Your help is needed on this, as this is the first FAQ about Spinal Cord Injury known to be assembled on the Internet. Because the general public and scientific consensus is that there is currently no particular ìcureî for spinal cord paralysis, this FAQ will remain under constant construction for the forseeable future. You are therefore invited and encouraged to provide ongoing suggestions, data, new questions and new answers.
After preparing a basic, novice-level FAQ for the alt.med.cure-paralysis newsgroup, we were fortunate to have an unexpected professional or advanced-level extension written by Dr. Wise Young. This FAQ then, comes to you in 2 sections. Section 1 is the basic, and Section 2 is the advanced (meaty and interesting part).
1. What is paralysis?
2. What is spinal cord injury? Quadriplegia and paraplegia?
3. What organizations and institutions are currently placing emphasis
on work that leads to an eventual cure of paralysis?
4. What related organizations would be considered as support groups
for those with spinal cord paralysis?
5. What periodicals, articles, and books, videos can I read or view about
paralysis?
6. Is there a need for an all-inclusive Database that would include all
research that has relevance to the cure for paralysis?
7. What is meant by the terms "complete" and "incomplete"
spinal cord injury?
8. How are spinal injuries caused?
9. What are the demographics of spinal-cord-injured individuals today?
10. How is sexuality affected by spinal cord injury?
11. Where should spinal-cord-injured persons go for rehabilitation?
12. What happens within the body when the spinal cord is injured?
13. What is the immediate axonal reaction to "transection" of the
spinal cord?
14. What is the structure of nerve cells?
15. What is a nerve impulse?
16. What are synapses?
17. What is meant by cytoarchitectural lamination of the spinal gray?
18. What does the spinal cord look like and what does it do?
19. What happens when nerve fibers regrow?
20. What are some of the demyelinating agents that could possibly be used
to clear the path for axonal regeneration?
21. How is glutamate toxicity neutralized?
22. At the acute stage, how can long-term consequences be reduced?
Does methylprednisolone (MP) really do much good? Is it dangerous
or still in the experimental stage?
23. GM-1 (Sygen) has been written and talked about for a few years
now. How effective is it as an SCI treatment?
24. Does a spinal cord injured individual usually get some "return"
after a period of weeks, months, or years?
25. What about the actual existence of scar tissue in the human
spinal cord? Many have declared that the reason axons don't regenerate
is that the scar formation at the lesion site prevents them from growing.
26. So when are we going to see the cure for paralysis?
1. With regard to spinal cord injuries, what are the associated causes of mortalities? 2. How do you explain some of the differences between the NSCIA statistics and those discovered in your NASCIS studies, particularly in regard to incomplete vs. complete injuries? 3. How do you explain some of the differences between the NSCIA statistics and those discovered in your NASCIS studies, particularly in regard to the number of spinal cord injuries? 4. What is atraumatic spinal cord injury, and why is it important that we understand some of the related manifestations and treatments? 5. Have there been any recent breakthroughs in fertility issues of spinal cord injury? 6. What really happens in primary spinal cord injury? What are the toothpaste theory and the chain theory as they relate to primary injury? 7. How can we better understand the processes that occur in secondary spinal cord injury? 8. How important are the effects of demyelination and remyelination in spinal cord injury? 9. Are there any recent breakthroughs in regeneration that help us to understand the potential for regrowth of damaged CNS neurons and axons? 10. What is GM-1, and what does it do? 11. Many of us have believed that methylprednisolone (MP) has been approved by the FDA for acute spinal cord injury. What is the current status?
1. Q: What is paralysis?
A: Partial or complete loss of function, especially when involving the
motion or sensation in a part of the body.
2. Q: What is spinal cord injury? Quadriplegia and paraplegia?
A: A lesion of the spinal cord that results in paralysis of certain
areas of the body, along with the corresponding loss of sensation.
Paraplegia refers to paralysis from approximately the waist down
and quadriplegia refers to paralysis from approximately the shoulders
down.
Most spinal cord injuries result in loss of sensation and function
below the level of injury, including loss of controlled function of
the bladder and bowel. See "Nomenclature of Spinal Vertebrae".
3. Q: What organizations and institutions are currently placing
emphasis on work that leads to an eventual cure of paralysis?
A: American Paralysis Association
APA Spinal Cord Injury Hotline
Paralyzed Veterans of America
New York University
http://www.med.nyu.edu/MASCIS.html
Miami Project to Cure Paralysis
http://gsni.com/mia-proj
Spinal Cord Society
Karolinska Institute
http://www.mic.ki.se/Diseases/c10.html
Cure Paralysis Now
https://cureparalysis.org/
4. Q: What related organizations would be considered as support groups
for those with spinal cord paralysis?
A: National Spinal Cord Injury Association
The National Institute of Neurological Disorders and Stroke (NINDS)
Paralyzed Veterans of America (PVA)
Canadian Paraplegic Association
5. Q: What periodicals, articles, and books, videos can I read
or view about paralysis?
A: Periodicals--
îNew Mobilityî a monthly magazine by Miramar Communications
Email:
The Spinal Cord Injury Newsletter by Dr. Cheryl M. Chanaud
E-mail: http://home.aol.com/Mednewspub
Articles--
From New Mobilityís February 1996 issue, you will find
what is perhaps the most comprehensive lay version of the
current status of ìcureî that is readily available.
Books--
îQuest for Cure: Restoring Function After Spinal Cord Injury
by Sam Maddox. Published by the PVA. Available thru
ìSpinal Networkî by Sam Maddox. $37.95/softcover.
"Surgery of the Spinal Cord" by Drs. Robert Holtzman and
Bennet Stein Published by Springer-Verlag New York, Inc.
Videos-- 1)You can borrow any of a whole list of paralysis-related
videos. Please note that there is a refundable deposit of $25, but no charge
to borrow thru Spinal Cord Injury Network International 3911 Princeton
Drive
Santa Rosa, California 9 - CORD
FAX : or 800-548-CORD This network was founded in 1986
by Lennice Ambrose after her eighteen year old son, Richard, became a
paraplegic in an automobile accident,
2) "Changes", "Outside", and "Survivors" are available from
Access . Produced by Barry Corbet, author of the classic
book ìOptionsî.
6. Q: Is there a need for an all-inclusive Database that would include all
research that has relevance to the cure for paralysis?
A: The magnitude and complexity of the challenge seems to require
that such a Database be constructed. The practicality and usefulness
of such a database also seems apparent. One unremitting result would
be the ongoing, inherent disputations as to what issues and subject matter
is appropriate for such a database, and what is a ìwaste of effortî.
Despite
the drawbacks, and inevitable pitfalls, such a database is currently under
construction. If you or someone you know would like to contribute
information to it, please email: .
7. Q: What is meant by the terms "complete" and "incomplete"
spinal cord injury?
A: Dr. Wise Young explains it this way: "The clinical term
ëincomplete' when applied to spinal cord injury indicates that the
patient has some sensory or motor function below the lesion level.î
As defined recently in the International and American Spinal Injury
Association (ASIA) Neurological Classification of Spinal Cord Injury,
the term has been given an even more specific meaning, indicating a
person with preservation of motor or sensory function in the last sacral
segment (S4-5). This definition gets around the problem often encountered
in the clinical setting of a patient who has an injury at a given level, some
preserved sensation or motor function or several segments, and then no
function below that level. By defining incomplete as having some function
at the lowest level of the spinal cord, the definition becomes
unambiguous.
A more controversial term relates to the word ëcomplete' when applied to
spinal cord injury. By the ASIA definition, a person that does not have
preserved sacral sensory or motor function should be ëcomplete'.
Unfortunately, the term has connotations of complete loss and a finality
that is not desirable. Some patients with complete loss of neurological
function below the lesion level may still recover several segments,
especially when treated shortly after injury."
8. Q: How are spinal injuries caused?
A: Until the most recent figures were released by NSCIA in August,
1995, these were considered as the major causes of spinal cord injuries.
See Answer to # 4 and Dr. Wise Youngís statistics in Section 2 for all
the most recent demographics. One of the most surprising findings is
that acts of violence have now overtaken falls as the second most
common source of spinal cord injury, as of the 1995 findings.
Previous To 1995:
Motor vehicles 48%
Falls 21%
Sports 14% (66% of which are caused in diving accidents)
Violence 15%
Other 2%
9. Q: What are the demographics of spinal-cord-injured individuals
today?
