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

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Review

Guidelines for the conduct of clinical trials for spinal cord injury as
developed by the ICCP panel: spontaneous recovery after spinal cord injury
and statistical power needed for therapeutic clinical trials
JW Fawcett*,1, A Curt2, JD Steeves2, WP Coleman3, MH Tuszynski4, D Lammertse5, PF Bartlett6, AR Blight7,
V Dietz8, J Ditunno9, BH Dobkin10, LA Havton10, PH Ellaway11, MG Fehlings12, A Privat13, R Grossman14,
JD Guest15, N Kleitman16, M Nakamura17, M Gaviria13 and D Short18
1
Cambridge University Centre for Brain Repair, Robinson Way, Cambridge, UK; 2ICORD, University of British
Columbia and Vancouver Coastal Health Research Institute, Vancouver, BC, Canada; 3WPCMath, Buffalo, NY, USA;
4
Center for Neural Repair, University of California, San Diego, La Jolla, CA, USA; 5Craig Hospital, Englewood, CO,
USA; 6Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; 7Acorda Therapeutics,
Hawthorne, NY, USA; 8Spinal Cord Injury Center, Balgrist University Hospital, Zurich, Switzerland; 9Jefferson
Medical College, Thomas Jefferson University, Philadelphia, PA, USA; 10Department of Neurology, University of
California Los Angeles, Geffen School of Medicine, Neurologic Rehabilitation and Research Program, Los Angeles, CA,
USA; 11Department of Movement & Balance, Division of Neuroscience & Mental Health, Imperial College London,
Charing Cross Campus, London, UK; 12University of Toronto, Krembil Neuroscience Center, Head Spine and Spinal
Cord Injury Program, Toronto Western Hospital, Toronto, Ontario, Canada; 13Institut des Neurosciences – CHU St
Eloi, INSERM U-583, Montpellier cedex, France; 14Department of Neurosurgery, Baylor College of Medicine,
Houston, TX, USA; 15Department of Neurological Surgery, Lois Pope LIFE Center, Miami, FL, USA; 16National
Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; 17Department of Orthopaedic Surgery,
Keio University, School of Medicine, Tokyo, Japan; 18Midlands Centre for Spinal Injuries, Robert Jones and Agnes
Hunt Orthopaedic and District Hospital NHS Trust, Oswestry, Shropshire, UK

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an
international panel tasked with reviewing the methodology for clinical trials in spinal cord
injury (SCI), and making recommendations on the conduct of future trials. This is the first of
four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting
consequences for achieving statistically significant results in clinical trials. We have reanalysed
data from the Sygen trial to provide some of this information. Almost all people living with SCI
show some recovery of motor function below the initial spinal injury level. While the
spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited
and predictable, recovery in incomplete SCI patients (American spinal injury Association
impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor
complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial
preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast
majority of recovery occurs in the first 3 months, but a small amount can persist for up to18
months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as
motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as
measured by changes in ASIA motor scores, power calculations suggest that the number of
subjects required to achieve a significant result from a trial declines considerably as the start of
the study is delayed after SCI. Trials of treatments that are most efficacious when given soon
after injury will therefore, require larger patient numbers than trials of treatments that are
effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A
patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor
will have to be balanced against the possibility that some treatments will be more effective in
incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate
assessment of AIS grade cannot be made before the start of the trial, will require large subject
numbers and/or better objective assessment methods.
Spinal Cord advance online publication, 19 December 2006; doi:10.1038/sj.sc.3102007

*Correspondence: J Fawcett, Cambridge University Centre for Brain Repair, Robinson Way, Cambridge CB2 2PY, UK
 SCI trial guidelines
JW Fawcett et al
2

Keywords: spinal cord injury; clinical trial; clinical examination; clinical assessment; power
calculation; ASIA; motor system; sensory system

General background and overall goals reasons for this focus are because of the substantial risks
and potential benefits of these types of treatments, and
The annual incidence of spinal cord injury (SCI) varies because some of these types of treatments have either
by region from o20 per million people to 450 per been offered without completing a clinical trial or will
million people (eg, see http://www.campaignforcure.org/ soon enter clinical trials.
globalsum.htm). However, as life expectancy after SCI Over the past 2 decades, a small number of major SCI
approaches that of the able-bodied population, the clinical trials have been undertaken and completed,
worldwide number of survivors has continued to grow including investigations of the neuroprotective benefits
to over 2 million people. of Methylprednisolone,1–5 GM-1 (Sygen),6,7 and Gacy-
The list of experimental interventions, therapies, and clidine (GK-11).8 Each of these trials provided valuable
devices that have been developed in animal models to data that has been most useful to the ICCP Clinical
improve functional outcomes after SCI is extensive; Guidelines Panel. Of these therapeutic interventions
more importantly several of these will need to undergo only methylprednisolone given within 8 h of injury
clinical trials in the near future. Some early stage SCI showed statistically significant efficacy for the treatment
clinical trials have recently been started and several of SCI, and none are currently used as standard
more are at a late stage of preclinical maturity. In treatments worldwide. Nevertheless, these trials have
addition, some experimental therapies have been intro- highlighted some of the difficulties that will be faced by
duced into clinical practice without a clinical trial being future trials teams. These include the choice of an
completed. appropriate and valid primary clinical end point,
Thus, there was a need for an international forum selection of trial participants, stratification of subjects,
where all aspects of clinical trial design could be and the coordination and standardization of trial
discussed. The International Campaign for Cures of protocols across multiple participating centers.
SCI Paralysis (ICCP) decided to support an interna- In short, the SCI field has yet to reach agreement on
tional workshop of leading SCI researchers, clinical the conduct of a valid and effective SCI clinical trial.
investigators and companies engaged in the develop- This series of articles contains a discussion and set of
ment of SCI treatments to discuss the many issues recommendations on the many factors that must be
surrounding the translation of relevant research to a considered when designing clinical trials in SCI. We
clinical trial. This meeting took place in Vancouver on hope these initial guidelines will provide a basis for the
20–21 February 2004.1 One of the meeting outcomes design of trials and for future revisions leading to
was a vote by the participants to establish a panel to continually improving generations of valid SCI clinical
bring forward more detailed guidelines on how to trial protocols.
develop future SCI clinical trials.
The ICCP is an affiliation of ‘not for profit’
organizations, which aims to facilitate the translation Introduction
of valid treatments for SCI paralysis. The panel’s travel This paper, the first from the ICCP SCI Clinical
and accommodation expenses have been supported by Guidelines Panel, is concerned with the assessment of
the following ICCP member organizations: Christopher the available data on the natural history of the recovery
Reeve Foundation (USA), Institut pour la Recherche of neurologic and functional outcomes following SCI.
sur la Moëlle Epinière (FRA), International Spinal The current literature on rates and degrees of sponta-
Research Trust (UK), Japan Spinal Cord Foundation, neous recovery is reviewed, presented and compared. In
Miami Project to Cure Paralysis (USA), Paralyzed addition, calculations have been made from the data
Veterans of America (USA), Rick Hansen Man In from the Sygen trial to estimate the size of study groups
Motion Foundation (CAN), SpinalCure Australia, and that would need to be recruited into a clinical trial to
Spinal Research Fund of Australia, with ICORD provide statistically significant results, using one of the
(International Collaboration On Repair Discoveries) in measures of neurological outcome that was used for the
Vancouver providing all logistical coordination. The Sygen study.
membership of the panel is shown on the list of authors
for this and the three accompanying papers, with all
panel members volunteering their time and effort. Spontaneous recovery and trial design
The ICCP SCI Clinical Guidelines Panel elected to The general picture of recovery after spinal injury is well
direct the initial set of guidelines towards the design of known. A proportion of patients with severe sensor-
clinical trials for the rapidly increasing number of imotor loss will achieve a partial or almost complete
experimental cell-based and pharmaceutical drug treat- neurological recovery, particularly if they have some
ments for protection or repair of the injured spinal cord, retained neurological function below the level of injury.
whether this is at the acute or chronic stage of SCI. The As time after injury progresses, more definitive
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
3

