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Study of the effects of "chronic scar" on axonal growth in spinal cord injury

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    #16
    Originally posted by kz
    dr. young,
    hi, how about gunshot wound that caused "complete" asia A paralyis,when the bullet hit the bone and did not even hit the spinal cord (soft tissue) ? what is the main reason of "complete" asia paralysis when the bullet hit the spine (bone) and it did not even hit the soft tissue ? what kind of scar exist in this kind of situation ?what is the main reason of "complete" asia A paralysis in this kind of situation (this is my situation)? what is causing the disruption of spinal cord in this kind of situation ? is this kind of injury harder to cure or easier compare to contusion ,or it does not matter at all when it comes to any kind of treatment (cure) ? please explain this kind of injury a little more.
    thanks so much
    Tissue and cell parts are elastic. If you stretched them slowly, they can stretch quite a lot perhaps 2-3x. However, if you stretch them too far or too fast, they break. Axons are a lot like rubber bands. The critical breaking velocity for them is about 0.5 meters/second.

    A contusion of the spinal cord with a weight that is dropped from 12.5-75.0 mm height compresses the spinal cord at the rate of 0.4-1.2 meters/sec. Because the spinal cord is really like a tube of jello, the only directions that the spinal cord can go when it is compressed is longitudinal.

    Paradoxically, myelinated axons are the first and most sensitive to stretch. The reason is that most of the axon is covered with myelin except for areas between the myelin, called nodes of Ranvier. Since the parts of axons that are covered with myelin do not stretch as much, all the stretch is concentrated on the nodes of Ranvier.

    The gray matter of the spinal cord, however, is damaged due to shearing forces that occur with the spinal cord is indented. Also, the shearing forces can damage blood vessels that cause bleeding into the spinal cord. Blood is toxic to the tissue and contributes to the damage.

    Now, a bullet can damage the spinal cord without penetrating into the spinal cord. In addition to possibly causing bone to indent the spinal cord, a bullet can also produce a shock wave that transmits through the spinal cord. The damage produced by the bullet depends on the velocity of the shock wave.

    While such "shock" waves have long been blamed for gunshot wounds, please note that many studies have suggested that these shock waves have been overestimated. Due to public protest, the U.S. government has stopped experiments involving gunshot wounds of the spinal cord in animals. However, studies carried out in China suggest that the bullet can pass close to the spinal column but will not damage the spinal cord unless the bullet contacts the spinal column bone.

    Wise.

    Comment


      #17
      Originally posted by Buck_Nastier
      I wonder if other scientists, or researchers, pay as much attention to your research
      as you do to with theirs?
      I don't know. Lots of people don't listen to me, including many on this site.

      Wise.

      Comment


        #18
        Originally posted by Wise Young
        I don't know. Lots of people don't listen to me, including many on this site.

        Wise.
        I didn't mean anything negative by my post, i'm just impressed with
        how much you know about everyone elses research. It's great that
        we are able to get all this info at one site. Thanks.

        Comment


          #19
          Originally posted by Wise Young
          This is true. It is the reason many doctors are reluctant to cut into the spinal cord unless they have to (like in the case of a spinal cord tumor). It is one of the reasons why I have been uncomfortable with the surgery being carried out in Portugal where they cut out a part of the spinal cord that supposedly has the "scar". Several animal studies have suggested that if the dura is carefully closed after the injury and prevented from adhering to the spinal cord, fibroblast invasion in to the injury site is limited. In the ChinaSCINet, we are planning to introduce the cells through a small puncture as opposed to cutting into spinal cord.

          I have now studied contused spinal cords of animals for over 20 years. In general, contused spinal cords do not show thick deposits of collagen inside the spinal cord at the injury site. Collagen is made by fibroblasts. While there may be some collagen deposits on the surface of contused spinal cord, especially where there is adhesion between the spinal cord and arachnoid, these are usually limited to the surface. By the way, the spinal cord contain extracellular matrix molecules that prevent migration of cells that the spinal cord considers to be "peripheral". For example, generally fibroblasts and Schwann cells (which the spinal cord treats as peripheral cells) injected into the spinal cord will not migrate far from the injection site into the surrounding cord.

          For many years, the Schwab group in Switzerland used the so-called "over-hemisection" model to examine regeneration. However, a number of years ago, they adopted our contusion model. I found the Tuzynski paper particularly interesting because they cut into the spinal cord and find that the resultant "scar" does not seem to impede axonal growth in the cervical spinal cord.