A: Special thanks to Lyman Phillips of NSCIA for providing this
up-to-date comprehensive data. Also note in Section 2, an interesting
in-depth extension of this data by Dr. Wise Young.
We have very little information about disease-induced spinal cord injury, except brief descriptions of the diseases. The following information relates to traumatic spinal cord injury. It was compiled primarily by researchers at the University of Alabama using data from the regional SCI Centers funded by NIDRR. For more information on spinal cord injury statistics call --the National Spinal Cord Injury Statistical Center, Birmingham, Alabama.
Most researchers feel that these numbers represent significant under- reporting. Injuries not recorded include cases where the patient instantaneously or soon after the injury, cases with little or no remaining neurological deficit, and people who have neurologic problems secondary to trauma, but are not classified as SCI. Researchers estimate that an additional 20 cases per million (4860 per year) die before reaching the hospital.
--5 years post-injury:
88% of single people with SCI were still single vs.
65% of the non-SCI population
81% of married people with SCI were still married vs.
89% of the non-SCI population
--Employment status among persons between 16 and 59 years of age at injury
Employed 58.8%
Unemployed 41.2%
(includes: students, retired, and homemakers)
--Employed 8 years post-injury:
Paraplegic 34.4%
Quadriplegic 24.3%
People who return to work in the first year post-injury usually return to the same job for the same employer. People who return to work after the first year post-injury either worked for different employers or were students who found work.
Overall, slightly more than 1/2 of all injuries result in quadriplegia. However, the proportion of quadriplegics increase markedly after age 45, comprising 2/3 of all injuries after age 60 and 87% of all injuries after age 75.
92% of all sports injuries result in quadriplegia.
Most people with neurologically complete lesions above C-3 die before receiving medical treatment. Those who survive are usually dependent on mechanical respirators to breathe.
50% of all cases have other injuries associated with the spinal cord injury.
Over 37% of all cases admitted to the Spinal Cord Injury System sponsored by the NIDRR arrive within 24 hours of injury. The mean time between injury and admission is 6 days.
Only 10-15% of all people with injuries are admitted to the NIDRR SCI system. The remainder go to CARF facilities or to general hospitals in their local community.
It is now known that the length of stay and hospital charges for acute care and initial rehabilitation are higher for cases where admission to the SCI system is delayed beyond 24 hours.
Average length of stay (1992):
Quadriplegics 95 days
Paraplegics 67 days
All 79 days
Average charges (1990 dollars) Note: Specific cases are considerably higher.
Quadriplegics $118,900
Paraplegics $ 85,100
All $ 99,553
Source of payment acute care:
Private Insurance 53%
Medicaid 25%
Self-pay 1%
Vocational Rehab 14%
Worker's Comp 12%
Medicare 5%
Other 2%
Ongoing medical care: (Many people have more than one source of payment.)
Private Insurance 43%
Medicare 25%
Self-pay 2%
Medicaid 31%
Worker's Compensation 11%
Vocational Rehab 16%
Private Residence 92%
Nursing Home 4%
Other Hospital 2%
Group Home 2%
There is no apparent relationship between severity of injury and nursing home admission, indicating that admission is caused by other factors (i.e. family can't take care of person, medical complications, etc.) Nursing home admission is more common among elderly persons.
Each year 1/3 to 1/2 of all people with SCI are re-admitted to the hospital. There is no difference in the rate of re-admissions between persons with paraplegia and quadriplegia, but there is a difference between the rate for those with complete and incomplete injuries.
A: Sexual function, as in all other human bodily systems, is controlled by the central nervous system. Thus, any injury to the central nervous system will affect sexual function. The question is to what extent function and sensation will be affected with injuries at various levels and degrees of severity. Also, in what ways do the symptoms manifest themselves in males v. females. As one can imagine, this is a vast and complex subject that cannot be adequately treated in just a few paragraphs. You may want to read Sam Maddox's book Spinal Network where he treats this subject among many others, quite adequately.
In general, experts say that the best way to determine your own level of function is to learn how your body and mind react in certain situations. Complete and open communication and exploration between partners is recommended. In addition, a current project being conducted by Dr. Todd Linsenmeyer is attempting to find ways to enhance the fertility of SCI males. He explains that there are two causes of this infertility -- poor semen quality and ejaculatory dysfunction. The problem with ejaculatory dysfunction has largely been solved with use of electroejaculation. However, poor semen quality, particularly sperm motility, continues as an unresolved problem. It is generally accepted that a significant number of SCI men have abnormalities of spermatogenesis as well. There have been no prospective clinical studies of spermatogenesis, sperm motility, or sperm function following SCI. Our preliminary data have shown that spermatogenesis may begin shortly after SCI in rats. Poor semen quality has also been noted 2-4 weeks after SCI in men. Neither clinical nor animal studies have identified mechanisms responsible for these impairments, but his study is not yet completed (1996).
11. Q: Where should spinal-cord-injured persons go for rehabilitation?
A: The National Spinal Cord Injury Association (NSCIA at ) maintains a current list of all accredited programs... over 50 in all. Some factors to consider in choosing a facility:
1. Reputation/word of mouth.
2. Proximity to home, family, friends.
3. Availability of facilities needed/wanted for one's specific rehab objectives. For example, FES, occupational therapy, attitudes of staff, etc.
12. Q: What happens within the body when the spinal cord is injured?
A: Synaptic connections are interrupted. A sequence of 3 stages rapidly ensues:
1. The impact of force that exceeds the backbone's protective design damages nerve cells.
2. Acute: loss of normal blood flow, swelling of tissue, breakdown of cell structure, and loss of myelin sheath.
a). The flow of ionic current is disrupted when the higher concentrated calcium ions on the exterior of the nerve cells break through their respective cell membranes to flood the interior of these neurons. In the process of regaining a balance of pressures in the ionic concentrations, calcium sets off a series of self-destructive cellular events. Phospholipase enzymes, that digest tissue, are released from the broken cell membrane. This results in the release of free radicals that satisfy the imbalance by attacking nearby "good" cells. This sets off a process called lipid peroxidation. Since this oxygen breakdown of essential cell lipids will lead to more swelling by water entering tissue from the blood and cerebrospinal fluids, cell break- down accelerates with the release of toxic substances that affect blood flow. Glutamate, the main excitatory transmitter, is an amino acid messenger in normal neuronal communication, but in large doses glutamate expresses its toxicity by overloading neuronal circuits.
b) Other neural substances are released by injury, such as serotonin, catecholamines, and endorphins.
c) Some studies suggest that astrocytes emit a growth inhibiting effector molecule that prevents regrowth of axons.
13. Q: What is the immediate axonal reaction to "transection" of the spinal cord?
A: The very first event after disruption of an axon (whether by spinal cord transection or contusion) is the instantaneous escape of axoplasm from both the proximal and distal ends of the axon. The axons will naturally become swollen, but axoplasmic transport attempts to prepare axons to regenerate. This regeneration is common in the PNS, but not in the CNS. Other factors influenced by the transection of axons are found in the myelin sheath, supporting glial cells, and in the microvasculature. The interaction of factors affecting axonal regeneration can be observed at the axonal tip.
The axoplasmic leakage creates an almost immediate gap in the axoplasmic column within the otherwise intact myelin sheath tube. Within a few hours of transection the axonal tips of large fibers are set back from the injury site leaving smaller fibers at the cut end.
The leakage of axoplasm stops within a few hours of transection as the axon tip is lined by axolemma within an hour, and layers of collapsed myelin form a septum in front of the axonal tip.
The process of "axonal autotomy" begins approximately one day after transection and continues for about a week. It is a process whereby the tips of axons degenerate by a means of terminal club rupture, and then retrograde as much as 1 cm from the point of original transection.
The terminal club rupture is significant. Among the axoplasmic contents that build up and escape, are lysosomes (which contain more than 50 enzymes, all hydrolytic and with acid pH optima). The escaping lysosomes could be activated and lead to autolysis of the surrounding spinal cord tissue resulting in the destruction of the heretofore smaller intact fibers passing near the ruptured terminal clubs.
After the one week period the final terminal club is formed at a distance of 1 to 2 mm or more from the site of transection and does not rupture again.
