A review and update of experiment and clinical studies of spinal cord injury
A REVIEW AND UPDATE OF EXPERIMENT AND CLINICAL
STUDIES OF SPINAL CORD INJURYl 1 2
0 Norman Don Memorial Lecture, International Conferencoen Recent Advances in Neuro? traumatology , 21
1 Supported in part by NINCDS programme grant
2 By W. F. COLLINS, M.D. Cushing Professor of Surgery, Chief, Section of Neurological Surgery, Yale University School of Medicine , New Haven, Connecticut, U,S.A , USA
I WOULD like to express my appreciation for the invitation to give this lecture honouring Professor Norman Dott. I first met Professor Dott when I was a resident and later had a chance to get to know him better when I was a young neurosurgical faculty member. He was one of the giants of neurosurgery, and he was one giant that on meeting did not disappoint a neophyte. He was gentlemanly, academically caustic in a conference or discussion, was confident, but not overbearing, and judged people by his own and sometimes unusual standards. He almost overwhelmed me by spending time listening to some work I was doing to support a hypothesis about pain. I might add, his comments were pertinent and helpful even though the subject was not of prime interest to him. Norman Dott did what every young neurosurgeon hopes he or she can do. He became a master surgeon, contribu ted to the development of his chosen field and trained pupils to continue his influence. Perhaps one of the reasons for his success was his ability to get succintly to the heart of the matter. Sometimes when I do a transsphenoidal approach to the pituitary, I remember his brief but caustic comment when I told him early in my career that I was not using the approach, because I had been taught it resulted in inadequate resections. He implied I hadn't thought the situation through. I quote him, certainly not word for word but in the sense of his meaning, 'No matter what you were taught, you should know the major reason remains that the patients do better'. Perhaps we, working in the area of spinal cord injury, are missing something that will allow 'the patients to do better'. I an certain, he would like us to find that something. The title of my talk is A Review and Update of Experimental and Clinical Studies of Spinal Cord Injury . You will have to allow me in condensing such a broad subject to emphasise my interests and not be upset if this prejudice omits some aspects that you feel are important. I am certain that all of you are aware that a professor of neurosurgery cannot and does not physically nor even conceptually do all the work he presents from his department. Since I will try to present a considerable amount of work in a brief time and cannot give individual credit to my co-workers for what they contributed, I would like to thank them for making this lecture possible and for making my professional life more interesting and satisfying. The National Institute of Neurological Communicative Diseases and Stroke (NINCDS) of the National Institutes of Health in the
United States has for the past decade supported centres for the study of
the acute care of spinal cord injury, and Yale has received one of these
centre grants. I wish to thank the Institute, for without their support our
experimental groupcould not have functioned nor even existed in its present
It was not until late in the last century that progress was made in the
study of spinal cord injury. The early impact models of Schamus (1890),
Watson (1891) and Spiller (1899), (Dohrmann, 1972), produced varied
histological changes but suggested the possibility that a progressive lesion
occurred following the injury. To study this lesion, a reproducible stand?
ardised spinal cord lesion was required and, Allen in 19II and 1914, de?
veloped the drop weight model capable of producing graded lesions
quantified as gm/cm of impact measured by the product of the weight times
the distance it was dropped. With this model, descriptions of partial and
complete lesions, the low threshold of the grey matter to contusion, the
resulting central haemorrhagic changes and the cavitation that occurs follow?
ing an impact injury have evolved
(McVeigh, 1923; Ferraro, 1927; Ducker
et ai., 1971)
. Modifications of the Allen model have been the most com?
monly used experimental model for the study of spinal cord injury. There
have been other models. Cajal (Ramon Y Cajal, 1982) in the second decade
of this century studied the changes that occurred at the site of a sharp
transverse lesion of the mammallian spinal cord and described the formation
of axonal terminal end-bulbs that appear similar but larger than the growth
cones of peripheral nerves. He also described the autolysis of 200to 700
microns of the edge of the spinal cord at both borders of the lesion.
Another model that has had considerable study is the compressive injury
model as used by Tarlov and his co-workers and Tator and his co-workers.
Tarlov (1953, 1954a, 1954b, 1957) used an epidural balloon for rapid and
slow compression and Tator and his co-workers
(Tator, 1972; Deecke and
Tator, 1973; Tator, 1973; Rivlin and Tator, 1977; Rivlin and Tator, 1978)
first used a compressing circumferential sleeve and more recently a spring
clip. While the compressive models improve the reproducibility of the
lesion, a question as to the model's relationship to the clinical situation of
an acute impact remains. In all models the same process described by
Cajal occurs but over a larger area, contributes to the cavitation that follows
cord injury and the process has been proposed as one of the barriers to
spinal cord regeneration. The process has been shown to proceed in trans?
verse, caudal and rostral directions, and has been used in support of the
concept of a progressive secondary injury.
A major impetus for the experimental study of spinal cord injury has
been this concept of secondary injury or the hypothesis that response of
the spinal cord to injury causes a portion of the resulting neurological dys?
function. Using a variation of the Allen drop weight model, one of the
first to test experimentally that hypothesis, was Freeman and his co?
workers in the late 1940Sand early 1950Swho proposed that loss of vascular
perfusion secondary to pial encasement of an oedematous haemorrhagic con?
tused spinal cord was the cause of secondary injury
(Freeman and Wright,
1953; Joynes and Freeman, 1963)
. They reported an improvement in ex?
pected neurological dysfunction when myelotomy or hypertonic solution
was used as a treatment for graded impact injury. In the 1960sAlbin and
White and their co-workers
(Albin et ai., 1968)
reported a protected effect
of local hypothermia on primate and canine spinal cord when applied within
a few hours of impact injury, proposing that hypometabolism protected the
injured spinal cord from secondary injury. This suggested a metabolic
cause of the secondary injury. No evidence from the clinical use of
myelotomy, solute diuretics or local hypothermia has supported these
experimental findings although it must be said that none of the clinical
studies to test these therapies was designed to overcome the problems that
are inherent in clinical studies of spinal cord injury. Osterholm in the
(Osterholm and Mathews, 1972a)
proposed that accumulation of
norepinephrine at the site of injury caused localized vasoconstriction and
membrane disruption. He supported this hypothesis by showing the pro?
tective effect of alpha methyltyrosine an inhibitor of the synthesis of
norepinephrine in decreasing the central haemorrhagic changes
and Mathews, 1972b)
. These studies were an impetus to the NI NCD S
to support more work on experimental spinal cord injury and, therefore,
were valuable, but their results failed to stand up to further investigation.
