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Spinal Cord (2007) 45, 206–221 & 2007 International Spinal Cord Society All rights reserved 1362-4393/07 $30.00 Guidelines for the conduct of clinical trials for spinal cord injury (SCI)as developed by the ICCP panel: clinical trial outcome measures JD Steeves*,1, D Lammertse2, A Curt1, JW Fawcett3, MH Tuszynski4, JF Ditunno5, PH Ellaway6, MG Fehlings7,JD Guest8, N Kleitman9, PF Bartlett10, AR Blight11, V Dietz12, BH Dobkin13, R Grossman14, D Short15,M Nakamura16, WP Coleman17, M Gaviria18 and A Privat18 1ICORD, University of British Columbia (UBC) and Vancouver Coastal Health (VCH) Research Institute, Vancouver,BC, Canada; 2Craig Hospital, Englewood, CO, USA; 3Cambridge University Centre for Brain Repair, Robinson Way,Cambridge, UK; 4Center for Neural Repair, University of California at San Diego, La Jolla, CA, USA; 5JeﬀersonMedical College, Thomas Jeﬀerson University, Philadelphia, PA, USA; 6Department of Movement and Balance,Division of Neuroscience and Mental Health, Imperial College London, Charing Cross Campus, London, UK; 7University of Toronto, Krembil Neuroscience Center, Head Spine and Spinal Cord Injury Program, Toronto WesternHospital, Toronto, Ontario, Canada; 8Department of Neurological Surgery and the Miami Project to Cure Paralysis,Lois Pope LIFE Center, Miami, FL, USA; 9National Institute of Neurological Disorders and Stroke, NIH, Bethesda,MD, USA; 10Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; 11AcordaTherapeutics, Hawthorne, NY, USA; 12Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland; 13Department of Neurology, University of California Los Angeles, Geﬀen School of Medicine, Neurologic Rehabilitationand Research Program, Los Angeles, CA, USA; 14Baylor College of Medicine, Department of Neurosurgery, OneBaylor Plaza, Houston, TX, USA; 15Midlands Centre for Spinal Injuries, Robert Jones and Agnes Hunt Orthopaedicand District Hospital NHS Trust, Oswestry, Shropshire, UK; 16Department of Orthopaedic Surgery, Keio University,School of Medicine, Tokyo, Japan; 17WPCMath, Buﬀalo, NY, USA; 18Institut des Neurosciences – CHU St Eloi,INSERM U-583, Montpellier, France 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 fourpapers. It examines clinical trial end points that have been used previously, reviews alternativeoutcome tools and identiﬁes unmet needs for demonstrating the eﬃcacy of an experimentalintervention after SCI. The panel focused on outcome measures that are relevant to clinicaltrials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are ofthree main classes: (1) those that provide an anatomical or neurological assessment for theconnectivity of the spinal cord, (2) those that categorize a subject's functional ability to engagein activities of daily living, and (3) those that measure an individual's quality of life (QoL). TheAmerican Spinal Injury Association impairment scale forms the standard basis for measuringneurologic outcomes. Various electrophysiological measures and imaging tools are indevelopment, which may provide more precise information on functional changes followingtreatment and/or the therapeutic action of experimental agents. When compared to appropriatecontrols, an improved functional outcome, in response to an experimental treatment, is thenecessary goal of a clinical trial program. Several new functional outcome tools are beingdeveloped for measuring an individual's ability to engage in activities of daily living. Suchclinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measuresoften do not correlate tightly with the above outcome tools, but may need to form part of Phase3 trial measures.
Spinal Cord (2007) 45, 206–221. doi:10.1038/sj.sc.3102008; published online 19 December 2006 Keywords: spinal cord injury; clinical trial; neurologic assessment; outcome measures; functional recovery *Correspondence: J Steeves, ICORD, University of British Columbia The second International Campaign for Cures of spinal (UBC) and Vancouver Coastal Health (VCH) Research Institute, c/o2469-6270 University Boulevard, Vancouver, BC, Canada V6T 1Z4 cord injury Paralysis (ICCP) Clinical Guidelines Panel SCI trial guidelines 2JD Steeves et al meeting focused on the outcome measures to be used Spinal Injury Association (ASIA) scale would be during spinal cord injury (SCI) clinical trials for the an example of such an assessment. This would also evaluation of a therapeutic intervention. Given the small include assessments of neurological capacity that are number of clinical trials that have been undertaken for independent of the environment (eg electrophysio- SCI, it is not surprising that until now there has been logical recordings or imaging assessments). If these little opportunity to develop agreement as to the most outcome tools can be shown to accurately predict appropriate and accurate clinical end points (ie outcome the long-term functional beneﬁts (clinical endpoints) measures) for demonstrating the eﬃcacy of an experi- resulting from a therapeutic intervention, they can mental therapeutic intervention.1 The various possible also be thought of as surrogate end points.
outcome measures with their advantages and disadvan- (b) Assessments of the abilities of a patient with SCI tages are reviewed in this article.
to perform activities associated with everyday life.
Examples would be the Functional IndependenceMeasure (FIM) and the Spinal Cord Independence Challenges for assessing SCI outcomes or beneﬁts of Measure (SCIM). Functional evaluations may be a more direct measurement of a clinically meaningful In terms of designing a speciﬁc SCI clinical trial with the change in the functional capacity of a study subject, most accurate assessment of neurological or functional but the changes in functional outcomes may not outcome, a consideration of the following issues is always be the result of a demonstrated change in spinal–neurological activity or connectivity. Inshort, any change in a person's functional capacityafter SCI may be due to adaptive changes (or Phase of clinical trial, as primary and secondary plasticity) within and/or without the central nervous outcome measures and thresholds are likely to diﬀer system (CNS), including environmental accommo- or evolve from Phase 1 (safety) to Phase 3 (therapeutic dations and/or alternative compensatory strategies.
(c) Assessments of an individual's level of participation Level of spinal injury, including the extent of the zone in societal activities. Quality of life (QoL) can be of partial preservation (ZPP).
deﬁned as a person's perception of his position in Severity of spinal injury (varying degrees of incom- life, within the context of both his personal and plete to complete sensorimotor loss).
society's values and culture, and relate to his Time since injury (early acute to late chronic; ie from personal concerns, standards and goals. The short unstable to more stable functional capacities after SCI) form 12- or 36-item medical outcomes health survey Appropriate nature of outcome measure to the (SF-12 and SF-36) are examples of a QoL survey.
capacity or capability being evaluated (eg sensori-motor impairment, autonomic function, personal Improvement of functional abilities, reﬂected in functional capacity, performance, or community activities of daily living (see above) will be the most participation). Diﬀerent clinical targets normally meaningful and valued outcomes. However, the early require distinct outcome assessment tools.
phase clinical trials (Phase 1 and 2) that have been Sensitivity of outcome measure (ie detection threshold).
completed to date (using pharmaceutical therapeutics), Accuracy and validation of outcome assessment tool.
have focused on assessment of neurological connectivity Reliability of measurements between assessments by to provide ‘proof of principle' measures. It is likely that a single investigator and between investigators (ie neurological assessments will continue to be used as intra- and inter-rater reliability).
primary outcome measures, indicating the likelihood Feasibility for using selected outcome measurement that a treatment will improve the functional capacities tools in a particular center or across multiple centers.
and performance of a subject in later phases of clinical Adoption of standardized outcome assessment proce- studies. However, no experimental intervention will be dures and data sets across multiple trial centers.
considered eﬀective for the treatment of people livingwith SCI unless it improves their ability to function and We will discuss these and other inﬂuences as they engage in everyday life within their society. Outcome impact the selection of outcome measures for SCI assessment tools that accurately and sensitively demon- clinical trials.
strate such beneﬁts will need to be incorporated into themore deﬁnitive and conﬁrmatory Phase 3 clinical trials.
