Amie B. McLain

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.

Skeletal muscle signaling associated with impaired glucose tolerance in spinal cord-injured men and the effects of contractile activity

The mechanisms underlying poor glucose tolerance in persons with spinal cord injury (SCI), along with its improvement after several weeks of neuromuscular electrical stimulation-induced resistance exercise (NMES-RE) training, remain unclear, but presumably involve the affected skeletal musculature. We, therefore, investigated skeletal muscle signaling pathways associated with glucose transporter 4 (GLUT-4) translocation at rest and shortly after a single bout of NMES-RE in SCI (n = 12) vs. able-bodied (AB, n = 12) men. Subjects completed an oral glucose tolerance test during visit 1 and ≈90 NMES-RE isometric contractions of the quadriceps during visit 2. Muscle biopsies were collected before, and 10 and 60 min after, NMES-RE. We assessed transcript levels of GLUT-4 by quantitative PCR and protein levels of GLUT-4 and phosphorylated- and total AMP-activated protein kinase (AMPK)-α, CaMKII, Akt, and AS160 by immunoblotting. Impaired glucose tolerance in SCI was confirmed by higher (P < 0.05) plasma glucose concentrations than AB at all time points after glucose ingestion, despite equivalent insulin responses to the glucose load. GLUT-4 protein content was lower (P < 0.05) in SCI vs. AB at baseline. Main group effects revealed higher phosphorylation in SCI of AMPK-α, CaMKII, and Akt (P < 0.05), and Akt phosphorylation increased robustly (P < 0.05) following NMES-RE in SCI only. In SCI, low skeletal muscle GLUT-4 protein concentration may, in part, explain poor glucose tolerance, whereas heightened phosphorylation of relevant signaling proteins (AMPK-α, CaMKII) suggests a compensatory effort. Finally, it is encouraging to find (based on Akt) that SCI muscle remains both sensitive and responsive to mechanical loading (NMES-RE) even ≈22 yr after injury.

MECHANOSENSITIVITY MAY BE ENHANCED IN SKELETAL MUSCLES OF SPINAL CORD–INJURED VERSUS ABLE-BODIED MEN

We investigated the effects of an acute bout of neuromuscular electrical stimulation–induced resistance exercise (NMES‐RE) on intracellular signaling pathways involved in translation initiation and mechanical loading–induced muscle hypertrophy in spinal cord–injured (SCI) versus able‐bodied (AB) individuals. AB and SCI individuals completed 90 isometric knee extension contractions at 30% of maximum voluntary or evoked contraction, respectively. Muscle biopsies were collected before, and 10 and 60 min after NMES‐RE. Protein levels of α7‐ and β1‐integrin, phosphorylated and total GSK‐3α/β, S6K1, RPS6, 4EBP1, and FAK were assessed by immunoblotting. SCI muscle appears to be highly sensitive to muscle contraction even several years after the injury, and in fact it may be more sensitive to mechanical stress than AB muscle. Heightened signaling associated with muscle mechanosensitivity and translation initiation in SCI muscle may be an attempted compensatory response to offset elevated protein degradation in atrophied SCI muscle. Muscle Nerve 50: 599–601, 2014

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury.

Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNFαR, TNFα, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF-κB, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (≈22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNFαR and TWEAK R gene expression and NF-κB signaling (higher TWEAK R and phospho-NF-κB p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-κB signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle.

Prediction of sexual function following spinal cord injury: a case series

IntroductionSpinal Cord Injury (SCI) affects sexual response based on the level and degree of completeness of injury. By using the International Standards for the Neurologic Classification of SCI in conjunction with lumbo-sacral reflexes these effects can be predicted. The International Standards for the Assessment of Autonomic Function after SCI (ISAFSCI) document the impact of SCI on sexual responses including psychogenic and reflex arousal (erection or lubrication), orgasm, ejaculation, and sensation of menses. Responses are described based upon a 0 to 2 scale with 0 being absent, 1 altered, and 2 normal response. Additionally, the lesion is described as supraconal, conal or infraconal.Case presentationWe present 4 representative cases of the impact of SCI on sexual responses and course of treatment. Case 1 describes a complete supraconal lesion above T6 with upper motor neuron syndrome. Case 2 describes a supraconal complete lesion including the T11-L2 segment. Case 3 describes an infraconal (cauda equina) lesion with lower motor neuron syndrome. Case 4 is theoretical and describes a supraconal lesion above T6 with upper motor neuron syndrome, partial sensation in T11-L2 dermatomes, and other medical comorbidities.DiscussionNeurologic examination combined with reflex testing allows prediction of sexual responses after SCI. It would be useful for version 2.0 of the ISAFSCI to assist clinicians in determining the anticipated changes, whether their patients are functioning as anticipated sexually after SCI or whether other concerns also require treatment.