We were interested in Osterholm's hypothesis since there are drugs, safer
than alpha methyltyrosine, that can inhibit synthesis of biogenic amines.
The concentration of norepinephrine in normal cat spinal cord varies from
level to level (Rawe et at., 1972a) but no increase of norepinephrine was
found at the site of an experimentally produced contusive injury
et at., 1974; Rawe et at., 1977b; Rawe et at., 1977C)
. Alpha methyltyrosine
causes hypotension and we could duplicate the decrease in central
haemorrhage that he found, with hypotension, which, however, caused
increase in the resultant neurological deficit.
Let me take a few minutes to discuss the impact model of spinal cord
injury. There are many problems in using it and they should be considered
when evaluating experimental studies (Collins and Kauer, 1979). Physio?
logical factors that alter blood flow or metabolism, alter outcome, and the
minimal controls in any experimental spinal cord injury model must include,
body temperature, blood pressure, P02, PCo2 and blood pH
(de la Torre
and Boggan, 1980)
. Many studies have failed to consider these controls
and entered variables that make interpretations of the result difficult or
impossible. A major technique in studying possible causes of secondary
injury is to determine the effect of various treatment regimes on expected
neurological dysfunction following an injury
(Ducker and Hamit, 1969;
Campbell et at., 1973; de la Torre, 1981)
. It is thus important that
experimental spinal cord injury outcome be predictably consistent. Several
studies have assumed that in the Allen model a particular gm/cm force as
measured by weight size and distance dropped defines a lesion and its
expected neurological deficit. Our laboratory has shown a correlation of
resultant neurological deficit and size of spinal cord lesion measured both
in volume and maximum cross sectional diameter. Dohrmann, Panjabi and
Banks (1978) measuring volume size of the lesion showed no correlation
between volume of the lesion and gm/cm measurements of the drop weight
model or impounder velocity but rather a correlation with energy and impact
transmitted. They demonstrated a five fold difference in lesions produced
by a 400gm/cm impact in the cat when height and weight were changed
to keep this product constant. Other variables in the Allen model such as
the type of animal, size of the weight, shape of the impact surface, not using
or using an impounder resting on the dura and its shape and type of spinal
column fixation all alter the type and extent of the lesion produced (Tator,
1972). It is important that any technique used is carefully evaluated in the
laboratory using it, and continually checked as a control during any ex?
perimental study, to be certain an unobserved variable has not appeared,
or a variable altered, altering the expected outcome. Another concept when
evaluating a study of secondary injury is that of the trauma-dose curve
(Collins and Kauer, 1979). It is apparent that at the lower end or low
impact portion of the curve that almost all therapies as well as time will
improve the neurological loss which is usually transient and, therefore, the
ability to evaluate a therapy is difficult. At the high impact end of the
curve only regeneration might be expected to work since physical inter?
ruption of fibers may have occurred. There is a sharp straight slope of the
trauma-dose, neurological deficit curve in our laboratories in the cat showing
both the narrow range where our model of impact injury can be used to
study therapy and the single expotential quality of the curve suggesting
that a single factor, impact itself, is the major determinant of the curve.
Our studies as well as studies from other laboratories have indicated
that changes in spinal blood flow and the production of oedema may alone
or in combination be a factor in secondary injury
(Griffiths, 1976; Stewart
and Wagner, 1979)
. Post experimental spinal cord blood flow has been
measured in our laboratories by the hydrogen clearance method and by
carbon-14 antipyrine autoradiography
(S enter and Venes, 1978; Senter and
. The studies demonstrate loss of autoregulation 30 to 40
minutes after injury with decrease in local spinal blood flow, with post
injury decrease in systemic blood pressure, and increase in local spinal cord
blood flow with elevation in blood pressure. Both post injury hypotension
and hypertension, the latter probably secondary to increased central
haemorrhage, cause increased neurological deficit. More recent work has
shown that reactivity of the local blood vessels to changes in pH and PCo2
remains at a time when autoregulation to pressure has been lost and these
complex combinations may explain some of the discrepancies reported in
many post experimental spinal cord injury blood flow studies. Although
the amount of oedema and its distribution does roughly correlate with the
amount of force applied to the cord, in the intermediate zone of the trauma?
dose curve which appears to be the most important portion of the curve to
study, the amount of oedema formation and its extent does not correlate
with neurological loss. The distribution of oedema following an impact
injury as seen in fluorescent histological studies with fluorosine tagged
albumin as the agent being photographed, is along white matter tracts of
( S tewart and Wagner, 1979)
. It can extend considerable distances
cephalad and rostrad and is reminiscent of the white matter spread seen in
cerebral hemisphere injuries. Studies attempting to alter the extent and
distribution of oedema have not been as fruitful as had been expected.
The agents used have included both hypertonic solutions and steroids.
Our emphasis in the laboratory has shifted to the study of early changes
in the axons, that is, within hours of injury and its relation to oedema and
blood flow rather than just the study of oedema following impact injury.