As there are antagonistic forces at work between the force of the axonal transport and the encasing myelin barrier, the only mechanism that could result in axonal regeneration seems to be the removal of the myelin encasement without rupture of the terminal club. This is precisely what occurs in the CNS of lower vertebrates that exhibit axonal elongation after transection.
The crucial difference in sheath structure is the presence of the neurilemmal basal lamina in the PNS and its absence in the CNS. In the PNS the basal lamina tube covers the myelin and the node, thus providing a continuous channel for the terminal club to pass through. It may be possible that the expanding force of the terminal club could be converted by the restraint of the basal lamina into a forward movement. Axonal regeneration could then begin.
14. Q: What is the structure of nerve cells?
A: Nerve cells have three basic structural aspects:
a) the nerve cell body,
b) a set of delicate, multiple "receiving" antennae that are actually extensions from the nerve cell body; these are termed dendrites, and carry impulses towards the cell body, and
c) a single long "sending" fiber that, in humans, can extend for one yard (3 feet) or more; this is termed the axon and carries impulses away from the nerve cell body. The dendrites and axons are called "nerve fibers and can be thought of as long delicate "tentacles" emanating from the nerve cell; electrical impulses are conducted along the "outer skin" of the tentacles; this "skin" is known scientifically as the plasma membrane and is continuous from the dendrite to the cell body, to the axon. The plasma membrane is made of precisely arrayed molecules of lipids (fats) and proteins.
15. Q: What is a nerve impulse?
A: An electrical current is carried along the plasma membrane (outer skin) nerve, and it may "start" in one of three ways:
a) spontaneous "ignition" of the nerve cell body,
b) removal of a suppressor impulse, and
c) reception of an electrical impulse from other nerve cells.
16. Q: What are synapses?
A: These are the junctions between the "sending" fibers of one nerve cell, to the "receiving" fibers of other nerve cells. The axon (sending fiber) ends in multiple branches, each of which has a button-like enlargement that nearly touches the "receiving" fibers of the other nerve cell bodies. Nerve cells "talk" to each other via synapses
17. Q: What is meant by cytoarchitectural lamination of the spinal gray?
A: There are nine distinct cellular laminae in the gray matter surrounding the central canal which are present in some form at all spinal levels. However, there are differences in configuration of laminae at the various segmental levels that constitute regions with characteristic cytological features. Lamina I, for example, is a thin veil of gray substance that caps the surface of the posterior horn and bends around its margins, while Lamina IX consists of several distinct clusters of large somatic motor neurons that occupy somewhat different positions within the anterior gray horn at various spinal levels.
18. Q: What does the spinal cord look like and what does it do?
A: The cord in humans may be likened to a coaxial cable, about one inch in diameter, and is a continuation of the brain. It looks like firm, white fat; nerves extend out from the cord to the muscles, skin and bones, to control movement, receive sensations and regulate bodily excretions and secretions. The 31 pairs of spinal nerves divide the cord into the following segments: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal.
19. Q: What happens when nerve fibers regrow?
A: The nerve cell body remains intact, and only the "sending" or "receiving" fibers have to regrow as longer extensions from the nerve cell body. The peripheral nerves, outside the brain and spinal cord can do this quite easily. But within the brain and spinal cord there is much impediment to such regrowth.
20. Q: What are some of the demyelinating agents that could possibly be used to clear the path for axonal regeneration?
A: Possibilities: trypsin
21. Q: How is glutamate toxicity neutralized?
A: By blocking the 3 kinds of receptors that glutamate acts upon. Glutamate-blocking drugs, such as the phenothizines, have been used to successfully block the NMDA (N-methyl-D-aspartate) receptor. In experimental models, this has resulted in a reduction of functional loss and significantly improved motor recovery in brain and spinal cord injury.
22. Q: At the acute stage, how can long-term consequences be reduced? Does methylprednisolone (MP) really do much good? Is it dangerous or still in the experimental stage?
A: The appropriate use of Methylprenisolone (MP) represents one of the most significant advances in acute SCI treatment of our era. Although MP is indicated for most acute spinal cord injuries, there appears to be little therapeutic benefit in some cases. Probably the most obvious case where MP is not indicated is where the spinal cord has actually been penetrated. Even massive steroid doses do not seem to reduce the zone of injury under such circumstances.
Dr. Wise Young's group at NYU, the Neurosurgery Laboratory, and The National Acute Spinal Cord Injury Study II (NASCIS II) concluded in 1990 that high-dose methylprednisolone (MP) administered within 8 hours of injury improves neurologic recovery after acute SCI. It is currently the only universally recognized SCI treatment to provide significant neurological improvement in the acute injury.
23. Q: GM-1 (Sygen) has been written and talked about for a few years now. Are there any clinical human trials underway? If so, how does one enroll?
A: The best answer comes from Dr. Fred H. Geisler:
A) Most acute spinal cord injured patients throughout North America are potential candidates for the study. They are entered into the study after admission or transfer to one of the participating study centers (22 in the United States and 3 in Canada). If the patient is not admitted to one of the participating centers within 72 hours of the injury, then they cannot be entered into the study. Any patient can request to be transferred to a participating facility (see list below). If the patient is considering transferring to a study center, both the patient and family members should check with the physicians at the existing facility regarding the safety of a transfer. The physicians at the study center should also be consulted prior to transferring the patient to ensure that the patient meets all of the entrance criteria.
Q) When will the results of the current Sygen symbol 210 \f "Symbol" \s 12 (GM 1) study be known?
A) Patient enrollment is expected to terminate in January 1997 and a 6-month follow up of all patients will be completed in July 1997. Initial results of this study should be available to the scientific community by late summer or fall of 1997.
Q) Is Sygen symbol 210 \f "Symbol" \s 12 Ý(GM 1) useful in the treatment of chronic spinal cord injury to restore neurologic function?
A) Currently there is no valid scientific information to support the efficacy of Sygen symbol 210 \f "Symbol" \s 12 Ý(GM 1) relative to chronic spinal cord injury. A large randomized study involving chronic spinal cord injury is planned in the future after completion of the acute spinal cord injury study. However, it will be several years before any results are known.
The study medication is administered intravenously for 29 days followed by intravenous or intramuscular administration for an additional 28 days. Follow-up neurologic evaluations are performed at 1 month, 2 months, 6 months and 12 months after initiation of treatment.
The study is being conducted in 25 neurotrauma centers throughout North America with a total planned enrollment of 720 patients completing the entire one year follow up. The enrollment period is expected to terminate in January 1997. The first patient was admitted into the study on April 13, 1992, and as of MayÝ10, 1996, 645 patients have been entered into this study. This is the largest acute spinal cord injury drug study conducted to date.
All patients initially receive the standard MPSS treatment per the recommendations of NASCISÝ2(1). The study medication (Sygen symbol 210 \f "Symbol" \s 12 or placebo) is administered after completing the 24 hour MPSS treatment. Patients were initially block randomized (1:1:1) to receive 1 of 3 regimens (placebo, low dose Sygen symbol 210 \f "Symbol" \s 12 or high dose Sygen symbol 210 \f "Symbol" \s 12 ). Following the Extramural Monitoring Committee recommendations of May 11, 1994, it was decided that patients would no longer be randomized into one of the two Sygen dose levels. Thus, all patients are currently block randomized (1:1) to receive 1 of 2 regimens (placebo and one dose of Sygen symbol 210 \f "Symbol" \s 12 ).
Patients were initially stratified within each center on the basis of spinal cord injury level and severity of injury:
A. Spinal Level
a. Cervical Cl - C7 (including C7 - Tl disc
space)
b. Thoracic Tl - T10 (starting at the top
of the Tl body)
B. Severity (See Appendix I)
a. ASIA Impairment Scale A
b. ASIA Impairment Scale B
c. ASIA Impairment Scale C and D
At the onset of the study, patients were randomized into six strata: 1)Ýcervical A; 2)Ýcervical B; 3)Ýcervical C and D; 4)Ýthoracic A; 5)Ýthoracic B; and 6)Ýthoracic C and D. Consequent to recommendation of the Extramural Monitoring Committee (EMC) at its May 11, 1994 meeting, because of an age related imbalance in randomization, patients were then also stratified by age: "younger" (age symbol 35 \f "MathematicalPi 1" \s 12 29 years) versus "older" (age symbol 46 \f "MathematicalPi 1" \s 12 29 years). Thus, the six initial strata were converted into twelve strata.