assessments and predictions of eventual functional functional abilities of the patient, which also depend
outcome can be made, especially in patients with on motivation, rehabilitation, fitness and other
neurologically complete SCI. An experimental treatment factors affecting the individual.
that is delivered within 24 h of SCI would, therefore, be (b) Functional assessment: evaluation of the subject’s
delivered to a group of subjects where many will show ability to perform Activities of Daily Living (ADL).
significant spontaneous recovery, unrelated to the These tests focus on issues related to the rehabilita-
treatment received. Therefore, to demonstrate statisti- tion of the patient, and may change independently
cally significant results, such a trial would have to of neurological outcomes or CNS connectivity;
recruit a large number of participants. Conversely, a patients with the same neurological scores may
trial of an experimental intervention started much later therefore, have rather different functional abilities.
in the course of post-SCI recovery would require fewer
subjects because there is by this time little change from The clinical trials completed to date have focussed on
baseline in the absence of treatment. It will, therefore, be forms of assessment that provide information on
important for those designing trials to know the neurological damage (eg AIS grades or ASIA motor
relationship between efficacy and how soon after injury and sensory scores). It is likely that these neurological
the treatment is initiated. scores will be among the primary outcome measures
The main objective of this paper is to gather together indicating whether an experimental intervention has
previously published data that will allow researchers to demonstrated acceptable risk (safety) and therapeutic
understand the degree of spontaneous recovery in activity or beneficial effect in phase 1 and 2 trials. These
different patient groups at different times after SCI outcome measures will probably be backed up by
and to calculate the size of study groups required for a further physiological tests of connectivity, as described
clinical trial beginning at a particular time following in the accompanying paper (SCI Trial Guidelines 2).9
However, no SCI therapy will be considered effective for
injury. As initially published, much of the previous trial
the treatment of patients unless it improves the ability of
data lack the statistical details needed to make these
patients to function in their daily routines or activities.
power calculations, because measures of variance were
not included in some of the key publications. We have Tools and assessment procedures that accurately char-
acterize such benefits need to be incorporated into
addressed this by re-analysing some of the data from the
definitive phase 3 clinical trials.
control group and the combined control and treatment
groups of the largest and most detailed trial of a
treatment for spinal injury yet attempted, the Sygen Sources of data
trial.6,7 The panel reviewed numerous studies and data reports
A challenge encountered by the panel is that the data about SCI recovery. Three large, double-blind, placebo-
have generally not been presented in a format that controlled pharmaceutical trials focussed on acute
relates to the probable recovery patterns that are neuroprotection and rehabilitation in SCI are reported
anticipated for many of the treatments currently being in the literature; the National Acute Spinal Cord Injury
contemplated. The current and upcoming SCI clinical Study (NASCIS), Sygen and GK-11 trials.2–8 The data
trials focus on neuroprotection, axonal regeneration, from the placebo-control groups in these studies allow
promotion of neural plasticity or a combination of these the natural history of recovery from injury to be
mechanisms. It is probable that the principal clinical examined within the context of a randomized controlled
benefits of these treatments will be seen in the spinal trial (RCT). In addition, there have been a number of
segments immediately below the site of SCI. Data studies of long-term outcomes after SCI that provide
relating to the recovery patterns in these segments, and valuable information on expected recovery rates,10–12
the relationship between recovery and distance below as well as some recently unpublished data from the
the lesion therefore become particularly important. European Multicenter study in Spinal Cord Injury
(EMSCI).

Methods of assessment
The assessment methodologies used in previous clinical 1. The series of three NASCIS trials examined treatment
studies fall into two main categories: with methylprednisolone, naloxone and tirilazad
mesalate, all initiated within a few hours of spinal
injury. For ethical reasons, only the second trial
(a) Neurological scoring, including measures of: (1) the (NASCIS II) included a true placebo group. The first
completeness of the lesion, measured using the AIS trial assumed efficacy based on long established
impairment scale or equivalent; (2) the level of anecdotal use, and compared low and relatively high
lesion, defined by the lowest neurologically func- doses of methylprednisolone over a 10-day regimen.
tional spinal segment; and (3) the grading of the When no difference in functional outcome was seen,
motor and sensory abilities, using the ASIA motor the ethical hurdle was reduced and the second trial
and sensory scores (or an equivalent). These compared three groups: placebo, 23 h methylpredni-
objective neurological scores assess the remaining solone treatment, and naloxone. Patients were exam-
connections within the spinal cord, but not the ined on admission to hospital emergency room, mostly
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
4