Table I lists drugs and treatments that have been shown to have an
effect on the expected outcome of neurological deficit produced by experi?
mental spinal cord injury
(Black and Markowitz, 1971; Campbell et al.,
1974; Hedeman et al., 1974a; Hedeman et al., 1974b; Lewin et al., 1974;
Flamm et at., 1977; Nemecek, 1978; de la Torre and Boggan, 1980; Dolan
et at., 1980; Brodner et at., 1981; Faden et at., 1981a; Faden et at., 1981b;
Hall and Braughler, 1981; Means et at., 1981; Young et at., 1981; Braughler
and Hall, 1982; Flamm et at., 1982; Hall and Braughler, 1982)
. The changes
in the expected neurological deficits in the above protocols have been con?
firmed by more than one laboratory but almost all agents have in some
study failed to show an effect in one or more other laboratories, which is
one of the reasons I mentioned the controls necessary and the trauma dose
curve concept in impact models. Taking the entire group together the
experimental results indicate that some process or combination of processes
produce a secondary injury that may be amenable to therapy. Whether this
is caused by altered blood supply, oedema, breakdown of organelles and
the release of lysosomal enzymes, by disruption of the adjacent tissues from
the pressure of the enlarging end-bulbs, by calcium influx into the cut end
of the axons, by prostaglandin cascade effect on the surrounding tissue, by
local biogenic amine concentration, or by some unknown factor or a com?
bination of these remain unproven hypotheses. I will not go into the
hypotheses of the mechanisms proposed on the basis of results obtained
from experimental treatment protocols but rather summarise my interpreta?
tion as follows:
I. A secondary injury results from the reaction of the spinal cord to
2. There is more than one mechanism causing the injury.
3. Aberations in spinal cord blood flow including alterations in micro?
circulation may be a factor. Agents causing vasoconstriction, vaso?
dilitation, alteration in endothelial cell integrity, and/or changes in
platelet aggregation may alone or in combination contribute to the
4. Biochemical and mechanical alteration of cell membranes are another
factor. The possible biochemical agents are many.
5. While oedema formation may contribute to the mechanical
disruption of membranes, it appears to be an epiphenomena, well
tolerated within wide ranges both of extent and amounts in white
A major limiting factor with experiments concerning secondary injury
have been that they consist mainly of recording phenomena related to the
effect of different therapy and have not examined in an organised fashion
the mechanisms involved. These basic mechanism areas must be studied
and since the numbers of possible factors present at the site of injury
precludes a treatment shotgun approach, the defining of basic mechanisms
involved, and the time sequence of their activity, appears to be the direction
While the difficulties involved in the evaluation of the experimental
studies of spinal cord injury are a problem, these difficulties are ex?
ponentially increased in number and complexity in the evaluation of the
clinical aspects of spinal cord injury. An aspect not involved in animal
studies is that of the impact of spinal cord injury on society. Not counting
the loss of productivity of the victims, the direct medical care costs of new
spinal cord injuries in the United States, is over a half billion dollars a year
and with the present life expectancy of spinal cord injured patients and
medical care necessary for their survival, the resulting medical cost total is
well past a billion and a half dollars a year. The majority of these costs
in the United States are born by the Federal Government even in our
private medical care society. To plan for the effective use of such sums
of money, accurate epidemiological studies were required and the National
Institutes of Health have supported epidemiological studies as well as
experimental and clinical studies of spinal cord injury in order to determine
what is needed and what might be done both for the victim and for society .
In the past few decades a number of epidemiological studies have been
published that have shown marked variations in incidence, severity and
costs of spinal cord injury. Table II is an example of the variations in the
reported incidences of spinal cord injury from four countries, with three
of the studies coming from the North American continent and two from
the United States
(Benes, 1968; Gehrig and Michaelis, 1968; Sutton, 1973;
Botteral et ai., 1975; Kraus et ai., 1975; Webb et ai., 1978)
. Despite similar
conditions in the North American areas studied, there is almost a four fold
difference in incidence and almost a five fold difference among the different
countries. Part of the problem is what constitutes a reported case and how
is it identified. Kraus' study from California with the highest incidence
of 55 per million included all injuries, those that died before admission to
a hospital, those that were admitted, those that were seen but not admitted,
and those identified by any means within a defined population. The same
study showed an incidence of hospital admissions of about 33 per million,
similar to the 28 per million shown by Webb et al.
(Webb et al., 1978)
of our group at Yale in 1975-76. That survey was of all spinal cord injury
hospital admissions in Connecticut. Bracken et al. (Bracken et al., 1981)
of our faculty, in trying to develop a less costly method used identified
hospital discharge codes in the data bank of the National Center for Health
Statistics and a subset to correct for multiple admissions, and arrived at a
figureof approximately 40per million spinal cord injury hospital admis ions
per year. A 1980study of the National Institute of Health using a selective
population survey arrived at a figure of 50per million population/year. I
mention these variations in the studies not to criticise the studies but to
point out the problems that have arisen in attempting to define as simple
a portion of the clinical problem as the incidence of the event of spinal cord
injury in our population. There is, with more sophisticated techniques, a
concensus being attained in this quest of an incidence at about 45/mil/
pop/yr in the United States. No such concensus is being approached in
other aspects of the problems of spinal surgery.
The British Isles are famous in our medical meetings, and our mal?
practice courts for non-interventional care of spinal cord injury with the
results from the Stoke Mandeville group being the basis to indicate that
the non-surgical postural reduction approach is more effective than the
relatively common concept in the States of rapid reduction and frequently
early surgical intervention (Frankel et al., 1967). I would like to review a
few of these clinical studies. Table III is to briefly remind you of the
Frankel Functional Classification of spinal cord injury that can be used for
A-No sensory or motor function
B-Incomplete sensory-No motor function
C-Incomplete sensory-No useful motor function
D-Incomplete sensory-Useful motor function
E-Normal function-May have spasticity
comparing different series. The A group is a total lesion and the E group
is normal function with or without abnormal reflexes. In order to decrease
variables, I have picked cervical spinal cord injuries. There are enough
variables in any clinical series to please the most dedicated biostatistician and
using one anatomical area helps limit if not overcome some of these variables.
