Discrepancies between clinical assessments of sensory function and electrical perceptual thresholds after incomplete chronic cervical spinal cord injury.

STUDY DESIGN: Prospective experimental. OBJECTIVES: To compare sensory function as revealed by light touch and pin prick tests of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the electrical perceptual threshold (EPT) exams in individuals with chronic incomplete cervical spinal cord injury (SCI). SETTING: Pittsburgh, United States. METHODS: EPT was tested using cutaneous electrical stimulation (0.5 ms pulse width, 3 Hz) in 32 healthy controls and in 17 participants with SCI over key points on dermatomes C2 to T4 on each side of the body. Light touch and pin prick ISNCSCI scores were tested at the same key dermatomes in SCI participants. RESULTS: In controls, EPT values were higher in older males (1.26±0.2 mA, mean±s.d.) compared with younger males (1.0±0.2 mA) and older females (0.9±0.2 mA), regardless of the dermatome and side tested. Fifteen out of the seventeen SCI participants showed that the level of sensory impairment detected by the EPT was below the level detected by the ISNCSCI (mean=4.5±2.4, range 1-9). The frequency distribution of EPTs was similar to older male controls in dermatomes above but not below the ISNCSCI sensory level. The difference between EPT and ISNCSCI sensory level was negatively correlated with the time post injury. CONCLUSIONS: The results show that, in the chronic stage of cervical SCI, the EPT reveals spared sensory function at lower (~5) spinal segments compared with the ISNCSCI sensory exam. It is hence found that the EPT is a sensitive tool to assess recovery of sensory function after chronic SCI.

Pelvic floor muscle training in spinal cord injury and its impact on neurogenic detrusor over-activity and incontinence.

STUDY DESIGN: Two case studies. OBJECTIVES: To determine whether 6 weeks of regular pelvic floor muscle training (PFMT) can improve the strength and endurance of voluntary contractions in incomplete spinal cord injury and reduce neurogenic detrusor over-activity (NDO) and incontinence. SETTING: The London Spinal Cord Injury Centre, Stanmore, London, UK. METHODS: A 6-week programme of PFMT was conducted in two male subjects with stable supra-sacral motor incomplete (AIS C and D) spinal cord injuries. Clinical evaluations before and after training comprised measures of strength and endurance of voluntary pelvic floor contractions both objectively by anal canal-pressure measurements and subjectively using the modified Oxford grading system. NDO was determined by standard urodynamic tests of bladder function and incontinence measured by the International Consultation on Incontinence Questionnaire-Urology. RESULTS: Both subjects improved the strength and endurance of their pelvic floor muscle contractions by over 100% at the end of training. After training, Subject 1 (AIS D) was able to reduce bladder pressure during over-activity almost completely by voluntarily contracting the pelvic floor muscles. Subject 2 (AIS C) achieved a lesser reduction overall after training. Continence improved only in subject 1. CONCLUSION: These case studies provide evidence that a 6-week programme of PFMT may have a beneficial effect on promoting voluntary control of NDO and reduce incontinence in selected cases with a motor incomplete spinal cord lesion.

Reliability of the electrical perceptual threshold and Semmes-Weinstein monofilament tests of cutaneous sensibility.

STUDY DESIGN: Prospective experimental. OBJECTIVES: To compare the reliability and repeatability of the electrical perceptual threshold (EPT) and Semmes-Weinstein monofilament (SWM) tests for cutaneous sensibility. EPT and SWM tests have potential as quantitative and sensitive adjuncts to the American Spinal Injuries Association (ASIA) Impairment Scale (AIS) assessment of spinal cord injury (SCI). SETTING: London, UK. METHODS: EPT and SWM tests were carried out on 40 neurologically healthy individuals (20 male). One examiner carried out all the tests. Each individual was examined for EPT and SWM sensitivity at ASIA key points on four dermatomes (C4, T1, T6, L4) on both sides of the body. The tests were repeated after an interval of approximately 1 week. Intra-rater reliability was determined using intra-class correlation coefficients (ICC). Repeatability was determined using the method of Bland and Altman. RESULTS: There were no significant differences in the mean values of EPT or SWM between assessments for any dermatome. Significant difference in mean values for both EPT and SWM were observed between some dermatomes. ICC ranged from 0.67 to 0.81 for the EPT and from 0.46 to 0.61 for the SWM. Higher ICC for the EPT compared with the SWM was again revealed when male and female subjects were assessed separately. Correlation between EPT and SWM was weak or (largely) absent. CONCLUSION: EPT has better reliability than SWM in healthy subjects. However, as both tests have the potential to add sensitivity and resolution to the AIS assessment, a further comparison of their repeatability in SCI is warranted.