within 12 h after injury, and an average time from clinical trials and survey studies to measure neurological
injury to treatment of 8.9 h. In this second study,2,3 recovery. Two types of measure are included. The
487 patients were enrolled, of whom 171 were in the completeness of the SCI is graded by the AIS (AIS
placebo group, and outcomes measured at 6 weeks, 6 grades A–E). The motor and sensory abilities of patients
months and 1 year. The third NASCIS study4,5 did not are described by the ASIA motor and sensory scores
have a placebo-control group, because following its that constitute the International Standards for Classifi-
apparent efficacy in the NASCIS II study it was cation of SCI. Recovery can be measured by conver-
considered that to deny some form of methylpredni- sions in the AIS and/or by changes in the ASIA motor
solone treatment would be unethical. and sensory scores. By repeated measures, over the
2. Sygen (GM-1 ganglioside) was originally studied in a continuum from the acute to chronic stage of SCI, the
single-center pilot trial that recruited 37 patients. A time profile of changes, as well as the absolute amount
significant drug effect was found (P 0.034) in the of neurologic recovery, can be determined.
proportion of patients able to improve by two grades
on the AIS (one of 14 on placebo, seven of 14 on
Sygen). This trial was followed by a larger study that
recruited 760 patients in 28 centers in the US and Completeness of the lesion, measured using the AIS
Canada (see Supplementary Table 1). Patients were The AIS grades patients from A (sensorimotor com-
started on the study medication within 3 days of plete) to B (motor complete, sensory incomplete), C and
injury, usually on day 2, and outcomes were measured D (motor and sensory incomplete), E (normal). The
at intervals up to 1 year. All patients received the same Sygen study used the Modified Benzel classification,
regimen of methylprednisolone as in the active group which has grades from 1 to 7. The main difference from
of NASCIS 2, starting within 8 h. The primary the AIS is the expansion of AIS D into three separate
outcome measure was the ability to improve at least Benzel grades. Translation from AIS grades to Benzel is
two grades between the AIS at baseline and the Benzel as follows: grade1 ¼ AIS A, 2 ¼ B, 3 ¼ C, 4 ¼ D, 5 ¼ D,
Scale (an expansion of AIS) at 26 weeks. 6 ¼ D, 7 ¼ E (details in Geisler et al6,7).
3. A prospective phase 2 RCT of an NMDA receptor All studies report a considerable degree of conversion
blocker, Gacyclidine (GK11), as an early neuropro- in AIS grade over the first year after SCI, from a
tective treatment (within 2 h of SCI) was completed sensorimotor complete injury (AIS A) to sensory
in France and involved over 250 patients with 67 incomplete (AIS B) or a sensory and motor incomplete
placebo-control subjects.8 (AIS C-D) status. Although the data collection in the
4. The USA Model Systems studies11 examined out- studies was performed at different times and under
comes in 3585 patients admitted to several spinal rather different conditions and/or trial designs, the
injury centres. The initial examination was performed findings seem to be robustly similar (Figure 1). The
within 1 week of injury. Of these, motor score conversion rates vary greatly depending on the grading
changes were measured over 1 year in 1636 patients. of the patient at admission to the study. Thus, 80% of
5. Waters et al10 followed the outcome of 61 complete the initial AIS A patients remain as AIS A, with about
tetraplegic patients with lesions between C4 and C7. 10% converting to AIS B (ie some sensory function) and
The patients were first examined upon admission to about 10% of the initial AIS A patients regaining some
the spinal injury unit, which was o30 days from the motor function (ie AIS C). The data shown in Figure 1
time of injury, and followed-up for up to 2 years. includes both tetraplegic and paraplegic levels of SCI.
6. Kirshblum et al12 undertook a longitudinal assess- The EMSCI data on spontaneous AIS conversion
ment of neurological recovery in 987 people living percentages indicates some differences between AIS A
with SCI at 1 and 5 years after SCI. tetraplegic and paraplegic patients with the tetraplegic
7. EMSCI is a group of 14 spinal injury centres. The patients demonstrating almost twice the percentage of
group is developing a set of trial protocols that will be recovery for conversion to AIS B and AIS D from AIS
used in the forthcoming trials, including a Novartis- A (Figure 2).
sponsored trial of an anti-Nogo-A antibody (AT- In patients initially assessed as AIS B or AIS C (ie
355). The group has detailed spontaneous recovery incomplete SCI) the extent of spontaneous recovery was
information on 217 acute traumatic SCI patients that significantly greater compared to AIS A. The sponta-
have been clinically followed with repeated neurolo- neous 1 year neurologic recovery rate varied from study
gical assessments extending for 1 year after injury. to study, but AIS B conversion to AIS C was between 15
This data has not been published previously and we and 40% and AIS B conversion to AIS D was also
provide only a brief summary of their findings. reported to be as much as 40% in two of the three
Further information is available on www.emsci.org. studies. AIS C conversion to AIS D was between 60 and
80% of all the patients examined. In the Sygen trial,
where the AIS D grade was subdivided into three Benzel
classifications, 95% of patients were reported to have
Neurological recovery after SCI
shown an improvement of at least one classification
As outlined above, the ASIA protocols (or equivalents) level, although few AIS D patients converted to
are the most frequently used assessment tool in SCI complete normality.
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
5

Figure 1 Percent AIS conversion from initial examination (within 3 days to 4 weeks of SCI) to the 1 year anniversary date after
SCI. Data are from the US Model Systems, Sygen and EMSCI databases

in human clinical trials. Changes in ASIA motor scores

or some functional outcome measure may be more
useful readouts of therapeutic efficacy (see accompany-
ing paper, Steeves et al9). However, AIS grades can be of
substantial value for the inclusion or exclusion of
potential trial participants, as well as in the stratification
of subjects into separate trial cohorts.

Time profile (stages) of recovery in the AIS

Over what time period does the change in neurologic
or functional recovery after SCI occur? In Figure 3, we
have plotted data provided from the EMSCI database,
Figure 2 Comparison of percentage conversion of AIS Grade showing the time at which a change in AIS grade was
in AIS A tetraplegic and paraplegic patients from the EMSCI noted in 67 of the 217 patients who showed any change,
database at the 1 year anniversary date after SCI independent of SCI level (ie includes all subjects AIS A
through AIS D). Approximately, 80% of these 67
Thus, in clinical trials involving AIS C or AIS D patients showed a conversion within the first 3 months
subjects, there is a potential ‘ceiling effect’ for the use of after injury. However, at later time points some AIS
AIS grades where the assessment for the therapeutic conversions were still observed.
activity or benefit of an intervention cannot be Reanalysis of the Sygen data shows that, of 716
differentiated statistically from the neurologic improve- patients, 250 were able to show ‘marked recovery,’
ment that is due to spontaneous recovery. Conversely, meaning improvement of at least 2 grades in the Benzel
relying on the conversion from AIS A to another AIS Scale between the first examination at 2 days and 1 year.
grade as a primary clinical end-point may be too Of these 250, 62 were first able to meet this criterion at
demanding a threshold for demonstrating therapeutic the 4-week-exam, 80 first met it at 8 weeks, 50 at 16
efficacy (ie potentially insensitive to all but the largest of weeks, 38 at 26 weeks and 20 at 52 weeks. Thus, 57% of
treatment effects). those who eventually reached this stringent standard of
Therefore, it is unlikely that the conversion of AIS recovery had already done so within 2 months, and 77%
grades will be of value for assessing the potentially had done so by 3 months. Some recovery did, however,
subtle beneficial effects of experimental SCI treatments continue throughout the observation period. A total of
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
6