Categories of outcome assessments Clinical trial phases and corresponding categories Assessment methodologies for evaluating a clinical endpoint for an SCI trial fall into three main categories: of outcome measures (a) Assessments aimed at describing the neurological The objectives of Phase 1 trials can be quite varied, from connectivity of the spinal cord, irrespective of the the initial exploration of tolerability, through study of ability of the patient to functionally use those human pharmacokinetics and metabolism, to identiﬁca- connections in everyday activity. The American tion of the maximum safely tolerated dose of a SCI trial guidelines 2 candidate therapeutic (see also Lammertse et al2). A deterioration, as well as to subsequently track any Phase 1 trial is speciﬁcally designed to evaluate the changes in the ASIA score. An improvement in ASIA safety of the intervention and expose any adverse or scores is a possibility during a Phase 1 trial, indicating toxic side eﬀects, usually in small numbers of subjects possible eﬃcacy of the treatment, but this is not the with a simple open label design. Participant's who primary reason for including an ASIA assessment at this choose to take part in a Phase I trial may experience stage of clinical study. An ASIA assessment, just before signiﬁcant risks with a limited probability of receiving randomization of a subject to a clinical trial study arm, individual beneﬁt. Preliminary Phase 2 (proof of concept can be most useful to assure that the candidate meets all or evidence of activity) data are sometimes collected inclusion criteria and whether the participating subjects during a Phase 1 trial, but only to develop a preliminary should be stratiﬁed (into a sub-category) on the basis of sense of potential eﬃcacy and to assist in the identiﬁca- their ASIA score, so only appropriately matched tion of appropriate outcome measures to be used in experimental and control subjects are compared there- subsequent properly powered Phase 2 or 3 trials. Many of the currently conceived therapeutics for the possible Inclusion of ongoing standardized ASIA assessments treatment of SCI involve an invasive intervention, such is warranted on the grounds that this examination: (1) as the direct infusion of a drug or cellular transplant has been widely adopted throughout the world, enabling into, or around the injured spinal cord. As a conse- the comparison of data between centers, (2) can be quence, healthy volunteers (without SCI) are unlikely to readily undertaken with a minimum of equipment, and be recruited for a Phase 1 SCI clinical trial of this type.
(3) can provide important reference data between SCI is a heterogeneous disorder in terms of level of diﬀerent phases of a clinical trial or with previous trial spinal injury, severity of injury and timing of treatments (historical) data. In several previous randomized control after injury. Some types of SCI (eg central cord trials (RCT),4–8 motor and sensory assessments, com- syndrome and cauda equina injuries) have higher parable with the current ASIA standards have been used spontaneous rates of overall sensory and motor as an overall indicator of the general severity of recovery. Thus, they may not be the best subjects to neurological impairment after SCI (especially in terms be included with other types of traumatic SCI during of segmental motor function, see below).
a Phase 1 or Phase 2 trial, as they could increase Later in this document, we will discuss when and how the variability of the outcome data. They may also be often an ASIA assessment should be undertaken, the inappropriate, based on the proposed mechanism of strengths and limitations of the ASIA examination, the action for the experimental intervention.
separation of upper and lower limb ratings, as well as Patients with complete ASIA A thoracic injuries are the intra- and inter-rater reliability of the ASIA frequently suggested as being the ‘preferred' group of assessment (see below).
SCI participants for early phase SCI clinical trials. Byconﬁning the administration of the experimental ther-apeutic to the thoracic cord, it is probable that any adverse eﬀects on spinal function would not seriously During a Phase 2 study (sometimes referred to as the alter a person's functional capabilities (ie not spread to Proof of Concept level), an exploratory evaluation of more rostral cervical levels and compromise arm, hand eﬃcacy becomes more prominent, with the objective or respiratory function). Complete ASIA A, thoracic- of determining potential eﬀect size and variability of an injured patients are a small proportion of total SCI experimental therapy in comparison to a useful control cases, and there are, as yet, no validated outcome group. Information is gained regarding choice of measures for changes in thoracic cord motor function optimal end points for a larger Phase 3 conﬁrmatory (although some are under development, see below).
trial of eﬃcacy. During a Phase 2 trial, additional Sensory function can be evaluated using the ASIA information is also obtained regarding safety. Combined examination or other measures.
Phase 1/2 trials, where safety and bioactivity of the General Phase 1 trial safety outcome measures therapeutic are evaluated together can often occur when include: ongoing assessment of standard vital signs, the Phase 1 trial does not involve healthy subjects and physical examination data (eg temperature, respiration, is restricted to people having the clinical disorder. It is heart rate, and blood pressure), clinical laboratory tests possible for SCI clinical trials to be designed in this (eg hematology and urine analysis), as well as the manner. Nevertheless, the data from such a combined appearance of any systemic adverse event (observed or Phase 1/2 trial must be able to satisfy the essential reported by a trial subject). Depending on the ther- outcome end points for each respective trial phase.
apeutic drug or cell line being evaluated and the route of The preferred Phase 2 design would be a RCT where administration, other Phase 1 safety outcome measures each participant is recruited prospectively and randomly may include the evaluation of unintended eﬀects on the assigned to either the experimental or control arm of the CNS or other body tissues, including infection, inﬂam- study and where the investigators and, if at all possible mation, or immune reactions.
the participants, are blinded to which study arm they A more speciﬁc measure of neurological state is the have been assigned. If available, Phase 2 trials could ASIA assessment3 to determine whether there is any employ surrogate end points, which are expected to be change in neurological level or any sensorimotor predictors of functional improvement, to estimate SCI trial guidelines 2JD Steeves et al presumed eﬀective doses, and to allow trials of shorter In the absence of a more sensitive and accurate outcome duration and smaller size to be conducted.
tool, such ASIA assessments enable any initial detri-ments or beneﬁts to be identiﬁed and followed.
The Panel strongly recommends that ASIA assessors undergo standardized training with an intra- and inter- Phase 3 (therapeutic conﬁrmatory) trials are generally rater reliability test being completed at the end of the the deﬁnitive clinical trial phase and typically under- training session. Follow-up training of the same taken as a RCT. The object is to conﬁrm the preliminary examiners should be undertaken at reasonable intervals evidence obtained at the Phase 2 stage with a statistically (eg every 6–12 months) by the same qualiﬁed trainers.
signiﬁcant clinical beneﬁt of the therapeutic in a wider This is especially important when it is necessary to group of subjects across multiple study centers. For a undertake the clinical trial at more than one site.
more detailed discussion of Phase 3 and Phase 4trial Although the ASIA assessment paradigm seems simple stages, see accompanying article – SCI Guidelines 4 in its description, experience has indicated that rigorous (Lammertse et al2).
adherence to the deﬁnitions, based on training, is SCI therapies conceived as early interventions or necessary to obtain consistent data that can be mean- acute stage treatments are likely to be administered ingfully compared both within and across clinical within days of spinal injury and it is important that the studies or centers.
outcome tools have the ability to accurately and Previous SCI clinical trial experience4–8 suggests that sensitively track meaningful changes across a broad requiring the improvement of one or two ASIA grades chronological timeframe. Several assessment tools are over and above spontaneous recovery (eg ASIA B to available or are being developed, each with their ASIA C or ASIA D), as a primary outcome end point individual strengths and limitations. We will discuss (to document the beneﬁt of a therapeutic intervention), each separately.
may be too demanding a threshold (ie is a relativelyinsensitive measure for a therapeutic eﬀect). A candidate ASIA impairment scale therapeutic with a very large eﬀect size could beaddressed with such a challenging clinical point.
