International standards for neurological classification of spinal cord injury: cases with classification challenges.

The International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) is routinely used to determine levels of injury and to classify the severity of the injury. Questions are often posed to the International Standards Committee of the American Spinal Injury Association (ASIA) regarding the classification. The committee felt that disseminating some of the challenging questions posed, as well as the responses, would be of benefit for professionals utilizing the ISNCSCI. Case scenarios that were submitted to the committee are presented with the responses as well as the thought processes considered by the committee members. The importance of this documentation is to clarify some points as well as update the SCI community regarding possible revisions that will be needed in the future based upon some rules that require clarification.

International Standards for Neurological Classification of Spinal Cord Injury: cases with classification challenges.

The International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) is routinely used to determine the levels of injury and to classify the severity of the injury. Questions are often posed to the International Standards Committee of the American Spinal Injury Association regarding the classification. The committee felt that disseminating some of the challenging questions posed, as well as the responses, would be of benefit for professionals utilizing the ISNCSCI. Case scenarios that were submitted to the committee are presented with the responses as well as the thought processes considered by the committee members. The importance of this documentation is to clarify some points as well as update the SCI community regarding possible revisions that will be needed in the future based upon some rules that require clarification.

The association of assistive mobility devices and social participation in people with spinal cord injuries.

OBJECTIVE: We assumed that assistive technology in mobility devices (that is, wheelchairs with external power and driving modified vehicle (MV) with or without driving on wheelchair) may facilitate social participation for wheelchairs users who have spinal cord injuries (SCIs). This study examined the relationship between mobility devices and social participation in this population. METHODS: We included 2986 individuals who had received initial rehabilitation at one of 18 regional centers of the Model Spinal Cord Injury System in the United States, had been interviewed between 2004 and 2010, and were wheelchair users (use a wheelchair > or = 40 h per week and cannot ambulate 150 feet at home). We performed secondary panel-data analysis using a mixed-effect model on data from 3498 follow-up interviews. Participation (measured by the Craig Handicap Assessment and Reporting Technique-Short Form (CHART-SF) and employment status) and the use of wheelchair and MV were recorded. RESULTS: Among the participants, 33% drove an MV, and 44% used an external-powered wheelchair. The use of an MV was positively related to employment and CHART-SF score, regardless of driving directly or driving with a wheelchair. People who drove an MV were found to have approximately two more business associates to contact to once a month and ∼2 additional days out of home per week compared with those without an MV. No significant association was shown between the type of wheelchair used and participation. CONCLUSION: The use of an MV was found to be positively associated with social participation in an SCI population.

United States (US) multi-center study to assess the validity and reliability of the Spinal Cord Independence Measure (SCIM III).

STUDY DESIGN: Multi-center, prospective, cohort study. OBJECTIVES: To assess the validity and reliability of the Spinal Cord Independence Measure (SCIM III) in measuring functional ability in persons with spinal cord injury (SCI). SETTING: Inpatient rehabilitation hospitals in the United States (US). METHODS: Functional ability was measured with the SCIM III during the first week of admittance into inpatient acute rehabilitation and within one week of discharge from the same rehabilitation program. Motor and sensory neurologic impairment was measured with the American Spinal Injury Association Impairment Scale. The Functional Independence Measure (FIM), the default functional measure currently used in most US hospitals, was used as a comparison standard for the SCIM III. Statistical analyses were used to test the validity and reliability of the SCIM III. RESULTS: Total agreement between raters was above 70% on most SCIM III tasks and all κ-coefficients were statistically significant (P<0.001). The coefficients of Pearson correlation between the paired raters were above 0.81 and intraclass correlation coefficients were above 0.81. Cronbach's-α was above 0.7, with the exception of the respiration task. The coefficient of Pearson correlation between the FIM and SCIM III was 0.8 (P<0.001). For the respiration and sphincter management subscale, the SCIM III was more responsive to change, than the FIM (P<0.0001). CONCLUSION: Overall, the SCIM III is a reliable and valid measure of functional change in SCI. However, improved scoring instructions and a few modifications to the scoring categories may reduce variability between raters and enhance clinical utility.

Outcome measures in spinal cord injury: recent assessments and recommendations for future directions.

STUDY DESIGN: Review by the spinal cord outcomes partnership endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations. OBJECTIVES: Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. METHODS: a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI. RESULTS: Imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain and psychosocial tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention. CONCLUSION: Significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial.

International standards to document remaining autonomic function after spinal cord injury.

