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.

Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial.

4-Aminopyridine (4-AP) is a potassium (K+) channel blocking agent that has been shown to reduce the latency and increase the amplitude of motor evoked potentials (MEPs) elicited with transcranial magnetic stimulation (TMS) in patients with chronic spinal cord injury (SCI). These effects on MEPs are thought to reflect enhanced conduction in long tract axons brought about by overcoming conduction deficits due to focal demyelination and/or by enhancing neuroneuronal transmission at one or more sites of the neuraxis. The present study was designed to obtain further evidence of reduced central motor conduction time (CMCT) and to determine whether MEPs could be recorded from paretic muscles in which they were not normally elicited. MEPs were elicited with TMS being delivered to subjects (n = 25) pre- and post-administration of 4-AP (10 mg capsule) or placebo. The principal finding was that 4-AP lowered the stimulation threshold, increased the amplitude and reduced the latency of MEPs in all muscles tested, including those that were unimpaired, but did not alter measures of the peripheral nervous system (i.e., M-wave, H-reflex, F-wave). These 4-AP-induced changes in MEPs were significantly greater than those seen with placebo (p < 0.05). The primary implication of these results is that a low dose of 4-AP (immediate-release formulation) appears to improve the impaired central motor conduction of some patients with incomplete SCI. This is most likely attributable to overcoming conduction deficits at the site of injury but may also involve an increase in cortical excitability.

Conditioning lower limb H-reflexes by transcranial magnetic stimulation of motor cortex reveals preserved innervation in SCI patients.

Conditioning of lower limb H-reflexes by transcranial magnetic stimulation of motor cortex was used to detect preserved innervation in patients with long-standing spinal cord injury (SCI). Cortical stimulation was delivered at intensities suprathreshold or subthreshold for evoking motor evoked potentials (MEPs). The conditioning (C) cortical stimulation preceded the test (T) H-reflex stimulus at intervals between C-T: 10-300 msec. Conditioned H-reflex profiles in control subjects (n = 10), following both suprathreshold and subthreshold cortical conditioning, yielded evidence of early (C-T: 10-30 msec) and late arriving (C-T: 60-130 msec) excitatory inputs to the lateral gastrocnemius (LG) motoneuron pool. Demonstration of late inputs following subthreshold cortical conditioning suggested the inputs are mediated by slow conducting or oligosynaptic descending motor tracts, as distinct from afferent consequences of short latency MEPs. In SCI patients (n = 11) the conditioned H-reflex profile varied according to the patients' ASIA impairment rating. Higher functioning SCI patients (ASIA level C and D) revealed evidence of both early and late arriving inputs to the lumbosacral motoneuron pool whereas patients with more severe impairments (ASIA levels A and B) most often failed to exhibit early or late periods of H-reflex facilitation in LG. In three patients (i.e., 1 ASIA B; 2 ASIA C) the cortical modulation of H-reflex amplitudes yielded evidence of preserved corticospinal innervation that was not detectable by other MEP reinforcement procedures. These results introduce the cortical conditioning procedure as a sensitive means of detecting latent corticospinal and/or bulbospinal innervation in SCI patients consistent with the emerging neuropathological picture of preserved axonal integrity in descending motor tracts in the face of extensive functional loss.

Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury.

