremity motor score (LEMS), ASIA Impairment Scale (AIS) grade, and Spinal Cord Independence Measure (SCIM) over the first year after SCI. RESULTS: AIS grade conversions were limited. Sensory scores exhibited minimal mean change, but high variability in both rostral and caudal directions. Pin-prick and light touch sensory levels, as well as neurological level, exhibited minor changes (improvement or deterioration), but most subjects remained within one segment of their initial injury level after 1 year. Recovery of LEMS occurred predominantly in subjects with low thoracic SCI. The sensory zone of partial preservation (ZPP) had no prognostic value for subsequent recovery of sensory levels or LEMS. However, after mid or low thoracic SCI, ≥3 segments of sensory ZPP correlated with an increased likelihood for AIS grade conversion. CONCLUSION: The data suggest that a sustained deterioration of three or more thoracic sensory levels or loss of upper extremity motor function are rare events and may be useful for tracking the safety of a therapeutic intervention in early phase acute SCI clinical trials, if a significant proportion of study subjects exhibit such an ascent.

Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.

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.

Recent trends in mortality and causes of death among persons with spinal cord injury.

OBJECTIVE: To identify and quantify trends in mortality and causes of death among persons with spinal cord injury. DESIGN: Cohort study. SETTING: Model spinal cord injury care systems and Shriner's Hospitals spinal cord injury units throughout the United States. PATIENTS: A total of 28,239 consecutive persons admitted to the model system or to a Shriner's Hospital within 1 year of injury. MAIN OUTCOME MEASURE: Length of survival and cause of death. RESULTS: Among persons who were admitted to the model system within 1 day of injury, the odds of dying during the first postinjury year were reduced by 67% for persons injured between 1993 and 1998 relative to persons injured between 1973 and 1977 after adjusting for trends in age, gender, race, neurologic level of injury, Frankel grade, ventilator status, etiology of injury, sponsor of care, and model system where treatment occurred. However, mortality rates after the first anniversary of injury, which had also been declining from 1973 to 1992, increased 33% for persons injured between 1993 and 1998 relative to persons injured between 1988 and 1992. Respiratory disease was the only cause of death after the first anniversary of injury for which the relative odds increased meaningfully during the latest time period (76% increase over 1988-1992 compared to all other causes). CONCLUSION: While great improvements in life expectancy have been achieved since the Model SCI Systems program began, current data support the need for renewed efforts to improve the prevention and treatment of the complications of spinal cord injury.

Surgical treatment of posttraumatic cystic and tethered spinal cords.

Posttraumatic syringomyelia as a cause of progressive neurologic deterioration has been well described. More recently, the noncystic posttraumatic tethered cord has been associated with identical progressive neurologic deterioration. A retrospective analysis of patients treated surgically with spinal cord untethering and/or cyst shunting to arrest a progressive myelopathy from a posttraumatic tethered and/or cystic cord was performed. Emphasis was on outcome using the American Spinal Injury Association (ASIA) sensory and motor scoring systems. During an 18-month period from May 1993 to December 1994, 70 patients with spinal cord injury were operated upon for tethered and/or cystic spinal cords because of a progressive myelopathy and deteriorating ASIA sensory/motor scores. Fifty-nine patients had follow-up data 1 year postoperatively. At the 1 year follow-up, there was small improvement in light touch sensory scores (0.67 points), pinprick scores (1.3 points), and motor scores (0.41 points) demonstrating that the progression of the myelopathic process was arrested. Thirty-four of these 59 patients had no previous surgery to their spinal cords. At 1 year follow-up, light touch scores improved on average 2.38 points, pinprick scores 3.88 points (p < 0.05), and motor scores 1.47 points, suggesting better outcome with first-time surgery. Of this latter group, 64.3% regained a lost function, 62.5% saw improvement in spasticity, 55.6% had substantial improvement in neurogenic pain, and 95.8% felt that surgery prevented further neurologic deterioration.

Technetium-99m-MAG3 renal studies in spinal cord injury patients: normal range, reproducibility, and change as a function of duration and level of injury.

