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Thread: Spinal cord necessary and sufficient for recovery

  1. #21
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    Dr. Young:

    In starting this post you made the following observation:

    "Many people may seem to have more sufficient spinal cord remaining on MRI to support function but we must remember that MRI cannot show the axons or their myelination. Perhaps about a third of people with spinal cord injury will benefit from remyelination therapy."

    ...which I noticed the very first time I looked at my MRIs, within the first two weeks of my injury. Also, I have read elsewhere on these threads that demyelination occurs over the several months that follow acute SCI. However, my functional condition was largely unchanged over this entire period. In fact, it remained substancially unchanged for the first three years after my accident....except for my regaining the use of my upper extremities and some sensation within a month of the accident, which my doctors attributed to spinal shock wearing off. Which leads me to make the following suggestion (which I may have made before).

    Is it possible that recoverable neural functions remain chronically lost through the permanent metabolic impairment of largely uninjured tissues?

    In the rest of the body, long term metabolic impairment can only be naturally reversed by two synergistic avenues:

    1. the removal of the cause of the impairment
    2. the usage of the impaired organ or limb

    But consider, the traumatically injured spinal cord is a bundle of paralysed nerves that CAN'T be used!!! Furthermore, although spinal cord blood flow returns to normal over much of the cord, it remains permanently limited at and near the lesion, therefore insuring that uninjured tissues local to the lesion are metabolically starved! And because the cord is a large point to point series circuit, it's metabolic disruption at any point would insure the total dysfunction of neural transmissions between affected sections above and below that point. Such paralysis would therefore be caught in a permanent catch 22.

    James Kelly

    [This message was edited by James Kelly on February 15, 2002 at 01:23 AM.]

  2. #22
    Senior Member Jeff's Avatar
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    JOC

    After injury, the distal part of axons [the severed portion going away from the injury site] dies rather quickly. There's no way to reconnect the severed halves. Axons must regrow from the injury site all the way up or down to their targets.

    ~See you at the SCIWire-used-to-be-paralyzed Reunion ~

  3. #23
    Senior Member Scorpion's Avatar
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    Originally posted by Jeff:

    After injury, the distal part of axons [the severed portion going away from the injury site] dies rather quickly. There's no way to reconnect the severed halves. Axons must regrow from the injury site all the way up or down to their targets.
    See, I'm not sure I 'get' that. I've heard and read it before, but don't quite 'get' it. Why, if my spinal cord is working below the injury site (sensation, reflexes, spasticity) would an axon need to grow from the C-5/6 area all tje way down my back, or up from the C-5/6 level to the brain?

    First, it seems that mechanically, the spinal cord that's already there is going to block axons from growing though. Second, I believe peripheral nerve axons grow very slowly, at about 1 inch per year (?), so the idea that once the therapy is applied I'll have to wait over 20 years seems pretty futile.

    ~Rus

    "Life's a bitch, but I love her."

  4. #24
    Jim,

    You are right that "demyelination" does occur over several months after injury, in regions surrounding the injury. That loss of myelin is probably related to the loss of axons. The axons that have been disconnected from the cell bodies die. It is interesting that they don't die immediately. In animal studies, for example, serotonergic axons (which emanate almost complete from the brainstem) don't die for at least a week after injury. So, axons get some sustenance from their environment. Recent evidence even suggest that axons possess some limited protein synthesis capability at the synapse. However, eventually, the axons will die because they are no longer connected to a cell body. When the axons die, you can see all these "empty" myelin tubes. Since oligodendroglial cells myelinate as many as 20 axons, I suspect that the oligodendroglial cells themselves don't die unless and until most of the axons that they myelinate dies.

    That is why, I believe, there is a wave of apoptosis that occurs at 1-2 weeks after injury in the degenerating white matter tracts above and below the injury site in rats. This was first discovered in the rat spinal cord contusion model in 1997 and is now a well-accepted feature of spinal cord injury but the functional significance of this wave of cell death is still unclear. If the axons die and the demyelination is secondary to that, it is clearly not the cause of the functional loss.

    Regarding blood flow at the injury site, I do not believe that there is any evidence that there is ischemia at the injury site for long times after injury. It is true that blood flow falls at 3-4 hours after injury and may be low for a few days. This was the subject of my earliest studies of spinal cord injury. The ischemia theory of spinal cord injury was dominant in the early 1980's and I never accepted this theory because it was also apparent that there were other reasons for depression of metabolism (i.e. calcium entry into cells and mitochondrial pathology) that would result in depression of blood flow. There is a recent study (which I posted in the Research Forum) from the Miami Project that reports that the injury site is rapidly vascularized after injury. I have looked many injured spinal cords and there is always evidence of extensive vascularization (greater than normal) at the injury site starting several days and continuing for many months after injury. So, there is little evidence that there is continuing ischemia (reduced blood flow) at the injury site that continues or develops at the injury site.