However, an intervention with a potentially smaller As mentioned above, the ASIA Impairment Scale has eﬀect size might require a more sensitive outcome become a standardized and routinely adopted classiﬁca- measure, such as a statistically signiﬁcant change in tion for most patients suspected of suﬀering a SCI.3 It ASIA motor score.
is especially useful for classiﬁcation of motor-completeand sensory-complete SCI (ASIA A) as well as motor-complete, sensory-incomplete SCI (ASIA B). During the acute stages of SCI, there have been concerns about how In many respects, the ASIA motor score is considered more soon after injury the ASIA examination can provide reliable than the ASIA sensory score in predicting useful prognostic information about the eventual degree functional outcome after SCI.12 The Panel recommends of impairment. It has been argued that an ASIA that upper and lower limb motor scores should be assessment within the ﬁrst 24h may not provide an compiled separately as the upper-extremity motor score accurate prognosis and that a later 72 h examination is (UEMS) and lower-extremity motor score (LEMS). This a more reliable indicator, as the patient is medically enables a change in motor function to be more clearly more stable.9–11 At chronic time points (greater than tracked and recorded as speciﬁc to either the cervical or 12 months after SCI), the ASIA assessment may not lumbar levels (Table 1). Separation of the motor scores into capture the most important aspects of functional UEMS and LEMS also reduces the inﬂuence that a large changes after SCI. Nevertheless, it is still valuable for change in the functional strength in one or a few muscles classifying and stratifying participants for a clinical trial.
might have on the interpretation of therapeutic beneﬁt.
Functional tests (see below) are perhaps more useful In general, establishing a functionally meaningful primary outcome tools for chronic studies.
ASIA motor score threshold to document the beneﬁt of Regardless of these concerns, it is essential that steps a therapeutic intervention is dependent both on the level should be taken to standardize and optimize the and severity of the SCI,13 as well as the degree of accuracy of the ASIA assessment. For all patients being spontaneous recovery after SCI with conventional considered for entry into a trial, the clinical trial treatment (Table 2 and Fawcett et al11). As shown in center(s) must conduct an independent and blind ASIA Table 2, previous studies have indicated that a low- assessment, just before randomization to the therapeutic cervical, ASIA A-injured patient is likely to sponta- intervention or relevant control treatment. Subsequent neously improve about 10 ASIA motor points during follow-up ASIA assessments should also be undertaken the ﬁrst year after SCI.7,8,14,15 Thus, to demonstrate the at relevant time points over the course of recovery, as eﬃcacy of a therapeutic intervention, a response deﬁned for that trial (eg ﬁrst few weeks, ﬁrst couple of to treatment of an additional 10-point improvement in months, and then at ﬁxed intervals, every few months, the ASIA motor score (eﬃcacy threshold now being throughout the duration of the study) in the same 20 point) might be considered a valid primary outcome blinded fashion, and preferably by the same examiner.
end point (cf Fawcett et al11).
SCI trial guidelines 2 Key muscles used for ASIA motor score assessment, with muscle grades categorizing functional assessment of each muscle's contraction Key muscles for ASIA motor score assessment and primary level of spinal innervation Elbow ﬂexors (biceps brachialis) – C5 Wrist extensors (extensor carpi radialis longus and brevis) – C6 Elbow extensor (triceps) – C7 Finger ﬂexors (ﬂexor digitorum profundus, middle ﬁnger) – C8 Finger abductors (abductor digiti minimi, little ﬁnger) – T1 Upper Extremity Motor Score (UEMS) Hip ﬂexors (iliopsoas) – L2 Knee extensors (quadriceps) – L3 Ankle dorsiﬂexors (tibialis anterior) – L45 Long toe extensors (extensor hallucis longus) – L5 Ankle plantar ﬂexors (gastrocnemius, soleus) – S1 Lower Extremity Motor Score (LEMS) Total ASIA motor score ( ¼ 100 for both sides) ASIA muscle grades: 0 ¼ total paralysis; 1 ¼ palpable or visible contraction; 2 ¼ active movement, gravity eliminated; 3 ¼ activemovement, against gravity; 4 ¼ active movement, against some resistance; 5 ¼ active movement Spontaneous' improvement in ASIA motor scores for complete and incomplete cervical SCI at 1 year Initial ASIA classiﬁcation of Geisler et al.
Marino et al.
Waters et al.
cervical-level SCI 12.3713.7 (n ¼ 264) 9.6712.7 (n ¼ 808) 14+18.8 (n ¼ 61) 37.1727.8 (n ¼ 88) 28.2725.6 (n ¼ 242) 32.0+22.3 (n ¼ 12) 43.0720.4(n ¼ 295) 51.9718.1 (n ¼ 105) 25.7+20.1 (n ¼ 215) Diﬀerent eﬃcacy thresholds would need to be after SCI for people with ASIA C and D classiﬁcations speciﬁed for a response at each level and severity of (Table 2), which is on top of their initial ASIA motor SCI. For example, the spontaneous recovery of ASIA B score. Thus, an ASIA motor score ‘ceiling eﬀect' may cervical patients, 1 year after a cervical SCI, has been make it diﬃcult to discriminate a statistical diﬀerence reported to be about 30 motor points (Table 2), and thus between the ASIA motor scores of SCI participants in might require an additional 20 point improvement to the experimental and control arms of a study. In short, indicate a clinically meaningful beneﬁt for an interven- the spontaneous ASIA motor score may become so high tion. Such a threshold would allow demonstration of within the recovery period that a treatment eﬀect will beneﬁt with a reasonable number of trial subjects.
not be detectable. Therefore, a functional test (see However, these requirements could be complicated by a below) may be a more appropriate primary outcome ‘ceiling' in ASIA motor scores. As no ASIA motor score tool for ASIA C and ASIA D trial participants.
is collected between T2 and L1, only a physiological Statistically speaking, the use of ASIA motor scores assessment of motor connectivity could be reliably as a primary outcome end point is perhaps most useful undertaken with the thoracic region (see below). It for SCI subjects initially enrolled in a clinical trial as should be noted that the absolute diﬀerence in the either ASIA A or ASIA B. The obvious drawback for number of ASIA motor points between an experimental ASIA A and ASIA B subjects is that they initially have and appropriately matched control group is not as motor-complete spinal injuries and it may be diﬃcult to important as whether a statistically valid diﬀerence produce or discern a clinically meaningful improvement exists and whether that magnitude of diﬀerence confers in their ASIA motor score.
a clinical beneﬁt (ie an improved functional outcome) to For reasons arising from the underlying physiology the person with SCI.
and the natural history of spontaneous recovery, the Finally, several studies have reported a substantial ASIA motor scores may not always represent a normal, (25–50) motor point improvement over the ﬁrst year bell-shaped curve and this may make normal-theory SCI trial guidelines 2JD Steeves et al statistical procedures like the t-test and analysis of with AIS grade A and fewer patients with grade C are variance incorrect in small samples. As diﬀerent inclu- disproportionately assigned to the test treatment, then sion and exclusion criteria can aﬀect the representation that treatment will appear artiﬁcially of less beneﬁt of these subgroups in the total composition of the study as ASIA grade A subjects will probably always exhibit sample (cf Tuszynski et al16), estimates of the standard the smallest treatment eﬀect, (2) even if the outcome deviation based on one trial may be inaccurate in of the trial is positive, any randomization imbalance predicting the standard deviation in a new trial. In a will provide ammunition for skeptics to ﬁnd post hoc large sample, the number of patients with low or zero rationalizations for disbelieving otherwise sound results, change in the ASIA motor scores, can skew the (3) even if there is no randomization imbalance at all, distribution to the left and leave a large peak. In any there is still the possibility that the test treatment will be case, the changes can still show ‘ceiling' eﬀects in people less eﬀective in certain groups. For example, it is likely with mild SCI.