Table IV is a review of three modern series--one the Stoke Mandeville
series and the other two from the States and one not so modern series
(Hartwell, 1917; Frankel et al., 1967; Young and Dexter 1978; Maynard
et al., 1979)
. The vertical axis of each box is the functional grading on
admission to and the horizontal axis on discharge from the hospital. Thus,
as in the Southwest Region series a patient with a 'C' on admission and an
'A' on discharge deteriorated while one with a 'B' on admission and a 'D'
on discharge improved. Unchanged patients form an oblique line from
the upper left hand corner, that is, the 'AA', 'BB' to the lower right hand
corner of each block. In case you are discouraged with the present treatment
of spinal cord injury, the fourth box was made by extrapolation of data
presented by James Hartwell in an article published in 1917 in the Boston
Medical and Surgical Journal (Hartwell, 1917). It consisted of a series of
133 cases of spinal cord injury admitted to the Massachusetts General
Hospital between 1900and 1914, 34 patients had cervical spinal cord in?
juries. The only change in that box is that the 'A' discharge line is mortality
because with one exception no one with a complete lesion on admission
survived, and that exception died I I months after admission. The causes
of spinal cord injury in the Boston series had a different distribution than
modern series with 62 per cent caused by falls, 19 per cent from forces that
cause acute flexion, such as, sports or falling objects, 5 per cent from
altercations, with no mention of gunshot wounds and 8 per cent from vehicle
accidents. The majority of the vehicles accidents involved trains but one
was an automobile accident. Twenty-three of the cervical spinal cord injury
patients were X-rayed and twelve fractures were diagnosed. The use of
X-ray for diagnosis was just starting and a comment was made of the
difficulty in diagnosing fractures of the cervical spinal column with an
anterior/posterior X-ray and the difficulty in obtaining lateral X-rays of
the lower cervical spine. Eleven of the 34 patients underwent lamin?
ectomies, 7 within the first 24 hours and 9 within the first week, evidence
for some historical continuity of opinion in the States. There were 10
postoperative deaths including one patient each in 'B' and 'C' category
on admission to the Massachusetts General Hospital. The eleventh patient
who improved after a laminectomy from an 'A' on admission to a 'C',
developed complications and remained at the hospital until he died 8 months
later from renal failure. While listed as a complete lesion on admission,
at post-mortem examination he showed a significant portion of the spinal
cord intact and Mixter and Chase reported this case in 19?4 as evidence
of the value of laminectomy in protecting the injured spinal cord
and Chase, 1904)
. Dr Hartwell, however, concluded from this series that
laminectomy was not of value and postulated that at least two patient might
have had functional return if they had not been operated upon and that the
remainder benefited only by having their agony shortened by the surgery.
This attitude of despair concerning spinal cord injured patients pre?
vailed up to and through most of World War II, even though Riddoch and
Head in England during World War I had shown that paraplegic patients
could survive when given the correct care. With these surviving patients,
Riddoch in 1917,
settled the long standing argument as to
whether the isolated human spinal cord functioned and, therefore, laid the
groundwork for possible treatment by techniques of regeneration. He
demonstrated spinal reflexes in the human and their loss with sepsis and
joint contraction. The spinal cord injury patients however who survived
often became nonfunctional chronic nursing patients, addicted to opiates
and usually succumbed within a year or two to urinary tract dysfunction,
sepsis from decubiti and/or pulmonary disease. It was the concepts and the
enthusiasm of Sir Ludwig Guttmann in England who almost single handedly
changed this. He believed and demonstrated that with appropriate care
the associated complications of spinal cord injury could be controlled in?
definitely and that with rehabilitation the spinal cord injury victim could
be returned to an independent productive life. This led to the Stoke
Mandeville Centre concept and the results led to changes throughout the
entire western world as to how spinal cord injury should be handled. His
success was so great that his concepts of the treatment of spinal cord injury
became almost revered and in much of the western world questioning and
investigation of the early care of the injured spinal cord patient ceased.
Although the rehabilitation results were spectacular compared to what had
preceeded, the return of spinal cord function has remained almost un?
changed from the time of Riddoch to the present. No scientifically valid
effort to study clinically the hypothesis arising from experimental studies,
was made until a few years ago. A patient with a spinal cord injury,
although now often capable of self care and productive work, has no more
significant possibility of return of spinal cord function with treatment in
1982 than he did in 1917 nor have his physicians attained any scientifically
valid new information to use to increase those chances. But to return to
the other series to illustrate two points. They are what happened among
these series to patients with complete lesions on admission and what percent
of patients deteriorated with treatment. At first glance the fact that 8 per
cent of the Stoke Mandeville total functional loss or 'A' admission patients
improved to a functional level would document the superiority of their
treatment. However, the California series also had an 8 per cent improve?
ment even though 29 per cent received early operations and almost all had
rapid reduction of their fracture. Maynard in the California group reviewed
the five charts that constitute that 8 per cent and found all had some impair?
ment of consciousness at the time of the first examination. Other reasons
for improvement in total lesions in other series are very early admission
with improvement in the first few hours after injury, or inadequate ad?
mission neurological evaluations for any reason. In my opinion with any
of the presently used treatment regimes, a series of spinal cord injury patients
that has more than an occasional complete lesion patient showing functional
return, indicates the authors of that series have either discovered the Holy
Grail of spinal cord injury, have a largenumber of admissions within minutes
of injury, or have an error in admission examinations. I intellectually
cannot believe that slow reduction, and non concern for compression of
the spinal cord for days is that sought for Grail.