UNLABELLED: The normal range, reproducibility, and change as a function of duration and level of injury for Tc-99m-MAG3 renal studies were quantitated in spinal cord injury (SCI) patients. METHODS: Five SCI patients without evidence of renal disease in each of four groups: less than 2 months, 2-12 months, 1-2 years, and greater than 2 years from time of injury, were each studied twice. There were at least two patients with paraplegia and two with tetraplegia in each group. Renal clearance (camera based method), percent function in each kidney, time of peak renal parenchymal activity, and half time of parenchymal activity following the peak were evaluated. The peak and half times were determined with regions of interest (ROIs) over the entire kidney and over just the cortex. All results were compared to normal ranges previously established in normal subjects of the same age range using the same methodology. RESULTS: Renal clearance in the less than 2 month SCI patients was not significantly different from normal subjects in either paraplegic or in tetraplegic individuals. However, clearance in tetraplegics was increased by 28.5% at 2-12 month, increased by 50.6% at 1-2 years, and decreased by 25.9% at greater than 2 years compared to normal subjects (all P < 0.02). Clearance in those with paraplegia showed a similar, but less marked, trend (P = NS). The time of peak parenchymal activity when measured with cortical ROIs did not vary among patient groups or level of injury, but was increased compared to normal subjects (P < 0.05). The percent function in each kidney and half time following the peak were symmetrical, did not differ among patient groups or with level of injury, and did not differ from normal subjects. The parenchymal peak time was significantly shorter with cortical rather than renal ROIs in all patient groups (P < 0.05). In serial studies in the same patient the percent standard deviation in total renal clearance was less than between single studies in different patients, but the decrease was significant for only the right kidney (P < 0.03), and the decrease was not as great as in normal subjects. In addition, the percent standard deviation for percent function in each kidney was significantly less than the percent standard deviations in single studies (P < 0.02). There were no significant differences between intra- and interpatient studies for any other parameter. CONCLUSION: We conclude that: (1) renal clearance measured with Tc-99m-MAG3 in tetraplegic patients increases significantly during the first 2 years following injury and decreases significantly thereafter; there is a similar, but much less marked, trend in paraplegics, (2) parenchymal peak times with cortical ROIs occur later for SCI patients than for normal subjects, and (3) there is more intrapatient variation in total renal clearance and percent renal clearance on a side in SCI patients than in normal subjects suggesting that it may be harder to study SCI patients reproducibly. These findings should be taken into account when performing and interpreting Tc-99m-MAG3 renal studies in SCI patients.

Neurorehabilitation of lightning and electrical injuries.

Lightning and electrical (L/E) injuries can be among the most dramatic of all events that damage the nervous system. The three major classes of neurologic sequelae that require the expertise of the neurorehabilitationist are: (1) cerebral disorders, either global or focal; (2) neuropsychologic sequelae; and (3) spinal cord injury. Neurorehabilitation management necessary for each of these three areas will be discussed. From the viewpoint of the neurorehabilitationist, therapy principles are the same for L/E trauma as for other more common forms of injury. The goal is to maximize the functional return given the specific impairment.

Utilization and effectiveness of methylprednisolone in a population-based sample of spinal cord injured persons.

The announcement and publication of the second National Acute Spinal Cord Injury Study (NASCIS II) project's findings regarding the role of high dose methylprednisolone in improving neurological outcomes following acute traumatic spinal cord injury generated widespread excitement and interest. To determine the association between this interest and actual use and implementation of the protocol, Colorado's comprehensive population-based spinal cord injury surveillance data were examined. The medical records of 218 SCI survivors injured between May 1, 1990 and December 31, 1991, and of 145 persons spinal cord injured 2 years later, during 1993, were reviewed to determine the rapidity and extent of NASCIS II implementation by Colorado's hospitals, factors associated with use and non-use of the protocol, changing usage trends over time, and the short term neurological outcomes of patients who received the protocol. Clear documentation of the protocol's usage was present for only 46% of the reported patients' medical records in 1990-91, and 61% in 1993. Small, emergency triage facilities were significantly more likely to use the protocol than larger acute care hospitals, and patients with initially incomplete injuries were less likely to receive the drug. There were no significant differences in neurological outcomes, using the Frankel classification system, between those who received the protocol and those who did not. The limitations and implications of these findings are discussed.

Rehabilitation in spinal cord disorders. 3. Comprehensive management of spinal cord injury.

This self-directed learning module highlights advances in the management of the person with a spinal cord deficit. Traumatic spinal cord injury is being used as the model, but the principles apply to all patients with spinal cord deficits. This article is part of the chapter on rehabilitation of spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. Specifically, this section contains information regarding prehospital care, acute assessment and management, primary rehabilitation by systems, sexuality and psychosocial issues, management of pain and spasticity, functional goals, the role of functional electrical stimulation, and long-term follow-up.

Rehabilitation in spinal cord disorders. 1. Epidemiology, prevention, and system of care of spinal cord disorders.

This self-directed learning module highlights current concepts of the epidemiology, prevention, and systematic treatment of spinal cord disorders. It is part of the chapter on rehabilitation of spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This article contains information regarding the incidence, prevalence, and causes of spinal cord injury, methods of prevention, and the components of a comprehensive system of care for spinal cord injury.

Rehabilitation in spinal cord disorders. 2. Anatomy, pathogenesis, and research for neurologic recovery.

This self-directed learning module highlights advances in this topic area. It is part of the chapter on rehabilitation in spinal cord disorders in the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This article contains learning objectives on the anatomy of the spine and spinal cord, pathogenesis of spinal cord trauma, mechanisms of spinal fractures and dislocations, causes of nontraumatic spinal cord disorders, and research on neurologic recovery. Advances that are covered in this section include various experimental animal models for producing spinal cord injury and new approaches to limit damage in acute injury and to promote recovery in chronic injury.

Rehabilitation in spinal cord disorders. 4. Outcomes and issues of aging after spinal cord injury.

This self-directed learning module highlights current concepts in outcomes and issues of aging in spinal cord injury. It is part of the chapter on rehabilitation in spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This article includes discussion of the measurement of impairment, disability, and handicap, and outcomes with respect to employment, long-term adjustment, aging, life expectancy, and causes of death in spinal cord injury.