The potassium (K+) channel-blocking agent 4-aminopyridine (4-AP) is currently being investigated for its potential therapeutic value in patients with spinal cord injury (SCI). The present study was designed to test the hypothesis that 4-AP ameliorates central motor conduction deficits in individuals with SCI. Oral 4-AP (10 mg) was administered to 19 (n = 19) SCI subjects with stable neurological deficits. Their response to the drug was monitored using motor evoked potentials (MEPs) following transcranial magnetic stimulation of motor cortex and various measures of segmental or peripheral reflex activity (F-waves, H-reflex, and M-response) recorded from lower limb muscles. The mean MEP amplitude in the extensor digitorum brevis muscle (left) was significantly (p < .05) increased from x = .25 +/- .42 mV to x = .59 +/- 1.04 mV at 2 h after drug administration, and the cortical stimulation threshold was reduced (p < .05) by 5.8%. Similar results were obtained in all subjects exhibiting MEPs (n = 13) and in all muscles (n = 6) studied. These changes were maintained at 4 h postdrug. MEP latencies were reduced in all subjects who initially exhibited abnormally prolonged MEP latencies relative to control group (n = 13) values. F-wave, H-reflex, and M-response values (latency and amplitude) were not systematically altered by 4-AP, leading to the conclusion that it was central motor conduction that was enhanced. This interpretation was supported by observed reductions in central motor conduction time (CMCT) in the majority of SCI subjects from whom CMCT measurements were obtained, two of whom anecdotally reported improved motor control after 4-AP, and by increased MEP:M-wave amplitude ratios. The MEP:M-wave ratios indicated that the magnitude of the effect of 4-AP on motoneuron recruitment was not large, in absolute terms (<4% motoneuron pool), but was appreciable relative to the initial level of motoneuron recruitment. These results provide the first statistically significant, objective evidence of improved functioning of the neuromuscular system in chronically injured SCI subjects receiving 4-AP and suggest that the improvements are mediated through enhanced central conduction. The results further support the emerging view that pharmaceutical management of central conduction deficits may prove to be a useful therapeutic strategy for some patients with long-standing SCI.

Randomized double-blind crossover trial of fampridine-SR (sustained release 4-aminopyridine) in patients with incomplete spinal cord injury.

A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of fampridine-SR over placebo on patient satisfaction (McNemar's test, p2 < 0.05) and quality of life scores (p2 < 0.01). Sensory scores (p1 < 0.01), including both pin prick (p1 = 0.059) and light touch (p1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p1 < 0.01) all yielded evidence of benefit of fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p2 < 0.05) reduced when patients received fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of fampridine-SR in SCI patients.

Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury.

This study characterized the proinflammatory cytokines, interleukin-2 (IL-2) and tumor necrosis factor alpha (TNFalpha), the antiinflammatory cytokines, IL-4 and IL-10, autoantibodies specific for GM1 ganglioside (anti-GM1), IgG and IgM, and myelin-associated glycoprotein (anti-MAG), in the sera of infection-free, chronic (>12 months), traumatically injured SCI patients (n = 24). Healthy able-bodied subjects (n = 26) served as controls. The proinflammatory cytokines and anti-GM1 antibodies were of particular interest as they have been implicated in an autoimmune "channelopathy" component to central and peripheral conduction deficits in various chronic neuroinflammatory diseases. Antibody and cytokine titers were established using enzyme-linked immunosorbent assays (ELISA). The mean anti-GM(1) (IgM) titer value for the SCI group was significantly higher (p < 0.05) than controls. The SCI group also demonstrated significantly higher titers (p < 0.05) of IL-2 and TNF alpha than controls. No differences were found between the SCI group and control group mean levels of IL-4 or IL-10. Overall, the serum of 57% of SCI patients contained increased levels of autoantibodies or proinflammatory cytokines relative to control values. These results provide preliminary support for the hypothesis that chronic immunological activation in the periphery occurs in a subpopulation of chronic SCI patients. It remains to be established whether elevated serum titers of proinflammatory cytokines and autoantibodies against GM1 are beneficial to the patients or whether they are surrogate markers of a channelopathy that compounds the neurological impairment associated with traumatic axonopathy or myelinopathy.

4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury.

4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI.

Pharmacokinetics of an immediate-release oral formulation of Fampridine (4-aminopyridine) in normal subjects and patients with spinal cord injury.

Plasma concentration profiles of the K+ channel-blocking compound Fampridine were obtained from (1) control subjects (n = 6) following oral administration of doses of 10, 15, 20, and 25 mg and (2) patients with spinal cord injury (SCI) (n = 11) following a single oral dose of 10 mg of an immediate-release formulation. Plasma concentrations were determined using a reversed-phase ion-pair high-performance liquid chromatography (HPLC) assay with ultraviolet light detection employing liquid extraction. The drug was rapidly absorbed with a tmax approximately 1 hour for both groups; tmax was independent of dose. Cmax and AUC0-infinity were linearly related to dose, and t 1/2 was 3 to 4 hours for both groups. There were no obvious differences in the (10-mg) plasma concentration profiles between control subjects and SCI patients. The drug was well tolerated, with only mild and transient side effects of light-headedness, dysesthesias, and dizziness.