          Wise.
          Thank you. In my case it was an AVM that had to be cut out surgically (last option after many embolization attempts). It was done in Phoenix at BNI in 2002. I would think if there was Collagen in there or some kind of a scar it would show on MR, but in my case the MR images looks like a healthy cord now, still I’m incomplete paralyzed from T4. There was some questions regarding tethering just after the surgery but it showed that it was not the case and that there was space between the cord and the spinal channel. I’m reading your comment here regarding carefully closing the dura with great interest and wonder if you know how this was done in the US in 2002 since I have no papers on how this part of the procedure was carried out. The surgeon who did the surgery was Robert (Bob) F. Spetzler. Also, how can future treatments be carried out if “we” don’t know what to treat? Are there better MR equipment nowadays to see more details, I’ve read a bit about PET scan as well, could this also be a way to determine the state of a injured cord. Seems to me like there is a little “don’t know what’s wrong” gap here as for future cures for SCI. PS. Thank you for posting the Tuzynski paper.
          Last edited by Leif; 10 Oct 2006, 7:14 AM.

          Comment


            #20
            Are there histology/pathology slides of contused HUMAN spinal cords, enough to make observations? Is there a review paper somewhere on the pathology?

            Comment


              #21
              Originally posted by Leif
              Thank you. In my case it was an AVM that had to be cut out surgically (last option after many embolization attempts). It was done in Phoenix at BNI in 2002. I would think if there was Collagen in there or some kind of a scar it would show on MR, but in my case the MR images looks like a healthy cord now, still I’m incomplete paralyzed from T4. There was some questions regarding tethering just after the surgery but it showed that it was not the case and that there was space between the cord and the spinal channel. I’m reading your comment here regarding carefully closing the dura with great interest and wonder if you know how this was done in the US in 2002 since I have no papers on how this part of the procedure was carried out. The surgeon who did the surgery was Robert (Bob) F. Spetzler. Also, how can future treatments be carried out if “we” don’t know what to treat? Are there better MR equipment nowadays to see more details, I’ve read a bit about PET scan as well, could this also be a way to determine the state of a injured cord. Seems to me like there is a little “don’t know what’s wrong” gap here as for future cures for SCI. PS. Thank you for posting the Tuzynski paper.
              Leif,

              As you know, I think that Bob Spetzler is one of the best neurosurgeons in the world.

              I am concerned by repeated statements from people suggesting that they need to see something on their MRI's to justify or explain their spinal cord injury. While MRI's provide much information, they provide relatively low resolution image (±1 mm) that cannot show individual axons (1-5 microns) or even capillaries (7-10 microns). With contrast, they might be able to show a "blush" that can show increased vascularity. So, it is possible for a person to have loss of all axons traversing a given area of the spinal cord and for the MRI scan to show relatively little change in the acutely injured spinal cord.

              On the other hand, it is rather unusual for the MRI to show nothing at all in a person with chronic "complete" spinal cord injury. If you have had significant loss of cells and axons, the spinal cord should show some atrophy. There should also be an increase in MRI signal at the injury site resulting from the increased extracellular space and water content of the tissue. Finally, there should be changes in the vascularity and myelination of the spinal cord, both of which should show up in MRI.

              Collagen is a protein. If you have a very high concentration of collagen that excludes cells and water content, it may cause some subtle changes of MRI signal. However, at the collagen concentrations that one expects of a "scar", there should not be enough MRI change to be obvious. One does not see "scar" in the spinal cord with MRI. If MRI were able to detect "scar", it would be used for this purpose. It is not.

              I have been posting here until I am blue in the face concerning the obstacles to regeneration in the spinal cord. They include:
              • The loss of tissue at the injury site and absence of guidance factors at the injury site that would encourage axonal growth.
              • The shortage of long-term growth factor stimulation of axonal regeneration over periods of months and years
              • The growth inhibitory factors that are present at the injury site and surrounding cord, including chondroitin-6-sulfate proteoglycans, nogo, ephrins, and other growth inhibitors.