This study is conducted along strict scientific guidelines and in cooperation with the U.S. Food &Drug Administration (FDA). In order to be considered for entry into the study, the patient must meet the following inclusion criteria: 1)Ýpatient age 12 to 70Ýyears; 2)Ýrestoration of blood pressure within 8 hours of injury; 3)Ýstandard MPSS therapy initiated within eight hours of the injury; 4)Ýa motor deficit attributable to an acute spinal cord injury with the sum of motor strengths in the five ASIA motor groups of one leg symbol 35 \f "MathematicalPi 1" \s 12 15 points; 5)Ýstudy medication initiated within 72 hours of the injury and after the conclusion of MPSS therapy; 6)Ýpatient written informed consent obtained.
Additionally, if the patient meets any of the following exclusion criteria, then the patient is not entered: 1)Ýdirect spinal cord damage as a result of a gunshot wound or other penetrating trauma; 2)Ýtraumatic spinal cord anatomic transaction; 3)Ýpresence of cauda equina damage, major brachial or lumbar plexus injury; 4)Ýsignificant head trauma or multitrauma; 5)Ýsignificant systemic disease; 6)Ýpre-existing polyneuropathy, focal or multifocal neuropathy, myelopathy or radiculopathy; 7)Ýpresence of any medical condition which can interfere with assessment of spinal cord function; 8)Ýhistory of Guillain-BarrÈ syndrome; 9)Ýpsychoactive substance use disorder six months prior to injury; 10)Ýhistory of major depression, schizophrenia, paranoia or other psychotic disorder; 11) women who are pregnant or nursing; 12)Ýhistory of life-threatening allergic reaction; l3) poor likelihood of patient being available for follow-up evaluation; 14)Ýinability to communicate effectively with the neurological examiner.
The main statistical test of this study is to determine whether the percentage of large improvers is increased with the addition of Sygen symbol 210 \f "Symbol" \s 12 . The two groups of patients (Sygen symbol 210 \f "Symbol" \s 12 and placebo) are compared based on their improvement from baseline utilizing the ASIA Impairment Scale(2), (Appendix I) and at six months utilizing the Modified Benzel Classification Scale(3), (Appendix II). Patients will be considered to have attained marked recovery if they have obtained: 1)Ýa two grade improvement, if the initial ASIA Impairment Scale grade is A or B; or 2)Ýa three grade improvement, if the initial ASIA Impairment Scale grade is C or D. Clearly, changes as large as these increase both the patient function and quality of life significantly. The ASIA Motor Score(2) (AppendixÝIII) is also collected at baseline and all follow up examinations to aid in secondary analysis.
Ideally, medical treatment would help to reverse the neurologic deficit, but acute spinal cord injury has been extraordinarily resistant to effective treatment. Recent animal models involving spinal cord injury suggest that pharmacologic intervention can improve neurologic outcome(5). Within the last five years, studies using animal models of spinal cord injury have shown enhanced neurologic recovery utilizing several drug therapies including gangliosides(6). These data may apply to humans. The pharmacologic agents tested may decrease cell death and enhance regeneration or recovery of the remaining injured cells.
In an effort to determine if these animal data could apply to humans, double-blind, controlled clinical trials have been conducted. These trials have provided new hope for pharmacologic management of spinal cord injury.
The First National Acute Spinal Cord Injury Study 1 (NASCIS 1)(7) showed that an intravenous infusion of 100 mg or 1000 mg of MPSS did not have a significant effect on recovery from spinal cord injury(8). A statistically significant recovery of neurologic function was shown when massive doses of MPSS administered within 8 hours of injury were used in NASCIS 2(1) (a 30Ýmg/kg bolus intravenously administered, 2100 mg in a 70 kg person, followed by 5.4 mg/kg/hr for 23 hours).
In a separate recently reported study(9), Sygen symbol 210 \f "Symbol" \s 12 was compared with placebo in the treatment of acute spinal cord injury. Treatment was instituted within 72 hours of injury and administered daily for 18 to 32 days. Patients were followed for one year. Neurologic status was assessed by means of the American Spinal Injury AssociationÝ(ASIA) Impairment Scale and the ASIA Motor Score(2). Analyses revealed that patients treated with Sygen symbol 210 \f "Symbol" \s 12 recovered significantly as assessed by both scales and that the increased recovery in the Sygen symbol 210 \f "Symbol" \s 12 treated group was attributable to initially paralyzed muscles regaining useful motor strength rather than to paretic muscles gaining more strength. This study provides evidence that Sygen symbol 210 \f "Symbol" \s 12 enhances the recovery of neurologic function in human spinal cord injuries and provides the rationale for a larger study involving Sygen symbol 210 \f "Symbol" \s 12 .
Gangliosides are complex acidic glycolipids that are particularly abundant in the nervous system. They form a major component of the cell membrane and are predominantly located in the outer leaflet of the cell's membrane bilayer(10-12).
In-vitro and in-vivo evidence from various experimental studies indicate that Sygen symbol 210 \f "Symbol" \s 12 may have both an acute and chronic beneficial effect on damaged CNS tissue(13). The acute effect has recently been attributed to the "Receptor Abuse Dependent Antagonist" (RADA), a property of GM 1. At the site of neural injury, excessive quantities of excitatory amino acid neurotransmitters are released which overstimulate associated amino acid receptors (i.e. receptor abuse) and neurons, leading to cell injury and death. The RADA property of GM 1 prevents these toxic consequences without interfering with the normal physiologic functions of amino acid neurotransmitters on undamaged neural tissue. The well-described chronic effect of GM 1, (the ability of gangliosides to stimulate the growth of nerve cells and the regeneration of damaged nervous tissues) is likely due to the ability of GM 1 to potentiate the effect of natural trophic factors including nerve growth factor(13).
The current study proposes to examine recovery of neurologic function after human spinal cord injury and confirm the Sygen symbol 210 \f "Symbol" \s 12 results previously reported (9,11,14). Since most institutions now include high dose MPSS treatment within 24 hours, patients in this study will also receive MPSS treatment per the NASCISÝ2 recommendtions.
The initial clinical trial utilizing Sygen symbol 210 \f "Symbol" \s 12 for spinal cord injury(9), consisted of 100Ýmg Sygen symbol 210 \f "Symbol" \s 12 intravenously administered daily. This was the maximum safe dose according to data available at the time the initial human investigation was initiated. In order to enhance the potential chronic effect, treatment has been extended to approximately two months in the current study.
Grade B Incomplete - Sensory but no motor function is preserved below the neurologic level and extends through the sacral segments S4-5.
Grade C Incomplete - Motor function is preserved below the neurologic level, and the majority of key muscles below the neurologic level have a muscle grade <3.
Grade D Incomplete - Motor function is preserved below the neurologic level, and the majority of key muscles below the neurologic level have a muscle grade symbol 179 \f "Symbol" \s 12 3.
Grade E Normal - Motor and sensory function is normal.
I. No motor or sensory function is preserved in the sacral segments S4 5.
II. Sensory but no motor function is preserved in the sacral segments S4 5.
III. Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade <3. Patient is unable to walk.
IV. Some functional motor control below the level of injury that is significantly useful (i.e., assist in transfers) Patient is unable to walk.
NOTE: Patient must be able to transfer from a wheelchair to a bed with one leg bearing weight and pivoting (assistance* is allowed but the patient must be able to independently perform the weight bearing on one leg).
V.* Motor function allows walking with assistance* or unassisted, but significant problems secondary to lack of endurance or fear of falling limit patient mobility. Patient has limited walking ability.
NOTE: Must be able to ambulate at least 25 feet.
VI.** Ambulatory without assistance and without significant limitations other than one or both of the following: Difficulties with micturition; slightly dyscoordinated gait. Patient has unlimited walking ability.
NOTE: Must be able to ambulate at least 150 feet without assistance.
VII.** Neurologically intact with the exception of minimal deficits that cause no functional difficulties.
NOTE: Patient must have a neurologically normal gait and be able to walk without assistance or assistive devices (highest possible score).
Assistance is defined as an individual providing minimal contact assistance (i.e., maintain balance so that the patient is expending at least 75% of the effort in performing the task).