is another dilemma. Based on the available data, it

might be suggested that the chronic state is only attained
12 months after SCI (where the preceding 6 months have
indicated no change in functional capacity, thereby
providing a stable baseline).
By default, all time points in between acute and
chronic are classified as subacute, but in the case of
human SCI, this could then be a time period almost as
long as a year! Admittedly, these are far from rigorous
(or satisfactory) timeframes, but there is little available
evidence to support more rigid definitions until more
precise information is available about any time limita-
tions on the pathophysiology of human SCI. Functional
Figure 3 Timeframe at which patients in the EMSCI study recovery during the subacute period can be highly
showed an AIS grade conversion. A total of 67 subjects of 217 variable and the panel did not reach consensus on a
participants showed a conversion, independent of SCI level or further subdivision of this time period. Given the highly
severity variable nature of the subacute state after SCI,
investigators are cautioned that they may need to
stratify trial cohorts, on the basis of time after SCI, to
170 patients were able to improve by at least 1 AIS/ draw meaningful conclusions.
Benzel grade between baseline and 4 weeks, 148 did so As, neurologic recovery after SCI is non-linear,
between weeks 4 and 8, 132 improved between weeks 8 especially within any subacute period, clinical investi-
and 16, 109 between weeks 16 and 26, and 67 between gators will wish to know the conversion rate from the
weeks 26 and 52. beginning of their study, whenever that commences. For
A recent study by Kirshblum et al12 examined the instance, if the study is to begin 8 weeks after SCI, the
degree of AIS conversion between 1 and 5 years after relevant data might be the changes in AIS grade between
SCI in 987 subjects. They noted that 5.6% of people, 8 weeks and 1 year after SCI. We have re-examined the
who were neurologically complete (AIS A) 1 year after Sygen database in order to provide this analysis. The
SCI, still converted to an incomplete injury by year 5 (ie AIS grade outcomes of patients in the Sygen database
over the next 4 years), with 3.5% converting to AIS B who were AIS A (which equals Benzel 1) at 3 days, are
and about 1% to either AIS C or AIS D. then plotted at 4, 8, 16, 26 and 52 weeks, with different
When does the spontaneous conversion of neurologic plots for patients with cervical and thoracic injuries.
recovery begin to stabilize after SCI? This information is Tables and graphs showing the full set of data are
important in the design of clinical trial protocols, as well presented as Supplementary Figure 1. We present four
as for establishing appropriate outcome threshold values graphs from this data set as Figure 4, to show that the
to demonstrate a statistically significant clinical benefit change in Benzel grade between the beginning of a study
for any experimental intervention, including late reha- starting at 3 days after SCI is much greater than the
bilitation strategies. change observed when the study commences at 8 weeks
Depending on the therapeutic target SCI clinical trials after SCI (both trials concluding at 1 year after SCI).
will begin at various times after injury. It is somewhat These new calculations and the EMSCI data show that a
of an arbitrary decision as to when you classify SCI as few patients who have previously shown no improve-
acute, subacute or chronic and likely to depend on the ment can convert to a higher grade even months after
targeted pathophysiology or mode and mechanism of injury. Even patients who are AIS A at 4 and 8 weeks
the therapeutic intervention being investigated. The after SCI can still show significant spontaneous
Panel examined the changes for a number of different improvement.
neurologic measures and functional capacities after SCI
over time. We reviewed the variability of these values at
Motor recovery after SCI
any given timepoint, as well as the known neuropatho-
logical mechanisms and neuro-repair potential asso- Motor assessments were made in all the studies using the
ciated with these timepoints from a number of ASIA scale or an equivalent. In current research, the
preclinical and clinical SCI studies. Whatever timepoint upper and lower extremity scores are usually given
is chosen for the commencement of a clinical trial using separately, but this was generally not the case in the
an experimental treatment, it should be supported by studies we reviewed. As the ASIA motor assessment
appropriate preclinical data testing with a similar time only covers five spinal levels in the cervical and lumbar
frame (scaled for human studies). regions, with no scores at the thoracic levels there are
There is little doubt that an experimental treatment ceiling effects. Thus, a patient with a C7 injury could
administered within the first 3 days of SCI would be only be demonstrated to have two levels or 20 points
currently viewed as an acute treatment. How long the of improvement down to T1. Any further improvement
acute stage of human SCI persists is presently an open could not be scored because it would affect thoracic
question. When exactly the chronic SCI state is achieved motor levels. All studies have reported an increase in
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
7

Figure 4 Benzel grades at various times after SCI calculated from the Sygen database. (a) shows the outcomes for subjects who
were initially cervical 1 (which equates to cervical A or Benzel grade 1) when the baseline measurement started at 3 days, (b) shows
the outcome pattern for subjects who were cervical 1 (which equates to Benzel 1 or AIS A) at 8 weeks. (c) and (d) show cervical 2
(equals cervical B or Benzel 2) subjects with the baseline starting at either 3 days and 8 weeks

ASIA motor scores during the first year after SCI. The should be remembered that given the time between the
numbers of motor points gained during the first year are NASCIS study and the more recent adoption of the
rather consistent between studies. As with conversion ASIA Impairment Scale there are differences between
of AIS grades, incomplete SCI patients show greater the motor scoring systems which means that the data
degrees of motor recovery than AIS A patients. The cannot be compared directly. ASIA utilizes 10 muscles
overall increases found in four studies are shown on each side of the body for a maximum total score
graphically as Figure 5. The recovery rates in the AIS (20  5) of 100; whereas NASCIS used 14 muscles on
C and D group are probably greater than shown in this only one side of the body for a maximum total score of
graph, but there is a ceiling to the increase that can be 70. The following data is for 43 subjects in which the
shown in the ASIA motor score, as described above. initial ASIA assessment was made within 8 h. The
The Sygen database also contains data on thoracic observed motor recovery after 1 year was 4.6 points for
level SCI. Thoracic AIS A patients showed a mean AIS A subjects, 31.3 points for AIS B subjects, and 12.9
increase of 4.5 motor points over the first year, and motor points for AIS C and D subjects combined.
thoracic B patients showed a 22.7 point increase. The
presentation of the Sygen data in Geisler et al6 did not
include statistical analysis, making it impossible to Motor recovery at intermediate time points
perform power calculations. However, these statistics In many of the published studies, ASIA motor
are now presented in Supplementary Figure 2. examinations were made at various times after SCI
Motor recovery over the first year after SCI was also until the end of the study 1 year after SCI. For example,
examined in the NASCIS II trial control group.3 It the study by Waters et al10 followed the outcome of 61
Spinal Cord
 SCI trial guidelines
JW Fawcett et al
8

Figure 6 Change in ASIA motor score for sensorimotor

complete (AIS A) patients within initial two years after SCI
(Waters et al.10). Note that most rapid improvement occurs
within the first 6 months after SCI and is essentially maximal
after 12 months

concluding at 52 weeks after SCI. This new presentation

provides some of the necessary data needed to perform
power calculations for trials that might begin with an
experimental intervention at different time points after
SCI. These power calculations appear in a later section
of this paper. The full set of tables is presented as
Supplementary Figure 2. We show representative plots
here (Figure 7) where we have plotted recovery curves
from some of the Sygen motor recovery data.