The use of the neurologic exam to predict awareness and control of lower urinary tract function post SCI

Study Design:Cross-sectional study.Objectives:To assess whether T11–L2 sensation is significantly associated with perception of bladder filling and whether S3–S5 sensation is significantly associated with potential for voluntary voiding after spinal cord injury (SCI).Setting:Alabama, United States.Methods:A total of 79 men and women with SCI, and 40 able-bodied (AB) subjects, ages 19–60, seen in an outpatient academic medical center clinic, underwent International Standards for Neurological Classification of SCI (ISNCSCI) assessment along with urodynamic testing to assess lower urinary tract (LUT) function. X2 test was performed to compare: (1) bladder sensation across T11–L2 groups classified by total sensory scores and (2) ability to voluntarily void across S3–S5 scores.Results:Persons with greater ability to perceive pinprick and light touch sensation in the T11–L2 dermatomes were more likely to perceive bladder filling both via self-report and by urodynamics. However, persons with greater sensation at T6–T9 and S3–5 also had a greater likelihood of perceiving bladder filling. Subjects with greater preservation of sensation in S3–5 reported greater ability to initiate and control voiding.Conclusion:Findings suggest ISNCSCI results along with self-report can be used to predict potential for bladder control.Sponsorship:National Institute of Disability and Rehabilitation Research.

Paralytic and non-paralytic muscle adaptations to exercise training vs. high protein diet in individuals with long-standing spinal cord injury

This study compares the effects of an 8-wk isocaloric high-protein (HP) diet versus a combination exercise (Comb-Ex) regimen on paralytic vastus lateralis (VL) and nonparalytic deltoid muscle in individuals with long-standing spinal cord injury (SCI). Fiber-type distribution, cross-sectional area (CSA), levels of translation initiation signaling proteins (Erk-1/2, Akt, p70S6K1, 4EBP1, RPS6, and FAK), and lean thigh mass were analyzed at baseline and after the 8-wk interventions. A total of 11 participants (C5-T12 levels, 21.8 ± 6.3 yr postinjury; 6 Comb-Ex and 5 HP diet) completed the study. Comb-Ex training occurred 3 days/wk and consisted of upper body resistance training (RT) in addition to neuromuscular electrical stimulation (NMES)-induced-RT for paralytic VL muscle. Strength training was combined with high-intensity arm-cranking exercises (1-min intervals at 85-90%, V̇o2peak) for improving cardiovascular endurance. For the HP diet intervention, protein and fat each comprised 30%, and carbohydrate comprised 40% of total energy. Clinical tests and muscle biopsies were performed 24 h before and after the last exercise or diet session. The Comb-Ex intervention increased Type IIa myofiber distribution and CSA in VL muscle and Type I and IIa myofiber CSA in deltoid muscle. In addition, Comb-Ex increased lean thigh mass, V̇o2peak, and upper body strength ( P < 0.05). These results suggest that exercise training is required to promote favorable changes in paralytic and nonparalytic muscles in individuals with long-standing SCI, and adequate dietary protein consumption alone may not be sufficient to ameliorate debilitating effects of paralysis. NEW & NOTEWORTHY This study is the first to directly compare the effects of an isocaloric high-protein diet and combination exercise training on clinical and molecular changes in paralytic and nonparalytic muscles of individuals with long-standing spinal cord injury. Our results demonstrated that muscle growth and fiber-type alterations can best be achieved when the paralyzed muscle is sufficiently loaded via neuromuscular electrical stimulation-induced resistance training.

A high-protein diet or combination exercise training to improve metabolic health in individuals with long-standing spinal cord injury: a pilot randomized study