STUDY DESIGN: Experts opinions consensus. OBJECTIVE: To develop a common strategy to document remaining autonomic neurologic function following spinal cord injury (SCI). BACKGROUND AND RATIONALE: The impact of a specific SCI on a person's neurologic function is generally described through use of the International Standards for the Neurological Classification of SCI. These standards document the remaining motor and sensory function that a person may have; however, they do not provide information about the status of a person's autonomic function. METHODS: Based on this deficiency, the American Spinal Injury Association (ASIA) and the International Spinal Cord Society (ISCoS) commissioned a group of international experts to develop a common strategy to document the remaining autonomic neurologic function. RESULTS: Four subgroups were commissioned: bladder, bowel, sexual function and general autonomic function. On-line communication was followed by numerous face to face meetings. The information was then presented in a summary format at a course on Measurement in Spinal Cord Injury, held on June 24, 2006. Subsequent to this it was revised online by the committee members, posted on the websites of both ASIA and ISCoS for comment and re-revised through webcasts. Topics include an overview of autonomic anatomy, classification of cardiovascular, respiratory, sudomotor and thermoregulatory function, bladder, bowel and sexual function. CONCLUSION: This document describes a new system to document the impact of SCI on autonomic function. Based upon current knowledge of the neuroanatomy of autonomic function this paper provides a framework with which to communicate the effects of specific spinal cord injuries on cardiovascular, broncho-pulmonary, sudomotor, bladder, bowel and sexual function.

Vital capacity in tetraplegics twenty years and beyond.

OBJECTIVES: To observe the trends in vital capacity (VC) over time in tetraplegics 20 years and more after injury, the effects of age at injury, severity of injury and gender on this trend. METHODS: The medical records of all spinal cord injured persons admitted to a regional spinal injury center from January 1960 to December 1996 were reviewed. Fifty-seven patients had documented post-rehabilitation VC (mean 1.3+/-1.1 years) and VC at 10 (mean 11.8+/-2.69) and 20 (20.60+/-2.67) years post injury and beyond. RESULTS: The mean age at injury was 23.2+/-9.1 years. Severity of injury when classified according the system proposed by Coll et al were: Group 1: C1-4 Frankel A injury: 11.6%, Group 2: C5-8 Frankel A injury: 55.6%, Group 3: C2-8 Frankel B and C: 29.8% and Group 4: C2-8 Frankel D: 3.5% respectively. The mean VC at initial, 10 and 20 years post injury was 2586+/-948, 2803+/-940 and 2525+/-818 cc respectively. Multivariate analysis of variance revealed that there was significant difference in VC over a 20 year period, (F(2,54)=8.43, P<0.05). The difference between VC at 10 years and VC at 20 years accounted for the 19.8% of the variance in VC over time (F(1,55)=12.35, P<0.05). Age at injury, gender and severity of injury did not have a significant influence on the rate of decline in VC. Analysis of a subset of 26 patients who were followed up more than 20 years post injury (range 22 to 34.5 years) revealed similar, with a greater drop in the VC from 10 years post injury (F(1,23)=6.52, P<0.05). In this subset of patients, the mean VC at initial injury was 2840.9+/-847.3 cc, at 10 years was 2549.6+/-750.3 cc, at 20 years was 2400.9+/-724.1 cc and beyond 20 years was 2194.2+/-738.7 cc. There was no significant difference in mean VC between non smokers and ex/current smokers at initial, 10 and 20 years post injury, using the independent t-test (P>0.05). CONCLUSION: Vital capacity in tetraplegics declines significantly over the years, with a greater decline occurring at more than 20 years post injury.

Altered motor control and spasticity after spinal cord injury: subjective and objective assessment.

This study of measures of spasticity, or altered motor control, compares the clinically used Ashworth scale with a method based on surface electromyographic (sEMG) recordings called brain motor control assessment (BMCA) in a group of 97 subjects with spinal cord injury (SCI) and varying levels of motor dysfunction. In this paper, we describe how sEMG-derived scores relate to the severity of spasticity as judged clinically. When sEMG data from passive movements from the BMCA were analyzed by Ashworth category, we found that when the sEMG data were averaged for a limb, there was a significant difference between scores for those with Ashworth 0 vs. 2 and 3, and 1 vs. 2 and 3 (p<0.001), but not between 0 and 1. Analysis of the individual muscle scores improved the discrimination between Ashworth categories. Superiority of sEMG data over Ashworth category as an objective quantification of altered motor control ("spasticity") is argued.

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

Gain in functional ability during medical rehabilitation as related to rehabilitation process indices and neurologic measures.