Rate of motor recovery

All studies give fairly consistent data on the rate and
timing of functional recovery. The rate of recovery is
Figure 5 Motor recovery, measured in ASIA motor points, rapid during the first three months and motor improve-
over the first year after SCI in AIS A, B and C/D patients. The
rates of recovery in the Model systems, Sygen and EMSCI
ment is almost complete by 9 months, but ultimately
studies are compared only plateaus at 12 to 18 months after SCI. This can be
seen from the motor recovery graphs in Figures 7 and 8.
These figures also show that the rate and extent of
complete tetraplegic patients with lesions between C4 recovery is greater in patients with incomplete lesions.
and C7. The patients were first examined at admission to Rate of motor recovery was examined explicitly in
a rehabilitation spinal injury unit (within 30 days of several studies. For example, Figure 8 shows a graph
SCI). The cumulative motor recovery of these patients is from a review by Burns and Ditunno13 which presents
shown in Figure 6. In short, cervical-injured AIS A a typical picture and is taken from previous data.14
patients showed a mean improvement in motor score of Ditunno et al15 examined the rate of motor recovery
10 by the end of 1 year after SCI and this only improved in a different way, by examining motor recovery in the
to 11 by the end of the second year after SCI. right biceps of motor complete (AIS A and AIS B) and
The most complete data come from the Sygen study. incomplete (AIS C and AIS D) SCI subjects, classified as
We have reanalysed the Sygen data, and now provide C4 right motor level. The biceps is primarily supplied by
information that is not in the original paper. First, we motor innervation from the immediately adjacent C5
show the standard deviations for the mean improvement spinal level. The results from 40 patients, 27 motor
in motor score over the 1 year assessment period of the complete and 13 incomplete show progressive recovery,
study (Supplementary Figure 2). Second, in order to fastest over the first 3 months, with a large proportion of
assist those investigators designing studies which do not patients (70% of complete SCI and 90% of incomplete
begin immediately after SCI, we have recalculated the SCI subjects) showing recovery from a grade of either 0/
rates of motor recovery, assuming that subjects are 5 (complete) or 2/5 (incomplete) to a useful motor grade
randomised, assigned an AIS grade and admitted to the (3/5 or better) within 12 months of the initial injury.
study at various time points during the first year after
SCI. We have calculated changes in motor scores from
participants who were AIS A or AIS B starting at 4, 8, Motor recovery in the segments close below the lesion It
16 and 26 weeks after SCI, with all assessments is probable that several of the prospective treatments
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Figure 7 Motor recovery of Cervical AIS A (a), thoracic AIS A (b), cervical AIS B (c), thoracic AIS B (d) patients, calculated
from the Sygen database, using the placebo-group data. The solid lines show recovery from the beginning of the study, as in
Geisler et al.6,7 In order to demonstrate expected recovery rates for studies beginning at 4, 8, 16 or 26 weeks after SCI, recovery
rates are shown for if the study were to start at such delayed treatment times. The data are therefore not confounded by patients
who converted to a different AIS grade between day 3 and a delayed start time of 4, 8, 16 or 26 weeks after SCI

that will undergo SCI trials will have their maximum Changes in function versus distance below the lesion A
effect within spinal levels just below the injury. There is small retrospective study from Vancouver16 examined
therefore, a need for data on spontaneous recovery rates return of motor function at adjacent distal levels below
in these spinal segments. The issue is complicated by the the neurological level as determined using the ASIA
existence of a zone of partial preservation (ZPP) in most motor scores. Figure 9 is a graph (based on the data
patients with complete injuries, where some motor in Table 4 from the paper), which shows the number
capacity remains. Moreover, this zone varies in size of tetraplegic patients that either do or do not recover
from patient to patient. Spinal levels below the ASIA useful motor function (grade 3/5 or better) after 2 or
motor level where there is some measurable muscle more years following SCI. The results emphasize that
function clearly lie within the zone of partial preserva- most motor recovery occurs within the first level below
tion. Of particular interest for clinical trials may be the the ASIA motor level (100% for incomplete tetraplegic
first or second motor level at which there is zero SCI and 56% for complete tetraplegics). Furthermore,
function. However, if the initial neurological assessment there is very little or no recovery at more than two spinal
was performed early, there is often some significant levels below the initial ASIA level.
spontaneous motor recovery within these segments, Waters et al10 also examined recovery of function in
which might therefore be considered to be within the spinal levels below the injury level for complete (AIS A)
ZPP. In principle recovery within the ZPP could be due tetraplegic patients. The observations at 1 year, based
to both CNS and peripheral plasticity, while recovery on initial assessment within 30 days of SCI, were that
beyond the ZPP would probably require at least some 57% of the 88 cases showed improvement from 0/5 to
CNS repair (eg axon regeneration). 1/5 strength in the immediately adjacent level (first zero-
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JW Fawcett et al
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segment above was initially graded 2.5 out of 5, 100%

of patients regained function to a grade of 3 in the next
segment below. If the segment above was initially only
rated a grade of 1–2.5 out of 5, then 75–80% of patients
regained grade 3 or better function in the next segment
below. However, if the segment above was initially
assessed a grade of 0, then only 25–30% of patients
regained function to a grade of 3 in the next segment
below.
The timing and extent of motor recovery within the
ZPP was examined by Ditunno et al.17 They examined
the time course of recovery in muscles with no voluntary
movement (grade 0) compared with muscles with some
preserved motor function (grades 1 or 2), but less than a
functional (antigravity) grade 3 muscle level. Initial
ASIA assessment was within one week of SCI. Figure 10
shows the percent of patients achieving grade 3 or better
Figure 8 Motor recovery for complete and incomplete spinal in impaired muscles, showing higher levels of recovery
cord injury patients over the first 2.5 years after SCI (Waters14; in muscles that were grade 1–2 compared with grade 0.
Burns and Ditunno13). Note the most dramatic improvements The conclusion from this study, and others from this
occur over the first 9 months, although a completely stable research group, is that recovery in muscles with some
plateau (baseline) may not be achieved until 18 months after voluntary function is both faster and more complete
SCI, depending on the severity and level of the injury than in muscles that initially have no function. The great
(incomplete tetraplegia taking the longest to stabilize) majority of improvement appears to occur within the
first 9 months after SCI.