Absorption characteristics of sustained-release 4-aminopyridine (fampridine SR) in patients with chronic spinal cord injury.

Fampridine SR (4-aminopyridine) is a potassium channel-blocking drug currently being investigated for its therapeutic efficacy in ameliorating central conduction deficits due to demyelination in patients with spinal cord injury (SCI). The present open-label pharmacokinetic trial examined the absorption characteristics of a sustained-release form of the drug in 25 SCI subjects with chronic incomplete injuries. The overall group mean Cmax of 27.7 +/- 6.2 ng/mL occurred at a tmax of 3.4 +/- 1.4 hours. AUC0-12 was 210.5 +/- 49.5 ng/mL.h. For paraplegics, AUCtmax was 76.02 +/- 33.28 and for tetraplegics was significantly less at 51.25 +/- 20.36 (p = 0.037). A statistically significant difference in the initial rate and extent of absorption, but not in total 4-AP bioavailability over the 12-hour study period, was evident between tetraplegic patients, 0.60 +/- 0.23, and paraplegic patients, 0.39 +/- 0.14 (p = 0.02). There was a linear correlation (p < 0.05) between the neurological level of injury and Cmax/AUCtmax. These results confirm and extend previous observations of different rates of drug absorption among SCI patients with lesions above and below the sympathetic outflow (T6) and provide evidence of the absorption characteristics of this sustained-release form of 4-aminopyridine, which is helpful for optimal dosing.

Incidence of peripheral neuropathy in the contralateral limb of persons with unilateral amputation due to diabetes.

Eighty persons with first-time, nontraumatic amputation, mean age 66.7 yrs +/- 12.6 (1 SD) were examined to determine the extent of peripheral neuropathy (PN) present in the intact limb. Thirty-eight (47.5%) of the subjects had confirmed diabetes mellitus (DM); in those subjects, vibration sense (73.3%), temperature sense (42.1%), and nociception (71.1%) were decreased or absent in the intact limb. The prevalence of sensory impairment was significantly less in nondiabetic subjects in whom vibration sense 46.5% (p < 0.02), temperature sense 16.3% (p < 0.01), and nociception 32.6% (p < 0.02) were decreased or absent. Using a scale that stages the severity of PN, a significant difference (p < 0.001) in the distribution was found between these two groups. Only one person with known DM had no evidence of PN. Twenty-eight out of 42 nondiabetic subjects had evidence of PN. Eighty percent of all subjects had PN. This study confirms the significant potential for PN in persons with DM and presents new evidence of a significant incidence of neuropathy in nondiabetic individuals with amputation. The finding of unexpected peripheral nerve compromise is an important consideration in the treatment of persons with peripheral vascular disease who are at risk for amputation and for persons with amputation who depend on the intact limb for stability and ambulation.

Establishing evidence-based physical activity guidelines: methods for the Study of Health and Activity in People with Spinal Cord Injury (SHAPE SCI).

STUDY DESIGN: Prospective, observational cohort study. OBJECTIVES: This paper describes the rationale and methodology for the Study of Health and Activity in People with Spinal Cord Injury (SHAPE SCI). The study aims to (1) describe physical activity levels of people with different injury levels and completeness, (2) examine the relationship between physical activity, risk and/or presence of secondary health complications and risk of chronic disease, and (3) identify determinants of physical activity in the SCI population. SETTING: Ontario, Canada. METHODS: Seven hundred and twenty men and women who have incurred a traumatic SCI complete self-report measures of physical activity, physical activity determinants, secondary health problems and subjective well-being during a telephone interview. A representative subsample (n=81) participate in chronic disease risk factor testing for obesity, insulin resistance and coronary heart disease. Measures are taken at baseline, 6 and 18 months. CONCLUSION: SHAPE SCI will provide much-needed epidemiological information on physical activity patterns, determinants and health in people with SCI. This information will provide a foundation for the establishment of evidence-based physical activity guidelines and interventions tailored to the SCI community.