OBJECTIVE: To determine the incremental value of neurologic and rehabilitation process indices in predicting gain in functional abilities during rehabilitation after spinal cord injury (SCI) and to describe a model for program evaluation that provides unbiased comparisons of rehabilitation process and normative comparison of individual patient gains in functional ability. STUDY DESIGN: Multiple regression including variables in a prespecified hierarchical fashion. Linear models are formulated to gauge the incremental value of neurologic measures and rehabilitation process indices when investigating the rehabilitation process and the outcome of medical rehabilitation. RESULTS: All measures and indices vary in predictable and expected manners across individual centers and injury groups; moreover, each has demonstrated the capacity to provide unique information to the investigation of the rehabilitation process. The comprehensive set of variables accounts for 52.8% of the variance in self-care gain and 53.3% of the variance in mobility gain. The rehabilitation process indices together contribute 15% of the variance of self-care gain and over 18% of the explained variance in mobility gain. CONCLUSION: Forecasting gain in functional ability of patients in the domains of self-care and mobility may be enhanced when measures of neurologic impairment are supplemented with rehabilitation process indices. In addition, technical enhancements in measurement of rehabilitation process indices and gain in functional ability provide objective comparison of individual center differences and individual patient gains.

Follow-up study of individuals with high tetraplegia (C1-C4) 14 to 24 years postinjury.

OBJECTIVE: To determine the life circumstances and psychosocial status of individuals with respirator-assisted and respirator-independent high tetraplegia an average of 19 years after spinal cord injury. DESIGN: Survey data were analyzed separately for ventilator-assisted and ventilator-independent groups. SETTING: Three spinal cord injury rehabilitation centers in California, Colorado, and Texas. SUBJECTS: Eighty-two individuals with CI-C4 tetraplegia between 14 and 24 years postinjury who had received acute inpatient rehabilitation. MAIN OUTCOME MEASURES: Demographics, health care utilization patterns, activities of daily living (Katz Level of Free Time Activities Scale), self esteem (Rosenberg Self Esteem Scale), quality of life, and employment. RESULTS: Self esteem and quality of life were, reported as high. Most subjects had some form of health care insurance. More than 90% lived in private homes. Approximately one third of cases had at least a college degree, yet only one quarter reported being employed. One fifth of individuals were married. Almost half of ventilator-independent cases and one quarter of ventilator-assisted cases lived in households with income of less than $20,000 per year. Mean hospital days in the past year were 11 for the ventilator-independent group and 6 for the ventilator-assisted group. The latter group required more nursing level care, significantly more hours of care, and more paid attendants over the year. Ninety-five percent of individuals reported being "glad to be alive." CONCLUSIONS: Assistance in the areas of socialization, financial status, personal assistance services, transportation, and entry into competitive employment were defined as needed. Quality of life was higher than expected, considering the substantial physical limitations of the group. The sample was almost unanimously glad to be alive, including all ventilator-assisted individuals.

DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition.

TAS-103 is a novel anticancer drug that kills cells by increasing levels of DNA cleavage mediated by topoisomerase II. While most drugs that stimulate topoisomerase II-mediated DNA scission (i.e., topoisomerase II poisons) also inhibit the catalytic activity of the enzyme, they typically do so only at concentrations above the clinical range. TAS-103 is unusual in that it reportedly inhibits the catalytic activity of both topoisomerase I and II and does so at physiologically relevant concentrations [Utsugi, T., et al. (1997) Jpn. J. Cancer Res. 88, 992-1002]. Without a topoisomerase activity to relieve accumulating torsional stress, the DNA tracking systems that promote the action of TAS-103 as a topoisomerase II poison would be undermined. Therefore, the effects of TAS-103 on the catalytic activity of topoisomerase I and II were characterized. DNA binding and unwinding assays indicate that the drug intercalates into DNA with an apparent dissociation constant of approximately 2.2 microM. Furthermore, DNA strand passage assays with mammalian topoisomerase I indicate that TAS-103 does not inhibit the catalytic activity of the type I enzyme. Rather, the previously reported inhibition of topoisomerase I-catalyzed DNA relaxation results from a drug-induced alteration in the apparent topology of the nucleic acid substrate. TAS-103 does inhibit the catalytic activity of human topoisomerase IIalpha, apparently by blocking the DNA religation reaction of the enzyme. The lack of inhibition of topoisomerase I catalytic activity by TAS-103 explains how the drug is able to function as a topoisomerase II poison in treated cells.

5,7-Disubstituted analogues of the mixed topoisomerase I/II poison N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA): DNA binding and patterns of cytotoxicity.

DACA is a DNA-intercalating agent and dual topoisomerase (topo) I/II inhibitor currently in clinical trial as an anticancer drug. Substitutions in the acridine ring of DACA have significant effects on biological activity, with 5-substituted analogues being more potent but relatively less active against cell lines that underexpress topo II, and the converse for 7-substituted analogues. A small series of 5,7-disubstituted analogues was therefore prepared and evaluated. The compounds were prepared by CDI-assisted coupling of the appropriate acridine acids. When these contained no or only one halogen atom, they could be prepared by Al/Hg amalgam reduction of the corresponding acridine acids. However, this method could not be used to prepare dihalogen-substituted acridine acids due to substantial dehalogenation, and these intermediates were synthesized via cyclization of the appropriate aldehydes to give the acridines directly. These compounds showed enhanced DNA binding compared with the parent DACA, indicating that the known favourable influence of 5-substituents on DNA binding is retained. Cell line studies showed that the 5,7-disubstituted compounds retained both the broad-spectrum effectiveness of the 7-monosubstituted analogues and the higher cytotoxic potency of the 5-monosubstituted analogues. The 7-chloro-5-methyl and 5-chloro-7-methyl analogues showed comparable in vivo antitumour activity to DACA in the subcutaneous colon 38 model, but were substantially more potent (optimal doses of 60 mg/kg compared with 200 mg/kg for DACA).