Light touch and pin prick disparity in the International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI).

STUDY DESIGN: Retrospective review. OBJECTIVES: The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) assesses cutaneous sensibility through light touch (LT) and sharp-dull discrimination, referred to as pin prick (PP). This project aimed to confirm a tendency for LT to score higher than PP in SCI subjects and discuss possible reasons for such disparity. SETTING: Single site cohort study, the London Spinal Cord Injury Centre, United Kingdom. METHODS: A retrospective analysis of LT and PP scores of 99 spinal cord injury subjects at the time of discharge (median 5 months) from acute care and rehabilitation in the London Spinal Cord Injury Centre was conducted. Subjects were aged 10-88 years (median 44 years; 78 men, 74 traumatic, 25 non-traumatic). There were 40 American Spinal Injury Association (ASIA) Impairment Scale (AIS) A, 7 B, 18 C and 34 D subjects. RESULTS: A disparity (P<0.001) was found between LT (64.5±3.2, mean±s.e.) and PP (54.7±2.9) AIS sensory scores. A similar difference in score (LT>PP) was registered both for traumatic and non-traumatic injury, but was greater for incomplete than for complete injury. Despite the difference, LT was well correlated with PP (R=0.87, P<0.001). Spinal segmental level of injury was determined more frequently by PP alone (43 of 99) than by LT (10 of 99) alone. CONCLUSION: The discrepancies between LT and PP could relate to the greater complexity of the PP test or a difference in the extent of injury to the posterior columns (LT) and spinothalamic (PP) tracts. Further interpretation would benefit from additional electrophysiological sensory tests.

Segmental influence of slowly-adapting cutaneous mechanoreceptors on gamma motoneurones revealed by cross-correlation of unit discharges in the cat.

Cross-correlations between the discharges of individual cutaneous afferents and gamma motoneurones have been constructed in the spinal, decerebrated cat. The discharges of single receptors in the sural nerve field from the heel were recorded in dorsal root ganglia. Background discharges of gamma motoneurones and the responses to heel stimulation were recorded from cut filaments of the muscle nerve to gastrocnemius medialis of the same leg. Slowly-adapting afferents were stimulated by steady application of a probe to the receptive field whereas rapidly-adapting afferents required continuous movement to sustain discharge of a receptor. Cross-correlation between the discharges of 17 out of 39 slowly-adapting, type-1 (SA1) mechanoreceptors and gamma motoneurones revealed sharp increases in probability of gamma motoneurone discharge that were delayed with respect to the afferent discharge. The peaks were of short duration with widths at half maximum in the range 2-7 ms and rise times of 1 to 4 ms. Deducting peripheral conduction times gave central delays of 3-6.5 ms for gamma motoneurone facilitation. These delays were comparable to those of gamma motoneurone excitation seen in response to electrical stimulation of the sural nerve at 1.5 to 4 times threshold. No short duration peaks were seen in correlograms between hair follicle (n = 29) or slowly-adapting type-2 (SA2) (n = 11) afferents and gamma motoneurones. It is concluded that a single impulse from a SA1 afferent from the hairy skin of the heel is able to facilitate the discharge of gamma motoneurones to the ipsilateral gastrocnemius muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical limits for detecting change in the cumulative sum derivative of the peristimulus time histogram.

The peristimulus time histogram (psth) provides a means of correlating the discharges of neurones with other events. The cumulative sum (cusum) derived from the psth facilitates the detection of small changes in the psth that may be obscured by random fluctuations in counts. The cusum integrates differences from the mean control level of counts in the psth. Any signal in the data that is related to the stimulus appears as a slope in the cusum. Psth's constructed from the rhythmic discharges of single neurones are shown to contain periodical fluctuations in counts that arise from refractoriness. This periodicity results in a cusum which deviates less from the horizontal line than predicted from a Poisson distribution of points. The more regular the spike train, i.e., the lower the coefficient of variation of the distribution of interspike intervals, the flatter is the cusum. The theory of stochastic point processes is used to derive an algorithm for calculating the best approximation of variance of the cusum. Significance limits set at 3 standard deviations of the cusum are shown to provide a good fit to cusums for unit discharges over a wide range of coefficients of variation (0.09-0.60).

Characteristics of habituation of the sympathetic skin response to repeated electrical stimuli in man.