Relationship between electromyographic activity of the vastus lateralis while standing and the extent of bilateral simulated knee-flexion contractures.

The effect of simulated bilateral knee-flexion contractures (KFC) on the electromyographic (EMG) activity of the vastus lateralis was studied by testing 10 normal subjects using surface EMG to test the hypothesis that the activity of the knee extensors would increase as a function of the severity of the contracture. The root mean square of the EMG activity was determined from four 4-s samples taken at 30-s intervals, during 2 min of standing in each of five positions of simulated KFC (0 degree, 10 degrees, 20 degrees, 30 degrees and 40 degrees). A randomly balanced order of conditions was used. KFC were simulated in each subject by means of an adjustable line from the subject's waist to the sole of each foot. An analysis of variance was used to contrast EMG activity, and a significant difference was found between each of the positions (P less than 0.05). The mean (+/- 1 SD) EMG activity, expressed as a percentage of the maximum voluntary contraction, was 0.3% (+/- 0.2) at 0 degree, 7.6% (+/- 5.6) at 10 degrees, 10.9% (+/- 7.6) at 20 degrees, 16.6% (+/- 12.4) at 30 degrees and 24.0% (+/- 14.0) at 40 degrees. A linear relationship was found (r2 = 0.986), expressed by the equation y = 0.62 + 0.56 x, where y represents EMG activity and x represents the extent of simulated KFC (P = 0.0007). The results provide insight into the increased knee extensor activity necessary to stand with KFC and underline the importance of treating this common disorder.

Medical problems affecting musicians.

The physical demands of performing on musical instruments can cause pain, sensory loss, and lack of coordination. Five cases illustrate common problems. Knowledge of the interaction between the technique of playing the instrument and the particular musician can help physicians diagnose and resolve problems.

The effects of simulated knee-flexion contractures on standing balance.

The effects of simulated unilateral and bilateral knee-flexion contractures on standing balance were studied by testing 15 normal subjects on a Kistler force platform. Postural sway (mediolateral and anteroposterior travel) and the mean position of the center of pressure (as a percentage of the distance between the midlines of the feet and from heels to toes) were determined from 20 s of data. Unilateral and bilateral knee-flexion contractures of 15 degrees and 30 degrees were simulated for each subject by means of an adjustable line from the subject's waist to the sole of each foot. Paired t tests were used to compare balance parameters while standing with the simulated contractures with those during relaxed standing. Mediolateral travel increased by a mean difference of 3.6 cm with a 30 degree unilateral contracture (P less than 0.01) and by 5.0 cm with 30 degrees bilateral contractures (P less than 0.01). Anteroposterior travel increased by 4.7 cm (P less than 0.05) and 8.8 cm (P = 0.08) with 15 degrees and 30 degrees bilateral contractures, respectively. With a unilateral contracture of 30 degrees, the center of pressure shifted 15.6% (P less than 0.0005) toward the unflexed side, changes that were not eliminated by correction of the induced leg-length discrepancy. The center of pressure moved anteriorly by 8.3% with 30 degrees bilateral contractures (P less than 0.001). The results provide insight into how knee-flexion contractures alter standing balance, and underline the importance of preventing and treating this common disorder.

Effects of induced hypothermia on somatosensory evoked potentials in patients with chronic spinal cord injury.

We have investigated the effects of mild whole body hypothermia on the amplitude and latency of somatosensory evoked potentials (SEPs) in control subjects (n = 12) and patients (n = 15) with chronic compressive or contusive spinal cord injury (SCI). Mild hypothermia (-1 degree C) was induced by controlled circulation of propylene glycol through a 'microclimate' head and vest garment while reductions in oral and limb temperatures were monitored. Cooling induced a delayed onset and reduced amplitude of tibial nerve SEPs in control subjects. All SCI patients with recordable SEPs (n = 11) showed similarly delayed onset of the cortical response. In contrast to the controls, nine of the 11 SCI patients showed an increase in amplitude of cortical SEPs. In three of these patients the increase in amplitude exceeded 100% of the precooling values. The cooling-induced changes in SEP amplitude and latency reversed on rewarming for both groups. The cooling-induced increases in cortical SEP amplitude support the a priori hypothesis that cooling would enhance central conduction in some SCI patients with conduction deficits due to focal demyelination.

Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases.

Preclinical trials of intravenously administered 4-Aminopyridine (4-AP) have demonstrated transient improvements in neurological function in patients with longstanding spinal cord injury (SCI). The present report describes three patients with SCI who responded favourably in preclinical trials and who were subsequently administered oral (capsule) 4-AP (10 mg b.i.d. or t.i.d.) over a 4 month interval. The three patients (two male: 1 female) all had incomplete tetraplegia (ASIA levels C and D) with the neurological level of the lesion between C5-C7. Following the administration of 4-AP the patients demonstrated marked and sustained reductions in upper (n = 1) or lower extremity (n = 2) spasticity. Other clinical benefits of 4-AP were reduced pain (n = 1), restored muscle strength (n = 3), improved sensation (n = 2), voluntary control of bowel function (n = 1), and sustained penile tumescence (n = 2). The patients exhibited improved hand function (n = 1), enhanced mobility in transfers and gait (n = 2), with improved energy and endurance. Only trivial side effects (transient light-headedness) were observed. In one case, the enhanced neurological function allowed the patient to stand with support for the first time post injury (16 years). The time course of therapeutic response to the initial dose matched the pharmacokinetic elimination profile derived from serum and urine analysis. There was no evidence of renal or hepatic toxicity with prolonged use. These results indicate a therapeutic benefit of oral 4-Aminopyridine in the management of various neurological deficits in a select group of SCI patients.

Classifying incomplete spinal cord injury syndromes: algorithms based on the International Standards for Neurological and Functional Classification of Spinal Cord Injury Patients.

OBJECTIVE: To develop an objective and uniform means for classifying patients with incomplete spinal cord injury (SCI) according to SCI syndromes. DESIGN: Criteria for assigning the syndromes (defined by the International Standards for Neurological and Functional Classification of SCI Patients) were operationalized by means of sensory and motor scores and were incorporated into a set of six independent algorithms and two composite algorithms. SETTING: A regional SCI rehabilitation center in Canada. PATIENTS: SCI patients (n = 56) with incomplete injuries (American Spinal Injury Association classes B, C, D) and stable neurologic deficits. RESULTS: Individual algorithms allowed the highest classification rate but with some patients meeting the criteria for more than one syndrome. A composite, differential allocation algorithm, with selected thresholds at decision nodes, yielded a classification rate approximating that of the individual algorithms but without double classifications. CONCLUSIONS: The composite algorithm provided an objective and standardized means of assigning patients to syndromes based on clinically measurable sensory and motor scores. The thresholds used to implement criteria and the order of decision nodes greatly influenced the outcomes and may be adjusted to suit the needs of the classification, that is, embracing liberal or stringent criteria. Controversy remains about the interpretation of some syndromes, and many patients remain unclassifiable because of mixed clinical presentation.

Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury.

4-Aminopyridine (4-AP) is a K+ channel blocking agent that enhances nerve conduction through areas of demyelination by prolonging the duration of the action potential and increasing the safety factor for conduction. We have investigated the effects of 4-AP (24 mg total dose-intravenous) in 6 patients with spinal cord injury (3 complete, 3 incomplete) with the intent of overcoming central conduction block, or slowing, due to demyelination. Vital signs remained stable and only mild side effects were noted. The 3 patients with incomplete injuries all demonstrated enhanced volitional EMG interference patterns and one patient exhibited restored toe movements. The changes were reversed on drug washout. There were no changes in segmental reflex activities. These results are consistent with those obtained from 4-AP trials with animal models of spinal cord injury, showing modest therapeutic benefit attributable to enhanced central conduction.