Calories from carbohydrates: energetic contribution of the carbohydrate moiety of rebeccamycin to DNA binding and the effect of its orientation on topoisomerase I inhibition.

BACKGROUND: Only a few antitumor drugs inhibit the DNA breakage-reunion reaction catalyzed by topoisomerase. One is the camptothecin derivative topotecan that has recently been used clinically. Others are the glycosylated antibiotic rebeccamycin and its synthetic analog NB-506, which is presently in phase I of clinical trials. Unlike the camptothecins, rebeccamycin-type compounds bind to DNA. We set out to elucidate the molecular basis of their interaction with duplex DNA, with particular emphasis on the role of the carbohydrate residue. RESULTS: We compared the DNA-binding and topoisomerase-I-inhibition activities of two isomers of rebeccamycin that contain a galactose residue attached to the indolocarbazole chromophore via an alpha (axial) or a beta (equatorial) glycosidic linkage. The modification of the stereochemistry of the chromophore-sugar linkage results in a marked change of the DNA-binding and topoisomerase-I- poisoning activities. The inverted configuration at the C-1' of the carbohydrate residue abolishes intercalative binding of the drug to DNA thereby drastically reducing the binding affinity. Consequently, the alpha isomer has lost the capacity to induce topoisomerase-I-mediated cleavage of DNA. Comparison with the aglycone allowed us to determine the energetic contribution of the sugar residue. CONCLUSIONS: The optimal interaction of rebeccamycin analogs with DNA is controlled to a large extent by the stereochemistry of the sugar residue. The results clarify the role of carbohydrates in stereospecific drug-DNA interactions and provide valuable information for the rational design of new rebeccamycin-type antitumor agents.

Cembrene A and a congeneric ketone isolated from the paracloacal glands of the Chinese alligator (Alligator sinensis).

A diterpene hydrocarbon and diterpene ketone isolated from the paracloacal gland secretions of the Chinese alligator (alligator sinensis) were examined by GC-MS and 1H-NMR, 13C-NMR, and IR spectroscopy, and identified as 4,8,12-trimethyl-1-(1-methylethenyl)-3,7,11-cyclotetradecatrien e (cembrene A, 1) and its congeneric ketone, 4,8,12-trimethyl-1-(1-methylethenyl)-3,7-cyclotetradecadien- 10-one (2), respectively. This is the first report of cembrene A from a vertebrate; the ketone has not been described previously.

Effectiveness of gabapentin in controlling spasticity: a quantitative study.

The purpose of this investigation was to study the effectiveness of gabapentin in controlling spasticity in persons with spinal cord injury (SCI) using a surface EMG-based quantitative assessment technique called the brain motor control assessment (BMCA). Six men from a Veterans Affairs Medical Center with spasticity due to traumatic SCI were studied as part of a multi-center, placebo-controlled, cross-over, clinical trial of gabapentin. Spasticity was evaluated using multi-channel surface EMG recordings of muscles in the lower extremities, abdomen and low back before and during treatment with oral gabapentin or placebo. Gabapentin or placebo was given orally in doses 400 mg three times daily for 48 h. Following a 10 day wash-out period subjects were crossed-over to receive the medication not received the first time. This was followed by an elective open-label extension. Group results during the controlled trial did not reach statistical significance at the dosage used. One subject demonstrated a dramatic improvement in spasticity that was apparent both clinically and with the BMCA. Other subjects demonstrated modest improvements which were seen in the BMCA but not recognized clinically. During the open label extension, the four subjects who participated experienced important clinical improvements with higher doses (to 3600 mg/day). These improvements were often in components of spasticity in which the BMCA had detected subclinical changes during the cross-over trial. A seventh subject was studied using the BMCA at doses of 1200 mg T.I.D. gabapentin, off gabapentin and 800 mg T.I.D. gabapentin and demonstrated quantitatively a dose-related effect with higher doses of gabapentin which matched clinical observations. Gabapentin at doses of 400 mg T.I.D. may be effective in controlling some features of spasticity in persons with SCI. Higher doses provide greater control of spasticity, and controlled studies using higher doses are needed to evaluate gabapentin's efficacy.