Does the lack of deterioration in the Stoke Mandeville series demon?
strate the superiority of the method? The California series also had no
deterioration. The common denominator of both series is they are spinal
cord injury centres not acute trauma hospitals. One bias may be that the
referred patients have rehabilitation potential and the patients with other
injuries, cardiovascular disease or other medical conditions are either not
referred or referred when these conditions are stable. The Southwest
Region series contains admission exams to acute hospitals and has the highest
deterioration rate of these three series. Finally and perhaps most import?
antly, it should be noted that in reporting the Stoke Mandeville patients,
the series is defined as follow, and I quote 'All patients who had had
operations on the spine before admission-all patients who died in the first
three months or who were discharged from Stoke Mandeville Hospital
prematurely for any reason-are excluded from analysis'. The number
and condition of these patients are not discussed further. From a statistical
point of view, a major bias could exist with their exclusion.
I know I have been critical of the Stoke Mandeville series, not because
I do not appreciate what has been accomplished there, but with critical
review even their series does not disprove the hypothesis that is based on
evaluation of many series and my personal experience. The hypothesis is
that no treatment of spinal cord injury that is within the bounds of good
medical care can be shown to be superior to any other. I conclude that none
of these present series or any other series demonstrate a statistically
significant better or worse result from one form of therapy rather than from
It is suggested from the experimental studies of spinal cord injury that
there is some loss of function of the spinal cord that relates to the response
of the nervous system to injury that may be controlled by therapy. In the
clinical situation this may apply to only a portion of the cases and have
limited effect but even that limited effect can have significance to the social
problem and may mean the difference of nervous system functional life
rather than a mechanical functional life for the individuals helped. Patients
with rapid onset of complete loss of spinal cord function following injury
are not likely to be the group where the effectiveness of any treatment can
be demonstrated and I conclude, that since there is no evidence to support
that any specific treatment of spinal cord injury is better we morally can
and medically should develop prospective randomised studies in order to
study and improve the acute treatment of spinal cord injury. These almost
certainly will have to be multicentre studies since experimental data indicates
that at the most the first 48 hours is the window for treatment and probably
only the first 4-12 hours, the promising portion of the trauma-dose curve is
the one containing partial lesions and there are multiple variables requiring
large numbers of cases for statistical significance to be obtained. There is
a paucity of cases in any one centre or even one area of the country that
can fulfill the requirements for a satisfactorily rated study.
We have made a start with a randomised collaborative study but it is
only just a start. In 1977 we submitted to the NINCD S followinga two-year
feasibility study, a project to evaluate low-dose, high-dose steroids in the
treatment of spinal cord injury to be organised at Yale. The steriod used
was methylprednisolone with high-dose protocol of a 1000mgm loading
dose and 1000mgm per day for 10 days and the low dose of 100mgm
loading and 100mgm per day. I personally would have preferred a study
that included a placebo arm but even though there is no clinical evidence
that steroids are of value in spinal cord injury we could not get agreement
of the various centres proposed for the study to use a placebo. The reasons
were both moral in that they believe the experiental studies showed that it
had value, and medicolegal, feeling that any physician not using steroids
might be open to a malpractice suit. The first patient to enter the study
was on 17 February 1979 and the last on 6 November 1981. Three
hundred and thirty patients that were randomised into the two steroid treat?
ments. The types and frequency of injuries are shown in Table V. Of
the randomised patients, 24 were excluded for various reasons. The
excluded patients were evenly distributed between the two steroid protocols
and have been analysed to show that there is no bias caused by their
exclusion. The UpJohn Corporation provided the two doses of methyl?
prednisolone in uniquely numbered look alike packages and organised
random codes. They otherwise did not participate in any aspect of the trial.
An advisory committee was established by the NIN CD S to monitor the
REVIEW AND UPDATE OF SP INAL CORD INJURY
conduct of the trial and data collection and an analysis was conducted to
monitor intermediate results with only two investigators, myself and an
epidemiologist, Dr Bracken, being aware of the assignment of patients in
the randomisation during the study. Standard forms for reporting the
history, neurological examination, treatment and complications were de?
veloped during the previous two-year feasibility study. The only significant
difference between the two treatments modes was a higher rate of wound
infection in the high steroid group. The results of the study will be pub?
lished this coming year. Only 6 weeks and 6 months follow-up are available
at this time since the complete evaluation for the one year follow-up cannot
be done until mid-I983. Five groups of patients were looked at and a
multivariate analysis was done of the results, Quadriplegia with total sensory
loss or Frankel Grade A and paraplegia with total sensory loss also a Frankel
Grade A were combined as were quadriplegic with partial sensory loss and
paraplegic with partial sensory loss or a Frankel Grade B, while those with
some motor function and variable sensory loss or Frankel Grades C and D
were combined as a group (Table VI). At 6 weeks there was a trend that
suggested that the high-dose steroids may be having some effect in the C
and D group but it was not statistically significant and at 6 months there
does not appear to be a statistical difference between the patients in high?
dose vs the patients in low-dose groups.
I know of the cost and the amount of work that was done attempting
to evaluate a single drugtwo dose treatment and it produced a negative result.
We as physicians must realise that any treatment which has been considered
to alter the acute care of the spinal cord injured patient must be evaluated
in a similar fashion. Anything less than this is not acceptable but no
evaluation is even less acceptable.
In the few remaining minutes I would like to discuss the directions
we are taking at Yale in our continuing work with spinal cord injury.
One is a continuation of animal models in spinal cord injury in the hopes of
defining mechanisms of secondary injury more accurately. Another is the
continuation of the clinical series of prospective treatment protocols, and
the third is the study of central nervous system regeneration. We have
decided to study regeneration in the central nervous system because we
believe it is the only hope for the majority of spinal cord injury victims.
Some 20 odd years ago, I worked on central nervous system regeneration
and after a few years came to the conclusion that none of the models we
were using nor the methods available were able to answer even the simple
question as to the ability of central nervous system neurons to regenerate.