    On the other hand, I think that there may be another cause of ischemia that develops in chronic spinal cord injury. Specifically, over several months, inflammatory scarring in the spinal cord, adhesion between the spinal cord and the dura, and occlusion of the subarachnoid space (where the cerebrospinal fluid passes) probably contributes to reduced flow at the injury site. The situation is not unlike an edematous leg. In the leg, there is reduction in the lymphatic clearance, increased pressure with slow venous flow, and this in turn contributes to a slow ischemic process. Especially if there is then development of a syringomyelic cyst (which is evidence of disturbed cerebrospinal fluid flow), there may be ischemia in a percentage of people with spinal cord injury.

    We have now spent the past 6 months trying to document this phenomenon in detail in the contused rat spinal cord. The more I look at the spinal cords, the more that I am convinced that cerebrospinal fluid flow plays a critical role in the metabolism of the spinal cord. This may be one of the reasons why untethering of the spinal cord is beneficial. The main problem with all the untethering surgery is that we don't have a particularly good way of preventing retethering after the surgery.

    The above is one of the reasons why I am very interested in the procedure that Carl Kao uses. He decompresses and untethers the cord, clearing out all the adhesions, and then places omental tissues on the spinal cord. As I understand it, this is a free omental transplant (without an attached blood vessel). Thus, it is not bringing additional blood supply to the injury site. However, it may present a barrier against scarring.

    Please, it is important that people do not jump to the conclusion that the Carl Kao procedure is more effective than many others that neurosurgeons have used over the years. For many years, neurosurgeons have used fat, muscle, and other tissues to cover the spinal cord and try to prevent readhesion. While all these materials seem to work for a year or two, they lead to readhesion of the spinal cord several years later, often worse than before. In addition, there have now been at least four clinical trials of omentum transplants that have not shown significant neurological recovery. So, in my opinion, the jury is still out regarding omental transplants and whether or not it improves recovery and prevents readhesion of the spinal cord.

    Note that Gliatech (a company founded by Jerry Silver) does have a product (Adcon) on the market that stops scarring of the spinal cord. This material, however, also prevents healing of the dura and the material was withdrawn from the market several years ago because it may result in continuing cerebrospinal fluid leaks. The company is struggling to get this material back on the market. I believe that it is an important tool that neurosurgeons should have and it is a matter of applying it at the proper time to avoid some of the problems associated with its inhibition of healing of the dura. Note that a CSF leak is a terrible complication. I believe that Nature evolved the scarring ability of the dura to prevent CSF leaks. At the injury site, the dura often doubles and triples in thickness over a period of several days, in an seeming effort to seal of any possible leaks. That is probably the reason why we can operate on the brain, opening up the dura in the process, without getting a higher incidence of CSF leaks.

    I apologize for such a long posting.

    Wise.

  5. #25
    Scorpion,

    Let me focus first on descending axons in the following discussion.

    Before your injury, neurons in your brain sent long axons that went all the way to the lower spinal cord. Some of these axons were excitatory, i.e. that activated neurons in the lower spinal cord. Most of the axons were inhibitory, i.e. they modulate the activity of the neurons.

    When you are injured, the axons are damaged and the axons that were separated from the cell body die. However, the neurons that they contacted remain alive. In fact, because most of the descending axons are inhibitory. That is why the neurons below the injury site become hyperexcitable. This is reflected in spasticity (increased reflexes) and even spasms (spontaneous movements).

    Regeneration is the process by which axons grow from the injury site to the original targets that they innervated. It is not enough for axons to cross the "gap". They have to go back to their original targets. It is true that the spinal cord is incredibly plastic (i.e. the spinal cord can find alternative ways to get signals down to the lower spinal cord) and if axons can get across the injury site and make synapses (connections) with neurons on the other side, some of the neurons on the other side may be able to relay messages to the original targets. However, this is not a suitable solution because coordinated movements require fast transmission of signals from the brain to the lower spinal cord. The reliability of the signalling also is important.

    Finally, let me comment briefly on the sensory signals that must come up the spinal cord. Sensation is critical for full recovery. There are two types of sensations. One type is the one that you feel, i.e. touch, pain, and joints. Such sensations are of course important for a person to feel that that part of the body belongs to him or her. Pain is critical for a person to protect the limb. That is why people with sensory loss but motor preservation are at risk of damaging themselves.