OBJECTIVES: To study the effect of repeating electrical peripheral nerve stimulation on latency, duration and amplitude of the sympathetic skin response (SSR). METHODS: SSRs were elicited in all limbs by median and peroneal nerves stimuli. In 10 subjects, 20 stimuli were applied at random time intervals (15-20 s). Another test was performed in 7 subjects using the same protocol, but switching the stimulation site every 5 or 10 stimuli without warning. RESULTS: The mean amplitude of right palmar response to right peroneal nerve stimulation decreased from 5.05+/-0.76 (SEM) mV at the first stimulus to 1.23+/-0.42 mV at the 20th stimulus (P<0.001). The latency did not change significantly (1473+/-82 to 1550+/-90 ms, P>0.1), while the duration increased (1872+/-356 to 3170+/-681 ms, P<0.001). Stimulation and recording at other sites showed similar trends. Changing the stimulation site failed to alter the adaptation process in terms of amplitude, latency or duration. CONCLUSIONS: Changes in amplitude and duration of the SSRs to repeated electrical stimuli can occur in presence of constant latency and appear to be independent of the source of sensory input. Peripheral sweat gland mechanisms may be involved in the loss of amplitude and increase in duration of the SSR during habituation.

Corticospinal function in severe brain injury assessed using magnetic stimulation of the motor cortex in man.

We have assessed corticospinal function in 19 post-coma patients severely brain-injured by anoxia or physical trauma. Eleven patients were unresponsive (Category 1) and eight demonstrated minimal, non-verbal responses to simple commands (Category 2). Motor evoked potentials (MEPs) could be elicited in hand and leg muscles in nine Category 1 and all eight Category 2 patients in response to transcranial magnetic stimulation (TMS). In comparison with normal subjects, threshold to TMS was significantly elevated in Category 1 but not in Category 2. Central conduction times were within the normal range except for two patients (one in each category) in whom they were prolonged. The variability in MEP amplitude to constant TMS was not significantly different from normal in either category. The size of MEPs recorded simultaneously in different hand muscles were correlated in all three groups. The presence of H-reflexes in hand muscles was associated with an absence of MEPs or a high threshold to TMS. Variability of MEPs was substantially greater than that of H-reflexes. We conclude that brain injury of a severity that may preclude consciousness and voluntary movement does not invariably predicate a non-functional motor cortex and corticospinal system.

Clinical neurophysiology in the prognosis and monitoring of traumatic spinal cord injury.

Preclinical studies for the repair of spinal cord injury (SCI) and potential therapies for accessing the inherent plasticity of the central nervous system (CNS) to promote recovery of function are currently moving into the translational stage. These emerging clinical trials of therapeutic interventions for the repair of SCI require improved assessment techniques and quantitative outcome measures to supplement the American Spinal Injuries Association (ASIA) Impairment Scales. This chapter attempts to identify those electrophysiological techniques that show the most promise for provision of objective and quantitative measures of sensory, motor, and autonomic function in SCI. Reviewed are: (1) somatosensory evoked potentials, including dermatomal somatosensory evoked potentials, and the electrical perceptual threshold as tests of the dorsal (posterior) column pathway; (2) laser evoked potentials and contact heat evoked potentials as tests of the anterior spinothalamic tract; (3) motor evoked potentials in limb muscles, in response to transcranial magnetic stimulation of the motor cortex as tests of the corticospinal tract, and the application of the technique to assessment of trunk and sphincter muscles; and (4) the sympathetic skin response as a test of spinal cord access to the sympathetic chain.

Action of 5 Hz repetitive transcranial magnetic stimulation on sensory, motor and autonomic function in human spinal cord injury.

OBJECTIVE: To assess the effectiveness of physiological outcome measures in detecting functional change in the degree of impairment of spinal cord injury (SCI) following repetitive transcranial magnetic stimulation (rTMS) of the sensorimotor cortex. METHODS: Subjects with complete or incomplete cervical (or T1) SCI received real and sham rTMS in a randomised placebo-controlled single-blinded cross-over trial. rTMS at sub-threshold intensity for upper-limb muscles was applied (5 Hz, 900 stimuli) on 5 consecutive days. Assessments made before and for 2 weeks after treatment comprised the ASIA (American Spinal Injuries Association) impairment scale (AIS), the Action Research Arm Test (ARAT), a peg-board test, electrical perceptual test (EPT), motor evoked potentials, cortical silent period, cardiovascular and sympathetic skin responses. RESULTS: There were no significant differences in AIS outcomes between real and sham rTMS. The ARAT was increased at 1h after real rTMS compared to baseline. Active motor threshold for the most caudally innervated hand muscle was increased at 72 and 120 h compared to baseline. Persistent reductions in EPT to rTMS occurred in two individuals. CONCLUSIONS: Changes in cortical motor threshold measures may accompany functional gains to rTMS in SCI subjects. SIGNIFICANCE: Electrophysiological measures may provide a useful adjunct to ASIA impairment scales.