We compared the effects of an 8‐week iso‐caloric high‐protein (HP) diet versus a combined exercise regimen (Comb‐Ex) in individuals with long‐standing spinal cord injury (SCI). Effects on metabolic profiles, markers of inflammation, and signaling proteins associated with glucose transporter 4 (GLUT‐4) translocation in muscles were evaluated. Eleven participants with SCI completed the study (HP diet: n = 5; Comb‐Ex: n = 6; 46 ± 8 years; C5‐T12 levels; American Spinal Injury Association Impairment Scale A or B). The Comb‐Ex regimen included upper body resistance training (RT) and neuromuscular electrical stimulation‐induced‐RT for paralytic quadriceps muscles, interspersed with high‐intensity (80–90% VO2 peak) arm cranking exercises 3 days/week. The HP diet included ~30% total energy as protein (carbohydrate to protein ratio <1.5, ~30% energy from fat). Oral glucose tolerance tests and muscle biopsies of the vastus lateralis (VL) and deltoid muscles were performed before and after the trial. Fasting plasma glucose levels decreased in the Comb‐Ex (P < 0.05) group compared to the HP‐diet group. A decrease in areas under the curve for insulin and TNF‐α concentrations was observed for all participants regardless of group assignment (time effect, P < 0.05). Although both groups exhibited a quantitative increase in insulin sensitivity as measured by the Matsuda Index, the change was clinically meaningful only in the HP diet group (HP diet: pre, 4.6; post, 11.6 vs. Comb‐Ex: pre, 3.3; post, 4.6). No changes were observed in proteins associated with GLUT‐4 translocation in VL or deltoid muscles. Our results suggest that the HP‐diet and Comb‐Ex regimen may improve insulin sensitivity and decrease TNF‐α concentrations in individuals with SCI.

Differences in glucose metabolism among women with spinal cord injury may not be fully explained by variations in body composition

OBJECTIVE To investigate the differences in glucose metabolism among women with paraplegic, and tetraplegic spinal cord injury (SCI) in comparison to their able-bodied (AB) counterparts after adjusting for differences in body composition. DESIGN Cross-sectional study. After an overnight fast, each participant consumed a 75-g glucose solution for oral glucose tolerance test (OGTT). Blood glucose, insulin, and C-peptide concentrations were analyzed before and 30, 60, 90, and 120 minutes after ingesting glucose solution. Insulin sensitivity index (ISI) was estimated using the Matsuda index. Percentage fat mass (%FM) and total body lean mass (TBLM) were estimated using data from dual-energy x-ray absorptiometry. Visceral fat (VF) was quantified using computed tomography. Outcome measures were compared among groups using analysis of covariance with %FM (or VF) and TBLM as covariates. SETTING Research university. PARTICIPANTS Women (N=42) with SCI (tetraplegia: n=8; paraplegia: n=14) and their race-, body mass index-, and age-matched AB counterparts (n=20). INTERVENTIONS Not applicable. RESULTS At fasting, there was no difference in glucose homeostasis (glucose, insulin, C-peptide concentrations) among 3 groups of women. In contrast, glucose, insulin, and C-peptide concentrations at minute 120 during OGTT were higher in women with tetraplegia versus women with paraplegia and AB women (P<.05, adjusted for TBLM and %FM). In addition, women with tetraplegia had lower ISI (P<.05, adjusted for TBLM and %FM) versus AB women. These differences remained after adjusting for VF and TBLM. CONCLUSION Our study confirms that impaired glucose metabolism among women with tetraplegia may not be fully explained by changes in their body composition. Future studies exploring additional factors involved in glucose metabolism are warranted.

Upper extremity motor training of a subject with initially motor complete chronic high tetraplegia using constraint-induced biofeedback therapy

IntroductionThe purpose of this case study was to determine if a subject with chronic high tetraplegia (C3 AIS A) could learn to use an initially paralyzed upper extremity on the basis of training procedures alone.Case presentationInitially, an AIS examination revealed no purposive movement below the neck other than minimal shoulder movement. Training was carried out weekly over 39 months. Training began based on electromyographic biofeedback; the electrical activity of a muscle (biceps or triceps) was displayed visually on a computer monitor and the subject was encouraged to progressively increase the magnitude of the response in small increments on a trial-by-trial basis (i.e., shaping). When small, overt movements began to appear; these were, in turn, shaped so that their excursion progressively increased. Training then progressed to enable lifting the arm with the aid of the counterweight of a Swedish Help Arm. Mean movement excursions in the best session were: internal rotation 52.5 cm; external rotation 26.9 cm; shoulder extension 22.1 cm; shoulder flexion 15.2 cm; pronation/supination 120°; extension of index finger (D2) 2.5 cm. Movements were initially saltatory, becoming smoother over time. With the Swedish Help Arm, the subject was able to lift her hand an average of 24.3 cm in the best session with 0.7 kg counterweight acting at the wrist (1.9 J of work).DiscussionResults suggest in preliminary fashion the effectiveness of this approach for improving upper extremity function after motor complete high tetraplegia. Thus, future studies are warranted. Possible mechanisms are discussed.