              In my opinion, doctors who believe that collagenous scars are the primary obstacles to regeneration of contused spinal cord have not spent much time looking at contused spinal cords or reading the spinal cord injury literature. While collagenous scars may play a role in penetrating wounds of the spinal cord where the dura is not repaired and fibroblasts are allowed to invade into the spinal cord, I don't think that it plays a major role in contused spinal cords. That is why I question, for example, the surgical approach taken in Portugal.

              I am very willing to consider any evidence that doctors may have of collagenous scar formation in injured spinal cord. I agree that collagenous scars can develop if one cuts the spinal cord and allows fibroblasts to invade into the spinal cord but this is simply not what most people with spinal cord injuries have. When I first started doing spinal cord injury research, I too believed that glial scars are a major reason for the failure of regeneration. However, this dogma has been debunked many times over and it continues to crop up over and over again, usually from researchers who transect the the spinal cord or cut the spinal cord without repairing the dura in order to injure the spinal cord.

              Unfortunately, I hear this dogma echoed in the comments of the people here on these forums without much evidence to support the dogma. Many people seem to think that the reason why they have no regeneration in their spinal cords is because they have "scar" at the injury site. The evidence for this view is very limited. Yes, it may be true for people who have had penetrating wounds of their spinal cord. Yes, it may be true for people who have had surgery of the spinal cord where the surgeon did not try to attain tight closure of the dura to avoid fibroblast invasion into the spinal crod. And, yes, there may be some collagen producing fibroblasts at the surface of the injured spinal cord where adhesive scars have developed between the spinal cord and surrounding membranes. However, the notion that there is a dense collagenous scar inside the spinal cord that is obstructing regenerating axons in a majority of patients is simply wrong, in my opinion.

              In the early 1990's, Martin Schwab and his colleagues revolutionized thinking about regneration of the spinal cord by showing that an antibody against a protein called Nogo allowed regeneration in rat spinal cords. They were able to encourage regeneration of the spinal cord without addressing the issue of "scar" (whether glial or fibroblast). In the contused spinal cords, there is usually little collagen at the injury site. Most of the therapies that have reported to regenerate the spinal cords did not do anything to eliminate glial or collagenous scars.

              Surgical removal of tissues at the injury site is more likely to produce collagenous scar than a contusive injury of the spinal cord. That is the reason why I am so skeptical of the approach taken by Carlos Lima and his surgical team in Lisbon, where they actually remove a piece of the spinal cord in order to transplant olfactory mucosa, which by the way contains many fibroblasts. My criticisms of this procedure seems to have fallen on deaf ears. It doesn't make sense to me based on many years of experience with spinal cord injury.

              Given the above comments, you are probably wondering I am not more critical of Spetzler's removal of your AVM nidus. I was involved in and participated in the some of the pioneering studies of interventional neuroradiological treatments of spinal cord AVM's by Alejandro Berenstein at NYU Medical Center in the early 1980's. I have seen many cases of AVM that have been successfully treated with embolization as opposed to surgical removal. However, in the hands of a skillful neurosurgeon, it is possible to remove a superficial AVM without compromising the spinal cord. I believe that surgical removal of an spinal cord AVM is most successful in patients who have a superficial AVM without significant loss of function. However, there are no systematic comparisons of embolization and surgical removal. In your case, you had many embolizations that were apparently ineffective before you opted for surgical removal.

              Wise.
              Last edited by Wise Young; 10 Oct 2006, 2:33 PM.

              Comment


                #22
                Dr. Young

                As I am reading your post I wonder about my son's injury. His spinal cord and vertebrae was completely penetrated. The bullet basically travelled through the T4 vertebrae entering on the left side and exiting on the right. Given the extend of this type of injury is there any hope for him?
                When the time comes for a "cure" would this type of injuries be the hardest to repair?

                Thank you
                Andrea
                My mouth is like a magician's hat, never know what might come out of it.