Development of quantitative and sensitive assessments of physiological and functional outcome during recovery from spinal cord injury: a clinical initiative.

The ability to detect physiological changes associated with treatments to effect axonal regeneration, or novel rehabilitation strategies, for spinal cord injury will be challenging using the widely employed American Spinal Injuries Association (ASIA) impairment scales (AIS) for sensory and motor function. Despite many revisions to the AIS standard neurological assessment, there remains a perceived need for more sensitive, quantitative and objective outcome measures. The purpose of Stage 1 of the Clinical Initiative was to develop these tools and then, in Stage 2 to test them for reliability against natural recovery and treatments expected to produce functional improvements in those with complete or incomplete spinal cord injury (SCI). Here we review aspects of the progress made by four teams involved in Stage 2. The strategies employed by the individual teams were (1) application of repetitive transcranial magnetic stimulation (rTMS) to the motor cortex in stable (chronic) SCI with intent to induce functional improvement of upper limb function, (2) a tele-rehabilitation approach using functional electrical stimulation to provide hand opening and grip allowing incomplete SCI subjects to deploy an instrumented manipulandum for hand and arm exercises and to play computer games, (3) weight-assisted treadmill walking therapy (WAT) comparing outcomes in acute and chronic groups of incomplete SCI patients receiving robotic assisted treadmill therapy, and (4) longitudinal monitoring of the natural progress of recovery in incomplete SCI subjects using motor tests for the lower extremity to investigate strength and coordination.

Sweat production and the sympathetic skin response: improving the clinical assessment of autonomic function.

The aim of this project was to establish the relationship between sweat production and the electrodermal events comprising the sympathetic skin response to arousal stimuli. A series of randomly timed magnetic stimuli were applied to the neck of healthy human volunteers. Sympathetic skin responses and the associated sweat responses were recorded from the palms of both hands. Sympathetic skin responses typically had a biphasic shape consisting of a negative initial potential (palm relative to dorsum of hand) followed by a positive deflection. Sweat production was positively correlated with amplitude of the second positive deflection of the sympathetic skin response and negatively correlated with the amplitude of the initial negative deflection. For subjects showing only an initial negative sympathetic skin response, sweat release was low or not detectable. During habituation, the negative initial wave increased relative to the second positive wave, and sweat production fell. The strong correlation between the positive wave of the sympathetic skin response and sweat production suggests that the former may provide a quantitative functional measure of sudomotor activity in situations when it is impractical to measure the amount of sweat produced in the startle response. Thus, the positive component of the biphasic sympathetic skin response may be employed in clinical assessment of the functional efficacy of the sympathetic sudomotor system.

Spinal projection of spindle afferents of the longissimus lumborum muscles of the cat.

The connections and monosynaptic projections of muscle spindle afferents of individual heads of the longissimus lumborum have been studied in cats by natural stimulation, by electrical stimulation and by spike-triggered averaging from single identified afferents. The spindle afferents were classified by sensitivity to vibration and by the effect of succinylcholine on their response to ramp-and-hold muscle stretches. Axonal conduction and synaptic effects were recorded as field potentials and focal synaptic potentials during systematic exploration of the spinal cord in segments L1 to L4 with extracellular metal microelectrodes, singly and in linear arrays. Ascending branches of afferent axons within the cord had a significantly higher mean conduction velocity (CV: 56.5 m s(-1)) than descending branches (40.8 m s(-1)). The CV of ascending branches was significantly positively correlated with a measure of the strength of intrafusal bag(2) muscle fibre contacts, but not to a measure of bag(1) contacts. Two sites of monosynaptic excitatory projection in the cord were identified, namely to the intermediate region (laminae V, VI and VII) and to ventral horn region (laminae VIII and IX). In tests of 154 single afferents, signs of central projection were detected for 60, providing 122 regions of maximum negative focal synaptic potentials (FSPs) of mean amplitude 7.51 microV. Their longitudinal spacing indicated that axons gave off descending collaterals at intervals of 1.5-3.5 mm. Based on the amplitude of FSPs, the projection of secondary afferents is stronger than that of primaries in the intermediate region and possibly also in the ventral horn region. Evidence is also presented that spindle afferent input from different heads of the longissimus converges into any given spinal segment and that input in one spinal root projects to adjacent segments. It is concluded that the organization of the longissimus monosynaptic spindle input favours relatively tonic and diffuse stretch reflexes.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials.

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to 18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.