**No assistive devices (braces, prostheses, special adaptive shoes, canes, crutches or walkerettes) may be used to attain grades V, VI, or VII.
Key muscles in upper Extremities
Elbow flexion (biceps C5)
Wrist extension (wrist extensors C6)
Elbow extension (triceps C7)
Finger flexion (distal phalanx of middle finger) (flexor profundus
C8)
Finger abduction (little finger) (hand intrinsics Tl)
Key muscles in lower Extremities
Hip flexion (iliopsoas Ll, L2, L3)
Knee extension (quadriceps femoris L2, L3, L4)
Ankle dorsiflexion (tibialis anterio L4, L5)
Great toe extension (ext hallucis longus L5, Sl)
Ankle plantar flexion (gastrocnemius Sl, S2)
Each key muscle is assessed on a 0 to 5 point scale of strength:
0 = Total paralysis
1 = Palpable or visible contraction
2 = Active movement, full range of motion with gravity eliminated
3 = Active movement, full range of motion against gravity
4 = Active movement, full range of motion against moderate resistance
5 = (Normal) Active movement, full range of motion against normally
surmountable resistance.
An additional motor assessment is made of the voluntary anal contraction.
Sponsor:
Roberto Fiorentini, President
FIDIA Pharmaceutical Corperation
1401 Eye Street, NW, Suite 900
Washington, DC 20005
Coordinating Centers:
Fred H. Geisler, M.D., Ph.D.
Principal Investigator, Sygen Acute SCI Study
Director, Comprehensive Spinal Care Center
Chicago Institute of Neurosurgery and Neuroreasearch
Suite 800
2515 North Clark Street
Chicago, Illinois 60614
(312)
William P. Coleman, Ph.D.
Principal Investigator, Sygen Acute SCI Study
Department of Mathematics and Statistics
University of Maryland at Baltimore
Baltimore, MD 21228
Active patient enrollment sites/investigators:
J. Alteveer, M.D.
Division of Emergency Medical Services
Robert Wood Johnson Medical Center
One Cooper Plaza
Camden, NJ 08103
G. Bennett, M.D.
University of Buffalo
State University of New York
Department of Neurosurgery
School of Medicine and Biomedical Sciences
3 Gates Circle
Buffalo, NY 14209
E. Benzel, M.D.
Professor and Chief of Neurosurgery
University of New Mexico
School of Medicine
2211 Lomas Blvd., N.E.
Albuquerque, NM 87131
C. Branch, M.D.
Department of Neurosurgery
Bowman Gray School of Medicine
Medical Center Boulevard
Winston-Salem, NC 2
R. Bucholz, M.D.
Division of Neurosurgery
St. Louis University
3635 Vista Ave. at Grand Boulevard
PO Box 15250
St. Louis, MO 6
J. Burgess, M.D.
Institute of Research &Education
3300 Gallows Road
Falls Church, VA 22046
H. Engelhard, M.D., Ph.D.
Streeterville Center
Northwestern University Medical Center
233 East Erie Street, Suite 500
Chicago, IL 6
M. Fehlings, M.D.
The Toronto Hospital
Toronto Western Division
Suite 2-417
399 Bathurst Street
Toronto, Ontario M5T 288
M. Fazl, M.D.
Sunnybrook Health Science Centre
A-138
2075 Bayview Avenue
New York, Ontario M4N 3M5
K. Foley, M.D.
Semmes-Murphey Clinic
930 Madison Avenue
Memphis, TN 38103
M. Sean Grady, M.D.
Associate Professor of Neurologic Surgery
University of Washington School of Medicine
Harborview Medical Center
325 Ninth Avenue, ZA-86
Seattle, WA 98104
P. W. Hitchon, M.D.
Division of Neurosurgery
University of Iowa Hospital :&Clinics
200 Hawkins Drive
Iowa City, IA 52242
K. Holloway, M.D.
Division of Neurological Surgery
Medical College of Virginia
8th Floor West Hospital
South Wing
1200 East Broad Street
Richmond, VA 23298
D. Lammertse, M.D.
Director
Craig Hospital
3425 S. Clarkson
Englewood, CO 80110
P. Lane, M.D.
Director
Trauma Services
Victoria Hospital
375 South Street
London, Ontario N6A 4G5
Canada
D. Maiman, M.D., Ph.D.
Medical Director
The Spinal Cord Injury Center
Medical College of Wisconsin
Froedtert Memorial Lutheran Hospital
9200 W. Wisconsin Ave.
Milwaukee, WI 53226
L. Marshall, M.D.
UCSD Medical Center
Dept. of Neurosurgery
200 W. Arbor Drive
San Diego, CA 9
D. McBride, M.D.
Neurological Surgery
Harbor/UCLA Medical Center
Box 424
1000 West Carson Street
Torrance, CA 90509
M. Miner, M.D., Ph.D.
Chairman
Ohio State University Hospital
Division of Neurosurgery
473 West 12th Street, Upham Hall
Room N007
Columbus, OH 4
W. Robinson, M.D.
MIEMSS
University of Maryland Hospital
Room TBR #56
22 South Greene Street
Baltimore, MD 21201
M. Rosner, M.D.
Univ. of Alabama Hospital
UAB Station Division of
Neurosurgery
MEB 516
1813 Sixth Avenue South
Birmingham, AL 35294
P. Stewart, M.D.
Charlotte Rehabilitation Hospital
1100 Blythe Boulevard
Charlotte, NC 28203
D. Thompson, M.D.
The Mercy Hospital of Pittsburgh
1400 Locust Street
Pittsburgh, PA 1
P. Werner, M.D.
Spinal Cord Injury Project
Santa Clara Valley Medical Center
950 S. Bascom Avenue, Box A421
San Jose, CA 95128
J. Wilberger, M.D.
Dept. of Neurosurgery
Allegheny General Hospital
320 E. North Avenue
Pittsburgh, PA 1
A: First of all, you are probably tired of hearing that each spinal injury is unique and quite different from all others. But there are some generalities that help describe the majority of spinal cord injuries. Most immediately sustain what is referred to as "spinal shock". The most obvious symptom is paralysis due to swelling of the spinal cord. This paralysis can improve as the swelling of the cord subsides, which can begin within 3 weeks or more after the initial injury. But then, eventually the improvement most people experience is that their "level" descends at least one level and sometimes two levels below their injury site within a year, especially if they have received methylprednisolone shortly after injury.
25. Q: What about the actual existence of scar tissue in the human spinal cord? Many have declared that the reason axons don't regenerate is that the scar formation at the lesion site prevents them from growing.
A: There is some controversy now as to whether the scar even exists in the injured spinal cord. Some recent autopsy studies suggest that there is no scar in most cases, and only modest scarring in others.
26. Q: So when are we going to see the cure for paralysis?
A: Unknown. We might each see it at different times and in different ways. It is said that some paralyzed individuals will consider themselves cured if they regain bowel and bladder control. Some quads may consider a cure to mean that they can live independently, living the lifestyle of their choice. Who knows, maybe one of the reasons we haven't seen "the cure" as yet, is that we haven't really defined it. What is the cure to you? Probably most want to experience a return to the level of function and sensation that was there prior to the injury.
Whatever you perceive the cure to be, consider for a moment, the possibility that the elements of the cure for paralysis have already been hypothesised in more detail and clarity than is generally understood. Consider the progress in our time of some of the most brilliant minds in history. Some of you could undoubtedly point out areas that merit serious study and experimentation. I'm going to leave you with just one. Please take the time to shoot it full of holes and provide us with another target.
This concept comes from Dr. Robert HÅ Ç É Ñ Ö Ü á à â ä ã å ç é è ê ë í ì î ï ñ ó ò ô ö õ ú ù û ü Ý ° ¢ £ § ¬ ¶ ß ® © ´ ¨ Æ Ø ± ¾ ¥ µ ¼ SS ª º ! æ ø ¿ ¡ ¬ Æ x 0 « » ` À Ã Õ ¦ 9 " " ' ' ÷ × ÿ } ¤ Ð ð Þ þ ý · Â Ê Á Ë È Í Î S echt-Nielsen, as found in the book, "Surgery of the Spinal Cord" by Drs. Robert Holtzman and Bennet Stein. "Let's say, for example, there is a traumatic injury to a spinal cord. What I am suggesting here is that perhaps under certain circumstances the patient's own tracts could be the source of cells that could assist with the regeneration process.