Sensory recovery after SCI

Sensory function and changes in sensory level are often
described as changes in ASIA sensory score after injury.
However, in many studies, recovery of sensory function
was not taken as a primary outcome measure. This was
because ASIA sensory examination often provided
somewhat variable results within individual patients.
In addition, the sensitivity of the ASIA sensory score is
limited with only three grades of sensation being scored
for detecting a light touch or pin prick stimulus, where
0 ¼ absent, 1 ¼ impaired and 2 ¼ normal in the affected
dermatome.
Figure 9 Recovery of useful motor function in spinal
segments below the ASIA motor level (Fisher et al16). The
figure shows the percentage of patients who initially either had Data from the Sygen study
no motor function (muscle grade ¼ 0) or minimal muscle The rates of sensory recovery in patients from the Sygen
strength (grade 1–2) who subsequently recovered some useful study starting at the beginning of the study are shown in
function at each spinal level below the initially defined level of Figure 11, and the statistics are in Supplementary Figure
motor lesion 3. We have also made new calculations, as with the
motor data shown in Figure 7. In these, we have
rated) 1 year after injury, while only 27% improved to provided recovery data relevant to trials that might be
3/5 or better (ie useful motor function). In the second started at later time points. We have taken the patients
adjacent motor segment below the level of lesion, only who were Cervical A or B and Thoracic A or B and then
4% of patients showed any measurable strength (1/5), show the subsequent sensory score recovery at 4, 8, 16,
and only 1% (one patient) regained useful motor 26 and 52 weeks, out of a maximum of 112 (26
recovery (3/5 or better). dermatomes on left and 26 on right side with a
There is some evidence that the motor grade of the maximum score of 2 for each dermatome), and we have
lowest functional level affects the probability that provided recovery data for patients graded AIS A and B
function will return in the level below it, although this at 4, 8, 16 and 26 weeks. The complete data are provided
is based on groups of only 20 or so patients with C5 and in Supplementary Figure 3.
C6 injuries. Burns and Ditunno13 reviewed the prob- It has been suggested that preservation of pinprick
ability of useful motor recovery (to grade 3 or more) one sensation may predict motor recovery in persons with
level below a level with some detectable function. If the motor complete, sensory incomplete (AIS B) SCI.
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Recently, the Sygen data was used to re-examine this subjects who remained complete from a set of 61
possibility.18 The retrospective examination of 131 AIS subjects classified as complete at admission. The
B patients indicated that a higher percentage of apparent degree of recovery is more modest than that
individuals with sacral sparing of pinprick sensation obtained from the Sygen sensory assessments.
(within 72 h of SCI) were ambulating at 26 or 52 weeks
after SCI, although this did not reach statistical
significance. However, preservation of sacral pinprick Data from the NASCIS study
at 4 weeks after SCI was significant for predicting The scale for the NASCIS sensory scores is rather
ambulation at 1 year after SCI. If lower extremity (L2– different from that used in the Sygen study. The same
S1 dermatomes) pinprick sensation was maintained in dermatomes are scored but unilaterally, and assigned
50% or more of the dermatomes then a significant a three point score from 1 to 3 instead of 0 to 2. The
proportion of patients would recover ambulatory increases in sensory scores from baseline from the two
function. Thus, the preservation of pinprick sensation sets of data can therefore be compared by doubling
appears to be useful in predicting motor recovery.18 the values from the NASCIS data set. The recovery
In Table 1, we show the sensory recovery data from of sensory scores after 1 year in 43 placebo-treated
Waters et al10 for a subset of 55 AIS A tetraplegic complete and incomplete SCI subjects (with baseline
assessment within 8 h of SCI) for AIS A subjects were
5.5 points for light touch and 5.1 points for pinprick
sensation. Likewise, for AIS B participants, the im-
provement in sensory scores were 10.8 for light touch
and 15.8 for pinprick; whereas for combined data from
AIS C and D subjects indicate a possible ‘ceiling effect’
as the improvements were only 3.0 for light touch and
9.2 for pinprick.

Prognostic value of the ASIA examination at early

assessment times
For a neuroprotective treatment, the sooner the treat-
ment is applied, the more likely it will be effective. Thus,
another key issue will be when a reliable baseline ASIA
classification can be established for a person with SCI.
For numerous reasons, such as spinal shock, medical
Figure 10 Motor recovery over time within the zone of instability, concomitant brain injury or coma, the ASIA
partial preservation (redrawn from data in Ditunno et al17) assessment within the first 24 h of SCI can be inherently

Figure 11 Sensory recovery data from the Sygen study. The cumulative increases in light touch and pinprick sensory scores from
a baseline of 3 days after SCI are shown

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Table 1 Mean ASIA sensory score changes for tetraplegic ASIA A subjects, relative to a baseline assessment one month after SCI
(from Waters et al10)

Re-examination at 2 month 3 month 4 month 5 month 6 month 1 year 2 year 3 year

n (# subjects) 55 55 55 47 37 34 20 12
Light touch 0.7 1.2 1.3 1.6 1.7 2.3 2.5 2.6
Sharp touch 0.7 0.7 1.0 1.3 1.5 1.9 2.2 2.7