                Comment


                  #23
                  Surgical removal of tissues at the injury site is more likely to produce collagenous scar than a contusive injury of the spinal cord. That is the reason why I am so skeptical of the approach taken by Carlos Lima and his surgical team in Lisbon, where they actually remove a piece of the spinal cord in order to transplant olfactory mucosa, which by the way contains many fibroblasts. My criticisms of this procedure seems to have fallen on deaf ears. It doesn't make sense to me based on many years of experience with spinal cord injury.
                  I'm not sure exactly who you are referring to when you say your critisms fell on deaf ears, but I was considering have either the Lima procedure or the cells4health procedure done when I first got home from rehab and decided against it because of your thoughts on them. I am grateful to you for this, because I know that I would have gained very little from having them done, and I would probably be in financial trouble now. So please don't think that you aren't helping anyone just because others still have the procedures done, and Carlos Lima is still removing part of the cord.
                  "There's too many things to get done, and I'm running out of days" 3 Doors Down

                  Comment


                    #24
                    Glimmer of Hope

                    Originally posted by Buck_Nastier
                    I didn't mean anything negative by my post, i'm just impressed with
                    how much you know about everyone elses research. It's great that
                    we are able to get all this info at one site. Thanks.
                    I agree! I suffered a C4 complete diving accident 6/5/06. Although there's a lot of promising research going on (not enough---thanks a lot BUSH) I'm always confronted with my own concerns about being A-a complete injury & B-an old injury, in the event that a "cure" is found. I get scared that since I won't be a few days post injury that these methods of regeneration won't work for me. I'm glad to hear that there is reason to still have hope & appreciate all that you do.
                    www.christinasymanski.com

                    Comment


                      #25
                      Originally posted by Wise Young
                      Leif,

                      I am concerned by repeated statements from people suggesting that they need to see something on their MRI's to justify or explain their spinal cord injury. While MRI's provide much information, they provide relatively low resolution image (±1 mm) that cannot show individual axons (1-5 microns) or even capillaries (7-10 microns). With contrast, they might be able to show a "blush" that can show increased vascularity. So, it is possible for a person to have loss of all axons traversing a given area of the spinal cord and for the MRI scan to show relatively little change in the acutely injured spinal cord.

                      On the other hand, it is rather unusual for the MRI to show nothing at all in a person with chronic "complete" spinal cord injury. If you have had significant loss of cells and axons, the spinal cord should show some atrophy. There should also be an increase in MRI signal at the injury site resulting from the increased extracellular space and water content of the tissue. Finally, there should be changes in the vascularity and myelination of the spinal cord, both of which should show up in MRI.

                      Wise.
                      I am meeting my son's (T11 - T12 incomplete since feb 06) consultant on Monday 16/10/06 for a review on his recent MRI. I had hoped he could give me some idea about the extent of my son's SCI and potential for recovery. After reading your comments on MRI I am not sure what to expect.

                      What information should I reasonably expect to get from this meeting. They did a MRI of the full cord as this is only his 2nd MRI since the injury and there is some consultants think his injury is lower as he can move his hip flexors and sensation on his upper legs.

                      Could the MRI show nothing even though there is extensive damage? What is the point of the MRI? What will give a high enough resolution image and in what cases could we request such a scan? Can you explain "blush" - "increased vascularity"?

                      I know there isn't a cure but I want to get something which will make the phyiso in the Rehab to adapt his therapy to aim for a walking recovery rather than "he has a SCI so get use to life in a wheelchair" He is only 4.

                      Comment


                        #26
                        Originally posted by macska
                        As I am reading your post I wonder about my son's injury. His spinal cord and vertebrae was completely penetrated. The bullet basically travelled through the T4 vertebrae entering on the left side and exiting on the right. Given the extend of this type of injury is there any hope for him?
                        When the time comes for a "cure" would this type of injuries be the hardest to repair?

                        Thank you
                        Andrea
                        Andrea,

                        Many studies have shown that there is not a great deal of difference in the recovery or lack of recovery between spinal cords with penetrating and non-penetrating injuries.

                        There is not enough clinical experience with use of regenerative treatments on this type of injury to come to any conclusion whether they will respond or not respond to the treatments. However, you should be reassured that the main model used by Schwab to assess IN-1 as a treat of spinal cord injury is the over-hemisection model, which cuts about 2/3rds of the spinal cord. Many of the regenerative therapies were tested in the over-hemisection model or the transection model.

                        Wiuse.

                        Comment


                          #27
                          Originally posted by soimumireland
                          I am meeting my son's (T11 - T12 incomplete since feb 06) consultant on Monday 16/10/06 for a review on his recent MRI. I had hoped he could give me some idea about the extent of my son's SCI and potential for recovery. After reading your comments on MRI I am not sure what to expect.

                          What information should I reasonably expect to get from this meeting. They did a MRI of the full cord as this is only his 2nd MRI since the injury and there is some consultants think his injury is lower as he can move his hip flexors and sensation on his upper legs.

