Jane T.C. Hsieh

The Health and Life Priorities of Individuals with Spinal Cord Injury: A Systematic Review

Determining the priorities of individuals with spinal cord injury (SCI) can assist in choosing research priorities that will ultimately improve their quality of life. This systematic review examined studies that directly surveyed people with SCI to ascertain their health priorities and life domains of importance. Twenty-four studies (a combined sample of 5262 subjects) that met the inclusion criteria were identified using electronic databases (Medline, EMBASE, CINAHL, and PsycINFO). The questionnaire methods and domains of importance were reviewed and described. While the questionnaires varied across studies, a consistent set of priorities emerged. Functional recovery priorities were identified for the following areas: motor function (including arm/hand function for individuals with tetraplegia, and mobility for individuals with paraplegia), bowel, bladder, and sexual function. In addition, health, as well as relationships, emerged as important life domains. The information from this study, which identified the priorities and domains of importance for individuals with SCI, may be useful for informing health care and research agenda-setting activities.

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 ∼1 hour for both groups; tmax was independent of dose. Cmax and AUC0‐∞ were linearly related to dose, and t1/2 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.

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.

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 lightheadedness) 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.

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.

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 in complete injuries. The overall group mean Cmax of 27.7 ± 6.2 ng/mL occurred at a tmsx 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.

Reinforcement of subliminal flexion reflexes by transcranial magnetic stimulation of motor cortex in subjects with spinal cord injury

A 20 msec train (500 Hz; 0.1-0.2 msec duration) of percutaneous electrical stimulation (ES) applied to the plantar surface was used to condition muscle responses evoked in tibialis anterior (TA) by transcranial magnetic stimulation of the motor cortex in 8 subjects with traumatic spinal cord injury (SCI). The intensity of conditioning ES was adjusted to just subthreshold for evoking flexion reflexes in TA and was delivered at conditioning-test (C-T) intervals of 15-60 msec prior to cortical stimulation. Four subjects with clinically complete SCI revealed no muscle response to cortical stimulation or following combined subliminal percutaneous ES and cortical stimulation. Four subjects (3 clinically incomplete and 1 complete injury) demonstrated muscle responses with a latency of 70-80 msec time-locked to the percutaneous ES when the conditioning subliminal stimulation was delivered at C-T: 15-40 msec. These responses, resembling suprathreshold flexion reflexes, reflect the convergence of excitatory afferent and cortical inputs and provide evidence of preserved corticospinal innervation to the L4-5 segmental motoneuron or interneuron pools. In 3 of the subjects this preserved corticospinal influence was evident despite absence of motor evoked potentials (MEPs) following cortical stimulation. The effect of the combined electrical and cortical stimulation in yielding suprathreshold flexion reflexes, instead of the facilitated MEPs seen in control subjects, appears to be related to slowed central conduction, prolonged temporal dispersion of the motoneuron facilitation following cortical stimulation and segmental reflex changes associated with disrupted modulation of interneuronal pathways. The results show this conditioning paradigm to be useful in revealing preserved corticospinal innervation in some SCI subjects with absent MEPs.

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.

Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.

Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of fampridine (fampridine-SR, 10–25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration–time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6–3.7 hours) and eliminated (plasma half-life, 5.6–7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using fampridine-SR in patients with chronic SCI are currently underway.

Neuropathic Pain Post Spinal Cord Injury Part 1: Systematic Review of Physical and Behavioral Treatment

BACKGROUND Neuropathic pain has various physiologic and psychosocial aspects. Hence, there is a growing use of adjunct nonpharmacological therapy with traditional pharmacotherapy to reduce neuropathic pain post spinal cord injury (SCI). OBJECTIVE The purpose of this study was to conduct a systematic review of published research on nonpharmacological treatment of neuropathic pain after SCI. METHODS MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing nonpharmacological treatment of pain post SCI. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a treatment or intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention was being studied. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale. RESULTS The 16 articles selected for this review fell into 1 of 2 categories of nonpharmacological management of pain after SCI: physical and behavioral treatments. The pooled sample size of all studies included 433 participants. Of the 16 studies included, 7 were level 1, 3 were level 2, and 6 were level 4 studies. CONCLUSIONS Physical interventions demonstrated the strongest evidence based on quality of studies and numbers of RCTs in the nonpharmacological treatment of post-SCI pain. Of these interventions, transcranial electrical stimulation had the strongest evidence of reducing pain. Despite a growing body of literature, there is still a significant lack of research on the use of nonpharmacological therapies for SCI pain.