    The other type of sensory signals go to your brainstem, cerebellum, midbrain... these signals are what allow sensory feedback and coordination. Speed and reliability of sensory signals is essential for walking and other behaviors. We are not conscious of this feedback but it goes on all the time and is essential for coordinated movement. Standing, walking, running, balance, etc. all depend on this other sensory information pouring into the brainstem. It is what coordinates your vestibular system. Finally, before initiating any movement, your brain first sets up the posture of the body. This postural setup is what allows a person to take a step without falling over. Taking a step means the rest of the body must be reset to balance the loss of weight support by the lifted leg. Although some of the postural mechanisms are in the spinal cord, communication between the spinal cord and the brain is essential. For example, when we close our eyes, we can continue standing because our vestibulospinal system interacting with our proprioceptive system can detect and correct changes of posture that would lead to falling.

    Wise.

  6. #26
    Regarding the growth rate of axons... they are slow but not that slow. Peripheral axons grow at the rate of 1 millimeter per day, not one inch a year. For example, if you crush a nerve at the elbow and lose all sensation and movement below the elbow, recovery takes several months.

    Axonal growth rate is probably similar to the rate at which hair can grow. So, for example, if you have a C4/5 injury, the axons need to grow from about the middle of your neck down to the L1-L2 bony segment (where most of the spinal gray matter for L1-S5 spinal segments are located). L1 is just below the rib cage.

    You can use your imagination to fill in the rest. The distance is probably on the order of half a meter or about 500 millimeters. Thus, with both feet flooring the gas pedal, axons should be able to make that distance in less than two years. Of course, the route that the axons take may be quite tortuous, they can get hung up, lost, or otherwise delayed.

    The time it takes for axons to regenerate is probably the main reason why larger animals never evolved regeneration as a mechanism of survival and recovery. Before the 1950's, almost all people who had cervical spinal cord injury died within a few weeks after injury. Having regenerative genes does not improve survival of the animals and therefore most larger animals cannot and do not rely on regeneration as its mechanism of recovery.

    Instead, a much more effective mechanism to assure survival of animals after spinal cord injury is to have redundant pathways and plasticity of the lower spinal cord to function with much fewer connecctions than normal. That is why animals can lose half of their spinal cord but can recover walking within a week or two. That is also one of the reasons why people who have "incomplete" spinal cord injury recover so well after injury. We can lose up to 90% of our axons, especially if it occurs slowly, and still function reasonably well.

    The speed by which the loss of axons occur is important. If one lost axons a little bit at a time, over a period of months, there may be little or no perceptible loss of function until close to 90% of the axons are lost. This is frequently seen in patients who have slow-growing tumors of the spinal cord. On the other hand, many people who lose 90% of their spinal cord at a time do not recover. I believe that this is because such injuries may cause demyelination of the remaining axons, resulting in loss of function for several months. Learned non-use may play a role in continuing lack of recovery.

    Wise.

  7. #27
    Senior Member Scorpion's Avatar
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    Wise, thanks so much for the in-depth explanation. It's been a while since I studied this stuff.

    Now, I 'get' it.

    But the length of time it will take for the axons to find their way is still disheartening. I guess since I have sensation (though not 'normal') I may recover full normal sensation in a relatively short span of time once therapies arrive.

    *sigh*

    ~Rus

    "Life's a bitch, but I love her."

  8. #28
    Senior Member Jeff's Avatar
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    Scorpion

    Sensation returns quicker in quads primarily because of the shorter distance from the injury site to the brain stem. I think being incomplete might mean there are living axons that are a great bridge through the injury site.

    Lower injuries have a lot longer road for sensation return. Higher injuries have a lot longer road for full motor return but should see upper motor return quickly, like getting off of vents and use of the hands back.

    ~See you at the SCIWire-used-to-be-paralyzed Reunion ~

  9. #29
    Senior Member Scorpion's Avatar
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    Originally posted by Jeff:

    Higher injuries have a lot longer road for full motor return but should see upper motor return quickly, like getting off of vents and use of the hands back.
    True, and as we quads know, every little bit helps!

    I just wish they could give us B&B and sex back first. It'd make waiting for the rest oh so much more bearable. (I have sensation & sexual function--it just ain't the same)



    ~Rus

    "Life's a bitch, but I love her."

  10. #30

    Hands back

    Jeff,

    I'm pretty sure that hand function is one of the last functions to return (correct me if I'm wrong Dr. Young). Also, isn't it funny the differences between people on what they want back first. Unlike Scorpion, I could wait for a cure as long as I had my hands back. More independence I guess.

    Deb

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