I swore, at that time, I would not get involved with central nervous system
regeneration experimentation again, but now the question of central nervous
system neuronal regeneration can be answered in the affirmative but whether
central nervous system neurons can functionally regenerate, and what starts,
stops and controls the process cannot be answered. Working with Professor
Cohen in the Department of Biology, Professor Shepard in Anatomy and
Dr Van den Pol in my department, we have two models of spinal cord re?
generation and a model of neuronal regeneration that can be asked these
questions. The first is in the Lamprey eel that does functionally regenerate
a transected spinal cord and whose giant reticulo-spinal neurons make it
possible to follow the course of individual identifiable fibers during re?
(Wood and Cohen, 1979)
. Preliminary observations suggest
anatomical junctions, including gap junctions, their numbers and positions
on the regenerating axon and not glial or fibrous scar limit the amount of
spinal cord regeneration in the Lamprey. They also suggest that electrical
fields may alter both initial fibre die back and nondirectional branching.
The second model is in the rat and is a study of a hypothalmic spinal tract
that contains neurophysin. Its fibres can be identified by immunohisto?
chemical techniques proximally and distally to a spinal cord lesion. This
allows identification of regenerating fibers coming from the proximal end
of a tract in a lesioned spinal cord. This model will allow studies in a
mammal to check the findings of the Lamprey model. The third model
of regeneration can be asked more basic questions of neuronal reorganisation
during regeneration by studying olfactory neurons in the mouse and sala?
(Greer and Shepherd, 1982)
. These have been demonstrated to
regenerate. All three models are under active investigation. While the
work is a long way from any application to the clinical theatre, the models
allow questions to be asked and data that can be evaluated to be
In summary, although considerable advances have been made in the
care of the total patient with spinal cord injury, little has been accom?
plished in improving the spinal cord functional result. No clinical therapy
for spinal cord injury has shown superiority in accomplishing the goal of
protecting the spinal cord from further loss of function after injury or
reversing the initial injury and no clinical studies have given support for
the hypothesis that secondary injury is important in determining resulting
neurological deficits. The need to clarify the problems of secondary injury
is apparent but prevention of injury and techniques to re-establish spinal
cord function after an injury are the most likely way of altering the problems
faced by victims of spinal cord injury. Neurosurgeons probably have to be
optimistic in order to continue in neurosurgery but even so the present
models for regeneration are so interesting that I hope my career can extend
as long as it will be necessary to study these and other models that are
certain to be developed. I am too old to believe that we can prevent our
population from killing or maiming themselves and, therefore, I hope that
sometime in the future a Dott lecturer can announce that techniques for
functional regeneration of the central nervous system are available or at
least close to hand, I certainly cannot, but I believe a future lecturer will.
ALBIN , M. S. , WHITE , R. J. , ACOSTA-RuAG. , et al. ( 1968 ). Study of functional recovery produced by delayed cooling after spinal cord injury on primates . J. Neurosurg. , 29 , II3 - 120 .
ALLENA , . R. ( 191I ). Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column . J. A.M. A ., 57 , 878 - 890 .
ALLENA ,. R. ( 1914 ). Remarks on the histopathological changes in the spinal cord due to impact. An experimental study . J. Nerv. Ment. Dis. , 41 , 141 - 147 .
BENESV ,. ( 1968 ). Spinal cord injury . Bailliere ,London.
BLACKP , . , MARKOWITZR , . S. ( 1971 ). Experimental spinal cord injury in monkeys: comparison of steroids and local hypothermia . Surg. Forum , 22 , 408 - 411 .
BOTTERAEL., H. , JOUSSEA ,. T., KRAUS , A. S. et al. ( 1975 ). A model for the future care of acute spinal cord injuries . Can. J. Neuro. Sci. , 2 , 361 - 380 .
BRACKENM ,., FREEMAND ,. H. & HELLENBRANKD. ,( 1981 ). Incidence of acute traumatic hospitalized spinal cord injury in the United States, 1970 - 1977 . Am. J. Epidemiology, 113 , 615 - 622 .
BRAUGHLERJ., M. & HALL , E. D. ( 1982 ). Correlation of methyl prednisolone levels in cat spinal cord with its effects on (Na+ + K+) -ATPhase lipid peroxidation and alpha motor neurone function . J. Neurosurg. , 56 , 838 - 844 .
BRODNERR ,. A., VANGILDERJ , . c. & COLLINSW,. F. ( 1981 ). Experimental spinal cord trauma: Potentiation by alcohol . J. Trauma , 124 - 129 .
CAMPBELLJ ,. B., DECRESCITOV,. & TOMASULAJ,. ( 1973 ). Experimental treatment of acute spinal cord contusion in the cat . Surg . Neurol., I, 102 .
CAMPBELLJ ,. B., DECRESCITOV,., TOMASULAJ ,. J. et al. ( 1974 ). Effects of antifibrinolytic and steroid therapy on the contused spinal cords of cat . J. Neurosurg., 40 , 726 - 733 .
COLLINSW ,. F. & KAUERJ ,. S. ( 1979 ). The past and future of animal models used for spinal cord trauma . In Neural Trauma , Popp, A. J. et al. (eds),Raven Press,New York.
DEECKE , L. & TATOR, c. H. ( 1973 ). Neurophysiological assessment of afferent and efferent conduction in the injured spinal cord . J. Neurosurg. , 39 , 65 - 74 .
DE LA TORREJ ,. C. ( 1981 ). Spinal Cord Injury: review of basic and applied research . Spine, 6 , 315 - 335 .
DE LATORREJ ,. c. & BOGGAN , J. E. ( 1980 ). Neurophysiological monitoring in rat spinal cord trauma . Exp. Neurol. , 70 , 356 .
DOLAN , E. J. , TATORC ,. H. & ENDRENYIR, . ( 1980 ). The value of decompression for acute experimental spinal cord compression injury . J. Neurosurg. , 53 , 749 - 755 .