Let's go on to the next idea. The next step would be to operate and remove the damaged area...why not go in and simply remove all of that material by making extremely careful cuts to establish a prepared surface in a known condition.
Now, immediately, instead of having a delay of hours between the trauma and the time any attention is available, after these cuts are made one could insert a microchannel plate in less than a minute, so that many of the results of trauma that are processes that take minutes or hours to evolve would never have a chance to evolve. The idea of this is that you would use something like a cyanoacrylic cement and the microchannel plate would be literally cemented on, on a small-scale basis, to the tissue to create a completely closed surface. (There is a technology in electronics for building plates, or actually cylinders, of any size, with holes in those cylin- ders of sizes ranging from one micron up to hundreds of microns if you want, virtually any size holes you want, and these can be made relatively inexpensively and can be cut and machined.)
Then you finish the repair, immobilizing it and so forth, and of course the idea is that the insides of these tubes have been cultured with Schwann cells, but perhaps astrocytes are more useful so that the physical and chem- ical medium that would promote axon growth is there.
The main concomitant of the use of this is that any gray matter connec- tions within this region are eliminated forever. There is no hope of restor- ing those, but at least there is some possibility of having fibers transit the region."
"My thought was having astrocytes or Schwann cells cultured in this microchannel plate before it is inserted. You have a quarter of a million holes all larger than Betz cell axons that could be coated. The microchannel plate could then be precision cut and "glued" in place. I think that over the long haul there promises to be a lot of useful interaction between this subject and medicine ..."
A: Associated causes of mortalities. There is a relatively high association of other trauma besides spinal cord injury in people admitted to hospital. One must be very careful not to assume that all people diagnosed as having spinal cord injury have *only* spinal cord injury. The NSCIA data does not cull out people who have associated head injuries or other kinds of body trauma in addition to spinal cord injury. In fact, the statement that "50% of all cases have other injuries associated with the spinal cord injury" confirms. In such a case, one cannot assume that the mortality rate is due to spinal cord injury per se. In NASCIS 2 (), over 91% of the people admitted to the trial and randomized to therapy survived over 1 year. In NASCIS 3 (), the number is closer to 94% 6-month survival. NSCIA data must include a number of multi-trauma patients. The 85% 10-year survival statistics also may be referring to patients who presumably were spinal injured as long ago as 1977 or whenever the database first started. There is no question that mortality rates have been declining, even during the time that I have been in the field (since 1977). Finally, I think that the statement regarding "most people with neurologically complete lesions above C-3 die before receiving medical treatment" is less true today than a decade ago. The data is simply not very good because there is inadequate documentation of spinal cord injury in people who do not get to the hospital for a diagnosis. If they get to the hospital, they are getting medical therapy. Finally, I believe a major cause of death after spinal cord injury is suicide or a disease called despair and the cure is a vaccine called hope. Suicides need not be overt but simply a failure to thrive, a loss of financial resources to care for one's body, and substance abuse. Little or no hard statistics exist on these issues.
2. Q: How do you explain some of the differences between the NSCIA statistics and those discovered in your NASCIS studies, particularly in regard to incomplete vs. complete injuries?
A: Incomplete vs. complete injury statistics. The statistics on this varies depending on the group that is collecting the data. The data from NSCIA suggests that 45% of injuries are "complete" since 1988. NASCIS 2 from had 64% incidence of "complete" injuries. I had heard that NASCIS 3 "complete" rates were coming close to the NSCIA rate but the actual NASCIS 3 has about 51% "complete" injuries from . It may be because the 14 NASCIS centers are tertiary trauma care centers and a number of so-called "incomplete" patients may have been kept by the initial care hospitals or emergency rooms. There is, however, general agreement among all the physicians that I know that the number of "complete" injuries is declining. The extent to which this is due to methylprednisolone is unclear. The change in the definition of complete versus incomplete injuries may also lead to some changes in the number... for example, a lot of patients may be classified as "incomplete" even though they are missing their sacral segmental function. Note that the NASCIS 3 definition and all ASIA definitions since 1991 are based on the new ASIA classification which should increase the number of "complete" patients.
3. Q: How do you explain some of the differences between the NSCIA statistics and those discovered in your NASCIS studies, particularly in regard to the number of spinal cord injuries?
A: Number of acute spinal cord injuries in the U.S. every year. The number that is cited is relatively low and almost all the epidemiologists in the field believe that the number is 10,000 or greater per year. Incidentally, I doubt that the number is undercounted due to mortality before admission to the hospital since a lot of early statistical counts were made on the basis of DRG or admission diagnoses from hospital coded data. What is much more likely is that spinal cord injury is missed (due to the patient being unconscious, an inadequate neurological examination, or such rapid recovery during the first few hours that the diagnosis is not made), not the primary diagnosis (for example, a patient with a gunshot wound of the belly with the bullet grazing the spinal column and causing transient paralysis may not be classified as a spinal cord injury), or seen in a hospital that does not contribute to survey.
4. Q: What is atraumatic spinal cord injury, and why is it important that we understand some of the related manifestations and treatments?
A: Atraumatic spinal cord injury. This is probably the most under- reported class of spinal cord injury. In my opinion, these causes of spinal cord injury far outnumber overt trauma, perhaps by a factor of four. I have been keeping the statistics of neurosurgical cases in our department at NYU Medical Center. Approximately 20% of the neurosurgical cases at NYU involve people with some form of neurological deficits associated with spinal cord damage. This represents about 400 patients per year. Only about 20% of these patients have had traumatic spinal cord injury; while this may simply represent the demographics of NYU Medical Center, I believe that our experience is not atypical of most neurosurgical services around the country. The important thing to remember is that effective treatments of traumatic spinal cord injury also will be useful for atraumatic causes of spinal cord injury. There is a large community of paralyzed people out there who are not classified as spinal cord injured but suffer from the same losses. Atraumatic spinal cord injury include:
A. aortic aneurysms and subsequent surgery for repair that leaves about 50% of the people suffering some degree of sensory and motor loss.
B. tumors, i.e. metastatic tumors to the spinal column and cord (e.g. breast carcinoma often spread to the spinal column) and intrinsic tumors of the spine cord (e.g. intramedullary astrocytomas, benign cysts, germ cell line tumors, etc
C. Radiation-induced myelopathies. This is the most common complication from high dose radiation used to treat lung and breast cancers.
D. Infections. Tuberculosis of the spine is still exceedingly common in third world countries but is relatively uncommon in the United States. However, there are many cases of paralysis relating to abscesses in the spinal column. Viruses are a common infectious cause of spinal cord injuries. There is a condition called transverse myelitis which results from an unknown and probably infectious viral cause. It would be of interest to estimate the incidence of transverse myelitis and I are certain that there are probably several hundred cases per year in the United States. Certainly polio is a special kind of virus that attacks one type of spinal neuron. But there are viruses that attack oligodendroglial cells. This of course does not include multiple sclerosis (MS, see below). Of course, AIDS is an important cause of spinal injury as well.
E. Arteriovenous malformations. Probably we see more these cases at NYU than any place else in the world but there are 200-250 such cases that are admitted to NYU Medical Center for AVM's and other vascular abnormalities leading to paralysis.
F. Scoliosis and congenital deformities of the spinal column leading to paralysis and sensory loss. A substantial number of children are paralyzed due to spina bifida. Incidentally, spinal canal stenosis is a frequent complication of children with Down's syndrome. It is estimated that close to 5% of such patients require surgical correction of scoliosis and canal stenosis to relieve neurological deficits during their lives. Scoliosis is actually very common in the general population, occurring in approximately 2% of young peri-pubertal females in the United States. Only about 20% require surgical or orthotic therapies. I estimate (just off the top of my head... from having screened a group of 200 such patients at Stanford when I was a medical student) that perhaps 10% of these have some kind of neurological deficits, albeit mild. Some simple arithmetic indicate that we have very large numbers here. If there are 10 million girls in the United States of the ages of 10-18, this means that there may be as many as 200,000 girls with scoliosis and 20% of these would be 40,000 girls with neurological deficits relating to scoliosis.