unreliable as a predictor of the subject’s future treatment. For trials where the treatment is to be given
functional disability or capacity. Assessment at 72 h within the first 3 days after SCI, it may be prudent to
after SCI is generally accepted as having a more exclude patients where the clinical examination may not
accurate prognostic value. provide reliable information.
This issue was examined specifically by Brown et al19
Motor complete (AIS A and AIS B) patients (n ¼ 29) Number of subjects for valid statistically significant
were examined within 24 h of SCI, then again at 72 h
SCI clinical trials
and at several times up to 3 months after SCI to
determine how well the motor exam at each time point A key consideration in trial design is the number of
predicted subsequent functional recovery (to muscle patients that need to be recruited and enrolled in a
strength grades of 4 or 5) at 3 months. The study clinical trial in order to achieve a significant result. We
examined the strongest muscle within the ZPP. Between have reanalysed the control arm data from the Sygen
24 and 72 h, 47% of patients with a grade 3 strength in study6 in order to calculate the number of patients in
the selected muscle showed a decline in strength to grade each arm of the study required to show a statistically
1 or 2, while 17% of those with grade 1–2 increased to significant difference between an experimental and
grade 3. A total of 71% of the subjects with a grade 3 control group for a RCT of an experimental treatment
strength in the selected muscle at 24 h showed recovery for SCI. We have used the whole Sygen database for the
to grade 4 or 5, compared to 33% of those with grade calculations shown in Figure 12 because the placebo
1–2, a difference that was not statistically significant. group is too small to provide reliable figures; all the
However, all of the 11 subjects with a grade 3 muscle calculations are shown in Supplementary Figure 4.
strength at 72 h showed recovery to grade 4 or 5 by 3 These calculations are based solely on the ASIA motor
months, while only 28% of those with a grade of 1 or 2 score, and trials designed using more sophisticated,
recovered to grade 3 or above, which was a significant more accurate or composite outcome assessments may
difference. The conclusion is that the 72 h examination require fewer numbers. However, these calculations
provides a better prediction of outcome in motor provide an indication of the number of subjects that
complete (AIS A and B) patients, while the 24 h might be required in a study and how the magnitude of
examination is not as reliable. It may be noteworthy spontaneous recovery can influence those numbers.
that the primary difference in this small study appeared We have used two assumed treatment effects, a
to be due to those subjects whose strength declined difference of either 5 or 10 points in the ASIA motor
between 24 and 72 h and did not subsequently recover. subscore between the experimental and control groups.
The reliability of the initial and second examination These are relatively modest treatment effects, and trial
in motor complete patients was also examined by Burns group sizes would be considerably smaller if the
et al.20 Patients were examined initially within 48 h of designated clinical end point motor score was a larger
SCI, again within a week before discharge and then 1 difference (eg 20 point difference in ASIA motor scores).
year after SCI. The early examination was classified as As the trials of different treatments might begin at
unreliable if there were factors affecting cognition (eg, different times, and because functional capabilities
traumatic brain injury, drug effects, psychological become less variable with time after injury, we have
disorders), communication (patient on ventilator, lan- made calculations assuming a clinical trial might begin
guage barriers) or other considerations that would at various times after SCI. For instance, a trial of a
undermine confidence in the examination. As can be neuroprotective substance might begin as soon after a
seen from the data below (Table 2), there was a higher spinal injury as possible, while a trial of a regeneration/
rate of apparent recovery in the patients with an repair-inducing treatment might begin within 1–4 weeks,
unreliable initial (o48 h) examination. The conclusion and, finally, a trial of a neural plasticity-inducing
was that a reliable initial examination may be as reliable intervention might begin at almost any time, including
as a second, later examination. during the chronic state of SCI (eg 412 months after
From these data, it is clear that it is desirable to injury). A graphical representation of these results is
perform a detailed neurologic examination and ASIA shown in Figure 12.
assessment just before randomization of patients into For example, if the SCI trial were confined to Cervical
trial groups and as close as possible to the initiation of AIS A patients enrolled immediately after SCI (eg a
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JW Fawcett et al
13

Table 2 Reliability of the ASIA examination within 48 h after SCI. ASIA assessments that were thought to be unreliable resulted
in a higher number of subsequent ASIA grade conversions (Burns et al20)

Assessed
ASIA Examination Reliability Asia Grade Thought to be Reliable Thought to be Unreliable
Initial Admission ASIA grade (o48 h) A (n ¼ 38) B (n ¼ 13) A (n ¼ 43) B (n ¼ 9)
Subsequent ASIA Grade at second A 37 0 39 0
exam (usually within one week of initial B 1 10 4 9
admission exam; n ¼ 103) C 0 2 0 0
D 0 1 0 0

Initial Admission ASIA grade (o48 h) A (n ¼ 30) B (n ¼ 10) A (n ¼ 23) B (n ¼ 5)

Subsequent ASIA Grade at one year or A 28 0 19 0
later (n ¼ 68) B 2 4 1 2
C 0 3 2 3
D 0 3 1 0
Number of subjects for valid statistically-significant SCI clinical trials

neuroprotective treatment) and powered to show a muscles, but only if they were one segment below the
statistically significant difference of 10 ASIA motor ZPP. Recovery two segments below the most caudal
points between the experimental and control groups, it segment of the ZPP rarely occurs.
would be necessary to enrol approximately 60 subjects Some sensory recovery occurs after SCI, on roughly
for each arm of the study, but over 230 subjects if the the same time course as motor recovery. The magnitude
difference was reduced to five motor points. However, for the recovery of sensory function may appear to be
for AIS B cervical-injured candidates in a similar trial less than or more variable than motor recovery, as the
design the numbers increase dramatically to 277 and limited (3 point) scale for the ASIA sensory assessment
1105, respectively, because of the magnitude and and the need to rely on a subject’s perception makes
variability of motor recovery. Fortunately, because the it less sensitive (more variable) than ASIA motor
rate of spontaneous recovery decreases with time after assessments.
SCI, the number of patients that would have to be While the spontaneous recovery of motor function in
recruited into a trial becomes smaller as the initiation of people with motor-complete SCI is fairly limited and
treatment is delayed. The full set of tables for these predictable, recovery in incomplete SCI patients (AIS C
calculations is presented in Supplementary Figure 4. The and AIS D) is both more substantial and highly
sample size (power) calculations produce very similar variable. Therefore, relatively smaller trial sample sizes
results when performed using the data from the placebo- may be possible when undertaking a trial with subjects
control group alone or with the combined data from having AIS A or AIS B SCI, but trials involving
both the experimental and control arms of the Sygen incomplete SCI patients, or trials where an accurate
study. assessment of AIS grade cannot be made prior to the
start of the trial (eg early application of a neuroprotec-
tive agent), will require larger numbers of subjects,
Summary randomized to an experimental or placebo-control study
Almost all people with SCI show some recovery of arm.
motor function below the initial ASIA injury level. In
patients with motor complete lesions (AIS A and AIS B)
Recommendations
the majority of this functional return is likely to occur
within the ZPP. Thus, a muscle group that has some The data presented in the current literature come from
degree of minimal function early after SCI has a higher assessment methodologies that were designed mainly to
probability of regaining some behaviourally useful aid the prediction of outcomes for the purposes of
function (muscle grade 3 or higher) with time. Recovery rehabilitation and long-term care. For future clinical
also appears to be particularly probable in myotomes trials further forms of assessment will be used, as
with sensory preservation. This recovery may be discussed in the second document in this series (Steeves
sufficient to reclassify the ASIA injury level to a lower et al9). For trials of regeneration/repair or plasticity-
spinal level. The vast majority of this recovery occurs in inducing interventions, we believe that clinical motor
the first 3 months, but a small amount of ongoing data might be more useful if presented in a different
recovery can persist for up to 18 months or occasionally form. This is because these recovery processes are likely
longer. to affect segments near the lesion, with a declining effect
It is not clear from most previous studies how much further from the lesion. It will be important to document
of the motor recovery is seen below the ZPP. In some recovery relative to the number of levels below the
of the studies there was recovery in some zero-rated lesion, and whether recovery occurred within or beyond
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JW Fawcett et al
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Figure 12 Graphs result from a re-analysis of the Sygen database, using combined data from both placebo and treatment groups.
They show the projected number of patients/subjects per treatment arm that would have to be recruited into a clinical trial were the
desired significance level ¼ 0.05. Calculations were performed on the basis of a treatment effect having a difference of 5 or 10 ASIA
motor points between the experimental treatment group and the control group