that the target and functional recovery mechanisms These technical statistical problems suggest why it available in a subject with an ASIA C injury will diﬀer may sometimes be attractive to use a binary (success/ from those in a patient with an ASIA A injury, (4) even failure) criterion as a trial's primary outcome measure, aside from the question of power it may be scientiﬁcally rather than an ordinal variable like the ASIA motor and clinically important at the end of the trial to know score. Although binary variables always have a com- if there are eﬀect diﬀerences among identiﬁable cohorts pletely known, parametric probability distribution that or subgroups, and (5) any result is more scientiﬁcally can be used by statisticians conﬁdently, they are likely to credible if hypothesized in advance than if found ad hoc mask underlying clinical complexities and/or variability.
or post hoc. Therefore, the most important covariates Some reports have expressed the ASIA motor score should be identiﬁed during trial design and included in as the ‘percent deﬁcit recovered.' Although this strategy the primary analysis. Indeed, a major purpose of the has an appealing rationale, it also has a potential current series of papers is to provide designers with danger. It may be that a mild SCI injury, with only a few historical data that can be used in calculations, points in ASIA motor deﬁcit, has a larger chance for sensitivity analyses, and simulations that can help a spontaneous recovery. Thus, this method would allow designer to determine whether a planned trial is likely to mildly injured patients to have disproportionate weight succeed (see Lammertse et al2).
in one direction, whereas patients with severe motor There are three means available to deal with deﬁcit would count heavily in the other direction as they covariates and subgroups: (1) to include them as strata are least likely to improve. The method of presenting the in a block randomization, (2) to model them as explicit ASIA score as the number of motor points changed terms in the trial's single, prospectively speciﬁed from baseline can give more potential weight to the ‘primary eﬃcacy analysis', and (3) to include them in severely spinal injured group (whether you use an prospectively speciﬁed secondary analyses. None of individual baseline or the mean of the subgroup), as these approaches is unrestrictedly useful and trial they have numerically more room to improve. Perhaps designers should probably employ all three.
the best solution might be to use the number of motor Stratiﬁed randomization only protects against rando- points changed, but to compensate by stratifying the mization imbalance, not diﬀerences in eﬀect size. Also, subject population into cohorts or subgroups on the it would be a bad idea to include too many factors as basis of the initial classiﬁcation of ASIA impairment strata, as, if the block size becomes large compared to scale (AIS) severity.
the recruitment at the individual centers, too many Adjusting for baseline diﬀerences has been used, as in incomplete blocks will be left at the end of the trial and the NASCIS III study.6 Simply introducing a baseline this would precisely defeat the purpose.
term in an analysis of covariance may not be suﬃcient, Identifying and restricting the number of study as the amount of correction required may be diﬀerent covariates to a small number normally has the eﬀect for patients with mild, moderate, and severe SCI in a of increasing power (in the overall test, rather than in manner that is not linearly proportional across the range the individual subgroup tests) and therefore decreasing of SCI severity. Also, this introduces a mathematical the necessary number of study subjects (ie sample size).
relation between the outcome variable (the change in In general terms, unexplained variability is reduced ASIA motor score) and the predictor (the initial baseline when individuals are considered within their own more score) that could make the envelope of data points homogeneous subgroup, and this increases statistical depart from the commonly assumed model, where the power. However, if relatively unimportant covariates scatter of the data above and below the regression line are included ‘for completeness,' then statistical tests will has a normal distribution with uniform variance.
exact a penalty and the power will actually be less and The outcome of a trial can depend strongly on its not more. Also, as the number of factors rises, it may mixture of population subgroups and clinical covariates require very considerable skill in analysis and inter- (also see Lammertse et al2). In order to design a clinical pretation to tease out any treatment eﬀect.
trial properly, it is important to recognize and distin- Given the small number of SCI clinical trials guish the diﬀerent questions and problems: (1) as the completed to date, identifying important covariates is natural history (ie spontaneous recovery) is diﬀerent for not yet an exact science (cf Tuszynski et al16). We have diﬀerent SCI severities. For example, if more patients reanalyzed some of the GM-1 trial data and found that SCI trial guidelines 2 baseline AIS is a very strong covariate as is the level of or as a valid outcome measure has long been recognized.
injury (eg cervical or thoraco-lumbar). Certain types of The ordinal 3-point scale for light touch (normal, spinal injuries (eg a suspected central cord or conus abnormal, or absent) is highly variable at diﬀerent injury or one not involving a fracture dislocation) have a assessment times and between ASIA assessors. The prognostic value (usually for a signiﬁcant spontaneous ASIA pin-prick score appears to be the more useful functional recovery). Younger patients with incomplete clinical measure of preserved spinal sensory function (eg injuries recover better than older ones; but younger sacral sparing in people with an ASIA B classiﬁcation), patients tend to be more severely injured so that, on the as well as a predictor for future recovery.19,20 The ASIA whole, their recovery is no better. Other possibilities (use light touch score does not necessarily correlate with of spinal surgery or direct admission to tertiary care) did subsequent sensory functions accurately and does not not have a readily detectable eﬀect in the GM-1 study.7,8 seem to be particularly useful as an SCI clinical trial The ICCP Clinical Guidelines Panel is continuing outcome measure.
to examine the raw data from previous SCI trials todetermine if a valid therapeutic threshold for ASIA Quantitative sensory testing motor scores can be established for diﬀerent levels andseverities of SCI.
Quantitative sensory testing (QST) is emerging as apotential adjunct to the neurological exam in theevaluation of sensory dysfunction after SCI.21–23 Com- Zone of partial preservation monly, QST has used quantitatively controlled thermal Below the most caudal ‘functional' ASIA motor level (warm and cool), mechanical (monoﬁlaments/von Frey (ASIA motor grade of 3, 4, or 5) the ZPP consists of hairs) and vibratory stimuli (eg 100 Hz) with psycho- those myotomes and dermatomes that remain partially physical scaling against established normative values, innervated (Table 1), but at a level that may not be to diﬀerentiate the contributions from small and large functionally meaningful (eg ASIA motor grade of 1 or diameter peripheral sensory aﬀerent projections or 2). The exact numbers of segments, so aﬀected, make up distinguish the contributions of ascending spinal sensory the ZPP. The term is used only when there is a motor- pathways (spinothalamic and dorsal columns, respec- complete spinal injury. As outlined in the preceding tively). QST measures appear to correlate with somato- article,11 it is often diﬃcult to discern the mechanism sensory-evoked potential (SSEP) recordings and with underlying any neurological or functional improvement ASIA sensory scores.
when it occurs within the ZPP; it could be due to central Although further validations of QST techniques are repair (plasticity, sprouting, or regeneration) and/or due required, QST appears to be a more sensitive technique to similar peripheral modiﬁcations, such as peripheral than the ASIA sensory score, but it is a time-consuming sprouting, as some muscles are innervated from multiple evaluation. With repeated measures, QST might be spinal segments.17 considered as a secondary outcome measure of spinal There is little doubt that improved recovery of cord function. Nevertheless, the Panel currently has function within the ZPP can provide new and mean- more conﬁdence in the sensitivity, accuracy, reliability, ingful capabilities for a person with SCI, especially those and reproducibility of motor function tests than in QST, individuals with a cervical level injury. All the same, the primarily because QST can be a lengthy procedure with ZPP can also complicate the accurate interpretation of a number of highly variable stimulation parameters. A therapeutic action because the extent of recovery within recent simple adjunct for the sensory evaluation of SCI, the ZPP can be variable. Spontaneous changes within which overcomes some of the complexities of the QST, the ZPP introduce ‘background noise' into the determi- is the electrical perceptual threshold (EPT) test.24 EPT nation of therapeutic eﬃcacy. There was general supplies a measure of sensory threshold for each agreement that functional changes within the ZPP need dermatome and provides a more quantitative map of to be interpreted with caution.18 Any improvement the level and completeness of SCI, including the in function ascribed to an experimental intervention that is conﬁned to the ﬁrst two segments caudal to thelast functional ASIA motor level may be due to plastic changes within the ZPP rather than to the formationof new spinal connections across the level of injury.