G. Osteo-, rheumatic, disc, and other forms of arthritis of the spinal column with associated spinal cord damage. By the way, in Japan, more than 50% of the people who have spinal cord injury have severe osteo- or arthritic disease of the spinal cord with spinal canal stenosis and a condition called OPLL. Although the most frequent manifestation of disc disease is pain, the main reason for surgery is neurological loss. While many people do not consider these cases "true" spinal cord injury, I submit that they are indeed spinal cord injuries... just incomplete injuries that tend to respond to surgical therapies that remove the cause of spinal cord compression.
H. Multiple sclerosis. While many people do not think of MS as spinal cord injury, there is no question that the spinal cord is involved in almost all cases of MS. In fact, one of the criteria for diagnosis of MS is the presence of neurological deficits related to demyelination in the spinal cord and of the visual or some other supraspinal system. There are probably about 35,000 people with MS in the United States alone. MS is primarily a white matter disease and the spinal cord contains more white matter than any other part of the central nervous system
I. Unknown causes. Every year, we see dozens of people who become paralyzed from unknown degenerative changes in the spinal cord, unrelated to compression or any known cause. For example, the brother of a man from Scandinavia has been calling me about a progressive spinal cord atrophy which has left him paralyzed. Most of these patients are not classified as spinal cord injury but the consequences are similar.
5. Q: Have there been any recent breakthroughs in fertility issues of spinal cord injury?
A: Fertility in spinal cord injury. There has recently been a break- through at Miami Project which suggests strongly that men with spinal cord injury secrete semen that inhibits sperm motility. Semen is produced by two organs... the prostate gland and the lining of the vasa. At Miami, in studies of large numbers of men, they found that if they take the sperm of spinal-injured men and suspend them in semen from uninjured men, the sperm regains its motility. This is an enormous breakthrough. The cause is actually quite interesting. Apparently, semen production is controlled by the sympathetic nervous system which is of course affected by spinal cord injury. There is actually beginning to be quite a substantial literature on this subject and this is an area where enormous advances have been made in the last few years, advances that have not yet been reflected in textbooks or widely disseminated among physicians, except those who specialize in the fertility of spinal-injured males.
6. Q: What really happens in primary spinal cord injury? What are the toothpaste theory and the chain theory as they relate to primary injury?
A: Primary spinal cord injury. From my perspective, it is useful to segregate primary mechanical disruption of axons and secondary processes that damage axons further. From a reading of the literature, one might get the impression that secondary injury is more important. The reason is that primary injury can destroy as much as 90% of the axons in the spinal cord and the patients still (because they are incomplete) will recover substantial function. Secondary injury takes on an important role because they compromise the survival and function of the axons that have survived the primary injury. Primary spinal cord injury is unfortunately not as well understood as it should be. In my opinion, one of the best studies on the subject comes from Andrew Blight who proposed essentially what I call the toothpaste and chain theories of primary axonal injury in the spinal cord. It has long been known that trauma to the spinal cord causes a central hemorrhagic necrosis. The central part of the spinal cord dies first and generally a rim of white matter is preserved. Andy showed clearly that there is not only a centrifugal distribution of surviving axons but that large axons are particularly susceptible to traumatic injury. This is exactly opposite of what happens if you make the spinal cord ischemic with slow compression of the spinal cord which depresses the cord of blood flow. In such cases, the small axons are the first to die and are most vulnerable.
A. The toothpaste theory. The spinal cord is encased in a relatively non-distensable membrane called the dura. The dura is extremely tough and is difficult to cut with a knife and dural tears are rare in spinal cord injury. This is one of the main reasons why spinal cord "transections" seldom occur. In the operating room, when you look at a freshly injured spinal cord, you often cannot see from the surface where the spinal cord has been hit or compressed except from the fracture pattern of the bone surrounding the cord. In any case, if you press a non-distensable tube, there is only two directions that the contents of the dural sac can go... either rostrally or caudally. Axons are generally quite distensable. Like rubber bands, they can elongate to over twice their normal length without breaking if you stretch them slowly at less than 0.5 m/sec. However, if you pull on them fast, they break. The threshold for the breaking is somewhere between 0.5 to 1.0 m/sec. When the speed of the this rostrocaudal movement exceeds 1 m/sec, axons break. Broken axons tend to retract. They form the terminal club endings that you see after injury. More important, Andy modeled the velocity of tissue movements in the spinal cord with a contusion. It turns out that the tissue in the middle of the spinal cord moves much more than the tissue close to the dural surface. I call this the toothpaste theory because if you compress a toothpaste tube, the toothpaste in the middle of the tube comes out first. The paste close to the tube surface comes out last. I believe that the distribution of tissue velocities in the rostral/caudal directions concentrates the most stretching and shearing forces in the central part of the spinal cord, thereby leading to central hemorrhagic necrosis. The spinal cord seem to be everted itself during evolution in recognition of this physical phenomenon. Unlike the rest of the brain where the deeper structures are often the most critical, the most crucial spinal tracts seem to be situated close to the dural surface. That is why patients (who have huge cysts in the spinal cord and a thin rim of white matter close to the pial surface) can recover motor and sensory function despite loss of more than 90% of their spinal cord. In cats, preservation of a 0.2 mm layer of spinal cord white matter close to the pial surface can support impressively normal appearing locomotor capability.
B. The chain theory. Andy noted that large myelinated axons are more susceptible to trauma than smaller unmyelinated axons, in direct contrast to the greater vulnerability of small unmyelinated axons to anoxia or ischemia of the spinal cord. This seems to be paradoxical. After all, large myelinated axons should be the toughest structures, well supported by multiple layers of membrane. A closer analysis reveals why large myelinated axons are vulnerable to trauma. Myelin only covers segments of the axon. Each myelination segment in human is perhaps 1-2 cm long at most, interpersed with nude areas called the Nodes of Ranvier. These areas are what carry the action potential signals for so-called saltatory conduction. In any case, a chain is only as strong as its weakest link. In the large myelinated axon, its weakest links are the nodes of Ranvier. In fact, because the myelinated portions of the axon are stiff and do not stretch well, almost all the stretch and shear forces are concentrated on the Nodes of Ranvier. These nodes break. That is why I call this the chain theory. The nodes are the weakest link. Incidentally, this is the basis of the diffuse white matter damage that is the dominant theory of traumatic brain injury.
7. Q: How can we better understand the processes that occur in secondary spinal cord injury?
A: I classify secondary injury processes into three major types (which not surprisingly are more than casually linked).
1. Calcium mediated mechanisms. Inside cells, calcium ionic activity is very low, approximately 0.0001 mM compared to 1.0 mM outside of cells. Thus, any break in the membranes result in a huge inrush of calcium into cells. Fortunately cells possess an abundance of substances that bind calcium and therefore keep it at a very low level. When these calcium binding proteins are exhausted, however, intracellular calcium activity rises to high levels. It turns out that almost all cellular enzymes are to some degree sensitive to calcium. Thus an abnormal rise of intracellular calcium activity will shut down all metabolic and other activities of the cells. There are many routes by which calcium can enter cells, i.e. through membrane holes, through calcium channels, and through neurotransmitter receptors. Calcium also binds to mitochondria, interrupting electron transport and causing a large release of oxygen free radicals in the process.
2. Free radical mechanisms. Free radicals are uquibitous intermediates of multiple biochemical reactions. A free radical is a molecule with a free electron in the outer orbital. The most common and best understood free radical is the oxygen free radicals or superoxide. Superoxide or O* are converted by superoxide dysmutase (SOD) to hydrogen peroxide (H2O2) which then is broken down by catalase. In the presence of an overwhelming amount of H202 or inadequate levels of catalase, H2O2 is converted to hydroxyl radicals or OH*. Free radicals react with proteins and lipids. In the case of lipids, free radicals cause lipid peroxides which react with other lipids, forming a chain reaction that propagates the damage. Mitochondria are an important source of oxygen free radicals. Also free fatty acids, particularly arachidonic acid, produce free radicals when converted into prostaglandins. Central nervous tissues also possess very high levels of antioxidants, molecules that react with free radicals. Soluble antioxidants in the brain and spinal cord includes ascorbic acid (vitamin C) and glutathione. Lipid antioxidants include alpha tocopherol (vitamin E). These antioxidants are present in higher concentrations than in any other tissues, in millimolar concentrations. These antioxidants decline with tissue damage and necrosis of the spinal cord typically coincides with the complete depletion of such antioxidants.
