Chiaramente, ogni formato ha i propri vantaggi e svantaggi comprare amoxil senza ricetta per effettuare un acquisto, non è necessario fornire la prescrizione medica.
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;
*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-
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),
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
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.
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
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
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-
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
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
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
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.
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
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
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La médecine Thermale, une alternative thérapeutique.3IndicationsNouvelles orientations en médecine thermale, l'Ecole Thermale du Stress . 4Recherche thermaleétude STOP TAG . 6étude SPECth . 7Crénothérapie et dépression .8Étude "Burn out" professionnel .8Crénothérapie et fibromyalgie . 9Thermalisme et qualité de vie .10Prescription de la cure thermale .11 La médecine thermale, une alternative thérapeutique
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