DOHRMANNG ,. J. ( 1972 ). Experimental spinal cord trauma. A historical review . Arch. Neurol. , 27 , 468 - 473 .
DOHRMANNG ,., PANJABIM ,. & BANKSD,. ( 1978 ). Biomechanics of experimental spinal cord trauma . J. Neurosurg. , 48 , 993 - 1001 .
DUCKER , T. B. & HAMIT , H. I. ( 1969 ). Experimental treatments of acute spinal cord injury . J. Neurosurg. , 30 , 693 - 697 ?
DUCKER , T. B. , KINDT , G. W. & LEMPE , R. G. ( 1971 ). Pathological findings in acute experimental spinal cord injury . J. Neurosurg. , 35 , 700 .
EIDELBERGE ,. , STRAEHLEDY. , ERSPAMERR, . & WATKINSc,. F. ( 1977 ). Relationship between residual hindlimb-assisted locomotion and surviving axons after incomplete spinal cord injuries . Exp. Neurol. , 56 , 312 - 322 .
FADEN , A. I. , JACOBST ,. P. & HOLADAYJ,. W. ( 198Ia ). Opiate antagonists improve neurologic recovery after spinal cord injury . Science , 211 , 493 - 494 .
FADEN , A. I. , JACOBS, T. P. , MONGEY ,E. et al. ( 198Ib ). Endorphins in experimental spinal injury: therapeutic effect of naloxone . Ann. Neurol., 10 , 326 - 332 .
FERRAROA , . ( 1927 ). Experimental medullary concussion of the spinal cord in rabbits: histological studies of the early stages . Arch. Neurol. Psychiat. , 18 , 357 - 373 .
FLAMM , E. S. , DEMOPOULOSH , . B., SELIGMANM,. L. et al. ( 1977 ). Ethanol potentiation of central nervous system trauma . J. Neurosurg. , 46 , 328 - 335 .
FLAMM , E. S. ,YOUNG, W. , DEMOPOULOSH,. B. et al. ( 1982 ). Experimental spinal cord injury: treatment with naloxone . Neurosurg. , 10 , 227 - 231 .
FRANKELH ,. L., HANCOCKD ,. O., HYSLOPG ,. et al. ( 1967 ). The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia . Paraplegia , 7 , 179 - 192 .
FREEMANL ,. W. & WRIGHT, T. W. ( 1953 ). Experimental observations of concussion and contusion of the spinal cord . Am. Surg. , 137 , 433 - 443 .
GEHRIG , R. & MICHAELISL,. S. ( 1968 ). Statistics of acute paraplegia and tetraplegia on a national scale . Switzerland,I96<r67. Paraplegia , 6 , 93 -- 95 .
GREER , C. A. , SHEPHERDG ,. M. ( 1982 ). Mitral cell degeneration in the neurological mutant mouse PCD . Brain Res. , 235 , 156 - 161 .
GRIFFITHS !,. R. ( 1976 ). Spinal cord blood flow after acute experimental cord injury in dog . J. Neurol. Sci. , 27 , 247 .
HALL , E. D. , BRAUGHLE RJ., M. ( 1981 ). Acute effects of intravenous gluocorticoid pretreatment on the in vitro peroxidation of cat spinal cord tissue . Exp. Neurol. , 73 , 321 - 324 .
HALL , E. D. , BRAUGHLE RJ., M. ( 1982 ). Glucocorticoid mechanisms in acute spinal cord injury: A review and therapeutic rationale . Surg . Neurol., 15 , 320 - 322 .
HARTWELLJ., B. ( 1917 ). An analysis of 133 fractures of the spine treated at the Massachusetts General Hospital . Boston Med. Surg. J., 177 , 31 - 41 .
HEDEMANL , . S., SHELLENBERGME R.K ,. & GORDONJ,. H. ( 1974a ). Studies in experimental spinal cord trauma. Part I: Alterations in catecholamine levels . J. Neurosurg. , 40 , 37 - 43 ?
HEDEMANL ,. S. & SIL , R. ( 1974b ). Studies in experimental spinal cord trauma. Part 2: Comparison of treatment with steroids low molecular weight dextran and catecholamine blockade . J. Neurosurg. , 40 , 46 - 51 .
JOYNESJ ,. & FREEMANL, . W. ( 1963 ). Urea and spinal cord trauma . Neurol. , 13 , 69 - 72 .
KRAUS , J. F. , FRANTIC ,. E., RIGGINS ,R. S. et al. ( 1975 ). Incidence of traumatic spinal cord lesions . J. Chronic Dis ., 28 , 471 - 492 .
KRAUSJ ,. F. ( 1980 ). Injury to the head and spinal cord . Suppl.J. Neurosurg. The National Head and Spinal Cord Injury Survey . 53 , S3 - SI0 .
LEWIN , M. G. , HAUSEBRUTR ,. R. & PAPPIUS, H. M. ( 1974 ). Clinical characteristics of traumatic spinal cord edema in cats. Effects of steroids on potassium depletion . J. Neurosurg. , 40 , 65 - 75 ?
MCVEIGH , J. F. ( 1923 ). Experimental cord crushes with special reference to the mechanical factors involved and subsequent changes in the area of the cord affected . Arch. Surg. , 7 , 573 - 600 .
MAYNARDF ,. M., REYNOLDSG , . G., FOUNTAINS , . et al. ( 1979 ). Neurological prognosis after traumatic quadriplegia . J. Neurosurg. , 50 , 611 - 616 .
MEANS , E. D. , ANDERSOND ,. K., WATER , T. R. et al. ( 1981 ). Effect of methylprednisolone in compression trauma to feline spinal cord . J. Neurosurg. , 55 , 200 - 208 .
MIXTER , S. J. & CHASEH ,. M. ( 1904 ). Operation in spinal cord injuries . Annal. Surg. , 39 , 495 - 511 .