Electrophysiological measurements such as SSEP, elec- Furthermore, there was recognition that in many tromyographic (EMG), and motor-evoked potential previous therapeutic studies clear chronological descrip- (MEP) recordings provide objective data (latencies and tion of ZPP function has been lacking; future trials amplitudes) for assessing spinal conductivity that can be should make provision to clearly describe changes in analyzed by a blinded investigator in the form of truly segments adjacent to the level of spinal injury.
quantitative values, in contrast to measures such as theASIA scores that are a nonlinear ordinal scale.27–31Furthermore, electrophysiological recordings have the ASIA sensory score advantage that they can be performed on comatose or The lack of sophistication of the ASIA sensory score for otherwise unresponsive subjects. EMG recordings are accurately describing preserved sensory levels after SCI useful in the assessment of function, both in response SCI trial guidelines 2JD Steeves et al to voluntary eﬀort or when combined with electrical or autonomic dysreﬂexia, which results in episodes of magnetic stimulation of peripheral nerves (reﬂexes) or uncontrolled hypertension. The recognition and man- motor cortex (ie MEP).
agement of cardiovascular dysfunctions following SCI Complementary to the neurological assessment, a represent challenging clinical issues, as well as important combination of SSEP, MEP and/or EMG measure- therapeutic targets since cardiovascular disorders in the ments provides information about spinal cord function acute and chronic stages of SCI are the cause of death that is not retrievable by other clinical means and may in individuals with SCI.42,43 have additional value in predicting functional out- As sympathetic vasomotor control is disrupted below comes.32,33 Changes in conduction velocity and the the level of a complete sensorimotor SCI lesion, reﬂex magnitude of the compound action potentials, as an vasodilatation owing to local heating of the skin in outcome measure, must be interpreted with caution. An people with chronic SCI is diminished.44 Thus, it has increased conduction velocity may accurately reﬂect a been suggested that assessment of reﬂex vasodilatation remyelination of ﬁber tracts, which could be the targeted may be a useful noninvasive outcome measure to detect aim of a SCI trial, but in itself, may not herald the the preservation of any central autonomic pathways recovery of function or improvement in neurological after SCI and possibly to document any change in spinal condition.34,35 Strong correlations between AIS scores autonomic functions after a therapeutic interven- and electrophysiological measurements are not always evident.36 In general, the Panel felt that electrophysio- Tracking standard vital signs is imperative through- logical measures were most useful when combined with out the entire phase of any clinical trial, especially as the other outcome tools and could be useful in determining inﬂuence of the ANS on any of these measured the mechanism of therapeutic action.37,38 functions is well established. Interestingly, measurementof the sympathetic skin response (SSR) has beensuggested to delineate the level and extent of spinal Assessment of thoracic cord function sympathetic function, as a measure of autonomic Currently, there are no agreed methods for assessing dysfunction.22,32,41,46 It may reveal an incomplete lesion motor levels in the thoracic cord, although sensory levels in terms of autonomic function in cases of complete are assessed during the standard ASIA examination.
motor and sensory injury.47 However, SSR remains This is a signiﬁcant problem for determining the a controversial measure22 of overall spinal function and, potential eﬃcacy of an intervention, given the expecta- if adopted as an outcome measure, should be limited tion that it is safer to perform initial human studies in to testing the eﬃcacy of an intervention on ANS func- patients with a thoracic level injury. The electrophysio- tion and used in conjunction with a number of other logical studies described in recent papers22,39 provide outcome measures. Further development of valid out- methods aimed at detecting changes in motor and come tools for the assessment of ANS function after autonomic function, as well as providing information on SCI is imperative.
the level and completeness of injury to the thoracic cord.
Motor assessments have been developed using transcra- Imaging assessments nial magnetic stimulation to elicit MEPs in paraspinal,intercostal, and abdominal muscles. Quantitative mea- Magnetic resonance imaging (MRI) has become a sures that appear to be promising include: thresholds, cornerstone of radiologic technique to detect the latencies, and recruitment (input/output curves) of location (and to some degree the severity) of an acute MEPs from trunk muscles innervated at diﬀerent SCI, as well as to detect possible complications arising thoracic levels.40 Mechanically evoked reﬂexes, recorded during chronic SCI, such as syringomyelia. At present, as EMGs in paraspinal muscles, also show abnormal- MRI along with computerized axial tomography and ities directly related to the level of spinal injury.40 X-ray images are useful diagnostic tools and potentially In summary, these tests may be used to indicate helpful for screening participants to be included or functional improvement or deterioration following excluded from a clinical trial.
treatment. However, the innervation of trunk muscles MRI has been useful in determining the extent of cord by multiple thoracic spinal levels means that the compression,48–50 outlining hemorrhages and edema resolution of these motor techniques is not as precise after human spinal injury and in the near future, might as might be achieved in the cervical cord. The tests may be useful in monitoring progressive changes in spinal be used to indicate motor level within two or three levels cord tracts, such as demyelination after spinal injury.
(plus or minus).
Indeed, recent data from the Spine Trauma StudyGroup, indicates that the extent of cord compressionand the presence of hemorrhage and cord swelling are Autonomic function testing highly predictive of ASIA motor score outcomes at one, The accurate evaluation of impaired autonomic nervous 1 year post-SCI.50 system (ANS) function after SCI is currently limited. In MRI has also been proposed as a potential SCI addition to the motor and sensory deﬁcits associated assessment tool after a therapeutic intervention, and as with SCI, coincident ANS impairments are common (cf a means of tracking implanted cells. In experimental Claydon et al41). Individuals with SCI often exhibit models of SCI, diﬀusion tensor imaging (DTI) can SCI trial guidelines 2 delineate both disrupted and intact axonal ﬁber tracts Lower limb function within the spinal cord, as well as the orientation of glial For clinical trials involving people with motor-incom- scarring surrounding a spinal lesion.51 With further plete SCI (ASIA C and ASIA D), at acute, subacute, development, MR technologies may develop a useful and chronic SCI stages, several validated tests of ambulatory performance have been developed, includ- accurately predict the long-term functional beneﬁts ing the Walking Index for Spinal Cord Injury (WISCI) of an experimental intervention after SCI (cf Schwartz and a number of timed walking tests.54,55 WISCI is a 21-level hierarchical scale of walking based on physical Nevertheless, MRI is still largely a qualitative assistance, need of braces and devices, with an ordinal measure and quantitative standards, in relation to range from 0 (unable to walk) to 20 (walking without functionally measured SCI outcomes, will need to be assistance for at least 10 m). It is an example of a more developed and validated before MRI can be used as an sensitive and precise scale for rating a speciﬁc functional outcome tool (cf Miller52). It is hoped that MRI and activity in people with incomplete SCI. WISCI is Magnetic Resonance Spectroscopy technologies will currently a valid outcome measure for strategies directed rapidly mature, with more sophisticated algorithms to improve ambulation by subjects with incomplete (including DTI and functional MRI), such that imaging will become a valuable non-invasive assessment tool.