3. Inflammatory mechanisms. Biological tissues, particularly the brain and spinal cord, are loaded with specialized families of enzymes that seemingly work alongside free radicals to break down proteins and lipids. For example, these include proteases, phospholipases, and lipoxygenases. Many by-products of these enzyme reactions are inflammatory, i.e. they attract white blood cells (such as neutrophils and macrophages) and also activate native central nervous system cells called microglia to convert into macrophages. Byproducts of lipid breakdown produce highly inflammatory molecules or cytokines that activate cells. For example, lipoxygenase and cycloxygenases generate prostaglandins and leukotrienes from arachidonic acid, among the most potent of all cytokines. Prostaglandins have widespread effects on cells, producing vasoconstriction of vascular tissues and attract inflammatory cells. By the way, aspirin (and indomethacin and ibuprofen) is a cycloxygenase inhibitor. Many cytokines are also growth factors. So, we have come around in full circle. Calcium, free radicals, and endogenous tissue enzymes work in concert to destroy dead or dying cells, producing cytokines that attract inflammatory cells that add to the fray. The byproducts of these reactions stimulate growth and repair. It turns out the methylprednisolone is one of the most potent anti- inflammatory molecule and is also is a free radical scavenger as well. It therefore has prominent effects on all three classes of reaction; this probably explains its beneficial effects when given in very high doses shortly after injury.
8. Q: How important are the effects of demyelination and remyelination in spinal cord injury?
A: Demyelination and remyelination. Most of the attention in spinal cord injury is paid to neurons. However, there are two other classes of cells in the spinal cord: the astrocytes and oligodendroglia. The former are capable of growth and mitosis. The latter are like neurons in that they have very limited ability to reproduce themselves. Oligodendroglia myelinate axons. Both primary and secondary injury kills oligodendroglia, causing demyelination of axons. Demyelinated axons do not conduct action potentials well. In the late 1980's, Andrew Blight discovered that demyelination is an important contributor to continuing neurological deficits in spinal cord injury. Demyelination is probably one of the major reasons why recovery takes so long to occur. Partial remyelination occurs. Several drugs (for example 4-aminopyridine) increase excitability of demyelinated axons and can improve the ability of the axons to conduct action potentials. For this reason, much of spinal cord injury research is now focused on treatments that improve axonal conduction and stimulate remyelination of the spinal cord. 4-aminopyridine was found to improve function in spinal-injured animals and was tested in about 33 patients in the past 5 years, showing beneficial effects on perhaps 30% of the patients. We are now planning several major clinical trials. Remyelination can be improved with factors that stimulate growth and proliferation of oligodendroglia, as well as by transplantation of exogenous oligodendroglia or Schwann cells which are the cells that myelinate peripheral nerves. Schwann cells actually invade into the injury site from the nerve roots in as many as 50% of spinal-injured cats and Dick Bunge has described similar invasions of Schwann cells in chronic injured human spinal cords. Because most patients have residual axons and we know that approximately 10% of the axons in the spinal cord can support functional recovery, remyelination is likely to produce significant functional improvement in a large minority of human spinal cord injury. In fact, I believe that treatments that improve the function of surviving axons will be the first effective therapies for chronic spinal cord injury in humans.
9. Q: Are there any recent breakthroughs in regeneration that help us to understand the potential for regrowth of damaged CNS neurons and axons?
A: Regeneration. Neurons and axons are believed to be incapable of growth. The past decade of research suggests that this is not true. The major breakthroughs in the field comes from three findings:
1. Central axons can grow in the peripheral nerve environment. Alberto Aguayo reported this in the early 1980's. He stuck peripheral nerves into the brain and spinal cord, finding the brain and spinal axons will invade into the peripheral nerve and grow long distances in the nerve. Unfortunately, when he stuck the other end of the peripheral nerve back into brain or spinal cord, the growing axons stop when they reach the other end. The axons will not grow back into the central nervous system. Aguayo proposed that there must be something inhibiting axonal growth in central nervous tissues.
2. Proteins in central white matter inhibit axonal growth. Martin Schwab found that axons don't like to grow in the presence of oligodendroglia in culture. Growing axons will stop when they meet oligodendroglia in culture dishes. Martin proceeded to find out what oligodendroglia possess that is causing this inhibition. The first step that he took was to develop antibodies against different fractions of oligodendroglia components. One of the antibodies, called IN1, remarkably blocks the growth inhibiting effects of oligodendroglia. When he applied it to injured spinal cords, he was able to get regeneration for the first time in spinal cord.
3. Growth factors. The brain and spinal cord contain growth factors. In the late 1980's, an entire family of brain-derived neurotrophic factors closely related to nerve growth factor or NGF was discovered. NGF is called neurotrophin 1 or NT3. At least three other members of the family have been discovered and their genes are known. One of these is called NT3 strongly stimulates spinal axonal growth. When combined with a growth factor called neurotrophin 3 (NT3), Schwab was able to get function regeneration in the animals. Other growth factors that are attracting a great deal of interest at the present includes fibroblast growth factor (FGF). In addition, much evidence suggest that cellular adhesion molecules, particularly one called L1 (discovered by Melitta Schachner) may combine both growth factor stimulation and antagonism of axonal growth inhibitor. It turns out that L1 is present during development in the spinal cord and is present in peripheral nerves. Blockade of L1 in peripheral nerve stops growth there. Finally, Melitta Schachner recently put the gene for L1 into the adult mouse (a transgenic mouse) so that astrocytes express L1. She found that the optic nerves in these mice will regenerate. We are now looking at L1 in spinal cord injury.
10. Q: What is GM-1, and what does it do?
A: It is not clear what GM1 does. GM1 stands for monosialic ganglioside. The number 1 stands for the presence of a sialic acid on the first position on the ganglioside. Gangliosides are lipids with a carbohydrate attached to them. Normally, 1% of the lipids in the central nervous system are gangliosides. There are many gangliosides, including GM2, GD2, etc. These represent gangliosides in the second position (i.e. GM2) and with two (GD) or more sialic acid residues. Because gangliosides are normally present in the tissue, it is unclear what adding GM1 to the bloodstream of patients and animals do. However, many studies suggest strongly that GM1 stimulates growth of peripheral nerves and some studies suggest that it does the same thing in the brain as well. There is also some evidence suggesting the GM1 may be neuroprotective although this evidence is weak and difficult to reproduce. We recently found for example that GM1 appears to antagonize the effects of methylprednisolone in spinal cord injury.
Fred Geisler's work pushed the field further by showing that GM1 given for a period of several weeks seems to improve neurologic recovery in people after spinal cord injury. Unfortunately, the study involved only 37 patients (half treated with GM1) and all treated with methylprednisolone. This was deemed to be too small to be convincing and thus a larger multicenter trial is being carried out. This trial has now recruited over 600 patients with the goal of 800 patients by next year. We will find out by 1997 whether or not GM1 actually improves neurologic recovery in patients with spinal cord injury. My personal belief is the GM1 is a "pro-inflammatory" drug, i.e. it stimulates inflammation. Inflammation has been reported by many investigators to stimulate nerve growth. This would explain the fact the GM1 antagonizes the effects of methylprednisolone as well as its general growth promoting effects. Incidentally, it is important that you do not propagate misleading information about GM1.
First, to my knowledge, Christopher Reeve did not receive GM1 or at least not a full course of the drug. Second, the work of Judith Walker has been strongly criticized by many people and I do not believe the results of her study. Fred Geisler is now heading the definitive clinical trial on the subject
11. Q: Many of us have believed that methylprednisolone (MP) has been approved by the FDA for acute spinal cord injury. What is the current status?
A: Although methylprednisolone is widely used in the United States, it has not been approved by the FDA for spinal cord injury as an indication. Lack of approval does not mean that FDA does not think that it works or that physicians cannot give the drug. The main obstacle for the FDA to approval is that they require two placebo-controlled clinical trial.
After the strong positive results in NASCIS 2, the group felt strongly that a second placebo-controlled trial would be unethical, since this means that a large number of spinal cord injury patients would be forced to forgo the benefits of methylprednisolone. As it turns out, a clinical trial was completed last year in Japan which basically confirmed the work of NASCIS. To my knowledge, they are carrying a trial in France which omits methylprednisolone.
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