NAFTCHIN , . F., DEMENY , M. , DECRESCITOV ,. et al. ( 1974 ). Biogenic amine concentration in traumatize spinal cords of cat. Effect of drug therapy . J. Neurosurg. , 40 , 52 - 57 .
NEMECEKS ,. ( 1978 ). Morphological evidence for microcirculatory disturbances in experimental spinal cord trauma . In Advances in Neurology , Vol. 20 , Cervos-Navarro , J . (ed.),Raven Press,New York.
OSTERHOLMJ., L. & MATHEWS , G. J. ( 1972a ). Altered neorpinephrine metabolism following experimental spinal cord injury. Part I: Relationships to hemorrhagic necrosis and post wound neurological defects . J. Neurosurg. , 36 , 386 - 394 .
OSTERHOL MJ. , L. & MATHEWS , G. J. ( 1972b ). Altered norepinephrine following experimental spinal cord injury. Part 2: Protection against traumatic spinal cord hemorrhagic necrosis by norepinephrinesynthesis blockade with alpha methyl tyrosine . J. Neurosurg. , 36 , 395 - 401 .
RAMON , Y CAJAL , S. Degeneration and regeneration of the nervous system . R. M. May (Translation)Oxford University Press,London, 1928 .
RAWE , S. E. , COPELANDP ,. M. & ROTH , R. H. ( 1977a ). Segmental norepinephrine and dopamine levels in cat spinal cord . Life Sci ., 21 , 1409 - 1416 .
RAWE , S. E. , ROTHR ,. H., BOADLE-BIBEMR,. & COLLINSW, . F. ( 1977b ). Norepinephrine levels in experimental spinal cord trauma. Part I: Biochemical study of hemorrhagic necrosis . J. Neurosurg. , 46 , 342 - 349 .
RAWE , S. E. , ROTH , R. H. & COLLINSW ,. F. ( 1977c ). Norepinephrine levels in experimental spinal cord trauma. Part 2: Histopathological study of hemorrhagic necrosis . J. Neurosurg. , 46 , 350 - 357 ?
RIDDOCH , F. ( 1917 ). The reflex functions of the completely divided spinal cord in man compared with those associated with less severe lesions . Brain , 40 , 264 - 402 .
RIVLINA ,. S. & TATOR,c. H. ( 1977 ). Objective clinical assessment of motor fUnctionafter experimental spinal cord injury in the rat . J. Neurasurg. , 49 , 577 - 581 .
RIVLIN , A. S. & TATORc,. H. ( 1978 ). Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat . Surg . Neural., 10 , 39 - 43 .
SCHAMUSH ,. ( 1890 ). Bertrage zur pathologischeu anatomie der Riickenmarkserschiittering . Virchaus Arch., U2 , 470 - 495 .
SENTERH , . J. & VENESJ ,. L. ( 1978 ). Altered blood flow and secondary injury in experimental spinal cord trauma . J. Neurasurg. , 49 , 569 - 578 .
SENTERH , . J., VENESJ , . L., KAUERJ ,. S. ( 1979 ). Alteration of post-traumatic ischemia in experimental spinal cord trauma by a central nervous system depressant . J. Neurasurg. , 50 , 207 - 216 .
SPILLERW , . G. ( 1899 ). A critical summary of recent literature on concussion of the spinal cord with some original observations . Am. J. Med. Sci. , 118 , 190 - 198 .
STEWARTW ,. B. & WAGNERF ,. C. ( 1979 ). Vascular permeability changes in contused feline spinal cord . Brain Res. , 169 , 163 - 167 .
SUTTONN , . G. ( 1973 ). Injuries of the spinal cord: the management of paraplegia and tetraplegia . Butterworths,London.
TARLOVI ,. M. ( 1957 ). Spinal cord compression mechanisms of paralysis and treatment . C. C. Thomas Publ.
TARLOVI ,. M., KLINGERH ,. & VITALESS, . ( 1953 ). Spinal cord compression studies: I. Experimental techniques to produce acute and gradual compression . Arch. Neural. Psychiatry , 70 , 813 - 819 .
TARLOVI ,. M. & KLINGERH ,. (1954a). Spinal cord compression studies. II. Time limits for recovery after acute compression in dogs . Arch. Neural. Psychiatry , 71 , 271 - 280 .
TARLOVI ,. M. ( 1954b ). Spinal cord compression studies. III. Time limits for recovery after gradual compression in dogs . Arch. Neural. Psychiatry , 71 , 588 - 597 .
TATORC ,. H. ( 1972 ). Acute spinal cord injury: a review of recent studies of treatment and pathophysiology . Ganad. Med . Ass. J., 107 , 143 - 150 .
TATORC ,. H. & DEEKE , L. ( 1973 ). Value of normothemic perfusion, hypothermic perfusion and durotomy in the treatment of experimental acute spinal trauma . J. Neurasurg. , 39 , 52 - 64 .
WATSONB ,. A. ( 1891 ). An experimental study of lesions arising from severe concussions . Gentralbl Allgem. Pathal. , 2 , 74 .
WEBB , S. B. , BERZINSE,. & WENDGARTNEetRal. ( 1978 ). First year hospitalization costs for the spinal cord injured patient . Paraplegia , 15 , 311 - 318 .
WOOD , M. R. & COHENM,. J. ( 1979 ). Synaptic regeneration in identified neurons of the lamprey spinal cord . Science , 206 , 344 - 347 .
YOUNG , J. S. & DEXTERW,. R. ( 1978 ). Neurological recovery distal to the zone injury in 172 cases of closed traumatic spinal cord injury . Paraplegia , 16 , 39 - 40 .
YOUNG , W. , FLAMN , B. D. , DEMOPOULOSH , ., TOMASULAJ ,. J. & DECRESCITOV ,. ( 1981 ). Effect of naloxone on post-traumatic ischemia in experimental spinal contusion . J. Neurasurg. , 55 , 209 - 219 .