Although the WISCI has been validated as a qualitative outcome measure for the assessment ofstanding and walking after incomplete SCI, the opinion of the ICCP Clinical Guidelines Panel is that a moreaccurate assessment may be provided by a combination General considerations of WISCI and some of the more quantitative timed For chronic SCI studies (greater than 12 months after walking tests. Such quantitative walking tests include initial SCI), ASIA assessments may not be a suﬃcient the timed up and go, time taken for a 10-min walk test tool as an outcome measure, especially for studies on (10 MWT) or one of the many similar variants (25, 30 ft, incomplete SCI where the ASIA motor score is likely to 8 m) and the distance traversed during a 6-min walk be substantial and highly variable between individuals.
test.55 There may be some redundancy between tests like Nevertheless, an ASIA assessment, before randomiza- the 10 MWT and the 6-min walk and it may be tion, is valuable for classifying and stratifying partici- pragmatically easier to undertake a short timed walk pants in a clinical trial. At acute and sub-acute stages test as the more routine walking assessment, especially after SCI, the value of functional outcome tools is less in trials that involve centers, which may not have clear, especially for motor-complete SCI (ASIA A and adequate facilities for measurement of longer duration ASIA B), which are likely to be the initial subjects in early Phase trials. If the expected therapeutic beneﬁtis modest, a dramatic improvement in functionalperformance may not be readily evident. Nevertheless, Upper limb function functional outcome assessments should be undertaken The number of people surviving with a cervical level as a secondary outcome measure.
spinal injury has risen dramatically over the past few There was agreement from the ICCP Clinical Guide- decades and cervical SCI now accounts for approxi- lines Panel that an improvement in the measurable mately 50% of all people living with a SCI. Thus, performance of meaningful function is necessary for any validating a functional outcome tool to assess arm and therapeutic intervention to be universally accepted as hand capacity after a cervical spinal injury was identiﬁed beneﬁcial (for a review, see Ditunno et al53). The World as a top priority by the Panel.
Health Organisation (WHO), speciﬁcally the Interna- At the present time, there is a lack of agreement on tional Classiﬁcation of Functioning, Disability and what might be the most useful test of arm and hand Health (or ICF), has rigorously deﬁned function function after SCI (for a review, see van Tuijl et al56).
and impairment, as well as activities of life and disability Many of the scales developed have been deemed too (see below). ICF-1 is a health sphere of inﬂuence insensitive to track small, but potentially meaningful functional gains. The majority of tests have been things, body functions and structures, activities and developed within the domains of stroke or hand surgery, participation. In short, reduced function in a body but less often to describe the impairment and course of structure can result in diﬃculty executing an activity of hand function recovery after SCI, particularly for acute daily living.
tetraplegic patients. Many previous studies examined ICF complements the WHO's International Classiﬁ- tetraplegics after functional reconstructive surgery of the cation of Diseases (ICD; eg latest version is ICD-10) and upper limb or application of a hand neuroprosthesis and is currently being reviewed for the next iteration, ICF-2.
did not provide randomized control data.
ICF is useful to understand and measure functional It is generally accepted that the assessment of hand outcomes after SCI and all clinical researchers are function has to include several components including: encouraged to become familiar with these classiﬁcations (1) proximal arm and trunk stabilization (reaching out), and deﬁnitions (http://www3.who.int/icf/).
as well as placement of the arm and hand, (2) sensory SCI trial guidelines 2JD Steeves et al testing of at least two sensory qualities (touch sensation, Comprehensive functional outcome tools vibration, temperature, two-point discrimination, pro- The FIM was ﬁrst developed in the 1980s (cf Stineman prioception), (3) manual muscle testing of intrinsic et al63). The FIM is a proprietary global disability (small hand muscles) and extrinsic muscles (forearm) outcome assessment tool, which has been used for rating involved in hand control, (4) description of diﬀerent the functional performance of individuals, with a variety grasp forms (like pulp and lateral pinch), and (5) the of diﬀerent disorders and disabilities, on a series of eﬀect of tenodesis on hand function, speciﬁcally for ADL. It has been used as the functional outcome opening and closing of ﬁngers and the ﬁst.
measure in many trials, such as the NASCIS III clinical The Quadriplegia Index of Function (QIF) was trial.6 Because of its application to a broad range of developed in the 1980s57 as a scale for evaluating 10 disabilities, it has become a standard tool for decisions areas of self-care and mobility for people living with on support and reimbursement as a person re-integrates tetraplegia. The QIF has been noted to be a better back into their home community (ie it has been called indicator of motor recovery than the FIM (when a ‘burden of care' tool). For the purposes of SCI clinical compared with ASIA motor scores) and a more sensitive trials, some of the FIM subsections are not directly measure of small gains in arm function.58,59 relevant to people living with SCI (eg communication One of the more established hand function assessment and social cognition) and FIM scores, and ASIA motor tools is the Sollerman test60 although the test was not scores are not tightly correlated.58,59 developed for SCI. The Sollerman test has limited A more recently developed functional measure is the resolution for hand function in tetraplegics, requires Spinal Cord Independence Measure (SCIM) and it specialized equipment, and is a long duration examina- appears to be a more sensitive and accurate functional tion (60–90 min). Another common test is the Manual assessment for ADL after SCI. SCIM has now gone Muscle Test, which has been used to evaluate handgrip through a few iterations64–66 and is undergoing further strength, although it has been criticized as not sensitive reﬁnement in multinational studies. The SCIM is a 100- enough to distinguish small or moderate changes in point disability scale developed speciﬁcally for SCI with human subjects.61 emphasis on 18 activities associated with: The Action Research Arm Test looks at diﬀerent types of pinches and provides a qualitative scoring, but 1. self-care (feeding, bathing, dressing, grooming), has been mainly applied in stroke patients. The Jebsen max. ¼ 20 points (Taylor test) is most frequently used in stroke and 2. respiration and sphincter management (ventilation, includes writing, lifting cans, simulated feeding, stacking bladder, bowel, use of toilet), max. ¼ 40 points checkers, and picking up paper clips and coins.
(clinically weighted) However, it does not detect changes of intrinsic muscles 3. mobility (in bed, transfers, indoors and outdoors, and allows compensatory trunk and shoulder move- wheelchair, walking), max. ¼ 40 points.
ments to accomplish any tasks.
Preliminary ﬁndings suggest that the SCIM may be a Other upper limb outcome assessment tools have more relevant and a useful outcome tool for SCI clinical recently been introduced. As an example, there is the trials than the FIM. However, the well-established motor capacities scale (MCS).62 This scale was devel- nature of FIM may slow the adoption of SCIM. It oped and tested in France with the participation of 52 may be too much to expect that one comprehensive motor-complete C5–C7 tetraplegics, although some had functional outcome tool will accurately and sensitively received restorative upper limb surgery. The MCS track all SCI clinically meaningful beneﬁts after a initially involved 36 items associated with activities of therapeutic intervention; a number of functional out- daily living (ADL), including: transfers, repositioning in come measures may be required initially.
a prone and seated position, use and control of eithera manual or powered wheelchair, bilateral reaching to apredetermined target, and bilateral hand grasping. High inter-rater reliability (correlation coeﬃcient of 0.99) was QoL assessments for people with SCI have been noted for the MCS, as was a high correlation with the intensely debated as clinical trial endpoint tools (cf Sollerman test (correlation coeﬃcient of 0.96). Initial Dijkers et al67). The inclusion of a QoL assessment is correlation with ASIA motor scores was lower (0.74).
often recommended as one outcome measure to be Because of redundancies, this list has now been reduced included in any clinical trial assessment, though often as to 31 items associated with ADL. The MCS is under- a secondary outcome. WHO deﬁnes QoL as a person's going further testing and validation.
perception of his position in life within the context of the A Toronto group recently developed the Tetraplegia culture and value systems in which he lives and in Hand Measure, which combines a modiﬁed Sollerman test relation to his goals, standards, and concerns. As with quantitative assessments of sensory function. A outlined above, WHO published the ICF in 2002 with Zurich group developed a hand function test, which also three distinctive dimensions: uses certain key elements of the Sollerman test. Aninitiative is now underway across Canada, the UnitedStates, and Europe to develop an integrated hand function 1. body structure and function/impairment at organ test as a valid assessment tool for SCI clinical trials.