                          Could the MRI show nothing even though there is extensive damage? What is the point of the MRI? What will give a high enough resolution image and in what cases could we request such a scan? Can you explain "blush" - "increased vascularity"?

                          I know there isn't a cure but I want to get something which will make the phyiso in the Rehab to adapt his therapy to aim for a walking recovery rather than "he has a SCI so get use to life in a wheelchair" He is only 4.
                          An MRI does provide a great deal of useful information concerning the spinal cord. It will show, for example, if there is a disc pressing on the spinal. It will show if there is a syringomyelic cyst. It will show if there is demyelination. It will show if there is atrophy of the spinal cord. It should generally show the location of the injury site and whether he has had a double injury.

                          I had recently posted another article in this forum that suggest that neurological examinations of children are imprecise in children under five years of age (/forum/showthread.php?t=70382). Your brief description suggests that your son has a partial injury, that he has some preservation of function far below his injury site. This usually has good prognostic implications.

                          Wise.

                          Comment


                            #28
                            While I cannot claim to know as much as a researcher with decades of experience under his or her belt, I have read a great deal of specialized literature in the 16 months I have been off work since my accident. From the beginning, and from a merely intuitive standpoint, I focused on the importance of scar tissue, before I even knew anything on the topic. Prior to my injury, I always believed that CNS cells can and do regenerate, and suspected that a variety of reasons, biological, biochemical, and behavioral, are to blame for the lack of recovery in these injuries. I initially posted a q. on scar tissue, months ago, to which Dr Wise replied with the hemisection vs contusion model. My subsequent reading has convinced me of the following: we know a lot about rats, and a whole lot less about humans. There have been way too few pathological specimens of human spinal cord to study in depth. While the rat and the human genome are very similar, arguably the human CNS exhibits a much greater degree of complexity, and different adaptive mechanisms. From my point of view, whether there is more or less collagen deposited by fibroblasts is a moot point. Obviously there is going to be some collagen, particularly when the integrity of tissues is compromised, and let´s not forget that a contusion does not imply that this does not happen. The "scar" in SCI is an agglomerate of glial cells, debris, and collagen, that poses a physical and biochemical barrier to the connection of axons to their targets. Because tracts in the human SCI are so numerous and specialized, the axon has also to be at the right spot in the 3D configuration of the cord, lest we find methods to dock these axons to their specific tract (cerebellospinal, rubrospinal, corticospinal, etc) bypassing the straight route. The "scar" does not mean that regeneration won´t be possible. But it does mean that, in order to overcome its barrier, a lot more needs to be known on what makes an axon recognize a specific tract target, and a lot more needs to be done to create a less hostile environment for axon growth. Simply put, very little is known to date in HUMAN spinal cord. Each SCI is different, every SCI different, each mechanism of injury not exactly the same. I doubt a lab can produce a batch of rats as heterogeneusly injured as the gang at Carecure. Rats have something to their advantage, and that is that they TRY to ambulate after SCI, nonstop. This way they generate the electrochemical impulses that are needed for regeneration and that direct axons to their intended, volitional targets. Humans in wheelchairs generate no such impulses in particular for motor activity. Maybe sensory return is more prevalent because impulses are generated nonstop by sensory stimuli in the environment.
                            Like Chris Reeve said, "Man, to be a rat!"

                            Comment


                              #29
                              Cripply. Since the cord is very complex and consists of several 100 millions of axons and there are probably some 20.000 inter neurons in each vertebral segment and we also know that plasticity occur in the spinal cord why is it so important that axon has to be at the right spot in the 3D configuration of the cord. The cord is built by a variety of neural networks (se image below), could not that result in that some signals could find other ways than originally designed and still work as for future therapies? I think it could.

                              Comment


                                #30
                                Originally posted by Wise Young
                                Cripply, if you use a knife and cut the spinal cord, there is fibroblast invasion and a fibrous scar does occur. However, if you contuse the spinal cord, only glial proliferation occurs at the edges of the lesion site. Penetrating wounds of the spinal cord can cause fibrous scars. Contusions do not. Most people have contusions.

                                Wise.
                                Wise,

                                So basically I have a fibrous scar that is tethering my cord causing some of my pain. Is that correct?

                                Pam

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