the ZPP. Such data would also provide important Glossary of definitions
information for understanding the mechanism of action
for the development of subsequent generations of (Additional glossaries are included in the three accom-
therapeutics. It will therefore, be useful to have patient panying papers)
data presented in terms of segments below the accu- A booklet and training manual is available from the
rately described neurological ASIA level. It will also be ASIA that summarizes the AIS scale and clinical
important to map the ZPP for each subject, to correlate assessment protocol.
this with the ASIA lesion level, as well as that defined (http://www.asia-spinalinjury.org/publications/index.
by imaging (CT or MRI) and to differentiate between html)
recovery of function within the ZPP and recovery Neurological Level of spinal injury is generally the
beyond this zone, as this more likely to be repair of lowest segment of the spinal cord with normal sensory
spinal origin. and motor function on both sides of the body. However,
The panel therefore, decided that it will be useful to the spinal level at which normal function is found often
perform additional analyses of the major existing differs on each side of the body, as well as in terms of
databases in order to provide two types of information preserved sensory and motor function. Thus, up to four
that are not present in the current literature. In view of different segments may be identified in determining the
the likelihood that recovery of function following neurological level and each of these segments is recorded
treatments will be concentrated close to the level of separately and a single level descriptor is not used.
injury, it would be very useful to present some of the Please note that the level of spinal column injury may
existing trial data in a format which shows recovery of not correlate with the neurological level of SCI.
function relative to distance below the neurologic level ASIA (American Spinal Injury Association) Impair-
of injury. A reanalysis of the Sygen database and ment Scale (or AIS) describes the completeness of a
possibly others will be made for this purpose. spinal injury. An individual with an AIS A grade has no
The numbers of patients required to demonstrate a motor or sensory function at the level of S4–S5 sacral
significant difference between an experimental and segments. AIS B has some sensory function below the
control arm of a clinical trial will be relatively large if neurological level, including S4–5, but not motor
the trial begins soon after injury and if the clinical function. AIS C has some motor function below the
endpoint relies solely on differences in AIS grades or neurological level, but more than half of the key muscles
motor scores, as in most previous SCI trials. In order involved have a muscle strength score which is o3
that SCI clinical trials can be undertaken in a more (Figure 1). AIS D has motor function below the
effective manner (with a manageable number of neurological level but more than half of the key muscles
subjects) and within a reasonable time frame, alternative have a muscle grade of 3 or more. AIS E indicates
methods for analysing motor, sensory and autonomic normal motor and sensory function.
function need to be validated as clinical outcome tools. Tetraplegia (quadriplegia) is the term used to refer to
These approaches are discussed in the second paper of loss of motor and/or sensory function due to damage
this series. to the spinal cord, with impairment of the upper
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JW Fawcett et al
15

extremities as well as trunk, legs and pelvic organs. This preservation of impaired motor or sensory function
implies damage to the spinal cord at or above the C8 (usually, but not always, within a few segments of the
level. neurological level).
Paraplegia is the equivalent term used to refer to The Benzel scale is a variant of the AIS classification
functional loss below the level of the upper extremities, that was used for the Sygen trial, in which the AIS grade
which may involve loss of motor and/or sensory D is expanded. Grade 1 ¼ AIS A, Grade 2 ¼ AIS B,
function within the trunk, and/or the lower extremities. Grade 3 ¼ AIS C, Grade 4 ¼ AIS D, Grade 5 ¼ AIS D,
This implies damage to the spinal cord below the level of Grade 6 ¼ AIS D, Grade 7 ¼ AIS E. For a full
C8 and may include damage to conus medullaris or description see Coleman and Geisler.21
cauda equine (ie neural tissue within the spinal canal).
Complete and incomplete SCI are other terms used to
describe the overall severity of SCI. Technically, SCI is
classified as complete if there is no motor or sensory Acknowledgements
function preservation in the sacral (most caudal) spinal We are grateful for the support of The International Campaign
segments. Thus, incomplete SCI is where there is some for Cures of spinal cord injury Paralysis (ICCP), which
preserved motor or sensory function at the lowest sacral provided the funding for the authors’ travel and accommoda-
spinal level (S4/5). There can be extensive variability in tion expenses. The ICCP represents the following member
the degree of preserved function after incomplete SCI. organizations: Christopher Reeve Foundation (USA), Institut
ASIA sensory and motor assessments form the basis pour la Recherche sur la Moëlle Epinière (FRA), International
for the International Standards for Neurological and Spinal Research Trust (UK), Japan Spinal Cord Foundation,
Functional Classification of SCI (the ASIA Interna- Miami Project to Cure Paralysis (USA), Paralyzed Veterans of
tional Standards) and are conducted in the supine America (USA), Rick Hansen Man In Motion Foundation
position and involve a qualitative grading of sensory (CAN), SpinalCure Australia, and Spinal Research Fund of
Australia. We thank the European Multicenter study in Spinal
responses to touch and pinprick at each of 28 Cord Injury (EM-SCI) for sharing their data on spontaneous
dermatomes along each side of the body and a recovery after spinal cord injury. ICORD (International
qualitative grading of the strength of contraction within Collaboration On Repair Discoveries) in Vancouver provided
10 representative (key) muscles, primarily identified with all logistical coordination and support. All panel members
a specific spinal level, 5 for the upper extremity (C5–T1) (authors) volunteered their time and effort. Finally, we are
and 5 for the lower extremity (L2–S1) on each side of most grateful for the input and constructive comments from a
the body (Table 1). countless number of SCI investigators over the past 2.5 years.
ASIA motor score is calculated by assigning to one
muscle group, innervated and primarily identified with
a specific spinal level, a score between 0 (no detectable References
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JW Fawcett et al
16

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Supplementary Information accompanies the paper on the Spinal Cord website (http://www.nature.com/sc)

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