SCI trial guidelines 2 2. activity/activity limitation at personal level functional limb movement and in its more severe forms 3. participation/restriction at societal level.
may result in chronic pain, muscle contracture, andpermanent muscle shortening. Several treatments have Several QoL surveys have been developed, along two been developed to minimize spastic symptoms, including paths, and are illustrated by the two following examples: systemic or intrathecal Lioresal (Baclofen) and (morerecently) the direct intramuscular injections of Botuli- 1. SF-36 (Medical Outcomes Study 36-item Short Form num toxin (Botox) into speciﬁc aﬀected muscles.
health survey) is a proﬁle where the investigator The level of spasticity is known to vary over time, thus determines the domains of life that are pertinent and a single clinical assessment will not necessarily reﬂect the assumption is that the same domains are accurately an individual's overall level of spasticity. The important to all people in that group. SF-36 reﬂects principal clinical outcome measure for spasticity has the perspective and choices made by the ‘outsider' been the long-established Ashworth Scale or the (investigator) rather than the subjective point of view modiﬁed Ashworth Scale, even though both scales have of the ‘insider' (subject).
less than ideal inter-rater reliability71 and have a poor 2. SWLS (satisfaction with life survey) is an example of correlation with self-rated assessments of spasticity.70 an alternate self-reported appraisal, where statements The scale determines the amount of resistance felt (eg I am satisﬁed with my life) are rated on a 7-point during the passive displacement of a limb, but it does Likert-type scale (ranging from ‘strongly disagree' to not accurately account for the dependence of the ‘strongly agree'). SWLS is an example of a more resistance to the velocity of the stretch, which can be global QoL where the individual (insider) is allowed highly variable from examiner to examiner.
to either adjust the weighting of a domain or in somecases self-nominate a domain as to its relativeimportance on their QoL. This can make compar- isons between subjects or between study armsdiﬃcult.
It has been suggested that over 50% of people livingwith SCI reported experiences of chronic neuropathic Thus, QoL tools are either investigator-determined pain. Agreement on classifying pain (as musculoskeletal, (eg SF-36), enabling statistical comparisons between an neuropathic, or visceral forms) after SCI has been experimental and control group or they are more elusive, but the classiﬁcation of Siddall et al72 has been individualized (eg SWLS), allowing the participating widely quoted. Sharp, stabbing, or burning pain within subject to weigh the value (importance) of any the dermatomes at or just above the level of SCI is often individual ﬁeld in the self-assessment of their own QoL.
termed at-level neuropathic pain, whereas similar types In terms of SCI clinical trials of pharmaceutical drugs of pain below the level of the lesion have been called or cell-based transplants, especially during Phase 1 and below-level neuropathic pain.
2, the former type of QoL survey (eg SF-36) is not There are a few RCTs that have evaluated the beneﬁts suitable as a primary outcome measure, and should only of gabapentin73 and lidocaine74 for the treatment of be used in combination with other types of outcome neuropathic pain after SCI (for a review, see Finnerup data (eg ASIA motor scores or a functional outcome and Jensen75). Nevertheless, causing pain as a result of measure). Which precise QoL survey is best suited to an experimental treatment is also a major concern, a speciﬁc SCI trial has not been determined. It may be especially as some of the emerging therapeutics have the advisable to use more than one type of assessment.
potential to stimulate axonal ﬁber outgrowth or func- The concern of the Panel was that any choice made by tional plasticity within central pain pathways. Thus, the a subject during a QoL survey might accurately relate to Panel felt that inclusion of speciﬁc pain measures would a change in QoL, but be unrelated to an observable be an important component of SCI therapeutics' change in neurological impairment or functional capa- outcome testing. The most straightforward assessment city. Likewise, a small but signiﬁcant improvement in would rely on patient's self-reports of any increased pain neurological function might not inﬂuence the responses during treatment. Several tools have been developed, on a QoL survey. The consensus of the Panel was that including the visual analogue scale76 and the neuro- changes in neurological function or functional outcomes pathic pain scale77 Nevertheless, these may not always should be used as the primary measure for Phase 1 or provide an accurate reﬂection of neuropathic pain, 2 SCI clinical trials that evaluate the activity of a especially as an individual's emotional health and/or pharmaceutical or cell-based transplant intervention.
social interactions can modify pain perception.
In an acute or subacute situation, the source of an individual's pain may be diﬃcult to locate or originate outside the CNS pain sphere (eg result from concomi- A velocity-dependent, abnormal increase in muscle tone tant injury to another body tissue or due to a preceding with exaggerated tendon jerks is one deﬁnition of condition). Clinical trials may want to consider a more spasticity,68 which is a common complication of SCI direct measure for a change in central pain threshold.
and a variety of other CNS disorders.69,70 Spasticity can For example, components of the QST and/or EPT may lead to incoordination of muscle action, reduced be useful evaluations (cf Savic et al25, Savic et al26).
SCI trial guidelines 2JD Steeves et al There are many pain perception surveys available, Valid and clinically meaningful sensory assessment including the well-known McGill pain questionnaire.78 tools for SCI remain a challenge where current However, which pain assessment is the most accurate assessment tools are either inadequate or insuﬃciently and easiest to use is a matter of debate. In more chronic validated. Electrophysiological assessment tools exist SCI situations, pain management is an important and would beneﬁt from broader application and clinical goal. One approach to mapping whether a pain standardization. Such evaluations are currently under- management strategy is having a meaningful beneﬁt is to way. Likewise, there is a need to develop a number of assess how pain intensity interferes with ADL. Two clinically valid autonomic function tests.
common measurement scales of pain interference, the An improvement in the measurable performance of graded chronic pain (GCP) disability scale and three a meaningful function or behavior is necessary for any versions of the brief pain inventory (BPI), have recently therapeutic intervention to be universally accepted as been examined for their reliability and validity as pain clinically beneﬁcial. Thus, accurate and sensitive func- assessment tools in a survey of 127 people living with tional outcome measures are critical to SCI clinical trials chronic pain after SCI.79 The self-report data asked and this will be especially true for any Phase 3 studies.
questions on how pain interfered with ADL. Needless to The FIM scale is not speciﬁc to SCI and not suitable, say, increasing pain intensity caused increased inter- although the recently developed SCIM assessment may ference with ADL. Both GCP and the three diﬀerent be a more speciﬁc and accurate outcome tool for length versions of the BPI were found to be internally detecting clinical end points in SCI. The continued consistent and related to the reported level of pain development and validation of tests that quantify highly relevant behaviors such as walking or hand function are Another issue is to carefully distinguish between most important; such tools may have greater utility for neuropathic and normal musculoskeletal pain. A documenting the subtle beneﬁt of a therapeutic than a therapy that restores some normal pain sensation may more global scale of disability.
make a patient aware of conditions that were previously The inclusion of QoL measures in SCI trials is unfamiliar to the spinal injured individual, such as important, but which precise QoL survey is best suited lower-back pain or other forms of normal, internally to a speciﬁc SCI trial and their importance in the overall referenced visceral pain.
assessment of an intervention has not been determined.
It may be best to use more than one type of assessment.
The concern of the Panel was that any choice made by Summary and recommendations for the future a subject during a QoL survey might be unrelated to an Objective outcome measures are critical in designing observable change in neurological or functional out- useful SCI therapeutic clinical trials. Diﬀerent clinical come. Likewise, a small, but signiﬁcant, improvement in targets (eg sensorimotor tasks, autonomic function, neurological function might not inﬂuence the responses personal functional capacity, performance, or commu- on a QoL survey, which are often governed by attitude nity participation) normally require distinct and appro- and social integration and not by physical disability.
priate outcome assessment tools, which have been Given the paucity of Phase 3 SCI clinical trial validated as both sensitive and accurate.
experiences and thus the emerging nature of SCI clinical The most common outcome assessment tools cur- studies, the current opinion of the Panel was that rently being employed are the ASIA impairment grades changes in neurological function or functional outcomes and ASIA motor scores. The accuracy of initial and should be used as the primary measure for Phase 1 or 2 subsequent ASIA examinations is essential to ascribing SCI clinical trials designed to evaluate the safety and/or a therapeutic beneﬁt in neurological recovery. For provide evidence of activity of a pharmaceutical or cell- example, a candidate drug or cell transplant with a very based transplant intervention. Neurological function large eﬀect size might rely on statistically signiﬁcant tests should remain an element of the outcome assess- diﬀerences in ASIA grades between the experimental ment in Phase 3 trials.
and control arms of an SCI study. However, anintervention with a potentially smaller eﬀect size mighttarget a more speciﬁc and sensitive neurological out- Glossary of deﬁnitions come measure, such as a statistically signiﬁcant diﬀer-ence between experimental and control groups for the (Additional glossaries are included in the three accom- ASIA motor score.
Establishing valid treatment eﬀect thresholds for Neurological level of spinal injury is generally the ASIA motor scores requires calculation of the sponta- lowest segment of the spinal cord with normal sensory neous improvement of ASIA motor scores for each and motor function on both sides of the body. However, severity and level of SCI within ‘untreated' control the spinal level at which normal function is found often populations. Such an initial evaluation is now being diﬀers on each side of the body, as well as in terms of undertaken by the ICCP Clinical Guidelines Panel.
preserved sensory and motor function. Thus, up to four Nevertheless, any ﬁrst table of ASIA motor score diﬀerent segments may be identiﬁed in determining the thresholds will require ongoing monitoring and updat- neurological level and each of these segments is recorded ing to maintain relevance.
separately and a single-level descriptor is not used. Note SCI trial guidelines 2 that the level of spinal column injury may not correlate UEMS is the upper extremity motor score which is a with the neurological level of SCI.
maximal 50-point subset of the ASIA motor score for ASIA (American Spinal Injury Association) Impair- the representative arm and hand muscles.
ment Scale (or AIS) describes the completeness of a Motor level is deﬁned as the most caudal spinal level spinal injury (see Marino et al3). An individual with an as indexed by the key muscle group for that level having ASIA A grade has no motor or sensory function at the a muscle strength of 3 or above while the key muscle for level of S4–S5 sacral segments. ASIA B has some the spinal segment above is normal ( ¼ 5).
sensory function below the neurological level, including ASIA sensory score is calculated by testing a point on S4–S5, but not motor function. ASIA C has some motor the dermatome for each spinal level from C2 to S4–5 for function below the neurological level, but more than both light touch and pin-prick sensation. Each point is half of the key muscles involved have a muscle strength assigned a score from 0 (absent sensation) through 1 score that is less than 3 (Table 1). ASIA D has motor (abnormal sensation) to 2 (normal sensation). This gives function below the neurological level but more than half a possible maximum score of 56 on each side for of the key muscles have a muscle grade of 3 or more.
a maximum total of 112 each for light touch and ASIA E indicates normal motor and sensory function.
Tetraplegia (quadriplegia) is the term used to refer to Sensory level is deﬁned as the spinal segment loss of motor and/or sensory function owing to damage corresponding with the most caudal dermatome having to the spinal cord, with impairment of the upper a normal score of 2/2 for both pin-prick and light touch.
extremities as well as trunk, legs, and pelvic organs.
Zone of partial preservation (ZPP) is only used when This implies damage to the spinal cord at or above the SCI is complete and refers to those segments below the neurological level of injury where there is some Paraplegia is the equivalent term used to refer to preservation of impaired motor or sensory function functional loss below the level of the upper extremities, (usually, but not always, within a few segments of the which may involve loss of motor and/or sensory function within the trunk, and/or the lower extremities.
This implies damage to the spinal cord below the levelof C8 and may include damage to conus medullarisor cauda equine (ie neural tissue within the spinal We are grateful for the support of The International Campaign Complete and incomplete SCI are other terms used to for Cures of spinal cord injury Paralysis (ICCP), which describe the overall severity of SCI. Technically, SCI is provided the funding for the authors' travel and accommoda- classiﬁed as complete if there is no motor or sensory tion expenses. The ICCP represents the following member function preservation in the sacral (most caudal) spinal organizations: Christopher Reeve Foundation (USA), Institut segments. Thus, incomplete SCI is when there is pour la Recherche sur la Moe¨lle Epinie re (FRA), InternationalSpinal Research Trust (UK), Japan Spinal Cord Foundation, some preserved motor or sensory function at the lowest Miami Project to Cure Paralysis (USA), Paralyzed Veterans of sacral spinal level (S4–5). There can be extensive America (USA), Rick Hansen Man In Motion Foundation variability in the degree of preserved function after (CAN), SpinalCure Australia, and Spinal Research Fund of incomplete SCI.
Australia. We thank the European Multicenter study in Spinal ASIA Sensory and Motor Assessments form the basis Cord Injury (EM-SCI) for sharing their data on spontaneous for the International Standards for Neurological and recovery after spinal cord injury. ICORD (International Functional Classiﬁcation of Spinal Cord Injury (the Collaboration on Repair Discoveries) in Vancouver provided ASIA International Standards) and are conducted in the all logistical coordination and support. All panel members supine position and involve a qualitative grading of (authors) volunteered their time and eﬀort. Finally, we are sensory responses to touch and pin-prick at each of 28 most grateful for the input and constructive comments from acountless number of SCI investigators over the past 2.5 years.
dermatomes along each side of the body and aqualitative grading of the strength of contraction within10 representative (key) muscles, primarily identiﬁed witha speciﬁc spinal level, 5 for the upper extremity (C5–T1) and 5 for the lower extremity (L2–S1) on each side of the 1 Steeves J, Fawcett J, Tuszynski M. Report of International Clinical Trials Workshop on spinal cord injury February ASIA Motor Score is calculated by assigning to one 20–21, 2004, Vancouver, Canada. Spinal Cord 2004; 42: muscle group, innervated and primarily identiﬁed with a speciﬁc spinal level, a score between 0 (no detectable 2 Lammertse D et al. Guidelines for the conduct of clinical contraction) and 5 (active movement and a full range trials for spinal cord injury (SCI) as developed by theInternational Campaign for Cures of spinal cord Paralysis of movement against maximum resistance). C5–T1 and (ICCP) Panel: Clinical trial design. Spinal Cord 2006 L2–S1 are tested, giving 10 levels on each side of the [E-pub ahead of print: 19 December 2006; doi:10.1038/ body for a possible maximum score of 100.
LEMS is the lower extremity motor score which is a 3 Marino R et al. International standards for neurological maximal 50-point subset of the ASIA motor score for classiﬁcation of spinal cord injury (6th edn). J Spinal Cord the representative leg and foot muscles.
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International Journal of Medicine Research ISSN: 2455-7404; Impact Factor: RJIF 5.42 www.medicinesjournal.com Volume 1; Issue 2; May 2016; Page No. 148-151 Effects of bisoprolol and nebivolol on the spectrum of essential amino acids in the blood serum of patients with unstable angina 1 Zavalskaya TV, 2 Dr. Lizogub VG